PAGENO="0001" CANCER-CAUSING CHEMICALS-PART 1 Safety of Cosmetics and Hair Dyes HEARINGS BEFORE THE SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS OF THE COMMITTEE ON INTERSTATE AND FOREIGN COMMERCE HOUSE OF REPRESENTATIVES NINETY-FIFTH CONGRESS SECOND SESSION ON TI~E REVIEW OF THE ADEQUACY OF EXISTING LAWS DE- SIGNED TO PROTECT THE PUBLIC FROM EXPOSURE TO CAN- CER CAUSING AND OTHER TOXIC CHEMICALS IN HAIR DYES AND COSMETIC PRODUCTS JANUARY 23 AND 26; FEBRUARY 2 AND 3, 1978 Serial No. 95-91 Printed for the use of the Committee on Interstate and Foreign Commerce U.S. GOVERNMENT PRINTING OFFICE 24-6000 WASHINGTON: 1978 PAGENO="0002" COMMITTEB ON INTERSTATE AND ~`OREIGN COMMERCE HARLEY 0. STAGGERS, West Virginia, Cha4rman JOHj~i B. MOSS, California JOHN I~. DINGELL, Michigan PAULO. ROGERS, Florida LIONEL VAN DEERLIN, California FRED B. ROONEY, Pennsylvania JOHN M. MURPHY, New York DAVXD B. SATTERFIELD II, Virginia BOB ECKHARDT, Texas. RIChARDSON PREYER, North Carolina CHARLES J. CARNEY, Ohio RALPH H. METCALFE, Illinois JAMES H. SCHEUER, New York RICHARD L. OTTINGER, New York HENRY A. WAXMAN, California ROBERT (BOB) KRUEGER, Texas TIMOTHY E. WIETH, Colorado PHILIP R. SHARP, Indiana JAMES J. FLORIO, New Jersey ANTHONY TOBY MOFFETT, Connecticut JIM SANTINI, Nevada ANDREW MAGUIRE, New Jersey MART~ A. RUSSO, Illinois BDWARD J. MARKEY, Massachusetts THOMAS A. LUKEN, Ohio DOUG WALOREN, Pennsylvania BOB GAMMAGE, Texas ALBERT GORE, JR., Tennessee BARBA~ItA A. MIKULSKI, Maryland W. B. WILLIAMSON, Chief Clerk and Staff Director KENNETH J. PAINTER, First Assistant Clerk ELEANOR A. DINKIN5, Assistant Clerk WILLIAM L. BURNS, Printing Editor JIM SANTINI, Nevada THOMAS A. LUKEN, Ohio DOUG WALGREN, Pennsylvania ALBERT GORE, JR., Tennessee CHARLES J. cARNEY, Ohio HENRY 4~ WAXMAN, California PHILIP B. SHARP, Indiana ANTHONY TOBY MOFFETT, Connecticut ANDREWMAGUIRE, New Jersey ROBERT (BOB) KRUEGER, Texas HARLEY 0. STAGGERS, West Virginia (ExOfficio) ELLIOT A. SEGAL, Health Task Force Director LESTER 0. BRoWN, Special Assistant SUSAN LEAL, Counsel KATHERINE C. MEYERS, Special Assistant ALLEGRA MCMANLTS, Staff Assistant LOwELL DODGE, Oversight Ta8k Force Director JOHN GALLOWAY, Energy Task Force Director JOHN MCELROY ATKISSON, Counsel to the SubcommQtee JAMES L. NELLIGAN, Operations Director J. THOMAS GREENE, Coun8el to the Chairman BERNARD J. WUNDER, Jr., Minority Counsel SAMUEL L. DEVINE, Ohio* JAMES T. BROYHILL, North Carolina TIM LEE CARTER, Kentucky CLARENCE J. BROWN, Ohio JOE SKUBITZ, Kansas JAMRS M. COLLINS, Texas LOUIS FREY, JR., Florida NORMAN F. LENT, New York 1iDWARD R. MADIGAN, Illinois CARLiOS J. MOOREIIEAD, Caiifornia MATTHEW J. RINALDO, New Jersey W. HENSON MOORE, Louisiana DAVE STOCKMAN, Michigan MARC L. MARKS, Pennsylvania SUBOOMMITTHE ON OVHRSIGHT AND INVESTIGATIONS JOHN B. MOSS, California, Chairman JAMES M. COLLINS, Texas NORMAN F. LENT, New York MATTHEW J. RINALDO, New Jersey DAVE STOCKMAN, Michigan MARC L. MARKS, Pennsylvania SAMUEL L. J)EVINE, Ohio (Ex Officio) (II) PAGENO="0003" CONTENTS Hearings held on- Page January 23, 1978 1 January 26, 1978 89 February 2, 1978 213 February 3, 1978 Testimony of- Ahart, Gregory J., Director, Human Resources Division, General Accounting Office 351 Baier, Edward J., Deputy Director, National Institute for Occupa- tional Safety and Health, Center for Disease Control, Department of Health, Education, and Welfare 50 Cooper, Richard, Chief Counsel, Food and Drug Administration, Public Health Service, Department of Health, Education, and Welfare 368 Corbett, John F., Ph. D. chairman, Hair Dye Technical Committee, Cosmetic, Toiletry & F~ragrance Association Inc 90, 214, 314 Dach, Leslie, science associate, Environmental Defense Fund 214 Estrin, Norman F., Ph. D., vice president, science, Cosmetic, Toiletry & Fragrance Association, Inc 90 Fine, David H., Ph. D., senior scientist, Thermo Electron Corp 334 Fraumeni, Joseph, Jr. M.D., Chief, Environmental Epidemiology Branch, Division of Oancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Department of Health, Edu- cation, and Welfare 4 Griesemer, Richard A. D.V.M., Ph D., Associate Director for Car- cinogenesis Testing i'rogram, Division of Cancer Cause and Pre- vention, National Cancer Institiite, National Institutes of Health, Departmer~t of Health, Education, and Welfare 4 Highland, Joseph, Ph. D., director, Toxic Chemicals Program, Envi- ronmental Defense Fund 214 Hutt, Peter Barton, counsel, Cosmetic, Toiletry & Fragrance Asso- ciation, Inc 90 Johnson, Anita, staff attorney, Environmental Defense Fund 214 Jojokian, Albert B., Assistant Director, Human Resources Division, General Accounting Office 351 Kennedy, Hon. Donald, Ph. D., Commissioner, Food and Drug Administration, Public Health Service, Department of Health, Education, and Welfare 368 Linz, James, Supervisory Auditor, Human Resources Division, Gen- eral Accounting Office 351 Merritt, James H., president, Cosm,etic Toiletry & Fragrance Asso- ciation, Inc 90 Page, Norbert P., D.V.M., Chief, Priorities and Research Analysis Branch, Division of Criteria Documentation ~nd Standards Devel- opment, National Institute for Occupational Safety and Health Center for Disease Control, Department of Health, Education anci Welfare 50 Roberts, Howard R., Ph. D., Director Bureau of Foods, Food and Drug Administration, Public Health ~ervice, Department of Health, Education and Welfare 368 Scheuplein, ~Robert J., Ph. D., Chief, Dermal and Ocular Toxicity Branch, Division of Toxicity, Bureau of Foods, Food and Drug Administration, Public Health Service, Department of Health, Education, and Welfare_ - 368 Upton, Arthur C., M.D., Director, National Cancer Institute, Na- tional Institutes of Health, Department of Health, Education, and Welfare Walrath, Judy, Ph. D., school of medicine, Yale University 346 (III) PAGENO="0004" Iv Additional material submitted for the record by: Cosmetic, Toiletry & Fragrance Association, Inc.: "Cosmetic Ingredient Review Procedures," revised (includes amendments approved by CIR steering committee and CTFA board of directors as of. December 20, 1976) 97 Draft report to the legislative planning group of CTFA, dated February 8, 1974, Arthur D. Little, Inc 145 List of companies, product tested, and results re nitrosamines 187 General Accounting Office: List of products containing ingredients with toxic effects listed in the 1977 CTFA cosmetic. ingredient dictionary as reported in the 1976 NIOSH Registry of Toxic Effects of Chemical Substances 361 Uses reported to FDA by cosmetic manufacturers of cosmetic ingredients banned by the European Economic Community directive 365 Health, Education, and Welfare Department: Award fee arrangement-Tracor Jitco 48 Costs to exploit existing capability * 29 Occupational carcinogens, NIOSH recommendations - . 53 Table indicating chemical tested, date animal was killed, date pathology completed, date pathology confirmed, and date of draft report 16 Oversight and Investigations Subcommittee, Committee on Inter- state and Foreign Commerce: Abstract-cancer incidence amongst cosmetologists 190 Correspondence dated May 21 and June 21, 1977- between Chairman Moss and National Institutes of Health re hair dyes and hairdye constituents 24 Excerpt from: Some Negative Findings (Polio, Smallpox, Tetitnus and Diptheria-Vaccines; Beauticians) and Evalua-. tion of Risks 197 Graph of final reports compared to projected reports by the National Cancer Institute 9 Letter dated January 5, 1978, with attachment from Dr. Grie- semer, National Cancer Institute, to Chairman Moss re preliminary data on NCI's bioassays of hair dyes and related chemicals 3 Letter dated January 11, 1978, with attachment~ from Robert W. Morgan, M.D., professor, University of Toronto, to Chairman Moss re results of study concerning the relation- ship of hair dyes to bladder cancer 209 Letter dated January 17, 1978, from J. Wister Meigs, M.D., director, clinical professor, epidemiology, Connecticut Cancer Epidemiology Program, to Chairman Moss re opinion that cosmetologists in Connecticut had not experienced an excess overrisk of cancer 192 Letter dated January 20, 1978, from Alvan R. Feinstein, M.D., professor of medicine and epidemiology7 Yale University 8chool of Medicine, to Mr. Com~er Fay, vice president, Clairol re comments on "Restropective Survey of Cancer in Rela- ~ion to Occupation, by Decoufie, et al, and a manuscript draft, preliminary report entitled, "Occupational Characteristics of Disabled Pemale Workers," by J. Kennedy and R. Spirtas 62 Letter dated January 30, 1978, from Alvan R. Feinstein, M.D., professor of Medicine and Epidemiology, Yale University, to Chairman Moss re critical review of studies of hairdressers. and cosmetologists performed by Dr. E. Cuyler Hammond and by Dr. J. Wister Meigs 344 Letter dated February 24, 1978, with attachments, from J. Donald Millar, M.D., Assistant Surgeon General, Acting Director, NIOSH, to Chairman Moss re comments from Dr. Irving I~essler and Dr. Alvan Feinstein on two NIOSH studies indicating that cosmetologists and hairdressers may be at increased risk of cancer -- * 78 PAGENO="0005" V Additional material submitted for the record by-Continued Oversight and Investigations Subcommittee-Continued Meftiorandum dated January 21 1978, from Irving I. I~essler, M.D., Dr. P. IL, professor 0! epidemiology, Johns Hopkins University, to Dr. John Menkart, Clairol, Inc., re evaluation of the NIOSH Rosweil Park Memorial Institute study oited in the January 13, NIOSH Current Intelligence Bulletin 66 Toxic effects of ingredients listed in the 1977 CTFA cosmetic ingredient dictionary as reported in the 1976 NIOSH Registry of Toxic Effects of Chemical Substances 358 Thormo Electron Corp., table 5-some examples of known and suspected human exposure to N-nitroso compounds 338 Appendix A: Chart 1-List of chemicals in bioassay program that are hair dye ingredients Chart 2-Selected examples of chemicals listed in the bioassay program 396 Appendix 13: Affidavit of Dr. Bruce N. Ames conceruing hair dye chemicals 397 Hair Dye Components: Review of Mutagenicity and Other Short- Term Tests, Cheryl Gold and Bruce N. Ames, Department of Biochemistry, University of California 399 Hair Dyes Are Muta~genic: Identification of a Variety of Mttta- genic Ingredients, Bruce N. Ames, H. 0. Kammen, and Edith Yamasaki - 427 Interview with Dr. Bruce Ames, a biochemist and geneticist, Univer- sity of California at Berkeley, on Thursday, January 12, 1978, with Lester Brown of the Subcommittee staff 432 Appendix C-Letter dated February 3, 1978, from Stephen M. $rown, M.D., M.P.H. Head, Epidemiology Program National Institute of Environment ~Iealth Sciences, to Chairman 1~'Ioss re studies linking cancer with human exposure to hair dyes 452 Appendix D-Letter dated February 14, 1978, from Grover C. Wrenn, Director, Health Standards Programs, Department of Labor, to Chair man Moss with statement attached 455 ORGANIZATIONS REPRESENTED AT H1~ARINGS Cosmetic, Toiletry & Fragrance Association, Inc.: Corbett John F. Pb. D., chairman, Hair Dye Technical Committee. Estrin, I~orman 1?., Ph. D., vice president, science. Hutt, Peter Barton, counsel. Merritt, James H., president. Environmental DefenSe Fund: Dach, Leslie, science associate. Highland, Joseph, Ph. D., director, Toxic Chemicals Program. Johnson, Anita, staff attorney. General Accounting Office, Human Resources Division: Ahart, Gregory J., Director. Jojokian, Albert B., Assistant Director. Linz, James, Supervisory Auditor. Health, Education, and Welfare Department: Baier, Edward J., Deputy Director, National Institute for Occupational Safety and Health, Center for Disease Control Cooper, Richard, Chief Counsel, Food and Drug Administration, Public Health Service. Fraumeni, Joseph, Jr., M.D., Chief Environmental Epidemiology Branch, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutues of Health. Griesemer, Richard A., D.V.M., Ph. D., Associate Director for Carcino- genesis Testing Program, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health. Kennedy, Hon. Donald, Ph. D., Commissioner, Food and Drug Adminis- tration, Public Health Service. PAGENO="0006" VI ORGANIZATIONS REPRESENTED AT HEARINGS-Continued Health, Education, and Welfare Department-Continued Page, Norbert P., D.V.M., Chief, Priorities and Research Analysis Branch, Division of Criteria Documentation and Standards Development, National Institute for Occupational Safety and Health, Center for Disease Control. Roberts, Howard R., Ph. D.~ Director, Bureau of Foods, Food and Drug Administration, Public Health Service. Scheuplein, Robert J., Ph. D., Chief, Dermal and Ocular Toxicity Branch, Division of Toxicity, Bureau of Foods, Food and Drug Administration, Public Health Service. Upton, Arthur C., M.D., Director, National Cancer Institute, National Institutes of Health. Thermo Electron Corp., David H. Fine, Ph. D., senior scientist. PAGENO="0007" CANCER-CAUSING CHEMICALS Safety of Cosmetics and Hair Dyes MONDAY, JANUARY 23, 1978 hOUSE OF RFIPRESENTATWES, SUBCOMMITTEE ON OVERSIGHT AND INVESTIGA!flONS, Co1~MrrrEE ON INTERSTATE ANI) FoREIGN COMMERCE, - WclAslthigton, D.C. The subcommittee met, pursuant to notice, at 10 a.m. in room 2141, Rayburn House Office Building, Hon. John E. Moss (chairman) presiding. Mr. Moss. The committee will be in order. I am pleased today to open this set of hearings on cancer-causing agents in the environment. Last year our subcommittee held related hearings on carcinogenic flame-retardant chemicals, including Tris, a chemical found in children's sleepwear. At that time, I noted that evidence continued to accumulate indicating that the vast majority of cancer is caused by environmental factors. Unfortunately, this evi- dence continues to accumulate. It is my hope that, during this set of hearings, we will learn more about the sources of cancer~causing chemi- cals and what action needs to be taken to eIimin~te consumer exposure to them. This Nation took a major step toward the conquest of cancer in December 1971, when the National Cancer Act was signed into law. At that time a new era began, one which was designed to find and eliminate the sources of cancer. The importance of eliminating sources of cancer cannot be over- stated. The final report of the national panel of cancer cOnsultants published in 1971 stated: Cancer is the No. 1 health concern of the American people. Of the 200 million Americans alive today, 50 million will develop cancer at present rates of incidence, and 34 million will die of this painful and often ugly disease if better methods of prevention and treatment are not disoovered. In 1974, about 345,000 lives were lost to cancer; $1.8 billion was spent on hospital care for cancer; and patients and society lost 1.8 million work-years due to this disease. In May of this year, I stated that I believed "the cancer plan established in 1971 to vigorously pursue all avenues toward ending cancer in our lifetine appears to be floundering." I still believe this is trüe~ During the 94th Congress, this subcommittee examined examples of industrial sources and occupational exposure to carcinogens. Several days of hearings weye held ln Washington and Newark, N.J., dn this (1) PAGENO="0008" 2 topic.' During the 95th Congress we held hearings in Cincinnati,2 Ohio, to examine the problem of organic chemical contamination of drinking water, particularly contamination of Ohio River drinking water by the toxic chemical, carbon tetrachloride. We also have re- viewed the adequacy of existing laws in protecting the public from exposure to toxic flame-retardant chemicals in the environment.~ Today we expect to examine several aspects of the National Cancer Institute's efforts to discover the sources of cancer. NOl's research program in the area of environmental causes of cancer centers around its bioassay testing program. Chemicals are selected for carcinogenicity testing if NCI believes they are potentially dangerous and may be inhaled, ingested, or absorbed. Budget and manpower restrictions have limited the number of chemicals that can be tested; and although over 700 new chemicals are developed each year and there are 3.5 million chemicals now in exist- ence, Qnly 437 chemicals are now part of this program. Since NCI places only 60 chemicals a year "on test" in this program, it would take decades for it to test the approximately 1,800 chemicals now on the NIOSH suspected carcinogens list. There are several links in the chain that must function properly for this program to be effective. They include: One, proper monitoring of the entire universe of chemicals for po- tentially dangerous substances; Two, effective management of the chemical carcinogenesis testing program; Three, the timely dissemination of the program's findings to appro- priate regulator agencies; and Four, utilization of these findings by the regulatory agencies. We will carefully examine these links today. In order to gain a more inrdepth understanding of thes~ issues, we will focus our attention upon potentially carcinogenic ingredients in hair dyes and the production and use of the industrial chemical 1 ,~ dichloroethane. Recently, the subcommittee was informed by NCI that several ingredients in hair dyes besides 2,4 diaminoanisole are carcinogenic. If this is true, consumers utilizing hair dye products containing these ingredients may be facing an unnecessary risk of cancer. During the second and third days of these hearings, we hope to explore this ques- tion indepth since more than 25 million Americans may be at risk. We welcome Dr. Arthur Upton, Director of the National Cancer Institute and Mr. Edward J. Baier, Deputy Director of the National Institute for Occupational Safety and Health to discuss these impor- tant matters with us. I understand that Congressman Maguire would like to be recog- nized at this point. Mr. Maguire? Mr. MAGiYIRIc. Thank you, Mr. Chairman. A former Acting Director of the National Cancer Institute stated in 1977 that most cancers are theoretically preventable if we identify I "Enviromne,it~l Causes of Cancer," hearings held by the Subcommittee on Oversight and Investiga tions, Committee On Interstate and Foreign Commerce, May 28 and Sept. 20, 1976-serial No. 94-14i. "CarbOn Tetraajiloride Contamination of Public Drinking Water," hearings held by the Subcommittee on Oversight and Investigations, Committee on Interstate and Foreign Commerce, Apr. 13, i977-serlal. No. 95-29. "Regulation of Cancer-Causing Flame.Retardant Chemicals and Governmental Coordination of Test. ing of Toxic Chemicals," hearings held by the Subcommittee on Oversight and Investigations, Committee on Interstate and Foreign Commerce, May ii, 13, and i6, 1977-serial No. 95-33. - PAGENO="0009" 3 causative agent~, avoid exposure to them, and eliminate them from the environment Other experts, including a number of outstanding cancer research scientists, have gone sO far as to indicate that 60 to 90 percent of human cancers result from exposure to environmental carcinogens. Nobel Laureate Dr. James Watson concluded as early as 1975, "It makes most sense, rather than striving for early detection; to spend most of this National Cancer Institute money to see that known environmental carcinogens are kept away from the American public But such a goal will bring NOT into direct conflict with very powerful industrial lobbies. And at least when I was on the National Cancer Advisory Board there was a noted reluctance for the NOT to take on any regulatory role." In view of the recognized significance of environmental factors in the causation of c~ancer, it is distressing to realize how limited a pro- portion of the NOT cancer program budget is directed toward efforts to limit our exposure to these substances. Why is this so? Any attempt to reduce the exposure of the American public to carcinogenic substances must rely quite heavily on testing procedures designed to measure their carcinogenicity. This testing system should function in such a way that it can deal effectively with both the potentially dangerous materials currently in use and the large number of new substances being introduced in one form or another every yeI~r. The carcinogenesis testing program of the NOT has the responsibility for testing substances for their potential carcinogenicity. The per- formance of the program to date is gi'ossly inadequate~ For example, it has been stated that NOT currently has the capacity for placing 60 new substances on test annually. This number is wholly inadequate in view of the estimated 1,800 suspected carc nogens listed by the National Institute for Occupational Safety and Health and the approximately400 new cOmpounds entering the environment annually, some of which may be carcinogenic. In addition, available evidence indicates that the test system is functioning well below the stated capacity. Why is this so? A major snag in the testing system occurs at the level of reporting. For reasons that are~ not clear to ~ne, reports of positive carcinogenic findings move amazingly slowly through the clearinghouse process Consequently, there is a delay in the dissemination of this vital information to the appropriate regulatory agencies, resulting in the prolongation of our exposur~ to the toxic effects of the chemicals. What can be done to improve the efficiency of the system? Why is there a problem with reporting test results? Since the inception of the National Cancer Institute in 1937, the Congress has voted for steadily increasing appropriations. This reflects the concern of this country about the increasing death toll from this dreaded disease. And, because of the numbers involved, one might even call it a ~plague. In New Jersey, my home State, we have the highest toll of all. The depth of our Nation's concern about the extent of cancer was demonstrated quite vividly in our willingness to embrace the concept of the so-called "War on Cancer" in 1971 However, it appears that 6 years and billions of dollars lat~r, little has changed neither in research emphasis nor in cancer's grip on America's lives. PAGENO="0010" 4 The time has come for us to take a hard look at where we are and what direction we should take in the fight against cancer Has this money-now over $800 million a year-been wasted? Or has a sig- nificant portion of it been wasted? Are lives being saved? Can we do better? These are the vital questions we must address in these hearings. Thank you very much, Mr. Chairman. Mr. Moss. At this time the Chair will call the first witnesses: Dr. Arthur Upton, Director of the National Cancer Institute. He is accompanied by Dr. Richard A. Griesemer, Associate Director for Carcinogenesis Testing Program, and Dr. Joseph Fraumeni, Chief, Environmental Epidemiology Branch, Division of Cancer Cause and Prevention. Gentlemen, will you come forward. At this time the Chair will administer the oath to the witnesses. Dr. Upton, will each of the persons accompanying you give testimony? Dr. UPTON. Yes, sir. Mr. Moss. Do you solemnly swear that the testimony you are about to give this subcommittee shall be the truth, the whole truth, and nothing but the truth, so help you God? Dr. UPTON. I do. Dr. GRIESEMER. I do. Dr. FRAUMENI. I do. / Mr. Moss. Doctor, we are pleased to welcome you. TESTIMONY OP ARTHUR C. UPTON, M.D., DIRECTOR, NATIONAL CANCER INSTITUTE, NATIONAL INSTITUTES OF HEALTH, DE PARTMENT OP HEALTH, EDUCATION, AND WELFARE, ACCOM- PANIED. BY RICHARD A. GRIESEMER, D.V.M., PH. D., ASSOCIATE DIREC~rOR FOR CARCINOGENESIS TESTING PROGRAM, DIVISION OP CANCER CAUSE AND PREVENTION; AND JOSEPH PRAUMENI, JR., M.D., CHIEP, ENVIRONMENTAL EPIDEMIOLOGY BRANCH, DIVISION OP CANCER CAUSE AND PREVENTION Dr. UPTON. Thank you, Mr. Chairman. My name is Arthur Upton. I am the Director of the National Can- cer Institute. Mr. Chairman and members of the subcommittee, I am honored to appear before you today to present the activities of. the National Cancer Institute as they relate to the cause and prevention of cancer. Appearing with me to answer questions are two members of my staff, Dr. Richard Griesemer, Associate Director for Carcinogenesis Test- ing, and Dr. Joseph Frai~meni, Chief of the Exivironmental Epi- demiology Branch. With the support, dedication, and commitment of the Congress, the President, and the people, we have been able since 1971 to mount a comprehensive nationwide program of research, demonstration, and education on cancer. The goal of the national cancer program is to develop the means to recbice the toll of cancer in man which despite significant advances in research is a major health problem whose im- pact has been slowly but constantly increasing over the past 50 years. PAGENO="0011" 5 Cause and prevention research has one of our highest priorities because prevention offers the best hope for ultimate control of cancer Our greatest involvement in this area is in environmental carcino- genesis, due to the increasing evidence, that a majority of cancers are environmentally related. Scientists do not agree comp1etely on which factors. in the environ- ment may increase human risk to cancer. There is general agreement that cigarette smoking has contributed to about 40~ percent of cancers in men in the United States, and to a lower, although increasing, percentage of cancers in women. This large segment of the cancer burden consists mainly of lung cancer, but also includes cancers of the throat, esophagus, bladder, and pancreas. Efforts in cause and prevention to understand the origins of human cancer are reflected by a spectrum of research approaches First we are studying ~known carcinogens, such as radiation-including ultra- violet light-tobacco, and chemicals such `as drugs and hormones. Second, we are supporting animal studies to screen chemicals for carcinogenic potential At the same time, we also are emphasizing research to improve these testing procedures At the present time, approximately 90 chemicals are being tested in animals. Experiments on an additional 64 chemicals are being analyzed and reports are being prepared Another 100 chemicals will be started on. test this year The testing is managed and directly supervised by the National cancer Institute with support from a prime con.tractor~ Tracor Jitco Third, we have expanded efforts to identify patterns of the occur- rence of cancer in our population as it relates to the environment These activities include followup of NCI's cancer mapping studies which include efforts to identify population groups at high risk of cancer, through community and, occupational studies, as well as by an examination of the effects of drugs, hormones, and radiation Other studies examine the role of nutrition in susceptibility to cancer. Fourth, we support research on the basic mechanisms of how normal cells become ca~cero'us. The solutions to the many problems involved in the prevention of the 100 or more forms of cancer will not come rapidly or easily. Many scientists believe that cancer is. the result of a complex interaction of cellular events, with hereditary information, chemical agents, radia- tion, and viruses all playing a role in one or another instance The problem of the role of chemicals in cancer is by itself immense Estimates of the number of chemicals in the world exceed 7 million and the chemical abstracts registry now lists 4,500,000 different entries Relatively few of these chemicals have been tested for car~ cinogenicitry in animals Some 16,000 reports of animal experiments of various sorts have been published Most of them are not definitive, but some evidence for earcmogenicity has been established in animals for about 400 chemicals. ` ` Even fewer chemicals have been established as carcinogens for humans-roughly 30 to 35, depending on the criteria used. These chemicals that are carcinogenic for man also are carcinogenic for animals with two exceptions-arsenic and benzene, which we believe have not yet been adeqnately teated in animals., PAGENO="0012" 6 Each animal experiment requires about 4 years and costs about $300,000. Together with limited laboratory facilities and a shortage of personnel trained to conduct animal tests for carcinogenicity, the Nation's capacity for carcinogenesis testing is severely limited. The presently available resources for carcinogenesis testing in the world are estimated to permit testing of between 200 and 500 chemicals per year. It should be emphasized that even if all chemicals could be tested for carcinogenicity, only a small portion of the problem would be solved To predict the risk to man from known animal carcinogens, one also must know something about the dose levels that are carcinogenic, the relative poten~cy of the carcinogen, the routes of exposure to which man is~susceptible, and the relative ability of human `tissues to detox- ify, metabolize, and excrete carcinogens. Moreover, man rarely is exposed to large doses of single carcinogens. Instead, man usually is exposed `intermittently to smaller doses of many carcinogens. Two or more carcinogens acting in combination may be mutually inhibitory, additive, or multiplicative in their effects. This reflects in part the fact that there are different kinds of carcinogens, some of which act largely to promote the cancer-inducing effects of others. Chemical testing by the National Institutes of Health-primarily the National Cancer Institute-began as a research effort and was expanded to its current level largely as a demonstration and feasibility study to develop means to fill the perceived' Federal needs. Among HEW agencies, the Food and Drug Administration, the National InstitutO for Occupational Safety and Health, the National Institute of Environmental Health Sciences, and the National Cancer Institute all conduct some chemical-testing activities. The National Cancer Institute studies constitute the majority of these. It is noteworthy in this connection that cancer is only one of the health impacts of chem- ical exposure. The state of the art for testing other long-term health effects is as yet similarly primitive. We believe that the role of Government will need to change over the next `decade, from one of providing major support for chronic toxicity testing to one of primary concern with the development and validation of nOw test methods and quality control of testing con- ducted by industry. For the interim, we are concerned that allocating resources to expand our testing program may occur at the expense of research needed to improve testing methods. It is of major impor- tance that the role of the NCI-and of HEW-in chemical testing be critically examined within the context of the needs and respon- sibilities of the various regulatory agencies. The NCI animal bioassay effort for chemical carcinogens can merely detect a chemical's potential for causing cancer in humans. Its results' cannot tell us whether a particular chemical will cause human cancer, hut' they may alert us to a presumptive risk and thus serve as a basis for further studies of the chemical in question. As a screening method, the bioassay consists of administration of a single chemical at two dose ~1eve1s to rodents of two species and both sexes. Rodent species are used for the screening process beôause of their relatively short lifespans, their well-understood biological behavior, and the high rate of correlation between rodent carcinogen- PAGENO="0013" 7 icity and the small number of known human carcinogens. In the interest of tosting as large a; niiniber of chemicals as is economically feasible, a given chemical is usually given to only 50 animals of each sex and species at each dOse level. Because of the small number of animals tested and theirbrief lifetimes as compared to that Of humans, one of the dose levels is set as high as possible to maximize the chance that a carcinogen will not go through tha; screen undetected. For this same reason, the route of administration for the chemical is selected to permit exposure of as many body organs as possible. Each animal test requires about 4 years, including design, adminis- tration of the chemical, and analysis of the results. Because of the cost of these experiments, both in time and dollars, chemical selection is a critical part of the testing process, At the present time, selection depends on information concerning extent of human exposure as well as what is known concerning the biological effects of a given chemical and any other similar chemical. Production data, information on dispersion into the environment, chemical structure, and mutagenicity data, for example, are examined by a chemical selection working group composed of scientists from NOT and 10 other Federal agencies. This group nominates chemicals for testing. Their nominations then go to a chemical selection subgroup of the Clearinghouse on Environmental Carcinogens, a chartered advisory body of non-Government members that meets in open session to make recommendations to NOT. Additional information on chemicals selected for testing comes to NOT as a result of these discussions, and the final decision to test is made by NOT staff. Similar review procedures with other clearinghouse subgroups con- cerned with experimental design and data evaluation provide review of the testing protocol and results After review, the institute publishes a report of the findings, announced in the Federal Register, and in- forn~is the public via the media. Copies of the report are sent. to other Federal agencies. Additional information on some chemicals alsO is sent to physicians concerned with occupational medicine, industrial and labor organizations, and environmental and consumer groups. S In addition to the clearinghouse activitiCs, the National Cancer Institute is represented on a number of interagency committees con- cerned with Federal activities in environmental toxicology. It is noteworthy that the four principal regulatory agencies-Food and Drug Administration, Environmental Protection Agency, Consumer Product Safety Commission, and Occupational Safety and Health Administration-have recently formed an interagency regulatory liaison group for the purpose of coordinating and pooling their re- sources and activities in the area of environmental toxicology. They have also made overtures to NOT, NIEHS, and NIOSH to join them in a common approach to problems of mutual interest~ NIEHS has a growing interest in the development of test methods for mutagenicity and teratogenicity, as well as for other toxicity indicators. NOl and NIEHS are cooperating in the development of a program aimed at testing the animals in the cancer bioassay program for other toxicities. When fully operational, this will greatly increase PAGENO="0014" 8 the benefit derived from the NOT bioassay program. Thus, to a sig- nificant degree, the NOT and NIEHS are embarked on an extension of testing, from carcinogenicity to a whole range of toxic effects. My colleagues and I shall be pleased to answer any questions. Mr. Chairman, this concludes my statement. Mr. Moss. Thank you, Doctor. At this time, the chair recognizes the gentleman from New Jersey, Mr. Maguire. Mr. MAGUIRE. Thank you, Mr. Chairman. At the outset T want to say that T am gratified with the approach that Dr. Upton has taken at NOT since he was appointed to this very important position. But we do have a serious problem of past perfor- mance and of emphasis. Just to highlight a bit more of what T think the problem is, I would like to point out that in July 1977, NOT promised this subcommittee that 119 final reports on cancer-causing substances would be completed by January 1, 1978. In fact, earlier in the year a promise of 230 reports have been made However, as of January 1, 1978, only 20 final reports have actually been made available. Doctor, why is the number of completed tests and completed reports so far below what we were promised? Dr. UPTON. Mr. Maguire, may T refer that question please to Dr. Griesemer, who is in charge of the testing program? Mr. MAGIJIRE. As you wish. Dr. GRIESEMER. Mr. Maguire, we have reached about 80 percent of our goal in analyzing and reporting the results of some experiments with some 200 chemicals. T should go back to explain to the committee that a great many experiments were started at about the same time as recorded on the chart on the wall. Tn 1974 and 1975, the majority of those experi- ments were completed in animals at about the same time. That does not complete the experiment, however; because the animals then are sacrificed, and the pathologists have to analyze the tissues-- Mr. MAGUIR1D. Presumably, Doctor, all of that was known when these estimates were made. Everybody knew what the process was. Yet, if you look at that graph on the wall, you find a total of 20- the red line out at the right-hand side of January 1978, as opposed to the 119 that was promised the subcommittee and the 230-the green line at the top-that was earlier promised. [The graph referred to follows:] PAGENO="0015" 9 Graph of Final Reports Compared to Projected Reports by the National Cancer Institute Number of Final Reports 240 220 200 180 160 140 120 100 80 60 40 20 0 NUMBER OF FINAL REPORTS ~ ~20 * ~NoA~OoRTi, V~A 119 FINAL REPORTS - PROMISED I HEW L 230 Final Reports Promised to Labor4lEW Appràpriations Subcommittee by 111fl8 March July January 1977 1977 1978 *Of a total of 437 chemicals in Bioassay Program Jan. 16, 1978 PAGENO="0016" 10 Dr. GRIESEMER. Let me adjdress the numbers, if I may. Mr. MAGUIRE. Everybody knew what. the process was; presumably the projections were made in full knowledge of what the process was. Yet, we get--that isn't anything like an 80-percent performance; that's less than 10 percent. Dr. GRIESEMER. As of today, we have completed experiments on 92 chemicals. These have been submitted for publication and referred to the Clearinghouse on Environmental Carcinogens. We have 68 additional chemicals in draft form where the material has been col- lated ai~d~, on those that are positive, transmitted to the regulatory agencies. This is a total of 160 out of 201 chemicals in the backlog of chemicals on which we are working. Of the remaining- Mr. MAGUIRE. On the final report-4he final report is not available on most of those. And a final report is the only thing on the basis of which action can be taken. Therefore, as long as test results are being analyzed and draft reports are being circulated, people are still at hazard. Is that not correct? Dr. GRIESEMER. I believe you are referring to printed reports on which we do not put our emphasis. It is most important that the information about the potential carcinogenicity of chemicals be reported to the public and to the regulatory agencies as fast as possible. In order to do that, we have concentrated on compiling the informa- tion. As I said, we have done that now on 160 chemicals. That inf or- mation has been transmitted to regulatory agencies. Of the 40 re- maining chemicals, there are problems in quality assurance which require additional review; and those will be out in the next, several months. Mr. MAGUIRE. My understanding, though, is that regulatory agencies-at least this is what they tell us-feel unable to act on the basis of a draft report. As long as that is true, the public is at jeopardy. Dr. GRIESEMER. What we call our final report is the one on which 92 have now been completed. It takes several more months for them to be printed and published. But that is not an important factor in this process because the information has been transmitted to every- one long before the printing process. So we have concentrated not on- Mr. MAGUIRE. Does the public know about this- Dr. GRIESEMER. Yes; these studies are all dispatched openly- Mr. MAGUIRE. Prior to the final report being prepared? DR. GRIESEMER. Yes; they are discussed openly in public forum. Mr. MAGtYIRE. Of course, even when we get final reports, as we did with hair dyes, we get them about 100 years after the first knowledge that scientists had that there was a problem of carcinogenicity with hair dyes. And at least since 1955, as I understand it, we have had test data that confirm those suspicions of 100 years ago. Yet, now finally, 2 years after the work was completed, we are beginning to get some action. What are we going to do about that problem of the timelag during which people are exposed to cancer? Dr. GRIESEMER. No one is more aware of the need to protect the public than we, Mr. Maguire. PAGENO="0017" 11 At present there is no timelag. Several years ago there was. Mr. MAGUIRE. So, these gaps in that chart are going to disappear. Is that what you are saying. Dr. GRIESEMER. Those gaps are not real. The real numbers are that 160 out of 201 have been repGrted already. The others are nearly finished. So, aside from the few that require review pathology, all of theni will have been reported in the next several months. Mr. MAGUIRE. I think that is a very optimistic reading of the facts. Thank you, Mr. Chairman. Mr. Moss. The time of the gentleman has expired. The Chair recognizes the gentleman from Pennsylvania, Mr. Marks. Mr. MARKS. Thank you, Mr. Chairman. Dr. Upton, I am wondering if you, sir, and/or the other gentlemen, believe that there should be a single Federal policy for identifying and regulating carcinogens? Or should we continue on the path that we have been where agencies such as FDA and EPA and the rest formulate their own respective policies? Dr. UPTON. Mr. Marks, I believe there ought to be a single Federal policy~ I have been very much encouraged m the short time I have been at the National Cancer Institute to see the development of a coordinated and concerted effort in this direction. Mr. MARKS. What has been done? I noted in your statement there seems to be a voluntary coming together, but nothing very serious. Dr. UPTON. The four major regulatory agencies-Consumer Prod- uct Safety Commission, Environmental Protection Agency, FDA, and OSHA-have agreed to meet regularly. The heads of the agencies meet regularly in what is known as the Interagency Regulatory Liaison Group. They are now undertaking a joint review of research needs and research resources relating to the whole `atea of .eiivironmental toxicology. Mr. MARKS. Doctor, I must assume that this is being done on a voluntary basis. Dr. UPTON. To my knowledge, that is correct. The four agencies-known colloquially as the Council of Four- have invited the National Cancer Institute, the National Institute of. Environmental Health Sciences, and the National Institute on Occu- pational Safety and Health to meet with them to review jointly our efforts and our perception of need in this same domain, environmental toxicology. Mr. MARKS. What has ~been the response from these agencies, lncludinE NOT? Dr. UPTON. We were overjoyed to have such a meeting just before Christmas and have undertaken to assemble all of our data that relate to activities in environmental toxicology and to arr~y our data in the same format as has been selected by the Council of Four. I would hope that within another week or two, we can report our information to them and that shortly thereafter it will be possible for another meeting at which research agencies and the regulatory agen- cies can sit down together and see what the needs of the Nation are and how the agencies can best work together to form a common policy to address those needs. 24-600 0 - 78 - 2 PAGENO="0018" 12 I can assure you that I feel deeply convinced that this problem area is an enormous one and that NOT must intensify its efforts in this area. Without the liaison and the coordination that may be possible through the meeting that I referred to, the Council of Four, long-range plan- ning on our part would be very difficult. So, I see this as a very important step toward the constructive and realistic and adequate planning that we must make and the programing that we must accomplish if we are to serve the Nation well in this area of need. Mr. MARKS. What about the other agencies that have been invited to join? Has their response been the same? Dr. UPTON. At the meeting I attended there were indeed repre- sentatives from NIEHS and NIOSH. I detect no disinclination to be - involved in this common effort. Mr. MARKS. You are answering it in the negative by saying that you see no disinclination. Was it affirmative? Did they agree that there are difficulties in doing this, but we are going to do it? Dr. UPTON. It was affirmative; yes, sir. Mr. MARKS. What have been some of the difficulties in bringing this about before this t~ime? And what are the difficulties as you see them now? Dr. UPTON. I confess to you that 1 don't have an adequate knowl- edge of the history. I came to the National Cancer Institute in August, and my experience dates from that time. I think what we have witnessed over the last decade or more in this problem area is a growing awareness o. need. I think that until the relatFv~eIy recent past, although it had been recognized that there were hazards in the environment-carcinogenic hazards-the evidence that these might be important in low-dose levels, levels of the sort to which the population is exposed, had not been widely recognized or accepted. There is still, as you know, controversy as to the nature of the dose response relationship. But I think, with evidence from quantitative epidemiological studies of irradiated populations and of some populations exposed to chemicals of various kinds, there has been less and less willingness to assume the existence of so-called safe tolerance or threshold levels, and more concern about the possible combined effects of small quantities of materials in our environment. This has spurred growing concern and, naturally, growing effort to deal with this problem. I think that what we are seeing is probably the dawn of a new era, if you will, in the assessment of cost versus benefit, the degree to which it is necessary or desirable for society to regulate the substances which it adds to its food supply, the water it drinks, the environment in which it lives. I think to most of us regulation is unwholesome, undesirable. We don't want someone telling us what we must or must not do. On the other hand, to the extend that we are all prisoners of the environ- ment, we want to know the facts; and we want to arrive at societal policies that aire acceptable in terms of the risk they entail to all of us. As we have emphasized, I think the existing methodology to arrive at these assessments is still crude. Again, until recently, I don't think many scientists would have advocated the expenditure of colossal amounts of money, colossal numbers of man-years, to routine testing PAGENO="0019" in mice or rats. The tests themselves are limited in what information they can provide to us. With growing concern about the environment, obviously some scaling-up of the:effort is called for. Mr MARKS Doctor, obviously one of the problems involved ~n iegulating carcinogens seems to be the probleni of identifying them The animal feeding studies are not only very costly but are time- consuming. What efforts have you undertaken to develop screening tests that are reliable, fast, and inexpensive? Dr. UPTON. At the present time, about half of the total dollar invest- ment in our bioassay program, which, at the present time, amounts to roughly $23 million per annum overall, about half of that amount is going into the refinement of test methodologies leading to improved short~tèrm. tests as well as improved understanding of the interpreta- tion of long-term tests.. Perhaps Dr. Griesemer would like 1~o expand on this, if you wish more information. Mr~ MARKS. if he can rather quickly. I think our time is almost up. Mr. Moss. The Chair will permit Dr. Griesemer to complete the answer. Dr. ORIESEMER. Thank you. It is obvious that we cannot test all of the chemicals that need to be tested. We have a concerted effort to find alternatives, including the battery of short-term assays that you have alluded to~ Mr. Moss. Does that answer the gentleman's question? Mr. MARKS. Yes. Mr. Moss. The Chair recognizes the gentleman from Pennsylvania, Mr. Waigren. Mr. WALGREN. Thank you, Mr. Chairman. In answer to the las~t question, was it said that $23- - Dr UPTON $23 million per year is the current budget for our bio- assay program, roughly one-half of which is devoted to refinement in test methodology. Mr. WALGREN. So, we are spending $11.5 million to improve testing. Dr. UPTON. At the present time, that is correct. Mr. WALOREN. And to try to develop methods that would be more convincing or more direct. Dr. UPTON. That. is the sum allocated within the bioassay program. I think it is only proper to point out that much~ o~ the ancillary research in the Institute is dedicated to an understanding of the cancer process itself, out of which I think it can be expected that new knowl- edge will lead to improvements in test procedures. Within, the bioassay program itself the effort at test refinement is funded at roughly $12 million per year. Mr. WALGREN. The bioassay program is one program of several programs that you are conducting? Dr. UPTON. That is correct. Mr. WALGREN. What amounts are resez~ved for &ttempts to improve testing validity in the other programs? Dr. UPTON. The other programs do not devote themselves directly to testing. So, sums are not earmarked in the other budgets for test reflnement as such But in many of the other programs that concern the mechanism of carcinogenesis-studies on. the action of chemicals, PAGENO="0020" 14 how chemicals are metabolized, how they react with sites in target cells, how the cells then behave and evolve into malignant growth- these. kinds of studies can ultimately be expected to provide informa- tion that will lead to improved tests in the bioassay program. Mr. WALOREN. So, there is no budgetary ~way to see whether an increased effort is being made to develop more convincing testing methods. Dr. UPTON. I think there is such a method. I think it would require a detailed analysis of all of the activities in the carcinogenesis program area. This would be possible. We have not attempted to do this to date. It could be done. It is not beyond doing. Mr. WALGREN. I am sort of interested in that because, on an insti- tutional basis,_when the public does not believe the test, then the political will isIost~t~ implement the perhaps-needed remedy and, to the degree that the public is not prepared in this country even to accept other countries' tests on rats, to convince them to change our 1ifesty1e~. I would be very interested to know what your Institute is doing to try to either improve the convincing power of those tests- that is a very critical function you have. I would hope that there would be a way to get at it budgetarily to see that an effort is being made in that direction. I wanted to go back to what I took to be the thrust of Mr. Maguire's questions. It has to do with the difficulty that regulatory agencies have in being reluctant to rely on nonfinal reports as to the danger of these substances. It takes so long apparently to get these reports into a final form. Mr. Maguire's thrust on the subject was that the reports are not yet in final form. Do I understand that there is a final report on this substance that is known as 1,2 dichloroethane? Dr. GKIESEMER. Yes, there is a final report; I brought a copy with me. Mr.' WALGREN. And- Dr. GRIESEMER. Final in the sense that it has been interpreted and validated by NOT. Mr. WALGREN. Has that report been published? Dr. GRIESEMER. No. It will be submitted for publication today. It will appear at the clearinghouse meeting on March 6 for open review. Mr. WALGREN. You say it will be submitted for-. Dr. GRIEs~iER. For publication as a technical report by the Natioiial Cancer Institute. Mr. WALGREN. And then where is that disseminated? Dr. GRIESEMER. We have a mailing list of several thousand who receive the report. It is also announced in the Federal Register, as available from the National Cancer Institute. Mr. WALGREN. I see. And do you expect them to receive that imminently? Dr. GRIESEMER. It takes perhaps 1 to 2 months for the printing process and the announcement in the Federal Register. Mr. WALOREN. Now, do I understand that the draft report on this compound was completed in March of 1974? Dr. GRIESEMER. No, that is not correct. Mr. WALOREN. When was the draft report on this compound completed? PAGENO="0021" 15 `Dr. GRIESEMER. The draft report was completed last week. The NCI's validation and interpretation was completed last week. Mr. WALóRi~x. All right- Mr. Moss. Will the gentleman yield? Mr. WALGEEN. Yes. Mr. Moss. I believe the gentleman was addressing himself to the completion date for the animal studies rather than the preliminary report. And if Dr. Griesemer would address himself in responding to the date of the completion of the animal studies. Dr. GKIESEMER. The animal study for 1,2 dichloroethane in the mouse was completed in April of 1974 and for, the rat in May of 1974. Mr. WALGREN. Looking at that time from April-May of 1974 to the completion of the preliminary report last week, what happened in that time? Dr. GRIESEMER. Ordinarily it would take perhaps 6 or 8 months to analyze the data and write a report. One should have expected a report within a year. I do not know why my predecessors did not do that. The analysis in this case began after November of 1977, when a team of people was put together to address this.problem. Mr. WALGREN. And there is no indication in the files whatsoever why that apparently went silent for that period of time? Dr. GRIESEMER. Well, it, along with the other 200 chemical experi- ments, were not analyzed and reported during about a 2-year period. There are indications in the files of why that may have been. But, since I was not here, I do not really know the answer to your question. Mr. WA'LGREN. What are the indications in the file? Dr. GRIEsE~ii~R. There apparently was a lack of an adequate number of staff people to address this issue. Also, no one had ever attempted to analyze a large number of experiments before. So, methods and groups of people had to be assembled. Methods had to be developed' for this purpose. The NCI did recognize that respon- sibility and created the carcinogenesis testing program operationally in July of 1977. It has only been in the last 15 or 18 months that attention has been given to this problem of numbers of chemical experiments that were uncompleted. , . Mr. WALGREN. Well, I am not talking about numbers of uncom- pleted; I am talking about these particular results. , Apparently, there was indication that there was potential harm. It was put in a file that then lay dormant. Dr. GRIESEMER. That's correct. Mr. WALGREN. Can you address the same concern as to the chemicals in hair dyes? Have they lain dormant?: Dr. GRIESEMER. Yes, they were part of the large group of experi- ments that were uncompleted. I ~have the dates. on each of the in- dividual hair dyes so far as when the animals were killed, if you wish. But in general they were around 1974 and 1975. Mr. WALGREN. I would think that perha,~s we ought to hold the record open there for whatever could be submitted on the date- Mr. Moss. Without objection, we will hold the record. We will have the gentleman get together with staff to more precisely define. his request. And then we will ask that the agency submit the specific data requested. [The following table was received for the record:] PAGENO="0022" Date Date Date Date Last Pathology Pathology Draft Chemical Sacrifice Completed Confirmed Report N-phenyl-p-phenylenediamine 12/74 10/20/76 10/10/77 11/77 2-nitro-p-phenylenediamine 8/74 5/75 In review p-phenylenediamine HCL 2/76 4/77 In review 4-nitro-o-phenylenediamine 10/75 9/76 In review 1-phenyl-3-methyl-5-pyrazole 4/76 12/76 In review -- - 2,5-toluenediamine sulfate 2/75 7/76 4/77 7/77 4-amino-2-nitrophenol 8/76 12/76 1/78 Est. 2/78 2,4-diaminoanisole sulfate 4/75 7/76 8/17 10/77 Direct Black 38 8/77 1/78 1/78 Est. 2/78 Direct Blue 6 8/77 1/78 1/78 Est. 2/78 Resorcinol** 12/72 9/73 2,4_toluenediamine* 6/72 7/73 12/77 m_phenylenediamine* 3/72 7/73 12/77 * Not standard bioassay but exploratory studies ** Not standard bioassay, skin painting study. PAGENO="0023" 17 Mr. Moss. The Chair recognizes the gentleman from Tennessee, Mr. Gore. Mr. GORE. Thank you, Mr. Chairman. Dr. Griesemer, you said that the printing process would take 1 to 2 months. Does that include the approval and review that you also mentioned? Dr. GRIESEMER. No; that is just the printing process itself~ Mr. GORE. flow much does the approval and review take? Dr. GRIE5EMER. On the average, it takes 5 months for the quality assurance program and the NCI staff review. Mr. GORE. At what stage is this report you say that you have brought with you-you said that it is ready to be submitted? Dr. GRIESEMER. It is completed by NCI and is ready to go to the printers. Mr. GORE. Oh, I thought it had to go to the review board. Dr. GRIESEMER. It will, but it will also go to the National Clearing~ house on Environmental Carcinogens, for scientific review. They will assess the adequacy of the study and NCI's interpretations. But, in general, that does not affect the printing process. Mr. GORE. I see. So, the public and the scientific community will have this report in their hands late next month? Dr. GRIESEMER. Whenever it's printed; yes. It will be made publik~, obviously, on March 6. The regulatory agencies have already received copies. Mr. Moss. Would the gentleman yield? I think this record is now becoming somewhat obfuscated by state- ments made here that tern! to make very unclear the nature of a final report. Now, a final report is not issued, is it, until such time as the review process is completed? Dr. GRIESEMER. If thé~Iearinghouse were to find substantial differences which- Mr. Moss. You can answer it ~yes or no, can't you? It is not* a final report until that clearing process is completed. Is that correct? Dr. GRIESEMER. That is incorrect. Mr. Moss. All right; you go ahead. then and correot us. Dr. GRIESEMER. It is a final report when we have completed our review. Mr. Moss. Well, that's exactly what I said: Until the review is completed, it is not a final report. Dr. GRIESEMER. The cl~.aringhouse is an advisory ~om~nittce-~-- Mr. Moss. Do you ever revise a report after clearinghouse procedure? Dr. GRTESEMER. Rarely. Mr. Moss. Do you ever? Dr. GRIESEMER. No. We incorporate their suggestions--' Mr. Moss. Could 7ou? Dr. GRIESEMER. As a looseleaf in the report- Mr. Moss~ Could you? . Dr. GRIESEMER. We could reprint a copy if necessary. Mr. Moss. And you say there has never been a revision following that-the review procedure. PAGENO="0024" 18 Dr. GRIESEMER. To my knowledge, there has not been a revision. Mr. Moss. And how comprehensive is your knowledge? Because staff tells me to the contrary. Dr. GRTESEMER. I have attended all the meetings. Mr. Moss. All the meetings for how long? Dr. GRIESEMER. All the meetings of the clearinghouse for review of our final reports. Mr. Moss. For how long? t'r. GRIE5EMER. During the last year. Mr. Moss. Did it only come into being during the last year? Dr. GRIESEMER. Yes. The clearinghouse began in December of 1976. Mr. Moss. As soon as you are finished, Mr. Gore, we will have the spelling out of the procedure step by step so that we know actually what constitutes a final report upon which a regulatory agency may rely. Mr~ GORE. I think the significance of this cannot be overstated really. Our job is not to make you uncomfortable at the witness table but to find out why the job has not been done that should have been done. It is of such overriding importance because of the goal that we all want to reach, and that is combating cancer as effectively as pos- sible. It seems from the testimony that there is a lot of buckpassing going on somewhere. You are attempting to say that the final report does not have any significance. Yet, when we had the Tris hearings, the Consumer Product Safety Commission came up here and said, "We have to wait until the final report comes in. We can't do anything on a draft." The chairman just got this letter from the Environmental Protection Agency on ethylene dichloride. He encloses NCI's findings. The Environment'~il Protection Agency says, "Please note that it is a draft." OSHA responds to another inquiry from the subcommittee, "A complete written report on these experiments was still in draft stages." That makes it very easy, you see, for these other agencies to pass the buck. They say, "Well, it's still a draft." If you were in one of those agencies, would you advise them to go to court on the basis of a draft before the final report was available? Dr. GRIE5EMER. The regulatory agency requires validated data. The answer to your question is a lengthy one. Mr. Chairman, I would be happy to address it when you wish. Mr. Moss. If the gentleman from Tennessee desires it. Mr. GORE. Maybe it's not fair to ask you for a yes-or-no answer to that. I think the answer is no. If I were in a regulatory agency and I were confronted with a decision tç go to court or not-go to court and there was a draft report and NCI said, "Well, we'll have the final report soon; it will just be a few more months, 5 or 6 more months. The studies have been completed, but maybe a few years from now we'll get a final report." You know, it puts them in a position where there is the bureaucratic disease of passing the buck and waiting until all the ducks are in a row. I mean, that dynamic just naturally takes over, it seems to me; that seems obvious. There is the fact that only 20 final reports have been done when you said that 200 would be done by this date. I think that fact still stands. PAGENO="0025" 19 You can. talk. all you want to about the significance of having com~ pleted drafts for so many of them. But the fact i~ you did not meet your goals. The fact is that the importance of meeting those goals is something that cannot be overestimated. We are just trying to see what can be done to speed that process up. I do not want a lengthy answer to the earlier question, but please comment on that if you would. Dr. GRIESEMER. We are attempting to act responsibly in trans- mitting, this very important information to the public as rapidly as is obtained. It is necessary that the information be scientifically accurate as well as transmitted rapidly. The process involved starts back at the very beginning; that agencies know which chemicals we're testing. They tell us which ones they are interested in. We endeavor, at their request to keep them supplied with information on the progress of the experiments. Hence, the draft reports, telephone calls, many kinds of communications. At the time we have validated the results and analyzed them, we notify the regulatory agencies that that is our final interpretation. It is possible for them then to take regulatory actions. We do not believe that they should wait for a printed copy which takes several more months-~-- Mr. `GoRE. They do. .Dr. GRIESEMER. The information is not changed from the draft to the printed copy. Mr. GORE. They do; they believe they~ should wait until the final report apparently; at least. that's what t~iey tell us. The public is facing the danger of cancer caused by substances put into the environment so long as there is no action taken. Now, you pass the buck to them; they pass the buck back to you. We are over- seeing that process, trying to improve it. And I do not think it's the most helpful thing to say., "Well, they should act on the basis of a draft report." The fact of the matter is they should have a final report as quickly as is humanly possible. Dr. GRIESEMER. They are getting the completed NOl report as fast as is humanly possible, then it becomes their responsibility to act, not ours. Mr. GORE. You said, Dr. Upton, that, with growing concern about the environmental causes of cancer, some scaling-up may be called for. It seems to me that there is more than growing concern. It seems to me-well, I have been told that the consensus among scientists today is that somewhere between 60 and 85 percent of all the cancer that is discovered in people is caused by substances that are put into the environment as a result of man's activity. Yet, only 20 percent of your budget is oriented toward those kinds of' causes of cancer. Shouldn't more money out of your budget be directed toward seek- lngout and preventing environmental causes of cancer? Dr. UPTON. Mr. Gore, I could not agree `with you more. I think that this is, as I strove to emphasize, an area on which we are seeking to place greater emphasis. We are, I think, constrained in science to achieve an equitable balance between the opportunities that exist in the research area and the need that may exist for progress in that area. Clearly, from my testimony, from the tenor of remarks this morning, PAGENO="0026" 20 I think we all agree that there needs to be more emphasis on the as- sessment of risk associated with the environment. Since I have come to NCI, I have taken some steps to mount several reviews of this problem area so that we can determine what the op- portunities are and how best to exploit them. In the area of testing, I think it is safe to say that the degree to which the NCI budget should go into the application of routine tests as opposed to the refinement of test methodology is a moot question. Traditionally, the National Cancer Institute has viewed itself as a research organization, `not one that should devote its energies and resources to routine applications. We do have, by virtue of chronological developments, the largest single bioassay program in existence. Dr. Griesemer has told me that he thinks that we could increase our numbers of compounds being tested to 100 within the near future if we could put some more money into the program; but that 100 a year might come close to saturating the available resources within the country. I have told him that I would like to move and saturate those resources, move to 100 this year if we can so do. Mr. GORE. Let me put that answer in the context that I think it should be viewed in. The Chemical Abstracts Registry now lists about 4.5 million chemicals that are in use to4ay. Only 1,600 have been tested; 400 suggest some carcinogenicity in animals. Now, if 100 per year is going to saturate the process, then we need to dramatically change the process. Dr. UPTON. I think that is one of the most serious issues we face: How many should we be testing as a Nation. It is this question that we are trying to address with the council Of four, with NIOSH, with NIERS. We are trying to develop a plan to equip the Nation to do the testing on the scale that needs to be done. Mr. Moss. The Chair recognizes the gentleman from California, Mr. Waxman. Mr. WAXMAN. Thank you, Mr. Chairman. Dr. Upton, I understand your institute has discovered that some of the chemicals used in hair dyes are carcinogenic. Is that correct? Dr. UPTON. Tests in the rodent systems have indicated carcino- genicity at high-dose levels; that is correct. Mr. WAXMAN. Again, we have information that another commonly used product may cause cancer. When I go back home and talk to people in my district I find that they feel ,fru~trated ançl confused about the war on cancer. I hear people say that they worry about cancer like they do about muggers: There's nothing they can do about either. Now, you are a scientist. You've studied cancer. Your institute is a leader in the war on cancer. Should people avoid using chemical products that contain carcino- gens? Will it make any difference? Dr. UPTON. Mr. Waxman, I think it is a misconception that every- thing causes cancer. I think with growing numbers of agents that have been shown to produce cancers in animals there is a tendency to throw up one's hands and say, "Everything is carcinogenic; it's hopeless." But I think that is not the case. PAGENO="0027" 21 I think the record of experimentation with rodent systems discloses that~ the majority of substances are not carcinogenic at high dose levels in the standard test procedure. It turns out that the compounds that we have been reporting on were selected in advance by cancer investigators because they were suspect to begin with. Mr. WAXMAN; Dr. Upton, I am not saying that people are con- cerned that everything causes cancer. It is just that when they hear another announcement from the National Cancer Institute or some other governmental agency that something causes cancer-~-particu- larly if it is something they have been using for years-they adopt the attitude, "Well, if I'm going to get cancer, I'm going to get cancer; I might just as well continue dyeing my hair, using saccharin, or smoking cigarettes." If pepple stop using a hazardous product that they have used for years, will it have any positive effect on their health? Or is it something that they ought to be very fatalistic about and continue to use? Dr. UPTON. If we take the cigarette anak~gy, I think evidence sug- gests that cessation of smoking reduces risk. So that, if there is a lesson there, I think the lesson is that we can help ourselves by avoiding exposure or continuation of exposure to agents that cause cancer. Mr. WAXMAN. In other words, you are saying that people who have smoked cigarettes and stopped have a reduced risk of lung cancer than those who continue sornoking? Dr. UPTON. That is correct. Mr. WAXMAN. The assumption would be that those who stop using hair dyes containing chemical carcinogens may well reduce the risk of getting cancer. Is that correct? Dr. UPTON. My expectation would be that the eventual risk of developing the disease will be related to the total accumulated dose of the carcinogen; if one ceases exposure, one stops accumulating dose, and to that degree stops accumulating increased risk. Unfortunately, as we have tried to emphasize, our knowledge of these problems is still rudimentary. So, it is not possible for us to quantify' risk estimates. Mr. WAXMAN. But we do know that chemicals that are carcinogenic may well and probably do-either by themselves or in combination with other carcinogens-cause cancer somewhere down the line, 10, 15, 20 years from now. Is that correct? Dr. UPTON. This possibility cannot be excluded. There is a pre- sumption of risk. Mr. WAXMAN. So, isn't it prudent for people to stop using products when they find out that they contain carcinogens which may increase their risk of cancer? Dr. UPTON. Yes, sir. I would say that it is prudent. I' think that ,the decision frequently devolves upon the individual. If there is a perceived benefit associated with a certain practice, there may be a presumptive risk; and the individual h~s to attempt for himself or herself to weigh the risk and benefit. When it is a product that goes into foodstuffs that everyone eats off the shelf of the grocery store,. it is more difficult to allow the individual to exercise that kind of- PAGENO="0028" 22 Mr. WAXMAN. Do you think there is any kind of benefit to be derived from hair dyes that contain carcinogens? There are other products, I assume, on the market that can be used. Dr. UPTON. That is the crux of the matter: Are there safe alterna- tives? If there are, then most people, I suppose, would opt for the safer alternative. But, if there are not-we use radiation in medical practice. We know that radiation can cause cancer. We do not know categorically that the small doses of radiation involved in a chest X-ray increase the risk of cancer, but we can't exclude that possibility. So, we think it is prudent to minimize such radiation. Mr. WAXMAN. But there's a situation where there is a benefit. Dr. UPTON. There is clearly in that situation a benefit. We try to titrate benefit against risk, keeping the risk always a small as possible. I think the same analogy will be carried over into chemicals of various kinds, drugs, food processing agents, and so on. Mr. WAXMAN, But the point that I hear over and over again- and I really feel it is important to have this clarified for people-is that, if they do avoid products with carcinogens in them, they have a chance to avoid getting cancer. Continuing to use those products greatly increases the risk of cancer. Even if consumers have used this products extensively in the past, isn't it prudent for them to discon- tinue their use? Dr. UPTON. That is correct. Mr. WAXMAN. This is a frustration I think people have because they keep hearing about new discoveries that some commonly used chemicals are dangerous. They hear about it, and they start assuming that either everything is going to cause cancer or that the risk is ex- aggerated. If we ask people to be prudent in their own use of products, don't we in government have a responsibility to encourage a market- place free from carcinogens? Dr. UPTON. I would think so. Mr. WAXMA.N. A very important part of the war on cancer, as I see it, is prevention. It is as important-and maybe even more impor- tant-as trying to find a cure. Certainly trying to prevent cancer has got to~ be a high priority. Dr. UPTON. I would think that is correct. We need to have the facts. We need then to arrive at prudent evaluation sand socially acceptable policies. Mr. WAXMAN. Do you have any ideas how we can improve our credibility when we tell people that there is a dangerous sustance in the marketplace and that, in using that substance or that chemical or that product, they increase their chances of getting cancer? It seems to me the Government has lost a tremendous amount of credibility. People sort of throw up their hands and say, "Oh, another warning from some government bureaucrat," They don't take Gov- ernment warnings seriously. This is particularly disturbing to me because one out of four people in this country will get cancer; that's a terrifying figure. Do you have any thoughts on that? Dr. UPTON. It is an immense problem. I think that ultimately it devolves on education, ur~derstanding as much as one can know about the facts today, about how one can go from the facts as we see PAGENO="0029" 28 them to the development of prudent lifestyles and `prudent policies. What is prudent for one person may not necessarily be acceptable to the next. So, there' will have to ~be some open discussion, some ex- change of dissenting points of view. Unfortunately, today the science of the matter is not cut and dIy. There are honest scientific differences of opinion about evidence and how one can interpret it. Mr. WAXMAN, Thank you very much. You have been very helpful. Mr. Moss. The gentleman's time has expired. The Chair recognizes the gentleman from Ohio, Mr. Luken. Mr. LUKEN. Thank you, Mr. Chairman. Dr. Upton, 1 just arrived and do not have any extensive questions. I am wondering about something that occurs to the general public. When talking about hair dyes, and processed foods, water pollutants, and air pollutants that are part of our industralized society, do you come to the conclusion that cancer is, per se, more prevalent in this kind of environment than in a more natural environment without such exposure? Dr UPTON The data for rates of cancer in American women-if we discount the changes that we can attribute to cigarette smoking-do not suggest an increasing risk, despite the fact that we have industri- alized, But it is complicated. The rate of stomach cancer has gone down dramatically. - I think that the answer to your question, at the present time, can only be couched very tentatively. We do know from studies in animals from some epidemiological evidence, occupational groups, that some of the agents that you refer to, products of an industrial age, can increase the risk of cancer. So, one would suppose that, everything else being the same, if the population were systematically exposed to those agents willy-nilly, the effects would be an increase in the risk of cancer. - As I say, with industrialization- Mr LUKEN But don't we have statistics, don't we have surveys? Dr. `UPTON. The incidence of stomach cancer has come down dramatically, I would like to ask Dr. Fraumeni if he would be willing to speak to these questions because he is'an epidemiologist who' has followed the data very, closely. Dr. FRAUMENI. I would say that, for a great many cancers-and by this I mean some of the major cancers that affect people in the. United States and in Western countries-the rates are much higher than they are in underdeveloped countries. I think that we can attribute this to various aspects of modern civilization such as cigar- ette smoking, dietary factors, occupational exposures, certain drugs, and the like. Mr. LUKEN. That is conclusive in your opinion. Dr. FRAUMENI. I would think so. Mr. LUKEN. Then `we had better be about the business of controlling it. ` - Dr. FRAUMENT. Identifying and contreiling. Mr. LUKEN. Dr. Upton, about the NOT bioassay program testing for potential carcinogenicity of hair dye ingredients: I would like to refer you to and introduce into the record a subcommittee letter to PAGENO="0030" 24 NCI dated May 21, 1977 and an NCI letter to the subcommittee dated June 21, 1977. You are being furnished a copy of that now. Mr. Moss. The Chair asks unanimous consent that the letter referred to by the gentleman from Ohio, Mr. Luken, together with the response from NCI, be included in the record at this point. Is there objection? Hearing none, such will be the order of the coramittee. [The correspondence referred to follows:] CONGRESS OF THE UNITED STATES, HOUSE OF REPRESENT4TIVES, SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS OF' THE COMMITTEE ON INTERSTATE AND FOREIGN COMMERCE, Washington, D.C., May ~1, 1977. Dr. Guy R. NEWELL, Acting Director, National Cancer Institute, National Institutes of Health, Bethesda, Md. DISAR DR. NEWELL: The Subcommittee on Oversight and Investigations has been conducting inquiries into governmental actions to protect the public from exposure to potentially dailgerous chemicals. We are particularly interested in tests how in progress on chemicals in consumer products. We would appreciate your response to the following inquiries concerning the poteittial hazards of hair dyes and hair dye constituents: 1. What tests are now underway involving hair dyes or hair dye constituents? 2. When will these tests be completed? 3. If any tests were completed, what were the results? 4. Has NCI made any calculations as to the size of the population at risk? 5. What additional hair dyes or hair dye constituents will NCI be testing in the future? 6. Does NCI have all the information it needs to properly test for the safety of commercially produced hair dyes? If ~ny reports on the potential carcinogenicity of hair dyes or hair dye constit- uents have been completed or are in draft form, the Subcommittee requests that these reports be forwarded to it. If you have any questions concerning these requests, please contact Lester Brown at (202) 225-5365. We would appreciate your response to these inquiries by June 10, 1977. Thank you tor your cooperation. Sincerely, JOHN E. Moss, Chairman. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH, Bethesda, Md., .Iune ~1, 1977. Hon. JOHN E. Moss, Chairman, Subcommittee on Oversight and Investigations, Committee on Interstate and Foreign Commerce, House of Representatives, Washington, D.C. DEAR MR. CHAIRMAN: This letter is in response to your inquiry of May 21 addressed to Dr. Guy R. Newell regarding hair dyes and hair dye constituents. Question No. 1: The following chemicals identified as hair dyes, hair dye coit- stituents, or related materials, are presently being tested for carcinogenicity in the .Carcinogenesis Bioassay Program, Division of Cancer Cause and Preiien- tion, National Cancer Institute: 4-Amino-2-Nitrophenol Phenyl-3-Methoxypyrazolone 0-Anisidine-Hydrochloride M-Phenylendiamine Dihydrochloride 4-Chloro-0-Phenylendiamine 0-Phenylendiamine Dihydrochloride 2,4-Diaminoanisole P-Phenylendiamine Dihydrochloride P-Diaminobenzene P-Phenyleiidiamine, N-Phenyl, Diaminonitrobenzene Hydrochloride 4-Methyl-M-Phenyldiamine Resorcin 4-Nitro-0-Phenylene Diamine P-Tolylendiamine Sulfate 4-Methoxyaniline Hydrochloride PAGENO="0031" 25 Question No. 2: The animal treatment phase of the studies has been completed and technical reports should be available in nbout eight months. Question No. 3: The outcome of the experiments is not yet known because the data and information generated in these experiments has not been verified A summary of available data, the Experimental Design Status Report (EDSR) and the Individual Animal Pathology Report (Table II) are being forwarded under separate cover. Question No. 4: The, size of the population exposed to hair dyes, hair dye components and related materials has to the best of our knowledge not been determined. Question No. 5: In the future other hair dyes will be considered for carcino- genesis testing along with other environmental chemicals. The limited resources for testing necessitates that selection of chemicals and setting priorities for their testing be accomplished, through the due processes of the Chemical Selection Working Group. Question No. 6: The objective of bioassay testing as presently performed in our program is primarily to determine the carcinogenic potential of chemicals iii animals. Further toxicology testing for general human safety evaluation is presently the requirement of the regulatory agencies and the manufacturers Additional studies, such as the penetration of the skin by the chemicals, will probably be required. I hope this information will prove useful. Sincerely yours, SIDNEY SIEGEL, Ph.D., Coordinator, Injorrnaiion Activities, Carcinogen Bioassay and Program Resources Branch, Carcinogenesis Program, DCCP. Mr. LUKEN. Are you familiar with the document? Dr. UPTON. I do not think I have seen it before, Mr. Luken. Mr. LUKEN. Is it something you could refer to quickly? Dr. UPTON. Yes, sir. Mr LUKEN On that date, the subcommittee wrote inquiring about the testing of hair dye ingredieuts. In your return letter, you stated that NOl was testing some 16 hair dye ingredients and related ma- terials. Why were these particular materials selected? Dr. UPTON. Mr. Luken, may I refer that question to Dr. Griesemer? Mr. LUKEN. Yes. Dr. GRIESEMER. These were selected from among the universe of chemicals on a itumber of bases, including human exposure or evidence related to human exposure, such as the production rates. Second, it was on the basis of suspected biological effects such as toxicity or mutagenicity: the same- criteria that are applied tO all the chemicals in the test. Mr. LUKEN. Are they part of a family or a class then? Dr. GRIESEM~R. There is a use category, -but there also are some subcategories of chemicals within the use category. Mr. LUKEN. Is there a commou structure in these groups of chem- icals which is suspicious? Dr. GRIESEMER.. We tend to select representative chemical -types and those with the greatest production among a long list of chemicals, some 162 hair dye ingredients and related chemicals. Obviously we cannot test them all; so we selected chemical examples. Mr. LUKEN. To date you have annouticed that there are two hajr dye ingredients-2,4-diaminoanisole suif ate and 2,4-toluenediamine- that are careinogemc in animals under NOl tests However, in vitro mutagenicity tests - on hair dye and hair dye ingredients suggest several other ingredients may be potent mutagens and potential carcinogens; right? - PAGENO="0032" 26 Dr. GRIESEMER. Correct. Mr. LUKEN. Do you believe there is some correlation between this mutagenicity-especially considering the Ames test results-and car- cinogenicity? Dr. GRIESEMER. Yes. In this category of chemicals the relationship between mutagenicity and carcinogenicity is very close. So that if a chemical is mutagenic it would make us very suspicious. Mr. LUKEN. In your opinion then mutagens are, in and of them- selves, dangerous? Dr. GRIE5EMER. Yes. Mr. LUKEN. Is there a significant difference of opinion on that in the literature? Dr. GRIESEMER. I do not believe so. Mutagens are hazardous. Mr. LUKEN. There is no difference of opinion as. to whether or not they are hazardous; but is there as to the degree of hazard? Dr. GRIESEMEE. There is some indecision about prediètability of carcinogenicity from knowledge of mutagenicity. Mr. LUKEN. Could you discuss that a little bit? Dr. GRIE5EMER. In some of the major published studies, the association between mutagenicity and carcinogenicity is on the order of 85 or 90 percent; that is a good correlation. However, not all classes of chemicals have been tested for mutagenicity. Certainly not many for carcinogenicity. And there are some classes of chemicals where the association is very poor-in the metals, for example. So, we cannot use mutagenicity data alone to establish the carcino.- genicity of chemicals. They still have to be either tested in animals or one has to determine their carcinogenicity for man by epidemiologic studies. Mr. LUKEN. What is the Ames test? Dr. GRIESEMER. That is a ba~terial test for mutagenicity. Mr. LUKEN. What is your opinion as to the validity of the Ames test? Dr. GRIESEMER. It is a good test for mutagenicity and, in some chemical classes, is a strong indicator of possible carcinogenicity. Mr, LUKEN. Some chemical classes? Dr. GRIESEMER. Yes. Those in which the hair dyes fall, there appears to be a good correlation. Mr. LUKEN. I have no further questions. Mr. Moss. The gentleman's time has expired. The Chair recognizes the gentleman from New Jersey, Mr. Binaldo. Mr. RINALDO. Thank you very much, Mr. Chairman. Doctor, it has been estimated, I understand, that 90 percent of cancer is caused by environmental factors. Would you agree or disagree with that statement, and could you tell me why? Dr. UPTON. I am acquainted with that estimate. I could not dis- pute it. It is based largely on comparison of rates of cancer at dif- ferent organ sites in various parts of the world. The difference between those parts of the world with the highest incidence of cancer at a given site and those parts of the world with the lowest incidence may vary by a factor of as much as 50. If one averages over all sites of the body the overall differences between high regions and low regions, if the differences are related to the environment and not genetic factors, then perhaps up to 90 percent of cancers are environmentally related. PAGENO="0033" 27 Mr. RIxALDO. In other words, you say that there is a certain amount of truth to the statement that about 90 percent of the cancer in this country could be caused by environmental causes, and the other 10 percent by nonenvironmental causes or factors? Dr. UPTON. That is correct. Mr. RINALDO. If we get down to the percentage of cancer that is caused by environmental factors in the United States, could you give me some estimate of how that would break down, for example, smoking, the so-called western diet-the way we eat, not the specific chemicals in the food-and exposure to chemicals in consumer prod~ ucts? Dr. UPTON. Mr. Rinaldo, may I refer that question to Dr. Frau- meni? Mr. RINALDO. Yes. Dr. FRAUMENI. Mr. Rinaldo, it has been estimated that perhaps 40 percent of cancers in American men are related to cigarette smok- ing. In American women, it is on the order of. 15 percent. For occupa- tional exposures, the estimates ar~ a little uncertain; but they probably are on the order of 10 percent or under in men. Medicinal exposures, such as exogenous estrogens used for treat~ ment of menopausal symptoms, contribute perhaps on the order of 5 p~ercent and probably less. Dietary exposures appear to be extremely important. The esti- mates here are vague because there is a great deal of research going on now to try to identify the specific nutritional constituents and mechanisms that are responsible. But there is much indirect circum- stantial evidence to suggest that nutritional factors account for a sizable percentage of cancers in both sexes. Mr. RINALDO. We still did not get down to the exposure to chemicals in consumer products. You only gave two sets of statistics there. You started out with statistics pertaining to smoking: 40 percent in males and 15 percent in females But what would you say would be the total, if you add exposure to chemicals in consumer products? Could you give some percentage for that? Dr. FRAUMENI. I do not think we can.. We are lacking the epidemio- logic information at this point to estimate the contribution of this class of chemicals. I think some may speculate on a range, but I do not know with any precision what that range is. I think we just need to step up our research in epidemiology-and in experimental studies- to try to detect the specific carcinogenic hazards involved. Mr. RINALDO. You state you don't know what the range is. But if we take smoking, diet, alcohol, maybe automobile emissions and exhaust from trucks and engines, sunlight and other radiation, air contamination, maybe water contamination, occupational exposure to chemicals, and the other factors, such as drugs, which you said amounted to under. 5 percent, and~* then subtract that from 100, shouldn't we come up with some idea very simply of what it is? Dr. FRAUMENL I am not sure what you mean by consumer products. Mr. RINALDO. I think I have pretty much run the gamut. Dr. FRAUMENI. If you are talking about chemical carcinogens, I would say that these account for the bulk of human cancer; there is no question in my mind about that. 24-600 0 - 78 - 3 PAGENO="0034" 28 Mr. RINALDO. Let me rephrase your answer. Are you stating that chemical carcinogens account for the bulk of cancer as a result of chemical carcinogens in consumer products? Dr. FRAUMENI. Chemical carcinogens may be represented by a dietary factor, a tobacco constituent, an occupational agent, or other exposures. I think all would fall into the class of chemical carcinogens. Mr. RINALD0. But I still want to take it a step further. Let's elim- inate smoking and diet. Then we come up with chemical carcinogens in other consumer products. Now, when you get down to that residue, what range would you attribute to that particular group? Dr. FRATJMENL I would be guessing. Mr. RINALDO. I would be interested in hearing your educated guess. If you have 40 percent, for example, in the male due to smoking and 10 percent from occupational exposure to chemicals, 5 percent for other causes; we are up to 55. What percentage would you say is caused by the diet? You mention that as being extremely important. Dr. FRAUMENI. I think it is a large percentage. Mr. RINALDO. We are up to 55. The largest it could be is 45. Dr. FRAUMENI. I must point out that the percentages are going to go well over 100 percent. For many tumors we are dealing with inter- actions between environmental agents such as occupational exposure in combination with tobacco. So, to try to bring it up to* 100 percent, I think, would be unreasonable at this stage of knowledge. Mr. RINALDO. Because it is caused from more than Dr. FRAUMENI. It is caused from combinations of agents. Mr. RINALDO. I understand that. But don't you think we can get this down to the point where we can get some fairly reasonable range for this. I am trying to isolate the exposure to chemicals in consumer products as differentiated from alcoholic beverages, the diet, and cigarette smoking. Dr. FRAUMENL I am not sure we can at this time. I think our knowl- edge is still incomplete from an epidemiologic standpoint. Mr. RINALDO. Do you believe that animal feeding studies which ex- pose rats, mice, and other animals to large amounts of a substance over a short period of time have consensus support in the scientific community for predicting carcinogenicity in human beings? Dr. UPTON. I think that the majority of workers in carcinogenesis accept the association between carcinogenic effects in animals and carcinogenic effects in humans. So, I think the majority of workers would accept the evidence as a basis for the assumption of presump- tive risk, given carcinogenic effects in an animal test, high doses, short- or long-term exposure. This, then, constitutes a presumptive basis for presumptive risk in man. Mr. RINALDO. Would this be your response to the argument that animal bioassays give the animals doses so high that they may induce cancer because it overwhelms detoxification mechanisms which pro- tect humans from the smaller doses that we meet in real life? Dr. UPTON. That is one of the uncertainties: Whether, if the same agent were encountered in humans over a longperiod of `time, because the dose is smaller and because the human differs in metabolic capa- bilities, the outcome would be different. We simply do not know now. Mr. RINALDO., The uncertainties are apparently overwhelming. Dr. UPTON. The uncertainties are overwhelming at this stage. PAGENO="0035" 29 Mr. RINALDO. What is your total budget? Dr. UPTON. This year we are budgeted around $872 million. Mr. RINALDO. In light of all these uncertainties and the failure to give even broad ranges and estimates and the difficulty you have in answering some of these questions, could you tell me what percentage of that $872 million is going to new tests? Dr. UPTON. A very small percentage of the total budget. You mentioned that at the present time $12 million is being devoted to testing as such. We have decided to increase the rate of testing in the coming year so as to essentially exploit totally the existing capability. Clearly, this is a very small step toward a very large problem. I would not contend that this is an adequate step. I think it is as much as we can do at this moment because the resources are limited. Obviously, the Nation needs a critical look at the problem area and a plan which deals in an adequate and socially acceptable, socially responsible manner. We are working with the other research agencies- NIERS, NIOSH-and with the regulatory agencies to arrive at an assessment of need and a coordinated plan. Mr. RINALDO. For the record, Dr. Upton, I would like you to submit what plans NOT has for increasing the amount of your budget that will be going to new tests. Dr. UPTON. I would be happy to do that. Mr. Moss. Without objection, the record will be held open at this point to receive that material. [The following information was received for the record.] CosTs To ExPLoIT EXISTING CAPABILITY The standardized animal carcinogenicity testing capacity presently available in U S laboratories would permit up to 120 chemicals to be placed on test each year Current NCI contract levels of testing involve placing approximately 60 chemicals on testper year with a particular chemical remaining on test for approximately 3 years. To increase NCI levels of testing to 120 chemicaLs per year will require annual increases in funding of approximately $6 mfflion over a 3-year period, at which point funding will st~bihze The1 present $12 million testing cost would rise to about $18 million in FY 1979, to $2~ million in FY 1980, and to $30 million in FY 1981. At that point the present long-term testing capacity would be saturated with 360 chemicals on test (120 annual). Mr. Moss. The chair is concerned over the fact that I do not know what a final report is; or, if I understand what it is alleged to be, then I am puzzled as to why we have a review procedure that takes place on the scientific accuracy of it after it has been fihalized and printed. I have in my hand here a report "Bioassay of 1,2 dichioroethane for possible carcinogemcity, second draft for DEG review, October 13, 1977." Underneath that is written in your handwriting, I believe, Dr. Griesemer, "unverified." Is this the draft report that is circulated to the regulatory agencies? Dr. GRIESEMER. No. Mr. Moss. This is not the draft report. What would that be? Would it be a final draft? Dr. GRIESEMER. Yes. Mr. Moss. And would bear "final draft" on its cover? Dr. GnIE5EMER. It says "final draft" or "camera ready" and is accompanied by a cover letter that identifies it as having been verified. PAGENO="0036" 30 I might point out that the draft in your hand may very well have been sent to whoever requested it, either under freedom of information or through intergovernmental channels. Mr. Moss. Well, it may have been. Let us then narrow down who routinely wou]d receive it outside of the agency itself. Dr. GRIE5EMER. Yes. At the time our draft is completed and is now a -final draft- Mr. Moss. No; I want to know who had received the second draft. Dr. GRIESEMER. I have no idea who might have received a second draft. Whoever requested it. Mr. Moss. We have no set routine then for distribution of the second draft. All right. Following this draft, a final draft is prepared. Dr. GRIESEMER. Yes. Mr. Moss. And reviewed within the agency for accuracy. Dr. - GRIE5EMER. Yes. Mr. Moss. And that goes to scientific accuracy as well. Dr. GRIESEMER. Yes. Mr. Moss. Then it is a final report and is printed; is that correct? Dr. GRIESEMER. Yes. Mr. Moss. It then goes to the review group, the advisory group. Dr. GRIESEMER. Before printing, a copy of the same material that goes to the printer's goes to regulatory agencies and to the clearing- house- Mr. Moss. Let's just stay with what I am talking about. Dr. GRIESEMER. The final printed copy is distributed through the announcement in the Federal Register. Mr. Moss. Now, does that occur before or after review by the advisory commit1~ee? Dr. GRIESEMER. After. Mr. Moss. All right, let's get back to the period before the review by the advisory committee. What is the distribution at that point? You have a printed report- Dr. GRIESEMER. To the regulatory agencies and to the clearing- house members. Mr. Moss. And is it sent to them as a final report? Dr. GREISEMER. Yes. Mr. Moss. Without any caveat that they should be alert to any possible changes that might occur as a result of the review procedure? Dr. GRIESEMEE. No; no caveats. Mr. Moss. All right, what is the value of the review procedure? Dr. GRIESEMEE. It first serves to review the entire process in public so that, if mistakes are ma~de, they will be recognized and can still be corrected. Mr. Moss. Wouldn't a prudent operation call for that kind of review before and not after publication and distribution? Dr. GRIESEMER. The only reason we do not do it that way is the very urgent need to inform the regulatory agencies of the findings of the study. Mr. Moss. The urgent need to inform them, even though it might be incorrect. Dr. GRIESEMER. The data will not change; only the interpretation might change. PAGENO="0037" 31 Mr. Moss. The data will not `change. Then: why the review after the publication? Let me say, Doctor, that I am well in my 26th year here; and I cannot think of anyone else that prepares a document in its final form and distributes it and then reviews it, It makes no sense to this member. Dr. GRIESEMER. Again, Mr. Chairman, the reason for submitting, for sending the regulatory agencies the material that we have is for reguiatory purp9sos to protect the public. Mr. Moss, Then that requires that it be extremely accurate, as accurate as humanly possible; doesn't it? Dr. GRIESEMER. That is correct. Mr. Moss. Therefore, why should you be less prudent in making certain that it is accurate for them than you are for the general public? Dr. GRIEsEMEI~. I'm sorry. I don't understand the question. Mr. Moss. Well, I don't understand the review. And I am trying to get it in some rational context. Why does the review occur after publication? Dr. GRIESEMER. The primary purpose of the review is for a public hearing. Mr. Moss. If it has any value, why doesn't it occur before publica- tion? Dr. GRIESEMER. Because we feel it most important that the data be transmitted in order to protect the public. If one waits a month or two for not only that review but many other reviews that take place after our data is released, then people may be unnecessarily exposed to hazardous' chemicals. Mr. Moss. Why do you have the review at the stage where it occurs? Dr. GRIESEMER. Primarily for a ~public hearing and partly to assure the staff that their review has been adequate. And that has been the case- Mr. Moss. Then, in context with an ` earlier response you gave me when we had our first discussion of this, that you know of no instance of a change as a result of the review, who don't we eliminate the review? Either that or have it occur before publication. Dr. GRIESEMER. That is under consideration at present. Mr. Moss. Well then, I strongly urge that it either be made mean- ingful or that it be eliminated. And I think we will be able to. have a consensus on that when the committee writes its report. It does not seem worth while to me at all. On the matter of the projected final reports, how many final reports in the group under discussion last March have now been completed? Dr. GRIESEMER. Ninety-two. Mr. Moss, Ninety-two final reports. That means they have been published? Dr. GRIESEMER. Twenty have, been published. and 20 have been submitted to the open literature. So, about 40 have reached the publication stage. . Mr. Moss. Put in literature for what purpose? . Dr. GRIESEMER. For the scientific community. Mr. Moss. For the scientific review, the review within- PAGENO="0038" 32 Dr. GRIESEMEB. No; not the review. They have been submitted to biomedical journals for publication rather than published in a technical report series. Mr. Moss. Well, at what point in publication do they become a final report? Is it not~published in the Federal Register? Dr. GRIESEMER. The answer to that-publication in the Federal Register-is 20. Mr. Moss. Well, then you have 20 fiuial reports. You were not the one who testified-I think it was Dr. Newall- before the Appropriations Committee on March 7, 1977. But at the moment of discussion of final reports anticipated by the end of th~ year, when a response of 230 was given the committee, Dr~ Newell knew all about the interim procedures that are involved in the handling of a report; didn't he? Dr. GRIESEMER. Yes. Mr. Moss. I believe you were then with the agency in July of 1977. Dr. GRIESEMER. Yes. Mr. Moss. When the information given before this committee. indicated that there would be 119, a reduction of 111 in the estimate. Am I correct on that? Dr. GRIESEMER. I don't know, but it sounds reasonable. Mr. Moss. Well, it shouldn't only be reasonable; it should be ac- curate, Dr. GRIESEMER. I have no reason to believe it is not accurate; I accept your word. Mr. Moss. You gave us a list of the reports, and all we did was .to tabulate it, It came out 119. So, that was a more careful, perhaps, evaluation of the potential for issuing of reports. But 20 is 99 short. of 119. And so we have `99 fewer reports than we were promised as of January 1. I believe it is true that, in the context of the hearings of the Appro- priations Committee and the hearings of this subcommittee, that our interest was on the adequacy of the staff and resources of the Agency to handle the reports. And when `we are told that we will get 119 and we get 20 it does not help in trying to plan legislative recommendations. It certainly is not helpful to the Appropriations Committee in deter- mining as it was there that less than 10 percent of the number promised were actually delivered. Perhaps, if the whole story was laid on the table at the time of the hearing, with all of the hedging about that we now hear, it might have been possible that we wou.d have. ~ia~d more, resources made available to handle reports. Dr. GRIESEMER. Mr. Chairman, I am sorry if it appears there is hedging. I am not attempting to hedge at all. You are quite right about the 20 chemicals. I might point out, however, that we have transmitted to regulatory agencies informa- tion oil a great many chemicals. We have identified in the last 15 months 82 animal carcinogens. We would not have had some of the testimony this morning and questions related to hair dyes, for example, if we were not doing our jobs. Mr. Moss. I have checked~ with a number of agencies as to the relative value of the draft reports, the reports other than final PAGENO="0039" 33 reports, in the agencies in the regulatory field, agencies under the jurisdiction, of the subcommittee. They have taken the position without exception that they cannot act on other than final report data. Do you know of any instance where they have acted on other than final report data? Dr. GRIESEMER. No. Mr. Moss. Then we must, for purposes of regulatory use, deter~ mine only or rely solely upon final reports. Doesn't that appear to be reasonable? Dr. GRIESEMER. On NOT's final reports, yes. Mr. Moss. That's right. And therefore; whatever the stage might be-interim, between the draft, whatever the number of the draft, and the final report-it is of no value to agencies for regulatory purposes. Dr. GRIESEMER. It may serve to increase their awareness of a prob- lem that may give them time to respond. Mr. Moss. But they are regulators. They are not just to be aware; they are supposed to regulate, Doctor. Dr. GRIESEMER. In order to regulate, they have to gather rnforma- tion related to the chemicals in question. Mr. Moss. And therefore the value of the work of your agency to the regulators is measured in the number of final reports made available to them Dr. GRIESEMER. Yes; and in their quality. Mr Moss The Chair yields to the gentleman from Tennessee Mr. GoRE. Thank you, Mr. Chairman. The prepared remarks of Dr. Upton, I think, clarify a little bit the importance of this review procedure in determining whether or not a report is final. He said here this morning. "After review the Institute publishes a report of the findings announced in the Federal Register and informs the public via the media." You have testified that as much as 90 percent of cancer may be environmentally caused; and, the effort to attack that problem is through these testing procedures. You told us earlier that you were going to have 119 test results finalized, printed, reported to the public. You have only done 20.1 think that there is hedging to the extent that the kind of response that would be most helpful to us and to the people that we represent is for you to say, "Yes, we failed to meet our goal. here are the reasons .why. Here's what we propose to do to improve the process in the future." But, instead, you insist on focusing all this attention on, "Well, yes, only 20 have been printed, but 80 more have been submitted in various stages." But the public does nOt find out about any of those. The public has not been told about the hazards in any of those sub- stances and will not be until the review process is completed To that extent, it is playing ~with words to say that it is a final report when the public is not even told about it. And to say that the scientific community is given the statistical results and pretend that that somehow is a substitute for letting the public know that X, Y, Z products increase the hazard that they have of getting cancer. Thank you, Mr. Chairman. PAGENO="0040" 34 Mr. Moss. The Chair recognizes Mr. Segal, counsellor the committee. Mr. SEGAL. Mr. Chairman, I would like to ask permission to insert in the record a letter that was submitted to you dated January 5, 1978 which has a two-page attachment to it entitled "National Cancer Institute Bioassays." Mr. Moss. The Chair is going to ask unanimous consent that such documents as have been supplied to Members in their hearing folder be permitted to be inserted in the record as determined necessary for the completionof the reccrd. Is there objection? Hearing none, such will be the order. [The letter and attachment referred to follow:] PAGENO="0041" 35 DEPARTMENT OF HEALTHr EDUCATION. AND WELFARE PUCLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH CETHESDA, MARYLAND 20014 `Januar~r 5, 3.978 NATIONAL CANCER INSTITUTE * .". ~p._ * * em Dear Mr. Chaii~an: . in response to the telephone request of Mr. Elliott Seg~l.. of your staff on December 22, 1977, I have enclosed copies of the preliminary data. presently available on the National Cancer Institute1s `(Nd' s) bioassays of hair dyes and telated chemicals. Added to the list of hair dye ingredients being tested for carcinogenicity by MCI are two azo dyes, direct black 38 and direct blue 6, which we understand are found in some temporary rinses, and semi..pexmanent hair dye products. Data on. seven of. the chemicals are in the form of drafts of technical reports Clist enclosed) ~~hich are still being evaluated by MCI. Data on six other chemicals are in the form of individual animal pathology tables, raw data. which have not yet been verified by MCI. Data on three chemicals are in manuscript form (resubmitted to the Journal of Toxicology and Environmental Healt~), and data on one chemical are in the reprint of a publiàhed paper. my inspection of the preliminary data, the following chemicals eppear to be carcinogenic for animals: 4..amino-~2~.nitrophenol, 2,4~'diami.noanisole sulfate, direct black 38, direct blue 6; 2~nitro~l,4~phenylenediaxnine, 2,4-toluenediaxnine, o-anisidine, 4-chloro-l,2-pbenylenediamine, and 1,2-~phenylened.taaine. Three of the chemicals (4~~amino~.2.nitrophenol, o~-anisidine, and 4.ch1oro~'l,2-pbenylenàdiaznine) are associated with. bladder cancers. The possibility that chemicals not designated as carcinogens may be carcinogenic in animals cannot be excluded until the analyses are completed. . The Honorable John H. Moss * . Chairman, Subcommittee on OversLght and Investigation Committee on Interstate and * * Foreign Commerce House of Representatives Washington, D.C. 20515 PAGENO="0042" 36 * Page 2 - The Honorable John H. l4oss ~ll of the draft technical reports and the data in the individual animal ~o~ogy tab]ás Cwhich will be incorporated into, the technical reports) are presently being.reviewed by NCZ to insure scientific accur4cy. lqb.en verified and con~letëd, the technical reports will be reviewed by the Carcinpgenesis Testing Program's advisqry committee (the clearinghouse on Environiental Carcinogens), published, ~nd' announced in the Pederal Register. * .* . . As additional information becomes available, ye. ebail be.ha~py to ~keep you informed. * * * . Sincerely, -4'.. * Richard A. Griesemer, .p.V.Z4., Ph.D. * Associate Director for. Carcinogenesis Testing Program * Division of Cancer Cause and Prevention. 15. Enclosures PAGENO="0043" - (Synonymn * HAIR 4_ami2~ni~ro5theno1* (o-nitro-p-aminophenol) 2,4-diaminoanisole sulfate * (4-methoxy-m-phenylenediamine) direct black 38 direct blue 6 2-nitro-l,4-phenylenediamine (2-nitrà-'p-phenylenediamine) 2,4-toluenediamine (m-toluenediamine) 4-nitro-l,2-phenylenediasine * (4-nitro-o-phenylenediamine) l-phenyl-3-methyl-5-pyrazolone (3-methyl-l-phenyl-5-pyrazolone) N-pbenyi-l,4-phenylenediamine (N-phenyl-p-phenylenediamine) l.,3-phenylenediamine (m-phenylenediamine) l,4_phenylenediamine* (p-phenylenediamine) resorcinol** 2, 5-toluenediaifline (p~to1uenediamine) NCI BIORESAYS Preliminary Results DYE INGREDIENTS carcinogenic carcinogenic carcinogenic carcinogenic carcinogenic carcinogenic CAS Number' 00119-34-6 00615-05-4 00072-57-1 02602-46-2 05307-14-2 0005-80-7 00099-56-9 00089-25-8 02198-59-6 00541-69-5 00624-18-0 00108-46-3 06369-59-1 Available Data Individual Animal Pathology Table * Draft Technical Report Draft Technical Report Draft Technical Report Individual Animal Pathology Table Submitted to 3. Toxicol. Environ. Health Individual Animal Pathology Table Individual Animal Pathology Table Draft Technical Report Submitted to J.Toxicol. Environ. Health Individual Animal Pathology Table Published in Toxiáol. A~pl. Pharmacql. 1974 Draft Technical Report PAGENO="0044" *9km tests for carcinogenicity negative. **Skin tests for carcinogenicity negative; no other tests in progress. Available Data Individual Animal Pathology Table Draft Technical Report Submitted to.7. Toxicol. Environ. Health Draft Technical Report Nd BIOASSAYS - Page 2 Chemical CR5 Number . (Synonymn) * Preliminary Results RELATED. CHEMICALS 00134-29-2 o-anisidine carcinogenic (2-methoxyaniline) 00095-83-0 * 4-chloro-l,2-phenylenediamine carcinogenic (4-chloro-o-phenylenediaaine) 00615-28-1 1-2-phenylenediamine carcinogenic (o-phenylenediamine) 20265-97-8 p-anisidine (4-methoxyaniline) PAGENO="0045" 39 Mr. SEGAL. I would just like to pursue the point raised by the chairman on when actions are taken and the public is aware of interim reports versus final reports. I would like Dr. Upton to address this question: On Sunday, December 25, 1977, on the program issues and answers, you were quoted as advising consumers not to use pro- ducts that contain 2,4 diaminoanisole and indicated, "I wouldn't want to use hair dyes on my hair knowing what I know about the possible risks." Looking at the letter of January 5, 1978, there are three additional compounds listed that are indicated as potentially causing bladder cancer. The first on the list is 4-amino-2-nitrophenol. And under the submission to us, it says "preliminary results, carcinogenic." On the second page, there is an o-anisidine, which is listed as carcinogenic, and a 4-chloro-ortho-phenylenediamine which is also listed as carcinogenic. Would you, Dr.. Upton, make this same statement about these three compounds as you made about 2,4 DAA? Dr. UPTON. Mr. Segal, I have not reviewed those data on the other two. So, I would not be .pre~ared at the moment to comment on them. Mr. SEGAL. Would you, Dr. Griesemer? Dr. GRIESEMER. I can add to the record that we have completed- first of all, that we are testing 13 hair dye product ingredients for carcinogenicity in animals. One of those, resorcinol, has been tested only by skin painting and was found not to be carcinogenic under those conditions and need not concern us more. On the other 12, we have completed in-house studies on five of them. Four are carcinogenic in animals, according to ou~ interpretation. Two others- Mr. SEGAL. Can you identify the four. The list that was submitted to us contains more than four. Dr. GRIFISEMER. Yes. 4-amino-2-nitrophenol, 2,4-diaminoanisole sulfate, direct black 38, direct blue 6, 2~nitro-1,4-phenylenediamine, and 2,4-toluenediamine are six chemicals that. we have tested that we belie've are carcinogenic for animals. On four of those the studies are completed. The other two are not yet completed, but the evidence is almOst certainly that they are carcinogenic. Mr. SEGAL. Does that mean that the ones on page two-the two methoxy compounds, the 4-chloro, are not yet complete? Dr. GRIE5EMER. Yes. On page two, there are four chemicals that we understand are not ingredient~ in hair dyes. So, I did not address that issue. One of them is completed, the 1,2-phenylenecliamine is an animal carcinogen according to our interpretation. And two others have sufficient information again to make it almost certain that they are animal carcinogens: those are the ortho~anisidine and 4-chloro.-1 ,2- phenylenediamine. Again, the latter three are thought not .to be in hair dyes but are mtermediates in hair dye production. Mr. SEGAL. Sticking with the six that you, indicated were cancer- causing agents listed on the first page of the report, has all of this information on these chemicals been transmitted to the regulatory agencies, for example, FDA? PAGENO="0046" 40 Dr. GRIESEMER. The package that was submitted as a status porret to this subcommittee has also been transmitted to Commissioner Kennedy of the FDA. M?. SEGAL. Was that an unusual procedure because we had asked for it? Or do you do that routinely? Dr. GRIESEMER. No; that was an unusual procedure. Mr. SEGAL. It was unusual. Dr. GRIESEMER. Yes. Mr. SEGAL. Of the ones that are listed as draft technical report, are you suggesting to FDA that they take regulatory action based on the draft report? Dr. GRIESEMER. No. Mr~ SEGAL. What would you suggest to them? Dr. GRIESEMER. That they wait for the final verified report. Mr. SEGAL. And these final verified reports are the same reports that-Wall three of them, if you look at the chart [see p. 9]-had been promised by the end of this year. Is that not cOrrect? Dr. GRIESEMER. Two of them are experiments that were just begun this year and were completed in 90 days. That is the direct black 38 and the direct blue 6- Mr. SEGAL. Excluding the colors. Dr. GRIESEMER. The others are part of that group of chemicals. Mr. SEGAL. So, the other four, excluding the two pertaining to colors, only one has been in a final report submitted to FDA; and the other three are in some form of draft. Is that right? Dr. GRIESEMER. One of them has been-yes, that is correct: Mr. SEGAL. The final report, the 2,4 DAA has not yet been printed in the Federal Register: Dr. GRIESEMER. That is correct. Mr. SEGAL. So, of all of the chemicals, the six known cancer-causing agents, none of them have come out in the final report form; is that right? Dr. GRIESEMER. That is correct. Mr. SEGAL. Thank you, Mr. Chairman. Mr. Moss. Mr. Maguire? Mr. MAGUIRE. Thank you, Mr. Chairman. In responding to Mr. Waxman's questions earlier, Dr. Upton-and I gather you said the same thing on television in December-you indicated that it would be prudent for those who dye their hair not to use these particular hair dyes. Now, that leads to the question of whether or not, given the scientific information which we now have, those ingredients should be removed from the hair dye products. Would you agree that they should be? Dr. UPTON. Mr. Maguire, I think that question is a difficult one. The data do not enable a confident assessment of risk to human popu- lations. I would certainly favor labeling of the package in a way ~that informs the consumer of the presumption of risk. I am not a regulator. My experience is. in the field of research. I would not feel confident going so far today as to say that those ma- terials should be banned from hair dye preparations. I think that one of the issues inevitably is whether there are acceptable alternatives. If there are none, should the consumer have the option to determine for himself or herself. We permit the sale of cigarettes. To my mind PAGENO="0047" 41 the evidence linking cigarette consumption to cancer in humans is overwhelming. But the consumer has the right to determine whether or not to smoke. I would not choose to use the hair dyes that contain these com- pounds. To deny others that opportunity, given the lack of evidence we have in the human, seems tome perhaps to go too far at this point in time. Mr. MAGUIRE. Under the law, Dr. Upton-I am referring to the Food, Drug, and Cosmetic Act-there is a section OO1A, which is very curious. It reads, "A cosmetic shall be deemed to be adulterated if it bears or contajns any poisonous or deleterious substance which may render it injurious to users under the conditions of use prescribed in the labeling thereof or under such conditions of use as are customary .or usual." Then it goes on: `Provided that this provision shall not apply to coal tar hair dye." That is the only exception in this paragraph I have done a little research on it. Apparently Congress is at fault in this case for having acceded to a request from lobbyists representing the hair dye industry at that time for the inclusion of this exception. Would you feel that there was merit in having this exception in the law? Or would you recommend to the Congress that that exception be eliminated-whatever may be the answer to my earlier question. Dr UPTON Again, Mr Maguire, I confess that ~[ am not closely enough involved with the regulatory process to feel confident of my judgment. I think these are societal issues. They are issues that obvi- ously fall to your purview. I do not equate a hair dye preparation with food on the grocery store shelves. Mr. MAOUIRE. All right; but that is not really the issue. The issue is whether, in your judgment, there is any basis for making a special category of all of the cosmetics that we might be dealing with for coal tar hair dyes in the law. In other words, every other cosmetic is subject to this test of safety. Coal tar~hair dyes have been specifically excluded by the Congress, not from particular findings with respect to whether they cause cancer or not, but from the very process itself of making a determination. Is there any possible justification for that in your judgment? Dr. lIPTON. I know of no scientific justification. Mr. MAGUIRE. I thank you. Mr Chairman, it is my intention to introduce legislation to elimi- nate this extremely unwise and unmerited special provision in the law for coal tar hair dyes. I think they should be subject to the same process and the same testing procedures and the same test of judg- ment that apply to each and every other cosmetic under the law. That does not prejudge the issue with respect to the scientific findings. That simply says that they should be dealt with as every other cosmetic is dealt with. I do be1ieve~ given the scientific data that ~we have, that it is enormously important that we plug that loophole if we are going to protect American citizens. Thank you, Mr. Chairman. Mr. Moss. The Chair recognizes the gentleman from Pennsylvania, Mr. Marks. PAGENO="0048" 42 Mr. MARKS. Thank you, Mr. Chairman. We were talking a moment ago about perhaps there ought to be a consumer's choice to determine what one should do or not do. That leads us to testing. That leads us to credibility. What can we believe? I remember the go-around on saccharin where it appeared as if-at one point at least the public was told that one would have to ingest 850 cans of a certain type of liquid a day for many years before one could approach the type of tests that were made to come up with the results. In the case of hair dyes, why would you use animal feeding studies where hair dyes were ingested in them? Should not chemicals be tested in a manner consistent with their use? Then, when it finally comes out, people can at least have some faith and understanding based on the tests that were used. Dr. UPTON. I think, wherever it is feasible to do so, studies ought to use routes of administration more nearly comparable to the routes of administration that are associated with use in practice. The bio- assay experiments were intended as screening procedures. They were set up in a way that permitted a large number of compounds to be tested under standard conditions and to insure that many tissues of the body did, in fact, come into contact with the agent in question. I do not think that one can argue that this. particular bioassay experiment was designed specifically to look at the hazards associated with use of compounds as hair dyes. The fact of the matter is, however, that, Qnce in the body, the agents travel to various organs and, as we see, produce tumors in the thyroid, in the skin, in the glands of the skin; so that, even though the dye substances were taken in the body by mouth, carcinogenic effects on the skin resulted. Mr. MARKS. Did you perform a topical treatment test with hair dyes, Doctor? If so, what were your results? Dr. UPTON. I am not aware that these have been done in the bio- assay program. Perhaps Dr. Griesemer has other information. Dr. GR~ESEMER. Yes; there were three skin painting studies which did not reveal carcinogenicity under those conditions. Mr. MARKS. Did or did not? Dr. GRIESEMER. Three chemicals. Mr. MARKS. That did not? Dr. GRIESEMER. Did not. Mr. MARKS. Thank you. Mr. MAGUIRE. Will the gentleman yield? Mr. MARKS. Yes. Mr. MAGU1RE. Is it your understanding scientifically that those studies did not show cancer causation because the material was not absorbed through the, skin? Or, alternatively, if it was absorbed through the skin, that, once it got inside the body, it did not travel and become a carcinogen? Dr. ~RIES~MER. I believe the reason some of the experiments that have been published-and perhaps one of ours-did not reveal cancer is that the doses that can enter the body through the skin are limited. Using small numbers of animals, if one wants to demonstrate that a chemical has the capacity to produce cancer, one has to use large amounts and reach all the parts of the body. PAGENO="0049" 43 Mr. MAGtTIRE. Would you then say that it `is not possible to say on the basis of skin painting studies alone that the product or the substance is safe? Dr. GRTES~MEE. Skin painting is a good first experiment, but by itself is not enough. Mr. MAGUIRE. What would be your comment then on the public statements bythe Cosmetic, Toiletry, and Fragrance Association that their studies-which were of this sort-prove that the coal tar hair dyes are in fact safe? Dr. GRTESEMER~ We have demo~istrated that some of the chemicals are animal carcinogens. We believe a. wider analysis is needed to de- termine whether or not they pose a risk to man. Dr. UPTON. Might I comment on that point, too, Mr. Chairman? Mr. Moss. Indeed. Dr. UPTON. I think' one of the serious limitations in the animal studies that we are looking at and discussing is the relatively small numbers used. If one uses 50 animals in the dose group. then one would miss a 1 percent carcinogenic effect; there aren't enough animals to demonstrate it. `But clei~rly a 1-percent effect in a population of 200 million people would be 2 million victims. Mr. MAGUIRE. Excuse me, Doctor; are you talking about the skin painting studies or the feeding studies? Dr. UPTON. In either case, if the numbers of animals are small, one has to have a large effect to detect it. If, in the painting experiment, the doses that were delivered are small, the number of animals are small, one might have to greatly increase the numbers of animals to `see a small effect, an effect which, in the human population, would still be too large to be accep~table. Mr. MAoimun. The CTFA has also criticized your studies. In addition to having critics criticize their studies, they have criticized your studies on the ground that the doses were massive and that they were feeding studies, which is not the condition under which the dyes are used by human beings. I `think you have given partial responses to that kind of criticism in your earlier answer. But would you like to summarize as to why you do or do not feel that those criticisms are valid? `Dr. GRIESEMER. I think it is important to recognize that a series of experiments are required to evaluate the risks from chemicals. The test for carcinogenicity alone, because of its objective, requires that very large doses be used and as many animals as is economically feasible, by whatever route will' permit the chemical to enter the body. If then one finds no cancers,~ one ha~s some confidence in not studying that chemical any further but doing additional experiments on those that `do pose a problem. Mr. MAGUIRE. I `thank the gentlemen from' Pennsylvania for yielding. ` Mr. Moss. Does the gentleman from Pennsylvania have any further questions? Mr. MARKS. Nothing more, Mr. Chairman; thank you. Mr. Moss. Does the gentleman from. Tennessee desire recognition? Mr. GORE. Yes, Mr. chairman. Mr. Moss. The gentleman is. recognized. 24-600 0 . 78 - 4 PAGENO="0050" 44 Mr. GoRE. Dr. Upton, on page 6 of your testimony you describe briefly the process that you go through to select, chemicals to be tested. In light of the fact that your resources are so limited, in light of the fact that there are 4.5 million chemicals in our environment and you have the ability, you say, to test only as many as 100 each year, how could a university professor, for example, who determines through his or her own work that a particular substance is carcinogenic plug into your process? Can they make recommendations to the review board, the chemical selection subgroup? Dr. UPTON.. Yes, indeed. The meetings of that group can receive information from any and all sources. We fund a substantial volume of grant-supported activity in this area. So, in addition to the work in the bioassay program, which is done largely on contract, a great many experiments are done through the grant mechanism. I think the Institute is anxious to receive any and all indications of potential carcinogenicity so that it can explore where needed. Mr. GORE. Are you aware of any kind of pressure from particular industry groups not to test particular substances? Dr. UPTON. I have been unaware of such pressure. Dr. Griesemer? Dr~ GRIESEMER. I have not received any either. Mr.. GORE. That's good. I have some difficulty in getting a clear view of what this Nation's response ought to be to environmental causes of cancer. One way to look at it is to say that if we have got 4.5 million chemicals and 90 percent of cancer may be caused by artificial substances put into the environment, then we are not really going to cure or prevent cancer unless we dramatically escalate this Nation's effort to seek out those among. the 4.5 million chemicals that clearly are carcinogenic, inform the public about it, and escalate our efforts to protect the public from those substances. If we got 4.5 million and we are doing 100 a year, am I wrong in concluding that this is just a pitiful response by this country to the threat that we are facing? Dr. UPTON. Mr. Gore, I think it is an inadequate response. I think we must increase the effort. I despair of being able within our life- times to do enough animal testing to deal with the thousands of com- pounds that are there. I think we badly need more effective short- term tests. Reference was made to the Ames test and the fact that it is not 100 percent predictive of responses in animals. We need to understand better what the exceptions are, why it does not predict more effectively. There are classes of carcinogens that are negative in the' Ames test now-the so-called promoting agents. I think that through a combination of approaches epidemiological studies of the human population itself, such as Dr. Fraumeni described to us, looking for high-risk groups, trying to determine the causative factors underlying changes to high risk and also improving our knowl- edge of the cancer process so that we can devise more effective test methods and experimental systems-all of these have to be made. Our effort will be to develop over a broad front more vigorous and more effective approach to this problem. Mr. GORE. Yes; but you cannot do it unless you get the money from the Congress. And we cannot do it unless there is the support PAGENO="0051" 45 from the people. And the people are not going to be willing to do it until they really understand the magnitude Of this threat. It is the second leading cause of death in the country. In terms of the heartache and so forth, it is right up there. Mr. Waxman was talking earlier about the general public reaction to environmental causes of cancer. Maybe we need to develop a language that the scientific community can use to' communicate with the public to have a regulate update of what substances-three columns: What substances cause cancer in our view; second column, what products they appear in; third column, w~hat is the percentage risk relative to other causes of cancer that we are aware of. We could really publicize that information and let the public know what this threat is so `that they can put pressure on their elected representatives to face up to this challenge. I am in favor of doing it. I think we ought to dramatically escalate our efforts to cure and pre- vent cancer. But it is tough to get the additional money that we really desperately need to formulate a responsive policy in this area. The public is not made aware of what the threat is. Mr. MARKS Would the gentleman yield? Mr. GORE. Yes. Mr. MARKS. May I mention that also in that we would need the necessity of setting forth the testing procedures that were used so that people would have the credibility of being able to believe these things that you are now suggesting. That would be a' very important part of that program. Mr. GORE. Thank you, Mr. Chairman. Mr. Moss. The gentleman from California, Mr. Waxman, is recognized. Mr. WAXMAN. Thank you, Mr. Chairman. Dr. Griesemer, it is my understanding that chemicals are placed on the bioassay list each year because there is some suspicion that there is a relationship between the chemical and it's possibility of being a mutagen. Is that a proper understanding? Dr. GRIESEMER. If we know that the chemical is mutagenic, it tips the scales a little stronger toward testing rather than not testing that chemical. But the major criteria are human exposure and other evi- dences of biologic effects in animals or man. Mr. WAXMAN. Biological effects? * Dr. GRIESEMER. Yes; toxicity or perhaps an incomplete study on carcinogenicity as well as mutagenicity and teratology and all the rest. * Mr. WAXMAN. So, you may not have any evidence of a chemical being a mutagen, you may not have any evidence of an adverse effeôt, but would you then select a chemical substance solely because as its widespread use'in the environment? Dr. GRIESEMER. There are a few chemicals that have been selected solely because, there is tremendous human exposure. Mr. WAXMAN. I was interested to note that on the list I have before me of chemicals tentatively selected for testing by NCI is ascorbic acid; popularly known as vitamin' C. There have been those who have suggested that this is a natural substance that may have a beneficial effect in treating cancer as well as many other diseases. What is the rationale for including vitamin C on the bioassay list? PAGENO="0052" 46 Dr. GRIESEMER. Again, it was selected primarily because of large human exposure to rather large doses. You are quite correct; in some experimental situations, vitamin C appears to have an anticarcino- genic effect-which may make the design of the experiment a little more difficult. Mr. WAXMAN. Was there any other reason other than its prevalent use in the environment, that it was selected? Dr. GRIESEMER. I am sure there were other reasons; but, without reviewing all the information in the record, I do not know. Mr. WAXMAN. Perhaps we can get that information. Dr. GRIESEMER. We are attempting to test some endogenous chemi- cals, or chemicals that are essential for life. Mr. WAxMAN. Could you explain to me "endogenous"? Dr. GRIESEMER. Those that may be taken in excessive amounts under some conditions. Mr. WAxMAN. I notice that castor `oil is also scheduled for bioassay testing. Dr. GRIESEMER. Yes. There are some natural products that are being tested. You may know that there are some very potent carcino- gens .that occur naturally such as aflatoxin in the mold. So, part of our program is a systematic approach to exploring areas of possible carcinogenicity such as natural products or endogenous substances. Mr. WAXMAN. Thank you very much. Thank you, Mr. Chairman. Mr. Moss. The chair recognizes the gentleman from New Jersey, Mr. Rinaldo. Mr. RINALDO. Thank you very much, Mr. Chairman. I am still very much interested in the budget that you have. I was taking a look at it earlier. As we agree, it is $872 million. Twenty percent. of that budget is used for testing on environmental causes of cancer.~Only 1.4 percent is spent for the development of new tests. What in your opinion is the most important part of that budget, and how are you spending the money? Dr. UPTON. I am not sure which part you are asking about. Mr. RINALDO. I do not want to go through the. entire budget. I was just giving you two instances of how it is broken down percentage- wise. Dr. UPTON. You asked which part of the budget is most important; the whole budget or the carcinogenesis? Mr. RINALDO. To what area do you assign top priority? Dr. UPTON. At the present time, the environmental carcinogenesis area, in my view, deserves top priority: What can we be doing to in- crease the effectiveness of cancer prevention? Mr. RINALDO. You said that it deserves top priority. Dr. UPTON. Yes Mr. RINALDO. Is it now getting top priority? Dr. UPTON. It is getting top priority in our planning and our pro- jections for the future. * Mr. RINALDO. Does the National Cancer Institute conduct any tests itself? Dr. UPTON. Within our own facilities? Mr. RINALDO. Yes. PAGENO="0053" 47 Dr. UPToN. I am not certain that we do conduct any bioassay tests within our own facilities. Our own animal space is extremely limited. Mr. RINALDO. Do you contract out all the tests? Dr. UPTON. To my knowledge, all the bioassay testing is done on contract outside the Institute's own animal space principally because we have no adequate animal space on the campus. Mr. RINALDO. How do you select the firm or individuals who are awarded the contracts? Dr. UPTON. The selection of contractors was undertaken before my arrival. I would like to ask Dr. Griesemer if he can speak to that. Dr. GRIESEMER. It is a competitive process with presite visits and a continuing review of all the facilities that might be available in the country. All of them are notified when contracts are being considered. So, it is the ordinary competitive process that one goes through for any contract. Mr. RINALDO. Does NOT specifically select- Dr. GRIESEMER. Yes. Mr. RINALDO. You do? Dr. GErE5EMER. We make the selection. Mr. RINALDO. It was my understanding you went through a firm who- Dr. GRIE5EMER. We have support from a client contractor, Tracor- Jitco, who assist us in evaluating laboratories and in visiting labora- tories. But we make the decisions. Mr. RINALDO. They assist you. I assume they receive a management fee for this assistance? Dr. GRIESEMER. Yes. Mr. RiNALDO. What is the amount of fee that they receive? Dr. GRIESEMER. I cannot answer the question~ It is a total con- tract fee, and I do not know th~ amount. It is: somewhere in the vicinity-their total costs are somewhere in the vicinity of 15 percent of those contracts with which they deal. But their award fee is much smaller than that. I am sorry. I do not know the amount. We can provide that for the record. Mr. RINALDO. Mr. Chairman, I would like to have that. Mr. Moss. Without objection, the record will be held at this point to rece~ve the material. [The following information was received for the record:] PAGENO="0054" 48 Award Fee Arrangement--TracorJitco - Tracor Jitco Contract No. NO1CP 43350 provides for an award fee except for the first year of the contract which included a base fixed fee and an award fee. An amount for the award fee pool is established from which award fee amounts are determined by evaluations of the contractor's performance by an NCI Performance Evaluation Board. Fee amounts established by the contract and reimburseable costs are as fOllows: Cost $38,011,930 Base Fixed Fee 77,729 Available Award Fee 3,208,554 Pool Fee amounts awarded to date compared to amounts available to date: Performance Period Amount Awarded Award Fee Available 3/1/74-6/30/74 $21,980 $27,138 7/1/74-10/31/74 23,067 27,138 11/1/74-2/28/75 23,339 27,138 3/1/75-5/31/75 22,523 27,138 ~6/l/75-9/30/75 161,458 258,333 10/1/75-1/31/76 151,125 258,333 2/1/76-5/31/76 159,650 258,333 6/1/76-9/30/76 125,292 258,333 10/1/76-1/31/77 90,933 258,333 2/1/77-5/31/77 102,042 258,333 6/1/77-10/31/77 145,958 258,333 PAGENO="0055" 49 Mr. RINALDO. Would you say that this is the most efficient manner in which NCI can1 operate? Or do you think that you could operate. more efficiently and get more value, more testing, more data per dollar spent? Dr. GRIESEMER. Yes, that contract runs through May of 1979. We are in the process of reviewing our whole management of the operation. There are other options which we are considering. It has been, in the last 1~ years a very cost effective operation. Mr. RINALDO. In other words, are you stating that there is a good possibility that, when the contract runs out in May of 1979, there will be a neW method? Dr. GRIESEMER. It is possible. Mr. RINALDO. I have no further questions, Mr. Chairmam. Mr. Moss. Are there further questions? If not, the witnesses will be excused with the thanks of the com- mittee. The committee will stand in recess until 2 o'clock, when we will again convene in this hearing room. [Whereupon, at 12:30 ~ the subcommittee stood in recess.] AFTER RECESS [The subcommittee reconvened at 2 p.m., Hon. John E. Moss, presiding.] Mr. Moss. The subcommittee will be in order. At this time I would like to invite Edward J. Baier, Deputy Direc- tor, National Institute for Occupational Safety and Health. He is accompanied by Dr. Norbert Page, Chief, Priorities and Re- search Analysis Branch, Division of Criteria Documentation and Standards Development. Gentlemen, would you be sworn? Do you solemnly swear that the testimony you are about to give this subcommittee shall be the truth, the whole truth, and nothing but the truth? Mr. BAlER. I do. Dr. PAGE~ I do. Mr Moss Would you identify yourselves for the record? Mr. BAlER. I am Ed Baier. Dr. PAGE. I am Dr. Page. Mr. BAlER. Mr. Chairman, would you prefer that I read my state- ment, or would you prefer that I highlight it? Mr Moss Mr Baier, whichever way you feel most effectively assists you in telling us what you want to tell us will be fine Mr. BAlER. Then I will go through the statement. Mr. Moss. Very well. . S Please proceed. PAGENO="0056" 50 TESTXMONY OF EDWARD J. BAlER, DEPUTY DIRECTOR, NATIONAL INSTITUTE POR OCCUPATIONAL SAFETY AND HEALTH, CENTER FOR DISEASE CONTROL, DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, ACCOMPANIED BY NOREEItT P. PAGE, D.V.M., CHIEF, PRIORITIES AND RESEARCH ANALYSIS BRANCH, DIVI- SION OF CRITERIA DOCUMENTATION AND STANDARDS DEVEL- OPMENT Mr. BAlER. Mr. Chairman, and members of the subcommittee, I am Edward J. Baier, Deputy Director of the National Institute for Occupational Safety and Health-NIOSH. Accompanying me toda is Dr. Norbert P. Page, Chief of the NIOSH Priorities and Researc Analysis Branch. We are pleased to appear before you today to discuss the role of NIOSH in investigating certain chemical causes of cancer. You asked us to discuss two specific chemicals: ethylene dichloride, an intermediate in the production of other chemicals, including vinyl chloride, and 2,4-diaminoanisole, which is used in certain hair and fur dye formulations. Under the Occupational Safety and Health Act, NIOSH is. respon- sible for conducting occupational safety and health research, recom- mending standards to the Occupational Safety and Health Adminis- tration (OSHA) and providing technical assistance in evaluating employee exposures. NIOSH and OSHA share manpower development and training responsibilities. In developing criteria for recommended standards, we attempt to evaluate all available data relevant to establishing an occupational standard and place particular importance on data indicating animal or human carcinogenicity and other chronic health effects., When we receive new information on the carcinogenicity of a chem- ical substance or physical agent, we may issue a Current Intelligence Bulletin, providing background information on the chemical, includ- ing its known toxicity to man and animals, known producers and users, estimated extent of occupational exposure, and precautions which can be taken to reduce the hazard. These bulletins are now distributed to over 5,000 members of the occupational safety and health community, Government agencies, management, labor, public interest groups, a~d others. As a result of the evaluation of new data, we decide what further action may be necessary. This may include developing new or revised criteria docu- rnents for transmittal to OSHA and conducting additional epidemio- logic or laboratory research to better characterize the hazard. ETHYLENE `DICHLORIDE In 1972, the Institute developed a priority list of chemical and physical agents based on the number of workers exposed and the known toxicity of the agents. Relatively high on that list were a num- ber of chlorinated hydrocarbon solvents, including ethylene dichioride. Approximately 10 billion pounds of ethylene dichloride are con- sumed each year in the United States by a variety of industries. Most of it is used as an intermediate in the production of other chemicals, including vinyl chloride, 1,1 ,1-trichloroethane, trichloroethylene, perchloroethylene, vinylidene chloride, and ethyleneamines. PAGENO="0057" 51 Occupational exposure to ethylene dichloride in those processes is minimal. A total of 2 million workers may receive some exposure to ethylene dichioride, with perhaps 200,000 receiving a substantial exposure primarily during its use as a solver t in textile cleaning and metal degreasing, in certain adhesives, and as a component in fumi- gants. Low level exposure of ~as station attendants can also occur from its use as a gasoline additive. In March of 1976, NIOSH transmitted a criteria document to the Department of Labor recommending a tenfold reduction' in the existing Federal standard for ethylene dichloride from 50 to 5 parts per million parts of air-ppm. This recommendation was based on reports of adverse effects on the nervous system and liver of workers exposed to 10-15 ppm ethylene dichloride. Exposure at higher levels was also reported to affect the cardiac and respiratory systems. We further advised nursing mothers not to work with ethylene dichloride since the chemical has been found in the milk of exposed mothers. In addi- tion to an environmental limit, NIOSH made recommendations for medical examinations, labeling and posting requirements~ personal protective equipment and clothing, informing employees of hazards, work practices, and moRitoring and recordkeeping procedures. When the criteria document was transmitted to OSHA in March 1976, there were no reports that ethylene dichloride caused cancer in animals or man. We did note that information on this subject was inadequate and that the National Cancer Institute (NCI) was con- ducting bioassay tests on the chemical. In December of 1977, NCI reported preliminary results from those tests indicating that male and female rats and mice fed ethylene dichiOride for 78 weeks had significant excesses of site-specific malig- nant and nonmalignant tumors. NIOSH is currently analyzing these preliminary results and is awaiting NCI's final report. The Institute is also preparing a Current Intelligence Bulletin which will advise the occupational health com-~ munity as to the potential significance of those preliminary NCI data. If the final results of the NCI study on ethylene dichloride establish it to be carcinogenic, the Institute will transmit revised recommenda- tions to the Occupational Safety and Health Administration. Addi- tional recommendations will also be made for appropriate medical monitoring, respiratory protection, engineering controls, and work practices. 2,4-DIAMINOANISOL~ This past fall, NIOSH learned' that a preliminary analysis of National Cancer Institute data indicated that laboratory rats and mice fed 2,4-diaminoanisole sulhite experienced a significant excess of site specific malignant tumors as compared with controls. On January 13, NIOSH issued a. Current Intelligence Bulletin recom- mending that 2,4-diaminoanisole--.also known as 4-methoxy-m- pheylenediamine-and . its salts be handled in the workplace as if they were human carcinogens. . Approximately three out of four current oxidation or permanent~ hair dye formulations. contain 2,4-diaminoanisole or its sulfate salt, ac- counting for about $200 million in annual retail sales. Although NIOSH is unaware of any current domestic production of 2,4-diaminoanisole, PAGENO="0058" 52 approximately 25,000 pounds a year are imported. NIOSH estimates that about 400,000 workers have potential occupational exposure, primarily hairdressers and cosmetologists. A relatively small number of fur dyers are also exposed to the chemical. NIOSH has conducted two epidemiologic studies that suggest excess cancer among cosmetologists. One study indicates an excess of genital cancer among hairdressers and cosmetologists. The other, which has not yet been completed, suggests excess cancer of a number of organ systems among this occupational group. It should be rec- ognized that hairdressers and cosmetologists are also exposed to a wide variety of other chemicals and that the epidemiologic studies do not clearly demonstrate a casual connection between hair dyes and cancer. Nevertheless, we believe that the studies give additional cause for concern. NIOSH has also been informed that unpublished data recently acquired by the Food and Drug Administration [FDA] indicate that 2,4-diaminoanisole penetrates the skin and enters the system of both man and the rhesus monkey. There are other rpports indicating that 2,4-diaminoanisole is mutagenic in bacterial systems and in the fruit- fly-Drosophila. These reports are of interest because correlations have been suggested between mutagenicity in bacterial systems and carcinogenic potential in higher systems. As an interim and prudent measure, pending further evaluation of the carcinogenicity of 2,4-diaminoanisole, NIOSH recommends that occupational exposure to 2,4-diaminoanisole and its salts be minimized by engineering and workpractice controls. In particular, skin exposure should be avoided. Although substitution is a possible control measure, NIOSH rec- ommends that caution be exercised in selecting substitutes for dye formulations and other products containing 2,4-diaminoanisole. Al- ternatives should be fully evaluated for possible human health effects. This is particularly important in view of the many questions that have been raised recently regarding the safety Of numerous components of hair dye formulations. These two examples illustrate some of the kinds and sources of data that contribute to our evaluation of carcinogenicity. As shown in the accompanying table, we receive information on carcinogenicity from a variety~ of sources, including the National Cancer Institute bioassay program, the published scientific literature, industry studies, and NIOS}L~sponsored studies. Such hazards may be identified by epidemiologic studies of people who ha~e been exposed to suspect chemical agents as..welias by animal experiments. After reviewing all available information, including biological effects and exposure conditions, NIOSH determines the need for recommended occupational standards and specific preventive measures, as well as further research to better assess the potential hazards. Mr. Chairman, this concludes my prepared testimony. Dr. Page and I will be happy to answer any questions you or members of your sub- committee may have. Mr. Moss. Without objection, the table attached to your statement will be included in the record at this point. [The table referred to follows:] PAGENO="0059" OCCUPATIONAL CARCINOGENS* Substance source of Data Industry conducted/ Published scientific sponsored studies NCI bioassay NIOSH literature (unpublished) data data ~17ltnuie x ~ X X X 1Benzene X X ..Benzid~ine I ~Berylliu~ X ~!~Beta-Napbthyla.ine X ~1i$eta-Propiolactone X H~Bis.-Chloromethyl Ether X U~arbon Tetrachloride X X fflfchlorofo~ X I :UJ~0m11~M (VI) X. X -certain coimpounds- - ~~oal Tar Products X -coal tar, coal tar pitch creosote- 4oheO~~~ Ealisions X X z:~Pioxane X X ;wII~thyleneimine X .t~DKeP0fle X X 1~f$ethyl ~hloro.ethyl Ether X ~$-NitrosodIaeLhylaaine X Nickel, Inorganic X X x x x ~!~inyl chloride x x llh:et7lenin0tIn0t~1~ X H1~3,3-Dichlorobenzidine (and X its salts) *NI0SH Recoendations PAGENO="0060" OCCUPATIONAL CARCINOGENS* Page 2 Substance Source of Data Industry conducted/ Published scientific sponsored ~tudies NCI bioassay NIOSH literature (unpublished) data data 4-Aminodiphenyl X 4-DimethylanLinoazobenzene X 4-Nitrobiphenyl X 4 4'Methylene bis X (2-chioroaniline). ~hloroprene + x Dibromochloro propane . X Ethylene Dibroside + X X Isopropyl Alcohol + X -possible cancer threat in the manufacturing process- Tetrachioroethylene + X *NIOSH Recommendations +Stated as ~ potential for cancer PAGENO="0061" 55 Mr. Moss~ I would ask if your use of the figures $2 million in reading the second paragraph on page 4 of your statement was an inadvertent error or a deliberate correction. The statement says: "$200 million." Mr. BAlER. Yes, that figure is correct. Mr. Moss. The Chair recognizes the gentleman from New Jersey, Mr. Maguire. Mr. MAGtTIRE. Mr. Baier, what do you recommend be done by workers in the workplace to minimize their exposure to this cancer~ causing substance? Mr. BALER. You mean the two specific chemicals or the one specific chemical? Mr. MAGUIRE. Yes, 2,4-diaminoanisole. Mr. BALER. In our Current Intelligence Bulletin we were primarily concerned that skin contact be avoided and that any exposure to the mist or the material itself be avoided. Mr. MAGUIRE. You do that by what-putting on a pair of golves, for example? Mr. BALER. Yes. Mr. MAGUIRE. Some kind of suit that protects you? Mr. BAlER. It could be. Mr. MAGUILE. You make sure that you do not breathe in any of the vapors; is that correct? Mr. BALER. There are a number of respiratory protective devices that are used in industry. There are also others that are used in operating rooms. These are slightly different. The designs are different. We were not thinking of a diver's mask or anything like that. Mr~. MAGUIRE. I would like to know what you were thinking of. Mr. BALER; All right. Mr. MAGIJIRE. What would be appropriate? Dr. PAGE. As a practical measure we would avoid skin exposure by the use of gloves for the cosmetologists and hairdressers and perhaps provide s&me protection tO minimize exposure to customers or clients and so on. Mr. MAGUIEE. You already have them ill. Dr. PAGE. This would be to prevent exposure-unecessary exposure to the skin of the clients also. Mr. MAGUIRE. This is the point I was getting to. If we have 400,000 workers that are exposed in a ~ay which you regard as potentially hazardous to them and you recommend that they wear gloves, and not allow any of it to touëh their skin, et cetera, the thought that occurs to me is that of~ course we have tens of millions of women all across the country-and some men-who put hair dyes on their scalp and their skin as a result of applying it to their hair. Presumably that is also .a serious matter; is it not, if the scientific data, on the basis that you have acted, are such as to suggest that workers should be protected. Surely the general public should also be; would you not think so? Mr. BAlER. Yes. Mr. MAGUIItE. What happens when OSHA receives a Current Intelligence Bulletin? Are they able' to act or do they, in fact, act when they receive such an intelligence bulletin from you? PAGENO="0062" 56 Mr. BAlER. We have a very close working relationship under the Occupational Safety and Health Act with the Occupational Safety and Health Administration. We try to conduct regular meetings to discuss policy issues and regular meetings of staff at the working level of both agencies. When we first hear of a problem, we communicate with representa- tives of OSHA. As we progress and transmit the Current Intelligence Bulletin to them, we are in a position then to at least work together to develop some kind of a proposed standard. This has been done in several instances that we can enumerate such as acrylonitrile and the 14 carcinogens which they now regulate. There was a close working relationship where we reviewed the exist- ing data together. I cannot speak for how they will take any Current Intelligence Bulletin. Mr. MAcwIRE. Perhaps you could tell us what precisely has oc- curred since you made the data on 2,4-diaminoanisole available in Deceiiiber and formalized it in a Current Intelligence Bulletin in January. Mr. BAlER. We have transmitted it as an official- Mr. MAGUIRE. There have been no meetings to follow up on that? Mr. BAlER., Not yet. Mr. MAGUIRE. Do you anticipate there will be? Mr; BAlER. Yes, I would anticipate there would be. Mr. MAGUIRE. Have any meetings been scheduled? Mr. BAlER. Not at the present time. Mr. MAGUIRE. Would it be a safe assumption to think that at the conclusion of this hearing a meeting might be scheduled? Mr. BAlER. Routinely we meet monthly, so that will come up at our next meeting. Mr. MAGTJIRE. This is a routine matter? Mr. BAlER. No, I said routinely we meet-monthly-and this would be one of the items on the agenda at the next meeting. Mr. MAGUIRE. You were here for the hearing this morning; were you not? Mr. BAlER. Yes. Mr. MAGUIRE. You are then aware of the new information pre- sented today from NCI about the possible presence of other carcino- gens, in addition to the 2,4-diaminoanisole in hair dyes? Mr. BAlER. Yes, I am. Mr. MAcwIRE. What are your intentions with respect to those additional substances in hair dyes? Are you planning to publish more bulletins? Do you have data which you regard as adequate upon which to act? What is the current status with respect to those additional cancer hazards? Dr. PAGE. We have not yet received this information from NCI, but when we do, we will determine the presence of these other com- ponents In hair dyes. Upon such a review I would guess that we will either issue another Current Intelligence Bulletin or attempt to addressed the problem of hair dye components in general. We have not had an opportunity to review any of the other data at this point. PAGENO="0063" 57 * Mr. MAGIJIRE. One final question. Mr. Moss. We will have to suspend at this point. We will suspend until 5 minutes after the last record vote. We have a series of recorded votes which will now take place on the House floor. It would be my judgment that we will be about 25 minutes, but nevertheless it will be 5 minutes after the last vote is taken. The subcommittee will stand in recess. [Brief recess.J Mr. Moss. The subcommittee will come back to order. Mr. MAGUIRE. Mr. Baier, I read section 601(a) from the Food, Drug, and Cosmetic Act to Dr. Upton and asked for his comment on it. Mr. BALER. I remember that; yes. Mr. MAGUIRE. Then I will not need to read it again. I would like to know if there was any justification for excluding coal-tar hair dyes as the one and only exclusion under the law from the process of determining safety. Would you see any justification in that exclusion? I admit to you that Congress wrote it. It is in there because the Congress of the United States decided to put it in, not because of anything your agency did or anything anybody else proposed. Mr. BALER. We were discussing that. Actually, we see no justifica- tion for excluding them because you can synthetically manufacture chemicals which look like coal-tar chemicals also. Mr. MAGUntE. Do you plan any additional studies to determine the possible effects of carcinogenic substances in hair dyes on workers' health? Are there any other studies `contemplated at this point other than those that have been conducted? Mr. BALER. The role of NIOSH is much different from that of NCI. We are looking at occupations and trying to characterize exposures to either hazardous chemicals or hazardous physical agents within those occupational groups. Mr. MAGUIRE. You will not yourselves conduct the study or any further studies? Mr BALER Not along the lines that you were just discussing That is more in the realm of NOT. Mr. MAGUIRE. What about epidemiology? Mr. BALER. That is different. Dr. PAGE. I might like to talk about this also. At this time we are attempting to find an additional study popuh~- tion, like hairdressers and cosmetologists, to do a more definitive epidemiolo~ical study. In addition, we are looking for a cohort or a group of workers who are exposed to even higher levels, like formulators of hair dye prepara- tions, to see if they could be entered into an epidemiological study. We also have another study in mind. It is not a~Iong the line of carcmogenicity. There is some concern also, for stillbirths. and birth defects So, NIOSH is attempting to study this aspect This would be done by an interagency agreement, perhaps with the National Center for Health Statistics.. Mr. MAGTYIRE. Do you have any projected completion dates for any of this work? PAGENO="0064" 58 Dr. PAGE. No. We first have to look at the population for study before we can actually lay plans for the experiments or studies. Mr. BAlER. What we may try to do also is to characterize exposures to various things within, let us say, the workplace of the cosmetolo- gists. Mr. MAGTJIRE. The image keeps returning to my mind of someone workitig on someone's hair and having to wear gloves in order to prevent any skin exposure. Then there is, of course, the person on whom the work is being done and who is protected in no way whatso- ever. That is an image which ought to at least be an~ilyzed very carefully by this committee and by the relevant Government agencies. Do you have any final comments on any of the questions or any other observations that you would like to make which have not been elicited thus far? Mr. BArER. There is one thing that I would like to bring out. We have mentioned a current intelligence bulletin several times. I think it might be worthwhile to at least put into the record just what that is. Fundamentally it is just an informational piece. We say: "Here is a problem that we want to bring to the attention of various people." We tell why we have a concern for a particular substance or a process or whatever it might be. If it is a chemical, then we give some indication of who makes it and what the risks are, what kind of occupations these people have, how many of them there are and that type of thing. Then we give some idea as to what you might do in the meantime. It is just a quick mechanism to get information out of the files and out of the "in box" so to speak, and into the mainstream of things. Mr. MAGUIRE. Does that get released to the. press? Mr. BArER. Yes. The press does get copies. Mr. MAGUIRE. Thank you very much, Mr. Chairman. Mr. Moss. The Chair recognizes Mr. Segal, counsel for the com- mittee. M~. SEGAL. Mr. Baier, I would like to ask just one or two more questions about the 2,4-diaminoanisole and then the ethylenedichloride. Mr. Maguire asked about the epidemiology. You indicated there were further studies gOing on. Do you feel those studies cited in your report, current intelligence bulletin are significant studies to de- termine that the safety is in question? You mentioned conflict in your report, that is, in your presentation. Could you comment on the conflict and how you intend to resolve it? Mr. BArER. Yes. The current intelligence bulletin has quite a long list of references. One of the two NIOSH studies that we referred to is not a final report. They represent preliminary indications that there might be a problem. They should be viewed as surveillance techniques, to select areas for more in-depth evaluation. Dr. Page, would you want to add some more? Dr. PAGE. I do not have anything to add at this point. PAGENO="0065" 59 Mr. SEGAL. Would you say that the epidemiology at this point was not the main reason which led you to put out this statement to inform the American public that this is a potential danger? Mr. BAlER. As I mentioned in what I said about the current intelli- gence bulletin, it is an alert mechanism to bring out that there may be a problom here. Certainly we will gather more information. There will other sources of information coming to us. There are tumor registries that we may want to look at. We may want to compare types of tumor registry cases with specific occupations. This is an on-going surveillance effort. A surveillance effort is simply looking for problem areas. Mr. SEGAL. What about the other scientific evidence? The Ames test showed mutagenicity. Do you consider that significant? Mr. BAlER. Yes, but I would rather Dr. Page discuss that. Dr. PAGE. I think with the combination of the mutagenicity test and the bioassay test results, we do have some evidence that is sub- stantial for the potential ftir carcino~enicity. It does not necessarily mean that it really will occur, that is, that cancer will be found in high numbers in the th~posed human population. But my own personal opinion is this. Even without the epidemiolo~- ical data, there is sufficient reason to be concerned, and I feel it warrants the current intelligence bulletin. Mr. SEGAL. So that would be the Ames test, that is, the tests on the fruitfiies and what else? The laboratory tests on absorption? Are you convinced that application externally results in absorption into the human body; is that right? Dr. PAGE. Yes, I think the data which has recently come from the Food and Drug Administration points out that absorption is certainly possible with this chemical. So, on that basis, you have to be concerned for the internal distribution of the chemical within the body and possible carcinogenicity of internal organs. Mr. SEGAL. We also heard and received information this morning that there were several other chemicals, depending on bow many you counted, as many as eight additional ones involved in aspects of hair dyes. Do you have similar information that might lead you to addi- tional intelligence bulletins? Dr. PAGE. At this time I am not aware of having this information in NIOSH. Mr. BAlER. We have a list of chemicals that are used. This is why I mentioned to Mr. Maguire that we may want to characterize just what exposures the cosmetologist is subject to. We have sponsored a number of surveillance studies and one that comes quickly to~ mind is a death certificate study over a 20-year period. In this study we found that workers in certain occupations tend to die of a similar cause. So then we have to go back into the working environment to find out what is in there that could trigger off that effect. So, this now is really the initial blush of the problem, so to speak, and by looking into what is in that work site in depth, we will have a much better appreciation for the chemicals that may be present. 24-600 Q . 78 - 5 PAGENO="0066" 60 This is another reason why we also said in our statement, and we also said in the Current Intelligence Bulletin, that we did not just want an arbitrary substitution of other ehemicals until we know what the effects of those are. We are dealing with chemicals that take a long time from exposure to ê~fects. We are talking about 15, 20, 25, or 30 years, even. These are the kinds of problems we have. This is why we just do not want an arbitrary substitution of a chemical. We do not want to have another problem 20 years from now. Mr. SEGAL. Switching for a moment from an intelligence bulletin, namely the one involved in 2-4-diaminoanisole, to ethylene dichloride, you published something different which was a criteria document. Could you tell us how much more standing that has? Mr. BAlER. A criteria document is just about all we know about a chemical, group of chemicals or a process. It may also be a physical agent or a safety problem. It is all we know about something at a point in time, including a very thorough search and evaluation of the available literature. From beginning to end we take from about 10 to 15 months to develop a criteria document and some take even longer. Since it takes time to gather all that information on a substance and determine how to analyze it and what analyses of biological specimens must be made and how to inform the worker and so on- it is time consuming. Since we want to get some information out in a hurry, we issue a current intelligence bulletin. I guess what really triggered off the beginning of the Current In- telligence Bulletin was when vinyl chlorlde first appeared as causing angiosarcoma of the liver of exposed workers. We developed an emer- ency report which we transferred to OSHA. They went for a temporary emergency standard for vinyl chloride and proceeded with rulemaking. So, this, I think, was the very first situation which brought to our attention the need to responed quickly to a new problem which in turn lead to development of Current Intelligence Bulletins. Mr. SEGAL. With reference to ethylene dichioride, you issued the criteria document in March 1976, recommending a change in the stand- ard of 50 parts per million down to 5? Mr. BAlER. But it was based on the. effects on the liver and cardiac effects and not on cancer. It was only recently that we learned there was a potential for carcinogenicity. We are still waiting for a final report from NCI. And, if, in fact, it is a carcinogenic chemical-and I understand from this morning that it is-then we will proceed to rec- ommend to OSHA even more stringent controls. Mr.~$EGAL. How often does OSHA take your recommendations? I take itin this particular. instance, which has been since March 1976- which. is almost 2 years-that you made your previous recommenda- tion. Has that been incorporated? Mr. BAlER. No, it has not. Mr. SEGAL. What is your batting average with them? Mr. BAlER. I guess we have transmitted in the neighborhood of 80 criteria documents. I do not know really what the actual number of standards are; maybe 5, 6, or 7; somewhere in that neighborhood. Mr. SEGAL. Five of the 80 have been implemented? PAGENO="0067" 61 Mr. BAlER. Promulgated into regulations. Mr. SEGAL. So less than 10 percent would be a safe, guess? Mr. BAlER. Oh, yes. Mr. SEGAL. It is not appropriate to ask you why or should we ask them that when they come? Mr. BATER. We are in hEW. They are part of the Labor Depart- ment. Mr. SEGAL. That is all I have, Mr. Chairman., Mr. Moss. Mr. Wunder? Mr. WUNDER. Mr. Baier, I would like to direct your attention to page 4 of your statement wherein you mention two epidemiological studies. Would those studies be "A Retrospective Survey of Cancer in Relation to Occupation" by P. De~oufle, et al., and "Occupational Characteristics of Disabled Female Workers: A Descriptive Study" by Kennedy and Spirtas? Mr. BAlER. Yes. Mr. `WUNDER. Are those the same two studies that are mentioned in your mtelhgence bulletin dated January 13, 1978? Mr. BAlER. Yes. Mr. WUNDER. Mr. Chairman, at this time the clerk has two doc- uments that I would ask be passed out to. the Members `and to the witnesses. Mr. Moss. Without objection, these documents will be placed into the record at this point. [Testimony resumes on p. 76.] [The ma~erial referred to follows:] PAGENO="0068" 62 Yale'University New Haven, Connecticut 06510 January 20, 1978 SCHOOL OP MEDICINE 333 Cedar Street Mr. Conner Fay Robert W'ood Johnson Vice President, CLAIROL Clinical Scholar Program 345 Park Avenue New York, New York 10022 ALVAN 5. FEINSTEIN, M.D., Program Director Dear Mr. Pay: (203) 436-8787 As I indicated to you by telephone, Learn writing these comments as a Professor of Epidemiology who is interested in the reputation of my profession,' and who is cOncerned about the way in which statistical data can be abused to the detriment of the public. I do not wish to receive, and shall not accept, any personal stipend for setkding you these comments, which you are free to use in any way you wish. At some fUture date, however, I nay want to incorporate these remarks in a paper I shall prepare for submission for publication in a scientific journal. I am commenting on two documents: I: "A Retrospective Survey of Cancer in Relation to Occupation" by P. . Decoufle, K. Stanislawczyk, L. Houten, I.D.J. Bross, and E. Viadana. Contract No. HSM 99-13-5. Issued as a NIOSH Research Report, by the U.S. Dept. of H.E.W. II: A manuscript marked "DRAPT, Preliminary Report" and titled "Occupational Characteristics of Disabled Female Workers: A Descriptive Studyby .1. Kennedy and R. Spirtas, of N.I.0.S.H., Cihcinnati. My comments are as follows: I. "Retrospective Surv~py..." by Decoufle et al. The authors used the "case-control" technique to conduct essentially 22 studies. In each study, the "cases" consisted of patients found at Roswell Park Memorial. Institute to have a cancer in one of twenty-two different sites, during the period 1956 to 1965. The "controls" consisted of patients referred to the same Institute and found to have "non-neoplastic" diseases. For all cases and controls, the investigators compared the prevalence of 72 different occupations as pà'ssible etiologic agents. In standard performance of such studies, an odds ratio (which the authors incorrectly call a "risk ratio") would be calculated for the presence or absence of that occupation. The standard table would be as follows: NO. OF PATI TS WITH CANCER NO CANCER Pts. Having Suspected a b Occupation Pta. Not Having Suspected c d Occupation PAGENO="0069" 63 Mr. Conner Fay 2 - Januavy 20, 1978 The odds ratio would be calculated as (axd)*(bXc), If the odds ratio *~ceeds 1, with a P value that is statistically significant, and with a 95% donfidence interval that does ~ include 1, the result suggests an elevated risk for that occupation for the selected cancer. In the procedure used by these investigators, the suspected occupation was not compared against its absence. Instead, the investigators used "clerical jobs" as the comparative group. The remaining procedures used by the authors have the following gross flaws and fallacies: j~ExPo5ure to Hair Dyes Although the suspàcted etiologic agent is hair dyes, no effort was made to distinguish whether the petsons occupationally labelled as "Hairdressers and cosmetologists" actually used or were exposed to hair dyes. Since the category in-' cludes electrologists, manicurists, beauty school teachers, shampooers, etc., the quest for scientific evidence would have included an inquiry to determine whether the patients were in fact exposed to hair dye. 2. - Risk and "Dose" 0. E~oøuF5 `A second important item of scientific evidence in such studies is the dose-response curYe Was the risk of cancer greatet in people who bad used hair dyes in large amounts or for longer durations of employment? The investigators made no effort to obtain such evidence. 3. Capricious Statistic~ When 22 different cancers are examined for 72 different occupations, a great many "positive" or "significant" relationships can be expected to occur capri- ciously by chance alone. In fact, using a P level of .05 for "statistical significance during the examination of 1584 (..72x22) tables, one would expect to find 79 relation- ships (~l584x.O5) that emerge as "statistically significant" even if there is actually ~ association between any of the occupations and any of the cancers. On pages 6-9, the authors mention some of the many Other "significant" relationships they found dug~Lng the multiple statistical analyses. To guard against these caprices during "data-dredging" research of this type, cautious investigators customarily make stringent demands before accepting a * relationship as "statistically significant". Although the stringency will vary accord- ing to different principles, many careful investigators -~ aware of the "multiple comparison" problem - would insist on P values, below * 001 before calling any of these * relationships "significant". Some investigators might demand P values that are even smaller. The current investigators, however, were willing to assign statistical significance to grossly over-inflated P values,, at levels (of .01 to .05) that are at leaSt ten times, and perhaps 100 time~,larger than they ~b~uld be for decision-making. 4. Confidence Intervals When euffiOientiy large numbers of `people are investigated, almost any PAGENO="0070" 64 Mr. Conner Pay - 3 - January 20, 1977 statistical test of random probability will yield a "significant" resuld. for this reason, knowledgeable epidemiologists always test the ~redision of an odds ratio by calculating a 95% confidence interval around it. This process involves calculating the "standard error" of the odds ratio, and using the formula .0 ± .1.96 x s * e. (0), where 0- odds ratio, and s.c. (0) - standard error. In the formula given by 3 .L. FleiSs on page 66 of his standard textbook, "Statistical Methods for Rates and Pro- portiocs", if the four cells of the table are a, b, c, d, the odds ratio, 0-adxbc; and ____________ s.c. ~ In Tables marked "C" and "D" on pages marked 160 and 176 in the material avail.able to me from this report, the investigators provide the data that allow confidence intervals to be calculated for "hairdressers and cosmetologists" for the diverse cancers, including the three ("ovary, uterus, and lymphomas") that are par- ticülarly "indicted" on page 7 of this report. A re-appraisal of these data does not confirm the results claimed by the authors and does not support or sustain any of the "indictments". In all tl3ree instances, the 95% confidence interval around the odds ratio includes the value of 1. In cancer of the ovary, for example, the confidence interval runs from .071 to 5.11, indicating that the "true" risk ratio may even be as low as .071, which suggests that the occupation has a "protective" effect against ovarian cancer. Furthermore, in corpus uteri, the odds ratios offered in the tables (values of 3.00 and 2.82) are incorrect. They are much lower (in the range of 1.5) and the results are ~ statistically significant by the chi-.square test. In lymphomas, the tabulated data on pages 55, 61, 3.60, and 176 show nothing significant~ and do not sustain the claim made on page 7 of the text. (I can- not understand why the occupation is said to have "unusual cancer experience" with lyznphomas.) 5. The Assembled Group Only for a reader who leaves the investigators' discourse to look at the actual. data does it become apparent that the entire occupational indictment here is base~ on a total series of at most 97 hairdresser-cosmetologists among the entire "25,416 individuals" admitted for Suspected tumors to Roswell Park Institute dqring l956-1.965~ The 6 uterine cancers, 10 ovarian cancers, and 5 lymphomas fàund in those i~f'ha1rdressers constitute the total number of cancers on which all these conclusions are based. No useful statistical analyses can be performed when the numbers are so tiny and when the series of patients is so non-representative of any defined group. II. "Occupational Characteristics,.." by 1(ennedy and Spirtas This paper, which the authors label a "descriptive study", contains a listing of the "proportional morbidity rates" for different conditions in different occupational groups, as noted for women receiving Social Security Worker Disability Allowances during 1969-1972. People doing "Administration" and "Education" had the highest rates of "neoplasms". Their respective values of 153 and 148 were about 20% higher than the 126 noted for cosmetologists. Other partitions are used for other neoplasms and .conditions. No data are supplied to denote how many people were examined in each category; or the biases in occupation associated with submission of social security In the particular comparisons performed for the three `main' cancers, at most 37 "hairdressers and cosmetologists" were included. PAGENO="0071" 65 Mr. Conner Fay January 20, 1978 claims; or any other elemental requirement of objecti~Ye, careful scientific reporting. For example, the authors do not indicate that their category of "cosmetologists" includes barbers, masseurs, and beth attendants, as well as embalmers. The authors also make no cousnent on the strikingly high rates of disability found, for cancers and other major ailments, in the occupations of education and administration. * * * In sumeary, I am astonished to learn that eltbet one of these ~two reports has been regarded as an "epidemiologic study". I cannot think of any epidemiologists, who respect either themselves or epidemiologic science, who would want to ~be associ- ated with either study; or who would give either study any scientific credibility. In fact, I look forward to disseminating both these projects to students, so that they can see excellent examples of bad research and what to avoid in doing "epidemiologic studies". The second paper has such poor organization, content, and quality that it would be unacceptable as an essay project from a first~'year graduate student. The first of the two papers has better form; and shows at least a minimal regard for presentation of data - but here too, the investigators have violated almost every scientific stanaard that would be required for research to be regarded as objective, reasonable, and worthy of attention.~ As a taxpayer, I am distresSed tb find NIOSH supporting work that is so poor that whatever is fount cannot be believed. La an epidemiologic scientist, I am appalled that the title o* "epidemiolo'gi~ study" has been applied to "research" of such extra~ ordinarily low quality. Sincerely yours, Alvan 1. Feinstein, M.D. Professor of Medicine and Epidemiology ARP:abn PAGENO="0072" 66 THE JOHNS HOPKINS UNIVERSITY School of Hygiene and Public Health Department of Epidemiology 615 North Wolfe Street Baltimore, Maryland 21205 TO: Dr. John Menkart, Clairol, Inc., 2 Hlachley Rd., StSxnford, CT. FROM: Irving I. Kessler, M.D., Dr. P.M., Professor of Epidemiology DATE: January 21, 1978 You have asked me to evaluate the NIOSH Roswell Park Memorial Ins1~ttute study, which was cited in the January 13, NIOSH Current Intelligence Bulletin recommending that 2, 4-DAA be handled in the work place as a human carcinogen. Due to time limitations, my comments and observations are limited to those portions of the NIQSH research report "A Retrospective Survey Of Cancer In Relation To Occupation" which you provided. These deal with general background, methodology, results, discus- sion, summary findings, occupational groups studied, statistiøal tables dealing with "hairdressers and cosmetologists" and the technical appendix (pp. 1-15, 37, 55, 61,160, 176, 196, 197). On the basis of my review of this information, I have prepared the attached critique of the Roswell study. This covers both general observations and those portions dealing with "hairdressers and Cosmetologists" in particular. I understand you are sending me the full NIOSH report, and I will, of course, advise you if anything in the balance of the report necessitates revision of my current evaluation. CONCLUSIONS: The NIOSH finding that hairdressers and cosmetologists show ~an unusual cancer experience for three sites: ovary, uterus, and lymphomas" appears to be unwarranted for a number of reasons. The cancer patients seen at the Roswell Park Memorial Institute are, by the investigators' own description, highly Selected and not necessarily representative of the universe of cancer patients. Their definition of "hairdresser and cosmetologist" includes a highly heterogeneous group of women lumped together into a single. risk category. Certainly.many of them do not work with hair dyes., For these women in the so-called "hairdresser and cosmetologist" category, the actual number of cancer cases was very small, and, in th~ authors' own words, "A seemingly high relative risk based on only a few cases should be interpreted cautiously." DISCUSSION: Utilizing self-recorded occupational information ~btained from a group of cancer patients seen at one highly PAGENO="0073" 67 Dr. John Menkart January 21, 1978 Page2 selective cancer hospital, the investigators suggest that cancers of the ovary, corpus uterus, and lymphoma are associated with the hairdresser and cosmetology industry Their conclusions are probably unwarranted for a number of reasons. These include the following: S 1) The cancer patients seen at the Roswell Park Memorial Institute are acknowledged by the investigators to be highly selected, rather than representative of the universe of cancer patients; 2) The investigators' definition of the hairdresser and cosmetology industry was highly non-specific. Included in this category were cosmetology consultants, electrolo- gists, wig stylists, beauty culture teachers, as well as managers and owners of beauty parlors. Thus, a highly heterogenous group of women exposed and not exposed to a widevariety of beauty products were lumped together into a single risk category; 3) The occupational histories were recorded by the patients themsei,ves, Such self-administered questionnaires are suspect to some extent because of the wide variety of women filling them out. These would include women varying in intelligence, social class, and language ability, as well as their motivation to fill in the answers and to fill them in completely; 4) More than one-half of all the recorded occupations were not included in the analysis or were lumped into the control category on the basis of a prior assumption that "clerical occupations are relatively free of health hazards," I Yet some of the occupations excluded, such as "misce]7laneous crafts," and "laborers,." might well have been,hazardous ones; 5) Occupatio~s for which duration of employment was unknown were arbitrarily excluded and no information offered~ as to the number of such patients; 6) ~or womer in the hairdresser category, the actual numbers of cancer cases was so small as to make impossible an analysis which would control for the large variety of potential confounding factors which might very well have explained the observed results. Only age Was adjusted for in mOst of the analyses and, even this, only in terms of a rough dichotomy between women under 60. and 60+. No documentation was offered in regard to the specific age comparability of the cancer cases and control. PAGENO="0074" 68 Dr. John Menkart January 21, 1978 Page 3 None of the criticism leveled against this study shduld in any way be construed as criticism of the professional abilities of * the investigators, a number of whom are colleagues personally known to me. Rather, it is my intention in this critique to * direct further attention to the limitations inherent in this study, many of which are fully described by the investigators themselves in their discussion. IXK/kp Dictated, but not read. Attachment PAGENO="0075" s~ntar: `fuesday aornlnZ, April $ ?p~Jeleage: W~~NESDAY AM's, April 6 EXCER~ED FI~OM: DIPHTHERIA-VACC ~ALuATToN~ E. CUYLER HAMMOND, .Se.D. (64), Vice President for Epidemiology aid Statistics, American Cancer Society. Dr. ESamond was born in Baltimore, lid., and received his Doctor of Science degree (Sc.D.) from Johna Hopkins UniverSity. Es j~oLned the American Cancer Society in 1946 after serving in the U.S. Army Air Force as Aset. Chief of the Statistics division, office of the Air Surgeon. Prior to this he served four years with the Division of Industrial Hygiene. Dr. Hammond also is adjunct professor in coimounity medicine, Mt. Sinai School of Medicine; a member of the scientific advisory panel of Research to Prevent Blindness * Inc.; associate editor of Enrironsantal Research; advisory editor of ~a~k Cancer Journal for C1ii~4apa end a member of the Board of Directors and past president of the New Vora~ Academy of Sc~1.,wm,. AMERICAN CANCER SOCIETY , i~iws SERVICE 770 YNIOD AV$NU$ #40* Y000* N.Y. 10011 1212? 371.2000 (V 69 1nerican Cancer Society's NINETEENTH SCIENCE WRITEPS' SEMINAR Sarasota Hyatt House Sarasota, Florida Aprtl1~. 6, 3.977 F I TETANUS AND SOME NEGATIVE FINDINGS (POLIO. SMALL FOX.. a~ Rrctc PAGENO="0076" 70 SOME NEGATIVE FINDINGS (POZIO~ SMALL POX, TETANUS AND TRERIA~VACCINES; BEAUTICIANS) AND EVALUATION OF RISKS E. Cuyler Hanmtond, Sc.D. .extreme t..,the-othex. S~rne people are alarmed, to a far greater degree than is~ ~ They fear to eat anything but natural food grown without man~made fertilizers and insecti~~ cides and with nothing added later. They think that air pollution will cause them to die of cancer as will contact with rt~anifold products of industry. They do not ask "what is harmful?" They ask "what, if anything, is safe?" Sone workers are fearful of losing their jobs in these tines of ~inemployment. For example, a friend of mine, who had reason .to suspect that a certain substance with which he woçks is Carcinogenic, recently said to us: "For God sake don't ~ that it causes cancer. If you~do, it will be banned and 1 will lose my job. At my age, I will never be able to find any other decent job." This is n~t an uncommon attitude. PAGENO="0077" 71 `Hammond page. 2 A growing number of people are becominq annoyed if not ~engry abotit the whole affair. . "What are they going to prohibit next? Sex?" Many of these people express the opinion that government and scientists should stop their meddling and leave people alone. They are also becoming highly skeptical of pronOuncements made by "authorities" including medical and scientific "authorities"~ U this attitude becomes widesprea&, it will seriously endanger our efforts to control cancer. It is not our object to frighten people. It is not our' object to pu~ people out of work; and it is certainly not our object to take all pleasure out of life. Our object is to reduce the risk of cancer in so far as it is feasible to do so. Feasibility depends upon many elements, not the least of which are public attitudes. ~ real~siâ `attitudes is t~.,frankty admit the `limitations `in our present knowledge and in ~ `we" know' and wb~t"we"oriIy S~~bCt''And when we speak of rIsk, express the degree of risk in terms which are meaningful to the, average person. exc.iting.~and receive wide attention in both the scientific press and public news media.' Negative findings - those which seem to PAGENO="0078" 72 Hammond page 3 show that a substance is hazm~ess - tend to be dull and there.. fore usually receive little attention. Poth~s~-reason1Iwil3~ s4art by describing several hegative findings. They are~ of i~n~ Verest on3~y in that they tend to counteract unwarranted fears., Beauticians There has been speculation that some, and perhaps many, of the various chemical agents used by or on women for beauti- fication are carcinogenic. This has caused worry among many women especially among those most heavily exposed: beauticians. Epidemiologic evidence is now available on this matter. Over 1,000,000 men and women in 25 states were enrolled in a long term study by volunteer workers of the American Can- cer Society. Upon enroliment, each of them answered a lengthy queètionnaire. ?~dingspreeented below are based upon data a~vailable after 13 years of trabing. Of some 589,000 female sub4ects all of whom were over the age of 30 and most of whom we~e over the age of 115 at the start of the study - 5,125 said that they were beauticians. By the matched group procedure, we matched the beauticians with non.~be;uticians on age, race, education, place of residence (large metropolitan area vs rural or less populated area), amount of cigarette smoking, past history of cancer, and past history ofheart disease. Matches were found for 5,117 of the 5,125 beauticians. In most. instances, many non-beauticians were found as matches for each of the 5,117 beauticians. This. increased the `statis- tIcal, stability of the findings. PAGENO="0079" 73 Hammond Page Ls~ Durinj the course of the study, 32]. of the beauticians died, Adjusted for the size of the two groups and standardized for age, 351 of the~beauticians died, This small difference (in favor of the beauticians) is not statistically significant. 113 of the beauticians died of cancer, Adjusted for size of the two groups, 115 of the non~~beauticians dIed of cancer. T1s~vtrti~a11y nodlfferenee. There-was not a single site of cancer from which s~nificant1y more beauticians than non.-beauticians died. The findings were essentially the same during each of twelve successive years of tracIng. IC..~xposure_as&oci~ate&.with-..the occupation of beautician has resulted in an increase in death rates from cancer of any s~terthe increase is too small to show up in a study of over 5~,OOO people over a period of 13 years~ It could be that some "beauty aid" introduced in recent years is highly carcinogenic but has not been used sufficiently long for the effects to become apparent, Therefore~in spite of our findings, I belIeve that all recently introduced "beauty aids" (and those proposed for introduction) should be tested for possible carcinogenic effects. Polio Vaccine(SV~O) Research carried out by virologists between ].9514 and early 1961 revealed that some batches of polio vaccine produced up to that time were contaminated with living sImIan virus 1~O (SV 140). (Later, leading virologists told me that they thought that most if not all of the batches produced up to that time were at least PAGENO="0080" TABLE I PROBABILITY OF SU?.VIVING TO AGES 65 AND 75 AND LIFE EX?ECTANC~ FOR U.S. WHITE MALES STARTING AT AGE 20 a) If Death Rates are Increased from hge 20 on by:. b) If Death Rates are Increased from Age 40 on by: U.S. White Males 1974 1% 2% Prob. Surviving from - Age 20 to Age 65 (%) 70.73 70.49 70.24 . Prob. Surviving from Age 20 to Age 75 (%) 44.13 43.77 43.41 Life Expectancy at Age 20 (yrs.) 50.95 50.83 50.71 5% 7% 10% 69.52 69.03 69.32 42.35 41.66 40.64 50.39 50.15 49.83 15% 67.14 39.00 49 * 31 25% 64.85 35.91 48.34 U.S. White Males 1974 1% Prob. Surviving from Age 20 to Age 65 (%) 70.73 70.52 Prob. Surviving from Age 20 to Age 75 (%) 44.13 43.79 Life Expectancy at Age 20 (yrs.) . 50.95 50.85 50% 59.44 29.19 46.23 50% 60.60 29.76 46.93 200% 35.16 8.31 38.36 200% *37.98 8.98 40.61 2% 70.30 43.44 50.75 100% 49.93 19.26 42.93 100% 51.88 20.02 44.22 5% 7% 10% 69.65 69.22 68.58 42.43 41.77 40.80 50.45 50.26 -49.98 15% 67.53 39.22 49.54 25% 65.47 36.25 48.71 PAGENO="0081" TA!3LR II PERCENT OF DEAT!13 FROM 2~LL CAUSES FOR SELECTED cAUSES OF DEATh 0 h1hit.~ Ma1~s, U.S. 1974 CE CROUP 20-»=9 30-39 40-49 ~0-59 60-69 70-7~ SOf (.~t~~Of Death ~ All Causes 100.000 100.000 100.000 100.000 100.0ü~ 100.OoO 10O.0~O .~i1 ~ 6.649 11.010 18.727 23.~38 24.393 20.456 12.949. ii'rg 0.122 1.997 6.819 9.319 9.214 6.107 2.240 C~1on-R..ctum 0.216 1.147 1.696 2.458 2.921 2.803 1.158 StXfl~..CiI 0.037 0.315 .0.750 G~879 0.~76 0.974 0.165 Livar 0.048 0.137 0.243 0.338 0.393 0,326 0.206 Pmcruas 0.041 0.366 0.929 1.346 1.321 1.108 0.654 * 0.011 0.014 0.130 0.570 1.511. 2.660 2.744 ti~idder 0.004 0.0U2 0.226 0.458 0.738 0.916 0.762 k~idncy 0.059 0.247 . 0.598 0.700 0.614 0.427 0.215 Lcukeittia 1.024 1.261 0.709 0.701 0.156 0.7~3 0.646 tt.Cl)t.~.'tE1C IIt~rt Diseasi 0.898 11.390 31.880 39.265 40.480 40.819 42.466 PAGENO="0082" 76 Mr. WUNDER. Mr. Baier, what you have been provided is first a letter from Dr. Alvan Feinstein of Yale to a Mr. Fay of Clairol, and second a memorandum from Dr. Kessler of Johns Hopkins, a professor of epidemiology, to Dr. Menkart of Clairol. I would like to read several portions of Dr. Feinstein's letter first wherein he discusses those two studies that you conducted. On page 4 of Dr. Feinstein's letter he says: In summary, I am astonished to learn that either one of these two reports has been regarded as an "epidemiologic study." J cannot think of any epidemiologists, who respect either themselves or epidemiologic science, who would want to be associated with either study; or who would give either study any scientific credibility. S In fact, I look forward to disseminating both these projects to students, so that they can see excellent examples of bad research and what to avoid in doing "epidemiologic studies." The second paper has such poor organization, content, quality, that it would be unacceptable as an essay project from a first-year graduate student. Dr. Fernstein goes on to say: As a taxpayer, I am distressed to find NIOSH supporting work that is so poor that whatever is found cannot be believed. As an epidemiologic scientists, I am appalled that the title of "epidemiologic study" has been applied to "research" of such extraordinarily low quality. I know that this is the first you have seen of these letters, but do you have any immediate reaction? Mr. BAlER. Fundamentally, there are different kinds of epidemi- ologic studies. Mr. WUNDER. What is the difference between the two? Mr. BAlER. One is if we are just trying to identify trends as opposed to an in-depth evaluation of the environment and its effects on worker sickness and death. The former is the type of epidemiology that I think is being referred to here. The purpose of this study was simply to say: "Is there a problem in certain occupations?" Primarily we were looking at females. A lot of work has been published on males. Most standard mortality rates are based on white males. We do not have very good data on certain minorities, ethnic groups or women. The purpose of these studies is simply to say: "How are women~being affected as a result of their jobs?" Then' from there you go into the more in-depth detailed study of the type that Yale University could design, or that NIOSH could design. Dr. Page, would you like to add to that or comment on it? Dr. PAGE. I think the point that Mr. Baier is making is good. These were more like surveillance studies of. population without really trying to look at the specific cause first, rather than going into an in-depth study for an association; for example, cancer in hairdressers. So, it is pointing toward potential problems for further study. Mr. WUNDER. I think the point is this. If you look on page one of Dr. Feinstein's letter, I think he addresses that point in this sense. He says: As I indicated to you by telephone, I am writing these comments as Professor of Epidemiology who is interested in the reputation of my profession, and who is concerned about the way in which statistical data can be abused to the detriment of the public. S PAGENO="0083" 77 What Dr. Feinstein is talking about here is that you published the results of these two studies and indicate that they suggest excess cancer among cosmetologists and it would lead one to believe that there is rather good information on it. Do you have any comment on that? Dr. PAGE. There is only one comment I would make here. That is to counter to Dr. Feinstein's comments. These NIOSH reports, prior to publication, were reviewed by a number of other epidemiologists. They have had a critical review. They do have deficiencies. NIOSH is not trying to cover these up and say that they are definitive studies. Mr. WTJNDER. How many cosmetologists were there out of this 25,000 sample? Would 97 be the right figure? Dr. PAGE. I believe 97 is correct for the Roswell Park Memorial Institute study. Mr. WTJNDEE. Were all those actually people who would have handled hair dye, or did they include such things as manicurists, wig stylists, and the like? Dr. PAGE. It was a broad category. There were others in there that did not actually handle the hair dye. It is hard to separate out the types. Mr. WUNDER, Mr. Chairman, these two documents were just pro- vided to the NIOSH witnesses. So, I wonder if we ~ould ask them to do an analysis of Dr. Feinsteiii's, comments and have those submitted for the record? Mr. Moss. The record will be held open at this point to receive the comments of the agency On the letter of Dr. Feinstein. Without objection, so ordered. [Testimony resumes on p. 88.] [The following letter was received for the record :J PAGENO="0084" 78 (~) ~ DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE f PUBLIC HEALTH SERVICE r~ `~ CENTER FOR D$SEASE CONTROL - -. (JATIONAL NST~Tu'rE FOR SAFETV~ 5600 ROCKVILLE, FEB 241978 The Honorable John H. Moss Chairman, Subcommittee on Oversight a4d Investigations Committee on Interstate and Foreign Comme~'ce House of Representatives Washington, D.C. 20515 Dear Mr. Chairman: This is in response to the request from your Subcommittee regarding comments from Dr. Irving Kessler and Dr. Alvan Feinstein on two NIOSH stu~ies indicating that cosmetologists and hairdressers may be at increased risk of cancer. In addition to responding to the specific* comments these reviewers made on the two studies at the request of Claix'ol, Inc., I vould like to discuss why NIOSH conducts these kinds of studies. The two studies in question, "A Retrospective Survey of Cancer in Relation to Occupation," by P. Decoufle, et. al., and the preliminary * report, "Occupational Characteristics of Disabled Female Workers: A Descriptive Study" by Kennedy and Spirtas, were related to projects * `within the Illness Effects Section of the NIOSH Surveillance Branch. This section seeks to identify ocdupational groups exhibiting unusual patterns of mortality or morbidity that may be related to hazardous exposures in the workplace. Because there is no national system for reporting occupational disease, NIOSH must `rely to a large extent om~ existing data bases in identifying high risk occupational groups. The Decoufle study was based on data collected at Roswell Park Memorial Institute, which specializes in cancer.research. The Kennedy and `Spirtas study was based on data from the Social Security Administration file of awards to disabled workers. The costs of such studies are relatively small. The contract cost for the former study was $96,Qoo and the interagency agreement to assemble data for the latter study was $6,000. The techniques NIOSH used in these hypothesis-generating studies are well.established in the fields of occupational and environmental health. Similar studies include a 1950 Occupational Mortality Study on Males (Guralnick, NCHS), the 1959-1962 Disability Study on Male Workers PAGENO="0085" 79 ~P~ge 2 - The Honorable John H. Moss (Occupational Health Program, P115 and the Bureau of Disability Insurax~ce, SSA), and the Registrar General's Report (England and Wales). Recently, the occupational and environz~ental health scientific community made statements that support and recommend more research of this nature: (1) Environmental Monitoring, A Report to the U.S. EPA from the Study Group on Environmental Monitoring, Committee on National Statistics, Environmental Studies Board, Numerical Data Advisory board, Assembly of Mathematical and T'bysieal Sciences, and the 1~ational Research Council; and. (2) Report from the .NIOSH Task Force on Occupational Health Surveillance. It is important to keep in mind ,that the NIOSH Current Intelligence Bulletin 19 on 2,k-Diaminoanisole clearly states that although the two NIOSH studies suggest an association between cancer and employment as cosmetologists, the studies did not attribute any exceSs incidence of cancer to exposure to hair dyes. Enclosed is our response to some of the main points raised by Dr. Feinstein and Dr. Kessler about the NIOSH studies.. Sincerely yours, ~ ~ .»=~ [J. Donald M$lar, M.D. ( Assistant Smfrgeon General -. -. Acting Director: 2~Epclosures -* - - PAGENO="0086" 80 EESPONSE TO DR. KESSLER' S COMMENTS ON ROSWELL PARK. STUDY ISSUE: The pa1~ients seen at Roswell Park Memorial Institute (RPMI) are~not representative of cancer ~atie~its generally. RESPONSE: Patient non-representativeness would introduce bias if Roswell cancer patients were compared with cancer patients outside R?MI; however, in the Study they were compared with R?vlPI non-cancer patients. As stated on page 5 of the NIOSH report, "These phenomena, due to referral patterns characteristic of a single hospital do not necessarily introduce significant bias in the analyses presented here as long as there are no systematic differences between referral patterns for cancer patients having a particular kind of employment history and non-cancer patients with the same employment history." ISSUE: Specificity of occupational coding schemes RESPONSE: The detailed coding Dr. Kessler recommends would require the incorpora- tion of not only the patient's occupation but also his exposure history. Such information was not available to the investigators from the computerized file used for analysis. Since the usual effect of heterogeneous groups is to dilute. any specific effect, it may be that the group at highest exposure was at even greater risk than hypothesized by this study. ISSUE: . . Only small numbers of patients were involved. RESPONSE: Of the 25,1416 patients admitted to RPMI, 13,9149 had cancer; the co*parable groups without cancer were drawn from the remainder. Some of the 25,1416 patients were excluded fPom the study since they bad benign neoplasms or did not fit into the selected occupations for study (see Item 6). At the time of this study, the RPMI data was unique. If significant results are found based on 97 cosmetologists, then a larger study might be expected to show even more significant results. ISSUE: Choice of "control" occupations was questionable. RESPONSE: Clerical controls were chosen because they were expected to be relatively free from exposure to carcinogens. Even if the clerical patients have some exposure to carcinogens, it seens unlikely that they would be exposed to the same agents as the occupational group oLinterest. Besides, the effect of some unknown hazard to clerks would be expected to weaken any difference in cancer experience between clerks and cosmetologists. PAGENO="0087" 81 ISSUE: NIOSH Study was influenc~ed by previous speculations RESPONSE: Surely no one study can meet all the qualifications specified to contrbl all confounding factors in the study *ithout an exceptional amount of time or cost invested. It is common to refer to other studies w~4ch both support or contradict data. It is essential to consider all possible evidence when interpreting data from a single epidemiologic study. We have written the Boswel]. Park staff to request their responses to the following points, since they have the original data available to them: a. questionnaire design and administration. b. Descriptive data on numbers of controls, and demographic details. c. Selection and coding of occupations. PAGENO="0088" 82 `RESPONSE TO DR. FEINSTEIN'S CO1~1ENTS ON ROSWELL PARK STUDY ISSUE: Exposure to Hair Dyes RESPONSE: Nowhere does the Roswell Park Study state that there was any suspected etiologic agent. The purpose of this study was to generate, not to test, hypotheses. Inclusion of heterogeneous groups could be expected to mask an etiologic agent in one of the groups. Thus, the appropriate reaction to these results is to try to sharpen the hypothesis in further studies aimed at possible etiologic agents which, we agree, would include hair dyes. ISSUE: Risk and "Dose" of Exposure RESPONSE: No data were available in this study which would allow computation of dose-response curves. To our knowledge, none of the other epidemiologic studies had such information either. In general there is a lack of industrial hygiene sampling results to assess the dose received by a cosmetologist. NIO~H has requested such information from Clairol (see letter to Mr. Connor Pay of January 25, l9T8). ISSUE: Capricious Statistics RESPONSE: The authors address this point in the text. In hypothesis generating surveillance studies, the established convention is to allow the overall alpha level to rise in order to hold down the beta risk. In epidemiologic terms the approach used sacrifices "specificity" in order to allow for greater "sensitivity", since these are two types of risks involved which must be accounted for. The "decision-making" that NIOSH does is to recommend criteria fQr standards. No regulatory measures are taken by our agency. The difficult decision involves when and what information should be disseminated. ISSUE: Confidence Intervals RESPONSE: Dr. Feinstein has used formula 5.19 from Fleiss' book which is appropriate for "gauging the pre~ision of the estimated odds ratio; but not in testing its significance" (Fleiss p. 1~6). The more appropriate formula from Fleiss for estimating the confidence interval when the odds ratio is used as an estimate of relative risk involves formulas 5.20 and 5.33. If, for example, one uses these formulas for cancer of the ovary, one finds that, contrary to Dr. Feinstein's computations, the confidence ir~terval runs from l.~42 to 6.29, which implies a statistically significant association between employment as a cosmetologist and ovarian, cancer. We have rechecked the calculations PAGENO="0089" 83 in question and find them to be correctly reported according t.O the stated methodology. The contractor chose a procedure for estimating the relative risk which adjusted for age, something Dr. Feinstein's calculations did not do. The formula used by the contractor was applied consistently throughout all calculations which meant that there was no a priori reason to expect cosmetologists to show significant results. ISSUE: The Assembled Group RESPONSE: First of all Dr. Feinstein's letter has a typographical error. In line 6, the number "37" should be "97'~~ Second, he misses the point that if positive results are detected in such a small group, then it may indicate a serious problem in the larger population of all cosmetologists. PAGENO="0090" 84 ~RESPONSE TO DR. FEII'TSTEIN'S COMMENTS ON SSA DISABILITY STUDY Preliminary Draft - Occupational Characteristics for Disabled Female Worker~: A Descriptive Study. This study has not yet been completed or released as a final report by NIOSH. Preliminary results of the study were discussed in a ten-minute presentation before the Occupational Health and Safety Section of the American Public Health Association (APHA). A copy of the APHA presentation was released to Clairol, the Cosmetic, Toiletry and Fragrance Association, and others requesting these data. The intent of the APHA presentation was to demonstrate a technique used in surveillance to identify ocoupational groups which may be experiencing highe~ rates of disease so that further in-depth studies of those groups might be carried out. It was stated in the APHA presentation that only selected disease categories or occupational groups would be discussed, but that a final report would include more categories and groups. The final report is scheduled to be completed in June 1978. The preliminary presentation examines 23 selected occupational groups categorized according to the Dictionary of Occupational Titles, 3rd edition and included codes 330-339 (defined in the study as cosmetology). One criticism was that the category grouping was too broad to address cosmetologists and hairdressers alone. Since this was a preliminary finding, further analyses will be made in more detail which are specific to code 33»=, hairdressers and cosmetologists. We might add that more than 90 percent of the broad group studied (330-339) were coded as 332. The coded occupation refers to a disabled worker's usual occupation. There is also a classification to distinguish those employed fewer than five years from all others. All of these variables will be discussed in the final report. Our use of the preliminary results on disabled female workers classified in the broad category of cosmetology for the bulletin was to point out additional reason for concern since it is believed that hairdressers and cosmetologists comprise the largest portion of workers with potential exposure to 2,~-diarninoaniso1e. The preliminary findings referred to the selected disabling conditions as defined in the International Classifi- cation of Diseases (Adapted) for an estimated 5,861 disabled female workers within the broad category of cosmetology. This estimate was made from a sample of approximately 700 cosmetologists and was derived on a probability basis from all female disability awards during the period 1969-1972, The sample is considered representative of the overall national total, while most of the other studies are not as readily extrapolated. The Social Security Disability data did show a number of elevated proportional morbidity ratios (PMbR's) for specific primary malignant neoplasms. Other occupational groups studied showed elevated PMbR's which will also be considered for possible further study. However, no other PAGENO="0091" 85 - `~occupe~tional group showed more elevated PMbE's for the selected primary malignant neoplasms than the occupational group, cosmetology. Comments made on the ten minute APEA presentation of the study (by Dr. A. Feinste~n) should be viewed as premature. The final report of the study will include presentation of methodology, complete results with detailed tables, and discussion of occupations, disabling conditions, and the nature of the data received from the SSA. Before the disability study is published., NIOSH will subject the study to scientific and technical review. This review will include three persons outside of NIOSH (two from academia). We would also welcome comments and criticism from pther interested persons during the review process. PAGENO="0092" DEPARTMENT OF HEALTH EDUCATION AND WELFARE PUBLIC HEALTH SERVICE CEPATER FOR OISRASR CONTROL January 25, 1978 NATIONAL INSTITUTE FOR 0CCUPAT~ONUL S ETTANDITSU RO$RRT A. TAFT LARORATORIES Mr.* Conner N. Pay . . - Vice President for Corporate Affairs . . Clairol . ..: .. . 345 Park Avenue . .. . - New Pork, New York 10022 . . Dear Mr. Pay: . . ... This letter is in response to your letter dated January 17, 1978. With regard to the Social Security Data, . we think it will be possible to focus our analysis on the specific subcategory of cosmetologists and hairdressers (DOT code 332). On the matter of the Roswell Park Study, we are consulting the contractor to determine the poásibility of reanalyzing this data. - Your.last sentence, expressing an interest in the degree to which cosmetologists are exposed to hair coloring, raises an important issue. I would have thought that your industry would already have such informa.~ tion as part of your responsibility for assuring the safety of the products you sell. Surely you must have access to industrial hygiene and epidemiologic surveys of beauty shops as well as your own manufacturing facilities. I suggest that you contact the appropriate medical and/or industrial hygiene staff in your company (or industry) to provide an answer to the type and quantity of hazardous exposures in the formulating, manufactur~ lug and application of hair collorings as well as other related products. If you could provtde NIOSH with copies of available reports, we cou~.d try to. incorporate the information into our analysis. Alternatively, we may be able to do a more rigorous epidemiologic study by utilizing information from payroll records, pension files, work history files and. death certificates from an appropriate manufacturing facility. Please let me know what sources of information you are. able to find. Because of the extensive use of hair dyes in our society, there is a critical need for a more in.depth evaluation of the health and 86 i.~. PAGENO="0093" 87 Page 2 Mr. Conner M. Pay, 1/25/78 environment of workers in the industry who would seem to be at highest exposure to Suspected hazards. We look forward to your continued cooperation in this important matter. * * * * Sincerely yours, Robert Spirtas, Dr. P.R. chief, Illness Effects Section Surveillance Branch Division o~ Surveillance, Bazard* * * Evaluations, and yield Studiëè" PAGENO="0094" 88 Mr. WUNDER. Thank you, Mr. Chairman. I have no further questions. Mr~ Moss. Additionally the staff will be instructed to have a similar evaluation made of the studies of Clairol and of the Institute, that is, the studies which have been submitted to this cOmmittee in order that we mt~y have an independent evaluation of those studies as well as of the NIOSH studies [see p. 344]. Mr. Moss. Are there any other further questions? If not, the committee wants to thank you two gentlemen for your apj~earance. The committee will now stand adjourned until next Thursday morning at 10 o'clock when we will meet in room 2322. [Whereupon at 3:30 p.m., the committee adlourned to reconvene on Thursday, January 26, 1978, in room 2322 Rayburn House Office Building.] PAGENO="0095" CANCER-CAUSIN~ CHEMICALS Safety of Cosmetics and Hair Dyes THURSDAY,' J~ANUARY 26, :1978 HousE oi~ REPRESENTAnVES, SuBCO1~MITTEE ON OVERSIGHT. AND INVESTIGATIONS, COMMIrFEE ON INTERSTATE AND FOREIGN COMMEÜCE, Wa~sMngto%, D.C. The subcommittee met pursuant to notice, at 10 a m , in room 2322, Rayburn house Office Building, Hon. John E. Moss (chairman) presiding. Mr. Moss. The committee `will be in order. Today we begin the second day of hearings on the war on cancer. We will focus our attention on the safety of hair dyes and other cos- metic products. Specifically, the Cosmetic, Toiletry, and Fragrance Association-. CTFA-has issued statements that scientific evidence now exists to confirm the safety of cosmetic products. We hope to explore their contentions in depth. On Monday, this subcommittee was informed by the National Cancer Institute that at least six hair dye ingredients have been shown to be carcinogenic in animals. Two of these ingredients are benzidine derivatives, a known human carcinogen. Staff further informs me that at least five of these ingredients can now be found in hair dye prod.- ucts on shelves throughout the Nation. We expect to hear information at these hearings that carcinogens may not only be in hair dyes,~ but in other cosmetic products. Nitro- samines, a class of potent carcinogens, have been found in significant `concentrations in numerous consumer products We intend to find out how extensive `this danger is to humans. We also intend to determine the steps that industry has taken to remove potentially dangerous ingredients from its products. Since the Food and Drug Administration.'has limited powers to force removal of ingredients .from cosmetic products, the public may have no re- course but to stop using such products, altogether or continue to use them iand face an unnecessary risk. (89) PAGENO="0096" 90 Questions we hope to have answered today include: - Has the hair dye industry taken steps to remove carcinogenic ingredients from its products. Should the hair dye exemption in the Food, Drug, and Cosmetic Act be removed? Do nitrosamines in cosmetics pose a potential hazard? Has the cosmetic industry conducted proper tests to assure the safety of cosmetic products? Obviously, the lives of millions of Americans will be affected by these answers. I would like to welcome the representatives from the Cosmetic, Toiletry, and Fragrance Association, the Environmental Defense Fund, and Dr. David Fine to address these and other questions posed by the subcommittee. At this time I am pleased to recognize Dr. James H. Merritt, presi-~ dent of the Cosmetic, Toiletry, and Fragrance Association. He is ac- companied by Norman F. Estrin, vice president for science; John F. Corbett, chairman of the Hair Dye Technical Committee; and Peter Barton Hutt, counsel. Gentlemen, will you all be testifying? Mr. MERRITT. Yes; we will. Mr. Moss. Will you stand and be sworn in? / Do you solemnly swear that the testimony you are about to give this subcommittee is the truth, the whole truth, and nothing but the truth, so help you God? [Chorus of "I do's" by witnesses.] Mr. Moss. Identify yourself to the reporter for the hearing record, please. Dr. CORBETT. Dr. Corbett. Dr. ESTRIN. Dr. Estrin. Mr. MERRITT. Mr. Merritt. Mr. HUTT. Mr. Hutt. Mr. Moss. Mr. Merritt, you may proceed. TESTIMONY OP NAMES H. MERRITT, PRESIDENT, TEE COSMETIC,', TOILETRY, AND FRAGRANCE ASSOCIATION, INC., ACCOMPANIED BY NORMAN F, ESTRIN, FE. D., VICE PRESIDENT, SCIENCE; bEN P. C~RBETT, PH. D., CHAIRMAN, HAIR DYE TECHNICAL COMMIT- TEE; AND PETER BARTON HUTT, COUNSEL Mr. MERRITT. Mr. Chairman and members of the subcommittee, my name is James H. Merritt. I am president of the Cosmetic, Toil- etry, and Fragrance Association-CTFA-the national trade associ- ation of the cosmetic industry. I am accompanied today by three others in order that we might provide you accurate and authoritative responses to questions you raise. Those with me are: Dr. JohnCorbe1~t, chairman, CTFA Hair Dye Technical Committee and vice president, technology, Clairol, Inc.; Dr. Norman F. Estrin, vice president, CTFA; and Peter Barton Hutt, CTFA counsel and partner, Covington and Burling. CTFA represents approximately 225 manufacturers and distrib- utors of cosmetic products, and about 200 manufacturers and dis- PAGENO="0097" 91 tributors of cosmetic product ingredients and supplies. CTFA mem- bers. manufacture approximately 90 percent of the volume of cos- metic products distributed in the United States, The cosmetic industry accounts for about $9 billion of retail sales in the United States yearly and provides the livelihood for literally millions of people in this country. CTFA is appearing today, at your request. To summarize, we believe that: Cosmetic products are safe, and are among the safest products of any kind consumers can buy. FDA has adequate legal authority to take appropriate regulatory action to protect the public against unsafe cosmetics. The cosmetic industry has initiated many programs to meet its obligation to the public to assure the safety of the products it markets. We are aware of no reliable evidence that cosmetics contribute to human cancer. We believe that Dr. Upton's statements, made in his testimony on Monday, fully support our position. Cosmetics have been used for centuries. We find evidence of them in every recorded civilization. For thousands of years, men and women have created cosmetic products, from whatever raw materials were available, to help satisfy their fundamental human need for self- assurance and self-esteem. Modern industry has simply improved upon these . traditional product forms by making them far purer, safer, and more attractive than ever before. * Cosmetics are manufactured and distributed by companies which range from very small to very large. Cosmetic products are marketed through every form of retail channel, including retail stores, mail order, and door-to-door salespersons. Cosmetics cover a broad range of products, from perfume and lip- stick to deodorants, toothpaste, and shaving cream. Because many cosmetic products are oriented toward the fashion industry, they are, like fashion, subject to very rapid change. These product changes utilize well-recognized ingredients that have been used in hundreds of cosmetic products for years, and thus represent no significant change in the safety of the product. Cosmetic products have an enviable safety record. In September 1973, the panel on chemicals and~ health of the President's Science Advisory Committee issued a report published by the National Science Foundation which concluded with respect to cosmetics: From what may be judged human experience, the incidence of injury is small. In the total pattern of environmental risks, those from cosmetics are both in- frequent and slight. While there are no formal pretesting or preclearance requirements for cos- metics, the total effect of individual and informal review-usually private rather than governmental-together with the innocuousness of most materials used, has made the injury rate fairly low by comparison with other widely prevalent sources of hazard. It seems likely, though solid information is lacking, that the actual injury rate from cosmetics has declined, while the complaint rate has increased as a result of greater óonsumer awareness of the Food and Drug Administration as a regula- tory agency, and of the existence of legal and insurance remedies. Company records show that reactions to cosmetics are rarely serious and are almost invariably transient and reversible. We are unaware that any case of cancer has ever been shown to have been caused by any cosmetic. 24-600 0 - 78 - 7 PAGENO="0098" 92 Cosmetics were~ first included under Federal regulatory controls in the Federal Food, Drug, and Cosmetic Act of 1938. The legislative history of that act does not reveal, however, any general allegation that cosmetics as a whole had produced substantial consumer harm. It was recognized that some cosmetic products-like food, drugs, and all other consumer items-do on occasion produce al1er~ic re- actions. The legislative history clearly reveals Congress did not intend that cosmetic products or other consumer products be removed from the market because of these isolated reactions. Congress concluded that the benefits of cosmetics outweighed the risks caused by their use. The cosmetic provisions of the 1938 Act contain a broad array of legal sanctiOns under which FDA can protect consumers against potential harm from cosmetics. CTFA believes that these provisions are adequate, and that no additional legislation is necessary to protect the public. Regulatory action taken under the present law during the past few years readily demonstrates the breadth of present FDA authority over cosmetics. CTFA has not on any occasion instituted legal action to challenge the authority of FDA to undertake this typO of regulatory action. We have, on occasion, contested the factual basis for proposed action, but not the legal authority. Where there is an adequate factual basis for informing consumers about possible product hazards, for example, we have not opposed the action taken. A very brief review of some of the FDA regulations promulgated in the past few years will demonstrate that the agency does not lack the legal authority necessary to impose regulatory requirements where they are warranted. Under the Color Additive Amendments of 1960, FDA has enormous authority to require safety testing for all color ingredients. CTFA is now sponsoring carcinogenicity retesting for 10 color additives, as requfred by FDA. The FDA regulation requiring ingredient labeling for cosmetics is effective. The regulation requires that all retail cosmetic packaging list the ingredients in descending order of predominance with the exception of flavor and fragrance. It is more informative than food ingredient labeling because it requires specific designation of color ingredients, and is far more informative than drug ingredient labeling which requires declaration only of active ingredients. Any cosmetic which has not been adequately substantiated for safety prior to marketing is required by an FDA regulation to bear the warning statement that "the safety of this product has not been determined." In addition to these particular regulations, FDA has taken action under its general authority, to prevent the marketing of adulterated and misbranded products both through the requirement of recalls and by direct legal action in the courts. In short, there is no evidence that any product which has been shown to produce substantial harm to humans remains on the market today through lack of FDA regulatory authority. , . , CTFA strongly supports the concept of safety substantiation, firmly beliOving that it is the obligation of every manufacturer and dis- tributor not to market any cosmetic whhth has not been substantiated for safety. CTFA. has not challenged the legal authority of FDA to PAGENO="0099" 93 promulgate its regulation requiring safety substantiation, and has over the years established many programs designed to help industry meet its obligation to the public even before it became a legal require- ment. A brief summary of some of the more important CTFA pro- grams is as follows. CTFA inaugurated its scientific program 30 years ago with the establishment of analytical standards for ingredients commonly used in cosmetics. In the past 10 years it has formed scientific commit- tees of qualified experts to analyze and resolve scientific questions dealing with microbiology, pharmacology and toxicology, quality assurance, color safety, hair coloring, ingredient nomenclature, and a wide variety of other subjects. CTFA regularly develops and dissemi- nates standards for raw material specifications, testing methods, and ingredient descriptions, as well as technical guidelines to help insure the quality and safety of finished products. OTFA initiated and submitted three major petitions to FDA, on the basis of which FDA has promulgated regulations governing volun- tary registration of cosmetic product manufacturing plants, filing of cosmetic product formulas, and filing of cosmetic product experience reports. The following statistics reflect voluntary industry participa- tion in these three programs as of September 30, 1977. About 900 cosmetic plants have been registered with FDA, representing about 85 percent of the volume of cosmetics sold in the United States. Some 23,500 cosmetic formulas have been submitted to FDA, repre- senting about 80 percent of the volume of cosmetics sold in the United States. About 125 companies were participating in the product experience reporting program, representing about 50 percent of the volume of cosmetics sold in the United States. We believe that this voluntary program represents a major source of important informa- tion to FDA and to the public that would otherwise not be available, on which valid r~gulatory programs can be based. CTFA has submitted to FDA a petition requesting that FDA promulgate regulations governing goo4 manufacturin~ practices in making cosmetic products. We hope that FDA will publish a proposed regulation in the near future. CTFA has recently undertaken a major program to review the safety of cosmetic ingredients. All available published and unpub- lished data on individual ingredients will be compiled and submitted for review by an independent expert panel of eminent scientists. The expert panel members have been required to meet the same strict conflict.of-interest standards as are applied to members of Federal Government advisory committees. The review process is modeled directly after current FDA safety review programs, and includes a consumer liaison selected by consumer organizations, an industry liaison, and an FDA contact person. I am submitting for the record, the procedures that govern this review. We believe that it represents the most comprehensive and open safety review ever undertaken by private industry.. Mr. Moss. Without objection, it will be inserted in the record at * this point following your statement [see p. 97]. Mr. MERRITT. In response to the recent discovery reports that nitro- samiiies may be formed as contaminants in cosmetic ingredients or cosmetic products, OTFA immediately organized a program to PAGENO="0100" 94 refine and improve the detection methodology and to analyze common cosmetic ingredients to determine the source of any nitrosamine con- tamination. CTFA recognizes that nitrosamines serve no function in cosmetics and is committed to eliminating them or reducing them to the lowest level feasible. Nitrosamines do, of course, occur naturally in the human body and throughout our environment, and are found in air, water, and many other categories of consumer products. CTFA has carefully reviewed the recent allegation that certain hair dye ingredients are carcinogenic in test animals. On the basis of all of the available animal tests, and considering the many flaws in the National Cancer Institute test, we do not believe that allegation is scientifically supportable. We are' concerned `that NIOSH has chosen to rely on two epidemio- logical studies that have been severely criticized and has chosen to ignore the two definitive epidemiology studies in the field-the Amer- ican Cancer Society's study which covered 5,000 actual hairdressers and matched groups of 5,000 nonhairdressers, and the NCI-funded Yale University study which covered 12,000 hairdressers and, 12,000 school teachers. Both studies showed no link between hair dyes and cancer. For that reason, we believe that the totality of the available scienti- fic information does not support a warning to consumers. Certainly if any information is provided to consumers it should be presented in a complete and balanced way so that a fully informed choice can be made, and not by a cryptic warning that is designed more to scare consumers than to help them make a reasoned decision. The concern about hair dyes and the exemption for hair dyes in Section 601 (a) of the Act has been blown out of all proportion. Cer- tainly, before any action is taken by Congress to reconsider the statu- tory provisions for hair dyes the matter should be thoroughly re- viewed by an independent scientific body like the National Academy of Sciences. We listened very carefully to the testimony given Monday by the distinguished Director of the National Cancer Institute, Dr. Upton. We are in virtually complete agreement with the statements he made. Let me summarize his major points: One, the NCI bioassay program was not intended to, and does not, provide a definitive evaluation of the carcinogenic potential of hair dye ingredients in humans. It was intended as a screening test, and therefore used very high dose feeding levels. If a substance is not shown to be carcinogenic in the animal bioassay there need be no further concern about it; if it is shown to be carcinogenic in the animal bio- assay, it should be subjected to further testing and analysis in order to determine whether there is any human risk. Two, there is substantial scientific controversy, among qualiflçd experts, with respect to many important issues relating to animal testing for carcinogenicity: for example, wliiether high-dose levels overwhelm a test animal's detoxification defenses and therefore are not appropriate; whether animal data are reliable in predicting human risk; and whether there is a threshhold below which a proven car- cinogen will nonetheless have no effect. As to these scientific issues, the uncertainties are overwhelming. PAGENO="0101" 95 Three, the incidence of cancer in women in the United States is decreasing. If cancer of the lung-which NOT attributes primarily to smoking-is disregarded, this decrease is substantial. Four, the NOT bioassay studies are an insufficient scientific basis to justify banning any hair dye found to be carcinogenic in test ani- mals. The proper response to the possibility of risk from any con- sumer product is a "societal issue," not a scientific issue. What is prudent action for one consumer is not acceptable to all consumers. Consumers should have a right to determine, for themselves, the risks that they are willing' to accept. Banning any hair dye ingredient is going too far at this time. We join in Chairman Moss' concern about NOT's inability to re- lease the final reports on substances in the NOT bioassay testing pro- gram on an expeditious and consistent basis. All of the reports on hair dye substances should have been completed aTid released at the same time. This would then have permitted a more rational basis for action by both industry and FDA, the regulatory agency that must deal with this issue. One cannot consider reformulation of hair dyes, or the availability of alterntive ingredients, by approaching the matter on a piecemeal basis. CTFA fully supports the concept of the Interagency Regulatory Liaison Group. We will soon be recommending that the concept of classifying substances according to potential carcinogenic risk pro- posed by the Occupational Safety and Health Administration last October be expanded and applied to all of the regulatory agencies participating in the IRLG. A consistent and coordinated govern- mental policy in this area is essential to Government, consumer, labor, and industry interests alike. CTFA recognizes that, as science progresses, more and more ques- tions will be raised about all consumer products, including cosmetics. We feel that unwarranted regulator action will be taken on the basis of hypothetical concerns, without careful assessment of the actual risks involved and without adequate recognition of the benefits that the American public obtains from cosmetic products. To the vast majority of consumers, the contributions of cosmetics to self-assurance and self-esteem are as important as the nutritional and medical bene- fits of foods and drugs. We are in complete agreement with the suggestion made by Mr. GOre on Monday that the American people should be given a chart showing the various possible sources of cancer and the relative risks involved from each source. We would, indeed, expand this suggestion to show the various other sources of hazard-such as driving in auto- mobiles and flying in airplanes-and the relative risk that each of those entails. This would, for the first time, put the issue of risk in perspective. Consumers would have a basis for making fully informed choices. The cosmetic industry is confident that, faced with this risk informa- tion, consumers would be reassured about the relative safety of its products. We must all recognize that we do not live in a risk-free society. The risks that we all assumed in flying to Washington or driving to this hearmg are, in our opinion, far more certain than any hypothetical PAGENO="0102" 96 risk raised by cosmetic products. Indeed, the risks posed by cosmetics can be calculated to be far smaller than the risks associated with many other consumer products. We are convinced that any fair evaluation of all the available evidence shows that cosmetics do not present a substantial risk of harm to consumers. We believe taht both Congress and the general public recognize the value of cosmetic products and that unwarranted attempts at overregulation would be rejected by the Congress and the American people. Thank you, Mr. Chairman. We will attempt and endeavor to answer any questions you or any members of the subcommittee have or members of your staff have. [Testimony resumes on p. 121] [The review procedure referred to follows:] PAGENO="0103" 97 * Cosmetic Ingredient Review 1133 Fifteenth Street, NW., Suite 1275, WashIngton, D.C. 20005 * 202~-331-0651 COSMETIC INGREDIENT REVIEW * PROCEDURES REVISED (Includes amendments approved by CIR Steering Committee and C~FA Board of Directors as of December 20, 1976) PAGENO="0104" 98 COSMETIC INGREDIENT REVIEW PROCEDURES TABLE OF CONTENTS Part A - General 1 Sec. 1 - ~Definitions 1 Sec. 2 - Purpose of the Cosmetic Ingredient Review 2 Sec. 3 - Interpretation and Amendment of Procedures 2 Part B - The Cosmetic Ingredient Review Steering Committee and Staff . . . 2 Sec. 10 - Organization of the Cosmetic Ingredient Review 2 Sec. 11 - Separation and Independence of the Cosmetic Ingredient Review Staff from the CTFA Staff 3 Sec. 12 - Director 3 Sec. 13 - Administrator . 3 Sec. 14 - Scientific Coordinator 4 Part C - The Cosmetic Ingredient Review Expert Panel and Liaison Representatives 4 Sec. 20 - Members of the Expert Panel and Liaison Representatives . . 4 Sec. 21 - Nominations and Selection of Members of the Expert Panel. . 4 Sec. 22 - Selection of Liaison Representatives to the Expert Panel. . 5 Sec. 23 - Rights and Responsibilities of Liaison Representatives to the Expert Panel 5 Sec. 24 - Compensation of Expert Panel Members and Liaison Representatives 6 Sec. 25 - Chairman of the Expert Panel 7 Sec. 26 - Ex Parte Contacts with the Expert Panel 7 Sec. 27 - Compilation of Background Materials for Members of the Expert Panel and Liaison Representatives 7 Part D - The Cosmetic Ingredient Review Procedures 7 Sec. 30 - Compilation of Safety Data and Information and Review by the Expert Panel 7 Sec. 31 - Meetings of the Expert Panel 12 Sec. 32 - Additional Rules for the Expert Panel 13 Sec. 33 - Consultation by the Expert Panel with Other Persons . . . . 13 PAGENO="0105" 99 Sec. 34 - Portions of Expert Panel Meetings 13 Sec. 35 - Notice of Public Hearing and fleeting of the Expert Panel. . 14 Sec. 36 - Determination to Close Portions of Expert Panel Meetings. . 14 Sec. 37 - Administrative Remedies 15 Sec. 38 - Written Submissions to the Expert Panel 15 Sec. 39 - Conduct of a Public Hearing Before the Expert Panel . . . . 15 Sec. 40 - Minutes and Reports of Expert Panel Meetings 17 Sec. 41 - Transcripts of Expert Panel Meetings 17 Sec. 42 - Expert Panel Determinations 18 Sec. 43 - Tentative Report of the Expert Panel 18 Sec. 44 Final Report of the Expert Panel 18 Sec. 45 - Amendment of a Final Report 18 Part E - Public Notice and Availability of Records 19 Se~c. 50 - Public Notice 19 Sec. 51 - Availability of Records for Public Disclosure . 19 Sec. 52 - Public Documents Room 20 Sec. 53 - Public Inq~uiries and Requests for the Cosmetic Ingredient Review Records 21 PAGENO="0106" 100 COSMETIC INGREDIENT REVIEW PROCEDURES Part A -- General Section 1. Definitions. (a) "Act". means the. Federal Food, Drug, and Cosmetic Act. (b) "Cosmetic' means (1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles; except that it shall not include soap. (C) "Cosmetic ingredient" means any chemical substance used as a component ib the manufacture of a cosmetic product, but shall not include a proprietary mixture. (d) "Cosmetic product" means a finished cosmetic the manufacture of which has been completed. (e) "Commercial distribution" of a cosmetic product means annual gross sales J4~ excess of $1,000 for the product. (f) "Chemical description" means a concise definition of the chemical composition using standard chemical nomenclature so that the chemical structure or structures of the components of the ingredient would be clear to a practicing chemist, When the composition cannot be described chemically, the substance shall be described in terms of its source and processing. - (g) "Flavor" means any natural or synthetic substance or substances used solely to impart a taste to a cosmetic product. (h) `Fragrance' means any natural or synthetic substance or substances used solely to impart an odor to a cosmetic product. (i) "Cosmetic Ingredient Review" means the Cosmetic Ingredient Review pro- gram conducted pursuant'to these procedures. (j) "CTFA' means The Cosmetic, Toiletry and Fragrance Association, Inc. (k) "Director' means the Director of the Cosmetic Ingredient Review, who shall have the authority and responsibilities established in Section 12 of these procedures. (1) "Administrator' means the Administrator of the Cosmetic Ingredient Review, who shall have the authority and responsibilities established in Se~tion 13 of these procedures. (m) `Scientific Coordinator' means the Scientific Coordinator of the Cosmetic Ingredient Review, who shall also be the Executive Secretary of the Expert Panel, who shall have the authority and responsibilities established in Section 14 of these procedures. (n) `Expert Panel" means the Cosmetic Ingredient Review Expert Panel, which shall be established and shall have the authority and responsibilities established in Part C of these procedures and shall conduct the Cosmetic Ingredient Review program in accordance with the procedures established in Part D of these proce- dures. PAGENO="0107" 101 - 2~ (0) "Executive Secretary" means the Executive Secretary of the Expert Panel, who shall be the Scientific Coordinator and shall have the authority and responsi- bilities established in Section 14 of these procedures. (p) "Safe" or "safety" means ho evidence in the available information that demonstrates or suggests reasonable grounds to suspect a hazard to the public under the conditions of use that are now current or that might reasonably be expected in the future, ~ a low incidence of minor adverse reactions (as shown in animal or human testing or product experience). Such information includes, but is not limited, to, the chemical structure of the ingredient, published and unpublished tests on the ingredient and products containing the ingredient, signi- ficant human experience on products containing the ingredient during marketing, and information on similar o.r related substances. A lack of information about an ingredient shall not be sufficient to justify a determination of safety. (q) "Conditions of use" for an ingredient or product include (1) the amount of an ingredient used in a product, (2) the intended and reasonably foreseeable areas of use (fj~, use that is subject to ingestion or inhalation or contact with mucous membranes or is in the area of the eye), and (3) directions for use and against misuse in labeling. Section 2. Purpose of the Cosmetic ingredient Review. The purpose of the Cosmetic Ingredient Review is to determine those cosmetic' ingredients for which there is a reasonable certainty in the judgment of competent scientists that the ingredient is safe under its conditions of use. ~ption 3. interpretation and Amendment of Procedures. (a) if any dispute arises as to the proper interpretation or application of these procedures, a majority vote of the Steering Committee shall be final and binding with respect to such matter. (b) These procedures may be amended by a two-thirds vote of the Steering Committee, .Vith the approval of the CTPA Board of Directors. The Administrator shall give public notice of any amendment of these procedures. Part B -- The Cosmetic Ingredient Review Steering Committee and Staff Section 10. Organization, of, the Cosmetic Ingredient Review. (a) General policy and dIrection for the Cosmetic ingredient ~eview shall be given by a Steering Committee., A quorum of the steering Committee shall consist of three members. Any matter before the Steering Committee shall be decided by a majority vote of the mmmbers present at the time except where other- wise specifically provided in these procedures. T)~e steering Committee shall consist of the following members: (1) The President of CTPA, who shall serve as the Chairman of the Steering Committee. (2) A dermatologist, who shall represent the American Academy of Dermatology. (~) A toxicologist, who shall represent the Society of Toxicology. (4) The Chairman of the CTFA Scientific Adivso'ry Committee. (5) The CTFA Vice President for Science. PAGENO="0108" 102 (b) The Cosmetic Ingredient Review staff shall consist of a Director, who shall report to the Cosmetic Ingredient Review Steering Committee, and the Administrator and the Scientific Coordinator, who shall report to the Director. The Director, Administrator, and Scientific Coordinator may in turn utilize such other personnel as is necessary and appropriate to carry out their authority and responsibilities established in Sections 12-14 of these procedures. Section 11. Separation and Independence of the Cosmetic Ingredient Review Staff from the CTFA Staff. (a) The Cosmetic Ingredient Review staff shall be employees of or consul- tants to CTFA but shall be separate and independent from the CTFA staff. No person on the Cosmetic Ingredient Review staff may also serve on the CTFA staff. The Cosmetic Ingredient Review staff may obtain supplies and services through the central facilities of CTFA. Contact between the Cosmetic Ingredient Review staff and the CTFA staff shall be kept to the minimum n~ecessary to conduct the affairs of the Cosmetic Ingredient Review efficiently and effectively. CTFA staff shall be treated by the Cosmetic Ingredient Review staff the same as any other member of the public ~ all CTFA staff shall sign the visitors log when visiting the Cosmetic Ingredient Review offices). (b) The Cosmetic Ingredient Review staff shall follow all personnel policies and procedures established in the CTFA Procedures Manual, except that the Director shall be responsible for all required approvals within the authority granted to him under Section 12 of these procedures. Section 12. Director. (a) The Director shall be appointed by the CTFA President, with the ap- proval of the Chairman of the CTFA Board of Directors and the Chairman of the CTFA Scientific Advisory Committee. (b) The Director shall hire and direct the activities of the Cosmetic Ingredient Review staff in order to implement these procedures effectively and efficiently. The Director shall report to and be subject to the direction and control of the Steering Committee with respect to policy and budget within the following limitations: (1) The CTFA Board of Directors shall determine the budget and per- sonnel limits for the Cosmetic Ingredient Review. (2) The Steering Committee shall periodically review all Cosmetic Ingredient Review expenditures ~ document reproduction, Communications, accounting, and office space expenditures) to determine that they are within the budget. (3) All Cosmetic Ingredient Review contracts and capital expenditures shall be reviewed and approved by the Steering Committee prior to execution. (4) All Cosmetic Ingredient Review office supplies shall be obtained through CTFA central purchasing unless otherwise approved by the Steering Com- mittee. / (c) The Administrator or Scientific Coordinator may simultaneously serve as the Acting Director in the absence of the Director, or as the Director. Section 13. Administrator: The Administrator, under the direction of the Director, shall have authority and responsibility for daily administration of the Cosmetic Ingredient Review staff and Expert Panel. This shall include receipt of all documents submitted by any interested person with respect to the Cosmetic Ingredient Review, distribution of all data and infotmation to the Expert Panel, arranging for all aspects of the PAGENO="0109" 103 -4- meetings of the Expert Panel, including public notice thereof~ serving as secre- tary to the Steering Committee, and all similar administrative functions. Section 14. scientific Coordinator. The Scientific Coordinator, under the direction of the Director, shall have authority and responsibility to perform all of the scientific functions of the Cosmetic Ingredient Review staff~(including, but not limited to, the information science function and obtaining all necessary Scientific Literature Reviews) and of the Expert Panel (including,but not limited to,preparing minutes of all Meetings, drafting scientific position papers, and otherwise serving as Executive Secretary to the Expert Panel). Part C - The Cosmetic Ingredient Review Expert Panel and Liaison Representatives Section 20. Members of the Expert Panel and Liaison Representatives. (a) Members of the Expert Panel shall possess the following qualifications: (1) Members shall possess expertise relevant to the review of the safety of cosmetic ingredients. They shall have diverse professional education, training, and experience so that the Expert Panel will reflect a balanced composi- tion of sufficient scientific expertise to handle the issues that come before it. (2) Members shall be required to meet the same conflict of interest standards as are applicable under Federal law to special government employees. (3) Liaison representatives shall be selected by the interested organizations as provided in Section 22 of these procedures. Technical expertise with the subject matter with which the Expert Panel is involved shall not be a requirement. (b) Members appointed to the Expert Panel and liaison representatives shall continue to serve for the duration of the Expert Panel or until they resign or are removed from membership for cause by the Steering Committee. Cc) An Expert Panel member may be removed from membership by the Steering Committee for good cause. Good cause shall include but not be limited to exces- sive absenteeism from Expert Panel meetings, a demonstrated bias which interferes with the ability to render objective advice, or failure to abide by these proce- dures. Cd) There shall ordinarily be seven members of the Expert Panel, each mem- ber having an equal vote. The Expert Panel shall begin to function, and may continue to function, as long as there are not less than five members. Section 21. NominatiOns and Selection of Members of the Expert ne]. Ca) The Administrator shall give public notice requesting nominations for members of the Expert Panel. The notice shall invite the submission of nomina- tions for members from any interested individual as well as from consumer, industry, and professional organizations, within 90 days of such notice. (b) Any interested person may nominate one or more qualified person(s) as a member of the Expert Panel. Nominations shall include a complete curriculum vitae of the nominee, and shall state that the nominee is aware of the nomination, is willing to serve as a member of the Expert Panel, and appears to have no conflict of interest which would preclude membership on the Expert. Panel. Cc) Members of t'he Expert Panel shall serve as individuals and not as representatives of any group or organization which nominated them or with which they may be affiliated. PAGENO="0110" 104 (d) The Steering Committee shall appoint the members of the Expert Panel from among those who have been nominated. Appointment shall be decided by a four-fifths vote of all current members of the Steering Committee. Appointment shall be on the basis of scientific competence, expertise in an area relevant to the Cosmetic Ingredient Review, balance of scientific disciplines within the Expert Panel, willingness to devote sufficient time and energy to the review, and the lack of any disqualifying conflict of interest. (a) All data and information relating to the nomination and selection of the members of the Expert Panel shall be maintained by the Administrator in a confidential file. (f) Vacancies in the membership of the Expert Panel shall be filled by the Steering Committee either from prior nominations or in the same way that members are initially nominated and selected. Section 22. Selection of Liaison Representatives to the Expert Panel. (a) The Administrator shall request that each of the following interests designate a liaison representative to the Expert Panel: (1) The Food and Drug Administration, in accordance with the provi- sions of proposed 21 C.F.R. 2.21(d). (2) Organizations representing consumer interests. (3) CTFA. (b) Liaison representatives to the Expert Panel shall be limited to three persons, one representing each of the listed interests. Those interests may, however, designate different liaison representatives for purposes of the review of different categories of cosmetic ingredients or similar considerations. At no time may there be more than one liaison representative to the Expert Panel from any one of the interests listed in Section 22(a) of these procedures with respect to any specific cosmetic ingredient. (C) Because liaison representatives for government, consumer, and industry interests have no vote, their selection shall be solely by the interests they represent and shall be without regard to the conflict of interest principles for special government employees that are applicable to the members of the Expert Panel. (~) Vacancies in the liaison representatives to the Expert Panel shall be filled in the same way that liaison representatives are initially selected. Section 23. Rights and Responsibilities of Liaison Representatives to the Expert Panel. (a) A liaison representative to the Expert Panel selected to represent and serve as a liaison with interested individuals, associations, and organizations, shall haVe the same rights as members of the Expert Panel except that: (1) A liaison representative shall not vote on any matter before the Expert Panel. (2) A liaison representative shall not have access to confidential data and information that are not availakle for public disclosure pursuant to Section 51(b), of these procedures. Accordingly, a liaison representative shall not be present at any portion of an Expert Panel meeting which is closed for the presentation of confidential data pursuant to Section 34(c) or the discussion of confidential data pursuant to Sections 34(d) and 36(b) (2) of these procedures which are prohibited from public disclosure pursuant to Section 51(b) of these procedures. PAGENO="0111" 105 -6- (b) A liaison representative of the Expert Panel is subject to, and shall abide by, all aspects of these procedures and any rules and regulations adopted by the Expert Panel pursuant to Section 32 of these procedures. Cc) It is the responsibility of the liaison representatives to the Expert Panel to represent the government, consumer, and industry interests in all delib- erations. (1) The consumer and industry liaison representative does not repre- sent any particular organization or group, but rather represents a]). interested persons within the class which he is selecteâ to represent. Accordingly, any in- terested person within the class represented by that liaison representative shall have access to all written statements or oral briefings related to the Expert Panel prepared by the liaison representative for distribution to any person out- side the Expert Panel. (2) Liaison representatives shall review all official Expert Panel minutes to assure their completeness and accuracy. (3) The liaison representative shall act as a liaison with and con- duit between the Expert panel and the interested persons whom he represents, and shall transmit requests for information from the Expert Panel and relevant data, information, and views to the Expert Panel. He shall take the initiative in con- tacting interested persons whom he represents, to seek out relevant data, infor- mation, and views, and to relate the progress of the Expert Panel. (4) The industry liaison representative shall represent all members of the industry, and not any particular association, company, product, or ingredi- ent. Ii a matter comes before the Expert Panel that directly or indirectly affects the company which employs the industry liaison representative, he need not absent himself during the discussion or c~ecline to participate in the dis- cussion. The industry liaison representative shall not discuss his company's position as such, but may discuss any matter in general terms. All presentations and discussions of scientific data and their interpretation on behalf of a com- pany shall occur in open session, except as provided in Section 34(c) of these procedures. (5) A liaison representative to the Expert Panel shall not make any presentation to the Expert Panel during a hearing conducted by the Expert Panel. (6) Although a liaison representative is serving in a representative capacity, he shall exercise restraint in performing his functions and shall not engage in unseemly advocacy or attempt to exert undue influence over members of the Expert Panel. Cc) A liaison representative to the Expert Panel may be removed by the Steering Committee for failure to comply with the provisions of this section or the other sections of these procedures. Zn the event of removal of a liaison representative, the interests which he has represented shall be requested to select a new liaison representative. Section ~4. CompensatiOn of Expert ?anel ~embe~. (a) All members of the Expert Panel and liaison representatives shall receive a consultant fee of $400 per day and be reimbursed for their travel expenses and all Other out-of-pocket expenses, unless such compensation and reim- bursement is waived. (b) An Expert Panel member or liaison representative notwithstanding his primary residence, while in attendance at meetings of the Expert Panel, will be paid whether the meetings are held in his city of residence or elsewhere. Cc) An Expert Panel member or liaison representative who participates in a specific assignment for the Expert Panel, at the request of the Cosmetic PAGENO="0112" 106 Ingredient Review, will be paid at an hourly rate of $50 when he perfotms his work at home, place of business, or elsewhere, and at a daily rate when he is required to travel outside of his commuting area to perform his assignment. An Expert Panel member or liaison representative will not be paid for time spent on normal preparatiofi for a meeting of the Expert Panel. Cd) Salary while in travel status is authorized when an Expert Panel member or liaison representative has his ordinary pursuits interrupted for the substan- tial portion of an additional day beyond the day or days on which he performs services, and as a consequence he sustains a loss in his regular compensation. This applies on weekends and holidays~ if the Expert Panel member or liaison repre- sentative suffers a loss in income he would otherwise earn on that day. For travel purposes, a substantial portion of a day is defined as 50 percent of the working day, and the traveller will be paid at a daily rate. Section 25. Chairman of the Expert Panel. (a) The Steering Committee shall selecit a Temporary Chairman of the Expert Panel from among the members, who shall serve as the Temporary Chairman for the initial organizational meetings. Thereafter, the Expert Panel shall determine its own Chairman from among the members, who may serve on a permanent or on a rotating basis. (b) The Expert Panel Chairman shall have the authority to conduct hearings and meetings, including the authority to adjourn any hearing or meeting whenever he determines adjournment to be advisable, to discontinue disccnssion of a parti- cular matter, to conclude the open portion of a meeting in accordance with Section 36 of these procedures, or to take any other action in furtherance of a fair and expeditious hearing or meeting. Section 26. Ex Parte Contacts With the Expert Panel. (a) There shall be no cx parts Oontacts between the members of the Expert Pat~iel and anyone other than a liaison representative to the Expert Panel or a member of the Cosmetic Ingredient Review staff with respect to any matter relating to the Cosmetic Ingredient Review, except that: (1) The Steering Committee may meet with the Expert Panel or any members thereof or any liaison representatives to discuss the work of the Expert Panel. (2) A member of the Expert Panel may, in his discretion, initiate discussions with any other scientist for the purpose of obtaining data, infor- mation, or views with respect to any scientific issue. (b) If any person initiates an cx parte contact with a member of the Expert Panel other than as permitted by paragraph (a) of this section, such member shall refer such person to the Cosmetic Ingredient Review staff for advice on the pro- cedures for submission of data, information, and views to the Expert Panel. Section 27. Compilation of Background Materials for Hembers of the Expert Panel jand Liaison Representatives. The Administrator shall prepare and provide to Expert Panel members and liaison representatives a complete compilation of background materials bearing upon their duties and responsibilities. Part D -- The Cosmetic Ingredient Review Procedures Section 30. Compilation of Safety Data and Information and Review by the Expert - Panel. (a) The Steering Committee shall develop a tentative priority list(s) for the systematic review of all cosmetic ingredients presently used in commercially distributed cosmetic products. This tentative priority list(s) shall be based PAGENO="0113" 107 upon the frequency of use (i.e., the number of different products in which an ingredient is used), availakUityof chemical specifications or descriptions, any known questions about safety, and the availability of sufficient data and information for the Expert Panel to make an informed scientific judgment on safety. (1) For those cosmetic ingredients for which no particular priority can be established, their priority shall be determined by a statistically reliable randomization. (2) For those cosmetic ingredients which are also subject to other existing safety reviews, their inclusion and priority shall be determined pursuant to paragraph (i) of this section. (b) The tentative priority list(s) shall be made publicly available and 90 days will be provided for public comment on it. (c) The Expert Panel shall review the tentative priority list(s) and all comments received on it, make any revisions it concludes appropriate, and adopt a final priority list(s). The final priority list(s) shall determine the `order in which cosmetic ingredients are reviewed under the Cosmetic Ingredient Review. The Expert Panel may at any time revise the final priority list(s) either to add new ingredients or to revise the priority of existing ingredients. (d) On the basis of the tentative and final priority list(s) the Scientific Coordinator shall develop or obtain Scientific Literature Reviews for each cos- meti~ ingredient (or, where appropriate, closely related groups of cosmetic ingredients), which shall consist of a bibliography of the domestic and foreign toxicological literature and any other major domestic and foreign scientific literature, a description of each literature reference, and a summary of the information found for each ingredient. (1) The Scientific Coordinator may either contract for the preparation of each Scientific Literature Review or prepare it himself. (2) As soon as it is available, each Scientific Literature Review will be made public and 90 days will be provided for public comment on it. (3) If the Scientific Coordinator concludes that there is insufficient scientific literature to justify the preparation of a Scientific Literature Review, the Administrator shall give public notice that no Scientific Literature Review will be prepared for the ingredient involved. (e) Upon the public notice of the availability of a Scientific Literature Review, or that no Scientific Literature Eeview will be prepared, all interested persons will be provided 90 days to submit to the Administrator data, information, and views relevant to the safety of the cosmetic ingredient involved. A person may submit any particular piece of information without identifying the source of that information. To be considered, ten copies of the data and views,shall be submitted, preferably bound, indexed, and on standard size paper (approximately 8 1/2 by 11 inches). All submissions shall be in the following format: COSMETIC INGREDIENT REVIEW INFORMATION I. The CTPA adopted name(s) and tradename(s) of the cosmetic ingredient(s) involved, the name of the manufacturer, and if it does not meet the specifications in any of the information sources designated in the CTFA Cosmetic Ingredient Dictionary a statement to that effect and the specifications that are applicable. II. Comments, if any, on the completeness and accuracy of the Scientific Literature Review for the ingredient. III. A statement setting forth the number of products con- taining the ingredient manufactured or distributed by the person 24-600 0 76 - 6 PAGENO="0114" 108 making the submission, and the pertinent letter for each indica- ting the range of the concentration of the ingredient for each product, as is shown in the information submitted to the Food and Drug Administration on Form FD-2512 (Cosmetic Product Ingredient Statement), 21 C.F.R. 720.4(d) (1). IV. Animal safety data. A. All animal safety data not included in the Scientific Literature Review on the individual cosmetic ingredient. B. All animal safety data not included, in the Scientific Literature Review on combinations of the individual Cosmetic ingredient. C. All animal safety data not included in the Scientific ~.iterature Review on cosmetic products or other products con- taining the individual cosmetic ingredient as one component. V. Human safety data (including exposure during clinical testing, in occupational settings, and through product use). A. All human safety data not included in the Scientific Literature Review on the individual cosmetic ingredient. B. All human safety data not included in the Scientific Literature Review on combinations of the individual cosmetic ingredients. C. All human safety data not contained in the Scientific Literature Review on cosmetic products or other products con- taining the individual cosmetic ingredient as one component, including results of significant human experience during marketing. Such data may include relevant Forms FD-2704 (Cosmetic Product Experience Report), FD-2705 (Cosmetic Product Unusual Experience Report), and FD-2706 (Summary Report of Cosmetic Product Rxperi- ence by Product Categories), 21 .C.F.R. Part 730. VI. Other Relevant Safety Information. VII. Conditions of use. A. A statement that the ingredient is or is not used in a cosmetic which falls into the following general use classifi- cations. 1. Eye area use. 2. Subject to incidental ingestion. 3. Subject to incidental inhalation. 4. Mucous membrane use. 5. All other uses ~ skin, hair, and nails). B. A statement indid~t'ing the use classifications for each of the products in which the ingredient is used by the manufac- turer or distributor, as specified iTt Food and Drug Administra- tion Form FD-25l2 (Cosmetic Product Ingredient Statement), 21 C.F.R. 720.4(c). C. Information on any other relevant conditions of use ~ directions for use an4 against misuse). VXII. A summary of the data and views setting forth the rationale for the conclusion that the ingredient is or is not safe for its intended use. (f) Upon the public notice of the availability of a Scientific Literature Review, CTFA and any other interested person may submit to the Administrator a chemical description of the ingredient involved, if one is available. (g) Upon expiration of the time permitted for receipt of all of the perti- nent data and information, the Scientific Coordinator shall prepare a final PAGENO="0115" 109 - 10 - compilation of relevant data and information for presentation to the Expert Panel. That compilation shall include: (1) The Scientific Literature Review. (2) All comments received on the Scientific Literature Review. (3) All submissions of data and information not con- tained in the Scientific Literature Review. (4) All chemical descriptions submitted. (h) The Expert Panel may, in its discretion, accept late submissions and new data relating to any ingredient at any time prior to its tentative report on that ingredient. (i) To minimize duplication of effort, the inclusion and priority of cog- * metic ingredients which are also subject to other existing safety reviews shall be * deterznined as fàllows except with respect to any specific ingrèd~ent fot which the Expert Panel, with the approval of the Steering Committee, has assigned a special priority for good cause. (1) Color Additives. All color additives shall be excluded from the Cosmetic Ingredient Review because their safety is determined under Section 706 of the Act and 21 C.F.R. Parts 8 and 9. (2) OTC Drug Active Ingredients. The Expert Panel shall defer evalu- ation of a cosmetic ingredient which is also used as an active ingredient in an OTC drug, and thus is subject to review under t1~e Food and Drug Administration OTC drug review established in 21 C.F.R. Part 330, until after the final monograph for the relevant OTC drug Category (or, if there is more than one, the last rele- vant OTC drug category) is published by the Food and~flrug Administration pursuant to 21 C.F~.R. 330.10(a) (9) and shall then determine whether all safety information relevant to cosmetic use of the ingredient was available to the OTC drug review and whether the cosmetic ~se of the ingredient presents any additional safey con- siderations not adequately covered by the OTC drug review. The Expert Panel shall adopt those conclusions of the OTC 4rug review which it concludes adequately cover cosmetic use of the ingredient and shall conduct its own evaluation of those cos- metic uses not adequately covered by the OTC drug review. (3) Food Flavors. The Expert Panel shall defer evaluation of a cos- metic flavor ingredient which is also used as a flavor in food, and thus is sub- ject to review under the FASEB-FDA review of flavor ingredients which are GRAS or food additives described in ~art II of the Federal Register of July 26, 1973 (38 F.R. 20036 et seq.) and Part II of the Federal Register of September 23, 1974 (39 F.R. 34172 et seq.), until after the final regulation for the ingredient is published by the Food and Drug Administration and shall then determine whether all safety information relevant to cosmetic use of the ingredient was available to the FASEB-FDA review and whether the cosmetic ~ise of the ingredient presents any additional safety considetations.not adequately covered by the FASEm-FDA review. The Expert Panel shall adopt those conclusions of the FASEB-FDA review which it concludes adequately cover cosmetic use of the ingredient and shall conduct its own evaluation of those cosmetic uses not adequately covered by the FASEB-FDA review. (4) GRASFood Ingredients. The Expert Panel shall defer evaluation of C Cosmetic ingredient which is also used as an ingredient in a food on the basis that it has been determined to be GRAS or subject to a prior sanction, and thus is subject to review under the FASEB-FDA review described in Part TI of the * Federal Register for July26, 1973 (38 F.R. 20036 et seq.) and Part II of the Federal Register for September 23, 1974 (39 F.R. 34172 et seq.), until after the final regulation is promulgated for the ingredient by the Food and Drug Ad~ini- stration and shall then determine whether all safety information relevant to PAGENO="0116" 110 - 11 - cosmetic use of the ingredient was available to the FASEB-FDA review and whether the cosmetic use of the ingredient presents any additional safety considerations not adequately covered by the FASEB-FDA review. The Expert Panel shall adopt those conclusions of the FASEB-FDA review which it concludes adequately cover cosmetic use of the ingredient and shall conduct its own evaluation of those cosmetic uses not adequately covered by FASEB-FDA review. (5) Food Additives. In evaluating a cosmetic ingredient which is also used as a food additive, and thus is subject to a food additive regulation pro- mulgated by the Food and Drug Administration in 21 C.F.R. Part 121, the Expert Panel shall review the food additive petition and all related documents which the Food and Drug Administration makes available to determine whether all safety infor- mation relevant to cosmetic use of the ingredient was available to the Food and Drug Administration and whether the cosmetic use of the ingredient presents any additional safety considerations not adequately covered by the Food and Drug Administration approval of the food additive regulation. The Expert Panel shall adopt those conclusions of the Food and Drug Administration approval which it concludes adequately cover cosmetic use of the ingredient and shall conduct its own evaluation of those cosmetic uses not adequately covered by the Food and Drug Administration approval. (6) Fragrance Ingredients. All fragrance ingredients shall be exclud- ed from the Cosmetic Ingredient Review because their safety is being determined by the Research Institute for Fragrance Materials (RIFM). (7) Food and Drug Administration Regulations. All matters which are the subject of a final regulation promulgated by the Food and Drug Administration shall be excluded from the Cosmetic Ingredient Review. (8) New Drug Applications. In evaluating a cosmetic ingredient which is also used as an inactive or active ingredient in an OTC or prescription drug for which the Food and Drug Administration has at any time approved or permitted to become effective a New Drug Application, the Expert Panel shall review all related documents which the Food and Drug Administration makes available to determine whether all safety information relevant to cosmetic use of the ingredi- ent was available to the Food and Drug Administration and whether the cosmetic use of the ingredient presents any additional safety considerations not adequately covered by the Food and Drug Administration action on the New Drug Application. The Expert Panel shall adopt those conclusions of the Food and Drug Administration action which it concludes adequately cover cosmetic use of the ingredient and shall conduct its own evaluation of those cosmetic uses not adequately covered by the Food and Drug Administration action. (j) An ingredient shall be reviewed in accordance with the priority assigned to it pursuant to this section. - (1) Upon presentation of all pertinent data and information to the Expert Panel pursuant to paragraph (g) of this section, an ingredient shall be considered to be under review by the Expert Panel. An ingredient shall remain under review by the Expert Panel until the Expert Panel issues a final report on it pursuant to Section 44 of these procedures. (2) If the Expert Panel concludes that the available data and infor- mation are insufficient to determine such ingredient, under each relevant condi- tion of use, as either safe or not safe, it shall decide the type of further data or information required and the time period within which it might reasonably be obtained. Any such decision shall be set forth fully in the minutes of the Expert Panel meeting. (A) Upon the public availability of the minutes of any such meeting pursuant to Section 51 of these procedures, the Administrator shall give public notice of any such decision. (B) Within 90 days after such public- notice, any interested person may inform the Expert Panel that work adequate and appropriate to resolve the questions raised about the ingredient will be undertaken. PAGENO="0117" 111 - 12 - (C) A progress report on any work undertaken pursuant to such a commitment shall be filed with the Cosmetic Ingredient Review every January 1 and July 1 until completion. (0) if such a commitment is undertaken, the ingredient shall remain under review by the Expert Panel and the Expert Panel shall defer prepara- .tion of a tentative report pursuant to Section 43 of these procedures and a final report pursuant to Section 44 of these procedures until completion of the work involved, unless the Expert Panel determines that the work is not being pursued promptly and diligently or that interim results indicate a reasonable likelihood that a health hazard exists. (E) upon completion of the work undertaken pursuant to such a commitment, the Expert Panel shall review all available data and information and shall issue a tentative report pursuant to Section 43 of these procedures and a final report pursuant to Section 44 of these procedures. (3) If the Expert Panel determines pursuant to paragraph (j) (2) of this section that the available data and information are insufficient to determine such ingredient, under any specific condition of use, as either safe or not safe, and no one undertakes the work to obtain the required data and information in accordance with paragraph (j) (2) of this section, the Expert Panel shall determine that there is a lack of information needed to make a determination and insuff i- cient industry interest in the ingredient at that time to justify obtaining the needed information and shall issue a tentative report pursuant to Section 43 of these procedures and a final report pursuant to SeCtion 44 of these procedures. Section 31. Meetings of the Expert Panel. (a) The Expert Panel will meet as gften and for as long as is appropriate to review the data submitted to it and to prepare a report containing its con- clusions and recommendations with respect to the safety of cosmetic ingredients. (b) The Expert Panel shall co~ivene at the call of the Chairman. The Administrator shall be responsible for giving appropriate notice to all Expert Panel members and liaison representatives for distributing all pertinent infor- mation, for all travel and meeting arrangements, and for similar administrative support. (c) All Expert Panel meetings shall be held in Washington, D.C., or the immediate vicinity, unless there are compelling reasons for a different location. A different location may be approved by the Steering Committee for good cause. (d) The Expert Panel may,, with the approval of the Steering Committee, con- duct on-site visits relevant to the work of the Expert Panel. (a) A quorum for the Expert Panel shall be five members of the Expert Panel. Any matter before the Expert Panel shall be decided by a majority vote of the members present at the time, except that any final report shall be voted upon by all current members of the Expert Panel. Any current member of the Expert Panel may file a Separate report with additional or minority views. (f) Subject to availability of space, any interested person may attend any portion of any Expert Panel meeting which is not closed. (g) Any portion of a meeting shall be closed by the Expert Panel Chairman when matters which have been determined closed in accordance with Section 36 of these procedures are to be discussed. Where a portion of the meeting is closed, the closed portion shall be held after the conclusion of the open portion when- ever practicable. (h) Any Expert Panel member or liaison representative may take notes during Expert Panel meetings and report and discuss the deliberations of the Expert Panel PAGENO="0118" 112 - 13 - after a meeting is completed and before official minutes or a report is available, within such rules and regulations as are adopted by the Expert Panel in accordance with Section 32 of these procedures. (1) There shall be no attribution of individual views expressed in a closed session or revealing of numerical votes. (2) There shall be no reporting or discussion with respect to any particular matter where the Expert Panel specifically so directs, ~ where deliberations are incomplete or involve a sensitive decision whichih~uld not be released prematurely. (3) There shall be no reporting or disclosure with respect to data or information prohibited from public disclosure pursuant to Section 51(b) of these procedures. (4) Any notes or minutes kept or report prepared by any Expert Panel member or liaison representative shall have no status or effect whatever unless adopted as or incorporated into the official minutes or report by the Expert Panel. It shall be the responsibility of each Expert Panel member and liaison representa- tive to make certain that the official minutes and reports are complete and accurate and fully reflect what happened at any meeting he attended. Section 32. Additional Rules for the Expert Panel. (a) In addition to the rules established in these procedures, the Expert Panel may, with the concurrence of the Steering Committee, adopt additional rules which are not inconsistent with these procedures. (b) Such additional rules shall be included in the minutes of the meeting when adopted and in the materials compiled pursuant to Section 27 of these pro- cedures and shall be available for public disclosure pursuant to Section 51(a) of these procedures. Section 33. COnsultation by the Expert Panel with Other Persons. (a) The Expert Panel may consult with any person who may have data, infor- mation, or views relevant to any matter pending before the Expert Panel and, with the approval of the Director, may compensate such person and reimburse his expenses. (b) Any interested person may submit to the Expert Panel a written request that it consult with specific persons who may have data, information, or views relevant to any matter pending before the Expert Panel. Such requests shall state why the specified person should be consulted and, if payment is requested, why the views of that person cannot reasonably be furnished to the Expert Panel by any other means. The Expert Panel, may, in its discretion deny or grant such a request and, if payment is requested, with the approval of the Director, may compensate such person and reimburse his expenses. Section 34. Portions of Expert Panel Meetings. An Expert Panel meeting shall have the following separable portions: (a) The open public hearing. Every Expert Panel meeting shall include an open portion which shall constitute a public hearing during which any interested person may present data, information, or views, orally or in writing, relevant to the Expert Panel's agenda or other work. Such hearing shall be conducted in accordance with Section 39 of these procedures. PAGENO="0119" 113 - 14 (b) The open panel discussion. The Expert Panel shall discuss any matter pending before it in an open portion of its meeting unless the meeting has been closed with respect to that matter pursuant to Section 36 of these procedures. No public participation is permissible during the open panel discussion portion of the meeting except with the consent of the Chairman of the Expert Panel. (c) The closed presentation of data. Data~ and information which are pro- hibited from public disclosure pursuant to the provisions bf Section 51(b) of these procedures shall be presented to the members of the Expert Panel in a closed portion of its meeting. (d) The closed panel deliberations. Deliberations with respect to matters pending before the Expert Pane~. may b& made in a closed portion of its meeting upon an appropriate determination by the chairman pursuant to Section 36 of these procedures. Section 35. Notice of Public Hearing and Meeting of the Expert Panel. (a) At least fifteen days before any meeting of the Expert Panel, the Administrator shall give public notice of such meeting. (b) Such notice shall include: (1) The date, time, and place of the hearing and meeting. (2) A list of all agenda items. (3) If any portion of the meeting is closed, a statement of the time of the open and closed portions. (4) The time specifically set aside for oral statements by interested persons and for other public participation. (5) The name, address, and telephone number of the persons specif i- cally responsible for the administrative support for that hearing and meeting. (6) A statement that written submissions may be made to the Expert Panel at any time pursuant to Section 38 of these procedures. Section 36. Determination to Close Portions of Expert Panel ~4eetings. (a) No Expert Pane~1. meeting shall be entirely closed unless no one requests an opportunity to make a presentation at the open portion for public participation. A portion of an Expert Panel meeting may be closed only pursuant to a determina- tion by the Chairman, reflected in the minutes of the meeting, in accordance with this section. (b) The following rules shall govern the closing of a portion of an Expert Panel meeting: (1) Any determination to close a portion of a meeting shall restrict such closing to the shortest time possible consistent with the policy established in this section. (2) Portions of meetings during which matters are considered that are prohibited from public disclosure pursuant to Section 51(b) o~ these procedures shall be closed. (3) Portions of meetings during which the Expert Panel deliberates on the safety of cosmetic ingredients may be closed upon the determination of the Chairman that it is essential to close such portion of such meeting to protect the free exchange of internal views and to avoid undue interference with Expert Panel operations. PAGENO="0120" 114 - 15 - (ö) A matter which is properly considered in en Open portion of an Expert Panel meeting may instead be considered in a closed portion only if it is so inextricably intertwined with matters to be discussed in a closed portion that it is not feasible to separate them or discussion of the matter in an open portion would compromise or impinge upon the matters to be discussed in the closed portion. (d) A closed portion of an Expert Panel meeting shall be attended only by Expert Panel members, liaison representatives, and the Cosmetic Ingredient Review employees, except as provided in Section 34(c) of these procedures for presenta- tion of data and information which are prohibited from public disclosure pursuant to Section 51(b) of these procedures. Any person making a presentation described in Section 34(c) may be accompanied by a reasonable number of employees, consul- tants, GF other persons with whom he has a commercial arrangement. If any person other than an Expert Panel member, a liaison representative, a Cosmetic Ingredi- ent Review employee, or a person making a presentation described in Section 34(c) attends a portion of an Expert Panel meeting, that portion shall be open to attendance by any interested person. Section 37. Administrative Remedies. Any person who alleges non-compliance by the Expert Panel or the Cosmetic Ingredient Review staff with any provision of these procedures may request appropriate relief from the Steering Committee. Section 38. Written submissions to the Expert Panel. (a) Ten copies of all written submissions for the Expert Panel shall be sent to the Administrator, unless an applicable public notice specifies otherwise. (b} At the request of the Expert Panel, the Administrator may at any time issue a public notice requesting the submission to the Expert Panel of written data, information, and views pertaining to any matter being reviewed by the Expert Panel. Such notice shall specify the format in which the submission shall be made, the number of copies to be submitted, and the time within which submission shall be made. (c) Any interested person may submit to the Expert Panel, through the Administrator, written date, information, or views on any matter being reviewed by the Expert Panel. Voluminous data shell be accompanied by a summary. (1) Any such submission shall be distributed to each Expert Panel member and liaison representative, either by mail or at the next Expert Panel meeting, end shall be considered by the Expert Panel in its review of the matter. (2) The Expert Panel may establish, and shall give public notice of, a cut-off date after which submissions relating to any matter shall no longer be received or considered. (d) The Scientific Coordinator, through the Administrator, shell provide for the Expert Panel and liaison representatives all scientific data and informa- tion he concludes to be relevant to any matter being reviewed by the Expert Panel. Any member of the Expert Panel or liaison representative shall, upon request, also be provided any additional material available to the Cosmetic Ingredient Review which he believes appropriate for an independent judgment on the matter, ~ raw data underlying any summary or report. Section 39. Conduct of a Public Hearing Before the Expert Panel. (a) For each Expert Panel meeting, the open portion for public participa- tion which constitutes a public hearing pursuant to Section 34(a) of these PAGENO="0121" 115 - 16 - procedures, shall be at least one hour long unless the public participation does not last that long, and may last for whatever time the Expert Panel Chairman determineS will facilitate the work of the Expert Panel. The public notice issued pursuant to Section 35 of these procedures shall designate the time specifically reserved for such public hearing, which shall ordinarily be the first portion of the meeting. Further public participation in any open portion of the meeting pursuant to Section 34(b) of these procedures shall be solely at the discretion of the Expert Panel Chairman. (b) Any interested person who wishes to be assured of the right to make an oral presentation at a particular Expert Panel hearing shall so inform the Admini- strator or other designated Cosmetic Ingredient Review employee, orally or in writing, prior to the Expert Panel meeting. (1) Such person shall state the qeneral nature of the presentation and the approximate time requested. Whenever possible, all written data and infor- mation to be discussed by that person at the Expert Panel hearing shall be fur- nished in advance to the Administrator or other desiqnated Cosmetic Ingredient Review employee. Such written material shall be mailed to the Expert Panel members and liaison representatives in advance of the meeting if time permits, and other- wise will be distributed to- the Expert Panel members and liaison representatives when they arrive at the meeting. Such mailing or distribution shall be undertaken only by the Cosmetic Ingredient Review staff unless the Administrator specifically permits the person making the presentation to mail or distribute such material. (2) Prior to the Expert Panel hearing, the Administrator or other designated Cosmetic Ingredient Review employee shall determine the amount of time allocated to each person for his oral presentation and the time that oral presentation is scheduled to begin. Each person shall be so informed in writing or, if the time prior to the hearing is short, by telephone. Joint presentations may be required by persons with common interests. (c) The Chairman of the Expert Panel shall preside at the hearing and shall be accompanied by other Expert Panel members and liaison representatives who shall serve as a panel in conducting the hearing (d) Each person may use his allotted time in whatevè~ way he wishes, con- sistent with a reasonable and orderly hearing. A person may be accompanied by any number of additional persons, and may present any written data, information, or views for the consideration of the Expert Panel. (e) If a person is not present at the time specified for his presentation, the persons following will appear in order. An attempt will be made to hear any such person at the conclusion of the hearing. Any interested persons attending the hearing who did not request an opportunity to make an oral presentation shall be given an opportunity to make an oral presentation at the conclusion of the hearing, in the discretion of the Chairman, to the extent that time permits. (f) The Chairman, other members of the Expert Panel, and liaison representa- tives may question any person during or at the conclusion of his presentation. No other person attending the hearing may question a person making a presentation. The Chairman may allot additional time to any person when he concludes that it is justifiable, but may not reduce the time allotted for any person without his con- sent. (g) Public participants may question an Expert Panel member or a liaison representative only with that person's permission and only about matters before the Expert Panel. (h) The hearing shall be informal in nature, and the rules of evidence shall not apply. No motions or objections relating to the admissibility of data, infor- mation, and views shall be made or considered, but other participants may comment upon or rebut all such data, information, and views. No participant may interrupt the presentation of another participant at any hearing for any reason. PAGENO="0122" 116 - 17 - ~ection,4O. Minutes and Reports of Expert Panel Meetings. (a) The Executive Secretary or other designated Cosmetic Ingredient Review employee shall prepare detailed minutes of all Expert Panel meetings, except that less detailed minutes may be prepared for open portions of meetings which are transcribed or recorded. The accuracy of all minutes shall be approved by the Expert Panel and certified by the Expert Panel Chairman. Such approval and certification may be accomplished by mail and by telephone. (b) The minutes shall include: (1) The time and place of the meeting. (2) The names of the Expert Panel members, the Cosmetic Ingredient Review staff, and the liaison representatives as well as the names and affilia- tions or interests of public participants attending the meeting. (3) A copy of or reference to all written information made available for consideration by the Expert Panel at the meeting. (4) A complete and accurate description of matters discussed and conclusions reached. Such description shall be kept separately for the following portions of the meeting to facilitate their public disclosure: the open portion specified. in Section 34(a.) and (b), any closed portion during which a presentation is made pursuant to Section 34(c), and any closed deliberative portion pursuant to Section 34(d). The minutes of a closed deliberative portion of a meeting shall not refer to Expert Panel members by name, except upon their request, or to data or information prohibited from public disclosure under Section 51(b) of these procedures. Any such inadvertent references which do occur shall be deleted prior to public disclosure. (5) A copy of or reference to all reports received, issued, or approved by the Expert Panel. (6) The extent to which the meeting is open and closed to the public. (7) The extent to public participation, including a list of members of the public who presented oral or written statements. Section 41. Transc~pts of Expert Panel Meetings. (a) A transcript or recording is not required for any portion of an Expert Panel meáting. (b) The Expert Panel shall decide whether any portion or all of its meet- ings shall be transcribed or recorded and, if so, by what means. Any such tran- scription or recording shall be arranged by the Administrator. (c) If a transcript or recording of an open portion of an Expert Panel meeting is made by the Cosmetic Ingredient Review staff, or is made by an inter- ested person and is submitted to the Cosmetic Ingredient Review, it shall be included in the record of the Expert Panel proceedings. (d) If a transcript or recording of any closed portion of an Expert Panel meeting is made, it shall not be included in the records of the. Expert Panel pro- ceedings~ that are available for public disclosure. Any. such transcript or recording shall be retained as confidential. The Chairman of the Expert Panel may, in his discretion, permit discussion without transcription or recording during any closed portion of an Expert Panel meeting that is otherwise being transcribed or recorded. (e) Any person attending any open portion of an Expert Panel meeting may, consistent with the orderly conduct of the meeting, record or otherwise take his PAGENO="0123" 117 - 18 - own transcript of the meeting. No person attending any closed portion of any Expert Panel meeting may record or otherwise take his own transcript of the meeting, except for an official transcript or recording arranged by the Administra- tor. Section 42. Expert Panel Determinations. On the basis of all data and information submitted to it, the Expert Panel shall determine whether each ingredient, under each relevant condition of use, is safe, or not safe, or there is a lack of information needed to make a determina- tion and insufficient industr~r ini~erest in the ingred~ent at that time to justify obtaining the needed information. Upon making such a determination, the Expett Panel shall issue a tentative report pursuant to Section 43 of these procedures and a final report pursuant to Section 44 of these procedures. Section 43. Tentative Report of the Expert Panel. (a) Prigr to issuing a final report as described in Section 44 of these procedures, the Expert Panel shall issue a tentative report. (b) The tentative report of the Expert Panel shall meet all of the re~ui~ements established for a final report in Sections 44 (a) and (b) of these procedures. (c) The public notice of the availability of the tentative report shall provide 90 days within which any interested person may submit comments on the tentative report and a request for oral hearing before the Expert Panel on the tentative report. (d) An oral hearing shall ~e granted by the Expert Panel on a tentative report of the Expert Panel for good cause shown. Any such oral hearing shall be conducted pursuant to the provisions of Section 39 of these procedures. - Section 44. ~ Report of the Expert Panel. (a) With respect to each cosmetic ingredient (or, where appropriate, c~osely related group of cosmetic ingredients), the Expert Panel shall issue a final report. The final report shall state the determination o~ the Expert Panel in accordance with Section 42 of these procedures with respect to each ingredient and any relevant conditions of its use.. (b) The final report shall contain the complete conclusions and recommen- dations of the Expert Panel with respect to the ingredient involved, including a full explanation of the reasons for those conclusions and recommendations and references to the scientific information bn which the Expert Panel relies. (c) The final report shall refer and respond to each point made in any submission or oral statement made with respect to the tentative report pursuant to Section 43 of these procedures. (d) The Scientific Coordinator shall arrange for the publication of eacI~ final report in an appropriate scientific journal. The Administrator shall other- wise arrange for public dissemination of the final report. Section 4S. Amendment of a~ F'inal Report. (a) Any interested person who believes that a final report is incorrect may petition the Expert Panel to amend the final report to correct such error. The Administrator shall give public notice of any such petition and all pro- ceedings of the Expert Panel with respect to any such petition shall be conducted pursuant to these procedures. PAGENO="0124" 118 - 19 - (b) A petition to amend a final report pursuant to this section shall ordinarily be based upon new data and information not previously reviewed by the Expert Panel. Such a petition shall be used primarily after the further data and information requested by the Expert Panel in the final report with respect to an ingredient, under each revelant conditiqn of use, has been obtained, so that the Expert Panel can proceed with final determination with respect to that ingredient* or condition. (c) A determination by the Expert Panel with respect to a petition for amendment of the final report shall be handled in the same way as the initial determination by the Expert Panel. The Expert Panel shall first issue a tentative report in accordance with Section 43 and then a final report in accordance with Section 44. ~rt E -- Public Notice and Availability of Records Section 50. Public Notice. (a) The Administrator shall give public notice of the availability of all Scientific Literature Reviews, the meetings of the Expert Panel, decisions and reports of the Expert Panel, and all other similar information, in both of the following two ways: (1) Such notice shall be mailed to a permanent mailing list consisting of representative members of the press (including interested newspapers, trade press, consumer publications, professional publications, and others) and represen- tative interested organizations (including consumer, professional, and business organizations). (2) Such notice shall also be given by mailing it to specific individ- uals who have demonstrated a continuing interest through direct participation in the Cosmetic Ingredient Review except for individuals who are members of organi- zations to which notice is provided. (b) Any interested intividual or or9anization may request that it be placed on the mailing list for all public notices by written application to the Adam- istratàr.. Any such request shall be accompanied by a statement of the need of such individual for such notices. The Steering Committee may, in its discretion, impose a fee for providing such notices to all individuals, which shall be no greater than the actual expense involved in providing them. Section 51. Availability of Records for Public Disclosure. (a) The following records relating to the Cosmetic Ingredient Review shall be available for public disclosure at the following time, except as otherwise provided in paragraph (b) of this section: (1) The minutes of each Steering Committee meeting, after they have been approved by the Steering Committee and certified by the Steering Committee Chairman. (2) Each Scientific Literature Review, at the time it is completed and available in printed form. (3) Each chemical description, at the time that it is submitted to the Administrator. (4) Each submission of safety information pursuant to Section 30(e) of these procedures, at the time it is received by the Administrator. (5) The written information made available for consideration by the Expert Panel at any meeting, at the same time that it is made available. (6) Any transcript or recording of any open portion of an Expert Panel meeting, as soon as it is available. PAGENO="0125" 119 - 20 - (7) The minutes of any open portion of an Expert Panel meeting, after they have been approved by the Expert Panel and certified by the Expert Panel Chairman. (8) All written data, information, or views submitted to the Expert Panel at any open portion of a meeting, as soon as they are so submitted. (9) The minutes or portions thereof of any closed Executive portion of a meeting: (i) For any matter not directed tobe maintained as confidential pursuant to Section 31(h) (2) of these procedures, after they have been approved by the Expert Panel and certified by the ~Expert Panel Chairman. (ii) For any matter dir~c~ed to be maintained as confidential pursuant to Section 31(h) (2) of these ~ocedures, after the matter relevant to those minutes or portions thereof as~cted upon by the Expert Panel or upon a determination by the Expert Panel that such minutes or portions thereof may be made available for public disclosure without undue interference with the opera- tions of the Expert Panel. (10) Any formal advice o~ report of the Expert Panel, after it has been issued by the Expert Panel. (11) Any other Expert Panel records relating to the matter involved, except transcripts and recordings of closed portions of Expert Panel meetings, after the matter relevant to those records is acted upon by the Expert Panel, or upon a determination by the Expert Panel that such records may be made available for public disclosure without undue interference with the operations of the Expert Panel. (b) The following records relating to the Cosmetic Ingredient Review shall not be available for public disclosure: (1) Records relating to any cosmetic ingredient which has been deter- mined by the Food and Drug Administration tO be exempt from public disclosure pursuant to 21 C.P.R. 701.3(a) and 720.8(a). (2) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and info]~mation shall be available for public disclosure only in accordance with the regulations established by the Food and brug Administration for public disclosure of such data and information in 21 C.F.R. 4.111(c) (3). (3) All data and information relative tO the nomination and selection of the members of the Expert Panel and liaison representative, in accordance with Section 21(e) of these procedures. (4) A transcript or recording of any closed portion of an Expert Panel meeting, in accordance with Section 41(d) of these procedures. Section 52. Public Documents Room. (a) The Administrator shall establish a Public Documents Room, where one copy of all records available for public disclosure relating to the Cosmetic Ingredient Review shall be stored and available for public review. The Public Documents Room shall have adequate space for interested persons to examine such documents. (b) Any person who uses the Public Documents Room shall sign a log showing his name, affiliation, time of entry and exit, and a general description of the documents reviewed. PAGENO="0126" 120 -21- Section 53. Public Inquiries and Requests for the Cosmetic Ingredient Review Records. (a) Public inquiries on all matters relating to the Cosmetic Ingredient Review shall be directed to: Administrator, Cosmetic Ingredient Review, 1133 Fifteenth Street, N.W., Washington, DC 20005, Telephone (202) 331-0651. (b) All requests for records relating to the Cosmetic Ingredient Review, including records of the Expert Panel, shall be made to the Administrator. (c) Copies of records that are publicly available pursuant to these pro- cedures shall be made, upon request, for a fee that will reflect the actual cost of the labor and materials involved. The Administrator, with the approval of the Steering Committee, shall maintain a current price schedule for such copying. PAGENO="0127" 121 Mr. Moss. Thank you very much. Mr. Gore? Mr. GORE. Thank you, Mr. Chairman. I appreciate your testimony, Mr. Merritt. I appreciate your wilhing~ ness to help us get to the truth in this matter. I think you put it into the context that I think this issue arises within, cancer is not the second leading cause of death in the country. The new figures indicate that as much as 90 percent of all cancers in America may be caused by substances put into the environment by man. Around 33 million women use hair dyes. Now tests have indicated that many ingredients of these hair dyes are carcinogenic in animals. You dispute the test methodology in your testimony this morning. One reference. you made was to the Yale study as supporting your characterization of these tests. However, I have an abstract of the Yale study which indicates that cosmetologists were found to have an increased risk of acute leukemia. In October of last year the Director of the Connecticut Cancer Epidemiology program wrote to the vice president for research of Clairol informing Clairol of the results of this test saying that cosmeto- logists had more cancer of the uterus and cervix and that they had higher r~tes of acute leukemia. Now, the other tests show or appear to show that these ingredients are carcinogenic in animals. They have shown, for some time, that these ingredients are mutagenic and that they have the capacity to cause birth defects. With 33 million women using these products, how can you justify saying that the law does not need to be changed? Let me read to you from the present law. I know you are very familiar with it. 21 U.S.C. Section 361(a), If food and drug and cosmetic contains any poisonous or deleterious substance which may render it injurious to users under the conditions of use prescribed in the labeling thereof or under such conditions of use as are customary or usual, provided that this provision shall not apply to cold tar hair dye. I have only been here a year, but I know bow the lobbying process works. I have seen it work already. It is obvious to me what happened. Your lobby was effective in getting an extension of your products and your industry. Now the tests indicate that that exception is not warranted at all. Why do you think that law should not be changed? Mr. MERRITT. Mr. Gore, you have raised two basic questions in your comments. One of these deals with the question of science as embodied in a specific re~port. The other relates to law. With your indulgence I would first like to ask Dr. Corbett to respond to the scientific question which you have raised in that specific epidemiology study. M~. GORE. That would be fine. Dr. CORBETP. In the Yale study-and this was. a comparison be- tween 12,000 cosmetologists and beauticians and 12,000 school teachers-the results found an excess of cervical cancer and of acute leukemia among the cosmetologists... Dr. Meigs said-and I think this is well-supportable-that it is well known that. cervical cancer is higher among lower socio-ecónomic groups than it is among the higher socio-economic groups. PAGENO="0128" 122 By contrast, among the teacher group there is a higher level of breast cancer. This, again, runs in line with the expected result based on these socio-economic statuses. In respect to the acute leukemia, Dr. Meigs said in his report that he believed that this was due to the surprising absence of any acute leukemia among the teacher group and that this was a subject for further investigation and not a subject for conclusion to be made at this time. Mr. :G ORE. How can you say it's safe if the conclusion is that further investigation is needed? You say there is no evidence at all- Dr. CORBETT. There have been other studies which one can relate with the Yale study that show no excess leukemia. Mr. GORE. What about the NCI tests? I want to get back to the point of law but we have had many examples of testimony from doctors who work for industries and who spend most of their time telling the industry that products are safe. I want to know your impression of the NCI test and the Ames test. Dr. COREETT. First of all, I would like to point out that in spite of the existence of 601 (a) which many people might claim exonerates the hair coloring industry from doing anything at all, it was in fact the industry that undertook the first, second, and third phases of testing of hair dye ingredients or hair dye compositions for safety. The safety studies carried out by the Cosmetic, Toiletry, and Fragrance Association preceded the studies that were done by the National Cancer Institute. They were done under conditions which we believe to be more realistic. According to the NCI guidelines they are more appropriate for evaluating the carcinogenicity of the material under the conditions of use. The NOT feeding study was a feeding study involving massive doses. NOT determined initially the maximum dosage that could be fed to an animal without resulting in 9 days-although in this case I think it was considerably less than that-in more than a-10 percent weight loss. No pathology was done on those animals to see whether, other than weight loss, there had been any sort of acute damage done. We question very much the level that was used in the NOT feeding study. I believe we made a mistake in saying that the higher dose was changed arbitrarily during the course of the study. What actually happened was that the lower dose level of the original study was ehmi- nated and a new and arbitrary higher dose group was inserted some 3 months after the beginning of the study. In our laboratories I have carried out a short-term experiment in which we fed the level used in the NOT study at the high-dose level for 2,4 Diaminoanisole to rats. After 5 days granules appear in the thyroid glands of the animals. These are not normal animals. We are attempting at the moment to show, and we believe we will, that the quantity fed resulted in a diversion of the thyroid stimulating hor- mone. Again, the animals under those conditions would not be con- sidered normal metabolic animals. Mr. Moss. Excuse me. We will let you finish but when this question is finished we will have to recognize the next member. Mr. GORE. Go ahead and complete your answer. Dr. CORBETT. Since the major observation in this test was that there was a high level of thyroid cancer in male and female rats and PAGENO="0129" 123 mice-that is four groups of animals-and a complete absence of in- crease in that form of cancer in the lower dose group, we question whether this particular test does not show indeed a threshhold level below which the material is safe and, therefore, is not grounds on which to say that this material represents a hazard to man. Mr. GORE. Thank you. Mr. Moss. The Chair recognizes the gentleman from New York, Mr. Lent. Mr. LENT. Thank you, Mr. Chairman. Mr. Merritt, if you would refer to page 9 of your statement, you indicate in the second paragraph that you agree with Dr. Upton's testimony last Monday. In that testimony he said, at least in part that because the NOT's animal tests showed that some hair dye in- gredients cause cancer in laboratory animals that this constitutes pre- sumptive risk in man. I wonder whether you would agree with that statement and if so if you could explain why you would, or why you would not if you do not agree with it. Mr. MERRITT. Here again, Mr. Lent, this is a scientific question dealing with risks and presumption of theoretical risks. Perhaps, Dr. Corbett might have a comment with respect to that. Mr. CORBETT. In the absence of any other data, I would agree entirely with Dr. Upton that any positive result in a bioassay study is a presumptive risk. In other words, it raises th~ question: Is this material safe? The NCI bioassay program, as Dr. Upton said in his prepared statement, was in fact a screening test that was regarded by its originators as the cheapest and quickest way of sorting out chemicals that needed further biological evaluation and those that did not. It was not intended by the people who designed the tests that the results of those tests should be used for regulatory purposes. I think I should explain the reason for this. If one is to carry out bioassay studies which are meaningful one should really spend between 2 and 5 years studying the metabolism of the material that is to be tested in order to see whether there are changes as the dose changes and so on. This is expensive and tedious. So it was felt, first,. that you would eliminate as many chemicals as possible by doing the high-level feeding studies and then take those that needed further evaluation and do more definitive studies on them. Mr LENT Let me see if I understand this as a layman What you are saying is that you are not in disagieement with Dr. Upton or even the results of the NOT tests insofar as they were conducted. But what you are saying is that they should not be applied to the hair dye in- dustry because what we had here was simply an effort at screening or weeding out the most potentially harmful ingredients and that this screening process took place by massive ingestion by animals, labora- tory animals, of these ingredients. Has the NOT, so far as you are aware now, gone on to complete the remaining analysis and testing of those ingredients found to be presumptively harmful? Mr. CORBETT. As far as I am aware the great purpose of the original bioassay program, due to the pressures being applied on NOT, will never be fulfilled. Essentially when they finished these massive maxi- 24-600 0 - 78 - 9 PAGENO="0130" 124 mum tolerated dose feeding studies they stopped studying those chemicals at that point and have gone on to something else. Possibly rightly I think that it is regarded that if a positive is found, then the onus of demonstration of the safety of the material falls on those people in society who wish to use it. I think that the cosmetic industry has demOnstrated that it accepts its responsibility. We have spent 10 years now doing animal tests. At every point during those 10 years we were engaged in some sort of animal testing on hair dye in- gredients and formulations in order to establish their safety. We believe that we had done this before the results of the NCI test came out. Mr. LENT. In all the years that you `have been conducting these tests and that Mr. Merritt ~has been in this business and with the increasing consumer awareness these days and the high incidence of consumer liability cases, has there ever been a case that you know of or that anyone on this witness panel would know of where a lawsuit has been settled against the hair dye industry predicated on evidence indicating that cancer was the result of using a hair dye? Dr. CORBETT. As far as I am concerned, I'm certain that I have never heard of one. Mr. LENT. Mr. Hutt? Mr. HUTT. I know of none. Mr. LENT. I was handed a release this morning as I came into the room from the Environmental Defense Fund wherein-and they are going to testify later today so perhaps you will have the opportunity to rebut what they may say, but they are announcing that a recent study indicated that mice whose skin was painted with two permanent hair dye preparations had a higher number of liver tumors than animals that were not exposed to the dyes. Can you tell us, Dr. Corbett, if you are familiar with this claim and what your reaction to it is? Dr. CORBETT. I read that this morning. I presume that they are talking about a study that was carried by the industry, the final results of which became available to me 2 weeks ago. I sent a copy of the report to the committee staff. The conclusion of that report was that there was no difference between the test groups and the control groups. I have had the opportunity this morning to look quickly through the ED]? testimony that is intended to be given this after- noon. I notice that each time there is a citation of a higher level of cancer on one of the test groups, as opposed to the control group, that there are only one or two control groups mentioned. If my recollection is correct, when we set up that study there were three control groups. There were three common control groups. The results of all three should have been stated if a fair evaluation were to be given. I do~ not know who the EDF used as its expert in interpreting this animal data, but he obviously comes to very different conclusions frOm those of the people at the Eppley Research Institute in Nebraska whom, as I understand it, are among the leading experts in interpre- tation of animal data. Mr. LENT. I have no further questions. Mr. Moss. The Chair recognizes the gentleman from California, Mr. Waxman. PAGENO="0131" 125 Mr. WAXMAN. Thank you, Mr. Chairman. Mr. Gore asked two questions. The second question was not answered. His question was prefaced by a very serious charge that the cosmetic industry lobbied Congress successfully for ~an exclusion for coal tar hair dyes. Can you explain to us why there is an exemption in the act and the scientific justification for it? Mr. MERRITT. Mr. Waxman, you are now talking about a legal question. With the permission of the committee,. I would like to ask Mr. Hutt to respond to that exemption and the implications of it. - Mr. HUTT. Mr. Waxman, the origin of the exemption in section 601(a) for coal tar hair dyes arose because of lobbying not so much by the cosmetic industry as by the beauty and barber groups in this country. Their livelihood depended upon the use of coal tar hair dyes for hair dye purposes. They were concerned that there would be, in a regulatory agency, insufficient recognition that coal tar hair dyes produce a low rate of reaction among consumers and that if proper care is taken in deter- ming whether a consumer reacts ahead of time that.rate of reaction would be reduced still further or eliminated. In short, they asked Congress to make in the law a benefit-risk determination very similar to the' benefit-risk determination that this committee of Congress and the entire Congress recently made with regard to saccharin.. They said that they recognized that there will be a low rate of reaction but that warnings and information to consumers and a requirement for adequate testing of consumers before use of this product should be sufficient to keep that to an acceptable minimum. Mr. WAXMAN. I appreciate that answer and I find it fascinating. What you are saying in effect is that the law `provides that the public will be protected from poisonous or deleterious substances which may render cosmetics injurious to users under the conditions of the use pre- scribed in the labeling. Then, the law says that the provision protecting the public from hazardous cosmetics will not apply to coal tar hair dyes. As I understand your testimony, the coal tar exemption was included in the law as a result of lobbying, from the beautician industry-a group whose livelihood was very much affected by Government pressing too deeply into the safety of coal tar hair dyes. Mr. HUTT. In my opinion the exemption probably was unnecessary to achieve the intended purpose because I think that the Food and Drug Administration would have recognized, as it does for niany other consumer products, that a low rate of allergic reaction can be expected. Nonetheless, that was the purpose of the Congress in putting it into the act. Mr. WAXMAN. Let me probe this a little bit with the testimony given by Mr. Merritt. Here we have an example of an exemption put into the law by a group that wanted to protect its economic interests. The industry was afraid that if the law applied strict safety require- ments to this particular kind of dye, then it would hurt the industry. I want to say that I believe that the beautician industry was sincere in thinking that there was probably a minimal risk. I also want to say that I believe you are smcere' in thinking that there is probably PAGENO="0132" 126 minimal risk in the kinds of dangers that the public might have in using your products. On the other hand, your testimony. implies that; "Even if there is a risk, it's a societal issue and not a scientific issue." "What is prudent action for one consumer is not acceptable to all consumers." You also point out that: "The contributions of cosmetics to self-assurance and self esteem are ~ts important as the nutritional and medical benefits of foods and drugs." What I'm trying to probe with you is this. I wonder whether your sense of economic concern and the success of your industry is not making you lean over pretty far to try to justify that maybe there is no risk. As Members of Congress, we are charged with trying to look out for the public interest-which includes the success of industries in this country that do not produce products harmful to the public. I wonder whether we ought to look at the assurances of your industry with a certain amount of caution. We're talking about cancer. We are talking about serious health risks. I am sure that you knowingly. would not want to have people get cancer from your products. But cancer is the result sometimes of not just one substance but the combination of a number of carcinogens to which we are exposed in our environment. I would be interested in your response to that. Also I want to point out one other thing before you answer. You said you agreed with everything that Dr. Upton had to say. One thing that Dr. Upton said very clearly was this. Whatever the regula- tors might do, as a scientist he would urge people personnally not to use dyes which contain chemicals the NCI finds to be carcinogenic. I assume you do not agree with that. Mr. MERRITT. Lt me take these in reverse order if I may. I have never asked my wife or three daughters if they use hair colors and they have never volunteered the information. But in all my contacts with the industry scientists and sitting through the meetings I have heard nothing that would cause me to recommend to my family that they not use hair dyes if they so chose. Mr. WAXMAN. But we have the head of the National Cancer Insti- tute who says that he would recommend to his family, friends, and others that they not use these hair dyes. He is a scientist. I assume you are not a scientist. Mr. MERRITT. I am not a scientist. I am an administrator. But I am exercising that choice we believe the public should have. I believe in my heart that they are safe enough that I would not recommend to my family that they refrain from them, based on all the discussions that I have been in. I have not been in all of them but I have been in many of them. Mr. WAXMAN. What is safe enough when 1 out of 4 people in this country will get cancer? We have determined that 90 percent of human cancers are caused by carcinogens that have been picked up in the environment. We now find that there are carcinogens in some hair dyes. How safe is it to expose people to that kind of risk? You talk about the dangers of driving here in a storm. I assume you would want your car to be in good order and the tires to be sufficient to carry the car and to grip the road, and the brakes to be working. You would PAGENO="0133" 127 not want to expose yourself to unnecessary, risks. Aren't we talking about exposing the public to unnecessary risks? Mr. MERRITT. Driving here this morning I rode' in a taxicab which encountered several potholes. Even though the tires may have been in good shape perhaps they might have damaged them for the next passenger. Mr. WAXMAN. You want government to fix those potholes? Mr. GORE. That's a loaded question. Mr. MERRITT. Thank goodness for a little levity this morning. Let me say this. This is a very complex scientific issue. The `question of the benefits and the potential risks, as I stated in my statement, I believe should be referred to an organization similar to the National Academy of Sciences and let them go into this entire safety question and the risks involved. You mentioned Dr. `Upton's statistics of 1 out of 4 perhaps getting cancer. Mr. Gore referred to the number of those which come from the environment. I happen to be a nonsmoker. But some of that environ- ment in which I live is the exhaled smoke from others. I have the choice of remaining with some of my friends who use tobacco or refraining from being with them. I happen to choose' to continue to associate with them. I believe we should look at all the risks we face and I believe we should make many judgments on all chemicals rather than indict a single chemical ingredient based on one particular test. Let's evaluate all the data. Let's make a balanced scientific judg- ment. - Mr~ WAXMAN. Do you think a balanced scientific judgment means t'hat we have to prove in fact or beyond a reasonable doubt or with a preponderance of'the evidence that there is a danger from chemicals that are in the cosmetics? Or is it enough to have a suspicion that would lead reasonable, expert, scientific opinion to conclude that there is a real danger that hair dy~e consumers may increase their risk of cancer? Cancer is not like a caustic, quick acting poison. Cancer has a long latency period lasting 10, 20, or 30 years. This latency period gives the public a false sense of security that there is nothing wrong with using a substance because they don't get the deleterious re- sults immediately. Perhaps a chemical in these hair dyes will cause cancer 10 or 15 years. later? Perhaps a chemical in these dyes will act in combination with other substances to cause cancer. Mr. MERRITT. I think you are getting into a very scientific issue here. You are talking about presumptive risk versus potential risk. Dr. Corbett, do you have any comment? Mr. WAXMAN. I don't want a scientific explanation. I want to dis- cuss the societal question that you posed. Are we willing to let society take this kind of chance until we get scientific proof positive that the danger exists? Or, at some point do we say that there is a risk sufficient for us to be concerned and that we have to do something to protect the public from this risk either by, No. 1, letting them know they are taking this risk or, No. 2, in some circumstances removing the product from the market when safer products could be substituted or when the nature of the risk is unacceptable. PAGENO="0134" 128 Mr. MERRITT. I believe that the decisions made should be made reasonably and basically on the preponderance of examination of all data and not on a single study. Mr. Moss. The time of the gentleman has expired. The Chair recognizes the gentleman from Pennsylvania, Mr. Marks. Mr. MARKS. Thank you, Mr. Chairman. Mr. Merritt, because ofi other appointments I will have to be leaving soon and I will not have an opportunity to hear some of the other testimony. But I would like to ask you if you could comment on some statements that apparently will be made here this afternoon or later this rnornin~. I wonder if you might comment on the statements as we go through it sentence-by-sentence and indicate if it in fact is true and if so what your thoughts are about it. The first statement is this, I am quoting. "As is true for other cosmetic products, FDA has no statutory authority to require that manufacturers test the products before they enter the marketplace." Is that correct? Mr. MERRITT. T would like to refer that to Mr. Hutt with your permission. That is a legal question. Mr. HVTT. Mr. Marks, that is untrue; The Food and Drug Admin- istration has issued a regulation which requires, as the testimony indicated, that all cosmetics be substantiated'for their safety prior to their being marketed. A failure to do that would require a warning on the front panel of the label of the cosmetic. It would be required to state that the safety of the product has not been determined. Tech- nically one could put out a product with that label on it. But as a practical matter that regulation means that FDA is requiring the product to be substantiated for safety prior to the marketing. Mr. MARKS. Or stated that they haven't. Mr. HUTT. Yes. Mr. MARKS. But they don't have to be. Mr. HUTT. They do not have to he but there is not to my knowledge one cosmetic product marketed with that statement on it. Mr. Moss. The Chair must acquaint the gentleman with the (act that the rules of this House provide that if you read from a document, you must identify it. I haven't the slightest idea what you are reading from. Mr. MARKS. I would be glad to, Mr. Chairman. I am sorry that I did not before. This is from the summary of the testimony that will be offered by the Environmental Defense Fund before this committee. Mr. Moss. Thank you. Mr. MARKS. The second comment is: A cosmetic producer does not violate the law even if it fails to conduct a single safety test either before or after introducing a new product. Is that correct? Mr. IIUTT. The same answer I gave before would apply here, Congressman Marks. Mr. MARKS. I am quoting again: "Moreover, the FDA has no authority to require the cosmetic manufacturers to provide the necessary information that would enable the Agency to conduct its own premarket evaluation." PAGENO="0135" 129 Is your answer. the same? `Mr. IIUTT. That is true. But I would go on to say that the industry has, as Mr. Merritt testified a few moments ago, begun its own program under which all of the published and unpublished scientific information on safety of all cosmetic ingredients will be compiled and made public as soon as they are compiled. Mr. MARKS. The next statement: Manufacturers cannot be compelled to submit ingredient lists, consumer com- plaints or test data to the agency. Is that correct? Mr. HUTT. ~That is correct. That is, why the CTFA petitioned the Agency for the three re~nlations governing voluntary submission of information to FDA by industry. Mr. MARKS. "Consumer products, such as hair dyes, sold for use in beauty salons, do not even have' to `be labeled with the ingredients they contain."~ Is that correct? Mr. HUTT. That is correct. The Fair Packaging and Labeling Act, under which ingredient labeling is required by FDA, applies only to products sold at retail and not to other products. Mr. MARKS. "Cosmetic manufacturers are not required to inform the FDA that they or their products even exist." Is that correct? Mr. HIJTT. That is covered by the regulations governing voluntary submission of information to FDA by industry. That is correct. Mr~ MARKS. I want to ask you something. In the opinion of the industry-and perhaps Mr. Merritt ought now to answer this question-do you `not think that the FDA, under law, ought to have the opportunity to have those things that I have just mentioned that it does not already have? That is, without it being voluntary. Mr. MERRITT. Congressman,. we proposed a three-point voluntary program which, number one, would ask manufacturers to register the manufacturing facilities with FDA. Number two, ~tbey would submit their formulations to the Food and' Drug Administration. And num- ber three, it would provide regular reporting of product experience to We have testified, and we'wouid not object if those three regulations became mandatory. Going one step further in Senate testimony 2 years ago, we testi- fied that we would not object to a requirement of safety substantiation, as outlined at that time, or if that data were required to~-be made available to the Food and Drug Administration upon request. Mr. MARKS. When was this voluntary request made of the industry, that is, how long ago? Mr. HUTT. Are you asking when the petitions were filed with the Food and Drug Administration? Mr. MARKS. Yes. ` . Mr. HTJTP.. Approximately 1971, I believe. Mr. MERRITT. It was 1970 and 1971. Mr. HIJTT. I think they may have been over a 2-year period. I do not recall. PAGENO="0136" 130 * Mr. MARKS. In 1971 are you suggesting that you went to the indus- try and asked them-- Mr. HUTT. We went to the FDA. Mr. MARKS. Yes; with petitions. But you talk about voluntary compliance with many of the matters that are not law at the present time. I am asking you this. Basically when did you first go to the industry and ask them to voluntarily comply? When was that-about 6 years ago? Mr. MERRITT. I would say it was 10 years ago when we started to plan the whole program. Before an association can take an action, it must determine the consensus of the industry. The industry supported the voluntary proposals. We believe the data supplied to the Food and Drug Administration provides a sound base on which the Food and Drug Administration can take regulatory action. Mr. MARKS. I am curious about this. How much of the industry complied-100 percent; 90 percent; 80 percent? Mr. MERRITT. Interestingly enough, in the Food and Drug Law Institute Conference-I believe it was in early December-it was reported that nearly 900 manufacturing establishments had registered. The reference was made to the number of smokestacks which the Food and Drug Administration had on its records. They revealed about 20. percent of those were uncovered by the voluntary registra- tion program of manufacturing facilities, which proves that the Food and Drug Administration has gained substantial information from this program. Mr. MARKS. I think it also suggests that you are not answering my question. Mr. MERRITT. I apologize. Mr. MARKS. You may not have understood. I am concerned about your industry. Mr. HtTTT. I think the information is contained on pages 6 and 7 of our testimony where it is stated that, for example, with respect to registration with FDA, 900 client plants have registered. That represents about 85 percent of the volume of cosmetics sold in the United States. We have not attempted to break that down accord- ing to the percent of volume of products sold by CTFA members. Typically some smaller cosmetic companies are not members of the association. Mr. MARKS. What happened to those petitions you presented in 1971? Mr. }IUTT. They were adopted by the Food and Drug Administra- tion and they are currently regulations under which companies may voluntarily submit the three types of information. They were promul- gated by FDA as regulations and are in the Code of Federal Regula- tions today. Mr. MARKS. Are there any matters that I have mentioned here under which the FDA does not have statutory authority? Would you have any objection to their having statutory authority over these? Mr. MERRITT. Are you referring to the questions that you read out? Mr. MARKS. Yes. Let us start with the statutory authority to require that. manufacturers test their products before they enter the market- place. PAGENO="0137" 131 Do you have any objection to that? Mr. MERRITT. I think we do, sir, because cosmetics are basically safe. We believe there are so many similarities among. these products that these products should be substantiated and evaluated prior to marketing to determine whether a test is necessary. To do that, the manufacturer must look at the chemical composition and the ingredients and the purity of those ingredients and the stability and the effect of their intermixing. The exposure conditions must be looked at. The volume used in the concentration and the rout of exposure and the frequency of adminis- tration must be looked at. The known data which is in the literature and in their files- Mr. MARKS. Excuse me, Mr. Merritt. I am sorry to interrupt you. My time is running out. I see the chairman with the gavel. Answer me yes or no. Perhaps you have. You do object to the FDA having statutory authority to require manufacturers to test their products before they enter the marketplace; is that right? Mr. HTJTT. But there is no CTFA objection to the requirement of safety substantiation, which may be done on the basis of preexisting information rather than new testing. Mr. Moss. Excuse me. I think it might be helpful to permit the mem- ber to secure answers to his questions. If you will kindly confine yourself to very brief, concise answers, we would appreciate it. He asked for a yes or no answer. Mr. MARKS. Thank you, Mr. Chairman. Mr. Moss. Please continue. I realize you have to ieave. Mr. MARKS. I will take another moment. Mr. MERRITT. Mr. Chairman, on quick perusal I believe we would have no objections to the rest. Mr. MARKS. You have no objection to a cosmetic producer conduct- ing safety tests, either before or after iutroducing~ a new product; is that right? Mr. MERRITT. I said for the balance of the questions. First, I think you make an evaluation of the product to determine if tests are neces- sary. If so, you do the test to further substantiate the safety. For the balance of the points here, I do not believe on a quick perusal we would have any objection. Mr. MARKS. Thank you very much. Thank you, Mr. Chairman. Mr. Moss. The Chair recognizes the gentleman from Ohio, Mr. Luken. Mr. LUKEN. If the chair would permit an attempt at levity, perhaps your testimony might be characterized by some of the members as similar to a statement made by "Mo" Udall at the Roast last night. He stated that FDA has just banned births on the ground that they will inevitably lead to death. Would you make the argument, sir, that you, manufacturers of hair dyes, would like to be in the same position that the tobacco industry is in? Mr. MERRITT. I am not sure I know about- Mr. LUKEN. I am talking about without subsidies, of course. Mr. MERRITT. Thank you for additional levity. PAGENO="0138" 132 I am not sure I know enough about the legal requirements for the tobacco industry in their labeling. Perhaps Mr. Hutt might respond to that iiicomparing the legal requirements here to the legal requirements of the tobacco industry. Mr. }IUTT. I am not sure, Mr. Luken, that I can answer that ques- tion. I am not sure .of the precise intent of your question. Mr. LUKEN. I think we have to look at the overall requirements. You are certainly arguing fairness, I assume. I am trying to understand the position here. There is an exemption in the law for hair dyes. Of course, tobacco is not covered at all. It has a similar effect. I just wondered if you see any distinction. Mr. HUTT. The basic position of OTFA is that there is insufficient evidence of risk to justify any kind of drastic regulatory action, speqifically with respect to the hair dye ingredients that have been tested by the NOT. So, in that respect, I think the industry would say that it is not in the same position as the tobacco industry. Mr. LUKEN. Not as to the degree of risk? Mr. JIUTT. Yes; as a factual matter. But with regard to the issue of. consumer freedom of choice to decide what risk to accept and what risks not to accept, the industry believes that is a fundamental principle that should apply to these products, as well indeed of all consumer products, as long as the risk is just not outrageous, like poison. Mr. LUKEN. Do you oppose the proposed labeling of FDA with respect to hair dyes? Mr. HTJTT. With respect to that proposal, the industry has not yet filed its comments, Mr. Luken. I anticipate that it will take the position that the factual evidence is, at this moment, insufficient to justify a warning to consumers. If any of that information should be given to consumers, it should be given in a more complete and bal- anced way rather than through a single sentence warning. There are many other consumer products that presently do not bear warning that pose a much greater risk of cancer and a greater risk to health `than do hair dyes. Mr. LUKEN. One of the other members was pursuing that point in a similar vein. But we agree, as I think Mr. Merritt agreed, that the tests do show enough to indicate a presumptive risk, which we described it as. Maybe that term does not really apply in its usual sense because "presumptive" means pretty strong-but I took it by your response that you did not really mean that it is a pretty strong indication, but that there was just some presumption by reason of the fact that these tests show that under certain circumstances, they can be carcinogenic. But with that presumptive risk present, can we tell the FDA that they should not require labeling? Mr.'~HUTT. I believe Dr. Upton, when `he referred to "presumptive risk," said that what was then needed to determine whether there was'a human risk, was to look at all the Qther available data and to do additional testing. The CTFA view is that until that further analysis is done-and that is the term he used, "further analysis"-a warning would be premature. PAGENO="0139" 133 Mr. LUKEN. Then you would not agree that the presumptive risk, whose requirements have been met by the tests so far, is sufficient to permit or require warning?. Mr. HUTP. I believe the industry will file comments taking that position, yes. Mr. LUKEN. I think you know pretty well what the industry is going to do. Mr. HUTP. The difficulty we are faced with is this. We sit here as an association. The association has not yet had an opportunity to meet and decide on its views. That is why I have to speak somewhat tentatively. Mr. LUKEN. I might say that I have some sympathy with the risk-benefit theorum that you espouse. But as to the requirements for testing, I remain with some questions about that. I think we all, on this panel, remain with questions about that. Mr. HUTT. Mr. Luken, I think there was some confusion that was raised. The cosmetic industry, as a whole, and the CTFA certainly believe that the safety of any cosmetic should be evaluated and sub- stantiated before that cosmetic is put on the market. We have never said anything, to my knowledge, to the contrary. Mr. LUKEN. Are we talking about voluntary? Mr. HTJTT. Even mandatory. Even under law. CTFA has not op- posed a legal requirement for safety substantiation. What the industry is concerned about would be a law that would require that every change in every cosmetic be required to be tested in a way that would result in massive duplicative testing. That is why when Mr. Marks raised the question: "Should every cosmetic be tested before it goes on the market?", the answer was: "Not necessarily, because there is so much testing of common ingredi- ents which has gone on in the past that duplicative testing may not be required for every product." Mr. LUKEN. Are you not concerned especially abput the smali.busi- ness members of your association as to the burdens that may be placed on them if the industry is not able to test collectively, rather than by individual firms? Mr. HUTT. That is true. A cosmetic company might put out a new lipstick and do nothing more than change 200 prior formulations in a very small way. To require that each new product be subject to duplicative testinj would be a waste of this country's toxicological testing resources. As Dr. Upton said, they are in very, very short sup- ply. We should use them where they are important. But CTFA supports safety substantiation, without question, for every cosmetic. Mr. Moss. The, Chair recognizes the gentleman from California, Mr. Waxman. Mr. WAXMAN. I have some additional questions which I would like to pursue with the witnesses, I would like to know whether there are any benzidine-based dyes currently in use by hair dye manufacturers? Mr. MERRITT. Mr. Waxman, with your indulgence, I would clarify one point you asked earlier. Concerning Dr.. Upton's comments the other day, D~. Upton did not urge others not to use hair dyes~ He said he would not use them, PAGENO="0140" 134 but people should make their own decisions. That should be based on all available facts. Mr. WAXMAN. Let me interrupt you. I was there. I do not know what information you have, but Dr. Upton indicated he was not a regula- tor and that the decision as to whether hair dyes should be taken off the market or whether a warning label ought to be required is a deci- sion of a regulator. He is a scientist. From a scientific point of view, he thought 4-MMPD was a sufficiently dangerous substance for him not to want his family or others to use it. It is the decision of the regulator, however, to decide whether it should be taken off the market. But my question now to you is this: Are benzidine-based dyes currently in use in hair dye products that are sold in this country? Mr. MERRITT. I am not a scientist. I wonder at this point if I might again call on Dr. Corbett who is intimately connected with this subject. Dr. CORBETT. The materials that you referred to as benzidine-based dyes are dyestuffs which are made from benzidine. They do not resemble benzidine in final form. Mr. WAXMAN. Are they for sale as one of the constitutents of hair dyes, which are sold freely today to the American people? Mr. CORBETT. This question was asked of us about 3 weeks ago. Mr. Moss. Dr. Corbett, you can answer that question. They are or they are not. We do irot want a narrative wi.th each response. The Chair wants to be very fair to you, but the Chair will also be fair to the members of this panel. They are entitled to very concise responses. That is all you have to give. We do not want the history.. We can find that out from the staff. Dr. CORBETT. I am sorry, Mr. Chairman. The answer, however, cannOt be yes or no. There were three products which were manu- factui~ed, as we understand it, up until sometime early or late last year. They are still available, but are no longer being manufactured in 1978. Mr. WAXMAN. Why are they not being manufactured? Dr. CORBETT. The manufacturer apparently dropped them from the line. Mr. WAXMAN. Do you know whether that was due to a conclusion by the manufacturer that benzidine-based dyes were dangerous? Dr. CORBETT. I have difficulty because it is not the company for which I am employed. I am not privy to their reasons. Mr. WAXMAN. Do you consider benzidine-derived dyes to be safe? Dr. CORBETT. I consider them to be dangerous for ingestion be- cause it is well known if they are ingested they will degrade to give benzidine. However, they are high molecular weight materials which probably would not diffuse through the skin. I do not know ior sure, but when I look at the formula I think that they will not go through the skin. Mr. WAXMAN. Do you know for sure what they will not be absorbed through the skin? Dr. CORBETT. No, I do not. This is a guestimate based on what I do know about which materials do go through the skin and which do not. Mr. WAXMAN. If they were absorbed, would you consider that dangerous? PAGENO="0141" 135 Dr. CORBETT. If they were, yes. Mr. WAXMAN. Are you aware of the fact that the benzidine- based dyes tested by NCI were found to produce tumors after 90 days? The scientists at NCI found the results "striking" in producing tumors after such a short period of time. They considered the dyes to be potent carcinogens? Dr. CORBETT. I think this is not a surprising result. It is consistent with the results from feeding benzidine itself. But I would point out that a recent paper by Dr. Bingham on the carcinogenicity of benzidine suggests that it may be necessary to work in a benzidine plant for at least 5 years before you run a real risk of getting bladder cancer from exposure to benzidine. Mr. WAXMAN. Is it your feeling that benzidine derived dyes are not a danger because you do not believe they are absorbed through the skin? Dr. CoRBI~TT. I do not believe it is absorbed. If it were absorbed, the quantities to which a human would be exposed would be miniscule. As I said, Dr. Bingham's paper on followups of benzidine workers suggested that quite a large exposure was needed before there was a possibility of developing bladder cancer. Mr. WAXMAN. It is your scientific opinion that there is a threshold level for benzidine products? Dr. CORBETT. You could ask that of each scientist and each scientist will give you one or another answer. I think that the whole data that exists on carcinogenicity can be fully explained on the basis of a threshold theory. Mr. WAXMAN. I see. So you think there is a threshold for benzidine products? Dr. CORBETT. I think there is. I think human experience shows there must be. Mr. WAXMAN. Human experience? What does that mean? You are a scientist. You have looked at all the studies. Have you done studies on human beings to come up with that conclusion? Dr. CORBETT. Allow me to clarify one thing that was said a number of times during this hearing on Monday, and repeated again today. The impression has been given that 90 percent of human cancer, being of environmental origin, is due to synthetie chemicals. This is a totally wrong impression. In my mind it runs counter to the war on cancer or to getting any success in it. We heard testimony that cigarettes contribute to a large percentage, diet contributes a large percentage, radiation contributes a significant percentage, and ultraviolet light contributes a percentage. All of these are environmental factors and are included in that 90 percent. When you get to the bottom line, Dr. Ernst Wynder of the American Health Foundation estimated that no more than 5 percent of human * cancer is due ~o synthetic organic chemicals, as opposed to natural Organic chemicals. Mr. WAXMAN. You obviously can "out-science" talk me. But this is a product [indicating] that one of my aides purchased off the shelf in a retail establishment here in Washington, D.C. It contains a chemical called "Direct Blue 6" which was the subject of the recent NCI study. NOl found it to be highly carcinogenic. They PAGENO="0142" 136 determined that there was a danger because "Direct Blue 6" may be absorbed through the skin. You told me that the industry is no longer manufacturing products containing this chemical. Is that correct? Dr. OOEEETT. That is what I understand, yes. Mr. WAXMAN. Why don't you know why the industry has stopped manufacturing hair dye products containing "Direct Blue 6"? Why can't you tell us whether it is due to a recognition of the potential health danger which you refuse to acknowledge? Mr. MERRITT. I might interject, please. Mr. Moss. Let us wait for the response. Mr. WAXMAN. This is a scientist from the cosmetiô industry and I want to find out why some of the members of the industry do not know what Others are doing and why they have not voluntarily taken benzidine-derived dyes off the market? Dr. CORBETT. That is commercial information. I will try to find out. I think it may be just prudent business sense that made them take it off. Mr. WAXMAN. I think it is prudent business sense not to put some- thing on the market that contains benzidine-a substance we know is clearly carcinogenic. I think we found out that this is a serious enough matter that tumors were found in test animals after only 90 days. NOT concluded these dyes were potent carcinogens and may well be dangerous. Then you tell me you do not even know why the industry took these dyes off the market. This bottle of hair dye rinse was purchased within the last couple of days. People right now are able to purchase products containing benzidine. Dr. OORBETT. With due respect, I am under oath and I do not know the reason they took it off. I have not discussed it with them. `Mr. WAXMAN. Are you aware of the fact that Japan banned ben~ zidine in 1971? Dr. OORBETT. But this does not contain benzidine. It contains disaso dyes that are derived from benzidine. They, in chemical char- acter, are different from benzidine itself. Mr. WAXMAN. They are derivatives, are they not? Dr. CORBETT. Yes, but that is the same as saying aspirin is a benzi- dine derivative. It does not mean anything. Mr. WAXMAN. Did not NOT determine that benzidine-based dyes convert to benzidine in the human body? Dr. OORBETT. When ingested, yes. Mr. WAXMAN. The question, then, is whether it is ingested. Dr. CORBETT. I said that. Mr. WAxMAN. Mr. Merritt, your testimony is: To the vast majority of consumers, the contributions of cosmetics to self-assur- ance and self-esteem are as important as the nutritional and medical benefits of foods and drugs. Are you telling us that it is as important, that is, that it is more important to look good than to feel good? Mr. MERRITT. T think looking good and feeling good perhaps could be equally important to many people. On the other hand, there are certain individuals to which one might be better than the other. PAGENO="0143" 137 Mr. WAXMAN. Really? I see. So, some individuals ought to have cancer and others not? ~Mr. MERRITT. You are taking that out of context. Mr. WAXMAN. I am disturbed by your willingness to make, the evaluation that for some people it is so important to look good that it is worth taking the risk that they are going to get cancer. I find that appalling. Is that what you are saying? Mr. MERRITT. No, not m that context. What about cigarettes? Mr. WAXMAN. Aren't you just throwing some smoke up in the air? Mr. Moss. With all due respect, we are not dealing with cigarettes today. We have wrestled with that problem over a period of time in the past. We will do it again, but not today. Mr. WAXMAN. I also want to say something in relationship to ciga- rettes. The fact that there are people who subject themselves to a greater risk of cancer and heart disease by smoking cigarettes is no excuse for allowing multi million-dollar industries to go ahead and poison the American people with additional carcinogens. I hope this is not something you would argue with. Mr. Moss. The gentleman's time has expired. The Chair recognizes' the gentleman from New York, Mr. Lent. Mr. LENT. Thank you, Mr. Chairman. Dr. Upton of the National Cancer Institute testified on Monday that: The crux of the matter with respect td hair dyes is whether or not there are so-called safe alternatives. Can you' tell us whether there are any alternatives available in the production of hair dyes that could avoid using the chemicals identified by NCI as possibly cancer-causing? Mr. MERRITT. I would have to defer to Dr. Corbett on that point. Dr. CORBETT. It is possible to make hair dyes using a variety of materials from amongst those which we currently use. However, we find ourselves in a very difficult position at the moment. The NCI has under. test some 10-and I am always differing on this figure with members of your staff, Mr. Chairman-but there are 10 hair dye ingredients and not 13 in the program. But for some of these we do not have the results. For me to discuss whether, based on legislation resulting from the NCI tests, we would be able to continue manufacturing hair dyes or not, I think I would have to say that we cannot tell until we know a~l of the data. I could make a hair dye today that does not use 2, 4-diaminoanisole or either of the two materials that are mentioned that were used in hair dyes. However, there are other dyes on this list that was up on the wall in the hearing room on Monday for which we do not know the results and without which I would be totally unable to make a permanent hair colOr product. ,, ` We hoped that the NCI would be able to bring together and issue at the same time all of the `reports on the hair dyes in the bioassay program so that we can consider whether we can continue to manu- facture the type of product that the American public is used to without using the dyes found to be animal carcinogens by NCI. PAGENO="0144" 138 But I have to come back again to the fact that I would prefer to stay with materials on which we have 70 years of use experience, with no apparent harm to the user or to those who `are professionally exposed and a lot of animal testing. Mr. LENT. `~ ou say you have had 70 years of experience of use of these dyes without any. evidence of death, cancer, et cetera, ever having been domonstrated. Why is it, then, that the results of these massive animal feedings and screening tests show cancer resulting in laboratory animals? Dr. CORBETT. In the case of 2, 4-diaminoanisole, we have a situation which may well be something which no one would have suspected, namely, that the material is a thyroid stimulant, or thyroid-depressing agent, as well as being useful for a hair dye. It is being fed at such a level that it upsets the hormonal balance of the animal and produces physical deposits in the thyroid. That results in secondary cancer. This is a very strong possibility in view of the results. This is why we question the validity of that test in determining that 2, 4-diaminoanisole is a chemical carcinogen. Mr. LENT. This is strangely reminiscent of the saccharin coritro- versy where the Canadian rats were fed the massive doses of saccharin. Certain conclusions were drawn from that. There is an important difference here in that human beings do not ordinarily ingest hair dyes, whereas they do saccharin. So, it would seem to me just on a very superficial level that the case that has been presented against the hair dyes is substantially weaker than was presented against saccharin. Someone said that there were 34 or 38 million people in this country who use hair dyes. Is that correct? Dr. COEBETT. It s.ounds like a reasonable figure. Mr. LENT. What percentage of them, do you estimate, are women, and what percentage are men? Dr. CORBETT. Men have always been a little reticent to admit to this. We have never really had good figures. I have always guessed that probably 80 to 90 percent of these users are women. Mr. LENT. Where do we find the greatest incidence of cancer with respect to sex as between men and women? Do women have the greatest incidence, or men? Dr. CORBETT. Men. Mr. LENT. So, men have the greatest incidence of cancer in this country, notwithstanding the fact that 80 to 90 percent of the users of hair dyes are females; `is that right? Dr. CORBETT. That is correct. Mr. LENT. What kind of conclusion could a scientist draw from that? That is a large sampling, I am sure. Dr. COEBETT. Scientists are very reticent to draw absolute conclu- sions on that sort of data, but I do find it comforting to recognize that 10 percent of American women were using hair dyes 25 years ago. During the subsequent 25 years, there has been a decrease in most forms of female cancer, as attested to by the American Cancer Society and by agencies of the Federal Government when testifying before Congress. PAGENO="0145" 139 On this basis I think a priori there seems to be no risk. I would want more detailed studies. You mentioned saccharin. I notice in this morning's New York Times that the National Cancer Institute and FDA have announced they are going to jointly carry out an epidemiology study on 9,000 people for 18 months in 9 States to determine whether saccharin causes bladder cancer. I would welcome such a study for hair dyes. In fact, the National Cancer Institute, the hair color industry, and the Environmental Defense Fund had the first meeting of a. joint scientific committee last week, at which time we told the other two representative groups that we were trying to evaluate what sort of epidemiology is required on top of what we already have. Mr. LENT. Have there ever been any tests conducted with labora- tory animals wherein instead of feeding the dye to them, they put it on their skin or on their coats? Dr. CORBETT. Yes.. Mr. LENT. Have these types of tests ever been carried out with respect to laboratory animals? Dr. CORBETT. This is exactly the type of testing that the industry has done in its safety evaluation programs, starting over 10 years ago. The technique is to apply the hair dyes to the clipped skin of rats and mice and to leave the material in contact with the skin indefi- nitely rather than to wash it off, and to do this as frequently as phys- ically possible. This way we believe we get an exaggeration of about 300-fold over human experience. After doing this for the whole lifetime, in the case of five groups of animals that have been completed already with 2,4-diaminoanisole, we have never elicited any response. A total of 900 animals have been studied. Mr. LENT. You had a control group that you put something else on their coat and you had a test group that you applied hair dye to?. Dr. CORBETT. We put on a hair dye mixture simulating the product use by women. Mr. LENT. Have the results of these tests ever been turned over to the NCI? Dr. COREETT. Not as yet because they have yet to discuss the results on hair dyes at their clearinghouse. We have been compiling information to submit to members of the clearinghouse sometime during February for them to consider our data alongside the Insti- tute's data. Mr. LENT. Thank you, Mr. Chairman. Mr. Moss. The Chair recognizes the gentleman from Tennessee, Mr. Gore. Mr. GORE. Thank you, Mr. Chairman. Mr. Merritt, you said in your testimony that you support the removal of nitrosamines from cosmetics. Does that constitute a recognition that they are hazardous? Mr. MERRITT. This constitutes a recognition of nitrosamines as a contaminant in cosmetics, yes. It is a possible contaminant. Mr. GORE. There are lots and lots of products that have nitros- amines. There is a lengthy list. Reading over this list1 I recognize lots of common products. 24-600 0 - 78 - 60 PAGENO="0146" 140 How can it be removed if the Government has no authority to do it? Mr. MERRITT. Would you repeat the question? Mr. GORE. Are you proposing a voluntary removal of nitrosamines? Dr. CORBETT. No, we are not proposing only a voluntary removal. I would like to ask Dr. Estrin, who is our scientific vice president, and who has been working on the subject, with our industry task force since last summer, to respond. Mr. GORE. I do not want a long medical response on it. I want to know"whether you wo~ild recommend Government authority to have the removal of nitrosamines from cosmetic products. Mr. MERRITT. I would think they have the authority now under the present Federal Food, Drug, and Cosmetic Act. Mr. GORE. If they do not, you would recommend that they would have it? Mr. MERRITT. I think they do have it now. Mr. GORE. All right. What if it is not a contaminant, but part of,' the product itself, an ingredient? Let us say it is formed from the interaction of the ingredients. Then how do you deal with it? Mr. MERRITT. There again, I am not a scientist. I would have to defer to Dr. Estrin on how you deal with the' scientific interaction of the chemicals. / But .1 will tell you that our goal is to reduce the level of that con~ taminant to its absolute lowest possible level. Mr. GORE. Why? Mr. MERRITT. Basically that is our policy with respect to every undesired chemical. Mr. GORE. Why is it undesirable? Why do you not want it in there? Mr. MERRITT. Because we want to produce the safest possible product under any circumstance. Mr. GORE. It is not safe? Mr. MERRITT. I am assuming from your comment that it is not safe. I am telling you that it is our policy and our goal-- Mr. GORE. Would you make the same assumption o~i other ingre- dients if I mentioned them and institute a program to remove them also? Mr. MERRITT. If you can get rid of them and still have a product, yes. Mr. GORE. Suppose you cannot get rid of them? Suppose they cause cancer, then what? Mr. MERRITT. We are right back to a benefit-risk analysis, with the consumer making a judgment based on knowledge of the risk and all the data. Mr. GORE. Are you willing to accept the proposition that nitrosa- mines cause cancer? Mr. MERRITT. I am not willing to accept it. On the basis of not being a scientist, I have to- Mr. GORE. I would like a brief answer, then I would like to get it from your scientific team there. Mr. ESTRIN. Many nitrosamines do cause cancer in animals. There is no evidence that they cause cancer in human beings. PAGENO="0147" 141 Mr. GORE. Then we are back at the animal-human juncture. Is it not true that the scientific community pretty well recognizes the validity of animahtesting, however, for carcinogenicity? Mr. ESTRIN. I have a paper before me by Dr. Tennenbaum on environmental nitroso compounds and their implications for public health. I do not want to read the whole paragraph, but it says in conclusion: It has to be said at the outset that it is exceedingly difficult, on the basis of present knowledge, and a definitive conclusion cannot be reached at this time. He is referring to the possible implications for man for these animal carcinogenicity tests~ Mr. GORE. To your knowledge, how many times has the scientific community found a substance that causes cancer in humans that does not cause it in animals? Mr. ESTRIN. I have no information ab6ut that. Dr. CORBETT. Arsenic and apparently benzene. This was testi- mony from Monday. I remember that. Mr. GORE. So of all the substances known to be carcinogenic, there are only two that have found to be carcinogenic in humans and not in animals? Dr. CORBETT. There are only 30 compounds known to be carcino- genic in man, so ont of all the substances there are only two. Mr. GORE. Would that indicate to you that there is some validity to animal testing? Dr. CORBETT. It does not at all. Mr. Moss. Would the gentleman yield to the Chair for a moment? Mr. GORE. Certainly. Mr. Moss. If there is no validjty to animal testing, then why do you, in your laboratories, undertake to use animals for testing purposes? Are you engaged in a useless exercise. Dr. CORBETT. Mr. Chairman, with respect to your asking me to try to be brief-and you have forced me in that position- Mr. Moss. I have not forced `you in that position. I have asked you to be brief, but not to the point where you could not respond, but not to give narratives. Dr. CORBETT. I did not `mean to imply that there was no validity in animal testing. ` Mr. Moss. Now we have a qualification. There is validity to anima1 testing, then? Dr. CORBETT. Yes. Mr. Moss. Is there total validity to any testing? Dr. CORBETT. Not' in animals, no. Mr. Moss. In any of the testing that you do, is there total validity to any of it? Dr. CORBETT~ It depends on what you state the objective to be in the first place. Mr. Moss. Do you have a total objective? Dr. CORBETT. Yes. Mr. Moss~ Do you have total validity to the testing, then? Dr. CORBETT. If we set in our test the objective to demonstrate, as far as possible, by means which represent the route of human exposure, that certain materials are safe, then those tests are as valid as possible. PAGENO="0148" 142 Mr. Moss. You remind me of a story about the late Senator from Tennessee, Estes Kefauver, who said that he would like to have a one- handed scientist because everytime he talked with them, he heard them say: "But on the other hand." As a result, anything they told him was equivocal and somewhat meaningless. I am afraid that is what we are hearing here. Mr. GORE. You say you know some one-handed lawyers? Dr. COREETT. Yes. Mr. Moss. The Chair does not fall into the category of being a lawyer. Mr. GORE. Nor do I, Mr. Chairman, I hasten to add. I have heard of one-handed Congressmen, though. To be realistic about it, there scarcely has ever been a substance that has been found to be carcinogenic in every known species of animals, like nitrosamines, which do not show up to be carcinogenic. Let us be realistic about it. You have said there are only 30 known human carcinogens. Some of the~ are in hair dyes. That is what we are talking about. You~ have benzidine, for example. If you are willing to accept the validity of animal studies for nitro- samines, then it seems inconsistent to turn right around and say that you are not willing to accept the validity of those tests for other sub- stances that we are talking about here. It seems inconsistent to me. If you would like to comment, go ahead, and then I will yield to my colleague from New Jersey. Dr. CORBETT. I thinkI have to mention one thing here with regard to animal tests that show human carcinogenicity. Dr. John Weisburger, who actually started the NCI program, was telling me that in the next edition of his book he is going to write up an observation which he has recently made, that when one finds those compounds which are known human carcinogens and then tests them in animals, that the effects are quite dramatic. We mentioned one here this morning with regard to benzidine. You get 100 percent of cancers in the animals in a very short period of time. The things we have seen coming out of the NCI bioassay program with respect to hair dyes have not been that sort of results at all. They have been totally different types of results with four or five tumors here and massive thyroid tumors in the case of 2,4- diaminoanisole, and not at all consistent with the type of results that one got with human carcinogens. I must unload the premise that we have some of these human carcinogens in hair dyes. That is n&t true. Mr. GORE. What about this [indicating]? Dr. CORBETT. That has not been proved a human carcinogen other than by oral route. Mr. GORE. It is benzidine. It is on the list. There are 36 here. One of them is in this [indicating]. . Dr. CORBETT. That contains a. compound derived from benzidine. Mr. GORE. It contains a benzidine derivative which you, Dr. Corbett, have testified is converted into benzidine in the human body. PAGENO="0149" 143 Dr. CORBETT. If it gets into the human body. Mr. GORE. Are hair dyes absorbent? They are designed to he absorbent; right? Dr. CORBETT. That product is a temporary product which is designed to paint on the surface of the hair. Mr. GORE. Does the human body absorbe hair dyes? Dr. CORBETT. There are three classes of hair dyes: permanent, semipermanent, and temporary. Mr. GORE. Does the human body absorb all of them? Dr. CORBETT. No, not as far as we know. Permanent and semi- permanent can be absorbed, yes, but temporary is not even designed to penetrate into the hair fibers. It is designed to stay on the surface. Mr. GORE. Do you know for certain that the others are not ab- sorbed by the human body? Dr. CORBETT. It is my scientific judgment, but I do not know for certain. I think those dyes are too large to go into the human body through the skin. Mr. Moss. The time of the gentleman has expired. The Chair recognizes the gentleman from New Jersey, Mr. Maguire. Mr. Moss. I am sorry; Mr. Rinaldo. Mr. RINALDO. Mr. Merritt, on page 1 of your statement you say that the cosmetic industry accounts for about $9 billion of retail sales in the United States annually. Could you give us a rough idea of how much the industry spends on testing its products before marketing? Mr. MERRITT. We have no idea. We do not collect any statistics of that sort-that is, any operating ratio figures-because of possible antitrust implications. Mr. RINALDO. You could not give us any percentage? Mr. MERRITT. We do not have any figures of that sort. Mr. RINALDO. Do you perform more tests before marketing as opposed to after marketing? Mr. MERRITT. I would assume so. I would be virtually positive in every case that that would be true. Mr. RINALDO. What percentage of tests are performed prior to marketing a product as opposed to after a product is already on the market? Mr. MERRITT. I have no idea, but we could try to get those figures for you. Mr. RINALDO. Can you tell me whether or not the tests you do per- form are the same kinds of tests that the NCI performs? Mr. MERRITT. I would assume, in some cases, that the tests would. be the same as those conducted by NCI. However, I could not say and do not know with respect to many categories. Mr. RINALDO. Could you tell us in what areas or in what respect the tests are different than the tests performed by NCI. Mr. MERRITT. I think the NCI test is designed to screen those chemicals, which by their chemical structure, appear t~ be most likely to cause cancer. We are looking at finished products. Mr. RINALDO. It is my understanding from testimony, and from my knowledge of the subject matter, that when we talk about pretesting, it is defined differently than premarket approval. They are two different actual topics. PAGENO="0150" 144 What effect would the premarket approval have on your industry, if any? Mr. MERRITT. I think it could have a very severe effect on industry, as well as on the entire scientific community in its goals to find solutions to other problems. For premarket testing, Arthur D. Little did a survey for us 2 years ago in whjch they numbered the literally millions of animals and slides which would have to be reviewed by pathologists if this were required for the products on the market. The cost of the tests at that time would exceed the annual sales of the industry. It would take 30 years to complete that. Mr. Moss. If the gentleman will yield, could you supply that study for this record? Mr. MERRITT. We will supply that study for the record. Mr. Moss. Thank you. Without objection, that will be inserted into the record at this point. The results and the study. Mr. MERRITT. Yes, we will. [Testimony resumes on p. 179.] [The following material requested was received for the record.] PAGENO="0151" 145 DRAYf REPORT TO THE * LEGISLATIVE PLANNING GROUP Or~1~K I- S1Th~RY AND C0NCLUSIOI~ * Puhdamental characteristics of the cosmetic and toiletries industry are the large number of different products that it produces and offers for sale at any given time, and the annual rate of introduction of new products. A conservative estimate of the number of products mow available to retail outlets is about 25,500. According to the proposed Eagleton Bill (S.863), testing of all of these existing products would have to be completed within two and one-half years from the date of enactment of the legislation. Using the conservative number of 25,500 cosmetic products and ingredients outlined in this report, the minimum total number of animals required for the testing program proposed in the Eagleton Bill would be 38,154,000 rats, 60,879,000 mice, 6,826,000 rabbits, 504,000 dogs, and 96,000 guinea pigs. This requirement, in addition to animals needed for studies in other programs would severely tax the present animal breeding facil~ties. Por some products, the monkey might be the pi~e- f erred species, particularly for inhalation tests, and the number in- volved would probably necessitate expansfon of breeding facilities since most of the primates now used in research are imported and are currently in short supply. The total. cost of the testing program, if conducted on the estimated 25,500 products and ingredients, would appear to be at least $6,625,450,000. While the cost is not the limiting factor, it is worthy of consideration. Using the test methods described in the report, it ~iould require about 30 years to complete the program as outlined in the Eagleton Bill * One of the pr~.mary limiting factors is the small number of qualified pathologists (1,340) estimated to be currently available for evaluations of the 1,070,000,000 or so slides which would be produced. 76302 February 8, 1974 Arthur 1) Little Inc PAGENO="0152" 146 We assume that additional pathologists and other scientists wo~ild be added to the work force each year, but new products requiring similar testing will also be introduced. We understand that the overall number of cosmetic products has been increasing each year by perhaps 10%. Data collected strongly indicate that the laboratory facilities currently available for the required safety testing are inadequate to complete the studies in a time period near the two and one-half years required in th~e Eagleton Bill. The severe research impact of the requirements of the Eagleton Bill can be readily illustratrd if one assumes the utilization of all of the estimated 1,340 experimental and veterinary pathologists on a half-time basis. With this restriction one might evaluate about 2,000 products in the required two and one-half year period. (John A. Wenninger n the Food Drug and Cosmetic Law Journal, April 1972, pg. 213, reports ."one of the larger costnet~Lc manufacturers.. .produces over 2,000 sep- arate cosmetic products, exclusive of shade variations, and introduces about 50 new pioducts each year.") The effect of testing the 2,000 products, which is~ less than 10% of those currently on the market, would by this estimate have a strong and adverse impact on such major research programs as the testing of new drugs, food additives, agricultural and industrial chemicals and chemotherapeutic agents which must compete for the same facilities and ~ersonne1. The need for insuring the safety of products to be used by man is clear. However, it also is obvious that priorities must be assigned to ensure the most appropriate utilization of our research facilities and our scientific personnel. PAGENO="0153" 147 test animals or subjects, (3) the approximate duration of the test, and (4) the estimated cost of the test. The results of these analyses are shown in Table IV. For this study we also sought and obtained quantitative infor- * nation relating to the number of independent and captive industrial facilities capable of carrying out safety testing, and the number of toxicologists, pharmacologists, and experimental and veterinary patholo- gists availab)~e to supervise and execute such tests. We also conducted interviews with personnel at the National Cancer Institute to ascertain the rate of build-up of their program and of their facilities for screening various materials for carcinogenic activity. We were especially interested in the number of chemicals which the NCI had under test during the fiscal year 1973, and in the rate of introduction of new chemicals into their testing program. Since the level of- the testing effort recommended in the pro- posed Eagletbn bill, 5.863, will be largely determined by the number of cosmetic products and ingredients to be tested, at the very start of this program we attempted to obtain a reliable measure of the number of these products in "commercial distribution." We started by preparing a list of companies engaged in the manufacture of cosmetic and toiletries products and ingredients (see attachment). While this program was under way, we learned that the CTPA had sent out questionnaires to approximately 750 cosmetic and toiletries manufacturers requesting information on the number of products they had in "commercial distribution," as well as the number of new products they had introduced during the past year. Of the questionnaires sent out, 196 replies were returned. Only the information obtained from the questionnaires, as well as from the ingredients listed in the CTFA Cosmetic Ingredient Dictionary, 1973, ~First Edition, published by the Cosmetic, Toiletry, and Fragrance Association, was used to deter- mine the number of products and ingredients to be tested. We felt that any figures obtained by an extrapolation of these data could prove unreliable and that it was therefore wiser to use omly the documented numbers. PAGENO="0154" 148 III - ECONOMIC CHARACTERIZATION OF THE INDUSTRY This section presents some of the most significant aspects of the economic picture of the cosmetic and toiletries industry. For the purposes of this discussion, economics involves estimates of the number of companies engaged in the manufacture of cosmetic and toiletries products, the dollar value of sales, both at the manufacturers' and the retail level, the most active companies in the industry, retail sales for the various categories of products made and sold by the industry, and the average rate of growth of retail sales of toiletries and cosmetic products. In Section IV we shall consider. the number of products in "commercial distribution" and the rate of introduction of new products on a~per annum basis. While' it is estimated that about thirty companies account for about 85. percent of total in~Iustry sales at the manufacturers' level, many companies contribute to the remaining 15 percent. The estimaeed number of firms in the entire industry, is difficult to ascertain, and our current estimate is about 1785. (See appended document.) The U.S. Department of Commerce reports that industry sales at the manufacturers' level amounted to $4.24 billion in 1972. Measured at the retail level, industry sales for 1972 are reported as $5.3 billion. Table `I pres~nts the retail sales of cosmetrc and toiletries products for the years 1965 to 1972. Table II lists representative companies according to volume of cosmetic and toiletries sales ranging from $10 million per year to over $500 million per year. An examination of the rate of change of the, retail sales reported for the industry over the past few years indicates the rate of growth for the cosmetic segment of the industry to be about 10 percent per anrnnn, and that for toiletries, approximately 7 percent per annum. It should be noted that material shortages now experienced in many other industries will probably adversely affect the rate of growth of the cosmetic and toiletries industry, at `least over the next year. In addition to the above information, we have presented in Table III retail sales reported in terms of various product categories. PAGENO="0155" 149 TABLE I - RETAIL SALES OF COSMETICS & TOILETRIES 1965-1972 Retail Sales ($000,000) Cosmetics Toiletries Total 1965 1,062 - 2462 3,224 1966 1,169 2,389 3,558 1967 1,243 2,551 3,794 1968 1,359 2,725 4,084 - 1969 1,457 2,931 4,388, 1970 1,573 3,145 4,71k 1971 1,695 3,394 5,089 1972 1,815 3,509 5,314 Source: ~~g~Trade News 1965-1970, Product Management (October, 1973), and Arthur D. Little, Inc. Estimates PAGENO="0156" TABLE II - COMPANIES ACTIVE IN COSMETICS AND TOILETRIES, 1972 Total C&T Sales as I of Total Corporate Sales Corporate Sales C&T Sales I Domestic C.T. (MN$) (MM$) 100% 1005 70% 337.E 640E 50% Sub Totals 1645 35% 420 95% * ~panz Over $500 Million Avon Products, Inc. Colgate-Palmolive Co. Helena Rubinstein & toiletries Over $200 Million Bristol-Myers Co. * Clairol, B-M Products, Luzier The Procter & Gamble Co. Revlon, Inc. Johnson & Johnson Corp. The Gillette Co. Personal Care Division * Toiletries Division American Cyanamid Co. John H. Breck Inc., Shulton Norton Simon Inc. Max Factor & Co. 1005.3 1905.9 1201.2 3514.4 438.6 1317.7 870.5 U.S. C&T Sales (NM $) 700 320E 400 10% 77% 350 336 67% 70% * 235 235 * 28% 370 * 70% 260 38% 330 50% 165 70% * 161 40% 80 1358.9 17% 230E 1385.3 14% -* 200E Sub Totals *~3*~ 1536 PAGENO="0157" * Total C&T Sales as I of Total ~~pany ~q~p1orate Sales Corporate.Sales C&T Sales I Domestic C.T. U.S. C&T Sales (MM $) (~4j( 5) (~g~ $) * 5100-200 Million Alberto-Culver Co. 182.7 93% 170 83% * 142 Chesebrough-Pond's Inc. 350.8 46% 162 50% 81 Ponds, Prix~ce MatchabeUi, ICC Paberge, Inc. 145.1 87% * 126E 90% 113 Rayette, Faberge, Polly Bergen * Pfizer, Inc. 1093.4 11% l2OE 75% 90 Leeming/Pacquin Division, * Coty The Mennen Co. 100.0 100ZE 100 * Estee Lauder Inc.. 100.OE 100ZE * ~ 100 Squibb Corporation 769.5 13% 100 85% 85 Lanvin - Charles of the Ritz Line Sub Totals 878 * * 511+ 550-100 Million Schering-Plough Corp. 504.2 19%. 95 80% 76 Maybelline Co., * * * Coppertone Corp. * Lever Brothers Company * * 75E 100% 75E Eli Lilly & Company 819.7 9% 76 29% . 22 Elizabeth Arden Sales Corp. .* * * Helene Curtis Industries, Inc. 59.3 * 100% 59 83% 49 PAGENO="0158" Total C&TSale.s as % of Total ~~pany~ Corporate Sales Corporate Sales C&T Sales %_Domestic C.T. U.S. C&T Sales (MM$) (NM$) (1*I$) American Brands 2998.9 1.8% 53 83% 44 The Andrew Jergens Co. Noxéll Corp. 83.5 93% 78 83% 64 Sub Totals 436 329 $20-50 Million Bonne Bell Inc. 30.0 100% 30 100% 30 Smith Kline & Trench Labs. 402.3 7% 28 100% * 28 Love Cosmetics, Sea & Ski Merle Norman Cosmetics Inc. 28 100% 28 * 100% . 28 MEM Company Inc. 28 100% 28 100% 28 English Leather, Capucci DART Industries 888 3% 27 50% 14 (Vanda - Beauty Counselor) * $lO-20 Million Johnson Prodt~cts Co.,.Inc. 17.6 100% 17.6 100% 17.6 The Nestle-Lemur Co.. 10.1 100% 10.1 100% 10.1 Sources: Product Management (September 1973), Fortune (October 1973), Dun & Bradstreet Inc., Conpany Annual Reports, Arthur D. Little, Inc. Estimates PAGENO="0159" TABLE III - RETAIL SALES THROUGH ALL OUTLETS OF MAJOR CATEGORIES OF COSMETICS & TOILETRIES 1965, 1970, 1972 Hair Preparations Makeup Preparations Oral Hygiene Products Men's Toiletries External Persona]. Deodorants Fragrances Toilet Soaps Face Creams Hand Preparations Misc. md. Suntan Preparations Total 17 859 16 14 763 14 11. 566 11 .9 466 ~9 8 448 8 7 366 7 4 4 3 1965 1970 1972 Category $MM Z of Total $MM Zof Total $T'IM Zof Total 23 l;262 24 24 17 14 12 5. 7 9 1,083 803 661 521 430 380 333 771 540 465 374 176 236 299 154 132 77 5~ 217 239 4 174 4 198 2 116 2 147 3,224 iOO 4,718 100 5,314 100 Sources: Drug Trade News, Product Management, and Arthur D. Little, Inc. Estimates PAGENO="0160" 154 To determine the number of ingredients, we counted the materials listed by chemical nameçin~ the CTI?A Cosmeti redip~iOflar1~4 and obtained a total of l,52l.~ When we attempted to obtain an estimate of the number ot fragrances and commercially available components used for formulating fragrances for this purpose, we contacted several fragrance industry representatives. They were, however, unable to supply actual numbers and, instead, suggested a method they believed to be reasonable for estimating the number of Fragrances sold: by taking somewhere between 5 percent to 15 percent less than the number of individual cos- metic and toiletries product entities, we can obtain an estimate of the number of fragrances. If we assume that 85 percent'of the number of products reported' by the 197 companies responding to the CTFA question- naire had di~fe~ent fragrances, the estimated number of fragrances amounts to 2l,~00. - For estimating the extent of safety testing required under the pro- posed Eagleton legislation, we employed the number 25,500 products and in- gredients. We believe this to be a very conservative base, for the following .reasons (1) The totkl number of cosmetic prociucts obtained from' the responses to the questionnaire sent by the ~TFA were gained from 197 companies, or 26 percent of thope queried. Furthermore, we estimate (see attachment) that the number of firms in the industry exceeds 1,700. Thus, the product number is based on a small percentage of the firms that comprise this industry. While many of the companies that did respond are the larger manufacturers and therefore account' for a larger percentage of the ~5roducts than their number indicates, it is clear that there are many more than the 25,500 cosmetic products and ingredients produced and sold by the industry. PAGENO="0161" 155 (2) The product number base, 25,500, does not include almost 1,000 ingredients listed in the CTPA Dictionary4 under their chemical names. The figure also does not take into account the fact that, whi],e 1,521 materials are listed by chemical name, many of these compounds are made by more than one manufacturer and are not identical in all chemical and physical properties. If the ingredients are counted on the basis of trade names, the number obtained would be 4,968. This estimate of 25,500 compounds and ingredients does nçt include irigredi~nts listed by trade name. (3) Neither the number of fragrances nor commercially available components used for'forinulating fragrances are included in the 25,500 figure. As indicated above, by one method of estimation, the number of fragrances sold to the cosmetic and toiletries companies that responded to the CTFA questionnaire would amount to 21,000. (4). It' is also important to note that one of the distinguish- ing characteristics of the cosmetic and toiletries industry is the, rate at which new products are introduced into the market. As stated `above, almost 4,000 new products were introduced last year by the 197 companies responding to the CTFA questionnaire. We have not considered this factor in our discussion on safety testing, presented in a later section of this report. We recogniI~ that many cosmetic and toiletries products and ingredients that are n'bw offered for sale have been subjected to `some safety testing, though it is generally of a short-term nature. We have considered this fact in our study. 24.600 0 - 78 - 11 PAGENO="0162" 156 SOURCES 1, S.863, Cosmetic Safety Act of 1973, Introduced February 15, 1973: Sec. 103(b). A proposal, to amend the Federal Food, Drug and Cosmetic Act: Sec. 201(i). 2. The American Heritage Dictionary of the English Language, pub- lished by American Heritage Publishing Co., Inc. A Houghton }lifflin Company, 1973 Edition. 3. S.863, Cosz~etic Safety Act of 1973, Introduced February 15, 1973: Sec. 201. A proposal to amend the Federal Food, Drug and Cosmetic Act: Sec. 201. 4. CTFA Cosmetic Ingredient plctionary, 1973, First Edition, pub- lished by the Cosmetic, Toiletry and Fragrance Association. PAGENO="0163" 157 V.- DESCRIPTION AND BRIEF DISCUSSION OF TESTS FOR PRO~~~ SAFETY REQ~RED BY THE EAGLETON BLL The following description o~ tests required asa minimum by the Eagleton Bill should be considered only as guidelines and not as firm requirements of a particular agency, administration or department. In fact, opinions of many scientists are known to differ somewhat, not only as to the~number and type of animals to be employed, by what route, and how long they should be dosed and subsequently observed, but even which is the most appropriate test method. It is generally agreed, how- ever, that testing protocols should be flexible enough to accommodate products with different pharmaèo]ogical characteristics. Therefore, the test methods briefly described here represent our understanding of those which in the opinion of qualified experts appe5r to'produce the most reliable data under the present state of the art. The number of animals, duration of the tests, costs~ ~tc. are often presented as a range to reflect the various methods currently employed in a variety of labcra- tories. See Table IV. A. ~reclinfc~i~ 1. Acute oral toxicity"4 - Six groups of 10-20 male and 10-20 female rats or mice are given a single oral dose of the test mate- rial at graduated dose levels (generally spaced at 0.1 log dose intervals). This is most of teu admit~istered by intubation. The animals are observed for gross signs of systemic toxicity, pharmacological effects and mor- tality frequently on the day of dosing, and at' least once daily during the observation -period o~ 2-4 weeks. Autopsies are performed `on animals that succumb. and on preferably all or at least selected survivors. It is recomaended that two species of `animals be used to reveal possible * species differences in toxicity. The Lb50 value and slope o~ the dose response curve are calculated by one of the approved~thetbbds - such ~s the Cornfield4fat*tel modification of Karber's6 method. PAGENO="0164" TABLE IV MINIMUM REQUIREMENTS FOR SAFETY TESTS REQUIRED BY EAGLETON BILL EIFOARIATIOW 109011OR SUGGESTED USURER 09 4815*1.0 APPROXIMATE _b7~EACLET~!_!!74~ TEST ~(57~ 00 TEST SUBJECTS 5000T108 COBOBENTS ESTIMATED 01ST/F EXPOSURE I.cboll.d *ot.ri.1. D.gr~ of ins.nti.n ~ ,,i11 ~ ~ ~ 9008b D.gros of inh.lotion LonGs .Saholotign rot 6 72 hr. .sti.co. of th. qoaotity of the prod- R.gr.t of PAont.O*.gO 0.0 `bLob Right be ob.qrb.d by 5*0. obsorption POroR000onna 600 absorption 910 6 .~ 72 hr. Sadiol.b.i1.d nstorLol itt.rt and abrod.d .60*. 4855*1. STUDIES * Mitoopothelogy staloatiESsrsooonsndsd Short-ORES - Lost. Oral .0'.. 6 greops 10-20 5 6 10-20 9 (120-240) 2-4 oaks at 011 do.ags 1oo~1.. 01000-2000 - rot 6 g*otps 10-20 5 6 10-20 F (120-240) 2-4 o..k. In S*bolotion sEodis. a lisitod nosb.r 1000-2500 Schalotion rat 6 gr..pa 10-20 * & 10-20 F (120-240) 2-4 n..ka of ~nk.y~ n.y b. noro appropriate for 1000-2000 tORt satsrioi*. - d.r..1 (intano 0550-1000 * ORdabOOdcd.kin) rabbit 4grc.ap.-4-6 (167 2onnks IO505*0O5r5.abooR.o.~.tost. night.b. d..Srcbl.. - Subsotto - oral Jrot 6 group. 10-20 0 10-20 F (120-2405 1-3 nootb. 910,000-30,000 idos 4 gr~p* 2-4 0 2-4 F (16-32) 1-3 .000ltg MO St 00a 1 t.d !EOR SF - iobal*ti*n Oat 6 groops 5-10 8 6 5-10 F (60-120) 1-3 natO'. 0 50 509 nay 0 *000 Oppropratsop 7~15 000 - d.o.d rabbit 3-4 groups 6-8 (24-32) 21-90 day. *° ARt *000rials. 5,000-10,500 FDA Adnisory Cosnittos (1971) s.oonn.rdsd Long-t.o. - Chronic - oral Jsoasa 4 groups 50 8 50 P (4007 2 ynor. inoladitg rsprodottjot ttody. 0.0 tonbins 585,000-150,055 Irot 4 gro.sps 50 S 50 F (400) 2 years ohrotio tocitity cod ooroiong..ioioy tsnt- - ioholnnion ~.oo.. 4 ~rotpa 50 8 6 50 F (400) 2 yoaro ing. Rooosn.od ooposorn fron tr000ptiot 05,000-150,000 irot 4 grcaps 305 6 50 P (400) 2 yoors to dRain. d.*nal rabbit 3-4 groop. In inOslatino gtadios a united nossbnr 59,000-85,000 10-20 8 6.10-20 P (80-160) 2 ysor. of nonkcys nay ho noru spproprioto for Rondosly brad "Lifotin." eon, toot n00501ols. - Carcin.g.no.0. {.000s 4 group. 50 S 6 50 F (400) 2-2 1/2 yoor. 2 y..r dog stody tot eon iar.d 085,000-150,000 tio.ol 25 S 6 25 F/oro.p 2-2 1/2 years - M.tog.ne.i, * - doniaast 1.thal souos 3 cr0.9. 10 8 & 30 P/,r..h (7508) 3 south. - host s.di.n.d .ou.o 4 groops 3-10 (12-80) 1-2 nottbo Solcassilo on Rho test orgonion - ~oj~tios rot 20 gro.p. 3-5 (60-100) 48 houra-l oh 1,000-2,500 - Tarotogassuis {rs.t 4 srcup. 13-25 5 & 25-50 F (152-300) 6-9 esoks $25 000-33 009 rabbit 4 gra.po 5-10 5 & 10-15 P (60-109) 6-9 nooks- I A - Skin rabbit 6-12 (6-12) 72 hr - 2 .h... 0300-600 - Ey. rabbit 6-12 (6-12) 1-3 eke, 300-6 - Othon *50005 . 300-600 .ssbs0n.s rabbit or 000-2000 dog 6'12 (612) 48-72 ho. Photosonsitiaing rabbit 9-12 (9-12) 2-3no.ka - 309-500 SAFETY FACTOR . to Dr. too Prlod.ao (FDA) - at o 000 cession (1973). Vio,r hold by nose noports. SUSAN EXPESIENCE Cootsot Snoaioi,ity~ p~50~ t.sn. hu.an. 100 5 6 100 F Photes..sltiotty (200) ~6o..ka 010,000-25,000 PAGENO="0165" 159 2. Acute in1ialationto~ç~ç4t4 - Six groups of 10-20 male and 10-20 female rats are placed in inhalation chambers and exposed under controlled conditions for one hour to graduated atmospheric concentrations of the test material in gaseous or aerosol form. The rats are observed during the exposure period and daily for 2-4 weeks for gross signs of systemic toxicity. Autopsies are performed on animals which die and on all or selected survivors. - A limited number of monkeys may be more appropriate for some test materials. 3. Acute dermal toxicity~'4 - -Four groups of 4-6 rabbits are prepared by clipping the hair from the trunk. Half of the animals are further prepared by making epidermal abrasions e~tery two or three centimeters longitudinally and sufficiently deep to penetrate the stratum corneum but not deep enough to produce bleeding. A rubber or plastic slee~je i~ placed on each animal and the test material is iptro- duced under the sleeve at graduated dose levels. After 24 hours çhe sleeves are removed, the volume of unabsorbed material is measured, the skin reactions are noted and the animal is cleaned and placed in metab- olism cages for a two-week observation period. The animals are checked for gross signs of toxicity and blood and urine are examined for abnor- malities. Autopsies are. performed on animals that die and on all or selected survivors. 4. Subacute oral toxic1t~ - It *is recommended that at least two species of animals be employed in this test to indicate if there are species differences in toxicity. Six groups of 10-20 male and 10-20 female rats and four groups of 2-4 male aed 2-4 female dogs are given daily oral doses of the material at graduated dose levels for 1-3 months. The animals are observed for general condition, food and water consumption and gross signs of toxicity. At regular intervals blood chemistry, hematglogy and urinalysis tests are carried out. All animals are autopsied at death orat sacrifice at the completion of the study and examined for orgam weights and gross and microscopic pathology. PAGENO="0166" 160 5. Subacute inhalation toxic~.t~ - Six groups of 5-10 male and 5-10 female rats are exposed daily for 1-7 hours to graduated atmospheric concentrations of the test material vapor or mist, or for two continuous spray exposures (preferrably several hours apart) to an aerosol preparation for graduated periods of time (e.g. 30 seconds). Observations are made on syaptomatology, food and water intake, body weight and of the blood for morphological changes. At the conclusion of the study all animals are sacrificed and autopsied. }Iistopathological examination is carried out on all major organs. Additional data on the lung and chest effects may be obtained by comparing radiographs taken prior to and immediately following a series of ex~wsures. A limited number of monkeys may be more appropriate for some test materials. 6. Subacute dermal toxicit~~ - Four groups of 6-8 rabbits are dosed daily ior 90 days by application to clipped intact and/or abraded skin at graduated dose levels. In some cases it may be a4equate to use three groups of six rabbits dosed daily for 21 days on clipped intact and abraded skin. In both cases the animals are observed throughout the study for symptomatology, food and water consumption and body weight. Blood and urine are examined periodically. All animals are autopsied at the conclusion of the experiment. Histopathological evaluations are generally restricted to the area of application and major organs. 7. Chronic oral toxiciç~~ - At least four groups of about 50 male and 50 female rats or mice are administered daily oral doses of the test material. This is most often introduced into the diet. If carcinogenicity testing is to be combined in the same study, the number o~ animals in each group should be at least 50 males and 50 females. Several animals of each sex at each dose level may be sacrificed at intervals, e.g. 6, 12 and 18 months, for examination, Throughout the Study the animals are observed for gross signs of toxicity, food and PAGENO="0167" 161 water consumption, body weight and the appearance of tumors. At regular inter~vals blood and urine samples are examined. At the conclusion of the study allanimals are sacrificed and autopsied. The principal organs are wejghed and preserved for histopathologic~al examination. If dogs are used in evaluating chronic toxicity carcinogenicity, the study should be continued for about seven years. The FT~A Advisory Committee2 in 1971 recommended that chronic toxicity testing should involve exposure from'conception until death, and that chronic studies should include reproduction tests. 8. Chronic Inhalation toxic4~,y~ - may be desirable for products whose use involves exposure primarily by jnhalatipn. The procedure is the same as in the 90-day subacute study, except, that exposure should continue for 2 years. The number of animals to be examined is similar to the chronic aral study. If monkeys are the- -appropriate species 4-8 ~ and 4-8 ?/dosage level are udlized. , - 9. Chronic dermal toxic~y - may be necessary for preparations which are usually applied to the skin daily for long periods of time. The procedure is similar to the subacute dermal toxicity test but with greater numbers of animals. 10. Carcinogenesis3!~ - As noted above "lifetime" carcinogenesis studies in rodents may be combined with chronic toxicity testing to elitsi- nate some duplication of effort. At the present time the only recommended methods for carcinogenesis testing are "lifetime" (2-2 1/2 years) studies in rodents or seven-year studies in dogs. More raptd screening methods utilizing other species, microbiological techniques, etc. are being investigated for reliability. One of the more promising of these involves injecting the test material into a pregnant hamster and removing the exposed embryos 48 to 72 hours later. The embryonic cells are grown in tissue culture. Cancerous transformation is detected by standard PAGENO="0168" 162 microscopic study of colony morphology. Neoplastic transformation is confirmed by injecting the transformed cells into healthy x-irradiated weanling hamsters to see if they produce tumors. Changes. in colony morphology can often be seen within two weeks. In the trials to date three to 16 weeks were required for tumors to develop in the healthy animalS, although the animals were observed for one year. If this method is confirmed as being reliable it would result in considerable savings of both cost and time in earcinogenesis testing. - 11. Mutagenici~y~ - There is no one, recommended method for deteeting mutagenic effects due to a chemical. Methods with a high degree of presumptive human relevance include invivo cytogenetics, the host- mediated assay, and the dominant lethal assay. In the dominant lethal assay three groups of 10 males (mice or rats) are treated by an appropriate route and are mated during sequen- tial weekly periods with groups of untreated virgin females (3 per male) for a total ~f 8 weeks. The females are sacrificed in mid-pregnancy (Day 12 or 13 for mice) and scored for total implants comprising early and late fetal deaths and living fetuses. In the host mediated assay an indicator organism (Salmonella) is injected into the peritoneal cavity of a mammal. About four groups of 3-10 host animals (mice or rats) are then treated with the test compdtind by an appropriate route other than ~intraperitoneal. Several hours later the hosts are killed and the indicator organism is recovered and scored for mutants. In the in vivo cytogenetics assay the test compound is administered to four groups of 4 animals (mice or rats) by an appropriate route. Bone marrow and/or lymphocyte samples are taken at intervals by biopsy or at sacrifice of the animals and the chromosomes are examined. 12. Teratogenesis2 - It is recommended that studies of PAGENO="0169" 163 teratogenesis be carried out in at least two species. The mouse, rat, hamster and rabbit are suitable species. Four groups of at least 25 female rats or 15 female rabbits are treated with the test material by an appropriate route for at least 14 days prior to mating and during pregnancy. The day sperm are detected in a vaginal smear is considered Day 0. All dams are observed daily for changes in appearance or behavior. Autopsies are performed on all animals that die. Surviving animals are sacrificed at Day 20 or 21 for mice and rats, respectively and Day .30 for. rabbits an~ the fetuses and reproductive organs are examined. The number of dead and resorbed and living fetuses are recorded. The fetuses are examined for external, visceral and skeletal malformations. 13. Skin irritation"4 - Primary irritation of the skin is measured by a patch-test technique on the abraded and intact skin of a minimum of six albino rabbits per preparation tested. Equal numbers of exposures are made on abraded and intact skin. The abrasions should cut through the stratum corneuin, but not into the derma. These animals often are observed for 2 weeks to monitor lesions and their return to nQrtnal condition. The test substance is introduced under a one-inch patch and the animals is immobilized and wrapped if rubberized cloth or plastic for 24 hours. The skin is examined at the end of the 24-hour period and again at 72 hours. 14. Eye irritation1'4 - The test material is instilled into one eye of 6-12 albino rabbits. The other ~ye serves as the control. In one-third of the animals the treated eye is left unwashed. In the remaining animals the eye is washed two seconds or four seconds follow- ing treatment. The eye is examined at 24, 48 and 72 hours and at 4 and 7 days after treatment or as long as injury persists. 15. Irritation of other mucous, rnembranes~ - For some prepar- ations it may be necessary to determine irritation to vaginal or penile mucosa. For the former the dog is the species of choice - although the. rabbit is the preferred species for other tests on mucous membranes. PAGENO="0170" 164 The preparation is applied as directed and in excessive amounts to 6-12 animals. Reactions are read at 1, 2, 24, 48 and 72 hours after application. 16. Skin sensitization1'4 - The hair on the back and flanks of 6-12 male guinea pigs is removed by close clipping. The material being tested is injected intracutaneously every other day or three times weekly until.a total of ten injections have been given. The injections are made at rahdom over the back and upper flanks. Two weeks after the tenth injection a retest injection is made just below the region of the previous injections. After 24 hours readings are made of the dIameter, height and color of reaction ~re compared with the reactions after the initial injections. 17. PhotosensitIzation1 - Nine-twelve albino rabbits are exposed to UV irradiation to determine the amount which constitutes a suberythemal dose. Six of the rabbits are then treated with the test substance. All of the rabbits are exposed once daily until a total of 10 exposures (2' weeks) has been made. The degree of photosensitization is determined by comparison of the local effects in the treated and untreated subjects. B. Clinical 1. Skin sensitization1 Human tests should employ at least 200 individuals (100 male and 100 female) covering a range of ages appropriate for the product. The test material is applied by patch to an area on the arms or back. The patch is removed after 24 hours and a reading of the reaction is made. The area of erythema and edema is measured. The subjects are given a day's rest and then given a second patch application. This procedure is repeated until a series of ten consecutive exposures has been completed. The subjects are then given 10 to 14 day's rest after which a challenge dose is applied once. A comparison ~s made of reactions observed during the ten sensitizing PAGENO="0171" 165 doses with the reaction following the challenge dose. In some cases a "use" test where the product is distributed to a large test panel for use according to directions is conducted. However, the method lacks supervision and is generally considered leas satisfactory. 2. Photosensitiza~i~çp, Photosensitizing potential of a material is tested by determining the reaction to 1W irradiation follow- ing treatment with the material. A large populatLon of appropriate subjects is necessary for adeqtiate testingand the testshotjld only be made if animal testing has failed to provide evidence of photosensitization. PAGENO="0172" 166 SOURCES 1. Association of .Food and Drug Officials of the United States * "Appraisal of Safety of Chemicals in Foods, Drugs and Cosmetics" 1959. 2. Food and Drug Administration Advisory Committee on Protocols for Safety Evaluations: Panel on Reproduction Report on Reproduction Studies i0 the Safety Evaluation of Food Additives and Pesticide * Residues. Toxicol. Appl. Pharmacol. 16:264-296, 1970. 3. Food and Drug Administration Advisory Committee on Protocols for Safety Evaluation: Panel on Carcinogenesis Report on Cancer Testing in the Safety Evaluation, of Food Additives and Pesticides. Toxicol. Appl. Pharmacol. 20:419-438, 1971. 4. M. J. Thomas and P. A. Majors. "Animal, Human and Microbiological Testing of Cosmetic Products." J. Soc. Cosmet. Chem. 24:135-146, 1973. 5. Anon. Screening for Chemical Carcinogens. Lab Animal Sept.-Oct.: 39-40, 1973.' 6. CQrnfie1d~and Mantel. J.A.S.A. 45:193, 1950. 7. Health and Welfare, Canada. The Testing of Chemicals for Carcinogenicity, Mutagenicity, Terat~ogenicity. September 1973. PAGENO="0173" 167 VI A - DISCUSSION OF PERSONNEL REQUIREN~NTS FOR PRODUCT SAFETY TESTING In safety testing of foods, drugs and cosmetics the scientific and professional staff most likely to be involved are toxicologists, pharmacologists and pathologists. To estimate the present number of scientists with these specialties, the 1972-1973 membership lists of the Society of Toxicology, The American Society of Pharmacology and Experi- in~ntal Therapeutics, The American Society for Experimental Pathology and The American College of Veterinary Pathologists were examined. There is some overlap in memberships of these societies so an attempt was made to ensure that individuals with dual or multiple memberships would not be counted more than once. From these membership rosters it was deter- mined that the numbers of active U.S. members employed in academia, in- dustry or government are 344 toxicologists, 1595 pharmacologists, 1078 experimental ,pathologists and 262 veterinary pathologists. Among these, 10 toxicologists, 155 pharmacologists and 247 pathologists are assdciated with hospital and medical centers and may be engaged full time it~ clini- cal actiyities. These figures may also g4ve some indication of the relative numbers of personnel available to do clinical studies as compared to prec~inica1 studies. It is reasonable to assume that among these specialists needed fox safety testing the most limiting would be the number of pathologists, since pathologists would be required to interpret the microscope slides produced in the course of testing. No other scientist could properly perform this task. The need for an adequate number of qualified patholo- gists was underlined only last month by the designation of the training of experimental pathologists as a critical area among the National Cancer Plan Project Areas. It was estimated above that there are 1078 experi- mental pathologists and 262 veterinary pathologists active in the United States. It was assumed that members of the American College of Patholo~- gists would be either engaged full time in patient-oriented work and PAGENO="0174" 168 hospital-related research, or, if interestedin outside research, would be listed among the members of the American Society for Experimental Pathology. Therefore, it was assumed that there are now about 1340 pathologists available in this country who could participate in safety testing. It was further assumed that those pathologists who might be interested in participating in the safety evaluation of cosmetics would be able to spend not more than half of their time on this work because of current cbmipitments in other areas. We recognized that the amount of time required by the pathologist to evaluate each slide could vary tremendously depending on the nature of the lesions involved. However, if one assumes that the average number of slides that might be evaluated per day by a pathologist is 200, each cont~a1ning one or more sections of a given organ, the number of slides resulting from cosmetic safety evaluations which each pathologist might be able to process would be 100 per day or 500 per week. Using these figures the total work load capa- bilities of the pathologists presently available would be 670,000 slides per week.. The proposed Eagleton Bill requires that each product ~nd each ingredient of cosmetics, fragrances and tbiletries be tested for safety. As noted in a previous section of this report, the total number of cur- rently existing products and ingredients has not yet been determi'i~ed. However, the number of products is now definitely known to exceed 24,000 and the number of ingredients appears to be in the order of 1500. The testS required for each cosmetic product would, of course, vary with the nature of the product and its proposed use. Since the number of each type of cosmetic (face powder, lipstick, perfume, after-shave lotion, deodorant, etc.) contributing to the total number of products is not known at this time, for the purpose of estimating the work load involved, we have assumed that one third of the products would require testing by only one route of administration e.g. oral; one third would require test- ing by two routes e.g. oral and dermal; and one third would require test- in~ by three routes e,g. oral, dermal and inhalation. Concerning the ingredients,it may be adequate to test by one route of administration only. PAGENO="0175" 169 Using these estimates, 9500products and ingredie~nts would be tested by one route, 8000 by two routes and 8000 by three routes. For the relatively complete testing by each route of administra- tion as outlined in Table IV a minimum number of animals (mice, rats, rai~bits, dogs etc.), used in acute, subacute, chronic, carcinogenesis and irritation of mucous membrane studies on which micropathology would be required would be 1576 for test materials administered by the oral route only, 1712 for materials tested by oral and dermal routes and 3102 for materials tested orally, dermally and by inhalation. The number of slides for each animal varies depending on the species and on the test performed but might conservatively average, about 20 slides per animal. Therefore, there would be 31,520 slides produced for each product tested by one route, 34,240 for each product tested by two routes and 62,040 for each product tested by three routes. These figures do not include the slides produced in testing for mutagenicity since these slides often are evaluated by inicrobiologists and cytogeneticists and might not neces- sitate a pathologist. Using the number of products and ingredients esti- mated above, tile total number of slides produced would be 299,440:000 for materials tested by one route, 273,920,000 for materials tested by two routes and 496, 320,000 for the materials tested by three routes. The number of slides produced in testing all of the cosmetic products and ingredients currently on the market, therefbre, might be 1,069,680,000, all of which must be interpreted by a qualified pathologist. Since the estimated additional work load which the available pathologists might be able to assume is 670,000 slides per wtek, it would take approximately 1597 weeks or about 30 years to evaluate the slides generated in this program. PAGENO="0176" 170 NUMBER OF NENUERS or THE SOCIETY OF TOXICOLOGY Member' s Designation of Principal Activity No. Academic (A) 179 Government(G) 103 Industry (I) 202 Consultant (C) 31 Retired (R) 13 Other (0) 13 * Not indicated 74 AGorAGC 10 ACorACR 13 CRorCO 2 AIC, IC,. ICO, ICR, `AGIC, Al, 10, dO 18 - 658 Total number of members . . . . . 658 Foreign members 75 Retired or semi-retired 17 No. of active U. S. members 566 No. of members who are also members of one or more of the Societies of Pharmacology and Experimental Therapeutics and Experi- mental Pathology or the American College of Veterinary Pathologists 232 No. of Toxicologists not included in other' societies 334 *(Apparently a similar distribution'of activities as those indicating). PAGENO="0177" 171 ANERICAN SOCIETY FOR PHARMACOLOGY AN]) EXPERIMENTA THERAPEUTICS Total Number of Members - 1856 Honorary Members - 3 Retired Men~bers L15 Foreign Members 95 Members also ~nembers of Society for Exptl. Pathology ______ Number of Active U. S. Members 1637 Members in Private Practice 42 Members in Academia, industry or government 1595 Of these active members 155 are associated with hospitals and medical centers or drug abuse centers. Many of these may be involved full time in clinical practice. AMERICAN SOCIETY FOR EXPERIMENTAL PATHOLOGY Total Number of Members 12«=O Honorary Members .17 Retired Members . 60 Foreign Members 64 Number of Active U. S. Members 1109 Members in Private Practice 33. Members in Academia, industry or government 1078 Of these active members 247 are associated with hospital and medical centers. Many of these may be involved full time in clinical practice. 24-600 0 - 78 - 12 PAGENO="0178" 172 AMERICAN COLLEGE OF VETERINARY PATHOLOGISTS Total Number of Members 315 Foreign Members * 28 Number who are members of the Society for Experimental Pathology 25 Members not included in other societies 262 SCIENTIFIC MANPOWER ENGAGED IN R&D ACTIVITIES IN THE PHARMACEUTICAL INDUSTRY An indication of the demand for scientists and technicians (physicians, veterinarians, pathologists, toxicologists, pharmacologists, biochemists, chemists, biologists, pharmacists, botanists, microbiologists, nutritionists, etc.) for res~arch and development in the life sciences can be gained from viewing as a grouj~ the scientific and professional staff engaged ib R&D in the laboratories of the ethical pharmaceutical industry. These laboratories are reportedly the second largest performers of medical and health related research in the United States. Non-profit institutions (colleges and universities, hospital and research institutes) are the single largest performers and the laboratories and clinics of the federal government rank third. Public Health Service Publication No. 1443, Resources for Medical Research, Report No. 8, March, 1966, entitled "Trends in R&D Manpower in the Pharmaceutical Industry, 1959-65 and 1968" is used as the principal information source. The data in the report are based on information supplied, on a voluntary basis, by 100 member firms of the Pharmaceutical Manufacturers Association with the consolidated data PAGENO="0179" 173 analysis being performed by National Institutes of Health. The 100 companies included in the survey are estimated to represent more than 907. of the total ethical pharmaceutical industry sales and probably about that same percentage of R&D manpower. The R&D staff of pharmaceutical companies increased from 11,400 in 1959 to an estimated 16,400 in 1965 with a projected need of 19,000 by the end of i96~8. For the entire period the R&D staff had increased at an annual rate of 6%. The Pharmaceutical Manufacturers Association reports that in 1972 the R&D staff of pharmaceutical companies increased to an estimated 21,000. It is further estimated that more than three-fifths of the medical and biological scientists employed by industry in R&D activi- ties are on the staff of pharmaceutical companies. - Table 5 summarizes the trends in en~p1oyment of R&D manpower in the pharmaceutical industry, from 1959 to 1965 with estimates of R&D staff in 1968 and ~972~. TABLE 5. R&D MANPOWER IN THE pHARNAq~EuncAL INDUSTRY BY TYPE OF STAFF, i959-197Z~ Ty~e of Staff 1959 1960 1961 1964 1965 1968. l9t2 Scientific and Professional 6,632 7,155 7,336 8,047 8,890 10,430 11,040 Technicians and Supporting 4~780 5~16Q 6,128 7,008 7~QQ ~ Total R&D Mat~power 11,412 12,915 13,464 15,055 16,390 18,915 21,065 `Dept. HE&W PHS Publication 1443, Pharmaceutical Mt gs. Ass'n., Arthur D. Little, Inc. PAGENO="0180" 174 The estimated number of full-time employees engaged by the pharmaceutical industry in R&D activities during 1972 according to level of education are summarized in Table 61. TABLE 6 Doctoral Less Than U.S. Type of Staff Degree MD BS Bachelor's Total Scientific and Professional 4,030 2,080 4,440 490 11,040 Technicians - 35 265 4,410 4,710 Supporting 250 255 485 4,325 5,315 U.S. Total ~4,280 2,-370 5,190 9,225 21,065 `Pharmaceutical Mfgs. Ass'n. estimates. During the last 11 years (1961-1972) the pharmaceutical industry's R&D staff has jncresed by approximately 8,000, and over the same time period has maintained a high degree of stability in terms of the makeup of its R&D staff. About 55% of the total R&D staff are scientists and professionals, and 45% are technicians and supporting staff (Chart 1). In 1961, of the total R&D staff by level of training approximately 25% held doctoral degrees, 10% master's degrees, 25% bachelor's degrees and 4GZ less than bachelor's degrees. In the scientific and professional staff category approximately 39% held doctoral degrees in 1964. In the same category in 1972 approximately 37% held doctoral degrees. Table 7 is a summary comparison for the years 1964 and 1972 of the estimated total scientific and professional staff engaged in R&D in the pharmaceutical industry by level of training.' TABLE 7 Scientific and Professional Staff Level of Training 1964 Percent 1972 Percent Doctoral 3,118 38.7 4,030 36.5 Less Than Doctoral ~ 61.3 7,010 63.5 Total 8,047 100.0 11,040 100.0 1Dept. }IE&W PHS Publication 1443, Pharmaceutical Mfgrs. Ass'n., Arthur D. Little, Inc. PAGENO="0181" 22,000 20,000 18,000 16,000 14,000 12,000 tiumber of 10,000 R&D 8,000 Personnel 6,000 4,000 2,000 175 1961 1964 1965 16390 15055 - - -# 13464 3 54' J~L ~i~ZZ~ 21065 18915 / Technicians Supporting Staff Scientific & Professional : Staff CHART 1 R&D Manpower In. the Pharmaceutical Industry by Type of Staff 1961 - 19721 1Dept. HEW PHS Publication 1443, Pharmaceutical Manufacturers Assoc., Arthur D. Little, Inc. PAGENO="0182" 176 VI-B PRELIMINARY ESTIMATES OF FACILITIES AVAILABLE FOR CONDUCTING PRODUCT SAFETY TESTING The Animal Welfare Act of 1966 (Public Law 89-544) as ammended by the Animal Welfare Act of 1970 (Public Law 91-579) (7 U.S.C. 2131 at seq.) requires the registration of all laboratory facilities including those in acaçlemia, hospitals, industry, research institutes, etc., that utilize animals for research purposes including product safety testing. A current listing of the registered research facilities in the United States appeared in the Federal Register, Vol. 37, No. 147, July 29, 1972. This listing, along with a more recent listing of additions to the published list obtained from the U.S.D.A., shows a total of 775 registered research facilities in the United States including Puerto 4Uco. A review of the listing was made to establish the types of facilities in ~rder to further determine the potential number of. laboratories that could be considered available to conduct the tests described in Sec. V of this report and contained in the proposed legis- lation (Eagleton Bill). The table below summarizes the results of a review of the regis- tered research facilities listing. . Type of Facility Total Number Universities and Hospitals 510 Industrial (Captive) 125 Independent 104 Government (Federal, State, County) 14 Other (Zoos, Museums, Associations, etc.) 22 Total 755 PAGENO="0183" 177 A review `of the 1972 American Council of Independent Labora- tories, Directory of Toxicology Laboratories indicates a total of 23 independent toxicology laboratories. Across check ~f this directory with the U.S.D.A. registered research facilities listing further indicates that only 7 of the 23 are registered research facilities. It is highly unlikely that even all of the 104 independent registered research facilities out of the total of 775 listed would be available to perform the preclinical (animal) studies required in the proposed legislation. PAGENO="0184" 178 VI-C OVERVIEW OF PERSONFEL AND FACILITIES It is readily apparent from the information presented above that additional bioscientific personnel and facilities will be required to evaluate the more than 25,500 cosmetic products and their ingredients as required by the proposed Eagleton Bill. A realistic indication of how rapidly such a prograa might he initiated and expanded can be oh- tamed by examining the growth record of the NCI Carcinogenesis Program. Under this program the work is carried out by outside contractors in addition to the NCI Frederick Cancer Research Center1 which was insti- tuted about 2 1/2 years ago. . This large-scale bioassay program is designed to determine the carcinogenicity and chronic toxicity in rats and mice of chemicals including insecticides, herbicides, commercial products and industrial compounds selected by the NCI. The test proto- col states that fifty males and fifty females of each species are given each compound at the maximum test dose (MTD) end 1/2 MTD. Twenty control animals of edch sex are used for each compound. After necropsy 32 tissues from each animal will be examined histologically. We understand that in 1961-62 the initial Field Studies, as they were designated at that time, were conducted by about 4 contractors and were concerned with the effects of about 30 compounds. We also understand that about 300 compounds will be under study during 1974. Approximately 30 of these compounds will be investigated at the NCI Frederick Cancer Research Center, the remainder by contractors. Using this example two factors appear clear: 1) If one attempts to gather appropriate personnel and facilities, building an entirely new organ- ization such as the Frederick Center to conduct toxicity studies, more than 2 years would be required for its assembly and the anticipated initial capacity might be about 30 compounds/year; 2) Growth within the NCI Carcinogenesis Program, in terms of the number of compounds/year which have been studied from 1962-1973, has been in the order of 30 expanding to 300 or an increase of about 30 compounds/year. Comparing these figures with ~ cosmetic products and their ingredients to be evaluated shows the staggering nature of the task outlined in the Eagleton Bill. 1Carcinogenesis Program - Second Annual Collaborative Conference, November 25-29, 1973 El Tropicano Motel, San Antonio, Texas. PAGENO="0185" i79 Mr. RINALDO. Let us go now to the pretesting. Would an absolute requirement, a statutory requirement, that all products be pretested, have any such detrimental effect? Mr. MERRITT. Here again, Congressman, the difference between premark~t testing and premarket evaluation becomes very important. When. you have a number of products-and I recognize the need to be brief here-in which the changes are very minor and the experience of those ingredients for possible chemical reaction is minimal, then a premarket evaluation may show that the anticipated result would not be one of detriment to the consumer. Testing, then, is not necessary. If that evaluation results in a finding that testing should be done, then it is up to the manufacturer to substantiate the safety of that product by testing before he markets it. Mr. RINALDO. I take it you contend that the manufacturer should substantiate the safety of the product on a voluntary basis? Mr. MERRITT. That is required by regulation by the Food and Drug Adniinistration. Mr. RINALDO. Is there really good reason not to require a mandatory pretesting? Mr. MERRITT. Pretesting? Mr. RINALDO. Yes. Mr. MERRITT. If you mandate a litany of tests, you could overload the scientific community to such an extent that it could not handle all the tests that would be required. Mr. RINALDO. Let us go another step further down the line. It is my understanding that you believe that the current system-safety substantiation with FDA oversight-is sufficient to protect the public. Dr. Upton testified that. there exist something like 4~ million chem- icals while testing capacity is only 200 to 500 tests a year. How can we be so sure that the current safeguards are enough, based upon such a small testing capacity? In other words, is it not the fact that we really do not know? You are telling me, and the committee, I assume, that you feel you have enough information. You feel you can protect the industry and that you can get by with this minimal amount of pre-test, but you really are not sure are you? I do not think you can say with any degree of certainty that you are positive that you are performing enough tests, or that you are really getting at the crux of the problem. Is this correct? Mr. MERRITT. I think basically the National Cancer Institute's screening program is designed to attack the problem you are talking about. They would pick those chemicals where the priority seems highest and test those. We believe that th~ priorities and the allocation of resources should identify the areas where the injury is most likely to result and attack those problems. Mr. RINALDO. From their testimony, I gathered~ that they are spending, in my opinion, an inadequate amount of money on tests and that certainly it has to be bolstered and increased. If my belief is correct, that the amount of i~oney spent on testing has to be increased, do you feel that this is solely a function of the PAGENO="0186" 180 NOT? Do you feel it is a governmental function? Do you think it is an industry function? Or, do you feel it is some combination? Certainly I think, we can all agree that more testing must be done. Mr. MERRITT. Yes. I think it is a combination of responsibility. It is a responsibility of the regulatory agency, the National Cancer Institute, and the industry itself. CTFA, as one step in this effort, developed and established the cosmetic ingredient review program to conduct such a study on a concentrated basis of all ingredients used in the industry. We `have named an independent expert panel. We have permitted consumers and the Food and Drug Administration to name representatives to that panel and to meet with the panel to do, on a cooperative basis, an open and independent review with a gathering of all the data of all chemicals known to be used in the industry. They will develop a priority for review of those chemicals and will solicit all industry, governmental, and consumer input into this program. That expert panel, then, independent as it is, and which meets the Federal advisory committee requirements for independence, conducts an ongoing review of these ingredients and does this on a cooperative basis to keep the cost to the public-as well as to `the industry-to a minimum. They make that data and the results of that review avail- able to the entire industry, the scientific community, the regulatory agencies, and the public. Mr. RINALDO. Do you feel that would be adequate? Mr. MERRITT. We feel it goes a long way in the present state of the'art in being adequate. Mr. RINALDO. But then you say in your statement, however, and I will quote you: "Consumers should have the right to determine for themselves the risks they are willing to take." I am concerned. I wonder whether the consumer really knows what type of risk he is subjecting his body to; that is, whether there is a risk of cancer when he uses these products. Therefore, I do not particularly understand the statement. I think it is a highly significant one, but when you say that the consumers should have the right to determine the risk for themselves, I think we are really placing the burden on the wrong shoulders. Mr. MERRITT. We are saying that the consumer should have the right to make the judgment and to accept or reject the risk based on the total body of science involved. Mr. RINALDO. Mr. Chairman, may I follow up? Mr. Moss. Yes. Mr. RINALDO. If you say that, and if we accept that as true, then why, do you oppose the FDA's labeling requirement? Specifically, if T were to agree with you and say: "Well, let us let the consumer make the judgment himself," then I would hope the consumer would have the benefit of some kind of warning; perhaps some labeling requirement to advise him of the potential risk. Otherwise, he is making the determination in a complete vacuum. Mr. MERRITT. Mr. Hutt commented on that. Perhaps he could comment again. Mr. HTJTT. Let me try to be very brief on that. PAGENO="0187" 181 The industry at this point has nOt come to a final conclusion. Therefore, we have some difficulty giving the definitive position of CTFA on this. However, the tentative position is that there is insufficient factual information to justify singling out hair dyes for a specific warning. The other part of this is this. There are many other hazards in consumer products that every one of us subjects ourselves to every day that are far more serious and bear no warning. The OTFA does not believe that there is any justificatIon for singling out one product that poses a relatively small risk and not pointing out- Mr. RINALDO. You are not answering the question as far as labeling goes. If you are opposed to the FDA labeling, then what kind of label would you be in favor of? Mr. HUTT. Mr. Gore suggested that consumers ought to be given the information on the relative risks of all hazards. For example- and I will just use one-the Food and Drug Administration has esti- mated that its current guidelines for afiatoxin contamination of peanuts will result in 66 bladder cancers per 100,000 lifetimes. That is much higher than any risk that one can imagine or could possibly calculate under any theory for hair dyes. Yet, with that risk, there is no label warning for peanuts. What CTFA says is: If you are going to tell the public about risks from hair dyes, then you must also tell the public about risks from caffine that is shown to be an animal carcino- gen, egg yolks and egg whites that have been shown to be animal carcinogens, and tannin in tea that has been shown to be an animal carcinogen- Mr. Moss. The Chair has been indulgent. We have gone considerably over the time allocated. While it is an interesting narrative, `it is not really all important in helping the committee make the decision that `it is going to make in connection with these hearings. I think it is demonstrated that you are all' capable of talking at considerable length, but not necessarily constructively nor inst1~uctively. The Chair recognizes the gentleman from New'Jersey, Mr. Maguire. Mr. MAGUIRE. Thank you, Mr. Chairman. Mr. Merritt, in the early 1970's, an ingredient in hair dyes, 2,4- toluenediamine, was found to be a carcinogen. After this information was made public, the hair dye industry removed it from its products. Is that correct? Mr.' MERRITT. I believe that~tO be correct. Dr. Corbett is much more fully informed on those details than~I ani. Mr. MAGUIRE. Let us aesume that* is correct unless somebody has information to `the contrary. Why was it removed? Mr. MERRITT. I would again have to defer to Dr. Corbett on that point. Mr. MAGUIRE. You do not know the answer to that? Mr. MERRITT. I do not. We want to provide informative answers. Dr. Corbett is an expert and a scientist. I prefer that he answer that. Mr. MAGUIRE. ~Dr. Corbett? PAGENO="0188" 182 Dr. CORBETT. It was removed because there were reports that under conditions of feeding animals 2,4-toluenediamine, that were carried out in Japan, cancers were produced in the liver. The industry, at that time, having no data of its own on that particular ingredient, felt ~t wisest to drop its use. Mr. MAGUIRE. A situation analogous to the one we have today with respect to DAA? Dr. CORBETT. Not at all. Mr. MAGUIRE. The word "fatuous" is defined in the dictionary as "delusive, self-deceiving, complacently or unconsciously stupid." I have had time to reflect here as I have listened to this discussion that perhaps that adjective is descriptive of what we are hearing today from you gentlemen. Did you replace TDA with another chemical? Dr. CORBETT. Yes. Mr. MAGUIRE. What was that? Dr. CORBETT. It was m-phenylenediamine. Mr. MAGUIRE. Is that similar to, or the same as, 2-4-diaminoani- sole? Dr. CORBETT. It is not the same material; no. Mr~ MAGUIRE. Is it in the same family or class? Dr. CORBETT. It is a m-diamine; yes. Mr. MAGUIRE. Did you increase the use of 2-4 diaminoanisole after you removed the 2,4-TDA from your product? Dr. C0RBETT. No. I am afraid your adviser has a lot of misinforma- tion. Mr. MAQUIRE. I did not ask for your gratituous comment. I am asking the questions. You may supply me with the answers. But you are aware that the two compounds, TDA and DAA, have almost identical chemicals; is that correct? Dr. CORBETT. They are similar, but I would not say "almost identjcal." There is a significant difference. Mr. MAGUIRE. Are you also aware that many biochemists would, by looking at 2-4---DAA believe that the chances are more than 50 percent, that because of its structural similarity to 2,4-TDA, react almost the same, that is, that it would also be a mutagen and a potential carcinogen? Dr.. CORBETT. I do not think they would come to that conclusion just be looking at the structure. As I said., it has a very significant difference. Mr. MAGUIRE. But you have had data from the Ames test, I believe, since 1975, with respect to specific tests on these specific chemicals, have you not? Dr. CORBETT. Yes, in terms of the Ames test. Mr. MAGiJIRE. According to testimony that we have from Dr. Ames, those results have been duplicated by other tests; is that correct? Dr. CORBETT. I have repeated that test myself and have gotten the same results; yes. Mr. MAGUIRE. We have TDA removed and you indicate that the test showed carcinogenic property with respect to animals. Here today you are telling us that you have no intention, as I understand PAGENO="0189" 183 it, of doing anything about DAA, despite tests which show mutagenic- ity and carcinogenicity. It seems to me that is an anomaly, to put the most gentle word upon it. Do you still believe that TDA should be excluded from your products? Dr. CORBETT. I think I have to answer the question at length. 1 have answered all the other questions briefly. The situation today does not give rise to an anomalous or fatuous comment on our part. In 1970, we had no data on 2,4-TDA. We did not even bother to gather data on 2,4,-TDA, but we removed it from our product there and then. Today we are in a situation where we can cite already five groups of animals that have been exposed topically throughout their lifetime to hair dye compositions containing 2,4-diaminoanisole without a problem. The other difference is this 2,4-diaminoanisole is used at a rate- and I think you have an accurate figure but I will have to do it off the top of my head because I do not have it with me-of about 15,000 pounds a year; 2,4-TDA was used at about 100 pounds a year. I would not be prepared to fall back on the epidemiological evide nce of a long term exposure of the whole female hair dye user population to 100 pounds of a compound a year, but I am certainly prepared to fall back on it in respect of such widespread uses as has occurred with 2,4-diaminoanisole. So, I think it is a perfectly logical position that we take and not an anomalous one at all. Mr. MAGuIRE. Are you familjar with the scientific notion that it is impossible to define a safe threshold with respect to a carcinogen? Dr. COEBETT. I am familiar with the notion; yes. Mr. MAGUIRE. Is it one which you embrace or reject as a scientist? Dr. COEEETT. I just look at both sides. I cannot come down on one side or the other. I have read and accepted the development of theories which show that you can produce a mathematical model to show that the threshold theory could indeed be true. One of the things that I think is a misunderstanding about- Mr. MAGUIRE. The evidence seems to point to the truth of a linear hypothesis. What about that? Mr. OOREETT. I would not say that is true at all. Not all of the evidence. In fact, the tests which you are citing in terms of an animal test went from a very high level of thyroid tumors at one dose level and at a dose level that was only one-half of that, it went to no thyroid tumors in excess- Mr. MAGUIRE. So you are undecided on that point? Dr. CORBETT. It is* a position on which all scientists are undecided. Mr. MAGUIRE. In that case, let us assume for a moment that you are right about that, which, of course, you are not. Quite a number of scientists are very much convinced that there is no threshold. Certainly none that we can identify now. We have hact testimony to that effect~ In the event, though, that you are right, as a matter of public policy-and that is what we on this side of the table are coneertLed PAGENO="0190" 184 with-would you say that it makes sense to act to protect the public when we have tests which show carcinogenicity? I remind you that there are very few compounds that show those properties. Or, in the case of doubt, and assuming again that you are correct, do we simply continue to expose the public to those substances? Dr. CORBETT. I am sorry. I lost the thread of your question half- way through. Mr. MAGUIRE. Mr. Merritt, do you have an answer to the question? Mr. MERRITT. I think you have to look at the benefit and balance it with the risk involved. Mr. MAGUIRE. How do you justify the difference between TDA and DAA, Mr. Merritt? One has been taken out and the other has been left in. Mr. MERRITT. At the time TDA was removed, it was because there was an alternative. But with respect to the other, there is no alternative. Mr. MAGUIRE. There is no alternative? Mr.MERRITT. That is correct. Mr~ MAGUIRE. Have you pursued, over the last 40 years, since you received your exemption for hair dyes, a study of alternatives? Mr.,. MERRITT. I am sure the industry has looked, at every possible chemical for use in hair dyes. Mr. Moss. Have you really? The gentleman's time has expired. At this point the Chair recognizes Mr. Elliot Segal of the staff. Mr. SEGAL. Mr. Merritt, to clarify a point made before with respect to nitrosamines, are you testifying that end-products containing nitrosamines are safe or not safe? Mr: MERRITT. We do not know at ~this point. We take the position that nitrosamines are contaminants. Mr. SEGAL. Would you testify that a product containing mtro- samines presents a risk to its users, whether it is a contaminant or an ingredient? Mr. MERRITT. Not having been involved in all of the discussions, with your permission, I will defer that to Dr. Estrin, our scientific vice president, who has been in those committee discussions and has heard discussions and points of view that I have not heard. Mr1 SEGAL. Dr. Estrin? Dr.~. ESTRIN. It is true that there is no evidence that there is risk to human beings through the presence of nitrosamines in products. It is the association's position that these are contaminants that must be removed or brought to the lowest level possible. Mr. SEGAL. Are you testifying that it is a risk? Dr.' ESTRIN. I am testifying that I do not know what risks there are through the use of nitrosamines. But on the other hand, since they are contaminants, we are trying desperately to remove them from our products. Nitrosamines, as you know, are present everywhere in the environ- ment. They are made by our own digestive systems, through reactions of nitrites and amines. They are present in food products. Dr~ Fine will testify later that they are present- Mr, Moss. Again, unless it is necessary for the purpose of the record,, we know this. We have heard it many times. It does not do us any good to have it repeated time and time again. PAGENO="0191" 185 Please be brief. Mr. SEGAL. Do you believe that nitrosamines are carcinogenic? Dr. ESTRIN. Some nitrosamines have been shown to be carcinogenic in animals. To my knowledge none have been shown to be carcinogenic in human beings. Mr. SEGAL. Then you would presume they are not safe, that is, that they present a risk in any product, whether it is a contaminant or whether it is in there as an essential ingredient, if it is used by human beings, and has a potential risk? Is that not true? Dr. ESTRIN. The question is how much of a potential risk. Mr. SEGAL. Is it infinitesimal to a gross risk or any risk at all? Dr. ESTRIN. I would have no way of knowing. I have no way of knowing, becauae there is no evidence that it is a human carcinogen. Mr. SEGAL. And, yet, in your statement you say that you haveS taken all the steps to immediately convene a group and immediately remove these from all the products that are known. What if you cannot remove them? Are you then prepared to say that you are going to leave them in? Dr. ESTRIN. When we find that we can reduce them to the lowest possible level, or eliminate them, then we will have to deal with the question of benefit-risk just like we will have to do with every other consumer product that contains like materials. Mr. SEGAL. Are they on the market now? Are there products that contain nitrosamines now on the shelves of stores? Dr. ESTRIN. I would guess that there are. Dr. Fine published in March 1977, that there were 27 products that he examined. Excuse me, 13 of these products contained- Mr. Moss. We know that. We have the Fine study. Mr. SEGAL. Let us go through them. Max Factor ultralucent whipped cream makeup. Does that have, or does it not have, nitros- amines in it now? Dr. ESTRIN. I would not know. I would not know about a particular product. Mr. SEGAL. Do you dispute Dr. Fine's studies and findings? Dr. ESTRIN. I am not personally qualified to tell you. But I can tell y~ou that many of our manufacturers sent duplicative samples to Dr. Fine and not in all cases were the results reproducible. This is a sophisticated new technique. A lot more wOrk has to be done on it. We have confidence that it is a good technique and we are using that technique as part of our research program, which is to screen comprehensively the ingredients used in cosmetic products for nitrosamine content. Mr. SEGAL. Are there any products that were named by Dr. Fine, and confirmed by FDA, as showing nitrosamines that you have done a test on, and that you have determined do not contain nitrosamines? Dr. ESTRIN. I have personally not done tests. Mr. SEGAL. Has anybody within the Cosmetic, Toiletry, and Fragrance Association done any such tests? Mr. MERRITT. We have not done tests on. finished products. Our sole goal is looking at the ingredients and the possible causative factors of nitrosamine contamination of ingredients rather than finished products. PAGENO="0192" 186 Mr. SEGAL. So you have no reason to believe that the 25 products identified by Dr. Fine's study a containing nitrosamines do not contain nitrosamines today. Is that correct? Mr. MERRITT. We do not have any reason to believe it is true or untrue. Dr. ESTRIN. Of those 25 products, 13 nitrosamines at higher than traces leveli~. You said that 25 contained nitrosamines. Mr. SEctAL. Let me revise the question and ask you if the 13 that have more than trace levels, in those 13 that he found contained nitrosamines, are you prepared to say that you know or do not know whether they contain them? Dr. E5TRIN. I do not know personally. Mr. SEGAL. Nobody within CTFA is prepared to say that they have either tested these or confirmed the absence or presence? Dr. ESTRIN. I receive reports from a few companies that they had sent samples to Dr. Fine of the same material and received noncon- firmatory findings. Other companies did receive confirmatory findings. I do not know the names of the particular products and the particular companies off-hand. Mr. SEGAL. Mr. Chairman, could we have those supplied for the record; that is, the names of those companies? Mr. Moss. The material you have just described will be supplied for the record at this point. Is there objection to holding the record open to receiving it? Hearing none, such will be the order. [The following material was received for the record:] PAGENO="0193" 187 Avon Products, Inc. Avon Topaze 100 ngfg 9 West 57th St. Lot #33096 New York, N.Y. Revlon Research Center Revlon Young Blush >40 ng/g 945 Zerega Ave. Lot #621 Bronx, N.Y. Max Factor, Irt~. Max Factor Ultralucent 25,000* ngfg 1655 McCadden Place Whipped Creme Make-up 48,000 ng/g Hollywood, CA 90028 Revlon Research Revlon Moon Drops 3,700 ngfg 945 Zerega Ave. Lot #551 Bronx, N.Y. Helena Rubenstein, Inc. Helena Rtibenstein >1,200 nglg 300 Park Ave. Silk Fashion New York, N.Y. Lot #F11 Max Factor, Inc. Ma~t Factor Ultralucent trace~ 1655 NcCadden Place Waterproof Makeup Hollywood, CA 90028 Lot #509 Johnson & Johnson Research Johnsons's Baby Lotion 100 nglg H. Research Bldg. tracet Rte. #1 No. Brunswick, N.J. Westwood Pharmaceuticals, Inc. Ken Lotion trace~ 468 Zewitt St. Lot IJK'l4 Buffalo, N.Y. Noxell Corporatiba Noxzema Skin Cteam 8~ ngfg 11050 York Road Lot #2754 Baltimore, ND tt 0~ren Laboratories Nutraderm Dry ND P.O. Box 34630 Skin Lotiot~ Dallas, TX Lot #5M251 24.600 0 78 13 PAGENO="0194" 188 NAME AND COMPANY uuui RESULTS Beirsclorf, Inc. Nivea Cream Lotion trace~ P.O. Box 529 Lot. 116241 Duke Place S. Norwalk, CT Gillette Company Gillette Deep Magic trace~ Prudeittial Tower Building Lot #2366 Boston, M& Sea & Ski Corporation Sea & Skin Suntan trace~ Henley & James Labs. Lotion P.O. Bc'x 8082 Lot #11314 Philadelphia, PA Almay, Inc. Almay Deep Mist traces 562 5th Ave. . Extra Rich Lotion New York, N.Y. . Lot #504 Scholl, Inc. Scholl Cocoa Butter . 213 West Shore Lotion Lot //504 trace Chicago, IL Scholl Rough Skin Remover >140 ng/g Bain de Soleil Bain de Soleil 47 ngfg Div. of Lanvin-Charles of the Suntan Creme Ritz Lot #922 New York, N.Y. Leeming-Pacquin Extra Strength >22 ngfg Division of Pfizer, Inc. Desitin 235 E. 42nd St. New York, N.Y. Clairol, Inc. Clairol Herbal 260 ngfg 2 BI*nchley Road Essence Stamford, CT JohnBreck, Inc. Breck Shampoo traca~ 697 Route #46 . Dry Hair Clifton, N.J. Lot #4177 Rogers Wholesalers, Inc. PPP Baby Shampoo 100 ng/g (Distributor of Product) Lot //F29H 122-20 Nerrick Blvd. Jamaica, N.L Gilman Brothers, Inc. PPP Baby Shampoo 100 ng/g (Distributor of Product) Lot #F29H 20 Freeport St. Dorchester, NA PAGENO="0195" NAME AND COMPANY 189 PRODUCT The Nennen Company Hanover Ave. t~rristown, N.J. Sterliog Winthrop Research Inst. Rerinsselaier, N.Y. Proctor and Gamble, Inc.. P.O~. Box 599 Cincinnati, OH Wella Corpora1~ion 524 Grand Ave. Englewood, N.J. Clairol, Inc. 2 Blathley Road Stamford, CT Helene Curtfs, Inc. Nennen Baby Magic Shampoo Lot #5JH Diaperene Cradól Lot #Sl350L Head & Shbulders Shampoo Lot 1!~065686, Wella Balsam Lot #5r14 Clairol Creme .68 nglg Formula Hair Color * Identity of NDE1A confirmed by high resolution mass spectrometry Trace, Less than 10 ng/g ND, Less than 1 ngfg trace~ NDtt >70 ~ng/g tracet Hel~iie Curtis . . >27 ngfg Everynight Extra~-Body Conditioner Lot #1094 PAGENO="0196" 190 Mr. SEGAL. Dr. Corbett, I would like to switch to a statement you make concerning hair dyes on October 17, 1977: There is now a substantial body of research sponsored by the hair coloring industry, and by respected outside scientists, which confirms the safety of hair dyes. Who were the outside respected scientists? Mr. CORBETT. I must say I think "supports" would have been a better word to use, rather than "confirms." Mr. Moss. Would you speak up? Mr. CORBETT. I said that I now think that "supports" would have been a better word than "confirms." Mr. SEGAL. You would not today use the phrase you used on Octo- ber 17 that confirms the safety? You would like to change it? Mr. CORBETT. I think it might be interpreted to mean that I really believe that one could prove absolute safety. Of course, I do not be- lieve that. Mr. SEGAL. Let us use your revised statement with "supports" versus "confirms." Could you identify those scientists that you feel, that is, that you identified in that study of that time or your statement at that time, who support the safety of hair dyes? Mr. CORBETT. Yes. This work was done virtually all in independent laboratories. Mr. SEGAL. I am asking for names of individuals. Mr. CORBETT. But I have to look up some of them because I do not know who was the responsible person for the studies that were done. Mr. SEGAL. Would you include Dr. Hammond? Mr. CORBETT. Yes. Mr. SEGAL. How about Dr. Meigs? Mr. CORBETT. Yes. Mr. SEGAL. What about Dr. Kinlen? Mr. CORBETT. Yes. Mr. SEGAL. What about Dr. Morgan? Mr. CORBETT. Yes. Mr. SEGAL. Dr. Urbach? Mr. CORBETT. Yes. Mr. SEGAL. You would at least include those individuals? Mr. CORBETT. This is what I said. If you want a comprehensive list, then read the list of people who published the work. That is what you have just done. Mr. SEGAL. Mr. Chairman, I would like to have inserted in the record at this point an abstract of a study done under the supervision of Dr. Meigs of Yale. Mr. Moss. Is there objection? Hearing none, that will be the order. [The abstract referred to follows:] ABSTRACT-CANCER INCIDENCE AMONGST COSMETOLOGISTS (By Judy Wairath, Yale University) The purpose of this study was to determine whether cancer incidence rates among cosmetologists differ from normal. The population under study included all cosmetologists in Connecticut who began hairdressing school before December 31, 1965. School teachers in Connecticut were used as a comparison group and were matched individually to the cosmetologists by year of birth and sex. Cancer PAGENO="0197" 191 incidence rates for the Connecticut population, specific for age, sex, calendar year and cancer site were also compared with the observed incidence rates of the cosine- tologists. Cancer cases were ascertained through linkage of the files of the study subjects and matched comparison subjects with the files of the Connecticut Tumor Registry. There did not appear to be an excess risk of cancer amongst the cosmetologists in any site, with the exception of acute leukemia. This pre- liminary finding does, however, need additional investigation. Mr. SEGAIJ. You have seen this before. This is the one that was alluded to by Congressman Gore in earlier testimony where he read- and I will read it again: Cancer cases were ascertained through linkage of our files. . . There did not appear to be an excess risk of cancer amongst the cosmetologists in any site, with the exception of acute leukemia. Is acute leukemia a form of cancer? Dr. CORBI~TT. Yes. Mr. SEGAL. Would you say that finding a significant excess of acute leukemia does not conform with the statement made on page 8 of your testimony that: There is no direct link found by these two definitive studies showing a link between hair dyes and cancer? Dr. CORB1~YrP. I think I answered this question earlier by saying that Dr. Meigs is asking himself the question as to whether the excess was due to the apparent absence of any cases of acute leukemia among the teacher group. This is something he particularly wishes to study. But there are other studies that have gone over the broad range of different sites of cancer which come down on the side of there being no difference and no excess. Mr. SEGAL. We are talking about one of the individuals and one of the studies which you defined as one of the two definitive studies. One of the two definitive studies found an excess of acute leukemia and ended up indicating that more wo~rk needed to be done on its confirmation. Is that not right? Dr. CORBETT. Dr. Meigs said this. There was a letter to me on this subject: "Our concern about leukemia is based on the results of tables 7.5, 7.9, and 7.11, as well as section 9, pages 74-76. "These raise the question of whether some aspect of the work--" Mr. Moss. The Chair will have to interrupt until the item being read is identified and the members are in possession of a copy of it. This is a hearing, after all. It is for the purpose of informing the Members of Congress. Dr. CORBETT. I am sorry. I thought it was a letter he wrote to me. In fact, it is a letter that he wrote to you. Mr. Moss. I do not care what it is. I want to know what you are reading from. There is no process of intellectual osmosis going on here. I want to know what we are discussing. I have the letter now. Dr. CORBETT. It is dated January 17, 1978. Mr. Moss. Do the other members have the document? [Document passed out to members.] [The letter referred to follows:] PAGENO="0198" 192 CONNECTICUT CANCER EPIDEMIOLOGY PROGRAM PROGRAM COUNCIL Connecticut Cancer Epidetniology Unit ~n College Street Connectkut State Dept. of Health New Haven, Connecticut o6~ao Connecticut State Medical Society i :~L.i.L~~fj~ (uo~) 436-59n4 University of Connecticut Yale University J. Wtsmtt Metes, M.D., Director January 17, 1978 John S Moss Chairman Subnctmmittee on Oversight and Investigations of the Committee on Interstate and Foreign Commerce WASHINGTON D.C. 20515 9ear Mr. Moss: Thank you for your inquiry of December 28, 1977 in which you quoted a* statement of the Cosmetic, Toiletry and Fragrance Association (CTFA) and noted that I had been identified as the scientist who had provided information about our study of cancer risks in cosmetologists. Our Opinion that cosmetologists ?in Connecticut had not experienced an excess overall risk of cancer was based o~a preliminary report. It is confirmed by the complete report, which is en- closed for your use, in the form of the copyrighted dissertation prepared by .ludy Walrath, Ph.D., entitled "Cancer Incidence Amongst Cosmetologi~ts." The research was conducted by Dr. Walrath with consultation from Cohn White, M.B., B.S., Professor of Public Health (Biometry) and me, with support from the National Cancer Institute, Grant # l-ROl-CA-2O89O-O[~. This first study leaves several important questions unanswered and we are necking support for a second study to increase the size of the cosmetologist group by about 401, and try to ascertain complete follow-up for all cosmetol- ogists. Nevertheless, I believe we can provide comments that can help you and members of your Committee at this time. With respect to CTFA, we have had considerable technical assistance from them, as well as a small grant ($2500) in each of two years, to assist us with our work in this occupational health problem. it is essential that our interpretations of results be presented as ~clearly and unequivocally as possible to all persons with interests in this lubject. Accordingly, we are providing CTPA with copies of this correspondence. At a time when questions about "conflict of interest" are asked frequently, it is appropriate to explain our relationship with CTFA. One of their principal members, Clairol, Inc., has a plant as well as headquarters in Connecticut. We have received and will continue to solicit information from Clairol about their manufacturing processes as well as chemicals and processes pertinent to the PAGENO="0199" 193 3. W. Meigs to Mr. Moss, continued . occupational and consumer uses of their products in particular and other materials used by cosmetologists and the public. We have not solicited nor received pay- aent for consultant services froa either CTFA or Clairol. With respect to your first question, we assumed that licensure as a cos- metologisl implied substantial, frequent contact with hair care and other cosmetic preparations, in amounts greater on the average than would be experienced by persons in other occupational groups. Many different chemicals and combinations have been involved in these contacts over the years to Which our ~idy applies. Our observations of cosmetologists at wor1t~onfiraed that they havi ~pportunity for many different kinds of exposures., The evidence that cosmetologists in Connecticut have almost certainly, as a group, had far greater exposure to hair care a~d other cosmetic preparations than teachers, as a group, permitted us to design the study without including interviews with either cosmetologists or teachers. We do not expect to interview, persons in either group at this time. We were concerned with poseible health risks of any or all substances used regularly by cosmetologists in their occu- pation, and our study cannot distinguish hypothetical risks limited to hair dyes or any other specific hair care or other preparation used by cosmetologists. The question whether use of hair dyes, in particular, has been associated with greater than expected incidence o~ bladder cancer will be addressed in Con~ec~icut during the year 1978. Our Unit ~s cooperating in a national study sponSored by the Congress, the Food and flrug Administration aqd the National Cancer Institute, on environmental ~isk factors, particularly saccharin and other non-nutritive sweeteners, among persons who develop bladder cancer during 1978. Both cases and suitably selected control subjects will be interviewed and questions about hair dyes are included in the interview schedule. Results should be avail- able in early 1979. Your second question opens up a etudy design issue. We selected teachers as a matched comparison group for cosmetologists because we had access to their licensure records and because they were generally comparable to cosmetologists with regard to income. Our results show differences between the cancer experience of the two groups that are reasonably attributable to so-called "class" or cultural differences for which income alone would not be a good indicator, You may have noted that the total group of teachers experienced significantly more cancers of the breast and of the body of the uterus (uterine corpus) than the total group of cosmetologists. This result is not consistent with some pre- vious reports that beauticiafls have had a higher than expected risk for these two cancers. Our result would, however, fit the hypothesis that among the cohorts we studied, teachers, and especially the older teachers might have had socio- cultural characteristics differing from cosmetologists. Such characteristics as higher proportion of single persona, later ages at marriage and of first pregnancies, have been shown to associate with higher than expected breast cancer PAGENO="0200" 194 J. W, Meigs to Mr. Moss, continued . rates and lower than expected cervical cancer rates. Dr. Wairath's results on cervical cancer occurrence among cosmetologists compared with teachers are consistent with this socio-cultural hypothesis. Uterine corpus cancer risk has varied in relation to use of exogenous estrogens. We have no information about uses of estrogens by either cosmetologists or teachers. With respect to the latter part of your second question and your third questio~T, 1 hav~ `already noted the probable socio-cultural differences between teachers and cosmetologists in Connecticut that tend to limit our ability to draw firm conclusions ab~ut occupational risk factors. This first study was designed to learn whether large excess cancer risks had been experienced by cosmetologists. No significant overall difference was found between the cancer experience of the two groups. Dr. Walrath dealt with the limitations of cosmetologist-teacher comparisons by assessing the experience of cosmetologists for whom definite follow-up infor- mation was available and comparing it with the experience for the total Connecticut population of similar sex, age and time period. This latter information was available from the Connecticut Tumor, Registry, which has been in operation since 1935. The problem of this second method of cancer risk assessment was that, for the initial study, incomplete follow-up information for cosmetologists reduced the total person-years of risk that could be used for the statistical calculations. Nevertheless, the results from this work were generally in support of the cos- metologist-teacher comparisons. The method made it possible to calculate the expected number of cases of cancer for any desired grouping of cosmetologists and then to compare the number of cases of that cancer observed in the `selected group with the number expected for such a group if the members had had average Connecticut experience. Results of application of this method are presented in Dr. Walrath's report. Tables 7.5, pp 98, 99; 7.9, pp 104, 105; and 7.11, pp 107, 108 provide summaries. Table 7.5 shows that the total number of cancers observed among cosmetologists was about 72% of the expected total (71-73% depending on the method of calculstion). This figure is called the Standardized Incidence Ratio (SIR). Table 7.11 gives results adjusted to take account of an assumed "~iealthy worker effect." The assumption is made that persons who reach working age and are healthy enough to take jobs are less likely to develop cancer than the general population of com-. parable ages. ror Table 7.11, the SIR is adjusted upward to 100% so that the risks of cancers relative to each other can be detected more readily. Table 7.5 shows that there were fewer than expected cases o~ cancer of the breast, uterine cervix, body of uterus and ovary than expected. Although you did not ask about lung' cancer, the question of lung cancer risk among cosmetologists has been raised. You may wish to note that the SIR for lung cancer was 78% (Table 7.5), while the adjusted SIR (Table 7.11) was about 100%. PAGENO="0201" ~95 .1. W. Meigs to Mr. Moss, continued . Our concern about leukemia is based on the results of 1~ables 7.5, 7.9 and 7.11 as well as section 9, pp, 74-76. These raise the question whether some aspect of work as a cosmetologist may contribute to the development of leukemia. Table 7.9 does not suggest anincreased risk with increased exposure, but a slight excess number of cases over the expected value was noted in 4 of 5 cx- posure groups. We believe these results, when coupled with a ~1apanese report (Ishimura, see ref. on p. 137) are sufficient to justify a second, more comp].~te and intensive study of cosmetologists in Connecticut. If work as a cosmetologist increases the risk of leukemia to persons in that occupation, it is essential to interpret such a possibility with full appreciation of the uncertainties about practical implications. Any one or a combination of several materials or perhaps working conditions of cosmetologists might be important. Information available at this time provides us with no basis for an assessment of the carcinogenic risks of any particular chemical, This issue relates to your 4th question. We believe out s~tudy ii~4i'catCs that cosmetologists have not experienced excess risks of cancer in gen*al, since their overall Standardized Incidence Ratio was about 72Z of expected and the so~ called "healthy worker effect" is often associated with SIR values above that level. This does not imply that there are no specific cancer risks in this occupation. There may be a small excess risk for leukemia and this question should be investigated further. Our study, like other epidemiological studies, cannot be used to prove "safety". The results seem at this time to be consistent with the view that none of the materials with which cosmetologists in Connecticut had contact after 1938 was a highly carcinogenic material. Such materials included, but were not limited to hair dyes. If you have further questions I should be pleased to try to answer them. Sincetely yours, J. Wister ~deigs, M. Director Clinical Professor, Epidemiology JWM:lp cc: Dr. John Corbett PAGENO="0202" 196 Mr. MERRITT. Mr. Chairman, while that is being distributed, may I make a comment with respect to epidemiological studies? Mr. Moss. Is it responsive to any inquiry? Mr. MERRITT. It is related to the subject. Mr. Moss. Is it responsive, to the inquiry. on discussion now? Mr. MERRITT. We will hold it until later. I was trying to save the committee's time. Mr. Moss. That will be fine. Dr. Corbett, you may proceed. Dr. CORBETT. This is not the letter I thought it was. In the letter he wrote to me, he did not go as far as this, but his conclusion is that: "The' results are sufficient to justify a second and more complete and intensive study of cosmetologists in Connecticut." As I pointed out, there were a number of studies also where no excess of leukemia occurred. Mr. SEGAL. Were they the two definitive studies you referred to on page 8 of your `testimony? Di~. CORI~ETT. Yes. Mr. SEGAL. Which of the other two definitive studies are there? You' identify here: "We are concerned NIOSH has chosen to rely on two epidemiological studies." This is page 8 of your prepared state- ment by CTFA. "And ignore two definitive epidemioiogical studies." One is the American Cancer Society and the other is the Yale funded one, which we are now talking about. You are talking about other tests beyond those? Dr. CORBETT. No; we are talking about just these tests. Mr. SEGAL. We are saying that one of the two tests was the one that found an excess of acute leukemia; is that right? Dr. CORBETT. Yes. Mr. SEGAL. And suggests there be further followup work on that; is that right? Dr. CORBETT. Yes. Mr. SEGAL. Does that confirm the safety of hair dyes? Dr. CORBETT. It does not confirm the safety of hair dyes. Mr. SEGAL. It does or does not? Dr. CORBETT. In absolute terms, no, but in general terms with the data that we have from other sources, yes. We have animal data- Mr. SEGAL. We are talking about epidemiology. Let us stay with that. You have identified two definitive ones. We have talked about one of them. You have, in effect, changed the testimony. Now you say these studies confirm the safety and the definitive study shows no risk. We have now identified leukemia and we have identified a need for a followup study, and, therefore, a potential risk. Is that not correct? Dr. CORBETT. A possibility; yes. Mr. SEGAL. Let us now ask about the second epidemiological study, that is, the other definitive one, which is Dr. Hammond's study. For identification purposes I would like to ask that a presentation of Dr. Hammond's, which was made in April 1977, which is in the member's folders, be inserted into the record at this point. Mr. Moss. Is there objection? Hearing none, such is the order. PAGENO="0203" 197 [The material referred to follows:] AMERICAN CANCER SOCIETY NEWS SERVICE 777 THIRD AVENUE NEW YORK. N.Y. $007 /UI1$~iCan Cau~er Society's I2t2~ 377.2E00 NINETEEIITR SCIENCE WRITEP.S' SEMINAR - Sd~asota Hyatt House Sarasota, Florida April 1 6, 1977 TI TI' ~es'~ntation: Tuesday morning, April 5 For Release: W~NESDAY AM's, April 6 -- EXCERPTED FROM: ~OME NECATIV~ FI~DING~P~~J SMALl POX~ TETANUS AND DIPRTHERL~-VACC~NE~; B!LUTICIA~S)~ AND EVALUATION OF RISKS E. CUYLER HIIMOND, Sc.D. (64), Vice President for Epidemiology and Statistics, Mterican Cancer Society. Dr. Hammond was born in Baltimore, Md., and received his Doctor of Science degree (Sc.D.) from Johns Hopkins tTtiiversity. He joined the American Cancer Society in 1946 after serving in the U.S. Army A~r Force as Asst. Chief of the statistics div1s~on, office of the Air Surgeon. Prior to this he served four years with the Division of Industrial Hygiene. Dr. Hammond also is adjunct professor in community medicine, Mt. Sinai School of Medicine; a member of the scientific advisory panel of Research to Prevent Blindness, Inc.; assocIate editor of Environmantal Research; advisory editor of Ca-A Cancer .~ournal for C1I~ici~~; and a member of the Board of Directors and past presIdent of the New Yora Academy of Son,'eo PAGENO="0204" 108 SOME NEGATIVE FIflDINGS (POLTO, SNALL POX, TETANUS AND DIPHTRERIA~VACCINtS~ BEAUTICIANS) ~D EVALUATION OF RISKS E. Cuyler Hanunond, Sc.D. Z~,.ø~peMedPt~j*~vrk `~thi ~ o~heb1ico-c~rc±nocsrd~~carc inogens-in ~ ectremc~ tthe~oth~. Some people are alarmed., to a far greater degree than is ~ They fear to eat anything but natural food grown without nan-made fertilizers and insenti- cides and with nothing added later. They think that air pollution will cause then to die of cancar as will contact with manifold products of industry. They do not ask `what is harmful? They ask "what, if anything, is safe?" Some workers are fearful of losing their jobs in these tines of unemployment. For example, a friend of mine, who had reason to suspect that a certain substance with which he works is carcinogenic, recently said to us: `For God sake don't prove that it causes cancer. If you do, it will be banned and I wifl ldse my job. At my age, I will never be able to find any other decent job." This is not an uncommon attitude. PAGENO="0205" 199 H~inn~ond `~pàge2 A growing number of people are becoming annoyed if not angry about the whole affair. "What are they going to prohibit next? Sex?" Many of these people express the opinion that government and scientists should stop their meddling and leave people alone. They are also becoming highly skeptical of pronouncements made by "authorities" including medical and scientific "authprities". If this attitude becomes widespread, it will seriotisly endanger our efforts to control cancer. It is not our object to frighten people. It is not our object to put people Out of work; and it is certainly not our object to take all pleasure out of life. Our object is to reduce the risk of cancer in so far as it is feasible to do so. reas3.bility depends upon many elements, riot the least of which are public attitudes. In ny~opinioti~thbt'~w~y to develop realistic attitudes is t~frankly adlait the limitations in~ our present knowledge and in ~ between what we knew and wI~r-weoiily stispéct.' And when we speak of risk, express the degree of risk in terms which are me~ningLul to the aver~ine ~ ~ t.t) .l~ exciting and j~e~V wide ~ttCfltiOfl in both the i~flj~ ~OSS arid pu±~iic r.ewe Lt~~c~.' Negative findings ~ ~.`h~eh seem to L~ ~, ~f PAGENO="0206" 200 Hammond page 3 sho* that a substance is harmless - tend to be dull and there- fore usually receive little attention. Fo~th-i-sreason,-IwilL s~tart b~ describing several negative findings. They areof in- t~erest only in that they tend to counteract unwarranted fears~. Beauticians There has been speculation that some, and perhaps many, of the various chemical agents used by or on women for beauti- ficataon are carcinogenic. This has caused worry among many women - especIally among those most heavily exposed: beauticians. Epidemiologic evidence is now available on this matter. Over 1,000,000 men and women in 25 states were enrolled in a long term study by volunteer workers of the American Can- cer Society. Upon enrol0.memt, each of them answered a lengthy questionnaire. P~ndings~presentedbeloware based upon data ay~ilable after 13 years of trabimg. Of some 589,000 female subjects - all of whom were over the age of 30 and most of whom w~!e over the age of 145 at the start of the study - 5,125 said that they were beauticians. By the matched group procedure, we matched the beauticians with non-beauticians on age, race, education1 place of residence (large metropolitan area vs rural or less populated area), amount of cigarette smoking, past history of cancer, and past history of heart disease. Matches were found for 5,117 of the 5,125 beauticians. In most instances, many non-beauticians were found as matches for each of the 5,117 beauticians. This increased the statisrn- tlcal stability of the findings. PAGENO="0207" 201 Hammond Page ~ During the course of the st~d7, 32]. of the beauticians died. Adjustedfor the sIze of the tw~ gr~~ and standardized for age, 351 of the~beauticians dIed, ThIs smal- difference (in favor of the beauticians) is not statIstical].]! sigrIficant. 113 of the beauticIans dIed of cancer. Adjusted for size of the two groups, 115 of the ncri~-beauticians dIed of cancer. p~~"1s'virtual1y no dIfference. There-was not a single site of cancer from which significantly more beauticians than non_beauticians d~.ed. The fIndings were essentIally the same during each of twelve successive years of tracIng. I~exposure~associate&with.the occupation of beaUticiam has resulted in an increase in death rates from cancer of any s~t~;~the increase Is too small to show up in a study of over 5,000 people over a period of 13 years. It could be that soz~e "beauty aid" introduced in recent years is highly carcinogenic but tins not been used suff~.cieflt1Y long for the effects to become atparent, *Therefore~in spite ~of our fIndIngs, I belIeve that all recently introduced "beauty aids" (and those proposed for introductidn) should be tested for possible carcinogenic effects. Polio Vaccine (SV 9~~) Research carried cut by virologists between ].9514 and early 1961 revealed that some batches of polio vaccine produced up to that time were contaminated, with living simian virus )4Q (SV LW). (Later, leading virologlsts told me that they thought that most if not all of the batches produced up to that time were at least PAGENO="0208" TABLE I b) If Death Rates are Increased from Age 40 on by: PROBABILiTY OF SURVIVING TO AGES 65 AND 75 AND LIFE EXFECTArIC! FOR U.S. WHITE MM.ES STANTING AT AGE 20 a) If Death Rates are Increased from Age 20 on by: U.S. White Males 1974 1% 2% 5% 7% 10% 15% 25% 70.73 70.49 70.24 69.52 69.03 68.32 67.14 64.85 44.13 43.77 43.41 42.35 41.66 40.64 39.00 35.91 Prob. Surviving from Age 20 to Age 65 (%) Prob. Surviving from Age 20 to Age 75 (%) Life Expectancy at Age 20 (yrs.) Prob. Surviving from Age 20 to Age 65 (%) Prob. Surviving from Age 20 to Age 75 (%) Life Expectancy at Age 20 (yrs.) U.S. White Males 1974 70.73 44.13 50.95 50% 59.44 29.19 46.23 50% 60.60 29.76 46.93 1% 70.52 43.79 50.85 100% 49.93 19.26 42.93 100% 51.88 20.02 44.22 70.30 43.44 50.75 200% 35.16 8.31 38.36 200% 37.98 8.98 4 0.61 5% 69.65 42.43~ 50.45 7% 10% 69.22 68.58 41.77 40.80 50.26 49.98 15% 67.53 39.22 49.54 25% 65.47 36.25 48.71 PAGENO="0209" PA!3LR II PERCENT OF DEATUS FROM ALL CAUSES FOR SELECTED CAUSES OF DEA~1I White_Males, U.S. 1974 (.~,lx~! of Death 20-~9 30-39 -s-- ACE GROUP 4(3-49 50-~9 60-69 70-79 80+ all. Cavises 100.000 100.000 100.000 100.000 100.000 100.000 100.000 .41 ~`jc.~:ar 11.11/0 10,727 1i.rg 0.122 1.997 6.819 9.319 9.214 6.107 2.240 C~i~nL~;ctUtTh 0.216 1.147 1.696 2.458 2.921 2.803 1.158 `3Lc~e~ch 0.037 fl*315 .0.750 0.079 0.976 0.974 0.765 Liver 0.048 0.137 0.243 0.338 (3.393 0.326 0.206 Pancrt~as 0.041 0.366 0.929 1.346 1.321 1.108 0.654 ProaL.tto 0.03.1 0.014 0.130. 0.570 1.511 2.660 2.744 0i.~dder 0.004 u.082 0.226 0.458 0.738 0.916 0.762 Eidney 0.059 0.247 . 0.598 0.70~J 0.614 0.127 0.215 Lcukeiuia 1.024 1.261 0.789 0.701 0./56 0.793 0.646 1~c1)eu:ic Ht~rt Disease 0.898 11.390 31.880 39.265 40.400 40.819 42.466 PAGENO="0210" 204 Mr. SEGAL. On Monday of this week, Dr. Corbett, we had testi- mony presented into the record criticizing the two NIOSH reports by Dr. Alvin Feinstein. He described, in his criticizing the NIOSH report, the following gross flaws and fallacies. This was entered into the record on Monday. Point No. 1: Although the suspected ediologic agent is hair dyes, no effort was made to dis- tinguish whether the person's occupation was labeled as hairdressers and cosme- tologists actually used or was exposed to hair dyes. Did Dr. Hammond meet this criteria? Dr. CORBETT. I do not know. Mr. SEGAL. I must state, Mr. Chairman, that he was asked that question yesterday. He indicated he did not. Since the category includes electrologists, manicurists, beauty schoolteachers, shampooers, requests for scientific evidence would have included an inquiry to determine whether the patients were, in fact, exposed. Do you know whether an inquiry was made to find out whether these cosmetologists in Dr. Hammond's study were, in fact, inter- viewed? Dr. CORBETP. No. Mr. SEGAL. You do not know, or you know they were not? DR. CORBETT. I do not know that they were interviewed on every question. Mr. SEGAL. Dr. Hammond indicated to us that they were not. The second important gross flaw and fallacy described by Dr. Feinstein was: A second important item of scientific evidence is the dose response curve. Was the risk of cancer greater in people who had used hair dyes in larger amounts and for longer periods of employment? The investigators made no effort to obtain such evidence. Have you, or do you know whether or not Dr. Hammond ever obtained such evidence? Dr. CORBETT. I think he followed them for 13 years. I do not know that he asked them when they started in the profession of hair dressing. I think he made the assumption that since they were between 30 and 40 years old at the start of the study, that they had already been in the profession for a number of years. Mr. SEGAL. In a telephone conversation with him yesterday, he indicated that he did not make an effort to obtain such evidence. Now, we find that the first two gross flaws and fallacies described by Dr. Feinstein refer to the same gross flaws and fallacies in the study that you declare as one of the two definitive studies on epidemiology. Do you still feel that would hold, that is, that you would stand behind Dr. Hammond's study as a definitive study on epidemiology? Dr. CORBETT. I think it is superior to the one that Dr. Feinstein- Mr. SEGAL. That is not the question. Do you feel that it is a defin- itive study on the epidemiology of hair dyes? Dr. CORBETP. As far as it goes, yes. Mr. SEGAL. May I read to you the last paragraph of Dr. Hammond's statement? It says: These findings- PAGENO="0211" 205 it is the last three paragraphs~ These findings were essentially the same during each of the 12 successive years of tracing. If exposure associated with the occupation of the beauticians has resulted in an increase in death rates from cancer or any other site, the increase is too small to show up in a study of oyer 5,~OO people over a period of 13 years. ~Do you know whether ~scientists generally feel that the period of time of 13 years is sufficient to determine cancer? lDr. CORBETT. They do not. I think this is on~ of the misunderstand- ings there has been about Dr. Hammond's study. There is an assump- tion that they all became hairdressers on day 1 of that 13 years. I am sure that assumption is not justified. Mr. S1~GAL. Do you know how many of them had exposures of greater than 20 years out of the 5,000? Dr. CORBETT. It would seem likely, given the fact- Mr. SEGAL. Do you know how many? Dr. OORBEPT. No. Mr SEGAL The last paragraph says "It could be that some beauty aid . . ."-and I am not sure what he means by "beauty aid"-but would you know what he means by that, Dr. Corbett? [No response.] Mr. SEGAL. introduced in recent years as highly carcinogenic, but has not been used sufficiently for the effects to become apparent. Therefore, in spite of our findings, I believe that our recently introduced beauty aids and those proposed for intro- duction should be tested for possible carcinogenic effects~ Would you think that confirms safety of hair dyes? Dr. COR~ETT. The hair dyes-as I have told you before this morning-have been in use for 70 years. They are not recently introduced. Mr. SEGAL. Have they all been the same formulation? Dr. CORBETT. As a chemist in this industry, I hide my head in shame and say so: "Yes. We have very few new materials introduced into hair dyes." Mr. SEGAL. What about the general statement: "Some beauty aid introduced in ~recent years could be highly carcinogenic."? Have you introduced any new ingredients in hair dyes in the last 70 years? Mr. OORBETT. Oh, yes. In the last 70 years, yes. Mr. SEGAL. Do you think it is possible that a hair dye would fall within this categorization of a "beauty aid"? Mr. CORBEPT. Yes; I would think so. Mr. SEGAL. So, based on the conclusion that he makes here, it is possible that hair dyes are. within the purview of his study? They might be classified as possibly introduced in the last several years as being highly carcinogenic? Would that be the case? Dr. OORBETT. It could, yes. Whether it is likely, or not, is a subject for considerable debate. Mr. SEGAL. You mentioned before when we were talking about the epidemiology-and I apologize for having cut you off at that point because I intend to get to it now-but there was the issue of absorption. PAGENO="0212" 206 We are talking about animal studies. There have been studies done by the National Cancer Institute that have identified six agents causing cancer in animals. Is that not true? Dr. OORBETT. I believe so; yes. Mr. SEGAL. For identification purposes, if you have the same chart that we had on Monday, these include: 4-amino~2~nitrophenol; 2,4-diarninoanisole sulfate; direct black 38; direct blue 6; 2-nitro- 1 ,4-phenylenediamine; and 2,4-toluenediamine. Is that correct? Dr. CORBETT. That is correct. Mr. SEGAL. An answer that you gave earlier this morning was that-and at that point you were only talking about 2,4-DAA-but you said it was found to cause cancer at high doses and therefore presented a potential risk. Is that correct? Dr. CORBETT. In the absence of other data, yes. Mr. SEGAL. In the absence of other data, you were prepared to say that 2,4.DAA presents a potential risk based on animal studies; is that correct? Dr. CORBETT. Yes, Mr. SEGAL. Would you make that same claim for the other five? Yo~ have already said that in different ways on direct black 38 and direct blue 6, that they were benzidine-derivatives that converted to benzidine in the body; is that correct? Dr. CORBETT. That is correct. Mr. SEGAL. Would you make the same statement for the remaining three? Dr. CORBETT. The remaining three are the ones on which we have animal test data of our own. Mr. SEGAL. Were these feeding studies or skin paintings? Dr. CORBETT. Skin painting studies. Mr. SEGAL. Do you have data on feeding studies? Dr. CORBETT. No. Mr. SEGAL. You have no feeding data at all on any of the other three? Dr. CORBETT. Not for carcinogenicity. Mr. SEGAL. All right. The next question, then, is this. Relative to absorption, do you believe that these ingredients that are placed on the scalp are absorbed into the human body? Dr. CORBETT. It was precisely the recognition of this that got us to institute our safety testing program back in the late 1960's. Mr. SEGAL. And absorption goes into the bloodstream of human beings? Dr. C0RBETT. Yes. Mr. SEGAL. And presumably is excreted or retained in the human body; is that right? One or the other or a combination? Dr. CORBETT. Or change or decomposed, et cetera. Mr. SEGAL. Do you know for sure that all of the absorbed material is excreted? Dr. CORBETT. No; we do not. Mr. SEGAL. Do you know for sure that a portion of it is retained in the human body? Dr. CORBETT. No; we do not know that either. Mr. SEGAL. You have studies, however, that indicate that 80 to 90 percent is excreted within 3 or 4 or 5 days; is that right? Dr. CoRB~TT. Yes. PAGENO="0213" 207 Mr. S~GAL. Would that lead you to subtract from 100 percent and say that in some cases, after 5 days, a portion of that material ab- sorbed might remain in the human body? Dr. CORBETT. If you qualify it by the word "might," then I could agree with it. One of the problems with that type of experimentation is that there is never 100 percent recovery, even if you take the body, mascerate it, and determine the amount in the body and the amount that came out. It never comes to 100 percent. The methodology is not that accurate. Mr. SEGAL. Do you know what happens to the amount that is retained in the human body? Dr. COEBETT. We do not even know it is. Mr. SEGAL. Have you done studies to determine that? Dr. CORBETT. If we would have done that, we would have known that some is retained. We do not know it. Mr. SEGAL. Does that lead you to then come out with the con- clusion that you cannot tell with assurety that hair dyes are safe? You cannot confirm and you cannot even support that hair dyes are s.afe because you do not know what happens to the material when it goes into the human body. Is that right? Dr. CORBETT. I think one does not have to know everything in order to support a particular proposition. So, I think I can say "supports." Mr. SEGAL. You would not say "confirms" or "proves"? Dr. CORBETT. I find it difficult, as a scientist, to keep being asked: "Will I say that hair dyes are safe in the absolute sense?" when everybody knows I cannot say that. As a scientist, I cannot. Mr. SEGAL. But it is difficult for the American people to understa~id that when on October 17, 1977, you said: "There is now a substantial body of research, sponsored by the hair coloring industry, and by respected outside scientists, which confirms the safety of hair dyes." You are now saying that you do not believe that it confirms the safety of hair dyes. Dr. CORBETT. Each piece of evidence on its own confirms. It does not mean confirms in the absolute sense. I can get into a rhe- torical argument, but I am sure we do not want to. We are talking about one word. Mr. SEGAL. But we are also talking about how one describes to the American public the safety and nonsafety of hair dyes. Dr. CORBETT. If you really believe that the word "supports" would mean something really different to the American public than the word "confirms," then I apologize. I do not think it would be recognized as a particularly different word, which is the reason that it was in there in the first place. Mr. SEGAL. We have gone down the list. Mr. Moss. Let me get that again. I am a little puzzled. You care- fully used the term "support" as a substitute for "confirms"? Dr. CORBETT. Yes. Mr. Moss. Now you say that you doubt if the American public discerns any significant difference? Dr. CORBETT. I do not think it is inconsistent. PAGENO="0214" 208 Mr. Moss. I have been representing the American public for 30 years in public life. I have high regard for its intelligence. I think it knows the difference between "support" and "confirm." It is partic- ularly trUe when you relate the results of a scientific test or experiment or study. There is a great difference. It is not a simple matter of insignificant semantics. It is a matter of very substantive intent on your own. part. You want to change the word from "confirm" because it does not "confirm" to "support" which might tend that at some point in the future to "confirm." But in only "supports" at the moment? Dr. CORBETT. Yes. Mr. Moss. There is a great difference. Dr. CORBETP. I said so at the beginning of the session. Mr. Moss. You have not weighted the significance of your own careful choice of words, or you do not demonstrate very much respect for the intelligence of this large body of consumers. Dr. CORBETP. I assure you it is the former. Mr. Moss. I am glad to hear that it is the former. Mr. SEGAL. Just to continue without going through each individual scientific study that you indicated in the past that was used to confirm..-and now you are saying "support," we asked each one of the sciei~tists that was on the list that I mentioned before: Dr. Kinlen, Dr. Morgan, Dr. Hammond, and Dr. Urbach, whether they felt their materials supported it. We used the word "confirm" of the safety of hair dyes. Without exception, all of them said that would not be confirmed. Many of them in response indicated that they could not support- and I will use the word "support"-a positive conclusion from a negative finding. Do you believe that you can support a positive conclusion from a negative finding? Dr. CORBETT. That sounds a little tautological to me. Mr. SEGAL. There is a significant difference, Dr. Corbett, if on one hand you say, as Dr. Kinlen said-and I guess I will have to ask- Dr. CORBETT. It is exactly the same question you asked before: "Can I prove absolute safety?" I have already answered no. You have asked the question in a different way this time. Mr. ~EGAL. I am willing to understand that you no longer say you can confirm, but I am willing to ask this. Do you believe that these scientists will support your position? Dr. COEBETT. I cannot understand why they would not say that it "supports" the position. Mr. ~EGAL. I would like to read the letter from Dr. Morgan sent to Chairman Moss. I ask that it be inserted into the record. Mr. Moss. Without objection, so ordered. [The letter referred to follows :1 PAGENO="0215" 209 FACULTY OF MEDICINE `~ DEPARTMENT OF PREVENTIVE MEDIC1NE AND BIOSTATISTICS p~' / ~ UNIVEIISITY OF TORONTO 90 Gerrard StW Toronto Ontario January 11, 1978 Mr. John E. Moss HOuse of Representatives Chairman Subcommittee on Oversight and Investigations Congress of the United States of America Washington, D.C. 20515 Dear Mr. Moss: Enclosed you will find a copy of the results of our study conceroing the relationship of liairdyes to bladder cancer. I would emphasize that this study was used by the industry without the consent of any of the authors. Although ~e were unable to find any relation- ship between hair dye use and bladder cancer, it is possible that such a relationship may occur and be detectable with larger numbers of patients. This does not mean that I believe our study "confirms the safety of hair dyes." Rather, we have failed to demonstrate any asso- ciation between hair dye use and bladder cancer. Although I am cautious abqut interpreting our own results, I would, hope that your committee would be equally cautious in the evaluation of non-human data to assess eafety of compounds for humans. Tours sincerely, RWM/smk Robert W. ~oxg~n, M.D. -Professor End. PAGENO="0216" 210 troduce new ideas and bring about de- 3. The medical development team velopment without suppressing local mi- should provide for a flexible, planned tiative. Accordingly, after 4 years the phase-out period in order to afford team was withdrawn slowly, the last predictability and avoid suppressing * MEDICO .phyaician leaving in 1968. local initiative. Since that time the hospital has been 4. An educational program must be without any foreign staff. This policy conducted on a continuous basis as it was adhered to despite many requests is essential that permanent trainhd for a longer period of service and such counterpart personnel be available. * local comment towards the end of the 5. Outsiders should never compete project as "this hospital will stop de- with the locally available service but * . veloping as soon as you leave." add to it something that is new and In November 1976 I returned to the unavailable. Klsang District Hospital to see what 6. It in bad policy to supply dis- * :.::~: had happened to our project and to posable equipment funded from abroad; visit old friends. I found that progress only reusable equipment should be in- had continued at a rapid rate and that troduced. all the innovations we had introduced Unquestionably the great improve- were functioning in an expanded form ment n economic conditions in Malay The central sterile supply room h~ sia in the last decade has resulted in ~ operated at full capacity since we left improvement of medical services and and now s ppli s two ope at g rooms has been the most important factor in ~ instead of one. The blood bank was the improvement of Malaysian mcdi- functioning well An enlargement to the cine However the Kluang District library and a lecture room had been Hospital would never have progressed added. A completely new and larger without the help and leadership of the laboratory had been built, was well CARE-MEDICO team. It was the staffed and was capable of carrying out opinion of the physicians and other an extensive range of complex bacterio- hospital staff that CARE-MEDICO logic studies. Two roentgenogram ma- had concentrated the development into chines were functioning and the inten- a short space of time, after which ::: sive care unit was busy and had been progress was easier. moved closer to the operating room. Thanks go to the many individual Full electronic monitoring and resusci- donors, volunteers and staff of CARE- * . ~ tation were available. MEDICO and particularly to the many The change was remarkable con interested Malaysians both in govern sidering the situation in 1964 when ment and in the private sector, who the hospital had only a small outpatient helped over the last decade to make department with dispensary, several this Canadian project a success. wards only one operating room and JOHN R TAYLOR MD FRcs(cl a small laboratory where only a few 67O~ Finch Ave. W tents could be performed. Toronto, Oct. It was the opinion of the medical staff that CARE-MEDICO had shown Hair dyes and bladder cancer * .::~ the way with a pilot project of hospital development that was later duplicated To the editor: Recent work has dem- in many district hospitals in she region. onstráted the mutageniciey of hair dyes ::::~ It was encouraging that many young, in bacterial mutant systems.1' By far recently graduated physicians at one the greatest number of dyes are known time considered the addition of a labo- to be absorbed through the skin and, ratory, an intensive care unit, a central therefore, on the assumption that most sterile supply room and an improved carcinogens are also mutagens,3 dyes ..".:. operating room to be the norm in hos- must be regarded as potential car- * ::::::; pital development. cinogens in man. It is speculated The lessons we learned from thin un- that the carcinogenic or mutagenic ef- dertaking can be summarized as fol- fects of these chemicals may be due * .... lows: to their extensive reaction with deoxyri- * 1. Development plans should be in- bonucleic acid.4-' atituted in consultation with the local Although the results of earlier tents government and only after considerable performed on dogs and rodents did not time is spent working in the hospital indicate that hair dyes are carcino- to reach conclusions as to what the gens" there is some preliminary epi- hospital can beat use. demiologic evidence for this belief in ~. S~ve~ ~l h.spitvl departments should the higher incidence of bladder cancer be developed to a certain equal level iii l.aiber~, hairdressers and beauti- simultaneously rather than in sequence, cians.e~ However, a study from Massa- on the principle that, for example, the chusetts discovered no excess risk operating room, laboratory, blood bank, among female hairdressers.i Searle and hospital wards and intensive care unit colleagues found some carcinogenic are interdependent, activity in their tests on mice. Four CMA JOURNAL/NOVEMBER 19, 1977/VOL. 117 lt3t PAGENO="0217" ~w z o m 2. - y -3 3 PAGENO="0218" 212 Mr. SEGAL. It says: Enclosed you will find a copy of the results of our study concerning the relation- ship of hairdye~ to bladder cancer. I would emphasize that this study was used by the industry without the consent of any of the authors. Although we were unable to find any relationship between hair dye use and bladder cancer, it is possible that such a relationship may occur and be detectable with larger numbers of patients. This does not mean that I believe our study "confirms the safety of hair dyes." Rather, we have failed to demonstrate any association between hair dye use and bladder cancer. Do you think that letter can be used by you to say that Dr. Morgan supports the safety of hair dyes? Dr. CORBETP. I do not believe I ever used that letter. It was not written to me. Mr. SEGAIJ. No, but you used Dr. Morgan, from the Faculty of Medicine, Department of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Canada, as one of the individuals who, at that time, was used by you to confirm the safety of hair dyes. I am now asking: "Do you think that this letter should be used by you to indicate this supports the safety of hair dyes?" Dr. COBBETT. Although I am cautious about interpreting our own results, I would hope that your committee would, be equally cautious in the evaluation of nonhuman data to assess the safety of compounds for humans. I do not see why not. His final sentence is again another way of expressing the fact that one cannot prove absolute safety. So, you get this equivocation all the time. It certainly supports the absence of a relationship between bladder cancer and hair dyes. Mr. SEGAL. He says: "We have failed to demonstrate any associa- tion." Does that support safety? Mr. COEBETT. It supports the position that is part and parcel of the safety of hair dyes, namely, that there is no association between hair dyes and the development of cancer. That certainly supports the position. I cannot see where you are going with this argument. Mr. SEGAL. I have no further questions, Mr. Chairman. Mr. Moss. The Chair wants to try now to come to a determination for future scheduling. It is quite obvious that it will not be possible, due to the nature of floor business now underway in the House Cham- ber, to conclude these hearings today. The Chair is of the opinion that we can dispense with the witnesses now before us. Does any member at this point have questions to direct to these particular witnesses? If not, the Chair will excuse them with the thanks of the committee. We will announce very promptly, as soon as the Chair determines the a~vai1abi1ity of members for tomorrow, whether or not we can hear witnesses tomorrow or will have to defer for a week. With that, the committee will stand adjourned at this time. [Whereupon, at 12:40 p.m., the committee adjourned, subject to the call of the Chair.] PAGENO="0219" CANCER-CAUSING CHEMICALS Safety of Cosmetics and Hair Dyes THUR8DA~,. PEBRUARY 2, 1978 HousE o~ REPRESENTATIVES, SUBCOMMITr~E ON Ov~nsIGnT AND INVESTIGATIONS, COMMITTEE ON INTERSTATE AND FOREIGN COMMERCE, Wa8hington, D.C. The subcommittee met, pursuant to notice, at 10 a.m., in room 2322, Rayburn House Office Building, Hon. Andrew Maguire pre- siding [Hon. John E. Moss, chairman]. Mr. MAGUIRE. The subcommittee will hem order. Today we begin the third day of hearings on the "War .on Cancer." We will cOntinue our focus on the safety of hair dyes and other cos- metic products Earlier in this series, the subcommittee was informed by the National Cancer Institute-NCI-that at least six hair dye ingredients have been shown to be carcinogenic in animals. Two of these ingredients are benzidine derivatives-a known human carcinogen. On the second day of hearings, we heard from representatives of the Cosmetic, Toiletry and Fragrance Association-CTFA-that they acknowledge the existence of nitrosamines, an extremely per- vasive animal carcinogen, in numerous cosmetic products and were committed to the elimination of these chemicals from their products. Today, we will hear from Dr. David Fine who will present his scientific results on nitrosamines in cosmetics. With respect to the issue of hair dyes, CTFA representatives acknowledged that ingredients of hair dyes were found to be muta~ genic by the Ames test and that hair dye ingredients found by the Cancer Institute to be carcinogenic could be absorbed into the human body and find their way into the human blood stream. Testimony was also received demonstrating that industry' studies are not available to determine whether these carcinogenic agents are retained, or significantly metabolized into deleterious agents inside the human body. Dr. John Corbett from CTFA testified that as much as 10 percent of the amount of hair dye that is absorbed into the human body might remain~there for a period of at least 3, 4, or 5 days. There were several unanswered questions resulting from previous testimony. We hope that testimony presented today will shed addi- tional light upon these issues. These include, with respect to nitros- amines, whether they are absorbed into the human. body and whether the industry tests of ingredients as opposed to final products are appropriate. In addition, with respect to hair dyes, the issue of (213) PAGENO="0220" 214 whether undertaking only skin painting studies is appropriate for determination of safety will also be addressed. I would first like to call upon Dr. Joseph Highland with the Environ- mental Defense Fund. TESTIMONY OP JOSEPH HIGHLAND, PH. D., DIRECTOR, TOXIC CHEMICALS PROGRAM, ENVIRONMENTAL DEFENSE FUND, AND LESLIE DACH, SCIENCE ASSOCIATE, ACCOMPANIED BY ANITA JOHNSON, STAFF ATTORNEY, EDP; AND JOHN P. CORBETT, PH. D~, CHAIRMAN, HAIR DYE TECHNICAL COMMITTEE, THE COSMETIC TOILETRY AND FRAGRANCE ASSOCIATION Dr. HIGHLAND. Thank you, Mr. Chairman. I would like to thank you and the members of the committee for the opportunity to appear here today. We will present a brief summary of the written statement which we have given to the committee and hope that written state- ment will be incorporated into the record. Mr. MAGUIRE. Without objection your full statement will be printed in the record [see p. 220]. Dr. HIGHLAND. I am Dr. Joseph Highland, director of the toxic chemicais program of the Environmental Defense Fund. With me today on my right is Leslie Dach, science associate at EDF. EDF is a nonprofit public interest group with over 45,000 members. It has long advocated the elimination of unnecessary human exposure to toxic chemicals. In May and again in September of 1977 EDF testi- fied before this committee on the regulation by the Consumer Products Safety Commission on flame retardant Tris. In October 1977 EDF petitiot~ed the Food and Drug Administration to require that all hair dyes containing 4-methoxy-m-phenylenediamine carry a label warning consumers of the cancer hazard posed by this chemical. FDA proposed regulations accepting this petition in the Federal Register January 6, 1977. In comments submitted to FDA on January 11, 1978, EDF has also asked that the provisional approval for the use of the color additive lead acetate in hair dyes be terminated. Lead acetate causes cancer in animals and has been shown to pene- trate the skin of humans. We are here today to discuss the health hazards posed by cosmetics. Over $7 billion worth of cosmetics are sold each year. Currently there are over 24,000 different cosmetic formulations containing about 8,000 ingredients. The American people are thus exposed to thousands of cosmetic ingredients about which little if any health effects infor- mation is available. We ~an expect that many of these chemicals in cosmetics that we put on our faces, hands, and heads enter our bodies. Some, like hair dyes ingredients, absorb through the skin. Others, like lipsticks, are ingested. In light of such vast human exposure and the potential for harm, it can no longer be considered acceptable to allow the market- ing of untested cosmetic ingredients. The legitimate concerns for public health and well-being demand that action be taken immediately to insure that every cosmetic product sold the American people is safe for use. PAGENO="0221" 215 You have heard a presentation by the Cosmetic, Toiletry & Fragrance Association. What CTF4 has offered is a standard plea for self-regulation. They agreed to the need for safety substantiation prior to marketing but want to do it themselves by their own protocols and without the involvement of the Food and Drug Administration. This is simply unacceptable. They contend that cosmetics are safe but they offer no scientific proof to establish this fact. Even when faced with a situation in which N-nitrosodiethanola- mine, a known carcinogen, is present in a variety of widely used cosmetic products, the industry continues to question whether this contaminant poses a potential hazard to public health and has failed to take the necessary steps to resolve this critical issue. Moreover, a careful review of the scientific evidence on what CTFA claims is one of the best tested cosmetic products-hair dyes-clearly reveals that their* pronouncements of safety are unsubstantiated by fact. CTFA asserts that Congress, by its own declarations, in 1938, concluded that the benefits of cosmetics outweigh the risks caused by their use. Obviously, the 1938 Food, Drug and Cosmetic Act was an. attempt by Congress to insure public protection, not a declaration accepting risk. But the events over the past decades indicate that there is immedjate need today to revise the Food, Drug and Cosmetic Act to better insure consumer protection. CTFA claims that FDA already has substantial and sufficient authority to regulate cosmetic products. Such a. statement borders on being ludicrous in light of the fact that, in reality, FDA has no statutory authority to require that manufacturers test their products before they enter thefl marketplace. A cosmetic producer does not violate the law even if it fails to conduct a single safety test either before or after introducing a new product. Moreover, the FDA has no authority to require cosmetic manu- facturers to provide the necessary information that would enable the agency to conduct its own premarket and evaluation. Manufacturers cannot be compelled to submit ingredient lists, consumer complaints, or test data to the agency. Consumer products, such as hair dyes, sold for use in beauty salons do not have to be labeled with th~ ingredients they contain. Cosmetic manufacturers are not even required to inform the FDA that they or their products exist. Last week, in these hearings, OTFA claimed that further regulatory authority was not needed by the FDA because the agency already has promulgated regulations requiring any manufacturer who fails to substantiate the safety of cosmetic~ products to include~ the following statement on the product label. I' quote, "Warning, the safety of this product has not been determined." . This regulation has never been enforced by the FDA. The agency authority to issue it has been questioned. Even if it were enforced, it would be inadequate for the following reasons. The FDA has no authority to inspect or require the submission of data on which the manufacturer's safety claim is based. No definition of safety is provided and the tests on which, the safety is to be deter- mined are not described. PAGENO="0222" 216 Moreover, the ~v~arning label as worded does not identify it for the consumer whether an actual risk exists, and if it does, what the nature of that risk is. Consumers could conceivably face shelves of cosmetics full of such labeled products and be unable to make a judgment as to which ~f the products to avoid~ Finally, CTFA contends that its own safety programs are sufficient to insure the protection of public health. But the history of hair dyes is a striking example of the contrary. Mr. Dach and I would like to briefly review that history before offering our closing remarks. Almost 33 million Americans regularly dye their hair. This figure represents nearly 40 percent over the age of 15 and almost 50 percent of all women over the age of 40. Consumers spend over $300 million a year on hair dyes. The vast majority of hair dyes are known as. coal tar dyes because the dye chemicals used to be derived from coal tar from the distillation of bituminous coal. It is these dyes that we will focus our remarks on. It is these dyes that the industry contends have been shown to be safe for use. Our written testimony reviews in detail the scientific evidence compiled to date upon which a judgment of safety or risk must be made. We believe without a doubt that this evidence fails to establish the safety of hair dyes. Rather, it supports our contention that very real risks exist to consumers using these products. Mr. Dach will now summarize the data on five important parameters relating to hair dye risk: absorption, teratogenicity, mutagenicity, carciziogenicity, and epidemiology. TESTIMONY OF LESLIE DACH Mr. DAd. Everything we know about hair dye ingredients indi- cates that they penetrate the skin. All hair dye ingredients so far tested, whether semipermanent or permanent, including chemicals similar to the structure of the benzidine-derived dyes discussed last week that have been put on the skin of animals or man, have been subsequently detected in their bloodstreams. Bruce Ames has estimated that approximately 1 percent of the coloring agents in hair dyes are absorbed in the bloodstream each time a person dyes their hair. Over a lifetime of use this clearly results in significant absorption from a toxicological perspective. If a hair dye chemical has toxic properties, we can therefore expect people using that dye to be at risk. It has~ become clear recently from scientific studies that hair dye ingredients do possess toxic properties. Recently, scientific studies have shown that some hair dye ingredients cause birth defects in animals and may therefore pose similar risks to humans. Recently published data shows that a permanent hair dye ingredi- ent, 2,5-toluenediamine, causes malformations of the face, head, and ribs from the offspring of mothers who have received a single injection of this ingredient during pregnancy. In the second study fetuses of pregnant mice whose skin was painted with permanent hair dye had a statistically significant increase in skeletal malformations when compared to fetuses whose mothers were not exposed to the dye. While these results are not definitive for PAGENO="0223" 217 assessing human risk, they are clearly a cause for concern considering the large number of pregnant women who regularly dye their hair. Moreover, they clearly indicate that industry's claims of safety are not accurate. The two positive animal studies I have mentioned. are especially significant in light of the frequently higher sensitivity of humans compared to animals to the chemical induction pf birth defects. For example, humans are approximately 60 times more sensitive than mice and 700 times more sensitive than hamsters to the teratogenic effects of thalidomide. The skin painting study I have described is also of interest because it was industry study and points out again the problems of allowing industry to conduct their own safety tests according to their own protocol and then entrusting determinations of safety to industry's scientists. The doses used in the study were clearly below the doses recom mended by scientific and regulatory bodies for animal teratogenicity tests aimed at assessing human risk. In addition, despite the statis- tically significant results described~ the authors concluded without providing adequate evidence for that conclusion that the results were not biologically significant. Hair dye ingredients and hair dyes have also been shown to be mutagenic in a variety of tests including the Ames test and tests for mutagenesis, and drosophila, and mammalian cells in culture. As Dr. Griesemer, from NOT, concluded last week these tests are highly predictive of carcinogencity. For example, the Ames test has been shown to corrrectly identify approximately 9 out of 10 carcinogenic chemicals. Positive results in mutation assays are also of concern because of the number of genetic diseases which are apparent in the human popuia~. tion. Ames tested 150 out of 169, that is, he found that 150 out of 169 permanent hair dyes that he tested were positive in his test. Similarly most of the 25 semipermanent hair dyes he tested were also positive. The mutagenic properties of a number of other permanent, semi- permanent temporary hair dyes have been corroborated by other scientists and other types of tests. In addition, a number of permanent and semipermanent hair dye 4ngredients have also been shown~to be positive. Phe correlation between mutageni~ity and carcinogenicity has been borne out by National Cancer Tnstjtute tests. Five currently used hair dye ingredients are positive in these carcinogenesis bioassays. These ingredients are used in a majority of permanent hair dyes and in a number of semipermanent hair dyes. OTFA's claims that these NOT studies are irrelevant to human risks are unfounded. Although the NOT bioassays are part of a screening program, they are adequately scientific to assess human risk. One need not conduct further studies to justify regulatory action. Indeed, alimajor Federal regulatory agencies-OSHA, EPA, FDA, and OPSO-have used maximum tolerated dose studies as a basis for identifying and regulating chemicals which pose a human carcinogenic risk. PAGENO="0224" 218 For example, the proposed OSHA cancer policy states: * Testing of animals at constant high exposure levels at or approaching the maxi- mum tolerated dose is not inappropriate and is indeed required to overcome statistical insensitivity of laboratory bioassays conducted with a limited number of animals. Federal agencies have repeatedly used maximum tolerated dOse feeding studies to regulate chemicals to which people are exposed through the skin. For example, the Consumer Product Safety Com- mission has banned the flame retardant chemical Tris on the basis of an NCI feeding study although the vast route of exposure to humans was through the skin. Quoting the OSHA cancer policy: In cases where compounds are absorbed by experimental animals, and circu- lated systemically, it seems reasonable to regard the route of administration as irrelevant to weigh the potential risks to men. Again, two Federal regulatory agencies have relied on these NCI tests on hair dyes to justify actions. FDA in its January 6 Federal Register nOtice proposing requirement of labeling and posters in beauty parlors relied on these NCI studies. Similarly NIOSH in its warning to people employed in beauty salons also relied on the NCI findings. In addition to criticizing the NCI studies, CTFA further claims that its own skin painting studies demonstrate the safety of hair dyes. To the contrary these studies do nothing of the kind. The doses used are simply too small to compensate for the small number of animals. For these reasons these studies have been criticized by numerous scientists in the scientific literature. For example, Bruce Ames has commented that one of the studies cited by industry could not have detected a chemical that increased cancer by 5 percent. Five percent cancer rate in the population of people who dye their hair would be about 1.6 million cancer cases a year. Clearly safety cannot be determined by an experiment that leaves this much to be desired. Moreover, EDF's analysis of the latest industry skin painting study indicates that even under the conditions used in that assay with mice where the skin was painted with eitli~r one or two permanent hair dyes had a higher number'of benign liver tumors of the type that often become malignant compared to animals not exposed to the dyes. Yet, industry continues to claim that these studies confirm the safety of hair dyes. There has been much discussion of the epidemiological evidence on hair dyes. It is our conclusion that epidemiological studies do not in any way contradict these positive animal findings of carcinogenicity. Indeed if anything, they suggest elevated cancer risk for people classi- fied as beauticians, cosmetologists, or hairdressers. In addition to the NIOSH study discussed last week, three other studies have shown increased cancer rates for people in this occupa- tional category. No matter what criticisms industry may level at these studies, they certainly cannot be turned around and held up as proof of safety. The committee has already publicly examined the two epidemio- logical studies held by CTFA as definitive. The tests done on hair dye users similarly do not indicate the saf ety of hair dyes. They either have not looked at enough cancer sites or PAGENO="0225" 219 have not allowed for the necessary period of time to expire between the exposure to the dye and onset of symptoms that could be detected in a study. Dr. HIGHLAND. The evidence summarized by Mr. Dach leaves no doubt that CTFA's contention that hair dye products are safe is scientifically unfounded. The American public deserves something more than unsupported claims of safety. They must be provided with a regulatory process that insures that their health and safety will not be jeopardized merely for the sale of another commercial product. Such a regulatory process does not exist today. Mr. Merritt of the CTFA suggested last week that prior to enact- ment of legislation which would create an adequate regulatory struc- ture that a National Academy of Sciences panel be convened to re- view the critical scientific issue. Such an effort would be pointless and create further unwarranted delays in the establishment of an effective regulatory process. NAS panels have looked at these scientific issues before in the cases of chlordane and hetachiorate, and most recently for drinking water. They have found that the evidence such as that currently available on hair dyes is sufficient to trigger regulations to protect public health and even cause a product to be removed from the market. New legislation is clearly and critically needed which will require premarket approval of new cosmetic ingredients based on the evalua- tion of well-defined toxilogical safety data. FDA must be notified of the existence of all current cosmetic formulations and any intent to introduce new formulations into the marketplace. All health and safety data must be public information and available to all for critical scientific review. All cosmetics must be required to carry full and complete labeling information so that consumers know what chemicals they are being exposed to. For cosmetics that are currently being marketed, a review of poten- tial health and safety problems associated with use must be under- taken. For far too long the legitimate concerns of the Congress, the FDA, and the public over the safety of cosmetics have gone un- answered. It is time now to enact legislation to insure human safety and well-being, and to provide the FDA with sufficient resources so that this critical area of human exposure to potentially hazardous chemicals is properly regulated. This completes our statement. Obviously we will be glad to answer any questions. Before I stop I would like to introduce Ms. Anita Johnson who is the staff attorney at EDF. Thank you very much. [Testimony resumes on p. 304.] [Dr. Highland's and Mr. Dach's prepared statement follows:] 24-600 0 - 78 - 15 PAGENO="0226" 220 Environmental. ~ Defense )IJ)I Fund* 1525 18th Street, NW, Washington, D.C. 20036 * 202/833-1484 January 25, 1978 TESTIMONY OF THE ENVIRONMENTAL DEFENSE FUND BEFORE THE SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATION OFTHE HOUSE COMMITTEE ON INTERSTATE AND FOREIGN COMMERCE ON THE SUBJECT OF COSMETIC SAFETY OffiCEs *1: EAST SETAUKET. NY (MAIN OPFICEU NEW YORK CITY (PROGRAM SUPPORT OPFIOEI: WASHINGTON OCi SERKELEY, CALIFORNIA; DENVER. COLORADO P100.0 on 100% R*oycldPapot. PAGENO="0227" 221 TABLE. OF CONTENTS 58 68 72 75 77. 82 1 4 25 31 37* Introduction Chemistry and Use of Hair Pyes Absorption Mutagenicity Animal carcinogenicity Epidemiology : Teratoger~icity Regulatory Authority. * Proposals for Legislative changes * References * * Appendix A PAGENO="0228" 222 Introduction Good Morning. Mr. Chairman, members of the Coimoittee, I am Dr. Joseph Highland, Director of the Toxic Chemicals Program of the Environmental Defense Fund (EDF). With me today is Leslie Dach, Science Associate at EDF. EDF is a non-profit, publig interest group with over 45,000 members that has long advocated elimination of unnecessary human exposure to toxic chemicals. In May and again in September, 1977, EDF testified before this Committee on the regulation by the Consumer Products Safet~ Commission of the flame retardant Tris. In October 1977, EDF petitioned the FDA to require all hair dyes containing 4-methoxy-m-phenylenediamine (4HMPp) to carry a label warning consumers of the cancer hazard posed by 4MZWD. FDA proposed regulations accepting this petition in the Federal Register of January 6, 1977. In comments submitted to FDA on January 11, 1976, EDF has also asked that the provisional approv~l for the use of the color additive lead acetate in haiz~ dyes be terminated. Lead acetate causes cancer in animals and has been shown to penetrate the skin. We are here today to discuss the health hazards posed by cosmetics. Over 7 billion dollars worth of, cosmetics are sold each year. Currently there are over 24,000 different cosmetic formulations containing about 8,000 ingredients. Each year this number increases. This amounts to about 9 billion units a year, or 45 units for each 1/ man, woman arid child in America. Thus, the American people are exposed to thousands of cosmetic ingredients, ~ngredients about which we have little, if any, health effects information. We simply don't PAGENO="0229" 223 know what these chemicals can do to people. Nor, given the prosent stacuatory ar.ci regulatory situation, are we likely to find out. FDA cannot require manufacturers to conduct safety tests. It can't even demand to see the results of tests, no matter how shocking they may be, no matter how many consumers may be hurt. And FDA claims not to have the resources to do the tests themselves. We can expect many of the chemicals in cosmetics that we put on our faces, hands and heads to enter our bodies. Some, like hair dye ingredients, absorb through the skin. Others, like lipsticks, are ingested. Thus, toxic cosmetic ingredients can be expected to cause illness and perhaps death among consumers. We needn't here repeat the gruesome statistics that describe the cancer epidemic in America, or the portion of those statistics that can be attributed to environ- mental causes. What needs emphasis is the responsibility of govern- ment and industry to minimize exposure to chemicals that have the ability to kill us. The Cosr~etics, Toiletry and Fragrance Association (CT?A), the trade association representing industries which sell about $300 million of hair dyes a year, tells us that cosmetics are safe, that there is little reason for concern. Certainly, they cannot claim that they have tested even a small proportion of cosmetic ingredients for safety. And to claim that the evidence to date reveals no substantial hazard merely emphasizes the lack of safety testing currently under- way. Furthermore, contrary to CTFA's claims, scientific evidence developed over the last year clearly shows that cosmetics pose a number of serious health hazards. PAGENO="0230" 224 For example, scientists have recently shown that N-Nitro- sodiethanolaisine, a compound known to cause cancer in animals and a member of a family of compounds (the nitrosarnines) that are potent carcinogens in all species looked at so far, is present in a wide variety of skin care products, shampoos, lotions, and cosmetics. Another example -- and this brings us to the focus of our testimony here today -- is the National Cancer Institute's (NCI) recent findings that 6 hair dye ingredients cause cancer in animals, and thus pose a presumptive carcinogenic risk to humans. PAGENO="0231" 225 Chemistry and Use of Hair Dyes About 33 million American women regularly dye their hair. This figure represents nearly 40% of all women over the age of 13 and almost 50% of women ovet 40 years old. Consumers spend over 300 2/ rAillion dollars a year on hair dyes. The vast majority of hair dyes are known as coal tar dyes, because the dye chemicals used to be derived from coal tar, tar obtained through distillation of bituminous coal. A small propor- tion of dyes use metallic or vegetable colors. In the following discussion we will focus on the coal tar dyes. A number of companies market coal tar dyes. These include * Clairol, Cosmair, Alberto Culver, Revlon, Redken, Toni, Ozon, and Helene Curtis. Clairol, a subsidiary of Bristol Myers, has about * 70% of the U.S. hair dye market. Cosmair's subsidiary, L'Oreal, has about 15 to 20%. About 12 to 15% of Bristol Myers' U.S. profits 3/ derive from sales of Clairol hair dyes. There are three types of coal tar dyes. Temporary hair dyes or color rinses are used to add highlights and brightness to natural color, improve shades of grey hair, and blend unevenly-colored hair. The first rinses were introduced in 1922, and were patterned after 4/ similar products used to color textiles. Itinses are usually applied to the baàe of the hair, and combed through to the ti~p. The dyes are deposited on the hair fiber and usually do not actually penetrate the fiber. Thus they wash out during shampooing. The desired color is obtained through the use of a mixture of colored chemicals. The chemicals used are acid dyes of the type used in PAGENO="0232" 226 -5- 5/ wool dyeing (see Figure 1). * 0 NH__QCH OcJi - Aod Vic~et 43 HO3S..ONN)~fll~00H SOH Tortrazre (yeilow) The second type of dyes, semi-permanent dyes, last a bit longer, wearing off after sevexal shampoos. They are.often used to blend streaked hair, to improv~ the col~ring of white or gray hair, or to acid highlights to naturally blonde 1~air. Again, the desired shade is acheived through use of a combination of dyes. The chemicals used are usually aromatic airines, such as nitrophenylenediames, and aitroaminophenols. Typical dyes and their colørs are shown in Table 1. Semi-permanent ciyes are usually applied to hair in a shampoo base for 20-40 minutes before being rinsed out. The most widely-used dyes, accounting for. about 75% of the market, are the permanent dyes, first introduced as a standard commercial product in 1910. The dyes use small, colorless, low molecular weight chemicals, usually aromatic aniines such as 2,4DAA, which penetrate PAGENO="0233" 227 Table 1 6/ ~es Used in Semi-Permanent Nair Colors Chemical Name CTFA Dictionary Name Color 2-'Nitro p-phenylenediamine 2-Nitro-p-phenylenediamifle I~ed 4~Nitro-o-phenYleflOdiamine 4-Nitro-o-phenY lenediainine Yellow 2-Amino- 4-nitrophenol 2-Amino- 4-nitrophenOl Yellow C.l. Acid Orange #3 Acid Orange #3 Orange the hair shaft. They are then oxidized by hydrogen peroxide into larger, colored molecules which become locked inside the hair. The resulting color is not removed by shampoo, and monthly dyeing i~ generally needed only to color new hair growth. In addition to hydrogen peroxide, two types of dye chemicals, are used in permanent dyes, primary intermediates and couplers, to give the desired color. These dyes also contain other components, including stabilizers, detergents, anti-oxidizers and alkalizers.~ The primary intermediates are usually ortho or para aromatic diamines or para aminophenols. Present in excess amounts they are oxidized by the hydrogen peroxide to reactive intermediates which yield colored products when joined with either unoxidized primary intermediates or couplers. The couplers are usually meta diamines, mets aninophenols, mete phenols or pyrazolones. 2,4DAA, for example, is a coupler. In a typical hair dye reaction (see figure 2,page 7) with 2,4DAA, the primary intermediate, for example paraphenylenediamine, is oxidized to form p-benzoquinone diimine. This diimine reacts with 2,4DAAto give a triaminodiphenylarnine, which then undergoes oxidation to the 2-aittinoindamine dye. The indainine dye is a violet-blue color. PAGENO="0234" 228 Figure 2 NHL NH OO4~ -~r~---> () ÷ NHz NH ?AMP~ENYLNEDW~ VASZ~nr~ONEDUMP4E 2'~ DM N~cxN2c~L Z.PMINO%NDAM~NE T~AOPHEt'~YA~1N~ Because a typical hair dye oontains several couplers and primary intermediates, numerous colored dye products are formed. The combina- tion of these products dtermines the final shade. The hair dye chemicals identified as carcinogenic by the National Cancer Institute are used in the vast majority of permanent hair dyes and a number of semi-permanent dyes. Based on information supplied to FDA by industry in a voluntary registration program, over 400 permanent hair dyes contain 4MMPD (2,4DAA) or its sulfate salt (see Table 2 ). About 300 permanent or semi-permanent hair dyes contain 2NPPD or its sulfate salt (see Table 3 ). Over 70 hair dyes list PAGENO="0235" 220 4A2N1 as an ingredient (see Table 4). The Government Accounting Office (GAO) reported that 7 temporary dyes contain Direct Black 38 8/ and one temporary dye contains Direct Blue 6. Because the voluntary registration may i~ot result in FDA's having a complete list of hair dyes containing a given ingredient, the numbers cited above may be short of the actual number of products containing a given ingredient. * Regardless of the exact total, it is clear that the vast majority øf hair dyes contain at least one cancer-causing ingredient, ax)d that * therefore the vast majority of ~33 million Americans are at risk. PAGENO="0236" L1Oroal Preference Salon Formula Blue Black Ddrk Brown Datk Ash Brown Medium Brown Medium Ash Brown Light Brown Light Ash Brown Dark Ash Blonde Medium Ash Blonde Ash Blonde Light Ash Blonde Dur~ished Copper Reddish Blonde Lighter Gold Light Reddish Blonde L'Oreal Preference Permanent Crerse-In Nair Color Blue Black Soft Black Dark Brown Dark Ash Brown Nadium Brown Medium Ash Brown Light Brown Light Ash Brown Dark Ash Blonde Ash Blonde Light Ash Blonde Extra Light Ash Blonde Lightest Auburn onde Auburn Medium Ash Blonde L'Oreal Drabber Moonlight L'Oreai~ Drabber Moonmist L'Oreal Excellence Permanent Flair Color Blue Black Dark Brown Medium Brown Light Brown Light Ash Brown Medium Ash Blonde Ash Blonde Light Ash Blonde Very Light Ash Blonde Natural Black Deep Ash Brown L'Oreal Preference Perfect Blonds Light Beige Soft beige Perfect Platinum Ash Perfect Deep Ash L'Oreal Super Blonde Toners * Super Light Beige Super Soft Beige Super Platinum Ash Light Platinum Ash Silver Beige L'Oreal Excellence Permanent Shampoo-In Color * Blue Black * Dark Brown Medium Brown Light Brown Light AshBrown Deep Ash Blonde Medium Ash Blonde * Ash Blonde Light Ash Blonde Very Light Ash Blonde Burnished Copper Platinum Ash Tawny Ash Frosted Beige Natural Black Deep Ash Brown Soft Ash Brown 230 ABLE ~ L'Oreal Young Blonde Ash Gentle N~T~Li~htener PAGENO="0237" TABLE 2 (continund) L'Oreal Excel'enCe Creme Sh~uspoo Color Blue Black Dark Brown Brown Light Drown Light Ash Brown Deep Ash Blonde Medium Ash Blonde Ash Blonde Light Ash Blonde Pearl Ashene Extra Light Ash Blonde Extra Z~ight Beige Blonde Platinum Ash Tawny Ash * BeigeArgant bark Ash Brown Medium Ash Brown Dark Drabber * Light Drabber Miss Clairol~ Hair Color Bath Arctic Blonde- Autumn Mist Berrywood Black Azure Black Velvet Blue Black Chestnut Brown Coffee Brown Ermine Flame Flaxen Blonde Golden Apricot Mazy Mist Money Red -. * Lt~ Smokey Ash Blonde Medium Smokey Ash Blonde Moongold Moonhaze MooBlit.-BrQwn----- - Red~Oak Sable Brown-~ Soft Mist Starlight Suntlonde Brown- - - £u~iJ.t. BrowA_ Sunset Brown Sunny Auburfl Topaz Winter Wheat Clairol Nice and~ Natural Ash Brown Natural Black Natural Blue Black Natural Dark Auburn Natural Dark Brown Natural Deep Auburn Natural Light Ash Blonde Natural Light Ash Brown Natural Light Auburn Natural Light Beige Blonde Natural Light Brown Natural Medium Ash Blonde Natural Medium Brown Natural Pale Ash Blonde Natural Pale Blonde Natural Tawny Auburn Miss Clairol Shampoo Formula Autumn Mist Black Azure Black . Velvet Chestnut Brown Coffee Brown Coppertone Flame ~Flaxen Blonde Go),den Apricot Moongold * Moonhaze Noonlit BrOwn -Red Ginger Sable Brown Sparkling Sherry Sunbronze Sunlit Brown Topaz Winter Wheat Miss Clairol Creme ~`ornula Arctic Blonde Autumn Mist Black Azure Black Velvet Chestnut Brown Cof fee Brown Coppertone Ermine Flame Flaxen Blonde * Golden Apricot Money Red 231 .1 PAGENO="0238" 232 TABLE 2 (continued) Miss Clairol Crerne Formula (Cant' d) Moongold Cherry Silver Moo~haze Moonlit Brown Sable Brown Sparkling Sherry Starlight Sunblor~de Brown Sun Bronze Sunlit Brown Sunset Brown Sunny ~uhurn Topaz Winter Wheat Clairol Balsam Color Ash Blonde Auburn Black Dark Ash Brown Dark Blonde Darkest Brown Golden Brown Palest Ash Blonde Palest Blonde Light Brown Medium Ash Brown Medium Golden Brown Light Ash Blonde Clairel True Brunette Light Golden Brown Medium Ash Brown Medium Brown Dark Ash Brown Dark Sable Brown Darkest Brown Deep Reddish Brown Black ~ç~~p~nde Completely Beige Completely Flaxen Completely Honey Completely Platinum Completely Towhead Clairol R~d Fashion Cherry Silver Pink Silver Sun Silver Clairol Naturally Blonde Autumn Ash Cool White Dusky Fawn Evening Ash * Fair-Haired Blonde Natural Pearl Opaline Amber Opalina Ash Opaline Beige Platinum Breeze Platinum Surf Sifted Sand Silver Treasure Softly Blonde Sumner Haze Sunny Beige Sun Touch - Swedish Crystal Swedish Taffy Truly Beige Willow Blonde Clairol 5-minute Color Black Blonde Dark Brown Light Brown Medium Brown Cool Ash Dark Ash Gentle Platinum Golden Blonde Light Beige Light Platinum Lightest Blonde True Beige Whisper White White Platinum Lady Clairol Lady Lights Golden Whisper Hazy Honey Honeysuckle Blonde Moon Beige Moonlit Ice Spun Honey Starlit Sand Touch o~ Taffy Clairol Futuretone Non-Asn~o~ia Toner PAGENO="0239" TABLE 2 (continued) Clairol Creme Toner Baby Pearl Blush Pearl Champagne Beige Champagne Ice Champagne Parfait Champagne Sherbet Champagne Toast ~xtra Light Platinum Honey Chiffon Ivory Chiffon Mood Mist Platinum Beige Silver Beige Silver Platinum Sterling Pearl Sunshine Flonde Tan Pearl White Beige Breck Hair Color Dark Brown Palest Blonde Ultra Light Blonde Medium Ash Blonde Dark Ash Blonde Light Ash Drown Medium Brown Natural Black Clairol Sal c~Srunettes - Light Golden Ash ~edium GoldenAsli Dark Ash Light Smokey Brown Light Golden Ash MediumSmokey Brown Darkest Smokey. Brown Helene Curtis Coloressence Creme Hair Color Light Drabber Dark Drabber Light Ash Blonde Ultra Light Ash Blonde Pastel Blonde Medium Brown Light Brown Dark Brown Dark Ash Blonde Dark )~uburn Light Auburn Black * Medium Gold Brown * Helene Curtis Ultra Coloreseence Creme Color * Baroque Black Sunburst Brown Light Drabber Ivory Blond Heather Blond Autumn Blond * Gossamer Blond - Keavenly Brown Pecan * Helene Curtis Ultra Tone Creme ~oner OzonCreme Color Rich Light Auburn * Rich Light Brown *Rich Dark Brown Rich (Lig1~t Drab Toner) Rich Dark Drab Toner * Rich. Light Golden Brown Rich Dark Drab Blonde Rich Black & Blue Black * Rich Real Copper Riøh Medium Brown * Rich Bright Red Revlon Colorsilk Light Ash Brown Medium Ash Blonde Medium Warm Brown 233 Clairol Sunn~er Blonde Lightener Frosty White Whisper Blond Miriam Collins Hair Dye Blue Pearl Hair Dye Stardust Tones Exotic Lite Silver Blonde Toner Gardenia ~Beige Toner Honey Dew Beige Toner Moon Light ~lon6e toner Pearl Platinum PAGENO="0240" TAL~I.~ 2 (cor~tinu~a~ ion Colorsilk (cont'd) Medium Drown Light Brown Pale Ash Blonde Dark Ash Blonde Strawberry Blonde Medium Ash Brown Medium Dark Brown Dark Brown Brown Black Black Blue Black Revlon Younghair Natural Color Toner Medium Smoky Brown Light Smoky Brown Dark Smoky Brown Light Ash Brown Medium Ash Brown Laght Brown Dark Brown Black Smoky. Blonde Natural Medium Brown Redken Custom Cretne Colour Sable Brown Ebony A~h True Ash Dark Blonde A~h Crane Blonde BlOnde Ash Lightest Blor.de Ash Ultra White Silver ~Ultra White Blonde Redken/Lapinal Amino Color Dark Golden Brown Nedium Coide~ Brown Dark Natural Ash Brown Medium Natural Ash Brrwn Light Natural Ash Brown D~rk Natural Ash Blonde Medium Natural Ash Blonde Lightest Natural Ash Brown Rodken Drabber Smoky Blonde Blue Lady COLOR RINSES AND SEMI-PER~1ANENT HAIR DYES DO NOT CONTAIN 4-MMPD. 234 * Redken Hair Toner Silver Platinum Blue Snow Sterling Silver Redken Tender Toner Hair Color Creme Creme Mauve Pearl Platinum Honey Mist Redken Pastel Poner Hair Color Ultra Light Platinum Toni Hair Color for Innocent~ Black Light Brown Medium Brown Dark Brown Pale Ash Blonde Ash Blonde Light As1~ Blonde PAGENO="0241" 235 ~NN~N~ I I Z~~I I Ii I I ~ ~ ~ ~ ~I. 24~6OO 0 - 18 - 16 PAGENO="0242" TABIE 3 (contilsuod) HAiR OYE PP000CIs CoNToFNI~o _ - - CBS NO. 005307147 BPI0040_P_PHOLENEOIAMINE - NIT P_?VYLFNIUIAMIPAI R4ANY HAYES 01/19/78- * CPIs HUMMER - - - - -- - - CBS * ~ * - - CLAIROL INC F0035059 EOO35060 F0035079 FOO3SRMR FOO350~g F0035168 F4035]73 P0035174 P0035176 F0035107 F00351R) F003516s FOT3SIFS MISS CLAIROL SHAMPOO FORMULA BLACK AZURE - 5?S - - - -- - 005307142 NICE AND EASY NOTUIOAI MLti BLACY 174 005307142 TRUE BRUNETTE LEER REODI5HPTROWN - - 005307142 bobs CARE P-FAIR COLOR 100105 jR~;coj 00570714? GREAT 5Ay LIGHT RLDIUM OPOAFA -----------005307142 -. GREAT DAY DOOR RAVo,. (JLACO - 00530714? MISS CLAIROL HAIr COLOR BATH ELOPE - - -- - - *~__~ ~*__ 0O5307I~ HISS CLAIROL HAIR CP-;LUR PlATO-I COP O-TG1E 00030714? HISS CLAIROL HAIR COLOR BATH 5PARGLING 500IRRY - - - - 005307142 MISS CLAIROL HAIR COLOR BATH RED CIGSEP 005307147 RED 0050100 FIRL SILVER. - *~ -- ~~~~0053o7L45* RED FASHION SiN SILVER 005307142 RED FASHION PINK SILVER - -- - -- - - *-__ - ----__-~~ - - - -- 0TS3u7l4~ CEO FASHION * P00351MB P0035193 - P0035194 P0035190 P0035199 F00352OT - sItvrR 005307147 FIVE MINUTE COLOR AG-TURN --*-__* ---_- --__**__~ - ------__ ---00530714? GlEE AGO EASY NATURAL PALE 05H 0105SF 00530 7142 NICE AND EASY NATUTYVL LIEU-iT HE 151 NICE ASS EASY NATURAL ISA 600RN 0O53O7l~.?ç- NICE OTTO EASY NATURAL ROLE EUOrrcSE - - - - - - -- - - - - - * - -- - - 000)0 7147 NICE ASP) PA5~ P0035751 PIATUPOL LIGHT ASH YTOPiDE 005307142 NICE AND EASY - - - P0035707 F0O35203 P0035704 NATURAL OFOLUEN 6LONOE - - - - - - - - - ------ 005)0714? NICE AND EASY NATURAL MEDIUM ASH ALOSDE bOS3G7ISY NICE ANT EASY NATURAL REDDiSH BLONDE ~-~-----OCS307042__ NICE A~4D EASY P0A3570,S NATURAL LIEU-U AUUJRN 005307142 - NICE AND FAST * P0035701 NATURAL OARs AUBURN - - - - -- - - -*- - - - --_ 0OS307I~7 P-lICE ASS EASY P0035707 NATO-PAL LIGHT ASO P0005 005307142 NICE AND EASY ~. P00302DB - FAO3S?o9 P0035226 P0035227 NATURAL LIGHT BOORS - - - -- - - - -- - 005307142 GilL AND EASY FJ0TIRRL MFDIUP- RVORs 005307162 NICE 051) EAST NATURAL 000o RROWN ~ -_--_-0IS307142 - CAERE TONER COOARPRGNE BEIGE 005)07142 COOERE - P0035720 SILVER BEIGE - - *~ - - -- - - -oooooiio.~ CR101 TONO-io P0035231 ROTE BEIGE - 806307142 CUbE TONEP P0035237 - - P0030234 P0035235 HONEy CoIFFOs - - - - ----*--- - - - - 00530714? CRLAE TONER i'FACiO CHIFFON 005307142 CRIME TOIlER CAIR0000GI ICE - -- - ~ CAERE F003523N TONER CIPRAPASGE SACARET 005707142 CAERE * P0035737 TONER C000PAGNC PARFAIT - - - - - **~ -- - - 000307142 - CRIME TONER P0030744 TOAST 005307142 NATURALLY - - - FF030245 P0035746 310551 PLATINUM SURE - - - - -- - - 005307142 LAGY CLAIROL ENVY LIUHOS 0005 BEIGE - - 814 00530714, HOPJPALLT MlT'TUE NATURAL HO AOL -- - -- ~--000o7042_ COMPLETE RLONSE * COMCsF TELl 00511 115 000307142 LADY CLA100L . LIE-ABS AOi3O5UCYLE BLONDE 012 - 005307142 PJATTJRBLLY - P0035247 - lAITA-MAIRLI) 01091)1 406 - 00530714? COMPLETE RLO~D)E - - - . - * - - -- -- - - P003524$ COOPLETELY RE 16 167 - - - - - 00530 7142 - LADY CLAIROL EAQY LIYRTS 5PUN HONEY Alt 005307142 NATURALLY ELOIADE GUTSY REbEL -- -. - 457 - ---- 0053071&2 -- 1000 CLAIROL LADY - -3020 HOlly 018 0003A7142 NATURALLY BLONDE TALLY 01161 PAGENO="0243" TABLE 3 (continued) 01/19/70 - HAIR DYE PRODUCTS * CONTAIN~ND *__._SSS5......_SS.SSSSCAS NO. 0R5307142_2-N1TPDP-PHENTLENEDIkMINE~__ RITRO-P-PHENYLONFDIAMINE OPIS - - BRAND NAMES S.- - - - ---_-.--. - -. .- -- CÁO - -- - * NUMBER - CLAIROl. INC - #0035250 COMPLETE BLONDE COMPLETELY TOWHEAD - -- 161 -. * __--- ----------- ------------ - --- -005307L42 -- - 1Aç>Y CLAIROL LADY LIC$TS TOUCH OF TAFFY - 822 5 005301142 * - - NATURALLY BLONDE SIFTED SAND -. 410. - ~~__-__- __~-_ ~_ 0OS307l4~ #0035251 COMPLETE BLONDE COMPLETELY ASH BLONDE 163 - 005307142 .S__LADY CLAIROLLAQY LIGHTS STARLIT SATAD_ 824_____~ 00530744?-- * NATURALLY BLONDE SWEDISH CRYSTAL 411 005307142 #0035252 NATURALLY BLONDE AUTUMN ASH - - _:.____-__------------- *-----------005307142 #0035253 NATURALLY RLONOE EVENING ASH - 005307142 - - - #00-35254 NATURALLY BLONDE 00512 FAWN - - - ~_~___-- - ___------------~~--- -~ -------- 005307162 00035255 NAtURALLY RLOFAUE SOFTLY BLONDE 005307142 - #0035256 NATURALLY BLONDE SUN TOUCH - __.__~ - 005302162 -_ - #0035257 NATURALLY BLONDE AItLOB OLONDE - 005307142 - #8035255 NATURALLY BLONDE 8LONDL GLOW ____________~ ______ 005-307162- #0035259 MISS CLAIROL HAIR COT_OR OATH SUNLIT BROWN 5 005307142 - #0035260 MISS CLAIROL HAIR COLOR OATH POOFALII BROWN. ~ _.___ .._____._-_--_-_---------~-~~--~ 005307142 10035161 MISS CLAIROL HAIR COLDS BATH WiNTER WHEAT - 00G3G7C42~ F0035262 MISS CLAIROL HAIR COLOR BATH SPRING HONEY___S.___. - - _fl053OZlA2i-~_. * #0035263 MISS CLAIROL AlP COLOR BATH AUTUMN MIST 00S307i4?~ #0135204 NATURALLY BLONDE OPALINC AMBER - _!_________________~_~_~_______.___00G307142L #0025265 NATURALLY BLONDE OPALINE -BEIGE - 005307142 #0035266 NATURALLY BLONDE 0PALINE ASPi ~ __---------005307042 #0035267 MISS CLAIROL CRETE FORMULA ARTIC BLONDE - 00530714? - - . #0035268 MISS.CLADROL CRANE -FORMULA HONEY ALO 029 - ~_..i1lS3OX142__ MISS CLAIROL HAIR COLOR OATH HONEY 740 - 029 005307142 - #0031269 MISS CLAIROL CREHL FORMULA SUNNY AUBURN - _..~_.-031 MISS CLAIROL HAIR COLOR BATH SUNNY AUBURN 031 00530?L42 - - 10035)55 NATURALLY BLONDE SWEDISH TAFFY - - ___~__________ S_S _______SS 005307142 #0035411 MISS CLAIROL HAIR COLON MATH HONEY RED 005-307142 #0135412 MISS CLAIROL HAIR COLOR MATH SUNNY AUBURN 00510714Z.__ #0035424 MISS CLAIROL CREME FOJOp(JLA SUNYILONUE BROWN - 00530714? F6135425 14155 CLAIROL CRANE FORMULA SUNSET BROWN - ~ 005307142 -#0035427 FUTUTETONE NON AMUDFTIA TONER OARS ASH 005307142 - 10035428 FOTURETORE NON 0MMONIA TONER COOL ASH - --- - ------ _~------------------ 0~S3G~1~2 - - F0035429 IUTURETDFAE HON AMMONIA TOWER LIGHTEST BLONDE - 0053*7142 - #0035430 FUTURETONE NON AMMONIA TONER OOLDEN OLONDE.__S._ 0~S3O7142_- 10035431 FUTUAFATSONE TON AMMONIA TONER LIGHT BEIGE 005007142 - 1003541Y EUTLIRETONE NON DM40514 TOOlER TRUE BEIGE - - -_-_--- ---- - -- *----- 005301142 -- 10035453 MISS CLAIROL HAIR COLON MATH S(TNSCT BROWN 00-5307142 10035450 MISS CLAIROL HAIR COLUY-( BATH SUFBLONT)E BROWN - - - - -- -- __*_. ____-_--_---- - ___- 005307142-- F0035517 MISS CLAIROL HOER COT_OH BATH LACTIC BLONDE 005307142 -- - #0035534 FUTARTETONE NON AMMONIA TONER OEPiTLE.PLATlNUN____.___-___._--~ - - ____~_0053I714Z--- #0035635 FUTUPETONE FIGS AMMONIA TONER ROISTER WHItE * - * 005307142 #0035545 MISS CLAIROL HAIR COLOR BATH PEORYW000 - - __-- - - 005300142 F0035S52 M155 CLAIROL HAIR COLOR BATH DID (TAR 005307142 - #0035553 BEAUTIFUL BROWNS CEDAR-RED BRYAN S - -- ----- - -- - - ------ 005307142 F053556' BEAUTIFUL OPYRNS OYSW000 140DM 005301142 FOO3T5(l NICE AND FAST NATURAL 1AROY AUBURN 111 -- _ __.____- _ * F0035S~2 PICE AND FAST NATURAL DEER AUWIS~UN 005357142 P0*35569 FYDOUSLTCOIE ND AMMONIA TUOOA SOFT STRAWBERRY - - 005307142 PAGENO="0244" Tz~rJJ 3 (cer:tir7ucd) 01/jR/IA - - s*Io url IH(h:;JCTS .. - .. ~. -- - - _. COO HO, 009397162 ~-S11-P-v1fN0uJ*HI6t._~_ On IR3_1_P#~EL1t0IrILRI.~t COIS bOL9U 880(5 - - - ... 1. - . . coo 88119 CLAIROL 11.0 F u095575 8159 (17140'. HaIR 001CR BATH RLO?C-FST GOLD - . - - .--.-- ~- -- .---- .--..- 00593174/ 1753.574 HISS CL87~n1 `~AIR ~0t0 f0)~ (83n7r)551 IfIrl 0053371.- F1O3~-~i 15755 CL'!~-L (~1E I n'nj7 A I fAt 511518 - . -. . - . . --. -- 009th... ~355r9 `155 01*1~11 CA[H~ IC4~n.tA C0R~o 511410 10031129 R05S&a C/TSR ~ f(.Af ~ 010501 - .. ___.__ . ___________________----- 10035702 51.01 F;"i-t OTIS 1IG~9 GOLLIP ASH 003 00535714 0003570o 1-3s5 CL'lAOL HAIR CCLOi4 6110 &LU-OLICA Si ____~_____~-. - 00~7jii4 Fc53575~ CAErE 11.10 0000 FIST 33' 0053077 11035709 CR11-C Tt~fP SU?4SIIOE 8101.00 334 - ----- ------ - - ---- --- - - 000)oll.-: COSMAIR fEC 10010300 tOFLAT tFCEtI0650 COORS 5820050- COLOR 6.1 1151 ASH IROOH__.___ -. ._~~~00S)07L1. L'tO'EEE. E':U.LEhCE IA~(L7T 807* COLCO to t ic-it Iso -OOwW . - 0011.0071.. L'O~ AL ICFIIEPI.1 P0k'ot'rT s.o'4n-o~ In COnCH 65 LIGhT 1517 800oN - - ____~~___ - 0003071-.. 100)9321 (`00081 OXCILLCSI ~ so~0C COLt 7.1 0F7~ A~ 81.0101 0003070': 1'O~1oL FCIIL(61 RfoA4~T c-lOGO 1 COLO- To 0% 14- 05H E0oHIlt. - - ._____ __~____ 0013010%:: 15019302 (`nISAI. t0-CL11PO1 COOP-I Sh~-Pc-0 Cl-IC-S 7,15 013111 ASPI 001n.%1 OAloJcIl'-2 -- - .. I'oOCAL 11.1110%-Cl fE4'lILIT *I° COIlS 7 1//A ~It}1Lo-T ASH BLOIrOL_ -.__________________ . 005107142 (`00701 IoCItl*#SC P -~1NT 5158--OS In Cn0GH 7 1/4 A 81011)1 AS-I 61000 C00i714/ 10019393 I'S-ALAl loClziLSCL (`1150 515015035 IOLCA 0.1 ASH Is003L - _______ - 000307142 1'OOEOI 11(0701 110000107 rsI° CoLt? HA 0511 1.1.5/1 00514114? (`001*1 I'CCILIP.CE VHon.'rt 51o1-ç-~ IS COLCo PA 151 HLCP-IO( .. ._________~_~. 035307747 10019304 1'O-'EOL 110(ILOPCE CAP-PIE SHAH'0O COLOR 8.11 04.-IC-SI BLOSTlE 00530714 .- - - 1'O~1AL EYC(111N01 1181-'AnLPr! 081* COLOR 6 I//A 0808781.57 IIL000E_._ ~- 00530114 100071 O'C'IIESCE P041451ST S-4A~7-c-3 So CC,nc0 6 1/2* (15*51580771 SLOHOC 050)C71- 10059365 L'O~tot. 0000LL(P4/E CAll-pt 5-008 r~ 00100 9 080111 5c-& - ... - - _ - .o_.__ - - _. -- ~. ~C533l74 IOAIAL I000(LCo.01 P(ObRn78n1 I `1~ COO 9 PASTEL E'.~51n( 1053071~ - - L'081*L EoCtLl0%-C1 PE6'nAoIst 500*700 717 COIL-n I 705111 IL040C -- .___~._______ _-_ 00530710. 10019306 LOOP-AT.. 1/CF11ISCL Cr100 coA.-A53 CO1O~ 9.1 11100 ASH 61.0101 0C33C714~ - -- l'OPIAl E'TOLLIT/L FCPrur0T 8013 CDLI-- 9* 110111 0SHILO::OL__ - 1000*1 toCILTEsCI 10800SnSI 5TLr3~0O fIn COLcA 98 LIGHT ASP Buo*OC 0-053-70%- 100)9307 ~0:11tL (/01111601 Cl-I-I Solo-eD 0/1.009.1016101 8681111 - - __ __-__--- 00530714. - 10*781 E'~LL1~Ct CFL~1 5157HPC~ 10104 9.IuA 1915 LIST ASP 610101 - 00010/1': - (`00(01 (051111-401 1-t0.-A:4151 01* CO1~'3 9 1/00 vOl-p 11007 ASH 0101-31 - ~~__._ - 00037744 * t'O(OL 71017(14(1 11 --o-n1'-nf 5~A"?0O 1w (1104 5 I//A VOPY LIGHT 0511 01 005337)c 10019308 L'OE;L (,C~L11NC1 011151 SATA-0030 C/LC~ 905 (oTIs LI0151bLl&C0L0-IEaC ______________________________-00530014L 10719359 L'OSt*L 7711111011 C01~-L ~(La?55 0014l- 4) (&~o In~lAN 0003-371' * - - - LOPC0L (P011115(1. II ~MIIntii1 8*10 10t00 41 0A44 *t;sjoPi * __ ~_-. 01031714 100C01 (1011114(1 610010111 500090/ 14 COLCA 46 SARO AUBURN 03~3Ch1'r 18019310 1001*1 ErlEtlTrrCt CAb-I 015715200 (0100 43 610 IIP-cy - - _~_ ._____-__-_-~------ 401.30114/ 1'OQ( *1 110CO1IP.C1 IIA1ASET.1 5085100 II: (0/1007 70 410) PE#P*Y 005301141 1001931L L'0El~ 1/11111011. CrIol S0A~25) 1011.0 64 110151 013089 --000111714? - L'IIOIIL (`01111011 0L8571lnT 010 COLOR 77 11401 AT/HURlO 005371142 L'00111 110(1(1801 114°R*SLI01 515120,0 IN COLtS 62 IbAro At700RN - - -_- -.------------ 005 107142 * 100193(2 (`1.71*1 1/CILILl-CI 71800847 SOARP0Q IN Cr3108 11 500041515(0 Cul-PER 000117147 : 10)19313 1'O1EAL 1*017 11901 CHERT S-A*000 CCLO7 8.3 0018114 P-L0~0( -~-------- --. --- -. --- 0*5307142 l'oo*C 100IILIP.C1 PC-AASLOT 00*1100 Is (0104 73 1-111-114 PILOtrUC 005307142 1(019314 L'C°EAL t'01111011 CPCPIE $A~25Q IfliOR B.'. 011-olSo 510~*O1 - -_-__- ~- ~- -~--- (`001*1 (1(111011 11*01,641 58*15000 111 COLOR S~0 410)150 8107100 005327142 - (00)9315 L'O'L*Ll/ClllLrC( COIPIC SH*IPOO (-010~4 010057 01IS~J~~~, ~ ~__._.-15_-____ PAGENO="0245" TABLE 3 (continued) Co -. *1/19fl8 . * - -- - -*---,*---- --- --~ . . CAS P;0._ - . (pis .~. . - 14218 DYC PRODUCIS .- -. --_ -- - ...--.--- - ---_---~ -- - tOS121NEsG 7142 _Z-til 1P0-PPp~EN!LDt011510t Ni 000-P-4sU400142041 0"lr~~ -r 81O~ fl2~S -~ - ~--- - . .. ---- _-*----- - -. ____~ ..~~CA$.-- C0514114 0P4C - . 10019312 t'O~AL C1t1t~tCt PMA~t4T 55*MPOG 114 cote' #01 RCi~c IOE - -- -.-- ~ - . - 10019300 i'O*f *1 1,C1I.1ENC £1211 2H~-~OQ £0120 pL*0]PP4 £544 10 0oS3001'Z £xcu.isCE S(P4A'1t40 P4A'POO IN C0LC-4 IOIP4UM 251 lOP - -. ~.__.__..--------- 53571.2 -- o~'ooE#t F00193U ~ ~ C~fP~ 0.~(~OP ~ £~M lID 0053271'2 * ..1P424L L1C(ILSC( c~*'4t041 ~PO~ IN C0209 T&1!.12214 100 -- - 10021041 1~Wt&t. C(11F4C2 ~ S~0"'-0C C{1OP 4.1 A~0 £204 12005 023201.- * ._ - - -- L'C~At. (`CEt.tChCS 1 Mt-2251 14A1~ COt-OS 4.2 0~EP #514 550004 . - ~__ .__.____-__--------- (`2~(*t~ Cti1~1.CF~ PC P°o'.1'41. S~00 IN £25040 4.2 01(9 *541 8470*21 0CS~57I'? `C0L1(1C1. C2L~2t4~-~'PCO COLOP 2.1 tD14~ £51 853*5 ~ 002)071~? . 10025182 * 1'05001 (tOtlfNCC 9(99*4751 A04'fl3 IN C0I.P4 5.4 St-IT *210 85044 OOS3olP-2 - -- - 10021183 2~0*L (`Ct.1(Nt~( C~t"( 7~10"P0O C2IOP.7.Z COPS I4410ESCCUT PIDNOf Ik1)tcCO'OT 210NflP~ - CP430714? - 10021104 L'0~F&t. 1%CELt.F1sC CPEM( 54'2550 Ct-sOP A.? POISIUM - - - roQ7jP45 1~0PCA1 Is 11.50422 (P101 SI'~PO0 C2t.(~R 9.7 11290 .I010CSCPN1 2L0001 ._-__-_--____--.-.--*------ - L'0~!At 33005. Rt0O~3P PS~' 211012 H*jP t124l41t~P . - - 1002-1194 L0~(Lt. P2(1(0(04CC 10 .~P41*! P45045 1.4 ISAIR CCII? LISI4L*Sli OR0b4*8k___~.__..-~------------------- t'200L1. F'(1P4ftC( 5~t(~. 4 0&tLA-tl4~T *54 (42C4*'* (`.1 057271k. P~'P4C5 ~9'AI-tT C2" 15 1-4*P4. Cut-3M CARs_4SH_Bt001OLJA....~ 71 (050-744 - 5'OPF*I P21111204CC ROt--CS 52-901* 12470 10021197 1*00(01 PP&1P4E4(~ ~50-11 P40-Il IN 1401.1 CC(25 1410 *28.81.3802.7. ~ ~ - 010?1*1 12(1502Nd 2*105 17o-9012 COltill *5)' 5IO04C 7.15 0123270-2 - 1002*149 t'O*fAt P2-1040.5C6 ~1~''(~~ C~E~C IS H*P4 COIlS £28 810801 PA..__.........----------------- 0253C704Z 4.1 0453711'? (`COAt- 24CFOPEP.CI 5*101 194ot't* £58 910119051 p *5.257 (241401 30 p42540 COl_00 pft37E(.$LQ#575.9 0453571 - 1,000*1 74(f (0212-CS 511(70 42451* 9*701:1. 5*_~59( ~ oCr(4'P4C F.1~8f.o241 C~41T5 14 P4010 CObS £7IRO *0800414 48 . - 4053011-4 1(721204 1~O0f £1 10-021202 12(100*1 P~F1(4ENC 91490.2*1 C4'24 55 P4*14 £0100 Lid-HI *01014(4 69 - P47-3274' - 1.05101 F~E1P4E?-C1 001125(4221121*102041 *~c-~* o-& £4243055 PItA 011231 71- - 011221206 1 ~P4~4t- P'-2F2'-(570 Pf14 2412120 20591 04 -*10 C~ 311 -- - *.*. -- * - L~ootE. PojF0j114o;( oozes 110-331* 10-2 1004142 43 8053271' lipNTfcI *374404421 718 - 144021207 15~2f Al Pr(1c0(1.-45( p1Pp#1-5~1 C40'E 05 - 1201(01 P11PoP4~ 11105 1~ot2t-t Suo#lS'110 C-JPPF~ 7.4 ..____.-_~-*-*-_ ~ .. £053270- PP(141(PEP~~0- P4t~L I~ sAle Ct-I-OS 0101401 *U43UR~4R04 02S30-71- 100212411 1024AL . r1E1'1-INC( 4*415 P1~u11 PIIIZOISN P*.O'42E *,4 *- -. ._*._~_________._ 1,43~41.1 10521209 1'5141 pPIFO2-EN( 01*7't51#I (4.1~t 1* 1.215 Cø13~ 202020 14104401 *o - P453074- - - - 10(75*0-CL 5*1.125 *2-0121* LC1.0114-PL07tO5 P.3._... 1153172- - 21(110(7(1 5*149 1C.0'(2* 2(44 C0(~3 IN s*1R COLOR 9.03 1.09 201.. (~5:07I- - 10421219 150041 0-05034(2-lI ~#tt4 0,57j0* 112-90 P14)2124 911.11 4.4 - . COS37~i-- - 20571211 t'2of#l 044CF~44(2.C( 9(53111 PICNIc PPPI(CT L1P4T 2(161 lolL 002)071'- 10021212 (`02121. - - 544(9 1101-31 14..1~ 0412212 512.40 (4010.1. 1147* . - - - . . -**- ~ - - * - - 1"0-10I * 10021213 L'C4~2t 14(110(1.11 10~I~Ct 52~;9$ IESFICT 54-17 2-1.11.1. 10 18 . 0053770 - - - - - - - - 134101 c.~(P 5125.21 4Q~f4 5pP(P SC-1T 9(160 1304 .. - 00521214 1.12121 457 F7*F17( Pl1-14C1 o2025 01*1(21 P1*11OH *SH 10 IC 712 . 5445P 44.0401. tjt.P* 5t-1'PP P1ATtsu~ ~P4 ICTC . (153071-- (0*(A1 0~211~0~5 5(I(~T 1-04)02404 10007(1 (1t(~ OS' 10 00 . 0053'1 5~O.)( 73I'S s12414 12410C01( 921(5 1041 -. . - -- . .* (P43:70- -* 10024278 (.53071 - 1CC'4779 100101 ~P40 04.00424 `2'2S ~t419 (15041 21011500 1004 - -. -* 20024284 19*0514 2071* 441221. 9*-.4S 501(4 sIt-v(Q 11.14(. 5011 PAGENO="0246" - ----`- *--- -- -- CAS TABLE 3 (continued) 01/19/18 5408 DAt P0000CIS - ,~ CONTAINISO - ,. - ., CAR SO. 008307142 - _________________ _______ TLITROP-PH(NyLCNEOI4M4~j( BRAWL) (LAMES CAIS - NU°AYER GILLETTE Cu PEPSONAL ~5IO~ ç~)"( P00)6449 lUST HOOP COLOR FOR INNOCENT COLOR GOLDEN BROWS 310 (COLOR SOLI -_ - ~---~- --------- 005301442 P0045450 TONI HAIR COLOR POP INN(UCLP'(T COLOR MLDflJPO GOLDEN BROWN 330 (COLOR ROLl 005307142 P00)6451 1081 5010 COLOR POP INNOCENT COLOR 721 RLOPLU)E 110 (COLOR 5011 , -- ~ - - ___ - 005307142 -P001045'( 10(41 (`(AIR COLOR FOR iNNOCENT COLOR AURU,UPA( 220 (COlOR SOIL 005307142 .FOOIH4SS TONi HAIR COLOR FOR INNOCENT COLOR AULAiRS BLONDE 180,(COLOR SOLL,,.._________ _____________ P00-44450 TOLL! HAIR COLOR POP INNOCENT COLOR HONEY 810506 (70 (COLOR 501) 005301142 -` HELENE CUJQT)$ )SDU5TPIE~ INC - -~ - - - - -- - - - P0010355 UlTRA TONE CAERE 103-ER HONEY COIR 305 005301142 P0011377 ULTRA TOOL COERL TONER GOLD ACCERLTE0 076 -- --- ------ ------ ---- - ------------- - 005307442- P00(135/ (ULTRA COLAPESNFNCE CAUSE COLOR SLUNR1jRST POowU~ HO 3~ 005307142 P00113&.ULTRA- TONE CAERE 100CR IVORY BLUSH 11-1,, -005307142---_ Pooiiys ULTRA COLOPESSENCE CPC-E COLOP STOPLICIT REQ 3-IC 33 005307142 P0011446 ULTRA COLORSSENCE CREPE COLOR RUOUTRIL HOlE MC 45 - ___- - ~ 005307142 ULTRA COLOPESSENCE COEME COLA? COEDER (LOW NC 44 005307142 - ((LISA CGLOTLLSSENCE CPLP4E COCOS PELT RAY HO 67 - - - ----- --------- ------ -005307(42- P0011440 ((1102 COLOPESSEPLCE CAERE COLOR SlOb HLOSLU SC 42 005307(42', - - -- - -- (ULT4A COLOTLSSEPCL CAERE COLOR OCEANiC P1040 HO 26,,,,,,,,,,_,,.~,,_,__,,,,,_,, ULTRA COLOPEYSENCE CREST COLOR S0RTUGTIHE bLOND 41 27 005307142° P001)470 ULTRA COLOTESSEPACE CAERE LOLOR SPOoR SATIN -(C 48, - - ~ --__--_ -- ---- 005307142 - ULTRA COLORESSELCE CAERE COLOR WAlSiT AC ST 005307142 - P001)473 ULTRA CTL~RESSEPCL CAERE COLOR INIOUSE FED MC 06 ____ __- - ~--._ -- - ------- -015307162 P00)1474 COLOOESAENCE CRERERLIR COLOR 31R P701(04 "(OAR STOWS 005307)42 - -. , -- - COLORT'SSLNCE CR151 PAIR COLOR 43 MEOIUM HEO'BROws __________- __-_ -----005307(4/_. P0011478 COLARFSSENCE CAERE (AIR COLOR 33 1 tORT OAR-P BROwS- 005307142 COLOOESSECE C°CME HAIR COLOR 44 (00 PLC-ALE - - - - -- -------_ ---- - - -- ---.--__--_ -- -- - -- - 0053o7j~ - COLELESSELCE CPEMC HAIR EULER 47 (`ALE (`UEO bLONDE 005307142 P0011479 COLONCASEICE CAERE HAIL COLOR 420256 AUFLURN ______ -.---__ ~-----~----_-__~ 005307142 - COL000'SSESCE CAERE (AlA COLOR 46 11051 OL,HOLN 005307142 P0011404 COLOPESSEPOCE CR00, HAIR COLOR 31 0250,WAP:f R300PE ~ -005307242-,- F001I453 COLOPEALEPLCE CAERE HAILL COLOR 49 (CUILLIANT RED 00531-7147 P1(01 140 COLOPESSLPLCE CAERE (21(0 CoL OR 56 IVLTENOE 3-TOO ,,-. ,,,_,____~ ~ - ---- 0053A7l4~ - 308(1 H RRCCN INC PROIROi ARLCK 5010 COLOR NO 7 LIUPT GOLDEN BLONDE ~, , - ,,,,, - -- ~ ---- - 005307142 - 00019810 (URECO (`(AIR COlOR PLO (S LIMO RADAR - 0053-07142 - -- P0017571 (URECE HAIR COLOR NO 24 (`(OLDEN A$UAER,4LONQE,_,,,-_ -005-307042--- FP0IA0872 0)22Cc HAIR COLOR NO ?1 LIE/IT LOoN 005307142 P00-18013 BOECN ((AIR COCOA 8029 004008 SCOURS -- --_-_ 00S307(42, - ~A0(A876 H0ECR (LAIR COLOR NO 1 ULTRA LIGHT RLONOE * - 005307142 P0015019 0R0c ~AI5 COLOR N) 1611(51 *574 dROWN --------- *---- - - --005307042- P00103-RD 00610 HAIR COLOR LEO (6.5 GINGERHROwN - 005307142 MIRIAM COIL INS P3-I'- PEACH LAOS CV - - ___________________ _______________ P0029123 lI~i LULIOHI RED 1033 - 005307(42 P0022327 hAT P000ISM 710500 (03 - - - - - - ----------- ---005317142 P0072320 (LAIR DYE REAL COPPER 1044 - 005307142 P0022379 (`(AIR EYE IICL-T 003-URN )R65 - -- - ---- --- --- -------------00S307142 P0072311 (LOlA TOP LOE001SIL RAYON (047 . 005307142 P0022337 TORCH 010s0 PEI0E - - * ____ ______________________ P00?2341 TOILER FROSTY ~EIOE - 000307(42 - - - P0022342 lOsER rPTSTY ~ - ~ ~ --------~--.~ ~~`.-~---- PAGENO="0247" - TABLE 3 (continued) - 01/19/78 - HAIR DYE PRODUCTS . __ COo4TAINlN~, ~. .. CAR NO. - O05307R42~ ?-NlTRO-P-PHENULENEOIAHlNE.~_________________________ NITPO~P~PHENYLENEOIHUIP4E CPOS - . BRA190TIAPES - - _~_ CAS 005 P*OD~CTS 017 --EOG14UM- 0705 CACHE COLOR RICH LTOHT AUBURN . -- - -- __-_ __- -_-.----.---- 005307142-- 70014119 DON CPEM COLOR RICH LIGHT BROwN 005397142 FDO~4I2O 0705 CPEVF COlOR RICH REDDISH BOORS - . . -- - -_ 005307142 T0014I24 0705 CREPE COLOR RICH LIGHT HOsCo ILONDE u053o7147 70014125 0205 CRIME COLOR RICH LIGHT HONEY SOLO _.__~_________ __~~___..__~___C053l2142---- - 70014120 02DM CREPE COLOR RICH LIGHT ODLOEN BRORN - 005307102 700I402R 0/ON CRLMF COLOR RICH lARK DRAB BLONDE . __- _--. --_----------- - --- -. -.005307142 - 7001412) 0705 CORNS COLOR RICH CHAHPAGG RL0000E - 005307142 - (0914131 0705 CREME COLOR RICH MEDIUM ASH PL090E - . ____-------- ---- 0003o71'.2--- - 70014-13/ 0705 CALME COLOR RICH REDDISH BLONLIE 005307042 - 10004133 0/ON CPEKE COLOR RJCH REAL COPPER - ~ _~_~00530i142-- - #001413H 0205 ~EHE COLOR RICH HONEY BLONDE 005307142 - 70014139 0705 COENE COLOR RICH BPEOHT RED -- -- .~.. _~___._00S307142_-_ - 70014140 0705 CPEMF COLOR RICH PALE CHAMPAGNE BLONDE - 005307142 - - PLOVER LAROEAT001ES INC - -. ...___.~_ ___________ -- - - #0000106 TICELED PINE NO 300 CUSTOM CREPE COLOUR 005307142 FP0IPIO8RUPOUNOY WINE NO 100 CUSTOM CREMECOLOUR_._ __..0Tl53A7142~~ -. #0016110 100)175 FLUME NO 344 CURIO-i CREME COLOUR - - 00S307L42~ - 70011594 11051 STRAWBERRY 1110510 NO 700 CUSTOM ClICHE COLOUR... ... - _._-__---------------- ~---- -- - -.--. 005307142- #007.8001 PUSSy ELAiC in 41.6 CUSTOM CREPE COLOUR 005307142 ~0o~77~ REOcEN/LAPINAL AMINO COLOR tIGHTEST GOLOEUA 800AM 40 - -- _-.__-..------- -.-----~ ---.---.- --005307142 . - #0008271 PFDcETI,LAPINUL AMINO COLOR PEOIUM 0010(P) OPOWN 20 005307142 - 70010272. 7EDTEN/L&PINAL AMINO COLOR DARN GOLDEN BROWN IG__._ _. . 005307142--- - 7*0)8273 RCOKEH/AAPINAL AMINO COLOR LIGHTEST NATURAL ASH 88005 005307142 7OU18274 RET)SITR/LAP1NAL AMINO COLOR 110)11 NATURAL ASH BROWN ~ -- ~~~--------~- ~~-~------------ - 0*5307142- - F.00i91»=75 PLORRR/LAOP)AL AMINO COLOR 4001DM NATURAL ASH BROWN 244 000530F1~.2 - - #0000276 PEOKEN/LARINAL AMINO COLOR MEDIUM NATURAL ASH BEOTIDE 65 - .____-._----- _~-- ------005307542 #0018277 1(~4çEP)/~ADI5R~ AMINO COLOR OARS NATURAL ASIA BLONDE SN - 005400714? -- - - - #0018/lB RLOICET-AfL.AWINAL AMINO COLOR 0)097 NATURAl AStS.8600N1N_______________________________________ -----005307142----. 70018279 MAflOAEN1LARINRL AMINO COlOR 5411K GOLDEN 01040 SO 005307142 - - EOOIR280 REETEN/LARINEL AMINO COLOR 11091 GOLDEN HIGHS _____.____.______ 005307142 #Q010?R1 RCONEN/l.APINRL AMINO COLOR MEDIUM C.OLOEN BLONDE 60 005327142 -. REVICHONC ---------.-.----.-.--- ----------- . - -. #0018474 REVLON COLORSILS 115)00 ASH BROWN - 005007142 ._._.#00I0475 REVLON COL0050LS 400009 4SH RLONE ._~ --_______ 00S30714Z-~ - 70018476 ~E(LON CT)) OTSILK lEnTIl WARM BROWN 005307142 - . - #007.6477 PEvLOT COLURSILE MEDIUM BROWN - . ..... .--- --_- - __-. 00530714? - 10001)470 1FVLOI COACOlcIIE 11090 BROWN 007307142 70018479 ~VLOM COLOATILS 0710(5 BLONDE -- --. -- - 005307147 -- - #0010706 REVLON COIflOcILS POLE ASH BLONDE . . 005302047 - -- - - .F09107*H - REVLON CR1084118 LI~1T GOLDEN HL000E ~ _____~-__~ _..__....005307142-.. - 7701P77.9 P~VLON CO ORSILS 0377 ASH 81050 - 005307142 * #0018710 REVLON COLONSILA SVHA44ERRY 0101101 - - __ - 005301)62 - - 70010711 REvLON CT)) DOlLS 810119 AUBURN . 005307142 - #0R19712 REVLON CR1015111) DABS BROOMS - - -... ----- 005307142 * 100)8103 0*5)05 CC-IOOSIL1) BEDIM A5H BROWN - 00530712 - - F0I1P71~ RI/ION CCLOPcIL.N MEDIUM I)ARB 40049 - - - - - _____________ -..__AAS3)7142- * 1001071S REVLON C5.OHSILK 001 RPOMN - 0053071'? - 70019716 PEvt0s COIDAYIIs A/FAN IA AF~ - -r PAGENO="0248" TLBLE 3 (ccntinu~c.i) - 01/19/SR 1401Q DsE ~~ofl'iCic . . ~ -- Co 1* - CR5 NO. C5530?142 ?-N1Tk9-PHfS(LENEo!oM1~ .._~ ~ ._~__._ C~1S .. NPAHO NAMES - - HUM (P PEVtO!',P(ALIslIC (0050910 YOIJHGHMJP 000IJPP-t. COL0~ TOMOR OM-~ ASH RNOWPI . .. -- oos3o~1- (0051018 YOIJ5UP4AIP tICS MI.O1U~ SMOMY 81080 00530?)- t00?1J379 VOUTUHAIR UCI 1551 -14050 444-089 . . - - . . - - . Q0~3~7~ (00504100 Y0IJ15444)P UCI O'~~( S'Usy YQOIPI 0053011-S - - -- F410?10(41 Y055TM4AI° HC7 LISP] f-1~ R~0S ..._. ..L.... ~ ~ - CGS3S71~' )001RO2 yOkjU(,4019 OCT 841)00-' ASH pACIWN 005304. F&0~'1Y']3 Y0J144~-'4A!R OCT (3544] 400814 - 0053071. (0021494 Y]405H817 `444 00.40 tM~ 0053571. (0021005 00~'oG4-PoTY 441 434t.C4c - - - - . -- . -. . -- -- - - - . - 70021895 Y44U05-]A30 ICY S~05I FLOODS 0053071' - - - - 1002)597 Y0,35(4818 OCT 45050 -_._..__~_ ____. ~._.___~_.___._._~_ - __-_~___-__ 10021898 S0451,#48IP tIC] 0000004 0(01(40 80O~34 ooS3o?l~s CARSOOI 1PODIJCTS CO . - FOO12'192 G(IDEFOOY DA54~ `H LOVELY PERMA74CNT S40SM4'OO Ill HAflOCOLUT kI A1004UR4I - -- - - - PAGENO="0249" TABLE 3 (continued) 01/10/78 0*10 Dv( PRO7flJCTS - - C7P4T* 11111-IS - - - - - - - CAS ~*O. 977061*50 -- 2_5ITPQ_P_P140MYt.ENEO1l~11M~ SuLfATE.-___------------------------------ CPIS BP*NU PIAM[5 COS - - Rt.U'cEN LSROIIATOPIES INC ~ - ~0*11Q)5 HSt)ltlM STOIW1-EI100 5~5157f 115 1-OS CuSTO1 COLOUO 977O6111~Cl -- 000)8702 171(0 014111 ~0 647 CUSTOI' CRIME C~L~u~ - - ___-_- __~----- _9770611157 000)5013 TIll-Ut) p10500 #0 401- CUSTOM CR101 (010178 9770617)50 -- - - - 008180)7 (1701 010.00 500 CUSTOM ~ COLOUR - --C -- - -. -- --C- -- ._ .. 100100)8 81*1-C #0 533 CUSTOM 10111 CR10110 9770611-50 PAGENO="0250" TABLE4 ---.---. -~ ---------- -- 81/19/16 HAIR 0E P000UCTS - CONTAINIAG - - - - -. .- -- - ~ ~ - CA5 NO. CO0119346 4.AAI40~2_N1TRQpME,AOL BRAND UAH(5 CAS LOIS BE 1 * ..~. CLAIROL INC - - - - _________ 10034015 MISS CLAIROL. SHAMPOO FORMULA P-T00000LD 000115346 10035160 MISS CLAIROL DAITT COLOR BOTH FLAOE,4 BLONDE - - - - - - - -- -- -- - - - ---~---__- ------___-___.. - 000119366 - 10035(58 MISS CLAIROL 1010 CC~ol MATH FLAT-P 000119340 - - 10035169 MISS CLAIROL HAIR COLOR 041(4 TOPAZ - -_ - -- - -._-_. - - -- -- 0001143.6 - - 10035172 MISS CLAIROL HAIR COLOR (OATH 5014 MRON/I- -. F0135173 HISS CLAIROL HAIR.COLOR (OATH C04'PLPTOSE - 10035174 MISS CLAIROL ((AIR COLOR HATI S2APLI0 SHERRY 0001193.6 -.... Foo:5116 MISS CLAIROL HOIM COLOR A3ATH RED SIIAPOB - - ---------------------------------- --000119346 -- * 10035103 1(0 FASHION 04)14 SILvER 000119345 - F003S1~4 RED FASHION P1140 SILVER- - _--__- --__~ - -- ~ 000119366 - - 10035165 RED E0Sl1IO'1 CHERRY SILVER 0001 17346 -- - 10034106 SILVER DROPS*~~* --~ - -- 000115366.. - FC0351V1 FIVE MI44IJTE (01041 BEOPIOE 0001193'.6 * 10035100 FIVE MINUTE CRUX AURORA - - _**_ **_ *~_ 00Sl15J.~ 100)5193 NICE A140 EASY NATURAL PALL A5H RLOI4OE - . 000119346 100)5194 NICE 6140 EASY NATURAL LIGHT BEIGE HLONOE . _*~ 0001153~'. - E003519v NICE A-ID EASY NVT~3PY1 ASH (WORN 000114145 1 F 0034213 CAERE. TQDPR 50 TOWHEAD -. 0TCl14340~~ - 10034214 CAERE TOsFA IOU SANDY EL000L 0001(93461-I 10035245 CAERE TONER 00000 LITE A - - - -- *~ - - - ** - - 0000193661 10034210 CPEOE 101410 EXTRA LITE B 000114346 10034217 CPC~E TOIlER EXTRA LITE 5ILOERY RLOUDE . - - - - - -- -- 000414346 100340(8 CAERE T0414 5110(0 SPOsE 000(19346 10035719 CAERE TONER SILVER OLD - - - - ~ 10035220 CAERE TONOR POOY4RIA(O BLONDE 000(14340 - 10034221 C0EX'E TOS5R STRAW.4E000 BLONDE -- ------- - - ---- --_- -- -- - _---_ - 0001193.6 - 10035223 CRE'E TOIlER 0110(41 PLATINUM . 000119346 - 14035220 CAERE T0TAFç C000IADSE ELIDE - - 0501(93o6 -- - 10035221 CECRE 00011 SILVER OLIVE OOA1(93-5 - -- 1003527 CREXE TOIlER NOSE OLIVE ______________ 10134229 CREME TOIlER (IUTT(PCUP FF105 001IIflos 10035230 CAERE TEllER 100.41 CHTFFO14 ** *~_ - 000119340 10035031 CAERE TONER ~04EY CHIFFON 000(14366 - 10035734 CAERE TONER C(IARPAGNE ICE _*~ ~ CO0I4s3~ 10035239 CAERE (ONTO CHOYPO9sE SHEERLy 000110046 * 10034239 CPLAL 10059 CHAPPRUSE PARFAlI _________ - 10035?37 CRL"E 104(0 EIIARPA&.E TOAST 0001IS3'.6 - *. 10030238 CAERE 0044CR MARS PEAPL - - -- - -- -"~- - - ------------------- -000115346 -- * 1003004S LAOS CLAIROL LADY LIGHTS MOON (((bE 814 000119346 - - NATURALLY ELOSLIE NATURAL PEARL - . -- 405 - * - _. ~ ~ --000114346 10035240 COMPLETE RL000E COMPLETELY HONEY 165 000119346 LADY. CLAIXOL LADY LIGHTS XOYIE240CKL( $LONOE_.._ ________ NATURALLY ALO.DE (AlA-HAIRED RL040L 406 . 000119346 00035247 COMPLETO RLONDE COMPLETELY OLIVE - 167 - - . 000119346 - * LADY CLAIROL LAOY LIGHTS SPUN HONEY - 816 090119346 -~ NATURALLY BLOUSE SOT-lAY BEIGE - - 407 - - - _*___ - -_ 0001193,4 10034248 LADY CLAIROL EAOY LIGHTS HA7Y MOlLY 818 000119345 KATUPALLY 01045 TRULY REIGI 408 __._._ ~ 001I1936A_ * F003S7~9 COMPLETE BLONDE COMPLFTEL0 FLAXEN 169 000119140 - LAOS CLAIROL LAOS LIG4ITSM(ILDEUA.HISPER - ~. `~RRX~ ~I00T)I(5(46 ~ PAGENO="0251" CPIS NLT'BER CAS -- - .-. - - - -- - -- ------ - - --- - - - * CLAIR(!L INC *~ - rooTS2o1 UR000ALEY 4104.ETE 5401406 HA7E - 409 000119346 .00035250 COMPLETE BLONDE COMPLLTELO TOWYTCOD * - 161 - .. __-_-__---.-- _~_- -- -0001193.6 - 1600 CLOIPOL SOY LIGHTS TOUCH or TAUI-T- 822 000113546 TIAIORALIY 1400400. SIFTLU 0040 410 - - ___. - _____ 006113)47 00035251 CR871001 010601 COMPIITILY ASH 0104400. 063 oRG - LADY CLAIROL LADY LIGHTS 0129111 5260 ___.______824~ ________ ~-000I19346 -- * - NATURALLY 010401 SwEDISH CRYSTAL 411 000119346 - - - 10035252 N4100ALLY BLONDE AU1000 ASH - - .. . _----_----.- 000019346 -- - 00025253 TAATIJRALIY RLOI.Dt-EVRNING ASH - O0O1193oY~ - - 00035256 000000ILo 01050 IUS~Y FAWN - -- ---- --------- - *-- - 000119346 - 09015255 NATURALLY 0104,1* SOFTLY 610500. 000119346 0000S256 NATURALLY OLOsUL SUN TOUCH - ____~_.~ -- 000119346-- -- 00035257 NATURALLY 1107401 WILLOW T3LO'-&DE - - 000119346 00035259 NATURALLY 13L0440E 010606 GLOW .~_* -- -- ____..*.*____ -- 000119346 - - 00035259 MOSS CLAIROL #40114 COLOR OATH SU7&IT BROWN 000119346 00035260 HISS CLAIPOL HAIR COLOR OATH MOONLIT BROWN .._*_- - _-~-_-.- ___._---__- 000119346 - - 00035290 14155 CLAIPOL HAIR CR1041 BATH 016110 WHFAT 0001193464 00035262. HISS CLAIROL -4019 CR100 OATH 5RPI~40 HONEL...L.._.___._..~_ 0001I9340~., * 00035263 MISS CLAIROL lAIR COLOR MATH 0010413 MIST 0001193460. - 10035264 NATURALLY BL0NUE OPALINE 1140AM ---- *.* *~.._-~~~-.--...-----.- -~ 00O1I9346~ 10035265 NATURALLY BLONDE OPALINE I4EIOE - 000111346 -, 00035266 NATURALLY 010601 0001160. ASH - -- ~_-- ---.--*- ---**-.---.--*-- -.- __. --_---.. 0001)93.6-- 00035355 NATURALLY BLONDE. SWEDISH TAFFY 000119346 - ~ 00356.9 NICE.400 EASY 64001001 LIGHT BEIGE BLONOE8103_._..________ - 00035654 NICE *00 EASY NAT~0AL PALL ASH BLOOLTE 1101 000119346 02014 00000CTS DIV - *._-*-. _...___-__-.-___*---_- __--.-----.--------------- - * 00004010 02010 CR0.4-IF COLOR RICH LIGHT AUBURN 000119346 - -- - 0001.120 0700 CR1140 COLOR RICH REDDiSH 000014 -. - *. ..____. ..___*_____--~-----------.------ 000119346 00016126 0200 CRIME COLOR RICH L1HHT GOLDEN BROWN 000119066 * *____f0016032..OZON CARRIE COLOR RICH 60.001514 PLOIIUC._...._... -- 10014133 0_ON C~E14E COLOR RICH HEAL COPPER - 000119361 -- 00014130 0200 CRETE COLOR RICH BRIGHT RED ...._ _._ - - ..._.___~_ ..._ *__________*- 000119346 - - R6O.(1PW LABORATORIES INC - - - 00012009 CHEMPAGNI BLONDE HO 1040 CUSTOM CRIME COLOUR - ~.~*~~--.--------* ---------------- *~---- ---_--000119366 - - - 00018016 WICHITA WHEAT `40 9?6 CUSTOM CRIMP COLOUR - 000119)46 - 00018476 REvLON COLOPSTLT( MEllON WARM I~ROwN 800119346 00018710 REVLON COL085ILK STRAWBERRY BLONDE - *.... - -_*____-*- - ---- - *--- 000119346 100)071) REVLON COLORSIEK RECTUM AUBURN 000)19346 - * 00010712 REVLON COLORSILK 10006 AUBURN - * - - - - - - - - -- *-------.- - -_- -- - - ---.- 000119346 - - RIVLGWR0ALISTIC - - 10020007 *YOUNITHAIR NCT 64)00400. - ___ ..___~__._.~___..____._____.0001I9346 - -- 10021088 YOt,NOHAIR OCT NATURAL MEDIUM 80046 000119)46 CARSON PRODUCTS CO - . -- --- - FOO18~i92 GODEFROY 0917K `14 LOVELY PERMAT$EHT STIAM000IPR HAIRCOLOR KIT 600086 - * TAT3LE 4 (continued) - - 01/19/78 HAIR Dvi PRODUCTS CONT616INS - - -. -- - - -- - * - - - - - COO NO. 000119346 - 4~VMIH02NITROPNEP40L BRAPSI NOMAD -- --. PAGE 2------- PAGENO="0252" 246 -25- Absorption Numerous scientific studies indicate that the aromatic Compounds used as dyeing agents in hair dyes can penetrate human skin. Indeed, to the best of our knowledge, all hair dye ingredients so far tested have entered the bloodstream of the species tested. Moreover, Maibach at al. have demonstrated that the scalp is a preferred cite of absorption, allowing about 4 times as much penetration as the forearm. In studi.es with semipermanent hair dye chemicals numerous authors 10/ have demonstrated penetration. Frenkel and Drody showed percutaneous 11/ absorption of Mc blue #1 in rats and rabbits. Maibach ~t al. detected hair dye chemicals from two commercially distributed sgmi- permanent dyes in the urine of humans, rats and rabbits after their 12/ hair or fur was dyed with the product. Two authors have raported urine discoloration in women, suggesting presence of dye chemicals in the urino, after hair dyeing with commercially availablo semi- permanent dyes. Similar results have been observed with permanent hair dye ingredients. Exploratory akin penetration studies conducted for FDA 13/ by Feldmann and Maibach indicated that 4~kPD is found in the urine of humans and monkeys after applicotion to the skin. l4~ labeled 4Mi~TD was applied to the forearm of 6 adult males for 24 hours and urine collected for 5 days. The estimated mean total penetration durini this five-day period was 3% of tha applied amount. l4' Kiase et al. applied MPD, P?D ar.d 2,5TDA to the abdom~n of dogs. All three compounds penet~ated the skin, as determined by blood or urine measurements taken ofter the 3 hours of application. PAGENO="0253" 247 -26- Oepending on the solvent in which the PPD was applied, either 1.1% or 6.7% PPO was absorbed. Anout 2.9% 2,STDA was absorbed. If hydrogen peroxide was added to the ?PD before application, no pene- tration was recorded. Howaver, the measureft~ent technique used was sensitive only to about .2% absorption. 2,5TDA was found in the urine of dogs following £pplication of 2,STbA and hydrogen peroxide. No 2,STDA' was found £n the blood, but the limit of the measurement technique was also 0.2%. NieCe and Rauschetmeasured the absorption of 2,5TDA through human skin. The hair of 5 persons was dyed with a simplified hair dye prapardtion contain~Og 2,5TDA, hydrogen pero*ide and the coupler resorcinol for 40 minutes. The hair and scdlp were then thoroughly washed. The authors found that an avetage amOunt of 3.66 mg per persoi~ of the diacetyl derivative.of 2,5TDA was excreted in the urine during the two days after dyeing. Based on calculations derived from injecting a known amount of 2,5TDA intO humans, the authors calculated that 4.6 xr~ or 0.33% of the applied 2,5TDA was absorbed. The penetration of 2,BTDA in rats and dogs has also been studied 16/ byHruby. Animals wete exposed to radioactively-labeled 2,5TDA in hair dye formulations containing other primary intermedietes and couplers. The fothulations, similar to coxrme~cially available hair dyes, were mixed with hydrogen peroxide before application. In the rat studies, the dye formulations were applied for 30 minutes and than the skin was washed and dried. After 24 hours the animals were sacrificed~ In the dog studies the formulation was applied for 3 hours and then the skin was wanhed and dried. Blood, urine and PAGENO="0254" 248 -27- feces were collected for 5 days. Results indicated that 0.21l%± 0.04% 2,5TDA absorbed through rat skin from a formulation containing 4.0% 2,5TDA. 5.2% ofthe radioactivity remained in the siteof application, suggesting that absorption may continue even after thorough washing. If so, absorption would exceed the 0.211% measured after the 24-hour sampling period. 0.208% 2,5TOA absorbed through rat skin from a formulation containing 3% 2,5TDA. 9.3% of the radioactivity remained in the skin at the site of application. Approximately 0.218% of 2,5TDA absorbed through the skin of the dogs tested. 17/ Feldmann and Maibach have shown that labeled 2,4TDA is absorbed in significant amounts through monkey and human akin. The authors estimate, based on measurements taken over a 120-hour period, that approximately 46% of the applied 2,4TDA penetrated the skin of monkeys and approximately 2O~ penetrated the forearm of humans. In a similar study with labeled PPD, about 12.7 ± 7% per person of the applied PPD was found oVer. a 5-day pétiod in the urine of six human 18/ subjects. This figure was not corrected for retention in the body.. Skin penetration of PPD is also supported by the repeated association of PPD-containing hair dye products with the development 19/ of cutaneous reactions in humans. All of the studies described so far have measured only the absorption of the primary intermediate or couplers. No measurement has been made of the absorption of the inultiringed colored products of the hair dye process. However, studies with multiringed aromatic PAGENO="0255" 249 -28- compounds similar in structute to the colored products of permanent * hair dyes strongly suggest that these products are also absorbed. For example, the semi-permanent hair dye chemicals described earlier in 20/ this section. are multiringed aromatic compounds. Kiese et al. report that the multiringed compound, l3androwski's base, formed while dyeing hair with permanent hair dyes containing PPD and hydrogen peroxide, absorbs through the skin of dogs. Similarly, there is extensive evidence that the aromatic amine, and known human carcinogen, 23/ benzidine absorbs through the skin. Evidence also exists for the absorption of other aromatic amine carcinogens. Based on this kind of supportive evidence, Mies concludes that ag mt~ch as 1% of hair dye amines (primary intermediates, couplers, and colored multi- ringed products) are absorbed by the average person using a 22/ commercially available, permanent hair dye. The studies descFibed above, quantifying the absorption of primary intermediates or couplers from commercially available perma- nent hair dyes, ~upport a general claim that anywhere from 0.2 to 0.35% of ~he amount of each chemical applied to the scalp is absorbed through the skin when a person dyes their hair. Based on this percentage, it is cflear that consumer exposure to hair dye chemicals can be considerable. As an exaipplo, the average person dyeing his or her hair once a month, using a dye with an average amount of 2,4DAA (600/mg dyeing), puts 7.2.g of 2,4DAA on their heads each year. Using the 0.33% absorption figure for 2,STDA, one can estimate the absorption occurring from the use ~f2,'4t~AA~~see Table 5 , page ~/ It i~'clear that several factors influence the validity of this comparison-..th~ relative rates of absorption through the skin of 2,4 DAA and 2,S'-diatnin~toluene and the pèrcènt of each comp~ound placed on the scalp available for absorption. While these factors may differ for both compounds, quantitative information on each is nor available at this time. PAGENO="0256" 250 -29- TABLE 5 Absorption of 2,4DAA Amount of 2,4DAA in Product Estimated Amount of 2,~4!~ Absorbed~j~~g~ As Percent of Product Monthli Yearly 600 ]. 2 24 1200 2 4 48 3000 5 10 120 for example, where 1 per cent or 600 mg of the product is 2,4DAA, the estimated yearly absorption is 24 mg. Theze estimates of absorption are consistent with the data of 2~' Ames et al.~ As mentioned, Ames concluded that "a woman under- going one hair dyeing (with about 4g of amines) could absorb as much as 40 mg (1%) of hair dye chemicals (precursors, products and side products) through the scalp." Assuming that hair dyeing occurs monthly, this is equivalent to 480mg absorbed per year. In a formulation currently under test for carcinogenicity by the CTFA, 2,4DAA is present as 2% of the total product and approximately 25% of the unreacted amnines. Our estimate in Table 5 that 48 mg of 2,4DAA would be absorbed from such a formulation seems reasomable because 2,4DM comprises over 25% of the ur~reacted `amines and 48 mg is only 10% of the total amount of amines estimated by Ames to be absorbed. Clearly, data on the rate of formation of products and side products and the rates of absorption of all precursors, pro- ducts and side products must be known to quantify precisely the absorption of 2,4DAA. It is interesting to compare the estimated amount of 2,4DAA absorbed with the amount of the known human aromatic amine carcinogen PAGENO="0257" 251 -~30- benzidine needed to cause a significant increase in cancer rates. Such a comparison is not intended to imply that these chemicals have the same carcinogenit potency. The validity of such an assumption is unknown. However, such a comparison is meaningful in evaluating human exposure to 2,4DAA. An estimated cumulative dose of 200 mg/kg of benzidine gave 52% tumors among a group of workers; an estimated cumulative dose of 50 mg/kg gave 22% tumors among another group. A woman dyeing her hair with a dye containing 5% 2,4DAA would receive a cumulative dose of approximately 50 mg/kg in only twenty years. Many people dye their hair for that period of time. It is clear that a consumer's exposure to 2,4DAA over a life- time of hair dyeing can approximate levels of occupational exposure to the known human carcinogen benzidene that have resulted in unacceptable cancer incidences. This is clearly a cause for concern. Moreover, this c~omparison is based solely On the absorption of one coupler. A person using hair dyes will aleo absorb similar amounts * of other primary intermediates and couplers, and unknown but signifibant~ amounts of multiringed products. 24.600 0 78 . 17 PAGENO="0258" 252 -31- Mutagenici~y~ A number of hair dye chemicals and commercially available hair dye products cause gene or chromosome mutations in bacterial cells, mammalian cells, or insects. Gene or point mutations are changes in the base pair sequence of DNA. Chromosome mutations involve changes in the number or structure of chromosomes. The induction of mutations by hair dyes is significant to human disease incidence for two broad reasons. First, numerous crippling human diseases are caused by mutations, for example, mongolism. Second, a positive result in certain tests for mutagenicity is considered a highly reliable predictor of a chemical's cancer-causing .ability. The Ames test for bacterial mutations and the test for morphological transformation of mammalian cells in culture, for example, accurately 24/ identify about nine out of ten cancer-causing chemicals.The Occupational Safety and Health Administration's cancer policy accepts a positive result in assays for mutagenesis in bacteria, yeast, prosophila, mammalian Somatic or germinal cells, DNA damage or repair or in vitro neoplastic transformation of mammalian cells in lieu of a second animal bioassay as sufficient to ic~entify a carcinogenic 25/ chemical Gene Mutations 26/ Ames, et al. tested 169 permanent hair dyes for mutagenicity in the bacteria Salmonella typhimuriun. The dyes, made by 8 different companies, were bought by the author *at two local drug stores. One hundred and fifty out of the 169 formulatiofls tested were mutagenic, with mutagenic hair dyes found in the product line of each company tested. The authors also tested 18 individual chemicals in PAGENO="0259" 253 -32-- permanent hair dye formulatiorts. Nine of the 18 were intitagenic. The mtttagenic compounds, beginning with the most strongly inutagenic, were: 2,4DAA, 4-NOPD, 2-NPPD, 2,5t)AA, 2ASNP, MPD, OPD, 2A4NP, and 2,5TDA. The authors also reported marked increase in the mutagenicity of certain hair dye chemicals after mixing with hydrogen peroxide. The mutagenicity of three para-dianiino compounds, PPD, 2,5DAA, and 2,5TDA was dramatically increased after oxidation by hydrogen peroxide; mutagenicity of the latter two ccmpounds irtoreased over 40-fold, 27/ Similarly, preliminary results of NCI experiments indioate that the oxidation products of 2,4DAA, PPD and hydrogen peroxide are many * times more mutagenic in the Ames test than 2,4DAA alone. These results are especially significant for assessing human risk posed by hair dye use because large amounts of these oxidation products * are formed on.a person's head during the dyeing process. Ames et. al also examined 25 semi-permanent hair dyes. Most of * these were mutagenic in the Ames test.. A number of hair dyes were tested for mutagenicity in Salmonella * by Searle, et al. These dyes were proprietary preparations and therefore their ingredients were not~ reported by the authors. Seven of the 11 dyes were strongly mutagenic. Of these, six did not require microsomal activation. Thin layer chromatography on the mutaqenic dyes indicated that 6 of the 7 dyes contained fractions o~ high mutagenicity correspoth5ing to 2-NNPD and/or 4-NOPD. 4-NOPD Was about 3 times more potent than 2-NPPD. The identity o~ the mutagenic agent in the one hair dye that required microsomal activation was not precisely identified, The dye, however, was noted to contain an azo-dye metal derivative and an amino nitrophenol. PAGENO="0260" 254 -33.- 29/ Venitt and Searle tested numerous semi-permanent, permanent and temporary hair dyes for mutagenicity on the Ames teèt. Neither the names of the products nor all their ingredients were revealed. All eight semi-permanent dyes were mutagenic. Most of the products contained 2-NPPD and/or 4-NOPD. Similarly, all thirteen permanent dyes were mutagenic after S-9 activation. Three hair dye ingredients, OPD, MPD and PPD, were mutagenic after S-9 activation. Significantly, mutagenic activity increased when hydrogen peroxide (H202) was mixed with the individual ingredients. Six temporary hair dyes were also investigated. All were mutagenic after 5-9 activation. 30/ In the Ames tests by Sugimurá numerous semi-permanent and permanent hair dye ingredients were found to be mutagenic. Specifi- cally, the following ingredients .were positive: 2NPPD, 4NOPD, 2A4NP, 2A5NP, 2,4TDA, 2,5TDA, 2,4DAA, 2,515AA, OPD, MPD and PPD. The mutagenicity of 4NOPD and 2,SDAA were also demonstrated in Salmonella 31/ * by Mohn and deSerres. 4NOPD and 2,4DAA are alsomu.tagenic.in 32/ yeast. - 33/ Palmer et al~Thested hair dye ingredients for mutagenicity in mammalian cells. NPD, 2NPPD, and 4NOPD were positive. 2,4DAA gave a questionable response and 2,SDAA was negative. However, the assay was carried out without microsomal activation. Chromosome Mutations Several, studies have shown that hair dyes and their ingredients 34/ cause chromosome mutations in cultured mammalian cells. Searle et al. PAGENO="0261" 255 -34- found that 2NPPD causes a considerable number of chromosome and chromatid gaps and breaks in cultures of human peripheral blood lymphocytes. Cells incubated with 4NOPD do not show chromosome mute- 35/ tions. Xirkland and VenitEreported that Chinese hamster cells cultured with 4NOPD and 2NPPD have a marked increase in the percentage of metaphases containing chromosome aberrations and in the number of aberrations per cell. Benedict indicated that 4NOPD and 2NPPD also cause chromatid breaks in cultured hamster cells, and that 2bPPD exposure. results in abnormal metaphases of the type related to malignant transformation and oncogenesis. In addition, Benedict~ pepørted that 2NPPD and 4NOPD cause morphological transformation of cultured mouse cells. The transformAtions are of the type that usually produce sarcomas when injected ihto immuno suppressed mice. Animal Studies -~ B]ijleVen found that PPD, 2,4DAA, 2,4!tDA and 4NOPD induce sex-linked recessive lethal mutations in Droso~hila melanogas~ç~. The peak mutagenic activity occurred in metabolically active sperm cells. 38/. Hossack and Richardson tested hair dye ingredients for muta- genicity using the rat micronucleus test. All of the following chemicals were negative: PPD, 2,4DAA, 4NOPD, 2NPPD, PAP, MAP, 2A4NP and 2,STDA. Prom the perspective of predicting chemical c5cino~-- genicity, this test has a high number of false negatives. 40/ Burnett at al. reported no dominant lethal effect in rats of 2NPPD, 4NOPD, MPD, OPD, PPD, 2,5TDA, 2,4DAA, 2,5DAA, 2A4NP, 2ASNP and 4A2NP~ ~he relevance of these results for predicting carcinO- genicity is marred by the high number of false negatives reported. PAGENO="0262" 256 -35.. for carcinogenic compounds £n dominant lethal tests. Moreover, the doses and number of animals used were too small to assure accurate resu~Lts. Summary Table 6 on page 36 summarizes the positive mutagenicity data for hair dye ingredients. Table 7 lists ingredients whose mt~ta- genicity is increased by mixing with hydrogen peroxide. TABLE 7 Ingredients with Increased Mutagenic Activity on Ames Test After Mixing with Hydrogen Peroxide (H202) 2,5DAA PPD 2,5TDA 2, 4DAA opo MPD It is obvious that a large number of hair dye ingredients are muta- genic in a variety of tests, including measures of gene and chromosomal mutations in bacteria, yeast, Drosophila and a variety of cultured mammalian cells. The studies described above also indicate that a majority of marketed hair dyes, permanent, semi- permanent and temporary, are mutagenic. In light of the correlation between mutagenicity and carcinogenesis and the potential for human genetic di~ease, these results must be considered alarming. PAGENO="0263" TABLE 6 Animal Pounds Carcino- Tests for Mutagenicity used/yr gem Mammalian Mammalian Mouse Chromosome Morphological ~gredients Ames Yeast Lymphoma Mutations Transformation Orosophila 2,4DAA Ames Moyer Blijleven 25,000 yes Sugimura 4~0PD Vennitt & Moyer Palmer Kirkland ~Benedict Blijieven 7,500 Searle Benedict Móhn, Ames Sugimura Searle 2,5DAA 2,5DAA Ames Sugilnura Mohn. 7 2A5NP Ames Sugimura 500 7 ~ cr MPD Ames Palmer 500 7 Vennitt & Searle Sugimura 2A4NP Ames 1,000 ? 2,5TDA Ames Sugimura 22,000 no PPD+H202 Ames 2NPPD Sugimura Palmer Searle. Benedict 24,000 yes Searle, Ames Venitt & Searle OPD Venitt & Searle Sugimura PPD Venitt & Searle BlijleVefl 75,000 Sugirnura PAGENO="0264" 258 -37- Animal Carcinogeni~~ The carcinogenicity of hair dye formulations and individual hair dye chemicals has been evaluated in animals through inges- tion and skin painting studies. These studies, reviewed below, indicate clearly that exposure to hair dyes and hair dye ingre- dients either through ingestion or skin painting, results i~n an increased incidence of tumors. Specifically, NCI data indicates that 2,4DAA, 4A2NP, direct black 38, direct blue 6, 2NPPD and 2,4TDA are carcinogenic iii rodents. Feeding Studies 42/ A recent report from the NCI summarizing the results of a study in which 2,4DAA was fed to mice and rats concluded, "Under the conditions of this bioassay, technica3~.qrade 2,4 diaminoanisole sulfate was carcinogenic to both sexes o~ both species." The NCI ~periment was conducted according to Standard carctnogenesrs bioassay protocols. Rats (Fisher P344) of both sexes were fed ad libitum diets containing either 1200 (low dose), 5000 (high dose) or 0 (control groups) parts per million (ppm) of 2,4 DAA. There were 50 rats in each group (except for the male rat high dose control group, which had 49). Similarly, three groups, each containing 50 male and 50 female mice (A.R. Schmidt B6C3P1) were placed on ad libitum diets containing 1200 (low dose), 2400 (high dose) or 0 (control group) ppm 2,4 DM. After approximately two years, the animals were sacrificed and pathologically examined for cancer. Results of these examinations PAGENO="0265" Adenocarcinoma, NOS; 4% Papillary Adenocarcinoma;~ (2/43) Follicular-Cell Carcinoma; or Papillary Cystadeno- carcinoma, tCS P~denocarcinoma, NOB; 4% Papillary Adenocarcinoma;. (2/4B) Pollicular-Cell Menoma; Pollicülar-Ceil Carcinoma; Papillary Cystadcnoma UO~; or Papillary Cystadenocarcinoma, NOB In the high dose group the number of rat8 having either one of three groups of thyroid. tumors or adenocarcinoma, NOB was significantly greater than the correapondizr~ control gtoup. ~/ The figure indicates the ratio of twnór bearing animals found to the total number of animals examined. ~J The p values listed were determined by the Fisher exact test. 259 38- are pre~sented in Tables 8 - 17. Male rats showed a statistically significant increase in a wide spectrum of thyroid tumors (Table 8). *TABLE8 Tncidence of Thyroid Tumors in Male P~a~ ~pe of Tumor Incidence of Tumor Low Dose High Dose ~w High Control Control Dose Dose Adenocarcinonta, NOB 4% 0% 2% 29% (2/45)tJ. (0/48) . (3/47) (14/49) P 0.05- C--Cell Adunoma or. Carcinoma . 2% (1/45) 2% 9% 20% (1/48) (4/47) (11/49) p~0.O5 0% 4% 35% (0/48) (2/47) (17/49) p(0 .05 0% 4% 40% (0/48) (2/47) (20/49) p<0.O5 PAGENO="0266" 260 * -39- A statistically significant increase of epithelial tumors of the integumentary system was aino observed among male rats. These tumors were fow}d in the skin (Table ~), the preputial gland (Tablo l~, and the ear canal'and zymbal gland (Table 11)'. TABLE 9* Incidence of Skin Tumor in Male_~ts Low Dose Control 0% (0/4 6) Incidence of Tunio~ ifigh Dose Low High Control Dose Dose 0% 0% 10% (0/48) (0/48) (5/49) p<0.O5 Type of Tumor Squamous-Cell Carcinoma Basal-Cell Carcinoma Sabaceous Menocarcinoma Sebaceous Adenoma Fibrosis. Fibrosarcoma Squamous-Cell Carcinoma, Baa al-Cell Carcinoma, or Sebaceous Adenocarcinoma All Tumors 0% (0/46) (0/48) 0% * 0% (0/46) * (0/48) 0% 0% (0/46) (0/48) 0% (0/46) (0/48) 0% 0% (0/46) (0/48) 0% 0% (0/46) (0/48) 0% 0% (0/46) (0/48) 2% 4% (1/48) (2/49) 2% 6% (1/40) (3/49) 0% 2% (0/48) (1/49) 8% 2% (3/48) (1/49) * 2% (1/48) 4% (2/48) 2% (1/49) 18% (9/49) , . p.<0.05 12% (6/48) 24% (12/49) p7 PAGENO="0345" 3~9 Dr. FINE. These are some examples of known human exposures to N-nitrosamine compounds. This is an attempt at this. Someofle is inhaling air and there is a certain N~nitrosamine level at a certain factory. They may be eating a bacon sandwicWor they may be working with pesticides or working with cosmetics. How do you try to relate the exposure? What we have done is to assume a normal lifestyle with a person working in a city who may inhale 10 cubic meters of air a day, and a person using cosmetics may apply 1 gram of cosmetics to their face a day. From this you can begin to correlate at least what the different exposures are. bgesting of'foods at the very most could be about 1 microgram per day of nitrosodiethanolamine or N-nitrosodiethanolamine, exposure to cutting'fluids, may be anything from 25 to 250 micrograms per day by inhalation and up to 25,000 by contact with the skin. Cosmetics, with a single application of the ones we have looked at, could be anything between 50 and 100 micrograms per day. * Smoking a pack of cigarettes of 20 cigarettes a day would. account for about 3 or 4 micrograms per day. So, one can `begin to correlate `these numbers. What this still does not take into account is two aspects. No. 1, the different exposure :routes Some of these are by inhalation or skin cofrtact or ingestion. Secondly, the various relative toxicity of a' compound should be taken into account. Sonie are relatively potent carcinogens and some are moderate. At the present time I do not thiñk' `any scientist can make a better correlation than that. We dO not know' how to extrapo~ late, beyond that kind of ~uimbers which you can calculate and have confidence in. The restis guess. Ms. LEAL. Last week there were questions raised by CTFA between drawing conclusions `or drawing a link between eancer~causing agents in animala and their applicability to humans. Can you cothment on that?. . ` Dr FINE As a resoai ch chemist, I think that is out of my line of "expertise. I would be getting into areas that I know very little about. Ms. L~AL. Do you know of any' scientific knowledge that would' shed some light on~that? ` ,` ` Dr. FINE. Let me quote some things about N ~nitrosamines which are known. `. ** There are about 130 N-nitrosammes which baire been-or corn- pouhds, to be `more s'cientificalW' correct, which have ~been tested in animal experiments. Of these, aboutfr 100, or 70 percent approximately, are, or havO~ been shown to be, carcinogenic in animal experiments. The animals which have been studied., of which there have been 18 different sp6ciesT, include the rat, mouse, hamster, Chinese hamster, guinea pig, rabbit, dog, trout, parakeet, and monkey If it is carcino~ genie in one species, it is carcinogenic in the other species. In the case of the N-nitrosamines, the sites of the tumors vary, sometimes depending on how it was obtained, that is, whether it was by mgestion oi~ inhalation) and also the chemical structure of the nitroso ~cornpounds. Tumors that -have been `produced' can' be in the kidney, larynx, or lung, or ~brain, deponding `on' the ~trueture.' PAGENO="0346" 340 This body of evidence is in the literature about the nitroso com- pounds with animal experiments. There have been studies at very low doses going down to feeding an animal at doses as low as a part per million, in the case of three N-nitrosamines. In the case of N~nitrosodiethylamine, a study in Germany, showed that one part per million in the diet of 100 animals was statis- tically significant and gave tumors above the background. That is abQut the lowest dose that has been looked at with N-nitrosamines. As for human studies, there are no studies that I have seen-posi- tive or negative-on looking to see if humans are, that is, if there is any epidemiological data related to N-nitrosamines. The reason there are not any studies is that until 3 years ago N-nitrosamines were not known to be a major problem with man. They were known to be potent animal carcinogens and to be present in foods at low levels. But a human population had not been identified to which they had been exposed, so that an epidemiologist could go out and study it. At the present time there are now three or four such populations. You have rocket fuel workers in Baltimore and certain pesticide agricul- tural workers and people who use cosmetics and machinists who use cutting fluids. I know of several ongoing epidemiological studies which are be- ginning to see if there is a correlation, but so far that correlation has not been made. People are just beginning to try. To say that there is no correlation has to be qualified with the fact that no one has looked at it. Ms. LEAL. Thank you, Dr. Fine, Thank you, Mr. Chairman. Mr, MAGUIRE. You talked about shelitime. Have you attempted to define in any way the relationship between the formation of N-nitrosamines in products and periods of time on the shelf or after the cosmetic is actually placed in the container? Dr. FINE. We have just begun to do those studies now in our laboratory. It was only a couple of months ago that we found that the O~nitro compounds, on particular one in cosmetics called bronopol, could act as a nitrosating agent. In fact, it was more efficient at the neutral condition in a cosmetic than sodium nitrate would have been. It created more N-nitrosamines than sodium nitrate would have. With that finding, we now have the studies underway. We do not yet have any data on that. I would like to comment here on what that leads into, Mr. ChaiF- man. There has been a lot of discussion this morning and last Thurs- day, which I heard, on testing ingredients. In one case in the original study we looked at two ladies' makeups, the same color, the same shade, and by the same manufacturer. One was water based and one was some other base. In one we found the highest level that we reported which was 50,000 parts per billion. In the other we found nothing. Mr. MAGUIRE. Which was which? Dr. FINE. I do not recall the name. It is in the data. Here we have a situation where apparently many of the ingredients were identical. One or two of them may have been changed, or the concentratlon changed, I do not know what the change was. PAGENO="0347" 341 But that~ingredient which was o~hanged made all th~ differenèe in forming the N-nitrosamines and in not forming them. So, if you are testing ingredients only you have to be very careful that the ingre- dients are inert and are not reacting with time with the products. Otherwise you can test a lot of ingredients. and certify them safe under any kind of test that you can think of and then find that there still is a hazard in the final product.~ Mr. MAOUIRE. Apparently there also are combinations of ingre- dients which do not result in hazardous findings~; is that right? Dr. Fii~. Oertainly~ From the chemistry one can develop classes of compounds, which when mixed with each other are quite innocuous, or other products that they may form with time which are quite innocuone Mr. MAGUIRE. Does this imply that there are now in existence safe substitutes that would preclude our having this difficulty with certain cosmetics containing N-nitrosamines? Dr. FINE. I would have to answer "Yes" for the following two reasons. In some cosmetics we found very high levels of N-nitros- arnines and in others we found very low levels. If we know what the ingredients were in the low levels, those products. are obviously, comp~redto the high levels, relatively safe. It is, therefore, possible to manufacturer or make cosmetics which do not contain Lnitrosamines. We have now found that certain bacteriacides can form the N~nitros- amine when mixed with the amine in the cosmetic. However, there seem to be cosmetics on the market which contain other bacteriacides or other ways of preventing bacteria growing in the cosmetic~ with time. So, it would seem that it is a very soluble problem. Something similar arose with pesticides at these hearings sometime back. Some companies had very high levels of dimethylnitrosamine in their pesticide products. The problem was they were marketing their products in cans which had been treated with sodium nitrite. They took the sodium nitrite out of their cans anxi their problem almost went away. I think in the cosmetic area, paying attention to what the in~redi- ents are and how they react, will probably solve the problem. Many companies already have that solution. Mr MAGUIRE Are these chemical reactons which result in N-nitros- amines a function simply of the chemical componen'ts in the mixture, or are they also variable in relation to changes in temperature or agitation or any other factors? Dr. FINE. Mainly the constituents. A temperatureii~ almost any chemical reaction would tend to increase the rate The higher the the temperature, the more rapid the rate of chemical reaction Similarly is the agitation The more rapidly you agitate, the more you mix things, and the more rapidly it will go But- Mr MAGUIRE But you feel the big~ disparities you have found in essentially similar products are the result of the chemical constituents rather than these other factors; is that right?~ Dr. FINE. Thatis correct. ~- Also, we feel we have the explanation in that we now have found that some of the ingredients that cosmetics contain both the precursors I PAGENO="0348" 342 which form the N-nitrosamines. Two are needed and they are both in the cosmetics. Mr. MAGUIRE. The C-nitro compond that you are talking about, is that a newly found compound which nobody knew about or nobody knew that it had nitrosating qualities? Dr. FINE. It was a known compound and widely used. There are other very widely known compounds which have very similar chemical structures. Although we have not tested them specifically, we would expect them to form N~nitrosamines. Some of these are used as dyes in cosmetics and some of them are used as bacteriacides in cosmetics and some of them are used as perfumes. Many perfumes are C-nitro compounds. This does not only apply to cosmetics. Many pesticides are 0-nitro compounds. We believe the same chemistry would help explain the problem in cosmetics. Mr. MAGUIRE. Have you received any support from NSF or anybody else to continue this kind of work? What is the status of your research now with respect to examining some to these additional questions? Dr. FINE. Our funding from the National Science Foundation is to look at the generic problem of N-nitrosamines in the evnironment. We have looked at chemistry, pesticides, and cosmetics, which are just a few examples of the chemistry. The way the program was set up when we got our support from NSF, we could not get into too much depth with anyone, because these aspects fell under the control of different agencies in this case, the Food and Drug Administration. So, and we do not have continue support of work on cosmetics. Work that we have on-going is that we are planning to do some absorption studies. We are hoping that the FDA may support that in the future. Mr. MAGUIRE. With respect to cosmetics? Dr. FINE. Yes. That is not being supported by the NSF. That is our own support. As far as the chemistry is concerned, the mechanisms of how N- nitrosamines are formed, again, we are hoping we can get support to continue our work. Mr. MAGUIRE. Are there any other categories that you are planning to work on now with respect to a preliminary assessment of the N- nitrosamine question? You mentioned pesticides in cutting oils, and now cosmetics. Are there other categories? Dr. FINE. The categories we are looking at are chemicals of com- merce: industrial chemicals, pharmaceutical drugs, and things like shoe polishes and floor waxes- Mr. MAGUIRE. You are going to do that? Dr. FINE. Some of them actually are in progress. Mr. MAGUIRE. I see. You indicated that the information about N-nitrosamines in cos- metics had been transmitted some time ago to the FDA. Dr. FINE. That is correct. Mr. MAGUIRE. Have you received from them directly, or do you have, any indirect information as to what, if anything, they have done on either matter?. PAGENO="0349" 343 Dr. Fi~. We have had several meetings with FDA where in one cas e they came to see our labs. .1 havebeen down to see FDA scientists on several occasions since then. We discussed with them our latest findings on the mechanism of w hat may be happening. in cosmetics about 5 or 6 weeks ago. We have s ubmitted to FDA research proposals for continuing this work. We d o notknow~ yet what the outcome of that will be. Mr MAGmEE But they have not, to your knowledge, taken any action with respect to the cosmetics in questior~? I am talking about as far as their availability to the public is concerned Dr FINE My understanding, or what I have been told, is that they do not have the jurisdiction to restrict the sale of cosmetics Mr MAGUIRE Do you know whether they have notified the manufacturers, or hare you notified the ma~ufácturers in any formal way as. to the results? Dr. FINE. We notified, when the results were released initially in March of last year, the manufacturers by telegram under the signature of the National Science Foundation, notifying each manufacturer of the findings in the~particular product. Mr. MAGUTRE. Dr. Fine, we want to thank you very much.' `We appreciate your testimony. We `would like to add a person to the witness list today. We would like to call Judy Wairath of the Yale University School of Medicine. Please conic ftrward to be sworn in. Do you promise to tell the truth, the whole 4ruth, and nothing but the truth; so help you God? [Witness answered "I do."] Mr. MAGU.IRE. Thank you,~Dr. Wairath for' agreeing to testify today. ` Mr. Segal? Mr. SZaLUA. First I would like to request that a letter that was received by Chairman ~Tohn Moss today be inserted Into the record at this point. It is a letter from a Dr. Aivan R. Feinstein of Yale University, School of Medicine, commenting upon the report that Dr Walrath was the senior editor on It is in relation to the point ~a~scd earlier this morning by Dr Corbett on whether or not the subcommittee has had an opportunity to evaluate the two studies grought forth by the industry at their prior testimony last week. ` ~ . ~One of' the' two was the study done by `Dr. Waltath and Dr. J. Wister Meigs You will note in the letter that l~r. Fèinstein is the same individual who found serious flaws, gross flaws in the two NIOSH studies, and he ends up. s~~ing very complimentary things about the methodology usediti the Walrath-Meigs.study. Mr~ MAGUIRE. Without objection, that letter will be placed in the record at this point: [The letter referred to follows:] PAGENO="0350" cr~. q. o I -` ~ SCHOOL OF b{EDICINE 333 cedar Street Robert lVood Jo/news Clinical Scholar Program ALVAN ~t. FEINSTEIN, M.D., Program Director (203) 436-8 787 On January 25, 1978, I was telephoned by Elliot Segal, of your staff, requesting me to send you a critical review, of studies of hairdressers and cos- metologists performed by Dr. E. Cuyler Hammond and by Dr. J. Wister Meigs. Although Mr. Segal said he would send me copies of both studies, I have not yet received the Hammond report. A copy of the Meigs study, of which the principal investigator was Judy Walrath, was sent to me (apparently at Segal's request) by Dr. Nalgs. My com- meOta here are therefore confined to the Walreth-Meigs study, "Cancer Incidence Among Cosmetologists", which is currently in the form of a dissertation, dated December, 1977, submitted by Walrath for the Ph.D. degree from Yale University. The study is a longitudinal investigation of a cohort of 12~O7 Connecticut cosmetologists who began hairdressing school before December 31, 1965; and of a matched cohort of 11,463 Connecticut schoolteachers. Both cohorts were assembled "retrospectively!': the cosmetology group, from license registration data available since 1938 at the Connecticut State Health Department; and the schoolteachers, from data at the Connecticut State Department of Education Certification. The subseqtient occurrence of cancer i~ both groups was determined by linkage ~- via names, birth years, and other pertinent information -- with data contained in the Connecticut Tumo RegiStry. The linkage activities were performed "blindly", withOut kn9wledge of each person's occupation. The total subsequent occurrence of cancer, as well as the occurrence of cancer in specific Sites, was noted for the cosmetologists and compared against the analo- gous occurrence rates, in a matched, pairs analysis, for the schoolteachers; and, in cohort analysis, *for the corresponding general population of Connecticut. The inferential and analytic statistical procedures used in both the matched pair and cohort analyses appear to be impeccable, with appropriate usage of Beers interpolatio McNemar chi-square tests, Fisher exact tests, and several methods for computing stan- dardibed incidence ratios. In the cohort analysis, the investigators found that the cosmetologists had a substantially ~ rate of cancer, in total ar~d for almost every specific site, than woul4 be expected froa the corresponding rates of the general Connecticut population. Thi~distinction is attributable to the bits of the "healthy worker effect" that tends to make any .occupatSonal group healthier ttan the general population. In the matched pair analyses, the schoolteachers had a higher rate for total cancer than the cos- metologists. For individual sites of cancer, the rates showed statistically significa differences in favor of the cosmetologists for cancers of the breast a~0~eproductive system; and in favor of the schoolteachers for leukemia. In view of the,/1ifferent can sites fpr which comparisons were made, occasional differences in favor of either occupational' group can be expected toocçurby chance. 344 Yale University' New Havece, Co,z,jecticut 06510 January 30, 1978 John E. Moss Chairman, Subcommittee on Oversight and Investigations of the Committee on £jtterstate and Foreign Commerce House of Representatives Washington, D.C. 20515 Dear Mr. Moss: PAGENO="0351" 345 John E. 1465s January 30, 1978' The results indicate that the tOtal risk of cancer for cosmetologists is certainly no higher than for the general population, Snd is slightly (but not significantly) lover than for a matched group of schoolteachers. ~Yith respect to individual cancer sites, the results found in this cohort study contradict the results of previous.case..control studies suggesting that cosnietologists have elevated rates of cancers in the breast, lung, bladder, ovary, and uterus. You have Seen my letter to Conner ~ay, dated January 20, 1978, containing a re- view of~,two stn4ies sponsored by NIOSfl and~performed by, Decoufle ~t al. and by I~erinedy et al. Unlike those two previous studies, the Walrath4leigs investigation was perfora with careful attention t6 scientific `detailg, anSlyzed with eXcellent metho4s, ,and die cussed with admirab),e scientific caution, The authors have t1~oughtful1y constdered all of the difficulties assodiated ~qith any epidemiologic research of this type and have pointed out the problems involved in de4ing with the basic data as well as the issues in linkage. The questions being asked about `the risk of cancer, from hair dyes cannot be approached wit~i experimental research in humans and would not be answerable for decade if investigated as a prospectiv~ cohort study. The best way to try to answer the question now is with a large "tet~ospective" cohort study, which is precisely what Walrath and Meigs have accomplished. A8 good scientists, they have cited the potentia biases that are inherent in such a study, but they also indicate the absence of evidenc to suggest that the potentia'l biaaea actually occurred. Purthermore, every one of the potential problems discussed by Wairath and Meigs is abundantly present in the previou `two studies, although not discussed by the othan ~thers. If not an optimal compariso group for the cosmetologists, the teachers investigated by Wairath-Meigs are obviously as comparable a control group as the non-specific "clerks" used by Decoufle et al. and are ob~2Lously better than the lack of any specified control group iz~ the Keonedystudy In the ~alrath-Meigs~ study,. futthermote, the licensure info,rination provides objective co~nfirmation of dccupational data that were obtained `subjechvely and neither checked nor verified' in the other two studies. Walrdth and Meigs ~l~o prbvide data for risks accordingto duration of exposure~'an important scientific feature that is wholly absent from the other two reports. Finally, and most cogently, the SJalrath-Meigs in- vestigation is a population-based cohort study with a specific hypothesis. It is not the' type of data-d~edgittg activity -- using populations of unktiówri origins ahd biases and s~a~ing no advapce hypothes~s -- that vas performed in the other two studies. In his telephone convetsation with mS, Elliot Segal S'~id someone had~ suggest~ that the Walrath-M~i~s study had ~Ow `quality and cdttained the samesort of defects present in the tvo NIOSH-aponsored tepQrts. Since the Walrath4teigs investigati9n is of ex- cellent quality, and is so~óbviously Superior to the other two studies, this suggestior could come only' from someone who lacks familiarity with Standards for scientific epidemiologic research. I understand that you are eager to have this review as soon as possible. I am therefore sending it now. When the Rammond document arrives, I shall comment on it separately. Sitlcerely' youñ, ` Alvan R, Feinatein, M.D. PrOfesse~ of Medicine and Epidemiology ARF :mbn PAGENO="0352" 346 Mr. SEGAL. I would first like to ask Dr. Wairath if she could identify for the record her training in the field of epidemiology. TESTIMONY OP IUDY WALRATH, PH.. D., SCHOOL OP MEDICINE, YALE UNIVERSITY Dr. WALRATH. I received my Ph. D. in epidemiology and public health from Yale University. Mr. SEGAL. Dr. Wairath, among the findings that were listed in your i~eport was there a significant increase statistically of acute leu.. kemia among cosmetologists as compared with the control group. Co~ild you comment on that? Dr. WALRATH. Yes. When compared, the control group with schoolteachers had no cases, but in the cosmetologists there were seven acute leukemia cases. This result was statistically significant, but due to the small num- bers, I believe that further research should be done to confirm this. I do not believe that should be overlooked, however, Mr. SEGAL. The industry, in its testimony, indicated that your study was one of two that demonstrated no direct link between cancer and hair dyes. Based on your study, would you come to the same conclusion? Dr. WALRATH. `No. One cannot draw a positive conclusion from negati~ve findings, which essentially is what we had overall in the study. I was testing to see if there was any difference in the cancer incidence between the schoolteachers and the cosmetologists. This hypothesis cannot be rejected on the basis of statistical evidence, but neither can it be accepted with a lack of this information. Mr. SEGAL. Would you conclude from your findings and your con- clusions that more work needs to be done and that the safety of hair dyes is something that remains, at least in question? Dr. WALRATiI. Yes. I believe that more research should be done. Mr. `SEGAL. I have no further questions, Mr. Chairman.'' `Mr.. MAGUIRE. Dr. Wairath, are there any additional comments that you would like to make on this subject? Dr. WALRATH. I do not believe so, no. Mr. MAGUIRE. Mr. Wunder? Mr. WUNDER. Thank you, Mr. Chairman. Hav~e you seen Dr. Feinstein's letter? Dr. WALRATH. Yes. Mr. WUNDER. If you look on page 2 in the first paragraph, he says: The results indicate that the total risk of cancer for cosmetologists is certainly no higher than for the general population, and is slightly (but not significantly) lower than for a matched group of schoolteachers. Are those the results? Is that accurate? Dr. WALRAPH. Yes, it is. Overall cancer sites combined, there was no difference between the cosmetologists and the schoolteachers, and overall, when compared with the Connecticut population there was no difference. Mr. WUNDER. Explain to me the statement you made about the positive results from negative findings What exactly does that mean? Dr. WALRATH. I am saying that overall there is no indication that there i& a risk of cancer among cosmetologists, but I am saying that PAGENO="0353" 347 this lack if information to prove this does not indicate safety or no risk. Mr. WONDER. You cannot prove safety on this basis; is that right? Dr. WALRATH. Yes. Mr. WUNDER. Because the schoolteachers and the cosmetologists came out lower, that is, the cosmetologists came out lower than the schoolteachers and that, in of itself, does not prove safety; is that what you are saying? Dr. WALRATH, That is correct. Mr. WUNDER. What about leukemia? Is that consistent with other findings, other epidemiological studies in this area? Or is that some- thing new that you came up with? Dr. WALRATH. I think that has not been found in any other studies on cosmetologists. Mr. WUNDER. To what do you attribute that? Dr. WALRATH. I am not able to say5. Mr. WUNDER. I see, Let me ask you this. In your study, and I notice in the letter it says that your group was from licensed registration from .the Connecticut State Health Department. Dr. WALRATH. Yes. Mr. WUNDER. So this group of cosmetologists wquld not include shampooers and electrologists and manicurists and that sort; would it? Dr. WALRATH. The group included 77 manicurists, I believe. The rest were, all licensed hairdressers who were all qualified to do all duties of hairdressing; shampooing, hair dying and haircutting `and so on. Mr. WUNDER. There were 77 manicurists? Dr. `WALRATH. Yes. Mr. WUNDER. Was there anything-what about the manicurists versus the cosmetologists versus the schoolteachers? Can you break those out? Dr. WALRATH. I am sorry. I do not understand. Mr. WUNDER. You had 77 out of the 12,000 which were manicurists? Dr. WALRATH. Yes. Mr. WUNDER. Did they have any higher degree of cancer in. any sites than the cosmetologists or the schoolteachers? Dr. WALRATH. They did not. S Mr. WUNDEE. Were they lower?' Dr. WALEATH. I believe there wasonly one case among the 77. but the numbers were too small to draw any conc1usi~r~' Mr. WUNDER. Thank you. Thank you, Mr. Chairman. ` Mr. MAGUIRE. Thank you, Dr. Walrath. The subcommittee will stand adjourned until tomorrow at 10 a.m., `in this same room. [Whereupon, at 2:20 p.m., the subcommittee adjourned to recon- * vene at 10 a.m., Friday, February 3, 1D78, in room 2322 RHOB.] 24-600 0 - `78 - 23 PAGENO="0354" PAGENO="0355" CANCI~R-CAUSING CHEMICALS Safety of Cosmetics and Haii~ Dyes P1~TDAZ FEBBV~AR~ 3, 1978 HOVSE or REPRESENTATIVES, SURC0MMITrEE ON OVERSIGIIT AND INVESTIGATIONS, COMMITTEE ON INTERSTATE AND FO1~EIGN COMMERCE, Wa$hington, D.C. The subcommittee met, pursuant to notice, at 10 a.m. in room 2322, Rayburn House Office Building, Hon. Andrew Maguire presidmg [Hon. John E. Moss, chairman]. Mr. MAGIYIRE. The subcommittee will come to order. Today, we conclude this series of hearings on the war on cancer Over the past 2 weeks we have heard testimony from scientists and industry officials on the topic of whether hair dyes and other cosmetic products are safe More specificially, we have explored the issue of whether ingredients in cosmetic and hair-dye products pose an in- creased risk of cancer to users. The evidence collected to date suggests that we must. 1oo1~ more carefully at not only the safety of these products but the adequacy of the statutory authority granted to the Food and Drug Administra- tion-FDA-in this area. I believe that testimony before this subcommittee strongly suggests that the cosm~ti~ section of the Foo~l, Drug, and Cosmetic Act be scrutinized for adequacy. Proper regulation of the safety of cosmetic products is essential Dr Robett Scheuplem of FDA estima,tes that the average American places 10 to 40 pounds of soa~ps, toiletries, and: cosmetics qn his or her skin annually~ Scientific studies indicate that some ingredients penetrate the skin and reach the bloodstream. Research, however, has not yet demonstrated what happens when these substances enter the blood stream Are some of them retained in body tissues? Do they metabolize into more dangerous substances? These are questions which remain unanswered Nevertheless, information presented to this subcommittee suggests that numerous carcinogens, mutagens, and other toxins are in cosmetic products I believe we must be concerned about not only the acute effects of these chemicals but also the chronic effects, One important question which must be answered is Are we sub- jecting the public to an increased and unreasonable risk of cancer or other adverse health effects through the use of these products? In effect, are we needlessly gambling with the public health? (349) PAGENO="0356" 350 The cosmetic industry has stated that cosmetic and hair-dye prod- ucts are safe. Unfortunately, the evidence presented thus far leads me to question this conclusion. The cosmetic industry has stated that few consumers have adverse reactions to cosmetic products. Information provided to the subcom- mittee indicates, however, that cosmetics may "injure 60,000 per- sons-mostly women-annually so seriously as to restrict activity for 1 day or require medical attention." The testimony presented to the subcommittee raises serious ques- tions about the adequacy of industry's testing of cosmetics. Further- more, the record seems to indicate that FDA does not have adequate authority to protect the public from the potential hazards presented by these products. After a careful review of all the information before me, I believe one conclusion must be made-the coal-tar hair-dye exemption must be removed. There is no logical reason why coal-tar hair-dye products should be given special treatment under the law, especially in light of increasing evidence that these products contain carcinogenic ingredients. I wOuld like to announce today that I, along with Chairman Moss and several of my colleagues, will jointly sponsor legislation to remove the hair-dye exmption from section 601 of the Food, Drug, and Cos- metic Act. Today, I hope we will obtain answers to some of the questions raised over the last 2 weeks. I welcome CommissionGr Donald Kennedy of the Food and Drug Administration and Mr. Gregory J. Ahart of the General Accounting Office. I hope, gentlemen, you can assist us in determining whether further congressional action is needed to protect the public from potentially harmful ingredients in hair dyes and other cosmetic products. Mr. Walgren, do you have an opening statement? Mr.. WALOREN. I would like to reinforce at the outset of the hear- ings the seriousness with which the committee considers the findings. We conclude a set of hearings that have revealed serious inadequacies in the protection of the American public from potentially harmful ingredients in cosmetics, cosmetics that are sold by the most tempting advertisements without any way for the public to understand that it is running severe risks. There is no statutory authority for the FDA to require notification by maitufacturers that they are even producing a cosmetic product or that they are introducing a new product or introducing new ingredielits. Thus, there appears to be no mechanism for the FDA to assure that these manufacturers are honestly representing their products to the public, let alone whether such manufacturers have gone through and considered reasonable safety consideration before the introduction of a product. We have heard testimony which indicates that our present practice really exposes the American public to severe potential, but severe, harm given the fact that we now understand the skin to be a part of the body which readily absorbs material from the outside rather than being an impermeable membrane. PAGENO="0357" 351 As the situation now stands, the public must rely on the industry and its assurance regarding the safety of these products. I am afraid that the profit motive alone, wheu you consider the dollars involved in the marketing of a cosmetic product, that the profit motive alone should make us skeptical of safety assurances from those who have an interest in the marketing of a product. The testimony we have heard more than confirms the need for such skepticism I want to express my appreciation to the various witnesses who have come before the committee and those who are here today. I think that the American public has much to benefit from your views, and I trust that out of these hearings will come some sub- stantial improvement in the projection that we can provide to the public in an area that it really has no way of understanding what protections it should require; that is, to protect itself from severe risks of cancer and the like. Thank you, Mr. Chairman. Mr. MAGUIEE. Thank you. Our first witness today will be Mr. Gregory J. Ahart, Director, Human Resources Division, General Accounting Office. Gentlemen, we will have to swear you in. Would you please stand? Do you swear to tell the truth, the whole truth, and nothing but the truth, so help you God? [Chorus of I do's from three witnesses.] Mr. MAOUIRE. Please proceed. TESTIMONY OP GREGORY J. AEART, DIRECTOR, HUMAN RE~ SOURCES DIVISIOI~, GENERAL ACCOUNTING OPPICE, ACCOM- PANIED BY ALBERT B JOJOKIAN, ASSISTANT I)IR~CTOR, HUMAN EESOIfltCES DIVISION, AND JAMES LINZ, SUPERVISORY AUDITOR, HUMAN RESOURCES DIVISION* Mr. AHART. Thank you, Mr. Chairman. I would like to introduce my associates at the table. On my left is Mr Albert B Jojokian, Assistant Director, Human Resources Divi- sion, who is responsible for Our work at the FDA. On my right is Mr. James Linz .on Mr. Jojokian's staff who has direct responsibility for the work we are going to testify on this morning. We are pleased to be here this morning to discuss our report to the subcommittee entitled: "Cancer and Coal Tar Hair Dyes: An Unregulated Hazard to Consumers"-HRD--78-22, December 6, 1977-and the results of our broader review of the Food and Drug Administration's (FDA's) regulation of cosmetics. Our work has been directed to determining whether: (1) Coal tar hair dyes and other cosmetics pose an unnecessary hazard to consumers; (2) FDA has sufficient legislative authority to effectively regulate cosmetics; an4 (3) FDA has effectively used its existing authority. FDA's authority to regulate cosmetics in interstate commerce is derived from the. Federal Food, Drug, and Cosemetic Act, and the Fair Packaging and Labeling Act. PAGENO="0358" 3~2 The Food, Drug, and Cosmetic Act requires that a cosmetic be: Free of substances that may make it injurious; packaged in a safe and n ondeceptive container; produced under sanitary conditions; and, labeled with information about the product's manufacturer, packer, or distributor, and the quantity of its contents. FDA has authority under the Fair Packaging and Labeling Act to require that a cosmetic label list the product's ingredients. Before highlighting the results of our review of cosmetics regulation in general, I would like to briefly discuss our report to the subcom- mittee on coal tar hair dyes and subsequent developments. COAL TAR HAIR DYES AbQut 33 million women use hair dyes to temporarily or permanently change their hair color. There is increasing evidence that some colors used in coal tar hair dyes-the dyes most widely used-may. carry a significant risk of cancer to users. However, exemptions in the Food Drug, and Cosemtic Act do not permit FDA to regulate coal tar hair dye products effectively; they bar FDA from banning or restrict- ing the use of cancer-causing coal tar hair dyes. Coal tar hair dyes are divided into three groups-temporary, semi- permanent, and permanent-depending on the type of coal tar color used, the method used to apply the dye, and the permanence of the color. Colors known or suspected of causing cancer reportedly are being used in all three types of coal tar hair dyes. Specificially: Temporary hair dyes may contain coal tar colors shown to cause cancer :dn laboratory animals and banned by FDA for use in other cosmetic products. Temporary and semipermanent hair dyes may contain azo colors derived from benzidine, a known human carcinogen. Such colors contain benzidine as a contaminant, and some cf the colors may break down in the body and release benzidine. Other coal tar colors available for use in temporary or semiperma- nent hair dyes have reportedly caused cancer in laboratory animals. Evidence frcm screening tests or animal studies indicate that several coal tar colors used in permanent hair dyes, including toluene-2,4- diamine and 2,4-diaminoanisole, may cause cancer. Several studies have demonstrated that coal tar hair dye ingredients are absorbed through the skin and scalp. Subsequent to release of our report to the subcommittee, newspaper articles quoted the Cosmetic, Toiletry, and Fragrance Association- CTFA-as stating that no major hair dye manufacturer has used benzidine-derived azo colors in their products since 1973. However, we purchased eight temporary rinses at Rockville, Md., drug stores containing one or more benzidine-derived azo colors. The manufac- turer of these rinses is a CTFA member. Generally, a cosmetic is considered adulterated if it contains any poisonous or deleterious substance. However, coal tar hair dyes whose labeling contains a prescribed statutory warning concerning possible skin irritation and blindness are exempt from these provisions. In addition, a cosmetic is considered adulterated if it contains a color additive not approved for safety by FDA under the color additive PAGENO="0359" 353 pr ovisions of the Food, Drug, and.. Cosmetic Act. Again, ~however, coal tar hair dyes are exempted. We recommended that Congress repeal the exemptions for coal tar hair dyes. A cosmetic is considered misbranded if its labeling is false .or mis- leRding. Although coal tar hair dyes. are subject. to FDA labeling re- quiren~ents, the FDA has not used this authority to require a cancer warning on labels of coal tar hair dyes containing known human or animal carcinogens. We recommended in our report that FDA evaluate safety data on coal tar hair dye. ingredients and require, where applicable, a cancer or other appropriate warning statement on product labels. On January 6, 1978, FDA published in the Federal Register a proposal to require that labels of hair dyes containing 2,4-diamino- anisole carry a cancer-warning statement A determination has not yet, been made on the need for a similar statement on labels of hair dyes containing other. ingredients suspected of causing cancer. OTHER COSMETIC HAZARDS Results of our broader cosmetics review indicat~ that some cosmetic products may pose significant hazards *to consumers. Specifically: Ingredients listed in the CTFA Cosmetic ingredient Dictionary as available for use in cosmetic products include "about 100 ingredients t~iat the National Institute of Qccupational Safety and Health's Registry of ~Foxic Effects of Chemical Substances lists as suspected carcinogens. In addition, 24 ingredients listed in the dictionary are suspected cf causing birth defects, and 20 may cause adverse effects on the nervous system', including headaches, drowsiness, and con- vulsions. Many different routes of exposure and species of animals were used in the studies referenced by the NIOSH Registry. The applicability of the, test methods and' results to cosmetics exposure has not been evaluated. Certain cosm~etic products including bubble baths,' shampoos, and feminine sprays have `been associated, with many consumer complaints. Hairsprays have been shown to cause a lung. disease which may lead toward lung malignancy. FDA has received several reports of vision loss resulting from the use of microbially contaminated eye makeup 1~tesu1ts of an FDA- sponsored study published in 1974 showed that about half of the eye makeup tested after it was partially used by cOnsumers contaii~ed bacterial. contaitdnation. . " Serious burns, including at least one death, have been reported from the use of flammable ~osmetics. ..;~ NEED. ~OR ADDITIONAL LEGISLATIVE AUTHORITY Before 1972, FDA did not have a formal program'to control cosmetic products. Since then, FDA has' established several regulations, de- signed to improve its control o~v-er cosmetics However, because FDA lacks adequate legislative authority, the effectiveness of many of its regulatory efforts has been limited. .. PAGENO="0360" 354 For example, FDA established regulations providing for the regis- tration of cosmetic manufacturers and packers, and the filing of cosmetic product ingredient and product experience reports by manufacturers, packers, and distributors. But FDA does not have authority to require compliance with the regulations. As a result, voluntary compliance has been limited. As of December 31, 1977: Only 896-40 percent-of the approximately 2,200 cosmetic manufacturers and packers FDA had identified had registered; Only 768 of the estimated 4,000 to 5,000 cosmetic manufacturers, packers, and distributors had filed ingredient statements; and Only 130 of the 4,000 to 5,000 cosmetic manufacturers, packers, and distributors had filed product experience reports. An FDA regulation also requires that labeling of cosmetics that have `not been adequately tested for safety bear a warning to that effect. However, this regulation cannot be effectively enforced be- cause FDA does not have authority to require cosmetic manufacturers to test their products for safety or make their test results avaliable to FDA. In addition, many manufacturers have refused FDA inspectors access to manufacturing records such as qualitative and quantitative formulas, sales or shipping records, and consumer complaint files because FDA lacks authority to require manufacturers to permit access to such records. Legislation-S. 2365-has been introduced in the 95th Congress to amend the F.D. & C. Act to provide FDA with additional authority to regulate cosmetics. BETTER USE OF EXISTING AUTHORITY Although FDA's efforts to regulate cosmetic products have been hampered by the lack of adequate legislative authority, many im- provements in FDA's regulation of cosmetics could be made under its existing authority. FDA has authority to: (1) Inspect cosmetic plants and collect and test cosmetic samples; (2) Establish manufacturing standards; (3) Take regulatory action against violative manufacturers; (4) Restrict the use of hazardous cosmetic ingredients and require appropriate precautionary labeling on cosmetic products; (5) Require manufacturers to prove the safety of color additives used in cosmetics; and (6) Establish by regulation, tests to be used in evaluating cosmetic safety~ Our review indicates that FDA has not effectively used its authority to regulate cosmetics. For example: (1) FDA has not inspected most cosmetic manufacturers' plants or sampled most of their products for compliance with the F.D. & C. Act. Only about half of the known cosmetic establishments were inspected between 1968 and 1975. Since 1975, FDA identified about 1,000 additional manufacturers, which it had never inspected because they had been unknown to the agency. (2) FDA has not established manufacturing criteria to determine whether adequate methods, facilities, and controls are used in all phases of manufacturing and distribution of cosmetics. According to PAGENO="0361" 3J~5 a summary in its. 1975 Compliance Program Guidance Manual, FDA inspectOrs found during establishment inspections that: Less than 33 percent of the firms had established raw material specifications. Less than 50 percent maintained adequate batch control records. Less than 15 percent tested equipment for microbial contamination Only 20 percent tested the effectiveness of the preseryative system used in their cosmetics. Only 25 percent maintained an inventory system adequate to facilitate a recall. According to an FDA official, about 75 percent of a~ sample of over 300 firms inspected since 1976 had deficiencies in their manu- facturing practices. (3) When violations of the Food, Drug, and Cosmetic. Act are identi- fied, FDA can seize the violative prOduct, enjoin a manufacturer from shipping the product in interstate commerce, or prosecute the firm violating the act. Manufacturers are notified of violations through issuance of citations, regulatory letters, and information letters, depending on the nature and severity of the violation. Between 1974 and 1976, FDA identified over 400 violations of the cosmetic provisions of the Food, Drug~ and Cosmetic Act, which the agency found warranted some form of regulatory action, yet only about 140 regulatory actions-including seizures, prosecutions, injunc- tions, citations, and issuance of regulatory and information letters- were taken. Fifty-four of those actions involved one violative product. I might mentioil that I do not believe any prosecutions were ini- tiated or citations issued during that period. (4) Establishing regulations to prohibit or limit the use of an in- dividual ingredient, or require the use of a specific warning statement on the label, is an effective way to increase consumer safety with. regard to a specific product or category of products. As of January 1, 1978, FDA had established ingredient standards governing the use of only 11 ingredients in cosmetics, and had required precautionary labeling only on feminine sprays, aerosols containing chlorofluorocarbon propellants, and aerosol cosmetics in self- pressurized containers. Some ingredients banned ~r restricted for usO in coSmetics in other count~ries are avail~bi~for use without resti~lction in the United States. For example, nine ingredients banned for use in cosmetics by a Euro- pean Economic Community directive adopted by several öountries were reported to FDA by cosmetic manufacturers as being used in cosmetics in the United States. A FDA official told us that FDA has nOt ascertained the basis for restricting the use of these ingredients in other countries. . Similarly, the Consumer Product Safety Commission has estab- lished regulations requiring that specific warning statements be placed on the labels of household products containing certain toxic ingredients, but FDA has not establi~hed similar regulations governing the use of these ingredients in cosmetics. (5) The 1960 Color Additive Amendments to the. F.D. & C. Act require FDA to establish regulations listing color additives that are safe for use in. cosmetics. however, as of December 19~77, the safety of about 25 color additives available for use in cosmetics had not been PAGENO="0362" 356 established. In one case-caramel----FDA permitted the continued use of the color additive for 15 years before a color additive petition was filed. That petition did not contain all of the required safety studies and FDA has given the petitioner until 1980 to complete additional studies. (6) FDA has not established by regulation specific tests to be used in evaluating the safety of cosmetic products. Without such regula- tions, FDA may not be able to use the tests for enforcement purposes. For example, FDA attempted to prosecute a shampoo manufacturer for marketing an adulterated shampoo, but the evidence it used to show that the shampoo was hazardous was not acceptable because it had not established by regulation the appropriateness of the test used by the agency to evaluate the safety of the shampoo. Mr. Chairman, that completes my prepared statement. We will be happy to answer any questions that you or other members of the subcommittee may have. Mr. MAGUIRE. Thank you, Mr. Ahart. Mr. Lester Brown, special assistant on the subcommittee staff, will begin the questioning. Mr. BROWN. Thank you, Mr. Chairman. Mr. Ahart, on page five of your statement you declare: Ingredients listed in the CTFA Cosmetic Ingredient Dictionary as available for use in cosmetic products include about 100 ingredients that the National Institute of Occupational Safety and Health's Registry of Toxic Effects of Chemical Sub- stances lists as suspected carcinogens. You also point out: * * * 24 ingredients listed in the dictionary are suspect~d of causing birth defects and 20 may cause adverse effects on the nervous system. * * * [Indicating] Is this the document you cite in your testimony as: "The CTFA Cosmetic Ingredient Dictionary"? Mr. AHART. Yes. Mr. BROWN. This is the 1977 issue of the dictionary; is that right? Is that the latest edition? Mr. AHART. Yes. Mr. BROWN. Your research indicates that at least 100 substances included in this dictionary as ingredients that are available for use in cosmetics may pose a hazard to consumers; is that correct? Mr. ~EART. That is correct. They are listed by NIOSH as being suspected carcinogens. Mr. BROWN. Are consumers or cosmetic manufacturers provided with information in this dictionary indicating that these substances may pose a hazard? Mr. AHART. I do not believe the dictionary itself would indicate that to consumers. Of course, consumers probably would not have access to the dictionary anyway. They would only know what is on the label of the cosmetic that they purchase. Mr. ~ROwN. But readers of the dictionary would not be provided with any information on potential health hazards; is that right? Mr. AHART. I think that is correct. Let me ask Mr. Linz. Mr. LINZ. That is correct. PAGENO="0363" 357 Mr. BROWN. Do you have a list of the ingredients that you cite in your testimony as being either on the NIOSH suspect carcinogen list or among those chemicals suspected of causing birth defects, and adverse effects on the nervous system? Mr. AHART. Yes; we do. We have a list with us. Mr BROWN Mr Chairman, I would like to introduce into the record a copy of the list entitled: "Toxic Effects of Ingredients Listed in the 1977 CTFA Cosmetic Ingredient Dictionary as Reported in the 1976 NIOSH Registry of Toxic Effects of Chemical Substances." Mr. MAGUIRE. Without objection, it will be included in the record at this point. [The list referred to follows:] PAGENO="0364" 358 * - Toxic Effects of Ingredients Listed In the 1977 CTFA Cosmttic Ingredient Dictionary As Reported in the 1976 NIOSH Registry of Toxic Effects of Chemical Subs lances Suspected Carcinogens 1. Acacia 2. Acid Blug 9 3. Acid Blue 9 Aimnoniuni Salt 4.. Acid Blue 74 : 5. Acid Green 5 (formerly FD&C Green No. 2) 6. Acid Red 18 7. Acid Red 27 (formerly FD&C Red No. 2) 8. Acid Red 87 9. Acid Violet 49 (formerly FD&C Violet No.. 1) 10. Acid Yellow 73 Sodium Salt 11. Alcohol 12. Basic Orange 2 (IARC a/ Determination: Animal Carcinogen) 13. Basic Violet 10 14. Boric Acid 15. Butyrolactone (IARC Determination: Indefinite) 16. Calcium Carrageenan (IARC Determination: Animal Suspect) 17. Calcium Saccharin (FDA Determination: Animal Carcinogen, Hunan Suspect) 18. Captan 19. Carrageenan (IARC Determination: Animal Suspect) 20. Chloramine-T 21. Chloroacetic acid 22. Cholesterol (IARC Determination: Indefinite) 23. Chromium Oxide Greens (IARC Determination: Animal Suspect) 24. * Coal Tar (NCI Determination: Human Carcinogen) 25. Coumarin (IARC Determination: Animal Carcinogen) 26. D&C Blue No. 1 Aluminum Lake 27. D&C Blue No. 2 Aluminum Lake 28. D&C Blue No. 4 29. D&C Green No. 3 Aluminum Lake 30. D&C Red No. 4 Aluminum Lake 31. D&C Red No. 9 (IARC Determination: Indefinite) 32. D&C Red No. 9 Barium Lake (IARC Determination: Indefinite) 33. D&C Red No. 9 Barium/Strontium Lake (IARC Determination: Indefinite) 34. D&C Red No. 9 Zirconium Lake (IARC Determination: Indefinite) 35. D&C Red No. 17 (IARC Determination: Indefinite) 36. D&C Red No. 19 37. D~.C Red No. 19 Aluminum Lake 38. D&C Red No. 19 Barium Lake 39. D&C Red No. 19 Zirconium Lake 40. D&C Red No. 22 41. D&C Yellow No. 6 Aluminum Lake 42: L~C Yellow No. 8 43. Dehydroacetic acid 44. Dinethoxane * 45. Dimethyl Sulfate (IARC Determination: Human Suspect) 46. Disperse Yellow 3 (IARC Determination: Indefinite) 47. Ethyl Carbonate 48. Ethylene Oxide (IARC Deteru~nation: Indefinite) 49. Ethylene Urea 50. Ethynylestradiol (IARC Determination: Aninal Carcinogen) 51. FD&C Blue No. 1 52. FD&C Blue No. I Aluminum Lake 53. FD&C Blue No. 2 . 54. FD&C Blue No. 2 Aluminum Lake * * 55. FD&C Green No. -3 ~-. -: ~. - I 56. FD&C Red No. 4 (IARC Determination: Negative) 57. FD&C Yellow No. 6 (IARC Deten?mination: Indefinite) 58. FD&C Yellow No. 6 Aluminun Lake (IARC Determination: Indefinite) 59. Formaldehyde - PAGENO="0365" 359 60. HG Red No.6 (IARC Determination: Animal Carcinogen) 61. Hydroquinone 62. HydroxystearicAci4 63. Iron Oxides (IARC Determination:-~ Indefinite) 64. Krameria Extract `: 65. Lactose 66. Lead Acetate (EPA 1~eteriniziation: Animal Suspect) 67. Maleic Anhydride 68, Methenamine- 69. Methyihydroxystearate 70. Methyl Methacrylate " 71. Methyl Oleate ` ` 72. Methyl Stearate 73. Nylon 74. Oleic Acid 75. Oxyquinoline 76. Oxyquinoline Sulfate 77. Paraffin. 78, PEG-8 79. Phenol (EPA Determination: Animal Suspect)' 80, Phenyl Mercuric Acetate ` * 81. Pigment Red 53 (IARC Determination: Indefinite)' 82. Pigment Red 53:1 (IARC Determination: Indefinite) 83. Polyethylene 84. Polysorbate 80 85. Polyvinyl Alcohol 86. Propyl Alcohol 87. Propylene Oxide 88. `PVP 89. Ricinoleic Acid 90. Saccharin (FDA Determination: Amimal Carcinogen, Human Suspect) 91. Silver 92. Sodium Saccharin (FDA Determination: Animal Carcinogen, Human Suspect) 93. Solvent Red `23 (IARCDeterminatión: Indefinite) 94. Sorbic Acid (EPA Determination: Animal Suspect) 95. Succinic Anhydride 96. ~fhiourea (IARC Determination: Animal Carcinogen) 97. Toluene (EPA Determination: Animal `Suspect) 98. Trichioroethylene (IARC Determination: Animal Suspect) 99. Tristearin 100. Ultramarine Green (IARC DeterinInation: Animal Suspect) 101. Zinc Chloride , , ,~uspected Teratoge~~ 1, Acid Red 27 2. 6..Aminocaproic Acid, 3. BHT- 4. `3utyl Methacrylate 5. Captan. 6, Carbon Dioxide 7. Cetrimonium Bromide 8. Dibutyl Phthalate 9. Dimethyl Phthalate 10. Dioctyl Phthalate .11. EDTA 12. Ethyl Methacrylate 13. Hexachiorophene 14, Lead Acetate 15. Lithium ChlorLde 16. ME~C 17. Nitrous Oxide 18. Phenyl Mercuric Acetate 19. Retinol 20. Retinyl Palmitate 21. Salicylamide 22. Sodium Chloride 23. Sodium Salicylate 24, .Theophylline PAGENO="0366" 360 Netvous System Effects 1. Acetone 2. 3oric Acid 3. p-Cymene 4. Dibutyl Phthalate 5. Ethylene Dichioride 6. Hexachlorophene 7. MEK 8. Methoxyethanol 9. Methyl Alcohol 10. Methylene Chloride 11. Methyl Methacrylate 12. Phenacetin 13. Sodium Fluoride 14. Sodium Salicylate 15. Sodium Sulfite 16. Tetrachioroethylene 17. Theophylline 18. Toluene 19. Trjchloroethane 20. Trichloroethylene a/International Agency for Research in Cancer, World Health Organization PAGENO="0367" 361 * Mr. BROWN. Mr. Ahart, do you have proof that any of these in-~ gredients are now being used in cosmetic products that are available to consumers today? Mr. AHART. Yes; we do. In fact, my staff purchased, within the last couple of days, several products that do contain some of these chemicals We would be happy to talk about those We have a list of those, and also samples available. Mr. MAGUIRE. Do you have samples with you? Mr. AHART. Yes; we do. Mr. MAGUIRE. Could you produce those now? Mr. AHAwi~. Yes. Mr. MAGUIRE. Do you have a list of those with you? Mr AHART Yes, we do have a list that we can supply for the record Mr. MAGIJIRE. Without bb~ectiQn, the record will be held open to include this list. [The list referred to follows:] Phillips Toothpaste-Sodium Carrageenan, Sodium Saccharin. Nivea Basis-Coumarin-IARC-Animal Positive includes skin painting study. Vanseb-T Tar Shampoo-Coal Tar-Known human carcinogen (NCI). Clairol Kindness Instant Protein Hair Conditioner-PVP-sus~p. carcinogen. Grecian Formula-Lead Acetate-Suspect Carcinogen and Teratogin is ab- sorbed through the scalp; (IARC Review: Animal Pô~ltive). Max Factor Maxi-Wear Nail Guard-Tolvene (EPA Det.-Animal Suspect). Sally Hansen Creme Hard as Nails with Nylon-Tolvene (EPA Det -Animal Suspect) Dibut~l Phth late (Susp. Teratogen). Max Factor Eye P~cil-EHT-~-suspe~ted teratogen. Revlon Super Crystalline-Tolvene-(EPA Det.-Animal Suspect). Dibutyl phthalate-susp. teratogen. Coty Vitamin A-D Soft'NRich Body Lotion-Retinyl Palmitate-Susp. Teratogen. Helena Rubenstein Contour Lift Fiim-Carrageenan (IAR~-Animal Suspect). Max Factor Super Lash Maker-BHT-Suspected Teratogen. Helena Rubenstein Ultra Feminine Emollient Cleansing Cream EDTA~~Lsus~ pected teratogen. Clrnique Clarifying Lotion 2-trxchloroethylene-(IARC Det -Animal Sus- spect) currently under test at NCI. Mr MAGUIRE Could you read that list for us, Mr Ahart? Mr. AHART. It is only about 14 products, Mr. Chairman. It has Phillips toothpaste which contains sodium carrageemn and also sodium saccharin. The Nivea and Basis soap contain coumarin which ~s an animal carcinogen. Available data includes a skin painting study. Mr. Linz is more familiar with this list than I am. Perhaps 1 should turn it over to him Mr. MAGUIRE. Perhaps he could just identify the products and tell us what is known about each one and what the basis of the suspicion is in each case. * * Mr LINz This [indicating] is reported to contain coumarin These are the Nivea and Basis soaps Coumarin is an animal carcinogen according to an agency of the World Health Organization One of the studies upon winch they made the determmtion is a skin painting study. * * * * * This [mdicatingj is Max Factor Maxi-Wear sail Guard containing toluene which EPA suspeets to be a carcinogen. PAGENO="0368" ~62 Mr. MAcmIRE. Is that the same type of substance included in the hair dyes? Mr. LINz. It is not. Mr. MAGUIRE. It is different? Mr. LINz. Yes. This [indicating] is the Coty Vitamin A-D Soft'N Rich Body Lotion containing retinyl palmitate which is a suspect teratogen, meaning it may cause birth defects. Mr. MAGUIRE. Birth defects? Mr. LINz. Yes. This [indicating] is a Max Factor eye pencil. It contains BHT as a preservative, which is also suspected of causing birth defects. This [indicating] is Helena Rubenstein Contour Lift Film which contains carrageenin. Again, it is a suspect carcinogen. This [indicating] is Helena Rubenstein Ultra Feminine Emollient Cleansing Cream which contains EDTA, another suspected teratogen This [indicating] is a Max Factor Super Lash Maker which contains BHT and it is suspected of causing birth defects. This [indicating] is another nail product, Sally Hansen Creme Hard as Nails With Nylon, which contains both toluene which is a suspected carcinogen, and dibu.tyl phthalate, which is suspected ofcausing birth defects. We have a Revlon Super Crystalline nail enamel [indicating] which contains toluene and dibutyl phthalate also. I think we have gone through the whole list. Mr. MAGUIRE. I have three up here with me. This [indicating] is Clairol Kindness instant protein hair condi- tioner. What do you have on that? Mr. LINZ. It contains PVP which is a suspected carcinogen. Mr. MAGUIRE. And this one [indicating] is Vanseb-T Tar Shampoo with protein. Mr. LINZ. That contains coal tar, which is a known carcinogen, according to the National Cancer Institute. Mr. MAGUIRE. This is Grecian Formula 16. Mr. LINz. That contains lead acetate, which, according to an agency of the World Health Organization, is a known animal carcino- gen and also is suspected of causing birth defects. Mr. MAGUIRE. A known animal carcinogen and evidence of birth defects? Mr. LINZ. Yes. Mr. MAGUIRE. And there is evidence that it is absorbed through the skin? Mr. L~LNZ. Yes. Mr. WALGREN. I notice, Mr. Chairman, that under the Grecian Formula 16, it says: "Used by Millions of Men." Mr. MAGUIRE. I am afraid to go home and look in the cabinet. Mr. Ahart, in your statement, you indicate that you had purchased eight temporary hair dyes at random and that all of these contained one or more benzidine-derived azo colors. We have been told by the CTFA representative that the temporary hair dyes do not contain any of these substances which we are discussing. PAGENO="0369" 363 In' view of that statement about the absence of these derivatives in hair dyes, what conclusion would you come to about the statement as against the facts as you found them when you purchased the hair dyes? Are we talking here about something that is misleading, or is there any possibility that they could b~ deliberately misleading? What is your judgment on this? Mr. AHART. I do no know if `it is' deliberately misleading or not, but it is certainly misleading. Whether or not the people making the statement had information on the ingredients used in all the products, I do not know. The ,product in question,' I think-w~ have it here-is a Roux brand, Fanciful Rinse It is made by a member of the CTFA However, this `manufacturer had not' submitted the ingredient statement to FDA under the voluntary' program. So, unless the manufacturer dis- closes the ingredients, it may be' that no one `would `know. I do not know if that ingredient is listed on the label or not. Mr. Linz, is it? Mr. LINz. It is. Mr. AHART. But you would have to look at the label or get the information from the manufacturer. Mr. MAGUIRE. The bottom line, I take it, is that the public is being deceived on this' particular point by CTFA. They say that there is not any of the stuff in the `temporary hair dyes. Then you go out and find, in 8 cases-and I guess it was 8 out, of 8, was it not? Mr AHART It was eight different kinds of this [indicating] particu- lar product or the same brand of product in different colors with the same thing in it. Mr. MAGUIRE. They all had benzidine-derived azo colors? Mr. ARART. That is correct. Mr. MAGUJEE. You report that hair sprays ha~ve been shown to cause a lung disease which may lead toward malignancy. What is that disease and how widespread is it? Mr. AHART. Mr. Linz, could you answer that? This was a study made out in Utah, a carefully designed study. Mr. Lixz. It is a disease known as pulmonary thesaurosis. I am not sure whether that is the correct pronunciation or not. Mr. MAGUIRE. We will make sure that we spell' that properly. Tell us about it. Mr. LINz. The symptoms are a cough and shortness of breath. It can lead- Mr. MAGUIRE. It looks like pulmonary thesaurosis; how is that? `Mr, L1NZ. You did better than I did. It is characterized by spots' on the'chest X-ray, shortness `of breath, and a mild cough. It can lead to more severe changes leading toward lung malignancy. Mr. MAGUIRE. How widespread is it? Mr. LINZ. This was based on a survey of hair dressers in Utah. The NIOSH conclusion was based on a sample of" 262 student cos- metologists and 213 graduate cosmetologists `from Utah. They were compared to a group of 569 people matched by age, history, and region. 24-600 0 - 78 - 24 PAGENO="0370" 364 The prevalence of the disease seemed to be 22.5 percent in graduate beauticians. They say that is a significant increase over what was seen in the student cosmetologists or the control group. The highest prevalence of the disease was in small salons were there was not adequate ventilation, the report says. Mr. MAGUIRE. You referred to ingredients being sold in this country which are banned in other countries, Mr. Ahart. Has the FDA tested and approved as safe those ingredients? Mr. AHART. I do not think it is a question of testing or approving them as safe. They are banned in other countries. FDA has never gone to the other countries and found the basis for the ban in the other countries or the restriction on their* use in other countries. Mr. MAGUIRE. What are some of those ingredients? Mr. AHART. I have a listing here. Several are banned by the Euro- pean Economic Community. The fist is antimony potassium tartrate which is used in hair tonics, dressings and other grooming aids. Barium sulfide is another which is used in shaving preparations. There is a chemical product called brucine, which i~ also used in preshave and aftershave lotions and feminine sprays, underarm deodorants and other personal cleansing products, as well as hair tonics, dressings, and hair grooming aids. Cantharides is also used in hair tonics and dressings. Hydroxyanisole is used in lipstick, moisturizing creams, lotions, powders, sprays, and mascara. Iodine, which ~is used in personal cleanliness products is another. Phenol, which is used in hair tonics, dressings, and other grooming aids and douches and skin care preparations is another as well as trichresyl phosphate, which is used in nail polish or enamel. The last one I have here is tetrachloroethylene which is used in eye makeup preparations. Mr. MAGUIRE. Without objection, that list, in its entirety, will appear in the record at this point. [The following material was received for the record:] PAGENO="0371" 365 ~ turer! ~ Economic Co~tiit Directive Antim~Lpotassiumtartrate (1 product). Hair tonics, dressings,, arid other grooming aids at conlentrations of 0.1 percent or less. ~arium..sulf~,4~ (1 product) Shaving preparations at concentration of 10 `to 25 percent. Bruethe (6 products) Preshave and aftershave lotions, feminine sprays, underarm deQdorants, ~ind other persenal cleanliness proiiucts,. and hair tonics, dressings, and other hair grooming aids at cotations of 0.1 percentbr less. - Cantharid~s (1 product) Hair tonics, dressings, and other hair groomthg aids at concentrations of 0.1 percent or less `~o~2~ (5 products) Lipstick, moisturizing creams, lotions, powders, and sprays, and mascara at concentrations of 0.3. pertexit or less iodine (1 product) Personal cleanliness products at concentrations of I. to 5'percent. ~ (4products) Hair tonics, dressings, and other grooming aids, skin care preparations, and douches at concentrations of 1 percent or less. Tricresyl ph ,pha.te (7 products)' Nail polish and enamel at' concentrations `of S percent or less. Tetrachloroeth~y~ene (I product) Eye makeup preparations at concentrations of 50 percent or less. PAGENO="0372" 366 Mr. MAGIJIRE. Mr. Ahart, you have made serious charges about FDA's failure to use its existng authority. Would you care to speculate on why that authority has not been used? Mr. AHART. `I here are probably several reasons. I think until recently there has not been a great deal of public pressure or public information or public suspicion, I might guess, about the danger of cosmetic products. I think FDA, over the years, has to some degree, responded to pressure and public information. if cosmetics were not being touted today, they would not get as much emphasis as other things that FDA is being pressured on. Second, there may be a problem in the adequacy of resources to do the kind of things that need to be done to cover the inspections and so on. Also, there may be some discouragement among FDA people be- cause they do have rather limited authority in the cosmetic area. There might be some discouragement to really put a lot of pressure into this area, particularly if there is no public complaint or public response. So, I think it is a combination of all of those factors. FDA could probably speak better than I could to the reasons for that. Mr. MAGUIRE. Would you comment further on your statement that FDA has not established, by regulation, specific tests to be used in evaluating the safety of cosmetics? I am particularly concerned, obviously, about the implications of that for enforcement. Mr. AHART. As I pointed out in my statement, FDA is handicapped when it takes enforcement action if there is not an established test by regulation to evaluate the safety of the products. It cannot very well go into court on some basis other than something established by regulation and use that as the basis for enforcement. So, unless those regulations are in effect, it is very difficult for them to go after anyone on the basis of safety. It is also difficult in this case because in the case of cosmetics there is no premarket clearance required. The burden of proof as to the lack of safety of the product really falls on FDA rather than on the manufacturer as it would in the case of drugs and other things. So the burden of proof is with the Government, and that makes a difficult problem as well. Mr. MAGUIRE. So, first of all, FDA has not used its existing author- ity. Specifically they have not issued regulations in cases, even under the current very weak law, they might have done so; is that correct? Mr. AHART. That is correct. Mr. MAGUIRE. Would you say, in addition, that even if they do issue regulations and do use that authority, that in some cases they have no further authority to require compliance with those regula- tions? Would that be a correct statement as well? Mr. AELART. They would have the authority to require compliance had they established the regulation and carried the burden of proof showing that a product was not safe. Then they would have authority to ban the product and get an injunction and enjoin the manufacturer from putting it on the market and so on. But the burden of proof would still be on FDA to prove the lack of safety of the product as opposed to what is done in other cases, PAGENO="0373" 367' to put the bnrd~ti on the manufacturer or distributor or packager to show that the product being put out in the public arena is safe under the conditions of use specified. S Mr. MAGUIRE. Would that be your recommendation with respect to how cosmetics ought to be handled? S Mr. AHART. That the burden of proof should be on the manu- facturer? Yes, Mr. Chairman. S Mr. MAGUIRE: Mr. Waigren, do you have some questions? Mr. WALGREN. It is true that the~ FDA has attempted to provide some kind of regulation in this area, and yet' they have run into a lack of, at least, cooperation from the industry; is that not correct? Mr. AHART. It is correct in the sense that the regulations' that they do have ~re generally the ones that the industry would comply with only on a voluntary basis in terms of the filing of the ingredient statements, the regtsterirxg of manufacturers' plants, and filing product experience reports. ` They do have the regulations `out. So there is a degree of compliance. It is a verysmall percentage of the universe in terms of the number of establishments. Probably a larger part of the universe, in terms of the quantity of products. , S But, no, they do not have the authority to force compliance with those regulations. Mr. WALGR~N. But the' FDA has' asked cosmetic manufacturers to regi~'ter with them and relatively law have?' Mr. AHART. I believe about 40 percent have. ` Mr. WALGREN. And the FDA has asked manufacturers to file ingredient statements with them and relatively few have; is that correct? S Mr. AHART. That is correct. ` Mr. WALGREN. And the FDA has asked manufacturers to file experience reports, and almost no one has; is that correct? Mr. AHART. That is correct. Mr. WALGREN. We do not even know how many xuai~ufacturers there are. There' is a guess between 4,000 and 5,000; ~is that right? Mr. AHART. That is correct. That figure includes manufacturers, packers, and distributors. ., S Mr. WALGREN. And the FDA has actually" made some onsite attempts to inspect consumer complaint files and have been refused? Mr. AHART. That is correct. They do not have the. statutoi5r' au- thority to demand access to those files. Mr. WALGREN., That is all I have, Mr. Chairman. Mr. MAGUIBE. In summary then, Mr. Ahart, there needs to be, some substantial improvements, I ~take it, in your view, in the way that we handle exposure to cancer-causmg or potential ca~cer-causrng substances in cosmetics? S And, in particular, we need to improve the way the FDA operates in this area; is that correct? S Mr. AHART. I think in two aspects. We need to `improve the~ law to give the FDA more authority to do the kinds of things that need to be done and then FDA, in turn., has to take that burden and use its authority to protect the public in this area Mr. MAGIYIRE. Would you care to go into more detail at this point on your suggestions as to' what new authority FDA should have from this Congress? PAGENO="0374" 368 Mr. AHART. We will be shortly releasing a draft report to FDA for comment which will make specific proposals for legislative change and what kind of authorities they should have. I think it might be better to wait and get their reaction as to how they feel about it before we would want to state specifically what they should be. Certainly registration of manufacturers, packagers, and distributors would be appropriate; and a requirement of mandatory filing of ingredient statements would be appropriate. A shifting of the burden from the Government to the industry would be appropriate. There will be other things. Certainly we ~i ill be recommending these. * Mr. MAGUIRE. Thank you very much, gentlemen, for your testimony. Our next witness is the Honorable Donald Kennedy, Commissioner of the Food and Drug Administration. Gentlemen, would you p]ease rise so I can swear you in. Do you swear to tell the truth, the whole truth, and nothing but the truth, so help you God? [Chorus of I do's from four witnesses.] Mr. MAGUIRE. Commissioner, would you introduce your associates? TESTIMONY OP HON. DONALD KENNEDY, Ph. D., COMMISSIONER, FOOD AND DRUG ADMINISTRATION, PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE; AC- COMPANIED BY: RICHARD COOPER, CHIEF COUNSEL, FDA; HOW- ARD IL ROBERTS, Ph. D., DIRECTOR, BUREAU OF FOODS, FDA; AND ROBERT L SCHEUPLEIN, Ph. D., CHIEF, DERMAL AND OCU- LAR TOXICITY BRANCH, DIVISION OF TOXICITY, BUREAU OP FOODS, FDA Dr. KENNEDY. I would be happy to. To my extreme left is Dr. Howard Roberts, Director of the Bure au of Foods. rro may immediate left is Robert Scheuplein, a toxicologist in the Bureau of Foods scientific staff. To my right is Richard Cooper, the Chief Counsel of the Food and Drug Administration. Mr. MAGUIRE. Thank you. You may proceed. Dr. KENNEDY. Mr. Chairman, I will not read all of my statement to you. We will submit it~ and other materials for the record. Mr. MAGUIRE. Without objection, your testimony will appear in its entirety following your summation [see p. 373]. Dr. KENNEDY. I might say that we are very glad to be here today to discuss our mutual concerns about potentially dangerous chemical in cosmetics. The Food, Drug, and Cosmetic Act is designed to afford protection to the public from harmful foods, drugs, and cosmetics. We agree with you that it has long contained a serious loophole. We lia~e, in the past, asked repeatedly for legislation to close that loophole. As you know, in enacting the 1938 provisions of the act, Congress exempted the coal tar hair dyes from the adulteration pro- visions as long as products containing these chemicals bear the PAGENO="0375" 369' caution `stat~ment prescribed, by `section 601(a) of the act and advise that a. patch test be mad~ prior to use. As you probably know, one of the most important ingredients in hair dyes which you have been discussing in these hearings, Mr. chairman, is paraphenylenediámine, a known sensitizer. It was, in fact, the sensitization problem which is associated with that compound that led to the exemption. It has the effect of exempt- ing products containing coal tar hair dyes entirely from the adultera- tion provisions of the act for any problem they present I will be prepared, Mr. Chairman, if you would wish us to, to go in a little bit to the chemistry of hair dying and to the kinds of prob- lems that are now encountering with coal tar hair dyes. I tbink'~I will let that,go unless `you ask for it at the end. Suffice to say for the moment that one can roughly divide the compounds used in permanent hair dyes into a class of largely ,meta cOmpounds which are used as coordinators, couplers, modulators; and a group of pyra compounds which include pyraphenylenediamine and pyralenediamine, which are the primary oxidizing agents. it is members of the first group of compounds which have produced the first results off the .Natioxi~1 Cancer Institute's testing line. As you know, we have `proposed mandatory , warning statements for one of these, the compound 4-methoxy-m-phylenediame [4-MMPD] That is a' compound"that you will also hear referred to as 2,4- diaminoanisole. `In this same class of compounds is one which the National Cancer Institute has told us and you that they are ubout ready to give us a final report on, that is, 2,4-tolueñediamine, although our information indicates that is nor used any longer if positive results are confirmed. NCI will be giving that to us in March. We will include it in Our label warning requirement proposal. We do have, and are submitting to you-you probably will have had it from other sources anyway-a chart that indicates the other chemicals in th'is hair dye group that are `being te~'ted, and indications to which it appears that they will or will not prove to be carcinogenic. I should add one incidental note, Mr. Chairman. Coal tar colors are mariufacturered from a basic petrocheniical ingreçlient, benezine toluene and napthalene. .~ .` `. At one tnme these chemicals were produced almost entirely from coal tar So, the hair dye products were named coal tar hair dyes An increased recent demand for these feed stocks and other indus- trial uses httd Iea~d to an alternate source of `the synthesis from petro- leum But ~i~' does not make any differeiice at all whether coal tar colors are, derived from coal tar or `petroleum. `They are chemically identical and they receive 4denticai. regulatory treatment. A few epidemiological studies of human exposure to hair dye ingredients have been conducted recently. You have heard about some of this research and you know that it provides conflicting data,. In Order to resolve some of the issues, FDA,,. and the, National Institute of `EnvirOnmental Health Sciences a~'d the Oan~er Institute are going to plan a workshop to evaluate hair dye products all together In addition, our interagency working group on special problems in cancer epidemiology, composed of scientists from our agency and the National Cancer Institute, is preparing an assessment of the epi- PAGENO="0376" 370 demiology of hair dye usage. Their report will be part of materials considered by the workshop. I might just add that in our review at this time it is hard to draw any definite conclusion from the epidemiological data on one side or the other. We intend to require warnings on any coal-tar hair dye when evidence of possible danger to the public so warrants them. But our ability to protect the public, particularly from the risk associated with long-term use of hair dyes, will continue to be severely limited until Congress repeals the exemptions for coal tar hair dye products. We have long stated that the coal tar exemptions of section 601 (a) and (e) and 602(e) should be repealed. I hope these hearings, Mr. Chairman, will help to stimulate con- gressional interest in accomplishing this legislative change. Turning now to benzidine-derived dyes, these are direct dyes that have also been implicated as carcinogenic because it may not be possible to make them without their containing some free benzidine which, as has been pointed out to you before, is a known carcinogen. Under the current law we cannot require cosmetic manufacturers to report their formulations. We must rely instead on our voluntary reporting program and on inspection of labels of marketed products. For that reason, subject to these defects, we really cannot be sure how extensive benzidine-derived hair dye ingredients are being used today. But we are trying to find out. The committee has also been interested in another problem that troubles us quite a lot; it has to do with N-nitrosodiethanolamine, which I will call NDELA. Recent studies indicate that this chemical may be present in many cosmetics, in amounts in some single analyses that we find quite alarming. Triethanolamine, diethanolamine and related amines are widely used as cosmetic ingredients, particularly in shampoos, bubble bath products, and all types of creams and cream lotions. Triethanolamine, when reacted with a fatty acid to form a soap, is an emulsifier that permits the mixing of oil and water. Triethanol- amine is also present in cosmetics as the salt of a number of detergents and foaming agents. Diethanolamine is primarily a component of a wide variety of diethanol fatty acid amines that serve as foam boosters, stabilizers, and conditioners in shampoos and related products~ The difficulty with the NDELA problem, and in fact of N-nitros- amines in general, whether one fin.s them in products or iii biological systems, is that very often they form as a consequence of reaction between components of a product; that is, they are not there in the actual, manufacturing of the product. In fact, the N-nitrosating agents, the nitrites and the nitrates, which react with the amines which I have just described, many enter the cosmetic as a contaminating agent, a component of another ingredient. For that reason, it is a little difficult to keep track of these circum- stances which predictably give rise to the product of N-nitrosamines. Butwhatever the source of the nitrate or nitrite or othernitrosating agents-and it may be either a nitrite or a nitrate-the nitrosating agent may react with the amine in the presence of, ~ reducing agent to form N-nitrosamines. PAGENO="0377" 371 This reaction can happen during the manufactui'~r or' the storage of a product, and it' may be very, sensitive to the differences in formulation. The analyses for the detection of NDELA at the levels that are necessary to evaluate its presence in human cosmetics are very, very new. You will have heard from Dr. Fine abouthis remarkable progress in developing such a method. As soon as we heard late last spring of that new technology, we installed it as quickly as we could in the Agency. We are now tooled up to do this kind of~ analysis ourselves. In recent weeks we have'confirnied Dr. Fine's findings of NDELA in high levels in a couple of products We are extending this analytical program to conduct `a surveillance of NDELA contamination in commercially marketed cosmetics. We are also conducting laboratOry studies on `the skin penetration of NDELA, which is another impor- tant issue in estimating its human hazards. We have also urged the cosmetic industry to accelerate its in- vestigation of the origin of the nitrosamine contamination in cos- metics and the best means of reducing or eliminating it. FDA will support such efforts whenever possible. We have urged the industry to pay very heavy attention to this problem. Finally', I w'as requested to discuss the chemical, 1 ,2-Dichloroethan, which is also known as ethylene dichioride. There is preliminary data from the NCI bioassy that suggests tha't it produces cancer in test animals. . So far as we know it is no longer used in cosmetics. It was once a component in a few nail enamels, but according to' our voluntary registration data-and again you know of the defects in that-these products that we knew contained it were reformulated in 1975. It is used as an aid in food processing, often as a fungicide. Under the conditions of the use of this chemical, and the nature of the products in which it is permitted,, the amount of ethylene dichloride, if any, that remains in the finished food, is extremely small But we are reevaluating the food additive uses in a lot of the NOI data, and we.will have a regulatory response to offer if one is necessary, as soon as that analysis is complete. The fumigant uses are the responsibility of the EPA, and through the four agency coalition we have informed the EPA of the need to reevaluate those uses. I might add that there now fortunately is an effective mechanism for sharing such information. The Interagency Regulatory Liaison Group, composed of ourselves, EPA, OSHA, and CPSC tries to inter- act to improve the working coordination among the four agencies in matters related to the protection of the public and the environment from the adverse effects of toxic and hazardous substances. Let me just summarize, Mr. ~Chairman, by `saying that we have tried to focus in our testimony on the several different types of chemicals which have one common element; they are already marketed products that are the subject of safety concerns generated by our new capacity to produce' esti~nates of hazards that we' were unable to `reach before. , ` .. I believe it is important for Congress and the public to understand that questions about the safety of these substances, especially new evidence of carcinogeniOity, will continue to come to our attention. PAGENO="0378" 372 This process of questioning accepted products and chemicals, sub- jecting them to our increasingly sophisticated analytic and testing methods, and dealing with new conclusions about their safety, is, I think, a terribly necessary and socially useful process. It does, however, produce a lot of public alarm when compounds or materials that have come to be regarded with a certain trust-and even affection-come up presenting problems. But I think we need to move vigorously in the direction of taking regulatory action. Of course, we hope for the strongest congressional support that we can get. I would conclude by urging again that the exemptions of coal tar hair dyes from the adulteration provisions of the act be repealed. We are reviewing other aspects of the cosmetic provisions, some of which were mentioned by the GAO people in their testimony earlier this morning. We hope for revision to cure such infirmaties as the lack of a requirement that the industry conducts safety testing, the lack of authority to require submission of safety substantiation data or other reports and records, the lack of authority to require adverse reaction reporting, the lack of authority to require even the submission of product formulations or registration of cosmetic manufacturers, and our severely limited inspection authority. As the law now stands, cosmetics are the only products for which the legal burden rests on FDA to prove a hazard to the public, rather than on the industry to demonstrate that their product has been tes ted in accordance with currently accepted methodology, and that it is safe. [Dr. Kennedy's prepared statement follows:] PAGENO="0379" 373 STATEMENT BY * ~* DONALD KENNEDY COMMISSIONER * ~FOOD AND DRUG ADMINISTRATION PUBLIC HEALTH SERVICE DEPARTMENT O~ HEALTH, EDUCATION, AND WELFARE BEFORE THE SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS COMMITTEE ON INTERSTATE AND FOREIGN COMMERCE HOUSE OF REPRESENTATIVES FEBRUARY 3, 1978 PAGENO="0380" 374 Mr. Chairman: I am pleased to be here today to discuss our mutal concerns about potentially dangerous chemicals in cosmetics. Recent findings that some chemicals in hair dyes are carcinogenic in animals, have made this a subject with considerable national visibility. The Federal Food, Drug, and Cosmetic Act, which is designed to afford protection to the public from harmful foods, drugs, and cosmetics, has long contained a serious loophole. In enacting the 1938 provisions of the Act, Congress exempted the `coal-tar hair dyes from the adulteration provisions as long as products containing these chemicals bear the caution statement prescribed by section 601(a) of the Act and advise that a patch test be made prior to use. The statement also includes a warning against the use of these types of dyes on eye lashes ~and eye brows. One of the most important ingredients in hair dyes is paraphenylenediamine, a known sensitizer, that is, a product which induces allergic reactions. However, this ingredient is essential in the oxidation (permanent) hair dyes; hence, the exemption was originally granted subject to labeling requiring a patch test. Coal-tar dyes were also exempted from the color additive reguirements of the Act. Coal-Tar Hair Dyes Coal-tar colors are manufactured from the basic chemicals benzene, toluene, and naphthalene. Because at one time these chemicals were derived almost exclusively from coal-tar, the hair dye products were named `coal-tar' dyes. Increasec: recent demand PAGENO="0381" 375 for benzene, toluene, and naphthalene has led to an alternate sou~ce of the hair dye chemicals from petroleum. Whether "coa-l~tar" colors are derived from coaltar or petroleum, they are chemically Identical. We believe that they should therefore receive identical regulatory treatment~ In 1972 the FbA asked the National Cancer Institute (Nd) to test some of these chemicals in its çarcinogenesiS bioassay program. Reports about the likely hazard of certain chemicals in permanent hair dyes have been the focus of our attention over the past several months. Results are now available for a few of these chemicals and should be available shOrtly on the remaining ones. 4~methoxy~~'pheflYlenediamine (4-MMPD) sulfate which is also referred to as 2,4-diaminoanisole (2,4-DAA) has been determined to be carcinogenic in two species of laboratory animals. These findings apply equally to the free amine, the form ol~ the dye which is present on the scalp du~ing haiV~ dying. As you. kflow, any chemical which has yielded positive results In such tests must be viewed as a possible hazard to humans. Because human and animal testing have demonstrated 4-MMPD penetrates the skin, the finding that It is a carcinogen is very disturbing. Although the Agency cannot ban 4..MMPD, we did propose a regulation to require a warning On the label of products that contain this chemical. This, coupled with ~ requirement for warning `posters in beauty salons, will alert people' to the hazard ~o that aonsumers can make an informed choice about whether to use these products. PAGENO="0382" 376 We intend to take necessary regulatory action for any other chemical component of coal-Star hair dyes that may be absorbed during use and that we determine poses a cancer risk based on our review of the results of the NCI `carcinogenic bioassay testing program or any other appropriate tests. Although our information indicates that 2,4-toluenediamine (2,4 IDA) is no longer used, if positive results are confirmed we will include it In our label warning requirement proposal. Preliminary data on other chemicals being tested indicate that several others may be added to the warning requirements in the near future. A few epidemiological studies of human exposure to hair dye ingredients have been conducted recently. This research provides conflicting data and In order to resolve some of the issues FDA, NIEHS, and NCI are planning a workshop to evaluate hair dye products. In addition, our Interagency Working Group onSpecial Problems in Cancer Epidemiology, composed of scientists from NCI and FDA is preparing an assessment of the epidemiology of hair dye usage. Their report will be a part of material considered by the workshop. We intend to require warnings on any coal-tar hair dye when evidence of possible danger to the public so warrants them. But our ability to protect the public, particularly from the risks associated with long-term use of hair dyes, will continue to be severely limited until Congress repeals the exemptions for coal-tar hair dye products. We have long stated that the "coal-tar' exemptions of sections 601(a) and (e), and 602(e) should be repealed. I hope these hearings will help to stimulate Congressional interest in accomplishing this legislative change. PAGENO="0383" 377 zidjjie-Derived Dyes Our attention has also focused on se~ieral benzidiné.derlved dyes that may still be ~Used in nonpermanent hair dyes. These "direct" dyes have also been tmplicated as carcinogenic agents, because it may not be possible to make them without containing some free benzidine, a known carcinogen. Under current law we cannot require cosmetic manufacturers to report their formulations, and we must.rely on our voluntary reporting program and inspection of' labels of marketed products. Thus, we are tiot sure how extensively benzidine-derived hair dye ingredients are being used today; We are now determining whether these ingredients are still present in marketed hair dyes. N-Nitrosodiethanol~mine Another animal carcinogen, n-nitrosodiethanolamine (NDELA), Is also being studied by the Agency. Recent studfes indicate that this chemical may be present in many cosmetics through chemical reactfon of an amine with a nitrosating agent in the finished product. Triethanolamine, diethanolamine and related amines are widely used as cosmetic ingredients, particularly in shampoos, bubble bath products, and all types of creams and cream lotions. Triethanolamine, when reacted with a fatty acid~ to form a soap, i an emulsifier that permits the mixing of oil and water. Triethanolamine is also present in cosmetics as the salt of a number of detergents and ~ôaming agents. Diethanolamine is primarily a. compánent of a Wide varL~ty of diethanol fatty acid amides that serve as foam bodsters, stabilizers, and conditioners in shampoos and related products. PAGENO="0384" 378 We know little about the formation of nitrosamines in cosmetics from these amines. Nitrosating agents such as nitrites and nitrates are not usually used as cosmetic ingredients, but may enter a cosmetic as a "contaminating" component of another ingredient. Other nitrosating agents may also contribute to the presence of NOELA. Whatever the source of the nitrite, nitrate, or other nitrosating agent, it may react with the amine in the presence of a reducing agent to form nitrosamine. This reaction may occur during the manufacture or storage of the product. Although analytical methods for identification of nitrosamines have been available for some time, those for the analysis for NOELA at the required levels of detection are quite new. Furthermore, little is known about the hazard of NOELA under conditions of its presence in cosmetics. These matters are now being studied by the Agency. The Agency has taken several steps to obtain the scientific information necessary to resolve the NDELA issue: 1. We have established an analytical program to determine the extent of NDELA contamination in cosmetics. This will be used to conduct a broad surveillance of the NOELA contamination in commercially marketed cosmetics. 2. We are conducting laboratory studies on the skin penetration of NOELA. The Bureau of Foods and the National Center for Toxicological Research have also begun developing test protocols in case additional animal studies are needed. PAGENO="0385" 379 3. We have urged the cosmetic industry to accelerate its investigations of the orign of the nitrosamine contamination in cosmetics and the best means of reducing or eliminating it. FDA will support such efforts whenever possible. l,2-Dichloroethane (Ethylene Dichloride) Mr. Chairman, you asked specifically that I discuss. the chemical 1,2-dichioroethane, also known as ethylene dichloride. Preliminary data from an NCI bioassay suggest that this chemical produced cancer in test animals. We believe that it is no longer used in cosmetics. It was once a component of a few nail enamels; according to our voluntary registration data, however, these products were reformulated in 1975. In addition, It is used as a food processing aid. There are 11 approved food uses including solvents, adhesives, spice extracts, and fumigation of certain grains and grain mill machinery. Under the conditions for use of this chemical, and the nature of the products in which it is permitted, results in only a negligible quantity of ethylene dichioride if any migrates to finished food products. We are now reevaluating these food additive uses in light of the MCI data. Bureau of Drugs scientists have checked their records and do not find 1,2-dichloroethane to be listed as either an active or inactive ingredient in drug products. The fumigant uses are now the responsibility of EPA. We have advised EPA of the need to reevaluate these uses of this compound. 24-600 0 - 78 - 25 PAGENO="0386" 380 As you know, NCI alerted us to their verified findings on this chemical last November. In addition to taking steps to evaluate this information within FDA, we have also shared the information with other agencies responsible for the regulation of toxic substances. Fortunately, there is now an effective mechanism for sharing such information. You are probably aware of the steps taken some months ago ty the FDA, EPA, OSHA, and CPSC in establishing the rnteragency Regulations Liaison Group (IRLG). This is an effort to improve substantially the working coordination among these four agencies in matters relating to protection of the public and the environment from the adverse effects of toxic and hazardous substances. The IRL~ is aware of the preliminary data on l,2-dichloroethane, and any action FDA decides to take will be coordinated with that of the other three agencies in that group. Should we conclude that ethylene dichloride poses a human health hazard in products we regulate,we will takeappropriate regulatory action, including delisting of approved food additive uses. Conclusion My discussion today has focused on several different types of chemicals which have one common element--they are all the subject of safety concerns generated by new scientific information. I believe it is important for Congress and the public to understand that questions about PAGENO="0387" 381 the safe use of substances, especially new evidence of earcinogenicity, will continue to come to our attention. This process of questioning accepted products and chemicals, subjecting them to our increasingly sophisticated analytic and testing methods, and dea'ing with new conclusions about their safety is a beneficial one. Continuing reevaluation in the light of new evidence and new st~ndards must be a routine part of FDA's work. The regulatory changes that result from this process should be taken as a sign that the system is working and not, as has so often been the case, as a cause for accusation and alarm. Rapid changes in scientific knowledge and capability often requires that legislative authority be updated. Once again, I would like to urge that the ex~emptions of coal-tar hair dyes from the adulteration provisions of the Act be repealed. We are reviewing other aspects of the cosmetic provisions of the Act to determine the need of change. Areas we are looking at include: lack of a statutory requirement that the industry conduct safety testing and lack of authority ~to require submiss ion of safety substantiation data or. any other records and reports, lack of.authority to require adverse reaction reporting, lack of authority to require even the submission of product formulations or registration of cosmetic manufacturers, an~severely limited inspection authority. As the la~i now stands, cosmetics are the only product for which the legal burden rests with FDA to p~ove a hazard to the public rather than on the industry to demonstrate thatthelr product has been tested in accordance with currently accepted methodology and Is safe. . Thank you Mr. Chairman. I will be pleased to answer anyquestions you and the other members of the Subcomittee may have. PAGENO="0388" 382 Mr. MAGUIRE. Thank you very much, Commissioner. Mr. Brown? Mr. BROWN. Dr. Kennedy, as a scientist, do you believe that a product which has been found to be a mutagen under the Ames test and other short-term mutagenicity tests and which may be absorbed through the skin, should be placed in a cosmetic product? Dr. KENNEDY. I think probably not, Mr. Brown. As you know, the concordance between the Ames test and long-term tests, that is, animal tests for carcinogenicity is good, but not perfect. I think there are serious questions as to whether the Ames test is yet ready to be used as the final arbitrator of regulatory action. I think it should be used, and is now being used as a means to identify and prioritize those compounds that need serious attention from limited testing facilities in other areas. I myself hope that enough short-term tests will be developed so that a serial-battery of such tests will eventually be able to service and relieve us of some of the terrible resource demands of chronic mammal toxicology testing. I do not think that day is quite here yet. Mr. BROWN. Would you consider a cosmetic product containing such an ingredient safe? Dr. KENNEDY. I would consider it as a strong presumption against its safety. Mr. BROWN. If a substitute ingredient could be found for this ingredient-the ingredient that is found positive in the Ames test and other short-term mutagenicity tests-which is negative in the Ames test and other short-term mutagenicity tests, would you be more likely to substitute this ingredient for the one which was positive in the Ames test, absent other scientistfic data? Dr. KENNEDY. Oh, yes. You mean, were I a formulator in the industry? Mr. BROWN. Yes. Dr. KENNEDY. I would certainly do that, if for no other reason than to make my product more secure against adverse regulatory action in the future. Mr. BROWN. Furthermore, if you knew that an ingredient in a cosmetic product was found to be a carcinogen under the massive dose animal experiments for carcinogenicity conducted by the National Cancer Institute, and you knew that this ingredient might be absorbed through the skin, would you consider the cosmetic products containing this ingredient to be safe? Dr. KENNEDY. No. I think one would have to make the strong presumption in that case that they were unsafe. The phrasing of your question that gave me a little pause, Mr. Brown, was: "likely to penetrate the skin." I think the issue of skin penetration is an important issue. I would prefer that one be on somewhat firmer ground than "likely," but certainly positive results in chronic carcinogenicity studies, and the membership in a molecular family of things that are known to pene- trate skin easily, would convince me that it ought to be gotten out of the product. Mr. BROWN. As the law currently stands, however, you feel you would have to prove skin penetration before you take any action on a product like this; is that right? PAGENO="0389" 383 Dr. KENNEDY. I think that is a ~mattei of interpretation. I am not certain about that. Mr. BROWN. Yesterday, Dr. Corbett, a scientist for the cosmetic industry stated that be personally favored premarket testing of cosmetic products, and I underline "personally." He stated, however, that be was opposed to making premarket testing mandatory because it would mean that every time an in- gredient in a product increased or decreased by perhaps 1 percent, the industry would be forced to test the product over again before it would be allowed to be put on the market. Is this your conception of what a premarket testing program would require? Dr. KENNEDY. No. We are anxious to have some premarket testing authority, but that does not mean that we will apply it to every small change in formulation. I think that, like most statutory authorities, we would be disposed to try to apply it sensibly~. It is like any other resource allocation problem. We could not find all the time to read all the safety test results that would result from every miniscule change in a product formulation. That would be a poor way to use our resources. We would like to be able to require premarket safety substantiation of important product ingredients. I would go further and say that because I think interaction is important in cosmetics, that we might want to be able to require safety tests of significant new combinations. Mr. BROWN. Let me askyou a few questions about your present statutory authority. Please tell me if you agree or disagree with the following statements. "As a practical matter, the FDA may react only after it discovers an adulterated or misbranded cosmetic in the marketplace." Dr. KENNEDY. I am a little unclear, Mr. Brown, about what you are expecting here. You want my reaction? Mr. BROWN. Do you believe that this is generally the case under the current authority? Dr. KENNEDY. I am anxoius not to give too much away here. I find our authority is infirm and deficient in this regard, but there is a good deal that we can accomplish by regulation. I would say that there is less clarity in our ability than we would like, but that some can be accomplished by regulation. Mr. BROWN. But the fact is you need to first prove that the product may be adulterated or misbranded; is that right? Dr. KENNEDY. You are right about the burden. Mr. COOPER. We would have to satisfy a court that the product is either adulterated or misbranded. However, we might ease that burden somewhat in advance by going through a rulemaking proceed- ing in which we established our position with respect to, let us say, ingredients that might constitute adulterants. We would go into court relying on a regulation rather than having to make an individual factual case. But ultimately we would have to be in court. Mr. BROWN. Another statement I would like you to react to is this: "Under the current statutory scheme, the FDA cannot require that the manufacturers test for safety prior to marketing the product." Dr. KENNEDY. I think you already have my reaction to that. We would like the authority to require that, where we think it is necessary. PAGENO="0390" 384 Mr. BROWN. Another statement is this: "The cosmetic producers do not violate the act if they fail to conduct a single safety test, either before or after introducing a new product." Dr~ KENNEDY. Again, we would like the authority to require that. Mr. BROWN. "FDA has no authority to require that the companies provide necessary information that would enable the agency to con- duct its own premarket review." Would you react to that? Dr. KENNEDY. Yes; as a part of any premarket review, we would require access to the data in order to conduct our own evaluation. Mr. BROWN. "Manufacturers cannot be compelled to submit in- gredient lists, consumer complaints, or test data." Dr. KENNEDY. That is true. We wish it were not. Mr. BROWN. "Cosmetic companies are not required to inform the FDA that they, or their products, exist." Dr. KENNEDY. That is correct also. Again, as I said in my state- ment, we would like to have registration authority. Mr. BROWN. Dr. Kennedy, your answers seem to indicate that in the area of cosmetic regulation, the power to regulate, or at least much of the power to regulate, belongs to each individual cosmetic company, and that the standard for what is safe is determined and controlled by those individual companies. Dr. KENNEDY. In the absence of a specific statutory mandate to require test data and plant and product registration, and to do in- spections, one relies, out of necessity, on programs that are essentially voluntary. So, I think your description is right. You 11 ave heard correctly from the GAO that our success in obtaining those data voluntarily has not been as good as we would like. Mr. BROWN. Thank you, Mr. Chairman. Mr. WALGREN [presiding]. Commssioner, when you say that you would like to have registration authority, has the FDA ever asked the Congress to provide that authority? Dr. KENNEDY. Yes; we have. Unless I am very much mistaken, I believe that all, of at least most, of the features that we have de- scribed as being important but missing were parts of the bills in- troduced last year and in previous years on the Senate side. In our comments on legislation in previous Congresses we came out in favor of every one of those provisions. There was a bill by Congressman Paul G. Rogers on the House side that also had all of those provisions in it. So, we are on record repeatedly in this area, that is, of being in favor of those provisions. Mr. WALGREN. So we could translate your statement that you would like to have that authority to mean that you believe you need that authority and that you would like to see legislation which would provide that authority? Dr. KENNEDY. Yes. Mr. WALGREN. Would the administration support a bill to that effect? Dr. KENNEDY. The previous administration supported our position and I have every reason to believe that it would be warmly supported again. PAGENO="0391" 385 Mr. WALOREN. That would include registration authority or the authority to require anyone producing a cosmetic to at least let the officials in the Government who are concerned about chemical safety know that they are operating in* the area and it1 would include the requirement to disclose the ingredients of products which they put on the commercial market, I suppose. But what about requiring at least the report of harmful effects that they may receive? Dr. KENNEDY. Yes ;~ we have asked that adverse reaction reporting be make, that is, for us to have the authority to require adverse reaction reporting as well. Mr. WALGREN. And that would be mandatory? Dr. KENNEDY. Yes. We would make it mandatory. Mr. WALGREN. Do you feel that the public responsibility could be discharged effectively without that authority? Dr. KENNEDY. It is very much more difficult-some of it cannot be discharged at all. This gets me into a comment on the GAO's earlier testimony-I think they are correct in saying that the FDA has not, in the past, fully used its existing regulatory authority, that is, the existing statutory authority to pursue these matters as inten- sively as one might desire. But, I would like to add to the reasons that the GAO witnesses gave you a much more important one in our view. If you have a a variety of important public health protection responsibilities under your act-and I ask you to recall that our responsibilities over drug safety and over food safety are perhaps even more compelling than our responsibilities over cosmetic safety-that is, if you have three different portions of your act, and under two of them you have relatively clear statutory authority, and under the third you have relatively unclear authority, then only a silly manager overinvests in the area where the authority is weak because his resources get chewed up for very little outcome. Mr. WALGREN. I would like to understand a little bit more where we are in the knowledge of skin absorption and what have been our efforts recently. Commissioner Kennedy ~ays that we are conducting laboratory studies on skin penetration on NDELA. How large an effort is that? What kind of tests are being run, and is the state of our knowledge changing? Dr. KENNEDY. I think it is a little too soon to say that the state of our knowledge is changing. After all, this is a recent prog.ram. Remember, the data reported by Dr. Fine are substantially less than a year ~1d, and from a dead standing stop we had to work up both an analytical capability for NDELA and assign the personnel and equip- ment to mount the effort and move it forward. We also had to put in place the skin penetration studies that form the second part of that research. Dr. Roberts may be able to tell us something about the extent of resources or Dr. Scheuplein may. Dr. ROBERTS. As part of the Division of Toxicity in the Bureau of Foods, there is a Dermal and Ocular Toxicity. Branch. We have, at the present time, five people. Two of those peopla are now working on skin penetration of NDELA. PAGENO="0392" 386 This study began about a month ago as a continuation of a prior study of about 6 months ago that had to be suspended when one of our people was transferred. We expect that the results of this skin penetration study will be ready within a month. Mr. WALGREN. How long has that study been going on? Dr. ROBERTS. The present study with the personnel we have on hand has been going on just about 1 month. It is a continuation of an earlier one that had to be suspended because of the fact that the person we had for the study was transferred. Mr. WALGREN. So you have one man full time for 2 months in this effort at this point? Dr. ROBERTS. That is right. Mr. WALGREN. And, you have five people involved in some way in skin penetration or only two of those were involved in skin penetration? Dr. ROBERTS. 0niy two of those. We have five people for the whole Dermal and Ocular Toxicity Branch. Mr. WALGEEN. Five people for the whole Branch? Dr. KENNEDY. The Dermal and Ocular Toxicity Branch of the Toxicity Division is what we are talking about. I assume you are talking about professionals in that number. Is that right? Dr. ROBERTS. No. Dr. KENNEDY. No. Then that is total people. Mr. WALGREN. Total people? Dr. KENNEDY. Yes. Mr. WALGREN. So, of the five, perhaps only three are actually work- ing on the products and the others may be staff support; is that right? Dr. ROBERTS. Right. Mr. WALGREN. The industry that we are trying to deal with is a $9 billion industry. Dr. KENNEDY. Yes; I think that is correct. I might insert here, Mr. Walgren, that it is quite characteristic of the Food and Drug Administration that not all of its research is per- formed in-house; that is, it would be typical of most parts of the Bureau of Drugs or the Bureau of Foods that if we had a problem of this sort that we needed to get solved, rather than taking on extra personnel or redirecting existing research personnel from other efforts that might be equally important, we would attempt to find sources of contract help outside. In this particular case, the newness of the information that has raised these concerns has made it necessary to do it by internal re- allocation of what you have just heard is a rather thin resource. We probably will be supporting, through grant and contract mechanisms, some outside work as well. Mr. WALGREN. Where did the estimate of the 40 pounds per year come from? Dr. ROBERTS. That is a projected estimate based on the retail sales of toiletries, cosmetics, and soaps. It turns out that, based on such, an estimate, one can estimate that about 3.7 million pounds of soaps toiletries, and cosmetics will be sold in 1978. If you divide that number by an estimated target population of either 200 million or 100 million or what have you, you can see that the estimated use per person is roughly from 10 to 40 pounds per year. PAGENO="0393" a87 Dr. WALGREN. Is there any relationship between physical applica- tion and absorption rates, or are we talking about the absorption and skin penetration of really molecular-level chemicals? Dr. ROBERTS. I am not sure I really understand that question. Dr. KENNEDY. I think, Mr. Walgren, you are really asking what kinds of skin penetration figures we are really dealing with, are you not? I mean, how much of any particular molecular species is likely to go through the skin. That varies terribly widely. There are some compounds that are just very insoluble in the kinds of material of which animal skin and human skin is made that go through or penetrate very poorly. So even a very thinly applied dose, even on a relatively permeable part of the skin, like the scalp, of only a few thousandths of a percent might go through. On the other hand, there are some compounds that are quite per- meable and that pass through the skin readily. Unfortunately, the so-called coal-tar hair. dyes are among the more permeable compounds that we know of. The figures that various re- search groups have been able to produce for penetration of those dyes vary a little bit, but they are running around 1, 2, or 3 percent. In some experiments, they are substantially more. So it is possible in fact, at least in some animal species and perhaps in humans, that with repeated application to the skin of these com- pounds, one could reach blood concentrations of the same order as one could reach by feeding the animals. Mr. WALGREN. The reason this interests me is that we are under such criticism for getting the Government involved in the areas they should not be involved in. It does not seem obvious to the public that we should be involved in these, that is. I think, in general, for someone who has never thought about the subject before, cosmetics are not usually thought of as being ab- sorbed into the system. Therefore, that is a new, and, I think, very essential idea for the public at large anyway. What you are saying is that our knowledge has not particularly changed in that area. So, I am wondering if we are thinking of moving into this area, that in order to set a basic or to make it accepta4ble to the public to put even 2 months of man-hours work on it, whether or not we should be emphasizing skin absorption and perhaps being able to demonstrate exactly what is going on to the layman. Without that, I see a great resistance from the public to taking this seriously. Dr. KENNEDY. I think that is true. I know the feeling of being accused of getting involved in areas that people would rather not see a regulatory agency get involved in. I agree with you that it is very im- portant that we try to get some public understanding for the serious- ness of these problems. I would like to emphasize, though, that dermal toxicity is not a new phenomenon, although it is not often considered in terms of cosmetics. Many of the more damaging pesticide exposures, for example, in farmworkers and others, are dermal exposures. The Occupational Safety and llealth Administration worries about dermal exposure in connection with a great many workplace toxic substances hazards. PAGENO="0394" 388 I hope you will help us with this, but I think what we need is a more concerted Government-wide effort on all aspects of toxic chemicals hazards. We need more work on inhalation toxicology and on dermal toxicology. We need a better national epidemiological system. The Food and Drug Administration is responsible for only a small piece of this. But I think that many other agencies would also tell you that they have relatively small resource commitments to these kinds of problems. One of the things that I hope will come out of our four agency al- liance is significantly more cross-Federal attention to these sorts of problems. I am grateful for the opportunity to say so. Mr. WALGREN. Well, we certainly cannot be accused of having put very much Federal effort into skin penetration at this point, if that is the degree of specific focus research that we have done on that; is that correct? Dr. KENNEDY. I would not want to confuse you. You have heard about a specific project dealing with the skin penetration of a particular product or a compound of newly generated concern. That does not represent the total number of scientist-years that FDA normally puts into all issues of skin penetration. Although I can tell you that would not sound very large either. Mr. WALGREN. Mr. Maguire? Mr. MAGUIRE. Dr. Kennedy, I asked Mr. Ahart earlier about FDA's failure to use, in the past, its existing authority. He said there was not enough pressure, and he said there was a lack of resources. I would like you to answer the same question. Why has FDA not been using its authority, in your judgment? Dr. KENNEDY. I think the reasons that Mr. Ahart mentioned are probably reasons that have played some role. I would like to be able to sit here and tell you, Mr. Maguire, that the Food and Drug Administration never allocates its resources accord- ing to pressure. But you and I both know that would be foolish. Mr. MAGUIRE. That was going to be a followup question. Dr. KENNEDY. So, obviously, there is public pressure. Bringing to our attention problems-by the public, by the Congress and by sci- entists who perform outside of the Agency-is an important allocation pressure. But, as I said in response to an earlier question to Mr. Walgren, I think the more important reason is that if you have important public health responsibilities in three different areas, and if each of them lays compelling claims to your resources, and in one of those areas you have manifestly inadequate statutory authority, and in the other two it is at least better, then a wise man is going to allocate more heavily to where he is going to get a return. Mr. MAGUIRE. You have been quite critical today of the existing 1 aw in your statement. At the conclusion of your statement you made a number of recommendations for improvements. Is the administration prepared to submit to this Congress proposed legislation to protect people more adequately against cancer-causing substances in cosmetics or other toxic substances in cosmetics? Dr. KENNEDY. Yes, Mr. Maguire, I think we are prepared to par- ticipate with committees of the Congress and Members of the Congress in drafting and designing legislation. PAGENO="0395" 389 Mr. MAGTJIRE. Will you actually make a proposal, or has that not yet been decided? Dr. KENNEDY. I do not think that has yet been decided. As you know, there has been, in recent Congresses, activity on the House and Senate side with regard to new cosmetics legislation. FDA has supported it. The Department of Health, Education, and Welfare has supported it. As a department, we have supported the kinds of provisions that we have discussed. So, the sorts of proposals we would make are out there and are clear enough. Mr. MAGUIRE. I do not think they really are. The~e is nothing quite as clear as submitting your own piece of legislation which really does provide an impetus which otherwise is absent. Mr. Eagleton, for example, for some time has had a varitey of rec~- ommendations. But we need the impetus that your leadership would provide, or at least your endorsement of a specific set of recommen- dations that are more detailed than what we have had from you today. Dr. KENNEDY. We would be delighted to do that. We have endorsed very specific recommendations in the past. I am not prepared to tell you here and now this morning, not having been asked the question before, whether there will be an administra- tion cosmetics bill. But I am certainly prepared to tell you that I think my colleagues in the department and I are prepared to suppc~rt the sorts of provisions that we have discussed and to help you to work it into language that will be agreeable to all of us, or at least almost all of us, and to work with you to support it. Mr. MAGUIRE. Excellent. Thank you. With respect to the 100 ingredients in the CTFA dictionary which we have here [indicating], it has 100 things that NIOSH has said are suspect, or that they are known carcinogens. What are you doing about that list now, if anything? Dr. KENNEDY. A number of the compounds on that list, and a number of the ingredientscited from the GAQ "drugstore" that we had here this morning on the table, are compounds that are now under test. I hope we will know fairly soon something about their status that says more th'an "suspect." Even the more robust provisions of the other part~ of the Federal Food, Drug, and Cosmetic Act do not allow us tQ hoist a compound from the marketplace on the basis of suspicion of ~arcinogenesis. Mr. MAGUIRE. But we have products on the shelves right now which are purchased by tens of millions of people. across this country. We have Grecian Formula shampoo, and Kindness hair conditioner, et cetera. I know that people are concerned. .. So the question i~ this. What will you do and how quickly will you do it? . Dr. KENNEDY. We will undertake product removals and undertake the addition of warning statements as promptly as we can, following the submission of data and following the development of data that constitute clear enough proof of carcinogenicity or other forms of toxicity where we have a reasonable chance of defending that regula- tory action in the courts. .~ . PAGENO="0396" 390 Mr. MAGUIRE. But FDA is going to have to develop that data; is that right? Dr. KENNEDY. We cannot develop all of it. We do not have facilities for long-term chronic toxicity testing that would allow us to investi- gate even a tiny fraction of the compounds on the NIOSH suspect list. The National Cancer Institute, and the Department, through con- tract, have had, and are having, some of them tested. But I have to say that it will be some time before we get around to testing all of the possibly hazardous substances that are now in cosmetics. It!will be sometime even before we get around to testing all of the possibly hazardous substances that are in foods. Mr. MAGUIRE. Do you believe that the animal feeding studies con- ducted at the National Cancer Institute are a sufficient scientific basis on which to act? Dr. KENNEDY. I would rather not make a blanket statement about that, Mr. Maguire, but the ones that we have reviewed and that we have begun action on, like the one on 2,4-diaminoanisole, we certainly regard as adequate. I am not eliminating the possibility that an NCI- funded contract study, for example, might not come in with a defect. Mr. MAGUIRE. My question really goes to the question of whether the feeding studies of animals are, in your judgment, a legitimate scientific basis on which to make a regulatory decision. There has been a lot of discussion about that in these and other hearings. Dr. KENNEDY. If I did not believe that, I would be back in California teaching biology. Mr. MAGUIRE. Thank you. Mr. WALGREN. I gather that until that time that we and the Ameri- can public will continue to rely on the guarantees that we already have as displayed on the Kindness Shampoo package, which is: "If product or performance defective Good Housekeeping guarantees re- placement or refund to consumer." Mr. Wunder? Mr. WUNDER. Thank you, Mr. Chairman. Dr. Kennedy, the FDA has had regulatory authority, albeit not what you think appropriate and necessary, for 40 years. Is that true? Dr. KENNEDY. Regulatory authority for what? Mr. WUNDER. Over cosmetics. Dr. KENNEDY. Yes, some regulatory authority. Mr. WUNDER. Yes. I assume that FDA has kept up with the literature and what is going on in the cosmetics industry, to some degree; is that right? Would that be a fair statement? Dr. KENNEDY. Yes. Mr. WUNDER. Let me ask you this. This goes to the public alarm issue. Do you know of any studies where birth defects have been linked to the use of these cosmetics? Dr. KENNEDY. Do you mean birth defects- Mr. WUNDER. In humau beings. Dr. KENNEDY. Linked epidemiologically to the use of cosmetics? Mr. WUNDER. In any respect. Dr. KENNEDY. I do not know of any offhand, but I will ask my colleagues for help. Until a few months ago this was not literature that I tracked terribly carefully. PAGENO="0397" 391 There are ingredients, some ingredients in cosmetics that I think look to be teratogenic in animal studies, but that is not the question that you asked. Mr. WUNDER. So there are none; is that the answer? Dr. KENNEDY. None known to me. Mr. WUNDER. None known to anybody on the panel? Dr. KENNEDY. That is correct. Mr. WUNDER. Are there any studies linking the use of cosmetics with cancer in human beings? Dr. KENNEDY. Well, that depends on which side you take in the interpretation of the epidemiological studies done on beauticians, cosmetologists, and users of beauty shop products. My own view of the matter is that it is not possible to decide yet, but there are people who believe that they are indicative. Mr. WUNDER. Let us take any of the diseases known to modern man. Is there any study linking any disease with the use of cosmetic products? Let us leave out cancer for the moment. Dr. KENNEDY. Yes. There are some eye infections. There are certainly skin irritations and sensitation problems that have been associated- Mr. WUNDER. Aside from those. The 1938 act-it was the eye situation that brought that about. Dr. KENNEDY. Yes. Mr. WUNDER. They knew about the irritation problem in 1938 because that was discussed in the hearings then. But other than those, what about it? Dr. KENNEDY. We did ban vinyl chloride in cosmetics in occupa- tional studies, but that was a propellant. Perhaps that is not respon- sive. Mr. WUNDER. You were asked a question by Mr. Brown about the Ames test. The question was this: If there was an ingredient, a compound, that failed the Ames test, but there was a substitute that passed the Ames test, would you use the substitute? You said: "Yes." Dr. KENNEDY. Yes. Mr. WUNDER. The question that was asked of Dr. Corbett yesterday about the Ames test was along these lines, along these similar lines, but his answer was-and I would like to get your reaction to it: If there was a compound that we had used for maby years and it failed the Ames test, but we otherwise had a track record of safety, then I would not go to some new compound without any track record of safety. What is your reaction to that statement? That was the thrust of Dr. Corbett's testimony. Dr. I~ENNEDY. I understand. It all depends on what you mean by "track record." There are a lot of compounds that have been out there in the marketplace which most people are prepared to say are safe because they have not yet been able to affiliate the use of that compound with any health problem. But, in fact, as we know, even for devastatingly dangerous com- pounds that affiliation can be subtle and difficult to perceive. After all, in the ~94O's everyone thought that tobacco was safe. Everyone PAGENO="0398" 392 would have asserted very stoutly, as the tobacco industry did, that there was no problem with it. So, if by "track record" you mean the general public perception that people are not keeling over and dying, I guess I have to tell you I am not very reassured by that. Mr. WUNDER. I see. The thrust of it was along these lines. If you had some evidence, and then you go into something that you do not know anything about, that is, if those were the options, and if that was the concern of Dr. Corbett, that is, that you do not know anything about this one because it has not been tested- Mr. MAGUIRE. If the gentleman will yield, I think it is also important to recognize that we are talking about the Ames test and we are talking about a test which can be conducted in a matter of days. I do believe that Dr. Corbett also said that if he had a negative result, that is, a result that showed that there was no tumorigenic activity or muta- genic activity in this case, excuse me, and another ingredient which showed that there was, then he would take the one where there was not. So, given that we are talking about the Ames test, and the period of time that we are talking about, and in getting results on any sub- stance which we might want to look at, is indeed a very short period of time. Mr. WTJNDER. According to my recollection, those were cases where you had two new products and one passed and one failed. I have no further questions, Mr. Chairman. Thank you very much. Mr. WALGREN. The Chair will recognize Mr. Brown. Mr. BROWN. Dr. Kennedy, I have a few more questions. These specifically relate to the actions you are about to take to place a warning label on hair dyes containing 4-methoxy-m-phenyl- enediamine. Last week, the Cosmetic, Toiletry, and Fragrance Association asserted that FDA was basing its action on only one test. Can you react to that statement? Dr. KENNEDY. I think that there are results on two species in that case, so I do not know really where that comes from. Let me hasten to say that I do not think you have to have two. Mr. BROWN. But aren't we really talking about a whole range of tests. Did not FDA consider other types of testing in making its decision? I am talking about tests besides carcinogenicity tests. Dr. KENNEDY. We certainly looked at a range of data. I thought what you were asking for was this. Which of the chronic toxicology studies do you consider critical? Obviously, we look at everything, including several different skin penetration experiments, some of which are better than others. Mr. BROWN. Just as a final question, Dr. Kennedy, if you were in the position where you were considering dying your hair, with the knowledge, that you now have, concerning the possible risk involved, would you use a coal tar hair dye? Dr. KENNEDY. I am grateful that this subcommittee always gives me an opportunity-I am unmotivated in that direction, Mr. Brown. I do not think it would do a thing for me. But even if it did, I think I would give it a miss. PAGENO="0399" 393, Mr. WALGEEN. Dr. Kennedy, I think you should know that accord- ing to whoever makes this Grecian Formula, you are "foregoing the social and business advantages and the personal satisfaction that comes with the more youthful look." Dr. KENNEDY. I knew that before I started turning gray, Mr. Walgren. Mr. WALGEEN. Well, we appreciate your testimony, and we want to thank all of the witnesses who came to the hearing today. Although we make light of this in some ways, it does not have a thing to do with the seriousness of the problem. Thank you very much. The hearing is adjourned. [Whereupon, at 11:55 a.m., the hearing adjourned.J PAGENO="0400" PAGENO="0401" CHART 1 k List of Chemicals in Bioassay Program That Are Hair Dye Ingredients C,, CHEMICAL NAME ~ DATE "ON" TEST DATE "OFF" TEST DATE FINAL REPORT PROMISED TO LABOR-HEW SUBCOMMITTEE DATE FINAL REPORT PROMISED TO OVERSIGHT AND iNVESTIGATIONS SUBCOMMITTEE DRAFT REPORT AVAILABLE (TECHNICAL REPORT) (DATE) FINAL REPORT AVAILABLE (DATE) 1, 3-Phenylenediamine 1/70 1/12 12/77 3178 - - 1, 4-Phenylenediamine 2/73 5176 12/77 5/78 - - 2, 5-Toluenediamine 3/72 2/75 7/77 10/77 7/77 - 0-Anisidine 3/74 3/76 2/78 5/78 - - 4-Chloro-1, Z~PhenyIenediamine 3/73 4/75 6/77 9/77 12/77 - 1-2-Phenylenediarnine 6/70 6/72 12177 3178 - - P-Anisidine Hydrochloride 3/74 3/76 1/78 4/78 12/77 - 4-Amino-2 Nitrophenol 3/74 3/76 10/77 4/78 - - 2, 4-Biaminoanisole Sulfate 4/72 3/75 11/77 2/78 12/77 - 4-Nitro-P-Phenylenediamine 6/72 8/74 6/77 3/78 - - 2, 4-Tohienediamine 1-Phenyl-3-Methyl-5-Pyrazolone 10/73 2/76 3/78 12/77 12/78 - - 10/73 12/75. 6/78 - - N-Phenyl-1, 4-Phenylenediamine 2/73 12/74 8/77 4/78 - - Sources: National Cancer Institute testimony before labor-HEW Subcommittee, Committee on Appropriations, U.S. House of Representatives, 95th Congress, 1st Session, March 7, 1977. Letter from Or, Gay Newell, Acting Director, National Cancer Institute to Committee on Interstate and Foreign Commerce, U.S. House of Representatives, Subcommittee on Oversight and Investigations, July 7, 1977. Jan. 16, 1978 PAGENO="0402" CHART 2 Selected Examples of Chemicals Listed in the Bioassay Program DATE DRAFT DATE FINAL REPORT REPORT FINAL REPORT PROMISED TO AVAILABLE FINAL DATE DATE PROMISEDTO OVERSIGHTAND (TECHNICAL REPORT CHEMICAL NAME USE "ON" TEST "OFF" TEST LABOR-HEW SUBCOMMITTEE INVESTIGATIONS SUBCOMMITTEE REPORT) (DATE) AVAILABLE (DATE) Acenaphthene, 5-Nitro- Chemical intermediate or catalyst 1/73 12/75 8/77 11/77 - - Ethane, 1, 1-Dichloro Solvents 4/72 5/74 5/71 10/77 5/77 - Daconil DaunOmycin Pesticide 2/72 4/69 6/74 8/71 6/77 1/78 9/77 4/78 6/77 - - - Pharmaceuticals/biologicals Diphefl~tamine, 4-Nitroso- Miscellaneous categories 7/12 9/74 9/71 12/77 - - Hydrazine, 1, 1-Diphenyl- Chemical reagent 4/72 3/75 8/77 11/77 - - Lead Acetate Dye or dye manufacture 8/12 9/74 3/78 6/78 - - Tryptophan, 1- Vinbiastine Food or food additives 2/73 5/69 2/75 5/71 11/77 1/78 2/78 4/78 - - - - Pharmaceuticals/biologicals Acetic Acid, Nitrilotri Other 2/73 2/75 4/77 3/77 - 4/77 Dapsone Malathion Phenol Pharmaceuticals/biologicals 5/72 12/71 10/75 5/74 4/74 2/79 8/77 6/77 2/80 10/77 10177 2/80 8/77 6/77 - 1/78 - - Pesticide Pharmaceuticals/biologicals Sources: National Cancer Institute testimony before Labor-HEW Subcommittee, Committee on Appropriations. U.S. House of Representatives, 95th Congress. 1st Session, March 7,1971, Letter from Dr. Guy Newell, Acting Director, National Cancer Institute to Committee on Interstate and Foreign Commerce, U.S. House of Representatives, Subcommittee on Oversight and Investigations, July 1, 1977. Jan. 16, 1978 PAGENO="0403" APPENDIX B written on request of the Federal Trade Comi ssion UNIVERSITY OF CALIFORNIA, BERKELEY BERKELEY~ DAVIS IRVINE LOS ANGELES `RIVERSIDE' SAN DIEGO SAN FRANCISCO SANTA BABBASA `SANTA CIWZ DEPARTMENT OF BIOCHEMISTRY BERKELEY, CALIFORNIA 94720 February 17, 1978 AFFIDAVIT OF DR. BRUCE N. AMES CONCERNING HAIR DYE CHEMICALS I, Dr. Bruce N. Ames, being duly sworn, do hereby state my reasons for believing that the use of hair dyes containing the chemicals listed below* poses a significant risk to consumers. The risk amply justifies requiring a warning to users in advertising and labeling. I am a Professor of Biochemistry at the University of California at Berkeley, and have worked for 15 years in the area of chemicals which cause cancer and mutations. I am a member of the National Academy of Sciences and was appointed by President Ford to the National Cancer Advisory Board (the Board of Directors of the National Cancer Institute). I enclose a C.V. (Appendix 1). I believe the six listed chemicals pose a risk to humans for the following reasons: 1. The chemicals are~mutagens. That is, they belong to a small group of chemicals which damage DNA, the genetic material. They have the potential. therefore, to cause birth defects and long-term genetic damage. For this reason, pregnant women should be especially cautious about using such products. All of the listed chemicals were mutagenic when tested in the Salmonella (Ames) Test (Appendix 2). Subsequently, they have been found to be mutagenic when tested in a variety of other test systems, inc1udin~ Drosophila (fruitflies), and cultured human or other mammalian cells. A review of the current status of these tests is presented for each chemical in Appendix 3. Most, if not all, chemicals which are mutagens are also carcinogens. The ability of the Salmonella test to predict carcinogenicity has been extensively analyzed~iiing several hundred chemicals with known cancer~ causing properties. The test achieved a high degree of accuracy and did particularly well with carcinogenic aromatic amines similar in structure to numerous hair dye chemicals. (397) PAGENO="0404" 398 Affidavit/Bruce N. Ames - 2 - February 17, 1978 The excellent agreement between the Sa1monell~ mutagenicity results and the other test systems establishes these chemicals as mutagens. The industry has tested many of the hair dye chemicals in the dominant lethal test and reported negative results~. This test, however, is well known to miss many important classes of carcinogens and, in particular, has not been validated for the class of aromatic amines, which includes the hair dye Ingredients and such well known human carcinogens as ~-naphthy1amine and benzidine. 2. The chemicals are carcinogens it~ animals. The National Cancer Institute has indicated that the listed chemicals have been shown to cause cancer in rodents in tests being completed by the National Cancer Institute. These tests further support the relevance of results in the short-term tests to potential hazards of hair dyes. 3. There is a risk to humans. Hair dye chemicals have been shown to penetrate the scalp in sigilificant quantities. This, together with the high correlation between human and animal carcinogens, suggests a definite risk to those using hair dyes containing the listed chemicals. In evaluating this risk, it is important to consider that the development of human cancers will lag twenty years or more behind the initial exposure. Since hair dye use has increased over recent decades, it is quite possible that any human effects of hair dye use will be increasingly evident in the future. Furthermore, since the chemicals are also all mutagens, they may pose a risk of birth defects and possibly genetic damage to future generations. Bruce N. Ames Professor of Biochemistry BNA/ssk * 2,4-diaminoanisole 2-nitro-p-phenylenediamine 4-amino-2-ni trophenol p-phenylenediamine Direct Black #38 o-phenylenediamine (possibly no longer used) Appendix 1: C.V. of Dr. Ames Appendix 2: Ames et al., Hair Dyes are Mutagenic Appendix 3: GQ1d i~iW~mes, Hair Dye Components: Review of Mutagenicity Appendix 4: Interview with Lester Brown PAGENO="0405" 399 27 January 1978 revised: 15 February 1978 Testimony for House of Representatives Oversight Committee Hearing on Cosmetics Hair Dye Components: Review of Mutagenicity and Other Short4erm Tests Cheryl Gold and Bruce N. Ames Depa~~tment of Biochemistry University of California Berkeley, California 94720 PAGENO="0406" 400 SUMMARY In 1975, Ames, Kammen and Yamasaki found the following 11 hair dye chemicals were mutagenic in Salmonella: 2,4-diaminoanisole, 2,4-diamino- toluene (dropped from use because of carcinogenicity), rn-phenylenediamine, 2,5-diaminoanisole, 2,5-diaminotoluene, p-phenylenediamine (after mixing with peroxide), 2-nitro-p-phenylenediamine, 4-nitro-o-phenylenediamine, o-phenylenediamine, 2-amino-5-nitrophenol, and 2-amino-4-nitrophenol. In addition, 4-amino-2-nitrophenol has since been shown to be a mutagen in the Salmonella (Ames) test, as have Disperse Blue #1 and Direct Black #38. So far, 7 of these compounds, 2,4-diaminoanisole, 2,4-diaminotoluene, 2-nitro- p-phenylenediamine, 4-nitro-o-phenylenediamine, m-phenylenediamine, p-phenylene- diamine, and 2,5-diaminoanisole, have been tested and found to be active in other short-term tests. To this date, six of these chemicals, 2,4-diamino- anisole, 2-nitro-p-phenylenediamine, 4-amino-2-nitrophenol, o-phenylenediamine, p-phenylenediamine, and Direct Black #38, appear to be carcinogens in NCI animal tests. In addition, three other hair dye related ingredients, o-anisidine, 4-chloro-o-phenylenediamifle, and Direct Blue #6, appear to be carcinogens in the NCI animal tests: the first two are mutagens, and the latter hasn't been tested but is similar in structure to the known mutagens Pontacyl Sky Blue 4BX and Direct Black #38. Three chemicals which are not mutagenic in Salmonella, N-phenyl-p- phenylenediamine, l-phenyl-3-methyl-pYraZOlOne, and resorcinol, do not appear to be carcinogens in the NCI animal tests. PAGENO="0407" 401 Many of the following hair dye ingredients are under study by the National Cancer Institute. In addition to cancer tests, many of the compounds have been tested in a number of short-term tests, such as mutagenicity using our Salmonella/liver test, gene mutation using mouse lymphoma cells, chromosome damage and morphological transformatio~1 in mammalian cells, mutagenicity in Drosophila, and sister chromatid exchange. These chemicals will be presented first. An NCI index number is given, and CAS numbers may also be included. Full citations for references are listed in the appendix. The list which follows this compendium contains all other hair dye chemicals under study by the National Cancer Institute. PAGENO="0408" 402 OCH3 2,4-diaminoanisole NH2 (4-methoxy-m-phenylenediamine = 4MMPD) [also sulfate salt = 4MMPDS] CANCER TEST (NCI# = C01989, sulfate) REFERENCES (CAS# 615-05-4, sulfate) positive 14 SHORT TERM TESTS RESULTS Salmonella (Ames) very strong mutagen 1,4,20 (TA1538 +S9: 4000 revertants/50 ig [1]) Drosophila mutagen 3 Mouse lymphoma questionable response, however 15 activation was not used; author believes test will not be definitive until activation is used Reference to use in hair dyes PAGENO="0409" CANCER TE~I~ (NCI# = C02302, C01832 [sulfate]) (CAS# = 95~80~7) positive (preliminary result of Nd) positive (rat sarcomas) positive (rat liver carcinomas) __ RESULTS __________________ mutagen (TA1538 1-59: 270 revertants/100 ~g [1]) ___________ mutagen ______________ morphological transformatlQns observed Note: This compound was formerly used in hair dyes but was taken off the niarket when it was found to cause cancer In animals. 403 m-tol uenedi amine (2 ,4-di ami notol uene) [also sulfate salt] SHORT TERM TESTS Salnonel la (Anies~ Drosop~~j,i~ ~ hamster cells 14 21 8 1 ,20 3,5 17 24.600 0 78 27 PAGENO="0410" 404 NH2 `HCl m-phenyl enedi amine' 2HC1 0 NH2 HC1 CANCER TEST* REFERENCES test has been completed; results appear negative 14 SHORT TERM TESTS RESULTS Salmonella (Ames) mutagen 1,20 (TA1538 +S9: 330 revertants/lO0 ~ig [1]) Mouse lymphoma mutagen 11,15 Reference to use in hair dyes * Note: m-phenylenediamine is listed as NCI Compound 24 in NCI Technical Reports, September 1976 PAGENO="0411" 2,5-diaminoanisole CANCER TEST not under test by MCI 405 REFE~ENCE~ SHORT TERM TESTS Salmonella (Ames) E~cherichia coil i,2o 13 RESULTS mutagen mutagen Reference to use in hair dyes PAGENO="0412" 406 test has been completed; final results have not been determined RESULTS __________________ weak mutagen (TA1538 +S9: 40 revertants/lOO iig [1]) 2,5.~toluenedlamine SO~ CANCER TEST (NCI # C01832) (CAS # = 6369-59-1) REFERENCES 14 However, upon treatment of the chemical with peroxide, there is a 40-fold increase in mutagenicity SHORT TERM TESTS Salmo~ie11a (Ames) OTHER TESTS Terato~eni city in mice 1 ,2O RESULTS teratogen 26 Reference to use in hair dyes PAGENO="0413" 407 NR2 RC1 p-phenylenediamine'HCl (1,4-phenylenedlamine) N}~ `HCl CANCER TEST (NCI# = C03930) RE~ERENc~ positive in rats 18 positive (preliminary result of Nd) 14 SHORT TERM TESTS RESULTS Salmonella (Ames) very strong mutagen after addition of 1,20 peroxide (TA1538 +S9: 2400 revertants/20 ug Cl]) ~ros~h la mutagen . 3 Reference to use in hair dyes PAGENO="0414" 408 2~ni tro-p~phenyl enedi amine (2-nitro-l ,4-phenylenediamine) CANCER TEST (NCI# = C02222) (CAS# = 5307-14-2) positive (preliminary result of NCI) NH2 NO2 L~J NH2 REFERENCES 14 SHORT TERM TESTS Salmonella (Ames) Escherichia coli Yeast Chinese hamster cells Sister chromatid exchan9e in Chinese hamster cells Mouse lymphoma Mouse cells Human lymphocytes RESULTS mutagen (TA1538 +S9: 700 revertants/50 ~ig [1]) mutagen mutagen chromosome aberration positive 16 1 ,20 13 27 7,9 mutagen showed chromosomal breakage and had exchange figures, morphological transformation observed chromosomal aberration observed 15 2 19 Reference to use in hair dyes 1 ,23 PAGENO="0415" SHORT TERM TESTS Salmonella (Ames) Escherichia cpfl Yeast Drosophi 1 a Mouse lymphoma Mouse cells 1 ,20 13 27 3,5 15 2 7,9 16 409 NH2 4-nitro-o-phenylenediamine NH2 0 CANCER TEST (~cI# C03941) N02 (CAS# = 99-56-9) test has been completed; results have not been announced as yet RE FE REN C ES 14 RESULTS mutagen (TA1538: 3300 revertants/50 ~tg [1]) mutagen mutagen mutagen mutagen significant number of chromosome breaks and rearrangements, morphological tra~isformatiOnS observed chromosomal damage (breaks and exchanges), aberrations positive Chinese hamster Sister chromatid exchange in Chinese hamster cells Reference to use in hair dyes 1 ,23 PAGENO="0416" 410 NH2 o-phenylenediamine NH2 .RC]. CANCER TEST* REFERENCES positive (preliminary NCI result) 14 SHORT TERM TESTS RESULTS Salmonella (Ames) mutagen 1,20,22 (TA1538 +59: 145 revertants/lOO ~ig [1]) mutagenic activity was increased when 22 peroxide was added Reference to use in hair dyes * Note: o-phenylenediamine is listed as NCI Compound 25 in NC~ Technical Reports, September 1976 PAGENO="0417" CANCER TEST not under test by NCI 411 2ami no-S-ni trophenol NO2 ~ SHORT TERM TESTS Salmonella (Ames) RESULTS mutagen REFERENCES 1 ,20 Reference to use in hair dyes PAGENO="0418" 412 2-amino~4-nitropheno1 NO2 CANCER TEST REFERENCES not under test by MCI SHORT TERM TESTS RESULTS Salmonella (Ames) mutagen 1,20 Reference to use in hair dyes 1 PAGENO="0419" C~~i~SI ~NCT# C03963) pøs~tive (pre~1mfn~ry ,~e~u1t) SH0~T TERM, 1E~TS Tiorleli a iAm~1 SLJ~IS muta~efl (1A1538 +$~ 50 ~`evè~tants/100 ~kç~ [6]) 6,20,25 Reference to use in heir dyes 10 41~3 4-amin~-2~ni trop.hertOl ~FE~tNCES 14 PAGENO="0420" 414 NH2 0 NH2 Disperse Blue #1 (1 ,4,5,8-tetraaminoanthraquinone) Q NH2 0 NE2 CANCER TEST (NCI# = C54900) RErEREJ~CES~ES under test 14 SHORT TERM TESTS RESULTS Salmonella (Ames) mutagen 24 (TA1 537 +S9) Reference to use in hair dyes 23 PAGENO="0421" 415 Direct Black #38 CANCER TEST REFERENCES positive 14 SHORT TERM TESTS RESULTS Salmonella (Ames) mutagen 25 (TA98 +S9: 294 revertants/100 ~g [25]) Reference to use in hair dyes 28 PAGENO="0422" 416 1~irect Blue #6 CANCER T~ST REFERENCES posilive 14 SHORT TERM TESTS RESULTS not tested Reference to use in hajr dyes 28 PAGENO="0423" 4~ch1 oro-Ophenyl enëdiarhir~e ~ (NCI# CO~292) positive (pre~iminary ~e~u1t) 417 14 SI1OJ~T, 1~ERr~ TE~r$~ ~P11~1~8.. (i!ie~j RESULTS mutagen (TA1538 +S9: 96 revertants/400 ~~g) ~fer'ence to u~e in hair dyes 10 25 PAGENO="0424" o-anisidine 418 CANCER TEST (NCI# = C03747, hydrochloride) (CAS# = 134-29-0) positive (preliminary result) __________________ RESULTS __________________ mutagen (TA1538 + Norharman +S9: 45 revertants/50 ~ig) REFERENCES 14 SHORT TERM TESTS Sa1mo~ne1la (Ames) 25 Reference to use in hair dyes 10 PAGENO="0425" 4th N~phenyl .-p-phenylenediamine CAP1CER TESt (NCI# C02233) REFERENcI$ negative (preliminary result) 14 SHORT TERM TESTS RESULTS ~1mone1la (Ame~) not, a mutagen ~eference to use In hair dyes 10 24-600 0 - 78 - 28 PAGENO="0426" 420 1 phenyl-3 methyl-5-pyrazolone CANCER TE~1 REFERENCES negative (preliminary result) 14 SHORT TERM TESTS RESULTS Salmonella (Ames) not a mutagen 25 Reference to use in hair dyes 10 PAGENO="0427" 421 resorcinol (1,3~banganedio1) CN~CER TEST REFERENCES negative 14 SHORT TERM TESTS RESULTS S~1rn~ne11a (Ames) not a mutagen 1 Reference to use in hair dyes 10 PAGENO="0428" 422 OTHER HAIR DYE RELATED CHEMICALS UNDER STUDY BY NCI Preliminary result Evidence of use ncer test in hair dyes C03758 p-anjsidine hydrochlorj~e 10 C03305 4~chi oro-m-phenylenediamine P'p'(methylene)-bis~(N,N_ dimethylanil me) C54911 Acid Orange #3 23 C04159 IC Blue #1 C54897 HC Blue #2 C54922 HC Red #3 PAGENO="0429" 423 REFERENCES 1. Ames, B. N., Kammen, H. 0., and Yamasaki, E. (1975): Hair dyes are mutagenic: Identification of a variety of mutagenic Ingredients. Proc. Natl. Acad~Sci. USA 72: 2423-2427. 2. BenedIct, W. F. (1976): Morphological transformation and chromosome aberrations produced by two hair dye components. Nature~Q,: 368-369. 3. Bli,jleven, W. 0. H. (1977): Mutageniclty of four hair dyes in Drosophila rne1anogaste~. Mutat. ~ 48: 181-186. 4. Dybing, E., and Thorgelrsson, S. S. (1977): Metabolic activation of 2,4-diaminoanisole, a hair-dye component. I. Role of cytochrome P-450 metabolism in mutagenicity ~p,vi~rp~. Blochem., Phar,~. 26: 729-734. 5. Fahmy, M. J., and F~ahmy, 0. G. (1977): Mutagenicity of hair dye components relative to the carcinogen benzidine in Drosophi1a~anoq~$i~~. Mutat. Res. 56t 31-38. 6. Garner, R. C., and Nutman, C. A. (1977): TestIng of some azo dyes and their reduction `products for mutagenicity using ~pionei,,.typ,h1mur1i~!, TA 1538. Mutat, Res. 44: 9-19. 7. Ishidate, M., Jr., and Odashima, S. (1977): Chromosome tests with 134 compounds on Chinese hamster cells i~yj~.r~--a screening test for chemical carcinogens. ~ ~ 337-354. 8. Ito, N., Hiasa, Y., Konishi, Y., and Maruganii, M. (1969): The development of carcinoma In liver of rats treated with rn-toluylenediamlne and the synergistic and antagonistic effects with other chemicals. c~rcer, Research 29: 1137-1145. PAGENO="0430" 424 9. Kirkland, D. J., and Venitt, S. (1976): Cytotoxicity of hair colourant constituents: Chromosome damage induced by two nitrophenylenedlamines in dultur~d Chinese hamster cells. Mutat. Res. 40: 47-56. 10. Narzulli, F. N., Green, S., and Maibach, H. I. (1978): Hair dye toxicology. In Hair and Hair Disease, C. E. Orfanos, ed. (Stuttgart and New York: Gustav Fischer Verlag, in press). 11. Matheson, D., and Creasy, B. (1976): Use of the LS17GY (TK~"') mouse 1ym~homa cell line coupled with an in vitro microsomal enzyme activation system to study chemical promutagens. Paper presented at the Seventh Annual Meeting of the Environmental Mutagen Society, March 12-15, 1976, Atlanta, Georgia. 12. Merck Index (1976). Ninth edition. F~ahway, New Jersey: Merck & Co., Inc. 13. Mohn, 0. R., and de Serres, F. J. (1975): On the mutagenk activity of some hair dyes. Paper presented at the Fifth Annual Meeting of the European Environmental Mutagen Society in Florence, Italy. 14. NCI Bioassay Program. Richard A. Grie~emer, Associate Director for Carcinogenesis Testing Program, Division of Cancer Cause and Prevention, National Institutes of Health, Bethesda, Maryland 20014. 15. Palmer, K. A., Denunzio, A., and Green, S. (in press). The mutagenic assay of some hair dye components using the thymidine Kinase 1ocu~ of L5178Y mouse lymphoma cells. J.Env, Path. and Toxico1~ 16. Perry, P. E., and Searle, C. E. (1977): Introduction of sister chromatid exchanges. in Chinese hamster cells by the hair dye constituents 2-nitro-p- pheny1ene~liamine and 4-nitro-o-phenylenediamine. Mutat. Res. 56: 20~-21O. PAGENO="0431" 425 17, Pienta, R. J,, Shah, ti, J., Lebherz~ N, B., UI, and Andrews, A. W. (1977): Correlaticrn ~f bacterial mutagenicity and hamster cell trans~ fprmation with tumorigenicity induced by 2,4-toluenediamine. Cancer Letters 3: 45-52, 18. Saruta, N., Yamaguchi, S., and Nakatomi, V. (1958): Sarcoma produced by subdermal administr~tiOfl of p~raphenylenediamine. K1ushuJ. Med,Sci, 9: 94. 19. Searle, C, E., Harnden, 0. 6., Venltt, S., and Gyde, 0. H. B. (1975): Carcinogenicity and niutagenicitY tests of some hair colourantS and constituents. Nature 255: 506-507. 20. Sugimura, T. (1975). Paper presented at the Fourth Joint Conference for Evaluating Environmental tlutagenesls and Carcinogenesis, Seattle, Washington, 21, Umeda, N. (1955): Production of rat sarcoma by injections of propylene glycol solution of rn.toluenediamine, GAMN~: 597-606. 22. Venitt, S., and Searle, C. E. (1976). Mutagenicity and possible carcinogenicitY of hair colourants and constituents. INSERM Symposia Series, Vol, 52, IARC Scientific Publications No. 13. Envirl PollutIon and CarciflQg~pj9 Risk, pp. 263-272. 23. Wernick, T., Lanman, B. N,, and Fraux, J, L, (1975). Chronic toxicity, teratolo9ic, and reproduction studies with hair dyes. Ig~col.Al. Pharmacol. 32: 450-460. 24. Brown, J. P., and Brown, R. J. (1976), Mutagenesis by 9,10_anthraquinofle derivatives and related compounds in Salmonefla tyfihlmurium. Mutat.Re$, 40: 203-224. PAGENO="0432" 426 2S. Yamasaki, E., and Ames, B. N. (unpublished). 26. Inouye, M., and Murakami, U. (1977): Teratogenicity of 2,5-diaminotoluene, a hair-dye constituent in mice. Fd. Cosmet. Toxicol. 15: 447-451. 27. Vernon Mayer, FDA, personal communication 10/20/77 with Or. J. Highland, from Testimony of the ~nvironmental Defense Fund Before the Subcommittee on Oversight and Investigation of the House Committee on Interstate and Foreign Commerce on the Subject of Cosmetic Safety. January 25, 1976. 28. Cancer and coal tar hair dyes: An unregulated hazard to consumers. U.s, Gener4l Accounting Office, December ~, 1977. (From EDF reference in #27.) PAGENO="0433" `Proc. Nc~ Amid. 8cs~ USA Vol 72, No. 6, pp. 2423-2427, June 1975 427 Hair Dyes Are Mutagenic: Identification of a Variety of Mutagenic Ingredients Qsairdyea as poasibiehuinan carcinogens and mutagene/2,4.ilianxinoanleole/2,4..dismi,iotoluone) BIIUCE N. AMES, H. 0. KATVIMEN, AND EDITh YAMASAKE Biochemistry Department, Ui,iversity of (~aiifornia, Berkeley, Calif. 54720 5 Contributed by Itruce N. Amoco, 111 arch 13, 1076 ABSTRACT We have previously described a sensitive bacterial teat for detecting carcinogens as snutagens. We chow here that 89% (150/169) of contmuercialoxidative..iype (hydrogen peroxide) hair dye, formulations are mmmtagenic in this teat. Of the 18 coniponents of these lists dyes, nine show varioua degrees of mutagenicitys 2,4-dian,inoanisolc, 4..nitro..o.plsenyiencdianiine, 2-nitro-p-phonylcne,ii. amine, 2,5-diaminoanls,sle, 2-amino.5.nitrophenol, en- phenylenediamine, o-phenylenedian,inc, 2-amino.4- nitrephenol, and 2,5-diaminotoluene, Three hair dye com- ponents (p~phenyienediamine, 2,5-diaminotoiuene, and 2,5-diaoninoanisole) become strongly mutsgenic after oxidation by lt,O,s tue mutagenic product of p-phenyiene.. diasnine is identified as the known trinser, Bsndrowskl's base. 2,4*Diaminotoiuene, a -hair dye component until recently, is also shown to be mutagenics this compound has been shown to be a carcinogen in rats, and is used in large amounts in the polyurethane foam industry. About 20,000,000 people (mostly women), dye their hair in the U.S. and the hag*rd could be, considerable if these chcsni. eels areactualiy mutagenleand carcinogenic in humans. We have previously described a very sem~sitive and simph' bacterial test for detecting chemical mutagelie (1-3), Ph' compounds are tested on petri idats with specially cum- strutted mutants of Salmonella typhisturism no tester straits. Several tester straits were selected for sensitivity awl timed. fleity in being reverted from a histidi,,c' requirement back to prototrophy by a variety of mnutageur, One strain (TA1535) detects mutagene lancing base-pair subetitutione and two (TA1537 and TA1538) detect various- kinds of framrshift mutagens. In additiosi to the histiditmo mutation, we have added to each tester strain two additional mutations that greatly Increase its sensitivity to mutagens: otto causes lose of the excision repair system and the other loss of the iipo. polysaecharide barrier that coats the surface of the bat- tern (2). A large number of carcinogens have been shown to be mutagens which cause base-pair substitutions in our test (1-3). Other earcinogenswitharomaticrings have been shows, to cause fraineshift mutations (2-6). We have showi, that by adding a microsontal activation system of rat (or lttssmmast autopsy) liver tothe petri plates, a wide varietyofearoinogene can be detected as scutagens after they have been mn,'tnb- olized to their active forms (refo. 3, 7-9; amid unpublished data~. Thus, an important sheet of mammalian motaboliossi can be duplicated in an in vitro test. The present work stems from a biochemistry class experi- ment in which hundreds of commercial products were tented for mutagenicity. Only two iwoducts were found to be touts- genie: cigarette smoke tar (8) and-nit oxidative-typc hair dyo. Since 20,000,000 people (10), main'y women, dye their Isair - in the ~1.S. we have made a detailed study of hair dye mute. gemlicity. `lIe two usia types of lair lyre sro tic "semi.pcrnnanrit'' - it lirect `lot dyes ml il "ix'rsntstet" or oxilative-type dyes is, which 1i50, is usem~ ttt oxidize ttrsttttitic (hatnnmrs will, tie prsehssctiost of larg,'r ,tl,,r,',l ss,ohecsml,,o whirls ire trappc(i is tIme hair olmaft. V,~s have com,ctsttrate,l 0mm tIme oxidative- type dyes simmer they ace(sszt for about 750/c (11) of the $250,000,000/year lair dye smmrkct. `i'l,c oxid,,tive lye pack- agt cossiists of cern bottle gosttais,ittg a mixture of aromatic tsntsmeo, aromatic J,itro sls'rivatives, and phestols iii a vehicle liqssitl (12, 13), mttsi a bottle of 11,0, with whirl, it is mixed insmneliately before moe. REStJL'i'S We first te'otsMl must 3(1 e,ximlativm'-type l,air lye fom'smmulatiomss fir reves'sisss~ of sir ,mtas,,lar,l toter ,`t-stmsmie. Alimost all of lIen' wets' sm,utagetit' n-I,,', teote,l os st-miss TA1538, i,,,Iicat- itsg tIme lrodctits of fs'tssnesl~ift-ty~s' - mutation. Strait `l'Ah53.5 ems ,s,t rev,'rt.,.,l, isahieatis,g a lack of base-pair sssl,stittmtitm, ssmsmtathmt,o; tIn' ,mth,'r frasn,'slift tests'r strain, `i'Ah1137, wills a tliilt'r'nI s~o',ihicity Is,, mess sot reverlel, We lniv,', tl,,'r,'form., owl strait, .TAI53K I, test 169 ,liiT,'r,'nt oxhhativm'4y~o' sly' formt,jslntlosis; t-lmm'sc memo' all tim l1rsxl,a'ts we eosmld fistsl its two heal 1mg stores. E,tslm l,air lye ltr'ltara- tin,, Its seem listed botlm before amni aftm.m mixing with, 11,0,. A fs'w typical exatm,plt'o ace simow, in Table I a,,td Fig. 1. Ahsmiset all sf time dyes wire s1lmite snistagemie: 150 of 169 tested sir 20%, mmd almost mill retais,t'h activity miter pes'oxile treat- ssss's~t. We testeth prtohmsrt litton of eight thifferesst ,`oms,m,assies: (-`imsimol lime. (Mhnss,lnsm-is, `l'om,,'r Natssrahly ihio,mde, Miss (ittiroi (`recite Forsmnla litmir (~smlor lIatim, ilahsasmm (~olor (`ostditiosmimtg Shmatstpoo-itt lhnirenlor, (`owe Tosser Salos~ Forsmmnha Oil i$Imasnpsos `l'imtt, ihorsm llhomm,hm Lotiom, `!`os,er, `I'rsme Ibrummetto Time `l'rsme-('oior ihitir Color, Nice's, Easy); Jolts 11. hhreck, lsmc. (Iheatstifmsi Ihair ilrcek hair (~olor); Revlomm (Revlon cohorsilk); Ahbem't~-CuhPer (`o. (For Iirtssmettes Only); `Fussy Cosmetics, lime. (Ogiht'ic Shanmpoo-im, (`onshitioeimtg hair Color); (`ossmmmtir, isse, (L'Ors'ah l5referemice l5ertnastestt (`resmue-im, iistireohssr, L'Oreal Exeelhs'm,ee l't'rssssts'mtt hair (`csissr); `rite (uiihettc' (n (`l'ommi Shtamnltcmo-casy lhaire-ohtsri,mg for lstn,sa'mtt (`oler); ltoimx l4ml,orttt,ries 1st. (ltosmx fasteitonc cr55155' Hair `lint). Mntngem,ie hmmtir slyt.s were fotmm,sl in every hair thye h,rohlmct line tinted. `l'abhsm I shows that sonic of thìe hyes were mmumtagemmie tlim'eethy, witimout msmicronosmumi aetiva- tloms, wlscreas titers requiresl mnicroeomai aetivatios, (athditlomm of 6-9 mix). ha athhitioss, sonic of time thyes Were m~ot mtstagcit~e umstli they were mm,ix,'tI with hi./)s. `l'Itsms, tlmem'e msisst se at least three hitlerm'mmt iigri'shk'mtts resisomioibsbe for sssstngesmicity. Eighsteest shihfes'esst s,hss'ntis'alo are seed is oxitl,stivsm hs,mir dyes Its tIme U.S. us mishshitk,sm to limOs misish tIssue 1mm tIme vs'h,lcle liquid (C. Burnett, jmer~omnl eomsmssummlesttiomm), aismsi imshtsstry PAGENO="0434" 428 Medical Sciences: Ames .1 aL Ppoc. Na& Aced. Sci. USA 72(1975) f--ayMS Brsse Ttnne 1. Mulagenic aclivily of hair dyes - in reverting stPain TAJSS8 4 Revestant colonies per spot° I Mixedwith I Hair dyof Ha04 -59 +89 -59 +59 Medium Golden Brown no. 612 555 176 294 173 (Clairol Balsam Color) Natural Dark Brown no. 120 131 151 84 244 4 (Clairol Nios'N Easy) Pale Ash Blonde no. 120 2 69 0 35 * (Toni Innocent Color) MediumBrownilo.17 0 3 0 267 (Breck Shampoo.in Hair Color) Fr Light Golden Brown no. 7 4 0 0 3 (Breck Shampoo.in Hair Color) Pro. 1. S5ot tests on petri plates showing the mutagenicity of various hair dyes on strain TA1538: Moonhase no. 32 (Miss * Control values have been subtracted (<12 colonies). The Clairol), Moonlit Mink no. 360 (Clairol Born Blonde), Wild dyes were found to be sterile. Values greater than 10 colonies Fire no.32 ltoux fancitone) (all tested without peroxide), and overthe control valuewereinterpreted aspositive. Frivolous Fawn no.23 (Roux fancitone) (mixed with H,O, as per t A drop (about 40 pl) of a freshly opened bottle of hair color instructions). The procedure was as described in Table 1. Con- was spotted on a petri plate containing tester strain TA1538 tool plates without hair dyes are on the right. Plates B, but not in a thin agar overlay (3) and, where indicated, 5.9 Mix (3)con- A, contain liver microsomes (S.9 Mix). Smokey Ash Brown no. taming ~at liver homogenate from rate induced with Aroclor 775 end Natural Black no.83 (Clairol Loving Care) are semi- l254wasadded (8). permanent, non.oxidativetypedyes(seetexl). (The hair dye was mixed (in a sterile tube) with an equal volume of hydrogen peroxide supplied by the manufacturer, has kindly supplied them to us. The results of mutagenicity as per instructions. Since the drop size was the same (40 grl), tests are shown in FIg. 2. Nine of the hair dye chemicals the numbere should be doubled to make them comparable to the tested are mutagenic and their potenciea in reverting ~ uninixeddye. TAl538covera200-foldrange. Wealsoshow the mutagenicity . of 2,4.dzamsnotoluene, a chemical that was removed from hair ________ _____________________ dyes in 1971 after it was shown to be a carcinogen when fed * to rats (14). The hair dye component that was most active 4055 400 in reverting TA1538 is the very closely related compound 2,4- / / .noarsn diaminoanisole (a CH5O- group is substituted for a CII,- /L / group) which we find is about 30 times more active than the I // / toluene derivative. Addition of human (3) or rat liver micro- am II ioo / a~eacs.S.~. comes gives very similar results with these two compounds. ee..ae // . / We have previously shown that many carcinogenic aromatic .~ ~J ft / s~'s amines or aromatic nitro compounds revert strain TA1538 1 /1 / (3, 9). For example, we have repeated our dose-response 2005 // 20 / ~ curve for benxidine2HC1 (3), an aromatic diamine which is .! / ~ / a carcinogen for humans, and find it similar in activity to ~ I I as45 . .,ssnsz m-phenylenediamine. The dose-response curves have been 1, / duplicated with the purest chemicals available commercially ices fj zoo / (Aldrich orEsstman).Nevertheless,manyofthes000mpOunds 1 7 . ~ are easily oxidized in sir and it is quite poesible that these / - °~ (or other) impurities could account for the inutagenicity of ______ some of the less active compounds (see below). 0~ z~o e~ so ~ The aromatic amines (Fig. 2) all require activation with mcrcsomes (5-9) for mutagenesis; this is characteristic of a 5,55405 Csngs,i,id 555 POtTS Plate variety of aromatic amine carcinogens (3, 5, 7-9). Nitro Foo.2. Dost-vesponas curves of the mutagsnicity of hair dye carcinogens, such as 2-nitrofiuorene, mutate the bacteria dssanicals for tester strain TA1538. Reversion was determined without inicrosomal activation (2, 9) because the bacteria on petit plates by incorporating the chemical mutagen, bacteria, contain nitro reductases which activate them (asdo roam- and microsoanal activation system where indicated (ass legend to malian cells). Thus, 4-nitro-o.phenylenediamine could account ~ R~tewere~7