Over-the-Counter Sunscreen Drug Products-Regulatory Status of Enzacamene, 10026-10035 [2015-03884]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 80, Number 37 (Wednesday, February 25, 2015)]
[Proposed Rules]
[Pages 10026-10035]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2015-03884]


=======================================================================
-----------------------------------------------------------------------

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-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: https://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.

[[Page 10027]]

    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 https://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 https://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, Sec.  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 pre- and 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.''
---------------------------------------------------------------------------

    \1\ For 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 Sec.  
330.14(a)(2)). This document will refer simply to new ``active 
ingredients,'' since that is the condition under consideration.
---------------------------------------------------------------------------

    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 Sec.  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

[[Page 10028]]

the SIA was enacted, FDA had not issued a TEA feedback letter or 
otherwise responded to that submission.
---------------------------------------------------------------------------

    \2\ These include FDA-1978-N-0018-0744-0756 (Sup 24, 25, 26, 27 
and 28), Request to Reopen 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.
---------------------------------------------------------------------------

    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 
(Sec.  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 (Sec.  
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 (Sec.  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

[[Page 10029]]

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 (\14\C) formulations of enzacamene. In one study (Note 8) 
a \14\C-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 \14\C-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 \14\C-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

[[Page 10030]]

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 single-dose 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 Sec.  330.10(a)(2), which includes 
documented case reports and identification of expected or frequently 
reported side effects (Sec.  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\
---------------------------------------------------------------------------

    \3\ See 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).
---------------------------------------------------------------------------

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

[[Page 10031]]

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
    [cir] Oral toxicity (rats, dogs) (Note 16)
    [cir] Dermal toxicity (rats) (Note 17)
    [cir] Intraperitoneal toxicity (rats) (Note 18)
    [cir] Mucosal irritation (rabbits) (Note 19)
    [cir] Skin irritation and sensitization (guinea pigs) (Note 20)
    [cir] Phototoxicity potential (mice) (Note 21)
    [cir] Photosensitization (guinea pig) (Note 22)
 Repeat-dose toxicity studies
    [cir] 17 days oral (rat) (Note 23)
    [cir] 4 weeks oral (rat) (Note 24)
    [cir] 13 weeks oral (rat) (Note 25)
    [cir] Liver enzyme induction study (rat) (Note 26)
 Genotoxicity and mutagenicity assays
    [cir] Chromosome aberration assay (Chinese hamster V79 cells) (Note 
27)
    [cir] Mutagenicity (Salmonella typhimurium) (Note 28)
    [cir] Photomutagenicity (S. typhimurium, Escherichia coli) (Note 
29)
 Reproductive and developmental toxicity studies
    [cir] Orienting tests for embryotoxicity (rabbit) (Note 30)
    [cir] Toxicological investigation (incubated hen's egg) (Note 31)
    [cir] 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[szlig] but showed inconsistent binding activity at 
ER[alpha] 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

[[Page 10032]]

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-yet-unknown 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 (Sec.  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 well-
controlled 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.
---------------------------------------------------------------------------

    \4\ The 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.
---------------------------------------------------------------------------

    The current standard procedure for SPF testing is described in 
FDA's regulations in Sec.  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 
Sec.  201.327(i), an SPF standard formulation comparator arm should be 
another component of the study design.
---------------------------------------------------------------------------

    \5\ Although 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.
---------------------------------------------------------------------------

    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

[[Page 10033]]

applications that contain specified active ingredients included in the 
stayed sunscreen monograph, those additional claims are permitted, but 
not required (Sec.  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: https://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

[[Page 10034]]

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 https://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 https://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 https://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 https://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 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/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 https://www.fda.gov/downloads/drugs/GuidanceComplianceRegulatoryInformation/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 Whole-Body 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[deg] S60 
adopted during the 16th plenary meeting of June 24, 2008 (available 
at https://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_141.pdf).
7. Jim[eacute]nez-D[iacute]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.

[[Page 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. Seidlov[aacute]-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[oslash]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 Region-Specific 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 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance/UCM074911.pdf).
27. ICH, Guidance for Industry, ``S1B Testing for Carcinogenicity of 
Pharmaceuticals,'' July 1997 (available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074916.pdf).
28. ICH, ``S1C(R2) Dose Selection for Carcinogenicity Studies of 
Pharmaceuticals SIC(R2)'' (Revision 1), September 2008 (available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/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 https://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 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/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