[Federal Register: August 27, 2007 (Volume 72, Number 165)]
[Proposed Rules]
[Page 49069-49122]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr27au07-15]
[[Page 49069]]
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Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 347 and 352
Sunscreen Drug Products for Over-the-Counter Human Use; Proposed
Amendment of Final Monograph; Proposed Rule
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 347 and 352
[Docket No. 1978N-0038] (formerly Docket No. 78N-0038)
RIN 0910-AF43
Sunscreen Drug Products for Over-the-Counter Human Use; Proposed
Amendment of Final Monograph
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a proposed
rule that would amend the final monograph (FM) for over-the-counter
(OTC) sunscreen drug products as part of FDA's ongoing review of OTC
drug products. This amendment addresses formulation, labeling, and
testing requirements for both ultraviolet B (UVB) and ultraviolet A
(UVA) radiation protection. FDA is issuing this proposed rule after
considering public comments and new data and information that have come
to FDA's attention. This rule proposes to lift the stays of 21 CFR
347.20(d) and 21 CFR Part 352 when FDA publishes a final rule based on
this proposed rule.
DATES: Submit written or electronic comments by November 26, 2007.
Submit written or electronic comments on FDA's economic impact
determination by November 26, 2007. Please see section X of this
document for the effective and compliance dates of any final rule that
may publish based on this proposal.
ADDRESSES: You may submit comments, identified by Docket No. 1978N-
0038 and RIN number 0910-AF43, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency
name, docket number and regulatory information number (RIN) for this
rulemaking. All comments received may be posted without change to
http://www.fda.gov/ohrms/dockets/default.htm, including any personal
information provided. For additional information on submitting
comments, see the ``Request for Comments'' heading of the SUPPLEMENTARY
INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number, found in brackets in the heading of this
document, into the ``Search'' box and follow the prompts and/or go to
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Matthew R. Holman, Office of
Nonprescription Products, Center for Drug Evaluation and Research, Food
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 5414,
Silver Spring, MD 20993, 301-796-2090.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
II. Summary of Major Changes to the FM
A. Ingredients
B. UVB (SPF) Labeling
C. UVA Labeling
D. Indications
E. Warnings
F. Directions
G. UVB Testing
H. UVA Testing
III. FDA's Tentative Conclusions on the Comments
A. General Comments on OTC Sunscreen Drug Products
B. Comments on Tanning and Tanning Preparations
C. Comments on Specific Sunscreen Active Ingredients
D. General Comments on the Labeling of Sunscreen Drug Products
E. Comments on the Labeling of Sunscreen Drug Products With UVA
Protection
F. Comments on the Labeling of Sunscreen Drug Products With High
SPF Values
G. Comments on Indications for Sunscreen Drug Products
H. Comments on Directions for Sunscreen Drug Products
I. General Comments on SPF Testing Procedure
J. Comments on the Sunscreen Standard for SPF Testing Procedure
K. Comments on Artificial Light Sources for SPF Testing Procedure
L. Comments on the Design/Analysis of SPF Testing Procedure
M. General Comments on UVA Testing Procedure
N. Comments on UVA Testing Procedure Design and Testing Criteria
O. Comments on the Photostability of Sunscreen Drug Products
IV. FDA's Tentative Conclusions and Proposals
V. Analysis of Impacts
A. Background
B. Number of Products Affected
C. Cost to Relabel
D. Cost to Test or Retest Products for UVA Protection
E. Total Incremental Costs
F. Small Business Impact
G. Analysis of Alternatives
VI. Paperwork Reduction Act of 1995
VII. Environmental Impact
VIII. Federalism
IX. Request for Comments
X. Proposed Effective and Compliance Dates
XI. References
I. Background
In the Federal Register of May 12, 1993 (58 FR 28194), FDA
published a notice of proposed rulemaking in the form of a tentative
final monograph (TFM) for OTC sunscreen drug products. In the TFM, FDA
proposed the conditions under which OTC sunscreen drug products would
be considered generally recognized as safe and effective (GRASE), under
section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act)
(21 U.S.C. 321(p)), and not misbranded, under section 502 of the act
(21 U.S.C. 352).
In the Federal Register of April 5, 1994 (59 FR 16042), FDA
reopened the administrative record until July 31, 1994, to allow
additional submissions on UVA-related issues and announced a public
meeting for May 12, 1994, to discuss UVA testing procedures. As
explained in that Federal Register notice, the TFM included proposed
UVB (i.e., 290-320 nm) testing and labeling. The sun protection factor
(SPF)
[[Page 49071]]
test and corresponding labeling reflects the level of protection
against sunburn, which is caused primarily by UVB radiation. The TFM
also explained the importance of protection against UVA radiation
(i.e., 320-400 nm), the other UV component of sunlight (58 FR 28194 at
28232 and 28233). The TFM referenced published UVA test methods but did
not propose a method (58 FR 28194 at 28248 to 28250). Rather, the TFM
stated that a product could be labeled as ``broad spectrum'' or a
similar claim if it protected against UVA radiation. Thus, FDA held the
1994 public meeting to gather further information about an appropriate
UVA test method and labeling.
In the Federal Register of June 8, 1994 (59 FR 29706), FDA proposed
to amend the TFM (and reopened the comment period until August 22,
1994) to remove five proposed sunscreen ingredients from the TFM
because of lack of interest in establishing United States
Pharmacopeia--National Formulary (USP-NF) monographs. FDA also
reiterated that all sunscreen ingredients must have a USP-NF monograph
before being included in the FM for OTC sunscreen drug products.
In the Federal Register of August 15, 1996 (61 FR 42398), FDA
reopened the administrative record until December 6, 1996, to allow
additional submissions on zinc oxide and titanium dioxide as well as
sunscreen photostability. FDA also announced a public meeting for
September 19 and 20, 1996, to discuss the safety and efficacy of these
two ingredients and photostability of sunscreens in general.
In the Federal Registers of September 16, 1996 (61 FR 48645) and
October 22, 1998 (63 FR 56584), FDA amended the TFM to add the UVA-
absorbing sunscreen ingredients avobenzone and zinc oxide to the
proposed list of monograph ingredients. FDA also proposed indications
for these ingredients. As a result of this amendment to the TFM, in the
Federal Register of April 30, 1997 (62 FR 23350), FDA announced an
enforcement policy allowing interim marketing of OTC sunscreen drug
products containing avobenzone.
On November 21, 1997, Congress enacted the Food and Drug
Administration Modernization Act of 1997 (FDAMA). 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.'' FDA identified the UVB portions of the
monograph (and related provisions on water resistant test methods and
cosmetic labeling) as items that could be finalized within the
timeframe set by FDAMA. Because of outstanding issues related to the
development of testing standards and labeling for UVA radiation
protection, FDA deferred final action on these items.
Therefore, in the Federal Register of May 21, 1999 (64 FR 27666),
FDA published the FM for OTC sunscreen drug products in part 352 (21
CFR part 352) with an effective date of May 21, 2001, but deferred UVA
testing and labeling for future regulatory action. FDA stated that more
time was required to review comments from interested parties on active
ingredients, labeling, and test methods for products intended to
provide UVA protection. This proposed amendment to the FM for OTC
sunscreen drug products will complete the FM by addressing both UVB and
UVA testing and labeling.
In the Federal Register of June 8, 2000 (65 FR 36319), FDA reopened
the administrative record of the rulemaking for OTC sunscreen drug
products to allow for specific comment on high SPF and UVA radiation
testing and labeling. FDA also extended the effective date for the FM
to December 31, 2002.
In the Federal Register of December 31, 2001 (66 FR 67485), FDA
stayed the December 31, 2002, effective date of the FM for OTC
sunscreen drug products in part 352 until we provided further notice in
a future issue of the Federal Register. FDA took this action because we
planned to amend part 352 to address formulation, labeling, and testing
requirements for both UVB and UVA radiation protection. This document
proposes such changes. This document also proposes an effective date
related to publication of an amended FM (see section X of this
document). The existing stay of the effective date for part 352 remains
in effect at this time.
In the Federal Register of June 20, 2002 (67 FR 41821), FDA
published a technical amendment to change the names of four sunscreen
active ingredients in Sec. 352.10 of the monograph to be consistent
with name changes that appeared in USP 24. The new names, which are
simpler and more convenient, are meradimate for menthyl anthranilate,
octinoxate for octyl methoxycinnamate, octisalate for octyl salicylate,
and ensulizole for phenylbenzimidazole sulfonic acid. Because the names
became official on March 1, 2001, manufacturers could begin using them
at any time after that date.
In the Federal Register of June 4, 2003 (68 FR 33362), FDA issued a
final rule establishing conditions under which OTC skin protectant
products are generally recognized as safe and effective and not
misbranded. This final rule lifted the stay of 21 CFR part 352 to amend
the final monograph for OTC sunscreen drug products to include
sunscreen-skin protectant combination drug products. This final rule
concluded by placing a stay on both part 352 and on Sec. 347.20(d).
The proposed rule that is the subject of this document provides UVA
testing and labeling that is necessary on sunscreen and sunscreen-skin
protectant combination drug products. This proposed rule, therefore,
proposes that the stays of both part 352 and Sec. 347.20(d) be lifted
when this rule is finalized. These stays will be maintained until a
final rule based on this proposed rule becomes effective.
In the Federal Register of September 3, 2004 (69 FR 53801), FDA
delayed the implementation date for OTC sunscreen drug products subject
to the final rule that established standardized format and content
requirements for the labeling of OTC drug products (i.e., Drug Facts
rule). FDA explained that we postponed the Drug Facts implementation
date because we did not expect to complete the final amendment of the
sunscreen monograph to include UVA testing and labeling by the Drug
Facts implementation date of May 16, 2005 (64 FR 13254 at 13273 and
13274, March 17, 1999). Thus, FDA delayed the implementation date of
the Drug Facts rule with respect to OTC sunscreen drug products until
further notice to avoid issuing successive relabeling requirements for
sunscreen drug products at two closely related time intervals, as
required by the Drug Facts rule and the final amendment to the
sunscreen monograph.
II. Summary of Major Changes to the FM
In response to the TFM and FM, FDA received substantial data and
information regarding UVA and UVB active ingredients, claims, and
testing procedures, as well as on other issues addressed in this
document. FDA summarizes these issues and proposed changes to the FM in
this section.
A. Ingredients
FDA proposes to add combinations of avobenzone with zinc oxide and
avobenzone with ensulizole as permitted combinations of active
sunscreen ingredients in the FM (see section III.C, comment 7 of this
document).
[[Page 49072]]
B. UVB (SPF) Labeling
The FM allowed specific labeled SPF values up to, but not
exceeding, 30. OTC sunscreen drug products with SPF values greater than
30 could be labeled with the collective term ``30+.'' In this
amendment, FDA proposes to increase the specific labeled SPF value to
50 and revise the collective term to ``50+.'' FDA will consider higher
specific labeled SPF values upon receipt of adequate, validated data
(see section III.F, comment 15 of this document).
In addition, FDA proposes to revise the following FM labeling:
The phrase ``sun protection'' to ``sunburn protection''
where used in Sec. Sec. 352.3(b)(1), (b)(2), (b)(3), and (d) and
352.52(e)(1)(i), (e)(1)(ii), and (e)(1)(iii) (see section III.D,
comment 10 of this document); and
Section 352.50(a) to include the term ``UVB'' before the
term ``SPF'' on the principal display panel (PDP), along with the
product category designation (PCD) (see section III.E, comment 14 of
this document).
FDA also proposes to revise the PCD SPF ranges in Sec.
352.3(b)(1), (b)(2), and (b)(3) (proposed Sec. 352.3(c)(1) through
(c)(4)) to reflect the following:
The current standard public health message concerning use
of sunscreens,
The proposed increase of the labeled SPF value to ``50+,''
and
The proposed addition of the term ``UVB'' before the word
``sunburn.''
Proposed Sec. 352.3(c)(4) contains a new PCD of ``highest UVB sunburn
protection product'' for products that provide an SPF value over 50.
FDA further proposes to revise current Sec. 352.3(b)(1) and (b)(2) to
replace the current category descriptors of ``minimal'' and
``moderate'' with the terms ``low'' and ``medium,'' respectively. FDA
considers the new terms to be simpler and uniform with the proposed UVB
and UVA ``Uses'' statements. Proposed changes to PCDs and category
descriptors also occur in proposed Sec. 352.52(e)(1) (see section
III.D, comment 13 and section III.G, comment 16 of this document). In
addition, FDA proposes optional UVB radiation protection statements
(see proposed Sec. 352.52(e)(2) and (e)(3)).
C. UVA Labeling
FDA proposes new labeling to designate the level of UVA protection
on the PDP of OTC sunscreen drug products. FDA proposes the use of
symbols (``stars'') in conjunction with a descriptor (i.e., ``low,''
``medium,'' ``high,'' or ``highest''). FDA also proposes to add new
Sec. 352.50(b) specifying the required PDP labeling for OTC sunscreen
products tested in accordance with the proposed UVA testing procedures
in Sec. Sec. 352.71 and 352.72 (see section III.E, comment 14 and
section III.N, comment 45 of this document).
D. Indications
The FM allowed the following two UVB indications in Sec.
352.52(b)(1):
``helps prevent sunburn''
``higher SPF gives more sunburn protection''
In this amendment, FDA proposes to revise the first statement to
read ``low,'' ``medium,'' ``high,'' or ``highest'' ``UVB sunburn
protection'' in proposed Sec. 352.52(b)(1)(i) through (b)(1)(iv). FDA
is proposing to revise the additional indications in Sec. 352.52(b)(2)
to reflect the new PCD ranges in proposed Sec. 352.3(c) (e.g., SPF of
2 to under 12 becomes SPF of 2 to under 15) and create the new PCD
range over SPF 50. These proposed revisions are based upon the revised
PCD categories in proposed Sec. 352.3(c) (see section III.G, comment
16 of this document). FDA proposes that the second statement in current
Sec. 352.52(b)(1) (``higher SPF gives more sunburn protection'') no
longer be required and proposes an additional indication regarding UVA
protection (see proposed Sec. 352.52(b)(2)(v)).
In proposed Sec. 352.52(b)(2)(v), FDA includes a new indication
for UVA protection that involves selection of the appropriate
descriptor (``low,'' ``medium,'' ``high,'' or ``highest'') to describe
the level of protection. In proposed Sec. 352.52(b)(2)(vi), FDA
includes a modified version of the sunburn ``Uses'' statement required
by proposed Sec. 352.52(b)(1)(i) through (b)(1)(iv) when the
additional statement in proposed Sec. 352.52(b)(2)(v) is used and
bears the same category descriptor as the SPF value (e.g., medium UVA/
UVB protection from sunburn) (see section III.G, comment 17 of this
document).
E. Warnings
FDA is proposing to shorten the warning in Sec. 352.52(c)(1)(ii)
(proposed Sec. 352.52(c)(3)) under the subheading ``Stop use and ask a
doctor if'' from ``[bullet] rash or irritation develops and lasts'' to
``[bullet] skin rash occurs.''
FDA proposes removing the optional ``sun alert'' product
performance statement (current Sec. 352.52(e)(2)) and requiring a
revised ``sun alert'' statement in the ``Warnings'' section (proposed
Sec. 352.52(c)(1)). FDA proposes that this revised statement be
required on all OTC sunscreen drug products except lip cosmetic-drug
and lip protectant-sunscreen products subject to Sec. 352.52(f), which
are not required to include this statement under proposed Sec.
352.52(f)(1)(v) and (f)(1)(vi) (see section III.G, comment 19 of this
document). The statement in proposed Sec. 352.52(c)(1) reads as
follows: ``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.'' FDA proposes that the statement
appear in bold type as the first statement in the ``Warnings'' section.
F. Directions
FDA proposes changes to the directions to reduce the likelihood
that OTC sunscreen drug products are underapplied. Section
352.52(d)(1)(i) currently provides manufacturers the option to select
one or more of the following terms: ``liberally,'' ``generously,''
``smoothly,'' or ``evenly.'' FDA is proposing to allow the choice of
one of two required terms (i.e., ``liberally'' or ``generously'') and
to include ``evenly'' as an additional optional term. FDA is proposing
to eliminate the term ``smoothly'' because it is vague.
FDA also proposes to add a new direction ``apply and reapply as
directed to avoid lowering protection'' (proposed Sec.
352.52(d)(1)(ii)). Because new information demonstrates the importance
of sunscreen reapplication, FDA also proposes to make the optional
directions in paragraph (d)(2) a requirement. As a result of this
change, FDA is proposing to remove the current language in paragraph
(d)(3) because it is no longer necessary. Instead, FDA is proposing, in
paragraph (d)(3), required information for products that do not satisfy
the water resistant testing procedures in Sec. 352.76. FDA is also
proposing a required reapplication statement in Sec. 352.52(d)(1)(ii).
The reapplication information in current Sec. 352.52(d)(2) appears in
proposed Sec. 352.52(d)(2) and (d)(3) of this document (see section
III.H, comment 22 of this document).
G. UVB Testing
FDA is proposing to revise the SPF (UVB) testing procedure (see
section III, paragraphs I through L of this document) and to move the
SPF testing procedure currently in Sec. Sec. 352.70 through 352.73 to
proposed Sec. 352.70. FDA proposes a padimate O/oxybenzone sunscreen
standard in Sec. 352.70 that will be required for testing sunscreen
products with SPF values over 15. Manufacturers may use either this
padimate O/oxybenzone standard
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or the homosalate standard to test products with SPF values of 2 to 15.
FDA proposes a high pressure liquid chromatography (HPLC) method to
replace the spectrophotometric method used to assay the homosalate and
padimate O/oxybenzone standards.
FDA proposes the following modifications to the SPF testing
procedure:
Specifications for the solar simulator in Sec. 352.71
(proposed Sec. 352.70(b)),
Instructions for the application of test materials and
response criteria in Sec. 352.72 (proposed Sec. 352.70(c)), and
Doses and determination of minimal erythema dose (MED) in
Sec. 352.73 (proposed Sec. 352.70(d)).
FDA proposes to continue requiring a finger cot to be used in the
application of sunscreen standard and test product as specified in
Sec. 352.72(e) (proposed Sec. 352.70(c)(5)). However, FDA now
proposes that the finger cot be pretreated. These two proposed UVB
testing changes also apply to UVA in vivo testing.
H. UVA Testing
FDA proposes a combination of spectrophotometric (in vitro) and
clinical (in vivo) UVA test procedures in proposed Sec. Sec. 352.71
and 352.72, respectively. To assure UVA protection for ``water
resistant'' and ``very water resistant'' sunscreen products, FDA
proposes that the in vivo UVA test be conducted after the appropriate
water immersion period for OTC sunscreen drug products making a UVA
claim. Therefore, FDA proposes modification of Sec. 352.76 to state
that the water resistance claim applies to the SPF and, if appropriate,
UVA values determined after the appropriate water immersion period as
described in proposed Sec. 352.70 and, if appropriate, proposed Sec.
352.72.
III. FDA's Tentative Conclusions on the Comments
A. General Comments on OTC Sunscreen Drug Products
(Comment 1) Several comments asked that FDA provide more time to
comply with requirements of the FM in order to avoid an adverse
economic impact on the suncare industry and consumers. The comments
described the seasonal dynamics of the suncare industry (i.e., products
are sold in two marketing cycles over a period of 18 months) and stated
that the industry would need more time to develop products that meet
the FM requirements and allow for shipment of the previous year's
returns. The comments mentioned times from 2 to 3 years after
publication of the FM as appropriate or necessary for implementation.
Several of these comments added that the date should be in the June/
July time period because the shipping season is practically over at
that time and manufacturing for the next season is just beginning.
FDA understands the seasonal nature of the sunscreen industry and
the time required for product testing and relabeling. FDA is also aware
that more than 1 year may be needed for implementation. FDA is
proposing an 18- to 24-month implementation date and will try to have
it coincide with the June/July time period (see section XI of this
document).
(Comment 2) One comment requested that FDA and the Federal Trade
Commission (FTC) take steps to make sure that sunscreen manufacturers
provide information to the American public to help them understand and
use the Ultraviolet Index (UVI) to determine their risk of sunburn.
The National Weather Service, the Environmental Protection Agency
(EPA), and the Centers for Disease Control and Prevention (CDC)
developed the UVI, which has been in use since 1995. This index is an
indication of the amount of UV radiation reaching the surface of the
earth as a function of ozone data, atmospheric pressure, temperature,
and cloudiness and is generated for 58 cities around the United States.
Usage information required by the OTC sunscreen drug product
monograph applies regardless of the UVI value. Therefore, FDA believes
that UVI information need not be required in the monograph for the safe
and effective use of these products and should not be included in the
``Drug Facts'' labeling. However, manufacturers who wish to do so may
voluntarily include such information in their labeling outside the
``Drug Facts'' box.
(Comment 3) One comment requested that FDA make clear, through
either the FM for skin protectant or sunscreen drug products, or both,
that combination products containing sunscreen and skin protectant
ingredients may be lawfully marketed.
Section 347.20(d) of the skin protectant FM (21 CFR 347.20(d)),
which published in the Federal Register of June 4, 2003 (68 FR 33362),
provides for combinations of sunscreen ingredients and specific skin
protectant ingredients. The final rule for OTC skin protectant drug
products also included an amendment to the sunscreen FM, adding new
Sec. 352.20(b), which allows combinations of sunscreen and skin
protectant active ingredients. Thus, both monographs now state the same
conditions for lawfully marketing these combination products. The
existing language in Sec. Sec. 347.20(d) and 352.20(b) would include
the two new combinations that FDA is proposing to add to the sunscreen
monograph (see section II.A, comment 7 of this document).
B. Comments on Tanning and Tanning Preparations
(Comment 4) One comment requested that the effective date of Sec.
740.19 (21 CFR 740.19) be extended to December 31, 2002, consistent
with the delay of the effective date for Sec. 310.545(a)(29) and
(d)(31), part 352, and Sec. 700.35 (65 FR 36319). The comment stated
that singling out Sec. 740.19 to become effective earlier might
constitute an arbitrary and capricious decision by FDA.
The May 21, 1999, final rule set a 2-year effective date (May 21,
2001) for Sec. 310.545(a)(29) and (d)(31), part 352, and Sec. 700.35.
In the Federal Register of June 8, 2000 (65 FR 36319), FDA extended the
effective date for compliance with Sec. 310.545(a)(29) and (d)(31),
part 352, and Sec. 700.35 until December 31, 2002, to provide time for
completion of a more comprehensive UVA/UVB FM for OTC sunscreen drug
products. On December 31, 2001, FDA then stayed the effective date of
part 352 (but not Sec. 310.545(a)(29) and (d)(31), and Sec. 700.35)
until further notice (66 FR 67485). FDA took this action because we are
amending part 352 to address formulation, labeling, and testing
requirements for both UVA and UVB radiation protection. The May 21,
1999, final rule also set a 1-year effective date (May 22, 2000) for
new Sec. 740.19, which addresses a warning statement for cosmetic
suntanning preparations that do not contain a sunscreen active
ingredient. These products are not subject to the monograph for OTC
sunscreen drug products in part 352. FDA considered this warning to be
sufficiently important for safety reasons when we issued the final rule
(64 FR 27666 at 27669) to require a 12-month effective date as opposed
to the 24-month effective date for the other sections of the rule.
Further, FDA's primary reason for extending the effective date of those
other sections to December 31, 2002, and then staying part 352 to
address formulation, labeling, and testing requirements for both UVA
and UVB protection, was to allow FDA to develop a comprehensive UVB/UVA
final monograph. This reason does not apply to Sec. 740.19.
Accordingly, FDA did not extend the effective date for Sec. 740.19,
and Sec. 740.19 is in effect at this time. FDA concludes that this
[[Page 49074]]
decision is not arbitrary and capricious, but is based on valid health
concerns related to the products subject to the warning requirement in
Sec. 740.19.
(Comment 5) One comment requested that FDA and FTC take steps to
ensure sunscreen manufacturers inform consumers that their natural skin
pigmentation provides protection from sunlight. The comment stated that
these adaptive individuals might not require a daily application of a
sunscreen. Another comment submitted a copy of a patent for an
electronic sensor device to measure solar radiation. The comment stated
that the personal device could alert consumers to their level of UV
exposure so they could either come out of the sun or apply a sunscreen
to avoid sunburn and skin cancer.
FDA has no objection to sunscreen manufacturers informing consumers
that their natural skin pigmentation provides protection from sunlight.
However, FDA has no basis to require such information as part of the
required labeling for OTC sunscreen drug products. Thus, manufacturers
may include this information in labeling outside of the ``Drug Facts''
box, but are not required to include this information. FDA considers
the comment regarding the UV measuring device to be outside the scope
of this rulemaking, which evaluates the safety, effectiveness, and
labeling of OTC drug products.
C. Comments on Specific Sunscreen Active Ingredients
(Comment 6) Several comments requested that dihydroxyacetone (DHA)
be added to the monograph as a single active ingredient for UVA
protection. The comments claimed that DHA alone provides an SPF of 2 to
4. One comment claimed that a 15 percent topical solution of DHA
provided a photoprotective factor of 10 in the UVA region. Other
comments contended that the brown color produced by DHA, resembling
melanin, should potentiate the action of sunscreens. Another comment
stated that DHA alone is not a sunscreen, but forms a sunscreen when
combined with lawsone. The comment cited unpublished observations by
two independent investigators that the melanoidins of DHA-induced skin
pigment resemble melanin in that they absorb UVB strongly, with
decreasing absorbance through the UVA region and into visible light.
The comment added that, because DHA alters the structure of the skin
surface, it is, by definition, a drug.
One comment provided information on the safety and UVA
effectiveness of DHA alone (Ref. 1). Safety studies included the
following:
Oral and dermal toxicity studies,
A chronic skin painting carcinogenicity study in mice,
Comedogenecity tests in rabbits,
Repeated insult patch test in humans, and
Photoallergy tests.
Effectiveness studies consisted of published articles using either
humans or photosensitized rats. Another comment discussed
investigations with DHA on psoriasis patients sensitized with 8-
methoxypsoralen (8-MOP).
FDA is not proposing to include DHA in the monograph as a single
active ingredient in OTC sunscreen products. Although there were no
product submissions to the Advisory Review Panel on Topical Analgesic,
Antirheumatic, Otic, Burn, and Sunburn Prevention and Treatment Drug
Products (the Panel) using DHA as a sunscreen ingredient, the Panel
discussed available scientific evidence for DHA as a single sunscreen
ingredient. The Panel concluded that DHA is not a sunscreen but a
cosmetic; it is a sunscreen only when used with lawsone (43 FR 38206 at
38215 to 38216, August 25, 1978). Although one comment stated that DHA
alters the structure of the skin, it did not provide data to support
this claim. Thus, at this time, FDA agrees with the Panel that DHA is a
cosmetic.
FDA acknowledges that DHA is the subject of an approved color
additive petition and its safety as a color additive has been
established. However, the submitted chronic (life-span) skin painting
study in mice does not support the safe use of DHA as a sunscreen
because no group of mice was included in the study to determine the
possible photocarcinogenic effect of DHA. This effect needs to be
studied because DHA is associated with carbonyl compounds known to
react with pyrimidine bases in the presence of UV radiation, and it
appears to be a potent inducer of thymine dimers, premutagenic
deoxyribonucleic acid (DNA) lesions. Therefore, its safety, in terms of
the type, extent, and location of photo-induced DNA damage, is of
concern and should be determined. Whether DHA contributes or promotes
UV carcinogenesis is not known.
The submitted studies on the effectiveness of DHA as a single UVA
sunscreen ingredient add only qualitative information. Many of the
studies utilized animal models; few included human subjects. One study
involved only five subjects, three with erythropoietic protoporphyria
and two with polymorphic light eruptions. Another study involved six
subjects sensitized with 8-MOP. In both studies, too few subjects were
enrolled, and the study subjects were not representative of the average
sunscreen user.
Well-controlled clinical trials with DHA alone are lacking.
Although some investigations described by the comments suggest that DHA
may help protect the normal skin of psoriasis patients, concerns remain
about the usefulness of DHA products in the OTC market. For example,
one comment stated that photoprotection provided by DHA depends upon
the way the product polymerizes in the stratum corneum and that
polymerization depends on the skin of each individual. Therefore, the
photoprotection provided by DHA varies from person to person and has to
be determined for each person by diffuse reflectance spectroscopy.
Given these statements, it is not clear how appropriate OTC drug
product labeling could be written to aid consumers in proper selection
and use of a DHA sunscreen.
FDA concludes that current information is inadequate to include DHA
in the monograph as a single sunscreen ingredient. None of the comments
provided information to establish the appropriate number of consecutive
product applications and the timing of these applications (how far
apart or how soon before sun exposure) that are necessary to achieve
the desired protection using products containing various concentrations
of DHA. In two submitted studies, a preparation containing 3 percent
DHA was applied six times prior to sun exposure and a preparation
containing 15 percent DHA preparation was applied one time 24 hours
prior to sun exposure, respectively (Ref. 1). The comments did not
include any information on appropriate regimens for various skin types,
which is necessary because the level of photoprotection provided by DHA
is dependent on skin type. Therefore, based upon this lack of
information, it is not clear how to state appropriate label directions
for consumer use. FDA needs additional information from clinical
studies to determine the effective concentration of DHA in sunscreen
product formulations and the frequency and timing of product
application.
(Comment 7) One comment submitted data to support the combination
of avobenzone with ensulizole and avobenzone with zinc oxide (Ref. 2).
The safety data included the following:
A repeat insult patch test,
A phototoxicity study, and
A photoallergy study.
The effectiveness data involved a clinical study using the in vitro
``critical wavelength'' (CW) method and the in
[[Page 49075]]
vivo ``protection factor A'' (PFA) method to support the UVA radiation
protection potential of the combination products. The PFA test data
were from a double blind clinical study using five sunscreen
formulations.
The safety studies demonstrated that the following combinations of
active ingredients have a low potential for irritation, allergenic
sensitization, and phototoxicity:
3 percent or less avobenzone with 2 percent ensulizole
3 percent or less avobenzone with 5 percent zinc oxide
The data further suggested that the photoallergenic potential of
avobenzone is not augmented by its combination with either ensulizole
or zinc oxide.
The clinical study using the PFA in vivo method demonstrated that
the following combinations of active ingredients are significantly more
effective than 1.5 percent ensulizole or 3 percent zinc oxide alone in
protecting against UVA radiation:
3 percent avobenzone with 1.5 percent ensulizole
3 percent avobenzone with 4 percent zinc oxide
FDA's detailed comments on the safety and effectiveness studies are on
file in the Division of Dockets Management (Ref. 3).
FDA considers the data submitted by the comment sufficient to
support the safety and effectiveness of avobenzone with ensulizole and
avobenzone with zinc oxide when used in the concentrations established
for each ingredient in Sec. 352.10 of the sunscreen monograph.
Accordingly, FDA is proposing to amend Sec. 352.20(a)(2) by adding
ensulizole and zinc oxide.
Marketing of products containing avobenzone with ensulizole and
avobenzone with zinc oxide will not be permitted unless and until the
following three actions occur:
1. The comment period specific to this proposal closes.
2. FDA has evaluated all comments on these combination products
submitted in response to the proposal.
3. FDA publishes a Federal Register notice announcing our
determination to permit the marketing of OTC sunscreen drug products
containing these combinations.
D. General Comments on the Labeling of Sunscreen Drug Products
(Comment 8) One comment agreed that the labeling modifications
allowed by the FM in Sec. 352.52 for OTC sunscreen products marketed
as a lipstick or labeled for use only on specific small areas of the
face (e.g., lips, nose, ears, and/or around eyes) are appropriate for
these products. Based on the labeling in Sec. 352.52, the comment
proposed eight additional modifications for all other OTC sunscreen
products regardless of package size:
1. Delete ``Drug Facts'' title because it is inappropriate and
unnecessary for sunscreens.
2. Omit ``Purpose'' because it is repetitive of the statement of
identity on the PDP and ``Uses'' information.
3. Revise ``higher SPF gives more sunburn protection'' in ``Uses''
to read ``higher SPF products give more sun protection, but are not
intended to extend the time spent in the sun,'' and require this
statement only on products with an SPF value over 30.
4. Omit ``For external use only'' warning because it is self-
evident for sunscreen products.
5. Revise ``When using this product [bullet] keep out of eyes.
Rinse with water to remove'' to read ``Keep out of eyes.''
6. Revise ``Stop use and ask a doctor if [bullet] rash or
irritation develops and lasts'' to read ``Stop use if skin rash
occurs.''
7. Omit barlines, hairlines, and box enclosure.
8. Allow the option to list inactive ingredients in a different
location on the label or in labeling accompanying the product.
The comment stated that these modifications would allow reduced Drug
Facts labeling for all OTC sunscreen drug products.
The comment contended that sunscreen products meet all of FDA's
criteria for reduced labeling (64 FR 13254 at 13270):
Packaged in small amounts,
High therapeutic index,
Extremely low risk in actual consumer use situations,
A favorable public health benefit,
No specified dosage limitation, and
Few specific warnings and no general warnings (e.g.,
pregnancy or overdose warnings).
The comment added that OTC sunscreen products are a unique category
substantially different from most other types of OTC drug products
because they are recommended for use on a daily basis to prevent
serious disease. The comment concluded that FDA's rationale for
standardized labeling format and content requirements does not
necessarily transfer to OTC sunscreen products and specifically not to
drug-cosmetic products with a sunscreen.
When FDA created the standardized labeling format and content
requirements (i.e., ``Drug Facts'' labeling) for OTC drug products, we
recognized that some product packages were too small to accommodate all
of the required labeling. Therefore, under Sec. 201.66(d)(10) (21 CFR
201.66(d)(10)), FDA allows labeling format modifications for all OTC
drug products sold in small packages. In the final rule establishing
``Drug Facts'' labeling, FDA also stated that we may allow reduced
labeling requirements beyond those specified under Sec. 201.66(d)(10)
for OTC drug products that meet the criteria listed in the preceding
paragraph (see section III.D, comment 9 of this document).
In the final rule for OTC sunscreen drug products (64 FR 27666 at
27681 to 27682), FDA recognized that some OTC sunscreen drug products
meet these criteria for reduced labeling. Specifically, FDA identified
OTC sunscreen drug products that qualify for the small package
specifications in Sec. 201.66(d)(10) and are labeled for use only on
specific small areas of the face as meeting the criteria for reduced
labeling. Therefore, FDA allows content and format modifications for
these products under Sec. 352.52(f). FDA allows further modifications
for lip products containing sunscreen because these products for small
areas of the face are sold in even smaller packages than the other
sunscreen products marketed under Sec. 352.52(f) (68 FR 33362 at
33371; 64 FR 13254 at 13270). FDA believes that sunscreen products
labeled for use only on small areas of the face, including lip products
containing sunscreen, serve an important public health need and FDA
does not want to discourage manufacturers from marketing these products
(64 FR 13254 at 13270).
FDA does not find it appropriate to extend the labeling
modifications for OTC sunscreen drug products marketed under Sec.
352.52(f) to all OTC sunscreen drug products. FDA disagrees with the
comment's argument that all sunscreen products meet the criteria for
reduced Drug Facts labeling (64 FR 13254 at 13270), because most
sunscreen products are not sold in small packages. Therefore, because
sunscreen products do not generally meet all of the criteria for
reduced Drug Facts labeling, FDA is not proposing reduced labeling for
all OTC sunscreen products.
FDA does not consider sunscreens as a unique category substantially
different from other types of OTC drug products because they are
recommended for use on a daily basis to prevent serious disease, as
argued by the comment. Other OTC drug products are used on a daily
basis, some to prevent serious disease and some for other reasons. For
example, anticaries drug products are
[[Page 49076]]
used daily to prevent dental caries. Antiperspirant drug products can
be used daily to reduce underarm wetness. FDA has concluded that these
various products should generally be labeled using the standardized
content and format in Sec. 201.66. The standardized labeling allows
consumers to more easily recognize that these products are, in fact,
drug products and to more easily read and understand the labeling
information.
The same principle applies when the product is a drug cosmetic
product (e.g., sunscreen moisturizer or antiperspirant deodorant).
Consumers need to be informed that the product has a drug effect, and
the uniform Drug Facts labeling for all OTC drug and drug cosmetic
products helps convey this message. FDA applied this rationale when it
finalized the requirements in the final rule that established Sec.
201.66.
FDA agrees that some OTC sunscreen drug products meet the criteria
for reduced information for safe and effective use (64 FR 13254 at
13270, 64 FR 27666 at 27681 to 27682). However, FDA disagrees with most
of the modifications proposed by the comment for all package sizes of
OTC sunscreen products. FDA disagrees with deletion of the ``Drug
Facts'' title and the ``Purpose'' information because many sunscreen
products do not meet the parameters for reduced Drug Facts labeling.
FDA disagrees that the ``Purpose'' information is repetitive and,
therefore, disagrees that it may be omitted where there is sufficient
labeling space. The ``Purpose'' section is a standard part of Drug
Facts labeling and is intended to inform consumers which ingredients
are sunscreens in a product. This information is even more important
when a sunscreen is marketed in a combination product. For example, in
a sunscreen skin protectant drug product, the ``Purpose'' section
informs consumers which ingredients are sunscreens and which are skin
protectants.
FDA has revised the ``Uses'' section and deleted the statement
``higher SPF gives more sunburn protection'' (see section III.G,
comment 16 of this document). FDA disagrees with omitting the ``For
external use only'' warning for all OTC sunscreen drug products. FDA
finds no basis to exclude all OTC sunscreen products from this
requirement. Likewise, FDA finds no reason to omit the two standard
subheadings that accompany the warning statements, as proposed by the
comment. Further, FDA disagrees with the comment's suggestion to omit
the statement ``Rinse with water to remove.'' This is useful
information if a sunscreen product gets into the eyes. FDA agrees with
part of the proposed shortened warning for OTC sunscreen drug products
to ``Stop use if skin rash occurs'' in place of ``Stop use and ask a
doctor [bullet] if rash or irritation develops and lasts.'' Therefore,
FDA is proposing to amend Sec. 352.52(c)(1)(ii) (proposed Sec.
352.52(c)(3)) to state: ``Stop use and ask a doctor if [bullet] skin
rash occurs.''
FDA finds no reason to omit barlines, hairlines, or the box
enclosure for all OTC sunscreen drug products regardless of package
size. These labeling formats help consumers identify a product as a
drug and help make labeling information easier to read and understand.
Thus, they should be included when package size allows. The FM already
allows horizontal barlines and hairlines and the box enclosure to be
omitted if a small package meets the criteria in Sec. Sec. 352.52(f)
and 201.66(d)(10).
Finally, FDA has no basis to provide an option for sunscreen
products to list inactive ingredients in labeling that accompanies the
products. FDA interprets section 502(e)(1)(A)(iii) of the act (21
U.S.C. 352(e)(1)(A)(iii)) as requiring the inactive ingredients to be
listed on the outside container of a retail package or on the immediate
container if there is no outside container or wrapper (Sec.
201.66(c)). Because this information, by law, must appear either on the
outside container or immediate container of the product, FDA does not
find a basis for allowing an option to list the inactive ingredients in
a different location, such as other labeling accompanying the product.
In accordance with Sec. 201.66(c)(8), the inactive ingredients must be
listed on the product label in the ``Drug Facts'' box.
(Comment 9) Two comments supported extending the labeling in Sec.
352.52(f) for products intended for use only on specific small areas of
the face and sold in small packages to all OTC sunscreen products. The
comments contended that all OTC sunscreen drug products meet most of
FDA's criteria for products that require minimal information for safe
and effective use (64 FR 13254 at 13270) (see section III.G, comment 8
of this document).
The first comment added that FDA should permit the labeling
modifications in Sec. 352.52(f) for the following products:
Makeup products (as defined in 21 CFR 720.4(c)(7)) with
sunscreen, and
Lotions and moisturizers for the hands or face with
sunscreen in containers of 2 ounces (oz) or less (by weight or liquid
measure).
The comment added that most facial makeup products are typically
packaged in small containers. The comment stated that to meet any of
FDA's concerns that lotions and moisturizers sold in larger packages
may be used over the entire body despite labeling that restricts use to
the face or hands, FDA could limit the flexible labeling to containers
of 2 oz or less. Furthermore, the comment added that containers of 2 oz
or less could not feasibly include the full OTC drug labeling.
The second comment contended that the modified labeling in Sec.
352.52(f) is particularly compelling for color cosmetic products for
the face that contain sunscreens (i.e., ``facial makeups with
sunscreen''). The comment added that these products and OTC sunscreen
drug products for use only on specific small areas of the face have the
same overall safety profile, and, therefore, FDA should allow these
products to be labeled similarly.
A third comment strongly disagreed with a specific labeling
exemption for makeup with sunscreen and moisturizer products for use on
the face and hands. The comment contended that an exemption would not
be in the best interest of consumers. The comment also argued that
consumer confusion and subsequent misuse of sunscreen products,
particularly failure to apply adequate amounts of sunscreen or to
reapply a product after certain activities, will occur if FDA permits
reduced labeling for these products. The comment added that many
consumers use face and hand cosmetic products with sunscreen as their
primary and only source of UV radiation protection for those areas of
the body. Moreover, consumers are more likely to use these products
properly if they contain full sunscreen drug labeling. The comment
concluded that makeup foundations, tints, blushes, rouges, and
moisturizers that are intended to be used on a daily or frequent basis
to protect against the adverse health and skin aging effects of acute
and chronic sun exposure must be labeled as drugs similar to other OTC
sunscreen products.
FDA is not proposing to extend the labeling modifications in Sec.
352.52(f), which is specific for products used only on small areas of
the face and sold in small packages, to all OTC sunscreen products. FDA
has determined that most OTC sunscreen products should have full drug
labeling information using the standardized content and format in Sec.
201.66 to ensure the safe and effective use of these products. In
establishing the labeling modifications in Sec. 352.52(f),
[[Page 49077]]
FDA determined how the labeling information for sunscreen drug
products, including drug cosmetic products, could best be presented on
products with limited labeling space and still provide consumers with
adequate information to use these products safely and effectively.
Although any sunscreen products sold in small packages that meet the
criteria in Sec. 201.66(d)(10) are allowed the format exemptions under
that section, FDA is also proposing content exemptions for sunscreen
products marketed under Sec. 352.52(f). FDA is proposing these
exemptions under Sec. 352.52(f) because sunscreen products labeled for
use only on small areas of the face and sold in small packages are
generally sold in packages substantially smaller than other sunscreen
products, even those sunscreen products labeled for other uses that
meet the criteria in Sec. 201.66(d)(10).
FDA continues to believe that requiring full Drug Facts labeling on
sunscreen products used only on specific small areas of the face and
sold in small packages (i.e., Sec. 352.52(f)) would discourage
manufacturers from marketing some of these products for drug use. Many
of these products, such as sunscreen-lip protectant products, are sold
in extremely small packages that cannot accommodate the required
labeling even with the format exemptions allowed under Sec.
201.66(d)(10). As explained in a number of rulemakings (64 FR 27666 at
27681 to 27682; 68 FR 33362 at 33371; 64 FR 13254 at 13270), these
products meet the criteria for additional reduced labeling. Removal of
these products from the OTC market would have a negative impact on
public health. FDA believes that the benefit of UV radiation protection
provided by these products outweighs the need for manufacturers to
include all sunscreen labeling information. In contrast, FDA believes
manufacturers of sunscreen products that are not within the scope of
Sec. 352.52(f) will continue to market their products even though full
Drug Facts labeling is required. Unlike sunscreen products that meet
Sec. 352.52(f), the package size of products that do not meet Sec.
352.52(f) will accommodate full Drug Facts labeling.
Although FDA is not extending the labeling modifications in Sec.
352.52(f) to all OTC sunscreen products, as requested by the first and
second comments, we are allowing these labeling modifications for
certain makeup with sunscreen products. Specifically, these labeling
modifications would apply to makeup with sunscreen products that are
labeled for use only on specific small areas of the face and that meet
the criteria in Sec. 201.66(d)(10). However, FDA does not agree that
these labeling modifications should apply to all makeup products
identified in Sec. 720.4(c) (21 CFR 720.4(c)) that contain sunscreen,
because most are not sold in small packages and, therefore, do not meet
all of the criteria for reduced labeling (64 FR 13254 at 13270). Thus,
most of these products can accommodate full Drug Facts labeling, and
FDA finds no reason to extend the labeling modifications in Sec.
352.52(f) to all makeup with sunscreens products.
As explained in the previous paragraph, the labeling modifications
in Sec. 352.52(f) apply to makeup with sunscreen products labeled for
use only on specific small areas of the face and sold in small
packages. FDA also believes that any sunscreen products that are used
only on specific small areas of the face and sold in small packages
meet FDA's reduced labeling criteria regardless of whether they are
drug or drug-cosmetic products. Therefore, FDA is proposing to amend
the heading of Sec. 352.52(f) to read as follows: ``Products,
including cosmetic-drug products, containing any ingredient identified
in Sec. 352.10 labeled for use only on specific small areas of the
face (e.g., lips, nose, ears, and/or around the eyes) and that meet the
criteria established in Sec. 201.66(d)(10) of this chapter.''
In addition, FDA is proposing to extend the labeling exemptions,
with some modifications, currently allowed for lipsticks in Sec.
352.52(f)(1)(vi) to the following lip products with sunscreen, as
defined in Sec. 720.4(c):
Lipsticks,
Lip products to prolong wear of lipstick,
Lip gloss, and
Lip balm.
FDA has identified lip products to prolong wear of lipstick as ``makeup
fixatives'' under Sec. 720.4(c)(7)(viii). Lip gloss and lip balm fall
under ``other makeup preparations'' in Sec. 720.4(c)(7)(ix). As long
as these lip products with sunscreen are used only on specific small
areas of the face and are sold in small packages (i.e., meet the
criteria in Sec. 201.66(d)(10)), they would meet FDA's reduced
labeling criteria. As discussed earlier in this comment, FDA believes
not allowing Drug Facts labeling exemptions for these products would
discourage manufacturers from marketing some of these products for drug
use. In proposed Sec. 352.52(f)(1)(vi), FDA is proposing to extend the
labeling modifications for lipsticks to other lip cosmetic products
containing sunscreen and clarifying that the labeling modifications in
Sec. 352.52(f) apply to both sunscreen and makeup with sunscreen
products. Furthermore, because lip products with sunscreen have
substantially less labeling space than the nonlip products with
sunscreen used only on specific small areas of the face and sold in
small packages, proposed Sec. 352.52(f)(1)(vi) allows more labeling
exemptions for lip products with sunscreen than other products that are
within the scope of Sec. 352.52(f).
(Comment 10) Several comments recommended changing the acronym
``SPF'' from ``sun protection factor'' to ``sunburn protection factor''
because the latter definition is more descriptive of the use of OTC
sunscreen drug products and avoids giving consumers the impression of
solar invincibility and a false sense of security.
FDA agrees. In Sec. 352.52(b) of the sunscreen FM, FDA included
only indications for sunburn protection (e.g., ``helps prevent
sunburn'') (64 FR 27666 at 27691). In this document, FDA is proposing
to change the word ``sun'' to ``sunburn'' in Sec. 352.3(b)(1), (b)(2),
(b)(3), and (d) and Sec. 352.52(e)(1)(i), (e)(1)(ii), and (e)(1)(iii).
Manufacturers can continue to use existing labeling until the
compliance dates of a final rule based on this proposal. However, FDA
encourages manufacturers to revise any labeling that states ``sun
protection'' attributed to sunscreen active ingredient(s) to the new
term ``sunburn protection'' as early as possible.
(Comment 11) Some comments questioned the constitutionality of the
FM's labeling provisions. Specifically, the comments contended that the
FM's prohibition on the labeling of SPF products over 30, its
restrictions on skin aging claims, and its limitation of the
indications for use for OTC sunscreen drug products all violate the
first amendment to the U.S. Constitution. The comments asserted that
these bans on allegedly truthful labeling in the FM go well beyond
constitutionally permissible restrictions on commercial free speech.
One comment contended that FDA had failed to meet its burden to
demonstrate that the claims at issue are misleading or that the
restrictions on speech directly advance any substantial governmental
purpose. In addition, the comment claimed that any interest FDA has
asserted in restricting the speech at issue is served equally well, if
not better, by regulations that do not restrict speech to the same
extent as FDA's regulations.
[[Page 49078]]
FDA disagrees with the comments for the following reasons. OTC drug
monographs establish conditions under which ingredients for certain OTC
uses are generally recognized as safe and effective (GRASE) and are not
misbranded. General recognition of safety and effectiveness in an OTC
drug monograph means that experts qualified by scientific training and
experience recognize the conditions as safe and effective for OTC
marketing for the use recommended or suggested in the product's
labeling. An OTC drug monograph establishes, among other things,
specific indications that are appropriate for the safe and effective
use of a drug. An OTC drug product with labeled indications different
than those set forth in an applicable OTC drug monograph would not be
considered GRASE.
OTC drug monographs allow manufacturers to market those products
satisfying the monograph standard without requiring the specific
approval of the product by means of a new drug application (NDA) under
section 505 of the act. FDA has issued numerous OTC drug monographs for
certain categories of OTC drug products. If an OTC drug product subject
to a final monograph is labeled for indications that differ from those
set forth in the monograph, then it would be a ``new drug'' under
section 201(p) of the act. In order to be legally marketed and
distributed in interstate commerce, the drug manufacturer would be
required to obtain approval from FDA for that product, and those
conditions varying from the monograph, in an NDA under section 505 of
the act.
All OTC drug monographs place limits on the conditions that have
been found acceptable for inclusion in the monograph by an
administrative rulemaking process based on scientific data. Here, FDA
set certain limits on the labeling of sunscreen drug products in the
final rule, such as the prohibition on specific SPF values over 30,
certain skin aging claims, and other indications for use. FDA is
maintaining similar labeling restrictions in this proposed rule with
respect to skin aging claims and other indications proposed by the
comments. Also, as described elsewhere in this document, the revised
``sun alert'' in the ``Warnings'' section does not include any skin
aging claims (see section III.G, comment 19 of this document). However,
FDA is proposing to increase the SPF labeling limit from 30 to 50,
based on additional data that was submitted subsequent to the issuance
of the FM. FDA is also proposing that the term ``SPF 50+'' can be used,
rather than the term ``SPF 30+'' allowed in the FM. This increase in
the SPF labeling limit addresses, in part, the comments' request that
FDA allow specific labeled SPF values over 30.
Elsewhere in this document, FDA explains the reasons for the
specific labeling proposals, such as the required SPF labeling, revised
``sun alert'' in the ``Warnings'' section of the Drug Facts box, and
indications for use (see section III.F, comment 15 and section III.G,
comments 16, 17, and 19 of this document). FDA also explains our denial
of specific labeling claims suggested by the comments, including the
prohibition on specific SPF values over a certain threshold (SPF 50),
skin aging claims, and additional indications for use (see section
III.F, comments 15 and 17 of this document). As noted earlier in this
comment, any variation from these labeling conditions in the monograph,
if finalized, would cause an OTC sunscreen drug product to be a new
drug requiring an approved NDA before it could be legally marketed in
the United States.
The labeling requirements in this proposed rule would not violate
the first amendment. FDA's requirements for the disclosure of
information in the labeling of OTC sunscreen drug products are
constitutionally permissible because they are reasonably related to the
Government's interest in promoting the health, safety, and welfare of
consumers and because they are not an ``unjustified or unduly
burdensome'' disclosure requirement that offends the first amendment
(see Zauderer v. Office of Disciplinary Counsel, 471 U.S. 626, 651
(1985); see also Ibanez v. Florida Dep't of Bus. and Prof'l Regulation,
512 U.S. 136, 146 (1994)). The reasonable relationship between the
required labeling disclosures proposed herein and the Government's
interest is plain here.
The proposed labeling disclosures addressed by the comments, such
as the SPF value, indications for use, and revised ``sun alert,'' would
contribute directly to the safe and effective use of OTC sunscreen drug
products. The SPF value and indications for use are critical components
of labeling that allow consumers to understand more clearly a sunscreen
product's use in preventing sunburn and relative level of UVA/UVB
protection. As explained elsewhere in this document, the revised ``sun
alert'' we propose to require in the ``Warnings'' section would help
consumers understand more clearly the role of sunscreens as part of a
comprehensive sun protection program (see section III.F, comment 19 of
this document). The greater consumer understanding resulting from all
of these labeling conditions would promote directly the proper use of
sunscreens, which, in turn, would better ensure the protection of
public health.
In addition, it would not be ``unduly burdensome'' to sunscreen
manufacturers to require these labeling disclosures. Finally, it is
important to note that a sunscreen manufacturer could pursue
alternative labeling conditions for its product by filing an NDA with
the appropriate evidence demonstrating the product's safety and
effectiveness under the proposed conditions.
In any event, FDA believes that the labeling requirements outlined
in this proposed rule would pass muster when analyzed under the four-
part test for restrictions on commercial speech set fourth by the
Supreme Court in Central Hudson Gas & Electric Corporation v. Public
Service Commission, 447 U.S. 557 (1980). Under the test, the first
question is whether the commercial speech at issue is false,
misleading, or concerns unlawful activity, because such speech is
beyond the first amendment's protection and may be prohibited. If the
speech is truthful, nonmisleading, and concerns lawful activity, the
Government may nonetheless regulate it if the government interest
asserted to justify the regulation is substantial, the regulation
directly advances the asserted governmental interest, and the
regulation is no more extensive than necessary to serve the government
interest (Id. at 566). The Supreme Court has explained that the last
element of the 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, 109 S.Ct. 3028, 3032-35
(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. Thus, if the speech to be
regulated concerns lawful activity and is not inherently or actually
misleading, the remainder of the test applies (see In re R.M.J., 455
U.S. 191, 203 (1982)).
Based on the data currently available, FDA believes that the
labeling statements proposed by the comments (i.e., specific SPF values
above FDA's established threshold, skin aging claims, and certain other
indications) would not be protected speech and may be prohibited under
the first prong of the Central Hudson test. FDA has tentatively
determined that these proposed labeling statements would be inherently
misleading on OTC sunscreen products sold and, thus,
[[Page 49079]]
misbrand the products under section 502(a) and 201(n) of the act.
Because FDA believes these labeling statements are inherently
misleading, they would not be subject to protection under the first
prong of the Central Hudson test.
With respect to the labeling limitations for SPF values, based on
current data, FDA believes that the labeling of sunscreens with
specific SPF values greater than 50 would be inherently misleading. As
discussed elsewhere in this document, FDA is concerned with the
accuracy and reproducibility of test results showing protection greater
than SPF 50 due to the lack of adequate validation data (see section
III.F, comment 15 of this document). FDA had the same concern with SPF
values above 30 when we published the FM in 1999. At that time, FDA had
only received data demonstrating that the SPF test produces accurate
results for products with SPF values of 30 or less. Since publication
of the FM, FDA has received additional SPF testing data for sunscreen
products with SPF values between 30 and 50 (Ref. 13). However, FDA has
not received any data for sunscreen products with SPF values greater
than 50. The data submitted to FDA indicate that the SPF test is
accurate and reproducible for sunscreen products with SPF values up to
50 (Ref. 13). However, these data cannot be extrapolated to SPF values
above 50. Thus, FDA is proposing to allow specific labeled SPF values
only up to 50.
Increasing variability in test results is likely with increasing
SPF values. If there is large variability in test results, then the SPF
value determined from the test is not accurate (i.e., an SPF 60 product
may not actually be an SPF 60 product). The submitted data demonstrated
that variability is not an issue for sunscreen products with SPF values
up to 50. However, FDA is concerned that variability will become an
issue for sunscreen products with SPF values over 50.
For those sunscreens with SPF values above 50, FDA is proposing
that the labeling can denote such values by a ``50+'' designation. As
discussed elsewhere in this document, FDA has sufficient assurance that
a result over 50 from the required SPF test is, in fact, greater than
50 and can be labeled ``50+'' (see section III. F, comment 15 of this
document). Thus, FDA believes that the term ``50+'' is truthful and
nonmisleading on the label of OTC sunscreen drug products for which the
SPF test in the monograph has indicated an SPF value greater than 50.
However, without proper validation of specific SPF values above 50,
there is no assurance that the specific values themselves are in fact
truthful and not misleading. Thus, labeling of specific values above
SPF 50 without appropriate validation (which FDA currently lacks) would
be inherently misleading. As noted elsewhere, FDA invited any
interested parties to submit such validation data for consideration by
FDA and possible inclusion of specific values above SPF 50 in the FM.
With respect to anti-aging, skin cancer, and sun damage claims
proposed by the comments, as discussed elsewhere in this proposed rule,
FDA is concerned that these statements would be false or misleading due
to lack of sufficient data in support of these claims (see section
III.F, comment 17 of this document). FDA has reviewed the submitted
articles concerning UV-induced skin damage (i.e., premature aging and
cancer) along with the articles obtained from a search of scientific
literature (Refs. 26 through 34). As discussed elsewhere, although FDA
has concluded that the studies support the conclusion that exposure to
UV rays increase the risk of premature skin aging, the study data fails
to show that sunscreen use alone helps prevent premature skin aging and
skin cancer for several reasons (see section III. F., comment 17 of
this document).
First, with respect to premature skin aging, the studies have not
completely defined the action spectrum for the majority of UV
radiation-induced effects on human skin. Second, the inability to
identify the exact UVB and UVA wavelengths that induce each
histological change in skin derives from the study designs. Without
knowing which UVB and UVA wavelengths induce each histological change
in the skin, FDA is unable to determine which wavelengths are most
important to causing skin aging and cannot determine the action
spectrum for aging. Third, the studies did not examine the chronic,
long-term consequences of UV radiation exposure in human skin. Fourth,
although the studies that examined the ability of sunscreens to protect
against UV radiation-induced histological changes in the skin provide
useful data, it is difficult for FDA to conclude that sunscreen use
alone helps prevent skin aging based on these studies.
Likewise, FDA is not aware of data demonstrating that sunscreen use
alone helps prevent skin cancer. Like skin aging, these are studies
examining the effects of sunscreen drug products on short-term factors
for skin cancer, such as sunburn and other cellular damage. However, it
is difficult to extrapolate these short-term adverse effects of UV
radiation to a long-term, chronic effect such as skin cancer. In
addition, like skin aging, the complete action spectrum for skin cancer
is not known at this time.
For all these reasons, FDA has tentatively concluded that the
available evidence fails to show that sunscreen use alone helps
prevents skin cancer or premature skin aging. Thus, the anti-aging,
skin cancer, and sun damage claims proposed by the comments would be
false or misleading due to lack of sufficient data in support of these
claims. For example, the statement proposed by one comment that
sunscreen use ``may help prevent sun-induced skin damage, such as
premature skin aging'' would be inherently misleading to consumers by
suggesting that sunscreen use alone may help prevent premature skin
aging. As explained in this response, the available data fail to show
that sunscreen use alone helps prevent premature skin aging and skin
cancer.
As described elsewhere, FDA is proposing a revised ``sun alert'' so
that the labeling of OTC sunscreen drug products include the most
accurate information, based on the available scientific evidence,
concerning the relationship of sunscreen use to the prevention of
sunburn, skin cancer, and premature skin aging caused by UV exposure
(see section III.F, comment 19 of this document). The revised ``sun
alert'' also includes a statement about limiting sun exposure and
wearing protective clothing because FDA has tentatively determined that
it is critical for consumers to understand the role of sunscreen use in
a comprehensive sun protection program. As FDA has explained, the
available evidence strongly suggests that consumers rely more heavily
on sunscreens alone without taking other protective measures against
sunlight, particularly when the labeling of products indicates the
potential for greater protection (see section III.F, comment 19 of this
document). By indicating the potential for greater protection than is
supported by the available evidence, the proposed anti-aging, skin
cancer, and other related claims would mislead consumers into relying
more heavily on sunscreens alone. Such excessive reliance would
undermine consumers' protection from the sun and, thus, FDA's public
health mission.
FDA has also preliminarily determined that the proposed labeling
statements would concern unlawful activity which are not protected
speech under the first prong of the Central Hudson test.
[[Page 49080]]
FDA is proposing specific conditions in the monograph under which
OTC sunscreen drug products would be GRASE. Elsewhere, FDA explains how
the labeling statements proposed by the comments would not be
appropriate monograph indications for these sunscreen products (see
section III.G, comment 17 of this document). Thus, the proposed
labeling statements outside the proposed indications of the final
monograph, as FDA proposes to revise it, would promote a sunscreen drug
product for use as an unapproved new drug, which is illegal. In
addition, any variation in the statements in a ``Warnings'' section of
a final monograph, such as the revised ``sun alert'' statement in this
proposed rule, would be outside the monograph conditions and, thus,
would promote the product as an unapproved new drug. The marketing and
distribution in interstate commerce of an OTC sunscreen drug product
with such labeling variations would be prohibited under sections 301(d)
and 505(a) of the act. Speech promoting such an illegal activity may be
restricted without violating the first amendment (Central Hudson, 447
U.S. at 563-564).
If a manufacturer could circumvent the requirements and
restrictions imposed by a final monograph by including nonmonograph
labeling statements, or excluding required monograph statements, based
on its own assertions of the alleged appropriateness and truthfulness
of the statements, then such activity would significantly undermine the
monograph system and FDA's assurance that OTC drugs are safe and
effective for their labeled conditions. FDA has assessed the labeling
statements proposed by the comments and preliminarily determined that
they are not justified by the available scientific evidence as GRASE
conditions for the monograph. Instead, in order to legally market a
sunscreen drug product with such labeling statements, an interested
manufacturer would have to submit an NDA to FDA with the appropriate
evidence to show the safety and effectiveness of the drug under the
proposed nonmonograph labeling conditions. Requiring premarket FDA
review and authorization of such nonmonograph drug claims ensures that
such claims will be evaluated by a public health agency that has
scientific and medical expertise so that only products that are safe
and effective will be permitted to be sold for therapeutic purposes.
Although this preliminary-determination that the labeling
statements at issue would be inherently misleading and would concern
unlawful activity would obviate the need for FDA to address the other
three prongs of the Central Hudson test, we believe that the labeling
requirements proposed in this document would satisfy each of the parts
of this test. With respect to the second prong, FDA's interest in the
required labeling disclosures and prohibitions addressed by the
comments would contribute directly to the safe and effective use of
these OTC sunscreen drug products, which is critical for the protection
of public health. FDA's interest in protecting the public health has
been previously upheld as a substantial government interest under
Central Hudson (see Pearson v. Shalala, 164 F.3d 650, 656 (D.C. Cir.
1999) (citing Rubin v. Coors Brewing Co., 514 U.S. 476, 484-485
(1995)).
The proposed labeling requirements would directly advance this
interest, thereby satisfying the third prong of the Central Hudson
test. By requiring labeling disclosure of the SPF value, the proposed
revised ``sun alert,'' and indications for use, FDA can better assure
that consumers understand more clearly the use of sunscreens in
preventing sunburn, their relative UVA/UVB protection, and their role
as part of a comprehensive sun protection program. The greater consumer
understanding resulting from all of these labeling conditions would
promote directly the proper use of sunscreens, which, in turn, would
better ensure the protection of the public health.
Likewise, this proposed rule's exclusion from the monograph of the
labeling statements proposed by the comments also directly advances
FDA's public health interest. FDA has preliminarily determined from the
available evidence that these statements would not be appropriate
conditions for OTC use under the monograph. Thus, the statements would
directly undermine the protection of public health. In addition, it is
important to note that the Pearson court, in assessing whether the
specific dietary supplement regulations at issue directly advanced
FDA's stated public health goals under the third prong of the Central
Hudson test, explained that its findings under this prong did not apply
to drugs, where ``the potential harm is presumably much greater'' than
other products (Pearson, 164 F. 3d at 656, n 13).
Finally, under the fourth prong of the Central Hudson test, there
are not numerous and obvious (Cincinnati v. Discovery Network, 507 U.S.
410, 418 n. 13 (1993)) alternatives to the required labeling statements
or labeling prohibitions proposed herein. Consumers are accustomed to
using the label as their primary source of information about a drug
product's contents and use. Neither a public education campaign, nor
encouraging OTC drug product manufacturers to provide information, such
as that in the proposed revised ``sun alert,'' to consumers by other
means, would ensure that people have the information they need about
sunscreen products at the point of sale or use. Likewise, with respect
to the alternative labeling statements proposed by the comments, FDA's
proposed indications and revised ``sun alert'' present the relevant
public health information to consumers in the clearest and most direct
manner. Thus, FDA's proposed indications and prohibition of other
labeling statements are not more extensive than necessary. In this way,
the required labeling disclosures and prohibitions proposed in this
document would meet the fourth prong of the test.
Furthermore, the proposed prohibition of claims in a final
monograph does not prevent such claims from being approved in an NDA.
As explained previously, a final monograph sets forth those conditions,
including labeling, under which an OTC drug product would be considered
GRASE and not misbranded. In issuing monographs, FDA considers whether
the available scientific evidence demonstrates that OTC drug products
within a therapeutic category are GRASE. A final monograph does not
constitute an FDA decision regarding an NDA for an OTC drug proposing
variations in these conditions. Thus, FDA's proposals in this document
would not prohibit any interested manufacturer from filing an NDA, with
the appropriate evidence, for any variations from the monograph
labeling conditions. Because of this significant available option to
manufacturers for proposing alternative labeling statements, FDA's
proposed labeling requirements and prohibitions are not more extensive
than necessary.
In conclusion, FDA believes it has complied with its burdens under
the first amendment to support the labeling requirements of this
proposed rule.
(Comment 12) One comment stated that voluntary professional
labeling can be provided to physicians that will allow them to select
or recommend sunscreen products for their patients' needs, based on
more detailed information describing the quantity (protection factor)
and the range of UV protection (e.g., UVB, UVA, or UVB/UVA protection).
Another comment stated that FDA should not require professional
labeling because complete
[[Page 49081]]
and accurate product labeling should be available to all consumers, not
just to their health care providers.
FDA defines professional labeling in OTC drug monographs as
labeling that is provided to health professionals but not to the
general public (i.e., not directly to consumers) (for example, see
Sec. 331.80 (21 CFR 331.80)). In the final rule, FDA stated that it
would consider professional labeling, such as protection against
photosensitization reactions, if data were received (64 FR 22666 at
27674). FDA has not received any data to date. Therefore, FDA is not
proposing any professional labeling in this document. FDA will consider
professional labeling for OTC sunscreen drug products in the future if
specific supportive data are provided.
(Comment 13) Some comments objected to the ranges of SPF values
that define the product category designations (PCDs) in Sec. 352.3(b).
Stating that standard public health messages recommend use of a
sunscreen with at least an SPF of 15, the comments contended that the
``moderate'' PCD (SPF values of 12 to under 30) may cause consumers to
believe that SPF values of less than 15 provide adequate protection.
One comment further stated that if the PCD range is from SPF 12 to 29,
manufacturers will only produce the minimum SPF value as they can use
less active ingredients and get the same PCD classification.
As discussed in the final rule (64 FR 27666 at 27681), the PCD
ranges in Sec. 352.3(b) and Sec. 352.52(e) reflect a modified,
simpler, combined version of the previously proposed five PCDs and the
``Recommended Product Guide.'' However, FDA agrees with the comments
that the current standard public health message from public health
organizations generally recommends use of a sunscreen with an SPF value
of at least 15 (see section III.G, comment 19 of this document). We
also agree that allowing SPF values below 15 in any but the lowest PCD
range may appear to contradict this message. Therefore, FDA is
proposing to modify the PCD SPF value range in proposed Sec.
352.3(c)(1) from ``2 to under 12'' to ``2 to under 15'' and in proposed
Sec. 352.3(c)(2) from ``12 to under 30'' to ``15 to under 30.'' FDA is
also proposing to replace the PCD terms ``minimal'' and ``moderate''
with the simpler terms ``low'' and ``medium,'' respectively, and to use
these simpler terms for the UVA radiation protection categories (see
section III.E, comment 14 of this document). These labeling changes
will provide consumers with familiar and consistent terms describing
both UVA and UVB radiation protection.
FDA disagrees with the comment contending that manufacturers will
only produce the minimum SPF value in a given PCD range because they
can use less active ingredients and get the same PCD classification.
Section 352.50 of the current FM requires the SPF value to appear on a
sunscreen product's PDP. This proposed rule would not change that
requirement. Thus, while the PCD provides additional information about
the SPF value, consumers seeking higher SPF values can readily identify
such products by the SPF value stated on a sunscreen product's PDP.
E. Comments on the Labeling of Sunscreen Drug Products With UVA
Protection
(Comment 14) Many comments discussed ways to categorize, phrase,
and display UVA/UVB radiation protection on an OTC sunscreen drug
product label. All of the comments stated that the SPF value should
retain preeminence on the label's PDP and be the consumers' criteria
for choosing an OTC sunscreen product. Some comments recommended that
UVA radiation protection be stated on the PDP in descriptive words or
simple phrases, rather than numbers or symbols, for the following
reasons:
Simplicity,
Clarity,
To avoid confusion with SPF, and
To maximize consumer comprehension.
Some comments referenced consumer research, discussed in subsequent
paragraphs, to support this recommendation (Refs. 4 and 5).
One comment suggested the following labeling statements:
``Protects against UVA rays''
``screens out UVA rays''
``shields from UVA rays''
``broad spectrum sunscreen''
``UVA/UVB protection''
``provides protection against both UVB and UVA rays''
other truthful and nonmisleading statements describing a
quantification of the product's UVA radiation protection
The comment stated that quantification of the UVA radiation protection
should be allowed in labeling, but not required, so that consumers can
have additional product performance information to help them select
appropriate products.
Another comment stated that UVA radiation protection should be
labeled only as grades of effectiveness (multiple levels) for the
following reasons:
UVA radiation irritation induces various skin reactions
(e.g., erythema, pigment darkening, skin cancer, and photodermatitis),
and
Some action spectra of damages have not been determined.
This comment referred to The Japan Cosmetic Industry Association (JCIA)
Measurement Standards for UVA Protection Efficacy (Ref. 6), which
recommend labeling UVA protection as three grades: (1) PA+, (2) PA++,
or (3) PA+++.
Several comments recommended two categories of UV protection
labeling based on the ratio of UVA radiation protection factor to SPF
value:
``with UV protection'' if ratio equals 0.20
``with extra UV protection'' if ratio equals 0.25
The proposed ratio is based on the UVA radiation protection factor as
determined by the persistent pigment darkening (PPD) test method (see
section III.N, comment 46 of this document). These comments stated
that, because the ratio of damage from solar UVB radiation to that of
solar UVA radiation is 80:20 over a day, a sunscreen must protect
against an 80:20 ratio of UVB to UVA radiation. The comments also
recommended that products labeled ``with UV protection'' or ``with
extra UV protection'' exhibit absorbance of 360 nanometers (nm) and
longer wavelengths.
Another comment suggested two categories to state overall UV
radiation protection: ``regular'' and ``broad spectrum.'' The comment
proposed that the ratio of a sunscreen product's SPF value to its UVA
protection factor be the single criterion for the ``broad spectrum''
designation, with the maximum ratio no greater than 4:1. For example,
an SPF 16 product would need to provide a UVA protection factor of at
least 4 to be designated ``broad spectrum.''
One comment disagreed with the previous comment, stating that there
is no supportable scientific basis for the relevance of the 4:1 ratio.
The comment argued that the ratio inappropriately combines, in the same
equation, SPF values obtained with a solar simulator and solar
irradiance values at low sun angles.
Another comment suggested that sunscreen products with an SPF value
of 2 or greater must have a UVA protection factor of at least 2 to be
labeled ``UVA/UVB'' or ``broad spectrum protection.'' The comment
stated that products with SPF values of at least 15 and UVA protection
factors of at least 4 may be labeled ``extra (or extended or enhanced)
UVA protection.'' The comment stated that these criteria are
independent of test method and should apply to any of the proposed UVA
radiation test methods.
Another comment proposed establishing PCDs based on the UVA
[[Page 49082]]
radiation protection value obtained by the PPD test method. The comment
suggested four PCDs that would enable consumers to choose the desired
levels of protection:
``moderate''
``high''
``very high''
``extra''
Another comment recommended three PCDs:
``low UVA protection''
``moderate UVA protection''
``maximum UVA protection''
Another comment suggested using the five PCDs proposed in the TFM (58
FR 28194 at 28295) and added a UVA protection factor number for each
PCD based on the immediate pigment darkening (IPD) test method.
Two comments recommended a four-star rating system to describe UVA
radiation protection. The comments stated that this system, based on
the ratio of UVA to UVB radiation absorbance, would provide a simple
method for consumers to determine the protective nature of an OTC
sunscreen drug product. The absorbance ratio would range from 0 for
products exhibiting no protection against UVA radiation to 1 for
products exhibiting equal absorption at all wavelengths throughout the
UVA/UVB radiation spectrum. Using this ratio, products would be
classified in one of the following five categories:
0 to < 0.2 = no UVA radiation protection claim
0.2 to < 0.4 = Moderate ([starf])
0.4 to < 0.6 = Good ([starf][starf])
0.6 to < 0.8 = Superior ([starf][starf][starf])
0.8 plus = Maximum ([starf][starf][starf][starf])
Another comment recommended a five point rating system using the
``critical wavelength'' (CW) ([lgr]c) test method. This
system uses a scale analogous to the star rating system to assign
products a ``broad spectrum'' rating as follows:
[lgr]c < 325 = ``0''
325 < [lgr]c < 335 = ``1''
335 < [lgr]c < 350 = ``2''
350 < [lgr]c < 370 = ``3''
370 < [lgr]c = ``4''
Several comments supported a single claim, such as ``provides broad
spectrum protection against UVB and UVA radiation,'' based on
determining a sunscreen pass/fail CW ([lgr]c). Comments that
supported this ``broad spectrum protection'' claim stated that, in
combination with SPF, it provides simple and accurate labeling that is
easily understood by consumers. The comments referred to a research
study that suggested this approach to UVA radiation protection labeling
was superior for consumer comprehension and ease of product selection
(Ref. 7). Other comments provided consumer research data, discussed
elsewhere in this comment, suggesting this approach was least preferred
by consumers (Refs. 4 and 8).
One comment stated that UVA radiation protection claims should be
allowed for sunscreen products with SPF values of 4 and higher. The
comment added that, for products claiming to protect against UVA and
UVB radiation, a minimum UVA protection factor of 2 should be required
if the SPF value is less than or equal to 12.
Several comments stated that sunscreen drug products labeled as
``full spectrum'' or ``broad spectrum'' should protect consumers from
substantially all of the harmful effects of the sun, including sunburn
associated with UVA radiation. According to one comment, sunscreen drug
products labeled ``full spectrum'' or ``broad spectrum'' that do not
protect against nearly all UVB and UVA radiation wavelengths seriously
risk misleading consumers into believing they are fully and completely
protected from the dangers of the sun. One comment recommended using
the claim ``full spectrum'' rather than ``broad spectrum'' to describe
products that attenuate more than 90 percent of UVA radiation and are
at least SPF 15. The comment suggested no UVA radiation protection
claims be allowed if the product is below SPF 15.
In support of their proposed UVA labeling, a number of comments
provided results from consumer research studies that assessed consumer
labeling preferences for stating UVA radiation protection. One comment
described a 1996 survey (Ref. 4) in which 275 subjects compared two
labeling systems:
3-level descriptive (``light,'' ``intermediate,'' or
``extended'' ``UVA protection'') and
Grapho/numerical (a bar graph indicating a level, 0, 4, 8,
or 12, with the corresponding number appearing alongside the graph).
The comment stated that the survey data suggested that, while equally
able to understand both types of labels, the panelists preferred the
grapho/numerical system over the descriptive system.
Another comment described two consumer research studies, conducted
in 1994 and 1995 (Ref. 9), in which 235 subjects compared three
potential UVA radiation labeling options:
Numerical (2, 3, or 5),
Symbolic (4 stars with 1, 2, 3, or 4 stars filled), and
3-level descriptive (labeled blank if no UVA radiation
protection provided or labeled ``UVA and UVB Protection'' or ``UVB Plus
Extended UVA Protection,'' depending on the level of UVA radiation
protection provided).
The studies included focus group discussions and indepth interviews.
The comment stated that the data suggested that a numeric designation
for UVA radiation protection (in addition to the SPF value) created
confusion for consumers and that symbols (i.e., stars) misled consumers
into giving equal or greater importance to the UVA radiation rating
compared to the SPF value. The comment concluded that a descriptive
approach better conveyed to consumers the added benefit of UVA
protection without detracting from the SPF value.
Another comment described two consumer research studies conducted
in 1999 (Ref. 7) in which 2,238 consumers assessed three sunscreen
product labeling systems:
A pass/fail descriptive (labeled blank if no UVA
protection provided (i.e., fails) or labeled ``Broad Spectrum UVA and
UVB Protection'' if UVA radiation protection provided (i.e., passes)),
A 3-level descriptive (labeled blank if no UVA radiation
protection provided or labeled ``UVA and UVB Protection'' or ``UVB Plus
Extended UVA Protection,'' depending on the level of UVA radiation
protection provided), and
A 3-level grapho/numerical (a bar graph indicating a
level, 4, 8, or 12, with the corresponding number appearing alongside
the graph).
The comment stated that the data suggested the pass/fail descriptor,
``broad spectrum,'' was significantly superior to the other labels and
recommended that FDA use this labeling to designate UVA radiation
protection.
Another comment described a consumer research study conducted in
2000 (Ref. 8) at 20 urban and suburban shopping malls in which 1,921
subjects ranked four labeling systems:
4-level numerical,
4-level symbolic,
4-level descriptive, and
Pass/fail descriptive (``with/without broad spectrum UVA/
UVB protection'').
The numerical labeling system was shown as Arabic numerals ``1, 2, 3,
4'' with the number ``2'' highlighted. The descriptor labeling system
was shown as the words ``Minimum, Moderate, High, Maximum'' with the
word ``Moderate'' highlighted. The symbolic labeling system was shown
as a picture of four stars with two stars highlighted.
[[Page 49083]]
The comment concluded that the subjects had a significant
preference for a labeling system based on descriptive words or numbers
because of clarity, specificity, and ease of comprehension. Subjects
least preferred the pass/fail system because they found it unclear,
nonspecific, and lacking sufficient information to compare sunscreen
products. This study also revealed that the numerical labeling system
was one of the top two choices because numbers were ``clearer, more
specific, and easier to understand.'' Age, gender, and educational or
ethnic background were reported as not affecting the study results.
In the TFM for OTC sunscreen drug products (58 FR 28194 at 28233),
FDA proposed to allow claims relating to ``broad spectrum protection''
or ``UVA radiation protection'' for OTC sunscreen products that meet
the following two criteria:
1. Contain sunscreen active ingredients with absorption spectra
extending to 360 nm or above, and
2. Demonstrate meaningful UVA radiation protection using
appropriate testing procedures to be developed.
In the FM for OTC sunscreen drug products (64 FR 27666 at 27672), FDA
stated that UVA radiation labeling of OTC sunscreen drug products could
continue in accordance with the TFM and its amendments until addressed
in a future issue of the Federal Register. Elsewhere in this document,
FDA is proposing test methods for determining the UVA radiation
protection potential of an OTC sunscreen drug product (see section
III.N, comment 46).
FDA believes that the existing data do not clearly define the
relationship between UVA radiation and skin damage. The principal
reason for not better understanding this relationship is that the
action spectra for specific types of UVA radiation-induced skin damage
(i.e., which wavelengths of UVA cause which types of skin damage) have
not been established. However, most scientific data demonstrate that
UVA radiation is harmful to the skin. Thus, until these action spectra
are known, FDA believes that more protection against UVA radiation
damage is better for consumers' health. Therefore, FDA believes it is
important, as with the SPF value, to designate UVA radiation protection
in a straightforward manner that consumers clearly understand.
FDA proposes that the UVA radiation protection of an OTC sunscreen
drug product determined from these UVA test methods be designated on
the PDP using a combination of category descriptors (i.e., ``low,''
``medium,'' ``high,'' or ``highest'') and stars (i.e., symbols) similar
to those described by some of the comments. The category descriptors
and stars will designate relative levels of UVA radiation protection as
measured by the UVA radiation test methods. The level of UVA radiation
protection identified on the label reflects the following:
A numerical ``UVA protection factor'' (from the clinical
test), and
A numerical ratio of UVA I (340 to 400 nm) radiation
absorption to UVB/UVA (290 to 400 nm) radiation absorption (from the in
vitro test).
The test that indicates the lowest level of UVA radiation protection
determines the level identified on the label. For example, if the
clinical test indicates ``low'' protection and the in vitro test
indicates ``medium'' protection for a product, the product is labeled
as providing ``low'' UVA radiation protection. This system comprises
four categories of UVA radiation protection as described in table 1 of
this document.
Table 1.--Overall UVA Protection of a Sunscreen Drug Product
------------------------------------------------------------------------
Star category Category descriptor
------------------------------------------------------------------------
[starf][star14][star14][star14] Low
[starf][starf][star14][star14] Medium
[starf][starf][starf][star14] High
[starf][starf][starf][starf] Highest
------------------------------------------------------------------------
Some of the comments argued that the UVB radiation protection
labeling is more important than UVA radiation protection and should be
emphasized in the labeling over UVA radiation protection. FDA disagrees
with the comments and proposes that the UVA radiation protection
designation appear on the PDP along with the SPF value in an equally
prominent manner that does not conflict with the SPF value. Because
action spectra for UV-induced skin damage have not been clearly
defined, FDA is unable to specify labeling for OTC sunscreen drug
products that indicates what ranges of UV radiation are most harmful to
consumers. In other words, FDA cannot conclude whether UVB or UVA
radiation is more harmful to humans based on the scientific data
collected to date. Therefore, FDA considers both UVB and UVA radiation
protection equally important at this time because scientific data
demonstrates that both have harmful effects on the skin.
So that consumers consider UVB and UVA radiation protection equally
in selecting an OTC sunscreen drug product, FDA is proposing a number
of labeling requirements. Under this proposal, the font size of the
stars and category descriptors for UVA radiation protection must be the
same size as the SPF value and its descriptors. All four stars must
appear and be preceded by the term ``UVA'' and followed by the
appropriate category descriptor (e.g., UVA
[starf][starf][starf][star14] High). All star borders and the color
inside a solid star must be the same while the color of ``empty'' stars
must be lighter and distinctively different than solid stars. The color
inside a solid star must be distinctively different than the background
color. The stars must be filled in starting with the first star on the
left and must appear in a straight horizontal line.
As requested by some comments, an OTC sunscreen drug product that
does not provide the minimum UVA protection, as determined by the
proposed UVA test methods, may only display an SPF value on the PDP. An
OTC sunscreen drug product is not required to provide UVA protection
and may bear only a sunburn (UVB/SPF) protection claim. However, FDA is
proposing that a sunscreen product that does not provide at least a
``low'' level of UVA protection include the following statement on the
PDP: ``no UVA protection.'' This statement must be the same font size
as the SPF value and its descriptor. FDA is not proposing four empty
stars because we are concerned that consumers may confuse products
providing no UVA protection (i.e., four empty stars) with those
providing the highest UVA protection (i.e., four filled stars).
In developing this UVA radiation protection labeling, FDA has
particularly considered the label comprehension studies (Refs. 4, 7, 8,
and 9). These studies used multiple methodologies and report a diverse
range of preferences for each labeling system:
Category descriptors,
Graphics,
Symbols,
Numerics, and
``Pass/fail'' descriptors.
The diverse results and varying methodology make it difficult to
identify a clear preference for one labeling system. However, the
studies indicate an overall preference for category descriptors.
In agreement with the studies, FDA is proposing category
descriptors to indicate the relative level of UVA radiation protection.
As discussed in preceding paragraphs, FDA believes consumers should
consider UVB and UVA radiation protection equally when selecting an OTC
sunscreen drug product. For this reason, FDA is proposing that stars be
used with category descriptors. FDA believes that
[[Page 49084]]
the category descriptor and star labeling for UVA radiation protection
will give it equal prominence with UVB radiation protection (i.e.,
category descriptor and SPF) on the PDP.
FDA is not proposing grapho/numeric labeling because we are
concerned that consumers may be confused by a second number on the PDP
(i.e., in addition to the SPF value). FDA is also not proposing any of
the simple two-category designations suggested by the comments:
With/without UVA protection,
With UVA protection/with extra UVA protection, or
Regular/broad spectrum protection.
FDA agrees with one of the comments, which argued that these types of
statements are misleading. FDA does not consider this labeling as
providing consumers with enough information about the magnitude of UVA
protection offered by an OTC sunscreen product. However, FDA does not
object to the use of the following four statements for OTC sunscreen
drug products that satisfy the requirements of proposed Sec. 352.73
for a labeled UVA protection value:
``broad spectrum sunscreen'',
``provides [select one of the following: `UVB and UVA,' or
`broad spectrum'] protection'',
``protects from UVB and UVA [select one of the following:
`rays' or `radiation']'', and
[select one of the following: ``absorbs'' or ``protects'']
``within the UVA spectrum''.
These statements may appear elsewhere in product labeling outside the
``Drug Facts'' box or enclosure but not intermixed with the information
required on the PDP under Sec. 352.50. FDA agrees with some comments
that these statements, by themselves, may be misleading by implying
that a sunscreen protects against nearly all UVB and UVA radiation.
However, FDA does not believe these optional statements will be
misleading in the context of the entire label, because the relative
level of UVB and UVA protection must be stated on sunscreen product
labels (alongside these more general statements).
Although none of the studies combined labeling systems as proposed
in this document, FDA believes the studies support use of category
descriptors and symbols together. One study suggested that symbols may
imply importance over SPF values (Ref. 9). However, FDA believes
consumers will not place greater importance on UVA protection because
we are proposing a required statement to inform consumers about the
importance of both UVB and UVA protection. We are proposing to require
one of the following statements on the PDP of all OTC sunscreen drug
products:
``UV rays from the sun are made of UVB and UVA. It is
important to protect against both UVB & UVA rays.''
``UV rays from the sun are made of UVB and UVA. It is
important to protect against both UVB & UVA rays to prevent sunburn and
other skin damage.''
FDA believes that the use of one of these statements, along with the
proposed UVB and UVA radiation protection labeling, including the
format requirements described in preceding paragraphs, will lead
consumers to view UVB and UVA radiation protection as equally
important.
In addition, this statement will educate consumers about UVA
radiation, which will be a new term and concept to many consumers. The
proposed statement should help consumers better understand the new UVB
and UVA labeling when it is initially introduced to the OTC market.
Thus, FDA believes that the consumer label comprehension studies, along
with the proposed educational statement about UVB and UVA radiation,
support the stars and descriptor UVA radiation protection labeling
proposed in this document. Moreover, a similar ``star rating system''
for UVA radiation protection (i.e., the Boots Star System) has been
used to label sunscreen products throughout Europe for over 10 years.
To prevent consumer confusion about UV radiation protection, FDA is
proposing changes to UVB radiation protection labeling (i.e., the SPF
value). SPF values indicate how effective a sunscreen product is in
protecting against sunburn. By displaying the relative level of sunburn
protection on the sunscreen drug product PDP in terms of an SPF value,
consumers can choose their desired level of UVB radiation protection.
To further improve consumers' understanding of the sunburn protection
level provided by a certain sunscreen product, FDA is proposing to
require descriptive terms of relative sunburn protection (i.e.,
``low,'' ``medium,'' ``high,'' and ``highest'') to accompany the SPF
value on the PDP. FDA is further proposing that the SPF value must be
preceded by the term ``UVB'' to further differentiate the SPF value
from the UVA symbol/descriptor on the PDP. FDA believes that numerical
labeling for UVB protection, symbolic labeling for UVA protection, and
the same descriptive labeling for UVB and UVA protection will allow
consumers to easily understand and choose from relative levels of UVB
and UVA radiation protection.
FDA is aware that consumers have used and become accustomed to
choosing OTC sunscreen drug products based on the SPF value for many
years. Likewise, FDA believes that, over a period of time, consumers
will similarly become accustomed to the proposed labeling using symbols
and descriptors to designate relative UVA radiation protection.
Furthermore, FDA believes consumer familiarity with similar star rating
systems (e.g., movies, hotels, and restaurants) used for many years in
the United States provide a basis for consumers' understanding of this
proposed labeling for OTC sunscreen drug products.
FDA is providing a number of examples of how the UVA/UVB protection
designations could appear on the PDP.
[[Page 49085]]
[GRAPHIC] [TIFF OMITTED] TP27AU07.003
FDA believes that, as with SPF values, identifying the relative
level of UVA radiation protection provides the most useful information
for consumers. Consumers who desire more protection from the sun will
be able to identify products with higher UVB (SPF) and UVA radiation
protection. FDA agrees with the comments that a product must provide at
least some minimum level of UVA radiation protection (as with SPF
values) to be labeled as providing UVA radiation protection. Therefore,
FDA is proposing minimum criteria for the lowest UVA category in its
proposed test procedures (see section III.N, comment 46 of this
document).
F. Comments on the Labeling of Sunscreen Drug Products With High SPF
Values
(Comment 15) Several comments objected to FDA limiting specific
labeled SPF values ``up to but not above 30.'' The comments stated that
data and information supplied to FDA since publication of the sunscreen
FM demonstrate that SPF values over 30 can be safely tested with
accuracy. The comments also argued that removing the limit will not
lead to consumers spending more time in the sun when using high SPF
sunscreens in comparison to low SPF sunscreens. To address that point,
one comment proposed labeling to help reduce potential consumer misuse
of sunscreens with SPF values over 30: ``higher SPF products give more
sun protection, but are not intended to extend the time spent in the
sun.'' Another comment noted that the SPF value, in addition to proper
sunscreen application and reapplication, is only part of a
comprehensive sun protection program.
Other comments explained the need for high SPF sunscreen products.
The comments contended that consumers and physicians are familiar with
and want the many currently marketed sunscreens that are labeled as
``SPF 45, SPF 50, etc.'' Thus, the comments argued that U.S. consumers
will be at a disadvantage within the international community, because
products providing SPF values over 30 are available in other countries.
In addition, the comments stated that many prominent medical
authorities maintain the need for high SPF sunscreens for individuals
at ``high risk'' based on medical and/or occupational concerns and
individuals who desire increased protection from photoaging and
lengthy/intensive sun exposure situations. The comments argued that the
need for high SPF sunscreens is supported by findings that UV exposures
in several cities are considerably higher than previously recognized
and because high SPF products can reduce cumulative UV exposure. The
comments stated that consumer desire for high SPF products is
demonstrated by sales data showing that products with an SPF value of
45 are one of the fastest growing segments of the total sunscreen
market.
The remaining comments discussed the consequences of limiting the
specific labeled SPF value. For example, one comment noted that if
manufacturers cannot state the SPF level above 30, they will no longer
have an incentive to fund research for better sunscreens. In addition,
manufacturers may reformulate products to reduce active ingredients
and, thus, reduce the level of UV protection. A comment argued that
another adverse consequence results from most consumers failing to
achieve the labeled SPF value because they do not apply enough
sunscreen and/or reapply it too infrequently. Because high SPF products
can help make up for such improper use, limiting the specific labeled
SPF value to 30 has a negative impact on UV protection.
A foreign industry organization suggested an upper limit for
labeled SPF values of 50+ and provided three reasons:
Unreasonably high SPF values will lead consumers to expect
``too much effectiveness'' from sunscreen products.
Higher concentrations of sunscreen active ingredients are
not ``in the interest of safety.''
Higher SPF values will invite excessive, meaningless
competition in the industry.
The comment explained that competition would be meaningless because the
amount of UV protection provided by products with SPF values above 50
is not significantly greater than products with an SPF of 50.
Another comment from a sunscreen manufacturer agreed with FDA's
concern about the possibility of increasing variability when testing
high SPF sunscreens. The comment suggested a modified ``binomial'' test
method and labeling requirements for SPF values over 20 that would
allow for high SPF products.
Another comment submitted a published survey of 208 sunbathers on
Miami's South Beach during July 2001 with the goal of measuring UV
radiation exposure and probable injury (Ref. 10). The ``worst case''
scenario identified by the survey was based on sunbathers with Type I
skin (persons most sensitive to sunlight who burn easily and never tan)
exposed to UV radiation near the longest day and highest sun angle of
the year at the ``southern-most major beach'' in the United States. The
survey was a followup to one conducted in 1993 with 62 sunbathers and
evaluated by FDA in the FM (64 FR 27666 at 27674). The 2001 survey
determined MEDs absorbed by the following three steps:
1. Measuring incident UV radiation (using three dosimeters),
2. Multiplying by an adjusting factor for skin type (using a 30
percent
[[Page 49086]]
increase in sensitivity between skin types), and
3. Dividing by the SPF worn by the sunbather.
The survey suggests that sunbathers with Type I skin might receive a
cumulative dose of 49.5 MEDs with 8 hours of exposure. The comment
concluded that, while SPF values up to, and including, 50 are
warranted, values over 50 are unwarranted in any condition for sunburn
protection.
Two comments submitted testing data for sunscreens with SPF values
between 30 and 50 using the test method in the FM. The comments
concluded that the test method was valid for these high SPF values. In
addition, one comment indicated that a very water resistant test for an
SPF 45 to 50 sunscreen would take nearly 4.5 hours using the skin types
of subjects in the SPF testing procedures in the FM (i.e., skin types
I, II, and III) (Ref. 13). The comment concluded that it is beyond the
practical endurance capabilities of many people in the test to spend
more than 5 to 6 hours in front of a UV radiation lamp and that fatigue
can lead to errors in test results. The comment also noted that the
potential for intra and interlaboratory variability in test results
increases as sunscreen SPF values increase.
FDA concluded in the FM (64 FR 27666 at 27675) that test methods
supported specific SPF label values up to 30. FDA invited interested
persons to submit data in support of high SPF test methods and to
consider proposed methods for communicating the level of protection in
labeling. Data and information on high SPF testing and labeling were
submitted to FDA at, and following, public meetings on July 22, 1999,
and October 26, 1999, and after reopening of the administrative record
(65 FR 36319) (see section III.I, comment 24 of this document) (Refs.
11 and 12).
FDA continues to be aware that many OTC sunscreen products with
specific labeled SPF values over 30 are currently marketed, both
nationally and internationally, and are increasingly used by consumers
and recommended by health professionals (64 FR 27666 at 27675). FDA
agrees that these products should be available for those sun-sensitive
consumers who require such products based upon personal knowledge,
planned sun exposure, geographical location, or advice of a health
professional. FDA previously noted the lack of any known safety
problems for sunscreen products with SPF values greater than 30 (64 FR
27666 at 27675). The comment that argued higher concentrations of
sunscreen active ingredients are not ``in the interest of safety'' did
not supply any new data to support its contention. FDA will continue to
monitor adverse drug experience reports for sunscreen drug products
reported to its Medwatch program and in the medical literature.
As noted by one comment, some researchers have raised the concern
that sunscreen use may lead to increased sun exposure. The
``compensation hypothesis'' states that consumers who use high SPF
sunscreens spend more time in the sun and/or use less protective
clothing. The only double blind, randomized trial that addressed this
issue showed a significant increase in sun exposure time when comparing
use of SPF 30 to SPF 10 (Ref. 14). In addition, two retrospective
survey studies showed that sun exposure time is longer when using
sunscreen compared to not using sunscreen (Refs. 15 and 16). Other
studies cited by the comment to support the premise that the
``compensation hypothesis'' is incorrect and either did not provide
data about the length of sun exposure or the study method did not allow
for data interpretation (Refs. 17 through 20). Based on all of this
data, FDA believes that some consumers may increase total UV exposure
through over-reliance on sunscreens. The apparent divergent results on
the validity of the ``compensation hypothesis'' between studies may
indicate that sun protection behaviors vary greatly for each person.
More specifically, there is a spectrum of attitudes about the sun, from
those individuals who seek dark suntans to those who seek to avoid the
sun and consequent UV skin damage (Ref. 21). Such evidence underscores
the need for adequate labeling so consumers can make informed decisions
regarding their use of OTC sunscreen drug products.
FDA agrees that the SPF value is one factor in a comprehensive sun
protection program. However, the SPF is only a measure of protection
from erythema (i.e., UVB radiation-induced sunburn) and does not
measure protection from other UV skin damage, such as that induced by
UVA radiation. While increased short wavelength UVA radiation
protection generally increases with increasing SPF values, studies
using in vivo or in vitro UVA radiation testing methods demonstrate
that sunscreen products with the same SPF values can have markedly
different levels of UVA protection, especially for long wavelength UVA
radiation (Refs. 22 and 23). These studies also indicate that a
specific high SPF product can provide much less UVA radiation
protection than a product with a much lower SPF value. Elsewhere in
this document, FDA is proposing UVA radiation testing methods and
labeling that will categorize the relative levels of protection
provided by the SPF and UVA values of the sunscreen product (see
section III.E, comment 14 and section III.N, comment 45 of this
document), allowing consumers to compare products and choose the levels
of UVB and UVA radiation protection desired.
An SPF 30 sunscreen product may provide adequate sunburn protection
for many consumers. However, FDA believes that appropriately tested and
labeled high SPF value sunscreen products should be available for
consumers who desire or need high levels of UV protection, in
particular, those who burn easily. Such products would do the
following:
Help compensate for inadequate application and/or
reapplication,
Provide additional sunburn protection during intense UV
radiation conditions,
Help reduce cumulative UV radiation exposure (when used in
conjunction with other measures to reduce overall sun exposure), and
Generally provide consumers incremental increases in
sunburn protection.
FDA agrees that SPF values should be supported by scientific
evidence. In the FM, FDA limited the specific labeled SPF value to 30.
At that time, FDA had only received data demonstrating that the SPF
test produces accurate results for products with SPF values of 30 or
less. Since publication of the FM, FDA has received additional SPF
testing data for sunscreen products with SPF values between 30 and 50
(Ref. 13). However, FDA has not received any data for sunscreen
products with SPF values greater than 50. The data submitted to FDA
indicate that the SPF test is accurate and reproducible for sunscreen
products with SPF values up to 50 (Ref. 13). However, these data cannot
be extrapolated to SPF values above 50. Thus, FDA proposes to allow
specific labeled SPF values up to 50.
FDA agrees with the sunscreen manufacturer that increasing
variability in test results is likely with increasing SPF values. If
there is large variability in test results, then the SPF value
determined from the test is not accurate (i.e., an SPF 50 product may
not actually be an SPF 50 product). The submitted data demonstrate that
variability is not an issue for sunscreen products with SPF values up
to 50. However, FDA is concerned that variability will become an issue
for sunscreen products with SPF values over 50.
[[Page 49087]]
FDA recognizes that future data may demonstrate that variability
may not be a problem for sunscreen products with SPF values over 50.
Therefore, FDA will consider specific SPF values greater than 50 upon
receipt of data demonstrating that accurate and reproducible results
can be obtained from the SPF test for sunscreen products with SPF
values over 50. Generally, such data should include results from
multiple laboratories using the same sunscreen formulations and using
the SPF test proposed in this document, along with a statistical
analysis of the overall results. In addition, FDA believes that the
modified ``binomial'' test method submitted by one comment has merit
for high SPF sunscreens and is requesting others' views on this method
during the comment period for this rulemaking (see section III.I,
comment 24 of this document).
In the FM (64 FR 27666 at 27675), FDA disagreed with the comment
that manufacturers would have no incentive to fund research for better
sunscreens and may reformulate to less protective products if there is
an upper limit to specific labeled SPF values. Although FDA would not
want to decrease research incentive, FDA is more concerned about valid
scientific data demonstrating the ability of multiple laboratories to
accurately and reproducibly determine SPF values. However, FDA does not
believe it is necessary to arbitrarily limit specific labeled SPF
values. To the contrary, both in the FM and in this proposal, FDA has
specifically stated that high SPF sunscreens should be available for
those individuals desiring such products. The maximum allowable
specific labeled SPF value, both in the FM and in this proposal, is
based upon the review of data and information submitted to FDA. FDA
purposely did not limit labeled SPF values at 30 in the FM. Instead,
FDA used the value of ``30+,'' pending the receipt of adequate data to
support any higher specific label values.
Similarly, in this document, FDA is proposing the collective value
``50+.'' FDA has sufficient assurance that a result over 50 from the
required SPF test is, in fact, greater than 50 and can be labeled
``50+.'' Thus, FDA believes that the term ``SPF 50+'' is truthful and
nonmisleading on the label of OTC sunscreen drug products for which the
SPF test in the monograph has indicated an SPF value greater than 50.
FDA believes that allowing manufacturers to label sunscreens as ``SPF
50+'' may encourage further research in human skin photobiology and the
development of safe and effective sunscreen drug products with specific
SPF values over 50. As explained earlier in this comment, FDA is not
proposing that the specific value over 50 be stated in the labeling
because there is no data, at this time, demonstrating the accuracy and
reproducibility of the specific value over 50. Based upon the proposed
labeling, improvements to SPF testing methods, and specific high SPF
test data, FDA is proposing to modify the labeled SPF values in current
Sec. 352.50(a)(1) and (a)(2) by changing the SPF values from ``30'' to
``50.''
G. Comments on Indications for Sunscreen Drug Products
(Comment 16) One comment requested that the ``Uses'' statement,
``higher SPF gives more sunburn protection,'' be omitted except for
products with an SPF over 30. This and other comments suggested that
FDA's labeling concerns regarding high SPF sunscreens could be
alleviated if the following statement was required on sunscreens over
SPF 30: ``Higher SPF products give more sun protection, but are not
intended to extend the time spent in the sun.''
FDA is proposing to revise the sunscreen FM ``Uses'' statement
``helps prevent sunburn'' and delete the ``Uses'' statement ``higher
SPF gives more sunburn protection'' in current Sec. 352.52(b). The
first indication, ``helps prevent sunburn,'' is being revised to one of
the following, which would be required on all sunscreens:
``low UVB sunburn protection''
``medium UVB sunburn protection''
``high UVB sunburn protection''
``highest UVB sunburn protection''
The relative level of sunburn protection is determined from the SPF
value:
low = SPF 2 to under 15
medium = SPF 15 to under 30
high = SPF 30 to 50
highest = SPF over 50
Thus, relative descriptors (low, medium, high, and highest) describe
SPF values, which are relative and not absolute levels of sunburn
protection intended to help consumers determine differences in sunburn
protection offered by different sunscreen products (see section III.I,
comment 23 of this document).
FDA considers it important that consumers be made aware of the
relative level of sunburn protection provided by a product in addition
to its indication for sunburn protection. Individuals may select a low,
medium, high, or highest sunburn protection product to meet their
specific needs. The descriptor ``UVB'' is included to describe the
predominant rays that are screened. The phrase ``helps prevent'' is
being deleted because it is duplicative and no longer necessary. This
phrase would only lengthen the ``Uses'' statement. Furthermore,
consumers will now be able to equate a product's UVB radiation
protection rating (i.e., SPF value) directly to the relative level of
sunburn protection.
The second indication ``higher SPF gives more sunburn protection''
is no longer needed because the relative level of sunburn protection is
provided in the new ``Uses'' statements. In addition, without
clarification, the statement may encourage consumers to spend more time
in the sun. Clarification is necessary because, as discussed in comment
19 of this document, surveys reveal that consumers spend more time in
the sun with increasingly higher SPF sunscreen products (Refs. 14, 15,
and 16). Therefore, FDA is not allowing this statement in the ``Uses''
section. However, under proposed Sec. 352.52(e)(2), FDA is proposing
the following optional statement under ``Other information'' or
anywhere outside of the ``Drug Facts'' box or enclosure: ``higher SPF
products give more sun protection, but are not intended to extend the
time spent in the sun.'' The phrase ``but are not intended to extend
the time spent in the sun'' is additional information not included in
the FM indication. FDA believes this revised indication statement will
discourage consumers from spending more time in the sun when using a
higher SPF product.
FDA is proposing additional revisions in ``Uses'' in Sec.
352.52(b)(1) to include UVA claims and other information (see section
III.G, comments 17 and 18 of this document). The proposed revisions
will help consumers to more fully understand the uses and expected
results for individual sunscreen products. These changes are necessary
because the PDP for a sunscreen product will now include two
performance ratings (see section III.E, comment 14 of this document):
The well-accepted SPF value and new descriptor rating for
UVB radiation protection, and
A new star/descriptor rating for UVA radiation protection.
Consequently, FDA considers it important that the ``Uses'' statements
in the ``Drug Facts'' box accurately reflect product claims related to
specific indications, UVA and UVB radiation, and the level of
anticipated protection (low, medium, high, or highest) determined by
the UVA and UVB product ratings. As with the introduction of SPF
labeling years ago, it will take the combined efforts of government,
manufacturers, consumer organizations, and the health care
[[Page 49088]]
community to educate consumers to fully understand these labeling
initiatives to enhance their safe and effective use of sunscreen
products.
(Comment 17) One comment stated that FDA's ``sun alert'' statement
in the FM recognized that sun-induced skin damage can contribute to
photoaging and increase the risk of skin cancer. This statement reads:
``Sun alert: Limiting sun exposure, wearing protective clothing, and
using sunscreens may reduce the risks of skin aging, skin cancer, and
other harmful effects of the sun.'' The comment urged FDA to allow
other truthful use statements, such as the following:
``helps protect against skin damage caused by the sun''
``helps protect against skin aging caused by the sun''
``regular use helps protect against certain forms of skin
cancer caused by the sun''
``helps protect against fine lines and wrinkles caused by
the sun''
``helps protect against pigmentary changes due to sun
exposure''
Another comment urged FDA to include the first three use statements
suggested by the first comment, as well as ``helps protect against the
harmful effects of the sun'' and ``helps protect against (select one:
`casual,' `incidental,' `intermittent,' or `daily') sun exposure.'' The
comment contended that, when used effectively as part of a sun
protection program, sunscreens may prevent very serious disease
conditions.
Another comment provided citations from the medical literature to
support its contention that claims of sunscreens preventing skin cancer
induction may be false, deceptive, misleading, and unsubstantiated. The
comment mentioned an article by Garland (Ref. 25) that states the
following: ``No epidemiological studies were identified that showed a
protective effect of use of chemical sunscreen on risk of melanoma or
other cutaneous malignancies in humans.'' The comment also mentioned an
article by Gasparro (Ref. 24) that states the following: ``Although
some have promoted daily use (of sunscreen) for the prevention of
premature aging of the skin and the prevention of skin cancer, actual
data are lacking to support these recommendations.''
FDA has reviewed the submitted articles concerning UV-induced skin
damage (i.e., premature aging and cancer) along with articles obtained
from a search of the scientific literature (Refs. 26 through 34). Many
of the articles involved preclinical data, which can be difficult to
extrapolate to consumer (human) actual use conditions. FDA believes
that the articles with clinical data provide more meaningful results,
as they can be easily extrapolated to consumer actual use conditions.
Therefore, FDA is focusing discussion in this document on the clinical
studies. In agreement with Garland (Ref. 25) and Gasparro (Ref. 24),
FDA does not believe, as a whole, that the studies demonstrate that
sunscreens alone help prevent skin aging or skin cancer.
Some of the clinical studies examined the role of UVB and UVA
radiation in producing histological changes indicative of skin aging
due to the sun. Lowe et al. demonstrated that high doses of UVA
radiation (320 to 400 nm) increased melanization of human skin more
than lower doses of UVA or solar simulating UV radiation at 290 to 400
nm (Ref. 26). Seite et al. demonstrated that melanization of human skin
increased with exposure to UVB/UVA radiation at 290 to 400 nm (Ref. 32)
and UVA radiation at 330 to 440 nm (Ref. 27). Seite et al. also showed
that human skin hydration decreased after chronic exposure to UV
radiation at the wavelengths studied.
Five studies revealed stratum corneum thickening produced by both
UVB and UVA radiation (Refs. 26 through 29 and 32). Stratum granulosum
thickening was transiently induced after 6 weeks of exposure to UV
radiation (UVB/UVA) at 290 to 400 nm (Ref. 32). The same effects were
seen with solar simulated radiation and high and low doses of UVA
radiation after 12 weeks of exposure (Ref. 26). Viable epidermal
thickening was seen after 6 weeks of exposure to UV radiation at 290 to
400 nm in one study (Ref. 32) and after 9 days of exposure to UVA
radiation at 335 to 345 nm in another study (Ref. 31).
Inflammation and lysozyme deposition along the dermal elastic
fibers were increased more in human skin exposed to UVA than UVB
radiation (Refs. 26, 28, 29, and 31). Sunburn cell appearance, a
typical response to UVB radiation, was also found to be present after
exposure to different UVA radiation regimens in two studies (Refs. 28
and 31) but not found in a third study (Ref. 27). Thus, FDA concludes
that these studies demonstrated that both UVB and UVA radiation induce
histological changes associated with skin aging.
Four of these studies focused on the histological changes within
the skin induced by UVB and UVA radiation and explored the ability of
sunscreens to protect human skin against these changes (Refs. 29, 30,
32, and 33). The first study suggested that an SPF 29 sunscreen
prevented the development of solar elastosis, a condition in which skin
loses its elasticity after chronic exposure to the sun (Ref. 33).
However, these method and data analyses raise questions about the
validity of the reported conclusion:
Discrepancies were noted concerning demographic
characteristics of subjects, sunscreen application, and compliance
rates.
Skin biopsy data at all three time points in the study
were available from only 10 of the 35 subjects.
The only statistically significant difference between the
sunscreen and placebo treatment groups was achieved in a computerized
evaluation of solar elastosis at baseline and 24 months.
The second study demonstrated significant contribution of a
sunscreen in preventing UV radiation-induced skin damage (Ref. 32). The
use of sunscreens with absorption spectra covering the 290 to 400 nm
range prevented all of the effects of chronic exposure (6 weeks) to UV
radiation evaluated in the study. The third study showed a
photoprotective effect of an SPF 15 sunscreen product from damage
induced by short term exposure to UVB radiation (Ref. 30). The fourth
study showed that a UVB only sunscreen did not provide protection
against chronic exposure to UVA radiation (Ref. 29).
The studies provide evidence that both UVB and UVA radiation induce
histological changes in the skin consistent with skin aging. Thus, the
studies support the conclusion that exposure to UV rays increases the
risk of premature skin aging. However, the study data fails to show
that sunscreen use alone helps prevent premature skin aging for several
reasons. First, the studies have not completely defined the action
spectrum for the majority of UV radiation-induced effects on human
skin. While studies demonstrate that a given histological change, such
as thickening of the stratum corneum, is induced by certain wavelengths
within the UVB and UVA region, studies have not examined the ability of
the remaining UVB and UVA regions outside of these wavelengths to
induce the same change. For example, studies may have shown that 290 nm
to 310 nm and 360 nm to 400 nm radiation induce stratum corneum
thickening, but it is not known whether 311 nm to 359 nm radiation
induces the same histological change.
Second, the inability to identify the exact UVB and UVA wavelengths
that induce each histological change in the skin derives from the study
designs. Each study differed in the following parameters:
[[Page 49089]]
UV radiation wavelengths,
UV exposure regimens,
Sunscreen doses,
Sunscreen application techniques, and
Endpoints.
Therefore, FDA cannot combine all of the data from these studies to
define a complete action spectrum for each histological change in the
skin. Furthermore, the action spectrum for each histological change
would need to be combined to define a single action spectrum for skin
aging, which is a cumulation of these histological changes. Without
knowing which UVB and UVA wavelengths induce each histological change
in the skin, FDA is unable to determine which wavelengths are most
important in causing skin aging and cannot determine the action
spectrum for aging.
Third, the studies did not examine the chronic, long-term
consequences of UV radiation exposure in human skin. Thus, it is not
possible for FDA to extrapolate the data to longer time points at which
the short-term histological changes may cumulate to produce visible
signs of skin aging.
Fourth, although the studies that examined the ability of
sunscreens to protect against UV radiation-induced histological changes
in the skin provide useful data, it is difficult for FDA to conclude
that sunscreens alone help prevent skin aging based on these studies.
The number of participants in each study was relatively small, with
only 10 to 35 subjects per study. Different sunscreen formulations,
with differing absorption spectra, were used in each study. As
explained previously, these studies do not identify exactly which UVB
and UVA wavelengths contribute the most to skin aging (i.e., the
studies do not define the skin aging action spectrum). For all of these
reasons, the studies do not prove that sunscreens alone help prevent
premature skin aging.
Likewise, FDA is not aware of data demonstrating that sunscreens
alone help prevent skin cancer. It has been known for many years that
UV radiation increases the risk of skin cancer. It has also been known
for many years that a higher incidence of sunburn earlier in life
corresponds to a higher incidence of skin cancer later in life.
However, FDA is not aware of any studies demonstrating that the use of
sunscreens alone decreases the risk of skin cancer. Like skin aging,
there are studies examining the effects of sunscreens on short-term
factors for skin cancer, such as sunburn and other cellular damage.
However, it is difficult to extrapolate these short-term adverse
effects of UV radiation to a long-term, chronic effect such as skin
cancer. In addition, like skin aging, the complete action spectrum for
skin cancer is not known at this time.
Unlike skin cancer and premature skin aging, FDA has evidence that
sunscreens alone help prevent sunburn. The SPF test measures the
effectiveness of sunscreens with sunburn (erythema) as the endpoint.
Thus, the impact of sunscreens on sunburn can be measured directly. In
contrast, it is difficult to measure directly the impact of sunscreens
on skin cancer or premature skin aging because these are long-term,
cumulative adverse effects of UV exposure.
Thus, for all of the reasons discussed in this comment, FDA
concludes that the available evidence fails to show that sunscreens
alone help prevent skin cancer or premature skin aging. Based on this
conclusion, FDA is not proposing the indication statements proposed by
the first and second comments, because these claims are for protection
from premature skin aging, skin cancer, and related factors (e.g.,
``helps protect against skin aging caused by the sun''). FDA also is
not proposing claims that sunscreens protect against ``casual,
incidental, intermittent, or daily'' sun exposure, as proposed by the
second comment, because the studies do not support these claims.
Furthermore, FDA considers these terms as lacking sufficient meaning to
be useful to consumers.
As described elsewhere in this document (see section III.G, comment
19), FDA is proposing to require a revised ``sun alert'' statement in
the form of a new warning. The new warning statement is based on FDA's
review of the available evidence concerning UV exposure and skin
cancer, premature skin aging, and other skin damage. The new warning
statement clarifies that UV exposure from the sun increases the risk of
skin cancer, premature skin aging, and other skin damage. In addition,
the new warning statement specifies that consumers should use
complementary sun protection measures along with sunscreen (i.e., limit
sun exposure and wear protective clothing). FDA has concluded from the
available evidence that it is important to adopt a complete sun
protection program (sunscreen, sun avoidance, and protective clothing)
to decrease UV exposure. In fact, the second comment argued for new
indication statements by considering the sunscreen use as part of such
a sun protection program (i.e., in conjunction with limiting time in
sun and wearing protective clothing). Thus, the second comment, along
with the third comment, seemed to agree with FDA's conclusions in this
proposed rule concerning the need for consumers to use sunscreens in
conjunction with other sun protection measures.
In addition, the reference in the new warning statement to
sunscreen use combined with limiting sun exposure and wearing
protective clothing is consistent with recommendations by other public
health organizations. For example, the World Health Organization's
International Agency for Research on Cancer (IARC) (Ref. 21) makes the
following assessments and recommendations:
There is inadequate evidence in humans for a cancer
preventative effect of sunscreens against basal cell or malignant
melanoma cancers.
There is only limited evidence for a preventive effect of
sunscreens against squamous cell cancer.
Sunscreens should not be the first choice for skin cancer
prevention or used as the sole agent for protection against UV
radiation.
Likewise, the CDC recommends that sunscreens be used as a complementary
measure in an overall sun protection program (Ref. 35).
FDA believes that additional information from controlled clinical
studies is needed to better understand the role of sunscreens in
preventing premature skin aging and skin cancer. Studies examining
premature skin aging (using solar radiation or simulated solar
radiation) are needed to determine the following in humans:
Measurable skin properties such as elasticity, collagen/
elastin ratios and properties, wrinkling, pigmentation changes and
visual grades, leading to accepted quantitative definitions of
chronological and sun-induced skin aging;
The relationship between sunlight exposure and skin aging,
stratified by skin type;
An action spectrum for photoaging of skin;
A dose response for UV radiation-induced skin aging;
Quantitative estimates of realistic ``worst case,'' long-
term exposures to sunlight in relevant UVA and UVB radiation spectral
ranges (i.e., the level of UVB and UVA protection needed); and
How UV radiation-induced processes that occur at a given
wavelength affect UV radiation-induced processes that occur at other
wavelengths.
Similar information is needed for skin cancer, except that studies
should examine the different types of skin
[[Page 49090]]
cancer, rather than examining different skin properties. In addition,
IARC has provided recommendations for research on skin cancer
prevention and sunscreens. These recommendations can also be used as a
guide in designing studies to examine the role of sunscreens in
preventing premature skin aging due to the sun (Ref. 21). FDA
encourages interested parties to submit study protocols to FDA for
review to ensure that studies are as informative as possible. FDA also
invites comments by interested parties on the feasibility and validity
of surrogate endpoints for studies to determine whether the use of
sunscreens alone help prevent skin cancer, premature skin aging, or
other skin damage.
(Comment 18) As discussed in section III.E of this document, FDA
received several comments discussing ways to categorize, phrase, and
display UVA/UVB radiation protection on an OTC sunscreen drug product
label. In the amendment to include avobenzone in the monograph (61 FR
48645 at 48655), FDA proposed the following indications for UVB and UVA
radiation protection by sunscreen drug products containing avobenzone:
1. ``Broad spectrum sunscreen'';
2. ``Provides'' (select one of the following: ``UVB and UVA,'' or
``broad spectrum'') ``protection'';
3. ``Protects from UVB and UVA'' (select one of the following:
``Rays'' or ``radiation'');
4. (Select one of the following: ``Absorbs,'' ``Protects,''
``Screens,'' or ``Shields'') ``throughout the UVA spectrum''; and
5. ``Provides protection from the UVA rays that may contribute to
skin damage and premature aging of the skin''.
Likewise, in the amendment to include zinc oxide in the monograph (63
FR 56584 at 56588), FDA proposed similar labeling for UVA and UVB
radiation protection for products containing zinc oxide (substituting
the word ``within'' for the word ``throughout'' in the fourth
statement). FDA did not include these indications in the FM but has
allowed their use until the UVA portion of the monograph is
established.
FDA has reconsidered these UVA protection indications. FDA is
proposing to allow all of them except the fifth statement. In proposed
Sec. 352.52(e), the first four statements are optional statements
allowed for products that demonstrate UVA protection according to the
proposed testing (see section III.N, comment 45 of this document). The
statements can only be included in labeling outside of the ``Drug
Facts'' box. Within the ``Drug Facts'' box, FDA is proposing one of the
following UVA indication statements, depending on the level of UVA
protection provided by a product:
``low UVA protection''
``medium UVA protection''
``high UVA protection''
``highest UVA protection''
The level of protection (i.e., low, medium, high, or highest) is
determined from the UVA rating obtained from product testing (see
section III.N, comment 45 of this document). Manufacturers who wish to
combine the ``Uses'' statements about UVA protection and UVB sunburn
protection may do so if the descriptors (i.e., levels of protection)
are the same. For example, if the levels of UVA and UVB protection are
medium, the ``Use'' may read: ``medium UVA/UVB sunburn protection''.
FDA is not including the fifth indication because FDA does not
consider ``skin aging'' or ``skin damage'' claims adequately supported
at this time. As discussed elsewhere in this document (see section
III.G, comment 19), FDA is proposing a statement in the ``Drug Facts''
box that informs consumers that sunscreens may reduce the risks of skin
aging, skin cancer, and other harmful effects from the sun when used in
a regular program that relies upon limiting sun exposure and wearing
protective clothing. Therefore, FDA believes the fifth indication
statement would mislead consumers by not discussing sun exposure and
protective clothing.
(Comment 19) As discussed in section III.G of this document, FDA
received several comments concerning the ``sun'' alert statement. In
Sec. 352.52(e)(2) of the FM, FDA included the optional statement:
``Sun alert: Limiting sun exposure, wearing protective clothing, and
using sunscreens may reduce the risks of skin aging, skin cancer, and
other harmful effects of the sun.'' This statement's emphasis of the
need for a comprehensive sun protection program (64 FR 27666 at 27679)
was based on the findings of numerous groups, including the following:
The American Academy of Dermatology (AAD),
The CDC,
The Australian Government; and
The New Zealand Government.
These groups have recommended that sunscreens be considered an adjunct
to other UV protection strategies, such as avoiding the sun near
midday, seeking shade, and wearing protective clothing and hats.
The FM provided that the ``sun alert'' appear under the heading
``Other information'' or anywhere outside of the ``Drug Facts'' box or
enclosure. At that time, FDA encouraged manufacturers to voluntarily
include this statement in labeling, make it available at the point of
purchase, and/or make it available through consumer education programs.
FDA is now proposing a revised ``sun alert'' statement be required
in the ``Warnings'' section of the ``Drug Facts'' box. FDA is proposing
the statement to read as follows: ``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. FDA is proposing
that the statement appear in bold type as the first statement in the
``Warnings'' section. FDA believes the statement is most appropriate in
the ``Warnings'' section because it warns consumers that effective
protection from the sun does not involve only the application of
sunscreens, as many consumers believe. In addition, it warns consumers
that UV radiation not only increases the risk of sunburn but also
increases the risk of skin cancer and premature skin aging, which many
consumers may not know. FDA believes the new warning will encourage
consumers to use sunscreen, limit time in the sun, and wear protective
clothing to reduce UV exposure. Because of the importance of warning
statements and the need for consumers to receive a uniform message
concerning such warnings, no variations in wording are allowed under
Sec. 330.1(c)(2).
FDA acknowledges that the new warning statement differs from the
wording of the voluntary ``sun alert'' in the FM. These differences are
based on FDA's assessment of the additional evidence available since
publication of the FM in 1999. As explained in comment 17 of this
document, FDA does not believe that the available data support a claim
concerning the use of sunscreen and a reduction in the risk of
premature skin aging and skin cancer. The revised wording of the
statement more accurately reflects the scientific conclusions that can
be drawn from this evidence.
FDA is proposing the warning because we continue to be concerned
about adequate consumer understanding of a sun protection program that
includes sun avoidance and wearing protective clothes along with
sunscreen use. This proposed rule provides for even higher SPF values
and a new rating system for UVA protection. Consumers may believe that
sunscreens with higher SPF values (especially with UVA protection)
provide complete UV radiation protection. Subsequently, consumers may
prolong sun exposure
[[Page 49091]]
because they think higher SPF values equate to longer times in the sun
without burning. FDA is aware of a double-blind, randomized clinical
study that showed a significant increase in sun exposure time of
persons using high SPF sunscreens compared to persons using low SPF
sunscreens (Ref. 14). In addition, two questionnaire-based surveys
showed that sun exposure time is prolonged for persons using sunscreens
compared to persons not using sunscreens (Refs. 15 and 16). By
educating consumers about a sun protection program, we believe
requiring this new proposed warning will decrease the likelihood of
consumers spending more time in the sun when using a sunscreen.
The new proposed warning also informs consumers that use of
sunscreens alone is not the sole measure of protection from UV
exposure, even with the use of high SPF products that provide UVA
protection. Although it is well established that sunscreens protect
against UV radiation, the following factors affect the level of
protection provided by a sunscreen for each individual:
Variations between individuals,
UV radiation absorption,
Ability of sunscreens to adhere to and be absorbed by the
skin,
Exposure conditions, and
Conditions of use (e.g., inadequate application amount or
reapplication frequency).
Therefore, FDA agrees with the numerous groups that promote sunscreen
use as part of a total sun protection program.
FDA reviewed the relationship between sunscreen use and skin cancer
incidence in the scientific literature and did not find confirmatory
evidence that sunscreens alone protect against the development of skin
cancer. The incidence of skin cancer continues to rise in the United
States. The incidence of the most serious form of skin cancer,
malignant melanoma, grew 6.1 percent per year during the 1970s (Refs.
14 and 36). The rate is still rising an average 2.8 percent annually,
with a rate of 14.3 percent per 100,000 persons in 1997. Melanoma is
one of the top 10 cancers, by incidence, for persons with white skin.
The American Cancer Society (ACS) estimated the following statistics
concerning skin cancer in 2007 (Ref. 37):
More than 1 million new cases of curable basal cell and
squamous cell carcinomas would be detected,
Approximately 59,940 new cases of malignant melanoma would
be diagnosed, and
An estimated 8,110 persons would die from melanoma and
2,000 persons would die from other skin cancers.
Skin cancer affects roughly the same number of people as all other
cancers combined. In view of the continuing increase in the incidence
of all types of skin cancer and the lack of data demonstrating that
sunscreens alone prevent skin cancer, FDA considers the new warning
important for the protection of the public health.
FDA is proposing that the new warning be required on all OTC
sunscreen drug products except lip cosmetic-drug and lip protectant-
sunscreen products subject to Sec. 352.52(f). FDA continues to believe
that all sunscreen products should have labeling to ensure that
consumers are adequately protected against overexposure to UV radiation
(64 FR 27666 at 27673). Thus, sunscreen products labeled for use only
on specific small areas of the face and sold in small packages (i.e.,
sunscreen products subject to Sec. 352.52(f)) must include the new
warning. The only sunscreen products not required to include the new
warning are those lip cosmetic-drug and lip protectant-sunscreen
products subject to Sec. 352.52(f), as proposed in Sec.
352.52(f)(1)(ii). FDA is making this proposal because lip cosmetic and
lip protectant products are often sold in packages that are
substantially smaller than those of other products that fall under
Sec. 352.52(f). FDA believes requiring the new warning on lip
cosmetic-sunscreen and lip protectant-sunscreen products may discourage
manufacturers from marketing these products because it requires a
significant amount of labeling space.
FDA has limited labeling requirements as much as possible for
sunscreen products subject to Sec. 352.52(f). However, FDA believes
consumers are at great risk for UV-induced skin damage, including
cancer, on the face. Therefore, consumers who purchase products
specifically for use on the face need to be informed about the
information contained in the new warning. Although these products are
marketed in small package sizes, FDA has determined that the products'
labeling needs to include this important information in order to
protect consumers.
(Comment 20) One comment stated that consumers who use color
cosmetics or facial moisturizers with sunscreens make the informed
decision to purchase them as an additional benefit to their cosmetic
use. The comment contended that a significant number of people with
dark skin types, who do not burn easily, purchase sunscreens to provide
protection from the sun damage that is not immediately recognizable.
For these reasons, the comment requested claims such as the following:
``helps protect against casual or incidental or
intermittent daily sun exposure''
``helps protect against the harmful effects of the sun''
Another comment acknowledged that facial makeups with sunscreen provide
protection from sunburn, but that is not the primary reason why
consumers use these products. The comment contended that requiring the
``sunburn'' indication would be inappropriate and misleading labeling
for most facial makeups with sunscreen. The comment, instead, requested
a claim such as ``protects against the harmful rays of the sun.''
FDA notes that the second comment acknowledged that facial makeups
with sunscreen provide protection from sunburn. Not every consumer who
uses color cosmetics or facial makeups with sunscreen meets the
following criteria:
Has a dark skin type, or
Uses these products solely to provide protection from sun
damage that is not immediately recognizable.
As noted in section III.D, comment 9 of this document, many consumers
use facial products with sunscreen as their primary and only source of
sunscreen protection for that area of the body. As discussed in section
III.G, comment 16 of this document, sunscreen products will be required
to bear a claim of low, medium, high, or highest UVB sunburn
protection. FDA does not consider it inappropriate or misleading for
color cosmetic or facial makeup products containing sunscreens to have
this sunburn protection claim of low, medium, high, or highest.
Sunscreen products that provide UVA radiation protection may also
bear a claim about the level of protection. In addition, all OTC
sunscreen products, except lip cosmetic-drug and lip protectant-
sunscreen products subject to Sec. 352.52(f), will be required to bear
the revised ``sun alert'' statement, which is now included in the
``Warnings'' section of the ``Drug Facts'' box. FDA considers the
information in this new ``Warnings'' statement much more beneficial to
consumers than the statements proposed by the comments. FDA rejected
the terms ``casual, incidental, and intermittent,'' as explained in
section III.G, comment 17 of this document.
[[Page 49092]]
H. Comments on Directions for Sunscreen Drug Products
(Comment 21) Several comments requested alternative directions for
makeup with sunscreen products. One comment requested ``apply smoothly
or evenly before sun exposure and/or as needed.'' The comment added
that ``before sun exposure'' may not always be appropriate as these
makeup products are not exclusively or even primarily used for
protection against sun exposure. A second comment requested ``apply
smoothly or evenly before sun exposure and reapply as needed.'' A third
comment did not suggest any specific language, but requested
flexibility to recognize the product's primary use as a makeup, while
providing adequate information about the sunscreen component. This
comment added that the direction to consult a doctor for children under
6 months of age was clearly unnecessary for facial makeup with
sunscreen because these products cannot reasonably be expected to be
used on children that age.
FDA agrees that flexibility is appropriate for the directions for
makeup with sunscreen products. Elsewhere in this document, FDA is
proposing to allow labeling modifications for makeup with sunscreen
products used only on specific small areas of the face and sold in
small packages (see section III.D, comment 9 of this document). Those
modifications include modified directions for cosmetic lip products
containing sunscreen that are within the scope of proposed Sec.
352.52(f). FDA is not extending the proposed modifications to all
makeup with sunscreen products. Makeup with sunscreen products not
labeled only for specific small areas of the face may be applied to a
large area of the face or other areas of the body. As explained later
in this comment, FDA would have concerns with the modifications being
applied to these products.
Whether intentional or not, makeup with sunscreen products may be
the primary sunscreen for many consumers. A recent study examined
sunscreen use patterns (Ref. 48). Participants were instructed to apply
sunscreen every day. Of those who used sunscreen infrequently, the
majority spent some time outdoors with 11 percent spending the majority
of their time outdoors. These same participants explained that they did
not believe sunscreen was necessary because of their planned
activities. The authors cited this finding in advocating educating
consumers on the need for sunscreen for frequent incidental sun
exposure in addition to intentional sun exposure, such as sunbathing.
For these reasons, FDA considers it important that consumers using
makeup with sunscreen products not labeled for use only on specific
small areas of the face recognize that these products are sunscreens
and use them appropriately to maximize UV protection. Therefore, FDA is
not proposing modified directions for these makeup with sunscreen
products.
(Comment 22) One comment requested that FDA require sunscreen
manufacturers to provide accurate and appropriate instructions about
how much sunscreen should be applied to the body. The comment also
suggested that a warning about the dangers of sunburn from applying
suboptimal amounts be included in sunscreen product labeling. A second
comment stated that it was not aware of any study indicating that
consumers use adequate amounts of sunscreen. The comment supplied data
and other information concerning the dependency of the SPF value on the
total quantity of sunscreen applied (Ref. 49).
Section 352.52(d)(1) currently provides manufacturers the option to
select one or more of the following application terms for a sunscreen
product: ``liberally, generously, smoothly, or evenly.'' Manufacturers
may also include optional directions that state ``[bullet] reapply as
needed or after towel drying, swimming, or (select one of the
following: `sweating' or `perspiring').'' In the final rule, FDA had
concluded that the directions in Sec. 352.52(d)(1) to apply
``liberally'' or ``generously'' convey the appropriate message to
ensure that consumers adequately apply the sunscreen (64 FR 27666 at
27679).
Several studies suggest that, in practice, consumers may apply
amounts of sunscreen below the density of 2 milligrams/square
centimeter (mg/cm\2\), which is the amount of product required for the
SPF determination in Sec. 352.72(e) (proposed Sec. 352.71(e)). These
data suggest that consumers may apply as little as 0.5 to 1.0 mg/cm\2\
(Refs. 50 through 54). One comment reported that, to achieve the rated
protection over the whole body, a typical adult with a surface area of
1.73 square meters (m\2\) would need to apply 35 milliliters (mL) of
sunscreen, roughly one-third of a 4 oz bottle per application (Ref.
55). Studies indicate that SPF values determined at an application rate
of 1 mg/cm\2\ are approximately 50 percent of those determined at 2 mg/
cm\2\, and when applied at 0.65 mg/cm\2\, the SPF values are 20 to 30
percent of those determined at 2 mg/cm\2\ (Refs. 49, 50, and 51).
Gasparro notes that statements such as ``apply liberally and
frequently'' are too vague to be informative (Ref. 24).
FDA is concerned that, in practice, consumers may be getting less
protection than the labeled SPF value and believes that further
information should be included in the labeling for sunscreen drug
products to reduce the likelihood of underapplication. FDA believes
that this information is better communicated as revised product
directions rather than a warning. FDA is, therefore, proposing to
revise Sec. 352.52(d)(1). The directions will continue to state that
OTC sunscreen drug products should be applied ``liberally'' or
``generously'' because it would be cumbersome to specify quantitative
amounts for all possible body areas and the various uses on the label.
However, FDA is proposing to make optional the directions in Sec.
352.52(d)(1)(i) to apply ``evenly.'' FDA believes that this term, if
used alone, may not convey the appropriate message to ensure that
consumers apply sufficient sunscreen. In addition, FDA is proposing to
remove the term ``smoothly'' from Sec. 352.52(d)(1)(i) because FDA
considers that term to be vague and it may have different meanings to
different consumers. FDA also believes this term is more likely to
result in product underapplication.
In addition to labeling directing consumers to apply sufficient
amounts of sunscreen, FDA is also proposing to revise the labeling
requirements concerning reapplication of the sunscreen product. In
Sec. 352.52(d) of the FM, the general reapplication statement ``and as
needed'' was the only required information. FDA made specific
reapplication directions in Sec. 352.52(d)(2) of the FM optional in an
effort to equalize requirements between sunscreens with and without
water resistant claims (64 FR 27666 at 27681). FDA now believes that
more detailed reapplication directions must be included on all OTC
sunscreen products, because sunscreens may be underapplied as suggested
by the comments.
FDA came to this conclusion after reviewing studies concerning
sunscreen reapplication as well as recommendations of public health
organizations. Wright, et al. suggests that inadvertent sunburn may be
due to the failure to use and reapply sunscreen appropriately (Ref.
56). Study subjects who reapplied sunscreen every 1 to 2 hours and
after swimming did not report sunburn. Rigel et al. reported that, even
under intense solar conditions, those reapplying an SPF 15
[[Page 49093]]
sunscreen every 2 hours or sooner were five times less likely to
sunburn compared to those who reapplied every 2.5 or more hours (Ref.
57). The AAD (Refs. 38, 58, and 59), the ACS (Ref. 60), and the EPA
(Ref. 40) recommend reapplying sunscreens every 2 hours or sooner and
also recommend application to all exposed areas of the body (Refs. 60,
61, and 62).
Because the frequency of application appears to be critical for
proper protection, FDA is proposing to add the statement ``apply and
reapply as directed to avoid lowering protection.'' In addition, FDA is
proposing to further revise the directions in Sec. 352.52(d) to
include the following reapplication statement: ``reapply at least every
2 hours.'' Likewise, for those products making a water resistant claim,
FDA is proposing to include the number of minutes (i.e., 40 or 80) that
the product maintains its water resistance before the ``swimming/
sweating'' term. FDA believes these additional proposed directions will
alert consumers about the hazards of using insufficient amounts of
sunscreen product and encourage reapplication after the appropriate
time. FDA considers these specific, informative reapplication
statements, instead of ``and as needed,'' to be necessary on all OTC
sunscreen products. FDA is also proposing the optional direction
``apply to all skin exposed to the sun.'' FDA is proposing that this
direction be optional because we believe most consumers know to apply
sunscreen to all exposed skin. However, if a sunscreen product can
accommodate this direction, it will serve to remind consumers that all
exposed skin is susceptible to UV damage. These proposed directions, as
a whole, should serve to better protect consumers, particularly those
who tend to underapply sunscreen, from overexposure to the sun.
Accordingly, FDA is proposing to change Sec. 352.52(d) to read as
follows:
(d) Directions. * * *
(1) For products containing any ingredient in Sec. 352.10. (i)
The labeling states ``[bullet] 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''.
(ii) The labeling states ``[bullet] apply and reapply as
directed to avoid lowering protection''.
(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 products that satisfy the water resistant or very water
resistant testing procedures identified in Sec. 352.76. The
labeling states ``[bullet] 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 Sec. 352.76, respectively] swimming or [select one of
the following: `sweating' or `perspiring'] and after towel drying.
Otherwise, reapply at least every 2 hours''.
(3) For products that do not satisfy the water resistant or very
water resistant testing procedures identified in Sec. 352.76. The
labeling states ``[bullet] reapply at least every 2 hours and after
towel drying, swimming, or [select one of the following: `sweating'
or `perspiring']''.
As discussed in the FM (64 FR 27666 at 27679), manufacturers who have
data to support different reapplication directions based on specific
substantiation information may submit the information for approval of
those directions via an NDA deviation as provided in Sec. 330.11 (21
CFR 330.11).
I. General Comments on SPF Testing Procedure
(Comment 23) One comment suggested that the SPF test incorporate an
amount of product that more closely reflects the amount applied by
consumers. More specifically, the comment requested that FDA replace
the 2 mg/cm\2\ required in Sec. 352.72(e) (proposed Sec.
352.70(c)(5)) to a value between 0.5 and 1.0 mg/cm\2\. The comment
argued that the protection afforded during actual usage may be only
one-quarter to one-half the labeled SPF value (see section III.H,
comment 22 of this document). The comment also suggested that SPF could
be stated using descriptive terms, such as ``light,'' ``moderate,'' or
``heavy'' protection, instead of a numerical value.
FDA is not proposing the suggested change in test method at this
time. This issue was discussed in detail in the TFM (58 FR 28194 at
28264 to 28266). The majority of comments advocated continuing the use
of an application density of 2 mg/cm\2\. The current comment did not
provide data demonstrating the suitability of a smaller test amount.
FDA is concerned that a uniform distribution of sunscreen over the test
area might be difficult using a smaller amount of sunscreen. Further,
the standard application density used worldwide in the SPF test is 2
mg/cm\2\ (Ref. 63).
FDA agrees that SPF values do not reflect exact levels of sunburn
protection that consumers receive under actual use conditions. The
required SPF test is a clinical test conducted with strict control over
factors such as product application density. However, under actual use
conditions, these factors are not controlled and vary greatly. The
actual level of sunburn protection under consumer use conditions is
affected by a number of factors. Some of the key factors are
Application density,
Reapplication frequency,
Skin type (e.g., burns easily versus never burns),
Time of day during sun exposure, and
Geographical location during sun exposure.
Thus, SPF values reflect relative and not absolute levels of sunburn
protection.
Although SPF values do not convey actual levels of sunburn
protection, when comparing multiple sunscreen products, SPF values
enable consumers to determine which products provide the most sunburn
protection. For example, FDA believes most consumers would correctly
identify an SPF 20 product as providing more sunburn protection than an
SPF 10 product. Thus, lowering the sunscreen application density would
not be necessary to more accurately reflect the degree of relative
sunburn protection.
FDA agrees that, in addition to bringing SPF values closer to
representing absolute levels of protection, lowering the sunscreen
application density might also reduce some of the inaccuracies and
limitations encountered when testing high SPF sunscreen products. Thus,
FDA invites interested parties to submit data supporting a smaller
application density for SPF testing of all sunscreen dosage forms in
accordance with Sec. 352.77. However, developing a single global
method and labeling would require a coordinated effort between the
regulatory agencies in many countries around the world. Because FDA
does not have data to validate the SPF test using a lowering sunscreen
density, FDA is proposing directions that we believe will encourage
consumers to apply greater densities of sunscreen (i.e., closer to 2
mg/cm\2\) (see section III.H, comment 22 of this document).
FDA does not find that there are sufficient benefits for using
descriptors instead of numerical values for SPF on the PDP. Consumers
are familiar with numerical SPF values from over 20 years of usage. As
described in section III.G, comment 16 of this document, FDA believes
that the use of descriptors in combination with numerical values on the
PDP may be beneficial to consumer understanding of the level of sunburn
protection provided by a product. Thus, as explained in comment 16, FDA
is proposing to include a descriptive term of relative sunburn
protection (i.e., low, medium, high, or highest) with the proposed
sunburn protection statement in the ``Uses''
[[Page 49094]]
section and on the PDP. The intent of this dual descriptive and
numerical sunburn protection measure is to allow consumers to more
easily differentiate the level of sunburn protection provided by
different sunscreen products. In addition, this proposed labeling for
sunburn protection is similar to the proposed UVA protection labeling
(see section III.G, comment 14 of this document).
FDA is also aware of sunscreen drug products marketed in dosage
forms that may not be addressed by current SPF testing procedures. The
SPF testing procedure described in Sec. 352.72 (proposed Sec. 352.70)
references oils, lotions, creams, gels, butters, pastes, and ointments.
FDA invites interested parties to submit SPF testing modifications for
new dosage forms (e.g., mousses, foams, and towelettes) in accordance
with Sec. 352.77.
(Comment 24) One comment recommended a pass/fail (binomial) test to
determine SPF values (Ref. 49). The test would demonstrate that
subjects have no reaction to a quantity of UV energy equivalent to an
expected SPF value (for products passing the test). For example,
subjects being tested with a product with an expected SPF value of 30
would be dosed only at the SPF 30 level, and the product would either
pass or fail. A product passing this test would actually have an SPF
value of 30 or over, whereas a product failing this test would have an
SPF value below 30. The comment argued that while the monograph SPF
test is probably adequate for products with low SPF values, it is not
adequate for testing high SPF products because differences in solar
simulators can provide as much as a 200 percent variation in results
depending on the formulation. The comment further argued that an
impossibly high number of subjects would be required for the current
SPF method to obtain a 95 percent confidence level and that the test
exposes subjects to a potentially dangerous condition, sunburn.
According to the comment, the average MED for each skin type can be
predicted from existing solar simulator calibration data. During the
pass/fail test, each test subject is screened for skin type and then
given a first day range of energy that does not exceed the expected
MED. The comment proposed using a panel of five subjects. Using the MED
information obtained on the first day, each subject is given four UV
radiation exposures corresponding to the expected SPF value. Each
subsite is then evaluated for erythema. If six or more of the 20
subsites show perceptible erythema, the product fails, as there would
be less than a 95 percent probability the actual SPF value was higher
than the expected SPF value. If less than six subsites show perceptible
erythema, the product passes, as there would be greater than a 95
percent probability that the actual SPF value was more than the
expected SPF value. The comment proposed the following:
Table 2.--Probability Table
------------------------------------------------------------------------
Maximum no. of
No. of subjects failures Probability
------------------------------------------------------------------------
1 (n=4) 0 0.0625\1\
2 (n=8) 2 0.0352
3 (n=12) 3 0.0200
4 (n=16) 5 0.0383
5 (n=20) 5 0.0207
------------------------------------------------------------------------
\1\ n is not sufficient to make a 95 percent prediction
The comment further proposed that if all eight subsites of the first
two subjects pass, then the product passes and the remaining three
subjects would not be evaluated. The probability of this happening
would be 1/256 unless the product is over the expected SPF value.
FDA agrees that, currently, there may not be enough experience and
test data for products with SPF values of 30 and over on which to
determine the sample size needed to obtain an acceptable 95 percent
confidence interval. As discussed in section III.L, comment 37 of this
document, to account for increased variability in SPF values for
sunscreens with SPF values over 30, FDA proposes to increase the sample
size to at least 25 subjects. Therefore, the comment may be correct in
arguing that large numbers of subjects may be required for testing
products with high SPF values. FDA believes that the pass/fail test has
merit and could provide a reasonable substitute for the current SPF
method for products with expected SPF value of 30 or higher. However,
before the method can be accepted, method validation data are required
that demonstrate the method can be performed satisfactorily by multiple
laboratories using the same sunscreen formulation(s). FDA invites such
data.
If the pass/fail method is accepted, FDA may stipulate that the
method be used only for products with SPF values of 30 and higher
because of the large number of subjects that would be required for high
SPF products under the current test method. A pass/fail method would
require fewer test subjects. Low SPF products can be adequately tested
under the current method without large numbers of subjects. In
addition, FDA would likely require that all 20 subsites be evaluated
even if the first 2 subjects pass. Further, using standard probability
computer software, FDA calculates that the values for the maximum
number of failures in table 2 of this document for subjects one through
five should be 0, 1, 2, 4, and 5, respectively, rather than the values
provided by the comment.
FDA would also consider three modifications to the method described
by the comment and invites comment. First, each subject may have test
successes and failures due to multiple subsites on each subject.
Statistically, these will not be independent observations, which is a
condition needed for a binomial probability calculation. Therefore, FDA
is considering that a test panel should consist of 20 to 25 subjects
and that only one site be tested on each subject. A pass/fail
determination would be made for each individual.
Second, as an alternate, a double sampling plan based on Taylor's
Guide to Acceptance Sampling may replace the five-layered plan proposed
by the comment (Ref. 64). With the double sampling plan, two subjects
are tested simultaneously with up to a maximum of four subjects, each
having four subsites tested. If no more than one of the first eight
subsites has perceptible erythema, the product passes. If three to
eight subsites have perceptible erythema, the product fails. If exactly
two of the eight subsites have perceptible erythema, then the second
group of two subjects is tested. If two to four subsites from four
subjects have perceptible erythema, the product passes. Otherwise, the
product fails. According to this scheme, if probability p = 0.10 that
the product tested would produce any recognizable erythema, then the
probability = 0.95 that the product will pass. If probability p = 0.5
that the product tested would produce any recognizable erythema, then
the probability = 0.05 that the product will pass.
Third, an alternative to the probability calculation is a margin of
error approach. With this method, a margin of error for the expected
SPF value is defined before testing. The margin of error is used to
determine the tolerability interval around the expected SPF value. The
90 percent confidence interval for the product's test result (one
result per subject) must fall within the tolerability interval to be
labeled with that SPF value. For example, if a 10 percent margin of
error is claimed for a product with an expected SPF value of 40, then
the tolerability interval would be 40 4, or 36 to 44. If
the related 90 percent confidence interval is from 37 to 43, an SPF
value of 40 is assigned to the product. If the related 90 percent
[[Page 49095]]
confidence interval is from 35 to 45, an SPF value of 40 could not be
assigned to the product and the product may be retested at an expected
SPF of 30.
FDA invites discussion of these suggested modifications to the
comment's pass/fail method for testing sunscreen drug products having
an SPF value of 30 or higher.
(Comment 25) One comment described an in vitro method it developed
for simultaneously predicting SPF and assessing photostability. The
method utilizes a 150 watt xenon arc lamp to irradiate sunscreen
applied at a level of 1 to 2 mg/cm\2\ to a flat collagen membrane
substrate placed in the opening of an integrating sphere attached to a
spectroradiometer. The spectral irradiance of the source and the
spectral irradiance of the substrate alone are measured from 290 to 400
nm, at 1 nm intervals. The spectral irradiance transmitted by the
sunscreen/substrate combination is measured at 1 minute intervals until
the total erythemal-effective dose transmitted by the sunscreen exceeds
1 MED, where 1 MED equals 0.02 erythema-effective Joules (J)/cm\2\.
Each 1 minute interval represents two to three MEDs. The time course of
the sunscreen's SPF is then computed (Ref. 65). This information
reveals the photostability of a sunscreen. If a sunscreen is
photostable, it will not decompose when exposed to UV radiation, and
the SPF will not change with increasing UV exposure. If a sunscreen is
not photostable, it will decompose when exposed to UV radiation, and
the SPF will decrease with increasing UV exposure. Another comment
asked FDA to consider replacing the human SPF test with equivalent in
vitro technology and chemical engineering, but did not suggest a
suitable method.
FDA does not agree that an in vitro method is adequate to replace
the in vivo SPF test. In vitro tests are generally inadequate as the
sole measure of SPF because substrates cannot mimic sweating, skin
absorption, or certain interactions with skin that influence SPF. Some
sunscreen ingredients do not behave similarly in vitro and in vivo. At
this time, the comment's method has not been validated, and the chosen
substrate has not been demonstrated to possess penetration
characteristics and surface chemistry similar to human skin.
The described in vitro method does have potential utility for
measuring photostability of a sunscreen product. Measuring the
erythemal-effective dose transmitted through the sunscreen in vitro
over time seems like a reasonable approach. However, portions of the
method require further exploration. Items such as the cut-off to define
photostability need further explanation and validation. It should also
be pointed out that the current SPF test method does not directly
measure photostability, but it accounts for photostability. More
specifically, the SPF value is determined after a sunscreen is exposed
to UV radiation, so the SPF represents UVB protection provided by
whatever fraction of the sunscreen has not decomposed.
FDA agrees that in vitro tests are generally rapid and less
expensive than in vivo tests and, for SPF measurements, would reduce
exposure of human subjects to UV radiation. FDA is willing to consider
alternate methods for SPF testing if they are adequately supported with
data and are shown to be equivalent to established in vivo methods by
collaborative studies. If the methods are equivalent, then the same SPF
values should be determined for each sunscreen tested according to the
SPF method and the alternate method. The comments have not provided
data from such studies. Therefore, FDA is not proposing to include the
described in vitro method in the monograph at this time.
(Comment 26) Several comments urged FDA to revise Sec. 352.72(h)
and reinstate the requirement for determining MED at 16 to 24 hours
after exposure, rather than 22 to 24 hours. The comments submitted data
showing that, for an SPF 30 product and for the 8 percent homosalate
standard, determining the MED at 16 or 24 hours does not result in any
clinical or statistical difference in the SPF (Refs. 66 and 67).
Comments argued that immediate pigmentation fades rapidly and does not
interfere with MED readings. One comment further argued that the 16 to
24 hour time is universally accepted by the European Union, Australia,
and Japan and FDA should adopt this time in the interest of
international harmonization.
The Panel recommended that the MED be evaluated 16 to 24 hours
after exposure (43 FR 38206 at 38262). FDA proposed a post exposure
time of 22 to 24 hours based upon information provided by comments to
the Panel's report that immediate pigmentation may persist with higher
doses of UV radiation up to 24 hours or, in some cases, for 36 to 48
hours after prolonged exposure (58 FR 28194 at 28268 to 28269).
Comments had indicated that immediate pigmentation might interfere with
an investigator's perception of minimally perceptible erythema.
FDA agrees that these new data show no significant difference in
MED readings at 16 and 24 hours. Thus, FDA is proposing to revise the
MED determination time in Sec. Sec. 352.72(h) and 352.73(c) (proposed
Sec. Sec. 352.70(c)(8) and 352.70(d)(3), respectively) from ``22 to 24
hours'' to ``16 to 24 hours.''
J. Comments on the Sunscreen Standard for SPF Testing Procedure
(Comment 27) Several comments suggested that standard controls with
SPF values of 15 or higher be developed to test high SPF sunscreen
products. One comment stated that such standards would improve test
accuracy and provide a consistent and adequate benchmark for
compliance. One comment mentioned use of a control SPF 15 formula
routinely in SPF evaluation and considered it a more valuable control
than the 8-percent homosalate SPF 4 standard. Another comment supplied
``round-robin,'' collaborative SPF testing data from 7 laboratories on
a total of 153 subjects with 2 potential SPF 15 sunscreen standard
preparations, ``Formulation A'' on 147 subjects and ``Formulation B''
on 146 subjects (Refs. 13, 68, and 69). The comment concluded that
differences between the two preparations were not significant (p=0.653)
but ``Formulation B'' was preferred due to its less complex formula and
slightly more consistent results. The comment added that the data
showed that different laboratories can obtain valid, reproducible
results when testing high SPF sunscreens. Another comment stated that
it provided test results on 20 subjects using an SPF 25 product as the
control (Ref. 70). Three comments suggested that the European Cosmetic,
Toiletry, and Perfumery Association (COLIPA) ``European low SPF
Standard Code Number COL492/1 (formerly the DIN standard)'' be included
in the OTC sunscreen drug product monograph as a permissible standard
sunscreen preparation, in addition to the 8-percent homosalate
standard, and that either standard should be allowed in the SPF testing
procedures. The comments contended that this approach will serve to
permit international marketing and eliminate duplicative testing.
Another comment asked FDA to adopt the JCIA SPF 15 ``P3'' standard, but
did not provide supporting data.
The comment concerning the SPF 25 control provided data from
comparative tests on 20 subjects, using the 8-percent homosalate
standard, an SPF 15 sunscreen drug product, and an SPF 25 sunscreen
drug product (Ref. 70). FDA finds that this study is inadequate to
support the comment's request because the study did not do the
following:
[[Page 49096]]
Include sufficient numbers of subjects,
Address suitability of the standard across different
laboratories, and
Document some properties required in a sunscreen standard
to test high SPF sunscreen products.
The following properties of a sunscreen standard were not addressed
but need to be addressed:
Low level of interlaboratory variation,
Sensitivity to experimental error, and
Ease of preparation with a reasonable degree of accuracy.
These data are also needed for the JCIA standard.
Although comments provided data on 20 subjects in each of 4
laboratories using the COLIPA COL492/1 standard, FDA is not proposing
to include this standard as an alternate to the 8-percent homosalate
standard because we do not believe that using the COL492/1 standard
will make the monograph method comparable to the European method, as
other differences exist between the two methods. For example, the
monograph method requires 20 evaluable subjects, while the European
method requires only 10 evaluable subjects. Therefore, the COL492/1
standard is a valid standard under the European method but may not be a
valid standard under the monograph method. Finally, FDA finds that the
8-percent homosalate standard is a suitable control for testing
sunscreen drug products with SPF 15 or below (see section III.J,
comment 28 of this document).
FDA agrees with the comment that the submitted collaborative data
from seven laboratories support ``Formulation B'' as an appropriate SPF
15 sunscreen standard. The mean SPF for ``Formulation B'' was 16.3 in
146 subjects tested, with 1.7 percent standard error of the mean, and
laboratory means ranging from SPF 15.6 to 18.5. Therefore, FDA is
proposing to include the ``Formulation B'' SPF 15 standard in the FM to
be used for sunscreen drug products with an SPF value over 15 (optional
for SPF values of 2 to 15).
(Comment 28) One comment noted that there are two recognized
standard control formulations:
1. An 8-percent homosalate preparation with an SPF value of 4
(Sec. 352.70(b) of the FM), and
2. Formulation B (padimate O/oxybenzone) with an SPF value of 15.
The comment stated that the function of the standard formulation is
quality assurance for method control and not as a calibration standard
to bracket specific SPF ranges. The comment claimed that the 8-percent
homosalate SPF 4 standard is appropriate to test products at any SPF
level and that the choice of whether to use the SPF 4 or SPF 15 control
formulation should rest with the manufacturer. Several other comments
agreed with this comment.
Another comment provided data using the 8-percent homosalate
standard to test product formulations with estimated SPF values of 15,
30, and 45 on 20 subjects (Ref. 67). The comment concluded that the
data showed testing procedures in the FM can differentiate high SPF
sunscreens using the homosalate SPF 4 standard. The comment requested
that the homosalate SPF 4 standard be allowed to be used for products
with an SPF value over or below 15.
FDA does not consider the data adequate to support the suggestion
that the 8-percent homosalate standard currently used to evaluate
sunscreen drug products with SPF values up to 15 is equally applicable
to products with SPF values over 15 (Ref. 67). The study had the
following deficiencies:
Did not include sufficient numbers of subjects,
Did not address suitability of the standard across
different laboratories, and
Did not document certain properties required in a
sunscreen standard to test high SPF sunscreen products.
The following sunscreen standard properties were not addressed but need
to be addressed:
Low level of interlaboratory variation, and
Sensitivity to experimental error.
FDA agrees that the two standards are method controls rather than
calibration tools. As such, the standard used should approximate the
expected SPF of the product being tested to better verify that all
aspects of the testing method are performing properly at the expected
SPF level.
Using the SPF 4 standard to measure SPF values over 15 is more
likely to produce erroneous results than using a standard with an SPF
of 15. In measuring SPF values over 15, much higher light energies (J/
cm\2\) are used in comparison to measuring SPF values below 15.
Problems in the accurate quantitation of high light intensities may not
be detected if the SPF 4 standard is used for SPF values over 15. While
the SPF 4 standard may give acceptable results for products with SPF
values over 15 in some studies, the extrapolation of these results to
approximately 4 to 13 fold higher light energies used to test products
with SPF values over 15 may be erroneous in other studies. Better
assurance of an accurate SPF value is obtained by using a standard that
is closer in SPF value to the sunscreen product being tested.
The use of an SPF 15 standard would be reasonable to test products
with SPF values below 15. SPF 15 is in the middle (geometrically) of
the 4 to 50 range. The ratio of SPF 15 to SPF 4 is 3.75, and the ratio
of SPF 50 to SPF 15 is 3.33. Thus, there would be equal coverage of all
ranges. Therefore, FDA is proposing that Formulation B may be used to
test sunscreen drug products with SPF 2 and over, and is required for
testing sunscreen drug products with SPF over 15 (proposed Sec.
352.70(a)(1)(ii)). The 8-percent homosalate standard may be used for
testing sunscreen drug products with SPF of 2 to 15.
(Comment 29) Several comments suggested that a modern, HPLC method
is superior to the older spectrophotometric assay in Sec. 352.70(c) of
the FM. One comment provided technical information about the HPLC
method and stated that it is now commonly used by analytical
laboratories to assay sunscreen formulations (Ref. 71). Although this
HPLC assay method was used in the study of two SPF 15 sunscreen
standard preparations (see section III.J, comment 27 of this document),
one comment noted that there are limited data on this method with the
SPF 15 control formulation because FDA has not yet published this
formula as an accepted standard.
FDA agrees that an HPLC method is superior to the
spectrophotometric method, which was originally published by FDA in
1978, in specificity and precision. Validation data provided by the
comment documented the following:
Specificity,
Accuracy,
Limit of detection,
Linearity,
Precision, and
Reproducibility of the method.
The validation data included chromatograms and demonstrated that the
HPLC method is suitable for both the SPF 4 and SPF 15 standards.
Further, FDA validated the method in its laboratories and concludes
that the method is acceptable for quality control and regulatory
purposes (Ref. 72). Finally, the spectrophotometric method has not been
validated for the SPF 15 standard, and the HPLC method has been
validated for both the SPF 4 and SPF 15 standards. Therefore, FDA is
proposing to revise Sec. 352.70 to replace the outdated
spectrophotometric method with the HPLC method and to
[[Page 49097]]
use the HPLC method to assay both the SPF 4 and SPF 15 standards.
(Comment 30) Two comments disagreed with the requirement in Sec.
352.70(a) for concomitant use of a standard sunscreen for each SPF
test. One comment suggested that a standard could be run twice yearly.
Another comment suggested that data to evaluate proper laboratory test
procedures could be obtained from panels of a standard run as part of
``the ongoing laboratory operation.'' A third comment stated that a
standard preparation should be run each time an SPF determination is
made.
FDA discussed this issue in comment 78 of the TFM (58 FR 28194 at
28253 to 28254). FDA disagreed with one comment that the standard could
be run once or twice a year and reaffirmed the Panel's recommendation
that concomitant testing is necessary in SPF determinations to ensure
uniform evaluation of OTC sunscreen drug products and to serve as an
internal indicator of experimental errors. The comments requesting a
change did not provide any supporting data. In the absence of
supporting data, FDA is not persuaded to change the concomitant use
requirement in Sec. 352.70(a).
(Comment 31) One comment suggested that there is a need for a
specific source to maintain and supply sunscreen standards. The comment
contended that a few testing laboratories are reporting differences in
the tested SPF of the 8-percent homosalate standard preparation
depending on whether the standard is prepared by the laboratory or
purchased from one company that manufactured this standard. The comment
stated that either the testing procedures or the standard itself have
changed since the original formula was published (earlier standard SPF
values were 3.7/3.8 to 4.2/4.3 with an average of 4.1, while current
values are 4.3 to 4.9/5.0).
Data supporting the reliability and wide acceptance of the 8-
percent homosalate standard preparation were previously discussed in
the TFM (58 FR 28194 at 28250 through 28252). The comment did not
provide any data to support its contention concerning discrepancies in
the SPF of 8-percent homosalate standard preparations and FDA is not
aware of any new data that support the need for a specific source to
maintain and supply this standard. The standard is a control to
validate the testing procedure, equipment, and facilities rather than a
calibration tool for setting SPF values of sunscreen products. FDA
considers the parameters established in Sec. 352.70 of the FM adequate
to assure a uniform standard and is not requiring that a specific
source maintain and supply the sunscreen standard at this time.
K. Comments on Artificial Light Sources for SPF Testing Procedure
(Comment 32) Several comments suggested that FDA replace the
specifications in Sec. 352.71 that state ``sun at a zenith angle of
10[deg]'' and ``less than 1 percent of its total energy output
contributed by nonsolar wavelengths shorter than 290 nm'' with the
COLIPA table of ``percent erythemal contribution'' as the spectral
power distribution standard for the light source used in the SPF test
procedures (Ref. 73). The comments suggested that the spectra of
currently used solar simulators (especially around 290 nm and above 350
nm) could cause overestimation of SPF values for high SPF sunscreens.
Because shorter wavelengths can make a very large contribution to
erythema, the comments stated that small errors in the 290 nm region of
solar simulator spectra could have considerable effects. The comments
noted that spectral power deficiencies above 350 nm may give
artificially high SPF values for sunscreen drug products that absorb
poorly in the long wavelength UVA region.
The comments added that there is general agreement in the industry
that Sec. 352.71 should be revised to permit compliance with the
COLIPA standard for solar simulators. The comments further recommended
one modification to the COLIPA standard: The energy for wavelengths
below 290 nm should be limited to ``less than 0.1 percent'' rather than
``less than 1.0 percent,'' as stated in the COLIPA standard. The
comments stated that a more restrictive specification of ``0.01
percent,'' as mentioned by FDA (65 FR 36319 at 36321), would result
more in testing the limits of the measurement spectroradiometer rather
than the true output of the solar simulator. One comment that supported
the COLIPA standard subsequently suggested that the spectral limits be
further narrowed to prevent excessive variability of SPF values for
certain sunscreen products (Ref. 74).
One comment discussed the calculations to obtain the source
spectral specification according to COLIPA (Ref. 73). In the COLIPA
table, the source spectral specification is described in terms of
cumulative erythemal effectiveness by successive wavebands. The
erythemal effectiveness of each waveband is expressed as a percentage
of the total erythemal effectiveness from 250 nm to 400 nm, or as the
Percentage Relative Cumulative Erythemal Effectiveness (%RCEE).
According to the COLIPA specifications and consistent with Sec.
352.71, wavelengths below 290 nm should be excluded from any source by
appropriate filters. Likewise, wavelengths above 400 nm should be
limited as much as possible and are not included in the calculation of
%RCEE. Because RCEE values are calculated as relative percentages,
measuring the spectral irradiance in absolute energy units is not
necessary. Relative units are sufficient. The spectral irradiance of
the source is multiplied by the Commission International de L'Eclairage
(CIE) (1998) standard skin erythemal action spectrum to obtain the
erythemal effectiveness of the source. The spectral erythemal
effectiveness values of the source spectrum are then integrated from
250 nm to the various successive reference wavelength values shown in
the COLIPA table in order to produce the cumulative erythemal
effectiveness for each spectral waveband, and the total erythemal
effectiveness is calculated up to 400 nm. Finally, the %RCEE is
calculated at the reference waveband as the percentage ratio of the
cumulative erythemal effectiveness in each of these wavebands to the
total integrated value from 250 nm to 400 nm.
Based on these calculations, the COLIPA table includes limits up to
400 nm. In contrast, when FDA requested comments on this issue, we
included a modified COLIPA table that includes limits up to 350 nm (65
FR 36319 at 36321). However, the modified COLIPA table published by FDA
was erroneous. FDA agrees with the comment (and COLIPA) that it is
necessary to include all UV erythemal wavelengths (i.e., up to 400 nm)
when standardizing solar simulator output. As argued by the comment,
the erythemal contribution from long-wavelength UVA radiation (i.e.,
350 nm to 400 nm) can become important when a high SPF product is
tested. However, FDA believes that the limits for the 290 to 350
waveband should be changed from 93.5 to 99.0 percent to 93.5 to 98.5
percent. This modification will address some of the errors in SPF that
are attributed to the lack of match between the solar simulator and
actual solar spectra. FDA invites comments on these proposed changes.
FDA does not agree, at this time, with the comment's suggestion to
further narrow the COLIPA standard to the spectral limits that it
proposed. The comment based its suggestion on a theoretical argument
and did not supply the complete emission spectra of the
[[Page 49098]]
four solar simulators used in its two referenced studies. There may be
significant differences in the 290 to 350 nm range in these studies
that can account for the reported differences in SPF test results.
Further, FDA has concerns about the ability of currently used solar
simulators to meet the comment's suggested spectral standard and
invites comments on the changes suggested by the comment.
FDA agrees with the comments that the COLIPA approach provides a
more appropriate description for solar simulators. FDA's original
proposal that solar simulators have a spectral power distribution
``similar to sunlight at a zenith angle of 10[deg]'' is nonquantitative
and may not be practical, considering the types of solar simulators
that are generally available. Accordingly, FDA is proposing to revise
the first part of Sec. 352.71 (proposed Sec. 352.70(b)) as follows:
(b) Light source (solar simulator)--(1) Emission spectrum. A
solar simulator used for determining the SPF of a sunscreen drug
product should be filtered so that it provides a continuous emission
spectrum from 290 to 400 nanometers (nm) with * * * the following
percentage of erythema-effective radiation in each specified range
of wavelengths:
Solar Simulator Emission Spectrum
------------------------------------------------------------------------
Wavelength range (nm) Percent erythemal contribution
------------------------------------------------------------------------
< 290 < 0.1
290-310 46.0-67.0
290-320 80.0-91.0
290-330 86.5-95.0
290-340 90.5-97.0
290-350 93.5-98.5
290-400 93.5-100.0
------------------------------------------------------------------------
(Comment 33) Several comments suggested the following revisions to
the light source (solar simulator) requirements in Sec. 352.71:
Delete the ``out of band'' specification that not more
than 5 percent of a solar simulator's total energy output can be
contributed by wavelengths longer than 400 nm.
In place of this 5 percent ``out of band'' limitation,
allow a limit such as 1,250 to 1,500 watts/square meter (W/m\2\) on the
total solar simulator irradiance delivered to the skin for all
wavelengths.
One comment provided data comparing solar simulators with and
without a 50 percent neutral density filter to demonstrate that there
is no measurable impact of heat load on the outcome of SPF testing
(Ref. 13). The comment stated that thermal overload does not occur for
COLIPA-compliant solar simulators operated at or below a total
irradiance limit of 1,500 W/m\2\. The comments added that the ``out of
band'' specification is not possible with existing solar simulators and
new systems would need to be designed, tested, manufactured, and
distributed to provide equipment capable of meeting this specification.
The comments concluded that replacing the ``out of band'' specification
with a limit would improve the testing of all products, including high
SPF products.
FDA believes that it is important to limit total energy delivered
to the skin during the SPF test so that skin temperature does not reach
a point that may compromise dose reciprocity. FDA concurs with the
comments and is proposing to replace the ``out of band'' specification
in Sec. 352.71 (proposed Sec. 352.70(b)) with a limit of 1,500 W/m\2\
on total solar simulator irradiance between 250 and 1,400 nm.
(Comment 34) Two comments recommended that FDA change the solar
simulator specification in Sec. 352.71 from ``good beam uniformity
(within 10 percent) in the exposure plane'' to ``the delivered dose to
the UV exposure sites be within 10 percent of the prescribed dose with
good beam uniformity'' (without defining ``good beam uniformity''). The
comments contended that although ``reasonable'' or ``good'' beam
uniformity is desirable, beam uniformity within 10 percent is virtually
impossible to measure or achieve for the vast majority of solar
simulators.
FDA agrees that ``dose'' accuracy is a critical variable and the
delivered dose to the UV exposure sites should be within 10 percent of
the prescribed dose. Because FDA considers quantification of ``good
beam uniformity'' to be an important issue, it is keeping a
specification for this parameter. However, FDA believes that a
specification of 20 percent is more achievable than the proposed 10
percent. Beam uniformity can be measured with broadband UV detectors
that have been modified to provide a small input aperture to the
detector. For example, for a single beam simulator with a subsite
exposure area of approximately 1 cm\2\, an appropriate input aperture
would be 0.25 cm\2\. Beam uniformity can then be checked by making a
measurement in the center of each of the four quadrants of the exposure
field. These readings should be within 20 percent of the peak reading.
The same principle can be applied to larger exposure fields.
Additionally, the average of these four readings should be within 10
percent of the prescribed dose for a given exposure site. In addition,
FDA is proposing a requirement that places a quantifiable limit of 20
percent on time related fluctuations of the radiation emissions of the
solar simulator.
Accordingly, FDA is proposing to revise portions of Sec. 352.71
(proposed Sec. 352.70(b)(2)) to read as follows:
(2) Operation. A solar simulator should have no significant time
related fluctuations (within 20 percent) in radiation emissions
after an appropriate warmup time and good beam uniformity (within 20
percent) in the exposure plane. The average delivered dose to the UV
exposure site must be within 10 percent of the prescribed dose.
(Comment 35) Several comments recommended that the last sentence of
Sec. 352.71 be modified to include additional requirements for the
periodic testing of solar simulators. The comments suggested that
periodic measurements be made twice a year and that measurements be
done after changes in the optical filtering components.
FDA agrees with the comments and is proposing to revise the last
part of Sec. 352.71 (proposed Sec. 352.70(b)(3)) to read as follows:
(3) Periodic measurement. To ensure that the solar simulator
delivers the appropriate spectrum of UV radiation, the emission
spectrum of the solar simulator must be measured every 6 months 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 radiometric device
that is sensitive primarily to UV radiation. The broadband
radiometric device should be calibrated using side by side
comparison with the spectroradiometer at the time of the semiannual
spectroradiometric measurement of the solar simulator. 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.
L. Comments on the Design/Analysis of SPF Testing Procedure
(Comment 36) Several comments contended that the series of seven
exposure doses in Sec. 352.73(c) should be modified to eliminate the
two doses placed symmetrically around the middle exposure. One comment
provided data comparing the seven-exposure series against the five-
exposure series and concluded that the seven-exposure series did not
increase the precision of the test (Ref. 66).
[[Page 49099]]
Comments also argued that the seven-exposure series would require
longer testing times, thus increasing exposure risk and discomfort to
subjects, and that the five-exposure series is as accurate as the
seven-exposure series even at high SPF values.
FDA discussed its rationale for seven versus five exposure doses in
the TFM (58 FR 28194 at 28269 to 28272). FDA sought an exposure format
that would provide better accuracy and precision to SPF measurements,
particularly at higher SPF values. FDA reasoned that the seven-exposure
series in Sec. 352.73(c), with two additional exposures symmetrically
placed around the middle exposure of the geometric series, would
increase precision and eliminate possible overestimation of the true
SPF value of a product with a high SPF.
FDA has evaluated the data and other information submitted by the
comments and agrees they demonstrate that the additional two exposure
doses do not make the test more precise. Therefore, FDA is proposing to
modify Sec. 352.73(c) (proposed Sec. 352.70(d)(3)) as follows:
* * * Administer a series of five UV radiation doses expressed
as J/m\2\-eff (adjusted to the erythema action spectrum calculated
according to paragraph (d)(1) of this section) to the subsites
within each test site on a subject using an accurately calibrated
solar simulator. The five UV doses will be a geometric series as
described in paragraph (d)(2) of this section, where the middle
exposure represents the expected SPF. For products with an expected
SPF less than 8, use exposures that are the product of the initial
unprotected MED times 0.64X, 0.80X, 1.00X, 1.25X, and 1.56X, where X
equals the expected SPF of the test product. For products with an
expected SPF between 8 and 15, use exposures that are the initial
unprotected MED times 0.69X, 0.83X, 1.00X, 1.20X, and 1.44X, where X
equals the expected SPF of the test product. For products with an
expected SPF greater that 15, use exposures that are the initial
unprotected MED times 0.76X, 0.87X, 1.00X, 1.15X, and 1.32X, where X
equals the expected SPF of the test product. * * *
(Comment 37) Several comments suggested changes to the number of
subjects per test panel in Sec. 352.72(g). One comment suggested
deletion of the phrase ``with the number fixed in advance by the
investigator.'' The comment reasoned that if the first 20 subjects
provided data that can be evaluated, risk to human subjects could be
curtailed by not impaneling another 5 subjects. Other comments
recommended using 10 to 20 subjects, arguing that the criterion for
accuracy should not be the number of subjects, but the relative
deviation of individual SPF measurements. One comment used absorbance
instead of the SPF value to calculate the number of subjects required
for high SPF products and proposed a binomial test method to reduce the
number of subjects (see section III.I, comment 24 of this document).
Another comment stated that the 20 of 25 subject limitation may be an
issue for products with high SPF values due to the high variability in
the responses obtained and suggested that the number of subjects be
increased when evaluating sunscreen products with high SPF values.
As discussed in section III.I, comment 24 of this document, the
binomial test method deserves further investigation and may prove to be
a reasonable approach as additional data and experience become
available. In addition, based on the current SPF test method, FDA
agrees with the comment recommending deletion of the requirement to fix
the number of subjects per panel in advance. This requirement is
unnecessary because the panel is limited to a range of 20 to 25
subjects (under current Sec. 352.72(g)). Thus, if 20 subjects produce
valid data in accordance with proposed Sec. 352.70(c)(9), then it
would be unnecessary to test additional subjects. In addition, some
subjects may not produce valid data in accordance with proposed Sec.
352.70(c)(9) (e.g., no erythema produced), requiring testing of
additional subjects (not exceeding 25 subjects). FDA agrees that the
number of subjects should be based on error about the mean SPF, but
disagrees that the minimum number of subjects can be lowered to 10. As
described later in this comment, FDA has reevaluated the proposed
minimum number of subjects based on error about the mean SPF.
FDA agrees with one comment that more subjects are needed when
testing products with high SPF values. FDA believes that a minimum
sample size of 20 subjects is adequate for products with an expected
SPF value of 30 or less. However, current data and experience with
products having SPF values over 30 are not sufficient to determine an
appropriate sample size. Therefore, to account for increased
variability in SPF values for sunscreens with SPF values over 30, FDA
proposes to increase the sample size to at least 25 subjects. FDA
invites data demonstrating an appropriate panel size for sunscreens
with SPF values over 30. At this time, FDA is proposing to revise Sec.
352.72(g) (proposed Sec. 352.70(c)(7)) as follows:
(7) Number of subjects--(i) For products with an expected SPF
value under 30. A test panel shall consist of 20 to 25 subjects with
at least 20 subjects who produce valid data for analysis. Data are
valid unless rejected in accordance with paragraph (c)(9) of this
section. If more than 5 subjects are rejected based on paragraph
(c)(9) of this section, the panel is disqualified, and a new panel
must be created.
(ii) For products with an expected SPF of 30 or over. A test
panel shall consist of 25 to 30 subjects with at least 25 subjects
who produce valid data for analysis. Data are valid unless rejected
in accordance with paragraph (c)(9) of this section. If more than 5
subjects are rejected based on paragraph (c)(9) of this section, the
panel is disqualified, and a new panel must be created.
In the 1978 advance notice of proposed rulemaking (ANPRM), the
Panel recommended that studies enroll at least 20 subjects, adding that
``the standard error shall not exceed 5 percent of the
mean'' (43 FR 38206 at 38261). Following publication of the ANPRM, FDA
held a public meeting on January 26, 1988 (52 FR 33598 at 33600 to
33601). During that meeting, attendees argued the following four points
related to the number of subjects:
1. Test panels should consist of at least 20 subjects.
2. The size of the test panel should be fixed in advance.
3. The limitation that the standard error should be less than
5 percent should not apply.
4. The testing procedures should make it clear that the addition of
subjects to the test panel to achieve the desired minimum is acceptable
under specific conditions (58 FR 28194 at 28267).
In the 1993 TFM, FDA based Sec. 352.72(g) on these comments and the
Panel's recommendation.
The calculations of the sample size and confidence interval in
Sec. 352.72(g) are based on the assumption that there is a normal
distribution about the mean (i.e., a bell curve). Based on this
assumption, the t-test is used for statistical analysis. Based on the
t-test, FDA calculated that a panel of 20 subjects should result in an
acceptable error about the mean. However, in some cases, a panel of 10
subjects would probably result in an error about the mean that is
unacceptably large. There is inherently higher variability in testing
and, consequently, larger error about the mean for products with high
SPF values. Therefore, FDA believes a greater number of subjects is
necessary when testing products with high SPF values. FDA believes a
panel of 25 to 30 subjects should result in an acceptable error about
the mean for products with high SPF values. FDA invites additional data
demonstrating adequate numbers of subjects, especially for products
with high SPF values.
(Comment 38) One comment stated that one factor affecting the SPF
of a
[[Page 49100]]
product is the erythemal threshold of the skin, or MED(US). The comment
argued that SPF decreases with increasing erythemal threshold. The
comment maintained that, because MED(US) varies only with skin type,
the MED(US) of each subject in a test group should be within reasonably
similar limits. The comment suggested that the MED(US) of each subject
should be 50 to 150 percent of the median MED(US). The comment also
suggested that subjects with an MED(US) that is twice the median should
be excluded regardless of skin type.
FDA is not proposing the revisions suggested by the comment. FDA
based Sec. 352.73(b), which describes determination of an MED(US), on
the Panel recommendation in the ANPRM. The procedure for determining
MED(US) requires irradiation of subjects with a geometric series of UV
doses. When developing this procedure, the Panel explained that the
geometric series provides the same relative level of uncertainty
independent of the subject's sensitivity to UV light (i.e., independent
of skin type) (43 FR 38206 at 38266). Thus, the Panel disagreed that
skin type affects MED(US). The comment did not provide any data or
other information demonstrating that skin type, in fact, affects
MED(US). FDA is not aware of any data demonstrating this phenomenon.
FDA will revise the proposed test criteria if we receive data or
information demonstrating that the criteria are not appropriate or
other criteria are more suitable.
(Comment 39) Several comments urged FDA to reduce the minimum 1
cm\2\ test subsite area in Sec. 352.72(d)(2). One comment proposed the
minimum test subsite area be decreased to 0.5 cm\2\. Two comments
suggested that the test subsite area be defined by minimum diameters of
0.8 cm (circular area of 0.5 cm\2\) and 0.15 cm (circular area of 0.017
cm\2\), respectively.
The comment supporting the 0.5 cm\2\ test subsite area referenced a
study published in 1987 (Ref. 75) that was mentioned in relation to
artificial light sources in comment 86 of the TFM (58 FR 28258 to
28261). This study was designed to evaluate the FDA sequential
technique of dosing using a single-port solar simulator (SPSS), a
series sequential method using a multi-port xenon arc solar simulator
(MPSS), and the Deutsches Institut f[uuml]r Normung (DIN) simultaneous
technique of dosing using an Osram Ultravitalux lamp. Five sunscreen
formulations with SPF values from 4 to 15 were tested. The authors
suggested that there was little systematic difference in estimates
obtained using the SPSS and MPSS, but there was a large systematic
deviation between the FDA and DIN methods. As this study was not
designed specifically to compare irradiation areas, three different
test subsite areas were used, and none was 0.5 cm\2\. FDA cannot
determine the suitability of a 0.5 cm\2\ test subsite area compared to
a 1 cm\2\ test subsite area based on this study.
The comment advocating the 0.8 cm test subsite diameter argued that
setting a lower area limit has the following four benefits:
Does not preclude the use of larger irradiation areas,
Will not affect the accuracy of resulting measurements,
Permits lower wattage lamps as well as liquid light guides
that have apertures of 0.8 cm diameter, and
Provides more skin area for testing.
The comment provided statistical analysis of a study comparing multi-
port and single-port solar simulators (Ref. 66). SPF 15 or SPF 4
products were tested along with the homosalate standard sunscreen. Two
subsite areas were exposed to the multi-port solar simulator, and two
were exposed to the single-port solar simulator. The comment concluded
that similar SPF values are determined using the two types of solar
simulators. However, the study report did not include details such as
subject selection, product application, or specifications for the solar
simulators. More importantly, the study report did not specify the size
of each subsite. Thus, FDA cannot draw any conclusions regarding
appropriate test subsite area from the submitted study.
The comment supporting the 0.15 cm test subsite diameter referenced
two studies (Ref. 76). Significant discrepancies in the information
submitted for the first study prevented evaluation of this study. The
comment did not submit full details of the second study. Therefore, FDA
could not reach any conclusions from the submitted studies.
FDA agrees, in principle, with the advantages of a smaller test
subsite area. The Panel stated that, depending on instrumental design,
irradiation test subsite areas less than 1 cm\2\ can be utilized and
that test subsite diameters greater than 0.4 cm present no difficulty
in determining skin erythema (43 FR 38206 at 38260). While FDA does not
consider the information provided by the comments adequate to support
the suggested test subsite areas, it recognizes that considerable
advances have been made since the Panel met. However, FDA requires data
demonstrating that the monograph test produces valid and reproducible
results using a smaller test subsite area before amending the monograph
test. FDA will consider a reduction in test subsite area if adequate
supporting data are provided. The studies should do the following:
Compare the smaller subsite area to 1 cm\2\ on the same
subjects,
Utilize high SPF products as well as products with SPF
values below 15, and
Demonstrate comparable results among several laboratories.
(Comment 40) Several comments either agreed or disagreed with the
blinding procedures for the application of test materials described in
Sec. 352.72(e). One comment stated that unblinded SPF testing is bad
science, and that exposure sites within test areas should always be
randomized no matter how many products are being tested. Another
comment stated that the blinding procedure is an unnecessary
complication and does not contribute to the accuracy of the test. One
comment agreed that, in order to approximate true blinding, the
individual who grades erythemal responses should not be the same
clinician who applied the test materials. Another comment contended
that it is not reasonable to randomly irradiate test sites with varying
doses of UV radiation. One comment recommended making the use of finger
cots optional because some product vehicles are incompatible with
finger cot material. Another comment suggested that the amount of
product remaining on the finger cot is a source of variability in the
SPF test and suggested that the extent of this variability be fully
evaluated.
FDA agrees with the comments that favor blinding and randomization
and is not proposing to remove the blinding and randomization
requirements from Sec. 352.72(e) (proposed Sec. 352.70(c)(5)).
According to Sec. 352.72, blinding and randomization is required only
when two or more sunscreen drug products are being evaluated at the
same time. Because a test product is always tested in conjunction with
the standard sunscreen, FDA proposes to delete the statement, ``If only
one sunscreen drug product is being tested, testing subsites should be
exposed to varying doses of UV radiation in a randomized manner.''
Section 352.72(h) (proposed Sec. 352.70(c)(8)) specifies that the
person who evaluates the MED responses must not be the same person who
applied the sunscreen or administered the dose of UV radiation. The
comments that disagreed did not provide evidence demonstrating that
these requirements are unnecessary.
With regard to the suggestion that the use of finger cots be made
optional, the
[[Page 49101]]
Panel's review of data found that numerous investigators have obtained
more reproducible results by spreading a product using a finger cot
than by spreading with a glass or plastic rod (43 FR 38206 at 38261).
FDA agrees with the comment that some formulations may be chemically
incompatible with latex finger cots, but there are finger cots composed
of other materials that should be compatible with these sunscreens.
Therefore, to increase reproducibility in sunscreen application, FDA is
proposing to revise the application requirement in Sec. 352.72(e)
(proposed Sec. 352.70(c)(5)) to read as follows:
* * * 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. Pretreatment is meant to ensure that sunscreen is
applied at the correct density of 2 mg/cm\2\.
FDA urges manufacturers of sunscreen drug products to investigate the
extent of variability in the SPF test that may be caused by various
applicators.
(Comment 41) One comment addressed illumination at the test site in
Sec. 352.72(h) and recommended that a level of at least 1,000 lux be
used. The comment contended that 450 to 550 lux is too low to provide
adequate illumination for reading erythema.
As discussed in the TFM, the Panel recommended an incandescent or
warm fluorescent illumination source but did not specify a required
illumination level (58 FR 28194 at 28269). In the TFM, FDA agreed with
the Panel about the illumination source. FDA also proposed that the
illumination level be 450 to 550 lux. The comment did not provide any
data to support its contention that 1,000 lux is the appropriate
illumination level. Thus, FDA is not revising the lux range in Sec.
352.72(h) (proposed Sec. 352.70(c)(8)) at this time. FDA invites data
and information on levels of illumination currently used to evaluate
MED responses in SPF testing laboratories and will consider adequately
supported alternatives.
(Comment 42) One comment stated that the third sentence in Sec.
352.73(b) should be modified to read: ``* * * wherein each exposure
dose is 25 percent greater than the previous exposure dose to maintain
the same relative uncertainty * * *.'' The comment explained that
defining the exposure dose in terms of ``time'' is incorrect.
FDA discussed the Panel's definition of dose in terms of time
intervals in comment 84 of the TFM (58 FR 28194 at 28256 to 28257). FDA
stated that it is more accurate to express dose as the ``erythema-
effective exposure,'' in units that define the total amount of
erythema-effective energy applied to the testing subsite (i.e., as J/
m\2\). FDA discussed replacing ``exposure time interval'' with
``erythema-effective exposure (dose),'' but inadvertently used
``exposure time interval'' instead of ``dose'' in Sec. 352.73(b). FDA
agrees that Sec. 352.73(b) (proposed Sec. 352.70(d)(2)) should be
modified and is amending this section as the comment suggested.
(Comment 43) Several comments suggested an alternative statistical
procedure for calculating product SPF values and PCD in current Sec.
352.73(d). The comments argued that the procedure described in the FM
would result in significant lowering of SPF values. The comments
advocated clinical equivalency testing (i.e., using a lower one-sided
95 percent confidence interval or a one-sided t test, with a delta of 5
percent). The comments noted that an upper and lower bound equivalency
procedure with a delta of 20 percent would be an appropriate procedure.
The comments added that SPF is not a precise value, but rather a valid
estimate of product performance. Another comment suggested using the
mean of the results to find the actual number and then round-off
(either up or down) to the nearest whole number.
FDA is not proposing to modify the calculation of product SPF
values and PCD in Sec. 352.73(d) (proposed Sec. 352.70(d)(4)) at this
time. The distinct advantage of the t-test is that it provides a simple
computational procedure for a statistical test that makes inferences
about the population. The SPF is determined to be the largest whole
number that is excluded by a lower one-sided 95 percent confidence
interval. Simply finding a mean value, as one comment suggested, is not
adequate because such a value does not provide information about the
validity of the test (e.g., standard deviation) that should be taken
into consideration.
FDA's evaluation of the equivalency testing approach for
calculating SPF values indicates the method is less stringent than the
FM method. The proposed equivalency test is essentially testing the
following hypothesis:
H0: micro <= 0.95L versus Ha: micro > 0.95L
where: H0 = null hypothesis
Ha = alternative hypothesis
micro = population mean
L = confidence limit
FDA acknowledges that the equivalency test may be a valid method for
determining SPF. In many cases, the same SPF would be determined for a
sunscreen using either the equivalency test or the FM method. However,
in some cases, a higher SPF would be determined for a sunscreen using
the equivalency test than would be determined using the FM method. By
contrast, a higher SPF would never be determined for a sunscreen using
the FM method than would be determined using the equivalency test.
Thus, the FM method results in a more conservative SPF value than the
equivalency test. FDA believes it is in the best interest of public
health to label sunscreens with the more conservative SPF value. If FDA
adopted the equivalency test after over 30 years of using the FM
method, consumers may, in some cases, overestimate the protection
provided by a sunscreen based on a higher SPF number resulting from the
equivalency test.
M. General Comments on UVA Testing Procedure
(Comment 44) Many comments discussed UVA radiation action spectra
and skin damage (erythema, photocarcinogenesis, DNA damage,
photosensitivity reactions, photoaging, mutagenicity, and
immunosuppression). Some comments described various types of solar-
induced skin damage and the wavelengths contributing to the specific
biological events. Some comments stated that UVA II radiation (320 to
340 nm) is much more damaging than UVA I radiation (340 to 400 nm).
Other comments stated that there is presently no convincing
evidence that the action spectra for damage from UV radiation have been
clearly defined. One comment stated that until the separate dangers and
risks of each portion of the UVB and UVA radiation action spectra are
precisely and scientifically identified and quantified, FDA should
consider the entire UVA radiation range as having significant
biological risk. Another comment stated that protection against all UVA
radiation wavelengths would seem to be both desirable and prudent
considering the present state of our knowledge.
FDA agrees that the action spectra for various harmful effects on
human skin from chronic UVA radiation have not been clearly defined and
that it may be misleading to associate damage with any specific action
spectrum based upon current knowledge. Information provided by comments
suggests a relatively greater role for UVA radiation than UVB radiation
in long-term sun damage even though there is little consensus about the
amount of UVA radiation protection required. Therefore, FDA is
proposing UVA radiation test methods that assess protection throughout
the UVA spectrum (see section III.N, comment 45 of this document).
[[Page 49102]]
N. Comments on UVA Testing Procedure Design and Testing Criteria
(Comment 45) FDA is proposing that both an in vitro and an in vivo
test be conducted to determine UVA radiation protection. The proposed
in vitro test is the ratio of long wavelength UVA absorbance (UVA I) to
total UV absorbance (i.e., UVB + UVA). The proposed in vivo test is the
PPD test, which is similar to the SPF test except the endpoint is
pigment darkening rather than erythema. FDA is proposing that UVA
labeling consist of a UVA rating reflecting both the in vitro and in
vivo test results. The rating will be the lowest ``high'' protection,
then the sunscreen would be labeled as providing ``medium'' UVA
protection.
FDA is proposing these UVA testing requirements based on many
comments submitted in response to the TFM that contained data and
information on possible test methods (and combinations or modifications
of these methods). The comments discussed the following in vivo and in
vitro test procedures:
IPD,
PPD,
PFA,
Photosensitivity methods,
UVA radiation protection percent,
Diffey/Robson method and modifications of that method,
Standards Association of Australia,
Diffuse reflectance method,
Skin\2\ method, and
Psoralen photoadduct method.
On May 12, 1994, FDA held a public meeting to discuss these UVA
radiation testing procedures (Ref. 77).
One comment suggested using either or both PPD and erythema skin
responses to measure the UVA radiation protection effectiveness of OTC
sunscreen drug products. The comment maintained that these two test
methods have the following similarities:
Same UVA radiation source,
Same dose range, and
Similar post exposure time lags for observation.
The only difference is in the skin types used, thus giving a variable
balance in PPD and erythema responses. The comment added that such a
combination of methods has the following advantages:
Reproducibility and stability,
Relevance,
Persistence of skin response through 1 to 24 hours,
Independence of source flux and accuracy,
Utilization for static as well as for water resistance
photoprotective predictions, and
Practicability, convenience, and safety.
Stating that there is currently no convincing evidence that the
action spectrum for UVA radiation damage has been clearly defined,
another comment suggested that protection from UV radiation be measured
using two factors based on the degree of attenuation of UV radiation
across the full spectrum. One factor, the SPF value, is erythemally
weighted and gives an indication of the power of protection provided by
the product. The second factor should take into account the shape of
the transmittance curve measured by either in vivo or in vitro means.
The comment stated that it is potentially dangerous to associate skin
damage with any single action spectrum (e.g., IPD, PPD, or PFA). The
comment argued that all of these indicators are wavelength-specific and
protection from specific wavelengths does not mean protection from
damage. The comment added that if only the erythema action spectrum is
used, it virtually ignores the effects of wavelengths over 320 nm. The
comment contended that using an SPF value augmented by the shape of the
transmission curve would give consumers the information necessary to
make an effective and safe judgment about the protection provided by a
sunscreen drug product. For example, the comment noted that a product
with a high SPF and a uniform high level of attenuation across the
spectrum (i.e., equal attenuation at all UVB and UVA wavelengths) will
provide the most protection. The comment added that, at a later date,
if sufficient evidence becomes available to describe a credible UVA
radiation damage spectrum, this combined system could be used by
convoluting the attenuation curve with the action spectrum curve.
One comment proposed a modification (``critical wavelength'') of
the Diffey/Robson test method (Refs. 78 and 79). The comment noted
that, when people are outdoors, they are not exposed to only UVB or UVA
radiation but are exposed to solar UV radiation, which always contains
both. In addition, biological effects against which people may wish to
be protected are caused by all wavelengths in the solar UV radiation
spectrum. The comment contended that investigators should not be
exposing subjects to sources of radiation with spectra that have no
practical application and using irrelevant biological effects as
endpoints (e.g., IPD).
The comment proposed to assess the UVA radiation protection
potential of an OTC sunscreen drug product by first
spectrophotometrically determining the absorption spectrum of the
product throughout the UV radiation range. Then, one calculates the
wavelength value [lgr]c (the ``critical wavelength''), where
the area under the absorption spectrum from 290 nm to [lgr]c
is 90 percent of the integral of the absorption spectrum from 290 to
400 nm, and uses a five-point scale to classify products as follows:
Table 3.--Broad Spectrum Rating Based on Critical Wavelength
------------------------------------------------------------------------
Critical Wavelength (nm) Broad Spectrum Rating
------------------------------------------------------------------------
[lgr]c < 325 0
325 < = [lgr]c < 335 1
335 < = [lgr]c < 350 2
350 < = [lgr]c < 370 3
370 < [lgr]c 4
------------------------------------------------------------------------
The comment concluded that this test method makes no underlying
assumptions about the form of action spectra for either acute or
chronic photobiological damage. Because the efficiency of UV radiation
to induce a given photobiological endpoint tends to decrease with
increasing wavelength, the method utilizes wavelength intervals for
classifying the ``broad spectrum'' rating, which increases in an
approximately logarithmic manner.
One comment submitted a protocol for the ``critical wavelength''
(CW) modification of the Diffey/Robson method for classifying the
relative degree of UVA radiation protection of sunscreen drug products
(Ref. 80). The comment addressed product photostability by pre-
irradiation of the sunscreen product with a UV radiation dose
corresponding to one-third the labeled SPF value. The comment reported
recommendations based on the results of a round-robin evaluation of the
proposed CW method involving six laboratories using four test sunscreen
formulations with various substrates. The comment concluded that the CW
method is a convenient, reproducible in vitro method for measuring the
uniformity of sunscreen absorbance spectra across the UV radiation
spectrum to classify products into broad UVA radiation protection
categories.
In response to the June 8, 2000, reopening of the administrative
record for the rulemaking for OTC sunscreen drug products (65 FR
36319), FDA received additional comments on UVA radiation testing
methods. While all comments supported some type of testing to
differentiate the UVA radiation protection potential of sunscreen
products, they disagreed
[[Page 49103]]
about the use of in vivo versus in vitro testing methods.
Comments from a group of sunscreen product manufacturers contended
that an in vivo test method, such as PPD or PFA, best describes the
photoprotective characteristics of a sunscreen drug product. These
comments stated that an in vivo method measures the actual effect of
UVA radiation on the skin and estimates the expected product
performance under actual use conditions.
One comment presented test data that suggested PPD and PFA values
are comparable (Ref. 6). The comment stated that an advantage of the
PFA method is that it allows inclusion of skin type I, whereas the PPD
test is conducted on darker skin types (II and III). However, the
comment added that the PPD test has been accepted since 1996 by the
JCIA for the assessment of UVA radiation protection efficacy of
sunscreen products.
One comment contended that the PPD test should be used for the
following reasons:
It requires a relatively low dose of UV radiation.
The reaction is stabilized in 2 to 4 hours.
The test subject is left with no mark of irradiation and
receives little or no injury.
The test can be conducted with high precision.
Another comment stated that PPD values demonstrate the same correlative
benefits that exist for SPF values and, therefore, do not give false
impressions of magnitude. Another comment stated that products with the
same SPF can have different levels of UVA radiation protection. Thus,
PFA or PPD is not redundant with the SPF value.
Comments from other sunscreen product manufacturers opposed an in
vivo method to determine UVA radiation protection. One of these
comments stated that in vivo tests expose human subjects to doses of
UVA radiation with unknown human health consequences. The comment added
that because exposure to UVA radiation alone is never encountered in
nature, full spectrum light is most relevant for product evaluations.
This comment contended that PFA values are redundant with SPF testing
because of an overemphasis on short wavelength UVA radiation (UVA II),
and PFA values give a false impression of the magnitude of absorption
differences. For example, the comment stated that two products with PFA
values of 5 and 10 may attenuate 80 and 90 percent of UVA radiation,
respectively. Thus, the real difference is small. The comment further
stated that the proposed in vivo methods modeled after the SPF test
generate protection factors that are protocol dependent and of
indeterminate clinical relevance, as none are surrogates for long term
concerns like cancer and photoaging. Another comment added that the PPD
and PFA tests do not adequately assess the breadth of UVA radiation
protection and that the biologic effects of full spectrum UV radiation
differ from the effects of isolated wavelengths.
Several comments recommended using an in vitro method, and most
considered the CW method as appropriate. One comment stated that CW
allows for broad spectrum activity regardless of SPF so that, if
consumers use a low SPF product, they will at least have the option of
choosing one that provides a wide breadth of activity. Another comment
stated that CW provides a simple, reproducible, and adaptable method
that can account for sunscreen photostability and insure UVA radiation
protection that is both commensurate with and independent from the SPF
value. Another comment added that CW accounts for proportionality
because, in order for a sunscreen to maintain a given CW, protection
from both long and short UVA radiation wavelengths must increase as UVB
radiation protection increases.
Several comments stated that the CW threshold should be 370 nm for
a ``broad spectrum'' claim on a sunscreen. Other comments recommended a
threshold of 360 nm. One comment stated that if FDA were to arbitrarily
select a standard higher than 360 nm, it would cause a major
reformulation effort within the industry, higher prices to consumers,
and a shortage of ``broad spectrum'' products in the OTC marketplace.
The comments did not provide data to support the use of a specific
threshold number in relation to the prevention of specific
photobiological effects.
Other comments opposed the CW method as not appropriate. One
comment, which favored an in vivo method, stated that the CW method,
based on an arbitrary, nonbiological criterion, fails to provide an
accurate measure of the protection efficacy of a sunscreen product.
This comment provided data to demonstrate that a significant failure of
the CW method is its inherent inability to differentiate UVA radiation
protection levels of sunscreen products relative to biological
endpoints (e.g., premature skin aging) (Ref. 23). A second comment
agreed with this assertion, while a third comment expressed concern
that CW measurements may be misleading because two products can have
the same CW with very different UVA radiation absorbance curves and,
thus, provide different protection for consumers.
Some comments stated that a combination of methods may be
appropriate for assessing the complete UVA radiation protection
potential of a sunscreen product. One comment suggested combining
either the PPD or PFA method with an in vitro method for a meaningful
and rigorous test of both the magnitude and breadth of the biological
protection (i.e., the level of protection and the UVB and UVA
wavelengths that are protected against) provided by a sunscreen
product. Another comment stated that complete assessment of a sunscreen
product's UVA radiation protection must include both of the following:
An in vitro measurement of the absorbance above 360 nm
(i.e., demonstrate adequate breadth of absorbance), and
An in vivo measurement of the quantity of UV radiation
protection (i.e., demonstrate adequate magnitude of absorbance).
Other comments stated that a combination of the in vivo SPF method and
the in vitro CW method provide a complete description of a product's
inherent photoprotective characteristics with the SPF value describing
the amplitude of protection and CW providing a reliable measure of the
product's spectral absorption capability.
One comment suggested a UVA/UVB radiation proportionality scheme.
The comment referred to FDA's previous discussions about UVA/UVB
radiation proportionality (Refs. 11 and 81) and a recommendation from
the AAD that ``an increase in SPF of a sunscreen must be accompanied by
a proportional increase in the UVA protection value'' (Ref. 82). The
comment added that the proportional contribution to sunburn from solar
UVB and UVA radiation is 80 to 20 (4 to 1), respectively, and that this
relationship gives the minimum UVA radiation attenuation needed to
provide proportional UVA/UVB radiation protection for any SPF value.
The comment concluded that a minimum UVA protection value of 2 should
be required even at low SPF levels with proportionately higher UVA
protection values for higher SPF values.
One comment suggested that the UVA protection value should be
determined with an in vivo method while CW is appropriate to determine
spectral broadness. Another comment stated that CW accounts for
proportionality because both long and short UVA radiation protection
must increase as UVB radiation protection increases in
[[Page 49104]]
order for a sunscreen to maintain a given CW. Another comment provided
data (Ref. 23) for two products with the same CW value but different
SPF values and concluded that the product with the higher SPF value did
not provide greater UVA protection. Other comments stated that there is
no biological basis for establishing strict UVB/UVA radiation
proportionality and that the establishment of this kind of ratio is
arbitrary.
The AAD (Ref. 83) referenced an international consensus conference
on UVA radiation protection of sunscreens and recommended the
following:
1. Both an in vitro and an in vivo testing method must be used to
measure UVA radiation protection.
2. CW is the preferred method of in vitro testing for a broad
spectrum claim (with a threshold for this claim at 370 nm).
3. CW must be combined with an in vivo method such as either PPD or
PFA.
4. There must be a minimum four-fold increase in PPD or PFA value
in the presence of a sunscreen (relative to the absence of sunscreen).
In the Federal Registers of May 12, 1993 (58 FR 28194 at 28248 to
28250), September 16, 1996 (61 FR at 48645 at 48652), and October 22,
1998 (63 FR 56584 at 56587), FDA discussed photosensitivity and
erythemal UVA radiation testing procedures for OTC sunscreen drug
products. Criteria discussed for UVA radiation claims included the
requirement for an absorption spectrum extending to 360 nm or above,
plus the demonstration of meaningful UVA radiation protection via
testing procedures. IPD/PPD, PFA, photosensitivity, and in vitro UVA
radiation testing methodologies were also discussed at a public meeting
on May 12, 1994 (Ref. 77).
The selection of an appropriate UVA radiation testing procedure for
OTC sunscreen drug products has been difficult for a number of reasons.
The scientific community does not agree on which testing procedure is
most appropriate. For example, Cole discusses the virtues and
shortcomings of a variety of in vivo and in vitro test methods (Ref.
84). In addition, each test procedure has its own distinct advantages
and disadvantages, as discussed in the following paragraphs.
FDA believes the IPD test method provides an appropriate endpoint
for determining UVA protection, because pigment darkening is caused
primarily by UVA (and not UVB) radiation. This method is advantageous
over other suggested test methods in that it uses low doses of
radiation and, therefore, exposes subjects to less risk than other
suggested test methods. On the other hand, the IPD response has not
been shown to represent a direct or surrogate endpoint for biological
damage. The IPD response is also extremely difficult to read.
The PFA test method uses endpoints that reflect actual damage that
can occur to normal skin as a result of UVA radiation exposure (i.e.,
erythema or tanning). The erythema action spectra may be similar to the
action spectra of known chronic skin damage (e.g., solar elastosis)
(Ref. 85). However, the PFA test method may not determine protection
against skin melanoma or other skin damage thought to be caused by
chronic exposure to UVA radiation (Refs. 29 and 86).
The CW method can assess how broadly a sunscreen can absorb across
the UV radiation spectrum, but provides no information concerning
product performance after interaction with human skin. While in vivo
methods to assess UVA radiation protection may have possible sources of
variability similar to the SPF test (e.g., test product application,
differences in light sources, etc.), in vitro methods also possess
possible sources of inherent variability (e.g., test product
evaporation time, substrate orientation, instrumentation, use with
color change sunscreen formulations, etc.).
In general, FDA would prefer the standard UVA radiation test method
to have a clinically significant endpoint. After reviewing the data and
information provided by the comments, FDA agrees that there is no
convincing evidence that the action spectra for all possible types of
UVA-induced damage have been clearly defined and that no one method is
without disadvantages. At this time, FDA agrees with the recommendation
provided by the AAD and other comments that an in vivo method is
appropriate in combination with an in vitro testing method to assess
the UVA radiation protection.
Because the action spectrum for UVA-induced skin damage is not
clearly known, FDA considers it necessary to measure both the magnitude
and breadth of UVA protection. The magnitude of UVA absorbance is a
measure of how well a product absorbs UVA radiation. The magnitude of
UVA absorbance is best measured by an in vivo method. An in vivo method
measures a biological response on the skin (e.g., pigment darkening)
and, therefore, correlates to actual use conditions. The breadth of the
UVA absorbance is a measure of how broadly a product absorbs UVA
radiation across the entire UVA radiation spectrum. Breadth can best be
determined by appropriate in vitro test methods.
At this time, FDA believes a combination of existing in vivo and in
vitro UVA radiation testing methods addresses the inadequacies of
either method when used alone and provides a more complete UVA
radiation attenuation profile for use in labeling OTC sunscreen drug
products. Requiring the two test methods will ensure that both the
magnitude and breadth of UVA protection is determined. As discussed
later in this response, the proposed UVA labeling will reflect the
results of both tests and, therefore, will reflect magnitude and
breadth of UVA protection. FDA believes that the methods and labeling
currently being proposed provide the best assurance for consumers to
receive adequate protection across the entire UVA radiation spectrum.
FDA is proposing the PPD method as the in vivo part of the test to
determine UVA radiation protection of a sunscreen drug product. This
test assesses UVA radiation attenuation by measuring UVA radiation-
induced tanning, a direct effect induced by UVA exposure. The PPD test
is relatively easy to perform and relies on a stable, biological
endpoint that can describe the magnitude of UVA radiation protection of
sunscreen products. It is similar to the SPF determination as it is a
ratio of a minimum pigmenting dose (MPD) on unprotected skin to that on
protected skin. The endpoint is the PPD response, which is the stable,
lasting residual part of the immediate pigment darkening or blue gray
pigment that develops immediately during exposure to UVA radiation and
quickly fades at the end of exposure. It provides consumers with a
means to specifically compare the amount of UVA radiation protection
between products and select an appropriate sunscreen product. The PPD
test has been shown to produce reliable, reproducible data and to
distinguish between varying levels of UVA radiation attenuation (Refs.
87 and 88). It has been shown to detect protection provided by ``broad
spectrum'' sunscreens against both short and long wavelength UVA
radiation. The endpoint is a stable skin response that is linearly
dependent on the amount of UVA radiation that enters the viable
epidermis. FDA also agrees with one comment that a UVA protection value
of 2 should define the lowest end of acceptable PPD test results
relative to the consideration of acceptable UVA radiation claims (see
proposed Sec. 352.72(d)(3)). FDA considers it desirable to incorporate
measurable UVA radiation protection at all SPF
[[Page 49105]]
levels for products that claim to protect against both UVB and UVA
radiation.
As one comment noted, the PPD test has been accepted and validated
as the JCIA method since 1996 (Ref. 23) and is one of two in vivo
methods suggested by the AAD (Ref. 83). Although data provided to FDA
indicate that the PPD and PFA in vivo tests provide comparable results
(Ref. 6), the PPD test provides the practical benefit of a shorter post
exposure reading time. FDA agrees with the comments that PPD values are
not redundant with SPF values as sunscreen drug products with the same
SPF value can have very different levels of UVA radiation protection as
measured by the PPD test. Accordingly, FDA is including the PPD method
in proposed Sec. 352.72 as part of the testing to determine the UVA
radiation protection potential of an OTC sunscreen drug product.
FDA agrees with the comments that suggested modifications to the
PPD method (i.e., the JCIA standard). Therefore, FDA is proposing
modifications to the PPD method. One group of sunscreen manufacturers
suggested that the previously validated ``high SPF'' padimate O/
oxybenzone standard sunscreen under consideration by FDA (see section
III.J, comment 27 of this document) should also be used as the control
formulation for in vivo UVA radiation testing (Ref. 6). Based upon data
provided by the comment, FDA is proposing the referenced ``high SPF''
padimate O/oxybenzone standard sunscreen for use as the standard
sunscreen in the in vivo UVA radiation test in proposed Sec. 352.72.
FDA invites comment on the suitability of this formulation as a UVA
radiation test standard, on alternative standards, and on preparation/
assay/validation data for any suggested alternatives.
FDA also notes that the JCIA light source specification states that
``UV rays shorter than 320 nm shall be excluded through the use of an
appropriate filter.'' FDA considers it important to set an exact limit
for this specification and is proposing that optical radiation from the
light source between 250 and 320 nm be less than 0.1 percent of the
optical radiation between 320 and 400 nm. Also, the observation of
pigment darkening in the JCIA standard is at 2 to 4 hours post
irradiation. FDA notes that it appears the pigment darkening is most
stable about 3 hours or more after post irradiation (Ref. 89), and is
thus proposing that this observation occur at 3 to 24 hours post
irradiation. This time range provides increased flexibility in the test
method without sacrificing accuracy.
As the current state of technology allows for an instrumental
measurement/quantification of skin color via spectral reflectance, FDA
also invites comments regarding colorimetry as a method of evaluating
pigment darkening. By avoiding the subjectivity of detecting pigment
change by the human eye, the reproducibility of the PPD method should
increase. Colorimetry could likewise be used in SPF testing if
submitted data demonstrated increased accuracy and reproducibility of
colorimetry over visual inspection.
As the PPD method is similar, overall, to the SPF method, FDA is
also proposing that the directions for the PPD method be similar to
those for the SPF test for determining MPDs on unprotected skin,
individual UVA protection factors, test product UVA protection factors,
and PCDs. Further, as discussed in section III.L, comment 37 of this
document regarding the SPF test, FDA is proposing that a PPD test panel
consist of 20 subjects who produce valid data, similar to the panel
size for sunscreens having SPF values less than 30.
FDA is concerned, however, that use of the PPD method alone could
result in some products yielding high UVA radiation protection factors
without having broad absorbance throughout the UVA radiation spectrum
due to strong absorbance in the UVA II region. In other words, a
sunscreen could absorb high levels of UVA II but very little UVA I and
achieve a high UVA rating under the PPD method. Therefore, FDA is
proposing that an in vitro method be used (to assess the breadth of
absorbance across the UV radiation spectrum) in conjunction with the
PPD method to more completely assess a product's UVA radiation
protection.
FDA disagrees with the comments that the CW method should be used
as the in vitro testing method and proposes using a modification of the
Boots adaptation of the Diffey/Robson method (Ref. 90). Both the CW and
the in vitro test proposed by FDA measure the absorbance of a sunscreen
product using in vitro spectrophotometry. However, FDA's proposed
method calculates the ratio of long wavelength UVA absorbance (UVA I)
to total UV absorbance to provide a measure of the relative UVA I
radiation protection provided by a sunscreen drug product. FDA believes
that this test, in combination with the PPD method, provides a better
assessment of overall UVA radiation protection.
The Boots adaptation of the Diffey/Robson test method assesses the
absorbance of a sunscreen drug product over the UV radiation range from
290 to 400 nm by measuring the quantity of UV radiation transmitted
through surgical tape (Transpore\TM\ tape) before and after application
of a sunscreen drug product. The test product (2 mg/cm\2\) is applied
to the textured surface of the Transpore\TM\ tape. A xenon arc solar
simulator is used as the UV radiation source. Transmitted UV energy is
collected and measured at 5 nm intervals over the UVB and UVA radiation
range, which provides a profile of UV radiation absorbance.
Mathematical calculations are made separately of the areas under the
UVB and UVA radiation parts of the curve. The ratio below the curve is
determined as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.004
As the ratio increases, the degree of UVA radiation protection
increases.
FDA is concerned that this method, as described in previous
paragraphs, determines the ratio of the entire UVA to UVB radiation
spectra. Therefore, a sunscreen drug product that absorbs strongly in
the UVA II radiation area, but does not absorb strongly in the UVA I
radiation area, might still have an adequate ratio of UVA to UVB
radiation protection to fulfill the test requirements, but would not
provide adequate protection in the UVA radiation region where
absorbance is lacking. FDA believes that this deficiency can be
corrected by revising the calculations to take into account the ratio
of UVA I and/or UVA II individually to UV radiation. Some comments were
concerned that UVA II radiation may be the portion of the UVA spectrum
most represented in the PPD test. FDA agrees that the UVA II spectrum
is well represented by the PPD test. Therefore, to provide for a more
balanced method, FDA is proposing that the in vitro component of the
monograph UVA radiation method only need provide a measure of the
relative UVA I radiation absorbance.
FDA is proposing to measure UVA I radiation absorbance relative to
UV radiation absorbance rather than relative to UVB radiation
absorbance. If UVA I radiation protection is measured relative to UVB
radiation, then the test does not account for UVA II radiation
protection. FDA's proposed modification of the Boots adaptation of the
Diffey/Robson method accounts for the entire UV radiation spectrum.
Further, the ratio of UVA I radiation to UV radiation has a convenient
finite range and allows for the use of defined values to categorize UVA
radiation protection.
[[Page 49106]]
FDA is proposing a modified Boots adaptation of the Diffey/Robson
method instead of the CW method. The CW determination only reveals the
shortest wavelength at which 90 percent of total UVB and UVA radiation
is absorbed by a sunscreen. Thus, this method does not directly reveal
the breadth of UV absorption, whereas the modified Boots adaptation of
the Diffey/Robson method does. This point is demonstrated by data
submitted by one comment (Ref. 23). The comment submitted the UV
absorption spectra of two sunscreens having nearly identical SPF and CW
values. The absorption spectra demonstrate that two sunscreens with
similar CWs can have significantly different UVA absorption spectra.
The ratios of UVA I/UV radiation absorbance for these formulations were
markedly different: 0.85 and 0.52. Thus, FDA believes that the ratio
method generally allows for better discrimination of products with
these types of absorbance spectra.
FDA is also concerned that the activity of the sunscreen
ingredients in the product may be diminished by exposure to UV
radiation, i.e., that the sunscreen ingredients in the product might
not be photostable. Therefore, in order to account for changes in
absorbance as a function of UV radiation exposure, FDA is proposing to
revise the Boots modification of the Diffey/Robson method by
incorporating pre-irradiation dose (PID), which is defined as follows
(see section III.O, comment 46 of this document):
PID (J/m\2\-eff) = SPF * 1 MED * 2/3,
where 1 MED = 200 J/m\2\-eff
FDA is also concerned about specifying the use of Transpore\TM\
tape (used in the original Diffey/Robson method), an artificial
substrate that mimics the surface topography of human stratum corneum.
When sunscreen emulsions are applied to Transpore\TM\ tape (Refs. 7 and
77), the emulsions may experience a micro environment that differs from
human skin in several key aspects, including the following:
Lack of electrolyte effect,
Lack of moisturization/humectant plasticization of the
substrate,
Differences in pH and wetting effects, and
Different degrees of sunscreen penetration and retention
by the substrate.
The fourth aspect, different degrees of penetration and retention, is
especially significant for oil soluble sunscreen ingredients. One
comment suggested that either roughened quartz plates or a synthetic
collagen should be used as the substrate, noting that COLIPA has used
quartz plates for its in vitro studies and that quartz plates are
reusable and inert. Diffey et al. have also used quartz plates as the
substrate for the CW method (Ref. 91). Accordingly, at this time, FDA
is proposing that roughened quartz plates be specified as the substrate
in the in vitro portion of its UVA test method. FDA requests comment
regarding the suitability and availability of quartz plates and other
possible substrates.
FDA agrees with one comment that there is no biological basis for
establishing a strict UVA to UVB ratio and that such a ratio would be
arbitrary. FDA is proposing that data from the proposed in vitro and in
vivo tests be integrated into a single labeled UVA rating. Similar to
suggestions from some comments, FDA is proposing the categories of low,
medium, high, and highest (corresponding to one, two, three, and four
``stars,'' respectively). Based on test data submitted by one comment
(Ref. 6), FDA is proposing that test results for each in vitro or in
vivo test be categorized as follows:
Table 4.--UVA Rating Categories
------------------------------------------------------------------------
Category In vitro result In vivo result
------------------------------------------------------------------------
Low 0.2 to 0.39 2 to under 4
Medium 0.40 to 0.69 4 to under 8
High 0.70 to 0.95 8 to under 12
Highest greater than 0.95 12 or more
------------------------------------------------------------------------
FDA is aware of the difficulty for current sunscreen formulations to
meet the ``highest'' category and believes that allowing such a
category will foster additional research and development in this area.
FDA is proposing that the overall UVA radiation category for use in
product labeling be the lowest category determined by the in vitro and
in vivo test results. For example, if the test results for a sunscreen
indicate an in vitro category of ``low'' and an in vivo category of
``high'' (or the reverse), then the overall UVA classification on the
sunscreen product label would be ``low'' (i.e., the lower of the two
categories). FDA believes that using the lower of the two categories
takes into account the following situations:
A product that has a high in vivo rating because of
substantial UVA II absorbance, but a low in vitro rating because of
poor UVA I absorbance, or
A product that has a low in vivo rating because of poor
UVA II absorbance, but a high in vitro rating because of substantial
UVA I absorbance.
FDA is further proposing that each overall UVA radiation category
correspond to and (on product labeling) be used with the following
number of graphical representations in the form of solid ``stars'':
Table 5.--Graphical UVA Rating Based on Category
------------------------------------------------------------------------
Combined Category Rating Star Rating
------------------------------------------------------------------------
Low [starf][star14][star
14][star14]
Medium [starf][starf][star1
4][star14]
High [starf][starf][starf
][star14]
Highest [starf][starf][starf
][starf]
------------------------------------------------------------------------
FDA invites comment on these proposed test methods/criteria and
encourages the continued development of biologically meaningful test
procedures.
O. Comments on the Photostability of Sunscreen Drug Products
(Comment 46) Various comments discussed the photostability of OTC
sunscreen formulations and active ingredients. One comment stated that
photostability is important because many sunscreen ingredient
combinations with avobenzone are not believed to be photostable. This
comment stressed that a sunscreen drug product should maintain most of
its UVA and UVB radiation protection throughout the expected consumer
time in the sun. Another comment stated that the integrity of a
sunscreen drug product depends on its degree of photostability and that
a photostable product should maintain its protection over a wide range
of UV radiation spectra.
Some comments supported a standard method using pre-irradiation to
account for photostability of sunscreen ingredients. One comment
favoring the CW method for measuring UVA radiation protection submitted
a formula to establish a pre-irradiation dose to assess photostability
(Ref. 7). This comment stated that pre-irradiation provides a
reasonable estimate of what a consumer might expect when using the
product and stressed that the dose should be both full spectrum (290 to
400 nm) and sufficient to detect significant changes in CW as a
function of UV radiation exposure. This comment considered its pre-
irradiation dose of solar-simulated UV radiation to be equivalent to
about 1 1/2 hours of noonday sun or 3 hours of sun exposure in the
early morning or late afternoon. One comment noted that avobenzone-
containing formulations can be photostabilized by the addition of
suitable ingredients and supported a protocol developed by Sayre and
Dowdy for measuring UVA radiation protection
[[Page 49107]]
following a measured exposure of the test formulation to solar
radiation (290 to 400 nm) (Ref. 92).
Another comment stressed the importance of a standard pre-
irradiation dose and included data suggesting that a ``UVB-only''
sunscreen product formulation, at high pre-irradiation doses, could
qualify for UVA ``broad spectrum'' labeling by the CW method (Ref. 23).
This comment concluded that pre-irradiation does not always account for
photostability and appears to be very formulation specific.
Another comment submitted an in vitro method for simultaneously
predicting SPF and assessing photostability of sunscreen formulas (Ref.
65). The comment stated that pre-irradiation with measured UV radiation
doses has permitted more accurate in vitro estimates of SPF.
FDA agrees that it is important to address the photostability for
sunscreen drug product formulations. Unstable product formulations
present the problem of degradation of product effectiveness during
actual use. The assessment of overall protection provided by such
formulations is difficult due to product effectiveness being heavily
dependent on the UV radiation exposure dose. Sayre and Dowdy
demonstrated, through a series of in vitro studies, how the UV
radiation transmission of an avobenzone containing formula changes with
UV radiation exposure and that most of the loss of protection occurred
in the UVA radiation spectrum (Ref. 92).
FDA is proposing to address photostability by adding a pre-
irradiation step to the in vitro test method for measuring UVA
radiation protection (see section III.N, comment 45 of this document).
As noted in the scientific literature, the choice of a pre irradiation
dose is ``somewhat arbitrary, yet critical to the outcome of the test''
(Ref. 84). FDA received one comment with supporting data for a proposed
pre-irradiation dose (Ref. 7). The comment suggested using a dose
equivalent to the SPF times 2 J/cm\2\ multiplied by a factor of 2/3.
The comment stated that 2 J/cm\2\ from a xenon arc solar simulator with
1 millimeter (mm) WG-320 and 1 mm UG-5 filters was equivalent to one
MED. Because all solar simulators used by the industry may not use this
exact filter combination and the spectral transmittance of filters can
vary from lot to lot, FDA is proposing to specify the pre-irradiation
dose in terms of ``erythemal effective dose.'' The erythemal effective
dose of a solar simulator can by calculated as described in proposed
Sec. 352.70(d) by weighting the output spectrum of the solar simulator
with the reference action spectrum for erythema as defined by CIE. A
typical weighted value (J/m\2\-eff) for an MED in a Skin Type II
individual is 200 J/m\2\-eff (Ref. 93). Thus, FDA is proposing to use
the following formula to determine the required pre-irradiation dose:
PID (J/m\2\-eff) = SPF * 1 MED * 2/3
where 1 MED = 200 J/m\2\-eff
In considering the selection of the appropriate pre-irradiation
dose of solar-simulated UV radiation, FDA agrees that the maximum pre-
irradiation exposure would be a dose of UV radiation that equaled the
SPF of the product times the MED. However, FDA believes that this
calculated dose is probably greater than the dose that a sunscreen
product would incur during typical consumer usage. Thus, the dose was
reduced by a factor of one-third to represent a more reasonable
exposure condition.
IV. FDA's Tentative Conclusions and Proposals
FDA tentatively concludes that the FM for OTC sunscreen drug
products should be amended to include the combinations of avobenzone
with ensulizole and avobenzone with zinc oxide when used in the
concentrations established for each ingredient in Sec. 352.10 (see
section III.C, comment 7 of this document). However, before marketing
may begin, the comment period for this proposal must end and FDA must
publish another Federal Register notice setting forth our determination
concerning interim marketing before publication of the final rule for
OTC sunscreen drug products. FDA followed this procedure previously for
avobenzone as a single active ingredient and in combination with some
GRASE active ingredients other than ensulizole or zinc oxide (62 FR
23350).
FDA considers the UVA-related labeling in this proposal to
supersede the labeling proposed in the TFM and its amendments of
September 16, 1996, and October 22, 1998. While the prior proposed
labeling can continue to be used until a FM is issued, FDA encourages
manufacturers of OTC sunscreen drug products to voluntarily implement
the UVA-related labeling changes as soon as possible after publication
of this proposal, especially if product relabeling occurs in the normal
course of business. We note, though, that any relabeling prior to
issuance of the FM is subject to the possibility that FDA may change
some of the labeling requirements as a result of comments filed in
response to this proposal.
Mandating warnings in an OTC drug monograph does not require a
finding that any or all of the OTC drug products covered by the
monograph actually caused an adverse event, and FDA does not so find.
Nor does FDA's requirement of warnings repudiate the prior OTC drug
monographs and monograph rulemakings under which the affected drug
products have been lawfully marketed. Rather, as a consumer protection
agency, FDA has determined that warnings are necessary to ensure that
these OTC drug products continue to be safe and effective for their
labeled indications under ordinary conditions of use as those terms are
defined in the act. This judgment balances the benefits of these drug
products against their potential risks (see 21 CFR 330.10(a)).
FDA's decision to act in this instance need not meet the standard
of proof required to prevail in a private tort action (Glastetter v.
Novartis Pharmaceuticals Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To
mandate warnings, or take similar regulatory action, FDA need not show,
nor do we allege, actual causation. For an expanded discussion of the
case law supporting FDA's authority to require such warnings without
evidence of actual causation, see Labeling of Diphenhydramine-
Containing Drug Products for Over-the-Counter Human Use, final rule (67
FR 72555, December 6, 2002).
V. Analysis of Impacts
FDA has examined the impacts of this proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive
Order 12866 directs 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). Under the Regulatory
Flexibility Act, if a rule has a significant economic impact on a
substantial number of small entities, an agency must analyze regulatory
options that would minimize any significant impact of the rule on small
entities. Section 202(a) of the Unfunded Mandates Reform Act requires
that agencies prepare a written statement of anticipated costs and
benefits before proposing any rule that may result in an expenditure in
any one year by State, local, and tribal governments, in the aggregate,
or by the private sector, of
[[Page 49108]]
$100 million (adjusted annually for inflation).
FDA believes that this proposed rule is consistent with the
principles set out in the Executive Order 12866 and in these two
statutes. The proposed rule is not a significant regulatory action as
defined by the Executive order and, therefore, is not subject to review
under the Executive order. Further, because this proposed rule is not
expected to result in any 1-year expenditure that would exceed $100
million adjusted for inflation, FDA need not prepare additional
analyses under the Unfunded Mandates Reform Act. Because the rule may
have a significant economic impact on a substantial number of small
entities, this section of the preamble constitutes FDA's regulatory
flexibility analysis.
An analysis of the costs and benefits of this regulation, conducted
under Executive Order 12866, was discussed in the FM (64 FR 27666 at
27683 to 27686), which was later stayed (66 FR 67485). This analysis
reflects the incremental costs of the revised or new requirements in
this proposed amendment of the FM.
A. Background
The purpose of this document is to amend the conditions under which
OTC sunscreen drug products are generally recognized as safe and
effective (GRASE) and not misbranded. This amendment addresses
formulation, labeling, and testing requirements for both UVB and UVA
radiation protection.
Manufacturers would not need to reformulate their sunscreen
products to comply with the proposed requirements. Manufacturers also
would not need to retest their sunscreen products for UVB protection
(i.e., they would not need to retest for SPF). The labeled SPF value
determined from the SPF test in the FM would not likely change if a
sunscreen product was retested using the modifications to the SPF test
proposed in this document. In addition, manufacturers who have tested
and labeled their sunscreen products as ``SPF 30+'' can relabel their
products with the specific SPF value above 30 (but no greater than 50)
without retesting.
However, all manufacturers would incur some relabeling costs due to
proposed revisions to both the PDP and the Drug Facts section of the
product label. If manufacturers wish to label their sunscreen products
as providing UVA protection, then manufacturers of those sunscreen
products would also incur UVA testing costs. Because UVA testing is not
required, some manufacturers will choose not to test for UVA protection
and the labeling for those sunscreens will state, ``No UVA
Protection.''
B. Number of Products Affected
Estimating the number of products affected is difficult because we
lack data on the number of products currently marketed. Our Drug
Listing System currently does not have accurate information on the
number of marketed OTC sunscreen products, especially the drug-cosmetic
combination products. Proprietary databases that track retail sales of
OTC drugs and other products do not distinguish cosmetics containing
sunscreens from other cosmetic products and their surveys do not
include many of the outlets where sunscreen products are sold. Based on
earlier estimates (64 FR 27666 at 27684) and our knowledge of the
industry, we assume there are about 3,000 OTC sunscreen drug products
(different formulations, not including products that differ only by
color), including drug-cosmetic combinations, and about 12,000
individual stock keeping units (SKUs) (individual products, packages,
and sizes). All 12,000 SKUs will need to be relabeled, but
manufacturers can choose whether to test their sunscreen products for
UVA protection. We assume that about 75 percent (2,250) of the
sunscreen products would be tested for UVA protection. We request
comment on the accuracy of this assumption.
C. Cost to Relabel
The cost to relabel varies greatly depending on the printing method
and number of colors used. The majority of sunscreen products are
packaged in plastic bottles or tubes with the label printed directly on
the container or applied as a decal or paper label during the packaging
process. The proposed labeling requirements impact both the PDP and the
Drug Facts section of the package and would be considered a major
redesign.
Frequent label redesigns are typical for OTC sunscreen products,
with redesigns generally implemented every 1 to 2 years for a product.
To the extent that a scheduled redesign coincides with the regulatory-
mandated relabeling, the impact on the manufacturer will be negligible.
We used a model developed for FDA by the consulting firm RTI to
derive an estimate of the cost to relabel sunscreen products (Ref. 94).
The model was developed to estimate the cost of food labels. However,
we believe that the graphic and design estimates from that study are an
appropriate proxy for the costs that would be incurred by OTC sunscreen
manufacturers. RTI estimated that graphic design and prepress and
engraving costs would range from $1,970 to $13,800 per SKU depending on
the type of packaging and printing method used. There would also be
administrative costs to account for contracting costs and obtaining
final approvals for the new labels. RTI estimated administrative costs
to range from $360 to $880 depending on the size of the firm. For this
analysis, we are assuming an average design price of $7,000 per SKU and
average administrative costs of $600 per SKU.\1\ Therefore, the total
relabeling cost per SKU would be $7,600 (i.e., $600 + $7,000).
While all sunscreen SKUs would need to be relabeled to comply with
the proposed rule, we estimate that the timing of the scheduled
relabeling would coincide with the regulatory-mandated changes for 50
percent of the SKUs (i.e., 6,000 SKUs). We estimate the total labeling
cost of the proposed labeling changes for the SKUs with the coinciding
scheduled redesign would be 50 percent of the administrative cost
(i.e., $300). Therefore, the total one-time cost to industry for
relabeling would be about $47.5 million (i.e., (6,000 x $7,600) +
(6,000 x $300)).
---------------------------------------------------------------------------
\1\ We did not select the midpoint of the ranges because of the
large number of private label products that have lower design and
administrative costs than branded goods.
---------------------------------------------------------------------------
D. Cost to Test or Retest Products for UVA Protection
This proposed rule will result in testing costs for products that
make UVA protection claims. The approximate costs are $2,200 for in
vivo UVA testing and $200 for in vitro UVA testing. Based on the number
of sunscreen products currently labeled as providing UVA protection, we
estimate that 75 percent (2,250) of the sunscreen products will be
tested according to the proposed UVA tests. Therefore, FDA estimates a
one-time UVA testing cost of approximately $5.4 million (i.e., 2,250 x
$2,400).
E. Total Incremental Costs
The estimated total one-time incremental cost of this proposed rule
is $53 million (i.e., $47.5 million + $5.4 million). The incremental
cost for the UVA testing could be less should the rule become final
because many manufacturers may voluntarily comply with the proposed
rule when reformulating current products or marketing new products.
Although the FM is not effective, manufacturers of sunscreen products
comply with the
[[Page 49109]]
UVB (SPF) test in the FM for nearly all sunscreen products. Therefore,
it is likely that manufacturers of sunscreen products will also
voluntarily comply with the proposed UVA tests in this document.
It should also be noted that sunscreen products that are already
distributed by the effective date of the FM will not be required to be
relabeled or retested in conformity with these FM conditions, unless
these products are subsequently relabeled or repackaged after the
effective date. Therefore, there is no one-time cost associated with
disposing of sunscreens that are already on the market at the time of
the rule's effective date.
F. Small Business Impact
In the FM (64 FR 27666 at 27685), FDA estimated that 78 percent of
the 180 domestic companies that manufacture OTC sunscreen products
would be considered a small business (defined as fewer than 750
employees). FDA cannot estimate with certainty the number of small
firms that will need to test or retest their OTC sunscreen products to
provide for UVA protection claims, but projects that approximately 75
percent of all products may need to be tested for UVA protection. Costs
will vary by firm, depending on the number of products requiring
testing. The firm-specific impact may vary inversely with the volume of
product sales, because per unit costs will be lower for products with
high volume sales. Thus, the relative economic impact of product
retesting may be greater for small firms than for large firms. 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.
G. Analysis of Alternatives
FDA could have proposed only an in vivo or an in vitro test for
UVA. FDA recognizes that requiring only the in vitro test would mean
significantly less cost to manufacturers. However, the proposed in vivo
test measures the magnitude of UVA protection. The proposed in vitro
test measures the breadth of UVA protection. FDA believes it is
important to conduct both tests to determine the magnitude and breadth
of UVA protection.
FDA plans to grant an extended compliance period when this proposed
rule is finalized. Given the seasonal nature of these products, FDA is
concerned that some manufacturers may not have sufficient time to
incorporate labeling changes without disrupting their production
schedules. By providing an additional 6 months to implement the
changes, compliance costs to manufacturers will be reduced.
In addition, FDA reduced compliance costs when we chose to stay the
labeling requirements for the FM (64 FR 27666), sparing industry the
cost of an additional regulatory-mandated label change. In the stay,
FDA estimated a cost savings of $1.5 million to industry. It should be
noted that labeling costs were significantly less in the FM than in
this proposed rule primarily because we assumed in the FM that the
majority of relabeling would coinside with scheduled voluntary label
redesigns at no additional cost. Manufacturers were also able to avoid
or postpone incurring an additional industry total of $5 million when
FDA chose to stay the UVB testing requirements of the FM.
FDA invites public comment regarding any substantial or significant
economic impact that this proposed rule would have on manufacturers of
OTC sunscreen drug products. Comments regarding the impact of this
rulemaking on such manufacturers should be accompanied by appropriate
documentation. FDA is providing a period of 90 days from the date of
publication of this proposed rule in the Federal Register for comments
to be developed and submitted. FDA will evaluate any comments and
supporting data that are received and will reassess the economic impact
of this rulemaking in the final rule.
VI. Paperwork Reduction Act of 1995
FDA tentatively concludes that the labeling requirements in this
document are not subject to review by the Office of Management and
Budget because they do not constitute a ``collection of information''
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.).
Rather, the proposed labeling statements 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)).
VII. 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.
VIII. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized as proposed, would have a preemptive
effect on State law. 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.'' Section 751 of the Federal Food, Drug, and Cosmetic Act (the
act) (21 U.S.C. 379r) is an express preemption provision. Section
751(a) of the act (21 U.S.C. 379r(a)) provides that ``no State or
political subdivision of a State may establish or continue in effect
any requirement--* * * (1) that relates to the regulation of a drug
that is not subject to the requirements of section 503(b)(1) or
503(f)(1)(A); and (2) that is different from or in addition to, or that
is otherwise not identical with, a requirement under this Act, the
Poison Prevention Packaging Act of 1970 (15 U.S.C. 1471 et seq.), or
the Fair Packaging and Labeling Act (15 U.S.C. 1451 et seq.).''
Currently, this provision operates to preempt States from imposing
requirements related to the regulation of nonprescription drug
products. Section 751(b) through (e) of the act outlines the scope of
the express preemption provision, the exemption procedures, and the
exceptions to the provision.
This proposed rule, if finalized as proposed, would amend the
labeling and include new UVA testing for OTC sunscreen drug products.
Any final rule would have a preemptive effect in that it would preclude
States from issuing requirements related to the labeling and testing of
OTC sunscreen drug products that are different from or in addition to,
or not otherwise identical with a requirement in the final rule. This
preemptive effect is consistent with what Congress set forth in section
751 of the act. Section 751(a) of the act displaces both State
legislative requirements and State common law duties. We also note that
even where the express preemption provision in section 751(a) of the
act is not applicable, implied preemption may arise (see Geier v.
American Honda Co., 529 US 861 (2000)).
FDA believes that the preemptive effect of the proposed rule, if
finalized as proposed, would be consistent with Executive Order 13132.
Section 4(e) of the Executive order provides that ``when an agency
proposes to act through adjudication or rulemaking to preempt State
law, the agency shall provide all
[[Page 49110]]
affected State and local officials notice and an opportunity for
appropriate participation in the proceedings.'' FDA is providing an
opportunity for State and local officials to comment on this
rulemaking.
IX. Request for Comments
In the Federal Register of January 10, 2005 (70 FR 1721), FDA
announced the availability of a final guidance for industry entitled
``Labeling for Topically Applied Cosmetic Products Containing Alpha
Hydroxy Acids as Ingredients.'' The purpose of this guidance is
twofold:
To educate consumers about the potential for increased
skin sensitivity to the sun from the topical use of cosmetics
containing alpha hydroxy acids (AHAs) as ingredients.
To educate manufacturers to help ensure that their
labeling for cosmetic products containing AHAs as ingredients is not
false or misleading.
As discussed in the guidance, AHAs may increase skin sensitivity to
UV radiation. Therefore, FDA recommends that manufacturers of cosmetic
products containing AHAs include the following warning:
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.
The guidance addresses only cosmetic products containing AHAs and
does not address sunscreen drug products containing AHAs (i.e., drug-
cosmetic products). FDA is considering an additional warning or
direction for sunscreen drug products containing AHAs similar to the
warning for the cosmetic products described in the guidance for
industry. However, FDA invites interested parties to submit comments
and data regarding such labeling. In particular, FDA would like the
following questions addressed:
1. Does the body of existing evidence on AHAs and skin sensitivity
warrant voluntary or mandatory labeling on OTC sunscreen drug products
containing AHAs regarding possible risks of increased sun damage (e.g.,
sunburn)?
2. If additional labeling is warranted, what information should be
conveyed in the labeling and why?
Comments along with supporting data will help enable FDA to determine
how and what information, if any, related to UV hypersensitivity due to
AHAs in sunscreen-cosmetic products should be communicated to
consumers. FDA will also be evaluating any comments or data submitted
in response to the final guidance for cosmetic products containing
AHAs.
In addition to AHAs, FDA seeks comment on titanium dioxide and zinc
oxide formulated in particle sizes as small as a few nanometers. FDA
addressed issues concerning micronized sunscreen ingredients in the FM
(64 FR 27666 at 27671 to 27672). The FM stated that FDA did not
consider micronized titanium dioxide to be a new ingredient but rather
a specific grade of the same active ingredient. The FM also stated that
FDA was aware of concerns about potential risks associated with
increased dermal penetration of such small particles. However, the FM
explained that, based on the safety data submitted to FDA before
publication of the FM, FDA was not aware of any evidence at that time
demonstrating a safety concern from the use of micronized titanium
dioxide in sunscreen products (64 FR 27666 at 27671 to 27672).
FDA recognizes that more sunscreens containing small particle size
titanium dioxide and zinc oxide ingredients enter the market each year.
FDA is interested in receiving comments and data about these sunscreen
ingredients and products that contain these ingredients, their safety
and effectiveness, and how they should be regulated. FDA received a
citizen petition shortly before publication of this document that,
among other things, raises these issues. FDA is currently evaluating
the citizen petition, which is filed as CP17 in Docket No. 1978N-0038.
FDA encourages other parties to submit additional data or information
on the safety and effectiveness of sunscreen ingredients formulated in
particle sizes as small as a few nanometers.
On April 14, 2006, FDA announced in the Federal Register that we
were planning a public meeting on FDA-regulated products containing
nanotechnology materials (71 FR 19523). As explained in the notice, the
purpose of the meeting was to help FDA further its understanding of
developments in nanotechnology materials that pertain to FDA-regulated
products. The meeting was held on October 10, 2006, and FDA has
received comments from interested members of the public which have been
filed in the docket for this public meeting (Docket No. 2006N- 0107).
Some of these comments concern sunscreen ingredients formulated with
nanotechnology materials. FDA will file any comments concerning
sunscreen ingredients formulated in nanometer particle sizes received
in response to this proposed rule in the docket for this rulemaking and
the citizen petition (Docket No. 1978N-0038) and the docket for the
nanotechnology meeting.
X. Proposed Effective and Compliance Dates
FDA is proposing that any final rule that may issue based on this
proposal become effective 18 months after its date of publication in
the Federal Register. The compliance date for products with annual
sales less than $25,000 would be 24 months after publication of the
final rule in the Federal Register.
XI. References
The following references are on display in the Division of Dockets
Management (see ADDRESSES) under Docket No. 1978N-0038 and may be seen
by interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Comment No. CP6.
2. Comment Nos. CP8, C548, SUP22, and C555.
3. Comment Nos. LET166 and LET169.
4. Comment No. C538.
5. Comment No. C576.
6. Comment No. C565.
7. Comment No. C581.
8. Comment No. C567.
9. Comment No. C515.
10. Comment No. C597.
11. Comment No. MM22.
12. Comment No. MM21.
13. Comment No. C573.
14. Autier, P. et al., ``Sunscreen Use and Duration of Sun
Exposure: a Double-blind, Randomized Trial,'' Journal of the
National Cancer Institute, 91(15):1304-1309, 1999.
15. Reynolds, K.D. et al., ``Predictors of Sun Exposure in
Adolescents in a Southeastern U.S. Population,'' Journal of
Adolescent Health, 19(6):409-415, 1996.
16. Robinson, J.K., D.S. Rigel, and R.A. Amonette, ``Summertime
Sun Protection Used by Adults for Their Children,'' Journal American
Academy of Dermatology, 42(5):746-753, 2000.
17. Gallagher, R.P. et al., ``Broad-spectrum Sunscreen Use and
the Development of New Nevi in White Children: A Randomized
Controlled Trial,'' Journal of the American Medical Association,
283(22):2955-2960, 2000.
18. Stender, I.M., J.L. Andersen, and H.C. Wulf, ``Sun Exposure
and Sunscreen Use among Sunbathers in Denmark,'' Acta Dermato-
Venereologica, 76:31-33, 1996.
19. Zitser, B.S. et al., ``A Survey of Sunbathing Practices on
Three Connecticut State Beaches,'' Connecticut Medicine, 60(10):591-
594, 1996.
20. Green, A. et al., ``Daily Sunscreen Application and
Betacarotene Supplementation in Prevention of Basal-cell and
Squamous-cell Carcinomas of the Skin: a Randomized Controlled
Trial,'' The Lancet, 354:723-729, 1999.
21. IARC Handbooks of Cancer Prevention Volume 5 Sunscreens, H.
Vainio, ed., International Agency for Research on Cancer, Lyon,
France, p. 62, 2001.
22. Diffey, B.L. et al., ``In Vitro Assessment of the Broad-
spectrum Ultraviolet Protection of Sunscreen Products,'' Journal of
the
[[Page 49111]]
American Academy of Dermatology, 43(6):1024-1035, 2000.
23. Comment No. C572.
24. Gasparro, F.P., ``Sunscreens, Skin Photobiology, and Skin
Cancer: the Need for UVA Protection and Evaluation of Efficacy,''
Environmental Health Perspectives, 108 Suppl 1:71-78, 2000.
25. Garland, C.F., F.C. Garland, and E.D. Gorham, ``Lack of
Efficacy of Common Sunscreens in Melanoma Prevention'' in
Epidemiology, Causes and Prevention of Skin Diseases, Grob, J.J. et
al. eds., Blackwell Science Ltd., Malden, MA, pp. 151-159, 1997.
26. Lowe, N.J. et al., ``Low Doses of Repetitive Ultraviolet A
Induce Morphologic Changes in Human Skin,'' Journal of Investigative
Dermatology, 105(6):739-743, 1995.
27. Seite, S. et al., ``Effects of Repeated Suberythemal Doses
of UVA in Human Skin,'' European Journal of Dermatology, 7:204-209,
1997.
28. Lavker, R.M. et al., ``Quantitative Assessment of Cumulative
Damage from Repetitive Exposures to Suberythemogenic Doses of UVA in
Human Skin,'' Photodermatology, Photoimmunology, and Photomedicine,
62(2):348-352, 1995.
29. Lavker, R.M. et al., ``Cumulative Effects from Repeated
Exposures to Suberythemal Doses of UVB and UVA in Human Skin,''
Journal of the American Academy of Dermatology, 32(1):53-62, 1995.
30. Elmets, C.A., A. Vargas, and C. Oresajo, ``Photoprotective
Effects of Sunscreens in Cosmetics on Sunburn and Langerhans Cell
Photodamage,'' Photodermatology, Photoimmunology, and Photomedicine,
9(3):113-120, 1992.
31. Lavker, R., and K. Kaidbey, ``The Spectral Dependence for
UVA-induced Cumulative Damage in Human Skin,'' Journal of
Investigative Dermatology, 108(1):17-21, 1997.
32. Seite, S. et al., ``A Full-UV Spectrum Absorbing Daily Use
Cream Protects Human Skin Against Biological Changes Occurring in
Photoaging,'' Photodermatology, Photoimmunology, and Photomedicine,
16(4):147-155, 2000.
33. Boyd, A.S. et al., ``The Effects of Chronic Sunscreen Use on
the Histologic Changes of Dermatoheliosis,'' Journal of the American
Academy of Dermatology, 33(6):941-946, 1995.
34. Comment No. CP15.
35. Center for Disease Control and Prevention, ``Guidelines for
School Programs To Prevent Skin Cancer'' in Morbidity and Mortality
Weekly Report, 1-18, 2002.
36. Ries, A.G. et al., ``The Annual Report to the Nation on the
Status of Cancer, 1973-1997, with a Special Section on Colorectal
Cancer,'' Cancer, 88(10):2398-2424, 2000.
37. Cancer Facts and Figures 2007, American Cancer Society,
Inc., 2007.
38. Sun Safety Tips, The American Academy of Dermatology, 1999.
39. Skin Cancer: Preventing America's Most Common Cancer 2001
Choose Your Cover, Centers for Disease Control and Prevention, 2001.
40. The Sun, UV, and You: A Guide to SunWise Behavior,
Environmental Protection Agency, 1999.
41. Sun Protection Facts to Help You Prevent Skin Cancer,
American Cancer Society, 2000.
42. What You Need to Know About Skin Cancer, National Cancer
Institute, 1998.
43. Committee on Environmental Health, American Academy of
Pediatrics, ``Ultraviolet Light: A Hazard to Children,'' Pediatrics,
104:328-333, 1999.
44. Green, A. et al., ``Site Distribution of Cutaneous Melanoma
in Queensland,'' International Journal of Cancer, 53:232-236, 1992.
45. Franceschi, S. et al., ``Site Distribution of Different
Types of Skin Cancer: New Aetiological Clues,'' International
Journal of Cancer, 67:24-28, 1996.
46. Raasch, B. et al., ``Body Site Specific Incidence of Basal
and Squamous Cell Carcinoma in an Exposed Population, Townsville,
Australia,'' Mutation Research, 422:101-106, 1998.
47. Osterlind, A., K. Hou-Jensen, and O.M. Jensen, ``Incidence
of Cutaneous Malignant Melanoma in Denmark 1978-1982. Anatomic Site
Distribution, Histologic Types, and Comparison with Non-melanoma
Skin Cancer,'' British Journal of Cancer, 58:385-391, 1988.
48. Neale, R., G. Williams, and A. Green, ``Application Patterns
Among Participants Randomized to Daily Sunscreen Use in a Skin
Cancer Prevention Trial,'' Archives of Dermatology, 138:1319-1325,
2002.
49. Comment No. C584.
50. Steinberg, C., and O. Larko, ``Sunscreen Application and its
Importance for Sun Protection Factor,'' Archives of Dermatology,
121:1400-1402, 1985.
51. Stokes, R., and B. Diffey, ``How Well Are Sunscreen Users
Protected?,'' Photodermatology, Photoimmunology, and Photomedicine,
13:186-188, 1997.
52. Sayre, R.M. et al., ``Product Application Technique Alters
the Sun Protection Factor,'' Photodermatology, Photoimmunology, and
Photomedicine, 8:222-224, 1991.
53. Azurda, R.M. et al., ``Sunscreen Application Technique in
Photosensitive Patients: a Quantitative Assessment and the Effect of
Education,'' Photodermatology, Photoimmunology and Photomedicine,
16:53-66, 2000.
54. Bech-Thomsen, N., and H.C. Wulf, ``Sunbather's Application
of Sunscreen is Probably Inadequate to Obtain Sun Protection Factor
Assigned to the Preparation,'' Photodermatology, Photoimmunolology
and Photomedicine, 9:242-244, 1992.
55. Diffey, B., ``People Do Not Apply Enough Sunscreen for
Protection,'' British Medical Journal, 313:942, 1996.
56. Wright, M.W. et al., ``Mechanisms of Sunscreen Failure,''
Journal of the American Academy of Dermatology, 44:781-784, 2001.
57. Rigel, D. et al., ``American Academy of Dermatology's
Melanoma/Skin Cancer Detection and Prevention Month Press Release,''
April 25, 2001.
58. The ABCs for Fun in the Sun Educational Pamphlet, The
American Academy of Dermatology, 1999.
59. Ultraviolet Index--What You Need to Know, The American
Academy of Dermatology, 1996.
60. Sun Basics-Skin Protection Made Simple for Everyone Under
the Sun, American Cancer Society, Inc., 1999.
61. Skin Protection Guide for Everyone Under the Sun. A Parents
Guide to Sun Protection, American Cancer Society, Inc., 1999.
62. Can Melanoma Be Prevented?, American Cancer Society, Inc.,
2001.
63. Diffey, B., ``Has the Sun Protection Factor Had Its Day?,''
British Medical Journal, 320:176-177, 2000.
64. Taylor, W.A., ``Double Sampling Plan'' in Guide to
Acceptance Sampling, R. R. Donnelly & Sons, U.S.A., pp. 117-142,
1992.
65. Comment No. C574.
66. Comment No. C405.
67. Comment No. C404.
68. Comment No. C111.
69. Comment No. RPT7.
70. Comment No. C442.
71. Comment No. SUP29.
72. Memorandum from W.H. DeCamp, FDA, to C. Ganley, FDA, July 7,
2000.
73. Comment No. CP12.
74. Comment No. SUP33.
75. Gabriel, K.L. et al., ``Sun Protection Factor Testing:
Comparison of FDA and DIN Methods,'' Journal of Toxicology-Cutaneous
and Ocular Toxicology, 6:357-370, 1987.
76. Comment No. C491.
77. Comment No. TR2.
78. Diffey, B.L., ``A Method for Broad Spectrum Classification
of Sunscreens,'' International Journal of Cosmetic Science, 16:47-
52, 1994.
79. Diffey, B.L., and J. Robson, ``A New Substrate to Measure
Sunscreen Protection Factors Throughout the Ultraviolet Spectrum,''
Journal of the Society of Cosmetic Chemists, 40:127-133, 1989.
80. Comment No. RPT9.
81. Comment No. LET170.
82. Press Release: ``The Future of Sunscreen Labeling:
Recommendations of the Consensus Conference on UVA Protection of
Sunscreens Convened by the American Academy of Dermatology,'' New
York, NY, April 26, 2000.
83. Lim, H.W. et al., ``American Academy of Dermatology
Consensus Conference on UVA Protection of Sunscreens: Summary and
Recommendations,'' Journal of the American Academy of Dermatology,
44:505-508, 2001.
84. Cole, C., ``Sunscreen Protection in the Ultraviolet A
Region: How to Measure Effectiveness,'' Photodermatology,
Photoimmunology, and Photomedicine, 17:2-10, 2001.
85. Comment No. C137.
86. Setlow, R.B., et al., ``Wavelengths Effective in Induction
of Malignant Melanoma,'' Proceedings of the American Academy of
Science, U.S.A., 90:6666-6670, 1993.
87. Moyal, D. et al., ``UVA Protection Efficacy of Sunscreens
Can Be Determined by the Persistent Pigment Darkening (PPD) Method
(Part 2),'' Photodermatology, Photoimmunology, and Photomedicine,
16:250-255, 2000.
88. Moyal, D. et al., ``Determination of UVA Protection Factors
Using the Persistent Pigment Darkening (PPD) Method as the Endpoint
(Part 1) Calibration of the Method,'' Photodermatology,
Photoimmunology, and Photomedicine, 16:245-249, 2000.
[[Page 49112]]
89. Chardon, A. et al., ``Persistent Pigment-Darkening Response
as a Method for Evaluation of Ultraviolet A Protection Assays'' in
Sunscreens: Development, Evaluation, and Regulatory Aspects, 2nd
edition, Marcel Dekker, Inc., New York, NY, pp. 559-582, 1997.
90. Comment No. TS3.
91. Diffey, B.L. et al., ``Suncare Product Photostability: a Key
Parameter for a More Realistic In Vitro Efficacy Evaluation,''
European Journal of Dermatology, 7:226-228, 1997.
92. Sayre, R.M., and J. Dowdy, ``Photostability Testing of
Avobenzone,'' Cosmetics and Toiletries, 114:85-86, 88, 90-91, 1999.
93. Urbach, F., ``Man and Ultraviolet Radiation'' in Human
Exposure to Ultraviolet Radiation: Risks and Regulations, Passchier,
W.F. and Bosnjakovic, B.F.M. (eds.), Elsevier Science, New York, NY,
pp. 3-6, 1987.
94. 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, Revised January 2003.
List of Subjects
21 CFR Part 347
Labeling, Over-the-counter drugs.
21 CFR Part 352
Labeling, Over-the-counter drugs, Incorporation by reference.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 347 and 352 be amended as follows:
PART 347--SKIN PROTECTANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN
USE
1. The authority citation for 21 CFR part 347 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
2. FDA is proposing to lift the stay of Sec. 347.20(d) as
published at 68 FR 33362, June 4, 2003.
PART 352--SUNSCREEN DRUG PRODUCTS FOR OVER THE COUNTER HUMAN USE
3. The authority citation for 21 CFR part 352 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
4. FDA is proposing to lift the stay of 21 CFR part 352 as
published at 68 FR 33362, June 4, 2003.
5. Section 352.3 is amended by redesignating paragraphs (b) through
(d) as (c) through (e), respectively; revising newly redesignated
paragraphs (c) and (e); and adding new paragraph (b) to read as
follows:
Sec. 352.3 Definitions.
* * * * *
(b) Minimal pigmenting dose (MPD). The quantity of erythema-
effective energy (expressed as Joules per square meter) required to
produce the first perceptible pigment darkening.
(c) Product category designation (PCD). A labeling designation for
sunscreen drug products to aid in selecting the type of product best
suited to an individual's complexion (pigmentation) and desired
response to ultraviolet (UV) radiation.
(1) Low UVB sunburn protection product. A sunscreen product that
provides a sunburn protection factor (SPF) value of 2 to under 15.
(2) Medium UVB sunburn protection product. A sunscreen product that
provides an SPF value of 15 to under 30.
(3) High UVB sunburn protection product. A sunscreen product that
provides an SPF value of 30 to 50.
(4) Highest UVB sunburn protection product. A sunscreen product
that provides an SPF value over 50.
* * * * *
(e) Sunburn protection factor (SPF) value. The UV energy required
to produce an MED on protected skin divided by the UV energy required
to produce an MED on unprotected skin, which may also be defined by the
following ratio: SPF value = MED (protected skin (PS))/MED (unprotected
skin (US)), where MED(PS) is the minimal erythema dose for protected
skin after application of 2 milligrams per square centimeter of the
final formulation of the sunscreen product, and MED(US) is the minimal
erythema dose for unprotected skin (i.e., skin to which no sunscreen
product has been applied). In effect, the SPF value is the reciprocal
of the effective transmission of the product viewed as a UV radiation
filter.
6. Section 352.20 is amended by revising paragraph (a)(2) to read
as follows:
Sec. 352.20 Permitted combinations of active ingredients.
* * * * *
(a) * * *
(2) Avobenzone in Sec. 352.10(b) may be combined with one or more
sunscreen active ingredients identified in Sec. 352.10(c), (e), (f),
(i) through (l), (n), (o), (q), and (r) in a single product when used
in the concentrations established for each ingredient in Sec. 352.10.
The concentration of each active ingredient must be sufficient to
contribute a minimum SPF of not less than 2 to the finished product.
The finished product must have a minimum SPF of not less than the
number of sunscreen active ingredients used in the combination
multiplied by 2.
* * * * *
7. Section 352.50 is revised to read as follows:
Sec. 352.50 Principal display panel of all sunscreen drug products.
(a) UVB sunburn protection designation--(1) For products with an
SPF of 2 to under 15. The labeling states ``UVB SPF [insert tested SPF
value of the product] low''.
(2) For products with an SPF of 15 to under 30. The labeling states
``UVB SPF [insert tested SPF value of the product] medium''.
(3) For products with an SPF of 30 to 50. The labeling states ``UVB
SPF [insert tested SPF value of the product] high''.
(4) For products with an SPF over 50. The labeling states ``UVB SPF
50 [select one of the following: `plus' or `+'] highest''. Any
statement accompanying the marketed product that states a specific SPF
value over 50 or similar language indicating a person can stay in the
sun more than 50 times longer than without sunscreen will cause the
product to be misbranded under section 502 of the Federal Food, Drug,
and Cosmetic Act (the act) (21 U.S.C. 352).
(b) UVA protection designation--(1) For products not providing UVA
protection according to Sec. 352.73. The labeling states ``no UVA
protection''.
(i) The UVA protection designation shall appear on the principal
display panel along with the UVB protection designation in an equally
prominent manner that does not conflict with the UVB protection
designation.
(ii) The font size of the UVA protection designation shall be the
same size as the UVB protection designation.
(2) For products providing UVA protection according to Sec.
352.73. The labeling states ``UVA [select one of the following in
accordance with Sec. 352.73: `[starf][star14][star14][star14] Low,'
`[starf][starf][star14][star14] Medium,' `[starf][starf][starf][star14]
High,' or `[starf][starf][starf][starf] Highest']''.
(i) The UVA protection designation shall appear on the principal
display panel along with the UVB protection designation in an equally
prominent manner that does not conflict with the UVB protection
designation.
(ii) The font size of the UVA protection designation shall be the
same size as the UVB protection designation.
(iii) All star borders and the color inside a solid star shall be
the same while the color of ``empty'' stars must be lighter and
distinctly different than solid stars. The color inside a solid star
should be distinctly different than the background color.
(iv) The stars are to be filled in starting with the first star on
the left and
[[Page 49113]]
are to appear in a straight horizontal line.
(c) Select one of the following: ``UV rays from the sun are made of
UVB and UVA. It is important to protect against both UVB & UVA rays.''
or ``UV rays from the sun are made of UVB and UVA. It is important to
protect against both UVB & UVA rays to prevent sunburn and other skin
damage.''
(d) For products that satisfy the water resistant sunscreen product
testing procedures in Sec. 352.76. The labeling states (select one of
the following: ``water,'' ``water/sweat,'' or ``water/perspiration'')
``resistant.''
(e) For products that satisfy the very water resistant sunscreen
product testing procedures in Sec. 352.76. The labeling states
``very'' (select one of the following: ``water,'' ``water/sweat,'' or
``water/perspiration'') ``resistant.''
8. Section 352.52 is amended by revising paragraphs (b), (c), (d),
(e), the heading of paragraph (f), paragraphs (f)(1)(ii) through
(f)(1)(vi) to read as follows:
Sec. 352.52 Labeling of sunscreen drug products.
* * * * *
(b) Indications. The labeling of the product states, under the
heading ``Uses,'' all of the phrases listed in paragraph (b)(1) of this
section that are applicable to the product and may contain any of the
additional phrases listed in paragraph (b)(2) of this section, as
appropriate. Other truthful and nonmisleading statements, describing
only the uses that have been established and listed in this paragraph
(b), may also be used, as provided in Sec. 330.1(c)(2) of this
chapter, subject to the provisions of section 502 of the act (21 U.S.C.
352) relating to misbranding and the prohibition in section 301(d) of
the act (21 U.S.C. 331(d)) against the introduction or delivery for
introduction into interstate commerce of unapproved new drugs in
violation of section 505(a) of the act (21 U.S.C. 355(a)).
(1) For products containing any ingredient in Sec. 352.10. (i) For
products with an SPF of 2 to under 15. The labeling states
``[bullet]\1\ low UVB sunburn protection''.
---------------------------------------------------------------------------
\1\ See Sec. 201.66(b)(4) of this chapter for definition of
bullet symbol.
---------------------------------------------------------------------------
(ii) For products with an SPF of 15 to under 30. The labeling
states ``[bullet] medium UVB sunburn protection''.
(iii) For products with an SPF of 30 to 50. The labeling states
``[bullet] high UVB sunburn protection''.
(iv) For products with an SPF over 50. The labeling states
``[bullet] highest UVB sunburn protection''.
(v) For products not providing UVA protection according to Sec.
352.73. The labeling states ``[bullet] no UVA protection.''
(vi) For products providing UVA protection according to Sec.
352.73. The labeling states ``[bullet] [select one of the following in
accordance with Sec. 352.73: `Low,' `medium,' `high,' or `highest']
UVA protection''.
(vii) For products that satisfy the water resistant testing
procedures identified in Sec. 352.76. The labeling states ``[bullet]
retains SPF after 40 minutes of [select one or more of the following:
`activity in the water,' `swimming,' `sweating,' `perspiring,'
`swimming/sweating,' or `swimming/perspiring']''.
(viii) For products that satisfy the very water resistant testing
procedures identified in Sec. 352.76. The labeling states ``[bullet]
retains SPF after 80 minutes of [select one or more of the following:
`activity in the water,' `swimming,' `sweating,' `perspiring,'
`swimming/sweating,' or `swimming/perspiring']''.
(2) Additional indications. In addition to the indications provided
in paragraph (b)(1) of this section, the following may be used for
products containing any ingredient in Sec. 352.10:
(i) For products with an SPF of 2 to under 15. Select one or both
of the following: ``[Bullet] provides low protection against [select
one of the following: `sunburn' or `sunburn and tanning']'' or
``[bullet] for skin that sunburns minimally''.
(ii) For products with an SPF of 15 to under 30. Select one or both
of the following: ``[Bullet] provides medium protection against [select
one of the following: `sunburn' or `sunburn and tanning']'' or
``[bullet] for skin that sunburns moderately''.
(iii) For products with an SPF of 30 to 50. Select one or both of
the following: ``[Bullet] [select one of the following: `provides high'
or `high'] protection against [select one of the following: `sunburn'
or `sunburn and tanning']'' or ``[bullet] for skin highly sensitive to
sunburn''.
(iv) For products with an SPF over 50. Select one or both of the
following: ``[Bullet] [select one of the following: `provides highest'
or `highest'] protection against [select one of the following:
`sunburn' or `sunburn and tanning']'' or ``[bullet] for skin extremely
sensitive to sunburn''.
(v) If the UVA descriptor in Sec. 352.52(b)(1)(vi) is the same as
the SPF descriptor in Sec. 352.52(b)(1)(i) through (b)(1)(iv), then
the statement in Sec. 352.52(b)(1)(i) through (b)(1)(iv) may be
combined with the statement in Sec. 352.52(b)(1)(vi) as follows:
``[Bullet] [select one of the following descriptors in accordance with
Sec. Sec. 352.70 and 352.73: `low,' `medium,' `high,' or `highest']
UVB sunburn/UVA protection''.
(c) Warnings. The labeling of the product contains the following
warnings under the heading ``Warnings:''
(1) The labeling states in bold type ``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.''
(2) The labeling states ``When using this product [bullet] keep out
of eyes. Rinse with water to remove.''
(3) The labeling states ``Stop use and ask a doctor if [bullet]
skin rash occurs''.
(d) 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
(e.g., cream, gel, lotion, oil, spray, etc.) may also be included.
(1) For products containing any ingredient in Sec. 352.10. (i) The
labeling states ``[bullet] 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''.
(ii) The labeling states ``[bullet] apply and reapply as directed
to avoid lowering protection''.
(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 products that satisfy the water resistant or very water
resistant testing procedures identified in Sec. 352.76. The labeling
states ``[bullet] 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 Sec.
352.76, respectively] swimming or [select one or more of the following:
`sweating' or `perspiring'] and after towel drying. Otherwise, reapply
at least every 2 hours''.
(3) For products that do not satisfy the water resistant or very
water resistant testing procedures identified in Sec. 352.76. The
labeling states ``[bullet] reapply at least every 2 hours and after
towel drying, swimming, or [select one of the following: `sweating' or
`perspiring']''.
(e) Statement on product performance--(1) For products containing
any ingredient identified in
[[Page 49114]]
Sec. 352.10. The following product category designation (PCD) labeling
claims may be used under the heading ``Other information'' or anywhere
outside of the ``Drug Facts'' box or enclosure and shall not be
intermixed with the information required under Sec. 352.50(a).
(i) For products with an SPF of 2 to under 15. The labeling states
``low sunburn protection product''.
(ii) For products with an SPF of 15 to under 30. The labeling
states ``medium sunburn protection product''.
(iii) For products with an SPF of 30 to 50. The labeling states
``high sunburn protection product''.
(iv) For products with an SPF over 50. The labeling states
``highest sunburn protection product''.
(2) For products containing any ingredient identified in Sec.
352.10. The following labeling statement may be used under the heading
``Other information'' or anywhere outside of the ``Drug Facts'' box or
enclosure and shall not be intermixed with the information required
under Sec. 352.50(a). The labeling states ``higher SPF products give
more sun protection, but are not intended to extend the time spent in
the sun''.
(3) For products containing any ingredient identified in Sec.
352.10 and that satisfy the requirements in Sec. 352.73 for a labeled
UVA protection value. The following labeling statements may be used
anywhere outside of the ``Drug Facts'' box or enclosure and shall not
be intermixed with the information required under Sec. 352.50(a).
(i) The labeling states ``broad spectrum sunscreen''.
(ii) The labeling states ``provides [select one of the following:
`UVA and UVB,' or `broad spectrum'] protection''.
(iii) The labeling states ``protects from UVA and UVB [select one
of the following: `rays' or `radiation']''.
(iv) The labeling states ``[select one of the following: `absorbs'
or `protects'] within the UVA spectrum''.
(f) Products, including cosmetic-drug products, containing any
ingredient identified in Sec. 352.10 labeled for use only on specific
small areas of the face (e.g., lips, nose, ears, and/or around the
eyes) and that meet the criteria established in Sec. 201.66(d)(10) of
this chapter. * * *
(1) * * *
* * * * *
(ii) The indication required by Sec. 201.66(c)(4) of this chapter
may be limited to the following: ``Use [in bold type] helps prevent
sunburn.''
(iii) The warnings required by Sec. 201.66(c)(5)(i) through
(c)(5)(ix) of this chapter may be limited to the following: ``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. [in bold type]'' ``[bullet] keep out of eyes'' ``[bullet]
stop use if skin rash occurs.''
(iv) The warning in Sec. 201.66(c)(5)(x) of this chapter may be
limited to the following: ``Keep out of reach of children.''
(v) For lip protectant products containing any ingredient
identified in Sec. 352.10. The heading and the indication required by
Sec. 201.66(c)(4) of this chapter may be limited to ``Use [in bold
type] helps prevent sunburn and chapped lips''. The warnings required
in paragraph (f)(1)(iii) of this section may be limited to the
following: ``Stop use if skin rash occurs.'' The warning required in
paragraph (f)(1)(iv) of this section may be omitted. The directions in
paragraphs (d)(2) and (d)(3) of this section may be limited to the
following: ``apply liberally and reapply at least every 2 hours for
sunburn protection''.
(vi) For lipsticks, lip products to prolong wear of lipstick, lip
gloss, and lip balm containing any ingredient identified in Sec.
352.10 and identified in Sec. 720.4(c)(7) of this chapter. The
labeling is identical to that in paragraph (f)(1)(v) of this section
except the heading and the indication required by Sec. 201.66(c)(4) of
this chapter are limited to ``Use [in bold type] helps prevent
sunburn''.
* * * * *
9. Section 352.60 is amended by revising paragraphs (c) and (d) to
read as follows:
Sec. 352.60 Labeling of permitted combinations of active
ingredients.
* * * * *
(c) Warnings. The labeling of the product states, under the heading
``Warnings,'' the warning(s) for each ingredient in the combination, as
established in the warnings section of the applicable OTC drug
monographs, except that the warning for skin protectants in Sec.
347.50(c)(3) of this chapter is not required for permitted combinations
containing a sunscreen and a skin protectant identified in Sec.
352.20(b). For products marketed as a lip protectant with sunscreen,
Sec. 352.52(f)(1)(vi) applies.
(d) Directions. The labeling of the product states, under the
heading ``Directions,'' directions that conform to the directions
established for each ingredient in the directions sections of the
applicable OTC drug monographs, unless otherwise stated in this
paragraph. When the time intervals or age limitations for
administration of the individual ingredients differ, the directions for
the combination product may not contain any dosage that exceeds those
established for any individual ingredient in the applicable OTC drug
monograph(s), and may not provide for use by any age group lower than
the highest minimum age limit established for any individual
ingredient. For permitted combinations containing a sunscreen and a
skin protectant identified in Sec. 352.20(b), the directions for
sunscreens in Sec. 352.52(d) must be used. For products marketed as a
lip protectant with sunscreen, Sec. 352.52(f)(1)(vi) applies.
10. Sections 352.70 through 352.73 are revised as follows:
Subpart D--Testing Procedures
Sec.
352.70 SPF testing procedure.
352.71 UVA in vitro testing procedure.
352.72 UVA in vivo testing procedure.
352.73 Determination of the labeled UVA protective value.
* * * * *
Sec. 352.70 SPF testing procedure.
(a) Standard sunscreens--(1) Laboratory validation. A standard
sunscreen shall be used concomitantly in the testing procedures for
determining the SPF value of a sunscreen drug product to ensure the
uniform evaluation of sunscreen drug products.
(i) For products with an SPF of 2 to 15. The standard sunscreen
shall be an 8-percent homosalate preparation with a mean SPF value of
4.47 (standard deviation = 1.28). In order for the SPF determination of
a test product to be considered valid, the SPF of the standard
sunscreen must fall within the standard deviation range of the expected
SPF (i.e., 4.47 1.28). Optionally, the standard sunscreen
in paragraph (a)(1)(ii) of this section may be used.
(ii) For products with an SPF over 15 (optional for SPF values of 2
to 15). The standard sunscreen shall be an SPF 15 formulation
containing 7 percent padimate O and 3 percent oxybenzone with a mean
SPF value of 16.3 (standard deviation = 3.43). In order for the SPF
determination of a test product to be considered valid, the SPF of the
standard sunscreen must fall within the standard deviation range of the
expected SPF (i.e., 16.3 3.43).
(2) Standard homosalate sunscreen--(i) Preparation of the standard
homosalate sunscreen. (A) The standard homosalate sunscreen is prepared
from two different preparations (preparation
[[Page 49115]]
A and preparation B) with the following compositions:
Composition of Preparation A and Preparation B of the Homosalate
Standard Sunscreen
------------------------------------------------------------------------
Ingredients Percent by weight
------------------------------------------------------------------------
Preparation A
------------------------------------------------------------------------
Lanolin 5.00
Homosalate 8.00
White petrolatum 2.50
Stearic acid 4.00
Propylparaben 0.05
------------------------------------------------------------------------
Preparation B
------------------------------------------------------------------------
Methylparaben 0.10
Edetate disodium 0.05
Propylene glycol 5.00
Triethanolamine 1.00
Purified water USP 74.30
------------------------------------------------------------------------
(B) Preparation A and preparation B are heated separately to 77 to
82 [deg]C, with constant stirring, until the contents of each part are
solubilized. Add preparation A slowly to preparation B while stirring.
Continue stirring until the emulsion formed is cooled to room
temperature (15 to 30 [deg]C). Add sufficient purified water to obtain
100 grams of standard sunscreen preparation.
(ii) High performance liquid chromatography (HPLC) assay of the
standard homosalate sunscreen. Assay the standard homosalate sunscreen
preparation by the following method to ensure proper concentration:
(A) Reagents. (1) Acetic acid, glacial, ACS grade.
(2) Isopropanol, HPLC grade.
(3) Methanol, HPLC grade.
(4) Homosalate, USP reference standard.
(B) Instrumentation. Equilibrate a suitable liquid chromatograph to
the following or equivalent conditions:
Column....................... Ultrasphere ODS 150 x 4.6 millimeters (5
microns), or Ultrasphere ODS 250 x 4.6
millimeters (5 microns)
Mobile Phase................. 85:15:0.5 methanol:water:acetic acid
Flow Rate.................... 1.5 milliliters per minute
Temperature.................. Ambient
Detector..................... UV spectrophotometer at 308 nanometers
Attenuation.................. As needed
Injection Amount............. 10 microliters
(C) Standard preparation. (1) Accurately weigh 0.50 gram of
homosalate USP reference standard into a 250-milliliter volumetric
flask. Dissolve and dilute to volume with isopropanol. Mix well.
(2) Accurately pipet 20.0 milliliters of the homosalate solution
(described in paragraph (a)(2)(ii)(C)(1) of this section) into a 100-
milliliter volumetric flask. Dilute to volume with isopropanol and mix
well. This is the standard preparation.
(D) Sample preparation. (1) Accurately weigh 2.0 grams of sample
into a 100-milliliter volumetric flask.
(2) Add approximately 75 milliliters of isopropanol and heat with
swirling until the sample is evenly dispersed.
(3) Cool to room temperature (15 to 30 [deg]C) and dilute to volume
with isopropanol. Mix well.
(4) Pipet 25.0 milliliters of this sample preparation into a 100-
milliliter volumetric flask and dilute to volume with isopropanol. Mix
well.
(E) System suitability. (1) Three replicate injections of the
standard preparation (described in paragraph (a)(2)(ii)(C)(2) of this
section) will yield a relative standard deviation of not more than 2.0
percent calculated on peak areas for homosalate.
(2) In case a system fails to meet this criterion, adjusting the
mobile phase or replacing the column may be necessary to obtain
suitable chromatography.
(F) Analysis. (1) Inject 10 microliters of the standard preparation
(described in paragraph (a)(2)(ii)(C) of this section) in triplicate
and collect data for about 15 minutes or until both homosalate (two
isomers) peaks have completely eluted.
(2) Similarly inject 10 microliters of each sample preparation.
(3) The system suitability requirements must be met.
(G) Calculation. Sum the peak areas of the two homosalate isomers
for each injection and calculate the percent (weight/weight) homosalate
content in the sample preparation as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.005
(3) Standard padimate O/oxybenzone sunscreen--(i) Preparation of
the standard padimate O/oxybenzone sunscreen. The standard sunscreen is
prepared from four different parts (parts A, B, C, and D) with the
following compositions:
Composition of the Padimate O/Oxybenzone Standard Sunscreen
------------------------------------------------------------------------
Ingredients Percent by 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
Propylparaben................................... 0.10
------------------------------------------------------------------------
Part B..................................................................
------------------------------------------------------------------------
Purified water USP.............................. 71.60
Sorbitol solution............................... 5.00
[[Page 49116]]
Triethanolamine, 99 percent..................... 1.00
Methylparaben................................... 0.30
------------------------------------------------------------------------
Part C..................................................................
------------------------------------------------------------------------
Benzyl alcohol.................................. 0.50
------------------------------------------------------------------------
Part D..................................................................
------------------------------------------------------------------------
Purified water USP.............................. QS1
------------------------------------------------------------------------
\1\ Quantity sufficient to make 100 grams
(A) Step 1. Add the ingredients of Part A into a suitable stainless
steel kettle equipped with a propeller agitator. Mix at 77 to 82 [deg]C
until uniform.
(B) Step 2. Add the water of Part B into a suitable stainless steel
kettle equipped with a propeller agitator and begin mixing and heating
to 77 to 82 [deg]C. Add the remaining ingredients of Part B and mix
until uniform. Maintain temperature at 77 to 82 [deg]C.
(C) Step 3. Add the batch of Step 1 at 77 to 82 [deg]C to the batch
of Step 2 at 77 to 82 [deg]C, and mix until smooth and uniform. Slowly
cool the batch to 49 to 54 [deg]C.
(D) Step 4. Add the benzyl alcohol of Part C to the batch of Step 3
at 49 to 54 [deg]C. Mix until uniform. Continue to cool batch to 35 to
41 [deg]C.
(E) Step 5. Add sufficient water of Part D to the batch of Step 4
at 35 to 41 [deg]C to obtain 100 grams of standard sunscreen
preparation. Mix until uniform. Cool batch to 27 to 32 [deg]C.
(ii) HPLC assay of the standard padimate O/oxybenzone sunscreen. To
ensure that the standard sunscreen contains proper amounts of padimate
O and oxybenzone, analyze it against USP reference standards for
padimate O and oxybenzone in a high performance liquid chromatography
procedure using the following parameters:
(A) Reagents. (1) Acetic acid, glacial, ACS grade.
(2) Isopropanol, HPLC grade.
(3) Methanol, HPLC grade.
(4) Oxybenzone, USP reference standard.
(5) Padimate O, USP reference standard.
(B) Instrumentation. Equilibrate a suitable liquid chromatograph to
the following or equivalent conditions:
Column....................... Ultrasphere ODS 250 x 4.6 millimeters (5
microns), or Supelcosil LC-18 DB 250 x
4.6 millimeters (5 microns)
Mobile Phase................. 85:15:0.5 methanol:water:acetic acid
Flow Rate.................... 1.5 milliliters per minute
Temperature.................. Ambient
Detector..................... UV spectrophotometer at 308 nanometers
Attenuation.................. As needed
Injection Amount............. 10 microliters
(C) Standard preparation. (1) Weigh 0.50 gram of oxybenzone
reference standard into a 250-milliliter volumetric flask. Dissolve and
dilute to volume with isopropanol. Mix well.
(2) Weigh 0.50 gram of padimate O reference standard into a 250-
milliliter volumetric flask. Dissolve and dilute to volume with
isopropanol. Mix well.
(3) Pipet 3.0 milliliters of the oxybenzone solution and 7.0
milliliters of the padimate O solution into a 100-milliliter volumetric
flask. Dilute to volume with isopropanol and mix well. This is the
standard preparation.
(D) Sample preparation. (1) Weigh 1.0 gram of sample into a 50-
milliliter volumetric flask.
(2) Add approximately 30 milliliters of isopropanol and heat with
swirling until the sample is evenly dispersed.
(3) Cool to room temperature (15 to 30 [deg]C) and dilute to volume
with isopropanol. Mix well.
(4) Pipet 5.0 milliliters of this sample preparation into a 50-
milliliter volumetric flask and dilute to volume with isopropanol. Mix
well.
(E) System suitability. (1) Three replicate injections of the
standard preparation (described in paragraph (a)(3)(ii)(C) of this
section) will yield a relative standard deviation of not more than 2.0
percent calculated on peak areas for oxybenzone and padimate O.
(2) A calculated resolution between the oxybenzone and padimate O
peaks will be not less than 3.0.
(3) In case a system fails to meet this criterion, adjusting the
mobile phase or replacing the column may be necessary to obtain
suitable chromatography.
(F) Analysis. (1) Inject 10 microliters of the standard preparation
(described in paragraph (a)(3)(ii)(C) of this section) in triplicate
and collect data for about 15 minutes or until the padimate O peak has
completely eluted. Elution order is oxybenzone, then padimate O.
(2) Similarly inject 10 microliters of each sample preparation.
(3) The system suitability requirements must be met.
(G) Calculation. Calculate the percent (weight/weight) of each
sunscreen ingredient in the sample preparation as follows:
(1) Oxybenzone (percent weight)
[GRAPHIC] [TIFF OMITTED] TP27AU07.006
(2) Padimate O (percent weight)
[GRAPHIC] [TIFF OMITTED] TP27AU07.007
(b) Light source (solar simulator)--(1) Emission spectrum. A solar
simulator used for determining the SPF of a sunscreen drug product
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 solar simulator irradiance for all wavelengths
between 250 and 1400 nm and the following percentage of erythema-
effective radiation in each specified range of wavelengths:
[[Page 49117]]
Solar Simulator Emission Spectrum
------------------------------------------------------------------------
Wavelength range (nm) Percent erythemal contribution
------------------------------------------------------------------------
< 290 < 0.1
290-310 46.0-67.0
290-320 80.0-91.0
290-330 86.5-95.0
290-340 90.5-97.0
290-350 93.5-98.5
290-400 93.5-100.0
------------------------------------------------------------------------
(2) Operation. A solar simulator should have no significant time
related fluctuations (within 20 percent) in radiation emissions after
an appropriate warmup time and good beam uniformity (within 20 percent)
in the exposure plane. The average delivered dose to the UV exposure
site must be within 10 percent of the prescribed dose.
(3) Periodic measurement. To ensure that the solar simulator
delivers the appropriate spectrum of UV radiation, the emission
spectrum of the solar simulator must be measured every 6 months 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 radiometric device that is sensitive
primarily to UV radiation. The broadband radiometric device should be
calibrated using side by side comparison with the spectroradiometer at
the time of the semiannual spectroradiometric measurement of the solar
simulator. 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.
(c) General testing procedures--(1) Medical history. Obtain a
medical history from each subject with emphasis on the effects of
sunlight on his/her skin. Determine that each subject is in good
general health with skin type I, II, or III (as described in this
paragraph).
Skin Type and Sunburn and Tanning History (Based on first 30 to 45
minutes of sun exposure after a winter season of no sun exposure).
I: Always burns easily; never tans (sensitive).
II: Always burns easily; tans minimally (sensitive).
III: Burns moderately; tans gradually (light brown) (normal).
IV: Burns minimally; always tans well (moderate brown) (normal).
V: Rarely burns; tans profusely (dark brown) (insensitive).
VI: Never burns; deeply pigmented (insensitive).
Determine that the subject is not taking topical or systemic medication
that is known to alter responses to ultraviolet radiation and that the
subject has no history of sensitivities to topical products and/or
abnormal responses to sunlight, such as a phototoxic or photoallergic
response.
(2) 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 subject 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 increase skin permeability to ultraviolet radiation.
(3) Informed consent. Obtain legally effective written informed
consent from all subjects.
(4) Test site delineation--(i) Test site. A test site is the
location on the back for determining the subject's initial and final
minimal erythema dose (MED) for unprotected skin and for determining
SPF values after application of the sunscreen standard and the test
sunscreen product(s). There typically are 4 to 6 test sites for each
subject. Test sites should be located on the back between the beltline
and the shoulder blades (scapulae) and lateral to the midline. Each
test site shall be a minimum of 50 square centimeters, e.g., 5 x 10
centimeters. Outline the test sites to which the sunscreen standard and
the test sunscreen product(s) will be applied with indelible ink. If
the subject is to receive the doses of ultraviolet radiation in an
upright (seated) position, draw the lines on the skin with the subject
upright (seated). If the subject is to receive the doses of ultraviolet
radiation while prone, draw the lines with the subject prone.
(ii) Test subsite. Test subsites are the locations to which
ultraviolet radiation is administered within a test site. At least 5
test subsites will receive UV doses within each test site. Test
subsites will be at least 1 square centimeter (cm\2\) in area and will
be separated from each other by at least 1 cm. Mark the location of
each test subsite with indelible ink.
(5) Application of test materials. Apply the test sunscreen product
and the standard sunscreen at 2 milligrams per square centimeter (mg/
cm\2\) to their respective test sites to establish standard films. Test
sites will be randomly located on the back in a blinded manner. 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. Pretreatment
is meant to ensure that sunscreen is applied at the correct density of
2 mg/cm\2\.
(6) Waiting period. Before exposing the test site areas after
applying a product, wait at least 15 minutes.
(7) Number of subjects--(i) For products with an expected SPF under
30. A test panel shall consist of 20 to 25 subjects with at least 20
subjects who produce valid data for analysis. Data are valid unless
rejected in accordance with paragraph (c)(9) of this section. If more
than 5 subjects are rejected based on paragraph (c)(9) of this section,
the panel is disqualified, and a new panel must be created.
(ii) For products with an expected SPF of 30 or over. A test panel
shall consist of 25 to 30 subjects with at least 25 subjects who
produce valid data for analysis. Data are valid unless rejected in
accordance with paragraph (c)(9) of this section. If more than 5
subjects are rejected based on paragraph (c)(9) of this section, the
panel is disqualified, and a new panel must be created.
(8) Response criteria. In order that the person who evaluates the
MED responses is not biased, he/she must not be the same person who
applied the sunscreen drug product to the test site or administered the
doses of UV radiation. After UV radiation exposure from the solar
simulator is completed, all immediate responses shall 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 minutes. After the immediate
responses are noted, each subject shall shield the exposed area from
further UV radiation until the MED response is evaluated. Determine the
MED 16 to 24 hours after exposure. Evaluate the erythema
[[Page 49118]]
responses of each test site using either tungsten or warm white
fluorescent lighting that provides 450 to 550 lux of illumination at
the test site. For the evaluation, the test subject should be in the
same position used when the test site was irradiated. For each test
site, determine the smallest UV dose that produced redness reaching the
borders of the test subsite. The MED is the quantity of erythema-
effective energy required to produce the first perceptible, redness
reaction with clearly defined borders at 16 to 24 hours post-exposure.
To determine the MED, there must be at least one subsite that received
a smaller UV dose and does not produce redness as well as a subsite(s)
with somewhat more intense redness. For subsites showing an erythema
response, the maximal exposure should be no more than twice the total
energy of the minimal exposure.
(9) Rejection of test data. Reject test data if the exposure series
fails to elicit an MED response on either the treated or unprotected
skin sites; or all subsites within a test site show more intense
responses than the threshold erythema response; 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 read.
(d) Determination of SPF--(1) Determination of erythema action
spectrum. (i) Use the following erythema action spectrum as weighting
factors to calculate the erythema-effective exposure produced by a
solar simulator:
Vi ([lgr]) = 1.0 (250 < [lgr] < 298 nm)
Vi ([lgr]) = 100.094 * (298 -
[lgr]) (298 < [lgr] < 328 nanometers)
Vi ([lgr]) = 100.015 * (140 -
[lgr]) (328 < [lgr] < 400 nanometers)
(ii) Integrate the erythemally-effective spectral irradiance over
wavelength and time to calculate the erythema-effective UV dose
delivered by a solar simulator as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.008
(iii) The erythema action spectrum may be determined using a
handheld radiometer with a response weighted to match the spectrum in
``CIE S 007/E Erythemal Reference Action Spectrum and Standard Erythema
Dose,'' dated 1998, which is incorporated by reference in accordance
with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from CIE
Central Bureau, Kegelgasse 27, A-1030, Vienna, Austria, or may be
examined at the Center for Drug Evaluation and Research, 10903 New
Hampshire Ave., Bldg. 22, Silver Spring, MD, or at the Office of the
Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC.
It is advisable to measure the solar simulator output 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 (d)(1)(i) of this section) at the time of the
semiannual spectroradiometric measurement of the solar simulator.
(2) Determination of MED of unprotected skin. Administer a series
of five UV radiation doses expressed as J/m\2\-eff (adjusted to the
erythema action spectrum calculated according to paragraph (d)(1) of
this section) to the subsites within each test site on a subject using
an accurately calibrated solar simulator. Use the series of five
exposures to the unprotected test site to determine the initial
unprotected MED. Select the doses that are a geometric series
represented by (1.25\n\), wherein each exposure dose is 25 percent
greater than the previous exposure dose to maintain the same relative
uncertainty (expressed as a constant percentage), independent of the
subject's sensitivity to UV radiation. Usually, the UV radiation for
determining the initial unprotected MED is administered the day prior
to applying the sunscreen product and standard sunscreen, and the
responses then are evaluated immediately prior to applying the
sunscreen product and sunscreen standard. Determine the final
unprotected MED on the same day that UV radiation is administered to
the sunscreen-protected test sites. Use the final unprotected MED
(MED(US)) in calculating SPF.
(3) Determination of individual SPF values. Administer a series of
five UV radiation doses expressed as J/m\2\-eff (adjusted to the
erythema action spectrum calculated according to paragraph (d)(1) of
this section) to the subsites within each test site on a subject using
an accurately calibrated solar simulator. The five UV doses will be a
geometric series as described in paragraph (d)(2) of this section,
where the middle exposure represents the expected SPF. For products
with an expected SPF less than 8, use exposures that are the product of
the initial unprotected MED times 0.64X, 0.80X, 1.00X, 1.25X, and
1.56X, where X equals the expected SPF of the test product. For
products with an expected SPF between 8 and 15, use exposures that are
the initial unprotected MED times 0.69X, 0.83X, 1.00X, 1.20X, and
1.44X, where X equals the expected SPF of the test product. For
products with an expected SPF greater that 15, use exposures that are
the initial unprotected MED times 0.76X, 0.87X, 1.00X, 1.15X, and
1.32X, where X equals the expected SPF of the test product. The MED is
the smallest erythemally-effective UV dose required to produce mild
redness within the subsite border at 16 to 24 hours post-exposure.
Calculate the SPF value of each sunscreen product and sunscreen
standard using the MED of sunscreen-protected skin (MED(PS)) and the
final unprotected skin MED (MED(US)) as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.009
(4) Determination of the test product SPF and PCD. Use data from at
least 20 test subjects with n representing the number of subjects used.
First, compute the SPF value for each subject as stated in paragraphs
(d)(2) and (d)(3) of this section. Second, compute the mean SPF value,
x, and the standard deviation, s, for these subjects. Third, obtain the
upper 5-percent point from Student's t distribution table with n-1
degrees of freedom. Denote this value by t. Fourth, compute ts/
[radic]n. Denote this quantity by A (i.e., A = ts/[radic]n). Fifth,
calculate the SPF value to be used in labeling as
[[Page 49119]]
follows: The label SPF equals the largest whole number less than x - A.
Sixth and last, the sunscreen product is classified into a PCD as
follows: If 50 + A < x, the PCD is Highest; if 30 + A < = x < = 50 + A,
the PCD is High; if 15 + A < = x < 30 + A, the PCD is Medium; if 2 + A
< = x < 15 + A, the PCD is Low; if x < 2 + A, the product shall not be
labeled as an OTC sunscreen drug product and may not display an SPF
value.
Sec. 352.71 UVA in vitro testing procedure.
(a) Light source for transmittance/absorbance measurements. The
light source should satisfy the requirements for solar simulators
described in Sec. 352.70(b).
(b) Substrate. Use optical-grade quartz plate suitable for
substrate spectrophotometry that has been roughened on one side.
(c) Sample holder. The sample holder should hold the substrate in a
horizontal position to avoid flowing of the sunscreen drug product from
one edge of the substrate to the other. It should be mounted as close
as possible to the input optics of the spectroradiometer 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 substrate will be placed on the upper surface of the
sample holder.
(d) Spectroradiometer input optics. Unless the spectroradiometer is
equipped with an integrating sphere, an ultraviolet radiation diffuser
should be placed between the sample and the input optics of the
spectroradiometer. 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 spectroradiometer
is not collimated. The spectroradiometer input slits should be set to
provide a bandwidth that is less than or equal to 5 nanometers.
(e) Sunscreen drug product application to substrate. The accuracy
of the test depends upon the application of a precisely controlled
amount of sunscreen product with a uniform distribution over the
application area of the substrate. The product is applied at 2
milligrams per square centimeter to the substrate. To achieve uniform
distribution over the substrate, the sunscreen product should be
applied in a series of small dots over the application area of the
substrate and then spread evenly using a gloved finger. A very light
spreading action for a short period of time (approximately 10 seconds)
should be used when distributing the product to ensure complete
coverage without excessive buildup of product in the troughs of the
substrate.
(f) Pre-irradiation to account for differences in photostability.
To account for potentially varying degrees of photostability between
sunscreen drug products, irradiate the sunscreen product on the
substrate with a dose of UV radiation equal to the SPF of the sunscreen
product multiplied by 200 J/m\2\-eff multiplied by 2/3. A UV radiation
dose of 200 J/m\2\-eff is equivalent to one minimal erythema dose
(MED). The UV dose to be delivered is determined by multiplying the
light source spectral irradiance action spectrum for erythema in ``CIE
S 007/E Erythemal Reference Action Spectrum and Standard Erythema
Dose,'' at each wavelength, integrating over wavelength, and
multiplying the integral by the exposure time. ``CIE S 007/E Erythemal
Reference Action Spectrum and Standard Erythema Dose,'' dated 1998, is
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR
part 51. Copies are available from CIE Central Bureau, Kegelgasse 27,
A-1030, Vienna, Austria, or may be examined at the Center for Drug
Evaluation and Research, 10903 New Hampshire Ave., Bldg. 22, Silver
Spring, MD 20993, or at the Office of the Federal Register, 800 North
Capitol St. NW., suite 700, Washington, DC.
(g) Calculation of the spectral transmittance at each wavelength
interval. The dynamic range of the measurement system and the intensity
of the light source should be sufficiently high that signals measured
at all UV wavelengths (290 to 400 nanometers) through a highly
absorbing sunscreen product are above the noise level of the
measurement system. Spectral irradiance will be measured at 5 nanometer
intervals, from 290 to 400 nanometers. At least 12 measurements of
spectral irradiance transmitted through the substrate without sunscreen
drug product present will be obtained from different locations on the
substrate surface (C([lgr])1, C([lgr])2,
C([lgr])3, . . . C([lgr])12). In addition, a
minimum of 12 measurements of spectral irradiance transmitted through
the substrate with the sunscreen drug product present will be similarly
obtained after pre-irradiation of the sunscreen drug product
(P([lgr])1, P([lgr])2, P([lgr])3, . .
. P([lgr])12). The mean transmittance for wavelength [lgr],
T([lgr]), is the ratio of the mean of the C([lgr]) values to the mean
of the P([lgr]) values, as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.010
The standard deviation, s, associated with the spectral transmittance
is evaluated using Taylor's approximation, as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.011
where C([lgr]) = mean of the measurements of C at wavelength [lgr].
P([lgr]) = mean of the measurements of P at wavelength [lgr].
s(C([lgr])) = standard deviation of the measurements of C at wavelength
[lgr].
s(P([lgr])) = standard deviation of the measurements of P at wavelength
[lgr].
s(C([lgr])) is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.012
s(P([lgr])) is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.013
This calculation gives 23 spectral transmittance values with associated
standard deviations, one for each 5 nanometer wavelength increment from
290 to 400 nanometers. The standard deviation values will provide an
indication of the uniformity of sunscreen drug product spreading during
application to the substrate. The coefficient of variation, which is
the standard deviation divided by the mean, and expressed as a
percentage, should be less than 10 percent.
(h) Calculation of the UVA I/UV ratio. (1) Spectral transmittance
values, T([lgr]), are converted into absorbance values, A([lgr]), by
taking the negative logarithm of
[[Page 49120]]
the spectral transmittance value as follows:
A([lgr]) = -log T([lgr])
The calculation yields 23 monochromatic absorbance values in 5
nanometer increments from 290 to 400 nanometers.
(2) The index of UVA I protection is calculated as the area (per
unit wavelength) under the UVA I portions of a plot of wavelength
versus A([lgr]), divided by the area (per unit wavelength) under the
total curve, as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.014
UVA I area per unit [lgr] is given as:
[GRAPHIC] [TIFF OMITTED] TP27AU07.015
UV area per unit [lgr] is given as:
[GRAPHIC] [TIFF OMITTED] TP27AU07.016
where: A([lgr]) = effective absorbance given as -log T([lgr])
d([lgr]) = wavelength interval between measurements
B([lgr]) = any biological action spectrum factor
Because no appropriate biological action spectrum for UVA radiation
damage has been universally accepted, no action spectrum is specified.
The value of B([lgr]) is, therefore, equal to 1.0 for all wavelengths.
(3) The integrals in the formulae in paragraphs (h)(1) and (h)(2)
of this section are evaluated using Simpson's Rule for irregular areas,
which states:
Area = h/3 x [Y0 + Y2m + 4(Y1 +
Y3 . . . + Y2m-1) + 2(Y2 +
Y4 + . . . Y2m-2)]
In this equation, Y0, Y1, Y2, . . .
Y2m are the lengths of 2m parallel lines drawn vertically to
divide the area under the curve of a graph into 2m-1 segments of equal
width, h. In practice, the values of Y0, Y1,
Y2, . . . Y2m are the A([lgr]) values determined
and h is the wavelength interval at which the spectral transmittance is
determined (i.e., 5 nanometers).
(4) UVA I area per unit wavelength (aUVA I/[lgr]) is calculated as
follows:
aUVA I/[lgr] = 5/3 x [A340 + A400 +
4(A345 + ... + A395) + 2(A350 +
A360 + A370 + ... + A390)]/60
UV area per unit wavelength (aUV/[lgr]) is calculated as follows:
aUV/[lgr] = 5/3 x [A290 + A400 +
4(A295 + A305 + A315 + ... +
A395) + 2(A300 + A310 + ... +
A390)]/110
UVA I/UV ratio is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.017
(i) Category determination of the UVA I/UV ratio. Perform at least
5 separate determinations of the UVA I/UV ratio, from which the mean
can be calculated. Using the mean, the sunscreen drug product is
classified by in vitro UVA I/UV ratio as follows:
UVA I/UV Ratio Category
0.20 to 0.39 Low
0.40 to 0.69 Medium
0.70 to 0.95 High
greater than 0.95 Highest
Sec. 352.72 UVA in vivo testing procedure.
(a) Standard sunscreen. A standard sunscreen shall be tested
concomitantly in the procedure for determining the UVA protection
factor (UVA-PF) value by means of persistent pigment darkening to
ensure the uniform evaluation of sunscreen drug products. The standard
sunscreen shall be a preparation containing 7 percent padimate O and 3
percent oxybenzone as specified in Sec. 352.70(a)(3). For the test to
be valid, the measured mean UVA-PF value of the standard preparation
shall be 3.2 with a standard deviation less than or equal to 0.5.
(b) Light source. The light source used for determining the UVA-PF
value of a sunscreen drug product shall provide a continuous emission
spectrum in the range of 320 to 400 nanometers. The ratio of UVA I (340
to 400 nanometers) to UVA II (320 to 340 nanometers) in the final beam
shall be close to that of sunlight, i.e., emitted UVA II shall be 8 to
20 percent of the total UVA radiation. Optical radiation from 250 to
320 nanometers shall be less than 0.1 percent of the optical radiation
between 320 to 400 nanometers. Exclude visible and infrared light to
avoid the darkening effects of visible light and the effect of heat.
Perform monitoring and maintenance of the light source as specified in
Sec. 352.70(b)(3).
(c) General testing procedures--(1) Medical history. Obtain a
medical history from each subject with emphasis on the effects of
sunlight on his/her skin. Determine that each subject is in good
general health and has skin type II or III (as described in this
paragraph).
Skin Type and Sunburn and Tanning History (Based on first 30 to 45
minutes of sun exposure after a winter season of no sun exposure).
I: Always burns easily; never tans (sensitive).
II: Always burns easily; tans minimally (sensitive).
III: Burns moderately; tans gradually (light brown) (normal).
IV: Burns minimally; always tans well (moderate brown) (normal).
V: Rarely burns; tans profusely (dark brown) (insensitive).
VI: Never burns; deeply pigmented (insensitive).
Determine that the subject is not taking topical or systemic medication
that is known to alter responses to ultraviolet radiation and that the
subject has no history of sensitivities to topical products and/or
abnormal responses to sunlight, such as a phototoxic or photoallergic
response.
(2) Physical examination. The physical examination shall be
conducted as specified in Sec. 352.70(c)(1).
(3) Informed consent. Obtain legally effective written informed
consent from all subjects.
(4) Test site delineation--(i) Test site. A test site is the
location on the back for determining the subject's initial and final
minimal pigmenting dose (MPD) for unprotected skin and for determining
UVA-PF values after application of the sunscreen standard and the test
sunscreen product(s). There typically are 4 to 6 test sites for each
subject. Test sites should be located on the back between the beltline
and the shoulder blades (scapulae) and lateral to the midline. Each
test site shall be a minimum of 50 square centimeters (cm\2\) (i.e., 5
x 10 centimeters). Outline the test sites to which the sunscreen
standard and the test sunscreen product(s) will be applied with
indelible ink. If the subject is to receive the doses of ultraviolet
radiation in an upright (seated) position, draw the lines on the skin
with the subject upright (seated). If the subject is to receive the
doses of ultraviolet radiation while prone, draw the lines with the
subject prone.
(ii) Test subsite. Test subsites are the locations to which
ultraviolet radiation is administered within a test site. At least 5
test subsites will receive UV doses within each test site. Test
subsites will be at least 1 cm\2\ in area and will be separated from
each other by at least 1 cm. Mark the location of each test subsite
with indelible ink.
(5) Application of test materials. Apply the test sunscreen product
and the standard sunscreen as specified in Sec. 352.70(c)(5).
(6) Waiting period. Before exposing the test site areas after
applying a product, wait at least 15 minutes.
(7) Number of subjects. A test panel shall consist of 20 to 25
subjects with at least 20 subject who produce valid data for analysis.
Data is valid unless rejected in accordance with Sec. 352.70(c)(9). If
more than 5 subjects are rejected based on Sec. 352.70(c)(9), the
panel is disqualified, and a new panel must be created.
[[Page 49121]]
(8) Response criteria. In order that the person who evaluates the
MPD responses is not biased, he/she must not be the same person who
applied the sunscreen drug product to the test site or administered the
doses of UV radiation. After UV radiation exposure from the solar
simulator is completed, all immediate responses shall 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 minutes. After the immediate
responses are noted, each subject shall shield the exposed area from
further UV radiation until the MPD response is evaluated. Determine the
MPD 3 to 24 hours after exposure. Evaluate the pigmentation responses
of each test site using either tungsten or warm white fluorescent
lighting that provides 450 to 550 lux of illumination at the test site.
For the evaluation, the test subject should be in the same position
used when the test site was irradiated. For each test site, determine
the smallest UV dose that produced mild pigmentation reaching the
borders of the test subsite. The MPD is the smallest UV dose required
to produce the first perceptible pigment darkening at 3 to 24 hours
post-exposure. To determine the MPD, there must be at least one subsite
that received a smaller UV dose and does not produce pigmentation as
well as a subsite(s) with somewhat more intense pigmentation. For
subsites showing pigmentation, the maximal exposure should be no more
than twice the total energy of the minimal exposure.
(9) Rejection of test data. Reject test data if the exposure series
fails to elicit an MPD response on either the treated or unprotected
skin sites, or all subsites within a test site show more intense
responses than the threshold pigmentation response, 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 MPD is read.
(d) Determination of UVA-PF values--(1) Determination of MPD of
unprotected skin. Administer a series of five UV radiation doses
expressed as Joules per square meter to the subsites within each test
site on a subject using the light source described in paragraph (b) of
this section. Use the series of five exposures to the unprotected test
site to determine the initial unprotected MPD. Select the doses that
are a geometric series represented by (1.25\n\), wherein each exposure
dose is 25 percent greater than the previous exposure dose to maintain
the same relative uncertainty (expressed as a constant percentage),
independent of the subject's sensitivity to UV radiation. Usually, the
UV radiation for determining the initial unprotected MPD is
administered the day prior to applying the sunscreen product and
standard sunscreen, and the responses are then evaluated immediately
prior to applying the sunscreen product and sunscreen standard.
Determine the final unprotected MPD on the same day that UV radiation
is administered to the sunscreen-protected test sites. Use the final
unprotected MPD (MPD(US)) in calculating UVA-PF.
(2) Determination of individual UVA-PF values. Administer a series
of five UV radiation doses expressed as Joules per square meter to the
subsites within each test site on a subject using the light source
described in paragraph (b) of this section. The five UV doses will be a
geometric series as described in paragraph (d)(1) of this section,
where the middle exposure represents the expected UVA-PF. Use exposures
that are the product of the initial unprotected MPD times 0.64X, 0.80X,
1.00X, 1.25X, and 1.56X, where X equals the expected UVA-PF of the test
product. The MPD is the smallest UV dose required to produce
pigmentation at 3 to 24 hours post-exposure. Calculate the UVA-PF value
of each sunscreen product and sunscreen standard using MPD of
sunscreen-protected skin (MPD(PS)) and the final unprotected MPD
(MPD(US)) as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.018
(3) Determination of test product UVA-PF and UVA product category
designation (PCD). Use data from at least 20 test subjects with n
representing the number of subjects used. First, compute the UVA-PF
value for each subject as stated in paragraph (d)(2) of this section.
Second, compute the mean UVA-PF value, x, and the standard deviation,
s, for these subjects. Third, obtain the upper 5-percent point from
Student's t distribution table with n-1 degrees of freedom. Denote this
value by t. Fourth, compute ts/[radic]n. Denote this quantity by A
(i.e., A = ts/[radic]n). Fifth, calculate the UVA-PF value to be used
in labeling as follows: The label UVA-PF equals the largest whole
number less than x - A. Sixth and last, the drug product is classified
into a PCD as follows: If 12 + A < = x, the PCD is Highest; if 8 + A < =
x < 12 + A, the PCD is High; if 4 + A < x < 8 + A, the PCD is Medium;
if 2 + A < = x < 4 + A, the PCD is Low; if x < 2 + A, the product shall
not display a UVA-PF value.
Sec. 352.73 Determination of the labeled UVA protection value.
Test the sunscreen product in accordance with Sec. Sec. 352.71 and
352.72. The UVA category on the principal display panel (PDP) of the
tested sunscreen product, as specified in Sec. 352.50, shall be the
lower of either the UVA I/UV ratio category determined in Sec.
352.71(j) or the UVA-PF product category designation (PCD) determined
in Sec. 352.72(d)(3). If the product does not attain at least a
``low'' category rating for both the UVA-PF and the UVA I/UV ratio, the
product shall not display a UVA claim. State the final combined
category rating (i.e., the lower of either the UVA I/UV ratio or UVA-PF
PCD categories) on the PDP of the product along with the corresponding
number of stars for that combined category rating as follows:
Combined Category Rating Star Rating
Low [starf][star14][star14][st
ar14]
Medium [starf][starf][star14][sta
r14]
High [starf][starf][starf][star
14]
Highest [starf][starf][starf][star
f]
11. Section 352.76 is amended by revising the introductory
paragraph and paragraphs (a) introductory text, (a)(6), (b)
introductory text, and (b)(10) to read as follows:
Sec. 352.76 Determination if a product is water resistant or very
water resistant.
The general testing procedures in Sec. 352.70(c) shall be used as
part of the following tests, except where modified in this section. An
indoor fresh water pool, whirlpool, and/or jacuzzi maintained at 23 to
32 [deg]C shall be used in these testing procedures. Fresh water is
clean drinking water that meets the standards in 40 CFR part 141. The
pool and air temperature and the relative humidity shall be recorded.
(a) Procedure for testing the water resistance of a sunscreen
product. For sunscreen products making the claim of ``water
resistant,'' the label SPF and, if appropriate, UVA values shall be the
label SPF and UVA values determined after 40 minutes of water immersion
using the following procedure for the water resistance test:
* * * * *
(6) Begin light source exposure to test site areas as described in
Sec. 352.70(b) and, if appropriate, Sec. 352.72(b).
(b) Procedure for testing a very water resistant sunscreen product.
For
[[Page 49122]]
sunscreen products making the claim of ``very water resistant,'' the
label SPF and, if appropriate, UVA values shall be the label SPF and
UVA values determined after 80 minutes of water immersion using the
following procedure for the water resistance test:
* * * * *
(10) Begin light source exposure to test site areas as described in
Sec. 352.70(b) and, if appropriate, Sec. 352.72(b).
Dated: August 10, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 07-4131 Filed 8-23-07; 8:45 am]
BILLING CODE 4160-01-S