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NDMA BENZOYL PEROXIDE 13-WEEK RAT/MOUSE ONCOGENICITY STUDIES

This article was originally published in The Tan Sheet

Executive Summary

NDMA BENZOYL PEROXIDE 13-WEEK RAT/MOUSE ONCOGENICITY STUDIES are expected to begin by the end of the year. In an Oct. 20 letter to FDA, the Nonprescription Drug Manufacturers Association noted that it has "completed several 14-day studies to allow selection of the appropriate vehicle and dosages for the 13-week topical dose range-finding studies on benzoyl peroxide" and that "we intend to begin the 13-week studies as soon as possible." Revised protocols for the 13-week rat/mouse studies were included with the Oct. 20 letter. In an Oct. 26 response, FDA told NDMA that it would "provide feedback" on the 13-week study protocols as well as on reports from the 14-day studies "as soon as we complete our review" of the documents. NDMA expects to proceed with long-term, chronic oncogenicity studies soon after the 13-week studies are completed, assuming that they confirm the selected dose and vehicle. The 13-week studies "will give information on the expected [maximum tolerated dose] for the subsequent chronic oncogenicity studies" in mice and rats, the association noted. NDMA reported that benzoyl peroxide in acetone and in carbopol gel was applied to the backs of B6C3Fl mice in the 14-day studies. "These studies showed clear evidence of gross and histopathological effects in the skin but no evidence of systemic toxicity," NDMA told the agency. Similar results were observed when applying benzoyl peroxide in acetone and in carbopol gel to the backs of F344 rats in similar 14-day, repeat-dose studies, NDMA stated. Based on the results of the 14-day experiments in mice and rats, NDMA concluded that "the carbopol gel is the most suitable vehicle for oncogenicity evaluation of benzoyl peroxide." Regarding dose selection for the 13-week studies, NDMA said that the 14-day studies using carbopol gel as a vehicle showed that the ideal doses would be zero, 15, 45, 75 and 150 mg per day for rats, and zero, five, 15, 25, and 50 mg per day for mice. "The highest dose selected for both the rat study (50%, 150 mg/day) and the mouse study (50%, 50 mg/day) is the highest concentration that can be stably suspended in carbopol," NDMA noted. NDMA said it plans to "have complete histopathology evaluations conducted on all groups in the chronic oncogenicity studies," and that it is presently conducting "in vitro skin penetration studies to help understand the pharmacokinetics of topically applied benzoyl peroxide." Specifically, NDMA told FDA that it is "comparing skin penetration of multiple doses of benzoyl peroxide in carbopol vehicle in mouse and human skin explants." NDMA's Benzoyl Peroxide Study Group began looking into potential benzoyl peroxide tumorigenicity prior to FDA's decision in August 1991 to downgrade benzoyl peroxide from Category I (safe and effective) to Category III (data insufficient to permit classification). At that time, the agency said that additional data would be needed to determine if the ingredient is tumorigenic after studies in animals showed that benzoyl is a tumor promoter in rodents. Subsequently, FDA's Dermatologic Drugs Advisory Committee recommended in March 1992 that benzoyl peroxide-containing products remain on the market pending the results of ongoing carcinogenicity studies. In July of that year, NDMA met with the agency to discuss the oncogenicity studies at an "OTC feedback" meeting. According to FDA's most recent "unified regulatory agenda" published on Oct. 25, a proposed label warning for "topical drug products containing benzoyl peroxide" is slated for publication in February. The proposal is expected to solicit comments on the Dermatologic Drugs Advisory Committee's recommendation that benzoyl should remain on the market but that product labeling should indicate that there is a paucity of data on the ingredient's safety ("The Tan Sheet" April 26, In Brief). The proposal also is expected to request information specifically on whether teenagers, who are considered the target consumer group for benzoyl peroxide-containing products, heed the directions on over-the-counter drug labels. Benzoyl peroxide is used in a number of OTC anti-acne products including SmithKline Beecham's Oxy line and Clear by Design medicated gel, as well as Advanced Polymer Systems' Exact cream. On a separate matter relating to benzoyl peroxide, NDMA also told the agency on Oct. 20 that it is planning to use high-dose UV light as the positive control rather than 8-methoxypsoralen in upcoming photocarcinogenicity studies with benzoyl peroxide. The photocarcinogenicity studies are expected to commence "later this fall," NDMA said. FDA agreed with NDMA that "there would be no significant value in the use of 8-MOP" and advised the association to proceed with those studies.
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