[Federal Register Volume 64, Number 98 (Friday, May 21, 1999)]
[Rules and Regulations]
[Pages 27666-27693]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-12853]


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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 (m2)) on the left side of the equation E =  
Vi () * I (), whereas the right side of 
the equation is in terms of irradiance (Watts/m2). 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 =  Vi () * I 
() * texp''

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:
    Costyx =  j NxAx(1/x), 
where j = 1 to (x-y)
    Total Costy = Costy6 + Costy3 + 
Costy2
    where:
    x = life of labeling in years (2, 3, or 6)
    y = phase-in period in years
    Nx = number of SKU's with labeling life of x years, 
and
    Ax = 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  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:
    Vi () = 1.0 (250 <  < 298 nm)
    Vi () = 1.00.094 (298 - ) 
(298 <  < 328 nanometers)
    Vi () = 1.00.015 (139 - ) 
(328 <  < 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 (1.25n), 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/ n. Denote 
this quantity by A (i.e., A = ts/ 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