[Federal Register Volume 76, Number 117 (Friday, June 17, 2011)]
[Rules and Regulations]
[Pages 35620-35665]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-14766]
[[Page 35619]]
Vol. 76
Friday,
No. 117
June 17, 2011
Part IV
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 201, 310, and 352
Sunscreen Drug Products for Over-the-Counter Human Use; Final Rules and
Proposed Rules
Federal Register / Vol. 76 , No. 117 / Friday, June 17, 2011 / Rules
and Regulations
[[Page 35620]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 201 and 310
[Docket No. FDA-1978-N-0018] (Formerly Docket No. 1978N-0038)
RIN 0910-AF43
Labeling and Effectiveness Testing; Sunscreen Drug Products for
Over-the-Counter Human Use
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing this
document to address labeling and effectiveness testing for certain
over-the counter (OTC) sunscreen products containing specified active
ingredients and marketed without approved applications. This document
addresses labeling and effectiveness testing issues raised by the
nearly 2,900 submissions that we received in response to the sunscreen
proposed rule of August 27, 2007 (2007 proposed rule). The document
also identifies specific claims that render a product that is subject
to this rule misbranded or would not be allowed on any OTC sunscreen
product marketed without an approved application. The document does not
address issues related to sunscreen active ingredients or certain other
issues regarding the GRASE determination for sunscreen products. The
document requires OTC sunscreen products to comply with the content and
format requirements for OTC drug labeling contained in the 1999 Drug
Facts final rule (published in the Federal Register of March 17, 1999,
by lifting the delay of implementation date for that rule that we
published on September 3, 2004).
DATES: Effective Date: This final rule is effective June 18, 2012. For
additional information concerning this effective date, see section X in
the preamble of this document. The incorporation by reference of a
certain publication listed in this rule is approved by the Director of
the Federal Register as of June 18, 2012.
Compliance Date: The compliance date for all products subject to
this final rule with annual sales less than $25,000 is June 17, 2013.
The compliance date for all other products subject to this final rule
is June 18, 2012.
Implementation date: FDA is lifting the delay of implementation
date for Sec. 201.66 as published at 69 FR 53801, September 3, 2004.
FOR FURTHER INFORMATION CONTACT: Reynold Tan, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, rm. 5411, Silver Spring, MD 20993, 301-796-
2090.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Overview of Document
A. Rulemaking History
B. Scope of This Document
C. Issues Outside the Scope of This Document
D. Enforcement Policy
E. Summary of Major Revisions to the Labeling and Testing
Requirements Included in the 2007 Proposed Rule
II. Administrative and Other Issues
III. Principal Display Panel (PDP) Labeling
A. SPF Statement
B. Broad Spectrum Statement
C. Water Resistance Statement
D. UVB and UVA Educational Statement
IV. Drug Facts Labeling
A. Active Ingredients/Purpose
B. Uses
C. Warnings
D. Directions
E. Constitutionality of Labeling Statements Regarding Skin
Cancer and Skin Aging
F. Other Information
G. Reduced Labeling
V. Miscellaneous Labeling Outside Drug Facts
VI. SPF Test Parameters
A. Solar Simulator
B. Sunscreen Standards
C. Test Subjects
D. Test Sites and Subsites
E. Finger Cot
F. Application Amount
G. Water Resistance
VII. SPF Test Issues (Other Than Test Parameters)
A. Pass/Fail (Binomial) SPF Test
B. Photostability
C. In Vitro SPF Test
D. Anti-Inflammatory Ingredients
VIII. Broad Spectrum Test
A. In Vivo Test Method: Not Required
B. In Vitro Test Method: Critical Wavelength
C. Critical Wavelength Test Parameters
IX. Analysis of Impacts
A. Final Regulatory Impact Analysis
B. Small Business Impact (Final Regulatory Flexibility Analysis)
X. Paperwork Reduction Act of 1995
XI. Environmental Impact
XII. Federalism
XIII. References
I. Overview of Document
A. Rulemaking History
This section of the document does not discuss every regulatory
action associated with OTC sunscreen products. It highlights the major
regulatory actions that are related to the regulatory actions being
taken in this document. For a complete list of all regulatory actions
associated with OTC sunscreen products, please refer to our Web site:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm072134.htm.
In the Federal Register of May 12, 1993 (58 FR 28194), we published
a proposed rule for OTC sunscreen products that identified active
ingredients we tentatively considered to be generally recognized as
safe and effective (GRASE), as well as associated labeling and sun
protection factor (SPF) testing to be required for these OTC sunscreen
products (the 1993 proposed rule). The SPF test and corresponding
labeling reflect the level of protection against sunburn, which is
caused primarily by UVB radiation. The 1993 proposed rule also
explained the importance of protection against UVA radiation (58 FR
28194 at 28232 and 28233). The proposed rule referenced published UVA
test methods but did not propose a specific method (58 FR 28194 at
28248 to 28250). Rather, the proposed rule stated that a sunscreen
product could be labeled as ``broad spectrum,'' or labeled with a
similar statement, if it protected against UVA radiation as
demonstrated by one of the published UVA tests or a similar test.
In April 1994, we reopened the administrative record to allow
additional submissions concerning UVA-related issues. We also announced
a public meeting to be held in May 1994 to discuss UVA testing
procedures (59 FR 16042, April 5, 1994). We held the public meeting to
gather more information to help us determine the most appropriate UVA
test method and labeling.
In November 1997, Congress enacted the Food and Drug Administration
Modernization Act of 1997 (FDAMA), which addressed OTC sunscreen
products among other FDA issues. Section 129 of FDAMA stated that ``not
later than 18 months after the date of enactment of this Act, the
Secretary of Health and Human Services shall issue regulations for
over-the-counter sunscreen products for the prevention or treatment of
sunburn.'' We then determined that the GRASE active ingredients, SPF
testing requirements, and related labeling were issues that we could
finalize within the timeframe set by FDAMA. Because we had not
previously proposed specific UVA testing and labeling requirements, we
did not have sufficient time to finalize these UVA requirements within
the FDAMA timeframe.
In the Federal Register of May 21, 1999, we published a final rule
for OTC
[[Page 35621]]
sunscreen products (64 FR 27666). The 1999 sunscreen final rule added
the sunscreen monograph (regulations) in part 352 (21 CFR part 352) and
included an effective date of May 2001. The 1999 sunscreen final rule
stated that we would publish a proposed rule outlining UVA testing and
labeling requirements at a future date. In 2000, we extended the
effective date for the 1999 sunscreen final rule to December 2002 (65
FR 36319, June 8, 2000).
In December 2001, we stayed the December 2002 effective date of the
1999 sunscreen final rule indefinitely. We took this action because we
planned to revise part 352 to add UVA testing and labeling requirements
so that OTC sunscreen products would be tested and labeled for both UVB
and UVA radiation protection. We included these revisions in a proposed
rule that published in the Federal Register of August 27, 2007 (72 FR
49070). The 2007 proposed rule identified UVA testing and labeling that
we proposed should be required for all OTC sunscreen products. The
proposed rule also revised SPF testing and corresponding labeling from
the 1999 final rule. The proposed rule did not lift the existing stay
of the effective date for part 352.
On September 3, 2004 (69 FR 53801), we delayed until further notice
the implementation date for the Drug Facts final rule (64 FR 13254,
March 17, 1999) (21 CFR 201.66) for OTC sunscreen products. The Drug
Facts final rule (21 CFR 201.66) establishes general labeling format
and content requirements for all OTC drugs. We explained that we
postponed the implementation date for general Drug Facts labeling
requirements for sunscreens because we did not expect to issue the
sunscreen final rule containing UVA testing and product-specific
labeling requirements (i.e., this document) by the Drug Facts
implementation date of May 2005. Therefore, we delayed the
implementation date until further notice to prevent sunscreen product
manufacturers from having to relabel their products at two closely
related time intervals, as initially required by the 1999 Drug Facts
final rule and the 1999 sunscreen final rule.
B. Scope of This Document
This final rule establishes the labeling and testing requirements
for OTC sunscreen products containing specific ingredients or
combinations of ingredients and marketed without an approved
application under section 505 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 355) (the FD&C Act). The requirements in this final rule
will help ensure that these currently marketed sunscreen products are
appropriately labeled and tested for both UVA and UVB protection. In
addition, the requirements in this final rule will help ensure the
proper use of these sunscreens and greater consumer protection from the
damaging effects of UV radiation. This final rule also identifies
claims that render a product that is subject to this rule misbranded or
are not allowed on any OTC sunscreen drug product marketed without an
approved application.
As described in the previous section of this document, we issued
the 2007 proposed rule as a proposed amendment to the sunscreen
monograph requirements in 21 CFR part 352 primarily to establish UVA
testing and labeling requirements so that all OTC sunscreen products
marketed under the sunscreen monograph would be tested and labeled for
both UVB and UVA radiation protection. Sunscreen active ingredients,
UVB testing, UVB labeling, and other conditions under which sunscreens
would be considered GRASE and not misbranded had been addressed in the
1999 (stayed) final rule. In response to the 2007 proposed rule,
however, we received submissions from the public concerning all aspects
of the sunscreen monograph (i.e., the conditions specified in the 1999
final rule and the 2007 proposed rule). As discussed further in this
section, some of the issues regarding the monograph conditions raised
in the public submissions will require further evaluation by us.
Therefore, we are not issuing a final monograph with GRASE conditions
for sunscreens in this document. Instead, we are publishing this final
rule establishing labeling and the effectiveness testing upon which it
relies, which applies to the same sunscreens that were the subject of
the 2007 proposed rule to amend the monograph, because it is in the
best interest of public health to publish this final rule while we work
on remaining issues that need to be addressed in order to publish a
final monograph. This labeling will help ensure that these products are
not misbranded by providing specific indications, directions, warnings,
and other important information to help consumers select and use them
appropriately.
In this final rule, then, we are codifying in 21 CFR part 201
requirements for OTC sunscreen products containing specified active
ingredients and marketed without approved applications under section
505 of the FD&C Act (21 U.S.C. 355) (hereafter referred to as
``covered'' products). With respect to these covered products, this new
section 21 CFR 201.327 includes requirements for labeling and the
effectiveness testing upon which it relies. Because we have not yet
resolved all of the issues regarding conditions under which sunscreens
are GRASE and not misbranded, the stay of 21 CFR part 352 remains in
effect. Although we are not yet codifying these labeling and related
effectiveness testing provisions in the monograph regulation, they do
embody the agency's current determination on appropriate regulation of
these aspects of sunscreens that were previously identified as falling
within the monograph in part 352, and supersede the prior approach
embodied in the never-effective provisions of 21 CFR part 352 subparts
C and D. While this rule does not lift the stay of part 352, we are
lifting the delay of implementation date for the Drug Facts labeling
requirements of 21 CFR 201.66. In addition, this rule codifies certain
specific claims that render a covered product misbranded or are not
allowed on any OTC sunscreen drug product marketed in the United States
without an approved application.
We note that all provisions of new 21 CFR 201.327 and the
amendments to 310.545 included in this rule apply only to the
aforementioned covered products, and references in this document to
``covered'' products recognize this limitation. Manufacturers of
sunscreen products that are already being marketed pursuant to an
approved application can contact FDA's Center for Drug Evaluation and
Research to discuss supplemental submissions that would enable them to
include labeling on their products like that specified in this final
rule.
C. Issues Outside the Scope of This Document
There are a number of issues that were raised in public submissions
responding to the 2007 proposed rule that are outside the scope of this
document. The issues fall into two categories:
GRASE determination for sunscreen products and active
ingredients
Issues affecting multiple OTC drug monographs
As explained below, in this document, we are not addressing these
issues related to determining the GRASE status of sunscreen products or
sunscreen active ingredients and are not addressing the issues
described below affecting multiple OTC drug monographs.
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1. Issues Regarding GRASE Determination for Sunscreen Products and
Active Ingredients
A large number of submissions on the 2007 proposed rule raised
issues related to the conditions that define what constitutes a GRASE
finished OTC sunscreen product, irrespective of its active ingredients.
These included over 1000 submissions requesting that we limit the
monograph to sunscreens that offer broad spectrum protection and have
SPF values of 15 or higher. Because this final rule is a labeling rule,
and not a monograph, we do not address these issues here but plan to
address them in future rulemakings regarding the monograph and
conditions for general recognition of safety and effectiveness.
This rule also does not address issues related to the GRASE status
of sunscreen active ingredients that are included in the 2007 proposed
rule (proposed 21 CFR 352.10 and 352.20). We received 20 submissions
raising questions about the safety of ingredients in sunscreens (Ref.
1). Ten of the submissions specifically asked that we ensure that none
of the ingredients are carcinogenic. Others asked that we ensure that
all ingredients in sunscreens are safe without citing a specific
concern. We intend to address carcinogenicity and other safety
considerations related to sunscreen active ingredients in a future
rulemaking.
We also received submissions requesting that we increase the GRASE
concentration of avobenzone from 3 percent to 5 percent (Ref. 1).
Another submission points out that there are two USP \1\ monographs for
zinc oxide:
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\1\ United States Pharmacopeia.
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Zinc oxide (Ref. 2)
Zinc oxide neutral (Ref. 3)
The submission would like us to clarify that zinc oxide in OTC
sunscreen products can meet the specifications of either USP monograph
(Ref. 1). We intend to address all of these issues regarding GRASE
determination for sunscreen active ingredients in future rulemakings.
In addition, we received two submissions requesting that we
classify three new ingredients not previously marketed in the United
States as GRASE: bemotrizinol, bisoctrizole, and octyl triazone (Ref.
1). We found these active ingredients eligible for review under the OTC
drug monograph system in 2003 (octyl triazone) and 2005 (bemotrizinol
and bisoctrizole) (68 FR 41386, July 11, 2003, and 70 FR 72449,
December 5, 2005). We are currently reviewing the safety and
effectiveness data submitted for these and other sunscreen active
ingredients found eligible for potential addition to the monograph.
When we complete our review, we will issue proposed rules stating our
tentative conclusions on the safety and effectiveness of all of these
ingredients.
2. Issues Affecting Multiple OTC Drug Monographs
This final rule also does not address three issues raised in
response to the 2007 sunscreen proposed rule that are not specific to
sunscreen products. Because these issues apply more generally to
multiple categories of OTC drug products, we are not addressing these
issues in this final rule, which is limited to OTC sunscreen products.
The first issue concerns the inclusion of expiration dates on
sunscreen labels. We received 12 submissions requesting that we require
OTC sunscreen products to be labeled with an expiration date (Ref. 1).
Currently, regulations in 21 CFR 211.137(h) do not require that an
expiration date be included in labeling if an OTC drug product does not
have any dosage limitations and is stable for at least 3 years. This
regulation applies to many OTC drug products, including sunscreen
products. Any modification of the existing regulations would require
publication of a proposed rule addressing all OTC drug products
affected by the expiration date regulations.
The second issue concerns the term ``final monograph.'' One
submission argued that we should not use this term because it is
inaccurate (Ref. 1). As the submission states, ``FDA is to continually
evaluate products, so nothing is ever finalized.'' This issue applies
to monographs representing all categories of OTC drug products.
Therefore, we are not addressing the issue in this document.
The third issue concerns the country of origin listing for all
ingredients (i.e., both active and inactive ingredients) on a sunscreen
drug product. We received a submission requesting that we provide the
country of origin for each ingredient. The submission also requested
that manufacturers be required to provide specific details about what
each ingredient does in the product. This issue applies to all OTC drug
products and, therefore, we are not addressing it in this document.
D. Enforcement Policy
As noted, no final monograph is currently in effect for OTC
sunscreen drug products, and in its absence, questions may arise
regarding FDA's enforcement policy for OTC sunscreen products marketed
without approved applications. To clarify expectations for industry,
elsewhere in this issue of the Federal Register, we are announcing the
availability of a draft guidance document, explaining the agency's
intended enforcement policy for these products until a final sunscreen
monograph becomes effective.
E. Summary of Major Revisions to the Labeling and Effectiveness Testing
Included in the 2007 Proposed Rule
In response to the 2007 proposed rule, we received almost 2,900
submissions from the public. Of these submissions, over 2,500 expressed
general support for the proposed rule and urged us to finalize and
implement the new rule quickly. Three hundred twenty-five of the
submissions raised approximately 90 specific issues related to the
proposed rule. We have addressed the issues specifically relating to
labeling and effectiveness testing in this final rule. Based on the
submissions received, and the information and data included in those
submissions or otherwise available to us, we have re-evaluated our
position on several issues in the 2007 proposed rule and made several
changes to our proposed labeling and testing requirements. Tables 1, 2,
4, and 5 in this document summarize the labeling and effectiveness
testing requirements included in the 2007 proposed rule as well as the
labeling and effectiveness testing required by this final rule:
Table 1: PDP Labeling (discussed in section III)
Table 2: Drug Facts Labeling (discussed in section IV)
Table 4: SPF Test (discussed in section VI)
Table 5: Broad Spectrum Test (discussed in section VIII)
Rather than summarizing all of the revisions to the labeling and
testing included in the 2007 proposed rule, we are highlighting what we
consider to be the most important revisions in this section of the
document.
We made the following changes to the proposed labeling:
1. The proposed UVA ``star rating'' is not required on the PDP.
2. A combined ``Broad Spectrum SPF'' statement is required on the
PDP for sunscreen products that pass the broad spectrum test
established in new 21 CFR 201.327(j). To pass the broad spectrum test,
the amount of UVA protection must increase as the SPF value increases.
3. For sunscreen products that pass the broad spectrum test
established in new 21 CFR 201.327(j) and have SPF
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values of 15 or higher in accordance with the SPF test in 21 CFR
201.327(i):
a. The ``Sun Alert'' warning proposed as the first warning in 2007
is not required (Warning proposed located in 21 CFR 352.52(c)(1)).
b. A new indication statement may be included to inform consumers
that using the product ``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.''
c. A new direction statement has been added informing consumers
that exposure to the sun increases the risk of skin cancer and early
skin aging and providing a list of specific sun protection measures
that can decrease this risk.
4. For any OTC sunscreen product that does not pass the broad
spectrum test in 21 CFR 201.327(j), or that are broad spectrum with an
SPF value less than 15, this final rule, like the 2007 proposed rule,
requires that the first warning indicate the adverse consequences of
spending time in the sun. The wording of this warning has been revised
to state, ``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.''
We also made the following changes to the effectiveness testing
proposed in 2007:
1. The number of subjects required in the SPF test has been reduced
from 20 subjects to 10 subjects.
2. One in vitro test is required to demonstrate broad spectrum
protection rather than the two previously proposed tests (an in vitro
test and an in vivo test).
3. The broad spectrum test is a pass/fail test based on the
critical wavelength value of 370 nm \2\.
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\2\ Nanometers.
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II. Administrative and Other Issues
Some of the submissions that we received following publication of
the 2007 proposed rule made the following requests involving
administrative issues (Ref. 1):
Extend the comment period of the 2007 proposed rule.
Lift the stay on 21 CFR part 352, imposed in 2001 (66 FR
67485).
Allow interim marketing of products containing avobenzone
with ensulizole and avobenzone with zinc oxide.
Set an effective date for this final rule other than the
18 months proposed in the 2007 proposed rule.
Revise the preemption language included in the 2007
proposed rule by deleting any references regarding the rule's potential
preemption of State tort law.
Our positions on these issues are discussed in the remainder of this
section of the document.
All of the requests to extend the comment period were submitted
before the November 28, 2007 Federal Register notice in which we
extended the comment period of the 2007 proposed rule (72 FR 67264). In
that notice, we extended the close of the comment period from November
26, 2007, to December 26, 2007. We have not received any more requests
to extend the comment period since December 2007.
With regard to requests to lift the stay of 21 CFR part 352 (the
OTC sunscreen monograph), as already discussed, our 2007 proposed rule
anticipated amending the testing and labeling provisions of that
monograph and subsequently lifting the stay. However, comments received
on the 2007 proposed rule not only addressed labeling and effectiveness
testing for final sunscreen formulations, but also raised other issues
about the monograph conditions for OTC sunscreen products that require
further consideration. As a result, we are not finalizing amendments to
part 352 at this time nor lifting the stay placed on that section as
enacted in 1999 (66 FR 67485). Rather, this final rule establishes in
21 CFR 201.327 labeling requirements and the effectiveness testing upon
which it relies for covered OTC sunscreen drug products. We intend to
lift the stay on part 352 when we reach our final conclusions on the
conditions under which sunscreen products are GRASE and not misbranded,
including a determination regarding sunscreen active ingredients, and
publish a revised final monograph. In the interim, the labeling and
effectiveness testing provisions of this rule apply to covered OTC
sunscreen products.
We received a request that we allow interim marketing of avobenzone
combinations in proposed Sec. 352.20(a)(2) prior to issuing a final
rule for part 352. Subject to our enforcement discretion, we will
continue to allow the marketing of avobenzone combinations provided for
in the 1999 sunscreen final rule. However, we are not allowing
marketing of the additional avobenzone combinations discussed in the
2007 proposed rule until we reach a final conclusion on the GRASE
determination for sunscreen active ingredients and combinations of
those ingredients.
We are requiring that this final rule become effective in 1 year,
even though we considered 18 months in the 2007 proposed rule (72 FR
49070 at 49110). We are allowing products with annual sales less than
$25,000 to comply with this rule in 2 years, as stated in the 2007
proposed rule. In response to the proposed rule, we received one
submission arguing that we should require this final rule to become
effective in 1 year (Ref. 1). The submission stated that a later
effective date would have a negative public health impact. We received
eight submissions arguing that we should extend the effective date from
the proposed 18 months to 3 years (Ref. 1). The submissions listed the
following reasons for allowing more than 18 months:
Repackaging
Relabeling
Testing/retesting
Removing products from market
Impact on small businesses
The most common argument was that more time would be needed to test/
retest OTC sunscreen products for broad spectrum protection in
accordance with both the in vitro and in vivo UVA test methods included
in the proposed rule.
We agree with the submission which stated that it would be
beneficial for consumers to have this rule become effective within 1
year. As explained in section VIII.A of this document, we are not
requiring manufacturers to demonstrate broad spectrum protection by
conducting in vivo and in vitro tests. This final rule requires that
manufacturers conduct only the simpler and less expensive nonclinical
in vitro test to demonstrate broad spectrum protection. In vitro tests
are substantially shorter than in vivo tests. Therefore, we are setting
an effective date for this rule 1 year from the date of publication in
the Federal Register. However, we are providing two years for all
products with annual sales less than $25,000 to comply with this rule.
In addition, in order to ensure that limited testing laboratory
capacity does not result in sunscreen shortages during the transition
to the new rule, we intend to exercise enforcement discretion for a
period of time with regard to the SPF test for certain OTC sunscreen
products on the market by June 17, 2011 (see our draft guidance
entitled ``Guidance for Industry: Enforcement Policy--OTC Sunscreen
Drug Products Marketed Without An Approved Application'' announced
elsewhere in this issue of the Federal Register).
The submissions stating that additional time is necessary for
[[Page 35624]]
repackaging and relabeling did not submit any information or data to
support these arguments (Ref. 1). The argument that more than 18 months
is needed to remove non-compliant products from the market is not
valid. In the 2007 proposed rule, we indicated that sunscreen products
which are already distributed by the effective date of the final rule
would not be expected to be relabeled or retested in conformity with
the final rule conditions unless these products were subsequently
relabeled or repackaged after the effective date (72 FR 49070 at
49109). Consistent with this statement, we do not expect non-compliant
products introduced or delivered for introduction into interstate
commerce prior to the compliance dates specified for this final rule to
be removed from the market.
We received a submission that expressed concern about the agency's
preemption discussion in the 2007 proposed rule (72 FR 49070 at 49109
and 49110) and requested that we delete any discussion regarding the
rule's potential preemption of State tort law (Ref. 1). The submission
claimed that we exceeded our authority when we stated that section
751(a) of the FD&C Act displaces both State legislative requirements
and State common law duties. The submission argued that Congress
intended to preserve State common law claims by including section
51(e), which exempts State product liability claims from express
preemption under section 751(a) of the FD&C Act. The commenter appears
to have construed our statement in a way that would nullify section
751(e) of the FD&C Act. We did not intend to suggest that section
751(a) of the FD&C Act preempts State product liability claims, whether
based on State legislative enactments or common law, because section
751(e) exempts such actions from the express preemption provision in
section 751(a). However, it is important to note that section 751(e) of
the FD&C Act exempts only those common law claims that are based on
State product liability law. Our revised preemption discussion in
section XII remains consistent with applicable law.
The submission also requested that we delete any references to
implied preemption. In this final rule, we have omitted any statement
regarding implied preemption because, although implied preemption may
arise, such scenarios are necessarily case-specific. Section XII of
this document makes clear that the sole statutory provision giving
preemptive effect to the final rule is section 751 of the FD&C Act.
III. Principal Display Panel (PDP) Labeling
In response to the 2007 sunscreen proposed rule, we received 45
submissions requesting that we revise the proposed principal display
panel (PDP) labeling (Ref. 1). We are revising the PDP labeling based,
in part, on these submissions (see table 1 of this document). We have
decided that the PDP labeling included in this document will simplify
the purchase decision for consumers by allowing them to more easily
find important information included on the PDP.
Table 1--Summary of PDP Labeling in the 2007 Proposed Rule and This Final Rule Using a Broad Spectrum SPF 30
Water Resistant Sunscreen Product as Example A and an SPF 6 Sunscreen That Is Not Broad Spectrum and Not Water
Resistant as Example B
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Labeled information 2007 Proposed rule This final rule
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Effectiveness Rating \1\............. Example A: Example A:
``UVB SPF 30 High'' ``Broad Spectrum SPF 30''
``UVA [starf][starf][starf][star14] High''
Example B: Example B:
``UVB SPF 6 Low'' ``SPF 6''
``No UVA Protection''
Water Resistance..................... Example A: Example A:
``Water Resistant'' ``Water Resistant (40
minutes)''
Example B: Example B:
No statement on water resistance No statement on water
resistance
Educational Statement................ Examples A & B: Examples A & B:
``UV rays from the sun are made of UVB and No educational statement
UVA. It is important to protect against
both UVA and UVB rays.''
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\1\ The UVA rating in the 2007 proposed rule is a four-tier rating (low, medium, high, highest). The UVA testing
in this final rule is pass/fail--a product is either allowed or not allowed to include a broad spectrum
statement depending on results of the test described in new 21 CFR 201.327(j) (see section VIII of this
document).
A. SPF Statement
In the 2007 sunscreen proposed rule, we proposed redefining the
acronym ``SPF'' as the ``sunburn protection factor.'' We also proposed
that the term ``UVB SPF'' would be required on the PDP of all OTC
sunscreen products (proposed 21 CFR 352.50(a)). This term would be
followed by the numerical value determined from SPF testing and one of
the following descriptors: ``low,'' ``medium,'' ``high,'' or
``highest.'' For example, a sunscreen product could have contained the
statement ``UVB SPF 40 High'' on the PDP.
We received 12 submissions regarding the SPF statement in response
to the 2007 sunscreen proposed rule (Ref. 1). Collectively, the
submissions made the following requests:
1. Do not change the definition of SPF to ``sunburn protection
factor''
2. Remove UVB from ``UVB SPF''
3. Redefine the ``highest'' product category descriptor to include
SPF 50
4. Require SPF values expressed in multiples of 5
5. Label SPF as the percent of UVB radiation screened
As discussed in the remainder of this section, we agree with the first
and second requests, but are not granting the other three requests.
In this final rule, unlike the 2007 proposed rule, we have no
express definitional section. However, we identify ``SPF'' as an
abbreviation for ``sun protection factor'' in new 21 CFR 201.327(a)(1),
and use it consistently in this way throughout the rule. This use of
the term SPF is identical to the definition in the 1999 stayed
sunscreen final rule (64 FR 27666). For products that are not broad
spectrum, the term ``SPF'' will appear on the PDP with the numerical
SPF value calculated according to the test method in new 21
[[Page 35625]]
CFR 201.327(i). For broad spectrum sunscreen products, the term ``Broad
Spectrum SPF'' will appear on the PDP along with the numerical SPF
value calculated according to the test method in new 21 CFR 201.327(i).
The term ``UVB'' will not be required as part of the SPF statement.
We are also not requiring the descriptor (e.g., ``high'' or ``low'').
We included these two requirements in the 2007 proposed rule because we
had concluded that the requirements would help consumers understand the
side-by-side SPF numerical rating in conjunction with the UVA star
rating, which included the term ``UVA'' and the same descriptors (72 FR
49070 at 49084). As discussed in section III.B of this document, the
UVA star rating is not being included in this final rule, and as
discussed below, we have concluded that neither the term ``UVB'' nor
the descriptor is necessary for consumers to understand the
effectiveness statement.
Neither the term ``UVB'' nor a descriptor (e.g. ``low'' or
``high'') had been included on sunscreen labels prior to our 2007
proposal, and consumers had been able to make purchase and use
decisions based on SPF values alone. Under this final rule, the SPF
value will be expressed on the PDP by including the term ``SPF,''
followed by the numerical value determined from the SPF test, similar
to how it has appeared on the labels of OTC sunscreen products for more
than 30 years. As described in section III.B of this document, for
products passing the critical wavelength test in new 21 CFR 201.327(j),
the SPF value statement will be expressed as ``Broad Spectrum SPF''
followed by the numerical SPF value calculated according to the test
method in 21 CFR 201.327(i).
We received five submissions objecting to the definition of SPF as
``sunburn protection factor'' and only one submission supporting the
definition (Ref. 1). The submissions objecting to the definition argued
that, if the term ``sunburn protection factor'' is used, consumers may
mistakenly assume that a higher SPF value means a higher probability of
sunburn. Additionally, they argued that sunscreen products protect
against various harmful effects of sun exposure, such as early skin
aging and skin cancer, in addition to protecting against sunburn. Some
submissions suggested that the term ``sunburn protection factor'' will
lead consumers with darker skin to assume that they do not need
sunscreen products because they do not burn easily (Ref. 1).
We agree with the arguments provided by the submissions suggesting
that the term ``sunburn protection factor'' may be misleading. In the
2007 sunscreen proposed rule, we revised the definition of SPF from
``sun protection factor'' to ``sunburn protection factor'' because we
thought that the new definition was more descriptive of what an SPF
value represents (72 FR 49070 at 49077). The SPF value is determined
from a clinical test with sunburn as the endpoint. However, for broad
spectrum sunscreen products, the SPF statement also serves as a
relative measure of the magnitude of broad spectrum protection (Ref.
4). In this final rule, while we do not codify a separate definitional
section, we continue to use the term ``SPF'' to mean ``sun protection
factor,'' as we had done in the 1999 final rule (21 CFR 201.327(a)(1)).
In this final rule, we are also revising the effectiveness
statement so that the term ``UVB'' is not required before the term
``SPF,'' as proposed in the 2007 proposed rule (proposed 21 CFR
352.50(a)). We received six submissions requesting this revision (Ref.
1). These submissions argued that ``UVB SPF'' is an incorrect
representation of the SPF value determined from a test using a solar
stimulator that emits both UVA and UVB radiation. The submissions point
out that sunburn is not caused solely by UVB radiation. It is well
known that UVA radiation contributes up to 20 percent of the skin's
sunburn response (Refs. 5 and 6). One submission points out that if a
sunscreen product blocked 100 percent of the incident UVB radiation and
none of the erythemally effective UVA radiation, the sunscreen product
would have SPF values no higher than 11 (if only 9 percent or 1/11 of
UV radiation reaches the skin) (Ref. 4).
We agree that UVA radiation contributes to the development of
sunburn. Although the contribution of UVA to sunburn is less than UVB,
it is still significant (Ref. 5). Further, as stated in the
submissions, protection against UVA radiation is necessary to achieve
higher SPF values (Ref. 5). We proposed including the term ``UVB'' in
the SPF statement in the 2007 proposed rule to help consumers
understand that the SPF effectiveness rating is different from the UVA
effectiveness (star) rating being proposed (72 FR 49070 at 49084).
However, as discussed elsewhere in this final rule we are not requiring
a UVA effectiveness rating on the PDP (see section III.B.). Therefore,
the term ``UVB'' is not necessary as part of the SPF statement. In this
final rule, we are not requiring the term ``UVB'' be placed before the
term ``SPF.''
In the 2007 sunscreen proposed rule, we stated that the SPF value
should be followed by one of the descriptors ``low,'' ``medium,''
``high,'' or ``highest'' (proposed 21 CFR 352.50(a)). The proposed
descriptors were included to help consumers understand the SPF value
because the label would have included identical descriptors for the UVA
star rating. As discussed in section III.B. of this document, we are
not requiring a UVA effectiveness rating on the PDP. Therefore,
descriptors are no longer required to distinguish the SPF value from
the UVA rating on a sunscreen label. Because we are not requiring a
descriptor after the SPF value on the PDP in this document, the request
to include SPF 50 sunscreen products in the ``highest'' category is no
longer relevant.
We received two other requests for revision to the SPF statement
with which we do not agree. First, a submission stated that SPF values
should only be labeled in multiples of five to be consistent with SPF
labeling recommendations by the European Commission (Ref. 7). Second,
one request from a submission suggested that SPF values should be
expressed as the percent of UV absorption. The submission argued that
the current SPF values are misleading because consumers believe an SPF
15 sunscreen product is not very protective even though it screens 93
percent of UV radiation.
We do not agree with either submission. Based on SPF test data we
have reviewed, we find that SPF values for sunscreen products generally
can be determined with a precision that allows the products to be
labeled with SPF values in intervals of less than 5 units (Ref. 1).
Therefore, there is no mathematical or statistical basis for
restricting SPF values to multiples of five. Contrary to the second
request, consumers have relied on SPF values for over 30 years and are
familiar with this format. Therefore, expressing SPF values as
percentages may be confusing. It would imply that the stated percentage
of the entire UV spectrum is absorbed by a sunscreen. However, the SPF
values only reflect protection against the portion of the UV spectrum
that causes sunburn. Additionally, the percentages of UV radiation
screened that the submission notes are theoretical. The percentages are
determined in a laboratory setting and not under actual use conditions.
For example, laboratory tests may show that an SPF 15 sunscreen absorbs
93 percent of UV rays, but, under actual use conditions, the level of
protection provided by an SPF 15 sunscreen product may be significantly
below 93 percent. There are a number of factors
[[Page 35626]]
that lead to this decreased protection, the most important being under-
application of the sunscreen product (72 FR 49070 at 49092). Therefore,
if SPF values were expressed as percentages, consumers might mistakenly
believe that the sunscreen products they are using provide more
protection than they really do provide under actual use conditions.
B. Broad Spectrum Statement
In response to the 2007 proposed rule, we received over 50
submissions collectively making the following four requests regarding
the UVA effectiveness rating (Ref. 1):
1. Do not require UVA 4-star rating system.
2. Do not require ``no UVA protection'' statement if a product does
not protect against UVA radiation.
3. Do not require the UVA statement to be the same size as the SPF
statement.
4. Perform label comprehension studies prior to implementing
proposed PDP labeling.
The submissions included arguments, but no data, to support these
requests.
We agree with the first and second requests. However, we are not
granting the third and fourth requests. Our reasons for these decisions
are explained below, but we first summarize the related provisions of
this final rule. We are not requiring a star rating or descriptors to
indicate the level of UVA protection as proposed. Instead, to indicate
the level of UVA and UVB protection, we are establishing a pass/fail
broad spectrum test and a broad spectrum labeling statement. If a
sunscreen product passes the broad spectrum test (see section VIII.B.
of this document), under this final rule, the PDP of the product must
include the statement ``Broad Spectrum SPF [insert numerical SPF value
resulting from testing under paragraph (i) of this section],'' without
any ``UVA'' reference (Sec. 201.327(a)(1)(i)). We are requiring the
Broad Spectrum SPF statement to appear as continuous text with no
intervening text or graphics. We are also requiring that the entire
text be the same font style, size and color on the same background
color. (Sec. 201.327(a)(1)(ii)).
With regard to the submissions received, nearly all of the 50+
submissions argued against requiring the 4-star rating system to
display the level of UVA protection on the PDP of OTC sunscreen
products (Ref. 1). Many submissions stated that the presence of stars
and a number (SPF) on the PDP will lead to consumer confusion. Some
submissions argued that consumers may be confused when determining
whether a star is filled or empty, thereby not knowing the UVA
protection level. Other submissions argued that consumers are familiar
with star ratings, but that the star rating for items such as movies
and hotels are based on recommendations and not rigorous data. They
suggested several options for labeling UVA protection, such as a
numerical rating or another symbol other than stars.
Some submissions suggested that the UVA rating should be
proportional to the SPF value but requested that there not be two
ratings on the PDP. The submissions cited the European Commission's
recommendation that UVA protection increase as the SPF value increases
(Ref. 7). The European Commission recommends a minimum UVA protection
factor equal to at least one-third of the labeled SPF or a critical
wavelength of at least 370 nm, but does not recommend that the actual
value of the UVA protection factor or critical wavelength be displayed.
The European Commission recommends that the main indicator of sun
protection be the SPF value. Broad spectrum protection is indicated by
a symbol on sunscreen labels--the acronym ``UVA'' enclosed within a
circle the diameter of which should not exceed the height of the SPF
value.
We agree with the submissions that the UVA star rating would likely
be confusing in conjunction with the numerical SPF rating. We also
agree with the submissions requesting that UVA protection should be
proportional to the SPF value. We are requiring such proportionality in
the broad spectrum test described in this document. Because of this
proportionality, there is no longer a need for a separate UVA rating.
Instead of a rating, we are requiring a ``broad spectrum'' statement on
the PDP if a product has a critical wavelength equal to or greater than
370 nm. This pass/fail ``broad spectrum'' statement is consistent with
the recommendations in the submissions citing the recommendations of
the European Commission.
As noted, several submissions responding to our proposal for a
separate UVA rating with stars suggested that consumer comprehension
testing should be performed before the proposed labeling is
implemented. We agree with the submissions that consumer comprehension
data can be very helpful in formulating labeling changes. In fact, in
conjunction with our 1993 proposal to allow products to be labeled as
``broad spectrum'' if they contained sunscreen active ingredients that
absorbed UVA radiation (58 FR 28194 at 28233), we requested label
comprehension study data to allow us to determine consumer
understanding of the terms ``broad spectrum,'' ``UVA,'' and ``UVB'' (58
FR 28194 at 28243). Unfortunately, the data we received were not
sufficient to allow us to determine the level of consumer understanding
of these terms (72 FR 49070 at 49081 through 49085), and we received no
further consumer comprehension data in response to the 2007 proposal to
require the UVA star rating. While we acknowledge the value of consumer
comprehension data, for reasons explained below, we conclude that
conducting consumer comprehension testing is not necessary in this case
in light of the labeling we have selected for the final rule.
First, submissions suggesting consumer testing were responding to
the UVA star rating in the proposed rule, the value of which would have
been based on the results of two tests (72 FR 49070 at 49081 through
49085). As noted, we agree with the submissions suggesting that the
2007 UVA labeling proposal was likely to be confusing. Elsewhere in the
document, we also discuss our final choice of a pass-fail test for
establishing UV protection (section VIII.B). As a result of these
changes in the underlying test method and the submissions on the
proposed labeling, we have incorporated a much simpler labeling
statement in this final rule. This statement designates as ``broad
spectrum'' those products that are demonstrated to have a critical
wavelength of at least 370 nm, using the test in new 21 CFR 201.327(j).
Second, unlike in 1993 when we first sought consumer data on the
term ``broad spectrum'', and unlike the UVA star rating that we
proposed in 2007, consumers are now likely to be familiar with the term
``broad spectrum'' as included in this document because some sunscreen
manufacturers have labeled sunscreen products as ``broad spectrum'' for
over 20 years. For example, the Johnson and Johnson ``Sundown Broad
Spectrum'' line of sunscreens was on the market in 1988 (Ref. 8). As
already noted, in our 1993 proposed rule, we not only sought consumer
data, but in fact proposed that products be permitted to be labeled as
``broad spectrum'' if they contained sunscreen active ingredients that
absorbed UVA radiation, although we did not at that time propose to
require a specific test to demonstrate UVA protection (58 FR 28194 at
28233). We continued to allow this statement in the 1999 sunscreen
final rule (64 FR 27666 at 27666 through 27667).
Many consumers may also be familiar with the term ``broad
spectrum'' because
[[Page 35627]]
of public health campaigns and news articles about the importance of
broad spectrum UV protection over the last two decades. For example, an
article appearing in Working Woman magazine in 1990 urged women to
``make sure to look for the term `broad spectrum' on the label of a
sunscreen'' because ``it means you're getting protection from both
types of radiation'' (Ref. 9).
For consumers not already familiar with the term ``broad
spectrum,'' the additional indication statement allowed in this
document for certain broad spectrum sunscreen products should help
consumers recognize the benefit of these products. Under ``Uses'' in
Drug Facts, broad spectrum sunscreen products with an SPF value of 15
or higher are allowed the following indication statement: ``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'' (new 21 CFR 201.327(c)(2)).
In addition, educational campaigns about sun protection will
further inform consumers about the benefits of using sunscreens that
include the term ``broad spectrum'' on their labels and have an SPF
value of 15 or higher. We expect consumers to learn that a sunscreen
labeled with the statement ``Broad Spectrum SPF'' 15 or higher, when
used as directed with other sun protection measures, offers more
comprehensive protection against sun-induced skin damage than that
provided by a sunscreen that is not broad spectrum or that are broad
spectrum with an SPF value less than 15.
It is important to note that the broad spectrum test required in
this document captures both UVB and UVA protection for the
effectiveness of a sunscreen product. The broad spectrum test is not
limited to UVA wavelengths as was the case with the proposed test (see
section VIII.B of this document). By requiring that a broad spectrum
sunscreen provide both UVB and UVA protection in a pass/fail test, the
amount of UVA protection for a sunscreen product that passes the test
must increase as the SPF increases. For example, a Broad Spectrum SPF
40 sunscreen product provides greater protection against both UVB and
UVA than a Broad Spectrum SPF 20 sunscreen product. In contrast, an SPF
40 sunscreen product that is not broad spectrum provides more UVB
protection than a SPF 20 sunscreen product that is not broad spectrum,
but may not provide more UVA protection.
This proportionality between UVB and UVA protection is important
because consumers have been accustomed to basing their purchase
decision concerning protection level primarily on the SPF value, and
only secondarily on indications of whether or not the sunscreen
provides broad spectrum protection. For example, a consumer seeking
lower protection may have chosen an SPF 15 sunscreen product, whereas a
consumer seeking higher protection may have chosen an SPF 40 sunscreen
product. By creating a clear and standardized ``yes/no'' indicator
regarding broad spectrum protection, these final labeling requirements
will enable consumers to make better and more informed purchase
decisions by looking to see if a product has a ``Broad Spectrum SPF''
value on the label. Thus, the ultimate purchase decision would be based
on the numerical value associated with the Broad Spectrum SPF
statement. For products offering broad spectrum protection, the Broad
Spectrum SPF value on the PDP will not only indicate the relative level
of protection against UVB radiation but will also reflect the level of
UVA protection, with increasing SPF values indicating greater
protection against both UVA and UVB radiation. For broad spectrum
products, linking the amount of UVA protection to the SPF value, is
consistent with the approach taken in Europe (Ref. 7).
For broad spectrum products, we are requiring the broad spectrum
statement on the PDP to appear in combination with the SPF statement.
For example, an SPF 40 sunscreen product which passes the broad
spectrum test will be labeled ``Broad Spectrum SPF 40'' in a uniform
font style, size, and color and with the same background color. This
placement will help consumers recognize that the particular sunscreen
product is broad spectrum in conjunction with the SPF value. As
previously explained, the broad spectrum statement and SPF value
together will provide a relative measure of both UVB and UVA
protection. Combining the broad spectrum and SPF statements will help
consumers become more aware of the importance of broad spectrum
protection.
Under the 2007 proposed rule, if an OTC sunscreen product was not
tested for or did not protect against UVA radiation, the statement ``No
UVA protection'' would have been required on the PDP (proposed 21 CFR
352.50(b)(1)). Ten submissions argued against requiring this statement
(Ref. 1). Some submissions argued that this statement is misleading
because all sunscreen products provide some UVA protection. Submissions
also stated that a negative statement is inconsistent with the OTC Drug
Review because a drug should only describe the indications for which it
is effective. Other submissions suggested that we should require all
sunscreen products to provide UVA and UVB protection, making this
statement unnecessary.
We have concluded that the ``No UVA Protection'' statement is not
necessary and could be misleading. Under this final rule, the labeling
on the PDP of sunscreens no longer refers the type of UV radiation (UVA
or UVB) protection offered; rather, products that pass the critical
wavelength test in 201.327(j) are labeled with ``Broad Spectrum SPF''
values. Under this labeling, consumers who see ``UVA'' on the PDP, even
if it is part of the statement ``No UVA Protection,'' may mistakenly
believe that the product offers UVA protection. To eliminate this
potential misunderstanding, we are not including the ``No UVA
Protection'' statement on the PDP.
In contrast to four submissions requesting that we make the UVA
statement less prominent than the SPF statement, we are requiring the
SPF and broad spectrum statements to be equally prominent on the PDP by
appearing as a combined statement. The four submissions stated that
they believe UVB radiation contributes more to skin cancer and
photodamage than UVA radiation and argued that more prominence should
be given to the SPF statement. However, none of the submissions
included data to support this argument. Some submissions suggested that
consumers are familiar with SPF ratings and that providing another
rating with similar prominence may mislead and confuse consumers.
It is well known that both UVA and UVB radiation contribute to
photodamage and skin cancer (Refs. 6-7 and 10-12). Therefore, in our
view, providing consumers with information about the effectiveness of a
sunscreen product for UVA and UVB radiation protection is equally
important. We are requiring that the broad spectrum statement be
displayed in combination with the SPF statement. The two statements
must not be interrupted with any graphics or text. In addition, the
broad spectrum statement must be the same font style, size, and color
as the SPF statement with the same background color. It is important
for consumers to evaluate both statements when making a purchase
decision. By requiring this information to be presented with identical
prominence on the PDP, consumers should be able to quickly and easily
identify sunscreen products that provide broad spectrum protection, as
well as the SPF of all sunscreen products. While we are not requiring a
negative statement on the
[[Page 35628]]
PDP of products that do not pass the critical wavelength test in new
301.327(j), we caution that such products may be misbranded if they
include statements regarding UVA protection; such statements may
misleadingly imply that the product provides benefits that are similar
or superior to those of products labeled with Broad Spectrum SPF
values.
C. Water Resistance Statement
In the 2007 sunscreen proposed rule (proposed 21 CFR 352.52), we
allowed the PDP of OTC sunscreen products to contain the statement
``water resistant'' if a sunscreen product was shown to retain the
labeled SPF value after 40 minutes of water immersion, or ``very water
resistant'' if a sunscreen product was shown to retain the labeled SPF
value after 80 minutes of water immersion, according to the test in
proposed 21 CFR 352.76. We simultaneously proposed that the ``Uses''
section of labeling (not the PDP) indicate specifically whether the
product had been established to be water resistant for 40 minutes or 80
minutes, and included specific directions addressing times for
reapplication of each product, dependent on its level of water
resistance (proposed 21 CFR 352.52(b)(1)(vii), (b)(1)(viii), (d)(2),
and (d)(3); 72 FR 49070 at 49113). In this document, we are revising
the PDP to contain the statement ``water resistant (40 minutes)'' or
``water resistant (80 minutes)'' as determined by the water resistance
test in new 21 CFR 201.327(i)(7). We are removing this information from
the indications section of Drug Facts (section IV.B of this document).
We continue to include directions based on the duration of water
resistance established under the new water resistance test (section
IV.D of this document).
One submission stated that including information about water
resistance in the indications section as well as in the directions
section is ``redundant and confusing'' (Ref. 1). The submission
recommended that we delete the indications statement. We agree with the
submission. To eliminate redundancy and simplify the labeling for
consumers, we are relocating the information formerly contained within
the indication statement to the PDP.
The content of the labeling as a whole is the same as that included
in the 2007 proposed rule. However the proposed statement on the PDP
did not clearly and accurately convey to consumers the difference
between ``water resistant'' and ``very water resistant'' sunscreen
products. For example, knowing that a sunscreen product is ``very water
resistant'' does not give any indication of how much time a consumer
can safely spend in the water. Under the 2007 proposed rule, a consumer
would have had to read either the ``Uses'' or the ``Directions''
section of the Drug Facts label to determine the duration of water
resistance for a sunscreen product (proposed 21 CFR 352.52(b)(1)(vii)
and (b)(1)(viii) and proposed 21 CFR 352.52(d)(2) and (d)(3),
respectively; 72 FR 49070 at 49113).
Providing, on the PDP, specific information about the actual time
(40 or 80 minutes) a consumer can expect a sunscreen product to retain
its labeled SPF value is likely to be more helpful to consumers because
the information is displayed in one place--on the PDP and not on
different parts of the labeling. The revised statements ``water
resistant (40 minutes)'' or ``water resistant (80 minutes)'' should
make it clearer and easier for consumers to understand water resistance
as part of their purchase decision. This water resistance information
continues to be reinforced by information in the directions regarding
reapplication.
D. UVB and UVA Educational Statement
In the 2007 sunscreen proposed rule, we proposed that the following
educational statement be included on the PDP of all OTC sunscreen
products (proposed 21 CFR 352.50(c)): ``UV rays from the sun are made
of UVB and UVA. It is important to protect against both UVB and UVA
rays to prevent sunburn and other skin damage.''
We received four submissions regarding the UVB and UVA educational
statement in response to the 2007 sunscreen proposed rule (Ref. 1). The
submissions made the following requests:
Do not require the educational statement on the PDP or
Combine the educational statement with the sun alert
statement and include the combined statement in the ``Other
Information'' section of the Drug Facts label.
We considered including the proposed educational statement on the
PDP. We concluded that this information is not critical for effective
use of sunscreen products, particularly since we are no longer
requiring other PDP statements to refer separately to UVA and UVB
protection. An understanding that the sun produces ultraviolet (UV)
rays or that there are two types of UV rays that reach the earth's
surface is not necessary to ensure the safe and effective use of
sunscreen products. The explanation of these concepts on sunscreen
labeling is potentially confusing and could raise additional questions
about their meaning. We could not determine a succinct educational
statement that would not also be potentially misleading. Therefore, we
have concluded that an educational statement should not be required on
the PDP.
As noted, submissions also requested that the proposed educational
statement be combined with proposed sun alert, included in the proposed
rule as a warning. In section IV.C of this document, we address
submissions on the sun alert warning, and explain our decision to
incorporate the information regarding the role of certain sunscreens in
reducing the risk of skin cancer and early skin aging into a new
indication and accompanying directions for sunscreens with Broad
Spectrum SPF values of 15 or higher. We are retaining a modified
warning to be included as the first warning on sunscreen products that
are either not broad spectrum or that are broad spectrum with an SPF
value less than 15. Because we are not requiring an educational
statement on the PDP and are either eliminating or modifying the
proposed sun alert warning, the request to combine these two statements
is no longer relevant.
IV. Drug Facts Labeling
In September 2004 (69 FR 53801), we delayed the May 16, 2005,
implementation date for the Drug Facts final rule (21 CFR 201.66) for
OTC sunscreen products until further notice). The Drug Facts final rule
(21 CFR 201.66) establishes general labeling format and content
requirements for all OTC drugs. With the additional exception of
certain OTC drug products in ``convenience size'' packages (see 67 FR
16304 at 16306 (April 5, 2002), other OTC drug products are already
required to comply with 201.66. We delayed implementation of 201.66 for
sunscreens so as to avoid the potential that sunscreen manufacturers
would have to relabel their products twice within a short time period
if a final rule specifying labeling for sunscreens published shortly
after the original May 2005 implementation date for the general content
and format requirements of the Drug Facts final rule. We published the
notice of delay for OTC sunscreens' implementation of the Drug Facts
final rule so that such products could simultaneously implement both
the general labeling provisions of that rule and the specific labeling
provisions for sunscreens when we published a sunscreen labeling final
rule. We are now lifting the stay on the implementation of the Drug
Facts final
[[Page 35629]]
rule for OTC sunscreen products. In this document, we are requiring the
same implementation date for the regulations set forth in this labeling
and testing final rule (21 CFR 201.327) and in the Drug Facts final
rule (21 CFR 201.66) as applied to these sunscreen products.
This action will benefit both consumers and manufacturers.
Consumers will benefit by having sunscreen labeling presented in the
Drug Facts format that they are familiar with. Manufacturers benefit
because they will achieve compliance with two rules through one
labeling revision (rather than following the more expensive course of
making two labeling changes at two different times).
In 2003 (68 FR 33362, June 4, 2003), we also stayed the part of the
skin protectant monograph that describes GRASE combinations of skin
protectant and sunscreen active ingredients (21 CFR 347.20(d)). Because
this document addresses the labeling and testing of sunscreen products
and not the GRASE status of individual sunscreen active ingredients, we
are not lifting the stay of 21 CFR 347.20(d).
This document requires much of the Drug Facts labeling included in
the 2007 proposed rule. However, we have made several revisions to the
proposed labeling. These revisions are discussed in detail throughout
the remainder of this section. In addition, table 2 of this document
summarizes these revisions as follows:
Table 2--Summary of Drug Facts Labeling Included in the 2007 Proposed Rule and This Final Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Drug facts section 2007 Proposed rule This final rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Active Ingredients/Purpose......... Name and amount of ingredient(s) followed by Name and amount of ingredient(s) followed by
``sunscreen'' ``sunscreen.''
Uses............................... [low, medium, high, or highest] UVB sunburn for all sunscreen products: ``helps prevent
protection sunburn.''
[low, medium, high, or highest] UVA protection Optional, for sunscreen products with Broad
retains SPF after 80 minutes of activity in the Spectrum SPF values of 15 or higher, ``if used as
water directed with other sun protection measures (see
Directions), decreases the risk of skin cancer and
early skin aging caused by the sun.''
Warnings........................... UV exposure from the sun increases the risk of skin For sunscreen products that are not broad spectrum or
cancer, premature skin aging, and other skin damage. It for products that are broad spectrum with an SPF value
is important to decrease UV exposure by limiting time in less than 15, Skin Cancer/Skin Aging Alert [in bold
the sun, wearing protective clothing, and using a font]: Spending time in the sun increases your risk of
sunscreen. 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.
For all sunscreens:
For external use only For external use only
Do not use on damaged or broken skin
Stop use and ask a doctor if skin rash occurs Stop use and ask a doctor if rash occurs
When using this product keep out of eyes. Rinse with When using this product keep out of eyes. Rinse with
water to remove. water to remove.
Keep out of reach of children. If swallowed, get medical Keep out of reach of children. If swallowed, get medical
help or contact a Poison Control Center right away. help or contact a Poison Control Center right away.
Directions......................... Non-Water Resistant Product Non-Water Resistant Product
apply liberally [ minutes] before sun apply liberally 15 minutes before sun exposure
exposure use a water resistant sunscreen if swimming or
reapply at least every 2 hours and after towel sweating
drying, swimming, or sweating reapply at least every 2 hours
apply and reapply as directed to avoid lowering children under 6 months: Ask a doctor
protection
children under 6 months: Ask a doctor
Water Resistant Product Water Resistant Product
apply liberally [ minutes] before sun apply liberally 15 minutes before sun exposure
exposure
reapply after 40 [or 80] minutes of swimming or reapply:
sweating and after towel drying. Otherwise, reapply at after 40 [or 80] minutes of swimming or
least every 2 hours. sweating
apply and reapply as directed to avoid lowering immediately after towel drying
protection at least every 2 hours
children under 6 months: Ask a doctor children under 6 months: Ask a doctor
Water Resistant and Non-Water Resistant Products Water Resistant and Non-Water Resistant Products
No statement For sunscreens with Broad Spectrum SPF values of 15 or
higher:
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:
limit time in the sun, especially from 10 a.m.-
2 p.m.
wear long-sleeved shirts, pants, hats, and
sunglasses.
Inactive Ingredients............... List inactive ingredients in alphabetical order List inactive ingredients in alphabetical order.
Other Information.................. No required statements protect this product from excessive heat and
direct sun.
Questions?......................... No required statements No required statements.
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 35630]]
A. Active Ingredients/Purpose
We received one submission regarding the listing of active
ingredients and one submission requesting that we provide specific
details about what each ingredient does in the product (Ref. 1). One of
these submission also requested that we require listing of the
percentage of each active ingredient next to the ingredient name.
We are not making any changes to the ``Active ingredients/Purpose''
section of the Drug Facts label. The general OTC labeling regulations
specify that the ``quantity of each active ingredient per dosage unit''
be listed with the established name of each active ingredient (21 CFR
201.66(c)(2)). Therefore, every sunscreen product is already required
to include the active ingredient names followed by the percentage
(weight per volume) in the ``Active ingredients/Purpose'' section, as
requested by the first submission.
We are not requiring specific details about what each ingredient
does in the product. The function of each active ingredient in an OTC
drug product is already required to be listed by 21 CFR 201.66(c)(3),
which specifies that the ``Active ingredients/Purpose'' section of the
label list the ``general pharmacologic categories or principal intended
actions of each active ingredient.'' There is not currently a
requirement to list the purpose of inactive ingredients on OTC drug
labels. This information is not needed to safely and effectively use
sunscreen products. Therefore, in this document, we are not requiring
the purpose of inactive ingredients to be listed on sunscreen labels.
B. Uses
1. Indications Statements Proposed in the 2007 Proposed Rule
The 2007 proposed rule included three indication statements under
``Uses'' in Drug Facts:
1. Level of UVB sunburn protection (proposed 21 CFR
352.52(b)(1)(i)-(b)(1)(iv))
2. Level of UVA protection (proposed 21 CFR 352.52(b)(1)(v) and
(b)(1)(vi))
3. Extent of water resistance (proposed 21 CFR 352.52(b)(1)(vii)
and (b)(1)(viii))
The first statement would have appeared on all monograph sunscreen
products. The second statement would only have appeared on monograph
sunscreen products providing UVA protection. The third statement would
only have appeared on monograph sunscreen products that are water
resistant for either 40 or 80 minutes. We received numerous submissions
from the public concerning these statements following publication of
the 2007 proposed rule (Ref. 1).
We are not requiring these indication statements in this final
rule. Instead, all sunscreen products covered by this rule will be
required to include the indication statement ``helps prevent sunburn,''
as required in the 1999 sunscreen final rule (64 FR 27666; new 21 CFR
201.327(c)(1)). We are requiring this statement instead of the first
proposed statement (level of UVB sunburn protection) because we agree
with submissions arguing that sunburn is not caused solely by UVB
radiation (Ref. 1). We also agree with submissions arguing that the SPF
value by itself on the PDP informs consumers of the level of sunburn
protection, so a separate description of the level of sunburn
protection does not need to be included as an indication.
In addition, sunscreen products covered by this rule that provide
broad spectrum protection according to the test in new 21 CFR
201.327(j) and have SPF values of 15 or higher, may include the
following indication statement (new 21 CFR 201.327(c)(2)(i)): ``if used
as directed with other sun protection measures (see Directions),
decreases the risk of skin cancer and early skin aging caused by the
sun.'' This statement replaces the second proposed indication
statement. We are allowing this statement for certain sunscreens
covered by this rule based on available clinical studies, the fact that
UV radiation from the sun is harmful, and the scientific understanding
that substantially limiting overall UVB and UVA exposure reduces the
risk of skin cancer and early skin aging.
As discussed in the remainder of this section of the document, it
is critical that the indication statement regarding skin cancer and
early skin aging includes information about using the products as
directed and following other sun protection measures (listed under the
heading Directions). We have concluded that the reference to other sun
protection measures is necessary to ensure that the consumer's overall
UV exposure is substantially decreased. A consumer who relies on the
use of a sunscreen with Broad Spectrum SPF value of 15 or higher alone
may not obtain a meaningful net decrease from the risk of skin cancer
or early skin aging if, because he or she is wearing the sunscreen, the
consumer spends more time in the sun and/or wears less protective
clothing. In fact, reliance on sunscreen use alone, without also
employing other sun protection measures, could actually result in an
increase in the consumer's overall UV exposure. Therefore, if the
indication statement regarding decreasing risk of skin cancer and early
skin aging does not include the information about using the product as
directed, which includes following other sun protection measures, the
statement will be considered misleading (and thus make a sunscreen
product misbranded) (new 21 CFR 201.327(c)(3)). Similarly, sunscreen
products covered by the rule that provide broad spectrum with SPF
values between 2 and 15 or do not provide broad spectrum protection
should not state or imply that the use of a sunscreen product alone
will reduce the risk of skin cancer or early skin aging. Doing so would
cause the product to be misbranded.
We are not including the third proposed indication statement
(regarding water resistance) in this document. As already discussed,
under this final rule, information about water resistance is included
on the PDP, as well as under ``Directions'' in Drug Facts (see sections
III.C and IV.D of this document). We conclude that information about
the water resistance of a sunscreen product is more effectively and
accurately presented on the PDP and as a direction than as an
indication statement. The extent of water resistance informs a consumer
about how long the SPF value is retained following water exposure and,
therefore, how long an interval can elapse before reapplying the
sunscreen product (40 or 80 minutes). In addition, the PDP requirements
in this document include the time interval as part of the water
resistance statement, so that consumers can readily distinguish between
products on this basis when making purchasing decisions. Because we
include water resistance on the PDP and under ``Directions,'' we are
not including a separate indication statement about water resistance in
this document.
2. Statement Regarding Skin Cancer and Early Skin Aging
a. Submissions Arguing For a Skin Cancer and Early Skin Aging
Indication
As already stated, in this final rule we have adopted, for the
first time, an indication for skin cancer and early skin aging for
sunscreen products covered by the rule that have Broad Spectrum SPF
values of 15 or higher. In our 2007 proposed rule, we had included
indication statements that indicated the degree of protection against
both UVB and UVA radiation but that linked UVB protection only to
sunburn prevention and did not expressly link UVA
[[Page 35631]]
protection to any specific health benefit (proposed 21 CFR 352.52(a)).
At the same time, however, we had proposed both an educational
statement on the PDP stating that UV rays from the sun are made of both
UVB and UVA and that it is important to protect against both types of
radiation to prevent sunburn and other skin damage (proposed 21 CFR
352.50 (c)). We also proposed a ``sun alert'' statement as the first
warning. This first warning read, ``UV exposure from the sun increases
the risk of skin cancer, premature skin aging, and other skin damage.
It is important to decrease UV exposure by limiting time in the sun,
wearing protective clothing, and using a sunscreen.'' (proposed 21 CFR
352.52(c)(1)).
In response to our proposed rule, we received a total of 12
submissions asking that we include a specific statement regarding
reduction in risk of skin cancer and early skin aging as an indication
for covered sunscreens (Ref. 1). The submissions asked that we allow an
indication statement informing consumers that the regular, consistent,
or continued use of a sunscreen product reduces or helps reduce the
risk or chance of developing skin damage, early skin aging, and some
types of skin cancer (Ref. 1). These submissions also supported our
proposed requirement of a ``sun alert'' on the labeling to inform
consumers of the need to limit time in the sun and wear protective
clothing. The submissions came from sunscreen manufacturers and public
health organizations including the American Academy of Dermatology, the
American Cancer Society, and the Skin Cancer Foundation. Many of the
submissions provided references to studies that they argued support the
inclusion of this indication statement. One submission specifically
requested that we allow an anti-aging claim (without mention of skin
cancer), and one other submission argued that no sunscreen can claim to
prevent cancer (Ref. 1). We received no new data to accompany these
requests for a separate indication that the regular use of sunscreen
decreases the risk of skin cancer and early skin aging. However, on
reconsideration of the data reviewed prior to the 2007 proposed rule,
we agree with the argument that the data underpinning our proposed
education statement and warning are sufficient to support an
appropriately qualified skin cancer and premature skin aging indication
for one subset of sunscreens covered by this rule--those that have
Broad Spectrum SPF values of 15 or higher. As a result, our final rule
provides different labeling for these sunscreens than for sunscreens
covered by the rule that are not broad spectrum or that provide broad
spectrum with SPF values less than 15. In addition, we conclude that
such an indication should not be included in the Warnings section of
Drug Facts. We have concluded that, as proposed in 2007, the second
sentence of the first warning (i.e., the ``Sun Alert'' warning) is an
implied indication: ``It is important to decrease UV exposure by
limiting time in the sun, wearing protective clothing, and using a
sunscreen.'' Because it follows a warning that ``UV exposure from the
sun increases the risk of skin cancer, premature skin aging, and other
forms of skin damage,'' the second sentence implies that using any
sunscreen, regardless of SPF value or broad spectrum protection, and
following other sun protection measures will decrease the risks of skin
cancer, early skin aging, and other consequences of UV exposure to the
sun. We have concluded, based on a reconsideration of data previously
reviewed in the 2007 proposed rule, that, if consumers use broad
spectrum sunscreens with SPF values of 15 or higher and follow other
sun protection measures, they can reduce their risk of skin cancer and
early skin aging. For these products, we agree with the public
submissions that this information is most appropriately placed as an
indication (i.e., under Uses) with a reference to the need to use the
product as directed with other sun protection measures. For these
products, we include under the heading Directions, specific reference
not only to regularly use sunscreens with Broad Spectrum SPF values of
15 or higher (the subset of sunscreens for which the indication is
allowed) but also to employ the other listed sun protection measures
listed under Directions. For sunscreen products covered by this rule
that are not Broad Spectrum or that are broad spectrum with an SPF
value less than 15, however, we conclude that existing data are
insufficient to support an indication for reducing risk of skin cancer
or early skin aging. In the sections that follow, we explain the
specific scientific basis for our conclusion, as well as explain our
rationale for the specific framing of the labeling, as included in the
final rule, for both subsets of the sunscreens covered by the final
rule--those that have Broad Spectrum SPF values of 15 or higher and
those that do not have Broad Spectrum or that are Broad spectrum with
SPF values less than 15.
b. Limiting Overall UV Exposure Reduces Risk of Skin Cancer and Early
Skin Aging
For drugs subject to OTC monographs, like sunscreen products,
indication statements about the effectiveness of the drug products must
be supported with scientific data (21 CFR 330.10(a)(4)(ii)). In order
for an OTC drug to be considered generally recognized as effective
(GRAE), there must be a reasonable expectation that, in a given
proportion of the target population, the drug will provide clinically
significant relief of the type claimed (21 CFR 330.14(a)(4)(ii)). Based
on the available data concerning the harmful effects of UV radiation
and sunscreen UV protection, we have concluded that sunscreens, in
conjunction with the critical behavioral steps of limiting time in the
sun particularly during the midday hours and wearing protective
clothing (long sleeve shirt, pants, hat, and sunglasses), provide
``clinically significant relief'' in reducing the risk of skin cancer
and early skin aging. Based on the available data, we have limited this
claim to broad spectrum sunscreen products with an SPF value of 15 or
higher.
UV radiation from the sun has been associated with nonmelanoma skin
cancers since 1927 and with melanomas since 1952 (Ref. 13). It is
estimated that as much as 90 percent of melanomas and nonmelanomas are
caused by sun exposure (Ref. 5). In 1992, the International Agency for
Research on Cancer (IARC), under the auspices of the World Health
Organization, identified UV radiation as a human carcinogen \3\ (Ref.
14). More recently, broad spectrum UV radiation was listed as a human
carcinogen in the National Toxicology Program's 11th Report on
Carcinogens issued in 2005 (Ref. 15). It is important to note that this
report indicates that UVB and UVA radiation across the spectrum are
known human carcinogens, but that either UVB radiation alone or UVA
radiation alone is ``reasonably anticipated to be a human carcinogen.''
This classification is due to the fact that the exact wavelengths of UV
radiation that cause different harmful effects (e.g., DNA damage or
loss of skin elasticity) have not yet been identified. It is clear,
though, that broad spectrum UV radiation causes skin cancer. Broad
spectrum UV radiation has also been shown to cause other types of skin
damage, including early skin aging (Refs. 6 and 16). Therefore, we
agree
[[Page 35632]]
with the principle that a reduction, of sufficient magnitude, in broad
spectrum UV exposure should reduce the risk of harmful effects to the
skin, including skin cancer and early skin aging.
---------------------------------------------------------------------------
\3\ A carcinogen is anything that is known to cause the
development of cancer. UV radiation is known to cause skin cancer.
---------------------------------------------------------------------------
Broad spectrum sunscreens, by absorbing UVA and UVB radiation,
decrease consumer exposure to both types of UV radiation from the sun
that reach the earth's surface. Other critical behavioral steps, such
as limiting time in the sun and wearing protective clothing, also
decrease consumer exposure to UVA and UVB radiation. After considering
the submissions and other available data, we have concluded that a
claim for the reduction in risk of skin cancer and early skin aging is
appropriate for certain sunscreen products, when the claim also
includes the requirement that consumers use the product as directed and
the Directions specify other sun protection measures be followed (see
section IV.D of this document). We are basing this claim on the
scientific understanding of the harm from UVA and UVB radiation and the
absorption and/or reflection of that UV radiation by broad spectrum
sunscreens, as well as data from studies concerning sunscreen use and
the development of skin cancer or precursors of skin cancer (section
IV.B.2.c of this document).
For a sunscreen to be effective (i.e., provide ``clinically
significant relief'') in reducing the risk of skin cancer and early
skin aging, consumers must not increase their overall exposure to UV
radiation by overreliance on sunscreen use. Other behavioral factors
could account for such an increase, such as the amount of time spent in
the sun and the use of protective clothing. If consumers rely on
sunscreen use to spend more time in the sun and/or to wear less
protective clothing, then consumers could actually increase their
overall UV exposure, which would eliminate the effectiveness of
sunscreen use in reducing the risk of skin cancer and early skin aging.
To illustrate this point, it is helpful to consider what has been
termed the ``compensation hypothesis.'' As we noted in the 2007
proposed rule, the compensation hypothesis states that consumers who
wear high SPF sunscreens generally spend more time in the sun and/or
wear less protective clothing (72 FR 49070 at 49086). If the hypothesis
is true, consumers would not reduce their risk of skin cancer or early
skin aging because their overall UV exposure increases, even though a
properly applied (and reapplied) sunscreen absorbs UV radiation and
helps prevent sunburn. We cited two retrospective studies which support
the compensation hypothesis in the 2007 proposed rule (72 FR 49070 at
49086). Reynolds et al. published a study in 1996 finding, in a study
of 509 sixth-graders, that adolescents who used sunscreen on both
Saturday and Sunday of a Labor Day weekend spent significantly more
time in the sun than those who used sunscreen only one day or not at
all (Ref. 17). In the second study, parents of 503 children, aged less
than 2 to 12 years, were surveyed as to parental attitudes about their
children's sun exposure (Ref. 18). The authors reported that
``sunscreen use in children was significantly associated with longer
duration of sun exposure'' (Ref. 18).
Increased overall UV exposure might, in fact, increase the risk of
skin cancer and early skin aging, despite the proper use of sunscreens.
Likewise, if consumers limit time in the sun, especially during midday,
and wear more protective clothing (such as broad brimmed hats, long
pants, and long sleeve shirts) while outside, but do not use sunscreens
for areas of the skin exposed to the sun (such as parts of face and
neck), then the consumer may not decrease the risk of skin cancer and
early skin aging for sun-exposed areas. For these reasons, for products
that are entitled to include an indication for reducing the risk of
skin cancer and early skin aging, we continue to direct consumers to
follow a comprehensive sun protection program that includes use of
sunscreens with Broad Spectrum SPF values of 15 or higher, limiting
time in the sun, and wearing protective clothing, similar to the sun
protection measures discussed in the 2007 proposed rule (72 FR 49070 at
49089). Nearly identical multi-step behavioral sun protection programs
are advocated by a number of medical and public health organizations,
including the American Academy of Dermatology, the Skin Cancer
Foundation, and the American Cancer Society.
We have concluded that a comprehensive sun protection approach is
critical to ensure that consumers who are seeking to obtain a reduction
in the risk of skin cancer and early skin aging limit their overall sun
exposure. Without the reduction in consumers' overall UV exposure, even
a sunscreen with Broad Spectrum SPF value of 15 or higher may not be
effective in decreasing the risk of skin cancer and early skin aging.
As discussed below, the available clinical studies do not control for
these behavioral factors and, therefore, do not demonstrate that even
this subset of sunscreens alone reduce the risk of skin cancer and
early skin aging. However, based on the scientific understanding of the
harm from UV exposure and our assessment of the study data, we have
concluded that if consumers use sunscreens with Broad Spectrum SPF
values of 15 or higher, limit time in the sun especially during the
midday hours, and wear protective clothing when exposed to the sun, the
resulting reduction in overall UV exposure will reduce the risk of skin
cancer and early skin aging. Therefore, there is sufficient evidence of
``clinically significant relief'' to justify the indication and related
directions for this subset of products, as set forth in the rule.
However, we conclude that the omission of prominent information in the
indication regarding the need for other sun protection measures would
misbrand the product, as would the omission of the associated direction
specifying these measures. Indeed, it would suggest a different
indication than that which available evidence supports. Consequently,
we have included in this final rule a new provision indicating that
``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 FD&C Act (21 U.S.C. 352).'' (new 21 CFR
201.327(c)(3)).
c. Available Scientific Data
We are not aware of any data other than what we reviewed in the
2007 proposed rule that evaluate the effectiveness of sunscreens in
reducing the risk of skin cancer or early skin aging for healthy
subjects. One more recent study, published in 2009, found that regular
use of Broad Spectrum SPF 50+ sunscreen ``may prevent'' the development
of actinic keratoses and non-melanoma skin cancer in immune-compromised
organ transplant recipients (Ref. 19). We have not relied on this study
in reaching our conclusions regarding OTC sunscreens, because we do not
consider the immune-compromised study population to be representative
of the general population.
We have re-evaluated the data originally reviewed in preparing the
2007 proposed rule to determine whether those data support allowing the
indication for all sunscreen products or only for certain sunscreen
products. Based on our re-evaluation, we have concluded that the data
is supportive of an indication for broad spectrum sunscreens having SPF
values of at least 15. Further, we have determined that, while the
existing evidence does not support a claim for the use of any sunscreen
alone, it does support an indication that the combination of using
[[Page 35633]]
a sunscreen with Broad Spectrum SPF value of 15 or higher along with
other sun protection measures, reduces the risk of skin cancer and
early skin aging, consistent with other positions in the 2007 proposed
rule (72 FR 49070 at 49087 through 49090).
To date, there are no clinical studies demonstrating that use of
any sunscreen alone can prevent skin cancer. There are two prospective
\4\ studies that directly examine the role of sunscreen products in
preventing skin cancer. Although it did not show any difference in
primary endpoints, a large 1999 study conducted in Australia
demonstrated that people who applied a Broad Spectrum SPF 15 sunscreen
product on a daily basis over a 4.5 year period had a lower overall
incidence of one type of skin cancer, squamous cell carcinoma, on the
head, neck, arms, and forearms than study participants who did not
apply sunscreen (28 cases in the broad spectrum sunscreen group vs. 46
cases in the group not using broad spectrum sunscreen) (Ref. 20). In an
extension of that study, van der Pols et al. evaluated the same
population of subjects over an additional 8 years, and found that the
sunscreen users continued to have a statistically significant lower
incidence of squamous cell carcinoma over the entire 12.5 year period
(Ref. 21). Neither study found that daily sunscreen use had any
measurable effect on the most common form of skin cancer, basal cell
carcinoma. Further, we are not aware of any studies examining the
effect of sunscreen use on the development of melanoma, which is the
deadliest form of skin cancer.
---------------------------------------------------------------------------
\4\ A prospective study is designed to study subjects under pre-
specified conditions. These studies differ from retrospective
studies that try to prove hypotheses by assessing past experiences.
Generally, prospective studies are superior to retrospective studies
in demonstrating drug effectiveness.
---------------------------------------------------------------------------
Although data from clinical studies addressing the specific end
points of cancer is limited, some prospective studies have evaluated
the effects of regular sunscreen use on the development of surrogate
skin lesions that can be precursors to cancer: actinic keratoses and
melanocytic nevi. A small percentage of actinic keratoses progress to
squamous cell carcinomas (Ref. 22). At least four studies have
demonstrated that the number of actinic keratoses is lower for
individuals regularly using sunscreens with Broad Spectrum SPF values
of 15 or higher (Refs. 23 through 26). We are not aware of any studies
examining the potential effects on surrogate skin lesions of sunscreens
that either are not broad spectrum or are broad spectrum with SPF
values less than 15.
Two prospective studies have shown that regular use of a Broad
Spectrum SPF 30 sunscreen reduces the risk of developing melanocytic
nevi, which can progress into melanomas (Ref. 22). In a 2000 study,
Gallagher et al. examined the formation of new melanocytic nevi in 393
Canadian school children. The group of children given Broad Spectrum
SPF 30 sunscreen product had fewer new nevi over the course of the
three year study than did children not given sunscreen products or
advice on sunscreen use (Ref. 27). The difference was small (24 v. 28
nevi, respectively), but statistically significant (p = 0.048). In a
follow-up study published in 2005, Lee et al. evaluated the same group
of children for differences in melanocytic nevi by location on the body
and demographic factors (Ref. 28). These investigators found that the
sunscreen group had significantly fewer new nevi on the trunk than the
control group (p = 0.05).
With respect to the role of sunscreen products in decreasing the
risk of early skin aging, we are aware of only indirect evidence that
sunscreen use decreases early skin aging. One recent study demonstrated
that a broad spectrum sunscreen product can reduce the extent of solar
UV-induced damage to factors associated with early skin aging even when
the SPF value is less than 10 (Ref. 29). Although this study was small,
evaluating only 12 Caucasian subjects, it shows the importance of broad
spectrum protection. These findings have been corroborated in a large
number of studies using broad spectrum sunscreens with SPF values
ranging from 19 to 50, as reported by Fourtanier et al. in two recent
reviews (Refs. 10 and 30).
Neither those studies evaluating the long term effect of regular
sunscreen use on the development of skin cancer and early skin aging
nor those evaluating the long term effect of sunscreen use on surrogate
markers for these conditions were adequately controlled. Such studies,
which must take place over many years, make adequate controls extremely
difficult, if not impossible to implement. For example, one cannot
control for time and duration of exposure, application and re-
application amounts, or use of supplemental behavioral measures such as
wearing protective clothing for a study which takes place over several
years.
Despite their limitation, the results of the short-term
effectiveness studies are consistent with our understanding that
measures which significantly reduce UV exposure decrease the risk of
skin cancer and early skin aging. UVA and UVB radiation is the only
known external risk factor for skin cancer and early skin aging.
Therefore, measures that significantly reduce both UVA and UVB exposure
should decrease the risk of skin cancer and early skin aging. Based on
this understanding, limiting time in the sun, wearing protective
clothing and using a broad spectrum sunscreen with an SPF value of 15
or higher should decrease the risk of skin cancer and early skin aging.
Using a broad spectrum sunscreen with an SPF value of 15 or higher
ensures adequate breadth and magnitude of UVA and UVB protection. For
these products, the broad spectrum test measures breadth and SPF test
measures magnitude of UV protection. Consistent with this scientific
principle, the short-term effectiveness studies demonstrate a decrease
in the development of surrogates for skin cancer and early skin aging.
Thus, we have concluded that the available evidence supports our
finding that sunscreen products, in conjunction with limiting time in
the sun and wearing protective clothing, reduce the risk of developing
skin cancer or early skin aging.
d. Indication Limited to Covered Sunscreens With Broad Spectrum SPF
Values of 15 or Higher
In light of the submissions requesting that we reframe our labeling
information regarding sunscreen use and reduced risk of skin cancer and
premature skin aging as an indication, we re-evaluated skin cancer and
aging studies discussed in the 2007 proposed rule to determine whether
the skin cancer and early skin aging indication should apply to all
sunscreen products or be limited to certain sunscreen products.
Available data support this indication only for broad spectrum
sunscreens with SPF values of 15 or higher. Several reports have
indicated that UV-induced skin damage associated with both skin cancer
and early skin aging can be reduced by the use of broad spectrum
sunscreens (Refs. 10 and 29 through 31). In a direct comparison of a
broad spectrum sunscreen and a non-broad spectrum sunscreen with the
same SPF, Moyal and Fourtanier found that the broad spectrum sunscreen
provided significantly better protection from UV radiation-induced
immunosuppression, a factor associated with both skin cancer and early
skin aging (Ref. 32). Furthermore, the National Toxicology Program
classified broad spectrum UV radiation as a known human carcinogen
because it is not clear which UVB and/or UVA wavelengths contribute to
the development of cancer (Ref. 15).
[[Page 35634]]
Therefore, available data indicate that a broad spectrum sunscreen is
necessary to reduce the risk of skin cancer. Likewise, we do not know
which UVB and/or UVA wavelengths contribute to early skin aging.
Therefore, it is reasonable to conclude that reducing the risk of early
skin aging also requires a broad spectrum sunscreen (in conjunction
with limiting time in the sun and wearing protective clothing).
With regard to SPF value, the available study data concerning the
use of sunscreens in reducing the risk of skin cancer is based on
products with SPF values of 15 or higher. The sunscreen product used in
the 1999 Australian study on skin cancer (squamous cell and basal cell
carcinomas) had a Broad Spectrum SPF value of 16, and those that were
found to reduce actinic keratoses and nevi had SPF values ranging from
16 to 46. The studies on early skin aging make it difficult to know for
certain whether Broad Spectrum SPF values of 15 or higher are necessary
to reduce the risk of early skin aging. However, we conclude that the
data regarding the minimum sunscreen protection necessary to reduce the
risk of skin cancer can be extrapolated to early skin aging. In many
ways, the biological processes that take place in response to UV
radiation are similar for both conditions. For both skin cancer and
early skin aging, UV radiation causes damage in the skin that is not
completely repaired and leads to cancer, fine lines, wrinkles, etc.
Because the supporting data for a skin cancer claim are based on
products with SPF values of 15 or higher, we are only allowing the skin
cancer and early skin aging claim for covered sunscreen products that
are broad spectrum and have SPF values of at least 15. This rule does
not preclude approval of a new drug application including an indication
for reduction in risk of skin cancer and early skin aging for any
sunscreen product. To be approved, such an application must be
supported by the submission of adequate data. This rule also does not
preclude future amendment of the sunscreen monograph in 21 CFR part
352, if additional data are provided to support a similar indication
for other types of sunscreens.
e. Precedent for an Indication Statement That Includes Behavior
Modification
There is at least one other OTC drug product with an indication
statement that describes not only the drug's intended effect but also
one or more behavioral measures to ensure the effect. The indication
statement on the weight loss aid orlistat states that the product is to
be used ``for weight loss in overweight adults, 18 years and older,
when used along with a reduced-calorie and low-fat diet'' (Ref. 33).
The behavioral measure of reduced caloric intake is necessary for
consumers to experience weight loss. A low-fat diet is necessary for
consumers to avoid the undesirable side effect of diarrhea caused by
consuming a high-fat diet while taking orlistat.
The need to include reduced caloric intake as part of the
indication statement for orlistat is similar to the need for including
the use of other sun protection measures as part of the indication
statement for sunscreens. Orlistat increases the likelihood of weight
loss by preventing fat from being absorbed as food is digested in the
stomach and intestines. If consumers take orlistat and decrease their
caloric intake, they increase the likelihood of losing weight. However,
if consumers increase their caloric intake while taking orlistat, they
are less likely to lose weight. Orlistat's effect of preventing fat
absorption could be offset by the high number of calories being eaten.
Similarly, the reduction in UV exposure afforded by use of broad
spectrum sunscreens with SPF values of 15 or higher can be offset if
consumers increase their UV exposure by spending more time in the sun
and/or wearing less protective clothing. This increased overall
exposure could eliminate the effectiveness of sunscreen use in reducing
the risk of skin cancer and early skin aging.
The labeling of prescription cholesterol-lowering drug products
(i.e., statins) follows a similar principle by emphasizing that
reduction of cholesterol levels requires not only use of the drug
product but also a healthy diet. The National Institutes of Health
(NIH) specifies therapeutic lifestyle changes that can be followed to
lower levels of cholesterol in the blood (Ref. 34). These changes
include following a diet restricted in saturated fat and cholesterol,
exercising regularly, and managing weight. Used in conjunction with
cholesterol reducing drugs (currently available only by prescription),
these lifestyle changes improve the chance of effectively treating high
cholesterol levels.
Prescription cholesterol-lowering drug products include the
behavioral step of following a low fat diet in the indication statement
(Ref. 35). The body produces cholesterol, which the drug product
inhibits to produce the desired drug effect of lowering cholesterol
being made by the body. However, the total cholesterol circulating in
the blood reflects cholesterol made by the body plus cholesterol
absorbed from foods containing fats. Therefore, if consumers use a
statin and minimize the amounts of food containing fats in their diet,
then they will reduce the total cholesterol level in the blood.
However, if consumers do not minimize the amounts of food containing
fats in their diet, they may not reduce the total cholesterol in the
blood. The decreased cholesterol production in the body caused by the
statin may not be significant compared to the high amount of
cholesterol derived from food eaten by consumers.
In the same way that regularly taking an OTC weight loss aid or a
prescription cholesterol-lowering drug product without also following a
healthy diet may not result in the intended health effect, use of a
sunscreen with Broad Spectrum SPF value of 15 or higher without also
limiting time in the sun and covering sun-exposed areas may not result
in a net reduction in the risk of developing skin cancer or early skin
aging. For this reason, we are requiring that the indication statement
allowed on sunscreens with Broad Spectrum SPF values of 15 or higher
include all parts of the sun protection program and not suggest or
imply that use of a sunscreen alone reduces the risk of skin cancer or
early skin aging.
C. Warnings
We received submissions requesting that we revise warnings included
in the 2007 proposed rule and that we add new warnings not included in
the 2007 proposed rule (Ref. 1). In section IV.C.1 of this document, we
discuss one new and one revised warning included in this final rule. We
are adding the new warning ``Do not use on damaged or broken skin''
(new 21 CFR 201.327(d)(1)). We are revising the warning about skin rash
(proposed 21 CFR 352.52(c)(3)): ``Stop use and ask a doctor if skin
rash occurs'' to read ``Stop use and ask a doctor if rash occurs.''
In section IV.C.2 of this document, we discuss our revision to the
proposed ``Sun Alert'' warning. Under this final rule, the warning
proposed for all monograph sunscreens is replaced with an optional
indication and required direction on covered sunscreens with Broad
Spectrum SPF values of 15 or higher, while covered sunscreens that are
broad spectrum with SPF values less than 15 or that do not provide
broad spectrum protection will bear a revised warning, called the
``Skin Cancer/Skin Aging Alert.'' (new 21 CFR 201.327(d)(2)).
In section IV.C.3 of this document, we discuss three new warnings
that were requested in submissions, but are not
[[Page 35635]]
being included in this document. Submissions argued that we should add
warnings that the regular use of sunscreen products may cause vitamin D
deficiency and may reduce the photoprotective effects of tanning. We
also considered adding a warning concerning sunscreen products
containing alpha hydroxy acids (AHAs). We are not adding any of these
warnings because the available data do not support the need for these
warnings.
In summary, this document requires the following warnings on all
covered OTC sunscreen products (new 21 CFR 201.327(d)):
``Do not use on damaged or broken skin''
``Stop use and ask a doctor if rash occurs''
``When using this product keep out of eyes. Rinse with
water to remove.''
For all covered sunscreen products that either are not broad spectrum
or are broad spectrum with SPF values less than 15, this final rule
also requires a ``Skin Cancer/Skin Aging Alert'' as the first statement
under the heading Warnings. In addition to these warnings, all
sunscreen products are required to include the ``external use'' and
``keep out of reach of children'' warning statements required on all
topical OTC drug products (21 CFR 201.66(c)(5)(i) and (c)(5)(x)).
1. New and Revised Warnings for Damaged or Broken Skin and Rash
The new warning that we are requiring on all covered sunscreen drug
products reads, ``do not use on damaged or broken skin.'' We require
this warning or a similar warning for other topical OTC drug products:
Acne treatments (21 CFR 333.350(c)(3))
Skin protectants (21 CFR 347.50(c)(6))
Antiperspirants (21 CFR 350.50(c)(1))
The safety data for these ingredients are based on application to
intact (i.e., unbroken or undamaged) skin. We do not have data of the
safe use of these ingredients if the skin is not intact. For the same
reason, the warning appears on sunscreen products marketed under new
drug applications (NDAs).\5\ Therefore, in this document, we are
requiring this warning for all covered OTC sunscreen products, which
are marketed without approved applications (new 21 CFR
201.327(d)(1)(i)).
---------------------------------------------------------------------------
\5\ NDAs 21-501, 21-502, 21-471, and 22-009.
---------------------------------------------------------------------------
In addition to the new warning, we are revising the warning in
proposed 21 CFR 352.52(c)(3): ``Stop use and ask a doctor if skin rash
occurs.'' We are deleting the word ``skin'' so that the new warning
reads: ``Stop use and ask a doctor if rash occurs'' (new 21 CFR
201.327(d)(1)(iii)). We received two submissions arguing that the word
''skin'' is unnecessary in this warning because every rash is a skin
rash (Ref. 1). We agree and are removing the word to make the warning
more concise. Consumers will likely understand the warning without the
word ``skin.''
2. Revision of the Proposed ``Sun Alert'' Warning
In 2007, we proposed a warning, based on the ``Sun Alert''
statement cited in the 1999 stayed sunscreen final rule (64 FR 27666 at
27679), as the first statement under the heading Warnings for all
monograph sunscreen products regardless of SPF value or broad spectrum
protection (proposed 21 CFR 352.52(c)(1)). As proposed, this warning
would have stated, ``UV exposure from the sun increases the risk of
skin cancer, premature skin aging, and other skin damage. It is
important to decrease UV exposure by limiting time in the sun, wearing
protective clothing, and using a sunscreen.'' Submissions regarding
this proposed warning are discussed in section IV.B.2 of this document.
As noted there, we agree that, as proposed, this warning included an
implied indication that all sunscreens reduce the risk of skin cancer
and skin aging. Under this final rule, we are no longer requiring a
``Sun Alert'' or similar warning on broad spectrum sunscreens with SPF
values of 15 or higher covered by the rule. This decision is based on
our re-evaluation of the available scientific data. We are now
permitting an indication stating that, used as directed with other sun
protection measures, these sunscreens reduce the risk of skin cancer
and premature skin aging (new 21 CFR 201.327 (c)(2)).
For these products we are also requiring a new direction statement
(new 21 CFR 201.327(e)(1)(iv)). The direction states:
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 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
We have concluded that information about decreasing sun exposure
and wearing protective clothing is more appropriate in ``Directions''
than in ``Warnings.'' These measures, in addition to use of a sunscreen
with Broad Spectrum SPF value of 15 or higher, are necessary for the
consumers' sun protection as part of a comprehensive program.
For covered sunscreen products that do not provide broad spectrum
protection or those that do provide broad spectrum protection with SPF
values less than 15, we conclude that a warning regarding the risks of
skin cancer and skin aging remains necessary. In light of comments
received on the ``Sun Alert'' warning proposed in 2007, however, we are
revising the text to read as follows: ``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.''
(new 21 CFR 201.327(d)(2). The title ``Skin Cancer/Skin Aging Alert''
more accurately and specifically conveys the nature of the warning that
follows than the proposed ``Sun Alert'' warning, particularly since the
products that will bear this statement are indicated to help prevent
sunburn, one consequence of sun exposure. The first sentence of this
warning is a factual statement similar in content to the opening
statement of the warning proposed in 2007. Like the proposed ``Sun
Alert'' warning, this statement alerts consumers to risks they continue
to incur from sun exposure, the conditions under which they will make
use of the product. The second sentence clarifies for users the limits
on the benefits that the product in hand has been established to
provide, specifying that these products have been shown to help prevent
sunburn but have not been shown to reduce the risk of skin cancer or
early skin aging. Inclusion of this warning is critical to help ensure
that consumers do not mistakenly conclude that all sunscreens have been
demonstrated to provide the same benefits. It will reinforce the
distinction between sunscreens indicated only for preventing sunburn
(those that have broad spectrum with SPF values below 15 or that are
not broad spectrum) and sunscreens that have also been shown to reduce
the risk of skin cancer and early skin aging when used as directed with
other sun protection measures (those with Broad Spectrum SPF values of
15 or higher). This warning serves a similar purpose to one required on
cosmetic suntanning preparations that do not contain a sunscreen
ingredient, which likewise is intended to assist consumers in
distinguishing among products that they might otherwise confuse. (See
21 CFR 740.19).
[[Page 35636]]
3. Warnings Requested in Submissions But Not Included in This Final
Rule
We considered adding the following three warnings:
Sunscreens may reduce the photoprotective effects of
tanning
Increased sun sensitivity caused by alpha hydroxy acids
(AHAs) in sunscreen products
Regular use of sunscreen products may cause vitamin D
deficiency
However, as discussed in this section of the document, we conclude that
these warnings are not needed for the safe and effective use of
sunscreen products.
We received a submission arguing that we should require the
following warning on all OTC sunscreen products containing UVA-
protective active ingredients (Ref. 1): ``The use of this product will
prevent the development of photo-protective facultative pigmentation,
a.k.a., a tan.'' The submission implies that UVA protection is not only
unnecessary but harmful to consumers. No data were included in the
submission.
We agree that tanning caused by UVA radiation offers some
protection against sunburn. However, tanning, particularly when
attributable to prolonged exposure to UVA radiation in tanning beds or
booths, may also have harmful effects on the skin (Refs. 36 and 37). In
addition, one study suggests that the protective effects of tanning are
small, as a tan only appears to provide an SPF value of approximately 4
(Ref. 36). As stated in the 2007 proposed rule (72 FR 49070 at 49083),
we do not know which UVA wavelengths cause specific types of damage
(e.g., skin cancer or early skin aging). We continue to assert,
however, that protection against UVA radiation is important for
consumers' health (72 FR 49070 at 49083). We have concluded that the
warning suggested in the submission is not in the best interest of
public health because the warning discourages consumers from using
broad spectrum sunscreen products. Therefore, we are not requiring any
warning related to tanning.
We are not adding any additional warnings to sunscreen products
containing AHAs. In the 2007 proposed rule, we requested comment on the
need for additional warnings or directions on sunscreen products
combined with AHAs (72 FR 49070 at 49110). We made this request in
response to a 2005 guidance that we issued for cosmetic products
containing alpha hydroxy acids (70 FR 1721, January 10, 2005). The
guidance recommends the following warning be included on cosmetic
products containing alpha hydroxy acids: ``Sunburn Alert: This product
contains an alpha hydroxy acid (AHA) that may increase your skin's
sensitivity to the sun and particularly the possibility of sunburn. Use
a sunscreen and limit sun exposure while using this product and for a
week afterwards.''
Many cosmetic products containing alpha hydroxy acids also contain
sunscreens because the sunscreen helps protect the skin made sensitive
to the sun by the alpha hydroxy acids. The guidance does not address
products combining alpha hydroxy acids and sunscreens.
Two submissions stated that additional warnings are not necessary
on these products (Ref. 1). We agree with these submissions. We
considered added a warning or other labeling to inform consumers that
AHAs contained in some sunscreen products may make the consumer more
likely to sunburn. However, the sunscreen component of such products
would, in fact, protect consumers from sunburn. Furthermore, we have
concluded that the addition of sunscreen active ingredients to AHA-
containing cosmetic products provides valuable UV protection for
consumers. Therefore, at this time, we have concluded that a warning
about AHA is not necessary on OTC sunscreen products.
The other new warning requested in submissions relates to vitamin D
deficiency. We received six submissions arguing that consumers should
be warned that frequent sunscreen use may result in vitamin D
deficiency (Ref. 1). The submissions cite articles discussing the
negative effects of vitamin D deficiency, such as growth retardation,
rickets, and osteoporosis (Ref. 38). The submissions include numerous
published articles concerning vitamin D, but only four clinical studies
that directly examine the effect of sunscreen use on vitamin D levels.
In the remainder of this section, we discuss the four studies included
in submissions, as well as three additional studies that we located
through a literature search. Collectively, the studies do not
demonstrate that the use of sunscreen causes vitamin D deficiency.
The term ``vitamin D'' refers to several forms of the vitamin, but
the two forms important to humans are vitamin D2
(ergocalciferol) and vitamin D3 (cholecalciferol) (Ref. 39).
Vitamin D2 is obtained by eating vitamin D-rich foods such
as fish or food fortified with vitamin D. The skin makes vitamin
D3 when it is exposed to sunlight (Ref. 40) and, therefore,
vitamin D production may vary depending on the following factors: (1)
Skin pigmentation, (2) age, (3) clothing, (4) season, (5) latitude, (6)
time of day, (7) weather conditions, and (8) sunscreen application
(Refs. 40-43). Vitamin D deficiency has long been associated with
Ricketts, but recent research suggests that vitamin D deficiency may
also be associated with other diseases (Ref. 38). However, the
threshold of vitamin D blood levels that constitutes a deficiency is
currently being re-evaluated by scientific experts (Refs. 40, 44, and
45).
To determine whether sunscreen use causes vitamin D deficiency, we
reviewed four clinical studies included in the submissions that
explored the effect of sunscreen use on vitamin D levels as well as
three studies that we identified in a literature search:
Matsuoka et al 1987 (Ref. 46)
Matsuoka et al 1988 (Ref. 47)
Marks et al. 1995 (Ref. 48)
Farrerons et al. 1998 (Ref. 49)
Kimlin et al., 2007 (Ref. 50)
Cusack et al., 2008 (ref. 51)
Hoesl et al., 2010 (Ref. 52).
All but one of these studies assessed 25-hydroxyvitamin D levels
because 25-hydroxyvitamin D is typically used as the biological marker
for vitamin D (in the D2 or D3 form) (Ref. 53).
Much of the data available in the literature involves nonclinical
studies, which can be difficult to extrapolate to consumer (human)
actual use conditions. Studies with clinical data provide more
meaningful results because, if adequately designed, they can be more
easily extrapolated to consumer actual use conditions. Therefore, we
are focusing discussion in this document on the clinical studies.
In the 1987 study by Matsuoka et al., four subjects applied a
sunscreen product with an unknown SPF to the entire body, while four
control subjects did not apply any topical product (Ref. 46). All of
the subjects were exposed to 1 MED \6\ of UV radiation (260-330 nm \7\)
and then vitamin D3 levels were monitored for 15 days. The
subjects using sunscreen product applied the sunscreen product 1 hour
before UV exposure. The level of vitamin D3 was determined
one day before UV exposure to serve as the baseline measure.
---------------------------------------------------------------------------
\6\ MED refers to the lowest dose of UV radiation that produces
perceptible reddening of the skin.
\7\ Nanometers.
---------------------------------------------------------------------------
The level of vitamin D3 in the control group (no
sunscreen) increased significantly over baseline 1 day after UV
exposure (from ~2 ng/ml \8\ to 25 ng/ml) and then decreased gradually,
returning to baseline 15 days after UV exposure. In contrast, the
levels of vitamin D3 in the sunscreen group did
[[Page 35637]]
not change significantly from the baseline level (5 ng/ml) at each time
point.
---------------------------------------------------------------------------
\8\ Nanograms per milliliter.
---------------------------------------------------------------------------
Based on this preliminary study, Matsuoka et al. conducted another
study in 1988 (Ref. 47). This study enrolled 40 subjects from Illinois
and Pennsylvania with 20 subjects in the control group and 20 subjects
in the sunscreen group. Each time they went outdoors for 1 year, the
subjects in the sunscreen group, who had a history of skin cancer,
applied a sunscreen product with an unknown SPF to all sun-exposed
areas of the body.
Serum 25-hydroxyvitamin D levels were measured in each group at the
conclusion of the study and were significantly lower in the sunscreen
group than the control group: 40.2 and 91.3 nmol/L,\9\ respectively.
The difference in 25-hydroxyvitamin D levels between the two groups was
statistically significant (p < 0.001).
---------------------------------------------------------------------------
\9\ Nanomoles per liter.
---------------------------------------------------------------------------
Marks et al. conducted a randomized, double-blind controlled
clinical study over a summer period in Australia (Ref. 48). In this
study, 113 subjects over 40 years old who exhibited at least one solar
keratosis (a precursor of carcinoma of the skin) were recruited and
divided into two groups. The first group of 56 subjects applied an SPF
17 sunscreen cream. Fifty-five subjects in the control group applied a
placebo cream. Subjects in both groups were asked to apply their cream
on the head, neck, forearm and dorsal side of each hand once a day in
the morning and more frequently if sweating, swimming, or involved in
activities that might rub off the cream.
The mean levels of 25-hydroxyvitamin D rose significantly by almost
the same amount in both groups over the period of the study. The mean
level in the placebo group increased by 12.8 mmol/L, whereas the mean
level in the sunscreen group increased by 11.8 mmol/L. The difference
between these increases from baseline values was not statistically
significant.
In 1998, Farrerons et al. carried out a study to examine the
effects of sunscreen use on vitamin D levels in elderly individuals
(Ref. 49). In this 2-year study, 24 subjects (10 men and 14 women with
a mean age of 71 years) were enrolled in the sunscreen group. The
subjects had actinic keratosis, basal cell carcinoma, or squamous cell
carcinoma. None of the subjects had previously used sunscreen products,
but were instructed to apply an SPF 15 sunscreen product to sun-exposed
areas of the body each morning, avoid mid-day sun, and wear UV-
protective clothing during the spring and autumn. The control group of
19 subjects did not use sunscreen product, but had the same skin
characteristics. Mean serum levels of 25-hydroxyvitamin D were measured
at eight different time points (four in the autumn and four in the
spring) over the two-year study period.
The mean serum levels of 25-hydroxyvitamin D were statistically
lower in the sunscreen group as compared to the control group at one
spring and one autumn time point (p < 0.05). However, the mean serum
levels of 25-hydroxyvitamin D were not statistically different between
the groups at the other 6 spring and autumn time points.
In 2007, Kimlin et al. reported that there was ``no association''
between use of sunscreens with SPF values higher than 15 and blood
levels of 25-hydroxyvitamin D in a study of 126 Australian adults 18-87
years of age (Ref. 50). However, the authors stated that mean levels of
25-hydroxy vitamin D increased with increasing frequency of sunscreen
use. Interestingly, study ``participants who `usually' or `almost
always' wore a hat when outdoors'' were significantly more likely to
have higher serum 25-hydroxy vitamin D levels than those who wore hats
less often (Ref. 50). On the other hand, study participants who usually
or almost always wore long sleeve shirts or pants while outside were
statistically more likely to have lower serum 25-hydroxyvitamin D
levels than those who wore these types of protective clothing less
often (Ref. 50).
In 2008, Cusack et al. reported that decreased levels of 25-
hydroxyvitamin D levels were only ``weakly correlated'' with sunscreen
usage in 52 Irish patients with cutaneous lupus erythematosus (Ref.
51). This study population was specifically selected because patients
with lupus are particularly sensitive to exposure to the sun. While an
analysis of the effects of daily sunscreen use on serum levels of 25-
hydroxyvitamin D showed the relationship between these two parameters
to be significant, a multivariate analysis of the same data was not
significant (Ref. 51).
Most recently, in 2010, Hoesl et al. reported ``no statistically
significant association'' between serum levels of 25-hydroxyvitamin D
and use of the sunscreen drometrizole trisiloxane in a cohort of 15
patients with Xeroderma pigmentosum (Ref. 52). Like those with lupus
ertythematosus, patients with Xeroderma pigmentosum are extremely
sensitive to the sun. The authors reported that reductions in serum
levels of 25-hydroxyvitamin D are ``not associated with any type or
duration of sun protection applied by these patients'' (Ref. 52).
These seven clinical studies are inconclusive because the results
were contradictory. Two studies suggest that sunscreens decrease
vitamin D levels and the other five studies suggest that sunscreens do
not decrease vitamin D levels. In addition, the studies were relatively
small, only enrolling 8 to 126 subjects. The study with the greatest
number of participants was inconclusive showing that people who
regularly used sunscreens and wore hats had increased levels of vitamin
D, whereas people who regularly wore pants outside had decreased levels
(Ref. 50).
Because the preponderance of currently available data suggests that
sunscreen use does not cause clinically meaningful decreases in vitamin
D levels (i.e., decreases that lead to vitamin D deficiency and/or
disease caused by low levels of vitamin D), we are not including a
warning regarding vitamin D deficiency on OTC sunscreen products. In
addition, determining whether decreases in vitamin D levels result in
vitamin D deficiency is especially difficult because the threshold of
vitamin D blood levels that constitutes a deficiency is currently being
re-evaluated by scientific experts (Refs. 38, 44, and 45). We recognize
that certain subpopulations may be at increased risk of vitamin D
deficiency, as pointed out in one submission. However, there are many
factors that determine the amount of sun exposure necessary to ensure
adequate vitamin D levels (e.g., geographical location, season, skin
pigmentation, dietary vitamin D intake). Because of these many other
factors, it is difficult for us to determine a meaningful message in
sunscreen product labeling for consumers, especially in the absence of
conclusive data. If we become aware of data from adequate and well-
controlled studies demonstrating that regular use of sunscreen causes
vitamin D deficiency, we will re-evaluate this issue.
D. Directions
We received numerous submissions requesting that we revise
directions included in the 2007 proposed rule (Ref. 1). In response to
those requests and our reevaluation of OTC sunscreen labeling, we are
revising the following directions:
``Reapply after [select one of the following: `40 minutes
of' or `80 minutes of' '' for products that satisfy either the water
resistant or very water resistant test procedures in proposed
paragraphs 352.76(a) and (b), respectively] swimming or [select one of
the
[[Page 35638]]
following: `sweating' or `perspiring'] and after towel drying.
Otherwise, reapply at least every 2 hours'' (proposed 21 CFR
352.52(d)(2)).
``Reapply at least every 2 hours after towel drying,
swimming, or sweating'' (proposed 21 CFR 352.52(d)(3)).
These two directions are the reapplication instructions for water
resistant and non-water resistant products, respectively. We also
received five submissions requesting that we revise the direction:
``Apply [select one of the following: `liberally' or `generously']
[and, as an option: `and evenly'] [insert appropriate time interval, if
a waiting period is needed] before sun exposure'' (proposed 21 CFR
352.52(d)(1)(i)). As discussed in this section, we are not revising
this direction statement.
In addition to the revisions to these provisions (described in more
detail in this section of the document), we are no longer requiring the
following proposed direction: ``Apply and reapply as directed to avoid
lowering protection'' (proposed 21 CFR 352.52(d)(1)(ii)).
As already discussed, for covered sunscreen products with Broad
Spectrum SPF values of 15 or higher, we are requiring the following
direction:
``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 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''
(new 21 CFR 201.327(e)(1)(iv)). For these products, this direction most
appropriately conveys the information proposed in the ``Sun Alert''
warning included in the 2007 proposed rule, and provides the necessary
directions to complement the new indication permitted for these
products.
In addition to the required directions, we will allow the optional
direction heading ``for sunscreen use'' (new 21 CFR 201.327(e)(1)(i)).
1. Revised Directions
We are revising the directions for water resistant sunscreen
products (new 21 CFR 201.327(e)(2)) to read:
Reapply:
After 40 [or 80] minutes of swimming or sweating
Immediately after towel drying
At least every 2 hours
We are also revising the directions for non-water resistant sunscreen
products (new 21 CFR 201.327(e)(3)) to read: ``[Bullet] reapply at
least every 2 hours [bullet] use a water resistant sunscreen if
swimming or sweating.'' These revisions should clarify the directions.
We are removing reapplication directions concerning swimming and
sweating from non-water resistant products because these products
should not be used when swimming or sweating. Instead, we are requiring
more accurate directions instructing consumers to use a different
sunscreen product--a water resistant sunscreen product--if swimming or
sweating.
We considered revising the 2-hour reapplication timeframe because
some of the submissions objected to this specific timeframe (Ref. 1).
The submissions argued that we should require the word ``often''
instead of a 2-hour reapplication timeframe because there are no data
supporting this timeframe. The submissions also point out that the
American Academy of Dermatology (AAD) no longer supports a 2-hour
timeframe, even though we cited AAD as supporting the 2-hour timeframe
in the 2007 proposed rule (72 FR 49070 at 49093).
In its submission following the 2007 proposed rule, the AAD does
not state its support for the 2-hour timeframe. However, all of the
public education materials from AAD instruct consumers to reapply
sunscreen at least every 2 hours (Refs. 54 through 58). In addition,
other public health organizations such as the Centers for Disease
Control and Prevention (CDC) and the U.S. Environmental Protection
Agency (EPA) recommend reapplication at least every 2 hours (Refs. 59
and 60).
We disagree with the submissions stating that data do not support
this timeframe. In the 2007 proposed rule, we described two studies
demonstrating a significantly decreased sunburn risk if sunscreen
product were applied at least every 2 hours (72 FR 49070 at 49092
through 49093). Wright et al. found that subjects who reapplied
sunscreen every 1 to 2 hours and after swimming were not sunburned
(Ref. 61). Similarly, Rigel et al. reported that people who reapplied
sunscreen every two hours or sooner were five times less likely to
sunburn compared to those who reapplied sunscreen only after 2.5 hours
or longer (Ref. 62).
One of the submissions following the 2007 proposed rule included
results from a computer-simulation of sunscreen product reapplication
based on a mathematical model (Ref. 1). The results of this simulation
suggested that sunscreen products should be reapplied 15 to 30 minutes
after sun exposure begins. The results also suggested that further
reapplication of sunscreen product is necessary after vigorous activity
that could remove sunscreen product, such as swimming, toweling,
excessive sweating, or rubbing. No other reapplication time is
suggested. The usefulness of this study in determining whether to
revise the directions is limited. In particular, we do not know whether
this simulation was validated, because it has not been confirmed with
clinical studies. Until we receive clinical studies demonstrating that
consumers do not experience skin damage when sunscreen is reapplied at
longer timeframes, we will continue to require the 2-hour reapplication
timeframe. As discussed in the 1999 final rule, manufacturers may seek
approval of different reapplication directions by submitting specific
and substantive supporting data to us under an NDA deviation (described
in 21 CFR 330.11).
2. Proposed Directions Not Being Revised
We are not revising proposed 21 CFR 352.52(d)(1)(i): ``Apply
[select one of the following: `Liberally' or `generously'] [and, as an
option: `And evenly'] [insert appropriate time interval, if a waiting
period is needed] before sun exposure.'' Several submissions requested
that we allow ``smoothly'' to be included in this statement (Ref. 1).
However, we continue to consider this word to be vague (72 FR 49070 at
49072 and 49092). Some submissions also requested that we include a
specific application amount in place of the terms ``generously'' and
``liberally'' (Ref. 1). For example, the submissions suggested that the
statement could read ``apply 2 tablespoonsful.'' The submissions argued
that more specific directions would lead to consumers applying more
sunscreen product, reflecting the 2 milligrams per square centimeter
(mg/cm\2\) used during the SPF test. However, specifying a certain
amount in the directions will not accomplish this goal. The amount of
sunscreen product that needs to be applied to reach 2 mg/cm\2\ varies
for each sunscreen product and depends on the amount of skin surface
area being covered. For example, the volume of sunscreen oil applied to
the neck and face will differ greatly from the amount needed to apply a
sunscreen lotion to every sun-exposed area of the body. Therefore, we
are continuing to require the terms ``generously'' and ``liberally.''
3. Proposed Directions Not Being Required
We are not requiring the proposed statement ``apply and reapply as
directed to avoid lowering protection'' (proposed 21 CFR
352.52(d)(1)(ii)). We included this statement in the 2007
[[Page 35639]]
proposed rule because reapplication time appears to be critical to
achieve proper sun protection (72 FR 49070 at 49093). However, we have
concluded that this statement is redundant with more specific
reapplication directions and may confuse consumers. It is not clear
that consumers will understand the intent of this statement to
emphasize the need to follow reapplication instructions. Therefore, we
are not requiring the statement in this document.
4. New Directions Resulting From Submissions on the Proposed Rule
For covered sunscreens with Broad Spectrum SPF values of 15 or
higher, we are requiring a new Directions statement that emphasizes the
need not only to regularly use such a sunscreen, but also to follow
other sun protection measures. For these sunscreens, the statement will
read, ``[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
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 (new 21 CFR
201.327(e)(1)(iv)). This statement is taken from the proposed warning
``UV exposure from the sun increases the risk of skin cancer, premature
skin aging, and other skin damage. It is important to decrease UV
exposure by limiting time in the sun, wearing protective clothing, and
using a sunscreen.'' (proposed 21 CFR 352.52(c)(1)). As discussed in
section IV.C. of this document, this warning is no longer being
required for sunscreens with Broad Spectrum SPF values of 15 or higher.
Rather, as discussed in section IV.B of this document, submissions
suggested that the information proposed as a warning is better
understood as an indication, with the supporting conditions for
achieving effectiveness. As described in section IV.B, on reexamination
of the scientific data, we agree that an appropriately limited
indication for reduction in risk of skin cancer and early skin aging is
supported for sunscreens with Broad Spectrum SPF values of 15 or
higher. For these products, the direction instructs users how to use
the product in a manner that supports that indication.
In this final rule, we are being more specific about the need to
limit time in the sun especially during the midday hours of 10 a.m. to
2 p.m. when the intensity of solar radiation is greatest because the
sun is at its zenith (i.e., directly overhead). In our 1993 proposed
rule, we stated that, ``on any day of the year, the intensity of the UV
energy of sunlight is greatest between 10 a.m. and 2 p.m.'' (58 FR
28194 at 28199). We have concluded that this information is important
to consumers trying to protect themselves from the sun and are
including the information in the new direction statement. This change
is also responsive to the concerns of two submissions on the portion of
the proposed sun alert that referred to ``limiting time in the sun,''
both of which suggested alternatives intended to provide more concrete
information for consumers to act on (Ref. 1).
Several submissions argued that we should allow different Drug
Facts labeling for cosmetics containing sunscreens so that consumers
will apply the product appropriately for its intended cosmetic use
(Ref. 1). For example, the submissions argued that reapplication every
2 hours may not be appropriate for cosmetic-sunscreen products. We
disagree with these submissions. Cosmetic-sunscreen combinations that
are intended for use as drugs require adequate labeling for their drug
use. (See 21 CFR 700.35). The Drug Facts label communicates information
to the consumer so that the cosmetic-sunscreen product can be used
safely and effectively. To help consumers understand that the sunscreen
directions apply to the use of the product as a drug, for sun
protection, we are allowing the optional statement ``for sunscreen
use:'' to appear as the first line under ``Directions.'' Consumers who
are using these products primarily for cosmetic use will be more likely
to understand that they might not receive the intended sun protection
if they do not follow the directions in the Drug Facts label.
E. Constitutionality of Labeling Statements Regarding Skin Cancer and
Skin Aging
Two submissions questioned the constitutionality of the labeling
provisions in the 2007 sunscreen proposed rule. Specifically, the
submissions contended that our proposed restriction on any claims about
the prevention of skin cancer, early skin aging, and related skin
damage would violate the sunscreen manufacturers' commercial speech
rights under the First Amendment to the U.S. Constitution.
In the 2007 proposed rule preamble, we had concluded that our
proposed restriction on claims about the prevention of skin cancer,
early skin aging, and related skin damage would be permissible under
the First Amendment, in part, because, at that time, we tentatively
concluded that there were insufficient scientific data to support
inclusion of such claims in the sunscreen monograph. As described
elsewhere in this document, we received numerous submissions in
response to the 2007 proposed rule, some of which contained references
to clinical studies we had reviewed in preparing the 2007 proposed rule
about the effectiveness of sunscreens in protecting against the harmful
effects of UV radiation. As already described in section IV.B.2, based
in part on our re-evaluation of the data from these studies, as well as
the scientific fact that reducing exposure to both UVB and UVA
radiation by a substantial amount (i.e., equivalent to that provided by
a broad spectrum sunscreen with an SPF value of 15 or higher) decreases
the risk of damaging the skin, we find that the science supports the
conclusion that one subset of sunscreens covered by this rule, broad
spectrum sunscreen products with an SPF value of 15 or higher, in
conjunction with limiting time in the sun and wearing protective
clothing, reduce the risk of developing skin cancer and early skin
aging. Our conclusion is reflected in the permissible indication
described in this final rule for covered products with Broad Spectrum
SPF values of 15 or higher. Although we have decided to permit a claim
about the prevention of skin cancer and early skin aging for certain
covered sunscreens, as requested in the submissions, we have
nevertheless conducted a First Amendment analysis of our requirements
concerning the skin cancer/early skin aging claim in this final rule
(hereinafter ``skin cancer/early aging indication''), as well as the
``Skin Cancer/Skin Aging Alert'' required as a warning for covered
products that do not provide broad spectrum protection with an SPF
value of 15 or higher. For the following reasons, we have concluded
that these requirements do not violate the First Amendment.
This rule establishes effectiveness testing methods and labeling
that are appropriate for the safe and effective use of OTC sunscreen
products covered by this rule. Any covered sunscreen product that
deviates from the requirements set forth in this labeling regulation
and any other applicable labeling regulation would be considered
misbranded under section 502 of the FD&C Act. In particular, sunscreen
products covered by this rule would be misbranded if they are labeled
with a skin cancer/early aging indication but
[[Page 35640]]
do not provide broad spectrum protection with an SPF value of 15 or
higher. Such products would also be misbranded if they do not include
the ``Skin Cancer/Skin Aging Alert'' described in this rule (see 21 CFR
201.327(d)(2)). Covered sunscreen products that do provide broad
spectrum protection with an SPF value of 15 or higher would be
misbranded if they are labeled with the permissible skin cancer/early
aging indication but do not include reference to the need to use the
product as directed with other sun protection measures (21 CFR
201.327(c)(3)). Manufacturers of covered sunscreen products that comply
with the labeling requirements in this document would not be subject to
enforcement actions on the basis that the products are misbranded,
provided they comply with all other requirements under section 502 of
the FD&C Act. Because this rule applies only to products marketed
without approved applications, manufacturers who wish to deviate from
the testing or labeling requirements in this document may do so by
means of a new drug application (NDA) under section 505 of the FD&C
Act.
We have concluded that the labeling requirements in this rule
satisfy the applicable tests governing commercial speech, as set forth
by the Supreme Court. The requirements for the ``Skin Cancer/Skin Aging
Alert'' and the information in the skin cancer/early aging indication
about using the product as directed with other sun protection measures,
are permissible under the First Amendment because they are reasonably
related to the Government's interest in protecting public health (see
Zauderer v. Office of Disciplinary Counsel, 471, U.S. 626, 651 (1985)).
We are requiring covered sunscreen products that do not provide
broad spectrum protection with an SPF value of 15 or higher to include
the ``Skin Cancer/Skin Aging Alert'' under the ``Warnings'' heading on
the label to ensure that consumers are aware of the continued risks of
skin cancer and early skin aging that occur from sun exposure, the
conditions under which they will be using the product, and that they
understand that the product has been shown only to help protect against
sunburn. Without this warning, consumers could fail to distinguish
between these sunscreen products and other sunscreen products that have
been proven to help provide protection against skin cancer and early
skin aging. Providing this information is important for consumers to be
able to make informed choices about the selection and use of
sunscreens.
For covered sunscreen products that do provide broad spectrum
protection with an SPF value of 15 or higher, we are requiring that the
additional information about using the product as directed with other
sun protection measures be included in the indication so that consumers
are not misled about how to use these sunscreens effectively or about
the conditions under which these sunscreens are effective. Use of a
sunscreen alone--even a broad spectrum sunscreen with an SPF value of
15 or higher--has not been shown to reduce the risk of skin cancer or
early skin aging if a consumer increases overall UV exposure by
spending greater time in the sun and/or wearing less protective
clothing. The additional information required in the skin cancer/early
aging indication about using the product as directed with additional
sun protection measures clarifies how the use of sunscreens is part of
a comprehensive sun protection program. Displaying this information
elsewhere would underemphasize its importance in relation to the use of
these sunscreens for protection against skin cancer and early skin
aging (see N.Y. State Rest. Ass'n v. N.Y. City Bd. of Health, 556 F.3d
114 (2d Cir. 2009); see also 21 U.S.C. 352(c)). Thus, these disclosure
requirements will promote the proper use of covered sunscreens and are,
therefore, reasonably related to the Government's interest in
protecting public health.
Our requirements concerning the skin cancer/early aging indication
would also be permissible under the First Amendment using the
analytical framework provided in Central Hudson Gas & Electric
Corporation v. Public Service Commission, 447 U.S. 557 (1980). Under
Central Hudson, commercial speech that is false, misleading, or
concerns unlawful activity is not entitled to protection under the
First Amendment. While commercial speech that concerns lawful activity
and is not misleading receives some protection under the First
Amendment, it may nonetheless be regulated by the Government if the
following conditions are met: (1) The asserted governmental interest is
substantial; (2) the regulation directly advances the asserted
governmental interest; and (3) the regulation is not more restrictive
than necessary to serve that interest (Id. at 566). The Supreme Court
has explained that the last element of the Central Hudson test is not a
``least restrictive means'' requirement but, rather, requires narrow
tailoring (i.e., ``a fit that is not necessarily perfect, but
reasonable'' between means and ends) (Board of Trustees of the State
Univ. of N.Y. v. Fox, 492 U.S. 469, 480 (1989)). In subsequent
decisions, the Court has also clarified that ``misleading'' in the
first element of the test refers to speech that is inherently or
actually misleading.
Based on the data currently available, we have concluded that the
following statements or omissions would be false or inherently
misleading: (1) Use of the skin cancer/early aging indication on the
labeling of a sunscreen product that does not provide broad spectrum
protection with an SPF value of 15 or higher, (2) the omission of the
``Skin Cancer/Skin Aging Alert'' under the ``Warnings'' heading of the
labeling for sunscreen products that do not provide broad spectrum
protection with an SPF value of 15 or higher, and (3) use of the skin
cancer/early aging indication that omits the required information about
using the product as directed with other sun protection measures.
Use of the skin cancer/premature aging indication on the labeling
of covered sunscreen products that do not provide broad spectrum
protection with an SPF value of 15 or higher would be false or
inherently misleading for several reasons. As discussed elsewhere in
this document, only broad spectrum UV radiation is classified as a
known human carcinogen, according to the National Toxicology Program.
Therefore, covered sunscreen products that do not provide broad
spectrum UV protection may not reduce the risk of skin cancer.
Furthermore, since the precise wavelengths of UV radiation that cause
skin cancer and early skin aging are unknown, a covered sunscreen
product that only provides protection against part of the UV spectrum
may not ensure a reduction in the risk of developing skin cancer or
early skin aging. In addition, all of the scientific data that support
the skin cancer/early aging indication for certain covered sunscreens
were derived from studies that used sunscreen products with an SPF
value of 15 or higher. Therefore, the skin cancer/early aging
indication would be false or inherently misleading on covered sunscreen
products that do not provide this level of protection, because there is
a lack of any evidence demonstrating that these products would reduce
the risk of skin cancer or early skin aging. Similarly, omitting the
``Skin Cancer/Skin Aging Alert'' on these products, which are
identified on their labels as ``sunscreens,'' would be inherently
misleading because consumers who are using these products for sun
protection would not be sufficiently alerted to the fact that these
products have been shown only to
[[Page 35641]]
protect against sunburn, while sun exposure also increases the risks of
skin cancer and early skin aging.
A skin cancer/early aging indication on a covered product with
Broad Spectrum SPF value of 15 or higher that omits the required
information about using the product as directed with other sun
protection measures would also be false or inherently misleading
because sunscreen use alone has not been shown to reduce the risk of
skin cancer or early skin aging if a consumer increases overall UV
exposure by spending greater time in the sun and/or wearing less
protective clothing. As discussed above in this section and elsewhere
in this document, without the reduction in consumers' overall UV
exposure, a covered sunscreen product may not be effective in reducing
consumers' risk of skin cancer and early skin aging.
We also conclude that the labeling claims and omissions described
above would cause the product to be misbranded and, therefore, relate
to an unlawful activity. As described earlier in this section and
elsewhere in this document, labeling regulations establish certain
requirements that help ensure the safe and effective use of OTC drug
products. The false or misleading labeling described above would cause
covered products to be misbranded under section 502 of the act.
Therefore, such labeling would concern the illegal sale of misbranded
drugs. Under the Central Hudson test, then, we have not violated the
First Amendment with these requirements, which simply prohibit false or
inherently misleading labeling.
Although we conclude that the labeling described above would not be
entitled to First Amendment protection under the threshold inquiry of
the Central Hudson test, we conclude that our regulation directly
advances a substantial Government interest and is no more extensive
than necessary, and therefore would also pass muster under the test's
three remaining steps. Under the first remaining step, we have a
substantial interest in protecting public health (see Pearson v.
Shalala, 164 F.3d 650, 656 (DC Cir. 1999) (citing Rubin v. Coors
Brewing Co., 514 U.S. 476, 484-485 (1995)).
Under the second remaining step of the Central Hudson test, our
labeling requirements discussed in this section directly advance the
Government's interests in protecting public health because they help
ensure that covered sunscreen products are adequately labeled for safe
and effective use by consumers.
As stated previously in this document, scientific evidence only
supports the skin cancer/premature aging indication for sunscreen
products that provide broad spectrum protection with an SPF value of 15
or higher. Allowing the skin cancer/early aging indication on sunscreen
products for which it is not scientifically supported would lead to
consumers unjustifiably relying on such products for protection against
skin cancer and early skin aging. Furthermore, the ``Skin Cancer/Skin
Aging Alert'' allows consumers to be aware that spending time in the
sun increases their risk of skin cancer and early skin aging, and that
products on which this alert appears have not been shown to provide
this type of protection. The requirement for information in the skin
cancer/early aging indication about using sunscreens as directed with
sun protection measures also directly advances our interest in
protecting public health because these elements are essential for
consumers to reduce their overall UV exposure and, consequently, their
risk of developing skin cancer and early skin aging. Thus, these
requirements directly advance the Government's interest in protecting
public health through the safe and effective use of sunscreens.
Under the final remaining step of the Central Hudson test, our
requirements concerning the skin cancer/early aging indication are not
more restrictive than necessary, because there are not numerous and
obvious alternatives (Cincinnati v. Discovery Network, 507 U.S. 410,
418 n. 13 (1993)) to achieve the Government's substantial interests. By
permitting the skin cancer/early aging indication only for covered
sunscreen products with Broad Spectrum SPF values of 15 or higher, and
requiring the ``Skin Cancer/Skin Aging Alert'' for products that do not
offer this level of protection, we are ensuring that consumers do not
mistakenly rely on sunscreen products that have not been demonstrated
to be effective for protection against skin cancer and early skin
aging. In addition, labeling that omits a statement regarding the use
of other sun protection measures as directed from the skin cancer/early
aging indication could lead to consumers foregoing other sun protection
measures, thereby negating the protective effect of the sunscreen.
Including a statement in the skin cancer/early aging indication
regarding the need to follow other sun protection measures as well as
the related directions ensures that consumers understand how to use
sunscreens to reduce their risk of skin cancer and early skin aging.
It is important to note that manufacturers of OTC sunscreens
covered by this rule have several alternatives for adding labeling
information that is not included in this labeling regulation. For
example, such manufacturers can file an NDA under section 505 of the
FD&C Act or submit a petition under 21 CFR 10.30 to amend the labeling
regulation. In either case, the manufacturer need only submit the
requisite evidence to support the indication or other labeling for the
product that differs from that addressed by the regulation. Therefore,
we are not being more restrictive than necessary when these viable
alternatives are available for manufacturers.
Reacting to the fact that our proposed rule did not permit any
indication statement for any sunscreen regarding prevention of skin
cancer and early skin aging, one submission asserted that we must
consider use of a disclaimer as an alternative means of addressing the
limits of the product's effectiveness. As noted previously in this
document, this final labeling regulation permits an appropriately
limited indication for broad spectrum sunscreens with SPF values of 15
or higher--one stating that when used as directed with other sun
protection measures, such products decrease the risk of skin cancer and
early skin aging caused by the sun. The claim is authorized for this
subset of covered sunscreen products because available scientific data
discussed elsewhere in this document are sufficient to substantiate the
claim for these products. Because we have included a skin cancer/early
skin aging claim in these labeling regulations, we no longer view the
submission's request as being applicable.
In any event, we note that the use of disclaimers on drug labeling
to qualify inadequately supported or unapproved indications is not an
effective, less restrictive means of achieving FDA's substantial
interests in protecting public health and preserving the integrity of
its premarket approval systems. Indeed, disclaimers on drug labeling
would severely undermine the Government's interests here. For over 100
years, Congress has charged FDA with enforcing misbranding laws to
protect public health. In 1962, Congress amended the FD&C Act to
require that all new drugs be approved as both safe and effective prior
to marketing. Congress found that a premarket approval system,
requiring specific types of supporting evidence (see 21 U.S.C. 355(d)),
and misbranding provisions, among other requirements, were necessary to
avoid further tragedies involving unsafe and ineffective drugs. Using
disclaimers for drugs would completely undermine the
[[Page 35642]]
regulatory framework established by Congress for the protection of
public health. FDA's labeling regulations help ensure the safety and
effectiveness of OTC drugs and establish the conditions under which a
drug is not misbranded under the FD&C Act. If a manufacturer of a
covered sunscreen would like to label its sunscreen product in a way
that does not conform to this labeling regulation, it cannot circumvent
the premarket NDA process.
In summary, we conclude that the labeling requirements provided in
this document do not violate the First Amendment.
F. Other Information
We received submissions requesting that we add a new statement
about storage conditions under ``Other information'' in the Drug Facts
label (Ref. 1). The submissions argued that sunscreen products in
containers are often exposed to heat when used at the beach, swimming
pools, etc. The concern expressed in the submissions was that heat
could cause sunscreen formulations inside containers to change,
resulting in less sun protection. We agree with the submissions.
Sunscreen products within containers should not be exposed to direct
sun and can be protected by wrapping them in towels and/or keeping them
in shaded environments (e.g., under an umbrella and/or in a purse or
bag). Consumers could also store sunscreen product containers in
coolers while outside during hot periods. In this final rule we are
requiring the following statement in the ``Other information'' section
of the Drug Facts label: ``[Bullet] protect the product in this
container from excessive heat and direct sun'' (new 21 CFR 201.327(f)).
In addition to the statement about storage conditions, we received
numerous submissions requesting that we relocate the proposed ``sun
alert'' warning to the ``Other information'' section of the Drug Facts
label. The submissions argued that the ``sun alert'' is an educational
statement and not a warning: ``UV exposure from the sun increases the
risk of skin cancer, premature skin aging, and other skin damage. It is
important to decrease UV exposure by limiting time in the sun, wearing
protective clothing, and using a sunscreen.''
As already discussed, in light of our re-evaluation of the evidence
supporting the indications for sunscreens, we have made changes to the
labeling to more accurately convey appropriate information to consumers
about the benefits, directions, and limitations of two different groups
of products covered by the rule--those that provide broad spectrum
protection with an SPF value of 15 or higher, and those that do not. We
do not agree that this information belongs under the heading ``Other
information'' but have included it in modified form under the headings
Uses and Directions for products with Broad Spectrum SPF values of 15
or higher (new 201.327(c)(2) and (e)(2), and under a revised ``Skin
Cancer/Skin Aging Alert'' under the heading Warnings for other
sunscreens (new 201.327(d)(2)).
In this document, we are also removing the optional ``Other
information'' statements in proposed 21 CFR 352.52(e):
1. ``Low,'' ``medium,'' ``high'' or ``highest'' ``sunburn
protection product''
2. ``Higher SPF products give more sun protection, but are not
intended to extend the time spent in the sun.''
According to the 2007 proposed rule, these statements could appear in
``Other information'' or anywhere outside Drug Facts. However, in this
rule, we have revised the labeling and are no longer requiring the
principal display panel to characterize the level the sunburn
protection. Rather, for broad spectrum products, the rule requires only
the statement ``Broad Spectrum SPF [fill in tested SPF value]'' to
appear on the principal display panel. In light of this revised
approach to labeling, we are concerned that including the
characterizations of the product as providing ``low,'' ``medium,''
``high'' or ``highest'' ``sunburn protection would be confusing or
misleading, and are no longer including it as an option.
We have concluded that the second statement, although truthful, is
not necessary. Consumers likely understand the first part of this
statement (higher SPF values represent more sun protection) based on
the long-standing inclusion on SPF values on OTC sunscreen products.
The second part of the statement (higher SPF products are not intended
to extend time spent in the sun) is redundant with the information
already provided under ``Uses'' and ``Directions,'' particularly
concerning the need for limiting time in the sun (see sections IV.B and
IV.D). Although we are not requiring inclusion of the second statement
under ``Other information,'' the statement may appear outside the Drug
Facts label because it is truthful and nonmisleading.
G. Reduced Labeling
Five submissions requested changes to our proposed regulations
allowing reduced labeling for sunscreen products sold in small packages
(i.e., packages which meet the requirements in 21 CFR 201.66(d)(10))
that are labeled for use only on small areas of the face. One
submission stated that all cosmetic products labeled with sunscreen
indications should be required to include all sunscreen product
labeling.
After reassessing the criteria for reduced labeling, we are not
allowing the reduced labeling included in the 2007 proposed rule. OTC
drug labeling regulations (21 CFR 201.66(d)(10)) allow reduced labeling
for any OTC drug product sold in a small package, including sunscreen
products. In the 2007 proposed rule, we proposed additional reductions
in labeling for three types of sunscreen products sold in small
packages and intended for use on small areas of the face:
Proposed 21 CFR 352.52(f)(1)(i)-(f)(1)(iv): Sunscreen
products sold in small packages and labeled for use specifically on the
lips, nose, ears, and/or around the eyes (i.e., small areas of the
face)
Proposed 21 CFR 352.52(f)(1)(v): Sunscreen-lip protectant
combination products sold in small packages
Proposed 21 CFR 352.52(f)(1)(vi): Sunscreen products
formulated as lipsticks, lip products that prolong wear of lipstick,
lip gloss, and lip balms
Three submissions argued that we should not restrict labeling
exemptions only to sunscreen products sold in small packages and
labeled for use on small areas of the face. The submissions stated that
reduced labeling provisions should apply to all sunscreen products sold
in small packages whether or not they are labeled for use on small
parts of the face. Two of the submissions argued that such a
restriction violates the Administrative Procedures Act (APA). The
submissions cite Bracco Diagnostics, Inc., v. Shalala 963 F. Supp. 20,
27-28 (D.D.C. 1997) as evidence that the courts oppose regulations
requiring ``two sets of similar products to run down two sets of
separate [regulatory] tracks * * * for no apparent reason.''
In this document, we continue to allow the reduced labeling
specified in 21 CFR 201.66(d)(10). Therefore, if the information listed
under Drug Facts requires more than 60 percent of the total available
surface area, the Drug Facts labeling can be reduced by making the
formatting changes specified in 21 CFR 201.66(d)(10)(i)-(d)(10)(v).
However, in contrast to the 2007 proposed rule, we are not allowing
additional reductions in labeling for any sunscreen products.
When we proposed the additional reduced labeling, we recognized
that many of the sunscreen products sold in
[[Page 35643]]
small packages and labeled for use on small areas of the face could not
accommodate full Drug Facts labeling. However, in the last several
years, manufacturers have introduced new label designs that permit full
Drug Facts labeling on very small packages. For example, some stick
products, including lip protectant-external analgesic combinations
marketed in 0.15 oz. amounts, have been labeled with wrap-around labels
that contain full Drug Facts labeling. If these products can be labeled
to accommodate full Drug Facts labeling, then all sunscreen products
should be able to accommodate full Drug Facts labeling. Requiring full
Drug Facts labeling should not discourage manufacturers from including
sunscreen ingredients because of limited labeling space, as stated in
the 2007 proposed rule (72 FR 49070 at 49075 through 49077). Therefore,
in this document, we are eliminating all of the allowances for reduced
labeling in proposed 21 CFR 352.52(f). Sunscreen products can only have
reduced labeling for formatting if they meet the criteria in 21 CFR
201.66(d)(10).
V. Miscellaneous Labeling Outside Drug Facts
We received several submissions regarding various performance
claims, including comments asking us to allow claims for protection
immediately upon application (instant protection) and for extended
duration between applications (extended wear) and comments asking us
not to allow terms such as ``sunblock,'' ``waterproof,'' and
``sweatproof'' (Ref. 1). These kinds of claims were not included in the
2007 proposed rule (Ref. 1).
We are not including labeling in 21 CFR 201.327 permitting these
claims on OTC sunscreen products covered by the rule. The current
record does not contain support for any of these kinds of claims. To
clarify the status of these kinds of claims, we are finalizing two
provisions. We include instant protection and extended wear claims,
which are claims that we think may be capable of substantiation, in 21
CFR 310.545(a)(29)(ii). While these claims may not be included on
products marketed without approved applications, including them in this
provision makes it clear that these claims may be substantiated for an
individual product by the submission of adequate data in an NDA.
We agree with the submissions that argue that ``sunblock,''
``waterproof,'' and ``sweatproof'' claims are false or misleading, as
we have stated in previous sunscreen rulemakings (58 FR 28194 at 28228;
64 FR 27666 at 27676 through 27680). These terms are essentially
exaggerations of performance that FDA does not think can be
substantiated. Accordingly, in this final rule, we codify these as
terms or phrases that would be false or misleading on covered products,
and are therefore prohibited (21 CFR 201.327(g)).
In addition to submissions requesting that we allow certain
labeling outside Drug Facts, we also received a submission requesting
that we require information about the UV index (UVI). A stated in the
2007 proposed rule, we have determined that the usage information
provided on OTC sunscreen products applies regardless of the UVI value
(72 FR 49070 at 49073). Therefore, we will allow but do not require
information about the UV index to be included on sunscreen products
outside the Drug Facts label.
A submission requested that we require that the UV index appear on
sunscreen product labels because this information would help consumers
understand and use the UV index to determine their risk of sunburn. The
UV index was developed in 1995 by the National Weather Service,
Environmental Protection Agency, and Centers for Disease Control and
Prevention to provide a forecast of the expected risk of overexposure
to UV rays. The UV index is calculated using ozone data, atmospheric
pressure, temperature, and cloudiness. As stated in the 2007 proposed
rule, we are not requiring labeling of UV index information because it
is not necessary for consumers to understand this index in order to
safely and effectively use OTC sunscreen products (72 FR 49070 at
49073). However, manufacturers may include truthful and nonmisleading
information about the UV index in the labeling outside of Drug Facts if
they choose.
We also received a submission requesting that we allow a claim of
``instant protection'' and to allow claims for extended periods of
protection between applications (i.e., longer than the 2 hours
specified in ``Directions'' in the 2007 proposed rule). The submission
argued that several marketed products provide sunburn protection
immediately upon application, as demonstrated by test results included
in the submissions. In this document, SPF testing requires a 15-minute
waiting period between sunscreen application and UV exposure of the
test site. It appears that the submitted test method included the same
15-minute waiting period. Therefore, the assertion that this product
provides ``instant protection'' does not appear to be substantiated. We
also did not receive any data regarding claims for extended periods of
use, so it is not clear whether these claims are truthful. Claims that
a product provides for an extended period of protection between
applications or immediately upon application would have to be supported
by data. Therefore, these claims could be made only under approved new
drug applications (NDAs) with the required data.
In this document, we are specifically identifying these claims as
not allowed on any OTC sunscreen product, regardless of SPF value or
broad spectrum protection, without an approved application containing
sufficient substantiation to support the claim. (new 21 CFR
310.545(a)(29)(ii)):
Instant protection or protection immediately upon
application
Claims for ``all-day'' protection or extended wear claims
citing a specific number of hours of protection that are inconsistent
with the directions for application in 21 CFR 201.327.
In addition, we are identifying the terms ``sunblock''
``waterproof,'' and ``sweatproof'' as false and misleading, as we have
stated in previous sunscreen rulemakings:
Sunblock (64 FR 27666 at 27679 and 27680)
Sweatproof (58 FR 28194 at 28227 through 28228)
Waterproof (58 FR 28194 at 28227 through 28228).
We have previously identified these claims as ones that would
render a product misbranded but are addressing them again in this
document because OTC sunscreen products currently marketed without
approved applications continue to contain the claims. In this final
rule, we are listing these false and misleading terms in 21 CFR
201.327(g). These terms may not be included on any OTC sunscreen
products covered by the rule.
Finally, in the 2007 proposed rule, we proposed to specify other
optional statements that could be included outside of Drug Facts in
proposed 21 CFR 352.52(e)(3):
``Broad spectrum sunscreen''
``Provides [select one of the following: `UVA and UVB' or
`broad spectrum'] protection''
``Protects from UVA and UVB [select one of the following:
`rays' or `radiation']''
``[Select one of the following: `absorbs' or `protects']
within the UVA spectrum.''
This final rule is not a monograph, and we do not consider it
necessary in this rule to codify optional statements for use outside of
``Drug Facts.'' The labeling required in this document
[[Page 35644]]
should provide consumers with the information that they need to safely
and effectively use the sunscreen products that it addresses. Under
this final rule, products marketed without approved applications that
provide broad spectrum protection according to the test in new 21 CFR
201.327(j) of this document will be identified on the PDP by use of the
term ``Broad
Spectrum SPF.'' In light of this requirement in the rule for use of
the term ``broad spectrum'' on these particular products, including a
statement anywhere in the labeling of a product that does not pass the
broad spectrum test in 21 CFR 201.327(j) that suggests or implies that
the product provides broad spectrum protection would misbrand that
product. We likewise caution against references to ``UVA'' (or ``UVA/
UVB'') protection on products that do not provide broad spectrum
protection as demonstrated by the test in 21 CFR 201.327(j). Such
labeling would misbrand the products if it misleadingly suggests that
the products provide protection that is equivalent or greater to that
provided by products labeled with ``Broad Spectrum SPF'' values or is
otherwise false or misleading.
VI. SPF Test Parameters
The 2007 proposed rule included the SPF test from the 1999 final
rule with revisions to a few test parameters. In response to the 2007
proposed rule, we received numerous submissions requesting that we
revise additional test parameters (Ref. 1). In this document, we have
rewritten the regulations describing the SPF test in an effort to make
it easier to read and understand and to more closely follow the order
in which steps of the SPF testing procedure are conducted. We have also
made several revisions to the test parameters. However, we did not make
all of the revisions requested in the submissions. Table 4 of this
document summarizes test parameters that we considered revising. The
table identifies the parameters that we are changing in this document
as well as those that we are not changing. Detailed discussion of each
test parameter appears throughout the remainder of this section.
Table 4--Summary of SPF Test Parameters Included in the 2007 Proposed
Rule and This Final Rule
------------------------------------------------------------------------
2007 Proposed rule This final rule
------------------------------------------------------------------------
21 CFR 352.70(a). Standard sunscreens 21 CFR 201.327(i)(2). SPF
standard
Two standards: One standard:
8% homosalate (SPF 2-- <= 15) 7% padimate, 3%
oxybenzone (all SPFs)
7% padimate, 3% oxybenzone (SPF > 15)
HPLC reference standard: HPLC reference standard:
no limits set for accuracy of limit set to within 5% of
oxybenzone & padimate O theoretical for accuracy
of oxybenzone & padimate
O
21 CFR 352.70(b). Light source (solar 21 CFR 201.327(i)(1). UV
simulator) source (solar simulator)
Emission spectrum specifications: Emission spectrum
specifications:
(1) COLIPA \1\ 1994 (Ref. 63) (1) COLIPA \1\ 2006 (Ref.
64)
(2) no specifications for UVA (2) specifications for
UVA I and UVA II
percentages of total UV
Calibration: Calibration:
every 6 months at least annually
Total irradiance: Total irradiance:
1500 Watts/square meter (W/m\2\) 1500 Watts/square meter
(W/m\2\)
Beam uniformity: Beam uniformity:
within 20 percent within 20 percent
21 CFR 352.70(c)(7). Number of subjects 21 CFR 201.327(i)(3). Test
subjects
SPF < 30: All SPFs:
20-25 subjects; >= 20 valid results 10-13 subjects;
>= 10 valid results
SPF >= 30:
25-30 subjects; >= 25 valid results
21 CFR 352.70(c)(4). Test site delineation/ 21 CFR 201.327(i)(4)(i) and
subsite (ii). Test site/subsite
test site area: test site area:
>= 50 cm\2\ >= 30 cm\2\
test subsite area: test subsite area:
>= 1 cm\2\ >= 0.5 cm\2\
Distance between subsites: Distance between subsites:
>= 1 cm >= 0.8 cm
21 CFR 352.70(c)(5). Application of test 21 CFR 201.327(i)(4)(iii).
materials Applying test materials
Application amount: Application amount:
2 milligrams per square centimeter (mg/ 2 milligrams per square
cm\2\) centimeter (mg/cm\2\)
Presaturation of finger cot: Presaturation of finger cot:
Required not required
Water-resistant statement requirements: Water-resistant statement
requirements:
20 minute water immersion times 20 minute water immersion
times
20 minute drying times 15 minute drying times
21 CFR 352.70(d)(3). Determination of 21 CFR 201.327(i)(5). UV
individual SPF values exposure
Definitions of MED: Definitions of MED:
(1) MED(PS) = MED for protected skin (1) ssMEDp = MED for skin
protected by sunscreen
standard
(2) MED(US) = MED for unprotected skin (2) tpMEDp = MED for skin
protected by test
product
(3) initial MEDu = MED
for unprotected skin
prior to testing test
product
(4) final MEDu = MED for
unprotected skin
determined when testing
test product
UV doses for MED(US): UV doses for initial MEDu:
[[Page 35645]]
five doses number of doses not
specified
21 CFR 352.70(c)(8) Response criteria 21 CFR 201.327(i)(5). UV
exposure
Maximal UV exposure: Maximal UV exposure:
``no more than twice the total energy not specified
of the minimal exposure''
------------------------------------------------------------------------
\1\ Draft test method entitled ``International Sun Protection Factor
(SPF) Test Method'' developed by the European Cosmetic, Toiletry and
Perfumery Association (COLIPA).
We are not making some of the requested changes to certain test
parameters because we lack adequate data to determine whether these
changes would change the accuracy or reproducibility of the SPF test.
We are making changes to some test parameters based on the following
developments since the 2007 proposed rule published:
New data (submitted by the public or published in the
scientific literature)
Technical improvement of SPF testing equipment
Accumulating experience in the performance of SPF testing
Efforts towards international harmonization of SPF testing
procedures
In support of the requested changes, several submissions (Ref. 1)
cited differences between the SPF test in the 2007 proposed rule and
the COLIPA SPF test (Ref. 64). The COLIPA SPF test is a joint effort by
the cosmetic industry trade associations in Europe, Japan, South
Africa, and the United States to harmonize SPF test procedures. The
International Organization for Standardization (ISO) is currently
developing an SPF test method. Because harmonization of testing methods
is important, we are actively involved in the ISO working group
responsible for developing methods for assessing the efficacy of sun
protection products.
We are revising our proposed SPF test method to be as consistent as
possible with the COLIPA SPF test. We acknowledge the merits of
harmonizing test methods and are an active participant in ongoing
harmonization efforts. However, some of the test parameters in this
document differ from comparable parameters in the COLIPA SPF test
because we have concluded that the data do not support using the COLIPA
SPF test parameters. Throughout the remainder of this section, we
discuss whether test parameters in this document match or do not match
those in the COLIPA SPF methods.
A. Solar Simulator
Several submissions recommended adopting the solar simulator
specifications in the COLIPA SPF test (Ref. 1). We are revising solar
simulator specifications to:
Allow the use of smaller beam, multiport simulators
Adjust the relative cumulative erythemal effectiveness
(RCEE) range specifications for each wavelength band
Specify that UVA II (320-340 nm) and UVA I (340-400 nm)
irradiance should equal or exceed 20 percent and 60 percent,
respectively, of the total UV (290-400 nm) irradiance
Change the regular calibration period from every 6 months
to at least once a year
These changes are consistent with the COLIPA SPF test. More
importantly, these revisions will allow the SPF test to continue to be
accurate and reproducible. For example, we received calibration data
demonstrating that solar simulators and their UV lamps are stable for
periods longer than 1 year. Therefore, the requirement in the 2007
proposed rule to calibrate every 6 months is unnecessary. The test
results should be the same whether calibration is done annually or
every 6 months.
In contrast, we are not changing the following solar simulator
specifications because changes to these specifications could reduce
test accuracy and/or reproducibility:
Total irradiance limit of 1500 W/m\2\
Total irradiance range of 250-1400 nm
20 percent beam uniformity requirement.
These test specifications differ from the COLIPA SPF test, which
recommends a 1600 W/m\2\ limit and a 10 percent beam uniformity
requirement.
Two submissions (Ref. 1) objected to limiting total solar simulator
irradiance to 1500 W/m\2\ for all wavelengths between 250 and 1400 nm
(proposed 21 CFR 352.70(b)(1)). We proposed the 1500 W/m\2\ limit
because we were concerned that solar simulators operating above this
limit could cause excessive heat. Excessive heat could harm test
subjects and/or cause loss of dose reciprocity, the correlation between
UV dose and resulting erythema. One submission argued that no data
indicate that exceeding 1500 W/m\2\ causes excessive heat or affects
SPF test results. The submission argued that higher intensities should
be allowed as long as they are thermally tolerated by test subjects,
because allowing higher intensities enables faster SPF testing.
We are not changing the 1500 W/m\2\ total irradiance limit. We do
not have data demonstrating that exceeding 1500 W/m\2\ leads to loss of
dose reciprocity. However, we conclude that the limit should be
retained to protect test subjects. The COLIPA SPF test cites a study
showing that total irradiance of 1600 W/m\2\ induces heat and pain in a
majority of test subsites, and recommends keeping total irradiance
below 1600 W/m\2\ (Ref. 64). Therefore, we are keeping the 1500 W/m\2\
total irradiance limit (new 21 CFR 201.327(i)(1)(i)).
One submission also objected to the 250-1400 nm range over which
total irradiation should be monitored (Ref. 1). The submission argued
that portable spectroradiometers are typically incapable of measuring
wavelengths out to 1400 nm. According to the submission, emissions from
longer wavelengths have not been shown to affect SPF testing.
We are not changing the requirement that total irradiation be
monitored over a range of 250-1400 nm. We have concluded that
monitoring over this range of wavelengths helps protect SPF test
subjects from being exposed to undesirable, unnecessary radiation. The
requirement should not impose undue hardship, because longer
wavelengths can be monitored using a thermopile, pyroelectric, or
similar detectors.
We received two submissions addressing the requirement in proposed
21 CFR 352.70(b)(2) that a solar simulator have ``good beam uniformity
(within 20 percent) in the exposure plane'' (Ref. 1). One submission
argued that advances in equipment and monitoring allow for a stricter
beam uniformity requirement (<20 percent), which would result in less
variability in SPF test results. Another submission argued that the
beam uniformity
[[Page 35646]]
requirement is only important for large diameter beams and has no
impact on SPF testing using small beams.
We are not changing the 20 percent beam uniformity requirement
because accurate determination of SPF values relies upon good beam
uniformity for all beam sizes. In the 2007 proposed rule, we described
how small diameter beams can be tested for beam uniformity (see 72 FR
49070 at 49098). The submission requesting stricter requirements did
not include data showing that current solar simulators can reasonably
be expected to have beam uniformity less than 20 percent. We conclude
that a 20 percent beam uniformity requirement is adequate to produce
reliable SPF results. Therefore, we are keeping the requirement that
solar simulators demonstrate good beam uniformity (within 20 percent)
in new 21 CFR 201.327(i)(1) (iii).
B. Sunscreen Standards
The 2007 proposed rule include two sunscreen standards for use in
SPF testing. The two proposed sunscreen standards were a 7 percent
padimate O/3 percent oxybenzone standard (mean SPF value of 16.3) and
an 8 percent homosalate standard (mean SPF value of 4.47). For SPF
testing of sunscreen products with SPF values of 2 to 15, either the
padimate O/oxybenzone standard or the homosalate standard would have
been required to be tested along with the test sunscreen product. Tests
for sunscreen products with SPF values over 15 would have required use
of the padimate O/oxybenzone standard.
We received two requests to include an additional sunscreen
standard with an SPF value of 30 or higher to test sunscreen products
with SPF values of 30 or more (Ref. 1). Neither request specified any
particular sunscreen standard formulation with an SPF in this range. If
a particular sunscreen standard formulation were specified, we would
also need validation data to support including the additional sunscreen
standard in the monograph. Therefore, we are not including a sunscreen
standard with an SPF value of 30 or more in this document.
We also received a request to include the JCIA SPF 15 `P3'
sunscreen standard containing 0.5-percent avobenzone, 3-percent octyl
methoxycinnamate, and 2.78-percent phenylbenzimidazole sulfonic acid.
To support including the ``P3'' standard, the request included a table
showing mean, maximum, and minimum SPF values from tests conducted in
labs in Europe, Japan, Australia, and South Africa. We recognize that
the ``P3'' standard has been widely used and is included in the COLIPA
SPF test, but we are not including the ``P3'' standard in this
document. In the 2007 proposed rule (72 FR 49070 at 49095 to 49095), we
requested further data to show that testing using the ``P3'' standard
could be performed with:
Low level interlaboratory variation
Sufficient sensitivity to detect experimental error
A reasonable degree of accuracy
The submitted data (i.e. the table of SPF values) fail to show that the
``P3'' standard meets these performance requirements because they do
not show:
Individual lab results
The number of tests conducted in each lab
The number of test subjects used in each test
Calculated standard errors for each test
Without these data, we cannot assess interlaboratory variability,
sensitivity to experimental error, or test result accuracy. In
addition, the advantage of using the ``P3'' standard instead of the
padimate O/oxybenzone standard is unclear, because both these standards
have approximately the same SPF value of 16. Therefore, we are not
including the ``P3'' standard in this document.
We are also eliminating the proposed homosalate standard with an
SPF value of 4.47 because the padimate O/oxybenzone standard with an
SPF value of 16.3 is adequate for validating all test methodologies. In
the 2007 proposed rule, we stated that the sunscreen standards were
``method controls rather than calibration tools.'' As a method control,
the purpose of the sunscreen standard is verifying proper and
consistent performance of test equipment and procedures, rather than
verifying the accuracy of the SPF value determined for sunscreen test
products. Therefore, we conclude that it is not critical for the SPF
value of the sunscreen standard to be close to the SPF value of the
sunscreen test product. It is more important that the sunscreen
standard demonstrate consistency of test performance. Consequently, we
have concluded that including multiple sunscreen standards is
unnecessary, and that the padimate O/oxybenzone standard is a suitable
sunscreen standard for all sunscreen products. We favor including the
padimate O/oxybenzone standard over the homosalate standard because the
homosalate standard was only proposed for use for SPF testing of
sunscreen products with SPF values lower than 15. Because most
currently marketed sunscreen products have SPF values of 15 or higher,
the padimate O/oxybenzone standard is used much more frequently than
the homosalate standard.
We received one submission identifying errors in the ``Composition
of the Padimate O/Oxybenzone Standard Sunscreen'' table that appears in
the 2007 proposed rule. As suggested by the submission, we are moving
the inactive ingredient ``propylparaben'' from ``Part A'' to ``Part
B,'' as it appears in the COLIPA SPF test. We are not revising the
listing of the inactive ingredient ``glyceryl monostearate'' to read
``glyceryl monostearate (Glyceryl Stearate SE),'' as suggested. The
United States Pharmacopeia defines ``glyceryl monostearate'' as an
``emulsifying and/or solubilizing agent,'' which adequately describes
the ingredient that is appropriate for use in the formulation.
C. Test Subjects
In the 2007 proposed rule, we proposed requiring the following
numbers of test subjects providing valid results:
20 to 25 subjects for sunscreen products with SPF less
than 30
25 to 30 subjects for sunscreen products with SPF value of
30 or more
We explained that a minimum of 20 subjects would be required to provide
an acceptably accurate SPF result (i.e., low standard error of the
mean). We had concluded that sunscreen products with SPF values of 30
or more required a greater number of test subjects because we suspected
higher test result variability for these sunscreen products. However,
the data used for determining appropriate test subject numbers were
limited and dated. Therefore, we invited submission of additional data
demonstrating what subject numbers would be adequate.
Several submissions recommend requiring 10 to 25 test subjects as
in the COLIPA SPF test (Ref. 1). These submissions include data
demonstrating that SPF testing can be performed with suitable accuracy
and precision with as few as 10 test subjects. The submissions further
argued that SPF testing using a minimum of 10 test subjects has been
practiced globally for many years, even for sunscreen products with
high SPF values.
We agree with the submissions and are lowering the number of test
subjects required for SPF testing. We are requiring that a test panel
produce a minimum of 10 valid test results. A maximum of three subjects
may be rejected from the panel. Therefore, if 3 subjects would be
rejected, a test panel would have had to include 13 subjects.
We are reducing the number of test subjects in this document
because the
[[Page 35647]]
data we received demonstrate that SPF testing can be conducted with
adequate accuracy and precision using as few as 10 test subjects, even
when testing high SPF products. The submissions include SPF test
results for several sunscreen formulations using panels of 20 to 25
test subjects. We randomly selected 10 subjects within each of these
panels to determine if using fewer subjects significantly decreased
test accuracy and precision. For each of these panels, the mean SPF
value and standard error calculated from a randomly selected subset of
10 subjects were not significantly different from those calculated from
all 20 to 25 subjects in the panel. Therefore, these data indicate that
using as few as 10 test subjects will not compromise SPF test accuracy
or precision. Consequently, fewer test sites and subsites need to be
tested and fewer test results need to be rejected, thereby decreasing
the number of test subjects needed. Our revised SPF test subject number
requirement is similar to the COLIPA SPF test requirement. The only
significant difference related to test subject number is that we are
not including a statistical requirement or allowing individual subjects
to be added incrementally to a test panel as allowed under the COLIPA
SPF test.
D. Test Sites and Subsites
Several submissions requested the following revisions of the
minimum size specifications for test sites and subsites proposed in the
2007 proposed rule (Ref. 1):
Test site: proposed 50 cm\2\ revised to 30 cm\2\
Test subsite: proposed 1 cm\2\ revised to 0.5 cm\2\
Subsite separation: proposed 1 cm revised to 0.8 cm
According to the submissions, these smaller revised minimum sizes would
allow multiport solar simulators to be used, while the larger proposed
sizes would not. These revised specifications have also been adopted in
the COLIPA SPF test (Ref. 64).
We are revising the test site and subsite size specifications as
requested by these submissions. Our previously proposed specifications
were based on single port solar simulators. Some new multiport solar
simulators cannot meet these proposed specifications. In the 2007
proposed rule, we stated that reducing test site/subsite size
specifications would be considered if data were submitted showing that
these reductions would not compromise testing accuracy (72 FR 49070 at
49100). New data show that SPF testing can still be accurately
performed using the recommended reduced test site/subsite size
specifications (Ref. 1). Therefore, we are revising the test site/
subsite size specifications to accommodate new equipment and to
harmonize our specifications with global SPF test methods.
E. Finger Cot
In the 2007 proposed rule, we proposed that a finger cot,
presaturated with sunscreen, be used to apply the sunscreen in the SPF
test (proposed 21 CFR 352.70(c)(5)):
Use a finger cot compatible with the sunscreen to spread the
product as evenly as possible. Pretreat the finger cot by saturating
with the sunscreen and then wiping off material before application.
Preteatment is meant to ensure that sunscreen is applied at the
correct density of 2 mg/cm \2\.
We received one submission that objected to the use of finger cots
because consumers do not typically use finger cots when applying
sunscreens (Ref. 1). Other submissions argued that the presaturation
requirement for finger cots is unnecessary and introduces variability
in applied amounts (Ref. 1). Other submissions requested the optional
use of sponge applicators for testing powder formulations, because they
argued that sponge applicators distribute powder formulations more
evenly than finger cots (Ref. 1). We are not addressing issues
regarding the use of sponge applicators for the testing of powders in
this rule. Elsewhere in this issue of the Federal Register, we publish
an advance notice of proposed rulemaking that discusses sunscreen
dosage forms, including powders. We may address this issue in a future
rulemaking..
While we acknowledge that consumers do not use finger cots to apply
sunscreens, we are continuing to require the use of finger cots in the
SPF test. The use of finger cots seems to increase reproducibility of
test results, which was why we originally proposed requiring use of
finger cots (72 FR 49070 at 49100 through 49101). We agree with the
submissions that the presaturation requirement is unnecessary and are
removing this requirement. We proposed requiring finger cot
presaturation to prevent sunscreen product from adhering to the finger
cot instead of being transferred to the test subject's skin, resulting
in sunscreen product being applied at less than the intended 2 mg/cm
\2\. We received study results showing that a residual amount of
sunscreen product may adhere to non-presaturated finger cots, but the
amount was small (approximately 2 percent) (Ref. 1). In this study,
each of 100 finger cots (without presaturation) was weighed before and
after sunscreen product application at 2 mg/cm \2\ (100 mg sunscreen
product applied over 50 cm \2\). However, the study did not include a
comparison to presaturated finger cots. Therefore, it is difficult to
determine the effect of presaturation on residual sunscreen amounts.
In addition, we reassessed the basis for presaturation. We are now
concerned that performing the presaturation step may lead to
overestimation of SPF values, because the residual amount normally left
on a finger cot with presaturation may increase the amount of sunscreen
applied to the skin This could lead to overestimation of SPF values.
Overestimation of SPF may, in turn, lead to increased incidence of
sunburn because consumers may anticipate greater protection than a
sunscreen product actually provides. This overestimation risk is a
sufficient basis to remove the presaturation step from the proposed SPF
test method.
We also received data showing that testing without the
presaturation step can produce highly reproducible results (Ref. 1). In
a test of 20 subjects without the presaturation step, a control
sunscreen product yielded a mean SPF value of 4.19 with a standard
error of 0.06 (i.e., 1.4 percent error), while a test sunscreen product
yielded a mean SPF value of 15.54 with a standard error of 0.22 (i.e.,
1.4 percent error). These errors are small, suggesting that the
calculated SPF values did not vary significantly between test subjects.
If lack of presaturation increased variability, then the errors would
be expected to be larger. Therefore, we are removing the presaturation
requirement because of the risk of overestimation of SPF values and our
conclusion that the removal of the presaturation step will not affect
the reproducibility of SPF test results.
F. Application Amount
We are continuing to require that 2 mg/cm\2\ sunscreen product be
applied for the SPF test (proposed 21 CFR 352.70(c)(5); new 21 CFR
201.327(i)(4)(iii)). Several submissions argued for a lower application
amount that better reflects the actual amount used by consumers, which
they argued is commonly 1 mg/cm\2\ or less (Ref. 1). These submissions
argued that the unrealistically high 2 mg/cm\2\ application amount
results in SPF values that overstate the actual sun protection provided
by the amounts consumers typically apply. Other submissions supported
the 2 mg/cm\2\ application amount (Ref. 1). These submissions argued
that SPF values are relative, not absolute, values that allow
comparison of sun protection provided
[[Page 35648]]
by different sunscreen products. According to the submissions, changing
the application amount will affect the ability of consumers to make
this comparison.
We are not changing the sunscreen product application amount
because we have concluded that the advantages of continuing to require
2 mg/cm\2\ exceed the disadvantages of lowering the amount. Requiring
the 2 mg/cm\2\ sunscreen product application amount is consistent with
SPF test methods used in other countries. The 2 mg/cm\2\ application
amount is being used in Europe, Australia, Canada, Korea, and Japan
(Refs. 65-67). If we lower the application amount, sunscreen products
available in the United States will have significantly lower SPF values
than similar products available in other countries. This discrepancy in
SPF values is counterproductive to our global harmonization efforts and
would likely mislead consumers traveling to other countries about the
SPF protection of foreign sunscreen products.
Another advantage of continuing to require a 2 mg/cm\2\ sunscreen
product application amount is greater reproducibility of SPF test
results. Bimczok et al. compared the SPF values determined using
sunscreen product application amounts of 0.5, 1, and 2 mg/cm\2\ (Ref.
68). The SPF values determined using 2 mg/cm\2\ sunscreen product were
more reliable and reproducible than SPF values determined using the
lower application amounts. A sunscreen product application amount of 2
mg/cm\2\ is a large enough amount to allow visualization of the
distribution of sunscreen product as it is applied. This allows for
more consistent and uniform application of the sunscreen used in
testing. Therefore, the 2 mg/cm\2\ sunscreen product application amount
is more likely to generate reproducible results.
G. Water Resistance
In the 2007 proposed rule, sunscreen products tested with two 20-
minute immersion periods (i.e., 40 minutes total) would be allowed to
include a ``water resistant'' statement and sunscreen products tested
with four 20-minute immersion periods (i.e., 80 minutes total) would be
allowed to include a ``very water resistant'' statement. There is a 20-
minute drying period between each immersion period. For example, a
``water resistant'' sunscreen product would be tested by having test
subjects in the water for 20 minutes, out of the water for 20 minutes,
and in the water for 20 minutes.
We received various requests to revise the test (Ref. 1). One
submission recommended longer water immersion times equal to those in
water resistance tests used in Australia and New Zealand. Another
submission included data from an in vitro water resistance test to
support removing the in vivo water resistance test. A third submission
stated the test should be eliminated because it is not validated and
requires too much time. Further, the submission argued that directions
for frequent reapplication make the test unnecessary.
We are continuing to include a water resistance test because water
resistance is an important property of sunscreen products that can
benefit consumers. The water resistance test indicates that a sunscreen
product's labeled SPF protection is retained for a certain period of
time after immersion in water. This is useful information to consumers.
Therefore, we conclude that a water resistance statement based on the
test should be allowed (see section III.C of this document).
We are not changing the 20-minute water immersion periods or the
number of immersion periods required. We based these time periods on
marketing data indicating that individuals at the beach or the pool
spend an average of 21 minutes in the water and go into the water an
average of 3.6 times (43 FR 38206 at 38263, August 25, 1978). We have
not received any other data supporting different time periods. We have
concluded that more or longer water immersion periods are not needed.
We are, however, reducing the drying period from 20 minutes to 15
minutes. We are making this change to decrease the time required for
testing. Shorter testing time may increase test accuracy and
reproducibility, especially for high SPF sunscreens that retain their
water resistance for 80 minutes. In addition, 15 minutes is adequate
time to allow for drying. It is possible that sunscreens may lose water
resistance with repeated wetting and drying. However, we have concluded
that a 15-minute drying period mimics consumer behavior and ensures
that the water resistant properties of a sunscreen do not change with
multiple cycles of water immersion and drying.
VII. SPF Test Issues (Other than Test Parameters)
A. Pass/Fail (Binomial) SPF Test
Several submissions requested the optional use of a pass/fail
(binomial) test to determine the SPF value of a sunscreen product (Ref.
1). These submissions promote the pass/fail test because it would
expose fewer subjects to UV irradiation, cost less, and save time. The
pass/fail test is based on the hypothesis that a sunscreen product of a
certain SPF has a 50:50 probability of preventing the MED response when
irradiated with a UV dose correlated with that SPF. For example, a
sunscreen product with an expected SPF value of 30 or more should
prevent the MED response in greater than 50 percent of test subsites
irradiated with a UV dose equivalent to 30 times the UV dose that
causes the MED response on unprotected skin. If a test sunscreen
product prevents the MED response in a significant number of the
subsites (i.e., significantly more subsites that ``pass'' versus
``fail''), then the test sunscreen product would be allowed to be
labeled with the SPF correlated to the UV dose.
We are not including the optional use of a pass/fail test for SPF
testing. We considered a pass/fail SPF test in the 2007 proposed rule
(72 FR 49070 at 49094 to 49095). We stated that a pass/fail test could
be a reasonable substitute for our proposed SPF test for sunscreen
products with SPF values of 30 or more if certain modifications were
made and validation data demonstrated that the test could be performed
similarly between labs.
In response to our invitation for public comment, one submission
included two studies comparing a pass/fail SPF test to the proposed SPF
test: (1) A single center study of four sunscreen products with
different SPF values and (2) a multicenter (four laboratories) study of
two high SPF sunscreen products. After reviewing these data, we have
determined that the pass/fail test has the following drawbacks:
Each test subsite evaluation is biased towards ``pass''
because the evaluator expects that no skin reaction should occur on
subsites protected by the test sunscreen product.
The test fails to reject test sites where all of the
subsites show positive responses or all of the subsites show negative
responses.
The validity of treating each subsite as an independent
variable is questionable.
The test endpoint (any observed reaction) differs from the
endpoint in the proposed SPF test (clearly defined erythema).
A passing test result for the sunscreen standard does not
demonstrate that the test is being performed correctly.
Test results do not include data for water resistant
sunscreen products.
Allowing this test as an option would yield products with
different UV
[[Page 35649]]
protection levels labeled with the same SPF.
SPF test methods developed by various standards-setting
organizations do not include a pass/fail test.
The study report includes statistical errors that
overstate the statistical power of the test to distinguish whether a
test sunscreen product provides significant UV protection.
Therefore, we are not including a pass/fail test in the SPF test
procedure, because including a pass/fail test would present numerous
complications and the available data indicate that a pass/fail test has
disadvantages compared to the SPF test included in this document.
B. Photostability
Several submissions expressed concern about the loss of UV
protection by sunscreen products due to breakdown of ingredients from
exposure to sunlight (Ref. 1). These submissions recommended a test to
ensure that sunscreen products exposed to sunlight retain sufficient UV
protection. Submitted data show that the composition of sunscreen
products can change from exposure to UV radiation. The submissions
argue that the published photostability studies are inconclusive
because the studies employ artificial test conditions that may not be
appropriately extrapolated to actual use of sunscreens:
Tested sunscreen active ingredients were contained in
solutions rather than in typical sunscreen product formulations
Tested sunscreen products contained active ingredients
that are not representative of the active ingredients included in
typical sunscreen products
Products were tested over a limited range of the UV
spectrum
The submissions argue that understanding the photostability of
sunscreen active ingredients alone is not useful. Rather, the
submissions argue that it is critical to understand the photostability
of sunscreen active ingredients as part of an overall sunscreen
product.
We agree that the available data have limitations. Although the
submissions argue that the inconclusive data support including a test
for photostability, we have concluded that the data do not justify
requiring a photostability test at this time. We are not able to
establish specific photostability test procedures or specifications
based on the available data. We have not received data validating the
performance of a photostability test, nor have we received data
demonstrating that the effectiveness of any particular sunscreen
product is significantly diminished because of photodegradation. We
maintain that the proposed SPF test procedure does account for
photostability to some extent, because the SPF test exposes sunscreen
products to UV radiation before an SPF value is determined.
Consequently, sunscreen products susceptible to photodegradation have
correspondingly lower SPF values. One submission argued that the SPF
test does not fully account for photostability because the solar
simulator emission spectrum is different than natural sunlight.
However, this difference is an unavoidable limitation in testing
because solar simulators cannot perfectly replicate natural sunlight.
We acknowledge that UV radiation can change the composition of
sunscreen products if the products are not photostable, as demonstrated
by the submitted data. However, we are not certain that these data are
applicable under actual use conditions. The data regarding the effects
of UV radiation on the protection provided by sunscreen active
ingredients are limited and inconclusive. Therefore, we are not
creating a photostability test as part of the SPF test procedure in
this document.
C. In Vitro SPF Test
One submission suggested replacing the proposed in vivo SPF test
with an in vitro SPF test (Ref. 1). An in vitro SPF test would have
advantages of faster performance, lower expense, and no exposure of
subjects to UV radiation.
We agree that an in vitro SPF test has these advantages. However,
we are not replacing the in vivo SPF test with an in vitro SPF test for
the same reasons we stated in the 2007 proposed rule (72 FR 49070 at
49095). One shortcoming of an in vitro test is the lack of data on the
performance characteristics of in vitro test substrates, such as quartz
or artificial skin. In the 2007 proposed rule, we stated that data
failed to show that a substrate adequately mimicked the physiological
characteristics of human skin. We stated that we would consider an in
vitro test if validating data demonstrated that the performance of the
in vitro test was equivalent to the in vivo test. We have not received
adequate data to validate an in vitro SPF test. Therefore, we are not
including an in vitro test in this document.
D. Anti-Inflammatory Ingredients
One submission recommended requiring a test to verify that
sunscreen products do not contain anti-inflammatory ingredients that
significantly decrease erythemic response to UV radiation (Ref. 1). The
submission did not identify specific anti-inflammatory ingredients. The
submission argued that, by decreasing the erythemal response, these
ingredients could falsely inflate SPF values determined in SPF testing.
In addition, these anti-inflammatory ingredients may increase the
likelihood of unwanted harmful effects from sun exposure because
sunburn, a cue to avoid sun exposure, would be less evident.
Although the submission raises a serious concern, we are not aware
of any data confirming that this problem exists. Therefore, a test to
show that anti-inflammatory ingredients may be decreasing erythemic
response to UV radiation is not required at this time. It seems
unlikely that anti-inflammatory ingredients will affect SPF values
because their anti-erythemic effect is relatively short-lived compared
to the 16-24 hour interval between UV exposure and erythema observation
in the SPF test.
VIII. Broad Spectrum Test
In this document, we are referring to testing involving the UVA
part of the spectrum as ``broad spectrum testing.'' The term ``broad
spectrum'' more accurately describes the test as covering the full
extent of the terrestrial solar UV spectrum (i.e., UVA and UVB
radiation). Section VIII.A. of this document provides our rationale for
no longer requiring an in vivo test assessing the persistent pigment
darkening associated with UVA radiation. Section VIII.B. of this
document explains why the in vitro test should be changed from a
modified Diffey-Robson ratio to the critical wavelength test. Section
VIII.C. defines the testing parameters to be employed in evaluating the
critical wavelength of an OTC sunscreen product.
A. In Vivo Test Method: Not Required
We stated in the 2007 proposed rule that an assessment of UVA
protection should include determination of both the magnitude and
breadth of absorption in the UVA part of the spectrum (72 FR 49070 at
49102 through 49106). We proposed that an in vivo Persistent Pigment
Darkening (PPD) test be used to evaluate the magnitude of absorption
and an in vitro test be used to evaluate the breadth of absorption. The
PPD test, a modification of the PPD test accepted by JCIA \10\ since
1996, is almost identical to the SPF test. It is recognized as a
standard for the in vivo assessment of UVA protection by the JCIA and
the European Commission
[[Page 35650]]
(Ref. 7). The most significant differences in the PPD test compared to
the SPF test are (1) the light source emits only UVA radiation (320-400
nm) and (2) the endpoint is darkening of the skin (tanning) rather than
reddening of the skin (erythema).
---------------------------------------------------------------------------
\10\ Japanese Cosmetic Industry Association.
---------------------------------------------------------------------------
We have concluded that the PPD test is not necessary to establish
that a sunscreen product provides protection against UVA radiation. The
magnitude of absorption over the solar terrestrial UV portion of the
spectrum (both UVA and UVB) can be effectively assessed based on the
SPF test in combination with a pass/fail broad spectrum in vitro test
(see Section VIII.B of this document). If sunscreen products pass the
in vitro broad spectrum test, then the amount of UVA radiation
protection, as well as UVB radiation protection, must increase as the
SPF value increases. For example, a Broad Spectrum SPF 40 sunscreen
product must provide more UVB and UVA radiation protection than a Broad
Spectrum SPF 20 sunscreen product.
For sunscreen products that pass the in vitro broad spectrum test,
we have concluded that the SPF and PPD tests are redundant of each
other, but we have reasons to prefer the SPF test. The SPF and PPD
tests are both clinical and indicative of the magnitude of absorbance
of UV radiation. Furthermore, both tests depend on the skin type of the
individual. The SPF test measures skin reddening, which is due
primarily to UV radiation in the UVB and UVA II regions (290-340 nm).
The PPD test measures skin darkening, which is due primarily to UV
radiation in the UVA II part of the spectrum (320-340 nm). Therefore,
the UV radiation range covered by the PPD test is also covered by the
SPF test. In both tests, the endpoint is indicative of how much UV
radiation is absorbed. As the magnitude of UV radiation absorbance
increases for a sunscreen product, both the SPF and PPD ratings
increase.
We have identified several disadvantages of the PPD test as
described in the proposed rule (72 FR 49070 at 49103):
Human subjects are exposed to high doses of UVA radiation
with unknown health consequences.
Exposure to UVA radiation alone (i.e., in the absence of
UVB radiation) is never encountered in nature, and the biological
effects of such exposure may differ greatly from those due to exposure
to natural sunlight.
Because it is unclear how tanning relates to the harmful
effects of sunlight, it is unclear whether persistent pigment darkening
represents a clinically meaningful endpoint.
Other disadvantages are pointed out by Nash et al. (Ref. 4):
The physical properties of sunscreen products may differ
when sunscreen products are exposed to UVA radiation alone.
The PPD test is expensive, time consuming, and labor
intensive.
The ability to identify small differences in pigmentation
requires a high degree of expertise and interpretation of pigmentation
changes will be dependent on the examiner.
There may be a high degree of variability in test results
between subjects in the same test panel as well as between different
test panels for the same sunscreen product.
The test results may not be reproducible between labs.
Because of these disadvantages of conducting the PPD test, and the
fact that information obtained from such tests is already provided by
SPF testing for sunscreen products that pass the in vitro broad
spectrum test, we are eliminating the requirement to conduct a PPD or
any other in vivo UVA test in this final rule.
B. In Vitro Test Method: Critical Wavelength
Many submissions objected to our proposal to use a modification of
the Boots adaptation of the Diffey/Robson ratio as an in vitro measure
of UVA protection (Ref. 1). The Diffey/Robson ratio evaluates UVA
protection relative to UVB protection. The ratio is calculated as the
area under the absorbance curve in the UVA region (320-400 nm) divided
by the area under the absorbance curve in the UVB region (290-320 nm).
As the degree of protection against UVA radiation increases, the ratio
increases.
We proposed a modification of this ratio to be calculated as the
area under the absorbance curve in the UVA I region (340-400 nm)
divided by the area under the absorbance curve over total UVB and UVA
range (290-400 nm). We indicated that this modification was necessary
because we were concerned that a sunscreen product absorbing strongly
in the UVA II region (320-340 nm), but not absorbing strongly in the
UVA I region, might produce a disproportionately high ratio value (72
FR 49070 at 49105). We would not consider this sunscreen product to be
a good broad spectrum sunscreen product even though it has a high ratio
value. We noted the importance of ensuring that protection extends well
into the UVA I region (340-400 nm), because neither SPF nor PPD
measurements provide much information about the longer wavelengths of
UVA radiation. Therefore, we modified the ratio to give more emphasis
to the UVA I area under the absorbance curve.
Many submissions argued that we should require a determination of
critical wavelength rather than the proposed ratio to determine broad
spectrum protection (Ref. 1). We agree with the arguments made in the
submissions. Therefore, in this document, we are requiring that broad
spectrum protection be assessed by determining the critical wavelength
of a sunscreen formulation. The submissions noted the following
disadvantages with the proposed ratio:
The 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.
A large ratio could result if one or more ingredients
absorb radiation in the shorter wavelength UVA II region but not at all
or only minimally in the longer wavelength UVA I region. For example,
oxybenzone absorbs radiation at 340-360 nm, and inclusion of this
ingredient at higher concentrations might result in a high ratio even
though it does not provide true broad spectrum protection.
The proposed ratio is not a validated measure of UVA
protection and is not used anywhere else in the world.
To achieve high ratios with existing GRASE active
ingredients, the concentrations of ingredients that absorb in the UVB
and UVA II parts of the spectrum have to be reduced, lowering
protection in these parts of the spectrum (i.e., the SPF has to be
lowered to increase the ratio).
We agree that our proposed ratio is not the most appropriate in
vitro measure of broad spectrum protection. In agreement with many of
the submissions, we have concluded that the ratio places too much
emphasis on absorption in the UVA I part of the spectrum. Although
there is some evidence that UVA I radiation contributes to immune
suppression and an increase in p53-positive cells, the effects of UVA I
radiation on these processes are 100 to 1000 times less than the
effects attributed to UVB and UVA II radiation (Ref. 4). We also
acknowledge that there is no experience using the proposed ratio.
Further, we received some data in the submissions that demonstrate the
need to reduce SPF values in order to achieve high ratio values. We are
concerned that, in an effort to gain UVA protection, consumers may be
more susceptible to
[[Page 35651]]
sunburn because SPF values could be lower in products with higher
ratios.
In agreement with many of the submissions, we have concluded that
the critical wavelength method provides a better measure of broad
spectrum protection. The critical wavelength ([lambda]c) is
derived from the same data as the modified ratio. The critical
wavelength is the wavelength at which the area under the absorbance
curve represents 90 percent of the total area under the curve in the UV
region. This is expressed mathematically as:
[GRAPHIC] [TIFF OMITTED] TR17JN11.001
In this expression, A([lambda]) is the mean absorbance at each
wavelength, and d[lambda] is the wavelength interval between
measurements.
Like the proposed ratio, the critical wavelength measures the
breadth of the UV absorbance curve. Unlike the proposed ratio, the
critical wavelength does not emphasize certain parts of the UV
spectrum, but is a measure of absorbance across the entire solar
terrestrial UV spectrum (UVB and UVA radiation). Sunscreen products
offering primarily UVB protection would have a critical wavelength less
than 320 nm, whereas those providing both UVB and UVA protection would
have critical wavelengths between 320 and 400 nm.
The critical wavelength method is simple, reproducible, and
inexpensive. It has been used by sunscreen manufacturers to evaluate
UVA protection for over a decade and is one of the most commonly used
UVA tests. This is evidenced by the organizations that recommend its
use for determining broad spectrum protection, including the European
Commission, the American Academy of Dermatology, the American Society
for Dermatologic Surgery, and the Skin Cancer Foundation (Ref. 1).
In this document, we are requiring that sunscreen products have a
critical wavelength of at least 370 nm (the mean value must be equal to
or greater than 370 nm) to be labeled as providing broad spectrum
protection (see section VIII.B.). This differs from the tiered rating
(low, medium, high, and highest) that we included in the 2007 proposed
rule (proposed 21 CFR 352.50(b)(2)). We have concluded that the
threshold critical wavelength for a broad spectrum statement should be
370 nm. This wavelength is sufficiently difficult to achieve and will
ensure that sunscreen products meeting this threshold provide a
significant amount of broad spectrum protection. On the other hand, it
is not so difficult to formulate sunscreen products to achieve this
critical wavelength that manufacturers cannot develop broad spectrum
sunscreen products. We have concluded that UV radiation in the range of
370--400 nm is not very harmful based on the available action spectra
for sunburn and skin cancer. We conclude that most of the harmful
effects from the sun are caused by UV radiation in the range of 290--
370 nm. Further, we conclude that critical wavelength (breadth of UVB
and UVA protection) coupled with the SPF value (magnitude of UVB and
UVA protection) provides a complete measure of broad spectrum
protection provided by a sunscreen product.
C. Critical Wavelength Test Parameters
Although the proposed ratio and critical wavelength calculations
are different, both tests are based on the construction of a
transmittance curve over the range of UV wavelengths from 290 to 400
nm. We received several submissions requesting that we change or, in
some cases, better define aspects of the methodology used to measure
transmittance over these wavelengths (Ref. 1). Although the
submissions, in most cases, referred specifically to the proposed ratio
test, the points made regarding methodology apply equally to the
critical wavelength test.
We are making several revisions to the section we referred to as
the ``UVA in vitro testing procedure'' in the 2007 proposed rule
(proposed 21 CFR 352.71). To more accurately describe the test as
covering both the UVB and UVA regions of the spectrum, we now refer to
the test as the ``broad spectrum test.'' The revisions are listed in
Table 5 in the order in which they appear in this section of the
document.
Table 5--Summary of Revisions to the Proposed in Vitro Broad Spectrum Test Included in This Final Rule
----------------------------------------------------------------------------------------------------------------
Revised test parameter 2007 proposed rule This final rule
----------------------------------------------------------------------------------------------------------------
Plate................................ Quartz plate (21 CFR 352.71(b)) PMMA\1\ plate (21 CFR
201.327(j)(1)(i))
Term ``spectroradiometer''........... Spectroradiometer Spectrometer
(21 CFR 352.71(c) and (d)) (21 CFR 201.327(j)(1)(ii),
(iv), and (v))
Light source for transmittance Solar simulator Produce a continuous spectral
measurements. (21 CFR 352.71(a)) distribution of UV radiation
from 290 to 400 nanometers
(21 CFR 201.327(j)(1)(iii)
Input optics: Bandwidth.............. 5 nanometers 1 nanometer
(21 CFR 352.71(d)) (21 CFR 201.327(j)(1)(iv))
Dynamic range of the spectrometer.... Not specified Sufficient to measure
transmittance accurately
through highly absorbing
sunscreen (21 CFR
201.327(j)(1)(v))
Application of sunscreen drug product 2.0 mg/cm\2\ with single-phase spreading 0.75 mg/cm\2\ with 2-phase
to plate. (21 CFR 352.71(e)) spreading (21 CFR
201.327(j)(2))
Pre-Irradiation dose................. Proportional to SPF value (21 CFR Fixed at 800 J/m\2\-eff (21
352.71(f)) CFR 201.327(j)(3))
Number of transmittance measurements. 12 measurements of mean transmittance on 5 5 measurements of mean
different plates (21 CFR 352.71(g) and transmittance on 3 different
(i)) plates (21 CFR 201.327(j)(4)
and (6))
Calculation of critical wavelength... Not applicable 21 CFR 201.327(j)(7))
----------------------------------------------------------------------------------------------------------------
\1\ Polymethylmethacrylate
[[Page 35652]]
We re-organized the broad spectrum test parameters in this final
rule so that they are listed in the order that the test is done. This
section of the document begins with a description of the plates to be
used and the requirements for UV spectrometry. The next section
addresses application of the sunscreen product to the plate, and the
following section addresses the pre-irradiation procedure. The last
sections included under broad spectrum test parameters address
measuring the amount of radiation transmitted through the sunscreen
product, converting these measurements to absorbance values, and
calculating the critical wavelength of a sunscreen product.
All of the proposed test parameters were re-evaluated in the
preparation of this document. Some of the parameters did not require
revision. Test parameters not revised include:
Sample holder
Input optics (other than slit width)
Light source for pre-irradiation
Calculation of mean transmittance values
Calculation of mean absorbance values
The parameters defined in this section are based on our review of
submitted data (Ref. 1) and peer-reviewed literature. Wherever possible
and consistent with sound science, we have attempted to harmonize the
parameters with existing standards, including those of the European
Commission (Ref. 7) and COLIPA (Ref. 69). As stated earlier in this
document, we are also actively involved in the ISO working group
responsible for developing methodologies for assessing sun protection
(both UVB and UVA protection).
1. Plate
Many submissions argued that we should specify that roughened PMMA
(polymethylmethacrylate) plates be used as a substrate rather than
roughened quartz included in the 2007 proposed rule (Ref. 1). The
submissions stated that they prefer PMMA plates because these plates
are:
Less expensive than quartz
Disposable--no need to clean or re-roughen
Readily available with roughened surface
Validated in COLIPA ring tests and in widespread use for
more than a decade
Recommended by the European Commission and COLIPA
We agree with these submissions and are specifying, in this
document, that PMMA plates be used as the substrate in this document.
We are specifying the use of PMMA plates primarily because the vast
majority of validation data we have reviewed was collected using PMMA
rather than quartz plates. Further, we agree with the submissions
noting that PMMA plates are less expensive than quartz and, therefore,
can be disposable. The disposability of the PMMA plates will eliminate
the requirements for cleaning and re-roughening the surface
characteristic of quartz plates.
Consistent with COLIPA, we are also specifying the degree of
roughness and size of the application area on these plates. Plates
should be roughened on one side to a three-dimensional surface
topography measure (Sa) between 2 and 7 micrometers. These Sa values
are supported by validation studies (Ref. 70) and are comparable to
those recommended by COLIPA (Ref. 69). The application area must be at
least 16 square centimeters with no side shorter than 4 centimeters. We
are also replacing the word ``substrate'' with the simpler and more
widely used term ``plate.''
These changes are included in 21 CFR 201.327(j)(1)(i) of this
document. Specifying standardized roughness and size parameters will
result in more accurate and reproducible intra- and inter-laboratory
measurements of broad spectrum photoprotection. Because these PMMA
plates of specified roughness and size are already being used in many
parts of the world and are recommended by COLIPA, we have concluded
that they can be employed in broad spectrum testing in this country
with minimal expense or training of personnel.
2. ``Spectroradiometer'' vs. ``Spectrometer''
Four submissions asked us to replace the term ``spectroradiometer''
with the more generally used term ``spectrophotometer'' (Ref. 1). We
originally chose the term ``spectroradiometer'' because UV radiation is
not detectable by the human eye and, therefore, is not gauged by
photometry (which measures visible light). However, the term
``spectrophotometer'' is often used interchangeably with the term
``spectroradiometer.'' In this document, we are replacing the term
``spectroradiometer'' with the more inclusive term ``spectrometer.''
Use of the term ``spectrometer'' allows the use of either a
spectroradiometer or spectrophotometer and will make the language more
consistent with current COLIPA guidelines (Ref. 69).
3. Light Source for Transmittance Measurements
Four submissions (Ref. 1) asserted that it is inappropriate to
specify a solar simulator as the light source for measuring
transmittance (proposed 21 CFR 352.71(a)). Three of the submissions
argued that radiation emitted from a solar simulator is filtered such
that there is very low energy output in the UV region below 300 nm
(Ref. 1). One submission noted that a light source filtered in this way
cannot provide sufficient energy to measure transmittance through
highly absorbing sunscreen products. The same submission suggested that
there may not be enough transmittance at wavelengths less than 300 nm
to exceed the noise level of the system even in the absence of a
sunscreen product (when transmittance should be maximal).
We agree with the submissions and, in 21 CFR 201.327(j)(1)(iii) of
this document, are specifying that the light source for transmittance
measurements provide continuous, full spectrum radiation from 290 to
400 nanometers. The use of such a light source should maximize
instrument transmission properties while retaining full sensitivity. We
note that this type of light source is recommended by COLIPA (Ref. 69).
4. Wavelength Interval Between Transmittance Measurements
Two submissions argued that we should reduce the wavelength
intervals between transmittance measurements from the proposed 5 nm to
1 nm (Ref. 1). The submissions stated that specifying a smaller
interval would produce more accurate results and noted that current
spectrometers are capable of making measurements at 1 nm intervals. We
agree with the submissions. Additionally, we are aware that the COLIPA
guideline (Ref. 69) specifies that transmittance measurements are to be
taken at 1 nm intervals. Therefore, we are revising the required input
slit bandwidth in this document to specify that it be less than or
equal to 1 nm (new 21 CFR 201.327(j)(1)(iv)). We are also revising the
measurement interval (new 21 CFR 201.327(j)(4)) to state that
transmittance values should be measured at 1 nm intervals.
5. Dynamic Range of the Spectrometer
We are adding new 21 CFR 201.327(j)(1)(v) to specify that the
dynamic range of the spectrometer be ``sufficient to measure
transmittance accurately through a highly absorbing sunscreen product
at all UV
[[Page 35653]]
wavelengths (between 290 and 400 nm).'' The information in this section
had been included in the section entitled ``Calculation of the spectral
transmittance at each wavelength interval'' in the proposed rule
(proposed 21 CFR 352.71(g)). We considered requiring a minimum dynamic
range of 2.2 absorbance units, as specified in the COLIPA guidelines
(Ref. 69). However, we have concluded that it is not necessary to
include this requirement because nearly all current spectrometers are
capable of measuring a dynamic range of 2.2 absorbance units or better.
6. Application of Sunscreen Product to PMMA Plate
Thirteen submissions (Ref. 1) expressed one or more concerns over
the method by which we proposed applying sunscreen product to the plate
(proposed 21 CFR 352.71(e)). Eleven of the thirteen submissions
recommended we reduce the amount applied from 2 milligrams per square
centimeter (mg/cm\2\) to between 0.75 and 1.2 mg/cm\2\. Three
submissions suggested we specify that the sunscreen product be applied
with a better defined spreading action. Two submissions requested we
consider requiring that a saturated fingertip be used to apply the
product rather than a gloved finger.
We are reducing the application amount in this document because
transmittance of UV radiation through a film of 2 mg/cm\2\ thickness is
low and, therefore, can result in inaccurate and/or irreproducible
measures of UVA protection. UV detectors have a range of UV radiation
that they can accurately measure referred to as the dynamic range. If
UV radiation is outside the dynamic range (either lower or higher),
measurements from the detector become less accurate and often less
reproducible. We received validation data demonstrating that
application amounts lower than 2 mg/cm\2\ are more accurate and
reproducible than an application of 2 mg/cm\2\ (Ref. 1). The 2007
proposed rule required an application amount of 2 mg/cm\2\ because this
is the amount specified in the proposed in vivo SPF and PPD tests. We
are not including the PPD test in this document and we have concluded
that consistency with the SPF test is not warranted given the concerns
about inaccurate and/or irreproducible results with an application
amount of 2 mg/cm\2\ in the in vitro UVA method. A reduced application
amount is consistent with the COLIPA guidelines (Ref. 69). Both of
these documents specify an application amount of 0.75 mg/cm\2\. Data we
have reviewed from the Personal Care Product Council demonstrate that
application of 0.75 to 1.0 mg/cm\2\ results in good transmission within
the dynamic range of UV detectors (Ref. 1). Therefore, in this
document, we are reducing the application amount to 0.75 mg/cm\2\ to
ensure the UV radiation transmitted through sunscreens is within the
dynamic range of UV detectors (21 CFR 201.327(j)(2)).
We are also specifying the type of spreading action to be employed
when applying sunscreen product to a plate. One submission noted that
the type of spreading action employed would depend on the type of
product being applied. The submission argued that it might take 30
seconds to evenly spread thicker water resistant creams, but only 10
seconds to evenly spread lotions or oils. We recognize that the very
light spreading action for 10 seconds we proposed may not be sufficient
to evenly distribute all dosage forms on a plate (proposed 21 CFR
352.71(e)). One submission provided data from a ring test involving 7
different laboratories showing that the UVAI/UV absorbance ratio is
affected by the amount of pressure applied during application. A second
submission referenced a paper by Ferrero et al. which shows that light
pressure applied to some sunscreen products results in different ratios
than application with greater pressure (Ref. 70). Both submissions
recommended adopting a two-phase application process like that
recommended by COLIPA (Ref. 69).
We agree that a two-phase spreading action is a more effective
means of achieving a film of uniform thickness and distribution for a
variety of sunscreen dosage forms than is the proposed 10 seconds of
light spreading. This type of spreading action is more reflective of
actual use than the method we proposed. Therefore, we are harmonizing
the standard with the COLIPA guidelines by specifying that a two-phase
process be used. Section 201.327(j)(2) in this document specifies that
``spreading should be done with a very light spreading action for
approximately 30 seconds followed by spreading with greater pressure
for approximately 30 seconds.''
Two submissions argued that we should specify a saturated fingertip
be used rather than a gloved finger. We do not agree for the reasons
specified in section VI.E of this document.
7. Pre-Irradiation Dose
Several submissions expressed concern that the pre-irradiation dose
we proposed to account for differences in photostability is too high,
particularly if we reduce the application amount (Ref. 1). We proposed
that the pre-irradiation dose be proportional to the SPF value of a
sunscreen product (proposed 21 CFR 352.71(f)). This was to account for
the possibility that consumers may spend more time in the sun with
higher SPF products. Proportional pre-irradiation dosing is also
recommended in the testing procedure published by COLIPA (Ref. 69). In
these documents, the pre-irradiation dose is determined relative to the
UVA protection factor. Pre-irradiation dose increases as the UVA
protection factor increases.
Two submissions suggested that we use a fixed or absolute dose
rather than a relative dose proportional to the SPF value of a
sunscreen product (Ref. 1). The submissions noted that, at the same
time and location on the earth's surface, all sunscreen products are
exposed to the same intensity of sunlight. Therefore, sunscreen
products with higher SPF values or UVA protection factors should not be
exposed to higher pre-irradiation doses.
We agree with these two submissions. It is appropriate to evaluate
sunscreen product photostability using a fixed exposure intensity. We
have data demonstrating that avobenzone-containing sunscreen products
undergo almost complete photodegradation when exposed to doses between
2 and 3 MEDs \11\ (Ref. 71). At a dose of 4 MEDs, there were no further
decreases in UVB and UVA absorption of five different sunscreen
products containing 2.5- to 3- percent avobenzone. These data reflect
the worst case scenario for photodegradation because avobenzone appears
to be the least photostable active ingredient in the sunscreen
monograph. Therefore, all sunscreen products marketed under the
monograph are likely to be completely degraded after 4 MEDs. Based on
this data, we are specifying a fixed pre-irradiation dose equivalent to
4 MEDs. As we noted in the 2007 proposed rule, one MED for a skin type
II individual is 200 J/m\2\-eff (72 FR 49070 at 49107). Therefore, in
this document, we are specifying a pre-irradiation dose of 4 times 200
J/m\2\-eff (800 J/m\2\-eff).
---------------------------------------------------------------------------
\11\ Minimal erythema dose--the lowest UV dose that produces
skin reddening (erythema).
---------------------------------------------------------------------------
8. Number of Transmittance Measurements
Two submissions (Ref. 1) stated that requiring 12 transmittance
measurements on each plate as proposed is excessive and not
statistically warranted (proposed 21 CFR 352.71(g)). One submission
provided data showing that there are no significant differences in
UVAI/UV ratios calculated based on 3, 5, 8, or 12
[[Page 35654]]
sub-sites per plate. The submission argued that we should reduce the
number of required test sites per sample to 6. The other submission
proposed that we require only one transmittance measurement per plate.
The submission suggested that, rather than taking multiple measurements
from several small areas on the plate, one measurement could be made
over a relatively broad area.
One of the submissions also argued that it is not necessary to
evaluate transmittance on five different plates (proposed 21 CFR
352.71(j)). The submission provided data showing that the UVAI/UV ratio
for an SPF 15 sunscreen product is not significantly different whether
it is measured on 1, 2, 3, or 5 plates (with 12 measurements per
plate). We note that the COLIPA guidelines (Ref. 69) recommend that 3
separate plates be used.
We agree with the submissions that requiring 12 discrete
measurements on each plate is not necessary to obtain an accurate
transmittance spectrum. The submitted data demonstrate that there are
no significant differences in UVAI/UV ratios based on 3, 5, 8, or 12
test sites. Similarly, we agree with the submissions that requiring
measurements for five plates is not necessary to obtain an accurate
transmittance spectrum. Determining 12 transmittance measurements on
five plates, as proposed, results in a total of 60 transmittance
measurements. Based on the submitted data, a total of 15 transmittance
measurements should produce an accurate transmittance spectrum.
Therefore, we are requiring 5 or more measurements on at least 3
different plates (21 CFR 201.327(j)(6) in this document.
9. Determination of Critical Wavelength
Critical wavelength is to be determined as described in section
VIII.B of this document.
IX. Analysis of Impacts
A. Final Regulatory Impact Analysis
We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, 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 agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). OMB has determined that this final rule is a significant
regulatory action under Executive Order 12866. Consistent with
Executive Order 13563, the approach taken here maintains ``flexibility
and freedom of choice for the public,'' above all by providing
``information for the public in a form that is clear and intelligible.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because we lack information characterizing the
number of products by firm-size and because most affected entities are
considered small, we conclude that this final rule will have a
significant economic impact on a substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $136 million, using the most current (2010) Implicit
Price Deflator for the Gross Domestic Product. We do not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
1. Background
The purpose of this rule is to finalize labeling and testing
conditions under which OTC sunscreen drug products marketed without
approved applications are not misbranded. This rule addresses labeling
and testing requirements for both UVB and UVA radiation protection. The
rule modifies the existing SPF test, specifies a test for broad
spectrum protection, and requires changes to the product label that
affect both the front of the package (the principal display panel or
PDP) and the Drug Facts section. In addition, the rule lifts the stay
of effective date applied to the 1999 Drug Facts labeling final rule
(64 FR 13254) specifically for sunscreen products (66 FR 67485). All
manufacturers of sunscreens will incur some labeling costs due to
revisions to both the PDP and the Drug Facts section of the product
label (see section IX.A.4 of this document). In addition, many
manufacturers will incur additional broad spectrum testing costs unless
they have already tested their products according to the broad spectrum
test required in this rule. Manufacturers of sunscreens will also incur
SPF testing costs (see section IX.A.5 of this document). Some
manufactures will also have to relabel products that are currently
labeled with claims that are not allowed under this final rule (Sec.
201.327(g) and Sec. 310.545(a)(29)(ii)).
2. Benefits
As discussed in section IV.B of this document, the regular use of a
Broad Spectrum SPF 15 or higher sunscreen product, when combined with
limiting time in the sun and wearing clothing to protect sun-exposed
areas, reduces the risk of skin cancer and early skin aging. The
National Cancer Institute estimates that there are more than one
million new cases of non-melanoma skin cancer and more than 68,000 new
cases of melanoma per year in the United States (Refs. 72 and 73).
According to the National Cancer Institute, about 8,700 persons will
die of melanoma in 2010. Fatal cases of non-melanoma skin cancer are
less common but nonetheless number several hundred per year. The
labeling requirements in this rule, in conjunction with implementing
the format and content requirements in 21 CFR 201.66, which were stayed
for sunscreens but are being lifted in this rule, will provide
consumers with clear and concise information about sunscreen use and
protection, and about the role of sun exposure in increasing the risk
of skin cancer and early skin aging. Consumers will be able to more
easily identify products that reduce the risks of skin cancer and early
skin aging, when used as directed. The new requirements for product
testing will ensure the accuracy of the SPF value and broad spectrum
claim on the product label.
Although we are unable to quantify the effects of clear and concise
information, the final rule will provide clearer and more consistent
information on the benefits of certain sunscreens in regard to skin
cancer risk reduction than is available on current labels. By requiring
better information on levels of protection, the rule should contribute
to reduced exposure to UVB and UVA radiation and thereby reduce the
incidence of skin cancer.
The benefits from reduced incidence of skin cancer will equal the
value of the illnesses averted. The most appropriate measure of that
value is based on the average willingness to pay to reduce the
probability of skin cancer. We would then multiply the value per
illness averted by the likely number of illnesses averted to determine
the benefits of this final rule. Because we lack estimates of the
likely numbers of illnesses averted, we present estimates of the value
per
[[Page 35655]]
illness averted to illustrate the gains per averted case.
We estimated the value per case of preventing skin cancer for fatal
and non-fatal cases of melanoma and non-melanoma skin cancer. The
estimated average medical cost of treatment, lost productivity, and
willingness to pay to avoid some symptoms and other effects represents
a plausible lower bound on willingness to pay to avoid a non-fatal case
of skin cancer. For melanoma, the estimated total cost is about $2,860
per non-fatal case; for non-melanoma skin cancer, the total cost is
about $1,400 per non-fatal case; (Refs. 74 and 75).
The largest potential public health gains from this final rule
would likely come from averted deaths. We can calculate the monetary
value of averted fatal cases as either the value of statistical lives
saved or the value of statistical life-years saved. Although skin
cancers occur at all ages, most cases occur at older ages. For that
reason, we estimate the benefit from preventing fatal cases using the
value of life years saved. According to the National Cancer Institute,
the average age of death from melanoma is 68 (Ref. 73); life expectancy
for a person between the ages of 68 and 69 is about 16 years (Ref. 76).
If we discount the average years of life saved for averted fatal
melanoma with rates of 3 and 7 percent, we get discounted statistical
life-years saved equal to 12.6 and 9.4 years. The various studies of
fatal cases of non-melanoma skin cancer find mean or median ages of
death in the 77 to 82 range (Refs. 77-79). The life expectancy for
someone between the ages of 79 and 80 is about 9 years (Ref. 76). If we
discount the average years of life saved for fatal non-melanoma skin
cancers with discount rates of 3 and 7 percent, we get discounted years
saved equal to 7.9 and 6.5 years.
In other analyses of life-years saved, we have used values for a
statistical life-year in the $107,000 to $322,000 range (74 FR 33030,
July 9, 2009; updated to current prices). For this illustrative
analysis, we use a medium value of $214,000 per statistical life-year.
We multiply the value of a statistical life-year by the discounted
life-years saved per fatal case of melanoma, which yields $2.69 million
using a 3 percent rate of discount and $2.02 million using a 7 percent
rate of discount. If we multiply the value of a statistical life-year
by discounted life-years saved per fatal case of non-melanoma skin
cancer, we get $1.67 million using a 3 percent rate of discount and
$1.39 million using a 7 percent rate of discount.
The development of melanoma and non-melanoma skin cancer from
chronic exposure to sunlight, as well as any preventative effects of
sunscreen (or any other intervention), occur with a long lag. To
estimate the monetary value of an averted case of melanoma or non-
melanoma skin cancer through combining other protective measures with
increased broad spectrum and at least SPF 15 protection, we adjust for
the lag between increased protection and a decrease in the incidence of
non-melanoma skin cancer. The only available long-term study finds a
minimum lag of 5 years before any significant risk reduction would
occur (Refs. 20 and 21). Substantial reductions occur with a much
longer lag, probably 15 to 25 years; we use a 20-year lag in this
illustrative analysis. With a 20-year lag discounted at 3 percent, the
value per averted statistical case of non-fatal melanoma is $1,586; if
we discount for at 7 percent, the value per averted case is $740. With
a 20-year lag discounted at 3 percent per year, the monetary value per
averted statistical case of non-melanoma skin cancer is $773; if we
discount at 7 percent, the value per averted case is $361.
For fatal cases, with the 20-year lag discounted at 3 percent per
year, the monetary value per averted statistical case of fatal melanoma
is $1.49 million; discounted at 7 percent, the value per averted fatal
case is $520,000. With a 20-year lag and a 3 percent rate of discount,
the discounted value per averted case of non-melanoma skin cancer is
$920,000 million; with a 7 percent rate of discount, value per averted
fatal case is $360,000.
We have four estimates of the discounted value per averted cases of
melanoma and non-melanoma skin cancer, with values corresponded to non-
fatal and fatal cases. The annual benefits of this final rule will be
the numbers of cases of each type averted multiplied by the value of
each type. We do not, however, have estimates of the numbers of actual
or statistical cases that will be averted. Although there is wide
agreement among experts that the use of more effective sunscreens
reduces the risk of sun-related skin cancer, we are unaware of any
studies that quantify the reduced risk. Without quantitative estimates
of the risk reduction associated with broad spectrum protection, we are
unable to quantity the overall effects of this final rule on public
health.
3. Number of Products Affected
Estimating the number of products affected by this rule is
difficult because we do not have complete data on the number of OTC
sunscreen products currently marketed. Our Drug Listing System does not
have accurate information on the number of marketed OTC sunscreen
products. In the 2007 proposed rule (72 FR 49070 at 49108), we
estimated that there were about 3,000 OTC sunscreen drug products,
including cosmetic products containing sunscreen, with about 12,000
SKUs.\12\
---------------------------------------------------------------------------
\12\ SKUs refers to ``stock keeping units,'' which are
individual products, packages, and sizes.
---------------------------------------------------------------------------
In response to the 2007 proposed rule, we received a submission
arguing that our estimates of the number of products and SKUs were low
but the submission did not suggest a corrected value. We contracted
with the consulting firm Eastern Research Group (ERG) to profile the
sunscreen market and assess the cost to reformulate a sunscreen
product. ERG's full report can be found in Docket No. FDA-1978-N-0018
(Ref. 80). ERG did an extensive search using the internet and other
sources and found fewer dosage forms and SKUs than we had estimated.
ERG estimates that there are about 3,065 to 3,600 SKUs. More recently,
the new FDA labeling cost model estimates that about 3,591 sunscreen
SKUs are marketed, with up to 2,348 different formulations. Because
these data are based on a recent survey of the market, we conclude that
they are more representative of the number of products affected than
the estimates in the proposed rule. For this analysis, we therefore use
3,591 SKUs to represent the number of affected sunscreen labels and
2,348 for the number of formulations.
To comply with the rule, sunscreen products currently marketed as
providing broad spectrum protection that were already tested using the
test method in this rule will have to be re-labeled but will not have
to be retested for broad spectrum protection. Other products will be
tested for broad spectrum protection and, if they pass and, will be
relabeled with the broad spectrum protection claim. Manufacturers may
also choose to reformulate their products to pass the test or
discontinue production of the products.
We have not attributed any reformulation costs to this final rule
but realize that some manufacturers may choose to reformulate their
product if it does not pass the broad spectrum test.
4. Cost To Relabel Sunscreen Products
The cost to relabel varies greatly depending on the printing method
and number of colors used. In the 2007 proposed rule, we stated that
the majority of sunscreen products are packaged in plastic bottles or
tubes with the label printed directly on the
[[Page 35656]]
container or applied as a decal or paper label during the packaging
process.
The labeling requirements in this rule will change both the PDP and
the Drug Facts section of the package and are considered a major
redesign. Frequent label redesigns are typical for OTC sunscreen
products, with redesigns generally implemented every 1 to 2 years. If a
scheduled redesign coincides with relabeling required by this rule, the
incremental labeling cost will be lower than if the labeling change
takes place before scheduled changes. To estimate the cost to relabel,
we are assuming that all products will be relabeled and none are
discontinued.
In the 2007 proposed rule, we used a model developed for us by the
consulting firm RTI International to derive an estimate of the cost to
relabel sunscreen products (Ref. 81). The model was developed to
estimate the cost of food labels, which are similar to the labels on
the products affected by this final rule. In response to the 2007
proposed rule, we received a submission disagreeing with our estimates
of how sunscreens are packaged and the cost to relabel these products
(Ref. 1). The submission argued that many sunscreen products,
particularly sunscreen-cosmetic combinations, have a secondary
container and, therefore, an additional label. The submission also
argued that some sunscreen products would require a fold-out label or
new secondary carton to accommodate the labeling required in this rule.
Furthermore, the submission argued that relabeling these products would
cost $15,000 to $17,000 per SKU. The submission did not include any
data or information to support its estimate.
We agree that cosmetic packaging and labeling is generally more
costly than OTC drug labeling. We also agree that manufacturers of
sunscreen-cosmetic products would use the packaging norm of the
cosmetic industry because those are the products they are competing
with. The cost estimates we are using now demonstrate a large variation
in the price per SKU to account for the differences in packaging. If
the standard content and format changes required by the OTC labeling
final rule (64 FR 13254) are being implemented for the first time,
there could be increases in the size of container and carton labels.
Since we are allowing, in this rule, for a compliance period of 1 year
for most products but 2 years for products with low sales volume
($25,000 annually), inventory losses for unused packaging and labels
are minimized and accounted for in this analysis.
For this final rule, we use the new FDA labeling cost model
developed by RTI International, which includes estimates for changing
sunscreen labels. The one-time costs for a major labeling change to
sunscreen labels are $7,454 to $18,785, depending on the type of
labeling and packaging. The medium estimate is $11,572 per major
labeling changes. These costs include mostly labor and materials, with
some cost for lost inventory.
We estimate that the timing of scheduled relabeling will coincide
with the relabeling required by this rule for 50 percent of the 3,591
SKUs . We estimate the total labeling cost for the SKUs with coinciding
scheduled redesign would be minimal administrative costs or about $550
($310 to $790). Therefore, the total one-time cost for relabeling would
be about $13.9 million to $35.1 million, with a medium estimate of
$21.8 million (1,796 x $11,572 + 1,796 x $550).
5. Cost To Test or Retest Products To Determine SPF Values
Manufacturers will incur SPF testing costs because the rule
requires labeling for OTC sunscreen products to include SPF values
determined in accordance with the specific test method that it
describes. We will publish draft guidance entitled ``Guidance for
Industry: Enforcement Policy--OTC Sunscreen Drug Products Marketed
Without An Approved Application'' that describes our intended
enforcement policy regarding these OTC sunscreen products. In the draft
guidance, we propose to exercise enforcement discretion for a period of
2 years after the publication of this final rule with regard to the SPF
testing requirements for certain OTC sunscreen products on the market
prior to June 17, 2011. We estimate that 65 to 75 percent of sunscreen
reformulations, or 1,526 to 1,761 will require SPF retesting. The cost
of an SPF test depends on whether the product is also making water
resistance claims and the SPF value being tested; the cost of water
resistant testing is much higher than static testing (see Table 6). In
their analysis of the sunscreen market ERG found that about 5 percent
of products claimed water resistance and SPF values less than 30, 3
percent of products claimed water resistance with SPF greater than 30,
while the remaining 92 percent could use the static SPF test. We use
those percentages to estimate total SPF testing costs of $3.2 to $5.9
million (see Table 6). The midpoint of estimated SPF testing costs is
$4.6 million.
Table 6--Cost of SPF Testing
--------------------------------------------------------------------------------------------------------------------------------------------------------
Estimated number of Cost of test Total cost
formulations ---------------------------------------------------------------
Type of test --------------------------------
Low High Low High Low High
--------------------------------------------------------------------------------------------------------------------------------------------------------
Water resistant, SPF < 30............................... 76 88 $4,500 $4,860 $343,395 $427,923
Water resistant, > 30................................... 46 53 4,500 5,130 260,037 271,018
SPF static test......................................... 1,404 1,620 1,900 3,240 2,667,798 5,249,189
-----------------------------------------------------------------------------------------------
Total Cost for SPF testing.......................... .............. .............. .............. .............. 3,217,230 5,948,130
--------------------------------------------------------------------------------------------------------------------------------------------------------
6. Cost to Test or Retest Products for Broad Spectrum Protection
In the proposed rule, we estimated that about 75 percent of
sunscreen products would need to be tested for broad spectrum
protection. We received a submission arguing that our estimate was too
low and that at least 90 percent of products would need to be tested
(Ref. 1). The argument in the submission was based on the four-tier UVA
star rating in the proposed rule. The submission stated that sunscreen
products with ``low,'' one-star protection would need to be tested. We
have now changed the rating criteria to pass-fail, where a critical
wavelength of at least 370 nm is necessary to make the broad spectrum
statement. Over the years, there has been a steady increase in the
number of products with claims of broad spectrum protection. A recent
survey of marketed products found that 65 percent of the products
surveyed met the criteria for the broad spectrum statement (Ref. 82).
Products that were tested in accordance with the broad
[[Page 35657]]
spectrum test in this rule would not need to be re-tested.
Because the broad spectrum test in this rule is different than the
proposed test, we assume that all affected products would need to be
tested. In the 2007 proposed rule, we estimated a one-time testing cost
of approximately $5.4 million for products that have broad spectrum
protection claims. This estimate was based on 2,250 sunscreen products
(75 percent of marketed products) being tested with a test cost of
$2,400. The test costs were estimated as $2,200 for the proposed in
vivo test and $200 for the proposed in vitro test. In this rule, we are
not requiring the in vivo test.
In response to the proposed rule, we received two submissions
arguing that our estimate of $200 for the cost of the in vitro test was
too low (Ref. 1). The first submission states that the cost of an in
vitro test is $500, and the second states that the cost is $800. The
first submission, from a sunscreen manufacturer, states that $500 is
the price charged by an independent testing laboratory to test its
product. The second submission does not provide any basis for its
estimate. Although the in vitro test in this rule is different than the
in vitro test in the 2007 proposed rule, the cost to conduct the tests
is the same. ERG found that the cost of the test ranges from $300 to
$800 (Ref. 80). Assuming all affected marketed product formulations
(1,526 to 1,761 formulations) will be tested for broad spectrum
protection at a cost ranging from $300 to $800, the total cost to test
sunscreen products for broad spectrum protection is estimated to be
$457,860 to $1,408,800 [(1,526 x $300) to (1,761 x $800)].
7. Total Incremental Costs
Because we took steps earlier to mitigate the impact of labeling
changes on the sunscreen industry by staying the requirements in
earlier rules, the labeling costs in this rule incorporate the labeling
costs from three final rules:
1. 1999 OTC drug labeling final rule (64 FR 13254)
2. 1999 Sunscreen final rule (64 FR 27666)
3. This rule.
Manufacturers were able to postpone compliance costs when we chose to
stay the labeling requirements for the 1999 final rule that
standardized the format and content requirements for labeling OTC drug
products (21 CFR part 201), which would have become effective for all
sunscreens by 2005 (69 FR 53801). We include, as part of labeling
costs, the cost of increased container labels and package size to
accommodate the Drug Facts format.
The estimated total one-time incremental cost of this rule range
$17.6 to 42.5 million [($13.9 million labeling cost + $3.2 million SPF
testing cost + $0.5 million broad spectrum testing cost) to ($35.1
million labeling cost + $5.9 million SPF testing cost + $1.4 million
broad spectrum testing cost)]. The medium estimated one-time
incremental costs are $27.3 million. Annualized over 10 years, the
costs are $2.1 to $5 million using a 3 percent rate of discount and
$2.5 to $6.1 million using a 7 percent rate of discount. Annualized
medium costs are $3.2 million using a 3 percent rate of discount and
$3.9 million using a 7 percent rate of discount. If some manufacturers
of sunscreen products have already complied with the 1999 final rule
and would not otherwise have to relabel products as a result of this
final rule, then these estimates may overstate actual total costs.
8. Analysis of Alternatives
The principal alternatives we identified were the inclusion of
several provisions from the 2007 proposed rule. In the 2007 proposed
rule, we required in vivo and in vitro tests for determining UVA
protection. In this rule, we have eliminated the in vivo test
requirement, reducing compliance costs by about $5 million. We also
proposed labeling on the PDP that would indicate the level of UVA
protection. In this rule, we changed the in vitro test to one that
measures both UVB and UVA protection (i.e., broad spectrum protection).
We also established a pass/fail broad spectrum protection statement on
the PDP in place of a UVA rating.
We considered requiring a negative statement on the PDP indicating
that a product did not have broad spectrum protection if it failed the
in vitro test. Numerous submissions from manufacturers opposed this
requirement, and we are concerned that the statement could be
misinterpreted by consumers. Moreover, as noted previously, this
alternative is beyond the scope of this final rule, which applies only
to products that do provide broad spectrum protection.
B. Small Business Impact (Final Regulatory Flexibility Analysis)
We estimate that about 78 percent of the approximately 100 domestic
companies that manufacture OTC sunscreen products would be considered
small business entities (defined by the Small Business Administration
as having fewer than 750 employees). Because most affected entities are
considered small, we conclude that this final rule will have a
significant economic impact on a substantial number of small entities.
Consequently, this analysis, together with other relevant sections of
this document, serves as the Final Regulatory Flexibility Analysis, as
required under the Regulatory Flexibility Act.
The average one-time incremental cost per firm will be about
$185,000 to $445,000, with a medium of about $285,000. This burden,
described in more detail in section IX.A of this document, includes
labeling costs, SPF testing costs, and broad spectrum testing costs.
The economic impact will vary by firm, depending on the number of
products requiring testing and the number of SKUs requiring labeling.
Also, firm-specific impact will vary inversely with the product sales;
the per firm burden will be lower for firms with products with high
sales volumes. Because the relative economic impact of product
retesting is greater for products with lower sales volume, which could
disproportionately affect smaller firms, we are providing a longer
implementation period (2 years) for products with annual sales of less
than $25,000. Because the OTC drug industry is highly regulated, all
firms are expected to have access to the necessary professional skills
on staff or to have contractual arrangements to comply with the testing
requirements of this rule.
X. Paperwork Reduction Act of 1995
This final rule contains certain information collection provisions
that are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).
Specifically, the final rule establishes requirements for SPF labeling
based on specified testing of covered products, (21 CFR 201.327(a)(1)
and (i)). This rule also lifts the delay of implementation date for
Sec. 201.66 (21 CFR 201.66), the general OTC Drug Facts labeling
format regulation, which has applied to all OTC sunscreen products (69
FR 53801). The information collections associated with Sec. 201.66
have been approved in accordance with the PRA under OMB Control Number
0910-0340, but this approval does not currently include application of
these provisions to OTC sunscreens. (76 FR 9022, February 16, 2011).
The lifting of the stay of effective date of Sec. 201.66 for OTC
sunscreens will modify this information collection.
Elsewhere in this issue of the Federal Register, in accordance with
section 3506(c)(2)(A) of the PRA (44 U.S.C.
[[Page 35658]]
3506(c)(2)(A)), we are publishing a 60-day notice soliciting public
comment on the collections of information resulting from this final
rule and will then submit these information collection provisions to
OMB for approval. These requirements will not be effective until we
obtain OMB approval. We will publish a notice concerning OMB approval
of these requirements in the Federal Register prior to the effective
date of this final rule.
With the exceptions noted above, we conclude that the other
provisions of this rule are not subject to OMB review under the PRA.
Section 201.327 contains 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. The requirements for
obtaining certain medical history information and informed consent from
test subjects (21 CFR 201.327(i)(3)(ii) and (i)(3)(iv)) are not
collections of information because information collected from subjects
of clinical testing does not constitute information under 5 CFR
1320.3(h)(5). There are no recordkeeping provisions associated with the
SPF and broad spectrum testing (i.e., effectiveness testing) described
in this rule. The burdens of SPF testing as relevant to labeling (third
party disclosures) are addressed in the notice published elsewhere in
this issue of the Federal Register.
XI. Environmental Impact
FDA has determined under 21 CFR 25.31(a) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
XII. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. Section 4(a) of the Executive order
requires agencies to ``construe * * * a Federal statute to preempt
State law only where the statute contains an express preemption
provision or there is some other clear evidence that the Congress
intended preemption of State law, or where the exercise of State
authority conflicts with the exercise of Federal authority under the
Federal statute.'' The sole statutory provision giving preemptive
effect to the final rule is section 751 of the 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 effects of
this rule are consistent with Executive Order 13132.
XIII. References
The following references are on display in the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20857, under Docket No. FDA-1978-N-0018
(formerly 1978N-0038) and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday. (FDA has verified all Web site
addresses, but FDA is not responsible for any subsequent changes to the
Web sites after this document publishes in the Federal Register.
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8. Document No. FDA-1978-N-0018-0692 in Docket No. FDA-1978-N-0018.
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10. Fourtanier, A. et al., ``Sunscreens Containing the Broad-
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20. Green, A. et al., ``Daily Sunscreen Application and
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21. van der Pols, J. C. et al., ``Prolonged Prevention of Squamous
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23. Araki, K. et al., ``Incidence of Skin Cancers and Precancerous
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24. Darlington, S. et al., ``A Randomized Controlled Trial to
Assess
[[Page 35659]]
Sunscreen Application and Beta Carotene Supplementation in the
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25. Naylor, M. F. et al., ``High Sun Protection Factor Sunscreens
in the Suppression of Actinic Neoplasia,'' Archives of Dermatology,
131:170-175, 1995.
26. Thompson, S. C. et al., ``Reduction of Solar Keratoses by
Regular Sunscreen Use,'' New England Journal of Medicine, 329:1147-
1151, 1993.
27. Gallagher, R. P. et al., ``Broad-Spectrum Sunscreen Use and the
Development of New Nevi in White Children: A Randomized Controlled
Trial,'' The Journal of the American Medical Association, 283:2955-
2960, 2000.
28. Lee, T. K. et al., ``Site-Specific Protective Effect of Broad-
Spectrum Sunscreen on Nevus Development Among White Schoolchildren in a
Randomized Trial,'' Journal of the American Academy of Dermatology,
52:786-792, 2005.
29. Seite, S. and A. Fourtanier, ``The Benefit of Daily
Photoprotection,'' Journal of the American Academy of Dermatology,
58:S160-S166, 2008.
30. Fourtanier, A. et al., ``Protection of Skin Biological Targets
by Different Types of Sunscreens,'' Photodematology, Photoimmunology,
and Photomedicine, 22:22-32, 2006.
31. Young, A. R. et al., ``The Detrimental Effects of Daily Sub-
Erythemal Exposure on Human Skin In Vivo Can Be Prevented by a Daily-
Care Broad-Spectrum Sunscreen,'' Journal of Investigative Dermatology,
127:975-978, 2007.
32. Moyal, D. D. and A. M. Fourtanier, ``Broad-Spectrum Sunscreens
Provide Better Protection From Solar Ultraviolet-Simulated Radiation
and Natural Sunlight-Induced Immunosuppression In Human Beings,''
Journal of the American Academy Dermatology, 58:S149-54, 2008.
33. ``Label Information for Alli\TM\ Weight Loss Aid,'' http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021887lbl.pdf,
November 23, 2009.
34. ``Your Guide to Lowering Your Cholesterol with TLC. Therapeutic
Lifestyle Changes,'' NIH Publication No. 06-5235, 2005.
35. ``Lipitor'' in Physicians' Desk Reference, ed., Thomson
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36. ``The Risks of Tanning,'' http://www.fda.gov/Radiation-EmittingProducts/RadiationEmittingProductsandProcedures/Tanning/ucm116432.htm, October 21, 2009.
37. Dowdy, J. C. et al., ``Indoor Tanning Injuries: An Evaluation
of FDA Adverse Event Reporting Data,'' Photodermatology Photoimmunology
Photomedicine, 25:216-220, 2009.
38. Holick, M. F. and T. C. Chen, ``Vitamin D Deficiency: A
Worldwide Problem with Health Consequences,'' The American Journal of
Clinical Nutrition, 87:1080S-1086S, 2008.
39. Cable News Network, ``Vitamin D is Hot! Here's How to Get it,''
http://www.cnn.com/2008/HEALTH/diet.fitness/05/20/cl.vitamin.d/index.html, October 31, 2008.
40. Holick, M. F., ``Sunlight, UV-Radiation, Vitamin D and Skin
Cancer: How Much Sunlight do We Need?,'' Advances in Experimental
Medicine and Biology, 624:1-15, 2008.
41. Maxwell, J. D., ``Seasonal Variation in Vitamin D,''
Proceedings of the Nutrition Society, 53:533-543, 1994.
42. Salih, F. M., ``Effect of Clothing Varieties on Solar
Photosynthesis of Previtamin D3: An in Vitro Study,'' Photodermatology,
Photoimmunology, and Photomedicine, 20:53-58, 2004.
43. Webb, A. R., ``Who, What, Where and When-Influences on
Cutaneous Vitamin D Synthesis,'' Progress in Biophysics and Molecular
Biology, 92:17-25, 2006.
44. Institute of Medicine, ``Vitamin D'' in Dietary Reference
Intakes For Calcium, Phosphorus, Magnesium, Vitamin D, And Flouride,
National Academies Press, Washington, DC, 250-287, 1997.
45. Wolpowitz, D. and B. A. Gilchrest, ``The Vitamin D Questions:
How Much Do You Need And How Should You Get It?,'' Journal of the
American Academy of Dermatology, 54:301-17, 2006.
46. Matsuoka, L. Y. et al., ``Sunscreens Suppress Cutaneous Vitamin
D3 Synthesis,'' Journal of Clinical Endocrinology and Metabolism,
64:1165-1168, 1987.
47. Matsuoka, L. Y. et al., ``Chronic Sunscreen Use Decreases
Circlulating Concentrations of 25-hydroxyvitamin D. A preliminary
Study,'' Archives of Dermatology, 124:1802-1804, 1988.
48. Marks, R. et al., ``The Effect of Regular Sunscreen Use on
Vitamin D Levels in an Australian Population. Results of a Randomized
Controlled Trial,'' Archives of Dermatology, 131:415-421, 1995.
49. Farrerons, J. et al., ``Clinically Prescribed Sunscreen (Sun
Protection Factor 15) Does not Decrease Serum Vitamin D Concentration
Sufficiently Either to Induce Changes in Parathyroid Function or in
Metabolic Markers,'' British Journal of Dermatology, 139:422-427, 1998.
50. Kimlin, M. et al., ``Does a High UV Environment Ensure Adequate
Vitamin D Status?'' Journal of Photochemistry and Photobiology B.
Biology, 89:139-147, 2007.
51. Cusack, C et al., ``Photoprotective Behavior and Sunscreen Use:
Impact on Vitamin D Levels in Cutaneous Lupus Erythematosus,''
Photodermatology, Photoimmunology, and Photomedicine, 24:260-267, 2008.
52. Hoesl, M. et al., ``Vitamin D Levels of XP-Patients Under
Stringent Sun Protection,'' European Journal of Dermatology, 20:457-
460, 2010.
53. Zerwekh, J. E., ``Blood Biomarkers of Vitamin D Status,''
American Journal of Clinical Nutrition, 87:1087S-1091S, 2008.
54. The American Academy of Dermatology, ``Sun Protection for
Children,'' http://www.aad.org/public/publications/pamphlets/sun_sunprotection.html, February 1, 2009.
55. The American Academy of Dermatology, ``Actinic Keratoses,''
http://www.aad.org/public/publications/pamphlets/sun_actinic.html,
February 1, 2009.
56. The American Academy of Dermatology, ``The Sun and Your Skin,''
http://www.aad.org/public/publications/pamphlets/sun_sun.html,
February 1, 2009.
57. The American Academy of Dermatology, ``The Darker Side of
Tanning,'' http://www.aad.org/public/publications/pamphlets/sun_darker.html, February 1, 2009.
58. The American Academy of Dermatology, ``Skin Cancer,'' http://www.aad.org/public/publications/pamphlets/sun_skin.html, February 1,
2009.
59. Centers for Disease Control and Prevention, ``Sunscreen for
Your Sun Day,'' http://www.cdc.gov/cancer/skin/chooseyourcover/index.htm, October 23, 2009.
60. ``Sunwise Program: Action Steps for Sun Safety,'' http://www.epa.gov/sunwise/actionsteps.html, February 1, 2009.
61. Wright, M.W. et al., ``Mechanisms of Sunscreen Failure,''
Journal of the American Academy of Dermatology, 44:781-784, 2001
62. Rigel, D., ``American Academy of Dermatology's Melanoma/Skin
Cancer Detection and Prevention Month Press Release,'' April 25, 2001.
63. European Cosmetic, Toiletry and Perfumery Association (COLIPA);
JCIA; CTFA-SA; CTFA, ``Sun Protection Factor Test Method,'' 1994.
64. European Cosmetic, Toiletry and Perfumery Association (COLIPA);
JCIA; CTFA-SA; CTFA, ``International Sun
[[Page 35660]]
Protection Factor (SPF) Test Method,'' 2006.
65. Standards Australia and Standards New Zealand, ``Australian/New
Zealand Standard Sunscreen Products Evaluation and Classification,''
AS/NZS 2604:1998,'' 1998.
66. Health Canada, ``Category IV Monograph Sunburn Protectants.
Procedure for Determining an SPF,'' 2002.
67. Korea Food and Drug Administration, ``Korean Measurement
Standards for UV Protection Efficacy,'' 2001.
68. Bimczok, R. et al., ``Influence of Applied Quantity of
Sunscreen Products on the Sun Protection Factor--A Multicenter Study
Organized by the DGK Task Force Sun Protection,'' Skin Pharmacology and
Physiology, 20:57-64, 2007.
69. COLIPA (The European Cosmetics Association), ``Method for the
In Vitro Determination of UVA Protection Provided by Sunscreen
Products,'' COLIPA Guidelines, 2007a.
70. Ferrero, L. et al., ``Importance of Substrate Roughness for In
Vitro Sun Protection Assessment,'' IFSCC Magazine, 9:97-108, 2006.
71. Sayre, R. M. and J. C. Dowdy, ``Photostability Testing of
Avobenzone,'' Cosmetics and Toiletries, 114:85-91, 1999.
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73. National Cancer Institute, ``Surveillance Epidemiology and End
Results: Melanoma of the Skin,'' http://seer.cancer.gov/statfacts/html/melan.html, November 10, 2010.
74. Bickers, D.R. et al., ``The Burden of Skin Diseases: 2004,''
Journal of the American Academy of Dermatology, 55:490-500, 2006.
75. Freedberg, K.A. et al., ``Screening for Mealignant Melanoma: A
Cost-Effective Analysis,'' Journal of the American Academy of
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Life tables, 2005,'' National Vital Statistics Reports, 58:1-132, 2010.
77. Lewis, K.G. and M.A. Weinstock, ``Nonmelanoma Skin Cancer
Mortality (1988-2000),'' Archives of Dermatology, 140:837-842, 2004.
78. Nolan, R.C., M. T.-L. Chan, and P.J. Heenan, ``A
Clinicopathologic Review of Lethal Nonmelanoma Skin Cancers in Western
Australia,'' Journal of the American Academy of Dermatology, 52:101-
108, 2005.
79. Girschik, J. et al., ``Deaths from Non-Melanoma Skin Cancer in
Western Australia,'' Cancer Causes & Control, 19:879-885, 2008.
80. Eastern Research Group (2010) ``Sunscreen Drug Formulations for
Over-the-Counter Human Use,'' Task Order No. 21, Contract No. 223-03-
8500.
81. RTI International, ``FDA Labeling Cost Model, Final Report,''
prepared by Mary Muth, Erica Gledhill, and Shawn Karns, RTI. Prepared
for Amber Jessup, FDA Center for Food Safety and Applied Nutrition,
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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.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
201 is amended as follows:
PART 201--LABELING
0
1. The authority citation for 21 CFR part 201 continues to read as
follows:
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. Section 201.327 is added to subpart G to read as follows:
Sec. 201.327 Over-the-counter sunscreen drug products; required
labeling based on effectiveness testing.
The following provisions apply to sunscreen products containing
aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, ensulizole,
homosalate, meradimate, octinoxate, octisalate, octocrylene,
oxybenzone, padimate O, sulisobenzone, titanium dioxide, trolamine
salicylate, or zinc oxide, alone or in combination. The provisions do
not apply to sunscreen products marketed under approved new drug
applications or abbreviated new drug applications.
(a) Principal display panel. In addition to the statement of
identity in paragraph (b) of this section, the following labeling shall
be prominently placed on the principal display panel:
(1) Effectiveness claim. (i) For products that pass the broad
spectrum test in paragraph (j) of this section. (A) The labeling states
``Broad Spectrum SPF [insert numerical SPF value resulting from testing
under paragraph (i) of this section]''.
(B) Prominence. The Broad Spectrum SPF statement shall appear as
continuous text with no intervening text or graphic. The entire text
shall appear in the same font style, size, and color with the same
background color.
(ii) For sunscreen products that do not pass the broad spectrum
test in paragraph (j) of this section. The labeling states ``SPF
[insert numerical SPF value resulting from testing under paragraph (i)
of this section]''. The entire text shall appear in the same font
style, size, and color with the same background color.
(2) Water resistance statements. (i) For products that provide 40
minutes of water resistance according to the test in paragraph
(i)(7)(i) of this section. The labeling states ``Water Resistant (40
minutes)''.
(ii) For products that provide 80 minutes of water resistance
according to the test in paragraph (i)(7)(ii) of this section. The
labeling states ``Water Resistant (80 minutes)''.
(b) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the drug as a
``sunscreen.''
(c) Indications. The labeling of the product states, under the
heading ``Uses,'' the phrases listed in this paragraph (c), as
appropriate. Other truthful and nonmisleading statements, describing
only the uses that have been established and listed in this paragraph
(c), 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 (the FD&C Act) relating to misbranding and the
prohibition in section 301(d) of the FD&C Act against the introduction
or delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the FD&C 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) of this chapter for definition of
bullet.
(2) For sunscreen products with a Broad Spectrum SPF value of 15 or
higher according to the tests in paragraphs (i) and (j) of this
section, the labeling may include the following statement in addition
to the indication in Sec. 201.327(c)(1): ``[Bullet] if used as
directed with other sun protection measures (see Directions [in bold
italic
[[Page 35661]]
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 FD&C 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 SPF values
of at least 2 but less than 15 according to the SPF test in paragraph
(i) of this section or that do not 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.''
(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 with a Broad Spectrum SPF value of 15 or
higher according to the tests in paragraphs (i) and (j) of this
section. 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)(7) 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)(7) of this section. The labeling states ``[bullet]
reapply at least every 2 hours [bullet] use a water resistant sunscreen
if swimming or sweating''.
(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 and 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 FD&C Act (21 U.S.C. 352).
(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 shall not apply to these products.
(i) SPF test procedure. (1) UV source (solar simulator). (i)
Emission spectrum. A single port or multiport solar simulator should be
filtered 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 should have the following percentage of
erythema-effective radiation in each specified range of wavelengths:
Solar Simulator Emission Spectrum
------------------------------------------------------------------------
Percent erythemal
Wavelength range (nm) 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 Sec.
201.327(i)(1)(ii) of this section.
(B) In addition, UVA II (320-340 nm) irradiance should equal or
exceed 20 percent of the total UV (290-400 nm) irradiance. UVA I (340-
400 nm) irradiance should 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 [lambda]:
(1) Vi ([lambda]) = 1.0 (250 < [lambda] <= 298 nm)
(2) Vi ([lambda]) = 10\0.094 * (298-[lambda])\ (298 <
[lambda] <= 328 nm)
(3) Vi ([lambda]) = 10\0.015 * (140-[lambda])\ (328 <
[lambda] 400 nm)
(B) Calculate the erythema-effective UV dose (E) delivered by a
solar simulator as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.002
Where Vi([lambda]) = erythema action spectrum weighting
factor at each wavelength [lambda]
I([lambda]) = irradiance (Watts per square meter) at each
wavelength [lambda]
t = exposure time (seconds)
Erythema-effective dose (E) is expressed as effective Joules per square
meter (J/m\2\-eff).
(C) The emission spectrum 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. http://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: http://
[[Page 35662]]
www/archives.gov/federal_register/code_offederal_regulations/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)(1)(ii)(A) of this section) at the
time of the annual spectroradiometric measurement of the solar
simulator as described in paragraph (i)(1)(iv) of this section.
(iii) Operation. A solar simulator should 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 should 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)(1)(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.
(2) SPF standard. (i) Preparation. The SPF standard should be a
formulation containing 7-percent padimate O and 3-percent oxybenzone.
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.
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.
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.
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.
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.
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.
(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 0.50 gram
(g) of oxybenzone USP reference standard into a 250-mL volumetric
flask. Dissolve and dilute to volume with isopropanol. Mix well.
(2) Weigh 0.50 g of padimate O USP reference standard into a 250-mL
volumetric flask. Dissolve and dilute to volume with isopropanol. Mix
well.
(3) Pipet 3.0 mL of the oxybenzone solution and 7.0 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)(2)(ii)(B) of this section). The relative standard deviation in peak
areas should not be more than 2.0 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] TR17JN11.003
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 3.0, 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 1.0 g of the SPF standard (described in paragraph
(i)(2)(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)(2)(D)(1) of this section and calculate the amount of oxybenzone and
padimate O as follows:
[[Page 35663]]
[GRAPHIC] [TIFF OMITTED] TR17JN11.004
(ii) The percent of oxybenzone and padimate O in the SPF standard
should be between 95 and 105.
(3) 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)(5)(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. 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.
(4) 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. At least five test
subsites should receive UV doses within each test site. Test subsites
should be at least 0.5 square centimeters (cm\2\) in area and should be
separated from each other by at least 0.8 cm. Each test subsite should
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)(5)) of this section. For water resistant
sunscreen products, proceed with the water resistance testing procedure
described in paragraph (i)(7) of this section after waiting at least 15
minutes.
(5) UV exposure. (i) Definition of minimal erythema dose (MED). 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. 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, administer a series of UV radiation doses expressed as J/m\2\-
eff (as determined according to paragraph (a)(2) 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 person who
evaluates the test subsites is not biased, he/she should not be the
same person who applied the sunscreen drug product to the test site or
administered the UV doses. After UV doses are administered, all
immediate responses should be recorded. 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
[[Page 35664]]
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 MED 16 to 24 hours after UV exposure. Because
erythema is evaluated 16 to 24 hours after UV exposure, the final
MEDu, ssMEDp, and tpMEDp are typically
determined the day following determination of the initial
MEDu. 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).
(6) Determination of SPF. (i) Calculate an SPF value for each test
subject (SPFi) as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.005
(ii) Calculate the mean
[GRAPHIC] [TIFF OMITTED] TR17JN11.009
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
labeled SPF value, which equals the largest whole number less than
[GRAPHIC] [TIFF OMITTED] TR17JN11.012
In order for the SPF determination of a test product to be considered
valid, the SPF value of the SPF standard should fall within the
standard deviation range of the expected SPF (i.e., 16.3
3.43).
(7) Determination of water resistance. The following procedure
should 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 should be recorded.
(i) Water resistance (40 minutes). The labeled SPF should be
determined after 40 minutes of water immersion using the following
procedure:
(A) Step 1: Apply the sunscreen as described in paragraph (d) 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 (d) of
this section.
Step 1. Expose test sites to UV doses as described in paragraph (e)
of this section.
(ii) Water resistance (80 minutes). The labeled SPF should be
determined after 80 minutes of water immersion using the following
procedure:
(A) Step 1: Apply the sunscreen as described in paragraph (d) 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 (d)
of this section.
(K) Step 11: Expose test sites to UV doses as described in
paragraph (e) of this section.
(j) Broad spectrum test procedure. (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 drug product
from one edge of the PMMA plate to the other. It should be mounted 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. The PMMA plate should be placed on the upper surface of the
sample holder with the roughened side facing up.
(iii) Light source. The light source should 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[reg] or quartz). The diffuser ensures that the radiation
received by the spectrometer is not collimated. The spectrometer input
slits should be set to provide a bandwidth that is less than or equal
to 1 nanometer.
(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 dots 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 (c) of this section.
(3) Sunscreen product pre-irradiation. To account for lack of
photostability, apply the sunscreen product to the PMMA plate as
described in paragraph (b) of this section and then irradiate with a
solar simulator described in section 352.70(b) of this chapter. The
irradiation dose should 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. After pre-irradiation
described in paragraph (c) of this section, mean transmittance values
should be
[[Page 35665]]
determined for each wavelength [lambda] over the full UV spectrum (290
to 400 nanometers). The transmittance values should be measured 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) should be obtained from
at least 5 different locations on the PMMA plate [C1([lambda]),
C2([lambda]), C3([lambda]), C4([lambda]), and C5([lambda])]. In
addition, a minimum of 5 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])]. The mean transmittance
for each wavelength,
[GRAPHIC] [TIFF OMITTED] TR17JN11.010
is the ratio of the mean of the C([lambda]) values to the mean of the
P([lambda]) values, as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.006
Where n >= 5
(5) Calculation of mean absorbance values. (i) Mean transmittance
values,
[GRAPHIC] [TIFF OMITTED] TR17JN11.010
are converted into mean absorbance values,
[GRAPHIC] [TIFF OMITTED] TR17JN11.011
at each wavelength by taking the negative logarithm of the mean
transmittance value as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.008
(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, mean absorbance
values should be determined from at least three individual PMMA plates.
Because paragraph (d) of this section requires at least 5 measurements
per plate, there should 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] TR17JN11.007
Where [lambda]c = critical wavelength
A([lambda]) = mean absorbance at each wavelength
d[lambda] = wavelength interval between measurements
A mean critical wavelength of 370 nm or greater is classified as broad
spectrum protection.
PART 310--NEW DRUGS
0
4. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,
263b-263n.
0
5. Section 310.545 is amended by revising paragraphs (a)(29) and
(d)(31) and by adding new paragraph (d)(40) to read as follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
(29) Sunscreen drug products.
(i) Ingredients.
Diethanolamine methoxycinnamate
Digalloyl trioleate
Ethyl 4-[bis(hydroxypropyl)] aminobenzoate
Glyceryl aminobenzoate
Lawsone with dihydroxyacetone
Red petrolatum
(ii) Any ingredients labeled with any of the following or similar
claims. Instant protection or protection immediately upon application.
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 21 CFR 201.327.
* * * * *
(d) * * *
(31) December 31, 2002, for products subject to paragraph
(a)(29)(i) of this section.
* * * * *
(40) June 18, 2012, for products subject to paragraph (a)(29)(ii)
of this section. June 17, 2013, for products with annual sales less
than $25,000.
Dated: June 9, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-14766 Filed 6-14-11; 8:45 am]
BILLING CODE 4160-01-P