[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