[Federal Register Volume 75, Number 42 (Thursday, March 4, 2010)]
[Rules and Regulations]
[Pages 9767-9777]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-4424]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 333

RIN 0910--AG00
[Docket Nos. FDA-1981-N-0114 and FDA-1992-N-0049] (formerly Docket Nos. 
1981N-0114A and 1992N-0311)


Classification of Benzoyl Peroxide as Safe and Effective and 
Revision of Labeling to Drug Facts Format; Topical Acne Drug Products 
for Over-The-Counter Human Use; Final Rule

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Final rule.

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SUMMARY:  We, the Food and Drug Administration (FDA), are issuing this 
final rule to include benzoyl peroxide as a generally recognized as 
safe and effective (GRASE) active ingredient in over-the-counter (OTC) 
topical acne drug products. In addition, this final rule includes new 
warnings and directions required for OTC acne drug products containing 
benzoyl peroxide. We are also revising labeling for OTC topical acne 
drug products containing resorcinol, resorcinol monoacetate, salicylic 
acid and/or sulfur to meet OTC drug labeling content and format 
requirements in a certain FDA regulation. This final rule is part of 
our ongoing review of OTC drug products and represents our conclusions 
on benzoyl peroxide in OTC acne drug products.

DATES:  Effective Date: This rule is effective on March 4, 2011.
    Compliance Date: The compliance date for products containing 
resorcinol, resorcinol monoacetate, salicylic acid, and/or sulfur 
subject to 21 CFR part 333 is March 4, 2015. The compliance date for 
products containing benzoyl peroxide subject to 21 CFR part 333 with 
annual sales less than $25,000 is March 2, 2012. The compliance date 
for products containing benzoyl peroxide subject to part 21 CFR part 
333 with annual sales of $25,000 or more is March 4, 2011.

FOR FURTHER INFORMATION CONTACT:  Matthew R. Holman, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, MS 5411, Silver Spring, MD 20993, 301-796-
2090.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Glossary
II. Purpose of this Final Rule
III. Past FDA Actions or Activities Related to this Final Rule
IV. FDA's Conclusions on Safety
    A. Genotoxicity
    B. Tumor Promotion With Chemical Initiation
    C. Tumor Promotion With Ultraviolet Initiation
    D. Carcinogenicity
    E. Photocarcinogenicity
    F. Epidemiological Data
    G. Overall Conclusion
V. FDA's Conclusions on Labeling
    A. Past FDA Requirements for Labeling
    B. Carton Labeling
    C. Consumer Package Insert
    D. Overall Conclusion
VI. Analysis of Impacts
    A. Need for and Objectives of the Rule
    B. Number of Products Affected
    C. Cost to Relabel
    D. Benefits of This Rule
    E. Alternatives and Steps Taken to Minimize Impacts on Small 
Entities
    F. Impact on Small Business
    G. Summary of Analysis
VII. Paperwork Reduction Act of 1995
VIII. Environmental Impact
IX. Federalism
X. References

I. Glossary

    <bullet> ANPR: Advance Notice of Proposed Rulemaking
    <bullet> CFR: Code of Federal Regulations
    <bullet> CHPA: Consumer Healthcare Products Association (formerly 
Nonprescription Drug Manufacturers Association)
    <bullet> Committee: Dermatologic Drugs Advisory Committee
    <bullet> FDA: Food and Drug Administration
    <bullet> FR: Federal Register
    <bullet> GRASE: Generally Recognized as Safe and Effective
    <bullet> NDA: New Drug Application--an application submitted to FDA 
to market a new drug under section

[[Page 9768]]

505 of the Federal Food, Drug, and Cosmetic Act (21 CFR part 314)
    <bullet> OTC: Over-the-Counter--medicines sold without a 
prescription
    <bullet> Panel: Advisory Review Panel on OTC Antimicrobial (II) 
Drug Products
    <bullet> SKU: Stock Keeping Unit--an identifier that is used by 
merchants to permit the systematic tracking of products and services 
offered to customers
    <bullet> TPA: 12-O-tetradecanoylphorbol 13-acetate--a powerful 
tumor promoter
    <bullet> U.S.C.: United States Code--compilation of Federal laws
    <bullet> UVA: Ultraviolet A radiation--ultraviolet radiation with a 
wavelength between 400 and 320 nanometers
    <bullet> UVB: Ultraviolet B radiation--ultraviolet radiation with a 
wavelength between 320 and 280 nanometers
    <bullet> UVR: Ultraviolet radiation--UVC, UVB, and UVA radiation 
(1-400 nanometers)
    <bullet> We: Food and Drug Administration

II. Purpose of this Final Rule

    This final rule establishes conditions under which OTC drug 
products containing benzoyl peroxide for the topical treatment of acne 
are GRASE and not misbranded. In the Federal Register of January 15, 
1985 (50 FR 2173), we published a proposed rule in which 2.5 to 10 
percent benzoyl peroxide is proposed GRASE for the topical treatment of 
acne (the 1985 proposed rule). In the Federal Register of August 7, 
1991 (56 FR 37622), we issued a proposed rule which proposed to 
classify benzoyl peroxide as category III (i.e., ``more-data-needed'') 
instead of category I (GRASE) based on safety concerns that arose at 
that time (the 1991 proposed rule). Following the 1991 proposed rule, 
new data were submitted to address our safety concerns. After reviewing 
the data, we now conclude that benzoyl peroxide can be adequately 
labeled to minimize the risks associated with benzoyl peroxide while 
delivering effective acne treatment. Therefore, we are classifying 
benzoyl peroxide as category I in this final rule.
    In addition, this final rule requires that OTC acne drug products 
containing benzoyl peroxide, resorcinol, resorcinol monoacetate, 
salicylic acid, and/or sulfur be relabeled. We revised the warnings and 
directions for these products such that they meet the content and 
format requirements in Sec.  201.66 (21 CFR 201.66). When the final 
rule for these products was established in 1991, we had not yet 
established Sec.  201.66. The revisions necessary to comply with the 
requirements of Sec.  201.66 were minimal.

III. Past FDA Actions or Activities Related to this Final Rule

    In the Federal Register of March 23, 1982 (47 FR 12430), we 
published an ANPR to establish a monograph for OTC topical acne drug 
products (the 1982 ANPR). The 1982 ANPR included the recommendations of 
the Advisory Review Panel on OTC Antimicrobial (II) Drug Products (the 
Panel). The Panel concluded that benzoyl peroxide, in concentrations of 
2.5 to 10 percent, is safe and effective for OTC topical use to treat 
acne. The Panel recognized that benzoyl peroxide is a dose-dependent 
skin irritant that can also lead to sensitization. Therefore, the Panel 
recommended the following warnings be included in labeling:
    <bullet> Do not use benzoyl peroxide on very sensitive skin.
    <bullet> Keep benzoyl peroxide products away from the eyes, lips, 
and mouth.
    <bullet> Benzoyl peroxide may bleach hair or dye fabric.
    The 1985 proposed rule proposed conditions under which OTC topical 
acne drug products are GRASE and not misbranded. We agreed with the 
Panel's recommendations, and the 1985 proposed rule proposed that 2.5 
to 10 percent benzoyl peroxide is GRASE for the treatment of acne. The 
1985 proposed rule also proposed requiring the benzoyl peroxide 
warnings recommended by the Panel.
    In the Federal Register of August 16, 1991 (56 FR 41008), we issued 
a final rule for OTC topical acne drug products (the 1991 final rule). 
In the 1991 final rule, we established conditions under which OTC 
topical acne drug products, except those containing benzoyl peroxide, 
are GRASE and not misbranded. We also issued the 1991 proposed rule 
which proposed to classify benzoyl peroxide as category III instead of 
category I (GRASE) based on safety concerns. Category III means that we 
need more data before we can properly classify benzoyl peroxide as 
GRASE. This proposed classification of benzoyl peroxide as Category III 
came after considering new safety data and information suggesting that 
benzoyl peroxide may initiate tumor formation and promote tumor 
development in animals. We stated in the 1991 proposed rule that it is 
unclear whether these findings in animals can be extrapolated to 
humans. We also stated that further studies were necessary to 
adequately assess the tumor promotion and carcinogenic potential of 
benzoyl peroxide. In the meantime, we noted that manufacturers could 
continue to market acne drug products containing benzoyl peroxide until 
the safety issues were resolved.
    To help us resolve the safety issues, we requested comments on the 
safety of these products, stating that we would discuss these issues 
with an Advisory Committee (Committee) shortly after the 1991 proposed 
rule published. In 1992, a few months after the 1991 proposed rule 
published, we discussed the available benzoyl peroxide safety and 
efficacy data at an Advisory Committee meeting. The Committee made the 
following recommendations:
    <bullet> New photocarcinogenicity studies on benzoyl peroxide 
should be conducted.
    <bullet> Current animal safety data regarding benzoyl peroxide 
should be conveyed in labeling.
    <bullet> Acne drug products containing benzoyl peroxide should stay 
on the market while new studies are being performed.
    The Committee's recommendations applied to both prescription and 
OTC acne drug products.
    During the Advisory Committee meeting, industry representatives 
stated that published studies in mice showed no evidence of benzoyl 
peroxide being photocarcinogenic (Refs. 1 and 2). However, the 
Committee concluded that the studies were insufficient to determine 
whether benzoyl peroxide is carcinogenic. The Committee indicated that 
the studies were inconclusive because none of the studies used 
sufficient numbers of mice and the mice should have been observed over 
their entire lifespan. Therefore, the Committee unanimously agreed that 
a new photocarcinogenicity study should be conducted.
    The Committee recommended, by a four-to-three vote (with one 
abstention), that the known safety data regarding the tumor promoting 
potential of benzoyl peroxide should be communicated to consumers. 
Because this data was inconclusive, the Committee unanimously agreed 
that the word ``cancer'' should not be included in the labeling of acne 
drug products containing benzoyl peroxide. The Committee was concerned 
that the word ``cancer'' would cause consumers to avoid using these 
products (even though the data were inconclusive). The Committee did 
not believe the data adequately demonstrated that benzoyl peroxide was 
unsafe, and they recognized that benzoyl peroxide is effective in 
treating acne. Therefore, the Committee unanimously recommended that 
acne drug products containing benzoyl peroxide should remain on the

[[Page 9769]]

market while the additional safety studies were being conducted.
    In the Federal Register of February 17, 1995 (60 FR 9554), we 
issued a proposed rule for all OTC and prescription acne drug products 
containing benzoyl peroxide in which we agreed with all of the 
Committee's recommendations (the 1995 proposed rule). When stating the 
need for additional safety studies, we noted that the Nonprescription 
Drug Manufacturers Association (since renamed Consumer Healthcare 
Products Association (CHPA)) was conducting photocarcinogenicity 
studies at that time. We also proposed labeling to communicate the 
results of the animal studies. The labeling included warnings and 
directions that would appear in the Drug Facts box of OTC acne drug 
products containing benzoyl peroxide. In addition, we proposed 
requiring package inserts for OTC and prescription acne drug products 
containing benzoyl peroxide. We requested that manufacturers 
voluntarily implement the proposed labeling as soon as possible. As 
recommended by the Committee, the proposed package inserts included the 
word ``tumor'' but not ``cancer.'' We also agreed with the Committee 
that these drug products should stay on the market. To support this 
position, we discussed human epidemiological studies conducted at that 
time suggesting that the use of benzoyl peroxide does not increase the 
risk of facial skin cancer in humans (Refs. 3 and 4).

IV. FDA's Conclusions on Safety

    We now conclude that benzoyl peroxide, in concentrations of 2.5 to 
10 percent, is GRASE for the OTC topical treatment of acne. This 
conclusion is based on safety data that we received and evaluated since 
publication of the 1995 proposed rule that proposed classifying benzoyl 
peroxide as Category III. As recommended by the Committee, these new 
data include studies examining the carcinogenic and photocarcinogenic 
potential of benzoyl peroxide. In addition to discussing these new 
studies in this section of the document, we provide a summary of 
earlier studies discussed in previous OTC acne drug product 
rulemakings. We believe the combined results of the earlier and new 
studies support the GRASE finding for benzoyl peroxide (see section 
IV.G of this document).

A. Genotoxicity

    In the 1991 proposed rule, we discussed studies suggesting that 
benzoyl peroxide may be genotoxic (56 FR 37622 at 37627 and 37628). 
Genotoxic substances are capable of causing genetic mutations and 
chromosomal changes that can contribute to the development of tumors 
and possibly cancer. Six in vitro studies examining deoxyribonucleic 
acid (DNA) breaks in various mammalian cells were reviewed in the 1991 
proposed rule. Benzoyl peroxide was shown to produce DNA breaks in five 
of the six studies. In addition, the 1991 proposed rule reviewed six 
Ames tests. The Ames test is a standard biological assay to assess the 
mutagenic potential of chemical compounds using the bacteria Salmonella 
typhimurium or Escherichia coli. Five of the tests demonstrate that 
benzoyl peroxide is not mutagenic, while one demonstrates it is a weak 
mutagen. Finally, we discussed three other in vitro genotoxicity 
studies in the 1991 proposed rule. One study suggests that benzoyl 
peroxide is not mutagenic, while two studies suggest that it is a weak 
mutagen.
    Even though some of the in vitro studies suggest that benzoyl 
peroxide may be a weak mutagen, the negative studies along with the 
overall genotoxicity profile do not warrant concluding that benzoyl 
peroxide is a genotoxic agent. In accordance with ICH S2A Guidelines 
(the guidelines), a single positive result in any genotoxicity assay 
does not necessarily mean that the test compound poses a genotoxic 
hazard to humans (Ref. 5). The guidelines state that ``any in vitro 
positive test result should be evaluated for its biological 
relevance.'' We believe that the positive genotoxicity results are 
likely due to the oxidative DNA damage caused by benzoyl peroxide, 
which has been shown in numerous studies (Refs. 6, 7, and 8). In 
humans, there are oxidative repair mechanisms that would likely prevent 
benzoyl peroxide from causing DNA damage (Ref. 9). Therefore, we 
believe there is no significant biological relevance of the mixed 
results from the in vitro genotoxicity studies.

B. Tumor Promotion Wth Chemical Initiation

    In the 1991 proposed rule, we discussed concerns that benzoyl 
peroxide may be a tumor promoter in the presence of a chemical tumor 
initiator (56 FR 37622 at 37631). A tumor promoter increases tumor 
formation and growth as well as conversion of benign tumors to 
malignant tumors after exposure to a tumor initiator (e.g., a chemical 
or UV radiation). However, a tumor promoter is not a carcinogen and 
exposure to a tumor promoter alone will not cause cancer. In the 1991 
proposed rule, we reviewed animal studies examining the ability of 
benzoyl peroxide to act as a tumor promoter in the presence of a 
chemical tumor initiator. The tumor promoter studies were conducted by 
applying a known tumor initiator at the beginning of a study and then 
later applying the suspected tumor promoter, benzoyl peroxide, at 
multiple times throughout the remainder of the study. Because tumor 
promotion was observed in almost all the studies, we concluded that 
benzoyl peroxide is a skin tumor promoter, in the presence of a 
chemical tumor initiator, in more than one strain of mice and other 
laboratory animals (56 FR 37622 at 37631). We continue to believe that 
benzoyl peroxide is a tumor promoter in animals when combined with a 
chemical tumor initiator.

C. Tumor Promotion with Ultraviolet Initiation

    In the 1991 proposed rule, we discussed a tumor promotion study in 
which ultraviolet (UV) radiation was the initiator (56 FR 37622 at 
37629). The backs of albino hairless mice were irradiated three times 
per week for 8 weeks. After completion of the UV irradiation cycles, 
benzoyl peroxide was applied to the backs 5 times per week for 50 
weeks. In this study, benzoyl peroxide was not a tumor promoter with UV 
initiation.
    There were no other UV initiation tumor promoter studies until 
after publication of the 1995 proposed rule, when CHPA submitted a new 
study entitled ``The Skin Tumor Promoting Potential of Benzoyl Peroxide 
Carbopol Gel Following UVR Initiation in SKH-1 Albino Mice'' (Ref. 10). 
The study compares benzoyl peroxide's tumor promoting capability on 
mice exposed to UV radiation to that of a known chemical tumor 
promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA). Six groups of 
mice were irradiated for 6 weeks (5 days per week) with a daily dose of 
0.2 joules per square centimeter ultraviolet B (UVB, 290-320 
nanometers) radiation. Another six groups of mice were not exposed to 
UVB radiation. After a 1-week rest period, benzoyl peroxide or TPA were 
applied on the mice as outlined in table 1 of this document. Acetone 
was also applied because TPA was dissolved in acetone, so acetone was a 
control. The test materials were applied to the backs and sides of the 
mice. The mice were treated for 40 weeks and then observed for a 12-
week treatment-free period.

[[Page 9770]]



                                     Table 1.--Treatment Groups in UV Initiation Tumor Promoter Study of Albino Mice
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                  Treatment Groups\1,\\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 promotion ability by comparing two 
endpoints in mice treated with vehicle and those treated with benzoyl 
peroxide as follows: (1) The percent of mice with tumors and (2) the 
number of tumors per mouse. At the end of the study, the percent of 
mice with tumors was the same in the vehicle-treated group (Group 7) 
and the group treated with 0.1 percent benzoyl peroxide (Group 8). The 
percent of mice with tumors in the groups treated with 1.5 or 5 percent 
benzoyl peroxide (Groups 8 and 9) was much higher than the vehicle or 
0.1 percent groups. The number of tumors per mouse in the groups 
treated with 1.5 or 5 percent benzoyl peroxide (Groups 8 and 9) was 
much higher than the vehicle or 0.1 percent groups. The results from 
this study suggest that benzoyl peroxide causes tumor promotion in a 
dose-dependent manner.
    The results from the study submitted in 1995 by CHPA and the study 
discussed in the 1991 proposed rule produced contradictory results. 
Therefore, it is difficult to draw any final conclusions regarding 
tumor promotion with benzoyl peroxide in the presence of UV radiation 
from these two studies. As with the genotoxicity studies, the 
biological relevance of the tumor promotion studies results needs to be 
determined. Drug dosing in tumor promoter studies does not reflect 
actual human use conditions, making it difficult to interpret the 
results and extrapolate to human use. The relevance of the animal tumor 
promoter study results to human safety can only be determined by 
carcinogenicity and photocarcinogenicity studies for benzoyl peroxide 
(see sections IV.D and E of this document).

D. Carcinogenicity

    We have reviewed a number of animal studies examining the 
carcinogenic potential of benzoyl peroxide and conclude that benzoyl 
peroxide is not a carcinogen. In the ANPR, the Panel cites data from 
two dermal animal carcinogenicity studies and a report to support their 
conclusion that benzoyl peroxide is not a carcinogen (47 FR 12430 at 
12443 to 12444). In the 1991 proposed rule, we stated that ``* * *[a] 
definitive study to assess the complete carcinogenicity of benzoyl 
peroxide has not, as yet, been conducted'' (56 FR 37622 at 37630). In 
that document, we state that benzoyl peroxide did not produce cancer in 
the following studies conducted on mice and rats that were not reviewed 
by the Panel (56 FR 37622 at 37623 to 37626):
    <bullet> Four studies using oral administration
    <bullet> Three studies using subcutaneous administration
    <bullet> Five studies using topical administration
    We explain that, because these studies were not of a sufficient 
duration, they were not sufficient to assess the carcinogenicity of 
benzoyl peroxide. We state that long-term (i.e., over the entire animal 
lifespan) carcinogenicity studies need to be conducted in two rodent 
species to understand whether benzoyl peroxide is a carcinogen with a 
long latency period (56 FR 37622 at 37631).
    After publication of the 1995 proposed rule, we collaborated with 
CHPA to develop carcinogenicity study protocols (Refs. 11 through 14). 
In 2001, CHPA submitted a mouse and a rat carcinogenicity study (Ref. 
15). Both studies were conducted using a carbopol benzoyl peroxide gel 
administered topically for 2 years. Neither study demonstrated that 
benzoyl peroxide is carcinogenic. In the mouse study, benzoyl peroxide 
was applied at doses of 1, 5, and 15 milligrams (mg) per mouse once 
daily to 6 square centimeters (cm\2\) on the dorsal skin. In the rat 
study, benzoyl peroxide was applied at doses of 5, 15, and 45 mg per 
rat once daily to 12 cm\2\ on the dorsal skin. The mice and rats were 
sacrificed at 52 weeks (interim sacrifice) or 104 weeks, and complete 
necropsies were performed. Both studies show that benzoyl peroxide had 
no effect on survival, body weight, food consumption, or gross 
pathology, and neither produced any evidence of systemic toxicity. The 
dosing used in the study (0.17, 0.83, and 2.5 mg per cm\2\) probably 
represents the dosing used by humans under actual use conditions. 
Because these studies were well-designed and conducted for the animals' 
lifespan, we believe they adequately exclude the possibility that 
benzoyl peroxide is a carcinogen with a short or long latency period.

E. Photocarcinogenicity

    Our review of a photocarcinogenicity study submitted after the 1995 
proposed rule suggest that benzoyl peroxide is not a photocarcinogen. 
The design of photocarcinogenicity studies is similar to that of the 
tumor promoter studies discussed in the previous section of this 
document but differ in the exposure to UV radiation. The tumor promoter 
studies are designed so that animals are exposed to UV radiation for a 
short time and then exposed to benzoyl peroxide (in the absence of UV 
radiation) for nearly the animals' entire lifespan. 
Photocarcinogenicity studies involve exposure to UV radiation and 
benzoyl peroxide simultaneously for the animals' lifespan.
    The 1991 proposed rule did not include a discussion of any 
photocarcinogenicity studies because none were available at the time. 
Two published photocarcinogenicity studies in mice, whose results had 
been reviewed at the 1992 Advisory Committee meeting, were discussed in 
the 1995 proposed rule. The studies showed no evidence that benzoyl 
peroxide is a photocarcinogen. The Advisory Committee, however, 
concluded that the studies were not adequate to fully resolve this 
issue because they did not include sufficient numbers of mice and they 
did not collect data throughout the animals' lifespan. We agreed with 
the Advisory Committee and requested new

[[Page 9771]]

photocarcinogenic studies in the 1995 proposed rule.
    In 1999, CHPA submitted a study examining the photocarcinogenic 
potential of benzoyl peroxide in mice (Ref. 10). The study is entitled 
``12-Month Topical Study to Determine the Influence of Benzoyl Peroxide 
on Photocarcinogenesis in Albino Hairless Mice Crl: SKH1(hr/hr)BR.'' 
The mice received single daily doses of UV radiation along with 0, 5, 
15, and 50 mg per milliliter benzoyl peroxide carbopol gel. The mice 
were dosed daily, Monday through Friday. On Monday, Wednesday, and 
Friday, the benzoyl peroxide was applied before irradiation. On Tuesday 
and Thursday, the benzoyl peroxide was applied after irradiation. 
Treatment was continued for 40 weeks, and then the mice were observed 
for an additional 12 weeks (52 weeks total). The number of tumors was 
recorded each week. This study shows a slight enhancement of UV-
mediated skin tumorigenesis by benzoyl peroxide at the low and mid 
doses. However, no enhancement was apparent at the high dose, as the 
number of tumors was similar to that in the control group. Because 
increased doses of benzoyl peroxide did not produce greater numbers of 
tumors, the study suggests that benzoyl peroxide is not 
photocarcinogenic in mice.

F. Epidemiological Data

    There have been several epidemiological studies conducted that 
provide information about whether there is a link between the use of 
benzoyl peroxide to tumor development, as discussed in the 1991 
proposed rule (56 FR 37622 at 37629 and 37630). None of the studies 
clearly associate the use of benzoyl peroxide with the development of 
skin cancer in humans. The largest of these studies evaluated 870 
subjects who developed skin cancer and 1,250 control subjects who did 
not develop skin cancer (matched for age, sex, and geographic location) 
(Ref. 4). The study authors concluded that the past history of acne was 
the second strongest correlation to the development of basal cell 
carcinoma, with a family history of cancer being the strongest 
correlation. Although the authors suggested that there may be a 
relationship between benzoyl peroxide use and skin cancer, data about 
subject use of acne treatments was not collected (e.g., whether 
subjects had used benzoyl peroxide). We are not aware of any relevant 
epidemiological studies published since 1991. Therefore, we do not have 
any epidemiological evidence demonstrating that benzoyl peroxide is a 
carcinogen in humans.

G. Overall Conclusion

    We are classifying benzoyl peroxide as GRASE. This conclusion is 
supported by the animal studies that suggest benzoyl peroxide is not 
carcinogenic or photocarcinogenic. Although some of the studies suggest 
that benzoyl peroxide is a tumor promoter with chemical initiators in 
animals, three studies demonstrate that benzoyl peroxide is not 
carcinogenic or photocarcinogenic in animals. We believe these three 
studies are more meaningful than the conflicting tumor promoter 
studies.
    As explained in this section of the document, we believe that 
consideration of all the findings supports the GRASE status of benzoyl 
peroxide. Even though benzoyl peroxide is known to be a skin irritant 
and sensitizer in humans (47 FR 12430 at 12444), we believe, with 
adequate labeling, these risks can be minimized in such a way that 
benzoyl peroxide is safe to use for acne.
    There were two safety signals that concerned us when we proposed to 
classify benzoyl peroxide as category III (i.e., more data needed to 
determine safety) instead of GRASE:
    <bullet> The ability of benzoyl peroxide to be a weak mutagen in 
vitro, and
    <bullet> The tumor promotion potential of benzoyl peroxide in the 
presence of a chemical initiator in animals
    No new safety signals have been identified since the 1991 proposed 
rule, despite the conduct of additional studies. We conclude that the 
additional rodent carcinogenicity and photocarcinogenicity studies 
conducted since the proposed rule justify a GRASE determination in 
spite of the mutagenic and tumor promoter potential of benzoyl 
peroxide.
    Although genotoxicity studies are useful, findings that a drug is 
mutagenic in these studies does not necessarily lead to a determination 
that the drug is unsafe. Genotoxicity studies are often preliminary 
studies in drug development that help provide a framework for how to 
proceed with future studies. Positive results with genotoxicity studies 
show that a drug has the potential to be a mutagen, thereby 
contributing to the development of tumors and possibly cancer. 
Consistent with the guidelines (Ref. 5), the genotoxicity study 
findings led to animal studies to determine the biological relevance of 
the evidence that benzoyl peroxide may be a weak mutagen in vitro. The 
animal studies subsequently conducted consist of animal tumor 
promotion, carcinogenicity, and photocarcinogenicity studies.
    The tumor promotion studies demonstrate that benzoyl peroxide is a 
tumor promoter in the presence of a chemical initiator. It is unclear 
from the studies whether benzoyl peroxide is a tumor promoter in the 
presence of UV radiation (as an initiator) because two studies are 
contradictory. As with the genotoxicity studies, the biological 
relevance of the tumor promotion studies results needs to be 
determined. Tumor promoter studies are not generally relied on solely 
in place of carcinogenicity studies. Drug dosing in tumor promoter 
studies does not reflect actual human use conditions, making it 
difficult to interpret the results and extrapolate to human use. The 
relevance of the animal tumor promoter study results to human safety 
can only be determined by carcinogenicity and photocarcinogenicity 
studies for benzoyl peroxide.
    Carcinogenicity studies are the most reliable non-clinical studies 
that can be extrapolated to humans for determining the long-term or 
chronic safety. These studies are conducted with topical application of 
benzoyl peroxide with and without UV irradiation (i.e., both 
carcinogenicity and photocarcinogenicity studies). Dermal 
carcinogenicity and photocarcinogenicity studies best represent actual 
use conditions for benzoyl peroxide. They are the benchmark for 
determining the carcinogenic potential of a drug. We believe that the 
negative findings in the carcinogenic and photocarcinogenic studies 
support a GRASE conclusion for benzoyl peroxide because they are more 
relevant to humans under conditions of actual use than genotoxicity or 
tumor promotion studies.

V. FDA's Conclusions on Labeling

    In addition to the labeling required for all OTC topical acne drug 
products, we are now requiring labeling that provides information 
related specifically to benzoyl peroxide. We are only requiring carton 
labeling and not consumer package insert labeling for benzoyl peroxide. 
This required benzoyl peroxide labeling is based on labeling that we 
previously proposed for the ingredient (discussed in section IV.A of 
this document). In addition, the required labeling reflects our safety 
assessment of benzoyl peroxide discussed in the previous sections of 
this document. We believe that the labeling required in this document 
is necessary for the safe and effective use of OTC topical acne drug 
products containing benzoyl peroxide.

[[Page 9772]]

    In addition to the labeling specific to benzoyl peroxide, we are 
revising labeling for all OTC acne drug products. We revised the 
warnings and directions for these products such that they meet the 
content and format requirements in Sec.  201.66. When the final rule 
for these products was established in 1991, we had not yet established 
Sec.  201.66.

A. Past FDA Requirements for Labeling

    In the 1985 proposed rule, we proposed warnings required for OTC 
acne drug products containing benzoyl peroxide:
    <bullet> Do not use benzoyl peroxide on very sensitive skin.
    <bullet> Keep benzoyl peroxide products away from the eyes, lips, 
and mouth.
    <bullet> Benzoyl peroxide may bleach hair or dye fabric.
    These warnings were specific to benzoyl peroxide and were not 
proposed for OTC acne drug products containing other active 
ingredients. These warnings come from recommendations made by the Panel 
in the 1982 ANPR.
    In the 1995 proposed rule, we proposed the following warning and 
direction appear on prescription and OTC drug products containing 
benzoyl peroxide:
    <bullet> Warning: ``When using this product, avoid unnecessary sun 
exposure and use a sunscreen.''
    <bullet> Direction: ``If going outside, use a sunscreen. (sentence 
in boldface type) Allow [insert name of benzoyl peroxide product] to 
dry, then follow directions in the sunscreen labeling. If irritation or 
sensitivity develops, discontinue use of both products and consult a 
doctor.''
    For OTC products, the 1995 proposed rule proposed that this 
labeling be required on the outer carton. For prescription products, 
the 1995 proposed rule proposed that this labeling appear in the 
patient package insert.
    In the 1995 proposed rule, we also proposed a series of questions 
and answers that would appear in a package insert and would explain the 
tumor promotion potential and sensitizing nature of benzoyl peroxide 
(60 FR 6554 at 6555 to 6556). The questions answered in the 1995 
proposed rule included the following:
    <bullet> What is in (insert brand name of benzoyl peroxide 
product)?
    <bullet> Does benzoyl peroxide cause tumors to grow in humans?
    <bullet> What should I do?
    This information essentially summarized the data from animal 
studies that led to the earlier proposed classification of benzoyl 
peroxide as category III. We suggested that it appear as a package 
insert for prescription and OTC products. This labeling in the 1995 
proposed rule stems from and agrees with the recommendations of the 
Committee, which met in 1992 to discuss benzoyl peroxide in acne drug 
products.

B. Carton Labeling

    We are requiring the warnings proposed in the 1985 proposed rule as 
well as the warning and direction proposed in the 1995 proposed rule 
(see section V.A of this document). Although we are revising the 
warnings and direction slightly, the overall meaning remains the same.
    This action relates to three submissions that we received in 
response to the 1995 proposed rule. These submissions argue that we 
should not require the proposed warning concerning sun exposure. Two of 
the submissions argue that there is no scientific evidence 
demonstrating a risk of photosensitivity in humans when using benzoyl 
peroxide (Refs. 16 and 17). They acknowledge the studies showing that 
benzoyl peroxide is a skin tumor promoter in rodents. However, they do 
not believe the results from rodent studies support a finding of 
significant human health risk. The third submission suggests that 
cleansers and soaps containing benzoyl peroxide be excluded from the 
required label warning ``use a sunscreen'' (Ref. 18). The submission 
concurs with the recommended label warning to ``use a sunscreen'' for 
benzoyl peroxide products. We proposed this warning be included on all 
OTC benzoyl peroxide products. However, the submission argues that the 
warning should only be required on products that are left on the skin 
because it would confuse consumers using products that are washed off 
after use.
    Since receiving these submissions, we have reviewed new data 
regarding the potential phototoxicity of benzoyl peroxide. The data 
shows that benzoyl peroxide is not a photocarcinogen in animals. 
Studies have also shown that 5 and 10 percent benzoyl peroxide 
preparations can decrease the skin's tolerance to UV radiation (i.e., 
increase sunburn) after repeated applications (Refs. 19 and 20). In 
addition, benzoyl peroxide can cause skin irritation, which may worsen 
with sun exposure. These adverse effects of benzoyl peroxide are 
important because drug products containing benzoyl peroxide are often 
used daily on sun-exposed areas of the body (e.g., face). The best ways 
to protect sun-exposed areas of the body are to cover them up, stay out 
of the sun, and to use a sunscreen. Therefore, we believe it is 
important to include information warning consumers to avoid unnecessary 
sun exposure and to use a sunscreen when using any drug products 
containing benzoyl peroxide.
    For the same reason, we are not exempting cleansers and soaps 
containing benzoyl peroxide from the ``use a sunscreen'' warning, as 
argued by the third comment. This warning is required for all OTC 
topical acne drug products containing benzoyl peroxide. We do not 
believe this warning (and the accompanying directions about sunscreen 
use) will confuse consumers. The warning is clear, simple, and applies 
to all OTC topical acne drug products containing benzoyl peroxide 
whether they are washed off or left on. We are moving this direction 
from the beginning of the directions section to the end. Whether a 
product is washed off or left on, the directions should instruct 
consumers to use the product and then apply a sunscreen. We believe 
this revision will prevent confusion about sunscreen use and adequately 
address the concern raised by the third submission.
    Accordingly, we are adding the following benzoyl peroxide warnings 
in this document (Sec.  333.350(c)(4)):
    <bullet> Do not use if you [bullet] have very sensitive skin 
[bullet] are sensitive to benzoyl peroxide.
    <bullet> When using this product [bullet] avoid unnecessary sun 
exposure and use a sunscreen [bullet] avoid contact with the eyes, 
lips, and mouth [bullet] avoid contact with hair and dyed fabrics, 
which may be bleached by this product [bullet] skin irritation may 
occur, characterized by redness, burning, itching, peeling, or possibly 
swelling. Irritation may be reduced by using the product less 
frequently or in a lower concentration.
    <bullet> Stop use and ask a doctor if [bullet] irritation becomes 
severe.
    In addition, we are adding a new direction for products containing 
benzoyl peroxide (Sec.  333.350(d)(2)) (21 CFR 333.350(d)(2))):
    <bullet> [bullet] if going outside, apply sunscreen after using 
this product. If irritation or sensitivity develops, stop use of both 
products and ask a doctor.
    We are also revising carton labeling to reflect OTC drug labeling 
format and content requirements (i.e., ``Drug Facts'') implemented 
after the 1995 proposed rule (Sec.  201.66).

C. Consumer Package Insert

    We received three submissions from healthcare organizations arguing 
that we should not require the patient and consumer package insert 
labeling proposed for OTC and prescription

[[Page 9773]]

benzoyl peroxide drug products in the 1995 proposed rule. One 
submission argues that the purpose of OTC labeling has never been to 
tell consumers everything that scientists have discovered, or might 
still be investigating, about a drug product and its ingredients (Ref. 
17). The second submission argues that information related to possible 
carcinogenicity should not be disseminated until the completion of 
valid epidemiologic studies (Ref. 16). The submission believes it is 
not helpful to imply a connection between benzoyl peroxide and sunlight 
in the absence of supporting epidemiological data. The third submission 
is concerned that the proposal to include patient package inserts with 
all topical acne drug products containing benzoyl peroxide will 
increase costs to the healthcare distribution system (Ref. 21). The 
submission argues that in order for written materials to accompany each 
package of a prescription drug product, manufacturers must switch from 
automated to manual packaging, which would be costly. In addition, the 
submission argues that the costs of applying the same requirement to 
OTC products would be even higher because OTC products are more 
numerous and are distributed in much greater volume.
    We agree with the submissions' request to not require a consumer 
package insert accompanying OTC topical acne drug products containing 
benzoyl peroxide. The purpose of including a consumer package insert is 
to disseminate as much information pertaining to the potential risks of 
using benzoyl peroxide containing drug products. We believe that the 
proposed carton labeling sufficiently informs the consumer of the 
potential risks of using these products. After reviewing the newly 
submitted data, we no longer see the need for a consumer package 
insert.
    We are not creating regulations requiring a patient package insert 
to accompany prescription topical acne drug products containing benzoyl 
peroxide because all prescription topical acne drug products are 
marketed under new drug applications (NDAs). The decision to include 
patient package inserts for prescription products should be done on a 
case-by-case basis. Prescription products containing benzoyl peroxide 
cannot be marketed until we review information submitted for a specific 
product and determine that the product is safe and effective. As part 
of this review, we determine labeling that is specific to the product. 
We have and will continue to require appropriate safety information 
about benzoyl peroxide in each prescription product as part of the NDA 
review and approval. Therefore, we do not believe that the proposed 
labeling needs to be included in monograph regulations.

D. Overall Conclusion

    In this document, we are requiring labeling specific to benzoyl 
peroxide containing drug products. Warnings for drug products 
containing benzoyl peroxide include the following: (Sec.  
333.350(c)(4)):
    <bullet> Avoiding unnecessary sun exposure
    <bullet> Not using on very sensitive skin
    <bullet> Keeping away from the eyes, lips, and mouth
    <bullet> Cautioning that benzoyl peroxide may bleach hair or dye 
fabric
    These warnings are not required for other acne active ingredients. 
However, warnings required for other acne active ingredients, such as 
``for external use only,'' are required for benzoyl peroxide. We are 
also requiring a direction for drug products containing benzoyl 
peroxide to use a sunscreen when going outside.
    We are not requiring a consumer package insert for drug products 
containing benzoyl peroxide. After reviewing the newly submitted data, 
we no longer see the need for a consumer package insert. We believe 
that the proposed carton labeling sufficiently informs the consumer of 
the potential risks of using these products. We are also not requiring 
a patient package insert to accompany prescription topical acne drug 
products containing benzoyl peroxide with this final rule. All 
prescription topical acne drug products are marketed under NDAs, which 
already require appropriate safety information about benzoyl peroxide 
in the labeling of each prescription product as part of the NDA review 
and approval. We do not believe that the proposed labeling needs to be 
included in monograph regulations.

VI. Analysis of Impacts

    We have examined the impacts of this final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). We believe that this 
final rule is not a significant regulatory action under the Executive 
order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. We lack the data to certify that this final rule 
will not have a significant economic impact on a substantial number of 
small entities. Therefore, we have prepared a final regulatory impact 
analysis.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $133 million, using the most current (2008) Implicit 
Price Deflator for the Gross Domestic Product. We do not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

A. Need for and Objectives of the Rule

    The purpose of this document is to revise the conditions for 
marketing OTC acne drug products. This final rule establishes that OTC 
acne drug products containing benzoyl peroxide are GRASE and 
establishes required labeling for these products. This final rule 
requires manufacturers of OTC acne products containing benzoyl peroxide 
to relabel their products and add new warnings and directions within 12 
months from the date of publication.
    This final rule also requires that the warnings and directions for 
OTC acne drug products containing resorcinol, resorcinol monoacetate, 
salicylic acid, and/or sulfur be revised to meet the content and format 
requirements in Sec.  201.66. We are allowing manufacturers up to 5 
years to comply with this provision. Frequent label redesigns are 
typical for OTC topical acne drug products, with redesigns generally 
implemented at least every 5 years for a product. Therefore, the 
regulatory-mandated relabeling will fall within this time period, 
minimizing the impact on the manufacturer of these products. There are 
no reformulation costs required by this rule.

B. Number of Products Affected

    Estimating the number of manufacturers and affected products is 
difficult because we lack data on products currently marketed. Our Drug 
Listing System currently does not have accurate information on the 
number of

[[Page 9774]]

marketed OTC acne drug manufacturers and products containing benzoyl 
peroxide. We used data from A. C. Nielsen to estimate the dollar sales 
and the number of stock keeping units (SKUs) that would be affected by 
this rule. Based on 2006 retail sales data, the total sales for 
approximately 330 affected SKUs were $263.0 million, or converting to 
2009 dollars, $278 million. However, there are likely some affected OTC 
acne products that we were unable to identify.
    Of the 330 affected SKUs, about 25 percent contain benzoyl peroxide 
and 75 percent contain other ingredients cited in this final rule 
(i.e., resorcinol, resorcinol monoacetate, salicylic acid, or sulfur). 
Most manufacturers of products containing benzoyl peroxide will need to 
relabel and add new warnings and directions within 1 year from the date 
of publication. Small entities with annual product sales of less than 
$25,000 will have up to 2 years to comply. Manufacturers of all other 
OTC acne drug products (containing resorcinol, resorcinol monoacetate, 
salicylic acid and sulfur) will have up to 5 years to relabel and 
conform to the OTC format and contents requirements in Sec.  201.66.

C. Cost to Relabel

    Estimates of relabeling costs for the types of changes required by 
this document vary depending on the following: (1) Whether the products 
are nationally branded or private label, (2) the printing method, and 
(3) the number of colors used. The costs of product relabeling are also 
dependent on the timing of the required labeling change. Most OTC 
manufacturers routinely schedule revisions of product labels every few 
years. To the extent that the timing of regulatory changes corresponds 
with routine labeling revisions by the company, the regulatory cost of 
relabeling is significantly reduced.
    We used a labeling cost model developed for FDA by the consulting 
firm RTI International (RTI) to derive an estimate of the cost to 
relabel OTC acne drug products (Ref. 22). The model was developed to 
estimate the cost of revising food and dietary supplement labels. The 
RTI model assumes that all manufacturers voluntarily revise their 
labeling every 3 years. We believe that the graphic and design 
estimates from the RTI model are an appropriate proxy for the costs 
that would be incurred by OTC acne drug product manufacturers. However, 
we are unable to use this model to forecast reductions in relabeling 
costs for year four and five of the implementation period.
    The RTI model estimates that the costs to revise labeling ranges 
from $2,700 to $6,600 for a 1-year implementation period. Assuming an 
average relabeling cost of $4,650 per SKU, the total one-time cost for 
80 SKUs containing benzoyl peroxide would be about $372,000 (80 SKUs x 
$4,650). To minimize the impact on small entities with annual sales 
less than $25,000, we are allowing up to 24 months for products 
containing benzoyl peroxide to be relabeled.
    All other manufacturers of acne treatment products containing 
resorcinol, resorcinol monoacetate, salicylic acid, and sulfur would 
need to revise their product labels to conform to the OTC format and 
contents requirements in Sec.  201.66. Based on the labeling cost 
model, the average incremental costs of conforming to the OTC format 
and content requirements are estimated to be $3,750 per SKU, assuming a 
maximum period of 3 years to comply. The total one-time costs to 
manufacturers to relabel the estimated 250 affected OTC SKUs is about 
$937,500 (250 SKUs x $3,750). Because the labeling cost model stops at 
a 3-year implementation period and these manufacturers would have up to 
5 years to incorporate these changes with routinely scheduled labeling 
changes, these relabeling costs would be reduced. However, we lack 
sufficient information to estimate the reduction.
    The present value of total one-time costs for relabeling all of the 
330 affected OTC acne treatment products is $1.1 million using a 7 
percent discount rate and $1.2 million using a 3 percent discount rate. 
The annualized total costs of compliance of this rule are $0.4 million 
using 7 percent and 3 percent discount rates over 3 years.
    Using the 2009 dollar value of annual retail sales for OTC acne 
products of $278 million, the annualized costs of compliance account 
for less than 0.2 percent of total annual OTC acne retail sales for all 
entities, for both a 7 percent and 3 percent discount rate over 3 
years. Because the period selected for annualization is typically much 
longer than 3 years, using a 3-year period maximizes annualized 
compliance costs for this analysis.

D. Benefits of this Rule

    The primary benefit of this final rule is that consumers will have 
standardized and consistent labeling information that is necessary for 
the safe use of OTC acne products affected by this rule. This final 
rule finds that OTC acne drug products containing benzoyl peroxide are 
GRASE and allows these products to remain on the market. This final 
rule will provide consumers with warnings and directions information 
that is needed for the safe use of OTC acne products containing benzoyl 
peroxide. This final rule also will require that the current monograph 
labeling information for OTC topical acne drug products containing 
resorcinol, resorcinol monoacetate, salicylic acid, and sulfur be 
consistently presented according to the OTC Drug Facts labeling 
requirements in 21 CFR part 201.
    With this final rule, there are now five GRASE active ingredients 
for OTC acne drug products. Consumers will continue to have a range of 
choices for OTC acne products with safety and use information uniformly 
presented. A uniform presentation of labeling information should help 
consumers compare similar products to make informed choices.

E. Alternatives and Steps Taken to Minimize Impacts on Small Entities

    For products containing benzoyl peroxide, we considered a longer 
implementation period, such as 2 years for all of the 80 SKUs, rather 
than only for those entities with annual sales less than $25,000. 
However, we believe it is important to provide the new warning 
statements and directions to consumers as soon as possible. We 
considered and rejected a shorter implementation period for all other 
OTC acne products to conform to the OTC format and content 
requirements. To provide maximum flexibility and to minimize burdens, 
we are allowing up to 5 years for firms to coordinate required labeling 
changes with planned revisions. We believe any longer implementation 
period is impractical and would unnecessarily delay the benefit of 
providing uniform format and content labeling to consumers who use OTC 
drug products for the treatment of acne.

F. Impact on Small Businesses

    The Small Business Administration defines an entity as small in the 
pharmaceutical manufacturing industry if the business has fewer than 
750 employees. Over 90 percent of manufacturers in the OTC 
pharmaceutical industry are classified as small. The average annual 
value of shipments for small entities in Pharmaceutical Manufacturing 
Preparation NAICS 325412 was $34.9 million in 2002\1\. Converting to 
2009 dollars, the average value of shipments

[[Page 9775]]

per small entity is $39.0 million. However, the Census data do not 
allow us to estimate the average value of shipments for OTC 
manufacturers.
---------------------------------------------------------------------------

    \1\ U.S. Department of Commerce, 2002 Economic Census of 
Manufacturers, ``Pharmaceutical Preparation Manufacturing: 2002,'' 
Industry Series, NAICS 325412, Table 4. Industry Statistics by 
Employment Size, December 2004.
---------------------------------------------------------------------------

    To estimate possible impacts on small entities, we used A. C. 
Nielsen total retail sales for all OTC acne products affected by this 
rule to calculate the annualized total cost of compliance as a 
percentage of annual sales. The annualized total costs of compliance of 
this rule are $0.4 million using 7 percent and 3 percent discount rates 
over 3 years.
    Table 2 of this document presents the annualized costs of 
compliance as a percent of total annual retail sales for OTC acne 
products by size of the affected entities. Although we have sales data 
for each SKU, we were unable to determine the firm size for certain 
private label SKUs because A. C. Nielsen does not reveal ownership 
information for certain store brands. These store brands are typically 
large chain stores. In addition, we combined the category for small 
entities with 11 other entities whose size information could not be 
found in financial listings.

            Table 2.--Annualized Compliance Cost as a Percent of OTC Acne Sales by Size of Entity\1\
----------------------------------------------------------------------------------------------------------------
                                                   Annualized Compliance Cost      Compliance Cost  (Percent of
                                                     (dollars in millions)                    Sales)
                   2009 Sales      Number of  ------------------------------------------------------------------
     Size         (dollars in         SKUs                                                                3%
                   millions)                    7%  discount   3%  discount rate    7 %  discount      discount
                                                    rate                                 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%
----------------------------------------------------------------------------------------------------------------
Private                     $6.1           48            $0.1               $0.1               1.0%         1.0%
 Label\2\
----------------------------------------------------------------------------------------------------------------
Total\3\                  $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 are less than 0.2 percent of 
total annual OTC acne retail sales for all entities. Private label 
entities compliance costs as a percent of OTC acne sales are about 1 
percent over 3 years. For small entities, the annualized costs over 3 
years are 0.3 percent annual sales for OTC acne products. These 
estimates represent maximum values because of the relatively short 
period used to annualize costs.
    These estimates do not account for the additional time granted to 
small entities to minimize the cost impacts. Industry routinely changes 
their OTC product labeling, and we have allowed for extended 
implementation periods to comply with this final rule. Therefore, we 
believe that it is unlikely that this final rule will have a 
significant economic impact on a substantial number of small entities. 
This final rule does not require any new reporting or recordkeeping 
activities.

G. Summary of Analysis

    This analysis shows that this final rule is not economically 
significant under Executive Order 12866. We have allowed flexible 
implementation periods to minimize the regulatory costs of revising 
labeling. We lack the data to certify that this final rule will not 
have a significant economic impact on a substantial number of small 
entities. Therefore, this analysis, together with other relevant 
sections of this document, serves as our Regulatory Flexibility 
Analysis, as required under the Regulatory Flexibility Act.

VII. Paperwork Reduction Act of 1995

    We conclude that the labeling requirements required in this rule 
are not subject to review by the Office of Management and Budget 
because they do not constitute a ``collection of information'' under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, 
the labeling statements are a ``public disclosure of information 
originally supplied by the Federal government to the recipient for the 
purpose of disclosure to the public'' (5 CFR 1320.3(c)(2)).

VIII. Environmental Impact

    We have determined under 21 CFR 25.31(a) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IX. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. Section 4(a) of the Executive order 
requires agencies to ``construe * * * a Federal statute to preempt 
State law only where the statute contains an express preemption 
provision or there is some other clear evidence that the Congress 
intended preemption of State law, or where the exercise of State 
authority conflicts with the exercise of Federal authority under the 
Federal statute.'' The sole statutory provision giving preemptive 
effect to the final rule is section 751 of the act (21 U.S.C. 379r). We 
believe that we have complied with all of the applicable requirements 
under the Executive order and have determined that the preemptive 
effects of this rule are consistent with Executive Order 13132.

X. References

    The following references are on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20857, and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday. FDA has verified the 
Web site addresses, but FDA is not responsible for any subsequent 
changes to the Web sites after this document publishes in the Federal 
Register.
    1. Iverson, O. H., ``Carcinogenesis Studies with Benzoyl 
Peroxide (Panoxyl Gel 5%),'' Journal of Investigative Dermatology, 
86:442-448, 1986.
    2. Iverson, O. H., ``Skin Tumorigenesis and Carcinogenesis 
Studies with 7,12-dimethylbenz [a] anthracene, Ultraviolet Light, 
Benzoyl Peroxide (Panoxyl Gel 5%) and Ointment Gel,'' 
Carcinogenesis, 9:803-809, 1988.
    3. Comment No. C4, 1981N-114A.
    4. Hogan, D. J. et al., ``A Study of Acne Treatments as Risk 
Factors for Skin Cancer of the Head and Neck,'' British Journal of 
Dermatology, 125:343-348, 1991.

[[Page 9776]]

    5. International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use: 
Guidance on Genotoxicity Testing and Data Interpretaion on 
Pharmaceuticals Intended for Human Use (S2(R1)), February 23, 2010. 
http://www.ich.org/lob/media/media4477.pdf.
    6. Giri, U., M. Iqbal, and M. Athar, ``Porphyrin-Mediated 
Photosensitization Has a Weak Tumor Promoting Activity in Mouse 
Skin: Possible Role of In Situ-Generated Reactive Oxygen Species,'' 
Carcinogenesis, 17:2023-2028, 1996.
    7. Kawanishi, S. et al., ``Site-Specific Oxidation at GG and GGG 
Sequences in Double-Stranded DNA by Benzoyl Peroxide as a Tumor 
Promoter,'' Biochemistry, 38:16733-16739, 1999.
    8. Kensler, T. et al., ``Role of Reactive Intermediates in Tumor 
Promotion and Progression,'' Progress in Clinical and Biological 
Research, 391:103-116, 1995.
    9. Matsumura, Y. and H. N. Ananthaswamy, ``Toxic Effects of 
Ultraviolet Radiation on the Skin,'' Toxicology and Applied 
Pharmacology, 195:298-308, 2004.
    10. Comment No. RPT3, 1981N-0114.
    11. Comment No. LET19, 1981N-0114.
    12. Comment No. LET20, 1981N-0114.
    13. Comment No. LET21, 1981N-0114.
    14. Comment No. LET22, 1981N-0114.
    15. Comment No. RPT4, 1981N-0114.
    16. Comment No. C3, 1992N-0311.
    17. Comment No. C4, 1992N-0311.
    18. Comment No. C1, 1992N-0311.
    19. Jeanmougin, M. and J. Civatte, ``Prediction of Benzoyl 
Peroxide Phototoxicity by Photoepidermotests After Repeated 
Applications. Preventative Value of a UVB Filter,'' Archives of 
Dermatological Research, 280 (Suppl): S90-S93, 1988.
    20. Jeanmougin, M. et al., ``Phototoxic Activity of 5% Benzoyl 
Peroxide in Man. Use of a New Methodology,'' Dermatologica, 167:19-
23, 1983.
    21. Comment No. C2, 1992N-0311.
    22. ``FDA Labeling Cost Model, Final Report'' prepared by Mary 
Muth, Erica Glendhill, and Shawn Karns, RTI International, Prepared 
for Amber Jessup, FDA Center for Food Safety and Applied Nutrition, 
RTI International, January 2003.

List of Subjects in 21 CFR Part 333

    Labeling, Over-the-counter drugs.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
333 is amended as follows:

PART 333--TOPICAL ANTIMICROBIAL DRUG PRODUCTS FOR OVER-THE-COUNTER 
HUMAN USE

0
1. The authority citation for 21 CFR part 333 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

0
2. Section 333.310 is revised to read as follows:


Sec.  333.310  Acne active ingredients.

    The active ingredient of the product consists of any of the 
following:
    (a) Benzoyl peroxide, 2.5 to 10 percent.
    (b) Resorcinol, 2 percent, when combined with sulfur in accordance 
with Sec.  333.320(a).
    (c) Resorcinol monoacetate, 3 percent, when combined with sulfur in 
accordance with Sec.  333.320(b).
    (d) Salicylic acid, 0.5 to 2 percent.
    (e) Sulfur, 3 to 10 percent.
    (f) Sulfur, 3 to 8 percent, when combined with resorcinol or 
resorcinol monoacetate in accordance with Sec.  333.320.

0
3. Section 333.320 is revised to read as follows:


Sec.  333.320  Permitted combinations of active ingredients.

    (a) Resorcinol identified in Sec.  333.310(b) may be combined with 
sulfur identified in Sec.  333.310(f).
    (b) Resorcinol monoacetate identified in Sec.  333.310(c) may be 
combined with sulfur identified in Sec.  333.310(f).

0
4. Section 333.350 is amended by revising paragraphs (c) and (d) and 
removing paragraph (e) to read as follows:


Sec.  333.350  Labeling of acne drug products.

* * * * *
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For products containing any ingredients identified in Sec.  
330.310.
    (i) The labeling states ``For external use only.''
    (ii) The labeling states ``When using this product [bullet] skin 
irritation and dryness is more likely to occur if you use another 
topical acne medication at the same time. If irritation occurs, only 
use one topical acne medication at a time.''
    (2) For products containing sulfur identified in Sec.  333.310(e) 
and (f).
    (i) The labeling states ``Do not use on [bullet] broken skin 
[bullet] large areas of the skin.''
    (ii) The labeling states ``When using this product [bullet] apply 
only to areas with acne.''
    (3) For products containing any combination identified in Sec.  
333.320. (i) The labeling states ``When using this product [bullet] 
rinse right away with water if it gets in eyes.''
    (ii) The labeling states ``Stop use and ask a doctor [bullet] if 
skin irritation occurs or gets worse.''
    (4) For products containing benzoyl peroxide identified in Sec.  
333.310(a).
    (i) The labeling states ``Do not use if you [bullet] have very 
sensitive skin [bullet] are sensitive to benzoyl peroxide.''
    (ii) The labeling states ``When using this product [bullet] avoid 
unnecessary sun exposure and use a sunscreen [bullet] avoid contact 
with the eyes, lips, and mouth [bullet] avoid contact with hair and 
dyed fabrics, which may be bleached by this product [bullet] skin 
irritation may occur, characterized by redness, burning, itching, 
peeling, or possibly swelling. Irritation may be reduced by using the 
product less frequently or in a lower concentration.''
    (iii) The labeling states ``Stop use and ask a doctor if [bullet] 
irritation becomes severe.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products applied containing any ingredient identified in 
Sec.  333.310. The labeling states ``[bullet] clean the skin thoroughly 
before applying this product [bullet] cover the entire affected area 
with a thin layer one to three times daily [bullet] because excessive 
drying of the skin may occur, start with one application daily, then 
gradually increase to two or three times daily if needed or as directed 
by a doctor [bullet] if bothersome dryness or peeling occurs, reduce 
application to once a day or every other day.''
    (2) For products applied and left on the skin containing benzoyl 
peroxide identified in Sec.  333.310(a).
    (i) The labeling states the directions in paragraph (d)(1) of this 
section.
    (ii) The labeling states ``[bullet] if going outside, apply 
sunscreen after using this product. If irritation or sensitivity 
develops, stop use of both products and ask a doctor.''
    (3) For products applied and removed from the skin containing any 
ingredient identified in Sec.  333.310. Products, such as soaps and 
masks, may be applied and removed and should include appropriate 
directions. All products containing benzoyl peroxide should include the 
directions in paragraph (d)(2)(ii) of this section.
    (4) Optional directions. In addition to the required directions in 
paragraphs (d)(1) and (d)(2) of this section, the product may contain 
the following optional labeling: ``Sensitivity Test for a New User. 
Apply product sparingly to one or two small affected areas during the 
first 3 days. If no discomfort occurs, follow the directions stated 
(select one of the following: `elsewhere on this label,' `above,' or 
`below').''


[[Page 9777]]


    Dated: February 25, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-4424 Filed 3-3-10; 8:45 am]
BILLING CODE 4160-01-S