[Federal Register Volume 61, Number 159 (Thursday, August 15, 1996)]
[Proposed Rules]
[Pages 42398-42401]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-20856]


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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


Discussion of the Photochemistry and Photobiology of Sunscreens; 
Public Meeting and Reopening of the Administrative Record

AGENCY: Food and Drug Administration, HHS.

ACTION: Notification of public meeting and reopening of the 
administrative record.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
meeting to obtain data and information on the photochemistry and 
photobiology of sunscreens. Meeting attendees are invited to address 
issues described in this notice. In addition, FDA is reopening the 
administrative record for the proposed rulemaking for over-the-counter 
(OTC) sunscreen drug products to allow for comment on matters 
considered in this notice and at the meeting. This meeting is part of 
the ongoing review of OTC drug products conducted by FDA.
DATES: The meeting will be held on September 19 and 20, 1996, 8:30 a.m. 
Submit notice of participation by September 6, 1996. Submit comments 
regarding matters discussed in this notice or raised at the meeting by 
December 6, 1996. The administrative record will remain open until 
December 6, 1996.

ADDRESSES: Submit notice of participation, and written comments to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. The meeting will be 
held at the Doubletree Hotel, Plaza I and II, 1750 Rockville Pike, 
Rockville, MD 20852, 301-468-1100.

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, FAX 301-827-2316.

SUPPLEMENTARY INFORMATION:

I. Background

    The agency believes that the use of sunscreen products is helpful 
as a component of a regimen for sun protection. A joint panel of the 
American Academy of Dermatology and the Centers for Disease Control and 
Prevention recently recommended the use of sunscreen products in 
addition to limiting exposure to ultraviolet (UV) radiation, wearing 
protective clothing, avoiding artificial tanning devices, and seeking 
shade when your shadow is shorter than your height (Ref. 1).
    The agency is not at this time proposing to amend the tentative 
final monograph for OTC sunscreen drug products published on May 12, 
1993 (58 FR 28194), and this notice does not intend to imply concerns 
about sunscreen agents as a class. However, recent scientific advances 
in understanding of the photochemistry and photobiology of sunscreen 
active ingredients have raised issues for discussion regarding use of 
sunscreen ingredients singly and in combinations; specifically, about 
zinc oxide and titanium dioxide. The agency is seeking to incorporate 
these recent scientific advances into the base of regulatory 
information supporting the final monograph for OTC sunscreen drug 
products.

II. Request for Data and Information

A. Photostability and photobiology of titanium dioxide and zinc oxide

    In the Federal Register of August 25, 1978 (43 FR 38206), the 
agency published an advance notice of proposed rulemaking to establish 
a monograph for OTC sunscreen drug products based on the report and 
recommendations of the Advisory Review Panel on OTC Topical Analgesic, 
Antirheumatic, Otic, Burn,

[[Page 42399]]

and Sunburn Prevention and Treatment Drug Products (the Panel). In its 
report (43 FR 38206 at 38250), the Panel stated that titanium dioxide 
is recognized as an effective opaque chemical for use as a physical 
sunscreen because it reflects and scatters both UV (290 to 400 
nanometers (nm)) and visible light (400 to 700 nm) radiation, rather 
than absorbing the rays, thereby providing a barrier for sun-sensitive 
individuals. The Panel concluded that titanium dioxide was both safe 
and effective for sunscreen use. The Panel classified zinc oxide as an 
inactive ingredient (43 FR 38206 at 38208) and did not review it for 
safety and effectiveness.
    In the tentative final monograph for OTC sunscreen drug products 
(58 FR 28194), the agency concurred with the Panel's recommendation on 
titanium dioxide and proposed to classify it as a Category I (generally 
recognized as safe and effective) sunscreen used alone or in 
combination with other Category I sunscreens (58 FR 28194 at 28295 to 
28296). The agency reviewed the data on zinc oxide that had been 
submitted to the Panel (one study) and other available data and 
concluded that the data were insufficient to determine effectiveness. 
The agency classified zinc oxide as a Category III (available data are 
insufficient to classify as safe and effective and further testing is 
required) sunscreen (58 FR 28194 at 28213). The agency is currently 
evaluating additional effectiveness data to support Category I status 
for zinc oxide in the final monograph for OTC sunscreen drug products.
    There has been a renewed interest in incorporating titanium dioxide 
and zinc oxide in sunscreen formulations because these ingredients may 
confer protection for a broad range of the UV spectrum. In addition, 
ultra-fine forms of these ingredients have been developed that are more 
esthetically pleasing (Refs. 2, 3, and 4).
    Sunscreens have been generally classified as chemical (organic) or 
physical (inorganic), depending on whether they absorb specific 
wavelength bands of UV radiation or reflect and scatter UV radiation. 
Although titanium dioxide and zinc oxide have been described as 
chemically inert ingredients that attenuate through reflection and 
scattering, new data and information indicate that they also absorb UV 
radiation, as well as scatter visible light (Ref. 5). Various authors 
(Refs. 5 through 10) 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 titanium dioxide and 
zinc oxide are irradiated with light containing energy greater than the 
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, titanium dioxide and 
zinc oxide have been used as photocatalysts to degrade organic 
substances and pesticides in the environment (Refs. 11 through 15). In 
addition, titanium dioxide is being currently developed as a 
photooxidative self-cleaning and/or biocidal coating for industrial 
surfaces (Ref. 16).
    In vitro, it has been demonstrated that titanium dioxide in the 
presence of UV radiation can be cytotoxic to certain cancer cells (HeLa 
cells and T-24 human bladder cancer cells) even though titanium dioxide 
or UV radiation alone were nontoxic under study conditions (Refs. 17 
and 18). Because these cells are transformed cell lines and are not 
normal human cells, the relevance of these in vitro findings to 
sunscreen use by humans (i.e., in sunlight) is not known for zinc oxide 
and titanium dioxide.
    Mineral components, particle size, surface area, crystalline 
structure, particle coatings, pH of the medium, differences in the 
refractive index of medium, and other properties of the formulation may 
affect the photocatalyst properties of titanium dioxide (Refs. 2 
through 5 and 19 through 22). These characteristics are not mentioned 
in the United States Pharmacopeia (USP) compendial monographs, which 
contain no discussion of trace ions that may affect the absorption band 
gap between the valence and conduction bands or electronic energy 
levels, e.g., the range of wavelengths that are absorbed.
    The agency would like to receive information and data that address 
the following issues: (1) Characterize the potential systemic 
absorption and long-term safety of the topical application of titanium 
dioxide and/or zinc oxide in sunscreen drug products; (2) ascertain 
whether titanium dioxide and/or zinc oxide in sunscreen drug products 
can, under conditions of combination with certain ingredients, time, 
temperature, and/or exposure to water, photocatalyze. If so, determine 
whether this occurs at a rate such that the effectiveness of the 
sunscreen drug products would be significantly reduced; and (3) 
determine whether current compendial monograph specifications are 
sufficient to ensure manufacture of safe and effective titanium dioxide 
and/or zinc oxide in sunscreen drug products.

B. Photochemistry and photobiology of sunscreen ingredients alone and 
in combination

    In the advance notice of proposed rulemaking for OTC sunscreen drug 
products (43 FR 38206), the Panel recommended that 21 ingredients be 
considered generally recognized as safe and effective as OTC 
sunscreens. Based on the available data, the Panel determined that 
these sunscreens could be used alone or in any combination (without 
reference to final formulation) as long as the finished product has a 
minimum sun protectant factor (SPF) of 2. For the majority of these 
ingredients, the available data consisted of short-term animal and 
human toxicity studies on individual ingredients in the absence of UV 
radiation.
    In the tentative final monograph for OTC sunscreen drug products 
(58 FR 28194), the agency concurred with most of the Panel's 
recommendations and classified 20 of the 21 ingredients as Category I 
sunscreens when used alone or in combination with other Category I 
sunscreens (58 FR 28194 at 28295 to 28296). Padimate A was classified 
as Category II (concentrations 5 percent or higher) and Category III 
(concentrations less than 5 percent) on the basis of data and 
information on its phototoxicity that was not available to the Panel at 
the time of its review (58 FR 28194 at 28211).
    Consumers' increased awareness of the need to protect themselves 
against the harmful effects of both UVA (320 to 400 nm) and UVB (290 to 
320 nm) radiation has created a demand for sunscreen products with 
higher SPF's and better broad-spectrum (290 to 400 nm) protection of 
longer duration. Manufacturers have responded by creating products with 
higher SPF's that claim to provide protection against both UVA and UVB 
radiation. Manufacturing products with such characteristics often 
requires that the products contain combinations of several Category I 
sunscreen ingredients (usually three or more) that absorb over 
different parts of the UV spectrum.
    The agency is interested in the photostability of sunscreen 
ingredients and the effects that a lack of stability could have on 
these sunscreen products. Some sunscreen ingredients may undergo 
photodegradation (Refs. 23 through 29), producing byproducts which may 
affect product safety or effectiveness (Refs. 30 through 35). 
Photodegradation of some active sunscreen ingredients may occur in the 
presence of certain inactive ingredients (Refs. 36 and 37).

[[Page 42400]]

    Therefore, the agency is interested in photostability methodologies 
for sunscreen ingredients. The agency would like to know how to test 
the photostability of sunscreen ingredients and to characterize 
potential byproducts in sunscreen product combinations and in different 
formulations.
    The agency is interested in data and information on the following 
issues: (1) The potential of active sunscreen ingredients, alone and in 
combination, to interact in the presence of UV radiation and/or certain 
inactive ingredients; (2) characterization of potential byproducts of 
such interactions and description of impact, if any, on safety or 
effectiveness of final sunscreen formulations; and (3) descriptive 
measurement methods and characterization of local or possible systemic 
effects in vivo.
    The agency has concluded that it would be in the public interest to 
hold a public meeting, in accordance with 21 CFR 10.65, to discuss the 
issues associated with the photochemistry and photobiology of 
sunscreens. The proposed rulemaking for OTC sunscreen drug products 
involves 21 CFR parts 352, 700, and 740; however, the discussion at the 
public meeting will be limited to proposed part 352, i.e., sunscreens 
for use as OTC drugs.
    Any individual or group interested in making a presentation at the 
meeting should contact Donald Dobbs (address above). Presentations 
should only address the issues listed in this notice. Persons 
interested in participating in the meeting must also send a notice of 
participation on or before September 6, 1996, to the Dockets Management 
Branch (address above). All notices of participation submitted should 
be identified with the docket number found in brackets in the heading 
of this notice and should contain the following information: Name, 
address, telephone number, business affiliation, if any, of the person 
desiring to make a presentation, summary of the presentation, and the 
approximate amount of time requested for the presentation.
    Groups having similar interests are requested to consolidate their 
comments and present them through a single representative. Depending on 
the time available and the number of participants, FDA may require 
joint presentations by persons with common interests. After reviewing 
the notices of participation, FDA will notify each participant of the 
schedule and time allotted to each person.
    The administrative record for the OTC sunscreen drug products 
rulemaking is being reopened to specifically allow for comments on 
matters raised in this notice and at the meeting. The agency requests 
data and information regarding the photochemistry and photobiology of 
sunscreens from any interested person. Any individual or group may, on 
or before December 6, 1996, submit to the Dockets Management Branch 
(address above), comments and data specifically limited and relevant to 
the issues in this notice or addressed at the meeting. Two copies of 
any comments are to be submitted, except that individuals may submit 
one copy. All comments are to be identified with the docket number 
found in brackets in the heading of this document. The administrative 
record will remain open until December 6, 1996.

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. Goldsmith, L., et al., ``Proceedings from the National 
Conference to Develop a National Skin Cancer Agenda,'' Journal of 
the American Academy of Dermatology, 34:822-3, 1996.
    2. Catlow, B., ``Formulating With Ultrafine TiO2,'' Seifen 
Oele Fette Wachse, 119:497-500, 1993.
    3. Alexander, P., ``Ultrafine Titanium Dioxide Makes the 
Grade,'' Manufacturing Chemist, 62:21,23, 1991.-
    4. Brown, M. W., and E. Galley, ``Testing UVA and UVB Protection 
from Microfine Titanium Dioxide,'' Cosmetics and Toiletries, 105:69-
73, 1990.
    5. Sayre, T., et al., ``Physical Sunscreens,'' Journal of the 
Society of Cosmetic Chemists, 41:103-109, 1990.
    6. Fox, M. A., ``Mechanistic Photocatalysis in Organic 
Synthesis,'' ``Photocatalysis: Fundamentals and Applications,'' John 
Wiley & Sons, New York, NY, pp. 421-455, 1989.
    7. Russell, J., et al., ``The Assessment of the OH Scavenging 
Action of Therapeutic Agents,'' Journal of Pharmaceutical & 
Biomedical Analysis, 12:863-866, 1994.
    8. Harbour, J. H., J. Tromp, and M. L. Hair, ``Photogeneration 
of Hydrogen Peroxide in Aqueous TiO2 Dispersions,'' Canadian Journal 
of Chemistry, 63:204-208, 1985.
    9. Rao, M. V., et al., ``Photosynthesis Production of H2 
and H2O2 on Semiconducting Oxide Grains in Aqueous 
Solutions,'' Journal of Physical Chemistry, 84:1987-91, 1980.
    10. Schwitzgebel, J., et al., ``Role of Oxygen Molecule and the 
Photogenerated Electron in TiO2-Photocatalyzed Air Oxidation 
Reactions,'' Journal of Physical Chemistry, 99:5633-38, 1995.
    11. Hidaka, H., et al., ``Photodegradation of Surfactants. XV: 
Formation of SO42-Ions in the Photooxidation of Sulfur-
Containing Surfactants,'' Chemosphere, 29:2619-2624, 1994.
    12. Minero, C., et al., ``Photocatalyzed Transformation of 
Nitrobenzene on TiO2 and ZnO,'' Chemosphere, 28:1229-1244, 
1994.
    13. 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.
    14. Mak, M. K. S., and S. T. Hung, ``Degradation of Neat and 
Commercial Samples of Organophosphate Pesticides in Illuminated 
TiO2 Suspensions,'' Toxicology and Environmental Chemistry, 
36:155-168, 1992.
    15. Borello, R., et al., ``Photocatalytic Degradation of DDT 
Mediated in Aqueous Semiconductor Slurries by Simulated Sunlight,'' 
Environmental Toxicology and Chemistry, 8:997-1002, 1989.
    16. Heller, A., ``Chemistry and Applications of Photocatalytic 
Oxidation of Thin Organic Films,'' Accounts of Chemistry Research, 
28:503-508, 1995.
    17. Cai, R., et al., ``Induction of Cytotoxicity by Photoexcited 
TiO2 Particles,'' Cancer Research, 52:2346-2348, 1992.
    18. Kubota, Y., et al., ``Photokilling of T-24 Human Bladder 
Cancer Cells With Titanium Dioxide,'' British Journal of Cancer, 
70:1107-1111, 1994.
    19. Anonymous, ``Formulators Fine-Tune Ti02-Based 
Screens,'' Manufacturing Chemist, 64:26,27,29, 1993.
    20. Tichy, S., ``Transparent TiO2 for UV Protection,'' 
Seifen Oele Fette Wachse, 118:612-620, 1992.
    21. 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.
    22. Macleod, T. M., and W. Fran-Bell, ``Study of Physical Light 
Screening Agents,'' British Journal of Dermatology, 92:149-156, 
1975.
    23. Roscher, N. M., et al., ``Photodecomposition of Several 
Compounds Commonly Used as Sunscreen Agents'' Journal of 
Photochemistry, Photobiology, and Chemistry, 80:417-21, 1994.
    24. Comment SUP20, Docket No. 78N-0038, Dockets Management 
Branch.
    25. Deflandre, A., and G. Lang, ``Photostability Assessment of 
Sunscreens; Benzylidene Camphor and Dibenzoylmethane Derivatives,'' 
International Journal of Cosmetic Science, 10:53-62, 1988.
    26. Flindt-Hansen, H., C. J. Nielsen, and P. Thune, 
``Measurements of the Photodegradation of PABA and Some PABA 
Derivatives,'' Photodermatology, 5:257-261, 1988.
    27. Stenberg, C., T. Mellstrand, and O. Larko, ``Stability of 
PABA after UV Radiation In Vivo and In Vitro,'' Photodermatology, 
4:201-204, 1987.
    28. Gasparro, F. P., ``UV-Induced Photo Products of Para-
Aminobenziod Acid,'' Photodermatology, 2:151-157, 1985.
    29. Broadbent, J. K., et al., ``Capillary Supercritical Fluid 
Chromatography Combined With Atmospheric Pressure Chemical 
Ionisation Mass Spectrometry for the Investigation of Photoproduct 
Formation in the Sunscreen Absorber 2-Ethylhexyl-p-

[[Page 42401]]

 Methoxycinnamate,'' Journal of Chromatography A, 732:101-110, 1996.
    30. Schallreuter, K. U., et al., ``Oxybenzone Oxidation 
Following Solar Irradiation of Skin: Photoprotection Verses 
Antioxidant Inactivation,'' Journal of Investigative Dermatology, 
106:583-586, 1996.
    31. Gasparro, F. P., ``The Molecular Basis of UV-Induced 
Mutagenicity of Sunscreens,'' FEBS letters, 336:184-185, 1993.
    32. Knowland, J. S., ``Reply of Dr. Knowland to Gasparro's 
Comment,'' FEBS letters, 336:186, 1993.
    33. Knowland, J., et al., ``Sunlight-Induced Mutagenicity of a 
Common Sunscreen Ingredient'' FEBS letters, 324:309-313, 1993.
    34. Shimoi, K., et al., ``Enhancing Effects of Cinoxate and 
Methyl Sinapate on the Frequencies on Sister-Chromatid Exchanges and 
Chromosome Aberrations in Cultured Mammalian Cells,'' Mutation 
Research, 212:213-221, 1989.
    35. Gallagher, C. H., et al., ``Ultraviolet Carcinogenesis in 
the Hairless Mouse Skin; Influence of the Sunscreen 2-Ethylhexyl-P-
Methoxycinnamate,'' Australian Journal of Experimental Biology & 
Medical Science, 62:577-588, 1984.
    36. Shaath, N. A., H. M. Fares, and K. K. Klien, 
``Photodegradation of Sunscreen Chemicals: Solvent Considerations,'' 
Cosmetics & Toiletries, 105:41-44, 1990.
    37. Agrapidis-Paloympis, L. E., R. A. Nash, and N. A. Shaath, 
``The Effect of Solvents on the Ultraviolet Absorbance of 
Sunscreens,'' Journal of the Society of Cosmetic Chemists, 38:209-
221, 1987.

    Dated: August 9, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-20856 Filed 8-14-96; 8:45 am]
BILLING CODE 4160-01-F