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Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 9767 United States in support of the U.S. PART 65—CERTIFICATION: AIRMEN with annual sales less than $25,000 is Armed Forces’ operation during some OTHER THAN FLIGHT March 2, 2012. The compliance date for period of time from September 11, 2001, CREWMEMBERS products containing benzoyl peroxide to termination of SFAR 100–2; subject to part 21 CFR part 333 with ■ 5. The authority citation for part 65 annual sales of $25,000 or more is (b) The person’s flight instructor continues to read as follows: March 4, 2011. certificate, airman written test report, or inspection authorization expired some Authority: 49 U.S.C. 106(g), 40113, 44701– FOR FURTHER INFORMATION CONTACT: 44703, 44707, 44709–44711, 45102–45103, Matthew R. Holman, Center for Drug time between September 11, 2001, and 45301–45302. 6 calendar months after returning to the Evaluation and Research, Food and United States or termination of SFAR Issued in Washington, DC, on February 22, Drug Administration, 10903 New 2010. Hampshire Ave., Bldg. 22, MS 5411, 100–2, whichever is earlier; and J. Randolph Babbitt, Silver Spring, MD 20993, 301–796– (c) The person complies with § 61.197 Administrator. 2090. or § 65.93 of this chapter, as [FR Doc. 2010–4580 Filed 3–3–10; 8:45 am] SUPPLEMENTARY INFORMATION: appropriate, or completes the BILLING CODE 4910–13–P appropriate practical test within 6 Table of Contents calendar months after returning to the I. Glossary United States, or upon termination of DEPARTMENT OF HEALTH AND II. Purpose of this Final Rule SFAR 100–2, whichever is earlier. HUMAN SERVICES III. Past FDA Actions or Activities 3. Required documents. The person Related to this Final Rule must send the Airman Certificate and/ Food and Drug Administration IV. FDA’s Conclusions on Safety or Rating Application (FAA Form 8710– Only 3 days Cure your A. Genotoxicity acnes! 1) to the appropriate Flight Standards 21 CFR Part 333 B. Tumor Promotion With Chemical District Office. The person must include Initiation RIN 0910—AG00 with the application one of the [Docket Nos. FDA–1981–N–0114 and FDA– C. Tumor Promotion With Ultraviolet following documents, which must show http://www.cureacnes.info 1992–N–0049] (formerly Docket Nos. Initiation the date of assignment outside the 1981N–0114A and 1992N–0311) D. Carcinogenicity United States and the date of return to E. Photocarcinogenicity Classification of Benzoyl Peroxide as F. Epidemiological Data the United States: Safe and Effective and Revision of G. Overall Conclusion (a) An official U.S. Government Labeling to Drug Facts Format; Topical V. FDA’s Conclusions on Labeling notification of personnel action, or Acne Drug Products for Over-The- A. Past FDA Requirements for equivalent document, showing the Counter Human Use; Final Rule Labeling person was a civilian on official duty for B. Carton Labeling the U.S. Government outside the United AGENCY: Food and Drug Administration, C. Consumer Package Insert States and was assigned to a U.S. Armed HHS. D. Overall Conclusion Forces’ operation some time between ACTION: Final rule. VI. Analysis of Impacts September 11, 2001, to termination of A. Need for and Objectives of the Rule SUMMARY: We, the Food and Drug B. Number of Products Affected SFAR 100–2; Administration (FDA), are issuing this C. Cost to Relabel (b) Military orders showing the person final rule to include benzoyl peroxide as was assigned to duty outside the United D. Benefits of This Rule a generally recognized as safe and E. Alternatives and Steps Taken to States and was assigned to a U.S. Armed effective (GRASE) active ingredient in Minimize Impacts on Small Entities Forces’ operation some time between over-the-counter (OTC) topical acne F. Impact on Small Business September 11, 2001, to termination of drug products. In addition, this final G. Summary of Analysis SFAR 100–2 ; or rule includes new warnings and VII. Paperwork Reduction Act of 1995 (c) A letter from the person’s military directions required for OTC acne drug VIII. Environmental Impact commander or civilian supervisor products containing benzoyl peroxide. IX. Federalism providing the dates during which the We are also revising labeling for OTC X. References person served outside the United States topical acne drug products containing resorcinol, resorcinol monoacetate, I. Glossary and was assigned to a U.S. Armed salicylic acid and/or sulfur to meet OTC • ANPR: Advance Notice of Proposed Forces’ operation some time between drug labeling content and format Rulemaking September 11, 2001, to termination of requirements in a certain FDA • CFR: Code of Federal Regulations SFAR 100–2. regulation. This final rule is part of our • CHPA: Consumer Healthcare 4. Expiration date. This Special ongoing review of OTC drug products Products Association (formerly Federal Aviation Regulation No. 100–2 and represents our conclusions on Nonprescription Drug is effective until further notice. benzoyl peroxide in OTC acne drug Manufacturers Association) products. • Committee: Dermatologic Drugs PART 63—CERTIFICATION: FLIGHT DATES: Effective Date: This rule is Advisory Committee CREWMEMBERS OTHER THAN effective on March 4, 2011. • FDA: Food and Drug srobinson on DSKHWCL6B1PROD with RULES PILOTS Compliance Date: The compliance Administration date for products containing resorcinol, • FR: Federal Register ■ 4. The authority citation for part 63 resorcinol monoacetate, salicylic acid, • GRASE: Generally Recognized as continues to read as follows: and/or sulfur subject to 21 CFR part 333 Safe and Effective Authority: 49 U.S.C. 106(g), 40113, 44701– is March 4, 2015. The compliance date • NDA: New Drug Application—an 44703, 44707, 44709–44711, 45102–45103, for products containing benzoyl application submitted to FDA to 45301–45302. peroxide subject to 21 CFR part 333 market a new drug under section VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00015 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info 9768 Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 505 of the Federal Food, Drug, and established § 201.66. The revisions that manufacturers could continue to Cosmetic Act (21 CFR part 314) necessary to comply with the market acne drug products containing • OTC: Over-the-Counter—medicines requirements of § 201.66 were minimal. benzoyl peroxide until the safety issues sold without a prescription were resolved. • Panel: Advisory Review Panel on III. Past FDA Actions or Activities To help us resolve the safety issues, OTC Antimicrobial (II) Drug Related to this Final Rule we requested comments on the safety of Products In the Federal Register of March 23, these products, stating that we would • SKU: Stock Keeping Unit—an 1982 (47 FR 12430), we published an discuss these issues with an Advisory identifier that is used by merchants ANPR to establish a monograph for OTC Committee (Committee) shortly after the to permit the systematic tracking of topical acne drug products (the 1982 1991 proposed rule published. In 1992, products and services offered to ANPR). The 1982 ANPR included the a few months after the 1991 proposed customers recommendations of the Advisory rule published, we discussed the • TPA: 12-O-tetradecanoylphorbol Review Panel on OTC Antimicrobial (II) available benzoyl peroxide safety and 13-acetate—a powerful tumor Drug Products (the Panel). The Panel efficacy data at an Advisory Committee promoter concluded that benzoyl peroxide, in meeting. The Committee made the • U.S.C.: United States Code— concentrations of 2.5 to 10 percent, is following recommendations: compilation of Federal laws safe and effective for OTC topical use to • New photocarcinogenicity studies • UVA: Ultraviolet A radiation— treat acne. The Panel recognized that on benzoyl peroxide should be ultraviolet radiation with a benzoyl peroxide is a dose-dependent conducted. wavelength between 400 and 320 skin irritant that can also lead to • Current animal safety data nanometers sensitization. Therefore, the Panel regarding benzoyl peroxide should be • UVB: Ultraviolet B radiation— recommended the following warnings conveyed in labeling. ultraviolet radiation with a Only 3 days be included in labeling: Cure your • Acne drug products containing acnes! wavelength between 320 and 280 • Do not use benzoyl peroxide on benzoyl peroxide should stay on the nanometers very sensitive skin. market while new studies are being • UVR: Ultraviolet radiation—UVC, • Keep benzoyl peroxide products performed. UVB, and UVA radiation (1–400 http://www.cureacnes.info away from the eyes, lips, and mouth. The Committee’s recommendations nanometers) • Benzoyl peroxide may bleach hair applied to both prescription and OTC • We: Food and Drug Administration or dye fabric. acne drug products. The 1985 proposed rule proposed During the Advisory Committee II. Purpose of this Final Rule conditions under which OTC topical meeting, industry representatives stated This final rule establishes conditions acne drug products are GRASE and not that published studies in mice showed under which OTC drug products misbranded. We agreed with the Panel’s no evidence of benzoyl peroxide being containing benzoyl peroxide for the recommendations, and the 1985 photocarcinogenic (Refs. 1 and 2). topical treatment of acne are GRASE proposed rule proposed that 2.5 to 10 However, the Committee concluded that and not misbranded. In the Federal percent benzoyl peroxide is GRASE for the studies were insufficient to Register of January 15, 1985 (50 FR the treatment of acne. The 1985 determine whether benzoyl peroxide is 2173), we published a proposed rule in proposed rule also proposed requiring carcinogenic. The Committee indicated which 2.5 to 10 percent benzoyl the benzoyl peroxide warnings that the studies were inconclusive peroxide is proposed GRASE for the recommended by the Panel. because none of the studies used topical treatment of acne (the 1985 In the Federal Register of August 16, sufficient numbers of mice and the mice proposed rule). In the Federal Register 1991 (56 FR 41008), we issued a final should have been observed over their of August 7, 1991 (56 FR 37622), we rule for OTC topical acne drug products entire lifespan. Therefore, the issued a proposed rule which proposed (the 1991 final rule). In the 1991 final Committee unanimously agreed that a to classify benzoyl peroxide as category rule, we established conditions under new photocarcinogenicity study should III (i.e., ‘‘more-data-needed’’) instead of which OTC topical acne drug products, be conducted. category I (GRASE) based on safety except those containing benzoyl The Committee recommended, by a concerns that arose at that time (the peroxide, are GRASE and not four-to-three vote (with one abstention), 1991 proposed rule). Following the 1991 misbranded. We also issued the 1991 that the known safety data regarding the proposed rule, new data were submitted proposed rule which proposed to tumor promoting potential of benzoyl to address our safety concerns. After classify benzoyl peroxide as category III peroxide should be communicated to reviewing the data, we now conclude instead of category I (GRASE) based on consumers. Because this data was that benzoyl peroxide can be adequately safety concerns. Category III means that inconclusive, the Committee labeled to minimize the risks associated we need more data before we can unanimously agreed that the word with benzoyl peroxide while delivering properly classify benzoyl peroxide as ‘‘cancer’’ should not be included in the effective acne treatment. Therefore, we GRASE. This proposed classification of labeling of acne drug products are classifying benzoyl peroxide as benzoyl peroxide as Category III came containing benzoyl peroxide. The category I in this final rule. after considering new safety data and Committee was concerned that the word In addition, this final rule requires information suggesting that benzoyl ‘‘cancer’’ would cause consumers to that OTC acne drug products containing peroxide may initiate tumor formation avoid using these products (even though benzoyl peroxide, resorcinol, resorcinol and promote tumor development in the data were inconclusive). The monoacetate, salicylic acid, and/or animals. We stated in the 1991 proposed Committee did not believe the data srobinson on DSKHWCL6B1PROD with RULES sulfur be relabeled. We revised the rule that it is unclear whether these adequately demonstrated that benzoyl warnings and directions for these findings in animals can be extrapolated peroxide was unsafe, and they products such that they meet the to humans. We also stated that further recognized that benzoyl peroxide is content and format requirements in studies were necessary to adequately effective in treating acne. Therefore, the § 201.66 (21 CFR 201.66). When the assess the tumor promotion and Committee unanimously recommended final rule for these products was carcinogenic potential of benzoyl that acne drug products containing established in 1991, we had not yet peroxide. In the meantime, we noted benzoyl peroxide should remain on the VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00016 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 9769 market while the additional safety benzoyl peroxide may be genotoxic (56 tumor promoter alone will not cause studies were being conducted. FR 37622 at 37627 and 37628). cancer. In the 1991 proposed rule, we In the Federal Register of February Genotoxic substances are capable of reviewed animal studies examining the 17, 1995 (60 FR 9554), we issued a causing genetic mutations and ability of benzoyl peroxide to act as a proposed rule for all OTC and chromosomal changes that can tumor promoter in the presence of a prescription acne drug products contribute to the development of tumors chemical tumor initiator. The tumor containing benzoyl peroxide in which and possibly cancer. Six in vitro studies promoter studies were conducted by we agreed with all of the Committee’s examining deoxyribonucleic acid (DNA) applying a known tumor initiator at the recommendations (the 1995 proposed breaks in various mammalian cells were beginning of a study and then later rule). When stating the need for reviewed in the 1991 proposed rule. applying the suspected tumor promoter, additional safety studies, we noted that Benzoyl peroxide was shown to produce benzoyl peroxide, at multiple times the Nonprescription Drug DNA breaks in five of the six studies. In throughout the remainder of the study. Manufacturers Association (since addition, the 1991 proposed rule Because tumor promotion was observed renamed Consumer Healthcare Products reviewed six Ames tests. The Ames test in almost all the studies, we concluded Association (CHPA)) was conducting is a standard biological assay to assess that benzoyl peroxide is a skin tumor photocarcinogenicity studies at that the mutagenic potential of chemical promoter, in the presence of a chemical time. We also proposed labeling to compounds using the bacteria tumor initiator, in more than one strain communicate the results of the animal Salmonella typhimurium or Escherichia of mice and other laboratory animals (56 studies. The labeling included warnings coli. Five of the tests demonstrate that FR 37622 at 37631). We continue to and directions that would appear in the benzoyl peroxide is not mutagenic, believe that benzoyl peroxide is a tumor Drug Facts box of OTC acne drug while one demonstrates it is a weak promoter in animals when combined products containing benzoyl peroxide. mutagen. Finally, we discussed three with a chemical tumor initiator. In addition, we proposed requiring other in vitro genotoxicity studies in the Only 3 days Cure your acnes! package inserts for OTC and 1991 proposed rule. One study suggests C. Tumor Promotion with Ultraviolet prescription acne drug products that benzoyl peroxide is not mutagenic, Initiation containing benzoyl peroxide. We while two studies suggest that it is a requested that manufacturers http://www.cureacnes.info weak mutagen. In the 1991 proposed rule, we voluntarily implement the proposed Even though some of the in vitro discussed a tumor promotion study in labeling as soon as possible. As studies suggest that benzoyl peroxide which ultraviolet (UV) radiation was the recommended by the Committee, the may be a weak mutagen, the negative initiator (56 FR 37622 at 37629). The proposed package inserts included the studies along with the overall backs of albino hairless mice were word ‘‘tumor’’ but not ‘‘cancer.’’ We also genotoxicity profile do not warrant irradiated three times per week for 8 agreed with the Committee that these concluding that benzoyl peroxide is a weeks. After completion of the UV drug products should stay on the genotoxic agent. In accordance with ICH irradiation cycles, benzoyl peroxide was market. To support this position, we S2A Guidelines (the guidelines), a applied to the backs 5 times per week discussed human epidemiological single positive result in any genotoxicity for 50 weeks. In this study, benzoyl studies conducted at that time assay does not necessarily mean that the peroxide was not a tumor promoter with suggesting that the use of benzoyl test compound poses a genotoxic hazard UV initiation. peroxide does not increase the risk of to humans (Ref. 5). The guidelines state There were no other UV initiation facial skin cancer in humans (Refs. 3 that ‘‘any in vitro positive test result tumor promoter studies until after and 4). should be evaluated for its biological publication of the 1995 proposed rule, relevance.’’ We believe that the positive IV. FDA’s Conclusions on Safety when CHPA submitted a new study genotoxicity results are likely due to the We now conclude that benzoyl entitled ‘‘The Skin Tumor Promoting oxidative DNA damage caused by peroxide, in concentrations of 2.5 to 10 Potential of Benzoyl Peroxide Carbopol benzoyl peroxide, which has been percent, is GRASE for the OTC topical Gel Following UVR Initiation in SKH-1 shown in numerous studies (Refs. 6, 7, treatment of acne. This conclusion is Albino Mice’’ (Ref. 10). The study and 8). In humans, there are oxidative based on safety data that we received repair mechanisms that would likely compares benzoyl peroxide’s tumor and evaluated since publication of the prevent benzoyl peroxide from causing promoting capability on mice exposed 1995 proposed rule that proposed DNA damage (Ref. 9). Therefore, we to UV radiation to that of a known classifying benzoyl peroxide as Category believe there is no significant biological chemical tumor promoter, 12-O- III. As recommended by the Committee, relevance of the mixed results from the tetradecanoylphorbol 13-acetate (TPA). these new data include studies in vitro genotoxicity studies. Six groups of mice were irradiated for examining the carcinogenic and 6 weeks (5 days per week) with a daily B. Tumor Promotion Wth Chemical dose of 0.2 joules per square centimeter photocarcinogenic potential of benzoyl Initiation ultraviolet B (UVB, 290–320 peroxide. In addition to discussing these new studies in this section of the In the 1991 proposed rule, we nanometers) radiation. Another six document, we provide a summary of discussed concerns that benzoyl groups of mice were not exposed to earlier studies discussed in previous peroxide may be a tumor promoter in UVB radiation. After a 1-week rest OTC acne drug product rulemakings. the presence of a chemical tumor period, benzoyl peroxide or TPA were We believe the combined results of the initiator (56 FR 37622 at 37631). A applied on the mice as outlined in table earlier and new studies support the tumor promoter increases tumor 1 of this document. Acetone was also srobinson on DSKHWCL6B1PROD with RULES GRASE finding for benzoyl peroxide formation and growth as well as applied because TPA was dissolved in (see section IV.G of this document). conversion of benign tumors to acetone, so acetone was a control. The malignant tumors after exposure to a test materials were applied to the backs A. Genotoxicity tumor initiator (e.g., a chemical or UV and sides of the mice. The mice were In the 1991 proposed rule, we radiation). However, a tumor promoter treated for 40 weeks and then observed discussed studies suggesting that is not a carcinogen and exposure to a for a 12-week treatment-free period. VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00017 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info 9770 Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations TABLE 1.—TREATMENT GROUPS IN UV INITIATION TUMOR PROMOTER STUDY OF ALBINO MICE Treatment Groups1,2 1 2 3 4 5 6 7 8 9 10 11 12 UVB irradiation - - - - - - + + + + + + Benzoyl peroxide - 0.1% 1.5% 5% - - - 0.1% 1.5% 5% - - TPA in acetone - - - - + - - - - - + - Acetone - - - - - + - - - - - + 1+ Denotes the presence of UVB radiation, TPA, or acetone. 2 - Denotes the absence of UVB radiation, TPA, or acetone. The study authors assessed tumor carcinogenicity studies and a report to survival, body weight, food promotion ability by comparing two support their conclusion that benzoyl consumption, or gross pathology, and endpoints in mice treated with vehicle peroxide is not a carcinogen (47 FR neither produced any evidence of and those treated with benzoyl peroxide 12430 at 12443 to 12444). In the 1991 systemic toxicity. The dosing used in as follows: (1) The percent of mice with proposed rule, we stated that ‘‘* * *[a] the study (0.17, 0.83, and 2.5 mg per tumors and (2) the number of tumors definitive study to assess the complete cm2) probably represents the dosing per mouse. At the end of the study, the Only 3 days carcinogenicity of benzoyl peroxide has Cure your used by humans under actual use acnes! percent of mice with tumors was the not, as yet, been conducted’’ (56 FR conditions. Because these studies were same in the vehicle-treated group 37622 at 37630). In that document, we well-designed and conducted for the (Group 7) and the group treated with 0.1 state that benzoyl peroxide did not animals’ lifespan, we believe they percent benzoyl peroxide (Group 8). The http://www.cureacnes.info produce cancer in the following studies adequately exclude the possibility that percent of mice with tumors in the conducted on mice and rats that were benzoyl peroxide is a carcinogen with a groups treated with 1.5 or 5 percent not reviewed by the Panel (56 FR 37622 short or long latency period. benzoyl peroxide (Groups 8 and 9) was at 37623 to 37626): much higher than the vehicle or 0.1 • Four studies using oral E. Photocarcinogenicity percent groups. The number of tumors administration Our review of a photocarcinogenicity per mouse in the groups treated with 1.5 • Three studies using subcutaneous study submitted after the 1995 proposed or 5 percent benzoyl peroxide (Groups administration rule suggest that benzoyl peroxide is not 8 and 9) was much higher than the • Five studies using topical a photocarcinogen. The design of vehicle or 0.1 percent groups. The administration We explain that, because these studies photocarcinogenicity studies is similar results from this study suggest that to that of the tumor promoter studies benzoyl peroxide causes tumor were not of a sufficient duration, they were not sufficient to assess the discussed in the previous section of this promotion in a dose-dependent manner. document but differ in the exposure to The results from the study submitted carcinogenicity of benzoyl peroxide. We state that long-term (i.e., over the entire UV radiation. The tumor promoter in 1995 by CHPA and the study animal lifespan) carcinogenicity studies studies are designed so that animals are discussed in the 1991 proposed rule need to be conducted in two rodent exposed to UV radiation for a short time produced contradictory results. species to understand whether benzoyl and then exposed to benzoyl peroxide Therefore, it is difficult to draw any peroxide is a carcinogen with a long (in the absence of UV radiation) for final conclusions regarding tumor latency period (56 FR 37622 at 37631). nearly the animals’ entire lifespan. promotion with benzoyl peroxide in the After publication of the 1995 Photocarcinogenicity studies involve presence of UV radiation from these two proposed rule, we collaborated with exposure to UV radiation and benzoyl studies. As with the genotoxicity CHPA to develop carcinogenicity study peroxide simultaneously for the studies, the biological relevance of the protocols (Refs. 11 through 14). In 2001, animals’ lifespan. tumor promotion studies results needs to be determined. Drug dosing in tumor CHPA submitted a mouse and a rat The 1991 proposed rule did not promoter studies does not reflect actual carcinogenicity study (Ref. 15). Both include a discussion of any human use conditions, making it studies were conducted using a photocarcinogenicity studies because difficult to interpret the results and carbopol benzoyl peroxide gel none were available at the time. Two extrapolate to human use. The relevance administered topically for 2 years. published photocarcinogenicity studies of the animal tumor promoter study Neither study demonstrated that in mice, whose results had been results to human safety can only be benzoyl peroxide is carcinogenic. In the reviewed at the 1992 Advisory determined by carcinogenicity and mouse study, benzoyl peroxide was Committee meeting, were discussed in photocarcinogenicity studies for applied at doses of 1, 5, and 15 the 1995 proposed rule. The studies benzoyl peroxide (see sections IV.D and milligrams (mg) per mouse once daily to showed no evidence that benzoyl E of this document). 6 square centimeters (cm2) on the dorsal peroxide is a photocarcinogen. The skin. In the rat study, benzoyl peroxide Advisory Committee, however, srobinson on DSKHWCL6B1PROD with RULES D. Carcinogenicity was applied at doses of 5, 15, and 45 mg concluded that the studies were not We have reviewed a number of animal per rat once daily to 12 cm2 on the adequate to fully resolve this issue studies examining the carcinogenic dorsal skin. The mice and rats were because they did not include sufficient potential of benzoyl peroxide and sacrificed at 52 weeks (interim sacrifice) numbers of mice and they did not conclude that benzoyl peroxide is not a or 104 weeks, and complete necropsies collect data throughout the animals’ carcinogen. In the ANPR, the Panel cites were performed. Both studies show that lifespan. We agreed with the Advisory data from two dermal animal benzoyl peroxide had no effect on Committee and requested new VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00018 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 9771 photocarcinogenic studies in the 1995 demonstrating that benzoyl peroxide is carcinogenicity, and proposed rule. a carcinogen in humans. photocarcinogenicity studies. In 1999, CHPA submitted a study The tumor promotion studies G. Overall Conclusion demonstrate that benzoyl peroxide is a examining the photocarcinogenic potential of benzoyl peroxide in mice We are classifying benzoyl peroxide tumor promoter in the presence of a (Ref. 10). The study is entitled ‘‘12- as GRASE. This conclusion is supported chemical initiator. It is unclear from the Month Topical Study to Determine the by the animal studies that suggest studies whether benzoyl peroxide is a Influence of Benzoyl Peroxide on benzoyl peroxide is not carcinogenic or tumor promoter in the presence of UV Photocarcinogenesis in Albino Hairless photocarcinogenic. Although some of radiation (as an initiator) because two Mice Crl: SKH1(hr/hr)BR.’’ The mice the studies suggest that benzoyl studies are contradictory. As with the received single daily doses of UV peroxide is a tumor promoter with genotoxicity studies, the biological radiation along with 0, 5, 15, and 50 mg chemical initiators in animals, three relevance of the tumor promotion per milliliter benzoyl peroxide carbopol studies demonstrate that benzoyl studies results needs to be determined. peroxide is not carcinogenic or Tumor promoter studies are not gel. The mice were dosed daily, Monday photocarcinogenic in animals. We generally relied on solely in place of through Friday. On Monday, believe these three studies are more carcinogenicity studies. Drug dosing in Wednesday, and Friday, the benzoyl meaningful than the conflicting tumor tumor promoter studies does not reflect peroxide was applied before irradiation. promoter studies. actual human use conditions, making it On Tuesday and Thursday, the benzoyl As explained in this section of the peroxide was applied after irradiation. difficult to interpret the results and document, we believe that consideration extrapolate to human use. The relevance Treatment was continued for 40 weeks, of all the findings supports the GRASE and then the mice were observed for an of the animal tumor promoter study status of benzoyl peroxide. Even though results to human safety can only be additional 12 weeks (52 weeks total). benzoyl peroxide is known to be a skin determined by carcinogenicity and Only 3 days Cure your acnes! The number of tumors was recorded irritant and sensitizer in humans (47 FR photocarcinogenicity studies for each week. This study shows a slight 12430 at 12444), we believe, with benzoyl peroxide. enhancement of UV-mediated skin adequate labeling, these risks can be Carcinogenicity studies are the most tumorigenesis by benzoyl peroxide at minimized in such a way that benzoyl reliable non-clinical studies that can be the low and mid doses. However, no http://www.cureacnes.info peroxide is safe to use for acne. extrapolated to humans for determining enhancement was apparent at the high There were two safety signals that the long-term or chronic safety. These dose, as the number of tumors was concerned us when we proposed to studies are conducted with topical similar to that in the control group. classify benzoyl peroxide as category III application of benzoyl peroxide with Because increased doses of benzoyl (i.e., more data needed to determine and without UV irradiation (i.e., both peroxide did not produce greater safety) instead of GRASE: carcinogenicity and numbers of tumors, the study suggests • The ability of benzoyl peroxide to photocarcinogenicity studies). Dermal that benzoyl peroxide is not be a weak mutagen in vitro, and carcinogenicity and photocarcinogenic in mice. • The tumor promotion potential of photocarcinogenicity studies best F. Epidemiological Data benzoyl peroxide in the presence of a represent actual use conditions for chemical initiator in animals benzoyl peroxide. They are the There have been several No new safety signals have been benchmark for determining the epidemiological studies conducted that identified since the 1991 proposed rule, carcinogenic potential of a drug. We provide information about whether despite the conduct of additional believe that the negative findings in the there is a link between the use of studies. We conclude that the additional carcinogenic and photocarcinogenic benzoyl peroxide to tumor rodent carcinogenicity and studies support a GRASE conclusion for development, as discussed in the 1991 photocarcinogenicity studies conducted benzoyl peroxide because they are more proposed rule (56 FR 37622 at 37629 since the proposed rule justify a GRASE relevant to humans under conditions of and 37630). None of the studies clearly determination in spite of the mutagenic actual use than genotoxicity or tumor associate the use of benzoyl peroxide and tumor promoter potential of promotion studies. with the development of skin cancer in benzoyl peroxide. humans. The largest of these studies Although genotoxicity studies are V. FDA’s Conclusions on Labeling evaluated 870 subjects who developed useful, findings that a drug is mutagenic In addition to the labeling required for skin cancer and 1,250 control subjects in these studies does not necessarily all OTC topical acne drug products, we who did not develop skin cancer lead to a determination that the drug is are now requiring labeling that provides (matched for age, sex, and geographic unsafe. Genotoxicity studies are often information related specifically to location) (Ref. 4). The study authors preliminary studies in drug benzoyl peroxide. We are only requiring concluded that the past history of acne development that help provide a carton labeling and not consumer was the second strongest correlation to framework for how to proceed with package insert labeling for benzoyl the development of basal cell future studies. Positive results with peroxide. This required benzoyl carcinoma, with a family history of genotoxicity studies show that a drug peroxide labeling is based on labeling cancer being the strongest correlation. has the potential to be a mutagen, that we previously proposed for the Although the authors suggested that thereby contributing to the development ingredient (discussed in section IV.A of there may be a relationship between of tumors and possibly cancer. this document). In addition, the benzoyl peroxide use and skin cancer, Consistent with the guidelines (Ref. 5), required labeling reflects our safety srobinson on DSKHWCL6B1PROD with RULES data about subject use of acne the genotoxicity study findings led to assessment of benzoyl peroxide treatments was not collected (e.g., animal studies to determine the discussed in the previous sections of whether subjects had used benzoyl biological relevance of the evidence that this document. We believe that the peroxide). We are not aware of any benzoyl peroxide may be a weak labeling required in this document is relevant epidemiological studies mutagen in vitro. The animal studies necessary for the safe and effective use published since 1991. Therefore, we do subsequently conducted consist of of OTC topical acne drug products not have any epidemiological evidence animal tumor promotion, containing benzoyl peroxide. VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00019 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info 9772 Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations In addition to the labeling specific to as a package insert for prescription and Therefore, we believe it is important to benzoyl peroxide, we are revising OTC products. This labeling in the 1995 include information warning consumers labeling for all OTC acne drug products. proposed rule stems from and agrees to avoid unnecessary sun exposure and We revised the warnings and directions with the recommendations of the to use a sunscreen when using any drug for these products such that they meet Committee, which met in 1992 to products containing benzoyl peroxide. the content and format requirements in discuss benzoyl peroxide in acne drug For the same reason, we are not § 201.66. When the final rule for these products. exempting cleansers and soaps products was established in 1991, we containing benzoyl peroxide from the B. Carton Labeling had not yet established § 201.66. ‘‘use a sunscreen’’ warning, as argued by We are requiring the warnings the third comment. This warning is A. Past FDA Requirements for Labeling proposed in the 1985 proposed rule as required for all OTC topical acne drug In the 1985 proposed rule, we well as the warning and direction products containing benzoyl peroxide. proposed warnings required for OTC proposed in the 1995 proposed rule (see We do not believe this warning (and the acne drug products containing benzoyl section V.A of this document). Although accompanying directions about peroxide: we are revising the warnings and sunscreen use) will confuse consumers. • Do not use benzoyl peroxide on direction slightly, the overall meaning The warning is clear, simple, and very sensitive skin. remains the same. applies to all OTC topical acne drug • Keep benzoyl peroxide products This action relates to three products containing benzoyl peroxide away from the eyes, lips, and mouth. submissions that we received in whether they are washed off or left on. • Benzoyl peroxide may bleach hair response to the 1995 proposed rule. We are moving this direction from the or dye fabric. These submissions argue that we should beginning of the directions section to These warnings were specific to not require the proposed warning the end. Whether a product is washed benzoyl peroxide and were not Only 3 days concerning sun exposure. Two of the Cure your acnes! off or left on, the directions should proposed for OTC acne drug products submissions argue that there is no instruct consumers to use the product containing other active ingredients. scientific evidence demonstrating a risk and then apply a sunscreen. We believe These warnings come from of photosensitivity in humans when this revision will prevent confusion recommendations made by the Panel in http://www.cureacnes.info using benzoyl peroxide (Refs. 16 and about sunscreen use and adequately the 1982 ANPR. 17). They acknowledge the studies address the concern raised by the third In the 1995 proposed rule, we showing that benzoyl peroxide is a skin submission. proposed the following warning and tumor promoter in rodents. However, Accordingly, we are adding the direction appear on prescription and they do not believe the results from following benzoyl peroxide warnings in OTC drug products containing benzoyl rodent studies support a finding of this document (§ 333.350(c)(4)): peroxide: significant human health risk. The third • Do not use if you [bullet] have very • Warning: ‘‘When using this product, submission suggests that cleansers and sensitive skin [bullet] are sensitive to avoid unnecessary sun exposure and soaps containing benzoyl peroxide be benzoyl peroxide. use a sunscreen.’’ excluded from the required label • When using this product [bullet] • Direction: ‘‘If going outside, use a warning ‘‘use a sunscreen’’ (Ref. 18). The avoid unnecessary sun exposure and sunscreen. (sentence in boldface type) submission concurs with the use a sunscreen [bullet] avoid contact Allow [insert name of benzoyl peroxide recommended label warning to ‘‘use a with the eyes, lips, and mouth [bullet] product] to dry, then follow directions sunscreen’’ for benzoyl peroxide avoid contact with hair and dyed in the sunscreen labeling. If irritation or products. We proposed this warning be fabrics, which may be bleached by this sensitivity develops, discontinue use of included on all OTC benzoyl peroxide product [bullet] skin irritation may both products and consult a doctor.’’ products. However, the submission occur, characterized by redness, For OTC products, the 1995 proposed argues that the warning should only be burning, itching, peeling, or possibly rule proposed that this labeling be required on products that are left on the swelling. Irritation may be reduced by required on the outer carton. For skin because it would confuse using the product less frequently or in prescription products, the 1995 consumers using products that are a lower concentration. proposed rule proposed that this washed off after use. • Stop use and ask a doctor if [bullet] labeling appear in the patient package Since receiving these submissions, we irritation becomes severe. insert. have reviewed new data regarding the In addition, we are adding a new In the 1995 proposed rule, we also potential phototoxicity of benzoyl direction for products containing proposed a series of questions and peroxide. The data shows that benzoyl benzoyl peroxide (§ 333.350(d)(2)) (21 answers that would appear in a package peroxide is not a photocarcinogen in CFR 333.350(d)(2))): insert and would explain the tumor animals. Studies have also shown that 5 • [bullet] if going outside, apply promotion potential and sensitizing and 10 percent benzoyl peroxide sunscreen after using this product. If nature of benzoyl peroxide (60 FR 6554 preparations can decrease the skin’s irritation or sensitivity develops, stop at 6555 to 6556). The questions tolerance to UV radiation (i.e., increase use of both products and ask a doctor. answered in the 1995 proposed rule sunburn) after repeated applications We are also revising carton labeling to included the following: (Refs. 19 and 20). In addition, benzoyl reflect OTC drug labeling format and • What is in (insert brand name of peroxide can cause skin irritation, content requirements (i.e., ‘‘Drug Facts’’) benzoyl peroxide product)? which may worsen with sun exposure. implemented after the 1995 proposed • Does benzoyl peroxide cause These adverse effects of benzoyl rule (§ 201.66). srobinson on DSKHWCL6B1PROD with RULES tumors to grow in humans? peroxide are important because drug • What should I do? products containing benzoyl peroxide C. Consumer Package Insert This information essentially are often used daily on sun-exposed We received three submissions from summarized the data from animal areas of the body (e.g., face). The best healthcare organizations arguing that we studies that led to the earlier proposed ways to protect sun-exposed areas of the should not require the patient and classification of benzoyl peroxide as body are to cover them up, stay out of consumer package insert labeling category III. We suggested that it appear the sun, and to use a sunscreen. proposed for OTC and prescription VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00020 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 9773 benzoyl peroxide drug products in the product as part of the NDA review and The Regulatory Flexibility Act 1995 proposed rule. One submission approval. Therefore, we do not believe requires agencies to analyze regulatory argues that the purpose of OTC labeling that the proposed labeling needs to be options that would minimize any has never been to tell consumers included in monograph regulations. significant impact of a rule on small everything that scientists have entities. We lack the data to certify that D. Overall Conclusion this final rule will not have a significant discovered, or might still be investigating, about a drug product and In this document, we are requiring economic impact on a substantial its ingredients (Ref. 17). The second labeling specific to benzoyl peroxide number of small entities. Therefore, we submission argues that information containing drug products. Warnings for have prepared a final regulatory impact related to possible carcinogenicity drug products containing benzoyl analysis. should not be disseminated until the peroxide include the following: Section 202(a) of the Unfunded completion of valid epidemiologic (§ 333.350(c)(4)): Mandates Reform Act of 1995 requires studies (Ref. 16). The submission • Avoiding unnecessary sun exposure that agencies prepare a written believes it is not helpful to imply a • Not using on very sensitive skin statement, which includes an connection between benzoyl peroxide • Keeping away from the eyes, lips, assessment of anticipated costs and and sunlight in the absence of and mouth benefits, before proposing ‘‘any rule that supporting epidemiological data. The • Cautioning that benzoyl peroxide includes any Federal mandate that may third submission is concerned that the may bleach hair or dye fabric result in the expenditure by State, local, proposal to include patient package These warnings are not required for and tribal governments, in the aggregate, inserts with all topical acne drug other acne active ingredients. However, or by the private sector, of $100,000,000 products containing benzoyl peroxide warnings required for other acne active or more (adjusted annually for inflation) will increase costs to the healthcare ingredients, such as ‘‘for external use in any one year.’’ The current threshold distribution system (Ref. 21). The Only 3 days only,’’ are required for benzoyl peroxide. Cure your after adjustment for inflation is $133 acnes! submission argues that in order for We are also requiring a direction for million, using the most current (2008) written materials to accompany each drug products containing benzoyl Implicit Price Deflator for the Gross package of a prescription drug product, peroxide to use a sunscreen when going Domestic Product. We do not expect manufacturers must switch from http://www.cureacnes.info outside. this final rule to result in any 1-year automated to manual packaging, which We are not requiring a consumer expenditure that would meet or exceed would be costly. In addition, the package insert for drug products this amount. submission argues that the costs of containing benzoyl peroxide. After reviewing the newly submitted data, we A. Need for and Objectives of the Rule applying the same requirement to OTC products would be even higher because no longer see the need for a consumer The purpose of this document is to OTC products are more numerous and package insert. We believe that the revise the conditions for marketing OTC are distributed in much greater volume. proposed carton labeling sufficiently acne drug products. This final rule We agree with the submissions’ informs the consumer of the potential establishes that OTC acne drug products request to not require a consumer risks of using these products. We are containing benzoyl peroxide are GRASE package insert accompanying OTC also not requiring a patient package and establishes required labeling for topical acne drug products containing insert to accompany prescription topical these products. This final rule requires benzoyl peroxide. The purpose of acne drug products containing benzoyl manufacturers of OTC acne products including a consumer package insert is peroxide with this final rule. All containing benzoyl peroxide to relabel to disseminate as much information prescription topical acne drug products their products and add new warnings pertaining to the potential risks of using are marketed under NDAs, which and directions within 12 months from benzoyl peroxide containing drug already require appropriate safety the date of publication. products. We believe that the proposed information about benzoyl peroxide in This final rule also requires that the carton labeling sufficiently informs the the labeling of each prescription warnings and directions for OTC acne consumer of the potential risks of using product as part of the NDA review and drug products containing resorcinol, these products. After reviewing the approval. We do not believe that the resorcinol monoacetate, salicylic acid, newly submitted data, we no longer see proposed labeling needs to be included and/or sulfur be revised to meet the the need for a consumer package insert. in monograph regulations. content and format requirements in We are not creating regulations § 201.66. We are allowing manufacturers VI. Analysis of Impacts requiring a patient package insert to up to 5 years to comply with this accompany prescription topical acne We have examined the impacts of this provision. Frequent label redesigns are drug products containing benzoyl final rule under Executive Order 12866 typical for OTC topical acne drug peroxide because all prescription and the Regulatory Flexibility Act (5 products, with redesigns generally topical acne drug products are marketed U.S.C. 601–612), and the Unfunded implemented at least every 5 years for under new drug applications (NDAs). Mandates Reform Act of 1995 (Public a product. Therefore, the regulatory- The decision to include patient package Law 104–4). Executive Order 12866 mandated relabeling will fall within this inserts for prescription products should directs agencies to assess all costs and time period, minimizing the impact on be done on a case-by-case basis. benefits of available regulatory the manufacturer of these products. Prescription products containing alternatives and, when regulation is There are no reformulation costs benzoyl peroxide cannot be marketed necessary, to select regulatory required by this rule. until we review information submitted approaches that maximize net benefits srobinson on DSKHWCL6B1PROD with RULES for a specific product and determine (including potential economic, B. Number of Products Affected that the product is safe and effective. As environmental, public health and safety, Estimating the number of part of this review, we determine and other advantages; distributive manufacturers and affected products is labeling that is specific to the product. impacts; and equity). We believe that difficult because we lack data on We have and will continue to require this final rule is not a significant products currently marketed. Our Drug appropriate safety information about regulatory action under the Executive Listing System currently does not have benzoyl peroxide in each prescription order. accurate information on the number of VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00021 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info 9774 Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations marketed OTC acne drug manufacturers The RTI model estimates that the final rule will provide consumers with and products containing benzoyl costs to revise labeling ranges from warnings and directions information peroxide. We used data from A. C. $2,700 to $6,600 for a 1-year that is needed for the safe use of OTC Nielsen to estimate the dollar sales and implementation period. Assuming an acne products containing benzoyl the number of stock keeping units average relabeling cost of $4,650 per peroxide. This final rule also will (SKUs) that would be affected by this SKU, the total one-time cost for 80 SKUs require that the current monograph rule. Based on 2006 retail sales data, the containing benzoyl peroxide would be labeling information for OTC topical total sales for approximately 330 about $372,000 (80 SKUs x $4,650). To acne drug products containing affected SKUs were $263.0 million, or minimize the impact on small entities resorcinol, resorcinol monoacetate, converting to 2009 dollars, $278 with annual sales less than $25,000, we salicylic acid, and sulfur be consistently million. However, there are likely some are allowing up to 24 months for presented according to the OTC Drug affected OTC acne products that we products containing benzoyl peroxide to Facts labeling requirements in 21 CFR were unable to identify. be relabeled. part 201. Of the 330 affected SKUs, about 25 All other manufacturers of acne With this final rule, there are now five percent contain benzoyl peroxide and treatment products containing GRASE active ingredients for OTC acne 75 percent contain other ingredients resorcinol, resorcinol monoacetate, drug products. Consumers will continue cited in this final rule (i.e., resorcinol, salicylic acid, and sulfur would need to to have a range of choices for OTC acne resorcinol monoacetate, salicylic acid, revise their product labels to conform to products with safety and use or sulfur). Most manufacturers of the OTC format and contents information uniformly presented. A products containing benzoyl peroxide requirements in § 201.66. Based on the uniform presentation of labeling will need to relabel and add new labeling cost model, the average information should help consumers warnings and directions within 1 year incremental costs of conforming to the compare similar products to make from the date of publication. Small OTC format and content requirements informed choices. Only 3 days Cure your acnes! entities with annual product sales of are estimated to be $3,750 per SKU, E. Alternatives and Steps Taken to less than $25,000 will have up to 2 years assuming a maximum period of 3 years Minimize Impacts on Small Entities to comply. Manufacturers of all other to comply. The total one-time costs to OTC acne drug products (containing http://www.cureacnes.info manufacturers to relabel the estimated For products containing benzoyl resorcinol, resorcinol monoacetate, 250 affected OTC SKUs is about peroxide, we considered a longer salicylic acid and sulfur) will have up $937,500 (250 SKUs x $3,750). Because implementation period, such as 2 years to 5 years to relabel and conform to the the labeling cost model stops at a 3-year for all of the 80 SKUs, rather than only OTC format and contents requirements implementation period and these for those entities with annual sales less in § 201.66. manufacturers would have up to 5 years than $25,000. However, we believe it is to incorporate these changes with important to provide the new warning C. Cost to Relabel statements and directions to consumers routinely scheduled labeling changes, Estimates of relabeling costs for the these relabeling costs would be reduced. as soon as possible. We considered and types of changes required by this However, we lack sufficient information rejected a shorter implementation document vary depending on the to estimate the reduction. period for all other OTC acne products following: (1) Whether the products are The present value of total one-time to conform to the OTC format and nationally branded or private label, (2) costs for relabeling all of the 330 content requirements. To provide the printing method, and (3) the number affected OTC acne treatment products is maximum flexibility and to minimize of colors used. The costs of product $1.1 million using a 7 percent discount burdens, we are allowing up to 5 years relabeling are also dependent on the rate and $1.2 million using a 3 percent for firms to coordinate required labeling timing of the required labeling change. discount rate. The annualized total costs changes with planned revisions. We Most OTC manufacturers routinely of compliance of this rule are $0.4 believe any longer implementation schedule revisions of product labels million using 7 percent and 3 percent period is impractical and would every few years. To the extent that the discount rates over 3 years. unnecessarily delay the benefit of timing of regulatory changes Using the 2009 dollar value of annual providing uniform format and content corresponds with routine labeling retail sales for OTC acne products of labeling to consumers who use OTC revisions by the company, the $278 million, the annualized costs of drug products for the treatment of acne. regulatory cost of relabeling is compliance account for less than 0.2 F. Impact on Small Businesses significantly reduced. percent of total annual OTC acne retail We used a labeling cost model sales for all entities, for both a 7 percent The Small Business Administration developed for FDA by the consulting and 3 percent discount rate over 3 years. defines an entity as small in the firm RTI International (RTI) to derive an Because the period selected for pharmaceutical manufacturing industry estimate of the cost to relabel OTC acne annualization is typically much longer if the business has fewer than 750 drug products (Ref. 22). The model was than 3 years, using a 3-year period employees. Over 90 percent of developed to estimate the cost of maximizes annualized compliance costs manufacturers in the OTC revising food and dietary supplement for this analysis. pharmaceutical industry are classified labels. The RTI model assumes that all as small. The average annual value of manufacturers voluntarily revise their D. Benefits of this Rule shipments for small entities in labeling every 3 years. We believe that The primary benefit of this final rule Pharmaceutical Manufacturing the graphic and design estimates from is that consumers will have Preparation NAICS 325412 was $34.9 srobinson on DSKHWCL6B1PROD with RULES the RTI model are an appropriate proxy standardized and consistent labeling million in 20021. Converting to 2009 for the costs that would be incurred by information that is necessary for the safe dollars, the average value of shipments OTC acne drug product manufacturers. use of OTC acne products affected by 1 U.S. Department of Commerce, 2002 Economic However, we are unable to use this this rule. This final rule finds that OTC Census of Manufacturers, ‘‘Pharmaceutical model to forecast reductions in acne drug products containing benzoyl Preparation Manufacturing: 2002,’’ Industry Series, relabeling costs for year four and five of peroxide are GRASE and allows these NAICS 325412, Table 4. Industry Statistics by the implementation period. products to remain on the market. This Employment Size, December 2004. VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00022 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 9775 per small entity is $39.0 million. annualized total costs of compliance of to determine the firm size for certain However, the Census data do not allow this rule are $0.4 million using 7 private label SKUs because A. C. us to estimate the average value of percent and 3 percent discount rates Nielsen does not reveal ownership shipments for OTC manufacturers. over 3 years. information for certain store brands. To estimate possible impacts on small Table 2 of this document presents the These store brands are typically large entities, we used A. C. Nielsen total annualized costs of compliance as a chain stores. In addition, we combined retail sales for all OTC acne products percent of total annual retail sales for the category for small entities with 11 affected by this rule to calculate the OTC acne products by size of the other entities whose size information annualized total cost of compliance as a affected entities. Although we have could not be found in financial listings. percentage of annual sales. The sales data for each SKU, we were unable TABLE 2.—ANNUALIZED COMPLIANCE COST AS A PERCENT OF OTC ACNE SALES BY SIZE OF ENTITY1 Annualized Compliance Cost Compliance Cost (dollars in millions) (Percent of Sales) Size 2009 Sales Number of (dollars in millions) SKUs 7% 3% 7% 3% discount discount rate discount rate discount rate rate Large $254.0 233 $0.3 $0.3 0.1% 0.1% Small $18.1 49 $0.1 $0.1 0.3% 0.3% Only 3 days Cure your acnes! Private Label2 $6.1 48 $0.1 $0.1 1.0% 1.0% Total3 $278.1 330 $0.4 $0.4 0.2% 0.2% 1 The use of a 3-year period for annualizing maximizes the value of compliance costs for this analysis. 2 Private label represents store brand and unknown brand names. http://www.cureacnes.info 3 Total sales and annualized compliance cost may not sum due to rounding. The annualized costs of compliance Flexibility Analysis, as required under exercise of State authority conflicts with are less than 0.2 percent of total annual the Regulatory Flexibility Act. the exercise of Federal authority under OTC acne retail sales for all entities. the Federal statute.’’ The sole statutory VII. Paperwork Reduction Act of 1995 Private label entities compliance costs provision giving preemptive effect to the as a percent of OTC acne sales are about We conclude that the labeling final rule is section 751 of the act (21 1 percent over 3 years. For small requirements required in this rule are U.S.C. 379r). We believe that we have entities, the annualized costs over 3 not subject to review by the Office of complied with all of the applicable years are 0.3 percent annual sales for Management and Budget because they requirements under the Executive order OTC acne products. These estimates do not constitute a ‘‘collection of and have determined that the represent maximum values because of information’’ under the Paperwork preemptive effects of this rule are the relatively short period used to Reduction Act of 1995 (44 U.S.C. 3501 consistent with Executive Order 13132. annualize costs. et seq.). Rather, the labeling statements These estimates do not account for the are a ‘‘public disclosure of information X. References additional time granted to small entities originally supplied by the Federal The following references are on to minimize the cost impacts. Industry government to the recipient for the display in the Division of Dockets routinely changes their OTC product purpose of disclosure to the public’’ (5 Management (HFA–305), Food and Drug labeling, and we have allowed for CFR 1320.3(c)(2)). Administration, 5630 Fishers Lane, rm. extended implementation periods to 1061, Rockville, MD 20857, and may be VIII. Environmental Impact comply with this final rule. Therefore, seen by interested persons between 9 we believe that it is unlikely that this We have determined under 21 CFR a.m. and 4 p.m., Monday through final rule will have a significant 25.31(a) that this action is of a type that Friday. FDA has verified the Web site economic impact on a substantial does not individually or cumulatively addresses, but FDA is not responsible number of small entities. This final rule have a significant effect on the human for any subsequent changes to the Web does not require any new reporting or environment. Therefore, neither an sites after this document publishes in recordkeeping activities. environmental assessment nor an the Federal Register. environmental impact statement is 1. Iverson, O. H., ‘‘Carcinogenesis Studies G. Summary of Analysis required. with Benzoyl Peroxide (Panoxyl Gel 5%),’’ This analysis shows that this final Journal of Investigative Dermatology, 86:442– rule is not economically significant IX. Federalism 448, 1986. under Executive Order 12866. We have We have analyzed this final rule in 2. Iverson, O. H., ‘‘Skin Tumorigenesis and allowed flexible implementation accordance with the principles set forth Carcinogenesis Studies with 7,12- periods to minimize the regulatory costs in Executive Order 13132. Section 4(a) dimethylbenz [a] anthracene, Ultraviolet srobinson on DSKHWCL6B1PROD with RULES of revising labeling. We lack the data to of the Executive order requires agencies Light, Benzoyl Peroxide (Panoxyl Gel 5%) to ‘‘construe * * * a Federal statute to and Ointment Gel,’’ Carcinogenesis, 9:803– certify that this final rule will not have 809, 1988. a significant economic impact on a preempt State law only where the 3. Comment No. C4, 1981N–114A. substantial number of small entities. statute contains an express preemption 4. Hogan, D. J. et al., ‘‘A Study of Acne Therefore, this analysis, together with provision or there is some other clear Treatments as Risk Factors for Skin Cancer of other relevant sections of this evidence that the Congress intended the Head and Neck,’’ British Journal of document, serves as our Regulatory preemption of State law, or where the Dermatology, 125:343–348, 1991. VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00023 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info 9776 Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 5. International Conference on § 333.310 Acne active ingredients. [bullet] are sensitive to benzoyl Harmonisation of Technical Requirements for The active ingredient of the product peroxide.’’ Registration of Pharmaceuticals for Human consists of any of the following: Use: Guidance on Genotoxicity Testing and (ii) The labeling states ‘‘When using (a) Benzoyl peroxide, 2.5 to 10 this product [bullet] avoid unnecessary Data Interpretaion on Pharmaceuticals Intended for Human Use (S2(R1)), February percent. sun exposure and use a sunscreen 23, 2010. http://www.ich.org/lob/media/ (b) Resorcinol, 2 percent, when [bullet] avoid contact with the eyes, media4477.pdf. combined with sulfur in accordance lips, and mouth [bullet] avoid contact 6. Giri, U., M. Iqbal, and M. Athar, with § 333.320(a). with hair and dyed fabrics, which may ‘‘Porphyrin-Mediated Photosensitization Has (c) Resorcinol monoacetate, 3 percent, be bleached by this product [bullet] skin a Weak Tumor Promoting Activity in Mouse when combined with sulfur in irritation may occur, characterized by Skin: Possible Role of In Situ-Generated accordance with § 333.320(b). Reactive Oxygen Species,’’ Carcinogenesis, redness, burning, itching, peeling, or (d) Salicylic acid, 0.5 to 2 percent. 17:2023–2028, 1996. (e) Sulfur, 3 to 10 percent. possibly swelling. Irritation may be 7. Kawanishi, S. et al., ‘‘Site-Specific (f) Sulfur, 3 to 8 percent, when reduced by using the product less Oxidation at GG and GGG Sequences in combined with resorcinol or resorcinol frequently or in a lower concentration.’’ Double-Stranded DNA by Benzoyl Peroxide (iii) The labeling states ‘‘Stop use and monoacetate in accordance with as a Tumor Promoter,’’ Biochemistry, 38:16733–16739, 1999. § 333.320. ask a doctor if [bullet] irritation becomes 8. Kensler, T. et al., ‘‘Role of Reactive ■ 3. Section 333.320 is revised to read severe.’’ Intermediates in Tumor Promotion and as follows: (d) Directions. The labeling of the Progression,’’ Progress in Clinical and product contains the following Biological Research, 391:103–116, 1995. § 333.320 Permitted combinations of active ingredients. information under the heading 9. Matsumura, Y. and H. N. ‘‘Directions’’: Ananthaswamy, ‘‘Toxic Effects of Ultraviolet Only 3 days (a) Resorcinol identified in Cure your acnes! Radiation on the Skin,’’ Toxicology and § 333.310(b) may be combined with (1) For products applied containing Applied Pharmacology, 195:298–308, 2004. sulfur identified in § 333.310(f). any ingredient identified in § 333.310. 10. Comment No. RPT3, 1981N–0114. (b) Resorcinol monoacetate identified The labeling states ‘‘[bullet] clean the 11. Comment No. LET19, 1981N–0114. http://www.cureacnes.info in § 333.310(c) may be combined with skin thoroughly before applying this 12. Comment No. LET20, 1981N–0114. product [bullet] cover the entire affected 13. Comment No. LET21, 1981N–0114. sulfur identified in § 333.310(f). 14. Comment No. LET22, 1981N–0114. ■ 4. Section 333.350 is amended by area with a thin layer one to three times 15. Comment No. RPT4, 1981N–0114. revising paragraphs (c) and (d) and daily [bullet] because excessive drying 16. Comment No. C3, 1992N–0311. removing paragraph (e) to read as of the skin may occur, start with one 17. Comment No. C4, 1992N–0311. follows: application daily, then gradually 18. Comment No. C1, 1992N–0311. increase to two or three times daily if 19. Jeanmougin, M. and J. Civatte, § 333.350 Labeling of acne drug products. needed or as directed by a doctor ‘‘Prediction of Benzoyl Peroxide * * * * * [bullet] if bothersome dryness or peeling Phototoxicity by Photoepidermotests After (c) Warnings. The labeling of the occurs, reduce application to once a day Repeated Applications. Preventative Value of product contains the following warnings or every other day.’’ a UVB Filter,’’ Archives of Dermatological Research, 280 (Suppl): S90–S93, 1988. under the heading ‘‘Warnings’’: (2) For products applied and left on 20. Jeanmougin, M. et al., ‘‘Phototoxic (1) For products containing any the skin containing benzoyl peroxide Activity of 5% Benzoyl Peroxide in Man. Use ingredients identified in § 330.310. identified in § 333.310(a). of a New Methodology,’’ Dermatologica, (i) The labeling states ‘‘For external 167:19–23, 1983. use only.’’ (i) The labeling states the directions in 21. Comment No. C2, 1992N–0311. (ii) The labeling states ‘‘When using paragraph (d)(1) of this section. 22. ‘‘FDA Labeling Cost Model, Final this product [bullet] skin irritation and (ii) The labeling states ‘‘[bullet] if Report’’ prepared by Mary Muth, Erica dryness is more likely to occur if you going outside, apply sunscreen after Glendhill, and Shawn Karns, RTI use another topical acne medication at using this product. If irritation or International, Prepared for Amber Jessup, the same time. If irritation occurs, only FDA Center for Food Safety and Applied sensitivity develops, stop use of both Nutrition, RTI International, January 2003. use one topical acne medication at a products and ask a doctor.’’ time.’’ List of Subjects in 21 CFR Part 333 (3) For products applied and removed (2) For products containing sulfur from the skin containing any ingredient identified in § 333.310(e) and (f). Labeling, Over-the-counter drugs. identified in § 333.310. Products, such (i) The labeling states ‘‘Do not use on as soaps and masks, may be applied and ■ Therefore, under the Federal Food, [bullet] broken skin [bullet] large areas removed and should include Drug, and Cosmetic Act and under of the skin.’’ (ii) The labeling states ‘‘When using appropriate directions. All products authority delegated to the Commissioner containing benzoyl peroxide should of Food and Drugs, 21 CFR part 333 is this product [bullet] apply only to areas with acne.’’ include the directions in paragraph amended as follows: (d)(2)(ii) of this section. (3) For products containing any PART 333—TOPICAL ANTIMICROBIAL combination identified in § 333.320. (i) (4) Optional directions. In addition to DRUG PRODUCTS FOR OVER-THE- The labeling states ‘‘When using this the required directions in paragraphs COUNTER HUMAN USE product [bullet] rinse right away with (d)(1) and (d)(2) of this section, the water if it gets in eyes.’’ product may contain the following srobinson on DSKHWCL6B1PROD with RULES ■ 1. The authority citation for 21 CFR (ii) The labeling states ‘‘Stop use and optional labeling: ‘‘Sensitivity Test for a part 333 continues to read as follows: ask a doctor [bullet] if skin irritation New User. Apply product sparingly to occurs or gets worse.’’ one or two small affected areas during Authority: 21 U.S.C. 321, 351, 352, 353, (4) For products containing benzoyl the first 3 days. If no discomfort occurs, 355, 360, 371. peroxide identified in § 333.310(a). follow the directions stated (select one ■ 2. Section 333.310 is revised to read (i) The labeling states ‘‘Do not use if of the following: ‘elsewhere on this as follows: you [bullet] have very sensitive skin label,’ ‘above,’ or ‘below’).’’ VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00024 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 9777 Dated: February 25, 2010. available on the site under ‘‘How To Use Department anticipates conducting in Leslie Kux, This Site.’’ FY 2013. Acting Assistant Commissioner for Policy. • Postal Mail, Commercial Delivery, We invite you to assist us in [FR Doc. 2010–4424 Filed 3–3–10; 8:45 am] or Hand Delivery: If you mail or deliver complying with the specific BILLING CODE 4160–01–S your comments about these interim final requirements of Executive Order 12866 regulations, address them to Anna and its overall requirement of reducing Hinton, U.S. Department of Education, regulatory burden that might result from 400 Maryland Avenue, SW., room these interim final regulations. Please DEPARTMENT OF EDUCATION 4W229, Washington, DC 20202. let us know of any further opportunities 34 CFR Part 280 Privacy Note: The Department’s policy for we should take to reduce potential costs comments received from members of the or increase potential benefits while RIN 1855–AA07 public (including those comments submitted preserving the effective and efficient by mail, commercial delivery, or hand administration of the program. [Docket ID ED–2010–OII–0003] delivery) is to make these submissions During and after the comment period available for public viewing in their entirety you may inspect all public comments Magnet Schools Assistance Program on the Federal eRulemaking Portal at http://www.regulations.gov. Therefore, about these interim final regulations by AGENCY: Office of Innovation and commenters should be careful to include in accessing Regulations.gov. You may also Improvement, Department of Education. their comments only information that they inspect the comments, in person, in ACTION: Interim final rule; request for wish to make publicly available on the room 4W229, 400 Maryland Avenue, comments. Internet. SW., Washington, DC 20202, between FOR FURTHER INFORMATION CONTACT: the hours of 8:30 a.m. and 4 p.m., SUMMARY: The Secretary amends the Eastern time, Monday through Friday of Anna Hinton, U.S. Department of regulations governing the Magnet Only 3 days Cure your acnes! Education, 400 Maryland Avenue, SW., each week except Federal holidays. Schools Assistance Program (MSAP) to room 4W229, Washington, DC 20202. Assistance to Individuals With provide greater flexibility to school Telephone: (202) 260–1816 or by e-mail: Disabilities in Reviewing the districts designing MSAP programs for FY10MSAPCOMP@ed.gov. Rulemaking Record the Fiscal Year (FY) 2010 grant http://www.cureacnes.info If you use a telecommunications competition announced in a notice device for the deaf (TDD), call the On request, we will supply an inviting applications for new awards Federal Relay Service (FRS), toll free at appropriate aid, such as a reader or published elsewhere in this issue of the 1–800–877–8339. print magnifier, to an individual with a Federal Register. These changes remove Individuals with disabilities may disability who needs assistance to provisions in the regulations that obtain this document in an accessible review the comments or other require districts to use binary racial format (e.g., braille, large print, documents in the public rulemaking classifications and prohibit the creation audiotape, or computer diskette) on record for these interim final of magnet schools that result in minority request to the contact person listed regulations. If you want to schedule an group enrollments in magnet and feeder under FOR FURTHER INFORMATION appointment for this type of aid, please schools exceeding the district-wide CONTACT. contact Anna Hinton, U.S. Department average of minority group students. This of Education, 400 Maryland Avenue, SUPPLEMENTARY INFORMATION: new flexibility is necessary to permit SW., room 4W229, Washington, DC school districts interested in receiving Invitation To Comment 20202. Telephone: (202) 260–1816 or by funds under this program to determine We invite you to submit comments e-mail: FY10MSAPCOMP@ed.gov. how best to meet program requirements regarding the removal of the regulatory Background while also taking into account provisions in these interim final intervening Supreme Court case law, The MSAP is a discretionary grant regulations. The MSAP regulations in 34 program that provides funds to local including the Court’s decision in CFR part 280, as amended by these Parents Involved in Community Schools educational agencies (LEAs) for ‘‘the interim final regulations, will govern the elimination, reduction, or prevention of v. Seattle School District No 1 et al., 551 FY 2010 MSAP competition. Any U.S. 701 (2007) (Parents Involved). minority group isolation in elementary changes made to these interim final and secondary schools’’ with substantial DATES: These regulations are effective regulations in light of comments would March 4, 2010. We must receive your proportions of minority students, and govern the next MSAP competition in ‘‘the development and design of comments by April 5, 2010. FY 2013. To ensure that your comments innovative educational methods and ADDRESSES: Submit your comments have maximum effect in developing the practices that promote diversity.’’ 20 through the Federal eRulemaking Portal final regulations, we urge you to U.S.C. 7231; 34 CFR 280.1. The or via postal mail, commercial delivery, identify clearly the specific section or Department awards grants to LEAs for or hand delivery. We will not accept sections of the interim final regulations magnet schools that are ‘‘part of an comments by fax or by e-mail. Please that each of your comments addresses approved desegregation plan’’ and submit your comments only one time, in and to arrange your comments in the ‘‘designed to bring students from order to ensure that we do not receive same order as the interim final different social, economic, ethnic, and duplicate copies. In addition, please regulations. We also are considering racial backgrounds together.’’ 20 U.S.C. include the Docket ID at the top of your issuing a notice of proposed rulemaking 7231b; 34 CFR 280. There are two types comments. (NPRM) that would propose provisions of MSAP desegregation plans: (1) srobinson on DSKHWCL6B1PROD with RULES • Federal eRulemaking Portal: Go to to replace those that are removed by Required desegregation plans ordered http://www.regulations.gov to submit these interim final regulations, although by a Federal or State court or agency of your comments electronically. we are not soliciting comments on an competent jurisdiction;1 and (2) Information on using Regulations.gov, NPRM at this time. Again, any changes including instructions for accessing subsequent to these interim final 1 The revisions in these interim final regulations agency documents, submitting regulations would apply to the next do not affect how the Department treats required comments, and viewing the docket is MSAP competition, which the desegregation plans under the MSAP. VerDate Nov<24>2008 16:20 Mar 03, 2010 Jkt 220001 PO 00000 Frm 00025 Fmt 4700 Sfmt 4700 E:\FR\FM\04MRR1.SGM 04MRR1 Do you suffering on acne? Remove your troubles immediately http://www.cureacnes.info
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