56584 Federal Register / Vol. 63, No. 204 / Thursday, October 22, 1998 / Proposed Rules at the FAA, Central Region, Office of the ADDRESSES: Submit written comments the effectiveness of as a Regional Counsel, Room 1558, 601 E. 12th to the Dockets Management Branch ingredient. Street, Kansas City, Missouri 64106. (HFA–305), Food and Drug In the proposed rule, the agency also Issued in Kansas City, Missouri, on Administration, 5630 Fishers Lane, rm. discussed the public health significance October 14, 1998. 1061, Rockville, MD 20852. of A (UVA) radiation and the Michael Gallagher, FOR FURTHER INFORMATION CONTACT: characteristics and proposed labeling of Manager, Small Airplane Directorate, Aircraft Donald Dobbs, Center for Drug OTC sunscreen drug products that claim Certification Service. Evaluation and Research (HFD–560), to provide protection from UVA [FR Doc. 98–28276 Filed 10–21–98; 8:45 am] Food and Drug Administration, 5600 radiation (58 FR 28194 at 28232 and BILLING CODE 4910±13±U Fishers Lane, Rockville, MD 20857, 28233). Testing procedures for 301–827–2222. sunscreen drug products with UVA radiation protection claims were SUPPLEMENTARY INFORMATION: DEPARTMENT OF HEALTH AND discussed in the proposed rule (58 FR HUMAN SERVICES I. Background 28194 at 28248 to 28250) and at a public In the Federal Register of August 25, meeting on May 12, 1994 (as noted in Food and Drug Administration 1978 (43 FR 38206), FDA published, the Federal Register of April 5, 1994 (59 FR 16042)). 21 CFR Part 352 under § 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance notice of In response to the proposed rule, four [Docket No. 78N±0038] proposed rulemaking to establish a manufacturers submitted data to monograph for OTC sunscreen drug support the effectiveness of zinc oxide RIN 0910±AA01 products. Proposed § 352.10 listed the as an OTC sunscreen active ingredient active ingredients to be generally for both ultraviolet B (UVB) and UVA Sunscreen Drug Products for Over-the- protection. Copies of the comments Counter Human Use; Amendment to recognized as safe and effective for use in these products. The Advisory Review received are on public display in the the Tentative Final Monograph; Dockets Management Branch (address Enforcement Policy Panel on OTC Topical Analgesic, Antirheumatic, Otic, Burn, and above). The four comments requested AGENCY: Food and Drug Administration, Prevention and Treatment Drug that the agency reclassify zinc oxide HHS. Products (the Panel) reviewed zinc from Category III to Category I status. ACTION: Notice of proposed rulemaking. oxide as both a sunscreen and skin II. The Agency’s Evaluation of the protectant. The Panel classified zinc Comments and Other Data SUMMARY: The Food and Drug oxide at concentrations of 1 to 25 Administration (FDA) is issuing a notice percent as a Category I skin protectant A. Effectiveness of Zinc Oxide of proposed rulemaking that amends the (43 FR 34628 at 34648, August 4, 1978). 1. Several comments evaluated the tentative final monograph (proposed Although zinc oxide was a labeled effectiveness of zinc oxide as a rule) for over-the-counter (OTC) ingredient in a marketed sunscreen sunscreen active ingredient in various sunscreen drug products. This product, the Panel classified zinc oxide formulations utilizing the sun amendment would establish conditions as an inactive ingredient (43 FR 38206 protection factor (SPF) test method in under which products containing zinc at 38208). the Panel report (43 FR 38206 at 38265 oxide as a sunscreen active ingredient In the Federal Register of May 12, and 38266). Using the testing are generally recognized as safe and 1993 (58 FR 28194), FDA published a procedures in the proposed rule (58 FR effective and not misbranded at notice of proposed rulemaking (tentative 28194 at 28298), the agency recalculated concentrations of up to 25 percent alone final monograph) for OTC sunscreen the SPF test results (as stated in the and 2 to 25 percent in combination with drug products. The agency discussed a tables in section II.A of this document) any proposed Category I sunscreen study submitted to the Panel using zinc after eliminating those results where the active ingredient except avobenzone. oxide alone and in combination with control was out of range. OTC marketing of such drug products is phenyl salicylate, another sunscreen Two studies evaluated the ability of being permitted pending establishment ingredient (58 FR 28194 at 28213). The zinc oxide-containing sunscreen drug under the OTC drug review of a final study was designed to measure the products to block sunburning radiation monograph covering sunscreen drug ability of zinc oxide (15 to 33.3 percent) (Ref. 1). In both studies, formulations products. This proposal is part of the to absorb ultraviolet (UV) radiation over containing either 4 percent or 25 ongoing review of OTC drug products a broad range of wavelengths. The percent zinc oxide, 2 percent conducted by FDA. agency concluded that the data were not (a proposed Category I DATES: Submit written comments by adequate to determine the effectiveness sunscreen ingredient (58 FR 28194 at January 20, 1999; written comments on of zinc oxide because the effectiveness 28295)), and a placebo were tested. The the agency’s economic impact data for zinc oxide used alone were vehicles consisted of commonly utilized determination by January 20, 1999. FDA limited to one subject. Therefore, the oils and emulsifiers and varied only in is proposing that any final rule based on agency classified zinc oxide in Category the concentration of the active this proposal become effective 12 III (available data are insufficient to ingredients and the amount of purified months after its date of publication in determine safety or effectiveness) (58 FR water. The results of these studies were the Federal Register. 38213) and requested data to support as follows:

TABLE 1.ÐSPF TEST DETERMINATIONS FOR FOUR FORMULATIONS

Test SPF Sunscreen Anticipated SPF Test SPF (Study 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 Federal Register / Vol. 63, No. 204 / Thursday, October 22, 1998 / Proposed Rules 56585

TABLE 1.ÐSPF TEST DETERMINATIONS FOR FOUR FORMULATIONSÐContinued

Test SPF Sunscreen Anticipated SPF Test SPF (Study 1) (Study 2)

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- sunscreen active ingredient in providing contained 11 percent octyl palmatate, percent zinc oxide formulation provides protection against sunburning radiation. 7.5 percent volatile silicone DC–245, more protection against sunburning Formulations containing 15 percent and 53.3 percent deionized water; the radiation than does the placebo. and 20 percent zinc oxide were tested 20-percent zinc oxide formulation However, as expected, the 25-percent against a control containing no zinc contained 9 percent octyl palmatate, 6.5 zinc oxide formulation provides the oxide (Ref. 2). The 3 formulations percent volatile silicone DC–245, and most protection against sunburning contained the same 12 ingredients at the 51.3 percent deionized water; and the radiation. The agency believes that these same concentrations except for the placebo contained 17 percent octyl results demonstrate the effectiveness of active ingredient, two inactive palmatate, 7.5 percent volatile silicone ingredients (octyl palmatate and volatile zinc oxide (up to 25 percent) as an OTC DC–245, and 62.3 percent deionized silicone DC–245), and deionized water. water. The results were as follows: The 15-percent zinc oxide formulation

TABLE 2.ÐSPF 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 Although these studies did not consistent with the effectiveness of zinc support the effectiveness of zinc oxide include a placebo, the agency believes oxide as a sunscreen active ingredient. as a sunscreen active ingredient. that the data support the effectiveness of 2. One comment (Ref. 1) measured the Five studies, done at two different 2 percent zinc oxide as a sunscreen UVA protection factor (PFA) for three laboratories, were designed to active ingredient. formulations: (1) 4 percent zinc oxide, demonstrate the effectiveness of zinc The SPF of two formulations (2) 2 percent oxybenzone, and (3) a oxide as a sunscreen active ingredient in containing 5 and 10 percent fine particle placebo. The vehicles consisted of different formulations (Ref. 3). In three size (10 to 70 nanometer (nm), average commonly utilized oils and emulsifiers studies, zinc oxide (2 percent in one 30 nm), pH neutral (7.3) zinc oxide was and varied only in the concentration of formulation and 6 percent in two studied using testing procedures that the active ingredients and the amount of formulations) was the only active purified water. The PFA values were ingredient. In two studies, zinc oxide were slightly modified by the addition determined using a modified test (2.5 percent or 7.5 percent) was of a range-finding technique (Ref. 4). method similar to the Panel’s proposed combined with (2.5 The two formulations contained the SPF test (43 FR 38206 at 38265 to percent), a proposed Category I same inactive ingredients at slightly 38266). For the PFA test method, the sunscreen ingredient (58 FR 28194 at different concentrations to account for 28295). The vehicle formulations the difference in concentration of zinc light source was modified to emit only without zinc oxide were not tested. The oxide. The results of this study were as UVA radiation (>99.2 percent). The results of the SPF testing were as follows: biological endpoint used in this test follows: method was a change in skin color, TABLE 4.ÐSPF TEST DETERMINA- either erythema (redness) or tanning TABLE 3.ÐSPF TEST DETERMINA- TIONS FOR TWO FORMULATIONS (browning) of the skin observed 16 to 24 TIONS FOR FIVE FORMULATIONS hours after the UV exposure. The lowest dose of UVA radiation that caused a Sunscreen Anticipated Test SPF Sunscreen Test SPF SPF minimally perceptible response was defined as the minimal response dose 2% Zinc oxide 2.99 5% Zinc oxide SPF 5 SPF 5.01 (MRD), which was determined for 6% Zinc oxide 6.16 10% Zinc SPF 10 SPF 9.10 unprotected skin (MRDu) and for the oxide 6% Zinc oxide 5.91 sunscreen protected skin (MRDp). The 2.5% Zinc oxide and 2.5% PFA was the ratio of (MRDp) divided by titanium dioxide 11.77 Although the vehicle formulations the (MRDu). The UVA determinations 7.5% Zinc oxide and 2.5% without zinc oxide were not tested, the titanium dioxide 20.52 for the three formulations were as agency believes that these results and follows: 56586 Federal Register / Vol. 63, No. 204 / Thursday, October 22, 1998 / Proposed Rules

TABLE 5.ÐPFA TEST DETERMINATIONS FOR THREE FORMULATIONS

Sunscreen Anticipated 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 Another comment (Ref. 2) included (Refs. 8 and 9). Various authors (Refs. 8 the 4 percent zinc oxide formulation the results of in vitro testing (‘‘Diffey and 10 through 13) have shown that was low, these results indicate that zinc method’’) of a formulation containing 15 these ingredients exhibit a oxide blocks radiation (320 to 340 nm) percent zinc oxide in a stable emulsion. semiconductor optical absorption gap. in the UVA II range. The transmittance data indicated UV They absorb most radiation at 3. Several comments submitted radiation blockage from 290 to 380 nm wavelengths shorter than the gap results of in vitro testing data. One and support the premise that zinc oxide (approximately 380 nm) and scatter comment (Ref. 1) used a Cary 2300 can protect against UV radiation, radiation at wavelengths longer than the Spectrophotometer to measure the including both UVB and UVA. gap. When zinc oxide and titanium spectral absorbance of three One comment (Ref. 3) included a dioxide are irradiated with light formulations: (1) 4 percent zinc oxide, spectral profile of attenuation for zinc containing energy greater than the band (2) 25 percent zinc oxide, and (3) 2 oxide alone in a cosmetic formulation gap (approximately 3 electron volts), an percent oxybenzone. The vehicles and from 1:1 and 3:1 combinations of electron from the valence band can be consisted of commonly utilized oils and zinc oxide and titanium dioxide. These excited to the conduction band, thus emulsifiers and varied only in the spectral profiles of zinc oxide in various creating an electron-hole pair. Because concentration of the active ingredients formulations demonstrated that zinc of these semiconductor properties, zinc and the amount of purified water. oxide as a single ingredient can provide oxide and titanium dioxide have been protection in both the UVB and UVA Albino hairless mouse stratum used as photocatalysts to degrade spectral regions. corneum/epidermis samples were organic substances and pesticides in the environment (Refs. 14 through 18). In prepared by mechanical removal of the B. Photochemistry and Photobiology of addition, titanium dioxide is being dermis using a dulled razor blade. The currently developed as a photooxidative samples were cut into 1-inch circles and Recent scientific advances in self-cleaning and/or biocidal coating for maintained in a hydrated state by understanding the photochemistry and industrial surfaces (Ref. 19). floating the samples (dermal side down) photobiology of sunscreen drug There are many formulation variables on a water bath. The absorbance of each products have raised many issues that may affect the photocatalytic skin sample was measured and regarding sunscreen active ingredients, µ capability of zinc oxide and titanium recorded. Ten microliters ( L) of including zinc oxide and titanium dioxide. Such variables include mineral sunscreen were applied to the skin dioxide. Because zinc oxide and components, particle size, surface area, substrate, allowed to dry for 15 minutes, titanium dioxide have many similar crystalline structure, particle coatings, and the absorbance measured. The physical characteristics and may be pH of the medium, differences in the absorbance of each sunscreen treated used in combination in OTC sunscreen refractive index of the medium, and sample was subtracted from the drug products, the following discussion other components in the formulation absorbance of the skin (without addresses both ingredients. (Refs. 5 through 8 and 10 through 23). sunscreen) to yield the absorbance of There has been renewed interest in These formulation variables are not the sunscreen. Five replicate using physical sunscreens, i.e., zinc mentioned in the United States measurements for each sunscreen oxide and titanium dioxide, in Pharmacopeia (USP) compendial formula were averaged and plotted with sunscreen formulations because these monograph for zinc oxide. In fact, the standard deviations at each 10 nm. ingredients may confer protection for a USP treats zinc oxide as a pure The spectral absorbance plots showed broad range of the UV radiation compound, without consideration of that zinc oxide has a relatively flat and spectrum. Some manufacturers have trace ions that may affect the absorption broad absorbance curve from 250 nm developed ultra fine forms of these band gap between the valence and through 370 nm with a sharp drop in ingredients in the range of 0.02 to 0.10 conduction bands or electronic energy absorbance beyond 370 nm and microns that are transparent on the skin, levels, i.e., the range of wavelengths that extending into the visible spectrum. may offer both UVA and UVB are absorbed. Comparison of the measurements of the protection, and are esthetically pleasing On September 19 and 20, 1996, the 4 percent zinc oxide with 25 percent (Refs. 5, 6, and 7). agency held a public meeting on the zinc oxide showed that the magnitude Sunscreens have been generally photostability, photochemistry, and of absorbance is related to the amount classified as chemical (organic) or photobiology of sunscreens in order to of zinc oxide in the formulation. The physical (inorganic) depending on gather more information related to the spectral absorbance plot of the 2 percent whether they absorb specific UV issues discussed previously (Ref. 24). As oxybenzone showed an absorbance peak radiation wavelengths or reflect and a result of this public meeting, in the at 250 nm, another at approximately 280 scatter UV radiation. Zinc oxide and Federal Register of August 15, 1996 (61 nm, followed by a gradual drop in titanium dioxide have been described as FR 42398), the administrative record for absorbance throughout the UVA physical sunscreen ingredients that the rulemaking for OTC sunscreen drug wavelengths (320 to 400 nm). These provide protection from UV radiation products was reopened until December measurements adequately demonstrated through reflection and scattering. 6, 1996, to allow for additional data and that zinc oxide absorbs radiation However, new data and information comment. The agency is evaluating all between 290 and 380 nm and, thus, indicate that they also absorb UV data and information received as a support effectiveness. radiation as well as scatter visible light result of the workshop and may discuss Federal Register / Vol. 63, No. 204 / Thursday, October 22, 1998 / Proposed Rules 56587 these recent scientific advances in oxide and avobenzone in combination the deficiency constitutes a potential future issues of the Federal Register. (Ref. 27) and will make a decision when hazard to health. For OTC combination its review is completed. drug products that were not marketed C. Conclusion In the notice of proposed rulemaking on or before May 11, 1972, and have not The agency believes that the results of for OTC sunscreen drug products, the been considered by an OTC advisory the studies using the SPF test to agency discussed minimum review panel, the CPG states that the demonstrate the effectiveness of zinc concentration requirements for OTC agency may propose to include the oxide adequately demonstrate that at a sunscreen ingredients (58 FR 28194 at combination in a final monograph. 2 to 25 percent concentration it provides 28214). The agency concluded that However, marketing of such a product protection against UVB radiation. effectiveness requirements (i.e., final generally may not proceed until after In the proposed rule for OTC product testing) make the use of the comment period has ended on the sunscreen drug products, the agency minimum concentration requirements proposal and a subsequent notice is stated that a sunscreen ingredient must unnecessary for single ingredient published in the Federal Register have an absorption spectrum extending products. However, because of its setting forth the agency’s determination to 360 nm or above in order for a concern that each ingredient in a concerning interim marketing. product containing that ingredient to combination drug product contributes to The agency is aware that a number of display UVA radiation protection claims the overall effectiveness of the product, sunscreen combination drug products in its labeling (58 FR 28194 at 28233). the agency tentatively concluded that containing zinc oxide have entered the The agency also stated that the product minimum concentration requirements market place during the pendency of the would have to demonstrate meaningful are necessary for combination sunscreen rulemaking for OTC sunscreen drug UVA radiation protection by satisfying drug products (i.e., until a method is products. Based upon the Panel’s ‘‘yet to be established’’ UVA radiation developed that can demonstrate the favorable evaluation of zinc oxide as a testing procedures that would be contribution of each OTC sunscreen skin protectant and zinc oxide’s long included in the monograph. The agency ingredient in a combination product). history of safe use at comparable levels described suggested interim UVA The agency received a number of in various drug and cosmetic products. radiation test procedures in the comments on this position. The agency Because these products are currently proposed rule (58 FR 28194 at 28248 to is currently evaluating these comments being marketed and provide a 28250) and in a notice of public meeting and will address them in the final significant health benefit to consumers, (59 FR 16042, April 5, 1994) to discuss monograph. the agency sees no reason to restrict such testing procedures. At this time, the agency considers the other products from entering the Although the agency continues to data submitted by the comments as marketplace until the agency publishes evaluate data and information for the supportive of the safety and a subsequent Federal Register notice to purpose of proposing a monograph effectiveness of up to 25 percent zinc permit interim marketing. Accordingly, method for determining UVA radiation oxide alone (if the finished product the agency, by this notice, has protection, it nevertheless finds there is provides at least an SPF 2) and 2 to 25 determined that it is appropriate at this ample data demonstrating that zinc percent zinc oxide in combination with time to allow the interim marketing of oxide provides protection against UVA any one or more of the other Category the OTC zinc oxide-containing products radiation. The agency plans to propose I sunscreen ingredients (except identified in proposed §§ 352.10 and a monograph method for determining avobenzone) at the concentrations for 352.20. The agency is considering UVA radiation protection (both without permitted combinations of sunscreen amending the CPG (Ref. 28) in the future and following water immersion or active ingredients in proposed § 352.20 to address special situations such as this perspiration) in a future issue of the (58 FR 28194 at 28295). Accordingly, one. Federal Register. Until the agency the agency is proposing to amend the Products containing zinc oxide proposes a monograph UVA radiation proposed monograph for OTC sunscreen require both UVA radiation protection testing method, the agency considers drug products to include zinc oxide in testing (as discussed in section II. C. of testing procedures similar to the UVA §§ 352.10 and 352.20. this document) and SPF testing of the protection factor method described finished product, as proposed in subpart above (Ref. 1), and those methods D. Enforcement Status D of the proposed monograph for OTC described by R. W. Gange et al. (Ref. 25) The Panel did not consider zinc oxide sunscreen drug products (58 FR 28194 and N. J. Lowe et al. (Ref. 26) as as a sunscreen active ingredient alone or at 28298 to 28301). If the products adequate for determining the UVA in combination products. The agency is contain UVA claims in their labeling, radiation protection potential of a not aware of any OTC sunscreen drug then they must be marketed with the finished OTC sunscreen drug product. products currently marketed with zinc labeling proposed in § 352.52 in this Based upon the Panel’s evaluation of oxide as the sole sunscreen ingredient. document. Products covered by this zinc oxide as a skin protectant and the The agency is aware that there are a monograph amendment may be long history of use of zinc oxide in number of combination sunscreen drug marketed pending issuance of the final various drug and cosmetic products, the products that contain zinc oxide. monograph for this drug class, subject to agency continues to believe that there An FDA Compliance Policy Guide the risk that the agency may adopt a are no safety concerns regarding the use (CPG) (Ref. 28) addresses the marketing different position in the final of zinc oxide as a sunscreen active of OTC drug products containing monograph that could require ingredient in concentrations up to 25 combinations of ingredients. Under this reformulation and/or relabeling, recall percent. In addition, the agency believes guide, FDA’s stated policy is that OTC or other regulatory action. Marketing of at this time that zinc oxide can be drug combinations that were such products with UVA labeling claims combined with any one or more of the commercially marketed in the United not in accord with the labeling proposed other Category I sunscreen ingredients States on or before May 11, 1972, and in this document may also result in in § 352.10 of the proposed rule with the that are not subject to a final regulatory action against the product, exception of avobenzone. The agency is monograph, should not be considered the marketer, or both. The final currently reviewing data and for regulatory action on the basis of monograph for OTC sunscreen drug information in support of the use of zinc suspected labeling deficiencies unless products will establish the final 56588 Federal Register / Vol. 63, No. 204 / Thursday, October 22, 1998 / Proposed Rules formulation, labeling, and testing 13. Schwitzgebel, J. et al., ‘‘Role of Oxygen alternatives and, when regulation is requirements for such products. Molecule and the Photogenerated Electron in necessary, to select regulatory Ti02–Photocatalyzed Air Oxidation approaches that maximize net benefits E. Labeling Reactions,’’ Journal of Physical Chemistry, (including potential economic, In addition to applicable labeling 99:5633–38, 1995. 14. Hidaka, H. et al., ‘‘Photodegradation of environmental, public health and safety, proposed in §§ 352.50 through 352.60 2- Surfactants. XV: Formation of SO4 Ions in and other advantages; distributive (58 FR 28194 at 28296 to 28298), the the Photooxidation of Sulfur-Containing impacts; and equity). Under the agency is proposing that the labeling for Surfactants,’’ Chemosphere, 29:2619–2624, Regulatory Flexibility Act, if a rule has sunscreen drug products containing 1994. a significant economic impact on a zinc oxide may include under their 15. Minero, C. et al., ‘‘Photocatalyzed substantial number of small entities, an ‘‘Indications’’ or ‘‘Uses’’ any of the Transformation of Nitrobenzene on Ti02 and agency must analyze regulatory options following phrases: (1) ‘‘Broad spectrum Zn0,’’ Chemosphere, 28:1229–1244, 1994. that would minimize any significant 16. Dieckmann, M. S., K. A. Gray, and P. sunscreen,’’ (2) ‘‘Provides’’ (select one of V. Kamat, ‘‘Photocatalyzed Degradation of impact of the rule on small entities. the following: ‘‘UVB and UVA’’ or Adsorbed Nitrophenolic Compounds on Title II of the Unfunded Mandates ‘‘broad spectrum’’) ‘‘protection,’’ (3) Semiconductor Surfaces,’’ Water Science Reform Act (2 U.S.C. 1501 et seq.) ‘‘Protects from UVB and UVA’’ (select Technology, 25:277–279, 1992. requires that agencies prepare a written one of the following: ‘‘rays’’ or 17. Mak, M. K. S., and S. T. Hung, statement and economic analysis before ‘‘radiation’’), (4) (Select one of the ‘‘Degradation of Neat and Commercial proposing any rule that may result in an following: ‘‘Absorbs,’’ ‘‘Protects,’’ Samples of Organophosphate Pesticides in expenditure in any 1 year by State, ‘‘Screens,’’ or ‘‘Shields’’) ‘‘within the Illuminated Ti02 Suspensions,’’ Toxicology local, and tribal governments, in the and Environmental Chemistry, 36:155–168, aggregate, or by the private sector, of UVA spectrum,’’ (5) ‘‘Provides 1992. protection from the UVA rays that may 18. Borello, R. et al., ‘‘Photocatalytic $100 million (adjusted annually for contribute to skin damage and Degradation of DDT Mediated in Aqueous inflation). premature aging of the skin.’’ Semiconductor Slurries by Simulated The agency believes that this Sunlight,’’ Environmental Toxicology and proposed rule is consistent with the III. References Chemistry, 8:997–1002, 1989. principles set out in the Executive Order The following references have been 19. Heller, A., ‘‘Chemistry and and these two statutes. The purpose of placed on display in the Dockets Applications of Photocatalytic Oxidation of this proposed rule is to add a new Management Branch (address above) Thin Organic Films,’’ Accounts of Chemistry ingredient, combinations of ingredients, and may be seen by interested persons Research, 28:503–508, 1995. and labeling for OTC sunscreen drug 20. Anonymous, ‘‘Formulators Fine-Tune between 9 a.m. and 4 p.m., Monday products that contain zinc oxide and to Ti02-Based Screens,’’ Manufacturing through Friday. Chemist, 64:26–29, 1993. allow manufacturers to market zinc 1. Comments No. RPT5 and CR7, Docket 21. Tichy, S., ‘‘Transparent Ti02 for UV oxide-containing sunscreen drug No. 78N–0038, Dockets Management Branch. Protection,’’ Seifen Oele Fette Wachse, products under the OTC drug 2. Comments No. C131, C352, and SUP21, 118:612–620, 1992. monograph system, which would be Docket No. 78N–0038, Dockets Management 22. Ortyl, T. T., and G. E. Peck, ‘‘Surface beneficial to small entities. The Branch. Charge of Titanium Oxide and Its Effect on proposed rule would also have a 3. Comments No. C140, C350, C513, and Dye Adsorption and Aqueous Suspension positive impact on the availability and LET145, Docket No. 78N–0038, Dockets Stability,’’ Drug Development and Industrial Management Branch. marketing of broad spectrum OTC Pharmacy, 17:2245–2268, 1991. sunscreen drug products by allowing 4. Comment No. C351, Attachment III, 23. Macleod, T. M., and W. Fran-Bell, Docket No. 78N–0038, Dockets Management ‘‘Study of Physical Light Screening Agents,’’ additional products to be marketed. Branch. British Journal of Dermatology, 92:149–156, Some manufacturers of currently 5. Catlow, B., ‘‘Formulating with Ultrafine 1975. marketed products may incur costs to TiO2,’’ Seifen Oele Fette Wachse, 119:497– 24. Comment No. TR3, Docket No. 78N– relabel their products should they wish 500, 1994. 0038, Dockets Management Branch. to include the new labeling information. 6. Alexander, P., ‘‘Ultrafine Titanium 25. Gange, R. W. et al., ‘‘Efficacy of a Such information may increase product Dioxide Makes the Grade,’’ Manufacturing Sunscreen Containing Butyl sales because of the broader uses Chemist, 62:21,23, 1991. Methoxydibenzoylmethane Against 7. Brown, M. W., and E. Galley, ‘‘Testing information being allowed. The agency Ultraviolet A Radiation in Photosensitized has been informed that relabeling costs UVA and UVB Protection from Microfine Subjects,’’ Journal of the American Academy Titanium Dioxide,’’ Cosmetics and Toiletries, of Dermatology, 15:494–499, 1986. of the type required by this proposed 105:69–73, 1990. 26. Lowe, N. J. et al., ‘‘Indoor and Outdoor rule generally average about $2,000 to 8. Sayre, R. et al., ‘‘Physical Sunscreens,’’ Efficacy Testing of a Broad Spectrum $3,000 per stock keeping unit (SKU) Journal of the Society of Cosmetic Chemists, Sunscreen Against Ultraviolet A Radiation in (individual products, packages, and 41:103–109, 1990. Psoralen-sensitized Subjects,’’ Journal of the sizes). The agency is aware of 16 9. Fox, M. A., ‘‘Mechanistic Photocatalysis American Academy of Dermatology, 17:224– manufacturers that together produce in Organic Synthesis,’’ in Photocatalysis: 230, 1987. less than 100 SKU’s of OTC sunscreen Fundamentals and Applications, John Wiley 27. Comment No. CP8, Docket No. 78N– & Sons, New York, pp. 421–455, 1989. drug products containing zinc oxide. 0038, Dockets Management Branch. There may be a few additional small 10. Russell, J. et al., ‘‘The Assessment of 28. ‘‘Food and Drug Administration the OH Scavenging Action of Therapeutic Compliance Policy Guide 7132b.16,’’ in OTC manufacturers or products in the Agents,’’ Journal of Pharmaceutical and Vol. 06ATFM, Docket No. 78N–0038, Dockets marketplace that are not identified in Biomedical Analysis, 12:863–866, 1994. Management Branch. the sources FDA reviewed. 11. Harbour, J. H., J. Tromp, and M. L. Hair, Manufacturers who wish to include the ‘‘Photogeneration of Hydrogen Peroxide in IV. Analysis of Impacts new labeling may elect to relabel their Aqueous Ti02 Dispersions,’’ Canadian FDA has examined the impacts of the products at the next scheduled labeling Journal of Chemistry, 63:204–208, 1985. 12. Rao, M. V. et al., ‘‘Photosynthesis proposed rule under Executive Order printing. Assuming that there are about 12866 and the Regulatory Flexibility Act 100 affected OTC SKU’s in the Production of H2 and H202 on Semiconducting Oxide Grains in Aqueous (5 U.S.C. 601–612). Executive Order marketplace, total one-time costs of Solutions,’’ Journal of Physical Chemistry, 12866 directs agencies to assess all costs relabeling would be $200,000 to 84:1987–91, 1980. and benefits of available regulatory $300,000 if all of the products were Federal Register / Vol. 63, No. 204 / Thursday, October 22, 1998 / Proposed Rules 56589 relabeled. The agency believes the VI. Environmental Impact value of not less than 2 as measured by actual cost could be lower because some The agency has determined under 21 the testing procedures established in manufacturers may not elect to relabel CFR 25.31(c) that this action is of a type subpart D of this part. their products at this time and some of that does not individually or * * * * * the label changes will be made by cumulatively have a significant effect on (3) * * * private label manufacturers that tend to the human environment. Therefore, (xxi) Zinc oxide 2 to 25 percent. use simpler and less expensive labeling. neither an environmental assessment * * * * * In addition, there should be minimal nor an environmental impact statement 4. Section 352.52 is amended by waste of existing labeling for any is required. adding paragraph (b)(2)(vii) to read as manufacturer who elects to relabel at follows: this next labeling printing. VII. Public Comment Manufacturers who wish to enter the Interested persons may, on or before § 352.52 Labeling of sunscreen drug marketplace with a new zinc oxide January 20, 1999, submit written products. sunscreen combination product will comments to the Dockets Management * * * * * incur the standard costs that all Branch (address above). Written (b) * * * manufacturers have when introducing a comments on the agency’s economic (2) * * * new product. impact determination may be submitted (vii) For products containing the The agency considered but rejected on or before January 20, 1999. Three active ingredient identified in several alternatives: (1) A delayed copies of all comments are to be § 352.10(v), the following labeling marketing period, and (2) an exemption submitted, except that individuals may statements may be used—(A) ‘‘Broad from coverage for small entities. The submit one copy. Comments are to be spectrum sunscreen.’’ delayed marketing period was rejected identified with the docket number (B) ‘‘Provides’’ (select one of the because similar products currently exist found in brackets in the heading of this following: ‘‘UVB and UVA’’ or ‘‘broad in the marketplace. The agency does not document and may be accompanied by spectrum’’) ‘‘protection.’’ consider an exemption for small entities a supporting memorandum or brief. (C) ‘‘Protects from UVB and UVA’’ appropriate because consumers who use Received comments may be seen in the (select one of the following: ‘‘rays’’ or these manufacturers’ products would office above between 9 a.m. and 4 p.m., ‘‘radiation’’). not have appropriate products for safe Monday through Friday. (D) (Select one of the following: and effective use. ‘‘Absorbs,’’ ‘‘Protects,’’ ‘‘Screens,’’ or List of Subjects in 21 CFR Part 352 This analysis shows that this ‘‘Shields’’) ‘‘within the UVA spectrum.’’ proposed rule is not economically Labeling, Over-the-counter drugs. (E) ‘‘Provides protection from the significant under Executive Order 12866 Therefore, under the Federal Food, UVA rays that may contribute to skin and that the agency has undertaken Drug, and Cosmetic Act, and under damage and premature aging of the important steps to reduce the burden to authority delegated to the Commissioner skin.’’ small entities. Nevertheless, some of Food and Drugs, it is proposed that Dated: October 10, 1998. entities could incur some impacts, 21 CFR part 352 (proposed in the William K. Hubbard, especially private label manufacturers Federal Register of May 12, 1993 (58 FR Associate Commissioner for Policy that provide labeling for a number of 28194) and amended in the Federal Coordination. affected products. Thus, this economic Register of September 16, 1996 (61 FR [FR Doc. 98–28274 Filed 10–21–98; 8:45 am] 48645)) be amended as follows: analysis, together with other relevant BILLING CODE 4160±01±F sections of this document, serves as the agency’s initial regulatory flexibility PART 352ÐSUNSCREEN DRUG PRODUCTS FOR OVER±THE± analysis, as required under the PANAMA CANAL COMMISSION Regulatory Flexibility Act. Finally, this COUNTER HUMAN USE analysis shows that the Unfunded 1. The authority citation for 21 CFR 35 CFR Part 117 Mandates Reform Act does not apply to part 352 is revised to read as follows: RIN 3207±AA48 the proposed rule because it would not Authority: 21 U.S.C. 321, 351, 352, 353, result in an expenditure in any 1 year 355, 360, 371. Marine Accidents: Investigations; by State, local, and tribal governments, Control; Responsibility in the aggregate, or by the private sector, 2. Section 352.10 is amended by of $100 million. adding paragraph (v) to read as follows: AGENCY: Panama Canal Commission. V. Paperwork Reduction Act of 1995 § 352.10 Sunscreen active ingredients. ACTION: Notice of proposed rulemaking; * * * * * request for comments. FDA tentatively concludes that the (v) Zinc oxide up to 25 percent. SUMMARY: The Panama Canal labeling requirements proposed in this 3. Section 352.20 is amended by document are not subject to review by Commission (Commission) proposes to revising paragraphs (a)(1) and (a)(3)(xxi) amend its regulations to limit its the Office of Management and Budget to read as follows: because they do not constitute a liability in marine accidents. The new ‘‘collection of information’’ under the § 352.20 Permitted combinations of active regulations will require potential Paperwork Reduction Act of 1995 (44 ingredients. claimants to carry insurance against U.S.C. 3501 et seq.). Rather, the (a) * * * marine accidents in an amount of $1 proposed amendment to the tentative (1) Two or more sunscreen active million to cover damages sustained by final monograph for OTC sunscreen ingredients identified in § 352.10(a), and their vessels at the Canal when drug products is a ‘‘public disclosure of (c) through (v) may be combined when transiting the waterway or navigating in information originally supplied by the used in the concentrations established waters adjacent thereto. Federal Government to the recipient for for each ingredient in paragraph (a)(3) of DATES: The agency must receive written the purpose of disclosure to the public’’ this section and the finished product comments on or before November 30, (5 CFR 1320.3(c)(2)). has a minimum sun protection factor 1998.