[Federal Register: May 21, 1999 (Volume 64, Number 98)]
[Rules and Regulations]
[Page 27666-27693]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr21my99-6]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 352, 700, and 740

[Docket No. 78N-0038]
RIN 0910-AA01

Sunscreen Drug Products For Over-The-Counter Human Use; Final
Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
in the form of a final monograph establishing conditions under which
over-the-counter (OTC) sunscreen drug products are generally recognized
as safe and effective and not misbranded as part of FDA's ongoing
review of OTC drug products. FDA is issuing this final rule after
considering public comments on the agency's proposed regulation, which
was issued in the form of a tentative final monograph, and new data and
information on sunscreen drug products that have come to the agency's
attention. FDA is also issuing final rules regarding the labeling of
certain cosmetic products to inform consumers that these products do
not provide protection from the sun.

EFFECTIVE DATES:  This regulation is effective May 21, 2001 for parts
310, 352, and 700 and is effective May 22, 2000 for part 740.

FOR FURTHER INFORMATION CONTACT: John D. Lipnicki, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In the Federal Register of August 25, 1978 (43 FR 38206), FDA
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance
notice of proposed rulemaking (ANPRM) to establish a monograph for OTC
sunscreen drug products, together with the recommendations of the
Advisory Review Panel on OTC Topical Analgesic, Antirheumatic, Otic,
Burn, and Sunburn Prevention Drug Products (the Panel), which was the
advisory review panel that evaluated data on the active ingredients in
this drug class. The agency's proposed regulation for OTC sunscreen
drug products, in the form of a tentative final monograph, was
published in the Federal Register of May 12, 1993 (58 FR 28194).
    In the Federal Register of June 8, 1994 (59 FR 29706), the agency
proposed to amend the tentative final monograph (and reopened the
comment period until August 22, 1994) to remove five sunscreen
ingredients because of a lack of interest in establishing United States
Pharmacopeia (USP) monographs: Digalloyl trioleate, ethyl 4-
[bis(hydroxypropyl)] aminobenzoate, glyceryl aminobenzoate, lawsone
with dihydroxyacetone (interest was subsequently shown in developing a
monograph for lawsone and dihydroxyacetone), and red petrolatum. The
agency also reiterated that all sunscreen ingredients must have a USP
monograph before being included in the final monograph for OTC
sunscreen drug products. This final rule includes those sunscreen
ingredients that have USP monographs.
    In the Federal Register of September 16, 1996 (61 FR 48645), the
agency amended the proposed rule to include avobenzone as a single
ingredient and in combination with certain other sunscreen ingredients
(interim marketing was allowed in the Federal Register of April 30,
1997 (62 FR 23350)). In the Federal Register of October 22, 1998 (63 FR
56584), the agency proposed to amend the tentative final monograph to
include zinc oxide as a single ingredient and in combination with any
proposed Category I sunscreen active ingredient except avobenzone.
    In the Federal Register of April 5, 1994 (59 FR 16042), the agency
reopened the administrative record and announced a public meeting to
discuss ultraviolet A (UVA) radiation claims and testing procedures. In
the Federal Register of August 15, 1996 (61 FR 42398), the agency
reopened the administrative record and announced a public meeting to
discuss the photochemistry and photobiology of sunscreens.
    This final monograph completes the tentative final monograph except
for

[[Page 27667]]

certain testing issues and UVA labeling, which the agency will discuss
in future issues of the Federal Register. Until then, UVA labeling may
continue in accord with the tentative final monograph and its
amendments. The agency advises that on or after May 21, 2001, no OTC
drug product that is subject to the monograph and that contains a
nonmonograph condition may be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application or abbreviated new drug
application. Further, any OTC drug product subject to this monograph
that is repackaged or relabeled after the effective date of the
monograph must be in compliance with the monograph regardless of the
date the product was initially introduced or initially delivered for
introduction into interstate commerce. Manufacturers are encouraged to
comply voluntarily as soon as possible.
    In response to the proposed rule on OTC sunscreen drug products and
subsequent reopenings of the administrative record, the agency received
433 comments. The comments included four petitions (Refs. 1 through 4)
requesting consideration of sunscreen ingredients that have been
marketed in Europe but not in the United States. The status of these
petitions is discussed in section II.C, comment 13 of this document.
One manufacturer requested an oral hearing before the Commissioner of
Food and Drugs if the agency mandated a limit on sun protection factor
(SPF) values in this final rule. Copies of the information considered
by the Panel, the comments and petitions, and the hearing request are
on public display in the Dockets Management Branch (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
All ``OTC Volumes'' cited throughout this document refer to information
on public display.
    A number of comments were filed in the Dockets Management Branch
after the dates the administrative record had officially closed. The
agency has considered these comments as ``feedback'' communications
under the OTC drug review procedures, as discussed in the Federal
Register of September 29, 1981 (46 FR 47740), and clarified in the
Federal Register of April 1, 1983 (48 FR 14050). When ``feedback''
material submitted after an administrative record has officially closed
directly influences or forms one of the bases for the agency's decision
on a matter in an OTC drug rulemaking proceeding, the agency adds it to
the administrative record without submission of a formal petition by an
interested party.
    The agency has included these data and information in the
administrative record and addressed them in this document. The agency
has considered the request for an oral hearing in its response to the
comment and believes it has adequately responded to the manufacturer
and that a hearing is not needed. As discussed in section II.G, comment
29 of this document, the agency is allowing the marketing of OTC
sunscreen drug products with SPF values above 30 under one collective
term (i.e., ``30 plus'' or ``30 +''). The agency will also consider
including labeling in the monograph with actual label SPF values on
products with SPF values over 30 when adequate data are submitted to
substantiate a testing procedure applicable to SPF values over 30.

II. The Agency's Conclusions on the Comments

A. General Comments on OTC Sunscreen Drug Products

    1. Several comments asked that the agency either exempt currently
marketed sunscreen products from the requirement for redetermining the
SPF or provide a 2-year implementation period. One comment requested a
3-year implementation period. The comments contended that the proposed
12-month implementation period would result in lost business and a
serious economic hardship for manufacturers, estimated to be 35 million
dollars for reformulating, retesting, and relabeling sunscreen
products.
    The agency agrees with the comments that the proposed 12-month
implementation period may cause undue economic burden on some
manufacturers of these products without a corresponding benefit to
consumers (see section VII of this document). As discussed in section
VII, a 24-month effective date would allow most firms to relabel
products during a normal relabeling cycle without incurring additional
costs. Accordingly, the final rule will be effective 24 months from the
date of this publication. Because this final rule provides testing
procedures that were proposed in the tentative final monograph,
currently marketed products that have already been tested by those
procedures will not need to be retested. However, sunscreen products
that have not been tested will need to be tested using the methods
described in this document. The agency intends to propose modified test
procedures in a future issue of the Federal Register and any necessary
retesting time will be specified when the final rule for testing
procedures publishes.
    2. Several comments recommended modifications to the definition of
minimal erythema dose (MED) in proposed Sec. 352.3(a). Some comments
objected to the presumption that erythema is a ``diffusing'' reaction
that starts from within the exposed site and moves outward in a dose
dependent manner, i.e., ``redness reaching the borders of the exposure
site.'' Other comments asserted that the definition is too limiting
because it may not be appropriate for all solar simulator
configurations (e.g., no template). Many comments recommended the
definition of MED used by the European Trade Association COLIPA (Ref.
5): ``The quantity of radiant energy required to produce the first
perceptible, unambiguous redness reaction with clearly defined
borders.'' Another comment recommended ``erythema-effective ultraviolet
radiation'' in place of ``radiant energy.''
    The agency agrees that the proposed definition of MED should be
modified for the reasons discussed by the comments and is revising
Sec. 352.3(a) in this final rule, as follows: ``Minimal erythema dose
(MED). The quantity of erythema-effective energy (expressed in Joules
per square meter) required to produce the first perceptible redness
reaction with clearly defined borders.'' The agency considers this
definition broad enough to encompass tests conducted with solar
simulator configurations with no template and consistent with COLIPA's
definition.
    3. One comment noted that the wavelength ranges for UVA, UVB, and
UVC radiation in the tentative final monograph differed from the
official ranges of the Commission International de L'Eclairage (CIE),
which are: (1) UVC-radiation of less than 280 nanometers (nm), (2) UVB-
280 to 315 nm, and (3) UVA-315 to 400 nm. The comment mentioned the
agreement reached at the 11th International Congress on Photobiology
(Ref. 6) on the short wavelength end of UVB radiation (280 or 290 nm)
and suggested that the scientific evidence supports 320 nm as the long-
wavelength boundary of UVB radiation.
    The agency agrees with the comment that the scientific evidence
supports 320 nm as the long-wavelength boundary of UVB radiation.
However, the short-wavelength boundary for UVB radiation has been
accepted as either 280 or 290 nm. Given that the comment did not
provide a compelling reason to change the proposed definition of UVB
radiation, the agency will continue to

[[Page 27668]]

define the boundaries of UVB radiation as 290 to 320 nm.
    4. Comments requested the agency to amend the definition of a
sunscreen active ingredient in proposed Sec. 352.3(c) to include
mechanisms other than absorption, to expand the UV range to include UVA
radiation, and to provide a minimum SPF value requirement. The comments
added that some proposed Category I active ingredients (e.g., menthyl
anthranilate and titanium dioxide) do not meet the proposed definition,
and that the definition is not interpretable without specifications for
measuring 85 percent absorbance.
    The agency discussed the need to modify the definition in a 1996
proposed amendment of the tentative final monograph (61 FR 48645 at
48646). The agency agrees that modifications should be to: (1) Include
mechanisms other than absorption, (2) redefine wavelengths, and (3)
remove the percent absorbance requirement. The agency does not agree
that a minimum SPF value should be included in the definition because
this information is more appropriately a characteristic of the final
formulation. Therefore, the agency has revised proposed Sec. 352.3(c)
in this document, to read: ``Sunscreen active ingredient. An ingredient
listed in Sec. 352.10 that absorbs, reflects, or scatters radiation in
the ultraviolet range at wavelengths of 290 to 400 nanometers.''
    5. One comment recommended that the agency reevaluate statements in
the tentative final monograph on the harmful nature of tanning. The
agency discussed the harmful effects of UV radiation-induced tanning in
the tentative final monograph (58 FR 28194 at 28238 to 28239). The
comment suggested that a natural tan reduces cumulative sun exposure
and may potentiate sunscreen effectiveness. The comment did not,
however, provide data or references to support this claim or to
otherwise cause the agency to change its position.
    6. One comment requested that the final monograph require
expiration dating and storage information in the labeling of OTC
sunscreen drug products. The comment noted that under 21 CFR 211.137,
OTC drug products with data demonstrating stability for 3 years and
without labeled dosage limitations are not required to include an
expiration date in their labeling. The comment stated that it was aware
of numerous cases that suggest these products may not be stable for 3
years.
    The agency requested the comment to provide data and information
about the specific products it was aware of (Ref. 7), but none were
subsequently provided. The agency is not currently aware of stability
problems that would require expiration dating for OTC sunscreen drug
products but will address such a requirement if data become available.
All sunscreen active ingredients included in the final monograph also
have a USP monograph that contains packaging and storage requirements
and standards for products containing these ingredients.
    7. Comments recommended that the agency establish procedures for
ensuring batch-to-batch SPF test results, and that it approve testing
laboratories and regulate their performance.
    Regulations already exist to assure that each batch of drug product
meets established specifications for the identity and strength of each
active ingredient. Specifically, 21 CFR 211.160 requires that product
specifications and laboratory controls be established and performed.
Although the agency would not require SPF testing on human subjects for
every batch produced, manufacturers need to assure conformance to their
finished product specifications. Further, any changes to the batch
formula would, at a minimum, require review and documentation by the
manufacturer's quality control unit to determine if SPF retesting is
necessary. Finally, 21 CFR 211.180 provides for the inspection of
records pertaining to production, control, and distribution of batches
of drug products. Thus, testing laboratories are subject to these
regulations.

B. Comments on the Drug/Cosmetic Status of Sunscreen Products

    8. One comment questioned whether sunscreen products should be
regulated as drugs. The comment asserted that such products are not
active in the mitigation or elimination of a disease condition, and
that sunscreen products have no more affect on the structure and
function of the body than ``being in physical shade.''
    The basis for the agency's determination that products intended for
use as sunscreens are subject to regulation as drugs under section
201(g)(1) of the Federal Food, Drug, and Cosmetic Act (the act) (21
U.S.C. 321(g)(1)) is set forth at length in the tentative final
monograph (58 FR 28194 at 28203 to 28206). Essentially, sunscreen
active ingredients affect the structure and function of the body by
absorbing, reflecting, or scattering the harmful, burning rays of the
sun, thereby altering the normal physiological response to solar
radiation. Proper use of sunscreen ingredients (see section II.L,
comment 51 of this document) may help to prevent skin damage and may
help reduce the risk of skin lesions, skin cancer, and other disease
conditions. Products that are marketed to achieve these important
health benefits meet the definition of a drug under section
201(g)(1)(B) and (g)(1)(C) of the act.
    9. One comment disagreed with the agency's tentative conclusion
that products containing a sunscreen ingredient, but labeled for the
purpose of obtaining an ``even tan,'' are subject to regulation as
drugs. According to the comment, such a product is subject to
regulation as a drug only if it bears a claim to treat or prevent
sunburn. The comment asserts that this has been the agency's consistent
approach since 1940.
    Another comment stated that sunless tanning products, used to
impart color without exposure to the sun, could be improved by adding a
sunscreen to provide users protection during their normal outside
activities. The comment requested that such products should be regarded
as cosmetics, because they would be used primarily for a cosmetic
effect, with the sunscreen protection serving only a secondary purpose.
    The agency thoroughly discussed the regulatory status of
``tanning'' products, including the basis for withdrawing its 1940
advisory opinion on sunburn and suntan preparations, in the tentative
final monograph (58 FR 28194 at 28203 to 28207, 28293 to 28294). As
discussed in the tentative final monograph, the presence of a sunscreen
active ingredient, in conjunction with labeling claims that the product
may be used, e.g., to permit tanning or to acquire an even tan,
generally establishes that the product's intended use is that of a
drug. Such products suggest, among other things, that the ingredients
in the product will allow the consumer to stay in the sun longer
without suffering skin damage (58 FR 28194 at 28204). Likewise,
products that claim to accelerate or stimulate the tanning process are
claiming, either expressly or impliedly, to stimulate the production of
melanin in the body. Such a claim to affect the structure or function
of the body renders the product subject to regulation as a drug under
section 201(g)(1) of the act (see 58 FR 28194 at 28293). Finally, a
sunless tanning product that contains a sunscreen ingredient, to
provide protection to the consumer, is subject to regulation as a drug.
The idea that the sunburn protection offered by the product may only be
a ``secondary'' feature for the consumer is not relevant. If an
intended use of the product is to provide users with sun protection
when they go

[[Page 27669]]

outside (as the comment suggests), then the product is subject to
regulation as a drug.
    On the other hand, products that do not make express or implied sun
protection claims, and do not contain sunscreen ingredients, may be
regarded as cosmetics under section 201(i) of the act. If the product
is intended solely to provide cosmetic effects on the skin (e.g., to
moisturize the skin while sunbathing), or solely to impart color to the
skin without exposure to the sun or other sources of light (i.e.,
sunless tanning), then the product may be marketed as a cosmetic. Such
products, however, must include a warning statement (discussed in this
section, comment 10 of this document) to inform the consumer that the
product does not provide any protection against sunburn. Products
marketed to enhance or permit tanning that do not contain a sunscreen
ingredient must be reviewed on a case-by-case basis to determine
whether the product is intended solely to provide a cosmetic benefit
(such as moisturizing) or whether the product is intended to enhance or
permit tanning by some other mechanism of action.
    The comments offered no other reasoning and no data to the
contrary, other than to suggest that the agency's approach would
encourage manufacturers to remove sunscreen ingredients from suntan
products and, thereby, expose consumers to even higher levels of
harmful ultraviolet rays. The agency is not persuaded that a
significant number of manufacturers will choose to reformulate their
products, to make them less safe for consumers, as a result of this
final rule. Moreover, consumers will continue to have an array of
sunscreen-containing products from which to choose. Finally, as
discussed below, certain tanning products (including sunless tanning
products) that do not contain sunscreen ingredients must bear a
prominent warning to the consumer. This will ensure that the consumer
is fully informed as to which products offer sun protection and which
do not.
    10. One comment requested that the signal word ``Caution'' replace
the signal word ``Warning'' preceding the following statement for
suntanning preparations: ``Warning--This product does not contain a
sunscreen and does not protect against sunburn.'' The comment stated
that the word ``Warning'' suggests safety hazards associated with these
products that are unrelated to sunburn. Another comment petitioned to
add a second sentence to the warning: ``Tanning in sunlight or under
tanning lamps can cause skin cancer and premature skin aging-even if
you don't burn.'' The comment concluded that the availability of
tanning products without a protective sunscreen ingredient is a serious
health issue and detrimental to public health. A third comment objected
to any such warnings on tanning products.
    The agency considers it an important public health issue that users
of suntanning products be alerted when these products do not contain a
sunscreen and do not protect against sunburn or other harmful effects
to the skin. Because suntanning products are intended for repeated use
under the sun or suntanning lamps while acquiring a tan, the agency
considers failure to provide information on hazards associated with
repeated, unprotected exposure to UV radiation to be a failure to
reveal material facts (see sections 201(n), 502(a), and 602(a) of the
act (21 U.S.C. 352(a) and 362(a))), especially in light of the
representations that are made for the product (e.g., suntanning).
Therefore, the agency is requiring the labeling of suntanning
preparations that do not contain a sunscreen ingredient (Sec. 740.19
(21 CFR 740.19)) to bear the following: ``Warning--This product does
not contain a sunscreen and does not protect against sunburn. Repeated
exposure of unprotected skin while tanning may increase the risk of
skin aging, skin cancer, and other harmful effects to the skin even if
you do not burn.'' The agency considers this information to be
sufficiently important, for safety reasons, to require a 12-month
effective date (as opposed to 24 months for the balance of the rule)
and to require the strongest possible signal word, i.e., ``Warning.''
    11. One comment disagreed with the proposal that hair care and nail
products that contain a sunscreen ingredient for a nontherapeutic use
(e.g., to protect the color of the product), and that use the term
``sunscreen'' in the labeling, must describe in the labeling the
functional role of the sunscreen. According to the comment, it is
highly unlikely that consumers would think that these products are
intended to protect the skin. If this requirement were finalized, the
comment requested that the agency permit the term ``sunscreen'' to
appear once anywhere in the labeling, with the purpose of the sunscreen
explained elsewhere in the labeling.
    The agency disagrees with the premise of this comment. The use of
the term ``sunscreen'' in labeling suggests that the product in some
way will protect the consumer from the harmful effects of the sun. The
health risks associated with relying on a product for protection from
the sun, when in fact the product does not provide such protection, are
sufficiently serious to require the type of disclosure outlined in the
proposed rule. Information about the purpose of a sunscreen ingredient
in a hair care or nail product will be useful to consumers to inform
them that the ingredient protects only the hair or only the color of
the product.
    This information need appear only once and can appear anywhere in
the labeling, provided the qualifying purpose appears prominently and
conspicuously and in conjunction with the word ``sunscreen.'' The
information may, e.g., be combined in a single statement, e.g.,
``Contains a sunscreen--to protect product color.'' This will ensure
that consumers will see and readily associate the two pieces of
information.
    12. Two comments objected to the use of an OTC drug rulemaking
process to change cosmetic labeling requirements, i.e., the addition of
a warning on certain tanning products and the labeling requirements for
hair care or nail products that contain a sunscreen for a
nontherapeutic use.
    The agency addressed this procedural concern, which was also raised
in response to the ANPRM, at length in the tentative final monograph
(58 FR 28194 at 28201 to 28202). The industry and consumers have had
ample notice of the fact that this proceeding included several cosmetic
labeling issues that arise out of the same facts and findings at issue
in developing the OTC drug monograph. It is not uncommon for the agency
to address in an OTC rulemaking document the status of, or the
regulation of, products that fall outside of the monograph. In this
instance, the cosmetic labeling issues were so closely related to the
OTC drug issues that a separate proceeding would have been overly
duplicative and inefficient.

C. Comments on Specific Sunscreen Active Ingredients

    13. Several comments noted that FDA had deferred a decision on the
citizen petitions requesting that sunscreen active ingredients marketed
solely in foreign countries be included in the OTC sunscreen monograph.
The comments urged FDA answer these petitions and establish a policy
concerning the inclusion of OTC sunscreens based solely on foreign data
and marketing experience.
    In the Federal Register of October 3, 1996 (61 FR 51625), the
agency published an ANPRM that addressed establishing eligibility
criteria for considering additional OTC conditions (i.e., OTC drug
active ingredients, indications, dosage forms, dosage

[[Page 27670]]

strengths, routes of administration, and active ingredient
combinations) in the OTC drug monograph system. These proposed criteria
would address how foreign or domestic OTC marketing experience could be
used to support the inclusion of an ingredient in an OTC drug
monograph. Specifically, the criteria would address how OTC marketing
experience in the United States or abroad could be used to meet the
statutory requirement under section 201(p) of the act of marketing ``to
a material extent'' and ``for a material time.'' ``Material extent''
and ``material time'' are needed to qualify a specific OTC drug
condition for consideration under the OTC drug monograph system.
    The decision on whether to proceed with a final rulemaking on this
subject will be based, in part, on the information and comments
submitted in response to the notice of proposed rulemaking that the
agency is preparing for publication in a future issue of the Federal
Register. Resolution of the pending sunscreen petitions must await the
outcome of any final rulemaking on this subject.
    14. One comment requested that the agency adopt simpler, more user-
friendly, names for several sunscreen ingredients: (1) Roxadimate for
ethyl-[bis(hydroxypropyl)] aminobenzoate, (2) lisadimate for glyceryl
aminobenzoate, and (3) diolamine methoxycinnamate for diethanolamine
methoxycinnamate. The comment claimed that these names had been adopted
or designated by the United States Adopted Names (USAN) Council. The
comment also requested that if USAN adopts a name for
phenylbenzimidazole sulfonic acid, FDA adopt this name as well. The
comment also suggested the use of the acronyms ``TEA'' and ``DEA'' for
triethanolamine and diethanolamine, respectively.
    The agency is including in this final monograph only those active
ingredients that are the subject of an official USP compendial
monograph that sets forth its standards of identity, strength, quality,
and purity (see section I of this document). In the Federal Register of
June 8, 1994, FDA deleted ethyl-[bis(hydroxypropyl)] aminobenzoate and
glyceryl aminobenzoate from the tentative final monograph due to the
lack of interest in establishing USP monographs for these ingredients.
Moreover, two sunscreen ingredients (including diethanolamine
methoxycinnamate) have been deferred from the final monograph due to
the lack of a current or proposed compendial monograph. Therefore, the
issue of whether a ``user-friendly'' name for these ingredients should
be developed or adopted need not be resolved in this proceeding at this
time. Similarly, TEA and DEA need not be addressed in this proceeding,
as triethanolamine is not a sunscreen active ingredient, and
diethanolamine is only used in the ingredient diethanolamine
methoxycinnamate which, as discussed, is not a monograph ingredient at
this time.
    With respect to the comment on the monograph ingredient
phenylbenzimidazole sulfonic acid, the agency agrees that if USAN or
the USP were to adopt a different or alternative name for this
ingredient, such a name could be used in the labeling of a product that
contains this ingredient. As discussed in comment 30 of the tentative
final monograph (58 FR 28194 at 28207 to 28209), the agency is using
the compendial name as the established name for each active ingredient.
    15. Two comments requested that the term ``PABA'' continue to be
allowed in labeling. The comments stated that the name aminobenzoic
acid is meaningless to consumers and physicians, who over the years
have learned to recognize this ingredient on the label as PABA. One
comment recommended the use of aminobenzoic acid in the ingredient list
and the use of PABA in other communications about the product. The
comment added that the term ``PABA-free'' should be allowed on products
that do not contain aminobenzoic acid. The other comment proposed
either to permit the listing of the ingredient as PABA or, if that is
unacceptable, as PABA (aminobenzoic acid).
    In comment 30 of the tentative final monograph (58 FR 28194 at
28207 to 28209), the agency discussed the issue of the appropriate
established name for this and other sunscreen ingredients. As the
agency stated in that discussion, the recognized compendial name for
aminobenzoic acid no longer includes the term PABA.
    The agency acknowledges, however, that the term PABA formerly was
part of the established name for this ingredient and that the use of
the term in consumer labeling has continued despite the change in the
compendial name. In addition, the agency agrees with the comment that
many consumers have learned to recognize this ingredient as, and only
as, PABA. The agency also recognizes that consumers seeking to avoid
the use of this ingredient for health-related reasons (e.g., allergy)
may, in this case, be misled if the term PABA were no longer permitted.
Some consumers may believe that a product that lists aminobenzoic acid
as an ingredient, but does not list PABA, is PABA-free. If such a
consumer has an allergy to aminobenzoic acid, the individual may suffer
adverse health consequences.
    For these reasons, and especially in light of the potential safety
concerns for certain consumers, the agency concludes that wherever the
ingredient aminobenzoic acid appears in the labeling of an OTC
sunscreen drug product, including labeling that notes the absence of
this ingredient, the descriptive term PABA must immediately follow the
established name, i.e., ``Aminobenzoic acid (PABA).'' Thus, e.g., a
product that is currently marketed as ``PABA-free'' would now be
required to state that the product is ``Aminobenzoic acid (PABA)-
free.'' This convention will allow consumers to begin to recognize that
the ingredient they may wish to avoid is ``aminobenzoic acid.'' After a
sufficient period of time, the agency will revisit the need for
consumer labeling to continue to bear the descriptive term PABA.
    16. One comment stated that claims of protection by artificial
melanin, melanin-containing products, and antioxidants should be
enumerated, well regulated, and defined.
    The agency agrees with the comment, but these claims are not
covered by this final monograph. Melanin and artificial melanins are
not recognized sunscreen active ingredients. Any product containing
melanin or artificial melanins as active ingredients and making sun
protection claims would have to seek marketing approval under a new
drug application (NDA).
    The agency is aware that claims of protection from antioxidants are
used in the labeling of some cosmetic products with or without a
sunscreen. The agency will ascertain the nature of any such claims
(drug or cosmetic) on a case-by-case basis.
    17. Several comments objected to the agency's proposal that OTC
sunscreen drug products must contain less than 500 parts per billion
(ppb) of N-methyl-N-nitrosoaminobenzoate octyl ester (NMPABAO) for
several reasons: (1) Toxicological studies indicate that NMPABAO does
not have mutagenic or suspected carcinogenic potential (Ref. 8), (2)
NMPABAO may be present in sunscreens containing padimate O only in
small amounts (ppb range) and the risks associated with NMPABAO are
very low, (3) NMPABAO decomposes quickly when exposed to UV radiation,
and (4) industry is aware not to formulate with known nitrosating
agents in the presence of amines in order to avoid nitrosamine
contamination of its products. Some comments stated that FDA's own
conclusions in the tentative

[[Page 27671]]

final monograph concerning the safety of both NMPABAO and padimate O do
not support the imposition of concentration limits for NMPABAO in
sunscreens nor do they justify the high cost of analyzing each batch of
sunscreen product for NMPABAO. One comment contended that any proposed
limit should apply to all nitrosamines and not just NMPABAO. The
comment stated that nitrosamines can be formed from any secondary or
tertiary amine. Several sunscreen active ingredients contain this
moiety in their chemical structure and many inactive ingredients are
secondary or tertiary amines. The comment concluded that targeting
NMPABAO falsely conveys that padimate O is a unique concern, resulting
in manufacturers using other ingredients to avoid costly testing and
negative implications.
    In the tentative final monograph, the agency did not propose a
concentration limit on NMPABAO. Rather, based on concerns that had been
raised, the agency asked for comment on whether it should consider
proposing a fixed limit. As discussed in the tentative final monograph
(58 FR 28194 at 28288 to 28293), toxicological studies support the
agency's belief that the risk associated with NMPABAO contamination of
sunscreen drug products is very low due to NMPABAO's low mutagenicity
and carcinogenicity potential and rapid decomposition in the presence
of UV radiation. The agency has not become aware of any new data or
information since the publication of the tentative final monograph
suggesting a safety concern with NMPABAO in sunscreen drug products.
Therefore, the agency has decided not to propose or otherwise include
in this final monograph a requirement that OTC sunscreen drug products
must contain less than 500 ppb of NMPABAO.
    In the tentative final monograph (58 FR 28194 at 28292), the agency
discussed its analysis for NMPABAO in 25 commercially available
sunscreen products. Of the 11 samples found to be contaminated with
NMPABAO, the four highest contained 2-bromo-2-nitro-1,3-propanediol, an
indirect nitrosating agent. The agency concluded that there would be no
nitrosamine contamination if these products were formulated without the
nitrosating agent. As noted by several of the comments, the industry is
aware not to formulate with known nitrosating agents in the presence of
amines in order to avoid nitrosamine contamination of its products.
    18. One comment submitted a reference to a subchronic oral toxicity
study in rats conducted with padimate O which a chemical manufacturer
had submitted to the Toxic Substance Control Act 8(e) coordinator of
the United States Environmental Protection Agency for consideration.
The study was a 4-week repeated dose study at doses of 0, 100, 300, and
1,000 milligrams (mg)/kilogram (kg)/day of padimate O administered by
gavage in a corn oil vehicle (10 to 15 rats/group/sex). The study
included a 4-week recovery period to assess the persistence or
reversibility of any toxic effects. At the end of the 4-week treatment
period, toxic effects were seen in four target organs: Testes,
epididymis, spleen, and liver. The no-observed-effect-level in this
study was 100 mg/kg/day for both males and females. Toxic effects
appeared reversible in the animals necropsied after the 4-week recovery
period with the exception of marked epididymal hypospermia at the 1,000
mg/kg/day dose (5/5 animals).
    The clinical relevance of this animal toxicity study is difficult
to assess. Padimate O was administered chronically and at very high
oral doses. Under normal use conditions, sunscreen drug products
containing padimate O are applied topically and used intermittently. In
addition, pharmacokinetic parameters were not calculated and the
different routes of administration (oral in this study versus topical
for sunscreen products) preclude calculation of a ``safety margin'' on
the basis of dose per unit of body weight or surface area. Similarly,
kinetic data are not available for a comparison of serum levels of drug
or metabolites. Literature searches indicate no published information
on the kinetics of padimate O with topical application in man. If
percutaneous absorption of padimate O does occur in man, it seems
likely that the peak and/or cumulative levels achieved with sunscreen
usage would be quite low compared to the systemic exposure achieved in
this animal toxicity study. Further, it is not known whether the
irreversible epididymal hypospermia found in the 1,000 mg/kg/day group
would also be reversible with more time.
    The agency has determined that this study does not present
sufficient data to exclude padimate O from the final monograph and that
an adequate safety margin exists for its use as an OTC sunscreen
ingredient.
    19. Two comments submitted safety and/or efficacy data to support
Category I status for micronized titanium dioxide (Refs. 9 and 10). One
comment stated that micronized titanium dioxide is not a new material
but is a selected distribution of existing material that provides
higher SPF values while being transparent and esthetically pleasing on
the skin. The comments added that micronized titanium dioxide meets all
safety and efficacy criteria and also meets the USP specifications for
purity except pure water content.
    Another comment asserted for the following reasons that micronized
titanium dioxide is a new ingredient with several unresolved safety and
efficacy issues: (1) It does not meet the definition of a sunscreen
opaque sunblock, (2) there is no control of particles to agglomerate,
which is critical to effectiveness, (3) no standards exist to ensure
integrity of coatings, (4) there are no performance-based standards of
identity; micronized titanium dioxide is not included in the USP, (5)
its photocatalyst potential, and (6) the potential for the smaller
particle size to accumulate under the skin.
    The agency finds the data with the comments supportive of monograph
status for micronized titanium dioxide. Acute animal toxicity,
irritation, sensitization, photoirritation, photosensitization, and
human repeat insult patch and skin penetration studies revealed no
deleterious effects. SPF values for four product formulations
containing from 4.4 to 10 percent micronized titanium dioxide were from
9 to 24 and support effectiveness as a sunscreen ingredient.
    The agency is aware that sunscreen manufacturers are using
micronized titanium dioxide to create high SPF products that are
transparent and esthetically pleasing on the skin. The agency does not
consider micronized titanium dioxide to be a new ingredient but
considers it a specific grade of the titanium dioxide originally
reviewed by the Panel. Fairhurst and Mitchnick (Ref. 11) note that
``fines'' have been part of commercially used titanium dioxide powders
for decades, and that a micronized product simply refers to a
refinement of particle size distribution. Based on data and information
presented at the September 19 and 20, 1996, public meeting on the
photobiology and photochemistry of sunscreens (Ref. 12), the agency is
not aware of any evidence at this time that demonstrates a safety
concern from the use of micronized titanium dioxide in sunscreen
products. While micronized titanium dioxide does not meet the proposed
definition of a sunscreen opaque sunblock, the agency has not included
the use of this term in the final monograph (see section II.L, comment
52 of this document). The potential for titanium dioxide particles to
agglomerate in formulation, which could result in lower SPF values, is
addressed by the final product SPF test.

[[Page 27672]]

 The SPF data that the agency reviewed (Ref. 9) did not indicate such a
problem.
    Micronized titanium dioxide meets current USP monograph
specifications for titanium dioxide with the exception that the
material contains more associated water. In both the July through
August 1996 and 1998 issues of the Pharmacopeial Forum (Refs. 13 and
14), the United States Pharmacopeial Convention published in-process
revision proposals to make the monograph for titanium dioxide more
applicable to ingredients used in sunscreen drug products. The agency
will work with the USP in the future to update this monograph as
necessary.
    20. One comment stated that it is unnecessary to set the maximum
limit of titanium dioxide at 25 percent.
     The Panel discussed the safety and effectiveness of 2 to 25
percent titanium dioxide in the ANPRM (43 FR 38206 at 38250) and the
agency concurred with the Panel's findings in the tentative final
monograph (58 FR 28194 at 28295). The comment submitted no data and the
agency has no data to support the use of titanium dioxide in sunscreen
drug products at concentrations higher than 25 percent.

D. Comments on Dosages for Sunscreen Drug Products

    21. Several comments objected to the minimum concentration
requirements for sunscreen active ingredients when used in combination
because they: (1) Are a less effective measurement of effectiveness
than a performance based SPF test, (2) impact on creativity and
innovation of new formulations (technological advances since
publication of the 1978 ANPRM have resulted in higher SPF values using
lower concentrations of active ingredients), (3) increase potential for
irritation and allergic reactions due to unnecessarily high
concentration levels of active ingredients, (4) contradict FDA's
position that the lowest effective dose of an active ingredient be used
to produce the desired treatment effect, (5) result in higher
manufacturing and consumer costs due to unnecessary levels of active
ingredients, and (6) affect international harmonization because Canada,
Australia, and the European Union have no concentration minimums for
active ingredients when used in combination.
    One comment petitioned the agency to amend proposed Sec. 352.20 of
the tentative final monograph to include a provision for formulating
combination sunscreen products at lower minimum concentrations. Two
comments submitted efficacy data to support lower concentrations of
sunscreen active ingredients when used in combination. One comment
(Ref. 15) submitted in vitro SPF testing data for several different
combinations. Although these data showed a statistically significant
increased efficacy for lower than minimum concentrations, they were not
predictive of the SPF values that would be obtained with human testing
and, therefore, were not used to support lower concentrations of
sunscreen active ingredients when used in combination. The other
comment (Ref. 16) submitted in vivo SPF testing data conducted
according to the procedure proposed in the tentative final monograph
(58 FR 28194 at 28298 to 28301) in which a selected cross section of
active ingredients were tested in pairs by substituting water or the
solvent system for the active ingredients. The data were evaluated
using a matched pairs comparison statistical hypothesis test procedure
and demonstrated that concentrations of sunscreen active ingredients
lower than the minimum concentrations proposed in Sec. 352.20(a)(2) for
combination products can provide a significant contribution to product
effectiveness.
    The agency recognizes that technological advances in sunscreen
formulation technology since 1978 have resulted in the ability to
formulate products with lower concentrations of active ingredients and
higher SPF values. The agency also recognizes that final product
testing, and not the concentration of the active ingredients in the
combination, ensures product effectiveness.
    Due to the recent advances in sunscreen formulation and the data
referenced previously, the agency is concerned that setting minimum
concentration requirements for active ingredients in sunscreen
combination drug products could subject consumers to unnecessary levels
of active ingredients. Therefore, the agency is only requiring the
maximum concentration limits in Sec. 352.10 for sunscreen active
ingredients when used in combination with another sunscreen or when the
combination is used with any other permitted active ingredient.
However, any such ingredient used in combination with one or more
sunscreen active ingredients must be consistent with the regulations in
Sec. 330.10(a)(4)(iv), i.e., each of the combined active ingredients
must make a contribution to the claimed effect, the combining of active
ingredients must not decrease the safety or effectiveness of any
individual active ingredient, and the combination must provide rational
concurrent therapy for a significant proportion of the target
population. Although the agency needs assurance that each ingredient is
contributing to the effectiveness of the product, it does not want to
impose unnecessary testing requirements on sunscreen product
manufacturers. Therefore, the agency is removing the minimum
concentration requirement for sunscreen active ingredients proposed in
Sec. 352.20 and is adding the requirement that: (1) The concentration
of each active sunscreen ingredient used in a combination product must
be sufficient to contribute a minimum SPF of not less than 2 to the
finished product, and (2) the finished product must have a minimum SPF
of not less than the number of the sunscreen active ingredients used in
combination multiplied by 2.

E. Comments on Labeling and Testing Procedures for UVA Sunscreen Drug
Products

    22. In the sunscreen tentative final monograph (58 FR 28194 at
28232 and 28233), the agency proposed to allow claims relating to
``broad spectrum protection'' or ``UVA radiation protection'' for
sunscreen products: (1) Containing sunscreen active ingredients with
absorption spectra extending to 360 nm or above, and (2) that
demonstrate meaningful UVA radiation protection using appropriate
testing procedures to be developed. The agency received numerous
comments concerning such claims and current scientific evidence
implicates UVA radiation as a major cause of, among other things,
photoaging of the skin (Refs. 17 through 20).
    In the Federal Register of September 16, 1996, and October 22,
1998, the agency proposed a specific skin damage and premature skin
aging claim for sunscreen products containing specific concentrations
of avobenzone or zinc oxide based upon the submission of data to
support claims of UVA radiation protection in such products. The agency
will address comments pertaining to measurement of UVA radiation
protection in sunscreen products and related UVA radiation protection
claims in a future issue of the Federal Register. Until then, UVA
labeling may continue in accord with the tentative final monograph and
its amendments.

F. General Comments on the Labeling of Sunscreen Drug Products

    23. Several comments requested that products containing sunscreen
ingredients as an adjunct to their main purpose (e.g., a daily
moisturizer or a lipstick with a sunscreen) be considered ``secondary
sunscreens'' (intended only for incidental or casual sun exposure), and
should be subject to different

[[Page 27673]]

labeling requirements from ``primary'' sunscreen products. A number of
comments likewise contended that some of the labeling requirements for
``beach'' or ``primary'' sunscreen products are not appropriate for
``non-beach'' or ``secondary'' sunscreen products.
    For example, the comments stated that neither the proposed
``Recommended Sunscreen Product Guide'' nor any other references to
sunburn or sunburn protection should be required for secondary
sunscreens. Some suggested that the warnings be reduced for secondary
sunscreens to a statement such as ``For external use only, keep out of
eyes. Discontinue use if signs of irritation appear.'' One comment
recommended that the statement of identity for a secondary sunscreen
should be its cosmetic function, e.g., ``moisturizer.'' Another
recommended stating the primary (cosmetic) function first, then the
secondary (drug) function, e.g., ``moisturizing face cream with
sunscreen (or with SPF ____ sunscreen).''
    The comments also suggested that secondary products be permitted to
bear certain labeling claims relating to aging, such as ``Helps reduce
the chance of skin aging caused by incidental (or casual) exposure to
the sun,'' or ``Helps reduce premature aging from incidental (or
casual) exposure to the sun.'' Some also requested the option of being
allowed to relate skin aging claims directly to sun exposure, to inform
consumers more clearly that sun protection is not the primary attribute
of the product, e.g., ``Provides moisture to facial skin throughout the
day while protecting facial skin from skin aging due to exposure to
sun.'' Other comments recommended that the proposed ``Sun alert''
statement or other references to ``skin cancer'' or other cancers
should not be required for secondary products.
    On the other hand, the agency also received comments opposing the
idea of recognizing ``primary'' and ``secondary'' or ``beach'' and
``non-beach'' categories of sunscreen products. One comment stated that
any product containing a sunscreen for the purpose of protection from
the sun's harmful effects should be held to the same standards as other
sunscreen products. Another comment disagreed with the idea of allowing
different sets of claims for ``primary'' and ``secondary'' products.
According to this comment, claims such as ``Helps reduce the chance of
skin aging'' are drug claims and should be regulated as such. Finally,
one comment stated that any sunscreen product (primary or secondary)
must have an SPF of 15 to 30 or higher to provide adequate protection,
whether for continuous beach exposure or everyday (incidental) sun
exposure.
    The agency agrees that all sunscreen products (whether drug only or
drug-cosmetic) should be held to the same standards (e.g., active
ingredient(s), testing requirements, and labeling). Regardless of what
type of product a consumer chooses for sun protection, the essential
information relevant to sun protection is the same. Thus, to ensure
that consumers are adequately protected from overexposure to the sun,
all products intended for use as sunscreens should have similar
labeling requirements, irrespective of their method of use and
irrespective of whether the sunscreen use is considered primary or
secondary to the product. Consistent with this approach, the agency has
developed uniform, streamlined labeling for all sunscreen products (see
sections II.I through II.L of this document).
    The agency also notes, however, that a number of the labeling
issues raised in these comments, including the issue of the
``Recommended Sunscreen Product Guide,'' are addressed elsewhere in
this document. In addressing these issues, the agency gave careful
consideration to the wide variety of products marketed for sunscreen
uses.
    Finally, the agency notes that under the recently issued
standardized OTC drug product labeling format (Sec. 201.66 (21 CFR
201.66)), manufacturers will not be allowed to commingle drug and
cosmetic claims within the ``Drug Facts'' portion of the labeling.
    24. One comment requested clarification of the agency's discussion
of the term ``anti-aging'' as a claim or as part of a trade name (58 FR
28194 at 28287). The comment was concerned that products containing no
sunscreen active ingredients and no sunscreen claims, but which are
sold under ``anti-aging'' trade names, would be subject to regulation
under the OTC drug sunscreen monograph.
    The use of ``anti-aging'' language in a product that made no
sunscreen claims and contained no sunscreen active ingredients would
not, as the comment asked, cause the product to fall within the scope
of the OTC sunscreen drug monograph. Such a product may, however, be
subject to regulation as a drug and as a new drug, under section
201(g)(1) and (p) of the act, or as a cosmetic under section 201(i), or
as both a drug and a cosmetic, depending upon all of the circumstances
surrounding its distribution. A product that is marketed under the
final OTC sunscreen drug monograph, but which uses anti-aging language
in the labeling to suggest or imply an unapproved therapeutic or
physiologic effect, would likely be subject to regulatory action as an
unapproved new drug (58 FR 28194 at 28286 to 28287; see comments 37 and
38 in section II.I of this document).
    25. Three comments contended that the terms ``natural,'' ``non-
chemical,'' and ``chemical free'' are false and misleading in the
labeling of OTC sunscreen drug products. The comments requested the
agency to restrict the use of these terms, especially for sunscreen
products containing titanium dioxide and zinc oxide.
    Generally, the appropriateness of these terms requires case-
specific analysis to determine whether their use would render the
product false or misleading in any particular (see sections 502(a) and
602(a) of the act). The agency notes, however, that the use of the
terms ``non-chemical'' and ``chemical-free'' in the labeling of an OTC
sunscreen drug product, to describe the ingredients contained in the
product, is likely to be considered unacceptable. Sunscreen drug
products contain active (and often inactive) ingredients that have been
obtained through a chemical process, or that have been formulated into
the finished product through a chemical process. The term ``natural''
is more likely to require context-specific analysis, particularly when
used in labeling to describe certain cosmetic aspects or uses of a
sunscreen product. The term ``natural,'' however, would not be
permitted to appear within the required OTC drug labeling of a
sunscreen product and is not considered to be interchangeable with any
of the final sunscreen monograph language.
    26. Four comments opposed any labeling that a sunscreen product
``does not provide UVA protection,'' contending that FDA's policy does
not require disclaimers of broader purposes for which products are not
useful. One comment added that an SPF 15 product must block UVA
radiation to be effective in preventing sunburn.
    Two comments argued that a ``negative warning'' would be useful and
necessary to warn and protect consumers and suggested ``Does not
provide broad spectrum UVA protection,'' or ``Caution: This product
does not provide protection from the recognized dangers of UVA rays
which may contribute to skin cancer and other chronic skin disease.''
    Labeling should primarily direct consumers towards the purposes for
which a product is considered useful. However, in establishing the
conditions for the safe and effective use of an OTC

[[Page 27674]]

drug product, the agency also must take into account, among other
things, the context in which a product is customarily marketed and the
potential that consumers may use the product for a use for which it may
not be beneficial (see sections 201(n) and 502(a) of the act;
Sec. 330.10(a)(3)).
    With these factors in mind, the agency will further evaluate
whether ``negative warnings'' or disclosure statements are needed when
it completes the UVA portion of the sunscreen monograph in a future
issue of the Federal Register.
    27. Four comments contended that the signal words ``Indications''
and ``Directions'' are not needed, take up valuable label space, and
should either not be required or be optional, especially for sunscreen-
containing drug products that have some ``traditional'' cosmetic uses
(e.g., lipsticks).
    The agency allows the signal word ``Use'' or ``Uses'' in place of
``Indication'' or ``Indications.'' This short signal word is useful for
consumers, appropriate for dual use products, and does not clutter
label space. Likewise, the agency concludes that the signal word
``Directions'' is useful for consumers and does not clutter label space
(64 FR 13254 at 13264 to 13268, March 17, 1999). The agency is
including Sec. 352.52(f) in this final monograph to provide labeling
modifications for sunscreen products that meet the small package
specifications in Sec. 201.66(d)(10) and are labeled for use on
specific small areas of the face (e.g., lips, nose, ears, and/or around
eyes). These products include many traditional cosmetics (e.g.,
lipstick or eye makeup) that may contain sunscreens. These products
will be allowed to present a condensed ``Uses'' section and may omit
directions for use if they are marketed in a lipstick form.
    28. One comment requested that the monograph include professional
labeling for both UVB and UVA radiation protection to assist health
professionals to select appropriate products. The comment recommended
inclusion of the absorption spectrum of each sunscreen in the product
and suggested that the labeling include information that the product:
(1) Protects against drug-induced photosensitization reactions induced
by UV radiation in the ranges ____ nm to ____ nm, and (2) other
truthful and nonmisleading statements describing both UVB and UVA
radiation protection against photosensitization reactions.
    The agency did not propose professional labeling in the tentative
final monograph, but did ask for data to be submitted (58 FR 28194 at
28210 and 28245). No data were received. The agency will consider
including this type of professional labeling in the monograph in the
future when specific supportive data are provided.

G. Comments on Sunscreen Drug Products With High SPF Values

    29. Numerous comments objected to the proposed maximum SPF value of
30 for OTC sunscreen drug products. The comments requested either that
the agency adopt no limit or a limit of SPF 50, for the following
reasons: (1) UV radiation exposure is increasing due to both lifestyle
changes and depletion of the atmospheric ozone layer, (2) skin cancer
rates are increasing and there is no safe threshold to prevent cancer,
(3) people using an SPF 30 sunscreen will have slight sunburn after
receiving their 30 MED and therefore should have available sunscreens
with higher SPF values, (4) high SPF sunscreens are needed for
extremely sun-sensitive people during periods of unavoidable intense or
lengthy sun exposure, and because of less than ideal usage by consumers
due to misjudging of their skin type and/or inadequate/infrequent
application, (5) there is a significant variation of skin types,
sensitivities, and UV radiation exposures among people, (6) formulation
techniques can increase SPF values without necessarily increasing
ingredient concentrations, (7) current information does not support an
association between high SPF products and safety concerns, and (8) high
SPF products provide for greater relative exposure times and decreased
UV radiation transmission. Three comments (Refs. 21, 22, and 23)
submitted supporting data.
    Some comments stated that ``High SPF'' (i.e., above SPF 30)
products are on the market and used by consumers, and that limiting SPF
values would stifle sunscreen product development and preventative
health benefits. Other comments argued that sunscreens with high SPF
values provide increased protection from ultraviolet radiation effects
such as photoimmunosuppression and are needed by those with
``dermatological problems.''
    In contrast, some comments supported the agency's proposal to limit
SPF values to 30 to stop the promotional ``bidding war'' or
``horsepower race.'' Another comment contended that real consumer
benefit is achieved through appropriate balance of SPF, substantivity,
UVA radiation protection, irritation potential, and cost, whereas SPF
values above 30 provide only ``incremental benefit'' and an unnecessary
increase in drug exposure.
     The data provided by the comments in support of allowing numerical
values above 30 were of only limited use. Data from a field survey of
62 sunbathers on Miami's South Beach during July 1993 (Ref. 21) did not
provide any reliable conclusions on the frequency or extent of solar
overexposure by light-skinned individuals or a benefit provided by
sunscreen products with an SPF value above 30 as: (1) The sample size
was small and the survey population did not represent a random sample,
(2) the MED was not determined under controlled conditions or
standardized procedure, and (3) full-day UVB radiation exposure was
based on crude extrapolation of weather data.
    Data from MED determinations on 1,332 people with skin types I, II,
and III, and UV radiation data for the month of June 1974 in 5 cities
in the United States (Ref. 22), support the contention that a sizeable
population may exist that is at risk to more than 30 MED's of UV
radiation per day. However, the data are insufficient for extrapolation
to the general population. The small sample size in this study limits
the sensitivity of the study and the study population did not represent
a random sample.
    Finally, data from animal studies (Ref. 23) showed that: (1)
Limiting sunscreen protection to SPF 30 may not be prudent if UV
radiation damage is not related to SPF; (2) a greater amount of
sunscreen is needed to completely inhibit some of the nonerythemogenic
damage caused by UV radiation, and (3) nonerythemogenic effects (e.g.,
photoimmunosuppression) occur with suberythemal doses of UV radiation
(as can be obtained with the use of low or high SPF sunscreens). While
the agency agrees that higher SPF values may provide for greater
relative exposure times, the SPF test is not the appropriate
measurement of protection from nonerythemogenic damage because SPF is
only a measure of erythema. The agency finds that the data from these
studies were not sufficient to either support or dismiss limiting the
maximum SPF value in this final rule.
    The agency continues to agree with the comments about overall
increases in both UV radiation exposure (58 FR 28194 at 28223), skin
cancer rates (58 FR 28194 at 28227), and the variation of skin types,
sensitivities, and UV radiation exposures among people (58 FR 28194 at
28222). The agency also agrees with the comment that a person using an
SPF 30 sunscreen could have a slight sunburn after being exposed to
their 30 MED (i.e., after their skin receives a MED). However, the
agency continues to believe that an SPF 30 sunscreen product provides
adequate

[[Page 27675]]

protection for the majority of consumers even under extreme conditions,
less than ideal usage, or in varying weather conditions (58 FR 28194 at
28225).
    On the other hand, the agency is also aware that many OTC sunscreen
products with SPF values above 30 are currently marketed and are
increasingly used by consumers. Numerous comments from health
professionals, consumers, and industry provide actual use information
in support of SPF values above 30 for what may be a substantial number
of sun-sensitive people in this country. Further, as numerous comments
noted: (1) There is a lack of data to correlate higher than SPF 30
sunscreen products with corresponding safety problems, and (2) modern
formulation techniques have resulted in higher SPF values using lower
active ingredient concentrations.
    Because of the numerous concerns from health professionals, new
data to support the need for SPF values above 30, and the lack of data
concerning safety problems with such SPF values, the agency concludes
that OTC sunscreen drug products with SPF values above 30 should be
available for those sun-sensitive consumers who require such products
based upon personal knowledge of their skin's susceptibility to
sunburn, experience with specific products, planned sun exposure, or
the recommendation of a health professional. The agency agrees with the
comments that higher SPF values generally can provide for greater
relative exposure times and decreased UV radiation transmission.
However, the agency continues to believe that the additional sunburn
protection provided by an SPF 30 sunscreen and, e.g., an SPF 50
sunscreen (i.e., about a 1.3 percent increase in absorption of
erythemal UV radiation) is extremely small for most people. The agency
is also concerned about the ability of current testing methods to
accurately and reproducibly determine SPF values for high SPF products
(see section II.M, comment 53 of this document). In addition,
nonlinearity of the SPF rating system is a concept difficult to explain
in the limited space on a product label. Therefore, the agency
concludes that the label SPF declaration for sunscreens with SPF values
above 30 should be limited to one collective term, which appears in
Sec. 352.50(a) of this document as follows: ``For products with SPF
values over 30. ``SPF 30'' (select one of the following: ``plus'' or
``+''). Any statement accompanying the marketed product that states a
specific SPF value above 30 or similar language indicating a person can
stay in the sun more than 30 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).''
    Numerous comments from dermatologists asked that a specific SPF 50
product be allowed to remain on the market because it is needed for the
``ultrasensitive patient'' and for patients with ``dermatological
problems.'' The agency has previously discussed the use of high SPF
sunscreen drug products to protect consumers with photosensitivity
diseases (58 FR 28194 28225) and the need to provide data for such uses
(see section II.F, comment 28 of this document) as the absorption
spectrum of a specific product, not necessarily the SPF, may be the
more clinically significant factor for such people.
    As discussed previously in this comment 29 of section II.G of this
document, the agency has concluded that the use of SPF label values
above 30 in OTC drug products is not supported at this time. The
agency, however, invites interested persons to continue developing the
test methods needed to measure high SPF values, and to submit the data
in support of such methods to FDA. If test methods are developed, the
agency also invites interested persons to consider proposed methods for
communicating in labeling the level of protection associated with high
SPF values (given the nonlinear nature of the SPF rating system). These
and other well-supported improvements to the methodology for accurately
and reproducibly measuring SPF values will be addressed, as
appropriate, in future issues of the Federal Register. Until then, OTC
sunscreen drug products are permitted to be labeled with SPF values no
higher than ``30+'' or ``30 plus.''
    Finally, the agency does not agree with the argument that limiting
SPF values would stifle sunscreen product development and preventative
health benefits. Undue emphasis for sunburn protection should not be
placed upon SPF value alone (i.e., ``single focus products''). As noted
by another comment, consumer benefit is achieved through appropriate
balance of several factors, including substantivity, UVA radiation
protection, and irritation potential.

H. Comments on Water Resistant Labeling and Testing for Sunscreen Drug
Products

    30. One comment agreed and several disagreed with proposed
Sec. 352.52(e)(2)(iii) and (e)(3)(iii) concerning sweat resistant
claims based upon water resistance testing instead of a specific sweat
resistance test. One comment submitted data from two sweat resistance
studies and two water resistance studies (Ref. 24) utilizing methods
proposed by the Panel in the ANPRM (43 FR 38206) and involving a total
of 117 subjects. The comment concluded that the water resistance test
is less stressful than the sweat resistance test.
    The agency does not find the data submitted in the studies
sufficient to support the comment's contention. The studies each
comprised distinct subject populations and addressed a single variable,
i.e., the effect of water exposure or induced sweating on a product's
SPF. Therefore, a comparison of mean SPF values across studies is not
the appropriate measure of relative ``stress'' associated with these
variables. The agency believes that a randomized, two-period crossover
study design in a single patient population would better have addressed
the comment's contention. Further, the Panel's sweat and water
resistance protocols provide qualitative information and were not
designed to provide comparative assertions requiring valid statistical
inferences. Thus, the agency is allowing water and sweat resistant
claims based upon the water resistance test procedures in Sec. 352.76
of this document.
    31. One comment contended that the ``water resistant'' labeling
proposed in Sec. 352.50(b)(1) and (c)(1) should not be required for
products labeled or purchased for uses other than swimming or bathing.
    The agency notes that the water resistance statements referenced by
the comment were not required unless the manufacturer wished to make
water resistant claims in the labeling of its sunscreen products. This
final rule also will not require a manufacturer to make a water
resistance claim for its sunscreen product, even if the product is
determined to be water resistant. However, a manufacturer wishing to
make water resistance claims must comply with Secs. 352.50(b) or (c)
and 352.52(b)(1)(ii) or (b)(1)(iii) of this document, as applicable for
``water resistant'' or ``very water resistant'' products.
    32. Several comments urged the agency to return to the
``waterproof'' and ``water resistant'' label claims proposed by the
Panel and to limit the labeled SPF value to only the SPF after water
resistance testing. Another comment requested only general guidelines
for claims such as ``water resistant'' or ``sweat resistant'' on the
basis that such claims reflect the inherent characteristics of specific
formulations and not sunscreen ingredients.

[[Page 27676]]

    The agency thoroughly discussed use of the terms ``waterproof'' and
``water resistant'' in the tentative final monograph (58 FR 28194 at
28228). The comments did not present any arguments or data that the
agency did not previously consider. In addition, the agency points out
that performance claims such as these for OTC sunscreen drug products
are based on final product formulation.
    The agency agrees with the comments that the more relevant SPF
value for products labeled ``water resistant'' or ``very water
resistant'' is the SPF value of the final product formulation following
water resistance testing. Therefore, in this document the agency is
limiting the SPF label declaration to the SPF after water resistance
testing and is modifying the testing procedures in Sec. 352.76 to
reflect deletion of the proposed dual SPF testing requirement for
sunscreen products with water resistant claims.
    33. Two comments suggested that ``water resistant'' labeling be
permitted for drug products retaining at least 80 percent of their SPF
value after static testing in pools and that any product meeting this
criterion could also be labeled ``sweat proof.'' The comments further
suggested that the term ``very water resistant'' should be permitted
for products retaining 90 to 98 percent of their SPF after testing.
    The agency disagrees with the comments. Simple immersion provides
neither an aqueous shear stress nor thermal challenge, and thus is an
inadequate assessment of water resistance. In addition, no
justification was offered for the respective threshold values of 80
percent and 90 to 98 percent.
    34. Several comments contended that the water resistance testing
procedures in Sec. 352.76 should be amended to allow for continuation
of the water exposure regimen beyond the 80 minute total and suggested
that the ``very water resistant'' claim be expanded beyond 80 minutes
for products meeting such testing requirements. One comment provided
data (Ref. 24) to support extended water resistance claims. Another
comment also proposed a testing protocol (Ref. 25) for an additional
claim of ``rubproof'' or ``abrasion proof.''
    The agency does not concur with an expansion of the ``very water
resistant'' claim. Although data submitted by the comment (Ref. 24)
show that under testing conditions products may retain their SPF values
for up to 270 minutes of water exposure, no usage data were presented
to refute the Panel's determination of an 80 minute upper exposure
limit (58 FR 28194 at 28277). In addition, the agency believes that for
consumers to compare products with multiple performance
characteristics, a labeling claim of ``very water resistant'' is best
supported by a uniform testing standard. Should the agency receive data
in the future indicating customary usage patterns in excess of 80
minutes of water exposure, it will reconsider this limit.
    35. One comment disagreed with the agency's proposal in the
tentative final monograph (58 FR 28194 at 28278) that manufacturers
determine the waiting periods for the most effective use of their
sunscreen products (i.e., the time between application and exposure to
the sun or water, if applicable). This information would then be
included in the directions for the product. The comment asserted there
is no reason to require a ``time versus efficacy'' study for every
sunscreen formula because studies show that products maintain their
efficacy for up to 8 hours.
    In the tentative final monograph, the agency did not propose a
specific method or testing procedure for the determination of a proper
waiting period because of the variation in sunscreen product dosage
forms and formulations. Instead, the agency allowed manufacturers to
make this determination. However, the agency did propose in
Sec. 352.52(d)(2) that a waiting period before sun or water exposure,
if applicable, be included in the labeling of sunscreen products for
their most effective use. In this final rule, the agency has included
the requirement for a waiting period in the sunscreen product
application statement in proposed Sec. 352.52(d)(1) for the reasons
stated in the tentative final monograph (58 FR 28278). The agency
continues to allow the manufacturer to determine both the necessity for
this statement (based on the product's formulation and dosage form) and
how the waiting period, if applicable, is determined.

I. Comments on Indications for Sunscreen Drug Products

    36. One comment urged the agency to more strongly state the
effectiveness of sunscreens (a specific claim was not suggested). The
comment cited a controlled study of a broad spectrum, SPF 17 sunscreen
on 431 Caucasian subjects over one summer in Australia (Ref. 26). The
study showed that the group using the sunscreen had significantly fewer
solar keratoses and more remissions than the control group. Another
comment expressed concern that use of the term ``help prevent skin
damage'' may mislead consumers to think that these products prevent
skin cancer and premature skin aging.
    The agency agrees that solar keratoses are a clinical sign of skin
damage. However, although sunscreens are associated with a
statistically significant decrease in solar keratoses after 1 or 2
years, the solar keratoses reduction in this study was small and
neither the clinical nor biological significance of this reduction has
been established. Most solar keratoses never become skin cancers and
typically resolve spontaneously (Refs. 27 and 28).
    Because of the wide variability possible in the formulation of
sunscreen products, not all sunscreen products are identical in their
UV radiation absorption characteristics. Sunscreen products may contain
active ingredients that absorb in different regions of the UVB
radiation spectrum (the primary cause of sunburn) or absorb in both the
UVB and different regions of the UVA radiation spectrum. Therefore,
even the degree/type of UV radiation protection reported in one study
using a specific sunscreen formulation may not be relevant to all
possible sunscreen products within the scope of this final monograph.
Further, the agency does not believe that it is prudent to extrapolate
claims for skin cancer or skin aging based upon a test designed to only
measure erythema (i.e., the SPF test).
    The agency has reviewed information concerning the mechanisms of
skin cancers and photoaging. UV radiation appears to have a dual role
in the induction of skin cancers as it can cause several varieties of
direct DNA damage (Refs. 23 and 29 through 32) plus suppress the immune
response to developing skin cancers (Refs. 33 through 37). This immune
suppression may be a critical variable as skin cancers, unlike other
cancer types, evoke a strong immune response (especially by Langerhans
cells and T-lymphocytes) (Ref. 38). In photoaging, there are multiple
sites in the skin that can be damaged by UV radiation (Ref. 17). For
example, recent studies support the concept that specific UV radiation-
induced enzymes (i.e., matrix metalloproteinases) can mediate
connective tissue damage and result in the premature aging effects seen
in skin exposed to UV radiation (Refs. 19 and 20). These data also
suggest that these mechanisms of carcinogenesis and photoaging can
occur from doses of UV radiation below that required to produce sunburn
(i.e., suberythemal doses). Thus, even if no sunburn has occurred with
the use of a sunscreen, the consumer cannot assume that sun-induced
skin damage that might contribute to the eventual development

[[Page 27677]]

of skin cancer or signs of photoaging has not occurred.
    The agency agrees with the comment that terms such as ``help
prevent skin damage'' may mislead consumers to think that sunscreen use
alone will prevent skin cancer and premature skin aging. However, the
agency believes that an appropriate statement can be used to inform
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 includes limiting sun exposure and wearing protective
clothing (see section II.L, comment 51 of this document).
    37. Several comments expressed concern that the statements ``Allows
you to stay in the sun up to (insert SPF of product up to 30) times
longer than without sunscreen protection'' and ``Provides up to (insert
SPF of product up to 30) times your natural protection from sunburn''
in proposed Sec. 352.52(b)(1)(iii) and (b)(1)(iv) may mislead consumers
as to the amount and degree of protection sunscreen products provide.
The comments were concerned that this message will convey a more
expansive meaning than intended and that consumers might be misled
about how long they can stay in the sun without risking any sun-induced
skin injury. One comment expressed additional concern because the SPF
value is only a laboratory test of a few minutes duration.
    One comment also objected to the unqualified use of terms such as
``shields from,'' ``protects from,'' ``filters'' or ``screens out'' the
``sun's rays,'' ``sun's harsh rays,'' or ``sun's harmful rays'' to
``help prevent skin damage'' proposed in Sec. 352.52(b)(1)(v) and
(b)(1)(vi). The comment expressed concern that these unqualified terms
could imply complete protection from the sun's harmful rays and may
mislead consumers by inducing a false sense of security when using
sunscreen products.
    As discussed in section II.I, comment 36 of this document, the
agency believes that sunscreen use alone will not prevent all of the
possible harmful effects due to the sun. Variation between individuals,
UV radiation absorption and substantivity of sunscreen products,
exposure conditions, and conditions of use cannot promise a precise
result for each individual. Thus, the agency agrees that these
statements could provide the wrong message and a false sense of
security to some consumers. The agency therefore is not including
proposed Sec. 352.52(b)(1)(iii) through (b)(1)(vi) in this final rule
and considers these and similar statements to be nonmonograph. For the
same reasons, the agency also considers extended wear claims concerning
a specific number of hours of ``protection'' (or similar terminology)
or an absolute claim such as ``all-day protection'' to be nonmonograph.
Instead, the agency is including an accurate, simpler, and less
confusing indication statement in this final rule using two bulleted
statements under the ``Uses'' heading, as follows: ``[bullet] helps
prevent sunburn'' and ``[bullet] higher SPF gives more sunburn
protection''.\1\
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4)
---------------------------------------------------------------------------

    38. Several comments contended that terms such as ``skin aging,''
``wrinkling,'' ``premature skin aging,'' or ``photoaging'' should be
permitted as indications for sunscreens, especially if protection is
provided in the UVA II (320 to 340 nm) radiation region. One comment
suggested that a label claim such as ``Helps reduce the chance of skin
aging caused by incidental (or casual) exposure to the sun'' may help
to further position the product as a cosmetic for consumers. The
comment also suggested an indication statement: ``Excessive, chronic
sun exposure can lead to premature photoaging of the skin,
characterized by drying, wrinkling and thinning of the skin. Regular
use of a sunscreen can help protect against this condition.''
    The agency discussed the use of terms such as ``skin aging,''
``wrinkling,'' ``premature skin aging,'' or ``photoaging'' on sunscreen
products in the tentative final monograph (58 FR 28194 at 28236 and
28287). As discussed in the response to comments 36 and 37, the agency
has determined that the labeling should describe the product's use in
preventing sunburn. A more expansive set of indications is currently
unsupported. The agency notes, however, that the final ``Sun alert''
statement (discussed in section II.L, comment 51 of this document) does
provide the consumer with information about the role of sunscreens in
reducing skin aging, in a context that ensures that the information
will not be misleading. The agency, however, is continuing to consider
whether certain sunscreens may provide protection against photoaging
(58 FR at 28287) and has discussed this in tentative final monograph
amendments for certain sunscreens containing avobenzone or zinc oxide
based upon specific data submitted to the agency (see section II.E,
comment 22 of this document). The agency will evaluate this issue
further when it completes the UVA portion of the sunscreen monograph,
in a future issue of the Federal Register.
    39. Several comments contended that the extensive labeling proposed
in the tentative final monograph was excessive. For environmental
concerns, the comments objected to the use of extra packaging materials
as a method of including added labeling. One comment disagreed with the
need for a specific statement of product indications on individual
units of non-beach products properly labeled with an SPF value, and
cited limitations on labeling space. The comment suggested that
manufacturers be given the option to provide off-package information at
the point-of-sale rather than be required to place the statement(s) on
each individual unit of the product.
    To balance the environmental and regulatory concerns, the agency
has streamlined labeling in this final monograph by significantly
reducing the amount of required labeling and making optional other
labeling that was proposed as required in the tentative final
monograph. The agency is also including Sec. 352.52(f) in this final
monograph to provide for additional labeling accommodations for
sunscreen products that meet the small package specifications in
Sec. 201.66(d)(10) and are labeled for use on specific small areas of
the face (e.g., lips, nose, ears, and/or around eyes) (see section IV,
comment 6 of this document).

J. Comments on Warnings for Sunscreen Drug Products

    40. One comment asked the agency to permit reduced warning
statements for lip balm products containing sunscreens based on their
safe market history. The comment argued that lip balms are not applied
to the eye area, and thus extensive eye warnings are not required. Two
comments cited the long history of safe use of lipstick products
containing sunscreens and suggested the reduced warning, ``Discontinue
use if signs of irritation appear.''
    The agency discussed its rationale for proposing an eye warning for
sunscreen-containing lip balms in comment 52 of the tentative final
monograph (58 FR 28194 at 28229 to 28232), noting that some lip balms
could be used on other areas of the face. However, the agency has
received neither data concerning adverse reactions due to the use of
sunscreen-containing lip balms near the eyes, nor information that such
products are normally used in the eye area. These products also are
consistent with the factors described in the final OTC standardized
content and format labeling rule (64 FR 13254 at 13270) for considering
additional labeling modifications. Accordingly, this final monograph
allows sunscreen-containing

[[Page 27678]]

lipsticks to omit the eye warning in proposed Sec. 352.52(c)(1)(i). As
discussed in Section II.J, comment 42 of this document, the wording of
this warning is modified in this final monograph. For lip balms, the
agency expects to adopt the same modification when it issues the final
monograph on OTC skin protectant drug products.
    The proposed warning in Sec. 352.52(c)(1)(iii) is now stated as a
bullet under the ``Stop use and ask a doctor if'' subheading as
follows: ``[bullet] rash or irritation develops and lasts.'' This
warning appears in Sec. 352.52(c)(1)(ii) in this document. Finally,
lipsticks (and lip balms, which will be addressed in the final
monograph on OTC skin protectant drug products) will not be required to
bear the ``For external use only'' warning. Accordingly, in this final
monograph, Sec. 352.52(c)(2) allows lipsticks to omit the warning in
Sec. 201.66(c)(5)(i).
    41. One comment requested that an eye irritancy warning need not be
required for products that contain titanium dioxide as the sole active
ingredient. The comment stated that titanium dioxide is an inert
inorganic oxide (and thus is chemically distinct from all other
Category I sunscreen active ingredients, which are organic compounds)
and is an FDA approved color additive for the eye area in both drugs
and cosmetics. The comment argued that determination of eye irritancy
should be based on total product formulation. A second comment
concurred that the labeling for inorganic sunscreens, which are not eye
irritants, should be differentiated from organic sunscreens, which may
be irritants in the eye.
    The agency agrees that the eye warning (proposed in
Sec. 352.52(c)(1)(ii)) is based on total formulation, not simply
presence of an ingredient. The agency's rationale was discussed in
comments 52 and 62 of the tentative final monograph (58 FR 28194 at
28229 to 28232 and 28241). Accordingly, this final monograph requires
all sunscreen-containing drug products to bear the eye warning in
Sec. 352.52(c)(1)(i). Only products formulated as a lipstick (and lip
balms, which will be addressed in the final monograph on OTC skin
protectant drug products) may omit this warning (see Sec. 352.52(c)(3)
of this document). The agency will consider omitting the eye warning
requirement for a particular formulation if data submitted in an NDA
deviation (Sec. 330.11 (21 CFR 330.11)) from the sunscreen monograph
demonstrate it is not an eye irritant.
    42. One comment suggested restating the proposed warnings in
Sec. 352.52(c)(1) more concisely, as follows: ``For external use only.
Keep out of eyes. If contact occurs, rinse thoroughly with water. If
irritation or rash occurs, discontinue use. Consult a doctor if problem
persists.''
    Since the tentative final monograph was published, the agency has
published a final rule revising the format and content requirements for
OTC drug product labeling (64 FR 13254). Section 201.66(c)(5)(i)
requires the warning ``For external use only'' for all topical drug
products not intended for ingestion. Therefore, it is not necessary to
state that warning in this document and the warning in proposed
Sec. 352.52(c)(1)(i) is not included in this final monograph. The
agency is shortening the proposed warning in Sec. 352.52(c)(1)(ii).
This warning appears in Sec. 352.52(c)(1)(i) in this document as a
bullet under the ``When using this product'' subheading as follows:
``[bullet] keep out of eyes. Rinse with water to remove.'' The agency
is stating the proposed warning in Sec. 352.52(c)(1)(iii) as a bullet
under the ``Stop use and ask a doctor if'' subheading as follows:
``[bullet] rash or irritation develops and lasts.'' This warning
appears in Sec. 352.52(c)(1)(ii) in this document. Section
201.66(c)(5)(x) requires the ``Keep out of reach of children'' and
accidental ingestion warning set forth in 21 CFR 330.1(g) for these
products.
    43. One comment contended that the proposed warning about
swallowing in Sec. 352.52(c)(1)(i) would not be needed for so-called
secondary sunscreen products because adults using these products
(which, according to the comment, have traditionally been marketed as
cosmetics) would know not to ingest them.
    As discussed in section II.J, comment 42 of this document, the
warning proposed in Sec. 352.52(c)(1)(i) has been superseded by the
warning required by Sec. 201.66(c)(5)(i). The new required warning no
longer contains the statement about not swallowing the product.

K. Comments on Directions for Sunscreen Drug Products

    44. Two comments stated that the proposed directions in
Sec. 352.53(d)(4) for lipsticks and make-up preparations are
unnecessary because these products are marketed primarily for their
cosmetic uses, which are self-evident. One comment contended that it is
unlikely that consumers will modify their habits of lipstick
application and usage simply because the product contains a sunscreen.
The other comment argued that failure to follow directions for these
products is unlikely to have serious consequences.
    The agency has determined that directions for use in the labeling
of lipstick products containing sunscreens would provide minimal
benefit to consumers and the omission of a directions statement is not
likely to have serious consequences (see section II.J, comment 40 of
this document). However, the agency believes that directions would be
useful for make-up products containing sunscreens because of the wide
variety of make-up products that are available. Therefore, the agency
is revising proposed Sec. 352.52(d)(4) to read: ``For products
formulated as a lipstick. The directions in paragraphs (d)(1) and
(d)(2) of this section are not required.'' The agency expects to
finalize the same modifications for lip balm products when it finalizes
the monograph for OTC skin protectant drug products.
    45. Several comments contended that the proposed direction,
``Children under 2 years of age should use sunscreen products with a
minimum SPF of 4,'' is misleading and has no scientific basis. Some
comments stated that the direction implies that an SPF 4 may be
adequate for children and noted that the Skin Cancer Foundation advises
use of SPF 15 or higher for both children and adults. The American
Academy of Dermatology questioned why children should not have the
benefit of a more highly protective sunscreen. Other comments suggested
that this direction should only be required for products with an SPF
lower than 4 because it would be nonsensical and a waste of label space
on products with higher SPF values.
    The agency agrees with the comments that this direction could
mislead parents into believing SPF 4 is adequate for children under 2
years of age. Therefore, the agency concludes it is not appropriate and
is not including it in Sec. 352.52(d) in this document.
    46. One comment stated that the words, ``adults and children 6
months of age and over'' in proposed Sec. 352.52(d)(1) are unnecessary
because there is a separate statement, ``Children under 6 months of
age: consult a doctor.'' Another comment suggested that lengthy
directions for use by children 6 months to 2 years of age are not
appropriate for many product types (e.g., a daily facial moisturizer
with a sunscreen) and should be revised to ``For adult use only.''
Another comment added that when ``For adult use only'' is used, then
warning and cautionary statements concerning use by children would not
be needed.

[[Page 27679]]

    The agency agrees with the comment that the statement, ``Children
under 6 months of age: consult a doctor,'' provides sufficient
information regarding the age limit for use and is retaining it under
Sec. 352.52(d) as a bullet with a small modification as follows:
``[bullet] children under 6 months of age: ask a doctor''. Therefore,
the agency is removing the phrase, ``Adults and children 6 months of
age and over.'' The proposed directions for children 6 months to 2
years of age referred to by the comments in Sec. 352.52(d)(1), (d)(2),
(d)(3), and (d)(5) stated: ``Children under 2 years of age should use
sunscreen products with a minimum SPF of 4.'' As discussed in section
II.K, comment 45 of this document, the agency concluded that this
direction was misleading and did not include it in Sec. 352.52(d) in
this document. The agency finds it unnecessary to include the direction
``For adult use only'' in this document because there are only two age
groups in the directions: Children under 6 months of age and all other
users of the product.
    47. One comment argued that the direction ``apply generously'' may
be responsible for some skin irritation complaints from consumers.
However, the comment did not provide data to support its position. The
comment contended that application of smaller amounts of sunscreen may
provide adequate coverage, but that in the case of sun protection, it
may be best to err on the generous side. Another comment maintained
that applying too little sunscreen may significantly lower protection
in a geometric rather than a linear fashion, e.g., an SPF 25 sunscreen
applied half as thick as the amount applied for the SPF test may only
have the effect of SPF 8.
    The agency agrees with the comments that adequate sunscreen should
be applied to achieve full labeled SPF protection. Therefore, the
agency concludes that the directions in Sec. 352.52(d)(1) of this final
monograph to apply ``liberally'' or ``generously'' convey the
appropriate message to ensure that consumers adequately apply the
sunscreen.
    48. One comment stated that the agency should permit firms to
provide reapplication instructions based on substantiation information
the firm possesses. The comment noted that some products may not need
to be applied as frequently as some select time period.
    The agency is including a general reapplication direction in
Sec. 352.52(d)(2). Manufacturers who have data to support reapplication
instructions based on specific substantiation information may submit
that information for approval via an NDA deviation as provided in
Sec. 330.11.

L. Comments on Product Performance Statements for Sunscreen Drug
Products

    49. Several comments recommended revisions to proposed
Sec. 352.52(e), the statement on product performance. For example, some
comments suggested that multiple superlative category designations
(e.g., ``high,'' ``very high,'' and ``ultra high'') may foster consumer
confusion about the level of protection each SPF provides. Other
comments stated that the current SPF scale does not encourage consumers
to use higher SPF products. Other comments disagreed with the
indication ``permits no tanning.''
    The agency has revised proposed Sec. 352.52(e) in this document by
condensing the five proposed product categories to three broader ones,
and has generalized the category designations. The new categories are:
minimal sunburn protection for products with SPF 2 to under 12;
Moderate sunburn protection for products with SPF 12 to under 30; high
sunburn protection for products with SPF 30 or above. These product
category designations (PCD) should appear under the ``Other
information'' heading and may also appear on the PDP. Further, products
are now described as providing minimal, moderate, or high protection
against tanning, thus deleting the reference to tanning prevention that
was proposed in Sec. 352.52(b)(2)(v)(B).
    50. Many comments opposed the ``recommended sunscreen product
guide'' in proposed Sec. 352.52(e)(4). Some comments noted that the
guide is incomplete because it only considers skin type and not
duration of exposure, season, geographic location, and other factors
that influence choice of product. Other comments stated that the guide
is deceptive and may encourage inappropriate use of lower SPF's for
protection. Several comments stated that labeling for many products is
too small to accommodate the guide. Other comments suggested that
information in the guide should be disseminated to consumers through
point of sale, television, and weather programs, rather than being
required in product labeling.
    The agency recognizes that various factors influence the purchase
of a sunscreen product, including skin type, geographic location, hours
exposed to the sun, and sun reflections. While the product guide was
intended as a general guidance for using these products, the agency
acknowledges that the guide is incomplete and could be confusing and
misleading to consumers. Accordingly, the agency is not including the
recommended sunscreen product guide in this document.
    51. Many comments requested that the ``Sun alert'' in proposed
Sec. 352.52(e)(6) be voluntary instead of required labeling and
suggested this information could better be disseminated at the point of
purchase or through consumer education programs. Some comments stated
that the ``Sun alert'' is too weak and suggested alternate language.
One comment observed that the ``Sun alert'' fails to warn consumers
that UV radiation may harm the immune system, impairing the body's
ability to fight infectious disease. The comment did not provide data
to support this claim.
    The agency agrees that the ``Sun alert'' should be optional on
product labeling. Further, the agency has reevaluated the ``Sun alert''
and concludes that its purpose should be to describe the role of
sunscreens in a total program to reduce harmful effects from the sun.
Marks (Ref. 39) has noted that sunscreens ``are normally recommended
for use as an adjunct to other protection,'' such as clothing, hats,
and avoidance of the sun near midday. The agency agrees with this
concept, as do many researchers (Ref. 40), the American Academy of
Dermatology (Ref. 41), Centers for Disease Control (Ref. 41), and the
Governments of Australia and New Zealand (Ref. 42). For this reason,
the agency has revised the ``Sun alert'' to include other protective
actions consumers can take, and has clarified possible results. The
agency is including skin cancer in the ``Sun alert'' instead of the
body's ability to fight infectious disease because, to date, skin
cancer is the best documented adverse effect of UV radiation on the
immune system (Ref. 43). Accordingly, Sec. 352.52(e)(2) in this
document provides the following optional ``Sun alert,'' which should
appear under the ``Other information'' heading and may also appear on
the PDP: ``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 agency encourages sunscreen
manufacturers to voluntarily include this ``Sun alert'' in the labeling
and to otherwise make it available at point of purchase and through
consumer education programs.
    52. Several comments suggested that the term ``sunblock,'' proposed
in the definition in Sec. 352.3(d) and as a labeling statement for
products containing titanium dioxide that provide an SPF of 12 to 30 in
Sec. 352.52(e)(5), not be included in the final monograph. Some

[[Page 27680]]

comments argued that the term is unclear and may mislead and confuse
consumers into thinking that the product blocks all of the sun, when in
fact it does not. One comment stated that no product available totally
blocks sun damage. Numerous other comments contended that the term
``sunblock'' should be applied to all sunscreen ingredients that
provide an SPF of 12 or higher, as such products block at least 90
percent of the sun's UV rays. One of the comments submitted a study
(Ref. 44) to show that micronized titanium dioxide absorbs short
wavelength UV radiation and reflects and scatters long wavelengths,
thereby functioning similarly to chemical UVB radiation sunscreens. The
comment contended that the method in which micronized titanium dioxide
performs as a sunscreen active ingredient further justifies the use of
the term ``sunblock'' for all sunscreen products with an SPF of 12 or
higher.
    The agency has decided not to include the term ``sunblock'' in the
final monograph and now considers this term nonmonograph. The agency's
intention in the tentative final monograph was to provide information
to consumers on the method of product performance, not to imply greater
protection from using a product labeled as a ``sunblock.'' The agency
is concerned that the term ``sunblock'' on the label of sunscreen drug
products will be viewed as an absolute term which may mislead or
confuse consumers into thinking that the product blocks all light from
the sun. For example, consumers might view an SPF 15 product labeled as
a sunblock as superior to a product labeled as an SPF 30 broad spectrum
sunscreen. As nonmonograph labeling, the term ``sunblock'' cannot
appear anywhere in product labeling.
    In addition, the proposed definition of ``sunscreen opaque
sunblock'' in Sec. 352.3(d) applied only to titanium dioxide and is
inconsistent with how micronized titanium dioxide functions as an
sunscreen active ingredient (Ref. 44). Further, it is the radiation
from the UV portion (290 to 400 nm) of the sun's spectrum that reaches
the earth's surface and may produce skin erythema, melanogenesis, and
cancer. The agency believes that claims of protection beyond 400 nm
(i.e., protection from visible and infra red light) are nonmonograph
and not within the scope of this document. Therefore, to provide clear
and consistent labeling, the agency is not including proposed
Secs. 352.3(d) and 352.52(e)(5) in this document.

M. Comments on Testing Procedures for Sunscreen Drug Products

    53. Several comments questioned the ability of current testing
methods to accurately and reproducibly determine SPF values for high
SPF products. Some comments contended that the spectra of currently
used solar simulators (especially around 290 nm and above 350 nm) could
cause overestimation of SPF for high SPF sunscreens and recommended use
of a specifications table that provided percent of erythemal
contribution by wavelength regions. Other comments submitted data in
support of a high-SPF sunscreen control following concerns expressed by
the agency in the proposed rule (58 FR 28194 at 28253 and 28254) that
data were not sufficient to demonstrate that the testing methods used
to evaluate sunscreen drug products with SPF values up to 15 are
equally applicable to evaluating sunscreen drug products with SPF
values above 15. Several comments submitted data and information that
questioned the ability of current testing methods to accurately and
reproducibly determine SPF values for high SPF products and requested
significant changes to proposed subpart D of Sec. 352.70. Other
comments requested changes to the testing procedures proposed in
subpart D of the sunscreen monograph that were unrelated to products
with high SPF values.
    The agency believes that the test method proposed in the tentative
final monograph (TFM), for measuring SPF values up to 30, represents at
this time a straightforward, well-understood, and sound method for
measuring these values. The agency therefore is finalizing the method
proposed in the TFM. The agency recognizes, however, that testing
methods in this area are evolving and that a number of comments raised
useful ideas for proposed improvements in the accuracy and
reproducibility of the agency's methodology. As discussed in response
to comment 29 of section II.G of this document, the agency is also
inviting interested persons to continue working on improving SPF
testing methods, toward the development of accurate methods for
measuring high SPF values. In future issues of the Federal Register, if
appropriate, the agency will consider proposed improvements to its
testing methodology.
    54. One comment contended that the calculation of erythema
effective exposure (E) serves no practical purpose in the calculation
of SPF because the E constant is common to both the numerator and
denominator of the equation. Another comment stated that the definition
of E is incorrect because it is defined as ``dose'' (Joules/square
meter (m<SUP>2</SUP>)) on the left side of the equation E = <greek-S>
V<INF>i</INF> (<greek-l>) * I (<greek-l>), whereas the right side of
the equation is in terms of irradiance (Watts/m<SUP>2</SUP>). The
comment also stated that the unit of time exposure (seconds) is missing
on the right side of the equation.
    The agency acknowledges that this calculation is not technically
necessary if the solar simulator emission spectrum does not change
between exposures to protected and unprotected skin. The same result
can then be obtained by measuring the difference (i.e., ratio) in time
required to produce erythema on protected versus unprotected skin.
However, the agency finds that the calculation of E provides valuable
information and is necessary to demonstrate how the MED was determined
during SPF testing. The agency agrees with the comment concerning the
missing variable of time (in seconds) in the calculation of E and,
accordingly, has modified the equation in Sec. 352.73 of this document
to read as follows: `` E = <greek-S> V<INF>i</INF> (<greek-l>) * I
(<greek-l>) * t<INF>exp</INF>''

III. Recent Developments

    In the Federal Register of October 22, 1998, the agency proposed to
amend the tentative final monograph to include zinc oxide as a single
ingredient and in combination with any proposed Category I sunscreen
active ingredient except avobenzone. Two comments supported the
proposal. One comment disagreed with the agency's exclusion of
avobenzone from combinations with zinc oxide. Two of the comments urged
the agency to expeditiously review and approve a citizen petition (Ref.
45) to recognize this combination.
    The agency has informed the petitioner that it is unable to approve
the combination without appropriate UVA radiation effectiveness data to
demonstrate the UVA radiation protection potential of zinc oxide in
combination with avobenzone (Ref. 46). The agency will reconsider this
combination for monograph status upon receipt of the appropriate data.
    This final rule includes monograph conditions for zinc oxide as a
sunscreen active ingredient at concentrations up to 25 percent when
used alone or in combination with any monograph sunscreen active
ingredient except avobenzone.

IV. Additional Changes

    1. The agency has determined that for an active ingredient to be
included in an OTC drug final monograph it is necessary to have
publicly available

[[Page 27681]]

chemical information that can be used by all manufacturers to determine
that the ingredient is appropriate for use in their products.
Compendial monographs include an ingredient's official name, chemical
formula, and analytical chemical tests to confirm the quality and
purity of the ingredient. These monographs establish public standards
for the strength, quality, purity, and packaging of ingredients and
drug products available in the United States.
    In the Federal Register of June 8, 1994, FDA deleted digalloyl
trioleate, ethyl 4-[bis(hydroxypropyl)] aminobenzoate, glyceryl
aminobenzoate, lawsone with dihydroxyacetone, and red petrolatum from
the tentative final monograph due to the lack of interest in
establishing USP compendial monographs for these ingredients. Lawsone
with dihydroxyacetone subsequently remained under agency consideration
due to increased interest by manufacturers in establishing a compendial
monograph. Of the 18 remaining sunscreen active ingredients under
consideration in the tentative final monograph (58 FR 28194 at 28295,
amended at 61 FR 48645 and 63 FR 56584), 16 (aminobenzoic acid,
avobenzone, cinoxate, dioxybenzone, homosalate, menthyl anthranilate,
octocrylene, octyl methoxycinnamate, octyl salicylate, oxybenzone,
padimate O, phenylbenzimidazole sulfonic acid, sulisobenzone, titanium
dioxide, trolamine salicylate, and zinc oxide) currently have
compendial monographs. Two (diethanolamine methoxycinnamate and lawsone
with dihydroxyacetone) do not have a current or proposed compendial
monograph.
    The agency is including in Sec. 352.10 of this document the 16
sunscreen active ingredients that currently have a compendial
monograph. The agency is reserving the appropriate paragraphs in
proposed Sec. 352.10 for the two active ingredients without compendial
monographs in case a monograph is developed for either ingredient.
Dihydroxyacetone has been proposed for a compendial monograph, but none
has been proposed for lawsone. Because these two active ingredients are
used in conjunction, lawsone must have a compendial monograph in order
for lawsone with dihydroxyacetone to be included in the sunscreen final
monograph.
    2. The agency has revised proposed Sec. 352.52(b) in response to
comments requesting reduction, streamlining, and flexibility of
sunscreen labeling and in accordance with new data reviewed by the
agency (see section II.I of this document). The agency has revised
proposed Sec. 352.52(b)(1) by: (1) Deleting references to any other
indication except that pertaining to the prevention of sunburn (see
section II.I, comment 37 of this document), (2) adding (in
Sec. 352.52(b)(2) of this final rule) guidance on SPF selection due to
simplification of the PCD in proposed Sec. 352.52(e)(1) and deletion of
the Recommended Product Guide in proposed Sec. 352.52(e)(4) (see
section II.L, comments 49 and 50 of this document), and (3) deleting
the quantitative claims (i.e., ``up to (insert SPF of product up to 30)
times'') and terms such as ``screens,'' ``shields,'' etc., concerning
sunburn protection throughout proposed Sec. 352.52(b) (see section
II.I, comment 37 of this document).
    3. The tentative final monograph allowed reduced labeling
directions on sunscreen products if formulated as a make-up
preparation, lipstick, lip balm, or skin preparation and labeled with
claims relating only to the prevention of ``lip damage,''
``freckling,'' or ``uneven coloration.'' Because there is no convincing
evidence that SPF testing predicts protection from anything but sunburn
(see section II.I, comment 36 of this document), the agency is not
including proposed Sec. 352.52(b)(1)(v), (b)(1)(vi), (d)(4), and (d)(5)
in this document. The agency will consider including such claims in the
monograph when specific supportive data are provided or a specific
clinically relevant final formulation test is developed.
    4. Numerous comments requested deletion of the dual SPF testing of
water resistant products in proposed Sec. 352.50(b)(2) and (c)(2). The
agency agrees with the comments (see section II.H, comment 32 of this
document) and has revised proposed Secs. 352.50(b)(2) and (c)(2) and
352.76 to require only the SPF value after water resistant testing.
Further, the agency has modified and made optional the reapplication
directions in proposed Secs. 352.52(d)(1) and (d)(2) (see section II.K,
comment 48 of this document). These changes to proposed Sec. 352.52(d)
provide flexibility by allowing manufacturers to expand on
reapplication information necessary for specific sunscreen formulations
and by equalizing requirements between products with and without water
resistance claims and between sunscreen drug and drug-cosmetic
products. Thus, the water resistance labeling in Sec. 352.52(b)(1)(ii)
and (b)(1)(iii) of this document should also serve as a directive for
reapplication of the product. In summary, for products making water
and/or sweat resistance claims, the agency has modified and combined
water resistance statements formerly in proposed Sec. 352.52(e)(2),
(e)(3), (d)(1), and (d)(2) into Sec. 352.52(b)(1)(ii) and (b)(1)(iii)
in this document.
    5. The agency has modified references to ``tanning'' and ``prolongs
exposure time'' in proposed Sec. 352.52(b)(2) by combining the PCD
claim in Sec. 352.52(e)(1) of this document with either the phrase
``protection against sunburn'' or ``protection against sunburn and
tanning.'' Based upon current information, the agency believes that the
terms proposed in the tentative final monograph could send the wrong
message relative to the dangers of even suberythemal UV radiation
exposure and give consumers a false sense of security concerning sun
exposure and sunscreen use. The agency has reduced and simplified the
other optional, additional indications in proposed Sec. 352.52(b)(2) to
reflect a modified, simpler, combined version of the PCD in proposed
Sec. 352.52(e)(1) (see section II.L, comment 49 of this document) and
the ``Recommended Product Guide'' in proposed Sec. 352.52(e)(4) (see
section II.L, comment 50 of this document). Because the agency has
deleted reference to use of the term ``Sunblock'' in proposed section
Sec. 352.52(e)(5) (see section II.L, comment 52 of this document), it
has deleted reference to ``Reflects the burning rays of the sun'' in
proposed Sec. 352.52(b)(3) for the same reasons.
    6. Several comments requested labeling exemptions or flexibility
for packages that are too small to accommodate all required
information. Some comments specifically requested flexible labeling for
products based upon their intended use, such as lipsticks and lip
balms.
    As discussed in the final rule establishing standardized format and
content requirements for the labeling of OTC drug products (64 FR 13254
at 13267 to 13268 and 13289), the agency has established specifications
for small packages in Sec. 201.66(d)(10). The agency also stated in the
final labeling rule that it will consider additional approaches for
accommodating certain small-package products in their respective OTC
drug monograph proceedings.
    The agency considers the required OTC drug labeling information
essential for the safe and effective use of these products and
important to consumers for selection of an appropriate product.
Nevertheless, the agency agrees that excessive labeling requirements
may discourage manufacturers from marketing certain products, such as
lipsticks or lip balms containing sunscreens, which provide significant
public health benefit.
    In this OTC drug rulemaking, the agency has included several
accommodations for products such as

[[Page 27682]]

lipsticks (and lip balms, which will be addressed in the final
monograph on OTC skin protectant drug products), taking into
consideration the intended uses of these products, the limited areas to
which these products are applied, and the overall safety profile of
these products, and other factors described in the final OTC labeling
rule (64 FR 13254 at 13270). The agency is including Sec. 352.52(f) in
this document to provide for labeling modifications for sunscreen
products that meet the small package specifications in
Sec. 201.66(d)(10) and are labeled for use on specific small areas of
the face (e.g., lips, nose, ears, and/or around eyes).
    7. The agency has revised Secs. 700.35 and 740.19 (21 CFR 700.35
and 740.19) in response to comments requesting clarification on whether
certain products will be subject to regulation as drugs (see section
II.B, comments 8 through 11 of this document). Section 700.35 has been
revised to make clear that, generally, products that make sun
protection claims, whether express or implied, are subject to
regulation as drugs. Only those products that contain a sunscreen
ingredient solely for a nontherapeutic, nonphysiologic use (e.g., as a
color additive, or to protect the color of the product such as in a
nail polish or hair coloring product) (see 58 FR at 28205), and which
include a labeling statement that accurately describes that use, may be
marketed as cosmetic products. Section 740.19 has been revised to make
clear that the term ``suntanning preparations'' does not include
products intended to provide sun protection or otherwise to affect the
structure or any function of the body. Suntanning preparations include
gels, creams, liquids, and other topical products that are intended to
provide cosmetic effects on the skin while tanning through exposure to
UV radiation (e.g., moisturizing or conditioning), or that are intended
to give the appearance of a tan by imparting color through the
application of approved color additives (e.g., dihydroxyacetone)
without the need for exposure to UV radiation (i.e., sunless tanning
products).

V. Conclusion

    The agency is issuing a final monograph establishing conditions
under which OTC sunscreen drug products are generally recognized as
safe and effective and not misbranded; 16 ingredients listed in
Sec. 352.10 are currently a monograph condition. Any drug product
labeled, represented, or promoted for use as an OTC sunscreen drug that
contains any of the nonmonograph ingredients listed in
Sec. 310.545(a)(29), or that is not in conformance with the monograph
(21 CFR part 352), may be considered a new drug within the meaning of
section 201(p) of the act and misbranded under section 502 of the act.
Such a drug product cannot be marketed for OTC sunscreen use unless it
is the subject of an approved application under section 505 of the act
(21 U.S.C. 355) and 21 CFR part 314 of the regulations. An appropriate
citizen petition to amend the monograph may also be submitted in accord
with 21 CFR 10.30 and Sec. 330.10(a)(12)(i). The agency will address
sunscreen active ingredients that have foreign marketing experience and
data at a future time. Any OTC sunscreen drug product initially
introduced or initially delivered for introduction into interstate
commerce after the effective date of the final rule for
Sec. 310.545(a)(29) or this document that is not in compliance with the
regulations is subject to regulatory action.

VI. References

    The following references are on display in the Dockets Management
Branch (address above) and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday.
    1. Comment No. CP1, Docket No. 78N-0038, Dockets Management
Branch.
    2. Comment No. CP2, Docket No. 78N-0038, Dockets Management
Branch.
    3. Comment No. CP3, Docket No. 78N-0038, Dockets Management
Branch.
    4. Comment No. CP7, Docket No. 78N-0038, Dockets Management
Branch.
    5. Comite de Liaison des Associations Europeenes de L'Industrie
de la Parfumerie, des Produits Cosmetiques et de Toilette (COLIPA),
SPF Test Method (Draft), The Recommendations of the COLIPA Task
Force ``Sun Protection Measurement,'' December 1992 in Comment No.
C00365, Docket No. 78N-0038, Dockets Management Branch.
    6. Peak, M. J., and J. C. van der Leun, ``Boundary Between UVA
and UVB,'' in Frontiers of Photobiology, edited by A. Shima et al.,
Excerpta Medica, Amsterdam, pp. 425-427, 1993.
    7. Comment No. LET 135, Docket 78N-0038, Dockets Management
Branch.
    8. Dunkel, V.C. et al., ``Evaluation of the Mutagenicity of an
N-Nitroso Contaminant of the Sunscreen Padimate O,'' Environmental
and Molecular Mutagenesis, 20:188-198, 1992.
    9. Comment No. C00364, Docket No. 78N-0038, Dockets Management
Branch.
    10. Comments No. C00397 and SUP21, Docket No. 78N-0038, Dockets
Management Branch.
    11. Fairhurst, D., and M. Mitchnick, ``Particulate Sun Blocks:
General Principles,'' in Sunscreens: Development, Evaluation, and
Regulatory Aspects, Marcel Dekker, Inc., New York, pp. 313-352,
1997.
    12. Comment No. TR3, Docket No. 78N-0038, Dockets Management
Branch.
    13. Pharmacopeial Forum, United States Pharmacopeial Convention,
Inc., Rockville, MD, 22(4):2635-2636, July through August 1996.
    14. Pharmacopeial Forum, United States Pharmacopeial Convention,
Inc., Rockville, MD, 24(4):6547-6548, July through August 1998.
    15. Comment No. C00406, Docket No. 78N-0038, Dockets Management
Branch.
    16. Comment No. C00404, Docket No. 78N-0038, Dockets Management
Branch.
    17. Kligman, L. H., and A. M. Kligman, ``Ultraviolet Radiation-
Induced Skin Aging,'' in Sunscreens: Development, Evaluation, and
Regulatory Aspects, Lowe, N. J., N. A. Shaath, and M. A. Pathak,
eds., Marcel Dekker, Inc., New York, pp. 117-137, 1997.
    18. Lavker, R., and K. Kaidbey, ``The Spectral Dependence for
UVA-Induced Cumulative Damage in Human Skin,'' The Journal of
Investigative Dermatology, 108:17-21, 1997.
    19. Fisher, G. J. et al., ``Pathophysiology of Premature Skin
Aging Induced by Ultraviolet Light,'' The New England Journal of
Medicine, 337:1419-1428, 1997.
    20. Lowe, N. J. et al., ``Low Doses of Repetitive Ultraviolet A
Induce Morphologic Changes in Human Skin,'' Journal of the American
Academy of Dermatology, 105:739-743, 1995.
    21. Comment No. C00282, Docket No. 78N-0038, Dockets Management
Branch.
    22. Comment No. C00365, Docket No. 78N-0038, Dockets Management
Branch.
    23. Comment No. C00531, Docket No. 78N-0038, Dockets Management
Branch.
    24. Comment No. C00128, Docket No. 78N-0038, Dockets Management
Branch.
    25. Comment No. SUP16, Docket No. 78N-0038, Dockets Management
Branch.
    26. Thompson, S. C., J. D. Jolley, and R. Marks, ``Reduction of
Solar Keratoses by Regular Sunscreen Use,'' The New England Journal
of Medicine, 329:1147-1151, 1993.
    27. Marks, R. et al., ``Spontaneous Remission of Solar
Keratoses: The Case for Conservative Management,'' British Journal
of Dermatology, 115:649-654, 1986.
    28. Marks, R., and G. Rennie, ``Malignant Transformation of
Solar Keratoses to Squamous Cell Carcinoma,'' The Lancet, 795-796,
1988.
    29. Kornhauser, A., W. G. Wamer, and L. A. Lambert, ``Cellular
and Molecular Events Following Ultraviolet Irradiation of Skin,'' in
Dermatotoxicology, F. N. Marzulli and H. I. Maibach, eds., Taylor &
Francis, Washington, pp. 189-220, 1996.
    30. Kraemer, K. H., ``Sunlight and Skin Cancer: Another Link
Revealed,'' Proceeds of the National Academy of Sciences U. S. A.,
94:11-14, 1997.
    31. Hurks, H. M. H. et al., ``In Situ Action Spectra Suggest
that DNA Damage Involved in Ultraviolet Radiation-Induced
Immunosuppression in Humans,'' Photochemistry and Photobiology,
66:76-81, 1997.
    32. Burren, R. et al., ``Sunlight and Carcinogenesis: Expression
of p53 and Pyrimidine Dimers in Human Skin Following UVA I, UVA I +
II and Solar Simulating Radiation,'' International Journal of
Cancer, 76:201-206, 1998.

[[Page 27683]]

    33. Hersey, P. et al., ``Analysis of the Effect of a Sunscreen
Agent on the Suppression of Natural Killer Cell Activity Induced in
Human Subjects by Radiation from Solarium Lamps,'' The Journal of
Investigative Dermatology, 88:271-276, 1987.
    34. Van Prague, M. C. G. et al., ``Effect of Topical Sunscreens
on the UV-Radiation-Induced Suppression of the Alloactivating
Capacity in Human Skin In Vivo,'' The Journal of Investigative
Dermatology, 97:629-633, 1991.
    35. Miyagi, T., A. M. Bhutto, and S. Nonaka, ``The Effects of
Sunscreens on UVB Erythema and Langerhans Cell Depression,'' The
Journal of Investigative Dermatology, 21:645-651, 1994.
    36. Seite, S. et al., ``Effects of Repeated Suberythemal Doses
of UVA in Human Skin,'' European Journal of Dermatology, 7:204-209,
1997.
    37. 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, 32:53-62, 1995.
    38. Baadsgaard, O., ``In Vivo Ultraviolet Irradiation of Human
Skin Results in Profound Perturbation of the Immune System,''
Archives of Dermatology, 127:99-109, 1991.
    39. Marks, R., ``Reduction of Actinic Keratoses by Sunscreens,''
in Sunscreens: Development, Evaluation, and Regulatory Aspects,
Lowe, N. J., N. A. Shaath, and M. A. Pathak, eds., Marcel Dekker,
Inc., New York, pp. 189-198, 1997.
    40. Dial, W. F., ``Mouse Study Creates Controversy Over the Use
of Sunscreens,'' Cosmetic Dermatology, 7:47-48, 1994.
    41. Goldsmith, L., et al., ``Proceedings from the National
Conference to Develop a National Skin Cancer Agenda,'' Journal of
the American Academy of Dermatology, 34:822-23, 1996.
    42. Standards Australia/Standards New Zealand, ``Sunscreen
Products--Evaluation and Classification,'' AS/NZS 2604, 1993.
    43. Beissart, S. and R. D. Granstein, ``UV-Induced Cutaneous
Photobiology,'' Critical Reviews in Biochemistry and Molecular
Biology, 31:381-404, 1995.
    44. Sayre, R. et al., ``Physical Sunscreens,'' Journal of the
Society of Cosmetic Chemists, 41:103-109, 1990.
    45. Comment No. CP8, Docket No. 78N-0038, Dockets Management
Branch.
    46. Comment No. LET166, Docket No. 78N-0038, Dockets Management
Branch.
    47. Food and Drug Administration, ``Supplement to the Economic
Impact Analysis of the Sunscreen Drug Products for Over-the-Counter
Human Use; Final Monograph,'' in OTC Vol. 06FR, Docket No. 78N-0038,
Dockets Management Branch.
    48. Eastern Research Group, Inc., ``Over-the-Counter Drug
Reformulation Changes,'' in OTC Vol. 06FR, Docket No. 78N-0038,
Dockets Management Branch.

VII. Analysis of Impacts

    FDA has examined the impacts of this final rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act (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). The agency believes that
this final rule is consistent with the principles identified in
Executive Order 12866. OMB has determined that the final rule is a
significant regulatory action as defined by the Executive Order and so
is subject to review. 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. Title II of the
Unfunded Mandates Reform Act requires that agencies prepare a written
assessment of anticipated costs and benefits before proposing any rule
that may result in an expenditure in any 1 year by State, local, and
tribal governments, in the aggregate, or by the private sector, of $100
million (adjusted annually for inflation) (2 U.S.C. 1532).
    Because the rule may have a significant economic impact on a
substantial number of small entities, this section of the preamble
constitutes the agency's Final Regulatory Flexibility Analysis. Because
the rule does not impose any mandates on State, local, or tribal
governments, or the private sector, that will result in an expenditure
in any 1 year of $100 million or more, FDA is not required to perform a
cost-benefit analysis according to the Unfunded Mandates Reform Act.
    An analysis of the costs and benefits of this regulation, conducted
under Executive Order 12291, was discussed in the tentative final
monograph for OTC sunscreen drug products (58 FR 28194 at 28294). The
agency received only one response to the specific request for data and
comment on the economic impact of this rulemaking. This comment
discussed the costs that would result from proposed changes in
sunscreen product labeling and testing methods. The agency's review of
this comment is included as follows.

A. Background

    The purpose of this document is to establish conditions under which
OTC sunscreen drug products are generally recognized as safe,
effective, and not misbranded. The document sets specific requirements
for appropriate monograph ingredients, labeling format and content, and
SPF value and water resistant testing. Although the agency cannot
quantify the overall expected benefits, each provision of the rule will
support the ability of consumers to take desired protective actions.
Monograph ingredients have been proven safe and effective assuring the
quality of sunscreen products. This benefits consumers because it
ensures that the product will provide ingredients that safely protect
against sunburn. The new product labeling will better inform consumers
about the sunburn protection provided by the products; and if
manufacturers choose to include the optional ``Sun alert'' labeling
statement, the product labeling can reference that the use of
sunscreens may reduce the risk of skin aging, skin cancer, and other
harmful effects of the sun. These labeling requirements, in conjunction
with the format requirements of the OTC uniform labeling rule (64 FR
13254) will provide clearer and more concise information that will
benefit consumers in at least four ways: (1) They will increase
understanding regarding the selection of sunscreen drug products, (2)
they will make product comparison easier, (3) they will enhance the
ability to make informed decisions regarding product purchases and
proper use, and (4) they will make it easier to distinguish between
sunscreen drug products that contain sunscreens and suntanning products
that do not. Finally, the new requirements for product testing will
assure the accuracy of the SPF value on the product label. By improving
the accuracy of these ratings, this requirement will provide further
assurance that consumers receive adequate sunburn protection.
    The rule will require all manufacturers and distributors (or their
agents) to relabel their OTC sunscreen drug products to comply with the
monograph language. The labeling of certain suntanning products that do
not contain sunscreens will need to include the new required warning
statement. In some cases, the labeling of cosmetics containing
sunscreens for nontherapeutic, nonphysiologic uses (e.g., to protect
hair from sun damage) will need to describe the cosmetic role of the
sunscreen ingredient(s). The SPF of some OTC sunscreen drug products
may need to be retested using the method described in the final
monograph. In addition, only products containing the active ingredients
included in this final rule will be generally recognized as safe,
effective, and not misbranded. Of the 18 active ingredients under
consideration in the proposed rule, 16 currently have the required USP/
N.F. compendial

[[Page 27684]]

monographs. The USP has not received applications for the remaining two
ingredients. If either of these active ingredients are not included in
the USP and added to the monograph by May 21, 2001, products containing
these ingredients would need to be reformulated to replace the
nonmonograph ingredient with a monograph ingredient, or the product
must be removed from the market.

B. Number of Products Affected

    Based on data from FDA's Drug Listing System, the agency estimates
that there are approximately 2,800 OTC sunscreen drug products
(different formulations, not including products that differ only by
color) and about 12,000 individual stockkeeping units (SKU's)
(individual products, packages, and sizes). All of the SKU's will need
to be relabeled, some will require new SPF testing, and those products
lacking approved active ingredients will need to be reformulated to
stay on the market.
    In addition, certain suntanning products and certain cosmetic
products containing sunscreens will have to be relabeled. As FDA's Drug
Listing System does not include suntanning products, the agency used
1995 data from A. C. Nielsen, a recognized provider of market data, to
estimate that approximately 550 suntanning SKU's will be affected by
the labeling requirements of this rule. New labels will also be needed
for cosmetic products that contain a sunscreen for a nontherapeutic use
and that include the word ``sunscreen'' or similar terms in product
labeling. The agency is unable to identify the number of these cosmetic
products, but does not believe that there are a large number of SKU's
in this category.

C. Cost to Relabel

    The relabeling costs for this rule will be moderated to the extent
that manufacturers coordinate labeling changes for the final sunscreen
monograph with labeling changes required by the recent rule
establishing uniform format and content for OTC drug product labeling
(64 FR 13254). These costs are not discussed in this analysis, however,
because they are already accounted for in the agency's analysis of its
OTC drug product labeling rule. That is, the agency's economic analysis
of that rule excluded redesign costs for all OTC drug products not
marketed under current NDA's or current final monographs, explaining
that the agency would attribute all redesign costs associated with
future final monographs to each final monograph rule as it published.
All redesign costs for this final sunscreen monograph therefore are
attributed to this rule alone.
    Approximately 12,000 sunscreen drug SKU's will have to be relabeled
within a 2-year implementation period to comply with the labeling
requirements of this final rule. In addition, approximately 550
suntanning SKU's will have to be relabeled within a 12-month
implementation period. (As noted previously, FDA could not estimate the
number of cosmetic products that contain a sunscreen for a
nontherapeutic use and that include the word ``sunscreen'' or similar
terms in product labeling. The agency believes, however, the relabeling
of this group of cosmetic products will impose a minimal economic
burden because some of these products already include the required
labeling, and most manufacturers revise these labels for marketing
considerations more frequently than the allowed 2-year phase-in period.
Therefore, the agency's estimates do not include a cost for relabeling
those products that contain sunscreens for a nontherapeutic,
nonphysiologic use.)
    Frequent labeling redesigns are a recognized cost of doing business
in the OTC drug industry, particularly for drug-cosmetic and seasonal
products. Thus, SKU's with labels that would normally be redesigned
within the implementation periods were assumed to incur no additional
costs. The cost for the remaining SKU's was calculated as the lost
value of the remaining life-years of the existing label design. FDA
estimates that labeling for the majority (90 percent) of the SKU's
affected by this final rule are redesigned at least every 2 years. Of
the remaining SKU's, the agency assumes that half would be redesigned
every 3 years and half every 6 years. Because the required labeling for
OTC sunscreen drug products now includes fewer words than the previous
language and the final rule contains a number of labeling modifications
for products used on small areas of the face (which are usually
marketed in small size packages), this rule is not expected to require
manufacturers to increase the package size or available labeling space.
(Although costs of redesigning labels for future final monographs were
excluded from FDA's analysis of its OTC drug product labeling rule,
costs for increased package sizes were considered in the analysis of
impacts for that regulation (64 FR 13254 at 13283)).
    FDA estimated the cost of redesign by counting only the value of
the label-years that would be lost, after adjusting for the length of
the traditional labeling cycle. The regulatory cost was calculated as
the product of the number of SKU's, the number of years of labeling
life lost, and the value of each year of labeling life lost (see 64 FR
13254 at 13278 through 13284).\2\
---------------------------------------------------------------------------

    \2\ Mathematically the following formula was used to calculate
the incremental relabeling costs:
    Cost<INF>yx</INF> = <greek-S> j N<INF>x</INF>A<INF>x</INF>(1/x),
where j = 1 to (x-y)
    Total Cost<INF>y</INF> = Cost<INF>y6</INF> + Cost<INF>y3</INF> +
Cost<INF>y2</INF>
    where:
    x = life of labeling in years (2, 3, or 6)
    y = phase-in period in years
    N<INF>x</INF> = number of SKU's with labeling life of x years,
and
    A<INF>x</INF> = amortized annual value of labeling with a life
of x years.
---------------------------------------------------------------------------

    Table 1 in section VIII.C of this document details FDA's estimates
of the distribution of relabeling costs resulting from the final rule.
A weighted average cost to redesign a label of $5,210 per SKU was used
to calculate the relabeling cost of sunscreen drug products, whereas a
weighted average cost of $6,620 per SKU was used to calculate the cost
of relabeling suntanning products. A detailed description of the cost
analysis is on file with the Docket Management Branch (Ref. 47). As
shown, the total incremental cost to relabel the approximately 12,000
sunscreen drug SKU's is about $1.5 million, while the cost to relabel
the approximately 550 suntanning SKU's was about $1.8 million. The
greater per SKU cost for relabeling suntanning products reflects the
shorter, 12-month, phase-in period. With a shorter phase-in period,
manufacturers are less able to incorporate labeling changes into
voluntary redesign cycles and, therefore, lose label inventory.

                      Table 1.--One-time Cost to Relabel Sunscreen and Suntanning SKU's ($)
----------------------------------------------------------------------------------------------------------------
                                                 Type of Product
-----------------------------------------------------------------------------------------------------------------
           Size of Company                       Drug                  Suntanning               Total Cost
----------------------------------------------------------------------------------------------------------------
Small\1\                                      649,283                1,128,700                1,777,983

[[Page 27685]]

Large                                         860,677                  691,800                1,552,477
Total Cost                                  1,509,960                1,820,500                3,330,460
----------------------------------------------------------------------------------------------------------------
\1\ See section VII.G of this document.

    The one comment that raised economic issues in response to the
tentative final monograph expressed concern about available labeling
space on small packages of sunscreen drug products. The comment stated
that all text needs to be concise. The agency considered this comment
in developing the final rule, which contains specific labeling
modifications for small packages and for sunscreen products used on
small areas of the face (e.g., lips, nose, ears, and/or around the
eyes).

D. Cost to Retest SPF

     FDA is uncertain about the number of OTC sunscreen drug products
that have not been tested using the monograph SPF test method. However,
the SPF test method in this document is essentially the same as the
method described in the proposed rule. If manufacturers have added new
products, made formulation changes, or otherwise needed to test or
retest the SPF of their products since 1993, they would probably have
used the most current (i.e., the proposed) test method. Therefore, the
agency estimates that from 15 to 30 percent of the sunscreen drug
products will require retesting as a result of this document. The cost
of the SPF test varies, depending on the product claim (water resistant
or very water resistant) and SPF factor tested, and ranges from $2,500
to $6,500. On the assumption that 50 percent of the traditional
sunscreen drug products, and none of the make-up type sunscreen
products, make water resistant claims, and 50 percent of the products
that make water resistant claims make very water resistant claims, the
estimated weighted average cost of the SPF test is $3,514. FDA
estimates the total cost of this requirement, therefore, to range from
$3.1 million to $6.1 millions (see the following Table 2).

          Table 2.--One-time Cost to Retest SPF Assuming 15 Percent or 30 Percent Compliance Rates ($)
----------------------------------------------------------------------------------------------------------------
                                                                    15 Percent Non-          30 Percent Non-
                        Size of Company                                compliance               compliance
----------------------------------------------------------------------------------------------------------------
Small                                                                1,300,000                2,600,000
Large                                                                1,800,000                3,500,000
Total Cost                                                           3,100,000                6,100,000
----------------------------------------------------------------------------------------------------------------

E. Cost to Reformulate

    Reformulation costs will depend on the number of products, if any,
that will have no active ingredients with completed USP compendial
monographs by the end of the implementation period. At the present
time, only two of the active ingredients being considered do not have a
USP monograph. According to the agency's drug listing system, two
products, manufactured by one company contain one of these ingredients.
The agency is not currently aware of other products in the marketplace
that contain these two ingredients.
    The cost to reformulate a product varies by the nature of the
reformulation, the type of product, and the size and complexity of the
company. Because OTC sunscreen drug products are well characterized
topical formulations, FDA estimates the cost to reformulate at about
$350,000 per product. Thus, on the assumption that the manufacturer
reformulates rather than removes the products from the market, the one-
time cost of reformulation for two products would be $700,000.

F. Total Incremental Costs

    The estimated total one-time incremental cost of this rule, using
the midpoint of the cost range for retesting and reformulation is $8.6
million (see Table 3 of this document). These estimates are based on 16
of the 18 active sunscreen ingredients under consideration having USP
compendial monographs. If a USP monograph is completed for the one
ingredient in these two products or if the two products are removed
from the market, the cost of reformulation would be eliminated.

G. Small Business Impact

    Based on the analysis of FDA's drug listing system and other data
described previously, there are about 180 domestic companies that
manufacture OTC sunscreen and suntanning products. Distributors were
not assigned costs because manufacturers of OTC drug products are
usually responsible for product labeling, testing, and formulation.
Approximately 78 percent of these firms meet the Small Business
Administration's definition of a small entity for this industry (less
than 750 employees).

                                Table 3.--Total Incremental Cost to Industry ($)
----------------------------------------------------------------------------------------------------------------
                         Relabel Products
   Size of   ----------------------------------------    Retest SPF\1\     Reformulation\2\          Total
   Company           Drug             Suntanning
----------------------------------------------------------------------------------------------------------------
Small             670,000           1,100,000           2,000,000                 n/a                 n/a
Large             840,000             700,000           2,600,000                 n/a                 n/a

[[Page 27686]]

Total Cost      1,510,000           1,800,000           4,600,000             700,000           8,610,000
----------------------------------------------------------------------------------------------------------------
\1\ Assumes 22.5 percent noncompliance (midpoint of range)
\2\ Assumes 2 products would require reformulation

    The rule will require manufacturers of sunscreens to relabel their
products. Some firms will need to retest the SPF of these products, and
one firm may have to reformulate or remove two products from the
market. Because of the 2-year implementation period, most firms will be
able to relabel during a normal relabeling cycle, at no additional
cost. FDA cannot estimate with certainty the number of small firms that
will need to retest or reformulate their OTC sunscreen products, but
projects that from 15 to 30 percent of all products may need to be
retested and that 2 products may need to be reformulated. Costs will
vary by firm, depending on the type and number of products requiring
relabeling, retesting, and reformulation. The firm-specific impact may
vary inversely with the volume of product sales, however, because per
unit costs will be lower for products with high volume sales. Thus, the
relative economic impact of product retesting or relabeling may be
greater for small firms than for large firms.
    Because of the 2-year phase-in period allowed for sunscreen drug
and drug-cosmetic products, which allows manufacturers the flexibility
to incorporate regulatory changes with voluntary/market-driven changes,
the economic impact of the relabeling requirement is relatively low
(approximately $3.3 million). However, for those small companies that
may have to relabel a substantial number of products, the out-of-pocket
costs could be significant.
    Also, the cost to a small company needing to reformulate a product,
estimated at approximately $350,000 would be significant. This impact
may be moderated by other options available, which may be more cost
effective than reformulation. For example, a manufacturer may be able
to substitute other formulations, shift production to a contract
manufacturer with an approved formulation, or temporarily remove the
product from the market and await the completion of a USP compendial
monograph for the ingredient. Because the OTC drug industry is highly
regulated, all firms are expected to have access to the necessary
professional skills on staff or to make contractual arrangements to
comply with the paperwork and other requirements of this rule.

H. Analysis of Alternatives

    The agency altered several proposed regulatory provisions to reduce
the economic burden of this rule on industry. For example, FDA
decreased the amount of required labeling and provided small package
accommodations for certain products. The labeling required by the
proposed rule would have increased the needed label and/or package size
for as many as 90 percent of the sunscreen products. Such size
adjustments could have imposed estimated additional one-time relabeling
costs of $18 million and annually recurring costs of $22 million (see
Eastern Research Group, ``Cost Impacts of the Over-the-Counter
Pharmaceutical Labeling Rule'' (Ref. 48)). Also, in response to the
comment (see section II.H, comment 32 of this document), the agency has
reconsidered its position on SPF testing of water resistant and very
water resistant products and eliminated the static test requirement for
these products. As the average cost of the static test is approximately
$2,800, the estimated savings to industry due to the elimination of
this test is about $750,000.
    The agency also considered a number of implementation alternatives
to this final rule. Generally, the agency allows only a 1-year
implementation period for final monographs. However, because most
sunscreen products are produced seasonally, the 2-year period will
substantially enhance the ability of the industry to relabel and
reformulate its products, if necessary, and sell its existing product
inventories. The 2-year period will also allow sunscreen manufacturers
to coordinate the required labeling changes with routine industry-
initiated labeling changes and changes required by the new OTC drug
product labeling final rule (64 FR 13254).
    A 3-year implementation period for sunscreen drug products was
considered, but the agency determined that a 2-year period provides
sufficient time to allow the required relabeling and product retesting
to be completed. The agency found that the savings to industry of
delayed implementation (estimated to be about $845,000) were not great
enough to justify delaying appropriate use and safety information to
consumers of OTC sunscreen drug products.
    Finally, the agency is providing a 12-month implementation period
for certain suntanning preparations to add new warning information. For
this category, consumers may believe that these products are providing
sun protection when, in fact, they do not. They may forego using other
products that have been demonstrated to be effective in providing sun
protection, believing that their tanning product provides some measure
of protection. Because the new warning for suntanning preparations
presents an important safety issue that needs to be conveyed to
consumers at the earliest possible date, the agency considered
requiring a 6-month implementation period for these products. However,
given the seasonal nature of these products, the agency was concerned
that some manufacturers may not have sufficient time to incorporate the
labeling change without disrupting their production schedules. By
providing an additional 6 months to implement the change, compliance
costs were reduced by $1.8 million.

VIII. Paperwork Reduction Act of 1995

    FDA 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
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)).

IX. Environmental Impact

    The agency has determined that under 21 CFR 25.31(c) this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore,

[[Page 27687]]

neither an environmental assessment nor an environmental impact
statement is required.

List of Subjects

21 CFR Part 310

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

21 CFR Part 352

    Labeling, Over-the-counter drugs.

21 CFR Part 700

    Cosmetics, Packaging and containers.

21 CFR Part 740

    Cosmetics, Labeling.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, 21 CFR
part 352 is added and 21 CFR parts 310, 700, and 740 are amended as
follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,
263b-263n.

    2. Section 310.545 is amended by adding paragraph (a)(29), by
revising paragraph (d) introductory text, by adding and reserving
paragraph (d)(30), and by adding paragraph (d)(31) to read as follows:

Sec. 310.545  Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (29) Sunscreen drug products.
Diethanolamine methoxycinnamate
Digalloyl trioleate
Ethyl 4-[bis(hydroxypropyl)] aminobenzoate
Glyceryl aminobenzoate
Lawsone with dihydroxyacetone
Red petrolatum
* * * * *
    (d) Any OTC drug product that is not in compliance with this
section is subject to regulatory action if initially introduced or
initially delivered for introduction into interstate commerce after the
dates specified in paragraphs (d)(1) through (d)(31) of this section.
* * * * *
    (30) [Reserved]
    (31) May 21, 2001 for products subject to paragraph (a)(29) of this
section.
    3. Part 352 is added to read as follows:

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

Subpart A--General Provisions

Sec.
352.1  Scope.
352.3  Definitions.

Subpart B--Active Ingredients

352.10  Sunscreen active ingredients.
352.20  Permitted combinations of active ingredients.

Subpart C--Labeling

352.50  Principal display panel of all sunscreen drug products.
352.52  Labeling of sunscreen drug products.
352.60  Labeling of permitted combinations of active ingredients.

Subpart D--Testing Procedures

352.70  Standard sunscreen.
352.71  Light source (solar simulator).
352.72  General testing procedures.
352.73  Determination of SPF value.
352.76  Determination if a product is water resistant or very water
resistant.
352.77  Test modifications.

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

Subpart A--General Provisions

Sec. 352.1  Scope.

    (a) An over-the-counter sunscreen drug product in a form suitable
for topical administration is generally recognized as safe and
effective and is not misbranded if it meets each condition in this part
and each general condition established in Sec. 330.1 of this chapter.
    (b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise
noted.

Sec. 352.3  Definitions.

    As used in this part:
    (a) Minimal erythema dose (MED). The quantity of erythema-effective
energy (expressed as Joules per square meter) required to produce the
first perceptible, redness reaction with clearly defined borders.
    (b) 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) Minimal sun protection product. A sunscreen product that
provides a sun protection factor (SPF) value of 2 to under 12.
    (2) Moderate sun protection product. A sunscreen product that
provides an SPF value of 12 to under 30.
    (3) High sun protection product. A sunscreen product that provides
an SPF value of 30 or above.
    (c) Sunscreen active ingredient. An active ingredient listed in
Sec. 352.10 that absorbs, reflects, or scatters radiation in the UV
range at wavelengths from 290 to 400 nanometers.
    (d) Sun 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.

Subpart B--Active Ingredients

Sec. 352.10  Sunscreen active ingredients.

    The active ingredient of the product consists of any of the
following, within the concentration specified for each ingredient, and
the finished product provides a minimum SPF value of not less than 2 as
measured by the testing procedures established in subpart D of this
part:
    (a) Aminobenzoic acid (PABA) up to 15 percent.
    (b) Avobenzone up to 3 percent.
    (c) Cinoxate up to 3 percent.
    (d) [Reserved].
    (e) Dioxybenzone up to 3 percent.
    (f) Homosalate up to 15 percent.
    (g) [Reserved].
    (h) Menthyl anthranilate up to 5 percent.
    (i) Octocrylene up to 10 percent.
    (j) Octyl methoxycinnamate up to 7.5 percent.
    (k) Octyl salicylate up to 5 percent.
    (l) Oxybenzone up to 6 percent.
    (m) Padimate O up to 8 percent.
    (n) Phenylbenzimidazole sulfonic acid up to 4 percent.
    (o) Sulisobenzone up to 10 percent.
    (p) Titanium dioxide up to 25 percent.
    (q) Trolamine salicylate up to 12 percent.
    (r) Zinc oxide up to 25 percent.

Sec. 352.20  Permitted combinations of active ingredients.

    The SPF of any combination product is measured by the testing
procedures established in subpart D of this part.

[[Page 27688]]

    (a) Combinations of sunscreen active ingredients. (1) Two or more
sunscreen active ingredients identified in Sec. 352.10(a), (c), (e),
(f), and (h) through (r) may be combined with each other 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.
    (2) Two or more sunscreen active ingredients identified in
Sec. 352.10(b), (c), (e), (f), (i) through (l), (o), and (q) may be
combined with each other 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.
    (b) [Reserved].
    (c) [Reserved].

Subpart C--Labeling

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

    In addition to the statement of identity required in Sec. 352.52,
the following labeling statements shall be prominently placed on the
principal display panel:
    (a) For products that do not satisfy the water resistant or very
water resistant sunscreen product testing procedures in Sec. 352.76.
(1) For products with SPF values up to 30. ``SPF (insert tested SPF
value of the product up to 30).''
    (2) For products with SPF values over 30. ``SPF 30'' (select one of
the following: ``plus'' or ``+''). Any statement accompanying the
marketed product that states a specific SPF value above 30 or similar
language indicating a person can stay in the sun more than 30 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).
    (b) For products that satisfy the water resistant sunscreen product
testing procedures in Sec. 352.76. (1) (Select one of the following:
``Water,'' ``Water/Sweat,'' or ``Water/Perspiration'') ``Resistant.''
    (2) ``SPF (insert SPF value of the product, as stated in paragraph
(a)(1) or (a)(2) of this section, after it has been tested using the
water resistant sunscreen product testing procedures in Sec. 352.76).''
    (c) For products that satisfy the very water resistant sunscreen
product testing procedures in Sec. 352.76. (1) ``Very'' (select one of
the following: ``Water,'' ``Water/Sweat,'' or ``Water/Perspiration'')
``Resistant.''
    (2) ``SPF (insert SPF value of the product, as stated in paragraph
(a)(1) or (a)(2) of this section, after it has been tested using the
very water resistant sunscreen product testing procedures in
Sec. 352.76).''

Sec. 352.52  Labeling of sunscreen drug products.

    (a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
``sunscreen.''
    (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 relating to
misbranding and the prohibition in section 301(d) of the act against
the introduction or delivery for introduction into interstate commerce
of unapproved new drugs in violation of section 505(a) of the act.
    (1) For products containing any ingredient in Sec. 352.10. (i)
``[bullet]\1\ helps prevent sunburn [bullet] higher SPF gives more
sunburn protection''.
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter.
---------------------------------------------------------------------------

    (ii) For products that satisfy the water resistant testing
procedures identified in Sec. 352.76. ``[bullet] retains SPF after 40
minutes of'' (select one or more of the following: ``activity in the
water,'' ``sweating,'' or ``perspiring'').
    (iii) For products that satisfy the very water resistant testing
procedures identified in Sec. 352.76. ``[bullet] retains SPF after 80
minutes of'' (select one or more of the following: ``activity in the
water,'' ``sweating,'' or ``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 that provide an SPF of 2 to under 12. Select one
or both of the following: [``[bullet]'' (select one of the following:
``provides minimal,'' ``provides minimum,'' ``minimal,'' or
``minimum'') ``protection against'' (select one of the following:
``sunburn'' or ``sunburn and tanning'')], or ``[bullet] for skin that
sunburns minimally''.
    (ii) For products that provide an SPF of 12 to under 30. Select one
or both of the following: [``[bullet]'' (select one of the following:
``provides moderate'' or ``moderate'') ``protection against'' (select
one of the following: ``sunburn'' or ``sunburn and tanning'')], or
``[bullet] for skin that sunburns easily''.
    (iii) For products that provide an SPF of 30 or above. 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''.
    (c) Warnings. The labeling of the product contains the following
warnings under the heading ``Warnings:''
    (1) For products containing any ingredient in Sec. 352.10. (i)
``When using this product [bullet] keep out of eyes. Rinse with water
to remove.''
    (ii) ``Stop use and ask a doctor if [bullet] rash or irritation
develops and lasts''.
    (2) For products containing any ingredient identified in
Sec. 352.10 marketed as a lipstick. The external use only warning in
Sec. 201.66(c)(5)(i) of this chapter and the warning in paragraph
(c)(1)(i) of this section are not required.
    (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)
``[bullet] apply'' (select one or more of the following, as applicable:
``liberally,'' ``generously,'' ``smoothly,'' or ``evenly'') ``(insert
appropriate time interval, if a waiting period is needed) before sun
exposure and as needed''.
    (ii) ``[bullet] children under 6 months of age: ask a doctor''.
    (2) In addition to the directions provided in Sec. 352.52(d)(1),
the following may be used for products containing any ingredient in
Sec. 352.10. ``[bullet] reapply as needed or after towel drying,
swimming, or'' (select one of the following: ``sweating'' or
``perspiring'').
    (3) If the additional directions provided in Sec. 352.52(d)(2) are
used, the phrase ``and as needed'' in Sec. 352.52(d)(1) is not
required.
    (4) For products marketed as a lipstick. The directions in
paragraphs (d)(1) and (d)(2) of this section are not required.

[[Page 27689]]

    (e) Statement on product performance--(1) For products containing
any ingredient identified in Sec. 352.10, the following PCD labeling
claims may be used under the heading ``Other information'' or anywhere
outside of the ``Drug Facts'' box or enclosure.
    (i) For products containing active ingredient(s) that provide an
SPF value of 2 to under 12. (Select one of the following: ``minimal''
or ``minimum'') ``sun protection product.''
    (ii) For products containing active ingredient(s) that provide an
SPF value of 12 to under 30. ``moderate sun protection product.''
    (iii) For products containing active ingredient(s) that provide an
SPF value of 30 or above. ``high sun 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. ``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.'' Any
variation of this statement will cause the product to be misbranded
under section 502 of the act.
    (f) Products labeled for use only on specific small areas of the
face (e.g., lips, nose, ears, and/or around eyes) and that meet the
criteria established in Sec. 201.66(d)(10) of this chapter. The title,
headings, subheadings, and information described in Sec. 201.66(c) of
this chapter shall be printed in accordance with the following
specifications:
    (1) The labeling shall meet the requirements of Sec. 201.66(c) of
this chapter except that the title, headings, and information described
in Sec. 201.66(c)(1), (c)(3), and (c)(7) may be omitted, and the
headings, subheadings, and information described in Sec. 201.66(c)(2),
(c)(4), (c)(5), and (c)(6) may be presented as follows:
    (i) The active ingredients (Sec. 201.66(c)(2) of this chapter)
shall be listed in alphabetical order.
    (ii) The heading and the indication required by Sec. 201.66(c)(4)
may be limited to: ``Use [in bold type] helps prevent sunburn.''
    (iii) The ``external use only'' warning in Sec. 201.66(c)(5)(i) of
this chapter may be omitted.
    (iv) The subheadings in Sec. 201.66(c)(5)(iii) through (c)(5)(vii)
of this chapter may be omitted, provided the information after the
heading ``Warnings'' states: ``Keep out of eyes.'' and ``Stop use if
skin rash occurs.''
    (v) The warning in Sec. 201.66(c)(5)(x) of this chapter may be
limited to the following: ``Keep out of reach of children.''
    (vi) For a lipstick, the warnings ``Keep out of eyes'' in
Sec. 352.52(f)(1)(iv) and ``Keep out of reach of children'' in
Sec. 352.52(f)(1)(v) and the directions in Sec. 352.52(d) may be
omitted.
    (2) The labeling shall be printed in accordance with the
requirements of Sec. 201.66(d) of this chapter except that any
requirements related to Sec. 201.66(c)(1), (c)(3), and (c)(7), and the
horizontal barlines and hairlines described in Sec. 201.66(d)(8), may
be omitted.

Sec. 352.60  Labeling of permitted combinations of active ingredients.

    Statements of identity, indications, warnings, and directions for
use, respectively, applicable to each ingredient in the product may be
combined to eliminate duplicative words or phrases so that the
resulting information is clear and understandable.
    (a) Statement of identity. For a combination drug product that has
an established name, the labeling of the product states the established
name of the combination drug product, followed by the statement of
identity for each ingredient in the combination, as established in the
statement of identity sections of the applicable OTC drug monographs.
For a combination drug product that does not have an established name,
the labeling of the product states the statement of identity for each
ingredient in the combination, as established in the statement of
identity sections of the applicable OTC drug monographs.
    (b) Indications. The labeling of the product states, under the
heading ``Uses,'' the indication(s) for each ingredient in the
combination as established in the indications sections of the
applicable OTC drug monographs, unless otherwise stated in this
paragraph. Other truthful and nonmisleading statements, describing only
the indications for use that have been established in the applicable
OTC drug monographs or listed in this paragraph (b), may also be used,
as provided by Sec. 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act
(the act) relating to misbranding and the prohibition in section 301(d)
of the act against the introduction or delivery for introduction into
interstate commerce of unapproved new drugs in violation of section
505(a) of the act.
    (1) In addition, the labeling of the product may contain any of the
``other allowable statements'' that are identified in the applicable
monographs.
    (2) For permitted combinations containing a sunscreen and a skin
protectant identified in Sec. 352.20(b).
    (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. For permitted combinations containing a sunscreen and a
skin protectant identified in Sec. 352.20(b).
    (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).

Subpart D--Testing Procedures

Sec. 352.70  Standard sunscreen.

    (a) 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. The standard sunscreen shall be an 8-percent
homosalate preparation with a mean SPF value of 4.47 (standard
deviation = 1.279). 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> 1.279) and the 95-percent confidence interval for the
mean SPF must contain the value 4.
    (b) Preparation of the standard homosalate sunscreen. (1) The
standard homosalate sunscreen is prepared from two different
preparations (preparation A and preparation B) with the following
compositions:

[[Page 27690]]

                    Composition of Preparation A and Preparation B of the 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 U.S.P................................                                                     74.30
----------------------------------------------------------------------------------------------------------------

    (2) 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.
    (c) Assay of the standard homosalate sunscreen. Assay the standard
homosalate sunscreen preparation by the following method to ensure
proper concentration:
    (1) Preparation of the assay solvent. The solvent consists of 1
percent glacial acetic acid (V/V) in denatured ethanol. The denatured
ethanol should not contain a UV radiation absorbing denaturant.
    (2) Preparation of a 1-percent solution of the standard homosalate
sunscreen preparation. Accurately weigh 1 gram of the standard
homosalate sunscreen preparation into a 100-milliliter volumetric
flask. Add 50 milliliters of the assay solvent. Heat on a steam bath
and mix well. Cool the solution to room temperature (15 to 30  deg.C).
Then dilute the solution to volume with the assay solvent and mix well
to make a 1-percent solution.
    (3) Preparation of the test solution (1:50 dilution of the 1-
percent solution). Filter a portion of the 1-percent solution through
number 1 filter paper. Discard the first 10 to 15 milliliters of the
filtrate. Collect the next 20 milliliters of the filtrate (second
collection). Add 1 milliliter of the second collection of the filtrate
to a 50-milliliter volumetric flask. Dilute this solution to volume
with assay solvent and mix well. This is the test solution (1:50
dilution of the 1-percent solution).
    (4) Spectrophotometric determination. The absorbance of the test
solution is measured in a suitable double beam spectrophotometer with
the assay solvent and reference beam at a wavelength near 306
nanometers.
    (5) Calculation of the concentration of homosalate. The
concentration of homosalate is determined by the following formula
which takes into consideration the absorbance of the sample of the test
solution, the dilution of the 1-percent solution (1:50), the weight of
the sample of the standard homosalate sunscreen preparation (1 gram),
and the standard absorbance value (172) of homosalate as determined by
averaging the absorbance of a large number of batches of raw
homosalate:
Concentration of homosalate = absorbance x 50 x 100 x 172 = percent
concentration by weight.

Sec. 352.71  Light source (solar simulator).

    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 similar to sunlight at sea level
from the sun at a zenith angle of 10  deg.; it has less than 1 percent
of its total energy output contributed by nonsolar wavelengths shorter
than 290 nanometers; and it has not more than 5 percent of its total
energy output contributed by wavelengths longer than 400 nanometers. In
addition, a solar simulator should have no significant time-related
fluctuations in radiation emissions after an appropriate warmup time,
and it should have good beam uniformity (within 10 percent) in the
exposure plane. To ensure that the solar simulator delivers the
appropriate spectrum of UV radiation, it must be measured periodically
with an accurately-calibrated spectroradiometer system or equivalent
instrument.

Sec. 352.72  General testing procedures.

    (a) Selection of test subjects (male and female). (1) Only fair-
skin subjects with skin types I, II, and III using the following
guidelines shall be selected:
Selection of Fair-skin Subjects
Skin Type and Sunburn and Tanning History (Based on first 30 to 45
minutes 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).
    (2) A medical history shall be obtained from all subjects with
emphasis on the effects of sunlight on their skin. Ascertain the
general health of the individual, the individual's skin type (I, II, or
III), whether the individual is taking medication (topical or systemic)
that is known to produce abnormal sunlight responses, and whether the
individual is subject to any abnormal responses to sunlight, such as a
phototoxic or photoallergic response.
    (b) Test site inspection. The physical examination shall determine
the presence of sunburn, suntan, scars, active dermal lesions, and
uneven skin tones on the areas of the back to be tested. The presence
of nevi, blemishes, or moles will be acceptable if in the physician's
judgment they will not interfere with the study results. Excess hair on
the back is acceptable if the hair is clipped or shaved.
    (c) Informed consent. Legally effective written informed consent
must be obtained from all individuals.
    (d) Test site delineation--(1) Test site area. A test site area
serves as an area for determining the subject's MED after application
of either the sunscreen standard or the test sunscreen product, or for
determining the subject's MED when the skin is unprotected (control
site). The area to be tested shall be the back between the beltline and
the shoulder blade (scapulae) and lateral to the midline. Each test
site area for applying a product or the standard

[[Page 27691]]

sunscreen shall be a minimum of 50-square centimeters, e.g., 5 x 10
centimeters. The test site areas are outlined with ink. If the person
is to be tested in an upright position, the lines shall be drawn on the
skin with the subject upright. If the subject is to be tested while
prone, the markings shall be made with the subject prone.
    (2) Test subsite area. Each test site area shall be divided into at
least three test subsite areas that are at least 1 square centimeter.
Usually four or five subsites are employed. Each test subsite within a
test site area is subjected to a specified dosage of UV radiation, in a
series of UV radiation exposures, in which the test site area is
exposed for the determination of the MED.
    (e) Application of test materials. To ensure standardized reporting
and to define a product's SPF value, the application of the product
shall be expressed on a weight basis per unit area which establishes a
standard film. Both the test sunscreen product and the standard
sunscreen application shall be 2 milligrams per square centimeter. For
oils and most lotions, the viscosity is such that the material can be
applied with a volumetric syringe. For creams, heavy gels, and butters,
the product shall be warmed slightly so that it can be applied
volumetrically. On heating, care shall be taken not to alter the
product's physical characteristics, especially separation of the
formulations. Pastes and ointments shall be weighed, then applied by
spreading on the test site area. A product shall be spread by using a
finger cot. If two or more sunscreen drug products are being evaluated
at the same time, the test products and the standard sunscreen, as
specified in Sec. 352.70, should be applied in a blinded, randomized
manner. If only one sunscreen drug product is being tested, the testing
subsites should be exposed to the varying doses of UV radiation in a
randomized manner.
    (f) Waiting period. Before exposing the test site areas after
applying a product, a waiting period of at least 15 minutes is
required.
    (g) Number of subjects. A test panel shall consist of not more than
25 subjects with the number fixed in advance by the investigator. From
this panel, at least 20 subjects must produce valid data for analysis.
    (h) Response criteria. In order that the person who evaluates the
MED responses does not know which sunscreen formulation was applied to
which site or what doses of UV radiation were administered, 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 include several types of typical responses
such as the following: An immediate darkening or tanning, typically
greyish or purplish in color, fading in 30 to 60 minutes, and
attributed to photo-oxidation of existing melanin granules; immediate
reddening, fading rapidly, and viewed as a normal response of
capillaries and venules to heat, visible and infrared radiation; and an
immediate generalized heat response, resembling prickly heat rash,
fading in 30 to 60 minutes, and apparently caused by heat and moisture
generally irritating to the skin's surface. After the immediate
responses are noted, each subject shall shield the exposed area from
further UV radiation for the remainder of the test day. The MED is
determined 22 to 24 hours after exposure. The erythema responses of the
test subject should be evaluated under the following conditions: The
source of illumination should be either a tungsten light bulb or a warm
white fluorescent light bulb that provides a level of illumination at
the test site within the range of 450 to 550 lux, and the test subject
should be in the same position used when the test site was irradiated.
Testing depends upon determining the smallest dose of energy that
produces redness reaching the borders of the exposure site at 22 to 24
hours postexposure for each series of exposures. To determine the MED,
somewhat more intense erythemas must also be produced. The goal is to
have some exposures that produce absolutely no effect, and of those
exposures that produce an effect, the maximal exposure should be no
more than twice the total energy of the minimal exposure.
    (i) Rejection of test data. Test data shall be rejected if the
exposure series fails to elicit an MED response on either the treated
or unprotected skin sites, or if the responses on the treated sites are
randomly absent (which indicates the product was not spread evenly), or
if the subject was noncompliant (e.g., subject withdraws from the test
due to illness or work conflicts, subject does not shield the exposed
testing sites from further UV radiation until the MED is read, etc.).

Sec. 352.73  Determination of SPF value.

    (a)(1) The following erythema action spectrum shall be used to
calculate the erythema effective exposure of a solar simulator:
    V<INF>i</INF> (<greek-l>) = 1.0 (250 < <greek-l> < 298 nm)
    V<INF>i</INF> (<greek-l>) = 1.0<SUP>0.094 (298 - </SUP><greek-l>)
(298 < <greek-l> < 328 nanometers)
    V<INF>i</INF> (<greek-l>) = 1.0<SUP>0.015 (139 - </SUP><greek-l>)
(328 < <greek-l> < 400 nanometers)
    (2) The data contained in this action spectrum are to be used as
spectral weighting factors to calculate the erythema effective exposure
of a solar simulator as follows:

BILLING CODE 4160-01-F

[[Page 27692]]

[GRAPHIC] [TIFF OMITTED] TR21MY99.000

BILLING CODE 4160-01-C
    (b) Determination of MED of the unprotected skin. A series of UV
radiation exposures expressed as Joules per square meter (adjusted to
the erythema action spectrum calculated according to Sec. 352.73(a)) is
administered to the subsite areas on each subject with an accurately
calibrated solar simulator. A series of five exposures shall be
administered to the untreated, unprotected skin to determine the
subject's inherent MED. The doses selected shall be a geometric series
represented by (1.25<SUP>n</SUP>), wherein each exposure time interval
is 25 percent greater than the previous time to maintain the same
relative uncertainty (expressed as a constant percentage), independent
of the subject's sensitivity to UV radiation, regardless of whether the
subject has a high or low MED. Usually, the MED of a person's
unprotected skin is determined the day prior to testing a product. This
MED(US) shall be used in the determination of the series of UV
radiation exposures to be administered to the protected site in
subsequent testing. The MED(US) should be determined again on the same
day as the standard and test sunscreens and this MED(US) should be used
in calculating the SPF.
    (c) Determination of individual SPF values. A series of UV
radiation exposures expressed as Joules per square meter (adjusted to
the erythema action spectrum calculated according to Sec. 352.73(a)) is
administered to the subsite areas on each subject with an accurately-
calibrated solar simulator. A series of seven exposures shall be
administered to the protected test sites to determine the MED of the
protected skin (MED(PS)). The doses selected shall consist of a
geometric series of five exposures, where the middle exposure is placed
to yield the expected SPF plus two other exposures placed symmetrically
around the middle exposure. The exact series of exposures to be given
to the protected skin shall be determined by the previously established
MED(US) and the expected SPF of the test sunscreen. For products with
an expected SPF less than 8, the exposures shall be the MED(US) times
0.64X, 0.80X, 0.90X, 1.00X, 1.10X, 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, the exposures shall be the MED(US) times 0.69X,
0.83X, 0.91X, 1.00X, 1.09X, 1.20X, and 1.44X, where X equals the
expected SPF of the test product. For products with an expected SPF
greater that 15, the exposures shall be the MED(US) times 0.76X, 0.87X,
0.93X, 1.00X, 1.07X, 1.15X, and 1.32X, where X equals the expected SPF
of the test product. The MED is the quantity of erythema-effective
energy required to produce the first perceptible, unambiguous redness
reaction with clearly defined borders at 22 to 24 hours postexposure.
The SPF value of the test sunscreen is then calculated from the dose of
UV radiation required to produce the MED of the protected skin and from
the dose of UV radiation required to produce the MED of the unprotected
skin (control site) as follows:
    SPF value = the ratio of erythema effective exposure (Joules per
square meter) (MED(PS)) to the erythema effective exposure (Joules
per square meter) (MED(US)).
    (d) Determination of the test product's SPF value and PCD. Use data
from at least 20 test subjects with n representing the number of
subjects used. First, for each subject, compute the SPF value as stated
in Sec. 352.73(b) and (c). Second, compute the mean SPF value, x, and
the standard deviation, s, for these subjects. Third, obtain the upper
5-percent point from the t distribution table with n-1 degrees of
freedom. Denote this value by t. Fourth, compute ts/ <radical>n. Denote
this quantity by A (i.e., A = ts/ <radical>n). Fifth, calculate the SPF
value to be used in labeling as follows: the label SPF equals the
largest whole number less than x - A. Sixth and last, the drug product
is classified into a PCD as follows: if 30 + A < x, the PCD is High; if
12 + A < x < 30 + A, the PCD is Moderate; if 2 + A < x < 12 + A, the
PCD is Minimal; if x < 2 + A, the product shall not be labeled as a
sunscreen drug product and shall not display an SPF value.

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

    The general testing procedures in Sec. 352.72 shall be used as part
of the following tests, except where modified in this section. An
indoor fresh water

[[Page 27693]]

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 shall be the label SPF value determined
after 40 minutes of water immersion using the following procedure for
the water resistance test:
    (1) Apply sunscreen product (followed by the waiting period after
application of the sunscreen product indicated on the product
labeling).
    (2) 20 minutes moderate activity in water.
    (3) 20-minute rest period (do not towel test sites).
    (4) 20 minutes moderate activity in water.
    (5) Conclude water test (air dry test sites without toweling).
    (6) Begin solar simulator exposure to test site areas as described
in Sec. 352.73.
    (b) Procedure for testing a very water resistant sunscreen product.
For sunscreen products making the claim of ``very water resistant,''
the label SPF shall be the label SPF value determined after 80 minutes
of water immersion using the following procedure for the very water
resistant test:
    (1) Apply sunscreen product (followed by the waiting period after
application of the sunscreen product indicated on the product
labeling).
    (2) 20 minutes moderate activity in water.
    (3) 20-minute rest period (do not towel test sites).
    (4) 20 minutes moderate activity in water.
    (5) 20-minute rest period (do not towel test sites).
    (6) 20 minutes moderate activity in water.
    (7) 20-minute rest period (do not towel test sites).
    (8) 20 minutes moderate activity in water.
    (9) Conclude water test (air dry test sites without toweling).
    (10) Begin solar simulator exposure to test site areas as described
in Sec. 352.73.

Sec. 352.77  Test modifications.

    The formulation or mode of administration of certain products may
require modification of the testing procedures in this subpart. In
addition, alternative methods (including automated or in vitro
procedures) employing the same basic procedures as those described in
this subpart may be used. Any proposed modification or alternative
procedure shall be submitted as a petition in accord with Sec. 10.30 of
this chapter. The petition should contain data to support the
modification or data demonstrating that an alternative procedure
provides results of equivalent accuracy. All information submitted will
be subject to the disclosure rules in part 20 of this chapter.

PART 700--GENERAL

    4. The authority citation for 21 CFR part 700 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 352, 355, 361, 362, 371, 374.

    5. Section 700.35 is added to subpart B to read as follows:

Sec. 700.35  Cosmetics containing sunscreen ingredients.

    (a) A product that includes the term ``sunscreen'' in its labeling
or in any other way represents or suggests that it is intended to
prevent, cure, treat, or mitigate disease or to affect a structure or
function of the body comes within the definition of a drug in section
201(g)(1) of the act. Sunscreen active ingredients affect the structure
or function of the body by absorbing, reflecting, or scattering the
harmful, burning rays of the sun, thereby altering the normal
physiological response to solar radiation. These ingredients also help
to prevent diseases such as sunburn and may reduce the chance of
premature skin aging, skin cancer, and other harmful effects due to the
sun when used in conjunction with limiting sun exposure and wearing
protective clothing. When consumers see the term ``sunscreen'' or
similar sun protection terminology in the labeling of a product, they
expect the product to protect them in some way from the harmful effects
of the sun, irrespective of other labeling statements. Consequently,
the use of the term ``sunscreen'' or similar sun protection terminology
in a product's labeling generally causes the product to be subject to
regulation as a drug. However, sunscreen ingredients may also be used
in some products for nontherapeutic, nonphysiologic uses (e.g., as a
color additive or to protect the color of the product). To avoid
consumer misunderstanding, if a cosmetic product contains a sunscreen
ingredient and uses the term ``sunscreen'' or similar sun protection
terminology anywhere in its labeling, the term must be qualified by
describing the cosmetic benefit provided by the sunscreen ingredient.
    (b) The qualifying information required under paragraph (a) of this
section shall appear prominently and conspicuously at least once in the
labeling in conjunction with the term ``sunscreen'' or other similar
sun protection terminology used in the labeling. For example:
``Contains a sunscreen--to protect product color.''

PART 740--COSMETIC PRODUCT WARNING STATEMENTS

    6. The authority citation for 21 CFR part 740 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 352, 355, 361, 362, 371, 374.

    7. Section 740.19 is added to subpart B to read as follows:

Sec. 740.19  Suntanning preparations.

    The labeling of suntanning preparations that do not contain a
sunscreen ingredient must display the following warning: ``Warning--
This product does not contain a sunscreen and does not protect against
sunburn. Repeated exposure of unprotected skin while tanning may
increase the risk of skin aging, skin cancer, and other harmful effects
to the skin even if you do not burn.'' For purposes of this section,
the term ``suntanning preparations'' includes gels, creams, liquids,
and other topical products that are intended to provide cosmetic
effects on the skin while tanning through exposure to UV radiation
(e.g., moisturizing or conditioning products), or to give the
appearance of a tan by imparting color to the skin through the
application of approved color additives (e.g., dihydroxyacetone)
without the need for exposure to UV radiation. The term ``suntanning
preparations'' does not include products intended to provide sun
protection or otherwise intended to affect the structure or any
function of the body.

    Dated: April 22, 1999.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 99-12853 Filed 5-20-99; 8:45 am]
BILLING CODE 4160-01-F