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

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