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

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.

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)

onograph 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)

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

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

ne 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

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

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

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

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)

teers (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

ation 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

ilable 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

sess 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

toxicity/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

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

ts (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

ed 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

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

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/

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/

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

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

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

itional 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

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

. 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

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

y 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

ate 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

,

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)

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

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

d.

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%

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

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

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)

ed. 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

tudies 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

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

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)

n

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.'')

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.

E. Enforcement Status

mate, 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.

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

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,''

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.

, 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.

ination 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

ule 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

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

ificant 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

nt 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.

* * * * *

R 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.

ive 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

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

, (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