27666 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations

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04/29/99 ...... PA STATE COLLEGE ...... UNIVERSITY PARK ...... 9/2846 VOR/DME RNAV or GPS RWY 6 AMDT 6 04/29/99 ...... PA STATE COLLEGE ...... UNIVERSITY PARK ...... 9/2847 VOR or GPS±B AMDT 9 04/29/99 ...... WI APPLETON ...... OUTAGAMIE COUNTY REGIONAL ... 9/2851 ILS RWY 3, AMDT 16C 04/30/99 ...... MO BUTLER ...... BUTLER MEMORIAL ...... 9/2875 GPS RWY 18, ORIG 04/30/99 ...... TX AUSTIN ...... AUSTIN-BERGSTROM INTL ...... 9/2879 ILS RWY 35L, AMDT 1 04/30/99 ...... TX AUSTIN ...... AUSTIN-BERGSTROM INTL ...... 9/2880 GPS RWY 35L, AMDT 1 04/30/99 ...... TX AUSTIN ...... AUSTIN-BERGSTROM INTL ...... 9/2881 GPS RWY 17R, AMDT 1 04/30/99 ...... TX AUSTIN ...... AUSTIN-BERGSTROM INTL ...... 9/2882 ILS RWY 17R, AMDT 1 05/1/99 ...... NH MANCHESTER ...... MANCHESTER ...... 9/3102 ILS RWY 2, AMDT 2 05/1/99 ...... NH MANCHESTER ...... MANCHESTER ...... 9/3103 ILS RWY 35, AMDT 19 05/04/99 ...... IL CHICAGO/AURORA ...... AURORA MUNI ...... 9/2970 VOR or GPS±A AMDT 1A 05/05/99 ...... IL CHICAGO/AURORA ...... AURORA MUNI ...... 9/2983 ILS RWY 9, AMDT 1A 05/06/99 ...... OH MIDDLETOWN ...... HOOK FIELD MUNI ...... 9/3009 LOC RWY 23, AMDT 7B 05/06/99 ...... OH MIDDLETOWN ...... HOOK FIELD MUNI ...... 9/3010 NDB or GPS RWY 23, AMDT 8A 05/06/99 ...... OH MIDDLETOWN ...... HOOK FIELD MUNI ...... 9/3011 NDB or GPS±A, AMDT 2A 05/10/99 ...... MN WORTHINGTON ...... WORTHINGTON MUNI ...... 9/3086 NDB or GPS RWY 29, ORIG 05/10/99 ...... MN WORTHINGTON ...... WORTHINGTON MUNI ...... 9/3088 ILS RWY 29, ORIG 05/10/99 ...... VA RICHMOND ...... CHESTERFIELD COUNTY ...... 9/3074 NDB or GPS RWY 33, AMDT 7A 05/10/99 ...... VA RICHMOND ...... CHESTERFIELD COUNTY ...... 9/3075 VOR/DME or GPS RWY 15, ORIG 05/10/99 ...... VA RICHMOND ...... CHESTERFIELD COUNTY ...... 9/3082 ILS RWY 33, ORIG

[FR Doc. 99–12949 Filed 5–20–99; 8:45 am] EFFECTIVE DATES: This regulation is glyceryl aminobenzoate, lawsone with BILLING CODE 4910±13±M effective May 21, 2001 for parts 310, dihydroxyacetone (interest was 352, and 700 and is effective May 22, subsequently shown in developing a 2000 for part 740. monograph for lawsone and dihydroxyacetone), and red petrolatum. DEPARTMENT OF HEALTH AND FOR FURTHER INFORMATION CONTACT: John The agency also reiterated that all HUMAN SERVICES D. Lipnicki, Center for Drug Evaluation and Research (HFD–560), Food and sunscreen ingredients must have a USP Food and Drug Administration Drug Administration, 5600 Fishers monograph before being included in the Lane, Rockville, MD 20857, 301–827– final monograph for OTC sunscreen 21 CFR Parts 310, 352, 700, and 740 2222. drug products. This final rule includes SUPPLEMENTARY INFORMATION: those sunscreen ingredients that have [Docket No. 78N±0038] USP monographs. I. Introduction In the Federal Register of September RIN 0910±AA01 In the Federal Register of August 25, 16, 1996 (61 FR 48645), the agency Sunscreen Drug Products For Over- 1978 (43 FR 38206), FDA published, amended the proposed rule to include The-Counter Human Use; Final under § 330.10(a)(6) (21 CFR avobenzone as a single ingredient and in Monograph 330.10(a)(6)), an advance notice of combination with certain other proposed rulemaking (ANPRM) to sunscreen ingredients (interim AGENCY: Food and Drug Administration, establish a monograph for OTC marketing was allowed in the Federal HHS. sunscreen drug products, together with Register of April 30, 1997 (62 FR ACTION: Final rule. the recommendations of the Advisory 23350)). In the Federal Register of Review Panel on OTC Topical October 22, 1998 (63 FR 56584), the SUMMARY: The Food and Drug Analgesic, Antirheumatic, Otic, Burn, agency proposed to amend the tentative Administration (FDA) is issuing a final and Sunburn Prevention Drug Products final monograph to include zinc oxide rule in the form of a final monograph (the Panel), which was the advisory as a single ingredient and in establishing conditions under which review panel that evaluated data on the combination with any proposed over-the-counter (OTC) sunscreen drug active ingredients in this drug class. The Category I sunscreen active ingredient products are generally recognized as agency’s proposed regulation for OTC except avobenzone. safe and effective and not misbranded as sunscreen drug products, in the form of In the Federal Register of April 5, part of FDA’s ongoing review of OTC a tentative final monograph, was 1994 (59 FR 16042), the agency drug products. FDA is issuing this final published in the Federal Register of reopened the administrative record and rule after considering public comments May 12, 1993 (58 FR 28194). announced a public meeting to discuss on the agency’s proposed regulation, In the Federal Register of June 8, 1994 ultraviolet A (UVA) radiation claims which was issued in the form of a (59 FR 29706), the agency proposed to and testing procedures. In the Federal tentative final monograph, and new data amend the tentative final monograph Register of August 15, 1996 (61 FR and information on sunscreen drug (and reopened the comment period until 42398), the agency reopened the products that have come to the agency’s August 22, 1994) to remove five administrative record and announced a attention. FDA is also issuing final rules sunscreen ingredients because of a lack public meeting to discuss the regarding the labeling of certain of interest in establishing United States photochemistry and photobiology of cosmetic products to inform consumers Pharmacopeia (USP) monographs: sunscreens. that these products do not provide Digalloyl trioleate, ethyl 4- This final monograph completes the protection from the sun. [bis(hydroxypropyl)] aminobenzoate, tentative final monograph except for

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00010 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations 27667 certain testing issues and UVA labeling, submission of a formal petition by an specified when the final rule for testing which the agency will discuss in future interested party. procedures publishes. issues of the Federal Register. Until The agency has included these data 2. Several comments recommended then, UVA labeling may continue in and information in the administrative modifications to the definition of accord with the tentative final record and addressed them in this minimal erythema dose (MED) in monograph and its amendments. The document. The agency has considered proposed § 352.3(a). Some comments agency advises that on or after May 21, the request for an oral hearing in its objected to the presumption that 2001, no OTC drug product that is response to the comment and believes it erythema is a ‘‘diffusing’’ reaction that subject to the monograph and that has adequately responded to the starts from within the exposed site and contains a nonmonograph condition manufacturer and that a hearing is not moves outward in a dose dependent may be initially introduced or initially needed. As discussed in section II.G, manner, i.e., ‘‘redness reaching the delivered for introduction into interstate comment 29 of this document, the borders of the exposure site.’’ Other commerce unless it is the subject of an agency is allowing the marketing of OTC comments asserted that the definition is approved new drug application or sunscreen drug products with SPF too limiting because it may not be abbreviated new drug application. values above 30 under one collective appropriate for all solar simulator Further, any OTC drug product subject term (i.e., ‘‘30 plus’’ or ‘‘30 +’’). The configurations (e.g., no template). Many to this monograph that is repackaged or agency will also consider including comments recommended the definition relabeled after the effective date of the labeling in the monograph with actual of MED used by the European Trade monograph must be in compliance with label SPF values on products with SPF Association COLIPA (Ref. 5): ‘‘The the monograph regardless of the date the values over 30 when adequate data are quantity of radiant energy required to product was initially introduced or submitted to substantiate a testing produce the first perceptible, initially delivered for introduction into procedure applicable to SPF values over unambiguous redness reaction with interstate commerce. Manufacturers are 30. clearly defined borders.’’ Another encouraged to comply voluntarily as comment recommended ‘‘erythema- soon as possible. II. The Agency’s Conclusions on the Comments effective ultraviolet radiation’’ in place In response to the proposed rule on of ‘‘radiant energy.’’ OTC sunscreen drug products and A. General Comments on OTC The agency agrees that the proposed subsequent reopenings of the Sunscreen Drug Products definition of MED should be modified administrative record, the agency for the reasons discussed by the received 433 comments. The comments 1. Several comments asked that the comments and is revising § 352.3(a) in included four petitions (Refs. 1 through agency either exempt currently this final rule, as follows: ‘‘Minimal 4) requesting consideration of sunscreen marketed sunscreen products from the erythema dose (MED). The quantity of ingredients that have been marketed in requirement for redetermining the SPF erythema-effective energy (expressed in Europe but not in the United States. The or provide a 2-year implementation Joules per square meter) required to status of these petitions is discussed in period. One comment requested a 3-year produce the first perceptible redness section II.C, comment 13 of this implementation period. The comments reaction with clearly defined borders.’’ document. One manufacturer requested contended that the proposed 12-month The agency considers this definition an oral hearing before the Commissioner implementation period would result in broad enough to encompass tests of Food and Drugs if the agency lost business and a serious economic mandated a limit on sun protection hardship for manufacturers, estimated conducted with solar simulator factor (SPF) values in this final rule. to be 35 million dollars for configurations with no template and Copies of the information considered by reformulating, retesting, and relabeling consistent with COLIPA’s definition. the Panel, the comments and petitions, sunscreen products. 3. One comment noted that the and the hearing request are on public The agency agrees with the comments wavelength ranges for UVA, UVB, and display in the Dockets Management that the proposed 12-month UVC radiation in the tentative final Branch (HFA–305), Food and Drug implementation period may cause monograph differed from the official Administration, 5630 Fishers Lane, rm. undue economic burden on some ranges of the Commission International 1061, Rockville, MD 20852. All ‘‘OTC manufacturers of these products without de L’Eclairage (CIE), which are: (1) Volumes’’ cited throughout this a corresponding benefit to consumers UVC–radiation of less than 280 document refer to information on public (see section VII of this document). As nanometers (nm), (2) UVB–280 to 315 display. discussed in section VII, a 24-month nm, and (3) UVA–315 to 400 nm. The A number of comments were filed in effective date would allow most firms to comment mentioned the agreement the Dockets Management Branch after relabel products during a normal reached at the 11th International the dates the administrative record had relabeling cycle without incurring Congress on Photobiology (Ref. 6) on the officially closed. The agency has additional costs. Accordingly, the final short wavelength end of UVB radiation considered these comments as rule will be effective 24 months from (280 or 290 nm) and suggested that the ‘‘feedback’’ communications under the the date of this publication. Because this scientific evidence supports 320 nm as OTC drug review procedures, as final rule provides testing procedures the long-wavelength boundary of UVB discussed in the Federal Register of that were proposed in the tentative final radiation. September 29, 1981 (46 FR 47740), and monograph, currently marketed The agency agrees with the comment clarified in the Federal Register of April products that have already been tested that the scientific evidence supports 320 1, 1983 (48 FR 14050). When by those procedures will not need to be nm as the long-wavelength boundary of ‘‘feedback’’ material submitted after an retested. However, sunscreen products UVB radiation. However, the short- administrative record has officially that have not been tested will need to wavelength boundary for UVB radiation closed directly influences or forms one be tested using the methods described has been accepted as either 280 or 290 of the bases for the agency’s decision on in this document. The agency intends to nm. Given that the comment did not a matter in an OTC drug rulemaking propose modified test procedures in a provide a compelling reason to change proceeding, the agency adds it to the future issue of the Federal Register and the proposed definition of UVB administrative record without any necessary retesting time will be radiation, the agency will continue to

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00011 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 27668 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations define the boundaries of UVB radiation 7), but none were subsequently 51 of this document) may help to as 290 to 320 nm. provided. The agency is not currently prevent skin damage and may help 4. Comments requested the agency to aware of stability problems that would reduce the risk of skin lesions, skin amend the definition of a sunscreen require expiration dating for OTC cancer, and other disease conditions. active ingredient in proposed § 352.3(c) sunscreen drug products but will Products that are marketed to achieve to include mechanisms other than address such a requirement if data these important health benefits meet the absorption, to expand the UV range to become available. All sunscreen active definition of a drug under section include UVA radiation, and to provide ingredients included in the final 201(g)(1)(B) and (g)(1)(C) of the act. a minimum SPF value requirement. The monograph also have a USP monograph 9. One comment disagreed with the comments added that some proposed that contains packaging and storage agency’s tentative conclusion that Category I active ingredients (e.g., requirements and standards for products products containing a sunscreen menthyl anthranilate and titanium containing these ingredients. ingredient, but labeled for the purpose dioxide) do not meet the proposed 7. Comments recommended that the of obtaining an ‘‘even tan,’’ are subject definition, and that the definition is not agency establish procedures for to regulation as drugs. According to the interpretable without specifications for ensuring batch-to-batch SPF test results, comment, such a product is subject to measuring 85 percent absorbance. and that it approve testing laboratories regulation as a drug only if it bears a The agency discussed the need to and regulate their performance. claim to treat or prevent sunburn. The modify the definition in a 1996 Regulations already exist to assure comment asserts that this has been the proposed amendment of the tentative that each batch of drug product meets agency’s consistent approach since final monograph (61 FR 48645 at established specifications for the 1940. 48646). The agency agrees that identity and strength of each active Another comment stated that sunless modifications should be to: (1) Include ingredient. Specifically, 21 CFR 211.160 tanning products, used to impart color mechanisms other than absorption, (2) requires that product specifications and without exposure to the sun, could be redefine wavelengths, and (3) remove laboratory controls be established and improved by adding a sunscreen to the percent absorbance requirement. performed. Although the agency would provide users protection during their The agency does not agree that a not require SPF testing on human normal outside activities. The comment minimum SPF value should be included subjects for every batch produced, requested that such products should be in the definition because this manufacturers need to assure regarded as cosmetics, because they information is more appropriately a conformance to their finished product would be used primarily for a cosmetic characteristic of the final formulation. specifications. Further, any changes to effect, with the sunscreen protection Therefore, the agency has revised the batch formula would, at a minimum, serving only a secondary purpose. proposed § 352.3(c) in this document, to require review and documentation by The agency thoroughly discussed the read: ‘‘Sunscreen active ingredient. An the manufacturer’s quality control unit regulatory status of ‘‘tanning’’ products, ingredient listed in § 352.10 that to determine if SPF retesting is including the basis for withdrawing its absorbs, reflects, or scatters radiation in necessary. Finally, 21 CFR 211.180 1940 advisory opinion on sunburn and the ultraviolet range at wavelengths of provides for the inspection of records suntan preparations, in the tentative 290 to 400 nanometers.’’ pertaining to production, control, and final monograph (58 FR 28194 at 28203 5. One comment recommended that distribution of batches of drug products. to 28207, 28293 to 28294). As discussed the agency reevaluate statements in the Thus, testing laboratories are subject to in the tentative final monograph, the tentative final monograph on the these regulations. presence of a sunscreen active harmful nature of tanning. The agency ingredient, in conjunction with labeling discussed the harmful effects of UV B. Comments on the Drug/Cosmetic claims that the product may be used, radiation-induced tanning in the Status of Sunscreen Products e.g., to permit tanning or to acquire an tentative final monograph (58 FR 28194 8. One comment questioned whether even tan, generally establishes that the at 28238 to 28239). The comment sunscreen products should be regulated product’s intended use is that of a drug. suggested that a natural tan reduces as drugs. The comment asserted that Such products suggest, among other cumulative sun exposure and may such products are not active in the things, that the ingredients in the potentiate sunscreen effectiveness. The mitigation or elimination of a disease product will allow the consumer to stay comment did not, however, provide condition, and that sunscreen products in the sun longer without suffering skin data or references to support this claim have no more affect on the structure and damage (58 FR 28194 at 28204). or to otherwise cause the agency to function of the body than ‘‘being in Likewise, products that claim to change its position. physical shade.’’ accelerate or stimulate the tanning 6. One comment requested that the The basis for the agency’s process are claiming, either expressly or final monograph require expiration determination that products intended impliedly, to stimulate the production dating and storage information in the for use as sunscreens are subject to of melanin in the body. Such a claim to labeling of OTC sunscreen drug regulation as drugs under section affect the structure or function of the products. The comment noted that 201(g)(1) of the Federal Food, Drug, and body renders the product subject to under 21 CFR 211.137, OTC drug Cosmetic Act (the act) (21 U.S.C. regulation as a drug under section products with data demonstrating 321(g)(1)) is set forth at length in the 201(g)(1) of the act (see 58 FR 28194 at stability for 3 years and without labeled tentative final monograph (58 FR 28194 28293). Finally, a sunless tanning dosage limitations are not required to at 28203 to 28206). Essentially, product that contains a sunscreen include an expiration date in their sunscreen active ingredients affect the ingredient, to provide protection to the labeling. The comment stated that it was structure and function of the body by consumer, is subject to regulation as a aware of numerous cases that suggest absorbing, reflecting, or scattering the drug. The idea that the sunburn these products may not be stable for 3 harmful, burning rays of the sun, protection offered by the product may years. thereby altering the normal only be a ‘‘secondary’’ feature for the The agency requested the comment to physiological response to solar consumer is not relevant. If an intended provide data and information about the radiation. Proper use of sunscreen use of the product is to provide users specific products it was aware of (Ref. ingredients (see section II.L, comment with sun protection when they go

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00012 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations 27669 outside (as the comment suggests), then you don’t burn.’’ The comment the product does not provide such the product is subject to regulation as a concluded that the availability of protection, are sufficiently serious to drug. tanning products without a protective require the type of disclosure outlined On the other hand, products that do sunscreen ingredient is a serious health in the proposed rule. Information about not make express or implied sun issue and detrimental to public health. the purpose of a sunscreen ingredient in protection claims, and do not contain A third comment objected to any such a hair care or nail product will be useful sunscreen ingredients, may be regarded warnings on tanning products. to consumers to inform them that the as cosmetics under section 201(i) of the The agency considers it an important ingredient protects only the hair or only act. If the product is intended solely to public health issue that users of the color of the product. provide cosmetic effects on the skin suntanning products be alerted when This information need appear only (e.g., to moisturize the skin while these products do not contain a once and can appear anywhere in the sunbathing), or solely to impart color to sunscreen and do not protect against labeling, provided the qualifying the skin without exposure to the sun or sunburn or other harmful effects to the purpose appears prominently and other sources of light (i.e., sunless skin. Because suntanning products are conspicuously and in conjunction with tanning), then the product may be intended for repeated use under the sun the word ‘‘sunscreen.’’ The information marketed as a cosmetic. Such products, or suntanning lamps while acquiring a may, e.g., be combined in a single however, must include a warning tan, the agency considers failure to statement, e.g., ‘‘Contains a sunscreen— statement (discussed in this section, provide information on hazards to protect product color.’’ This will comment 10 of this document) to inform associated with repeated, unprotected ensure that consumers will see and the consumer that the product does not exposure to UV radiation to be a failure readily associate the two pieces of provide any protection against sunburn. to reveal material facts (see sections information. Products marketed to enhance or permit 201(n), 502(a), and 602(a) of the act (21 12. Two comments objected to the use tanning that do not contain a sunscreen U.S.C. 352(a) and 362(a))), especially in of an OTC drug rulemaking process to ingredient must be reviewed on a case- light of the representations that are change cosmetic labeling requirements, by-case basis to determine whether the made for the product (e.g., suntanning). i.e., the addition of a warning on certain product is intended solely to provide a Therefore, the agency is requiring the tanning products and the labeling cosmetic benefit (such as moisturizing) labeling of suntanning preparations that requirements for hair care or nail or whether the product is intended to do not contain a sunscreen ingredient products that contain a sunscreen for a enhance or permit tanning by some (§ 740.19 (21 CFR 740.19)) to bear the nontherapeutic use. other mechanism of action. following: ‘‘Warning—This product The agency addressed this procedural The comments offered no other does not contain a sunscreen and does concern, which was also raised in reasoning and no data to the contrary, not protect against sunburn. Repeated response to the ANPRM, at length in the other than to suggest that the agency’s exposure of unprotected skin while tentative final monograph (58 FR 28194 approach would encourage tanning may increase the risk of skin at 28201 to 28202). The industry and manufacturers to remove sunscreen aging, skin cancer, and other harmful consumers have had ample notice of the ingredients from suntan products and, effects to the skin even if you do not fact that this proceeding included thereby, expose consumers to even burn.’’ The agency considers this several cosmetic labeling issues that higher levels of harmful ultraviolet rays. information to be sufficiently important, arise out of the same facts and findings The agency is not persuaded that a for safety reasons, to require a 12-month at issue in developing the OTC drug significant number of manufacturers effective date (as opposed to 24 months monograph. It is not uncommon for the will choose to reformulate their for the balance of the rule) and to agency to address in an OTC rulemaking products, to make them less safe for require the strongest possible signal document the status of, or the regulation consumers, as a result of this final rule. word, i.e., ‘‘Warning.’’ of, products that fall outside of the Moreover, consumers will continue to 11. One comment disagreed with the monograph. In this instance, the have an array of sunscreen-containing proposal that hair care and nail cosmetic labeling issues were so closely products from which to choose. Finally, products that contain a sunscreen related to the OTC drug issues that a as discussed below, certain tanning ingredient for a nontherapeutic use (e.g., separate proceeding would have been products (including sunless tanning to protect the color of the product), and overly duplicative and inefficient. products) that do not contain sunscreen that use the term ‘‘sunscreen’’ in the ingredients must bear a prominent labeling, must describe in the labeling C. Comments on Specific Sunscreen warning to the consumer. This will the functional role of the sunscreen. Active Ingredients ensure that the consumer is fully According to the comment, it is highly 13. Several comments noted that FDA informed as to which products offer sun unlikely that consumers would think had deferred a decision on the citizen protection and which do not. that these products are intended to petitions requesting that sunscreen 10. One comment requested that the protect the skin. If this requirement active ingredients marketed solely in signal word ‘‘Caution’’ replace the were finalized, the comment requested foreign countries be included in the signal word ‘‘Warning’’ preceding the that the agency permit the term OTC sunscreen monograph. The following statement for suntanning ‘‘sunscreen’’ to appear once anywhere comments urged FDA answer these preparations: ‘‘Warning—This product in the labeling, with the purpose of the petitions and establish a policy does not contain a sunscreen and does sunscreen explained elsewhere in the concerning the inclusion of OTC not protect against sunburn.’’ The labeling. sunscreens based solely on foreign data comment stated that the word The agency disagrees with the and marketing experience. ‘‘Warning’’ suggests safety hazards premise of this comment. The use of the In the Federal Register of October 3, associated with these products that are term ‘‘sunscreen’’ in labeling suggests 1996 (61 FR 51625), the agency unrelated to sunburn. Another comment that the product in some way will published an ANPRM that addressed petitioned to add a second sentence to protect the consumer from the harmful establishing eligibility criteria for the warning: ‘‘Tanning in sunlight or effects of the sun. The health risks considering additional OTC conditions under tanning lamps can cause skin associated with relying on a product for (i.e., OTC drug active ingredients, cancer and premature skin aging-even if protection from the sun, when in fact indications, dosage forms, dosage

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00013 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 27670 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations strengths, routes of administration, and developed or adopted need not be has an allergy to aminobenzoic acid, the active ingredient combinations) in the resolved in this proceeding at this time. individual may suffer adverse health OTC drug monograph system. These Similarly, TEA and DEA need not be consequences. proposed criteria would address how addressed in this proceeding, as For these reasons, and especially in foreign or domestic OTC marketing triethanolamine is not a sunscreen light of the potential safety concerns for experience could be used to support the active ingredient, and diethanolamine is certain consumers, the agency inclusion of an ingredient in an OTC only used in the ingredient concludes that wherever the ingredient drug monograph. Specifically, the diethanolamine methoxycinnamate aminobenzoic acid appears in the criteria would address how OTC which, as discussed, is not a monograph labeling of an OTC sunscreen drug marketing experience in the United ingredient at this time. product, including labeling that notes States or abroad could be used to meet With respect to the comment on the the absence of this ingredient, the the statutory requirement under section monograph ingredient descriptive term PABA must 201(p) of the act of marketing ‘‘to a phenylbenzimidazole sulfonic acid, the immediately follow the established material extent’’ and ‘‘for a material agency agrees that if USAN or the USP name, i.e., ‘‘Aminobenzoic acid time.’’ ‘‘Material extent’’ and ‘‘material were to adopt a different or alternative (PABA).’’ Thus, e.g., a product that is time’’ are needed to qualify a specific name for this ingredient, such a name currently marketed as ‘‘PABA-free’’ OTC drug condition for consideration could be used in the labeling of a would now be required to state that the under the OTC drug monograph system. product that contains this ingredient. As product is ‘‘Aminobenzoic acid (PABA)- The decision on whether to proceed discussed in comment 30 of the free.’’ This convention will allow with a final rulemaking on this subject tentative final monograph (58 FR 28194 consumers to begin to recognize that the will be based, in part, on the at 28207 to 28209), the agency is using ingredient they may wish to avoid is information and comments submitted in the compendial name as the established ‘‘aminobenzoic acid.’’ After a sufficient response to the notice of proposed name for each active ingredient. period of time, the agency will revisit rulemaking that the agency is preparing 15. Two comments requested that the the need for consumer labeling to for publication in a future issue of the term ‘‘PABA’’ continue to be allowed in continue to bear the descriptive term Federal Register. Resolution of the labeling. The comments stated that the PABA. pending sunscreen petitions must await name aminobenzoic acid is meaningless 16. One comment stated that claims of the outcome of any final rulemaking on to consumers and physicians, who over protection by artificial melanin, this subject. the years have learned to recognize this melanin-containing products, and 14. One comment requested that the ingredient on the label as PABA. One antioxidants should be enumerated, agency adopt simpler, more user- comment recommended the use of well regulated, and defined. friendly, names for several sunscreen aminobenzoic acid in the ingredient list The agency agrees with the comment, ingredients: (1) Roxadimate for ethyl- and the use of PABA in other but these claims are not covered by this [bis(hydroxypropyl)] aminobenzoate, (2) communications about the product. The final monograph. Melanin and artificial lisadimate for glyceryl aminobenzoate, comment added that the term ‘‘PABA- melanins are not recognized sunscreen and (3) diolamine methoxycinnamate free’’ should be allowed on products active ingredients. Any product for diethanolamine methoxycinnamate. that do not contain aminobenzoic acid. containing melanin or artificial The comment claimed that these names The other comment proposed either to melanins as active ingredients and had been adopted or designated by the permit the listing of the ingredient as making sun protection claims would United States Adopted Names (USAN) PABA or, if that is unacceptable, as have to seek marketing approval under Council. The comment also requested PABA (aminobenzoic acid). a new drug application (NDA). that if USAN adopts a name for In comment 30 of the tentative final The agency is aware that claims of phenylbenzimidazole sulfonic acid, monograph (58 FR 28194 at 28207 to protection from antioxidants are used in FDA adopt this name as well. The 28209), the agency discussed the issue the labeling of some cosmetic products comment also suggested the use of the of the appropriate established name for with or without a sunscreen. The agency acronyms ‘‘TEA’’ and ‘‘DEA’’ for this and other sunscreen ingredients. As will ascertain the nature of any such triethanolamine and diethanolamine, the agency stated in that discussion, the claims (drug or cosmetic) on a case-by- respectively. recognized compendial name for case basis. The agency is including in this final aminobenzoic acid no longer includes 17. Several comments objected to the monograph only those active the term PABA. agency’s proposal that OTC sunscreen ingredients that are the subject of an The agency acknowledges, however, drug products must contain less than official USP compendial monograph that the term PABA formerly was part 500 parts per billion (ppb) of N-methyl- that sets forth its standards of identity, of the established name for this N-nitrosoaminobenzoate octyl ester strength, quality, and purity (see section ingredient and that the use of the term (NMPABAO) for several reasons: (1) I of this document). In the Federal in consumer labeling has continued Toxicological studies indicate that Register of June 8, 1994, FDA deleted despite the change in the compendial NMPABAO does not have mutagenic or ethyl-[bis(hydroxypropyl)] name. In addition, the agency agrees suspected carcinogenic potential (Ref. aminobenzoate and glyceryl with the comment that many consumers 8), (2) NMPABAO may be present in aminobenzoate from the tentative final have learned to recognize this sunscreens containing padimate O only monograph due to the lack of interest in ingredient as, and only as, PABA. The in small amounts (ppb range) and the establishing USP monographs for these agency also recognizes that consumers risks associated with NMPABAO are ingredients. Moreover, two sunscreen seeking to avoid the use of this very low, (3) NMPABAO decomposes ingredients (including diethanolamine ingredient for health-related reasons quickly when exposed to UV radiation, methoxycinnamate) have been deferred (e.g., allergy) may, in this case, be and (4) industry is aware not to from the final monograph due to the misled if the term PABA were no longer formulate with known nitrosating agents lack of a current or proposed permitted. Some consumers may believe in the presence of amines in order to compendial monograph. Therefore, the that a product that lists aminobenzoic avoid nitrosamine contamination of its issue of whether a ‘‘user-friendly’’ name acid as an ingredient, but does not list products. Some comments stated that for these ingredients should be PABA, is PABA-free. If such a consumer FDA’s own conclusions in the tentative

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00014 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations 27671 final monograph concerning the safety submitted to the Toxic Substance the skin. The comments added that of both NMPABAO and padimate O do Control Act 8(e) coordinator of the micronized titanium dioxide meets all not support the imposition of United States Environmental Protection safety and efficacy criteria and also concentration limits for NMPABAO in Agency for consideration. The study meets the USP specifications for purity sunscreens nor do they justify the high was a 4-week repeated dose study at except pure water content. cost of analyzing each batch of doses of 0, 100, 300, and 1,000 Another comment asserted for the sunscreen product for NMPABAO. One milligrams (mg)/kilogram (kg)/day of following reasons that micronized comment contended that any proposed padimate O administered by gavage in titanium dioxide is a new ingredient limit should apply to all nitrosamines a corn oil vehicle (10 to 15 rats/group/ with several unresolved safety and and not just NMPABAO. The comment sex). The study included a 4-week efficacy issues: (1) It does not meet the stated that nitrosamines can be formed recovery period to assess the persistence definition of a sunscreen opaque from any secondary or tertiary amine. or reversibility of any toxic effects. At sunblock, (2) there is no control of Several sunscreen active ingredients the end of the 4-week treatment period, particles to agglomerate, which is contain this moiety in their chemical toxic effects were seen in four target critical to effectiveness, (3) no standards structure and many inactive ingredients organs: Testes, epididymis, spleen, and exist to ensure integrity of coatings, (4) are secondary or tertiary amines. The liver. The no-observed-effect-level in there are no performance-based comment concluded that targeting this study was 100 mg/kg/day for both standards of identity; micronized NMPABAO falsely conveys that males and females. Toxic effects titanium dioxide is not included in the padimate O is a unique concern, appeared reversible in the animals USP, (5) its photocatalyst potential, and resulting in manufacturers using other necropsied after the 4-week recovery (6) the potential for the smaller particle ingredients to avoid costly testing and period with the exception of marked size to accumulate under the skin. negative implications. epididymal hypospermia at the 1,000 The agency finds the data with the In the tentative final monograph, the mg/kg/day dose (5/5 animals). comments supportive of monograph agency did not propose a concentration The clinical relevance of this animal status for micronized titanium dioxide. limit on NMPABAO. Rather, based on toxicity study is difficult to assess. Acute animal toxicity, irritation, concerns that had been raised, the Padimate O was administered sensitization, photoirritation, agency asked for comment on whether chronically and at very high oral doses. photosensitization, and human repeat it should consider proposing a fixed Under normal use conditions, sunscreen insult patch and skin penetration limit. As discussed in the tentative final drug products containing padimate O studies revealed no deleterious effects. monograph (58 FR 28194 at 28288 to are applied topically and used SPF values for four product 28293), toxicological studies support the intermittently. In addition, formulations containing from 4.4 to 10 agency’s belief that the risk associated pharmacokinetic parameters were not percent micronized titanium dioxide with NMPABAO contamination of calculated and the different routes of were from 9 to 24 and support sunscreen drug products is very low due administration (oral in this study versus effectiveness as a sunscreen ingredient. to NMPABAO’s low mutagenicity and topical for sunscreen products) preclude carcinogenicity potential and rapid calculation of a ‘‘safety margin’’ on the The agency is aware that sunscreen decomposition in the presence of UV basis of dose per unit of body weight or manufacturers are using micronized radiation. The agency has not become surface area. Similarly, kinetic data are titanium dioxide to create high SPF aware of any new data or information not available for a comparison of serum products that are transparent and since the publication of the tentative levels of drug or metabolites. Literature esthetically pleasing on the skin. The final monograph suggesting a safety searches indicate no published agency does not consider micronized concern with NMPABAO in sunscreen information on the kinetics of padimate titanium dioxide to be a new ingredient drug products. Therefore, the agency O with topical application in man. If but considers it a specific grade of the has decided not to propose or otherwise percutaneous absorption of padimate O titanium dioxide originally reviewed by include in this final monograph a does occur in man, it seems likely that the Panel. Fairhurst and Mitchnick (Ref. requirement that OTC sunscreen drug the peak and/or cumulative levels 11) note that ‘‘fines’’ have been part of products must contain less than 500 ppb achieved with sunscreen usage would commercially used titanium dioxide of NMPABAO. be quite low compared to the systemic powders for decades, and that a In the tentative final monograph (58 exposure achieved in this animal micronized product simply refers to a FR 28194 at 28292), the agency toxicity study. Further, it is not known refinement of particle size distribution. discussed its analysis for NMPABAO in whether the irreversible epididymal Based on data and information 25 commercially available sunscreen hypospermia found in the 1,000 mg/kg/ presented at the September 19 and 20, products. Of the 11 samples found to be day group would also be reversible with 1996, public meeting on the contaminated with NMPABAO, the four more time. photobiology and photochemistry of highest contained 2-bromo-2-nitro-1,3- The agency has determined that this sunscreens (Ref. 12), the agency is not propanediol, an indirect nitrosating study does not present sufficient data to aware of any evidence at this time that agent. The agency concluded that there exclude padimate O from the final demonstrates a safety concern from the would be no nitrosamine contamination monograph and that an adequate safety use of micronized titanium dioxide in if these products were formulated margin exists for its use as an OTC sunscreen products. While micronized without the nitrosating agent. As noted sunscreen ingredient. titanium dioxide does not meet the by several of the comments, the industry 19. Two comments submitted safety proposed definition of a sunscreen is aware not to formulate with known and/or efficacy data to support Category opaque sunblock, the agency has not nitrosating agents in the presence of I status for micronized titanium dioxide included the use of this term in the final amines in order to avoid nitrosamine (Refs. 9 and 10). One comment stated monograph (see section II.L, comment contamination of its products. that micronized titanium dioxide is not 52 of this document). The potential for 18. One comment submitted a a new material but is a selected titanium dioxide particles to reference to a subchronic oral toxicity distribution of existing material that agglomerate in formulation, which study in rats conducted with padimate provides higher SPF values while being could result in lower SPF values, is O which a chemical manufacturer had transparent and esthetically pleasing on addressed by the final product SPF test.

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The SPF data that the agency reviewed ingredients when used in combination. Although the agency needs assurance (Ref. 9) did not indicate such a problem. One comment (Ref. 15) submitted in that each ingredient is contributing to Micronized titanium dioxide meets vitro SPF testing data for several the effectiveness of the product, it does current USP monograph specifications different combinations. Although these not want to impose unnecessary testing for titanium dioxide with the exception data showed a statistically significant requirements on sunscreen product that the material contains more increased efficacy for lower than manufacturers. Therefore, the agency is associated water. In both the July minimum concentrations, they were not removing the minimum concentration through August 1996 and 1998 issues of predictive of the SPF values that would requirement for sunscreen active the Pharmacopeial Forum (Refs. 13 and be obtained with human testing and, ingredients proposed in § 352.20 and is 14), the United States Pharmacopeial therefore, were not used to support adding the requirement that: (1) The Convention published in-process lower concentrations of sunscreen concentration of each active sunscreen revision proposals to make the active ingredients when used in ingredient used in a combination monograph for titanium dioxide more combination. The other comment (Ref. product must be sufficient to contribute applicable to ingredients used in 16) submitted in vivo SPF testing data a minimum SPF of not less than 2 to the sunscreen drug products. The agency conducted according to the procedure finished product, and (2) the finished will work with the USP in the future to proposed in the tentative final product must have a minimum SPF of update this monograph as necessary. monograph (58 FR 28194 at 28298 to not less than the number of the 20. One comment stated that it is 28301) in which a selected cross section sunscreen active ingredients used in unnecessary to set the maximum limit of active ingredients were tested in pairs combination multiplied by 2. of titanium dioxide at 25 percent. by substituting water or the solvent E. Comments on Labeling and Testing The Panel discussed the safety and system for the active ingredients. The Procedures for UVA Sunscreen Drug effectiveness of 2 to 25 percent titanium data were evaluated using a matched Products dioxide in the ANPRM (43 FR 38206 at pairs comparison statistical hypothesis 38250) and the agency concurred with test procedure and demonstrated that 22. In the sunscreen tentative final the Panel’s findings in the tentative final concentrations of sunscreen active monograph (58 FR 28194 at 28232 and monograph (58 FR 28194 at 28295). The ingredients lower than the minimum 28233), the agency proposed to allow comment submitted no data and the concentrations proposed in claims relating to ‘‘broad spectrum agency has no data to support the use § 352.20(a)(2) for combination products protection’’ or ‘‘UVA radiation of titanium dioxide in sunscreen drug can provide a significant contribution to protection’’ for sunscreen products: (1) products at concentrations higher than product effectiveness. Containing sunscreen active ingredients 25 percent. The agency recognizes that with absorption spectra extending to 360 nm or above, and (2) that D. Comments on Dosages for Sunscreen technological advances in sunscreen demonstrate meaningful UVA radiation Drug Products formulation technology since 1978 have resulted in the ability to formulate protection using appropriate testing 21. Several comments objected to the products with lower concentrations of procedures to be developed. The agency minimum concentration requirements active ingredients and higher SPF received numerous comments for sunscreen active ingredients when values. The agency also recognizes that concerning such claims and current used in combination because they: (1) final product testing, and not the scientific evidence implicates UVA Are a less effective measurement of concentration of the active ingredients radiation as a major cause of, among effectiveness than a performance based in the combination, ensures product other things, photoaging of the skin SPF test, (2) impact on creativity and effectiveness. (Refs. 17 through 20). innovation of new formulations Due to the recent advances in In the Federal Register of September (technological advances since sunscreen formulation and the data 16, 1996, and October 22, 1998, the publication of the 1978 ANPRM have referenced previously, the agency is agency proposed a specific skin damage resulted in higher SPF values using concerned that setting minimum and premature skin aging claim for lower concentrations of active concentration requirements for active sunscreen products containing specific ingredients), (3) increase potential for ingredients in sunscreen combination concentrations of avobenzone or zinc irritation and allergic reactions due to drug products could subject consumers oxide based upon the submission of unnecessarily high concentration levels to unnecessary levels of active data to support claims of UVA radiation of active ingredients, (4) contradict ingredients. Therefore, the agency is protection in such products. The agency FDA’s position that the lowest effective only requiring the maximum will address comments pertaining to dose of an active ingredient be used to concentration limits in § 352.10 for measurement of UVA radiation produce the desired treatment effect, (5) sunscreen active ingredients when used protection in sunscreen products and result in higher manufacturing and in combination with another sunscreen related UVA radiation protection claims consumer costs due to unnecessary or when the combination is used with in a future issue of the Federal Register. levels of active ingredients, and (6) any other permitted active ingredient. Until then, UVA labeling may continue affect international harmonization However, any such ingredient used in in accord with the tentative final because Canada, Australia, and the combination with one or more monograph and its amendments. European Union have no concentration sunscreen active ingredients must be minimums for active ingredients when consistent with the regulations in F. General Comments on the Labeling of used in combination. § 330.10(a)(4)(iv), i.e., each of the Sunscreen Drug Products One comment petitioned the agency combined active ingredients must make 23. Several comments requested that to amend proposed § 352.20 of the a contribution to the claimed effect, the products containing sunscreen tentative final monograph to include a combining of active ingredients must ingredients as an adjunct to their main provision for formulating combination not decrease the safety or effectiveness purpose (e.g., a daily moisturizer or a sunscreen products at lower minimum of any individual active ingredient, and lipstick with a sunscreen) be considered concentrations. Two comments the combination must provide rational ‘‘secondary sunscreens’’ (intended only submitted efficacy data to support lower concurrent therapy for a significant for incidental or casual sun exposure), concentrations of sunscreen active proportion of the target population. and should be subject to different

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00016 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations 27673 labeling requirements from ‘‘primary’’ 30 or higher to provide adequate language in the labeling to suggest or sunscreen products. A number of protection, whether for continuous imply an unapproved therapeutic or comments likewise contended that some beach exposure or everyday (incidental) physiologic effect, would likely be of the labeling requirements for ‘‘beach’’ sun exposure. subject to regulatory action as an or ‘‘primary’’ sunscreen products are not The agency agrees that all sunscreen unapproved new drug (58 FR 28194 at appropriate for ‘‘non-beach’’ or products (whether drug only or drug- 28286 to 28287; see comments 37 and ‘‘secondary’’ sunscreen products. cosmetic) should be held to the same 38 in section II.I of this document). For example, the comments stated standards (e.g., active ingredient(s), 25. Three comments contended that that neither the proposed testing requirements, and labeling). the terms ‘‘natural,’’ ‘‘non-chemical,’’ ‘‘Recommended Sunscreen Product Regardless of what type of product a and ‘‘chemical free’’ are false and Guide’’ nor any other references to consumer chooses for sun protection, misleading in the labeling of OTC sunburn or sunburn protection should the essential information relevant to sun sunscreen drug products. The comments be required for secondary sunscreens. protection is the same. Thus, to ensure requested the agency to restrict the use Some suggested that the warnings be that consumers are adequately protected of these terms, especially for sunscreen reduced for secondary sunscreens to a from overexposure to the sun, all products containing titanium dioxide statement such as ‘‘For external use products intended for use as sunscreens and zinc oxide. only, keep out of eyes. Discontinue use should have similar labeling Generally, the appropriateness of if signs of irritation appear.’’ One requirements, irrespective of their these terms requires case-specific comment recommended that the method of use and irrespective of analysis to determine whether their use statement of identity for a secondary whether the sunscreen use is considered would render the product false or sunscreen should be its cosmetic primary or secondary to the product. misleading in any particular (see function, e.g., ‘‘moisturizer.’’ Another Consistent with this approach, the sections 502(a) and 602(a) of the act). recommended stating the primary agency has developed uniform, The agency notes, however, that the use (cosmetic) function first, then the streamlined labeling for all sunscreen of the terms ‘‘non-chemical’’ and secondary (drug) function, e.g., products (see sections II.I through II.L of ‘‘chemical-free’’ in the labeling of an ‘‘moisturizing face cream with this document). OTC sunscreen drug product, to sunscreen (or with SPF ll The agency also notes, however, that describe the ingredients contained in sunscreen).’’ a number of the labeling issues raised in the product, is likely to be considered The comments also suggested that these comments, including the issue of unacceptable. Sunscreen drug products secondary products be permitted to bear the ‘‘Recommended Sunscreen Product contain active (and often inactive) certain labeling claims relating to aging, Guide,’’ are addressed elsewhere in this ingredients that have been obtained such as ‘‘Helps reduce the chance of document. In addressing these issues, through a chemical process, or that have skin aging caused by incidental (or the agency gave careful consideration to been formulated into the finished casual) exposure to the sun,’’ or ‘‘Helps the wide variety of products marketed product through a chemical process. reduce premature aging from incidental for sunscreen uses. The term ‘‘natural’’ is more likely to (or casual) exposure to the sun.’’ Some Finally, the agency notes that under require context-specific analysis, also requested the option of being the recently issued standardized OTC particularly when used in labeling to allowed to relate skin aging claims drug product labeling format (§ 201.66 describe certain cosmetic aspects or directly to sun exposure, to inform (21 CFR 201.66)), manufacturers will uses of a sunscreen product. The term consumers more clearly that sun not be allowed to commingle drug and ‘‘natural,’’ however, would not be protection is not the primary attribute of cosmetic claims within the ‘‘Drug Facts’’ permitted to appear within the required the product, e.g., ‘‘Provides moisture to portion of the labeling. OTC drug labeling of a sunscreen facial skin throughout the day while 24. One comment requested product and is not considered to be protecting facial skin from skin aging clarification of the agency’s discussion interchangeable with any of the final due to exposure to sun.’’ Other of the term ‘‘anti-aging’’ as a claim or as sunscreen monograph language. comments recommended that the part of a trade name (58 FR 28194 at 26. Four comments opposed any proposed ‘‘Sun alert’’ statement or other 28287). The comment was concerned labeling that a sunscreen product ‘‘does references to ‘‘skin cancer’’ or other that products containing no sunscreen not provide UVA protection,’’ cancers should not be required for active ingredients and no sunscreen contending that FDA’s policy does not secondary products. claims, but which are sold under ‘‘anti- require disclaimers of broader purposes On the other hand, the agency also aging’’ trade names, would be subject to for which products are not useful. One received comments opposing the idea of regulation under the OTC drug comment added that an SPF 15 product recognizing ‘‘primary’’ and ‘‘secondary’’ sunscreen monograph. must block UVA radiation to be or ‘‘beach’’ and ‘‘non-beach’’ categories The use of ‘‘anti-aging’’ language in a effective in preventing sunburn. of sunscreen products. One comment product that made no sunscreen claims Two comments argued that a stated that any product containing a and contained no sunscreen active ‘‘negative warning’’ would be useful and sunscreen for the purpose of protection ingredients would not, as the comment necessary to warn and protect from the sun’s harmful effects should be asked, cause the product to fall within consumers and suggested ‘‘Does not held to the same standards as other the scope of the OTC sunscreen drug provide broad spectrum UVA sunscreen products. Another comment monograph. Such a product may, protection,’’ or ‘‘Caution: This product disagreed with the idea of allowing however, be subject to regulation as a does not provide protection from the different sets of claims for ‘‘primary’’ drug and as a new drug, under section recognized dangers of UVA rays which and ‘‘secondary’’ products. According to 201(g)(1) and (p) of the act, or as a may contribute to skin cancer and other this comment, claims such as ‘‘Helps cosmetic under section 201(i), or as both chronic skin disease.’’ reduce the chance of skin aging’’ are a drug and a cosmetic, depending upon Labeling should primarily direct drug claims and should be regulated as all of the circumstances surrounding its consumers towards the purposes for such. Finally, one comment stated that distribution. A product that is marketed which a product is considered useful. any sunscreen product (primary or under the final OTC sunscreen drug However, in establishing the conditions secondary) must have an SPF of 15 to monograph, but which uses anti-aging for the safe and effective use of an OTC

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00017 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 27674 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations drug product, the agency also must take agency will consider including this type The data provided by the comments into account, among other things, the of professional labeling in the in support of allowing numerical values context in which a product is monograph in the future when specific above 30 were of only limited use. Data customarily marketed and the potential supportive data are provided. from a field survey of 62 sunbathers on that consumers may use the product for Miami’s South Beach during July 1993 G. Comments on Sunscreen Drug a use for which it may not be beneficial (Ref. 21) did not provide any reliable (see sections 201(n) and 502(a) of the Products With High SPF Values conclusions on the frequency or extent act; § 330.10(a)(3)). 29. Numerous comments objected to of solar overexposure by light-skinned With these factors in mind, the agency the proposed maximum SPF value of 30 individuals or a benefit provided by will further evaluate whether ‘‘negative for OTC sunscreen drug products. The sunscreen products with an SPF value warnings’’ or disclosure statements are comments requested either that the above 30 as: (1) The sample size was needed when it completes the UVA agency adopt no limit or a limit of SPF small and the survey population did not portion of the sunscreen monograph in 50, for the following reasons: (1) UV represent a random sample, (2) the MED a future issue of the Federal Register. radiation exposure is increasing due to was not determined under controlled 27. Four comments contended that both lifestyle changes and depletion of conditions or standardized procedure, the signal words ‘‘Indications’’ and the atmospheric ozone layer, (2) skin and (3) full-day UVB radiation exposure ‘‘Directions’’ are not needed, take up cancer rates are increasing and there is was based on crude extrapolation of valuable label space, and should either no safe threshold to prevent cancer, (3) weather data. not be required or be optional, people using an SPF 30 sunscreen will Data from MED determinations on especially for sunscreen-containing drug have slight sunburn after receiving their 1,332 people with skin types I, II, and products that have some ‘‘traditional’’ 30 MED and therefore should have III, and UV radiation data for the month cosmetic uses (e.g., lipsticks). available sunscreens with higher SPF of June 1974 in 5 cities in the United The agency allows the signal word values, (4) high SPF sunscreens are States (Ref. 22), support the contention ‘‘Use’’ or ‘‘Uses’’ in place of needed for extremely sun-sensitive that a sizeable population may exist that ‘‘Indication’’ or ‘‘Indications.’’ This people during periods of unavoidable is at risk to more than 30 MED’s of UV short signal word is useful for intense or lengthy sun exposure, and radiation per day. However, the data are consumers, appropriate for dual use because of less than ideal usage by insufficient for extrapolation to the products, and does not clutter label consumers due to misjudging of their general population. The small sample space. Likewise, the agency concludes skin type and/or inadequate/infrequent size in this study limits the sensitivity that the signal word ‘‘Directions’’ is application, (5) there is a significant of the study and the study population useful for consumers and does not variation of skin types, sensitivities, and did not represent a random sample. clutter label space (64 FR 13254 at Finally, data from animal studies (Ref. UV radiation exposures among people, 13264 to 13268, March 17, 1999). The 23) showed that: (1) Limiting sunscreen (6) formulation techniques can increase agency is including § 352.52(f) in this protection to SPF 30 may not be prudent SPF values without necessarily final monograph to provide labeling if UV radiation damage is not related to increasing ingredient concentrations, (7) modifications for sunscreen products SPF; (2) a greater amount of sunscreen current information does not support an that meet the small package is needed to completely inhibit some of association between high SPF products specifications in § 201.66(d)(10) and are the nonerythemogenic damage caused and safety concerns, and (8) high SPF labeled for use on specific small areas by UV radiation, and (3) products provide for greater relative of the face (e.g., lips, nose, ears, and/or nonerythemogenic effects (e.g., exposure times and decreased UV around eyes). These products include photoimmunosuppression) occur with many traditional cosmetics (e.g., lipstick radiation transmission. Three comments suberythemal doses of UV radiation (as or eye makeup) that may contain (Refs. 21, 22, and 23) submitted can be obtained with the use of low or sunscreens. These products will be supporting data. high SPF sunscreens). While the agency allowed to present a condensed ‘‘Uses’’ Some comments stated that ‘‘High agrees that higher SPF values may section and may omit directions for use SPF’’ (i.e., above SPF 30) products are provide for greater relative exposure if they are marketed in a lipstick form. on the market and used by consumers, times, the SPF test is not the appropriate 28. One comment requested that the and that limiting SPF values would measurement of protection from monograph include professional stifle sunscreen product development nonerythemogenic damage because SPF labeling for both UVB and UVA and preventative health benefits. Other is only a measure of erythema. The radiation protection to assist health comments argued that sunscreens with agency finds that the data from these professionals to select appropriate high SPF values provide increased studies were not sufficient to either products. The comment recommended protection from ultraviolet radiation support or dismiss limiting the inclusion of the absorption spectrum of effects such as maximum SPF value in this final rule. each sunscreen in the product and photoimmunosuppression and are The agency continues to agree with suggested that the labeling include needed by those with ‘‘dermatological the comments about overall increases in information that the product: (1) problems.’’ both UV radiation exposure (58 FR Protects against drug-induced In contrast, some comments 28194 at 28223), skin cancer rates (58 photosensitization reactions induced by supported the agency’s proposal to limit FR 28194 at 28227), and the variation of UV radiation in the ranges ll nm to SPF values to 30 to stop the promotional skin types, sensitivities, and UV ll nm, and (2) other truthful and ‘‘bidding war’’ or ‘‘horsepower race.’’ radiation exposures among people (58 nonmisleading statements describing Another comment contended that real FR 28194 at 28222). The agency also both UVB and UVA radiation protection consumer benefit is achieved through agrees with the comment that a person against photosensitization reactions. appropriate balance of SPF, using an SPF 30 sunscreen could have The agency did not propose substantivity, UVA radiation protection, a slight sunburn after being exposed to professional labeling in the tentative irritation potential, and cost, whereas their 30 MED (i.e., after their skin final monograph, but did ask for data to SPF values above 30 provide only receives a MED). However, the agency be submitted (58 FR 28194 at 28210 and ‘‘incremental benefit’’ and an continues to believe that an SPF 30 28245). No data were received. The unnecessary increase in drug exposure. sunscreen product provides adequate

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The comment On the other hand, the agency is also dermatologists asked that a specific SPF concluded that the water resistance test aware that many OTC sunscreen 50 product be allowed to remain on the is less stressful than the sweat resistance products with SPF values above 30 are market because it is needed for the test. currently marketed and are increasingly ‘‘ultrasensitive patient’’ and for patients The agency does not find the data used by consumers. Numerous with ‘‘dermatological problems.’’ The submitted in the studies sufficient to comments from health professionals, agency has previously discussed the use support the comment’s contention. The consumers, and industry provide actual of high SPF sunscreen drug products to studies each comprised distinct subject use information in support of SPF protect consumers with photosensitivity populations and addressed a single values above 30 for what may be a diseases (58 FR 28194 28225) and the variable, i.e., the effect of water substantial number of sun-sensitive need to provide data for such uses (see exposure or induced sweating on a people in this country. Further, as section II.F, comment 28 of this product’s SPF. Therefore, a comparison numerous comments noted: (1) There is document) as the absorption spectrum of mean SPF values across studies is not a lack of data to correlate higher than of a specific product, not necessarily the the appropriate measure of relative SPF 30 sunscreen products with SPF, may be the more clinically ‘‘stress’’ associated with these variables. corresponding safety problems, and (2) significant factor for such people. The agency believes that a randomized, modern formulation techniques have As discussed previously in this two-period crossover study design in a resulted in higher SPF values using comment 29 of section II.G of this single patient population would better lower active ingredient concentrations. document, the agency has concluded have addressed the comment’s Because of the numerous concerns that the use of SPF label values above contention. Further, the Panel’s sweat from health professionals, new data to 30 in OTC drug products is not and water resistance protocols provide support the need for SPF values above supported at this time. The agency, qualitative information and were not 30, and the lack of data concerning however, invites interested persons to designed to provide comparative safety problems with such SPF values, continue developing the test methods assertions requiring valid statistical the agency concludes that OTC needed to measure high SPF values, and inferences. Thus, the agency is allowing sunscreen drug products with SPF to submit the data in support of such water and sweat resistant claims based values above 30 should be available for methods to FDA. If test methods are upon the water resistance test those sun-sensitive consumers who developed, the agency also invites procedures in § 352.76 of this require such products based upon interested persons to consider proposed document. personal knowledge of their skin’s methods for communicating in labeling susceptibility to sunburn, experience the level of protection associated with 31. One comment contended that the with specific products, planned sun high SPF values (given the nonlinear ‘‘water resistant’’ labeling proposed in exposure, or the recommendation of a nature of the SPF rating system). These § 352.50(b)(1) and (c)(1) should not be health professional. The agency agrees and other well-supported improvements required for products labeled or with the comments that higher SPF to the methodology for accurately and purchased for uses other than values generally can provide for greater reproducibly measuring SPF values will swimming or bathing. relative exposure times and decreased be addressed, as appropriate, in future The agency notes that the water UV radiation transmission. However, issues of the Federal Register. Until resistance statements referenced by the the agency continues to believe that the then, OTC sunscreen drug products are comment were not required unless the additional sunburn protection provided permitted to be labeled with SPF values manufacturer wished to make water by an SPF 30 sunscreen and, e.g., an no higher than ‘‘30+’’ or ‘‘30 plus.’’ resistant claims in the labeling of its SPF 50 sunscreen (i.e., about a 1.3 Finally, the agency does not agree sunscreen products. This final rule also percent increase in absorption of with the argument that limiting SPF will not require a manufacturer to make erythemal UV radiation) is extremely values would stifle sunscreen product a water resistance claim for its small for most people. The agency is development and preventative health sunscreen product, even if the product also concerned about the ability of benefits. Undue emphasis for sunburn is determined to be water resistant. current testing methods to accurately protection should not be placed upon However, a manufacturer wishing to and reproducibly determine SPF values SPF value alone (i.e., ‘‘single focus make water resistance claims must for high SPF products (see section II.M, products’’). As noted by another comply with §§ 352.50(b) or (c) and comment 53 of this document). In comment, consumer benefit is achieved 352.52(b)(1)(ii) or (b)(1)(iii) of this addition, nonlinearity of the SPF rating through appropriate balance of several document, as applicable for ‘‘water system is a concept difficult to explain factors, including substantivity, UVA resistant’’ or ‘‘very water resistant’’ in the limited space on a product label. radiation protection, and irritation products. Therefore, the agency concludes that the potential. 32. Several comments urged the label SPF declaration for sunscreens agency to return to the ‘‘waterproof’’ with SPF values above 30 should be H. Comments on Water Resistant and ‘‘water resistant’’ label claims limited to one collective term, which Labeling and Testing for Sunscreen proposed by the Panel and to limit the appears in § 352.50(a) of this document Drug Products labeled SPF value to only the SPF after as follows: ‘‘For products with SPF 30. One comment agreed and several water resistance testing. Another values over 30. ‘‘SPF 30’’ (select one of disagreed with proposed comment requested only general the following: ‘‘plus’’ or ‘‘+’’). Any § 352.52(e)(2)(iii) and (e)(3)(iii) guidelines for claims such as ‘‘water statement accompanying the marketed concerning sweat resistant claims based resistant’’ or ‘‘sweat resistant’’ on the product that states a specific SPF value upon water resistance testing instead of basis that such claims reflect the above 30 or similar language indicating a specific sweat resistance test. One inherent characteristics of specific a person can stay in the sun more than comment submitted data from two formulations and not sunscreen 30 times longer than without sunscreen sweat resistance studies and two water ingredients.

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The agency thoroughly discussed use In addition, the agency believes that for The agency agrees that solar keratoses of the terms ‘‘waterproof’’ and ‘‘water consumers to compare products with are a clinical sign of skin damage. resistant’’ in the tentative final multiple performance characteristics, a However, although sunscreens are monograph (58 FR 28194 at 28228). The labeling claim of ‘‘very water resistant’’ associated with a statistically significant comments did not present any is best supported by a uniform testing decrease in solar keratoses after 1 or 2 arguments or data that the agency did standard. Should the agency receive years, the solar keratoses reduction in not previously consider. In addition, the data in the future indicating customary this study was small and neither the agency points out that performance usage patterns in excess of 80 minutes clinical nor biological significance of claims such as these for OTC sunscreen of water exposure, it will reconsider this this reduction has been established. drug products are based on final limit. Most solar keratoses never become skin product formulation. 35. One comment disagreed with the cancers and typically resolve The agency agrees with the comments agency’s proposal in the tentative final spontaneously (Refs. 27 and 28). that the more relevant SPF value for monograph (58 FR 28194 at 28278) that Because of the wide variability products labeled ‘‘water resistant’’ or manufacturers determine the waiting possible in the formulation of sunscreen ‘‘very water resistant’’ is the SPF value periods for the most effective use of products, not all sunscreen products are of the final product formulation their sunscreen products (i.e., the time identical in their UV radiation following water resistance testing. between application and exposure to the absorption characteristics. Sunscreen Therefore, in this document the agency sun or water, if applicable). This products may contain active ingredients is limiting the SPF label declaration to information would then be included in that absorb in different regions of the the SPF after water resistance testing the directions for the product. The UVB radiation spectrum (the primary and is modifying the testing procedures comment asserted there is no reason to cause of sunburn) or absorb in both the in § 352.76 to reflect deletion of the require a ‘‘time versus efficacy’’ study UVB and different regions of the UVA proposed dual SPF testing requirement for every sunscreen formula because radiation spectrum. Therefore, even the for sunscreen products with water studies show that products maintain degree/type of UV radiation protection resistant claims. their efficacy for up to 8 hours. reported in one study using a specific 33. Two comments suggested that In the tentative final monograph, the sunscreen formulation may not be ‘‘water resistant’’ labeling be permitted agency did not propose a specific relevant to all possible sunscreen for drug products retaining at least 80 method or testing procedure for the products within the scope of this final percent of their SPF value after static determination of a proper waiting monograph. Further, the agency does testing in pools and that any product period because of the variation in not believe that it is prudent to meeting this criterion could also be sunscreen product dosage forms and extrapolate claims for skin cancer or labeled ‘‘sweat proof.’’ The comments formulations. Instead, the agency further suggested that the term ‘‘very allowed manufacturers to make this skin aging based upon a test designed to water resistant’’ should be permitted for determination. However, the agency did only measure erythema (i.e., the SPF products retaining 90 to 98 percent of propose in § 352.52(d)(2) that a waiting test). their SPF after testing. period before sun or water exposure, if The agency has reviewed information The agency disagrees with the applicable, be included in the labeling concerning the mechanisms of skin comments. Simple immersion provides of sunscreen products for their most cancers and photoaging. UV radiation neither an aqueous shear stress nor effective use. In this final rule, the appears to have a dual role in the thermal challenge, and thus is an agency has included the requirement for induction of skin cancers as it can cause inadequate assessment of water a waiting period in the sunscreen several varieties of direct DNA damage resistance. In addition, no justification product application statement in (Refs. 23 and 29 through 32) plus was offered for the respective threshold proposed § 352.52(d)(1) for the reasons suppress the immune response to values of 80 percent and 90 to 98 stated in the tentative final monograph developing skin cancers (Refs. 33 percent. (58 FR 28278). The agency continues to through 37). This immune suppression 34. Several comments contended that allow the manufacturer to determine may be a critical variable as skin the water resistance testing procedures both the necessity for this statement cancers, unlike other cancer types, in § 352.76 should be amended to allow (based on the product’s formulation and evoke a strong immune response for continuation of the water exposure dosage form) and how the waiting (especially by Langerhans cells and T- regimen beyond the 80 minute total and period, if applicable, is determined. lymphocytes) (Ref. 38). In photoaging, suggested that the ‘‘very water resistant’’ there are multiple sites in the skin that claim be expanded beyond 80 minutes I. Comments on Indications for can be damaged by UV radiation (Ref. for products meeting such testing Sunscreen Drug Products 17). For example, recent studies support requirements. One comment provided 36. One comment urged the agency to the concept that specific UV radiation- data (Ref. 24) to support extended water more strongly state the effectiveness of induced enzymes (i.e., matrix resistance claims. Another comment sunscreens (a specific claim was not metalloproteinases) can mediate also proposed a testing protocol (Ref. suggested). The comment cited a connective tissue damage and result in 25) for an additional claim of controlled study of a broad spectrum, the premature aging effects seen in skin ‘‘rubproof’’ or ‘‘abrasion proof.’’ SPF 17 sunscreen on 431 Caucasian exposed to UV radiation (Refs. 19 and The agency does not concur with an subjects over one summer in Australia 20). These data also suggest that these expansion of the ‘‘very water resistant’’ (Ref. 26). The study showed that the mechanisms of carcinogenesis and claim. Although data submitted by the group using the sunscreen had photoaging can occur from doses of UV comment (Ref. 24) show that under significantly fewer solar keratoses and radiation below that required to produce testing conditions products may retain more remissions than the control group. sunburn (i.e., suberythemal doses). their SPF values for up to 270 minutes Another comment expressed concern Thus, even if no sunburn has occurred of water exposure, no usage data were that use of the term ‘‘help prevent skin with the use of a sunscreen, the presented to refute the Panel’s damage’’ may mislead consumers to consumer cannot assume that sun- determination of an 80 minute upper think that these products prevent skin induced skin damage that might exposure limit (58 FR 28194 at 28277). cancer and premature skin aging. contribute to the eventual development

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00020 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations 27677 of skin cancer or signs of photoaging has For the same reasons, the agency also 39. Several comments contended that not occurred. considers extended wear claims the extensive labeling proposed in the The agency agrees with the comment concerning a specific number of hours tentative final monograph was that terms such as ‘‘help prevent skin of ‘‘protection’’ (or similar terminology) excessive. For environmental concerns, damage’’ may mislead consumers to or an absolute claim such as ‘‘all-day the comments objected to the use of think that sunscreen use alone will protection’’ to be nonmonograph. extra packaging materials as a method of prevent skin cancer and premature skin Instead, the agency is including an including added labeling. One comment aging. However, the agency believes that accurate, simpler, and less confusing disagreed with the need for a specific an appropriate statement can be used to indication statement in this final rule statement of product indications on inform consumers that sunscreens may using two bulleted statements under the individual units of non-beach products reduce the risks of skin aging, skin ‘‘Uses’’ heading, as follows: ‘‘[bullet] properly labeled with an SPF value, and cancer, and other harmful effects from helps prevent sunburn’’ and ‘‘[bullet] cited limitations on labeling space. The the sun when used in a regular program higher SPF gives more sunburn comment suggested that manufacturers that includes limiting sun exposure and protection’’.1 be given the option to provide off- wearing protective clothing (see section 38. Several comments contended that package information at the point-of-sale II.L, comment 51 of this document). terms such as ‘‘skin aging,’’ rather than be required to place the 37. Several comments expressed ‘‘wrinkling,’’ ‘‘premature skin aging,’’ or statement(s) on each individual unit of concern that the statements ‘‘Allows ‘‘photoaging’’ should be permitted as the product. you to stay in the sun up to (insert SPF indications for sunscreens, especially if To balance the environmental and of product up to 30) times longer than protection is provided in the UVA II regulatory concerns, the agency has without sunscreen protection’’ and (320 to 340 nm) radiation region. One streamlined labeling in this final ‘‘Provides up to (insert SPF of product comment suggested that a label claim monograph by significantly reducing the up to 30) times your natural protection such as ‘‘Helps reduce the chance of amount of required labeling and making from sunburn’’ in proposed skin aging caused by incidental (or optional other labeling that was § 352.52(b)(1)(iii) and (b)(1)(iv) may casual) exposure to the sun’’ may help proposed as required in the tentative mislead consumers as to the amount to further position the product as a final monograph. The agency is also and degree of protection sunscreen cosmetic for consumers. The comment including § 352.52(f) in this final products provide. The comments were also suggested an indication statement: monograph to provide for additional concerned that this message will convey ‘‘Excessive, chronic sun exposure can labeling accommodations for sunscreen a more expansive meaning than lead to premature photoaging of the products that meet the small package intended and that consumers might be skin, characterized by drying, wrinkling specifications in § 201.66(d)(10) and are misled about how long they can stay in and thinning of the skin. Regular use of labeled for use on specific small areas the sun without risking any sun- a sunscreen can help protect against this of the face (e.g., lips, nose, ears, and/or induced skin injury. One comment condition.’’ around eyes) (see section IV, comment expressed additional concern because The agency discussed the use of terms 6 of this document). the SPF value is only a laboratory test such as ‘‘skin aging,’’ ‘‘wrinkling,’’ of a few minutes duration. ‘‘premature skin aging,’’ or J. Comments on Warnings for Sunscreen One comment also objected to the ‘‘photoaging’’ on sunscreen products in Drug Products unqualified use of terms such as the tentative final monograph (58 FR 40. One comment asked the agency to ‘‘shields from,’’ ‘‘protects from,’’ 28194 at 28236 and 28287). As permit reduced warning statements for ‘‘filters’’ or ‘‘screens out’’ the ‘‘sun’s discussed in the response to comments lip balm products containing sunscreens rays,’’ ‘‘sun’s harsh rays,’’ or ‘‘sun’s 36 and 37, the agency has determined based on their safe market history. The harmful rays’’ to ‘‘help prevent skin that the labeling should describe the comment argued that lip balms are not damage’’ proposed in § 352.52(b)(1)(v) product’s use in preventing sunburn. A applied to the eye area, and thus and (b)(1)(vi). The comment expressed more expansive set of indications is extensive eye warnings are not required. concern that these unqualified terms currently unsupported. The agency Two comments cited the long history of could imply complete protection from notes, however, that the final ‘‘Sun safe use of lipstick products containing the sun’s harmful rays and may mislead alert’’ statement (discussed in section sunscreens and suggested the reduced consumers by inducing a false sense of II.L, comment 51 of this document) does warning, ‘‘Discontinue use if signs of security when using sunscreen provide the consumer with information irritation appear.’’ products. about the role of sunscreens in reducing The agency discussed its rationale for As discussed in section II.I, comment skin aging, in a context that ensures that proposing an eye warning for sunscreen- 36 of this document, the agency believes the information will not be misleading. containing lip balms in comment 52 of that sunscreen use alone will not The agency, however, is continuing to the tentative final monograph (58 FR prevent all of the possible harmful consider whether certain sunscreens 28194 at 28229 to 28232), noting that effects due to the sun. Variation may provide protection against some lip balms could be used on other between individuals, UV radiation photoaging (58 FR at 28287) and has areas of the face. However, the agency absorption and substantivity of discussed this in tentative final has received neither data concerning sunscreen products, exposure monograph amendments for certain adverse reactions due to the use of conditions, and conditions of use sunscreens containing avobenzone or sunscreen-containing lip balms near the cannot promise a precise result for each zinc oxide based upon specific data eyes, nor information that such products individual. Thus, the agency agrees that submitted to the agency (see section II.E, are normally used in the eye area. These these statements could provide the comment 22 of this document). The products also are consistent with the wrong message and a false sense of agency will evaluate this issue further factors described in the final OTC security to some consumers. The agency when it completes the UVA portion of standardized content and format therefore is not including proposed the sunscreen monograph, in a future labeling rule (64 FR 13254 at 13270) for § 352.52(b)(1)(iii) through (b)(1)(vi) in issue of the Federal Register. considering additional labeling this final rule and considers these and modifications. Accordingly, this final similar statements to be nonmonograph. 1 See § 201.66(b)(4) monograph allows sunscreen-containing

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Consult a doctor if lipstick products containing sunscreens lip balms, the agency expects to adopt problem persists.’’ would provide minimal benefit to the same modification when it issues Since the tentative final monograph consumers and the omission of a the final monograph on OTC skin was published, the agency has directions statement is not likely to have protectant drug products. published a final rule revising the serious consequences (see section II.J, The proposed warning in format and content requirements for comment 40 of this document). § 352.52(c)(1)(iii) is now stated as a OTC drug product labeling (64 FR However, the agency believes that bullet under the ‘‘Stop use and ask a 13254). Section 201.66(c)(5)(i) requires directions would be useful for make-up doctor if’’ subheading as follows: the warning ‘‘For external use only’’ for products containing sunscreens because ‘‘[bullet] rash or irritation develops and all topical drug products not intended of the wide variety of make-up products lasts.’’ This warning appears in for ingestion. Therefore, it is not that are available. Therefore, the agency § 352.52(c)(1)(ii) in this document. necessary to state that warning in this is revising proposed § 352.52(d)(4) to Finally, lipsticks (and lip balms, which document and the warning in proposed read: ‘‘For products formulated as a will be addressed in the final § 352.52(c)(1)(i) is not included in this lipstick. The directions in paragraphs monograph on OTC skin protectant drug final monograph. The agency is (d)(1) and (d)(2) of this section are not products) will not be required to bear shortening the proposed warning in required.’’ The agency expects to the ‘‘For external use only’’ warning. § 352.52(c)(1)(ii). This warning appears finalize the same modifications for lip Accordingly, in this final monograph, in § 352.52(c)(1)(i) in this document as balm products when it finalizes the § 352.52(c)(2) allows lipsticks to omit a bullet under the ‘‘When using this monograph for OTC skin protectant the warning in § 201.66(c)(5)(i). product’’ subheading as follows: drug products. 41. One comment requested that an ‘‘[bullet] keep out of eyes. Rinse with 45. Several comments contended that eye irritancy warning need not be water to remove.’’ The agency is stating the proposed direction, ‘‘Children under required for products that contain the proposed warning in 2 years of age should use sunscreen titanium dioxide as the sole active § 352.52(c)(1)(iii) as a bullet under the products with a minimum SPF of 4,’’ is ingredient. The comment stated that ‘‘Stop use and ask a doctor if’’ misleading and has no scientific basis. titanium dioxide is an inert inorganic subheading as follows: ‘‘[bullet] rash or Some comments stated that the oxide (and thus is chemically distinct irritation develops and lasts.’’ This direction implies that an SPF 4 may be from all other Category I sunscreen warning appears in § 352.52(c)(1)(ii) in adequate for children and noted that the active ingredients, which are organic this document. Section 201.66(c)(5)(x) Skin Cancer Foundation advises use of compounds) and is an FDA approved requires the ‘‘Keep out of reach of SPF 15 or higher for both children and color additive for the eye area in both children’’ and accidental ingestion adults. The American Academy of drugs and cosmetics. The comment warning set forth in 21 CFR 330.1(g) for Dermatology questioned why children argued that determination of eye these products. irritancy should be based on total 43. One comment contended that the should not have the benefit of a more product formulation. A second proposed warning about swallowing in highly protective sunscreen. Other comment concurred that the labeling for § 352.52(c)(1)(i) would not be needed for comments suggested that this direction inorganic sunscreens, which are not eye so-called secondary sunscreen products should only be required for products irritants, should be differentiated from because adults using these products with an SPF lower than 4 because it organic sunscreens, which may be (which, according to the comment, have would be nonsensical and a waste of irritants in the eye. traditionally been marketed as label space on products with higher SPF The agency agrees that the eye cosmetics) would know not to ingest values. warning (proposed in § 352.52(c)(1)(ii)) them. The agency agrees with the comments is based on total formulation, not simply As discussed in section II.J, comment that this direction could mislead parents presence of an ingredient. The agency’s 42 of this document, the warning into believing SPF 4 is adequate for rationale was discussed in comments 52 proposed in § 352.52(c)(1)(i) has been children under 2 years of age. Therefore, and 62 of the tentative final monograph superseded by the warning required by the agency concludes it is not (58 FR 28194 at 28229 to 28232 and § 201.66(c)(5)(i). The new required appropriate and is not including it in 28241). Accordingly, this final warning no longer contains the § 352.52(d) in this document. monograph requires all sunscreen- statement about not swallowing the 46. One comment stated that the containing drug products to bear the eye product. words, ‘‘adults and children 6 months of warning in § 352.52(c)(1)(i). Only age and over’’ in proposed § 352.52(d)(1) products formulated as a lipstick (and K. Comments on Directions for are unnecessary because there is a lip balms, which will be addressed in Sunscreen Drug Products separate statement, ‘‘Children under 6 the final monograph on OTC skin 44. Two comments stated that the months of age: consult a doctor.’’ protectant drug products) may omit this proposed directions in § 352.53(d)(4) for Another comment suggested that warning (see § 352.52(c)(3) of this lipsticks and make-up preparations are lengthy directions for use by children 6 document). The agency will consider unnecessary because these products are months to 2 years of age are not omitting the eye warning requirement marketed primarily for their cosmetic appropriate for many product types for a particular formulation if data uses, which are self-evident. One (e.g., a daily facial moisturizer with a submitted in an NDA deviation comment contended that it is unlikely sunscreen) and should be revised to (§ 330.11 (21 CFR 330.11)) from the that consumers will modify their habits ‘‘For adult use only.’’ Another comment sunscreen monograph demonstrate it is of lipstick application and usage simply added that when ‘‘For adult use only’’ not an eye irritant. because the product contains a is used, then warning and cautionary 42. One comment suggested restating sunscreen. The other comment argued statements concerning use by children the proposed warnings in § 352.52(c)(1) that failure to follow directions for these would not be needed.

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The agency agrees with the comment submit that information for approval via the agency is not including the that the statement, ‘‘Children under 6 an NDA deviation as provided in recommended sunscreen product guide months of age: consult a doctor,’’ § 330.11. in this document. provides sufficient information 51. Many comments requested that L. Comments on Product Performance regarding the age limit for use and is the ‘‘Sun alert’’ in proposed Statements for Sunscreen Drug Products retaining it under § 352.52(d) as a bullet § 352.52(e)(6) be voluntary instead of with a small modification as follows: 49. Several comments recommended required labeling and suggested this ‘‘[bullet] children under 6 months of revisions to proposed § 352.52(e), the information could better be age: ask a doctor’’. Therefore, the agency statement on product performance. For disseminated at the point of purchase or is removing the phrase, ‘‘Adults and example, some comments suggested that through consumer education programs. children 6 months of age and over.’’ The multiple superlative category Some comments stated that the ‘‘Sun proposed directions for children 6 designations (e.g., ‘‘high,’’ ‘‘very high,’’ alert’’ is too weak and suggested months to 2 years of age referred to by and ‘‘ultra high’’) may foster consumer alternate language. One comment the comments in § 352.52(d)(1), (d)(2), confusion about the level of protection observed that the ‘‘Sun alert’’ fails to (d)(3), and (d)(5) stated: ‘‘Children each SPF provides. Other comments warn consumers that UV radiation may under 2 years of age should use stated that the current SPF scale does harm the immune system, impairing the sunscreen products with a minimum not encourage consumers to use higher body’s ability to fight infectious disease. SPF of 4.’’ As discussed in section II.K, SPF products. Other comments The comment did not provide data to comment 45 of this document, the disagreed with the indication ‘‘permits support this claim. agency concluded that this direction no tanning.’’ The agency agrees that the ‘‘Sun alert’’ was misleading and did not include it The agency has revised proposed should be optional on product labeling. in § 352.52(d) in this document. The § 352.52(e) in this document by Further, the agency has reevaluated the agency finds it unnecessary to include condensing the five proposed product ‘‘Sun alert’’ and concludes that its the direction ‘‘For adult use only’’ in categories to three broader ones, and has purpose should be to describe the role this document because there are only generalized the category designations. of sunscreens in a total program to two age groups in the directions: The new categories are: minimal reduce harmful effects from the sun. Children under 6 months of age and all sunburn protection for products with Marks (Ref. 39) has noted that other users of the product. SPF 2 to under 12; Moderate sunburn sunscreens ‘‘are normally recommended 47. One comment argued that the protection for products with SPF 12 to for use as an adjunct to other direction ‘‘apply generously’’ may be under 30; high sunburn protection for protection,’’ such as clothing, hats, and responsible for some skin irritation products with SPF 30 or above. These avoidance of the sun near midday. The complaints from consumers. However, product category designations (PCD) agency agrees with this concept, as do the comment did not provide data to should appear under the ‘‘Other many researchers (Ref. 40), the support its position. The comment information’’ heading and may also American Academy of Dermatology contended that application of smaller appear on the PDP. Further, products (Ref. 41), Centers for Disease Control amounts of sunscreen may provide are now described as providing (Ref. 41), and the Governments of adequate coverage, but that in the case minimal, moderate, or high protection Australia and New Zealand (Ref. 42). of sun protection, it may be best to err against tanning, thus deleting the For this reason, the agency has revised on the generous side. Another comment reference to tanning prevention that was the ‘‘Sun alert’’ to include other maintained that applying too little proposed in § 352.52(b)(2)(v)(B). protective actions consumers can take, sunscreen may significantly lower 50. Many comments opposed the and has clarified possible results. The protection in a geometric rather than a ‘‘recommended sunscreen product agency is including skin cancer in the linear fashion, e.g., an SPF 25 sunscreen guide’’ in proposed § 352.52(e)(4). Some ‘‘Sun alert’’ instead of the body’s ability applied half as thick as the amount comments noted that the guide is to fight infectious disease because, to applied for the SPF test may only have incomplete because it only considers date, skin cancer is the best documented the effect of SPF 8. skin type and not duration of exposure, adverse effect of UV radiation on the The agency agrees with the comments season, geographic location, and other immune system (Ref. 43). Accordingly, that adequate sunscreen should be factors that influence choice of product. § 352.52(e)(2) in this document provides applied to achieve full labeled SPF Other comments stated that the guide is the following optional ‘‘Sun alert,’’ protection. Therefore, the agency deceptive and may encourage which should appear under the ‘‘Other concludes that the directions in inappropriate use of lower SPF’s for information’’ heading and may also § 352.52(d)(1) of this final monograph to protection. Several comments stated appear on the PDP: ‘‘Limiting sun apply ‘‘liberally’’ or ‘‘generously’’ that labeling for many products is too exposure, wearing protective clothing, convey the appropriate message to small to accommodate the guide. Other and using sunscreens may reduce the ensure that consumers adequately apply comments suggested that information in risks of skin aging, skin cancer, and the sunscreen. the guide should be disseminated to other harmful effects of the sun.’’ The 48. One comment stated that the consumers through point of sale, agency encourages sunscreen agency should permit firms to provide television, and weather programs, rather manufacturers to voluntarily include reapplication instructions based on than being required in product labeling. this ‘‘Sun alert’’ in the labeling and to substantiation information the firm The agency recognizes that various otherwise make it available at point of possesses. The comment noted that factors influence the purchase of a purchase and through consumer some products may not need to be sunscreen product, including skin type, education programs. applied as frequently as some select geographic location, hours exposed to 52. Several comments suggested that time period. the sun, and sun reflections. While the the term ‘‘sunblock,’’ proposed in the The agency is including a general product guide was intended as a general definition in § 352.3(d) and as a labeling reapplication direction in § 352.52(d)(2). guidance for using these products, the statement for products containing Manufacturers who have data to support agency acknowledges that the guide is titanium dioxide that provide an SPF of reapplication instructions based on incomplete and could be confusing and 12 to 30 in § 352.52(e)(5), not be specific substantiation information may misleading to consumers. Accordingly, included in the final monograph. Some

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00023 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 27680 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations comments argued that the term is M. Comments on Testing Procedures for equation. Another comment stated that unclear and may mislead and confuse Sunscreen Drug Products the definition of E is incorrect because consumers into thinking that the 53. Several comments questioned the it is defined as ‘‘dose’’ (Joules/square product blocks all of the sun, when in meter (m2)) on the left side of the ability of current testing methods to Σ λ λ fact it does not. One comment stated accurately and reproducibly determine equation E = Vi ( ) * I ( ), whereas the that no product available totally blocks SPF values for high SPF products. Some right side of the equation is in terms of 2 sun damage. Numerous other comments comments contended that the spectra of irradiance (Watts/m ). The comment contended that the term ‘‘sunblock’’ currently used solar simulators also stated that the unit of time should be applied to all sunscreen (especially around 290 nm and above exposure (seconds) is missing on the ingredients that provide an SPF of 12 or 350 nm) could cause overestimation of right side of the equation. The agency acknowledges that this higher, as such products block at least SPF for high SPF sunscreens and calculation is not technically necessary 90 percent of the sun’s UV rays. One of recommended use of a specifications if the solar simulator emission spectrum the comments submitted a study (Ref. table that provided percent of erythemal does not change between exposures to 44) to show that micronized titanium contribution by wavelength regions. protected and unprotected skin. The dioxide absorbs short wavelength UV Other comments submitted data in radiation and reflects and scatters long same result can then be obtained by support of a high-SPF sunscreen control measuring the difference (i.e., ratio) in wavelengths, thereby functioning following concerns expressed by the similarly to chemical UVB radiation time required to produce erythema on agency in the proposed rule (58 FR protected versus unprotected skin. sunscreens. The comment contended 28194 at 28253 and 28254) that data that the method in which micronized However, the agency finds that the were not sufficient to demonstrate that calculation of E provides valuable titanium dioxide performs as a the testing methods used to evaluate sunscreen active ingredient further information and is necessary to sunscreen drug products with SPF demonstrate how the MED was justifies the use of the term ‘‘sunblock’’ values up to 15 are equally applicable determined during SPF testing. The for all sunscreen products with an SPF to evaluating sunscreen drug products agency agrees with the comment of 12 or higher. with SPF values above 15. Several concerning the missing variable of time The agency has decided not to comments submitted data and (in seconds) in the calculation of E and, include the term ‘‘sunblock’’ in the final information that questioned the ability accordingly, has modified the equation monograph and now considers this term of current testing methods to accurately in § 352.73 of this document to read as and reproducibly determine SPF values nonmonograph. The agency’s intention follows: ‘‘ E = Σ Vi (λ) * I (λ) * texp’’ in the tentative final monograph was to for high SPF products and requested provide information to consumers on significant changes to proposed subpart III. Recent Developments the method of product performance, not D of § 352.70. Other comments In the Federal Register of October 22, to imply greater protection from using a requested changes to the testing 1998, the agency proposed to amend the product labeled as a ‘‘sunblock.’’ The procedures proposed in subpart D of the tentative final monograph to include agency is concerned that the term sunscreen monograph that were zinc oxide as a single ingredient and in ‘‘sunblock’’ on the label of sunscreen unrelated to products with high SPF combination with any proposed drug products will be viewed as an values. Category I sunscreen active ingredient absolute term which may mislead or The agency believes that the test except avobenzone. Two comments confuse consumers into thinking that method proposed in the tentative final supported the proposal. One comment the product blocks all light from the monograph (TFM), for measuring SPF disagreed with the agency’s exclusion of values up to 30, represents at this time sun. For example, consumers might avobenzone from combinations with a straightforward, well-understood, and view an SPF 15 product labeled as a zinc oxide. Two of the comments urged sound method for measuring these sunblock as superior to a product the agency to expeditiously review and values. The agency therefore is labeled as an SPF 30 broad spectrum approve a citizen petition (Ref. 45) to finalizing the method proposed in the sunscreen. As nonmonograph labeling, recognize this combination. TFM. The agency recognizes, however, the term ‘‘sunblock’’ cannot appear The agency has informed the that testing methods in this area are anywhere in product labeling. petitioner that it is unable to approve evolving and that a number of the combination without appropriate In addition, the proposed definition of comments raised useful ideas for UVA radiation effectiveness data to ‘‘sunscreen opaque sunblock’’ in proposed improvements in the accuracy demonstrate the UVA radiation § 352.3(d) applied only to titanium and reproducibility of the agency’s protection potential of zinc oxide in dioxide and is inconsistent with how methodology. As discussed in response combination with avobenzone (Ref. 46). micronized titanium dioxide functions to comment 29 of section II.G of this The agency will reconsider this as an sunscreen active ingredient (Ref. document, the agency is also inviting combination for monograph status upon 44). Further, it is the radiation from the interested persons to continue working receipt of the appropriate data. UV portion (290 to 400 nm) of the sun’s on improving SPF testing methods, This final rule includes monograph spectrum that reaches the earth’s surface toward the development of accurate conditions for zinc oxide as a sunscreen and may produce skin erythema, methods for measuring high SPF values. active ingredient at concentrations up to melanogenesis, and cancer. The agency In future issues of the Federal Register, 25 percent when used alone or in believes that claims of protection if appropriate, the agency will consider combination with any monograph beyond 400 nm (i.e., protection from proposed improvements to its testing sunscreen active ingredient except visible and infra red light) are methodology. avobenzone. nonmonograph and not within the 54. One comment contended that the scope of this document. Therefore, to calculation of erythema effective IV. Additional Changes provide clear and consistent labeling, exposure (E) serves no practical purpose 1. The agency has determined that for the agency is not including proposed in the calculation of SPF because the E an active ingredient to be included in an §§ 352.3(d) and 352.52(e)(5) in this constant is common to both the OTC drug final monograph it is document. numerator and denominator of the necessary to have publicly available

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00024 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations 27681 chemical information that can be used references to any other indication § 352.52(b)(1)(ii) and (b)(1)(iii) in this by all manufacturers to determine that except that pertaining to the prevention document. the ingredient is appropriate for use in of sunburn (see section II.I, comment 37 5. The agency has modified references their products. Compendial monographs of this document), (2) adding (in to ‘‘tanning’’ and ‘‘prolongs exposure include an ingredient’s official name, § 352.52(b)(2) of this final rule) guidance time’’ in proposed § 352.52(b)(2) by chemical formula, and analytical on SPF selection due to simplification combining the PCD claim in chemical tests to confirm the quality of the PCD in proposed § 352.52(e)(1) § 352.52(e)(1) of this document with and purity of the ingredient. These and deletion of the Recommended either the phrase ‘‘protection against monographs establish public standards Product Guide in proposed sunburn’’ or ‘‘protection against for the strength, quality, purity, and § 352.52(e)(4) (see section II.L, sunburn and tanning.’’ Based upon packaging of ingredients and drug comments 49 and 50 of this document), current information, the agency believes products available in the United States. and (3) deleting the quantitative claims that the terms proposed in the tentative In the Federal Register of June 8, (i.e., ‘‘up to (insert SPF of product up to final monograph could send the wrong 1994, FDA deleted digalloyl trioleate, 30) times’’) and terms such as ‘‘screens,’’ message relative to the dangers of even ethyl 4-[bis(hydroxypropyl)] ‘‘shields,’’ etc., concerning sunburn suberythemal UV radiation exposure aminobenzoate, glyceryl aminobenzoate, protection throughout proposed and give consumers a false sense of lawsone with dihydroxyacetone, and § 352.52(b) (see section II.I, comment 37 security concerning sun exposure and red petrolatum from the tentative final of this document). sunscreen use. The agency has reduced monograph due to the lack of interest in 3. The tentative final monograph and simplified the other optional, establishing USP compendial allowed reduced labeling directions on additional indications in proposed monographs for these ingredients. sunscreen products if formulated as a § 352.52(b)(2) to reflect a modified, Lawsone with dihydroxyacetone make-up preparation, lipstick, lip balm, simpler, combined version of the PCD in subsequently remained under agency or skin preparation and labeled with proposed § 352.52(e)(1) (see section II.L, consideration due to increased interest claims relating only to the prevention of comment 49 of this document) and the by manufacturers in establishing a ‘‘lip damage,’’ ‘‘freckling,’’ or ‘‘uneven ‘‘Recommended Product Guide’’ in compendial monograph. Of the 18 coloration.’’ Because there is no proposed § 352.52(e)(4) (see section II.L, remaining sunscreen active ingredients convincing evidence that SPF testing comment 50 of this document). Because under consideration in the tentative predicts protection from anything but the agency has deleted reference to use final monograph (58 FR 28194 at 28295, sunburn (see section II.I, comment 36 of of the term ‘‘Sunblock’’ in proposed amended at 61 FR 48645 and 63 FR this document), the agency is not section § 352.52(e)(5) (see section II.L, 56584), 16 (aminobenzoic acid, including proposed § 352.52(b)(1)(v), comment 52 of this document), it has avobenzone, cinoxate, dioxybenzone, (b)(1)(vi), (d)(4), and (d)(5) in this deleted reference to ‘‘Reflects the homosalate, menthyl anthranilate, document. The agency will consider burning rays of the sun’’ in proposed octocrylene, octyl methoxycinnamate, including such claims in the monograph § 352.52(b)(3) for the same reasons. octyl salicylate, oxybenzone, padimate when specific supportive data are 6. Several comments requested O, phenylbenzimidazole sulfonic acid, provided or a specific clinically relevant labeling exemptions or flexibility for sulisobenzone, titanium dioxide, final formulation test is developed. packages that are too small to trolamine salicylate, and zinc oxide) 4. Numerous comments requested accommodate all required information. currently have compendial monographs. deletion of the dual SPF testing of water Some comments specifically requested Two (diethanolamine resistant products in proposed flexible labeling for products based methoxycinnamate and lawsone with § 352.50(b)(2) and (c)(2). The agency upon their intended use, such as dihydroxyacetone) do not have a current agrees with the comments (see section lipsticks and lip balms. or proposed compendial monograph. II.H, comment 32 of this document) and As discussed in the final rule The agency is including in § 352.10 of has revised proposed §§ 352.50(b)(2) establishing standardized format and this document the 16 sunscreen active and (c)(2) and 352.76 to require only the content requirements for the labeling of ingredients that currently have a SPF value after water resistant testing. OTC drug products (64 FR 13254 at compendial monograph. The agency is Further, the agency has modified and 13267 to 13268 and 13289), the agency reserving the appropriate paragraphs in made optional the reapplication has established specifications for small proposed § 352.10 for the two active directions in proposed §§ 352.52(d)(1) packages in § 201.66(d)(10). The agency ingredients without compendial and (d)(2) (see section II.K, comment 48 also stated in the final labeling rule that monographs in case a monograph is of this document). These changes to it will consider additional approaches developed for either ingredient. proposed § 352.52(d) provide flexibility for accommodating certain small- Dihydroxyacetone has been proposed by allowing manufacturers to expand on package products in their respective for a compendial monograph, but none reapplication information necessary for OTC drug monograph proceedings. has been proposed for lawsone. Because specific sunscreen formulations and by The agency considers the required these two active ingredients are used in equalizing requirements between OTC drug labeling information essential conjunction, lawsone must have a products with and without water for the safe and effective use of these compendial monograph in order for resistance claims and between products and important to consumers lawsone with dihydroxyacetone to be sunscreen drug and drug-cosmetic for selection of an appropriate product. included in the sunscreen final products. Thus, the water resistance Nevertheless, the agency agrees that monograph. labeling in § 352.52(b)(1)(ii) and excessive labeling requirements may 2. The agency has revised proposed (b)(1)(iii) of this document should also discourage manufacturers from § 352.52(b) in response to comments serve as a directive for reapplication of marketing certain products, such as requesting reduction, streamlining, and the product. In summary, for products lipsticks or lip balms containing flexibility of sunscreen labeling and in making water and/or sweat resistance sunscreens, which provide significant accordance with new data reviewed by claims, the agency has modified and public health benefit. the agency (see section II.I of this combined water resistance statements In this OTC drug rulemaking, the document). The agency has revised formerly in proposed § 352.52(e)(2), agency has included several proposed § 352.52(b)(1) by: (1) Deleting (e)(3), (d)(1), and (d)(2) into accommodations for products such as

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00025 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 27682 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations lipsticks (and lip balms, which will be § 310.545(a)(29), or that is not in 13. Pharmacopeial Forum, United States addressed in the final monograph on conformance with the monograph (21 Pharmacopeial Convention, Inc., Rockville, OTC skin protectant drug products), CFR part 352), may be considered a new MD, 22(4):2635–2636, July through August taking into consideration the intended drug within the meaning of section 1996. 14. Pharmacopeial Forum, United States uses of these products, the limited areas 201(p) of the act and misbranded under Pharmacopeial Convention, Inc., Rockville, to which these products are applied, section 502 of the act. Such a drug MD, 24(4):6547–6548, July through August and the overall safety profile of these product cannot be marketed for OTC 1998. products, and other factors described in sunscreen use unless it is the subject of 15. Comment No. C00406, Docket No. the final OTC labeling rule (64 FR 13254 an approved application under section 78N–0038, Dockets Management Branch. at 13270). The agency is including 505 of the act (21 U.S.C. 355) and 21 16. Comment No. C00404, Docket No. § 352.52(f) in this document to provide CFR part 314 of the regulations. An 78N–0038, Dockets Management Branch. for labeling modifications for sunscreen appropriate citizen petition to amend 17. Kligman, L. H., and A. M. Kligman, products that meet the small package ‘‘Ultraviolet Radiation-Induced Skin Aging,’’ the monograph may also be submitted in Sunscreens: Development, Evaluation, and specifications in § 201.66(d)(10) and are in accord with 21 CFR 10.30 and Regulatory Aspects, Lowe, N. J., N. A. labeled for use on specific small areas § 330.10(a)(12)(i). The agency will Shaath, and M. A. Pathak, eds., Marcel of the face (e.g., lips, nose, ears, and/or address sunscreen active ingredients Dekker, Inc., New York, pp. 117–137, 1997. around eyes). that have foreign marketing experience 18. Lavker, R., and K. Kaidbey, ‘‘The 7. The agency has revised §§ 700.35 and data at a future time. Any OTC Spectral Dependence for UVA-Induced and 740.19 (21 CFR 700.35 and 740.19) sunscreen drug product initially Cumulative Damage in Human Skin,’’ The in response to comments requesting introduced or initially delivered for Journal of Investigative Dermatology, 108:17– clarification on whether certain 21, 1997. introduction into interstate commerce 19. Fisher, G. J. et al., ‘‘Pathophysiology of products will be subject to regulation as after the effective date of the final rule drugs (see section II.B, comments 8 Premature Skin Aging Induced by Ultraviolet for § 310.545(a)(29) or this document Light,’’ The New England Journal of through 11 of this document). Section that is not in compliance with the Medicine, 337:1419–1428, 1997. 700.35 has been revised to make clear regulations is subject to regulatory 20. Lowe, N. J. et al., ‘‘Low Doses of that, generally, products that make sun action. Repetitive Ultraviolet A Induce Morphologic protection claims, whether express or Changes in Human Skin,’’ Journal of the implied, are subject to regulation as VI. References American Academy of Dermatology, drugs. Only those products that contain The following references are on 105:739–743, 1995. a sunscreen ingredient solely for a display in the Dockets Management 21. Comment No. C00282, Docket No. nontherapeutic, nonphysiologic use Branch (address above) and may be seen 78N–0038, Dockets Management Branch. 22. Comment No. C00365, Docket No. (e.g., as a color additive, or to protect by interested persons between 9 a.m. the color of the product such as in a nail 78N–0038, Dockets Management Branch. and 4 p.m., Monday through Friday. 23. Comment No. C00531, Docket No. polish or hair coloring product) (see 58 1. Comment No. CP1, Docket No. 78N– 78N–0038, Dockets Management Branch. FR at 28205), and which include a 0038, Dockets Management Branch. 24. Comment No. C00128, Docket No. labeling statement that accurately 2. Comment No. CP2, Docket No. 78N– 78N–0038, Dockets Management Branch. describes that use, may be marketed as 0038, Dockets Management Branch. 25. Comment No. SUP16, Docket No. 78N– 3. Comment No. CP3, Docket No. 78N– cosmetic products. Section 740.19 has 0038, Dockets Management Branch. 0038, Dockets Management Branch. 26. Thompson, S. C., J. D. Jolley, and R. been revised to make clear that the term 4. Comment No. CP7, Docket No. 78N– Marks, ‘‘Reduction of Solar Keratoses by ‘‘suntanning preparations’’ does not 0038, Dockets Management Branch. Regular Sunscreen Use,’’ The New England include products intended to provide 5. Comite de Liaison des Associations sun protection or otherwise to affect the Europeenes de L’Industrie de la Parfumerie, Journal of Medicine, 329:1147–1151, 1993. structure or any function of the body. des Produits Cosmetiques et de Toilette 27. Marks, R. et al., ‘‘Spontaneous Remission of Solar Keratoses: The Case for Suntanning preparations include gels, (COLIPA), SPF Test Method (Draft), The Recommendations of the COLIPA Task Force Conservative Management,’’ British Journal creams, liquids, and other topical of Dermatology, 115:649–654, 1986. products that are intended to provide ‘‘Sun Protection Measurement,’’ December 1992 in Comment No. C00365, Docket No. 28. Marks, R., and G. Rennie, ‘‘Malignant cosmetic effects on the skin while 78N–0038, Dockets Management Branch. Transformation of Solar Keratoses to tanning through exposure to UV 6. Peak, M. J., and J. C. van der Leun, Squamous Cell Carcinoma,’’ The Lancet, radiation (e.g., moisturizing or ‘‘Boundary Between UVA and UVB,’’ in 795–796, 1988. conditioning), or that are intended to Frontiers of Photobiology, edited by A. Shima 29. Kornhauser, A., W. G. Wamer, and L. give the appearance of a tan by et al., Excerpta Medica, Amsterdam, pp. 425– A. Lambert, ‘‘Cellular and Molecular Events imparting color through the application 427, 1993. Following Ultraviolet Irradiation of Skin,’’ in of approved color additives (e.g., 7. Comment No. LET 135, Docket 78N– Dermatotoxicology, F. N. Marzulli and H. I. 0038, Dockets Management Branch. Maibach, eds., Taylor & Francis, Washington, dihydroxyacetone) without the need for pp. 189–220, 1996. exposure to UV radiation (i.e., sunless 8. Dunkel, V.C. et al., ‘‘Evaluation of the Mutagenicity of an N-Nitroso Contaminant of 30. Kraemer, K. H., ‘‘Sunlight and Skin tanning products). the Sunscreen Padimate O,’’ Environmental Cancer: Another Link Revealed,’’ Proceeds of V. Conclusion and Molecular Mutagenesis, 20:188–198, the National Academy of Sciences U. S. A., 1992. 94:11–14, 1997. The agency is issuing a final 9. Comment No. C00364, Docket No. 78N– 31. Hurks, H. M. H. et al., ‘‘In Situ Action monograph establishing conditions 0038, Dockets Management Branch. Spectra Suggest that DNA Damage Involved under which OTC sunscreen drug 10. Comments No. C00397 and SUP21, in Ultraviolet Radiation-Induced products are generally recognized as Docket No. 78N–0038, Dockets Management Immunosuppression in Humans,’’ safe and effective and not misbranded; Branch. Photochemistry and Photobiology, 66:76–81, 16 ingredients listed in § 352.10 are 11. Fairhurst, D., and M. Mitchnick, 1997. 32. Burren, R. et al., ‘‘Sunlight and currently a monograph condition. Any ‘‘Particulate Sun Blocks: General Principles,’’ in Sunscreens: Development, Evaluation, and Carcinogenesis: Expression of p53 and drug product labeled, represented, or Regulatory Aspects, Marcel Dekker, Inc., New Pyrimidine Dimers in Human Skin Following promoted for use as an OTC sunscreen York, pp. 313–352, 1997. UVA I, UVA I + II and Solar Simulating drug that contains any of the 12. Comment No. TR3, Docket No. 78N– Radiation,’’ International Journal of Cancer, nonmonograph ingredients listed in 0038, Dockets Management Branch. 76:201–206, 1998.

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33. Hersey, P. et al., ‘‘Analysis of the Effect Executive Order 12866 directs agencies cannot quantify the overall expected of a Sunscreen Agent on the Suppression of to assess all costs and benefits of benefits, each provision of the rule will Natural Killer Cell Activity Induced in available regulatory alternatives and, support the ability of consumers to take Human Subjects by Radiation from Solarium when regulation is necessary, to select desired protective actions. Monograph Lamps,’’ The Journal of Investigative Dermatology, 88:271–276, 1987. regulatory approaches that maximize ingredients have been proven safe and 34. Van Prague, M. C. G. et al., ‘‘Effect of net benefits (including potential effective assuring the quality of Topical Sunscreens on the UV-Radiation- economic, environmental, public health sunscreen products. This benefits Induced Suppression of the Alloactivating and safety, and other advantages; consumers because it ensures that the Capacity in Human Skin In Vivo,’’ The distributive impacts; and equity). The product will provide ingredients that Journal of Investigative Dermatology, 97:629– agency believes that this final rule is safely protect against sunburn. The new 633, 1991. consistent with the principles identified product labeling will better inform 35. Miyagi, T., A. M. Bhutto, and S. in Executive Order 12866. OMB has consumers about the sunburn protection Nonaka, ‘‘The Effects of Sunscreens on UVB determined that the final rule is a Erythema and Langerhans Cell Depression,’’ provided by the products; and if The Journal of Investigative Dermatology, significant regulatory action as defined manufacturers choose to include the 21:645–651, 1994. by the Executive Order and so is subject optional ‘‘Sun alert’’ labeling statement, 36. Seite, S. et al., ‘‘Effects of Repeated to review. Under the Regulatory the product labeling can reference that Suberythemal Doses of UVA in Human Flexibility Act, if a rule has a significant the use of sunscreens may reduce the Skin,’’ European Journal of Dermatology, economic impact on a substantial risk of skin aging, skin cancer, and other 7:204–209, 1997. number of small entities, an agency harmful effects of the sun. These 37. Lavker, R. M. et al., ‘‘Cumulative must analyze regulatory options that labeling requirements, in conjunction Effects from Repeated Exposures to would minimize any significant impact with the format requirements of the Suberythemal Doses of UVB and UVA in of the rule on small entities. Title II of Human Skin,’’ Journal of the American OTC uniform labeling rule (64 FR Academy of Dermatology, 32:53–62, 1995. the Unfunded Mandates Reform Act 13254) will provide clearer and more 38. Baadsgaard, O., ‘‘In Vivo Ultraviolet requires that agencies prepare a written concise information that will benefit Irradiation of Human Skin Results in assessment of anticipated costs and consumers in at least four ways: (1) Profound Perturbation of the Immune benefits before proposing any rule that They will increase understanding System,’’ Archives of Dermatology, 127:99– may result in an expenditure in any 1 regarding the selection of sunscreen 109, 1991. year by State, local, and tribal drug products, (2) they will make 39. Marks, R., ‘‘Reduction of Actinic governments, in the aggregate, or by the Keratoses by Sunscreens,’’ in Sunscreens: product comparison easier, (3) they will private sector, of $100 million (adjusted enhance the ability to make informed Development, Evaluation, and Regulatory annually for inflation) (2 U.S.C. 1532). Aspects, Lowe, N. J., N. A. Shaath, and M. decisions regarding product purchases A. Pathak, eds., Marcel Dekker, Inc., New Because the rule may have a and proper use, and (4) they will make York, pp. 189–198, 1997. significant economic impact on a it easier to distinguish between 40. Dial, W. F., ‘‘Mouse Study Creates substantial number of small entities, sunscreen drug products that contain Controversy Over the Use of Sunscreens,’’ this section of the preamble constitutes sunscreens and suntanning products Cosmetic Dermatology, 7:47–48, 1994. the agency’s Final Regulatory Flexibility that do not. Finally, the new 41. Goldsmith, L., et al., ‘‘Proceedings from Analysis. Because the rule does not requirements for product testing will the National Conference to Develop a impose any mandates on State, local, or National Skin Cancer Agenda,’’ Journal of the assure the accuracy of the SPF value on tribal governments, or the private sector, the product label. By improving the American Academy of Dermatology, 34:822– that will result in an expenditure in any 23, 1996. accuracy of these ratings, this 1 year of $100 million or more, FDA is 42. Standards Australia/Standards New requirement will provide further not required to perform a cost-benefit Zealand, ‘‘Sunscreen Products—Evaluation assurance that consumers receive analysis according to the Unfunded and Classification,’’ AS/NZS 2604, 1993. adequate sunburn protection. 43. Beissart, S. and R. D. Granstein, ‘‘UV- Mandates Reform Act. Induced Cutaneous Photobiology,’’ Critical An analysis of the costs and benefits The rule will require all Reviews in Biochemistry and Molecular of this regulation, conducted under manufacturers and distributors (or their Biology, 31:381–404, 1995. Executive Order 12291, was discussed agents) to relabel their OTC sunscreen 44. Sayre, R. et al., ‘‘Physical Sunscreens,’’ in the tentative final monograph for drug products to comply with the Journal of the Society of Cosmetic Chemists, OTC sunscreen drug products (58 FR monograph language. The labeling of 41:103–109, 1990. 28194 at 28294). The agency received certain suntanning products that do not 45. Comment No. CP8, Docket No. 78N– contain sunscreens will need to include 0038, Dockets Management Branch. only one response to the specific request 46. Comment No. LET166, Docket No. for data and comment on the economic the new required warning statement. In 78N–0038, Dockets Management Branch. impact of this rulemaking. This some cases, the labeling of cosmetics 47. Food and Drug Administration, comment discussed the costs that would containing sunscreens for ‘‘Supplement to the Economic Impact result from proposed changes in nontherapeutic, nonphysiologic uses Analysis of the Sunscreen Drug Products for sunscreen product labeling and testing (e.g., to protect hair from sun damage) Over-the-Counter Human Use; Final methods. The agency’s review of this will need to describe the cosmetic role Monograph,’’ in OTC Vol. 06FR, Docket No. comment is included as follows. of the sunscreen ingredient(s). The SPF 78N–0038, Dockets Management Branch. of some OTC sunscreen drug products 48. Eastern Research Group, Inc., ‘‘Over- A. Background the-Counter Drug Reformulation Changes,’’ in may need to be retested using the OTC Vol. 06FR, Docket No. 78N–0038, The purpose of this document is to method described in the final Dockets Management Branch. establish conditions under which OTC monograph. In addition, only products sunscreen drug products are generally containing the active ingredients VII. Analysis of Impacts recognized as safe, effective, and not included in this final rule will be FDA has examined the impacts of this misbranded. The document sets specific generally recognized as safe, effective, final rule under Executive Order 12866, requirements for appropriate and not misbranded. Of the 18 active the Regulatory Flexibility Act (5 U.S.C. monograph ingredients, labeling format ingredients under consideration in the 601–612), and the Unfunded Mandates and content, and SPF value and water proposed rule, 16 currently have the Reform Act (2 U.S.C. 1501 et seq.). resistant testing. Although the agency required USP/N.F. compendial

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Because the required labeling ingredients are not included in the USP economic analysis of that rule excluded for OTC sunscreen drug products now and added to the monograph by May 21, redesign costs for all OTC drug products includes fewer words than the previous 2001, products containing these not marketed under current NDA’s or language and the final rule contains a ingredients would need to be current final monographs, explaining number of labeling modifications for reformulated to replace the that the agency would attribute all products used on small areas of the face nonmonograph ingredient with a redesign costs associated with future (which are usually marketed in small monograph ingredient, or the product final monographs to each final size packages), this rule is not expected must be removed from the market. monograph rule as it published. All to require manufacturers to increase the B. Number of Products Affected redesign costs for this final sunscreen package size or available labeling space. monograph therefore are attributed to (Although costs of redesigning labels for Based on data from FDA’s Drug this rule alone. future final monographs were excluded Listing System, the agency estimates Approximately 12,000 sunscreen drug from FDA’s analysis of its OTC drug that there are approximately 2,800 OTC SKU’s will have to be relabeled within product labeling rule, costs for sunscreen drug products (different a 2-year implementation period to increased package sizes were considered formulations, not including products comply with the labeling requirements in the analysis of impacts for that that differ only by color) and about of this final rule. In addition, regulation (64 FR 13254 at 13283)). 12,000 individual stockkeeping units approximately 550 suntanning SKU’s FDA estimated the cost of redesign by (SKU’s) (individual products, packages, will have to be relabeled within a 12- counting only the value of the label- and sizes). All of the SKU’s will need to month implementation period. (As years that would be lost, after adjusting be relabeled, some will require new SPF noted previously, FDA could not for the length of the traditional labeling testing, and those products lacking estimate the number of cosmetic cycle. The regulatory cost was approved active ingredients will need to products that contain a sunscreen for a calculated as the product of the number be reformulated to stay on the market. In addition, certain suntanning nontherapeutic use and that include the of SKU’s, the number of years of products and certain cosmetic products word ‘‘sunscreen’’ or similar terms in labeling life lost, and the value of each containing sunscreens will have to be product labeling. The agency believes, year of labeling life lost (see 64 FR 2 relabeled. As FDA’s Drug Listing System however, the relabeling of this group of 13254 at 13278 through 13284). does not include suntanning products, cosmetic products will impose a Table 1 in section VIII.C of this the agency used 1995 data from A. C. minimal economic burden because document details FDA’s estimates of the Nielsen, a recognized provider of market some of these products already include distribution of relabeling costs resulting data, to estimate that approximately 550 the required labeling, and most from the final rule. A weighted average suntanning SKU’s will be affected by manufacturers revise these labels for cost to redesign a label of $5,210 per the labeling requirements of this rule. marketing considerations more SKU was used to calculate the New labels will also be needed for frequently than the allowed 2-year relabeling cost of sunscreen drug cosmetic products that contain a phase-in period. Therefore, the agency’s products, whereas a weighted average sunscreen for a nontherapeutic use and estimates do not include a cost for cost of $6,620 per SKU was used to that include the word ‘‘sunscreen’’ or relabeling those products that contain calculate the cost of relabeling similar terms in product labeling. The sunscreens for a nontherapeutic, suntanning products. A detailed agency is unable to identify the number nonphysiologic use.) description of the cost analysis is on file of these cosmetic products, but does not Frequent labeling redesigns are a with the Docket Management Branch believe that there are a large number of recognized cost of doing business in the (Ref. 47). As shown, the total SKU’s in this category. OTC drug industry, particularly for incremental cost to relabel the drug-cosmetic and seasonal products. approximately 12,000 sunscreen drug C. Cost to Relabel Thus, SKU’s with labels that would SKU’s is about $1.5 million, while the The relabeling costs for this rule will normally be redesigned within the cost to relabel the approximately 550 be moderated to the extent that implementation periods were assumed suntanning SKU’s was about $1.8 manufacturers coordinate labeling to incur no additional costs. The cost for million. The greater per SKU cost for changes for the final sunscreen the remaining SKU’s was calculated as relabeling suntanning products reflects monograph with labeling changes the lost value of the remaining life-years the shorter, 12-month, phase-in period. required by the recent rule establishing of the existing label design. FDA With a shorter phase-in period, uniform format and content for OTC estimates that labeling for the majority manufacturers are less able to drug product labeling (64 FR 13254). (90 percent) of the SKU’s affected by incorporate labeling changes into These costs are not discussed in this this final rule are redesigned at least voluntary redesign cycles and, therefore, analysis, however, because they are every 2 years. Of the remaining SKU’s, lose label inventory.

TABLE 1.ÐONE-TIME COST TO RELABEL SUNSCREEN AND SUNTANNING SKU'S ($)

Type of Product Size of Company Drug Suntanning Total Cost

Small1 649,283 1,128,700 1,777,983

2 Mathematically the following formula was used where: Nx = number of SKU’s with labeling life of x to calculate the incremental relabeling costs: x = life of labeling in years (2, 3, or 6) years, and Σ Costyx = j NxAx(1/x), where j = 1 to (x-y) y = phase-in period in years Ax = amortized annual value of labeling with a Total Costy = Costy6 + Costy3 + Costy2 life of x years.

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TABLE 1.ÐONE-TIME COST TO RELABEL SUNSCREEN AND SUNTANNING SKU'S ($)ÐContinued

Type of Product Size of Company Drug Suntanning Total Cost

Large 860,677 691,800 1,552,477 Total Cost 1,509,960 1,820,500 3,330,460 1 See section VII.G of this document.

The one comment that raised not been tested using the monograph resistant or very water resistant) and economic issues in response to the SPF test method. However, the SPF test SPF factor tested, and ranges from tentative final monograph expressed method in this document is essentially $2,500 to $6,500. On the assumption concern about available labeling space the same as the method described in the that 50 percent of the traditional on small packages of sunscreen drug proposed rule. If manufacturers have sunscreen drug products, and none of products. The comment stated that all added new products, made formulation the make-up type sunscreen products, text needs to be concise. The agency changes, or otherwise needed to test or make water resistant claims, and 50 considered this comment in developing retest the SPF of their products since percent of the products that make water the final rule, which contains specific 1993, they would probably have used resistant claims make very water labeling modifications for small the most current (i.e., the proposed) test resistant claims, the estimated weighted packages and for sunscreen products method. Therefore, the agency estimates average cost of the SPF test is $3,514. used on small areas of the face (e.g., that from 15 to 30 percent of the FDA estimates the total cost of this lips, nose, ears, and/or around the eyes). sunscreen drug products will require requirement, therefore, to range from D. Cost to Retest SPF retesting as a result of this document. $3.1 million to $6.1 millions (see the FDA is uncertain about the number of The cost of the SPF test varies, following Table 2). OTC sunscreen drug products that have depending on the product claim (water

TABLE 2.ÐONE-TIME COST TO RETEST SPF ASSUMING 15 PERCENT OR 30 PERCENT COMPLIANCE RATES ($)

15 Percent Non-compli- 30 Percent Non-compli- Size of Company ance ance

Small 1,300,000 2,600,000 Large 1,800,000 3,500,000 Total Cost 3,100,000 6,100,000

E. Cost to Reformulate Because OTC sunscreen drug products completed for the one ingredient in are well characterized topical these two products or if the two Reformulation costs will depend on formulations, FDA estimates the cost to products are removed from the market, the number of products, if any, that will reformulate at about $350,000 per the cost of reformulation would be have no active ingredients with product. Thus, on the assumption that eliminated. completed USP compendial the manufacturer reformulates rather G. Small Business Impact monographs by the end of the than removes the products from the implementation period. At the present market, the one-time cost of Based on the analysis of FDA’s drug time, only two of the active ingredients reformulation for two products would listing system and other data described being considered do not have a USP be $700,000. previously, there are about 180 domestic monograph. According to the agency’s companies that manufacture OTC drug listing system, two products, F. Total Incremental Costs sunscreen and suntanning products. manufactured by one company contain The estimated total one-time Distributors were not assigned costs one of these ingredients. The agency is incremental cost of this rule, using the because manufacturers of OTC drug not currently aware of other products in midpoint of the cost range for retesting products are usually responsible for the marketplace that contain these two and reformulation is $8.6 million (see product labeling, testing, and ingredients. Table 3 of this document). These formulation. Approximately 78 percent The cost to reformulate a product estimates are based on 16 of the 18 of these firms meet the Small Business varies by the nature of the active sunscreen ingredients under Administration’s definition of a small reformulation, the type of product, and consideration having USP compendial entity for this industry (less than 750 the size and complexity of the company. monographs. If a USP monograph is employees).

TABLE 3.ÐTOTAL INCREMENTAL COST TO INDUSTRY ($)

Relabel Products Size of Company Retest SPF1 Reformulation2 Total Drug Suntanning

Small 670,000 1,100,000 2,000,000 n/a n/a Large 840,000 700,000 2,600,000 n/a n/a

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TABLE 3.ÐTOTAL INCREMENTAL COST TO INDUSTRY ($)ÐContinued

Relabel Products Size of Company Retest SPF1 Reformulation2 Total Drug Suntanning

Total Cost 1,510,000 1,800,000 4,600,000 700,000 8,610,000 1 Assumes 22.5 percent noncompliance (midpoint of range) 2 Assumes 2 products would require reformulation

The rule will require manufacturers of arrangements to comply with the and product retesting to be completed. sunscreens to relabel their products. paperwork and other requirements of The agency found that the savings to Some firms will need to retest the SPF this rule. industry of delayed implementation of these products, and one firm may (estimated to be about $845,000) were H. Analysis of Alternatives have to reformulate or remove two not great enough to justify delaying products from the market. Because of The agency altered several proposed appropriate use and safety information the 2-year implementation period, most regulatory provisions to reduce the to consumers of OTC sunscreen drug firms will be able to relabel during a economic burden of this rule on products. normal relabeling cycle, at no additional industry. For example, FDA decreased Finally, the agency is providing a 12- cost. FDA cannot estimate with the amount of required labeling and month implementation period for certainty the number of small firms that provided small package certain suntanning preparations to add will need to retest or reformulate their accommodations for certain products. new warning information. For this OTC sunscreen products, but projects The labeling required by the proposed category, consumers may believe that that from 15 to 30 percent of all rule would have increased the needed these products are providing sun products may need to be retested and label and/or package size for as many as protection when, in fact, they do not. that 2 products may need to be 90 percent of the sunscreen products. They may forego using other products reformulated. Costs will vary by firm, Such size adjustments could have that have been demonstrated to be depending on the type and number of imposed estimated additional one-time effective in providing sun protection, products requiring relabeling, retesting, relabeling costs of $18 million and believing that their tanning product and reformulation. The firm-specific annually recurring costs of $22 million provides some measure of protection. impact may vary inversely with the (see Eastern Research Group, ‘‘Cost Because the new warning for volume of product sales, however, Impacts of the Over-the-Counter suntanning preparations presents an because per unit costs will be lower for Pharmaceutical Labeling Rule’’ (Ref. important safety issue that needs to be products with high volume sales. Thus, 48)). Also, in response to the comment conveyed to consumers at the earliest the relative economic impact of product (see section II.H, comment 32 of this possible date, the agency considered retesting or relabeling may be greater for document), the agency has reconsidered requiring a 6-month implementation small firms than for large firms. its position on SPF testing of water period for these products. However, Because of the 2-year phase-in period resistant and very water resistant given the seasonal nature of these allowed for sunscreen drug and drug- products and eliminated the static test products, the agency was concerned that cosmetic products, which allows requirement for these products. As the some manufacturers may not have manufacturers the flexibility to average cost of the static test is sufficient time to incorporate the incorporate regulatory changes with approximately $2,800, the estimated labeling change without disrupting their voluntary/market-driven changes, the savings to industry due to the production schedules. By providing an economic impact of the relabeling elimination of this test is about additional 6 months to implement the requirement is relatively low $750,000. change, compliance costs were reduced (approximately $3.3 million). However, The agency also considered a number by $1.8 million. for those small companies that may of implementation alternatives to this have to relabel a substantial number of final rule. Generally, the agency allows VIII. Paperwork Reduction Act of 1995 products, the out-of-pocket costs could only a 1-year implementation period for FDA concludes that the labeling be significant. final monographs. However, because requirements in this document are not Also, the cost to a small company most sunscreen products are produced subject to review by the Office of needing to reformulate a product, seasonally, the 2-year period will Management and Budget because they estimated at approximately $350,000 substantially enhance the ability of the do not constitute a ‘‘collection of would be significant. This impact may industry to relabel and reformulate its information’’ under the Paperwork be moderated by other options available, products, if necessary, and sell its Reduction Act of 1995 (44 U.S.C. 3501 which may be more cost effective than existing product inventories. The 2-year et seq.). Rather, the labeling statements reformulation. For example, a period will also allow sunscreen are a ‘‘public disclosure of information manufacturer may be able to substitute manufacturers to coordinate the originally supplied by the Federal other formulations, shift production to a required labeling changes with routine government to the recipient for the contract manufacturer with an approved industry-initiated labeling changes and purpose of disclosure to the public’’ (5 formulation, or temporarily remove the changes required by the new OTC drug CFR 1320.3(c)(2)). product from the market and await the product labeling final rule (64 FR completion of a USP compendial 13254). IX. Environmental Impact monograph for the ingredient. Because A 3-year implementation period for The agency has determined that under the OTC drug industry is highly sunscreen drug products was 21 CFR 25.31(c) this action is of a type regulated, all firms are expected to have considered, but the agency determined that does not individually or access to the necessary professional that a 2-year period provides sufficient cumulatively have a significant effect on skills on staff or to make contractual time to allow the required relabeling the human environment. Therefore,

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(d) Sun protection factor (SPF) value. 21 CFR Part 352 352.10 Sunscreen active ingredients. 352.20 Permitted combinations of active The UV energy required to produce an Labeling, Over-the-counter drugs. ingredients. MED on protected skin divided by the UV energy required to produce an MED 21 CFR Part 700 Subpart CÐLabeling on unprotected skin, which may also be Cosmetics, Packaging and containers. defined by the following ratio: SPF 352.50 Principal display panel of all value = MED (protected skin (PS))/MED 21 CFR Part 740 sunscreen drug products. (unprotected skin (US)), where MED 352.52 Labeling of sunscreen drug (PS) is the minimal erythema dose for Cosmetics, Labeling. products. protected skin after application of 2 Therefore, under the Federal Food, 352.60 Labeling of permitted combinations of active ingredients. milligrams per square centimeter of the Drug, and Cosmetic Act, and under final formulation of the sunscreen authority delegated to the Commissioner product, and MED (US) is the minimal Subpart DÐTesting Procedures of Food and Drugs, 21 CFR part 352 is erythema dose for unprotected skin, i.e., added and 21 CFR parts 310, 700, and 352.70 Standard sunscreen. skin to which no sunscreen product has 740 are amended as follows: 352.71 Light source (solar simulator). been applied. In effect, the SPF value is 352.72 General testing procedures. the reciprocal of the effective PART 310ÐNEW DRUGS 352.73 Determination of SPF value. transmission of the product viewed as a 352.76 Determination if a product is water UV radiation filter. 1. The authority citation for 21 CFR resistant or very water resistant. part 310 continues to read as follows: 352.77 Test modifications. Subpart BÐActive Ingredients Authority: 21 U.S.C. 321, 331, 351, 352, Authority: 21 U.S.C. 321, 351, 352, 353, § 352.10 Sunscreen active ingredients. 353, 355, 360b–360f, 360j, 361(a), 371, 374, 355, 360, 371. 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, The active ingredient of the product 263b–263n. Subpart AÐGeneral Provisions consists of any of the following, within the concentration specified for each 2. Section 310.545 is amended by § 352.1 Scope. ingredient, and the finished product adding paragraph (a)(29), by revising (a) An over-the-counter sunscreen provides a minimum SPF value of not paragraph (d) introductory text, by drug product in a form suitable for less than 2 as measured by the testing adding and reserving paragraph (d)(30), topical administration is generally procedures established in subpart D of and by adding paragraph (d)(31) to read recognized as safe and effective and is this part: as follows: not misbranded if it meets each (a) Aminobenzoic acid (PABA) up to condition in this part and each general 15 percent. § 310.545 Drug products containing condition established in § 330.1 of this (b) Avobenzone up to 3 percent. certain active ingredients offered over-the- chapter. (c) Cinoxate up to 3 percent. counter (OTC) for certain uses. (b) References in this part to (d) [Reserved]. (a) * * * regulatory sections of the Code of (e) Dioxybenzone up to 3 percent. (f) Homosalate up to 15 percent. (29) Sunscreen drug products. Federal Regulations are to Chapter I of Title 21 unless otherwise noted. (g) [Reserved]. Diethanolamine methoxycinnamate (h) Menthyl anthranilate up to 5 Digalloyl trioleate § 352.3 Definitions. percent. Ethyl 4-[bis(hydroxypropyl)] aminobenzoate (i) Octocrylene up to 10 percent. Glyceryl aminobenzoate As used in this part: (a) Minimal erythema dose (MED). (j) Octyl methoxycinnamate up to 7.5 Lawsone with dihydroxyacetone percent. Red petrolatum The quantity of erythema-effective energy (expressed as Joules per square (k) Octyl salicylate up to 5 percent. * * * * * meter) required to produce the first (l) Oxybenzone up to 6 percent. (m) Padimate O up to 8 percent. (d) Any OTC drug product that is not perceptible, redness reaction with (n) Phenylbenzimidazole sulfonic in compliance with this section is clearly defined borders. acid up to 4 percent. subject to regulatory action if initially (b) Product category designation (o) Sulisobenzone up to 10 percent. introduced or initially delivered for (PCD). A labeling designation for introduction into interstate commerce (p) Titanium dioxide up to 25 percent. sunscreen drug products to aid in (q) Trolamine salicylate up to 12 after the dates specified in paragraphs selecting the type of product best suited percent. (d)(1) through (d)(31) of this section. to an individual’s complexion (r) Zinc oxide up to 25 percent. * * * * * (pigmentation) and desired response to § 352.20 Permitted combinations of active (30) [Reserved] ultraviolet (UV) radiation. (1) Minimal sun protection product. A ingredients. (31) May 21, 2001 for products subject sunscreen product that provides a sun The SPF of any combination product to paragraph (a)(29) of this section. protection factor (SPF) value of 2 to is measured by the testing procedures 3. Part 352 is added to read as follows: under 12. established in subpart D of this part.

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(a) Combinations of sunscreen active sunscreen product testing procedures in ‘‘minimum’’) ‘‘protection against’’ ingredients. (1) Two or more sunscreen § 352.76).’’ (select one of the following: ‘‘sunburn’’ active ingredients identified in (c) For products that satisfy the very or ‘‘sunburn and tanning’’)], or ‘‘[bullet] § 352.10(a), (c), (e), (f), and (h) through water resistant sunscreen product for skin that sunburns minimally’’. (r) may be combined with each other in testing procedures in § 352.76. (1) (ii) For products that provide an SPF a single product when used in the ‘‘Very’’ (select one of the following: of 12 to under 30. Select one or both of concentrations established for each ‘‘Water,’’ ‘‘Water/Sweat,’’ or ‘‘Water/ the following: [‘‘[bullet]’’ (select one of ingredient in § 352.10. The Perspiration’’) ‘‘Resistant.’’ the following: ‘‘provides moderate’’ or concentration of each active ingredient (2) ‘‘SPF (insert SPF value of the ‘‘moderate’’) ‘‘protection against’’ (select must be sufficient to contribute a product, as stated in paragraph (a)(1) or one of the following: ‘‘sunburn’’ or minimum SPF of not less than 2 to the (a)(2) of this section, after it has been ‘‘sunburn and tanning’’)], or ‘‘[bullet] for finished product. The finished product tested using the very water resistant skin that sunburns easily’’. must have a minimum SPF of not less sunscreen product testing procedures in (iii) For products that provide an SPF than the number of sunscreen active § 352.76).’’ of 30 or above. Select one or both of the ingredients used in the combination following: [‘‘[bullet]’’ (select one of the § 352.52 Labeling of sunscreen drug following: ‘‘provides high’’ or ‘‘high’’) multiplied by 2. products. (2) Two or more sunscreen active ‘‘protection against’’ (select one of the ingredients identified in § 352.10(b), (c), (a) Statement of identity. The labeling following: ‘‘sunburn’’ or ‘‘sunburn and (e), (f), (i) through (l), (o), and (q) may of the product contains the established tanning’’)], or ‘‘[bullet] for skin highly be combined with each other in a single name of the drug, if any, and identifies sensitive to sunburn’’. product when used in the the product as a ‘‘sunscreen.’’ (c) Warnings. The labeling of the (b) Indications. The labeling of the concentrations established for each product contains the following warnings product states, under the heading ingredient in § 352.10. The under the heading ‘‘Warnings:’’ ‘‘Uses,’’ all of the phrases listed in concentration of each active ingredient (1) For products containing any paragraph (b)(1) of this section that are must be sufficient to contribute a ingredient in § 352.10. (i) ‘‘When using applicable to the product and may minimum SPF of not less than 2 to the this product [bullet] keep out of eyes. contain any of the additional phrases finished product. The finished product Rinse with water to remove.’’ listed in paragraph (b)(2) of this section, must have a minimum SPF of not less (ii) ‘‘Stop use and ask a doctor if as appropriate. Other truthful and than the number of sunscreen active [bullet] rash or irritation develops and nonmisleading statements, describing ingredients used in the combination lasts’’. only the uses that have been established multiplied by 2. (2) For products containing any (b) [Reserved]. and listed in this paragraph (b), may ingredient identified in § 352.10 (c) [Reserved]. also be used, as provided in § 330.1(c)(2) marketed as a lipstick. The external use of this chapter, subject to the provisions only warning in § 201.66(c)(5)(i) of this Subpart CÐLabeling of section 502 of the act relating to chapter and the warning in paragraph misbranding and the prohibition in (c)(1)(i) of this section are not required. § 352.50 Principal display panel of all section 301(d) of the act against the (d) Directions. The labeling of the sunscreen drug products. introduction or delivery for introduction product contains the following In addition to the statement of into interstate commerce of unapproved statements, as appropriate, under the identity required in § 352.52, the new drugs in violation of section 505(a) heading ‘‘Directions.’’ More detailed following labeling statements shall be of the act. directions applicable to a particular prominently placed on the principal (1) For products containing any product formulation (e.g., cream, gel, display panel: ingredient in § 352.10. (i) ‘‘[bullet]1 lotion, oil, spray, etc.) may also be (a) For products that do not satisfy the helps prevent sunburn [bullet] higher included. water resistant or very water resistant SPF gives more sunburn protection’’. (1) For products containing any sunscreen product testing procedures in (ii) For products that satisfy the water ingredient in § 352.10. (i) ‘‘[bullet] § 352.76. (1) For products with SPF resistant testing procedures identified in apply’’ (select one or more of the values up to 30. ‘‘SPF (insert tested SPF § 352.76. ‘‘[bullet] retains SPF after 40 following, as applicable: ‘‘liberally,’’ value of the product up to 30).’’ minutes of’’ (select one or more of the ‘‘generously,’’ ‘‘smoothly,’’ or ‘‘evenly’’) (2) For products with SPF values over following: ‘‘activity in the water,’’ ‘‘(insert appropriate time interval, if a 30. ‘‘SPF 30’’ (select one of the ‘‘sweating,’’ or ‘‘perspiring’’). waiting period is needed) before sun following: ‘‘plus’’ or ‘‘+’’). Any (iii) For products that satisfy the very exposure and as needed’’. statement accompanying the marketed water resistant testing procedures (ii) ‘‘[bullet] children under 6 months product that states a specific SPF value identified in § 352.76. ‘‘[bullet] retains of age: ask a doctor’’. above 30 or similar language indicating SPF after 80 minutes of’’ (select one or (2) In addition to the directions a person can stay in the sun more than more of the following: ‘‘activity in the provided in § 352.52(d)(1), the following 30 times longer than without sunscreen water,’’ ‘‘sweating,’’ or ‘‘perspiring’’). may be used for products containing will cause the product to be misbranded (2) Additional indications. In addition any ingredient in § 352.10. ‘‘[bullet] under section 502 of the Federal Food, to the indications provided in paragraph reapply as needed or after towel drying, Drug, and Cosmetic Act (the act). (b)(1) of this section, the following may swimming, or’’ (select one of the (b) For products that satisfy the water be used for products containing any following: ‘‘sweating’’ or ‘‘perspiring’’). resistant sunscreen product testing ingredient in § 352.10: (3) If the additional directions procedures in § 352.76. (1) (Select one of (i) For products that provide an SPF provided in § 352.52(d)(2) are used, the the following: ‘‘Water,’’ ‘‘Water/Sweat,’’ of 2 to under 12. Select one or both of phrase ‘‘and as needed’’ in or ‘‘Water/Perspiration’’) ‘‘Resistant.’’ the following: [‘‘[bullet]’’ (select one of § 352.52(d)(1) is not required. (2) ‘‘SPF (insert SPF value of the the following: ‘‘provides minimal,’’ (4) For products marketed as a product, as stated in paragraph (a)(1) or ‘‘provides minimum,’’ ‘‘minimal,’’ or lipstick. The directions in paragraphs (a)(2) of this section, after it has been (d)(1) and (d)(2) of this section are not tested using the water resistant 1 See § 201.66(b)(4) of this chapter. required.

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(e) Statement on product ‘‘Warnings’’ states: ‘‘Keep out of eyes.’’ (1) In addition, the labeling of the performance—(1) For products and ‘‘Stop use if skin rash occurs.’’ product may contain any of the ‘‘other containing any ingredient identified in (v) The warning in § 201.66(c)(5)(x) of allowable statements’’ that are identified § 352.10, the following PCD labeling this chapter may be limited to the in the applicable monographs. claims may be used under the heading following: ‘‘Keep out of reach of (2) For permitted combinations ‘‘Other information’’ or anywhere children.’’ containing a sunscreen and a skin outside of the ‘‘Drug Facts’’ box or (vi) For a lipstick, the warnings ‘‘Keep enclosure. out of eyes’’ in § 352.52(f)(1)(iv) and protectant identified in § 352.20(b). (i) For products containing active ‘‘Keep out of reach of children’’ in (c) Warnings. The labeling of the ingredient(s) that provide an SPF value § 352.52(f)(1)(v) and the directions in product states, under the heading of 2 to under 12. (Select one of the § 352.52(d) may be omitted. ‘‘Warnings,’’ the warning(s) for each following: ‘‘minimal’’ or ‘‘minimum’’) (2) The labeling shall be printed in ingredient in the combination, as ‘‘sun protection product.’’ accordance with the requirements of established in the warnings section of (ii) For products containing active § 201.66(d) of this chapter except that the applicable OTC drug monographs. ingredient(s) that provide an SPF value any requirements related to For permitted combinations containing of 12 to under 30. ‘‘moderate sun § 201.66(c)(1), (c)(3), and (c)(7), and the a sunscreen and a skin protectant protection product.’’ horizontal barlines and hairlines identified in § 352.20(b). (iii) For products containing active described in § 201.66(d)(8), may be (d) Directions. The labeling of the ingredient(s) that provide an SPF value omitted. of 30 or above. ‘‘high sun protection product states, under the heading § 352.60 Labeling of permitted ‘‘Directions,’’ directions that conform to product.’’ combinations of active ingredients. (2) For products containing any the directions established for each Statements of identity, indications, ingredient in the directions sections of ingredient identified in § 352.10, the warnings, and directions for use, following labeling statement may be the applicable OTC drug monographs, respectively, applicable to each unless otherwise stated in this used under the heading ‘‘Other ingredient in the product may be information’’ or anywhere outside of the paragraph. When the time intervals or combined to eliminate duplicative age limitations for administration of the ‘‘Drug Facts’’ box or enclosure. ‘‘Sun words or phrases so that the resulting individual ingredients differ, the alert: Limiting sun exposure, wearing information is clear and understandable. directions for the combination product protective clothing, and using (a) Statement of identity. For a sunscreens may reduce the risks of skin combination drug product that has an may not contain any dosage that aging, skin cancer, and other harmful established name, the labeling of the exceeds those established for any effects of the sun.’’ Any variation of this product states the established name of individual ingredient in the applicable statement will cause the product to be the combination drug product, followed OTC drug monograph(s), and may not misbranded under section 502 of the by the statement of identity for each provide for use by any age group lower act. ingredient in the combination, as than the highest minimum age limit (f) Products labeled for use only on established in the statement of identity established for any individual specific small areas of the face (e.g., sections of the applicable OTC drug ingredient. For permitted combinations lips, nose, ears, and/or around eyes) monographs. For a combination drug containing a sunscreen and a skin and that meet the criteria established in product that does not have an protectant identified in § 352.20(b). § 201.66(d)(10) of this chapter. The title, established name, the labeling of the headings, subheadings, and information product states the statement of identity Subpart DÐTesting Procedures described in § 201.66(c) of this chapter for each ingredient in the combination, § 352.70 Standard sunscreen. shall be printed in accordance with the as established in the statement of following specifications: identity sections of the applicable OTC (a) Laboratory validation. A standard (1) The labeling shall meet the drug monographs. sunscreen shall be used concomitantly requirements of § 201.66(c) of this (b) Indications. The labeling of the in the testing procedures for chapter except that the title, headings, product states, under the heading determining the SPF value of a and information described in ‘‘Uses,’’ the indication(s) for each sunscreen drug product to ensure the § 201.66(c)(1), (c)(3), and (c)(7) may be ingredient in the combination as uniform evaluation of sunscreen drug omitted, and the headings, subheadings, established in the indications sections products. The standard sunscreen shall and information described in of the applicable OTC drug monographs, be an 8-percent homosalate preparation § 201.66(c)(2), (c)(4), (c)(5), and (c)(6) unless otherwise stated in this with a mean SPF value of 4.47 (standard may be presented as follows: paragraph. Other truthful and deviation = 1.279). In order for the SPF (i) The active ingredients nonmisleading statements, describing determination of a test product to be (§ 201.66(c)(2) of this chapter) shall be only the indications for use that have considered valid, the SPF of the listed in alphabetical order. been established in the applicable OTC standard sunscreen must fall within the (ii) The heading and the indication drug monographs or listed in this standard deviation range of the expected required by § 201.66(c)(4) may be paragraph (b), may also be used, as SPF (i.e., 4.47 ± 1.279) and the 95- limited to: ‘‘Use [in bold type] helps provided by § 330.1(c)(2) of this chapter, percent confidence interval for the mean prevent sunburn.’’ subject to the provisions of section 502 SPF must contain the value 4. (iii) The ‘‘external use only’’ warning of the Federal Food, Drug, and Cosmetic in § 201.66(c)(5)(i) of this chapter may Act (the act) relating to misbranding and (b) Preparation of the standard be omitted. the prohibition in section 301(d) of the homosalate sunscreen. (1) The standard (iv) The subheadings in act against the introduction or delivery homosalate sunscreen is prepared from § 201.66(c)(5)(iii) through (c)(5)(vii) of for introduction into interstate two different preparations (preparation this chapter may be omitted, provided commerce of unapproved new drugs in A and preparation B) with the following the information after the heading violation of section 505(a) of the act. compositions:

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COMPOSITION OF PREPARATION A AND PREPARATION B OF THE STANDARD SUNSCREEN

Ingredients Percent by weight

Preparation A Lanolin ...... 5.00 Homosalate ...... 8.00 White petrolatum ...... 2.50 Stearic acid ...... 4.00 Propylparaben ...... 0.05 Preparation B Methylparaben ...... 0.10 Edetate disodium ...... 0.05 Propylene glycol ...... 5.00 Triethanolamine ...... 1.00 Purified water U.S.P ...... 74.30

(2) Preparation A and preparation B (5) Calculation of the concentration of Skin Type and Sunburn and Tanning History are heated separately to 77 to 82 °C, homosalate. The concentration of (Based on first 30 to 45 minutes sun exposure with constant stirring, until the contents homosalate is determined by the after a winter season of no sun exposure.) of each part are solubilized. Add following formula which takes into I—Always burns easily; never tans preparation A slowly to preparation B (sensitive). consideration the absorbance of the II—Always burns easily; tans minimally while stirring. Continue stirring until sample of the test solution, the dilution (sensitive). the emulsion formed is cooled to room of the 1-percent solution (1:50), the III—Burns moderately; tans gradually (light ° temperature (15 to 30 C). Add sufficient weight of the sample of the standard brown) (normal). purified water to obtain 100 grams of homosalate sunscreen preparation (1 IV—Burns minimally; always tans well standard sunscreen preparation. gram), and the standard absorbance (moderate brown) (normal). (c) Assay of the standard homosalate value (172) of homosalate as determined V—Rarely burns; tans profusely (dark brown) sunscreen. Assay the standard (insensitive). by averaging the absorbance of a large VI—Never burns; deeply pigmented homosalate sunscreen preparation by number of batches of raw homosalate: the following method to ensure proper (insensitive). concentration: Concentration of homosalate = (2) A medical history shall be (1) Preparation of the assay solvent. absorbance x 50 x 100 x 172 = percent obtained from all subjects with The solvent consists of 1 percent glacial concentration by weight. emphasis on the effects of sunlight on acetic acid (V/V) in denatured ethanol. their skin. Ascertain the general health The denatured ethanol should not § 352.71 Light source (solar simulator). of the individual, the individual’s skin contain a UV radiation absorbing A solar simulator used for type (I, II, or III), whether the individual denaturant. determining the SPF of a sunscreen drug is taking medication (topical or (2) Preparation of a 1-percent solution product should be filtered so that it systemic) that is known to produce of the standard homosalate sunscreen provides a continuous emission abnormal sunlight responses, and preparation. Accurately weigh 1 gram of spectrum from 290 to 400 nanometers whether the individual is subject to any the standard homosalate sunscreen similar to sunlight at sea level from the abnormal responses to sunlight, such as preparation into a 100-milliliter sun at a zenith angle of 10 °; it has less a phototoxic or photoallergic response. (b) Test site inspection. The physical volumetric flask. Add 50 milliliters of than 1 percent of its total energy output examination shall determine the the assay solvent. Heat on a steam bath contributed by nonsolar wavelengths presence of sunburn, suntan, scars, and mix well. Cool the solution to room shorter than 290 nanometers; and it has ° active dermal lesions, and uneven skin temperature (15 to 30 C). Then dilute not more than 5 percent of its total tones on the areas of the back to be the solution to volume with the assay energy output contributed by solvent and mix well to make a 1- tested. The presence of nevi, blemishes, wavelengths longer than 400 percent solution. or moles will be acceptable if in the (3) Preparation of the test solution nanometers. In addition, a solar physician’s judgment they will not (1:50 dilution of the 1-percent solution). simulator should have no significant interfere with the study results. Excess Filter a portion of the 1-percent solution time-related fluctuations in radiation hair on the back is acceptable if the hair through number 1 filter paper. Discard emissions after an appropriate warmup is clipped or shaved. the first 10 to 15 milliliters of the time, and it should have good beam (c) Informed consent. Legally effective filtrate. Collect the next 20 milliliters of uniformity (within 10 percent) in the written informed consent must be the filtrate (second collection). Add 1 exposure plane. To ensure that the solar obtained from all individuals. milliliter of the second collection of the simulator delivers the appropriate (d) Test site delineation—(1) Test site filtrate to a 50-milliliter volumetric spectrum of UV radiation, it must be area. A test site area serves as an area flask. Dilute this solution to volume measured periodically with an for determining the subject’s MED after with assay solvent and mix well. This accurately-calibrated spectroradiometer application of either the sunscreen is the test solution (1:50 dilution of the system or equivalent instrument. standard or the test sunscreen product, or for determining the subject’s MED 1-percent solution). § 352.72 General testing procedures. (4) Spectrophotometric determination. when the skin is unprotected (control The absorbance of the test solution is (a) Selection of test subjects (male and site). The area to be tested shall be the measured in a suitable double beam female). (1) Only fair-skin subjects with back between the beltline and the spectrophotometer with the assay skin types I, II, and III using the shoulder blade (scapulae) and lateral to solvent and reference beam at a following guidelines shall be selected: the midline. Each test site area for wavelength near 306 nanometers. Selection of Fair-skin Subjects applying a product or the standard

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A test panel determining the smallest dose of energy tested while prone, the markings shall shall consist of not more than 25 that produces redness reaching the be made with the subject prone. subjects with the number fixed in borders of the exposure site at 22 to 24 (2) Test subsite area. Each test site advance by the investigator. From this hours postexposure for each series of area shall be divided into at least three panel, at least 20 subjects must produce exposures. To determine the MED, test subsite areas that are at least 1 valid data for analysis. somewhat more intense erythemas must square centimeter. Usually four or five (h) Response criteria. In order that the also be produced. The goal is to have person who evaluates the MED subsites are employed. Each test subsite some exposures that produce absolutely responses does not know which within a test site area is subjected to a no effect, and of those exposures that sunscreen formulation was applied to specified dosage of UV radiation, in a produce an effect, the maximal exposure which site or what doses of UV series of UV radiation exposures, in should be no more than twice the total radiation were administered, he/she which the test site area is exposed for energy of the minimal exposure. must not be the same person who the determination of the MED. (i) Rejection of test data. Test data applied the sunscreen drug product to shall be rejected if the exposure series (e) Application of test materials. To the test site or administered the doses of fails to elicit an MED response on either ensure standardized reporting and to UV radiation. After UV radiation the treated or unprotected skin sites, or define a product’s SPF value, the exposure from the solar simulator is if the responses on the treated sites are application of the product shall be completed, all immediate responses randomly absent (which indicates the expressed on a weight basis per unit shall be recorded. These include several product was not spread evenly), or if the area which establishes a standard film. types of typical responses such as the subject was noncompliant (e.g., subject Both the test sunscreen product and the following: An immediate darkening or withdraws from the test due to illness standard sunscreen application shall be tanning, typically greyish or purplish in or work conflicts, subject does not 2 milligrams per square centimeter. For color, fading in 30 to 60 minutes, and shield the exposed testing sites from oils and most lotions, the viscosity is attributed to photo-oxidation of existing further UV radiation until the MED is such that the material can be applied melanin granules; immediate reddening, read, etc.). with a volumetric syringe. For creams, fading rapidly, and viewed as a normal heavy gels, and butters, the product response of capillaries and venules to § 352.73 Determination of SPF value. shall be warmed slightly so that it can heat, visible and infrared radiation; and (a)(1) The following erythema action be applied volumetrically. On heating, an immediate generalized heat response, spectrum shall be used to calculate the care shall be taken not to alter the resembling prickly heat rash, fading in erythema effective exposure of a solar product’s physical characteristics, 30 to 60 minutes, and apparently caused simulator: especially separation of the by heat and moisture generally irritating Vi (λ) = 1.0 (250 < λ < 298 nm) formulations. Pastes and ointments shall to the skin’s surface. After the 0.094 (298 - λ Vi (λ) = 1.0 ) (298 < λ < 328 be weighed, then applied by spreading immediate responses are noted, each nanometers) on the test site area. A product shall be subject shall shield the exposed area λ 0.015 (139 - λ) λ spread by using a finger cot. If two or from further UV radiation for the Vi ( ) = 1.0 (328 < < 400 more sunscreen drug products are being remainder of the test day. The MED is nanometers) evaluated at the same time, the test determined 22 to 24 hours after (2) The data contained in this action products and the standard sunscreen, as exposure. The erythema responses of spectrum are to be used as spectral specified in § 352.70, should be applied the test subject should be evaluated weighting factors to calculate the in a blinded, randomized manner. If under the following conditions: The erythema effective exposure of a solar only one sunscreen drug product is source of illumination should be either simulator as follows: being tested, the testing subsites should a tungsten light bulb or a warm white BILLING CODE 4160±01±F

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BILLING CODE 4160±01±C subsite areas on each subject with an produce the MED of the protected skin (b) Determination of MED of the accurately-calibrated solar simulator. A and from the dose of UV radiation unprotected skin. A series of UV series of seven exposures shall be required to produce the MED of the radiation exposures expressed as Joules administered to the protected test sites unprotected skin (control site) as per square meter (adjusted to the to determine the MED of the protected follows: erythema action spectrum calculated skin (MED(PS)). The doses selected SPF value = the ratio of erythema effective according to § 352.73(a)) is administered shall consist of a geometric series of five exposure (Joules per square meter) (MED(PS)) to the subsite areas on each subject with exposures, where the middle exposure to the erythema effective exposure (Joules per square meter) (MED(US)). an accurately calibrated solar simulator. is placed to yield the expected SPF plus A series of five exposures shall be (d) Determination of the test product’s two other exposures placed SPF value and PCD. Use data from at administered to the untreated, symmetrically around the middle unprotected skin to determine the least 20 test subjects with n representing exposure. The exact series of exposures the number of subjects used. First, for subject’s inherent MED. The doses to be given to the protected skin shall selected shall be a geometric series each subject, compute the SPF value as be determined by the previously stated in § 352.73(b) and (c). Second, represented by (1.25n), wherein each established MED(US) and the expected compute the mean SPF value, x¯, and the exposure time interval is 25 percent SPF of the test sunscreen. For products standard deviation, s, for these subjects. greater than the previous time to with an expected SPF less than 8, the Third, obtain the upper 5-percent point maintain the same relative uncertainty exposures shall be the MED(US) times from the t distribution table with n-1 (expressed as a constant percentage), 0.64X, 0.80X, 0.90X, 1.00X, 1.10X, degrees of freedom. Denote this value by independent of the subject’s sensitivity 1.25X, and 1.56X, where X equals the t. Fourth, compute ts/ √n. Denote this to UV radiation, regardless of whether expected SPF of the test product. For quantity by A (i.e., A = ts/ √n). Fifth, the subject has a high or low MED. products with an expected SPF between calculate the SPF value to be used in Usually, the MED of a person’s 8 and 15, the exposures shall be the labeling as follows: the label SPF equals unprotected skin is determined the day MED(US) times 0.69X, 0.83X, 0.91X, the largest whole number less than x¯ - prior to testing a product. This MED(US) 1.00X, 1.09X, 1.20X, and 1.44X, where A. Sixth and last, the drug product is shall be used in the determination of the X equals the expected SPF of the test classified into a PCD as follows: if 30 + series of UV radiation exposures to be product. For products with an expected A < x¯, the PCD is High; if 12 + A < x¯ administered to the protected site in SPF greater that 15, the exposures shall < 30 + A, the PCD is Moderate; if 2 + subsequent testing. The MED(US) be the MED(US) times 0.76X, 0.87X, A < x¯ < 12 + A, the PCD is Minimal; should be determined again on the same 0.93X, 1.00X, 1.07X, 1.15X, and 1.32X, if x¯ < 2 + A, the product shall not be day as the standard and test sunscreens where X equals the expected SPF of the labeled as a sunscreen drug product and and this MED(US) should be used in test product. The MED is the quantity of shall not display an SPF value. calculating the SPF. erythema-effective energy required to (c) Determination of individual SPF produce the first perceptible, § 352.76 Determination if a product is values. A series of UV radiation unambiguous redness reaction with water resistant or very water resistant. exposures expressed as Joules per clearly defined borders at 22 to 24 hours The general testing procedures in square meter (adjusted to the erythema postexposure. The SPF value of the test § 352.72 shall be used as part of the action spectrum calculated according to sunscreen is then calculated from the following tests, except where modified § 352.73(a)) is administered to the dose of UV radiation required to in this section. An indoor fresh water

VerDate 06-MAY-99 15:32 May 20, 1999 Jkt 183247 PO 00000 Frm 00036 Fmt 4700 Sfmt 4700 E:\FR\FM\21MYR1.XXX pfrm07 PsN: 21MYR1 Federal Register / Vol. 64, No. 98 / Friday, May 21, 1999 / Rules and Regulations 27693 pool, whirlpool, and/or jacuzzi used. Any proposed modification or conspicuously at least once in the maintained at 23 to 32 °C shall be used alternative procedure shall be submitted labeling in conjunction with the term in these testing procedures. Fresh water as a petition in accord with § 10.30 of ‘‘sunscreen’’ or other similar sun is clean drinking water that meets the this chapter. The petition should protection terminology used in the standards in 40 CFR part 141. The pool contain data to support the modification labeling. For example: ‘‘Contains a and air temperature and the relative or data demonstrating that an alternative sunscreen—to protect product color.’’ humidity shall be recorded. procedure provides results of equivalent (a) Procedure for testing the water accuracy. All information submitted PART 740ÐCOSMETIC PRODUCT resistance of a sunscreen product. For will be subject to the disclosure rules in WARNING STATEMENTS sunscreen products making the claim of part 20 of this chapter. 6. The authority citation for 21 CFR ‘‘water resistant,’’ the label SPF shall be part 740 continues to read as follows: the label SPF value determined after 40 PART 700ÐGENERAL minutes of water immersion using the Authority: 21 U.S.C. 321, 331, 352, 355, 4. The authority citation for 21 CFR 361, 362, 371, 374. following procedure for the water part 700 continues to read as follows: resistance test: 7. Section 740.19 is added to subpart (1) Apply sunscreen product Authority: 21 U.S.C. 321, 331, 352, 355, B to read as follows: 361, 362, 371, 374. (followed by the waiting period after application of the sunscreen product 5. Section 700.35 is added to subpart § 740.19 Suntanning preparations. indicated on the product labeling). B to read as follows: The labeling of suntanning (2) 20 minutes moderate activity in preparations that do not contain a water. § 700.35 Cosmetics containing sunscreen sunscreen ingredient must display the (3) 20-minute rest period (do not ingredients. following warning: ‘‘Warning—This towel test sites). (a) A product that includes the term product does not contain a sunscreen (4) 20 minutes moderate activity in ‘‘sunscreen’’ in its labeling or in any and does not protect against sunburn. water. other way represents or suggests that it Repeated exposure of unprotected skin (5) Conclude water test (air dry test is intended to prevent, cure, treat, or while tanning may increase the risk of sites without toweling). mitigate disease or to affect a structure skin aging, skin cancer, and other (6) Begin solar simulator exposure to or function of the body comes within harmful effects to the skin even if you test site areas as described in § 352.73. the definition of a drug in section do not burn.’’ For purposes of this (b) Procedure for testing a very water 201(g)(1) of the act. Sunscreen active section, the term ‘‘suntanning resistant sunscreen product. For ingredients affect the structure or preparations’’ includes gels, creams, sunscreen products making the claim of function of the body by absorbing, liquids, and other topical products that ‘‘very water resistant,’’ the label SPF reflecting, or scattering the harmful, are intended to provide cosmetic effects shall be the label SPF value determined burning rays of the sun, thereby altering on the skin while tanning through after 80 minutes of water immersion the normal physiological response to exposure to UV radiation (e.g., using the following procedure for the solar radiation. These ingredients also moisturizing or conditioning products), very water resistant test: help to prevent diseases such as or to give the appearance of a tan by (1) Apply sunscreen product sunburn and may reduce the chance of imparting color to the skin through the (followed by the waiting period after premature skin aging, skin cancer, and application of approved color additives application of the sunscreen product other harmful effects due to the sun (e.g., dihydroxyacetone) without the indicated on the product labeling). when used in conjunction with limiting need for exposure to UV radiation. The (2) 20 minutes moderate activity in sun exposure and wearing protective term ‘‘suntanning preparations’’ does water. clothing. When consumers see the term not include products intended to ‘‘sunscreen’’ or similar sun protection (3) 20-minute rest period (do not provide sun protection or otherwise terminology in the labeling of a product, towel test sites). intended to affect the structure or any they expect the product to protect them (4) 20 minutes moderate activity in function of the body. water. in some way from the harmful effects of (5) 20-minute rest period (do not the sun, irrespective of other labeling Dated: April 22, 1999. towel test sites). statements. Consequently, the use of the William K. Hubbard, (6) 20 minutes moderate activity in term ‘‘sunscreen’’ or similar sun Associate Commissioner for Policy water. protection terminology in a product’s Coordination. (7) 20-minute rest period (do not labeling generally causes the product to [FR Doc. 99–12853 Filed 5–20–99; 8:45 am] towel test sites). be subject to regulation as a drug. BILLING CODE 4160±01±F (8) 20 minutes moderate activity in However, sunscreen ingredients may water. also be used in some products for (9) Conclude water test (air dry test nontherapeutic, nonphysiologic uses DEPARTMENT OF DEFENSE sites without toweling). (e.g., as a color additive or to protect the (10) Begin solar simulator exposure to color of the product). To avoid Office of the Secretary test site areas as described in § 352.73. consumer misunderstanding, if a cosmetic product contains a sunscreen 32 CFR Part 311 § 352.77 Test modifications. ingredient and uses the term The formulation or mode of ‘‘sunscreen’’ or similar sun protection OSD Privacy Program; Correction administration of certain products may terminology anywhere in its labeling, AGENCY: Department of Defense. require modification of the testing the term must be qualified by describing ACTION: Final rule; correction. procedures in this subpart. In addition, the cosmetic benefit provided by the alternative methods (including sunscreen ingredient. SUMMARY: This rules makes automated or in vitro procedures) (b) The qualifying information administrative corrections to the OSD employing the same basic procedures as required under paragraph (a) of this Privacy Program rule published on those described in this subpart may be section shall appear prominently and April 28, 1999.

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