[Federal Register Volume 61, Number 180 (Monday, September 16, 1996)]
[Proposed Rules]
[Pages 48645-48655]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-23547]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 352

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


Sunscreen Drug Products for Over-the-Counter Human Use; Amendment 
to the Tentative Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of 
proposed rulemaking that amends the tentative final monograph (proposed 
rule) for over-the-counter (OTC) sunscreen drug products. This 
amendment would establish conditions under which products containing 
avobenzone (Parsol 1789) are generally recognized as safe and 
effective and not misbranded at concentrations of up to 3 percent alone 
and 2 to 3 percent avobenzone in combination with the sunscreen 
ingredients cinoxate, diethanolamine methoxycinnamate, dioxybenzone, 
homosalate, octocrylene, octyl methoxycinnamate, octyl salicylate, 
oxybenzone, sulisobenzone, and/or trolamine salicylate. OTC marketing 
pursuant to this amendment may not begin until FDA publishes a 
subsequent notice in a future issue of the Federal Register. This 
proposal is in response to a citizen petition and is part of the 
ongoing review of OTC drug products conducted by FDA.

DATES: Written comments by October 16, 1996; written comments on the 
agency's economic impact determination by October 16, 1996. The agency 
is requesting comments within a 30-day period, instead of the normal 90 
days, so that the marketing status of OTC avobenzone-containing 
sunscreen drug products can be determined in an expeditious manner (see 
section II.E. of this document). FDA is proposing that any final rule 
based on this proposal become effective 12 months after its date of 
publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Desk copies of these written comments to Debra L. 
Bowen, Center for Drug Evaluation and Research (HFD-560), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-105), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2304.

SUPPLEMENTARY INFORMATION: 

I. Background

    In the Federal Register of August 25, 1978 (43 FR 38206), FDA 
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance 
notice of proposed rulemaking to establish a monograph for OTC 
sunscreen drug products. Proposed Sec. 352.10 listed the active 
ingredients to be generally recognized as safe and effective for use in 
these products. Avobenzone was not included in Sec. 352.10 at that 
time. Subsequently, a manufacturer petitioned the agency to reopen the 
administrative record for OTC sunscreen drug products and to include 
avobenzone, an ultraviolet A (UVA)

[[Page 48646]]

radiation-absorbing sunscreen ingredient, in the monograph based upon 
avobenzone's history of use in several countries other than the United 
States since 1981 (Ref. 1).
    In the Federal Register of May 12, 1993 (58 FR 28194), FDA 
published a notice of proposed rulemaking (tentative final monograph) 
for OTC sunscreen drug products. Although the petition to include 
avobenzone in the monograph was discussed in the proposal (58 FR 28194 
at 28210 and 28211), the agency stated that it had not reached a 
decision concerning the use of foreign marketing data as the sole basis 
to support the inclusion of an ingredient in the OTC drug review. The 
agency stated that it would not be in the public interest to unduly 
delay publication of the proposed rule for OTC sunscreen drug products 
and noted that a decision concerning the petition would be announced in 
a future issue of the Federal Register.
    In the proposed rule, the agency also discussed the public health 
significance of UVA radiation and the characteristics and proposed 
labeling of OTC sunscreen drug products that claim to provide 
protection from UVA radiation (58 FR 28194 at 28232 and 28233). Testing 
procedures for sunscreen drug products with UVA radiation protection 
claims were discussed in the proposed rule (58 FR 28194 at 28248 to 
28250) and at a public meeting on May 12, 1994 (as noted in the Federal 
Register of April 5, 1994 (59 FR 16042)).
    In response to the proposed rule, one cosmetic manufacturers' 
association, one professional association, one consumer, one U.S. 
Senator, two health care professionals, and seven manufacturers 
submitted comments. Copies of the comments received are on public 
display in the Dockets Management Branch (address above).
    On March 3, 1993, FDA received a petition (Ref. 2) requesting the 
agency to: (1) Reopen the rulemaking for OTC sunscreen drug products to 
include avobenzone as an active ingredient in the proposed rule for OTC 
sunscreen drug products; (2) permit broad spectrum combination 
sunscreen products containing avobenzone to be marketed with a range of 
sun protection factor (SPF) values; and (3) permit interim marketing of 
such products. The petitioner also made several subsequent submissions 
of data and other information (Refs. 3 through 8).
    Following publication of the proposed rule for OTC sunscreen drug 
products on May 12, 1993, the agency responded to the petition in 
letters dated August 19, 1993, October 27, 1993, May 9, 1994, and May 
9, 1996, and during meetings on May 11, 1994, March 6, 1995, and August 
11, 1995 (Refs. 9 through 15). The petitioner subsequently clarified 
and modified its requests (Ref. 3): (1) To include avobenzone alone and 
in combination with all of the proposed monograph sunscreen ingredients 
except the aminobenzoates; (2) to limit the concentration of avobenzone 
to 1 to 3 percent (if data do not support up to 5 percent); and (3) to 
utilize approved new drug application (NDA) labeling and proposed 
monograph labeling as guides in proposing labeling for avobenzone-
containing sunscreen drug products. Following the August 11, 1995 
meeting, a manufacturer, in support of the petition, publicly released 
safety data from its NDA (approved by the agency in December 1992) for 
an OTC sunscreen drug product (Shade UVAGuard SPF 15 lotion 
containing avobenzone, octyl methoxycinnamate, and oxybenzone) along 
with additional data and information concerning avobenzone (Refs. 16 
and 17). The first NDA for a sunscreen drug product 
(Photoplex containing avobenzone with padimate O) was 
approved in September 1988.

II. The Agency's Evaluation of the Petition and Other Data

A. General

    1. The petition requested that the agency reopen the rulemaking for 
OTC sunscreen drug products to include avobenzone as an active 
ingredient in the proposed rule for OTC sunscreen drug products. 
Several comments requested that the agency include avobenzone in the 
final monograph for these products. The petition and comments expressed 
concern about the potential hazards of UVA radiation and the need for 
making broad spectrum sunscreens widely available so that consumers can 
protect themselves from UVA as well as ultraviolet B (UVB) radiation. 
The petition contended that avobenzone has been marketed in the United 
States (and abroad) to a material extent and for a material time under 
generally safe and effective conditions.
    The agency has determined that avobenzone has been marketed in OTC 
sunscreen drug products for a material time and to a material extent. 
Avobenzone has been continuously marketed in the United States under 
NDA's for approximately 8 years and subject to the adverse event 
reporting requirements. Over 5,000,000 units of avobenzone containing 
products have been sold in the United States. Accordingly, the agency 
has determined that avobenzone can be considered in this rulemaking for 
OTC sunscreen drug products. This document amends the proposed rule to 
include avobenzone. Accordingly, the agency has determined that 
avobenzone can be included in the monograph for OTC sunscreen drug 
products. This document amends the proposed rule to include avobenzone.
    2. Several comments objected to the definition of a sunscreen 
active ingredient in proposed Sec. 352.3(c) (58 FR 28194 at 28295) 
which states: ``An active ingredient that absorbs at least 85 percent 
of the radiation in the UV range at wavelengths from 290 to 320 
nanometers, but may or may not transmit radiation at wavelengths longer 
than 320 nanometers.'' The comments contended that the proposed 
definition is inadequate because it fails to include safe and effective 
ingredients whose absorption maxima are in the UVA wavelength range of 
320 to 400 nanometers (nm).
    The agency is aware that avobenzone's maximum absorbance is in the 
UVA wavelength range and agrees with the comments that the proposed 
definition of a sunscreen active ingredient needs to be modified to 
represent ingredients that sufficiently absorb, reflect, or scatter 
radiation in the UVA wavelengths. As the proposed definition impacts 
other sunscreen ingredients, the agency intends to address this issue 
in a future issue of the Federal Register.

B. Safety of Avobenzone

    3. The petition (Ref. 2) requested that FDA include avobenzone as 
an active ingredient in the proposed monograph and permit broad 
spectrum combination sunscreen drug products with avobenzone to be 
marketed with a range of SPF values. The petition contended that 
avobenzone is generally recognized as safe based on substantial 
evidence consisting of the results of adequate and well-controlled 
published studies, unpublished data, safe domestic OTC marketing of two 
sunscreen drug products that are the subjects of approved NDA's, and 
several years of foreign marketing. The petition provided numerous 
published and unpublished studies in humans and animals (Refs. 2, and 3 
through 8) in support of the safety of avobenzone.
    An Australian clinical study (Ref. 6) evaluated the frequency of 
reactions to a SPF 15 broad spectrum sunscreen formulation containing 2 
percent avobenzone in combination with 8 percent octyl methoxycinnamate 
and another formulation containing only the cream base without the 
sunscreen active ingredients. This randomized, longitudinal, double-
blinded study involved 603 adults who were directed

[[Page 48647]]

to apply either the sunscreen or the cream based formulation daily for 
7 months.
    At the end of the 7-month study, 114 participants (18.9 percent) 
reported adverse skin reactions; 90 (14.9 percent of the 603 adults) 
had inflammatory skin reactions. Further testing confirmed that 45 of 
these 90 subjects had a history of allergic reactions. Patch testing of 
22 of these 45 subjects indicated that 4 who had positive patch-test 
reactions gave a history of cosmetic intolerance. A majority of the 
adverse responses were consistent with irritant reactions to both the 
sunscreen preparation and the cream base control. However, the data 
indicated that none of the participants who were patch tested because 
of reported inflammatory skin reactions tested positive to the 
sunscreen active ingredients alone. The agency finds this study 
provides additional support for the safety of 2 percent avobenzone with 
octyl methoxycinnamate and suggests that avobenzone is not a potent 
photosensitizer.
    The cumulative irritation potential of 8 test products was compared 
in an occlusive repeat insult patch test evaluation procedure on 25 
healthy adult volunteers (Ref. 6). Each test product contained 1 to 3 
percent avobenzone with various combinations of 2 to 7.5 percent octyl 
methoxycinnamate, 2 percent phenylbenzimidazole sulfonic acid, and/or 5 
percent micronized titanium dioxide. Patches were applied 3 times a 
week over a 2-week period and were removed after 48 hours (when applied 
on Monday and Wednesday) or 72 hours (when applied on Friday). Skin 
sites were evaluated on a scale of 0 to 4 (increasing severity) for 
skin irritation and sensitization reaction. The test product containing 
2 percent avobenzone in combination with 7.5 percent octyl 
methoxycinnamate was the only test product to demonstrate noticeable 
levels of irritation. However, a report included with the study 
indicated that these results were due to the emulsification system. 
Although only low levels of cumulative irritancy were observed with all 
but one formulation, the agency believes that additional subjects 
should have been tested in order to assess cumulative irritation 
potential in this study.
    Four clinical occlusive skin patch tests involving 199 subjects 
were conducted using 4 test formulations containing combinations of 
0.075 to 0.5 percent avobenzone and 7.5 to 8.0 percent octyl 
methoxycinnamate (Ref. 6). Each subject was patch tested with the test 
formulations for 48 and 72 hours, followed by an immediate and 24-hour 
observation reading for skin reactivity. No control group was included. 
The results of the study indicated that avobenzone was not a primary 
irritant and elicited no significant immediate or delayed skin reaction 
at the site of application. These data are supportive of the safety of 
low (0.075 to 0.5 percent) concentrations of avobenzone in combination 
with 7.5 to 8.0 percent octyl methoxycinnamate.
    A Canadian company provided a certification describing the number 
of consumer complaints of skin irritancy and sensitivity reactions 
associated with a sunscreen drug product containing 2 percent 
avobenzone, 8.5 percent octyl methoxycinnamate, and 2.2 percent 
phenylbenzimidazole sulfonic acid (Ref. 6). The company reported only 
four complaints of skin reactions related to the use of this product 
from January 1993 to June 1994, noting that over 180,000 liters (L) 
were marketed during this time period. Although the agency considers 
the very low number of complaints (based on the number of L sold) as 
supportive of the safety of 2 percent avobenzone in this combination 
product, the reported marketing history only covers an 18-month period.
    Skin sensitization potential of 4 percent avobenzone in combination 
with 7 to 7.5 percent octyl methoxycinnamate and 4.5 to 6.5 percent 
titanium dioxide was assessed in a study on the albino guinea pig (Ref. 
6). No sensitization reactions to either formulation were reported. A 
study (Ref. 6) on hairless mice compared and demonstrated the 
protective effect of two commercially available broad-spectrum 
sunscreens against chronic exposure to UVA irradiation (340 to 400 nm). 
One sunscreen product contained 3 percent avobenzone (the other active 
ingredients were not given) and the other contained 3 percent 
oxybenzone. The study also emphasized the importance of assessing the 
safety of the vehicle or base of the sunscreen product to minimize skin 
irritation or photodamage. The agency considers the preclinical safety 
data for avobenzone submitted by the comments to be adequate.
    The comment (Ref. 6) also included the following: (1) A statement 
from a company certifying that avobenzone had been used for 10 years in 
a wide variety of skin creams and sunscreen products (in combination 
with octyl methoxycinnamate and oxybenzone) without any material 
adverse biological effects, and (2) a table of sunscreen products 
marketed and sold in Canada that contain 2 to 5 percent avobenzone in 
combination with other active sunscreen ingredients. However, no other 
supporting data were provided with these documents.
    A clinical study (Ref. 7) assessed the cumulative dermal irritancy 
and allergic potential of a sunscreen product containing 2 percent 
avobenzone, 7.5 percent octyl methoxycinnamate, and 3.0 percent 
titanium dioxide. In this study, the sunscreen product was applied to 
the back of 50 adults under occlusive cutaneous test plasters. After 48 
hours (or 72 hours at the weekend), the plasters were removed and the 
test sites were evaluated 6 hours later to assess irritancy. The test 
sunscreen product was again applied to the same areas under cutaneous 
test plasters. This repetitive process covered a period of 3 weeks, 
followed by a 6-day pause, and then a challenge phase during which the 
sunscreen was reapplied to untreated areas of the back and removed 72 
hours after application. The test sites were examined 6 hours after 
removal of the plaster. The agency considers the cumulative irritancy 
and allergic potential assessment data from this study as supportive of 
the safety of 2 percent avobenzone.
    Utilizing a similar protocol, six clinical studies (Ref. 7) 
assessed the cumulative dermal irritancy and allergic potential of 
sunscreen products containing 0.2 to 1.5 percent avobenzone in 
combination with 1.5 to 7.5 percent octyl methoxycinnamate, 8 percent 
titanium dioxide, 0.6 to 3.45 percent methylbenzylidene camphor, and/or 
3.5 to 4.5 percent phenylbenzimidazole sulfonic acid. The investigators 
found no evidence that any of these sunscreen products caused 
cumulative irritation. The cumulative irritancy data are supportive of 
the safety of low (0.2 to 1.5 percent) concentrations of avobenzone. 
Phototoxicity assessments were reported for two products (containing 
1.0 and 1.5 percent avobenzone). However, two study summaries noted 
that the phototoxicity/photoallergenicity test protocols did not 
involve multiple applications of the products or multiple irradiation 
exposures of the test sites and can only be considered a phototoxicity 
assay. The agency concludes that the results from the two 
phototoxicity/photoallergenicity studies do not adequately address the 
phototoxicity or photoallergenicity of the test products.
    Six studies (Ref. 8) assessed the safety of the following four 
sunscreen drug products: (1) A gel containing 3 percent avobenzone in 
combination with 8.5 percent octyl methoxycinnamate, 3 percent 
oxybenzone, and 5 percent octyl salicylate; (2) a gel containing 3 
percent

[[Page 48648]]

avobenzone in combination with 8.5 percent octyl methoxycinnamate, 6 
percent oxybenzone, and 6 percent octyl salicylate; (3) a cream 
containing 3 percent avobenzone in combination with 8.5 percent octyl 
methoxycinnamate, 3 percent oxybenzone, and 5 percent octyl salicylate; 
and (4) a cream containing 3 percent avobenzone in combination with 8.5 
percent octyl methoxycinnamate, 6 percent oxybenzone, and 6 percent 
octyl salicylate. The studies included the following tests: (1) A 21-
day cumulative irritation test, (2) a phototoxicity test, (3) a 
photocontact allergy test, (4) a comedogenic potential test, (5) an in-
use irritation potential test in children, and (6) an in-use irritation 
potential test in adults.
    Results of the 21-day cumulative irritancy test (Ref. 8) indicated 
that the most frequently observed response to the cream and gel 
sunscreen formulations was minimally visible erythema. The agency notes 
that 3 of 23 subjects recorded a moderate erythema in response to the 
second sunscreen formulation, and 4 of 23 subjects recorded a moderate 
erythema reaction in response to the fourth formulation.
    The phototoxicity potential of these 4 products was assessed in 11 
adults (Ref. 8). Each product was applied to two skin sites with a 
third test site used as an untreated control. One set of treated test 
sites was covered with nonwoven cotton cloth and not irradiated. The 
second set of treated sites was irradiated first with 10 times the 
predetermined minimal erythema dose (MED) of UVA irradiation, then with 
0.5 times the predetermined MED of UVA/UVB irradiation. Both the 
untreated and treated test sites were later evaluated for any 
observable skin reactions at 5 minutes, 3 hours, and 24 hours after 
irradiation. Results indicated that all samples induced mild cutaneous 
responses at the 24-hour time period in several subjects. The authors 
of the study reported that the minimal erythema responses were 
considered to represent irritation to the test material, to the test 
procedure of tape stripping, or to the procedure of covering the sites 
between evaluation. The agency believes that additional subjects should 
have been tested in order to assess phototoxicity potential in this 
study.
    Photocontact allergy testing showed that the second and third 
products reacted at the 48-hour reading of the irradiated challenge 
sites with mild erythema. The study report concluded that there was no 
clinically identifiable evidence of photocontact allergic responses to 
any of the materials tested, although mild erythema reactions were 
reported with two products at the 48-hour readings.
    Two randomized, parallel-group, evaluator-blind, noncontrolled in-
use studies (Ref. 8) evaluated the irritation potential of 2 sunscreen 
formulations in 20 children and 20 adults. Each product contained 3 
percent avobenzone, 8.5 percent octyl methoxycinnamate, 6 percent octyl 
salicylate, and 6 percent oxybenzone (each in a different vehicle). The 
subjects applied the assigned product to their face/neck, arms, and 
legs at least twice a day for 2 weeks. A nine-point scale was used to 
grade the signs and symptoms of irritation at weeks 0 (before and after 
the first test product application), 1, and 2. Adverse events included 
itching and facial erythema. No serious treatment-related events were 
reported. Although these studies provided useful information concerning 
adverse events experienced during short-term actual use, the agency 
believes that additional subjects should have been tested in order to 
assess the in-use irritation potential of the test products.
    The primary irritation potential of a test product containing 2 
percent avobenzone, 8.5 percent octyl methoxycinnamate, and 2.2 percent 
phenylbenzimidazole sulfonic acid was evaluated in 15 adult subjects 
(Ref. 8). Negative (saline solution), mild positive (1 percent sodium 
lauryl sulfate in saline), and vehicle controls were included. Each 
subject received a single, approximately 24-hour contact application of 
each test material to the upper back area. Only 2 of the 15 subjects 
were reactive to the positive control. No clinically identifiable skin 
reactions were reported for the test product or vehicle. Another small 
study of primary irritation potential (Ref. 8) on 10 subjects tested a 
product containing 2 percent avobenzone, 7.5 percent octyl 
methoxycinnamate, and 4.5 percent oxybenzone and reported no primary 
irritant effect on the skin. The agency believes additional subjects 
should have been tested in these studies in order to assess the primary 
irritation potential of the test products.
    A well-controlled occlusive patch study of 106 adults (Ref. 8) 
assessed the primary irritation potential (contact sensitization) and 
allergenic sensitization potential of the following test and control 
products: (1) 3 percent avobenzone in combination with 7.5 percent 
octyl methoxycinnamate, (2) 3 percent avobenzone, (3) 7.5 percent octyl 
methoxycinnamate, and (4) cream vehicle for 3 percent avobenzone. The 
data indicated that no subjects experienced primary irritation or 
allergenic sensitization to any of the test products. The agency 
considers this study as supportive of the safety of the sunscreen 
formulation containing 3 percent avobenzone in combination with 7.5 
percent octyl methoxycinnamate.
    Three studies (Ref. 8) assessed the protective effect of sunscreen 
drug products containing 1 percent avobenzone in patients diagnosed 
with atopic dermatitis and in patients receiving photochemotherapy for 
psoriasis. Without a concurrent vehicle control, it is unclear whether 
protection and/or improvement of the disease was related to sunscreen 
ingredients. Further, isolated use of steroids and salicylic acid-
containing topical products may have interfered with the photocontact 
potential of the sunscreen formulation tested in the patients receiving 
photochemotherapy for psoriasis.
    Three clinical studies (Ref. 8) evaluated the allergic contact 
dermatitis potential, contact irritancy potential, or phototoxicity/
photoallergenicity potential, respectively, of test products containing 
1 to 3 percent avobenzone. The agency does not find these studies 
useful. The first two studies did not adhere to standard contact 
irritancy and allergenicity protocol as occlusive applications were not 
made on a daily basis. The third study did not adhere to the standard 
photomaximization test protocol as application of the test material was 
followed by exposure to non-erythemogenic UV radiation of 10 Joules per 
square centimeter (J/cm2) (instead of 3 MED's), and 24-hour skin 
patching of the test material followed rather than preceded 
irradiation.
    The photosensitization potential of 2 percent avobenzone alone and 
in combination with 7.5 percent octyl methoxycinnamate was assessed in 
a panel of 25 adult subjects (Ref. 8). Dimethylsulfoxide (DMSO) was 
incorporated in both test formulations. As it is not clear what effect 
DMSO may have had on the study results, the agency has not considered 
these data in assessing the safety of avobenzone.
    Data and other information submitted by another comment (Refs. 16 
and 17) consisted of summaries of preclinical safety studies, reports 
from clinical safety studies of various formulations containing 
avobenzone, adverse drug experience data, and photostability 
information. The reports included six clinical safety studies from an 
approved NDA for a sunscreen lotion that contains 3 percent avobenzone, 
3 percent oxybenzone, and 7.5 percent octyl methoxycinnamate. Four of 
the studies evaluated irritation/

[[Page 48649]]

sensitization, photoallergenicity, and phototoxicity potential. The 
other two studies were outdoor use tests. These data support the safety 
of 3 percent avobenzone alone and in combination with Category I 
cinnamates and benzophenones.
    The comment (Ref. 17) also included reports from six clinical 
safety studies concerning a prior formulation that contained 2 percent 
avobenzone, 2 percent oxybenzone, and 7.5 percent octyl 
methoxycinnamate. One report included a repeat insult patch test 
(protocol HST-1-84-25) designed to evaluate the primary irritation and 
sensitization potential of the formulation, the lotion vehicle, 4 
percent avobenzone in a petrolatum base, and 8 percent homosalate 
lotion. The study evaluated the test products under occlusive patch 
conditions during an initial 3-week induction phase, a 2-week rest (no 
treatment) phase, and a 1-week challenge phase. During the induction 
phase, occlusive patches impregnated with the test products were 
applied to the upper back of each subject and evaluated 24 to 48 hours 
after patch removal. During the challenge phase, occlusive patches were 
applied to the original induction phase sites and evaluated after 48 
hours (patches were applied and evaluated twice during this phase). Of 
the 162 healthy adults enrolled in the study, 154 (mean age 39.8) 
completed the study (individual data were not provided). Mean 
irritation scores for the avobenzone formulation ranged from 0.05 to 
0.24 during the nine induction phase observations and were 0.10 and 
0.18 during the two challenge phase observations. One subject exhibited 
a possible allergic reaction to the tape and all four test products. 
Application of the avobenzone formulation and a control product under 
home use conditions by this subject resulted in no reported adverse 
reactions. The investigator noted that this subject experienced ``non-
specific, multiple reactions, including to test tape.''
    Another report (Ref. 17) included a clinical study (protocol HST-5-
84-33) designed to evaluate the photoallergenicity potential of the 2 
percent avobenzone formulation, its lotion vehicle, and a product 
containing 3 percent oxybenzone plus 7 percent Padimate O. The study 
consisted of the determination of each subject's MED, a 3-week 
induction phase, a 10-day rest (no treatment) phase, and a 4-day 
elicitation phase. During the induction phase, two test sites for each 
product were outlined on the subject's back, the products were applied, 
and the sites remained under occlusive patches for 24 hours. After the 
24-hour period, the patches were removed and the sites were irradiated 
with three MED's of UVA/UVB radiation. The sites were evaluated 48 
hours later for reactions on an increasing severity scale of 0 to 3+. 
This process was repeated twice weekly for a total of six exposures. 
During the elicitation phase, test materials were applied to two sites 
adjacent to the induction sites and occluded for 24 hours. After 24 
hours, one of each set of elicitation test sites (the corresponding 
site in each set was shielded) and an untreated control site received 4 
J/cm2 of UVA radiation. All sites were evaluated at 48 and 72 
hours after irradiation.
    Six male and 19 female adults (all Caucasian and in good health) 
between 20 and 39 years of age (mean age 29.2) enrolled in and 
completed the study. No positive responses were reported at either 48 
or 72 hours. The investigator concluded that no detectable contact 
photosensitization potential was associated with any of the test 
materials. The agency considers this study as supportive of the safety 
of 2 percent avobenzone in combination with oxybenzone and octyl 
methoxycinnamate.
    Another report (Ref. 17) included a clinical study (protocol HST-7-
84-32) designed to evaluate the phototoxicity potential of the 2 
percent avobenzone formulation and 4 percent avobenzone in petrolatum. 
Seven female and three male adults (all Caucasian and in good health) 
between 18 and 63 years of age (mean age 29) enrolled in and completed 
the study. After the determination of each subject's MED, each test 
product was applied to two test sites on each subject's back, occluded 
for 24 hours, and then reapplied. Within 5 minutes after reapplication, 
one site for each product was shielded, and the other sites were 
irradiated with 1 MED of UVA/UVB radiation followed by 12 minutes of 
UVA radiation. One additional untreated test site was irradiated to 
serve as a control. Test sites were evaluated at 15 minutes, 24 hours, 
and 48 hours after irradiation on an increasing severity scale of 0 to 
+++. No positive reactions were reported for either test product. The 
agency considers this study as supportive of the safety of 2 percent 
avobenzone in combination with oxybenzone and octyl methoxycinnamate.
    Three clinical studies (protocols 92-8, 92-7, and 92-45) (Ref. 17) 
evaluated the safety of a formulation identified as H03-146, which 
contained a combination of 4 percent avobenzone, 5 percent oxybenzone, 
5 percent octyl salicylate, and 10 percent octocrylene in a lotion 
vehicle. Each study included other unidentified sunscreen products as 
comparative controls.
    Protocol 92-8 evaluated the irritation and sensitization potential 
of H03-146 in a modified Draize human repeat insult patch test (Ref. 
12). The 6-week study involved induction and challenge phases separated 
by a 14-day rest (notreatment) period. During the 3-week induction 
phase, an occlusive patch impregnated with H03-146 was applied to the 
upper back of subjects on each Monday, Wednesday, and Friday (a total 
of nine applications). The patches were removed by the subjects 24 
hours after application and evaluated 24-48 hours after patch removal. 
Responses were evaluated on a scale of 0 to 4 (increasing severity). 
After a 14-day period in which no patches were applied, a patch was 
then applied for 48 hours to a site adjacent to the original induction 
site on each subject and then evaluated. Although the protocol called 
for only one challenge patch, the procedure was repeated with an 
additional 48-hour patch.
    Of the 217 subjects who began the study, 205 (90 percent female and 
10 percent male) completed the study. Subjects were between 18 and 65 
years of age with 83 percent between 18 and 49 years of age. Irritation 
scores of 1 (macular, faint erythema involving at least 25 percent of 
the test area) were reported for 1 to 5 subjects after the second 
through ninth induction applications and for one subject after the 
first challenge application only. No test formulation-induced allergies 
or irritation scores above 1 were reported. The investigator concluded 
that the test formulation had very low irritation potential and induced 
no allergies. The comment's statistical analysis of results from the 
four lotions used in the study (using Friedman tests) noted that no 
significant differences were found between the lotions in regard to 
irritation at any time point. The agency considers this study as 
supportive of the safety of 4 percent avobenzone in combination with 
oxybenzone, octyl salicylate, and octocrylene.
    Protocol 92-7 evaluated the photoallergenicity potential of H03-146 
using a four-phase protocol. During the first phase, the MED was 
determined by administering a series of five doses of UV radiation, 
using a xenon arc solar simulator, to determine the lowest UV radiation 
dose that produced minimally perceivable erythema 16 to 24 hours later. 
During the induction phase, occlusive patches were applied to each 
subject for 24 hours followed by three times the MED in irradiation 
(UVA plus

[[Page 48650]]

UVB). This procedure was repeated twice weekly for 3 weeks, followed by 
a 10-day rest (notreatment) phase. The fourth phase consisted of a 
challenge phase involving the application of duplicate 24-hour 
occlusive patches to a different site followed by 4 J/cm2 UVA 
irradiation to one of the patched sites (the other served as an 
unirradiated control) plus an untreated site (an irradiated control). 
Responses were scored 48 and 72 hours later using a scale of 0 to 3 
(increasing severity).
    Of the 27 subjects who began the study, 26 (69 percent male and 31 
percent female) completed the study. Subjects were between 18 and 37 
years of age with 96 percent between 18 and 29 years of age. One out of 
the 26 subjects received a score of 1 (mainly erythema with little or 
no edema) during the challenge phase (no other reactions were 
reported). The reactive subject was rechallenged (with scores of 1 at 
48 hours and 2 at 72 hours) and subsequently patched to the test 
formulation vehicle and the vehicle plus each (singly) of the active 
ingredients in common with the two products tested in this study 
(avobenzone, oxybenzone, and octyl salicylate). Octocrylene (present in 
only one of the formulations) was not individually tested. Although no 
reactions were reported with any of the components, rechallenge with 
the original test products again elicited a reaction in this subject in 
both irradiated and control sites. The observed response in this 
subject was reported to be an allergic contact dermatitis and not a 
photocontact allergy. The investigator concluded that the test 
formulation was not photoallergenic. The agency considers the 
photoallergenicity data in this study as supportive of the safety of 4 
percent avobenzone in combination with oxybenzone, octyl salicylate, 
and octocrylene.
    Protocol 92-45 evaluated the photoirritation/phototoxicity 
potential of H03-146. The test formulation was applied to duplicate 
sites on the lower or mid-back of subjects, allowed to dry, and covered 
with an occlusive dressing (an adjacent control site was occluded 
without any application). After 24 hours, one test formulation patch 
and the untreated control patch (the irradiated control) were removed 
and immediately exposed to 20 J/cm2 of UVA irradiation. The other 
test formulation patch served as an unirradiated control. The presence 
of a wheal-and-flare response or erythema 5 to 10 minutes after 
irradiation was recorded. Delayed erythema and edema were evaluated 24 
and 48 hours after irradiation using a scale of 0 to 4 (increasing 
severity).
    Six male and 14 female subjects began and completed the study. 
Subjects ranged from 18 to 48 years of age with 95 percent between 18 
and 29 years of age. No immediate or delayed reactions suggestive of 
phototoxicity were reported. The investigator concluded that, under the 
conditions of the study, the test formulation did not possess a 
detectable phototoxicity potential in humans. The agency considers this 
study as supportive of the safety of 4 percent avobenzone in 
combination with oxybenzone, octyl salicylate, and octocrylene.
    Preclinical tests (Ref. 16) on a 3 percent avobenzone formulation 
included studies of skin and eye irritation in the rabbit, oral and 
subcutaneous acute toxicity in the mouse and rat, skin penetration in 
the pig, mutagenicity (Ames test), and photocarcinogenicity in the 
mouse. Preclinical tests on avobenzone (in the rabbit, rat, mouse, 
guinea pig, excised human skin, bacteria, or yeast) included five acute 
toxicity studies, three subchronic toxicity studies, three 
sensitization studies, six skin penetration studies, three mutagenicity 
studies, a phototoxicity study, a photoallergy study, and a teratology 
study. The preclinical data report concluded that no adverse effects 
were observed other than slight to moderate species specific dermal 
irritations. The citizen petition (Ref. 2) also included several 
preclinical studies previously reviewed by the agency, an additional 
mutagenicity study involving chromosome analysis of human peripheral 
blood lymphocytes, and two photomutagenicity studies. The agency 
considers the preclinical safety data for avobenzone to be adequate.
    The agency considers the safety data as providing sufficient 
evidence to demonstrate the low irritation, allergenic sensitization, 
photoallergenic, and phototoxic potential of 2 to 3 percent avobenzone 
alone and in combination with the proposed monograph cinnamate, 
benzophenone, salicylate, and/or diphenylacrylate sunscreen 
ingredients. However, the agency does not consider the data adequate to 
allow avobenzone to be combined with any and all proposed monograph 
sunscreen ingredients without similar supportive data.
    4. The petition maintained that avobenzone has extensive marketing 
experience in the United States based on the products marketed under 
approved NDA's. The petition also noted that avobenzone has been 
marketed ``as a safe and effective UV-A sunscreen filter'' throughout 
the world since 1981.
    The comment (Refs. 16 and 17) provided a summary of adverse drug 
experience (ADE) data for its 3 percent avobenzone product covering the 
period from January 1993 through December 31, 1995. The comment 
estimated a total complaint rate of 0.0067 percent for this period 
(based on reported sales of ``more than one million packages''). Annual 
percentages of the total ADE reports received during this period were 
reported as 44, 29, and 27 percent for the years 1993, 1994, and 1995, 
respectively. The majority of these complaints were typical of a 
topical sunscreen drug product. The highest ``percent of total 
complaints'' was reported in the categories of ``lack of efficacy'' (24 
percent), ``dermatitis/erythema/pruritus/edema'' (19 percent), and 
``rash'' (18 percent). ``Urticaria'' and ``allergic reaction'' 
accounted for 6.6 percent, and ``all other'' accounted for 22 percent. 
None of the reported ADE's was deemed serious in nature or confirmed as 
a causal relationship following complaint investigation. The actual 
number of complaints and an explanation of the ``all other'' category 
were not provided.
    The agency's Spontaneous Reporting System (SRS) has 59 reports of 
ADE's associated with this 3 percent avobenzone product from 1993 
through March 8, 1996 (all from domestic sources) (Ref. 18). These 59 
reports represented the following 107 reactions (more than one reaction 
per report):

                                    Table 1.--Adverse Drug Experience Reports                                   
----------------------------------------------------------------------------------------------------------------
              Reaction                      Total                      Reaction                      Total      
----------------------------------------------------------------------------------------------------------------
Rash                                                26                             Eye pain                   2 
No drug effect                                      19                     Vesicles, bullae                   2 
Application site                                                            Abnormal vision                   2 
reaction                                            10                                 Acne                   1 
Pruritus                                             8                            Arthrosis                   1 

[[Page 48651]]

                                                                                                                
Paresthesia                                          5                                     Chloasma           1 
Skin discoloration                                   4                                     Conjunctivitis     1 
Allergic reaction                                    3                   Maculopapular rash                   1 
Facial edema                                         3                     Peripheral edema                   1 
Pain                                                 3                          Lacrimation                   1 
Photosensitivity                                     3                      Lymphadenopathy                   1 
Urticaria                                            3                         Vasodilation                   1 
Contact dermatitis                                   2                          Exfoliative                     
Hyperesthesia                                        2                           dermatitis                   1 
----------------------------------------------------------------------------------------------------------------

    The agency finds that these ADE reports do not signal any alarming 
trend in numbers or types of reactions. No serious outcomes were 
reported.
    As discussed in section A., comment 1, of this document, avobenzone 
has been continuously marketed in the United States under NDA's for 
approximately 8 years. Although ADE incidence rates or drug safety 
comparisons cannot be made using SRS data alone, the agency believes 
the reports covering these approximately 8 years of OTC use support 
general recognition of the safety of avobenzone.
    5. The comment contended that the studies of effectiveness, 
phototoxicity, and photosensitization contained in its approved NDA 
show that its 3 percent avobenzone product remains effective and safe 
after exposure to UVA/UVB radiation and/or UVA radiation alone. The 
comment stated that clinical testing demonstrated that neither 
avobenzone nor any potential photodegradation products exhibited any 
phototoxic or photosensitization potential. The comment concluded that 
no performance or safety issues were identified relative to potential 
negative effects of photodegradation and that outdoor tests further 
confirm that performance was maintained despite any minor potential 
photodegradation or photolability.
    The comment included the results from an in vitro assessment of the 
photostability of four avobenzone-containing formulations (Table 2) 
(Ref. 17).

                                        Table 2.--Avobenzone Formulations                                       
----------------------------------------------------------------------------------------------------------------
                   Ingredient                         H03-084         H03-087         H03-088         H03-089   
----------------------------------------------------------------------------------------------------------------
Avobenzone                                              4.0%            4.0%            4.0%            4.0%    
Octocrylene                                             0.0%            5.0%            3.0%            3.0%    
Octyl methoxycinnamate                                  7.5%            7.5%            7.5%            7.5%    
Octylsalicyulate                                        5.0%            5.0%            5.0%            5.0%    
Oxybenzone                                              5.0%            4.0%            4.0%            4.0%    
----------------------------------------------------------------------------------------------------------------

    The assessment evaluated the amount of absorbance retained at three 
wavelengths (305 nm, 335 nm, and 355 nm) in thin films of each test 
formulation after exposure to direct sunlight in Memphis, TN, from 
approximately 10 am to 3 pm during the month of March. Measurements 
were made after 0, 1, 2.5, and 5 hours of exposure. After 5 hours of 
exposure, the following amounts of absorbance (percent recovered) were 
reported (Table 3):

                 Table 3.--Percent Absorbance Recovered                 
------------------------------------------------------------------------
                  Formula                     308nm     335nm     355nm 
------------------------------------------------------------------------
H03-084...................................    63.1      56.0      40.8  
H03-087...................................    70.4      61.3      44.0  
H03-088...................................    68.5      60.8      44.9  
H03-089...................................    68.0      60.0      43.8  
------------------------------------------------------------------------

    The photostability assessment report concluded that combinations of 
these five ingredients are sufficiently stable during sunlight exposure 
so that, even after 5 hours of exposure, the majority of the total 
original absorbance (and sunscreen effectiveness) is maintained. The 
report also noted that appropriate formulation techniques using 
monograph sunscreen ingredients can result in photostable formulations.
    As with other sunscreen ingredients, the agency has concerns 
related to the photostability of avobenzone alone and in combinations, 
the safety of photodegradation products, and the effect of 
photodegradation on product effectiveness (Refs. 12 and 15). FDA 
believes that the in vitro photostability assessment (which did not 
utilize the marketed formulation) may indicate a significant amount of 
photodegradation in the test formulations after 5 hours. No information 
was provided concerning the nature of the photodegradation products or 
their specific short-term or long-term safety profiles. Although these 
questions remain, the agency is presently not aware of any safety or 
effectiveness problems associated with the photostability of avobenzone 
alone or in combinations with the proposed monograph cinnamate, 
benzophenone, salicylate, or diphenylacrylate sunscreen ingredients. 
The agency intends to address the issue of photostability of all OTC 
sunscreen active ingredients in a future issue of the Federal Register.

C. Effectiveness of Avobenzone

    6. The petition asserted that avobenzone is generally recognized as 
an effective UVA radiation sunscreen ingredient, both alone and in 
combination with other UVA and UVB radiation sunscreen ingredients, 
based on published and unpublished studies and marketing experience 
with NDA-approved avobenzone-containing sunscreen drug products. The 
petitioner provided published studies in support of the effectiveness 
of avobenzone (Refs. 2 and 3).
    J. M. Menter (Ref. 19) stated that avobenzone has good blocking 
throughout the UVA region, with maximum absorbance at 340 to 350 nm. 
Gange, et al. (Ref. 20) and Lowe, et al. (Ref. 21), assessed the UVA 
radiation protection provided by a combination of 3 percent avobenzone 
plus 7 percent padimate O in humans photosensitized

[[Page 48652]]

with 8-methoxsalen (8-MOP). Both studies demonstrated that the 
combination was effective in providing protection against UVA radiation 
and provided significantly greater UVA radiation protection than either 
avobenzone alone or the other tested sunscreen formulations that did 
not contain avobenzone. Kaidbey and Barnes (Ref. 22) assessed the UVA 
radiation protection provided by various sunscreen formulations by 
evaluating immediate pigment darkening in humans. Products tested 
included a combination of avobenzone and oxybenzone and a combination 
of avobenzone, octyl salicylate, oxybenzone, and octocrylene 
(ingredient concentrations were not given). The study demonstrated that 
test formulations containing avobenzone plus oxybenzone provided more 
effective UVA radiation protection than the formulations without 
avobenzone, and that the multi-ingredient avobenzone-containing 
combination product appeared to be significantly more effective than 
the tested marketed products.
    Urbach (Ref. 23) and Lowe (Ref. 24) assessed the UVA radiation 
protection of 3 percent avobenzone alone and in combination with 7.5 
percent octyl methoxycinnamate in humans photosensitized with 8-MOP. 
Urbach also tested 2 percent avobenzone alone and in combination with 
7.5 percent octyl methoxycinnamate. The studies demonstrated that 2 to 
3 percent avobenzone (alone and in combination with octyl 
methoxycinnamate) was effective in providing protection against UVA 
radiation and that the combination product was significantly more 
effective than octyl methoxycinnamate alone in reducing UVA erythema. 
The petition also noted the agency's previous approval of NDA's for a 
sunscreen product containing 3 percent avobenzone and 7 percent 
padimate O, and a sunscreen product containing 3 percent avobenzone, 3 
percent oxybenzone, and 7.5 percent octyl methoxycinnamate.
    In the notice of proposed rulemaking for OTC sunscreen drug 
products, the agency proposed that an OTC sunscreen ingredient must 
have an absorption spectrum extending to 360 nm or above in order for a 
product containing that ingredient to display UVA radiation protection 
claims in its labeling (58 FR 28194 at 28233). The agency also stated 
that the product would have to demonstrate meaningful UVA radiation 
protection by satisfying ``yet to be established'' UVA radiation 
testing procedures that would be included in the monograph. The agency 
described suggested interim UVA radiation test procedures in the 
proposed rule (58 FR 28194 at 28248 to 28250) and in a notice of public 
meeting (59 FR 16042) to discuss such testing procedures.
    Although the agency continues to evaluate data and information 
relative to a monograph method for determining UVA radiation 
protection, it finds that the submitted studies provide sufficient 
evidence of the effectiveness of 2 to 3 percent avobenzone in 
protecting against UVA radiation. The agency also finds that the 
studies demonstrate that 2 to 3 percent avobenzone in combination with 
appropriate proposed monograph sunscreen ingredients can provide 
``broad spectrum'' protection (58 FR 28194 at 28232 and 28233). Any 
avobenzone-containing sunscreen drug product bearing this claim 
requires both UVA radiation protection testing and SPF testing of the 
finished product. The agency plans to propose a monograph method for 
determining UVA radiation protection (both without and following water 
immersion or perspiration) in a future issue of the Federal Register. 
Until the agency proposes a monograph UVA radiation testing method, the 
agency considers testing procedures similar to those described by R. W. 
Gange, et al. (Ref. 20) and N. J. Lowe, et al. (Ref. 21) as adequate 
for determining the UVA radiation protection potential of a finished 
OTC sunscreen drug product.

D. Conclusions

    The agency considers the safety studies discussed in section B., 
comment 3 of this document as providing sufficient evidence to 
demonstrate the low irritation, allergenic sensitization, 
photoallergenic, and phototoxic potential of 2 to 3 percent avobenzone 
alone and in combination with the proposed Category I cinnamate, 
benzophenone, diphenylacrylate, and/or salicylate sunscreen 
ingredients. ADE data have not revealed any alarming trends in the 
numbers or types of reactions nor any serious outcomes with this 
combination of sunscreen ingredients. The agency considers the warning 
statements proposed in Sec. 352.52(c)(1) as adequate for OTC sunscreen 
drug products that contain avobenzone (e.g., ``Discontinue use if signs 
of irritation or rash appear. If irritation or rash persists, consult a 
doctor.''). In addition, adequate and well-controlled studies using 
currently accepted methods demonstrated the effectiveness of 2 to 3 
percent avobenzone (alone and in combination with some proposed 
monograph sunscreen ingredients) in providing protection against UVA 
radiation. The agency's detailed comments and evaluation of the data 
are on file in the Dockets Management Branch (Ref. 12).
    FDA recognizes that the photostability of any topical product, 
particularly a sunscreen drug product, is an important safety and 
effectiveness consideration. Although more information will ultimately 
be required before the nature and safety profiles of avobenzone 
photodegradation products can be thoroughly assessed, the agency is 
presently neither aware of any known toxic breakdown product(s) for 
avobenzone formulations combined with proposed monograph sunscreen 
ingredients, nor is the agency aware of any systemic toxicity for 
avobenzone from a photodegradation product. FDA intends to further 
address the issue of photostability (and other aspects of final 
formulation safety testing) of all OTC sunscreen active ingredients in 
a future issue of the Federal Register.
    In the notice of proposed rulemaking for OTC sunscreen drug 
products, the agency discussed minimum concentration requirements for 
OTC sunscreen ingredients (58 FR 28194 at 28214). The agency concluded 
that effectiveness requirements (i.e., final product testing) make the 
use of minimum concentration requirements unnecessary for single 
ingredient products. However, because of its concern that each 
ingredient in a combination drug product contributes to the overall 
effectiveness of the product, the agency concluded that minimum 
concentration requirements are necessary for combination sunscreen 
products (i.e., until a method is developed that can demonstrate the 
contribution of each OTC sunscreen ingredient in a combination 
product).
    Thus, the agency considers the data submitted by the petition and 
the comment as supportive of the safety and effectiveness of up to 3 
percent avobenzone alone (if the finished product provides at least an 
SPF 2) and 2 to 3 percent avobenzone in combination with cinoxate, 
diethanolamine methoxycinnamate, dioxybenzone, homosalate, octocrylene, 
octyl methoxycinnamate, octyl salicylate, oxybenzone, sulisobenzone, 
and/or trolamine salicylate (at concentrations for permitted 
combinations of sunscreen active ingredients in Sec. 352.20 of the 
proposed rule for OTC sunscreen drug products). Accordingly, the agency 
is proposing to amend the proposed rule for OTC sunscreen drug products 
to include avobenzone in Secs. 352.10 and 352.20.

[[Page 48653]]

E. Enforcement Status

    No OTC drug advisory review panel considered avobenzone or 
avobenzone-containing combination drug products. In accordance with the 
agency's Compliance Policy Guide 7132b.16 (which describes the agency's 
enforcement policy regarding the marketing of OTC combination drug 
products not reviewed by an OTC drug advisory review panel) (Ref. 25), 
these combinations may not be marketed until the agency states by 
notice in the Federal Register that the combinations have been 
tentatively determined to be generally recognized as safe and effective 
and that OTC marketing of the combinations will be permitted under 
specified conditions. Before marketing may begin, the comment period 
for this proposal must end and then another Federal Register notice 
must be published setting forth the agency's determination concerning 
interim marketing before publication of the final rule. Any such 
interim marketing that might be allowed, pending issuance of the final 
monograph, is subject to the risk that the agency may adopt a different 
position in the final monograph that could require relabeling, recall, 
or other regulatory action.
    One comment maintained that there is a real and significant public 
health need for widely available avobenzone-containing sunscreen 
products that provide protection against the hazards associated with 
UVA and UVB radiation. To provide manufacturers with the extensive lead 
time necessary to make avobenzone-containing sunscreen products 
available by the 1997 summer season, the comment requested that the 
agency complete its determination concerning interim marketing no later 
than October 1, 1996.
    The agency considers it in the public interest to proceed with a 
determination of the marketing status of avobenzone as soon as possible 
because the addition of this ingredient to the proposed monograph would 
provide for wide availability of new combination sunscreen products 
that will provide consumers with broad spectrum protection. 
Accordingly, the agency is requesting comments regarding this proposed 
amendment in a period of 30 days (shorter than the normal 90 days) so 
that the marketing status of OTC avobenzone-containing sunscreen drug 
products can be determined in an expeditious manner.

F. Labeling

    The petition recommended using approved NDA labeling, which 
addresses both the UVA and UVB protection of the product, as 
appropriate for OTC sunscreen drug products containing avobenzone. 
Accordingly, in addition to applicable labeling proposed in 
Secs. 352.50 through 352.60 (58 FR 28194 at 28296 to 28298), the agency 
is proposing that the labeling for sunscreen drug products containing 
avobenzone may include under ``Indications'' any of the following 
phrases: (1) ``Broad spectrum sunscreen,'' (2) ``Provides (select one 
of the following: ``UVB and UVA,'' or ``broad spectrum'') protection,'' 
(3) ``Protects from UVB and UVA (select one of the following: ``Rays'' 
or ``radiation''),'' (4) (Select one of the following: ``Absorbs,'' 
``Protects,'' ``Screens,'' or ``Shields'') ``throughout the UVA 
spectrum,'' (5) ``Provides protection from the UVA rays that may 
contribute to skin damage and premature aging of the skin.''

III. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    (1) Comment No. CP4, Docket No. 78N-0038, Dockets Management 
Branch.
    (2) Comment No. CP5, Docket No. 78N-0038, Dockets Management 
Branch.
    (3) Comment No. C234, Docket No. 78N-0038, Dockets Management 
Branch.
    (4) Comment No. LET96, Docket No. 78N-0038, Dockets Management 
Branch.
    (5) Comment No. LET101, Docket No. 78N-0038, Dockets Management 
Branch.
    (6) Comment No. LET127, Docket No. 78N-0038, Dockets Management 
Branch.
    (7) Comment No. LET130, Docket No. 78N-0038, Dockets Management 
Branch.
    (8) Comment No. SUP18, Docket No. 78N-0038, Dockets Management 
Branch.
    (9) Comment No. LET95, Docket No. 78N-0038, Dockets Management 
Branch.
    (10) Comment No. LET105, Docket No. 78N-0038, Dockets Management 
Branch.
    (11) Comment No. LET118, Docket No. 78N-0038, Dockets Management 
Branch.
    (12) Comment No. LET141, Docket No. 78N-0038, Dockets Management 
Branch.
    (13) Comment No. MM11, Docket No. 78N-0038, Dockets Management 
Branch.
    (14) Comment No. MM12, Docket No. 78N-0038, Dockets Management 
Branch.
    (15) Comment No. MM13, Docket No. 78N-0038, Dockets Management 
Branch.
    (16) Comment No. LET138, Docket No. 78N-0038, Dockets Management 
Branch.
    (17) Comment No. SUP20, Docket No. 78N-0038, Dockets Management 
Branch.
    (18) Food and Drug Administration, Center for Drug Evaluation 
and Research, Adverse Drug Event Line Listing for Shade 
UVAGuard SPF 15 Lotion for the years 1993 through March 
1996, Docket No. 78N-0038, Dockets Management Branch.
    (19) Menter, J. M., ``Recent Developments in UVA 
Photoprotection,'' International Journal of Dermatology, 29:389-394, 
1990.
    (20) Gange, R. W., et al., ``Efficacy of a Sunscreen Containing 
Butyl Methoxydibenzoylmethane Against Ultraviolet A Radiation in 
PhotosensitizedSubjects,'' Journal of the American Academy of 
Dermatology, 15:494-499, 1986.
    (21) Lowe, N. J., et al., ``Indoor and Outdoor Efficacy Testing 
of a Broad Spectrum Sunscreen Against Ultraviolet A Radiation in 
Psoralen-sensitized Subjects,'' Journal of the American Academy of 
Dermatology, 17:224-230, 1987.
    (22) Kaidbey, K. H., and A. Barnes, ``Determination of UVA 
Protection Factors by Means of Immediate Pigment Darkening in Normal 
Skin,'' Journal of the American Academy of Dermatology, 25:262-266, 
1991.
    (23) Urbach, F. D., ``Protocol #HPT-670,'' unpublished report in 
C234, Docket No. 78N-0038, Dockets Management Branch.
    (24) Lowe, N. J., ``Protocol #GL/87-1,'' unpublished report in 
C234, Docket No. 78N-0038, Dockets Management Branch.
    (25) ``Food and Drug Administration Compliance Policy Guide 
7132b.16,'' in OTC vol. 06ATFM, Docket No. 78N-0038, Dockets 
Management Branch.

IV. Effective Date

    The agency advises that any final rule for OTC sunscreen drug 
products resulting from this proposed rule will be effective 12 months 
after its date of publication in the Federal Register. Any notice of 
enforcement policy allowing interim marketing will state its effective 
date. On or after the stated dates, any OTC drug product that is not in 
compliance with the notice of enforcement policy or the final rule may 
not be initially introduced or initially delivered for introduction 
into interstate commerce unless it is the subject of an approved 
application. Further, any OTC drug product subject to the final rule 
that is repackaged or relabeled after the effective date of the rule 
must be in compliance with the rule regardless of the date that the 
product was initially introduced or initially delivered for 
introduction into interstate commerce. Manufacturers are encouraged to 
comply voluntarily with the final rule at the earliest possible date.

V. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive

[[Page 48654]]

impacts; and equity). The agency believes that this proposed rule is 
consistent with the regulatory philosophy and principles identified in 
the Executive Order. In addition, the proposed rule is not a 
significant regulatory action as defined by the Executive Order and, 
thus, is not subject to review under the Executive Order.
    Under the Regulatory Flexibility Act, if a rule has a significant 
impact on a substantial number of small entities, an agency must 
analyze regulatory options that would minimize any significant impact 
of a rule on small entities. This proposed rule would allow 
manufacturers to market avobenzone-containing sunscreen drug products 
without having to obtain an approved NDA, as is currently required, and 
thus would be beneficial to small entities. The proposed rule would 
also have a positive impact on the availability and marketing of broad 
spectrum OTC sunscreen drug products by allowing additional products to 
be marketed. Thus, this proposed rule will not impose a significant 
economic burden on affected entities. Therefore, under the Regulatory 
Flexibility Act (5 U.S.C. 605(b)), the Commissioner of Food and Drugs 
certifies that the proposed rule will not have a significant economic 
impact on a substantial number of small entities. No further analysis 
is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on 
manufacturers of OTC sunscreen drug products. Comments regarding the 
impact of this rulemaking on such manufacturers should be accompanied 
by appropriate documentation. The agency is providing a period of 30 
days from the date of publication of this proposed rulemaking in the 
Federal Register for comments to be developed and submitted. The agency 
will evaluate any comments and supporting data that are received and 
will reassess the economic impact of this rulemaking in the preamble to 
the final rule.

VI. Paperwork Reduction Act of 1995

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

VII. Environmental Impact

    The agency has determined under 21 CFR 25.24(c)(6) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VIII. Public Comment

    Interested persons may, on or before October 16, 1996, submit 
written comments to the Dockets Management Branch (address above). Desk 
copies of these written comments should be submitted to Debra L. Bowen, 
Center for Drug Evaluation and Research (HFD-560), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857. Written 
comments on the agency's economic impact determination may be submitted 
on or before October 16, 1996. Three copies of all comments are to be 
submitted, except that individuals may submit one copy. Comments are to 
be identified with the docket number found in brackets in the heading 
of this document and may be accompanied by a supporting memorandum or 
brief. Received comments may be seen in the office above between 9 a.m. 
and 4 p.m., Monday through Friday.

List of Subjects 21 CFR Part 352

    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 352 (proposed in the Federal Register of May 
12, 1993, 58 FR 28194) be amended as follows:

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

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

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371).

    2. Section 352.10 is amended by redesignating paragraphs (b) 
through (t) as paragraphs (c) through (u) and by adding new paragraph 
(b) to read as follows:

Sec. 352.10  Sunscreen active ingredients.

* * * * *
    (b) Avobenzone up to 3 percent.
* * * * *
    3. Section 352.20 is amended by revising paragraphs (a) and (b) to 
read as follows:

Sec. 352.20  Permitted combinations of active ingredients.

    (a) Combinations of sunscreen active ingredients.
    (1) Two or more sunscreen active ingredients identified in 
Sec. 352.10(a), and (c) through (u) may be combined when used in the 
concentrations established for each ingredient in paragraph (a)(3) of 
this section and the finished product has a minimum sun protection 
factor value of not less than 2 as measured by the testing procedures 
established in subpart D of this part.
    (2) Two or more sunscreen active ingredients identified in 
Sec. 352.10(b), (c), (f), (i), (k), (l), (m), (n), (o), (s), and (u) 
may be combined when used in the concentrations established for each 
ingredient in paragraph (a)(3) of this section and the finished product 
has a minimum sun protection factor value of not less than 2 as 
measured by the testing procedures established in subpart D of this 
part.
    (3) Sunscreen active ingredients shall be used within the following 
concentrations when used in combination with another sunscreen or when 
the combination is used with any other permitted active ingredient:
    (i) [Reserved].
    (ii) Avobenzone 2 to 3 percent.
    (iii) Diethanolamine methoxycinnamate 8 to 10 percent.
    (iv) Digalloyl trioleate 2 to 5 percent.
    (v) Dioxybenzone 3 percent.
    (vi) Ethyl .4-[bis(hydroxypropyl)] aminobenzoate 1 to 5 percent.
    (vii) Glyceryl aminobenzoate 2 to 3 percent.
    (viii) Homosalate 4 to 15 percent.
    (ix) Lawsons 0.25 percent with dihydroxyacetone 3 percent.
    (x) Menthyl anthranilate 3.5 to 5 percent.
    (xi) Octocrylene 7 to 10 percent.
    (xii) Octyl methoxycinnamate 2.0 to 7.5 percent.
    (xiii) Octyl salicylate 3 to 5 percent.
    (xiv) Oxybenzone 2 to 6 percent.
    (xv) Padimate 0 1.4 to 8 percent.
    (xvi) Phenylbenzimidazole sulfonic acid 1 to 4 percent.
    (xvii) Red petrolatum 30 to 100 percent.
    (xviii) Sulisobenzone 5 to 10 percent.
    (xix) Titanium dioxide 2 to 25 percent.
    (xx) Trolamine salicylate 5 to 12 percent.
    (b) Sunscreen and skin protectant combinations.
    (1) Any single sunscreen active ingredient when used in the

[[Page 48655]]

concentration established in Sec. 347.10 may be combined with one or 
more skin protectant active ingredients identified in Sec. 347.10(a), 
(d), (e), (f), (h), (i), and (j) of this chapter, provided the finished 
product has a minimum SPF value of not less than 2 as measured by the 
testing procedures established in subpart D of this part and provided 
the product is labeled according to Sec. 352.60.
    (2) Two or more sunscreen active ingredients when used in the 
concentrations established in Sec. 352.20(a)(3) may be combined with 
one or more skin protectant active ingredients identified in 
Sec. 347.10(a), (d), (e), (f), (h), (i), and (j) of this chapter, 
provided the finished product has a minimum SPF value of not less than 
2 as measured by the testing procedures established in subpart D of 
this part and provided the product is labeled according to Sec. 352.60.
 * * * * *
    4. Section 352.52 is amended by adding a new paragraph (b)(2)(vi) 
and by revising the headings of paragraphs (b)(3), (c)(2), (d)(3) and 
(e)(5) to read as follows:

Sec. 352.52  Labeling of sunscreen drug products.

* * * * *
    (b) * * *
    (2) * * *
    (vi) For products containing the active ingredient identified in 
Sec. 352.10(b), the following labeling statements may be used--(A) 
``Broad spectrum sunscreen.''
    (B) ``Provides'' (select one of the following: ``UVB and UVA'' or 
``broad spectrum'') ``protection.''
    (C) ``Protects from UVB and UVA'' (select one of the following: 
``Rays'' or ``radiation'').
    (D) (Select one of the following: ``Absorbs,'' ``Protects,'' 
``Screens,'' or ``Shields'') ``throughout the UVA spectrum.''
    (E) ``Provides protection from the UVA rays that may contribute to 
skin damage and premature aging of the skin.''
    (3) For products containing the active ingredient identified in 
Sec. 352.10(t) that provide an SPF of 12 to 30, the following labeling 
statement may be used. * * *
    (c) * * *
    (2) For products containing the ingredient identified in 
Sec. 352.10(j)-- * * *
* * * * *
    (d) * * *
    (3) For products containing the ingredient identified in 
Sec. 352.10(j). * * *
* * * * *
    (e) * * *
    (5) For products containing the active ingredient identified in 
Sec. 352.10(t) that provide an SPF of 12 to 30, the following labeling 
statement may be used. * * *
* * * * *

    Dated: September 5, 1995.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-23547 Filed 9-13-96; 8:45 am]
BILLING CODE 4160-01-F