conclusion that a sunscreen containing trolamine salicylate would not
be GRASE. We note that, as with PABA, our review of more than 700
sunscreen brands sold in the United States suggests that trolamine
salicylate is no longer being marketed in sunscreens sold in the United
States (Ref. 63).
    a. Background. Trolamine salicylate is comprised of trolamine and
salicylic acid. Salicylic acid is a non-steroidal anti-inflammatory
drug (NSAID); it is the active moiety in aspirin, and has been widely
used as an analgesic (i.e., pain relieving), anti-pyretic (i.e., fever
reducing), and anti-inflammatory agent. In addition to these
properties, salicylic acid inhibits platelet aggregation, which in turn
inhibits blood coagulation. For this reason, some salicylic acid-
containing products (such as aspirin) are used by consumers to help
reduce cardiovascular adverse events, including myocardial infarction,
stent thrombosis, and transient ischemic attacks.
    Trolamine salicylate was included in the Stayed 1999 Final
Monograph for sunscreens at a concentration of up to 12 percent. It was
also proposed as a Category III active ingredient in the tentative
final monograph for OTC external analgesic drug products (External
Analgesic TFM) (``External Analgesic Drug Products for Over-the-Counter
Human Use; Tentative Final Monograph,'' 48 FR 5852 at 5855 (February 8,
1983)). The mechanisms of action for trolamine salicylate for these two
drug categories are very different; to be effective as an external
analgesic, trolamine salicylate must penetrate the skin and reach the
relevant sites of action. The available evidence clearly establishes
that trolamine salicylate is transdermally absorbed (Refs. 76 and 77).
To be effective as a sunscreen, however, trolamine salicylate must be
present on the surface of the skin so that it can reflect, scatter, or
absorb UV radiation.
    The directions for use for the two product categories differ
significantly as well. The current requirements for sunscreen labeling
include directions that the product should be applied to all skin
exposed to the sun, that it should be used ``regularly'' to decrease
the risk of skin cancer and early skin aging,\27\ and that it should be
reapplied at least every 2 hours (21 CFR 201.327). In contrast,
currently marketed external analgesic products containing trolamine
salicylate include directions for use stating that they should be
applied to ``affected areas,'' that they should be reapplied no more
than three to four

times a day, and that use should be discontinued after 7 days.\28\
---------------------------------------------------------------------------

    \27\ This direction applies to sunscreens with an SPF of 15 or
greater that are also broad spectrum.
    \28\ Based on an evaluation of product labeling available at
https://labels.fda.gov (accessed April 4, 2018). See also External
Analgesic TFM.
---------------------------------------------------------------------------

    b. Significant safety concerns associated with use of trolamine
salicylate as a sunscreen. FDA is concerned that use of trolamine
salicylate as an active ingredient in sunscreens could cause serious
detrimental health effects due to the anti-coagulation effects of
salicylic acid. FDA located two case reports of serious coagulation-
related adverse events associated with liberal dermal application of
trolamine salicylate. The first case involved a surgical patient who
experienced coagulopathy (impairment of the blood's ability to
coagulate) at surgical sites in connection with use of topical
trolamine salicylate (Ref. 76). Although the patient discontinued
aspirin use 2 weeks before surgery per her doctor's instructions, she
was unaware that use of a topical cream containing trolamine salicylate
should have been stopped as well, and continued liberal application of
the product to her knees for arthritis pain in the period leading up to
her surgery. Four hours after surgery, the patient returned to the
operating room bleeding profusely from all surfaces that had been
operated on and experiencing massive bilateral hematomas. She lost more
than 900 mL of blood.
    In the second case, a patient taking warfarin (an anticoagulant)
for atrial fibrillation and stroke prevention experienced a
considerable increase in prothrombin time (i.e., the time it takes for
blood to coagulate) after liberal application of trolamine salicylate
to his neck and shoulders for pain relief (Ref. 78). The patient's
prothrombin time had previously been in the therapeutic range of 1.3 to
1.5 times the control, but increased to 2.5 times the control during
trolamine salicylate use. When trolamine salicylate use was
discontinued, the patient's prothrombin time returned to 1.3 times the
control.
    FDA is also concerned that sunscreens containing trolamine
salicylate could lead to other adverse effects associated with
salicylic acid exposure. These include gastrointestinal distress and
hemorrhage, ototoxic effects (i.e., impacts on hearing),
hypersensitivity reactions, asthma exacerbations, acid-base imbalance,
salt and water retention, liver injury, and Reye's Syndrome (in
children). At high doses, acute salicylate toxicity (salicylism) may
occur. Early symptoms of salicylism include tinnitus, vertigo, nausea,
vomiting, and diarrhea; subsequent symptoms suggesting a more severe
intoxication include altered mental status (ranging from agitation to
lethargy), hyperpyrexia, noncardiac pulmonary edema, and coma.\29\
---------------------------------------------------------------------------

    \29\ The symptoms associated with both acute and chronic
salicylate toxicity are well established. Descriptions are available
from many sources, including: National Library of Medicine's
Toxicology Data Network (ToxNet), ``Salicylic Acid,'' September
2008, available at https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+672 (accessed March 27, 2018). FDA also
included a comprehensive summary of salicylism in 21 CFR 343.80.
---------------------------------------------------------------------------

    If trolamine salicylate were to be applied to all skin exposed to
the sun and reapplied every 2 hours as directed in sunscreen labeling,
the potential for transdermal absorption and systemic availability of
substantial amounts of salicylic acid raises significant concerns about
the potential for increased occurrence of the above-described adverse
events. This is a particular concern given the widespread use of other
OTC NSAID products with anti-inflammatory, analgesic, or anti-pyretic
effects, which, combined with the use of sunscreens containing
trolamine salicylate, may raise the anti-platelet effects experienced
by consumers to problematic levels. Concerns relating to transdermal
absorption may be especially acute for children, who have a higher
surface-area-to-body-weight ratio than adults. FDA proposes that the
above-described safety concerns are enough, by themselves, to support a
finding that trolamine salicylate is not GRASE for use in sunscreens,
and therefore, is a Category II active ingredient.
    c. Data gaps. In addition, there are several categories of data
about trolamine salicylate that FDA expects would be necessary to
support a positive GRASE determination for its use in sunscreen
products that are currently missing from the public record. For
example, there is insufficient clinical dermal sensitization,
irritation, and photosafety data for trolamine salicylate. Although the
transdermal absorption of trolamine salicylate is well established, the
record currently lacks a MUsT that would allow us to evaluate the
extent of exposure to this ingredient when it is used as a sunscreen.
Such data is important because it would allow FDA to interpret systemic
toxicity findings in animal toxicology studies in the context of the
amount likely to be absorbed from sunscreen use. Given the FDA
recommendation that a MUsT for sunscreen use include application to a
majority (75 percent at a minimum) of the body surface of each test
subject, the above described safety concerns (including the potential
for salicylism associated with exposure to high doses of trolamine
salicylate) would raise significant ethical concerns about the conduct
of a MUsT in these circumstances. Were it possible to ethically conduct
a MUsT for this ingredient, and if such a MUsT showed significant
transdermal absorption of trolamine salicylate, this would raise
questions about whether enough of this ingredient remains present on
the surface of the skin for it to function effectively as a sunscreen.
As we noted in section VII.B.4, such considerations ultimately weigh
into the risk-benefit calculus FDA uses to determine whether an active
ingredient would be GRASE for use in sunscreens.
    Although we have data addressing the toxicology profile of
salicylate, adequately detailed nonclinical DART studies for trolamine
and toxicokinetic data to interpret DART studies were also not found in
the public record. Adequate DART information, if it were available,
might reveal additional data needs (for example, to address any
potential hormonal effects that may be identified). Dermal
carcinogenicity data are available from the National Toxicology Program
for trolamine in acetone and trolamine alone (applied neat).\30\ In the
absence of toxicokinetic data to interpret existing carcinogenicity
studies, we cannot determine how the exposure in the animal studies
relates to human exposure to trolamine from the use of trolamine
salicylate as a sunscreen active ingredient.
---------------------------------------------------------------------------

    \30\ In mice, liver tumors were identified, providing evidence
of systemic absorption of trolamine, but the suspected mechanism of
action is likely not relevant to humans (Refs. 79 and 80). A causal
link between the proposed mechanism and tumor formation in mice is
lacking.
---------------------------------------------------------------------------

    d. Conclusion. For the reasons described above, FDA proposes that
trolamine salicylate is not GRASE for use in sunscreens. The safety
concerns associated with the use of trolamine salicylate as an active
ingredient in sunscreens are significant enough to support
classification of trolamine salicylate as a Category II ingredient. In
particular, the potential for transdermal absorption and systemic
availability of substantial amounts of salicylic acid in connection
with the exposure resulting from the use of trolamine salicylate in
sunscreens raises concerns about increased occurrence of the above-
described serious adverse events (including salicylism and serious
coagulation-related issues). The record also contains several
significant data gaps that would need to be addressed to support a
positive GRASE determination for trolamine salicylate.

Given the safety concerns described above, however, conducting the
clinical absorption testing recommended to address these gaps for use
as a sunscreen raises ethical concerns.

C. Ingredients Proposed as Category III

    The public record does not contain sufficient data to support a
positive GRASE determination for cinoxate, dioxybenzone, ensulizole,
homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate
O, sulisobenzone, oxybenzone or avobenzone at this time. Accordingly,
these ingredients are being proposed as Category III. In the sections
that follow, we discuss our review of the available safety evidence for
these ingredients and identify the existing data gaps.
1. Ingredients for Which the Record Contains Significant Data Gaps:
Cinoxate, Dioxybenzone, Ensulizole, Homosalate, Meradimate, Octinoxate,
Octisalate, Octocrylene, Padimate O, and Sulisobenzone
    The most significant gaps in the administrative record exist for
the following active ingredients: Cinoxate, dioxybenzone, ensulizole,
homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate
O, and sulisobenzone. We expect that data from all the types of studies
described in section VII will need to be submitted to support general
recognition of safety and effectiveness for each of these ingredients.
    Only three of these active ingredients (homosalate (Ref. 81)),
octinoxate (Refs. 81 to 84), and octisalate (Ref. 81), for example,
appear to have been evaluated in human absorption studies, and most of
the available absorption studies for these three ingredients had
significant limitations. For example, the studies use a limited number
of subjects or are based on only a single application of the sunscreen
active ingredient to a limited area of the body. Even with this limited
sunscreen exposure, some of these studies showed systemic availability
of the active ingredient (octinoxate (Refs. 83 and 84)). None of these
10 ingredients has been studied in an adequate and well-controlled MUsT
that would determine the amount of systemic exposure to the active
ingredients under conditions of maximal use.
    We note that a recent publication examining the relationship
between melting point, molecular weight, and the transdermal delivery
rates of the active ingredients in approved drug products shows that
products containing active ingredients with melting points and
molecular weights similar to many of these 10 sunscreen active
ingredients are among those successfully delivered transdermally--and
therefore available systemically (Ref. 85). This reinforces the
potential for transdermal absorption of and systemic exposure to these
sunscreen ingredients. The potential for such systemic exposure is a
concern because the available data are inadequate to determine either
the level of systemic exposure to these active ingredients or the
potential unintended consequences of such exposure. Given the lack of
chronic exposure toxicology data for these 10 ingredients--which makes
an evaluation of the dermal and systemic effects of chronic use
impossible--this is especially concerning. A number of these active
ingredients have also shown hormonal effects in mammalian assays
(homosalate (Refs. 86 to 92)) and padimate O (64 FR 27666 at 27671) and
in in vitro and in vivo assays (homosalate (Refs. 86 to 92), octinoxate
(Refs. 93 and 94),and octocrylene (Ref. 95). Although these findings
are only preliminary, we do not have adequate DART studies to enable us
to assess the impact of these potential hormonal effects on development
and reproduction.
    In addition, several of these 10 ingredients (homosalate (Refs. 81
and 84), octinoxate (Refs. 81 and 96 to 101), octisalate (Refs. 81, 84,
and 101 to 105),octocrylene (Refs. 95 and 106), padimate O (Ref. 100),
and sulisobenzone (Refs. 107 and 108)) have been studied in dermal
penetration studies, which show (in general, with the exception of
homosalate) that these ingredients permeate into the epidermis and/or
dermis. The studies show that there are several factors (including
vehicle composition and the presence of other active ingredients) that
can influence, and potentially increase, the permeation and/or
penetration of these ingredients.
    Because the record does not currently contain sufficient data to
support their safety, we are proposing that cinoxate, dioxybenzone,
ensulizole, homosalate, meradimate, octinoxate, octisalate,
octocrylene, padimate O, and sulisobenzone are Category III
ingredients. As previously noted, we expect that data from all the
types of studies described in section VII will be needed to support
general recognition of safety and effectiveness for these ingredients.
2. Ingredients for Which the Record Contains Fewer Data Gaps:
Oxybenzone and Avobenzone
    While the record does not currently contain sufficient data to
support positive GRASE findings for oxybenzone and avobenzone, we have
significantly more data for these two ingredients than for the
ingredients discussed in the preceding section. To help facilitate
submission of the remaining data, we describe the data gaps for these
two ingredients in greater detail below.
    a. Oxybenzone data. Although we located substantially more data on
oxybenzone than on the ingredients discussed in section VIII.C.1, our
review of the scientific literature, submissions to the sunscreen
monograph docket, and postmarket safety data publicly available through
FAERS revealed significant gaps in the data we expect to be necessary
to support a positive GRASE finding for use of oxybenzone at a
concentration of up to 6 percent in sunscreen products. The available
literature includes studies indicating that oxybenzone is absorbed
through the skin and can lead to significant systemic exposure, as well
as data showing the presence of oxybenzone in human breast milk,
amniotic fluid, urine, and blood plasma. The significant systemic
availability of oxybenzone (and, as discussed further below, the lack
of data evaluating the full extent of its absorption potential) is a
concern, among other reasons, because of questions raised in the
published literature regarding the potential for endocrine activity
with systemic oxybenzone exposure. Accordingly, we expect that a
positive GRASE finding for oxybenzone-containing sunscreens would
require, among other things, both a MUsT showing the degree of
oxybenzone absorption under maximal usage conditions and DART studies
that fully investigate its potential endocrine-disrupting effects. We
found neither in the existing record.
    The record also lacks systemic and dermal carcinogenicity studies
for oxybenzone; these (and toxicokinetic data) should also be provided
to support a positive GRASE finding for this ingredient. Finally, the
available literature also raises questions about the safety of use of
oxybenzone-containing sunscreens in young children because of the
potential for higher absorption and bioaccumulation of oxybenzone in
this population. As discussed in further detail in the sections that
follow, we invite input and comment on appropriate studies and/or age
restrictions to address these pediatric issues.
    b. Background of oxybenzone. Unlike zinc oxide and titanium
dioxide, both of which are inorganic (or physical) UV filters
consisting of metal oxides that primarily reflect or scatter UV
radiation,

oxybenzone is an organic (or chemical) filter, which absorbs UV
radiation. It belongs to a class of aromatic ketones known as
benzophenones and has a UV absorption profile covering both UVA and UVB
wavelengths (Ref. 109). Because of its superior UVA coverage,
oxybenzone was increasingly used through the early 1990s and ultimately
replaced PABA in sunscreen products (Ref. 110). Use of oxybenzone in
sunscreens increased when ``PABA-free'' sunscreens were introduced into
the market because of recognition that PABA and its esters induced
contact and photocontact allergic reactions (Ref. 110). As discussed
below, however, evidence shows that oxybenzone also has contact
allergenic and photoallergenic potential (Ref. 111). In addition to its
use as a sunscreen active ingredient, oxybenzone is used in, among
other things, perfumes, lipsticks, hair sprays, and conditioners as a
photostabilizer and/or fragrance enhancer (Refs. 112 to 114).
    c. Data showing transdermal absorption and significant systemic
availability of oxybenzone. Data that have become available since
publication of the Stayed 1999 Final Monograph suggest that the
transdermal absorption of oxybenzone is high (Refs. 82, 115, and 116).
One study involving sampling of plasma and urine following topical
application of an oxybenzone-containing formulation showed absorption
and significant systemic availability of oxybenzone (Ref. 82). In this
study, 15 men and 17 women were dosed once daily, applying a 10 percent
oxybenzone cream formulation to approximately 90 percent of the body's
surface area for 4 days. The figures below illustrate the plasma and
urine levels observed.
BILLING CODE 4164-01-P
[GRAPHIC] [TIFF OMITTED] TP26FE19.000

BILLING CODE 4164-01-C

[GRAPHIC] [TIFF OMITTED] TP26FE19.001

BILLING CODE 4164-01-C
    Although this study provides important information about the
significant absorption potential of oxybenzone, it does not obviate the
need for a MUsT. Among other things, once-daily application may result
in substantially lower systemic exposure than application at least
every 2 hours (as sunscreen labeling directs). This difference in
application frequency is a particular concern given that the data show
oxybenzone levels would still be increasing at the time of
reapplication if a 2-hour application window were observed.
Additionally, the cream formulation used in the study was not
formulated as a sunscreen product and may have contained ingredients
not typically used in sunscreen formulations, and/or lacked other
ingredients typically present. Because the formulation can have an
impact on absorption, the absorption results produced by the study may
not reflect absorption levels that would result from actual use of
oxybenzone-containing sunscreen products.
    Another study, which evaluated the transdermal absorption of a
marketed sunscreen containing 4 percent oxybenzone in 16 women and 9
men, showed prolonged systemic availability of oxybenzone following
topical exposure (Ref. 116). In this study, which was designed to
evaluate the effects of UV radiation on oxybenzone absorption, the
sunscreen was applied to study subjects twice daily for 5 days.
Although the study concluded that UV exposure did not significantly
affect the urinary excretion of oxybenzone, it provided further
evidence of the systemic availability of oxybenzone following topical
application and showed that renal excretion of oxybenzone continued for
5 days after the last application of the sunscreen. Although the use of
a commercial sunscreen formulation, and twice- rather than once-daily
sunscreen application are improvements over the formulation and
application frequency used in the previous study, twice-daily
application remains insufficient to approximate the recommended
application frequency of sunscreen products in real-world use.
Furthermore, because the study used a sunscreen with 4 percent rather
than the full 6 percent concentration of oxybenzone eligible for the
sunscreen monograph, its results may not fully reflect the absorption
that would result from use of a 6 percent oxybenzone-containing
product. To properly characterize the potential for absorption of
oxybenzone in sunscreen products and to determine a margin of safety
for use of oxybenzone at up to 6 percent in sunscreen products, we
expect that a MUsT will be needed.
    d. Inadequate data on oxybenzone's developmental and reproductive
toxicity. The significant systemic availability of oxybenzone following
topical application and the lack of data fully characterizing its
absorption levels are concerns, among other reasons, because of
literature suggesting that oxybenzone may have endocrine activity (see,
e.g., Refs. 88, 92, and 117). Dermal exposure to oxybenzone (in
acetone) in rats and mice and oral feeding of oxybenzone to rats and
mice resulted in reduced sperm density in males in 13-week general
toxicity studies conducted by the National Toxicology Program (NTP)
(Ref. 118). In female rats and mice, increased estrous cycle length was
observed in 13-week oral feeding studies.\31\ Importantly, the actual
effects of oxybenzone on female fertility were not evaluated. In a
preliminary dose range-finding pre- and postnatal development study in
rats, findings in male offspring indicated that cells in the testes
undergoing programmed cell death were increased in all oxybenzone-
exposed animals and that numbers of spermatocytes in the testes were
markedly reduced after oral feeding at oxybenzone (Ref. 119). Although
these findings are notable, they are all derived from dermal studies

with oxybenzone in acetone and oral feeding studies of oxybenzone;
these methods of exposure could potentially lead to higher levels of
systemic exposure to oxybenzone than with sunscreen use. Accordingly, a
MUsT and toxicokinetic data are needed to determine the relevance of
these findings to human use of oxybenzone as a sunscreen active
ingredient.
---------------------------------------------------------------------------

    \31\ These changes could potentially be addressed with
historical control data (Ref. 88).
---------------------------------------------------------------------------

    In humans, the endocrine effects of oxybenzone have been studied
with inconclusive results (see, e.g., Refs. 83, 120, and 121). In
biomonitoring studies of pregnant and lactating women, oxybenzone has
been detected in breast milk, amniotic fluid, and urine samples (Ref.
83, 120, and 121). High levels of oxybenzone in the urine of mothers
have been associated with: (1) Decreased birth weight in girls and (2)
increased birth weight and head circumference in boys, both of which
can be indications of endocrine effects (Ref. 83). This association is
particularly concerning given the widespread exposure of the U.S.
population to oxybenzone. Estimates suggest that oxybenzone (from all
sources) is present in the urine of 97 percent of the U.S. population,
and that oxybenzone concentrations are higher in women than in men
(possibly because women are more likely to use sunscreen and other
personal care products containing oxybenzone, leading to greater
cumulative exposure) (Ref. 83 and 115).
    Because current data suggest that oxybenzone may affect the human
endocrine system, FDA believes that a positive GRASE determination for
oxybenzone would require that its potential toxicities have been fully
explored, including through DART studies (fertility and early embryonic
studies in rodents, embryofetal development studies in rodent and
nonrodent species, and pre- and postnatal development studies in
rodents). In addition, as noted below, toxicokinetic data are needed to
interpret these studies. We note that, if the results of DART studies
do not resolve the concerns raised in the literature relating to
potential endocrine disruption, it may still be possible to resolve
these concerns through additional testing.\32\ In addition, because of
the potential risk posed by metabolites of oxybenzone (existing reports
suggest that some oxybenzone metabolites are more hormonally active
than the parent drug (Ref. 109)), we recommend that the analytical
method used in the MUsT be validated for both the parent and the
metabolites of interest (Ref. 115) to support a positive GRASE finding
for this ingredient. The results from the metabolite study will inform
whether additional nonclinical studies assessing oxybenzone's
metabolites should be conducted to support its safety. We note that the
NTP is currently conducting additional DART studies on oxybenzone
(although their embryofetal studies do not appear to include an
assessment in a nonrodent species) (Ref. 122).\33\
---------------------------------------------------------------------------

    \32\ For examples of the type of studies that could be explored
at that juncture see Ref. 21.
    \33\ As a reminder, such data must be generally available to be
considered as part of this rulemaking process. Once available, FDA
intends to review such data to determine whether it resolves
particular data concerns we have in this area.
---------------------------------------------------------------------------

    e. Inadequate carcinogenicity and toxicokinetic data for
oxybenzone. High population exposure to oxybenzone, coupled with a lack
of carcinogenicity testing for this ingredient, caused the National
Cancer Institute to nominate oxybenzone for toxicology testing in 1979
(Ref. 123). The NTP reports that 2-year oral (dosed feed)
carcinogenicity studies in rats and mice are in a draft report stage,
but results are not yet publicly available (Ref. 122). In addition, no
reports of either ongoing or planned dermal carcinogenicity studies for
oxybenzone have been published. To support a positive GRASE finding for
oxybenzone, carcinogenicity data from well-conducted dermal and
systemic carcinogenicity studies should be provided. Toxicokinetic data
in rodents (oral and dermal) and rabbits (oral) are also recommended;
these data could be obtained from either stand-alone studies or as part
of DART and dermal carcinogenicity studies.
    Our search of the available literature also revealed information
suggesting that oxybenzone may generate reactive oxygen species (ROS)
\34\ in the presence of UV light, but that this issue, and the harms
associated with it, have not been fully explored (Ref. 124). We invite
comment and input on the extent to which ROS generation is a concern
for sunscreens containing oxybenzone and whether additional data on
this topic are needed.
---------------------------------------------------------------------------

    \34\ Reactive oxygen species are ``a type of unstable molecule
that contains oxygen and that easily reacts with other molecules in
a cell. A buildup of ROS in cells may cause damage to DNA, RNA, and
proteins, and may cause cell death.'' https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=687227.
---------------------------------------------------------------------------

    f. Dermal safety of oxybenzone. The available data indicate that
oxybenzone (at concentrations up to 6 percent) has a favorable safety
profile with respect to irritation and sensitization potential. For
example, the North American Contact Dermatitis Group conducted an
analysis of patients who were patch tested for allergies between 2001
and 2010 (see, e.g., Ref. 125). From 2001 to 2008, oxybenzone was
tested at 3 percent; from 2009 to 2010, the concentration used for the
test was increased to 10 percent. Of the 23,908 patients patch tested,
only 82 patients (0.34 percent) had positive test patch results with
oxybenzone. In addition, a search of FAERS for case reports of
hypersensitivity reactions to oxybenzone-containing sunscreen products
resulted in only 31 cases (4 with anaphylaxis) between 1988 and 2011.
Because sufficient data exist to make a determination, we do not
consider additional dermal irritation or sensitization studies to be
necessary to support a positive GRASE finding for oxybenzone up to 6
percent. As is customary in clinical trials, however, we recommend that
dermal safety data for oxybenzone be collected during MUsT studies.
    Nevertheless, the overwhelming majority of results from available
studies (see, e.g., Refs. 125 to 136) addressing allergic contact
dermatitis for oxybenzone show that oxybenzone is an allergen for
persons with preexisting skin conditions. Because the evidence
establishing oxybenzone as a photoallergen in individuals with
photosensitivity is clear, no further dermal photosafety studies to
characterize this risk are needed. However, if we were to receive
adequate data to support a positive GRASE finding for oxybenzone, we
would consider requiring labeling language to address the risk of
allergic reactions associated with oxybenzone use. We invite comment on
whether such labeling should be required for sunscreens containing
oxybenzone and, if so, what that labeling should entail.
    g. Safety questions regarding use of oxybenzone in pediatric
populations. Sunscreens are currently labeled for use in children as
young as 6 months old. The available literature, however, includes
several publications that raise concerns about the use of sunscreens
containing oxybenzone in young children. Among these publications is a
2006 report from the Swedish Research Council noting that children
under the age of 2 years old have not fully developed the enzymes
believed to metabolize oxybenzone (Ref. 137), which suggests, in
theory, that small children may not be able to eliminate oxybenzone as
easily as adults. The possibility for bioaccumulation in children,
taken together with the potential increased absorption of oxybenzone in
young children (due to their greater body surface-area-to-weight ratio)
and the potential harms associated with absorption discussed above,

militates in favor of caution when using oxybenzone products in young
children. Accordingly, we are seeking any existing pediatric data on
the safety of oxybenzone use in children under 2 years old. We are also
requesting input on: (1) Whether additional data on the safety of
oxybenzone use in young children is necessary to support the use of
oxybenzone-containing sunscreens in children under 2 years of age
(taking into consideration the practical hurdles involved in conducting
studies in children of this age) or (2) whether sunscreen products
containing oxybenzone should instead be contraindicated for use in
children younger than 2 years (given, among other things, the
availability for use as sunscreen active ingredients of physical UV
filters like titanium dioxide and zinc oxide, which do not raise the
same questions about safe use in young children).
    h. Conclusion. Given the available data showing significant
transdermal absorption and systemic availability of oxybenzone, as well
as the potential for endocrine activity, we propose that oxybenzone is
not GRASE for use in sunscreens without further data. As described
above, a MUsT should be conducted to fully characterize the absorption
of oxybenzone and to calculate a margin of safety for human use. As
part of the MUsT, we believe that a study of oxybenzone's metabolites
in humans is also necessary; the results of this study will inform
whether additional nonclinical studies with metabolites are needed to
address potential endocrine effects. Given that oxybenzone demonstrates
significant systemic absorption, FDA believes that data on
carcinogenicity (both systemic and dermal) and developmental/
reproductive toxicity are likely to be needed to support the safety of
this ingredient, as are toxicokinetic data to bridge between animal and
human data. We seek any existing data on the pediatric safety of
oxybenzone. We also seek comment on whether additional safety data are
needed to support the use of sunscreens containing oxybenzone on
children under 2 years of age, as well as comment on whether these
sunscreens should be contraindicated for use in this population. We
note that, because of the risk of allergic reactions associated with
oxybenzone use, if we receive adequate data to support a positive GRASE
finding for oxybenzone, we may require labeling to address this risk.
We seek comment on whether such labeling should be required for
sunscreens containing oxybenzone and, if so, what such labeling
language should entail.
    In summary, table 3 shows the additional studies that FDA
anticipates would be necessary to support a positive GRASE finding for
sunscreens containing oxybenzone.

   Table 3--Summary of Recommendations: Studies for Oxybenzone Up to 6
                                 Percent
------------------------------------------------------------------------
    Safety studies FDA proposes are
      necessary to support a GRASE          Additional studies or data
             determination                          necessary?
------------------------------------------------------------------------
Pharmacological Studies:                 ...............................
    Human absorption (MUsT) (including   Yes.
     metabolite study in humans).
Nonclinical Safety Studies:              ...............................
    Toxicokinetics.....................  Yes.
    Dermal Carcinogenicity.............  Yes.
    Systemic Carcinogenicity...........  Yes.
DART: \1\..............................  Yes.
    Fertility and early embryonic
     development.
    Embryofetal development in two
     species (rodent and non-rodent).
    Prenatal and postnatal development.
Clinical Safety Testing:                 ...............................
    Skin irritation and sensitization..  No.
    Skin photoallergenicity and          No.
     phototoxicity.
    Pediatric studies..................  Seeking input on whether
                                          additional studies or
                                          contraindication are necessary
                                          to support the safety of
                                          sunscreens containing
                                          oxybenzone for children under
                                          2 years of age.
------------------------------------------------------------------------
\1\ As noted above, if DART studies do not resolve the concerns raised
  in the literature relating to potential endocrine disruption, it may
  be possible to resolve these concerns through additional testing.

    i. Avobenzone data. Our review of the available scientific
literature, submissions to the sunscreen monograph docket, and publicly
available FAERS data also revealed significant gaps in the data we
expect to be necessary to support a finding that avobenzone (at up to
either 3 percent or 5 percent, as discussed below) is GRASE for use in
sunscreens. Most critically, we encountered no studies examining the
absorption of avobenzone in vivo, and those in vitro studies we located
had several weaknesses that limit their usefulness in assessing the
potential absorption of avobenzone from formulated sunscreen products.
This is a concern given that, as explained in further detail below,
certain of avobenzone's chemical properties suggest that sunscreen
products containing avobenzone have a potential for absorption. There
are also other gaps in the record, including (as discussed below)
dermal carcinogenicity data, toxicokinetic data, and--potentially,
depending on the outcome of MUsT studies assessing the absorption of
avobenzone--systemic carcinogenicity and additional DART studies.
Accordingly, we propose to find that avobenzone is Category III.
    j. Background of avobenzone. Avobenzone, like oxybenzone, is an
organic (chemical) UV filter. Because avobenzone primarily absorbs
radiation in the UVA portion of the UV spectrum, it is typically
combined with another sunscreen active ingredient that provides
protection in the UVB range. Avobenzone exhibits greater
photoinstability than other UV absorbers; the available evidence shows
that avobenzone degrades quickly upon exposure to sunlight, which can
cause its efficacy to be decreased by between 50 and 90 percent after
60 minutes of exposure to sunlight (Refs. 138 and 139).\35\ To address
this, avobenzone is typically combined with a photostabilizer to
prevent rapid photodegradation (Refs. 138 and 139).
---------------------------------------------------------------------------

    \35\ Avobenzone's photodegradation also results in the formation
of free radicals, which could, in theory, create sensitization and
irritation responses and increase long-term risk of skin cancers and
photoaging (Ref. 139).

---------------------------------------------------------------------------

    k. Potential for absorption of avobenzone. Although avobenzone is
not soluble to any great extent in water, it is soluble in organic
solvents. These include oils (which are present on human skin),
alcohols, and other substances regularly included in sunscreen product
formulations. Although this solubility is not enough, by itself, to
determine whether transdermal absorption will take place, it is a
necessary precondition (Ref. 140). In addition, like the 10 active
ingredients described in section VIII.C.1, avobenzone's melting point
and molecular weight are similar to those of active ingredients in
approved drug products that are successfully delivered transdermally
and therefore available systemically (Ref. 85). As with the 10
sunscreen active ingredients previously discussed, this suggests a
potential for transdermal absorption of avobenzone.
    l. Lack of adequate data on transdermal absorption of avobenzone.
Nevertheless, our review of the available literature on avobenzone
failed to produce any studies evaluating the in vivo absorption of
avobenzone at 3 percent or higher under (or even approaching) maximal
usage conditions. While we were able to locate a few studies evaluating
avobenzone's absorption in vitro, these studies had a number of
weaknesses that significantly limited the conclusions that could be
drawn from them.
    The first in vitro study we located evaluated the penetration--
through excised human skin--of five sunscreen ingredients (including
avobenzone) that had been diluted in mineral oil and water (Ref. 100).
The study used a static cell technique. As discussed in section VIII.D,
in a static cell study, the test product (here, a sunscreen/mineral
oil/water formulation) is placed on the upper side of a membrane (here,
the excised skin) in the open donor chamber of a static cell, and a
sampling fluid is placed on the other side of the membrane in a
receptor cell. Diffusion of the ingredient (here the avobenzone) from
the topically applied product to and across the membrane is monitored
by examining sequentially collected samples of the receptor fluid. To
ensure that all transdermal penetration of the ingredient that takes
place is fully reflected in the receptor fluid, the receptor fluid must
be optimized for absorption (in other words, sink conditions must be
created in the fluid).
    In this study, the use of skin as the membrane in the system
allowed for an evaluation of the presence and depth of permeation via
skin stripping--the sequential application and removal of adhesive tape
to the skin samples. However, it is unclear whether the receptor phase
of the study created adequate sink conditions. In addition, the
formulations used in the study (which, as noted previously, consisted
of only water, mineral oil, and the sunscreen ingredient) did not
contain any of the other types of excipients (such as emollients,
stabilizers, or solubilizers) that can also function as permeation/
absorption enhancers and that are typically present in sunscreen
product formulations. The study results showed that there was
avobenzone present in the stratum corneum, the epidermis, and the
viable dermis of the skin used as the membrane, but not in the receptor
fluid. Although the lack of avobenzone in the receptor fluid is
encouraging, the other characteristics of the study limit its value in
assessing the actual absorption potential of avobenzone used in
sunscreen products.
    The second in vitro study (Ref. 141) we located suffered from
similar limitations. This study assessed the avobenzone permeation
observed using a static cell (as generally described above), and then
took the skin from the static cell and subjected it to multiple rounds
of tape stripping to assess the presence of avobenzone at various
levels of the skin. Following tape stripping, the skin was subjected to
digestion (i.e., the skin sample was subjected to a chemical treatment
that breaks down the cell membranes to release any sunscreen that might
be either bound to proteins or bound up in the cells).
    The study results showed significant retention of avobenzone in the
stratum corneum, a lesser amount in the epidermis, and none in the
dermis or receptor fluid. Like the previous study, however, the test
material used in this study did not include any of the permeation
enhancers typically included in commercial sunscreen formulations. It
is also unclear whether sink conditions existed in the receptor phase
of the study.
    The final in vitro study used a static cell to evaluate the
transdermal penetration of six sunscreen formulations collected from a
health spa that marketed its own line of skin care products (Ref. 96).
This study improved on the design of the previous two studies in
several respects. First, the receptor fluid contained ethanol, a
permeation enhancer often used in sunscreen products, which produced
sink conditions in the receptor phase. Secondly, to create favorable
conditions for absorption, the products were applied at a thickness of
20 mg/square centimeters (cm\2\) on the skin's surface (i.e., 10 times
the skin loading typically expected (Refs. 142 and 143)). In addition,
the study's use of commercially marketed sunscreen formulations (which,
as discussed above, typically contain multiple permeation/absorption-
enhancing excipients) more accurately reflects the absorption potential
of marketed sunscreen products.
    Despite these improvements, the usefulness of the study was limited
by its use of an analytical method that prevented the detection of any
avobenzone absorption below 100 ng/mL. This level of absorption is
hundreds of times higher than what is relevant for our considerations
in assessing the acceptable absorption level from a topically applied
product. The concentration of avobenzone used in the study (ranging
from 0.2 percent to 1 percent) is also significantly lower than what is
relevant for our current consideration of maximum concentration of this
ingredient. Although avobenzone was only absorbed to a very small
extent (between 3 percent and 3.96 percent) under these study
conditions, these weaknesses in the study's design significantly limit
the conclusions that can be reached from its results.
    Given that avobenzone's chemical properties suggest that it has a
potential for transdermal absorption in sunscreen products, the lack of
adequate data assessing its absorption in realistic sunscreen
formulations is a concern. We therefore expect that a MUsT
demonstrating the degree of absorption of avobenzone into the human
body under maximal use conditions will be needed to support a positive
GRASE determination for sunscreens containing avobenzone. Further, in
light of the above-described data showing avobenzone's
photoinstability, we also expect that, if sufficient data are provided
to support the safety of avobenzone, any future sunscreen monograph
including avobenzone as an active ingredient will include the
limitation that avobenzone is not GRASE for use in sunscreen products
unless it has been photostabilized (via use of a photostabilizing UV
filter or other photostabilizing ingredient/mechanism) to prevent its
photodegradation and (among other concerns) the attendant reduction in
avobenzone efficacy.
    Because photodegradation can reduce the amount of avobenzone
absorbed transdermally, we also expect that a MUsT sufficient to
support the general recognition of safety of avobenzone for sunscreen
use would need to test formulations of avobenzone that include a
photostabilizer. Including

photostabilizers in MUsT formulations will allow for accurate
assessment of absorption levels in final formulated sunscreen products
containing avobenzone. This proposal is consistent with our general
recommendation that materials evaluated under the MUsT paradigm
represent real-world sunscreen formulations, rather than overly
simplified solutions that fail to replicate the absorption potential of
marketed formulations. As noted in section VII.B.4, we encourage
sunscreen manufacturers to discuss their MUsT protocol with FDA before
beginning the trial.
    m. Data supporting dermal safety of avobenzone. The available
clinical dermal studies indicate that avobenzone at concentrations up
to 5 percent have a favorable safety profile with respect to potential
irritation, sensitization, and photosafety. In 2009, in conjunction
with a citizen petition \36\ (L'Oreal Petition, Docket No. FDA-1978-N-
0018-0675) asking FDA to take action to permit the marketing of
sunscreen products containing avobenzone up to 5 percent, L'Oreal USA
Products, Inc. (L'Oreal) submitted nine human repeat insult patch,
phototoxicity, and photoallergy studies with six different sunscreen
formulations containing avobenzone (3.4 percent, 4 percent, or 5
percent). The studies showed that the formulations were well tolerated
for topical use (i.e., essentially non-allergenic, non-irritating, and
non-sensitizing, with mild to moderate reactions occurring only rarely)
(L'Oreal Petition).\37\ A separate search of the available scientific
literature on the clinical safety of avobenzone did not reveal anything
to undermine these findings. Although the available literature included
a small number of reports of contact irritation and photosensitization
in connection with avobenzone-containing products, details about the
composition of the formulations at issue (and the concentrations of
avobenzone) were frequently missing from the literature, making it
difficult to determine the cause of these responses. A small number of
serious hypersensitivity reports for sunscreens containing avobenzone
were also located in FAERS. Because the sunscreens at issue usually
contained three or more active ingredients, however, it is difficult to
determine what caused the reaction. Because sufficient data exist to
make a determination, we do not consider additional dermal clinical
studies (including photosafety, irritation, or sensitization studies)
to be necessary to support the safety of this ingredient for sunscreen
use at up to 5 percent. As is customary in clinical trials, however, we
recommend that dermal safety data for avobenzone be collected during
MUsT studies.
---------------------------------------------------------------------------

    \36\ FDA-1978-N-0018-0675, two volume submission (February 20,
2009) (L'Oreal Petition).
    \37\ Id., volume I, pp. 5-8.
---------------------------------------------------------------------------

    n. Other nonclinical safety studies for avobenzone. Dermal
carcinogenicity studies have not been conducted for avobenzone. The
available data on the permeation of avobenzone suggest that it may
permeate into at least the dermis and epidermis, which means that it is
possible for avobenzone to impact skin tumor development. We therefore
expect that dermal carcinogenicity studies will be necessary to support
a positive GRASE finding for sunscreens containing this ingredient.
Available embryofetal development studies in rats and rabbits did not
reveal any findings of concern. However, our review of the nonclinical
data for avobenzone \38\ also revealed that toxicokinetic data
following repeat-dose exposure will be needed to interpret pivotal
nonclinical safety studies (including the embryofetal development
studies in rats and rabbits) once the MUsT data become available. (As
explained in section VII.B.4, these data are used to compare drug
levels achieved in animal studies with those observed in humans under
maximal exposure conditions.) In addition, if results of a MUsT
demonstrate that there is significant systemic absorption of
avobenzone, additional fertility and early embryonic development and
prenatal and postnatal development studies in rats will be needed to
support a positive GRASE finding. Depending on the results of the MUsT,
systemic carcinogenicity studies may also be needed.
---------------------------------------------------------------------------

    \38\ The available nonclinical data for avobenzone include acute
oral and dermal toxicity studies in rats; a 13-week oral toxicity
study in rats; a 28-day dermal toxicity study in rats; a 21-day
dermal toxicity study in rabbits; several in vitro genotoxicity
tests; an in vivo micronucleus test in mice, as well as a
sensitization test in guinea pigs; a primary skin irritation test in
rabbits; an ocular irritation test in rabbits; a phototoxicity study
in guinea pigs; a photoallergenicity study in guinea pigs; and
embryofetal development studies in rats and rabbits (Givaudan-Roure
Petition, Docket No. FDA-1978-N-0018-0751). Importantly, (except for
the embryofetal development studies) these studies are not
sufficient to resolve safety concerns for a chronically used
product.
---------------------------------------------------------------------------

    o. Avobenzone in combination with other sunscreen active
ingredients. As noted in section III.B, our finding in the Stayed 1999
Final Monograph that avobenzone was GRASE for use in sunscreens would
have allowed its combination only with certain other sunscreen active
ingredients (64 FR 27666 at 27688) because we did not have targeted
evidence to support the safety and effectiveness of avobenzone when
combined with the remaining active ingredients. We believe this
limitation was inconsistent with the approach to evaluating sunscreen
combinations that the Agency has generally taken throughout the OTC
Drug Review for sunscreens. For this reason, unless evidence is
submitted to suggest that there is a safety or efficacy concern
associated with the combination of avobenzone with another active
ingredient, we expect to conclude that a positive GRASE determination
for avobenzone will support its use in sunscreens either alone or in
combination with all other sunscreen active ingredients.
    p. L'Oreal request to increase concentration of avobenzone to 5
percent. Avobenzone is currently listed in the Stayed 1999 Final
Monograph at concentrations up to 3 percent. As described earlier, in
2009 FDA received a citizen petition from L'Oreal requesting, among
other things, that we amend the sunscreen monograph to increase the
allowable level of avobenzone to 5 percent (L'Oreal Petition at 1). In
the Stayed 1999 Final Monograph, the Agency determined that avobenzone
at concentrations up to 3 percent is an effective sunscreen active
ingredient. We now likewise conclude that the record contains
sufficient information to satisfy the effectiveness prong of the GRASE
standard for sunscreens containing avobenzone at concentrations up to 5
percent.
    As described above, data submitted with that L'Oreal Petition were
sufficient to establish that avobenzone at a concentration of up to 5
percent has a favorable safety profile with respect to potential
irritation, sensitization, and photosafety. To support a finding that
avobenzone at concentrations up to 5 percent is GRASE for use in
sunscreens, however, FDA expects that a MUsT evaluating the transdermal
absorption of avobenzone up to 5 percent, as well as dermal
carcinogenicity studies and toxicokinetic data for avobenzone at a
concentration of at least 5 percent, will also be needed. Depending on
the outcome of the MUsT, we may also need systemic carcinogenicity data
and additional DART studies, including fertility and early embryonic
development, and pre- and postnatal development studies in rats for
avobenzone at 5 percent. The record does not currently include any of
these data. However, if FDA were to receive sufficient data to support
a positive GRASE finding for avobenzone up to 5 percent, we would
expect to include

avobenzone at this percentage in a final sunscreen monograph.
    q. Conclusion. Given that: (1) Avobenzone's organic solubility,
molecular weight, and melting point suggest it has a potential for
transdermal absorption; (2) there is a lack of available data on the
transdermal absorption of avobenzone in vivo (including under maximal
use conditions); and (3) there are limitations in the available in
vitro studies assessing avobenzone absorption, we expect that a
properly designed MUsT will be necessary to support a positive GRASE
finding for avobenzone use in sunscreens. We expect that, to be GRASE
for sunscreen use, avobenzone will need to be photostabilized to
address its potential for degradation, and we therefore expect that any
future sunscreen monograph including avobenzone as an active ingredient
will include the limitation that avobenzone is not GRASE for use in
sunscreen products unless it has been photostabilized to prevent its
photodegradation. In addition, we believe that an adequate MUsT
evaluating the absorption potential of avobenzone will need to include
a photostabilizer to ensure that the potential transdermal absorption
of avobenzone from avobenzone-containing sunscreens is accurately
assessed.
    We also expect that dermal carcinogenicity and toxicokinetic data
will be necessary to support a positive GRASE finding for sunscreens
containing avobenzone. Depending on the outcome of a MUsT assessing the
absorption of avobenzone, systemic carcinogenicity testing and
additional DART studies, including fertility and early embryonic
development and pre- and postnatal development studies in rats may be
needed as well. We will also determine the extent to which additional
DART studies may be needed based on the results of the MUsT. Depending
on the results of the nonclinical and pharmacology studies for this
ingredient and the safety margin that is calculated from these results,
pediatric studies for avobenzone may also be needed to support the use
of sunscreens containing avobenzone in pediatric populations.

 Table 4--Summary of Recommendations: Studies for Avobenzone Up to 3 (or
                               5) Percent
------------------------------------------------------------------------
    Safety studies FDA proposes are
      necessary to support a GRASE          Additional studies or data
             determination                          necessary?
------------------------------------------------------------------------
Pharmacological Studies:
    Human absorption (MUsT) (including   Yes.
     metabolite study in humans).
Nonclinical Safety Studies:
    Toxicokinetics.....................  Yes.
    Dermal Carcinogenicity.............  Yes.
    Systemic Carcinogenicity...........  Dependent on results of the
                                          MUsT.
DART:
    Fertility and early embryonic        Dependent on results of the
     development.                         MUsT.
    Embryofetal development in two       No.
     species (rodent and non-rodent).
    Prenatal and postnatal development.  Dependent on results of the
                                          MUsT.
Clinical Safety Testing:
    Skin irritation and sensitization..  No.
    Skin photoallergenicity and          No.
     phototoxicity.
    Pediatric studies..................  Pediatric studies may be
                                          required depending on the
                                          outcome of the MUsT.
------------------------------------------------------------------------

D. Anticipated Final Formulation In Vitro Permeation Testing

    As noted earlier, a final sunscreen monograph will need to set out
the conditions under which any product marketed pursuant to it would be
GRASE and not misbranded. Variations among individual sunscreen product
formulations--in particular, characteristics of the specific vehicle
(e.g., the cream, lotion, or oil) in which active ingredients are
delivered--can affect the transdermal absorption of sunscreens, and
thus, have an impact on their safety and effectiveness. To address
this, FDA currently requires final formulation testing of OTC sunscreen
products to support labeled claims regarding their effectiveness--
namely, testing for SPF value as well as broad spectrum protection and
water resistance where those attributes are claimed in product
labels.\39\ For purposes of this proposed rule, we use the term final
formulation testing to refer to testing conducted on the sunscreen
product formulation to be marketed. Our expectation is that final
formulation testing would also generally be necessary to ensure that
the active ingredient in any given sunscreen formulation permitted
under the monograph would not be systemically absorbed beyond the
amount FDA determined to be safe.
---------------------------------------------------------------------------

    \39\ See Sec.  201.327 for the current labeling requirements,
and underlying testing, for OTC sunscreens containing one or more of
the 16 active ingredients that are addressed in this rulemaking, for
use in products marketed without approved NDAs. OTC sunscreens
marketed under NDAs provide similar information in their product-
specific applications to substantiate their labeling. For proposed
changes to Sec.  201.327, see codified section of this document. The
Stayed 1999 Final Monograph also required SPF testing of final
formulations as a GRASE condition. Elsewhere in this proposed rule,
we propose to establish monograph conditions in 21 CFR part 352 that
ensure that all sunscreens are tested for SPF in accordance with
Sec.  201.327(i) and achieve a minimum SPF of 2, and that certain
sunscreens pass the broad spectrum test in Sec.  201.327(j).
---------------------------------------------------------------------------

    The discussion that follows provides FDA's thinking about such
testing of final formulations, which we anticipate requiring in the
future for sunscreen products marketed under the sunscreen monograph
(unless FDA determines that the ingredient or ingredients contained in
the product are unlikely to be absorbed through the skin). Because this
testing would not be required for sunscreens containing only those
active ingredients proposed here as Category I (zinc oxide and titanium
dioxide), FDA has not yet reached a final determination as to the
particular parameters that might be required for such final formulation
testing. We anticipate that we may specify final formulation testing
requirements in the monograph in the future, however, as active
ingredients that we are now proposing as Category III may be included
in the monograph in the future if FDA receives data supporting their
GRASE status. Final formulation testing requirements applicable to such
ingredients would be established on an ingredient-specific basis,
taking into consideration the data provided to

support a positive GRASE determination for the specific ingredient (for
example, whether any safety signals are detected in well-conducted
nonclinical carcinogenicity and DART studies). We encourage interested
parties to provide information and comment for each sunscreen active
ingredient that is relevant to establishing this kind of final
formulation testing for each active ingredient.
    FDA's expectation is that this testing would not generally call for
an in vivo study. Instead, FDA expects that the conditions of marketing
specified for sunscreens containing a given active ingredient would
require manufacturers to perform in vitro permeation testing before
marketing each sunscreen formulation containing that ingredient.
Consistent with the approach for SPF and broad spectrum final
formulation testing set forth in Sec.  201.327 (for proposed changes to
Sec.  201.327, see codified section of this document), FDA anticipates
that it would not review the results of the in vitro permeation testing
before product marketing. Rather, FDA expects that any future
conditions pertaining to final formulation in vitro permeation testing
in the sunscreen monograph would include a requirement that
manufacturers maintain records of this testing, and that those records
be available for FDA inspection upon request.
    FDA anticipates establishing a standard control formulation for
each sunscreen active ingredient to be used in the in vitro permeation
testing of products containing that ingredient. The standard control
formulation would be the formulation that produces the highest in vivo
absorption in the MUsT. The results of in vitro permeation testing
using this control formulation would then be used as a bridge to a
corresponding level of in vivo absorption from the MUsT that is used to
establish the safety margin for the ingredient. Then, FDA anticipates
establishing conditions to ensure that final formulation in vitro
permeation testing would be conducted for each formulation intended to
be marketed, using the specified vertical diffusion cell described
below. The results of the in vitro permeation testing of each final
formulation would be compared to the absorption found in the standard
control formulation for the active ingredient it contains.
    In vitro permeation testing is a methodology that has been used in
dermal formulation development for over 30 years and, as used here,
specifically refers to use of the ``Vertical Diffusion Cell'' (Ref.
144). A vertical diffusion cell is comprised of three major units: (1)
An upper chamber (into which the sunscreen formulation is placed); (2)
the rate-limiting membrane (the prepared human skin); (3) and the lower
chamber/fluid channel (containing a receptor fluid that is evaluated to
determine how much of the sunscreen it ``receives'') (Refs. 145 to
147). The vertical diffusion cell system has been commercialized and is
available as both single and multiple unit models that can be
automated.
    Other relevant parameters FDA expects to consider in establishing
future requirements for in vitro permeation testing include (among
other things) the thickness and integrity of collected skin, storage
conditions used for collected skin, receptor fluid composition, skin
and receptor fluid temperature, the number of skin samples (and donors)
used, study duration, sampling period, application method, and number
of experimenters.
    We note that if a final sunscreen formulation contains a
combination of sunscreen active ingredients, FDA anticipates requiring
that this final formulation be tested against the standard control
formulations for each of the sunscreen active ingredients it contains.
As noted above, a standard control formulation might not be specified
for (and final formulation in vitro permeation testing might not be
necessary to establish safety for) a sunscreen containing a particular
active ingredient if FDA determines that the ingredient is unlikely to
be absorbed through the skin. As mentioned above, we therefore do not
propose to require final formulation in vitro permeation testing for
sunscreen formulations containing only zinc oxide and/or titanium
dioxide.
    In cases in which such testing is required, FDA anticipates that if
the in vitro permeation of each sunscreen active ingredient in the
final formulated product is equal to or less than the value obtained
from in vitro permeation testing of the standard control formulation
for that active ingredient, the product's safety margin would be
considered to fall within the parameters judged to be GRASE, and thus
to support marketing of the formulation. However, if the in vitro
permeation of the active ingredient from the specific final formulation
is greater than the value obtained from in vitro permeation testing of
the standard control formulation for that active ingredient, FDA
anticipates that the drug product(s) using that formulation would not
be considered GRASE. In that situation, the sponsor would have the
option to either: (1) Reformulate the product and conduct in vitro
permeation testing to establish that the reformulated product satisfies
the final formulation in vitro permeation testing requirements set out
in the sunscreen monograph or (2) seek NDA approval for the new
formulation.

IX. Additional Proposed Conditions of Use

A. Proposed Requirements Related to Dosage Form

    OTC sunscreens have been marketed in a variety of dosage forms over
the years. Responding in part to the growing market acceptance of spray
sunscreens, on June 17, 2011, FDA issued an ANPR addressing sunscreen
dosage forms (Dosage Forms ANPR) (76 FR 35669, June 17, 2011). The ANPR
identified dosage forms considered eligible or ineligible for review
and potential inclusion in the OTC sunscreen monograph, based on FDA's
knowledge, at that time, of their history of marketing before the OTC
Drug Review began in 1972. It also solicited specific information about
the safety, effectiveness, and directions for use of spray sunscreens.
1. Summary of Eligible and Ineligible Dosage Forms
    In this proposed rule, FDA is confirming that the following dosage
forms identified in the Dosage Forms ANPR are eligible for review and
potential inclusion in the OTC sunscreen monograph based on their
history of sunscreen marketing before 1972: Oil, lotion, cream, gel,
butter, paste, ointment, stick, spray, and powder. With the exception
of powder, FDA proposes that sunscreens in these dosage forms are GRASE
subject to certain conditions described below and elsewhere in this
proposed rule. We note that sunscreen powders were classified as
ineligible for review in the Dosage Forms ANPR because, at that time,
we were unable to identify any sunscreen products in powder form that
were marketed before the OTC Drug Review began. Based on marketing data
submitted to the ANPR docket and in a related citizen petition (Docket
No. 1978-N-0018-0741), we have determined that the powder dosage form
is eligible to be considered for inclusion in the OTC sunscreen
monograph. However, as described in section IX.A.4, we tentatively
conclude that additional safety and efficacy data will be necessary to
classify sunscreens in the powder dosage form as GRASE and include them
in the final monograph. We are proposing that sunscreens in all dosage
forms other than those identified as eligible for consideration above--

including wipes, towelettes, body washes, and shampoos--are new drugs
because we did not receive data showing that they were marketed prior
to 1972.
2. Overview of Comments on the Dosage Forms ANPR
    FDA received a total of 14 comments on the Dosage Forms ANPR. Six
of the comments provided no new data, but generally supported the
advantages of spray sunscreens, agreed with the need to address
concerns about spray sunscreens' performance and/or safety (especially
when used on children), opined that existing SPF methods would not need
to be modified for sprays, or (in most cases) agreed with FDA's
suggested directions for use. Other comments argued for the inclusion
of additional dosage forms identified as ineligible in the Dosage Forms
ANPR, but failed to provide supporting marketing data. One comment
contained marketing information showing that sunscreen products in
powder form, which we had previously identified as ineligible for the
monograph, had been marketed in the United States before 1972. The
remaining comments (all from industry) provided data and information
that directly or indirectly addressed questions raised in the Dosage
Forms ANPR concerning the safety, effectiveness, and labeling of spray
sunscreens. These comments are discussed in sections IX.A.3 and IX.A.4
below.
3. Safety and Effectiveness of Spray Sunscreens
    As we recognized in the Dosage Forms ANPR, compared to traditional
lotions, oils, and the like, spray sunscreens raise potential concerns
of both safety and efficacy that FDA must consider in determining
whether sunscreens in the spray dosage form would be GRASE. With
respect to efficacy, FDA must consider factors such as whether spraying
sunscreen rather than applying it by hand provides effective coverage
on exposed skin, how consumers use spray products, and whether current
test methods for SPF and broad spectrum protection can be relied on for
adequate labeling of spray products. With respect to safety, spray
sunscreens raise the question of potential harm from inhalation of
sunscreen components as well as potential flammability risks.
    a. Characteristics of sunscreen spray products. Spray sunscreens
use varying technologies to package and deliver a sunscreen formulation
as an aerosol spray, i.e., an airborne suspension of fine droplets or
particles. In some spray products, the sunscreen formulation is mixed
in a canister with a liquefied gas propellant that supplies the force
to generate an aerosol containing both dissolved sunscreen formulation
and propellant upon activation of a valve system. There are also pump
spray sunscreen products that are not packaged under pressure but
generate spray by applied mechanical force without the need for a
propellant. Many currently marketed spray sunscreen products use a
delivery technology referred to as a bag-on-valve system, in which the
sunscreen formulation is contained in a bag with an attached valve
inside a canister filled with propellant, so as not to mix the
sunscreen formulation and propellant ingredients. For purposes of this
document, a spray sunscreen product is one discharged from either a
pressurized or nonpressurized container, with the understanding that
the degree of atomization will likely vary according to the
formulation, the container system used, and the design of the spray
actuator, among other factors.
    b. Spray sunscreen performance and effectiveness. The Dosage Form
ANPR asked a series of questions relating to the performance and
effectiveness of spray sunscreens, including questions about the amount
of spray sunscreen typically applied by consumers, uniformity of
coverage, how frequently consumers reapply spray sunscreens, whether
consumers rub spray sunscreens into the skin when directed to do so and
the resulting effect on effectiveness, and whether--and if so, how--the
SPF and/or broad spectrum tests need to be modified to address
sunscreen sprays. The Dosage Forms ANPR also solicited studies
comparing spray sunscreens to other eligible dosage forms to see
whether the dosage forms are comparable.
    Four comments provided data from multiple studies examining and
comparing the performance of spray and lotion sunscreens on a variety
of parameters, including amounts applied, uniformity of coverage as
measured with UV filter photography, comparative SPF results, and
consumer ratings of ease and effectiveness of application, among
others. FDA's evaluation of the information submitted indicated that
key questions asked in the Dosage Forms ANPR were directly or
indirectly addressed by these studies. These studies indicated that
consumers like the convenience of spray sunscreens and adapt their use
of these products to achieve effective coverage. Data provided on
application uniformity lacked study reports and were difficult to
compare directly, but--taken together--they suggest a high degree of
uniformity between sprays and lotions in coverage of exposed skin, as
well as between different spray application scenarios such as spraying
directly on skin or spraying followed by rubbing. Information submitted
indicated that the amount of spray sunscreen dispensed is higher than
the amount dispensed for sunscreen lotions, and that consumers are more
likely to reapply sprays than lotions. There was no response from any
stakeholder regarding consumers' compliance with directions to rub a
spray sunscreen into the skin. However, data was provided suggesting
that rubbing spray sunscreens into the skin did not enhance
effectiveness. Based on these comments and the available data, we are
not proposing to require that labeling provide instructions to rub
spray sunscreens into the skin.
    Comments on the Dosage Forms ANPR also agreed, and we concur, that
the current FDA-required SPF and broad spectrum tests are appropriate
for evaluating the efficacy of sunscreens in spray dosage forms. SPF
testing requires application of a set amount of sunscreen (2 mg/cm\2\
on each test subject), which can readily be done for spray sunscreen
formulations. For example, comments on the Dosage Form ANPR stated that
the SPF testing of sunscreen spray products can be conducted following
the method described in the current rule by weighing out the liquid
form and applying it to the skin. This premise is supported by data
from SPF testing submitted in the comments. For example, one comment
submitted five SPF testing reports conducted on sprays using the FDA-
required methods, in which the expected SPF values for the test
formulations were almost identical to the SPF testing results. The same
logic applies to broad spectrum testing, which also uses a defined
amount of sunscreen by weight. Based on this information, we conclude
that the current and proposed SPF and broad spectrum testing methods
are also appropriate for spray dosage forms.
    c. Spray sunscreen safety. FDA has identified two primary safety
concerns specific to spray sunscreen dosage forms: (1) The potential
risk of respiratory harm from inhaling sunscreen ingredients and (2)
the potential flammability risk when consumers are exposed to flame or
heat before spray solvents have completely dried. For the reasons
described below, we believe that both potential risks can be acceptably
mitigated by proposed formulation limitations, labeling requirements,
and adequate testing, and

thus propose to establish these as additional conditions in the
monograph to ensure that sunscreen products in a spray dosage form
would be GRASE.
    d. Inhalational toxicity. Broadly speaking, the human respiratory
system consists of the upper respiratory tract (i.e., the airways of
the nose to the larynx) and lower respiratory tract (the trachea and
branching airways of the lung, including bronchi, bronchioles, and
alveoli) (see generally Refs. 148 and 149). Much of the respiratory
system is lined with a layer consisting of mucus cells and cilia that
mechanically propel inhaled particles out of the lower respiratory
tract toward the mouth, where they may be swallowed or expectorated
(Refs. 148 and 149). The most significant concern associated with any
product that may be accidentally inhaled is the potential risk of
adverse effects associated with deep lung deposition, which occurs when
particles in an aerosol (i.e., a suspension of airborne particles such
as a sunscreen spray) reach the unciliated airways in the lung.
Particles that can reach the unciliated airways of the deep lung are
described as respirable and may be associated with serious adverse
effects such as asthma, emphysema, bronchospasm, or chronic obstructive
pulmonary disease; particles that do not reach the deep lung may be
associated with less harmful adverse events such as local irritation of
the upper airway, coughing, or sneezing (Refs. 149 to 151). The
potential health risk associated with inhalation of hazardous aerosols
depends on how much of a toxic substance is deposited in a given region
of the respiratory tract and how much remains after physiological
clearance occurs through mechanisms such as coughing, sneezing,
mechanical transport, or, in the deep lung, engulfment by specialized
cells or other protective action (Refs. 148 and 152).
    The pathogenic potential of inhaled aerosols depends on where in
the respiratory tract a particle is deposited (Ref. 152). Whether spray
particles that enter the body through inhalation at the nose or mouth
will be deposited in the lung depends largely on their physical
characteristics: Most notably particle size, with the likelihood of
respirability increasing as particle size decreases (Refs. 148 to 153).
The effects of particle size on respirability of inhaled particles is
well studied. There is general agreement that particles greater than 10
micrometers ([mu]m) in diameter may enter the mouth and the airway up
to the larynx. Approximately 50 percent of particles up to 10 [mu]m in
diameter can penetrate beyond the larynx to the thoracic region of the
respiratory tract, while only particles smaller than 4 [mu]m reach the
unciliated airways and alveolar region of the lungs (see generally
Refs. 148 to 153). Thus, although there are little or no data on the
potential inhalation toxicity of particular spray sunscreen
ingredients, we are proposing that exposure to harmful levels of such
ingredients can effectively be minimized by imposing particle size
limitations on spray sunscreen products.
    Several comments on the Dosage Forms ANPR submitted results of
particle size distribution testing using available methods and
apparatus, with the aim of showing that exposure to inhaled sunscreen
products or ingredients would be minimal and thus unlikely to cause
adverse effects. The data submitted were similar and in some cases
overlapping. In an analysis of pooled particle size distribution data
from all submissions, representing 50 U.S.-marketed spray sunscreen
products, 32 had particles smaller than 4 [mu]m in diameter and thus
within the respirable portion of the total particle size distribution.
However, the great majority of the particle sizes observed were
nonrespirable. The highest percentage that any product had of particles
smaller than 4 [mu]m in diameter was 0.43 percent and the mean was 0.22
percent, which is extremely low.
    In addition to reviewing information from comments on the Dosage
Forms ANPR, FDA conducted its own analysis of particle size
distribution for 14 marketed spray sunscreens. In those tests, no
sunscreen had more than 10 percent of particles in sizes less than 10
[mu]m in diameter and only three had particles smaller than 5 [mu]m
(Ref. 154).
    To limit the risks of unintentional exposure and potential
associated adverse events to respirable particles in spray sunscreens,
we are proposing limits on the size of particles dispensed from the
consumer container for finished spray sunscreens in order for those
products to be GRASE. We propose that 90 percent of the particles
dispensed from the consumer container must be at least 10 [mu]m or
greater in order to limit exposure beyond the larynx, and to prevent
deposition in the deep lung, the minimum particle size dispensed from
the consumer container must be no less than 5 [mu]m. This limit was
chosen because it is the lowest whole number above the generally
accepted threshold (4 [mu]m) at which particles enter the unciliated
airway and because it allows for experimental error that may be
inherent in particle size measurements. Sunscreen products that do not
meet both limitations would not be GRASE because there is not
sufficient information in the record to support a positive finding
about their safety. We believe that, taken together, these two
limitations would significantly reduce inhalation risk from spray
sunscreens by reducing particle exposure to the larynx and deeper lung
tissues. The particle size data submitted in response to the Dosage
Forms ANPR also suggest that these limitations would be readily
achievable without unduly burdening sunscreen spray manufacturers.
    With the establishment of these two limits, FDA believes that the
risks of adverse events related to unintentional inhalation of spray
sunscreens will be minimal. Stakeholders asserted that the risk of
inhalation toxicity is already low, primarily based on particle size of
marketed sprays. Limited data on adverse event reports and animal
toxicity studies were also submitted in a few comments on the Dosage
Forms ANPR, but were inadequate to support the safety of spray
sunscreens in the absence of particle size limitations. If the particle
size limitations proposed here are adopted, however, we do not believe
that additional animal toxicity or other safety data need to be
provided to support a GRASE finding for spray sunscreens.
    We are proposing that particle size testing to demonstrate
compliance with the proposed limitations must be conducted on spray
products as they are dispensed from the consumer container as part of
the lot release testing that would be routinely completed as part of
current good manufacturing practice (CGMP) compliance under part 211
(21 CFR part 211). It is necessary to test the size of particles
dispensed from the consumer container to ensure that particle size
requirements are met under conditions of use by consumers.
    For purposes of these proposed particle size requirements, we are
using the term particle size broadly to mean the discrete unit emitted
from the spray container that is available for inhalation by a consumer
when the product is applied. If the particle dispensed from the
consumer container is a droplet that meets the size requirements, the
consumer will not accidentally inhale it into the deep lung. However,
if that same droplet breaks apart into smaller fractions when it is
dispensed from the consumer container, those fractions would be the
particles that must meet the size requirement to ensure that consumers
will not inadvertently inhale them past the larynx.
    We are not proposing a specific test methodology for spray
sunscreen particle size. Rather, sunscreen manufacturers would be
obligated to ensure that particle size testing for their

sunscreen sprays would be conducted on each lot of the final product as
dispensed from the consumer container in accordance with adequate
written specifications. USP General Chapter 601 part B provides
methodology and requirements for sprays, aerosols, and powders that
include methodology to determine droplet/particle size distribution,
and we expect to consider testing done in accordance with the USP as
adequate to meet this proposed requirement (Ref. 155).
    We note that several comments on the Dosage Forms ANPR expressed
concern about the potential inhalation risk from exposure to spray
sunscreens that contain nanomaterials (as both active and inactive
ingredients). One comment also recommended that FDA require the
presence of such ingredients to be disclosed on spray sunscreen labels.
FDA's approach to nanotechnology and nanomaterials in sunscreen
products is discussed in section VII.E. FDA is not now proposing
conditions of use, including labeling, for spray sunscreens that
distinguish based on the presence of nanomaterials because we are
proposing that any sunscreen spray that contains any particles smaller
than 5 [micro]m when it is dispensed from the consumer container would
not be GRASE. With respect to nanomaterials in spray sunscreens, we
note that the primary determinant of inhalation risk is the size of the
particles in emitted sprays, which may be larger than individual
formulation components. Nanoscale ingredients would not pass the
particle size limitations for spray sunscreens; therefore, if they were
to be detected when sprayed from the consumer container during particle
size testing, the sunscreen could not be marketed under the OTC
monograph.
    In addition to the proposed limitations on particle size for
sunscreen sprays and related testing, we are proposing to require that
the following labeling be included in the directions for sunscreen
sprays to minimize unintended inhalation:
     Hold container 4 to 6 inches from skin to apply.
     Do not spray directly into face. Spray on hands then apply
to face.
     Do not apply in windy conditions.
     Use in a well-ventilated area and avoid inhalation.
    This language is the same as that published in the Dosage Forms
ANPR. Its adoption was supported by comments on the Dosage Forms ANPR,
and the language is widely used on currently marketed spray sunscreens
consistent with the 2018 Final Guidance.
    e. Flammability risk. In July 2013, FDA issued a Consumer Update
regarding persons catching on fire while wearing spray sunscreen
products near an open flame:

    The Food and Drug Administration (FDA) has become aware of five
separate incidents in which people wearing sunscreen spray near
sources of flame suffered significant burns that required medical
treatment. The specific products reported to have been used in these
cases were voluntarily recalled from the market, so should no longer
be on store shelves. . . . In the five incidents reported to FDA,
however, the burns occurred after the sunscreen spray had been
applied. The ignition sources were varied and involved lighting a
cigarette, standing too close to a lit citronella candle,
approaching a grill, and in one case, doing some welding (Ref. 156).

These cases all involved a single manufacturer's product that has since
been voluntarily recalled. Review of adverse event reports since the
voluntary recall of this product indicates that no additional cases
involving spray sunscreens have been reported. However, sunscreens are
often used in very hot outdoor environments with high ambient air
temperatures. Sunscreens are also frequently used around sources of
flame or sparks, such as grills, bonfires, smoking, or other ignition
sources. To ensure safe use of spray sunscreens and to better inform
consumers about potential flammability risks, we are proposing to limit
the flammability and require flammability labeling of spray sunscreens
under the OTC sunscreen monograph.
    FDA's general labeling regulations for OTC drugs provide for OTC
monographs to require flammability labeling in suitable cases (Sec.
201.66(c)(5)(ii)(C)) (21 CFR 201.66(c)(5)(ii)(C))), and we have done so
for products such as topical antitussives (21 CFR 341.74) and wart
removers (21 CFR 358.150). As we did for those products, we are
proposing to require each spray sunscreen formulation to be labeled for
flammability in accordance with the testing methodology described in a
regulatory provision issued by the Consumer Product Safety Commission
(CPSC) (see 16 CFR 1500.43a). We have proposed to incorporate this
flash point testing methodology to address our concern regarding the
flammability of sunscreen in the spray dosage form after it has been
dispensed onto the skin. We therefore propose that all batches of
sunscreen spray products be tested for flammability in accordance with
16 CFR 1500.43a as part of batch release testing conducted in
accordance with CGMP requirements.
    We are also proposing to define three flammability categories for
use in regulating and labeling sunscreens: (1) Extremely flammable, (2)
flammable, and (3) combustible. These definitions refer to flash point
testing to be performed using the method described in 16 CFR 1500.43a.
These definitions are analogous to certain CPSC definitions located at
16 CFR 1500.3. Given the conditions under which sunscreens may be used,
we are proposing that spray sunscreens found to meet the definition of
extremely flammable in proposed Sec.  352.3(f) are not GRASE and may
not be marketed under the OTC sunscreen monograph. Products found to
meet the definition of flammable or combustible in proposed Sec.
352.3(g) or (h) would be required to include the following language in
the ``Warnings'' section of the drug facts labeling: [bullet]
``Flammable'' or ``Combustible'' [as applicable] followed by a colon
and the statement ``Keep away from fire or flame''.
    A further concern related to flammability is the time required for
volatile solvents in a spray product to dry on the skin before a
consumer can safely approach a source of heat or flame or can smoke
without danger of fire. Typical sunscreen spray formulations contain 50
to 80 percent of a volatile carrier, most commonly ethyl alcohol. These
volatile solvents are necessary to the formulation to allow the product
to be sprayed onto the skin. After spraying, the solvents are intended
to rapidly evaporate leaving a film of UV filters on the skin surface
as the product dries. Once a spray product is dry, the solvent is no
longer present so the flammability risk is low. However, prior to this
point, the flammability risk would be higher.
    We think that consumers should be warned to stay away from sources
of flame while a flammable or combustible sunscreen spray dries. For
this reason, we propose to require that each batch of a sunscreen spray
product that meets the definition of flammable or combustible at Sec.
352.3(g) or (h) be tested for drying time in accordance with written
specifications. If the drying time is less than 5 minutes, we propose
to require that the labeling state, ``Wait 5 minutes after application
before approaching a source of heat or flame, or before smoking.'' If
the drying time is at least 5 minutes but less than 10 minutes, we
propose that the labeling would state, ``Wait 10 minutes after
application before approaching a source of heat or flame, or before
smoking.'' We propose that a sunscreen spray that is flammable or
combustible and that takes 10 minutes or more to dry would not be GRASE
because of the possibility of consumers approaching sources of fire

during such an extended drying period. We invite comment on this
approach.
4. Powder Dosage Forms
    Although we have found powder sunscreens to be eligible for
consideration in the OTC sunscreen rulemaking, we have tentatively
determined that additional data as outlined below will be needed to
support a conclusion that sunscreens in this dosage form are GRASE and
to support consideration of appropriate labeling. Also, like sprays,
powder sunscreens pose the potential for unintended inhalation, and for
this reason, if admitted to the sunscreen monograph, the same
limitations as to particle size here proposed for sprays would be
expected to apply. For powder sunscreens that meet the particle size
limitations proposed for sprays, we do not expect that additional
toxicology data would be needed to address the potential health risks
associated with inhalation.
    One comment on the Dosage Forms ANPR provided data on SPF and broad
spectrum performance of five powder formulations, as well as data from
repeated insult patch tests and photosensitivity studies that were
asserted not to show any safety issues. FDA has conducted particle
distribution testing on five powder sunscreens. The powder sunscreens
tested had a larger proportion of relatively small particles compared
to the sprays. Only one of the five powder sunscreens would have
complied with the requirement we are considering that no more than 10
percent of the particles could be smaller than 10 [micro]m in diameter,
and that product was also the only one that would have met the
prospective limitation of no particles smaller than 5 [micro]m in
diameter (Refs. 153 and 154). Based on the data submitted, we believe
that (current and proposed) SPF and broad spectrum test methods are
appropriate for use with powder sunscreens, and we are not requesting
additional respiratory safety information for powders that meet the
same particle size limitations proposed for spray sunscreens.
    FDA invites comments and data on the following topics related to
powder sunscreens:
     What amounts of powder sunscreens do consumers typically
dispense?
     What amounts of powder sunscreens are effectively
transferred to the skin?
     How uniform is the sunscreen application across the sun-
exposed area of the skin?
     How frequently do consumers reapply the product?
     Does rubbing a powder into the skin change sunscreen
effectiveness?
     Are powder dosage forms water-resistant? If they are not
water-resistant, is a direction to reapply every 2 hours sufficient to
assure their safe and effective use?
     Can the powder dosage form be used safely and effectively
over all areas of skin exposed to the sun, or should this dosage form
be limited to the face?
     What factors, if any, should FDA consider in connection
with particle size limitations or test methods for sunscreen powders?
     Are there important differences among powder types (e.g.,
loose, compact) or applicators that would affect particle size testing?

FDA will evaluate data and information submitted in response to these
questions, as well as any other submitted or available data, to
determine whether additional data are needed to support a final GRASE
determination for this dosage form.

B. Proposed Maximum SPF and Broad Spectrum Requirements

    In the Stayed 1999 Final Monograph, FDA established SPF 30+ as the
maximum labeled SPF value for sunscreen monograph products, and
required that each sunscreen monograph active ingredient contribute a
minimum SPF of 2 to finished sunscreen products (64 FR 27666 at 27672,
27674 and 27675). The final monograph did not include any broad
spectrum protection provisions. In its 2001 decision to stay the final
monograph, however, FDA indicated that it was issuing the stay because
the Agency intended to amend the sunscreen monograph to address
requirements for both UVA and UVB radiation protection (66 FR 67485).
FDA later addressed these issues in the 2011 L&E Final Rule, which,
among other things: (1) Established optional broad spectrum labeling
based on satisfaction of a critical wavelength test, (2) created an
optional indication relating to skin cancer and early skin aging risk
reduction for broad spectrum products with an SPF of 15 or higher, and
(3) required a labeling warning for sunscreens that did not both
satisfy the broad spectrum test and provide an SPF of at least 15 (76
FR 35620 at 35626-35628) (L&E Final Rule). Concurrently with
publication of the L&E Final Rule, FDA issued a proposed rule to raise
the maximum labeled SPF value for sunscreen products containing
sunscreen monograph active ingredients to SPF 50+ (76 FR 35672, June
17, 2011).
    In the time since these 2011 publications, the body of evidence in
the published literature on UVA radiation (particularly UVA I
radiation) and its role in the development of skin cancer has grown.
This new data about the harms of UVA exposure is a significant concern
given, among other things, that with currently available sunscreens,
consumers may unknowingly accumulate excessively large UVA doses by
using sunscreens with high SPF values that either: (1) Do not pass
FDA's current critical wavelength-based broad spectrum test or (2) have
inadequate uniformity in their UVA protection. Because of these
concerns, we are making a number of proposals designed, among other
things, to couple a greater magnitude of UVA protection to increases in
SPF values.
1. Background
    UV radiation includes both UVA and UVB rays. UVB rays (i.e., those
with wavelengths from 290 to 320 nm) are higher energy, are much more
effective at producing sunburn, and produce greater amounts of cellular
damage (including DNA lesions, which can result in gene mutations
linked to skin cancers) (Refs. 157 and 158). UVA rays (i.e., those with
wavelengths from 320 to 400 nm) are lower energy and less effective at
producing sunburn, but make up the majority of UV radiation, and
penetrate much deeper into the skin, potentially causing oxidative
damage (through formation of ROS) to skin pigment cells (Ref. 159). UVA
rays also contribute to photo-aging (Ref. 157 and 160). Although the
current scientific literature attributes UV-signature DNA lesions
primarily to UVB wavelengths, UVA wavelengths can also produce DNA
lesions. Although UVA wavelengths produce DNA lesions to a
significantly lesser degree than UVB wavelengths do, DNA lesions
produced by UVA rays have been reported to have slower repair rates
(Ref. 157). UVA rays are comprised of UVA I rays (340 to 400 nm) and
UVA II rays (320 to 340 nm). As discussed below, until recently, UVA I
rays were generally not considered to contribute significantly to the
harms associated with UV exposure.
    Sunscreen products must be labeled with an SPF value calculated
using a standardized SPF testing procedure set forth in FDA regulations
(see Sec.  201.327(i)). ISO 17166 CIE S 007/E was approved for
incorporation by reference into Sec.  201.327(i) as of June 18, 2012
(76 FR 35619, June 17, 2011). The SPF test measures the amount of UV
radiation exposure it takes to cause

sunburn when a person is using a sunscreen compared with how much UV
exposure it takes to cause sunburn when the person is not using a
sunscreen. Sunscreens with increasing SPF values (up to a certain
point) have been demonstrated to provide increased sunburn protection.
Because SPF values represent a sunscreen's level of sunburn protection,
they are primarily (though not exclusively) an indicator of expected
protection from UVB radiation. To pass FDA's current test for broad
spectrum labeling (Sec.  201.327(j)), however, sunscreens must
demonstrate that, in addition to UVB protection, they also provide some
UVA protection.
    Only products that have been determined to have a minimum SPF value
of 15 and to pass our broad spectrum test may include statements in
their labeling indicating that they decrease the risk of skin cancer
and early skin aging caused by the sun when used as directed with other
sun protection measures (Sec.  201.327(c)(2)). In contrast, sunscreens
that have not been determined to provide both broad spectrum protection
and an SPF value of at least 15 must include a skin cancer/skin aging
alert warning to consumers that ``[s]pending time in the sun increases
your risk of skin cancer and early skin aging'' and that ``[t]his
product has been shown only to help prevent sunburn, not skin cancer or
early skin aging'' (Sec.  201.327(d)(2)).
2. Increased Evidence of Harms Associated With Exposure to UVA
Radiation
    Since publication of the 2011 L&E Final Rule and Max SPF PR, the
strength of scientific evidence linking UVA exposure to skin cancers
and other harms has increased. This evidence suggests that UVA
wavelengths continue generating DNA lesions hours after UV exposure
(Ref. 161) and that if left unrepaired, these DNA lesions can form UV-
induced mutations in many genes that have been detected in both
melanoma and nonmelanoma skin cancers (Refs. 162 to 165). Further,
unlike UVB-induced DNA lesions, which attenuate with skin depth, recent
evidence indicates that DNA lesions induced by UVA I exposure show the
opposite pattern, with both increased DNA lesions in the basal layer of
the epidermis (where melanocytes and proliferating keratinocytes
reside) and less efficient DNA lesion repair in the basal layer (Refs.
166 and 167).
    Damage to cells in the basal layer (if left unrepaired or if
inefficiently repaired) can lead to mutations in critical genes that
increase the possibility that normal cells will transform into cancer
cells. While inefficient DNA repair is a concern for all individuals
exposed to UV radiation, this concern is particularly acute in those
with xeroderma pigmentosum (a disease caused by a disorder of the DNA
repair system), who have extreme sensitivity to UV radiation, and who
develop both nonmelanoma skin cancer and melanoma with a high frequency
and very early in life (Ref. 168). In addition to the skin cancer-
related risks associated with UVA exposure, increasing evidence shows
that UVA I radiation also produces immunosuppression (Refs. 169 and
170). This, too, is a general concern for all individuals, but is
especially dangerous for certain at-risk populations (such as organ
transplant recipients and others on immunosuppressive drugs).
    Given the above-described evidence, we are concerned about the
existing potential for inadequate UVA protection in marketed sunscreen
products. This is a particular concern with respect to high SPF
sunscreen products that do not pass FDA's current critical wavelength-
based broad spectrum test or that (though they pass our current broad
spectrum test) have inadequate uniformity in their UVA protection.
Consumers using these products may, while successfully preventing
sunburn, accumulate excessively large doses of UVA radiation, thereby
exposing themselves to additional risks related to skin cancer and
early skin aging. The International Agency for Research on Cancer has
found that high SPF sunscreen products are associated with longer
intentional UV exposures (Ref. 171), raising the concern that use of
these products may result in significant doses of UVA radiation. We
note that concerns relating to inadequate UVA protection came up in
several comments we received in response to the 2011 Max SPF PR, and
that these comments raised particular concerns about inadequate UVA
protection in high SPF products. This concern has also grown over time
in the published literature (Refs. 172 to 175).
    For all of these reasons, we are proposing a number of steps
designed to couple a greater magnitude of UVA protection to increases
in SPF values. As discussed in further detail below, we are also making
proposals designed to address evidence of variability in SPF values and
evidence showing additional clinical benefits associated with SPF 60
sunscreens.
3. Broad Spectrum Proposals
    a. UVA I/UV ratio required to pass the broad spectrum test. We are
proposing certain changes to the requirements to pass the broad
spectrum test. Specifically, we are proposing to add to the current
broad spectrum test a requirement that products meet a UVA I/UV ratio
of 0.7 or higher. We note that the current broad spectrum test
procedure would remain unchanged \40\ and that this new ratio would be
calculated using data from the existing test, which should help
minimize burden on manufacturers.
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    \40\ We note that, as described in section IX.D.2.i, we are
proposing a minor revision in equipment specifications for the broad
spectrum test to respond to feedback that FDA received on this issue
and proposing some minor revisions to current language to make clear
our existing expectations.
---------------------------------------------------------------------------

    The current labeling regulation requires that sunscreens labeled as
broad spectrum achieve a critical wavelength of 370 nm or greater
(Sec.  201.327(j)). A sunscreen product's UV protection is often
displayed as a curve on a graph showing the amount of UV absorbance the
product provides at each wavelength in the UV spectrum (i.e., from 290
to 400 nm). The ``critical wavelength'' of the product is the
wavelength corresponding to 90 percent of the area under this curve.
Higher critical wavelengths, therefore, illustrate greater breadths of
UV protection across the 290 to 400 nm spectrum.
    Most sunscreen products--even if they achieve a critical wavelength
of 370 nm or greater and therefore meet the current criteria for broad
spectrum labeling--have historically covered the UVB and UVA II ranges
preferentially. Given how much of the UVA portion of the UV spectrum is
composed of UVA I radiation (see Figure 3 below) and given what we now
know about the risks associated with UVA exposure, and with UVA I
exposure in particular, ensuring that sunscreen products provide
adequate protection in the UVA I portion of the spectrum is critical.

[GRAPHIC] [TIFF OMITTED] TP26FE19.002

    We are therefore proposing to require that in order to pass the
broad spectrum test, a product must demonstrate that it provides a UVA
I/UV ratio of 0.7 or higher, indicating that the product provides a
minimum measure of UVA I radiation absorbance relative to total UV
radiation (i.e., UVB + UVA) absorbance, in addition satisfying to the
370 nm critical wavelength requirement. Requiring a UVA I/UV ratio of
0.7 or higher for broad spectrum products would mean that these
products would have a more uniform amount of radiation protection
across the UVA I, UVA II, and UVB ranges. This improved fidelity across
the UV spectrum is especially important for high SPF products which, as
discussed above, are associated with longer intentional sun exposure,
which in turn can result in significant doses of UVA radiation. This
proposed UVA I/UV ratio would also help eliminate the current potential
for a product labeled as broad spectrum that has a higher SPF value to
provide (unbeknownst to the consumer) poorer broad spectrum protection
than a product labeled as broad spectrum with a lower SPF value
(depending on the particular combination of active ingredients used in
the product and which parts of the UV spectrum they absorb). For
example, under the current testing regime, a sunscreen that is labeled
``broad spectrum SPF 30'' could provide less UVA protection than a
sunscreen labeled ``broad spectrum SPF 15.''
    We note that FDA first raised concerns relating to the adequacy of
UVA protection in sunscreen products in 2007 (see 72 FR 49070 at 49104
to 49107). At that time, we proposed a similar ratio to the one we are
proposing today as part of a different, more complex proposal for
testing and labeling to address broad spectrum protection that, among
other things, included both in vitro (spectrophotometric) and in vivo
(clinical) testing for UVA radiation, as well as a four-tier UVA star
rating labeling system. In response to comments describing purported
disadvantages of that proposal, including general comments that the
proposal was overcomplicated, specific comments on the proposed in
vitro testing method, and comments indicating that ``[t]he proposed
ratio places too much emphasis on the UVA I region, which is not
generally considered to contribute significantly to the harmful effects
of exposure to UV radiation'' (76 FR 35620 at 35650), we made a number
of changes to our 2007 proposal in the 2011 L&E Final Rule. Those
changes included elimination of the UVA I/UV ratio and adoption of the
above-described critical wavelength test for establishing broad
spectrum protection instead. As we noted in the preamble to the L&E
Final Rule, our decision not to require the UVA I/UV ratio at that time
was based, in part, on our agreement with comments stating that the
scientific evidence available at that time indicated that UVA I
exposure did not pose sufficient risk of harm to justify the emphasis
placed on it by the ratio, and that the critical wavelength test
provided a superior measure of broad spectrum protection (id. at
35650).
    As described above, in the time since issuance of the L&E Final
Rule, the body of evidence showing the harms of UVA exposure, and of
UVA I exposure, in particular, has grown significantly (Refs.

159, 161, 162, 166, 167, and 169). It is now clear that in addition to
producing the immunosuppression described above, UVA I exposure also
results in increasing DNA damage with increasing skin depth (in
contrast to UVB-induced DNA damage, which is reduced as skin depth
increases). In addition, given that UVA I is the predominant portion of
UVA radiation, new evidence (discussed in section IX.B.2) strengthening
the link between UVA radiation and skin cancer development raises our
concerns about the potential for inadequate protection in the UVA I
portion of the UV spectrum. Accordingly, we no longer agree with the
earlier comments suggesting that UVA I does not contribute
significantly to the harmful effects of exposure to UV radiation, or
with our 2011 conclusion that a UVA I/UV ratio requirement would
therefore place too much emphasis on this portion of the UV spectrum.
    We emphasize that we are not proposing to replace the existing
critical wavelength test, and that the proposed ratio would supplement
(and be calculated using data from) the existing broad spectrum test.
We also note that the UVA I/UV ratio we are proposing would result in a
level of UVA protection similar to what is achieved via the European
Union's recommended minimum UVA protection factor of \1/3\ of the
labeled SPF and via the United Kingdom's Boots 3-star rating (the
United Kingdom has for decades used a tiered star rating system based
on an alternative ratio method) (Refs. 173 and 174). We note that data
collected in 2009 about 330 sunscreen products commercially available
in the United States showed that, at that time, more than half of these
products already satisfied the broad spectrum test we are now proposing
(see Comment, Docket No. FDA-1978-N-0018-0690).
    b. Broad spectrum requirement for all products that are
=SPF 15. We are also proposing to require that all sunscreen
products with SPF values of 15 and above demonstrate that they provide
more uniform protection across the UVA I, UVA II, and UVB ranges of the
UV spectrum by satisfying FDA's revised broad spectrum test. This
proposal is designed to link increases in SPF value not only to
increases in UVB protection, but to increases in the magnitude of UVA
protection as well. We note that a consumer using a sunscreen that
provides robust protection against sunburn but that does not pass FDA's
revised broad spectrum test--and therefore provides inadequate UVA
protection--may fail to get out of the sun, thereby exposing themselves
to higher levels of UVA radiation than if they had not been protected
from sunburn. Given the increasing evidence of major health risks
associated with UVA exposure, we propose to find that such products
(those with SPF values of 15 and greater that do not provide sufficient
protection across the UV spectrum (as demonstrated by satisfying FDA's
revised broad spectrum requirement)) are not GRASE. At the same time,
we conclude that the evidence described above regarding the
contribution of UVA I to skin carcinogenesis, coupled with the evidence
reviewed in the 2011 L&E Final Rule (see 76 FR 35620 at 35630-35634),
supports the proposal to include sunscreen products that have an SPF of
15 or higher and also pass the revised broad spectrum test in the
sunscreen monograph with indications both for use to help prevent
sunburn and for use, as directed with other sun protection measures, to
reduce the risk of skin cancer and early skin aging caused by the sun.
As we indicated in the L&E Final Rule, the whole range of UV radiation,
and not specific wavelengths, is a human carcinogen, and the exact
wavelengths most responsible for these harmful effects are not known
(see id. at 35631, 35633). To assure that a clinically meaningful
reduction in the risks of skin cancer and early skin aging is achieved,
then, a product must contribute to substantially limiting overall UVB
and UVA exposure (see id. at 35630, 35631-35632), as will be assured by
our proposal to couple the enhanced breadth of protection across the
UVA spectrum provided by the revised pass criteria for the broad
spectrum test with the magnitude of protection assured by requiring a
minimum SPF of 15.
    By requiring that all sunscreens with SPF values of 15 or more
satisfy the (new) broad spectrum standard (including the new ratio
requiring proportionate protection), this proposal will also enable
consumers to select a product primarily by numerical (SPF) value on the
label, having assurance that, when used as directed, a product labeled
with a higher numerical SPF value provides proportionately more
protection not only against sunburn, but also against skin cancer and
skin aging than lower numbered products \41\ (provided that the product
provides an SPF of at least 15). In doing so, this proposal also
eliminates another source of potential confusion permitted by the
current labeling regime, in which a higher numbered product (for
example, one labeled SPF 30) may provide inferior protection against
UVA radiation than a lower numbered product (for example, one labeled
Broad Spectrum SPF 15).
---------------------------------------------------------------------------

    \41\ As noted in section III.A.2, only those broad spectrum
sunscreen products that have an SPF of 15 or higher have been shown
to help prevent skin cancer and early skin aging.
---------------------------------------------------------------------------

    c. Sunscreen products with SPFs <15. As noted above and in section
III.A.2, sunscreen products with SPF values below 15 have not been
shown to reduce the risk of skin cancer or early skin aging caused by
the sun, whether or not they provide broad spectrum protection. Because
of this limitation, we considered proposing to remove from the
monograph sunscreen products with SPF values lower than 15. However, as
the Surgeon General has acknowledged (Ref. 5), some consumers may seek
intentional sun exposure because (for example) they associate tanned
skin with attractiveness and health. These consumers may seek some
protection from sunburns and therefore, select a low SPF product (i.e.,
one with an SPF value below 15). If such products are removed from the
market, these consumers may choose not to use a sunscreen product at
all rather than use a broad spectrum product with an SPF of 15 or
above.
    Although the benefits of sunscreen products with SPFs below 15
(which are not indicated to reduce the risk of skin cancer or early
skin aging) are limited, FDA believes that the use of such products is
preferable to the use of no sunscreen at all. Thus, to provide sunburn
protection for these consumers, FDA is proposing that sunscreens with
SPF 2 to 14 that bear prominent labeling regarding their limited use
for sunburn prevention and the risks associated with spending time in
the sun (see sections IX.B.1 and IX.C) may remain on the market without
approved NDAs. Because products with SPFs below 15 have not been
demonstrated to reduce the risk of skin cancer, FDA is not proposing to
require products with SPF values under 15 to pass the broad spectrum
test. However, we seek comment on whether the limited benefits such
sunscreen products confer outweigh the risks of sunscreen drug exposure
and the potential false sense of security provided regarding UV
protection (i.e., whether such sunburn-only sunscreen products are
GRASE and should remain on the market without approved NDAs).
4. Maximum SPF Value Proposals
    a. Maximum labeled SPF value would be SPF 60+. In conjunction with
the broad spectrum proposals described above, we are also proposing to
raise the maximum labeled SPF value for

products containing sunscreen monograph active ingredients to SPF 60+.
Under this proposal, sunscreen products with SPF values of 60 or
greater would be labeled ``SPF 60+.''
    FDA has proposed to raise the maximum SPF value that sunscreens
marketed pursuant to the OTC Monograph System can display on their
labeling several times. In the 1978 notice of proposed rulemaking, we
proposed that such sunscreens be labeled with a maximum SPF value of 15
(43 FR 38206 at 38213 to 38214). In the 1999 final monograph, we
determined that that cap should be increased to SPF 30+ (64 FR 27666 at
27675). In 2007 (72 FR 49070 at 49085 to 49087) and then in 2011 (Max
SPF PR), we tentatively concluded that data existed to show that
sunscreens with labeled SPF values of up to 50+ provide additional
clinical benefit to consumers. Our proposal today to increase the
maximum labeled SPF value to 60+ is similarly based on data showing the
additional clinical benefit provided by SPF 60 sunscreen products when
those products also provide broad spectrum protection.
    In the 2011 Max SPF PR proposing an SPF 50+ cap, we noted that the
record, at that time, lacked adequate data demonstrating that sunscreen
products with SPF values above 50 provided additional meaningful
clinical benefit over and above what was provided by SPF 50 protection
(76 FR 35672 at 35672 to 35674). We requested data showing that such
clinical benefits existed (id.). In response to both the 2007 and 2011
proposals, we received comments providing citations to data showing the
additional meaningful clinical benefit provided by sunscreen products
with SPF values of 60 for certain at-risk populations when those
sunscreens also included broad spectrum protection. (See, e.g., Ulrich
et al. (showing statistically significant protection of organ
transplant recipients, who are highly susceptible to nonmelanoma skin
cancer, from squamous cell carcinoma with use of broad spectrum SPF 60
sunscreen) (Ref. 176); see also Comment FDA-1978-N-0018-0710, August
31, 2011, citing Kuhn et al. (showing statistically significant
prevention of skin lesions in topical lupus erythematosus patients with
use of broad spectrum SPF 60 sunscreen after exposure to either UVA I
source or UVA II/UVB source) (Ref. 177); Faurschou et al. (showing
prevention of urticarial reaction in subjects with idiopathic solar
urticaria with use of broad spectrum SPF 60 sunscreen) (Ref. 178);
Fourtanier et al. (showing lower levels of polymorphous light eruption
in subjects using broad spectrum SPF 60 versus SPF 50 products (Ref.
179)). Based on the additional meaningful clinical benefit provided by
broad spectrum SPF 60 sunscreens shown in these studies, we are
proposing to raise the maximum labeled SPF value to SPF 60+.
    Because the studies demonstrating the additional meaningful
clinical benefit provided by SPF 60 sunscreens all used sunscreens that
also provided broad spectrum protection, however, the additional
clinical benefit shown to exist at SPF 60 cannot be decoupled from the
broad spectrum protection provided by those products. That is, the
additional meaningful clinical benefit shown in these studies may have
been the result of the sunscreens' protection against rays in the UVB
range or in the UVA range, or both. For this reason, our proposal to
recognize the additional meaningful clinical benefit provided by
sunscreens with SPF values above 50 is consistent with, and dependent
upon, our proposal that all sunscreen products with SPF values of 15
and above be required to provide broad spectrum protection.
    Given the lack of data showing that sunscreens with SPF values
above 60 provide additional meaningful clinical benefit, however, we
are proposing not to allow labeled SPF values higher than 60+. Labeling
sunscreen products with SPF values higher than what has been shown to
provide additional meaningful clinical benefit could have unintended
negative consequences. For example, as discussed above, such products
may inadvertently promote extended solar exposures because consumers
feel protected and assume that the higher SPF value implies that
greater UV exposure is safe (see, e.g., Autier, et al., 2007 (Ref.
171)).
    b. Formulation cap for sunscreen products of SPF 80. Although we
are proposing that the maximum labeled SPF value will be SPF 60+, we
are proposing to permit the marketing of sunscreen products formulated
with determined \42\ SPF values up to 80. We are proposing to permit
this additional formulation margin in part because of the inherent
variability in SPF test results. A sunscreen product's SPF value is
calculated from measurements that are based on an investigator's visual
evaluation of an individual test subject's erythema response to a
series of UV doses administered in successive sites on the subject's
back. Because the administered UV dose series for the final minimal
erythema dose (MED) \43\ of a sunscreen with an expected SPF of 60
increases by 15 percent with each successive dose (see Sec.
201.327(i)(5)(iii)), a difference in judgment of one site in opposing
directions would result in up to approximately 30 percent variability
in the assessment of the amount of exposure that resulted in the
erythema.\44\
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    \42\ As used in this preamble, the determined SPF value is the
SPF value that equals the largest whole number less than SPF-(t*SE),
determined for a sunscreen product in accordance with Sec.
201.327(i). See also section IX.D.2.b, where we propose to define
this term in the regulation.
    \43\ The minimal erythema dose (MED) is the smallest UV dose
that produces perceptible redness of the skin (erythema) with
clearly defined borders at 16 to 24 hours after UV exposure (Sec.
201.327(i)(5)(i)).
    \44\ The determination of SPF for each subject is calculated via
a ratio of the MED of protected skin over the final MED of
unprotected skin. In a scenario in which the final MED of
unprotected skin is underestimated by 15 percent and the MED of
protected skin is overestimated by 15 percent, this would present
approximately 30 percent variability for the individual subject.
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    Allowing the marketing of sunscreen monograph products with
determined SPF test results up to 80 would, therefore, more fully
account for the range of variability in SPF test results for sunscreen
products labeled SPF 60+. We are also proposing this formulation margin
to provide manufacturers with additional formulation flexibility that
we hope will help facilitate the development of products with greater
UVA protection, given our expectation that active ingredients added for
the primary purpose of increasing UVA protection would contribute to a
sunscreen's determined SPF value as well. We seek comment on whether
SPF 80 is the appropriate formulation cap to accomplish these
objectives.
    We are proposing not to allow the marketing (without an approved
NDA) of sunscreen products with determined SPF values above SPF 80.
This proposal follows from the principle that if the addition of
ingredients to a drug does not provide additional clinical benefit but
potentially increases the risk associated with the drug, this shifts
the benefit-risk calculation and renders the drug not GRASE (see, e.g.,
76 FR 35673 at 35675). In light of this principle, we solicited
comments in 2011 on the appropriateness of a formulation cap for
sunscreen products (id.).
    Some of the comments that we received in response to the 2011 Max
SPF PR expressed concerns (in general) about the safety of unnecessary
exposure to sunscreen active ingredients. We received only one comment,
however, directly addressing the question of an SPF formulation cap.
That comment emphasized that there was no formulation limit in other
countries using an SPF labeling cap, and

that the list of permitted active ingredients in the monograph itself
establishes an SPF ceiling for the formulation as a whole. FDA rejects
the premise that the list of permitted active ingredients establishes
an adequate SPF cap for sunscreen formulations, as this theory does not
take into account the potential addition of new GRASE ingredients to
the list of active ingredients under the monograph. This comment also
appears to imply that the maximum concentration of each active
ingredient correlates specifically to a particular numerical
contribution to the total SPF value of the product. This has not been
established (see 64 FR 27666 at 27674 and 27675 (noting that
formulation techniques may enable increases in SPF without use of
higher concentrations of active ingredients)). In addition, as
mentioned in 2011 in the Max SPF PR (76 FR 35672 at 35674), the
theoretical increase in protection implied by higher SPF values
generated in a laboratory does not necessarily correspond to meaningful
additional sunburn protection for consumers in actual use conditions.
Given that a solar simulator in a lab can produce much higher UV doses
than a consumer would receive from the sun (even in the most extreme
situations), it is unlikely that a consumer could ever actually reach
the theoretical ceiling created by the list of permitted active
ingredients.
    Given the lack of demonstrated clinical benefit for sunscreens with
determined SPF values above SPF 60, and the potential for risks--
discussed elsewhere in this document--associated with exposure to