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                                                                                   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

                                              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
                                                                                                                             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

                                                                                                                                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

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                              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

                                                     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
                                                                                                                              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

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                                                                   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
                                                                                                                             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
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                                              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.

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                              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

                                              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

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                                                                   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

                                                                                                                             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.

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                              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
                                                                                                                             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

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                                                                   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

                                              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
                                                                                                                             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

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                              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
                                                                                                                             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
                                            Do you suffering on acne? Remove your troubles immediately
                                                                                       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 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.

                                                 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.

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                              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.
                                              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.’’
                                              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’).’’

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                                           Do you suffering on acne? Remove your troubles immediately
                                            Do you suffering on acne? Remove your troubles immediately
                                                                                   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

                                                                                                                               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
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                                              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

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