[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
ANPR: Advance Notice of Proposed Rulemaking
CFR: Code of Federal Regulations
CHPA: Consumer Healthcare Products Association (formerly
Nonprescription Drug Manufacturers Association)
Committee: Dermatologic Drugs Advisory Committee
FDA: Food and Drug Administration
FR: Federal Register
GRASE: Generally Recognized as Safe and Effective
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)
OTC: Over-the-Counter--medicines sold without a
prescription
Panel: Advisory Review Panel on OTC Antimicrobial (II)
Drug Products
SKU: Stock Keeping Unit--an identifier that is used by
merchants to permit the systematic tracking of products and services
offered to customers
TPA: 12-O-tetradecanoylphorbol 13-acetate--a powerful
tumor promoter
U.S.C.: United States Code--compilation of Federal laws
UVA: Ultraviolet A radiation--ultraviolet radiation with a
wavelength between 400 and 320 nanometers
UVB: Ultraviolet B radiation--ultraviolet radiation with a
wavelength between 320 and 280 nanometers
UVR: Ultraviolet radiation--UVC, UVB, and UVA radiation
(1-400 nanometers)
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:
Do not use benzoyl peroxide on very sensitive skin.
Keep benzoyl peroxide products away from the eyes, lips,
and mouth.
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:
New photocarcinogenicity studies on benzoyl peroxide
should be conducted.
Current animal safety data regarding benzoyl peroxide
should be conveyed in labeling.
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
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Treatment Groups\1,\\2\
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1 2 3 4 5 6 7 8 9 10 11 12
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UVB irradiation - - - - - - + + + + + +
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Benzoyl peroxide - 0.1% 1.5% 5% - - - 0.1% 1.5% 5% - -
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TPA in acetone - - - - + - - - - - + -
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Acetone - - - - - + - - - - - +
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\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):
Four studies using oral administration
Three studies using subcutaneous administration
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:
The ability of benzoyl peroxide to be a weak mutagen in
vitro, and
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:
Do not use benzoyl peroxide on very sensitive skin.
Keep benzoyl peroxide products away from the eyes, lips,
and mouth.
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:
Warning: ``When using this product, avoid unnecessary sun
exposure and use a sunscreen.''
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:
What is in (insert brand name of benzoyl peroxide
product)?
Does benzoyl peroxide cause tumors to grow in humans?
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)):
Do not use if you [bullet] have very sensitive skin
[bullet] are sensitive to benzoyl peroxide.
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.
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] 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)):
Avoiding unnecessary sun exposure
Not using on very sensitive skin
Keeping away from the eyes, lips, and mouth
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