Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 9767 

United States in support of the U.S. 

Armed Forces’ operation during some 

period of time from September 11, 2001, 

to termination of SFAR 100–2; 

(b) The person’s flight instructor 

certificate, airman written test report, or 

inspection authorization expired some 

time between September 11, 2001, and 

6 calendar months after returning to the 

United States or termination of SFAR 

100–2, whichever is earlier; and 

(c) The person complies with § 61.197 

or § 65.93 of this chapter, as 

appropriate, or completes the 

appropriate practical test within 6 

calendar months after returning to the 

United States, or upon termination of 

SFAR 100–2, whichever is earlier. 

3. Required documents. The person 

must send the Airman Certificate and/ 

or Rating Application (FAA Form 8710– 

1) to the appropriate Flight Standards 

District Office. The person must include 

with the application one of the 

following documents, which must show 

the date of assignment outside the 

United States and the date of return to 

the United States: 

(a) An official U.S. Government 

notification of personnel action, or 

equivalent document, showing the 

person was a civilian on official duty for 

the U.S. Government outside the United 

States and was assigned to a U.S. Armed 

Forces’ operation some time between 

September 11, 2001, to termination of 

SFAR 100–2; 

(b) Military orders showing the person 

was assigned to duty outside the United 

States and was assigned to a U.S. Armed 

Forces’ operation some time between 

September 11, 2001, to termination of 

SFAR 100–2 ; or 

(c) A letter from the person’s military 

commander or civilian supervisor 

providing the dates during which the 

person served outside the United States 

and was assigned to a U.S. Armed 

Forces’ operation some time between 

September 11, 2001, to termination of 

SFAR 100–2. 

4. Expiration date. This Special 

Federal Aviation Regulation No. 100–2 

is effective until further notice. 

PART 63—CERTIFICATION: FLIGHT 

CREWMEMBERS OTHER THAN 

PILOTS 

■ 4. The authority citation for part 63 

continues to read as follows: 

Authority: 49 U.S.C. 106(g), 40113, 44701– 

44703, 44707, 44709–44711, 45102–45103, 

45301–45302. 

PART 65—CERTIFICATION: AIRMEN 

OTHER THAN FLIGHT 

CREWMEMBERS 

■ 5. The authority citation for part 65 

continues to read as follows: 

Authority: 49 U.S.C. 106(g), 40113, 44701– 

44703, 44707, 44709–44711, 45102–45103, 

45301–45302. 

Issued in Washington, DC, on February 22, 

2010. 

J. Randolph Babbitt, 

Administrator. 

[FR Doc. 2010–4580 Filed 3–3–10; 8:45 am] 

BILLING CODE 4910–13–P 

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-TheCounter Human Use; Final Rule 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

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 


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9768 Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 

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 

§ 201.66 (21 CFR 201.66). When the 

final rule for these products was 

established in 1991, we had not yet 

established § 201.66. The revisions 

necessary to comply with the 

requirements of § 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 


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Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 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-Otetradecanoylphorbol 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. 


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TABLE 1.—TREATMENT GROUPS IN UV INITIATION TUMOR PROMOTER STUDY OF ALBINO MICE

Treatment Groups1,2

1 2 3 4 5 6 7 8 9 10 11 12 

UVB irradiation - - - - - - + + + + + + 

Benzoyl peroxide - 0.1% 1.5% 5% - - - 0.1% 1.5% 5% - - 

TPA in acetone - - - - + - - - - - + - 

Acetone - - - - - + - - - - - + 

1 + Denotes the presence of UVB radiation, TPA, or acetone. 

2 - Denotes the absence of UVB radiation, TPA, or acetone. 

The study authors assessed tumor 

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 (cm2) 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 cm2 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 

cm2) 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 


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Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 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. 


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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 

§ 201.66. When the final rule for these 

products was established in 1991, we 

had not yet established § 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 (§ 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 (§ 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 (§ 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 


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Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 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: 

(§ 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 

§ 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 regulatorymandated 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 


srobinson on DSKHWCL6B1PROD with RULES
9774 Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 

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. 

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 § 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 § 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 20021. Converting to 2009 

dollars, the average value of shipments 


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Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 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. 

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 ENTITY1

Size 2009 Sales 

(dollars in millions) 

Number of 

SKUs 

Annualized Compliance Cost 

(dollars in millions) 

Compliance Cost 

(Percent of Sales) 

7% 

discount rate 

3% 

discount rate 

7 % 

discount rate 

3% 

discount 

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 Label2 $6.1 48 $0.1 $0.1 1.0% 1.0% 

Total3 $278.1 330 $0.4 $0.4 0.2% 0.2% 

1The use of a 3-year period for annualizing maximizes the value of compliance costs for this analysis. 

2Private label represents store brand and unknown brand names. 

3Total 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. 


srobinson on DSKHWCL6B1PROD with RULES
9776 Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 

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. 

■ 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-THECOUNTER HUMAN USE 

■ 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. 

■ 2. Section 333.310 is revised to read 

as follows: 

§ 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 § 333.320(a). 

(c) Resorcinol monoacetate, 3 percent, 

when combined with sulfur in 

accordance with § 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 

§ 333.320. 

■ 3. Section 333.320 is revised to read 

as follows: 

§ 333.320 Permitted combinations of 

active ingredients. 

(a) Resorcinol identified in 

§ 333.310(b) may be combined with 

sulfur identified in § 333.310(f). 

(b) Resorcinol monoacetate identified 

in § 333.310(c) may be combined with 

sulfur identified in § 333.310(f). 

■ 4. Section 333.350 is amended by 

revising paragraphs (c) and (d) and 

removing paragraph (e) to read as 

follows: 

§ 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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’).’’ 


srobinson on DSKHWCL6B1PROD with RULES
Federal Register / Vol. 75, No. 42 / Thursday, March 4, 2010 / Rules and Regulations 9777 

1The revisions in these interim final regulations 

do not affect how the Department treats required 

desegregation plans under the MSAP. 

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 

DEPARTMENT OF EDUCATION 

34 CFR Part 280 

RIN 1855–AA07 

[Docket ID ED–2010–OII–0003] 

Magnet Schools Assistance Program 

AGENCY: Office of Innovation and 

Improvement, Department of Education. 

ACTION: Interim final rule; request for 

comments. 

SUMMARY: The Secretary amends the 

regulations governing the Magnet 

Schools Assistance Program (MSAP) to 

provide greater flexibility to school 

districts designing MSAP programs for 

the Fiscal Year (FY) 2010 grant 

competition announced in a notice 

inviting applications for new awards 

published elsewhere in this issue of the 

Federal Register. These changes remove 

provisions in the regulations that 

require districts to use binary racial 

classifications and prohibit the creation 

of magnet schools that result in minority 

group enrollments in magnet and feeder 

schools exceeding the district-wide 

average of minority group students. This 

new flexibility is necessary to permit 

school districts interested in receiving 

funds under this program to determine 

how best to meet program requirements 

while also taking into account 

intervening Supreme Court case law, 

including the Court’s decision in 

Parents Involved in Community Schools 

v. Seattle School District No 1 et al., 551 

U.S. 701 (2007) (Parents Involved). 

DATES: These regulations are effective 

March 4, 2010. We must receive your 

comments by April 5, 2010. 

ADDRESSES: Submit your comments 

through the Federal eRulemaking Portal 

or via postal mail, commercial delivery, 

or hand delivery. We will not accept 

comments by fax or by e-mail. Please 

submit your comments only one time, in 

order to ensure that we do not receive 

duplicate copies. In addition, please 

include the Docket ID at the top of your 

comments. 

• Federal eRulemaking Portal: Go to 

http://www.regulations.gov to submit 

your comments electronically. 

Information on using Regulations.gov, 

including instructions for accessing 

agency documents, submitting 

comments, and viewing the docket is 

available on the site under ‘‘How To Use 

This Site.’’ 

• Postal Mail, Commercial Delivery, 

or Hand Delivery: If you mail or deliver 

your comments about these interim final 

regulations, address them to Anna 

Hinton, U.S. Department of Education, 

400 Maryland Avenue, SW., room 

4W229, Washington, DC 20202. 

Privacy Note: The Department’s policy for 

comments received from members of the 

public (including those comments submitted 

by mail, commercial delivery, or hand 

delivery) is to make these submissions 

available for public viewing in their entirety 

on the Federal eRulemaking Portal at 

http://www.regulations.gov. Therefore, 

commenters should be careful to include in 

their comments only information that they 

wish to make publicly available on the 

Internet. 

FOR FURTHER INFORMATION CONTACT: 

Anna Hinton, U.S. Department of 

Education, 400 Maryland Avenue, SW., 

room 4W229, Washington, DC 20202. 

Telephone: (202) 260–1816 or by e-mail: 

FY10MSAPCOMP@ed.gov. 

If you use a telecommunications 

device for the deaf (TDD), call the 

Federal Relay Service (FRS), toll free at 

1–800–877–8339. 

Individuals with disabilities may 

obtain this document in an accessible 

format (e.g., braille, large print, 

audiotape, or computer diskette) on 

request to the contact person listed 

under FOR FURTHER INFORMATION

CONTACT. 

SUPPLEMENTARY INFORMATION: 

Invitation To Comment 

We invite you to submit comments 

regarding the removal of the regulatory 

provisions in these interim final 

regulations. The MSAP regulations in 34 

CFR part 280, as amended by these 

interim final regulations, will govern the 

FY 2010 MSAP competition. Any 

changes made to these interim final 

regulations in light of comments would 

govern the next MSAP competition in 

FY 2013. To ensure that your comments 

have maximum effect in developing the 

final regulations, we urge you to 

identify clearly the specific section or 

sections of the interim final regulations 

that each of your comments addresses 

and to arrange your comments in the 

same order as the interim final 

regulations. We also are considering 

issuing a notice of proposed rulemaking 

(NPRM) that would propose provisions 

to replace those that are removed by 

these interim final regulations, although 

we are not soliciting comments on an 

NPRM at this time. Again, any changes 

subsequent to these interim final 

regulations would apply to the next 

MSAP competition, which the 

Department anticipates conducting in 

FY 2013. 

We invite you to assist us in 

complying with the specific 

requirements of Executive Order 12866 

and its overall requirement of reducing 

regulatory burden that might result from 

these interim final regulations. Please 

let us know of any further opportunities 

we should take to reduce potential costs 

or increase potential benefits while 

preserving the effective and efficient 

administration of the program. 

During and after the comment period 

you may inspect all public comments 

about these interim final regulations by 

accessing Regulations.gov. You may also 

inspect the comments, in person, in 

room 4W229, 400 Maryland Avenue, 

SW., Washington, DC 20202, between 

the hours of 8:30 a.m. and 4 p.m., 

Eastern time, Monday through Friday of 

each week except Federal holidays. 

Assistance to Individuals With 

Disabilities in Reviewing the 

Rulemaking Record 

On request, we will supply an 

appropriate aid, such as a reader or 

print magnifier, to an individual with a 

disability who needs assistance to 

review the comments or other 

documents in the public rulemaking 

record for these interim final 

regulations. If you want to schedule an 

appointment for this type of aid, please 

contact Anna Hinton, U.S. Department 

of Education, 400 Maryland Avenue, 

SW., room 4W229, Washington, DC 

20202. Telephone: (202) 260–1816 or by 

e-mail: FY10MSAPCOMP@ed.gov. 

Background 

The MSAP is a discretionary grant 

program that provides funds to local 

educational agencies (LEAs) for ‘‘the 

elimination, reduction, or prevention of 

minority group isolation in elementary 

and secondary schools’’ with substantial 

proportions of minority students, and 

‘‘the development and design of 

innovative educational methods and 

practices that promote diversity.’’ 20 

U.S.C. 7231; 34 CFR 280.1. The 

Department awards grants to LEAs for 

magnet schools that are ‘‘part of an 

approved desegregation plan’’ and 

‘‘designed to bring students from 

different social, economic, ethnic, and 

racial backgrounds together.’’ 20 U.S.C. 

7231b; 34 CFR 280. There are two types 

of MSAP desegregation plans: (1) 

Required desegregation plans ordered 

by a Federal or State court or agency of 

competent jurisdiction;1 and (2) 


srobinson on DSKHWCL6B1PROD with RULES