Proposed Rule: Sunscreen Drug Products For Over-The-Counter Human Use Proposed Amendment of Final Monograph

Monday,
August 27, 2007
Part III
Department of
Health and Human
Services
Food and Drug Administration
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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49070 Federal Register / Vol. 72, No. 165 / Monday, August 27, 2007 / Proposed Rules
DEPARTMENT OF HEALTH AND 305), Food and Drug Administration, Sunscreen Drug Products With
HUMAN SERVICES 5630 Fishers Lane, rm. 1061, Rockville, UVA Protection
MD 20852. F. Comments on the Labeling of
Food and Drug Administration To ensure more timely processing of Sunscreen Drug Products With High
comments, FDA is no longer accepting SPF Values
21 CFR Parts 347 and 352 comments submitted to the agency by e- G. Comments on Indications for
[Docket No. 1978N–0038] (formerly Docket mail. FDA encourages you to continue Sunscreen Drug Products
No. 78N–0038) to submit electronic comments by using H. Comments on Directions for
the Federal eRulemaking Portal or the Sunscreen Drug Products
RIN 0910–AF43 agency Web site, as described in the I. General Comments on SPF Testing
Electronic Submissions portion of this Procedure
Sunscreen Drug Products for Over-the- J. Comments on the Sunscreen
paragraph.
Counter Human Use; Proposed Standard for SPF Testing Procedure
Instructions: All submissions received
Amendment of Final Monograph K. Comments on Artificial Light
must include the agency name, docket
AGENCY: Food and Drug Administration, number and regulatory information Sources for SPF Testing Procedure
HHS. number (RIN) for this rulemaking. All L. Comments on the Design/Analysis
comments received may be posted of SPF Testing Procedure
ACTION: Proposed rule.
without change to http://www.fda.gov/ M. General Comments on UVA
SUMMARY: The Food and Drug ohrms/dockets/default.htm, including Testing Procedure
Administration (FDA) is issuing a any personal information provided. For N. Comments on UVA Testing
proposed rule that would amend the additional information on submitting Procedure Design and Testing
final monograph (FM) for over-the- comments, see the ‘‘Request for Criteria
counter (OTC) sunscreen drug products Comments’’ heading of the O. Comments on the Photostability of
as part of FDA’s ongoing review of OTC SUPPLEMENTARY INFORMATION section of Sunscreen Drug Products
drug products. This amendment this document. IV. FDA’s Tentative Conclusions and
addresses formulation, labeling, and Docket: For access to the docket to Proposals
testing requirements for both ultraviolet read background documents or V. Analysis of Impacts
B (UVB) and ultraviolet A (UVA) comments received, go to http:// A. Background
radiation protection. FDA is issuing this www.fda.gov/ohrms/dockets/ B. Number of Products Affected
proposed rule after considering public default.htm and insert the docket C. Cost to Relabel
number, found in brackets in the D. Cost to Test or Retest Products for
comments and new data and
heading of this document, into the UVA Protection
information that have come to FDA’s
‘‘Search’’ box and follow the prompts E. Total Incremental Costs
attention. This rule proposes to lift the
F. Small Business Impact
stays of 21 CFR 347.20(d) and 21 CFR and/or go to the Division of Dockets
G. Analysis of Alternatives
Part 352 when FDA publishes a final Management, 5630 Fishers Lane, rm.
VI. Paperwork Reduction Act of 1995
rule based on this proposed rule. 1061, Rockville, MD 20852.
VII. Environmental Impact
DATES: Submit written or electronic FOR FURTHER INFORMATION CONTACT: VIII. Federalism
comments by November 26, 2007. Matthew R. Holman, Office of IX. Request for Comments
Submit written or electronic comments Nonprescription Products, Center for X. Proposed Effective and Compliance
on FDA’s economic impact Drug Evaluation and Research, Food Dates
determination by November 26, 2007. and Drug Administration, 10903 New XI. References
Please see section X of this document Hampshire Ave., Bldg. 22, rm. 5414,
for the effective and compliance dates of Silver Spring, MD 20993, 301–796– I. Background
any final rule that may publish based on 2090. In the Federal Register of May 12,
this proposal. SUPPLEMENTARY INFORMATION: 1993 (58 FR 28194), FDA published a
ADDRESSES: You may submit comments, notice of proposed rulemaking in the
identified by Docket No. 1978N–0038 Table of Contents form of a tentative final monograph
and RIN number 0910–AF43, by any of I. Background (TFM) for OTC sunscreen drug
the following methods: II. Summary of Major Changes to the FM products. In the TFM, FDA proposed
A. Ingredients the conditions under which OTC
Electronic Submissions B. UVB (SPF) Labeling sunscreen drug products would be
Submit electronic comments in the C. UVA Labeling considered generally recognized as safe
following ways: D. Indications and effective (GRASE), under section
• Federal eRulemaking Portal: http:// E. Warnings 201(p) of the Federal Food, Drug, and
www.regulations.gov. Follow the F. Directions Cosmetic Act (the act) (21 U.S.C.
instructions for submitting comments. G. UVB Testing 321(p)), and not misbranded, under
• Agency Web site: http:// H. UVA Testing section 502 of the act (21 U.S.C. 352).
www.fda.gov/dockets/ecomments. III. FDA’s Tentative Conclusions on the In the Federal Register of April 5,
Follow the instructions for submitting Comments 1994 (59 FR 16042), FDA reopened the
comments on the agency Web site. A. General Comments on OTC administrative record until July 31,
Sunscreen Drug Products 1994, to allow additional submissions
Written Submissions on UVA-related issues and announced a
B. Comments on Tanning and

Submit written submissions in the Tanning Preparations public meeting for May 12, 1994, to
following ways: C. Comments on Specific Sunscreen discuss UVA testing procedures. As
• FAX: 301–827–6870. Active Ingredients explained in that Federal Register
• Mail/Hand delivery/Courier (for D. General Comments on the Labeling notice, the TFM included proposed
paper, disk, or CD–ROM submissions): of Sunscreen Drug Products UVB (i.e., 290–320 nm) testing and
Division of Dockets Management (HFA– E. Comments on the Labeling of labeling. The sun protection factor (SPF)
Federal Register / Vol. 72, No. 165 / Monday, August 27, 2007 / Proposed Rules 49071
test and corresponding labeling reflects water resistant test methods and establishing conditions under which
the level of protection against sunburn, cosmetic labeling) as items that could be OTC skin protectant products are
which is caused primarily by UVB finalized within the timeframe set by generally recognized as safe and
radiation. The TFM also explained the FDAMA. Because of outstanding issues effective and not misbranded. This final
importance of protection against UVA related to the development of testing rule lifted the stay of 21 CFR part 352
radiation (i.e., 320–400 nm), the other standards and labeling for UVA to amend the final monograph for OTC
UV component of sunlight (58 FR 28194 radiation protection, FDA deferred final sunscreen drug products to include
at 28232 and 28233). The TFM action on these items. sunscreen-skin protectant combination
referenced published UVA test methods Therefore, in the Federal Register of drug products. This final rule concluded
but did not propose a method (58 FR May 21, 1999 (64 FR 27666), FDA by placing a stay on both part 352 and
28194 at 28248 to 28250). Rather, the published the FM for OTC sunscreen
on § 347.20(d). The proposed rule that is
TFM stated that a product could be drug products in part 352 (21 CFR part
the subject of this document provides
labeled as ‘‘broad spectrum’’ or a similar 352) with an effective date of May 21,
2001, but deferred UVA testing and UVA testing and labeling that is
claim if it protected against UVA
labeling for future regulatory action. necessary on sunscreen and sunscreen-
radiation. Thus, FDA held the 1994
FDA stated that more time was required skin protectant combination drug
public meeting to gather further
information about an appropriate UVA to review comments from interested products. This proposed rule, therefore,
test method and labeling. parties on active ingredients, labeling, proposes that the stays of both part 352
In the Federal Register of June 8, 1994 and test methods for products intended and § 347.20(d) be lifted when this rule
(59 FR 29706), FDA proposed to amend to provide UVA protection. This is finalized. These stays will be
the TFM (and reopened the comment proposed amendment to the FM for OTC maintained until a final rule based on
period until August 22, 1994) to remove sunscreen drug products will complete this proposed rule becomes effective.
five proposed sunscreen ingredients the FM by addressing both UVB and In the Federal Register of September
from the TFM because of lack of interest UVA testing and labeling. 3, 2004 (69 FR 53801), FDA delayed the
in establishing United States In the Federal Register of June 8, 2000 implementation date for OTC sunscreen
Pharmacopeia—National Formulary (65 FR 36319), FDA reopened the drug products subject to the final rule
(USP–NF) monographs. FDA also administrative record of the rulemaking that established standardized format
reiterated that all sunscreen ingredients for OTC sunscreen drug products to and content requirements for the
must have a USP–NF monograph before allow for specific comment on high SPF labeling of OTC drug products (i.e.,
being included in the FM for OTC and UVA radiation testing and labeling. Drug Facts rule). FDA explained that we
sunscreen drug products. FDA also extended the effective date for postponed the Drug Facts
In the Federal Register of August 15, the FM to December 31, 2002.
implementation date because we did not
1996 (61 FR 42398), FDA reopened the In the Federal Register of December
31, 2001 (66 FR 67485), FDA stayed the expect to complete the final amendment
administrative record until December 6,
December 31, 2002, effective date of the of the sunscreen monograph to include
1996, to allow additional submissions
on zinc oxide and titanium dioxide as FM for OTC sunscreen drug products in UVA testing and labeling by the Drug
well as sunscreen photostability. FDA part 352 until we provided further Facts implementation date of May 16,
also announced a public meeting for notice in a future issue of the Federal 2005 (64 FR 13254 at 13273 and 13274,
September 19 and 20, 1996, to discuss Register. FDA took this action because March 17, 1999). Thus, FDA delayed the
the safety and efficacy of these two we planned to amend part 352 to implementation date of the Drug Facts
ingredients and photostability of address formulation, labeling, and rule with respect to OTC sunscreen drug
sunscreens in general. testing requirements for both UVB and products until further notice to avoid
In the Federal Registers of September UVA radiation protection. This issuing successive relabeling
16, 1996 (61 FR 48645) and October 22, document proposes such changes. This requirements for sunscreen drug
1998 (63 FR 56584), FDA amended the document also proposes an effective products at two closely related time
TFM to add the UVA-absorbing date related to publication of an intervals, as required by the Drug Facts
sunscreen ingredients avobenzone and amended FM (see section X of this rule and the final amendment to the
zinc oxide to the proposed list of document). The existing stay of the sunscreen monograph.
monograph ingredients. FDA also effective date for part 352 remains in
proposed indications for these II. Summary of Major Changes to the
effect at this time.
ingredients. As a result of this In the Federal Register of June 20, FM
amendment to the TFM, in the Federal 2002 (67 FR 41821), FDA published a In response to the TFM and FM, FDA
Register of April 30, 1997 (62 FR technical amendment to change the received substantial data and
23350), FDA announced an enforcement names of four sunscreen active information regarding UVA and UVB
policy allowing interim marketing of ingredients in § 352.10 of the active ingredients, claims, and testing
OTC sunscreen drug products monograph to be consistent with name procedures, as well as on other issues
containing avobenzone. changes that appeared in USP 24. The
addressed in this document. FDA
On November 21, 1997, Congress new names, which are simpler and more
enacted the Food and Drug summarizes these issues and proposed
convenient, are meradimate for menthyl
Administration Modernization Act of changes to the FM in this section.
anthranilate, octinoxate for octyl
1997 (FDAMA). Section 129 of FDAMA methoxycinnamate, octisalate for octyl A. Ingredients
stated that ‘‘Not later than 18 months salicylate, and ensulizole for
after the date of enactment of this Act, FDA proposes to add combinations of
phenylbenzimidazole sulfonic acid.

the Secretary of Health and Human Because the names became official on avobenzone with zinc oxide and
Services shall issue regulations for over- March 1, 2001, manufacturers could avobenzone with ensulizole as
the-counter sunscreen products for the begin using them at any time after that permitted combinations of active
prevention or treatment of sunburn.’’ date. sunscreen ingredients in the FM (see
FDA identified the UVB portions of the In the Federal Register of June 4, 2003 section III.C, comment 7 of this
monograph (and related provisions on (68 FR 33362), FDA issued a final rule document).
B. UVB (SPF) Labeling OTC sunscreen products tested in § 352.52(f), which are not required to
The FM allowed specific labeled SPF accordance with the proposed UVA include this statement under proposed
values up to, but not exceeding, 30. OTC testing procedures in §§ 352.71 and § 352.52(f)(1)(v) and (f)(1)(vi) (see
sunscreen drug products with SPF 352.72 (see section III.E, comment 14 section III.G, comment 19 of this
values greater than 30 could be labeled and section III.N, comment 45 of this document). The statement in proposed
with the collective term ‘‘30+.’’ In this document). § 352.52(c)(1) reads as follows: ‘‘UV
exposure from the sun increases the risk
amendment, FDA proposes to increase D. Indications of skin cancer, premature skin aging,
the specific labeled SPF value to 50 and The FM allowed the following two and other skin damage. It is important
revise the collective term to ‘‘50+.’’ FDA UVB indications in § 352.52(b)(1): to decrease UV exposure by limiting
will consider higher specific labeled • ‘‘helps prevent sunburn’’ time in the sun, wearing protective
SPF values upon receipt of adequate, • ‘‘higher SPF gives more sunburn clothing, and using a sunscreen.’’ FDA
validated data (see section III.F, protection’’ proposes that the statement appear in
comment 15 of this document). In this amendment, FDA proposes to bold type as the first statement in the
In addition, FDA proposes to revise revise the first statement to read ‘‘low,’’ ‘‘Warnings’’ section.
the following FM labeling: ‘‘medium,’’ ‘‘high,’’ or ‘‘highest’’ ‘‘UVB
• The phrase ‘‘sun protection’’ to sunburn protection’’ in proposed F. Directions
‘‘sunburn protection’’ where used in § 352.52(b)(1)(i) through (b)(1)(iv). FDA FDA proposes changes to the
§§ 352.3(b)(1), (b)(2), (b)(3), and (d) and is proposing to revise the additional directions to reduce the likelihood that
352.52(e)(1)(i), (e)(1)(ii), and (e)(1)(iii) indications in § 352.52(b)(2) to reflect OTC sunscreen drug products are
(see section III.D, comment 10 of this the new PCD ranges in proposed underapplied. Section 352.52(d)(1)(i)
document); and § 352.3(c) (e.g., SPF of 2 to under 12 currently provides manufacturers the
• Section 352.50(a) to include the becomes SPF of 2 to under 15) and option to select one or more of the
term ‘‘UVB’’ before the term ‘‘SPF’’ on create the new PCD range over SPF 50. following terms: ‘‘liberally,’’
the principal display panel (PDP), along These proposed revisions are based ‘‘generously,’’ ‘‘smoothly,’’ or ‘‘evenly.’’
with the product category designation upon the revised PCD categories in FDA is proposing to allow the choice of
(PCD) (see section III.E, comment 14 of proposed § 352.3(c) (see section III.G, one of two required terms (i.e.,
this document). comment 16 of this document). FDA ‘‘liberally’’ or ‘‘generously’’) and to
FDA also proposes to revise the PCD proposes that the second statement in include ‘‘evenly’’ as an additional
SPF ranges in § 352.3(b)(1), (b)(2), and current § 352.52(b)(1) (‘‘higher SPF gives optional term. FDA is proposing to
(b)(3) (proposed § 352.3(c)(1) through more sunburn protection’’) no longer be eliminate the term ‘‘smoothly’’ because
(c)(4)) to reflect the following: required and proposes an additional it is vague.
• The current standard public health indication regarding UVA protection FDA also proposes to add a new
message concerning use of sunscreens, (see proposed § 352.52(b)(2)(v)). direction ‘‘apply and reapply as directed
• The proposed increase of the In proposed § 352.52(b)(2)(v), FDA to avoid lowering protection’’ (proposed
labeled SPF value to ‘‘50+,’’ and includes a new indication for UVA § 352.52(d)(1)(ii)). Because new
• The proposed addition of the term protection that involves selection of the information demonstrates the
‘‘UVB’’ before the word ‘‘sunburn.’’ appropriate descriptor (‘‘low,’’ importance of sunscreen reapplication,
Proposed § 352.3(c)(4) contains a new ‘‘medium,’’ ‘‘high,’’ or ‘‘highest’’) to FDA also proposes to make the optional
PCD of ‘‘highest UVB sunburn describe the level of protection. In directions in paragraph (d)(2) a
protection product’’ for products that proposed § 352.52(b)(2)(vi), FDA requirement. As a result of this change,
provide an SPF value over 50. FDA includes a modified version of the FDA is proposing to remove the current
further proposes to revise current sunburn ‘‘Uses’’ statement required by language in paragraph (d)(3) because it
§ 352.3(b)(1) and (b)(2) to replace the proposed § 352.52(b)(1)(i) through is no longer necessary. Instead, FDA is
current category descriptors of (b)(1)(iv) when the additional statement proposing, in paragraph (d)(3), required
‘‘minimal’’ and ‘‘moderate’’ with the in proposed § 352.52(b)(2)(v) is used information for products that do not
terms ‘‘low’’ and ‘‘medium,’’ and bears the same category descriptor satisfy the water resistant testing
respectively. FDA considers the new as the SPF value (e.g., medium UVA/ procedures in § 352.76. FDA is also
terms to be simpler and uniform with UVB protection from sunburn) (see proposing a required reapplication
the proposed UVB and UVA ‘‘Uses’’ section III.G, comment 17 of this statement in § 352.52(d)(1)(ii). The
statements. Proposed changes to PCDs document). reapplication information in current
and category descriptors also occur in § 352.52(d)(2) appears in proposed
proposed § 352.52(e)(1) (see section E. Warnings § 352.52(d)(2) and (d)(3) of this
III.D, comment 13 and section III.G, FDA is proposing to shorten the document (see section III.H, comment
comment 16 of this document). In warning in § 352.52(c)(1)(ii) (proposed 22 of this document).
addition, FDA proposes optional UVB § 352.52(c)(3)) under the subheading
radiation protection statements (see ‘‘Stop use and ask a doctor if’’ from G. UVB Testing
proposed § 352.52(e)(2) and (e)(3)). ‘‘[bullet] rash or irritation develops and FDA is proposing to revise the SPF
lasts’’ to ‘‘[bullet] skin rash occurs.’’ (UVB) testing procedure (see section III,
C. UVA Labeling FDA proposes removing the optional paragraphs I through L of this
FDA proposes new labeling to ‘‘sun alert’’ product performance document) and to move the SPF testing
designate the level of UVA protection statement (current § 352.52(e)(2)) and procedure currently in §§ 352.70
on the PDP of OTC sunscreen drug requiring a revised ‘‘sun alert’’ through 352.73 to proposed § 352.70.
products. FDA proposes the use of statement in the ‘‘Warnings’’ section FDA proposes a padimate O/
symbols (‘‘stars’’) in conjunction with a (proposed § 352.52(c)(1)). FDA proposes oxybenzone sunscreen standard in
descriptor (i.e., ‘‘low,’’ ‘‘medium,’’ that this revised statement be required § 352.70 that will be required for testing
‘‘high,’’ or ‘‘highest’’). FDA also on all OTC sunscreen drug products sunscreen products with SPF values
proposes to add new § 352.50(b) except lip cosmetic-drug and lip over 15. Manufacturers may use either
specifying the required PDP labeling for protectant-sunscreen products subject to this padimate O/oxybenzone standard
or the homosalate standard to test to 3 years after publication of the FM as monographs now state the same
products with SPF values of 2 to 15. appropriate or necessary for conditions for lawfully marketing these
FDA proposes a high pressure liquid implementation. Several of these combination products. The existing
chromatography (HPLC) method to comments added that the date should be language in §§ 347.20(d) and 352.20(b)
replace the spectrophotometric method in the June/July time period because the would include the two new
used to assay the homosalate and shipping season is practically over at combinations that FDA is proposing to
padimate O/oxybenzone standards. that time and manufacturing for the next add to the sunscreen monograph (see
FDA proposes the following season is just beginning. section II.A, comment 7 of this
modifications to the SPF testing FDA understands the seasonal nature document).
procedure: of the sunscreen industry and the time
B. Comments on Tanning and Tanning
• Specifications for the solar required for product testing and
Preparations
simulator in § 352.71 (proposed relabeling. FDA is also aware that more
§ 352.70(b)), than 1 year may be needed for (Comment 4) One comment requested
• Instructions for the application of implementation. FDA is proposing an that the effective date of § 740.19 (21
test materials and response criteria in 18- to 24-month implementation date CFR 740.19) be extended to December
§ 352.72 (proposed § 352.70(c)), and and will try to have it coincide with the 31, 2002, consistent with the delay of
• Doses and determination of June/July time period (see section XI of the effective date for § 310.545(a)(29)
minimal erythema dose (MED) in this document). and (d)(31), part 352, and § 700.35 (65
§ 352.73 (proposed § 352.70(d)). (Comment 2) One comment requested FR 36319). The comment stated that
FDA proposes to continue requiring a that FDA and the Federal Trade singling out § 740.19 to become effective
finger cot to be used in the application Commission (FTC) take steps to make earlier might constitute an arbitrary and
of sunscreen standard and test product sure that sunscreen manufacturers capricious decision by FDA.
as specified in § 352.72(e) (proposed provide information to the American The May 21, 1999, final rule set a 2-
§ 352.70(c)(5)). However, FDA now public to help them understand and use year effective date (May 21, 2001) for
proposes that the finger cot be the Ultraviolet Index (UVI) to determine § 310.545(a)(29) and (d)(31), part 352,
pretreated. These two proposed UVB their risk of sunburn. and § 700.35. In the Federal Register of
testing changes also apply to UVA in The National Weather Service, the June 8, 2000 (65 FR 36319), FDA
vivo testing. Environmental Protection Agency extended the effective date for
(EPA), and the Centers for Disease compliance with § 310.545(a)(29) and
H. UVA Testing Control and Prevention (CDC) (d)(31), part 352, and § 700.35 until
FDA proposes a combination of developed the UVI, which has been in December 31, 2002, to provide time for
spectrophotometric (in vitro) and use since 1995. This index is an completion of a more comprehensive
clinical (in vivo) UVA test procedures in indication of the amount of UV UVA/UVB FM for OTC sunscreen drug
proposed §§ 352.71 and 352.72, radiation reaching the surface of the products. On December 31, 2001, FDA
respectively. To assure UVA protection earth as a function of ozone data, then stayed the effective date of part 352
for ‘‘water resistant’’ and ‘‘very water atmospheric pressure, temperature, and (but not § 310.545(a)(29) and (d)(31),
resistant’’ sunscreen products, FDA cloudiness and is generated for 58 cities and § 700.35) until further notice (66 FR
proposes that the in vivo UVA test be around the United States. 67485). FDA took this action because we
Usage information required by the are amending part 352 to address
conducted after the appropriate water
OTC sunscreen drug product formulation, labeling, and testing
immersion period for OTC sunscreen
monograph applies regardless of the requirements for both UVA and UVB
drug products making a UVA claim.
UVI value. Therefore, FDA believes that radiation protection. The May 21, 1999,
Therefore, FDA proposes modification
UVI information need not be required in final rule also set a 1-year effective date
of § 352.76 to state that the water
the monograph for the safe and effective (May 22, 2000) for new § 740.19, which
resistance claim applies to the SPF and,
use of these products and should not be addresses a warning statement for
if appropriate, UVA values determined
included in the ‘‘Drug Facts’’ labeling. cosmetic suntanning preparations that
after the appropriate water immersion
However, manufacturers who wish to do do not contain a sunscreen active
period as described in proposed
so may voluntarily include such ingredient. These products are not
§ 352.70 and, if appropriate, proposed
information in their labeling outside the subject to the monograph for OTC
§ 352.72.
‘‘Drug Facts’’ box. sunscreen drug products in part 352.
III. FDA’s Tentative Conclusions on the (Comment 3) One comment requested FDA considered this warning to be
Comments that FDA make clear, through either the sufficiently important for safety reasons
FM for skin protectant or sunscreen when we issued the final rule (64 FR
A. General Comments on OTC 27666 at 27669) to require a 12-month
drug products, or both, that combination
Sunscreen Drug Products effective date as opposed to the 24-
products containing sunscreen and skin
(Comment 1) Several comments asked protectant ingredients may be lawfully month effective date for the other
that FDA provide more time to comply marketed. sections of the rule. Further, FDA’s
with requirements of the FM in order to Section 347.20(d) of the skin primary reason for extending the
avoid an adverse economic impact on protectant FM (21 CFR 347.20(d)), effective date of those other sections to
the suncare industry and consumers. which published in the Federal Register December 31, 2002, and then staying
The comments described the seasonal of June 4, 2003 (68 FR 33362), provides part 352 to address formulation,
dynamics of the suncare industry (i.e., for combinations of sunscreen labeling, and testing requirements for
products are sold in two marketing ingredients and specific skin protectant both UVA and UVB protection, was to
cycles over a period of 18 months) and ingredients. The final rule for OTC skin allow FDA to develop a comprehensive
stated that the industry would need protectant drug products also included UVB/UVA final monograph. This reason
more time to develop products that meet an amendment to the sunscreen FM, does not apply to § 740.19. Accordingly,
the FM requirements and allow for adding new § 352.20(b), which allows FDA did not extend the effective date
shipment of the previous year’s returns. combinations of sunscreen and skin for § 740.19, and § 740.19 is in effect at
The comments mentioned times from 2 protectant active ingredients. Thus, both this time. FDA concludes that this
decision is not arbitrary and capricious, • Oral and dermal toxicity studies, too few subjects were enrolled, and the
but is based on valid health concerns • A chronic skin painting study subjects were not representative
related to the products subject to the carcinogenicity study in mice, of the average sunscreen user.
warning requirement in § 740.19. • Comedogenecity tests in rabbits, Well-controlled clinical trials with
(Comment 5) One comment requested • Repeated insult patch test in DHA alone are lacking. Although some
that FDA and FTC take steps to ensure humans, and investigations described by the
sunscreen manufacturers inform • Photoallergy tests. comments suggest that DHA may help
consumers that their natural skin Effectiveness studies consisted of protect the normal skin of psoriasis
pigmentation provides protection from published articles using either humans patients, concerns remain about the
sunlight. The comment stated that these or photosensitized rats. Another usefulness of DHA products in the OTC
adaptive individuals might not require a comment discussed investigations with market. For example, one comment
daily application of a sunscreen. DHA on psoriasis patients sensitized stated that photoprotection provided by
Another comment submitted a copy of with 8-methoxypsoralen (8–MOP). DHA depends upon the way the product
a patent for an electronic sensor device FDA is not proposing to include DHA polymerizes in the stratum corneum and
to measure solar radiation. The in the monograph as a single active that polymerization depends on the skin
comment stated that the personal device ingredient in OTC sunscreen products. of each individual. Therefore, the
could alert consumers to their level of Although there were no product photoprotection provided by DHA
UV exposure so they could either come submissions to the Advisory Review varies from person to person and has to
out of the sun or apply a sunscreen to Panel on Topical Analgesic, be determined for each person by
avoid sunburn and skin cancer. Antirheumatic, Otic, Burn, and Sunburn diffuse reflectance spectroscopy. Given
FDA has no objection to sunscreen Prevention and Treatment Drug these statements, it is not clear how
manufacturers informing consumers Products (the Panel) using DHA as a appropriate OTC drug product labeling
that their natural skin pigmentation sunscreen ingredient, the Panel could be written to aid consumers in
provides protection from sunlight. discussed available scientific evidence proper selection and use of a DHA
However, FDA has no basis to require for DHA as a single sunscreen sunscreen.
such information as part of the required ingredient. The Panel concluded that FDA concludes that current
labeling for OTC sunscreen drug DHA is not a sunscreen but a cosmetic; information is inadequate to include
products. Thus, manufacturers may it is a sunscreen only when used with DHA in the monograph as a single
include this information in labeling lawsone (43 FR 38206 at 38215 to sunscreen ingredient. None of the
outside of the ‘‘Drug Facts’’ box, but are 38216, August 25, 1978). Although one comments provided information to
not required to include this information. comment stated that DHA alters the establish the appropriate number of
FDA considers the comment regarding structure of the skin, it did not provide consecutive product applications and
the UV measuring device to be outside data to support this claim. Thus, at this the timing of these applications (how far
the scope of this rulemaking, which time, FDA agrees with the Panel that apart or how soon before sun exposure)
evaluates the safety, effectiveness, and DHA is a cosmetic. that are necessary to achieve the desired
labeling of OTC drug products. FDA acknowledges that DHA is the protection using products containing
subject of an approved color additive various concentrations of DHA. In two
C. Comments on Specific Sunscreen petition and its safety as a color additive
Active Ingredients submitted studies, a preparation
has been established. However, the containing 3 percent DHA was applied
(Comment 6) Several comments submitted chronic (life-span) skin six times prior to sun exposure and a
requested that dihydroxyacetone (DHA) painting study in mice does not support preparation containing 15 percent DHA
be added to the monograph as a single the safe use of DHA as a sunscreen preparation was applied one time 24
active ingredient for UVA protection. because no group of mice was included hours prior to sun exposure,
The comments claimed that DHA alone in the study to determine the possible respectively (Ref. 1). The comments did
provides an SPF of 2 to 4. One comment photocarcinogenic effect of DHA. This not include any information on
claimed that a 15 percent topical effect needs to be studied because DHA appropriate regimens for various skin
solution of DHA provided a is associated with carbonyl compounds types, which is necessary because the
photoprotective factor of 10 in the UVA known to react with pyrimidine bases in level of photoprotection provided by
region. Other comments contended that the presence of UV radiation, and it DHA is dependent on skin type.
the brown color produced by DHA, appears to be a potent inducer of Therefore, based upon this lack of
resembling melanin, should potentiate thymine dimers, premutagenic information, it is not clear how to state
the action of sunscreens. Another deoxyribonucleic acid (DNA) lesions. appropriate label directions for
comment stated that DHA alone is not Therefore, its safety, in terms of the consumer use. FDA needs additional
a sunscreen, but forms a sunscreen type, extent, and location of photo- information from clinical studies to
when combined with lawsone. The induced DNA damage, is of concern and determine the effective concentration of
comment cited unpublished should be determined. Whether DHA DHA in sunscreen product formulations
observations by two independent contributes or promotes UV and the frequency and timing of product
investigators that the melanoidins of carcinogenesis is not known. application.
DHA-induced skin pigment resemble The submitted studies on the (Comment 7) One comment submitted
melanin in that they absorb UVB effectiveness of DHA as a single UVA data to support the combination of
strongly, with decreasing absorbance sunscreen ingredient add only avobenzone with ensulizole and
through the UVA region and into visible qualitative information. Many of the avobenzone with zinc oxide (Ref. 2).
studies utilized animal models; few
light. The comment added that, because The safety data included the following:
DHA alters the structure of the skin included human subjects. One study • A repeat insult patch test,
surface, it is, by definition, a drug. involved only five subjects, three with • A phototoxicity study, and
One comment provided information erythropoietic protoporphyria and two • A photoallergy study.
on the safety and UVA effectiveness of with polymorphic light eruptions. The effectiveness data involved a
DHA alone (Ref. 1). Safety studies Another study involved six subjects clinical study using the in vitro ‘‘critical
included the following: sensitized with 8–MOP. In both studies, wavelength’’ (CW) method and the in
vivo ‘‘protection factor A’’ (PFA) appropriate for these products. Based on recognized that some product packages
method to support the UVA radiation the labeling in § 352.52, the comment were too small to accommodate all of
protection potential of the combination proposed eight additional modifications the required labeling. Therefore, under
products. The PFA test data were from for all other OTC sunscreen products § 201.66(d)(10) (21 CFR 201.66(d)(10)),
a double blind clinical study using five regardless of package size: FDA allows labeling format
sunscreen formulations. 1. Delete ‘‘Drug Facts’’ title because it modifications for all OTC drug products
The safety studies demonstrated that is inappropriate and unnecessary for sold in small packages. In the final rule
the following combinations of active sunscreens. establishing ‘‘Drug Facts’’ labeling, FDA
ingredients have a low potential for 2. Omit ‘‘Purpose’’ because it is also stated that we may allow reduced
irritation, allergenic sensitization, and repetitive of the statement of identity on labeling requirements beyond those
phototoxicity: the PDP and ‘‘Uses’’ information. specified under § 201.66(d)(10) for OTC
• 3 percent or less avobenzone with 3. Revise ‘‘higher SPF gives more drug products that meet the criteria
2 percent ensulizole sunburn protection’’ in ‘‘Uses’’ to read listed in the preceding paragraph (see
• 3 percent or less avobenzone with ‘‘higher SPF products give more sun section III.D, comment 9 of this
5 percent zinc oxide protection, but are not intended to document).
The data further suggested that the extend the time spent in the sun,’’ and In the final rule for OTC sunscreen
photoallergenic potential of avobenzone require this statement only on products drug products (64 FR 27666 at 27681 to
is not augmented by its combination with an SPF value over 30. 27682), FDA recognized that some OTC
with either ensulizole or zinc oxide. 4. Omit ‘‘For external use only’’ sunscreen drug products meet these
The clinical study using the PFA in warning because it is self-evident for criteria for reduced labeling.
vivo method demonstrated that the sunscreen products. Specifically, FDA identified OTC
following combinations of active 5. Revise ‘‘When using this product sunscreen drug products that qualify for
ingredients are significantly more [bullet] keep out of eyes. Rinse with the small package specifications in
effective than 1.5 percent ensulizole or water to remove’’ to read ‘‘Keep out of § 201.66(d)(10) and are labeled for use
3 percent zinc oxide alone in protecting eyes.’’ only on specific small areas of the face
against UVA radiation: 6. Revise ‘‘Stop use and ask a doctor as meeting the criteria for reduced
• 3 percent avobenzone with 1.5 if [bullet] rash or irritation develops and labeling. Therefore, FDA allows content
percent ensulizole lasts’’ to read ‘‘Stop use if skin rash and format modifications for these
• 3 percent avobenzone with 4 occurs.’’ products under § 352.52(f). FDA allows
percent zinc oxide 7. Omit barlines, hairlines, and box further modifications for lip products
FDA’s detailed comments on the safety enclosure. containing sunscreen because these
and effectiveness studies are on file in 8. Allow the option to list inactive products for small areas of the face are
the Division of Dockets Management ingredients in a different location on the sold in even smaller packages than the
(Ref. 3). label or in labeling accompanying the other sunscreen products marketed
FDA considers the data submitted by product. under § 352.52(f) (68 FR 33362 at 33371;
the comment sufficient to support the The comment stated that these 64 FR 13254 at 13270). FDA believes
safety and effectiveness of avobenzone modifications would allow reduced that sunscreen products labeled for use
with ensulizole and avobenzone with Drug Facts labeling for all OTC only on small areas of the face,
zinc oxide when used in the sunscreen drug products. including lip products containing
concentrations established for each The comment contended that sunscreen, serve an important public
ingredient in § 352.10 of the sunscreen sunscreen products meet all of FDA’s health need and FDA does not want to
monograph. Accordingly, FDA is criteria for reduced labeling (64 FR discourage manufacturers from
proposing to amend § 352.20(a)(2) by 13254 at 13270): marketing these products (64 FR 13254
adding ensulizole and zinc oxide. • Packaged in small amounts, at 13270).
Marketing of products containing • High therapeutic index, FDA does not find it appropriate to
avobenzone with ensulizole and • Extremely low risk in actual extend the labeling modifications for
avobenzone with zinc oxide will not be consumer use situations, OTC sunscreen drug products marketed
permitted unless and until the following • A favorable public health benefit, under § 352.52(f) to all OTC sunscreen
three actions occur: • No specified dosage limitation, and drug products. FDA disagrees with the
1. The comment period specific to • Few specific warnings and no comment’s argument that all sunscreen
this proposal closes. general warnings (e.g., pregnancy or products meet the criteria for reduced
2. FDA has evaluated all comments on overdose warnings). Drug Facts labeling (64 FR 13254 at
these combination products submitted The comment added that OTC 13270), because most sunscreen
in response to the proposal. sunscreen products are a unique products are not sold in small packages.
3. FDA publishes a Federal Register category substantially different from Therefore, because sunscreen products
notice announcing our determination to most other types of OTC drug products do not generally meet all of the criteria
permit the marketing of OTC sunscreen because they are recommended for use for reduced Drug Facts labeling, FDA is
drug products containing these on a daily basis to prevent serious not proposing reduced labeling for all
combinations. disease. The comment concluded that OTC sunscreen products.
FDA’s rationale for standardized FDA does not consider sunscreens as
D. General Comments on the Labeling of labeling format and content a unique category substantially different
Sunscreen Drug Products requirements does not necessarily from other types of OTC drug products
(Comment 8) One comment agreed because they are recommended for use
transfer to OTC sunscreen products and

that the labeling modifications allowed specifically not to drug-cosmetic on a daily basis to prevent serious
by the FM in § 352.52 for OTC products with a sunscreen. disease, as argued by the comment.
sunscreen products marketed as a When FDA created the standardized Other OTC drug products are used on a
lipstick or labeled for use only on labeling format and content daily basis, some to prevent serious
specific small areas of the face (e.g., lips, requirements (i.e., ‘‘Drug Facts’’ disease and some for other reasons. For
nose, ears, and/or around eyes) are labeling) for OTC drug products, we example, anticaries drug products are
used daily to prevent dental caries. remove.’’ This is useful information if a containers of 2 ounces (oz) or less (by
Antiperspirant drug products can be sunscreen product gets into the eyes. weight or liquid measure).
used daily to reduce underarm wetness. FDA agrees with part of the proposed The comment added that most facial
FDA has concluded that these various shortened warning for OTC sunscreen makeup products are typically packaged
products should generally be labeled drug products to ‘‘Stop use if skin rash in small containers. The comment stated
using the standardized content and occurs’’ in place of ‘‘Stop use and ask that to meet any of FDA’s concerns that
format in § 201.66. The standardized a doctor [bullet] if rash or irritation lotions and moisturizers sold in larger
labeling allows consumers to more develops and lasts.’’ Therefore, FDA is packages may be used over the entire
easily recognize that these products are, proposing to amend § 352.52(c)(1)(ii) body despite labeling that restricts use
in fact, drug products and to more easily (proposed § 352.52(c)(3)) to state: ‘‘Stop to the face or hands, FDA could limit
read and understand the labeling use and ask a doctor if [bullet] skin rash the flexible labeling to containers of 2 oz
information. occurs.’’ or less. Furthermore, the comment
The same principle applies when the FDA finds no reason to omit barlines, added that containers of 2 oz or less
product is a drug cosmetic product (e.g., hairlines, or the box enclosure for all could not feasibly include the full OTC
sunscreen moisturizer or antiperspirant OTC sunscreen drug products regardless drug labeling.
deodorant). Consumers need to be of package size. These labeling formats The second comment contended that
informed that the product has a drug help consumers identify a product as a the modified labeling in § 352.52(f) is
effect, and the uniform Drug Facts drug and help make labeling particularly compelling for color
labeling for all OTC drug and drug information easier to read and cosmetic products for the face that
cosmetic products helps convey this understand. Thus, they should be contain sunscreens (i.e., ‘‘facial
message. FDA applied this rationale included when package size allows. The makeups with sunscreen’’). The
when it finalized the requirements in FM already allows horizontal barlines comment added that these products and
the final rule that established § 201.66. and hairlines and the box enclosure to OTC sunscreen drug products for use
FDA agrees that some OTC sunscreen be omitted if a small package meets the only on specific small areas of the face
drug products meet the criteria for criteria in §§ 352.52(f) and have the same overall safety profile,
reduced information for safe and 201.66(d)(10). and, therefore, FDA should allow these
effective use (64 FR 13254 at 13270, 64 products to be labeled similarly.
Finally, FDA has no basis to provide A third comment strongly disagreed
FR 27666 at 27681 to 27682). However,
an option for sunscreen products to list with a specific labeling exemption for
FDA disagrees with most of the
inactive ingredients in labeling that makeup with sunscreen and moisturizer
modifications proposed by the comment
accompanies the products. FDA products for use on the face and hands.
for all package sizes of OTC sunscreen
interprets section 502(e)(1)(A)(iii) of the The comment contended that an
products. FDA disagrees with deletion
act (21 U.S.C. 352(e)(1)(A)(iii)) as exemption would not be in the best
of the ‘‘Drug Facts’’ title and the
requiring the inactive ingredients to be interest of consumers. The comment
‘‘Purpose’’ information because many
sunscreen products do not meet the listed on the outside container of a retail also argued that consumer confusion
parameters for reduced Drug Facts package or on the immediate container and subsequent misuse of sunscreen
labeling. if there is no outside container or products, particularly failure to apply
FDA disagrees that the ‘‘Purpose’’ wrapper (§ 201.66(c)). Because this adequate amounts of sunscreen or to
information is repetitive and, therefore, information, by law, must appear either reapply a product after certain activities,
disagrees that it may be omitted where on the outside container or immediate will occur if FDA permits reduced
there is sufficient labeling space. The container of the product, FDA does not labeling for these products. The
‘‘Purpose’’ section is a standard part of find a basis for allowing an option to list comment added that many consumers
Drug Facts labeling and is intended to the inactive ingredients in a different use face and hand cosmetic products
inform consumers which ingredients are location, such as other labeling with sunscreen as their primary and
sunscreens in a product. This accompanying the product. In only source of UV radiation protection
information is even more important accordance with § 201.66(c)(8), the for those areas of the body. Moreover,
when a sunscreen is marketed in a inactive ingredients must be listed on consumers are more likely to use these
combination product. For example, in a the product label in the ‘‘Drug Facts’’ products properly if they contain full
sunscreen skin protectant drug product, box. sunscreen drug labeling. The comment
the ‘‘Purpose’’ section informs (Comment 9) Two comments concluded that makeup foundations,
consumers which ingredients are supported extending the labeling in tints, blushes, rouges, and moisturizers
sunscreens and which are skin § 352.52(f) for products intended for use that are intended to be used on a daily
protectants. only on specific small areas of the face or frequent basis to protect against the
FDA has revised the ‘‘Uses’’ section and sold in small packages to all OTC adverse health and skin aging effects of
and deleted the statement ‘‘higher SPF sunscreen products. The comments acute and chronic sun exposure must be
gives more sunburn protection’’ (see contended that all OTC sunscreen drug labeled as drugs similar to other OTC
section III.G, comment 16 of this products meet most of FDA’s criteria for sunscreen products.
document). FDA disagrees with omitting products that require minimal FDA is not proposing to extend the
the ‘‘For external use only’’ warning for information for safe and effective use labeling modifications in § 352.52(f),
all OTC sunscreen drug products. FDA (64 FR 13254 at 13270) (see section which is specific for products used only
finds no basis to exclude all OTC III.G, comment 8 of this document). on small areas of the face and sold in
sunscreen products from this The first comment added that FDA small packages, to all OTC sunscreen
requirement. Likewise, FDA finds no should permit the labeling products. FDA has determined that most
reason to omit the two standard modifications in § 352.52(f) for the OTC sunscreen products should have
subheadings that accompany the following products: full drug labeling information using the
warning statements, as proposed by the • Makeup products (as defined in 21 standardized content and format in
comment. Further, FDA disagrees with CFR 720.4(c)(7)) with sunscreen, and § 201.66 to ensure the safe and effective
the comment’s suggestion to omit the • Lotions and moisturizers for the use of these products. In establishing
statement ‘‘Rinse with water to hands or face with sunscreen in the labeling modifications in § 352.52(f),
FDA determined how the labeling for use only on specific small areas of and clarifying that the labeling
information for sunscreen drug the face and that meet the criteria in modifications in § 352.52(f) apply to
products, including drug cosmetic § 201.66(d)(10). However, FDA does not both sunscreen and makeup with
products, could best be presented on agree that these labeling modifications sunscreen products. Furthermore,
products with limited labeling space should apply to all makeup products because lip products with sunscreen
and still provide consumers with identified in § 720.4(c) (21 CFR 720.4(c)) have substantially less labeling space
adequate information to use these that contain sunscreen, because most than the nonlip products with
products safely and effectively. are not sold in small packages and, sunscreen used only on specific small
Although any sunscreen products sold therefore, do not meet all of the criteria areas of the face and sold in small
in small packages that meet the criteria for reduced labeling (64 FR 13254 at packages, proposed § 352.52(f)(1)(vi)
in § 201.66(d)(10) are allowed the format 13270). Thus, most of these products allows more labeling exemptions for lip
exemptions under that section, FDA is can accommodate full Drug Facts products with sunscreen than other
also proposing content exemptions for labeling, and FDA finds no reason to products that are within the scope of
sunscreen products marketed under extend the labeling modifications in § 352.52(f).
§ 352.52(f). FDA is proposing these § 352.52(f) to all makeup with (Comment 10) Several comments
exemptions under § 352.52(f) because sunscreens products. recommended changing the acronym
sunscreen products labeled for use only As explained in the previous ‘‘SPF’’ from ‘‘sun protection factor’’ to
on small areas of the face and sold in paragraph, the labeling modifications in ‘‘sunburn protection factor’’ because the
small packages are generally sold in § 352.52(f) apply to makeup with latter definition is more descriptive of
packages substantially smaller than sunscreen products labeled for use only the use of OTC sunscreen drug products
other sunscreen products, even those on specific small areas of the face and and avoids giving consumers the
sunscreen products labeled for other sold in small packages. FDA also impression of solar invincibility and a
uses that meet the criteria in believes that any sunscreen products false sense of security.
§ 201.66(d)(10). that are used only on specific small FDA agrees. In § 352.52(b) of the
FDA continues to believe that areas of the face and sold in small sunscreen FM, FDA included only
requiring full Drug Facts labeling on packages meet FDA’s reduced labeling indications for sunburn protection (e.g.,
sunscreen products used only on criteria regardless of whether they are ‘‘helps prevent sunburn’’) (64 FR 27666
specific small areas of the face and sold drug or drug-cosmetic products. at 27691). In this document, FDA is
in small packages (i.e., § 352.52(f)) Therefore, FDA is proposing to amend proposing to change the word ‘‘sun’’ to
would discourage manufacturers from the heading of § 352.52(f) to read as ‘‘sunburn’’ in § 352.3(b)(1), (b)(2), (b)(3),
marketing some of these products for follows: ‘‘Products, including cosmetic- and (d) and § 352.52(e)(1)(i), (e)(1)(ii),
drug use. Many of these products, such drug products, containing any and (e)(1)(iii).
as sunscreen-lip protectant products, are ingredient identified in § 352.10 labeled Manufacturers can continue to use
sold in extremely small packages that for use only on specific small areas of existing labeling until the compliance
cannot accommodate the required the face (e.g., lips, nose, ears, and/or dates of a final rule based on this
labeling even with the format around the eyes) and that meet the proposal. However, FDA encourages
exemptions allowed under criteria established in § 201.66(d)(10) of
§ 201.66(d)(10). As explained in a manufacturers to revise any labeling
this chapter.’’ that states ‘‘sun protection’’ attributed to
number of rulemakings (64 FR 27666 at In addition, FDA is proposing to
27681 to 27682; 68 FR 33362 at 33371; sunscreen active ingredient(s) to the
extend the labeling exemptions, with
64 FR 13254 at 13270), these products new term ‘‘sunburn protection’’ as early
some modifications, currently allowed
meet the criteria for additional reduced as possible.
for lipsticks in § 352.52(f)(1)(vi) to the
labeling. Removal of these products following lip products with sunscreen, (Comment 11) Some comments
from the OTC market would have a as defined in § 720.4(c): questioned the constitutionality of the
negative impact on public health. FDA • Lipsticks, FM’s labeling provisions. Specifically,
believes that the benefit of UV radiation • Lip products to prolong wear of the comments contended that the FM’s
protection provided by these products lipstick, prohibition on the labeling of SPF
outweighs the need for manufacturers to • Lip gloss, and products over 30, its restrictions on skin
include all sunscreen labeling • Lip balm. aging claims, and its limitation of the
information. In contrast, FDA believes FDA has identified lip products to indications for use for OTC sunscreen
manufacturers of sunscreen products prolong wear of lipstick as ‘‘makeup drug products all violate the first
that are not within the scope of fixatives’’ under § 720.4(c)(7)(viii). Lip amendment to the U.S. Constitution.
§ 352.52(f) will continue to market their gloss and lip balm fall under ‘‘other The comments asserted that these bans
products even though full Drug Facts makeup preparations’’ in on allegedly truthful labeling in the FM
labeling is required. Unlike sunscreen § 720.4(c)(7)(ix). As long as these lip go well beyond constitutionally
products that meet § 352.52(f), the products with sunscreen are used only permissible restrictions on commercial
package size of products that do not on specific small areas of the face and free speech.
meet § 352.52(f) will accommodate full are sold in small packages (i.e., meet the One comment contended that FDA
Drug Facts labeling. criteria in § 201.66(d)(10)), they would had failed to meet its burden to
Although FDA is not extending the meet FDA’s reduced labeling criteria. As demonstrate that the claims at issue are
labeling modifications in § 352.52(f) to discussed earlier in this comment, FDA misleading or that the restrictions on
all OTC sunscreen products, as believes not allowing Drug Facts speech directly advance any substantial
labeling exemptions for these products governmental purpose. In addition, the
requested by the first and second

comments, we are allowing these would discourage manufacturers from comment claimed that any interest FDA
labeling modifications for certain marketing some of these products for has asserted in restricting the speech at
makeup with sunscreen products. drug use. In proposed § 352.52(f)(1)(vi), issue is served equally well, if not
Specifically, these labeling FDA is proposing to extend the labeling better, by regulations that do not restrict
modifications would apply to makeup modifications for lipsticks to other lip speech to the same extent as FDA’s
with sunscreen products that are labeled cosmetic products containing sunscreen regulations.
FDA disagrees with the comments for addresses, in part, the comments’ promote directly the proper use of
the following reasons. OTC drug request that FDA allow specific labeled sunscreens, which, in turn, would better
monographs establish conditions under SPF values over 30. ensure the protection of public health.
which ingredients for certain OTC uses Elsewhere in this document, FDA In addition, it would not be ‘‘unduly
are generally recognized as safe and explains the reasons for the specific burdensome’’ to sunscreen
effective (GRASE) and are not labeling proposals, such as the required manufacturers to require these labeling
misbranded. General recognition of SPF labeling, revised ‘‘sun alert’’ in the disclosures. Finally, it is important to
safety and effectiveness in an OTC drug ‘‘Warnings’’ section of the Drug Facts note that a sunscreen manufacturer
monograph means that experts qualified box, and indications for use (see section could pursue alternative labeling
by scientific training and experience III.F, comment 15 and section III.G, conditions for its product by filing an
recognize the conditions as safe and comments 16, 17, and 19 of this NDA with the appropriate evidence
effective for OTC marketing for the use document). FDA also explains our demonstrating the product’s safety and
recommended or suggested in the denial of specific labeling claims effectiveness under the proposed
product’s labeling. An OTC drug suggested by the comments, including conditions.
monograph establishes, among other the prohibition on specific SPF values In any event, FDA believes that the
things, specific indications that are over a certain threshold (SPF 50), skin labeling requirements outlined in this
appropriate for the safe and effective use aging claims, and additional indications proposed rule would pass muster when
of a drug. An OTC drug product with for use (see section III.F, comments 15 analyzed under the four-part test for
labeled indications different than those and 17 of this document). As noted restrictions on commercial speech set
set forth in an applicable OTC drug earlier in this comment, any variation fourth by the Supreme Court in Central
monograph would not be considered from these labeling conditions in the Hudson Gas & Electric Corporation v.
GRASE. monograph, if finalized, would cause an Public Service Commission, 447 U.S.
OTC drug monographs allow OTC sunscreen drug product to be a 557 (1980). Under the test, the first
manufacturers to market those products new drug requiring an approved NDA question is whether the commercial
satisfying the monograph standard before it could be legally marketed in speech at issue is false, misleading, or
without requiring the specific approval the United States. concerns unlawful activity, because
of the product by means of a new drug The labeling requirements in this such speech is beyond the first
application (NDA) under section 505 of proposed rule would not violate the first amendment’s protection and may be
the act. FDA has issued numerous OTC amendment. FDA’s requirements for the prohibited. If the speech is truthful,
drug monographs for certain categories disclosure of information in the labeling nonmisleading, and concerns lawful
of OTC drug products. If an OTC drug of OTC sunscreen drug products are activity, the Government may
product subject to a final monograph is constitutionally permissible because nonetheless regulate it if the
labeled for indications that differ from they are reasonably related to the government interest asserted to justify
those set forth in the monograph, then Government’s interest in promoting the the regulation is substantial, the
it would be a ‘‘new drug’’ under section health, safety, and welfare of consumers regulation directly advances the
201(p) of the act. In order to be legally and because they are not an ‘‘unjustified asserted governmental interest, and the
marketed and distributed in interstate or unduly burdensome’’ disclosure regulation is no more extensive than
commerce, the drug manufacturer requirement that offends the first necessary to serve the government
would be required to obtain approval amendment (see Zauderer v. Office of interest (Id. at 566). The Supreme Court
from FDA for that product, and those Disciplinary Counsel, 471 U.S. 626, 651 has explained that the last element of
conditions varying from the monograph, (1985); see also Ibanez v. Florida Dep’t the test is not a ‘‘least restrictive means’’
in an NDA under section 505 of the act. of Bus. and Prof’l Regulation, 512 U.S. requirement but, rather, requires narrow
All OTC drug monographs place 136, 146 (1994)). The reasonable tailoring (i.e., ‘‘a fit that is not
limits on the conditions that have been relationship between the required necessarily perfect, but reasonable’’
found acceptable for inclusion in the labeling disclosures proposed herein between means and ends) (Board of
monograph by an administrative and the Government’s interest is plain Trustees of the State Univ. of N.Y. v.
rulemaking process based on scientific here. Fox, 109 S.Ct. 3028, 3032–35 (1989)). In
data. Here, FDA set certain limits on the The proposed labeling disclosures subsequent decisions, the Court has also
labeling of sunscreen drug products in addressed by the comments, such as the clarified that ‘‘misleading’’ in the first
the final rule, such as the prohibition on SPF value, indications for use, and element of the test refers to speech that
specific SPF values over 30, certain skin revised ‘‘sun alert,’’ would contribute is inherently or actually misleading.
aging claims, and other indications for directly to the safe and effective use of Thus, if the speech to be regulated
use. FDA is maintaining similar labeling OTC sunscreen drug products. The SPF concerns lawful activity and is not
restrictions in this proposed rule with value and indications for use are critical inherently or actually misleading, the
respect to skin aging claims and other components of labeling that allow remainder of the test applies (see In re
indications proposed by the comments. consumers to understand more clearly a R.M.J., 455 U.S. 191, 203 (1982)).
Also, as described elsewhere in this sunscreen product’s use in preventing Based on the data currently available,
document, the revised ‘‘sun alert’’ in the sunburn and relative level of UVA/UVB FDA believes that the labeling
‘‘Warnings’’ section does not include protection. As explained elsewhere in statements proposed by the comments
any skin aging claims (see section III.G, this document, the revised ‘‘sun alert’’ (i.e., specific SPF values above FDA’s
comment 19 of this document). we propose to require in the established threshold, skin aging claims,
However, FDA is proposing to increase ‘‘Warnings’’ section would help and certain other indications) would not
consumers understand more clearly the be protected speech and may be
the SPF labeling limit from 30 to 50,

based on additional data that was role of sunscreens as part of a prohibited under the first prong of the
submitted subsequent to the issuance of comprehensive sun protection program Central Hudson test. FDA has
the FM. FDA is also proposing that the (see section III.F, comment 19 of this tentatively determined that these
term ‘‘SPF 50+’’ can be used, rather than document). The greater consumer proposed labeling statements would be
the term ‘‘SPF 30+’’ allowed in the FM. understanding resulting from all of inherently misleading on OTC
This increase in the SPF labeling limit these labeling conditions would sunscreen products sold and, thus,
misbrand the products under section SPF values above 50, there is no these short-term adverse effects of UV
502(a) and 201(n) of the act. Because assurance that the specific values radiation to a long-term, chronic effect
FDA believes these labeling statements themselves are in fact truthful and not such as skin cancer. In addition, like
are inherently misleading, they would misleading. Thus, labeling of specific skin aging, the complete action
not be subject to protection under the values above SPF 50 without spectrum for skin cancer is not known
first prong of the Central Hudson test. appropriate validation (which FDA at this time.
With respect to the labeling currently lacks) would be inherently For all these reasons, FDA has
limitations for SPF values, based on misleading. As noted elsewhere, FDA tentatively concluded that the available
current data, FDA believes that the invited any interested parties to submit evidence fails to show that sunscreen
labeling of sunscreens with specific SPF such validation data for consideration use alone helps prevents skin cancer or
values greater than 50 would be by FDA and possible inclusion of premature skin aging. Thus, the anti-
inherently misleading. As discussed specific values above SPF 50 in the FM. aging, skin cancer, and sun damage
elsewhere in this document, FDA is With respect to anti-aging, skin claims proposed by the comments
concerned with the accuracy and cancer, and sun damage claims would be false or misleading due to lack
reproducibility of test results showing proposed by the comments, as discussed of sufficient data in support of these
protection greater than SPF 50 due to elsewhere in this proposed rule, FDA is claims. For example, the statement
the lack of adequate validation data (see concerned that these statements would proposed by one comment that
section III.F, comment 15 of this be false or misleading due to lack of sunscreen use ‘‘may help prevent sun-
document). FDA had the same concern sufficient data in support of these induced skin damage, such as
with SPF values above 30 when we claims (see section III.F, comment 17 of premature skin aging’’ would be
published the FM in 1999. At that time, this document). FDA has reviewed the inherently misleading to consumers by
FDA had only received data submitted articles concerning UV- suggesting that sunscreen use alone may
demonstrating that the SPF test induced skin damage (i.e., premature help prevent premature skin aging. As
produces accurate results for products aging and cancer) along with the articles explained in this response, the available
with SPF values of 30 or less. Since obtained from a search of scientific data fail to show that sunscreen use
publication of the FM, FDA has received literature (Refs. 26 through 34). As alone helps prevent premature skin
additional SPF testing data for discussed elsewhere, although FDA has aging and skin cancer.
sunscreen products with SPF values concluded that the studies support the As described elsewhere, FDA is
between 30 and 50 (Ref. 13). However, conclusion that exposure to UV rays proposing a revised ‘‘sun alert’’ so that
FDA has not received any data for increase the risk of premature skin the labeling of OTC sunscreen drug
sunscreen products with SPF values aging, the study data fails to show that products include the most accurate
greater than 50. The data submitted to sunscreen use alone helps prevent information, based on the available
FDA indicate that the SPF test is premature skin aging and skin cancer scientific evidence, concerning the
accurate and reproducible for sunscreen for several reasons (see section III. F., relationship of sunscreen use to the
products with SPF values up to 50 (Ref. comment 17 of this document). prevention of sunburn, skin cancer, and
13). However, these data cannot be First, with respect to premature skin premature skin aging caused by UV
extrapolated to SPF values above 50. aging, the studies have not completely exposure (see section III.F, comment 19
Thus, FDA is proposing to allow defined the action spectrum for the of this document). The revised ‘‘sun
specific labeled SPF values only up to majority of UV radiation-induced effects alert’’ also includes a statement about
50. on human skin. Second, the inability to limiting sun exposure and wearing
Increasing variability in test results is identify the exact UVB and UVA protective clothing because FDA has
likely with increasing SPF values. If wavelengths that induce each tentatively determined that it is critical
there is large variability in test results, histological change in skin derives from for consumers to understand the role of
then the SPF value determined from the the study designs. Without knowing sunscreen use in a comprehensive sun
test is not accurate (i.e., an SPF 60 which UVB and UVA wavelengths protection program. As FDA has
product may not actually be an SPF 60 induce each histological change in the explained, the available evidence
product). The submitted data skin, FDA is unable to determine which strongly suggests that consumers rely
demonstrated that variability is not an wavelengths are most important to more heavily on sunscreens alone
issue for sunscreen products with SPF causing skin aging and cannot without taking other protective
values up to 50. However, FDA is determine the action spectrum for aging. measures against sunlight, particularly
concerned that variability will become Third, the studies did not examine the when the labeling of products indicates
an issue for sunscreen products with chronic, long-term consequences of UV the potential for greater protection (see
SPF values over 50. radiation exposure in human skin. section III.F, comment 19 of this
For those sunscreens with SPF values Fourth, although the studies that document). By indicating the potential
above 50, FDA is proposing that the examined the ability of sunscreens to for greater protection than is supported
labeling can denote such values by a protect against UV radiation-induced by the available evidence, the proposed
‘‘50+’’ designation. As discussed histological changes in the skin provide anti-aging, skin cancer, and other
elsewhere in this document, FDA has useful data, it is difficult for FDA to related claims would mislead
sufficient assurance that a result over 50 conclude that sunscreen use alone helps consumers into relying more heavily on
from the required SPF test is, in fact, prevent skin aging based on these sunscreens alone. Such excessive
greater than 50 and can be labeled studies. reliance would undermine consumers’
‘‘50+’’ (see section III. F, comment 15 of Likewise, FDA is not aware of data protection from the sun and, thus,
this document). Thus, FDA believes that demonstrating that sunscreen use alone
FDA’s public health mission.

the term ‘‘50+’’ is truthful and helps prevent skin cancer. Like skin FDA has also preliminarily
nonmisleading on the label of OTC aging, these are studies examining the determined that the proposed labeling
sunscreen drug products for which the effects of sunscreen drug products on statements would concern unlawful
SPF test in the monograph has indicated short-term factors for skin cancer, such activity which are not protected speech
an SPF value greater than 50. However, as sunburn and other cellular damage. under the first prong of the Central
without proper validation of specific However, it is difficult to extrapolate Hudson test.
FDA is proposing specific conditions activity would obviate the need for FDA Consumers are accustomed to using the
in the monograph under which OTC to address the other three prongs of the label as their primary source of
sunscreen drug products would be Central Hudson test, we believe that the information about a drug product’s
GRASE. Elsewhere, FDA explains how labeling requirements proposed in this contents and use. Neither a public
the labeling statements proposed by the document would satisfy each of the education campaign, nor encouraging
comments would not be appropriate parts of this test. With respect to the OTC drug product manufacturers to
monograph indications for these second prong, FDA’s interest in the provide information, such as that in the
sunscreen products (see section III.G, required labeling disclosures and proposed revised ‘‘sun alert,’’ to
comment 17 of this document). Thus, prohibitions addressed by the comments consumers by other means, would
the proposed labeling statements would contribute directly to the safe ensure that people have the information
outside the proposed indications of the and effective use of these OTC they need about sunscreen products at
final monograph, as FDA proposes to sunscreen drug products, which is the point of sale or use. Likewise, with
revise it, would promote a sunscreen critical for the protection of public respect to the alternative labeling
drug product for use as an unapproved health. FDA’s interest in protecting the statements proposed by the comments,
new drug, which is illegal. In addition, public health has been previously FDA’s proposed indications and revised
any variation in the statements in a upheld as a substantial government ‘‘sun alert’’ present the relevant public
‘‘Warnings’’ section of a final interest under Central Hudson (see health information to consumers in the
monograph, such as the revised ‘‘sun Pearson v. Shalala, 164 F.3d 650, 656 clearest and most direct manner. Thus,
alert’’ statement in this proposed rule, (D.C. Cir. 1999) (citing Rubin v. Coors FDA’s proposed indications and
would be outside the monograph Brewing Co., 514 U.S. 476, 484–485 prohibition of other labeling statements
conditions and, thus, would promote (1995)). are not more extensive than necessary.
the product as an unapproved new drug. The proposed labeling requirements In this way, the required labeling
The marketing and distribution in would directly advance this interest, disclosures and prohibitions proposed
interstate commerce of an OTC thereby satisfying the third prong of the in this document would meet the fourth
sunscreen drug product with such Central Hudson test. By requiring prong of the test.
labeling variations would be prohibited labeling disclosure of the SPF value, the Furthermore, the proposed
under sections 301(d) and 505(a) of the proposed revised ‘‘sun alert,’’ and prohibition of claims in a final
act. Speech promoting such an illegal indications for use, FDA can better monograph does not prevent such
activity may be restricted without assure that consumers understand more claims from being approved in an NDA.
violating the first amendment (Central clearly the use of sunscreens in As explained previously, a final
Hudson, 447 U.S. at 563–564). preventing sunburn, their relative UVA/ monograph sets forth those conditions,
If a manufacturer could circumvent UVB protection, and their role as part of including labeling, under which an OTC
the requirements and restrictions a comprehensive sun protection drug product would be considered
imposed by a final monograph by program. The greater consumer GRASE and not misbranded. In issuing
including nonmonograph labeling understanding resulting from all of monographs, FDA considers whether
statements, or excluding required these labeling conditions would the available scientific evidence
monograph statements, based on its own promote directly the proper use of demonstrates that OTC drug products
assertions of the alleged appropriateness sunscreens, which, in turn, would better within a therapeutic category are
and truthfulness of the statements, then ensure the protection of the public GRASE. A final monograph does not
such activity would significantly health. constitute an FDA decision regarding an
undermine the monograph system and Likewise, this proposed rule’s NDA for an OTC drug proposing
FDA’s assurance that OTC drugs are safe exclusion from the monograph of the variations in these conditions. Thus,
and effective for their labeled labeling statements proposed by the FDA’s proposals in this document
conditions. FDA has assessed the comments also directly advances FDA’s would not prohibit any interested
labeling statements proposed by the public health interest. FDA has manufacturer from filing an NDA, with
comments and preliminarily determined preliminarily determined from the the appropriate evidence, for any
that they are not justified by the available evidence that these statements variations from the monograph labeling
available scientific evidence as GRASE would not be appropriate conditions for conditions. Because of this significant
conditions for the monograph. Instead, OTC use under the monograph. Thus, available option to manufacturers for
in order to legally market a sunscreen the statements would directly proposing alternative labeling
drug product with such labeling undermine the protection of public statements, FDA’s proposed labeling
statements, an interested manufacturer health. In addition, it is important to requirements and prohibitions are not
would have to submit an NDA to FDA note that the Pearson court, in assessing more extensive than necessary.
with the appropriate evidence to show whether the specific dietary supplement In conclusion, FDA believes it has
the safety and effectiveness of the drug regulations at issue directly advanced complied with its burdens under the
under the proposed nonmonograph FDA’s stated public health goals under first amendment to support the labeling
labeling conditions. Requiring the third prong of the Central Hudson requirements of this proposed rule.
premarket FDA review and test, explained that its findings under (Comment 12) One comment stated
authorization of such nonmonograph this prong did not apply to drugs, where that voluntary professional labeling can
drug claims ensures that such claims ‘‘the potential harm is presumably much be provided to physicians that will
will be evaluated by a public health greater’’ than other products (Pearson, allow them to select or recommend
agency that has scientific and medical 164 F. 3d at 656, n 13). sunscreen products for their patients’
Finally, under the fourth prong of the needs, based on more detailed
expertise so that only products that are

safe and effective will be permitted to be Central Hudson test, there are not information describing the quantity
sold for therapeutic purposes. numerous and obvious (Cincinnati v. (protection factor) and the range of UV
Although this preliminary- Discovery Network, 507 U.S. 410, 418 n. protection (e.g., UVB, UVA, or UVB/
determination that the labeling 13 (1993)) alternatives to the required UVA protection). Another comment
statements at issue would be inherently labeling statements or labeling stated that FDA should not require
misleading and would concern unlawful prohibitions proposed herein. professional labeling because complete
and accurate product labeling should be FDA disagrees with the comment This comment referred to The Japan
available to all consumers, not just to contending that manufacturers will only Cosmetic Industry Association (JCIA)
their health care providers. produce the minimum SPF value in a Measurement Standards for UVA
FDA defines professional labeling in given PCD range because they can use Protection Efficacy (Ref. 6), which
OTC drug monographs as labeling that less active ingredients and get the same recommend labeling UVA protection as
is provided to health professionals but PCD classification. Section 352.50 of the three grades: (1) PA+, (2) PA++, or (3)
not to the general public (i.e., not current FM requires the SPF value to PA+++.
directly to consumers) (for example, see appear on a sunscreen product’s PDP. Several comments recommended two
§ 331.80 (21 CFR 331.80)). In the final This proposed rule would not change categories of UV protection labeling
rule, FDA stated that it would consider that requirement. Thus, while the PCD based on the ratio of UVA radiation
professional labeling, such as protection provides additional information about protection factor to SPF value:
against photosensitization reactions, if the SPF value, consumers seeking • ‘‘with UV protection’’ if ratio equals
data were received (64 FR 22666 at higher SPF values can readily identify 0.20
27674). FDA has not received any data such products by the SPF value stated • ‘‘with extra UV protection’’ if ratio
to date. Therefore, FDA is not proposing on a sunscreen product’s PDP. equals 0.25
any professional labeling in this The proposed ratio is based on the UVA
document. FDA will consider E. Comments on the Labeling of radiation protection factor as
professional labeling for OTC sunscreen Sunscreen Drug Products With UVA determined by the persistent pigment
drug products in the future if specific Protection darkening (PPD) test method (see
supportive data are provided. (Comment 14) Many comments section III.N, comment 46 of this
(Comment 13) Some comments discussed ways to categorize, phrase, document). These comments stated that,
objected to the ranges of SPF values that and display UVA/UVB radiation because the ratio of damage from solar
define the product category designations protection on an OTC sunscreen drug UVB radiation to that of solar UVA
(PCDs) in § 352.3(b). Stating that product label. All of the comments radiation is 80:20 over a day, a
standard public health messages stated that the SPF value should retain sunscreen must protect against an 80:20
recommend use of a sunscreen with at preeminence on the label’s PDP and be ratio of UVB to UVA radiation. The
least an SPF of 15, the comments the consumers’ criteria for choosing an comments also recommended that
contended that the ‘‘moderate’’ PCD OTC sunscreen product. Some products labeled ‘‘with UV protection’’
(SPF values of 12 to under 30) may comments recommended that UVA or ‘‘with extra UV protection’’ exhibit
cause consumers to believe that SPF radiation protection be stated on the absorbance of 360 nanometers (nm) and
values of less than 15 provide adequate PDP in descriptive words or simple longer wavelengths.
protection. One comment further stated phrases, rather than numbers or Another comment suggested two
that if the PCD range is from SPF 12 to symbols, for the following reasons: categories to state overall UV radiation
29, manufacturers will only produce the • Simplicity, protection: ‘‘regular’’ and ‘‘broad
minimum SPF value as they can use less • Clarity, spectrum.’’ The comment proposed that
active ingredients and get the same PCD • To avoid confusion with SPF, and the ratio of a sunscreen product’s SPF
classification. • To maximize consumer value to its UVA protection factor be the
As discussed in the final rule (64 FR comprehension. single criterion for the ‘‘broad
27666 at 27681), the PCD ranges in Some comments referenced consumer spectrum’’ designation, with the
§ 352.3(b) and § 352.52(e) reflect a research, discussed in subsequent maximum ratio no greater than 4:1. For
modified, simpler, combined version of paragraphs, to support this example, an SPF 16 product would need
the previously proposed five PCDs and recommendation (Refs. 4 and 5). to provide a UVA protection factor of at
the ‘‘Recommended Product Guide.’’ One comment suggested the following least 4 to be designated ‘‘broad
However, FDA agrees with the labeling statements: spectrum.’’
comments that the current standard • ‘‘Protects against UVA rays’’ One comment disagreed with the
public health message from public • ‘‘screens out UVA rays’’ previous comment, stating that there is
• ‘‘shields from UVA rays’’
health organizations generally • ‘‘broad spectrum sunscreen’’ no supportable scientific basis for the
recommends use of a sunscreen with an • ‘‘UVA/UVB protection’’ relevance of the 4:1 ratio. The comment
SPF value of at least 15 (see section • ‘‘provides protection against both argued that the ratio inappropriately
III.G, comment 19 of this document). We UVB and UVA rays’’ combines, in the same equation, SPF
also agree that allowing SPF values • other truthful and nonmisleading values obtained with a solar simulator
below 15 in any but the lowest PCD statements describing a quantification of and solar irradiance values at low sun
range may appear to contradict this the product’s UVA radiation protection angles.
message. Therefore, FDA is proposing to The comment stated that quantification Another comment suggested that
modify the PCD SPF value range in of the UVA radiation protection should sunscreen products with an SPF value
proposed § 352.3(c)(1) from ‘‘2 to under be allowed in labeling, but not required, of 2 or greater must have a UVA
12’’ to ‘‘2 to under 15’’ and in proposed so that consumers can have additional protection factor of at least 2 to be
§ 352.3(c)(2) from ‘‘12 to under 30’’ to product performance information to labeled ‘‘UVA/UVB’’ or ‘‘broad
‘‘15 to under 30.’’ FDA is also proposing help them select appropriate products. spectrum protection.’’ The comment
to replace the PCD terms ‘‘minimal’’ and Another comment stated that UVA stated that products with SPF values of
‘‘moderate’’ with the simpler terms radiation protection should be labeled at least 15 and UVA protection factors
‘‘low’’ and ‘‘medium,’’ respectively, and only as grades of effectiveness (multiple of at least 4 may be labeled ‘‘extra (or
to use these simpler terms for the UVA
levels) for the following reasons: extended or enhanced) UVA

radiation protection categories (see • UVA radiation irritation induces protection.’’ The comment stated that
section III.E, comment 14 of this various skin reactions (e.g., erythema, these criteria are independent of test
document). These labeling changes will pigment darkening, skin cancer, and method and should apply to any of the
provide consumers with familiar and photodermatitis), and proposed UVA radiation test methods.
consistent terms describing both UVA • Some action spectra of damages Another comment proposed
and UVB radiation protection. have not been determined. establishing PCDs based on the UVA
radiation protection value obtained by and ease of product selection (Ref. 7). • 3-level descriptive (labeled blank if
the PPD test method. The comment Other comments provided consumer no UVA radiation protection provided
suggested four PCDs that would enable research data, discussed elsewhere in or labeled ‘‘UVA and UVB Protection’’
consumers to choose the desired levels this comment, suggesting this approach or ‘‘UVB Plus Extended UVA
of protection: was least preferred by consumers (Refs. Protection,’’ depending on the level of
• ‘‘moderate’’ 4 and 8). UVA radiation protection provided).
• ‘‘high’’ One comment stated that UVA The studies included focus group
• ‘‘very high’’ radiation protection claims should be discussions and indepth interviews. The
• ‘‘extra’’ allowed for sunscreen products with comment stated that the data suggested
Another comment recommended three SPF values of 4 and higher. The that a numeric designation for UVA
PCDs: comment added that, for products radiation protection (in addition to the
• ‘‘low UVA protection’’ claiming to protect against UVA and SPF value) created confusion for
• ‘‘moderate UVA protection’’ UVB radiation, a minimum UVA consumers and that symbols (i.e., stars)
• ‘‘maximum UVA protection’’ protection factor of 2 should be required misled consumers into giving equal or
Another comment suggested using the if the SPF value is less than or equal to greater importance to the UVA radiation
five PCDs proposed in the TFM (58 FR 12. rating compared to the SPF value. The
28194 at 28295) and added a UVA Several comments stated that comment concluded that a descriptive
protection factor number for each PCD sunscreen drug products labeled as ‘‘full approach better conveyed to consumers
based on the immediate pigment spectrum’’ or ‘‘broad spectrum’’ should the added benefit of UVA protection
darkening (IPD) test method. protect consumers from substantially all without detracting from the SPF value.
Two comments recommended a four- Another comment described two
of the harmful effects of the sun,
star rating system to describe UVA consumer research studies conducted in
including sunburn associated with UVA
radiation protection. The comments 1999 (Ref. 7) in which 2,238 consumers
radiation. According to one comment,
stated that this system, based on the assessed three sunscreen product
sunscreen drug products labeled ‘‘full
ratio of UVA to UVB radiation labeling systems:
spectrum’’ or ‘‘broad spectrum’’ that do
absorbance, would provide a simple
not protect against nearly all UVB and • A pass/fail descriptive (labeled
method for consumers to determine the
UVA radiation wavelengths seriously blank if no UVA protection provided
protective nature of an OTC sunscreen
risk misleading consumers into (i.e., fails) or labeled ‘‘Broad Spectrum
drug product. The absorbance ratio
believing they are fully and completely UVA and UVB Protection’’ if UVA
would range from 0 for products
protected from the dangers of the sun. radiation protection provided (i.e.,
exhibiting no protection against UVA
One comment recommended using the passes)),
radiation to 1 for products exhibiting
claim ‘‘full spectrum’’ rather than • A 3-level descriptive (labeled blank
equal absorption at all wavelengths
‘‘broad spectrum’’ to describe products if no UVA radiation protection provided
throughout the UVA/UVB radiation
that attenuate more than 90 percent of or labeled ‘‘UVA and UVB Protection’’
spectrum. Using this ratio, products
UVA radiation and are at least SPF 15. or ‘‘UVB Plus Extended UVA
would be classified in one of the
The comment suggested no UVA Protection,’’ depending on the level of
following five categories:
radiation protection claims be allowed if UVA radiation protection provided),
• 0 to < 0.2 = no UVA radiation
the product is below SPF 15. and
protection claim
• 0.2 to < 0.4 = Moderate (★) In support of their proposed UVA • A 3-level grapho/numerical (a bar
• 0.4 to < 0.6 = Good (★★) labeling, a number of comments graph indicating a level, 4, 8, or 12, with
• 0.6 to < 0.8 = Superior (★★★) provided results from consumer the corresponding number appearing
• 0.8 plus = Maximum (★★★★) research studies that assessed consumer alongside the graph).
Another comment recommended a labeling preferences for stating UVA The comment stated that the data
five point rating system using the radiation protection. One comment suggested the pass/fail descriptor,
‘‘critical wavelength’’ (CW) (λc) test described a 1996 survey (Ref. 4) in ‘‘broad spectrum,’’ was significantly
method. This system uses a scale which 275 subjects compared two superior to the other labels and
analogous to the star rating system to labeling systems: recommended that FDA use this
assign products a ‘‘broad spectrum’’ • 3-level descriptive (‘‘light,’’ labeling to designate UVA radiation
rating as follows: ‘‘intermediate,’’ or ‘‘extended’’ ‘‘UVA protection.
• λc < 325 = ‘‘0’’ protection’’) and Another comment described a
• 325 < λc < 335 = ‘‘1’’ • Grapho/numerical (a bar graph consumer research study conducted in
• 335 < λc < 350 = ‘‘2’’ indicating a level, 0, 4, 8, or 12, with the 2000 (Ref. 8) at 20 urban and suburban
• 350 < λc < 370 = ‘‘3’’ corresponding number appearing shopping malls in which 1,921 subjects
• 370 < λc = ‘‘4’’ alongside the graph). ranked four labeling systems:
Several comments supported a single The comment stated that the survey data • 4-level numerical,
claim, such as ‘‘provides broad suggested that, while equally able to • 4-level symbolic,
spectrum protection against UVB and understand both types of labels, the • 4-level descriptive, and
UVA radiation,’’ based on determining a panelists preferred the grapho/ • Pass/fail descriptive (‘‘with/without
sunscreen pass/fail CW (λc). Comments numerical system over the descriptive broad spectrum UVA/UVB protection’’).
that supported this ‘‘broad spectrum system. The numerical labeling system was
protection’’ claim stated that, in Another comment described two shown as Arabic numerals ‘‘1, 2, 3, 4’’
combination with SPF, it provides consumer research studies, conducted with the number ‘‘2’’ highlighted. The
simple and accurate labeling that is in 1994 and 1995 (Ref. 9), in which 235 descriptor labeling system was shown as
easily understood by consumers. The subjects compared three potential UVA the words ‘‘Minimum, Moderate, High,
comments referred to a research study radiation labeling options: Maximum’’ with the word ‘‘Moderate’’
that suggested this approach to UVA • Numerical (2, 3, or 5), highlighted. The symbolic labeling
radiation protection labeling was • Symbolic (4 stars with 1, 2, 3, or 4 system was shown as a picture of four
superior for consumer comprehension stars filled), and stars with two stars highlighted.
The comment concluded that the symbols) similar to those described by category descriptors for UVA radiation
subjects had a significant preference for some of the comments. The category protection must be the same size as the
a labeling system based on descriptive descriptors and stars will designate SPF value and its descriptors. All four
words or numbers because of clarity, relative levels of UVA radiation stars must appear and be preceded by
specificity, and ease of comprehension. protection as measured by the UVA the term ‘‘UVA’’ and followed by the
Subjects least preferred the pass/fail radiation test methods. The level of appropriate category descriptor (e.g.,
system because they found it unclear, UVA radiation protection identified on UVA ★★★✰ High). All star borders and
nonspecific, and lacking sufficient the label reflects the following: the color inside a solid star must be the
information to compare sunscreen • A numerical ‘‘UVA protection same while the color of ‘‘empty’’ stars
products. This study also revealed that factor’’ (from the clinical test), and must be lighter and distinctively
the numerical labeling system was one • A numerical ratio of UVA I (340 to different than solid stars. The color
of the top two choices because numbers 400 nm) radiation absorption to UVB/ inside a solid star must be distinctively
were ‘‘clearer, more specific, and easier UVA (290 to 400 nm) radiation different than the background color. The
to understand.’’ Age, gender, and absorption (from the in vitro test). stars must be filled in starting with the
educational or ethnic background were The test that indicates the lowest level first star on the left and must appear in
reported as not affecting the study of UVA radiation protection determines a straight horizontal line.
results. the level identified on the label. For As requested by some comments, an
In the TFM for OTC sunscreen drug example, if the clinical test indicates OTC sunscreen drug product that does
products (58 FR 28194 at 28233), FDA ‘‘low’’ protection and the in vitro test not provide the minimum UVA
proposed to allow claims relating to indicates ‘‘medium’’ protection for a protection, as determined by the
‘‘broad spectrum protection’’ or ‘‘UVA product, the product is labeled as proposed UVA test methods, may only
radiation protection’’ for OTC sunscreen providing ‘‘low’’ UVA radiation display an SPF value on the PDP. An
products that meet the following two protection. This system comprises four OTC sunscreen drug product is not
criteria: categories of UVA radiation protection required to provide UVA protection and
1. Contain sunscreen active as described in table 1 of this document. may bear only a sunburn (UVB/SPF)
ingredients with absorption spectra protection claim. However, FDA is
extending to 360 nm or above, and TABLE 1.—OVERALL UVA PROTEC- proposing that a sunscreen product that
2. Demonstrate meaningful UVA TION OF A SUNSCREEN DRUG does not provide at least a ‘‘low’’ level
radiation protection using appropriate of UVA protection include the following
testing procedures to be developed.
PRODUCT
statement on the PDP: ‘‘no UVA
In the FM for OTC sunscreen drug protection.’’ This statement must be the
Star category Category descriptor
products (64 FR 27666 at 27672), FDA same font size as the SPF value and its
stated that UVA radiation labeling of ★✰✰✰ Low descriptor. FDA is not proposing four
OTC sunscreen drug products could ★★✰✰ Medium empty stars because we are concerned
continue in accordance with the TFM ★★★✰ High
that consumers may confuse products
and its amendments until addressed in ★★★★ Highest
providing no UVA protection (i.e., four
a future issue of the Federal Register.
Some of the comments argued that the empty stars) with those providing the
Elsewhere in this document, FDA is
UVB radiation protection labeling is highest UVA protection (i.e., four filled
proposing test methods for determining
more important than UVA radiation stars).
the UVA radiation protection potential In developing this UVA radiation
of an OTC sunscreen drug product (see protection and should be emphasized in
protection labeling, FDA has
section III.N, comment 46). the labeling over UVA radiation
particularly considered the label
FDA believes that the existing data do protection. FDA disagrees with the
comprehension studies (Refs. 4, 7, 8,
not clearly define the relationship comments and proposes that the UVA
and 9). These studies used multiple
between UVA radiation and skin radiation protection designation appear
methodologies and report a diverse
damage. The principal reason for not on the PDP along with the SPF value in
range of preferences for each labeling
better understanding this relationship is an equally prominent manner that does
system:
that the action spectra for specific types not conflict with the SPF value. Because
• Category descriptors,
of UVA radiation-induced skin damage action spectra for UV-induced skin • Graphics,
(i.e., which wavelengths of UVA cause damage have not been clearly defined, • Symbols,
which types of skin damage) have not FDA is unable to specify labeling for • Numerics, and
been established. However, most OTC sunscreen drug products that • ‘‘Pass/fail’’ descriptors.
scientific data demonstrate that UVA indicates what ranges of UV radiation The diverse results and varying
radiation is harmful to the skin. Thus, are most harmful to consumers. In other methodology make it difficult to
until these action spectra are known, words, FDA cannot conclude whether identify a clear preference for one
FDA believes that more protection UVB or UVA radiation is more harmful labeling system. However, the studies
against UVA radiation damage is better to humans based on the scientific data indicate an overall preference for
for consumers’ health. Therefore, FDA collected to date. Therefore, FDA category descriptors.
believes it is important, as with the SPF considers both UVB and UVA radiation In agreement with the studies, FDA is
value, to designate UVA radiation protection equally important at this time proposing category descriptors to
protection in a straightforward manner because scientific data demonstrates indicate the relative level of UVA
that consumers clearly understand. that both have harmful effects on the radiation protection. As discussed in
FDA proposes that the UVA radiation skin. preceding paragraphs, FDA believes
protection of an OTC sunscreen drug So that consumers consider UVB and consumers should consider UVB and
product determined from these UVA UVA radiation protection equally in UVA radiation protection equally when
test methods be designated on the PDP selecting an OTC sunscreen drug selecting an OTC sunscreen drug
using a combination of category product, FDA is proposing a number of product. For this reason, FDA is
descriptors (i.e., ‘‘low,’’ ‘‘medium,’’ labeling requirements. Under this proposing that stars be used with
‘‘high,’’ or ‘‘highest’’) and stars (i.e., proposal, the font size of the stars and category descriptors. FDA believes that
the category descriptor and star labeling sunscreen product labels (alongside To prevent consumer confusion about
for UVA radiation protection will give it these more general statements). UV radiation protection, FDA is
equal prominence with UVB radiation Although none of the studies proposing changes to UVB radiation
protection (i.e., category descriptor and combined labeling systems as proposed protection labeling (i.e., the SPF value).
SPF) on the PDP. in this document, FDA believes the SPF values indicate how effective a
FDA is not proposing grapho/numeric studies support use of category sunscreen product is in protecting
labeling because we are concerned that descriptors and symbols together. One against sunburn. By displaying the
consumers may be confused by a second study suggested that symbols may imply relative level of sunburn protection on
number on the PDP (i.e., in addition to importance over SPF values (Ref. 9). the sunscreen drug product PDP in
the SPF value). FDA is also not However, FDA believes consumers will terms of an SPF value, consumers can
proposing any of the simple two- not place greater importance on UVA choose their desired level of UVB
category designations suggested by the protection because we are proposing a radiation protection. To further improve
comments: required statement to inform consumers consumers’ understanding of the
• With/without UVA protection, about the importance of both UVB and sunburn protection level provided by a
• With UVA protection/with extra UVA protection. We are proposing to certain sunscreen product, FDA is
UVA protection, or require one of the following statements proposing to require descriptive terms
• Regular/broad spectrum protection. on the PDP of all OTC sunscreen drug of relative sunburn protection (i.e.,
FDA agrees with one of the comments, products: ‘‘low,’’ ‘‘medium,’’ ‘‘high,’’ and
which argued that these types of • ‘‘UV rays from the sun are made of ‘‘highest’’) to accompany the SPF value
statements are misleading. FDA does UVB and UVA. It is important to protect on the PDP. FDA is further proposing
not consider this labeling as providing against both UVB & UVA rays.’’ that the SPF value must be preceded by
consumers with enough information • ‘‘UV rays from the sun are made of the term ‘‘UVB’’ to further differentiate
about the magnitude of UVA protection UVB and UVA. It is important to protect the SPF value from the UVA symbol/
offered by an OTC sunscreen product. against both UVB & UVA rays to prevent descriptor on the PDP. FDA believes
However, FDA does not object to the use sunburn and other skin damage.’’ that numerical labeling for UVB
of the following four statements for OTC FDA believes that the use of one of these protection, symbolic labeling for UVA
sunscreen drug products that satisfy the statements, along with the proposed protection, and the same descriptive
requirements of proposed § 352.73 for a UVB and UVA radiation protection labeling for UVB and UVA protection
labeled UVA protection value: labeling, including the format will allow consumers to easily
• ‘‘broad spectrum sunscreen’’, requirements described in preceding understand and choose from relative
• ‘‘provides [select one of the paragraphs, will lead consumers to view levels of UVB and UVA radiation
following: ‘UVB and UVA,’ or ‘broad UVB and UVA radiation protection as protection.
spectrum’] protection’’, equally important. FDA is aware that consumers have
• ‘‘protects from UVB and UVA In addition, this statement will used and become accustomed to
[select one of the following: ‘rays’ or educate consumers about UVA choosing OTC sunscreen drug products
‘radiation’]’’, and radiation, which will be a new term and based on the SPF value for many years.
• [select one of the following: concept to many consumers. The Likewise, FDA believes that, over a
‘‘absorbs’’ or ‘‘protects’’] ‘‘within the proposed statement should help period of time, consumers will similarly
UVA spectrum’’. consumers better understand the new become accustomed to the proposed
These statements may appear elsewhere UVB and UVA labeling when it is labeling using symbols and descriptors
in product labeling outside the ‘‘Drug initially introduced to the OTC market. to designate relative UVA radiation
Facts’’ box or enclosure but not Thus, FDA believes that the consumer protection. Furthermore, FDA believes
intermixed with the information label comprehension studies, along with consumer familiarity with similar star
required on the PDP under § 352.50. the proposed educational statement rating systems (e.g., movies, hotels, and
FDA agrees with some comments that about UVB and UVA radiation, support restaurants) used for many years in the
these statements, by themselves, may be the stars and descriptor UVA radiation United States provide a basis for
misleading by implying that a sunscreen protection labeling proposed in this consumers’ understanding of this
protects against nearly all UVB and document. Moreover, a similar ‘‘star proposed labeling for OTC sunscreen
UVA radiation. However, FDA does not rating system’’ for UVA radiation drug products.
believe these optional statements will be protection (i.e., the Boots Star System) FDA is providing a number of
misleading in the context of the entire has been used to label sunscreen examples of how the UVA/UVB
label, because the relative level of UVB products throughout Europe for over 10 protection designations could appear on
and UVA protection must be stated on years. the PDP.
FDA believes that, as with SPF values, want the many currently marketed A foreign industry organization
identifying the relative level of UVA sunscreens that are labeled as ‘‘SPF 45, suggested an upper limit for labeled SPF
radiation protection provides the most SPF 50, etc.’’ Thus, the comments values of 50+ and provided three
useful information for consumers. argued that U.S. consumers will be at a reasons:
Consumers who desire more protection disadvantage within the international • Unreasonably high SPF values will
from the sun will be able to identify community, because products providing lead consumers to expect ‘‘too much
products with higher UVB (SPF) and SPF values over 30 are available in other effectiveness’’ from sunscreen products.
UVA radiation protection. FDA agrees countries. In addition, the comments • Higher concentrations of sunscreen
with the comments that a product must stated that many prominent medical active ingredients are not ‘‘in the
provide at least some minimum level of authorities maintain the need for high interest of safety.’’
UVA radiation protection (as with SPF SPF sunscreens for individuals at ‘‘high • Higher SPF values will invite
values) to be labeled as providing UVA risk’’ based on medical and/or excessive, meaningless competition in
radiation protection. Therefore, FDA is occupational concerns and individuals the industry.
proposing minimum criteria for the who desire increased protection from The comment explained that
lowest UVA category in its proposed photoaging and lengthy/intensive sun competition would be meaningless
test procedures (see section III.N, exposure situations. The comments because the amount of UV protection
comment 46 of this document). argued that the need for high SPF provided by products with SPF values
sunscreens is supported by findings that above 50 is not significantly greater than
F. Comments on the Labeling of products with an SPF of 50.
Sunscreen Drug Products With High SPF UV exposures in several cities are
considerably higher than previously Another comment from a sunscreen
Values manufacturer agreed with FDA’s
recognized and because high SPF
(Comment 15) Several comments concern about the possibility of
products can reduce cumulative UV
objected to FDA limiting specific increasing variability when testing high
exposure. The comments stated that
labeled SPF values ‘‘up to but not above SPF sunscreens. The comment
consumer desire for high SPF products
30.’’ The comments stated that data and suggested a modified ‘‘binomial’’ test
information supplied to FDA since is demonstrated by sales data showing
method and labeling requirements for
publication of the sunscreen FM that products with an SPF value of 45
SPF values over 20 that would allow for
demonstrate that SPF values over 30 can are one of the fastest growing segments
high SPF products.
be safely tested with accuracy. The of the total sunscreen market. Another comment submitted a
comments also argued that removing the The remaining comments discussed published survey of 208 sunbathers on
limit will not lead to consumers the consequences of limiting the Miami’s South Beach during July 2001
spending more time in the sun when specific labeled SPF value. For example, with the goal of measuring UV radiation
using high SPF sunscreens in one comment noted that if exposure and probable injury (Ref. 10).
comparison to low SPF sunscreens. To manufacturers cannot state the SPF The ‘‘worst case’’ scenario identified by
address that point, one comment level above 30, they will no longer have the survey was based on sunbathers
proposed labeling to help reduce an incentive to fund research for better with Type I skin (persons most sensitive
potential consumer misuse of sunscreens. In addition, manufacturers to sunlight who burn easily and never
sunscreens with SPF values over 30: may reformulate products to reduce tan) exposed to UV radiation near the
‘‘higher SPF products give more sun active ingredients and, thus, reduce the longest day and highest sun angle of the
protection, but are not intended to level of UV protection. A comment year at the ‘‘southern-most major beach’’
extend the time spent in the sun.’’ argued that another adverse in the United States. The survey was a
Another comment noted that the SPF consequence results from most followup to one conducted in 1993 with
value, in addition to proper sunscreen consumers failing to achieve the labeled 62 sunbathers and evaluated by FDA in
SPF value because they do not apply
application and reapplication, is only the FM (64 FR 27666 at 27674). The

part of a comprehensive sun protection enough sunscreen and/or reapply it too 2001 survey determined MEDs absorbed
program. infrequently. Because high SPF by the following three steps:
Other comments explained the need products can help make up for such 1. Measuring incident UV radiation
for high SPF sunscreen products. The improper use, limiting the specific (using three dosimeters),
comments contended that consumers labeled SPF value to 30 has a negative 2. Multiplying by an adjusting factor
EP27AU07.003</GPH>
and physicians are familiar with and impact on UV protection. for skin type (using a 30 percent
increase in sensitivity between skin active ingredients are not ‘‘in the document, FDA is proposing UVA
types), and interest of safety’’ did not supply any radiation testing methods and labeling
3. Dividing by the SPF worn by the new data to support its contention. FDA that will categorize the relative levels of
sunbather. will continue to monitor adverse drug protection provided by the SPF and
The survey suggests that sunbathers experience reports for sunscreen drug UVA values of the sunscreen product
with Type I skin might receive a products reported to its Medwatch (see section III.E, comment 14 and
cumulative dose of 49.5 MEDs with 8 program and in the medical literature. section III.N, comment 45 of this
hours of exposure. The comment As noted by one comment, some document), allowing consumers to
concluded that, while SPF values up to, researchers have raised the concern that compare products and choose the levels
and including, 50 are warranted, values sunscreen use may lead to increased sun of UVB and UVA radiation protection
over 50 are unwarranted in any exposure. The ‘‘compensation desired.
condition for sunburn protection. hypothesis’’ states that consumers who An SPF 30 sunscreen product may
Two comments submitted testing data use high SPF sunscreens spend more provide adequate sunburn protection for
for sunscreens with SPF values between time in the sun and/or use less many consumers. However, FDA
30 and 50 using the test method in the protective clothing. The only double believes that appropriately tested and
FM. The comments concluded that the blind, randomized trial that addressed labeled high SPF value sunscreen
test method was valid for these high this issue showed a significant increase products should be available for
SPF values. In addition, one comment in sun exposure time when comparing consumers who desire or need high
indicated that a very water resistant test use of SPF 30 to SPF 10 (Ref. 14). In levels of UV protection, in particular,
for an SPF 45 to 50 sunscreen would addition, two retrospective survey those who burn easily. Such products
take nearly 4.5 hours using the skin studies showed that sun exposure time would do the following:
types of subjects in the SPF testing is longer when using sunscreen • Help compensate for inadequate
procedures in the FM (i.e., skin types I, compared to not using sunscreen (Refs. application and/or reapplication,
II, and III) (Ref. 13). The comment 15 and 16). Other studies cited by the • Provide additional sunburn
concluded that it is beyond the practical comment to support the premise that protection during intense UV radiation
endurance capabilities of many people the ‘‘compensation hypothesis’’ is conditions,
in the test to spend more than 5 to 6 incorrect and either did not provide • Help reduce cumulative UV
hours in front of a UV radiation lamp data about the length of sun exposure or radiation exposure (when used in
and that fatigue can lead to errors in test the study method did not allow for data conjunction with other measures to
results. The comment also noted that interpretation (Refs. 17 through 20). reduce overall sun exposure), and
the potential for intra and Based on all of this data, FDA believes • Generally provide consumers
interlaboratory variability in test results that some consumers may increase total incremental increases in sunburn
increases as sunscreen SPF values UV exposure through over-reliance on protection.
increase. sunscreens. The apparent divergent FDA agrees that SPF values should be
FDA concluded in the FM (64 FR results on the validity of the supported by scientific evidence. In the
27666 at 27675) that test methods ‘‘compensation hypothesis’’ between FM, FDA limited the specific labeled
supported specific SPF label values up studies may indicate that sun protection SPF value to 30. At that time, FDA had
to 30. FDA invited interested persons to behaviors vary greatly for each person. only received data demonstrating that
submit data in support of high SPF test More specifically, there is a spectrum of the SPF test produces accurate results
methods and to consider proposed attitudes about the sun, from those for products with SPF values of 30 or
methods for communicating the level of individuals who seek dark suntans to less. Since publication of the FM, FDA
protection in labeling. Data and those who seek to avoid the sun and has received additional SPF testing data
information on high SPF testing and consequent UV skin damage (Ref. 21). for sunscreen products with SPF values
labeling were submitted to FDA at, and Such evidence underscores the need for between 30 and 50 (Ref. 13). However,
following, public meetings on July 22, adequate labeling so consumers can FDA has not received any data for
1999, and October 26, 1999, and after make informed decisions regarding their sunscreen products with SPF values
reopening of the administrative record use of OTC sunscreen drug products. greater than 50. The data submitted to
(65 FR 36319) (see section III.I, FDA agrees that the SPF value is one FDA indicate that the SPF test is
comment 24 of this document) (Refs. 11 factor in a comprehensive sun accurate and reproducible for sunscreen
and 12). protection program. However, the SPF is products with SPF values up to 50 (Ref.
FDA continues to be aware that many only a measure of protection from 13). However, these data cannot be
OTC sunscreen products with specific erythema (i.e., UVB radiation-induced extrapolated to SPF values above 50.
labeled SPF values over 30 are currently sunburn) and does not measure Thus, FDA proposes to allow specific
marketed, both nationally and protection from other UV skin damage, labeled SPF values up to 50.
internationally, and are increasingly such as that induced by UVA radiation. FDA agrees with the sunscreen
used by consumers and recommended While increased short wavelength UVA manufacturer that increasing variability
by health professionals (64 FR 27666 at radiation protection generally increases in test results is likely with increasing
27675). FDA agrees that these products with increasing SPF values, studies SPF values. If there is large variability
should be available for those sun- using in vivo or in vitro UVA radiation in test results, then the SPF value
sensitive consumers who require such testing methods demonstrate that determined from the test is not accurate
products based upon personal sunscreen products with the same SPF (i.e., an SPF 50 product may not
knowledge, planned sun exposure, values can have markedly different actually be an SPF 50 product). The
geographical location, or advice of a submitted data demonstrate that
levels of UVA protection, especially for

health professional. FDA previously long wavelength UVA radiation (Refs. variability is not an issue for sunscreen
noted the lack of any known safety 22 and 23). These studies also indicate products with SPF values up to 50.
problems for sunscreen products with that a specific high SPF product can However, FDA is concerned that
SPF values greater than 30 (64 FR 27666 provide much less UVA radiation variability will become an issue for
at 27675). The comment that argued protection than a product with a much sunscreen products with SPF values
higher concentrations of sunscreen lower SPF value. Elsewhere in this over 50.
FDA recognizes that future data may products with specific SPF values over because it is duplicative and no longer
demonstrate that variability may not be 50. As explained earlier in this necessary. This phrase would only
a problem for sunscreen products with comment, FDA is not proposing that the lengthen the ‘‘Uses’’ statement.
SPF values over 50. Therefore, FDA will specific value over 50 be stated in the Furthermore, consumers will now be
consider specific SPF values greater labeling because there is no data, at this able to equate a product’s UVB radiation
than 50 upon receipt of data time, demonstrating the accuracy and protection rating (i.e., SPF value)
demonstrating that accurate and reproducibility of the specific value directly to the relative level of sunburn
reproducible results can be obtained over 50. Based upon the proposed protection.
from the SPF test for sunscreen products labeling, improvements to SPF testing The second indication ‘‘higher SPF
with SPF values over 50. Generally, methods, and specific high SPF test gives more sunburn protection’’ is no
such data should include results from data, FDA is proposing to modify the longer needed because the relative level
multiple laboratories using the same labeled SPF values in current of sunburn protection is provided in the
sunscreen formulations and using the § 352.50(a)(1) and (a)(2) by changing the new ‘‘Uses’’ statements. In addition,
SPF test proposed in this document, SPF values from ‘‘30’’ to ‘‘50.’’ without clarification, the statement may
along with a statistical analysis of the encourage consumers to spend more
overall results. In addition, FDA G. Comments on Indications for time in the sun. Clarification is
believes that the modified ‘‘binomial’’ Sunscreen Drug Products necessary because, as discussed in
test method submitted by one comment (Comment 16) One comment comment 19 of this document, surveys
has merit for high SPF sunscreens and requested that the ‘‘Uses’’ statement, reveal that consumers spend more time
is requesting others’ views on this ‘‘higher SPF gives more sunburn in the sun with increasingly higher SPF
method during the comment period for protection,’’ be omitted except for sunscreen products (Refs. 14, 15, and
this rulemaking (see section III.I, products with an SPF over 30. This and 16). Therefore, FDA is not allowing this
comment 24 of this document). other comments suggested that FDA’s statement in the ‘‘Uses’’ section.
In the FM (64 FR 27666 at 27675), labeling concerns regarding high SPF However, under proposed § 352.52(e)(2),
FDA disagreed with the comment that sunscreens could be alleviated if the FDA is proposing the following optional
manufacturers would have no incentive following statement was required on statement under ‘‘Other information’’ or
to fund research for better sunscreens sunscreens over SPF 30: ‘‘Higher SPF anywhere outside of the ‘‘Drug Facts’’
and may reformulate to less protective products give more sun protection, but box or enclosure: ‘‘higher SPF products
products if there is an upper limit to are not intended to extend the time give more sun protection, but are not
specific labeled SPF values. Although spent in the sun.’’ intended to extend the time spent in the
FDA would not want to decrease FDA is proposing to revise the sun.’’ The phrase ‘‘but are not intended
research incentive, FDA is more sunscreen FM ‘‘Uses’’ statement ‘‘helps to extend the time spent in the sun’’ is
concerned about valid scientific data prevent sunburn’’ and delete the ‘‘Uses’’ additional information not included in
demonstrating the ability of multiple statement ‘‘higher SPF gives more the FM indication. FDA believes this
laboratories to accurately and sunburn protection’’ in current revised indication statement will
reproducibly determine SPF values. § 352.52(b). The first indication, ‘‘helps discourage consumers from spending
However, FDA does not believe it is prevent sunburn,’’ is being revised to more time in the sun when using a
necessary to arbitrarily limit specific one of the following, which would be higher SPF product.
labeled SPF values. To the contrary, required on all sunscreens: FDA is proposing additional revisions
both in the FM and in this proposal, • ‘‘low UVB sunburn protection’’ in ‘‘Uses’’ in § 352.52(b)(1) to include
FDA has specifically stated that high • ‘‘medium UVB sunburn protection’’ UVA claims and other information (see
SPF sunscreens should be available for • ‘‘high UVB sunburn protection’’ section III.G, comments 17 and 18 of
those individuals desiring such • ‘‘highest UVB sunburn protection’’ this document). The proposed revisions
products. The maximum allowable The relative level of sunburn protection will help consumers to more fully
specific labeled SPF value, both in the is determined from the SPF value: understand the uses and expected
FM and in this proposal, is based upon • low = SPF 2 to under 15 results for individual sunscreen
the review of data and information • medium = SPF 15 to under 30 products. These changes are necessary
submitted to FDA. FDA purposely did • high = SPF 30 to 50 because the PDP for a sunscreen product
not limit labeled SPF values at 30 in the • highest = SPF over 50 will now include two performance
FM. Instead, FDA used the value of Thus, relative descriptors (low, ratings (see section III.E, comment 14 of
‘‘30+,’’ pending the receipt of adequate medium, high, and highest) describe this document):
data to support any higher specific label SPF values, which are relative and not • The well-accepted SPF value and
values. absolute levels of sunburn protection new descriptor rating for UVB radiation
Similarly, in this document, FDA is intended to help consumers determine protection, and
proposing the collective value ‘‘50+.’’ differences in sunburn protection • A new star/descriptor rating for
FDA has sufficient assurance that a offered by different sunscreen products UVA radiation protection.
result over 50 from the required SPF test (see section III.I, comment 23 of this Consequently, FDA considers it
is, in fact, greater than 50 and can be document). important that the ‘‘Uses’’ statements in
labeled ‘‘50+.’’ Thus, FDA believes that FDA considers it important that the ‘‘Drug Facts’’ box accurately reflect
the term ‘‘SPF 50+’’ is truthful and consumers be made aware of the relative product claims related to specific
nonmisleading on the label of OTC level of sunburn protection provided by indications, UVA and UVB radiation,
sunscreen drug products for which the a product in addition to its indication and the level of anticipated protection
for sunburn protection. Individuals may (low, medium, high, or highest)
SPF test in the monograph has indicated

an SPF value greater than 50. FDA select a low, medium, high, or highest determined by the UVA and UVB
believes that allowing manufacturers to sunburn protection product to meet product ratings. As with the
label sunscreens as ‘‘SPF 50+’’ may their specific needs. The descriptor introduction of SPF labeling years ago,
encourage further research in human ‘‘UVB’’ is included to describe the it will take the combined efforts of
skin photobiology and the development predominant rays that are screened. The government, manufacturers, consumer
of safe and effective sunscreen drug phrase ‘‘helps prevent’’ is being deleted organizations, and the health care
community to educate consumers to conditions. FDA believes that the sunscreen prevented the development of
fully understand these labeling articles with clinical data provide more solar elastosis, a condition in which
initiatives to enhance their safe and meaningful results, as they can be easily skin loses its elasticity after chronic
effective use of sunscreen products. extrapolated to consumer actual use exposure to the sun (Ref. 33). However,
(Comment 17) One comment stated conditions. Therefore, FDA is focusing these method and data analyses raise
that FDA’s ‘‘sun alert’’ statement in the discussion in this document on the questions about the validity of the
FM recognized that sun-induced skin clinical studies. In agreement with reported conclusion:
damage can contribute to photoaging Garland (Ref. 25) and Gasparro (Ref. 24), • Discrepancies were noted
and increase the risk of skin cancer. FDA does not believe, as a whole, that concerning demographic characteristics
This statement reads: ‘‘Sun alert: the studies demonstrate that sunscreens of subjects, sunscreen application, and
Limiting sun exposure, wearing alone help prevent skin aging or skin compliance rates.
protective clothing, and using cancer. • Skin biopsy data at all three time
sunscreens may reduce the risks of skin Some of the clinical studies examined points in the study were available from
aging, skin cancer, and other harmful the role of UVB and UVA radiation in only 10 of the 35 subjects.
effects of the sun.’’ The comment urged producing histological changes • The only statistically significant
FDA to allow other truthful use indicative of skin aging due to the sun. difference between the sunscreen and
statements, such as the following: Lowe et al. demonstrated that high placebo treatment groups was achieved
• ‘‘helps protect against skin damage doses of UVA radiation (320 to 400 nm) in a computerized evaluation of solar
caused by the sun’’ increased melanization of human skin elastosis at baseline and 24 months.
• ‘‘helps protect against skin aging more than lower doses of UVA or solar The second study demonstrated
caused by the sun’’ simulating UV radiation at 290 to 400 significant contribution of a sunscreen
• ‘‘regular use helps protect against nm (Ref. 26). Seite et al. demonstrated in preventing UV radiation-induced
certain forms of skin cancer caused by that melanization of human skin skin damage (Ref. 32). The use of
the sun’’ increased with exposure to UVB/UVA sunscreens with absorption spectra
• ‘‘helps protect against fine lines and radiation at 290 to 400 nm (Ref. 32) and covering the 290 to 400 nm range
wrinkles caused by the sun’’ UVA radiation at 330 to 440 nm (Ref. prevented all of the effects of chronic
• ‘‘helps protect against pigmentary 27). Seite et al. also showed that human exposure (6 weeks) to UV radiation
changes due to sun exposure’’ skin hydration decreased after chronic evaluated in the study. The third study
Another comment urged FDA to include exposure to UV radiation at the showed a photoprotective effect of an
the first three use statements suggested wavelengths studied. SPF 15 sunscreen product from damage
by the first comment, as well as ‘‘helps Five studies revealed stratum induced by short term exposure to UVB
protect against the harmful effects of the corneum thickening produced by both radiation (Ref. 30). The fourth study
sun’’ and ‘‘helps protect against (select UVB and UVA radiation (Refs. 26 showed that a UVB only sunscreen did
one: ‘casual,’ ‘incidental,’ ‘intermittent,’ through 29 and 32). Stratum granulosum not provide protection against chronic
or ‘daily’) sun exposure.’’ The comment thickening was transiently induced after exposure to UVA radiation (Ref. 29).
contended that, when used effectively 6 weeks of exposure to UV radiation The studies provide evidence that
as part of a sun protection program, (UVB/UVA) at 290 to 400 nm (Ref. 32). both UVB and UVA radiation induce
sunscreens may prevent very serious The same effects were seen with solar histological changes in the skin
disease conditions. simulated radiation and high and low consistent with skin aging. Thus, the
Another comment provided citations doses of UVA radiation after 12 weeks studies support the conclusion that
from the medical literature to support of exposure (Ref. 26). Viable epidermal exposure to UV rays increases the risk
its contention that claims of sunscreens thickening was seen after 6 weeks of of premature skin aging. However, the
preventing skin cancer induction may exposure to UV radiation at 290 to 400 study data fails to show that sunscreen
be false, deceptive, misleading, and nm in one study (Ref. 32) and after 9 use alone helps prevent premature skin
unsubstantiated. The comment days of exposure to UVA radiation at aging for several reasons. First, the
mentioned an article by Garland (Ref. 335 to 345 nm in another study (Ref. studies have not completely defined the
25) that states the following: ‘‘No 31). action spectrum for the majority of UV
epidemiological studies were identified Inflammation and lysozyme radiation-induced effects on human
that showed a protective effect of use of deposition along the dermal elastic skin. While studies demonstrate that a
chemical sunscreen on risk of fibers were increased more in human given histological change, such as
melanoma or other cutaneous skin exposed to UVA than UVB thickening of the stratum corneum, is
malignancies in humans.’’ The comment radiation (Refs. 26, 28, 29, and 31). induced by certain wavelengths within
also mentioned an article by Gasparro Sunburn cell appearance, a typical the UVB and UVA region, studies have
(Ref. 24) that states the following: response to UVB radiation, was also not examined the ability of the
‘‘Although some have promoted daily found to be present after exposure to remaining UVB and UVA regions
use (of sunscreen) for the prevention of different UVA radiation regimens in two outside of these wavelengths to induce
premature aging of the skin and the studies (Refs. 28 and 31) but not found the same change. For example, studies
prevention of skin cancer, actual data in a third study (Ref. 27). Thus, FDA may have shown that 290 nm to 310 nm
are lacking to support these concludes that these studies and 360 nm to 400 nm radiation induce
recommendations.’’ demonstrated that both UVB and UVA stratum corneum thickening, but it is
FDA has reviewed the submitted radiation induce histological changes not known whether 311 nm to 359 nm
articles concerning UV-induced skin associated with skin aging. radiation induces the same histological
damage (i.e., premature aging and Four of these studies focused on the
change.
cancer) along with articles obtained histological changes within the skin Second, the inability to identify the
from a search of the scientific literature induced by UVB and UVA radiation and exact UVB and UVA wavelengths that
(Refs. 26 through 34). Many of the explored the ability of sunscreens to induce each histological change in the
articles involved preclinical data, which protect human skin against these skin derives from the study designs.
can be difficult to extrapolate to changes (Refs. 29, 30, 32, and 33). The Each study differed in the following
consumer (human) actual use first study suggested that an SPF 29 parameters:
• UV radiation wavelengths, effects of UV radiation to a long-term, comment, along with the third
• UV exposure regimens, chronic effect such as skin cancer. In comment, seemed to agree with FDA’s
• Sunscreen doses, addition, like skin aging, the complete conclusions in this proposed rule
• Sunscreen application techniques, action spectrum for skin cancer is not concerning the need for consumers to
and known at this time. use sunscreens in conjunction with
• Endpoints. Unlike skin cancer and premature other sun protection measures.
Therefore, FDA cannot combine all of skin aging, FDA has evidence that In addition, the reference in the new
the data from these studies to define a sunscreens alone help prevent sunburn. warning statement to sunscreen use
complete action spectrum for each The SPF test measures the effectiveness combined with limiting sun exposure
histological change in the skin. of sunscreens with sunburn (erythema) and wearing protective clothing is
Furthermore, the action spectrum for as the endpoint. Thus, the impact of consistent with recommendations by
each histological change would need to sunscreens on sunburn can be measured other public health organizations. For
be combined to define a single action directly. In contrast, it is difficult to example, the World Health
spectrum for skin aging, which is a measure directly the impact of Organization’s International Agency for
cumulation of these histological sunscreens on skin cancer or premature Research on Cancer (IARC) (Ref. 21)
changes. Without knowing which UVB skin aging because these are long-term, makes the following assessments and
and UVA wavelengths induce each cumulative adverse effects of UV recommendations:
histological change in the skin, FDA is exposure. • There is inadequate evidence in
unable to determine which wavelengths Thus, for all of the reasons discussed humans for a cancer preventative effect
are most important in causing skin aging in this comment, FDA concludes that of sunscreens against basal cell or
and cannot determine the action the available evidence fails to show that malignant melanoma cancers.
spectrum for aging. sunscreens alone help prevent skin • There is only limited evidence for
Third, the studies did not examine the cancer or premature skin aging. Based a preventive effect of sunscreens against
chronic, long-term consequences of UV on this conclusion, FDA is not squamous cell cancer.
radiation exposure in human skin. proposing the indication statements • Sunscreens should not be the first
Thus, it is not possible for FDA to proposed by the first and second choice for skin cancer prevention or
extrapolate the data to longer time comments, because these claims are for used as the sole agent for protection
points at which the short-term protection from premature skin aging, against UV radiation.
histological changes may cumulate to skin cancer, and related factors (e.g., Likewise, the CDC recommends that
produce visible signs of skin aging. ‘‘helps protect against skin aging caused sunscreens be used as a complementary
Fourth, although the studies that by the sun’’). FDA also is not proposing measure in an overall sun protection
examined the ability of sunscreens to claims that sunscreens protect against program (Ref. 35).
protect against UV radiation-induced ‘‘casual, incidental, intermittent, or FDA believes that additional
histological changes in the skin provide daily’’ sun exposure, as proposed by the information from controlled clinical
useful data, it is difficult for FDA to second comment, because the studies do studies is needed to better understand
conclude that sunscreens alone help not support these claims. Furthermore, the role of sunscreens in preventing
prevent skin aging based on these FDA considers these terms as lacking premature skin aging and skin cancer.
studies. The number of participants in sufficient meaning to be useful to Studies examining premature skin aging
each study was relatively small, with consumers. (using solar radiation or simulated solar
only 10 to 35 subjects per study. As described elsewhere in this radiation) are needed to determine the
Different sunscreen formulations, with document (see section III.G, comment following in humans:
differing absorption spectra, were used 19), FDA is proposing to require a • Measurable skin properties such as
in each study. As explained previously, revised ‘‘sun alert’’ statement in the elasticity, collagen/elastin ratios and
these studies do not identify exactly form of a new warning. The new properties, wrinkling, pigmentation
which UVB and UVA wavelengths warning statement is based on FDA’s changes and visual grades, leading to
contribute the most to skin aging (i.e., review of the available evidence accepted quantitative definitions of
the studies do not define the skin aging concerning UV exposure and skin chronological and sun-induced skin
action spectrum). For all of these cancer, premature skin aging, and other aging;
reasons, the studies do not prove that skin damage. The new warning • The relationship between sunlight
sunscreens alone help prevent statement clarifies that UV exposure exposure and skin aging, stratified by
premature skin aging. from the sun increases the risk of skin skin type;
Likewise, FDA is not aware of data cancer, premature skin aging, and other • An action spectrum for photoaging
demonstrating that sunscreens alone skin damage. In addition, the new of skin;
help prevent skin cancer. It has been warning statement specifies that • A dose response for UV radiation-
known for many years that UV radiation consumers should use complementary induced skin aging;
increases the risk of skin cancer. It has sun protection measures along with • Quantitative estimates of realistic
also been known for many years that a sunscreen (i.e., limit sun exposure and ‘‘worst case,’’ long-term exposures to
higher incidence of sunburn earlier in wear protective clothing). FDA has sunlight in relevant UVA and UVB
life corresponds to a higher incidence of concluded from the available evidence radiation spectral ranges (i.e., the level
skin cancer later in life. However, FDA that it is important to adopt a complete of UVB and UVA protection needed);
is not aware of any studies sun protection program (sunscreen, sun and
demonstrating that the use of avoidance, and protective clothing) to • How UV radiation-induced
sunscreens alone decreases the risk of decrease UV exposure. In fact, the
processes that occur at a given

skin cancer. Like skin aging, there are second comment argued for new wavelength affect UV radiation-induced
studies examining the effects of indication statements by considering the processes that occur at other
sunscreens on short-term factors for skin sunscreen use as part of such a sun wavelengths.
cancer, such as sunburn and other protection program (i.e., in conjunction Similar information is needed for skin
cellular damage. However, it is difficult with limiting time in sun and wearing cancer, except that studies should
to extrapolate these short-term adverse protective clothing). Thus, the second examine the different types of skin
cancer, rather than examining different following UVA indication statements, time, FDA encouraged manufacturers to
skin properties. In addition, IARC has depending on the level of UVA voluntarily include this statement in
provided recommendations for research protection provided by a product: labeling, make it available at the point
on skin cancer prevention and • ‘‘low UVA protection’’ of purchase, and/or make it available
sunscreens. These recommendations • ‘‘medium UVA protection’’ through consumer education programs.
can also be used as a guide in designing • ‘‘high UVA protection’’ FDA is now proposing a revised ‘‘sun
studies to examine the role of • ‘‘highest UVA protection’’ alert’’ statement be required in the
sunscreens in preventing premature The level of protection (i.e., low, ‘‘Warnings’’ section of the ‘‘Drug Facts’’
skin aging due to the sun (Ref. 21). FDA medium, high, or highest) is determined box. FDA is proposing the statement to
encourages interested parties to submit from the UVA rating obtained from read as follows: ‘‘UV exposure from the
study protocols to FDA for review to product testing (see section III.N, sun increases the risk of skin cancer,
ensure that studies are as informative as comment 45 of this document). premature skin aging, and other skin
possible. FDA also invites comments by Manufacturers who wish to combine the damage. It is important to decrease UV
interested parties on the feasibility and ‘‘Uses’’ statements about UVA exposure by limiting time in the sun,
validity of surrogate endpoints for protection and UVB sunburn protection wearing protective clothing, and using a
studies to determine whether the use of may do so if the descriptors (i.e., levels sunscreen. FDA is proposing that the
sunscreens alone help prevent skin of protection) are the same. For statement appear in bold type as the
cancer, premature skin aging, or other example, if the levels of UVA and UVB first statement in the ‘‘Warnings’’
skin damage. protection are medium, the ‘‘Use’’ may section. FDA believes the statement is
(Comment 18) As discussed in section read: ‘‘medium UVA/UVB sunburn most appropriate in the ‘‘Warnings’’
III.E of this document, FDA received protection’’. section because it warns consumers that
several comments discussing ways to FDA is not including the fifth effective protection from the sun does
categorize, phrase, and display UVA/ indication because FDA does not not involve only the application of
UVB radiation protection on an OTC consider ‘‘skin aging’’ or ‘‘skin damage’’ sunscreens, as many consumers believe.
sunscreen drug product label. In the claims adequately supported at this In addition, it warns consumers that UV
amendment to include avobenzone in time. As discussed elsewhere in this radiation not only increases the risk of
the monograph (61 FR 48645 at 48655), document (see section III.G, comment sunburn but also increases the risk of
FDA proposed the following indications 19), FDA is proposing a statement in the skin cancer and premature skin aging,
for UVB and UVA radiation protection ‘‘Drug Facts’’ box that informs which many consumers may not know.
by sunscreen drug products containing consumers that sunscreens may reduce FDA believes the new warning will
avobenzone: the risks of skin aging, skin cancer, and encourage consumers to use sunscreen,
1. ‘‘Broad spectrum sunscreen’’; other harmful effects from the sun when limit time in the sun, and wear
2. ‘‘Provides’’ (select one of the used in a regular program that relies protective clothing to reduce UV
following: ‘‘UVB and UVA,’’ or ‘‘broad upon limiting sun exposure and wearing exposure. Because of the importance of
spectrum’’) ‘‘protection’’; protective clothing. Therefore, FDA warning statements and the need for
3. ‘‘Protects from UVB and UVA’’ believes the fifth indication statement consumers to receive a uniform message
(select one of the following: ‘‘Rays’’ or would mislead consumers by not concerning such warnings, no variations
‘‘radiation’’); discussing sun exposure and protective in wording are allowed under
4. (Select one of the following: clothing. § 330.1(c)(2).
‘‘Absorbs,’’ ‘‘Protects,’’ ‘‘Screens,’’ or (Comment 19) As discussed in section FDA acknowledges that the new
‘‘Shields’’) ‘‘throughout the UVA III.G of this document, FDA received warning statement differs from the
spectrum’’; and several comments concerning the ‘‘sun’’ wording of the voluntary ‘‘sun alert’’ in
5. ‘‘Provides protection from the UVA alert statement. In § 352.52(e)(2) of the the FM. These differences are based on
rays that may contribute to skin damage FM, FDA included the optional FDA’s assessment of the additional
and premature aging of the skin’’. statement: ‘‘Sun alert: Limiting sun evidence available since publication of
Likewise, in the amendment to include exposure, wearing protective clothing, the FM in 1999. As explained in
zinc oxide in the monograph (63 FR and using sunscreens may reduce the comment 17 of this document, FDA
56584 at 56588), FDA proposed similar risks of skin aging, skin cancer, and does not believe that the available data
labeling for UVA and UVB radiation other harmful effects of the sun.’’ This support a claim concerning the use of
protection for products containing zinc statement’s emphasis of the need for a sunscreen and a reduction in the risk of
oxide (substituting the word ‘‘within’’ comprehensive sun protection program premature skin aging and skin cancer.
for the word ‘‘throughout’’ in the fourth (64 FR 27666 at 27679) was based on the The revised wording of the statement
statement). FDA did not include these findings of numerous groups, including more accurately reflects the scientific
indications in the FM but has allowed the following: conclusions that can be drawn from this
their use until the UVA portion of the • The American Academy of evidence.
monograph is established. Dermatology (AAD), FDA is proposing the warning
FDA has reconsidered these UVA • The CDC, because we continue to be concerned
protection indications. FDA is • The Australian Government; and about adequate consumer understanding
proposing to allow all of them except • The New Zealand Government. of a sun protection program that
the fifth statement. In proposed These groups have recommended that includes sun avoidance and wearing
§ 352.52(e), the first four statements are sunscreens be considered an adjunct to protective clothes along with sunscreen
optional statements allowed for other UV protection strategies, such as use. This proposed rule provides for
products that demonstrate UVA even higher SPF values and a new rating
avoiding the sun near midday, seeking

protection according to the proposed shade, and wearing protective clothing system for UVA protection. Consumers
testing (see section III.N, comment 45 of and hats. may believe that sunscreens with higher
this document). The statements can only The FM provided that the ‘‘sun alert’’ SPF values (especially with UVA
be included in labeling outside of the appear under the heading ‘‘Other protection) provide complete UV
‘‘Drug Facts’’ box. Within the ‘‘Drug information’’ or anywhere outside of the radiation protection. Subsequently,
Facts’’ box, FDA is proposing one of the ‘‘Drug Facts’’ box or enclosure. At that consumers may prolong sun exposure
because they think higher SPF values • An estimated 8,110 persons would purchase sunscreens to provide
equate to longer times in the sun die from melanoma and 2,000 persons protection from the sun damage that is
without burning. FDA is aware of a would die from other skin cancers. not immediately recognizable. For these
double-blind, randomized clinical study Skin cancer affects roughly the same reasons, the comment requested claims
that showed a significant increase in number of people as all other cancers such as the following:
sun exposure time of persons using high combined. In view of the continuing
• ‘‘helps protect against casual or
SPF sunscreens compared to persons increase in the incidence of all types of
skin cancer and the lack of data incidental or intermittent daily sun
using low SPF sunscreens (Ref. 14). In exposure’’
addition, two questionnaire-based demonstrating that sunscreens alone
surveys showed that sun exposure time prevent skin cancer, FDA considers the • ‘‘helps protect against the harmful
is prolonged for persons using new warning important for the effects of the sun’’
sunscreens compared to persons not protection of the public health. Another comment acknowledged that
using sunscreens (Refs. 15 and 16). By FDA is proposing that the new facial makeups with sunscreen provide
educating consumers about a sun warning be required on all OTC protection from sunburn, but that is not
protection program, we believe sunscreen drug products except lip the primary reason why consumers use
requiring this new proposed warning cosmetic-drug and lip protectant- these products. The comment
will decrease the likelihood of sunscreen products subject to
contended that requiring the ‘‘sunburn’’
consumers spending more time in the § 352.52(f). FDA continues to believe
indication would be inappropriate and
sun when using a sunscreen. that all sunscreen products should have
misleading labeling for most facial
The new proposed warning also labeling to ensure that consumers are
makeups with sunscreen. The comment,
informs consumers that use of adequately protected against
instead, requested a claim such as
sunscreens alone is not the sole measure overexposure to UV radiation (64 FR
27666 at 27673). Thus, sunscreen ‘‘protects against the harmful rays of the
of protection from UV exposure, even sun.’’
with the use of high SPF products that products labeled for use only on specific
small areas of the face and sold in small FDA notes that the second comment
provide UVA protection. Although it is
packages (i.e., sunscreen products acknowledged that facial makeups with
well established that sunscreens protect
subject to § 352.52(f)) must include the sunscreen provide protection from
against UV radiation, the following
new warning. The only sunscreen sunburn. Not every consumer who uses
factors affect the level of protection
provided by a sunscreen for each products not required to include the color cosmetics or facial makeups with
new warning are those lip cosmetic- sunscreen meets the following criteria:
individual:
drug and lip protectant-sunscreen • Has a dark skin type, or
• Variations between individuals,
products subject to § 352.52(f), as
• UV radiation absorption, • Uses these products solely to
proposed in § 352.52(f)(1)(ii). FDA is
• Ability of sunscreens to adhere to making this proposal because lip provide protection from sun damage
and be absorbed by the skin, cosmetic and lip protectant products are that is not immediately recognizable.
• Exposure conditions, and often sold in packages that are As noted in section III.D, comment 9 of
• Conditions of use (e.g., inadequate substantially smaller than those of other this document, many consumers use
application amount or reapplication products that fall under § 352.52(f). FDA facial products with sunscreen as their
frequency). believes requiring the new warning on primary and only source of sunscreen
Therefore, FDA agrees with the lip cosmetic-sunscreen and lip protection for that area of the body. As
numerous groups that promote protectant-sunscreen products may discussed in section III.G, comment 16
sunscreen use as part of a total sun discourage manufacturers from of this document, sunscreen products
protection program. marketing these products because it will be required to bear a claim of low,
FDA reviewed the relationship requires a significant amount of labeling medium, high, or highest UVB sunburn
between sunscreen use and skin cancer space. protection. FDA does not consider it
incidence in the scientific literature and FDA has limited labeling inappropriate or misleading for color
did not find confirmatory evidence that requirements as much as possible for cosmetic or facial makeup products
sunscreens alone protect against the sunscreen products subject to containing sunscreens to have this
development of skin cancer. The § 352.52(f). However, FDA believes sunburn protection claim of low,
incidence of skin cancer continues to consumers are at great risk for UV- medium, high, or highest.
rise in the United States. The incidence induced skin damage, including cancer,
of the most serious form of skin cancer, on the face. Therefore, consumers who Sunscreen products that provide UVA
malignant melanoma, grew 6.1 percent purchase products specifically for use radiation protection may also bear a
per year during the 1970s (Refs. 14 and on the face need to be informed about claim about the level of protection. In
36). The rate is still rising an average 2.8 the information contained in the new addition, all OTC sunscreen products,
percent annually, with a rate of 14.3 warning. Although these products are except lip cosmetic-drug and lip
percent per 100,000 persons in 1997. marketed in small package sizes, FDA protectant-sunscreen products subject to
Melanoma is one of the top 10 cancers, has determined that the products’ § 352.52(f), will be required to bear the
by incidence, for persons with white labeling needs to include this important revised ‘‘sun alert’’ statement, which is
skin. The American Cancer Society information in order to protect now included in the ‘‘Warnings’’ section
(ACS) estimated the following statistics consumers. of the ‘‘Drug Facts’’ box. FDA considers
concerning skin cancer in 2007 (Ref. (Comment 20) One comment stated the information in this new ‘‘Warnings’’
37): that consumers who use color cosmetics statement much more beneficial to
• More than 1 million new cases of or facial moisturizers with sunscreens consumers than the statements
curable basal cell and squamous cell make the informed decision to purchase proposed by the comments. FDA
carcinomas would be detected, them as an additional benefit to their rejected the terms ‘‘casual, incidental,
• Approximately 59,940 new cases of cosmetic use. The comment contended and intermittent,’’ as explained in
malignant melanoma would be that a significant number of people with section III.G, comment 17 of this
diagnosed, and dark skin types, who do not burn easily, document.
H. Comments on Directions for incidental sun exposure in addition to at 2 mg/cm2 (Refs. 49, 50, and 51).
Sunscreen Drug Products intentional sun exposure, such as Gasparro notes that statements such as
(Comment 21) Several comments sunbathing. ‘‘apply liberally and frequently’’ are too
requested alternative directions for For these reasons, FDA considers it vague to be informative (Ref. 24).
makeup with sunscreen products. One important that consumers using makeup FDA is concerned that, in practice,
with sunscreen products not labeled for consumers may be getting less
comment requested ‘‘apply smoothly or
use only on specific small areas of the protection than the labeled SPF value
evenly before sun exposure and/or as
face recognize that these products are and believes that further information
needed.’’ The comment added that
sunscreens and use them appropriately should be included in the labeling for
‘‘before sun exposure’’ may not always
to maximize UV protection. Therefore, sunscreen drug products to reduce the
be appropriate as these makeup
FDA is not proposing modified likelihood of underapplication. FDA
products are not exclusively or even
directions for these makeup with believes that this information is better
primarily used for protection against
sunscreen products. communicated as revised product
sun exposure. A second comment (Comment 22) One comment directions rather than a warning. FDA
requested ‘‘apply smoothly or evenly requested that FDA require sunscreen is, therefore, proposing to revise
before sun exposure and reapply as manufacturers to provide accurate and § 352.52(d)(1). The directions will
needed.’’ A third comment did not appropriate instructions about how continue to state that OTC sunscreen
suggest any specific language, but much sunscreen should be applied to drug products should be applied
requested flexibility to recognize the the body. The comment also suggested ‘‘liberally’’ or ‘‘generously’’ because it
product’s primary use as a makeup, that a warning about the dangers of would be cumbersome to specify
while providing adequate information sunburn from applying suboptimal quantitative amounts for all possible
about the sunscreen component. This amounts be included in sunscreen body areas and the various uses on the
comment added that the direction to product labeling. A second comment label. However, FDA is proposing to
consult a doctor for children under 6 stated that it was not aware of any study make optional the directions in
months of age was clearly unnecessary indicating that consumers use adequate § 352.52(d)(1)(i) to apply ‘‘evenly.’’ FDA
for facial makeup with sunscreen amounts of sunscreen. The comment believes that this term, if used alone,
because these products cannot supplied data and other information may not convey the appropriate message
reasonably be expected to be used on concerning the dependency of the SPF to ensure that consumers apply
children that age. value on the total quantity of sunscreen sufficient sunscreen. In addition, FDA is
FDA agrees that flexibility is applied (Ref. 49). proposing to remove the term
appropriate for the directions for Section 352.52(d)(1) currently ‘‘smoothly’’ from § 352.52(d)(1)(i)
makeup with sunscreen products. provides manufacturers the option to because FDA considers that term to be
Elsewhere in this document, FDA is select one or more of the following vague and it may have different
proposing to allow labeling application terms for a sunscreen meanings to different consumers. FDA
modifications for makeup with product: ‘‘liberally, generously, also believes this term is more likely to
sunscreen products used only on smoothly, or evenly.’’ Manufacturers result in product underapplication.
specific small areas of the face and sold may also include optional directions In addition to labeling directing
in small packages (see section III.D, that state ‘‘[bullet] reapply as needed or consumers to apply sufficient amounts
comment 9 of this document). Those after towel drying, swimming, or (select of sunscreen, FDA is also proposing to
modifications include modified one of the following: ‘sweating’ or revise the labeling requirements
directions for cosmetic lip products ‘perspiring’).’’ In the final rule, FDA had concerning reapplication of the
containing sunscreen that are within the concluded that the directions in sunscreen product. In § 352.52(d) of the
scope of proposed § 352.52(f). FDA is § 352.52(d)(1) to apply ‘‘liberally’’ or FM, the general reapplication statement
not extending the proposed ‘‘generously’’ convey the appropriate ‘‘and as needed’’ was the only required
modifications to all makeup with message to ensure that consumers information. FDA made specific
sunscreen products. Makeup with adequately apply the sunscreen (64 FR reapplication directions in
sunscreen products not labeled only for 27666 at 27679). § 352.52(d)(2) of the FM optional in an
specific small areas of the face may be Several studies suggest that, in effort to equalize requirements between
applied to a large area of the face or practice, consumers may apply amounts sunscreens with and without water
other areas of the body. As explained of sunscreen below the density of 2 resistant claims (64 FR 27666 at 27681).
later in this comment, FDA would have milligrams/square centimeter (mg/cm2), FDA now believes that more detailed
concerns with the modifications being which is the amount of product required reapplication directions must be
applied to these products. for the SPF determination in § 352.72(e) included on all OTC sunscreen
Whether intentional or not, makeup (proposed § 352.71(e)). These data products, because sunscreens may be
with sunscreen products may be the suggest that consumers may apply as underapplied as suggested by the
primary sunscreen for many consumers. little as 0.5 to 1.0 mg/cm2 (Refs. 50 comments.
A recent study examined sunscreen use through 54). One comment reported FDA came to this conclusion after
patterns (Ref. 48). Participants were that, to achieve the rated protection over reviewing studies concerning sunscreen
instructed to apply sunscreen every day. the whole body, a typical adult with a reapplication as well as
Of those who used sunscreen surface area of 1.73 square meters (m2) recommendations of public health
infrequently, the majority spent some would need to apply 35 milliliters (mL) organizations. Wright, et al. suggests
time outdoors with 11 percent spending of sunscreen, roughly one-third of a 4 oz that inadvertent sunburn may be due to
the majority of their time outdoors. bottle per application (Ref. 55). Studies the failure to use and reapply sunscreen
These same participants explained that indicate that SPF values determined at appropriately (Ref. 56). Study subjects
they did not believe sunscreen was an application rate of 1 mg/cm2 are who reapplied sunscreen every 1 to 2
necessary because of their planned approximately 50 percent of those hours and after swimming did not
activities. The authors cited this finding determined at 2 mg/cm2, and when report sunburn. Rigel et al. reported
in advocating educating consumers on applied at 0.65 mg/cm2, the SPF values that, even under intense solar
the need for sunscreen for frequent are 20 to 30 percent of those determined conditions, those reapplying an SPF 15
sunscreen every 2 hours or sooner were one of the following: ‘40 minutes of’ or ‘80 protection under consumer use
five times less likely to sunburn minutes of’ for products that satisfy either the conditions is affected by a number of
compared to those who reapplied every water resistant or very water resistant test factors. Some of the key factors are
2.5 or more hours (Ref. 57). The AAD procedures in § 352.76, respectively] • Application density,
swimming or [select one of the following: • Reapplication frequency,
(Refs. 38, 58, and 59), the ACS (Ref. 60), ‘sweating’ or ‘perspiring’] and after towel
and the EPA (Ref. 40) recommend • Skin type (e.g., burns easily versus
drying. Otherwise, reapply at least every 2
reapplying sunscreens every 2 hours or never burns),
hours’’.
sooner and also recommend application • Time of day during sun exposure,
(3) For products that do not satisfy the
to all exposed areas of the body (Refs. water resistant or very water resistant testing and
60, 61, and 62). procedures identified in § 352.76. The • Geographical location during sun
Because the frequency of application labeling states ‘‘[bullet] reapply at least every exposure.
appears to be critical for proper 2 hours and after towel drying, swimming, or Thus, SPF values reflect relative and not
protection, FDA is proposing to add the [select one of the following: ‘sweating’ or absolute levels of sunburn protection.
statement ‘‘apply and reapply as ‘perspiring’]’’. Although SPF values do not convey
directed to avoid lowering protection.’’ As discussed in the FM (64 FR 27666 at actual levels of sunburn protection,
In addition, FDA is proposing to further 27679), manufacturers who have data to when comparing multiple sunscreen
revise the directions in § 352.52(d) to support different reapplication products, SPF values enable consumers
include the following reapplication directions based on specific to determine which products provide
statement: ‘‘reapply at least every 2 substantiation information may submit the most sunburn protection. For
hours.’’ Likewise, for those products the information for approval of those example, FDA believes most consumers
making a water resistant claim, FDA is directions via an NDA deviation as would correctly identify an SPF 20
proposing to include the number of provided in § 330.11 (21 CFR 330.11). product as providing more sunburn
minutes (i.e., 40 or 80) that the product protection than an SPF 10 product.
I. General Comments on SPF Testing Thus, lowering the sunscreen
maintains its water resistance before the Procedure
‘‘swimming/sweating’’ term. FDA application density would not be
believes these additional proposed (Comment 23) One comment necessary to more accurately reflect the
directions will alert consumers about suggested that the SPF test incorporate degree of relative sunburn protection.
the hazards of using insufficient an amount of product that more closely FDA agrees that, in addition to
amounts of sunscreen product and reflects the amount applied by bringing SPF values closer to
encourage reapplication after the consumers. More specifically, the representing absolute levels of
appropriate time. FDA considers these comment requested that FDA replace protection, lowering the sunscreen
specific, informative reapplication the 2 mg/cm2 required in § 352.72(e) application density might also reduce
statements, instead of ‘‘and as needed,’’ (proposed § 352.70(c)(5)) to a value some of the inaccuracies and limitations
to be necessary on all OTC sunscreen between 0.5 and 1.0 mg/cm2. The encountered when testing high SPF
products. FDA is also proposing the comment argued that the protection sunscreen products. Thus, FDA invites
optional direction ‘‘apply to all skin afforded during actual usage may be interested parties to submit data
exposed to the sun.’’ FDA is proposing only one-quarter to one-half the labeled supporting a smaller application density
that this direction be optional because SPF value (see section III.H, comment for SPF testing of all sunscreen dosage
we believe most consumers know to 22 of this document). The comment also forms in accordance with § 352.77.
apply sunscreen to all exposed skin. suggested that SPF could be stated using However, developing a single global
However, if a sunscreen product can descriptive terms, such as ‘‘light,’’ method and labeling would require a
accommodate this direction, it will ‘‘moderate,’’ or ‘‘heavy’’ protection, coordinated effort between the
serve to remind consumers that all instead of a numerical value. regulatory agencies in many countries
exposed skin is susceptible to UV FDA is not proposing the suggested around the world. Because FDA does
damage. These proposed directions, as a change in test method at this time. This not have data to validate the SPF test
whole, should serve to better protect issue was discussed in detail in the using a lowering sunscreen density,
consumers, particularly those who tend TFM (58 FR 28194 at 28264 to 28266). FDA is proposing directions that we
to underapply sunscreen, from The majority of comments advocated believe will encourage consumers to
overexposure to the sun. continuing the use of an application apply greater densities of sunscreen
Accordingly, FDA is proposing to density of 2 mg/cm2. The current (i.e., closer to 2 mg/cm2) (see section
change § 352.52(d) to read as follows: comment did not provide data III.H, comment 22 of this document).
(d) Directions. * * * demonstrating the suitability of a FDA does not find that there are
(1) For products containing any ingredient smaller test amount. FDA is concerned sufficient benefits for using descriptors
in § 352.10. (i) The labeling states ‘‘[bullet] that a uniform distribution of sunscreen instead of numerical values for SPF on
apply [select one of the following: ‘liberally’ over the test area might be difficult the PDP. Consumers are familiar with
or ‘generously’] [and, as an option: ‘and using a smaller amount of sunscreen. numerical SPF values from over 20
evenly’] [insert appropriate time interval, if a Further, the standard application years of usage. As described in section
waiting period is needed] before sun
exposure’’. density used worldwide in the SPF test III.G, comment 16 of this document,
(ii) The labeling states ‘‘[bullet] apply and is 2 mg/cm2 (Ref. 63). FDA believes that the use of descriptors
reapply as directed to avoid lowering FDA agrees that SPF values do not in combination with numerical values
protection’’. reflect exact levels of sunburn on the PDP may be beneficial to
(iii) As an option, the labeling may state protection that consumers receive under consumer understanding of the level of
‘‘[bullet] apply to all skin exposed to the actual use conditions. The required SPF sunburn protection provided by a
sun’’. test is a clinical test conducted with product. Thus, as explained in comment
(iv) The labeling states ‘‘[bullet] children strict control over factors such as 16, FDA is proposing to include a
under 6 months of age: ask a doctor’’.
(2) For products that satisfy the water product application density. However, descriptive term of relative sunburn
resistant or very water resistant testing under actual use conditions, these protection (i.e., low, medium, high, or
procedures identified in § 352.76. The factors are not controlled and vary highest) with the proposed sunburn
labeling states ‘‘[bullet] reapply after [select greatly. The actual level of sunburn protection statement in the ‘‘Uses’’
section and on the PDP. The intent of as there would be less than a 95 percent using standard probability computer
this dual descriptive and numerical probability the actual SPF value was software, FDA calculates that the values
sunburn protection measure is to allow higher than the expected SPF value. If for the maximum number of failures in
consumers to more easily differentiate less than six subsites show perceptible table 2 of this document for subjects one
the level of sunburn protection provided erythema, the product passes, as there through five should be 0, 1, 2, 4, and 5,
by different sunscreen products. In would be greater than a 95 percent respectively, rather than the values
addition, this proposed labeling for probability that the actual SPF value provided by the comment.
sunburn protection is similar to the was more than the expected SPF value. FDA would also consider three
proposed UVA protection labeling (see The comment proposed the following: modifications to the method described
section III.G, comment 14 of this by the comment and invites comment.
document). TABLE 2.—PROBABILITY TABLE First, each subject may have test
FDA is also aware of sunscreen drug successes and failures due to multiple
products marketed in dosage forms that No. of subjects Maximum no. Probability subsites on each subject. Statistically,
may not be addressed by current SPF of failures these will not be independent
testing procedures. The SPF testing observations, which is a condition
1 (n=4) 0 0.06251
procedure described in § 352.72 2 (n=8) 2 0.0352 needed for a binomial probability
(proposed § 352.70) references oils, 3 (n=12) 3 0.0200 calculation. Therefore, FDA is
lotions, creams, gels, butters, pastes, and 4 (n=16) 5 0.0383 considering that a test panel should
ointments. FDA invites interested 5 (n=20) 5 0.0207 consist of 20 to 25 subjects and that only
parties to submit SPF testing 1 n is not sufficient to make a 95 percent
one site be tested on each subject. A
modifications for new dosage forms prediction pass/fail determination would be made
(e.g., mousses, foams, and towelettes) in for each individual.
accordance with § 352.77. The comment further proposed that if Second, as an alternate, a double
(Comment 24) One comment all eight subsites of the first two subjects sampling plan based on Taylor’s Guide
recommended a pass/fail (binomial) test pass, then the product passes and the to Acceptance Sampling may replace
to determine SPF values (Ref. 49). The remaining three subjects would not be the five-layered plan proposed by the
test would demonstrate that subjects evaluated. The probability of this comment (Ref. 64). With the double
have no reaction to a quantity of UV happening would be 1/256 unless the sampling plan, two subjects are tested
energy equivalent to an expected SPF product is over the expected SPF value. simultaneously with up to a maximum
value (for products passing the test). For FDA agrees that, currently, there may of four subjects, each having four
example, subjects being tested with a not be enough experience and test data subsites tested. If no more than one of
product with an expected SPF value of for products with SPF values of 30 and the first eight subsites has perceptible
30 would be dosed only at the SPF 30 over on which to determine the sample erythema, the product passes. If three to
level, and the product would either pass size needed to obtain an acceptable 95 eight subsites have perceptible
or fail. A product passing this test percent confidence interval. As erythema, the product fails. If exactly
would actually have an SPF value of 30 discussed in section III.L, comment 37 two of the eight subsites have
or over, whereas a product failing this of this document, to account for perceptible erythema, then the second
test would have an SPF value below 30. increased variability in SPF values for group of two subjects is tested. If two to
The comment argued that while the sunscreens with SPF values over 30, four subsites from four subjects have
monograph SPF test is probably FDA proposes to increase the sample perceptible erythema, the product
adequate for products with low SPF size to at least 25 subjects. Therefore, passes. Otherwise, the product fails.
values, it is not adequate for testing high the comment may be correct in arguing According to this scheme, if probability
SPF products because differences in that large numbers of subjects may be p = 0.10 that the product tested would
solar simulators can provide as much as required for testing products with high produce any recognizable erythema,
a 200 percent variation in results SPF values. FDA believes that the pass/ then the probability = 0.95 that the
depending on the formulation. The fail test has merit and could provide a product will pass. If probability p = 0.5
comment further argued that an reasonable substitute for the current SPF that the product tested would produce
impossibly high number of subjects method for products with expected SPF any recognizable erythema, then the
would be required for the current SPF value of 30 or higher. However, before probability = 0.05 that the product will
method to obtain a 95 percent the method can be accepted, method pass.
confidence level and that the test validation data are required that Third, an alternative to the probability
exposes subjects to a potentially demonstrate the method can be calculation is a margin of error
dangerous condition, sunburn. performed satisfactorily by multiple approach. With this method, a margin of
According to the comment, the laboratories using the same sunscreen error for the expected SPF value is
average MED for each skin type can be formulation(s). FDA invites such data. defined before testing. The margin of
predicted from existing solar simulator If the pass/fail method is accepted, error is used to determine the
calibration data. During the pass/fail FDA may stipulate that the method be tolerability interval around the expected
test, each test subject is screened for used only for products with SPF values SPF value. The 90 percent confidence
skin type and then given a first day of 30 and higher because of the large interval for the product’s test result (one
range of energy that does not exceed the number of subjects that would be result per subject) must fall within the
expected MED. The comment proposed required for high SPF products under tolerability interval to be labeled with
using a panel of five subjects. Using the the current test method. A pass/fail that SPF value. For example, if a 10
MED information obtained on the first method would require fewer test percent margin of error is claimed for a
day, each subject is given four UV subjects. Low SPF products can be product with an expected SPF value of
radiation exposures corresponding to adequately tested under the current 40, then the tolerability interval would
the expected SPF value. Each subsite is method without large numbers of be 40 ± 4, or 36 to 44. If the related 90
then evaluated for erythema. If six or subjects. In addition, FDA would likely percent confidence interval is from 37 to
more of the 20 subsites show require that all 20 subsites be evaluated 43, an SPF value of 40 is assigned to the
perceptible erythema, the product fails, even if the first 2 subjects pass. Further, product. If the related 90 percent
confidence interval is from 35 to 45, an method require further exploration. readings at 16 and 24 hours. Thus, FDA
SPF value of 40 could not be assigned Items such as the cut-off to define is proposing to revise the MED
to the product and the product may be photostability need further explanation determination time in §§ 352.72(h) and
retested at an expected SPF of 30. and validation. It should also be pointed 352.73(c) (proposed §§ 352.70(c)(8) and
FDA invites discussion of these out that the current SPF test method 352.70(d)(3), respectively) from ‘‘22 to
suggested modifications to the does not directly measure 24 hours’’ to ‘‘16 to 24 hours.’’
comment’s pass/fail method for testing photostability, but it accounts for
sunscreen drug products having an SPF photostability. More specifically, the J. Comments on the Sunscreen Standard
value of 30 or higher. SPF value is determined after a for SPF Testing Procedure
(Comment 25) One comment sunscreen is exposed to UV radiation, so (Comment 27) Several comments
described an in vitro method it the SPF represents UVB protection suggested that standard controls with
developed for simultaneously predicting provided by whatever fraction of the SPF values of 15 or higher be developed
SPF and assessing photostability. The sunscreen has not decomposed. to test high SPF sunscreen products.
method utilizes a 150 watt xenon arc FDA agrees that in vitro tests are One comment stated that such standards
lamp to irradiate sunscreen applied at a generally rapid and less expensive than would improve test accuracy and
level of 1 to 2 mg/cm2 to a flat collagen in vivo tests and, for SPF measurements, provide a consistent and adequate
membrane substrate placed in the would reduce exposure of human benchmark for compliance. One
opening of an integrating sphere subjects to UV radiation. FDA is willing comment mentioned use of a control
attached to a spectroradiometer. The to consider alternate methods for SPF SPF 15 formula routinely in SPF
spectral irradiance of the source and the testing if they are adequately supported evaluation and considered it a more
spectral irradiance of the substrate alone with data and are shown to be valuable control than the 8-percent
are measured from 290 to 400 nm, at 1 equivalent to established in vivo homosalate SPF 4 standard. Another
nm intervals. The spectral irradiance methods by collaborative studies. If the comment supplied ‘‘round-robin,’’
transmitted by the sunscreen/substrate methods are equivalent, then the same collaborative SPF testing data from 7
combination is measured at 1 minute SPF values should be determined for laboratories on a total of 153 subjects
intervals until the total erythemal- each sunscreen tested according to the with 2 potential SPF 15 sunscreen
effective dose transmitted by the SPF method and the alternate method. standard preparations, ‘‘Formulation A’’
sunscreen exceeds 1 MED, where 1 MED The comments have not provided data on 147 subjects and ‘‘Formulation B’’ on
equals 0.02 erythema-effective Joules (J)/ from such studies. Therefore, FDA is not 146 subjects (Refs. 13, 68, and 69). The
cm2. Each 1 minute interval represents proposing to include the described in comment concluded that differences
two to three MEDs. The time course of vitro method in the monograph at this between the two preparations were not
the sunscreen’s SPF is then computed time. significant (p=0.653) but ‘‘Formulation
(Ref. 65). This information reveals the (Comment 26) Several comments
B’’ was preferred due to its less complex
photostability of a sunscreen. If a urged FDA to revise § 352.72(h) and
formula and slightly more consistent
sunscreen is photostable, it will not reinstate the requirement for
results. The comment added that the
decompose when exposed to UV determining MED at 16 to 24 hours after
data showed that different laboratories
radiation, and the SPF will not change exposure, rather than 22 to 24 hours.
with increasing UV exposure. If a The comments submitted data showing can obtain valid, reproducible results
sunscreen is not photostable, it will that, for an SPF 30 product and for the when testing high SPF sunscreens.
decompose when exposed to UV 8 percent homosalate standard, Another comment stated that it
radiation, and the SPF will decrease determining the MED at 16 or 24 hours provided test results on 20 subjects
with increasing UV exposure. Another does not result in any clinical or using an SPF 25 product as the control
comment asked FDA to consider statistical difference in the SPF (Refs. 66 (Ref. 70). Three comments suggested
replacing the human SPF test with and 67). Comments argued that that the European Cosmetic, Toiletry,
equivalent in vitro technology and immediate pigmentation fades rapidly and Perfumery Association (COLIPA)
chemical engineering, but did not and does not interfere with MED ‘‘European low SPF Standard Code
suggest a suitable method. readings. One comment further argued Number COL492/1 (formerly the DIN
FDA does not agree that an in vitro that the 16 to 24 hour time is standard)’’ be included in the OTC
method is adequate to replace the in universally accepted by the European sunscreen drug product monograph as a
vivo SPF test. In vitro tests are generally Union, Australia, and Japan and FDA permissible standard sunscreen
inadequate as the sole measure of SPF should adopt this time in the interest of preparation, in addition to the 8-percent
because substrates cannot mimic international harmonization. homosalate standard, and that either
sweating, skin absorption, or certain The Panel recommended that the standard should be allowed in the SPF
interactions with skin that influence MED be evaluated 16 to 24 hours after testing procedures. The comments
SPF. Some sunscreen ingredients do not exposure (43 FR 38206 at 38262). FDA contended that this approach will serve
behave similarly in vitro and in vivo. At proposed a post exposure time of 22 to to permit international marketing and
this time, the comment’s method has 24 hours based upon information eliminate duplicative testing. Another
not been validated, and the chosen provided by comments to the Panel’s comment asked FDA to adopt the JCIA
substrate has not been demonstrated to report that immediate pigmentation may SPF 15 ‘‘P3’’ standard, but did not
possess penetration characteristics and persist with higher doses of UV provide supporting data.
surface chemistry similar to human radiation up to 24 hours or, in some The comment concerning the SPF 25
skin. cases, for 36 to 48 hours after prolonged control provided data from comparative
The described in vitro method does tests on 20 subjects, using the 8-percent
exposure (58 FR 28194 at 28268 to

have potential utility for measuring 28269). Comments had indicated that homosalate standard, an SPF 15
photostability of a sunscreen product. immediate pigmentation might interfere sunscreen drug product, and an SPF 25
Measuring the erythemal-effective dose with an investigator’s perception of sunscreen drug product (Ref. 70). FDA
transmitted through the sunscreen in minimally perceptible erythema. finds that this study is inadequate to
vitro over time seems like a reasonable FDA agrees that these new data show support the comment’s request because
approach. However, portions of the no significant difference in MED the study did not do the following:
• Include sufficient numbers of SPF ranges. The comment claimed that values over 15 may be erroneous in
subjects, the 8-percent homosalate SPF 4 other studies. Better assurance of an
• Address suitability of the standard standard is appropriate to test products accurate SPF value is obtained by using
across different laboratories, and at any SPF level and that the choice of a standard that is closer in SPF value to
• Document some properties required whether to use the SPF 4 or SPF 15 the sunscreen product being tested.
in a sunscreen standard to test high SPF control formulation should rest with the The use of an SPF 15 standard would
sunscreen products. manufacturer. Several other comments be reasonable to test products with SPF
The following properties of a agreed with this comment. values below 15. SPF 15 is in the
sunscreen standard were not addressed Another comment provided data middle (geometrically) of the 4 to 50
but need to be addressed: using the 8-percent homosalate standard range. The ratio of SPF 15 to SPF 4 is
• Low level of interlaboratory to test product formulations with 3.75, and the ratio of SPF 50 to SPF 15
variation, estimated SPF values of 15, 30, and 45 is 3.33. Thus, there would be equal
• Sensitivity to experimental error, on 20 subjects (Ref. 67). The comment coverage of all ranges. Therefore, FDA is
and concluded that the data showed testing proposing that Formulation B may be
• Ease of preparation with a procedures in the FM can differentiate used to test sunscreen drug products
reasonable degree of accuracy. high SPF sunscreens using the with SPF 2 and over, and is required for
These data are also needed for the JCIA homosalate SPF 4 standard. The testing sunscreen drug products with
standard. comment requested that the homosalate SPF over 15 (proposed
Although comments provided data on SPF 4 standard be allowed to be used § 352.70(a)(1)(ii)). The 8-percent
20 subjects in each of 4 laboratories for products with an SPF value over or homosalate standard may be used for
using the COLIPA COL492/1 standard, below 15. testing sunscreen drug products with
FDA is not proposing to include this FDA does not consider the data SPF of 2 to 15.
standard as an alternate to the 8-percent adequate to support the suggestion that (Comment 29) Several comments
homosalate standard because we do not the 8-percent homosalate standard suggested that a modern, HPLC method
believe that using the COL492/1 currently used to evaluate sunscreen is superior to the older
standard will make the monograph drug products with SPF values up to 15 spectrophotometric assay in § 352.70(c)
method comparable to the European is equally applicable to products with of the FM. One comment provided
method, as other differences exist SPF values over 15 (Ref. 67). The study technical information about the HPLC
between the two methods. For example, had the following deficiencies: method and stated that it is now
the monograph method requires 20 • Did not include sufficient numbers commonly used by analytical
evaluable subjects, while the European of subjects, laboratories to assay sunscreen
method requires only 10 evaluable • Did not address suitability of the formulations (Ref. 71). Although this
subjects. Therefore, the COL492/1 standard across different laboratories, HPLC assay method was used in the
standard is a valid standard under the and study of two SPF 15 sunscreen standard
European method but may not be a valid • Did not document certain preparations (see section III.J, comment
standard under the monograph method. properties required in a sunscreen 27 of this document), one comment
Finally, FDA finds that the 8-percent standard to test high SPF sunscreen noted that there are limited data on this
homosalate standard is a suitable products. method with the SPF 15 control
control for testing sunscreen drug The following sunscreen standard formulation because FDA has not yet
products with SPF 15 or below (see properties were not addressed but need published this formula as an accepted
section III.J, comment 28 of this to be addressed: standard.
document). • Low level of interlaboratory FDA agrees that an HPLC method is
FDA agrees with the comment that the variation, and superior to the spectrophotometric
submitted collaborative data from seven • Sensitivity to experimental error. method, which was originally published
laboratories support ‘‘Formulation B’’ as FDA agrees that the two standards are
by FDA in 1978, in specificity and
an appropriate SPF 15 sunscreen method controls rather than calibration
precision. Validation data provided by
standard. The mean SPF for tools. As such, the standard used should
the comment documented the following:
‘‘Formulation B’’ was 16.3 in 146 approximate the expected SPF of the • Specificity,
subjects tested, with 1.7 percent product being tested to better verify that • Accuracy,
standard error of the mean, and all aspects of the testing method are • Limit of detection,
laboratory means ranging from SPF 15.6 performing properly at the expected SPF • Linearity,
to 18.5. Therefore, FDA is proposing to level. • Precision, and
include the ‘‘Formulation B’’ SPF 15 Using the SPF 4 standard to measure • Reproducibility of the method.
standard in the FM to be used for SPF values over 15 is more likely to The validation data included
sunscreen drug products with an SPF produce erroneous results than using a chromatograms and demonstrated that
value over 15 (optional for SPF values standard with an SPF of 15. In the HPLC method is suitable for both
of 2 to 15). measuring SPF values over 15, much the SPF 4 and SPF 15 standards.
(Comment 28) One comment noted higher light energies (J/cm2) are used in Further, FDA validated the method in
that there are two recognized standard comparison to measuring SPF values its laboratories and concludes that the
control formulations: below 15. Problems in the accurate method is acceptable for quality control
1. An 8-percent homosalate quantitation of high light intensities and regulatory purposes (Ref. 72).
preparation with an SPF value of 4 may not be detected if the SPF 4 Finally, the spectrophotometric method
standard is used for SPF values over 15. has not been validated for the SPF 15
(§ 352.70(b) of the FM), and

2. Formulation B (padimate O/ While the SPF 4 standard may give standard, and the HPLC method has
oxybenzone) with an SPF value of 15. acceptable results for products with SPF been validated for both the SPF 4 and
The comment stated that the function of values over 15 in some studies, the SPF 15 standards. Therefore, FDA is
the standard formulation is quality extrapolation of these results to proposing to revise § 352.70 to replace
assurance for method control and not as approximately 4 to 13 fold higher light the outdated spectrophotometric
a calibration standard to bracket specific energies used to test products with SPF method with the HPLC method and to
use the HPLC method to assay both the and is not requiring that a specific as the Percentage Relative Cumulative
SPF 4 and SPF 15 standards. source maintain and supply the Erythemal Effectiveness (%RCEE).
(Comment 30) Two comments sunscreen standard at this time. According to the COLIPA specifications
disagreed with the requirement in and consistent with § 352.71,
§ 352.70(a) for concomitant use of a K. Comments on Artificial Light Sources
wavelengths below 290 nm should be
standard sunscreen for each SPF test. for SPF Testing Procedure
excluded from any source by
One comment suggested that a standard (Comment 32) Several comments appropriate filters. Likewise,
could be run twice yearly. Another suggested that FDA replace the wavelengths above 400 nm should be
comment suggested that data to evaluate specifications in § 352.71 that state ‘‘sun limited as much as possible and are not
proper laboratory test procedures could at a zenith angle of 10°’’ and ‘‘less than included in the calculation of %RCEE.
be obtained from panels of a standard 1 percent of its total energy output Because RCEE values are calculated as
run as part of ‘‘the ongoing laboratory contributed by nonsolar wavelengths relative percentages, measuring the
operation.’’ A third comment stated that shorter than 290 nm’’ with the COLIPA spectral irradiance in absolute energy
a standard preparation should be run table of ‘‘percent erythemal units is not necessary. Relative units are
each time an SPF determination is contribution’’ as the spectral power sufficient. The spectral irradiance of the
made. distribution standard for the light source source is multiplied by the Commission
FDA discussed this issue in comment used in the SPF test procedures (Ref. International de L’Eclairage (CIE) (1998)
78 of the TFM (58 FR 28194 at 28253 73). The comments suggested that the standard skin erythemal action
to 28254). FDA disagreed with one spectra of currently used solar spectrum to obtain the erythemal
comment that the standard could be run simulators (especially around 290 nm effectiveness of the source. The spectral
once or twice a year and reaffirmed the and above 350 nm) could cause erythemal effectiveness values of the
Panel’s recommendation that overestimation of SPF values for high source spectrum are then integrated
concomitant testing is necessary in SPF SPF sunscreens. Because shorter from 250 nm to the various successive
determinations to ensure uniform wavelengths can make a very large reference wavelength values shown in
evaluation of OTC sunscreen drug contribution to erythema, the comments the COLIPA table in order to produce
products and to serve as an internal stated that small errors in the 290 nm the cumulative erythemal effectiveness
indicator of experimental errors. The region of solar simulator spectra could for each spectral waveband, and the
comments requesting a change did not have considerable effects. The total erythemal effectiveness is
provide any supporting data. In the comments noted that spectral power calculated up to 400 nm. Finally, the
absence of supporting data, FDA is not deficiencies above 350 nm may give %RCEE is calculated at the reference
persuaded to change the concomitant artificially high SPF values for waveband as the percentage ratio of the
use requirement in § 352.70(a). sunscreen drug products that absorb cumulative erythemal effectiveness in
(Comment 31) One comment poorly in the long wavelength UVA each of these wavebands to the total
suggested that there is a need for a region. integrated value from 250 nm to 400
specific source to maintain and supply The comments added that there is nm.
sunscreen standards. The comment general agreement in the industry that Based on these calculations, the
contended that a few testing laboratories § 352.71 should be revised to permit COLIPA table includes limits up to 400
are reporting differences in the tested compliance with the COLIPA standard nm. In contrast, when FDA requested
SPF of the 8-percent homosalate for solar simulators. The comments comments on this issue, we included a
standard preparation depending on further recommended one modification modified COLIPA table that includes
whether the standard is prepared by the to the COLIPA standard: The energy for limits up to 350 nm (65 FR 36319 at
laboratory or purchased from one wavelengths below 290 nm should be 36321). However, the modified COLIPA
company that manufactured this limited to ‘‘less than 0.1 percent’’ rather table published by FDA was erroneous.
standard. The comment stated that than ‘‘less than 1.0 percent,’’ as stated FDA agrees with the comment (and
either the testing procedures or the in the COLIPA standard. The comments COLIPA) that it is necessary to include
standard itself have changed since the stated that a more restrictive all UV erythemal wavelengths (i.e., up
original formula was published (earlier specification of ‘‘0.01 percent,’’ as to 400 nm) when standardizing solar
standard SPF values were 3.7/3.8 to 4.2/ mentioned by FDA (65 FR 36319 at simulator output. As argued by the
4.3 with an average of 4.1, while current 36321), would result more in testing the comment, the erythemal contribution
values are 4.3 to 4.9/5.0). limits of the measurement from long-wavelength UVA radiation
Data supporting the reliability and spectroradiometer rather than the true (i.e., 350 nm to 400 nm) can become
wide acceptance of the 8-percent output of the solar simulator. One important when a high SPF product is
homosalate standard preparation were comment that supported the COLIPA tested. However, FDA believes that the
previously discussed in the TFM (58 FR standard subsequently suggested that limits for the 290 to 350 waveband
28194 at 28250 through 28252). The the spectral limits be further narrowed should be changed from 93.5 to 99.0
comment did not provide any data to to prevent excessive variability of SPF percent to 93.5 to 98.5 percent. This
support its contention concerning values for certain sunscreen products modification will address some of the
discrepancies in the SPF of 8-percent (Ref. 74). errors in SPF that are attributed to the
homosalate standard preparations and One comment discussed the lack of match between the solar
FDA is not aware of any new data that calculations to obtain the source simulator and actual solar spectra. FDA
support the need for a specific source to spectral specification according to invites comments on these proposed
maintain and supply this standard. The COLIPA (Ref. 73). In the COLIPA table, changes.
standard is a control to validate the the source spectral specification is
FDA does not agree, at this time, with

testing procedure, equipment, and described in terms of cumulative the comment’s suggestion to further
facilities rather than a calibration tool erythemal effectiveness by successive narrow the COLIPA standard to the
for setting SPF values of sunscreen wavebands. The erythemal effectiveness spectral limits that it proposed. The
products. FDA considers the parameters of each waveband is expressed as a comment based its suggestion on a
established in § 352.70 of the FM percentage of the total erythemal theoretical argument and did not supply
adequate to assure a uniform standard effectiveness from 250 nm to 400 nm, or the complete emission spectra of the
four solar simulators used in its two solar simulators operated at or below a requirement that places a quantifiable
referenced studies. There may be total irradiance limit of 1,500 W/m2. limit of 20 percent on time related
significant differences in the 290 to 350 The comments added that the ‘‘out of fluctuations of the radiation emissions
nm range in these studies that can band’’ specification is not possible with of the solar simulator.
account for the reported differences in existing solar simulators and new Accordingly, FDA is proposing to
SPF test results. Further, FDA has systems would need to be designed, revise portions of § 352.71 (proposed
concerns about the ability of currently tested, manufactured, and distributed to § 352.70(b)(2)) to read as follows:
used solar simulators to meet the provide equipment capable of meeting (2) Operation. A solar simulator should
comment’s suggested spectral standard this specification. The comments have no significant time related fluctuations
and invites comments on the changes concluded that replacing the ‘‘out of (within 20 percent) in radiation emissions
suggested by the comment. band’’ specification with a limit would after an appropriate warmup time and good
FDA agrees with the comments that improve the testing of all products, beam uniformity (within 20 percent) in the
exposure plane. The average delivered dose
the COLIPA approach provides a more including high SPF products. to the UV exposure site must be within 10
appropriate description for solar FDA believes that it is important to percent of the prescribed dose.
simulators. FDA’s original proposal that limit total energy delivered to the skin (Comment 35) Several comments
solar simulators have a spectral power during the SPF test so that skin recommended that the last sentence of
distribution ‘‘similar to sunlight at a temperature does not reach a point that § 352.71 be modified to include
zenith angle of 10°’’ is nonquantitative may compromise dose reciprocity. FDA additional requirements for the periodic
and may not be practical, considering concurs with the comments and is testing of solar simulators. The
the types of solar simulators that are proposing to replace the ‘‘out of band’’
comments suggested that periodic
generally available. Accordingly, FDA is specification in § 352.71 (proposed
measurements be made twice a year and
proposing to revise the first part of § 352.70(b)) with a limit of 1,500 W/m2
that measurements be done after
§ 352.71 (proposed § 352.70(b)) as on total solar simulator irradiance
changes in the optical filtering
follows: between 250 and 1,400 nm.
(Comment 34) Two comments components.
(b) Light source (solar simulator)—(1)
Emission spectrum. A solar simulator used recommended that FDA change the FDA agrees with the comments and is
for determining the SPF of a sunscreen drug solar simulator specification in § 352.71 proposing to revise the last part of
product should be filtered so that it provides from ‘‘good beam uniformity (within 10 § 352.71 (proposed § 352.70(b)(3)) to
a continuous emission spectrum from 290 to percent) in the exposure plane’’ to ‘‘the read as follows:
400 nanometers (nm) with * * * the (3) Periodic measurement. To ensure that
delivered dose to the UV exposure sites the solar simulator delivers the appropriate
following percentage of erythema-effective
radiation in each specified range of be within 10 percent of the prescribed spectrum of UV radiation, the emission
wavelengths: dose with good beam uniformity’’ spectrum of the solar simulator must be
(without defining ‘‘good beam measured every 6 months with an
SOLAR SIMULATOR EMISSION uniformity’’). The comments contended appropriate and accurately calibrated
SPECTRUM that although ‘‘reasonable’’ or ‘‘good’’ spectroradiometer system (results should be
beam uniformity is desirable, beam traceable to the National Institute for
uniformity within 10 percent is virtually Standards and Technology). In addition, the
Wavelength range Percent erythemal
(nm) contribution impossible to measure or achieve for the solar simulator must be recalibrated if there
vast majority of solar simulators. is any change in the lamp bulb or the optical
< 290 < 0.1 FDA agrees that ‘‘dose’’ accuracy is a filtering components (i.e., filters, mirrors,
290–310 46.0–67.0 lenses, collimating devices, or focusing
critical variable and the delivered dose devices). Daily solar simulator radiation
290–320 80.0–91.0 to the UV exposure sites should be
290–330 86.5–95.0 intensity should be monitored with a
290–340 90.5–97.0 within 10 percent of the prescribed broadband radiometric device that is
290–350 93.5–98.5 dose. Because FDA considers sensitive primarily to UV radiation. The
290–400 93.5–100.0 quantification of ‘‘good beam broadband radiometric device should be
uniformity’’ to be an important issue, it calibrated using side by side comparison
(Comment 33) Several comments is keeping a specification for this with the spectroradiometer at the time of the
suggested the following revisions to the parameter. However, FDA believes that semiannual spectroradiometric measurement
light source (solar simulator) a specification of 20 percent is more of the solar simulator. If a lamp must be
achievable than the proposed 10 replaced due to failure or aging during a
requirements in § 352.71: phototest, broadband device readings
• Delete the ‘‘out of band’’ percent. Beam uniformity can be consistent with those obtained for the
specification that not more than 5 measured with broadband UV detectors original calibrated lamp will suffice until
percent of a solar simulator’s total that have been modified to provide a measurements can be performed with the
energy output can be contributed by small input aperture to the detector. For spectroradiometer at the earliest possible
wavelengths longer than 400 nm. example, for a single beam simulator opportunity.
• In place of this 5 percent ‘‘out of with a subsite exposure area of
band’’ limitation, allow a limit such as approximately 1 cm2, an appropriate L. Comments on the Design/Analysis of
1,250 to 1,500 watts/square meter (W/ input aperture would be 0.25 cm2. Beam SPF Testing Procedure
m2) on the total solar simulator uniformity can then be checked by (Comment 36) Several comments
irradiance delivered to the skin for all making a measurement in the center of contended that the series of seven
wavelengths. each of the four quadrants of the exposure doses in § 352.73(c) should be
One comment provided data exposure field. These readings should modified to eliminate the two doses
comparing solar simulators with and be within 20 percent of the peak placed symmetrically around the
without a 50 percent neutral density reading. The same principle can be middle exposure. One comment
filter to demonstrate that there is no applied to larger exposure fields. provided data comparing the seven-
measurable impact of heat load on the Additionally, the average of these four exposure series against the five-
outcome of SPF testing (Ref. 13). The readings should be within 10 percent of exposure series and concluded that the
comment stated that thermal overload the prescribed dose for a given exposure seven-exposure series did not increase
does not occur for COLIPA-compliant site. In addition, FDA is proposing a the precision of the test (Ref. 66).
Comments also argued that the seven- required for high SPF products and section. If more than 5 subjects are rejected
exposure series would require longer proposed a binomial test method to based on paragraph (c)(9) of this section, the
testing times, thus increasing exposure reduce the number of subjects (see panel is disqualified, and a new panel must
risk and discomfort to subjects, and that section III.I, comment 24 of this be created.
(ii) For products with an expected SPF of
the five-exposure series is as accurate as document). Another comment stated 30 or over. A test panel shall consist of 25
the seven-exposure series even at high that the 20 of 25 subject limitation may to 30 subjects with at least 25 subjects who
SPF values. be an issue for products with high SPF produce valid data for analysis. Data are
FDA discussed its rationale for seven values due to the high variability in the valid unless rejected in accordance with
versus five exposure doses in the TFM responses obtained and suggested that paragraph (c)(9) of this section. If more than
(58 FR 28194 at 28269 to 28272). FDA the number of subjects be increased 5 subjects are rejected based on paragraph
sought an exposure format that would when evaluating sunscreen products (c)(9) of this section, the panel is
provide better accuracy and precision to with high SPF values. disqualified, and a new panel must be
SPF measurements, particularly at As discussed in section III.I, comment created.
higher SPF values. FDA reasoned that 24 of this document, the binomial test In the 1978 advance notice of
the seven-exposure series in § 352.73(c), method deserves further investigation proposed rulemaking (ANPRM), the
with two additional exposures and may prove to be a reasonable Panel recommended that studies enroll
symmetrically placed around the approach as additional data and at least 20 subjects, adding that ‘‘the
middle exposure of the geometric series, experience become available. In standard error shall not exceed ± 5
would increase precision and eliminate addition, based on the current SPF test percent of the mean’’ (43 FR 38206 at
possible overestimation of the true SPF method, FDA agrees with the comment 38261). Following publication of the
value of a product with a high SPF. recommending deletion of the ANPRM, FDA held a public meeting on
FDA has evaluated the data and other requirement to fix the number of January 26, 1988 (52 FR 33598 at 33600
information submitted by the comments subjects per panel in advance. This to 33601). During that meeting,
and agrees they demonstrate that the requirement is unnecessary because the attendees argued the following four
additional two exposure doses do not panel is limited to a range of 20 to 25 points related to the number of subjects:
make the test more precise. Therefore, subjects (under current § 352.72(g)). 1. Test panels should consist of at
FDA is proposing to modify § 352.73(c) Thus, if 20 subjects produce valid data least 20 subjects.
(proposed § 352.70(d)(3)) as follows: 2. The size of the test panel should be
in accordance with proposed
* * * Administer a series of five UV fixed in advance.
§ 352.70(c)(9), then it would be
radiation doses expressed as J/m2-eff 3. The limitation that the standard
unnecessary to test additional subjects.
(adjusted to the erythema action spectrum error should be less than ± 5 percent
In addition, some subjects may not
calculated according to paragraph (d)(1) of should not apply.
this section) to the subsites within each test produce valid data in accordance with 4. The testing procedures should
site on a subject using an accurately proposed § 352.70(c)(9) (e.g., no make it clear that the addition of
calibrated solar simulator. The five UV doses erythema produced), requiring testing of subjects to the test panel to achieve the
will be a geometric series as described in additional subjects (not exceeding 25 desired minimum is acceptable under
paragraph (d)(2) of this section, where the subjects). FDA agrees that the number of specific conditions (58 FR 28194 at
middle exposure represents the expected subjects should be based on error about
SPF. For products with an expected SPF less 28267).
the mean SPF, but disagrees that the In the 1993 TFM, FDA based § 352.72(g)
than 8, use exposures that are the product of minimum number of subjects can be
the initial unprotected MED times 0.64X, on these comments and the Panel’s
lowered to 10. As described later in this recommendation.
0.80X, 1.00X, 1.25X, and 1.56X, where X
equals the expected SPF of the test product. comment, FDA has reevaluated the The calculations of the sample size
For products with an expected SPF between proposed minimum number of subjects and confidence interval in § 352.72(g)
8 and 15, use exposures that are the initial based on error about the mean SPF. are based on the assumption that there
unprotected MED times 0.69X, 0.83X, 1.00X, FDA agrees with one comment that is a normal distribution about the mean
1.20X, and 1.44X, where X equals the more subjects are needed when testing (i.e., a bell curve). Based on this
expected SPF of the test product. For products with high SPF values. FDA assumption, the t-test is used for
products with an expected SPF greater that believes that a minimum sample size of
15, use exposures that are the initial statistical analysis. Based on the t-test,
20 subjects is adequate for products FDA calculated that a panel of 20
unprotected MED times 0.76X, 0.87X, 1.00X, with an expected SPF value of 30 or
1.15X, and 1.32X, where X equals the subjects should result in an acceptable
expected SPF of the test product. * * *
less. However, current data and error about the mean. However, in some
(Comment 37) Several comments experience with products having SPF cases, a panel of 10 subjects would
suggested changes to the number of values over 30 are not sufficient to probably result in an error about the
subjects per test panel in § 352.72(g). determine an appropriate sample size. mean that is unacceptably large. There
One comment suggested deletion of the Therefore, to account for increased is inherently higher variability in testing
phrase ‘‘with the number fixed in variability in SPF values for sunscreens and, consequently, larger error about the
advance by the investigator.’’ The with SPF values over 30, FDA proposes mean for products with high SPF
comment reasoned that if the first 20 to increase the sample size to at least 25 values. Therefore, FDA believes a
subjects provided data that can be subjects. FDA invites data greater number of subjects is necessary
evaluated, risk to human subjects could demonstrating an appropriate panel size when testing products with high SPF
be curtailed by not impaneling another for sunscreens with SPF values over 30. values. FDA believes a panel of 25 to 30
5 subjects. Other comments At this time, FDA is proposing to revise subjects should result in an acceptable
recommended using 10 to 20 subjects, § 352.72(g) (proposed § 352.70(c)(7)) as
error about the mean for products with

arguing that the criterion for accuracy follows: high SPF values. FDA invites additional
(7) Number of subjects—(i) For products
should not be the number of subjects, with an expected SPF value under 30. A test data demonstrating adequate numbers of
but the relative deviation of individual panel shall consist of 20 to 25 subjects with subjects, especially for products with
SPF measurements. One comment used at least 20 subjects who produce valid data high SPF values.
absorbance instead of the SPF value to for analysis. Data are valid unless rejected in (Comment 38) One comment stated
calculate the number of subjects accordance with paragraph (c)(9) of this that one factor affecting the SPF of a
product is the erythemal threshold of there was a large systematic deviation using a smaller test subsite area before
the skin, or MED(US). The comment between the FDA and DIN methods. As amending the monograph test. FDA will
argued that SPF decreases with this study was not designed specifically consider a reduction in test subsite area
increasing erythemal threshold. The to compare irradiation areas, three if adequate supporting data are
comment maintained that, because different test subsite areas were used, provided. The studies should do the
MED(US) varies only with skin type, the and none was 0.5 cm2. FDA cannot following:
MED(US) of each subject in a test group determine the suitability of a 0.5 cm2 • Compare the smaller subsite area to
should be within reasonably similar test subsite area compared to a 1 cm2 1 cm2 on the same subjects,
limits. The comment suggested that the test subsite area based on this study. • Utilize high SPF products as well as
MED(US) of each subject should be 50 The comment advocating the 0.8 cm products with SPF values below 15, and
to 150 percent of the median MED(US). test subsite diameter argued that setting • Demonstrate comparable results
The comment also suggested that a lower area limit has the following four among several laboratories.
subjects with an MED(US) that is twice benefits: (Comment 40) Several comments
the median should be excluded • Does not preclude the use of larger either agreed or disagreed with the
regardless of skin type. irradiation areas, blinding procedures for the application
FDA is not proposing the revisions • Will not affect the accuracy of of test materials described in
suggested by the comment. FDA based resulting measurements, § 352.72(e). One comment stated that
§ 352.73(b), which describes • Permits lower wattage lamps as unblinded SPF testing is bad science,
determination of an MED(US), on the well as liquid light guides that have and that exposure sites within test areas
Panel recommendation in the ANPRM. apertures of 0.8 cm diameter, and should always be randomized no matter
The procedure for determining • Provides more skin area for testing. how many products are being tested.
MED(US) requires irradiation of subjects The comment provided statistical Another comment stated that the
with a geometric series of UV doses. analysis of a study comparing multi-port blinding procedure is an unnecessary
When developing this procedure, the and single-port solar simulators (Ref. complication and does not contribute to
Panel explained that the geometric 66). SPF 15 or SPF 4 products were the accuracy of the test. One comment
series provides the same relative level of tested along with the homosalate agreed that, in order to approximate true
uncertainty independent of the subject’s standard sunscreen. Two subsite areas blinding, the individual who grades
sensitivity to UV light (i.e., independent were exposed to the multi-port solar erythemal responses should not be the
of skin type) (43 FR 38206 at 38266). simulator, and two were exposed to the same clinician who applied the test
Thus, the Panel disagreed that skin type single-port solar simulator. The materials. Another comment contended
affects MED(US). The comment did not comment concluded that similar SPF that it is not reasonable to randomly
provide any data or other information values are determined using the two irradiate test sites with varying doses of
demonstrating that skin type, in fact, types of solar simulators. However, the UV radiation. One comment
affects MED(US). FDA is not aware of study report did not include details recommended making the use of finger
any data demonstrating this such as subject selection, product cots optional because some product
phenomenon. FDA will revise the application, or specifications for the vehicles are incompatible with finger
proposed test criteria if we receive data solar simulators. More importantly, the cot material. Another comment
or information demonstrating that the study report did not specify the size of suggested that the amount of product
criteria are not appropriate or other each subsite. Thus, FDA cannot draw remaining on the finger cot is a source
criteria are more suitable. any conclusions regarding appropriate of variability in the SPF test and
(Comment 39) Several comments test subsite area from the submitted suggested that the extent of this
urged FDA to reduce the minimum 1 study. variability be fully evaluated.
cm2 test subsite area in § 352.72(d)(2). The comment supporting the 0.15 cm FDA agrees with the comments that
One comment proposed the minimum test subsite diameter referenced two favor blinding and randomization and is
test subsite area be decreased to 0.5 cm2. studies (Ref. 76). Significant not proposing to remove the blinding
Two comments suggested that the test discrepancies in the information and randomization requirements from
subsite area be defined by minimum submitted for the first study prevented § 352.72(e) (proposed § 352.70(c)(5)).
diameters of 0.8 cm (circular area of 0.5 evaluation of this study. The comment According to § 352.72, blinding and
cm2) and 0.15 cm (circular area of 0.017 did not submit full details of the second randomization is required only when
cm2), respectively. study. Therefore, FDA could not reach two or more sunscreen drug products
The comment supporting the 0.5 cm2 any conclusions from the submitted are being evaluated at the same time.
test subsite area referenced a study studies. Because a test product is always tested
published in 1987 (Ref. 75) that was FDA agrees, in principle, with the in conjunction with the standard
mentioned in relation to artificial light advantages of a smaller test subsite area. sunscreen, FDA proposes to delete the
sources in comment 86 of the TFM (58 The Panel stated that, depending on statement, ‘‘If only one sunscreen drug
FR 28258 to 28261). This study was instrumental design, irradiation test product is being tested, testing subsites
designed to evaluate the FDA sequential subsite areas less than 1 cm2 can be should be exposed to varying doses of
technique of dosing using a single-port utilized and that test subsite diameters UV radiation in a randomized manner.’’
solar simulator (SPSS), a series greater than 0.4 cm present no difficulty Section 352.72(h) (proposed
sequential method using a multi-port in determining skin erythema (43 FR § 352.70(c)(8)) specifies that the person
xenon arc solar simulator (MPSS), and 38206 at 38260). While FDA does not who evaluates the MED responses must
the Deutsches Institut für Normung consider the information provided by not be the same person who applied the
(DIN) simultaneous technique of dosing the comments adequate to support the
sunscreen or administered the dose of

using an Osram Ultravitalux lamp. Five suggested test subsite areas, it UV radiation. The comments that
sunscreen formulations with SPF values recognizes that considerable advances disagreed did not provide evidence
from 4 to 15 were tested. The authors have been made since the Panel met. demonstrating that these requirements
suggested that there was little However, FDA requires data are unnecessary.
systematic difference in estimates demonstrating that the monograph test With regard to the suggestion that the
obtained using the SPSS and MPSS, but produces valid and reproducible results use of finger cots be made optional, the
Panel’s review of data found that that define the total amount of equivalency test than would be
numerous investigators have obtained erythema-effective energy applied to the determined using the FM method. By
more reproducible results by spreading testing subsite (i.e., as J/m2). FDA contrast, a higher SPF would never be
a product using a finger cot than by discussed replacing ‘‘exposure time determined for a sunscreen using the
spreading with a glass or plastic rod (43 interval’’ with ‘‘erythema-effective FM method than would be determined
FR 38206 at 38261). FDA agrees with exposure (dose),’’ but inadvertently using the equivalency test. Thus, the FM
the comment that some formulations used ‘‘exposure time interval’’ instead of method results in a more conservative
may be chemically incompatible with ‘‘dose’’ in § 352.73(b). FDA agrees that SPF value than the equivalency test.
latex finger cots, but there are finger cots § 352.73(b) (proposed § 352.70(d)(2)) FDA believes it is in the best interest of
composed of other materials that should should be modified and is amending public health to label sunscreens with
be compatible with these sunscreens. this section as the comment suggested. the more conservative SPF value. If FDA
Therefore, to increase reproducibility in (Comment 43) Several comments adopted the equivalency test after over
sunscreen application, FDA is suggested an alternative statistical 30 years of using the FM method,
proposing to revise the application procedure for calculating product SPF consumers may, in some cases,
requirement in § 352.72(e) (proposed values and PCD in current § 352.73(d). overestimate the protection provided by
§ 352.70(c)(5)) to read as follows: The comments argued that the a sunscreen based on a higher SPF
* * * Use a finger cot compatible with the procedure described in the FM would number resulting from the equivalency
sunscreen to spread the product as evenly as result in significant lowering of SPF test.
possible. Pretreat the finger cot by saturating values. The comments advocated
with the sunscreen and then wiping off clinical equivalency testing (i.e., using a M. General Comments on UVA Testing
material before application. Pretreatment is
lower one-sided 95 percent confidence Procedure
meant to ensure that sunscreen is applied at
the correct density of 2 mg/cm2. interval or a one-sided t test, with a (Comment 44) Many comments
FDA urges manufacturers of sunscreen delta of 5 percent). The comments noted discussed UVA radiation action spectra
drug products to investigate the extent that an upper and lower bound and skin damage (erythema,
of variability in the SPF test that may be equivalency procedure with a delta of photocarcinogenesis, DNA damage,
caused by various applicators. 20 percent would be an appropriate photosensitivity reactions, photoaging,
(Comment 41) One comment procedure. The comments added that mutagenicity, and immunosuppression).
addressed illumination at the test site in SPF is not a precise value, but rather a Some comments described various types
§ 352.72(h) and recommended that a valid estimate of product performance. of solar-induced skin damage and the
level of at least 1,000 lux be used. The Another comment suggested using the wavelengths contributing to the specific
comment contended that 450 to 550 lux mean of the results to find the actual biological events. Some comments
is too low to provide adequate number and then round-off (either up or stated that UVA II radiation (320 to 340
illumination for reading erythema. down) to the nearest whole number. nm) is much more damaging than UVA
As discussed in the TFM, the Panel FDA is not proposing to modify the I radiation (340 to 400 nm).
recommended an incandescent or warm calculation of product SPF values and Other comments stated that there is
fluorescent illumination source but did PCD in § 352.73(d) (proposed presently no convincing evidence that
not specify a required illumination level § 352.70(d)(4)) at this time. The distinct the action spectra for damage from UV
(58 FR 28194 at 28269). In the TFM, advantage of the t-test is that it provides radiation have been clearly defined. One
FDA agreed with the Panel about the a simple computational procedure for a comment stated that until the separate
illumination source. FDA also proposed statistical test that makes inferences dangers and risks of each portion of the
that the illumination level be 450 to 550 about the population. The SPF is UVB and UVA radiation action spectra
lux. The comment did not provide any determined to be the largest whole are precisely and scientifically
data to support its contention that 1,000 number that is excluded by a lower one- identified and quantified, FDA should
lux is the appropriate illumination sided 95 percent confidence interval. consider the entire UVA radiation range
level. Thus, FDA is not revising the lux Simply finding a mean value, as one as having significant biological risk.
range in § 352.72(h) (proposed comment suggested, is not adequate Another comment stated that protection
§ 352.70(c)(8)) at this time. FDA invites because such a value does not provide against all UVA radiation wavelengths
data and information on levels of information about the validity of the test would seem to be both desirable and
illumination currently used to evaluate (e.g., standard deviation) that should be prudent considering the present state of
MED responses in SPF testing taken into consideration. our knowledge.
FDA’s evaluation of the equivalency FDA agrees that the action spectra for
laboratories and will consider
testing approach for calculating SPF various harmful effects on human skin
adequately supported alternatives.
values indicates the method is less from chronic UVA radiation have not
(Comment 42) One comment stated
stringent than the FM method. The been clearly defined and that it may be
that the third sentence in § 352.73(b)
proposed equivalency test is essentially misleading to associate damage with
should be modified to read: ‘‘* * *
testing the following hypothesis: any specific action spectrum based
wherein each exposure dose is 25
H0: µ ≤ 0.95L versus Ha: µ > 0.95L
percent greater than the previous where: H0 = null hypothesis upon current knowledge. Information
exposure dose to maintain the same Ha = alternative hypothesis provided by comments suggests a
relative uncertainty * * *.’’ The µ = population mean relatively greater role for UVA radiation
comment explained that defining the L = confidence limit than UVB radiation in long-term sun
exposure dose in terms of ‘‘time’’ is FDA acknowledges that the equivalency damage even though there is little
incorrect. test may be a valid method for consensus about the amount of UVA
FDA discussed the Panel’s definition determining SPF. In many cases, the radiation protection required. Therefore,
of dose in terms of time intervals in same SPF would be determined for a FDA is proposing UVA radiation test
comment 84 of the TFM (58 FR 28194 sunscreen using either the equivalency methods that assess protection
at 28256 to 28257). FDA stated that it is test or the FM method. However, in throughout the UVA spectrum (see
more accurate to express dose as the some cases, a higher SPF would be section III.N, comment 45 of this
‘‘erythema-effective exposure,’’ in units determined for a sunscreen using the document).
N. Comments on UVA Testing • Practicability, convenience, and absorption spectrum of the product
Procedure Design and Testing Criteria safety. throughout the UV radiation range.
Stating that there is currently no Then, one calculates the wavelength
(Comment 45) FDA is proposing that
both an in vitro and an in vivo test be
convincing evidence that the action value λc (the ‘‘critical wavelength’’),
spectrum for UVA radiation damage has where the area under the absorption
conducted to determine UVA radiation
protection. The proposed in vitro test is
been clearly defined, another comment spectrum from 290 nm to λc is 90
suggested that protection from UV percent of the integral of the absorption
the ratio of long wavelength UVA
radiation be measured using two factors spectrum from 290 to 400 nm, and uses
absorbance (UVA I) to total UV
based on the degree of attenuation of UV a five-point scale to classify products as
absorbance (i.e., UVB + UVA). The radiation across the full spectrum. One
proposed in vivo test is the PPD test, follows:
factor, the SPF value, is erythemally
which is similar to the SPF test except weighted and gives an indication of the
the endpoint is pigment darkening TABLE 3.—BROAD SPECTRUM RAT-
power of protection provided by the ING BASED ON CRITICAL WAVE-
rather than erythema. FDA is proposing product. The second factor should take
that UVA labeling consist of a UVA LENGTH
into account the shape of the
rating reflecting both the in vitro and in transmittance curve measured by either
vivo test results. The rating will be the Critical Wavelength Broad Spectrum
in vivo or in vitro means. The comment (nm) Rating
lowest ‘‘high’’ protection, then the stated that it is potentially dangerous to
sunscreen would be labeled as associate skin damage with any single λc < 325 0
providing ‘‘medium’’ UVA protection. action spectrum (e.g., IPD, PPD, or PFA). 325 ≤ λc < 335 1
FDA is proposing these UVA testing The comment argued that all of these 335 ≤ λc < 350 2
requirements based on many comments indicators are wavelength-specific and 350 ≤ λc < 370 3
submitted in response to the TFM that 370 < λc 4
protection from specific wavelengths
contained data and information on does not mean protection from damage.
possible test methods (and The comment concluded that this test
The comment added that if only the
combinations or modifications of these method makes no underlying
erythema action spectrum is used, it
methods). The comments discussed the assumptions about the form of action
virtually ignores the effects of
following in vivo and in vitro test spectra for either acute or chronic
wavelengths over 320 nm. The comment
procedures: photobiological damage. Because the
contended that using an SPF value
• IPD, efficiency of UV radiation to induce a
augmented by the shape of the
• PPD, given photobiological endpoint tends to
transmission curve would give
• PFA, consumers the information necessary to decrease with increasing wavelength,
• Photosensitivity methods, make an effective and safe judgment the method utilizes wavelength
• UVA radiation protection percent, about the protection provided by a intervals for classifying the ‘‘broad
• Diffey/Robson method and sunscreen drug product. For example, spectrum’’ rating, which increases in an
modifications of that method, the comment noted that a product with approximately logarithmic manner.
• Standards Association of Australia, a high SPF and a uniform high level of One comment submitted a protocol
• Diffuse reflectance method, attenuation across the spectrum (i.e., for the ‘‘critical wavelength’’ (CW)
• Skin2 method, and equal attenuation at all UVB and UVA modification of the Diffey/Robson
• Psoralen photoadduct method. wavelengths) will provide the most method for classifying the relative
On May 12, 1994, FDA held a public protection. The comment added that, at degree of UVA radiation protection of
meeting to discuss these UVA radiation a later date, if sufficient evidence sunscreen drug products (Ref. 80). The
testing procedures (Ref. 77). becomes available to describe a credible comment addressed product
One comment suggested using either UVA radiation damage spectrum, this photostability by pre-irradiation of the
or both PPD and erythema skin combined system could be used by sunscreen product with a UV radiation
responses to measure the UVA radiation convoluting the attenuation curve with dose corresponding to one-third the
protection effectiveness of OTC the action spectrum curve. labeled SPF value. The comment
sunscreen drug products. The comment One comment proposed a reported recommendations based on the
maintained that these two test methods modification (‘‘critical wavelength’’) of results of a round-robin evaluation of
have the following similarities: the Diffey/Robson test method (Refs. 78 the proposed CW method involving six
• Same UVA radiation source, and 79). The comment noted that, when laboratories using four test sunscreen
• Same dose range, and people are outdoors, they are not formulations with various substrates.
• Similar post exposure time lags for exposed to only UVB or UVA radiation The comment concluded that the CW
observation. but are exposed to solar UV radiation, method is a convenient, reproducible in
The only difference is in the skin types which always contains both. In vitro method for measuring the
used, thus giving a variable balance in addition, biological effects against uniformity of sunscreen absorbance
PPD and erythema responses. The which people may wish to be protected spectra across the UV radiation
comment added that such a are caused by all wavelengths in the spectrum to classify products into broad
combination of methods has the solar UV radiation spectrum. The UVA radiation protection categories.
following advantages: comment contended that investigators In response to the June 8, 2000,
• Reproducibility and stability, should not be exposing subjects to reopening of the administrative record
• Relevance, sources of radiation with spectra that for the rulemaking for OTC sunscreen
• Persistence of skin response drug products (65 FR 36319), FDA
have no practical application and using

through 1 to 24 hours, irrelevant biological effects as endpoints received additional comments on UVA
• Independence of source flux and (e.g., IPD). radiation testing methods. While all
accuracy, The comment proposed to assess the comments supported some type of
• Utilization for static as well as for UVA radiation protection potential of an testing to differentiate the UVA
water resistance photoprotective OTC sunscreen drug product by first radiation protection potential of
predictions, and spectrophotometrically determining the sunscreen products, they disagreed
about the use of in vivo versus in vitro further stated that the proposed in vivo because two products can have the same
testing methods. methods modeled after the SPF test CW with very different UVA radiation
Comments from a group of sunscreen generate protection factors that are absorbance curves and, thus, provide
product manufacturers contended that protocol dependent and of different protection for consumers.
an in vivo test method, such as PPD or indeterminate clinical relevance, as Some comments stated that a
PFA, best describes the photoprotective none are surrogates for long term combination of methods may be
characteristics of a sunscreen drug concerns like cancer and photoaging. appropriate for assessing the complete
product. These comments stated that an Another comment added that the PPD UVA radiation protection potential of a
in vivo method measures the actual and PFA tests do not adequately assess sunscreen product. One comment
effect of UVA radiation on the skin and the breadth of UVA radiation protection suggested combining either the PPD or
estimates the expected product and that the biologic effects of full PFA method with an in vitro method for
performance under actual use spectrum UV radiation differ from the a meaningful and rigorous test of both
conditions. effects of isolated wavelengths. the magnitude and breadth of the
One comment presented test data that Several comments recommended biological protection (i.e., the level of
suggested PPD and PFA values are using an in vitro method, and most protection and the UVB and UVA
comparable (Ref. 6). The comment considered the CW method as wavelengths that are protected against)
stated that an advantage of the PFA appropriate. One comment stated that provided by a sunscreen product.
method is that it allows inclusion of CW allows for broad spectrum activity Another comment stated that complete
skin type I, whereas the PPD test is regardless of SPF so that, if consumers assessment of a sunscreen product’s
conducted on darker skin types (II and use a low SPF product, they will at least UVA radiation protection must include
III). However, the comment added that have the option of choosing one that both of the following:
the PPD test has been accepted since provides a wide breadth of activity. • An in vitro measurement of the
1996 by the JCIA for the assessment of Another comment stated that CW absorbance above 360 nm (i.e.,
UVA radiation protection efficacy of provides a simple, reproducible, and demonstrate adequate breadth of
sunscreen products. adaptable method that can account for absorbance), and
One comment contended that the PPD sunscreen photostability and insure • An in vivo measurement of the
test should be used for the following UVA radiation protection that is both quantity of UV radiation protection (i.e.,
reasons: commensurate with and independent demonstrate adequate magnitude of
• It requires a relatively low dose of from the SPF value. Another comment absorbance).
UV radiation. added that CW accounts for Other comments stated that a
• The reaction is stabilized in 2 to 4 proportionality because, in order for a combination of the in vivo SPF method
hours. sunscreen to maintain a given CW, and the in vitro CW method provide a
• The test subject is left with no mark protection from both long and short complete description of a product’s
of irradiation and receives little or no UVA radiation wavelengths must inherent photoprotective characteristics
injury. increase as UVB radiation protection with the SPF value describing the
• The test can be conducted with increases. amplitude of protection and CW
high precision. Several comments stated that the CW providing a reliable measure of the
Another comment stated that PPD threshold should be 370 nm for a ‘‘broad product’s spectral absorption capability.
values demonstrate the same correlative spectrum’’ claim on a sunscreen. Other One comment suggested a UVA/UVB
benefits that exist for SPF values and, comments recommended a threshold of radiation proportionality scheme. The
therefore, do not give false impressions 360 nm. One comment stated that if comment referred to FDA’s previous
of magnitude. Another comment stated FDA were to arbitrarily select a standard discussions about UVA/UVB radiation
that products with the same SPF can higher than 360 nm, it would cause a proportionality (Refs. 11 and 81) and a
have different levels of UVA radiation major reformulation effort within the recommendation from the AAD that ‘‘an
protection. Thus, PFA or PPD is not industry, higher prices to consumers, increase in SPF of a sunscreen must be
redundant with the SPF value. and a shortage of ‘‘broad spectrum’’ accompanied by a proportional increase
Comments from other sunscreen products in the OTC marketplace. The in the UVA protection value’’ (Ref. 82).
product manufacturers opposed an in comments did not provide data to The comment added that the
vivo method to determine UVA support the use of a specific threshold proportional contribution to sunburn
radiation protection. One of these number in relation to the prevention of from solar UVB and UVA radiation is 80
comments stated that in vivo tests specific photobiological effects. to 20 (4 to 1), respectively, and that this
expose human subjects to doses of UVA Other comments opposed the CW relationship gives the minimum UVA
radiation with unknown human health method as not appropriate. One radiation attenuation needed to provide
consequences. The comment added that comment, which favored an in vivo proportional UVA/UVB radiation
because exposure to UVA radiation method, stated that the CW method, protection for any SPF value. The
alone is never encountered in nature, based on an arbitrary, nonbiological comment concluded that a minimum
full spectrum light is most relevant for criterion, fails to provide an accurate UVA protection value of 2 should be
product evaluations. This comment measure of the protection efficacy of a required even at low SPF levels with
contended that PFA values are sunscreen product. This comment proportionately higher UVA protection
redundant with SPF testing because of provided data to demonstrate that a values for higher SPF values.
an overemphasis on short wavelength significant failure of the CW method is One comment suggested that the UVA
UVA radiation (UVA II), and PFA values its inherent inability to differentiate protection value should be determined
give a false impression of the magnitude UVA radiation protection levels of with an in vivo method while CW is
of absorption differences. For example, sunscreen products relative to biological appropriate to determine spectral
the comment stated that two products endpoints (e.g., premature skin aging) broadness. Another comment stated that
with PFA values of 5 and 10 may (Ref. 23). A second comment agreed CW accounts for proportionality
attenuate 80 and 90 percent of UVA with this assertion, while a third because both long and short UVA
radiation, respectively. Thus, the real comment expressed concern that CW radiation protection must increase as
difference is small. The comment measurements may be misleading UVB radiation protection increases in
order for a sunscreen to maintain a suggested test methods. On the other Breadth can best be determined by
given CW. Another comment provided hand, the IPD response has not been appropriate in vitro test methods.
data (Ref. 23) for two products with the shown to represent a direct or surrogate At this time, FDA believes a
same CW value but different SPF values endpoint for biological damage. The IPD combination of existing in vivo and in
and concluded that the product with the response is also extremely difficult to vitro UVA radiation testing methods
higher SPF value did not provide greater read. addresses the inadequacies of either
UVA protection. Other comments stated The PFA test method uses endpoints method when used alone and provides
that there is no biological basis for that reflect actual damage that can occur a more complete UVA radiation
establishing strict UVB/UVA radiation to normal skin as a result of UVA attenuation profile for use in labeling
proportionality and that the radiation exposure (i.e., erythema or OTC sunscreen drug products.
establishment of this kind of ratio is tanning). The erythema action spectra Requiring the two test methods will
arbitrary. may be similar to the action spectra of ensure that both the magnitude and
The AAD (Ref. 83) referenced an known chronic skin damage (e.g., solar breadth of UVA protection is
international consensus conference on elastosis) (Ref. 85). However, the PFA determined. As discussed later in this
UVA radiation protection of sunscreens test method may not determine response, the proposed UVA labeling
and recommended the following: protection against skin melanoma or will reflect the results of both tests and,
1. Both an in vitro and an in vivo other skin damage thought to be caused therefore, will reflect magnitude and
testing method must be used to measure by chronic exposure to UVA radiation breadth of UVA protection. FDA
UVA radiation protection. (Refs. 29 and 86). believes that the methods and labeling
2. CW is the preferred method of in
The CW method can assess how currently being proposed provide the
vitro testing for a broad spectrum claim
broadly a sunscreen can absorb across best assurance for consumers to receive
(with a threshold for this claim at 370
the UV radiation spectrum, but provides adequate protection across the entire
nm).
3. CW must be combined with an in no information concerning product UVA radiation spectrum.
vivo method such as either PPD or PFA. performance after interaction with FDA is proposing the PPD method as
4. There must be a minimum four-fold human skin. While in vivo methods to the in vivo part of the test to determine
increase in PPD or PFA value in the assess UVA radiation protection may UVA radiation protection of a sunscreen
presence of a sunscreen (relative to the have possible sources of variability drug product. This test assesses UVA
absence of sunscreen). similar to the SPF test (e.g., test product radiation attenuation by measuring UVA
In the Federal Registers of May 12, application, differences in light sources, radiation-induced tanning, a direct
1993 (58 FR 28194 at 28248 to 28250), etc.), in vitro methods also possess effect induced by UVA exposure. The
September 16, 1996 (61 FR at 48645 at possible sources of inherent variability PPD test is relatively easy to perform
48652), and October 22, 1998 (63 FR (e.g., test product evaporation time, and relies on a stable, biological
56584 at 56587), FDA discussed substrate orientation, instrumentation, endpoint that can describe the
photosensitivity and erythemal UVA use with color change sunscreen magnitude of UVA radiation protection
radiation testing procedures for OTC formulations, etc.). of sunscreen products. It is similar to
sunscreen drug products. Criteria In general, FDA would prefer the the SPF determination as it is a ratio of
discussed for UVA radiation claims standard UVA radiation test method to a minimum pigmenting dose (MPD) on
included the requirement for an have a clinically significant endpoint. unprotected skin to that on protected
absorption spectrum extending to 360 After reviewing the data and skin. The endpoint is the PPD response,
nm or above, plus the demonstration of information provided by the comments, which is the stable, lasting residual part
meaningful UVA radiation protection FDA agrees that there is no convincing of the immediate pigment darkening or
via testing procedures. IPD/PPD, PFA, evidence that the action spectra for all blue gray pigment that develops
photosensitivity, and in vitro UVA possible types of UVA-induced damage immediately during exposure to UVA
radiation testing methodologies were have been clearly defined and that no radiation and quickly fades at the end
also discussed at a public meeting on one method is without disadvantages. of exposure. It provides consumers with
May 12, 1994 (Ref. 77). At this time, FDA agrees with the a means to specifically compare the
The selection of an appropriate UVA recommendation provided by the AAD amount of UVA radiation protection
radiation testing procedure for OTC and other comments that an in vivo between products and select an
sunscreen drug products has been method is appropriate in combination appropriate sunscreen product. The PPD
difficult for a number of reasons. The with an in vitro testing method to assess test has been shown to produce reliable,
scientific community does not agree on the UVA radiation protection. reproducible data and to distinguish
which testing procedure is most Because the action spectrum for UVA- between varying levels of UVA radiation
appropriate. For example, Cole induced skin damage is not clearly attenuation (Refs. 87 and 88). It has been
discusses the virtues and shortcomings known, FDA considers it necessary to shown to detect protection provided by
of a variety of in vivo and in vitro test measure both the magnitude and ‘‘broad spectrum’’ sunscreens against
methods (Ref. 84). In addition, each test breadth of UVA protection. The both short and long wavelength UVA
procedure has its own distinct magnitude of UVA absorbance is a radiation. The endpoint is a stable skin
advantages and disadvantages, as measure of how well a product absorbs response that is linearly dependent on
discussed in the following paragraphs. UVA radiation. The magnitude of UVA the amount of UVA radiation that enters
FDA believes the IPD test method absorbance is best measured by an in the viable epidermis. FDA also agrees
provides an appropriate endpoint for vivo method. An in vivo method with one comment that a UVA
determining UVA protection, because measures a biological response on the protection value of 2 should define the
pigment darkening is caused primarily skin (e.g., pigment darkening) and, lowest end of acceptable PPD test
by UVA (and not UVB) radiation. This therefore, correlates to actual use results relative to the consideration of
method is advantageous over other conditions. The breadth of the UVA acceptable UVA radiation claims (see
suggested test methods in that it uses absorbance is a measure of how broadly proposed § 352.72(d)(3)). FDA considers
low doses of radiation and, therefore, a product absorbs UVA radiation across it desirable to incorporate measurable
exposes subjects to less risk than other the entire UVA radiation spectrum. UVA radiation protection at all SPF
levels for products that claim to protect As the current state of technology over the UV radiation range from 290 to
against both UVB and UVA radiation. allows for an instrumental 400 nm by measuring the quantity of UV
As one comment noted, the PPD test measurement/quantification of skin radiation transmitted through surgical
has been accepted and validated as the color via spectral reflectance, FDA also tape (TransporeTM tape) before and after
JCIA method since 1996 (Ref. 23) and is invites comments regarding colorimetry application of a sunscreen drug product.
one of two in vivo methods suggested by as a method of evaluating pigment The test product (2 mg/cm2) is applied
the AAD (Ref. 83). Although data darkening. By avoiding the subjectivity to the textured surface of the
provided to FDA indicate that the PPD of detecting pigment change by the TransporeTM tape. A xenon arc solar
and PFA in vivo tests provide human eye, the reproducibility of the simulator is used as the UV radiation
comparable results (Ref. 6), the PPD test PPD method should increase. source. Transmitted UV energy is
provides the practical benefit of a Colorimetry could likewise be used in collected and measured at 5 nm
shorter post exposure reading time. FDA SPF testing if submitted data intervals over the UVB and UVA
agrees with the comments that PPD demonstrated increased accuracy and radiation range, which provides a
values are not redundant with SPF reproducibility of colorimetry over profile of UV radiation absorbance.
values as sunscreen drug products with visual inspection. Mathematical calculations are made
the same SPF value can have very As the PPD method is similar, overall, separately of the areas under the UVB
different levels of UVA radiation to the SPF method, FDA is also and UVA radiation parts of the curve.
protection as measured by the PPD test. proposing that the directions for the The ratio below the curve is determined
Accordingly, FDA is including the PPD PPD method be similar to those for the as follows:
method in proposed § 352.72 as part of SPF test for determining MPDs on
the testing to determine the UVA unprotected skin, individual UVA
radiation protection potential of an OTC protection factors, test product UVA
sunscreen drug product. protection factors, and PCDs. Further, as
discussed in section III.L, comment 37 As the ratio increases, the degree of
FDA agrees with the comments that UVA radiation protection increases.
of this document regarding the SPF test,
suggested modifications to the PPD FDA is concerned that this method, as
FDA is proposing that a PPD test panel
method (i.e., the JCIA standard). described in previous paragraphs,
consist of 20 subjects who produce valid
Therefore, FDA is proposing determines the ratio of the entire UVA
data, similar to the panel size for
modifications to the PPD method. One to UVB radiation spectra. Therefore, a
sunscreens having SPF values less than
group of sunscreen manufacturers sunscreen drug product that absorbs
30.
suggested that the previously validated FDA is concerned, however, that use strongly in the UVA II radiation area,
‘‘high SPF’’ padimate O/oxybenzone of the PPD method alone could result in but does not absorb strongly in the UVA
standard sunscreen under consideration some products yielding high UVA I radiation area, might still have an
by FDA (see section III.J, comment 27 of radiation protection factors without adequate ratio of UVA to UVB radiation
this document) should also be used as having broad absorbance throughout the protection to fulfill the test
the control formulation for in vivo UVA UVA radiation spectrum due to strong requirements, but would not provide
radiation testing (Ref. 6). Based upon absorbance in the UVA II region. In adequate protection in the UVA
data provided by the comment, FDA is other words, a sunscreen could absorb radiation region where absorbance is
proposing the referenced ‘‘high SPF’’ high levels of UVA II but very little lacking. FDA believes that this
padimate O/oxybenzone standard UVA I and achieve a high UVA rating deficiency can be corrected by revising
sunscreen for use as the standard under the PPD method. Therefore, FDA the calculations to take into account the
sunscreen in the in vivo UVA radiation is proposing that an in vitro method be ratio of UVA I and/or UVA II
test in proposed § 352.72. FDA invites used (to assess the breadth of individually to UV radiation. Some
comment on the suitability of this absorbance across the UV radiation comments were concerned that UVA II
formulation as a UVA radiation test spectrum) in conjunction with the PPD radiation may be the portion of the UVA
standard, on alternative standards, and method to more completely assess a spectrum most represented in the PPD
on preparation/assay/validation data for product’s UVA radiation protection. test. FDA agrees that the UVA II
any suggested alternatives. FDA disagrees with the comments spectrum is well represented by the PPD
FDA also notes that the JCIA light that the CW method should be used as test. Therefore, to provide for a more
source specification states that ‘‘UV rays the in vitro testing method and proposes balanced method, FDA is proposing that
shorter than 320 nm shall be excluded using a modification of the Boots the in vitro component of the
through the use of an appropriate filter.’’ adaptation of the Diffey/Robson method monograph UVA radiation method only
FDA considers it important to set an (Ref. 90). Both the CW and the in vitro need provide a measure of the relative
exact limit for this specification and is test proposed by FDA measure the UVA I radiation absorbance.
proposing that optical radiation from absorbance of a sunscreen product using FDA is proposing to measure UVA I
the light source between 250 and 320 in vitro spectrophotometry. However, radiation absorbance relative to UV
nm be less than 0.1 percent of the FDA’s proposed method calculates the radiation absorbance rather than relative
optical radiation between 320 and 400 ratio of long wavelength UVA to UVB radiation absorbance. If UVA I
nm. Also, the observation of pigment absorbance (UVA I) to total UV radiation protection is measured relative
darkening in the JCIA standard is at 2 absorbance to provide a measure of the to UVB radiation, then the test does not
to 4 hours post irradiation. FDA notes relative UVA I radiation protection account for UVA II radiation protection.
that it appears the pigment darkening is provided by a sunscreen drug product. FDA’s proposed modification of the
most stable about 3 hours or more after Boots adaptation of the Diffey/Robson
FDA believes that this test, in

post irradiation (Ref. 89), and is thus combination with the PPD method, method accounts for the entire UV
proposing that this observation occur at provides a better assessment of overall radiation spectrum. Further, the ratio of
3 to 24 hours post irradiation. This time UVA radiation protection. UVA I radiation to UV radiation has a
range provides increased flexibility in The Boots adaptation of the Diffey/ convenient finite range and allows for
the test method without sacrificing Robson test method assesses the the use of defined values to categorize
EP27AU07.004</GPH>
accuracy. absorbance of a sunscreen drug product UVA radiation protection.
FDA is proposing a modified Boots quartz plates for its in vitro studies and be used with the following number of
adaptation of the Diffey/Robson method that quartz plates are reusable and inert. graphical representations in the form of
instead of the CW method. The CW Diffey et al. have also used quartz plates solid ‘‘stars’’:
determination only reveals the shortest as the substrate for the CW method (Ref.
wavelength at which 90 percent of total 91). Accordingly, at this time, FDA is TABLE 5.—GRAPHICAL UVA RATING
UVB and UVA radiation is absorbed by proposing that roughened quartz plates BASED ON CATEGORY
a sunscreen. Thus, this method does not be specified as the substrate in the in
directly reveal the breadth of UV vitro portion of its UVA test method. Combined Category Rating Star
absorption, whereas the modified Boots FDA requests comment regarding the Rating
adaptation of the Diffey/Robson method suitability and availability of quartz
Low ★✰✰✰
does. This point is demonstrated by data plates and other possible substrates. Medium ★★✰✰
submitted by one comment (Ref. 23). FDA agrees with one comment that High ★★★✰
The comment submitted the UV there is no biological basis for Highest ★★★★
absorption spectra of two sunscreens establishing a strict UVA to UVB ratio
having nearly identical SPF and CW and that such a ratio would be arbitrary. FDA invites comment on these
values. The absorption spectra FDA is proposing that data from the proposed test methods/criteria and
demonstrate that two sunscreens with proposed in vitro and in vivo tests be encourages the continued development
similar CWs can have significantly integrated into a single labeled UVA of biologically meaningful test
different UVA absorption spectra. The rating. Similar to suggestions from some procedures.
ratios of UVA I/UV radiation absorbance comments, FDA is proposing the
for these formulations were markedly categories of low, medium, high, and O. Comments on the Photostability of
different: 0.85 and 0.52. Thus, FDA highest (corresponding to one, two, Sunscreen Drug Products
believes that the ratio method generally three, and four ‘‘stars,’’ respectively). (Comment 46) Various comments
allows for better discrimination of Based on test data submitted by one discussed the photostability of OTC
products with these types of absorbance comment (Ref. 6), FDA is proposing that sunscreen formulations and active
spectra. test results for each in vitro or in vivo ingredients. One comment stated that
FDA is also concerned that the test be categorized as follows: photostability is important because
activity of the sunscreen ingredients in many sunscreen ingredient
the product may be diminished by TABLE 4.—UVA RATING CATEGORIES combinations with avobenzone are not
exposure to UV radiation, i.e., that the believed to be photostable. This
sunscreen ingredients in the product Category In vitro result In vivo result comment stressed that a sunscreen drug
might not be photostable. Therefore, in product should maintain most of its
order to account for changes in Low 0.2 to 0.39 2 to under 4
Medium 0.40 to 0.69 4 to under 8 UVA and UVB radiation protection
absorbance as a function of UV radiation throughout the expected consumer time
High 0.70 to 0.95 8 to under 12
exposure, FDA is proposing to revise the Highest greater than 0.95 12 or more in the sun. Another comment stated that
Boots modification of the Diffey/Robson the integrity of a sunscreen drug
method by incorporating pre-irradiation FDA is aware of the difficulty for product depends on its degree of
dose (PID), which is defined as follows current sunscreen formulations to meet photostability and that a photostable
(see section III.O, comment 46 of this the ‘‘highest’’ category and believes that product should maintain its protection
document): allowing such a category will foster over a wide range of UV radiation
PID (J/m2-eff) = SPF * 1 MED * 2/3, spectra.
where 1 MED = 200 J/m2-eff
additional research and development in
FDA is also concerned about this area. Some comments supported a standard
specifying the use of TransporeTM tape FDA is proposing that the overall method using pre-irradiation to account
(used in the original Diffey/Robson UVA radiation category for use in for photostability of sunscreen
method), an artificial substrate that product labeling be the lowest category ingredients. One comment favoring the
mimics the surface topography of determined by the in vitro and in vivo CW method for measuring UVA
human stratum corneum. When test results. For example, if the test radiation protection submitted a
sunscreen emulsions are applied to results for a sunscreen indicate an in formula to establish a pre-irradiation
TransporeTM tape (Refs. 7 and 77), the vitro category of ‘‘low’’ and an in vivo dose to assess photostability (Ref. 7).
emulsions may experience a micro category of ‘‘high’’ (or the reverse), then This comment stated that pre-irradiation
environment that differs from human the overall UVA classification on the provides a reasonable estimate of what
skin in several key aspects, including sunscreen product label would be ‘‘low’’ a consumer might expect when using
the following: (i.e., the lower of the two categories). the product and stressed that the dose
• Lack of electrolyte effect, FDA believes that using the lower of the should be both full spectrum (290 to 400
• Lack of moisturization/humectant two categories takes into account the nm) and sufficient to detect significant
plasticization of the substrate, following situations: changes in CW as a function of UV
• Differences in pH and wetting • A product that has a high in vivo radiation exposure. This comment
effects, and rating because of substantial UVA II considered its pre-irradiation dose of
• Different degrees of sunscreen absorbance, but a low in vitro rating solar-simulated UV radiation to be
penetration and retention by the because of poor UVA I absorbance, or equivalent to about 1 1/2 hours of
substrate. • A product that has a low in vivo noonday sun or 3 hours of sun exposure
The fourth aspect, different degrees of rating because of poor UVA II in the early morning or late afternoon.
penetration and retention, is especially absorbance, but a high in vitro rating One comment noted that avobenzone-
significant for oil soluble sunscreen because of substantial UVA I containing formulations can be
ingredients. One comment suggested absorbance. photostabilized by the addition of
that either roughened quartz plates or a FDA is further proposing that each suitable ingredients and supported a
synthetic collagen should be used as the overall UVA radiation category protocol developed by Sayre and Dowdy
substrate, noting that COLIPA has used correspond to and (on product labeling) for measuring UVA radiation protection
following a measured exposure of the simulator with the reference action Mandating warnings in an OTC drug
test formulation to solar radiation (290 spectrum for erythema as defined by monograph does not require a finding
to 400 nm) (Ref. 92). CIE. A typical weighted value (J/m2-eff) that any or all of the OTC drug products
Another comment stressed the for an MED in a Skin Type II individual covered by the monograph actually
importance of a standard pre-irradiation is 200 J/m2-eff (Ref. 93). Thus, FDA is caused an adverse event, and FDA does
dose and included data suggesting that proposing to use the following formula not so find. Nor does FDA’s requirement
a ‘‘UVB-only’’ sunscreen product to determine the required pre- of warnings repudiate the prior OTC
formulation, at high pre-irradiation irradiation dose: drug monographs and monograph
doses, could qualify for UVA ‘‘broad PID (J/m2-eff) = SPF * 1 MED * 2/3 rulemakings under which the affected
spectrum’’ labeling by the CW method where 1 MED = 200 J/m2-eff drug products have been lawfully
(Ref. 23). This comment concluded that In considering the selection of the marketed. Rather, as a consumer
pre-irradiation does not always account appropriate pre-irradiation dose of protection agency, FDA has determined
for photostability and appears to be very solar-simulated UV radiation, FDA that warnings are necessary to ensure
formulation specific. agrees that the maximum pre-irradiation that these OTC drug products continue
Another comment submitted an in exposure would be a dose of UV to be safe and effective for their labeled
vitro method for simultaneously radiation that equaled the SPF of the indications under ordinary conditions
predicting SPF and assessing product times the MED. However, FDA of use as those terms are defined in the
photostability of sunscreen formulas believes that this calculated dose is
act. This judgment balances the benefits
(Ref. 65). The comment stated that pre- probably greater than the dose that a
of these drug products against their
irradiation with measured UV radiation sunscreen product would incur during
potential risks (see 21 CFR 330.10(a)).
doses has permitted more accurate in typical consumer usage. Thus, the dose
was reduced by a factor of one-third to FDA’s decision to act in this instance
vitro estimates of SPF.
FDA agrees that it is important to represent a more reasonable exposure need not meet the standard of proof
address the photostability for sunscreen condition. required to prevail in a private tort
drug product formulations. Unstable action (Glastetter v. Novartis
IV. FDA’s Tentative Conclusions and Pharmaceuticals Corp., 252 F.3d 986,
product formulations present the Proposals
problem of degradation of product 991 (8th Cir. 2001)). To mandate
effectiveness during actual use. The FDA tentatively concludes that the warnings, or take similar regulatory
assessment of overall protection FM for OTC sunscreen drug products action, FDA need not show, nor do we
provided by such formulations is should be amended to include the allege, actual causation. For an
difficult due to product effectiveness combinations of avobenzone with expanded discussion of the case law
being heavily dependent on the UV ensulizole and avobenzone with zinc supporting FDA’s authority to require
radiation exposure dose. Sayre and oxide when used in the concentrations such warnings without evidence of
Dowdy demonstrated, through a series established for each ingredient in actual causation, see Labeling of
of in vitro studies, how the UV radiation § 352.10 (see section III.C, comment 7 of Diphenhydramine-Containing Drug
transmission of an avobenzone this document). However, before Products for Over-the-Counter Human
containing formula changes with UV marketing may begin, the comment Use, final rule (67 FR 72555, December
radiation exposure and that most of the period for this proposal must end and 6, 2002).
loss of protection occurred in the UVA FDA must publish another Federal V. Analysis of Impacts
radiation spectrum (Ref. 92). Register notice setting forth our
FDA is proposing to address determination concerning interim FDA has examined the impacts of this
photostability by adding a pre- marketing before publication of the final proposed rule under Executive Order
irradiation step to the in vitro test rule for OTC sunscreen drug products. 12866, the Regulatory Flexibility Act (5
method for measuring UVA radiation FDA followed this procedure previously U.S.C. 601–612), and the Unfunded
protection (see section III.N, comment for avobenzone as a single active Mandates Reform Act of 1995 (2 U.S.C.
45 of this document). As noted in the ingredient and in combination with 1501 et seq.). Executive Order 12866
scientific literature, the choice of a pre some GRASE active ingredients other directs agencies to assess all costs and
irradiation dose is ‘‘somewhat arbitrary, than ensulizole or zinc oxide (62 FR benefits of available regulatory
yet critical to the outcome of the test’’ 23350). alternatives and, when regulation is
(Ref. 84). FDA received one comment FDA considers the UVA-related necessary, to select regulatory
with supporting data for a proposed pre- labeling in this proposal to supersede approaches that maximize net benefits
irradiation dose (Ref. 7). The comment the labeling proposed in the TFM and (including potential economic,
suggested using a dose equivalent to the its amendments of September 16, 1996, environmental, public health and safety,
SPF times 2 J/cm2 multiplied by a factor and October 22, 1998. While the prior and other advantages; distributive
of 2/3. The comment stated that 2 J/cm2 proposed labeling can continue to be impacts; and equity). Under the
from a xenon arc solar simulator with 1 used until a FM is issued, FDA Regulatory Flexibility Act, if a rule has
millimeter (mm) WG-320 and 1 mm UG- encourages manufacturers of OTC a significant economic impact on a
5 filters was equivalent to one MED. sunscreen drug products to voluntarily substantial number of small entities, an
Because all solar simulators used by the implement the UVA-related labeling agency must analyze regulatory options
industry may not use this exact filter changes as soon as possible after that would minimize any significant
combination and the spectral publication of this proposal, especially impact of the rule on small entities.
transmittance of filters can vary from lot if product relabeling occurs in the Section 202(a) of the Unfunded
to lot, FDA is proposing to specify the normal course of business. We note, Mandates Reform Act requires that
pre-irradiation dose in terms of though, that any relabeling prior to agencies prepare a written statement of
‘‘erythemal effective dose.’’ The issuance of the FM is subject to the anticipated costs and benefits before
erythemal effective dose of a solar possibility that FDA may change some proposing any rule that may result in an
simulator can by calculated as described of the labeling requirements as a result expenditure in any one year by State,
in proposed § 352.70(d) by weighting of comments filed in response to this local, and tribal governments, in the
the output spectrum of the solar proposal. aggregate, or by the private sector, of
$100 million (adjusted annually for manufacturers will choose not to test for costs that would be incurred by OTC
inflation). UVA protection and the labeling for sunscreen manufacturers. RTI estimated
FDA believes that this proposed rule those sunscreens will state, ‘‘No UVA that graphic design and prepress and
is consistent with the principles set out Protection.’’ engraving costs would range from
in the Executive Order 12866 and in $1,970 to $13,800 per SKU depending
these two statutes. The proposed rule is B. Number of Products Affected
on the type of packaging and printing
not a significant regulatory action as Estimating the number of products method used. There would also be
defined by the Executive order and, affected is difficult because we lack data administrative costs to account for
therefore, is not subject to review under on the number of products currently contracting costs and obtaining final
the Executive order. Further, because marketed. Our Drug Listing System approvals for the new labels. RTI
this proposed rule is not expected to currently does not have accurate estimated administrative costs to range
result in any 1-year expenditure that information on the number of marketed from $360 to $880 depending on the
would exceed $100 million adjusted for OTC sunscreen products, especially the size of the firm. For this analysis, we are
inflation, FDA need not prepare drug-cosmetic combination products. assuming an average design price of
additional analyses under the Unfunded Proprietary databases that track retail $7,000 per SKU and average
Mandates Reform Act. Because the rule sales of OTC drugs and other products administrative costs of $600 per SKU.1
may have a significant economic impact do not distinguish cosmetics containing Therefore, the total relabeling cost per
on a substantial number of small sunscreens from other cosmetic SKU would be $7,600 (i.e., $600 +
entities, this section of the preamble products and their surveys do not $7,000).
constitutes FDA’s regulatory flexibility include many of the outlets where While all sunscreen SKUs would need
analysis. sunscreen products are sold. Based on to be relabeled to comply with the
An analysis of the costs and benefits earlier estimates (64 FR 27666 at 27684) proposed rule, we estimate that the
of this regulation, conducted under and our knowledge of the industry, we timing of the scheduled relabeling
Executive Order 12866, was discussed assume there are about 3,000 OTC would coincide with the regulatory-
in the FM (64 FR 27666 at 27683 to sunscreen drug products (different mandated changes for 50 percent of the
27686), which was later stayed (66 FR formulations, not including products SKUs (i.e., 6,000 SKUs). We estimate the
67485). This analysis reflects the that differ only by color), including total labeling cost of the proposed
incremental costs of the revised or new drug-cosmetic combinations, and about labeling changes for the SKUs with the
requirements in this proposed 12,000 individual stock keeping units coinciding scheduled redesign would be
amendment of the FM. (SKUs) (individual products, packages, 50 percent of the administrative cost
and sizes). All 12,000 SKUs will need to (i.e., $300). Therefore, the total one-time
A. Background
be relabeled, but manufacturers can cost to industry for relabeling would be
The purpose of this document is to choose whether to test their sunscreen about $47.5 million (i.e., (6,000 x
amend the conditions under which OTC products for UVA protection. We $7,600) + (6,000 x $300)).
sunscreen drug products are generally assume that about 75 percent (2,250) of
recognized as safe and effective D. Cost to Test or Retest Products for
the sunscreen products would be tested
(GRASE) and not misbranded. This UVA Protection
for UVA protection. We request
amendment addresses formulation, comment on the accuracy of this This proposed rule will result in
labeling, and testing requirements for assumption. testing costs for products that make
both UVB and UVA radiation UVA protection claims. The
protection. C. Cost to Relabel approximate costs are $2,200 for in vivo
Manufacturers would not need to The cost to relabel varies greatly UVA testing and $200 for in vitro UVA
reformulate their sunscreen products to depending on the printing method and testing. Based on the number of
comply with the proposed number of colors used. The majority of sunscreen products currently labeled as
requirements. Manufacturers also would sunscreen products are packaged in providing UVA protection, we estimate
not need to retest their sunscreen plastic bottles or tubes with the label that 75 percent (2,250) of the sunscreen
products for UVB protection (i.e., they printed directly on the container or products will be tested according to the
would not need to retest for SPF). The applied as a decal or paper label during proposed UVA tests. Therefore, FDA
labeled SPF value determined from the the packaging process. The proposed estimates a one-time UVA testing cost of
SPF test in the FM would not likely labeling requirements impact both the approximately $5.4 million (i.e., 2,250 x
change if a sunscreen product was PDP and the Drug Facts section of the $2,400).
retested using the modifications to the package and would be considered a E. Total Incremental Costs
SPF test proposed in this document. In major redesign.
addition, manufacturers who have Frequent label redesigns are typical The estimated total one-time
tested and labeled their sunscreen for OTC sunscreen products, with incremental cost of this proposed rule is
products as ‘‘SPF 30+’’ can relabel their redesigns generally implemented every $53 million (i.e., $47.5 million + $5.4
products with the specific SPF value 1 to 2 years for a product. To the extent million). The incremental cost for the
above 30 (but no greater than 50) that a scheduled redesign coincides UVA testing could be less should the
without retesting. with the regulatory-mandated rule become final because many
However, all manufacturers would relabeling, the impact on the manufacturers may voluntarily comply
incur some relabeling costs due to manufacturer will be negligible. with the proposed rule when
proposed revisions to both the PDP and We used a model developed for FDA reformulating current products or
the Drug Facts section of the product by the consulting firm RTI to derive an marketing new products. Although the
label. If manufacturers wish to label estimate of the cost to relabel sunscreen FM is not effective, manufacturers of
their sunscreen products as providing products (Ref. 94). The model was sunscreen products comply with the
UVA protection, then manufacturers of developed to estimate the cost of food
1 We did not select the midpoint of the ranges
those sunscreen products would also labels. However, we believe that the because of the large number of private label
incur UVA testing costs. Because UVA graphic and design estimates from that products that have lower design and administrative
testing is not required, some study are an appropriate proxy for the costs than branded goods.
UVB (SPF) test in the FM for nearly all their production schedules. By has determined that the proposed rule,
sunscreen products. Therefore, it is providing an additional 6 months to if finalized as proposed, would have a
likely that manufacturers of sunscreen implement the changes, compliance preemptive effect on State law. Section
products will also voluntarily comply costs to manufacturers will be reduced. 4(a) of the Executive order requires
with the proposed UVA tests in this In addition, FDA reduced compliance agencies to ‘‘construe * * * a Federal
document. costs when we chose to stay the labeling statute to preempt State law only where
It should also be noted that sunscreen requirements for the FM (64 FR 27666), the statute contains an express
products that are already distributed by sparing industry the cost of an preemption provision or there is some
the effective date of the FM will not be additional regulatory-mandated label other clear evidence that the Congress
required to be relabeled or retested in change. In the stay, FDA estimated a intended preemption of State law, or
conformity with these FM conditions, cost savings of $1.5 million to industry. where the exercise of State authority
unless these products are subsequently It should be noted that labeling costs conflicts with the exercise of Federal
relabeled or repackaged after the were significantly less in the FM than in authority under the Federal statute.’’
effective date. Therefore, there is no this proposed rule primarily because we Section 751 of the Federal Food, Drug,
one-time cost associated with disposing assumed in the FM that the majority of and Cosmetic Act (the act) (21 U.S.C.
of sunscreens that are already on the relabeling would coinside with 379r) is an express preemption
market at the time of the rule’s effective scheduled voluntary label redesigns at provision. Section 751(a) of the act (21
date. no additional cost. Manufacturers were U.S.C. 379r(a)) provides that ‘‘no State
F. Small Business Impact also able to avoid or postpone incurring or political subdivision of a State may
an additional industry total of $5 establish or continue in effect any
In the FM (64 FR 27666 at 27685), million when FDA chose to stay the requirement—* * * (1) that relates to
FDA estimated that 78 percent of the UVB testing requirements of the FM. the regulation of a drug that is not
180 domestic companies that FDA invites public comment subject to the requirements of section
manufacture OTC sunscreen products regarding any substantial or significant 503(b)(1) or 503(f)(1)(A); and (2) that is
would be considered a small business economic impact that this proposed rule different from or in addition to, or that
(defined as fewer than 750 employees). would have on manufacturers of OTC is otherwise not identical with, a
FDA cannot estimate with certainty the sunscreen drug products. Comments requirement under this Act, the Poison
number of small firms that will need to regarding the impact of this rulemaking Prevention Packaging Act of 1970 (15
test or retest their OTC sunscreen on such manufacturers should be U.S.C. 1471 et seq.), or the Fair
products to provide for UVA protection accompanied by appropriate Packaging and Labeling Act (15 U.S.C.
claims, but projects that approximately documentation. FDA is providing a 1451 et seq.).’’ Currently, this provision
75 percent of all products may need to period of 90 days from the date of operates to preempt States from
be tested for UVA protection. Costs will publication of this proposed rule in the imposing requirements related to the
vary by firm, depending on the number Federal Register for comments to be regulation of nonprescription drug
of products requiring testing. The firm- developed and submitted. FDA will products. Section 751(b) through (e) of
specific impact may vary inversely with evaluate any comments and supporting the act outlines the scope of the express
the volume of product sales, because per data that are received and will reassess preemption provision, the exemption
unit costs will be lower for products the economic impact of this rulemaking procedures, and the exceptions to the
with high volume sales. Thus, the in the final rule. provision.
relative economic impact of product This proposed rule, if finalized as
retesting may be greater for small firms VI. Paperwork Reduction Act of 1995 proposed, would amend the labeling
than for large firms. Because the OTC FDA tentatively concludes that the and include new UVA testing for OTC
drug industry is highly regulated, all labeling requirements in this document sunscreen drug products. Any final rule
firms are expected to have access to the are not subject to review by the Office would have a preemptive effect in that
necessary professional skills on staff or of Management and Budget because it would preclude States from issuing
to have contractual arrangements to they do not constitute a ‘‘collection of requirements related to the labeling and
comply with the testing requirements of information’’ under the Paperwork testing of OTC sunscreen drug products
this rule. Reduction Act of 1995 (44 U.S.C. 3501 that are different from or in addition to,
et seq.). Rather, the proposed labeling or not otherwise identical with a
G. Analysis of Alternatives
statements are a ‘‘public disclosure of requirement in the final rule. This
FDA could have proposed only an in information originally supplied by the preemptive effect is consistent with
vivo or an in vitro test for UVA. FDA Federal Government to the recipient for what Congress set forth in section 751
recognizes that requiring only the in the purpose of disclosure to the public’’ of the act. Section 751(a) of the act
vitro test would mean significantly less (5 CFR 1320.3(c)(2)). displaces both State legislative
cost to manufacturers. However, the requirements and State common law
proposed in vivo test measures the VII. Environmental Impact duties. We also note that even where the
magnitude of UVA protection. The FDA has determined under 21 CFR express preemption provision in section
proposed in vitro test measures the 25.31(a) that this action is of a type that 751(a) of the act is not applicable,
breadth of UVA protection. FDA does not individually or cumulatively implied preemption may arise (see Geier
believes it is important to conduct both have a significant effect on the human v. American Honda Co., 529 US 861
tests to determine the magnitude and environment. Therefore, neither an (2000)).
breadth of UVA protection. environmental assessment nor an FDA believes that the preemptive
FDA plans to grant an extended
environmental impact statement is effect of the proposed rule, if finalized

compliance period when this proposed required. as proposed, would be consistent with
rule is finalized. Given the seasonal Executive Order 13132. Section 4(e) of
nature of these products, FDA is VIII. Federalism the Executive order provides that ‘‘when
concerned that some manufacturers may FDA has analyzed this proposed rule an agency proposes to act through
not have sufficient time to incorporate in accordance with the principles set adjudication or rulemaking to preempt
labeling changes without disrupting forth in Executive Order 13132. FDA State law, the agency shall provide all
affected State and local officials notice In addition to AHAs, FDA seeks X. Proposed Effective and Compliance
and an opportunity for appropriate comment on titanium dioxide and zinc Dates
participation in the proceedings.’’ FDA oxide formulated in particle sizes as FDA is proposing that any final rule
is providing an opportunity for State small as a few nanometers. FDA that may issue based on this proposal
and local officials to comment on this addressed issues concerning micronized become effective 18 months after its
rulemaking. sunscreen ingredients in the FM (64 FR date of publication in the Federal
IX. Request for Comments 27666 at 27671 to 27672). The FM stated Register. The compliance date for
that FDA did not consider micronized products with annual sales less than
In the Federal Register of January 10, titanium dioxide to be a new ingredient
2005 (70 FR 1721), FDA announced the $25,000 would be 24 months after
but rather a specific grade of the same publication of the final rule in the
availability of a final guidance for active ingredient. The FM also stated
industry entitled ‘‘Labeling for Federal Register.
that FDA was aware of concerns about
Topically Applied Cosmetic Products potential risks associated with increased XI. References
Containing Alpha Hydroxy Acids as dermal penetration of such small The following references are on
Ingredients.’’ The purpose of this particles. However, the FM explained display in the Division of Dockets
guidance is twofold: that, based on the safety data submitted Management (see ADDRESSES) under
• To educate consumers about the to FDA before publication of the FM, Docket No. 1978N–0038 and may be
potential for increased skin sensitivity FDA was not aware of any evidence at seen by interested persons between 9
to the sun from the topical use of that time demonstrating a safety concern
cosmetics containing alpha hydroxy a.m. and 4 p.m., Monday through
from the use of micronized titanium Friday.
acids (AHAs) as ingredients. dioxide in sunscreen products (64 FR 1. Comment No. CP6.
• To educate manufacturers to help 2. Comment Nos. CP8, C548, SUP22, and
27666 at 27671 to 27672).
ensure that their labeling for cosmetic C555.
products containing AHAs as FDA recognizes that more sunscreens
3. Comment Nos. LET166 and LET169.
ingredients is not false or misleading. containing small particle size titanium
4. Comment No. C538.
As discussed in the guidance, AHAs dioxide and zinc oxide ingredients enter 5. Comment No. C576.
may increase skin sensitivity to UV the market each year. FDA is interested 6. Comment No. C565.
radiation. Therefore, FDA recommends in receiving comments and data about 7. Comment No. C581.
that manufacturers of cosmetic products these sunscreen ingredients and 8. Comment No. C567.
containing AHAs include the following products that contain these ingredients, 9. Comment No. C515.
warning: their safety and effectiveness, and how 10. Comment No. C597.
Sunburn Alert: This product contains an they should be regulated. FDA received 11. Comment No. MM22.
alpha hydroxy acid (AHA) that may increase a citizen petition shortly before 12. Comment No. MM21.
your skin’s sensitivity to the sun and 13. Comment No. C573.
publication of this document that, 14. Autier, P. et al., ‘‘Sunscreen Use and
particularly the possibility of sunburn. Use a among other things, raises these issues.
sunscreen and limit sun exposure while Duration of Sun Exposure: a Double-blind,
FDA is currently evaluating the citizen Randomized Trial,’’ Journal of the National
using this product and for a week afterwards.
The guidance addresses only cosmetic petition, which is filed as CP17 in Cancer Institute, 91(15):1304–1309, 1999.
products containing AHAs and does not Docket No. 1978N–0038. FDA 15. Reynolds, K.D. et al., ‘‘Predictors of
encourages other parties to submit Sun Exposure in Adolescents in a
address sunscreen drug products Southeastern U.S. Population,’’ Journal of
containing AHAs (i.e., drug-cosmetic additional data or information on the
safety and effectiveness of sunscreen Adolescent Health, 19(6):409–415, 1996.
products). FDA is considering an 16. Robinson, J.K., D.S. Rigel, and R.A.
additional warning or direction for ingredients formulated in particle sizes Amonette, ‘‘Summertime Sun Protection
sunscreen drug products containing as small as a few nanometers. Used by Adults for Their Children,’’ Journal
AHAs similar to the warning for the On April 14, 2006, FDA announced in American Academy of Dermatology,
cosmetic products described in the the Federal Register that we were 42(5):746–753, 2000.
guidance for industry. However, FDA planning a public meeting on FDA- 17. Gallagher, R.P. et al., ‘‘Broad-spectrum
regulated products containing Sunscreen Use and the Development of New
invites interested parties to submit Nevi in White Children: A Randomized
comments and data regarding such nanotechnology materials (71 FR
Controlled Trial,’’ Journal of the American
labeling. In particular, FDA would like 19523). As explained in the notice, the Medical Association, 283(22):2955–2960,
the following questions addressed: purpose of the meeting was to help FDA 2000.
1. Does the body of existing evidence further its understanding of 18. Stender, I.M., J.L. Andersen, and H.C.
on AHAs and skin sensitivity warrant developments in nanotechnology Wulf, ‘‘Sun Exposure and Sunscreen Use
voluntary or mandatory labeling on OTC materials that pertain to FDA-regulated among Sunbathers in Denmark,’’ Acta
sunscreen drug products containing products. The meeting was held on Dermato-Venereologica, 76:31–33, 1996.
October 10, 2006, and FDA has received 19. Zitser, B.S. et al., ‘‘A Survey of
AHAs regarding possible risks of
comments from interested members of Sunbathing Practices on Three Connecticut
increased sun damage (e.g., sunburn)? State Beaches,’’ Connecticut Medicine,
2. If additional labeling is warranted, the public which have been filed in the 60(10):591–594, 1996.
what information should be conveyed in docket for this public meeting (Docket 20. Green, A. et al., ‘‘Daily Sunscreen
the labeling and why? No. 2006N– 0107). Some of these Application and Betacarotene
Comments along with supporting data comments concern sunscreen Supplementation in Prevention of Basal-cell
will help enable FDA to determine how ingredients formulated with and Squamous-cell Carcinomas of the Skin:
and what information, if any, related to nanotechnology materials. FDA will file a Randomized Controlled Trial,’’ The Lancet,
UV hypersensitivity due to AHAs in any comments concerning sunscreen 354:723–729, 1999.
sunscreen-cosmetic products should be ingredients formulated in nanometer 21. IARC Handbooks of Cancer Prevention
Volume 5 Sunscreens, H. Vainio, ed.,
communicated to consumers. FDA will particle sizes received in response to International Agency for Research on Cancer,
also be evaluating any comments or data this proposed rule in the docket for this Lyon, France, p. 62, 2001.
submitted in response to the final rulemaking and the citizen petition 22. Diffey, B.L. et al., ‘‘In Vitro Assessment
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containing AHAs. docket for the nanotechnology meeting. of Sunscreen Products,’’ Journal of the
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UVA Protection and Evaluation of Efficacy,’’ 43. Committee on Environmental Health, Protection, American Cancer Society, Inc.,
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1997. of Different Types of Skin Cancer: New Donnelly & Sons, U.S.A., pp. 117–142, 1992.
26. Lowe, N.J. et al., ‘‘Low Doses of Aetiological Clues,’’ International Journal of 65. Comment No. C574.
Repetitive Ultraviolet A Induce Morphologic Cancer, 67:24–28, 1996. 66. Comment No. C405.
Changes in Human Skin,’’ Journal of 46. Raasch, B. et al., ‘‘Body Site Specific 67. Comment No. C404.
Investigative Dermatology, 105(6):739–743, Incidence of Basal and Squamous Cell 68. Comment No. C111.
1995. Carcinoma in an Exposed Population, 69. Comment No. RPT7.
27. Seite, S. et al., ‘‘Effects of Repeated Townsville, Australia,’’ Mutation Research, 70. Comment No. C442.
Suberythemal Doses of UVA in Human 422:101–106, 1998. 71. Comment No. SUP29.
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7:204–209, 1997. Jensen, ‘‘Incidence of Cutaneous Malignant FDA, to C. Ganley, FDA, July 7, 2000.
28. Lavker, R.M. et al., ‘‘Quantitative Melanoma in Denmark 1978–1982. Anatomic 73. Comment No. CP12.
Assessment of Cumulative Damage from Site Distribution, Histologic Types, and 74. Comment No. SUP33.
Repetitive Exposures to Suberythemogenic Comparison with Non-melanoma Skin 75. Gabriel, K.L. et al., ‘‘Sun Protection
Doses of UVA in Human Skin,’’ Cancer,’’ British Journal of Cancer, 58:385– Factor Testing: Comparison of FDA and DIN
Photodermatology, Photoimmunology, and 391, 1988. Methods,’’ Journal of Toxicology-Cutaneous
Photomedicine, 62(2):348–352, 1995. 48. Neale, R., G. Williams, and A. Green, and Ocular Toxicology, 6:357–370, 1987.
29. Lavker, R.M. et al., ‘‘Cumulative Effects ‘‘Application Patterns Among Participants 76. Comment No. C491.
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30. Elmets, C.A., A. Vargas, and C. Oresajo, 16:47–52, 1994.
50. Steinberg, C., and O. Larko, ‘‘Sunscreen
‘‘Photoprotective Effects of Sunscreens in 79. Diffey, B.L., and J. Robson, ‘‘A New
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Photodamage,’’ Photodermatology, Protection Factor,’’ Archives of Dermatology, Factors Throughout the Ultraviolet
Photoimmunology, and Photomedicine, 121:1400–1402, 1985. Spectrum,’’ Journal of the Society of
9(3):113–120, 1992. 51. Stokes, R., and B. Diffey, ‘‘How Well Cosmetic Chemists, 40:127–133, 1989.
31. Lavker, R., and K. Kaidbey, ‘‘The Are Sunscreen Users Protected?,’’ 80. Comment No. RPT9.
Spectral Dependence for UVA-induced Photodermatology, Photoimmunology, and 81. Comment No. LET170.
Cumulative Damage in Human Skin,’’ Journal Photomedicine, 13:186–188, 1997. 82. Press Release: ‘‘The Future of
of Investigative Dermatology, 108(1):17–21, 52. Sayre, R.M. et al., ‘‘Product Application Sunscreen Labeling: Recommendations of the
1997. Technique Alters the Sun Protection Factor,’’ Consensus Conference on UVA Protection of
32. Seite, S. et al., ‘‘A Full-UV Spectrum Photodermatology, Photoimmunology, and Sunscreens Convened by the American
Absorbing Daily Use Cream Protects Human Photomedicine, 8:222–224, 1991. Academy of Dermatology,’’ New York, NY,
Skin Against Biological Changes Occurring in 53. Azurda, R.M. et al., ‘‘Sunscreen April 26, 2000.
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16(4):147–155, 2000. Effect of Education,’’ Photodermatology, UVA Protection of Sunscreens: Summary and
33. Boyd, A.S. et al., ‘‘The Effects of Photoimmunology and Photomedicine, Recommendations,’’ Journal of the American
Chronic Sunscreen Use on the Histologic 16:53–66, 2000. Academy of Dermatology, 44:505–508, 2001.
Changes of Dermatoheliosis,’’ Journal of the 54. Bech-Thomsen, N., and H.C. Wulf, 84. Cole, C., ‘‘Sunscreen Protection in the
American Academy of Dermatology, ‘‘Sunbather’s Application of Sunscreen is Ultraviolet A Region: How to Measure
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34. Comment No. CP15. Protection Factor Assigned to the Photoimmunology, and Photomedicine, 17:2–
35. Center for Disease Control and Preparation,’’ Photodermatology, 10, 2001.
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American Cancer Society, Inc., 2007. 57. Rigel, D. et al., ‘‘American Academy of the Persistent Pigment Darkening (PPD)
38. Sun Safety Tips, The American Dermatology’s Melanoma/Skin Cancer Method (Part 2),’’ Photodermatology,
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Prevention, 2001. Academy of Dermatology, 1999. Pigment Darkening (PPD) Method as the
40. The Sun, UV, and You: A Guide to 59. Ultraviolet Index—What You Need to Endpoint (Part 1) Calibration of the Method,’’
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89. Chardon, A. et al., ‘‘Persistent Pigment- § 352.3 Definitions. ingredients used in the combination
Darkening Response as a Method for * * * * * multiplied by 2.
Evaluation of Ultraviolet A Protection (b) Minimal pigmenting dose (MPD).
Assays’’ in Sunscreens: Development,
* * * * *
The quantity of erythema-effective 7. Section 352.50 is revised to read as
Evaluation, and Regulatory Aspects, 2nd
edition, Marcel Dekker, Inc., New York, NY, energy (expressed as Joules per square follows:
pp. 559–582, 1997. meter) required to produce the first
perceptible pigment darkening. § 352.50 Principal display panel of all
90. Comment No. TS3.
(c) Product category designation sunscreen drug products.
91. Diffey, B.L. et al., ‘‘Suncare Product
Photostability: a Key Parameter for a More (PCD). A labeling designation for (a) UVB sunburn protection
Realistic In Vitro Efficacy Evaluation,’’ sunscreen drug products to aid in designation—(1) For products with an
European Journal of Dermatology, 7:226–228, selecting the type of product best suited SPF of 2 to under 15. The labeling states
1997. to an individual’s complexion ‘‘UVB SPF [insert tested SPF value of
92. Sayre, R.M., and J. Dowdy, (pigmentation) and desired response to the product] low’’.
‘‘Photostability Testing of Avobenzone,’’ (2) For products with an SPF of 15 to
ultraviolet (UV) radiation.
Cosmetics and Toiletries, 114:85–86, 88, 90– under 30. The labeling states ‘‘UVB SPF
91, 1999.
(1) Low UVB sunburn protection
product. A sunscreen product that [insert tested SPF value of the product]
93. Urbach, F., ‘‘Man and Ultraviolet
Radiation’’ in Human Exposure to Ultraviolet provides a sunburn protection factor medium’’.
Radiation: Risks and Regulations, Passchier, (SPF) value of 2 to under 15. (3) For products with an SPF of 30 to
W.F. and Bosnjakovic, B.F.M. (eds.), Elsevier (2) Medium UVB sunburn protection 50. The labeling states ‘‘UVB SPF [insert
Science, New York, NY, pp. 3–6, 1987. product. A sunscreen product that tested SPF value of the product] high’’.
94. RTI International, ‘‘FDA Labeling Cost provides an SPF value of 15 to under 30. (4) For products with an SPF over 50.
Model, Final Report,’’ prepared by Mary (3) High UVB sunburn protection The labeling states ‘‘UVB SPF 50 [select
Muth, Erica Gledhill, and Shawn Karns, RTI. product. A sunscreen product that one of the following: ‘plus’ or ‘+’]
Prepared for Amber Jessup, FDA Center for provides an SPF value of 30 to 50. highest’’. Any statement accompanying
Food Safety and Applied Nutrition, Revised (4) Highest UVB sunburn protection the marketed product that states a
January 2003. specific SPF value over 50 or similar
product. A sunscreen product that
List of Subjects provides an SPF value over 50. language indicating a person can stay in
* * * * * the sun more than 50 times longer than
21 CFR Part 347 without sunscreen will cause the
(e) Sunburn protection factor (SPF)
Labeling, Over-the-counter drugs. value. The UV energy required to product to be misbranded under section
21 CFR Part 352 produce an MED on protected skin 502 of the Federal Food, Drug, and
divided by the UV energy required to Cosmetic Act (the act) (21 U.S.C. 352).
Labeling, Over-the-counter drugs, produce an MED on unprotected skin, (b) UVA protection designation—(1)
Incorporation by reference. which may also be defined by the For products not providing UVA
Therefore, under the Federal Food, following ratio: SPF value = MED protection according to § 352.73. The
Drug, and Cosmetic Act, and under (protected skin (PS))/MED (unprotected labeling states ‘‘no UVA protection’’.
authority delegated to the Commissioner skin (US)), where MED(PS) is the (i) The UVA protection designation
of Food and Drugs, it is proposed that minimal erythema dose for protected shall appear on the principal display
21 CFR parts 347 and 352 be amended skin after application of 2 milligrams panel along with the UVB protection
as follows: per square centimeter of the final designation in an equally prominent
formulation of the sunscreen product, manner that does not conflict with the
PART 347—SKIN PROTECTANT DRUG UVB protection designation.
PRODUCTS FOR OVER-THE- and MED(US) is the minimal erythema
dose for unprotected skin (i.e., skin to (ii) The font size of the UVA
COUNTER HUMAN USE protection designation shall be the same
which no sunscreen product has been
1. The authority citation for 21 CFR applied). In effect, the SPF value is the size as the UVB protection designation.
part 347 continues to read as follows: reciprocal of the effective transmission (2) For products providing UVA
of the product viewed as a UV radiation protection according to § 352.73. The
Authority: 21 U.S.C. 321, 351, 352, 353,
355, 360, 371. filter. labeling states ‘‘UVA [select one of the
2. FDA is proposing to lift the stay of 6. Section 352.20 is amended by following in accordance with § 352.73:
§ 347.20(d) as published at 68 FR 33362, revising paragraph (a)(2) to read as ‘★✰✰✰ Low,’ ‘★★✰✰ Medium,’
June 4, 2003. follows: ‘★★★✰ High,’ or ‘★★★★ Highest’]’’.
(i) The UVA protection designation
PART 352—SUNSCREEN DRUG § 352.20 Permitted combinations of active shall appear on the principal display
ingredients. panel along with the UVB protection
PRODUCTS FOR OVER THE COUNTER
HUMAN USE * * * * * designation in an equally prominent
(a) * * * manner that does not conflict with the
3. The authority citation for 21 CFR (2) Avobenzone in § 352.10(b) may be UVB protection designation.
part 352 continues to read as follows: combined with one or more sunscreen (ii) The font size of the UVA
Authority: 21 U.S.C. 321, 351, 352, 353, active ingredients identified in protection designation shall be the same
355, 360, 371. § 352.10(c), (e), (f), (i) through (l), (n), size as the UVB protection designation.
4. FDA is proposing to lift the stay of (o), (q), and (r) in a single product when (iii) All star borders and the color
21 CFR part 352 as published at 68 FR used in the concentrations established inside a solid star shall be the same
for each ingredient in § 352.10. The
33362, June 4, 2003. while the color of ‘‘empty’’ stars must be

5. Section 352.3 is amended by concentration of each active ingredient lighter and distinctly different than
redesignating paragraphs (b) through (d) must be sufficient to contribute a solid stars. The color inside a solid star
as (c) through (e), respectively; revising minimum SPF of not less than 2 to the should be distinctly different than the
newly redesignated paragraphs (c) and finished product. The finished product background color.
(e); and adding new paragraph (b) to must have a minimum SPF of not less (iv) The stars are to be filled in
read as follows: than the number of sunscreen active starting with the first star on the left and
are to appear in a straight horizontal (v) For products not providing UVA § 352.52(b)(1)(vi) as follows: ‘‘[Bullet]
line. protection according to § 352.73. The [select one of the following descriptors
(c) Select one of the following: ‘‘UV labeling states ‘‘[bullet] no UVA in accordance with §§ 352.70 and
rays from the sun are made of UVB and protection.’’ 352.73: ‘low,’ ‘medium,’ ‘high,’ or
UVA. It is important to protect against (vi) For products providing UVA ‘highest’] UVB sunburn/UVA
both UVB & UVA rays.’’ or ‘‘UV rays protection according to § 352.73. The protection’’.
from the sun are made of UVB and labeling states ‘‘[bullet] [select one of (c) Warnings. The labeling of the
UVA. It is important to protect against the following in accordance with product contains the following warnings
both UVB & UVA rays to prevent § 352.73: ‘Low,’ ‘medium,’ ‘high,’ or under the heading ‘‘Warnings:’’
sunburn and other skin damage.’’ ‘highest’] UVA protection’’. (1) The labeling states in bold type
(d) For products that satisfy the water (vii) For products that satisfy the ‘‘UV exposure from the sun increases
resistant sunscreen product testing water resistant testing procedures the risk of skin cancer, premature skin
procedures in § 352.76. The labeling identified in § 352.76. The labeling aging, and other skin damage. It is
states (select one of the following: states ‘‘[bullet] retains SPF after 40 important to decrease UV exposure by
‘‘water,’’ ‘‘water/sweat,’’ or ‘‘water/ minutes of [select one or more of the limiting time in the sun, wearing
perspiration’’) ‘‘resistant.’’ following: ‘activity in the water,’ protective clothing, and using a
(e) For products that satisfy the very ‘swimming,’ ‘sweating,’ ‘perspiring,’ sunscreen.’’
water resistant sunscreen product ‘swimming/sweating,’ or ‘swimming/ (2) The labeling states ‘‘When using
testing procedures in § 352.76. The perspiring’]’’. this product [bullet] keep out of eyes.
labeling states ‘‘very’’ (select one of the (viii) For products that satisfy the very Rinse with water to remove.’’
following: ‘‘water,’’ ‘‘water/sweat,’’ or water resistant testing procedures (3) The labeling states ‘‘Stop use and
‘‘water/perspiration’’) ‘‘resistant.’’ identified in § 352.76. The labeling ask a doctor if [bullet] skin rash occurs’’.
8. Section 352.52 is amended by states ‘‘[bullet] retains SPF after 80 (d) Directions. The labeling of the
revising paragraphs (b), (c), (d), (e), the minutes of [select one or more of the product contains the following
heading of paragraph (f), paragraphs following: ‘activity in the water,’ statements, as appropriate, under the
(f)(1)(ii) through (f)(1)(vi) to read as ‘swimming,’ ‘sweating,’ ‘perspiring,’ heading ‘‘Directions.’’ More detailed
follows: ‘swimming/sweating,’ or ‘swimming/ directions applicable to a particular
perspiring’]’’. product formulation (e.g., cream, gel,
§ 352.52 Labeling of sunscreen drug (2) Additional indications. In addition lotion, oil, spray, etc.) may also be
products. to the indications provided in paragraph included.
* * * * * (b)(1) of this section, the following may (1) For products containing any
(b) Indications. The labeling of the be used for products containing any ingredient in § 352.10. (i) The labeling
product states, under the heading ingredient in § 352.10: states ‘‘[bullet] apply [select one of the
‘‘Uses,’’ all of the phrases listed in (i) For products with an SPF of 2 to following: ‘liberally’ or ‘generously’]
paragraph (b)(1) of this section that are under 15. Select one or both of the [and, as an option: ‘and evenly’] [insert
applicable to the product and may following: ‘‘[Bullet] provides low appropriate time interval, if a waiting
contain any of the additional phrases protection against [select one of the period is needed] before sun exposure’’.
listed in paragraph (b)(2) of this section, following: ‘sunburn’ or ‘sunburn and (ii) The labeling states ‘‘[bullet] apply
as appropriate. Other truthful and tanning’]’’ or ‘‘[bullet] for skin that and reapply as directed to avoid
nonmisleading statements, describing sunburns minimally’’. lowering protection’’.
only the uses that have been established (ii) For products with an SPF of 15 to (iii) As an option, the labeling may
and listed in this paragraph (b), may under 30. Select one or both of the state ‘‘[bullet] apply to all skin exposed
also be used, as provided in § 330.1(c)(2) following: ‘‘[Bullet] provides medium to the sun’’.
of this chapter, subject to the provisions protection against [select one of the (iv) The labeling states ‘‘[bullet]
of section 502 of the act (21 U.S.C. 352) following: ‘sunburn’ or ‘sunburn and children under 6 months of age: ask a
relating to misbranding and the tanning’]’’ or ‘‘[bullet] for skin that doctor’’.
prohibition in section 301(d) of the act sunburns moderately’’. (2) For products that satisfy the water
(21 U.S.C. 331(d)) against the (iii) For products with an SPF of 30 resistant or very water resistant testing
introduction or delivery for introduction to 50. Select one or both of the procedures identified in § 352.76. The
into interstate commerce of unapproved following: ‘‘[Bullet] [select one of the labeling states ‘‘[bullet] reapply after
new drugs in violation of section 505(a) following: ‘provides high’ or ‘high’] [select one of the following: ‘40 minutes
of the act (21 U.S.C. 355(a)). protection against [select one of the of’ or ‘80 minutes of’ for products that
(1) For products containing any following: ‘sunburn’ or ‘sunburn and satisfy either the water resistant or very
ingredient in § 352.10. (i) For products tanning’]’’ or ‘‘[bullet] for skin highly water resistant test procedures in
with an SPF of 2 to under 15. The sensitive to sunburn’’. § 352.76, respectively] swimming or
labeling states ‘‘[bullet]1 low UVB (iv) For products with an SPF over 50. [select one or more of the following:
sunburn protection’’. Select one or both of the following: ‘sweating’ or ‘perspiring’] and after
(ii) For products with an SPF of 15 to ‘‘[Bullet] [select one of the following: towel drying. Otherwise, reapply at least
under 30. The labeling states ‘‘[bullet] ‘provides highest’ or ‘highest’] every 2 hours’’.
medium UVB sunburn protection’’. protection against [select one of the (3) For products that do not satisfy the
(iii) For products with an SPF of 30 following: ‘sunburn’ or ‘sunburn and water resistant or very water resistant
to 50. The labeling states ‘‘[bullet] high tanning’]’’ or ‘‘[bullet] for skin extremely testing procedures identified in § 352.76.
UVB sunburn protection’’. sensitive to sunburn’’. The labeling states ‘‘[bullet] reapply at
(iv) For products with an SPF over 50. (v) If the UVA descriptor in least every 2 hours and after towel
The labeling states ‘‘[bullet] highest § 352.52(b)(1)(vi) is the same as the SPF drying, swimming, or [select one of the
UVB sunburn protection’’. descriptor in § 352.52(b)(1)(i) through following: ‘sweating’ or ‘perspiring’]’’.
(b)(1)(iv), then the statement in (e) Statement on product
1 See § 201.66(b)(4) of this chapter for definition § 352.52(b)(1)(i) through (b)(1)(iv) may performance—(1) For products
of bullet symbol. be combined with the statement in containing any ingredient identified in
§ 352.10. The following product ‘‘UV exposure from the sun increases paragraph. When the time intervals or
category designation (PCD) labeling the risk of skin cancer, premature skin age limitations for administration of the
claims may be used under the heading aging, and other skin damage. It is individual ingredients differ, the
‘‘Other information’’ or anywhere important to decrease UV exposure by directions for the combination product
outside of the ‘‘Drug Facts’’ box or limiting time in the sun, wearing may not contain any dosage that
enclosure and shall not be intermixed protective clothing, and using a exceeds those established for any
with the information required under sunscreen. [in bold type]’’ ‘‘[bullet] keep individual ingredient in the applicable
§ 352.50(a). out of eyes’’ ‘‘[bullet] stop use if skin OTC drug monograph(s), and may not
(i) For products with an SPF of 2 to rash occurs.’’ provide for use by any age group lower
under 15. The labeling states ‘‘low (iv) The warning in § 201.66(c)(5)(x) than the highest minimum age limit
sunburn protection product’’. of this chapter may be limited to the established for any individual
(ii) For products with an SPF of 15 to following: ‘‘Keep out of reach of ingredient. For permitted combinations
under 30. The labeling states ‘‘medium children.’’ containing a sunscreen and a skin
sunburn protection product’’. (v) For lip protectant products protectant identified in § 352.20(b), the
(iii) For products with an SPF of 30 containing any ingredient identified in directions for sunscreens in § 352.52(d)
to 50. The labeling states ‘‘high sunburn § 352.10. The heading and the must be used. For products marketed as
protection product’’. indication required by § 201.66(c)(4) of a lip protectant with sunscreen,
(iv) For products with an SPF over 50. this chapter may be limited to ‘‘Use [in § 352.52(f)(1)(vi) applies.
The labeling states ‘‘highest sunburn bold type] helps prevent sunburn and
10. Sections 352.70 through 352.73
protection product’’. chapped lips’’. The warnings required
are revised as follows:
(2) For products containing any in paragraph (f)(1)(iii) of this section
ingredient identified in § 352.10. The may be limited to the following: ‘‘Stop Subpart D—Testing Procedures
following labeling statement may be use if skin rash occurs.’’ The warning Sec.
used under the heading ‘‘Other required in paragraph (f)(1)(iv) of this 352.70 SPF testing procedure.
information’’ or anywhere outside of the section may be omitted. The directions 352.71 UVA in vitro testing procedure.
‘‘Drug Facts’’ box or enclosure and shall in paragraphs (d)(2) and (d)(3) of this 352.72 UVA in vivo testing procedure.
not be intermixed with the information section may be limited to the following: 352.73 Determination of the labeled UVA
‘‘apply liberally and reapply at least protective value.
required under § 352.50(a). The labeling
states ‘‘higher SPF products give more every 2 hours for sunburn protection’’. * * * * *
sun protection, but are not intended to (vi) For lipsticks, lip products to
prolong wear of lipstick, lip gloss, and § 352.70 SPF testing procedure.
extend the time spent in the sun’’.
(3) For products containing any lip balm containing any ingredient (a) Standard sunscreens—(1)
ingredient identified in § 352.10 and identified in § 352.10 and identified in Laboratory validation. A standard
that satisfy the requirements in § 352.73 § 720.4(c)(7) of this chapter. The sunscreen shall be used concomitantly
for a labeled UVA protection value. The labeling is identical to that in paragraph in the testing procedures for
following labeling statements may be (f)(1)(v) of this section except the determining the SPF value of a
used anywhere outside of the ‘‘Drug heading and the indication required by sunscreen drug product to ensure the
Facts’’ box or enclosure and shall not be § 201.66(c)(4) of this chapter are limited uniform evaluation of sunscreen drug
intermixed with the information to ‘‘Use [in bold type] helps prevent products.
required under § 352.50(a). sunburn’’. (i) For products with an SPF of 2 to
(i) The labeling states ‘‘broad * * * * * 15. The standard sunscreen shall be an
spectrum sunscreen’’. 9. Section 352.60 is amended by 8-percent homosalate preparation with a
(ii) The labeling states ‘‘provides revising paragraphs (c) and (d) to read mean SPF value of 4.47 (standard
[select one of the following: ‘UVA and as follows: deviation = 1.28). In order for the SPF
UVB,’ or ‘broad spectrum’] protection’’. § 352.60 Labeling of permitted
determination of a test product to be
(iii) The labeling states ‘‘protects from combinations of active ingredients. considered valid, the SPF of the
UVA and UVB [select one of the standard sunscreen must fall within the
* * * * *
following: ‘rays’ or ‘radiation’]’’. (c) Warnings. The labeling of the standard deviation range of the expected
(iv) The labeling states ‘‘[select one of product states, under the heading SPF (i.e., 4.47 ± 1.28). Optionally, the
the following: ‘absorbs’ or ‘protects’] ‘‘Warnings,’’ the warning(s) for each standard sunscreen in paragraph
within the UVA spectrum’’. ingredient in the combination, as (a)(1)(ii) of this section may be used.
(f) Products, including cosmetic-drug established in the warnings section of (ii) For products with an SPF over 15
products, containing any ingredient the applicable OTC drug monographs, (optional for SPF values of 2 to 15). The
identified in § 352.10 labeled for use except that the warning for skin standard sunscreen shall be an SPF 15
only on specific small areas of the face protectants in § 347.50(c)(3) of this formulation containing 7 percent
(e.g., lips, nose, ears, and/or around the chapter is not required for permitted padimate O and 3 percent oxybenzone
eyes) and that meet the criteria combinations containing a sunscreen with a mean SPF value of 16.3 (standard
established in § 201.66(d)(10) of this and a skin protectant identified in deviation = 3.43). In order for the SPF
chapter. * * * § 352.20(b). For products marketed as a determination of a test product to be
(1) * * * lip protectant with sunscreen, considered valid, the SPF of the
* * * * * § 352.52(f)(1)(vi) applies. standard sunscreen must fall within the
(ii) The indication required by (d) Directions. The labeling of the standard deviation range of the expected
§ 201.66(c)(4) of this chapter may be product states, under the heading SPF (i.e., 16.3 ± 3.43).
limited to the following: ‘‘Use [in bold ‘‘Directions,’’ directions that conform to (2) Standard homosalate sunscreen—
type] helps prevent sunburn.’’ the directions established for each (i) Preparation of the standard
(iii) The warnings required by ingredient in the directions sections of homosalate sunscreen. (A) The standard
§ 201.66(c)(5)(i) through (c)(5)(ix) of this the applicable OTC drug monographs, homosalate sunscreen is prepared from
chapter may be limited to the following: unless otherwise stated in this two different preparations (preparation
A and preparation B) with the following preparation by the following method to (2) Add approximately 75 milliliters
compositions: ensure proper concentration: of isopropanol and heat with swirling
(A) Reagents. (1) Acetic acid, glacial, until the sample is evenly dispersed.
COMPOSITION OF PREPARATION A AND ACS grade. (3) Cool to room temperature (15 to 30
PREPARATION B OF THE HOMOSALATE (2) Isopropanol, HPLC grade. °C) and dilute to volume with
STANDARD SUNSCREEN (3) Methanol, HPLC grade. isopropanol. Mix well.
(4) Homosalate, USP reference (4) Pipet 25.0 milliliters of this sample
Percent by standard.
Ingredients weight preparation into a 100-milliliter
(B) Instrumentation. Equilibrate a volumetric flask and dilute to volume
Preparation A
suitable liquid chromatograph to the with isopropanol. Mix well.
following or equivalent conditions: (E) System suitability. (1) Three
Lanolin 5.00 Column .............. Ultrasphere ODS 150 x 4.6 replicate injections of the standard
Homosalate 8.00 millimeters (5 microns), or preparation (described in paragraph
White petrolatum 2.50 Ultrasphere ODS 250 x 4.6
Stearic acid 4.00
(a)(2)(ii)(C)(2) of this section) will yield
millimeters (5 microns)
Propylparaben 0.05 Mobile Phase ..... 85:15:0.5 meth- a relative standard deviation of not more
anol:water:acetic acid than 2.0 percent calculated on peak
Preparation B Flow Rate .......... 1.5 milliliters per minute areas for homosalate.
Temperature ...... Ambient (2) In case a system fails to meet this
Methylparaben 0.10 Detector ............. UV spectrophotometer at 308
nanometers criterion, adjusting the mobile phase or
Edetate disodium 0.05 replacing the column may be necessary
Attenuation ........ As needed
Propylene glycol 5.00
Triethanolamine 1.00
Injection Amount 10 microliters to obtain suitable chromatography.
Purified water USP 74.30 (C) Standard preparation. (1) (F) Analysis. (1) Inject 10 microliters
Accurately weigh 0.50 gram of of the standard preparation (described
(B) Preparation A and preparation B homosalate USP reference standard into in paragraph (a)(2)(ii)(C) of this section)
are heated separately to 77 to 82 °C, a 250-milliliter volumetric flask. in triplicate and collect data for about
with constant stirring, until the contents Dissolve and dilute to volume with 15 minutes or until both homosalate
of each part are solubilized. Add isopropanol. Mix well. (two isomers) peaks have completely
preparation A slowly to preparation B (2) Accurately pipet 20.0 milliliters of eluted.
while stirring. Continue stirring until the homosalate solution (described in (2) Similarly inject 10 microliters of
the emulsion formed is cooled to room paragraph (a)(2)(ii)(C)(1) of this section) each sample preparation.
temperature (15 to 30 °C). Add sufficient into a 100-milliliter volumetric flask. (3) The system suitability
purified water to obtain 100 grams of Dilute to volume with isopropanol and requirements must be met.
standard sunscreen preparation. mix well. This is the standard (G) Calculation. Sum the peak areas of
(ii) High performance liquid preparation. the two homosalate isomers for each
chromatography (HPLC) assay of the (D) Sample preparation. (1) injection and calculate the percent
standard homosalate sunscreen. Assay Accurately weigh 2.0 grams of sample (weight/weight) homosalate content in
the standard homosalate sunscreen into a 100-milliliter volumetric flask. the sample preparation as follows:
(3) Standard padimate O/oxybenzone COMPOSITION OF THE PADIMATE O/ COMPOSITION OF THE PADIMATE O/
sunscreen—(i) Preparation of the OXYBENZONE STANDARD SUN- OXYBENZONE STANDARD SUN-
standard padimate O/oxybenzone SCREEN SCREEN—Continued
sunscreen. The standard sunscreen is
prepared from four different parts (parts Percent Percent
A, B, C, and D) with the following Ingredients by Ingredients by
weight weight
compositions:
Part A Oxybenzone ............................. 3.00

Propylparaben ......................... 0.10
Lanolin ..................................... 4.50
Cocoa butter ............................ 2.00 Part B
Glyceryl monostearate ............. 3.00
Stearic acid .............................. 2.00 Purified water USP .................. 71.60
EP27AU07.005</GPH>
Padimate O .............................. 7.00 Sorbitol solution ....................... 5.00
COMPOSITION OF THE PADIMATE O/ ensure that the standard sunscreen (D) Sample preparation. (1) Weigh 1.0
OXYBENZONE STANDARD SUN- contains proper amounts of padimate O gram of sample into a 50-milliliter
SCREEN—Continued and oxybenzone, analyze it against USP volumetric flask.
reference standards for padimate O and (2) Add approximately 30 milliliters
Percent oxybenzone in a high performance of isopropanol and heat with swirling
Ingredients by liquid chromatography procedure using until the sample is evenly dispersed.
weight the following parameters: (3) Cool to room temperature (15 to 30
Triethanolamine, 99 percent .... 1.00
(A) Reagents. (1) Acetic acid, glacial, °C) and dilute to volume with
Methylparaben ......................... 0.30 ACS grade. isopropanol. Mix well.
(2) Isopropanol, HPLC grade. (4) Pipet 5.0 milliliters of this sample
Part C (3) Methanol, HPLC grade. preparation into a 50-milliliter
(4) Oxybenzone, USP reference volumetric flask and dilute to volume
Benzyl alcohol ......................... 0.50
standard. with isopropanol. Mix well.
Part D (5) Padimate O, USP reference (E) System suitability. (1) Three
standard. replicate injections of the standard
Purified water USP .................. QS1 (B) Instrumentation. Equilibrate a preparation (described in paragraph
1 Quantity sufficient to make 100 grams suitable liquid chromatograph to the (a)(3)(ii)(C) of this section) will yield a
following or equivalent conditions: relative standard deviation of not more
(A) Step 1. Add the ingredients of Part
than 2.0 percent calculated on peak
A into a suitable stainless steel kettle Column .............. Ultrasphere ODS 250 x 4.6
areas for oxybenzone and padimate O.
equipped with a propeller agitator. Mix millimeters (5 microns), or
at 77 to 82 °C until uniform. Supelcosil LC-18 DB 250 x (2) A calculated resolution between
4.6 millimeters (5 microns) the oxybenzone and padimate O peaks
(B) Step 2. Add the water of Part B Mobile Phase ..... 85:15:0.5 meth-
into a suitable stainless steel kettle anol:water:acetic acid
will be not less than 3.0.
equipped with a propeller agitator and Flow Rate .......... 1.5 milliliters per minute (3) In case a system fails to meet this
begin mixing and heating to 77 to 82 °C. Temperature ...... Ambient criterion, adjusting the mobile phase or
Detector ............. UV spectrophotometer at 308
Add the remaining ingredients of Part B nanometers
replacing the column may be necessary
and mix until uniform. Maintain Attenuation ........ As needed to obtain suitable chromatography.
temperature at 77 to 82 °C. Injection Amount 10 microliters (F) Analysis. (1) Inject 10 microliters
(C) Step 3. Add the batch of Step 1 at of the standard preparation (described
77 to 82 °C to the batch of Step 2 at 77 (C) Standard preparation. (1) Weigh
0.50 gram of oxybenzone reference in paragraph (a)(3)(ii)(C) of this section)
to 82 °C, and mix until smooth and in triplicate and collect data for about
uniform. Slowly cool the batch to 49 to standard into a 250-milliliter volumetric
flask. Dissolve and dilute to volume 15 minutes or until the padimate O peak
54 °C. has completely eluted. Elution order is
(D) Step 4. Add the benzyl alcohol of with isopropanol. Mix well.
oxybenzone, then padimate O.
Part C to the batch of Step 3 at 49 to 54 (2) Weigh 0.50 gram of padimate O
reference standard into a 250-milliliter (2) Similarly inject 10 microliters of
°C. Mix until uniform. Continue to cool
volumetric flask. Dissolve and dilute to each sample preparation.
batch to 35 to 41 °C.
(E) Step 5. Add sufficient water of volume with isopropanol. Mix well. (3) The system suitability
Part D to the batch of Step 4 at 35 to 41 (3) Pipet 3.0 milliliters of the requirements must be met.
°C to obtain 100 grams of standard oxybenzone solution and 7.0 milliliters (G) Calculation. Calculate the percent
sunscreen preparation. Mix until of the padimate O solution into a 100- (weight/weight) of each sunscreen
uniform. Cool batch to 27 to 32 °C. milliliter volumetric flask. Dilute to ingredient in the sample preparation as
(ii) HPLC assay of the standard volume with isopropanol and mix well. follows:
padimate O/oxybenzone sunscreen. To This is the standard preparation. (1) Oxybenzone (percent weight)
(2) Padimate O (percent weight)

EP27AU07.007</GPH>
(b) Light source (solar simulator)—(1) emission spectrum from 290 to 400 and the following percentage of
Emission spectrum. A solar simulator nanometers (nm) with a limit of 1,500 erythema-effective radiation in each
used for determining the SPF of a watts per square meter (W/m2) on total specified range of wavelengths:
sunscreen drug product should be solar simulator irradiance for all
EP27AU07.006</GPH>
filtered so that it provides a continuous wavelengths between 250 and 1400 nm
SOLAR SIMULATOR EMISSION IV: Burns minimally; always tans well will be at least 1 square centimeter
(moderate brown) (normal). (cm2) in area and will be separated from
SPECTRUM V: Rarely burns; tans profusely (dark brown) each other by at least 1 cm. Mark the
(insensitive).
Wavelength range Percent erythemal VI: Never burns; deeply pigmented
location of each test subsite with
(nm) contribution indelible ink.
(insensitive).
(5) Application of test materials.
< 290 < 0.1 Determine that the subject is not taking Apply the test sunscreen product and
290–310 46.0–67.0 topical or systemic medication that is the standard sunscreen at 2 milligrams
290–320 80.0–91.0 known to alter responses to ultraviolet
290–330 86.5–95.0 per square centimeter (mg/cm2) to their
radiation and that the subject has no respective test sites to establish standard
290–340 90.5–97.0
290–350 93.5–98.5 history of sensitivities to topical films. Test sites will be randomly
290–400 93.5–100.0 products and/or abnormal responses to located on the back in a blinded
sunlight, such as a phototoxic or manner. Use a finger cot compatible
(2) Operation. A solar simulator photoallergic response. with the sunscreen to spread the
should have no significant time related (2) Physical examination. Conduct a product as evenly as possible. Pretreat
fluctuations (within 20 percent) in physical examination to determine the the finger cot by saturating with the
radiation emissions after an appropriate presence of sunburn, suntan, scars, sunscreen and then wiping off material
warmup time and good beam uniformity active dermal lesions, and uneven skin before application. Pretreatment is
(within 20 percent) in the exposure tones on the areas of the back to be meant to ensure that sunscreen is
plane. The average delivered dose to the tested. A suitable source of low power applied at the correct density of 2 mg/
UV exposure site must be within 10 UVA, such as a Woods lamp, is helpful cm2.
percent of the prescribed dose. in this process. If any of these (6) Waiting period. Before exposing
(3) Periodic measurement. To ensure conditions are present, the subject is not the test site areas after applying a
that the solar simulator delivers the qualified to participate in the study. The product, wait at least 15 minutes.
appropriate spectrum of UV radiation, presence of nevi, blemishes, or moles (7) Number of subjects—(i) For
the emission spectrum of the solar will be acceptable if in the physician’s products with an expected SPF under
simulator must be measured every 6 judgment they will neither compromise 30. A test panel shall consist of 20 to 25
months with an appropriate and the study, nor jeopardize subject safety. subjects with at least 20 subjects who
accurately calibrated spectroradiometer Subjects with dysplastic nevi should not produce valid data for analysis. Data are
system (results should be traceable to be enrolled. Excess hair on the back is valid unless rejected in accordance with
the National Institute for Standards and acceptable if the hair is clipped. paragraph (c)(9) of this section. If more
Technology). In addition, the solar Shaving is unacceptable because it may than 5 subjects are rejected based on
simulator must be recalibrated if there is remove a significant portion of the paragraph (c)(9) of this section, the
any change in the lamp bulb or the stratum corneum and temporarily panel is disqualified, and a new panel
optical filtering components (i.e., filters, increase skin permeability to ultraviolet must be created.
mirrors, lenses, collimating devices, or radiation. (ii) For products with an expected
focusing devices). Daily solar simulator (3) Informed consent. Obtain legally SPF of 30 or over. A test panel shall
radiation intensity should be monitored effective written informed consent from consist of 25 to 30 subjects with at least
with a broadband radiometric device all subjects. 25 subjects who produce valid data for
that is sensitive primarily to UV (4) Test site delineation—(i) Test site. analysis. Data are valid unless rejected
radiation. The broadband radiometric A test site is the location on the back for in accordance with paragraph (c)(9) of
device should be calibrated using side determining the subject’s initial and this section. If more than 5 subjects are
by side comparison with the final minimal erythema dose (MED) for rejected based on paragraph (c)(9) of this
spectroradiometer at the time of the unprotected skin and for determining section, the panel is disqualified, and a
semiannual spectroradiometric SPF values after application of the new panel must be created.
measurement of the solar simulator. If a sunscreen standard and the test (8) Response criteria. In order that the
lamp must be replaced due to failure or sunscreen product(s). There typically person who evaluates the MED
aging during a phototest, broadband are 4 to 6 test sites for each subject. Test responses is not biased, he/she must not
device readings consistent with those sites should be located on the back be the same person who applied the
obtained for the original calibrated lamp between the beltline and the shoulder sunscreen drug product to the test site
will suffice until measurements can be blades (scapulae) and lateral to the or administered the doses of UV
performed with the spectroradiometer at midline. Each test site shall be a radiation. After UV radiation exposure
the earliest possible opportunity. minimum of 50 square centimeters, e.g., from the solar simulator is completed,
(c) General testing procedures—(1) 5 x 10 centimeters. Outline the test sites all immediate responses shall be
Medical history. Obtain a medical to which the sunscreen standard and the recorded. These may include an
history from each subject with emphasis test sunscreen product(s) will be immediate darkening or tanning,
on the effects of sunlight on his/her applied with indelible ink. If the subject typically grayish or purplish in color,
skin. Determine that each subject is in is to receive the doses of ultraviolet which fades in 30 to 60 minutes; an
good general health with skin type I, II, radiation in an upright (seated) position, immediate reddening at the subsite, due
or III (as described in this paragraph). draw the lines on the skin with the to heating of the skin, which fades
Skin Type and Sunburn and Tanning subject upright (seated). If the subject is rapidly; and an immediate generalized
History (Based on first 30 to 45 minutes to receive the doses of ultraviolet heat response, spreading beyond the
subsite, which fades in 30 to 60
of sun exposure after a winter season of radiation while prone, draw the lines
no sun exposure). with the subject prone. minutes. After the immediate responses
I: Always burns easily; never tans (sensitive).
(ii) Test subsite. Test subsites are the are noted, each subject shall shield the
II: Always burns easily; tans minimally locations to which ultraviolet radiation exposed area from further UV radiation
(sensitive). is administered within a test site. At until the MED response is evaluated.
III: Burns moderately; tans gradually (light least 5 test subsites will receive UV Determine the MED 16 to 24 hours after
brown) (normal). doses within each test site. Test subsites exposure. Evaluate the erythema
responses of each test site using either more intense redness. For subsites exposed testing sites from further UV
tungsten or warm white fluorescent showing an erythema response, the radiation until the MED is read.
lighting that provides 450 to 550 lux of maximal exposure should be no more (d) Determination of SPF—(1)
illumination at the test site. For the than twice the total energy of the Determination of erythema action
evaluation, the test subject should be in minimal exposure. spectrum. (i) Use the following
the same position used when the test erythema action spectrum as weighting
(9) Rejection of test data. Reject test
site was irradiated. For each test site, factors to calculate the erythema-
data if the exposure series fails to elicit
determine the smallest UV dose that effective exposure produced by a solar
an MED response on either the treated simulator:
produced redness reaching the borders or unprotected skin sites; or all subsites
of the test subsite. The MED is the Vi (λ) = 1.0 (250 < λ < 298 nm)
within a test site show more intense Vi (λ) = 100.094 * (298 - l) (298 < λ < 328
quantity of erythema-effective energy responses than the threshold erythema nanometers)
required to produce the first perceptible, response; or the responses are Vi (λ) = 100.015 * (140 - l) (328 < λ < 400
redness reaction with clearly defined inconsistent with the series of UV doses nanometers)
borders at 16 to 24 hours post-exposure. administered; or the subject was (ii) Integrate the erythemally-effective
To determine the MED, there must be at noncompliant, e.g., the subject spectral irradiance over wavelength and
least one subsite that received a smaller withdraws from the test due to illness time to calculate the erythema-effective
UV dose and does not produce redness or work conflicts or does not shield the UV dose delivered by a solar simulator
as well as a subsite(s) with somewhat as follows:
(iii) The erythema action spectrum Select the doses that are a geometric product. For products with an expected
may be determined using a handheld series represented by (1.25n), wherein SPF between 8 and 15, use exposures
radiometer with a response weighted to each exposure dose is 25 percent greater that are the initial unprotected MED
match the spectrum in ‘‘CIE S 007/E than the previous exposure dose to times 0.69X, 0.83X, 1.00X, 1.20X, and
Erythemal Reference Action Spectrum maintain the same relative uncertainty 1.44X, where X equals the expected SPF
and Standard Erythema Dose,’’ dated (expressed as a constant percentage), of the test product. For products with an
1998, which is incorporated by independent of the subject’s sensitivity expected SPF greater that 15, use
reference in accordance with 5 U.S.C. to UV radiation. Usually, the UV exposures that are the initial
552(a) and 1 CFR part 51. Copies are radiation for determining the initial unprotected MED times 0.76X, 0.87X,
available from CIE Central Bureau, unprotected MED is administered the 1.00X, 1.15X, and 1.32X, where X
Kegelgasse 27, A–1030, Vienna, Austria, day prior to applying the sunscreen equals the expected SPF of the test
or may be examined at the Center for product and standard sunscreen, and product. The MED is the smallest
Drug Evaluation and Research, 10903 the responses then are evaluated erythemally-effective UV dose required
New Hampshire Ave., Bldg. 22, Silver immediately prior to applying the to produce mild redness within the
Spring, MD, or at the Office of the sunscreen product and sunscreen subsite border at 16 to 24 hours post-
Federal Register, 800 North Capitol St. standard. Determine the final exposure. Calculate the SPF value of
NW., suite 700, Washington, DC. It is unprotected MED on the same day that each sunscreen product and sunscreen
advisable to measure the solar simulator UV radiation is administered to the standard using the MED of sunscreen-
output before and after each phototest sunscreen-protected test sites. Use the protected skin (MED(PS)) and the final
or, at a minimum, at the beginning and final unprotected MED (MED(US)) in unprotected skin MED (MED(US)) as
end of each test day. This radiometer calculating SPF. follows:
should be calibrated using side by side (3) Determination of individual SPF
comparison with the spectroradiometer values. Administer a series of five UV
(using the weighting factors determined radiation doses expressed as J/m2-eff
according to paragraph (d)(1)(i) of this (adjusted to the erythema action (4) Determination of the test product
section) at the time of the semiannual spectrum calculated according to SPF and PCD. Use data from at least 20
spectroradiometric measurement of the paragraph (d)(1) of this section) to the test subjects with n representing the
solar simulator. subsites within each test site on a number of subjects used. First, compute
(2) Determination of MED of subject using an accurately calibrated the SPF value for each subject as stated
unprotected skin. Administer a series of solar simulator. The five UV doses will in paragraphs (d)(2) and (d)(3) of this
five UV radiation doses expressed as J/ be a geometric series as described in section. Second, compute the mean SPF
m2-eff (adjusted to the erythema action paragraph (d)(2) of this section, where value, x̄, and the standard deviation, s,
spectrum calculated according to the middle exposure represents the for these subjects. Third, obtain the
paragraph (d)(1) of this section) to the expected SPF. For products with an upper 5-percent point from Student’s t
EP27AU07.009</GPH>
subsites within each test site on a expected SPF less than 8, use exposures distribution table with n-1 degrees of
subject using an accurately calibrated that are the product of the initial freedom. Denote this value by t. Fourth,
solar simulator. Use the series of five unprotected MED times 0.64X, 0.80X, compute ts/√n. Denote this quantity by
exposures to the unprotected test site to 1.00X, 1.25X, and 1.56X, where X A (i.e., A = ts/√n). Fifth, calculate the
EP27AU07.008</GPH>
determine the initial unprotected MED. equals the expected SPF of the test SPF value to be used in labeling as
follows: The label SPF equals the largest should be set to provide a bandwidth reference in accordance with 5 U.S.C.
whole number less than x̄ - A. Sixth and that is less than or equal to 5 552(a) and 1 CFR part 51. Copies are
last, the sunscreen product is classified nanometers. available from CIE Central Bureau,
into a PCD as follows: If 50 + A < x̄, the (e) Sunscreen drug product Kegelgasse 27, A–1030, Vienna, Austria,
PCD is Highest; if 30 + A ≤ x̄ ≤ 50 + A, application to substrate. The accuracy or may be examined at the Center for
the PCD is High; if 15 + A ≤ x̄ < 30 + of the test depends upon the application Drug Evaluation and Research, 10903
A, the PCD is Medium; if 2 + A ≤ x̄ < of a precisely controlled amount of New Hampshire Ave., Bldg. 22, Silver
15 + A, the PCD is Low; if x̄ < 2 + A, sunscreen product with a uniform Spring, MD 20993, or at the Office of the
the product shall not be labeled as an distribution over the application area of Federal Register, 800 North Capitol St.
OTC sunscreen drug product and may the substrate. The product is applied at NW., suite 700, Washington, DC.
not display an SPF value. 2 milligrams per square centimeter to (g) Calculation of the spectral
the substrate. To achieve uniform transmittance at each wavelength
§ 352.71 UVA in vitro testing procedure. distribution over the substrate, the interval. The dynamic range of the
(a) Light source for transmittance/ sunscreen product should be applied in measurement system and the intensity
absorbance measurements. The light a series of small dots over the of the light source should be sufficiently
source should satisfy the requirements application area of the substrate and high that signals measured at all UV
for solar simulators described in then spread evenly using a gloved wavelengths (290 to 400 nanometers)
§ 352.70(b). finger. A very light spreading action for through a highly absorbing sunscreen
(b) Substrate. Use optical-grade quartz a short period of time (approximately 10 product are above the noise level of the
plate suitable for substrate seconds) should be used when measurement system. Spectral
spectrophotometry that has been distributing the product to ensure irradiance will be measured at 5
roughened on one side. complete coverage without excessive nanometer intervals, from 290 to 400
(c) Sample holder. The sample holder buildup of product in the troughs of the nanometers. At least 12 measurements
should hold the substrate in a horizontal substrate. of spectral irradiance transmitted
position to avoid flowing of the (f) Pre-irradiation to account for through the substrate without sunscreen
sunscreen drug product from one edge differences in photostability. To account drug product present will be obtained
of the substrate to the other. It should for potentially varying degrees of from different locations on the substrate
be mounted as close as possible to the photostability between sunscreen drug surface (C(λ)1, C(λ)2, C(λ)3, . . . C(λ)12).
input optics of the spectroradiometer to products, irradiate the sunscreen In addition, a minimum of 12
maximize capture of forward scattered product on the substrate with a dose of measurements of spectral irradiance
radiation. The sample holder should be UV radiation equal to the SPF of the transmitted through the substrate with
a thin, flat plate with a suitable aperture sunscreen product multiplied by 200 J/ the sunscreen drug product present will
through which UV radiation can pass. m2-eff multiplied by 2/3. A UV be similarly obtained after pre-
The substrate will be placed on the radiation dose of 200 J/m2-eff is irradiation of the sunscreen drug
upper surface of the sample holder. equivalent to one minimal erythema product (P(λ)1, P(λ)2, P(λ)3, . . . P(λ)12).
(d) Spectroradiometer input optics. dose (MED). The UV dose to be The mean transmittance for wavelength
Unless the spectroradiometer is delivered is determined by multiplying λ, T(λ), is the ratio of the mean of the
equipped with an integrating sphere, an the light source spectral irradiance C(λ) values to the mean of the P(λ)
ultraviolet radiation diffuser should be action spectrum for erythema in ‘‘CIE S values, as follows:
placed between the sample and the 007/E Erythemal Reference Action
input optics of the spectroradiometer. Spectrum and Standard Erythema
The diffuser will be constructed from Dose,’’ at each wavelength, integrating
any UV radiation transparent material over wavelength, and multiplying the
(e.g., Teflon or quartz). The diffuser integral by the exposure time. ‘‘CIE S The standard deviation, s, associated
ensures that the radiation received by 007/E Erythemal Reference Action with the spectral transmittance is
the spectroradiometer is not collimated. Spectrum and Standard Erythema evaluated using Taylor’s approximation,
The spectroradiometer input slits Dose,’’ dated 1998, is incorporated by as follows:
EP27AU07.013</GPH>
where C(λ) = mean of the measurements 290 to 400 nanometers. The standard
of C at wavelength λ. deviation values will provide an
indication of the uniformity of
P(λ) = mean of the measurements of P
sunscreen drug product spreading
at wavelength λ.
EP27AU07.012</GPH>
s(P(λ)) is calculated as follows: during application to the substrate. The

s(C(λ)) = standard deviation of the coefficient of variation, which is the
measurements of C at wavelength λ. standard deviation divided by the mean,
and expressed as a percentage, should

s(P(λ)) = standard deviation of the
EP27AU07.011</GPH>
be less than 10 percent.

measurements of P at wavelength λ.
This calculation gives 23 spectral (h) Calculation of the UVA I/UV ratio.
s(C(λ)) is calculated as follows: transmittance values with associated (1) Spectral transmittance values, T(λ),
standard deviations, one for each 5 are converted into absorbance values,
EP27AU07.010</GPH>
nanometer wavelength increment from A(λ), by taking the negative logarithm of
the spectral transmittance value as (i) Category determination of the UVA V: Rarely burns; tans profusely (dark
follows: I/UV ratio. Perform at least 5 separate brown) (insensitive).
A(λ) = -log T(λ) determinations of the UVA I/UV ratio, VI: Never burns; deeply pigmented
The calculation yields 23 from which the mean can be calculated. (insensitive).
monochromatic absorbance values in 5 Using the mean, the sunscreen drug Determine that the subject is not taking
nanometer increments from 290 to 400 product is classified by in vitro UVA I/ topical or systemic medication that is
nanometers. UV ratio as follows: known to alter responses to ultraviolet
(2) The index of UVA I protection is radiation and that the subject has no
UVA I/UV Ratio Category
calculated as the area (per unit history of sensitivities to topical
wavelength) under the UVA I portions 0.20 to 0.39 Low products and/or abnormal responses to
of a plot of wavelength versus A(λ), 0.40 to 0.69 Medium sunlight, such as a phototoxic or
divided by the area (per unit 0.70 to 0.95 High photoallergic response.
wavelength) under the total curve, as greater than 0.95 Highest (2) Physical examination. The
follows: physical examination shall be
§ 352.72 UVA in vivo testing procedure. conducted as specified in § 352.70(c)(1).
(a) Standard sunscreen. A standard (3) Informed consent. Obtain legally
sunscreen shall be tested concomitantly effective written informed consent from
in the procedure for determining the all subjects.
UVA protection factor (UVA–PF) value (4) Test site delineation—(i) Test site.
UVA I area per unit λ is given as: by means of persistent pigment A test site is the location on the back for
darkening to ensure the uniform determining the subject’s initial and
evaluation of sunscreen drug products. final minimal pigmenting dose (MPD)
UV area per unit λ is given as: The standard sunscreen shall be a for unprotected skin and for
preparation containing 7 percent determining UVA–PF values after
padimate O and 3 percent oxybenzone application of the sunscreen standard
as specified in § 352.70(a)(3). For the and the test sunscreen product(s). There
where: A(λ) = effective absorbance given test to be valid, the measured mean typically are 4 to 6 test sites for each
as -log T(λ) UVA–PF value of the standard subject. Test sites should be located on
d(λ) = wavelength interval between preparation shall be 3.2 with a standard the back between the beltline and the
measurements deviation less than or equal to 0.5. shoulder blades (scapulae) and lateral to
B(λ) = any biological action spectrum (b) Light source. The light source used the midline. Each test site shall be a
factor for determining the UVA–PF value of a minimum of 50 square centimeters
sunscreen drug product shall provide a (cm2) (i.e., 5 x 10 centimeters). Outline
Because no appropriate biological action continuous emission spectrum in the the test sites to which the sunscreen
spectrum for UVA radiation damage has range of 320 to 400 nanometers. The standard and the test sunscreen
been universally accepted, no action ratio of UVA I (340 to 400 nanometers) product(s) will be applied with
spectrum is specified. The value of B(λ) to UVA II (320 to 340 nanometers) in the indelible ink. If the subject is to receive
is, therefore, equal to 1.0 for all final beam shall be close to that of the doses of ultraviolet radiation in an
wavelengths. sunlight, i.e., emitted UVA II shall be 8 upright (seated) position, draw the lines
(3) The integrals in the formulae in to 20 percent of the total UVA radiation. on the skin with the subject upright
paragraphs (h)(1) and (h)(2) of this Optical radiation from 250 to 320 (seated). If the subject is to receive the
section are evaluated using Simpson’s nanometers shall be less than 0.1 doses of ultraviolet radiation while
Rule for irregular areas, which states: percent of the optical radiation between prone, draw the lines with the subject
Area = h/3 x [Y0 + Y2m + 4(Y1 + Y3 . . . +
320 to 400 nanometers. Exclude visible prone.
Y2m-1) + 2(Y2 + Y4 + . . . Y2m-2)]
and infrared light to avoid the darkening (ii) Test subsite. Test subsites are the
In this equation, Y0, Y1, Y2, . . . Y2m are effects of visible light and the effect of locations to which ultraviolet radiation
the lengths of 2m parallel lines drawn heat. Perform monitoring and is administered within a test site. At
vertically to divide the area under the maintenance of the light source as least 5 test subsites will receive UV
curve of a graph into 2m-1 segments of specified in § 352.70(b)(3). doses within each test site. Test subsites
equal width, h. In practice, the values of (c) General testing procedures—(1) will be at least 1 cm2 in area and will
Y0, Y1, Y2, . . . Y2m are the A(λ) values Medical history. Obtain a medical be separated from each other by at least
determined and h is the wavelength history from each subject with emphasis 1 cm. Mark the location of each test
interval at which the spectral on the effects of sunlight on his/her subsite with indelible ink.
transmittance is determined (i.e., 5 skin. Determine that each subject is in (5) Application of test materials.
nanometers).
EP27AU07.017</GPH>
good general health and has skin type II Apply the test sunscreen product and
(4) UVA I area per unit wavelength or III (as described in this paragraph). the standard sunscreen as specified in
(aUVA I/λ) is calculated as follows: Skin Type and Sunburn and Tanning § 352.70(c)(5).
aUVA I/λ = 5/3 x [A340 + A400 + 4(A345 + ... (6) Waiting period. Before exposing
+ A395) + 2(A350 + A360 + A370 + ... + A390)]/ History (Based on first 30 to 45 minutes
of sun exposure after a winter season of the test site areas after applying a
EP27AU07.016</GPH>
60 product, wait at least 15 minutes.

no sun exposure).
UV area per unit wavelength (aUV/λ) is (7) Number of subjects. A test panel
calculated as follows: I: Always burns easily; never tans shall consist of 20 to 25 subjects with
aUV/λ = 5/3 x [A290 + A400 + 4(A295 + A305 (sensitive). at least 20 subject who produce valid
+ A315 + ... + A395) + 2(A300 + A310 + ... + II: Always burns easily; tans minimally data for analysis. Data is valid unless
EP27AU07.015</GPH>
A390)]/110 (sensitive). rejected in accordance with

UVA I/UV ratio is calculated as follows: III: Burns moderately; tans gradually § 352.70(c)(9). If more than 5 subjects
(light brown) (normal). are rejected based on § 352.70(c)(9), the
IV: Burns minimally; always tans well panel is disqualified, and a new panel
EP27AU07.014</GPH>
(moderate brown) (normal). must be created.
(8) Response criteria. In order that the determine the initial unprotected MPD. follows: If 12 + A ≤ x, the PCD is
person who evaluates the MPD Select the doses that are a geometric Highest; if 8 + A ≤ x < 12 + A, the PCD
responses is not biased, he/she must not series represented by (1.25n), wherein is High; if 4 + A < x < 8 + A, the PCD
be the same person who applied the each exposure dose is 25 percent greater is Medium; if 2 + A ≤ x < 4 + A, the
sunscreen drug product to the test site than the previous exposure dose to PCD is Low; if x < 2 + A, the product
or administered the doses of UV maintain the same relative uncertainty shall not display a UVA–PF value.
radiation. After UV radiation exposure (expressed as a constant percentage),
§ 352.73 Determination of the labeled UVA
from the solar simulator is completed, independent of the subject’s sensitivity protection value.
all immediate responses shall be to UV radiation. Usually, the UV
recorded. These may include an Test the sunscreen product in
radiation for determining the initial
immediate darkening or tanning, accordance with §§ 352.71 and 352.72.
unprotected MPD is administered the
typically grayish or purplish in color, The UVA category on the principal
day prior to applying the sunscreen
which fades in 30 to 60 minutes; an display panel (PDP) of the tested
product and standard sunscreen, and
immediate reddening at the subsite, due sunscreen product, as specified in
the responses are then evaluated
to heating of the skin, which fades § 352.50, shall be the lower of either the
immediately prior to applying the
rapidly; and an immediate generalized UVA I/UV ratio category determined in
sunscreen product and sunscreen
heat response, spreading beyond the § 352.71(j) or the UVA–PF product
standard. Determine the final
subsite, which fades in 30 to 60 category designation (PCD) determined
unprotected MPD on the same day that
minutes. After the immediate responses in § 352.72(d)(3). If the product does not
UV radiation is administered to the attain at least a ‘‘low’’ category rating for
are noted, each subject shall shield the sunscreen-protected test sites. Use the
exposed area from further UV radiation both the UVA–PF and the UVA I/UV
final unprotected MPD (MPD(US)) in ratio, the product shall not display a
until the MPD response is evaluated. calculating UVA–PF.
Determine the MPD 3 to 24 hours after UVA claim. State the final combined
(2) Determination of individual UVA– category rating (i.e., the lower of either
exposure. Evaluate the pigmentation PF values. Administer a series of five
responses of each test site using either the UVA I/UV ratio or UVA–PF PCD
UV radiation doses expressed as Joules categories) on the PDP of the product
tungsten or warm white fluorescent per square meter to the subsites within
lighting that provides 450 to 550 lux of along with the corresponding number of
each test site on a subject using the light stars for that combined category rating
illumination at the test site. For the source described in paragraph (b) of this
evaluation, the test subject should be in as follows:
section. The five UV doses will be a
the same position used when the test geometric series as described in Combined Category Rating Star Rating
site was irradiated. For each test site, paragraph (d)(1) of this section, where
determine the smallest UV dose that the middle exposure represents the Low ★✰✰✰
produced mild pigmentation reaching expected UVA–PF. Use exposures that Medium ★★✰✰
the borders of the test subsite. The MPD are the product of the initial High ★★★✰
is the smallest UV dose required to Highest ★★★★
unprotected MPD times 0.64X, 0.80X,
produce the first perceptible pigment 1.00X, 1.25X, and 1.56X, where X 11. Section 352.76 is amended by
darkening at 3 to 24 hours post- equals the expected UVA–PF of the test revising the introductory paragraph and
exposure. To determine the MPD, there product. The MPD is the smallest UV paragraphs (a) introductory text, (a)(6),
must be at least one subsite that dose required to produce pigmentation (b) introductory text, and (b)(10) to read
received a smaller UV dose and does not at 3 to 24 hours post-exposure. Calculate as follows:
produce pigmentation as well as a the UVA–PF value of each sunscreen
subsite(s) with somewhat more intense § 352.76 Determination if a product is
product and sunscreen standard using water resistant or very water resistant.
pigmentation. For subsites showing MPD of sunscreen-protected skin
pigmentation, the maximal exposure The general testing procedures in
(MPD(PS)) and the final unprotected § 352.70(c) shall be used as part of the
should be no more than twice the total MPD (MPD(US)) as follows:
energy of the minimal exposure. following tests, except where modified
(9) Rejection of test data. Reject test in this section. An indoor fresh water
data if the exposure series fails to elicit pool, whirlpool, and/or jacuzzi
an MPD response on either the treated maintained at 23 to 32 °C shall be used
or unprotected skin sites, or all subsites (3) Determination of test product in these testing procedures. Fresh water
within a test site show more intense UVA–PF and UVA product category is clean drinking water that meets the
responses than the threshold designation (PCD). Use data from at standards in 40 CFR part 141. The pool
pigmentation response, or the responses least 20 test subjects with n representing and air temperature and the relative
are inconsistent with the series of UV the number of subjects used. First, humidity shall be recorded.
doses administered, or the subject was compute the UVA–PF value for each (a) Procedure for testing the water
noncompliant, e.g., the subject subject as stated in paragraph (d)(2) of resistance of a sunscreen product. For
withdraws from the test due to illness this section. Second, compute the mean sunscreen products making the claim of
or work conflicts or does not shield the UVA–PF value, x, and the standard ‘‘water resistant,’’ the label SPF and, if
exposed testing sites from further UV deviation, s, for these subjects. Third, appropriate, UVA values shall be the
radiation until the MPD is read. obtain the upper 5-percent point from label SPF and UVA values determined
(d) Determination of UVA–PF Student’s t distribution table with n-1 after 40 minutes of water immersion
values—(1) Determination of MPD of degrees of freedom. Denote this value by using the following procedure for the
t. Fourth, compute ts/√n. Denote this water resistance test:
unprotected skin. Administer a series of

five UV radiation doses expressed as quantity by A (i.e., A = ts/√n). Fifth, * * * * *
Joules per square meter to the subsites calculate the UVA–PF value to be used (6) Begin light source exposure to test
within each test site on a subject using in labeling as follows: The label UVA– site areas as described in § 352.70(b)
the light source described in paragraph PF equals the largest whole number less and, if appropriate, § 352.72(b).
(b) of this section. Use the series of five than x - A. Sixth and last, the drug (b) Procedure for testing a very water
EP27AU07.018</GPH>
exposures to the unprotected test site to product is classified into a PCD as resistant sunscreen product. For
sunscreen products making the claim of immersion using the following Dated: August 10, 2007.
‘‘very water resistant,’’ the label SPF procedure for the water resistance test: Jeffrey Shuren,
and, if appropriate, UVA values shall be * * * * * Assistant Commissioner for Policy.
the label SPF and UVA values (10) Begin light source exposure to [FR Doc. 07–4131 Filed 8–23–07; 8:45 am]
determined after 80 minutes of water test site areas as described in § 352.70(b) BILLING CODE 4160–01–S
and, if appropriate, § 352.72(b).

Proposed Rule: Sunscreen Drug Products For Over-The-Counter Human Use Proposed Amendment of Final Monograph

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Monday,

August 27, 2007

21 CFR Parts 347 and 352

B. Comments on Tanning and

phenylbenzimidazole sulfonic acid.

transfer to OTC sunscreen products and

requested by the first and second

the SPF labeling limit from 30 to 50,

FDA’s public health mission.

expertise so that only products that are

levels) for the following reasons: extended or enhanced) UVA

application and reapplication, is only the FM (64 FR 27666 at 27674). The

levels of UVA protection, especially for

SPF test in the monograph has indicated

processes that occur at a given

avoiding the sun near midday, seeking

exposure (58 FR 28194 at 28268 to

(§ 352.70(b) of the FM), and

FDA does not agree, at this time, with

error about the mean for products with

sunscreen or administered the dose of

have no practical application and using

FDA believes that this test, in

accuracy. absorbance of a sunscreen drug product UVA radiation protection.

environmental impact statement is effect of the proposed rule, if finalized

33362, June 4, 2003. while the color of ‘‘empty’’ stars must be

Part A Oxybenzone ............................. 3.00

Padimate O .............................. 7.00 Sorbitol solution ....................... 5.00

(2) Padimate O (percent weight)

filtered so that it provides a continuous wavelengths between 250 and 1400 nm

s(P(λ)) is calculated as follows: during application to the substrate. The

and expressed as a percentage, should

be less than 10 percent.

nanometer wavelength increment from A(λ), by taking the negative logarithm of

60 product, wait at least 15 minutes.

A390)]/110 (sensitive). rejected in accordance with

(moderate brown) (normal). must be created.

unprotected skin. Administer a series of

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