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

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; Enforcement Policy

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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

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

zinc oxide as a sunscreen active ingredient are generally recognized as

safe and effective and not misbranded at concentrations of up to 25

percent alone and 2 to 25 percent in combination with any proposed

Category I sunscreen active ingredient except avobenzone. OTC marketing

of such drug products is being permitted pending establishment under

the OTC drug review of a final monograph covering sunscreen drug

products. This proposal is part of the ongoing review of OTC drug

products conducted by FDA.

Dates: Submit written comments by January 20, 1999; written comments on

the agency's economic impact determination by January 20, 1999. 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, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Donald Dobbs, Center for Drug

Evaluation and Research (HFD-560), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-827-2222.

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. The Advisory Review Panel on OTC Topical Analgesic,

Antirheumatic, Otic, Burn, and Sunburn Prevention and Treatment Drug

Products (the Panel) reviewed zinc oxide as both a sunscreen and skin

protectant. The Panel classified zinc oxide at concentrations of 1 to

25 percent as a Category I skin protectant (43 FR 34628 at 34648,

August 4, 1978). Although zinc oxide was a labeled ingredient in a

marketed sunscreen product, the Panel classified zinc oxide as an

inactive ingredient (43 FR 38206 at 38208).

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. The agency discussed a study submitted

to the Panel using zinc oxide alone and in combination with phenyl

salicylate, another sunscreen ingredient (58 FR 28194 at 28213). The

study was designed to measure the ability of zinc oxide (15 to 33.3

percent) to absorb ultraviolet (UV) radiation over a broad range of

wavelengths. The agency concluded that the data were not adequate to

determine the effectiveness of zinc oxide because the effectiveness

data for zinc oxide used alone were limited to one subject. Therefore,

the agency classified zinc oxide in Category III (available data are

insufficient to determine safety or effectiveness) (58 FR 38213) and

requested data to support the effectiveness of zinc oxide as a

sunscreen ingredient.

In the proposed rule, the agency also discussed the public health

significance of ultraviolet A (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, four manufacturers submitted data

to support the effectiveness of zinc oxide as an OTC sunscreen active

ingredient for both ultraviolet B (UVB) and UVA protection. Copies of

the comments received are on public display in the Dockets Management

Branch (address above). The four comments requested that the agency

reclassify zinc oxide from Category III to Category I status.

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

A. Effectiveness of Zinc Oxide

1. Several comments evaluated the effectiveness of zinc oxide as a

sunscreen active ingredient in various formulations utilizing the sun

protection factor (SPF) test method in the Panel report (43 FR 38206 at

38265 and 38266). Using the testing procedures in the proposed rule (58

FR 28194 at 28298), the agency recalculated the SPF test results (as

stated in the tables in section II.A of this document) after

eliminating those results where the homosalate control was out of

range.

Two studies evaluated the ability of zinc oxide-containing

sunscreen drug products to block sunburning radiation (Ref. 1). In both

studies, formulations containing either 4 percent or 25 percent zinc

oxide, 2 percent oxybenzone (a proposed Category I sunscreen ingredient

(58 FR 28194 at 28295)), and a placebo were tested. The vehicles

consisted of commonly utilized oils and emulsifiers and varied only in

the concentration of the active ingredients and the amount of purified

water. The results of these studies were as follows:

Table 1.--SPF Test Determinations for Four Formulations

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

Test SPF (Study Test SPF

Sunscreen Anticipated SPF 1) (Study 2)

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

4% Zinc oxide SPF 2.5 SPF 3.01 2.79

25% Zinc oxide SPF 15.0 SPF 16.74 16.14

[[Page 56585]]

2% Oxybenzone SPF 3.0 SPF 3.98 3.39

Placebo SPF 1.5 SPF 1.46 1.33

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

These results indicate that the 4-percent zinc oxide formulation

provides more protection against sunburning radiation than does the

placebo. However, as expected, the 25-percent zinc oxide formulation

provides the most protection against sunburning radiation. The agency

believes that these results demonstrate the effectiveness of zinc oxide

(up to 25 percent) as an OTC sunscreen active ingredient in providing

protection against sunburning radiation.

Formulations containing 15 percent and 20 percent zinc oxide were

tested against a control containing no zinc oxide (Ref. 2). The 3

formulations contained the same 12 ingredients at the same

concentrations except for the active ingredient, two inactive

ingredients (octyl palmatate and volatile silicone DC-245), and

deionized water. The 15-percent zinc oxide formulation contained 11

percent octyl palmatate, 7.5 percent volatile silicone DC-245, and 53.3

percent deionized water; the 20-percent zinc oxide formulation

contained 9 percent octyl palmatate, 6.5 percent volatile silicone DC-

245, and 51.3 percent deionized water; and the placebo contained 17

percent octyl palmatate, 7.5 percent volatile silicone DC-245, and 62.3

percent deionized water. The results were as follows:

Table 2.--SPF Test Determinations for Three Formulations

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

Sunscreen Test SPF

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

15% Zinc oxide 15.29

20% Zinc oxide 16.57

Placebo 3.57

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

The agency believes these data also support the effectiveness of

zinc oxide as a sunscreen active ingredient.

Five studies, done at two different laboratories, were designed to

demonstrate the effectiveness of zinc oxide as a sunscreen active

ingredient in different formulations (Ref. 3). In three studies, zinc

oxide (2 percent in one formulation and 6 percent in two formulations)

was the only active ingredient. In two studies, zinc oxide (2.5 percent

or 7.5 percent) was combined with titanium dioxide (2.5 percent), a

proposed Category I sunscreen ingredient (58 FR 28194 at 28295). The

vehicle formulations without zinc oxide were not tested. The results of

the SPF testing were as follows:

Table 3.--SPF Test Determinations for Five Formulations

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

Sunscreen Test SPF

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

2% Zinc oxide 2.99

6% Zinc oxide 6.16

6% Zinc oxide 5.91

2.5% Zinc oxide and 2.5% titanium dioxide 11.77

7.5% Zinc oxide and 2.5% titanium dioxide 20.52

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

Although these studies did not include a placebo, the agency

believes that the data support the effectiveness of 2 percent zinc

oxide as a sunscreen active ingredient.

The SPF of two formulations containing 5 and 10 percent fine

particle size (10 to 70 nanometer (nm), average 30 nm), pH neutral

(7.3) zinc oxide was studied using testing procedures that were

slightly modified by the addition of a range-finding technique (Ref.

4). The two formulations contained the same inactive ingredients at

slightly different concentrations to account for the difference in

concentration of zinc oxide. The results of this study were as follows:

Table 4.--SPF Test Determinations for Two Formulations

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

Sunscreen Anticipated SPF Test SPF

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

5% Zinc oxide SPF 5 SPF 5.01

10% Zinc oxide SPF 10 SPF 9.10

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

Although the vehicle formulations without zinc oxide were not

tested, the agency believes that these results and consistent with the

effectiveness of zinc oxide as a sunscreen active ingredient.

2. One comment (Ref. 1) measured the UVA protection factor (PFA)

for three formulations: (1) 4 percent zinc oxide, (2) 2 percent

oxybenzone, and (3) a placebo. The vehicles consisted of commonly

utilized oils and emulsifiers and varied only in the concentration of

the active ingredients and the amount of purified water. The PFA values

were determined using a modified test method similar to the Panel's

proposed SPF test (43 FR 38206 at 38265 to 38266). For the PFA test

method, the light source was modified to emit only UVA radiation (>99.2

percent). The biological endpoint used in this test method was a change

in skin color, either erythema (redness) or tanning (browning) of the

skin observed 16 to 24 hours after the UV exposure. The lowest dose of

UVA radiation that caused a minimally perceptible response was defined

as the minimal response dose (MRD), which was determined for

unprotected skin (MRDu) and for the sunscreen protected skin

(MRDp). The PFA was the ratio of (MRDp) divided

by the (MRDu). The UVA determinations for the three

formulations were as follows:

[[Page 56586]]

Table 5.--PFA Test Determinations for Three Formulations

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

Anticipated

Sunscreen PFA Test PFA

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

4% Zinc oxide 2.00 2.36

2% Oxybenzone 2.00 2.27

Placebo 1.25 1.11

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

Although the PFA value reported for the 4 percent zinc oxide

formulation was low, these results indicate that zinc oxide blocks

radiation (320 to 340 nm) in the UVA II range.

3. Several comments submitted results of in vitro testing data. One

comment (Ref. 1) used a Cary 2300 Spectrophotometer to measure the

spectral absorbance of three formulations: (1) 4 percent zinc oxide,

(2) 25 percent zinc oxide, and (3) 2 percent oxybenzone. The vehicles

consisted of commonly utilized oils and emulsifiers and varied only in

the concentration of the active ingredients and the amount of purified

water.

Albino hairless mouse stratum corneum/epidermis samples were

prepared by mechanical removal of the dermis using a dulled razor

blade. The samples were cut into 1-inch circles and maintained in a

hydrated state by floating the samples (dermal side down) on a water

bath. The absorbance of each skin sample was measured and recorded. Ten

microliters (L) of sunscreen were applied to the skin

substrate, allowed to dry for 15 minutes, and the absorbance measured.

The absorbance of each sunscreen treated sample was subtracted from the

absorbance of the skin (without sunscreen) to yield the absorbance of

the sunscreen. Five replicate measurements for each sunscreen formula

were averaged and plotted with standard deviations at each 10 nm.

The spectral absorbance plots showed that zinc oxide has a

relatively flat and broad absorbance curve from 250 nm through 370 nm

with a sharp drop in absorbance beyond 370 nm and extending into the

visible spectrum. Comparison of the measurements of the 4 percent zinc

oxide with 25 percent zinc oxide showed that the magnitude of

absorbance is related to the amount of zinc oxide in the formulation.

The spectral absorbance plot of the 2 percent oxybenzone showed an

absorbance peak at 250 nm, another at approximately 280 nm, followed by

a gradual drop in absorbance throughout the UVA wavelengths (320 to 400

nm). These measurements adequately demonstrated that zinc oxide absorbs

radiation between 290 and 380 nm and, thus, support effectiveness.

Another comment (Ref. 2) included the results of in vitro testing

(``Diffey method'') of a formulation containing 15 percent zinc oxide

in a stable emulsion. The transmittance data indicated UV radiation

blockage from 290 to 380 nm and support the premise that zinc oxide can

protect against UV radiation, including both UVB and UVA.

One comment (Ref. 3) included a spectral profile of attenuation for

zinc oxide alone in a cosmetic formulation and from 1:1 and 3:1

combinations of zinc oxide and titanium dioxide. These spectral

profiles of zinc oxide in various formulations demonstrated that zinc

oxide as a single ingredient can provide protection in both the UVB and

UVA spectral regions.

B. Photochemistry and Photobiology of Sunscreens

Recent scientific advances in understanding the photochemistry and

photobiology of sunscreen drug products have raised many issues

regarding sunscreen active ingredients, including zinc oxide and

titanium dioxide. Because zinc oxide and titanium dioxide have many

similar physical characteristics and may be used in combination in OTC

sunscreen drug products, the following discussion addresses both

ingredients.

There has been renewed interest in using physical sunscreens, i.e.,

zinc oxide and titanium dioxide, in sunscreen formulations because

these ingredients may confer protection for a broad range of the UV

radiation spectrum. Some manufacturers have developed ultra fine forms

of these ingredients in the range of 0.02 to 0.10 microns that are

transparent on the skin, may offer both UVA and UVB protection, and are

esthetically pleasing (Refs. 5, 6, and 7).

Sunscreens have been generally classified as chemical (organic) or

physical (inorganic) depending on whether they absorb specific UV

radiation wavelengths or reflect and scatter UV radiation. Zinc oxide

and titanium dioxide have been described as physical sunscreen

ingredients that provide protection from UV radiation through

reflection and scattering. However, new data and information indicate

that they also absorb UV radiation as well as scatter visible light

(Refs. 8 and 9). Various authors (Refs. 8 and 10 through 13) have shown

that these ingredients exhibit a semiconductor optical absorption gap.

They absorb most radiation at wavelengths shorter than the gap

(approximately 380 nm) and scatter radiation at wavelengths longer than

the gap. When zinc oxide and titanium dioxide are irradiated with light

containing energy greater than the band gap (approximately 3 electron

volts), an electron from the valence band can be excited to the

conduction band, thus creating an electron-hole pair. Because of these

semiconductor properties, zinc oxide and titanium dioxide have been

used as photocatalysts to degrade organic substances and pesticides in

the environment (Refs. 14 through 18). In addition, titanium dioxide is

being currently developed as a photooxidative self-cleaning and/or

biocidal coating for industrial surfaces (Ref. 19).

There are many formulation variables that may affect the

photocatalytic capability of zinc oxide and titanium dioxide. Such

variables include mineral components, particle size, surface area,

crystalline structure, particle coatings, pH of the medium, differences

in the refractive index of the medium, and other components in the

formulation (Refs. 5 through 8 and 10 through 23). These formulation

variables are not mentioned in the United States Pharmacopeia (USP)

compendial monograph for zinc oxide. In fact, the USP treats zinc oxide

as a pure compound, without consideration of trace ions that may affect

the absorption band gap between the valence and conduction bands or

electronic energy levels, i.e., the range of wavelengths that are

absorbed.

On September 19 and 20, 1996, the agency held a public meeting on

the photostability, photochemistry, and photobiology of sunscreens in

order to gather more information related to the issues discussed

previously (Ref. 24). As a result of this public meeting, in the

Federal Register of August 15, 1996 (61 FR 42398), the administrative

record for the rulemaking for OTC sunscreen drug products was reopened

until December 6, 1996, to allow for additional data and comment. The

agency is evaluating all data and information received as a result of

the workshop and may discuss

[[Page 56587]]

these recent scientific advances in future issues of the Federal

Register.

C. Conclusion

The agency believes that the results of the studies using the SPF

test to demonstrate the effectiveness of zinc oxide adequately

demonstrate that at a 2 to 25 percent concentration it provides

protection against UVB radiation.

In the proposed rule for OTC sunscreen drug products, the agency

stated that a 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, April

5, 1994) to discuss such testing procedures.

Although the agency continues to evaluate data and information for

the purpose of proposing a monograph method for determining UVA

radiation protection, it nevertheless finds there is ample data

demonstrating that zinc oxide provides protection against UVA

radiation. 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 the UVA protection

factor method described above (Ref. 1), and those methods described by

R. W. Gange et al. (Ref. 25) and N. J. Lowe et al. (Ref. 26) as

adequate for determining the UVA radiation protection potential of a

finished OTC sunscreen drug product.

Based upon the Panel's evaluation of zinc oxide as a skin

protectant and the long history of use of zinc oxide in various drug

and cosmetic products, the agency continues to believe that there are

no safety concerns regarding the use of zinc oxide as a sunscreen

active ingredient in concentrations up to 25 percent. In addition, the

agency believes at this time that zinc oxide can be combined with any

one or more of the other Category I sunscreen ingredients in

Sec. 352.10 of the proposed rule with the exception of avobenzone. The

agency is currently reviewing data and information in support of the

use of zinc oxide and avobenzone in combination (Ref. 27) and will make

a decision when its review is completed.

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 tentatively concluded that

minimum concentration requirements are necessary for combination

sunscreen drug products (i.e., until a method is developed that can

demonstrate the contribution of each OTC sunscreen ingredient in a

combination product). The agency received a number of comments on this

position. The agency is currently evaluating these comments and will

address them in the final monograph.

At this time, the agency considers the data submitted by the

comments as supportive of the safety and effectiveness of up to 25

percent zinc oxide alone (if the finished product provides at least an

SPF 2) and 2 to 25 percent zinc oxide in combination with any one or

more of the other Category I sunscreen ingredients (except avobenzone)

at the concentrations for permitted combinations of sunscreen active

ingredients in proposed Sec. 352.20 (58 FR 28194 at 28295).

Accordingly, the agency is proposing to amend the proposed monograph

for OTC sunscreen drug products to include zinc oxide in Secs. 352.10

and 352.20.

D. Enforcement Status

The Panel did not consider zinc oxide as a sunscreen active

ingredient alone or in combination products. The agency is not aware of

any OTC sunscreen drug products currently marketed with zinc oxide as

the sole sunscreen ingredient. The agency is aware that there are a

number of combination sunscreen drug products that contain zinc oxide.

An FDA Compliance Policy Guide (CPG) (Ref. 28) addresses the

marketing of OTC drug products containing combinations of ingredients.

Under this guide, FDA's stated policy is that OTC drug combinations

that were commercially marketed in the United States on or before May

11, 1972, and that are not subject to a final monograph, should not be

considered for regulatory action on the basis of suspected labeling

deficiencies unless the deficiency constitutes a potential hazard to

health. For OTC combination drug products that were not marketed on or

before May 11, 1972, and have not been considered by an OTC advisory

review panel, the CPG states that the agency may propose to include the

combination in a final monograph. However, marketing of such a product

generally may not proceed until after the comment period has ended on

the proposal and a subsequent notice is published in the Federal

Register setting forth the agency's determination concerning interim

marketing.

The agency is aware that a number of sunscreen combination drug

products containing zinc oxide have entered the market place during the

pendency of the rulemaking for OTC sunscreen drug products. Based upon

the Panel's favorable evaluation of zinc oxide as a skin protectant and

zinc oxide's long history of safe use at comparable levels in various

drug and cosmetic products. Because these products are currently being

marketed and provide a significant health benefit to consumers, the

agency sees no reason to restrict other products from entering the

marketplace until the agency publishes a subsequent Federal Register

notice to permit interim marketing. Accordingly, the agency, by this

notice, has determined that it is appropriate at this time to allow the

interim marketing of the OTC zinc oxide-containing products identified

in proposed Secs. 352.10 and 352.20. The agency is considering amending

the CPG (Ref. 28) in the future to address special situations such as

this one.

Products containing zinc oxide require both UVA radiation

protection testing (as discussed in section II. C. of this document)

and SPF testing of the finished product, as proposed in subpart D of

the proposed monograph for OTC sunscreen drug products (58 FR 28194 at

28298 to 28301). If the products contain UVA claims in their labeling,

then they must be marketed with the labeling proposed in Sec. 352.52 in

this document. Products covered by this monograph amendment may be

marketed pending issuance of the final monograph for this drug class,

subject to the risk that the agency may adopt a different position in

the final monograph that could require reformulation and/or relabeling,

recall or other regulatory action. Marketing of such products with UVA

labeling claims not in accord with the labeling proposed in this

document may also result in regulatory action against the product, the

marketer, or both. The final monograph for OTC sunscreen drug products

will establish the final

[[Page 56588]]

formulation, labeling, and testing requirements for such products.

E. Labeling

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 zinc oxide may

include under their ``Indications'' or ``Uses'' 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'')

``within 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. Comments No. RPT5 and CR7, Docket No. 78N-0038, Dockets

Management Branch.

2. Comments No. C131, C352, and SUP21, Docket No. 78N-0038,

Dockets Management Branch.

3. Comments No. C140, C350, C513, and LET145, Docket No. 78N-

0038, Dockets Management Branch.

4. Comment No. C351, Attachment III, Docket No. 78N-0038,

Dockets Management Branch.

5. Catlow, B., ``Formulating with Ultrafine TiO2,''

Seifen Oele Fette Wachse, 119:497-500, 1994.

6. Alexander, P., ``Ultrafine Titanium Dioxide Makes the

Grade,'' Manufacturing Chemist, 62:21,23, 1991.

7. Brown, M. W., and E. Galley, ``Testing UVA and UVB Protection

from Microfine Titanium Dioxide,'' Cosmetics and Toiletries, 105:69-

73, 1990.

8. Sayre, R. et al., ``Physical Sunscreens,'' Journal of the

Society of Cosmetic Chemists, 41:103-109, 1990.

9. Fox, M. A., ``Mechanistic Photocatalysis in Organic

Synthesis,'' in Photocatalysis: Fundamentals and Applications, John

Wiley & Sons, New York, pp. 421-455, 1989.

10. Russell, J. et al., ``The Assessment of the OH Scavenging

Action of Therapeutic Agents,'' Journal of Pharmaceutical and

Biomedical Analysis, 12:863-866, 1994.

11. Harbour, J. H., J. Tromp, and M. L. Hair, ``Photogeneration

of Hydrogen Peroxide in Aqueous Ti02 Dispersions,''

Canadian Journal of Chemistry, 63:204-208, 1985.

12. Rao, M. V. et al., ``Photosynthesis Production of

H2 and H202 on Semiconducting Oxide

Grains in Aqueous Solutions,'' Journal of Physical Chemistry,

84:1987-91, 1980.

13. Schwitzgebel, J. et al., ``Role of Oxygen Molecule and the

Photogenerated Electron in Ti02-Photocatalyzed

Air Oxidation Reactions,'' Journal of Physical Chemistry, 99:5633-

38, 1995.

14. Hidaka, H. et al., ``Photodegradation of Surfactants. XV:

Formation of SO42- Ions in the Photooxidation

of Sulfur-Containing Surfactants,'' Chemosphere, 29:2619-2624, 1994.

15. Minero, C. et al., ``Photocatalyzed Transformation of

Nitrobenzene on Ti02 and Zn0,'' Chemosphere, 28:1229-

1244, 1994.

16. Dieckmann, M. S., K. A. Gray, and P. V. Kamat,

``Photocatalyzed Degradation of Adsorbed Nitrophenolic Compounds on

Semiconductor Surfaces,'' Water Science Technology, 25:277-279,

1992.

17. Mak, M. K. S., and S. T. Hung, ``Degradation of Neat and

Commercial Samples of Organophosphate Pesticides in Illuminated

Ti02 Suspensions,'' Toxicology and Environmental

Chemistry, 36:155-168, 1992.

18. Borello, R. et al., ``Photocatalytic Degradation of DDT

Mediated in Aqueous Semiconductor Slurries by Simulated Sunlight,''

Environmental Toxicology and Chemistry, 8:997-1002, 1989.

19. Heller, A., ``Chemistry and Applications of Photocatalytic

Oxidation of Thin Organic Films,'' Accounts of Chemistry Research,

28:503-508, 1995.

20. Anonymous, ``Formulators Fine-Tune Ti02-Based

Screens,'' Manufacturing Chemist, 64:26-29, 1993.

21. Tichy, S., ``Transparent Ti02 for UV

Protection,'' Seifen Oele Fette Wachse, 118:612-620, 1992.

22. Ortyl, T. T., and G. E. Peck, ``Surface Charge of Titanium

Oxide and Its Effect on Dye Adsorption and Aqueous Suspension

Stability,'' Drug Development and Industrial Pharmacy, 17:2245-2268,

1991.

23. Macleod, T. M., and W. Fran-Bell, ``Study of Physical Light

Screening Agents,'' British Journal of Dermatology, 92:149-156,

1975.

24. Comment No. TR3, Docket No. 78N-0038, Dockets Management

Branch.

25. Gange, R. W. et al., ``Efficacy of a Sunscreen Containing

Butyl Methoxydibenzoylmethane Against Ultraviolet A Radiation in

Photosensitized Subjects,'' Journal of the American Academy of

Dermatology, 15:494-499, 1986.

26. 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.

27. Comment No. CP8, Docket No. 78N-0038, Dockets Management

Branch.

28. ``Food and Drug Administration Compliance Policy Guide

7132b.16,'' in OTC Vol. 06ATFM, Docket No. 78N-0038, Dockets

Management Branch.

IV. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).

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). Under the Regulatory

Flexibility Act, if a rule has a significant economic impact on a

substantial number of small entities, an agency must analyze regulatory

options that would minimize any significant impact of the rule on small

entities.

Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et

seq.) requires that agencies prepare a written statement and economic

analysis before proposing any rule that may result in an expenditure in

any 1 year by State, local, and tribal governments, in the aggregate,

or by the private sector, of $100 million (adjusted annually for

inflation).

The agency believes that this proposed rule is consistent with the

principles set out in the Executive Order and these two statutes. The

purpose of this proposed rule is to add a new ingredient, combinations

of ingredients, and labeling for OTC sunscreen drug products that

contain zinc oxide and to allow manufacturers to market zinc oxide-

containing sunscreen drug products under the OTC drug monograph system,

which 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.

Some manufacturers of currently marketed products may incur costs

to relabel their products should they wish to include the new labeling

information. Such information may increase product sales because of the

broader uses information being allowed. The agency has been informed

that relabeling costs of the type required by this proposed rule

generally average about $2,000 to $3,000 per stock keeping unit (SKU)

(individual products, packages, and sizes). The agency is aware of 16

manufacturers that together produce less than 100 SKU's of OTC

sunscreen drug products containing zinc oxide. There may be a few

additional small manufacturers or products in the marketplace that are

not identified in the sources FDA reviewed. Manufacturers who wish to

include the new labeling may elect to relabel their products at the

next scheduled labeling printing. Assuming that there are about 100

affected OTC SKU's in the marketplace, total one-time costs of

relabeling would be $200,000 to $300,000 if all of the products were

[[Page 56589]]

relabeled. The agency believes the actual cost could be lower because

some manufacturers may not elect to relabel their products at this time

and some of the label changes will be made by private label

manufacturers that tend to use simpler and less expensive labeling. In

addition, there should be minimal waste of existing labeling for any

manufacturer who elects to relabel at this next labeling printing.

Manufacturers who wish to enter the marketplace with a new zinc oxide

sunscreen combination product will incur the standard costs that all

manufacturers have when introducing a new product.

The agency considered but rejected several alternatives: (1) A

delayed marketing period, and (2) an exemption from coverage for small

entities. The delayed marketing period was rejected because similar

products currently exist in the marketplace. The agency does not

consider an exemption for small entities appropriate because consumers

who use these manufacturers' products would not have appropriate

products for safe and effective use.

This analysis shows that this proposed rule is not economically

significant under Executive Order 12866 and that the agency has

undertaken important steps to reduce the burden to small entities.

Nevertheless, some entities could incur some impacts, especially

private label manufacturers that provide labeling for a number of

affected products. Thus, this economic analysis, together with other

relevant sections of this document, serves as the agency's initial

regulatory flexibility analysis, as required under the Regulatory

Flexibility Act. Finally, this analysis shows that the Unfunded

Mandates Reform Act does not apply to the proposed rule because it

would not result in an expenditure in any 1 year by State, local, and

tribal governments, in the aggregate, or by the private sector, of $100

million.

V. 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)).

VI. Environmental Impact

The agency has determined under 21 CFR 25.31(c) 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.

VII. Public Comment

Interested persons may, on or before January 20, 1999, submit

written comments to the Dockets Management Branch (address above).

Written comments on the agency's economic impact determination may be

submitted on or before January 20, 1999. 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 in 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) and amended in the Federal Register of September

16, 1996 (61 FR 48645)) be amended as follows:

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

1. The authority citation for 21 CFR part 352 is revised to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

2. Section 352.10 is amended by adding paragraph (v) to read as

follows:

Sec. 352.10 Sunscreen active ingredients.

* * * * *

(v) Zinc oxide up to 25 percent.

3. Section 352.20 is amended by revising paragraphs (a)(1) and

(a)(3)(xxi) to read as follows:

Sec. 352.20 Permitted combinations of active ingredients.

(a) * * *

(1) Two or more sunscreen active ingredients identified in

Sec. 352.10(a), and (c) through (v) 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) * * *

(xxi) Zinc oxide 2 to 25 percent.

* * * * *

4. Section 352.52 is amended by adding paragraph (b)(2)(vii) to

read as follows:

Sec. 352.52 Labeling of sunscreen drug products.

* * * * *

(b) * * *

(2) * * *

(vii) For products containing the active ingredient identified in

Sec. 352.10(v), 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'') ``within the UVA spectrum.''

(E) ``Provides protection from the UVA rays that may contribute to

skin damage and premature aging of the skin.''

Dated: October 10, 1998.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 98-28274 Filed 10-21-98; 8:45 am]

BILLING CODE 4160-01-F