CHAPTER

Miscellaneous Skin Care Products: Skin Bleaches and Others

INTRODUCTION This chapter includes brief descriptions of a variety of skin care products that by virtue of their claims are classified as over-the-counter (OTC) drugs in the United States. The principle of OTC drugs is not recognized in other countries and needs clarification. An OTC drug is one in which a specific ingredient (or a blend of ingredients) is claimed to benefit the user. The claimed benefit for the (drug or active) ingredient is alleviation or therapy of a medical condition. An example of such a condition is sunburn caused by incident solar irradiation. This condition is remedied by use of a sunscreen, which commonly includes an ultraviolet (UV)-absorbing compound. This makes the sunscreening agent and the finished product drugs, at least in the United States. The common acceptance of such products as cosmetics does not change their drug status in the United States; this has also been given some recognition in other jurisdictions by requiring identification of UV absorbers and limitations on their concentration in finished products. In accordance with U.S. regulations, advertising claims are strictly limited to those identified in a so-called OTC monograph. The monographs normally specify the concentration of the actives as well as various combinations. Warnings and directions for use are part of the labeling requirements in the United States. Infraction of these rules can result in action from the U.S. Food and Drug Administration (FDA). Although the monographs are the basis of the regulations, they include a wealth of scientific documentation that is useful to interested scientists and formulators. For this reason, the cited OTC monographs constitute recommended

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reading. In the discussion that follows only the highlights are noted; the pertinent monograph should be consulted before any development program is initiated. The rigid rules for monographs of OTC drugs in the United States require strict adherence by marketers to certain labeling regulations. These rules apply to all OTC drugs and include the following: Definition: Product activity Ingredient: Identity of active drug Statement of Identity: Acceptable terms for identifying product Indication: Intent of product Warnings: Potential hazards to user Directions: How to use product

For the sake of avoiding repetitive statements, the six U.S. labeling elements are provided only in some of the discussions of OTC drugs. SKIN BLEACHES Skin bleaches are products intended to lighten or remove unwanted coloration of the skin. Since they are designed to work by penetrating the skin and interfering with the pigment production by the skin cells and thus have an effect on the normal structure and function of the skin, they are regulated as drugs in the United States. The drive to reduce the pigmentation of sun-exposed skin is an ethnic or cultural phenomenon. Interference with melanin formation can be achieved by reducing the number of melanocytes in the skin (by applying a melanocytotoxic agent to the skin) or by interfering with the oxidation of tyrosine (by inhibiting the action of tyrosinase). The exact mechanism by which an agent achieves skin bleaching is not understood. Dermatologists as a group are convinced that melanin in the epidermis can protect skin against UV-induced skin damage. It comes as no surprise, therefore, that in many jurisdictions, interfering with melanin formation is considered a drug action. Nevertheless, in some cultures light skin is of great importance, and efforts are made to interfere with melanin synthesis. Details of how tyrosine is oxidized in vivo to melanin can be found in most textbooks of dermatology (see also Riley, P.A., The Evolution of Melanin, in Melanin: Its Role in Human Photoprotection, Zeisel, L., et al., eds., Valdenmar Publishing Co., Overland Park, Kansas, 1995).

REGULATORY STATUS OF SKIN BLEACHES IN THE UNITED STATES

Recognizing the drug nature of skin bleaches, the Food and Drug Administration (FDA) issued a Tentative Final OTC Drug Monograph, Fed Reg. 47,

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39108, on September 3, 1982. At the time of this writing, the FDA has not yet finalized this regulation. In this monograph the FDA has defined a skin bleaching active ingredient as an agent designed to bleach or otherwise lighten limited areas of hyperpigmented skin through the suppression of melanin pigment formation within skin cells. Any product that contains an ingredient with this activity and that makes claims asserting the product can bleach or lighten the skin falls under this monograph. This proposed monograph identifies only one active ingredient, hydroquinone at 1.5 to 2%. Even though this monograph has not been finalized, the use of hydroquinone at levels outside the 1.5 to 2% range, or the use of other active ingredients would be considered "non-monograph" and cannot be marketed at this time in the United States without an approved New Drug Application (NDA). In addition to the use of hydroquinone, the proposed monograph also allows some combination drug products, combining hydroquinone with any generally recognized sunscreen active ingredient. The labeling of the skin bleach must meet the requirements of the proposed monograph; the proposed monograph identifies specific wording for the statement of identity, indications (uses), warnings, and directions for use. These label elements are briefly discussed.

Statement of Identity
The statement of identity identifies the product by one of the following terms. Skin Skin Skin Skin Bleaching Agent Lightener Bleaching (dosage form, e.g., cream, lotion, or ointment) Lightening (dosage form, e.g., cream, lotion, or ointment)

Indications
After the signal word, "Indications," one of the following statement variations must appear. "For the gradual fading or lightening of dark (brownish) (select one of the following: discolorations, pigment, spots, blotches, or areas) in the skin such as (select one or more of the following: freckles, age or liver spots, or pigment in the skin that may occur in pregnancy, or from the use of oral contraceptives.)" In addition, if the product is a combination drug with a sunscreen, the following statement must also appear: "Contains a sunscreen to help prevent darkening from recurring."

Warnings
The labeling of the product must contain the following under the signal word "Warnings."

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"Avoid contact with the eyes. Some users of this product may experience a mild skin irritation. If skin irritation becomes severe, stop use and consult a doctor. Do not use on children under 12 years of age unless directed by a doctor." In addition, if the product is a combination drug containing a sunscreen, the following statement must also appear. "This product is not for use in the prevention of sunburn."

Directions
The labeling of the product must contain the following under the signal word "Directions." "Adults: apply a small amount as a thin layer on the affected area twice daily, or use as directed by a doctor. If no improvement is seen after 3 months of treatment, use of this product should be discontinued. Lightening effect of this product may not be noticeable when used on very dark skin. Children under 12 years of age: do not use unless directed by a doctor." In addition, if the product is not a sunscreen combination, add the following: "Sun exposure should be limited by using a sunscreen agent, a sun blocking agent, or protective clothing to cover bleached skin when using and after using this product in order to prevent darkening from recurring." If the product contains a sunscreen combination, substitute the following statement for the previous direction: "Sun exposure should be limited by using a sunscreen agent, a sun blocking agent, or protective clothing to cover bleached skin after treatment is completed in order to prevent darkening from recurring." In addition to the labeling requirements these drug products must also meet the general drug requirements. These include full ingredient labeling, compliance with drug current Good Manufacturing Procedures (GMP) and Drug Registration with the FDA. By the time this monograph finalizes, the labeling must also meet all the other requirements of the new OTC drug labeling regulations. In order to compound a skin bleaching product for the U.S. market, formulators are expected to add hydroquinone to a typical skin care product (cream or lotion), which may then be used in accordance with the directions provided above.

STATUS OF SKIN BLEACHING IN JAPAN

In Western Caucasian societies skin bleaching is not widely practiced, but it plays an important role in Japan and in other ethnic societies. Thus the Japanese legal restrictions on skin bleaching agents are much less restrictive than those in the United States. In addition, research on skin bleaching and the search for potential actives is of great importance to the Japanese cosmetic industry.

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Table 19.1 Antimelanogenic Skin Whitening Agents*

Melanocytotoxic agents Hydroquinones Hydroquinone monobenzylether Pyrocatechol -Butylcatechol Carbohydrate synthesis inhibitor Monensin Glucosamine Tunicamycin Deoxynojirimyein (5-amino-5-deoxyglucose) Tyrosinase inhibitor Azelaic acid Glutathione Cysteine Hinokitiol Kojic acid Arbutin Placenta extract Resorcinol Ellagic acid A-n-Butyl resorcinol Magnesium ascorbyl phosphate Matricaria chamomilla extract
* Approved for use by the Health and Welfare Administration.

The skin bleaching agents of choice are shown in Table 19.1. The exact mechanism that stimulates melanogensis after UVB exposure is still not fully understood.

UVB-INDUCED PIGMENTATION MECHANISM

Since human melanocyte culture became possible in 1984, various growth factors and chemokines have been reported to stimulate proliferation and melanogenesis of human melanocytes in culture. However, the physiological roles of these factors in epidermal pigmentation have not been clarified because they are cytokines of various origins. To clarify the linkage of cytokines between human melanocytes and human keratinocytes in stimulating epidermal pigmentation, the media derived from UV-exposed keratinocytes on DNA synthesis of human melanocytes were studied, showing that keratinocytes secrete relatively unknown melanogenic stimulatory factors in response to UVB exposure. It seemed reasonable to assume that the unknown factors would be responsible for stimulating melanization in the process of UVB

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pigmentation. Based on the studies by Imokawa and coworkers, the unknown factor acted both as a calcium mobilizer and as a stimulator of DNA synthesis, and was associated with endothelins. It became evident that UVB-exposed human skin secretes ET-1, Big ET-1, and IL-IO into the epidermis. ET-I receptors on melanocytes respond with enhanced DNA synthesis and melanogenesis. The investigations further established that interference with this endothelin-induced message reduced melanin pigmentation studies. This biochemical analysis forms the rationale for the regulatory acceptance in Japan of various skin bleaching agents (Table 19.1) [1]. In practice one or more of the compounds identified in Table 19.1 is incorporated into a typical skin care product (Chapter 18). The degree of bleaching depends on the frequency and duration of use. SOAP Soap, as a personal care item, does not conjure up the image or glamor that many other cosmetic items elicit. However, from a regulatory perspective, soap is one of the most complex and certainly more interesting products. Based on its composition and on the claims made for it, a "soap" can be a drug, or a cosmetic, or a drug and a cosmetic, or a household substance. This unusual situation arises from the "soap exemption" in the Federal Food, Drug, and Cosmetic Act (FDCA) In the Act a cosmetic is defined as follows: The term "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 such term shall not include soap. The underlined italics in the earlier definition emphasize and point out the statutory basis for the status of soap. The Act does not define what Congress intended soap to be. In order to fill that void and to create an effective scheme for regulating soap, the FDA issued a regulation defining the composition and criteria that a soap product must meet in order to qualify for the exemption (21 CFR 701.20): The FDA interprets the term "soap" to apply only to articles that meet the following conditions: (1) The bulk of the nonvolatile matter in the product consists of an alkali salt of fatty acids and the detergent properties of the article are due to the alkali-fatty acid compounds; and (2) The product is labeled, sold, and represented only as soap.

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Soaps as Household Substances

If a cleansing product meets the criteria as defined by the FDA, the product is not regulated by the FDA and becomes a household substance under the Consumer Product Safety Commission. As long as the soap product meets the safety requirements of the Consumer Product Act and the Hazardous Substance Act, it can be marketed without further effort. If this product is a consumer item sold to the consumer for use at home, the label must be in compliance with the Fair Packaging and Labeling Act (FPLA) administered by the Federal Trade Commission. This means that the label must contain an identity statement, the net contents, and the name and address of the manufacturer or distributor. The net contents and the name of the manufacturer or distributor are reasonably straightforward. The identity statement can be a word, phrase, or vignette that clearly informs the consumer of the product's use. Since ingredient labeling was enacted by the FDA under the FPLA for cosmetics, a soap that is a household substance does not require ingredient labeling. Furthermore, since it is not under FDA jurisdiction, this form of soap is not restricted to the use of FDA-approved color additives.

Cosmetic Soaps
A cleansing product that uses detergents as a replacement for or in combination with an alkali fatty acid soap is, by the above definition, a cosmetic. In addition, a soap product otherwise meeting the above definition but making cosmetic claims such as moisturizing or conditioning or some other noncleansing cosmetic claim is also a cosmetic. As a cosmetic this cleansing product is now under the jurisdiction of the FDA. If it is a consumer product, it must still meet all of the requirements of the FPLA as noted above, in addition to full cosmetic ingredient labeling. Note that the ingredient labeling for these products is in descending order of concentration. If the cleansing product is a professional product to be used only by beauticians, barbers, or some other beauty professional, and is not intended or represented for retail sale to the consumer, then it does not require ingredient labeling or an identity statement. Many professional cosmetics are ingredient labeled voluntarily as a matter of information to the professional beautician or stylist. When these professional products are voluntarily ingredient labeled, the industry practice has been to list the ingredients alphabetically. The identity statement for a soap bar meeting the FDA composition criteria but making other cosmetic claims should identify the product using appropriate terms. For the above examples, this might include terms such as "moisturizing soap" or "conditioning soap." A cosmetic cleansing product that uses nonsoap surfactants, in part or in total, as the cleansing agent, should not be represented

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as "soap." These products can use a wide range of terms for the identity statement including such terms as "moisturizing beauty bar" or "moisturizing cleanser." If the product is in liquid form, the FDA has not taken action against a product identified as "liquid soap" even though these products are detergent-based. The FDA has recognized that the term "liquid" qualifies the "soap" term. These cleansing products are also restricted to the usage of only approved color additives as identified by the FDA. Again there are several categories of soaps that are drugs. Any soap bar that is represented to be an antimicrobial or antiseptic soap is a drug. Although a deodorant soap by itself would be a cosmetic, any representation that it is effective because it kills bacteria makes the product a drug. A cleansing product intended for the treatment or mitigation of acne or some other skin condition would also be a drug. A product can be both a drug and a cosmetic, and then must meet the requirements of both categories. These drug products, when intended for sale or resale to consumers, must also meet the requirements of the F P L C As a drug these cleansing products are also subject to the provisions of any applicable OTC monographs. Unfortunately, at the time of this writing, the FDA has not finalized the monograph on skin antiseptics or medicated soaps. Therefore the indications, warnings, ingredients, and directions for use are not expressly clear-cut. Manufacturers and distributors of these products should adhere to the relevant tentative final monographs and continually monitor the FDA for new developments. The FDA has not yet identified many antimicrobial ingredients as category 1, safe and effective, for their intended use. Many of the active ingredients in use today may not be category 1 for antimicrobial products when the monograph is finalized. Any drug product that does not meet the requirements of an applicable OTC monograph is a new drug and must be the subject of an approved NDA. This can be a burdensome task for a consumer cleansing product. However, it should be noted that many antimicrobial soaps that have been on the market for some years do have approved NDAs. To further complicate this situation, the FDA has recently issued new labeling regulations for OTC drug products (Fed. Reg., page 13254, 3/19/99). As with all drug products, the active ingredients must be listed first using drug nomenclature. This is not always the same as the cosmetic terminology. New legislation now requires listing of the concentrations of all active ingredients for drugs. If the product is not a cosmetic, the inactive ingredients must be listed in alphabetical order. If the drug product is a cosmetic, the inactive ingredients become cosmetic ingredients and must be listed in descending concentration.

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Soap Manufacture
The processing of soap starts with alkali catalyzed hydrolysis of all types of naturally available fats and oils. Acidification yields a blend of fatty acids that can be processed to yield soap. Autoclaving of the fat stock yields the fatty acids directly, which can then be processed to generate neutralized soap. The wet base soap can be pumped into a heated agitated blender, a so-called crutcher, and blended with all types of additives. This hot blend is then poured into a mold for forming and cooling. Today, most soap bars are produced by drying, milling, and ultimately plodding, that is, extrusion. The processes require specialized equipment, and most "cosmetic" soap bars are manufactured by commercial soapers upon request by marketers.

SKIN PROTECTANT PRODUCTS

Historically, products for which skin protection claims are made have included protection from dryness, skin aging, chapping, wrinkling, windburn, sunburn, and many other skin conditions. Depending on the claims made, these products were regulated as cosmetics or drugs, or both. Traditionally, moisturizers and general skin treatments that related to the maintenance of normal skin hydration were treated as cosmetics. On the other hand, products that claim a therapeutic effect are considered drugs. Since the main intention of skin protectants is to protect the skin from some form of damage or other deleterious conditions, they are generally considered to be drug products. This rationale creates a clear distinction between skin protectant and skin treatment preparations; the latter form the basis for Chapter 18. The FDA has published a tentative OTC final monograph on skin protectants in the Federal Register of February 15, 1983 (U.S. Fed. Reg. 48, 6820, amended U.S. Fed. Reg. 59, 28767). In this monograph the FDA has defined a skin protectant as a drug that "protects injured, or exposed skin, or mucous membrane surface from harmful or annoying stimuli." The FDA has further subdivided the classification of skin protectants into several categories. These monographs contain the following definitions that relate to these products. 1. Skin Protectant. A drug which protects injured, or exposed skin, or mucous membrane surface from harmful or annoying stimuli. 2. Lip Balm. A drug product that relieves and prevents dryness, or chapping of the exposed surface of the lips. 3. Fever Blister or Cold Sore. TreatmentTherapy for a vesicle that occurs in the junction of the mucous membrane and the skin on the lips or nose, and is caused by the virus herpes simplex, type I. The highlights of this monograph detailing the permitted active ingredients and combinations, identity statement, indications, mandatory warnings, and

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directions for use have been included here for reference. However, when preparing packaging or labeling copy, one should consult the latest version of the official monograph.

ACTIVE INGREDIENTS
The list of active (drug) ingredients to a large degree overlaps upon the ingredients used in cosmetic skin care products (Chapter 18). a. b. c. d. e. f. g. h. i. j. k. 1. m. Allantoin0.5 to 2% Aluminum hydroxide gel0.15 to 5% Calamine1 to 25% Cocoa butter50 to 100% Dimethicone1 to 30% Glycerin20 to 45% Kaolin4 to 20% Petrolatum30 to 100% Shark liver oil3% White petrolatum30 to 100% Zinc acetate0.1 to 2% Zinc carbonate0.2 to 2% Zinc oxide1 to 25%

Combinations
a. Any two or more of the following as long as each ingredient is within the range prescribed earlier in the text. Allantoin, cocoa butter, petrolatum, shark liver oil, and white petrolatum. b. Any two or more of the following as long as each ingredient is within the range prescribed earlier in the text. Allantoin, cocoa butter, dimethicone, glycerin, petrolatum, shark liver oil, and white petrolatum. c. Any two or more of the following as long as each ingredient is within the range prescribed earlier in the text. Aluminum hydroxide gel, calamine, kaolin, zinc carbonate, and zinc oxide.

STATEMENT OF IDENTITY
The OTC label must include the statement of identity, "skin protectant," in addition to any established name for the drug.

INDICATIONS
One or more of the following statements must follow the signal word, "Indications." A. Products containing any of the active ingredients allantoin, cocoa butter, petrolatum, shark liver oil, and white petrolatum: "For the temporary protection of minor cuts, scrapes, bums and sunburn."

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B. Products containing any of the active ingredients allantoin, cocoa butter, dimethicone, glycerin, petrolatum, shark liver oil, and white petrolatum: "Helps prevent and temporarily protects chafed, chapped, cracked, or windbumed skin and lips." C Products containing any of the active ingredients aluminum hydroxide gel, calamine, kaolin, zinc carbonate, and zinc oxide: "Dries the oozing and weeping of poison ivy, poison oak, and poison sumac." As is customary with all OTC products, warning statements and directions for use must be shown. For details, the monograph should be consulted. This OTC monograph for skin protectants has been somewhat controversial since several of the active drug ingredients are materials that have been commonly used in topical cosmetic creams and lotions to moisturize and lubricate the skin surface. Although no attempt has yet been made to convert cosmetic skin moisturizers to drugs, the word "protects" has taken on some new meanings. Cosmetic moisturizers have been used for many years to help hydrate the skin and protect it from dryness. Until such time as this monograph is published as a final rule, this category will include a certain amount of guesswork. Products that adhere relatively closely to the tentative final monograph or products that have been in the marketplace for many years will undoubtedly continue to be marketed with little or no regulatory guidance. Products that make drug claims outside of the tentative final monograph or new products that use active ingredients not covered by the monograph may well receive FDA action. It is likely that the FDA will not be concerned with cosmetic products that make simple skin protection claims in their labeling copy as long as that protection is related to a specific cosmetic function. However, the use of the term "Skin Protectant" as the identity statement used in conjunction with the trade name for a skin care product is likely to be restricted to drug products. Cosmetic skin care products will probably require strictly cosmetic terms for their identity statements. SKIN ANTISEPTICS At the time of this writing the status of topical antiseptics is not completely resolved. Personal care products that make antimicrobial claims are considered to be drug products by the FDA; they should be in compliance with an OTC monograph or the subject of an approved NDA. The FDA has published several tentative final monographs that relate to these products in the Federal Register. On July 22, 1991, the FDA issued a tentative final monograph for First Aid Antiseptic Drug Products (U.S. Fed. Reg., 56, 33644). On June 17, 1994, they published a tentative final

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monograph for Health Care Antiseptic Drug Products. Neither of these monographs fully addresses the skin care products on the market today that make antiseptic claims. These monographs identify the category of drugs and the active ingredients that can be used. In addition, they indicate the mandatory identity statements, indications of use, warnings, and directions. Each of these monographs is described in this section. The following summaries are intended to be illustrative and provide general oversight. Active ingredients Ethyl alcohol Ethyl alcohol Benzalkonium chloride Benzethonium chloride Camphorated metacresol

Camphorated phenol Eucalyptol Hexylresorcinol Hydrogen peroxide Iodine (Tincture U.S.P.) Iodine (Topical Solution U.S.P.) Isopropyl alcohol Menthol Methylbenzethonium chloride Methyl salicylate Phenol Povidone-Iodine Thymol

48 to 95% by volume 26.9% (when used in combination as given in this text) 0.1 to 0.13 % 0.1 to 0.2% (camphor at 3 to 10.8% and metacresol at 1 to 3.6% in a ratio of 3 parts camphor to 1 part metacresol) (camphor at 10.8% and phenol 4.7%) in a light mineral oil, U.S.P. vehicle. 0.091% (when used in combination as noted in this text) 0.1% topical solution U.P.S.

50 to 91.3% by volume 0.042% (when used in combination as noted in this text) 0.13 to 0.5% 0.055 (when used in combination as noted in this text) 0.5 to 1.5% 5 to 10% 0.063% (when used in combination as noted in this text)

Tentative Final Monograph for First Aid Antiseptic Drug Products

In accordance with the Federal Food, Drug and Cosmetic Act, a representation of a drug as an antiseptic makes the product a germicide. An antiseptic

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containing drug product is applied topically to the skin to help prevent infection in minor cuts, scrapes, and burns.

Combinations
1. Any single first aid ingredient may be combined with any single external analgesic active ingredient. 2. Any single first aid ingredient may be combined with any single skin protectant active ingredient. 3. Ethyl alcohol at 26.9% may be combined with eucalyptol, menthol, methyl salicylate, or thymol at their prescribed concentrations. Statement of Identity, Indications, Warnings, and Directions for Use. These label or insert statements follow the general pattern established for OTC drug products.

TENTATIVE FINAL MONOGRAPH FOR HEALTH CARE ANTISEPTIC DRUG PRODUCTS Definitions
This monograph was further subdivided by the FDA to include several distinct end usages. Each of these uses was defined as follows. Antiseptic Drug. In accordance with the Federal Food, Drug and Cosmetic Act, a representation of a drug as an antiseptic shall be considered to be a germicide. A properly formulated drug product containing an ingredient included in the monograph that possesses in vitro activity against the microorganisms listed in the monograph is included. Health Care Antiseptic. This is an antiseptic containing drug product applied topically to the skin to help prevent infection or to help prevent crosscontamination. This category includes three different types of products: Antiseptic Handwash or Health Care Personnel Handwash Drug Product. This is an antiseptic containing preparation designed for frequent use; it reduces the number of transient microorganisms on intact skin to an initial baseline level after adequate washing, rinsing, and drying; it is broad spectrum, fast acting and, if possible, persistent. Patient Preoperative Skin Preparation Drug Product. This is a fast acting, broad spectrum, and persistent antiseptic containing preparation that significantly reduces the number of microorganisms on intact skin. Surgical Hand Scrub Drug Product. This is an antiseptic containing preparation that significantly reduces the number of microorganisms on intact skin; it is broad spectrum, fast acting, and persistent.

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Active Ingredients
The ingredients shown in this section are the approved actives for antiseptic handwash or health care personnel handwash drug products, patient preoperative skin preparation drug products, and surgical hand scrub drug products. 1. Ethyl alcohol60 to 95% by volume in an aqueous solution. 2. Povidone-iodine5 to 10% For patient preoperative skin preparation drug products the ingredients include those listed earlier and 3. Iodine (tincture U.S.P.) 4. Iodine (topical solution U.S.P.) 5. Isopropyl alcohol 70 to 91.3% by volume in an aqueous solution. No combinations of these ingredients were published in this monograph.

Statement of Identity
The statement of identity for products marketed under this monograph and intended for a single use is "antiseptic." In addition, the specific identity of the relevant subcategory must appear either here or be included in the "Indications" (or "Uses") section. The subcategories are: antiseptic handwash health care personnel handwash patient preoperative skin preparation surgical hand scrub. For multiple-use products the subcategories listed earlier must also appear in the "Directions" section preceding the specific directions for each use. It is apparent that this OTC drug category is not directly applicable to cosmetic preparations. The remaining label or insert statement (indication, warnings, and directions for use) follow the general pattern established for OTC drug products.

Recent Actions
Products Intended for Preoperative Skin Care Preparation and Surgical Hand Scrubbing are obviously not cosmetic and are, therefore, not discussed here. On the other hand, germicidal claims for cosmetic skin and body washes may not meet the requirements of the tentative monograph. For example, the proposed monographs do not address the antibacterial hand lotions that have become very popular. At the time of this writing the industry is commenting to the FDA about the safety and efficacy of topical antimicrobial creams and lotions. Within recent months, however, there has been some regulatory action against some of these currently marketed products. This is a little unusual since

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the FDA generally does not comment on OTC products whose safety is not at issue and that have been marketed with claims or conditions that do not completely match a proposed monograph. The first of these actions was a "Warning Letter" of May 6, 1998, addressing an antibacterial hand lotion with triclosan. The FDA contended that the product was intended for repeated use on the hands by the general public and health care professionals as an antiseptic moisturizer. The FDA asserted that the claims for the hand lotion were for "prophylatic antimicrobial barrier use." The second enforcement action was another "Warning Letter" sent on April 22, 1999, for a lotion. Claims for this product include: "long-lasting," "germ protection," and " . . . helps to reduce everyday germs that can cause infection and illness." The FDA considered that the claims for the antibacterial antiseptic lotion were for prophylactic antimicrobial barrier use and that the product was not generally recognized among scientific experts as safe and effective. The FDA cited the product as a new drug being marketed without an NDA. The latest enforcement action is a Federal Trade Commission (FTC) consent order against an antibacterial hand lotion with triclosan, stating that the seller did not have adequate substantiation for claims that were made in television and print advertising, as well as on the product label. The product has been advertised as a hand lotion that stops germs longer than washing alone, that it provides enough germ protection to stop germs for hours, and that it is the skin-caring way to stop germs while you moisturize. The FTC states that the seller has represented, expressly or by implication, that: 1. The product stops germs on hands longer than washing alone. 2. The product provides continuous protection from germs for hours. 3. The product is effective against disease-causing germs, such as cold and flu viruses. The FTC argues that although triclosan can reduce the number of germs on a user's hands, the degree and duration of germ protection have not been scientifically established. Although this order is an FTC action based on the advertising made for a product, it is highly likely that the FTC conferred with the FDA before taking any action. These regulatory actions are interesting at this point in time because they are an indication of the current viewpoint of the regulatory agency. Even though there has been no final action on this category of drug products by the FDA at the time of this writing, these actions may well represent the future direction for this category.

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DANDRUFF PRODUCTS The appearance of visible scalp scales on hair is commonly called dandruff. The precise nature of this phenomenon has not been established. It has been described as a chronic, noninflammatory scaling of the scalp. Many investigators consider dandruff to be a mild form of seborrhoeic dermatitis, while other investigators have considered the two conditions to be separate disorders. There is considerable evidence that dandruff is associated with Malassezia furfur, a dimorphic, lipophilic fungus found as part of the normal resident flora on human skin [2]. The yeast form, which is generally found on the scalp, is termed Pityrosporum ovale. M. furfur also appears to be associated with the appearance of seborrheic dematitis, psoriasis vulgaris, pityriasis versicolor, and other skin conditions. Despite these uncertainties, antidandruff agents to treat this condition have been available for a number of years. Products containing these agents, including shampoos, are considered drugs in the United States and are therefore regulated by the FDA. Table 19.2 lists many of the antidandruff agents commonly used in commercial products. The first five materials in the list have been classified by the FDA, at the concentrations given in the table, as generally safe and effective. These are the only antidandruff agents that can be used over the counter in the United States without the filing of a new drug application. The FDA recently approved a new drug application for the use of ketoconazole in over-the-counter antidandruff shampoos. Finally, the last antidandruff agent in the table, climbazole, is not approved for use in the United States. It can, however, be used in many countries in Europe, Asia, Africa, and Latin America.

Table 19.2 Commercial Antidandruff Agents

Antidandruff agent
Zinc pyrithione Zinc pyrithione Salicylic acid Sulfur Coal tar Selenium sulfide Selenium sulfide (micronized) Ketoconazole Climbazole Climbazole

Specified concentrations
0.3%-2% 0.1%-0.25% 1.8%-3% 2%-5% 0.5%-5% 1% 0.6% 1% 0.5%-2% 0.1%-0.5%

Type of formulation
Rinse-off Leave-on Rinse-off Rinse-off Rinse-off Rinse-off Rinse-off Rinse-off Rinse-off Leave-on

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Since the etiology of dandruff is still open to some argument, it is, perhaps, not surprising that there is some question concerning the exact mechanism of action of many of the antidandruff agents in Table 19.2. At least five of these agents, however, exhibit antimycotic activity against M. furfur, which strongly supports the assertion that this fungus is involved in the occurrence of dandruff. Most of the actives listed in Table 19.2 exhibit substantial antimycotic activity. Zinc pyrithione has been shown to exhibit both antibacterial and antifungal activity. The mode of action has been reported to be a disruption of the proton gradients across cell membranes [3]. More than one theory concerning the mechanism of action of selenium sulfide has also been proposed; it possesses antifungal activity. Climbazole and ketoconazole are potent antifungal agents, believed to inhibit synthesis of ergosterol, an essential component of fungal membranes. The effectiveness of salicylic acid does not appear to be a result of antifungal action but more likely a keratolytic action. This same mechanism may apply to coal tar preparations, although they may act as cytostatics. Formulating many of these antidandruff agents into shampoos can present problems in terms of stability, odor, and interactions with other raw materials. Selenium sulfide, sulfur, and zinc pyrithione are insoluble solids and require the use of suspending agents to ensure product stability. Zinc pyrithione is unstable outside of a pH range of 4.5 to 9.5. It may slowly degrade in the presence of light and should be packaged in opaque containers. Oxidizing agents, trace ferric ions, and chelating agents such as EDTA are incompatible with zinc pyrithione and must be avoided. It should be apparent that formulation of effective antidandruff products requires careful selection of auxiliary ingredients because they may alter the efficacy of the active. The final monograph allows a wide range of drug concentrations to account for these interactions. Personal care products intended for the treatment or control of dandruff, psoriasis, or seborrheic dermatitis are considered to be drugs and are subject to the requirements of the OTC final rule published in the Federal Register (56, 63554; December 4, 1991) and its amendment (Fed. Reg. 59,4000, January 28, 1994). Although this section is primarily concerned with antidandruff formulations, OTC products intended for the treatment of psoriasis or seborrheic dermatitis will also be considered. Since these conditions are generally treated in a manner similar to dandruff, their form and formulation are similar and often coincide with those of dandruff preparations. Most of these products are formulated as shampoos and are thus rinsed from the scalp relatively quickly. Some typical formulations are shown in this section.

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Ingredient

Model Antidandruff Shampoo Formula* Concentration Function

12%-20% 4-7% 2% 1-5% q.s. Cleansing agent Suspending agent Antidandruff agent Foam, viscosity booster pH control, fragrance, preservatives, color, water, etc.

Primary surfactant Dihydrogenated tallow phthalic acid amide Zinc pyrithione Amide Miscellaneous

*After Sejic, B., and Shapiro, I., Cosmet Toiletries 1992, 107(V), 103.

Antidandruff Shampoo with Zinc Pyrithione

A. Water B. Acrylates/Cio-3o alkyl acrylate cross-polymer C Sodium hydroxide, 18% D. Propylene glycol Sodium lauryl sulfate, 29% Sodium laureth-3 sulfate, 30% Cocamidopropyl betaine E. Polyquaternium-10 F. Water G. DMDM hydantoin Sodium hydroxide (18%) H Polyquaternium-30 Dimethicone copolyol Zinc pyrithione 48% Fragrance FD&C blue # 1 , 0 . 1 %
0

38.90% 1.00 0.10 5.00 16.00 16.00 4.00 0.25 12.00 0.30 1.30 1.00 0.20 2.50 0.40 1.05

Procedure. Disperse B in warm (45 C) A using rapid agitation. Reduce mixing speed and mix for 20 minutes. Partially neutralize with C Add D components in order shown to ABC using slow mixing. Disperse E and F, heat to help hydration. Add G; mix until uniform. Add E, F, and G to batch. Add H components in order shown to batch.

Antidandruff products can also be formulated in nonshampoo forms such as hairdressings or conditioners. Products in this category are formulated into two basic types depending on their form. Some products, such as hair conditioners, are designed to be rinsed from the hair shortly after application. From a regulatory perspective these products are similar to the shampoo products.

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Other antidandruff forms have been formulated to be left in the hair and not rinsed after application. These products are distinct from the rinse-off forms and do require slightly different labeling and, in some cases, different levels of active ingredients. As described, earlier these antidandruff products are drugs and subject to the OTC antidandruff final rule. As with all categories of OTC drugs, the composition and labeling for these products are closely controlled by the FDA. The OTC dandruff monograph requires specific compliance in five general areas: active ingredients, statements of identity, indications of usage, warnings, and directions for use. Since most of these vary slightly depending on the rinseoff/leave-on nature of the products, each of these forms will be tabulated in this section. A C T I V E INGREDIENTS The active ingredients for these products vary both with the intended use and with the rinseability of the formulation. Based on these considerations the active ingredients are identified below for their specific approved uses. Rinse-off products (including shampoos) The only active ingredients permitted at the present time for rinse-off products are as follows: For the treatment of dandruff, psoriasis, and/or seborrheic dermatitis: Coal tar 0.5-5%; salicylic acid 1.8-3% For the treatment of dandruff and/or seborrheic dermatitis: Selenium sulfide 1%. For the treatment of dandruff only: Zinc pyrithione 0.3-2%; sulfur 2-5%; selenium sulfide (micronized) 0.6%; the combination of sulfur and salicylic acid when both are used within their active level concentration ranges. For the treatment of seborrheic dermatitis only: Zinc pyrithione 0.95-2%. Leave-on products The only active ingredients permitted at the present time for leave-on products are as follows: For the treatment of dandruff, psoriasis, and seborrheic dermatitis: Coal tar 0.5-5%. When using this ingredient the labeling shall specify the identity and concentration of the coal tar, and its source; the other active is salicylic acid 1.8-3%. For the treatment of dandruff and seborrheic dermatitis: Zinc pyrithione 0.1-0.25%; selenium sulfide 1%. For the treatment of dandruff only: Sulfur 2-5%; selenium sulfide (micronized) 0.6%; the combination of sulfur and salicylic acid is sanctioned when both are used within their active level concentration ranges. In addition to the controlled use of these active ingredients, each product must be labeled with specific statements of identity, indications, warnings,

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and directions in compliance with the new OTC drug labeling regulations published in the Federal Register on March 17, 1999. The labeling regulations resemble those for other OTC drugs.

DRUG ASTRINGENTS
Drug astringents are subject to the final rule on astringent drug products (U.S Fed. Reg. 58, 54458, Oct. 21, 1993) and the amendment of June 3, 1994, Fed. Reg., 59, 28767). In these OTC monographs the FDA has defined these products narrowly as drug products that are "applied to the skin or mucous membranes for a local and limited protein coagulation effect." In line with this definition the only active ingredients approved for use as drug astringent products are aluminum acetate (0.13 to 0.5%), aluminum sulfate (46 to 63% based on the anhydrous equivalent) and Hamamelis Virginiana water (U.S.P.). The use of any other active ingredients or of these ingredients at concentrations outside the above ranges would make the product "non-monograph." The usual labeling requirements, including a statement of identity, indications, warnings, and directions, are required.

CORN/CALLUS REMOVER AND WART REMOVER DRUG PRODUCTS

Products that are intended to treat or remove corns, calluses, or warts are considered to be drugs under the Food and Drug Act. As such, any over-thecounter (OTC) products making claims for these effects must be in compliance with a final monograph for these indications. Although these categories are very similar, the FDA has separated wart removers from the corn and callus remover products and published two separate final monographs in the Federal Register. Both of these monographs were issued on August 14, 1990 (U.S. Fed. Reg. 55, 33245, 1990; U.S. Fed. Reg. 55, 33258, 1990); the amended U.S. Fed. Reg. 59, 60315, 1994. As with all OTC drugs, products making these claims must meet all of the monograph requirements for composition and labeling. In addition, as drug products, they must also meet the requirements for OTC labeling as published in the Federal Register of March 17, 1999. This includes full ingredient labeling and the identification of the percent of the active ingredients in the product. These monographs include several vehicles, for example, solutions or plasters.

Active Ingredients
The only active ingredients permitted in these products are various concentrations of salicylic acid in a variety of vehicles, which include adhesive plasters.

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Indications, directions, and warnings are those intended for topical drugs, not cosmetics. They are therefore not further discussed. REFERENCES 1. Imokawa, G., et al., The role of endothelin-1 in epidermal hyperpigmentation and signaling mechanisms of mitogenesis and melanogenesis, Pigment Cell Res., 1997, 10, 218-228. 2. Schmidt, A. and Rhl-Hrster, B., In vitro susceptibility of Malassezia furfur, Arzneim. Forsch. (Drug Res.), 1996, 46 (I), 442-444. 3. Ermolayeva, E., and Sanders, D., Mechanism of pyrithione-induced membrane depolarization of Neurospora crassa, Appl. Environ. Microbiol, 1995, 61(IX), 33855-3390.