[Federal Register Volume 63, Number 204 (Thursday, October 22, 1998)]
[Proposed Rules]
[Pages 56584-56589]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-28274]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 352

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


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

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 
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