[Federal Register Volume 72, Number 165 (Monday, August 27, 2007)]
[Proposed Rules]
[Pages 49070-49122]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 07-4131]



[[Page 49069]]

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Part III





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Parts 347 and 352



 Sunscreen Drug Products for Over-the-Counter Human Use; Proposed 
Amendment of Final Monograph; Proposed Rule

Federal Register / Vol. 72, No. 165 / Monday, August 27, 2007 / 
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 347 and 352

[Docket No. 1978N-0038] (formerly Docket No. 78N-0038)
RIN 0910-AF43


Sunscreen Drug Products for Over-the-Counter Human Use; Proposed 
Amendment of Final Monograph

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA) is issuing a proposed 
rule that would amend the final monograph (FM) for over-the-counter 
(OTC) sunscreen drug products as part of FDA's ongoing review of OTC 
drug products. This amendment addresses formulation, labeling, and 
testing requirements for both ultraviolet B (UVB) and ultraviolet A 
(UVA) radiation protection. FDA is issuing this proposed rule after 
considering public comments and new data and information that have come 
to FDA's attention. This rule proposes to lift the stays of 21 CFR 
347.20(d) and 21 CFR Part 352 when FDA publishes a final rule based on 
this proposed rule.

DATES: Submit written or electronic comments by November 26, 2007. 
Submit written or electronic comments on FDA's economic impact 
determination by November 26, 2007. Please see section X of this 
document for the effective and compliance dates of any final rule that 
may publish based on this proposal.

ADDRESSES:  You may submit comments, identified by Docket No. 1978N-
0038 and RIN number 0910-AF43, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following ways:
    <bullet> Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
    <bullet> Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.

Written Submissions

    Submit written submissions in the following ways:
    <bullet> FAX: 301-827-6870.
    <bullet> Mail/Hand delivery/Courier (for paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency 
name, docket number and regulatory information number (RIN) for this 
rulemaking. All comments received may be posted without change to 
http://www.fda.gov/ohrms/dockets/default.htm, including any personal 
information provided. For additional information on submitting 
comments, see the ``Request for Comments'' heading of the SUPPLEMENTARY 
INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number, found in brackets in the heading of this 
document, into the ``Search'' box and follow the prompts and/or go to 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:  Matthew R. Holman, Office of 
Nonprescription Products, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 5414, 
Silver Spring, MD 20993, 301-796-2090.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Summary of Major Changes to the FM
    A. Ingredients
    B. UVB (SPF) Labeling
    C. UVA Labeling
    D. Indications
    E. Warnings
    F. Directions
    G. UVB Testing
    H. UVA Testing
III. FDA's Tentative Conclusions on the Comments
    A. General Comments on OTC Sunscreen Drug Products
    B. Comments on Tanning and Tanning Preparations
    C. Comments on Specific Sunscreen Active Ingredients
    D. General Comments on the Labeling of Sunscreen Drug Products
    E. Comments on the Labeling of Sunscreen Drug Products With UVA 
Protection
    F. Comments on the Labeling of Sunscreen Drug Products With High 
SPF Values
    G. Comments on Indications for Sunscreen Drug Products
    H. Comments on Directions for Sunscreen Drug Products
    I. General Comments on SPF Testing Procedure
    J. Comments on the Sunscreen Standard for SPF Testing Procedure
    K. Comments on Artificial Light Sources for SPF Testing Procedure
    L. Comments on the Design/Analysis of SPF Testing Procedure
    M. General Comments on UVA Testing Procedure
    N. Comments on UVA Testing Procedure Design and Testing Criteria
    O. Comments on the Photostability of Sunscreen Drug Products
IV. FDA's Tentative Conclusions and Proposals
V. Analysis of Impacts
    A. Background
    B. Number of Products Affected
    C. Cost to Relabel
    D. Cost to Test or Retest Products for UVA Protection
    E. Total Incremental Costs
    F. Small Business Impact
    G. Analysis of Alternatives
VI. Paperwork Reduction Act of 1995
VII. Environmental Impact
VIII. Federalism
IX. Request for Comments
X. Proposed Effective and Compliance Dates
XI. References

I. Background

    In the Federal Register of May 12, 1993 (58 FR 28194), FDA 
published a notice of proposed rulemaking in the form of a tentative 
final monograph (TFM) for OTC sunscreen drug products. In the TFM, FDA 
proposed the conditions under which OTC sunscreen drug products would 
be considered generally recognized as safe and effective (GRASE), under 
section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) 
(21 U.S.C. 321(p)), and not misbranded, under section 502 of the act 
(21 U.S.C. 352).
    In the Federal Register of April 5, 1994 (59 FR 16042), FDA 
reopened the administrative record until July 31, 1994, to allow 
additional submissions on UVA-related issues and announced a public 
meeting for May 12, 1994, to discuss UVA testing procedures. As 
explained in that Federal Register notice, the TFM included proposed 
UVB (i.e., 290-320 nm) testing and labeling. The sun protection factor 
(SPF)

[[Page 49071]]

test and corresponding labeling reflects the level of protection 
against sunburn, which is caused primarily by UVB radiation. The TFM 
also explained the importance of protection against UVA radiation 
(i.e., 320-400 nm), the other UV component of sunlight (58 FR 28194 at 
28232 and 28233). The TFM referenced published UVA test methods but did 
not propose a method (58 FR 28194 at 28248 to 28250). Rather, the TFM 
stated that a product could be labeled as ``broad spectrum'' or a 
similar claim if it protected against UVA radiation. Thus, FDA held the 
1994 public meeting to gather further information about an appropriate 
UVA test method and labeling.
    In the Federal Register of June 8, 1994 (59 FR 29706), FDA proposed 
to amend the TFM (and reopened the comment period until August 22, 
1994) to remove five proposed sunscreen ingredients from the TFM 
because of lack of interest in establishing United States 
Pharmacopeia--National Formulary (USP-NF) monographs. FDA also 
reiterated that all sunscreen ingredients must have a USP-NF monograph 
before being included in the FM for OTC sunscreen drug products.
    In the Federal Register of August 15, 1996 (61 FR 42398), FDA 
reopened the administrative record until December 6, 1996, to allow 
additional submissions on zinc oxide and titanium dioxide as well as 
sunscreen photostability. FDA also announced a public meeting for 
September 19 and 20, 1996, to discuss the safety and efficacy of these 
two ingredients and photostability of sunscreens in general.
    In the Federal Registers of September 16, 1996 (61 FR 48645) and 
October 22, 1998 (63 FR 56584), FDA amended the TFM to add the UVA-
absorbing sunscreen ingredients avobenzone and zinc oxide to the 
proposed list of monograph ingredients. FDA also proposed indications 
for these ingredients. As a result of this amendment to the TFM, in the 
Federal Register of April 30, 1997 (62 FR 23350), FDA announced an 
enforcement policy allowing interim marketing of OTC sunscreen drug 
products containing avobenzone.
    On November 21, 1997, Congress enacted the Food and Drug 
Administration Modernization Act of 1997 (FDAMA). Section 129 of FDAMA 
stated that ``Not later than 18 months after the date of enactment of 
this Act, the Secretary of Health and Human Services shall issue 
regulations for over-the-counter sunscreen products for the prevention 
or treatment of sunburn.'' FDA identified the UVB portions of the 
monograph (and related provisions on water resistant test methods and 
cosmetic labeling) as items that could be finalized within the 
timeframe set by FDAMA. Because of outstanding issues related to the 
development of testing standards and labeling for UVA radiation 
protection, FDA deferred final action on these items.
    Therefore, in the Federal Register of May 21, 1999 (64 FR 27666), 
FDA published the FM for OTC sunscreen drug products in part 352 (21 
CFR part 352) with an effective date of May 21, 2001, but deferred UVA 
testing and labeling for future regulatory action. FDA stated that more 
time was required to review comments from interested parties on active 
ingredients, labeling, and test methods for products intended to 
provide UVA protection. This proposed amendment to the FM for OTC 
sunscreen drug products will complete the FM by addressing both UVB and 
UVA testing and labeling.
    In the Federal Register of June 8, 2000 (65 FR 36319), FDA reopened 
the administrative record of the rulemaking for OTC sunscreen drug 
products to allow for specific comment on high SPF and UVA radiation 
testing and labeling. FDA also extended the effective date for the FM 
to December 31, 2002.
    In the Federal Register of December 31, 2001 (66 FR 67485), FDA 
stayed the December 31, 2002, effective date of the FM for OTC 
sunscreen drug products in part 352 until we provided further notice in 
a future issue of the Federal Register. FDA took this action because we 
planned to amend part 352 to address formulation, labeling, and testing 
requirements for both UVB and UVA radiation protection. This document 
proposes such changes. This document also proposes an effective date 
related to publication of an amended FM (see section X of this 
document). The existing stay of the effective date for part 352 remains 
in effect at this time.
    In the Federal Register of June 20, 2002 (67 FR 41821), FDA 
published a technical amendment to change the names of four sunscreen 
active ingredients in Sec.  352.10 of the monograph to be consistent 
with name changes that appeared in USP 24. The new names, which are 
simpler and more convenient, are meradimate for menthyl anthranilate, 
octinoxate for octyl methoxycinnamate, octisalate for octyl salicylate, 
and ensulizole for phenylbenzimidazole sulfonic acid. Because the names 
became official on March 1, 2001, manufacturers could begin using them 
at any time after that date.
    In the Federal Register of June 4, 2003 (68 FR 33362), FDA issued a 
final rule establishing conditions under which OTC skin protectant 
products are generally recognized as safe and effective and not 
misbranded. This final rule lifted the stay of 21 CFR part 352 to amend 
the final monograph for OTC sunscreen drug products to include 
sunscreen-skin protectant combination drug products. This final rule 
concluded by placing a stay on both part 352 and on Sec.  347.20(d). 
The proposed rule that is the subject of this document provides UVA 
testing and labeling that is necessary on sunscreen and sunscreen-skin 
protectant combination drug products. This proposed rule, therefore, 
proposes that the stays of both part 352 and Sec.  347.20(d) be lifted 
when this rule is finalized. These stays will be maintained until a 
final rule based on this proposed rule becomes effective.
    In the Federal Register of September 3, 2004 (69 FR 53801), FDA 
delayed the implementation date for OTC sunscreen drug products subject 
to the final rule that established standardized format and content 
requirements for the labeling of OTC drug products (i.e., Drug Facts 
rule). FDA explained that we postponed the Drug Facts implementation 
date because we did not expect to complete the final amendment of the 
sunscreen monograph to include UVA testing and labeling by the Drug 
Facts implementation date of May 16, 2005 (64 FR 13254 at 13273 and 
13274, March 17, 1999). Thus, FDA delayed the implementation date of 
the Drug Facts rule with respect to OTC sunscreen drug products until 
further notice to avoid issuing successive relabeling requirements for 
sunscreen drug products at two closely related time intervals, as 
required by the Drug Facts rule and the final amendment to the 
sunscreen monograph.

II. Summary of Major Changes to the FM

    In response to the TFM and FM, FDA received substantial data and 
information regarding UVA and UVB active ingredients, claims, and 
testing procedures, as well as on other issues addressed in this 
document. FDA summarizes these issues and proposed changes to the FM in 
this section.

A. Ingredients

    FDA proposes to add combinations of avobenzone with zinc oxide and 
avobenzone with ensulizole as permitted combinations of active 
sunscreen ingredients in the FM (see section III.C, comment 7 of this 
document).

[[Page 49072]]

B. UVB (SPF) Labeling

    The FM allowed specific labeled SPF values up to, but not 
exceeding, 30. OTC sunscreen drug products with SPF values greater than 
30 could be labeled with the collective term ``30+.'' In this 
amendment, FDA proposes to increase the specific labeled SPF value to 
50 and revise the collective term to ``50+.'' FDA will consider higher 
specific labeled SPF values upon receipt of adequate, validated data 
(see section III.F, comment 15 of this document).
    In addition, FDA proposes to revise the following FM labeling:
    <bullet> The phrase ``sun protection'' to ``sunburn protection'' 
where used in Sec. Sec.  352.3(b)(1), (b)(2), (b)(3), and (d) and 
352.52(e)(1)(i), (e)(1)(ii), and (e)(1)(iii) (see section III.D, 
comment 10 of this document); and
    <bullet> Section 352.50(a) to include the term ``UVB'' before the 
term ``SPF'' on the principal display panel (PDP), along with the 
product category designation (PCD) (see section III.E, comment 14 of 
this document).
    FDA also proposes to revise the PCD SPF ranges in Sec.  
352.3(b)(1), (b)(2), and (b)(3) (proposed Sec.  352.3(c)(1) through 
(c)(4)) to reflect the following:
    <bullet> The current standard public health message concerning use 
of sunscreens,
    <bullet> The proposed increase of the labeled SPF value to ``50+,'' 
and
    <bullet> The proposed addition of the term ``UVB'' before the word 
``sunburn.''
Proposed Sec.  352.3(c)(4) contains a new PCD of ``highest UVB sunburn 
protection product'' for products that provide an SPF value over 50. 
FDA further proposes to revise current Sec.  352.3(b)(1) and (b)(2) to 
replace the current category descriptors of ``minimal'' and 
``moderate'' with the terms ``low'' and ``medium,'' respectively. FDA 
considers the new terms to be simpler and uniform with the proposed UVB 
and UVA ``Uses'' statements. Proposed changes to PCDs and category 
descriptors also occur in proposed Sec.  352.52(e)(1) (see section 
III.D, comment 13 and section III.G, comment 16 of this document). In 
addition, FDA proposes optional UVB radiation protection statements 
(see proposed Sec.  352.52(e)(2) and (e)(3)).

C. UVA Labeling

    FDA proposes new labeling to designate the level of UVA protection 
on the PDP of OTC sunscreen drug products. FDA proposes the use of 
symbols (``stars'') in conjunction with a descriptor (i.e., ``low,'' 
``medium,'' ``high,'' or ``highest''). FDA also proposes to add new 
Sec.  352.50(b) specifying the required PDP labeling for OTC sunscreen 
products tested in accordance with the proposed UVA testing procedures 
in Sec. Sec.  352.71 and 352.72 (see section III.E, comment 14 and 
section III.N, comment 45 of this document).

D. Indications

    The FM allowed the following two UVB indications in Sec.  
352.52(b)(1):
    <bullet> ``helps prevent sunburn''
    <bullet> ``higher SPF gives more sunburn protection''
    In this amendment, FDA proposes to revise the first statement to 
read ``low,'' ``medium,'' ``high,'' or ``highest'' ``UVB sunburn 
protection'' in proposed Sec.  352.52(b)(1)(i) through (b)(1)(iv). FDA 
is proposing to revise the additional indications in Sec.  352.52(b)(2) 
to reflect the new PCD ranges in proposed Sec.  352.3(c) (e.g., SPF of 
2 to under 12 becomes SPF of 2 to under 15) and create the new PCD 
range over SPF 50. These proposed revisions are based upon the revised 
PCD categories in proposed Sec.  352.3(c) (see section III.G, comment 
16 of this document). FDA proposes that the second statement in current 
Sec.  352.52(b)(1) (``higher SPF gives more sunburn protection'') no 
longer be required and proposes an additional indication regarding UVA 
protection (see proposed Sec.  352.52(b)(2)(v)).
    In proposed Sec.  352.52(b)(2)(v), FDA includes a new indication 
for UVA protection that involves selection of the appropriate 
descriptor (``low,'' ``medium,'' ``high,'' or ``highest'') to describe 
the level of protection. In proposed Sec.  352.52(b)(2)(vi), FDA 
includes a modified version of the sunburn ``Uses'' statement required 
by proposed Sec.  352.52(b)(1)(i) through (b)(1)(iv) when the 
additional statement in proposed Sec.  352.52(b)(2)(v) is used and 
bears the same category descriptor as the SPF value (e.g., medium UVA/
UVB protection from sunburn) (see section III.G, comment 17 of this 
document).

E. Warnings

    FDA is proposing to shorten the warning in Sec.  352.52(c)(1)(ii) 
(proposed Sec.  352.52(c)(3)) under the subheading ``Stop use and ask a 
doctor if'' from ``[bullet] rash or irritation develops and lasts'' to 
``[bullet] skin rash occurs.''
    FDA proposes removing the optional ``sun alert'' product 
performance statement (current Sec.  352.52(e)(2)) and requiring a 
revised ``sun alert'' statement in the ``Warnings'' section (proposed 
Sec.  352.52(c)(1)). FDA proposes that this revised statement be 
required on all OTC sunscreen drug products except lip cosmetic-drug 
and lip protectant-sunscreen products subject to Sec.  352.52(f), which 
are not required to include this statement under proposed Sec.  
352.52(f)(1)(v) and (f)(1)(vi) (see section III.G, comment 19 of this 
document). The statement in proposed Sec.  352.52(c)(1) reads as 
follows: ``UV exposure from the sun increases the risk of skin cancer, 
premature skin aging, and other skin damage. It is important to 
decrease UV exposure by limiting time in the sun, wearing protective 
clothing, and using a sunscreen.'' FDA proposes that the statement 
appear in bold type as the first statement in the ``Warnings'' section.

F. Directions

    FDA proposes changes to the directions to reduce the likelihood 
that OTC sunscreen drug products are underapplied. Section 
352.52(d)(1)(i) currently provides manufacturers the option to select 
one or more of the following terms: ``liberally,'' ``generously,'' 
``smoothly,'' or ``evenly.'' FDA is proposing to allow the choice of 
one of two required terms (i.e., ``liberally'' or ``generously'') and 
to include ``evenly'' as an additional optional term. FDA is proposing 
to eliminate the term ``smoothly'' because it is vague.
    FDA also proposes to add a new direction ``apply and reapply as 
directed to avoid lowering protection'' (proposed Sec.  
352.52(d)(1)(ii)). Because new information demonstrates the importance 
of sunscreen reapplication, FDA also proposes to make the optional 
directions in paragraph (d)(2) a requirement. As a result of this 
change, FDA is proposing to remove the current language in paragraph 
(d)(3) because it is no longer necessary. Instead, FDA is proposing, in 
paragraph (d)(3), required information for products that do not satisfy 
the water resistant testing procedures in Sec.  352.76. FDA is also 
proposing a required reapplication statement in Sec.  352.52(d)(1)(ii). 
The reapplication information in current Sec.  352.52(d)(2) appears in 
proposed Sec.  352.52(d)(2) and (d)(3) of this document (see section 
III.H, comment 22 of this document).

G. UVB Testing

    FDA is proposing to revise the SPF (UVB) testing procedure (see 
section III, paragraphs I through L of this document) and to move the 
SPF testing procedure currently in Sec. Sec.  352.70 through 352.73 to 
proposed Sec.  352.70. FDA proposes a padimate O/oxybenzone sunscreen 
standard in Sec.  352.70 that will be required for testing sunscreen 
products with SPF values over 15. Manufacturers may use either this 
padimate O/oxybenzone standard

[[Page 49073]]

or the homosalate standard to test products with SPF values of 2 to 15. 
FDA proposes a high pressure liquid chromatography (HPLC) method to 
replace the spectrophotometric method used to assay the homosalate and 
padimate O/oxybenzone standards.
    FDA proposes the following modifications to the SPF testing 
procedure:
    <bullet> Specifications for the solar simulator in Sec.  352.71 
(proposed Sec.  352.70(b)),
    <bullet> Instructions for the application of test materials and 
response criteria in Sec.  352.72 (proposed Sec.  352.70(c)), and
    <bullet> Doses and determination of minimal erythema dose (MED) in 
Sec.  352.73 (proposed Sec.  352.70(d)).
    FDA proposes to continue requiring a finger cot to be used in the 
application of sunscreen standard and test product as specified in 
Sec.  352.72(e) (proposed Sec.  352.70(c)(5)). However, FDA now 
proposes that the finger cot be pretreated. These two proposed UVB 
testing changes also apply to UVA in vivo testing.

H. UVA Testing

    FDA proposes a combination of spectrophotometric (in vitro) and 
clinical (in vivo) UVA test procedures in proposed Sec. Sec.  352.71 
and 352.72, respectively. To assure UVA protection for ``water 
resistant'' and ``very water resistant'' sunscreen products, FDA 
proposes that the in vivo UVA test be conducted after the appropriate 
water immersion period for OTC sunscreen drug products making a UVA 
claim. Therefore, FDA proposes modification of Sec.  352.76 to state 
that the water resistance claim applies to the SPF and, if appropriate, 
UVA values determined after the appropriate water immersion period as 
described in proposed Sec.  352.70 and, if appropriate, proposed Sec.  
352.72.

III. FDA's Tentative Conclusions on the Comments

A. General Comments on OTC Sunscreen Drug Products

    (Comment 1) Several comments asked that FDA provide more time to 
comply with requirements of the FM in order to avoid an adverse 
economic impact on the suncare industry and consumers. The comments 
described the seasonal dynamics of the suncare industry (i.e., products 
are sold in two marketing cycles over a period of 18 months) and stated 
that the industry would need more time to develop products that meet 
the FM requirements and allow for shipment of the previous year's 
returns. The comments mentioned times from 2 to 3 years after 
publication of the FM as appropriate or necessary for implementation. 
Several of these comments added that the date should be in the June/
July time period because the shipping season is practically over at 
that time and manufacturing for the next season is just beginning.
    FDA understands the seasonal nature of the sunscreen industry and 
the time required for product testing and relabeling. FDA is also aware 
that more than 1 year may be needed for implementation. FDA is 
proposing an 18- to 24-month implementation date and will try to have 
it coincide with the June/July time period (see section XI of this 
document).
    (Comment 2) One comment requested that FDA and the Federal Trade 
Commission (FTC) take steps to make sure that sunscreen manufacturers 
provide information to the American public to help them understand and 
use the Ultraviolet Index (UVI) to determine their risk of sunburn.
    The National Weather Service, the Environmental Protection Agency 
(EPA), and the Centers for Disease Control and Prevention (CDC) 
developed the UVI, which has been in use since 1995. This index is an 
indication of the amount of UV radiation reaching the surface of the 
earth as a function of ozone data, atmospheric pressure, temperature, 
and cloudiness and is generated for 58 cities around the United States.
    Usage information required by the OTC sunscreen drug product 
monograph applies regardless of the UVI value. Therefore, FDA believes 
that UVI information need not be required in the monograph for the safe 
and effective use of these products and should not be included in the 
``Drug Facts'' labeling. However, manufacturers who wish to do so may 
voluntarily include such information in their labeling outside the 
``Drug Facts'' box.
    (Comment 3) One comment requested that FDA make clear, through 
either the FM for skin protectant or sunscreen drug products, or both, 
that combination products containing sunscreen and skin protectant 
ingredients may be lawfully marketed.
    Section 347.20(d) of the skin protectant FM (21 CFR 347.20(d)), 
which published in the Federal Register of June 4, 2003 (68 FR 33362), 
provides for combinations of sunscreen ingredients and specific skin 
protectant ingredients. The final rule for OTC skin protectant drug 
products also included an amendment to the sunscreen FM, adding new 
Sec.  352.20(b), which allows combinations of sunscreen and skin 
protectant active ingredients. Thus, both monographs now state the same 
conditions for lawfully marketing these combination products. The 
existing language in Sec. Sec.  347.20(d) and 352.20(b) would include 
the two new combinations that FDA is proposing to add to the sunscreen 
monograph (see section II.A, comment 7 of this document).

B. Comments on Tanning and Tanning Preparations

    (Comment 4) One comment requested that the effective date of Sec.  
740.19 (21 CFR 740.19) be extended to December 31, 2002, consistent 
with the delay of the effective date for Sec.  310.545(a)(29) and 
(d)(31), part 352, and Sec.  700.35 (65 FR 36319). The comment stated 
that singling out Sec.  740.19 to become effective earlier might 
constitute an arbitrary and capricious decision by FDA.
    The May 21, 1999, final rule set a 2-year effective date (May 21, 
2001) for Sec.  310.545(a)(29) and (d)(31), part 352, and Sec.  700.35. 
In the Federal Register of June 8, 2000 (65 FR 36319), FDA extended the 
effective date for compliance with Sec.  310.545(a)(29) and (d)(31), 
part 352, and Sec.  700.35 until December 31, 2002, to provide time for 
completion of a more comprehensive UVA/UVB FM for OTC sunscreen drug 
products. On December 31, 2001, FDA then stayed the effective date of 
part 352 (but not Sec.  310.545(a)(29) and (d)(31), and Sec.  700.35) 
until further notice (66 FR 67485). FDA took this action because we are 
amending part 352 to address formulation, labeling, and testing 
requirements for both UVA and UVB radiation protection. The May 21, 
1999, final rule also set a 1-year effective date (May 22, 2000) for 
new Sec.  740.19, which addresses a warning statement for cosmetic 
suntanning preparations that do not contain a sunscreen active 
ingredient. These products are not subject to the monograph for OTC 
sunscreen drug products in part 352. FDA considered this warning to be 
sufficiently important for safety reasons when we issued the final rule 
(64 FR 27666 at 27669) to require a 12-month effective date as opposed 
to the 24-month effective date for the other sections of the rule. 
Further, FDA's primary reason for extending the effective date of those 
other sections to December 31, 2002, and then staying part 352 to 
address formulation, labeling, and testing requirements for both UVA 
and UVB protection, was to allow FDA to develop a comprehensive UVB/UVA 
final monograph. This reason does not apply to Sec.  740.19. 
Accordingly, FDA did not extend the effective date for Sec.  740.19, 
and Sec.  740.19 is in effect at this time. FDA concludes that this

[[Page 49074]]

decision is not arbitrary and capricious, but is based on valid health 
concerns related to the products subject to the warning requirement in 
Sec.  740.19.
    (Comment 5) One comment requested that FDA and FTC take steps to 
ensure sunscreen manufacturers inform consumers that their natural skin 
pigmentation provides protection from sunlight. The comment stated that 
these adaptive individuals might not require a daily application of a 
sunscreen. Another comment submitted a copy of a patent for an 
electronic sensor device to measure solar radiation. The comment stated 
that the personal device could alert consumers to their level of UV 
exposure so they could either come out of the sun or apply a sunscreen 
to avoid sunburn and skin cancer.
    FDA has no objection to sunscreen manufacturers informing consumers 
that their natural skin pigmentation provides protection from sunlight. 
However, FDA has no basis to require such information as part of the 
required labeling for OTC sunscreen drug products. Thus, manufacturers 
may include this information in labeling outside of the ``Drug Facts'' 
box, but are not required to include this information. FDA considers 
the comment regarding the UV measuring device to be outside the scope 
of this rulemaking, which evaluates the safety, effectiveness, and 
labeling of OTC drug products.

C. Comments on Specific Sunscreen Active Ingredients

    (Comment 6) Several comments requested that dihydroxyacetone (DHA) 
be added to the monograph as a single active ingredient for UVA 
protection. The comments claimed that DHA alone provides an SPF of 2 to 
4. One comment claimed that a 15 percent topical solution of DHA 
provided a photoprotective factor of 10 in the UVA region. Other 
comments contended that the brown color produced by DHA, resembling 
melanin, should potentiate the action of sunscreens. Another comment 
stated that DHA alone is not a sunscreen, but forms a sunscreen when 
combined with lawsone. The comment cited unpublished observations by 
two independent investigators that the melanoidins of DHA-induced skin 
pigment resemble melanin in that they absorb UVB strongly, with 
decreasing absorbance through the UVA region and into visible light. 
The comment added that, because DHA alters the structure of the skin 
surface, it is, by definition, a drug.
    One comment provided information on the safety and UVA 
effectiveness of DHA alone (Ref. 1). Safety studies included the 
following:
    <bullet> Oral and dermal toxicity studies,
    <bullet> A chronic skin painting carcinogenicity study in mice,
    <bullet> Comedogenecity tests in rabbits,
    <bullet> Repeated insult patch test in humans, and
    <bullet> Photoallergy tests.
Effectiveness studies consisted of published articles using either 
humans or photosensitized rats. Another comment discussed 
investigations with DHA on psoriasis patients sensitized with 8-
methoxypsoralen (8-MOP).
    FDA is not proposing to include DHA in the monograph as a single 
active ingredient in OTC sunscreen products. Although there were no 
product submissions to the Advisory Review Panel on Topical Analgesic, 
Antirheumatic, Otic, Burn, and Sunburn Prevention and Treatment Drug 
Products (the Panel) using DHA as a sunscreen ingredient, the Panel 
discussed available scientific evidence for DHA as a single sunscreen 
ingredient. The Panel concluded that DHA is not a sunscreen but a 
cosmetic; it is a sunscreen only when used with lawsone (43 FR 38206 at 
38215 to 38216, August 25, 1978). Although one comment stated that DHA 
alters the structure of the skin, it did not provide data to support 
this claim. Thus, at this time, FDA agrees with the Panel that DHA is a 
cosmetic.
    FDA acknowledges that DHA is the subject of an approved color 
additive petition and its safety as a color additive has been 
established. However, the submitted chronic (life-span) skin painting 
study in mice does not support the safe use of DHA as a sunscreen 
because no group of mice was included in the study to determine the 
possible photocarcinogenic effect of DHA. This effect needs to be 
studied because DHA is associated with carbonyl compounds known to 
react with pyrimidine bases in the presence of UV radiation, and it 
appears to be a potent inducer of thymine dimers, premutagenic 
deoxyribonucleic acid (DNA) lesions. Therefore, its safety, in terms of 
the type, extent, and location of photo-induced DNA damage, is of 
concern and should be determined. Whether DHA contributes or promotes 
UV carcinogenesis is not known.
    The submitted studies on the effectiveness of DHA as a single UVA 
sunscreen ingredient add only qualitative information. Many of the 
studies utilized animal models; few included human subjects. One study 
involved only five subjects, three with erythropoietic protoporphyria 
and two with polymorphic light eruptions. Another study involved six 
subjects sensitized with 8-MOP. In both studies, too few subjects were 
enrolled, and the study subjects were not representative of the average 
sunscreen user.
    Well-controlled clinical trials with DHA alone are lacking. 
Although some investigations described by the comments suggest that DHA 
may help protect the normal skin of psoriasis patients, concerns remain 
about the usefulness of DHA products in the OTC market. For example, 
one comment stated that photoprotection provided by DHA depends upon 
the way the product polymerizes in the stratum corneum and that 
polymerization depends on the skin of each individual. Therefore, the 
photoprotection provided by DHA varies from person to person and has to 
be determined for each person by diffuse reflectance spectroscopy. 
Given these statements, it is not clear how appropriate OTC drug 
product labeling could be written to aid consumers in proper selection 
and use of a DHA sunscreen.
    FDA concludes that current information is inadequate to include DHA 
in the monograph as a single sunscreen ingredient. None of the comments 
provided information to establish the appropriate number of consecutive 
product applications and the timing of these applications (how far 
apart or how soon before sun exposure) that are necessary to achieve 
the desired protection using products containing various concentrations 
of DHA. In two submitted studies, a preparation containing 3 percent 
DHA was applied six times prior to sun exposure and a preparation 
containing 15 percent DHA preparation was applied one time 24 hours 
prior to sun exposure, respectively (Ref. 1). The comments did not 
include any information on appropriate regimens for various skin types, 
which is necessary because the level of photoprotection provided by DHA 
is dependent on skin type. Therefore, based upon this lack of 
information, it is not clear how to state appropriate label directions 
for consumer use. FDA needs additional information from clinical 
studies to determine the effective concentration of DHA in sunscreen 
product formulations and the frequency and timing of product 
application.
    (Comment 7) One comment submitted data to support the combination 
of avobenzone with ensulizole and avobenzone with zinc oxide (Ref. 2). 
The safety data included the following:
    <bullet> A repeat insult patch test,
    <bullet> A phototoxicity study, and
    <bullet> A photoallergy study.
The effectiveness data involved a clinical study using the in vitro 
``critical wavelength'' (CW) method and the in

[[Page 49075]]

vivo ``protection factor A'' (PFA) method to support the UVA radiation 
protection potential of the combination products. The PFA test data 
were from a double blind clinical study using five sunscreen 
formulations.
    The safety studies demonstrated that the following combinations of 
active ingredients have a low potential for irritation, allergenic 
sensitization, and phototoxicity:
    <bullet> 3 percent or less avobenzone with 2 percent ensulizole
    <bullet> 3 percent or less avobenzone with 5 percent zinc oxide
The data further suggested that the photoallergenic potential of 
avobenzone is not augmented by its combination with either ensulizole 
or zinc oxide.
    The clinical study using the PFA in vivo method demonstrated that 
the following combinations of active ingredients are significantly more 
effective than 1.5 percent ensulizole or 3 percent zinc oxide alone in 
protecting against UVA radiation:
    <bullet> 3 percent avobenzone with 1.5 percent ensulizole
    <bullet> 3 percent avobenzone with 4 percent zinc oxide
FDA's detailed comments on the safety and effectiveness studies are on 
file in the Division of Dockets Management (Ref. 3).
    FDA considers the data submitted by the comment sufficient to 
support the safety and effectiveness of avobenzone with ensulizole and 
avobenzone with zinc oxide when used in the concentrations established 
for each ingredient in Sec.  352.10 of the sunscreen monograph. 
Accordingly, FDA is proposing to amend Sec.  352.20(a)(2) by adding 
ensulizole and zinc oxide.
    Marketing of products containing avobenzone with ensulizole and 
avobenzone with zinc oxide will not be permitted unless and until the 
following three actions occur:
    1. The comment period specific to this proposal closes.
    2. FDA has evaluated all comments on these combination products 
submitted in response to the proposal.
    3. FDA publishes a Federal Register notice announcing our 
determination to permit the marketing of OTC sunscreen drug products 
containing these combinations.

D. General Comments on the Labeling of Sunscreen Drug Products

    (Comment 8) One comment agreed that the labeling modifications 
allowed by the FM in Sec.  352.52 for OTC sunscreen products marketed 
as a lipstick or labeled for use only on specific small areas of the 
face (e.g., lips, nose, ears, and/or around eyes) are appropriate for 
these products. Based on the labeling in Sec.  352.52, the comment 
proposed eight additional modifications for all other OTC sunscreen 
products regardless of package size:
    1. Delete ``Drug Facts'' title because it is inappropriate and 
unnecessary for sunscreens.
    2. Omit ``Purpose'' because it is repetitive of the statement of 
identity on the PDP and ``Uses'' information.
    3. Revise ``higher SPF gives more sunburn protection'' in ``Uses'' 
to read ``higher SPF products give more sun protection, but are not 
intended to extend the time spent in the sun,'' and require this 
statement only on products with an SPF value over 30.
    4. Omit ``For external use only'' warning because it is self-
evident for sunscreen products.
    5. Revise ``When using this product [bullet] keep out of eyes. 
Rinse with water to remove'' to read ``Keep out of eyes.''
    6. Revise ``Stop use and ask a doctor if [bullet] rash or 
irritation develops and lasts'' to read ``Stop use if skin rash 
occurs.''
    7. Omit barlines, hairlines, and box enclosure.
    8. Allow the option to list inactive ingredients in a different 
location on the label or in labeling accompanying the product.
The comment stated that these modifications would allow reduced Drug 
Facts labeling for all OTC sunscreen drug products.
    The comment contended that sunscreen products meet all of FDA's 
criteria for reduced labeling (64 FR 13254 at 13270):
    <bullet> Packaged in small amounts,
    <bullet> High therapeutic index,
    <bullet> Extremely low risk in actual consumer use situations,
    <bullet> A favorable public health benefit,
    <bullet> No specified dosage limitation, and
    <bullet> Few specific warnings and no general warnings (e.g., 
pregnancy or overdose warnings).
The comment added that OTC sunscreen products are a unique category 
substantially different from most other types of OTC drug products 
because they are recommended for use on a daily basis to prevent 
serious disease. The comment concluded that FDA's rationale for 
standardized labeling format and content requirements does not 
necessarily transfer to OTC sunscreen products and specifically not to 
drug-cosmetic products with a sunscreen.
    When FDA created the standardized labeling format and content 
requirements (i.e., ``Drug Facts'' labeling) for OTC drug products, we 
recognized that some product packages were too small to accommodate all 
of the required labeling. Therefore, under Sec.  201.66(d)(10) (21 CFR 
201.66(d)(10)), FDA allows labeling format modifications for all OTC 
drug products sold in small packages. In the final rule establishing 
``Drug Facts'' labeling, FDA also stated that we may allow reduced 
labeling requirements beyond those specified under Sec.  201.66(d)(10) 
for OTC drug products that meet the criteria listed in the preceding 
paragraph (see section III.D, comment 9 of this document).
    In the final rule for OTC sunscreen drug products (64 FR 27666 at 
27681 to 27682), FDA recognized that some OTC sunscreen drug products 
meet these criteria for reduced labeling. Specifically, FDA identified 
OTC sunscreen drug products that qualify for the small package 
specifications in Sec.  201.66(d)(10) and are labeled for use only on 
specific small areas of the face as meeting the criteria for reduced 
labeling. Therefore, FDA allows content and format modifications for 
these products under Sec.  352.52(f). FDA allows further modifications 
for lip products containing sunscreen because these products for small 
areas of the face are sold in even smaller packages than the other 
sunscreen products marketed under Sec.  352.52(f) (68 FR 33362 at 
33371; 64 FR 13254 at 13270). FDA believes that sunscreen products 
labeled for use only on small areas of the face, including lip products 
containing sunscreen, serve an important public health need and FDA 
does not want to discourage manufacturers from marketing these products 
(64 FR 13254 at 13270).
    FDA does not find it appropriate to extend the labeling 
modifications for OTC sunscreen drug products marketed under Sec.  
352.52(f) to all OTC sunscreen drug products. FDA disagrees with the 
comment's argument that all sunscreen products meet the criteria for 
reduced Drug Facts labeling (64 FR 13254 at 13270), because most 
sunscreen products are not sold in small packages. Therefore, because 
sunscreen products do not generally meet all of the criteria for 
reduced Drug Facts labeling, FDA is not proposing reduced labeling for 
all OTC sunscreen products.
    FDA does not consider sunscreens as a unique category substantially 
different from other types of OTC drug products because they are 
recommended for use on a daily basis to prevent serious disease, as 
argued by the comment. Other OTC drug products are used on a daily 
basis, some to prevent serious disease and some for other reasons. For 
example, anticaries drug products are

[[Page 49076]]

used daily to prevent dental caries. Antiperspirant drug products can 
be used daily to reduce underarm wetness. FDA has concluded that these 
various products should generally be labeled using the standardized 
content and format in Sec.  201.66. The standardized labeling allows 
consumers to more easily recognize that these products are, in fact, 
drug products and to more easily read and understand the labeling 
information.
    The same principle applies when the product is a drug cosmetic 
product (e.g., sunscreen moisturizer or antiperspirant deodorant). 
Consumers need to be informed that the product has a drug effect, and 
the uniform Drug Facts labeling for all OTC drug and drug cosmetic 
products helps convey this message. FDA applied this rationale when it 
finalized the requirements in the final rule that established Sec.  
201.66.
    FDA agrees that some OTC sunscreen drug products meet the criteria 
for reduced information for safe and effective use (64 FR 13254 at 
13270, 64 FR 27666 at 27681 to 27682). However, FDA disagrees with most 
of the modifications proposed by the comment for all package sizes of 
OTC sunscreen products. FDA disagrees with deletion of the ``Drug 
Facts'' title and the ``Purpose'' information because many sunscreen 
products do not meet the parameters for reduced Drug Facts labeling.
    FDA disagrees that the ``Purpose'' information is repetitive and, 
therefore, disagrees that it may be omitted where there is sufficient 
labeling space. The ``Purpose'' section is a standard part of Drug 
Facts labeling and is intended to inform consumers which ingredients 
are sunscreens in a product. This information is even more important 
when a sunscreen is marketed in a combination product. For example, in 
a sunscreen skin protectant drug product, the ``Purpose'' section 
informs consumers which ingredients are sunscreens and which are skin 
protectants.
    FDA has revised the ``Uses'' section and deleted the statement 
``higher SPF gives more sunburn protection'' (see section III.G, 
comment 16 of this document). FDA disagrees with omitting the ``For 
external use only'' warning for all OTC sunscreen drug products. FDA 
finds no basis to exclude all OTC sunscreen products from this 
requirement. Likewise, FDA finds no reason to omit the two standard 
subheadings that accompany the warning statements, as proposed by the 
comment. Further, FDA disagrees with the comment's suggestion to omit 
the statement ``Rinse with water to remove.'' This is useful 
information if a sunscreen product gets into the eyes. FDA agrees with 
part of the proposed shortened warning for OTC sunscreen drug products 
to ``Stop use if skin rash occurs'' in place of ``Stop use and ask a 
doctor [bullet] if rash or irritation develops and lasts.'' Therefore, 
FDA is proposing to amend Sec.  352.52(c)(1)(ii) (proposed Sec.  
352.52(c)(3)) to state: ``Stop use and ask a doctor if [bullet] skin 
rash occurs.''
    FDA finds no reason to omit barlines, hairlines, or the box 
enclosure for all OTC sunscreen drug products regardless of package 
size. These labeling formats help consumers identify a product as a 
drug and help make labeling information easier to read and understand. 
Thus, they should be included when package size allows. The FM already 
allows horizontal barlines and hairlines and the box enclosure to be 
omitted if a small package meets the criteria in Sec. Sec.  352.52(f) 
and 201.66(d)(10).
    Finally, FDA has no basis to provide an option for sunscreen 
products to list inactive ingredients in labeling that accompanies the 
products. FDA interprets section 502(e)(1)(A)(iii) of the act (21 
U.S.C. 352(e)(1)(A)(iii)) as requiring the inactive ingredients to be 
listed on the outside container of a retail package or on the immediate 
container if there is no outside container or wrapper (Sec.  
201.66(c)). Because this information, by law, must appear either on the 
outside container or immediate container of the product, FDA does not 
find a basis for allowing an option to list the inactive ingredients in 
a different location, such as other labeling accompanying the product. 
In accordance with Sec.  201.66(c)(8), the inactive ingredients must be 
listed on the product label in the ``Drug Facts'' box.
    (Comment 9) Two comments supported extending the labeling in Sec.  
352.52(f) for products intended for use only on specific small areas of 
the face and sold in small packages to all OTC sunscreen products. The 
comments contended that all OTC sunscreen drug products meet most of 
FDA's criteria for products that require minimal information for safe 
and effective use (64 FR 13254 at 13270) (see section III.G, comment 8 
of this document).
    The first comment added that FDA should permit the labeling 
modifications in Sec.  352.52(f) for the following products:
    <bullet> Makeup products (as defined in 21 CFR 720.4(c)(7)) with 
sunscreen, and
    <bullet> Lotions and moisturizers for the hands or face with 
sunscreen in containers of 2 ounces (oz) or less (by weight or liquid 
measure).
The comment added that most facial makeup products are typically 
packaged in small containers. The comment stated that to meet any of 
FDA's concerns that lotions and moisturizers sold in larger packages 
may be used over the entire body despite labeling that restricts use to 
the face or hands, FDA could limit the flexible labeling to containers 
of 2 oz or less. Furthermore, the comment added that containers of 2 oz 
or less could not feasibly include the full OTC drug labeling.
    The second comment contended that the modified labeling in Sec.  
352.52(f) is particularly compelling for color cosmetic products for 
the face that contain sunscreens (i.e., ``facial makeups with 
sunscreen''). The comment added that these products and OTC sunscreen 
drug products for use only on specific small areas of the face have the 
same overall safety profile, and, therefore, FDA should allow these 
products to be labeled similarly.
    A third comment strongly disagreed with a specific labeling 
exemption for makeup with sunscreen and moisturizer products for use on 
the face and hands. The comment contended that an exemption would not 
be in the best interest of consumers. The comment also argued that 
consumer confusion and subsequent misuse of sunscreen products, 
particularly failure to apply adequate amounts of sunscreen or to 
reapply a product after certain activities, will occur if FDA permits 
reduced labeling for these products. The comment added that many 
consumers use face and hand cosmetic products with sunscreen as their 
primary and only source of UV radiation protection for those areas of 
the body. Moreover, consumers are more likely to use these products 
properly if they contain full sunscreen drug labeling. The comment 
concluded that makeup foundations, tints, blushes, rouges, and 
moisturizers that are intended to be used on a daily or frequent basis 
to protect against the adverse health and skin aging effects of acute 
and chronic sun exposure must be labeled as drugs similar to other OTC 
sunscreen products.
    FDA is not proposing to extend the labeling modifications in Sec.  
352.52(f), which is specific for products used only on small areas of 
the face and sold in small packages, to all OTC sunscreen products. FDA 
has determined that most OTC sunscreen products should have full drug 
labeling information using the standardized content and format in Sec.  
201.66 to ensure the safe and effective use of these products. In 
establishing the labeling modifications in Sec.  352.52(f),

[[Page 49077]]

FDA determined how the labeling information for sunscreen drug 
products, including drug cosmetic products, could best be presented on 
products with limited labeling space and still provide consumers with 
adequate information to use these products safely and effectively. 
Although any sunscreen products sold in small packages that meet the 
criteria in Sec.  201.66(d)(10) are allowed the format exemptions under 
that section, FDA is also proposing content exemptions for sunscreen 
products marketed under Sec.  352.52(f). FDA is proposing these 
exemptions under Sec.  352.52(f) because sunscreen products labeled for 
use only on small areas of the face and sold in small packages are 
generally sold in packages substantially smaller than other sunscreen 
products, even those sunscreen products labeled for other uses that 
meet the criteria in Sec.  201.66(d)(10).
    FDA continues to believe that requiring full Drug Facts labeling on 
sunscreen products used only on specific small areas of the face and 
sold in small packages (i.e., Sec.  352.52(f)) would discourage 
manufacturers from marketing some of these products for drug use. Many 
of these products, such as sunscreen-lip protectant products, are sold 
in extremely small packages that cannot accommodate the required 
labeling even with the format exemptions allowed under Sec.  
201.66(d)(10). As explained in a number of rulemakings (64 FR 27666 at 
27681 to 27682; 68 FR 33362 at 33371; 64 FR 13254 at 13270), these 
products meet the criteria for additional reduced labeling. Removal of 
these products from the OTC market would have a negative impact on 
public health. FDA believes that the benefit of UV radiation protection 
provided by these products outweighs the need for manufacturers to 
include all sunscreen labeling information. In contrast, FDA believes 
manufacturers of sunscreen products that are not within the scope of 
Sec.  352.52(f) will continue to market their products even though full 
Drug Facts labeling is required. Unlike sunscreen products that meet 
Sec.  352.52(f), the package size of products that do not meet Sec.  
352.52(f) will accommodate full Drug Facts labeling.
    Although FDA is not extending the labeling modifications in Sec.  
352.52(f) to all OTC sunscreen products, as requested by the first and 
second comments, we are allowing these labeling modifications for 
certain makeup with sunscreen products. Specifically, these labeling 
modifications would apply to makeup with sunscreen products that are 
labeled for use only on specific small areas of the face and that meet 
the criteria in Sec.  201.66(d)(10). However, FDA does not agree that 
these labeling modifications should apply to all makeup products 
identified in Sec.  720.4(c) (21 CFR 720.4(c)) that contain sunscreen, 
because most are not sold in small packages and, therefore, do not meet 
all of the criteria for reduced labeling (64 FR 13254 at 13270). Thus, 
most of these products can accommodate full Drug Facts labeling, and 
FDA finds no reason to extend the labeling modifications in Sec.  
352.52(f) to all makeup with sunscreens products.
    As explained in the previous paragraph, the labeling modifications 
in Sec.  352.52(f) apply to makeup with sunscreen products labeled for 
use only on specific small areas of the face and sold in small 
packages. FDA also believes that any sunscreen products that are used 
only on specific small areas of the face and sold in small packages 
meet FDA's reduced labeling criteria regardless of whether they are 
drug or drug-cosmetic products. Therefore, FDA is proposing to amend 
the heading of Sec.  352.52(f) to read as follows: ``Products, 
including cosmetic-drug products, containing any ingredient identified 
in Sec.  352.10 labeled for use only on specific small areas of the 
face (e.g., lips, nose, ears, and/or around the eyes) and that meet the 
criteria established in Sec.  201.66(d)(10) of this chapter.''
    In addition, FDA is proposing to extend the labeling exemptions, 
with some modifications, currently allowed for lipsticks in Sec.  
352.52(f)(1)(vi) to the following lip products with sunscreen, as 
defined in Sec.  720.4(c):
    <bullet> Lipsticks,
    <bullet> Lip products to prolong wear of lipstick,
    <bullet> Lip gloss, and
    <bullet> Lip balm.
FDA has identified lip products to prolong wear of lipstick as ``makeup 
fixatives'' under Sec.  720.4(c)(7)(viii). Lip gloss and lip balm fall 
under ``other makeup preparations'' in Sec.  720.4(c)(7)(ix). As long 
as these lip products with sunscreen are used only on specific small 
areas of the face and are sold in small packages (i.e., meet the 
criteria in Sec.  201.66(d)(10)), they would meet FDA's reduced 
labeling criteria. As discussed earlier in this comment, FDA believes 
not allowing Drug Facts labeling exemptions for these products would 
discourage manufacturers from marketing some of these products for drug 
use. In proposed Sec.  352.52(f)(1)(vi), FDA is proposing to extend the 
labeling modifications for lipsticks to other lip cosmetic products 
containing sunscreen and clarifying that the labeling modifications in 
Sec.  352.52(f) apply to both sunscreen and makeup with sunscreen 
products. Furthermore, because lip products with sunscreen have 
substantially less labeling space than the nonlip products with 
sunscreen used only on specific small areas of the face and sold in 
small packages, proposed Sec.  352.52(f)(1)(vi) allows more labeling 
exemptions for lip products with sunscreen than other products that are 
within the scope of Sec.  352.52(f).
    (Comment 10) Several comments recommended changing the acronym 
``SPF'' from ``sun protection factor'' to ``sunburn protection factor'' 
because the latter definition is more descriptive of the use of OTC 
sunscreen drug products and avoids giving consumers the impression of 
solar invincibility and a false sense of security.
    FDA agrees. In Sec.  352.52(b) of the sunscreen FM, FDA included 
only indications for sunburn protection (e.g., ``helps prevent 
sunburn'') (64 FR 27666 at 27691). In this document, FDA is proposing 
to change the word ``sun'' to ``sunburn'' in Sec.  352.3(b)(1), (b)(2), 
(b)(3), and (d) and Sec.  352.52(e)(1)(i), (e)(1)(ii), and (e)(1)(iii).
    Manufacturers can continue to use existing labeling until the 
compliance dates of a final rule based on this proposal. However, FDA 
encourages manufacturers to revise any labeling that states ``sun 
protection'' attributed to sunscreen active ingredient(s) to the new 
term ``sunburn protection'' as early as possible.
    (Comment 11) Some comments questioned the constitutionality of the 
FM's labeling provisions. Specifically, the comments contended that the 
FM's prohibition on the labeling of SPF products over 30, its 
restrictions on skin aging claims, and its limitation of the 
indications for use for OTC sunscreen drug products all violate the 
first amendment to the U.S. Constitution. The comments asserted that 
these bans on allegedly truthful labeling in the FM go well beyond 
constitutionally permissible restrictions on commercial free speech.
    One comment contended that FDA had failed to meet its burden to 
demonstrate that the claims at issue are misleading or that the 
restrictions on speech directly advance any substantial governmental 
purpose. In addition, the comment claimed that any interest FDA has 
asserted in restricting the speech at issue is served equally well, if 
not better, by regulations that do not restrict speech to the same 
extent as FDA's regulations.

[[Page 49078]]

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

[[Page 49079]]

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

[[Page 49080]]

    FDA is proposing specific conditions in the monograph under which 
OTC sunscreen drug products would be GRASE. Elsewhere, FDA explains how 
the labeling statements proposed by the comments would not be 
appropriate monograph indications for these sunscreen products (see 
section III.G, comment 17 of this document). Thus, the proposed 
labeling statements outside the proposed indications of the final 
monograph, as FDA proposes to revise it, would promote a sunscreen drug 
product for use as an unapproved new drug, which is illegal. In 
addition, any variation in the statements in a ``Warnings'' section of 
a final monograph, such as the revised ``sun alert'' statement in this 
proposed rule, would be outside the monograph conditions and, thus, 
would promote the product as an unapproved new drug. The marketing and 
distribution in interstate commerce of an OTC sunscreen drug product 
with such labeling variations would be prohibited under sections 301(d) 
and 505(a) of the act. Speech promoting such an illegal activity may be 
restricted without violating the first amendment (Central Hudson, 447 
U.S. at 563-564).
    If a manufacturer could circumvent the requirements and 
restrictions imposed by a final monograph by including nonmonograph 
labeling statements, or excluding required monograph statements, based 
on its own assertions of the alleged appropriateness and truthfulness 
of the statements, then such activity would significantly undermine the 
monograph system and FDA's assurance that OTC drugs are safe and 
effective for their labeled conditions. FDA has assessed the labeling 
statements proposed by the comments and preliminarily determined that 
they are not justified by the available scientific evidence as GRASE 
conditions for the monograph. Instead, in order to legally market a 
sunscreen drug product with such labeling statements, an interested 
manufacturer would have to submit an NDA to FDA with the appropriate 
evidence to show the safety and effectiveness of the drug under the 
proposed nonmonograph labeling conditions. Requiring premarket FDA 
review and authorization of such nonmonograph drug claims ensures that 
such claims will be evaluated by a public health agency that has 
scientific and medical expertise so that only products that are safe 
and effective will be permitted to be sold for therapeutic purposes.
    Although this preliminary-determination that the labeling 
statements at issue would be inherently misleading and would concern 
unlawful activity would obviate the need for FDA to address the other 
three prongs of the Central Hudson test, we believe that the labeling 
requirements proposed in this document would satisfy each of the parts 
of this test. With respect to the second prong, FDA's interest in the 
required labeling disclosures and prohibitions addressed by the 
comments would contribute directly to the safe and effective use of 
these OTC sunscreen drug products, which is critical for the protection 
of public health. FDA's interest in protecting the public health has 
been previously upheld as a substantial government interest under 
Central Hudson (see Pearson v. Shalala, 164 F.3d 650, 656 (D.C. Cir. 
1999) (citing Rubin v. Coors Brewing Co., 514 U.S. 476, 484-485 
(1995)).
    The proposed labeling requirements would directly advance this 
interest, thereby satisfying the third prong of the Central Hudson 
test. By requiring labeling disclosure of the SPF value, the proposed 
revised ``sun alert,'' and indications for use, FDA can better assure 
that consumers understand more clearly the use of sunscreens in 
preventing sunburn, their relative UVA/UVB protection, and their role 
as part of a comprehensive sun protection program. The greater consumer 
understanding resulting from all of these labeling conditions would 
promote directly the proper use of sunscreens, which, in turn, would 
better ensure the protection of the public health.
    Likewise, this proposed rule's exclusion from the monograph of the 
labeling statements proposed by the comments also directly advances 
FDA's public health interest. FDA has preliminarily determined from the 
available evidence that these statements would not be appropriate 
conditions for OTC use under the monograph. Thus, the statements would 
directly undermine the protection of public health. In addition, it is 
important to note that the Pearson court, in assessing whether the 
specific dietary supplement regulations at issue directly advanced 
FDA's stated public health goals under the third prong of the Central 
Hudson test, explained that its findings under this prong did not apply 
to drugs, where ``the potential harm is presumably much greater'' than 
other products (Pearson, 164 F. 3d at 656, n 13).
    Finally, under the fourth prong of the Central Hudson test, there 
are not numerous and obvious (Cincinnati v. Discovery Network, 507 U.S. 
410, 418 n. 13 (1993)) alternatives to the required labeling statements 
or labeling prohibitions proposed herein. Consumers are accustomed to 
using the label as their primary source of information about a drug 
product's contents and use. Neither a public education campaign, nor 
encouraging OTC drug product manufacturers to provide information, such 
as that in the proposed revised ``sun alert,'' to consumers by other 
means, would ensure that people have the information they need about 
sunscreen products at the point of sale or use. Likewise, with respect 
to the alternative labeling statements proposed by the comments, FDA's 
proposed indications and revised ``sun alert'' present the relevant 
public health information to consumers in the clearest and most direct 
manner. Thus, FDA's proposed indications and prohibition of other 
labeling statements are not more extensive than necessary. In this way, 
the required labeling disclosures and prohibitions proposed in this 
document would meet the fourth prong of the test.
    Furthermore, the proposed prohibition of claims in a final 
monograph does not prevent such claims from being approved in an NDA. 
As explained previously, a final monograph sets forth those conditions, 
including labeling, under which an OTC drug product would be considered 
GRASE and not misbranded. In issuing monographs, FDA considers whether 
the available scientific evidence demonstrates that OTC drug products 
within a therapeutic category are GRASE. A final monograph does not 
constitute an FDA decision regarding an NDA for an OTC drug proposing 
variations in these conditions. Thus, FDA's proposals in this document 
would not prohibit any interested manufacturer from filing an NDA, with 
the appropriate evidence, for any variations from the monograph 
labeling conditions. Because of this significant available option to 
manufacturers for proposing alternative labeling statements, FDA's 
proposed labeling requirements and prohibitions are not more extensive 
than necessary.
    In conclusion, FDA believes it has complied with its burdens under 
the first amendment to support the labeling requirements of this 
proposed rule.
    (Comment 12) One comment stated that voluntary professional 
labeling can be provided to physicians that will allow them to select 
or recommend sunscreen products for their patients' needs, based on 
more detailed information describing the quantity (protection factor) 
and the range of UV protection (e.g., UVB, UVA, or UVB/UVA protection). 
Another comment stated that FDA should not require professional 
labeling because complete

[[Page 49081]]

and accurate product labeling should be available to all consumers, not 
just to their health care providers.
    FDA defines professional labeling in OTC drug monographs as 
labeling that is provided to health professionals but not to the 
general public (i.e., not directly to consumers) (for example, see 
Sec.  331.80 (21 CFR 331.80)). In the final rule, FDA stated that it 
would consider professional labeling, such as protection against 
photosensitization reactions, if data were received (64 FR 22666 at 
27674). FDA has not received any data to date. Therefore, FDA is not 
proposing any professional labeling in this document. FDA will consider 
professional labeling for OTC sunscreen drug products in the future if 
specific supportive data are provided.
    (Comment 13) Some comments objected to the ranges of SPF values 
that define the product category designations (PCDs) in Sec.  352.3(b). 
Stating that standard public health messages recommend use of a 
sunscreen with at least an SPF of 15, the comments contended that the 
``moderate'' PCD (SPF values of 12 to under 30) may cause consumers to 
believe that SPF values of less than 15 provide adequate protection. 
One comment further stated that if the PCD range is from SPF 12 to 29, 
manufacturers will only produce the minimum SPF value as they can use 
less active ingredients and get the same PCD classification.
    As discussed in the final rule (64 FR 27666 at 27681), the PCD 
ranges in Sec.  352.3(b) and Sec.  352.52(e) reflect a modified, 
simpler, combined version of the previously proposed five PCDs and the 
``Recommended Product Guide.'' However, FDA agrees with the comments 
that the current standard public health message from public health 
organizations generally recommends use of a sunscreen with an SPF value 
of at least 15 (see section III.G, comment 19 of this document). We 
also agree that allowing SPF values below 15 in any but the lowest PCD 
range may appear to contradict this message. Therefore, FDA is 
proposing to modify the PCD SPF value range in proposed Sec.  
352.3(c)(1) from ``2 to under 12'' to ``2 to under 15'' and in proposed 
Sec.  352.3(c)(2) from ``12 to under 30'' to ``15 to under 30.'' FDA is 
also proposing to replace the PCD terms ``minimal'' and ``moderate'' 
with the simpler terms ``low'' and ``medium,'' respectively, and to use 
these simpler terms for the UVA radiation protection categories (see 
section III.E, comment 14 of this document). These labeling changes 
will provide consumers with familiar and consistent terms describing 
both UVA and UVB radiation protection.
    FDA disagrees with the comment contending that manufacturers will 
only produce the minimum SPF value in a given PCD range because they 
can use less active ingredients and get the same PCD classification. 
Section 352.50 of the current FM requires the SPF value to appear on a 
sunscreen product's PDP. This proposed rule would not change that 
requirement. Thus, while the PCD provides additional information about 
the SPF value, consumers seeking higher SPF values can readily identify 
such products by the SPF value stated on a sunscreen product's PDP.

E. Comments on the Labeling of Sunscreen Drug Products With UVA 
Protection

    (Comment 14) Many comments discussed ways to categorize, phrase, 
and display UVA/UVB radiation protection on an OTC sunscreen drug 
product label. All of the comments stated that the SPF value should 
retain preeminence on the label's PDP and be the consumers' criteria 
for choosing an OTC sunscreen product. Some comments recommended that 
UVA radiation protection be stated on the PDP in descriptive words or 
simple phrases, rather than numbers or symbols, for the following 
reasons:
    <bullet> Simplicity,
    <bullet> Clarity,
    <bullet> To avoid confusion with SPF, and
    <bullet> To maximize consumer comprehension.
Some comments referenced consumer research, discussed in subsequent 
paragraphs, to support this recommendation (Refs. 4 and 5).
    One comment suggested the following labeling statements:
    <bullet> ``Protects against UVA rays''
    <bullet> ``screens out UVA rays''
    <bullet> ``shields from UVA rays''
    <bullet> ``broad spectrum sunscreen''
    <bullet> ``UVA/UVB protection''
    <bullet> ``provides protection against both UVB and UVA rays''
    <bullet> other truthful and nonmisleading statements describing a 
quantification of the product's UVA radiation protection
The comment stated that quantification of the UVA radiation protection 
should be allowed in labeling, but not required, so that consumers can 
have additional product performance information to help them select 
appropriate products.
    Another comment stated that UVA radiation protection should be 
labeled only as grades of effectiveness (multiple levels) for the 
following reasons:
    <bullet> UVA radiation irritation induces various skin reactions 
(e.g., erythema, pigment darkening, skin cancer, and photodermatitis), 
and
    <bullet> Some action spectra of damages have not been determined.
This comment referred to The Japan Cosmetic Industry Association (JCIA) 
Measurement Standards for UVA Protection Efficacy (Ref. 6), which 
recommend labeling UVA protection as three grades: (1) PA+, (2) PA++, 
or (3) PA+++.
    Several comments recommended two categories of UV protection 
labeling based on the ratio of UVA radiation protection factor to SPF 
value:
    <bullet> ``with UV protection'' if ratio equals 0.20
    <bullet> ``with extra UV protection'' if ratio equals 0.25
The proposed ratio is based on the UVA radiation protection factor as 
determined by the persistent pigment darkening (PPD) test method (see 
section III.N, comment 46 of this document). These comments stated 
that, because the ratio of damage from solar UVB radiation to that of 
solar UVA radiation is 80:20 over a day, a sunscreen must protect 
against an 80:20 ratio of UVB to UVA radiation. The comments also 
recommended that products labeled ``with UV protection'' or ``with 
extra UV protection'' exhibit absorbance of 360 nanometers (nm) and 
longer wavelengths.
    Another comment suggested two categories to state overall UV 
radiation protection: ``regular'' and ``broad spectrum.'' The comment 
proposed that the ratio of a sunscreen product's SPF value to its UVA 
protection factor be the single criterion for the ``broad spectrum'' 
designation, with the maximum ratio no greater than 4:1. For example, 
an SPF 16 product would need to provide a UVA protection factor of at 
least 4 to be designated ``broad spectrum.''
    One comment disagreed with the previous comment, stating that there 
is no supportable scientific basis for the relevance of the 4:1 ratio. 
The comment argued that the ratio inappropriately combines, in the same 
equation, SPF values obtained with a solar simulator and solar 
irradiance values at low sun angles.
    Another comment suggested that sunscreen products with an SPF value 
of 2 or greater must have a UVA protection factor of at least 2 to be 
labeled ``UVA/UVB'' or ``broad spectrum protection.'' The comment 
stated that products with SPF values of at least 15 and UVA protection 
factors of at least 4 may be labeled ``extra (or extended or enhanced) 
UVA protection.'' The comment stated that these criteria are 
independent of test method and should apply to any of the proposed UVA 
radiation test methods.
    Another comment proposed establishing PCDs based on the UVA

[[Page 49082]]

radiation protection value obtained by the PPD test method. The comment 
suggested four PCDs that would enable consumers to choose the desired 
levels of protection:
    <bullet> ``moderate''
    <bullet> ``high''
    <bullet> ``very high''
    <bullet> ``extra''
Another comment recommended three PCDs:
    <bullet> ``low UVA protection''
    <bullet> ``moderate UVA protection''
    <bullet> ``maximum UVA protection''
Another comment suggested using the five PCDs proposed in the TFM (58 
FR 28194 at 28295) and added a UVA protection factor number for each 
PCD based on the immediate pigment darkening (IPD) test method.
    Two comments recommended a four-star rating system to describe UVA 
radiation protection. The comments stated that this system, based on 
the ratio of UVA to UVB radiation absorbance, would provide a simple 
method for consumers to determine the protective nature of an OTC 
sunscreen drug product. The absorbance ratio would range from 0 for 
products exhibiting no protection against UVA radiation to 1 for 
products exhibiting equal absorption at all wavelengths throughout the 
UVA/UVB radiation spectrum. Using this ratio, products would be 
classified in one of the following five categories:
    <bullet> 0 to < 0.2 = no UVA radiation protection claim
    <bullet> 0.2 to < 0.4 = Moderate ([starf])
    <bullet> 0.4 to < 0.6 = Good ([starf][starf])
    <bullet> 0.6 to < 0.8 = Superior ([starf][starf][starf])
    <bullet> 0.8 plus = Maximum ([starf][starf][starf][starf])
    Another comment recommended a five point rating system using the 
``critical wavelength'' (CW) ([lgr]<INF>c</INF>) test method. This 
system uses a scale analogous to the star rating system to assign 
products a ``broad spectrum'' rating as follows:
    <bullet> [lgr]<INF>c</INF> < 325 = ``0''
    <bullet> 325 < [lgr]<INF>c</INF> < 335 = ``1''
    <bullet> 335 < [lgr]<INF>c</INF> < 350 = ``2''
    <bullet> 350 < [lgr]<INF>c</INF> < 370 = ``3''
    <bullet> 370 < [lgr]<INF>c</INF> = ``4''
    Several comments supported a single claim, such as ``provides broad 
spectrum protection against UVB and UVA radiation,'' based on 
determining a sunscreen pass/fail CW ([lgr]<INF>c</INF>). Comments that 
supported this ``broad spectrum protection'' claim stated that, in 
combination with SPF, it provides simple and accurate labeling that is 
easily understood by consumers. The comments referred to a research 
study that suggested this approach to UVA radiation protection labeling 
was superior for consumer comprehension and ease of product selection 
(Ref. 7). Other comments provided consumer research data, discussed 
elsewhere in this comment, suggesting this approach was least preferred 
by consumers (Refs. 4 and 8).
    One comment stated that UVA radiation protection claims should be 
allowed for sunscreen products with SPF values of 4 and higher. The 
comment added that, for products claiming to protect against UVA and 
UVB radiation, a minimum UVA protection factor of 2 should be required 
if the SPF value is less than or equal to 12.
    Several comments stated that sunscreen drug products labeled as 
``full spectrum'' or ``broad spectrum'' should protect consumers from 
substantially all of the harmful effects of the sun, including sunburn 
associated with UVA radiation. According to one comment, sunscreen drug 
products labeled ``full spectrum'' or ``broad spectrum'' that do not 
protect against nearly all UVB and UVA radiation wavelengths seriously 
risk misleading consumers into believing they are fully and completely 
protected from the dangers of the sun. One comment recommended using 
the claim ``full spectrum'' rather than ``broad spectrum'' to describe 
products that attenuate more than 90 percent of UVA radiation and are 
at least SPF 15. The comment suggested no UVA radiation protection 
claims be allowed if the product is below SPF 15.
    In support of their proposed UVA labeling, a number of comments 
provided results from consumer research studies that assessed consumer 
labeling preferences for stating UVA radiation protection. One comment 
described a 1996 survey (Ref. 4) in which 275 subjects compared two 
labeling systems:
    <bullet> 3-level descriptive (``light,'' ``intermediate,'' or 
``extended'' ``UVA protection'') and
    <bullet> Grapho/numerical (a bar graph indicating a level, 0, 4, 8, 
or 12, with the corresponding number appearing alongside the graph).
The comment stated that the survey data suggested that, while equally 
able to understand both types of labels, the panelists preferred the 
grapho/numerical system over the descriptive system.
    Another comment described two consumer research studies, conducted 
in 1994 and 1995 (Ref. 9), in which 235 subjects compared three 
potential UVA radiation labeling options:
    <bullet> Numerical (2, 3, or 5),
    <bullet> Symbolic (4 stars with 1, 2, 3, or 4 stars filled), and
    <bullet> 3-level descriptive (labeled blank if no UVA radiation 
protection provided or labeled ``UVA and UVB Protection'' or ``UVB Plus 
Extended UVA Protection,'' depending on the level of UVA radiation 
protection provided).
The studies included focus group discussions and indepth interviews. 
The comment stated that the data suggested that a numeric designation 
for UVA radiation protection (in addition to the SPF value) created 
confusion for consumers and that symbols (i.e., stars) misled consumers 
into giving equal or greater importance to the UVA radiation rating 
compared to the SPF value. The comment concluded that a descriptive 
approach better conveyed to consumers the added benefit of UVA 
protection without detracting from the SPF value.
    Another comment described two consumer research studies conducted 
in 1999 (Ref. 7) in which 2,238 consumers assessed three sunscreen 
product labeling systems:
    <bullet> A pass/fail descriptive (labeled blank if no UVA 
protection provided (i.e., fails) or labeled ``Broad Spectrum UVA and 
UVB Protection'' if UVA radiation protection provided (i.e., passes)),
    <bullet> A 3-level descriptive (labeled blank if no UVA radiation 
protection provided or labeled ``UVA and UVB Protection'' or ``UVB Plus 
Extended UVA Protection,'' depending on the level of UVA radiation 
protection provided), and
    <bullet> A 3-level grapho/numerical (a bar graph indicating a 
level, 4, 8, or 12, with the corresponding number appearing alongside 
the graph).
The comment stated that the data suggested the pass/fail descriptor, 
``broad spectrum,'' was significantly superior to the other labels and 
recommended that FDA use this labeling to designate UVA radiation 
protection.
    Another comment described a consumer research study conducted in 
2000 (Ref. 8) at 20 urban and suburban shopping malls in which 1,921 
subjects ranked four labeling systems:
    <bullet> 4-level numerical,
    <bullet> 4-level symbolic,
    <bullet> 4-level descriptive, and
    <bullet> Pass/fail descriptive (``with/without broad spectrum UVA/
UVB protection'').
The numerical labeling system was shown as Arabic numerals ``1, 2, 3, 
4'' with the number ``2'' highlighted. The descriptor labeling system 
was shown as the words ``Minimum, Moderate, High, Maximum'' with the 
word ``Moderate'' highlighted. The symbolic labeling system was shown 
as a picture of four stars with two stars highlighted.

[[Page 49083]]

    The comment concluded that the subjects had a significant 
preference for a labeling system based on descriptive words or numbers 
because of clarity, specificity, and ease of comprehension. Subjects 
least preferred the pass/fail system because they found it unclear, 
nonspecific, and lacking sufficient information to compare sunscreen 
products. This study also revealed that the numerical labeling system 
was one of the top two choices because numbers were ``clearer, more 
specific, and easier to understand.'' Age, gender, and educational or 
ethnic background were reported as not affecting the study results.
    In the TFM for OTC sunscreen drug products (58 FR 28194 at 28233), 
FDA proposed to allow claims relating to ``broad spectrum protection'' 
or ``UVA radiation protection'' for OTC sunscreen products that meet 
the following two criteria:
    1. Contain sunscreen active ingredients with absorption spectra 
extending to 360 nm or above, and
    2. Demonstrate meaningful UVA radiation protection using 
appropriate testing procedures to be developed.
In the FM for OTC sunscreen drug products (64 FR 27666 at 27672), FDA 
stated that UVA radiation labeling of OTC sunscreen drug products could 
continue in accordance with the TFM and its amendments until addressed 
in a future issue of the Federal Register. Elsewhere in this document, 
FDA is proposing test methods for determining the UVA radiation 
protection potential of an OTC sunscreen drug product (see section 
III.N, comment 46).
    FDA believes that the existing data do not clearly define the 
relationship between UVA radiation and skin damage. The principal 
reason for not better understanding this relationship is that the 
action spectra for specific types of UVA radiation-induced skin damage 
(i.e., which wavelengths of UVA cause which types of skin damage) have 
not been established. However, most scientific data demonstrate that 
UVA radiation is harmful to the skin. Thus, until these action spectra 
are known, FDA believes that more protection against UVA radiation 
damage is better for consumers' health. Therefore, FDA believes it is 
important, as with the SPF value, to designate UVA radiation protection 
in a straightforward manner that consumers clearly understand.
    FDA proposes that the UVA radiation protection of an OTC sunscreen 
drug product determined from these UVA test methods be designated on 
the PDP using a combination of category descriptors (i.e., ``low,'' 
``medium,'' ``high,'' or ``highest'') and stars (i.e., symbols) similar 
to those described by some of the comments. The category descriptors 
and stars will designate relative levels of UVA radiation protection as 
measured by the UVA radiation test methods. The level of UVA radiation 
protection identified on the label reflects the following:
    <bullet> A numerical ``UVA protection factor'' (from the clinical 
test), and
    <bullet> A numerical ratio of UVA I (340 to 400 nm) radiation 
absorption to UVB/UVA (290 to 400 nm) radiation absorption (from the in 
vitro test).
The test that indicates the lowest level of UVA radiation protection 
determines the level identified on the label. For example, if the 
clinical test indicates ``low'' protection and the in vitro test 
indicates ``medium'' protection for a product, the product is labeled 
as providing ``low'' UVA radiation protection. This system comprises 
four categories of UVA radiation protection as described in table 1 of 
this document.

      Table 1.--Overall UVA Protection of a Sunscreen Drug Product
------------------------------------------------------------------------
           Star category                     Category descriptor
------------------------------------------------------------------------
[starf][star14][star14][star14]      Low
[starf][starf][star14][star14]       Medium
[starf][starf][starf][star14]        High
[starf][starf][starf][starf]         Highest
------------------------------------------------------------------------

    Some of the comments argued that the UVB radiation protection 
labeling is more important than UVA radiation protection and should be 
emphasized in the labeling over UVA radiation protection. FDA disagrees 
with the comments and proposes that the UVA radiation protection 
designation appear on the PDP along with the SPF value in an equally 
prominent manner that does not conflict with the SPF value. Because 
action spectra for UV-induced skin damage have not been clearly 
defined, FDA is unable to specify labeling for OTC sunscreen drug 
products that indicates what ranges of UV radiation are most harmful to 
consumers. In other words, FDA cannot conclude whether UVB or UVA 
radiation is more harmful to humans based on the scientific data 
collected to date. Therefore, FDA considers both UVB and UVA radiation 
protection equally important at this time because scientific data 
demonstrates that both have harmful effects on the skin.
    So that consumers consider UVB and UVA radiation protection equally 
in selecting an OTC sunscreen drug product, FDA is proposing a number 
of labeling requirements. Under this proposal, the font size of the 
stars and category descriptors for UVA radiation protection must be the 
same size as the SPF value and its descriptors. All four stars must 
appear and be preceded by the term ``UVA'' and followed by the 
appropriate category descriptor (e.g., UVA 
[starf][starf][starf][star14] High). All star borders and the color 
inside a solid star must be the same while the color of ``empty'' stars 
must be lighter and distinctively different than solid stars. The color 
inside a solid star must be distinctively different than the background 
color. The stars must be filled in starting with the first star on the 
left and must appear in a straight horizontal line.
    As requested by some comments, an OTC sunscreen drug product that 
does not provide the minimum UVA protection, as determined by the 
proposed UVA test methods, may only display an SPF value on the PDP. An 
OTC sunscreen drug product is not required to provide UVA protection 
and may bear only a sunburn (UVB/SPF) protection claim. However, FDA is 
proposing that a sunscreen product that does not provide at least a 
``low'' level of UVA protection include the following statement on the 
PDP: ``no UVA protection.'' This statement must be the same font size 
as the SPF value and its descriptor. FDA is not proposing four empty 
stars because we are concerned that consumers may confuse products 
providing no UVA protection (i.e., four empty stars) with those 
providing the highest UVA protection (i.e., four filled stars).
    In developing this UVA radiation protection labeling, FDA has 
particularly considered the label comprehension studies (Refs. 4, 7, 8, 
and 9). These studies used multiple methodologies and report a diverse 
range of preferences for each labeling system:
    <bullet> Category descriptors,
    <bullet> Graphics,
    <bullet> Symbols,
    <bullet> Numerics, and
    <bullet> ``Pass/fail'' descriptors.
The diverse results and varying methodology make it difficult to 
identify a clear preference for one labeling system. However, the 
studies indicate an overall preference for category descriptors.
    In agreement with the studies, FDA is proposing category 
descriptors to indicate the relative level of UVA radiation protection. 
As discussed in preceding paragraphs, FDA believes consumers should 
consider UVB and UVA radiation protection equally when selecting an OTC 
sunscreen drug product. For this reason, FDA is proposing that stars be 
used with category descriptors. FDA believes that

[[Page 49084]]

the category descriptor and star labeling for UVA radiation protection 
will give it equal prominence with UVB radiation protection (i.e., 
category descriptor and SPF) on the PDP.
    FDA is not proposing grapho/numeric labeling because we are 
concerned that consumers may be confused by a second number on the PDP 
(i.e., in addition to the SPF value). FDA is also not proposing any of 
the simple two-category designations suggested by the comments:
    <bullet> With/without UVA protection,
    <bullet> With UVA protection/with extra UVA protection, or
    <bullet> Regular/broad spectrum protection.
FDA agrees with one of the comments, which argued that these types of 
statements are misleading. FDA does not consider this labeling as 
providing consumers with enough information about the magnitude of UVA 
protection offered by an OTC sunscreen product. However, FDA does not 
object to the use of the following four statements for OTC sunscreen 
drug products that satisfy the requirements of proposed Sec.  352.73 
for a labeled UVA protection value:
    <bullet> ``broad spectrum sunscreen'',
    <bullet> ``provides [select one of the following: `UVB and UVA,' or 
`broad spectrum'] protection'',
    <bullet> ``protects from UVB and UVA [select one of the following: 
`rays' or `radiation']'', and
    <bullet> [select one of the following: ``absorbs'' or ``protects''] 
``within the UVA spectrum''.
These statements may appear elsewhere in product labeling outside the 
``Drug Facts'' box or enclosure but not intermixed with the information 
required on the PDP under Sec.  352.50. FDA agrees with some comments 
that these statements, by themselves, may be misleading by implying 
that a sunscreen protects against nearly all UVB and UVA radiation. 
However, FDA does not believe these optional statements will be 
misleading in the context of the entire label, because the relative 
level of UVB and UVA protection must be stated on sunscreen product 
labels (alongside these more general statements).
    Although none of the studies combined labeling systems as proposed 
in this document, FDA believes the studies support use of category 
descriptors and symbols together. One study suggested that symbols may 
imply importance over SPF values (Ref. 9). However, FDA believes 
consumers will not place greater importance on UVA protection because 
we are proposing a required statement to inform consumers about the 
importance of both UVB and UVA protection. We are proposing to require 
one of the following statements on the PDP of all OTC sunscreen drug 
products:
    <bullet> ``UV rays from the sun are made of UVB and UVA. It is 
important to protect against both UVB & UVA rays.''
    <bullet> ``UV rays from the sun are made of UVB and UVA. It is 
important to protect against both UVB & UVA rays to prevent sunburn and 
other skin damage.''
FDA believes that the use of one of these statements, along with the 
proposed UVB and UVA radiation protection labeling, including the 
format requirements described in preceding paragraphs, will lead 
consumers to view UVB and UVA radiation protection as equally 
important.
    In addition, this statement will educate consumers about UVA 
radiation, which will be a new term and concept to many consumers. The 
proposed statement should help consumers better understand the new UVB 
and UVA labeling when it is initially introduced to the OTC market. 
Thus, FDA believes that the consumer label comprehension studies, along 
with the proposed educational statement about UVB and UVA radiation, 
support the stars and descriptor UVA radiation protection labeling 
proposed in this document. Moreover, a similar ``star rating system'' 
for UVA radiation protection (i.e., the Boots Star System) has been 
used to label sunscreen products throughout Europe for over 10 years.
    To prevent consumer confusion about UV radiation protection, FDA is 
proposing changes to UVB radiation protection labeling (i.e., the SPF 
value). SPF values indicate how effective a sunscreen product is in 
protecting against sunburn. By displaying the relative level of sunburn 
protection on the sunscreen drug product PDP in terms of an SPF value, 
consumers can choose their desired level of UVB radiation protection. 
To further improve consumers' understanding of the sunburn protection 
level provided by a certain sunscreen product, FDA is proposing to 
require descriptive terms of relative sunburn protection (i.e., 
``low,'' ``medium,'' ``high,'' and ``highest'') to accompany the SPF 
value on the PDP. FDA is further proposing that the SPF value must be 
preceded by the term ``UVB'' to further differentiate the SPF value 
from the UVA symbol/descriptor on the PDP. FDA believes that numerical 
labeling for UVB protection, symbolic labeling for UVA protection, and 
the same descriptive labeling for UVB and UVA protection will allow 
consumers to easily understand and choose from relative levels of UVB 
and UVA radiation protection.
    FDA is aware that consumers have used and become accustomed to 
choosing OTC sunscreen drug products based on the SPF value for many 
years. Likewise, FDA believes that, over a period of time, consumers 
will similarly become accustomed to the proposed labeling using symbols 
and descriptors to designate relative UVA radiation protection. 
Furthermore, FDA believes consumer familiarity with similar star rating 
systems (e.g., movies, hotels, and restaurants) used for many years in 
the United States provide a basis for consumers' understanding of this 
proposed labeling for OTC sunscreen drug products.
    FDA is providing a number of examples of how the UVA/UVB protection 
designations could appear on the PDP.

[[Page 49085]]

[GRAPHIC] [TIFF OMITTED] TP27AU07.003

    FDA believes that, as with SPF values, identifying the relative 
level of UVA radiation protection provides the most useful information 
for consumers. Consumers who desire more protection from the sun will 
be able to identify products with higher UVB (SPF) and UVA radiation 
protection. FDA agrees with the comments that a product must provide at 
least some minimum level of UVA radiation protection (as with SPF 
values) to be labeled as providing UVA radiation protection. Therefore, 
FDA is proposing minimum criteria for the lowest UVA category in its 
proposed test procedures (see section III.N, comment 46 of this 
document).

F. Comments on the Labeling of Sunscreen Drug Products With High SPF 
Values

    (Comment 15) Several comments objected to FDA limiting specific 
labeled SPF values ``up to but not above 30.'' The comments stated that 
data and information supplied to FDA since publication of the sunscreen 
FM demonstrate that SPF values over 30 can be safely tested with 
accuracy. The comments also argued that removing the limit will not 
lead to consumers spending more time in the sun when using high SPF 
sunscreens in comparison to low SPF sunscreens. To address that point, 
one comment proposed labeling to help reduce potential consumer misuse 
of sunscreens with SPF values over 30: ``higher SPF products give more 
sun protection, but are not intended to extend the time spent in the 
sun.'' Another comment noted that the SPF value, in addition to proper 
sunscreen application and reapplication, is only part of a 
comprehensive sun protection program.
    Other comments explained the need for high SPF sunscreen products. 
The comments contended that consumers and physicians are familiar with 
and want the many currently marketed sunscreens that are labeled as 
``SPF 45, SPF 50, etc.'' Thus, the comments argued that U.S. consumers 
will be at a disadvantage within the international community, because 
products providing SPF values over 30 are available in other countries. 
In addition, the comments stated that many prominent medical 
authorities maintain the need for high SPF sunscreens for individuals 
at ``high risk'' based on medical and/or occupational concerns and 
individuals who desire increased protection from photoaging and 
lengthy/intensive sun exposure situations. The comments argued that the 
need for high SPF sunscreens is supported by findings that UV exposures 
in several cities are considerably higher than previously recognized 
and because high SPF products can reduce cumulative UV exposure. The 
comments stated that consumer desire for high SPF products is 
demonstrated by sales data showing that products with an SPF value of 
45 are one of the fastest growing segments of the total sunscreen 
market.
    The remaining comments discussed the consequences of limiting the 
specific labeled SPF value. For example, one comment noted that if 
manufacturers cannot state the SPF level above 30, they will no longer 
have an incentive to fund research for better sunscreens. In addition, 
manufacturers may reformulate products to reduce active ingredients 
and, thus, reduce the level of UV protection. A comment argued that 
another adverse consequence results from most consumers failing to 
achieve the labeled SPF value because they do not apply enough 
sunscreen and/or reapply it too infrequently. Because high SPF products 
can help make up for such improper use, limiting the specific labeled 
SPF value to 30 has a negative impact on UV protection.
    A foreign industry organization suggested an upper limit for 
labeled SPF values of 50+ and provided three reasons:
    <bullet> Unreasonably high SPF values will lead consumers to expect 
``too much effectiveness'' from sunscreen products.
    <bullet> Higher concentrations of sunscreen active ingredients are 
not ``in the interest of safety.''
    <bullet> Higher SPF values will invite excessive, meaningless 
competition in the industry.
The comment explained that competition would be meaningless because the 
amount of UV protection provided by products with SPF values above 50 
is not significantly greater than products with an SPF of 50.
    Another comment from a sunscreen manufacturer agreed with FDA's 
concern about the possibility of increasing variability when testing 
high SPF sunscreens. The comment suggested a modified ``binomial'' test 
method and labeling requirements for SPF values over 20 that would 
allow for high SPF products.
    Another comment submitted a published survey of 208 sunbathers on 
Miami's South Beach during July 2001 with the goal of measuring UV 
radiation exposure and probable injury (Ref. 10). The ``worst case'' 
scenario identified by the survey was based on sunbathers with Type I 
skin (persons most sensitive to sunlight who burn easily and never tan) 
exposed to UV radiation near the longest day and highest sun angle of 
the year at the ``southern-most major beach'' in the United States. The 
survey was a followup to one conducted in 1993 with 62 sunbathers and 
evaluated by FDA in the FM (64 FR 27666 at 27674). The 2001 survey 
determined MEDs absorbed by the following three steps:
    1. Measuring incident UV radiation (using three dosimeters),
    2. Multiplying by an adjusting factor for skin type (using a 30 
percent

[[Page 49086]]

increase in sensitivity between skin types), and
    3. Dividing by the SPF worn by the sunbather.
The survey suggests that sunbathers with Type I skin might receive a 
cumulative dose of 49.5 MEDs with 8 hours of exposure. The comment 
concluded that, while SPF values up to, and including, 50 are 
warranted, values over 50 are unwarranted in any condition for sunburn 
protection.
    Two comments submitted testing data for sunscreens with SPF values 
between 30 and 50 using the test method in the FM. The comments 
concluded that the test method was valid for these high SPF values. In 
addition, one comment indicated that a very water resistant test for an 
SPF 45 to 50 sunscreen would take nearly 4.5 hours using the skin types 
of subjects in the SPF testing procedures in the FM (i.e., skin types 
I, II, and III) (Ref. 13). The comment concluded that it is beyond the 
practical endurance capabilities of many people in the test to spend 
more than 5 to 6 hours in front of a UV radiation lamp and that fatigue 
can lead to errors in test results. The comment also noted that the 
potential for intra and interlaboratory variability in test results 
increases as sunscreen SPF values increase.
    FDA concluded in the FM (64 FR 27666 at 27675) that test methods 
supported specific SPF label values up to 30. FDA invited interested 
persons to submit data in support of high SPF test methods and to 
consider proposed methods for communicating the level of protection in 
labeling. Data and information on high SPF testing and labeling were 
submitted to FDA at, and following, public meetings on July 22, 1999, 
and October 26, 1999, and after reopening of the administrative record 
(65 FR 36319) (see section III.I, comment 24 of this document) (Refs. 
11 and 12).
    FDA continues to be aware that many OTC sunscreen products with 
specific labeled SPF values over 30 are currently marketed, both 
nationally and internationally, and are increasingly used by consumers 
and recommended by health professionals (64 FR 27666 at 27675). FDA 
agrees that these products should be available for those sun-sensitive 
consumers who require such products based upon personal knowledge, 
planned sun exposure, geographical location, or advice of a health 
professional. FDA previously noted the lack of any known safety 
problems for sunscreen products with SPF values greater than 30 (64 FR 
27666 at 27675). The comment that argued higher concentrations of 
sunscreen active ingredients are not ``in the interest of safety'' did 
not supply any new data to support its contention. FDA will continue to 
monitor adverse drug experience reports for sunscreen drug products 
reported to its Medwatch program and in the medical literature.
    As noted by one comment, some researchers have raised the concern 
that sunscreen use may lead to increased sun exposure. The 
``compensation hypothesis'' states that consumers who use high SPF 
sunscreens spend more time in the sun and/or use less protective 
clothing. The only double blind, randomized trial that addressed this 
issue showed a significant increase in sun exposure time when comparing 
use of SPF 30 to SPF 10 (Ref. 14). In addition, two retrospective 
survey studies showed that sun exposure time is longer when using 
sunscreen compared to not using sunscreen (Refs. 15 and 16). Other 
studies cited by the comment to support the premise that the 
``compensation hypothesis'' is incorrect and either did not provide 
data about the length of sun exposure or the study method did not allow 
for data interpretation (Refs. 17 through 20). Based on all of this 
data, FDA believes that some consumers may increase total UV exposure 
through over-reliance on sunscreens. The apparent divergent results on 
the validity of the ``compensation hypothesis'' between studies may 
indicate that sun protection behaviors vary greatly for each person. 
More specifically, there is a spectrum of attitudes about the sun, from 
those individuals who seek dark suntans to those who seek to avoid the 
sun and consequent UV skin damage (Ref. 21). Such evidence underscores 
the need for adequate labeling so consumers can make informed decisions 
regarding their use of OTC sunscreen drug products.
    FDA agrees that the SPF value is one factor in a comprehensive sun 
protection program. However, the SPF is only a measure of protection 
from erythema (i.e., UVB radiation-induced sunburn) and does not 
measure protection from other UV skin damage, such as that induced by 
UVA radiation. While increased short wavelength UVA radiation 
protection generally increases with increasing SPF values, studies 
using in vivo or in vitro UVA radiation testing methods demonstrate 
that sunscreen products with the same SPF values can have markedly 
different levels of UVA protection, especially for long wavelength UVA 
radiation (Refs. 22 and 23). These studies also indicate that a 
specific high SPF product can provide much less UVA radiation 
protection than a product with a much lower SPF value. Elsewhere in 
this document, FDA is proposing UVA radiation testing methods and 
labeling that will categorize the relative levels of protection 
provided by the SPF and UVA values of the sunscreen product (see 
section III.E, comment 14 and section III.N, comment 45 of this 
document), allowing consumers to compare products and choose the levels 
of UVB and UVA radiation protection desired.
    An SPF 30 sunscreen product may provide adequate sunburn protection 
for many consumers. However, FDA believes that appropriately tested and 
labeled high SPF value sunscreen products should be available for 
consumers who desire or need high levels of UV protection, in 
particular, those who burn easily. Such products would do the 
following:
    <bullet> Help compensate for inadequate application and/or 
reapplication,
    <bullet> Provide additional sunburn protection during intense UV 
radiation conditions,
    <bullet> Help reduce cumulative UV radiation exposure (when used in 
conjunction with other measures to reduce overall sun exposure), and
    <bullet> Generally provide consumers incremental increases in 
sunburn protection.
    FDA agrees that SPF values should be supported by scientific 
evidence. In the FM, FDA limited the specific labeled SPF value to 30. 
At that time, FDA had only received data demonstrating that the SPF 
test produces accurate results for products with SPF values of 30 or 
less. Since publication of the FM, FDA has received additional SPF 
testing data for sunscreen products with SPF values between 30 and 50 
(Ref. 13). However, FDA has not received any data for sunscreen 
products with SPF values greater than 50. The data submitted to FDA 
indicate that the SPF test is accurate and reproducible for sunscreen 
products with SPF values up to 50 (Ref. 13). However, these data cannot 
be extrapolated to SPF values above 50. Thus, FDA proposes to allow 
specific labeled SPF values up to 50.
    FDA agrees with the sunscreen manufacturer that increasing 
variability in test results is likely with increasing SPF values. If 
there is large variability in test results, then the SPF value 
determined from the test is not accurate (i.e., an SPF 50 product may 
not actually be an SPF 50 product). The submitted data demonstrate that 
variability is not an issue for sunscreen products with SPF values up 
to 50. However, FDA is concerned that variability will become an issue 
for sunscreen products with SPF values over 50.

[[Page 49087]]

    FDA recognizes that future data may demonstrate that variability 
may not be a problem for sunscreen products with SPF values over 50. 
Therefore, FDA will consider specific SPF values greater than 50 upon 
receipt of data demonstrating that accurate and reproducible results 
can be obtained from the SPF test for sunscreen products with SPF 
values over 50. Generally, such data should include results from 
multiple laboratories using the same sunscreen formulations and using 
the SPF test proposed in this document, along with a statistical 
analysis of the overall results. In addition, FDA believes that the 
modified ``binomial'' test method submitted by one comment has merit 
for high SPF sunscreens and is requesting others' views on this method 
during the comment period for this rulemaking (see section III.I, 
comment 24 of this document).
    In the FM (64 FR 27666 at 27675), FDA disagreed with the comment 
that manufacturers would have no incentive to fund research for better 
sunscreens and may reformulate to less protective products if there is 
an upper limit to specific labeled SPF values. Although FDA would not 
want to decrease research incentive, FDA is more concerned about valid 
scientific data demonstrating the ability of multiple laboratories to 
accurately and reproducibly determine SPF values. However, FDA does not 
believe it is necessary to arbitrarily limit specific labeled SPF 
values. To the contrary, both in the FM and in this proposal, FDA has 
specifically stated that high SPF sunscreens should be available for 
those individuals desiring such products. The maximum allowable 
specific labeled SPF value, both in the FM and in this proposal, is 
based upon the review of data and information submitted to FDA. FDA 
purposely did not limit labeled SPF values at 30 in the FM. Instead, 
FDA used the value of ``30+,'' pending the receipt of adequate data to 
support any higher specific label values.
    Similarly, in this document, FDA is proposing the collective value 
``50+.'' FDA has sufficient assurance that a result over 50 from the 
required SPF test is, in fact, greater than 50 and can be labeled 
``50+.'' Thus, FDA believes that the term ``SPF 50+'' is truthful and 
nonmisleading on the label of OTC sunscreen drug products for which the 
SPF test in the monograph has indicated an SPF value greater than 50. 
FDA believes that allowing manufacturers to label sunscreens as ``SPF 
50+'' may encourage further research in human skin photobiology and the 
development of safe and effective sunscreen drug products with specific 
SPF values over 50. As explained earlier in this comment, FDA is not 
proposing that the specific value over 50 be stated in the labeling 
because there is no data, at this time, demonstrating the accuracy and 
reproducibility of the specific value over 50. Based upon the proposed 
labeling, improvements to SPF testing methods, and specific high SPF 
test data, FDA is proposing to modify the labeled SPF values in current 
Sec.  352.50(a)(1) and (a)(2) by changing the SPF values from ``30'' to 
``50.''

G. Comments on Indications for Sunscreen Drug Products

    (Comment 16) One comment requested that the ``Uses'' statement, 
``higher SPF gives more sunburn protection,'' be omitted except for 
products with an SPF over 30. This and other comments suggested that 
FDA's labeling concerns regarding high SPF sunscreens could be 
alleviated if the following statement was required on sunscreens over 
SPF 30: ``Higher SPF products give more sun protection, but are not 
intended to extend the time spent in the sun.''
    FDA is proposing to revise the sunscreen FM ``Uses'' statement 
``helps prevent sunburn'' and delete the ``Uses'' statement ``higher 
SPF gives more sunburn protection'' in current Sec.  352.52(b). The 
first indication, ``helps prevent sunburn,'' is being revised to one of 
the following, which would be required on all sunscreens:
    <bullet> ``low UVB sunburn protection''
    <bullet> ``medium UVB sunburn protection''
    <bullet> ``high UVB sunburn protection''
    <bullet> ``highest UVB sunburn protection''
The relative level of sunburn protection is determined from the SPF 
value:
    <bullet> low = SPF 2 to under 15
    <bullet> medium = SPF 15 to under 30
    <bullet> high = SPF 30 to 50
    <bullet> highest = SPF over 50
Thus, relative descriptors (low, medium, high, and highest) describe 
SPF values, which are relative and not absolute levels of sunburn 
protection intended to help consumers determine differences in sunburn 
protection offered by different sunscreen products (see section III.I, 
comment 23 of this document).
    FDA considers it important that consumers be made aware of the 
relative level of sunburn protection provided by a product in addition 
to its indication for sunburn protection. Individuals may select a low, 
medium, high, or highest sunburn protection product to meet their 
specific needs. The descriptor ``UVB'' is included to describe the 
predominant rays that are screened. The phrase ``helps prevent'' is 
being deleted because it is duplicative and no longer necessary. This 
phrase would only lengthen the ``Uses'' statement. Furthermore, 
consumers will now be able to equate a product's UVB radiation 
protection rating (i.e., SPF value) directly to the relative level of 
sunburn protection.
    The second indication ``higher SPF gives more sunburn protection'' 
is no longer needed because the relative level of sunburn protection is 
provided in the new ``Uses'' statements. In addition, without 
clarification, the statement may encourage consumers to spend more time 
in the sun. Clarification is necessary because, as discussed in comment 
19 of this document, surveys reveal that consumers spend more time in 
the sun with increasingly higher SPF sunscreen products (Refs. 14, 15, 
and 16). Therefore, FDA is not allowing this statement in the ``Uses'' 
section. However, under proposed Sec.  352.52(e)(2), FDA is proposing 
the following optional statement under ``Other information'' or 
anywhere outside of the ``Drug Facts'' box or enclosure: ``higher SPF 
products give more sun protection, but are not intended to extend the 
time spent in the sun.'' The phrase ``but are not intended to extend 
the time spent in the sun'' is additional information not included in 
the FM indication. FDA believes this revised indication statement will 
discourage consumers from spending more time in the sun when using a 
higher SPF product.
    FDA is proposing additional revisions in ``Uses'' in Sec.  
352.52(b)(1) to include UVA claims and other information (see section 
III.G, comments 17 and 18 of this document). The proposed revisions 
will help consumers to more fully understand the uses and expected 
results for individual sunscreen products. These changes are necessary 
because the PDP for a sunscreen product will now include two 
performance ratings (see section III.E, comment 14 of this document):
    <bullet> The well-accepted SPF value and new descriptor rating for 
UVB radiation protection, and
    <bullet> A new star/descriptor rating for UVA radiation protection.
Consequently, FDA considers it important that the ``Uses'' statements 
in the ``Drug Facts'' box accurately reflect product claims related to 
specific indications, UVA and UVB radiation, and the level of 
anticipated protection (low, medium, high, or highest) determined by 
the UVA and UVB product ratings. As with the introduction of SPF 
labeling years ago, it will take the combined efforts of government, 
manufacturers, consumer organizations, and the health care

[[Page 49088]]

community to educate consumers to fully understand these labeling 
initiatives to enhance their safe and effective use of sunscreen 
products.
    (Comment 17) One comment stated that FDA's ``sun alert'' statement 
in the FM recognized that sun-induced skin damage can contribute to 
photoaging and increase the risk of skin cancer. This statement reads: 
``Sun alert: Limiting sun exposure, wearing protective clothing, and 
using sunscreens may reduce the risks of skin aging, skin cancer, and 
other harmful effects of the sun.'' The comment urged FDA to allow 
other truthful use statements, such as the following:
    <bullet> ``helps protect against skin damage caused by the sun''
    <bullet> ``helps protect against skin aging caused by the sun''
    <bullet> ``regular use helps protect against certain forms of skin 
cancer caused by the sun''
    <bullet> ``helps protect against fine lines and wrinkles caused by 
the sun''
    <bullet> ``helps protect against pigmentary changes due to sun 
exposure''
Another comment urged FDA to include the first three use statements 
suggested by the first comment, as well as ``helps protect against the 
harmful effects of the sun'' and ``helps protect against (select one: 
`casual,' `incidental,' `intermittent,' or `daily') sun exposure.'' The 
comment contended that, when used effectively as part of a sun 
protection program, sunscreens may prevent very serious disease 
conditions.
    Another comment provided citations from the medical literature to 
support its contention that claims of sunscreens preventing skin cancer 
induction may be false, deceptive, misleading, and unsubstantiated. The 
comment mentioned an article by Garland (Ref. 25) that states the 
following: ``No epidemiological studies were identified that showed a 
protective effect of use of chemical sunscreen on risk of melanoma or 
other cutaneous malignancies in humans.'' The comment also mentioned an 
article by Gasparro (Ref. 24) that states the following: ``Although 
some have promoted daily use (of sunscreen) for the prevention of 
premature aging of the skin and the prevention of skin cancer, actual 
data are lacking to support these recommendations.''
    FDA has reviewed the submitted articles concerning UV-induced skin 
damage (i.e., premature aging and cancer) along with articles obtained 
from a search of the scientific literature (Refs. 26 through 34). Many 
of the articles involved preclinical data, which can be difficult to 
extrapolate to consumer (human) actual use conditions. FDA believes 
that the articles with clinical data provide more meaningful results, 
as they can be easily extrapolated to consumer actual use conditions. 
Therefore, FDA is focusing discussion in this document on the clinical 
studies. In agreement with Garland (Ref. 25) and Gasparro (Ref. 24), 
FDA does not believe, as a whole, that the studies demonstrate that 
sunscreens alone help prevent skin aging or skin cancer.
    Some of the clinical studies examined the role of UVB and UVA 
radiation in producing histological changes indicative of skin aging 
due to the sun. Lowe et al. demonstrated that high doses of UVA 
radiation (320 to 400 nm) increased melanization of human skin more 
than lower doses of UVA or solar simulating UV radiation at 290 to 400 
nm (Ref. 26). Seite et al. demonstrated that melanization of human skin 
increased with exposure to UVB/UVA radiation at 290 to 400 nm (Ref. 32) 
and UVA radiation at 330 to 440 nm (Ref. 27). Seite et al. also showed 
that human skin hydration decreased after chronic exposure to UV 
radiation at the wavelengths studied.
    Five studies revealed stratum corneum thickening produced by both 
UVB and UVA radiation (Refs. 26 through 29 and 32). Stratum granulosum 
thickening was transiently induced after 6 weeks of exposure to UV 
radiation (UVB/UVA) at 290 to 400 nm (Ref. 32). The same effects were 
seen with solar simulated radiation and high and low doses of UVA 
radiation after 12 weeks of exposure (Ref. 26). Viable epidermal 
thickening was seen after 6 weeks of exposure to UV radiation at 290 to 
400 nm in one study (Ref. 32) and after 9 days of exposure to UVA 
radiation at 335 to 345 nm in another study (Ref. 31).
    Inflammation and lysozyme deposition along the dermal elastic 
fibers were increased more in human skin exposed to UVA than UVB 
radiation (Refs. 26, 28, 29, and 31). Sunburn cell appearance, a 
typical response to UVB radiation, was also found to be present after 
exposure to different UVA radiation regimens in two studies (Refs. 28 
and 31) but not found in a third study (Ref. 27). Thus, FDA concludes 
that these studies demonstrated that both UVB and UVA radiation induce 
histological changes associated with skin aging.
    Four of these studies focused on the histological changes within 
the skin induced by UVB and UVA radiation and explored the ability of 
sunscreens to protect human skin against these changes (Refs. 29, 30, 
32, and 33). The first study suggested that an SPF 29 sunscreen 
prevented the development of solar elastosis, a condition in which skin 
loses its elasticity after chronic exposure to the sun (Ref. 33). 
However, these method and data analyses raise questions about the 
validity of the reported conclusion:
    <bullet> Discrepancies were noted concerning demographic 
characteristics of subjects, sunscreen application, and compliance 
rates.
    <bullet> Skin biopsy data at all three time points in the study 
were available from only 10 of the 35 subjects.
    <bullet> The only statistically significant difference between the 
sunscreen and placebo treatment groups was achieved in a computerized 
evaluation of solar elastosis at baseline and 24 months.
    The second study demonstrated significant contribution of a 
sunscreen in preventing UV radiation-induced skin damage (Ref. 32). The 
use of sunscreens with absorption spectra covering the 290 to 400 nm 
range prevented all of the effects of chronic exposure (6 weeks) to UV 
radiation evaluated in the study. The third study showed a 
photoprotective effect of an SPF 15 sunscreen product from damage 
induced by short term exposure to UVB radiation (Ref. 30). The fourth 
study showed that a UVB only sunscreen did not provide protection 
against chronic exposure to UVA radiation (Ref. 29).
    The studies provide evidence that both UVB and UVA radiation induce 
histological changes in the skin consistent with skin aging. Thus, the 
studies support the conclusion that exposure to UV rays increases the 
risk of premature skin aging. However, the study data fails to show 
that sunscreen use alone helps prevent premature skin aging for several 
reasons. First, the studies have not completely defined the action 
spectrum for the majority of UV radiation-induced effects on human 
skin. While studies demonstrate that a given histological change, such 
as thickening of the stratum corneum, is induced by certain wavelengths 
within the UVB and UVA region, studies have not examined the ability of 
the remaining UVB and UVA regions outside of these wavelengths to 
induce the same change. For example, studies may have shown that 290 nm 
to 310 nm and 360 nm to 400 nm radiation induce stratum corneum 
thickening, but it is not known whether 311 nm to 359 nm radiation 
induces the same histological change.
    Second, the inability to identify the exact UVB and UVA wavelengths 
that induce each histological change in the skin derives from the study 
designs. Each study differed in the following parameters:

[[Page 49089]]

    <bullet> UV radiation wavelengths,
    <bullet> UV exposure regimens,
    <bullet> Sunscreen doses,
    <bullet> Sunscreen application techniques, and
    <bullet> Endpoints.
Therefore, FDA cannot combine all of the data from these studies to 
define a complete action spectrum for each histological change in the 
skin. Furthermore, the action spectrum for each histological change 
would need to be combined to define a single action spectrum for skin 
aging, which is a cumulation of these histological changes. Without 
knowing which UVB and UVA wavelengths induce each histological change 
in the skin, FDA is unable to determine which wavelengths are most 
important in causing skin aging and cannot determine the action 
spectrum for aging.
    Third, the studies did not examine the chronic, long-term 
consequences of UV radiation exposure in human skin. Thus, it is not 
possible for FDA to extrapolate the data to longer time points at which 
the short-term histological changes may cumulate to produce visible 
signs of skin aging.
    Fourth, although the studies that examined the ability of 
sunscreens to protect against UV radiation-induced histological changes 
in the skin provide useful data, it is difficult for FDA to conclude 
that sunscreens alone help prevent skin aging based on these studies. 
The number of participants in each study was relatively small, with 
only 10 to 35 subjects per study. Different sunscreen formulations, 
with differing absorption spectra, were used in each study. As 
explained previously, these studies do not identify exactly which UVB 
and UVA wavelengths contribute the most to skin aging (i.e., the 
studies do not define the skin aging action spectrum). For all of these 
reasons, the studies do not prove that sunscreens alone help prevent 
premature skin aging.
    Likewise, FDA is not aware of data demonstrating that sunscreens 
alone help prevent skin cancer. It has been known for many years that 
UV radiation increases the risk of skin cancer. It has also been known 
for many years that a higher incidence of sunburn earlier in life 
corresponds to a higher incidence of skin cancer later in life. 
However, FDA is not aware of any studies demonstrating that the use of 
sunscreens alone decreases the risk of skin cancer. Like skin aging, 
there are studies examining the effects of sunscreens on short-term 
factors for skin cancer, such as sunburn and other cellular damage. 
However, it is difficult to extrapolate these short-term adverse 
effects of UV radiation to a long-term, chronic effect such as skin 
cancer. In addition, like skin aging, the complete action spectrum for 
skin cancer is not known at this time.
    Unlike skin cancer and premature skin aging, FDA has evidence that 
sunscreens alone help prevent sunburn. The SPF test measures the 
effectiveness of sunscreens with sunburn (erythema) as the endpoint. 
Thus, the impact of sunscreens on sunburn can be measured directly. In 
contrast, it is difficult to measure directly the impact of sunscreens 
on skin cancer or premature skin aging because these are long-term, 
cumulative adverse effects of UV exposure.
    Thus, for all of the reasons discussed in this comment, FDA 
concludes that the available evidence fails to show that sunscreens 
alone help prevent skin cancer or premature skin aging. Based on this 
conclusion, FDA is not proposing the indication statements proposed by 
the first and second comments, because these claims are for protection 
from premature skin aging, skin cancer, and related factors (e.g., 
``helps protect against skin aging caused by the sun''). FDA also is 
not proposing claims that sunscreens protect against ``casual, 
incidental, intermittent, or daily'' sun exposure, as proposed by the 
second comment, because the studies do not support these claims. 
Furthermore, FDA considers these terms as lacking sufficient meaning to 
be useful to consumers.
    As described elsewhere in this document (see section III.G, comment 
19), FDA is proposing to require a revised ``sun alert'' statement in 
the form of a new warning. The new warning statement is based on FDA's 
review of the available evidence concerning UV exposure and skin 
cancer, premature skin aging, and other skin damage. The new warning 
statement clarifies that UV exposure from the sun increases the risk of 
skin cancer, premature skin aging, and other skin damage. In addition, 
the new warning statement specifies that consumers should use 
complementary sun protection measures along with sunscreen (i.e., limit 
sun exposure and wear protective clothing). FDA has concluded from the 
available evidence that it is important to adopt a complete sun 
protection program (sunscreen, sun avoidance, and protective clothing) 
to decrease UV exposure. In fact, the second comment argued for new 
indication statements by considering the sunscreen use as part of such 
a sun protection program (i.e., in conjunction with limiting time in 
sun and wearing protective clothing). Thus, the second comment, along 
with the third comment, seemed to agree with FDA's conclusions in this 
proposed rule concerning the need for consumers to use sunscreens in 
conjunction with other sun protection measures.
    In addition, the reference in the new warning statement to 
sunscreen use combined with limiting sun exposure and wearing 
protective clothing is consistent with recommendations by other public 
health organizations. For example, the World Health Organization's 
International Agency for Research on Cancer (IARC) (Ref. 21) makes the 
following assessments and recommendations:
    <bullet> There is inadequate evidence in humans for a cancer 
preventative effect of sunscreens against basal cell or malignant 
melanoma cancers.
    <bullet> There is only limited evidence for a preventive effect of 
sunscreens against squamous cell cancer.
    <bullet> Sunscreens should not be the first choice for skin cancer 
prevention or used as the sole agent for protection against UV 
radiation.
Likewise, the CDC recommends that sunscreens be used as a complementary 
measure in an overall sun protection program (Ref. 35).
    FDA believes that additional information from controlled clinical 
studies is needed to better understand the role of sunscreens in 
preventing premature skin aging and skin cancer. Studies examining 
premature skin aging (using solar radiation or simulated solar 
radiation) are needed to determine the following in humans:
    <bullet> Measurable skin properties such as elasticity, collagen/
elastin ratios and properties, wrinkling, pigmentation changes and 
visual grades, leading to accepted quantitative definitions of 
chronological and sun-induced skin aging;
    <bullet> The relationship between sunlight exposure and skin aging, 
stratified by skin type;
    <bullet> An action spectrum for photoaging of skin;
    <bullet> A dose response for UV radiation-induced skin aging;
    <bullet> Quantitative estimates of realistic ``worst case,'' long-
term exposures to sunlight in relevant UVA and UVB radiation spectral 
ranges (i.e., the level of UVB and UVA protection needed); and
    <bullet> How UV radiation-induced processes that occur at a given 
wavelength affect UV radiation-induced processes that occur at other 
wavelengths.
Similar information is needed for skin cancer, except that studies 
should examine the different types of skin

[[Page 49090]]

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

[[Page 49091]]

because they think higher SPF values equate to longer times in the sun 
without burning. FDA is aware of a double-blind, randomized clinical 
study that showed a significant increase in sun exposure time of 
persons using high SPF sunscreens compared to persons using low SPF 
sunscreens (Ref. 14). In addition, two questionnaire-based surveys 
showed that sun exposure time is prolonged for persons using sunscreens 
compared to persons not using sunscreens (Refs. 15 and 16). By 
educating consumers about a sun protection program, we believe 
requiring this new proposed warning will decrease the likelihood of 
consumers spending more time in the sun when using a sunscreen.
    The new proposed warning also informs consumers that use of 
sunscreens alone is not the sole measure of protection from UV 
exposure, even with the use of high SPF products that provide UVA 
protection. Although it is well established that sunscreens protect 
against UV radiation, the following factors affect the level of 
protection provided by a sunscreen for each individual:
    <bullet> Variations between individuals,
    <bullet> UV radiation absorption,
    <bullet> Ability of sunscreens to adhere to and be absorbed by the 
skin,
    <bullet> Exposure conditions, and
    <bullet> Conditions of use (e.g., inadequate application amount or 
reapplication frequency).
Therefore, FDA agrees with the numerous groups that promote sunscreen 
use as part of a total sun protection program.
    FDA reviewed the relationship between sunscreen use and skin cancer 
incidence in the scientific literature and did not find confirmatory 
evidence that sunscreens alone protect against the development of skin 
cancer. The incidence of skin cancer continues to rise in the United 
States. The incidence of the most serious form of skin cancer, 
malignant melanoma, grew 6.1 percent per year during the 1970s (Refs. 
14 and 36). The rate is still rising an average 2.8 percent annually, 
with a rate of 14.3 percent per 100,000 persons in 1997. Melanoma is 
one of the top 10 cancers, by incidence, for persons with white skin. 
The American Cancer Society (ACS) estimated the following statistics 
concerning skin cancer in 2007 (Ref. 37):
    <bullet> More than 1 million new cases of curable basal cell and 
squamous cell carcinomas would be detected,
    <bullet> Approximately 59,940 new cases of malignant melanoma would 
be diagnosed, and
    <bullet> An estimated 8,110 persons would die from melanoma and 
2,000 persons would die from other skin cancers.
    Skin cancer affects roughly the same number of people as all other 
cancers combined. In view of the continuing increase in the incidence 
of all types of skin cancer and the lack of data demonstrating that 
sunscreens alone prevent skin cancer, FDA considers the new warning 
important for the protection of the public health.
    FDA is proposing that the new warning be required on all OTC 
sunscreen drug products except lip cosmetic-drug and lip protectant-
sunscreen products subject to Sec.  352.52(f). FDA continues to believe 
that all sunscreen products should have labeling to ensure that 
consumers are adequately protected against overexposure to UV radiation 
(64 FR 27666 at 27673). Thus, sunscreen products labeled for use only 
on specific small areas of the face and sold in small packages (i.e., 
sunscreen products subject to Sec.  352.52(f)) must include the new 
warning. The only sunscreen products not required to include the new 
warning are those lip cosmetic-drug and lip protectant-sunscreen 
products subject to Sec.  352.52(f), as proposed in Sec.  
352.52(f)(1)(ii). FDA is making this proposal because lip cosmetic and 
lip protectant products are often sold in packages that are 
substantially smaller than those of other products that fall under 
Sec.  352.52(f). FDA believes requiring the new warning on lip 
cosmetic-sunscreen and lip protectant-sunscreen products may discourage 
manufacturers from marketing these products because it requires a 
significant amount of labeling space.
    FDA has limited labeling requirements as much as possible for 
sunscreen products subject to Sec.  352.52(f). However, FDA believes 
consumers are at great risk for UV-induced skin damage, including 
cancer, on the face. Therefore, consumers who purchase products 
specifically for use on the face need to be informed about the 
information contained in the new warning. Although these products are 
marketed in small package sizes, FDA has determined that the products' 
labeling needs to include this important information in order to 
protect consumers.
    (Comment 20) One comment stated that consumers who use color 
cosmetics or facial moisturizers with sunscreens make the informed 
decision to purchase them as an additional benefit to their cosmetic 
use. The comment contended that a significant number of people with 
dark skin types, who do not burn easily, purchase sunscreens to provide 
protection from the sun damage that is not immediately recognizable. 
For these reasons, the comment requested claims such as the following:
    <bullet> ``helps protect against casual or incidental or 
intermittent daily sun exposure''
    <bullet> ``helps protect against the harmful effects of the sun''
Another comment acknowledged that facial makeups with sunscreen provide 
protection from sunburn, but that is not the primary reason why 
consumers use these products. The comment contended that requiring the 
``sunburn'' indication would be inappropriate and misleading labeling 
for most facial makeups with sunscreen. The comment, instead, requested 
a claim such as ``protects against the harmful rays of the sun.''
    FDA notes that the second comment acknowledged that facial makeups 
with sunscreen provide protection from sunburn. Not every consumer who 
uses color cosmetics or facial makeups with sunscreen meets the 
following criteria:
    <bullet> Has a dark skin type, or
    <bullet> Uses these products solely to provide protection from sun 
damage that is not immediately recognizable.
As noted in section III.D, comment 9 of this document, many consumers 
use facial products with sunscreen as their primary and only source of 
sunscreen protection for that area of the body. As discussed in section 
III.G, comment 16 of this document, sunscreen products will be required 
to bear a claim of low, medium, high, or highest UVB sunburn 
protection. FDA does not consider it inappropriate or misleading for 
color cosmetic or facial makeup products containing sunscreens to have 
this sunburn protection claim of low, medium, high, or highest.
    Sunscreen products that provide UVA radiation protection may also 
bear a claim about the level of protection. In addition, all OTC 
sunscreen products, except lip cosmetic-drug and lip protectant-
sunscreen products subject to Sec.  352.52(f), will be required to bear 
the revised ``sun alert'' statement, which is now included in the 
``Warnings'' section of the ``Drug Facts'' box. FDA considers the 
information in this new ``Warnings'' statement much more beneficial to 
consumers than the statements proposed by the comments. FDA rejected 
the terms ``casual, incidental, and intermittent,'' as explained in 
section III.G, comment 17 of this document.

[[Page 49092]]

H. Comments on Directions for Sunscreen Drug Products

    (Comment 21) Several comments requested alternative directions for 
makeup with sunscreen products. One comment requested ``apply smoothly 
or evenly before sun exposure and/or as needed.'' The comment added 
that ``before sun exposure'' may not always be appropriate as these 
makeup products are not exclusively or even primarily used for 
protection against sun exposure. A second comment requested ``apply 
smoothly or evenly before sun exposure and reapply as needed.'' A third 
comment did not suggest any specific language, but requested 
flexibility to recognize the product's primary use as a makeup, while 
providing adequate information about the sunscreen component. This 
comment added that the direction to consult a doctor for children under 
6 months of age was clearly unnecessary for facial makeup with 
sunscreen because these products cannot reasonably be expected to be 
used on children that age.
    FDA agrees that flexibility is appropriate for the directions for 
makeup with sunscreen products. Elsewhere in this document, FDA is 
proposing to allow labeling modifications for makeup with sunscreen 
products used only on specific small areas of the face and sold in 
small packages (see section III.D, comment 9 of this document). Those 
modifications include modified directions for cosmetic lip products 
containing sunscreen that are within the scope of proposed Sec.  
352.52(f). FDA is not extending the proposed modifications to all 
makeup with sunscreen products. Makeup with sunscreen products not 
labeled only for specific small areas of the face may be applied to a 
large area of the face or other areas of the body. As explained later 
in this comment, FDA would have concerns with the modifications being 
applied to these products.
    Whether intentional or not, makeup with sunscreen products may be 
the primary sunscreen for many consumers. A recent study examined 
sunscreen use patterns (Ref. 48). Participants were instructed to apply 
sunscreen every day. Of those who used sunscreen infrequently, the 
majority spent some time outdoors with 11 percent spending the majority 
of their time outdoors. These same participants explained that they did 
not believe sunscreen was necessary because of their planned 
activities. The authors cited this finding in advocating educating 
consumers on the need for sunscreen for frequent incidental sun 
exposure in addition to intentional sun exposure, such as sunbathing.
    For these reasons, FDA considers it important that consumers using 
makeup with sunscreen products not labeled for use only on specific 
small areas of the face recognize that these products are sunscreens 
and use them appropriately to maximize UV protection. Therefore, FDA is 
not proposing modified directions for these makeup with sunscreen 
products.
    (Comment 22) One comment requested that FDA require sunscreen 
manufacturers to provide accurate and appropriate instructions about 
how much sunscreen should be applied to the body. The comment also 
suggested that a warning about the dangers of sunburn from applying 
suboptimal amounts be included in sunscreen product labeling. A second 
comment stated that it was not aware of any study indicating that 
consumers use adequate amounts of sunscreen. The comment supplied data 
and other information concerning the dependency of the SPF value on the 
total quantity of sunscreen applied (Ref. 49).
    Section 352.52(d)(1) currently provides manufacturers the option to 
select one or more of the following application terms for a sunscreen 
product: ``liberally, generously, smoothly, or evenly.'' Manufacturers 
may also include optional directions that state ``[bullet] reapply as 
needed or after towel drying, swimming, or (select one of the 
following: `sweating' or `perspiring').'' In the final rule, FDA had 
concluded that the directions in Sec.  352.52(d)(1) to apply 
``liberally'' or ``generously'' convey the appropriate message to 
ensure that consumers adequately apply the sunscreen (64 FR 27666 at 
27679).
    Several studies suggest that, in practice, consumers may apply 
amounts of sunscreen below the density of 2 milligrams/square 
centimeter (mg/cm\2\), which is the amount of product required for the 
SPF determination in Sec.  352.72(e) (proposed Sec.  352.71(e)). These 
data suggest that consumers may apply as little as 0.5 to 1.0 mg/cm\2\ 
(Refs. 50 through 54). One comment reported that, to achieve the rated 
protection over the whole body, a typical adult with a surface area of 
1.73 square meters (m\2\) would need to apply 35 milliliters (mL) of 
sunscreen, roughly one-third of a 4 oz bottle per application (Ref. 
55). Studies indicate that SPF values determined at an application rate 
of 1 mg/cm\2\ are approximately 50 percent of those determined at 2 mg/
cm\2\, and when applied at 0.65 mg/cm\2\, the SPF values are 20 to 30 
percent of those determined at 2 mg/cm\2\ (Refs. 49, 50, and 51). 
Gasparro notes that statements such as ``apply liberally and 
frequently'' are too vague to be informative (Ref. 24).
    FDA is concerned that, in practice, consumers may be getting less 
protection than the labeled SPF value and believes that further 
information should be included in the labeling for sunscreen drug 
products to reduce the likelihood of underapplication. FDA believes 
that this information is better communicated as revised product 
directions rather than a warning. FDA is, therefore, proposing to 
revise Sec.  352.52(d)(1). The directions will continue to state that 
OTC sunscreen drug products should be applied ``liberally'' or 
``generously'' because it would be cumbersome to specify quantitative 
amounts for all possible body areas and the various uses on the label. 
However, FDA is proposing to make optional the directions in Sec.  
352.52(d)(1)(i) to apply ``evenly.'' FDA believes that this term, if 
used alone, may not convey the appropriate message to ensure that 
consumers apply sufficient sunscreen. In addition, FDA is proposing to 
remove the term ``smoothly'' from Sec.  352.52(d)(1)(i) because FDA 
considers that term to be vague and it may have different meanings to 
different consumers. FDA also believes this term is more likely to 
result in product underapplication.
    In addition to labeling directing consumers to apply sufficient 
amounts of sunscreen, FDA is also proposing to revise the labeling 
requirements concerning reapplication of the sunscreen product. In 
Sec.  352.52(d) of the FM, the general reapplication statement ``and as 
needed'' was the only required information. FDA made specific 
reapplication directions in Sec.  352.52(d)(2) of the FM optional in an 
effort to equalize requirements between sunscreens with and without 
water resistant claims (64 FR 27666 at 27681). FDA now believes that 
more detailed reapplication directions must be included on all OTC 
sunscreen products, because sunscreens may be underapplied as suggested 
by the comments.
    FDA came to this conclusion after reviewing studies concerning 
sunscreen reapplication as well as recommendations of public health 
organizations. Wright, et al. suggests that inadvertent sunburn may be 
due to the failure to use and reapply sunscreen appropriately (Ref. 
56). Study subjects who reapplied sunscreen every 1 to 2 hours and 
after swimming did not report sunburn. Rigel et al. reported that, even 
under intense solar conditions, those reapplying an SPF 15

[[Page 49093]]

sunscreen every 2 hours or sooner were five times less likely to 
sunburn compared to those who reapplied every 2.5 or more hours (Ref. 
57). The AAD (Refs. 38, 58, and 59), the ACS (Ref. 60), and the EPA 
(Ref. 40) recommend reapplying sunscreens every 2 hours or sooner and 
also recommend application to all exposed areas of the body (Refs. 60, 
61, and 62).
    Because the frequency of application appears to be critical for 
proper protection, FDA is proposing to add the statement ``apply and 
reapply as directed to avoid lowering protection.'' In addition, FDA is 
proposing to further revise the directions in Sec.  352.52(d) to 
include the following reapplication statement: ``reapply at least every 
2 hours.'' Likewise, for those products making a water resistant claim, 
FDA is proposing to include the number of minutes (i.e., 40 or 80) that 
the product maintains its water resistance before the ``swimming/
sweating'' term. FDA believes these additional proposed directions will 
alert consumers about the hazards of using insufficient amounts of 
sunscreen product and encourage reapplication after the appropriate 
time. FDA considers these specific, informative reapplication 
statements, instead of ``and as needed,'' to be necessary on all OTC 
sunscreen products. FDA is also proposing the optional direction 
``apply to all skin exposed to the sun.'' FDA is proposing that this 
direction be optional because we believe most consumers know to apply 
sunscreen to all exposed skin. However, if a sunscreen product can 
accommodate this direction, it will serve to remind consumers that all 
exposed skin is susceptible to UV damage. These proposed directions, as 
a whole, should serve to better protect consumers, particularly those 
who tend to underapply sunscreen, from overexposure to the sun.
    Accordingly, FDA is proposing to change Sec.  352.52(d) to read as 
follows:
    (d) Directions. * * *
    (1) For products containing any ingredient in Sec.  352.10. (i) 
The labeling states ``[bullet] apply [select one of the following: 
`liberally' or `generously'] [and, as an option: `and evenly'] 
[insert appropriate time interval, if a waiting period is needed] 
before sun exposure''.
    (ii) The labeling states ``[bullet] apply and reapply as 
directed to avoid lowering protection''.
    (iii) As an option, the labeling may state ``[bullet] apply to 
all skin exposed to the sun''.
    (iv) The labeling states ``[bullet] children under 6 months of 
age: ask a doctor''.
    (2) For products that satisfy the water resistant or very water 
resistant testing procedures identified in Sec.  352.76. The 
labeling states ``[bullet] reapply after [select one of the 
following: `40 minutes of' or `80 minutes of' for products that 
satisfy either the water resistant or very water resistant test 
procedures in Sec.  352.76, respectively] swimming or [select one of 
the following: `sweating' or `perspiring'] and after towel drying. 
Otherwise, reapply at least every 2 hours''.
    (3) For products that do not satisfy the water resistant or very 
water resistant testing procedures identified in Sec.  352.76. The 
labeling states ``[bullet] reapply at least every 2 hours and after 
towel drying, swimming, or [select one of the following: `sweating' 
or `perspiring']''.
As discussed in the FM (64 FR 27666 at 27679), manufacturers who have 
data to support different reapplication directions based on specific 
substantiation information may submit the information for approval of 
those directions via an NDA deviation as provided in Sec.  330.11 (21 
CFR 330.11).

I. General Comments on SPF Testing Procedure

    (Comment 23) One comment suggested that the SPF test incorporate an 
amount of product that more closely reflects the amount applied by 
consumers. More specifically, the comment requested that FDA replace 
the 2 mg/cm\2\ required in Sec.  352.72(e) (proposed Sec.  
352.70(c)(5)) to a value between 0.5 and 1.0 mg/cm\2\. The comment 
argued that the protection afforded during actual usage may be only 
one-quarter to one-half the labeled SPF value (see section III.H, 
comment 22 of this document). The comment also suggested that SPF could 
be stated using descriptive terms, such as ``light,'' ``moderate,'' or 
``heavy'' protection, instead of a numerical value.
    FDA is not proposing the suggested change in test method at this 
time. This issue was discussed in detail in the TFM (58 FR 28194 at 
28264 to 28266). The majority of comments advocated continuing the use 
of an application density of 2 mg/cm\2\. The current comment did not 
provide data demonstrating the suitability of a smaller test amount. 
FDA is concerned that a uniform distribution of sunscreen over the test 
area might be difficult using a smaller amount of sunscreen. Further, 
the standard application density used worldwide in the SPF test is 2 
mg/cm\2\ (Ref. 63).
    FDA agrees that SPF values do not reflect exact levels of sunburn 
protection that consumers receive under actual use conditions. The 
required SPF test is a clinical test conducted with strict control over 
factors such as product application density. However, under actual use 
conditions, these factors are not controlled and vary greatly. The 
actual level of sunburn protection under consumer use conditions is 
affected by a number of factors. Some of the key factors are
    <bullet> Application density,
    <bullet> Reapplication frequency,
    <bullet> Skin type (e.g., burns easily versus never burns),
    <bullet> Time of day during sun exposure, and
    <bullet> Geographical location during sun exposure.
Thus, SPF values reflect relative and not absolute levels of sunburn 
protection.
    Although SPF values do not convey actual levels of sunburn 
protection, when comparing multiple sunscreen products, SPF values 
enable consumers to determine which products provide the most sunburn 
protection. For example, FDA believes most consumers would correctly 
identify an SPF 20 product as providing more sunburn protection than an 
SPF 10 product. Thus, lowering the sunscreen application density would 
not be necessary to more accurately reflect the degree of relative 
sunburn protection.
    FDA agrees that, in addition to bringing SPF values closer to 
representing absolute levels of protection, lowering the sunscreen 
application density might also reduce some of the inaccuracies and 
limitations encountered when testing high SPF sunscreen products. Thus, 
FDA invites interested parties to submit data supporting a smaller 
application density for SPF testing of all sunscreen dosage forms in 
accordance with Sec.  352.77. However, developing a single global 
method and labeling would require a coordinated effort between the 
regulatory agencies in many countries around the world. Because FDA 
does not have data to validate the SPF test using a lowering sunscreen 
density, FDA is proposing directions that we believe will encourage 
consumers to apply greater densities of sunscreen (i.e., closer to 2 
mg/cm\2\) (see section III.H, comment 22 of this document).
    FDA does not find that there are sufficient benefits for using 
descriptors instead of numerical values for SPF on the PDP. Consumers 
are familiar with numerical SPF values from over 20 years of usage. As 
described in section III.G, comment 16 of this document, FDA believes 
that the use of descriptors in combination with numerical values on the 
PDP may be beneficial to consumer understanding of the level of sunburn 
protection provided by a product. Thus, as explained in comment 16, FDA 
is proposing to include a descriptive term of relative sunburn 
protection (i.e., low, medium, high, or highest) with the proposed 
sunburn protection statement in the ``Uses''

[[Page 49094]]

section and on the PDP. The intent of this dual descriptive and 
numerical sunburn protection measure is to allow consumers to more 
easily differentiate the level of sunburn protection provided by 
different sunscreen products. In addition, this proposed labeling for 
sunburn protection is similar to the proposed UVA protection labeling 
(see section III.G, comment 14 of this document).
    FDA is also aware of sunscreen drug products marketed in dosage 
forms that may not be addressed by current SPF testing procedures. The 
SPF testing procedure described in Sec.  352.72 (proposed Sec.  352.70) 
references oils, lotions, creams, gels, butters, pastes, and ointments. 
FDA invites interested parties to submit SPF testing modifications for 
new dosage forms (e.g., mousses, foams, and towelettes) in accordance 
with Sec.  352.77.
    (Comment 24) One comment recommended a pass/fail (binomial) test to 
determine SPF values (Ref. 49). The test would demonstrate that 
subjects have no reaction to a quantity of UV energy equivalent to an 
expected SPF value (for products passing the test). For example, 
subjects being tested with a product with an expected SPF value of 30 
would be dosed only at the SPF 30 level, and the product would either 
pass or fail. A product passing this test would actually have an SPF 
value of 30 or over, whereas a product failing this test would have an 
SPF value below 30. The comment argued that while the monograph SPF 
test is probably adequate for products with low SPF values, it is not 
adequate for testing high SPF products because differences in solar 
simulators can provide as much as a 200 percent variation in results 
depending on the formulation. The comment further argued that an 
impossibly high number of subjects would be required for the current 
SPF method to obtain a 95 percent confidence level and that the test 
exposes subjects to a potentially dangerous condition, sunburn.
    According to the comment, the average MED for each skin type can be 
predicted from existing solar simulator calibration data. During the 
pass/fail test, each test subject is screened for skin type and then 
given a first day range of energy that does not exceed the expected 
MED. The comment proposed using a panel of five subjects. Using the MED 
information obtained on the first day, each subject is given four UV 
radiation exposures corresponding to the expected SPF value. Each 
subsite is then evaluated for erythema. If six or more of the 20 
subsites show perceptible erythema, the product fails, as there would 
be less than a 95 percent probability the actual SPF value was higher 
than the expected SPF value. If less than six subsites show perceptible 
erythema, the product passes, as there would be greater than a 95 
percent probability that the actual SPF value was more than the 
expected SPF value. The comment proposed the following:

                       Table 2.--Probability Table
------------------------------------------------------------------------
                               Maximum no.  of
     No. of subjects               failures              Probability
------------------------------------------------------------------------
1 (n=4)                    0                        0.0625\1\
2 (n=8)                    2                        0.0352
3 (n=12)                   3                        0.0200
4 (n=16)                   5                        0.0383
5 (n=20)                   5                        0.0207
------------------------------------------------------------------------
\1\ n is not sufficient to make a 95 percent prediction

The comment further proposed that if all eight subsites of the first 
two subjects pass, then the product passes and the remaining three 
subjects would not be evaluated. The probability of this happening 
would be 1/256 unless the product is over the expected SPF value.
    FDA agrees that, currently, there may not be enough experience and 
test data for products with SPF values of 30 and over on which to 
determine the sample size needed to obtain an acceptable 95 percent 
confidence interval. As discussed in section III.L, comment 37 of this 
document, to account for increased variability in SPF values for 
sunscreens with SPF values over 30, FDA proposes to increase the sample 
size to at least 25 subjects. Therefore, the comment may be correct in 
arguing that large numbers of subjects may be required for testing 
products with high SPF values. FDA believes that the pass/fail test has 
merit and could provide a reasonable substitute for the current SPF 
method for products with expected SPF value of 30 or higher. However, 
before the method can be accepted, method validation data are required 
that demonstrate the method can be performed satisfactorily by multiple 
laboratories using the same sunscreen formulation(s). FDA invites such 
data.
    If the pass/fail method is accepted, FDA may stipulate that the 
method be used only for products with SPF values of 30 and higher 
because of the large number of subjects that would be required for high 
SPF products under the current test method. A pass/fail method would 
require fewer test subjects. Low SPF products can be adequately tested 
under the current method without large numbers of subjects. In 
addition, FDA would likely require that all 20 subsites be evaluated 
even if the first 2 subjects pass. Further, using standard probability 
computer software, FDA calculates that the values for the maximum 
number of failures in table 2 of this document for subjects one through 
five should be 0, 1, 2, 4, and 5, respectively, rather than the values 
provided by the comment.
    FDA would also consider three modifications to the method described 
by the comment and invites comment. First, each subject may have test 
successes and failures due to multiple subsites on each subject. 
Statistically, these will not be independent observations, which is a 
condition needed for a binomial probability calculation. Therefore, FDA 
is considering that a test panel should consist of 20 to 25 subjects 
and that only one site be tested on each subject. A pass/fail 
determination would be made for each individual.
    Second, as an alternate, a double sampling plan based on Taylor's 
Guide to Acceptance Sampling may replace the five-layered plan proposed 
by the comment (Ref. 64). With the double sampling plan, two subjects 
are tested simultaneously with up to a maximum of four subjects, each 
having four subsites tested. If no more than one of the first eight 
subsites has perceptible erythema, the product passes. If three to 
eight subsites have perceptible erythema, the product fails. If exactly 
two of the eight subsites have perceptible erythema, then the second 
group of two subjects is tested. If two to four subsites from four 
subjects have perceptible erythema, the product passes. Otherwise, the 
product fails. According to this scheme, if probability p = 0.10 that 
the product tested would produce any recognizable erythema, then the 
probability = 0.95 that the product will pass. If probability p = 0.5 
that the product tested would produce any recognizable erythema, then 
the probability = 0.05 that the product will pass.
    Third, an alternative to the probability calculation is a margin of 
error approach. With this method, a margin of error for the expected 
SPF value is defined before testing. The margin of error is used to 
determine the tolerability interval around the expected SPF value. The 
90 percent confidence interval for the product's test result (one 
result per subject) must fall within the tolerability interval to be 
labeled with that SPF value. For example, if a 10 percent margin of 
error is claimed for a product with an expected SPF value of 40, then 
the tolerability interval would be 40 <plus-minus> 4, or 36 to 44. If 
the related 90 percent confidence interval is from 37 to 43, an SPF 
value of 40 is assigned to the product. If the related 90 percent

[[Page 49095]]

confidence interval is from 35 to 45, an SPF value of 40 could not be 
assigned to the product and the product may be retested at an expected 
SPF of 30.
    FDA invites discussion of these suggested modifications to the 
comment's pass/fail method for testing sunscreen drug products having 
an SPF value of 30 or higher.
    (Comment 25) One comment described an in vitro method it developed 
for simultaneously predicting SPF and assessing photostability. The 
method utilizes a 150 watt xenon arc lamp to irradiate sunscreen 
applied at a level of 1 to 2 mg/cm\2\ to a flat collagen membrane 
substrate placed in the opening of an integrating sphere attached to a 
spectroradiometer. The spectral irradiance of the source and the 
spectral irradiance of the substrate alone are measured from 290 to 400 
nm, at 1 nm intervals. The spectral irradiance transmitted by the 
sunscreen/substrate combination is measured at 1 minute intervals until 
the total erythemal-effective dose transmitted by the sunscreen exceeds 
1 MED, where 1 MED equals 0.02 erythema-effective Joules (J)/cm\2\. 
Each 1 minute interval represents two to three MEDs. The time course of 
the sunscreen's SPF is then computed (Ref. 65). This information 
reveals the photostability of a sunscreen. If a sunscreen is 
photostable, it will not decompose when exposed to UV radiation, and 
the SPF will not change with increasing UV exposure. If a sunscreen is 
not photostable, it will decompose when exposed to UV radiation, and 
the SPF will decrease with increasing UV exposure. Another comment 
asked FDA to consider replacing the human SPF test with equivalent in 
vitro technology and chemical engineering, but did not suggest a 
suitable method.
    FDA does not agree that an in vitro method is adequate to replace 
the in vivo SPF test. In vitro tests are generally inadequate as the 
sole measure of SPF because substrates cannot mimic sweating, skin 
absorption, or certain interactions with skin that influence SPF. Some 
sunscreen ingredients do not behave similarly in vitro and in vivo. At 
this time, the comment's method has not been validated, and the chosen 
substrate has not been demonstrated to possess penetration 
characteristics and surface chemistry similar to human skin.
    The described in vitro method does have potential utility for 
measuring photostability of a sunscreen product. Measuring the 
erythemal-effective dose transmitted through the sunscreen in vitro 
over time seems like a reasonable approach. However, portions of the 
method require further exploration. Items such as the cut-off to define 
photostability need further explanation and validation. It should also 
be pointed out that the current SPF test method does not directly 
measure photostability, but it accounts for photostability. More 
specifically, the SPF value is determined after a sunscreen is exposed 
to UV radiation, so the SPF represents UVB protection provided by 
whatever fraction of the sunscreen has not decomposed.
    FDA agrees that in vitro tests are generally rapid and less 
expensive than in vivo tests and, for SPF measurements, would reduce 
exposure of human subjects to UV radiation. FDA is willing to consider 
alternate methods for SPF testing if they are adequately supported with 
data and are shown to be equivalent to established in vivo methods by 
collaborative studies. If the methods are equivalent, then the same SPF 
values should be determined for each sunscreen tested according to the 
SPF method and the alternate method. The comments have not provided 
data from such studies. Therefore, FDA is not proposing to include the 
described in vitro method in the monograph at this time.
    (Comment 26) Several comments urged FDA to revise Sec.  352.72(h) 
and reinstate the requirement for determining MED at 16 to 24 hours 
after exposure, rather than 22 to 24 hours. The comments submitted data 
showing that, for an SPF 30 product and for the 8 percent homosalate 
standard, determining the MED at 16 or 24 hours does not result in any 
clinical or statistical difference in the SPF (Refs. 66 and 67). 
Comments argued that immediate pigmentation fades rapidly and does not 
interfere with MED readings. One comment further argued that the 16 to 
24 hour time is universally accepted by the European Union, Australia, 
and Japan and FDA should adopt this time in the interest of 
international harmonization.
    The Panel recommended that the MED be evaluated 16 to 24 hours 
after exposure (43 FR 38206 at 38262). FDA proposed a post exposure 
time of 22 to 24 hours based upon information provided by comments to 
the Panel's report that immediate pigmentation may persist with higher 
doses of UV radiation up to 24 hours or, in some cases, for 36 to 48 
hours after prolonged exposure (58 FR 28194 at 28268 to 28269). 
Comments had indicated that immediate pigmentation might interfere with 
an investigator's perception of minimally perceptible erythema.
    FDA agrees that these new data show no significant difference in 
MED readings at 16 and 24 hours. Thus, FDA is proposing to revise the 
MED determination time in Sec. Sec.  352.72(h) and 352.73(c) (proposed 
Sec. Sec.  352.70(c)(8) and 352.70(d)(3), respectively) from ``22 to 24 
hours'' to ``16 to 24 hours.''

J. Comments on the Sunscreen Standard for SPF Testing Procedure

    (Comment 27) Several comments suggested that standard controls with 
SPF values of 15 or higher be developed to test high SPF sunscreen 
products. One comment stated that such standards would improve test 
accuracy and provide a consistent and adequate benchmark for 
compliance. One comment mentioned use of a control SPF 15 formula 
routinely in SPF evaluation and considered it a more valuable control 
than the 8-percent homosalate SPF 4 standard. Another comment supplied 
``round-robin,'' collaborative SPF testing data from 7 laboratories on 
a total of 153 subjects with 2 potential SPF 15 sunscreen standard 
preparations, ``Formulation A'' on 147 subjects and ``Formulation B'' 
on 146 subjects (Refs. 13, 68, and 69). The comment concluded that 
differences between the two preparations were not significant (p=0.653) 
but ``Formulation B'' was preferred due to its less complex formula and 
slightly more consistent results. The comment added that the data 
showed that different laboratories can obtain valid, reproducible 
results when testing high SPF sunscreens. Another comment stated that 
it provided test results on 20 subjects using an SPF 25 product as the 
control (Ref. 70). Three comments suggested that the European Cosmetic, 
Toiletry, and Perfumery Association (COLIPA) ``European low SPF 
Standard Code Number COL492/1 (formerly the DIN standard)'' be included 
in the OTC sunscreen drug product monograph as a permissible standard 
sunscreen preparation, in addition to the 8-percent homosalate 
standard, and that either standard should be allowed in the SPF testing 
procedures. The comments contended that this approach will serve to 
permit international marketing and eliminate duplicative testing. 
Another comment asked FDA to adopt the JCIA SPF 15 ``P3'' standard, but 
did not provide supporting data.
    The comment concerning the SPF 25 control provided data from 
comparative tests on 20 subjects, using the 8-percent homosalate 
standard, an SPF 15 sunscreen drug product, and an SPF 25 sunscreen 
drug product (Ref. 70). FDA finds that this study is inadequate to 
support the comment's request because the study did not do the 
following:

[[Page 49096]]

    <bullet> Include sufficient numbers of subjects,
    <bullet> Address suitability of the standard across different 
laboratories, and
    <bullet> Document some properties required in a sunscreen standard 
to test high SPF sunscreen products.
    The following properties of a sunscreen standard were not addressed 
but need to be addressed:
    <bullet> Low level of interlaboratory variation,
    <bullet> Sensitivity to experimental error, and
    <bullet> Ease of preparation with a reasonable degree of accuracy.
These data are also needed for the JCIA standard.
    Although comments provided data on 20 subjects in each of 4 
laboratories using the COLIPA COL492/1 standard, FDA is not proposing 
to include this standard as an alternate to the 8-percent homosalate 
standard because we do not believe that using the COL492/1 standard 
will make the monograph method comparable to the European method, as 
other differences exist between the two methods. For example, the 
monograph method requires 20 evaluable subjects, while the European 
method requires only 10 evaluable subjects. Therefore, the COL492/1 
standard is a valid standard under the European method but may not be a 
valid standard under the monograph method. Finally, FDA finds that the 
8-percent homosalate standard is a suitable control for testing 
sunscreen drug products with SPF 15 or below (see section III.J, 
comment 28 of this document).
    FDA agrees with the comment that the submitted collaborative data 
from seven laboratories support ``Formulation B'' as an appropriate SPF 
15 sunscreen standard. The mean SPF for ``Formulation B'' was 16.3 in 
146 subjects tested, with 1.7 percent standard error of the mean, and 
laboratory means ranging from SPF 15.6 to 18.5. Therefore, FDA is 
proposing to include the ``Formulation B'' SPF 15 standard in the FM to 
be used for sunscreen drug products with an SPF value over 15 (optional 
for SPF values of 2 to 15).
    (Comment 28) One comment noted that there are two recognized 
standard control formulations:
    1. An 8-percent homosalate preparation with an SPF value of 4 
(Sec.  352.70(b) of the FM), and
    2. Formulation B (padimate O/oxybenzone) with an SPF value of 15.
The comment stated that the function of the standard formulation is 
quality assurance for method control and not as a calibration standard 
to bracket specific SPF ranges. The comment claimed that the 8-percent 
homosalate SPF 4 standard is appropriate to test products at any SPF 
level and that the choice of whether to use the SPF 4 or SPF 15 control 
formulation should rest with the manufacturer. Several other comments 
agreed with this comment.
    Another comment provided data using the 8-percent homosalate 
standard to test product formulations with estimated SPF values of 15, 
30, and 45 on 20 subjects (Ref. 67). The comment concluded that the 
data showed testing procedures in the FM can differentiate high SPF 
sunscreens using the homosalate SPF 4 standard. The comment requested 
that the homosalate SPF 4 standard be allowed to be used for products 
with an SPF value over or below 15.
    FDA does not consider the data adequate to support the suggestion 
that the 8-percent homosalate standard currently used to evaluate 
sunscreen drug products with SPF values up to 15 is equally applicable 
to products with SPF values over 15 (Ref. 67). The study had the 
following deficiencies:
    <bullet> Did not include sufficient numbers of subjects,
    <bullet> Did not address suitability of the standard across 
different laboratories, and
    <bullet> Did not document certain properties required in a 
sunscreen standard to test high SPF sunscreen products.
The following sunscreen standard properties were not addressed but need 
to be addressed:
    <bullet> Low level of interlaboratory variation, and
    <bullet> Sensitivity to experimental error.
    FDA agrees that the two standards are method controls rather than 
calibration tools. As such, the standard used should approximate the 
expected SPF of the product being tested to better verify that all 
aspects of the testing method are performing properly at the expected 
SPF level.
    Using the SPF 4 standard to measure SPF values over 15 is more 
likely to produce erroneous results than using a standard with an SPF 
of 15. In measuring SPF values over 15, much higher light energies (J/
cm\2\) are used in comparison to measuring SPF values below 15. 
Problems in the accurate quantitation of high light intensities may not 
be detected if the SPF 4 standard is used for SPF values over 15. While 
the SPF 4 standard may give acceptable results for products with SPF 
values over 15 in some studies, the extrapolation of these results to 
approximately 4 to 13 fold higher light energies used to test products 
with SPF values over 15 may be erroneous in other studies. Better 
assurance of an accurate SPF value is obtained by using a standard that 
is closer in SPF value to the sunscreen product being tested.
    The use of an SPF 15 standard would be reasonable to test products 
with SPF values below 15. SPF 15 is in the middle (geometrically) of 
the 4 to 50 range. The ratio of SPF 15 to SPF 4 is 3.75, and the ratio 
of SPF 50 to SPF 15 is 3.33. Thus, there would be equal coverage of all 
ranges. Therefore, FDA is proposing that Formulation B may be used to 
test sunscreen drug products with SPF 2 and over, and is required for 
testing sunscreen drug products with SPF over 15 (proposed Sec.  
352.70(a)(1)(ii)). The 8-percent homosalate standard may be used for 
testing sunscreen drug products with SPF of 2 to 15.
    (Comment 29) Several comments suggested that a modern, HPLC method 
is superior to the older spectrophotometric assay in Sec.  352.70(c) of 
the FM. One comment provided technical information about the HPLC 
method and stated that it is now commonly used by analytical 
laboratories to assay sunscreen formulations (Ref. 71). Although this 
HPLC assay method was used in the study of two SPF 15 sunscreen 
standard preparations (see section III.J, comment 27 of this document), 
one comment noted that there are limited data on this method with the 
SPF 15 control formulation because FDA has not yet published this 
formula as an accepted standard.
    FDA agrees that an HPLC method is superior to the 
spectrophotometric method, which was originally published by FDA in 
1978, in specificity and precision. Validation data provided by the 
comment documented the following:
    <bullet> Specificity,
    <bullet> Accuracy,
    <bullet> Limit of detection,
    <bullet> Linearity,
    <bullet> Precision, and
    <bullet> Reproducibility of the method.
The validation data included chromatograms and demonstrated that the 
HPLC method is suitable for both the SPF 4 and SPF 15 standards. 
Further, FDA validated the method in its laboratories and concludes 
that the method is acceptable for quality control and regulatory 
purposes (Ref. 72). Finally, the spectrophotometric method has not been 
validated for the SPF 15 standard, and the HPLC method has been 
validated for both the SPF 4 and SPF 15 standards. Therefore, FDA is 
proposing to revise Sec.  352.70 to replace the outdated 
spectrophotometric method with the HPLC method and to

[[Page 49097]]

use the HPLC method to assay both the SPF 4 and SPF 15 standards.
    (Comment 30) Two comments disagreed with the requirement in Sec.  
352.70(a) for concomitant use of a standard sunscreen for each SPF 
test. One comment suggested that a standard could be run twice yearly. 
Another comment suggested that data to evaluate proper laboratory test 
procedures could be obtained from panels of a standard run as part of 
``the ongoing laboratory operation.'' A third comment stated that a 
standard preparation should be run each time an SPF determination is 
made.
    FDA discussed this issue in comment 78 of the TFM (58 FR 28194 at 
28253 to 28254). FDA disagreed with one comment that the standard could 
be run once or twice a year and reaffirmed the Panel's recommendation 
that concomitant testing is necessary in SPF determinations to ensure 
uniform evaluation of OTC sunscreen drug products and to serve as an 
internal indicator of experimental errors. The comments requesting a 
change did not provide any supporting data. In the absence of 
supporting data, FDA is not persuaded to change the concomitant use 
requirement in Sec.  352.70(a).
    (Comment 31) One comment suggested that there is a need for a 
specific source to maintain and supply sunscreen standards. The comment 
contended that a few testing laboratories are reporting differences in 
the tested SPF of the 8-percent homosalate standard preparation 
depending on whether the standard is prepared by the laboratory or 
purchased from one company that manufactured this standard. The comment 
stated that either the testing procedures or the standard itself have 
changed since the original formula was published (earlier standard SPF 
values were 3.7/3.8 to 4.2/4.3 with an average of 4.1, while current 
values are 4.3 to 4.9/5.0).
    Data supporting the reliability and wide acceptance of the 8-
percent homosalate standard preparation were previously discussed in 
the TFM (58 FR 28194 at 28250 through 28252). The comment did not 
provide any data to support its contention concerning discrepancies in 
the SPF of 8-percent homosalate standard preparations and FDA is not 
aware of any new data that support the need for a specific source to 
maintain and supply this standard. The standard is a control to 
validate the testing procedure, equipment, and facilities rather than a 
calibration tool for setting SPF values of sunscreen products. FDA 
considers the parameters established in Sec.  352.70 of the FM adequate 
to assure a uniform standard and is not requiring that a specific 
source maintain and supply the sunscreen standard at this time.

K. Comments on Artificial Light Sources for SPF Testing Procedure

    (Comment 32) Several comments suggested that FDA replace the 
specifications in Sec.  352.71 that state ``sun at a zenith angle of 
10[deg]'' and ``less than 1 percent of its total energy output 
contributed by nonsolar wavelengths shorter than 290 nm'' with the 
COLIPA table of ``percent erythemal contribution'' as the spectral 
power distribution standard for the light source used in the SPF test 
procedures (Ref. 73). The comments suggested that the spectra of 
currently used solar simulators (especially around 290 nm and above 350 
nm) could cause overestimation of SPF values for high SPF sunscreens. 
Because shorter wavelengths can make a very large contribution to 
erythema, the comments stated that small errors in the 290 nm region of 
solar simulator spectra could have considerable effects. The comments 
noted that spectral power deficiencies above 350 nm may give 
artificially high SPF values for sunscreen drug products that absorb 
poorly in the long wavelength UVA region.
    The comments added that there is general agreement in the industry 
that Sec.  352.71 should be revised to permit compliance with the 
COLIPA standard for solar simulators. The comments further recommended 
one modification to the COLIPA standard: The energy for wavelengths 
below 290 nm should be limited to ``less than 0.1 percent'' rather than 
``less than 1.0 percent,'' as stated in the COLIPA standard. The 
comments stated that a more restrictive specification of ``0.01 
percent,'' as mentioned by FDA (65 FR 36319 at 36321), would result 
more in testing the limits of the measurement spectroradiometer rather 
than the true output of the solar simulator. One comment that supported 
the COLIPA standard subsequently suggested that the spectral limits be 
further narrowed to prevent excessive variability of SPF values for 
certain sunscreen products (Ref. 74).
    One comment discussed the calculations to obtain the source 
spectral specification according to COLIPA (Ref. 73). In the COLIPA 
table, the source spectral specification is described in terms of 
cumulative erythemal effectiveness by successive wavebands. The 
erythemal effectiveness of each waveband is expressed as a percentage 
of the total erythemal effectiveness from 250 nm to 400 nm, or as the 
Percentage Relative Cumulative Erythemal Effectiveness (%RCEE). 
According to the COLIPA specifications and consistent with Sec.  
352.71, wavelengths below 290 nm should be excluded from any source by 
appropriate filters. Likewise, wavelengths above 400 nm should be 
limited as much as possible and are not included in the calculation of 
%RCEE. Because RCEE values are calculated as relative percentages, 
measuring the spectral irradiance in absolute energy units is not 
necessary. Relative units are sufficient. The spectral irradiance of 
the source is multiplied by the Commission International de L'Eclairage 
(CIE) (1998) standard skin erythemal action spectrum to obtain the 
erythemal effectiveness of the source. The spectral erythemal 
effectiveness values of the source spectrum are then integrated from 
250 nm to the various successive reference wavelength values shown in 
the COLIPA table in order to produce the cumulative erythemal 
effectiveness for each spectral waveband, and the total erythemal 
effectiveness is calculated up to 400 nm. Finally, the %RCEE is 
calculated at the reference waveband as the percentage ratio of the 
cumulative erythemal effectiveness in each of these wavebands to the 
total integrated value from 250 nm to 400 nm.
    Based on these calculations, the COLIPA table includes limits up to 
400 nm. In contrast, when FDA requested comments on this issue, we 
included a modified COLIPA table that includes limits up to 350 nm (65 
FR 36319 at 36321). However, the modified COLIPA table published by FDA 
was erroneous. FDA agrees with the comment (and COLIPA) that it is 
necessary to include all UV erythemal wavelengths (i.e., up to 400 nm) 
when standardizing solar simulator output. As argued by the comment, 
the erythemal contribution from long-wavelength UVA radiation (i.e., 
350 nm to 400 nm) can become important when a high SPF product is 
tested. However, FDA believes that the limits for the 290 to 350 
waveband should be changed from 93.5 to 99.0 percent to 93.5 to 98.5 
percent. This modification will address some of the errors in SPF that 
are attributed to the lack of match between the solar simulator and 
actual solar spectra. FDA invites comments on these proposed changes.
    FDA does not agree, at this time, with the comment's suggestion to 
further narrow the COLIPA standard to the spectral limits that it 
proposed. The comment based its suggestion on a theoretical argument 
and did not supply the complete emission spectra of the

[[Page 49098]]

four solar simulators used in its two referenced studies. There may be 
significant differences in the 290 to 350 nm range in these studies 
that can account for the reported differences in SPF test results. 
Further, FDA has concerns about the ability of currently used solar 
simulators to meet the comment's suggested spectral standard and 
invites comments on the changes suggested by the comment.
    FDA agrees with the comments that the COLIPA approach provides a 
more appropriate description for solar simulators. FDA's original 
proposal that solar simulators have a spectral power distribution 
``similar to sunlight at a zenith angle of 10[deg]'' is nonquantitative 
and may not be practical, considering the types of solar simulators 
that are generally available. Accordingly, FDA is proposing to revise 
the first part of Sec.  352.71 (proposed Sec.  352.70(b)) as follows:
    (b) Light source (solar simulator)--(1) Emission spectrum. A 
solar simulator used for determining the SPF of a sunscreen drug 
product should be filtered so that it provides a continuous emission 
spectrum from 290 to 400 nanometers (nm) with * * * the following 
percentage of erythema-effective radiation in each specified range 
of wavelengths:

                    Solar Simulator Emission Spectrum
------------------------------------------------------------------------
       Wavelength range (nm)           Percent erythemal  contribution
------------------------------------------------------------------------
< 290                                < 0.1
290-310                              46.0-67.0
290-320                              80.0-91.0
290-330                              86.5-95.0
290-340                              90.5-97.0
290-350                              93.5-98.5
290-400                              93.5-100.0
------------------------------------------------------------------------

    (Comment 33) Several comments suggested the following revisions to 
the light source (solar simulator) requirements in Sec.  352.71:
    <bullet> Delete the ``out of band'' specification that not more 
than 5 percent of a solar simulator's total energy output can be 
contributed by wavelengths longer than 400 nm.
    <bullet> In place of this 5 percent ``out of band'' limitation, 
allow a limit such as 1,250 to 1,500 watts/square meter (W/m\2\) on the 
total solar simulator irradiance delivered to the skin for all 
wavelengths.
    One comment provided data comparing solar simulators with and 
without a 50 percent neutral density filter to demonstrate that there 
is no measurable impact of heat load on the outcome of SPF testing 
(Ref. 13). The comment stated that thermal overload does not occur for 
COLIPA-compliant solar simulators operated at or below a total 
irradiance limit of 1,500 W/m\2\. The comments added that the ``out of 
band'' specification is not possible with existing solar simulators and 
new systems would need to be designed, tested, manufactured, and 
distributed to provide equipment capable of meeting this specification. 
The comments concluded that replacing the ``out of band'' specification 
with a limit would improve the testing of all products, including high 
SPF products.
    FDA believes that it is important to limit total energy delivered 
to the skin during the SPF test so that skin temperature does not reach 
a point that may compromise dose reciprocity. FDA concurs with the 
comments and is proposing to replace the ``out of band'' specification 
in Sec.  352.71 (proposed Sec.  352.70(b)) with a limit of 1,500 W/m\2\ 
on total solar simulator irradiance between 250 and 1,400 nm.
    (Comment 34) Two comments recommended that FDA change the solar 
simulator specification in Sec.  352.71 from ``good beam uniformity 
(within 10 percent) in the exposure plane'' to ``the delivered dose to 
the UV exposure sites be within 10 percent of the prescribed dose with 
good beam uniformity'' (without defining ``good beam uniformity''). The 
comments contended that although ``reasonable'' or ``good'' beam 
uniformity is desirable, beam uniformity within 10 percent is virtually 
impossible to measure or achieve for the vast majority of solar 
simulators.
    FDA agrees that ``dose'' accuracy is a critical variable and the 
delivered dose to the UV exposure sites should be within 10 percent of 
the prescribed dose. Because FDA considers quantification of ``good 
beam uniformity'' to be an important issue, it is keeping a 
specification for this parameter. However, FDA believes that a 
specification of 20 percent is more achievable than the proposed 10 
percent. Beam uniformity can be measured with broadband UV detectors 
that have been modified to provide a small input aperture to the 
detector. For example, for a single beam simulator with a subsite 
exposure area of approximately 1 cm\2\, an appropriate input aperture 
would be 0.25 cm\2\. Beam uniformity can then be checked by making a 
measurement in the center of each of the four quadrants of the exposure 
field. These readings should be within 20 percent of the peak reading. 
The same principle can be applied to larger exposure fields. 
Additionally, the average of these four readings should be within 10 
percent of the prescribed dose for a given exposure site. In addition, 
FDA is proposing a requirement that places a quantifiable limit of 20 
percent on time related fluctuations of the radiation emissions of the 
solar simulator.
    Accordingly, FDA is proposing to revise portions of Sec.  352.71 
(proposed Sec.  352.70(b)(2)) to read as follows:
    (2) Operation. A solar simulator should have no significant time 
related fluctuations (within 20 percent) in radiation emissions 
after an appropriate warmup time and good beam uniformity (within 20 
percent) in the exposure plane. The average delivered dose to the UV 
exposure site must be within 10 percent of the prescribed dose.
    (Comment 35) Several comments recommended that the last sentence of 
Sec.  352.71 be modified to include additional requirements for the 
periodic testing of solar simulators. The comments suggested that 
periodic measurements be made twice a year and that measurements be 
done after changes in the optical filtering components.
    FDA agrees with the comments and is proposing to revise the last 
part of Sec.  352.71 (proposed Sec.  352.70(b)(3)) to read as follows:
    (3) Periodic measurement. To ensure that the solar simulator 
delivers the appropriate spectrum of UV radiation, the emission 
spectrum of the solar simulator must be measured every 6 months with 
an appropriate and accurately calibrated spectroradiometer system 
(results should be traceable to the National Institute for Standards 
and Technology). In addition, the solar simulator must be 
recalibrated if there is any change in the lamp bulb or the optical 
filtering components (i.e., filters, mirrors, lenses, collimating 
devices, or focusing devices). Daily solar simulator radiation 
intensity should be monitored with a broadband radiometric device 
that is sensitive primarily to UV radiation. The broadband 
radiometric device should be calibrated using side by side 
comparison with the spectroradiometer at the time of the semiannual 
spectroradiometric measurement of the solar simulator. If a lamp 
must be replaced due to failure or aging during a phototest, 
broadband device readings consistent with those obtained for the 
original calibrated lamp will suffice until measurements can be 
performed with the spectroradiometer at the earliest possible 
opportunity.

L. Comments on the Design/Analysis of SPF Testing Procedure

    (Comment 36) Several comments contended that the series of seven 
exposure doses in Sec.  352.73(c) should be modified to eliminate the 
two doses placed symmetrically around the middle exposure. One comment 
provided data comparing the seven-exposure series against the five-
exposure series and concluded that the seven-exposure series did not 
increase the precision of the test (Ref. 66).

[[Page 49099]]

 Comments also argued that the seven-exposure series would require 
longer testing times, thus increasing exposure risk and discomfort to 
subjects, and that the five-exposure series is as accurate as the 
seven-exposure series even at high SPF values.
    FDA discussed its rationale for seven versus five exposure doses in 
the TFM (58 FR 28194 at 28269 to 28272). FDA sought an exposure format 
that would provide better accuracy and precision to SPF measurements, 
particularly at higher SPF values. FDA reasoned that the seven-exposure 
series in Sec.  352.73(c), with two additional exposures symmetrically 
placed around the middle exposure of the geometric series, would 
increase precision and eliminate possible overestimation of the true 
SPF value of a product with a high SPF.
    FDA has evaluated the data and other information submitted by the 
comments and agrees they demonstrate that the additional two exposure 
doses do not make the test more precise. Therefore, FDA is proposing to 
modify Sec.  352.73(c) (proposed Sec.  352.70(d)(3)) as follows:
    * * * Administer a series of five UV radiation doses expressed 
as J/m\2\-eff (adjusted to the erythema action spectrum calculated 
according to paragraph (d)(1) of this section) to the subsites 
within each test site on a subject using an accurately calibrated 
solar simulator. The five UV doses will be a geometric series as 
described in paragraph (d)(2) of this section, where the middle 
exposure represents the expected SPF. For products with an expected 
SPF less than 8, use exposures that are the product of the initial 
unprotected MED times 0.64X, 0.80X, 1.00X, 1.25X, and 1.56X, where X 
equals the expected SPF of the test product. For products with an 
expected SPF between 8 and 15, use exposures that are the initial 
unprotected MED times 0.69X, 0.83X, 1.00X, 1.20X, and 1.44X, where X 
equals the expected SPF of the test product. For products with an 
expected SPF greater that 15, use exposures that are the initial 
unprotected MED times 0.76X, 0.87X, 1.00X, 1.15X, and 1.32X, where X 
equals the expected SPF of the test product. * * *
    (Comment 37) Several comments suggested changes to the number of 
subjects per test panel in Sec.  352.72(g). One comment suggested 
deletion of the phrase ``with the number fixed in advance by the 
investigator.'' The comment reasoned that if the first 20 subjects 
provided data that can be evaluated, risk to human subjects could be 
curtailed by not impaneling another 5 subjects. Other comments 
recommended using 10 to 20 subjects, arguing that the criterion for 
accuracy should not be the number of subjects, but the relative 
deviation of individual SPF measurements. One comment used absorbance 
instead of the SPF value to calculate the number of subjects required 
for high SPF products and proposed a binomial test method to reduce the 
number of subjects (see section III.I, comment 24 of this document). 
Another comment stated that the 20 of 25 subject limitation may be an 
issue for products with high SPF values due to the high variability in 
the responses obtained and suggested that the number of subjects be 
increased when evaluating sunscreen products with high SPF values.
    As discussed in section III.I, comment 24 of this document, the 
binomial test method deserves further investigation and may prove to be 
a reasonable approach as additional data and experience become 
available. In addition, based on the current SPF test method, FDA 
agrees with the comment recommending deletion of the requirement to fix 
the number of subjects per panel in advance. This requirement is 
unnecessary because the panel is limited to a range of 20 to 25 
subjects (under current Sec.  352.72(g)). Thus, if 20 subjects produce 
valid data in accordance with proposed Sec.  352.70(c)(9), then it 
would be unnecessary to test additional subjects. In addition, some 
subjects may not produce valid data in accordance with proposed Sec.  
352.70(c)(9) (e.g., no erythema produced), requiring testing of 
additional subjects (not exceeding 25 subjects). FDA agrees that the 
number of subjects should be based on error about the mean SPF, but 
disagrees that the minimum number of subjects can be lowered to 10. As 
described later in this comment, FDA has reevaluated the proposed 
minimum number of subjects based on error about the mean SPF.
    FDA agrees with one comment that more subjects are needed when 
testing products with high SPF values. FDA believes that a minimum 
sample size of 20 subjects is adequate for products with an expected 
SPF value of 30 or less. However, current data and experience with 
products having SPF values over 30 are not sufficient to determine an 
appropriate sample size. Therefore, to account for increased 
variability in SPF values for sunscreens with SPF values over 30, FDA 
proposes to increase the sample size to at least 25 subjects. FDA 
invites data demonstrating an appropriate panel size for sunscreens 
with SPF values over 30. At this time, FDA is proposing to revise Sec.  
352.72(g) (proposed Sec.  352.70(c)(7)) as follows:
    (7) Number of subjects--(i) For products with an expected SPF 
value under 30. A test panel shall consist of 20 to 25 subjects with 
at least 20 subjects who produce valid data for analysis. Data are 
valid unless rejected in accordance with paragraph (c)(9) of this 
section. If more than 5 subjects are rejected based on paragraph 
(c)(9) of this section, the panel is disqualified, and a new panel 
must be created.
    (ii) For products with an expected SPF of 30 or over. A test 
panel shall consist of 25 to 30 subjects with at least 25 subjects 
who produce valid data for analysis. Data are valid unless rejected 
in accordance with paragraph (c)(9) of this section. If more than 5 
subjects are rejected based on paragraph (c)(9) of this section, the 
panel is disqualified, and a new panel must be created.
    In the 1978 advance notice of proposed rulemaking (ANPRM), the 
Panel recommended that studies enroll at least 20 subjects, adding that 
``the standard error shall not exceed <plus-minus> 5 percent of the 
mean'' (43 FR 38206 at 38261). Following publication of the ANPRM, FDA 
held a public meeting on January 26, 1988 (52 FR 33598 at 33600 to 
33601). During that meeting, attendees argued the following four points 
related to the number of subjects:
    1. Test panels should consist of at least 20 subjects.
    2. The size of the test panel should be fixed in advance.
    3. The limitation that the standard error should be less than 
<plus-minus> 5 percent should not apply.
    4. The testing procedures should make it clear that the addition of 
subjects to the test panel to achieve the desired minimum is acceptable 
under specific conditions (58 FR 28194 at 28267).
In the 1993 TFM, FDA based Sec.  352.72(g) on these comments and the 
Panel's recommendation.
    The calculations of the sample size and confidence interval in 
Sec.  352.72(g) are based on the assumption that there is a normal 
distribution about the mean (i.e., a bell curve). Based on this 
assumption, the t-test is used for statistical analysis. Based on the 
t-test, FDA calculated that a panel of 20 subjects should result in an 
acceptable error about the mean. However, in some cases, a panel of 10 
subjects would probably result in an error about the mean that is 
unacceptably large. There is inherently higher variability in testing 
and, consequently, larger error about the mean for products with high 
SPF values. Therefore, FDA believes a greater number of subjects is 
necessary when testing products with high SPF values. FDA believes a 
panel of 25 to 30 subjects should result in an acceptable error about 
the mean for products with high SPF values. FDA invites additional data 
demonstrating adequate numbers of subjects, especially for products 
with high SPF values.
    (Comment 38) One comment stated that one factor affecting the SPF 
of a

[[Page 49100]]

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

[[Page 49101]]

Panel's review of data found that numerous investigators have obtained 
more reproducible results by spreading a product using a finger cot 
than by spreading with a glass or plastic rod (43 FR 38206 at 38261). 
FDA agrees with the comment that some formulations may be chemically 
incompatible with latex finger cots, but there are finger cots composed 
of other materials that should be compatible with these sunscreens. 
Therefore, to increase reproducibility in sunscreen application, FDA is 
proposing to revise the application requirement in Sec.  352.72(e) 
(proposed Sec.  352.70(c)(5)) to read as follows:
    * * * Use a finger cot compatible with the sunscreen to spread 
the product as evenly as possible. Pretreat the finger cot by 
saturating with the sunscreen and then wiping off material before 
application. Pretreatment is meant to ensure that sunscreen is 
applied at the correct density of 2 mg/cm\2\.
FDA urges manufacturers of sunscreen drug products to investigate the 
extent of variability in the SPF test that may be caused by various 
applicators.
    (Comment 41) One comment addressed illumination at the test site in 
Sec.  352.72(h) and recommended that a level of at least 1,000 lux be 
used. The comment contended that 450 to 550 lux is too low to provide 
adequate illumination for reading erythema.
    As discussed in the TFM, the Panel recommended an incandescent or 
warm fluorescent illumination source but did not specify a required 
illumination level (58 FR 28194 at 28269). In the TFM, FDA agreed with 
the Panel about the illumination source. FDA also proposed that the 
illumination level be 450 to 550 lux. The comment did not provide any 
data to support its contention that 1,000 lux is the appropriate 
illumination level. Thus, FDA is not revising the lux range in Sec.  
352.72(h) (proposed Sec.  352.70(c)(8)) at this time. FDA invites data 
and information on levels of illumination currently used to evaluate 
MED responses in SPF testing laboratories and will consider adequately 
supported alternatives.
    (Comment 42) One comment stated that the third sentence in Sec.  
352.73(b) should be modified to read: ``* * * wherein each exposure 
dose is 25 percent greater than the previous exposure dose to maintain 
the same relative uncertainty * * *.'' The comment explained that 
defining the exposure dose in terms of ``time'' is incorrect.
    FDA discussed the Panel's definition of dose in terms of time 
intervals in comment 84 of the TFM (58 FR 28194 at 28256 to 28257). FDA 
stated that it is more accurate to express dose as the ``erythema-
effective exposure,'' in units that define the total amount of 
erythema-effective energy applied to the testing subsite (i.e., as J/
m\2\). FDA discussed replacing ``exposure time interval'' with 
``erythema-effective exposure (dose),'' but inadvertently used 
``exposure time interval'' instead of ``dose'' in Sec.  352.73(b). FDA 
agrees that Sec.  352.73(b) (proposed Sec.  352.70(d)(2)) should be 
modified and is amending this section as the comment suggested.
    (Comment 43) Several comments suggested an alternative statistical 
procedure for calculating product SPF values and PCD in current Sec.  
352.73(d). The comments argued that the procedure described in the FM 
would result in significant lowering of SPF values. The comments 
advocated clinical equivalency testing (i.e., using a lower one-sided 
95 percent confidence interval or a one-sided t test, with a delta of 5 
percent). The comments noted that an upper and lower bound equivalency 
procedure with a delta of 20 percent would be an appropriate procedure. 
The comments added that SPF is not a precise value, but rather a valid 
estimate of product performance. Another comment suggested using the 
mean of the results to find the actual number and then round-off 
(either up or down) to the nearest whole number.
    FDA is not proposing to modify the calculation of product SPF 
values and PCD in Sec.  352.73(d) (proposed Sec.  352.70(d)(4)) at this 
time. The distinct advantage of the t-test is that it provides a simple 
computational procedure for a statistical test that makes inferences 
about the population. The SPF is determined to be the largest whole 
number that is excluded by a lower one-sided 95 percent confidence 
interval. Simply finding a mean value, as one comment suggested, is not 
adequate because such a value does not provide information about the 
validity of the test (e.g., standard deviation) that should be taken 
into consideration.
    FDA's evaluation of the equivalency testing approach for 
calculating SPF values indicates the method is less stringent than the 
FM method. The proposed equivalency test is essentially testing the 
following hypothesis:
H<INF>0</INF>: micro <= 0.95L versus H<INF>a</INF>: micro > 0.95L
where: H<INF>0</INF> = null hypothesis
H<INF>a</INF> = alternative hypothesis
micro = population mean
L = confidence limit
FDA acknowledges that the equivalency test may be a valid method for 
determining SPF. In many cases, the same SPF would be determined for a 
sunscreen using either the equivalency test or the FM method. However, 
in some cases, a higher SPF would be determined for a sunscreen using 
the equivalency test than would be determined using the FM method. By 
contrast, a higher SPF would never be determined for a sunscreen using 
the FM method than would be determined using the equivalency test. 
Thus, the FM method results in a more conservative SPF value than the 
equivalency test. FDA believes it is in the best interest of public 
health to label sunscreens with the more conservative SPF value. If FDA 
adopted the equivalency test after over 30 years of using the FM 
method, consumers may, in some cases, overestimate the protection 
provided by a sunscreen based on a higher SPF number resulting from the 
equivalency test.

M. General Comments on UVA Testing Procedure

    (Comment 44) Many comments discussed UVA radiation action spectra 
and skin damage (erythema, photocarcinogenesis, DNA damage, 
photosensitivity reactions, photoaging, mutagenicity, and 
immunosuppression). Some comments described various types of solar-
induced skin damage and the wavelengths contributing to the specific 
biological events. Some comments stated that UVA II radiation (320 to 
340 nm) is much more damaging than UVA I radiation (340 to 400 nm).
    Other comments stated that there is presently no convincing 
evidence that the action spectra for damage from UV radiation have been 
clearly defined. One comment stated that until the separate dangers and 
risks of each portion of the UVB and UVA radiation action spectra are 
precisely and scientifically identified and quantified, FDA should 
consider the entire UVA radiation range as having significant 
biological risk. Another comment stated that protection against all UVA 
radiation wavelengths would seem to be both desirable and prudent 
considering the present state of our knowledge.
    FDA agrees that the action spectra for various harmful effects on 
human skin from chronic UVA radiation have not been clearly defined and 
that it may be misleading to associate damage with any specific action 
spectrum based upon current knowledge. Information provided by comments 
suggests a relatively greater role for UVA radiation than UVB radiation 
in long-term sun damage even though there is little consensus about the 
amount of UVA radiation protection required. Therefore, FDA is 
proposing UVA radiation test methods that assess protection throughout 
the UVA spectrum (see section III.N, comment 45 of this document).

[[Page 49102]]

N. Comments on UVA Testing Procedure Design and Testing Criteria

    (Comment 45) FDA is proposing that both an in vitro and an in vivo 
test be conducted to determine UVA radiation protection. The proposed 
in vitro test is the ratio of long wavelength UVA absorbance (UVA I) to 
total UV absorbance (i.e., UVB + UVA). The proposed in vivo test is the 
PPD test, which is similar to the SPF test except the endpoint is 
pigment darkening rather than erythema. FDA is proposing that UVA 
labeling consist of a UVA rating reflecting both the in vitro and in 
vivo test results. The rating will be the lowest ``high'' protection, 
then the sunscreen would be labeled as providing ``medium'' UVA 
protection.
    FDA is proposing these UVA testing requirements based on many 
comments submitted in response to the TFM that contained data and 
information on possible test methods (and combinations or modifications 
of these methods). The comments discussed the following in vivo and in 
vitro test procedures:
    <bullet> IPD,
    <bullet> PPD,
    <bullet> PFA,
    <bullet> Photosensitivity methods,
    <bullet> UVA radiation protection percent,
    <bullet> Diffey/Robson method and modifications of that method,
    <bullet> Standards Association of Australia,
    <bullet> Diffuse reflectance method,
    <bullet> Skin\2\ method, and
    <bullet> Psoralen photoadduct method.
On May 12, 1994, FDA held a public meeting to discuss these UVA 
radiation testing procedures (Ref. 77).
    One comment suggested using either or both PPD and erythema skin 
responses to measure the UVA radiation protection effectiveness of OTC 
sunscreen drug products. The comment maintained that these two test 
methods have the following similarities:
    <bullet> Same UVA radiation source,
    <bullet> Same dose range, and
    <bullet> Similar post exposure time lags for observation.
The only difference is in the skin types used, thus giving a variable 
balance in PPD and erythema responses. The comment added that such a 
combination of methods has the following advantages:
    <bullet> Reproducibility and stability,
    <bullet> Relevance,
    <bullet> Persistence of skin response through 1 to 24 hours,
    <bullet> Independence of source flux and accuracy,
    <bullet> Utilization for static as well as for water resistance 
photoprotective predictions, and
    <bullet> Practicability, convenience, and safety.
    Stating that there is currently no convincing evidence that the 
action spectrum for UVA radiation damage has been clearly defined, 
another comment suggested that protection from UV radiation be measured 
using two factors based on the degree of attenuation of UV radiation 
across the full spectrum. One factor, the SPF value, is erythemally 
weighted and gives an indication of the power of protection provided by 
the product. The second factor should take into account the shape of 
the transmittance curve measured by either in vivo or in vitro means. 
The comment stated that it is potentially dangerous to associate skin 
damage with any single action spectrum (e.g., IPD, PPD, or PFA). The 
comment argued that all of these indicators are wavelength-specific and 
protection from specific wavelengths does not mean protection from 
damage. The comment added that if only the erythema action spectrum is 
used, it virtually ignores the effects of wavelengths over 320 nm. The 
comment contended that using an SPF value augmented by the shape of the 
transmission curve would give consumers the information necessary to 
make an effective and safe judgment about the protection provided by a 
sunscreen drug product. For example, the comment noted that a product 
with a high SPF and a uniform high level of attenuation across the 
spectrum (i.e., equal attenuation at all UVB and UVA wavelengths) will 
provide the most protection. The comment added that, at a later date, 
if sufficient evidence becomes available to describe a credible UVA 
radiation damage spectrum, this combined system could be used by 
convoluting the attenuation curve with the action spectrum curve.
    One comment proposed a modification (``critical wavelength'') of 
the Diffey/Robson test method (Refs. 78 and 79). The comment noted 
that, when people are outdoors, they are not exposed to only UVB or UVA 
radiation but are exposed to solar UV radiation, which always contains 
both. In addition, biological effects against which people may wish to 
be protected are caused by all wavelengths in the solar UV radiation 
spectrum. The comment contended that investigators should not be 
exposing subjects to sources of radiation with spectra that have no 
practical application and using irrelevant biological effects as 
endpoints (e.g., IPD).
    The comment proposed to assess the UVA radiation protection 
potential of an OTC sunscreen drug product by first 
spectrophotometrically determining the absorption spectrum of the 
product throughout the UV radiation range. Then, one calculates the 
wavelength value [lgr]<INF>c</INF> (the ``critical wavelength''), where 
the area under the absorption spectrum from 290 nm to [lgr]<INF>c</INF> 
is 90 percent of the integral of the absorption spectrum from 290 to 
400 nm, and uses a five-point scale to classify products as follows:

      Table 3.--Broad Spectrum Rating Based on Critical Wavelength
------------------------------------------------------------------------
      Critical Wavelength (nm)              Broad Spectrum Rating
------------------------------------------------------------------------
[lgr]c < 325                         0
325 <= [lgr]c < 335                  1
335 <= [lgr]c < 350                  2
350 <= [lgr]c < 370                  3
370 < [lgr]c                         4
------------------------------------------------------------------------

The comment concluded that this test method makes no underlying 
assumptions about the form of action spectra for either acute or 
chronic photobiological damage. Because the efficiency of UV radiation 
to induce a given photobiological endpoint tends to decrease with 
increasing wavelength, the method utilizes wavelength intervals for 
classifying the ``broad spectrum'' rating, which increases in an 
approximately logarithmic manner.
    One comment submitted a protocol for the ``critical wavelength'' 
(CW) modification of the Diffey/Robson method for classifying the 
relative degree of UVA radiation protection of sunscreen drug products 
(Ref. 80). The comment addressed product photostability by pre-
irradiation of the sunscreen product with a UV radiation dose 
corresponding to one-third the labeled SPF value. The comment reported 
recommendations based on the results of a round-robin evaluation of the 
proposed CW method involving six laboratories using four test sunscreen 
formulations with various substrates. The comment concluded that the CW 
method is a convenient, reproducible in vitro method for measuring the 
uniformity of sunscreen absorbance spectra across the UV radiation 
spectrum to classify products into broad UVA radiation protection 
categories.
    In response to the June 8, 2000, reopening of the administrative 
record for the rulemaking for OTC sunscreen drug products (65 FR 
36319), FDA received additional comments on UVA radiation testing 
methods. While all comments supported some type of testing to 
differentiate the UVA radiation protection potential of sunscreen 
products, they disagreed

[[Page 49103]]

about the use of in vivo versus in vitro testing methods.
    Comments from a group of sunscreen product manufacturers contended 
that an in vivo test method, such as PPD or PFA, best describes the 
photoprotective characteristics of a sunscreen drug product. These 
comments stated that an in vivo method measures the actual effect of 
UVA radiation on the skin and estimates the expected product 
performance under actual use conditions.
    One comment presented test data that suggested PPD and PFA values 
are comparable (Ref. 6). The comment stated that an advantage of the 
PFA method is that it allows inclusion of skin type I, whereas the PPD 
test is conducted on darker skin types (II and III). However, the 
comment added that the PPD test has been accepted since 1996 by the 
JCIA for the assessment of UVA radiation protection efficacy of 
sunscreen products.
    One comment contended that the PPD test should be used for the 
following reasons:
    <bullet> It requires a relatively low dose of UV radiation.
    <bullet> The reaction is stabilized in 2 to 4 hours.
    <bullet> The test subject is left with no mark of irradiation and 
receives little or no injury.
    <bullet> The test can be conducted with high precision.
Another comment stated that PPD values demonstrate the same correlative 
benefits that exist for SPF values and, therefore, do not give false 
impressions of magnitude. Another comment stated that products with the 
same SPF can have different levels of UVA radiation protection. Thus, 
PFA or PPD is not redundant with the SPF value.
    Comments from other sunscreen product manufacturers opposed an in 
vivo method to determine UVA radiation protection. One of these 
comments stated that in vivo tests expose human subjects to doses of 
UVA radiation with unknown human health consequences. The comment added 
that because exposure to UVA radiation alone is never encountered in 
nature, full spectrum light is most relevant for product evaluations. 
This comment contended that PFA values are redundant with SPF testing 
because of an overemphasis on short wavelength UVA radiation (UVA II), 
and PFA values give a false impression of the magnitude of absorption 
differences. For example, the comment stated that two products with PFA 
values of 5 and 10 may attenuate 80 and 90 percent of UVA radiation, 
respectively. Thus, the real difference is small. The comment further 
stated that the proposed in vivo methods modeled after the SPF test 
generate protection factors that are protocol dependent and of 
indeterminate clinical relevance, as none are surrogates for long term 
concerns like cancer and photoaging. Another comment added that the PPD 
and PFA tests do not adequately assess the breadth of UVA radiation 
protection and that the biologic effects of full spectrum UV radiation 
differ from the effects of isolated wavelengths.
    Several comments recommended using an in vitro method, and most 
considered the CW method as appropriate. One comment stated that CW 
allows for broad spectrum activity regardless of SPF so that, if 
consumers use a low SPF product, they will at least have the option of 
choosing one that provides a wide breadth of activity. Another comment 
stated that CW provides a simple, reproducible, and adaptable method 
that can account for sunscreen photostability and insure UVA radiation 
protection that is both commensurate with and independent from the SPF 
value. Another comment added that CW accounts for proportionality 
because, in order for a sunscreen to maintain a given CW, protection 
from both long and short UVA radiation wavelengths must increase as UVB 
radiation protection increases.
    Several comments stated that the CW threshold should be 370 nm for 
a ``broad spectrum'' claim on a sunscreen. Other comments recommended a 
threshold of 360 nm. One comment stated that if FDA were to arbitrarily 
select a standard higher than 360 nm, it would cause a major 
reformulation effort within the industry, higher prices to consumers, 
and a shortage of ``broad spectrum'' products in the OTC marketplace. 
The comments did not provide data to support the use of a specific 
threshold number in relation to the prevention of specific 
photobiological effects.
    Other comments opposed the CW method as not appropriate. One 
comment, which favored an in vivo method, stated that the CW method, 
based on an arbitrary, nonbiological criterion, fails to provide an 
accurate measure of the protection efficacy of a sunscreen product. 
This comment provided data to demonstrate that a significant failure of 
the CW method is its inherent inability to differentiate UVA radiation 
protection levels of sunscreen products relative to biological 
endpoints (e.g., premature skin aging) (Ref. 23). A second comment 
agreed with this assertion, while a third comment expressed concern 
that CW measurements may be misleading because two products can have 
the same CW with very different UVA radiation absorbance curves and, 
thus, provide different protection for consumers.
    Some comments stated that a combination of methods may be 
appropriate for assessing the complete UVA radiation protection 
potential of a sunscreen product. One comment suggested combining 
either the PPD or PFA method with an in vitro method for a meaningful 
and rigorous test of both the magnitude and breadth of the biological 
protection (i.e., the level of protection and the UVB and UVA 
wavelengths that are protected against) provided by a sunscreen 
product. Another comment stated that complete assessment of a sunscreen 
product's UVA radiation protection must include both of the following:
    <bullet> An in vitro measurement of the absorbance above 360 nm 
(i.e., demonstrate adequate breadth of absorbance), and
    <bullet> An in vivo measurement of the quantity of UV radiation 
protection (i.e., demonstrate adequate magnitude of absorbance).
Other comments stated that a combination of the in vivo SPF method and 
the in vitro CW method provide a complete description of a product's 
inherent photoprotective characteristics with the SPF value describing 
the amplitude of protection and CW providing a reliable measure of the 
product's spectral absorption capability.
    One comment suggested a UVA/UVB radiation proportionality scheme. 
The comment referred to FDA's previous discussions about UVA/UVB 
radiation proportionality (Refs. 11 and 81) and a recommendation from 
the AAD that ``an increase in SPF of a sunscreen must be accompanied by 
a proportional increase in the UVA protection value'' (Ref. 82). The 
comment added that the proportional contribution to sunburn from solar 
UVB and UVA radiation is 80 to 20 (4 to 1), respectively, and that this 
relationship gives the minimum UVA radiation attenuation needed to 
provide proportional UVA/UVB radiation protection for any SPF value. 
The comment concluded that a minimum UVA protection value of 2 should 
be required even at low SPF levels with proportionately higher UVA 
protection values for higher SPF values.
    One comment suggested that the UVA protection value should be 
determined with an in vivo method while CW is appropriate to determine 
spectral broadness. Another comment stated that CW accounts for 
proportionality because both long and short UVA radiation protection 
must increase as UVB radiation protection increases in

[[Page 49104]]

order for a sunscreen to maintain a given CW. Another comment provided 
data (Ref. 23) for two products with the same CW value but different 
SPF values and concluded that the product with the higher SPF value did 
not provide greater UVA protection. Other comments stated that there is 
no biological basis for establishing strict UVB/UVA radiation 
proportionality and that the establishment of this kind of ratio is 
arbitrary.
    The AAD (Ref. 83) referenced an international consensus conference 
on UVA radiation protection of sunscreens and recommended the 
following:
    1. Both an in vitro and an in vivo testing method must be used to 
measure UVA radiation protection.
    2. CW is the preferred method of in vitro testing for a broad 
spectrum claim (with a threshold for this claim at 370 nm).
    3. CW must be combined with an in vivo method such as either PPD or 
PFA.
    4. There must be a minimum four-fold increase in PPD or PFA value 
in the presence of a sunscreen (relative to the absence of sunscreen).
    In the Federal Registers of May 12, 1993 (58 FR 28194 at 28248 to 
28250), September 16, 1996 (61 FR at 48645 at 48652), and October 22, 
1998 (63 FR 56584 at 56587), FDA discussed photosensitivity and 
erythemal UVA radiation testing procedures for OTC sunscreen drug 
products. Criteria discussed for UVA radiation claims included the 
requirement for an absorption spectrum extending to 360 nm or above, 
plus the demonstration of meaningful UVA radiation protection via 
testing procedures. IPD/PPD, PFA, photosensitivity, and in vitro UVA 
radiation testing methodologies were also discussed at a public meeting 
on May 12, 1994 (Ref. 77).
    The selection of an appropriate UVA radiation testing procedure for 
OTC sunscreen drug products has been difficult for a number of reasons. 
The scientific community does not agree on which testing procedure is 
most appropriate. For example, Cole discusses the virtues and 
shortcomings of a variety of in vivo and in vitro test methods (Ref. 
84). In addition, each test procedure has its own distinct advantages 
and disadvantages, as discussed in the following paragraphs.
    FDA believes the IPD test method provides an appropriate endpoint 
for determining UVA protection, because pigment darkening is caused 
primarily by UVA (and not UVB) radiation. This method is advantageous 
over other suggested test methods in that it uses low doses of 
radiation and, therefore, exposes subjects to less risk than other 
suggested test methods. On the other hand, the IPD response has not 
been shown to represent a direct or surrogate endpoint for biological 
damage. The IPD response is also extremely difficult to read.
    The PFA test method uses endpoints that reflect actual damage that 
can occur to normal skin as a result of UVA radiation exposure (i.e., 
erythema or tanning). The erythema action spectra may be similar to the 
action spectra of known chronic skin damage (e.g., solar elastosis) 
(Ref. 85). However, the PFA test method may not determine protection 
against skin melanoma or other skin damage thought to be caused by 
chronic exposure to UVA radiation (Refs. 29 and 86).
    The CW method can assess how broadly a sunscreen can absorb across 
the UV radiation spectrum, but provides no information concerning 
product performance after interaction with human skin. While in vivo 
methods to assess UVA radiation protection may have possible sources of 
variability similar to the SPF test (e.g., test product application, 
differences in light sources, etc.), in vitro methods also possess 
possible sources of inherent variability (e.g., test product 
evaporation time, substrate orientation, instrumentation, use with 
color change sunscreen formulations, etc.).
    In general, FDA would prefer the standard UVA radiation test method 
to have a clinically significant endpoint. After reviewing the data and 
information provided by the comments, FDA agrees that there is no 
convincing evidence that the action spectra for all possible types of 
UVA-induced damage have been clearly defined and that no one method is 
without disadvantages. At this time, FDA agrees with the recommendation 
provided by the AAD and other comments that an in vivo method is 
appropriate in combination with an in vitro testing method to assess 
the UVA radiation protection.
    Because the action spectrum for UVA-induced skin damage is not 
clearly known, FDA considers it necessary to measure both the magnitude 
and breadth of UVA protection. The magnitude of UVA absorbance is a 
measure of how well a product absorbs UVA radiation. The magnitude of 
UVA absorbance is best measured by an in vivo method. An in vivo method 
measures a biological response on the skin (e.g., pigment darkening) 
and, therefore, correlates to actual use conditions. The breadth of the 
UVA absorbance is a measure of how broadly a product absorbs UVA 
radiation across the entire UVA radiation spectrum. Breadth can best be 
determined by appropriate in vitro test methods.
    At this time, FDA believes a combination of existing in vivo and in 
vitro UVA radiation testing methods addresses the inadequacies of 
either method when used alone and provides a more complete UVA 
radiation attenuation profile for use in labeling OTC sunscreen drug 
products. Requiring the two test methods will ensure that both the 
magnitude and breadth of UVA protection is determined. As discussed 
later in this response, the proposed UVA labeling will reflect the 
results of both tests and, therefore, will reflect magnitude and 
breadth of UVA protection. FDA believes that the methods and labeling 
currently being proposed provide the best assurance for consumers to 
receive adequate protection across the entire UVA radiation spectrum.
    FDA is proposing the PPD method as the in vivo part of the test to 
determine UVA radiation protection of a sunscreen drug product. This 
test assesses UVA radiation attenuation by measuring UVA radiation-
induced tanning, a direct effect induced by UVA exposure. The PPD test 
is relatively easy to perform and relies on a stable, biological 
endpoint that can describe the magnitude of UVA radiation protection of 
sunscreen products. It is similar to the SPF determination as it is a 
ratio of a minimum pigmenting dose (MPD) on unprotected skin to that on 
protected skin. The endpoint is the PPD response, which is the stable, 
lasting residual part of the immediate pigment darkening or blue gray 
pigment that develops immediately during exposure to UVA radiation and 
quickly fades at the end of exposure. It provides consumers with a 
means to specifically compare the amount of UVA radiation protection 
between products and select an appropriate sunscreen product. The PPD 
test has been shown to produce reliable, reproducible data and to 
distinguish between varying levels of UVA radiation attenuation (Refs. 
87 and 88). It has been shown to detect protection provided by ``broad 
spectrum'' sunscreens against both short and long wavelength UVA 
radiation. The endpoint is a stable skin response that is linearly 
dependent on the amount of UVA radiation that enters the viable 
epidermis. FDA also agrees with one comment that a UVA protection value 
of 2 should define the lowest end of acceptable PPD test results 
relative to the consideration of acceptable UVA radiation claims (see 
proposed Sec.  352.72(d)(3)). FDA considers it desirable to incorporate 
measurable UVA radiation protection at all SPF

[[Page 49105]]

levels for products that claim to protect against both UVB and UVA 
radiation.
    As one comment noted, the PPD test has been accepted and validated 
as the JCIA method since 1996 (Ref. 23) and is one of two in vivo 
methods suggested by the AAD (Ref. 83). Although data provided to FDA 
indicate that the PPD and PFA in vivo tests provide comparable results 
(Ref. 6), the PPD test provides the practical benefit of a shorter post 
exposure reading time. FDA agrees with the comments that PPD values are 
not redundant with SPF values as sunscreen drug products with the same 
SPF value can have very different levels of UVA radiation protection as 
measured by the PPD test. Accordingly, FDA is including the PPD method 
in proposed Sec.  352.72 as part of the testing to determine the UVA 
radiation protection potential of an OTC sunscreen drug product.
    FDA agrees with the comments that suggested modifications to the 
PPD method (i.e., the JCIA standard). Therefore, FDA is proposing 
modifications to the PPD method. One group of sunscreen manufacturers 
suggested that the previously validated ``high SPF'' padimate O/
oxybenzone standard sunscreen under consideration by FDA (see section 
III.J, comment 27 of this document) should also be used as the control 
formulation for in vivo UVA radiation testing (Ref. 6). Based upon data 
provided by the comment, FDA is proposing the referenced ``high SPF'' 
padimate O/oxybenzone standard sunscreen for use as the standard 
sunscreen in the in vivo UVA radiation test in proposed Sec.  352.72. 
FDA invites comment on the suitability of this formulation as a UVA 
radiation test standard, on alternative standards, and on preparation/
assay/validation data for any suggested alternatives.
    FDA also notes that the JCIA light source specification states that 
``UV rays shorter than 320 nm shall be excluded through the use of an 
appropriate filter.'' FDA considers it important to set an exact limit 
for this specification and is proposing that optical radiation from the 
light source between 250 and 320 nm be less than 0.1 percent of the 
optical radiation between 320 and 400 nm. Also, the observation of 
pigment darkening in the JCIA standard is at 2 to 4 hours post 
irradiation. FDA notes that it appears the pigment darkening is most 
stable about 3 hours or more after post irradiation (Ref. 89), and is 
thus proposing that this observation occur at 3 to 24 hours post 
irradiation. This time range provides increased flexibility in the test 
method without sacrificing accuracy.
    As the current state of technology allows for an instrumental 
measurement/quantification of skin color via spectral reflectance, FDA 
also invites comments regarding colorimetry as a method of evaluating 
pigment darkening. By avoiding the subjectivity of detecting pigment 
change by the human eye, the reproducibility of the PPD method should 
increase. Colorimetry could likewise be used in SPF testing if 
submitted data demonstrated increased accuracy and reproducibility of 
colorimetry over visual inspection.
    As the PPD method is similar, overall, to the SPF method, FDA is 
also proposing that the directions for the PPD method be similar to 
those for the SPF test for determining MPDs on unprotected skin, 
individual UVA protection factors, test product UVA protection factors, 
and PCDs. Further, as discussed in section III.L, comment 37 of this 
document regarding the SPF test, FDA is proposing that a PPD test panel 
consist of 20 subjects who produce valid data, similar to the panel 
size for sunscreens having SPF values less than 30.
    FDA is concerned, however, that use of the PPD method alone could 
result in some products yielding high UVA radiation protection factors 
without having broad absorbance throughout the UVA radiation spectrum 
due to strong absorbance in the UVA II region. In other words, a 
sunscreen could absorb high levels of UVA II but very little UVA I and 
achieve a high UVA rating under the PPD method. Therefore, FDA is 
proposing that an in vitro method be used (to assess the breadth of 
absorbance across the UV radiation spectrum) in conjunction with the 
PPD method to more completely assess a product's UVA radiation 
protection.
    FDA disagrees with the comments that the CW method should be used 
as the in vitro testing method and proposes using a modification of the 
Boots adaptation of the Diffey/Robson method (Ref. 90). Both the CW and 
the in vitro test proposed by FDA measure the absorbance of a sunscreen 
product using in vitro spectrophotometry. However, FDA's proposed 
method calculates the ratio of long wavelength UVA absorbance (UVA I) 
to total UV absorbance to provide a measure of the relative UVA I 
radiation protection provided by a sunscreen drug product. FDA believes 
that this test, in combination with the PPD method, provides a better 
assessment of overall UVA radiation protection.
    The Boots adaptation of the Diffey/Robson test method assesses the 
absorbance of a sunscreen drug product over the UV radiation range from 
290 to 400 nm by measuring the quantity of UV radiation transmitted 
through surgical tape (Transpore\TM\ tape) before and after application 
of a sunscreen drug product. The test product (2 mg/cm\2\) is applied 
to the textured surface of the Transpore\TM\ tape. A xenon arc solar 
simulator is used as the UV radiation source. Transmitted UV energy is 
collected and measured at 5 nm intervals over the UVB and UVA radiation 
range, which provides a profile of UV radiation absorbance. 
Mathematical calculations are made separately of the areas under the 
UVB and UVA radiation parts of the curve. The ratio below the curve is 
determined as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.004

As the ratio increases, the degree of UVA radiation protection 
increases.
    FDA is concerned that this method, as described in previous 
paragraphs, determines the ratio of the entire UVA to UVB radiation 
spectra. Therefore, a sunscreen drug product that absorbs strongly in 
the UVA II radiation area, but does not absorb strongly in the UVA I 
radiation area, might still have an adequate ratio of UVA to UVB 
radiation protection to fulfill the test requirements, but would not 
provide adequate protection in the UVA radiation region where 
absorbance is lacking. FDA believes that this deficiency can be 
corrected by revising the calculations to take into account the ratio 
of UVA I and/or UVA II individually to UV radiation. Some comments were 
concerned that UVA II radiation may be the portion of the UVA spectrum 
most represented in the PPD test. FDA agrees that the UVA II spectrum 
is well represented by the PPD test. Therefore, to provide for a more 
balanced method, FDA is proposing that the in vitro component of the 
monograph UVA radiation method only need provide a measure of the 
relative UVA I radiation absorbance.
    FDA is proposing to measure UVA I radiation absorbance relative to 
UV radiation absorbance rather than relative to UVB radiation 
absorbance. If UVA I radiation protection is measured relative to UVB 
radiation, then the test does not account for UVA II radiation 
protection. FDA's proposed modification of the Boots adaptation of the 
Diffey/Robson method accounts for the entire UV radiation spectrum. 
Further, the ratio of UVA I radiation to UV radiation has a convenient 
finite range and allows for the use of defined values to categorize UVA 
radiation protection.

[[Page 49106]]

    FDA is proposing a modified Boots adaptation of the Diffey/Robson 
method instead of the CW method. The CW determination only reveals the 
shortest wavelength at which 90 percent of total UVB and UVA radiation 
is absorbed by a sunscreen. Thus, this method does not directly reveal 
the breadth of UV absorption, whereas the modified Boots adaptation of 
the Diffey/Robson method does. This point is demonstrated by data 
submitted by one comment (Ref. 23). The comment submitted the UV 
absorption spectra of two sunscreens having nearly identical SPF and CW 
values. The absorption spectra demonstrate that two sunscreens with 
similar CWs can have significantly different UVA absorption spectra. 
The ratios of UVA I/UV radiation absorbance for these formulations were 
markedly different: 0.85 and 0.52. Thus, FDA believes that the ratio 
method generally allows for better discrimination of products with 
these types of absorbance spectra.
    FDA is also concerned that the activity of the sunscreen 
ingredients in the product may be diminished by exposure to UV 
radiation, i.e., that the sunscreen ingredients in the product might 
not be photostable. Therefore, in order to account for changes in 
absorbance as a function of UV radiation exposure, FDA is proposing to 
revise the Boots modification of the Diffey/Robson method by 
incorporating pre-irradiation dose (PID), which is defined as follows 
(see section III.O, comment 46 of this document):
PID (J/m\2\-eff) = SPF * 1 MED * 2/3,
where 1 MED = 200 J/m\2\-eff
    FDA is also concerned about specifying the use of Transpore\TM\ 
tape (used in the original Diffey/Robson method), an artificial 
substrate that mimics the surface topography of human stratum corneum. 
When sunscreen emulsions are applied to Transpore\TM\ tape (Refs. 7 and 
77), the emulsions may experience a micro environment that differs from 
human skin in several key aspects, including the following:
    <bullet> Lack of electrolyte effect,
    <bullet> Lack of moisturization/humectant plasticization of the 
substrate,
    <bullet> Differences in pH and wetting effects, and
    <bullet> Different degrees of sunscreen penetration and retention 
by the substrate.
The fourth aspect, different degrees of penetration and retention, is 
especially significant for oil soluble sunscreen ingredients. One 
comment suggested that either roughened quartz plates or a synthetic 
collagen should be used as the substrate, noting that COLIPA has used 
quartz plates for its in vitro studies and that quartz plates are 
reusable and inert. Diffey et al. have also used quartz plates as the 
substrate for the CW method (Ref. 91). Accordingly, at this time, FDA 
is proposing that roughened quartz plates be specified as the substrate 
in the in vitro portion of its UVA test method. FDA requests comment 
regarding the suitability and availability of quartz plates and other 
possible substrates.
    FDA agrees with one comment that there is no biological basis for 
establishing a strict UVA to UVB ratio and that such a ratio would be 
arbitrary. FDA is proposing that data from the proposed in vitro and in 
vivo tests be integrated into a single labeled UVA rating. Similar to 
suggestions from some comments, FDA is proposing the categories of low, 
medium, high, and highest (corresponding to one, two, three, and four 
``stars,'' respectively). Based on test data submitted by one comment 
(Ref. 6), FDA is proposing that test results for each in vitro or in 
vivo test be categorized as follows:

                     Table 4.--UVA Rating Categories
------------------------------------------------------------------------
     Category              In vitro result            In vivo result
------------------------------------------------------------------------
Low                 0.2 to 0.39                   2 to under 4
Medium              0.40 to 0.69                  4 to under 8
High                0.70 to 0.95                  8 to under 12
Highest             greater than 0.95             12 or more
------------------------------------------------------------------------

FDA is aware of the difficulty for current sunscreen formulations to 
meet the ``highest'' category and believes that allowing such a 
category will foster additional research and development in this area.
    FDA is proposing that the overall UVA radiation category for use in 
product labeling be the lowest category determined by the in vitro and 
in vivo test results. For example, if the test results for a sunscreen 
indicate an in vitro category of ``low'' and an in vivo category of 
``high'' (or the reverse), then the overall UVA classification on the 
sunscreen product label would be ``low'' (i.e., the lower of the two 
categories). FDA believes that using the lower of the two categories 
takes into account the following situations:
    <bullet> A product that has a high in vivo rating because of 
substantial UVA II absorbance, but a low in vitro rating because of 
poor UVA I absorbance, or
    <bullet> A product that has a low in vivo rating because of poor 
UVA II absorbance, but a high in vitro rating because of substantial 
UVA I absorbance.
FDA is further proposing that each overall UVA radiation category 
correspond to and (on product labeling) be used with the following 
number of graphical representations in the form of solid ``stars'':

            Table 5.--Graphical UVA Rating Based on Category
------------------------------------------------------------------------
             Combined Category Rating                    Star Rating
------------------------------------------------------------------------
Low                                                 [starf][star14][star
                                                     14][star14]
Medium                                              [starf][starf][star1
                                                     4][star14]
High                                                [starf][starf][starf
                                                     ][star14]
Highest                                             [starf][starf][starf
                                                     ][starf]
------------------------------------------------------------------------

FDA invites comment on these proposed test methods/criteria and 
encourages the continued development of biologically meaningful test 
procedures.

O. Comments on the Photostability of Sunscreen Drug Products

    (Comment 46) Various comments discussed the photostability of OTC 
sunscreen formulations and active ingredients. One comment stated that 
photostability is important because many sunscreen ingredient 
combinations with avobenzone are not believed to be photostable. This 
comment stressed that a sunscreen drug product should maintain most of 
its UVA and UVB radiation protection throughout the expected consumer 
time in the sun. Another comment stated that the integrity of a 
sunscreen drug product depends on its degree of photostability and that 
a photostable product should maintain its protection over a wide range 
of UV radiation spectra.
    Some comments supported a standard method using pre-irradiation to 
account for photostability of sunscreen ingredients. One comment 
favoring the CW method for measuring UVA radiation protection submitted 
a formula to establish a pre-irradiation dose to assess photostability 
(Ref. 7). This comment stated that pre-irradiation provides a 
reasonable estimate of what a consumer might expect when using the 
product and stressed that the dose should be both full spectrum (290 to 
400 nm) and sufficient to detect significant changes in CW as a 
function of UV radiation exposure. This comment considered its pre-
irradiation dose of solar-simulated UV radiation to be equivalent to 
about 1 1/2 hours of noonday sun or 3 hours of sun exposure in the 
early morning or late afternoon. One comment noted that avobenzone-
containing formulations can be photostabilized by the addition of 
suitable ingredients and supported a protocol developed by Sayre and 
Dowdy for measuring UVA radiation protection

[[Page 49107]]

following a measured exposure of the test formulation to solar 
radiation (290 to 400 nm) (Ref. 92).
    Another comment stressed the importance of a standard pre-
irradiation dose and included data suggesting that a ``UVB-only'' 
sunscreen product formulation, at high pre-irradiation doses, could 
qualify for UVA ``broad spectrum'' labeling by the CW method (Ref. 23). 
This comment concluded that pre-irradiation does not always account for 
photostability and appears to be very formulation specific.
    Another comment submitted an in vitro method for simultaneously 
predicting SPF and assessing photostability of sunscreen formulas (Ref. 
65). The comment stated that pre-irradiation with measured UV radiation 
doses has permitted more accurate in vitro estimates of SPF.
    FDA agrees that it is important to address the photostability for 
sunscreen drug product formulations. Unstable product formulations 
present the problem of degradation of product effectiveness during 
actual use. The assessment of overall protection provided by such 
formulations is difficult due to product effectiveness being heavily 
dependent on the UV radiation exposure dose. Sayre and Dowdy 
demonstrated, through a series of in vitro studies, how the UV 
radiation transmission of an avobenzone containing formula changes with 
UV radiation exposure and that most of the loss of protection occurred 
in the UVA radiation spectrum (Ref. 92).
    FDA is proposing to address photostability by adding a pre-
irradiation step to the in vitro test method for measuring UVA 
radiation protection (see section III.N, comment 45 of this document). 
As noted in the scientific literature, the choice of a pre irradiation 
dose is ``somewhat arbitrary, yet critical to the outcome of the test'' 
(Ref. 84). FDA received one comment with supporting data for a proposed 
pre-irradiation dose (Ref. 7). The comment suggested using a dose 
equivalent to the SPF times 2 J/cm\2\ multiplied by a factor of 2/3. 
The comment stated that 2 J/cm\2\ from a xenon arc solar simulator with 
1 millimeter (mm) WG-320 and 1 mm UG-5 filters was equivalent to one 
MED. Because all solar simulators used by the industry may not use this 
exact filter combination and the spectral transmittance of filters can 
vary from lot to lot, FDA is proposing to specify the pre-irradiation 
dose in terms of ``erythemal effective dose.'' The erythemal effective 
dose of a solar simulator can by calculated as described in proposed 
Sec.  352.70(d) by weighting the output spectrum of the solar simulator 
with the reference action spectrum for erythema as defined by CIE. A 
typical weighted value (J/m\2\-eff) for an MED in a Skin Type II 
individual is 200 J/m\2\-eff (Ref. 93). Thus, FDA is proposing to use 
the following formula to determine the required pre-irradiation dose:
PID (J/m\2\-eff) = SPF * 1 MED * 2/3
where 1 MED = 200 J/m\2\-eff
    In considering the selection of the appropriate pre-irradiation 
dose of solar-simulated UV radiation, FDA agrees that the maximum pre-
irradiation exposure would be a dose of UV radiation that equaled the 
SPF of the product times the MED. However, FDA believes that this 
calculated dose is probably greater than the dose that a sunscreen 
product would incur during typical consumer usage. Thus, the dose was 
reduced by a factor of one-third to represent a more reasonable 
exposure condition.

IV. FDA's Tentative Conclusions and Proposals

    FDA tentatively concludes that the FM for OTC sunscreen drug 
products should be amended to include the combinations of avobenzone 
with ensulizole and avobenzone with zinc oxide when used in the 
concentrations established for each ingredient in Sec.  352.10 (see 
section III.C, comment 7 of this document). However, before marketing 
may begin, the comment period for this proposal must end and FDA must 
publish another Federal Register notice setting forth our determination 
concerning interim marketing before publication of the final rule for 
OTC sunscreen drug products. FDA followed this procedure previously for 
avobenzone as a single active ingredient and in combination with some 
GRASE active ingredients other than ensulizole or zinc oxide (62 FR 
23350).
    FDA considers the UVA-related labeling in this proposal to 
supersede the labeling proposed in the TFM and its amendments of 
September 16, 1996, and October 22, 1998. While the prior proposed 
labeling can continue to be used until a FM is issued, FDA encourages 
manufacturers of OTC sunscreen drug products to voluntarily implement 
the UVA-related labeling changes as soon as possible after publication 
of this proposal, especially if product relabeling occurs in the normal 
course of business. We note, though, that any relabeling prior to 
issuance of the FM is subject to the possibility that FDA may change 
some of the labeling requirements as a result of comments filed in 
response to this proposal.
    Mandating warnings in an OTC drug monograph does not require a 
finding that any or all of the OTC drug products covered by the 
monograph actually caused an adverse event, and FDA does not so find. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
monographs and monograph rulemakings under which the affected drug 
products have been lawfully marketed. Rather, as a consumer protection 
agency, FDA has determined that warnings are necessary to ensure that 
these OTC drug products continue to be safe and effective for their 
labeled indications under ordinary conditions of use as those terms are 
defined in the act. This judgment balances the benefits of these drug 
products against their potential risks (see 21 CFR 330.10(a)).
    FDA's decision to act in this instance need not meet the standard 
of proof required to prevail in a private tort action (Glastetter v. 
Novartis Pharmaceuticals Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To 
mandate warnings, or take similar regulatory action, FDA need not show, 
nor do we allege, actual causation. For an expanded discussion of the 
case law supporting FDA's authority to require such warnings without 
evidence of actual causation, see Labeling of Diphenhydramine-
Containing Drug Products for Over-the-Counter Human Use, final rule (67 
FR 72555, December 6, 2002).

V. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule has a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act requires 
that agencies prepare a written statement of anticipated costs and 
benefits before proposing any rule that may result in an expenditure in 
any one year by State, local, and tribal governments, in the aggregate, 
or by the private sector, of

[[Page 49108]]

$100 million (adjusted annually for inflation).
    FDA believes that this proposed rule is consistent with the 
principles set out in the Executive Order 12866 and in these two 
statutes. The proposed rule is not a significant regulatory action as 
defined by the Executive order and, therefore, is not subject to review 
under the Executive order. Further, because this proposed rule is not 
expected to result in any 1-year expenditure that would exceed $100 
million adjusted for inflation, FDA need not prepare additional 
analyses under the Unfunded Mandates Reform Act. Because the rule may 
have a significant economic impact on a substantial number of small 
entities, this section of the preamble constitutes FDA's regulatory 
flexibility analysis.
    An analysis of the costs and benefits of this regulation, conducted 
under Executive Order 12866, was discussed in the FM (64 FR 27666 at 
27683 to 27686), which was later stayed (66 FR 67485). This analysis 
reflects the incremental costs of the revised or new requirements in 
this proposed amendment of the FM.

A. Background

    The purpose of this document is to amend the conditions under which 
OTC sunscreen drug products are generally recognized as safe and 
effective (GRASE) and not misbranded. This amendment addresses 
formulation, labeling, and testing requirements for both UVB and UVA 
radiation protection.
    Manufacturers would not need to reformulate their sunscreen 
products to comply with the proposed requirements. Manufacturers also 
would not need to retest their sunscreen products for UVB protection 
(i.e., they would not need to retest for SPF). The labeled SPF value 
determined from the SPF test in the FM would not likely change if a 
sunscreen product was retested using the modifications to the SPF test 
proposed in this document. In addition, manufacturers who have tested 
and labeled their sunscreen products as ``SPF 30+'' can relabel their 
products with the specific SPF value above 30 (but no greater than 50) 
without retesting.
    However, all manufacturers would incur some relabeling costs due to 
proposed revisions to both the PDP and the Drug Facts section of the 
product label. If manufacturers wish to label their sunscreen products 
as providing UVA protection, then manufacturers of those sunscreen 
products would also incur UVA testing costs. Because UVA testing is not 
required, some manufacturers will choose not to test for UVA protection 
and the labeling for those sunscreens will state, ``No UVA 
Protection.''

B. Number of Products Affected

    Estimating the number of products affected is difficult because we 
lack data on the number of products currently marketed. Our Drug 
Listing System currently does not have accurate information on the 
number of marketed OTC sunscreen products, especially the drug-cosmetic 
combination products. Proprietary databases that track retail sales of 
OTC drugs and other products do not distinguish cosmetics containing 
sunscreens from other cosmetic products and their surveys do not 
include many of the outlets where sunscreen products are sold. Based on 
earlier estimates (64 FR 27666 at 27684) and our knowledge of the 
industry, we assume there are about 3,000 OTC sunscreen drug products 
(different formulations, not including products that differ only by 
color), including drug-cosmetic combinations, and about 12,000 
individual stock keeping units (SKUs) (individual products, packages, 
and sizes). All 12,000 SKUs will need to be relabeled, but 
manufacturers can choose whether to test their sunscreen products for 
UVA protection. We assume that about 75 percent (2,250) of the 
sunscreen products would be tested for UVA protection. We request 
comment on the accuracy of this assumption.

C. Cost to Relabel

    The cost to relabel varies greatly depending on the printing method 
and number of colors used. The majority of sunscreen products are 
packaged in plastic bottles or tubes with the label printed directly on 
the container or applied as a decal or paper label during the packaging 
process. The proposed labeling requirements impact both the PDP and the 
Drug Facts section of the package and would be considered a major 
redesign.
    Frequent label redesigns are typical for OTC sunscreen products, 
with redesigns generally implemented every 1 to 2 years for a product. 
To the extent that a scheduled redesign coincides with the regulatory-
mandated relabeling, the impact on the manufacturer will be negligible.
    We used a model developed for FDA by the consulting firm RTI to 
derive an estimate of the cost to relabel sunscreen products (Ref. 94). 
The model was developed to estimate the cost of food labels. However, 
we believe that the graphic and design estimates from that study are an 
appropriate proxy for the costs that would be incurred by OTC sunscreen 
manufacturers. RTI estimated that graphic design and prepress and 
engraving costs would range from $1,970 to $13,800 per SKU depending on 
the type of packaging and printing method used. There would also be 
administrative costs to account for contracting costs and obtaining 
final approvals for the new labels. RTI estimated administrative costs 
to range from $360 to $880 depending on the size of the firm. For this 
analysis, we are assuming an average design price of $7,000 per SKU and 
average administrative costs of $600 per SKU.\1\ Therefore, the total 
relabeling cost per SKU would be $7,600 (i.e., $600 + $7,000).
    While all sunscreen SKUs would need to be relabeled to comply with 
the proposed rule, we estimate that the timing of the scheduled 
relabeling would coincide with the regulatory-mandated changes for 50 
percent of the SKUs (i.e., 6,000 SKUs). We estimate the total labeling 
cost of the proposed labeling changes for the SKUs with the coinciding 
scheduled redesign would be 50 percent of the administrative cost 
(i.e., $300). Therefore, the total one-time cost to industry for 
relabeling would be about $47.5 million (i.e., (6,000 x $7,600) + 
(6,000 x $300)).
---------------------------------------------------------------------------

    \1\ We did not select the midpoint of the ranges because of the 
large number of private label products that have lower design and 
administrative costs than branded goods.
---------------------------------------------------------------------------

D. Cost to Test or Retest Products for UVA Protection

    This proposed rule will result in testing costs for products that 
make UVA protection claims. The approximate costs are $2,200 for in 
vivo UVA testing and $200 for in vitro UVA testing. Based on the number 
of sunscreen products currently labeled as providing UVA protection, we 
estimate that 75 percent (2,250) of the sunscreen products will be 
tested according to the proposed UVA tests. Therefore, FDA estimates a 
one-time UVA testing cost of approximately $5.4 million (i.e., 2,250 x 
$2,400).

E. Total Incremental Costs

    The estimated total one-time incremental cost of this proposed rule 
is $53 million (i.e., $47.5 million + $5.4 million). The incremental 
cost for the UVA testing could be less should the rule become final 
because many manufacturers may voluntarily comply with the proposed 
rule when reformulating current products or marketing new products. 
Although the FM is not effective, manufacturers of sunscreen products 
comply with the

[[Page 49109]]

UVB (SPF) test in the FM for nearly all sunscreen products. Therefore, 
it is likely that manufacturers of sunscreen products will also 
voluntarily comply with the proposed UVA tests in this document.
    It should also be noted that sunscreen products that are already 
distributed by the effective date of the FM will not be required to be 
relabeled or retested in conformity with these FM conditions, unless 
these products are subsequently relabeled or repackaged after the 
effective date. Therefore, there is no one-time cost associated with 
disposing of sunscreens that are already on the market at the time of 
the rule's effective date.

F. Small Business Impact

    In the FM (64 FR 27666 at 27685), FDA estimated that 78 percent of 
the 180 domestic companies that manufacture OTC sunscreen products 
would be considered a small business (defined as fewer than 750 
employees). FDA cannot estimate with certainty the number of small 
firms that will need to test or retest their OTC sunscreen products to 
provide for UVA protection claims, but projects that approximately 75 
percent of all products may need to be tested for UVA protection. Costs 
will vary by firm, depending on the number of products requiring 
testing. The firm-specific impact may vary inversely with the volume of 
product sales, because per unit costs will be lower for products with 
high volume sales. Thus, the relative economic impact of product 
retesting may be greater for small firms than for large firms. Because 
the OTC drug industry is highly regulated, all firms are expected to 
have access to the necessary professional skills on staff or to have 
contractual arrangements to comply with the testing requirements of 
this rule.

G. Analysis of Alternatives

    FDA could have proposed only an in vivo or an in vitro test for 
UVA. FDA recognizes that requiring only the in vitro test would mean 
significantly less cost to manufacturers. However, the proposed in vivo 
test measures the magnitude of UVA protection. The proposed in vitro 
test measures the breadth of UVA protection. FDA believes it is 
important to conduct both tests to determine the magnitude and breadth 
of UVA protection.
    FDA plans to grant an extended compliance period when this proposed 
rule is finalized. Given the seasonal nature of these products, FDA is 
concerned that some manufacturers may not have sufficient time to 
incorporate labeling changes without disrupting their production 
schedules. By providing an additional 6 months to implement the 
changes, compliance costs to manufacturers will be reduced.
    In addition, FDA reduced compliance costs when we chose to stay the 
labeling requirements for the FM (64 FR 27666), sparing industry the 
cost of an additional regulatory-mandated label change. In the stay, 
FDA estimated a cost savings of $1.5 million to industry. It should be 
noted that labeling costs were significantly less in the FM than in 
this proposed rule primarily because we assumed in the FM that the 
majority of relabeling would coinside with scheduled voluntary label 
redesigns at no additional cost. Manufacturers were also able to avoid 
or postpone incurring an additional industry total of $5 million when 
FDA chose to stay the UVB testing requirements of the FM.
    FDA invites public comment regarding any substantial or significant 
economic impact that this proposed rule would have on manufacturers of 
OTC sunscreen drug products. Comments regarding the impact of this 
rulemaking on such manufacturers should be accompanied by appropriate 
documentation. FDA is providing a period of 90 days from the date of 
publication of this proposed rule in the Federal Register for comments 
to be developed and submitted. FDA will evaluate any comments and 
supporting data that are received and will reassess the economic impact 
of this rulemaking in the final rule.

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements in this 
document are not subject to review by the Office of Management and 
Budget because they do not constitute a ``collection of information'' 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). 
Rather, the proposed labeling statements are a ``public disclosure of 
information originally supplied by the Federal Government to the 
recipient for the purpose of disclosure to the public'' (5 CFR 
1320.3(c)(2)).

VII. Environmental Impact

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

VIII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized as proposed, would have a preemptive 
effect on State law. Section 4(a) of the Executive order requires 
agencies to ``construe * * * a Federal statute to preempt State law 
only where the statute contains an express preemption provision or 
there is some other clear evidence that the Congress intended 
preemption of State law, or where the exercise of State authority 
conflicts with the exercise of Federal authority under the Federal 
statute.'' Section 751 of the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 379r) is an express preemption provision. Section 
751(a) of the act (21 U.S.C. 379r(a)) provides that ``no State or 
political subdivision of a State may establish or continue in effect 
any requirement--* * * (1) that relates to the regulation of a drug 
that is not subject to the requirements of section 503(b)(1) or 
503(f)(1)(A); and (2) that is different from or in addition to, or that 
is otherwise not identical with, a requirement under this Act, the 
Poison Prevention Packaging Act of 1970 (15 U.S.C. 1471 et seq.), or 
the Fair Packaging and Labeling Act (15 U.S.C. 1451 et seq.).'' 
Currently, this provision operates to preempt States from imposing 
requirements related to the regulation of nonprescription drug 
products. Section 751(b) through (e) of the act outlines the scope of 
the express preemption provision, the exemption procedures, and the 
exceptions to the provision.
    This proposed rule, if finalized as proposed, would amend the 
labeling and include new UVA testing for OTC sunscreen drug products. 
Any final rule would have a preemptive effect in that it would preclude 
States from issuing requirements related to the labeling and testing of 
OTC sunscreen drug products that are different from or in addition to, 
or not otherwise identical with a requirement in the final rule. This 
preemptive effect is consistent with what Congress set forth in section 
751 of the act. Section 751(a) of the act displaces both State 
legislative requirements and State common law duties. We also note that 
even where the express preemption provision in section 751(a) of the 
act is not applicable, implied preemption may arise (see Geier v. 
American Honda Co., 529 US 861 (2000)).
    FDA believes that the preemptive effect of the proposed rule, if 
finalized as proposed, would be consistent with Executive Order 13132. 
Section 4(e) of the Executive order provides that ``when an agency 
proposes to act through adjudication or rulemaking to preempt State 
law, the agency shall provide all

[[Page 49110]]

affected State and local officials notice and an opportunity for 
appropriate participation in the proceedings.'' FDA is providing an 
opportunity for State and local officials to comment on this 
rulemaking.

IX. Request for Comments

    In the Federal Register of January 10, 2005 (70 FR 1721), FDA 
announced the availability of a final guidance for industry entitled 
``Labeling for Topically Applied Cosmetic Products Containing Alpha 
Hydroxy Acids as Ingredients.'' The purpose of this guidance is 
twofold:
    <bullet> To educate consumers about the potential for increased 
skin sensitivity to the sun from the topical use of cosmetics 
containing alpha hydroxy acids (AHAs) as ingredients.
    <bullet> To educate manufacturers to help ensure that their 
labeling for cosmetic products containing AHAs as ingredients is not 
false or misleading.
    As discussed in the guidance, AHAs may increase skin sensitivity to 
UV radiation. Therefore, FDA recommends that manufacturers of cosmetic 
products containing AHAs include the following warning:
    Sunburn Alert: This product contains an alpha hydroxy acid (AHA) 
that may increase your skin's sensitivity to the sun and 
particularly the possibility of sunburn. Use a sunscreen and limit 
sun exposure while using this product and for a week afterwards.
    The guidance addresses only cosmetic products containing AHAs and 
does not address sunscreen drug products containing AHAs (i.e., drug-
cosmetic products). FDA is considering an additional warning or 
direction for sunscreen drug products containing AHAs similar to the 
warning for the cosmetic products described in the guidance for 
industry. However, FDA invites interested parties to submit comments 
and data regarding such labeling. In particular, FDA would like the 
following questions addressed:
    1. Does the body of existing evidence on AHAs and skin sensitivity 
warrant voluntary or mandatory labeling on OTC sunscreen drug products 
containing AHAs regarding possible risks of increased sun damage (e.g., 
sunburn)?
    2. If additional labeling is warranted, what information should be 
conveyed in the labeling and why?
Comments along with supporting data will help enable FDA to determine 
how and what information, if any, related to UV hypersensitivity due to 
AHAs in sunscreen-cosmetic products should be communicated to 
consumers. FDA will also be evaluating any comments or data submitted 
in response to the final guidance for cosmetic products containing 
AHAs.
    In addition to AHAs, FDA seeks comment on titanium dioxide and zinc 
oxide formulated in particle sizes as small as a few nanometers. FDA 
addressed issues concerning micronized sunscreen ingredients in the FM 
(64 FR 27666 at 27671 to 27672). The FM stated that FDA did not 
consider micronized titanium dioxide to be a new ingredient but rather 
a specific grade of the same active ingredient. The FM also stated that 
FDA was aware of concerns about potential risks associated with 
increased dermal penetration of such small particles. However, the FM 
explained that, based on the safety data submitted to FDA before 
publication of the FM, FDA was not aware of any evidence at that time 
demonstrating a safety concern from the use of micronized titanium 
dioxide in sunscreen products (64 FR 27666 at 27671 to 27672).
    FDA recognizes that more sunscreens containing small particle size 
titanium dioxide and zinc oxide ingredients enter the market each year. 
FDA is interested in receiving comments and data about these sunscreen 
ingredients and products that contain these ingredients, their safety 
and effectiveness, and how they should be regulated. FDA received a 
citizen petition shortly before publication of this document that, 
among other things, raises these issues. FDA is currently evaluating 
the citizen petition, which is filed as CP17 in Docket No. 1978N-0038. 
FDA encourages other parties to submit additional data or information 
on the safety and effectiveness of sunscreen ingredients formulated in 
particle sizes as small as a few nanometers.
    On April 14, 2006, FDA announced in the Federal Register that we 
were planning a public meeting on FDA-regulated products containing 
nanotechnology materials (71 FR 19523). As explained in the notice, the 
purpose of the meeting was to help FDA further its understanding of 
developments in nanotechnology materials that pertain to FDA-regulated 
products. The meeting was held on October 10, 2006, and FDA has 
received comments from interested members of the public which have been 
filed in the docket for this public meeting (Docket No. 2006N- 0107). 
Some of these comments concern sunscreen ingredients formulated with 
nanotechnology materials. FDA will file any comments concerning 
sunscreen ingredients formulated in nanometer particle sizes received 
in response to this proposed rule in the docket for this rulemaking and 
the citizen petition (Docket No. 1978N-0038) and the docket for the 
nanotechnology meeting.

X. Proposed Effective and Compliance Dates

    FDA is proposing that any final rule that may issue based on this 
proposal become effective 18 months after its date of publication in 
the Federal Register. The compliance date for products with annual 
sales less than $25,000 would be 24 months after publication of the 
final rule in the Federal Register.

XI. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) under Docket No. 1978N-0038 and may be seen 
by interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Comment No. CP6.
    2. Comment Nos. CP8, C548, SUP22, and C555.
    3. Comment Nos. LET166 and LET169.
    4. Comment No. C538.
    5. Comment No. C576.
    6. Comment No. C565.
    7. Comment No. C581.
    8. Comment No. C567.
    9. Comment No. C515.
    10. Comment No. C597.
    11. Comment No. MM22.
    12. Comment No. MM21.
    13. Comment No. C573.
    14. Autier, P. et al., ``Sunscreen Use and Duration of Sun 
Exposure: a Double-blind, Randomized Trial,'' Journal of the 
National Cancer Institute, 91(15):1304-1309, 1999.
    15. Reynolds, K.D. et al., ``Predictors of Sun Exposure in 
Adolescents in a Southeastern U.S. Population,'' Journal of 
Adolescent Health, 19(6):409-415, 1996.
    16. Robinson, J.K., D.S. Rigel, and R.A. Amonette, ``Summertime 
Sun Protection Used by Adults for Their Children,'' Journal American 
Academy of Dermatology, 42(5):746-753, 2000.
    17. Gallagher, R.P. et al., ``Broad-spectrum Sunscreen Use and 
the Development of New Nevi in White Children: A Randomized 
Controlled Trial,'' Journal of the American Medical Association, 
283(22):2955-2960, 2000.
    18. Stender, I.M., J.L. Andersen, and H.C. Wulf, ``Sun Exposure 
and Sunscreen Use among Sunbathers in Denmark,'' Acta Dermato-
Venereologica, 76:31-33, 1996.
    19. Zitser, B.S. et al., ``A Survey of Sunbathing Practices on 
Three Connecticut State Beaches,'' Connecticut Medicine, 60(10):591-
594, 1996.
    20. Green, A. et al., ``Daily Sunscreen Application and 
Betacarotene Supplementation in Prevention of Basal-cell and 
Squamous-cell Carcinomas of the Skin: a Randomized Controlled 
Trial,'' The Lancet, 354:723-729, 1999.
    21. IARC Handbooks of Cancer Prevention Volume 5 Sunscreens, H. 
Vainio, ed., International Agency for Research on Cancer, Lyon, 
France, p. 62, 2001.
    22. Diffey, B.L. et al., ``In Vitro Assessment of the Broad-
spectrum Ultraviolet Protection of Sunscreen Products,'' Journal of 
the

[[Page 49111]]

American Academy of Dermatology, 43(6):1024-1035, 2000.
    23. Comment No. C572.
    24. Gasparro, F.P., ``Sunscreens, Skin Photobiology, and Skin 
Cancer: the Need for UVA Protection and Evaluation of Efficacy,'' 
Environmental Health Perspectives, 108 Suppl 1:71-78, 2000.
    25. Garland, C.F., F.C. Garland, and E.D. Gorham, ``Lack of 
Efficacy of Common Sunscreens in Melanoma Prevention'' in 
Epidemiology, Causes and Prevention of Skin Diseases, Grob, J.J. et 
al. eds., Blackwell Science Ltd., Malden, MA, pp. 151-159, 1997.
    26. Lowe, N.J. et al., ``Low Doses of Repetitive Ultraviolet A 
Induce Morphologic Changes in Human Skin,'' Journal of Investigative 
Dermatology, 105(6):739-743, 1995.
    27. Seite, S. et al., ``Effects of Repeated Suberythemal Doses 
of UVA in Human Skin,'' European Journal of Dermatology, 7:204-209, 
1997.
    28. Lavker, R.M. et al., ``Quantitative Assessment of Cumulative 
Damage from Repetitive Exposures to Suberythemogenic Doses of UVA in 
Human Skin,'' Photodermatology, Photoimmunology, and Photomedicine, 
62(2):348-352, 1995.
    29. Lavker, R.M. et al., ``Cumulative Effects from Repeated 
Exposures to Suberythemal Doses of UVB and UVA in Human Skin,'' 
Journal of the American Academy of Dermatology, 32(1):53-62, 1995.
    30. Elmets, C.A., A. Vargas, and C. Oresajo, ``Photoprotective 
Effects of Sunscreens in Cosmetics on Sunburn and Langerhans Cell 
Photodamage,'' Photodermatology, Photoimmunology, and Photomedicine, 
9(3):113-120, 1992.
    31. Lavker, R., and K. Kaidbey, ``The Spectral Dependence for 
UVA-induced Cumulative Damage in Human Skin,'' Journal of 
Investigative Dermatology, 108(1):17-21, 1997.
    32. Seite, S. et al., ``A Full-UV Spectrum Absorbing Daily Use 
Cream Protects Human Skin Against Biological Changes Occurring in 
Photoaging,'' Photodermatology, Photoimmunology, and Photomedicine, 
16(4):147-155, 2000.
    33. Boyd, A.S. et al., ``The Effects of Chronic Sunscreen Use on 
the Histologic Changes of Dermatoheliosis,'' Journal of the American 
Academy of Dermatology, 33(6):941-946, 1995.
    34. Comment No. CP15.
    35. Center for Disease Control and Prevention, ``Guidelines for 
School Programs To Prevent Skin Cancer'' in Morbidity and Mortality 
Weekly Report, 1-18, 2002.
    36. Ries, A.G. et al., ``The Annual Report to the Nation on the 
Status of Cancer, 1973-1997, with a Special Section on Colorectal 
Cancer,'' Cancer, 88(10):2398-2424, 2000.
    37. Cancer Facts and Figures 2007, American Cancer Society, 
Inc., 2007.
    38. Sun Safety Tips, The American Academy of Dermatology, 1999.
    39. Skin Cancer: Preventing America's Most Common Cancer 2001 
Choose Your Cover, Centers for Disease Control and Prevention, 2001.
    40. The Sun, UV, and You: A Guide to SunWise Behavior, 
Environmental Protection Agency, 1999.
    41. Sun Protection Facts to Help You Prevent Skin Cancer, 
American Cancer Society, 2000.
    42. What You Need to Know About Skin Cancer, National Cancer 
Institute, 1998.
    43. Committee on Environmental Health, American Academy of 
Pediatrics, ``Ultraviolet Light: A Hazard to Children,'' Pediatrics, 
104:328-333, 1999.
    44. Green, A. et al., ``Site Distribution of Cutaneous Melanoma 
in Queensland,'' International Journal of Cancer, 53:232-236, 1992.
    45. Franceschi, S. et al., ``Site Distribution of Different 
Types of Skin Cancer: New Aetiological Clues,'' International 
Journal of Cancer, 67:24-28, 1996.
    46. Raasch, B. et al., ``Body Site Specific Incidence of Basal 
and Squamous Cell Carcinoma in an Exposed Population, Townsville, 
Australia,'' Mutation Research, 422:101-106, 1998.
    47. Osterlind, A., K. Hou-Jensen, and O.M. Jensen, ``Incidence 
of Cutaneous Malignant Melanoma in Denmark 1978-1982. Anatomic Site 
Distribution, Histologic Types, and Comparison with Non-melanoma 
Skin Cancer,'' British Journal of Cancer, 58:385-391, 1988.
    48. Neale, R., G. Williams, and A. Green, ``Application Patterns 
Among Participants Randomized to Daily Sunscreen Use in a Skin 
Cancer Prevention Trial,'' Archives of Dermatology, 138:1319-1325, 
2002.
    49. Comment No. C584.
    50. Steinberg, C., and O. Larko, ``Sunscreen Application and its 
Importance for Sun Protection Factor,'' Archives of Dermatology, 
121:1400-1402, 1985.
    51. Stokes, R., and B. Diffey, ``How Well Are Sunscreen Users 
Protected?,'' Photodermatology, Photoimmunology, and Photomedicine, 
13:186-188, 1997.
    52. Sayre, R.M. et al., ``Product Application Technique Alters 
the Sun Protection Factor,'' Photodermatology, Photoimmunology, and 
Photomedicine, 8:222-224, 1991.
    53. Azurda, R.M. et al., ``Sunscreen Application Technique in 
Photosensitive Patients: a Quantitative Assessment and the Effect of 
Education,'' Photodermatology, Photoimmunology and Photomedicine, 
16:53-66, 2000.
    54. Bech-Thomsen, N., and H.C. Wulf, ``Sunbather's Application 
of Sunscreen is Probably Inadequate to Obtain Sun Protection Factor 
Assigned to the Preparation,'' Photodermatology, Photoimmunolology 
and Photomedicine, 9:242-244, 1992.
    55. Diffey, B., ``People Do Not Apply Enough Sunscreen for 
Protection,'' British Medical Journal, 313:942, 1996.
    56. Wright, M.W. et al., ``Mechanisms of Sunscreen Failure,'' 
Journal of the American Academy of Dermatology, 44:781-784, 2001.
    57. Rigel, D. et al., ``American Academy of Dermatology's 
Melanoma/Skin Cancer Detection and Prevention Month Press Release,'' 
April 25, 2001.
    58. The ABCs for Fun in the Sun Educational Pamphlet, The 
American Academy of Dermatology, 1999.
    59. Ultraviolet Index--What You Need to Know, The American 
Academy of Dermatology, 1996.
    60. Sun Basics-Skin Protection Made Simple for Everyone Under 
the Sun, American Cancer Society, Inc., 1999.
    61. Skin Protection Guide for Everyone Under the Sun. A Parents 
Guide to Sun Protection, American Cancer Society, Inc., 1999.
    62. Can Melanoma Be Prevented?, American Cancer Society, Inc., 
2001.
    63. Diffey, B., ``Has the Sun Protection Factor Had Its Day?,'' 
British Medical Journal, 320:176-177, 2000.
    64. Taylor, W.A., ``Double Sampling Plan'' in Guide to 
Acceptance Sampling, R. R. Donnelly & Sons, U.S.A., pp. 117-142, 
1992.
    65. Comment No. C574.
    66. Comment No. C405.
    67. Comment No. C404.
    68. Comment No. C111.
    69. Comment No. RPT7.
    70. Comment No. C442.
    71. Comment No. SUP29.
    72. Memorandum from W.H. DeCamp, FDA, to C. Ganley, FDA, July 7, 
2000.
    73. Comment No. CP12.
    74. Comment No. SUP33.
    75. Gabriel, K.L. et al., ``Sun Protection Factor Testing: 
Comparison of FDA and DIN Methods,'' Journal of Toxicology-Cutaneous 
and Ocular Toxicology, 6:357-370, 1987.
    76. Comment No. C491.
    77. Comment No. TR2.
    78. Diffey, B.L., ``A Method for Broad Spectrum Classification 
of Sunscreens,'' International Journal of Cosmetic Science, 16:47-
52, 1994.
    79. Diffey, B.L., and J. Robson, ``A New Substrate to Measure 
Sunscreen Protection Factors Throughout the Ultraviolet Spectrum,'' 
Journal of the Society of Cosmetic Chemists, 40:127-133, 1989.
    80. Comment No. RPT9.
    81. Comment No. LET170.
    82. Press Release: ``The Future of Sunscreen Labeling: 
Recommendations of the Consensus Conference on UVA Protection of 
Sunscreens Convened by the American Academy of Dermatology,'' New 
York, NY, April 26, 2000.
    83. Lim, H.W. et al., ``American Academy of Dermatology 
Consensus Conference on UVA Protection of Sunscreens: Summary and 
Recommendations,'' Journal of the American Academy of Dermatology, 
44:505-508, 2001.
    84. Cole, C., ``Sunscreen Protection in the Ultraviolet A 
Region: How to Measure Effectiveness,'' Photodermatology, 
Photoimmunology, and Photomedicine, 17:2-10, 2001.
    85. Comment No. C137.
    86. Setlow, R.B., et al., ``Wavelengths Effective in Induction 
of Malignant Melanoma,'' Proceedings of the American Academy of 
Science, U.S.A., 90:6666-6670, 1993.
    87. Moyal, D. et al., ``UVA Protection Efficacy of Sunscreens 
Can Be Determined by the Persistent Pigment Darkening (PPD) Method 
(Part 2),'' Photodermatology, Photoimmunology, and Photomedicine, 
16:250-255, 2000.
    88. Moyal, D. et al., ``Determination of UVA Protection Factors 
Using the Persistent Pigment Darkening (PPD) Method as the Endpoint 
(Part 1) Calibration of the Method,'' Photodermatology, 
Photoimmunology, and Photomedicine, 16:245-249, 2000.

[[Page 49112]]

    89. Chardon, A. et al., ``Persistent Pigment-Darkening Response 
as a Method for Evaluation of Ultraviolet A Protection Assays'' in 
Sunscreens: Development, Evaluation, and Regulatory Aspects, 2nd 
edition, Marcel Dekker, Inc., New York, NY, pp. 559-582, 1997.
    90. Comment No. TS3.
    91. Diffey, B.L. et al., ``Suncare Product Photostability: a Key 
Parameter for a More Realistic In Vitro Efficacy Evaluation,'' 
European Journal of Dermatology, 7:226-228, 1997.
    92. Sayre, R.M., and J. Dowdy, ``Photostability Testing of 
Avobenzone,'' Cosmetics and Toiletries, 114:85-86, 88, 90-91, 1999.
    93. Urbach, F., ``Man and Ultraviolet Radiation'' in Human 
Exposure to Ultraviolet Radiation: Risks and Regulations, Passchier, 
W.F. and Bosnjakovic, B.F.M. (eds.), Elsevier Science, New York, NY, 
pp. 3-6, 1987.
    94. RTI International, ``FDA Labeling Cost Model, Final 
Report,'' prepared by Mary Muth, Erica Gledhill, and Shawn Karns, 
RTI. Prepared for Amber Jessup, FDA Center for Food Safety and 
Applied Nutrition, Revised January 2003.

List of Subjects

21 CFR Part 347

    Labeling, Over-the-counter drugs.

21 CFR Part 352

    Labeling, Over-the-counter drugs, Incorporation by reference.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 347 and 352 be amended as follows:

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

    1. The authority citation for 21 CFR part 347 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    2. FDA is proposing to lift the stay of Sec.  347.20(d) as 
published at 68 FR 33362, June 4, 2003.

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

    3. The authority citation for 21 CFR part 352 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    4. FDA is proposing to lift the stay of 21 CFR part 352 as 
published at 68 FR 33362, June 4, 2003.
    5. Section 352.3 is amended by redesignating paragraphs (b) through 
(d) as (c) through (e), respectively; revising newly redesignated 
paragraphs (c) and (e); and adding new paragraph (b) to read as 
follows:


Sec.  352.3   Definitions.

* * * * *
    (b) Minimal pigmenting dose (MPD). The quantity of erythema-
effective energy (expressed as Joules per square meter) required to 
produce the first perceptible pigment darkening.
    (c) Product category designation (PCD). A labeling designation for 
sunscreen drug products to aid in selecting the type of product best 
suited to an individual's complexion (pigmentation) and desired 
response to ultraviolet (UV) radiation.
    (1) Low UVB sunburn protection product. A sunscreen product that 
provides a sunburn protection factor (SPF) value of 2 to under 15.
    (2) Medium UVB sunburn protection product. A sunscreen product that 
provides an SPF value of 15 to under 30.
    (3) High UVB sunburn protection product. A sunscreen product that 
provides an SPF value of 30 to 50.
    (4) Highest UVB sunburn protection product. A sunscreen product 
that provides an SPF value over 50.
* * * * *
    (e) Sunburn protection factor (SPF) value. The UV energy required 
to produce an MED on protected skin divided by the UV energy required 
to produce an MED on unprotected skin, which may also be defined by the 
following ratio: SPF value = MED (protected skin (PS))/MED (unprotected 
skin (US)), where MED(PS) is the minimal erythema dose for protected 
skin after application of 2 milligrams per square centimeter of the 
final formulation of the sunscreen product, and MED(US) is the minimal 
erythema dose for unprotected skin (i.e., skin to which no sunscreen 
product has been applied). In effect, the SPF value is the reciprocal 
of the effective transmission of the product viewed as a UV radiation 
filter.
    6. Section 352.20 is amended by revising paragraph (a)(2) to read 
as follows:


Sec.  352.20   Permitted combinations of active ingredients.

* * * * *
    (a) * * *
    (2) Avobenzone in Sec.  352.10(b) may be combined with one or more 
sunscreen active ingredients identified in Sec.  352.10(c), (e), (f), 
(i) through (l), (n), (o), (q), and (r) in a single product when used 
in the concentrations established for each ingredient in Sec.  352.10. 
The concentration of each active ingredient must be sufficient to 
contribute a minimum SPF of not less than 2 to the finished product. 
The finished product must have a minimum SPF of not less than the 
number of sunscreen active ingredients used in the combination 
multiplied by 2.
* * * * *
    7. Section 352.50 is revised to read as follows:


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

    (a) UVB sunburn protection designation--(1) For products with an 
SPF of 2 to under 15. The labeling states ``UVB SPF [insert tested SPF 
value of the product] low''.
    (2) For products with an SPF of 15 to under 30. The labeling states 
``UVB SPF [insert tested SPF value of the product] medium''.
    (3) For products with an SPF of 30 to 50. The labeling states ``UVB 
SPF [insert tested SPF value of the product] high''.
    (4) For products with an SPF over 50. The labeling states ``UVB SPF 
50 [select one of the following: `plus' or `+'] highest''. Any 
statement accompanying the marketed product that states a specific SPF 
value over 50 or similar language indicating a person can stay in the 
sun more than 50 times longer than without sunscreen will cause the 
product to be misbranded under section 502 of the Federal Food, Drug, 
and Cosmetic Act (the act) (21 U.S.C. 352).
    (b) UVA protection designation--(1) For products not providing UVA 
protection according to Sec.  352.73. The labeling states ``no UVA 
protection''.
    (i) The UVA protection designation shall appear on the principal 
display panel along with the UVB protection designation in an equally 
prominent manner that does not conflict with the UVB protection 
designation.
    (ii) The font size of the UVA protection designation shall be the 
same size as the UVB protection designation.
    (2) For products providing UVA protection according to Sec.  
352.73. The labeling states ``UVA [select one of the following in 
accordance with Sec.  352.73: `[starf][star14][star14][star14] Low,' 
`[starf][starf][star14][star14] Medium,' `[starf][starf][starf][star14] 
High,' or `[starf][starf][starf][starf] Highest']''.
    (i) The UVA protection designation shall appear on the principal 
display panel along with the UVB protection designation in an equally 
prominent manner that does not conflict with the UVB protection 
designation.
    (ii) The font size of the UVA protection designation shall be the 
same size as the UVB protection designation.
    (iii) All star borders and the color inside a solid star shall be 
the same while the color of ``empty'' stars must be lighter and 
distinctly different than solid stars. The color inside a solid star 
should be distinctly different than the background color.
    (iv) The stars are to be filled in starting with the first star on 
the left and

[[Page 49113]]

are to appear in a straight horizontal line.
    (c) Select one of the following: ``UV rays from the sun are made of 
UVB and UVA. It is important to protect against both UVB & UVA rays.'' 
or ``UV rays from the sun are made of UVB and UVA. It is important to 
protect against both UVB & UVA rays to prevent sunburn and other skin 
damage.''
    (d) For products that satisfy the water resistant sunscreen product 
testing procedures in Sec.  352.76. The labeling states (select one of 
the following: ``water,'' ``water/sweat,'' or ``water/perspiration'') 
``resistant.''
    (e) For products that satisfy the very water resistant sunscreen 
product testing procedures in Sec.  352.76. The labeling states 
``very'' (select one of the following: ``water,'' ``water/sweat,'' or 
``water/perspiration'') ``resistant.''
    8. Section 352.52 is amended by revising paragraphs (b), (c), (d), 
(e), the heading of paragraph (f), paragraphs (f)(1)(ii) through 
(f)(1)(vi) to read as follows:


Sec.  352.52   Labeling of sunscreen drug products.

* * * * *
    (b) Indications. The labeling of the product states, under the 
heading ``Uses,'' all of the phrases listed in paragraph (b)(1) of this 
section that are applicable to the product and may contain any of the 
additional phrases listed in paragraph (b)(2) of this section, as 
appropriate. Other truthful and nonmisleading statements, describing 
only the uses that have been established and listed in this paragraph 
(b), may also be used, as provided in Sec.  330.1(c)(2) of this 
chapter, subject to the provisions of section 502 of the act (21 U.S.C. 
352) relating to misbranding and the prohibition in section 301(d) of 
the act (21 U.S.C. 331(d)) against the introduction or delivery for 
introduction into interstate commerce of unapproved new drugs in 
violation of section 505(a) of the act (21 U.S.C. 355(a)).
    (1) For products containing any ingredient in Sec.  352.10. (i) For 
products with an SPF of 2 to under 15. The labeling states 
``[bullet]\1\ low UVB sunburn protection''.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

    (ii) For products with an SPF of 15 to under 30. The labeling 
states ``[bullet] medium UVB sunburn protection''.
    (iii) For products with an SPF of 30 to 50. The labeling states 
``[bullet] high UVB sunburn protection''.
    (iv) For products with an SPF over 50. The labeling states 
``[bullet] highest UVB sunburn protection''.
    (v) For products not providing UVA protection according to Sec.  
352.73. The labeling states ``[bullet] no UVA protection.''
    (vi) For products providing UVA protection according to Sec.  
352.73. The labeling states ``[bullet] [select one of the following in 
accordance with Sec.  352.73: `Low,' `medium,' `high,' or `highest'] 
UVA protection''.
    (vii) For products that satisfy the water resistant testing 
procedures identified in Sec.  352.76. The labeling states ``[bullet] 
retains SPF after 40 minutes of [select one or more of the following: 
`activity in the water,' `swimming,' `sweating,' `perspiring,' 
`swimming/sweating,' or `swimming/perspiring']''.
    (viii) For products that satisfy the very water resistant testing 
procedures identified in Sec.  352.76. The labeling states ``[bullet] 
retains SPF after 80 minutes of [select one or more of the following: 
`activity in the water,' `swimming,' `sweating,' `perspiring,' 
`swimming/sweating,' or `swimming/perspiring']''.
    (2) Additional indications. In addition to the indications provided 
in paragraph (b)(1) of this section, the following may be used for 
products containing any ingredient in Sec.  352.10:
    (i) For products with an SPF of 2 to under 15. Select one or both 
of the following: ``[Bullet] provides low protection against [select 
one of the following: `sunburn' or `sunburn and tanning']'' or 
``[bullet] for skin that sunburns minimally''.
    (ii) For products with an SPF of 15 to under 30. Select one or both 
of the following: ``[Bullet] provides medium protection against [select 
one of the following: `sunburn' or `sunburn and tanning']'' or 
``[bullet] for skin that sunburns moderately''.
    (iii) For products with an SPF of 30 to 50. Select one or both of 
the following: ``[Bullet] [select one of the following: `provides high' 
or `high'] protection against [select one of the following: `sunburn' 
or `sunburn and tanning']'' or ``[bullet] for skin highly sensitive to 
sunburn''.
    (iv) For products with an SPF over 50. Select one or both of the 
following: ``[Bullet] [select one of the following: `provides highest' 
or `highest'] protection against [select one of the following: 
`sunburn' or `sunburn and tanning']'' or ``[bullet] for skin extremely 
sensitive to sunburn''.
    (v) If the UVA descriptor in Sec.  352.52(b)(1)(vi) is the same as 
the SPF descriptor in Sec.  352.52(b)(1)(i) through (b)(1)(iv), then 
the statement in Sec.  352.52(b)(1)(i) through (b)(1)(iv) may be 
combined with the statement in Sec.  352.52(b)(1)(vi) as follows: 
``[Bullet] [select one of the following descriptors in accordance with 
Sec. Sec.  352.70 and 352.73: `low,' `medium,' `high,' or `highest'] 
UVB sunburn/UVA protection''.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings:''
    (1) The labeling states in bold type ``UV exposure from the sun 
increases the risk of skin cancer, premature skin aging, and other skin 
damage. It is important to decrease UV exposure by limiting time in the 
sun, wearing protective clothing, and using a sunscreen.''
    (2) The labeling states ``When using this product [bullet] keep out 
of eyes. Rinse with water to remove.''
    (3) The labeling states ``Stop use and ask a doctor if [bullet] 
skin rash occurs''.
    (d) Directions. The labeling of the product contains the following 
statements, as appropriate, under the heading ``Directions.'' More 
detailed directions applicable to a particular product formulation 
(e.g., cream, gel, lotion, oil, spray, etc.) may also be included.
    (1) For products containing any ingredient in Sec.  352.10. (i) The 
labeling states ``[bullet] apply [select one of the following: 
`liberally' or `generously'] [and, as an option: `and evenly'] [insert 
appropriate time interval, if a waiting period is needed] before sun 
exposure''.
    (ii) The labeling states ``[bullet] apply and reapply as directed 
to avoid lowering protection''.
    (iii) As an option, the labeling may state ``[bullet] apply to all 
skin exposed to the sun''.
    (iv) The labeling states ``[bullet] children under 6 months of age: 
ask a doctor''.
    (2) For products that satisfy the water resistant or very water 
resistant testing procedures identified in Sec.  352.76. The labeling 
states ``[bullet] reapply after [select one of the following: `40 
minutes of' or `80 minutes of' for products that satisfy either the 
water resistant or very water resistant test procedures in Sec.  
352.76, respectively] swimming or [select one or more of the following: 
`sweating' or `perspiring'] and after towel drying. Otherwise, reapply 
at least every 2 hours''.
    (3) For products that do not satisfy the water resistant or very 
water resistant testing procedures identified in Sec.  352.76. The 
labeling states ``[bullet] reapply at least every 2 hours and after 
towel drying, swimming, or [select one of the following: `sweating' or 
`perspiring']''.
    (e) Statement on product performance--(1) For products containing 
any ingredient identified in

[[Page 49114]]

Sec.  352.10. The following product category designation (PCD) labeling 
claims may be used under the heading ``Other information'' or anywhere 
outside of the ``Drug Facts'' box or enclosure and shall not be 
intermixed with the information required under Sec.  352.50(a).
    (i) For products with an SPF of 2 to under 15. The labeling states 
``low sunburn protection product''.
    (ii) For products with an SPF of 15 to under 30. The labeling 
states ``medium sunburn protection product''.
    (iii) For products with an SPF of 30 to 50. The labeling states 
``high sunburn protection product''.
    (iv) For products with an SPF over 50. The labeling states 
``highest sunburn protection product''.
    (2) For products containing any ingredient identified in Sec.  
352.10. The following labeling statement may be used under the heading 
``Other information'' or anywhere outside of the ``Drug Facts'' box or 
enclosure and shall not be intermixed with the information required 
under Sec.  352.50(a). The labeling states ``higher SPF products give 
more sun protection, but are not intended to extend the time spent in 
the sun''.
    (3) For products containing any ingredient identified in Sec.  
352.10 and that satisfy the requirements in Sec.  352.73 for a labeled 
UVA protection value. The following labeling statements may be used 
anywhere outside of the ``Drug Facts'' box or enclosure and shall not 
be intermixed with the information required under Sec.  352.50(a).
    (i) The labeling states ``broad spectrum sunscreen''.
    (ii) The labeling states ``provides [select one of the following: 
`UVA and UVB,' or `broad spectrum'] protection''.
    (iii) The labeling states ``protects from UVA and UVB [select one 
of the following: `rays' or `radiation']''.
    (iv) The labeling states ``[select one of the following: `absorbs' 
or `protects'] within the UVA spectrum''.
    (f) Products, including cosmetic-drug products, containing any 
ingredient identified in Sec.  352.10 labeled for use only on specific 
small areas of the face (e.g., lips, nose, ears, and/or around the 
eyes) and that meet the criteria established in Sec.  201.66(d)(10) of 
this chapter. * * *
    (1) * * *
* * * * *
    (ii) The indication required by Sec.  201.66(c)(4) of this chapter 
may be limited to the following: ``Use [in bold type] helps prevent 
sunburn.''
    (iii) The warnings required by Sec.  201.66(c)(5)(i) through 
(c)(5)(ix) of this chapter may be limited to the following: ``UV 
exposure from the sun increases the risk of skin cancer, premature skin 
aging, and other skin damage. It is important to decrease UV exposure 
by limiting time in the sun, wearing protective clothing, and using a 
sunscreen. [in bold type]'' ``[bullet] keep out of eyes'' ``[bullet] 
stop use if skin rash occurs.''
    (iv) The warning in Sec.  201.66(c)(5)(x) of this chapter may be 
limited to the following: ``Keep out of reach of children.''
    (v) For lip protectant products containing any ingredient 
identified in Sec.  352.10. The heading and the indication required by 
Sec.  201.66(c)(4) of this chapter may be limited to ``Use [in bold 
type] helps prevent sunburn and chapped lips''. The warnings required 
in paragraph (f)(1)(iii) of this section may be limited to the 
following: ``Stop use if skin rash occurs.'' The warning required in 
paragraph (f)(1)(iv) of this section may be omitted. The directions in 
paragraphs (d)(2) and (d)(3) of this section may be limited to the 
following: ``apply liberally and reapply at least every 2 hours for 
sunburn protection''.
    (vi) For lipsticks, lip products to prolong wear of lipstick, lip 
gloss, and lip balm containing any ingredient identified in Sec.  
352.10 and identified in Sec.  720.4(c)(7) of this chapter. The 
labeling is identical to that in paragraph (f)(1)(v) of this section 
except the heading and the indication required by Sec.  201.66(c)(4) of 
this chapter are limited to ``Use [in bold type] helps prevent 
sunburn''.
* * * * *
    9. Section 352.60 is amended by revising paragraphs (c) and (d) to 
read as follows:


Sec.  352.60   Labeling of permitted combinations of active 
ingredients.

* * * * *
    (c) Warnings. The labeling of the product states, under the heading 
``Warnings,'' the warning(s) for each ingredient in the combination, as 
established in the warnings section of the applicable OTC drug 
monographs, except that the warning for skin protectants in Sec.  
347.50(c)(3) of this chapter is not required for permitted combinations 
containing a sunscreen and a skin protectant identified in Sec.  
352.20(b). For products marketed as a lip protectant with sunscreen, 
Sec.  352.52(f)(1)(vi) applies.
    (d) Directions. The labeling of the product states, under the 
heading ``Directions,'' directions that conform to the directions 
established for each ingredient in the directions sections of the 
applicable OTC drug monographs, unless otherwise stated in this 
paragraph. When the time intervals or age limitations for 
administration of the individual ingredients differ, the directions for 
the combination product may not contain any dosage that exceeds those 
established for any individual ingredient in the applicable OTC drug 
monograph(s), and may not provide for use by any age group lower than 
the highest minimum age limit established for any individual 
ingredient. For permitted combinations containing a sunscreen and a 
skin protectant identified in Sec.  352.20(b), the directions for 
sunscreens in Sec.  352.52(d) must be used. For products marketed as a 
lip protectant with sunscreen, Sec.  352.52(f)(1)(vi) applies.
    10. Sections 352.70 through 352.73 are revised as follows:

Subpart D--Testing Procedures

Sec.
352.70 SPF testing procedure.
352.71 UVA in vitro testing procedure.
352.72 UVA in vivo testing procedure.
352.73 Determination of the labeled UVA protective value.
* * * * *


Sec.  352.70   SPF testing procedure.

    (a) Standard sunscreens--(1) Laboratory validation. A standard 
sunscreen shall be used concomitantly in the testing procedures for 
determining the SPF value of a sunscreen drug product to ensure the 
uniform evaluation of sunscreen drug products.
    (i) For products with an SPF of 2 to 15. The standard sunscreen 
shall be an 8-percent homosalate preparation with a mean SPF value of 
4.47 (standard deviation = 1.28). In order for the SPF determination of 
a test product to be considered valid, the SPF of the standard 
sunscreen must fall within the standard deviation range of the expected 
SPF (i.e., 4.47 <plus-minus> 1.28). Optionally, the standard sunscreen 
in paragraph (a)(1)(ii) of this section may be used.
    (ii) For products with an SPF over 15 (optional for SPF values of 2 
to 15). The standard sunscreen shall be an SPF 15 formulation 
containing 7 percent padimate O and 3 percent oxybenzone with a mean 
SPF value of 16.3 (standard deviation = 3.43). In order for the SPF 
determination of a test product to be considered valid, the SPF of the 
standard sunscreen must fall within the standard deviation range of the 
expected SPF (i.e., 16.3 <plus-minus> 3.43).
    (2) Standard homosalate sunscreen--(i) Preparation of the standard 
homosalate sunscreen. (A) The standard homosalate sunscreen is prepared 
from two different preparations (preparation

[[Page 49115]]

A and preparation B) with the following compositions:

    Composition of Preparation A and Preparation B of the Homosalate
                           Standard Sunscreen
------------------------------------------------------------------------
                 Ingredients                       Percent by weight
------------------------------------------------------------------------
Preparation A
------------------------------------------------------------------------
  Lanolin                                     5.00
  Homosalate                                  8.00
  White petrolatum                            2.50
  Stearic acid                                4.00
  Propylparaben                               0.05
------------------------------------------------------------------------
Preparation B
------------------------------------------------------------------------
  Methylparaben                               0.10
  Edetate disodium                            0.05
  Propylene glycol                            5.00
  Triethanolamine                             1.00
  Purified water USP                          74.30
------------------------------------------------------------------------

    (B) Preparation A and preparation B are heated separately to 77 to 
82 [deg]C, with constant stirring, until the contents of each part are 
solubilized. Add preparation A slowly to preparation B while stirring. 
Continue stirring until the emulsion formed is cooled to room 
temperature (15 to 30 [deg]C). Add sufficient purified water to obtain 
100 grams of standard sunscreen preparation.
    (ii) High performance liquid chromatography (HPLC) assay of the 
standard homosalate sunscreen. Assay the standard homosalate sunscreen 
preparation by the following method to ensure proper concentration:
    (A) Reagents. (1) Acetic acid, glacial, ACS grade.
    (2) Isopropanol, HPLC grade.
    (3) Methanol, HPLC grade.
    (4) Homosalate, USP reference standard.
    (B) Instrumentation. Equilibrate a suitable liquid chromatograph to 
the following or equivalent conditions:

 
 
 
Column.......................  Ultrasphere ODS 150 x 4.6 millimeters (5
                                microns), or Ultrasphere ODS 250 x 4.6
                                millimeters (5 microns)
Mobile Phase.................  85:15:0.5 methanol:water:acetic acid
Flow Rate....................  1.5 milliliters per minute
Temperature..................  Ambient
Detector.....................  UV spectrophotometer at 308 nanometers
Attenuation..................  As needed
Injection Amount.............  10 microliters
 

    (C) Standard preparation. (1) Accurately weigh 0.50 gram of 
homosalate USP reference standard into a 250-milliliter volumetric 
flask. Dissolve and dilute to volume with isopropanol. Mix well.
    (2) Accurately pipet 20.0 milliliters of the homosalate solution 
(described in paragraph (a)(2)(ii)(C)(1) of this section) into a 100-
milliliter volumetric flask. Dilute to volume with isopropanol and mix 
well. This is the standard preparation.
    (D) Sample preparation. (1) Accurately weigh 2.0 grams of sample 
into a 100-milliliter volumetric flask.
    (2) Add approximately 75 milliliters of isopropanol and heat with 
swirling until the sample is evenly dispersed.
    (3) Cool to room temperature (15 to 30 [deg]C) and dilute to volume 
with isopropanol. Mix well.
    (4) Pipet 25.0 milliliters of this sample preparation into a 100-
milliliter volumetric flask and dilute to volume with isopropanol. Mix 
well.
    (E) System suitability. (1) Three replicate injections of the 
standard preparation (described in paragraph (a)(2)(ii)(C)(2) of this 
section) will yield a relative standard deviation of not more than 2.0 
percent calculated on peak areas for homosalate.
    (2) In case a system fails to meet this criterion, adjusting the 
mobile phase or replacing the column may be necessary to obtain 
suitable chromatography.
    (F) Analysis. (1) Inject 10 microliters of the standard preparation 
(described in paragraph (a)(2)(ii)(C) of this section) in triplicate 
and collect data for about 15 minutes or until both homosalate (two 
isomers) peaks have completely eluted.
    (2) Similarly inject 10 microliters of each sample preparation.
    (3) The system suitability requirements must be met.
    (G) Calculation. Sum the peak areas of the two homosalate isomers 
for each injection and calculate the percent (weight/weight) homosalate 
content in the sample preparation as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.005

    (3) Standard padimate O/oxybenzone sunscreen--(i) Preparation of 
the standard padimate O/oxybenzone sunscreen. The standard sunscreen is 
prepared from four different parts (parts A, B, C, and D) with the 
following compositions:

       Composition of the Padimate O/Oxybenzone Standard Sunscreen
------------------------------------------------------------------------
                    Ingredients                       Percent by weight
------------------------------------------------------------------------
Part A..................................................................
------------------------------------------------------------------------
  Lanolin.........................................  4.50
  Cocoa butter....................................  2.00
  Glyceryl monostearate...........................  3.00
  Stearic acid....................................  2.00
  Padimate O......................................  7.00
  Oxybenzone......................................  3.00
  Propylparaben...................................  0.10
------------------------------------------------------------------------
Part B..................................................................
------------------------------------------------------------------------
  Purified water USP..............................  71.60
  Sorbitol solution...............................  5.00

[[Page 49116]]

 
  Triethanolamine, 99 percent.....................  1.00
  Methylparaben...................................  0.30
------------------------------------------------------------------------
Part C..................................................................
------------------------------------------------------------------------
  Benzyl alcohol..................................  0.50
------------------------------------------------------------------------
Part D..................................................................
------------------------------------------------------------------------
  Purified water USP..............................  QS1
------------------------------------------------------------------------
\1\ Quantity sufficient to make 100 grams

    (A) Step 1. Add the ingredients of Part A into a suitable stainless 
steel kettle equipped with a propeller agitator. Mix at 77 to 82 [deg]C 
until uniform.
    (B) Step 2. Add the water of Part B into a suitable stainless steel 
kettle equipped with a propeller agitator and begin mixing and heating 
to 77 to 82 [deg]C. Add the remaining ingredients of Part B and mix 
until uniform. Maintain temperature at 77 to 82 [deg]C.
    (C) Step 3. Add the batch of Step 1 at 77 to 82 [deg]C to the batch 
of Step 2 at 77 to 82 [deg]C, and mix until smooth and uniform. Slowly 
cool the batch to 49 to 54 [deg]C.
    (D) Step 4. Add the benzyl alcohol of Part C to the batch of Step 3 
at 49 to 54 [deg]C. Mix until uniform. Continue to cool batch to 35 to 
41 [deg]C.
    (E) Step 5. Add sufficient water of Part D to the batch of Step 4 
at 35 to 41 [deg]C to obtain 100 grams of standard sunscreen 
preparation. Mix until uniform. Cool batch to 27 to 32 [deg]C.
    (ii) HPLC assay of the standard padimate O/oxybenzone sunscreen. To 
ensure that the standard sunscreen contains proper amounts of padimate 
O and oxybenzone, analyze it against USP reference standards for 
padimate O and oxybenzone in a high performance liquid chromatography 
procedure using the following parameters:
    (A) Reagents. (1) Acetic acid, glacial, ACS grade.
    (2) Isopropanol, HPLC grade.
    (3) Methanol, HPLC grade.
    (4) Oxybenzone, USP reference standard.
    (5) Padimate O, USP reference standard.
    (B) Instrumentation. Equilibrate a suitable liquid chromatograph to 
the following or equivalent conditions:

 
 
 
Column.......................  Ultrasphere ODS 250 x 4.6 millimeters (5
                                microns), or Supelcosil LC-18 DB 250 x
                                4.6 millimeters (5 microns)
Mobile Phase.................  85:15:0.5 methanol:water:acetic acid
Flow Rate....................  1.5 milliliters per minute
Temperature..................  Ambient
Detector.....................  UV spectrophotometer at 308 nanometers
Attenuation..................  As needed
Injection Amount.............  10 microliters
 

    (C) Standard preparation. (1) Weigh 0.50 gram of oxybenzone 
reference standard into a 250-milliliter volumetric flask. Dissolve and 
dilute to volume with isopropanol. Mix well.
    (2) Weigh 0.50 gram of padimate O reference standard into a 250-
milliliter volumetric flask. Dissolve and dilute to volume with 
isopropanol. Mix well.
    (3) Pipet 3.0 milliliters of the oxybenzone solution and 7.0 
milliliters of the padimate O solution into a 100-milliliter volumetric 
flask. Dilute to volume with isopropanol and mix well. This is the 
standard preparation.
    (D) Sample preparation. (1) Weigh 1.0 gram of sample into a 50-
milliliter volumetric flask.
    (2) Add approximately 30 milliliters of isopropanol and heat with 
swirling until the sample is evenly dispersed.
    (3) Cool to room temperature (15 to 30 [deg]C) and dilute to volume 
with isopropanol. Mix well.
    (4) Pipet 5.0 milliliters of this sample preparation into a 50-
milliliter volumetric flask and dilute to volume with isopropanol. Mix 
well.
    (E) System suitability. (1) Three replicate injections of the 
standard preparation (described in paragraph (a)(3)(ii)(C) of this 
section) will yield a relative standard deviation of not more than 2.0 
percent calculated on peak areas for oxybenzone and padimate O.
    (2) A calculated resolution between the oxybenzone and padimate O 
peaks will be not less than 3.0.
    (3) In case a system fails to meet this criterion, adjusting the 
mobile phase or replacing the column may be necessary to obtain 
suitable chromatography.
    (F) Analysis. (1) Inject 10 microliters of the standard preparation 
(described in paragraph (a)(3)(ii)(C) of this section) in triplicate 
and collect data for about 15 minutes or until the padimate O peak has 
completely eluted. Elution order is oxybenzone, then padimate O.
    (2) Similarly inject 10 microliters of each sample preparation.
    (3) The system suitability requirements must be met.
    (G) Calculation. Calculate the percent (weight/weight) of each 
sunscreen ingredient in the sample preparation as follows:
    (1) Oxybenzone (percent weight)
    [GRAPHIC] [TIFF OMITTED] TP27AU07.006
    
    (2) Padimate O (percent weight)
    [GRAPHIC] [TIFF OMITTED] TP27AU07.007
    
    (b) Light source (solar simulator)--(1) Emission spectrum. A solar 
simulator used for determining the SPF of a sunscreen drug product 
should be filtered so that it provides a continuous emission spectrum 
from 290 to 400 nanometers (nm) with a limit of 1,500 watts per square 
meter (W/m\2\) on total solar simulator irradiance for all wavelengths 
between 250 and 1400 nm and the following percentage of erythema-
effective radiation in each specified range of wavelengths:

[[Page 49117]]



                    Solar Simulator Emission Spectrum
------------------------------------------------------------------------
       Wavelength range (nm)           Percent erythemal  contribution
------------------------------------------------------------------------
< 290                                < 0.1
290-310                              46.0-67.0
290-320                              80.0-91.0
290-330                              86.5-95.0
290-340                              90.5-97.0
290-350                              93.5-98.5
290-400                              93.5-100.0
------------------------------------------------------------------------

    (2) Operation. A solar simulator should have no significant time 
related fluctuations (within 20 percent) in radiation emissions after 
an appropriate warmup time and good beam uniformity (within 20 percent) 
in the exposure plane. The average delivered dose to the UV exposure 
site must be within 10 percent of the prescribed dose.
    (3) Periodic measurement. To ensure that the solar simulator 
delivers the appropriate spectrum of UV radiation, the emission 
spectrum of the solar simulator must be measured every 6 months with an 
appropriate and accurately calibrated spectroradiometer system (results 
should be traceable to the National Institute for Standards and 
Technology). In addition, the solar simulator must be recalibrated if 
there is any change in the lamp bulb or the optical filtering 
components (i.e., filters, mirrors, lenses, collimating devices, or 
focusing devices). Daily solar simulator radiation intensity should be 
monitored with a broadband radiometric device that is sensitive 
primarily to UV radiation. The broadband radiometric device should be 
calibrated using side by side comparison with the spectroradiometer at 
the time of the semiannual spectroradiometric measurement of the solar 
simulator. If a lamp must be replaced due to failure or aging during a 
phototest, broadband device readings consistent with those obtained for 
the original calibrated lamp will suffice until measurements can be 
performed with the spectroradiometer at the earliest possible 
opportunity.
    (c) General testing procedures--(1) Medical history. Obtain a 
medical history from each subject with emphasis on the effects of 
sunlight on his/her skin. Determine that each subject is in good 
general health with skin type I, II, or III (as described in this 
paragraph).
Skin Type and Sunburn and Tanning History (Based on first 30 to 45 
minutes of sun exposure after a winter season of no sun exposure).

I: Always burns easily; never tans (sensitive).
II: Always burns easily; tans minimally (sensitive).
III: Burns moderately; tans gradually (light brown) (normal).
IV: Burns minimally; always tans well (moderate brown) (normal).
V: Rarely burns; tans profusely (dark brown) (insensitive).
VI: Never burns; deeply pigmented (insensitive).

Determine that the subject is not taking topical or systemic medication 
that is known to alter responses to ultraviolet radiation and that the 
subject has no history of sensitivities to topical products and/or 
abnormal responses to sunlight, such as a phototoxic or photoallergic 
response.
    (2) Physical examination. Conduct a physical examination to 
determine the presence of sunburn, suntan, scars, active dermal 
lesions, and uneven skin tones on the areas of the back to be tested. A 
suitable source of low power UVA, such as a Woods lamp, is helpful in 
this process. If any of these conditions are present, the subject is 
not qualified to participate in the study. The presence of nevi, 
blemishes, or moles will be acceptable if in the physician's judgment 
they will neither compromise the study, nor jeopardize subject safety. 
Subjects with dysplastic nevi should not be enrolled. Excess hair on 
the back is acceptable if the hair is clipped. Shaving is unacceptable 
because it may remove a significant portion of the stratum corneum and 
temporarily increase skin permeability to ultraviolet radiation.
    (3) Informed consent. Obtain legally effective written informed 
consent from all subjects.
    (4) Test site delineation--(i) Test site. A test site is the 
location on the back for determining the subject's initial and final 
minimal erythema dose (MED) for unprotected skin and for determining 
SPF values after application of the sunscreen standard and the test 
sunscreen product(s). There typically are 4 to 6 test sites for each 
subject. Test sites should be located on the back between the beltline 
and the shoulder blades (scapulae) and lateral to the midline. Each 
test site shall be a minimum of 50 square centimeters, e.g., 5 x 10 
centimeters. Outline the test sites to which the sunscreen standard and 
the test sunscreen product(s) will be applied with indelible ink. If 
the subject is to receive the doses of ultraviolet radiation in an 
upright (seated) position, draw the lines on the skin with the subject 
upright (seated). If the subject is to receive the doses of ultraviolet 
radiation while prone, draw the lines with the subject prone.
    (ii) Test subsite. Test subsites are the locations to which 
ultraviolet radiation is administered within a test site. At least 5 
test subsites will receive UV doses within each test site. Test 
subsites will be at least 1 square centimeter (cm\2\) in area and will 
be separated from each other by at least 1 cm. Mark the location of 
each test subsite with indelible ink.
    (5) Application of test materials. Apply the test sunscreen product 
and the standard sunscreen at 2 milligrams per square centimeter (mg/
cm\2\) to their respective test sites to establish standard films. Test 
sites will be randomly located on the back in a blinded manner. Use a 
finger cot compatible with the sunscreen to spread the product as 
evenly as possible. Pretreat the finger cot by saturating with the 
sunscreen and then wiping off material before application. Pretreatment 
is meant to ensure that sunscreen is applied at the correct density of 
2 mg/cm\2\.
    (6) Waiting period. Before exposing the test site areas after 
applying a product, wait at least 15 minutes.
    (7) Number of subjects--(i) For products with an expected SPF under 
30. A test panel shall consist of 20 to 25 subjects with at least 20 
subjects who produce valid data for analysis. Data are valid unless 
rejected in accordance with paragraph (c)(9) of this section. If more 
than 5 subjects are rejected based on paragraph (c)(9) of this section, 
the panel is disqualified, and a new panel must be created.
    (ii) For products with an expected SPF of 30 or over. A test panel 
shall consist of 25 to 30 subjects with at least 25 subjects who 
produce valid data for analysis. Data are valid unless rejected in 
accordance with paragraph (c)(9) of this section. If more than 5 
subjects are rejected based on paragraph (c)(9) of this section, the 
panel is disqualified, and a new panel must be created.
    (8) Response criteria. In order that the person who evaluates the 
MED responses is not biased, he/she must not be the same person who 
applied the sunscreen drug product to the test site or administered the 
doses of UV radiation. After UV radiation exposure from the solar 
simulator is completed, all immediate responses shall be recorded. 
These may include an immediate darkening or tanning, typically grayish 
or purplish in color, which fades in 30 to 60 minutes; an immediate 
reddening at the subsite, due to heating of the skin, which fades 
rapidly; and an immediate generalized heat response, spreading beyond 
the subsite, which fades in 30 to 60 minutes. After the immediate 
responses are noted, each subject shall shield the exposed area from 
further UV radiation until the MED response is evaluated. Determine the 
MED 16 to 24 hours after exposure. Evaluate the erythema

[[Page 49118]]

responses of each test site using either tungsten or warm white 
fluorescent lighting that provides 450 to 550 lux of illumination at 
the test site. For the evaluation, the test subject should be in the 
same position used when the test site was irradiated. For each test 
site, determine the smallest UV dose that produced redness reaching the 
borders of the test subsite. The MED is the quantity of erythema-
effective energy required to produce the first perceptible, redness 
reaction with clearly defined borders at 16 to 24 hours post-exposure. 
To determine the MED, there must be at least one subsite that received 
a smaller UV dose and does not produce redness as well as a subsite(s) 
with somewhat more intense redness. For subsites showing an erythema 
response, the maximal exposure should be no more than twice the total 
energy of the minimal exposure.
    (9) Rejection of test data. Reject test data if the exposure series 
fails to elicit an MED response on either the treated or unprotected 
skin sites; or all subsites within a test site show more intense 
responses than the threshold erythema response; or the responses are 
inconsistent with the series of UV doses administered; or the subject 
was noncompliant, e.g., the subject withdraws from the test due to 
illness or work conflicts or does not shield the exposed testing sites 
from further UV radiation until the MED is read.
    (d) Determination of SPF--(1) Determination of erythema action 
spectrum. (i) Use the following erythema action spectrum as weighting 
factors to calculate the erythema-effective exposure produced by a 
solar simulator:
    V<INF>i</INF> ([lgr]) = 1.0 (250 < [lgr] < 298 nm)
    V<INF>i</INF> ([lgr]) = 10<SUP>0.094 * (298 -</SUP> 
<SUP>[lgr]</SUP><SUP>)</SUP> (298 < [lgr] < 328 nanometers)
    V<INF>i</INF> ([lgr]) = 10<SUP>0.015 * (140 -</SUP> 
<SUP>[lgr]</SUP><SUP>)</SUP> (328 < [lgr] < 400 nanometers)
    (ii) Integrate the erythemally-effective spectral irradiance over 
wavelength and time to calculate the erythema-effective UV dose 
delivered by a solar simulator as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.008

    (iii) The erythema action spectrum may be determined using a 
handheld radiometer with a response weighted to match the spectrum in 
``CIE S 007/E Erythemal Reference Action Spectrum and Standard Erythema 
Dose,'' dated 1998, which is incorporated by reference in accordance 
with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from CIE 
Central Bureau, Kegelgasse 27, A-1030, Vienna, Austria, or may be 
examined at the Center for Drug Evaluation and Research, 10903 New 
Hampshire Ave., Bldg. 22, Silver Spring, MD, or at the Office of the 
Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC. 
It is advisable to measure the solar simulator output before and after 
each phototest or, at a minimum, at the beginning and end of each test 
day. This radiometer should be calibrated using side by side comparison 
with the spectroradiometer (using the weighting factors determined 
according to paragraph (d)(1)(i) of this section) at the time of the 
semiannual spectroradiometric measurement of the solar simulator.
    (2) Determination of MED of unprotected skin. Administer a series 
of five UV radiation doses expressed as J/m\2\-eff (adjusted to the 
erythema action spectrum calculated according to paragraph (d)(1) of 
this section) to the subsites within each test site on a subject using 
an accurately calibrated solar simulator. Use the series of five 
exposures to the unprotected test site to determine the initial 
unprotected MED. Select the doses that are a geometric series 
represented by (1.25\n\), wherein each exposure dose is 25 percent 
greater than the previous exposure dose to maintain the same relative 
uncertainty (expressed as a constant percentage), independent of the 
subject's sensitivity to UV radiation. Usually, the UV radiation for 
determining the initial unprotected MED is administered the day prior 
to applying the sunscreen product and standard sunscreen, and the 
responses then are evaluated immediately prior to applying the 
sunscreen product and sunscreen standard. Determine the final 
unprotected MED on the same day that UV radiation is administered to 
the sunscreen-protected test sites. Use the final unprotected MED 
(MED(US)) in calculating SPF.
    (3) Determination of individual SPF values. Administer a series of 
five UV radiation doses expressed as J/m\2\-eff (adjusted to the 
erythema action spectrum calculated according to paragraph (d)(1) of 
this section) to the subsites within each test site on a subject using 
an accurately calibrated solar simulator. The five UV doses will be a 
geometric series as described in paragraph (d)(2) of this section, 
where the middle exposure represents the expected SPF. For products 
with an expected SPF less than 8, use exposures that are the product of 
the initial unprotected MED times 0.64X, 0.80X, 1.00X, 1.25X, and 
1.56X, where X equals the expected SPF of the test product. For 
products with an expected SPF between 8 and 15, use exposures that are 
the initial unprotected MED times 0.69X, 0.83X, 1.00X, 1.20X, and 
1.44X, where X equals the expected SPF of the test product. For 
products with an expected SPF greater that 15, use exposures that are 
the initial unprotected MED times 0.76X, 0.87X, 1.00X, 1.15X, and 
1.32X, where X equals the expected SPF of the test product. The MED is 
the smallest erythemally-effective UV dose required to produce mild 
redness within the subsite border at 16 to 24 hours post-exposure. 
Calculate the SPF value of each sunscreen product and sunscreen 
standard using the MED of sunscreen-protected skin (MED(PS)) and the 
final unprotected skin MED (MED(US)) as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.009

    (4) Determination of the test product SPF and PCD. Use data from at 
least 20 test subjects with n representing the number of subjects used. 
First, compute the SPF value for each subject as stated in paragraphs 
(d)(2) and (d)(3) of this section. Second, compute the mean SPF value, 
x, and the standard deviation, s, for these subjects. Third, obtain the 
upper 5-percent point from Student's t distribution table with n-1 
degrees of freedom. Denote this value by t. Fourth, compute ts/
[radic]n. Denote this quantity by A (i.e., A = ts/[radic]n). Fifth, 
calculate the SPF value to be used in labeling as

[[Page 49119]]

follows: The label SPF equals the largest whole number less than x - A. 
Sixth and last, the sunscreen product is classified into a PCD as 
follows: If 50 + A < x, the PCD is Highest; if 30 + A <= x <= 50 + A, 
the PCD is High; if 15 + A <= x < 30 + A, the PCD is Medium; if 2 + A 
<= x < 15 + A, the PCD is Low; if x < 2 + A, the product shall not be 
labeled as an OTC sunscreen drug product and may not display an SPF 
value.


Sec.  352.71   UVA in vitro testing procedure.

    (a) Light source for transmittance/absorbance measurements. The 
light source should satisfy the requirements for solar simulators 
described in Sec.  352.70(b).
    (b) Substrate. Use optical-grade quartz plate suitable for 
substrate spectrophotometry that has been roughened on one side.
    (c) Sample holder. The sample holder should hold the substrate in a 
horizontal position to avoid flowing of the sunscreen drug product from 
one edge of the substrate to the other. It should be mounted as close 
as possible to the input optics of the spectroradiometer to maximize 
capture of forward scattered radiation. The sample holder should be a 
thin, flat plate with a suitable aperture through which UV radiation 
can pass. The substrate will be placed on the upper surface of the 
sample holder.
    (d) Spectroradiometer input optics. Unless the spectroradiometer is 
equipped with an integrating sphere, an ultraviolet radiation diffuser 
should be placed between the sample and the input optics of the 
spectroradiometer. The diffuser will be constructed from any UV 
radiation transparent material (e.g., Teflon[reg] or quartz). The 
diffuser ensures that the radiation received by the spectroradiometer 
is not collimated. The spectroradiometer input slits should be set to 
provide a bandwidth that is less than or equal to 5 nanometers.
    (e) Sunscreen drug product application to substrate. The accuracy 
of the test depends upon the application of a precisely controlled 
amount of sunscreen product with a uniform distribution over the 
application area of the substrate. The product is applied at 2 
milligrams per square centimeter to the substrate. To achieve uniform 
distribution over the substrate, the sunscreen product should be 
applied in a series of small dots over the application area of the 
substrate and then spread evenly using a gloved finger. A very light 
spreading action for a short period of time (approximately 10 seconds) 
should be used when distributing the product to ensure complete 
coverage without excessive buildup of product in the troughs of the 
substrate.
    (f) Pre-irradiation to account for differences in photostability. 
To account for potentially varying degrees of photostability between 
sunscreen drug products, irradiate the sunscreen product on the 
substrate with a dose of UV radiation equal to the SPF of the sunscreen 
product multiplied by 200 J/m\2\-eff multiplied by 2/3. A UV radiation 
dose of 200 J/m\2\-eff is equivalent to one minimal erythema dose 
(MED). The UV dose to be delivered is determined by multiplying the 
light source spectral irradiance action spectrum for erythema in ``CIE 
S 007/E Erythemal Reference Action Spectrum and Standard Erythema 
Dose,'' at each wavelength, integrating over wavelength, and 
multiplying the integral by the exposure time. ``CIE S 007/E Erythemal 
Reference Action Spectrum and Standard Erythema Dose,'' dated 1998, is 
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR 
part 51. Copies are available from CIE Central Bureau, Kegelgasse 27, 
A-1030, Vienna, Austria, or may be examined at the Center for Drug 
Evaluation and Research, 10903 New Hampshire Ave., Bldg. 22, Silver 
Spring, MD 20993, or at the Office of the Federal Register, 800 North 
Capitol St. NW., suite 700, Washington, DC.
    (g) Calculation of the spectral transmittance at each wavelength 
interval. The dynamic range of the measurement system and the intensity 
of the light source should be sufficiently high that signals measured 
at all UV wavelengths (290 to 400 nanometers) through a highly 
absorbing sunscreen product are above the noise level of the 
measurement system. Spectral irradiance will be measured at 5 nanometer 
intervals, from 290 to 400 nanometers. At least 12 measurements of 
spectral irradiance transmitted through the substrate without sunscreen 
drug product present will be obtained from different locations on the 
substrate surface (C([lgr])<INF>1</INF>, C([lgr])<INF>2</INF>, 
C([lgr])<INF>3</INF>, . . . C([lgr])<INF>12</INF>). In addition, a 
minimum of 12 measurements of spectral irradiance transmitted through 
the substrate with the sunscreen drug product present will be similarly 
obtained after pre-irradiation of the sunscreen drug product 
(P([lgr])<INF>1</INF>, P([lgr])<INF>2</INF>, P([lgr])<INF>3</INF>, . . 
. P([lgr])<INF>12</INF>). The mean transmittance for wavelength [lgr], 
T([lgr]), is the ratio of the mean of the C([lgr]) values to the mean 
of the P([lgr]) values, as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.010

The standard deviation, s, associated with the spectral transmittance 
is evaluated using Taylor's approximation, as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.011

where C([lgr]) = mean of the measurements of C at wavelength [lgr].
P([lgr]) = mean of the measurements of P at wavelength [lgr].
s(C([lgr])) = standard deviation of the measurements of C at wavelength 
[lgr].
s(P([lgr])) = standard deviation of the measurements of P at wavelength 
[lgr].
s(C([lgr])) is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.012

s(P([lgr])) is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.013

This calculation gives 23 spectral transmittance values with associated 
standard deviations, one for each 5 nanometer wavelength increment from 
290 to 400 nanometers. The standard deviation values will provide an 
indication of the uniformity of sunscreen drug product spreading during 
application to the substrate. The coefficient of variation, which is 
the standard deviation divided by the mean, and expressed as a 
percentage, should be less than 10 percent.
    (h) Calculation of the UVA I/UV ratio. (1) Spectral transmittance 
values, T([lgr]), are converted into absorbance values, A([lgr]), by 
taking the negative logarithm of

[[Page 49120]]

the spectral transmittance value as follows:
A([lgr]) = -log T([lgr])
The calculation yields 23 monochromatic absorbance values in 5 
nanometer increments from 290 to 400 nanometers.
    (2) The index of UVA I protection is calculated as the area (per 
unit wavelength) under the UVA I portions of a plot of wavelength 
versus A([lgr]), divided by the area (per unit wavelength) under the 
total curve, as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.014

UVA I area per unit [lgr] is given as:
[GRAPHIC] [TIFF OMITTED] TP27AU07.015

UV area per unit [lgr] is given as:
[GRAPHIC] [TIFF OMITTED] TP27AU07.016

where: A([lgr]) = effective absorbance given as -log T([lgr])
d([lgr]) = wavelength interval between measurements
B([lgr]) = any biological action spectrum factor
Because no appropriate biological action spectrum for UVA radiation 
damage has been universally accepted, no action spectrum is specified. 
The value of B([lgr]) is, therefore, equal to 1.0 for all wavelengths.
    (3) The integrals in the formulae in paragraphs (h)(1) and (h)(2) 
of this section are evaluated using Simpson's Rule for irregular areas, 
which states:
Area = h/3 x [Y<INF>0</INF> + Y<INF>2m</INF> + 4(Y<INF>1</INF> + 
Y<INF>3</INF> . . . + Y<INF>2m-1</INF>) + 2(Y<INF>2</INF> + 
Y<INF>4</INF> + . . . Y<INF>2m-2</INF>)]
In this equation, Y<INF>0</INF>, Y<INF>1</INF>, Y<INF>2</INF>, . . . 
Y<INF>2m</INF> are the lengths of 2m parallel lines drawn vertically to 
divide the area under the curve of a graph into 2m-1 segments of equal 
width, h. In practice, the values of Y<INF>0</INF>, Y<INF>1</INF>, 
Y<INF>2</INF>, . . . Y<INF>2m</INF> are the A([lgr]) values determined 
and h is the wavelength interval at which the spectral transmittance is 
determined (i.e., 5 nanometers).
    (4) UVA I area per unit wavelength (aUVA I/[lgr]) is calculated as 
follows:
aUVA I/[lgr] = 5/3 x [A<INF>340</INF> + A<INF>400</INF> + 
4(A<INF>345</INF> + ... + A<INF>395</INF>) + 2(A<INF>350</INF> + 
A<INF>360</INF> + A<INF>370</INF> + ... + A<INF>390</INF>)]/60
UV area per unit wavelength (aUV/[lgr]) is calculated as follows:
aUV/[lgr] = 5/3 x [A<INF>290</INF> + A<INF>400</INF> + 
4(A<INF>295</INF> + A<INF>305</INF> + A<INF>315</INF> + ... + 
A<INF>395</INF>) + 2(A<INF>300</INF> + A<INF>310</INF> + ... + 
A<INF>390</INF>)]/110
UVA I/UV ratio is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.017

    (i) Category determination of the UVA I/UV ratio. Perform at least 
5 separate determinations of the UVA I/UV ratio, from which the mean 
can be calculated. Using the mean, the sunscreen drug product is 
classified by in vitro UVA I/UV ratio as follows:

 
               UVA I/UV Ratio                          Category
 
0.20 to 0.39                                  Low
0.40 to 0.69                                  Medium
0.70 to 0.95                                  High
greater than 0.95                             Highest
 

Sec.  352.72   UVA in vivo testing procedure.

    (a) Standard sunscreen. A standard sunscreen shall be tested 
concomitantly in the procedure for determining the UVA protection 
factor (UVA-PF) value by means of persistent pigment darkening to 
ensure the uniform evaluation of sunscreen drug products. The standard 
sunscreen shall be a preparation containing 7 percent padimate O and 3 
percent oxybenzone as specified in Sec.  352.70(a)(3). For the test to 
be valid, the measured mean UVA-PF value of the standard preparation 
shall be 3.2 with a standard deviation less than or equal to 0.5.
    (b) Light source. The light source used for determining the UVA-PF 
value of a sunscreen drug product shall provide a continuous emission 
spectrum in the range of 320 to 400 nanometers. The ratio of UVA I (340 
to 400 nanometers) to UVA II (320 to 340 nanometers) in the final beam 
shall be close to that of sunlight, i.e., emitted UVA II shall be 8 to 
20 percent of the total UVA radiation. Optical radiation from 250 to 
320 nanometers shall be less than 0.1 percent of the optical radiation 
between 320 to 400 nanometers. Exclude visible and infrared light to 
avoid the darkening effects of visible light and the effect of heat. 
Perform monitoring and maintenance of the light source as specified in 
Sec.  352.70(b)(3).
    (c) General testing procedures--(1) Medical history. Obtain a 
medical history from each subject with emphasis on the effects of 
sunlight on his/her skin. Determine that each subject is in good 
general health and has skin type II or III (as described in this 
paragraph).
Skin Type and Sunburn and Tanning History (Based on first 30 to 45 
minutes of sun exposure after a winter season of no sun exposure).
I: Always burns easily; never tans (sensitive).
II: Always burns easily; tans minimally (sensitive).
III: Burns moderately; tans gradually (light brown) (normal).
IV: Burns minimally; always tans well (moderate brown) (normal).
V: Rarely burns; tans profusely (dark brown) (insensitive).
VI: Never burns; deeply pigmented (insensitive).
Determine that the subject is not taking topical or systemic medication 
that is known to alter responses to ultraviolet radiation and that the 
subject has no history of sensitivities to topical products and/or 
abnormal responses to sunlight, such as a phototoxic or photoallergic 
response.
    (2) Physical examination. The physical examination shall be 
conducted as specified in Sec.  352.70(c)(1).
    (3) Informed consent. Obtain legally effective written informed 
consent from all subjects.
    (4) Test site delineation--(i) Test site. A test site is the 
location on the back for determining the subject's initial and final 
minimal pigmenting dose (MPD) for unprotected skin and for determining 
UVA-PF values after application of the sunscreen standard and the test 
sunscreen product(s). There typically are 4 to 6 test sites for each 
subject. Test sites should be located on the back between the beltline 
and the shoulder blades (scapulae) and lateral to the midline. Each 
test site shall be a minimum of 50 square centimeters (cm\2\) (i.e., 5 
x 10 centimeters). Outline the test sites to which the sunscreen 
standard and the test sunscreen product(s) will be applied with 
indelible ink. If the subject is to receive the doses of ultraviolet 
radiation in an upright (seated) position, draw the lines on the skin 
with the subject upright (seated). If the subject is to receive the 
doses of ultraviolet radiation while prone, draw the lines with the 
subject prone.
    (ii) Test subsite. Test subsites are the locations to which 
ultraviolet radiation is administered within a test site. At least 5 
test subsites will receive UV doses within each test site. Test 
subsites will be at least 1 cm\2\ in area and will be separated from 
each other by at least 1 cm. Mark the location of each test subsite 
with indelible ink.
    (5) Application of test materials. Apply the test sunscreen product 
and the standard sunscreen as specified in Sec.  352.70(c)(5).
    (6) Waiting period. Before exposing the test site areas after 
applying a product, wait at least 15 minutes.
    (7) Number of subjects. A test panel shall consist of 20 to 25 
subjects with at least 20 subject who produce valid data for analysis. 
Data is valid unless rejected in accordance with Sec.  352.70(c)(9). If 
more than 5 subjects are rejected based on Sec.  352.70(c)(9), the 
panel is disqualified, and a new panel must be created.

[[Page 49121]]

    (8) Response criteria. In order that the person who evaluates the 
MPD responses is not biased, he/she must not be the same person who 
applied the sunscreen drug product to the test site or administered the 
doses of UV radiation. After UV radiation exposure from the solar 
simulator is completed, all immediate responses shall be recorded. 
These may include an immediate darkening or tanning, typically grayish 
or purplish in color, which fades in 30 to 60 minutes; an immediate 
reddening at the subsite, due to heating of the skin, which fades 
rapidly; and an immediate generalized heat response, spreading beyond 
the subsite, which fades in 30 to 60 minutes. After the immediate 
responses are noted, each subject shall shield the exposed area from 
further UV radiation until the MPD response is evaluated. Determine the 
MPD 3 to 24 hours after exposure. Evaluate the pigmentation responses 
of each test site using either tungsten or warm white fluorescent 
lighting that provides 450 to 550 lux of illumination at the test site. 
For the evaluation, the test subject should be in the same position 
used when the test site was irradiated. For each test site, determine 
the smallest UV dose that produced mild pigmentation reaching the 
borders of the test subsite. The MPD is the smallest UV dose required 
to produce the first perceptible pigment darkening at 3 to 24 hours 
post-exposure. To determine the MPD, there must be at least one subsite 
that received a smaller UV dose and does not produce pigmentation as 
well as a subsite(s) with somewhat more intense pigmentation. For 
subsites showing pigmentation, the maximal exposure should be no more 
than twice the total energy of the minimal exposure.
    (9) Rejection of test data. Reject test data if the exposure series 
fails to elicit an MPD response on either the treated or unprotected 
skin sites, or all subsites within a test site show more intense 
responses than the threshold pigmentation response, or the responses 
are inconsistent with the series of UV doses administered, or the 
subject was noncompliant, e.g., the subject withdraws from the test due 
to illness or work conflicts or does not shield the exposed testing 
sites from further UV radiation until the MPD is read.
    (d) Determination of UVA-PF values--(1) Determination of MPD of 
unprotected skin. Administer a series of five UV radiation doses 
expressed as Joules per square meter to the subsites within each test 
site on a subject using the light source described in paragraph (b) of 
this section. Use the series of five exposures to the unprotected test 
site to determine the initial unprotected MPD. Select the doses that 
are a geometric series represented by (1.25\n\), wherein each exposure 
dose is 25 percent greater than the previous exposure dose to maintain 
the same relative uncertainty (expressed as a constant percentage), 
independent of the subject's sensitivity to UV radiation. Usually, the 
UV radiation for determining the initial unprotected MPD is 
administered the day prior to applying the sunscreen product and 
standard sunscreen, and the responses are then evaluated immediately 
prior to applying the sunscreen product and sunscreen standard. 
Determine the final unprotected MPD on the same day that UV radiation 
is administered to the sunscreen-protected test sites. Use the final 
unprotected MPD (MPD(US)) in calculating UVA-PF.
    (2) Determination of individual UVA-PF values. Administer a series 
of five UV radiation doses expressed as Joules per square meter to the 
subsites within each test site on a subject using the light source 
described in paragraph (b) of this section. The five UV doses will be a 
geometric series as described in paragraph (d)(1) of this section, 
where the middle exposure represents the expected UVA-PF. Use exposures 
that are the product of the initial unprotected MPD times 0.64X, 0.80X, 
1.00X, 1.25X, and 1.56X, where X equals the expected UVA-PF of the test 
product. The MPD is the smallest UV dose required to produce 
pigmentation at 3 to 24 hours post-exposure. Calculate the UVA-PF value 
of each sunscreen product and sunscreen standard using MPD of 
sunscreen-protected skin (MPD(PS)) and the final unprotected MPD 
(MPD(US)) as follows:
[GRAPHIC] [TIFF OMITTED] TP27AU07.018

    (3) Determination of test product UVA-PF and UVA product category 
designation (PCD). Use data from at least 20 test subjects with n 
representing the number of subjects used. First, compute the UVA-PF 
value for each subject as stated in paragraph (d)(2) of this section. 
Second, compute the mean UVA-PF value, x, and the standard deviation, 
s, for these subjects. Third, obtain the upper 5-percent point from 
Student's t distribution table with n-1 degrees of freedom. Denote this 
value by t. Fourth, compute ts/[radic]n. Denote this quantity by A 
(i.e., A = ts/[radic]n). Fifth, calculate the UVA-PF value to be used 
in labeling as follows: The label UVA-PF equals the largest whole 
number less than x - A. Sixth and last, the drug product is classified 
into a PCD as follows: If 12 + A <= x, the PCD is Highest; if 8 + A <= 
x < 12 + A, the PCD is High; if 4 + A < x < 8 + A, the PCD is Medium; 
if 2 + A <= x < 4 + A, the PCD is Low; if x < 2 + A, the product shall 
not display a UVA-PF value.


Sec.  352.73   Determination of the labeled UVA protection value.

    Test the sunscreen product in accordance with Sec. Sec.  352.71 and 
352.72. The UVA category on the principal display panel (PDP) of the 
tested sunscreen product, as specified in Sec.  352.50, shall be the 
lower of either the UVA I/UV ratio category determined in Sec.  
352.71(j) or the UVA-PF product category designation (PCD) determined 
in Sec.  352.72(d)(3). If the product does not attain at least a 
``low'' category rating for both the UVA-PF and the UVA I/UV ratio, the 
product shall not display a UVA claim. State the final combined 
category rating (i.e., the lower of either the UVA I/UV ratio or UVA-PF 
PCD categories) on the PDP of the product along with the corresponding 
number of stars for that combined category rating as follows:

 
          Combined Category Rating                    Star Rating
 
Low                                           [starf][star14][star14][st
                                               ar14]
Medium                                        [starf][starf][star14][sta
                                               r14]
High                                          [starf][starf][starf][star
                                               14]
Highest                                       [starf][starf][starf][star
                                               f]
 

    11. Section 352.76 is amended by revising the introductory 
paragraph and paragraphs (a) introductory text, (a)(6), (b) 
introductory text, and (b)(10) to read as follows:


Sec.  352.76   Determination if a product is water resistant or very 
water resistant.

    The general testing procedures in Sec.  352.70(c) shall be used as 
part of the following tests, except where modified in this section. An 
indoor fresh water pool, whirlpool, and/or jacuzzi maintained at 23 to 
32 [deg]C shall be used in these testing procedures. Fresh water is 
clean drinking water that meets the standards in 40 CFR part 141. The 
pool and air temperature and the relative humidity shall be recorded.
    (a) Procedure for testing the water resistance of a sunscreen 
product. For sunscreen products making the claim of ``water 
resistant,'' the label SPF and, if appropriate, UVA values shall be the 
label SPF and UVA values determined after 40 minutes of water immersion 
using the following procedure for the water resistance test:
* * * * *
    (6) Begin light source exposure to test site areas as described in 
Sec.  352.70(b) and, if appropriate, Sec.  352.72(b).
    (b) Procedure for testing a very water resistant sunscreen product. 
For

[[Page 49122]]

sunscreen products making the claim of ``very water resistant,'' the 
label SPF and, if appropriate, UVA values shall be the label SPF and 
UVA values determined after 80 minutes of water immersion using the 
following procedure for the water resistance test:
* * * * *
    (10) Begin light source exposure to test site areas as described in 
Sec.  352.70(b) and, if appropriate, Sec.  352.72(b).

    Dated: August 10, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 07-4131 Filed 8-23-07; 8:45 am]
BILLING CODE 4160-01-S