- Email: [email protected]
The cosmetic ingredient review—a safety evaluation program
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The Cosmetic Ingredient Review evaluation program
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Robert L. Elder, Sc.D. Washington, DC A review of the procedures, methods used, and the data that are required to evaluate the safety of cosmetic ingredients is presented. The results of the program and the limitations placed upon the use of some ingredients are discussed. (J AM AcA• DERMATOL11:1168-1174, 1984.)
The Cosmetic Ingredient Review (CIR) was established in 1976 by the Cosmetic, Toiletry and Fragrance Association (CTFA) to review and document information on the safety of ingredients as used in cosmetic products. The CIR program was to be the cornerstone of the cosmetic industry's self-regulatory effort. In serving this purpose it would also provide to dermatologists an authoritative source of safety test data on cosmetic ingredients. CTFA recognized that acceptance of the program and its results would depend on three major factors: (1) the safety review process had to be conducted with no cosmetic industry bias; (2) the Panel of Experts who would review the safety test data on each ingredient had to be given complete independence; and (3) the review process, the reports, and all of the data used in the safety evaluation had to be available for public and scientific scrutiny. These three major requirements were codified into formal, written procedures that established CIR as an independent, nonprofit organization, x CIR staff and all consultants were to be separate from CTFA and the cosmetic industry and must pass the same conflict of interest requirements stipulated for special federal government employees. All reports were to be discussed and Reprint requests to: Dr. Robert L. Elder, Director, Cosmetic Ingredient Review, 1110 Vermont Ave. N W , Suite 810, Washington, DC 20005.
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voted on in a public meeting before being released for a 90-day public comment period without prior industry review. And finally, all data, published or unpublished, used by the CIR Expert Panel would be available for public review. 1 The p r o g r a m Policy guidance for the CIR program is provided by a five-person Steering Committee chaired by the president of CTFA. William Jordan, M.D., professor of dermatology, Medical College of Virginia, was appointed by the American Academy of Dermatology in 1981 to succeed Richard L. Dobson, M.D., professor and chairman, Department of Dermatology, Medical University of South Carolina, who had been appointed by the Academy to serve on the Committee during its developmental stages. Joseph Borzelleca, Ph.D., professor of toxicology and pharmacology, Medical College of Virginia, was appointed to the Committee by the Society of Toxicology. Two scientists from industry--the current chairman of CTFA's Scientific Advisory Committee and CTFA's senior vice-president for Science--also serve on the Committee. The Steering Committee has no input into the scientific evaluations of the CIR Expert Panel. One of the Steering Committee's major responsibilities is the selection of the seven-member CIR Expert Panel. This is done following a public announcement requesting nominees. Current members of the CIR Expert Panel are as follows:
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Number 6 December, 1984
Karl H. Beyer, Jr., M.D., Ph.D., Sc.D. Chairman, Visiting Professor of Pharmacology Penn State Medical Center Arnold L. Schroeter, M.D. Professor of Dermatology, Mayo Clinic Mayo Medical School William O. Berndt, Ph.D. Dean for Graduate Studies and Research University of Nebraska Medical Center Ronald C. Shank, Ph.D. Professor of Toxicology, College of Medicine University of California, Irvine Wilma F. Bergfeld, M.D. Head Dermatopathology and Staff Dermatologist Cleveland Clinic Foundation Dietrich K. Hoffmann, Ph.D. Associate Director and Chief Division of Environmental Carcinogenesis American Health Foundation William W. Carlton, D.V.M., Ph.D. Professor of Veterinary Pathology and Toxicology Purdue University Three nonvoting members assist the Expert Panel and attend the public meetings. These include a consumer representative (appointed by the Consumer Federation of America), an industry liaison, and a Food and Drug Administration (FDA) "contact person." The Expert Panel meets six times per year. Three meetings are report drafting sessions and three meetings are for public review and discussion of the report under consideration.
Ingredient review priority Approximately 3,500 ingredients are listed for use in cosmetic formulations. Data voluntarily submitted by industry to the Food and Drug Administration (FDA) indicate that approximately one half of these are in use at any one time. The reported frequency of use in different cosmetic products may range from over 7,000 to only one or two uses. In preparing the 1984 CIR Ingredient Review Priority List, ingredients that were reported to the FDA as being used in at least twenty or more cosmetic formulations were evaluated. The priority order of ingredient review is established by using a weighted formula that includes
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factors for: ingredient concentration in cosmetic products, number of products containing the ingredient, frequency of consumer use, area of use, use by sensitive population subgroups, biologic activity, estimate of penetration, and frequency of consumer complaints about products containing the ingredient. The ingredient review priority list is reevaluated every 4 years. Ingredients specifically regulated by the FDA, such as color additives, are exempt from CIR review. Any ingredient that is being evaluated by the FDA under the OverThe-Counter Drug Review (OTC) or for use as a Direct Food Additive is deferred until that review is completed. Fragrance materials are being evaluated separately in a program sponsored by the Research Institute for Fragrance Materials (RIFM) and are not included in the CIR review program. The CIR ingredient review list is developed as described and then issued for public comment before it is forwarded with all the comments to the Expert Panel for their review and approval. The Expert Panel may at any time add, delete, or change the order of ingredient review without requesting concurrence by the Steering Committee. Analysis of the status of the most frequently used cosmetic ingredients is shown in Table I. The review process After prioritizing, the review of each ingredient goes through several stages. The staff of CIR prepares a Scientific Literature Review summarizing the published information and publicly requests any relevant published or unpublished data that the review does not already include. Individually, ingredient suppliers and cosmetic manufacturers have tested ingredients, as well as formulations, for many years. Although much of these data have been published, a significant portion are in industry files and not available for public or scientific review. The collection of these data and the test protocols used to produce the data are critical to the success of the program. At the end of a 90-day public comment period, all submitted data are incorporated into a document for consideration by a subgroup (Team) of the Expert Panel. From 25% to 75% of the data included in the CIR reports has not been published previously.
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Table I. Ingredients reported to the FDA to be used in twenty or more cosmetic formulations* No.
Reviewed by CIR Under review by CIR OTC or direct food additives Regulated ingredients RIFM (fragrance) Candidates for 1984 priority listing Total
182 62 136 99 18 231 728
*FDA: Cosmetic Product Formulation Data. Computer printout. Washington, DC, July 8, 1983.
Teams meet in a series of closed working sessions to evaluate the report and determine whether there are sufficient data upon which to base a conclusion. A document reflecting those considerations is then prepared for review by the full Expert Panel. After discussion of this document in public meetings of the full Panel, a Tentative Report is issued with one of three conclusions: (1) that the ingredient is safe as currently used, (2) that the ingredient is unsafe, or (3) that there is insufficient information for the Panel to make a determination of safety. It is significant that CIR procedures require documented evidence giving reasonable assurance o f safety before reaching the final determination. Lack of adverse information about an ingredient is not sufficient to justify a determination of safety. The Tentative Report is then made available for a 90-day public comment period. All comments in response to the Tentative Report are analyzed and submitted to the Expert Panel. A Final Report, incorporating any substantive changes resulting from public comment, is then released by the Expert Panel.
Data requirements The type and amount of data required for the Expert Panel to fulfill its charge that "there is a reasonable certainty in the judgment of competent scientists that [an] ingredient is safe under its conditions of u s e " may vary from one ingredient to another. 2 The adequacy of data for each ingre-
dient is judged on the basis of the ingredient's potential for human exposure in cosmetic products. Some formulations are applied to, and remain in, contact with the skin for extended periods of time; others are diluted and rapidly washed off. Dr. Karl H. Beyer, Jr., chairman of the Expert Panel, has noted that "the purpose of the Expert Panel is to determine the safety of an ingredient rather than how well the literature fulfills an adequate safety a s s e s s m e n t / " It is seldom that any safety assessment on a cosmetic, food, or drug has as much information as one would like. The Panel has rendered final decisions on the safety of an ingredient when the data were minimal but adequate for its intended use. Yet, in an equal number of cases the Panel has delayed its decision until additional tests were performed. The Panel has been extremely cautious when there were minimal data, particularly for those ingredients whose molecular structure, chemical characteristics, cosmetic use, and potential for biologic activity have warranted further investigation. When further data are needed, the public and the industry are notified through an Insufficient Data Announcement listing the types of data required by the Panel. If any party agrees to undertake the needed testing, the Panel defers the safety evaluation until the data are received. If there is no response to the request for additional data, a Final Report, containing the available data and the specific tests that are required before reasonable assurance of safety can be ascertained, is issued. (Nine Insufficient Safety Data Announcements have been issued.) Many cosmetic ingredients have been reviewed previously for safety by government and other scientific groups. FDA's GRAS Review for food safety and the OTC Drug Review, for example, are significant sources of data and safety evaluations for the Expert Panel. If an ingredient has been ruled as safe at equivalent concentrations for food use, the Panel would need less extensive additional test data on chronic and subchmnic effects. The Expert Panel's report on this ingredient would include the earlier evaluation and update the published review by including any new test data available after the government's report was
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issued. The Panel does, however, give special attention to any dermal and ocular data included in these earlier safety evaluations by including the detailed information in the CIR report. Data on mutagenicity, teratogenicity, and carcinogenesis are reviewed by the Panel. Often, thses data, or an ingredient with a similar molecular structure, have already been evaluated. The Panel uses this information in concluding "with reasonable certainty" that further testing is not required. In some specific cases the Panel has requested additional testing even though data on ingredients with similar chemical structures were available. For example, negative mutagenesis test data were available for benzophenone 1, 3, 4, 5, 9 and 11; however, the Expert Panel requested new tests for Benzophenone 2, 6, and 8 before a Final Report on those ingredients was issued. Data from metabolism and animal studies are carefully studied and considered for their applicability to human skin exposure. However, no report indicating a cosmetic ingredient is safe has been issued by the Expert Panel without human skin test data that confirmed the results found in animal tests. The test data for human skin irritation, sensitization, and photosensitization must be from tests conducted at ingredient concentrations at least as great as that of the normal concentration of ingredient use in cosmetic formulations. The Expert Panel has accepted negative ultraviolet light absorption data (UVA and UVB) for some cosmetic ingredients in lieu of additional human photosensitization test data when the ingredient's molecular structure indicated these wavelengths were not absorbed by the ingredient (and, therefore, one would not expect a chemical change to occur to transform the ingredient into a phototoxic agent). The determination of safety requires judgment. Rarely has any pure ingredient had every type of test data that can be obtained from a modern toxicologic testing laboratory. The Panel has accepted extensive finished product formulation test results when there are minimal, but equivalent, animal and human test results on the pure ingredient. The Panel's conclusions are always made on the basis of available data. Should new adverse
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Table II. Reports issued by CIR
Final reports Reports under review Total
No. of reports
Number of Ingredients included
65 23 96
182 62 244
data become available, the Panel reevaluates its previous conclusion and recommendations and issues an Addendum to the earlier report. RESULTS As of July 1, 1984, the Panel has issued sixtyfive Final Reports on 182 ingredients. Reports on another sixty-two ingredients are at various stages of development (Table II). In the course of completing these reports, the Panel has had to issue nine Insufficient Data Announcements. The cosmetic industry funded the needed test programs on all of these except one: O-Cymen-5-ol. Most of the requested test programs were completed by industry within 6 months of CIR's issuing the Insufficient Data Announcement. The Expert Panel has not released a report indicating any ingredient to date is unsafe. One report, O-Cymen-5-ol, was released stating that there were insufficient data to judge the safety of use of this ingredient in cosmetic products. Qualifications have been expressed in the conclusions of thirteen other reports on twenty-seven ingredients. The full reports on these ingredients present the discussions and rationale for these decisions. A summary of the Panel's conclusions on each of these fourteen reports is as follows: Report on O-Cymen-5-ol. There are a lack of safety test data on skin absorption, chronic oral toxicity, human skin sensitization, phototoxicity, photoallergenicity, and mutagenesis. The CIR Expert Panel concluded that the available data were insufficient to judge the safety of use of OCymen-5-ol in cosmetic products. Report on benzethonium chloride and methylbenzethonium chloride. Due to skin and ocular irritation above 5.0%, the conclusion is qualified for safe use at 0.5% in cosmetics applied to the
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T a b l e I l l . Ingredients sate for use in cosmetic products at present practices of use and concentration Acetylated lanolin Acetylated lanolin alcohol Almond meal Aluminum distearate Aluminum tristearate Ammonium laureth sulfate Ammonium stearate Avocado oil Beeswax Benzophenone 1 Benzophenone 2 Benzophenone 3 Benzophenone 4 Benzophenone 5 Benzophenone 6 Benzophenone 8 Benzophenone 9 Benzophenone 11 Butane Butylated hydroxyanisole Butylene glycol Calcium stearate Candelilla wax Caprylic/capric triglyceride Carnauba wax Ceresin Cetearyl octanoate Cetyl lactate Cetyl palmitate Choleth 24
Glyceryl stearate Glyceryl stearate SE Glycol distearate Glycol stearate Glycol stearate SE Hexylene glycol Hydrogenated lanolin Hydrolyzed collagen Hydroxylated lanolin Imidazolidinyl urea Isobutane Isodecyl oleate Isopentane Isopropyl lanolate Isopropyl myristate Isopropyl palmitate Isostearyl neopentanoate Japan wax Laneth 5 Laneth 9 acetate Laneth 10 acetate Laneth 16 Laneth 25 Lanolin Lanolin acid Lanolin alcohol Lanolin oil Laureth 4 Laureth 23 Lithium stearate
Decyl oleate Dehydroacetic acid Dibutyl phthalate Diisopropyl adipate Dimethicone copolyol Dimethyl phthalate Dioctyl adipate Dipropylene glycol
Magnesium stearate Microcrystalline wax Montan wax Myristyl lactate Myristyl myristate
Emulsifying wax N.F. Ethoxydiglycol
Nonoxynol 2 Nonoxynol 4
skin and 0.02% is safe for cosmetics used in the eye area. R e p o r t on 2 - b r o m o - 2 - n i t r o p r o p a n e - l , 3 - d i o l (BNPD). BNPD is a skin irritant at 1.0% and may interact with amines to form nitrosamines. The conclusion limits use to 0.1%. BNPD should not
Nonoxynol 8 Nonoxynol 9 Nonoxynol 10 Nonoxynol 12 Nonoxynol 14 Nonoxynol 15 Nonoxynol 30 Nonoxynol 40 Nonoxynol 50 Octyl dodecanol Octyl palmitate Oleyl alcohol Ozokerite Paraffin PEG 20 lanolin PEG 27 lanolin PEG 30 lanolin PEG 40 lanolin PEG 50 lanolin PEG 60 lanolin PEG 75 lanolin PEG 85 lanolin PEG 2 stearate PEG 6 stearate PEG 8 stearate PEG 12 stearate PEG 20 stearate PEG 32 stearate PEG 40 stearate PEG 50 stearate PEG 100 stearate PEG 150 stearate Polyamino sugar condensate Polybutene Polysorbate 20 Polysorbate 21 Polysorbate 40 Polysorbate 60 Polysorbate 61 Polysorbate 65 Polysorbate 80
Polysorbate 81 Polysorbate 85 Potassium-coco-hydrolyzed animal protein Potassium stearate Propane Propylene glycol stearate Propylene glycol stearate SE Quaternium- 18 Quaternium-18 Bentonite Quaternium-18 Hectorite Sodium dehydroacetate Sodium laureth sulfate Sodium stearate Sorbitan laurate Sorbitan oleate Sorbitan palmitate Sorbitan sesquioleate Sorbitan stearate Sorbitan trioleate Sorbitan tristearate Squalane Squalene Stearalkonium chloride Stearyl alcohol Sweet almond oil Synthetic beeswax Synthetic wax TEA-coco-hydrolyzed animal protein Vinyl acetate/crotonic acid Copolymer Wheat flour Wheat germ glycerides Wheat germ oil Wheat gluten Wheat starch Zinc stearate
be used under circumstances in which it may interact with amines and amides. R e p o r t on e a r b o m e r s 934, 910, 934P, 940, 941, and 962. Limited data are available at high cosmetic use concentrations, metabolism, mutagenesis, teratogenesis, carcinogenesis, as well as
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physicochemical characteristics. Available clinical data do, however, indicate low potential for skin irritation and sensitization. The conclusion states these ingredients are safe as used in cosmetics but the Panel qualifies that safety due to the limited data. R e p o r t on formaldehyde. Due to skin sensitization in some individuals, the concentration in cosmetic products should be as low as practicable, not to exceed 0.2%. It cannot be concluded that formaldehyde is safe for use in products that are intended to be aerosols. R e p o r t on isostearic acid. The conclusion states that this ingredient is safe for cosmetic use. However, concern is expressed on the potential to produce human comedogenicity. R e p o r t on methyl, ethyl, butyl, and propyl p a r a b e n s . These parabens are safe as cosmetic ingredients, but, due to the risk of increased sensitization, they are not recommended for use on damaged skin. R e p o r t on 2-nitro-p-phenylenediamine and 4-nitro-o-phenylenediamine. For those persons not sensitized, it is concluded that these two ingredients are safe as cosmetic ingredients. R e p o r t on p.phenylenediamine. This ingredient is a known sensitizer. For those persons not sensitized, it is concluded that this ingredient is safe as a hair dye ingredient. R e p o r t on propyi gallate. Human studies show significant sensitization at concentrations exceeding 10%. The conclusion states this ingredient is safe in cosmetic products at concentrations not exceeding 1.0%. R e p o r t on sodium borate and boric acid. These two ingredients are safe at concentrations less than, or equal to, 5.0%. Due to the increased absorption by damaged skin as compared to intact skin and available adverse animal test data, it is recommended that cosmetic products containing free sodium borate or boric acid at this concentration should not be used on infant skin or injured skin. R e p o r t on sodium lauryl sulfate and amm o n i u m lauryi sulfate. Both ingredients have been shown to be irritants following prolonged exposure at concentrations of 2.0% and greater.
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Possible hair loss and comedone formation have been reported. It is concluded that both ingredients are safe for discontinuous, brief use followed by thorough rinsing from the skin. For cosmetic products intended for prolonged contact with skin, concentrations should not exceed 1.0%. Report on triethanolamine (TEA), diethanolamine (DEA), and monoethanolamine (MEA). The Panel concludes that these ingredients are safe for brief discontinuous use followed by thorough rinsing from the skin. MEA should be used only in rinse-off products. Due to possible eye and skin irritation of TEA and DEA, products intended for prolonged contact should not exceed 5.0%. TEA and DEA should not be used in products containing N-nitrosating agents. Report on T E A - l a u r y l sulfate. Due to skin irritation at high concentration, the Panel recommends limiting the use concentration to a maximum of 10.5%. In fifty-one Final Reports on 154 ingredients, the Expert Panel has concluded that each ingredient is safe for use in cosmetic products at the present practices of use and concentration. They are listed in Table HI. The Board of Directors of CTFA added a final requirement when they approved the program in 1976. To assure the scientific adequacy and acceptance of all CIR Final Reports, the Board required that all reports were to be submitted to a refereed scientific journal for publication. Four collections of CIR reports have been reviewed and published in the American College of Toxicology's official journal.*,t,:~,w One collection was published in the Journal of Environmental Pathology and Toxicology, 2 Prior to journal publication, individual reports may be purchased from CIR. A listing of all reports and ingredients reviewed is available from the Admin-
*Elder RL, editor: Second Report of the Cosmetic Ingredient Review Expert Panel. J Am Coil Toxicol 1:1:177, 1982. ]Elder RL, editor: Third Report of the Cosmetic Ingredient Review Expert Panel. J Am Coil Toxicol 1:1-191, 1982. :i:Elder RL, editor: Fourth Report of the Cosmetle Ingredient Review Expert Panel. J Aln Coil Toxicol 2:1-178, 1983. w RL, editor: Fifth Report of the Cosmetic Ingredient Review Expert Panel. J Am Coll Toxicol 2:1-235, 1983.
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istrator, CIR, 1110 V e r m o n t Ave., N . W . , Suite 810, Washington, DC 20005.
SUMMARY Acceptance o f the p r o g r a m by the consumer, physician, industry, and g o v e r n m e n t can b e obtained only if the process reviews the n e e d e d scientific safety test data in an open f o r u m in which the data m a y be challenged b y any individual. The CIR program was designed and operates in a manner to meet this requirement. Sales and distribution of CIR reports are m a d e throughout the world; the inclusion and r e f e r e n c i n g of C I R reports in
major industry and government toxicologic safety data computer banks indicates that the results of the CIR E x p e r t Panel are being accepted as authoritative statements on the safety o f cosmetic ingredients. Subjecting these reports to a final external scientific review before publication in a recognized journal further supports this conclusion.
REFERENCES 1. Elder RL, editor: Cosmetic ingredients--their safety assessment. J Environ Pathol Toxicol 4:1-170, 1980. 2. Beyer KH: The Cosmetic Ingredient Review: A status report. Clin Ther 4:1-6, 1981.
ABSTRACTS A unique precipitating autoantibody against plasma thromboplastin antecedent associated with multiple apparent plasma clotting factor deficiencies in a patient with systemic lupus erythematosus Pooh MC, Saito H, Koopman WJ: Blood 63:1309-1317, 1984 As is well recognized, persons afflicted with systemic lupus erythematosus may produce autoantibodies that disturb coagulation profoundly and suddenly. In this case, factor 11 was inactivated. DetaiIs are given. P.C.A.
Systemic lupus erythematosns with paraproteinemia Rubin L, Urowitz MB, Pruzanski W: Arthritis Rheum 27:638-644, 1984 In the long-term prospective study of SLE in Toronto, of the 415 patients studied, nine (2.2%) had paraproteinemia, usually an IgG. No evidence of B cell lymphoma was discovered. P.C.A.
Local cutaneous recurrence after conservative excision of malignant melanoma Aitken DR, James AG, Carey LC: Arch Surg 119:643-646, 1984 Written by surgeons, this report notes that melanomas can be safely excised with a conservative (less than 5 cm) margin and that prognosis depends mostly on other factors. The group was followed up for a minimum of 5 years. P.C.A.
The effects of benzodiazepines on hormones in women with idiopathic hirsutism Dennerstein L, Callan A, Wame G: Prog Neuropsychopharmacol Biol Psychiatry 8:11-17, 1984 According to these authors in Australia, benzodiazepines may reduce androgens in some women with hirsutism. Do these popular medications reliably affect hormone balance? P.C.A.
Anaesthesia and severe skin disease Smith GB, Shribman A J: Anaesthesia 39:443-455, 1984 This is a review of the problems for an anaesthesiologist posed by various disorders of the skin, including urticaria pigmentosa, pemphigus, seleroderma, and more. P.C.A.
Lichen simplex chronicus during lithium treatment Shukla S, Mukherjee S: Am J Psychiatry 141:909-910, 1984 Persons who develop lichen simplex, as this patient did, while receiving lithium carbonate may have an adverse reaction not to the drug but to reentering ugly reality. When proper dermatologic topical therapy was established, the patient's eczema vanished and lithium therapy could be continued. P.C.A.
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The Cosmetic Ingredient Review evaluation program
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I
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a safety
Robert L. Elder, Sc.D. Washington, DC A review of the procedures, methods used, and the data that are required to evaluate the safety of cosmetic ingredients is presented. The results of the program and the limitations placed upon the use of some ingredients are discussed. (J AM AcA• DERMATOL11:1168-1174, 1984.)
The Cosmetic Ingredient Review (CIR) was established in 1976 by the Cosmetic, Toiletry and Fragrance Association (CTFA) to review and document information on the safety of ingredients as used in cosmetic products. The CIR program was to be the cornerstone of the cosmetic industry's self-regulatory effort. In serving this purpose it would also provide to dermatologists an authoritative source of safety test data on cosmetic ingredients. CTFA recognized that acceptance of the program and its results would depend on three major factors: (1) the safety review process had to be conducted with no cosmetic industry bias; (2) the Panel of Experts who would review the safety test data on each ingredient had to be given complete independence; and (3) the review process, the reports, and all of the data used in the safety evaluation had to be available for public and scientific scrutiny. These three major requirements were codified into formal, written procedures that established CIR as an independent, nonprofit organization, x CIR staff and all consultants were to be separate from CTFA and the cosmetic industry and must pass the same conflict of interest requirements stipulated for special federal government employees. All reports were to be discussed and Reprint requests to: Dr. Robert L. Elder, Director, Cosmetic Ingredient Review, 1110 Vermont Ave. N W , Suite 810, Washington, DC 20005.
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voted on in a public meeting before being released for a 90-day public comment period without prior industry review. And finally, all data, published or unpublished, used by the CIR Expert Panel would be available for public review. 1 The p r o g r a m Policy guidance for the CIR program is provided by a five-person Steering Committee chaired by the president of CTFA. William Jordan, M.D., professor of dermatology, Medical College of Virginia, was appointed by the American Academy of Dermatology in 1981 to succeed Richard L. Dobson, M.D., professor and chairman, Department of Dermatology, Medical University of South Carolina, who had been appointed by the Academy to serve on the Committee during its developmental stages. Joseph Borzelleca, Ph.D., professor of toxicology and pharmacology, Medical College of Virginia, was appointed to the Committee by the Society of Toxicology. Two scientists from industry--the current chairman of CTFA's Scientific Advisory Committee and CTFA's senior vice-president for Science--also serve on the Committee. The Steering Committee has no input into the scientific evaluations of the CIR Expert Panel. One of the Steering Committee's major responsibilities is the selection of the seven-member CIR Expert Panel. This is done following a public announcement requesting nominees. Current members of the CIR Expert Panel are as follows:
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Number 6 December, 1984
Karl H. Beyer, Jr., M.D., Ph.D., Sc.D. Chairman, Visiting Professor of Pharmacology Penn State Medical Center Arnold L. Schroeter, M.D. Professor of Dermatology, Mayo Clinic Mayo Medical School William O. Berndt, Ph.D. Dean for Graduate Studies and Research University of Nebraska Medical Center Ronald C. Shank, Ph.D. Professor of Toxicology, College of Medicine University of California, Irvine Wilma F. Bergfeld, M.D. Head Dermatopathology and Staff Dermatologist Cleveland Clinic Foundation Dietrich K. Hoffmann, Ph.D. Associate Director and Chief Division of Environmental Carcinogenesis American Health Foundation William W. Carlton, D.V.M., Ph.D. Professor of Veterinary Pathology and Toxicology Purdue University Three nonvoting members assist the Expert Panel and attend the public meetings. These include a consumer representative (appointed by the Consumer Federation of America), an industry liaison, and a Food and Drug Administration (FDA) "contact person." The Expert Panel meets six times per year. Three meetings are report drafting sessions and three meetings are for public review and discussion of the report under consideration.
Ingredient review priority Approximately 3,500 ingredients are listed for use in cosmetic formulations. Data voluntarily submitted by industry to the Food and Drug Administration (FDA) indicate that approximately one half of these are in use at any one time. The reported frequency of use in different cosmetic products may range from over 7,000 to only one or two uses. In preparing the 1984 CIR Ingredient Review Priority List, ingredients that were reported to the FDA as being used in at least twenty or more cosmetic formulations were evaluated. The priority order of ingredient review is established by using a weighted formula that includes
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factors for: ingredient concentration in cosmetic products, number of products containing the ingredient, frequency of consumer use, area of use, use by sensitive population subgroups, biologic activity, estimate of penetration, and frequency of consumer complaints about products containing the ingredient. The ingredient review priority list is reevaluated every 4 years. Ingredients specifically regulated by the FDA, such as color additives, are exempt from CIR review. Any ingredient that is being evaluated by the FDA under the OverThe-Counter Drug Review (OTC) or for use as a Direct Food Additive is deferred until that review is completed. Fragrance materials are being evaluated separately in a program sponsored by the Research Institute for Fragrance Materials (RIFM) and are not included in the CIR review program. The CIR ingredient review list is developed as described and then issued for public comment before it is forwarded with all the comments to the Expert Panel for their review and approval. The Expert Panel may at any time add, delete, or change the order of ingredient review without requesting concurrence by the Steering Committee. Analysis of the status of the most frequently used cosmetic ingredients is shown in Table I. The review process After prioritizing, the review of each ingredient goes through several stages. The staff of CIR prepares a Scientific Literature Review summarizing the published information and publicly requests any relevant published or unpublished data that the review does not already include. Individually, ingredient suppliers and cosmetic manufacturers have tested ingredients, as well as formulations, for many years. Although much of these data have been published, a significant portion are in industry files and not available for public or scientific review. The collection of these data and the test protocols used to produce the data are critical to the success of the program. At the end of a 90-day public comment period, all submitted data are incorporated into a document for consideration by a subgroup (Team) of the Expert Panel. From 25% to 75% of the data included in the CIR reports has not been published previously.
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Table I. Ingredients reported to the FDA to be used in twenty or more cosmetic formulations* No.
Reviewed by CIR Under review by CIR OTC or direct food additives Regulated ingredients RIFM (fragrance) Candidates for 1984 priority listing Total
182 62 136 99 18 231 728
*FDA: Cosmetic Product Formulation Data. Computer printout. Washington, DC, July 8, 1983.
Teams meet in a series of closed working sessions to evaluate the report and determine whether there are sufficient data upon which to base a conclusion. A document reflecting those considerations is then prepared for review by the full Expert Panel. After discussion of this document in public meetings of the full Panel, a Tentative Report is issued with one of three conclusions: (1) that the ingredient is safe as currently used, (2) that the ingredient is unsafe, or (3) that there is insufficient information for the Panel to make a determination of safety. It is significant that CIR procedures require documented evidence giving reasonable assurance o f safety before reaching the final determination. Lack of adverse information about an ingredient is not sufficient to justify a determination of safety. The Tentative Report is then made available for a 90-day public comment period. All comments in response to the Tentative Report are analyzed and submitted to the Expert Panel. A Final Report, incorporating any substantive changes resulting from public comment, is then released by the Expert Panel.
Data requirements The type and amount of data required for the Expert Panel to fulfill its charge that "there is a reasonable certainty in the judgment of competent scientists that [an] ingredient is safe under its conditions of u s e " may vary from one ingredient to another. 2 The adequacy of data for each ingre-
dient is judged on the basis of the ingredient's potential for human exposure in cosmetic products. Some formulations are applied to, and remain in, contact with the skin for extended periods of time; others are diluted and rapidly washed off. Dr. Karl H. Beyer, Jr., chairman of the Expert Panel, has noted that "the purpose of the Expert Panel is to determine the safety of an ingredient rather than how well the literature fulfills an adequate safety a s s e s s m e n t / " It is seldom that any safety assessment on a cosmetic, food, or drug has as much information as one would like. The Panel has rendered final decisions on the safety of an ingredient when the data were minimal but adequate for its intended use. Yet, in an equal number of cases the Panel has delayed its decision until additional tests were performed. The Panel has been extremely cautious when there were minimal data, particularly for those ingredients whose molecular structure, chemical characteristics, cosmetic use, and potential for biologic activity have warranted further investigation. When further data are needed, the public and the industry are notified through an Insufficient Data Announcement listing the types of data required by the Panel. If any party agrees to undertake the needed testing, the Panel defers the safety evaluation until the data are received. If there is no response to the request for additional data, a Final Report, containing the available data and the specific tests that are required before reasonable assurance of safety can be ascertained, is issued. (Nine Insufficient Safety Data Announcements have been issued.) Many cosmetic ingredients have been reviewed previously for safety by government and other scientific groups. FDA's GRAS Review for food safety and the OTC Drug Review, for example, are significant sources of data and safety evaluations for the Expert Panel. If an ingredient has been ruled as safe at equivalent concentrations for food use, the Panel would need less extensive additional test data on chronic and subchmnic effects. The Expert Panel's report on this ingredient would include the earlier evaluation and update the published review by including any new test data available after the government's report was
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issued. The Panel does, however, give special attention to any dermal and ocular data included in these earlier safety evaluations by including the detailed information in the CIR report. Data on mutagenicity, teratogenicity, and carcinogenesis are reviewed by the Panel. Often, thses data, or an ingredient with a similar molecular structure, have already been evaluated. The Panel uses this information in concluding "with reasonable certainty" that further testing is not required. In some specific cases the Panel has requested additional testing even though data on ingredients with similar chemical structures were available. For example, negative mutagenesis test data were available for benzophenone 1, 3, 4, 5, 9 and 11; however, the Expert Panel requested new tests for Benzophenone 2, 6, and 8 before a Final Report on those ingredients was issued. Data from metabolism and animal studies are carefully studied and considered for their applicability to human skin exposure. However, no report indicating a cosmetic ingredient is safe has been issued by the Expert Panel without human skin test data that confirmed the results found in animal tests. The test data for human skin irritation, sensitization, and photosensitization must be from tests conducted at ingredient concentrations at least as great as that of the normal concentration of ingredient use in cosmetic formulations. The Expert Panel has accepted negative ultraviolet light absorption data (UVA and UVB) for some cosmetic ingredients in lieu of additional human photosensitization test data when the ingredient's molecular structure indicated these wavelengths were not absorbed by the ingredient (and, therefore, one would not expect a chemical change to occur to transform the ingredient into a phototoxic agent). The determination of safety requires judgment. Rarely has any pure ingredient had every type of test data that can be obtained from a modern toxicologic testing laboratory. The Panel has accepted extensive finished product formulation test results when there are minimal, but equivalent, animal and human test results on the pure ingredient. The Panel's conclusions are always made on the basis of available data. Should new adverse
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Table II. Reports issued by CIR
Final reports Reports under review Total
No. of reports
Number of Ingredients included
65 23 96
182 62 244
data become available, the Panel reevaluates its previous conclusion and recommendations and issues an Addendum to the earlier report. RESULTS As of July 1, 1984, the Panel has issued sixtyfive Final Reports on 182 ingredients. Reports on another sixty-two ingredients are at various stages of development (Table II). In the course of completing these reports, the Panel has had to issue nine Insufficient Data Announcements. The cosmetic industry funded the needed test programs on all of these except one: O-Cymen-5-ol. Most of the requested test programs were completed by industry within 6 months of CIR's issuing the Insufficient Data Announcement. The Expert Panel has not released a report indicating any ingredient to date is unsafe. One report, O-Cymen-5-ol, was released stating that there were insufficient data to judge the safety of use of this ingredient in cosmetic products. Qualifications have been expressed in the conclusions of thirteen other reports on twenty-seven ingredients. The full reports on these ingredients present the discussions and rationale for these decisions. A summary of the Panel's conclusions on each of these fourteen reports is as follows: Report on O-Cymen-5-ol. There are a lack of safety test data on skin absorption, chronic oral toxicity, human skin sensitization, phototoxicity, photoallergenicity, and mutagenesis. The CIR Expert Panel concluded that the available data were insufficient to judge the safety of use of OCymen-5-ol in cosmetic products. Report on benzethonium chloride and methylbenzethonium chloride. Due to skin and ocular irritation above 5.0%, the conclusion is qualified for safe use at 0.5% in cosmetics applied to the
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T a b l e I l l . Ingredients sate for use in cosmetic products at present practices of use and concentration Acetylated lanolin Acetylated lanolin alcohol Almond meal Aluminum distearate Aluminum tristearate Ammonium laureth sulfate Ammonium stearate Avocado oil Beeswax Benzophenone 1 Benzophenone 2 Benzophenone 3 Benzophenone 4 Benzophenone 5 Benzophenone 6 Benzophenone 8 Benzophenone 9 Benzophenone 11 Butane Butylated hydroxyanisole Butylene glycol Calcium stearate Candelilla wax Caprylic/capric triglyceride Carnauba wax Ceresin Cetearyl octanoate Cetyl lactate Cetyl palmitate Choleth 24
Glyceryl stearate Glyceryl stearate SE Glycol distearate Glycol stearate Glycol stearate SE Hexylene glycol Hydrogenated lanolin Hydrolyzed collagen Hydroxylated lanolin Imidazolidinyl urea Isobutane Isodecyl oleate Isopentane Isopropyl lanolate Isopropyl myristate Isopropyl palmitate Isostearyl neopentanoate Japan wax Laneth 5 Laneth 9 acetate Laneth 10 acetate Laneth 16 Laneth 25 Lanolin Lanolin acid Lanolin alcohol Lanolin oil Laureth 4 Laureth 23 Lithium stearate
Decyl oleate Dehydroacetic acid Dibutyl phthalate Diisopropyl adipate Dimethicone copolyol Dimethyl phthalate Dioctyl adipate Dipropylene glycol
Magnesium stearate Microcrystalline wax Montan wax Myristyl lactate Myristyl myristate
Emulsifying wax N.F. Ethoxydiglycol
Nonoxynol 2 Nonoxynol 4
skin and 0.02% is safe for cosmetics used in the eye area. R e p o r t on 2 - b r o m o - 2 - n i t r o p r o p a n e - l , 3 - d i o l (BNPD). BNPD is a skin irritant at 1.0% and may interact with amines to form nitrosamines. The conclusion limits use to 0.1%. BNPD should not
Nonoxynol 8 Nonoxynol 9 Nonoxynol 10 Nonoxynol 12 Nonoxynol 14 Nonoxynol 15 Nonoxynol 30 Nonoxynol 40 Nonoxynol 50 Octyl dodecanol Octyl palmitate Oleyl alcohol Ozokerite Paraffin PEG 20 lanolin PEG 27 lanolin PEG 30 lanolin PEG 40 lanolin PEG 50 lanolin PEG 60 lanolin PEG 75 lanolin PEG 85 lanolin PEG 2 stearate PEG 6 stearate PEG 8 stearate PEG 12 stearate PEG 20 stearate PEG 32 stearate PEG 40 stearate PEG 50 stearate PEG 100 stearate PEG 150 stearate Polyamino sugar condensate Polybutene Polysorbate 20 Polysorbate 21 Polysorbate 40 Polysorbate 60 Polysorbate 61 Polysorbate 65 Polysorbate 80
Polysorbate 81 Polysorbate 85 Potassium-coco-hydrolyzed animal protein Potassium stearate Propane Propylene glycol stearate Propylene glycol stearate SE Quaternium- 18 Quaternium-18 Bentonite Quaternium-18 Hectorite Sodium dehydroacetate Sodium laureth sulfate Sodium stearate Sorbitan laurate Sorbitan oleate Sorbitan palmitate Sorbitan sesquioleate Sorbitan stearate Sorbitan trioleate Sorbitan tristearate Squalane Squalene Stearalkonium chloride Stearyl alcohol Sweet almond oil Synthetic beeswax Synthetic wax TEA-coco-hydrolyzed animal protein Vinyl acetate/crotonic acid Copolymer Wheat flour Wheat germ glycerides Wheat germ oil Wheat gluten Wheat starch Zinc stearate
be used under circumstances in which it may interact with amines and amides. R e p o r t on e a r b o m e r s 934, 910, 934P, 940, 941, and 962. Limited data are available at high cosmetic use concentrations, metabolism, mutagenesis, teratogenesis, carcinogenesis, as well as
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physicochemical characteristics. Available clinical data do, however, indicate low potential for skin irritation and sensitization. The conclusion states these ingredients are safe as used in cosmetics but the Panel qualifies that safety due to the limited data. R e p o r t on formaldehyde. Due to skin sensitization in some individuals, the concentration in cosmetic products should be as low as practicable, not to exceed 0.2%. It cannot be concluded that formaldehyde is safe for use in products that are intended to be aerosols. R e p o r t on isostearic acid. The conclusion states that this ingredient is safe for cosmetic use. However, concern is expressed on the potential to produce human comedogenicity. R e p o r t on methyl, ethyl, butyl, and propyl p a r a b e n s . These parabens are safe as cosmetic ingredients, but, due to the risk of increased sensitization, they are not recommended for use on damaged skin. R e p o r t on 2-nitro-p-phenylenediamine and 4-nitro-o-phenylenediamine. For those persons not sensitized, it is concluded that these two ingredients are safe as cosmetic ingredients. R e p o r t on p.phenylenediamine. This ingredient is a known sensitizer. For those persons not sensitized, it is concluded that this ingredient is safe as a hair dye ingredient. R e p o r t on propyi gallate. Human studies show significant sensitization at concentrations exceeding 10%. The conclusion states this ingredient is safe in cosmetic products at concentrations not exceeding 1.0%. R e p o r t on sodium borate and boric acid. These two ingredients are safe at concentrations less than, or equal to, 5.0%. Due to the increased absorption by damaged skin as compared to intact skin and available adverse animal test data, it is recommended that cosmetic products containing free sodium borate or boric acid at this concentration should not be used on infant skin or injured skin. R e p o r t on sodium lauryl sulfate and amm o n i u m lauryi sulfate. Both ingredients have been shown to be irritants following prolonged exposure at concentrations of 2.0% and greater.
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Possible hair loss and comedone formation have been reported. It is concluded that both ingredients are safe for discontinuous, brief use followed by thorough rinsing from the skin. For cosmetic products intended for prolonged contact with skin, concentrations should not exceed 1.0%. Report on triethanolamine (TEA), diethanolamine (DEA), and monoethanolamine (MEA). The Panel concludes that these ingredients are safe for brief discontinuous use followed by thorough rinsing from the skin. MEA should be used only in rinse-off products. Due to possible eye and skin irritation of TEA and DEA, products intended for prolonged contact should not exceed 5.0%. TEA and DEA should not be used in products containing N-nitrosating agents. Report on T E A - l a u r y l sulfate. Due to skin irritation at high concentration, the Panel recommends limiting the use concentration to a maximum of 10.5%. In fifty-one Final Reports on 154 ingredients, the Expert Panel has concluded that each ingredient is safe for use in cosmetic products at the present practices of use and concentration. They are listed in Table HI. The Board of Directors of CTFA added a final requirement when they approved the program in 1976. To assure the scientific adequacy and acceptance of all CIR Final Reports, the Board required that all reports were to be submitted to a refereed scientific journal for publication. Four collections of CIR reports have been reviewed and published in the American College of Toxicology's official journal.*,t,:~,w One collection was published in the Journal of Environmental Pathology and Toxicology, 2 Prior to journal publication, individual reports may be purchased from CIR. A listing of all reports and ingredients reviewed is available from the Admin-
*Elder RL, editor: Second Report of the Cosmetic Ingredient Review Expert Panel. J Am Coil Toxicol 1:1:177, 1982. ]Elder RL, editor: Third Report of the Cosmetic Ingredient Review Expert Panel. J Am Coil Toxicol 1:1-191, 1982. :i:Elder RL, editor: Fourth Report of the Cosmetle Ingredient Review Expert Panel. J Aln Coil Toxicol 2:1-178, 1983. w RL, editor: Fifth Report of the Cosmetic Ingredient Review Expert Panel. J Am Coll Toxicol 2:1-235, 1983.
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istrator, CIR, 1110 V e r m o n t Ave., N . W . , Suite 810, Washington, DC 20005.
SUMMARY Acceptance o f the p r o g r a m by the consumer, physician, industry, and g o v e r n m e n t can b e obtained only if the process reviews the n e e d e d scientific safety test data in an open f o r u m in which the data m a y be challenged b y any individual. The CIR program was designed and operates in a manner to meet this requirement. Sales and distribution of CIR reports are m a d e throughout the world; the inclusion and r e f e r e n c i n g of C I R reports in
major industry and government toxicologic safety data computer banks indicates that the results of the CIR E x p e r t Panel are being accepted as authoritative statements on the safety o f cosmetic ingredients. Subjecting these reports to a final external scientific review before publication in a recognized journal further supports this conclusion.
REFERENCES 1. Elder RL, editor: Cosmetic ingredients--their safety assessment. J Environ Pathol Toxicol 4:1-170, 1980. 2. Beyer KH: The Cosmetic Ingredient Review: A status report. Clin Ther 4:1-6, 1981.
ABSTRACTS A unique precipitating autoantibody against plasma thromboplastin antecedent associated with multiple apparent plasma clotting factor deficiencies in a patient with systemic lupus erythematosus Pooh MC, Saito H, Koopman WJ: Blood 63:1309-1317, 1984 As is well recognized, persons afflicted with systemic lupus erythematosus may produce autoantibodies that disturb coagulation profoundly and suddenly. In this case, factor 11 was inactivated. DetaiIs are given. P.C.A.
Systemic lupus erythematosns with paraproteinemia Rubin L, Urowitz MB, Pruzanski W: Arthritis Rheum 27:638-644, 1984 In the long-term prospective study of SLE in Toronto, of the 415 patients studied, nine (2.2%) had paraproteinemia, usually an IgG. No evidence of B cell lymphoma was discovered. P.C.A.
Local cutaneous recurrence after conservative excision of malignant melanoma Aitken DR, James AG, Carey LC: Arch Surg 119:643-646, 1984 Written by surgeons, this report notes that melanomas can be safely excised with a conservative (less than 5 cm) margin and that prognosis depends mostly on other factors. The group was followed up for a minimum of 5 years. P.C.A.
The effects of benzodiazepines on hormones in women with idiopathic hirsutism Dennerstein L, Callan A, Wame G: Prog Neuropsychopharmacol Biol Psychiatry 8:11-17, 1984 According to these authors in Australia, benzodiazepines may reduce androgens in some women with hirsutism. Do these popular medications reliably affect hormone balance? P.C.A.
Anaesthesia and severe skin disease Smith GB, Shribman A J: Anaesthesia 39:443-455, 1984 This is a review of the problems for an anaesthesiologist posed by various disorders of the skin, including urticaria pigmentosa, pemphigus, seleroderma, and more. P.C.A.
Lichen simplex chronicus during lithium treatment Shukla S, Mukherjee S: Am J Psychiatry 141:909-910, 1984 Persons who develop lichen simplex, as this patient did, while receiving lithium carbonate may have an adverse reaction not to the drug but to reentering ugly reality. When proper dermatologic topical therapy was established, the patient's eczema vanished and lithium therapy could be continued. P.C.A.