FDA's OTC SUNSCREEN TENTATIVE FINAL MONOGRAPH DROPS PADIMATE A

FDA's OTC SUNSCREEN TENTATIVE FINAL MONOGRAPH DROPS PADIMATE A from the approved list of active sunscreen ingredients in the agency's OTC panel report recommendations. Aside from moving padimate A to nonmonograph status, the TFM appearing in the May 12 Federal Register includes the other 20 active ingredients listed in the Aug. 25, 1978 advanced notice of proposed rulemaking. FDA said it "cannot determine a 'safe' level" of padimate A "from the information available." Based on three studies of the ingredient, the TFM concludes that "5% padimate A is a weak phototoxic agent." The agency noted that "large but obtainable doses of UVA in human subjects are required in order to elicit clinically evident effects from padimate A, particularly if maximization factors are present." FDA is classifying padimate A "at 5% and higher concentrations in Category II [not safe] and in concentrations less than 5% in Category III [not enough data]." Among the studies cited in the TFM is a phototoxicity trial of aminobenzoic acid and its esters conducted by Kaidbey and Kligman, et al. that appeared in the Archives of Dermatology in 1978. That study, which used a solar simulator to produce a high UVA dose, "shows that it is possible to elicit human cutaneous phototoxicity with 5% padimate A at UVA doses that may be encountered by individuals during prolonged, intense sunlight exposure," the TFM states. FDA also received a mice and swine study that found that padimate A is not phototoxic in those animals at a lower UVA dose. The notice adds that "further studies should be designed to test these lower concentrations using maximization as well as 'normal use' procedures." In addition, FDA placed zinc oxide in Category III in the TFM although the ingredient was not listed in the 1978 panel report. FDA noted that it received one comment on the ingredient that cited a 1946 study published in the Journal of the American Medical Association showing that zinc oxide at 33.3% in white petrolatum "demonstrated sunscreen properties," according to FDA. However, the study included only one subject, which FDA concluded is insufficient to support effectiveness of the ingredient as a sunblock. While padimate A was dropped from Category I, padimate O was placed in the TFM after FDA resolved safety concerns that stemmed from the discovery of a new nitrosamine associated with the ingredient in 1989. After studying padimate O for potential mutagenic and genotoxic effects and after analyzing the nitrosamine, the agency concluded in the TFM that padimate O "is a safe and effective OTC sunscreen ingredient" and that the presence of the nitrosamine "is the result of poor manufacturing practices." The TFM reports that the nitrosamine, N-methyl-N- nitrosoaminobenzoate octyl ester (NMPABAO), can be assayed using two different analytical methods developed by the agency and Schering-Plough. FDA said it recently analyzed 25 marketed sunscreens for the nitrosamine and found NMPABAO in 11 of the samples "at levels up to 21,020" parts per billion. The agency noted that four of the samples also contained an indirect nitrosating agent, 2-bromo-2-nitro-1,3-propanediol. "If these products were formulated without the nitrosating agent," the TFM concludes, "there would be no nitrosamine contamination." FDA said it is "considering establishing limits for the amount of NMPABAO that may be present in a sunscreen drug product." Although not included in the formal TFM, the document includes a proposal for comment "that OTC sunscreen drug products must contain less than 500 ppb" of the nitrosamine. Products surpassing the limit, FDA noted, "would be considered to be adulterated." Regarding safety concerns related to the presence of NMPABAO in sunscreens, FDA said the toxicological data available at the time "indicated that [the nitrosamine] does not have mutagenic or carcinogenic potential." FDA also noted that photostability studies have shown "that the nitrosamine decomposes rapidly when exposed to UV radiation." The agency concluded that the risk associated with NMPABAO contamination "is very low." In addition to padimate O (up to 8%), the Category I ingredients listed in the TFM include: aminobenzoic acid (up to 15%); cinoxate (up to 3%); diethanolamine methoxycinnamate (up to 10%); digalloyl trioleate (up to 5%); dioxybenzone (up to 3%); ethyl 4[bis(hydroxypropyl)] aminobenzoate (up to 5%); glyceryl aminobenzoate (up to 3%); homosalate (up to 15%); lawsone (up to .25%) with dihydroxyacetone (up to 3%); menthyl anthranilate (up to 5%); octocrylene (up to 10%); octyl methoxycinnamate (up to 7.5%); octyl salicylate (up to 5%); oxybenzone (up to 6%); phenylbenzimidazole sulfonic acid (up to 4%); red petrolatum (up to 100%); sulisobenzone (up to 10%); titanium dioxide (up to 25%); and trolamine salicylate (up to 12%). [See chart on page 14 for complete list of ingredients considered under the sunscreen TFM.] Under the TFM, FDA will allow the combination of two monographed sunscreen ingredients in an OTC sunscreen product. As a result of comments related to combination products, FDA agreed not to set lower limits for concentrations of the Category I ingredients in order to give companies greater flexibility in formulating combination products at lower SPF ranges. However, the TFM does propose minimum concentrations of the ingredients when used in combination products to ensure that each ingredient contributes to the product. The TFM also allows for sunscreen formulations with a minimum SPF of 2 that combine Category I sunscreen ingredients with certain Category I skin protectant ingredients, such as allantoin, cocoa butter, dimethicone, glycerin, petrolatum, shark liver oil and white petrolatum. FDA noted that it received one comment and three petitions covering the inclusion of four separate ingredients in the sunscreen rulemaking. However, none of the four ingredients, which have been available in Europe, received a Category I listing in the TFM. The comment, submitted by E. Merck, requested that 3-(4- methylbenzylidene)-camphor (also known as Eusolex 6300) be included in the monograph based on three studies in 70 subjects and on a marketing history in Europe and the U.S. during the 1970s. The company noted that the panel at one point in its deliberations recommended that the ingredient be placed in Category I but that the panel report put the ingredient in Category III. FDA concluded that it could not make a decision on the ingredient until the company was able to document the ingredient's marketing history. Because no new data or information has been submitted to support the ingredient's inclusion in the monograph, the TFM lists it as Category III. The three petitions relate to ethoxylated ethyl-4- aminobenzoate (also known as PEG-25 PABA), isoamyl-p- methoxycinnamate, and avobenzone (also known as Parsol 1789), which have all been marketed in Europe for at least 12 years. FDA said it "is currently considering these petitions, but has not yet reached a decision concerning the use of foreign marketing data as the sole basis to support the inclusion of an ingredient in the OTC drug review." The agency pointed out that any decision on the petitions also will affect Eusolex 6300. FDA added that it is "deferring a decision" on the three petitions in order not to "unduly delay publication" of the TFM and that a decision will be announced in "a future Federal Register notice." FDA decided that avobenzone is a "new drug" in 1986 and, therefore, requires an approved NDA for marketing. Two companies, Schering-Plough (Shade UVAguard) and Herbert Labs (Photoplex), now market in the U.S. avobenzone-containing sunscreen products that carry claims for blocking UVA rays. Chart omitted.