10026 Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 

14Table notes: (1) Aggregation exemptions were 

not used in computing the counts of unique 

persons; (2) the position data was for futures, 

futures options and swaps that are significant price 

discovery contracts (SPDCs). 

TABLE 11a—UNIQUE PERSONS OVER PERCENTAGES OF PROPOSED POSITION LIMIT LEVELS, JANUARY 1, 2013, TO

DECEMBER 31, 2014—Continued 

Commodity type/core referenced futures contract Percent of 

level 

Unique persons over level 

Spot month 

(physicaldelivery) 

Spot month 

(cash-settled) Single month All months 

80 49 63 7 9 

100 31 44 (*) 6 

500 — 5 — — 

NYMEX RBOB Gasoline (RB) ............................................. 60 97 57 26 30 

80 67 52 15 17 

100 36 37 11 12 

500 — (*) — — 

Metals 

COMEX Copper (HG) .......................................................... 60 12 — 61 62 

80 9 — 37 40 

100 4 — 29 30 

COMEX Gold (GC) .............................................................. 60 13 — 22 24 

80 9 — 14 14 

100 5 — 10 11 

COMEX Silver (SI) ............................................................... 60 9 — 34 32 

80 4 — 20 21 

100 (*) — 16 16 

NYMEX Palladium (PA) ....................................................... 60 9 — 12 13 

80 5 — 9 5 

100 (*) — 4 4 

NYMEX Platinum (PL) ......................................................... 60 11 — 29 29 

80 7 — 18 18 

100 (*) — 9 9 

Legend: 

* means fewer than 4 unique owners exceeded the level. 

— means no unique owner exceeded the level. 

NA means not applicable.14

Both comment periods will reopen on 

February 26, 2015, and will close on 

March 28, 2015. 

Issued in Washington, DC, on February 19, 

2015, by the Commission. 

Christopher J. Kirkpatrick, 

Secretary of the Commission. 

Note: The following appendix will not 

appear in the Code of Federal Regulations. 

Appendix to Position Limits for 

Derivatives and Aggregation of 

Positions Reopening of Comment 

Periods—Commission Voting Summary 

On this matter, Chairman Massad and 

Commissioners Wetjen, Bowen, and 

Giancarlo voted in the affirmative. No 

Commissioner voted in the negative. 

[FR Doc. 2015–03834 Filed 2–24–15; 8:45 am] 

BILLING CODE 6351–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 310 

[Docket Nos. FDA–2003–N–0196 (Formerly 

2003N–0233), FDA–1978–N–0018 (Formerly 

1978N–0038 and 78N–0038), and FDA–1996– 

N–0006 (Formerly 96N–0277)] 

Over-the-Counter Sunscreen Drug 

Products—Regulatory Status of 

Enzacamene 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed order; request for 

comments. 

SUMMARY: The Food and Drug 

Administration (FDA or the Agency) is 

issuing a proposed sunscreen order 

(proposed order) under the Federal 

Food, Drug, and Cosmetic Act (the 

FD&C Act), as amended by the 

Sunscreen Innovation Act (SIA). The 

proposed order announces FDA’s 

tentative determination that 

enzacamene is not generally recognized 

as safe and effective (GRASE) and is 

misbranded when used in over-thecounter (OTC) sunscreen products 

because the currently available data are 

insufficient to classify it as GRASE and 

not misbranded, and additional 

information is needed to allow us to 

determine otherwise. 

DATES: Submit either electronic or 

written comments on this proposed 

order by April 13, 2015. Sponsors may 

submit written requests for a meeting 

with FDA to discuss this proposed order 

by March 27, 2015. See section VI for 

the proposed effective date of a final 

order based on this proposed order. 

ADDRESSES: You may submit comments 

by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Written Submissions 

Submit written submissions in the 

following ways: 

• Mail/Hand delivery/Courier (for 

paper submissions): Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852. 


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1For purposes of OTC drug regulation, a 

‘‘condition’’ is defined as an active ingredient or 

botanical drug substance (or a combination of active 

ingredients or botanical drug substances), dosage 

form, dosage strength, or route of administration 

marketed for a specific OTC use, with specific 

exclusions (see § 330.14(a)(2)). This document will 

refer simply to new ‘‘active ingredients,’’ since that 

is the condition under consideration. 

2These include FDA–1978–N–0018–0744–0756 

(Sup 24, 25, 26, 27 and 28), Request to Reopen 

Continued 

Instructions: All submissions received 

must clearly identify the specific active 

ingredient (enzacamene) and the Docket 

Nos. FDA–2003–N–0196, FDA–1978–N– 

0018, and FDA–1996–N–0006 for this 

rulemaking. All comments received may 

be posted without change to http://

www.regulations.gov, including any 

personal information provided. For 

additional information on submitting 

comments, see the ‘‘Comments’’ heading 

of the SUPPLEMENTARY INFORMATION

section of this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http://

www.regulations.gov and insert the 

docket numbers, found in brackets in 

the heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852. 

Submit requests for a meeting with 

FDA to discuss this proposed order to 

Kristen Hardin (see FOR FURTHER

INFORMATION CONTACT). 

FOR FURTHER INFORMATION CONTACT: 

Kristen Hardin, Division of 

Nonprescription Drug Products, Center 

for Drug Evaluation and Research, Food 

and Drug Administration, 10903 New 

Hampshire Ave., Bldg. 22, Rm. 5491, 

Silver Spring, MD 20993–0002, 240– 

402–4246. 

SUPPLEMENTARY INFORMATION: 

I. Regulatory Background 

A. Regulatory and Statutory Framework 

The data and information addressed 

in this proposed order were originally 

submitted for review under FDA’s Time 

and Extent Application (TEA) 

regulation, § 330.14 (21 CFR 330.14), a 

process that has since been 

supplemented with new statutory 

procedures established in the SIA (Pub. 

L. 113–195), enacted November 26, 

2014. The discussion that follows 

briefly describes and compares the preand post-SIA processes as they apply to 

the regulatory status of enzacamene. 

The TEA regulation established a 

process through which a sponsor could 

request that an active ingredient or other 

OTC condition,1 particularly one not 

previously marketed in the United 

States, be added to an OTC drug 

monograph to enable compliant OTC 

drug products containing the condition 

to be marketed in the United States 

without an approved new drug 

application (NDA) or abbreviated new 

drug application (ANDA). Because this 

proposed order specifically addresses an 

OTC sunscreen active ingredient 

(enzacamene), the remainder of this 

discussion will refer only to ‘‘active 

ingredients.’’ 

Critical steps in a proceeding under 

the TEA regulation include the 

following: (1) FDA’s determination that 

an active ingredient had been marketed 

for the proposed OTC use for a material 

time and to a material extent (eligibility 

determination), and public call for 

submission of safety and efficacy data, 

followed by; (2) review of safety and 

efficacy data submitted by the sponsor 

or other interested parties; and (3) 

FDA’s initial determination that the data 

show the active ingredient to be either 

GRASE or not GRASE for OTC use 

under the applicable monograph 

conditions (including any new 

conditions rising from FDA’s review) 

(GRASE determination). Under the TEA 

regulation, FDA’s GRASE 

determinations are effectuated through 

notice and comment rulemaking to 

amend or establish the appropriate 

monograph. 

The TEA process in FDA regulations 

was supplemented by Congress’s 

enactment of the SIA. Among other 

amendments it makes to the FD&C Act, 

the SIA creates new procedures 

specifically for reviewing the safety and 

effectiveness of nonprescription 

sunscreen active ingredients, including 

those, such as enzacamene, that were 

the subject of pending TEA proceedings 

at the time the SIA was enacted. Like 

the TEA regulation, the SIA calls for an 

initial eligibility determination phase 

for nonprescription sunscreen active 

ingredients, followed by submissions of 

safety and efficacy data and a GRASE 

determination phase. However, the SIA 

requires FDA to make proposed and 

final GRASE determinations for 

nonprescription sunscreen active 

ingredients in the form of administrative 

orders rather than the multistep public 

rulemaking required by the TEA 

regulation, and establishes strict 

timelines for the necessary 

administrative actions. 

Among other requirements, no later 

than 90 days after the SIA was enacted 

(i.e., no later than February 24, 2015), 

FDA must publish a proposed sunscreen 

order in the Federal Register for any 

nonprescription sunscreen active 

ingredient, including enzacamene, for 

which, on the date of enactment, an 

eligibility determination had been 

issued under the TEA regulation and 

submissions of safety and efficacy data 

received, and for which a TEA feedback 

letter had not yet been issued (section 

586C(b)(4) of the FD&C Act (21 U.S.C. 

360fff–3(b)(4)), as amended by the SIA). 

Other provisions of the SIA that are not 

discussed in this proposed order 

address procedures applicable to other 

pending and future sunscreen active 

ingredient GRASE determinations, 

pending and future GRASE 

determinations for OTC products other 

than sunscreens, issuance of specified 

guidances and reports, and completion 

of pending sunscreen rulemakings, 

among others. 

A proposed sunscreen order under the 

SIA is an order containing FDA’s 

tentative determination proposing that a 

nonprescription sunscreen active 

ingredient or combination of 

ingredients: (1) Is GRASE and is not 

misbranded when marketed in 

accordance with the proposed order; (2) 

is not GRASE and is misbranded; or (3) 

is not GRASE and is misbranded 

because the data are insufficient to 

classify the active ingredient or 

combination of ingredients as GRASE 

and not misbranded, and additional 

information is necessary to allow FDA 

to determine otherwise (section 586(7) 

of the FD&C Act, as amended by the 

SIA). Publication of a proposed 

sunscreen order triggers several 

timelines under the SIA, including a 45- 

day public comment period, and a 30- 

day period in which a sponsor may 

request a meeting with FDA to discuss 

the proposed order. 

B. FDA’s Review of Enzacamene 

Buchanan Ingersoll submitted a TEA 

in 2002 on behalf of Merck KGaA under 

§ 330.14(c) seeking OTC monograph 

status for the sunscreen active 

ingredient enzacamene (also known as 

4-Methylbenzylidene Camphor (4-MBC) 

or Eusolex 6300) at concentrations up to 

4 percent for use in OTC sunscreen 

products (enzacamene TEA) (Note 1). 

FDA issued a TEA notice of eligibility 

for enzacamene on July 11, 2003 (68 FR 

41386), stating that enzacamene at 

concentrations of up to 4 percent is 

eligible to be considered for inclusion in 

the OTC sunscreen monograph (21 CFR 

part 352, currently stayed) and calling 

for submission of safety and 

effectiveness data for enzacamene. In 

response, a submission of data dated 

October 9, 2003, was made to the docket 

on behalf of Merck KGaA (enzacamene 

data submission) (Note 2), which 

referred to materials previously 

submitted to other dockets.2 At the time 


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Rulemaking Record Respect Sunscreen Drug 

Products for OTC, submitted on April 12, 1999 

(1999 enzacamene submission); FDA–1978–N– 

0018–0766, Citizen Petition (CP1), submitted on 

December 17, 1980; and Tracking number: 

805596eb Legacy Doc. ID, SUP 5, ‘‘Supplement 

from Rona Pearle’’ SUP5, submitted on August 15, 

1985. 

the SIA was enacted, FDA had not 

issued a TEA feedback letter or 

otherwise responded to that submission. 

In accordance with new section 

586C(b)(4) of the FD&C Act as amended 

by the SIA, we are issuing this notice as 

a proposed order for enzacamene. Based 

on our review of the available safety and 

efficacy data, we have made a tentative 

determination that enzacamene is not 

GRASE and is misbranded because the 

data are insufficient to classify it as 

GRASE and not misbranded for use in 

OTC sunscreens, and additional 

information is necessary to allow us to 

determine otherwise. The remainder of 

this proposed sunscreen order describes 

our review of the available safety and 

efficacy data, identifies additional data 

needed to demonstrate that enzacamene 

is GRASE for the requested use, and 

explains our rationale for specific 

conclusions and data requirements. 

This proposed order will be open for 

public comment (see DATES). The 

sponsor may request a meeting with 

FDA to discuss this proposed order (see 

DATES). We also invite the sponsor to 

submit additional safety and/or efficacy 

data to inform our further consideration, 

as publication of a final sunscreen order 

under the SIA for enzacamene will be 

contingent on receipt of such 

information. (See section 586C(b)(9)(ii) 

of the FD&C Act.) We specifically 

encourage the sponsor to discuss any 

proposed study protocols with us before 

performing the studies. 

II. Safety Data Considerations for OTC 

Sunscreen Products Containing 

Enzacamene 

In evaluating the safety of a proposed 

monograph active ingredient, FDA 

applies the following regulatory 

standard: Safety means a low incidence 

of adverse reactions or significant side 

effects under adequate directions for use 

and warnings against unsafe use as well 

as low potential for harm which may 

result from abuse under conditions of 

widespread availability. Proof of safety 

shall consist of adequate tests by 

methods reasonably applicable to show 

the drug is safe under the prescribed, 

recommended, or suggested conditions 

of use. This proof shall include results 

of significant human experience during 

marketing. General recognition of safety 

shall ordinarily be based upon 

published studies which may be 

corroborated by unpublished studies 

and other data (§ 330.10(a)(4)(i) (21 CFR 

330.10(a)(4)(i))). 

FDA’s OTC drug regulations generally 

identify the types of information that 

may be submitted as evidence that an 

active ingredient or other OTC drug 

condition is safe, as part of the 

consideration of whether an active 

ingredient or other condition is GRASE 

(§ 330.10(a)(2)). For convenience, this 

order uses the term ‘‘generally 

recognized as safe (GRAS)’’ to refer to 

that aspect of the GRASE determination. 

To apply the general OTC safety 

standard to each potential new 

condition, FDA uses its scientific 

expertise to determine what constitutes 

‘‘adequate tests by methods reasonably 

applicable to show the drug is safe 

under the prescribed, recommended, or 

suggested conditions of use.’’ In 

assessing what specific testing or other 

data are needed to adequately 

demonstrate the safety of enzacamene 

for use in sunscreen, FDA considers the 

circumstances under which OTC 

sunscreen products that could contain 

enzacamene would be used by 

consumers. 

When used as directed with other sun 

protection measures, broad spectrum 

OTC sunscreen products with a sun 

protection factor (SPF) value of 15 or 

higher strongly benefit the public health 

by decreasing the risk of skin cancer and 

premature skin aging associated with 

solar ultraviolet (UV) radiation, as well 

as by helping to prevent sunburn. 

(Sunscreens with lower SPF values, or 

without broad spectrum protection, also 

help prevent sunburn.) When used as 

directed by the required labeling, all 

OTC sunscreen products are applied 

liberally to the skin and reapplied 

frequently throughout the day 

(§ 201.327(e) (21 CFR 201.327(e))). 

Because the effects of UV exposure are 

cumulative, to obtain the maximum 

benefit, users of broad spectrum 

sunscreens with an SPF value of 15 or 

higher are directed to use such products 

regularly—on a routine basis (id.). Given 

these conditions of use, our safety 

evaluation of an OTC sunscreen active 

ingredient such as enzacamene must 

consider both short-term safety concerns 

(such as skin sensitization/irritation and 

photosafety) and potential concerns 

related to long-term sunscreen use, 

including potential systemic exposure 

via dermal absorption. 

The purpose of the safety testing 

described in this section II is to 

establish whether an OTC sunscreen 

product containing enzacamene and 

otherwise marketed under the 

conditions described in a final 

sunscreen order and in accordance with 

all requirements applicable to 

nonprescription drugs would be GRAS 

for use as labeled. To demonstrate that 

these requirements are met for 

enzacamene, initial safety testing should 

be performed using enzacamene as the 

sole active ingredient up to the highest 

concentration for which marketing 

status is sought and eligibility has been 

established: 4 percent. If initial testing 

suggests a particular safety concern 

associated with enzacamene (e.g., a 

hormonal activity), FDA may request 

additional studies to address that 

concern. 

A. Human Safety Data 

1. Human Irritation, Sensitization, and 

Photosafety Studies 

Studies of skin irritation, 

sensitization, and photosafety are 

standard elements in the safety 

evaluation of topical drug products that, 

like enzacamene-containing sunscreens, 

are applied to the skin repeatedly over 

long periods of time. FDA recommends 

separate studies for skin irritation and 

sensitization. Skin irritation studies 

should generally include at least 30 

evaluable subjects and should evaluate 

the test formulation (i.e., enzacamene in 

an appropriate test vehicle), the vehicle 

alone, and both negative and positive 

controls. Skin sensitization studies 

generally should include at least 200 

subjects and should evaluate the test 

formulation containing enzacamene, the 

vehicle, and a negative control. For both 

irritation and sensitization studies, test 

site applications should be randomized 

and the test observer blinded to the 

identities of the test formulations. 

FDA recommends that photosafety 

evaluation generally involve studies of 

skin photoirritation (phototoxicity) and 

skin photosensitization 

(photoallergenicity). General principles 

for designing and conducting 

photosafety studies are described in 

FDA guidance (Ref. 1). Photosafety 

studies, like sensitization and irritation 

studies, should be conducted using 

enzacamene 4 percent in an appropriate 

test vehicle, the vehicle alone, and a 

negative control. In addition, 

phototoxicity studies should include at 

least 30 evaluable subjects and 

photoallerginicity studies should 

include at least 45 evaluable subjects. 

Data Available for Enzacamene: Human 

Irritation, Sensitization, and Photosafety 

Studies 

We reviewed the submitted study 

reports for human safety studies, 

including a skin irritation and 

sensitization study of enzacamene 5 

percent in 30 subjects (Note 3); skin 


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irritation and sensitization study of 

enzacamene 5 percent in 10 subjects 

(Note 4); a photoirritation study of 4 

percent enzacamene in 5 subjects (Note 

5); and two photosensitization studies, 

one using 4 percent enzacamene in 5 

subjects and the other using an 

unknown concentration in 25 subjects 

(Notes 6 and 7). Although these studies 

suggest that enzacamene may not be a 

primary irritant, sensitizer, 

photosensitizer, or photoirritant, each of 

the submitted studies has limitations, 

such as inadequate sample size, lack of 

blinding, and lack of positive and 

negative controls, that prevent us from 

making definitive conclusions. In 

addition, protocol information, such as 

the inclusion and exclusion criteria 

used in subject selection, was not 

consistently provided. 

FDA concludes that the data 

submitted are not sufficient to assess the 

dermal safety of enzacamene and 

specifically its potential to cause 

irritation, sensitization, photoirritation, 

or photoallergenicity. We recommend 

submission of additional data from 

human irritation, sensitization, and 

photosafety studies to demonstrate that 

an OTC sunscreen containing up to 4 

percent enzacamene is not an irritant, 

sensitizer, photosensitizer, or 

photoirritant. 

2. Human Dermal Pharmacokinetic 

(Bioavailability) Studies 

Because sunscreens are topically 

applied, another important safety 

consideration for enzacamene for use in 

sunscreens is whether dermal 

application may result in skin 

penetration and systemic exposure to 

enzacamene, and if so, to what extent. 

A well-designed and -conducted human 

dermal pharmacokinetic study can be 

expected to detect and quantify the 

presence of enzacamene and/or any 

metabolites in blood or other bodily 

fluids that may have a bearing on safety, 

using recognized parameters such as 

bioavailability percentage, maximum 

plasma concentration (Cmax), time to 

maximum plasma concentration (Tmax), 

total area under the plasma 

concentration versus time curve (AUC), 

half-life, clearance, and volume of 

distribution. This information can help 

identify potential safety concerns and 

help determine whether an adequate 

safety margin for sunscreens containing 

enzacamene exists. FDA recommends 

that the pharmacokinetic studies 

performed on enzacamene also collect 

additional safety-related data from 

regularly scheduled physical 

examinations, collection of vital signs, 

and other measures, which may help 

capture adverse skin events or other 

potential safety signals. To ensure that 

maximum penetration of enzacamene 

has taken place and chances of it being 

detected are optimal, studies should 

continue until steady state is reached. 

General information and 

recommendations on the design and 

conduct of human pharmacokinetic 

studies can be found in FDA guidance 

(Ref. 2). To support a GRAS 

determination for enzacamene (up to 4 

percent), such a study should be 

conducted under maximal use 

conditions using enzacamene 4 percent 

in various vehicles, including vehicles 

that would be expected to enhance 

absorption. We encourage study 

sponsors to consult with us before 

conducting pharmacokinetic studies, 

because the properties of enzacamene 

bear on the optimal design. 

Data Available for Enzacamene: Human 

Dermal Pharmacokinetic 

(Bioavailability) and Clinical 

Pharmacology Studies 

We reviewed three submitted reports 

of dermal absorption studies in humans 

in which percutaneous absorption was 

estimated using radiolabeled (14C) 

formulations of enzacamene. In one 

study (Note 8) a 14C-labeled 5 percent 

formulation of enzacamene was applied 

to the lower arms of six volunteers for 

6 hours, followed by a 3-day collection 

of urine and feces. Investigators 

reported that approximately 54.6 

percent of the 14C-activity applied to the 

skin was recovered. An average of 0.76 

percent enzacamene was recovered in 

urine and 0.14 percent in the feces. In 

a second study (Note 9), investigators 

reported a total recovery of 98.2 percent 

and 90.7 percent overall recovery of the 

14C-activity applied to the skin from two 

volunteers, respectively. The third study 

report (Note 10) was similar to the 

previous two studies in terms of the 

general design. Following the analysis 

of the data from the planned six 

volunteers, two more volunteers were 

enrolled to evaluate the low observed 

recovery (54 to 69 percent) of the 

radiolabeled enzacamene. A different 

recovery schema was applied to these 

last two patients with satisfactory 

results in line with the previous studies. 

As to the utility of the aggregate data, 

we cannot draw definitive conclusions 

regarding the dermal absorption of 

enzacamene based on these studies. The 

overall number of subjects was low, the 

studies were single-dose studies, a 

limited surface area was exposed to the 

formulation, the recovery of 

radioactivity was variable, and finally 

no blood or other body fluids were 

sampled to provide direct information 

about systemic exposure. We also note 

that these studies were conducted in the 

1980s and the limit of analytical 

detection for enzacamene was much 

higher than it is today. 

A review of the published literature 

identified more recent studies related to 

the extent of absorption of enzacamene 

in humans after dermal application. A 

2004 article from Janjua et al. (Ref. 3) 

reports on the absorption from a 

formulation containing 10 percent 

enzacamene and 2 other active 

sunscreen ingredients after whole body 

application for 4 days in 15 healthy 

males and 17 postmenopausal females. 

The article provides only summary 

bioavailability information but claims 

that the maximum plasma 

concentrations were 20 milligrams (mg)/ 

milliliter (mL) in both men and women 

and that increasing plasma levels of 

enzacamene and metabolites were seen, 

suggesting the presence of 

accumulation. It is noted that thyroid 

function was also assessed during this 

study, but results are confounded by the 

simultaneous application of three active 

sunscreen ingredients. A 2006 article 

from Shauer et al. (Ref. 4) includes in 

vivo pharmacokinetic data from six 

healthy volunteers exposed to 4 percent 

enzacamene applied over 90 percent 

body surface area for a 12-hour period. 

The data are limited by the small 

number of subjects included; however, 

there was gender-related difference 

observed in those males who had blood 

levels that were approximately twice 

that of females. A 2008 article by Janjua 

et al. contains a more complete analysis 

of in vivo absorption for enzacamene in 

a 10 percent enzacamene formulation 

(Ref. 5). The levels of absorption were 

generally low but accumulation was 

observed. However, the age of the 

females enrolled in the study was 2 to 

3 times that of the males, confounding 

the interpretation of age or gender 

effects. 

Overall, the data available are 

incomplete for the assessment of human 

bioavailability (dermal absorption) of 

enzacamene. Accordingly, we request 

data from human pharmacokinetic 

studies to assess potential for and extent 

of systemic absorption. These studies 

should be performed under expected 

maximal-use conditions with the 

proposed maximum concentration as 

discussed previously. 

In addition to the bioavailability data 

described previously, three reports of 

clinical pharmacology studies were 

submitted that evaluate the potential 

effect of enzacamene on thyroid 

function. The first was a pilot study in 

which a 5 percent enzacamene 

formulation was applied twice, at 3- 

hour intervals, to the abdomen and back 


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3See 67 FR 3060 at 3069 (January 23, 2002) 

(agreeing that the absence of an adverse experience 

reporting system in a foreign country for drugs or 

cosmetics does not necessarily mean that a 

condition cannot be GRAS/E. The GRAS/E 

determination will be based on the overall quality 

of the data and information presented to 

substantiate safety and effectiveness). 

of four adult subjects (two males and 

two females) (Note 11). Subsequent 

increases in the thyroid analytes 

thyroid-stimulating hormone (TSH), T3, 

and T4 were observed in some subjects. 

Blood and urine levels of enzacamene 

were reported to have been measured 

but no data were reported. We consider 

the number of subjects in this study too 

small to draw conclusions about the 

safety of enzacamene. In addition, there 

were missing data and the report lacked 

information about whether subjects’ 

thyroid analyte levels exceeded normal 

levels. 

A second study evaluated the effect 

on thyroid function of topical 

application of 5 percent enzacamene (6 

grams (g) applied twice, at 3-hour 

intervals) in nine healthy volunteers 

(Note 12). This was a double-blind, 

placebo-controlled, crossover design 

study, and investigators reported that 

there was a statistically significant 

lowering of mean T3 and T4 values in 

the active treatment group at 24 hours 

after application. Although larger than 

the pilot study, this is a small singledose study and the changes reported 

were small relative to placebo and were 

of questionable clinical significance. 

Interpretation of the results is also 

hampered by the fact that some analytes 

(TSH and free T4) were below normal 

levels at baseline. 

A third study was a parallel-group, 

placebo-controlled design in which 48 

subjects received treatment with either 

enzacamene (5 g of a 6 percent 

enzacamene formulation per dose) or 

placebo twice daily for 14 days (Note 

13). According to the investigators, the 

results of the study did not reveal any 

significant differences in thyroid 

function tests between enzacamene and 

placebo, although there was a small 

between-group difference in thyroid 

volume gland decrease (a 1.7 percent 

reduction in the enzacamene arm and 

an increase of 3.1 percent in the placebo 

group). The quality of the study report 

submitted is inadequate to be used to 

verify the analyses, but no adverse 

events of hypothyroidism or 

hyperthyroidism or abnormal thyroid 

function tests were reported. 

The three clinical pharmacology 

studies submitted are insufficient either 

to substantiate or dismiss clinical 

concerns related to potential thyroid 

effects from enzacamene. We request 

submission of any additional clinical 

thyroid function data or analyses that 

have not yet been submitted to us, 

including any provided to the European 

Scientific Committee on Cosmetic 

Products and Nonfood Products 

(SCCNFP) to support its 2008 

conclusion that enzacamene at a 

concentration up to 4 percent is safe for 

use in finished cosmetic products for 

whole body application (Ref. 6). If, after 

full review of nonclinical toxicology 

data (discussed in section I.B of this 

proposed order) and any additional 

clinical data, concerns exist regarding 

enzacamene’s thyroid safety, we will 

recommend that additional clinical 

study be carried out. It is recommended 

that we be consulted regarding the study 

protocols prior to commencement of 

such investigations. 

3. Human Safety Data To Establish 

Adverse Event Profile 

An evaluation of safety information 

from adverse event reports and other 

safety-related information derived from 

commercial marketing experience of 

sunscreen products containing 

enzacamene, as well as from other 

sources, is a critical aspect of FDA’s 

safety review for enzacamene. The TEA 

regulation under which the original 

request for enzacamene was submitted 

specifically calls for submission of 

information on all serious adverse drug 

experiences, as defined in 21 CFR 

310.305(a) and 314.80(a), from each 

country where the active ingredient or 

other condition has been or is currently 

marketed as either a prescription or 

OTC drug; in addition, it calls for 

submission of all data generally 

specified in § 330.10(a)(2), which 

includes documented case reports and 

identification of expected or frequently 

reported side effects (§ 330.14(f)(1) and 

(f)(2)). To evaluate enzacamene, FDA 

continues to seek individual adverse 

drug experience reports, a summary of 

all serious adverse drug experiences, 

and expected or frequently reported side 

effects of the condition (id.). To assist in 

the Agency’s safety evaluation of 

enzacamene, FDA emphasizes our need 

for the following data: 

• A summary of all available reported 

adverse events potentially associated 

with enzacamene; 

• All available documented case 

reports of serious side effects 

• Any available safety information 

from studies of the safety and 

effectiveness of enzacamene in humans; 

and 

• Relevant medical literature 

describing adverse events associated 

with enzacamene. Submissions of 

adverse event data should also include 

a description of how each country’s 

system identifies and collects adverse 

events, unless this information has been 

previously submitted as part of 

enzacamene’s TEA package. 

Although we recognize that adverse 

event data from foreign marketing 

experience may reflect patterns of use 

and regulatory reporting requirements 

that differ from those in the United 

States, we nonetheless consider such 

information to be strongly relevant both 

to our overall GRASE assessment of 

enzacamene for use in sunscreens and 

to our consideration of potential 

product labeling. FDA recognizes that 

such information may not be available 

from all countries; where that is the 

case, please provide a written 

explanation for the lack of data. Overall, 

we seek sufficient data to characterize 

enzacamene’s adverse event profile.3

Data Available for Enzacamene: Human 

Safety Data To Establish Adverse Event 

Profile 

The 1999 enzacamene submission 

states that no complaints from 

customers concerning tolerance or 

adverse reactions had been reported for 

enzacamene by the cosmetic industry 

during the prior 10 years (Note 14). This 

information was referred to in the 2002 

TEA submission and the 2003 

enzacamene data submission. The 1999 

enzacamene submission also included a 

literature search for adverse reactions to 

enzacamene from the following 

databases: Medline (1966–1998), 

Derwent Drug File (1983–1998), and 

CCSearch (week 3 1998–week 48 1998) 

(Note 15). There were 17 articles 

reviewed which had been published or 

translated into English. Of these, 10 

articles describe contact dermatitis and 

resultant positive photopatch testing in 

one or two patients. The 7 other articles 

are literature or case series reviews of 

up to 400 patients, describing 

dermatologic adverse reactions to 

sunscreen use and subsequent 

photopatch testing. On the whole, these 

reports suggest that enzacamene has the 

potential to cause contact allergy and 

photocontact allergy. However, data 

from this literature have limitations. In 

some cases, the testing methodology 

used to determine that enzacamene is an 

allergen is not described. Also, some of 

the test formulations used are not 

described. It is conceivable that the 

observed reactions may have been 

specific to particular test formulations, 

including formulations containing other 

active ingredients. 

The submitted information and 

literature do not fulfill the criteria 

described previously. To support the 

evaluation of safety of enzacamene for 


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use in OTC sunscreens, we request that 

the sponsor either supplement the data 

already submitted, including more 

recent adverse drug experience data, or 

explain why such data cannot be 

provided. 

B. Nonclinical (Animal) Studies 

Another important element of FDA’s 

GRAS review of enzacamene for use in 

sunscreens is an assessment of data 

from nonclinical (animal) studies that 

characterize the potential long-term 

dermal and systemic effects of exposure 

to enzacamene. Even if the 

bioavailability data discussed in section 

II.A.2 suggest that dermal application is 

unlikely to result in skin penetration 

and systemic exposure to enzacamene, 

FDA still considers data on the effects 

of systemic exposure to be an important 

aspect of our safety evaluation of 

enzacamene. A determination that 

enzacamene up to 4 percent is GRASE 

for use in sunscreens would permit its 

use in as-yet-unknown product 

formulations, which might in turn alter 

the skin penetration of the active 

ingredient. Therefore, an understanding 

of the effects of enzacamene, were 

systemic exposure to occur, is critical to 

determine whether and how regulatory 

parameters can be defined to assure that 

all conforming enzacamene-containing 

sunscreens would be GRASE as labeled. 

FDA recommends animal testing of 

the potential long-term dermal and 

systemic effects of exposure to 

enzacamene because these effects 

cannot be easily assessed from previous 

human use. Taken together, the 

carcinogenicity studies, developmental 

and reproductive toxicity studies, and 

toxicokinetic studies described in 

sections II.B.1 through II.B.3 should 

provide the information needed to 

characterize both the potential dermal 

and systemic toxic effects and the levels 

of exposure at which they occur. These 

data, when viewed in the context of 

human exposure data, can be used to 

determine a margin of safety for use of 

enzacamene in OTC sunscreens. 

Data Available for Enzacamene: 

Nonclinical (Animal) Studies Generally 

The enzacamene submissions 

included data from the following types 

of nonclinical safety studies: 

• Acute-dose toxicity studies 

Æ Oral toxicity (rats, dogs) (Note 16) 

Æ Dermal toxicity (rats) (Note 17) 

Æ Intraperitoneal toxicity (rats) (Note 

18) 

Æ Mucosal irritation (rabbits) (Note 

19) 

Æ Skin irritation and sensitization 

(guinea pigs) (Note 20) 

Æ Phototoxicity potential (mice) (Note 

21) 

Æ Photosensitization (guinea pig) 

(Note 22) 

• Repeat-dose toxicity studies 

Æ 17 days oral (rat) (Note 23) 

Æ 4 weeks oral (rat) (Note 24) 

Æ 13 weeks oral (rat) (Note 25) 

Æ Liver enzyme induction study (rat) 

(Note 26) 

• Genotoxicity and mutagenicity assays 

Æ Chromosome aberration assay 

(Chinese hamster V79 cells) (Note 

27) 

Æ Mutagenicity (Salmonella 

typhimurium) (Note 28) 

Æ Photomutagenicity (S. 

typhimurium, Escherichia coli) 

(Note 29) 

• Reproductive and developmental 

toxicity studies 

Æ Orienting tests for embryotoxicity 

(rabbit) (Note 30) 

Æ Toxicological investigation 

(incubated hen’s egg) (Note 31) 

Æ Teratogenicity (rat) (Note 32) 

Based on the submitted studies, acute 

toxicity was low. However, the standard 

battery of tests detected findings that we 

will consider further as additional data 

become available to inform our GRAS 

assessment. Studies submitted by the 

sponsor showed an increase in thyroid 

weight and changes in thyroid function 

that included an increase in T3 and 

TSH, along with a decrease in T4. Other 

thyroid findings included follicular 

epithelium hypertrophy and 

hyperplasia. A decrease in adrenal and 

prostate weights, and alterations in 

ovarian weights (an increase was seen in 

some studies while decreased weight 

was noted in others), was documented 

with a no observed adverse effect level 

(NOAEL) of 25–30 mg/kilograms (kg)/

day (Note 33). 

To followup on these findings, we 

identified published literature that 

describes related enzacamene activity. A 

number of these articles indicate that 

exposure to enzacamene at high doses 

has been associated with hormonal 

changes. Among the in vitro findings 

(Refs. 7 through 16), a number of articles 

described the in vitro binding activity of 

enzacamene to estrogen (ER) and 

androgen (AR) receptors where it was 

able to bind to ER+ but showed 

inconsistent binding activity at ERa 

receptors. No androgenic activity and 

mixed results for antiandrogenic activity 

were also documented. 

Other effects of enzacamene included 

in vivo alterations of reproductive 

tissues and behavior in rats (Refs. 17 

through 25). Findings include decreased 

testis weight; increased prostate volume 

and altered duct development; delayed 

preputial separation; decreased prostate 

weight in males; and increased uterine 

weight, decreased ovarian weight, and 

altered sexual behavior in females. 

Overall, we cannot arrive at a final 

determination about the findings 

described in the literature until we 

receive a complete nonclinical 

assessment as described in sections 

II.B.1 through II.B.3. 

We did not receive data from 

toxicokinetic or dermal or systemic 

carcinogenicity studies. Upon 

assessment of all available information 

for enzacamene and based on the 

nonclinical studies currently 

recommended to support sunscreen 

development, the following nonclinical 

studies are recommended to support the 

safety of enzacamene: 

• Dermal and systemic 

carcinogenicity 

• Fertility 

• Prenatal/postnatal toxicity 

• Toxicokinetics 

Additional discussion of study 

findings and data gaps are provided in 

the following subsections. 

1. Carcinogenicity Studies: Dermal and 

Systemic 

FDA guidance recommends that 

carcinogenicity studies be performed for 

any pharmaceutical that is expected to 

be clinically used continuously for at 

least 6 months or ‘‘repeatedly in an 

intermittent manner’’ (Refs. 26, 27, and 

28). Because the proposed use of 

enzacamene in OTC sunscreens falls 

within this category, these studies 

should be conducted to help establish 

that enzacamene is GRAS for its 

proposed use. Carcinogenicity studies 

assist in characterizing potential dermal 

and systemic risks by identifying the 

type of toxicity observed, the level of 

exposure at which toxicity occurs, and 

the highest level of exposure at which 

no adverse effects occur (i.e., NOAEL). 

The NOAEL would then be used in 

determining the safety margin for 

human exposure to sunscreens 

containing enzacamene. 

Systemic carcinogenicity studies can 

also help to identify other systemic or 

organ toxicities that may be associated 

with enzacamene, such as hormonal 

effects. For example, the effect of 

persistent disruption of particular 

endocrine gland systems (e.g., 

hypothalamic-pituitary-adrenal axis), if 

any, can be captured by these assays. 

Data Available for Enzacamene: 

Genotoxicity Studies 

Enzacamene showed no evidence of 

DNA mutations in one standard Ames 

test. A chromosomal aberration assay 

using a Chinese hamster V79 cell line 


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4The upper bound of any concentration of 

enzacamene ultimately established in the OTC 

sunscreen monograph will be governed by the 

safety data, as well as by efficacy. 

5Although the SPF testing procedure is used 

primarily for final formulation testing of finished 

products marketed without approved NDAs, under 

the sunscreen monograph, it is equally applicable 

for determining whether or not a sunscreen active 

ingredient is GRAE. 

and a photomutagenicity assay were 

negative. Although these studies 

somewhat ease concerns about potential 

genotoxicity and mutagenicity, they 

were not definitive evaluations of 

potential toxic effects from long-term 

systemic or dermal exposure. 

Data Available for Enzacamene: 

Carcinogenicity Studies 

We did not receive dermal or systemic 

carcinogenicity studies. Assessments of 

both dermal and systemic 

carcinogenicity are recommended 

because sunscreen products containing 

enzacamene are expected to be applied 

over large portions of the body with 

multiple daily applications. In addition, 

as discussed previously, marketing of 

this product according to a final 

sunscreen order might permit its 

formulation in a variety of as-yetunknown vehicles that might have an 

impact on systemic absorption. 

Consequently, FDA seeks information 

on dermal and system carcinogenicity, 

in case of the possibility that systemic 

absorption could occur. 

2. Developmental and Reproductive 

Toxicity (DART) Studies (Ref. 29) 

FDA recommends conducting DART 

studies to evaluate the potential effects 

that exposure to enzacamene may have 

on developing offspring throughout 

gestation and postnatally until sexual 

maturation, as well as on the 

reproductive competence of sexually 

mature male and female animals. 

Gestational and neonatal stages of 

development may also be particularly 

sensitive to active ingredients with 

hormonal activity. For this reason, we 

recommend that these studies include 

assessments of endpoints such as 

vaginal patency, preputial separation, 

anogenital distance, and nipple 

retention, which can be incorporated 

into traditional DART study designs to 

assess potential hormonal effects of 

enzacamene on the developing 

offspring. We also recommend 

conducting behavioral assessments (e.g., 

mating behavior) of offspring, which 

may also detect neuroendocrine effects. 

Data Available for Enzacamene: DART 

Studies 

Potential reproductive and 

developmental effects from enzacamene 

were evaluated in two embryotoxicity 

studies and one teratogenicity study. 

Enzacamene did not show evidence of 

embryotoxicity in a pilot rabbit test and 

hen’s egg assay. In a teratogenicity study 

in rats with oral administration of single 

daily doses of 10, 30, and 100 mg/kg of 

enzacamene administered on days 6 to 

15 after conception, enzacamene was 

not found to be teratogenic in any of the 

treated groups. Additional DART testing 

is recommended to assess fertility and 

prenatal and postnatal development in a 

rodent model. 

3. Toxicokinetics (Ref. 30) 

We recommend conducting animal 

toxicokinetic studies because they 

provide an important bridge between 

toxic levels seen in animal studies and 

potential human exposure. Data from 

these studies can be correlated to 

potential human exposure via clinical 

dermal pharmacokinetic study findings. 

Toxicokinetic data could be collected as 

part of animal studies being conducted 

to assess one or more of the safety 

parameters described previously. 

Data Available for Enzacamene: 

Toxicokinetics 

No toxicokinetic data were submitted 

as part of any of the nonclinical studies, 

thus it is difficult to bridge from animal 

findings to potential human exposure. 

Toxicokinetic data should be collected 

as part of the animal studies to allow 

exposure comparisons between animals 

and humans. 

Toxicokinetic data are particularly 

important to the evaluation of 

enzacamene’s safety for use in 

sunscreens because enzacamene appears 

to have the potential to affect some 

endocrine-responsive endpoints. We 

need toxicokinetic data to develop more 

information about exposure parameters, 

in order to understand whether a margin 

of safety exists between the exposures 

that cause the effects in animals and 

estimated human exposures. Should we 

find, after review of a more complete 

nonclinical program, that additional 

clinical studies are warranted, we will 

provide additional recommendations 

regarding the design of the studies. 

III. Effectiveness Data Considerations 

for OTC Sunscreen Products Containing 

Enzacamene 

FDA’s evaluation of the effectiveness 

of active ingredients under 

consideration for inclusion in an OTC 

drug monograph is governed by the 

following regulatory standard: 

Effectiveness means a reasonable 

expectation that, in a significant 

proportion of the target population, the 

pharmacological effect of the drug, 

when used under adequate directions 

for use and warnings against unsafe use, 

will provide clinically significant relief 

of the type claimed. Proof of efficacy 

shall consist of controlled clinical 

investigations as defined in 21 CFR 

314.126(b). Investigations may be 

corroborated by partially controlled or 

uncontrolled studies, documented 

clinical studies by qualified experts, and 

reports of significant human experience 

during marketing. Isolated case reports, 

random experience, and reports lacking 

the details that permit scientific 

evaluation will not be considered. 

General recognition of effectiveness 

shall ordinarily be based upon 

published studies which may be 

corroborated by unpublished studies 

and other data (§ 330.10(a)(4)(ii)). For 

convenience, this order uses the term 

‘‘generally recognized as effective’’ 

(GRAE) when referring to this aspect of 

the GRASE determination. 

To evaluate the efficacy of 

enzacamene for use in OTC sunscreen 

products, FDA requests evidence from 

at least two adequate and wellcontrolled SPF studies showing that 

enzacamene effectively prevents 

sunburn. To determine that enzacamene 

is GRAE for use in OTC sunscreens at 

concentrations in a range with the 

proposed maximum strength of 4 

percent as requested, two adequate and 

well-controlled SPF studies of 

enzacamene at a lower concentration 

should be conducted according to 

established standards.4 These SPF 

studies should demonstrate that the 

selected concentration (below 4 percent) 

provides an SPF of 2 or more. 

The current standard procedure for 

SPF testing is described in FDA’s 

regulations in § 201.327(i).5 Further SPF 

tests for enzacamene should be 

performed as described in these 

regulations, using a test formulation 

containing enzacamene as the only 

active ingredient to identify its 

contribution to the overall SPF test 

results. (See the following subsection 

Data Available for Enzacamene: 

Effectiveness for further discussion of 

submitted SPF tests.) The study should 

also include a vehicle control arm in 

order to rule out any contribution the 

vehicle may have on the SPF test 

results. Finally, as described in 

§ 201.327(i), an SPF standard 

formulation comparator arm should be 

another component of the study design. 

Although current sunscreen testing 

and labeling regulations also specify a 

‘‘broad spectrum’’ testing procedure to 

support related labeling claims for 

certain OTC sunscreen products 

marketed without approved new drug 


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applications that contain specified 

active ingredients included in the 

stayed sunscreen monograph, those 

additional claims are permitted, but not 

required (§ 201.327(c)(2) and (j)). Under 

current regulations, sunscreen active 

ingredients need only be effective for 

the labeled indication of sunburn 

prevention, for which the SPF test can 

provide sufficient evidence. Consistent 

with this approach, we here do not 

request broad spectrum testing data for 

enzacamene. Broad spectrum protection 

is often, although not always, the result 

of the combined contribution of 

multiple active ingredients in a final 

sunscreen formulation. Thus, under the 

current regulations applicable to other 

sunscreens, the determination of 

whether an individual sunscreen 

product may be labeled as broad 

spectrum and bear the related additional 

claims is made on a product-specific 

basis, applying standard testing 

methods set forth in those regulations. 

If enzacamene is established to be 

GRASE for use in nonprescription 

sunscreens (based in part on the efficacy 

data requested here), the final order can 

likewise address broad-spectrum testing 

and related labeling conditions for final 

sunscreen formulations containing 

enzacamene. 

Data Available for Enzacamene: 

Effectiveness 

A total of 11 efficacy studies were 

submitted. Two studies, an in vitro 

assessment and a field study, both dated 

from the 1970s, did not use study 

designs that we consider valid for SPF 

assessment for a GRASE determination 

(Docket No. 78N–0038, OTC Volume 

060083, submitted December 18, 1973; 

Docket No. 78N–0038, OTC Volume 

060130, submitted November 1974). The 

other nine studies all tested enzacamene 

as the only active ingredient. These 

included two studies of 1.25 percent 

enzacamene and three studies of 2.5 

percent enzacamene, concentrations 

within the range found eligible for 

consideration of GRASE status in the 

Agency’s 2003 eligibility determination, 

and three studies of 5 percent 

enzacamene and one study of 10 percent 

enzacamene, concentrations above the 

maximum established to be eligible for 

consideration, which studies we do not 

further address in this proposed order. 

(FDA–1978–N–0018–0766, Citizen 

Petition (CP1), submitted December 17, 

1980.) In each of the five studies 

addressing enzacamene at 

concentrations of 1.25 percent and 2.5 

percent, enzacamene achieved a mean 

SPF of 2, but there is substantial 

variability in the data and it cannot be 

confirmed that that efficacy was 

established at any of the concentrations 

tested. In addition, none of these study 

reports specified the use of appropriate 

standard controls to validate the test 

results. Currently, there are insufficient 

data to support a finding that 

enzacamene is GRAE at concentrations 

up to 4 percent. 

To support a finding that enzacamene 

is GRAE at concentrations up to 4 

percent, we request data from two 

adequate and well-controlled SPF 

studies conducted according to 

established standards to demonstrate 

that the lowest selected concentration 

provides an SPF of 2 or more. Because 

no study has been identified that 

establishes that enzacamene is effective 

at a concentration of 4 percent, we also 

recommend that such a study be 

conducted and submitted. 

IV. Summary of Current Data Gaps for 

Enzacamene 

Based on our review of the available 

safety and efficacy data as discussed 

previously, we request the types of data 

listed in this section of the proposed 

order, at minimum, for us to reverse our 

tentative determination that 

enzacamene is not GRASE and is 

misbranded because the data are 

insufficient to classify enzacamene as 

GRASE and not misbranded, and 

additional data are necessary to allow us 

to determine otherwise. For additional 

information about the purpose and 

design of studies recommended to 

address these data gaps, please refer to 

the earlier sections of this proposed 

order referenced in parentheses. We 

welcome discussions on design of any 

of the studies prior to their 

commencement. We request the 

following types of data: 

• Safety Data (see section II) 

A. Human Clinical Studies 

1. Skin irritation/sensitization and 

photosafety (see section II.A.1) 

2. Human dermal pharmacokinetic 

(bioavailability) studies (see section 

II.A.2) 

The need for additional human safety 

studies (e.g., for evaluation of hormonal 

disruption) will be based on review of 

the completed nonclinical studies, as 

recommended in section IV.C. 

B. Human Safety Data To Establish 

Adverse Event Profile (II.A.3) 

1. A summary of all available reported 

adverse events potentially 

associated with enzacamene 

2. All available documented case reports 

of serious side effects 

3. Any available safety information from 

studies of the safety and 

effectiveness of sunscreen products 

containing enzacamene in humans 

4. Relevant medical literature describing 

adverse events associated with 

enzacamene 

Alternatively, the results of a 

literature search that found no reports of 

adverse events may be provided. In that 

case, detailed information on how the 

search was conducted should be 

provided. 

C. Nonclinical (Animal) Studies 

1. Dermal and systemic carcinogenicity 

(see section II.B.1) 

2. Fertility (see section II.B.2) 

3. Prenatal/postnatal development (see 

section II.B.2) 

4. Toxicokinetics (see section II.B.3) 

• Effectiveness Data (see section III) 

In order for concentrations of 

enzacamene up to 4 percent to be found 

to be GRASE for use in nonprescription 

sunscreen products as requested, at least 

two SPF studies showing effectiveness 

of a selected concentration lower than 4 

percent should be conducted. An 

efficacy study of enzacamene at 4 

percent is also recommended. 

V. Administrative Procedures 

A copy of this proposed order will be 

filed in the Division of Dockets 

Management in Docket Numbers FDA– 

2003–N–0196, FDA–1978–N–0018, and 

FDA–1996–N–0006. To inform FDA’s 

evaluation of whether this ingredient is 

GRASE and not misbranded for use in 

sunscreen products, we encourage the 

sponsor and other interested parties to 

submit additional data regarding the 

safety and effectiveness of this 

ingredient for use as an OTC sunscreen 

product. We also encourage the sponsor 

and other interested parties to notify us 

in writing of their intent to submit 

additional data. However, as noted 

previously, because the data submitted 

to date are not sufficient to support a 

determination that enzacamene is 

GRASE for use as an active ingredient 

in OTC sunscreen drug products, at 

present, OTC sunscreen products 

containing enzacamene may not be 

marketed without approval of an NDA 

(see section 586C(e)(1)(A) of the FD&C 

Act, as amended by the SIA). Data 

submissions relating to this proposed 

order should be submitted to Docket 

Numbers FDA–2003–N–0196, FDA– 

1978–N–0018, and FDA–1996–N–0006 

at the Division of Dockets Management 

(see ADDRESSES). In addition, you can 

submit the data through the Federal 

eRulemaking Portal at: http://

www.regulations.gov. Follow the 

instructions for submitting comments. 

Section 586C(b)(7) of the FD&C Act, 

as amended by the SIA, provides that 


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the sponsor may, within 30 days of 

publication of a proposed order (see 

DATES), submit a request to FDA for a 

meeting to discuss the proposed order. 

Submit meeting requests electronically 

to http://www.regulations.gov or in 

writing to the Division of Dockets 

Management (see ADDRESSES), identified 

with the active ingredient name 

enzacamene, the docket numbers found 

in brackets in the heading of this 

proposed order, and the heading 

‘‘Sponsor Meeting Request.’’ To 

facilitate your request, please also send 

a copy to Kristen Hardin (see FOR

FURTHER INFORMATION CONTACT). 

VI. Proposed Effective Date 

FDA proposes that any final 

administrative order based on this 

proposal become effective on the date of 

publication of the final order in the 

Federal Register. 

VII. Comments 

Similarly, section 586C(b)(6) of the 

FD&C Act, as amended by the SIA, 

establishes that a proposed sunscreen 

order shall provide 45 days for public 

comment. Interested persons wishing to 

comment on this proposed order may 

submit either electronic comments to 

http://www.regulations.gov or written 

comments to the Division of Dockets 

Management (see ADDRESSES). It is only 

necessary to send one set of comments. 

Identify comments with the active 

ingredient name (enzacamene) and the 

docket numbers found in brackets in the 

heading of this proposed order. 

Received comments on this proposed 

order may be seen in the Division of 

Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday, and 

will be posted to the docket at http://

www.regulations.gov. 

VIII. Notes 

1. FDA–2003–N–0196–0056, Time 

and Extent Application (TEA) Request 

to Reopen the Rulemaking Record; 

submitted August 21, 2002. 

2. FDA–2003–N–0196–0028, C1, 

dated October 9, 2003. 

3. FDA–1978–N–0018–0759 (Sup 25), 

Volume 2, Report 10, dated November 

27, 1972. 

4. FDA–1978–N–0018–0760 (Sup 26), 

Volume 3, Report 20, dated September 

8, 1982. 

5. FDA–1978–N–0018–0759 (Sup 25), 

Volume 2, Report 11, dated February 20, 

1980. 

6. FDA–1978–N–0018–0759 (Sup 25), 

Volume 2, Report 12, dated February 20, 

1980. 

7. FDA–1978–N–0018–0760 (Sup 26), 

Volume 3, Report 21, dated June 5, 

1985. 

8. FDA–1978–N–0018–0759 (Sup 25), 

Volume 2, Report 14, dated November 

29, 1982. 

9. FDA–1978–N–0018–0759 (Sup 25), 

Volume 2, Report 15, dated July 17, 

1984. 

10. FDA–1978–N–0018–0760 (Sup 

26), Volume 3, Report 16, dated July 8, 

1984. 

11. FDA–1978–N–0018–0760 (Sup 

26), Volume 3, Report 19, dated August 

1, 1981. 

12. FDA–1978–N–0018–0760 (Sup 

26), Volume 3, Report 18, dated July 2, 

1982. 

13. FDA–1978–N–0018–0762 (Sup 

28), Volume 5, Report 29, Study no. 43/ 

20792, dated October 18, 1995. 

14. FDA–1978–N–0018–0754 (Sup 

24), dated April 12, 1999. 

15. FDA–1978–N–0018–0755 (Sup 

24), Attachment 1, dated April 12, 1999. 

16. FDA–1978–N–0018–0758 (Sup 

24), Volume 1, Reports 1, 2, 3 and 4, 

Study no. 4/83/71, 4/130/73, 4/131/73, 

4/52/80. 

17. FDA–1978–N–0018–0758 (Sup 

24), Volume 1, Reports 2 and 3, Study 

no. 4/130/73 and 4/131/73. 

18. Id. 

19. Id. 

20. Id. 

21. FDA–1978–N–0018–0759 (Sup 

25), Volume 2, Report 8, dated October 

16, 1978. 

22. FDA–1978–N–0018–0759 (Sup 

25), Volume 2, Report 9, dated October 

16, 1978. 

23. FDA–1978–N–0018–0758 (Sup 

24), Volume 1, Report 5, dated May 5, 

1983. 

24. Id. 

25. FDA–1978–N–0018–0759 (Sup 

25), Volume 2, Report 7, dated April 26, 

1984. 

26. FDA–1978–N–0018–0760 (Sup 

26), Volume 3, Report 17, dated May 1, 

1984. 

27. FDA–1978–N–0018–0760 (Sup 

26), Volume 3, Report 22, Study no. 

LMP166, dated April 25, 1986. 

28. FDA–1978–N–0018–0759 (Sup 

25), Volume 2, Report 13, Study no. 4/ 

56/80, dated June 2, 1980. 

29. FDA–1978–N–0018–0761 (Sup 

27), Volume 4, Report 28, Study no. 40/ 

13/93, dated April 14, 1993. 

30. FDA–1978–N–0018–0760 (Sup 

26), Volume 3, Report 23, Study no. 4/ 

20/84, Experiment No. T9207. 

31. FDA–1978–N–0018–0761 (Sup 

27), Volume 4, Report 24 and 25, dated 

October 23, 1987, and October 26, 1987. 

32. FDA–1978–N–0018–0761 (Sup 

27), Volume 4, Report 26, Study no. 4/ 

43/88, Experiment No. T9305, dated 

September 14, 1983. 

33. FDA–1978–N–0018–0759 (Sup 

25), Volume 2, Report 7, dated April 26, 

1984. 

IX. References 

The following references have been 

placed on display in the Division of 

Dockets Management (see ADDRESSES) 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday, and are available 

electronically at http://

www.regulations.gov. (FDA has verified 

the Web site addresses in this reference 

section, but FDA is not responsible for 

any subsequent changes to the Web sites 

after this document publishes in the 

Federal Register.) 

1. FDA, Guidance for industry, ‘‘Photosafety 

Testing,’’ May 2003 (available at http:// 

www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/ucm079252.pdf). 

2. FDA, Guidance for Industry, ‘‘Guideline 

for the Format and Content of the Human 

Pharmacokinetics and Bioavailability 

Section of an Application,’’ February 

1987 (available at http://www.fda.gov/

downloads/drugs/GuidanceCompliance

RegulatoryInformation/Guidances/

ucm072112.pdf). 

3. Janjua, N.R., et al., ‘‘Systemic Absorption 

of the Sunscreens Benzophenone-3, 

Octyl-Methoxycinnamate, and 3-(4- 

Methyl-Benzylidene) Camphor After 

Whole Body Topical Application and 

Reproductive Hormone Levels in 

Humans.’’ Journal of Investigative 

Dermatology, vol. 123, pp. 57–61, 2004. 

4. Schauer, U.M., et al., ‘‘Kinetics of 3- 

(methylbenzlidene) Camphor in Rats and 

Humans After Dermal Application.’’ 

Toxicology and Applied Pharmacology, 

vol. 216(2), pp. 339–346, 2006. 

5. Janjua, N.R., et al., ‘‘Sunscreens in Human 

Plasma and Urine After Repeated WholeBody Topical Application.’’ Journal of 

the European Academy of Dermatology 

and Venereology, vol. 22, pp. 456–461, 

2008. 

6. Scientific Committee on Consumer 

Products (SCCP)/1184/08—SCCNFP 

opinion on 4-Methylbenzylidene 

camphor (4–MBC) Colipa n° S60 adopted 

during the 16th plenary meeting of June 

24, 2008 (available at http://

ec.europa.eu/health/ph_risk/

committees/04_sccp/docs/sccp_o_

141.pdf). 

7. Jime ́nez-Dı ́az, I., et al., ‘‘Simultaneous 

Determination of the UV-Filters Benzyl 

Salicylate, Phenyl Salicylate, Octyl 

Salicylate, Homosalate, 3-(4- 

Methylbenzylidene) Camphor and 3- 

Benzylidene Camphor in Human 

Placental Tissue by LC–MS/MS. 

Assessment of Their In Vitro Endocrine 

Activity.’’ Journal of Chromatography. B, 

Analytical Technologies in the 

Biomedical and Life Sciences, vol. 936, 

pp. 80–87, 2013. 

8. Gomez, E., et al., ‘‘Estrogenic Activity of 

Cosmetic Components in Reporter Cell 

Lines: Parabens, UV Screens and 

Musks.’’ Journal of Toxicology and 

Environmental Health, Part A, vol. 68, 

pp. 239–251, 2005. 


wreier-aviles on DSK5TPTVN1PROD with PROPOSALS
Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 10035 

9. Ma, R., et al., ‘‘UV Filters With 

Antagonistic Action at Androgen 

Receptors in the MDA–kb2 Cell 

Transcriptional-Activation Assay.’’ 

Toxicological Sciences, vol. 74(1), pp. 

43–50, 2003. 

10. Mueller, S.O., et al., ‘‘Activation of 

Estrogen Receptor Alpha and ERbeta by 

4-Methylbenzylidene-Camphor in 

Human and Rat Cells: Comparison With 

Phyto- and Xenoestrogens.’’ Toxicology 

Letters, vol. 142(1–2), pp. 89–101, 2003. 

11. Schlumpf, M., et al., ‘‘Estrogenic Activity 

and Estrogen Receptor Beta Binding of 

the UV Filter 3-Benzylidene Camphor. 

Comparison With 4-Methylbenzylidene 

Camphor.’’ Toxicology, vol. 199(2–3), pp. 

109–120, 2004. 

12. Schmutzler, C., et al., ‘‘Endocrine 

Disruptors and the Thyroid Gland—A 

Combined In Vitro and In Vivo Analysis 

of Potential New Biomarkers.’’ 

Environmental Health Perspectives, vol. 

115 (Supplement 1), pp. 77–83, 2007. 

13. Schreurs, R., et al., ‘‘Estrogenic Activity 

of UV Filters Determined by an In Vitro 

Reporter Gene Assay and an In Vivo 

Transgenic Zebrafish Assay.’’ Archives of 

Toxicology, vol. 76, pp. 257–261, 2002. 

14. Seidlova ́-Wuttke, D., et al., ‘‘Comparison 

of Effects of Estradiol With Those of 

Octylmethoxycinnamate and 4- 

Methylbenzylidene Camphor on Fat 

Tissue, Lipids and Pituitary Hormones.’’ 

Toxicology and Applied Pharmacology, 

vol. 214(1), pp. 1–7, 2006. 

15. S<eborg, T., et al., ‘‘Risk Assessment of 

Topically Applied Products.’’ 

Toxicology, vol. 236(1–2), pp. 140–148, 

2007. 

16. Tinwell, H., et al., ‘‘Confirmation of 

Uterotrophic Activity of 3-(4- 

Methylbenzylidine) Camphor in the 

Immature Rat.’’ Environmental Health 

Perspectives, vol. 110(5), pp. 533–536, 

2002. 

17. Durrer, S., et al., ‘‘Estrogen Sensitivity of 

Target Genes and Expression of Nuclear 

Receptor Co-Regulators in Rat Prostate 

After Pre- and Postnatal Exposure to the 

Ultraviolet Filter 4-Methylbenzylidene 

Camphor.’’ Environmental Health 

Perspectives, vol. 115 (Supplement 1), 

pp. 42–50, 2007. 

18. Durrer, S., et al., ‘‘Estrogen Target Gene 

Regulation and Coactivator Expression in 

Rat Uterus After Developmental 

Exposure to the Ultraviolet Filter 4- 

Methylbenzylidene Camphor.’’ 

Endocrinology, vol. 146(5), pp. 2130– 

2139, 2005. 

19. Faass, O., et al., ‘‘Female Sexual 

Behavior, Estrous Cycle and Gene 

Expression in Sexually Dimorphic Brain 

Regions After Pre- and Postnatal 

Exposure to Endocrine Active UV 

Filters.’’ Neurotoxicology, vol. 30(2), pp. 

249–260, 2009. 

20. Hofkamp, L., et al., ‘‘Region-Specific 

Growth Effects in the Developing Rat 

Prostate Following Fetal Exposure to 

Estrogenic Ultraviolet Filters.’’ 

Environmental Health Perspectives, vol. 

116(7), pp. 867–872, 2008. 

21. Maerkel, K., et al., ‘‘Sexually Dimorphic 

Gene Regulation in Brain as a Target for 

Endocrine Disrupters: Developmental 

Exposure of Rats to 4-Methylbenzylidene 

Camphor.’’ Toxicology and Applied 

Pharmacology, vol. 218(2), pp. 152–165, 

2007. 

22. Maerkel, K., et al., ‘‘Sex- and RegionSpecific Alterations of Progesterone 

Receptor mRNA Levels and Estrogen 

Sensitivity in Rat Brain Following 

Developmental Exposure to the 

Estrogenic UV Filter 4- 

Methylbenzylidene Camphor.’’ 

Environmental Toxicology and 

Pharmacology, vol. 19(3), pp. 761–765, 

2005. 

23. Schlumpf, M., et al., ‘‘In Vitro and In 

Vivo Estrogenicity of UV Screens.’’ 

Environmental Health Perspectives, vol. 

109(3), pp. 239–244, 2001. Erratum in: 

Environmental Health Perspectives, vol. 

109(11), p. A517, 2001. 

24. Schlumpf, M., et al., ‘‘Estrogenic Activity 

and Estrogen Receptor Beta Binding of 

the UV Filter 3-Benzylidene Camphor. 

Comparison With 4-Methylbenzylidene 

Camphor.’’ Toxicology, vol. 199(2–3), pp. 

109–120, 2004. 

25. Schlumpf, M., et al. ‘‘Endocrine Activity 

and Developmental Toxicity of Cosmetic 

UV Filters—An Update.’’ Toxicology, 

vol. 205(1–2), pp. 113–122, 2004. 

26. International Conference on 

Harmonization (ICH), Guidance for 

Industry, ‘‘The Need for Long Term 

Rodent Carcinogenicity Studies of 

Pharmaceuticals S1A,’’ March 1996 

(available at http://www.fda.gov/

downloads/Drugs/GuidanceCompliance

RegulatoryInformation/Guidance/

UCM074911.pdf). 

27. ICH, Guidance for Industry, ‘‘S1B Testing 

for Carcinogenicity of Pharmaceuticals,’’ 

July 1997 (available at http://

www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/

UCM074916.pdf). 

28. ICH, ‘‘S1C(R2) Dose Selection for 

Carcinogenicity Studies of 

Pharmaceuticals SIC(R2)’’ (Revision 1), 

September 2008 (available at http://

www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/

UCM074919.pdf). 

29. ICH Harmonized Tripartite Guideline for 

Industry, ‘‘Detection of Toxicity to 

Reproduction for Medicinal Products & 

Toxicity to Male Fertility S5(R2),’’ 2005 

(available at http://www.ich.org/

fileadmin/Public_Web_Site/ICH_

Products/Guidelines/Safety/S5_R2/

Step4/S5_R2__Guideline.pdf). 

30. ICH, Guideline for Industry, 

‘‘Toxicokinetics: The Assessment of 

Systemic Exposure in Toxicity Studies 

S3A,’’ March 1995 (available at http://

www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/

UCM074937.pdf). 

Dated: February 20, 2015. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2015–03884 Filed 2–24–15; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 310 

[Docket No. FDA–2008–N–0474] 

Over-the-Counter Sunscreen Drug 

Products—Regulatory Status of 

Ecamsule 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed order; request for 

comments. 

SUMMARY: The Food and Drug 

Administration (FDA or the Agency) is 

issuing a proposed sunscreen order 

(proposed order) under the Federal 

Food, Drug, and Cosmetic Act (the 

FD&C Act), as amended by the 

Sunscreen Innovation Act (SIA). The 

proposed order announces FDA’s 

tentative determination that ecamsule 

(also known as terephthalylidene 

dicamphor sulfonic acid) at 

concentrations up to 10 percent is not 

generally recognized as safe and 

effective (GRASE) and is misbranded 

when used in over-the-counter (OTC) 

sunscreen products because the 

currently available data are insufficient 

to classify it as GRASE and not 

misbranded, and additional information 

is needed to allow us to determine 

otherwise. 

DATES: Submit either electronic or 

written comments on this proposed 

order by April 13, 2015. Sponsors may 

submit written requests for a meeting 

with FDA to discuss this proposed order 

by March 27, 2015. See section VI for 

the proposed effective date of a final 

order based on this proposed order. 

ADDRESSES: You may submit comments 

by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Written Submissions 

Submit written submissions in the 

following ways: 

• Mail/Hand delivery/Courier (for 

paper submissions): Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. 

Instructions: All submissions received 

must clearly identify the specific active 

ingredient (ecamsule) and the Docket 

No. FDA–2008–N–1474 for this 


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