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37Cosmetic ToxicologyJOHN F. CORBETT, RAJ K. SHARMA, WILLIAM E. DRESSLERBristol-Myers Squibb Worldwide Beauty Care, Stamford, Connecticut
INTRODUCTION Decorative cosmetics and fragrances have been part of almost every culture for many thousands of years but a formal approach to the toxicological evaluation of cosmetic products has only evolved during the 20th century. Initially; the evaluation involved only dermal, ocular, and, in some cases, mucous membrane irritation toxicity and allergenicity via the Draize eye and skin tests in rabbits and guinea pigs. This was sometimes followed by clinical studies in humans. The recognition that the skin was not an impermeable barrier to topically applied materials required that systemic toxicity, including both acute and chronic effects, also be taken into account. For the most part, and for obvious reasons, ingredients used in products subject to incidental ingestion, such as lipstick, have received particular attention, followed by those used in the eye area and products applied to and left on the skin, while rinse-off products, except for hair dyes, have been of least concern. This chapter will consider the scope of testing that is generally accepted as desirable for cosmetic products, together with the chemical nature of the active ingredients used in selected specialized hair products such as dyes, bleaches, permanent waves, and straighteners. For other varied types of cosmetic products, use experience and some general principles regarding safety evaluation and risk assessment will be discussed. In addition, reference will be made to the particular requirements for and methods of reviews of safety data in the European Union, the United States and Japan.
C O S M E T I C SAFETY R E G U L A T I O N
The United StatesIn the U.S., the Food, Drug and Cosmetic Act designates the Food and Drug Administration as the agency responsible for cosmetic safety. For this purpose, the FDA has defined cosmetics as "articles to be rubbed, poured, sprinkled, or sprayed on or introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and articles intended for use as a component of any such articles; except that such term shall not include soap." The exemption for soap applies only to a composition consisting of an alkali metal salt of a fatty acid that is intended only for cleansing. Certain cosmetic products that are "intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease" are classified by FDA as drugs. This category includes sunscreen products, anticavity toothpastes, antiperspirants (as opposed to deodorants, which are "cosmetics"), antidandruff preparations, "medicated" skin lotions and liquids, skin protectants, and hair restorers. Under the regulations, the active ingredients in cosmetic drug products must be safe and effective according to the appropriate monograph covering the claimed indication. The only category of cosmetic ingredient subject to FDA approval is colors used for purposes other than dyeing the hair. There are only 36 "certified colors" and 23 "permitted" colors available for general use in cosmetics, and a further 7 that are permitted only forCopyright 9 1999 Academic Press. All rights of reproduction in any form reserved.
Corbett et al. tion." This definition covers many of the product categories that are considered to be over-the-counter drugs in the U.S. In common with the United States, cosmetics do not require premarket clearance in Europe. However, certain ingredients, notably colorants (other than hair dyes), preservatives, and sunscreens, do require approval before they can be used in cosmetic products. The list of permitted colorants (Annex IV) is broader than the U.S. list, comprising 157 materials. The approval process involves the submission of data via COLIPA, the European trade association, to the European Commission. The data is evaluated by a group of independent experts who make up the Scientific Committee for Cosmetology and Non-Food Products (SCCNFP) and who decide whether the ingredient can be accepted for listing in the appropriate Annex. Data requirements are similar to those listed above for the CIR. The General Toxicological Requirements for Cosmetic Ingredients (1996 revision) state: When requested, the manufacturer shall provide the Commission with the information set out below: 1. Acute toxicity 2. Dermal absorption 3. Dermal irritation 4. Mucous membrane irritation 5. Skin sensitization 6. Sub-chronic toxicity 7. Mutagenicity 8. Phototoxicityand Photomutagenciny (in case of UVfight absorbing substances) 9. Human data (if available) When considerable oral intake can be expected or when the data or dermal absorption do indicate a considerable penetration of the ingredients through the skin, taking into account the toxicological profile of the substance and its chemical structure, the following further information may be necessary: 10. Toxicokinetics 11. Teratogenicity,Reproduction toxicity, Carcinogenicity, and additional Genotoxicity. Additionally, there is now a legal requirement, forrealized in Article 7a of the sixth amendment to the Cosmetics Directive, that cosmetic companies hold a technical dossier of information on each of their products. This requirement applies to every cosmetic product, both retail and professional, including imported products. This dossier must include information or product composition, specifications, and method of manufacture, as well as an assessment of product safety carfled out by an appropriately qualified expert. The assessment must take account of the general toxico-
specific uses. In addition, a number of lakes of the soluble certified colors are available. For all other cosmetic ingredients, the safety evaluation is the responsibility of the manufacturer. In order to assist its members in this, the Cosmetic, Toiletry, and Fragrance Association (CTFA) established in 1976 the Cosmetic Ingredient Review (CIR) to review all the available data on an ingredient and to decide whether the ingredient is safe under the conditions of use. The CIR expert panel comprises six independent scientists as voting members and a nonvoting member representing each of the CTFA, the FDA, and the consumer. By 1996, the CIR had reviewed over 600 ingredients, finding 64% to be safe as used, 27% to be safe for use under defined conditions, 8% to have insufficient data, and five ingredients to be unsafe. The CIR expert panel currently requests the following as a minimum data requirement for reviewing the safety of the cosmetic ingredients that are on its priority list: 1. Current concentration of use data. 2. Chemistry data, including method of manufacture and impurities. 3. UV-absorption data; if absorption occurs in the UVA or UVB range, photosensitization data are needed. 4. Skin-irritation and -sensitization data at concentrations of use in humans. 5. Dermal-absorption data; if significant dermal absorption occurs, 28-day dermal-toxicity and development-toxicity data are needed. 6. Two genotoxicity studies, one using a mammalian system; if positive, a 2-year dermal carcinogenicity assay performed using NTP methods is needed. Additional studies may be requested based on the nature and use of the ingredient.
The European UnionIn the European Union, cosmetics are regulated under the Cosmetics Directive (76/768/EEC) of 1976 and amendments thereto. For the purpose of regulation, cosmetics are more broadly defined than in the United States, viz. "any substance or preparation intended to be placed in contact with various external parts of the human body (epidermis, hair system, nails, lips and external genitalia) and with the teeth or mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance a n d / o r correcting body odors a n d / or protecting them or keeping them in good condi-
Cosmetic Toxicology logical profile of the ingredients, their chemical structures, and the potential levels of exposure. The SCC is also responsible for recommending the listing of substances prohibited for use in cosmetics (Annex II) and substances that can be used with certain limitations with regard to product category, concentration, a n d / o r special labeling requirements (Annex III). In addition to these requirements, the EU regulation for the Notification of New Substances must be followed by companies introducing new chemicals. These regulations state that "a material is considered to be a new substahce within the EU if it is not listed in EINECS (European Inventory of Existing Chemical Substances)." EINECS is a closed list (closed in 1981), that is, no new substances can now be added. Substances not in EINECS must be notified according to Council Directive 92/32/EEC (seventh amendment to the EC Dangerous Substances Directive) prior to marketing in the EU. Notified substances are issued in ELINCS (European List of New Chemical Substances). ELINCS is an open list, that is, new substances may be added once notified according to the Directive. The precise contents of a notification depend on the quantity of the substance to be placed or already placed on the market. The notification system is banded, the information required increasing as the quantity of a substance placed on the market increases.
and medicated toothpastes. Lists for other categories are being developed. For countries other than those discussed here, ingredients acceptable in the United States a n d / o r Europe would usually be acceptable.
HAIR COSMETICS Permanent WavesThe conformational integrity of the hair fiber is maintained by various interactions between protein chains making up the cortex. These comprise polar (electrostatic