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Executive Summary

BENZOYL PEROXIDE "IS NOT CARCINOGENIC," NDMA MAINTAINS in a May 15 submission to FDA in response to a Feb. 1 feedback letter from the agency. The Nonprescription Drug Manufacturers Association submission states: "When the entire body of data relating to the safety of benzoyl peroxide is considered, the cumulative weight of all scientific evidence clearly indicates that benzoyl peroxide is not carcinogenic and thus is safe for its intended use in OTC drug products, and therefore fulfills monograph conditions." The NDMA submission is preparatory to an FDA feedback meeting on benzoyl peroxide scheduled for June 28. Benzoyl peroxide is currently Category I in the tentative final monograph for acne products. It is a standard anti-acne ingredient in OTC products such as Clearasil, Oxy and Fostex brands. In the feedback letter, FDA Division of OTC Drug Evaluation Director William Gilbertson said that the agency has "reviewed the currently available data and information submitted to support the safety of benzoyl peroxide used in OTC acne drug products and has determined that the definitive study to assess complete carcinogenicity of benzoyl peroxide (according to current criteria) has not been conducted." Further, the letter stated that "the possibility that benzoyl peroxide might be a weak, slow acting carcinogen cannot as yet be ruled out." FDA based its concerns on several factors: "evidence shows that benzoyl peroxide is a skin tumor promoter" in some laboratory animals; the ingredient "shares a spectrum of characteristic features with the true initiators (i.e., complete carcinogens)"; as an "initiator," benzoyl peroxide "may have a long latency period," and therefore "study duration is a critical issue"; "topical studies (which have shown only 'promotion') have been of short duration (about 52 weeks) which is insufficient to rule out the possibility of 'initiation'"; it "has shown weak mutagenic activity in the Ames test"; and "limited data from a single study in chicken eggs has attributed moderate fetotoxic and teratogenic activities to benzoyl peroxide." NDMA maintained that there has been a "misunderstanding of terminology pertaining to tumor initiation, promotion and progression, such that FDA's feedback letter misinterpreted the experimental data and reached an improper conclusion regarding the safety of benzoyl peroxide for use as an OTC treatment of acne." For example, NDMA's Benzoyl Peroxide Study Group asserted that FDA misunderstood the concept of tumor promotion. "Contrary to the generalizations in the FDA feedback letter,...there is no standard animal model for detecting potential human tumor promoters, and it is not known whether tumor promotion as demonstrated in mouse skin even occurs in human skin," the association said. "While benzoyl peroxide has been shown to have tumor promoting activity in certain selected animal models, there is no valid scientific basis on which to extrapolate this experimental finding to a determination of human carcinogenic risk," it added. The association disagreed with FDA's suggestion that the ingredient may have a long latency for carcinogenicity, stating that it is "speculation that is not supported by the available data." Benzoyl peroxide "has been shown to not be an initiator and has consistently been found to have no effect on tumor incidence in studies to assess complete carcinogenic potential," NDMA noted. Replying to FDA's request for additional in vitro testing on the ingredient, NDMA said it has already been "extensively" tested in vitro and that additional tests "would add little to the assessment of the safety of this material." In addition, FDA's observation that in one study the ingredient showed fetotoxic and teratogenic effects on chicken embryos "does not indicate that benzoyl peroxide is likely to be developmentally toxic in mammals," NDMA noted. In addition, the trade association plans to submit to FDA results of an epidemiologic study that was conducted in Canada and purportedly shows "there is no statistically significant association between benzoyl peroxide use and the subsequent development of skin cancer in humans." The final report of the study is "nearly complete," NDMA said. The group also reiterated its promise to conduct an additional animal study to provide further data on the ingredient's safety and said it is developing a protocol that will be submitted to FDA for review prior to initiation.

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