-hydroxyoctanoic acid, and -hydroxydecanoic acid (Reference 1).
Draft released for comment on December 2, 2002.
Comments and suggestions regarding this draft guidance should be submitted by January 31, 2003, to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, room 1061, Rockville, MD 20852. All comments should be identified with the Docket Number 00P-1378. For questions regarding this draft guidance contact Julie N. Barrows, (202) 418-3412.
U. S. Department of Health and Human Services
Food and Drug Administration
Center for Food Safety and Applied Nutrition (CFSAN)
December 2, 2002
This draft guidance represents the Agency's current thinking on labeling for topically applied cosmetic products containing alpha hydroxy acids as ingredients. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of applicable statutes and regulations.
FDA has considered evidence that suggests that topically applied cosmetic products containing alpha hydroxy acids (AHAs) may increase the sensitivity of skin to the sun while the products are used and for up to a week after use is stopped, and that this increased skin sensitivity to the sun may increase the possibility of sunburn. The purpose of this guidance is to educate manufacturers to help ensure that their labeling for AHA-containing cosmetic products is not false or misleading. As an interim measure, while FDA continues to review the data on AHAs to address the potential for this increased skin sensitivity to the sun, FDA is suggesting that the labeling of a cosmetic product that contains an AHA as an ingredient and that is intended for topical application to the skin or mucous membrane bear a statement that conveys the following information.
Sunburn Alert: This product contains an alpha hydroxy acid (AHA) that may increase your skin's sensitivity to the sun and particularly the possibility of sunburn. Use a sunscreen and limit sun exposure while using this product and for a week afterwards.
Alpha hydroxy acids are organic acids with a hydroxyl group on the carbon adjacent to the carboxylic acid group. The predominant AHAs present in cosmetic products are glycolic acid and lactic acid. Other AHAs used in cosmetic products include citric acid, -hydroxyoctanoic acid, and -hydroxydecanoic acid (Reference 1).
Starting in 1994, the Cosmetic, Toiletry, and Fragrance Association's Cosmetic Ingredient Review (CIR) Expert Panel, FDA's AHA Review Committee, and FDA reviewed the safety of topically applied AHAs in cosmetic products (References 2 through 4). The reviewers evaluated human clinical studies that investigated the effects of ultraviolet (UV) radiation on the skin after exposure to AHAs. The studies demonstrated that topically applied AHAs increase skin sensitivity to UV radiation during application and that this increased skin sensitivity to UV radiation diminishes after discontinuing application for a week.
Sensitivity to UV radiation is the main reason for the skin's sensitivity to the sun (Reference 5). Short-term exposure to the sun may cause sunburn and chronic long-term exposure to the sun may increase risk of premature skin aging (Reference 5). Experimental and epidemiological studies have demonstrated that prolonged exposure to the UV radiation in sunlight is a primary risk factor for certain types of skin cancer (References 6 through 8).
The human clinical studies reviewed by the CIR Expert Panel, FDA's AHA Review Committee, and FDA provided data for the effects of UV radiation on the skin after short-term (up to 12 weeks) topical exposure to AHAs. The evidence from the clinical studies suggests that increased skin sensitivity to UV radiation may increase the possibility of sunburn for consumers. Adverse experience reports by consumers of increased sunburn after AHA use support this conclusion (Reference 2). The increased skin sensitivity to UV radiation also may result in other harmful effects to the skin, but the data currently available to CFSAN are inconclusive on this point. CFSAN is publishing this guidance and the suggested labeling information as an interim measure to educate manufacturers to help ensure that their labeling is not false and misleading while FDA continues to review the data on AHA-containing products.
Since the early 1990's, there has been a proliferation of AHA-containing cosmetic products available commercially and in salons (Reference 2). AHAs have been formulated into skin products, make-up, hair products, nail products, bath products, colognes, and suntan preparations. Most AHA-containing products are "leave on" products that are intended for daily use on the skin or mucous membrane or are "discontinuous use" products that are intended to be applied to the skin for a short period of time (e.g., less than an hour) followed by thorough rinsing. Salon products are usually discontinuous use products.
In 1992, in its Voluntary Cosmetics Registration Program, FDA received the first four registrations of new lines of cosmetic products containing glycolic acid (Reference 2). (The information is an incomplete market history as the data are reported voluntarily.) By 1997, the registrations of cosmetic product lines containing glycolic acid increased to forty-two, as glycolic acid and lactic acid were added to previously marketed lines of products.
From 1992 to 1996 and from 1999 to 2000, FDA conducted two market surveys of AHA-containing skin care products and found that the predominant AHAs present in the products were glycolic acid and lactic acid (References 1 and 2). Other AHAs found were citric acid, -hydroxyoctanoic acid, and -hydroxydecanoic acid (Reference 1).
Between 1989 and 1991, FDA received five reports from consumers that described adverse dermatologic experiences from a line of cosmetic skin care products that were labeled as containing AHAs, including glycolic acid (Reference 2). The reported adverse experiences were similar and included pigmentary changes, burning, and swelling. FDA issued a warning letter to the manufacturer on May 13, 1992, and the products were withdrawn from the market. Although FDA analyses found that the products did not contain an AHA, but rather phenol and resorcinol, FDA became aware of the expanded use of AHAs as ingredients in cosmetic products. Between 1992 and 1993, FDA received 10 reports of adverse dermatologic experiences with products that were determined by FDA to contain AHAs. In 1994, the number of reports increased to 32. FDA received a total of 107 adverse dermatologic experience reports for AHA-containing skin care products between 1992 and 2000, with the maximum number in 1994. The reported adverse experiences include burning (43), dermatitis or rash (33), swelling (26), pigmentary changes (15), blisters or welts (13), skin peeling (12), itching (12), irritation or tenderness (6), chemical burns (6), and increased sunburn (3).
The Cosmetic, Toiletry, and Fragrance Association (CTFA) submitted a citizen petition, dated June 29, 2000, assigned FDA Docket No. 00P-1378/CP1, which advocated sun protection labeling for AHA-containing cosmetic products. The petition noted that products containing AHAs currently represent a significant portion of the $6 billion domestic United States skin care market; approximately 1500 stock-keeping units of skin care products contain AHAs.
In the petition, CTFA requested that FDA issue a regulation under 21 U.S.C. 362(a) establishing labeling requirements related to sun protection with use of cosmetic products containing AHAs. The petition proposed the following regulation for part 701 of the Code of Federal Regulations (21 CFR Part 701--Cosmetic Labeling):
The label and labeling of a cosmetic product that contains an alpha hydroxy acid ingredient that is intended to function as an exfoliant shall bear the following prominent and conspicuous statement:
"Sun Alert: Because this product may make your skin more sensitive to the sun, be certain you have adequate sunscreen protection while using this product and for a week after you discontinue use."
CTFA's CIR Expert Panel, FDA's AHA Review Committee, and FDA reviewed the safety of topically applied AHAs in cosmetic products (References 2 through 4). The reviewers evaluated human clinical studies that investigated the effects of ultraviolet (UV) radiation on the skin after exposure to glycolic acid and lactic acid, as well as salts and esters prepared from glycolic or lactic acids. The salts and esters included ammonium, calcium, potassium, and sodium glycolates; methyl, ethyl, propyl, and butyl glycolates; ammonium, calcium, potassium, sodium, and triethanolamine (TEA) lactates; methyl, ethyl, isopropyl, and butyl lactates; and lauryl, myristyl, and cetyl lactates.
The human clinical studies measured sunburn cell (SBC) formation and change in the minimal erythema dose (MED). SBCs are apoptotic skin cells that are produced in response to UV radiation, primarily UVB, and the MED is the minimal amount of UV radiation needed to cause the skin to redden (References 2 and 5). Both skin responses, SBC formation and erythema (skin reddening), are characteristic of sunburn (Reference 5). The studies also measured UV-induced cyclopyrimidine dimer (CPD) formation, which is a type of DNA damage.
CTFA's CIR Expert Panel concluded from human clinical studies that AHA ingredients in cosmetic products increase skin sensitivity to UV radiation (UVB or solar-simulating radiation), as measured by SBC formation, which was found on average to increase, and as measured by change in the MED, which was found on average to decrease (Reference 3). In its final report, published in 1998 (Reference 3), the CIR Expert Panel reported the following conclusion: "Based on the available information included in this report, the CIR Expert Panel concludes that Glycolic and Lactic Acid, their common salts and their simple esters, are safe for use in cosmetic products at concentrations <10%, at final formulation pH >3.5, when formulated to avoid increasing sun sensitivity or when directions for use include the daily use of sun protection. These ingredients are safe for use in salon products at concentrations <30%, at final formulation pH >3.0, in products designed for brief, discontinuous use followed by thorough rinsing from the skin, when applied by trained professionals, and when application is accompanied by directions for the daily use of sun protection."
FDA's AHA Review Committee, which met on February 12, 1997, and May 6, 1997, agreed that the evidence suggests that topical application of AHAs increases skin sensitivity to UV radiation, as measured by increased SBC formation and decreased MED (Reference 4). The Committee noted that in the human clinical studies they reviewed, a small proportion of people showed an amplified effect on increased SBC formation or decreased MED.
FDA has evaluated the CTFA citizen petition and the safety reviews of topical application of AHAs by the CIR Expert Panel and the AHA Review Committee. FDA also has reviewed in detail six human clinical studies that provide data for assessing increased skin sensitivity to UV radiation produced by use of topically applied cosmetic products containing AHAs (Reference 2). Five of the studies measured increased SBC formation and/or decreased MED. The sixth study measured increased CPD formation. The studies used solar-simulating radiation and/or UVB radiation for determining baseline MEDs and for determining changes in MED and SBC or CPD formation. Although the studies investigated the effects of glycolic acid, FDA believes that the effects of other types of AHAs used in cosmetic products may be the same.
The human clinical studies that measured increased SBC formation or decreased MED found that topical application of glycolic acid at concentrations as low as 4% and for as short a duration as 4 days can alter the skin's response to UV radiation. Furthermore, the skin's enhanced sensitivity to UV radiation continues during exposure to glycolic acid of up to 12 weeks. Thus, the studies suggest that there is no compensatory mechanism by which the skin moderates the effects of an AHA on sensitivity to UV radiation. The studies also found that increased skin sensitivity to UV radiation no longer is evident 1 week after discontinuing topical application of glycolic acid. This suggests that AHA-induced sensitivity to UV radiation is reversible. However, further studies are required to determine how the length of time of AHA use affects the time required for reversal of AHA-induced effects. Skin sensitivity to UV radiation, measured as UV-induced CPD formation, may increase after 4 weeks of topical application of glycolic acid. However, the increase found (8%) is not statistically significant and suggests that further studies are required to determine the effects of AHA exposure on UV-induced CPD formation. Finally, the addition of sunscreens to cosmetic products containing AHAs, under some conditions of use, may help counter increased skin sensitivity to UV radiation.
In most of the studies reviewed, a subset of subjects appeared to be more susceptible to the effects of glycolic acid on UV-induced increased SBC formation and decreased MED. This suggests that some individuals are more responsive than others to AHA-induced increased skin sensitivity to UV radiation. However, the studies did not identify any basis for identifying this subset of sensitive individuals as a wide range of skin types was implicated.
The human clinical studies provided data for the effects of UV radiation on the skin after short-term (up to 12 weeks) topical exposure to AHAs. The evidence from the clinical studies suggests that increased skin sensitivity to UV radiation may increase the possibility of sunburn for consumers. Adverse experience reports by consumers of increased sunburn after AHA use support this conclusion (Reference 2). The increased skin sensitivity to UV radiation also may result in other harmful effects to the skin, but the data currently available to CFSAN are inconclusive on this point.
FDA's National Center for Toxicological Research (NCTR) is currently investigating the effects of long-term exposure to AHAs, in a photocarcinogenicity study by the National Toxicology Program's Center for Phototoxicology (Reference 2). The purpose of the NCTR study is to allow quantitative determination of the effect AHA treatment (glycolic acid) has on the induction of mouse skin cancer (SKH-1 hairless mouse) by simulated solar radiation.
In its citizen petition, CTFA requested that the labeling statement informing consumers about measures to take when using AHA-containing cosmetic products should say "Sun Alert: Because this product may make your skin more sensitive to the sun, be certain you have adequate sunscreen protection while using this product and for a week after you discontinue use."
FDA has reviewed information on the elements of effective labeling statements (Reference 2). This information indicates that an effective labeling statement would begin with a signal phrase, identify the subject of the statement, identify the consequences of not heeding the statement, and provide instructions on what to do (or not do) to avoid these consequences. The information suggests that removal of any of these elements significantly decreases the perceived effectiveness of the statement.
Based on this information, FDA has developed an alternate suggested statement and encourages manufacturers to use the following labeling statement for AHA-containing cosmetic products: "Sunburn Alert: This product contains an alpha hydroxy acid (AHA) that may increase your skin's sensitivity to the sun and particularly the possibility of sunburn. Use a sunscreen and limit sun exposure while using this product and for a week afterwards." FDA's basis for its suggested labeling is as follows.
First, FDA suggests a change in the signal phrase in the AHA labeling statement from "Sun Alert" to "Sunburn Alert". Clinical studies indicate that increased skin sensitivity to the sun from topical application of AHA-containing cosmetic products increases the possibility of sunburn for consumers.
Section 352.52 (e)(2) of the CFR (21 CFR 352.52(e)(2)) provides for the following optional "Sun alert" in the labeling of over-the-counter (OTC) sunscreen drug products: "Sun alert: Limiting sun exposure, wearing protective clothing, and using sunscreens may reduce the risks of skin aging, skin cancer, and other harmful effects of the sun." The "Sun alert" statement for OTC sunscreen drug products is intended to inform consumers of measures to take in addition to use of sunscreens for countering the risks of sun exposure. The suggested statement for AHA-containing cosmetic products is intended to inform consumers of a very different issue--the increased possibility of sunburn from using AHA-containing cosmetic products, and the need to use sun protection when using the products and for a week afterwards. Thus, the intended messages to consumers for OTC sunscreen drug products and AHA-containing cosmetic products are very different. Therefore, FDA is suggesting a different signal phrase to help identify the different intent of the statement for AHA-containing cosmetic products.
Second, FDA believes that the suggested AHA labeling statement should identify to consumers the subject of the statement (the AHA ingredient contained in the cosmetic products). Therefore, FDA is including the phrase "This product contains an alpha hydroxy acid (AHA)" in its recommended statement.
Third, FDA believes that the suggested AHA labeling statement should tell consumers about the consequences of not heeding the statement (that use of AHA-containing cosmetic products may increase their skin's sensitivity to the sun, and that this increased skin sensitivity to the sun may increase the possibility of sunburn). Therefore, FDA is including the phrase "may increase your skin's sensitivity to the sun and particularly the possibility of sunburn" in its recommended statement.
Fourth, FDA believes that the AHA labeling statement should provide instructions on what consumers can do to avoid these consequences (how to minimize the possibility of sunburn). In the sunscreen monograph published in the Federal Register of May 21, 1999 (64 FR 27666), which established the optional "Sun alert" for OTC sunscreen drug products, FDA stated that the purpose of that statement is to describe the role of sunscreens in a total program to reduce harmful effects from the sun. The statement recommends limiting sun exposure and wearing protective clothing in addition to using sunscreens.
The CTFA petition requested that the AHA labeling statement recommend the use of "adequate sunscreen protection" and cited the conclusion of the CIR Expert Panel review of AHAs (Reference 3) as support for its recommended label statement. The Expert Panel's conclusion, however, recommends "daily use of sun protection," and does not specifically mention sunscreens. FDA concurs with the conclusion of the Expert Panel and therefore is recommending the language "use a sunscreen and limit sun exposure" to suggest actions to implement the Expert Panel's recommendation of "daily use of sun protection." The agency believes that it is important to emphasize both steps together as part of an overall program for reducing the possibility of sunburn when using AHA-containing products. Sunscreens are effective for minimizing the possibility of sunburn, but sunscreens come off. An important limitation for sunscreens is the need for their frequent application for continued effective sun protection. Therefore, in addition to using sunscreens, consumers also should be mindful of limiting sun exposure.
FDA notes that wearing protective clothing is only relevant to use of certain AHA-containing products (e.g., body lotions) and that this recommendation is not applicable to a major use of AHA-containing products (face creams and moisturizers). FDA is concerned that consumer confusion over a labeling statement on a face product that recommends consumers to "wear protective clothing" for minimizing the possibility of sunburn from AHA use might cause consumers to discount the important recommendations to "use a sunscreen and limit sun exposure." Therefore, the agency has not included the phrase "wear protective clothing" in its recommended labeling statement.
Finally, FDA has altered the phrase "for a week after you discontinue use" to the more user friendly "for a week afterwards" in accordance with the use of plain language in its publications.
In its citizen petition, CTFA requested that FDA establish labeling requirements that inform consumers about measures to take when using AHA-containing cosmetic products. FDA has reviewed the petition and other information about labeling statements on AHA-containing cosmetic products and other consumer products. FDA also has considered information on consumer awareness of increased skin sensitivity from use of AHA-containing cosmetic products.
Labeling statements on consumer products are often used for communicating product safety information (Reference 2). The function of a labeling statement depends on the information environment in which a statement will be perceived and the content of the statement.
If consumers are unaware of an identified risk associated with a product, the function of a labeling statement will be to convey new information to the consumers. An example is the safety information labeling statement required by FDA on iron-containing dietary supplements and drugs (Federal Register of January 15, 1997, 62 FR 2218), which states, "WARNING. Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately."
If consumers are aware of the identified risk, the labeling statement will function as a reminder of the recommended precaution. One example is the labeling statement required by the U.S. Department of Agriculture on retail raw meat and poultry products (Federal Register of March 28, 1994, 59 FR 14528), which states, "Safe Handling Instructions. This product was prepared from inspected and passed meat and/or poultry. Some food products may contain bacteria that could cause illness if the product is mishandled or cooked improperly. For your protection, follow these safe handling instructions. Keep refrigerated or frozen; thaw in refrigerator or microwave. Keep raw meat and poultry separate from other foods; wash working surfaces (including cutting boards), utensils, and hands after touching raw meat or poultry. Cook thoroughly. Keep hot foods hot; refrigerate leftovers immediately or discard." Another example is the labeling statement required by FDA on cartons of shell eggs (Federal Register of December 5, 2000, 65 FR 76092), which states, "Safe Handling Instructions: To prevent illness from bacteria: keep eggs refrigerated, cook eggs until yolks are firm, and cook foods containing eggs thoroughly."
FDA believes that, like the iron statement, the recommended AHA labeling statement would help convey new information to most consumers. Both kinds of labeled products (cosmetics and dietary supplements) are widely used, and FDA's focus group research suggests that many consumers are not aware of possible risks associated with use of either of these types of products (Reference 2).
FDA also believes that, like the meat and egg statements, the AHA labeling statement would function as a reminder of FDA's recommended precautions to consumers who are already aware of this information.
Consumers use cosmetic products to maintain or improve the appearance of the body. Focus group research suggests that consumers generally believe cosmetic products are safe for their intended uses (Reference 2). FDA does not know the extent of consumer awareness of increased skin sensitivity to the sun from the use of AHA-containing cosmetic products. FDA has published information about this issue in its magazine, FDA Consumer, in which FDA recommends precautions that consumers should take when using an AHA-containing product, including using an effective sunscreen (Reference 2). The information also is available on FDA's website at http://www.cfsan.fda.gov/. However, in July 2001, as an example, only about 0.003% of U.S. households visited this website for information on AHAs (Reference 2).
FDA has not observed that the effect of AHAs on increased skin sensitivity to the sun has been widely publicized in the media or popular press, unlike the effect of AHAs on skin irritation (Reference 2). (In the early 1990s, consumers frequently experienced skin irritation from using AHA-containing cosmetic products. This concern was widely publicized to consumers and was addressed by manufacturers reformulating their products (Reference 3).)
To help assure consumer awareness of the potential for increased skin sensitivity to the sun from topical use of AHA-containing cosmetic products, FDA suggests that such products should bear information on their labeling such as the "Sunburn Alert" that helps convey information about the need for sun protection to avoid sunburn. FDA expects that a label statement such as the recommended "Sunburn Alert" will be a source of new information about sun protection for most consumers, as well as a reminder of FDA's recommended precautions for consumers who are already aware of the need to use sun protection when using these products (Reference 2).
To provide guidance to manufacturers on when FDA recommends that products should bear "Sunburn Alert" labeling, the agency has tentatively identified these use conditions:
1. The product contains an AHA as an ingredient;
2. The product is intended for topical application to the skin or mucous membrane. The product may be a "leave on" product that is intended to remain on the skin or mucous membrane or it may be a "discontinuous use" product that is intended to be left on the skin for a short period of time (less than an hour) followed by thorough rinsing.
In its citizen petition, CTFA proposed that the regulation establishing labeling requirements for cosmetic products that contain an AHA as an ingredient be restricted to products that are intended to function as an exfoliant.
FDA has traditionally determined intended use for a product from statements in the product's labeling. Between 1992 and 2000, FDA personnel evaluated products containing AHAs from retail stores in the Washington, DC, area and compiled a survey of label claims made for the products (Reference 2). AHA-containing products are labeled with a variety of claims for benefits of use to the skin, including exfoliating, moisturizing, cleansing, wrinkle reducing, softening, smoothing, texture improvement, increased firmness and elasticity, improvement of photodamage, skin protection, effects on skin structure and composition, soothing, healing, renewing, revitalizing, scar reduction, anti-aging, anti-acne, skin tone evening, skin lightening, skin conditioning, astringent, and oxygen boosting. Most products are labeled with several claims.
FDA's surveys found that, in 64 consumer products, exfoliation claims were the most common and were made on 50% of the products. The next most common claims were for anti-aging (38%), wrinkle and line reduction (38%), and softening and smoothing (36%). For salon products, exfoliation claims also were the most common and were made on 64% of the 33 products surveyed. The next most common claims also were for anti-aging (18%), wrinkle and line reduction (15%), and softening and smoothing (15%).
The survey suggests, therefore, that only half of the AHA-containing products on the market have an intended use as an exfoliant, as determined by the presence of "exfoliant" claims on the product labeling. Even some salon products containing high levels of AHAs did not specify "exfoliation" as an intended use.
The evidence reviewed so far by FDA suggests the possibility of sunburn from any AHA-containing product and not merely products labeled for exfoliant use. Therefore, FDA suggests a statement such as the "Sunburn Alert" be included in the labeling for all AHA-containing products.
21 U.S.C. 362(a) provides that a cosmetic is misbranded if its labeling is false or misleading in any particular. 21 U.S.C. 321(n) amplifies what is meant by "misleading." This section states that in determining whether labeling is misleading, an individual should take into account the extent to which the labeling fails to reveal facts material to results which may occur from the use of the product as it is labeled or customarily used (see also 21 CFR 1.21).
Based on evidence reviewed so far (including safety reviews conducted by the CIR Expert Panel, the AHA Review Committee, and FDA), FDA currently believes that topically applied cosmetic products containing AHAs may increase skin sensitivity to the sun while the products are used and for up to a week after use is stopped, and that this increased skin sensitivity to the sun may increase the possibility of sunburn. FDA believes that this conclusion may be a material fact that manufacturers should disclose to users under 21 U.S.C. 362(a), 21 U.S.C. 321(n), and 21 CFR 1.21. Accordingly, FDA believes that if manufacturers inform users of AHA-containing products about the potential for increased skin sensitivity to the sun and particularly the possibility of sunburn, and what steps a user may take to avoid such consequences, this will help avoid the potential that the products are misbranded under 21 U.S.C. 362(a) and 21 U.S.C. 321(n).
CTFA's citizen petition requested that FDA issue a regulation in part 701 of the CFR (21 CFR Part 701--Cosmetic Labeling) establishing a sun alert labeling statement for AHA-containing cosmetic products. FDA is issuing this draft guidance entitled "Guidance for Industry: Labeling for Topically Applied Cosmetic Products Containing Alpha Hydroxy Acids as Ingredients" rather than a proposed regulation.
FDA is issuing this draft guidance pending the results of the NCTR study because the agency believes interim action is warranted to recommend that manufacturers label topically applied cosmetic products that contain AHAs to alert consumers of the need to use sun protection when using these products. After assessing the results of the photocarcinogenicity study and the effectiveness of any final guidance, the agency intends to determine if additional agency action is appropriate.
Copies of this draft guidance are available on FDA's website at http://www.cfsan.fda.gov/~dms/guidance.html. Submit electronic comments to http://www.fda.gov/dockets/ecomments.
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