Federal Register, Volume 84 Issue 38 (Tuesday, February 26, 2019)

[Federal Register Volume 84, Number 38 (Tuesday, February 26, 2019)]
[Proposed Rules]
[Pages 6204-6275]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-03019]

[[Page 6203]]

Vol. 84

Tuesday,

No. 38

February 26, 2019

Part II

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Parts 201, 310, 347, et al.

Sunscreen Drug Products for Over-the-Counter Human Use; Proposed Rule

Federal Register / Vol. 84 , No. 38 / Tuesday, February 26, 2019 /
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 310, 347, and 352

[Docket No. FDA-1978-N-0018] (Formerly Docket No. FDA-1978-N-0038)
RIN 0910-AF43

Sunscreen Drug Products for Over-the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is issuing
this proposed rule to put into effect a final monograph for
nonprescription, over-the-counter (OTC) sunscreen drug products. This
proposed rule describes the conditions under which FDA proposes that
OTC sunscreen monograph products are generally recognized as safe and
effective (GRASE) and not misbranded. It is being published as part of
the ongoing review of OTC drug products conducted by FDA. It is also
being published to comply with the Federal Food, Drug, and Cosmetic Act
(FD&C Act), as amended by the Sunscreen Innovation Act (SIA).

DATES: Submit either electronic or written comments. on the proposed
rule by May 28, 2019. Electronic comments must be submitted on or
before May 28, 2019. The https://www.regulations.gov electronic filing
system will accept comments until 11:59 p.m. Eastern Time at the end of
May 28, 2019. See section XII for proposed effective and compliance
dates of a final rule based on this document.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Comments received by
mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before the closing date.
Please be advised that safety and effectiveness data that are not
available to the public cannot be relied on to establish conditions
under which the OTC drugs described in this document of proposed
rulemaking are generally recognized as safe and effective. Accordingly,
you should not submit, and FDA generally does not intend to rely on,
any evidence of safety and effectiveness that bears a confidential mark
unless you include a statement that the information may be released to
the public. Similarly, if your submission includes safety and
effectiveness data or information marked as confidential by a third
party (such as a contract research organization or consultant), you
should either include a statement that you are authorized to make the
information publicly available or include an authorization from the
third party permitting the information to be publicly disclosed. If you
submit data without confidential markings in response to this document
and such data includes studies or other information that were
previously submitted confidentially (e.g., as part of a new drug
application), FDA intends to presume that you intend to make such data
publicly available.

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-1978-N-0018 (formerly Docket No. FDA-1978-N-0038) for ``Sunscreen
Drug Products for Over-the-Counter Human Use.'' Received comments,
those filed in a timely manner (see ADDRESSES), will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
Submit comments on information collection issues under the
Paperwork Reduction Act of 1995 to the Office of Management and Budget
(OMB) in the following ways:
Fax to the Office of Information and Regulatory Affairs,
OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, or email to
oira_submission@omb.eop.gov. All comments should be identified with

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the title, ``Sunscreen Drug Products for Over-the-Counter Human Use.''
The Agency encourages commenters also to submit their comments on
these paperwork requirements to the rulemaking docket (Docket No. FDA-
1978-N-0018), along with their comments on other parts of the proposed
rule.

FOR FURTHER INFORMATION CONTACT: Kristen Hardin, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 5443, Silver Spring, MD 20993, 240-402-
4246.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
A. Purpose and Coverage of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. FDA's Current Regulatory Framework
B. History of This Rulemaking
IV. Scope of This Rulemaking
V. Legal Authority
VI. Need for Additional Safety Information
A. Increased Consumer Exposure to Sunscreen Active Ingredients
B. Emerging Safety Concerns
VII. Framework for Evaluation of Safety Data
A. General
B. Clinical Safety Testing
C. Nonclinical Safety Testing
D. Postmarketing Safety Data
E. Sunscreens Containing Nanomaterials
VIII. Existing Safety Data for Sunscreen Active Ingredients
A. Ingredients Proposed as Category I
B. Ingredients Proposed as Category II
C. Ingredients Proposed as Category III
D. Anticipated Final Formulation In Vitro Permeation Testing
IX. Additional Proposed Conditions of Use
A. Proposed Requirements Related to Dosage Form
B. Proposed Maximum SPF and Broad Spectrum Requirements
C. Proposed PDP Labeling Requirements
D. Proposed Requirements Related to Final Formulation Testing
and Recordkeeping
E. Proposed Status of Sunscreen-Insect Repellent Combination
Products
X. Proposed Actions To Effectuate Lifting of Stay and Harmonize
Impacted Regulations
XI. Comment Period
XII. Proposed Effective/Compliance Dates
XIII. Preliminary Economic Analysis of Impacts
A. Introduction
B. Summary of Costs and Benefits
XIV. Analysis of Environmental Impact
XV. Paperwork Reduction Act of 1995
A. Labeling for Sunscreen Products and Associated Clinical
Testing
B. Regulatory Status of Testing Entities
C. Generating and Maintaining Records of SPF and Broad Spectrum
Testing
XVI. Federalism
XVII. Consultation and Coordination With Indian Tribal Governments
XVIII. References

I. Executive Summary

A. Purpose and Coverage of the Proposed Rule

The Food and Drug Administration (FDA or Agency) is publishing this
proposed rule as part of the regulatory proceeding to put into effect a
final monograph \1\ for nonprescription, OTC sunscreen drug products
under the OTC Drug Review. In 2011, FDA announced that ``we are
considering certain active ingredient safety issues further . . . In a
forthcoming rulemaking, we intend to request additional data regarding
the safety of the individual sunscreen active ingredients.'' (``Revised
Effectiveness Determination; Sunscreen Drug Products for Over-the-
Counter Human Use'' (Max SPF PR), 76 FR 35672 at 35673, June 17, 2011).
As described in further detail below, changed conditions in the nearly
20 years since publication of the final rule ``Sunscreen Drug Products
for Over the Counter Human Use'' (64 FR 27666, May 21, 1999) (now
stayed) (Stayed 1999 Final Monograph) have meant that additional safety
data are now needed to establish that certain of the active ingredients
listed in the Stayed 1999 Final Monograph are GRASE for use in
sunscreen products.\2\
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\1\ An OTC monograph establishes conditions under which certain
OTC drugs may be marketed without approved new drug applications
because they are generally recognized as safe and effective (GRASE)
and not misbranded. The proposed rule classifies active ingredients
and other conditions as Category I (proposed to be GRASE and not
misbranded), Category II (proposed to be not GRASE or to be
misbranded), or Category III (additional data needed).
\2\ Unless otherwise noted, references in this proposed rule to
sunscreen active ingredients and/or sunscreen products are to
sunscreen active ingredients or products marketed pursuant to the
OTC monograph system and subject to 21 CFR 201.327. Unless
specifically noted, references to sunscreen active ingredients and/
or sunscreen products in this notice do not refer to those marketed
pursuant to a new drug application (NDA) or an abbreviated new drug
application (ANDA). They also do not refer to sunscreen active
ingredients being evaluated under the new procedures set out in the
SIA (21 U.S.C. 360fff et seq).
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As detailed below, we emphasize that this proposed rule does not
represent a conclusion by FDA that the sunscreen active ingredients
included in the Stayed 1999 Final Monograph but proposed here as
Category III are unsafe for use in sunscreens. Rather, we are
requesting additional information on these ingredients so that we can
evaluate their GRASE status in light of changed conditions, including
substantially increased sunscreen usage and exposure and evolving
information about the potential risks associated with these products
since they were originally evaluated. While these additional data are
being developed and reviewed, FDA generally intends to follow the
enforcement approach discussed in section III.B with regard to
sunscreen products that contain those sunscreen active ingredients
included in the Stayed 1999 Final Monograph.
This proposed rule is also being published to comply with section
586E of the FD&C Act (21 U.S.C. 360fff-5), as amended by the SIA (21
U.S.C. ch. 9, sub. 5, part I, enacted November 26, 2014). The SIA calls
for FDA to issue a final OTC sunscreen monograph to be effective within
5 years of enactment of the SIA, or by November 26, 2019 (section
586E(a) of the FD&C Act). If the final OTC sunscreen monograph does not
include provisions related to the effectiveness of various sun
protection factor (SPF) levels and address all dosage forms known to
FDA to be used in sunscreens marketed in the United States without
approved new drug applications (NDAs), the SIA requires FDA, among
other things, to submit a report to Congress explaining these omissions
(section 586E(b) of the FD&C Act). As explained in section I.B, in this
proposed rule, FDA is addressing multiple conditions of use applicable
to sunscreen monograph products, including both the effectiveness of
various SPF values and all marketed sunscreen dosage forms (and intends
to do so in the final rule as well).
This proposed rule does not address the sunscreen active
ingredients that were originally submitted under the procedures
established in FDA's time and extent application (TEA) regulation
(Sec. 330.14 (21 CFR 330.14)) (67 FR 3074, January 23, 2002), and are
now being addressed through a process set forth in the SIA.

B. Summary of the Major Provisions of the Proposed Rule

1. Proposed GRASE Status of Active Ingredients Listed in the Stayed
1999 Final Monograph
a. Framework for evaluation of safety data. As previously noted,
changed conditions in the time since issuance of the Stayed 1999 Final
Monograph have meant that additional safety data are now needed to
establish that certain of the active ingredients listed in the Stayed
1999 Final Monograph are GRASE for use in sunscreen products in
accordance with the standards established in Sec. 330.10(a)(4) (21 CFR

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330.10(a)(4)). FDA's approach to the clinical safety evaluation of OTC
sunscreen active ingredients is based on our current scientific
understanding regarding the safety evaluation of topical drug products
for chronic use, and is therefore generally consistent with the safety
data needed to meet the requirements for approval of an NDA for a
chronic-use topical drug product (e.g., topical safety studies
(irritation, sensitization, and photosafety); bioavailability
(absorption); and evaluation of adverse events observed in clinical
studies). Postmarketing safety information is also relevant to our
safety evaluation.
Our current approach to the nonclinical safety evaluation of these
active ingredients takes into account their lengthy marketing history
in the United States. Unlike the nonclinical data required to meet the
standard for approval of chronic-use topical NDA products (which
include comprehensive nonclinical pharmacology and toxicology safety
testing), the approach to nonclinical safety testing reflected in this
proposed rule is largely focused on potential long-term adverse effects
or effects not otherwise readily detected from human use (i.e.,
carcinogenicity and reproductive toxicity).
b. Existing safety data for ingredients listed in Stayed 1999 Final
Monograph. In section VIII, we discuss our review of the scientific
literature, submissions to the sunscreen monograph docket, and adverse
event reports submitted to FDA's Adverse Event Reporting System (FAERS)
for the ingredients listed in the Stayed 1999 Final Monograph and
identify any existing gaps. Because our review of this evidence has
produced sufficient safety data on both zinc oxide and titanium dioxide
to support a proposal that sunscreen products containing these
ingredients (at concentrations of up to 25 percent) would be GRASE, we
are proposing that these ingredients are Category I. Our evaluation of
the available safety data for aminobenzoic acid (PABA) and trolamine
salicylate, however, has caused us to conclude that the risks
associated with use of these active ingredients in sunscreen products
outweigh their benefits. In the case of trolamine salicylate, these
risks include the potential for serious detrimental health effects
(including bleeding) caused by the anti-coagulation effects of
salicylic acid and increased risk of salicylate toxicity when this
ingredient is used in sunscreens. For PABA, the risks include
significant rates of allergic and photoallergic skin reactions, as well
as cross-sensitization with structurally similar compounds.
Accordingly, we are proposing that these two ingredients are Category
II.
Because the public record does not currently contain sufficient
data to support positive GRASE determinations for cinoxate,
dioxybenzone, ensulizole, homosalate, meradimate, octinoxate,
octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, or
avobenzone, we are proposing that these ingredients are Category III.
For example, the available literature includes studies indicating that
oxybenzone is absorbed through the skin to a greater extent than
previously understood and can lead to significant systemic exposure, as
well as data showing the presence of oxybenzone in human breast milk,
amniotic fluid, urine, and blood plasma. The significant systemic
availability of oxybenzone, coupled with a lack of data evaluating the
full extent of its absorption potential, is a concern, among other
reasons, because of questions raised in the published literature
regarding the potential for endocrine activity in connection with
systemic oxybenzone exposure. Nearly all of these sunscreen active
ingredients also have limited or no data characterizing their
absorption.
2. Proposed Requirements Related to Dosage Forms
In 2011, FDA published an Advance Notice of Proposed Rulemaking
(ANPR) that identified sunscreen dosage forms considered either
eligible or ineligible for inclusion in the sunscreen monograph, and
specifically requested comments on the safety and efficacy of spray
sunscreens. After considering comments received in response (and other
available data), we are proposing the following dosage forms as
Category I: Oils, lotions, creams, gels, butters, pastes, ointments,
and sticks. We are also proposing Category I status for spray
sunscreens, subject to testing necessary to minimize potential risks
from unintended inhalation (particle size restrictions) and
flammability (flammability and drying time testing), together with
related labeling requirements. We are proposing to add sunscreen
powders to the list of those eligible for inclusion in the monograph
and proposing that this dosage form is Category III; we expect that
powders would also be subject to particle size restrictions if found to
be GRASE in the final monograph. Finally, we are proposing that
sunscreens in all other dosage forms--including wipes, towelettes, body
washes, and shampoos--are new drugs because we did not receive data
showing that they were marketed prior to 1972, as required for
inclusion in the monograph.
3. Proposed Maximum Sun Protection Factor and Broad Spectrum
Requirements
In the Stayed 1999 Final Monograph, FDA established SPF 30+ as the
maximum labeled SPF value for sunscreen monograph products, and
subsequently proposed (in 2011) to raise this value to SPF 50+. Because
of evidence showing additional meaningful clinical benefit associated
with broad spectrum sunscreen products with an SPF of 60, we are now
proposing to raise the maximum labeled SPF value to SPF 60+. Given the
lack of data showing that sunscreens with SPF values above 60 provide
additional meaningful clinical benefit, we are proposing not to allow
labeled SPF values higher than 60+.
While our proposed cap for SPF labeling is SPF 60+, we are
proposing to permit the marketing of sunscreen products formulated with
SPF values up to 80. This formulation margin is intended to provide
manufacturers with formulation flexibility that we hope will: (1) Help
facilitate the development of products with greater Ultraviolet A (UVA)
protection and (2) more fully account for the range of variability in
SPF test results (discussed further in sections IX.B.4.b-c) for
sunscreen products labeled SPF 60+. We are proposing not to allow the
marketing (without an approved NDA) of sunscreen products with SPF
values above SPF 80.
In addition, since publication of the 2011 ``Labeling and
Effectiveness Testing; Sunscreen Drug Products for Over-the-Counter
Human Use'' (L&E Final Rule) (76 FR 35620, June 17, 2011) and Max SPF
PR, the body of scientific evidence linking UVA exposure to skin
cancers and other harms has grown significantly. This evidence raises
concerns about the potential for inadequate UVA protection in marketed
sunscreen products--particularly in high SPF sunscreen products that
either do not pass the current broad spectrum test or (though they pass
our current broad spectrum test) have inadequate uniformity in their
UVA protection. Consumers using these products may, while successfully
preventing sunburn, accumulate excessively large doses of UVA
radiation--thereby exposing themselves to additional risks related to
skin cancer and early skin aging.
To address these concerns, we are making a number of proposals
designed to couple a greater magnitude of UVA protection to increases
in SPF values. We are proposing to require that all sunscreen products
with SPF values of 15 and above satisfy broad spectrum

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requirements. Among other things, this proposal eliminates the
potential confusion permitted by the current labeling regime, in which
a higher numbered product (for example, one labeled SPF 30) may provide
inferior protection against UVA radiation than a lower numbered product
(for example, one labeled broad spectrum SPF 15). We are also proposing
to add to the current broad spectrum test a requirement that broad
spectrum products meet a UVA I/UV ratio of 0.7 or higher. Given how
much of the UVA portion of the ultraviolet (UV) spectrum is composed of
UVA I radiation, and given what we now know about the skin cancer risks
associated with UVA exposure, ensuring that sunscreen products provide
adequate protection in the UVA I portion of the spectrum is
critical.\3\ Because sunscreens with SPF 2 to 14 have not been
demonstrated to help reduce the risk of skin cancer and early skin
aging caused by the sun, whether or not they provide protection against
UVA radiation as well as ultraviolet B (UVB) radiation, we are not
proposing to require that they pass the revised broad spectrum test.
However, we seek comment on whether these low SPF products should
remain in the market.
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\3\ We note that because our proposal to raise the maximum
labeled SPF value to 60+ is based on studies that all used broad
spectrum sunscreens, the additional clinical benefit we are
proposing to recognize in sunscreen products with SPF values greater
than 50 cannot be decoupled from the broad spectrum protection
provided by those products. As a result, our proposal to raise the
maximum labeled SPF value to SPF 60+ is both consistent with and
dependent upon our proposal to require that all sunscreen monograph
products with SPF values of 15 and above satisfy our broad spectrum
requirements.
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Finally, we are proposing to require that sunscreen products with
SPF values of 15 or above be labeled with an SPF number corresponding
to the lowest number in a range of tested SPF results. For example,
sunscreens testing at SPF 15-19 would be labeled ``SPF 15''; those
testing at 40-49 would be labeled ``SPF 40.'' We are making this
proposal because new evidence has caused us to reexamine the
variability inherent in the SPF test (which relies on visual
assessments of erythema in human subjects). The data we reviewed
suggests that the clinical evaluation undertaken during SPF testing
creates variability that justifies the use of SPF ranges. As explained
further in sections IX.B.4.b-c, because this variability is exacerbated
at high SPFs, we are proposing that sunscreens testing at SPF 30 or
more be labeled in increments of 10 (i.e., SPF 30, SPF 40, SPF 50, with
a proposed maximum of SPF 60+), that sunscreens testing at SPF 15 to 29
be labeled in increments of 5 (i.e., SPF 15, SPF 20, SPF 25), and that
the requirement that labeled SPF values correspond to ranges (rather
than precise numerical values) is not necessary below SPF 15.
4. Proposed PDP Labeling Requirements
We are also proposing to partially revise the current requirements
for information that must appear on the principal display panel (PDP)
of sunscreen products. The PDP is the part of a product label that is
most likely to be viewed or examined when the product is displayed for
retail sale. A major feature of the PDP is the statement of identity
(SOI). We are proposing that the SOI consist of an alphabetical listing
of the sunscreen active ingredients in the product, followed by
``Sunscreen'' and the product's dosage form (such as lotion or spray).
This information would supplement other important elements of the PDP
(e.g., SPF, broad spectrum, and water resistance information) to
provide a succinct summary of the product's key characteristics on the
front of the package or container, permitting consumers to more readily
compare products and either select or avoid a given product
accordingly. For sunscreen products that have not been shown to help
prevent skin cancer or early skin aging caused by the sun, the SPF
statement would be followed by an asterisk (*) directing consumers to
see the ``Skin Cancer/Skin Aging alert'' elsewhere on the label.
Finally, to prevent required information from being obscured or
overwhelmed by other labeling features, we are revising the format
requirements for the SPF, broad spectrum, and water resistance
statements on the PDP.
5. Proposed Requirements Related to Final Formulation Testing Processes
and Recordkeeping
To ensure that FDA can assess compliance with our regulations, we
are proposing to require records of required final formulation testing
of sunscreen products to be maintained for 1 year after the product
expiration date, or, if the product is exempt from expiration dating
(as most sunscreens are), for 3 years after distribution of the last
lot labeled in reliance on that testing. In addition, we are proposing
to require responsible persons (defined in section IX.D.2.b) to keep
records of sunscreen formulation testing, and clarifying that required
records would be subject to FDA inspection. We are also proposing a
number of revisions to our labeling and testing regulations designed to
clarify FDA expectations about clinical final formulation testing
processes and to ensure that the testing of marketed sunscreen products
is conducted in a manner that both protects human subjects and produces
reliable results.
6. Proposed Status of Sunscreen-Insect Repellent Combination Products
The proposed rule also addresses sunscreen-insect repellent
products, which are jointly regulated by FDA as sunscreen drugs and by
the Environmental Protection Agency (EPA) as pesticides under the
Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). In 2007,
FDA and EPA both issued ANPRs requesting comment on the appropriate
regulatory status of these products. We are proposing to classify these
products as Category II because incompatibilities between FDA and EPA
labeling requirements prevent these products from being labeled in a
manner that sufficiently ensures safe and effective use of the
sunscreen component and provides adequate directions for use. In
addition, there are data suggesting that combining some sunscreen
active ingredients with the insecticide DEET may increase absorption of
either or both components.
7. Proposed Actions To Effectuate Lifting of Stay and Harmonize
Impacted Regulations
Finally, we are proposing to lift the stay on the 1999 Final
Monograph (subject to the revisions to parts 201, 310, 347, and 352 (21
CFR parts 201,\4\ 310, 347, and 352) described in this document), and
have proposed revisions to these regulations necessary to effectuate
the lifting of the stay and to harmonize any impacted regulations.
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\4\ We note that, for ease of comprehension, we have included in
this document the current provisions of 21 CFR 201.327 that we are
not proposing to revise along with the provisions of that regulation
that we are proposing to revise.
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C. Legal Authority

We are issuing this proposed rule under sections 201, 301, 501,
502, 503, 505, 510, 586E, 701, 702, 703, 704, and 721 of the FD&C Act
(21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360fff-5, 371, 372, 373,
374, and 379e) and under section 351 of the Public Health Service Act
(42 U.S.C. 262).

D. Costs and Benefits

[[Page 6208]]

clarify our expectations for testing and recordkeeping by entities that
conduct sunscreen testing, and address other sunscreen safety or
efficacy concerns, like combination sunscreen-insect repellents and
alternative dosage forms.
Consumers would benefit from less exposure to sunscreen products
containing active ingredients about which safety questions remain, less
exposure to sunscreen products labeled with potentially misleading sun
protection information, increased consumption of products with better
UVA protection, less exposure to flammable spray sunscreens, and less
exposure to spray and powder sunscreen products posing inhalation
risks. Consumers would also experience transaction cost savings. The
costs of the rule to sunscreen manufacturers include administrative
costs, costs to fill data gaps for active ingredients and powder dosage
forms, product formulation testing costs, and costs to reformulate and
relabel sunscreen products. Finally, testing entities would incur
recordkeeping costs if they do not already maintain adequate records of
testing equipment, methods, and observations in final formulation
testing.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

------------------------------------------------------------------------
Abbreviation/ acronym What it means
------------------------------------------------------------------------
ANDA................................. Abbreviated new drug application.
ANPR................................. Advance notice of proposed
rulemaking.
CFR.................................. Code of Federal Regulations.
DART................................. Developmental and reproductive
toxicity.
DEET................................. N,N-Diethyl-meta-toluamide.
EPA.................................. Environmental Protection Agency.
FAERS................................ FDA's Adverse Event Reporting
System.
FDA or Agency........................ Food and Drug Administration.
FD&C Act............................. Federal Food, Drug, and Cosmetic
Act.
FIFRA................................ Federal Insecticide, Fungicide,
and Rodenticide Act.
FR................................... Federal Register.
GRASE................................ Generally recognized as safe and
effective (or general
recognition of safety and
effectiveness).
ICH.................................. International Council for
Harmonisation of Technical
Requirements for Pharmaceuticals
for Human Use.
IND.................................. Investigational new drug
application.
IRB.................................. Institutional Review Board.
mL................................... Milliliter.
MUsT................................. Maximal usage trial.
NDA.................................. New drug application.
NDAC................................. Nonprescription Drugs Advisory
Committee.
Ng................................... Nanogram.
Nm................................... Nanometer.
NOAEL................................ No observed adverse effect level.
NPIC................................. National Pesticide Information
Center.
NTP.................................. National Toxicology Program of
the National Institutes of
Health.
OMB.................................. Office of Management and Budget.
OTC.................................. Over-the-counter.
PABA................................. Aminobenzoic acid.
ROS.................................. Reactive oxygen species.
SIA.................................. Sunscreen Innovation Act.
SPF.................................. Sun protection factor.
TEA.................................. Time and extent application.
TFM.................................. Tentative final monograph.
U.S.C................................ United States Code.
USP.................................. United States Pharmacopeia.
UVA.................................. Ultraviolet A.
UVB.................................. Ultraviolet B.
------------------------------------------------------------------------

III. Background

A. FDA's Current Regulatory Framework

In the following sections, we provide a brief description of
terminology used in the OTC Drug Review regulations as well as an
overview of OTC sunscreen products, their intended uses, and FDA's
regulation of them.
1. Terminology
a. OTC drug review. The OTC Drug Review is the process established
by FDA to evaluate the safety and effectiveness of OTC drug products
marketed in the United States before May 11, 1972, and to establish the
conditions under which they are considered to be GRASE and not
misbranded. As described further below, the OTC Drug Review is
generally conducted via a multiphase public rulemaking process (each
phase requiring a Federal Register publication), resulting in the
establishment of a monograph for an OTC therapeutic drug category.
b. Generally recognized as safe and effective (GRASE). An OTC drug
is ``generally recognized as safe and effective'' if it meets each of
the conditions contained in an applicable OTC final monograph, the
conditions contained in part 330 (21 CFR part 330), and any other
applicable regulatory and statutory requirements for OTC drugs,
including the labeling requirements in part 201.
c. Proposed, tentative final, and final monographs. The proposed
monograph, which is typically published in the form of an ANPR, is the
end product of the first phase of the rulemaking process described
above. After reviewing the report and recommendations of an expert
advisory review panel responsible for initially reviewing the safety,
effectiveness, and labeling of products in a given therapeutic
category, FDA publishes a proposed monograph (together with the report
and recommendations of the expert review panel) (see Sec.
330.10(a)(6)). After a period of public comment, FDA publishes a
tentative final monograph (TFM) (in the form of a proposed rule,
proposing conditions under which OTC drugs in the therapeutic class
being considered are GRASE and not misbranded (see Sec. 330.10(a)(7)).
Following public comment on the TFM, FDA publishes a final monograph in
FDA's regulations (see 21 CFR chapter I, subchapter D) codifying the
conditions under which products in the OTC therapeutic drug category
are GRASE and not misbranded (see Sec. 330.10(a)(9)). An OTC drug may
be legally marketed without an approved NDA or abbreviated new drug
application (ANDA) if it meets each of the conditions contained in an
applicable final monograph, the conditions contained in part 330, and
any other applicable regulatory and statutory requirements for OTC
drugs, including the labeling requirements in part 201.
d. Category I, II, and III classifications. In the course of
establishing an OTC monograph, active ingredients and other OTC drug
conditions are classified in one of three categories: Category I
(conditions under which a nonprescription drug in the therapeutic
category would be GRASE and not misbranded), Category II (conditions
that would result in the drug being classified as not GRASE and/or
misbranded) and Category III (conditions proposed to be excluded from
the final monograph because available data are insufficient to classify
them as either Category I or Category II) (see Sec. 330.10(a)(6)).
2. OTC Sunscreen Products Regulated Under the OTC Drug Review and Their
Intended Uses
OTC sunscreen drugs regulated under the OTC Drug Review are
topically applied products indicated to help prevent sunburn; some are
also indicated to decrease the risk of skin cancer and early skin aging
caused by exposure to the sun's UV radiation (when used as directed
with other sun protection measures) (see Sec. 201.327(c)). The active
ingredients in sunscreen products achieve these protective effects by
absorbing, reflecting, and/or scattering radiation in the UV range
(from 290 to 400 nanometers (nm)) (see section 586(10) of the FD&C Act
(21 U.S.C. 360fff(10)); see also Sec. 352.3(c) (21 CFR 352.3(c)),
stayed).
Sunscreen products must be labeled with an SPF value calculated
using a standardized SPF testing procedure set forth in FDA regulations
(in Sec. 201.327(i)). As discussed in further detail in section
IX.B.1, the SPF test

[[Page 6209]]

measures the amount of UV radiation exposure it takes to cause sunburn
when a person is using a sunscreen when compared with how much UV
exposure it takes to cause sunburn when the person is not using a
sunscreen. Because SPF values represent a sunscreen's level of sunburn
protection, they are primarily (though not exclusively) an indicator of
expected protection from UVB radiation (see section IX.B.1 for a
discussion of both UVB and UVA radiation).
To pass FDA's current test for the inclusion of the term ``broad
spectrum'' in labeling (which was established in the 2011 L&E Final
Rule), sunscreen products must demonstrate that, in addition to UVB
protection, they also provide UVA protection. Further, only products
that have been demonstrated both to provide broad spectrum protection
and to have a minimum SPF value of 15 have been shown to reduce the
risk of skin cancer and early skin aging caused by the sun (when used
as directed with other sun protection measures). By contrast,
sunscreens that have not been demonstrated to provide both broad
spectrum protection and an SPF value of at least 15 have only been
demonstrated to help prevent sunburn.\5\ Thus, under the 2011 L&E Final
Rule, passing the broad spectrum test in Sec. 201.327(j) (21 CFR
201.327(j)) is necessary, but not itself sufficient, to support
inclusion of a skin cancer indication in labeling, although any product
that passes the broad spectrum test may be labeled with the term
``Broad Spectrum'' in conjunction with its SPF value.
---------------------------------------------------------------------------

\5\ As described in further detail in section IXB.2, in the time
since the L&E Final Rule was issued in 2011, the body of evidence
about the role of UVA radiation in the development of skin cancer
has grown. As a result, FDA is making a number of proposals designed
(among other things) to couple a greater magnitude of UVA protection
to increases in SPF values.
---------------------------------------------------------------------------

B. History of This Rulemaking

1. The OTC Sunscreen Drug Review and FDA's Regulation of OTC Sunscreen
Drug Products
Our initial call for safety and efficacy data for sunscreen
products was issued in 1972 (37 FR 26456, December 12, 1972). The
resulting data submissions were reviewed by the Advisory Review Panel
on OTC Topical Analgesic, Antirheumatic, Otic, Burn, and Sunburn
Prevention and Treatment Products, whose panel report and recommended
monograph were published as an ANPR in 1978 (43 FR 38206, August 25,
1978). The ANPR contained a list of the 21 sunscreen active ingredients
\6\ that the panel recommended for classification as GRASE when used
under the conditions described in the panel's report (43 FR 38206 at
38219). In 1993, having reviewed the panel's report and related public
comments, FDA published a TFM (58 FR 28194, May 12, 1993) which (with
one exception--padimate A) proposed as GRASE all of the active
ingredients that had been included in the ANPR. The TFM also included
specified maximum concentrations at which the proposed ingredients
would be considered GRASE for use in sunscreens.
---------------------------------------------------------------------------

\6\ The ingredients were: Aminobenzoic acid, digalloyl
trioleate, 2-ethylhexyl 2-cyano-3,3-diphenylacrylate, glyceryl
aminobenzoate, menthyl anthranilate, padimate O, sulisobenzone,
cinoxate, dioxybenzone, ethylhexyl p-methoxycinnamate, homosalate,
oxybenzone, 2-phenylbenzimidazole-5-sulfonic acid, titanium dioxide,
diethanoloamine p-methoxycinnamate, ethyl 4-[bis (hydroxylpropyl)]
aminobenzoate, 2-ethylhexyl salicylate, lawsone with
dihydroxyacetone, padimate A, red petrolatum, and triethanolamine
salicylate.
---------------------------------------------------------------------------

In the years following the publication of the 1993 TFM, FDA removed
several additional ingredients from the TFM (see 59 FR 29706, June 8,
1994), as described at 64 FR 27666 at 27681, and proposed the inclusion
of two more.\7\ In 1999, FDA published a final sunscreen monograph,
which included the following 16 sunscreen active ingredients along with
the conditions (including maximum concentrations) under which these
ingredients would be considered GRASE for use in sunscreens: \8\
---------------------------------------------------------------------------

\7\ In 61 FR 48645 (September 16, 1996) (proposing that
avobenzone is GRASE up to 3 percent alone and 2 to 3 percent when in
combination with cinoxate, diethanolamine methoxycinnamate,
dioxybenzone, homosolate, octocrylene, octyl methoxycinnamate, octyl
salicylate, oxybenzone, sulisobenzone, and/or trolamine salicylate)
and 63 FR 56584 (October 22, 1998) (proposing that zinc oxide is
GRASE alone or in combination with any previously proposed GRASE
active ingredient except avobenzone). The list of active ingredients
was (and would continue to be) modified because of, among other
things, a lack of interest in developing United States Pharmacopeia
(USP) compendial monographs for certain of the active ingredients
originally proposed (see 64 FR 27666 at 27681).
\8\ See Sec. 352.10, now stayed; 64 FR 27666. The active
ingredient names used in that regulation, as originally published,
differ from those used in table 1, which are the current established
names for these active ingredients. We note that subsequent to the
publication of the Stayed 1999 Final Monograph, we issued another
final rule in 2002 amending the names used for four of those
ingredients to make them consistent with the renaming of those
ingredients in the corresponding USP monographs (67 FR 41821 at
41823, June 20, 2002). Under section 502(e) of the FD&C Act, drug
labels are required to bear the established name of each active
ingredient, and if FDA has not designated an official name under
section 508 of the FD&C Act (21 U.S.C. 358), the compendial name is
the established name. To comply with section 502(e) of the FD&C Act,
sunscreen drug products must therefore bear the current compendial
names for their active ingredients, and the current compendial names
are used throughout this document. Because the 2002 final rule that
changed those names was published after part 352 was stayed,
however, those amendments have not yet been incorporated into the
published monograph regulation.

Table 1--Sunscreen Active Ingredients Included in the Stayed 1999 Final
Monograph
------------------------------------------------------------------------
Maximum
Active ingredient concentration
(%)
------------------------------------------------------------------------
Aminobenzoic acid (PABA)................................ 15
Avobenzone.............................................. 3
Cinoxate................................................ 3
Dioxybenzone............................................ 3
Ensulizole.............................................. 4
Homosalate.............................................. 15
Meradimate.............................................. 5
Octinoxate.............................................. 7.5
Octisalate.............................................. 5
Octocrylene............................................. 10
Oxybenzone.............................................. 6
Padimate O.............................................. 8
Sulisobenzone........................................... 10
Titanium dioxide........................................ 25
Trolamine salicylate.................................... 12
Zinc oxide.............................................. 25
------------------------------------------------------------------------

Among other things, the Stayed 1999 Final Monograph established a
minimum SPF value of 2, and an SPF of 30+ as the maximum labeled SPF
value (64 FR 27666). FDA concluded that the above-listed ingredients
(at the listed concentrations) could also be used in combination, with
limited exceptions, provided that each active ingredient contributed a
minimum SPF of 2 to the finished product (64 FR 27666).\9\
---------------------------------------------------------------------------

\9\ An exception to this rule involving avobenzone was retained
from the TFM: The Stayed 1999 Final Monograph stated that avobenzone
may not be combined with PABA, phenylbenzimidazole sulfonic acid,
menthyl anthranilate, padimate O, titanium dioxide, or zinc oxide.
In 2007, we proposed to include in the monograph a condition
permitting the marketing of sunscreens containing avobenzone in
combination with either zinc oxide or ensulizole based on safety and
effectiveness data about these combinations provided to the docket
(``Sunscreen Drug Products for Over-the-Counter Human Use: Proposed
Amendment of Final Monograph'', 72 FR 49070 at 49074, August 27,
2007). As described in section VII.A, we now anticipate finalizing a
monograph that would permit all listed active ingredients to be
combined without limitation. This approach is consistent with the
approach to sunscreen combinations generally taken throughout the
OTC Drug Review for sunscreens.
---------------------------------------------------------------------------

The effective date for complying with the Stayed 1999 Final
Monograph was May 21, 2001. This deadline was extended (65 FR 36319,
June 8, 2000) and then stayed until further notice (66 FR 67485,
December 31, 2001) to provide additional time to resolve various
outstanding issues, such as the labeling and testing of finished OTC
sunscreen products. As a result, the

[[Page 6210]]

Stayed 1999 Final Monograph has never been in effect.
In 2011, FDA published a draft guidance for industry, ``Enforcement
Policy--OTC Sunscreen Drug Products Marketed Without an Approved
Application,'' addressing the circumstances under which FDA intended to
exercise its enforcement discretion with respect to certain marketed
OTC sunscreen products in the period until a final OTC sunscreen
monograph becomes effective. This guidance was finalized in May 2018
(2018 Final Guidance) (Ref. 1). Unless the failure to pursue regulatory
action poses a potential health hazard to the consumer, FDA generally
does not intend to object to the marketing of OTC sunscreen products
that do not have an approved NDA or ANDA provided that they: (1)
Contain as sunscreen active ingredients only the active ingredients or
combinations of active ingredients listed in 21 CFR 352.10 and 352.20
(both currently stayed); (2) do not make claims addressed in Sec. Sec.
201.327(c)(3) and (g) and 310.545(a)(29)(ii); (3) comply with the
requirements for OTC drugs set forth in part 201 and Sec. 330.1 (21
CFR 330.1), the requirements for adverse event reporting for OTC drugs
set forth in the FD&C Act (see section 760 (21 U.S.C. 379aa)), and the
provisions of the FD&C Act addressing adulteration; and (4) follow
applicable labeling and testing requirements for OTC sunscreens set
forth in Sec. 201.327.
2. Recent Significant Rulemakings Relevant to This Proposed Rule
Since publishing the Stayed 1999 Final Monograph, FDA has issued a
number of Federal Register notices relating to OTC sunscreens. Major
notices pertinent to today's proposed rule are summarized briefly in
table 2 below:

Table 2--Recent Significant Federal Register Notices Pertinent to This
Rule
------------------------------------------------------------------------
Federal Register notice Information in notice
------------------------------------------------------------------------
Insect Repellent-Sunscreen Drug We issued a notice stating that we
Products for Over-the-Counter were considering amending the
Human Use: Request for Stayed 1999 Final Monograph to
Information and Comments; 72 FR include conditions for marketing
7941, February 22, 2007. insect repellent-sunscreen drug
products and requested information
to form a regulatory position on
these products. The Environmental
Protection Agency, which regulates
the insect repellent component of
insect repellent-sunscreen
combinations, published a similar
notice concurrently with ours, also
seeking information and comment on
these products.
Sunscreen Drug Products for Over- We proposed to amend the Stayed 1999
the-Counter Human Use: Proposed Final Monograph to address, among
Amendment of Final Monograph; 72 other things, formulation,
FR 49070, August 27, 2007. labeling, and testing requirements
for both UVA and UVB radiation
protection.
Labeling and Effectiveness We issued a final rule establishing
Testing: Sunscreen Drug Products labeling and testing requirements
for Over-the-Counter Human Use for sunscreen products. Among other
(L&E Final Rule); 76 FR 35620, things, the L&E Final Rule
June 17, 2011. established optional broad spectrum
labeling, created an optional
indication relating to decreasing
the risk of skin cancer and early
skin aging for broad spectrum
products with an SPF of 15 or
higher, and required a labeling
warning for sunscreens that did not
both satisfy the broad spectrum
test and provide an SPF of at least
15.
2011 Proposed Rule: Revised We proposed to raise the limit on
Effectiveness Determination (Max the maximum permissible labeled SPF
SPF PR); 76 FR 35672, June 17, value for sunscreen products to
2011. ``50+.'' Among other things, we
sought comment on the
appropriateness of a formulation
cap for sunscreen products.
2011 ANPR and Request for Data and We issued an ANPR describing the
Information on Certain Dosage sunscreen dosage forms that we
Forms; 76 FR 35669, June 17, 2011. considered to be part of the OTC
Drug Review and thus eligible for
potential inclusion in a sunscreen
monograph, as well as those dosage
forms that we did not consider
eligible. We requested data to
enable us to ensure that the
administrative record would be
adequate to support GRASE
determinations for the eligible
sunscreen dosage forms. In
particular, we emphasized that
additional safety and efficacy data
would be needed to support final
monograph status for spray dosage
forms. We also announced that we
were issuing a draft guidance
document (discussed above)
explaining the Agency's intended
enforcement policy for sunscreens
marketed pursuant to the monograph
system, including with respect to
dosage forms. The Agency's approach
to enforcement of spray sunscreens
is now described in the 2018 Final
Guidance.
------------------------------------------------------------------------

IV. Scope of This Rulemaking

Eligibility for inclusion in an OTC monograph was originally
limited to active ingredients and other conditions that had been used
in drugs marketed in the United States prior to the inception of the
OTC Drug Review in 1972. After publication of the final sunscreen
monograph in 1999, FDA published its TEA regulation (Sec. 330.14), (67
FR 3060 at 3074, January 23, 2002), which sets forth criteria and
procedures by which OTC drugs initially marketed in the United States
after the OTC Drug Review began and OTC drugs without any U.S.
marketing experience can be considered for inclusion in the OTC drug
monograph system. Congress later passed the SIA, which, among other
things, supplements FDA's TEA regulations for OTC sunscreen drug
products (21 U.S.C. 360fff through 360fff-7) (2014).
This proposed rule addresses the GRASE status (and conditions of
use applicable to) sunscreen drug products containing active
ingredients listed in the Stayed 1999 Final Monograph. It does not
address the pending sunscreen active ingredients that were originally
submitted under the procedures established in the TEA regulation and
are now being addressed through the SIA process.\10\ As discussed
further in section VII, however, the safety data we described as
necessary to evaluate the safety and effectiveness of sunscreen
products containing those active ingredients are the same as what we
are now describing as needed to establish that the active ingredients
listed in the Stayed 1999 Final Monograph are GRASE for use in
sunscreen products. We are not revisiting the contribution that the
active ingredients listed in the Stayed 1999 Final Monograph make to
the effectiveness of sunscreens. The Agency has not received
information suggesting that it is necessary to revisit its prior
decision about the effectiveness of the active ingredients at this
time.
---------------------------------------------------------------------------

\10\ FDA's proposed sunscreen orders on each of these
ingredients can be found at https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/ucm434843.htm.
---------------------------------------------------------------------------

V. Legal Authority

We are issuing this proposed rule under sections 201, 301, 501,
502, 503, 505, 510, 586E, 701, 702, 703, 704, and 721 of the FD&C Act
and under section 351 of the Public Health Service Act (42 U.S.C. 262).

VI. Need for Additional Safety Information

A. Increased Consumer Exposure to Sunscreen Active Ingredients

Consumer exposure to sunscreen active ingredients has increased
dramatically since FDA began its initial safety evaluations of the
sunscreen active ingredients at issue in this proposed rule. Many
factors have influenced this increase, including the following:

[[Page 6211]]

Significant increases in the number and types of consumers
using sunscreen products (Refs. 2 and 3)
Sunscreen products containing a greater number of active
ingredients at greater concentrations (Ref. 4)
Increased awareness of the risks of sun exposure and
encouragement of routine sunscreen use by medical and public health
authorities (see, e.g., Ref. 5)
Evolving directions for use on sunscreen products instructing
consumers to use greater amounts of sunscreen per application and to
reapply sunscreen products more frequently (76 FR 35672 at 35678),
codified as Sec. 201.327)
Expanding availability and use of many different types of
sunscreen products, including daily-use products such as facial makeup,
moisturizing creams, and lipstick

Relatively few sunscreen products were in use when the U.S. Army
initially funded research into the development of effective sunscreen
products for use by military personnel on aircraft carriers (and others
routinely exposed to long periods of intense sunlight) during World War
II (Ref. 2). The reach of sunscreen products began to broaden when they
were later marketed for use specifically by consumers who sunburned
readily (i.e., fair-skinned individuals) in situations of intentional
sun exposure, such as sunbathing on a beach (Ref. 6). Sunscreen
products are now routinely used by a much broader range of consumers
for protection against many types of sun-induced skin damage, not just
sunburn. Accumulating data demonstrate that increased sun exposure
increases the risk of developing skin cancers and premature skin aging
(Ref. 2). To help reduce the risk of these types of sun-induced skin
damage, public health organizations (including FDA) have for years
urged consumers to use sunscreen products along with other sun-
protective behaviors like limiting time in the sun and wearing
protective clothing (Refs. 7, 8, and 9).
Another factor driving increased consumer exposure to sunscreen
active ingredients has been the introduction and widespread adoption of
sunscreen products with higher labeled SPF values. The maximum SPF
value proposed for sunscreen labeling has progressively increased from
SPF 15 in the 1978 panel report, to SPF 30+ in the Stayed 1999 Final
Monograph, to SPF 50+ in the 2011 Max SPF PR. To achieve these higher
SPFs, many currently marketed products are formulated with more active
ingredients combined together in higher concentrations than were
generally combined in products when FDA's review of OTC sunscreens
began. Increased knowledge about the role of UVA radiation in causing
skin damage has also encouraged the formulation of broad spectrum
products with combinations of active ingredients designed to achieve
protection against both UVA and UVB radiation. In addition, other
widely used products, such as facial makeup, moisturizing creams, and
lipsticks, have had sunscreen active ingredients added to their
formulations. These trends are reflected in the evolution of the
current labeling provisions for sunscreen products regulated under the
OTC monograph system.
Changes in the instructions for using these sunscreen products have
also contributed to increased use of, and exposure to, sunscreen active
ingredients. The labeling recommended by the advisory panel in 1978
simply instructed consumers to apply sunscreen products liberally and
to reapply after swimming or excess perspiration (43 FR 38206 at
38215). The labeling currently required, by contrast, encourages
consumers to always use a broad spectrum SPF 15 or higher product, to
use sunscreen products regularly, and to apply them generously/
liberally 15 minutes before sun exposure and at least every 2 hours or
more frequently when swimming or sweating (Sec. 201.327(e)).

B. Emerging Safety Concerns

In recent years, a growing body of data has suggested that the
transdermal absorption of some sunscreen active ingredients is greater
than previously thought, and thus may raise previously unevaluated
safety concerns, including the potential for reproductive,
developmental, or carcinogenic effects. As discussed in further detail
in section VIII.C.1.a, newly available information suggests, for
example, that there is the potential for toxicity associated with the
transdermal absorption and systemic availability of oxybenzone. This
new information about absorption and potential safety risks is
inadequate, by itself, to support an affirmative conclusion that
products containing the active ingredients at issue are not safe.
Coupled with the lack of clinical pharmacology and nonclinical safety
data for certain sunscreen active ingredients, however, it leads us to
conclude that, for some sunscreen active ingredients, the current
record does not include adequate evidence of safety to satisfy the
applicable legal standards for general recognition of safety and
effectiveness as set forth in Sec. 330.10.

VII. Framework for Evaluation of Safety Data

In light of these safety concerns, FDA held a meeting of its
Nonprescription Drugs Advisory Committee (NDAC) on September 4 and 5,
2014, to discuss the scope of safety testing that should be conducted
to support general recognition of safety and effectiveness for active
ingredients for use in nonprescription sunscreen products. FDA proposed
the following safety testing paradigm:

Clinical data:
Dermal irritation and sensitization testing
Phototoxicity and photoallergenicity testing
Human maximal use bioavailability studies
Postmarketing adverse event reports
Nonclinical (toxicology) data:
Dermal carcinogenicity
Systemic carcinogenicity
Developmental and reproductive toxicity (DART)
Toxicokinetics
Additional testing when data suggest a concern about other
long-term effects, such as endocrine effects

There was consensus among the committee members that FDA's proposed
framework was a good starting point (Ref. 10). In November 2015, FDA
published a draft guidance for industry, ``Over-the-Counter Sunscreens:
Safety and Effectiveness Data'' (Draft Safety and Effectiveness Data
Guidance) (see 80 FR 72975, November 23, 2015), which described and
requested comment on the safety and effectiveness data necessary to
determine whether an OTC sunscreen active ingredient or combination of
active ingredients evaluated under the SIA was GRASE when used under
specified conditions. FDA finalized this guidance in November 2016,
after considering public comment on its draft recommendations (Ref.
11).\11\ The recommendations in this guidance reflect FDA's scientific
expertise, existing technical guidance, experience from reviewing
safety and efficacy data submitted for GRASE review of sunscreen active
ingredients under the OTC Drug Review, and input from and

[[Page 6212]]

concurrence by outside scientific experts.
---------------------------------------------------------------------------

\11\ FDA's recommendations regarding the safety and
effectiveness data necessary to determine whether an OTC sunscreen
active ingredient (or combination of ingredients) evaluated under
the SIA was GRASE when used under specified conditions generally
remained unchanged in the final guidance.
---------------------------------------------------------------------------

All sunscreens marketed without an NDA are subject to the same
standard: General recognition of safety and effectiveness. Accordingly,
as noted previously, the data that we expect to be necessary to
evaluate the safety and effectiveness of the sunscreen monograph active
ingredients are the same as those we recommended as necessary to
evaluate the safety and effectiveness of sunscreen active ingredients
previously considered under the procedures established in the TEA
regulation and now being considered pursuant to the framework
established by the SIA (see Safety and Effectiveness Data Guidance
(Ref. 11)).
The studies described in this section are generally needed for FDA
to determine that a sunscreen active ingredient is GRASE for use in
nonprescription sunscreens. Specific data gaps for individual active
ingredients depend on the quality and quantity of available safety
data, and are identified in section VIII. As described in that section,
those active ingredients for which the existing public record contains
sufficient data to support a positive GRASE finding are proposed as
Category I. Those for which additional data are necessary are proposed
as Category III. In addition, in evaluating the existing safety data
for the active ingredients listed in the Stayed 1999 Final Monograph,
FDA determined that the risks associated with two of these ingredients
outweigh their benefits. As discussed in further detail in section
VIII.B, FDA is therefore proposing that these two ingredients are
Category II because sunscreens containing these ingredients would not
be GRASE.

A. General

FDA's OTC drug regulations identify the general types of safety
information that should be submitted as evidence that an OTC drug is
GRASE for use as labeled (Sec. 330.10(a)(2)) and the standard by which
safety is to be judged (Sec. 330.10(a)(4)(i)). When applying these
regulations to each drug, 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'' (Sec. 330.10(a)(4)(i)).
FDA recognizes the contribution that broad spectrum sunscreens with
an SPF value of 15 or higher can make to decreasing the risk of skin
cancer and early skin aging caused by the sun if used as directed with
other sun protection measures. To protect the public health, however,
it is also important for FDA to balance the potential benefits of these
sunscreen products to consumers against their potential risks.
Providing an adequate safety margin for OTC sunscreen active
ingredients and finished sunscreen products is a key element of FDA's
risk assessment. A safety margin calculation takes the highest animal
NOAEL and estimates a maximum safe level of exposure for humans.
Because animal studies do not always predict effects in humans, the
actual threshold for an effect in humans may be different (i.e., higher
or lower) than in the species tested. The human sensitivity to a drug
is often unknown. To account for this, the predicted safe exposure
level in humans that is reflected in the safety margin is well below
where toxicities were seen in animals.
In determining the specific testing and other data needed to
adequately demonstrate that an OTC sunscreen active ingredient is safe,
FDA considers both the circumstances under which OTC sunscreen products
are intended to be used by consumers (i.e., the conditions of use) and
current scientific knowledge and assessment technology. FDA's approach
to the clinical safety evaluation of OTC sunscreen active ingredients
is based on our current scientific understanding regarding safety
evaluation of topical drug products for chronic use, and thus is
generally consistent with the safety data requirements that would apply
to an NDA for a chronic-use topical drug product (i.e., topical safety
studies (irritation, sensitization, and photosafety); bioavailability
(absorption); and evaluation of adverse events observed in clinical
studies).\12\ In addition, the evaluation of adverse events reported
during the commercial marketing of sunscreen products containing the
ingredient and other postmarketing safety information is also relevant
to safety.
---------------------------------------------------------------------------

\12\ Chronic use is defined as continuous or intermittent use
for at least 6 months during the course of a lifetime.
---------------------------------------------------------------------------

FDA's approach to the nonclinical safety evaluation of these active
ingredients takes into account their lengthy marketing history in the
United States. In contrast to nonclinical data requirements for a
chronic-use topical drug product NDA, which include results from
comprehensive nonclinical pharmacology and toxicology safety testing,
the approach to nonclinical safety testing in this proposed rule is
largely focused on potential long-term adverse effects or effects not
otherwise readily detected from human use (i.e., carcinogenicity and
reproductive toxicity). Additional testing beyond what is described
below may be recommended for active ingredients for which data suggest
a concern about other long-term effects, such as hormonal disruption.
In addition, although sunscreen products are typically formulated
with two or more active ingredients, the framework described below
contemplates that testing will be performed using formulations that
include one active ingredient. Generally, unless data suggest that
there may be a safety or efficacy concern with a particular combination
of active ingredients, we anticipate that an active ingredient that is
found to be GRASE for use in sunscreens could be combined with other
active ingredients that are also GRASE for use in sunscreens. If data
suggest that there may be a safety or efficacy concern with a
particular combination of active ingredients (or active and inactive
ingredients), additional data may be necessary to support a positive
GRASE determination for sunscreens containing that combination.
The following sections describe the specific safety data that FDA
expects the Agency will need to determine whether an active ingredient
is GRASE for use in sunscreens.

B. Clinical Safety Testing

1. Human Dermal Safety Studies
Human dermal safety studies for topical products in which exposure
to light after application is anticipated generally consist of two sets
of studies--those conducted without specific exposure to light and
those conducted to assess reactions after UV exposure (photosafety
studies) (Ref. 12). The studies usually consist of dermal irritation
patch testing, dermal sensitization patch testing, dermal phototoxicity
testing, and dermal photoallergenicity testing.
Because marketed sunscreen products typically contain a combination
of active ingredients, and product formulations frequently change, it
is difficult to determine causal links between individual active
ingredients and reported irritation and hypersensitivity adverse events
associated with a particular product. Therefore, FDA generally expects
to use data from human dermal irritation studies, human dermal
sensitization studies, and human dermal photosafety studies, in
conjunction with postmarketing adverse event data, to inform GRASE
determinations and labeling. Nonetheless, in some cases, it may be
reasonable to omit human

[[Page 6213]]

dermal irritation studies, human dermal sensitization studies, and/or
human dermal photosafety studies, depending on the rigor of available
postmarketing safety information. For example, if FDA concludes that
there is a positive risk-benefit profile for a sunscreen active
ingredient, but that it is known to be a sensitizer, it may be possible
to develop safety labeling to address this risk without data generated
in the human dermal safety studies described below (see, e.g., section
VIII.C.1.a).
a. Human dermal irritation and sensitization studies. Studies of
dermal irritation and sensitization, using the repeat insult patch test
or other relevant tests, are elements in the safety evaluation of
topical drug products that, like sunscreens, are applied to the skin
repeatedly over long periods of time. Designed to detect the potential
for local dermatologic events with fewer subjects than might be
observed in larger clinical trials, these tests often employ product
application that is more frequent and/or for longer duration than
proposed clinical dosing. In dermal irritation studies, a test
substance is applied to a small pad (patch) and affixed to the test
subject's skin, usually on the back, to determine whether the
ingredient causes direct skin toxicity. Dermal sensitization studies
are conducted similarly but are designed to detect immunologically
mediated reactions, which require prior exposure to the allergen.
Nonprescription sunscreens regulated under the OTC monograph system
may be used in many product formulations, including those yet unknown.
Therefore, cumulative irritation studies that evaluate the sunscreen
active ingredient at the highest concentration for which a GRASE
determination is sought should be conducted using the ingredient in an
appropriate vehicle, using the vehicle alone, and using both negative
and positive controls. The evaluation should include scoring of
erythema, edema, and a papular response or skin erosion.
Dermal sensitization studies, conducted to detect immunologically
mediated reactions, should be conducted in three phases: (1) The
induction phase (3 weekly applications for 3 weeks); (2) the rest phase
(no product application for 10 to 14 days); and (3) the challenge phase
(patch applications to new sites for 48 hours with a confirmatory
rechallenge to exclude false positives).
Although FDA recommends separate dermal irritation and
sensitization studies, it may be appropriate to combine irritation and
sensitization studies in the same study as long as a sufficient number
of subjects are included for sensitization evaluation.
b. Human photosafety studies. Topically applied dermatologic drug
products should be tested for photosafety if they absorb light in the
UVA, UVB, or visible spectra. Photosafety evaluations of sunscreen
active ingredients that absorb light should consist of skin
photoallergenicity and skin phototoxicity testing. Photoallergy is an
immunologically mediated reaction to a chemical, initiated by the
formation of photoproducts (e.g., protein adducts) following a
photochemical reaction. Similar to dermal sensitivity testing described
above, photoallergy tests use an induction/rest/challenge/rechallenge
multiphase design to assess erythema, edema, and vesiculation.
Phototoxicity (or photoirritation) is an acute light-induced tissue
response to a photoreactive chemical. Phototoxicity testing typically
includes a test patch, a vehicle patch, and a sham patch application
for 24 hours, followed by UV light exposure of the test area. A second
set of patch application areas not irradiated with light serves as a
control. FDA expects that, to support a GRASE finding, photosafety
studies of sunscreen active ingredients that absorb light will need to
be conducted using the active ingredient at the highest concentration
for which a GRASE determination is sought in an appropriate vehicle,
using the vehicle alone, and with a negative control.
2. Human Absorption Studies/Maximal Usage Trial
Because nonprescription sunscreens are topically applied, a
critical safety consideration is whether dermal application results in
skin penetration and systemic exposure to their active ingredients and,
if so, to what extent. This information helps identify potential safety
concerns and helps determine whether an adequate safety margin exists
within which an active ingredient is GRASE for use in sunscreens.
The principal barrier to topical drug product penetration is the
multilayered, lipid-rich stratum corneum. The passage of any drug
product through this layer is influenced by many factors, including the
drug product's physicochemical features, molecular weight, and vehicle/
formulation properties. Vehicle/formulation properties are particularly
important because the choice of vehicle can markedly affect the
permeation potential of a drug product. Effects can range from simple
hydration of the stratum corneum by occlusive vehicles/formulations to
direct permeation enhancement by solvent effects on the lipids in the
stratum corneum. Products absorbed through the skin have the potential
to cause systemic adverse effects, affecting the safety assessment.
Because sunscreens are intended to work at the skin's surface, systemic
absorption may also lower efficacy, affecting the efficacy assessment.
Such considerations ultimately weigh into the risk-benefit calculus FDA
uses to determine whether an OTC sunscreen containing a given active
ingredient is GRASE.
Since the mid-1990s, topical product NDAs have included a Maximal
Usage Trial (MUsT) as part of the clinical pharmacology/bioavailability
assessment. A MUsT is designed to capture the effect of maximal use on
absorption into the blood with standard pharmacokinetic assessments
(e.g., Cmax, Tmax,\13\ area under the curve,
half-life, clearance, and volume of distribution) (for further
information about conduct of a MUsT, see Ref. 13). For a topical
product NDA, the MUsT is usually conducted in subjects with the disease
of interest, where disrupted skin is a feature. In situations where
disrupted skin is not a feature of the condition being treated or the
topical product is intended for prevention of disease (e.g.,
sunscreens), the MUsT for a topical product NDA should be conducted in
subjects with healthy, intact skin. The MUsT for a topical product NDA
is conducted with the specific product formulation for which approval
is sought applied at the upper limit of surface area involvement that
is studied in the phase 3 clinical trials and is proposed for labeling.
For example, if the proposed labeling of an acne product permits the
product to be used on up to 30 percent of body surface area, that would
be the coverage evaluated in the MUsT.
---------------------------------------------------------------------------

\13\ Cmax is the peak plasma concentration and
Tmax is the time to peak plasma concentration.
---------------------------------------------------------------------------

We expect that data from a MUsT will be needed to support an
adequate assessment of safety for most sunscreen active ingredients
(Ref. 10). Because sunscreen products regulated pursuant to the OTC
monograph system may include active ingredients in a variety of
formulations, FDA recommends that a MUsT be conducted under maximal use
conditions employing a minimum of four formulations, containing the
sunscreen active ingredient as the only active ingredient.\14\ These
formulations

[[Page 6214]]

should be prepared using vehicle/formulation systems that are
appropriate for sunscreen topical products (e.g., they are deployable
and spreadable) that represent real-world marketed formulations, and
that are expected to produce the highest in vivo absorption.
Justification for the formulations chosen, including results of in
vitro testing using a human cadaver skin permeation system (e.g.,
static cell, also known as vertical diffusion cell) (Refs. 14 and 15),
should be included in the study protocol. The protocol should contain
sufficient detail for others to reproduce the formulations and
manufacturing process.\15\
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\14\ We note, however, as described in section VIII.C.1.b, that
because of avobenzone's potential for photodegradation, we recommend
that a MUsT for avobenzone evaluate avobenzone in combination with a
photostabilizer. In some cases, sunscreen active ingredients (e.g.,
octocrylene) can serve as photostabilizers. In such cases, we expect
that the MUsT could include such ingredients.
\15\ FDA has issued draft guidance with recommendations for the
conduct of MUsT studies to support the safety of active ingredients
that are candidates for inclusion in a topical drug product under an
OTC Drug monograph (Ref. 16). When finalized, this guidance will
represent FDA's current thinking on this topic. FDA also encourages
persons who are interested in conducting a MUsT to support the
safety of an active ingredient to discuss proposed protocols with
the Agency.
---------------------------------------------------------------------------

FDA anticipates that the use of multiple formulations will help
identify the overall absorption potential of the sunscreen active
ingredient of interest. The MUsT should be conducted in subjects with
healthy, intact skin \16\ at the highest concentration of the
ingredient for which a GRASE determination is sought. Based on
recommended sunscreen use on all exposed skin, the exposed area should
include at least 75 percent of the body surface area. Data from the
formulation that produces the highest in vivo absorption would then be
used to determine the safety margin.
---------------------------------------------------------------------------

\16\ As discussed infra, the MUsT should be conducted on
healthy, intact skin because sunscreens are intended for prevention
rather than treatment.
---------------------------------------------------------------------------

The assay used in the MUsT should be properly validated according
to current good laboratory practices (21 CFR part 58). Additionally,
the Agency's most current guidance on bioanalytical method validation
may be found by searching at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. The assay's limit of quantitation-limit of
detection should be sufficiently low to allow a signal-to-noise ratio
that ensures confidence in detection of a concentration of 0.5 nanogram
(ng)/milliliter (mL) for the compound of interest in the receptor
fluid.
An important consideration for designing a MUsT is that it should
include testing for a duration that allows for the attainment of steady
state levels to ensure that maximum penetration of the ingredient has
taken place and to optimize the chances of the ingredient being
detected. Thus, for sunscreen active ingredients, FDA expects that
single application studies would be inadequate. Because the subjects in
a MUsT represent an enriched dataset in the upper range of exposures,
safety-related data (such as vital signs, adverse events) from the
study's regularly scheduled physical examinations should also be
collected. We strongly encourage consultation with FDA about MUsT
protocols before beginning the trial.
Finally, as discussed further in section VIII.D, if the sunscreen
active ingredient is determined to be GRASE for use in sunscreens, the
sunscreen monograph, when finalized, must set out the conditions under
which any future sunscreen containing that active ingredient will be
GRASE and not misbranded. As such a condition, FDA is considering
certain final formulation testing to address the potential for
transdermal absorption and its impact on safety. FDA anticipates that
the formulation that produces the highest in vivo absorption in the
MUsT would be appropriate to designate as a standard control
formulation for future in vitro human cadaver skin permeation system
testing (e.g., a static or vertical diffusion cell) of each final
sunscreen formulation that includes that active ingredient. If such
testing were included as a condition in a final sunscreen monograph,
and if in vitro permeation of the sunscreen active ingredient in the
final product formulation were equal to or less than the value from in
vitro testing of the standard control formulation (that was shown by
the MUsT to have the highest degree of systemic absorption), FDA
anticipates that the safety margin previously calculated would be
considered adequate to support the safety of the finished formulation.
3. Pediatric Considerations
Young children have a larger ratio of skin surface to body volume
than adults, which can increase a child's systemic exposure to
topically applied drug products. In addition, growing children have
greater potential to experience deleterious developmental effects from
drug exposure. If the calculated safety margin for an active ingredient
(based on nonclinical results and human MUsT) is relatively small, FDA
will exercise its scientific judgment to determine whether a sunscreen
active ingredient MUsT in young children or other studies are warranted
to ensure that the safety margin for marketed products containing the
ingredient is within an acceptable range for this population.

C. Nonclinical Safety Testing

1. Carcinogenicity Studies: Dermal and Systemic
FDA generally recommends carcinogenicity studies for any
pharmaceutical with an expected clinical use (either intermittent or
continuous) of at least 6 months (Ref. 17). The animal carcinogenicity
studies help characterize the potential tumor risks associated with use
of a sunscreen active ingredient in human beings by identifying any
observed tumors by type, the level of exposure at which tumors occur,
and the highest level of exposure at which no adverse effects occur,
referred to as the NOAEL. As noted earlier, FDA intends to use the
NOAEL in determining the safety margin for human exposure to sunscreens
containing the active ingredient. In addition to detecting carcinogenic
potential, carcinogenicity studies in animals can also help to identify
other systemic or organ toxicities that may be associated with the
sunscreen active ingredient.
FDA expects that a dermal carcinogenicity study involving
application of the test article to the skin of mice or rats for 2 years
will thus need to be conducted to support a GRASE finding for the
active ingredient unless the ingredient has been demonstrated not to
reach the viable layers of the skin where it could impact skin tumor
development. FDA also considers it important to study the effects of
systemic exposure if human bioavailability data show that dermal
application of a particular formulation results in skin penetration and
systemic exposure to the active ingredient. Therefore, we expect that a
second carcinogenicity study by a route that produces systemic exposure
will also be needed to support the safety of a sunscreen active
ingredient, if systemic exposure is observed in the bioavailability
data. This can be a 2-year study or a shorter (usually 6 months)
alternative carcinogenicity model, and it should be conducted in a
species different from that used in the dermal carcinogenicity study.
FDA notes that the absence of a carcinogenicity signal from an
alternative transgenic carcinogenicity study (e.g., TgRasH2 mouse)
would likely support the safety of a sunscreen active ingredient. If a
carcinogenicity signal were observed in such a study, however, the
study could not be used to support the safety of a sunscreen active
ingredient because there would be no basis for calculating

[[Page 6215]]

a safety margin with this study (Ref. 18). All carcinogenicity studies,
regardless of route, should assess a full panel of tissues.\17\
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\17\ FDA recommends submitting the carcinogenicity study
protocol(s) for review by FDA's Center for Drug Evaluation and
Research's (CDER's) Executive Carcinogenicity Assessment Committee
before initiating the studies. For further guidance regarding
carcinogenicity studies, see the FDA guidance for industry
``Carcinogenicity Study Protocol Submissions,'' May 2002 (available
at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm078924.pdf).
---------------------------------------------------------------------------

FDA expects that a systemic carcinogenicity study would not be
needed to support a GRASE determination for a sunscreen active
ingredient if an adequately conducted human pharmacokinetic MUsT
resulted in a steady state blood level less than 0.5 ng/mL, and an
adequately conducted toxicology program did not reveal any other safety
signals for the ingredient or any known structurally similar compound
indicating the potential for adverse effects at lower levels. The
threshold value of 0.5 ng/mL is based on the assessment that the level
would approximate the highest plasma level below which the carcinogenic
risk of any unknown compound would be less than 1 in 100,000 after a
single dose. This threshold value is consistent with the Threshold of
Toxicological Concern concept, which was applied to impurities in the
ICH guidance for industry ``M7 Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals to Limit Potential
Carcinogenic Risk'' (Ref. 19). FDA expects that the 0.5 ng/mL
concentration will be sufficiently above the assay's limit of
quantitation--limit of detection to allow a signal-to-noise ratio that
ensures confidence in either the derived concentrations (in the case of
``exaggerated'' values) or lack of concentrations.
2. Developmental and Reproductive Toxicity Studies
FDA expects that DART studies will need to be conducted to evaluate
the potential effects that exposure to the sunscreen active ingredient
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 (Ref. 20). As with systemic
carcinogenicity studies, we expect that studies to assess fertility and
early embryonic development, and pre- or postnatal toxicity in rats
will not be needed if an adequately conducted human MUsT shows a steady
state blood level less than 0.5 ng/mL, and an adequately conducted
toxicology program produces no signals indicating that the ingredient
(including its clinically relevant metabolites) or any known
structurally similar compound interacts with related pathways.\18\ We
expect that effects on embryofetal development will need to be assessed
in rats and rabbits in all cases.
---------------------------------------------------------------------------

\18\ Examples of such pathways could include endocrine function
and signaling pathways related to growth and development.
---------------------------------------------------------------------------

Gestational and neonatal stages of development may be particularly
sensitive to active ingredients with hormonal activity (endocrine
disruption). For this reason, these studies should 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 on
the developing offspring. Behavioral assessments (e.g., mating
behavior) of offspring, which may detect neuroendocrine effects, should
also be performed (Ref. 21).
3. Toxicokinetics (Ref. 22)
Animal toxicokinetic data should also be collected for sunscreen
active ingredients, as these data provide an important bridge between
toxic levels seen in animal studies and any potential human adverse
events associated with systemic exposure to the sunscreen's active
ingredient. Toxicokinetic measurements are usually obtained during the
course of ongoing nonclinical toxicity studies, such as carcinogenicity
or DART studies, rather than through separate studies.

D. Postmarketing Safety Data

In addition to the active ingredient safety data already described,
FDA's GRASE evaluation also takes into consideration publicly available
information about serious adverse drug experiences and known or
expected adverse effects associated with commercially marketed products
that contain the active ingredient(s) under consideration.

E. Sunscreens Containing Nanomaterials

We note that FDA is not proposing to categorically classify
sunscreen products manufactured using nanotechnology (or containing
nanomaterials) as GRASE or not GRASE solely based on this
characteristic. Nanotechnology is used to create, explore, or
manipulate materials measured in nanometers (nm) (billionths of a
meter), and has applications in a wide range of products, including OTC
sunscreens. Such materials generally have dimensions between
approximately 1 and 100 nm (Ref. 23). Materials at such small sizes can
have different chemical or physical properties or biological effects
compared to larger-scale counterparts, making possible a variety of
functional effects, and also potentially affecting the safety,
effectiveness, or regulatory status of FDA-regulated products.
FDA has not established regulatory definitions of nanotechnology,
nanomaterial, nanoscale, or other related terms. As described in FDA's
guidance for industry ``Considering Whether an FDA-Regulated Product
Involves the Application of Nanotechnology'' (Nanotechnology
Considerations Guidance) (Ref. 24), at this time, when considering
whether an FDA-regulated product involves the application of
nanotechnology, FDA asks
(1) Whether a material or end product is engineered to have at
least one external dimension, or an internal or surface structure, in
the nanoscale range (approximately 1 nm to 100 nm).
In addition, because materials or end products can also exhibit
related properties or phenomena attributable to a dimension(s) outside
the nanoscale range of approximately 1 nm to 100 nm that are relevant
to evaluations of safety, effectiveness, performance, quality, public
health impact, or regulatory status of products, we will also ask:
(2) Whether a material or end-product is engineered to exhibit
properties or phenomena, including physical or chemical properties or
biological effects, that are attributable to its dimension(s), even if
these dimensions fall outside the nanoscale range, up to 1 micrometer
([micro]m) (1,000 nm).
We will apply these considerations broadly to all FDA-regulated
products, including sunscreen products. For the purpose of this
proposed rule, we use the term ``nanomaterial'' generally to refer to
materials falling within either point 1 or 2 above. The use of this
term in this manner is consistent with its use in FDA's nanotechnology-
related guidances, including FDA's Nanotechnology Considerations
Guidance.
Nanomaterial forms of the active ingredients zinc oxide and
titanium dioxide have been used in marketed OTC sunscreens. In addition
to nanomaterial forms of zinc oxide and titanium dioxide, other
nanomaterials are also reported to have been used, or promoted or
studied for possible use, in sunscreen products (Ref. 25).

[[Page 6216]]

As discussed in further detail in section VIII.A, having examined
the scientific information in the record, including for nanomaterial
forms of zinc oxide and titanium dioxide, FDA is not now proposing
conditions of use for these two active ingredients under the sunscreen
monograph that distinguish nanomaterials from other forms of these
ingredients. As indicated above, FDA also does not propose to
categorically classify sunscreen products that are manufactured using
nanotechnology or contain nanomaterials as GRASE or not, solely on that
basis. Manufacturers of products containing nanomaterials marketed
under the OTC sunscreen monograph remain responsible for ensuring that
the product satisfies all applicable legal requirements. FDA encourages
manufacturers of such products to consult with FDA to facilitate a
mutual understanding of specific scientific or regulatory issues
relevant to their product.
FDA invites comment on the following topics:

Specific nanomaterials or types of nanomaterials that have
been used or proposed for use in OTC sunscreen products
Concerns about sunscreen product safety, effectiveness, or
quality associated with the use of nanomaterials in OTC sunscreen
products, with supporting data
Need for, and proposals of, specifications or limitations for
particular nanomaterials for use in OTC sunscreen products
Any particular nanomaterials that you believe should not be
permitted for use in OTC sunscreen products, along with supporting
scientific information
FDA's proposed regulatory approach and/or alternative
regulatory approaches to the use of nanomaterials in OTC sunscreen
products

VIII. Existing Safety Data for Sunscreen Active Ingredients

In the remainder of this section, we discuss the existing data and
data gaps for each of the sunscreen monograph active ingredients and
explain why we propose that these active ingredients are GRASE or not
GRASE for use in sunscreens. Those ingredients for which the existing
data are sufficient to support a positive GRASE determination are
proposed as Category I. Those ingredients for which additional data are
necessary before a GRASE determination can be made are proposed as
Category III. In cases where FDA's evaluation of the existing safety
data caused us to determine that the risks associated with the
ingredients outweigh their benefits, the ingredients are proposed as
Category II.

A. Ingredients Proposed as Category I

Based on our review of the publicly available data for these
ingredients, both zinc oxide and titanium dioxide are proposed as
Category I.
1. Zinc Oxide
Our review of the scientific literature, submissions to the
sunscreen monograph docket, and adverse event reports submitted to
FAERS has produced sufficient safety data on zinc oxide to support a
proposal that a sunscreen containing up to 25 percent zinc oxide would
be GRASE under the conditions proposed in this rulemaking and the
general conditions required in part 330. This proposal is based in
significant part on the existing, substantial evidence that zinc oxide
(including particles on the nanoscale, i.e., approximately 1 to 100 nm)
does not penetrate into or through human skin to any great extent and,
to the extent any de minimis penetration occurs, does not result in
adverse health effects, given the high levels of endogenous zinc in the
human system.
a. Background. Zinc oxide is an inorganic, mineral compound.
Because of its ability to reflect UVA wavelengths, zinc oxide is
frequently used in sunscreens to help establish broad spectrum
protection (Ref. 26). While larger particles of zinc oxide used in
sunscreens (greater than approximately 100 nm) may impart an opaque,
white color to the product, zinc oxide is also manufactured in smaller
particle sizes (less than approximately 100 nm) to reduce this white/
opaque appearance (Refs. 27 and 28). In addition to its use in
sunscreens, zinc oxide is also used in non-sunscreen ointments, pastes,
and lotions for various skin disorders because of its protective,
astringent, and antiseptic properties (Ref. 29).
b. Discussion. Zinc oxide is insoluble in water and largely
insoluble in biological fluids.\19\ This insolubility precludes the
possibility of its systemic absorption from topical application of
sunscreen products beyond a de minimis amount, even if zinc oxide is
included at its maximum eligible concentration of 25 percent and
regardless of the formulation of the product. The available studies on
the dermal penetration of zinc oxide, further discussed below, confirm
that its penetration--regardless of particle size--is primarily limited
to the upper layers of the non-living stratum corneum, with most
penetration occurring only into skin folds and furrows or hair
follicles. These studies show that zinc oxide particles do not
penetrate down into the viable dermis to any significant extent. Any de
minimis transdermal penetration that may occur does not result in
adverse health effects, because the tiny amount of zinc oxide particles
that achieve transdermal absorption, if any, would dissociate into zinc
and oxygen ions, both of which are naturally occurring elements in the
human body (Ref. 30). Zinc is the 14th most common element in the human
body and is essential for all living things; the average human body
contains about 2.0 to 2.5 grams of zinc, and normal dietary intake of
zinc is about 15 milligram (mg) per day (Refs. 30 and 31). Homeostatic
mechanisms in the body regulate zinc's absorption, distribution,
cellular uptake, and excretion (Ref. 31). Similarly, any oxygen
absorbed through the skin is nonharmful, as oxygen is plentiful in the
human body and essential for life.
---------------------------------------------------------------------------

\19\ We note that nanoscale zinc oxide can be solubilized to a
small extent in the presence of phosphate and lecithin at pH's that
are achievable on the skin. Even under these conditions, however,
the amount potentially absorbed is de minimis and far lower than
daily nutritional intake of zinc.
---------------------------------------------------------------------------

Our search of the literature on zinc oxide revealed four recent
studies about zinc oxide's penetration into human skin, which confirm
our expectations based on the physical properties of this compound. The
first two studies (conducted by Leite-Silva et al. and Darvin et al.)
examined the penetration of zinc oxide into the skin using multiphoton
tomography (Refs. 32 and 33). Both studies showed a lack of overall
permeation of zinc oxide beyond a few cell layers, except in the case
of furrows and wrinkles (Refs. 32 and 33). The second two studies--a
pilot and subsequent full trial conducted by Gulson et al.--evaluated
the penetration of nanoscale zinc oxide into the skin and the
bloodstream using a stable isotope tracing method (Refs. 34 and 35).
Although the Gulson studies found that a minimal amount of topically
applied zinc was absorbed, the absorption observed was at levels that
are orders of magnitude less than daily nutritional intake and well
below what would be of concern for a naturally occurring element in the
body subject to homeostatic mechanisms (Ref. 36). An additional porcine
study found (as discussed in our 2012 response to a citizen petition
submitted by the International Center for Technology Assessment and
others (Docket No. FDA-2006-P-0213-0003) (ICTA Petition Response)),
that although sunburn caused by UVB rays increased the penetration of
zinc oxide into the

[[Page 6217]]

non-living stratum corneum, there remained minimal penetration of zinc
oxide into the epidermal and dermal layers of the skin (Ref. 37).
Because topically applied zinc oxide particles do not enter systemic
circulation to any meaningful extent, we do not consider a MUsT to be
necessary to support the safety of this ingredient.
In addition to the studies described above, we also located two
studies evaluating the clinical safety of topically applied zinc oxide
in which zinc oxide (25 percent) was used as a medicated occlusive
dressing on the lower arms of healthy volunteers (Refs. 38 and 39). In
these studies (which were designed to maximize potential absorption and
identify any resulting adverse events), even with the increased dermal
or epidermal zinc levels resulting from occlusion, there still were no
adverse skin events. Our review of the available human dermal safety
studies on zinc oxide \20\ also identified data showing that test
material containing up to 25 percent zinc oxide did not induce human
irritant, photoirritant, allergic, or photoallergic reactions. No human
pathological phototoxicity or significant human photosensitization
reaction indicative of skin irritation were noted either. The
literature supporting the safety of skin protectant drug products
containing zinc oxide \21\ reinforce these clinical safety findings.
Our review in this area is also consistent with the conclusion of the
European Commission's Scientific Committee on Consumer Safety that the
use of nanoscale zinc oxide in sunscreens at a concentration of up to
25 percent does not pose a risk of adverse effects in humans after
topical application (Ref. 40).
---------------------------------------------------------------------------

\20\ This literature included three clinical safety studies
conducted by Hill Top Research, Inc. for Procter & Gamble regarding
(a) human sensitization (Study Reports 96-6635-76a and 96-6635-76b);
(b) human photoirritation/phototoxicity (Study Report 96-6634-76);
and (c) human photoallergenicity (Study Report 96-6633-76). See
Citizen Petition submitted by Proctor & Gamble, June 24, 1997 (FDA-
1978-N-0018-0639) and the ``Opinion concerning Zinc Oxide'' drafted
by the European Commission, Scientific Committee on Cosmetic
Products and Non-Food Products Intended for Consumers (SCCNFP),
which included five summaries of human clinical safety studies, all
evaluating zinc oxide 25 percent (Ref. 40).
\21\ See, e.g., Beeckman et al. (Ref. 41); 43 FR 34628 at
34641(August 4, 1978) (discussing use of zinc oxide 1 percent to 25
percent as a skin protectant active ingredient: ``Zinc oxide is
widely recognized as a skin protectant'' and ``No reports of topical
toxicity were found in the literature'' on zinc oxide).
---------------------------------------------------------------------------

A very small number of rash and hypersensitivity reports for
sunscreens containing zinc oxide were located in FAERS. With a single
exception, the sunscreens involved contained two or more active
ingredients, making it difficult to attribute causation to a specific
active ingredient. Unlike other sunscreen ingredients with a known
hypersensitivity risk, we did not identify any reports in FAERS or in
the literature with features suggestive of a causative link, such as
skin test results positive for zinc oxide. In addition, there is an
extremely large safety database of zinc oxide use in other topical
products, including for the treatment of diaper rash in infants. This
corroborates the negative results in human studies for irritation,
photoirritation, allergy, and photoallergy that support our proposed
finding regarding the safety of sunscreens containing this ingredient
under the conditions proposed. Reports of non-hypersensitivity-related
clinical safety issues with zinc oxide were infrequent and not serious.
For these reasons, we do not consider additional clinical studies
(including photosafety, irritation, or sensitization studies) to be
necessary for this ingredient.
Dermal carcinogenicity studies have not been conducted for zinc
oxide. In general, as discussed in section VII.C.1, adequate tests for
safety of an active ingredient for use in topical products for chronic
use (such as a sunscreen) would need to include dermal carcinogenicity
studies if the active ingredient reaches the viable layers of skin
where it could have a biological effect. Given the minimal penetration
of zinc oxide below the non-living stratum corneum, there is no
plausible mechanism by which zinc oxide could have an effect on skin
tumor development. We are therefore proposing to find that zinc oxide
is GRASE for use in sunscreens despite the lack of dermal
carcinogenicity studies studying this ingredient.
Based on the minimal systemic exposure resulting from dermally
applied zinc oxide, in particular when compared to endogenous zinc
levels, we see no need for further nonclinical studies to support the
safety of sunscreens containing zinc oxide, including systemic
carcinogenicity studies, developmental and reproductive toxicity
studies, or toxicokinetic studies.\22\
---------------------------------------------------------------------------

\22\ Our review of the available nonclinical safety literature
on zinc oxide included references for a 90-day dermal toxicity
study, genotoxicity, and limited developmental and reproductive
toxicity information. The review of this literature suggests that
genotoxicity, findings for zinc oxide are mixed, and that there is
minimal dermal toxicity in rodents after 90 days. (See Refs. 42 and
43.) Oral rat embryofetal toxicity studies showed some adverse
maternal and fetal effects, but only at very high doses (>200 mg/kg/
day) significantly higher than what is at issue here (Refs. 44 and
45).
---------------------------------------------------------------------------

c. Conclusion. Our review of the available data from both animal
and human studies and data on physical properties such as solubility
leads us to conclude that the transdermal absorption of zinc oxide--
regardless of particle size--from any topically applied sunscreen
formulation is extremely unlikely, and that any de minimis absorption
that may occur would not result in adverse health effects, given the
high levels of endogenous zinc. The very low likelihood of any systemic
absorption of zinc oxide in turn indicates that the safety margin for
zinc oxide is large; accordingly, consistent with our approach to
pediatric studies discussed in section VII.B.5, we do not consider
pediatric studies to be needed for this ingredient. We propose to find
that the currently available safety data provide sufficient evidence to
demonstrate the minimal absorption, low dermal irritation, low
allergenic sensitization and photoallergenicity, and low phototoxic
potential of zinc oxide--regardless of particle size--up to 25 percent,
and that these data support a finding that zinc oxide up to 25 percent
is GRASE for use in sunscreens under the proposed conditions.
Accordingly, we propose that zinc oxide is a Category I active
ingredient.
2. Titanium Dioxide
For similar reasons, we propose that titanium dioxide is also a
Category I active ingredient. Our review of information publicly
available in the scientific literature, submissions to the sunscreen
monograph docket, and FAERS has produced sufficient information to
support a proposal that a sunscreen product containing up to 25 percent
titanium dioxide would be GRASE under the conditions proposed in this
rulemaking and the general conditions required in part 330.
a. Background. Titanium dioxide is an inorganic mineral compound
consisting of small, crystalline-structured or amorphous particles. It
is widely used as an excipient and is currently listed as an inactive
ingredient in more than 60 approved drug products (including topical,
oral, and inhalation products, among others) (Ref. 46). Titanium
dioxide particles can be manufactured to have a variety of different
dimensions, shapes (such as spheres or rods), and crystal polymorphs
(such as anatase or rutile). Titanium dioxide (typically with particle
dimensions ranging from 200 to 300 nm) is manufactured as a white
powder for use as a white color pigment in pharmaceuticals.
Manufacturers have also introduced processes that produce

[[Page 6218]]

titanium dioxide with particle dimensions ranging from 15 to 50 nm to
reduce its white/opaque appearance. Titanium dioxide particles used in
sunscreens are also now often treated with chemical coatings (such as
silicones, metal oxides, or organic acids) that are bonded to the
exterior surface of the particles to, among other things, improve the
aesthetic characteristics of the final formulation.
b. Discussion. Titanium dioxide is essentially insoluble in water
and in biologic fluids (Ref. 47). As with zinc oxide, this lack of
solubility prevents the transdermal absorption of more than a de
minimis amount of titanium dioxide, regardless of either the
concentration of titanium dioxide or the formulation of the product
(Refs. 48 and 49). Further, unlike zinc oxide, which, if dissolved,
would dissociate into zinc and oxygen (Ref. 50), the chemical stability
of titanium dioxide is such that it does not dissociate under the
conditions that exist in (or on) the human body (Ref. 51). Even if
titanium dioxide were to dissociate into titanium and oxygen, titanium
is unreactive in physiologic conditions, and (for this, among other,
reasons) is frequently used in medical devices and structures implanted
in the human body (Refs. 51 and 52).
The available studies on the transdermal absorption of titanium
dioxide confirm that the skin is an effective barrier to the
penetration of titanium dioxide, regardless of particle size--including
those on the nanoscale (Refs. 53, 54, and 55). In our 2012 response to
the ICTA Petition mentioned earlier, we described the then available
information about the absorption of titanium dioxide nanomaterials and
concluded that the ``currently available literature indicates that
insoluble nanomaterials of titanium dioxide used in sunscreens do not
penetrate into or through human skin to produce adverse health effects
when applied topically'' (ICTA Petition Response at 26). Since that
time, our search of the available literature has not revealed anything
that would change this conclusion. Because topically applied titanium
dioxide particles do not enter systemic circulation to any meaningful
extent, we do not consider a MUsT to be necessary for this ingredient.
Given the lack of transdermal absorption of titanium dioxide beyond
a de minims amount and, as a result, the very low likelihood of any
systemic effects, we also do not consider additional nonclinical
studies (including systemic carcinogenicity, developmental and
reproductive toxicity, or toxicokinetic) to be necessary to support the
safety of this ingredient.\23\ Because titanium dioxide penetration
beyond the non-living stratum corneum and into the viable layers of the
skin is also minimal, as with zinc oxide, we do not consider dermal
carcinogenicity studies to be needed for titanium dioxide either.
---------------------------------------------------------------------------

\23\ We note that the available literature also includes data
showing that oral administration of relatively high doses of
titanium dioxide did not produce adverse fetal effects in rats. (See
Ref. 56.)
---------------------------------------------------------------------------

The inability of more than an extremely minimal amount of titanium
dioxide to reach viable tissues that could have an immunologic reaction
also prevents dermal irritation, sensitization reactions, and
photosafety issues for this ingredient. Our search of the available
literature on titanium dioxide identified nonclinical data reinforcing
this, showing that dermal toxicity after dermal application of titanium
dioxide in rodents is minimal (Refs. 57 to 60). Accordingly, we do not
consider additional clinical photosafety, irritation, or sensitization
studies to be necessary to support the safety of this ingredient. We
note that the available studies on titanium dioxide evaluate products
with titanium dioxide concentrations up to 10 percent. Given that the
physical properties of titanium dioxide both preclude its penetration
into or through the human skin regardless of concentration and make it
unlikely that there would be dermal photosafety, irritation, or
sensitization associated with titanium dioxide exposure (and that there
is no data to suggest such photosafety, irritation, or sensitization
would exist at higher concentrations), we propose that titanium
dioxide--regardless of particle size--is GRASE for use in sunscreens at
concentrations up to 25 percent, consistent with the level set in the
Stayed 1999 Final Monograph.
In evaluating whether titanium dioxide is GRASE for use in
sunscreen products, we have considered published literature indicating
that nanoscale titanium dioxide can exhibit photocatalytic properties
(Ref. 61). The literature indicates that the crystalline structure of
titanium dioxide particles plays a role in this photocatalytic
activity, and that the anatase crystalline polymorph is associated with
greater photocatalytic activity than the rutile polymorph (Ref. 61).
The European Commission has established limitations on the percentage
of anatase crystalline polymorph in titanium dioxide to minimize
photocatalytic activity.\24\ Coating titanium dioxide particles has
also been shown to minimize photocatalytic activity (and to limit
particle clumping, which can have an impact on how products blend).\25\
---------------------------------------------------------------------------

\24\ In a July 2013 opinion addressing the safe use of titanium
dioxide in sunscreen products, the European Commission's Scientific
Committee on Consumer Safety gave its opinion that titanium dioxide
particles consisting, among other things, of up to 5 percent anatase
crystal ``can be considered to not pose any risk of adverse effects
in humans after application on healthy, intact or sunburnt skin''
(Ref. 62). In 2016, this physicochemical parameter was incorporated
by the European Commission into its Regulation on Cosmetic Products
(Regulation (EC) No. 1223/2009 11/30/2009) permitting the use of
titanium dioxide as a UV filter or as a colorant in cosmetics. See
Regulation (EC) No 1143/2016 July 13, 2016.
\25\ Id.
---------------------------------------------------------------------------

In theory, if photocatalytic activity occurred when sunscreen
products containing nanoscale titanium dioxide were exposed to light,
it could result in the breakdown of other sunscreen active ingredients
in these products. We have no evidence, however, that this in fact
occurs in sunscreen products containing titanium dioxide or that there
are any other negative impacts resulting from such photocatalytic
activity. Accordingly, its potential for photocatalytic activity does
not undermine our conclusion that titanium dioxide is GRASE for use in
sunscreen products. Nonetheless, we invite comment (including
supporting data) on whether sunscreens containing titanium dioxide are
negatively impacted by the potential photocatalytic effects of that
ingredient and, if so, to what extent; and on additional regulatory
conditions, if any, that are necessary to address this potential issue.
We note, as well, that it is the responsibility of manufacturers to
ensure that any inactive ingredients used in a drug product marketed
pursuant to the OTC Drug Review, including coatings used to address
photocatalytic activity or for other purposes, are safe and suitable
for their intended use (see Sec. 330.1(e)). FDA encourages
manufacturers to contact the Agency regarding any specific coatings
that they are considering for use in a topical sunscreen.
c. Conclusion. Given the chemical properties of titanium dioxide as
insoluble and unreactive under physiologic conditions and the available
studies showing that titanium dioxide does not penetrate into the skin
or enter into systemic circulation to any meaningful extent, we
consider the available safety data adequate to support a proposal that
titanium dioxide is GRASE for use in sunscreens. As with zinc oxide,
our proposal rests in significant part on the data showing that
absorption of titanium dioxide into or through the skin is very
unlikely and

[[Page 6219]]

that any de minimis absorption that could theoretically occur would not
result in adverse health effects. As a result, the safety margin here
is large, and consistent with our approach to pediatric studies
discussed in section VII.B.5, we therefore consider pediatric studies
to be unnecessary for this ingredient.

B. Ingredients Proposed as Category II

FDA's review of the available safety data for PABA and trolamine
salicylate have caused us to conclude that the risks associated with
use of these ingredients in sunscreen products outweigh their benefits.
Accordingly, we are proposing that these two ingredients are Category
II.
1. Para-Aminobenzoic Acid
PABA use has decreased significantly in recent years because of,
among other things, its adverse effects on skin and its discoloring and
staining effect on clothing. Our review of more than 700 sunscreen
brands sold in the United States (Ref. 63) indicates that PABA is in
fact no longer being marketed in the United States.
A search of the scientific literature, submissions to the sunscreen
monograph docket, drug approval documents from FDA and the European
Medicines Agency, adverse event reports submitted to FAERS, and FDA
Advisory Committee meeting reports (among other sources) has produced
clinical safety data on PABA that supports a conclusion that a
sunscreen containing PABA would not be GRASE. The available clinical
information includes significant numbers of reports of allergic and
photoallergic skin reactions to PABA, with rates of PABA-induced skin
reactions potentially 8 percent or higher (Refs. 64 to 67). An 8
percent incidence is a serious concern: By comparison, only 34
hypersensitivity reactions associated with sunscreen products have been
identified in FAERS since 1969.\26\
---------------------------------------------------------------------------

\26\ Total sunscreen sales since 1969 are not readily available.
However, in 2016 a total of 161,882,779 sunscreen units were sold in
the United States (Ref. 68).
---------------------------------------------------------------------------

Further, PABA has the ability to cause cross-sensitization to
structurally similar aromatic amines and nitro compounds (i.e., it can
cause individuals exposed to it to develop sensitivity reactions to
similar compounds) (Ref. 69). The list of compounds at issue includes a
variety of widely used products, such as sulfonamide antibiotics
(commonly used to treat a variety of infections, from urinary tract
infections to certain types of pneumonia), thiazide diuretics (the
number one recommended treatment for hypertension for certain
communities), certain local anesthetics (such as benzocaine and
procaine), and dyes (including para-phenylenediamine (a hair dye) and
aniline dyes (used in medical products)) (Refs. 70, 71, and 72). Cross-
sensitization to these products is a serious concern, as widespread
PABA use could result in a significant increase in cross-reactivity
with these agents and the incidence of allergic and photoallergic
dermatitis, some of which are likely to be severe.
These safety issues alone are reason enough to find PABA not GRASE
for use in sunscreens. In addition, however, data obtained from the
urine samples of human subjects receiving topical PABA application
shows that PABA also penetrates the skin and enters systemic
circulation (Ref. 73). Because full MUsT studies for PABA have not been
done, it is unclear to what degree such transdermal absorption takes
place. However, one article in the published literature suggests that
there is an association between autoimmune disorder and PABA use (Ref.
71), and we found one report each of hepatotoxicity (Ref. 74) and
chronic interstitial nephritis (Ref. 75) after oral PABA
administration. Although it is difficult to determine causality on the
basis of such single reports, if a MUsT were to show absorption of
PABA, these reports could represent an additional safety concern.
In addition, genotoxicity findings with PABA use have been largely
negative in the absence of UV irradiation. Adequate assessments of the
dermal carcinogenicity potential of PABA are unavailable, as are DART
studies. If a MUsT were to show absorption of PABA, therefore,
necessary studies would include dermal and systemic carcinogenicity
studies, DART studies, and toxicokinetic studies. However, given that
the above-described safety concerns associated with PABA are
significant enough to place PABA in Category II, conducting such
testing is neither appropriate nor ethical. We propose that PABA is not
GRASE for use in sunscreens.
2. Trolamine Salicylate
We also propose that trolamine salicylate is not GRASE for use in
sunscreens, and is, like PABA, a Category II active ingredient. As
described in further detail below, there are significant safety
concerns associated with the use of trolamine salicylate in sunscreen
products. We propose that these concerns are sufficient to support a
conclusion that a sunscreen containing trolamine salicylate would not
be GRASE. We note that, as with PABA, our review of more than 700
sunscreen brands sold in the United States suggests that trolamine
salicylate is no longer being marketed in sunscreens sold in the United
States (Ref. 63).
a. Background. Trolamine salicylate is comprised of trolamine and
salicylic acid. Salicylic acid is a non-steroidal anti-inflammatory
drug (NSAID); it is the active moiety in aspirin, and has been widely
used as an analgesic (i.e., pain relieving), anti-pyretic (i.e., fever
reducing), and anti-inflammatory agent. In addition to these
properties, salicylic acid inhibits platelet aggregation, which in turn
inhibits blood coagulation. For this reason, some salicylic acid-
containing products (such as aspirin) are used by consumers to help
reduce cardiovascular adverse events, including myocardial infarction,
stent thrombosis, and transient ischemic attacks.
Trolamine salicylate was included in the Stayed 1999 Final
Monograph for sunscreens at a concentration of up to 12 percent. It was
also proposed as a Category III active ingredient in the tentative
final monograph for OTC external analgesic drug products (External
Analgesic TFM) (``External Analgesic Drug Products for Over-the-Counter
Human Use; Tentative Final Monograph,'' 48 FR 5852 at 5855 (February 8,
1983)). The mechanisms of action for trolamine salicylate for these two
drug categories are very different; to be effective as an external
analgesic, trolamine salicylate must penetrate the skin and reach the
relevant sites of action. The available evidence clearly establishes
that trolamine salicylate is transdermally absorbed (Refs. 76 and 77).
To be effective as a sunscreen, however, trolamine salicylate must be
present on the surface of the skin so that it can reflect, scatter, or
absorb UV radiation.
The directions for use for the two product categories differ
significantly as well. The current requirements for sunscreen labeling
include directions that the product should be applied to all skin
exposed to the sun, that it should be used ``regularly'' to decrease
the risk of skin cancer and early skin aging,\27\ and that it should be
reapplied at least every 2 hours (21 CFR 201.327). In contrast,
currently marketed external analgesic products containing trolamine
salicylate include directions for use stating that they should be
applied to ``affected areas,'' that they should be reapplied no more
than three to four

[[Page 6220]]

times a day, and that use should be discontinued after 7 days.\28\
---------------------------------------------------------------------------

\27\ This direction applies to sunscreens with an SPF of 15 or
greater that are also broad spectrum.
\28\ Based on an evaluation of product labeling available at
https://labels.fda.gov (accessed April 4, 2018). See also External
Analgesic TFM.
---------------------------------------------------------------------------

b. Significant safety concerns associated with use of trolamine
salicylate as a sunscreen. FDA is concerned that use of trolamine
salicylate as an active ingredient in sunscreens could cause serious
detrimental health effects due to the anti-coagulation effects of
salicylic acid. FDA located two case reports of serious coagulation-
related adverse events associated with liberal dermal application of
trolamine salicylate. The first case involved a surgical patient who
experienced coagulopathy (impairment of the blood's ability to
coagulate) at surgical sites in connection with use of topical
trolamine salicylate (Ref. 76). Although the patient discontinued
aspirin use 2 weeks before surgery per her doctor's instructions, she
was unaware that use of a topical cream containing trolamine salicylate
should have been stopped as well, and continued liberal application of
the product to her knees for arthritis pain in the period leading up to
her surgery. Four hours after surgery, the patient returned to the
operating room bleeding profusely from all surfaces that had been
operated on and experiencing massive bilateral hematomas. She lost more
than 900 mL of blood.
In the second case, a patient taking warfarin (an anticoagulant)
for atrial fibrillation and stroke prevention experienced a
considerable increase in prothrombin time (i.e., the time it takes for
blood to coagulate) after liberal application of trolamine salicylate
to his neck and shoulders for pain relief (Ref. 78). The patient's
prothrombin time had previously been in the therapeutic range of 1.3 to
1.5 times the control, but increased to 2.5 times the control during
trolamine salicylate use. When trolamine salicylate use was
discontinued, the patient's prothrombin time returned to 1.3 times the
control.
FDA is also concerned that sunscreens containing trolamine
salicylate could lead to other adverse effects associated with
salicylic acid exposure. These include gastrointestinal distress and
hemorrhage, ototoxic effects (i.e., impacts on hearing),
hypersensitivity reactions, asthma exacerbations, acid-base imbalance,
salt and water retention, liver injury, and Reye's Syndrome (in
children). At high doses, acute salicylate toxicity (salicylism) may
occur. Early symptoms of salicylism include tinnitus, vertigo, nausea,
vomiting, and diarrhea; subsequent symptoms suggesting a more severe
intoxication include altered mental status (ranging from agitation to
lethargy), hyperpyrexia, noncardiac pulmonary edema, and coma.\29\
---------------------------------------------------------------------------

\29\ The symptoms associated with both acute and chronic
salicylate toxicity are well established. Descriptions are available
from many sources, including: National Library of Medicine's
Toxicology Data Network (ToxNet), ``Salicylic Acid,'' September
2008, available at https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+672 (accessed March 27, 2018). FDA also
included a comprehensive summary of salicylism in 21 CFR 343.80.
---------------------------------------------------------------------------

If trolamine salicylate were to be applied to all skin exposed to
the sun and reapplied every 2 hours as directed in sunscreen labeling,
the potential for transdermal absorption and systemic availability of
substantial amounts of salicylic acid raises significant concerns about
the potential for increased occurrence of the above-described adverse
events. This is a particular concern given the widespread use of other
OTC NSAID products with anti-inflammatory, analgesic, or anti-pyretic
effects, which, combined with the use of sunscreens containing
trolamine salicylate, may raise the anti-platelet effects experienced
by consumers to problematic levels. Concerns relating to transdermal
absorption may be especially acute for children, who have a higher
surface-area-to-body-weight ratio than adults. FDA proposes that the
above-described safety concerns are enough, by themselves, to support a
finding that trolamine salicylate is not GRASE for use in sunscreens,
and therefore, is a Category II active ingredient.
c. Data gaps. In addition, there are several categories of data
about trolamine salicylate that FDA expects would be necessary to
support a positive GRASE determination for its use in sunscreen
products that are currently missing from the public record. For
example, there is insufficient clinical dermal sensitization,
irritation, and photosafety data for trolamine salicylate. Although the
transdermal absorption of trolamine salicylate is well established, the
record currently lacks a MUsT that would allow us to evaluate the
extent of exposure to this ingredient when it is used as a sunscreen.
Such data is important because it would allow FDA to interpret systemic
toxicity findings in animal toxicology studies in the context of the
amount likely to be absorbed from sunscreen use. Given the FDA
recommendation that a MUsT for sunscreen use include application to a
majority (75 percent at a minimum) of the body surface of each test
subject, the above described safety concerns (including the potential
for salicylism associated with exposure to high doses of trolamine
salicylate) would raise significant ethical concerns about the conduct
of a MUsT in these circumstances. Were it possible to ethically conduct
a MUsT for this ingredient, and if such a MUsT showed significant
transdermal absorption of trolamine salicylate, this would raise
questions about whether enough of this ingredient remains present on
the surface of the skin for it to function effectively as a sunscreen.
As we noted in section VII.B.4, such considerations ultimately weigh
into the risk-benefit calculus FDA uses to determine whether an active
ingredient would be GRASE for use in sunscreens.
Although we have data addressing the toxicology profile of
salicylate, adequately detailed nonclinical DART studies for trolamine
and toxicokinetic data to interpret DART studies were also not found in
the public record. Adequate DART information, if it were available,
might reveal additional data needs (for example, to address any
potential hormonal effects that may be identified). Dermal
carcinogenicity data are available from the National Toxicology Program
for trolamine in acetone and trolamine alone (applied neat).\30\ In the
absence of toxicokinetic data to interpret existing carcinogenicity
studies, we cannot determine how the exposure in the animal studies
relates to human exposure to trolamine from the use of trolamine
salicylate as a sunscreen active ingredient.
---------------------------------------------------------------------------

\30\ In mice, liver tumors were identified, providing evidence
of systemic absorption of trolamine, but the suspected mechanism of
action is likely not relevant to humans (Refs. 79 and 80). A causal
link between the proposed mechanism and tumor formation in mice is
lacking.
---------------------------------------------------------------------------

d. Conclusion. For the reasons described above, FDA proposes that
trolamine salicylate is not GRASE for use in sunscreens. The safety
concerns associated with the use of trolamine salicylate as an active
ingredient in sunscreens are significant enough to support
classification of trolamine salicylate as a Category II ingredient. In
particular, the potential for transdermal absorption and systemic
availability of substantial amounts of salicylic acid in connection
with the exposure resulting from the use of trolamine salicylate in
sunscreens raises concerns about increased occurrence of the above-
described serious adverse events (including salicylism and serious
coagulation-related issues). The record also contains several
significant data gaps that would need to be addressed to support a
positive GRASE determination for trolamine salicylate.

[[Page 6221]]

Given the safety concerns described above, however, conducting the
clinical absorption testing recommended to address these gaps for use
as a sunscreen raises ethical concerns.

C. Ingredients Proposed as Category III

The public record does not contain sufficient data to support a
positive GRASE determination for cinoxate, dioxybenzone, ensulizole,
homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate
O, sulisobenzone, oxybenzone or avobenzone at this time. Accordingly,
these ingredients are being proposed as Category III. In the sections
that follow, we discuss our review of the available safety evidence for
these ingredients and identify the existing data gaps.
1. Ingredients for Which the Record Contains Significant Data Gaps:
Cinoxate, Dioxybenzone, Ensulizole, Homosalate, Meradimate, Octinoxate,
Octisalate, Octocrylene, Padimate O, and Sulisobenzone
The most significant gaps in the administrative record exist for
the following active ingredients: Cinoxate, dioxybenzone, ensulizole,
homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate
O, and sulisobenzone. We expect that data from all the types of studies
described in section VII will need to be submitted to support general
recognition of safety and effectiveness for each of these ingredients.
Only three of these active ingredients (homosalate (Ref. 81)),
octinoxate (Refs. 81 to 84), and octisalate (Ref. 81), for example,
appear to have been evaluated in human absorption studies, and most of
the available absorption studies for these three ingredients had
significant limitations. For example, the studies use a limited number
of subjects or are based on only a single application of the sunscreen
active ingredient to a limited area of the body. Even with this limited
sunscreen exposure, some of these studies showed systemic availability
of the active ingredient (octinoxate (Refs. 83 and 84)). None of these
10 ingredients has been studied in an adequate and well-controlled MUsT
that would determine the amount of systemic exposure to the active
ingredients under conditions of maximal use.
We note that a recent publication examining the relationship
between melting point, molecular weight, and the transdermal delivery
rates of the active ingredients in approved drug products shows that
products containing active ingredients with melting points and
molecular weights similar to many of these 10 sunscreen active
ingredients are among those successfully delivered transdermally--and
therefore available systemically (Ref. 85). This reinforces the
potential for transdermal absorption of and systemic exposure to these
sunscreen ingredients. The potential for such systemic exposure is a
concern because the available data are inadequate to determine either
the level of systemic exposure to these active ingredients or the
potential unintended consequences of such exposure. Given the lack of
chronic exposure toxicology data for these 10 ingredients--which makes
an evaluation of the dermal and systemic effects of chronic use
impossible--this is especially concerning. A number of these active
ingredients have also shown hormonal effects in mammalian assays
(homosalate (Refs. 86 to 92)) and padimate O (64 FR 27666 at 27671) and
in in vitro and in vivo assays (homosalate (Refs. 86 to 92), octinoxate
(Refs. 93 and 94),and octocrylene (Ref. 95). Although these findings
are only preliminary, we do not have adequate DART studies to enable us
to assess the impact of these potential hormonal effects on development
and reproduction.
In addition, several of these 10 ingredients (homosalate (Refs. 81
and 84), octinoxate (Refs. 81 and 96 to 101), octisalate (Refs. 81, 84,
and 101 to 105),octocrylene (Refs. 95 and 106), padimate O (Ref. 100),
and sulisobenzone (Refs. 107 and 108)) have been studied in dermal
penetration studies, which show (in general, with the exception of
homosalate) that these ingredients permeate into the epidermis and/or
dermis. The studies show that there are several factors (including
vehicle composition and the presence of other active ingredients) that
can influence, and potentially increase, the permeation and/or
penetration of these ingredients.
Because the record does not currently contain sufficient data to
support their safety, we are proposing that cinoxate, dioxybenzone,
ensulizole, homosalate, meradimate, octinoxate, octisalate,
octocrylene, padimate O, and sulisobenzone are Category III
ingredients. As previously noted, we expect that data from all the
types of studies described in section VII will be needed to support
general recognition of safety and effectiveness for these ingredients.
2. Ingredients for Which the Record Contains Fewer Data Gaps:
Oxybenzone and Avobenzone
While the record does not currently contain sufficient data to
support positive GRASE findings for oxybenzone and avobenzone, we have
significantly more data for these two ingredients than for the
ingredients discussed in the preceding section. To help facilitate
submission of the remaining data, we describe the data gaps for these
two ingredients in greater detail below.
a. Oxybenzone data. Although we located substantially more data on
oxybenzone than on the ingredients discussed in section VIII.C.1, our
review of the scientific literature, submissions to the sunscreen
monograph docket, and postmarket safety data publicly available through
FAERS revealed significant gaps in the data we expect to be necessary
to support a positive GRASE finding for use of oxybenzone at a
concentration of up to 6 percent in sunscreen products. The available
literature includes studies indicating that oxybenzone is absorbed
through the skin and can lead to significant systemic exposure, as well
as data showing the presence of oxybenzone in human breast milk,
amniotic fluid, urine, and blood plasma. The significant systemic
availability of oxybenzone (and, as discussed further below, the lack
of data evaluating the full extent of its absorption potential) is a
concern, among other reasons, because of questions raised in the
published literature regarding the potential for endocrine activity
with systemic oxybenzone exposure. Accordingly, we expect that a
positive GRASE finding for oxybenzone-containing sunscreens would
require, among other things, both a MUsT showing the degree of
oxybenzone absorption under maximal usage conditions and DART studies
that fully investigate its potential endocrine-disrupting effects. We
found neither in the existing record.
The record also lacks systemic and dermal carcinogenicity studies
for oxybenzone; these (and toxicokinetic data) should also be provided
to support a positive GRASE finding for this ingredient. Finally, the
available literature also raises questions about the safety of use of
oxybenzone-containing sunscreens in young children because of the
potential for higher absorption and bioaccumulation of oxybenzone in
this population. As discussed in further detail in the sections that
follow, we invite input and comment on appropriate studies and/or age
restrictions to address these pediatric issues.
b. Background of oxybenzone. Unlike zinc oxide and titanium
dioxide, both of which are inorganic (or physical) UV filters
consisting of metal oxides that primarily reflect or scatter UV
radiation,

[[Page 6222]]

oxybenzone is an organic (or chemical) filter, which absorbs UV
radiation. It belongs to a class of aromatic ketones known as
benzophenones and has a UV absorption profile covering both UVA and UVB
wavelengths (Ref. 109). Because of its superior UVA coverage,
oxybenzone was increasingly used through the early 1990s and ultimately
replaced PABA in sunscreen products (Ref. 110). Use of oxybenzone in
sunscreens increased when ``PABA-free'' sunscreens were introduced into
the market because of recognition that PABA and its esters induced
contact and photocontact allergic reactions (Ref. 110). As discussed
below, however, evidence shows that oxybenzone also has contact
allergenic and photoallergenic potential (Ref. 111). In addition to its
use as a sunscreen active ingredient, oxybenzone is used in, among
other things, perfumes, lipsticks, hair sprays, and conditioners as a
photostabilizer and/or fragrance enhancer (Refs. 112 to 114).
c. Data showing transdermal absorption and significant systemic
availability of oxybenzone. Data that have become available since
publication of the Stayed 1999 Final Monograph suggest that the
transdermal absorption of oxybenzone is high (Refs. 82, 115, and 116).
One study involving sampling of plasma and urine following topical
application of an oxybenzone-containing formulation showed absorption
and significant systemic availability of oxybenzone (Ref. 82). In this
study, 15 men and 17 women were dosed once daily, applying a 10 percent
oxybenzone cream formulation to approximately 90 percent of the body's
surface area for 4 days. The figures below illustrate the plasma and
urine levels observed.
BILLING CODE 4164-01-P
[GRAPHIC] [TIFF OMITTED] TP26FE19.000

BILLING CODE 4164-01-C

[[Page 6223]]

[GRAPHIC] [TIFF OMITTED] TP26FE19.001

BILLING CODE 4164-01-C
Although this study provides important information about the
significant absorption potential of oxybenzone, it does not obviate the
need for a MUsT. Among other things, once-daily application may result
in substantially lower systemic exposure than application at least
every 2 hours (as sunscreen labeling directs). This difference in
application frequency is a particular concern given that the data show
oxybenzone levels would still be increasing at the time of
reapplication if a 2-hour application window were observed.
Additionally, the cream formulation used in the study was not
formulated as a sunscreen product and may have contained ingredients
not typically used in sunscreen formulations, and/or lacked other
ingredients typically present. Because the formulation can have an
impact on absorption, the absorption results produced by the study may
not reflect absorption levels that would result from actual use of
oxybenzone-containing sunscreen products.
Another study, which evaluated the transdermal absorption of a
marketed sunscreen containing 4 percent oxybenzone in 16 women and 9
men, showed prolonged systemic availability of oxybenzone following
topical exposure (Ref. 116). In this study, which was designed to
evaluate the effects of UV radiation on oxybenzone absorption, the
sunscreen was applied to study subjects twice daily for 5 days.
Although the study concluded that UV exposure did not significantly
affect the urinary excretion of oxybenzone, it provided further
evidence of the systemic availability of oxybenzone following topical
application and showed that renal excretion of oxybenzone continued for
5 days after the last application of the sunscreen. Although the use of
a commercial sunscreen formulation, and twice- rather than once-daily
sunscreen application are improvements over the formulation and
application frequency used in the previous study, twice-daily
application remains insufficient to approximate the recommended
application frequency of sunscreen products in real-world use.
Furthermore, because the study used a sunscreen with 4 percent rather
than the full 6 percent concentration of oxybenzone eligible for the
sunscreen monograph, its results may not fully reflect the absorption
that would result from use of a 6 percent oxybenzone-containing
product. To properly characterize the potential for absorption of
oxybenzone in sunscreen products and to determine a margin of safety
for use of oxybenzone at up to 6 percent in sunscreen products, we
expect that a MUsT will be needed.
d. Inadequate data on oxybenzone's developmental and reproductive
toxicity. The significant systemic availability of oxybenzone following
topical application and the lack of data fully characterizing its
absorption levels are concerns, among other reasons, because of
literature suggesting that oxybenzone may have endocrine activity (see,
e.g., Refs. 88, 92, and 117). Dermal exposure to oxybenzone (in
acetone) in rats and mice and oral feeding of oxybenzone to rats and
mice resulted in reduced sperm density in males in 13-week general
toxicity studies conducted by the National Toxicology Program (NTP)
(Ref. 118). In female rats and mice, increased estrous cycle length was
observed in 13-week oral feeding studies.\31\ Importantly, the actual
effects of oxybenzone on female fertility were not evaluated. In a
preliminary dose range-finding pre- and postnatal development study in
rats, findings in male offspring indicated that cells in the testes
undergoing programmed cell death were increased in all oxybenzone-
exposed animals and that numbers of spermatocytes in the testes were
markedly reduced after oral feeding at oxybenzone (Ref. 119). Although
these findings are notable, they are all derived from dermal studies

[[Page 6224]]

with oxybenzone in acetone and oral feeding studies of oxybenzone;
these methods of exposure could potentially lead to higher levels of
systemic exposure to oxybenzone than with sunscreen use. Accordingly, a
MUsT and toxicokinetic data are needed to determine the relevance of
these findings to human use of oxybenzone as a sunscreen active
ingredient.
---------------------------------------------------------------------------

\31\ These changes could potentially be addressed with
historical control data (Ref. 88).
---------------------------------------------------------------------------

In humans, the endocrine effects of oxybenzone have been studied
with inconclusive results (see, e.g., Refs. 83, 120, and 121). In
biomonitoring studies of pregnant and lactating women, oxybenzone has
been detected in breast milk, amniotic fluid, and urine samples (Ref.
83, 120, and 121). High levels of oxybenzone in the urine of mothers
have been associated with: (1) Decreased birth weight in girls and (2)
increased birth weight and head circumference in boys, both of which
can be indications of endocrine effects (Ref. 83). This association is
particularly concerning given the widespread exposure of the U.S.
population to oxybenzone. Estimates suggest that oxybenzone (from all
sources) is present in the urine of 97 percent of the U.S. population,
and that oxybenzone concentrations are higher in women than in men
(possibly because women are more likely to use sunscreen and other
personal care products containing oxybenzone, leading to greater
cumulative exposure) (Ref. 83 and 115).
Because current data suggest that oxybenzone may affect the human
endocrine system, FDA believes that a positive GRASE determination for
oxybenzone would require that its potential toxicities have been fully
explored, including through DART studies (fertility and early embryonic
studies in rodents, embryofetal development studies in rodent and
nonrodent species, and pre- and postnatal development studies in
rodents). In addition, as noted below, toxicokinetic data are needed to
interpret these studies. We note that, if the results of DART studies
do not resolve the concerns raised in the literature relating to
potential endocrine disruption, it may still be possible to resolve
these concerns through additional testing.\32\ In addition, because of
the potential risk posed by metabolites of oxybenzone (existing reports
suggest that some oxybenzone metabolites are more hormonally active
than the parent drug (Ref. 109)), we recommend that the analytical
method used in the MUsT be validated for both the parent and the
metabolites of interest (Ref. 115) to support a positive GRASE finding
for this ingredient. The results from the metabolite study will inform
whether additional nonclinical studies assessing oxybenzone's
metabolites should be conducted to support its safety. We note that the
NTP is currently conducting additional DART studies on oxybenzone
(although their embryofetal studies do not appear to include an
assessment in a nonrodent species) (Ref. 122).\33\
---------------------------------------------------------------------------

\32\ For examples of the type of studies that could be explored
at that juncture see Ref. 21.
\33\ As a reminder, such data must be generally available to be
considered as part of this rulemaking process. Once available, FDA
intends to review such data to determine whether it resolves
particular data concerns we have in this area.
---------------------------------------------------------------------------

e. Inadequate carcinogenicity and toxicokinetic data for
oxybenzone. High population exposure to oxybenzone, coupled with a lack
of carcinogenicity testing for this ingredient, caused the National
Cancer Institute to nominate oxybenzone for toxicology testing in 1979
(Ref. 123). The NTP reports that 2-year oral (dosed feed)
carcinogenicity studies in rats and mice are in a draft report stage,
but results are not yet publicly available (Ref. 122). In addition, no
reports of either ongoing or planned dermal carcinogenicity studies for
oxybenzone have been published. To support a positive GRASE finding for
oxybenzone, carcinogenicity data from well-conducted dermal and
systemic carcinogenicity studies should be provided. Toxicokinetic data
in rodents (oral and dermal) and rabbits (oral) are also recommended;
these data could be obtained from either stand-alone studies or as part
of DART and dermal carcinogenicity studies.
Our search of the available literature also revealed information
suggesting that oxybenzone may generate reactive oxygen species (ROS)
\34\ in the presence of UV light, but that this issue, and the harms
associated with it, have not been fully explored (Ref. 124). We invite
comment and input on the extent to which ROS generation is a concern
for sunscreens containing oxybenzone and whether additional data on
this topic are needed.
---------------------------------------------------------------------------

\34\ Reactive oxygen species are ``a type of unstable molecule
that contains oxygen and that easily reacts with other molecules in
a cell. A buildup of ROS in cells may cause damage to DNA, RNA, and
proteins, and may cause cell death.'' https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=687227.
---------------------------------------------------------------------------

f. Dermal safety of oxybenzone. The available data indicate that
oxybenzone (at concentrations up to 6 percent) has a favorable safety
profile with respect to irritation and sensitization potential. For
example, the North American Contact Dermatitis Group conducted an
analysis of patients who were patch tested for allergies between 2001
and 2010 (see, e.g., Ref. 125). From 2001 to 2008, oxybenzone was
tested at 3 percent; from 2009 to 2010, the concentration used for the
test was increased to 10 percent. Of the 23,908 patients patch tested,
only 82 patients (0.34 percent) had positive test patch results with
oxybenzone. In addition, a search of FAERS for case reports of
hypersensitivity reactions to oxybenzone-containing sunscreen products
resulted in only 31 cases (4 with anaphylaxis) between 1988 and 2011.
Because sufficient data exist to make a determination, we do not
consider additional dermal irritation or sensitization studies to be
necessary to support a positive GRASE finding for oxybenzone up to 6
percent. As is customary in clinical trials, however, we recommend that
dermal safety data for oxybenzone be collected during MUsT studies.
Nevertheless, the overwhelming majority of results from available
studies (see, e.g., Refs. 125 to 136) addressing allergic contact
dermatitis for oxybenzone show that oxybenzone is an allergen for
persons with preexisting skin conditions. Because the evidence
establishing oxybenzone as a photoallergen in individuals with
photosensitivity is clear, no further dermal photosafety studies to
characterize this risk are needed. However, if we were to receive
adequate data to support a positive GRASE finding for oxybenzone, we
would consider requiring labeling language to address the risk of
allergic reactions associated with oxybenzone use. We invite comment on
whether such labeling should be required for sunscreens containing
oxybenzone and, if so, what that labeling should entail.
g. Safety questions regarding use of oxybenzone in pediatric
populations. Sunscreens are currently labeled for use in children as
young as 6 months old. The available literature, however, includes
several publications that raise concerns about the use of sunscreens
containing oxybenzone in young children. Among these publications is a
2006 report from the Swedish Research Council noting that children
under the age of 2 years old have not fully developed the enzymes
believed to metabolize oxybenzone (Ref. 137), which suggests, in
theory, that small children may not be able to eliminate oxybenzone as
easily as adults. The possibility for bioaccumulation in children,
taken together with the potential increased absorption of oxybenzone in
young children (due to their greater body surface-area-to-weight ratio)
and the potential harms associated with absorption discussed above,

[[Page 6225]]

militates in favor of caution when using oxybenzone products in young
children. Accordingly, we are seeking any existing pediatric data on
the safety of oxybenzone use in children under 2 years old. We are also
requesting input on: (1) Whether additional data on the safety of
oxybenzone use in young children is necessary to support the use of
oxybenzone-containing sunscreens in children under 2 years of age
(taking into consideration the practical hurdles involved in conducting
studies in children of this age) or (2) whether sunscreen products
containing oxybenzone should instead be contraindicated for use in
children younger than 2 years (given, among other things, the
availability for use as sunscreen active ingredients of physical UV
filters like titanium dioxide and zinc oxide, which do not raise the
same questions about safe use in young children).
h. Conclusion. Given the available data showing significant
transdermal absorption and systemic availability of oxybenzone, as well
as the potential for endocrine activity, we propose that oxybenzone is
not GRASE for use in sunscreens without further data. As described
above, a MUsT should be conducted to fully characterize the absorption
of oxybenzone and to calculate a margin of safety for human use. As
part of the MUsT, we believe that a study of oxybenzone's metabolites
in humans is also necessary; the results of this study will inform
whether additional nonclinical studies with metabolites are needed to
address potential endocrine effects. Given that oxybenzone demonstrates
significant systemic absorption, FDA believes that data on
carcinogenicity (both systemic and dermal) and developmental/
reproductive toxicity are likely to be needed to support the safety of
this ingredient, as are toxicokinetic data to bridge between animal and
human data. We seek any existing data on the pediatric safety of
oxybenzone. We also seek comment on whether additional safety data are
needed to support the use of sunscreens containing oxybenzone on
children under 2 years of age, as well as comment on whether these
sunscreens should be contraindicated for use in this population. We
note that, because of the risk of allergic reactions associated with
oxybenzone use, if we receive adequate data to support a positive GRASE
finding for oxybenzone, we may require labeling to address this risk.
We seek comment on whether such labeling should be required for
sunscreens containing oxybenzone and, if so, what such labeling
language should entail.
In summary, table 3 shows the additional studies that FDA
anticipates would be necessary to support a positive GRASE finding for
sunscreens containing oxybenzone.

Table 3--Summary of Recommendations: Studies for Oxybenzone Up to 6
Percent
------------------------------------------------------------------------
Safety studies FDA proposes are
necessary to support a GRASE Additional studies or data
determination necessary?
------------------------------------------------------------------------
Pharmacological Studies: ...............................
Human absorption (MUsT) (including Yes.
metabolite study in humans).
Nonclinical Safety Studies: ...............................
Toxicokinetics..................... Yes.
Dermal Carcinogenicity............. Yes.
Systemic Carcinogenicity........... Yes.
DART: \1\.............................. Yes.
Fertility and early embryonic
development.
Embryofetal development in two
species (rodent and non-rodent).
Prenatal and postnatal development.
Clinical Safety Testing: ...............................
Skin irritation and sensitization.. No.
Skin photoallergenicity and No.
phototoxicity.
Pediatric studies.................. Seeking input on whether
additional studies or
contraindication are necessary
to support the safety of
sunscreens containing
oxybenzone for children under
2 years of age.
------------------------------------------------------------------------
\1\ As noted above, if DART studies do not resolve the concerns raised
in the literature relating to potential endocrine disruption, it may
be possible to resolve these concerns through additional testing.

i. Avobenzone data. Our review of the available scientific
literature, submissions to the sunscreen monograph docket, and publicly
available FAERS data also revealed significant gaps in the data we
expect to be necessary to support a finding that avobenzone (at up to
either 3 percent or 5 percent, as discussed below) is GRASE for use in
sunscreens. Most critically, we encountered no studies examining the
absorption of avobenzone in vivo, and those in vitro studies we located
had several weaknesses that limit their usefulness in assessing the
potential absorption of avobenzone from formulated sunscreen products.
This is a concern given that, as explained in further detail below,
certain of avobenzone's chemical properties suggest that sunscreen
products containing avobenzone have a potential for absorption. There
are also other gaps in the record, including (as discussed below)
dermal carcinogenicity data, toxicokinetic data, and--potentially,
depending on the outcome of MUsT studies assessing the absorption of
avobenzone--systemic carcinogenicity and additional DART studies.
Accordingly, we propose to find that avobenzone is Category III.
j. Background of avobenzone. Avobenzone, like oxybenzone, is an
organic (chemical) UV filter. Because avobenzone primarily absorbs
radiation in the UVA portion of the UV spectrum, it is typically
combined with another sunscreen active ingredient that provides
protection in the UVB range. Avobenzone exhibits greater
photoinstability than other UV absorbers; the available evidence shows
that avobenzone degrades quickly upon exposure to sunlight, which can
cause its efficacy to be decreased by between 50 and 90 percent after
60 minutes of exposure to sunlight (Refs. 138 and 139).\35\ To address
this, avobenzone is typically combined with a photostabilizer to
prevent rapid photodegradation (Refs. 138 and 139).
---------------------------------------------------------------------------

\35\ Avobenzone's photodegradation also results in the formation
of free radicals, which could, in theory, create sensitization and
irritation responses and increase long-term risk of skin cancers and
photoaging (Ref. 139).

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[[Page 6226]]

k. Potential for absorption of avobenzone. Although avobenzone is
not soluble to any great extent in water, it is soluble in organic
solvents. These include oils (which are present on human skin),
alcohols, and other substances regularly included in sunscreen product
formulations. Although this solubility is not enough, by itself, to
determine whether transdermal absorption will take place, it is a
necessary precondition (Ref. 140). In addition, like the 10 active
ingredients described in section VIII.C.1, avobenzone's melting point
and molecular weight are similar to those of active ingredients in
approved drug products that are successfully delivered transdermally
and therefore available systemically (Ref. 85). As with the 10
sunscreen active ingredients previously discussed, this suggests a
potential for transdermal absorption of avobenzone.
l. Lack of adequate data on transdermal absorption of avobenzone.
Nevertheless, our review of the available literature on avobenzone
failed to produce any studies evaluating the in vivo absorption of
avobenzone at 3 percent or higher under (or even approaching) maximal
usage conditions. While we were able to locate a few studies evaluating
avobenzone's absorption in vitro, these studies had a number of
weaknesses that significantly limited the conclusions that could be
drawn from them.
The first in vitro study we located evaluated the penetration--
through excised human skin--of five sunscreen ingredients (including
avobenzone) that had been diluted in mineral oil and water (Ref. 100).
The study used a static cell technique. As discussed in section VIII.D,
in a static cell study, the test product (here, a sunscreen/mineral
oil/water formulation) is placed on the upper side of a membrane (here,
the excised skin) in the open donor chamber of a static cell, and a
sampling fluid is placed on the other side of the membrane in a
receptor cell. Diffusion of the ingredient (here the avobenzone) from
the topically applied product to and across the membrane is monitored
by examining sequentially collected samples of the receptor fluid. To
ensure that all transdermal penetration of the ingredient that takes
place is fully reflected in the receptor fluid, the receptor fluid must
be optimized for absorption (in other words, sink conditions must be
created in the fluid).
In this study, the use of skin as the membrane in the system
allowed for an evaluation of the presence and depth of permeation via
skin stripping--the sequential application and removal of adhesive tape
to the skin samples. However, it is unclear whether the receptor phase
of the study created adequate sink conditions. In addition, the
formulations used in the study (which, as noted previously, consisted
of only water, mineral oil, and the sunscreen ingredient) did not
contain any of the other types of excipients (such as emollients,
stabilizers, or solubilizers) that can also function as permeation/
absorption enhancers and that are typically present in sunscreen
product formulations. The study results showed that there was
avobenzone present in the stratum corneum, the epidermis, and the
viable dermis of the skin used as the membrane, but not in the receptor
fluid. Although the lack of avobenzone in the receptor fluid is
encouraging, the other characteristics of the study limit its value in
assessing the actual absorption potential of avobenzone used in
sunscreen products.
The second in vitro study (Ref. 141) we located suffered from
similar limitations. This study assessed the avobenzone permeation
observed using a static cell (as generally described above), and then
took the skin from the static cell and subjected it to multiple rounds
of tape stripping to assess the presence of avobenzone at various
levels of the skin. Following tape stripping, the skin was subjected to
digestion (i.e., the skin sample was subjected to a chemical treatment
that breaks down the cell membranes to release any sunscreen that might
be either bound to proteins or bound up in the cells).
The study results showed significant retention of avobenzone in the
stratum corneum, a lesser amount in the epidermis, and none in the
dermis or receptor fluid. Like the previous study, however, the test
material used in this study did not include any of the permeation
enhancers typically included in commercial sunscreen formulations. It
is also unclear whether sink conditions existed in the receptor phase
of the study.
The final in vitro study used a static cell to evaluate the
transdermal penetration of six sunscreen formulations collected from a
health spa that marketed its own line of skin care products (Ref. 96).
This study improved on the design of the previous two studies in
several respects. First, the receptor fluid contained ethanol, a
permeation enhancer often used in sunscreen products, which produced
sink conditions in the receptor phase. Secondly, to create favorable
conditions for absorption, the products were applied at a thickness of
20 mg/square centimeters (cm\2\) on the skin's surface (i.e., 10 times
the skin loading typically expected (Refs. 142 and 143)). In addition,
the study's use of commercially marketed sunscreen formulations (which,
as discussed above, typically contain multiple permeation/absorption-
enhancing excipients) more accurately reflects the absorption potential
of marketed sunscreen products.
Despite these improvements, the usefulness of the study was limited
by its use of an analytical method that prevented the detection of any
avobenzone absorption below 100 ng/mL. This level of absorption is
hundreds of times higher than what is relevant for our considerations
in assessing the acceptable absorption level from a topically applied
product. The concentration of avobenzone used in the study (ranging
from 0.2 percent to 1 percent) is also significantly lower than what is
relevant for our current consideration of maximum concentration of this
ingredient. Although avobenzone was only absorbed to a very small
extent (between 3 percent and 3.96 percent) under these study
conditions, these weaknesses in the study's design significantly limit
the conclusions that can be reached from its results.
Given that avobenzone's chemical properties suggest that it has a
potential for transdermal absorption in sunscreen products, the lack of
adequate data assessing its absorption in realistic sunscreen
formulations is a concern. We therefore expect that a MUsT
demonstrating the degree of absorption of avobenzone into the human
body under maximal use conditions will be needed to support a positive
GRASE determination for sunscreens containing avobenzone. Further, in
light of the above-described data showing avobenzone's
photoinstability, we also expect that, if sufficient data are provided
to support the safety of avobenzone, any future sunscreen monograph
including avobenzone as an active ingredient will include the
limitation that avobenzone is not GRASE for use in sunscreen products
unless it has been photostabilized (via use of a photostabilizing UV
filter or other photostabilizing ingredient/mechanism) to prevent its
photodegradation and (among other concerns) the attendant reduction in
avobenzone efficacy.
Because photodegradation can reduce the amount of avobenzone
absorbed transdermally, we also expect that a MUsT sufficient to
support the general recognition of safety of avobenzone for sunscreen
use would need to test formulations of avobenzone that include a
photostabilizer. Including

[[Page 6227]]

photostabilizers in MUsT formulations will allow for accurate
assessment of absorption levels in final formulated sunscreen products
containing avobenzone. This proposal is consistent with our general
recommendation that materials evaluated under the MUsT paradigm
represent real-world sunscreen formulations, rather than overly
simplified solutions that fail to replicate the absorption potential of
marketed formulations. As noted in section VII.B.4, we encourage
sunscreen manufacturers to discuss their MUsT protocol with FDA before
beginning the trial.
m. Data supporting dermal safety of avobenzone. The available
clinical dermal studies indicate that avobenzone at concentrations up
to 5 percent have a favorable safety profile with respect to potential
irritation, sensitization, and photosafety. In 2009, in conjunction
with a citizen petition \36\ (L'Oreal Petition, Docket No. FDA-1978-N-
0018-0675) asking FDA to take action to permit the marketing of
sunscreen products containing avobenzone up to 5 percent, L'Oreal USA
Products, Inc. (L'Oreal) submitted nine human repeat insult patch,
phototoxicity, and photoallergy studies with six different sunscreen
formulations containing avobenzone (3.4 percent, 4 percent, or 5
percent). The studies showed that the formulations were well tolerated
for topical use (i.e., essentially non-allergenic, non-irritating, and
non-sensitizing, with mild to moderate reactions occurring only rarely)
(L'Oreal Petition).\37\ A separate search of the available scientific
literature on the clinical safety of avobenzone did not reveal anything
to undermine these findings. Although the available literature included
a small number of reports of contact irritation and photosensitization
in connection with avobenzone-containing products, details about the
composition of the formulations at issue (and the concentrations of
avobenzone) were frequently missing from the literature, making it
difficult to determine the cause of these responses. A small number of
serious hypersensitivity reports for sunscreens containing avobenzone
were also located in FAERS. Because the sunscreens at issue usually
contained three or more active ingredients, however, it is difficult to
determine what caused the reaction. Because sufficient data exist to
make a determination, we do not consider additional dermal clinical
studies (including photosafety, irritation, or sensitization studies)
to be necessary to support the safety of this ingredient for sunscreen
use at up to 5 percent. As is customary in clinical trials, however, we
recommend that dermal safety data for avobenzone be collected during
MUsT studies.
---------------------------------------------------------------------------

\36\ FDA-1978-N-0018-0675, two volume submission (February 20,
2009) (L'Oreal Petition).
\37\ Id., volume I, pp. 5-8.
---------------------------------------------------------------------------

n. Other nonclinical safety studies for avobenzone. Dermal
carcinogenicity studies have not been conducted for avobenzone. The
available data on the permeation of avobenzone suggest that it may
permeate into at least the dermis and epidermis, which means that it is
possible for avobenzone to impact skin tumor development. We therefore
expect that dermal carcinogenicity studies will be necessary to support
a positive GRASE finding for sunscreens containing this ingredient.
Available embryofetal development studies in rats and rabbits did not
reveal any findings of concern. However, our review of the nonclinical
data for avobenzone \38\ also revealed that toxicokinetic data
following repeat-dose exposure will be needed to interpret pivotal
nonclinical safety studies (including the embryofetal development
studies in rats and rabbits) once the MUsT data become available. (As
explained in section VII.B.4, these data are used to compare drug
levels achieved in animal studies with those observed in humans under
maximal exposure conditions.) In addition, if results of a MUsT
demonstrate that there is significant systemic absorption of
avobenzone, additional fertility and early embryonic development and
prenatal and postnatal development studies in rats will be needed to
support a positive GRASE finding. Depending on the results of the MUsT,
systemic carcinogenicity studies may also be needed.
---------------------------------------------------------------------------

\38\ The available nonclinical data for avobenzone include acute
oral and dermal toxicity studies in rats; a 13-week oral toxicity
study in rats; a 28-day dermal toxicity study in rats; a 21-day
dermal toxicity study in rabbits; several in vitro genotoxicity
tests; an in vivo micronucleus test in mice, as well as a
sensitization test in guinea pigs; a primary skin irritation test in
rabbits; an ocular irritation test in rabbits; a phototoxicity study
in guinea pigs; a photoallergenicity study in guinea pigs; and
embryofetal development studies in rats and rabbits (Givaudan-Roure
Petition, Docket No. FDA-1978-N-0018-0751). Importantly, (except for
the embryofetal development studies) these studies are not
sufficient to resolve safety concerns for a chronically used
product.
---------------------------------------------------------------------------

o. Avobenzone in combination with other sunscreen active
ingredients. As noted in section III.B, our finding in the Stayed 1999
Final Monograph that avobenzone was GRASE for use in sunscreens would
have allowed its combination only with certain other sunscreen active
ingredients (64 FR 27666 at 27688) because we did not have targeted
evidence to support the safety and effectiveness of avobenzone when
combined with the remaining active ingredients. We believe this
limitation was inconsistent with the approach to evaluating sunscreen
combinations that the Agency has generally taken throughout the OTC
Drug Review for sunscreens. For this reason, unless evidence is
submitted to suggest that there is a safety or efficacy concern
associated with the combination of avobenzone with another active
ingredient, we expect to conclude that a positive GRASE determination
for avobenzone will support its use in sunscreens either alone or in
combination with all other sunscreen active ingredients.
p. L'Oreal request to increase concentration of avobenzone to 5
percent. Avobenzone is currently listed in the Stayed 1999 Final
Monograph at concentrations up to 3 percent. As described earlier, in
2009 FDA received a citizen petition from L'Oreal requesting, among
other things, that we amend the sunscreen monograph to increase the
allowable level of avobenzone to 5 percent (L'Oreal Petition at 1). In
the Stayed 1999 Final Monograph, the Agency determined that avobenzone
at concentrations up to 3 percent is an effective sunscreen active
ingredient. We now likewise conclude that the record contains
sufficient information to satisfy the effectiveness prong of the GRASE
standard for sunscreens containing avobenzone at concentrations up to 5
percent.
As described above, data submitted with that L'Oreal Petition were
sufficient to establish that avobenzone at a concentration of up to 5
percent has a favorable safety profile with respect to potential
irritation, sensitization, and photosafety. To support a finding that
avobenzone at concentrations up to 5 percent is GRASE for use in
sunscreens, however, FDA expects that a MUsT evaluating the transdermal
absorption of avobenzone up to 5 percent, as well as dermal
carcinogenicity studies and toxicokinetic data for avobenzone at a
concentration of at least 5 percent, will also be needed. Depending on
the outcome of the MUsT, we may also need systemic carcinogenicity data
and additional DART studies, including fertility and early embryonic
development, and pre- and postnatal development studies in rats for
avobenzone at 5 percent. The record does not currently include any of
these data. However, if FDA were to receive sufficient data to support
a positive GRASE finding for avobenzone up to 5 percent, we would
expect to include

[[Page 6228]]

avobenzone at this percentage in a final sunscreen monograph.
q. Conclusion. Given that: (1) Avobenzone's organic solubility,
molecular weight, and melting point suggest it has a potential for
transdermal absorption; (2) there is a lack of available data on the
transdermal absorption of avobenzone in vivo (including under maximal
use conditions); and (3) there are limitations in the available in
vitro studies assessing avobenzone absorption, we expect that a
properly designed MUsT will be necessary to support a positive GRASE
finding for avobenzone use in sunscreens. We expect that, to be GRASE
for sunscreen use, avobenzone will need to be photostabilized to
address its potential for degradation, and we therefore expect that any
future sunscreen monograph including avobenzone as an active ingredient
will include the limitation that avobenzone is not GRASE for use in
sunscreen products unless it has been photostabilized to prevent its
photodegradation. In addition, we believe that an adequate MUsT
evaluating the absorption potential of avobenzone will need to include
a photostabilizer to ensure that the potential transdermal absorption
of avobenzone from avobenzone-containing sunscreens is accurately
assessed.
We also expect that dermal carcinogenicity and toxicokinetic data
will be necessary to support a positive GRASE finding for sunscreens
containing avobenzone. Depending on the outcome of a MUsT assessing the
absorption of avobenzone, systemic carcinogenicity testing and
additional DART studies, including fertility and early embryonic
development and pre- and postnatal development studies in rats may be
needed as well. We will also determine the extent to which additional
DART studies may be needed based on the results of the MUsT. Depending
on the results of the nonclinical and pharmacology studies for this
ingredient and the safety margin that is calculated from these results,
pediatric studies for avobenzone may also be needed to support the use
of sunscreens containing avobenzone in pediatric populations.

Table 4--Summary of Recommendations: Studies for Avobenzone Up to 3 (or
5) Percent
------------------------------------------------------------------------
Safety studies FDA proposes are
necessary to support a GRASE Additional studies or data
determination necessary?
------------------------------------------------------------------------
Pharmacological Studies:
Human absorption (MUsT) (including Yes.
metabolite study in humans).
Nonclinical Safety Studies:
Toxicokinetics..................... Yes.
Dermal Carcinogenicity............. Yes.
Systemic Carcinogenicity........... Dependent on results of the
MUsT.
DART:
Fertility and early embryonic Dependent on results of the
development. MUsT.
Embryofetal development in two No.
species (rodent and non-rodent).
Prenatal and postnatal development. Dependent on results of the
MUsT.
Clinical Safety Testing:
Skin irritation and sensitization.. No.
Skin photoallergenicity and No.
phototoxicity.
Pediatric studies.................. Pediatric studies may be
required depending on the
outcome of the MUsT.
------------------------------------------------------------------------

D. Anticipated Final Formulation In Vitro Permeation Testing

As noted earlier, a final sunscreen monograph will need to set out
the conditions under which any product marketed pursuant to it would be
GRASE and not misbranded. Variations among individual sunscreen product
formulations--in particular, characteristics of the specific vehicle
(e.g., the cream, lotion, or oil) in which active ingredients are
delivered--can affect the transdermal absorption of sunscreens, and
thus, have an impact on their safety and effectiveness. To address
this, FDA currently requires final formulation testing of OTC sunscreen
products to support labeled claims regarding their effectiveness--
namely, testing for SPF value as well as broad spectrum protection and
water resistance where those attributes are claimed in product
labels.\39\ For purposes of this proposed rule, we use the term final
formulation testing to refer to testing conducted on the sunscreen
product formulation to be marketed. Our expectation is that final
formulation testing would also generally be necessary to ensure that
the active ingredient in any given sunscreen formulation permitted
under the monograph would not be systemically absorbed beyond the
amount FDA determined to be safe.
---------------------------------------------------------------------------

\39\ See Sec. 201.327 for the current labeling requirements,
and underlying testing, for OTC sunscreens containing one or more of
the 16 active ingredients that are addressed in this rulemaking, for
use in products marketed without approved NDAs. OTC sunscreens
marketed under NDAs provide similar information in their product-
specific applications to substantiate their labeling. For proposed
changes to Sec. 201.327, see codified section of this document. The
Stayed 1999 Final Monograph also required SPF testing of final
formulations as a GRASE condition. Elsewhere in this proposed rule,
we propose to establish monograph conditions in 21 CFR part 352 that
ensure that all sunscreens are tested for SPF in accordance with
Sec. 201.327(i) and achieve a minimum SPF of 2, and that certain
sunscreens pass the broad spectrum test in Sec. 201.327(j).
---------------------------------------------------------------------------

The discussion that follows provides FDA's thinking about such
testing of final formulations, which we anticipate requiring in the
future for sunscreen products marketed under the sunscreen monograph
(unless FDA determines that the ingredient or ingredients contained in
the product are unlikely to be absorbed through the skin). Because this
testing would not be required for sunscreens containing only those
active ingredients proposed here as Category I (zinc oxide and titanium
dioxide), FDA has not yet reached a final determination as to the
particular parameters that might be required for such final formulation
testing. We anticipate that we may specify final formulation testing
requirements in the monograph in the future, however, as active
ingredients that we are now proposing as Category III may be included
in the monograph in the future if FDA receives data supporting their
GRASE status. Final formulation testing requirements applicable to such
ingredients would be established on an ingredient-specific basis,
taking into consideration the data provided to

[[Page 6229]]

support a positive GRASE determination for the specific ingredient (for
example, whether any safety signals are detected in well-conducted
nonclinical carcinogenicity and DART studies). We encourage interested
parties to provide information and comment for each sunscreen active
ingredient that is relevant to establishing this kind of final
formulation testing for each active ingredient.
FDA's expectation is that this testing would not generally call for
an in vivo study. Instead, FDA expects that the conditions of marketing
specified for sunscreens containing a given active ingredient would
require manufacturers to perform in vitro permeation testing before
marketing each sunscreen formulation containing that ingredient.
Consistent with the approach for SPF and broad spectrum final
formulation testing set forth in Sec. 201.327 (for proposed changes to
Sec. 201.327, see codified section of this document), FDA anticipates
that it would not review the results of the in vitro permeation testing
before product marketing. Rather, FDA expects that any future
conditions pertaining to final formulation in vitro permeation testing
in the sunscreen monograph would include a requirement that
manufacturers maintain records of this testing, and that those records
be available for FDA inspection upon request.
FDA anticipates establishing a standard control formulation for
each sunscreen active ingredient to be used in the in vitro permeation
testing of products containing that ingredient. The standard control
formulation would be the formulation that produces the highest in vivo
absorption in the MUsT. The results of in vitro permeation testing
using this control formulation would then be used as a bridge to a
corresponding level of in vivo absorption from the MUsT that is used to
establish the safety margin for the ingredient. Then, FDA anticipates
establishing conditions to ensure that final formulation in vitro
permeation testing would be conducted for each formulation intended to
be marketed, using the specified vertical diffusion cell described
below. The results of the in vitro permeation testing of each final
formulation would be compared to the absorption found in the standard
control formulation for the active ingredient it contains.
In vitro permeation testing is a methodology that has been used in
dermal formulation development for over 30 years and, as used here,
specifically refers to use of the ``Vertical Diffusion Cell'' (Ref.
144). A vertical diffusion cell is comprised of three major units: (1)
An upper chamber (into which the sunscreen formulation is placed); (2)
the rate-limiting membrane (the prepared human skin); (3) and the lower
chamber/fluid channel (containing a receptor fluid that is evaluated to
determine how much of the sunscreen it ``receives'') (Refs. 145 to
147). The vertical diffusion cell system has been commercialized and is
available as both single and multiple unit models that can be
automated.
Other relevant parameters FDA expects to consider in establishing
future requirements for in vitro permeation testing include (among
other things) the thickness and integrity of collected skin, storage
conditions used for collected skin, receptor fluid composition, skin
and receptor fluid temperature, the number of skin samples (and donors)
used, study duration, sampling period, application method, and number
of experimenters.
We note that if a final sunscreen formulation contains a
combination of sunscreen active ingredients, FDA anticipates requiring
that this final formulation be tested against the standard control
formulations for each of the sunscreen active ingredients it contains.
As noted above, a standard control formulation might not be specified
for (and final formulation in vitro permeation testing might not be
necessary to establish safety for) a sunscreen containing a particular
active ingredient if FDA determines that the ingredient is unlikely to
be absorbed through the skin. As mentioned above, we therefore do not
propose to require final formulation in vitro permeation testing for
sunscreen formulations containing only zinc oxide and/or titanium
dioxide.
In cases in which such testing is required, FDA anticipates that if
the in vitro permeation of each sunscreen active ingredient in the
final formulated product is equal to or less than the value obtained
from in vitro permeation testing of the standard control formulation
for that active ingredient, the product's safety margin would be
considered to fall within the parameters judged to be GRASE, and thus
to support marketing of the formulation. However, if the in vitro
permeation of the active ingredient from the specific final formulation
is greater than the value obtained from in vitro permeation testing of
the standard control formulation for that active ingredient, FDA
anticipates that the drug product(s) using that formulation would not
be considered GRASE. In that situation, the sponsor would have the
option to either: (1) Reformulate the product and conduct in vitro
permeation testing to establish that the reformulated product satisfies
the final formulation in vitro permeation testing requirements set out
in the sunscreen monograph or (2) seek NDA approval for the new
formulation.

IX. Additional Proposed Conditions of Use

A. Proposed Requirements Related to Dosage Form

OTC sunscreens have been marketed in a variety of dosage forms over
the years. Responding in part to the growing market acceptance of spray
sunscreens, on June 17, 2011, FDA issued an ANPR addressing sunscreen
dosage forms (Dosage Forms ANPR) (76 FR 35669, June 17, 2011). The ANPR
identified dosage forms considered eligible or ineligible for review
and potential inclusion in the OTC sunscreen monograph, based on FDA's
knowledge, at that time, of their history of marketing before the OTC
Drug Review began in 1972. It also solicited specific information about
the safety, effectiveness, and directions for use of spray sunscreens.
1. Summary of Eligible and Ineligible Dosage Forms
In this proposed rule, FDA is confirming that the following dosage
forms identified in the Dosage Forms ANPR are eligible for review and
potential inclusion in the OTC sunscreen monograph based on their
history of sunscreen marketing before 1972: Oil, lotion, cream, gel,
butter, paste, ointment, stick, spray, and powder. With the exception
of powder, FDA proposes that sunscreens in these dosage forms are GRASE
subject to certain conditions described below and elsewhere in this
proposed rule. We note that sunscreen powders were classified as
ineligible for review in the Dosage Forms ANPR because, at that time,
we were unable to identify any sunscreen products in powder form that
were marketed before the OTC Drug Review began. Based on marketing data
submitted to the ANPR docket and in a related citizen petition (Docket
No. 1978-N-0018-0741), we have determined that the powder dosage form
is eligible to be considered for inclusion in the OTC sunscreen
monograph. However, as described in section IX.A.4, we tentatively
conclude that additional safety and efficacy data will be necessary to
classify sunscreens in the powder dosage form as GRASE and include them
in the final monograph. We are proposing that sunscreens in all dosage
forms other than those identified as eligible for consideration above--

[[Page 6230]]

including wipes, towelettes, body washes, and shampoos--are new drugs
because we did not receive data showing that they were marketed prior
to 1972.
2. Overview of Comments on the Dosage Forms ANPR
FDA received a total of 14 comments on the Dosage Forms ANPR. Six
of the comments provided no new data, but generally supported the
advantages of spray sunscreens, agreed with the need to address
concerns about spray sunscreens' performance and/or safety (especially
when used on children), opined that existing SPF methods would not need
to be modified for sprays, or (in most cases) agreed with FDA's
suggested directions for use. Other comments argued for the inclusion
of additional dosage forms identified as ineligible in the Dosage Forms
ANPR, but failed to provide supporting marketing data. One comment
contained marketing information showing that sunscreen products in
powder form, which we had previously identified as ineligible for the
monograph, had been marketed in the United States before 1972. The
remaining comments (all from industry) provided data and information
that directly or indirectly addressed questions raised in the Dosage
Forms ANPR concerning the safety, effectiveness, and labeling of spray
sunscreens. These comments are discussed in sections IX.A.3 and IX.A.4
below.
3. Safety and Effectiveness of Spray Sunscreens
As we recognized in the Dosage Forms ANPR, compared to traditional
lotions, oils, and the like, spray sunscreens raise potential concerns
of both safety and efficacy that FDA must consider in determining
whether sunscreens in the spray dosage form would be GRASE. With
respect to efficacy, FDA must consider factors such as whether spraying
sunscreen rather than applying it by hand provides effective coverage
on exposed skin, how consumers use spray products, and whether current
test methods for SPF and broad spectrum protection can be relied on for
adequate labeling of spray products. With respect to safety, spray
sunscreens raise the question of potential harm from inhalation of
sunscreen components as well as potential flammability risks.
a. Characteristics of sunscreen spray products. Spray sunscreens
use varying technologies to package and deliver a sunscreen formulation
as an aerosol spray, i.e., an airborne suspension of fine droplets or
particles. In some spray products, the sunscreen formulation is mixed
in a canister with a liquefied gas propellant that supplies the force
to generate an aerosol containing both dissolved sunscreen formulation
and propellant upon activation of a valve system. There are also pump
spray sunscreen products that are not packaged under pressure but
generate spray by applied mechanical force without the need for a
propellant. Many currently marketed spray sunscreen products use a
delivery technology referred to as a bag-on-valve system, in which the
sunscreen formulation is contained in a bag with an attached valve
inside a canister filled with propellant, so as not to mix the
sunscreen formulation and propellant ingredients. For purposes of this
document, a spray sunscreen product is one discharged from either a
pressurized or nonpressurized container, with the understanding that
the degree of atomization will likely vary according to the
formulation, the container system used, and the design of the spray
actuator, among other factors.
b. Spray sunscreen performance and effectiveness. The Dosage Form
ANPR asked a series of questions relating to the performance and
effectiveness of spray sunscreens, including questions about the amount
of spray sunscreen typically applied by consumers, uniformity of
coverage, how frequently consumers reapply spray sunscreens, whether
consumers rub spray sunscreens into the skin when directed to do so and
the resulting effect on effectiveness, and whether--and if so, how--the
SPF and/or broad spectrum tests need to be modified to address
sunscreen sprays. The Dosage Forms ANPR also solicited studies
comparing spray sunscreens to other eligible dosage forms to see
whether the dosage forms are comparable.
Four comments provided data from multiple studies examining and
comparing the performance of spray and lotion sunscreens on a variety
of parameters, including amounts applied, uniformity of coverage as
measured with UV filter photography, comparative SPF results, and
consumer ratings of ease and effectiveness of application, among
others. FDA's evaluation of the information submitted indicated that
key questions asked in the Dosage Forms ANPR were directly or
indirectly addressed by these studies. These studies indicated that
consumers like the convenience of spray sunscreens and adapt their use
of these products to achieve effective coverage. Data provided on
application uniformity lacked study reports and were difficult to
compare directly, but--taken together--they suggest a high degree of
uniformity between sprays and lotions in coverage of exposed skin, as
well as between different spray application scenarios such as spraying
directly on skin or spraying followed by rubbing. Information submitted
indicated that the amount of spray sunscreen dispensed is higher than
the amount dispensed for sunscreen lotions, and that consumers are more
likely to reapply sprays than lotions. There was no response from any
stakeholder regarding consumers' compliance with directions to rub a
spray sunscreen into the skin. However, data was provided suggesting
that rubbing spray sunscreens into the skin did not enhance
effectiveness. Based on these comments and the available data, we are
not proposing to require that labeling provide instructions to rub
spray sunscreens into the skin.
Comments on the Dosage Forms ANPR also agreed, and we concur, that
the current FDA-required SPF and broad spectrum tests are appropriate
for evaluating the efficacy of sunscreens in spray dosage forms. SPF
testing requires application of a set amount of sunscreen (2 mg/cm\2\
on each test subject), which can readily be done for spray sunscreen
formulations. For example, comments on the Dosage Form ANPR stated that
the SPF testing of sunscreen spray products can be conducted following
the method described in the current rule by weighing out the liquid
form and applying it to the skin. This premise is supported by data
from SPF testing submitted in the comments. For example, one comment
submitted five SPF testing reports conducted on sprays using the FDA-
required methods, in which the expected SPF values for the test
formulations were almost identical to the SPF testing results. The same
logic applies to broad spectrum testing, which also uses a defined
amount of sunscreen by weight. Based on this information, we conclude
that the current and proposed SPF and broad spectrum testing methods
are also appropriate for spray dosage forms.
c. Spray sunscreen safety. FDA has identified two primary safety
concerns specific to spray sunscreen dosage forms: (1) The potential
risk of respiratory harm from inhaling sunscreen ingredients and (2)
the potential flammability risk when consumers are exposed to flame or
heat before spray solvents have completely dried. For the reasons
described below, we believe that both potential risks can be acceptably
mitigated by proposed formulation limitations, labeling requirements,
and adequate testing, and

[[Page 6231]]

thus propose to establish these as additional conditions in the
monograph to ensure that sunscreen products in a spray dosage form
would be GRASE.
d. Inhalational toxicity. Broadly speaking, the human respiratory
system consists of the upper respiratory tract (i.e., the airways of
the nose to the larynx) and lower respiratory tract (the trachea and
branching airways of the lung, including bronchi, bronchioles, and
alveoli) (see generally Refs. 148 and 149). Much of the respiratory
system is lined with a layer consisting of mucus cells and cilia that
mechanically propel inhaled particles out of the lower respiratory
tract toward the mouth, where they may be swallowed or expectorated
(Refs. 148 and 149). The most significant concern associated with any
product that may be accidentally inhaled is the potential risk of
adverse effects associated with deep lung deposition, which occurs when
particles in an aerosol (i.e., a suspension of airborne particles such
as a sunscreen spray) reach the unciliated airways in the lung.
Particles that can reach the unciliated airways of the deep lung are
described as respirable and may be associated with serious adverse
effects such as asthma, emphysema, bronchospasm, or chronic obstructive
pulmonary disease; particles that do not reach the deep lung may be
associated with less harmful adverse events such as local irritation of
the upper airway, coughing, or sneezing (Refs. 149 to 151). The
potential health risk associated with inhalation of hazardous aerosols
depends on how much of a toxic substance is deposited in a given region
of the respiratory tract and how much remains after physiological
clearance occurs through mechanisms such as coughing, sneezing,
mechanical transport, or, in the deep lung, engulfment by specialized
cells or other protective action (Refs. 148 and 152).
The pathogenic potential of inhaled aerosols depends on where in
the respiratory tract a particle is deposited (Ref. 152). Whether spray
particles that enter the body through inhalation at the nose or mouth
will be deposited in the lung depends largely on their physical
characteristics: Most notably particle size, with the likelihood of
respirability increasing as particle size decreases (Refs. 148 to 153).
The effects of particle size on respirability of inhaled particles is
well studied. There is general agreement that particles greater than 10
micrometers ([mu]m) in diameter may enter the mouth and the airway up
to the larynx. Approximately 50 percent of particles up to 10 [mu]m in
diameter can penetrate beyond the larynx to the thoracic region of the
respiratory tract, while only particles smaller than 4 [mu]m reach the
unciliated airways and alveolar region of the lungs (see generally
Refs. 148 to 153). Thus, although there are little or no data on the
potential inhalation toxicity of particular spray sunscreen
ingredients, we are proposing that exposure to harmful levels of such
ingredients can effectively be minimized by imposing particle size
limitations on spray sunscreen products.
Several comments on the Dosage Forms ANPR submitted results of
particle size distribution testing using available methods and
apparatus, with the aim of showing that exposure to inhaled sunscreen
products or ingredients would be minimal and thus unlikely to cause
adverse effects. The data submitted were similar and in some cases
overlapping. In an analysis of pooled particle size distribution data
from all submissions, representing 50 U.S.-marketed spray sunscreen
products, 32 had particles smaller than 4 [mu]m in diameter and thus
within the respirable portion of the total particle size distribution.
However, the great majority of the particle sizes observed were
nonrespirable. The highest percentage that any product had of particles
smaller than 4 [mu]m in diameter was 0.43 percent and the mean was 0.22
percent, which is extremely low.
In addition to reviewing information from comments on the Dosage
Forms ANPR, FDA conducted its own analysis of particle size
distribution for 14 marketed spray sunscreens. In those tests, no
sunscreen had more than 10 percent of particles in sizes less than 10
[mu]m in diameter and only three had particles smaller than 5 [mu]m
(Ref. 154).
To limit the risks of unintentional exposure and potential
associated adverse events to respirable particles in spray sunscreens,
we are proposing limits on the size of particles dispensed from the
consumer container for finished spray sunscreens in order for those
products to be GRASE. We propose that 90 percent of the particles
dispensed from the consumer container must be at least 10 [mu]m or
greater in order to limit exposure beyond the larynx, and to prevent
deposition in the deep lung, the minimum particle size dispensed from
the consumer container must be no less than 5 [mu]m. This limit was
chosen because it is the lowest whole number above the generally
accepted threshold (4 [mu]m) at which particles enter the unciliated
airway and because it allows for experimental error that may be
inherent in particle size measurements. Sunscreen products that do not
meet both limitations would not be GRASE because there is not
sufficient information in the record to support a positive finding
about their safety. We believe that, taken together, these two
limitations would significantly reduce inhalation risk from spray
sunscreens by reducing particle exposure to the larynx and deeper lung
tissues. The particle size data submitted in response to the Dosage
Forms ANPR also suggest that these limitations would be readily
achievable without unduly burdening sunscreen spray manufacturers.
With the establishment of these two limits, FDA believes that the
risks of adverse events related to unintentional inhalation of spray
sunscreens will be minimal. Stakeholders asserted that the risk of
inhalation toxicity is already low, primarily based on particle size of
marketed sprays. Limited data on adverse event reports and animal
toxicity studies were also submitted in a few comments on the Dosage
Forms ANPR, but were inadequate to support the safety of spray
sunscreens in the absence of particle size limitations. If the particle
size limitations proposed here are adopted, however, we do not believe
that additional animal toxicity or other safety data need to be
provided to support a GRASE finding for spray sunscreens.
We are proposing that particle size testing to demonstrate
compliance with the proposed limitations must be conducted on spray
products as they are dispensed from the consumer container as part of
the lot release testing that would be routinely completed as part of
current good manufacturing practice (CGMP) compliance under part 211
(21 CFR part 211). It is necessary to test the size of particles
dispensed from the consumer container to ensure that particle size
requirements are met under conditions of use by consumers.
For purposes of these proposed particle size requirements, we are
using the term particle size broadly to mean the discrete unit emitted
from the spray container that is available for inhalation by a consumer
when the product is applied. If the particle dispensed from the
consumer container is a droplet that meets the size requirements, the
consumer will not accidentally inhale it into the deep lung. However,
if that same droplet breaks apart into smaller fractions when it is
dispensed from the consumer container, those fractions would be the
particles that must meet the size requirement to ensure that consumers
will not inadvertently inhale them past the larynx.
We are not proposing a specific test methodology for spray
sunscreen particle size. Rather, sunscreen manufacturers would be
obligated to ensure that particle size testing for their

[[Page 6232]]

sunscreen sprays would be conducted on each lot of the final product as
dispensed from the consumer container in accordance with adequate
written specifications. USP General Chapter 601 part B provides
methodology and requirements for sprays, aerosols, and powders that
include methodology to determine droplet/particle size distribution,
and we expect to consider testing done in accordance with the USP as
adequate to meet this proposed requirement (Ref. 155).
We note that several comments on the Dosage Forms ANPR expressed
concern about the potential inhalation risk from exposure to spray
sunscreens that contain nanomaterials (as both active and inactive
ingredients). One comment also recommended that FDA require the
presence of such ingredients to be disclosed on spray sunscreen labels.
FDA's approach to nanotechnology and nanomaterials in sunscreen
products is discussed in section VII.E. FDA is not now proposing
conditions of use, including labeling, for spray sunscreens that
distinguish based on the presence of nanomaterials because we are
proposing that any sunscreen spray that contains any particles smaller
than 5 [micro]m when it is dispensed from the consumer container would
not be GRASE. With respect to nanomaterials in spray sunscreens, we
note that the primary determinant of inhalation risk is the size of the
particles in emitted sprays, which may be larger than individual
formulation components. Nanoscale ingredients would not pass the
particle size limitations for spray sunscreens; therefore, if they were
to be detected when sprayed from the consumer container during particle
size testing, the sunscreen could not be marketed under the OTC
monograph.
In addition to the proposed limitations on particle size for
sunscreen sprays and related testing, we are proposing to require that
the following labeling be included in the directions for sunscreen
sprays to minimize unintended inhalation:
Hold container 4 to 6 inches from skin to apply.
Do not spray directly into face. Spray on hands then apply
to face.
Do not apply in windy conditions.
Use in a well-ventilated area and avoid inhalation.
This language is the same as that published in the Dosage Forms
ANPR. Its adoption was supported by comments on the Dosage Forms ANPR,
and the language is widely used on currently marketed spray sunscreens
consistent with the 2018 Final Guidance.
e. Flammability risk. In July 2013, FDA issued a Consumer Update
regarding persons catching on fire while wearing spray sunscreen
products near an open flame:

The Food and Drug Administration (FDA) has become aware of five
separate incidents in which people wearing sunscreen spray near
sources of flame suffered significant burns that required medical
treatment. The specific products reported to have been used in these
cases were voluntarily recalled from the market, so should no longer
be on store shelves. . . . In the five incidents reported to FDA,
however, the burns occurred after the sunscreen spray had been
applied. The ignition sources were varied and involved lighting a
cigarette, standing too close to a lit citronella candle,
approaching a grill, and in one case, doing some welding (Ref. 156).

These cases all involved a single manufacturer's product that has since
been voluntarily recalled. Review of adverse event reports since the
voluntary recall of this product indicates that no additional cases
involving spray sunscreens have been reported. However, sunscreens are
often used in very hot outdoor environments with high ambient air
temperatures. Sunscreens are also frequently used around sources of
flame or sparks, such as grills, bonfires, smoking, or other ignition
sources. To ensure safe use of spray sunscreens and to better inform
consumers about potential flammability risks, we are proposing to limit
the flammability and require flammability labeling of spray sunscreens
under the OTC sunscreen monograph.
FDA's general labeling regulations for OTC drugs provide for OTC
monographs to require flammability labeling in suitable cases (Sec.
201.66(c)(5)(ii)(C)) (21 CFR 201.66(c)(5)(ii)(C))), and we have done so
for products such as topical antitussives (21 CFR 341.74) and wart
removers (21 CFR 358.150). As we did for those products, we are
proposing to require each spray sunscreen formulation to be labeled for
flammability in accordance with the testing methodology described in a
regulatory provision issued by the Consumer Product Safety Commission
(CPSC) (see 16 CFR 1500.43a). We have proposed to incorporate this
flash point testing methodology to address our concern regarding the
flammability of sunscreen in the spray dosage form after it has been
dispensed onto the skin. We therefore propose that all batches of
sunscreen spray products be tested for flammability in accordance with
16 CFR 1500.43a as part of batch release testing conducted in
accordance with CGMP requirements.
We are also proposing to define three flammability categories for
use in regulating and labeling sunscreens: (1) Extremely flammable, (2)
flammable, and (3) combustible. These definitions refer to flash point
testing to be performed using the method described in 16 CFR 1500.43a.
These definitions are analogous to certain CPSC definitions located at
16 CFR 1500.3. Given the conditions under which sunscreens may be used,
we are proposing that spray sunscreens found to meet the definition of
extremely flammable in proposed Sec. 352.3(f) are not GRASE and may
not be marketed under the OTC sunscreen monograph. Products found to
meet the definition of flammable or combustible in proposed Sec.
352.3(g) or (h) would be required to include the following language in
the ``Warnings'' section of the drug facts labeling: [bullet]
``Flammable'' or ``Combustible'' [as applicable] followed by a colon
and the statement ``Keep away from fire or flame''.
A further concern related to flammability is the time required for
volatile solvents in a spray product to dry on the skin before a
consumer can safely approach a source of heat or flame or can smoke
without danger of fire. Typical sunscreen spray formulations contain 50
to 80 percent of a volatile carrier, most commonly ethyl alcohol. These
volatile solvents are necessary to the formulation to allow the product
to be sprayed onto the skin. After spraying, the solvents are intended
to rapidly evaporate leaving a film of UV filters on the skin surface
as the product dries. Once a spray product is dry, the solvent is no
longer present so the flammability risk is low. However, prior to this
point, the flammability risk would be higher.
We think that consumers should be warned to stay away from sources
of flame while a flammable or combustible sunscreen spray dries. For
this reason, we propose to require that each batch of a sunscreen spray
product that meets the definition of flammable or combustible at Sec.
352.3(g) or (h) be tested for drying time in accordance with written
specifications. If the drying time is less than 5 minutes, we propose
to require that the labeling state, ``Wait 5 minutes after application
before approaching a source of heat or flame, or before smoking.'' If
the drying time is at least 5 minutes but less than 10 minutes, we
propose that the labeling would state, ``Wait 10 minutes after
application before approaching a source of heat or flame, or before
smoking.'' We propose that a sunscreen spray that is flammable or
combustible and that takes 10 minutes or more to dry would not be GRASE
because of the possibility of consumers approaching sources of fire

[[Page 6233]]

during such an extended drying period. We invite comment on this
approach.
4. Powder Dosage Forms
Although we have found powder sunscreens to be eligible for
consideration in the OTC sunscreen rulemaking, we have tentatively
determined that additional data as outlined below will be needed to
support a conclusion that sunscreens in this dosage form are GRASE and
to support consideration of appropriate labeling. Also, like sprays,
powder sunscreens pose the potential for unintended inhalation, and for
this reason, if admitted to the sunscreen monograph, the same
limitations as to particle size here proposed for sprays would be
expected to apply. For powder sunscreens that meet the particle size
limitations proposed for sprays, we do not expect that additional
toxicology data would be needed to address the potential health risks
associated with inhalation.
One comment on the Dosage Forms ANPR provided data on SPF and broad
spectrum performance of five powder formulations, as well as data from
repeated insult patch tests and photosensitivity studies that were
asserted not to show any safety issues. FDA has conducted particle
distribution testing on five powder sunscreens. The powder sunscreens
tested had a larger proportion of relatively small particles compared
to the sprays. Only one of the five powder sunscreens would have
complied with the requirement we are considering that no more than 10
percent of the particles could be smaller than 10 [micro]m in diameter,
and that product was also the only one that would have met the
prospective limitation of no particles smaller than 5 [micro]m in
diameter (Refs. 153 and 154). Based on the data submitted, we believe
that (current and proposed) SPF and broad spectrum test methods are
appropriate for use with powder sunscreens, and we are not requesting
additional respiratory safety information for powders that meet the
same particle size limitations proposed for spray sunscreens.
FDA invites comments and data on the following topics related to
powder sunscreens:
What amounts of powder sunscreens do consumers typically
dispense?
What amounts of powder sunscreens are effectively
transferred to the skin?
How uniform is the sunscreen application across the sun-
exposed area of the skin?
How frequently do consumers reapply the product?
Does rubbing a powder into the skin change sunscreen
effectiveness?
Are powder dosage forms water-resistant? If they are not
water-resistant, is a direction to reapply every 2 hours sufficient to
assure their safe and effective use?
Can the powder dosage form be used safely and effectively
over all areas of skin exposed to the sun, or should this dosage form
be limited to the face?
What factors, if any, should FDA consider in connection
with particle size limitations or test methods for sunscreen powders?
Are there important differences among powder types (e.g.,
loose, compact) or applicators that would affect particle size testing?

FDA will evaluate data and information submitted in response to these
questions, as well as any other submitted or available data, to
determine whether additional data are needed to support a final GRASE
determination for this dosage form.

B. Proposed Maximum SPF and Broad Spectrum Requirements

In the Stayed 1999 Final Monograph, FDA established SPF 30+ as the
maximum labeled SPF value for sunscreen monograph products, and
required that each sunscreen monograph active ingredient contribute a
minimum SPF of 2 to finished sunscreen products (64 FR 27666 at 27672,
27674 and 27675). The final monograph did not include any broad
spectrum protection provisions. In its 2001 decision to stay the final
monograph, however, FDA indicated that it was issuing the stay because
the Agency intended to amend the sunscreen monograph to address
requirements for both UVA and UVB radiation protection (66 FR 67485).
FDA later addressed these issues in the 2011 L&E Final Rule, which,
among other things: (1) Established optional broad spectrum labeling
based on satisfaction of a critical wavelength test, (2) created an
optional indication relating to skin cancer and early skin aging risk
reduction for broad spectrum products with an SPF of 15 or higher, and
(3) required a labeling warning for sunscreens that did not both
satisfy the broad spectrum test and provide an SPF of at least 15 (76
FR 35620 at 35626-35628) (L&E Final Rule). Concurrently with
publication of the L&E Final Rule, FDA issued a proposed rule to raise
the maximum labeled SPF value for sunscreen products containing
sunscreen monograph active ingredients to SPF 50+ (76 FR 35672, June
17, 2011).
In the time since these 2011 publications, the body of evidence in
the published literature on UVA radiation (particularly UVA I
radiation) and its role in the development of skin cancer has grown.
This new data about the harms of UVA exposure is a significant concern
given, among other things, that with currently available sunscreens,
consumers may unknowingly accumulate excessively large UVA doses by
using sunscreens with high SPF values that either: (1) Do not pass
FDA's current critical wavelength-based broad spectrum test or (2) have
inadequate uniformity in their UVA protection. Because of these
concerns, we are making a number of proposals designed, among other
things, to couple a greater magnitude of UVA protection to increases in
SPF values.
1. Background
UV radiation includes both UVA and UVB rays. UVB rays (i.e., those
with wavelengths from 290 to 320 nm) are higher energy, are much more
effective at producing sunburn, and produce greater amounts of cellular
damage (including DNA lesions, which can result in gene mutations
linked to skin cancers) (Refs. 157 and 158). UVA rays (i.e., those with
wavelengths from 320 to 400 nm) are lower energy and less effective at
producing sunburn, but make up the majority of UV radiation, and
penetrate much deeper into the skin, potentially causing oxidative
damage (through formation of ROS) to skin pigment cells (Ref. 159). UVA
rays also contribute to photo-aging (Ref. 157 and 160). Although the
current scientific literature attributes UV-signature DNA lesions
primarily to UVB wavelengths, UVA wavelengths can also produce DNA
lesions. Although UVA wavelengths produce DNA lesions to a
significantly lesser degree than UVB wavelengths do, DNA lesions
produced by UVA rays have been reported to have slower repair rates
(Ref. 157). UVA rays are comprised of UVA I rays (340 to 400 nm) and
UVA II rays (320 to 340 nm). As discussed below, until recently, UVA I
rays were generally not considered to contribute significantly to the
harms associated with UV exposure.
Sunscreen products must be labeled with an SPF value calculated
using a standardized SPF testing procedure set forth in FDA regulations
(see Sec. 201.327(i)). ISO 17166 CIE S 007/E was approved for
incorporation by reference into Sec. 201.327(i) as of June 18, 2012
(76 FR 35619, June 17, 2011). The SPF test measures the amount of UV
radiation exposure it takes to cause

[[Page 6234]]

sunburn when a person is using a sunscreen compared with how much UV
exposure it takes to cause sunburn when the person is not using a
sunscreen. Sunscreens with increasing SPF values (up to a certain
point) have been demonstrated to provide increased sunburn protection.
Because SPF values represent a sunscreen's level of sunburn protection,
they are primarily (though not exclusively) an indicator of expected
protection from UVB radiation. To pass FDA's current test for broad
spectrum labeling (Sec. 201.327(j)), however, sunscreens must
demonstrate that, in addition to UVB protection, they also provide some
UVA protection.
Only products that have been determined to have a minimum SPF value
of 15 and to pass our broad spectrum test may include statements in
their labeling indicating that they decrease the risk of skin cancer
and early skin aging caused by the sun when used as directed with other
sun protection measures (Sec. 201.327(c)(2)). In contrast, sunscreens
that have not been determined to provide both broad spectrum protection
and an SPF value of at least 15 must include a skin cancer/skin aging
alert warning to consumers that ``[s]pending time in the sun increases
your risk of skin cancer and early skin aging'' and that ``[t]his
product has been shown only to help prevent sunburn, not skin cancer or
early skin aging'' (Sec. 201.327(d)(2)).
2. Increased Evidence of Harms Associated With Exposure to UVA
Radiation
Since publication of the 2011 L&E Final Rule and Max SPF PR, the
strength of scientific evidence linking UVA exposure to skin cancers
and other harms has increased. This evidence suggests that UVA
wavelengths continue generating DNA lesions hours after UV exposure
(Ref. 161) and that if left unrepaired, these DNA lesions can form UV-
induced mutations in many genes that have been detected in both
melanoma and nonmelanoma skin cancers (Refs. 162 to 165). Further,
unlike UVB-induced DNA lesions, which attenuate with skin depth, recent
evidence indicates that DNA lesions induced by UVA I exposure show the
opposite pattern, with both increased DNA lesions in the basal layer of
the epidermis (where melanocytes and proliferating keratinocytes
reside) and less efficient DNA lesion repair in the basal layer (Refs.
166 and 167).
Damage to cells in the basal layer (if left unrepaired or if
inefficiently repaired) can lead to mutations in critical genes that
increase the possibility that normal cells will transform into cancer
cells. While inefficient DNA repair is a concern for all individuals
exposed to UV radiation, this concern is particularly acute in those
with xeroderma pigmentosum (a disease caused by a disorder of the DNA
repair system), who have extreme sensitivity to UV radiation, and who
develop both nonmelanoma skin cancer and melanoma with a high frequency
and very early in life (Ref. 168). In addition to the skin cancer-
related risks associated with UVA exposure, increasing evidence shows
that UVA I radiation also produces immunosuppression (Refs. 169 and
170). This, too, is a general concern for all individuals, but is
especially dangerous for certain at-risk populations (such as organ
transplant recipients and others on immunosuppressive drugs).
Given the above-described evidence, we are concerned about the
existing potential for inadequate UVA protection in marketed sunscreen
products. This is a particular concern with respect to high SPF
sunscreen products that do not pass FDA's current critical wavelength-
based broad spectrum test or that (though they pass our current broad
spectrum test) have inadequate uniformity in their UVA protection.
Consumers using these products may, while successfully preventing
sunburn, accumulate excessively large doses of UVA radiation, thereby
exposing themselves to additional risks related to skin cancer and
early skin aging. The International Agency for Research on Cancer has
found that high SPF sunscreen products are associated with longer
intentional UV exposures (Ref. 171), raising the concern that use of
these products may result in significant doses of UVA radiation. We
note that concerns relating to inadequate UVA protection came up in
several comments we received in response to the 2011 Max SPF PR, and
that these comments raised particular concerns about inadequate UVA
protection in high SPF products. This concern has also grown over time
in the published literature (Refs. 172 to 175).
For all of these reasons, we are proposing a number of steps
designed to couple a greater magnitude of UVA protection to increases
in SPF values. As discussed in further detail below, we are also making
proposals designed to address evidence of variability in SPF values and
evidence showing additional clinical benefits associated with SPF 60
sunscreens.
3. Broad Spectrum Proposals
a. UVA I/UV ratio required to pass the broad spectrum test. We are
proposing certain changes to the requirements to pass the broad
spectrum test. Specifically, we are proposing to add to the current
broad spectrum test a requirement that products meet a UVA I/UV ratio
of 0.7 or higher. We note that the current broad spectrum test
procedure would remain unchanged \40\ and that this new ratio would be
calculated using data from the existing test, which should help
minimize burden on manufacturers.
---------------------------------------------------------------------------

\40\ We note that, as described in section IX.D.2.i, we are
proposing a minor revision in equipment specifications for the broad
spectrum test to respond to feedback that FDA received on this issue
and proposing some minor revisions to current language to make clear
our existing expectations.
---------------------------------------------------------------------------

The current labeling regulation requires that sunscreens labeled as
broad spectrum achieve a critical wavelength of 370 nm or greater
(Sec. 201.327(j)). A sunscreen product's UV protection is often
displayed as a curve on a graph showing the amount of UV absorbance the
product provides at each wavelength in the UV spectrum (i.e., from 290
to 400 nm). The ``critical wavelength'' of the product is the
wavelength corresponding to 90 percent of the area under this curve.
Higher critical wavelengths, therefore, illustrate greater breadths of
UV protection across the 290 to 400 nm spectrum.
Most sunscreen products--even if they achieve a critical wavelength
of 370 nm or greater and therefore meet the current criteria for broad
spectrum labeling--have historically covered the UVB and UVA II ranges
preferentially. Given how much of the UVA portion of the UV spectrum is
composed of UVA I radiation (see Figure 3 below) and given what we now
know about the risks associated with UVA exposure, and with UVA I
exposure in particular, ensuring that sunscreen products provide
adequate protection in the UVA I portion of the spectrum is critical.

[[Page 6235]]

[GRAPHIC] [TIFF OMITTED] TP26FE19.002

We are therefore proposing to require that in order to pass the
broad spectrum test, a product must demonstrate that it provides a UVA
I/UV ratio of 0.7 or higher, indicating that the product provides a
minimum measure of UVA I radiation absorbance relative to total UV
radiation (i.e., UVB + UVA) absorbance, in addition satisfying to the
370 nm critical wavelength requirement. Requiring a UVA I/UV ratio of
0.7 or higher for broad spectrum products would mean that these
products would have a more uniform amount of radiation protection
across the UVA I, UVA II, and UVB ranges. This improved fidelity across
the UV spectrum is especially important for high SPF products which, as
discussed above, are associated with longer intentional sun exposure,
which in turn can result in significant doses of UVA radiation. This
proposed UVA I/UV ratio would also help eliminate the current potential
for a product labeled as broad spectrum that has a higher SPF value to
provide (unbeknownst to the consumer) poorer broad spectrum protection
than a product labeled as broad spectrum with a lower SPF value
(depending on the particular combination of active ingredients used in
the product and which parts of the UV spectrum they absorb). For
example, under the current testing regime, a sunscreen that is labeled
``broad spectrum SPF 30'' could provide less UVA protection than a
sunscreen labeled ``broad spectrum SPF 15.''
We note that FDA first raised concerns relating to the adequacy of
UVA protection in sunscreen products in 2007 (see 72 FR 49070 at 49104
to 49107). At that time, we proposed a similar ratio to the one we are
proposing today as part of a different, more complex proposal for
testing and labeling to address broad spectrum protection that, among
other things, included both in vitro (spectrophotometric) and in vivo
(clinical) testing for UVA radiation, as well as a four-tier UVA star
rating labeling system. In response to comments describing purported
disadvantages of that proposal, including general comments that the
proposal was overcomplicated, specific comments on the proposed in
vitro testing method, and comments indicating that ``[t]he proposed
ratio places too much emphasis on the UVA I region, which is not
generally considered to contribute significantly to the harmful effects
of exposure to UV radiation'' (76 FR 35620 at 35650), we made a number
of changes to our 2007 proposal in the 2011 L&E Final Rule. Those
changes included elimination of the UVA I/UV ratio and adoption of the
above-described critical wavelength test for establishing broad
spectrum protection instead. As we noted in the preamble to the L&E
Final Rule, our decision not to require the UVA I/UV ratio at that time
was based, in part, on our agreement with comments stating that the
scientific evidence available at that time indicated that UVA I
exposure did not pose sufficient risk of harm to justify the emphasis
placed on it by the ratio, and that the critical wavelength test
provided a superior measure of broad spectrum protection (id. at
35650).
As described above, in the time since issuance of the L&E Final
Rule, the body of evidence showing the harms of UVA exposure, and of
UVA I exposure, in particular, has grown significantly (Refs.

[[Page 6236]]

159, 161, 162, 166, 167, and 169). It is now clear that in addition to
producing the immunosuppression described above, UVA I exposure also
results in increasing DNA damage with increasing skin depth (in
contrast to UVB-induced DNA damage, which is reduced as skin depth
increases). In addition, given that UVA I is the predominant portion of
UVA radiation, new evidence (discussed in section IX.B.2) strengthening
the link between UVA radiation and skin cancer development raises our
concerns about the potential for inadequate protection in the UVA I
portion of the UV spectrum. Accordingly, we no longer agree with the
earlier comments suggesting that UVA I does not contribute
significantly to the harmful effects of exposure to UV radiation, or
with our 2011 conclusion that a UVA I/UV ratio requirement would
therefore place too much emphasis on this portion of the UV spectrum.
We emphasize that we are not proposing to replace the existing
critical wavelength test, and that the proposed ratio would supplement
(and be calculated using data from) the existing broad spectrum test.
We also note that the UVA I/UV ratio we are proposing would result in a
level of UVA protection similar to what is achieved via the European
Union's recommended minimum UVA protection factor of \1/3\ of the
labeled SPF and via the United Kingdom's Boots 3-star rating (the
United Kingdom has for decades used a tiered star rating system based
on an alternative ratio method) (Refs. 173 and 174). We note that data
collected in 2009 about 330 sunscreen products commercially available
in the United States showed that, at that time, more than half of these
products already satisfied the broad spectrum test we are now proposing
(see Comment, Docket No. FDA-1978-N-0018-0690).
b. Broad spectrum requirement for all products that are
=SPF 15. We are also proposing to require that all sunscreen
products with SPF values of 15 and above demonstrate that they provide
more uniform protection across the UVA I, UVA II, and UVB ranges of the
UV spectrum by satisfying FDA's revised broad spectrum test. This
proposal is designed to link increases in SPF value not only to
increases in UVB protection, but to increases in the magnitude of UVA
protection as well. We note that a consumer using a sunscreen that
provides robust protection against sunburn but that does not pass FDA's
revised broad spectrum test--and therefore provides inadequate UVA
protection--may fail to get out of the sun, thereby exposing themselves
to higher levels of UVA radiation than if they had not been protected
from sunburn. Given the increasing evidence of major health risks
associated with UVA exposure, we propose to find that such products
(those with SPF values of 15 and greater that do not provide sufficient
protection across the UV spectrum (as demonstrated by satisfying FDA's
revised broad spectrum requirement)) are not GRASE. At the same time,
we conclude that the evidence described above regarding the
contribution of UVA I to skin carcinogenesis, coupled with the evidence
reviewed in the 2011 L&E Final Rule (see 76 FR 35620 at 35630-35634),
supports the proposal to include sunscreen products that have an SPF of
15 or higher and also pass the revised broad spectrum test in the
sunscreen monograph with indications both for use to help prevent
sunburn and for use, as directed with other sun protection measures, to
reduce the risk of skin cancer and early skin aging caused by the sun.
As we indicated in the L&E Final Rule, the whole range of UV radiation,
and not specific wavelengths, is a human carcinogen, and the exact
wavelengths most responsible for these harmful effects are not known
(see id. at 35631, 35633). To assure that a clinically meaningful
reduction in the risks of skin cancer and early skin aging is achieved,
then, a product must contribute to substantially limiting overall UVB
and UVA exposure (see id. at 35630, 35631-35632), as will be assured by
our proposal to couple the enhanced breadth of protection across the
UVA spectrum provided by the revised pass criteria for the broad
spectrum test with the magnitude of protection assured by requiring a
minimum SPF of 15.
By requiring that all sunscreens with SPF values of 15 or more
satisfy the (new) broad spectrum standard (including the new ratio
requiring proportionate protection), this proposal will also enable
consumers to select a product primarily by numerical (SPF) value on the
label, having assurance that, when used as directed, a product labeled
with a higher numerical SPF value provides proportionately more
protection not only against sunburn, but also against skin cancer and
skin aging than lower numbered products \41\ (provided that the product
provides an SPF of at least 15). In doing so, this proposal also
eliminates another source of potential confusion permitted by the
current labeling regime, in which a higher numbered product (for
example, one labeled SPF 30) may provide inferior protection against
UVA radiation than a lower numbered product (for example, one labeled
Broad Spectrum SPF 15).
---------------------------------------------------------------------------

\41\ As noted in section III.A.2, only those broad spectrum
sunscreen products that have an SPF of 15 or higher have been shown
to help prevent skin cancer and early skin aging.
---------------------------------------------------------------------------

c. Sunscreen products with SPFs <15. As noted above and in section
III.A.2, sunscreen products with SPF values below 15 have not been
shown to reduce the risk of skin cancer or early skin aging caused by
the sun, whether or not they provide broad spectrum protection. Because
of this limitation, we considered proposing to remove from the
monograph sunscreen products with SPF values lower than 15. However, as
the Surgeon General has acknowledged (Ref. 5), some consumers may seek
intentional sun exposure because (for example) they associate tanned
skin with attractiveness and health. These consumers may seek some
protection from sunburns and therefore, select a low SPF product (i.e.,
one with an SPF value below 15). If such products are removed from the
market, these consumers may choose not to use a sunscreen product at
all rather than use a broad spectrum product with an SPF of 15 or
above.
Although the benefits of sunscreen products with SPFs below 15
(which are not indicated to reduce the risk of skin cancer or early
skin aging) are limited, FDA believes that the use of such products is
preferable to the use of no sunscreen at all. Thus, to provide sunburn
protection for these consumers, FDA is proposing that sunscreens with
SPF 2 to 14 that bear prominent labeling regarding their limited use
for sunburn prevention and the risks associated with spending time in
the sun (see sections IX.B.1 and IX.C) may remain on the market without
approved NDAs. Because products with SPFs below 15 have not been
demonstrated to reduce the risk of skin cancer, FDA is not proposing to
require products with SPF values under 15 to pass the broad spectrum
test. However, we seek comment on whether the limited benefits such
sunscreen products confer outweigh the risks of sunscreen drug exposure
and the potential false sense of security provided regarding UV
protection (i.e., whether such sunburn-only sunscreen products are
GRASE and should remain on the market without approved NDAs).
4. Maximum SPF Value Proposals
a. Maximum labeled SPF value would be SPF 60+. In conjunction with
the broad spectrum proposals described above, we are also proposing to
raise the maximum labeled SPF value for

[[Page 6237]]

products containing sunscreen monograph active ingredients to SPF 60+.
Under this proposal, sunscreen products with SPF values of 60 or
greater would be labeled ``SPF 60+.''
FDA has proposed to raise the maximum SPF value that sunscreens
marketed pursuant to the OTC Monograph System can display on their
labeling several times. In the 1978 notice of proposed rulemaking, we
proposed that such sunscreens be labeled with a maximum SPF value of 15
(43 FR 38206 at 38213 to 38214). In the 1999 final monograph, we
determined that that cap should be increased to SPF 30+ (64 FR 27666 at
27675). In 2007 (72 FR 49070 at 49085 to 49087) and then in 2011 (Max
SPF PR), we tentatively concluded that data existed to show that
sunscreens with labeled SPF values of up to 50+ provide additional
clinical benefit to consumers. Our proposal today to increase the
maximum labeled SPF value to 60+ is similarly based on data showing the
additional clinical benefit provided by SPF 60 sunscreen products when
those products also provide broad spectrum protection.
In the 2011 Max SPF PR proposing an SPF 50+ cap, we noted that the
record, at that time, lacked adequate data demonstrating that sunscreen
products with SPF values above 50 provided additional meaningful
clinical benefit over and above what was provided by SPF 50 protection
(76 FR 35672 at 35672 to 35674). We requested data showing that such
clinical benefits existed (id.). In response to both the 2007 and 2011
proposals, we received comments providing citations to data showing the
additional meaningful clinical benefit provided by sunscreen products
with SPF values of 60 for certain at-risk populations when those
sunscreens also included broad spectrum protection. (See, e.g., Ulrich
et al. (showing statistically significant protection of organ
transplant recipients, who are highly susceptible to nonmelanoma skin
cancer, from squamous cell carcinoma with use of broad spectrum SPF 60
sunscreen) (Ref. 176); see also Comment FDA-1978-N-0018-0710, August
31, 2011, citing Kuhn et al. (showing statistically significant
prevention of skin lesions in topical lupus erythematosus patients with
use of broad spectrum SPF 60 sunscreen after exposure to either UVA I
source or UVA II/UVB source) (Ref. 177); Faurschou et al. (showing
prevention of urticarial reaction in subjects with idiopathic solar
urticaria with use of broad spectrum SPF 60 sunscreen) (Ref. 178);
Fourtanier et al. (showing lower levels of polymorphous light eruption
in subjects using broad spectrum SPF 60 versus SPF 50 products (Ref.
179)). Based on the additional meaningful clinical benefit provided by
broad spectrum SPF 60 sunscreens shown in these studies, we are
proposing to raise the maximum labeled SPF value to SPF 60+.
Because the studies demonstrating the additional meaningful
clinical benefit provided by SPF 60 sunscreens all used sunscreens that
also provided broad spectrum protection, however, the additional
clinical benefit shown to exist at SPF 60 cannot be decoupled from the
broad spectrum protection provided by those products. That is, the
additional meaningful clinical benefit shown in these studies may have
been the result of the sunscreens' protection against rays in the UVB
range or in the UVA range, or both. For this reason, our proposal to
recognize the additional meaningful clinical benefit provided by
sunscreens with SPF values above 50 is consistent with, and dependent
upon, our proposal that all sunscreen products with SPF values of 15
and above be required to provide broad spectrum protection.
Given the lack of data showing that sunscreens with SPF values
above 60 provide additional meaningful clinical benefit, however, we
are proposing not to allow labeled SPF values higher than 60+. Labeling
sunscreen products with SPF values higher than what has been shown to
provide additional meaningful clinical benefit could have unintended
negative consequences. For example, as discussed above, such products
may inadvertently promote extended solar exposures because consumers
feel protected and assume that the higher SPF value implies that
greater UV exposure is safe (see, e.g., Autier, et al., 2007 (Ref.
171)).
b. Formulation cap for sunscreen products of SPF 80. Although we
are proposing that the maximum labeled SPF value will be SPF 60+, we
are proposing to permit the marketing of sunscreen products formulated
with determined \42\ SPF values up to 80. We are proposing to permit
this additional formulation margin in part because of the inherent
variability in SPF test results. A sunscreen product's SPF value is
calculated from measurements that are based on an investigator's visual
evaluation of an individual test subject's erythema response to a
series of UV doses administered in successive sites on the subject's
back. Because the administered UV dose series for the final minimal
erythema dose (MED) \43\ of a sunscreen with an expected SPF of 60
increases by 15 percent with each successive dose (see Sec.
201.327(i)(5)(iii)), a difference in judgment of one site in opposing
directions would result in up to approximately 30 percent variability
in the assessment of the amount of exposure that resulted in the
erythema.\44\
---------------------------------------------------------------------------

\42\ As used in this preamble, the determined SPF value is the
SPF value that equals the largest whole number less than SPF-(t*SE),
determined for a sunscreen product in accordance with Sec.
201.327(i). See also section IX.D.2.b, where we propose to define
this term in the regulation.
\43\ The minimal erythema dose (MED) is the smallest UV dose
that produces perceptible redness of the skin (erythema) with
clearly defined borders at 16 to 24 hours after UV exposure (Sec.
201.327(i)(5)(i)).
\44\ The determination of SPF for each subject is calculated via
a ratio of the MED of protected skin over the final MED of
unprotected skin. In a scenario in which the final MED of
unprotected skin is underestimated by 15 percent and the MED of
protected skin is overestimated by 15 percent, this would present
approximately 30 percent variability for the individual subject.
---------------------------------------------------------------------------

Allowing the marketing of sunscreen monograph products with
determined SPF test results up to 80 would, therefore, more fully
account for the range of variability in SPF test results for sunscreen
products labeled SPF 60+. We are also proposing this formulation margin
to provide manufacturers with additional formulation flexibility that
we hope will help facilitate the development of products with greater
UVA protection, given our expectation that active ingredients added for
the primary purpose of increasing UVA protection would contribute to a
sunscreen's determined SPF value as well. We seek comment on whether
SPF 80 is the appropriate formulation cap to accomplish these
objectives.
We are proposing not to allow the marketing (without an approved
NDA) of sunscreen products with determined SPF values above SPF 80.
This proposal follows from the principle that if the addition of
ingredients to a drug does not provide additional clinical benefit but
potentially increases the risk associated with the drug, this shifts
the benefit-risk calculation and renders the drug not GRASE (see, e.g.,
76 FR 35673 at 35675). In light of this principle, we solicited
comments in 2011 on the appropriateness of a formulation cap for
sunscreen products (id.).
Some of the comments that we received in response to the 2011 Max
SPF PR expressed concerns (in general) about the safety of unnecessary
exposure to sunscreen active ingredients. We received only one comment,
however, directly addressing the question of an SPF formulation cap.
That comment emphasized that there was no formulation limit in other
countries using an SPF labeling cap, and

[[Page 6238]]

that the list of permitted active ingredients in the monograph itself
establishes an SPF ceiling for the formulation as a whole. FDA rejects
the premise that the list of permitted active ingredients establishes
an adequate SPF cap for sunscreen formulations, as this theory does not
take into account the potential addition of new GRASE ingredients to
the list of active ingredients under the monograph. This comment also
appears to imply that the maximum concentration of each active
ingredient correlates specifically to a particular numerical
contribution to the total SPF value of the product. This has not been
established (see 64 FR 27666 at 27674 and 27675 (noting that
formulation techniques may enable increases in SPF without use of
higher concentrations of active ingredients)). In addition, as
mentioned in 2011 in the Max SPF PR (76 FR 35672 at 35674), the
theoretical increase in protection implied by higher SPF values
generated in a laboratory does not necessarily correspond to meaningful
additional sunburn protection for consumers in actual use conditions.
Given that a solar simulator in a lab can produce much higher UV doses
than a consumer would receive from the sun (even in the most extreme
situations), it is unlikely that a consumer could ever actually reach
the theoretical ceiling created by the list of permitted active
ingredients.
Given the lack of demonstrated clinical benefit for sunscreens with
determined SPF values above SPF 60, and the potential for risks--
discussed elsewhere in this document--associated with exposure to
sunscreen active ingredients, we propose not to permit the marketing
(without an approved NDA) of sunscreen products with determined SPF
values above SPF 80 (which reflects a formulation margin intended both
to give full effect to the SPF 60 limit and to enable formulation
flexibility).
c. Proposal for =SPF 15 labeling. Finally, we are
proposing to require that sunscreen monograph products with determined
SPF values of 15 or above be labeled with an SPF number corresponding
to the lowest number in a range of tested SPF results, as shown in
table 5.\45\ For example, sunscreens testing at SPF 15 to 19 would be
labeled ``SPF 15''; those testing at 40 to 49 would be labeled ``SPF
40.'' \46\
---------------------------------------------------------------------------

\45\ We note that the use of ranges to represent SPF values on
product labeling is already in use in Australia and the European
Union (Refs. 180 and 181).
\46\ The proposed labeled values are expressed in increments of
5 for products with determined SPF results of 15 to 29.9 (i.e., SPF
15, SPF 20, SPF 25), but for determined SPF results of 30 or more,
the proposed labeled values are expressed in increments of 10 (i.e.,
SPF 30, SPF 40, SPF 50, with a proposed maximum of SPF 60+.).
---------------------------------------------------------------------------

This proposal is designed to avoid misleading consumers about the
relative efficacy of sunscreen products, given the lack of clinical
data showing meaningful efficacy differences between closely grouped
SPF values. We note that in the 2011 L&E Final Rule, FDA declined a
request that SPF be labeled in multiples of five, stating that there
was no mathematical or statistical basis for this labeling approach
because SPF values could generally be determined with a precision that
allowed for SPF values to be labeled in intervals of less than five
units. New data showing variability both between tested SPF values for
individual study subjects and for determined SPF results achieved
across multiple labs testing the same sunscreen formulation (i.e.,
variability inherent in a clinical test that relies on visual
assessments) (FDA-1978-N-0018-0740, 2011; Ref. 182), however, has
caused us to reexamine this issue.
As described above, the clinical SPF test is conducted using a
solar simulator to administer several specified doses of UV radiation
that increase by 15 to 25 percent with each successive dose to a human
subject's back in both sunscreen-treated and untreated areas (with the
specific UV doses being derived from the expected SPF of the product
and a determination of the individual subject's UV sensitivity). The
clinical investigator then visually evaluates both the sunscreen-
treated and untreated areas of the subject's back to identify the areas
with perceptible skin redness (erythema) that has clearly defined
borders. Determining which of several areas on a single subject's back
should be considered to meet this ``clearly defined borders'' criteria
is an exercise of clinical judgment. Once the investigator has made
this judgment, he or she then records the smallest dose of UV radiation
it took to create an area with the observed skin reaction of erythema
with clearly defined borders. After assessing multiple individual test
subjects this way, the resulting UV exposure information is used in
calculating the determined SPF value of the sunscreen being tested. The
data we reviewed suggest that the clinical evaluation undertaken during
this process creates variability that justifies the use of SPF ranges.
For example, in a study using panels of five subjects, the mean SPF
values observed across multiple labs ranged from 54 to 82 for a target
SPF 80 (FDA-1978-N-0018-0740, 2011). This same study also evaluated a
scenario where a lab was not told the target SPF, but was rather given
a range of SPF 20 to 100 for a product with an expected SPF of 100. The
results showed that it was extremely difficult for labs to reproduce
the labeled SPF 100, with mean SPF values ranging from 37 to 75. In a
second study with multiple panels of 25 subjects that was controlled
and randomized, the determined SPF of two sunscreen formulations tested
across four labs ranged from 63 to 69 for a target SPF 70 and from 82
to 89 for a target SPF 90 (Ref. 182). Although the magnitude of the
differences observed in this second study were not statistically
significant, the fact that multiple labs determined different specific
numerical values for a single formulation suggests that the use of
labeled values representing ranges more accurately represents the sun
protection provided by a product, and therefore is appropriate to avoid
misleading consumers.
We note that variability in SPF values is exacerbated at high SPFs.
For example, individual test results with 30 percent variability from a
determined SPF value of 20 would range from SPF 14 to SPF 26;
individual test results with 30 percent variability from a determined
SPF value of 50 would range from SPF 35 to SPF 65. Accordingly, as
shown in table 5, we propose that the range of tested values reflected
in the labeled SPF number should be wider at higher SPF values and
narrower at lower ones, and that the requirement that labeled SPF
values correspond to ranges rather than precise numerical values is not
necessary below SPF 15.

Table 5--Proposed SPF Labeling Ranges
------------------------------------------------------------------------
Range of determined SPF values Associated labeled SPF value
------------------------------------------------------------------------
60-80..................................... 60+.
50-59..................................... 50.
40-49..................................... 40.
30-39..................................... 30.
25-29..................................... 25.
20-24..................................... 20.
15-19..................................... 15.
2-14...................................... Determined SPF Value.
------------------------------------------------------------------------

C. Proposed PDP Labeling Requirements

We are also proposing some revisions to the principal display panel
(PDP) for sunscreen products (the PDP is the portion of an OTC drug
product label that is most evident when the product is displayed for
retail sale (Sec. 201.60)). In addition to satisfying general OTC drug
labeling requirements found in part 201,

[[Page 6239]]

sunscreen product PDPs are currently required to satisfy specific
labeling requirements in Sec. 201.327. We are proposing to amend these
requirements for sunscreen PDP labeling (currently codified in Sec.
201.327(a) and (b), and (for the statement of identity of products that
also include skin protectants) in Sec. 201.327(h)) to help consumers
better understand, evaluate, and compare sunscreen products by
providing additional information on the PDP, and by ensuring the
prominence and readability of information required to appear on the
front of the container or package. We are also proposing to renumber
and consolidate provisions on PDP labeling and the statement of
identity (SOI) in Sec. 201.327(b) to incorporate new proposed
provisions in Sec. 201.327(a), as described in section IX.D.2.b of
this preamble. In addition, we are proposing that labeling a sunscreen
product in accordance with proposed Sec. 201.327(b) would be a
condition for marketing a sunscreen under the OTC sunscreen monograph
in part 352.
We are proposing to revise the current SOI, which is required to
appear on the PDP by both current and proposed Sec. 201.327.
Currently, the SOI for sunscreens under this regulation contains ``the
established name of the drug, if any'' and identifies the product as a
``sunscreen.'' The revised SOI would consist of an alphabetical listing
of all sunscreen active ingredients in the product using the names
shown in Sec. 201.327, followed by ``Sunscreen'' and the product's
dosage form (such as lotion or spray). In light of these proposed
changes to the SOI for sunscreens, we are also proposing harmonizing
changes to the provisions that address the SOI for products that
combine sunscreen and skin protectant active ingredients (proposed
Sec. 201.327(h) and cross-referenced in the sunscreen monograph in
Sec. 352.60 (21 CFR 352.60) and in the skin protectant monograph in
Sec. 347.60 (21 CFR 347.60)).
The proposal to list all active ingredients as part of the SOI is
generally consistent with SOI labeling of other OTC and prescription
drugs. Providing information about a product's active ingredients and
dosage form would supplement other important elements of the PDP (SPF,
broad spectrum, and water resistance information) to provide a succinct
summary of the product's key characteristics on the front of the
package or container. We expect that this approach would enable
consumers to more readily compare differing products and either select
or avoid a given product accordingly. As an indication that consumers
value information about a sunscreen's active ingredients, an analysis
of top-rated sunscreen product reviews on Amazon.com found that product
ingredients were listed as a positive factor in 17 percent of
responses, and a negative factor in 10 percent of responses (Ref. 183).
Based on a review of marketed sunscreen product labels, FDA is
concerned that the SOI may currently be obscured by the inclusion and
prominence of other printed or graphic information on the PDP. For this
reason, we also propose to require the SOI to appear in direct
conjunction with the most prominent display of the proprietary name, in
a boldface font at least one-fourth the size of the most prominent
printed matter on the PDP, and displayed so that the text is generally
parallel to the base of the packaging. We propose that the entire SOI
appear in the same font style, size, and color with the same background
color, and as continuous text with no intervening text or graphic
material other than text provided in accordance with the requirements
for the SOI for a product that also includes a skin protectant, where
applicable. These requirements would supplement, and not replace, the
general requirements regarding the PDP and SOI for all nonprescription
products in Sec. Sec. 201.60 and 201.61.
Proposed Sec. 201.327(b) would incorporate the ``Broad Spectrum
SPF,'' ``SPF,'' and ``Water Resistant'' statements that already must
appear on the PDP as described in current Sec. 201.327(a).
Additionally, for all products with SPF values below 15, we propose to
require that the SPF statement be followed by an asterisk (*) directing
the consumer to the statement ``*See Skin Cancer/Skin Aging Alert.'' We
propose that the quoted statement must appear in the bottom 30 percent
of the PDP. This statement is intended to draw the consumer's attention
to the Skin Cancer/Skin Aging Alert that would continue to be required
for these products as part of the ``Warnings'' in the Drug Facts
portion of the label (Sec. 301.327(d)), because there is evidence that
some sunscreen consumers are not reading this information in its
current location (Refs. 184 and 185).
Under the current regulation, the entirety of the ``Broad Spectrum
SPF'' or ``SPF'' statement, as applicable, must appear on the sunscreen
PDP in the same font style, size, and color and with the same
background color, and, if used, the ``Broad Spectrum SPF'' statement
must also appear as continuous text with no intervening text or
graphic. To further ensure the prominence and readability of
information that is important for consumers to evaluate and compare
sunscreen products, we propose that these statements must also appear
in bold typeface at least one-fourth the size of the most prominent
printed matter on the PDP, and as text generally parallel to the base
of the packaging.
The proposed new ``*See Skin Cancer/Skin Aging Alert'' statement
would also be required to appear in bold typeface at least one-fourth
the size of the most prominent printed matter on the PDP, and as text
generally parallel to the base of the packaging. In addition, the
entire statement would appear in the same font style, size, and color
with the same background color, and as continuous text with no
intervening text or graphic.
Finally, because water resistance is also an important
characteristic for consumers when choosing a sunscreen, we also propose
to apply comparable format requirements to the current ``Water
Resistant'' statement. The statement would also be required to appear
in bold typeface at least one-fourth the size of the most prominent
printed matter on the PDP, and displayed so that the text is generally
parallel to the base of the packaging. In addition, the entire
statement would appear in the same font style, size, and color with the
same background color, and as continuous text with no intervening text
or graphic.

D. Proposed Requirements Related to Final Formulation Testing and
Recordkeeping

We are also proposing a number of revisions in Sec. 201.327: (1)
To ensure that efficacy testing of the sunscreen formulation to be
marketed is conducted in a way that protects human subjects and
produces reliable results and (2) to enable FDA to assess compliance
with this section's provisions going forward. We also propose to make
compliance with these requirements a monograph condition in part 352.
1. General Approach to Final Formulation Testing
Current Sec. 201.327 includes technical instructions for
conducting the final formulation testing required to support the SPF
values, water resistance statements, and broad spectrum statements
shown in sunscreen product labeling. However, the current regulation
does not explicitly address important broader considerations that are
essential to ensure that final formulation testing is conducted and

[[Page 6240]]

documented in a way that verifiably provides for protection of human
subjects in SPF and water resistance testing, as well as ensuring the
reliability of all the testing data that underlies sunscreen labeling.
We expect that persons responsible for conducting final formulation
testing should already be following best practices in their current
testing programs. However, we are concerned that many entities may not
uniformly observe such practices and/or may not maintain the records
needed to document compliance with the final formulation testing
procedures set forth in Sec. 201.327. FDA's experience in conducting
inspections and other actions to verify testing under the current
provisions of Sec. 201.327 have suggested latent problems in these
areas. Although limited, this experience reinforces FDA's belief that
further clarification of regulatory expectations is necessary given the
public health importance of ensuring that sunscreen products are
effective and accurately labeled, and the broad range of entities that
may be involved in bringing sunscreen products to market. Thus, we are
proposing to incorporate FDA's current expectations more explicitly in
the revised provisions. The proposed provisions are broadly consistent
with current best practices for efficacy testing conducted in human
subjects, and are not expected to require significant changes by
reputable and experienced testing establishments. Key areas of concern
that are addressed by the proposed revisions include the following.
a. Protection of human subjects and oversight of clinical final
formulation testing. Ensuring that clinical final formulation testing
is both designed and conducted in a manner that will yield reliable
results is critical, as is ensuring the protection of the human
subjects on whom SPF and water resistance testing are conducted.
Existing provisions within the SPF test in Sec. 201.327(i)(3)(iv)
require that informed consent be obtained, but do not otherwise specify
what this should involve or how clinical final formulation testing
should be overseen. Across disciplines, testing involving human
subjects is ordinarily conducted under institutional review board (IRB)
oversight as a means of ensuring that informed consent and other human
subject protections are provided and ensuring the integrity of study
design and execution. FDA likewise expects that IRB review is already
routinely being obtained by many establishments for SPF and water
resistance testing.
Nonetheless, our experience in conducting inspections and other
actions to verify the reliability of final formulation testing under
the current provisions of Sec. 201.327 have raised some questions
about current practices. For example, FDA's observations have raised
questions about whether and how entities conducting final formulation
testing have put in place protocols and IRB oversight to ensure that
test subjects do not repeat participation in testing with a frequency
that could both compromise the ability to distinguish erythemic
reactions to the test article and raise other questions about human
subject protection. We are concerned that the lack of explicit
requirements with regard to IRB oversight, as well as the cursory
nature of the informed consent requirement in the current sunscreen
labeling regulation, may result in inconsistent practices in the
conduct of SPF testing that would compromise the reliability of
results. Among other things, IRB review is critical to verify the
adequacy of informed consent and to ensure that study protocols
incorporate appropriate inclusion/exclusion criteria for subject
selection (both to protect test subjects and to ensure the accuracy of
results).
b. Qualifications of study personnel. In some instances, it may not
be clear upon inspection whether all aspects of a study were conducted
by appropriately qualified personnel. For example, FDA would not
consider it adequate for a technician, rather than an appropriately
trained medical professional (such as, for example, a nurse or
dermatologist), to perform a physical examination for potential nevi,
moles, or other dermal lesions. As with all clinical and nonclinical
testing done to support labeling, the use of properly trained and
appropriately qualified personnel is essential to ensure the
reliability and accuracy of test results. Documentation of the
qualifications and training of personnel is also necessary to enable
FDA's efficient enforcement of the FD&C Act.
c. Documentation of equipment maintenance, study methods, and
observations. Failure to maintain adequate records of testing
equipment, methods, and observations can raise broad questions about
the reliability of final formulation testing. In FDA's experience since
the promulgation of current Sec. 201.327, there has been a lack of
uniformity in testing entities' approaches to recordkeeping for final
formulation testing, raising concerns about the adequacy of
recordkeeping procedures. Failure of testing entities to keep adequate
records to support final formulation testing may leave FDA unable to
verify that the UV doses provided in SPF and water resistance test
reports are accurate and valid. This is also true with respect to
documentation of emission spectrum, the percentage of erythema-
effective radiation contribution, and changes to solar simulator
components and the UV meter/dose controller system. Failure to
accurately calibrate and maintain equipment at one testing entity may
affect data across multiple clinical SPF testing studies and/or broad
spectrum testing for multiple different final formulations that are
ultimately sold under different labels. Inadequate recordkeeping may
interfere with efficient enforcement. We propose to address these
concerns and align the regulation with our existing expectations
through revised regulatory provisions that are described further in the
following sections.
2. Specific Regulatory Proposals
a. Consequences of failure to observe best practices. We propose to
clarify in the introductory paragraph of Sec. 201.327 that a product
is deemed misbranded if its labeling relies on the results of final
formulation testing that was not conducted in compliance with all of
the applicable provisions of Sec. 201.327. Unless testing is conducted
in compliance with all applicable provisions of Sec. 201.327, FDA does
not have adequate assurance that the labeling reliably reflects the
properties of the sunscreen product. Therefore, if final formulation
testing is not properly conducted in accordance with this section,
labeling a sunscreen with an SPF value or representation of water
resistance or broad spectrum properties based on that testing is a
misrepresentation to the consumer that the labeling reliably states the
product's properties, which should also be consistent with a system of
standardized sunscreen labeling that can be used to make cross-product
comparisons. We propose to incorporate the provisions of Sec.
201.327(a) through (l) into part 352 as conditions under which a
sunscreen is GRASE and not misbranded. If these provisions are
finalized, failure to comply with these conditions would make a drug
subject to regulatory action as misbranded and an unapproved new drug.
b. General obligations of responsible persons. We are aware that
many different business relationships involving numerous entities are
commonly used in the manufacturing, testing, and labeling of
nonprescription sunscreen drug products. To clarify the locus of
responsibility for ensuring that adequate final formulation testing
procedures are in place, and to clearly delineate responsibility for

[[Page 6241]]

recordkeeping related to final formulation testing, FDA proposes a new
defined term, responsible person.
We propose to define the term responsible person in a way that is
consistent with FDA's treatment of regulatory responsibilities for
other OTC drug products and that is in alignment with requirements for
adverse event reporting for over-the-counter drug products, in section
760(b)(1) of the FD&C Act. The proposed definition for responsible
person is ``the manufacturer, packer, or distributor whose name appears
on the labeling of a sunscreen product covered by this section.''
Defining responsible person in this way will enable FDA to better
assess compliance with Sec. 201.327 because it creates a chain of
responsibility that is immediately apparent from the product's
labeling. The responsible person, as identified on the labeling, is
ultimately responsible for ensuring that the product bearing its name
is labeled in accordance with the requirements of Sec. 201.327.
The proposed revision of Sec. 201.327(a) would broadly set forth
the general obligations of responsible persons with respect to final
formulation testing under Sec. 201.327(i) and (j), and it would make
clear that the responsible person is charged with ensuring that
sunscreen products are appropriately tested. The obligations of
responsible persons as enumerated in Sec. 201.327 are modeled after
those of investigational new drug application (IND) sponsors under part
312 (21 CFR part 312), but are somewhat modified to accommodate unique
aspects of clinical and nonclinical sunscreen formulation testing.
Because final formulation testing under Sec. 201.327(i) and (j) is
intended to verify the claimed properties of a final formulation, and
because this purpose is narrower in scope and duration than most
clinical testing performed under FDA's IND regulations in part 312, a
responsible person under proposed Sec. 201.327 would have
responsibilities that incorporate some of the traditional
responsibilities of investigators as well as those of sponsors under
part 312. For example, FDA proposes to clarify that responsible persons
must select appropriately qualified personnel to conduct testing,
ensure compliance with the requirements for IRB review and obtaining
informed consent, and monitor the compliance of personnel with
investigators' statements.
This proposed approach accounts for situations in which
investigators and other personnel conducting final formulation testing
are employees of the responsible person. We also propose to clarify
that the responsible person must ensure that investigators and other
personnel conducting investigations under Sec. 201.327(i) comply with
requirements related to human subject protection and the appropriate
conduct of clinical testing. We believe that this better reflects the
employer/employee relationships that are more common in connection with
final formulation testing rather than with clinical testing conducted
under an IND. These proposed provisions regarding selection of
personnel are also consistent with the existing obligations of
manufacturers under parts 210 and 211 (21 CFR parts 210 and 211), both
of which govern compliance with CGMPs.
The proposed revision of Sec. 201.327(a)(1) permits a responsible
person to transfer some or all of its obligations to another entity,
consistent with current industry practice, except for obligations with
respect to recordkeeping. The recordkeeping proposal is discussed in
section IX.D. Failure of an entity to comply with provisions of this
part governing responsibilities it has assumed would subject that
entity to the same regulatory action as if it were a responsible person
who had failed to comply with those obligations. This provision is
analogous to the provision in FDA's regulations at part 312 allowing
for transfer of obligations of IND sponsors.
c. Adequate clinical testing procedures and conditions. Although
current Sec. 201.327 requires ``legally effective written informed
consent from all test subjects'' (Sec. 201.327(i)(3)(iv)), it does not
address broader underlying requirements for conducting clinical
testing. In light of the concerns we identified regarding current
clinical testing procedures and conditions, we propose to amend Sec.
201.327 by adding paragraph (i)(1), ``Adequate Clinical Testing
Procedures and Conditions.'' We expect that final formulation testing
conducted in compliance with the proposals in this paragraph will be
more likely to ensure protection of human subjects while also more
reliably determining the SPF value and water resistance properties of
the final formulations being tested. Unless appropriate clinical
testing procedures and conditions are adhered to, FDA cannot have
confidence in the resulting labeled SPF and water resistance properties
of the product.
Proposed Sec. 201.327(i)1(B) and (C) have been added to make clear
that FDA's regulations governing informed consent (part 50 (21 CFR part
50)) and IRB approval of research (part 56 (21 CFR part 56)) apply to
clinical final formulation testing that is conducted under Sec.
201.327(i). In our view, as a matter of good clinical practice, IRB
approval should already be routinely currently obtained for clinical
final formulation testing under current Sec. 201.327 because it is
essential to producing results that are scientifically sound and
ethically appropriate. Because clinical final formulation testing
required to support labeling under current Sec. 201.327 is not
conducted under an IND or in support of a GRASE determination in the
OTC sunscreen monograph, it was not previously included explicitly in
the scope of testing covered by parts 50 and 56. We propose to rectify
this omission by explicitly cross-referencing parts 50 and 56 in
revised Sec. 201.327(i). This will clarify that both of these parts
apply to clinical final formulation testing and will resolve any
inconsistency in current practice.
The proposed reference to part 50 clarifies FDA's position that
legally effective written informed consent to participate in clinical
final formulation testing should share the same properties as informed
consent required for all other clinical testing covered by FDA's
regulations in part 50. Similarly, by referencing part 56, the proposal
ensures that final formulation testing is held to the same standards
for IRB review as other clinical testing covered by FDA's regulations.
In reviewing clinical protocols, IRBs have the ability to determine
whether the protocol is adequately designed to study the endpoints
sought, and to ensure that protocol elements, such as enrollment
criteria, adequately protect both human subjects and the scientific
rigor of the experiment.
d. Control of personnel. We propose to place responsibility on the
responsible person to ensure that investigators and other personnel
conducting clinical final formulation testing adhere to the
investigational plan, the signed investigator statement, and all
applicable regulations. We also propose to place responsibility on the
responsible person for ensuring human subjects' protection, including
through appropriately reporting changes in the testing to IRBs, and by
appropriately seeking prior IRB approval for any changes to the
testing, except where necessary to eliminate apparent immediate hazards
to human subjects. Under the proposed rule, responsible persons are
also expected to obtain from each investigator, and retain for their
records, a signed investigator statement. This is similar to what is
required of sponsors of INDs, and it helps to ensure that the
investigator is qualified, understands his or her obligations, and will
comply with the requirements of

[[Page 6242]]

this paragraph and with the protocol. It also enables better oversight
of clinical investigations by FDA because it creates a record of the
investigator's relevant experience and qualifications.
e. Research monitoring. A number of changes in Sec. 201.327(i)(1)
are being proposed to ensure adequate monitoring of clinical final
formulation testing. Revised Sec. 201.327(i)(1) would require that
responsible parties inform all investigators testing a formulation if
there are new observations about the drug, particularly with regard to
adverse events or safe use. This is necessary to ensure proper
communication between study personnel and protection of human subjects.
Responsible persons must also monitor the conduct of investigations to
ensure that clinical testing is being conducted in accordance with the
protocol and with applicable regulations. If a responsible person
discovers noncompliance by study personnel, then the responsible person
must either secure compliance or remove the noncompliant personnel from
conducting testing.
Finally, we propose to require that investigators report adverse
events and/or safety concerns to the responsible person, and that
investigators also provide responsible persons with final reports at
the conclusion of testing. We believe that this will ensure there is
appropriate documentation and communication of adverse events and/or
safety concerns that arise during testing. It will also ensure there is
a record of SPF testing conducted under Sec. 201.327(i) that can be
relied upon should questions related to a particular formulation arise
when the sunscreen formulation is marketed. The proposed requirements
are consistent with reporting required in the IND context, although,
because of the short duration of the clinical final formulation testing
conducted under Sec. 201.327(i), we are not proposing to require
annual reporting.
f. Test subject selection. We propose additional language regarding
the selection of test subjects in Sec. 201.327(i)(4). This is an area
in which FDA's inspections of testing entities have suggested a lack of
consistency. We are particularly concerned that inclusion/exclusion
criteria provide for adequate time between study and enrollment and
prior UV exposure, such as from participation in a previous SPF test,
sunbathing, or sunlamp use. Erythemal responses can remain for days
after sunbathing, and it is known that pigmentation development takes
up to a week after initial exposure and remains for weeks to months
(Ref. 186). SPF clinical studies should not include individuals who
have participated in sunbathing, tanning bed use, or another SPF
clinical study for at least the past 4 weeks or perhaps longer if UV-
induced responses remain. The proposed clarification regarding conduct
of physical examinations of test subjects reflects this consideration,
and our additional proposal for IRB review, addressed elsewhere, will
help ensure it is appropriately acted on.
g. Applicability of registration and CGMP requirements. Proposed
Sec. 201.327(k) reflects FDA's existing view that final formulation
testing conducted under Sec. 201.327 constitutes the ``manufacture''
of a drug. As such, this testing must be conducted in an establishment
registered in accordance with part 207 (21 CFR part 207) and section
510 of the FD&C Act. This interpretation is consistent with the
definition of manufacture in part 207, which includes ``each step in
the manufacture, preparation, propagation, compounding, or processing
of a drug . . . .'' (Sec. 207.1). The definition of manufacture as
used in part 207 also ``includes manipulation, sampling, testing, or
control procedures applied to the final product or to any part of the
process, including, for example, analytical testing of drugs for
another registered establishment's drug'' (id). Accordingly, a
sunscreen product labeled in reliance on final formulation testing done
in an unregistered establishment is misbranded under section 502(o) of
the FD&C Act. This interpretation is also consistent with FDA's
regulations in Sec. 330.1, which require that OTC monograph drug
products be manufactured in a registered establishment in order to be
generally recognized as safe and effective and not misbranded. The
incorporation of this provision in Sec. 201.327, therefore, is
intended to clarify an existing requirement for facilities performing
this type of testing.
We also propose to clarify that, as a manufacturing activity, final
formulation testing conducted under this paragraph is expected to be
done in accordance with CGMPs as set forth in parts 210 and 211 (see
Sec. 210.3(b)(12), indicating that for the purposes of parts 210 and
211, ``Manufacture, processing, packing or holding of a drug product
includes packaging and labeling operations, testing, and quality
control of drug products''). This is consistent with FDA's regulations
in Sec. 330.1, which require compliance with CGMPs as a condition for
OTC drug products to be GRASE and not misbranded when otherwise
marketed consistent with conditions in a final monograph. Adherence to
CGMP requirements in parts 210 and 211 includes compliance with the
requirements to keep certain records and to have appropriately trained
and qualified personnel. Failure to comply with CGMPs results in a
product being adulterated under section 501(a)(2)(B) of the FD&C Act.
h. Recordkeeping. To enable FDA to better monitor compliance with
the requirements of Sec. 201.327, we propose to include specific
recordkeeping requirements for final formulation testing. Accordingly,
proposed Sec. 201.327(l) clarifies what records of testing performed
under this section must be kept, by whom, and for how long. This
provision also allocates responsibility for records maintenance and
specifies what records must be made available to FDA for inspection.
Recordkeeping is essential for FDA to evaluate whether required testing
of final formulations is being conducted in accordance with Sec.
201.327(i) and (j), and to enable the Agency to investigate
postmarketing product failures or adverse events. Appropriate
recordkeeping also enables FDA to conduct better and more efficient
inspections of entities conducting final formulation testing.
These recordkeeping requirements are in alignment with what is
required for other types of manufacturing under CGMPs as set forth in
parts 210 and 211. The proposed provisions are intended to clarify how,
and for how long, records must be kept to substantiate required final
formulation testing. We are proposing that records of testing must be
kept by the responsible person (as newly defined in Sec. 201.327(a),
discussed previously), as well as by any other entity that actually
performs testing (under a transfer of obligations per Sec.
201.327(a)(1) or otherwise). Requiring that records be kept by both the
responsible person and the testing entity (if different) will enable
FDA to more easily identify records supporting the labeling of any
given final formulation even when the product is labeled with the
responsible person's information, but testing and manufacturing was
completed by a third party.
The proposed recordkeeping requirements reflect FDA's experience in
interacting with regulated industry. By requiring that records be kept
by both the responsible person and any other entity that performs final
formulation testing, the proposed rule will enable more efficient
enforcement of the FD&C Act by, for example, allowing FDA to identify
the source of formulation failures or apparent inconsistencies between
the product labeling and consumer experience. The proposed
recordkeeping requirements

[[Page 6243]]

will also assist FDA when it is conducting inspections of entities that
perform final formulation testing for a number of different responsible
persons and products, as we believe is the norm in this industry.
Having ready access to records reflecting the overall conduct of final
formulation testing during an inspection of such an entity is important
because it will enable FDA to identify potential systemic problems in
final formulation testing that may have an impact on the reliability of
results supporting the labeling of multiple different sunscreen
products marketed by a variety of responsible persons. We note that
these recordkeeping requirements should not be understood to mandate
duplicative records within the files of a single testing entity or
single responsible party. For example, if one investigator is
responsible for testing multiple final formulations, one copy of the
signed investigator statement and Curriculum Vitae (CV) would be
sufficient to support all formulations tested by that investigator.
Consistent with FDA's view that final formulation testing is
manufacturing, and thus is subject to CGMPs, equipment maintenance
records and other records documenting compliance with CGMPs are
expected to be maintained as required by parts 210 and 211.
Accordingly, we clarify in proposed Sec. 201.327(l) that records
documenting proper maintenance of equipment used in final formulation
testing must be kept, consistent with existing obligations in 21 CFR
211.68. In our view, this clarification will promote uniformity in
adherence to best practices and will help ensure more accurate and
reliable labeling of sunscreen products based on final formulation
testing. Additional specificity has been proposed here to clarify how
the more general recordkeeping provisions of part 211 apply to final
formulation testing. To provide assurance that the test results are not
compromised by faulty equipment maintenance or equipment failure, FDA
proposes that testing entities must keep documentation demonstrating
that equipment used for final formulation testing has been maintained
in accordance with established written specifications. This requirement
will enable FDA to more efficiently monitor compliance. Failure to keep
required records of final formulation testing will render a product
whose labeling relies on that testing adulterated under section
501(a)(2)(B) of the FD&C Act. Without recordkeeping, there is no
assurance that a sunscreen drug product has the identity and strength,
and meets the quality and purity characteristics, which it purports or
is represented to possess.
This proposal also elaborates on recordkeeping necessary to
document compliance with the requirements of proposed Sec. 201.327
regarding conduct of final formulation testing.
Proposed required records for SPF testing include records that: (1)
Identify the facility conducting the testing; (2) identify the
equipment used; (3) identify product samples and lots; (4) characterize
the SPF standard that is used; (5) document parameters for water
resistance testing; and (6) demonstrate compliance with the provisions
governing adequate clinical testing procedures and conditions. For
example, these would include documentation of IRB review, case
histories for each human subject (which must document protocol
deviations or injuries), administration of the sunscreen, and reading
of test results. These proposed recordkeeping obligations are
consistent with those required of parties engaged in human subjects
testing governed by other portions of FDA's regulations.
Required records of broad spectrum testing conducted under proposed
Sec. 201.327(j) would include those records necessary for identifying
the facility conducting the testing, providing information associated
with the sample, identifying equipment used, and documenting sunscreen
product application. These proposed requirements provide greater
specificity than existing requirements in FDA's CGMP regulations, and
are expected to increase uniformity in current practice.
We propose to clarify FDA's expectations regarding access to
records that responsible persons and other testing entities are
required to keep under this paragraph. These provisions are consistent
with FDA's inspection authorities in section 704 of the FD&C Act.
i. Minor proposed revisions to test procedures. In addition to the
changes discussed in section IX.D, we are proposing several
modifications to the technical instructions for sunscreen final
formulation testing (Sec. 201.327(i) and (j)) to clarify how the
testing should be conducted.
We are concerned that manufacturers conducting the SPF test
procedure may be relying on determinations of the initial minimal
erythema dose of unprotected skin (MEDu) generated too far in advance
of testing the sunscreen product. The current regulation in Sec.
201.327(i)(5) addresses four different determinations of MED for each
test subject: (1) An initial MED for unprotected skin (initial MEDu);
(2) a final MED for unprotected skin (final MEDu); (3) an MED for skin
to which the SPF standard has been applied (ssMEDp); and (4) an MED for
skin to which the sunscreen test product has been applied (tpMEDp). The
initial MEDu is used to set the UV exposures administered to determine
final MEDu, ssMEDp, and tpMEDp (see Sec. 201.327(i)(5)(iii)).
Although the regulation already requires that each of the MED
values be determined 16 to 24 hours after UV exposure, it merely notes
that the final MEDu, ssMEDp, and tpMEDp are ``typically determined the
day following determination of the initial MEDu'' (see current Sec.
201.327(i)(5)(iv)). Because the skin reactivity of a test subject
changes over time, we propose to clarify that the initial MEDu of a
person's unprotected skin must be determined no more than 1 day before
the UV exposures for final MEDu, ssMEDp, and tpMEDp are administered.
We are also clarifying that to calculate the SPF value for each test
subject, under proposed paragraph Sec. 201.327(i)(6), it is the
subject's final MEDu that should be used.
In our review of the testing requirements as part of this
rulemaking, we also revisited our position on the input slit bandwidth
specification in the in vitro broad spectrum test. In the 2011 L&E
Final Rule, we modified the in vitro broad spectrum test that was
proposed in the 2007 proposed rule to change the input slit
spectrometer bandwidth specification from <=5 nm to <=1 nm. After the
2011 final rule published, FDA received a comment from a spectrometer
manufacturer arguing that the 1 nm input slit bandwidth specification
was unreasonable. The manufacturer argued that common spectrometer
models that are currently used to test sunscreens cannot comply with
the <=1 nm input slit bandwidth specification, and those that can are
more expensive, more difficult to use, and take more time to use. The
manufacturer provided data that indicate that spectrometers with <=1 nm
input slit bandwidths do not produce more reliable results than
spectrometers with larger input slit bandwidths (see Comment, Docket
No. FDA-2010-D-0509-0004). In light of this submission, FDA reassessed
the input slit bandwidth parameters and concluded that <=5 nm will be
sufficient for the broad spectrum procedure. Although decreasing
bandwidth improves the ability to resolve closely spaced peaks (i.e.,
the spectral resolution), this is not a significant consideration for
in vitro broad spectrum testing of sunscreen products because
transmittance/absorbance curves for sunscreen

[[Page 6244]]

products are typically smooth with no individual sharp peaks.
Accordingly, we propose to revise Sec. 201.327(j)(1)(iv) to require
that spectrometer input slits be set to provide a bandwidth that is <=5
nm.
Establishing standardized testing procedures for sunscreen products
and basing the products' labeling on this testing not only helps assure
the safety and effectiveness of each product, it also provides
consumers with consistent information about the sun protection
properties of sunscreen products across brands, which in turn
facilitates consumer comparisons when selecting products. Accordingly,
we propose to delete the provision in Sec. 352.77 (21 CFR 352.77)
addressing test modifications or alternative testing procedures.
Section 352.77 indicates that such test modifications or alternative
testing procedures require submission of a petition in accordance with
Sec. 10.30 (21 CFR 10.30). The proposed removal of Sec. 352.77 does
not alter the existing ability of a firm or individual to petition the
Agency to amend the monograph (see Sec. Sec. 330.10(a)(12) and 10.30)
to change the conditions that apply to products marketed under its
provisions, such as to modify testing procedures for all products
having some particular set of characteristics. Rather, the proposed
deletion will clarify that the sunscreen monograph does not permit
variation for individual products from the standardized testing
procedures that are monograph conditions, because such variation could
undermine important values supported by standardization.
We are also proposing to correct a minor inaccuracy in the existing
regulatory language describing testing procedures. Specifically, Sec.
201.327(i)(1)(ii)(C) currently states that ``emission spectrum must be
determined using a handheld radiometer.'' As written, this statement is
inaccurate because a handheld radiometer cannot determine the emission
spectrum of a solar simulator. We propose to resolve this error by
clarifying that the handheld radiometer measures the solar simulator
radiation intensity rather than the emission spectrum. Finally, we have
proposed edits to certain provisions describing final formulation
testing procedures to clarify our long-standing intention that these
provisions of the test are requirements, not merely suggestions.

E. Proposed Status of Sunscreen-Insect Repellent Combination Products

1. Background
Sunscreen-insect repellent combination drugs are products used on
human skin that contain both a sunscreen drug component and an insect
repellent component. A list of insect repellent products on the EPA
website identified a number of such products as of November 2017
(including multiple products within a single brand line).\47\ Among
those products, the majority contained either N,N-Diethyl-meta-
toluamide (also called DEET) or IR3535 as the insect repellant, and a
few contained oil of citronella as the insect repellent. Combination
insect repellent-sunscreen products have been marketed in a variety of
dosage forms (see section IX.A for a discussion of dosage forms), with
labeled SPF levels ranging from 15 to 30 (Ref. 187). Some products are
also labeled as water resistant or very water resistant (Ref. 187). The
products are generally labeled for use without regard to age (Ref.
187).
---------------------------------------------------------------------------

\47\ EPA Product List (Ref. 187); a similar list of insecticide
products on the National Pesticide Information Center (NPIC) website
produced similar results (Ref. 188).
---------------------------------------------------------------------------

FDA regulates sunscreens as drug products under the FD&C Act, and
EPA concurrently regulates insect repellents as pesticides under
FIFRA.\48\ FIFRA defines a ``pesticide'' in relevant part as ``any
substance . . . intended for repelling . . . any pest,'' including
insects (7 U.S.C. 136)(u)). Before they can be marketed, most skin-
applied insect repellents must be registered by EPA, although a few
plant-derived insect repellent active ingredients are exempt from
registration because EPA has determined they present minimum risk
potential to humans (Ref. 189).
---------------------------------------------------------------------------

\48\ Some insect repellents are also regulated by FDA as human
drugs (e.g., pediculicides and scabicides intended to control
parasites on humans) or animal drugs (e.g., pesticide products for
oral administration to animals) (7 U.S.C. 136 et seq.); see also
``MOU 225-73-8010 Memorandum of Understanding Between the
Environmental Protection Agency and the United States Department of
Health, Education and Welfare Food and Drug Administration,''
(available at https://www.fda.gov/aboutfda/partnershipscollaborations/memorandaofunderstandingmous/domesticmous/ucm115873.htm (accessed April 17, 2018).
---------------------------------------------------------------------------

Sunscreen-insect repellent combination products have been marketed
in the United States since before the OTC review began, but they have
not previously been addressed in the rulemaking for the OTC sunscreen
monograph (72 FR 7941 at 7943). Both FDA and EPA have historically
declined to object to the marketing of these products pending the
issuance of a final sunscreen monograph, provided that the sunscreen
active ingredient(s) is listed in the stayed final monograph and the
insect repellent component is registered with the EPA (79 FR 7941 at
7943). In 2011, FDA issued a draft enforcement guidance intended for
manufacturers who market OTC sunscreen products without an approved
application, which recommended that manufacturers of sunscreen-insect
repellent combination products should comply as closely as possible
with FDA's sunscreen testing and labeling requirements in Sec.
201.327. This guidance was finalized in May 2018 (Ref. 1).
In the Federal Register of February 22, 2007 (72 FR 7941), FDA
issued a notice seeking public comments on sunscreen-insect repellent
combination products, and, in particular, whether FDA should amend the
OTC sunscreen monograph to add conditions for marketing insect
repellent-sunscreen drug products (FDA Call for Data or call for data).
The call for data summarized the regulatory status and history of both
sunscreens and insect repellents, and sought public input on a number
of issues (see table 6). On that same date (February 22, 2007, 79 FR
7979), EPA published a similar notice announcing that it was also
seeking information to determine how insect repellent-sunscreen
combination products should be regulated.

Table 6--Key Issues and Information Requests in FDA's 2007 Call for Data
------------------------------------------------------------------------
Key concerns and information
General issue requests
------------------------------------------------------------------------
Possible manufacturing conflicts.. Requested information about whether
there are known conflicts between
FDA and EPA manufacturing
requirements and, if so, how to
resolve them.
Asked how FDA should address EPA-
registered insect repellents in
finalizing the OTC sunscreen
monograph; which requirements
should FDA retain, revise, or
eliminate?
Inquired about manufacturer testing
of sunscreen-insect repellent
combination products and whether
any problems were encountered.
Possible formulation conflicts.... Requested comments on the
significance of published research
suggesting a potential formulation
conflict.

[[Page 6245]]

Possible labeling conflicts Labeling differences noted:
between OTC sunscreen monograph FDA uses ``warning''; EPA
and EPA registration requirements. uses ``caution'' (and only uses the
Note: Since publication of the word ``warning'' to indicate
call for data, FDA has toxicity levels).
established additional labeling Many differences in
regulations for certain OTC required warning/caution section
sunscreen products marketed headings.
without approved applications. Directions for sunscreen
However, the labeling concerns use call for liberal application
expressed in the call for data and frequent reapplication; EPA
remain relevant.. directions may limit where and how
to apply product and restrict
frequency of application.
Asked whether different directions
for use can be integrated without
leading to improper application,
overexposure to insect repellent,
and/or underexposure to sunscreen.
FDA requires the outside container
or wrapper of the retail package or
the immediate container label to
list all active and inactive
ingredients (see section
502(e)(1)(A)(iii) of the FD&C Act;
Sec. 201.66(c)). EPA requires
listing of the percentage of each
active ingredient, and the total
percentage of all ``inert'' or
``other'' ingredients, in the
pesticide. Inert ingredients are
not required to be identified
individually on the product except
in certain cases (in which case all
inert ingredients are listed).
Asked whether there is a way to
label combination sunscreen-insect
repellent drug products in a way
that satisfies both the
requirements of the FD&C Act and
the FIFRA, and whether ``inert''
ingredients under the FIFRA are
equivalent to ``inactive''
ingredients under the FD&C Act.
Safety issues..................... More safety data needed given
published animal studies indicating
increased absorption of DEET and
various sunscreens active
ingredients when the components are
combined. Asked for more safety
data on combined products.
Requested data on whether increased
absorption of a sunscreen
ingredient occurs when combined
with an insect repellent.
Information needed about incidence
of skin irritation from combination
products.
Effectiveness issues.............. Requested information on:
Possible effects of
insect repellent on sunscreen
SPF; possible decreased
sunscreen efficacy or increased
exposure to insect repellent
without greater efficacy
resulting from inconsistent
reapplication intervals.
Potential chemical or
physical incompatibilities between
particular sunscreens and insect
repellents.
Potential need to
specify minimum SPF for these
combinations.
Any potential
performance benefits of these
combination products other than
convenience.
Possible adjustments to
formulations to minimize
application time disparities.
------------------------------------------------------------------------

2. FDA's Evaluation of Sunscreen-Insect Repellent Combination Products
FDA has reviewed the comments submitted in response to FDA's and
EPA's calls for data, as well as pertinent scientific literature and
publicly available EPA regulatory documents. Based on that review, we
have tentatively concluded that sunscreen-insect repellent combination
products, as a class, are not GRASE (i.e., are Category II) and are
misbranded because conflicting labeling requirements for their
sunscreen and insect repellent components cannot be reconciled to
create labeling that will sufficiently ensure safe and effective use of
the sunscreen component, as well as adequate directions for use as a
sunscreen, as required by section 502(f) of the FD&C Act. Also, if we
did not have this labeling concern, we would still tentatively
determine that available data regarding the safety and effectiveness of
these products for their use as sunscreens are insufficient to classify
these sunscreen products as GRASE for such use (i.e., Category III).
Specifically, evidence suggests that interactions between some
sunscreen active ingredients and insect repellents may decrease safety
by increasing systemic absorption of one or both components, and
potential synergistic effects on the efficacy of sunscreen active
ingredients apparently have not been studied. Although the available
data are limited and not conclusive, they give rise to questions about
the safety and effectiveness of these products. Our reasons for these
tentative conclusions are detailed in the discussion that follows.
a. Public comments on the 2007 call for data. FDA received six
submissions in response to the 2007 call for data. None of the comments
included substantive data, although some cited published scientific and
medical literature, which is addressed in the following section of this
document. Five of the six comments were from manufacturers or a trade
association. Industry comments generally favored retaining joint
regulation between EPA and FDA (perhaps with enhanced coordination and
information-sharing) and amending the stayed OTC sunscreen monograph to
address sunscreen-insect repellent combinations. Several industry
comments claimed there was an absence of conflicting requirements
relating to manufacturing, formulation, and/or labeling. Others
suggested approaches for minimizing labeling conflicts, such as
permitting exemptions to FDA's Drug Facts labeling requirements to
accommodate EPA-required information, or placing FDA- and EPA-required
information in separate areas of the label. The remaining comment was
submitted by a medical association that opposed continued marketing of
sunscreen-insect repellent products, emphasizing concerns about
children's exposure to DEET. Industry comments favoring the continued
marketing of combination sunscreen-insect repellent drug products also
contended that combining sunscreen and insect repellent ingredients in
a single product is more convenient and cost-effective than using
separate products. Two comments stated that properly formulated,
tested, and labeled, combination products are better than the
unpredictable effects that could arise when consumers use two different
products. Regarding safety, one comment asserted various flaws in the
studies cited in the call for data that questioned the safety of these
combination products. (These studies are discussed in section
IX.E.2.d.)
In general, the comments that we received in response to the 2007
call for data were not accompanied or corroborated by data. Although
the comments did not identify further concerns relating to product
manufacturing or formulation, they did not adequately address FDA's
concerns about safety, effectiveness, and labeling of these products.
FDA renews its request for data to support labeling and safety for
sunscreens with insect repellent added.
b. Pesticide-related information. Pesticides that are or have been
used in combination products that also contain sunscreens include DEET,
IR3535, and oil of citronella. In evaluating combination insect
repellent-sunscreen products for the purposes of this rule, FDA defers
to EPA's expertise and authority regarding insect repellent
ingredients. We have not independently evaluated these pesticides, but
instead have focused on potential sunscreen-insect repellent ingredient
interactions and the feasibility of effectively labeling these
combination products for their use as sunscreens.

[[Page 6246]]

As of June 2017, DEET was by far the most commonly used insect
repellent. According to the EPA Product list, the amount of DEET in
combination sunscreen-insect repellent products ranged from 10 to 20
percent. DEET product labels recommend that users avoid over-
application, use just enough repellent to cover exposed skin and/or
clothing, and not apply to hands or near the eyes or mouth of young
children (Ref. 190). DEET-containing products listed on the EPA website
in 2017 had concentrations ranging from 5 percent to 98 percent and
provided protection from mosquitos for 2 to 12 hours, with many
products having protection times of 4 hours or more (Ref. 187). The
American Academy of Pediatrics recommends that repellents should
contain no more than 30 percent DEET when used on children, and that
insect repellent should not be used on children younger than 2 months
(Ref. 191).
EPA classifies the acute toxicity of insect repellents and other
pesticides into one of four toxicity categories (ranging from Category
I, highly toxic, to Category IV, practically nontoxic) (see 40 FR
156.62). DEET is classified in Category III based on EPA's review of
available animal studies, indicating slight acute toxicity for acute
oral, dermal, ocular, and inhalation tests in animals, and low acute
toxicity for the human health risk assessment (Ref. 192). Although DEET
is registered for use in humans of any age, adverse events related to
DEET toxicity have been documented and these events primarily relate to
the central nervous system. As summarized by Katz et al., DEET has been
associated with seizures and other central nervous system symptoms,
cardiovascular symptoms, and topical and allergic symptoms (Ref. 193).
Most reported cases of adverse or lethal events involved overuse or
otherwise incorrect use of the product (Ref. 193), and EPA concluded
that available data were insufficient to identify DEET as the cause of
the reported adverse events (Ref. 192). EPA is currently in the process
of updating its registration of a number of older pesticides, including
DEET, and is deferring decision on the regulatory status of combination
DEET/sunscreen products as described in the EPA Call for Data.\49\
However, EPA has stated that DEET does not pose a significant health
risk to the U.S. population.\50\
---------------------------------------------------------------------------

\49\ DEET 2014 reregistration interim review final decision
(EPA-HQ-OPP-2012-0162) (available at https://www3.epa.gov/pesticides/chem_search/reg_actions/reregistration/red_PC-080301_1-Apr-98.pdf (accessed April 17, 2018).
\50\ Id. In June 2014, EPA issued an interim review of DEET and
did not identify any specific new concerns. The proposed interim
registration review decision became final on September 24, 2014.
DEET 2014 reregistration interim review final decision (EPA-HQ-OPP-
2012-0162) (available at https://www.regulations.gov/document?D=EPA-HQ-OPP-2012-0162-0012 (accessed April 17, 2018).
---------------------------------------------------------------------------

IR3535 is classified by EPA as a biopesticide because it is
biochemically, functionally identical to beta-alanine, a naturally
occurring substance that repels insects (Ref. 194). IR3535 is
classified in Toxicity Category IV (practically nontoxic) for acute
oral, dermal, and inhalation toxicity and Category III (slightly toxic)
for eye irritation (Ref. 195). Overall, EPA has assessed IR3535 as not
harmful when ingested, inhaled, or used on skin (Ref. 195). Eye
irritation could occur if the chemical enters a person's eyes (Ref.
195). IR3535 is used at concentrations of 7.5 percent to 20 percent in
a popular line of sunscreen-insect repellent combination products (EPA
Product List) (Ref. 187). Products containing IR3535 identified on
EPA's website in summer 2017 had concentrations ranging from 7.5
percent to approximately 20 percent and listed protection time against
mosquitoes of 2 to 8 hours (EPA Product List) (Ref. 187).
Oil of citronella is a plant-derived biochemical insect repellent
(72 FR 7979 at 7981). Depending on its source, it may be categorized as
``Ceylon'' type or ``Java'' type. It is currently listed by EPA as a
minimum risk pesticide (registration generally not required if
formulated only with EPA-permitted inert ingredients and not labeled as
effective against disease-causing pests) (40 FR 152.25(f)). Oil of
citronella is also an approved food additive for use as a flavoring
agent in foods and beverages (Ref. 196). EPA has designated oil of
citronella as Toxicity Category III (slightly toxic) for acute oral
toxicity (Java type only), dermal toxicity, dermal irritation, and
acute eye irritation (both types), and Category IV (practically
nontoxic) for acute oral toxicity (Ceylon type) and acute inhalation
(Ref. 197). The National Pesticide Information Center (NPIC) fact sheet
on oil of citronella states that oil of citronella products should not
be used on children less than 6 months old (Ref. 198).
c. Disparities in required labeling of sunscreens and insect
repellents. FDA and EPA regulate the format and content of the labeling
of nonprescription sunscreen products and pesticides, respectively. FDA
regulations on nonprescription sunscreen labeling include the general
drug labeling regulations in subpart A of part 201; the ``Drug Facts''
format and other OTC drug labeling requirements in subpart B of part
201; and the sunscreen-specific labeling requirements that apply to
sunscreens marketed without an approved NDA, including those based on
the current requirements for SPF and broad spectrum testing in Sec.
201.327. The labeling of registered insect repellents is subject to EPA
labeling requirements under FIFRA (40 CFR 156), as well as specific
language specified in individual product registration documents.
Although the FDA and EPA labeling requirements for nonprescription
sunscreens and registered pesticides cover some of the same information
(such as ingredient lists, net quantity statements, and warnings/
precautions), there is considerable variation in the language, format,
and placement of common label elements between the two Agencies, while
other elements do not overlap.
Furthermore, both Agencies limit the degree to which a drug
manufacturer or pesticide registrant may depart from the prescribed
text, format, and/or location of required labeling elements. This is
particularly true for the wording and format of ``drug facts''
information for OTC drugs (see Sec. 201.66). Similarly, EPA
regulations state that although a registrant may choose to place non-
FIFRA-required information on a pesticide label, it may not replace,
obscure, conflict with, or supersede the FIFRA-required text (Ref.
199).
The intended uses of sunscreens and insect repellents are quite
different, as are the associated labeling requirements; in particular,
the instructions for using the two types of products are different.
Required labeling for OTC sunscreens marketed without approved NDAs
calls for reapplication at least every 2 hours (see Sec. 201.327(e)(3)
through (e)(4)). The duration of protection for insect repellents
varies according to the active ingredient and strength. Based on
information from the EPA product list, many insect repellent-sunscreen
products provide protection against mosquitoes and/or ticks for more
than 2 hours, and some provide protection for as many as 6 to 10 hours.
EPA has stated that it is ``concerned about consumer use of products
that contain sunscreens and DEET, since directions to reapply generally
and frequently may promote greater use of DEET than needed for
pesticidal efficacy and thus pose unnecessary exposure to DEET.\51\ The
Centers for Disease Control and Prevention (CDC) advises consumers

[[Page 6247]]

that ``products that combine sunscreen and repellent are not
recommended, because sunscreen may need to be reapplied more often and
in larger amounts than needed for the repellent component to provide
protection from biting insects.'' (Ref. 200). Similarly, the American
Academy of Pediatrics advises consumers not to use products that
combine DEET with sunscreen, in part because ``[t]hese products can
overexpose your child to DEET because the sunscreen needs to be
reapplied often'' (Ref. 201). Additionally, DEET is approved for use on
children with no age restriction (Ref. 202), whereas FDA labeling
states ``[bullet] children under 6 months of age, ask a doctor'' (see
Sec. 201.327(e)(1)(iv)).
---------------------------------------------------------------------------

\51\ DEET 2014 reregistration interim review final decision,
supra note 49, v.
---------------------------------------------------------------------------

The recommended manner of application also differs for sunscreens
and insect repellents. For example, the directions on the label for all
insect repellent products containing DEET say to apply just enough to
cover exposed skin, and avoid over-application (Ref. 190), whereas the
labeling of nonprescription sunscreens marketed without approved NDAs
calls for liberal or generous application (see Sec.
201.327(e)(1)(ii)). The EPA-mandated directions on the labels of DEET
products also state, ``Do not apply near eyes and mouth; apply
sparingly around ears; do not use under clothing'' (Ref. 190). Such
statements are potentially troublesome from the standpoint of sun
protection in light of surveillance data from Australia, which suggest
that the incidence of certain skin cancers is more frequent on highly
exposed areas of the body such as ears and the backs of hands (Refs.
203 and 204). The CDC advises consumers who need protection from both
sun and insects to apply sunscreen product first, followed by an insect
repellent (Ref. 200).
Additional disparities in the content and format of labeling
elements for sunscreens and registered insect repellents include the
following:
EPA pesticide labeling includes required elements that
generally must appear on the front panel of the label, such as the
ingredient statement (40 CFR 156.10(g)(2)), specified signal word such
as ``CAUTION'' (40 CFR 156.64), and child hazard warning (40 CFR
156.66), which could crowd or detract from drug information required to
appear on the principal display panel for drugs (see Sec. 201.60
(``The principal display panel shall be large enough to accommodate all
the mandatory label information required to be placed thereon by this
part.'')). Other labeling elements that only EPA requires include
registration numbers and manufacturing establishment numbers (40 CFR
156.10(a)).
FDA labeling for sunscreens uses the word ``warning'' (see
Sec. Sec. 201.66(c)(5) and 201.327(d)), while the EPA requirements
specify that pesticide products that, like DEET, IR3535, and oil of
citronella, meet the criteria of Toxicity Category III or IV as the
highest category by any route of exposure bear on the front panel
either no signal word or only the signal word ``CAUTION'' (40 CFR
156.64). In EPA labeling the word ``WARNING'' is used as a signal word
only for toxicity category II, which is a higher toxicity category than
that applicable to any insect repellent ingredients used in sunscreen-
insect repellent combination products (40 CFR 156.64(a)(2)).
FDA labeling uses the term ``directions'' (see Sec. Sec.
201.66(c)(6) and 201.327(e)), while EPA regulations use the term
``directions for use'' (see 40 CFR 156.10(i)(2)).
FDA calls for ingredients to be listed as ``active'' and
``inactive'' (see Sec. 201.66(b) through (c)), while EPA labeling uses
the term ``inert'' or ``other'' instead of ``inactive'' for all non-
pesticide ingredients (40 CFR 156.10(g)).
Given the extent of the disparities discussed above, FDA
tentatively concludes that attempting to merge the required labeling
for monograph sunscreens and insect repellents in a way that would
comply with both Agencies' requirements and permit adequate consumer
understanding and proper use would be impracticable. In this regard, we
specifically disagree with comments made in response to the 2007 FDA
Call for Data suggesting that acceptable ``merged'' labeling could be
crafted by varying the OTC sunscreen drug facts to include insect-
repellent-related information, and/or by providing EPA-required
labeling outside the drug facts box. We are particularly concerned that
consumers would be confused by the juxtaposition of two sets of
different and, in some cases, contradictory information in the labeling
about these products' dual intended uses. We are also concerned that
the sheer amount of required information would result in crowded,
difficult-to-read labels lacking in the clarity and prominence of
important safety and use information that are both required by FDA
regulations and vital to consumer comprehension. We solicit comment and
data about how to reconcile the labeling of suncreens and insect
repellents such that a combined product could meet FD&C Act
requirements for OTC sunscreen drugs.
d. FDA's review of published medical literature. The results of
FDA's literature review raise potential safety concerns about products
that combine sunscreen and insect repellent active ingredients. The
available data suggest that the dermal penetration and systemic
absorption of at least one combination of a sunscreen active ingredient
and an insect repellent is increased when both are present.
There have been some studies assessing the penetration of DEET and
the effects of DEET combined with sunscreen (particularly the active
ingredient oxybenzone) on dermal penetration. Ross et al. tested for
synergistic effects between DEET and oxybenzone using an in vitro mouse
skin diffusion model and showed substantial penetration of a 20 percent
DEET standard in ethanol, while penetration of sunscreen active
ingredients was not found (Ref. 205). Despite a lower DEET content (10
percent), a commercially marketed sunscreen formulation had a 6-fold
more rapid detection and a 3- to 4-fold greater penetration of DEET
than the 20 percent standard. Other diffusion tests using pigskin or
artificial membranes and various combinations of DEET and oxybenzone in
different media suggested an enhancing effect on dermal penetration of
both DEET and oxybenzone (Refs. 206 and 207). The same investigators
obtained similar results in a later in vitro study using human skin
(Ref. 207).
Kasichayanula et al. assessed the dermal absorption of DEET and
oxybenzone using an in vivo piglet model, in which samples were
collected from plasma, urine, and under the skin. Their results
indicated that the enhanced dermal penetration evidenced in the in
vitro studies translated to increased systemic exposure to both
oxybenzone and DEET (Refs. 208 and 209). Finally, a study by Yiin et
al. suggests that enhanced systemic absorption would also occur in
humans (Ref. 210). Yiin et al. used human urinary metabolites of DEET
and oxybenzone to evaluate the mutual enhancing effect on absorption of
these ingredients and concluded that their findings confirm that
concurrent use of DEET-containing insect repellent and oxybenzone-
containing sunscreen results in the enhancement of dermal absorption of
DEET when insect repellent (DEET) was applied first and then covered by
sunscreen (Ref. 210). The study authors suggested that placing
repellent spray on top of sunscreen lotion with no mixing seems to be
the best approach to diminish DEET penetration through the skin.
Although insect repellents and sunscreens are designed to exert
their

[[Page 6248]]

protective effects on the surface of the skin, the studies described
above suggest that combining a sunscreen and insect repellent in a
single product may result in unintended systemic exposure to the
sunscreen ingredient oxybenzone and the insect repellent ingredient
DEET. We acknowledge the study limitations cited by comments to the FDA
Call for Data, and that in vitro diffusion studies have their
limitations in terms of reflecting clinical use. We also note that many
of the studies tested formulated commercial products with multiple
sunscreen ingredients and excipients for which details were not given,
and it is unclear how this may have influenced the results. Although
we, therefore, do not view these data as conclusory, we have determined
that they raise a valid safety concern that warrants a tentative
conclusion that, even if one could overcome the misbranding and
associated safety and effectiveness concerns created by the
inconsistent application directions for sunscreens and insect
repellants, there would not be sufficient evidence to conclude that
combination sunscreen and insect repellent products are GRASE for
sunscreen use without further investigation.
Regarding future investigations that could assist FDA in
determining whether these products have sufficient evidence of safety
to be GRASE for use as sunscreen, we are not aware of any data that
define the extent of systemic exposure to either DEET or oxybenzone
that would occur with maximal exposure to a sunscreen-insect repellent
combination product. There also are few data from which to assess
whether there would be a similar enhancement of skin penetration for
other combinations of sunscreen and insect repellent active
ingredients. Moreover, without adequate human absorption studies under
maximal use conditions of particular sunscreen-insect repellent
combinations (i.e., a MUsT, as discussed in section VII.B.4), it is
difficult to evaluate potential risks associated with the use of such
combination products. Because of the potential synergistic interaction
between the sunscreen active ingredient and the insect repellent active
ingredient, human absorption data for the individual components would
not provide adequate data to estimate the level of systemic absorption.
Likewise, in vitro data would not be able to provide a reliable
estimate of the systemic exposure that would occur with such products'
use.
In terms of sunscreen active ingredient effectiveness, we have
little data from which to determine whether the presence of an insect
repellent would affect the determined SPF value of combination
sunscreen-insect repellent products. Montemarano et al. reported a
reduction in sunscreen efficacy because of concomitant use with insect
repellent. However, in that study, the sunscreen and insect repellent
ingredients were applied separately and were not part of a combination
product (Ref. 211).
With respect to efficacy, we recognize that the testing required by
Sec. 201.327 (both the current regulation and the regulation if
amended as proposed elsewhere in this proposed rule) to support labeled
SPF levels and other efficacy claims that may be made for certain OTC
sunscreen products could potentially mitigate concerns about the impact
of insect repellent active ingredients on sunscreen effectiveness.
However, we are not aware of any data evaluating the reliability of SPF
testing for sunscreen formulations that contain insect repellent
ingredients. There also is the possibility that increasing the amount
of the sunscreen active ingredient to compensate for any loss in
efficacy because of the presence of the insect repellent could result
in unnecessarily high exposure to the sunscreen active ingredient. For
these additional reasons, we tentatively conclude that even if other
concerns could be overcome, there is not currently sufficient evidence
to conclude that combination sunscreen-insect repellent products are
GRASE for use as sunscreens. We solicit comment on the data needs
identified above and tentative conclusions, including supporting data
and analysis. We also solicit data and information to address these
data needs.
3. Conclusion
FDA tentatively concludes that the inherent disparity in labeling
requirements that apply to sunscreens marketed under the OTC monograph
and insect repellents prevent the creation of labeling that will
sufficiently ensure safe and effective use of the sunscreen component
of sunscreen-insect repellent combination products, particularly in
connection with duration of action. We also conclude that these
conflicting requirements prevent these products from having adequate
directions for use as a sunscreen, and thus these products would be
misbranded under section 502(f) of the FD&C Act. In addition, even if
these issues could be overcome, existing safety concerns about
potential enhanced systemic absorption resulting from combining
individual sunscreen active ingredients and insect repellent
ingredients would also need to be addressed by further studies on both
combinations of individual sunscreen and insect repellent ingredients
and final formulations.
Existing data indicates there is a risk of systemic absorption of
insect repellent and/or a sunscreen active ingredient when both are
present. Additional data would be needed to identify any interactions
between specific sunscreen active ingredients and insect repellents, in
particular, to characterize any enhancement of skin penetration and/or
systemic absorption if the resulting data presents safety or
effectiveness concerns. As stated above, FDA would need adequate human
absorption studies, such as a MUsT, as part of the clinical safety
assessment (for more discussion on assessment of dermal absorption of
sunscreen active ingredients using MUsT, see section VII.B.4). The
effectiveness of sunscreen-insect repellent combination products is
also a continuing concern. For all of those reasons, we tentatively
determine that these products are not GRASE for nonprescription
sunscreen use. We solicit comment on this tentative determination.

X. Proposed Actions To Effectuate Lifting of Stay and Harmonize
Impacted Regulations

In the 2011 L&E Final Rule, FDA explained that although we were not
yet lifting the stay on the 1999 final monograph, the provisions set
forth in the L&E Final Rule reflected the Agency's position on the
appropriate testing and labeling of sunscreen products that were
previously identified as falling within the Stayed 1999 Final Monograph
(76 FR 35620 at 35621). We explained that Sec. 201.327 would therefore
supersede the prior approach to labeling and effectiveness testing
described in the never-effective provisions of part 352, subparts C and
D.
We are now proposing to lift the stay on the 1999 final monograph
(21 CFR part 352) while making certain changes in its provisions. To
fully effectuate this proposal, we are proposing several harmonizing
revisions to part 352 and Sec. 201.327. These changes remove certain
provisions from part 352 that were superseded by the 2011 L&E Final
Rule and, where applicable, replace them with appropriate cross
references to the applicable testing and labeling provisions in Sec.
201.327, as we propose to amend these regulations in this document. We
also have made minor revisions in parts 347, 352 and Sec. 201.327 to
improve readability and to correct certain typographical errors and
erroneous internal cross references.

[[Page 6249]]

We are also proposing revisions to certain provisions describing
requirements for products containing both sunscreen active ingredients
and skin protectant active ingredients to avoid duplication between
Sec. 201.327 and part 352 and to harmonize the requirements set forth
in those provisions. As in the past, the proposed sunscreen monograph
would include conditions under which a single product could include
certain sunscreen active ingredients as well as certain ingredients
determined to be GRASE for use in skin protectants under part 347 (see
proposed Sec. 352.20(b), as well as current Sec. 347.20(e) (21 CFR
347.20(e)). Current Sec. 201.327(h) allows for such products to
combine certain labeling statements applicable to each ingredient in
the product to eliminate duplicative words or phrases. The stayed
provisions of part 352 contain similar allowances for products that
contain both sunscreen and skin protectant active ingredients, but also
outline more detailed requirements for presenting such a product's
statement of identity, indications, warnings, and directions. We
propose to relocate the labeling requirements for such products from
Sec. 352.60 to Sec. 201.327(h), thereby consolidating labeling
conditions for these products in one section of the regulations. We
also propose to retain compliance with these labeling provisions as a
monograph condition for sunscreen/skin protectant products under both
parts 352 (the sunscreen monograph) and 347 (the skin protectant
monograph) by incorporating cross references to Sec. 201.327(h) in
Sec. 352.20(b)(4), and Sec. 352.60, and incorporating cross
references to Sec. Sec. 352.20 and 352.60 in Sec. Sec. 347.20(e), and
347.60.
Additionally, we propose to consolidate under new Sec. 310.549 (21
CFR 310.549) certain properties that render an OTC drug product offered
for use as sunscreen a new drug for which an approved NDA is required
prior to marketing. Section 310.545 (21 CFR 310.545) currently contains
several such provisions addressing specific ingredients and efficacy
claims. We propose to relocate these provisions from Sec. 310.545 to
Sec. 310.549. In addition, in the interest of completeness, we are
clarifying in Sec. 310.549 that labeling a product with claims that it
decreases the risk of skin cancer or early skin aging caused by the sun
if that product has an SPF of less than 15 when tested in accordance
with Sec. 201.327(i) and/or does not pass the broad spectrum test in
Sec. 201.327(j) renders the product a new drug.
Finally, we propose to add to Sec. 310.549 new characteristics
that would render a product a new drug. These characteristics include:
(1) Containing the ingredients we propose to classify as categories II
and III (see sections VIII.B-C); (2) being labeled, represented, or
promoted for use as a combined sunscreen-insect repellant (see section
IX.E); (3) failing to comply with provisions relating to maximum SPF
values and broad spectrum requirements (see section IX.B); and (4)
failing to conform to certain other sunscreen formulation and dosage
form conditions (see sections IX.A and D).

XI. Comment Period

We are providing a comment period of 90 days (see DATES). FDA will
also consider requests to defer further rulemaking with respect to a
specific sunscreen active ingredient to allow the submission of new
safety and/or effectiveness data to the record if such requests are
submitted to the docket within the initial 90-day comment period. FDA
will review all data and information submitted to the record in
conjunction with all timely and complete requests to extend. In
assessing whether to extend the comment period to allow for additional
time for studies to generate new data and information, FDA will
consider the data already in the docket along with any information that
is provided in any requests to extend. FDA will determine whether the
sum of the data, if timely submitted, is likely to be adequate to
provide all the data that are necessary to make a determination of
general recognition of safety and effectiveness.

XII. Proposed Effective/Compliance Dates

The proposed effective date of final regulations resulting from the
proposals described in this rulemaking is November 26, 2019 (see FD&C
Act section 586E). We recognize that industry will need time after
publication of any final regulations to comply with their provisions.
To allow for orderly implementation of final regulations and help
assure continued product availability to consumers, we would not expect
full compliance with such final regulations for units of sunscreen
product initially introduced or initially delivered for introduction
into interstate commerce, until 1 year after the effective date of the
final rule. We also would not expect full compliance, even after that
date, for units of product that were initially introduced or initially
delivered for introduction into interstate commerce before that date,
such as those remaining in retail outlets. Our current thinking on
implementation is informed in part by our understanding there are no
currently marketed sunscreen products that contain the active
ingredients we propose here as Category II. We solicit comment on this
proposed approach.

XIII. Preliminary Economic Analysis of Impacts

A. Introduction

We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and
13563 direct us to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 13771
requires that the costs associated with significant new regulations
``shall, to the extent permitted by law, be offset by the elimination
of existing costs associated with at least two prior regulations.'' We
believe that this proposed rule is a significant regulatory action as
defined by Executive Order 12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because many sunscreen manufacturers are small entities and
the one-time costs of the proposed rule represent a significant
fraction of annual revenue to sunscreen manufacturers, we find that the
proposed rule will have a significant economic impact on a substantial
number of small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $150 million, using the most current (2017) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
result in an expenditure in any year that meets or exceeds this amount.

[[Page 6250]]

We have developed a comprehensive preliminary regulatory impact
analysis that assesses the impacts of the proposed rule. We present a
summary of this analysis below.

B. Summary of Costs and Benefits

If finalized, the proposed rule would update and make effective
regulations to ensure the safety and effectiveness of sunscreen
products marketed under the OTC drug monograph. The rule would update
sunscreen product labeling standards, address the safety of sunscreen
active ingredients, revise and clarify our expectations for testing and
recordkeeping by entities that conduct sunscreen testing, and address
other sunscreen safety or efficacy concerns, like combination
sunscreen-insect repellents and alternative dosage forms.
Consumers would benefit from less exposure to sunscreen products
containing active ingredients about which safety questions remain, less
exposure to sunscreen products labeled with potentially misleading sun
protection information, increased consumption of products with better
UVA protection, less exposure to flammable spray sunscreens, and less
exposure to spray and powder sunscreen products posing inhalation
risks. Consumers would also experience transaction cost savings. The
costs of the rule to sunscreen manufacturers include administrative
costs, costs to fill data gaps for active ingredients and powder dosage
forms, product formulation testing costs, and costs to reformulate and
relabel sunscreen products. Finally, testing entities would incur
recordkeeping costs if they do not already maintain adequate records of
testing equipment, methods, and observations in final formulation
testing.
Table 7 summarizes the costs and benefits of the proposed rule, if
finalized. The annualized benefits of the proposed rule, if finalized,
would range from $0.00 million to $3.72 million at a 7 percent discount
rate and from $0.00 million to $3.62 million at a 3 percent discount
rate. Our primary estimate of annualized benefits would equal $0.91
million at a 7 percent discount rate and $0.88 million at a 3 percent
discount rate. The annualized costs of the proposed rule, if finalized,
would range from $15.57 million to $75.84 million at a 7 percent
discount rate and from $12.40 million to $60.42 million at a 3 percent
discount rate. Our primary estimate of annualized costs would be $47.55
million at a 7 percent discount rate and $37.79 million at a 3 percent
discount rate.\52\
---------------------------------------------------------------------------

\52\ The primary estimate of the costs is not the average of the
lower bound costs and the upper bound costs.

Table 7--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
----------------------------------------------------------------------------------------------------------------
Units
---------------------------------
Category Primary Low High Period Notes
estimate estimate estimate Year Discount covered
dollars rate (%) (years)
----------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized ($m/ $0.91 $0.00 $3.72 2017 7 20
year). 0.88 0.00 3.62 2017 3 20
Annualized Quantified 201.79 98.16 286.26 Increased use
(mil oz/year) \1\. of products
with improved
UVA
protection.
Annualized Quantified 51.42 19.43 83.41 Less exposure
(mil oz/year) \2\. to sunscreens
containing
active
ingredients
about which
safety
questions
remain.
Annualized Quantified 161.04 159.88 162.20 Less exposure
(mil oz/year) \3\. to sunscreens
with
potentially
misleading sun
protection
information.
Annualized Quantified 386.44 384.86 388.02 Less exposure
(mil oz/year) \4\. to spray and
powder
sunscreens
posing
inhalation
risks.
------------------------------------------------------------------
Qualitative.............. Quicker responses to adverse events, improved inspections, and
better protection of human subjects. Potential transaction cost
savings related to changes in the effort required to choose a
sunscreen.
----------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized ($m/ 47.55 15.57 75.84 2017 7 20
year). 37.79 12.40 60.42 2017 3 20
Annualized Quantified....
------------------------------------------------------------------
Qualitative.............. Recordkeeping costs to testing entities that do not already
maintain adequate records.
----------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized
Monetized ($m/year).
----------------------------------------------------------------------------------

[[Page 6251]]

From:
To:
------------------------------------------------------------------
Other Annualized
Monetized ($m/year).
----------------------------------------------------------------------------------
From:
To:
------------------------------------------------------------------
Effects: State, Local, or Tribal Government: None.
Small Business: Some small businesses could exit the sunscreen
market by discontinuing their products or going out of business.
Wages: None.
Growth: None.
----------------------------------------------------------------------------------------------------------------
\1\ Values represent the 2016 consumption of sunscreens that would provide improved UVA protection under the
proposed rule.
\2\ Value represent the 2016 consumption of sunscreens that contain active ingredients about which safety
questions remain.
\3\ Values represent the 2016 consumption of sunscreens with potentially misleading sun protection information.
\4\ Values represent the 2016 consumption of potentially inhalable spray sunscreens and powder sunscreens.

Table 8 shows the Executive Order 13771 summary over an infinite
time horizon. In this analysis we assume that the costs and cost
savings of the rule would end after 20 years. We estimate that this
rule generates $29.85 million in net annualized costs, discounted at 7
percent, over a perpetual time horizon. Based on these costs, this
proposed rule would be considered a regulatory action under E.O. 13771.

Table 8--E.O. 13771 Summary Table
[In $ millions 2016 dollars, over an infinite time horizon) 1
--------------------------------------------------------------------------------------------------------------------------------------------------------
Primary Lower bound Upper bound Primary Lower bound Upper bound
estimate (7%) (7%) (7%) estimate (3%) (3%) (3%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Present Value of Costs.................................. $456.33 $149.22 $730.46 $618.16 $201.53 $1,002.22
Present Value of Cost Savings........................... 0.00 0.00 0.00 0.00 0.00 0.00
Present Value of Net Costs.............................. 456.33 149.22 730.46 618.16 201.53 1,002.22
Annualized Costs........................................ 29.85 9.76 47.79 40.44 13.18 65.57
Annualized Cost Savings................................. 0.00 0.00 0.00 0.00 0.00 0.00
Annualized Net Costs.................................... 29.85 9.76 47.79 40.44 13.18 65.57
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ We assume that the benefits and costs of the proposed rule would diminish after 20 years. Negative values denoted in parentheses.

We have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the proposed rule. The full preliminary
analysis of economic impacts is available in the docket for this
proposed rule (Ref. 63) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

XIV. Analysis of Environmental Impact

We have determined under 21 CFR 25.31(c) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

XV. Paperwork Reduction Act of 1995

This proposed rule contains information collection provisions that
are subject to review by OMB under the Paperwork Reduction Act of 1995
(PRA) (44 U.S.C. 3501-3520). A description of these provisions is given
in the Description section of this document with an estimate of the
annual reporting, recordkeeping, and third-party disclosure burden.
Included in the estimate is the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.
FDA invites comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
Title: Sunscreen Drug Products for OTC Human Use.
Description: The proposed rule would amend FDA's current sunscreen
labeling regulation (Sec. 201.327) and sunscreen products monograph
(part 352) regarding product labeling, testing, and recordkeeping
requirements. We note that existing regulations (e.g., current Sec.
201.327) already require SPF testing and labeling. The information
collections associated with current testing, labeling, and
recordkeeping requirements have previously been approved in accordance
with the PRA under OMB control numbers 0910-0139, 0910-0717, and 0910-
0755. For more information about current regulations and their history,
see the Background and Scope sections of the

[[Page 6252]]

proposed rule (sections III and IV, respectively). The proposed rule
would also amend parts 310 and 347.
While the proposed provisions are broadly consistent with current
best practices for testing conducted in human subjects and are not
expected to require significant changes by reputable and experienced
testing establishments, the proposed rule clarifies and confirms the
application of existing requirements to sunscreens and adds certain new
requirements, particularly for labeling and recordkeeping. The purpose
of these changes is to help ensure that sunscreen testing is conducted
and documented in a way that verifiably provides for protection of
human subjects and increases the reliability of the testing data that
underlies sunscreen labeling, and to update the labeling requirements.
Description of Respondents: Affected entities include: (1)
``responsible persons,'' as defined in proposed Sec. 201.327(a); (2)
entities to which the responsible person transfers its obligations as
permitted under proposed Sec. 201.327(a)(1) (e.g., contract
manufacturers, contract testing entities, contract research
organizations); and (3) clinical investigators conducting the testing
(the investigator(s) required to submit investigator statements and
other materials to the responsible person).
FDA estimates that up to 772 entities could meet the proposed
definition of responsible person (equivalent to ``brands'' in the
economic analysis found in section XIII, Preliminary Analysis of
Economic Impacts). The estimate of 772 entities also includes nearly
all entities to which a responsible person might transfer its
obligations (``transferees''), such as contract manufacturers, contract
repackagers, contract distributors. For example, a manufacturer may be
a responsible person for one brand and a contract manufacturer for
another. However, in addition to the 772 entities and potential
transferees already described, we estimate that there are approximately
10 U.S.-based contract testing entities used by multiple responsible
persons to conduct sunscreen testing (e.g., contract laboratories and
contract research organizations). These 10 potential transferees are
not included in the 772 figure. Thus, for certain information
collections, the estimated respondent number may be 782. We note that
this estimate does not include non-U.S.-based contract testing
entities.
In addition to the 10 contract testing entities, FDA estimates that
approximately 10 of the estimated 772 responsible persons conduct their
own SPF or broad spectrum testing. Thus, we estimate that there are
approximately 20 entities that conduct covered sunscreen testing; we
estimate these entities have approximately 20 lead clinical
investigators to whom certain information collection obligations (e.g.,
reporting) may apply.

A. Labeling for Sunscreen Products and Associated Clinical Testing

The proposed rule includes third-party disclosure obligations for
responsible persons. The provisions may also apply to entities to which
the responsible persons transfer their responsibilities under section
201.327(a)(1) (``transferees''), depending on the scope of transferred
obligations. There are labeling-related information collections
(requirements include certain information on product labels) and a
related testing burden (requirements for certain clinical testing to
determine and support labeling information).
1. Labeling-Related Information Collection and Burden
Proposed Sec. 201.327(b) and Sec. 201.327(h)(1) amend certain
labeling requirements applicable to the PDP. Among other things,
proposed Sec. 201.327(b) sets forth labeling requirements for the
statement of identity and SPF value claims discussed in this section.
Proposed Sec. 201.327(h)(1) applies to the statement of identity for
sunscreen products that also contain skin protectant active
ingredients. Proposed Sec. 352.50 requires that the PDP labeling
comply with the requirements of Sec. 201.327(b). The SPF value
statements set forth in proposed Sec. 201.327(b) and referenced in
proposed Sec. 352.50 are based on the results of the testing required
in proposed Sec. 201.327(i) and proposed part 352 (Sec. 352.70).
a. Statement of identity. Proposed Sec. 201.327(b)(1) requires
that sunscreen drug products bear a statement of identity consisting of
the name of each sunscreen active ingredient listed in alphabetical
order, followed by ``Sunscreen'' and ``[Dosage form]'' (e.g.,
``Lotion'', ``Spray''). Proposed Sec. 352.52(a) requires the labeling
to contain a statement of identity in accordance with Sec. 201.327(b).
Proposed Sec. 201.327(h)(1) applies to sunscreen drug products
that also contain skin protectant active ingredients; it requires that
the product bear a statement of identity consisting of the name of all
sunscreen and skin protectant active ingredients in alphabetical order,
followed by ``Sunscreen/Skin Protectant'' and ``[Dosage form],''
presented in accordance with Sec. 201.327(b)(1)(ii). Proposed Sec.
352.60(a) requires that the product bear a statement of identity as set
forth in Sec. 201.327(h)(1). Proposed Sec. 352.20(b)(4) requires that
the product must be labeled in accordance with Sec. Sec. 201.327(h)
and 352.60. Proposed Sec. 347.60(a)(3) requires that the labeling of
the product bear the statement of identity set forth in proposed Sec.
352.60(a).
We note that current regulations already include a requirement that
OTC products bear a statement of identity (see Sec. 201.66). This
proposed rule would set forth the specific requirements just described
for sunscreen drug products and sunscreen drug products that also
contain skin protectant active ingredients. We believe this analysis
reflects the additional burden beyond current statement of identity
requirements.
b. SPF value. Proposed Sec. 201.327(b)(2) requires, among other
things, that the labeling display certain statements regarding the
product's SPF value; the statements must be supported by the testing
required by proposed Sec. 201.327(i) and referenced in proposed Sec.
352.70. As previously noted, certain SPF testing and labeling is
already required under current regulations. This analysis reflects the
estimated additional burden of the proposed changes to SPF testing and
labeling requirements.
c. Burden for proposed statement of identity and SPF value
information collections. The estimated burden for the statement of
identity and SPF value information collections just described is
provided in table 11 (Estimated Annual Third-Party Disclosure Burden).
For currently marketed OTC sunscreen products, FDA believes that
responsible persons need only complete the testing (or reanalyze
existing testing data) and relabel the product as required by the rule
one time, and may then continue to utilize the resultant labeling going
forward without additional burden. We estimate that 772 respondents
would need to complete this relabeling and related testing (if not
already done) or reanalysis of existing test results one time for up to
4,078 total products. In addition, there may be new products introduced
each year. We estimate that as many as 1,500 new OTC sunscreen product
stock keeping units (SKUs) may be introduced each year by up to 772
respondents. These new products must be tested and labeled with the SPF
value and broad spectrum results determined in the tests. We estimate
that the 1,500 new sunscreen SKUs represent 975 new formulations.

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Table 11, row 1 provides FDA's estimate that 772 respondents will
need to create PDP labeling for currently marketed sunscreen
formulations in accordance with the statement of identity and SPF value
requirements of proposed Sec. 201.327(b)(1), (b)(2), and (h)(1). This
would be a one-time burden, and FDA estimates 5.2824 responses per
respondent for a total of 4,078 responses. FDA estimates a burden of
0.5 hours per response. We estimate the total burden of this
recordkeeping to be 2,039 hours.
Table 11, row 2 provides FDA's estimate that up to 772 respondents
will need to create PDP labeling for new formulations each year in
accordance with the statement of identity and SPF value requirements of
proposed Sec. 201.327(b)(1), (b)(2), and (h)(1). FDA estimates 1.943
responses per respondent for a total of 1,500 responses. FDA estimates
a burden of 0.5 hours per response. We estimate the total burden of
this recordkeeping to be 750 hours.
Table 11, row 3 provides FDA's estimate that 20 respondents will
conduct SPF testing in accordance with Sec. 201.327(i) (to determine
the SPF value required by Sec. 201.327(b)(2)) for currently marketed
sunscreen formulations, if this has not already been done. This would
be a one-time burden. The estimated number of respondents reflects
FDA's assumption based on its knowledge of the existing market that, of
the 772 responsible persons, approximately 10 will conduct their own
final formulation testing under Sec. 201.327(i), while most will
delegate the responsibility for conducting final formulation testing to
the approximately 10 independent testing entities that FDA believes
conduct most final formulation testing. FDA estimates 111 responses per
respondent for a total of 2,220 responses. FDA estimates a burden of 24
hours per response. We estimate the total burden to be 53,280 hours.
Table 11, row 4 provides FDA's estimate that 20 respondents will
conduct SPF testing in accordance with Sec. 201.327(i) (to determine
the SPF value required by Sec. 201.327(b)(2)) for new sunscreen
formulations. FDA estimates 48.75 responses per respondent for a total
of 975 responses. FDA estimates a burden of 24 hours per response. We
estimate the total burden to be 23,400 hours.
Regarding proposed Sec. 352.70, because that section does not add
any additional labeling or testing-related information collections not
already addressed elsewhere (it incorporates the proposed SPF testing
requirements as a condition of the part 352 monograph), there is no
additional burden.
2. Clinical Testing-Related Information Collection and Burden
Proposed Sec. 201.327(i) contains requirements for clinical
testing of SPF values for inclusion on sunscreen product labeling. As
previously noted, current regulations already require SPF testing.
While FDA expects that SPF testing and some of the proposed
recordkeeping is already being done, the proposed changes are intended
to clarify existing requirements applicable to sunscreen drug products
and set forth certain new requirements intended to improve the
reliability of SPF testing and ensure the protection of human subjects.
Proposed Sec. 352.70 references the Sec. 201.327(i) testing
requirements and makes the referenced testing requirements part of the
monograph conditions of use.
Across disciplines, testing involving human subjects is ordinarily
conducted under IRB oversight as a means of ensuring that adequate
human subject protections are provided and to ensure the integrity of
study design and execution. Thus, in this proposed regulation, FDA is
proposing to apply certain human subject protection requirements to
sunscreens, with the aim of having a framework similar to that used in
the IND context, but tailored to sunscreen testing.
Information collections related to proposed Sec. 201.327(i) are
addressed in detail in the sections that follow. Regarding proposed
Sec. 352.70, as in the previous section, because the proposed change
does not add any additional labeling or testing-related information
collections not already addressed elsewhere (it cross-references the
proposed Sec. 201.327(i) testing requirements as a condition of the
part 352 monograph), there is no additional burden.
a. Investigator statements and notifications. Proposed Sec.
201.327(i), among other things, requires responsible persons to obtain
a signed investigator statement and an investigator CV, and to provide
certain notifications (e.g., notification of adverse drug experiences).
These may result in third-party disclosure or reporting requirements
for responsible persons (and entities to which they have transferred
relevant obligations) as well as for clinical investigators. As noted
above, our experience leads us to believe that most responsible persons
will transfer their obligations under Sec. 201.327(i) to the
approximately 20 entities that currently conduct clinical SPF testing.
This assumption is reflected in the estimates regarding the number of
respondents below.
b. Investigator statements, CVs, and related burden. Proposed Sec.
201.327(i)(1)(i) requires responsible persons to, among other things,
obtain a signed investigator statement from each investigator. Proposed
Sec. 201.327(i)(1)(iv)(B) requires responsible persons to obtain a
signed investigator statement and CV. In FDA's experience,
investigators for SPF testing are most often employed by the testing
entities, and we therefore believe this is a recordkeeping requirement
rather than a third-party reporting requirement. We request comment on
this assumption. As noted above, we estimate that responsible persons
will typically delegate this obligation to the approximately 20
entities conducting final formulation testing. We estimate that each
testing entity employs one clinical investigator to run the SPF testing
they conduct. One investigator may run multiple SPF tests, and so long
as the responsible person (or testing entity) has the investigator
statement and CV on file for each investigator, there need not be a
separate copy for each investigation.
Table 10, row 1 provides FDA's estimate that approximately 20
respondents will need to obtain and keep a signed investigator
statement and CV in accordance with Sec. 201.327(i)(1)(i) and
(i)(1)(iv)(B). FDA estimates 2 responses per respondent (1 CV and 1
investigator statement) for a total of 40 annual responses. FDA
estimates a burden of 0.6 hours per response. We estimate the total
burden of this recordkeeping to be 24 hours.
c. Notifications and related burden. Proposed Sec.
201.327(i)(1)(i) requires responsible persons to, among other things,
ensure that FDA and all participating investigators are promptly
informed of significant new adverse effects or risks with respect to
the drug. Proposed Sec. 201.327(i)(1)(v) requires responsible persons
to keep each participating investigator informed of new observations
about the drug, particularly with respect to adverse effects and safe
use. As mentioned above, like other obligations associated with testing
under proposed Sec. 201.327(i), we anticipate that this obligation
will be delegated in most instances to the approximately 20 entities
that currently conduct SPF testing on behalf of responsible persons.
Table 9, row 1 provides FDA's estimate that approximately 20
respondents will need to inform FDA and participating investigators of
significant new adverse effects or risks in accordance with Sec.
201.327(i)(1)(i) and

[[Page 6254]]

of new safety and other observations in accordance with Sec.
201.327(i)(1)(v). FDA estimates up to 40 responses per respondent for a
total of up to 800 annual responses. FDA estimates a burden of 0.5
hours per response. We estimate the total burden of this recordkeeping
to be 400 hours.
d. Informed consent, IRB review, and related burden. Proposed Sec.
201.327(i)(1)(ii) requires responsible persons to obtain informed
consent, as defined in part 50, before clinical final formulation
testing and proposed Sec. 201.327(i)(1)(iii) requires that clinical
testing under Sec. 201.327(i) be reviewed and approved by an IRB
meeting the requirements of part 56. These two proposed provisions make
clear that FDA's regulations governing informed consent (part 50) and
IRB approval of research (part 56) apply to clinical final formulation
testing conducted pursuant to Sec. 201.327(i).
Regarding proposed Sec. 201.327(i)(1)(ii) and (iii), the
information collections associated with FDA's regulations governing
informed consent (part 50) and IRB approval of research (part 56) have
previously been approved in accordance with the PRA under OMB control
number 0910-0755. FDA does not expect that proposed Sec.
201.327(i)(1)(ii) or (iii) would affect the number of recordkeepers,
records, reports, or associated burdens included in the existing
approval (0910-0755), but we invite stakeholders to comment if they
have a different view.
Proposed Sec. 201.327(i)(1)(vii) requires investigators to provide
safety reports and a final study report to the responsible person.
Although investigators are often employees of testing entities, we are
basing our estimate on our assumption the respondents in this case are
the investigators themselves because of the framing of the duty
proposed by the regulation.
Table 9, row 2 provides FDA's estimate that up to 20 respondents
will need to provide safety reports in accordance with Sec.
201.327(i)(1)(vii)(A). FDA estimates 24.4 responses per respondent for
a total of 488 annual responses. FDA estimates a burden of 0.5 hours
per response. We estimate the total burden of this recordkeeping to be
244 hours.
Table 9, row 3 provides FDA's estimate that up to 20 respondents
will need to provide a final report in accordance with Sec.
201.327(i)(1)(vii)(B). This will occur one time per study, with each of
the 20 investigators conducting multiple studies per year. FDA
estimates 48.75 responses per respondent for a total of 975 annual
responses. FDA estimates a burden of 3 hours per response. We estimate
the total burden of this recordkeeping to be 2,925 hours.
Proposed Sec. 352.40(i)(1) references limitations on particle size
for sunscreens in a spray dosage form. Proposed Sec. 352.40(i)(2) and
(3) proposes limitations on flammability and drying time for spray
sunscreen formulations. These proposed sections (Sec. 352.40(i)(1)
through (3)) make the referenced limitations on flammability and
particle size requirements part of the monograph conditions of use.
Proposed Sec. 352.40(i)(5) states that applicable requirements for
particle size, flammability, and drying time for spray sunscreens must
be verified through batch and lot testing as part of CGMP compliance
under part 211. Entities conducting testing required by these sections
must also comply with associated recordkeeping requirements, including
those set forth in parts 210 and 211.
The recordkeeping associated with ensuring compliance with Sec.
352.40(i)(5) (batch and lot testing to ensure compliance with particle
size, flammability, and drying time limitations) is considered to be
part of the manufacturers' CGMP requirements under parts 210 and 211
(OMB control number 0910-0139). While FDA believes that sunscreen
manufacturers are already included among the respondents counted for
that collection, and that many of those manufacturers who have spray
dosage products may already be conducting flammability and drying time
testing (e.g., many are including flammability statements and
information about drying time in current product labeling), the
proposed inclusion of these requirements in the sunscreen regulations
is new. The proposed rule specifies the particle size, flammability,
and drying time limitations that would be required for sunscreens in
spray dosage forms to be GRASE under the monograph. The proposed rule
also specifies that compliance with these limitations must be verified
through batch and lot testing. While this greater specificity as to
required testing might have a marginal effect on the burden associated
with recordkeeping for manufacturing facilities that are not already
conducting such testing, FDA believes that the total change would be
minimal in light of the total recordkeeping burden under parts 210 and
211, which is estimated across thousands of manufacturers of a wide
variety of drugs. We request comment on these assumptions. If FDA
determines that the assumptions are incorrect, then, concurrent with
publication of the final rule, FDA plans to amend its approved
information collection 0910-0139, if necessary, to adjust the
respective burden estimate(s) to account for any change. We request
comment on the accuracy of our assumptions and the resulting burden
estimate.

B. Regulatory Status of Testing Entities

Proposed Sec. 201.327(k) clarifies the regulatory status of final
formulation testing, including that final formulation testing conducted
pursuant to Sec. 201.327 constitutes ``manufacture'' of a drug. As
such, this testing must be conducted in an establishment registered in
accordance with part 207 and section 510 of the FD&C Act, and entities
conducting final formulation testing required by this section must
comply with CGMP and associated recordkeeping requirements, including
those set forth in Sec. 201.327(l) and in parts 210 and 211. As this
provision is intended only to clarify an existing requirement, it does
not create a new information collection.
Entities covered by this provision are already included in the
burden estimates for the information collections associated with
registration and listing requirements. Recordkeeping obligations
related to registration and listing under part 207 and section 510 of
the FD&C Act are part of FDA's approved information collection for part
207 (OMB control number 0910-0829). CGMP recordkeeping obligations are
part of FDA's approved information collection for part 211 (OMB control
number 0910-0139).

C. Generating and Maintaining Records of SPF and Broad Spectrum Testing

FDA is proposing specific recordkeeping requirements for SPF and
broad spectrum testing to enable FDA to better monitor responsible
persons' compliance with the requirements of Sec. 201.327.
Recordkeeping is essential for FDA to evaluate whether required testing
of final formulations is being conducted properly (both as to human
subject protection and as to study design) and to enable the Agency to
investigate postmarketing product failures or adverse events.
Appropriate recordkeeping also enables FDA to conduct better and more
efficient inspections of entities conducting final formulation testing.
The proposed recordkeeping requirements are in alignment with the
records required for other types of manufacturing under CGMPs as set
forth in parts 210 and 211.
Failure to maintain adequate records of testing equipment, methods,
and observations can raise broad questions

[[Page 6255]]

about the reliability of final formulation testing. In FDA's
experience, there has been a lack of uniformity in testing entities'
approaches to recordkeeping for final formulation testing, raising
concerns about the Agency's ability to assess the reliability of the
results of final formulation testing. The proposed regulation would
address these concerns, clarify FDA's expectations, and align the
regulation with current best practices.
a. Potential transfer of obligations. Proposed Sec. 201.327(a)(1)
permits a responsible person (defined in Sec. 201.327(a)) to transfer
some or all of its obligations to another entity (a ``transferee''),
except for obligations with respect to recordkeeping under Sec.
201.327(l). We note that this could create some situations in which
both the responsible person and the transferee would be required to
comply with applicable recordkeeping requirements. The proposed
provision would also require a written record of the transfer of
obligations to be maintained by both parties to the transfer.
Regarding the record of an obligation transfer, FDA believes that
it is usual and customary business practice for a written record of a
transfer of obligations to be maintained by both parties to the
transfer. FDA does not believe this requirement would incur any
additional recordkeeping burden and believes it would meet the
exception at 5 CFR 1320.3(b)(2). Regarding the potential for some
recordkeeping obligations to fall on both responsible persons and
transferees, although proposed Sec. 201.327(a)(1) does not itself
impose a specific requirement to generate records, it does create the
potential for some recordkeeping obligations to fall on both
responsible persons and transferees. In particular, if a responsible
person has delegated all other responsibilities under Sec. 201.327(i)
and (j), they would nonetheless need to maintain a copy of the records
of final formulation testing required by Sec. 201.327(l)(2) and (3).
We have included the burden associated with keeping this copy in our
assumption that there are 782 respondents for recordkeeping obligations
as described below (20 entities that conduct testing, 10 of whom are
also responsible persons, plus 762 responsible persons that delegate
their responsibility for conducting testing (e.g., to one of the 10
independent testing entities that are not themselves responsible
persons)). We invite comment on whether our estimates properly reflect
the recordkeeping obligations.
b. Maintenance records and related burden. Proposed Sec.
201.327(l)(1) addresses maintenance records. The proposed rule
clarifies that, as manufacturing, final formulation testing must comply
with CGMPs, and, accordingly, records documenting proper maintenance of
equipment used in final formulation testing must be generated and
maintained by testing entities, consistent with existing obligations in
part 211.
Regarding proposed Sec. 201.327(l)(1), the existing maintenance
record obligations are part of FDA's approved information collection
for part 211 (OMB control number 0910-0139), and FDA believes that most
of the respondents for this collection of information (the
approximately 20 entities we believe are conducting final formulation
testing) are already included among the recordkeepers counted for that
collection. The proposed rule provides greater specificity regarding
what information should be included in maintenance records maintained
by facilities conducting final formulation testing. While this greater
specificity might have a marginal effect on the burden associated with
recordkeeping for these facilities, and the number of respondents for
this requirement may need to be increased by 10 (to reflect contract
testing entities that may not be currently registered as
manufacturers), FDA believes that the total change would be minimal in
light of the total recordkeeping burden under parts 210 and 211, which
is estimated across thousands of manufacturers of a wide variety of
drugs. We request comment on these assumptions. If FDA determines that
the assumptions are incorrect, then, concurrent with publication of the
final rule, FDA plans to amend its approved information collection
under OMB control number 0910-0139 as necessary to adjust the
respective burden estimate(s) in order to account for any change.
c. SPF testing records and related burden. Proposed Sec.
201.327(l)(2) addresses SPF testing records and requires that
respondents keep records related to the identification of the entity
conducting the testing, the formulation being tested, equipment used,
investigators, SPF standards, specific subject and test result data,
and records demonstrating compliance with Sec. 201.327(i)(1) governing
the establishment of adequate clinical testing procedures and
conditions. This is important because failure of testing entities to
keep adequate records to support final formulation testing may leave
FDA unable to verify the reliability of the results of SPF testing.
Because one testing entity may conduct final formulation testing on
behalf of multiple responsible persons, an error at one testing entity
may affect data across multiple clinical SPF testing studies for
multiple different final formulations that are ultimately sold under
different labels.
In particular, proposed Sec. 201.327(l)(2) requires that, in
addition to any records required to be kept pursuant to parts 210 and
211, records of SPF testing must include: (1) Identification of the
testing entity; (2) the product identifier and expected SPF; (3)
characterization of the SPF standard sunscreen required by proposed
Sec. 201.327(i)(3) (lot number, manufacturing date, and results of
high performance liquid chromatography (HPLC) SPF standard assay); (4)
documentation linking any blinded samples with the product lot number
and formulation tested; (5) specific testing records for each human
subject (identification of the UV source used for testing and various
specific test results and the individual(s) who determined the values);
(6) the mean and standard deviation from SPFi values, standard error
and determined SPF value derived as set forth in proposed Sec.
201.327(i)(7); (7) records for water resistance testing of pool
temperature, air temperature, and relative humidity as required by
proposed Sec. 201.327(i)(8); and (8) records demonstrating compliance
with proposed Sec. 201.327(i)(1) requirements for adequate clinical
testing procedures and conditions (e.g., individual case histories and
documentation of IRB review).
Table 10, row 2 provides FDA's estimate that approximately 20
respondents will need to generate SPF testing records in accordance
with proposed Sec. 201.327(l)(2) for existing products that will be
reformulated. FDA estimates 85.5 records per recordkeeper for a total
of 1,710 records. This is a one-time burden. FDA estimates a burden of
24 hours per recordkeeping. We estimate the total burden of this
recordkeeping to be 41,040 hours.
Table 10, row 3 provides FDA's estimate that up to 20 respondents
will need to generate SPF testing records in accordance with proposed
Sec. 201.327(l)(2) for new formulations. FDA estimates 48.75 records
per recordkeeper for a total of 975 records. FDA estimates a burden of
24 hours per recordkeeping. We estimate the total burden of this
recordkeeping to be 23,400.
Table 10, row 4 provides FDA's estimate that up to 782 respondents
will need to keep SPF testing records in accordance with proposed Sec.
201.327(l)(2) for existing products that will be reformulated. This is
a one-time

[[Page 6256]]

burden. FDA estimates 2.1867 records per recordkeeper for a total of
1,710 records. FDA estimates a burden of 0.33 hours per recordkeeping.
We estimate the total burden of this recordkeeping to be 564.3 hours.
Table 10, row 5 provides FDA's estimate that up to 782 respondents
will need to keep SPF testing records in accordance with proposed Sec.
201.327(l)(2) for new formulations. FDA estimates 1.2468 records per
recordkeeper for a total of 975 records. FDA estimates a burden of 0.33
hours per recordkeeping. We estimate the total burden of this
recordkeeping to be 321.75 hours.
With regard to the testing-related estimates, we note that the
requirements for obtaining certain medical history information from
test subjects are not considered collections of information because
information collected from subjects of clinical testing does not
constitute information under 5 CFR 1320.3(h)(5), and that the
referenced informed consent and IRB requirements under parts 50 and 56
are covered by existing approvals, as previously discussed.
d. Broad spectrum testing records and related burden. Proposed
Sec. 201.327(l)(3) addresses broad spectrum testing records. The
proposed rule requires records related to the identification of the
entity conducting the testing, the formulation being tested, equipment
used, investigators, UV standards, sunscreen application, and specific
test result data. This is important because failure of testing entities
to keep adequate records to support broad spectrum testing may leave
FDA unable to verify the reliability of testing results. Failure at one
testing entity may affect data across multiple broad spectrum testing
studies for multiple different final formulations that are ultimately
sold under different labels.
In particular, proposed Sec. 201.327(l)(3) requires that records
of broad spectrum testing must include: (1) Identification of the
testing entity; (2) records of sample information (product identifier
and expected SPF, master key for blinded samples, sample number and
identifier code, polymethylmethacrylate (PMMA) plate surface topography
measurement, and sample holder orientation); (3) identification of each
UV source used for sunscreen product pre-irradiation; (4) records of
sunscreen product application (sample weights, equipment
identification); (5) measurements required by proposed Sec.
201.327(j)(4) to (6)); (6) records of critical wavelength and UVA1/UV
ratio values; (7) for each sample: The identity of the individual(s)
conducting specific testing steps; and (8) test dates for the broad
spectrum test conducted pursuant to Sec. 201.327(j), and sample report
forms and supporting data.
Table 10, row 6 provides FDA's estimate that approximately 20
respondents will need to generate broad spectrum testing records in
accordance with proposed Sec. 201.327(l)(3) for existing products. As
with records of SPF testing, this number of respondents reflects FDA's
assumption that most responsible persons will delegate responsibility
for conducting testing under Sec. 201.327(j) to the approximately 20
testing entities. FDA estimates 203.9 records per recordkeeper for a
total of 4,078 records. This is a one-time burden. FDA estimates a
burden of 1.5 hours per recordkeeping. We estimate the total burden of
this recordkeeping to be 6,117 hours.
Table 10, row 7 provides FDA's estimate that up to 20 respondents
will need to generate broad spectrum testing records in accordance with
proposed Sec. 201.327(l)(3) for new formulations. FDA estimates 48.75
records per recordkeeper for a total of 975 records. FDA estimates a
burden of 1.5 hours per recordkeeping. We estimate the total burden of
this recordkeeping to be 1,462.5 hours.
Table 10, row 8 provides FDA's estimate that up to 782 respondents
will need to keep broad spectrum testing records in accordance with
proposed Sec. 201.327(l)(3) for existing products. This is a one-time
burden. FDA estimates 5.215 records per recordkeeper for a total of
4,078 records. FDA estimates a burden of 0.17 hours per recordkeeping.
We estimate the total burden of this recordkeeping to be 693.3 hours.
Table 10, row 9 provides FDA's estimate that up to 782 respondents
will need to keep broad spectrum testing records in accordance with
proposed Sec. 201.327(l)(3) for new formulations. FDA estimates 1.2468
records per recordkeeper for a total of 975 records. FDA estimates a
burden of 0.17 hours per recordkeeping. We estimate the total burden of
this recordkeeping to be 165.75 hours.
The recordkeeping burden is estimated as described in the tables at
the end of the PRA discussion.
With the exceptions noted above, we conclude that the other
provisions of this rule are not subject to OMB review under the PRA.
The proposed changes to part 310 do not include any collections of
information subject to the PRA.
The remaining sections of part 347 do not include any collections
of information not already addressed in this analysis.
Section 201.327 and the remaining sections of part 352 either do
not contain an information collection subject to PRA, or contain
specific labeling information, including directions and warnings, which
are a ``public disclosure of information originally supplied by the
Federal Government to the recipient for the purpose of disclosure to
the public'' (5 CFR 1320.3(c)(2)) and, therefore, are not collections
of information.
FDA estimates the burden of this information collection as follows:

Table 9--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Activity and 21 CFR section Number of responses per Total annual Average burden per response Total hours
respondents respondent responses
--------------------------------------------------------------------------------------------------------------------------------------------------------
Inform FDA and investigators of significant 20 40 800 0.5 (30 minutes)......................... 400
new adverse effects or risks (Sec.
201.327(i)(1)(i)) and new safety and other
observations (Sec. 201.327(i)(1)(v)).
Investigators provide safety reports in 20 24.4 488 0.5 (30 minutes)......................... 244
accordance with Sec. 201.327(i)(1)(vii)(A).
Investigators provide a final report in 20 48.75 975 3........................................ 2,925
accordance with Sec. 201.327(i)(1)(vii)(B)
(one time per study).
----------------------------------------------------------------------------------------------------------
Total.................................... .............. .............. .............. ......................................... 3,569
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

[[Page 6257]]

Table 10--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Activity and 21 CFR section Number of records per Total annual Average burden per recordkeeping Total hours
recordkeepers recordkeeper records
--------------------------------------------------------------------------------------------------------------------------------------------------------
Obtain and keep a signed investigator 20 2 40 0.6 (36 minutes)......................... 24
statement and CV in accordance with Sec.
201.327(i)(1)(i) and (iv)(B).
Generate SPF testing records for existing 20 85.5 1,710 24....................................... 41,040
products (Sec. 201.327(l)(2)) (one-time).
Generate SPF testing records for new 20 48.75 975 24....................................... 23,400
formulations (Sec. 201.327(l)(2)).
Keep SPF testing records for existing 782 2.1867 1,710 0.33 (20 minutes)........................ 564.3
products (Sec. 201.327(l)(2)) (one-time).
Keep SPF testing records for new formulations 782 1.2468 975 0.33..................................... 321.75
(Sec. 201.327(l)(2)). (20 minutes).............................
Generate Broad Spectrum testing records for 20 203.9 4,078 1.5...................................... 6,117
existing products (Sec. 201.327(l)(3)).
Generate Broad Spectrum testing records for 20 48.75 975 1.5...................................... 1,462.5
new formulations (Sec. 201.327(l)(3).
Keep Broad Spectrum testing records for 782 5.215 4,078 0.17 (10 minutes)........................ 693.3
existing products (Sec. 201.327(l)(3)).
Keep Broad Spectrum testing records for new 782 1.2468 975 0.17 (10 minutes)........................ 165.75
formulations (Sec. 201.327(l)(3)).
----------------------------------------------------------------------------------------------------------
Total.................................... .............. .............. .............. ......................................... 773,788.6
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating or maintenance costs associated with this collection of information.

Table 11--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Activity and 21 CFR section Number of disclosures Total annual Average burden per disclosure Total hours
respondents per respondent disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
Create PDP labeling in accordance with 772 5.2824 4,078 0.5 (30 minutes)......................... 2,039
statement of identity and SPF value
requirements (Sec. 201.327(b)(1), (b)(2)
and (h)(1)) for currently marketed sunscreen
formulations (one-time burden).
Create PDP labeling in accordance with 772 1.943 1,500 0.5 (30 minutes)......................... 750
statement of identity and SPF value
requirements (Sec. 201.327(b)(1), (b)(2),
and (h)(1)) for new formulations.
Conduct SPF testing in accordance with Sec. 20 111 2,220 24....................................... 53,280
201.327(i) to determine SPF value for
currently marketed sunscreen formulations
(if not already done) (one-time burden).
Conduct SPF testing in accordance with Sec. 20 48.75 975 24....................................... 23,400
201.327(i) to determine SPF value for new
sunscreen formulations.
----------------------------------------------------------------------------------------------------------
Total.................................... .............. .............. .............. ......................................... 79,469
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating or maintenance costs associated with this collection of information.

In compliance with the PRA (44 U.S.C. 3407(d)), the Agency has
submitted the information collection provisions of this proposed rule
to OMB for review. These requirements will not be effective until FDA
obtains OMB approval. FDA will publish a notice concerning OMB approval
of these requirements in the Federal Register.

XVI. Federalism

We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. Section 4(a) of the
Executive order requires Agencies to ``construe . . . a Federal statute
to preempt State law only where the statute contains an express
preemption provision or there is some other clear evidence that the
Congress intended preemption of State law, or where the exercise of
State authority conflicts with the exercise of Federal authority under
the Federal statute.'' The sole statutory provision giving preemptive
effect to this proposed rule is section 751 of the FD&C Act (21 U.S.C.
379r). We have complied with all of the applicable requirements under
the Executive order and have determined that the preemptive effect of
this proposed rule, if finalized, would be consistent with Executive
Order 13132. Through publication of this proposed rule, we are
providing notice and an opportunity for State and local officials to
comment on this rulemaking.

XVII. Consultation and Coordination With Indian Tribal Governments

We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the rule does not contain policies that would have a
substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal

[[Page 6258]]

Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.

XVIII. References

The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.

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(113509) Technical Document'' (available at https://www3.epa.gov/pesticides/chem_search/reg_actions/registration/related_PC-113509_1-Feb-99.pdf), accessed March 27, 2018.
* 195. EPA, ``3-[N-Butyl-N-acetyl]-Aminopropionic Acid, Ethyl Ester
(113509) Fact Sheet'' (available at https://www3.epa.gov/pesticides/chem_search/reg_actions/registration/fs_PC-113509_01-Jan-00.pdf),
accessed March 27, 2018.
* 196. FDA, ``Food Additive Status List'' (available at https://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm091048.htm), accessed March 27, 2018.
* 197. EPA, ``Reregistration Eligibility Decision (R.E.D) Facts, Oil
of Citronella,'' February 1997 (available at https://www3.epa.gov/pesticides/chem_search/reg_actions/reregistration/fs_PC-021901_1-Feb-97.pdf), accessed March 27, 2018.
* 198. NPIC, ``Oil of Citronella General Fact Sheet'' (available at
http://npic.orst.edu/factsheets/citronellagen.pdf), accessed March
27, 2018.
* 199. EPA, Office of Pesticide Programs, Label Review Manual,
``Chapter 3: General Labeling Requirements,'' revised March 2018
(available at https://www.epa.gov/sites/production/files/2017-10/documents/chap-03-dec-2014.pdf), accessed March 27, 2018.
* 200. CDC, Travelers' Health, Chapter 2: The Pretravel
Consultation. J. Mutebi, W.A. Hawley, and W.G. Brogdon, ``Protection
against Mosquitoes, Ticks, and Other Arthropods'' (available at
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accessed March 27, 2018.
201. American Academy of Pediatrics, ``Tips for Using Repellents
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27, 2018.
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Non-Melanoma Skin Cancer in Western Australia,'' Cancer Causes and
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205. Ross, E.A., K.A. Savage, L.J. Utley, et al., ``Insect Repellant
Interactions: Sunscreens Enhance DEET (N,N-Diethyl-M-Toluamide)
Absorption,'' Drug Metabolism and Disposition, vol. 32, pp.783-785,
2004.
206. Gu, X., T. Wang, D.M. Collins, et al., ``In Vitro Evaluation of
Concurrent Use of Commercially Available Insect Repellent and
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152(6), pp. 1263-1267, 2005.
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Repellent DEET and the Sunscreen Oxybenzone Across Human Skin,''
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Analysis of Insect Repellent DEET, Sunscreen Oxybenzone and Five
Relevant Metabolites by Reversed-Phase HPLC with UV Detection:
Application to an In Vivo Study in a Piglet Model,'' Journal of
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Sciences, vol. 882(1-2), pp. 271-277, 2005.
209. Kasichayanula S., J.D. House, T. Wang, et al., ``Percutaneous
Characterization of the Insect Repellent DEET and the Sunscreen
Oxybenzone from Topical Skin Application,'' Toxicology and Applied
Pharmacology, vol. 223(2), pp. 187-194, 2007.
210. Yinn, L.M., J.N. Tian, and C.C. Hung, ``Assessment of Dermal
Absorption of DEET-Containing Insect Repellent and Oxybenzone-
Containing Sunscreen Using Human Urinary Metabolites,''
Environmental Science and Pollution Research International, vol. 22,
pp. 2062-2070, 2015.
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Repellents and the Efficacy of Sunscreens,'' The Lancet, vol.
349(9066), pp. 1670-1671, 1997.

List of Subjects

21 CFR Part 201

Drugs, Incorporation by reference, Labeling, Reporting and
recordkeeping requirements.

21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.

21 CFR Part 347

Labeling, Over-the-counter drugs.

21 CFR Part 352

Labeling, Over-the-counter drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, we propose
that 21 CFR parts 201, 310, 347, and 352 be amended as follows:

PART 201--LABELING

0
1. The authority citation for part 201 continues to read as follows:

[[Page 6264]]

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360,
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

0
2. Revise Sec. 201.327 to read as follows:

Sec. 201.327 Over-the-counter sunscreen drug products; required
labeling based on effectiveness testing.

The following provisions apply to an over-the-counter (OTC)
sunscreen drug product that is intended for application to the skin of
humans for purposes of absorbing, reflecting, or scattering radiation
in the ultraviolet (UV) range at wavelengths from 290 to 400 nanometers
(nm), and that contains one or more of the following as an active
ingredient: Avobenzone, cinoxate, dioxybenzone, ensulizole, homosalate,
meradimate, octinoxate, octisalate, octocrylene, oxybenzone, padimate
O, sulisobenzone, titanium dioxide, or zinc oxide, alone or in
combination. The provisions do not apply to OTC sunscreen drug products
marketed under approved new drug applications or abbreviated new drug
applications. The failure of a product covered by this section to
comply with any provision of this section, including the labeling of
such a product with any effectiveness claim based on testing that fails
to comply with any provision of this section, renders that product
misbranded under section 502 of the Federal Food, Drug, and Cosmetic
Act.
(a) General obligations of responsible persons. As used in this
section, a ``responsible person'' is the manufacturer, packer, or
distributor whose name appears on the labeling of a product covered by
this section. A responsible person must assure that final formulation
testing conducted on its product(s) pursuant to paragraphs (i) and (j)
of this section complies with all applicable provisions of this
section.
(1) Transfer of obligations. (i) A responsible person may transfer
responsibility for any or all of its obligations set forth in this
section to another entity (e.g., a contract research organization and/
or testing laboratory), except as set forth in paragraph (l)
(recordkeeping) of this section. Any such transfer must be described in
writing. If not all obligations are transferred, the writing is
required to describe each of the obligations being assumed by the
transferee. If all obligations are transferred, a general statement
that all obligations have been transferred is acceptable. Any
obligation not covered by the written description will be deemed not to
have been transferred. A written record of the transfer of obligations
must be maintained by both parties to the transfer for the time period
set forth in paragraph (l) of this section.
(ii) An entity that assumes any obligation(s) of a responsible
person must comply with the provisions of this section applicable to
the assumed obligation and will be subject to the same regulatory
action as a responsible person for failure to comply with any
obligation assumed under this section. Thus, all references to
``responsible person'' in this section apply to another entity (e.g., a
contract research organization or testing laboratory) to the extent
that it assumes one or more obligations of a responsible person.
(2) Personnel. A responsible person must select only investigators
and other personnel qualified by appropriate training and/or experience
to conduct final formulation testing pursuant to this section.
Personnel engaged in testing under this section must have the
education, training, and experience, or any combination thereof, to
enable that person to adequately perform their assigned functions.
(b) Principal display panel. The following labeling must be
prominently placed on the principal display panel:
(1) Statement of identity--(i) Placement. The principal display
panel of an over-the-counter sunscreen drug product bears a statement
of identity as one of its principal features. Except as set forth in
paragraph (h) of this section, the statement of identity consists of
the name of each sunscreen active ingredient in the product as
identified in this section, listed in alphabetical order and followed
by ``Sunscreen'' and ``[Dosage form]'' (e.g., ``Lotion'' ``Spray'').
(ii) Prominence. The statement of identity must appear on the
principal display panel in boldface type at least one-quarter as large
as the size of the most prominent printed matter on the principal
display panel, in lines generally parallel to the base on which the
package rests as it is designed to be displayed and in direct
conjunction with the most prominent display of the proprietary name or
designation. The entire text of the statement of identity must appear
in the same font style, size, and color with the same background color,
and as continuous text with no intervening text or graphic, other than
additional text provided in accordance with paragraph (h) of this
section.
(2) Effectiveness claim. For purposes of this section, the term
``determined SPF value'' refers to the SPF value that equals the
largest whole number less than SPF-(t*SE), determined for a sunscreen
product in accordance with paragraph (i) of this section.
(i) SPF Broad Spectrum Statement. For a product that has been shown
to pass the broad spectrum test in paragraph (j) of this section, the
labeling states ``Broad Spectrum SPF [insert the labeled SPF value
associated with the range into which the determined SPF value falls, as
set forth in the following table.]''

Table 1 to Paragraph (b)(2)(i)--SPF Labeling Ranges
------------------------------------------------------------------------
Range of determined SPF values Associated labeled SPF value
------------------------------------------------------------------------
60-80..................................... 60+.
50-59..................................... 50.
40-49..................................... 40.
30-39..................................... 30.
25-29..................................... 25.
20-24..................................... 20.
15-19..................................... 15.
2-14...................................... Determined SPF Value.
------------------------------------------------------------------------

(ii) SPF Statement. For a product that has not been shown to pass
the broad spectrum test in paragraph (j) of this section, the labeling
states ``SPF [insert labeled SPF value associated with the range into
which the determined SPF value falls, as set forth in the table in
paragraph (b)(2)(i) of this section]''.
(iii) For a product with a determined SPF value of at least 2 but
less than 15. The SPF statement is immediately followed by an asterisk
(``*''), and the associated statement ``*See Skin Cancer/Skin Aging
Alert'' appears in the bottom 30 percent of the principal display
panel.
(iv) Prominence of required statements. The SPF Broad Spectrum
statement, SPF statement, and ``*See Skin Cancer/Skin Aging Alert''
statement, as applicable, must appear in boldface type at least one-
quarter as large as the most prominent printed matter on the principal
display panel and in lines generally parallel to the base on which the
package rests as it is designed to be displayed. The entire text of the
Broad Spectrum SPF or SPF statement, as applicable, must appear in the
same font style, size, and color with the same background color and
must appear as continuous text with no intervening text or graphic. The
entire text of the ``See Skin Cancer/Skin Aging Alert'' statement, as
applicable, must appear in the same font style, size, and color with
the same background color and must appear as continuous text with no
intervening text or graphic.
(3) Water resistance statements--(i) For products that provide 40
minutes of water resistance according to the test in paragraph
(i)(8)(i) of this section. The

[[Page 6265]]

labeling states ``Water Resistant (40 minutes).''
(ii) For products that provide 80 minutes of water resistance
according to the test in paragraph (i)(8)(ii) of this section. The
labeling states ``Water Resistant (80 minutes).''
(iii) Prominence of water resistance statement. For all products
bearing a water resistance statement, the statement must appear in
boldface type at least one-quarter as large as the most prominent
printed matter on the principal display panel and in lines generally
parallel to the base on which the package rests as it is designed to be
displayed. The entire text of the water resistance statement must
appear in the same font style, size, and color with the same background
color, and as continuous text with no intervening text or graphic.
(c) Indications. The labeling of the product states, under the
heading ``Uses,'' the phrases listed in this paragraph, as appropriate.
Other truthful and nonmisleading statements, describing only the uses
that have been established and listed in this paragraph, may also be
used, as provided in Sec. 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act
relating to misbranding and the prohibition in section 301(d) of the
Federal Food, Drug, and Cosmetic Act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the Federal Food, Drug, and
Cosmetic Act.
(1) For all sunscreen products, the following indication statement
must be included under the heading ``Uses'': ``[bullet] helps prevent
sunburn''. See Sec. 201.66(b)(4) for definition of bullet.
(2) For sunscreen products that have been shown to pass the broad
spectrum test in paragraph (j) of this section and have a determined
SPF value of 15 or higher, the labeling may include the following
statement in addition to the indication in paragraph (c)(1) of this
section: ``[bullet] if used as directed with other sun protection
measures (see Directions [in bold italic font]), decreases the risk of
skin cancer and early skin aging caused by the sun''.
(3) Any labeling or promotional materials that suggest or imply
that the use, alone, of any sunscreen reduces the risk of or prevents
skin cancer or early skin aging will cause the product to be misbranded
under section 502 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 352).
(d) Warnings. The labeling of the product contains the following
warnings under the heading ``Warnings''.
(1) For all sunscreen products. (i) The labeling states ``Do not
use [bullet] on damaged or broken skin.''
(ii) The labeling states ``When using this product [bullet] keep
out of eyes. Rinse with water to remove.''
(iii) The labeling states ``Stop use and ask a doctor if [bullet]
rash occurs.''
(2) For sunscreen products that are broad spectrum with determined
SPF values of at least 2 but less than 15 according to the SPF test in
paragraph (i) of this section or that have not been shown to pass the
broad spectrum test in paragraph (j) of this section. The first
statement under the heading ``Warnings'' states ``Skin Cancer/Skin
Aging Alert [in bold font]: Spending time in the sun increases your
risk of skin cancer and early skin aging. This product has been shown
only to help prevent sunburn, not [in bold font] skin cancer or early
skin aging.''
(3) For products in a spray dosage form that meet the definition of
either the term ``flammable'' or the term ``combustible'' as defined in
Sec. 352.3(g) or (h) of this chapter, as applicable, when tested in
accordance with 16 CFR 1500.43a--(i) Labeling statement. The labeling
states [bullet] ``Flammable'' or ``Combustible'' (as applicable)
followed by a colon and the statement ``Keep away from fire or flame.''
(ii) For products that have a drying time of less than 5 minutes.
The labeling states [bullet] ``Wait 5 minutes after application before
approaching a source of heat or flame, or before smoking.''
(iii) For products that have a drying time of at least 5 minutes
but less than 10 minutes. The labeling states [bullet] ``Wait 10
minutes after application before approaching a source of heat or flame,
or before smoking.''
(e) Directions. The labeling of the product contains the following
statements, as appropriate, under the heading ``Directions.'' More
detailed directions applicable to a particular product formulation may
also be included.
(1) For all sunscreen products. (i) As an option, the labeling may
state ``For sunscreen use:''.
(ii) The labeling states ``[bullet] apply [select one of the
following: `liberally' or `generously'] [and, as an option: `and
evenly'] 15 minutes before sun exposure''.
(iii) As an option, the labeling may state ``[bullet] apply to all
skin exposed to the sun''.
(iv) The labeling states ``[bullet] children under 6 months of age:
Ask a doctor''.
(2) For sunscreen products that have been shown to pass the broad
spectrum test in paragraph (j) of this section and have a determined
SPF value of 15 or higher. The labeling states ``[bullet] Sun
Protection Measures. [in bold font] Spending time in the sun increases
your risk of skin cancer and early skin aging. To decrease this risk,
regularly use a sunscreen with a Broad Spectrum SPF value of 15 or
higher and other sun protection measures including: [bullet] limit time
in the sun, especially from 10 a.m.-2 p.m. [bullet] wear long-sleeved
shirts, pants, hats, and sunglasses''.
(3) For products that satisfy the water resistance test in
paragraph (i)(8) of this section. The labeling states ``[bullet]
reapply: [bullet] after [select one of the following determined by
water resistance test: `40 minutes of' or `80 minutes of'] swimming or
sweating [bullet] immediately after towel drying [bullet] at least
every 2 hours''.
(4) For products that do not satisfy the water resistance test in
paragraph (i)(8) of this section. The labeling states ``[bullet]
reapply at least every 2 hours [bullet] use a water resistant sunscreen
if swimming or sweating''.
(5) For sunscreen products in a spray dosage form. The labeling
states ``[bullet] Hold container 4 to 6 inches from the skin to apply.
[bullet] Do not spray directly into face. Spray on hands then apply to
face. [bullet] Do not apply in windy conditions. [bullet] Use in a
well-ventilated area and avoid inhalation''.
(f) Other information. The labeling of the product contains the
following statement under the heading ``Other information:'' ``[bullet]
protect the product in this container from excessive heat and direct
sun''.
(g) False or misleading claims. There are claims that would be
false and/or misleading on sunscreen products. These claims include but
are not limited to the following: ``Sunblock,'' ``sweatproof,'' and
``waterproof.'' These or similar claims will cause the product to be
misbranded under section 502 of the Federal Food, Drug, and Cosmetic
Act.
(h) Labeling of products containing a combination of sunscreen and
skin protectant active ingredients. Statements of identity,
indications, warnings, and directions for use, respectively, applicable
to each ingredient in the product may be combined to eliminate
duplicative words or phrases so that the resulting information is clear
and understandable. Labeling provisions in Sec. 347.50(e) of this
chapter do not apply to these products.
(1) Statement of identity. The statement of identity of a sunscreen
product that also contains one or more skin protectant active
ingredients, identified in Sec. Sec. 347.10(a), (d), (e), (g), h),

[[Page 6266]]

(i), (k), (l), (m), and (r) of this chapter, consists of the names of
all sunscreen and skin protectant active ingredients in alphabetical
order followed by ``Sunscreen/Skin Protectant'' and ``[Dosage form].''
The statement of identity must be prominently placed on the principal
display panel and presented in accordance with paragraph (b)(1)(ii) of
this section.
(2) Indications. The labeling of the product states, under the
heading ``Uses,'' any or all of the applicable indication(s) included
in Sec. 347.50(b) of this chapter or in paragraph (c) of this section.
Other truthful and nonmisleading statements, describing only the
indications for use that have been established in Sec. 347.50(b) of
this chapter or listed in paragraph (c) of this section, may also be
used, as provided by Sec. 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act
relating to misbranding and the prohibition in section 301(d) of the
Federal Food, Drug, and Cosmetic Act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the Federal Food, Drug, and
Cosmetic Act.
(3) Warnings. The labeling of the product states, under the heading
``Warnings,'' the applicable warnings for sunscreens in paragraph (d)
of this section and for skin protectants in Sec. 347.50(c) of this
chapter.
(4) Directions. The labeling of the product states, under the
heading ``Directions,'' any or all of the applicable directions for
sunscreens, as set forth in paragraph (e) of this section, and for skin
protectants, as set forth in Sec. Sec. 347.50(d) and 347.60(d) of this
chapter, unless otherwise stated in this paragraph. When the time
intervals or age limitations for administration of the individual
ingredients differ, the directions for the product may not contain any
dosage that exceeds those established for any individual ingredient in
the applicable OTC drug monograph(s), and may not provide for use by
any age group lower than the highest minimum age limit established for
any individual ingredient. When the directions for administration of
the sunscreen and skin protectant differ in any other way, the
directions for sunscreens in paragraph (e) of this section should be
used.
(i) Sun Protection Factor (SPF) testing--(1) Adequate clinical
testing procedures and conditions--(i) General obligations of
responsible persons for testing under this paragraph. Responsible
persons must provide investigators and other personnel engaged in SPF
testing with the information they need to conduct an investigation
properly; must obtain a signed investigator statement from each
investigator; must ensure proper monitoring of the investigation(s);
must ensure that the investigation(s) is conducted in accordance with
written general investigational plan(s) and protocol(s); must ensure
compliance with paragraphs (i)(1)(ii) and (iii) of this section; and
must ensure that FDA and all participating investigators are promptly
informed of significant new adverse effects or risks with respect to
the drug.
(ii) Informed consent. Effective informed consent, as defined in
part 50 of this chapter, must be obtained from all human subjects
before initiating clinical final formulation testing under this
paragraph (i).
(iii) Institutional review board (IRB) approval. Clinical testing
under this paragraph (i), must be reviewed and approved by an IRB
meeting the requirements of FDA's regulations in part 56 of this
chapter.
(iv) Control of personnel--(A) General obligations. A responsible
person is responsible for ensuring that investigators and other
personnel conducting any testing under this paragraph (i), conduct all
investigations in accordance with the signed investigator statement,
the investigational plan, and applicable regulations. Responsible
persons must ensure the implementation of adequate safeguards to
protect the rights, safety, and welfare of subjects under he
investigator's care. The responsible person must also ensure that
investigators or other study personnel will promptly report to the IRB
all changes in the clinical final formulation testing and all
unanticipated problems involving risk to human subjects or others, and
that investigators or other personnel will not make any changes in the
clinical final formulation testing without IRB approval, except where
necessary to eliminate apparent immediate hazards to human subjects.
(B) Obtaining information from the investigator. Before permitting
an investigator to begin participating in clinical final formulation
testing under this paragraph (i), the responsible person must obtain
the following:
(1) Investigator statement. A signed investigator statement
containing the name and address of the investigator and a commitment by
the investigator that he or she--
(i) Will conduct the testing in accordance with the relevant,
current protocol(s) and will only make changes in a protocol after
notifying the responsible person and the IRB, except when necessary to
protect the safety, the rights, or welfare of subjects;
(ii) Will comply with all requirements regarding the obligations of
clinical investigators and all other pertinent requirements in this
subpart;
(iii) Will personally conduct or supervise the described
investigation(s);
(iv) Will inform any potential subjects that the drugs are being
used for investigational purposes and will comply with the requirements
relating to obtaining informed consent (part 50 of this chapter) and
institutional review board review and approval (part 56 of this
chapter);
(v) Will report to the responsible person adverse experiences that
occur during the investigation(s);
(vi) Will ensure that all personnel assisting in the conduct of the
testing are informed about their obligations in meeting the above
commitments.
(2) Curriculum vitae. A curriculum vitae or other statement of
qualifications of the investigator showing the education, training, and
experience that qualifies the investigator to conduct the final
formulation testing pursuant to this paragraph (i).
(v) Informing investigators. The responsible person must, as the
overall investigation proceeds, keep each participating investigator
informed of new observations discovered by or reported to the
responsible person on the drug, particularly with respect to adverse
effects and safe use.
(vi) Review of ongoing investigations. (A) The responsible person
must monitor the progress of all clinical testing being conducted on
its final formulation pursuant to this paragraph (i).
(B) A responsible person who discovers noncompliance by an
investigator or other personnel with the signed agreement, the general
investigational plan, or the requirements of this paragraph (i) or
other applicable regulations (e.g., parts 50 and 56 of this chapter)
must promptly either secure compliance or end the investigator's or
other personnel's participation in testing conducted under this
paragraph (i).
(C) The responsible person must review and evaluate the evidence
relating to the safety and effectiveness of the final formulation as it
is obtained from the investigator.
(vii) Investigator reports--(A) Safety reports. An investigator
must immediately report to the responsible person any serious adverse
event, whether or not considered related to the final formulation,
including those listed in the protocol, and must include an

[[Page 6267]]

assessment of whether there is a reasonable possibility that the final
formulation being tested caused the adverse event. The investigator
must record nonserious adverse events and report them to the
responsible person according to the timetable specified in the
protocol.
(B) Final report. An investigator must provide the responsible
person with an adequate report shortly after completion of each
investigation conducted by that investigator for the responsible person
under this paragraph (i).
(2) UV source (solar simulator)--(i) Emission spectrum. Filter a
single port or multiport solar simulator so that it provides a
continuous emission spectrum from 290 to 400 nanometers (nm) with a
limit of 1,500 watts per square meter (W/m\2\) on total irradiance for
all wavelengths between 250 and 1,400 nm.
(A) The solar simulator must have the following percentage of
erythema-effective radiation in each specified range of wavelengths:

Table 2 to Paragraph (i)(2)(i)(A)--Solar Simulator Emission Spectrum
------------------------------------------------------------------------
Percent
Wavelength range (nm) erythemal
contribution 1
------------------------------------------------------------------------
<290.................................................. <0.1
290-300............................................... 1.0-8.0
290-310............................................... 49.0-65.0
290-320............................................... 85.0-90.0
290-330............................................... 91.5-95.5
290-340............................................... 94.0-97.0
290-400............................................... 99.9-100.0
------------------------------------------------------------------------
1 Calculation of erythema action spectrum described in paragraph
(i)(2)(ii) of this section.

(B) In addition, UVA II (320-340 nm) irradiance must equal or
exceed 20 percent of the total UV (290-400 nm) irradiance. UVA I (340-
400 nm) irradiance must equal or exceed 60 percent of the total UV
irradiance.
(ii) Erythema action spectrum. (A) Calculate the erythema action
spectrum weighting factor (Vi) at each wavelength [lgr]:

(1) Vi ([lgr]) = 1.0 (250 <[lgr] <=298 nm)
(2) Vi ([lgr]) = 10\0.094\ * (\298\ - [lgr]) (298 <[lgr]
<=328 nm)
(3) Vi ([lgr]) = 10\0.015\ * (\140\ - [lgr]) (328 <[lgr]
<=400 nm)

(B) Calculate the erythema-effective UV dose (E) delivered by a
solar simulator as follows:
[GRAPHIC] [TIFF OMITTED] TP26FE19.003

Where

Vi([lgr]) = erythema action spectrum weighting factor at
each wavelength [lgr]
I([lgr]) = irradiance (Watts per square meter) at each wavelength
[lgr]
t = exposure time (seconds)
Erythema-effective dose (E) is expressed as effective Joules per
square meter (J/m\2\-eff).

(C) The solar simulator radiation intensity must be determined
using a handheld radiometer with a response weighted to match the
spectrum in ISO 17166 CIE S 007/E entitled ``Erythemal reference action
spectrum and standard erythema dose,'' dated 1999 (First edition, 1999-
12-15; corrected and reprinted 2000-11-15), which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may
obtain a copy from the ISO Copyright Office, Case Postale 56, CH-1211,
Geneva 20, Switzerland, telephone +41-22-749-01-11 or fax +41-22-74-09-
47. https://www.iso.org. You may inspect a copy at the Center for Drug
Evaluation and Research, 10903 New Hampshire Ave., Bldg. 22, Silver
Spring, MD 20993, call 301-796-2090, or at the National Archives and
Records Administration (NARA). For information on the availability of
this material at NARA, call 202-741-6030, or go to: https://www.archives.gov/federal-register/cfr/ibr-locations.html. The solar
simulator output should be measured before and after each phototest or,
at a minimum, at the beginning and end of each test day. This
radiometer should be calibrated using side-by-side comparison with the
spectroradiometer (using the weighting factors determined according to
paragraph (i)(2)(ii)(A) of this section) at the time of the annual
spectroradiometric measurement of the solar simulator as described in
paragraph (i)(2)(iv) of this section.
(iii) Operation. A solar simulator must have no significant time-
related fluctuations (within 20 percent) in radiation emissions after
an appropriate warm-up time and demonstrate good beam uniformity
(within 20 percent) in the exposure plane. The delivered dose to the UV
exposure site must be within 10 percent of the expected dose.
(iv) Periodic measurement. To ensure that the solar simulator
delivers the appropriate spectrum of UV radiation, the emission
spectrum of the solar simulator must be measured at least annually with
an appropriate and accurately calibrated spectroradiometer system
(results should be traceable to the National Institute for Standards
and Technology). In addition, the solar simulator must be recalibrated
if there is any change in the lamp bulb or the optical filtering
components (i.e., filters, mirrors, lenses, collimating devices, or
focusing devices). Daily solar simulator radiation intensity should be
monitored with a broadband radiometer with a response weighted to match
the erythema action spectrum in ISO 17166 CIE S 007/E entitled
``Erythemal reference action spectrum and standard erythema dose,''
which is incorporated by reference in paragraph (i)(2)(ii)(C) of this
section. If a lamp must be replaced due to failure or aging during a
phototest, broadband device readings consistent with those obtained for
the original calibrated lamp will suffice until measurements can be
performed with the spectroradiometer at the earliest possible
opportunity.
(3) SPF standard--(i) Preparation. The SPF standard must be a
formulation containing 7-percent padimate O and 3-percent oxybenzone.

Table 3 to Paragraph (i)(3)(i)--Composition of the Padimate O/Oxybenzone
SPF Standard
------------------------------------------------------------------------
Percent by
Ingredients weight
------------------------------------------------------------------------
Part A:
Lanolin............................................. 4.50
Cocoa butter........................................ 2.00
Glyceryl monostearate............................... 3.00
Stearic acid........................................ 2.00
Padimate O.......................................... 7.00
Oxybenzone.......................................... 3.00
Part B:
Purified water USP.................................. 71.60
Sorbitol solution................................... 5.00
Triethanolamine, 99 percent......................... 1.00
Methylparaben....................................... 0.30
Propylparaben....................................... 0.10
Part C:
Benzyl alcohol...................................... 0.50
Part D:
Purified water USP.................................. QS 1
------------------------------------------------------------------------
\1\ Quantity sufficient to make 100 grams.

(A) Step 1. Add the ingredients of Part A into a suitable stainless
steel kettle equipped with a propeller agitator. Mix at 77 to 82 [deg]C
until uniform.
(B) Step 2. Add the water of Part B into a suitable stainless steel
kettle equipped with a propeller agitator and begin mixing at 77 to 82
[deg]C. Add the remaining ingredients of Part B and mix until uniform.
(C) Step 3. Add the batch of Step 1 to the batch of Step 2 and mix
at 77 to 82 [deg]C until smooth and uniform. Slowly cool the batch to
49 to 54 [deg]C.
(D) Step 4. Add the benzyl alcohol of Part C to the batch of Step 3
at 49 to 54 [deg]C. Mix until uniform. Continue to cool batch to 35 to
41 [deg]C.
(E) Step 5. Add sufficient water of Part D to the batch of Step 4
at 35 to 41 [deg]C to obtain 100 grams of SPF standard. Mix until
uniform. Cool batch to 27 to 32 [deg]C.

[[Page 6268]]

(ii) HPLC assay. Use the following high performance liquid
chromatography (HPLC) procedure to verify the concentrations of
padimate O and oxybenzone in the SPF standard:
(A) Instrumentation--(1) Equilibrate a suitable liquid
chromatograph to the following or equivalent conditions:

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

----------------------------------------------------------------------------------------------------------------
(i) Column.................................. C-18, 250 millimeters (mm) length, 4.6 mm inner diameter (5
microns).
(ii) Mobile Phase........................... 85:15:0.5 methanol: water: acetic acid.
(iii) Flow Rate............................. 1.5 milliliters (mL) per minute.
(iv) Temperature............................ Ambient.
(v) Detector................................ UV spectrophotometer at 308 nanometers.
(vi) Attenuation............................ As needed.
----------------------------------------------------------------------------------------------------------------

(2) Use HPLC grade reagents for mobile phase.
(B) Preparation of the HPLC reference standard. (1) Weigh 0.5 gram
(g) of oxybenzone USP reference standard into a 250-mL volumetric
flask. Dissolve and dilute to volume with isopropanol. Mix well.
(2) Weigh 0.5 g of padimate O USP reference standard into a 250-mL
volumetric flask. Dissolve and dilute to volume with isopropanol. Mix
well.
(3) Pipet 3 mL of the oxybenzone solution and 7 mL of the padimate
O solution into a 100-mL volumetric flask. Dilute to volume with
isopropanol and mix well.
(C) HPLC system suitability. (1) Make three replicate 10-microliter
injections of the HPLC reference standard (described in paragraph
(i)(3)(ii)(B) of this section). The relative standard deviation in peak
areas should not be more than 2 percent for either oxybenzone or
padimate O.
(2) Calculate the resolution (R) between the oxybenzone and
padimate O peaks from one chromatogram as follows:
[GRAPHIC] [TIFF OMITTED] TP26FE19.004

Where

to = retention time for oxybenzone
tp = retention time for padimate O
Wo = oxybenzone peak width at baseline
Wp = padimate O peak width at baseline
If the resolution (R) is less than 3, adjust the mobile phase or
replace the column.

(D) SPF standard assay. (1) The SPF standard is diluted to the same
concentration as the HPLC reference standard according to the following
steps:
(i) Step 1. Weigh 1 g of the SPF standard (described in paragraph
(i)(3)(i) of this section) into a 50-mL volumetric flask.
(ii) Step 2. Add approximately 30 mL of isopropanol and heat with
swirling until contents are evenly dispersed.
(iii) Step 3. Cool to room temperature (15 to 30 [deg]C) and dilute
to volume with isopropanol. Mix well.
(iv) Step 4. Pipet 5.0 mL of the preparation into a 50-mL
volumetric flask and dilute to volume with isopropanol. Mix well.
(2)(i) Inject 10-microliter of diluted SPF standard from paragraph
(i)(3)(ii)(D)(1) of this section and calculate the amount of oxybenzone
and padimate O as follows:
[GRAPHIC] [TIFF OMITTED] TP26FE19.005

(ii) The percent of oxybenzone and padimate O in the SPF standard
must be between 95 and 105.
(4) Test subjects--(i) Number of subjects. A test panel should
include enough subjects to produce a minimum of 10 valid test results.
A maximum of three subjects may be rejected from this panel based on
paragraph (i)(6)(v) of this section.
(ii) Medical history. (A) Obtain a medical history from each
subject with emphasis on the effects of sunlight on the subject's skin.
Determine that each subject is in good general health with skin type I,
II, or III as follows:
(1) Always burns easily; never tans (sensitive).
(2) Always burns easily; tans minimally (sensitive).
(3) Burns moderately; tans gradually (light brown) (normal).
(4) Burns minimally; always tans well (moderate brown) (normal).
(5) Rarely burns; tans profusely (dark brown) (insensitive).
(6) Never burns; deeply pigmented (insensitive).
(B) Skin type is based on first 30 to 45 minutes of sun exposure
after a winter season of no sun exposure. Determine that each subject
is not taking topical or systemic medication that is known to alter
responses to UV radiation. Determine that each subject has no history
of sensitivities to topical products and/or abnormal responses to
sunlight, such as a phototoxic or photoallergic response.
(iii) Physical examination. Conduct a physical examination to
determine the presence of sunburn, suntan, scars, active dermal
lesions, and uneven skin tones on the areas of the back to be tested.
Adequate time must have passed following any previous UV exposure
(e.g., participation in a prior SPF clinical study, tanning, etc.) so
that the test subject has no preexisting skin pigmentation at the time
of enrollment. A suitable source of low power UVA, such as a Woods
lamp, is helpful in this process. If any of these conditions are
present, the subject is not qualified to participate in the study. The
presence of nevi, blemishes, or moles will be acceptable if, in the
physician's judgment, they will neither compromise the study nor
jeopardize a subject's safety. Subjects with dysplastic nevi should not
be enrolled. Excess hair on the back is acceptable if the hair is
clipped. Shaving is unacceptable because it may remove a significant
portion of the stratum corneum and temporarily alter the skin's
response to UV radiation.
(iv) Informed consent. Obtain legally effective written informed
consent from all test subjects as required by paragraph (i)(1)(ii) of
this section.

[[Page 6269]]

(5) Sunscreen application--(i) Test site. Test sites are locations
on each subject's back, between the beltline and the shoulder blades
(scapulae) and lateral to the midline, where skin responses to UV
radiation are determined. Responses on unprotected skin (no test
material applied) and protected skin (sunscreen test product(s) or SPF
standard applied) are determined at separate unprotected and protected
test sites, respectively. Test sites should be randomly located in a
blinded manner. Each test site should be a minimum of 30 square
centimeters and outlined with indelible ink.
(ii) Test subsite. Test subsites are the locations to which UV
radiation is administered within a test site. Administer UV doses to at
least five test subsites within each test site. Test subsites must be
at least 0.5 square centimeters (cm\2\) in area and must be separated
from each other by at least 0.8 cm. Each test subsite must be outlined
with indelible ink.
(iii) Applying test materials. Apply the sunscreen test product and
the SPF standard at 2 milligrams per square centimeter (mg/cm\2\) to
their respective test sites. Use a finger cot compatible with the
sunscreen to spread the product as evenly as possible.
(iv) Waiting period. Wait at least 15 minutes after applying a
sunscreen product before exposing the test sites to UV radiation as
described in paragraph (i)(6) of this section. For water resistant
sunscreen products, proceed with the water resistance testing procedure
described in paragraph (i)(8) of this section after waiting at least 15
minutes.
(6) UV exposure and erythema reading--(i) Definition of minimal
erythema dose (MED). The minimal erythema dose (MED) is the smallest UV
dose (quantity of erythema-effective energy expressed as Joules per
square meter) that produces perceptible redness of the skin (erythema)
with clearly defined borders at 16 to 24 hours after UV exposure. The
MED for unprotected skin (MEDu) is determined on a test site
that does not have sunscreen applied. The MED for protected skin
(MEDp) is determined on a test site that has sunscreen
applied. An MEDp is determined for the SPF standard
(ssMEDp). An MEDp is determined for the sunscreen
test product (tpMEDp).
(ii) UV exposure for initial MEDu. For each test
subject, no more than 1 day before testing a product, determine the
initial MEDu by administering a series of UV radiation doses
expressed as J/m\2\-eff (as determined according to paragraph
(i)(2)(ii)(B) of this section) to the test subsites within an
unprotected test site using an accurately calibrated solar simulator.
Select doses that are a geometric series represented by 1.25\n\ (i.e.,
each dose is 25 percent greater than the previous dose).
(iii) UV exposure for final MEDu,
ssMEDp, and tpMEDp. For
each subject, determine the final MEDu,
ssMEDp, and tpMEDp by
administering a series of five UV doses to the appropriate test sites.
The middle dose (X) in each of these dose series (i.e., the third dose)
should equal the initial MEDu times the expected SPF. Note
that the expected SPF equals 1 and 16.3 for the final MEDu
and ssMEDp, respectively. The remaining UV doses in the
series depend upon the expected SPF value of the sunscreen test
product(s). For products with an expected SPF less than 8, administer
UV doses that increase by 25 percent with each successive dose (i.e.,
0.64X, 0.80X, 1.00X, 1.25X, and 1.56X). For products with an expected
SPF from 8 to 15, administer UV doses that increase by 20 percent with
each successive dose (i.e., 0.69X, 0.83X, 1.00X, 1.20X, and 1.44X). For
products with an expected SPF higher than 15, administer UV doses that
increase by 15 percent with each successive dose (i.e., 0.76X, 0.87X,
1.00X, 1.15X, and 1.32X).
(iv) Evaluation of test subsites. In order that the study personnel
who evaluates the test subsites is not biased, he/she should not be the
same study personnel who applied the sunscreen product to the test site
or administered the UV doses. After UV doses are administered, record
all immediate responses. These may include an immediate darkening or
tanning, typically grayish or purplish in color, which fades in 30 to
60 minutes; an immediate reddening at the subsite, due to heating of
the skin, which fades rapidly; and an immediate generalized heat
response, spreading beyond the subsite, which fades in 30 to 60
minutes. After the immediate responses are noted, each subject should
shield the exposed area from further UV radiation until the MED is
determined. Determine the final MEDu,
ssMEDp, and tpMEDp 16 to 24
hours after UV exposure. Evaluate the erythema responses of each test
subsite using either tungsten or warm white fluorescent lighting that
provides at least 450 lux of illumination at the test site. For the
evaluation, the test subject should be in the same position as when the
test site was irradiated.
(v) Invalid test data. Reject test data for a test subject if
erythema is not present on either the unprotected or protected test
sites; or erythema is present at all subsites; or the responses are
inconsistent with the series of UV doses administered; or the subject
was noncompliant (e.g., the subject withdraws from the test due to
illness or work conflicts or does not shield the exposed testing sites
from further UV radiation until the MED is determined).
(7) Determination of SPF. (i) Calculate an SPF value for each test
subject (SPFi) as follows:
[GRAPHIC] [TIFF OMITTED] TP26FE19.006

(ii) Calculate the mean
[GRAPHIC] [TIFF OMITTED] TP26FE19.007

and the standard deviation(s) from the SPFi values.
Calculate the standard error (SE), which equals s/[radic]n (where n
equals the number of subjects who provided valid test results). Obtain
the t value from Student's t distribution table corresponding to the
upper 5-percent point with n - 1 degrees of freedom. Determine the SPF
value that is equal to the largest whole number less than
[GRAPHIC] [TIFF OMITTED] TP26FE19.008

In order for the SPF determination of a test product to be considered
valid, the SPF value of the SPF standard must fall within the standard
deviation range of the expected SPF (i.e., 16.3 3.43).
(8) Determination of water resistance. To support labeling claims
of water resistance in accordance with paragraph (b) of this section,
the following procedure must be performed in an indoor fresh water
pool, whirlpool, and/or hot tub maintained at 23 to 32 [deg]C. Fresh
water is clean drinking water that meets the standards in 40 CFR part
141. The pool and air temperature and the relative humidity must be
recorded.
(i) Water resistance (40 minutes). Determine the SPF value after 40
minutes of water immersion using the following procedure:
(A) Step 1: Apply the sunscreen test product as described in
paragraph (i)(5) of this section.
(B) Step 2: Perform moderate activity in water for 20 minutes.
(C) Step 3: Rest out of water for 15 minutes. Do not towel test
site(s).
(D) Step 4: Perform moderate activity in water for 20 minutes.
(E) Step 5: Allow test sites to dry completely without toweling.
(F) Step 6: Apply the SPF standard as described in paragraph (i)(5)
of this section.
(G) Step 7: Expose test sites to UV doses as described in paragraph
(i)(6) of this section.
(ii) Water resistance (80 minutes). Determine the SPF value after
80 minutes of water immersion using the following procedure:

[[Page 6270]]

(A) Step 1: Apply the sunscreen test product as described in
paragraph (i)(5) of this section.
(B) Step 2: Perform moderate activity in water for 20 minutes.
(C) Step 3: Rest out of water for 15 minutes. Do not towel test
site(s).
(D) Step 4: Perform moderate activity in water for 20 minutes.
(E) Step 5: Rest out of water for 15 minutes. Do not towel test
site(s).
(F) Step 6: Perform moderate activity in water for 20 minutes.
(G) Step 7: Rest out of water for 15 minutes. Do not towel test
site(s).
(H) Step 8: Perform moderate activity in water for 20 minutes.
(I) Step 9: Allow test sites to dry completely without toweling.
(J) Step 10: Apply the SPF standard as described in paragraph
(i)(5) of this section.
(K) Step 11: Expose test sites to UV doses as described in
paragraph (i)(6) of this section.
(j) Broad spectrum testing--(1) UV Spectrometry--(i) Plate. Use
optical-grade polymethylmethacrylate (PMMA) plates suitable for UV
transmittance measurements. The plate should be roughened on one side
to a three-dimensional surface topography measure (Sa) between 2 and 7
micrometers and must have a rectangular application area of at least 16
square centimeters (with no side shorter than 4 cm).
(ii) Sample holder. The sample holder should hold the PMMA plate in
a horizontal position to avoid flowing of the sunscreen product from
one edge of the PMMA plate to the other. Mount the PMMA plate as close
as possible to the input optics of the spectrometer to maximize capture
of forward scattered radiation. The sample holder should be a thin,
flat plate with a suitable aperture through which UV radiation can
pass. Place the PMMA plate on the upper surface of the sample holder
with the roughened side facing up.
(iii) Light source. The light source must produce a continuous
spectral distribution of UV radiation from 290 to 400 nanometers.
(iv) Input optics. Unless the spectrometer is equipped with an
integrating sphere, an ultraviolet radiation diffuser should be placed
between the sample and the input optics of the spectrometer. The
diffuser will be constructed from any UV radiation transparent material
(e.g., Teflon or quartz). The diffuser ensures that the radiation
received by the spectrometer is not collimated. Set the spectrometer
input slits to provide a bandwidth that is less than or equal to 5
nanometers.
(v) Dynamic range of the spectrometer. The dynamic range of the
spectrometer should be sufficient to measure transmittance accurately
through a highly absorbing sunscreen product at all terrestrial solar
UV wavelengths (290 to 400 nm).
(2) Sunscreen product application to PMMA plate. The accuracy of
the test depends upon the application of a precisely controlled amount
of sunscreen product with a uniform distribution over the PMMA plate.
The product is applied at 0.75 mg per square centimeter to the
roughened side of the PMMA plate. The sunscreen product should be
applied in a series of small amounts over the entire PMMA plate and
then spread evenly using a gloved finger. Spreading should be done with
a very light spreading action for approximately 30 seconds followed by
spreading with greater pressure for approximately 30 seconds. The plate
should then be allowed to equilibrate for 15 minutes in the dark before
the pre-irradiation described in paragraph (j)(3) of this section.
(3) Sunscreen product pre-irradiation. To account for lack of
photostability, irradiate the PMMA plate with a solar simulator
described paragraph (i)(2) of this section. The irradiation dose must
be 4 MEDs which is equivalent to an erythemal effective dose of 800 J/
m\2\ (i.e., 800 J/m\2\-eff).
(4) Calculation of mean transmittance values. (i) After pre-
irradiation, determine the mean transmittance values for each
wavelength [lambda] over the full UV spectrum (290 to 400 nanometers).
Measure the transmittance values at 1 nanometer intervals. Measurements
of spectral irradiance transmitted for each wavelength [lambda] through
control PMMA plates coated with 15 microliters of glycerin (no
sunscreen product) must be obtained from at least five different
locations on the PMMA plate [C1([lambda]), C2([lambda]), C3([lambda]),
C4([lambda]), and C5([lambda])]. In addition, a minimum of five
measurements of spectral irradiance transmitted for each wavelength
[lambda] through the PMMA plate covered with the sunscreen product will
be similarly obtained after pre-irradiation of the sunscreen product
[P1([lambda]), P2([lambda]), P3([lambda]), P4([lambda]), and
P5([lambda])].
(ii) The mean transmittance for each wavelength is the ratio of the
mean of the C([lambda]) values to the mean of the P([lambda]) values,
as follows:
[GRAPHIC] [TIFF OMITTED] TP26FE19.009

Where

n >=5

(5) Calculation of mean absorbance values. (i) Mean transmittance
values,
[GRAPHIC] [TIFF OMITTED] TP26FE19.010

are converted into mean absorbance values,
[GRAPHIC] [TIFF OMITTED] TP26FE19.011

at each wavelength by taking the negative logarithm of the mean
transmittance value as follows:
[GRAPHIC] [TIFF OMITTED] TP26FE19.012

(ii) The calculation yields 111 monochromatic absorbance values in
1 nanometer increments from 290 to 400 nanometers.
(6) Number of plates. For each sunscreen product, determine mean
absorbance values from at least three individual PMMA plates. Because
paragraph (j)(4) of this section requires at least 5 measurements per
plate, there must be a total of at least 15 measurements.
(7) Calculation of the critical wavelength. The critical wavelength
is identified as the wavelength at which the integral of the spectral
absorbance curve reaches 90 percent of the integral over the UV
spectrum from 290 to 400 nm. The following equation defines the
critical wavelength:
[GRAPHIC] [TIFF OMITTED] TP26FE19.013

Where

[lambda]c = critical wavelength
A([lambda]) = mean absorbance at each wavelength
d[lambda] = wavelength interval between measurements

(8) Calculation of the UVA I/UV ratio. The ratio of UVA I/UV is
calculated as the area (per unit wavelength) under the UVA I portions
of a plot of wavelength versus A([lambda]), divided by the area (per
unit wavelength) under the total curve, as follows:
[GRAPHIC] [TIFF OMITTED] TP26FE19.014

Where

A([lambda]) = effective absorbance given as -log T([lambda])mean
absorbance at each wavelength,
d([lambda]) = wavelength interval between measurements
B([lambda]) = any biological action spectrum factor
Because no appropriate biological action spectrum for UVA radiation
damage has been universally accepted, no action spectrum is
specified. The value of B([lambda]) is, therefore, equal to 1.0 for
all wavelengths.

(9) Determination of broad spectrum protection. A product that has
both a mean critical wavelength of 370 nm or

[[Page 6271]]

greater, calculated in accordance with paragraph (j)(7) of this
section, and a mean UVA I/UV ratio of 0.70 or greater, calculated in
accordance with paragraph (j)(8) of this section, is determined to pass
the broad spectrum test.
(k) Regulatory status of final formulation testing and related
requirements. Final formulation testing required under this section is
considered a part of the manufacture of a sunscreen product. Therefore,
final formulation testing required under this section must be performed
in an establishment registered in accordance with part 207 of this
chapter and section 510 of the Federal Food, Drug, and Cosmetic Act.
Entities conducting final formulation testing required by this section
must also comply with current good manufacturing practices (CGMPs) and
associated recordkeeping requirements including those set forth in
paragraph (l) of this section and in parts 210 and 211 of this chapter.
Failure to comply with CGMPs or recordkeeping requirements will mean
that any product labeled in reliance on that testing will be
adulterated.
(l) Recordkeeping. Records required to be kept under this section
must be maintained for at least 1 year after the expiration date of all
products labeled in reliance on that testing or, in the case of certain
OTC drug products lacking expiration dating because they meet the
criteria for exemption under Sec. 211.137 of this chapter, 3 years
after distribution of the last lot of drug product bearing labeling
that relies on the testing. Recordkeeping requirements under this
section may not be transferred. Maintenance records required to be kept
under (l)(1) must be kept by the testing entity. Records of final
formulation testing as described in paragraphs (l)(2) and (3) of this
section must be kept by the responsible person and any entity that is
performing final formulation testing required by this section on behalf
of a responsible person pursuant to a transfer of obligations.
(1) Maintenance records. Entities performing final formulation
testing are expected to maintain equipment in accordance with paragraph
(k) of this section and, as applicable, parts 210 and 211 of this
chapter. Maintenance records must be kept for all equipment used for
final formulation testing under this section and must include:
(i) Documentation that equipment has been maintained in accordance
with established written specifications as required by paragraph (k) of
this section and parts 210 and 211 of this chapter; and
(ii) Documentation of characterization of UV sources including:
(A) Record of emission spectrum, total irradiance, and percent of
erythema-effective radiation contribution required by paragraph
(i)(2)(i) of this section;
(B) Record of each periodic measurement required by paragraph
(i)(2)(iv) of this section for each solar simulator;
(C) Record of each calibration, realignment, or change in
components of each solar simulator, or any changes to the broadband
radiometer (or UV meter/dose control system), required by paragraph
(i)(2)(iv) of this section; and
(D) Record of each solar simulator output measurement required by
paragraph (i)(2)(ii)(C) of this section.
(2) SPF testing records. In addition to any records required to be
kept pursuant to parts 210 and 211 of this chapter, records of SPF
testing performed pursuant to paragraph (i) of this section must
include:
(i) Identification of the entity that conducted the final
formulation testing, including the name and address of the
establishment(s) at which testing was carried out;
(ii) The sunscreen test product identifier and characterization of
the formulation being tested, including lot number, manufacture date,
and expected SPF;
(iii) Characterization of the SPF standard sunscreen required by
paragraph (i)(3) of this section, including:
(A) Lot number;
(B) Manufacturing date; and
(C) Results of HPLC SPF standard assay that verify compliance with
the concentrations of padimate O and oxybenzone in the SPF standard.
(iv) Documentation linking any blinded samples with the product
identifier.
(v) For each human subject, records of:
(A) The identification of the UV source used for testing on that
subject, including make, model, and serial number;
(B) Initial and final individual MED for unprotected skin
(MEDu), and the identity of the study personnel who
determined that value;
(C) Final MED for sunscreen test product protected skin
(tpMEDp), and the identity of the study personnel
who determined that value;
(D) Final MED for SPF standard sunscreen protected skin
(ssMEDp), and the identity of the study personnel
who determined that value; and
(E) Individual SPFi values, including all valid test
data and invalid test data for the test product and for the SPF
standard sunscreen, and the identity of the study personnel who
determined that value.
(vi) Records of the mean and standard deviation from
SPFi values, standard error, and determined SPF value
derived as set forth in paragraph (i)(7) of this section.
(vii) Records for water resistance testing of pool temperature, air
temperature, and relative humidity as required by paragraph (i)(8) of
this section.
(viii) Records demonstrating compliance with paragraph (i)(1) of
this section governing the establishment of adequate clinical testing
procedures and conditions, including, but not limited to:
(A) Case histories. Responsible persons are required to prepare and
maintain adequate and accurate case histories on each individual
participant enrolled in SPF testing performed under paragraph (i) of
this section. Case histories must record all observations and other
data pertinent to the investigation. Case histories include the case
report forms and supporting data (for example, signed and dated consent
forms, medical records including progress notes of the physician, the
individual's hospital chart(s), and the nurses' notes (if applicable)).
The case history for each individual participant must document that
informed consent was obtained pursuant to part 50 before each
individual's participation in the study. Case histories as required by
this section must include:
(1) Protocol deviations or injuries, if any; and
(2) Identification, by subject, of the study personnel who:
Examined the potential study site areas, who weighed and applied the
sunscreen, and who provided the UV irradiation.
(B) IRB review. Documentation that clinical research conducted
pursuant to paragraph (i) of this section was reviewed and approved by
a registered IRB as required by paragraph (i)(1)(iii) of this section.
(3) Broad spectrum testing records. Records of broad spectrum
testing conducted pursuant to paragraph (j) of this section must
include:
(i) Identification of the entity that conducted the final
formulation testing, including the name and address of the
establishment(s) at which testing was carried out;
(ii) Records of sample information, including:
(A) A sunscreen test product identifier and expected SPF. If the
samples used in testing under paragraph (j) of this section are
blinded, then records must include a master key that enables samples to
be re-identified. In all other cases, records must include a

[[Page 6272]]

master key that links samples used to a sunscreen test product
identifier.
(B) Sample number;
(C) Identifier code;
(D) Measurement of PMMA plate surface topography in micrometers;
and
(E) Sample holder orientation (vertical or horizontal).
(iii) Identification of each UV source used for sunscreen product
pre-irradiation, including make, model, and serial number.
(iv) Records of sunscreen product application, including:
(A) A record of all sample weights, including analytical balance;
and
(B) For all equipment used; make, model, and serial number;
(v) For each sample, all measurements required by paragraphs (j)(4)
to (6) of this section.
(vi) For each sample, records of critical wavelength and the UVA I/
UV ratio values required by paragraphs (j)(7) and (8) of this section.
(vii) For each sample: The identity of the study personnel who
weighed and applied the sunscreen to the PMMA plates; the identity of
the study personnel who provided the pre-irradiation; and the identity
of the study personnel, or, if calculated by software, what software,
calculated the mean transmittance, mean absorbance values, critical
wavelength, and UVA I/UV.
(viii) For each sample, the test dates for the broad spectrum test
conducted pursuant to paragraph (j) of this section, and sample report
forms and supporting data including, for example, spectral data, Excel
files containing transmittance or absorbance values, or any notes from
the lab investigator.
(4) Food and Drug Administration (FDA) inspection of records--(i)
Testing entity. Anentity performing final formulation testing under
this section, including a responsible person or an entity that has been
transferred any obligations of a responsible person under this section,
must, upon request from any properly authorized officer or employee of
FDA, at reasonable times, permit such officer or employee to have
access to, and copy and verify any records or reports of testing
pursuant to this section. The testing entity is not required to divulge
subject names unless the records of particular individuals require a
more detailed study of the cases, or unless there is reason to believe
that the records do not represent actual case studies, or do not
represent actual results obtained.
(ii) Responsible persons. A responsible person must upon request
from any properly authorized officer or employee of FDA, at reasonable
times, permit such officer or employee to have access to and copy and
verify any records and reports relating to final formulation testing
conducted under this section. Upon written request by FDA, the
responsible person must submit the records or reports (or copies of
them) to FDA. The responsible person must discontinue from further
participation in final formulation testing required by this section any
investigator who has failed to maintain or make available records or
reports of the investigation as required by this paragraph (l).

PART 310--NEW DRUGS

0
3. The authority citation for part 310 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 360hh-360ss, 361(a), 371, 374, 375, 379e, 379k-l; 42 U.S.C.
216, 241, 242(a), 262.

Sec. 310.545 [Amended]

0
4. Amend Sec. 310.545 by removing and reserving paragraphs (a)(29) and
(d)(31),and (40).
0
5. Add Sec. 310.549 to subpart E to read as follows:

Sec. 310.549 Drug products offered over-the-counter (OTC) for use as
sunscreen.

(a) Any drug product offered OTC for use as sunscreen and
identified in any of paragraphs (b) through (i) of this section is not
generally recognized as safe and effective and is regarded as a new
drug within the meaning of section 201(p) of the Federal Food, Drug,
and Cosmetic Act, for which an approved new drug application under
section 505 of the Federal Food, Drug, and Cosmetic Act and part 314 of
this chapter is required for marketing. In the absence of an approved
new drug application, such product is also misbranded under section 502
of the Federal Food, Drug, and Cosmetic Act. Products offered OTC for
use as sunscreen include those represented, labeled, or promoted as
sunscreen, or for use to help prevent sunburn, skin cancer, and/or skin
aging caused by the sun, or with similar claims or representations.
Clinical investigations designed to obtain evidence that any sunscreen
drug product covered by this section is safe and effective for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(b) A sunscreen drug product that contains any of the following
ingredients:
(1) Diethanolamine methoxycinnamate
(2) Digalloyl trioleate
(3) Ethyl 4-[bis(hydroxypropyl)] aminobenzoate
(4) Glyceryl aminobenzoate
(5) Lawsone with dihydroxyacetone
(6) Red petrolatum
(7) Trolamine salicylate
(8) Aminobenzoic acid
(9) Avobenzone
(10) Cinoxate
(11) Dioxybenzone
(12) Ensulizole
(13) Homosalate
(14) Meradimate
(15) Octinoxate
(16) Octisalate
(17) Octocrylene
(18) Oxybenzone
(19) Padimate O
(20) Sulisobenzone
(c) A sunscreen drug product that has a determined sun protection
factor (SPF) value, as defined in Sec. 352.3(d) of this chapter, of at
least 15 when tested in accordance with Sec. 201.327(i) of this
chapter, but that has not been shown to pass the broad spectrum test in
Sec. 201.327(j) of this chapter.
(d) A sunscreen drug product that has a determined sun protection
factor (SPF) value, as defined in Sec. 352.3(d) of this chapter, of
less than 2 or greater than 80 when tested in accordance with Sec.
201.327(i) of this chapter.
(e) A sunscreen drug product that has a determined sun protection
factor (SPF) value, as defined in Sec. 352.3(d) of this chapter, of
less than 15 when tested in accordance with Sec. 201.327(i) of this
chapter and/or that does not pass the broad spectrum test in Sec.
201.327(j) of this chapter, and labeled with any of the following or
similar claims:
(1) Decreases the risk of skin cancer caused by the sun; or
(2) Decreases the risk of early skin aging caused by the sun.
(f) A sunscreen drug product labeled with any of the following or
similar claims:
(1) Instant protection or protection immediately upon application;
or
(2) Claims for ``all-day'' protection or extended wear claims
citing a specific number of hours of protection that is inconsistent
with the directions for application in Sec. 201.327 of this chapter.
(g) A sunscreen drug product that is labeled, represented, or
promoted for use as a combined sunscreen-insect repellant.
(h) A sunscreen drug product that is in any dosage form other than
the following: Oil, lotion, cream, gel, butter, paste, ointment, stick,
or spray.
(i) A sunscreen drug product in a spray dosage form that has any of
the following properties:
(1) The product meets the definition of the term ``extremely
flammable'' as

[[Page 6273]]

defined at Sec. 352.3(f) of this chapter when tested in accordance
with 16 CFR 1500.43a;
(2) More than 10 percent of the particles dispensed from the
consumer container are smaller than 10 micrometers;
(3) Any of the particles dispensed from the consumer container are
smaller than 5 micrometers; or
(4) The product meets the definition of either the term
``flammable'' or the term ``combustible'' as defined at Sec. Sec.
352.3(g) or (h) of this chapter, as applicable, when tested in
accordance with 16 CFR 1500.43a and has a measured drying time of 10
minutes or more.

PART 347--SKIN PROTECTANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN
USE

0
6. The authority citation for part 347 continues to read as follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

0
7. Amend Sec. 347.20 by lifting the stay on paragraph (e) (previously
paragraph (d), redesignated at 74 FR 9765, March 6, 2009) and revising
paragraph (e) to read as follows:

Sec. 347.20 Permitted combinations of active ingredients.

* * * * *
(e) Combinations of skin protectant and sunscreen active
ingredients. Any one (two when required to be in combination) or more
of the skin protectant active ingredients identified in Sec.
347.10(a), (d), (e), (g), (h), (i), (k), (l), (m), and (r) of this
chapter may be combined with any single sunscreen active ingredient
identified in Sec. 352.10 of this chapter, or any permitted
combination of these ingredients identified in Sec. 352.20 of this
chapter, provided the product meets the conditions in Sec. 352.20(b)
of this chapter and is labeled according to Sec. Sec. 347.60 and
352.60 of this chapter.
0
8. Amend Sec. 347.60 by revising paragraphs (a), (b)(3), (c)(1), and
(d)(1) to read as follows:

Sec. 347.60 Labeling of permitted combinations of active ingredients.

* * * * *
(a) Statement of identity. (1) Except as set forth in paragraph
(a)(3) of this section, for a combination drug product that has an
established name, the labeling of the product states the established
name of the combination drug product, followed by the statement of
identity for each ingredient in the combination, as established in the
statement of identity sections of the applicable OTC drug monographs.
(2) Except as set forth in paragraph (a)(3) of this section, for a
combination drug product that does not have an established name, the
labeling of the product states the statement of identity for each
ingredient in the combination, as established in the statement of
identity sections of the applicable OTC drug monographs.
(3) For a product containing a combination of skin protectant and
sunscreen active ingredients, the labeling of the product bears the
statement of identity set forth in Sec. 352.60(a) of this chapter.
(b) * * *
(3) Combinations of skin protectant and sunscreen active
ingredients in Sec. 347.20(e). In addition to any or all of the
indications for skin protectant drug products in Sec. 347.50(b)(2)(i)
of this chapter, the required indications for sunscreen drug products
in Sec. 352.60(b) of this chapter must be used and any or all of the
additional indications for sunscreen drug products may be used.
(c) * * *
(1) For combinations containing a skin protectant and a sunscreen
identified in Sec. Sec. 347.20(e) and 352.20(b). The warnings in Sec.
352.60(c) of this chapter are used.
* * * * *
(d) * * *
(1) For combinations containing a skin protectant and a sunscreen
identified in Sec. Sec. 347.20(e) and 352.20(b). The directions in
Sec. 352.60(d) of this chapter are used.
* * * * *

PART 352--SUNSCREEN DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

0
9. The authority citation for part 352 continues to read as follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

0
10. Lift the stay of 21 CFR part 352.

Sec. 352.1 [Amended]

0
11. In paragraph (a), remove the words ``in a form suitable for topical
administration''.
0
12. Revise Sec. 352.3 to read as follows:

Sec. 352.3 Definitions.

As used in this part:
(a) [Reserved]
(b) [Reserved]
(c) Sunscreen active ingredient. An active ingredient listed in
Sec. 352.10 that absorbs, reflects, or scatters radiation in the
ultraviolet (UV) range at wavelengths from 290 to 400 nanometers.
(d) Determined sun protection factor (SPF) value. The SPF value
that equals the largest whole number less than SPF - (t * SE),
determined for a sunscreen product in accordance with Sec. 201.327(i)
of this chapter.
(e) Labeled sun protection factor (SPF) value. The SPF value
associated with the range into which the determined SPF value falls, as
set forth in the table in Sec. 201.327(b)(2)(i) of this chapter.
(f) Extremely flammable. The term ``extremely flammable'' applies
to any product that has a flashpoint at or below 20 [deg]F (-6.7
[deg]C) as determined by the test method described at 16 CFR 1500.43a,
except that any product having one component or more with a flashpoint
higher than 20 [deg]F (-6.7 [deg]C) that comprises at least 99 percent
of the total volume of the product is not considered to be extremely
flammable.
(g) Flammable. The term ``flammable'' applies to any product that
has a flashpoint above 20 [deg]F (-6.7 [deg]C) and below 100 [deg]F
(37.8 [deg]C) as determined by the test method described at 16 CFR
1500.43a, except that:
(1) Any product having one component or more with a flashpoint at
or above 100 [deg]F (37.8 [deg]C) that comprises at least 99 percent of
the total volume of the product is not considered to be flammable; and
(2) Any product containing 24 percent or less of water miscible
alcohols, by volume, in aqueous solution is not considered to be
flammable if the product does not present a significant flammability
hazard when used by consumers.
(h) Combustible. The term ``combustible'' applies to any product
having a flashpoint at or above 100 [deg]F (37.8 [deg]C) to and
including 150 [deg]F (65.6 [deg]C) as determined by the test method
described at 16 CFR 1500.43a, except that:
(1) Any product having one component or more with a flashpoint
higher than 150 [deg]F (65.6 [deg]C) that comprises at least 99 percent
of the total volume of the product is not considered to be combustible;
and
(2) Any product containing 24 percent or less of water miscible
alcohols, by volume, in aqueous solution is not considered to be
combustible if the product does not present a significant flammability
hazard when used by consumers.
0
13. Add Sec. 352.5 to subpart A to read as follows:

Sec. 352.5 Sun protection factor related conditions.

(a) The product has a determined SPF value of at least 2 but no
greater than 80.
(b) If the product has a determined SPF value of at least 15, it
also passes

[[Page 6274]]

the broad spectrum test in Sec. 201.327(j) of this chapter.
0
14. Revise Sec. 352.10 to read as follows:

Sec. 352.10 Sunscreen active ingredients.

The active ingredient of the product consists of any of the
following, under the conditions specified, including being within the
concentration specified for each ingredient:
(a) through (o) [Reserved]
(p) Titanium dioxide up to 25 percent
(q) [Reserved]
(r) Zinc oxide up to 25 percent.
0
15. Revise Sec. 352.20 to read as follows:

Sec. 352.20 Permitted combinations of active ingredients.

The determined SPF of any product containing a sunscreen active
ingredient is measured by the testing procedures established in Sec.
201.327(i) of this chapter.
(a) Combinations of sunscreen active ingredients. Two or more
sunscreen active ingredients identified in Sec. 352.10 may be combined
with each other in a single sunscreen product if all of the following
conditions are met:
(1) Each sunscreen active ingredient in the product must satisfy
the conditions established for its use in Sec. 352.10.
(2) The concentration of each sunscreen active ingredient must be
sufficient to contribute a minimum determined SPF of not less than 2 to
the finished product.
(3) The finished product must have a minimum determined SPF of not
less than the number of sunscreen active ingredients used in the
product multiplied by 2.
(b) Combinations of sunscreen and skin protectant active
ingredients. Any single sunscreen active ingredient identified in Sec.
352.10 or any combination of sunscreen active ingredients permitted
under paragraph (a) of this section may be combined with one or more
skin protectant active ingredients identified in Sec. Sec. 347.10(a),
(d), (e), (g), (h), (i), (k), (l), (m), and (r) of this chapter when
all of the following conditions are met:
(1) Each sunscreen active ingredient in the product must satisfy
the conditions established for its use in Sec. 352.10.
(2) The concentration of each sunscreen active ingredient must be
sufficient to contribute a minimum determined SPF of not less than 2 to
the finished product.
(3) The finished product must have a minimum determined SPF of not
less than the number of sunscreen active ingredients used in the
product multiplied by 2.
(4) The product must be labeled according to Sec. 201.327(h) of
this chapter and Sec. 352.60.
(c) [Reserved]
0
16. Add Sec. 352.30 to subpart B to read as follows:

Sec. 352.30 Route of administration.

The product is intended for topical administration.
0
17. Add Sec. 352.40 to subpart B to read as follows:

Sec. 352.40 Dosage forms.

The product is in one of the following dosage forms and meets any
additional conditions specified:
(a) Oil.
(b) Lotion.
(c) Cream.
(d) Gel.
(e) Butter.
(f) Paste.
(g) Ointment.
(h) Stick.
(i) Spray, provided that all of the following conditions are
satisfied:
(1) Size of particles as dispensed from the consumer container:
(i) No more than 10 percent of the particles dispensed from the
consumer container are smaller than 10 micrometers; and
(ii) None of the particles dispensed from the consumer container
are smaller than 5 micrometers.
(2) The product does not meet the definition of the term
``extremely flammable'' as defined in Sec. 352.3(f).
(3) If the product meets the definition of either the term
``flammable'' or the term ``combustible'' as defined at Sec. Sec.
352.3(g) or (h), as applicable, when tested in accordance with 16 CFR
1500.43a, the product also has a measured drying time of less than 10
minutes.
(4) The product is labeled as required by Sec. Sec. 201.327(d) and
(e)(5) of this chapter.
(5) Testing in accordance with part 211 of this chapter must
confirm that the product meets the conditions for particle size,
flammability, and drying time as required by this section and reflected
in the product labeling.
(i) Testing of each lot of product for size of particles dispensed
from the consumer container must be conducted in accordance with
adequate written specifications.
(ii) Flammability testing for each batch of product must be
conducted in accordance with the specifications set forth in 16 CFR
1500.43a.
(iii) If the product meets the definition of either the term
``flammable'' or ``combustible'' as defined at Sec. 352(g) or (h), as
applicable, when tested accordance with 16 CFR 1500.43a, drying time
for each lot of product must be conducted in accordance with adequate
written specifications.
0
18. Revise Sec. 352.50 to read as follows:

Sec. 352.50 Principal display panel of all sunscreen drug products.

The principal display panel labeling must comply with Sec.
201.327(b) of this chapter.
0
19. Revise Sec. 352.52 to read as follows:

Sec. 352.52 Labeling of products containing one or more sunscreen
active ingredients.

(a) Statement of identity. The labeling of the product contains the
statement of identity, in accordance with Sec. 201.327(b) of this
chapter.
(b) Indications. The labeling of the product contains the
indication statements identified in Sec. 201.327(c) of this chapter,
as appropriate, and subject to the conditions stated therein.
(c) Warnings. The labeling of the product contains the warnings in
Sec. 201.327(d) of this chapter, as applicable, under the heading
``Warnings:''
(d) Directions. The labeling of the product contains the statements
in Sec. 201.327(e) of this chapter, as applicable, under the heading
``Directions.''
(e) Other information. The labeling of the product contains the
statement in Sec. 201.327(f) of this chapter under the heading ``Other
information.''
(f) False or misleading claims. The labeling of the product must
not contain any claims that would be false and/or misleading on
sunscreen products, as outlined in Sec. 201.327(g) of this chapter.
0
20. Revise Sec. 352.60 to read as follows:

Sec. 352.60 Labeling of products containing a combination of
sunscreen and skin protectant active ingredients.

Statements of identity, indications, warnings, and directions for
use, respectively, applicable to each ingredient in the product may be
combined to eliminate duplicative words or phrases so that the
resulting information is clear and understandable. Labeling provisions
in Sec. 347.50(e) of this chapter shall not apply to these products.
(a) Statement of identity. The labeling of the product bears the
statement of identity, as set forth in Sec. 201.327(h)(1) of this
chapter.
(b) Indications. The labeling of the product states, under the
heading ``Uses,'' the applicable indication statements, as set forth in
Sec. 201.327(h)(2) of this chapter.
(c) Warnings. The labeling of the product states, under the heading

[[Page 6275]]

``Warnings,'' the applicable warning statements, as set forth in Sec.
201.327(h)(3) of this chapter.
(d) Directions. The labeling of the product states, under the
heading ``Directions,'' the applicable direction statements, as set
forth in Sec. 201.327(h)(4) of this chapter.
0
21. Revise subpart D to read as follows:
Subpart D--Final Formulation Testing
Sec.
352.70 SPF testing.
352.80 Broad spectrum testing.

Subpart D--Final Formulation Testing

Sec. 352.70 SPF testing.

The product is tested in accordance with Sec. 201.327(i) of this
chapter.

Sec. 352.80 Broad spectrum testing.

If the product's determined SPF value is at least 15, the product
is tested and shown to pass the broad spectrum test in Sec. 201.327(j)
of this chapter.

Dated: February 14, 2019.
Scott Gottlieb,
Commissioner of Food and Drugs.
[FR Doc. 2019-03019 Filed 2-21-19; 8:45 am]
BILLING CODE 4164-01-P