[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
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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
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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
