[Federal Register Volume 80, Number 37 (Wednesday, February 25, 2015)]
[Proposed Rules]
[Pages 10026-10035]
[FR Doc No: 2015-03884]

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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.

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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: 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 (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,<PHONE_NUMBER>.

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.''
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    \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.
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    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

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

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

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\
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    \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).
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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

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

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

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: 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

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.)

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(available at http://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 http://www.fda.gov/downloads/drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072112.pdf).
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9. Ma, R., et al., ``UV Filters With Antagonistic Action at Androgen
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10. Mueller, S.O., et al., ``Activation of Estrogen Receptor Alpha
and ERbeta by 4-Methylbenzylidene-Camphor in Human and Rat Cells:
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11. Schlumpf, M., et al., ``Estrogenic Activity and Estrogen
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12. Schmutzler, C., et al., ``Endocrine Disruptors and the Thyroid
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14. Seidlov[aacute]-Wuttke, D., et al., ``Comparison of Effects of
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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.
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18. Durrer, S., et al., ``Estrogen Target Gene Regulation and
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19. Faass, O., et al., ``Female Sexual Behavior, Estrous Cycle and
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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/GuidanceComplianceRegulatoryInformation/Guidance/UCM074911.pdf).
27. ICH, Guidance for Industry, ``S1B Testing for Carcinogenicity of
Pharmaceuticals,'' July 1997 (available at http://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
http://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 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/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


Atlanta Nonattainment Area Emissions Inventory for the 2008 8-Hour Ozone NAAQS: Submitted February 2015

Note: The Narrative and the Appendices not included in the narrative  are available
  from the links below.

Atlanta Nonattainment Area Emissions Inventory for the 2008 8-Hour Ozone NAAQS

Appendices

Appendix A: Annual and Summer Day 2011 Emission Calculations for the 15 Atlanta Nonattainment Counties

Appendix E: Hartsfield-Jackson Atlanta International Airport: Documentation for the CY 2011 Criteria Air Pollutant Emission Inventory

Appendix F: Emission Summaries

Appendix G: Additional Supporting Documentation- Georgia QAPP Documents

Appendix H: Additional Supporting Documentation- SESARM Documents

Appendix I: Additional Supporting Documentation- Emission Inventory Technical Support Documents


[Federal Register Volume 79, Number 165 (Tuesday, August 26, 2014)]
[Notices]
[Pages 50925-50926]
[FR Doc No: 2014-20319]

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DEPARTMENT OF HOMELAND SECURITY

Federal Emergency Management Agency

[Docket ID: FEMA-2014-0017; OMB No. 1660-0085]

Agency Information Collection Activities: Submission for OMB
Review; Comment Request; Crisis Counseling Assistance and Training
Program

AGENCY: Federal Emergency Management Agency, DHS.

ACTION: Notice.

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SUMMARY: The Federal Emergency Management Agency (FEMA) will submit the
information collection abstracted below to the Office of Management and
Budget for review and clearance in accordance with the requirements of
the Paperwork Reduction Act of 1995. The submission will describe the
nature of the information collection, the categories of respondents,
the estimated burden (i.e., the time, effort and resources used by
respondents to respond) and cost, and the actual data collection
instruments FEMA will use.

DATES: Comments must be submitted on or before September 25, 2014.

ADDRESSES: Submit written comments on the proposed information
collection to the Office of Information and Regulatory Affairs, Office
of Management and Budget. Comments should be addressed to the Desk
Officer for the Department of Homeland Security, Federal Emergency
Management Agency, and sent via electronic mail to
<EMAIL_ADDRESS>or faxed to<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Requests for additional information or
copies of the information collection should be made to Director,
Records Management Division, 500 C Street SW., Washington, DC 20472-
3100, facsimile number<PHONE_NUMBER>, or email address<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:
    Unauthorized Use of Draft Immediate Services Program (ISP)
Application: During April 2014, FEMA used the draft version of the ISP
application to evaluate whether the State of Washington needed the ISP
portion of the Crisis Counseling Program for the Washington State
mudslides that occurred on March 22, 2014. Washington State was
approved for the ISP portion of the Crisis Counseling Program and FEMA
only utilized the ISP draft application during this one incident. FEMA
will not use the ISP or RSP applications until OMB has approved both
forms for use. FEMA is disclosing the unauthorized use for transparency
purposes during the OMB review and approval process.

Collection of Information

    Title: Crisis Counseling Assistance and Training Program.
    Type of information collection: Revision of a currently approved
information collection.
    OMB Number: 1660-0085.
    Form Titles and Numbers: FEMA Form 003-0-1, Crisis Counseling
Assistance and Training Program, Immediate Services Program
Application; FEMA Form 003-0-2, Crisis Counseling Assistance and
Training Program, Regular Services Program Application; SF-424,

Application for Federal Assistance; SF-424A, Budget Information for
Non-Construction Programs; SF-425, Federal Financial Report; HHS
Checklist/08-2007; HHS Project Performance Site Location Form.
    Abstract: The CCP consists of two grant programs, the Immediate
Services Program (ISP) and the Regular Services Program (RSP). The ISP
and the RSP provide supplemental funding to States, U.S. Territories,
and Federally recognized Tribes following a Presidentially-declared
disaster. The grant programs provide funding for Training and Services,
including community outreach, public education, and counseling
techniques. States are required to submit an application that provides
information on Needs Assessment, Plan of Service, Program Management,
and an accompanying Budget.
    Affected Public: State, local, or Tribal Government.
    Estimated Number of Respondents: 150.
    Estimated Total Annual Burden Hours: 1,515 hours.
    Estimated Cost: The estimated annual cost to respondents for the
hour burden is $84,476.40. There are no annual costs to respondents
operations and maintenance costs for technical services. There is no
annual start-up or capital costs. The cost to the Federal Government is
$107,717.

    Dated: August 21, 2014.
Charlene D. Myrthil,
Director, Records Management Division, Mission Support Bureau, Federal
Emergency Management Agency, Department of Homeland Security.
[FR Doc. 2014-20319 Filed 8-25-14; 8:45 am]
BILLING CODE 9111-23-P


[Federal Register Volume 87, Number 17 (Wednesday, January 26, 2022)]
[Notices]
[Pages 4014-4015]
[FR Doc No: 2022-01520]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. CP21-6-000]

Spire Storage West, LLC; Notice of Revised Schedule for
Environmental Review of the Clear Creek Expansion Project

    This notice identifies the Federal Energy Regulatory Commission
staff's revised schedule for the completion of the environmental impact
statement (EIS) for Spire Storage West, LLC's Clear Creek Expansion
Project. The first notice of schedule, issued on August 26, 2021,
identified January 21, 2022 as the final EIS issuance date. However,
environmental staff is in the process of assessing various alternatives
raised during the draft EIS comment period. As a result, staff has
revised the schedule for issuance of the final EIS.

Schedule for Environmental Review

Issuance of the Notice of Availability of the final EIS March 15, 2022
90-day Federal Authorization Decision Deadline June 13, 2022

    If another schedule change becomes necessary, an additional notice
will be provided so that the relevant agencies are kept informed of the
project's progress.

Additional Information

    In order to receive notification of the issuance of the EIS and to
keep track of all formal issuances and submittals in specific dockets,
the Commission offers a free service called eSubscription. This can
reduce the amount of time you spend researching proceedings by
automatically providing you with notification of these filings,
document summaries, and direct links to the documents. Go to https://
www.ferc.gov/

ferc-online/overview to register for eSubscription.
    Additional information about the Project is available from the
Commission's Office of External Affairs at (866) 208-FERC or on the
FERC website (www.ferc.gov). Using the ``eLibrary'' link, select
``General Search'' from the eLibrary menu, enter the selected date
range and ``Docket Number'' (i.e., CP21-6), and follow the
instructions. For assistance with access to eLibrary, the helpline can
be reached at<PHONE_NUMBER>, TTY<PHONE_NUMBER>, or at
[email protected]. The eLibrary link on the FERC website also
provides access to the texts of formal documents issued by the
Commission, such as orders, notices, and rule makings.

    Dated: January 20, 2022.
Kimberly D. Bose,
Secretary.
[FR Doc. 2022-01520 Filed 1-25-22; 8:45 am]
BILLING CODE 6717-01-P


[Federal Register Volume 81, Number 167 (Monday, August 29, 2016)]
[Notices]
[Page 59220]
[FR Doc No: 2016-20607]

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ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OECA-2012-0697; FRL-9949-50-OEI]

Information Collection Request Submitted to OMB for Review and
Approval; Comment Request; NESHAP for Iron and Steel Foundries
(Renewal)

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Environmental Protection Agency has submitted an
information collection request (ICR), ``NESHAP for Iron and Steel
Foundries (40 CFR part 63, subpart EEEEE) (Renewal)'' (EPA ICR No.
2096.06, OMB Control No. 2060-0543), to the Office of Management and
Budget (OMB) for review and approval in accordance with the Paperwork
Reduction Act (44 U.S.C. 3501 et seq.). This is a proposed extension of
the ICR, which is currently approved through August 31, 2016. Public
comments were previously requested via the Federal Register (80 FR
32116) on June 5, 2015 during a 60-day comment period. This notice
allows for an additional 30 days for public comments. A fuller
description of the ICR is given below, including its estimated burden
and cost to the public. An Agency may neither conduct nor sponsor, and
a person is not required to respond to, a collection of information
unless it displays a currently valid OMB control number.

DATES: Additional comments may be submitted on or before September 28,
2016.

ADDRESSES: Submit your comments, referencing Docket ID Number EPA-HQ-
OECA-2012-0697, to: (1) EPA online using www.regulations.gov (our
preferred method), or by email to<EMAIL_ADDRESS>or by mail to:
EPA Docket Center, Environmental Protection Agency, Mail Code 28221T,
1200 Pennsylvania Ave. NW., Washington, DC 20460; and (2) OMB via email
to<EMAIL_ADDRESS>Address comments to OMB Desk Officer
for EPA.
    EPA's policy is that all comments received will be included in the
public docket without change including any personal information
provided, unless the comment includes profanity, threats, information
claimed to be Confidential Business Information (CBI), or other
information for which disclosure is restricted by statute.

FOR FURTHER INFORMATION CONTACT: Patrick Yellin, Monitoring,
Assistance, and Media Programs Division, Office of Compliance, Mail
Code 2227A, Environmental Protection Agency, 1200 Pennsylvania Ave.
NW., Washington, DC 20460; telephone number:<PHONE_NUMBER>; fax
number:<PHONE_NUMBER>; email address<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: Supporting documents which explain in detail
the information that the EPA will be collecting are available in the
public docket for this ICR. The docket can be viewed online at
www.regulations.gov, or in person at the EPA Docket Center, WJC West,
Room 3334, 1301 Constitution Ave. NW., Washington, DC. The telephone
number for the Docket Center is<PHONE_NUMBER>. For additional
information about EPA's public docket, visit: http://www.epa.gov/dockets.
    Abstract: Owners and operators of affected facilities are required
to comply with reporting and record keeping requirements for the
General Provisions (40 CFR part 63, subpart A), as well as for the
specific requirements at 40 CFR part 63, subpart EEEEE. This includes
submitting initial notification reports, performance tests and periodic
reports and results, and maintaining records of the occurrence and
duration of any startup, shutdown, or malfunction in the operation of
an affected facility, or any period during which the monitoring system
is inoperative. These reports are used by EPA to determine compliance
with the standards.
    Form Numbers: None.
    Respondents/affected entities: Iron and steel foundries.
    Respondent's obligation to respond: Mandatory (40 CFR part 63,
subpart EEEEE).
    Estimated number of respondents: 98 (total).
    Frequency of response: Initially, occasionally and semiannually.
    Total estimated burden: 30,000 hours (per year). Burden is defined
at 5 CFR 1320.3(b).
    Total estimated cost: $3,490,000 (per year), which includes
$400,000 in either annualized capital/startup or operation &
maintenance costs.
    Changes in the Estimates: There is an adjustment increase in the
total estimated burden and cost as currently identified in the OMB
Inventory of Approved Burdens. This increase is not due to any program
changes. The change in the burden and cost estimates occurred because
this ICR assumes that all existing respondents will have to familiarize
with regulatory requirements each year.
    There is a small adjustment decrease of $60 in the total capital
and O&M cost as currently identified in the OMB Inventory of Approved
Burdens. This decrease is not due to any program changes. The change in
estimates occurred because this ICR rounds totals to three significant
figures.

Courtney Kerwin,
Director, Regulatory Support Division.
[FR Doc. 2016-20607 Filed 8-26-16; 8:45 am]
 BILLING CODE 6560-50-P


[Federal Register Volume 85, Number 171 (Wednesday, September 2, 2020)]
[Notices]
[Page 54555]
[FR Doc No: 2020-19378]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. CP20-510-000]

Equitrans, L.P.; Notice of Request Under Blanket Authorization

    Take notice that on August 19, 2020, Equitrans, L.P. (Equitrans),
2200 Energy Drive, Canonsburg, Pennsylvania 15317, filed a prior notice
application pursuant to sections 157.205, 157.213(b), and 157.216(b) of
the Federal Energy Regulatory Commission's (Commission) regulations
under the Natural Gas Act (NGA), and Equitrans' blanket certificate
issued in Docket No. CP96-532-000. Equitrans proposes to convert the
Tepe 3900 injection/withdrawal storage well to an observation well,
remove the associated drip, and abandon-in-place 385 feet of six-inch-
diameter natural gas pipeline. Equitrans states that the cause for
converting the Tepe 3900 well is to mitigate future safety concerns due
to a recent hill slip in the vicinity of the well. Equitrans states
that conversion of the well will not impact the operational capability
of the Tepe Storage Field. Equitrans states the total cost for the
abandonment is 27,000 dollars. The Tepe 3900 storage well is part of
Equitrans' Tepe Storage Field located in Allegheny County,
Pennsylvania, all as more fully set forth in the application, which is
open to the public for inspection.
    In addition to publishing the full text of this document in the
Federal Register, the Commission provides all interested persons an
opportunity to view and/or print the contents of this document via the
internet through the Commission's Home Page (http://ferc.gov) using the
eLibrary link. Enter the docket number excluding the last three digits
in the docket number field to access the document. At this time, the
Commission has suspended access to the Commission's Public Reference
Room, due to the proclamation declaring a National Emergency concerning
the Novel Coronavirus Disease (COVID-19), issued by the President on
March 13, 2020. For assistance, contact FERC at
<EMAIL_ADDRESS>or call toll-free,<PHONE_NUMBER> or TYY,
(202) 502-8659.
    Any questions regarding this application should be directed to
Matthew Eggerding, Assistant General Counsel, Equitrans, L.P., 2200
Energy Drive, Canonsburg, PA 15317, or phone<PHONE_NUMBER>, or by
email<EMAIL_ADDRESS>    Any person or the Commission's staff may, within 60 days after
issuance of the instant notice by the Commission, file pursuant to Rule
214 of the Commission's Procedural Rules (18 CFR 385.214) a motion to
intervene or notice of intervention and pursuant to Section 157.205 of
the regulations under the NGA (18 CFR 157.205), a protest to the
request. If no protest is filed within the time allowed therefore, the
proposed activity shall be deemed to be authorized effective the day
after the time allowed for filing a protest. If a protest is filed and
not withdrawn within 30 days after the allowed time for filing a
protest, the instant request shall be treated as an application for
authorization pursuant to section 7 of the NGA.
    Pursuant to section 157.9 of the Commission's rules, 18 CFR 157.9,
within 90 days of this Notice the Commission staff will either:
Complete its environmental assessment (EA) and place it into the
Commission's public record (eLibrary) for this proceeding, or issue a
Notice of Schedule for Environmental Review. If a Notice of Schedule
for Environmental Review is issued, it will indicate, among other
milestones, the anticipated date for the Commission staff's issuance of
the final environmental impact statement (FEIS) or EA for this
proposal. The filing of the EA in the Commission's public record for
this proceeding or the issuance of a Notice of Schedule for
Environmental Review will serve to notify federal and state agencies of
the timing for the completion of all necessary reviews, and the
subsequent need to complete all federal authorizations within 90 days
of the date of issuance of the Commission staff's FEIS or EA.
    Persons who wish to comment only on the environmental review of
this project should submit an original and two copies of their comments
to the Secretary of the Commission. Environmental commenters will be
placed on the Commission's environmental mailing list, will receive
copies of the environmental documents, and will be notified of meetings
associated with the Commission's environmental review process.
Environmental commenters will not be required to serve copies of filed
documents on all other parties. However, the non-party commenter will
not receive copies of all documents filed by other parties or issued by
the Commission (except for the mailing of environmental documents
issued by the Commission) and will not have the right to seek court
review of the Commission's final order.
    The Commission strongly encourages electronic filings of comments
in lieu of paper using the eFile link at http://www.ferc.gov. In lieu
of electronic filing, you may submit a paper copy. Submissions sent via
the U.S. Postal Service must be addressed to: Kimberly D. Bose,
Secretary, Federal Energy Regulatory Commission, 888 First Street NE,
Room 1A, Washington, DC 20426. Submissions sent via any other carrier
must be addressed to: Kimberly D. Bose, Secretary, Federal Energy
Regulatory Commission, 12225 Wilkins Avenue, Rockville, Maryland 20852.

    Dated: August 27, 2020.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2020-19378 Filed 9-1-20; 8:45 am]
BILLING CODE 6717-01-P


[Federal Register Volume 87, Number 115 (Wednesday, June 15, 2022)]
[Notices]
[Pages 36199-36200]
[FR Doc No: 2022-12885]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

Notice of Request to Release Property at Charlotte Douglas
International Airport, Charlotte, NC (CLT)

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Federal Aviation Administration is requesting public
comment on a request by City of Charlotte, to release of land (8.62
acres) at Charlotte Douglas International Airport from federal
obligations.

DATES: Comments must be received on or before July 15, 2022.

ADDRESSES: Comments on this notice may be emailed to the FAA at the
following email address: FAA/Memphis Airports District Office, Attn:
Jamal R. Stovall, Community Planner, [email protected].
    In addition, one copy of any comments submitted to the FAA must be
mailed or delivered to Ms. Haley Gentry, Aviation Director, Charlotte
Douglas International Airport at the following address: 5601 Wilkinson
Blvd., Charlotte, NC 28208.

FOR FURTHER INFORMATION CONTACT: Jamal R Stovall, Community Planner,
Federal Aviation Administration, Memphis Airports District Office,
2600, Thousand Oaks Boulevard, Suite 2250, Memphis, TN 38118-2482,
[email protected]. The application may be reviewed in person at
this same location, by appointment.

SUPPLEMENTARY INFORMATION: The FAA proposes to rule and invites public
comment on the request to release property for disposal at Charlotte
Douglas International Airport, 5601 Wilkinson Blvd., Charlotte, NC
28208, under the provisions of 49 U.S.C. 47107(h)(2). The FAA
determined that the request to release property at

Charlotte Douglas International Airport (CLT) submitted by the Sponsor
meets the procedural requirements of the Federal Aviation
Administration and the release of these properties does not and will
not impact future aviation needs at the airport. The FAA may approve
the request, in whole or in part, no sooner than thirty days after the
publication of this notice.
    The request consists of the following:
    The City of Charlotte is proposing the release of airport property
totaling 8.620 acres. The 12-Parcels located along and in the vicinity
of Walkers Ferry Road were originally acquired under the Storm Water
Management Plan in connection with the third parallel runway. The
parcels subject to this release are non-aeronautical in use. The
Properties are currently being rezoned for industrial use. The
industrial (I-2) designation means the property will be used/sold for
general industrial purposes. Deed restrictions will subject the
Properties to appropriate height and use restrictions and an avigation
easement to ensure compatibility with the uses of the Airport nearby.
The property is located to the west of Interstate 485 and The Charlotte
Douglas International Airport, bordered on the south by Walkers Ferry
Road.
    This request will release this property from federal obligations.
This action is taken under the provisions of 49 U.S.C. 47107(h)(2).
    Any person may inspect the request in person at the FAA office
listed above under FOR FURTHER INFORMATION CONTACT.
    In addition, any person may, upon request, inspect the request,
notice and other documents germane to the request in person at the
Charlotte Douglas International Airport.

    Issued in Memphis, Tennessee, on June 7, 2022.
Tommy L. Dupree,
Manager, Memphis Airports District Office, Southern Region.
[FR Doc. 2022-12885 Filed 6-14-22; 8:45 am]
BILLING CODE 4910-13-P