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04/29/99 ....... PA STATE COLLEGE ........... UNIVERSITY PARK ............................. 9/2847 VOR or GPS–B AMDT 904/29/99 ....... WI APPLETON ..................... OUTAGAMIE COUNTY REGIONAL ... 9/2851 ILS RWY 3, AMDT 16C04/30/99 ....... MO BUTLER .......................... BUTLER MEMORIAL ........................... 9/2875 GPS RWY 18, ORIG04/30/99 ....... TX AUSTIN ........................... AUSTIN-BERGSTROM INTL ............... 9/2879 ILS RWY 35L, AMDT 104/30/99 ....... TX AUSTIN ........................... AUSTIN-BERGSTROM INTL ............... 9/2880 GPS RWY 35L, AMDT 104/30/99 ....... TX AUSTIN ........................... AUSTIN-BERGSTROM INTL ............... 9/2881 GPS RWY 17R, AMDT 104/30/99 ....... TX AUSTIN ........................... AUSTIN-BERGSTROM INTL ............... 9/2882 ILS RWY 17R, AMDT 105/1/99 ......... NH MANCHESTER ............... MANCHESTER .................................... 9/3102 ILS RWY 2, AMDT 205/1/99 ......... NH MANCHESTER ............... MANCHESTER .................................... 9/3103 ILS RWY 35, AMDT 1905/04/99 ....... IL CHICAGO/AURORA ....... AURORA MUNI ................................... 9/2970 VOR or GPS–A AMDT 1A05/05/99 ....... IL CHICAGO/AURORA ....... AURORA MUNI ................................... 9/2983 ILS RWY 9, AMDT 1A05/06/99 ....... OH MIDDLETOWN ................ HOOK FIELD MUNI ............................. 9/3009 LOC RWY 23, AMDT 7B05/06/99 ....... OH MIDDLETOWN ................ HOOK FIELD MUNI ............................. 9/3010 NDB or GPS RWY 23, AMDT 8A05/06/99 ....... OH MIDDLETOWN ................ HOOK FIELD MUNI ............................. 9/3011 NDB or GPS–A, AMDT 2A05/10/99 ....... MN WORTHINGTON ............. WORTHINGTON MUNI ....................... 9/3086 NDB or GPS RWY 29, ORIG05/10/99 ....... MN WORTHINGTON ............. WORTHINGTON MUNI ....................... 9/3088 ILS RWY 29, ORIG05/10/99 ....... VA RICHMOND ..................... CHESTERFIELD COUNTY ................. 9/3074 NDB or GPS RWY 33, AMDT 7A05/10/99 ....... VA RICHMOND ..................... CHESTERFIELD COUNTY ................. 9/3075 VOR/DME or GPS RWY 15, ORIG05/10/99 ....... VA RICHMOND ..................... CHESTERFIELD COUNTY ................. 9/3082 ILS RWY 33, ORIG

[FR Doc. 99–12949 Filed 5–20–99; 8:45 am]BILLING CODE 4910–13–M

DEPARTMENT OF HEALTH ANDHUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 352, 700, and 740

[Docket No. 78N–0038]

RIN 0910–AA01

Sunscreen Drug Products For Over-The-Counter Human Use; FinalMonograph

AGENCY: Food and Drug Administration,HHS.ACTION: Final rule.

SUMMARY: The Food and DrugAdministration (FDA) is issuing a finalrule in the form of a final monographestablishing conditions under whichover-the-counter (OTC) sunscreen drugproducts are generally recognized assafe and effective and not misbranded aspart of FDA’s ongoing review of OTCdrug products. FDA is issuing this finalrule after considering public commentson the agency’s proposed regulation,which was issued in the form of atentative final monograph, and new dataand information on sunscreen drugproducts that have come to the agency’sattention. FDA is also issuing final rulesregarding the labeling of certaincosmetic products to inform consumersthat these products do not provideprotection from the sun.

EFFECTIVE DATES: This regulation iseffective May 21, 2001 for parts 310,352, and 700 and is effective May 22,2000 for part 740.FOR FURTHER INFORMATION CONTACT: JohnD. Lipnicki, Center for Drug Evaluationand Research (HFD–560), Food andDrug Administration, 5600 FishersLane, Rockville, MD 20857, 301–827–2222.SUPPLEMENTARY INFORMATION:

I. IntroductionIn the Federal Register of August 25,

1978 (43 FR 38206), FDA published,under § 330.10(a)(6) (21 CFR330.10(a)(6)), an advance notice ofproposed rulemaking (ANPRM) toestablish a monograph for OTCsunscreen drug products, together withthe recommendations of the AdvisoryReview Panel on OTC TopicalAnalgesic, Antirheumatic, Otic, Burn,and Sunburn Prevention Drug Products(the Panel), which was the advisoryreview panel that evaluated data on theactive ingredients in this drug class. Theagency’s proposed regulation for OTCsunscreen drug products, in the form ofa tentative final monograph, waspublished in the Federal Register ofMay 12, 1993 (58 FR 28194).

In the Federal Register of June 8, 1994(59 FR 29706), the agency proposed toamend the tentative final monograph(and reopened the comment period untilAugust 22, 1994) to remove fivesunscreen ingredients because of a lackof interest in establishing United StatesPharmacopeia (USP) monographs:Digalloyl trioleate, ethyl 4-[bis(hydroxypropyl)] aminobenzoate,

glyceryl aminobenzoate, lawsone withdihydroxyacetone (interest wassubsequently shown in developing amonograph for lawsone anddihydroxyacetone), and red petrolatum.The agency also reiterated that allsunscreen ingredients must have a USPmonograph before being included in thefinal monograph for OTC sunscreendrug products. This final rule includesthose sunscreen ingredients that haveUSP monographs.

In the Federal Register of September16, 1996 (61 FR 48645), the agencyamended the proposed rule to includeavobenzone as a single ingredient and incombination with certain othersunscreen ingredients (interimmarketing was allowed in the FederalRegister of April 30, 1997 (62 FR23350)). In the Federal Register ofOctober 22, 1998 (63 FR 56584), theagency proposed to amend the tentativefinal monograph to include zinc oxideas a single ingredient and incombination with any proposedCategory I sunscreen active ingredientexcept avobenzone.

In the Federal Register of April 5,1994 (59 FR 16042), the agencyreopened the administrative record andannounced a public meeting to discussultraviolet A (UVA) radiation claimsand testing procedures. In the FederalRegister of August 15, 1996 (61 FR42398), the agency reopened theadministrative record and announced apublic meeting to discuss thephotochemistry and photobiology ofsunscreens.

This final monograph completes thetentative final monograph except for

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certain testing issues and UVA labeling,which the agency will discuss in futureissues of the Federal Register. Untilthen, UVA labeling may continue inaccord with the tentative finalmonograph and its amendments. Theagency advises that on or after May 21,2001, no OTC drug product that issubject to the monograph and thatcontains a nonmonograph conditionmay be initially introduced or initiallydelivered for introduction into interstatecommerce unless it is the subject of anapproved new drug application orabbreviated new drug application.Further, any OTC drug product subjectto this monograph that is repackaged orrelabeled after the effective date of themonograph must be in compliance withthe monograph regardless of the date theproduct was initially introduced orinitially delivered for introduction intointerstate commerce. Manufacturers areencouraged to comply voluntarily assoon as possible.

In response to the proposed rule onOTC sunscreen drug products andsubsequent reopenings of theadministrative record, the agencyreceived 433 comments. The commentsincluded four petitions (Refs. 1 through4) requesting consideration of sunscreeningredients that have been marketed inEurope but not in the United States. Thestatus of these petitions is discussed insection II.C, comment 13 of thisdocument. One manufacturer requestedan oral hearing before the Commissionerof Food and Drugs if the agencymandated a limit on sun protectionfactor (SPF) values in this final rule.Copies of the information considered bythe Panel, the comments and petitions,and the hearing request are on publicdisplay in the Dockets ManagementBranch (HFA–305), Food and DrugAdministration, 5630 Fishers Lane, rm.1061, Rockville, MD 20852. All ‘‘OTCVolumes’’ cited throughout thisdocument refer to information on publicdisplay.

A number of comments were filed inthe Dockets Management Branch afterthe dates the administrative record hadofficially closed. The agency hasconsidered these comments as‘‘feedback’’ communications under theOTC drug review procedures, asdiscussed in the Federal Register ofSeptember 29, 1981 (46 FR 47740), andclarified in the Federal Register of April1, 1983 (48 FR 14050). When‘‘feedback’’ material submitted after anadministrative record has officiallyclosed directly influences or forms oneof the bases for the agency’s decision ona matter in an OTC drug rulemakingproceeding, the agency adds it to theadministrative record without

submission of a formal petition by aninterested party.

The agency has included these dataand information in the administrativerecord and addressed them in thisdocument. The agency has consideredthe request for an oral hearing in itsresponse to the comment and believes ithas adequately responded to themanufacturer and that a hearing is notneeded. As discussed in section II.G,comment 29 of this document, theagency is allowing the marketing of OTCsunscreen drug products with SPFvalues above 30 under one collectiveterm (i.e., ‘‘30 plus’’ or ‘‘30 +’’). Theagency will also consider includinglabeling in the monograph with actuallabel SPF values on products with SPFvalues over 30 when adequate data aresubmitted to substantiate a testingprocedure applicable to SPF values over30.

II. The Agency’s Conclusions on theComments

A. General Comments on OTCSunscreen Drug Products

1. Several comments asked that theagency either exempt currentlymarketed sunscreen products from therequirement for redetermining the SPFor provide a 2-year implementationperiod. One comment requested a 3-yearimplementation period. The commentscontended that the proposed 12-monthimplementation period would result inlost business and a serious economichardship for manufacturers, estimatedto be 35 million dollars forreformulating, retesting, and relabelingsunscreen products.

The agency agrees with the commentsthat the proposed 12-monthimplementation period may causeundue economic burden on somemanufacturers of these products withouta corresponding benefit to consumers(see section VII of this document). Asdiscussed in section VII, a 24-montheffective date would allow most firms torelabel products during a normalrelabeling cycle without incurringadditional costs. Accordingly, the finalrule will be effective 24 months fromthe date of this publication. Because thisfinal rule provides testing proceduresthat were proposed in the tentative finalmonograph, currently marketedproducts that have already been testedby those procedures will not need to beretested. However, sunscreen productsthat have not been tested will need tobe tested using the methods describedin this document. The agency intends topropose modified test procedures in afuture issue of the Federal Register andany necessary retesting time will be

specified when the final rule for testingprocedures publishes.

2. Several comments recommendedmodifications to the definition ofminimal erythema dose (MED) inproposed § 352.3(a). Some commentsobjected to the presumption thaterythema is a ‘‘diffusing’’ reaction thatstarts from within the exposed site andmoves outward in a dose dependentmanner, i.e., ‘‘redness reaching theborders of the exposure site.’’ Othercomments asserted that the definition istoo limiting because it may not beappropriate for all solar simulatorconfigurations (e.g., no template). Manycomments recommended the definitionof MED used by the European TradeAssociation COLIPA (Ref. 5): ‘‘Thequantity of radiant energy required toproduce the first perceptible,unambiguous redness reaction withclearly defined borders.’’ Anothercomment recommended ‘‘erythema-effective ultraviolet radiation’’ in placeof ‘‘radiant energy.’’

The agency agrees that the proposeddefinition of MED should be modifiedfor the reasons discussed by thecomments and is revising § 352.3(a) inthis final rule, as follows: ‘‘Minimalerythema dose (MED). The quantity oferythema-effective energy (expressed inJoules per square meter) required toproduce the first perceptible rednessreaction with clearly defined borders.’’The agency considers this definitionbroad enough to encompass testsconducted with solar simulatorconfigurations with no template andconsistent with COLIPA’s definition.

3. One comment noted that thewavelength ranges for UVA, UVB, andUVC radiation in the tentative finalmonograph differed from the officialranges of the Commission Internationalde L’Eclairage (CIE), which are: (1)UVC–radiation of less than 280nanometers (nm), (2) UVB–280 to 315nm, and (3) UVA–315 to 400 nm. Thecomment mentioned the agreementreached at the 11th InternationalCongress on Photobiology (Ref. 6) on theshort wavelength end of UVB radiation(280 or 290 nm) and suggested that thescientific evidence supports 320 nm asthe long-wavelength boundary of UVBradiation.

The agency agrees with the commentthat the scientific evidence supports 320nm as the long-wavelength boundary ofUVB radiation. However, the short-wavelength boundary for UVB radiationhas been accepted as either 280 or 290nm. Given that the comment did notprovide a compelling reason to changethe proposed definition of UVBradiation, the agency will continue to



define the boundaries of UVB radiationas 290 to 320 nm.

4. Comments requested the agency toamend the definition of a sunscreenactive ingredient in proposed § 352.3(c)to include mechanisms other thanabsorption, to expand the UV range toinclude UVA radiation, and to providea minimum SPF value requirement. Thecomments added that some proposedCategory I active ingredients (e.g.,menthyl anthranilate and titaniumdioxide) do not meet the proposeddefinition, and that the definition is notinterpretable without specifications formeasuring 85 percent absorbance.

The agency discussed the need tomodify the definition in a 1996proposed amendment of the tentativefinal monograph (61 FR 48645 at48646). The agency agrees thatmodifications should be to: (1) Includemechanisms other than absorption, (2)redefine wavelengths, and (3) removethe percent absorbance requirement.The agency does not agree that aminimum SPF value should be includedin the definition because thisinformation is more appropriately acharacteristic of the final formulation.Therefore, the agency has revisedproposed § 352.3(c) in this document, toread: ‘‘Sunscreen active ingredient. Aningredient listed in § 352.10 thatabsorbs, reflects, or scatters radiation inthe ultraviolet range at wavelengths of290 to 400 nanometers.’’

5. One comment recommended thatthe agency reevaluate statements in thetentative final monograph on theharmful nature of tanning. The agencydiscussed the harmful effects of UVradiation-induced tanning in thetentative final monograph (58 FR 28194at 28238 to 28239). The commentsuggested that a natural tan reducescumulative sun exposure and maypotentiate sunscreen effectiveness. Thecomment did not, however, providedata or references to support this claimor to otherwise cause the agency tochange its position.

6. One comment requested that thefinal monograph require expirationdating and storage information in thelabeling of OTC sunscreen drugproducts. The comment noted thatunder 21 CFR 211.137, OTC drugproducts with data demonstratingstability for 3 years and without labeleddosage limitations are not required toinclude an expiration date in theirlabeling. The comment stated that it wasaware of numerous cases that suggestthese products may not be stable for 3years.

The agency requested the comment toprovide data and information about thespecific products it was aware of (Ref.

7), but none were subsequentlyprovided. The agency is not currentlyaware of stability problems that wouldrequire expiration dating for OTCsunscreen drug products but willaddress such a requirement if databecome available. All sunscreen activeingredients included in the finalmonograph also have a USP monographthat contains packaging and storagerequirements and standards for productscontaining these ingredients.

7. Comments recommended that theagency establish procedures forensuring batch-to-batch SPF test results,and that it approve testing laboratoriesand regulate their performance.

Regulations already exist to assurethat each batch of drug product meetsestablished specifications for theidentity and strength of each activeingredient. Specifically, 21 CFR 211.160requires that product specifications andlaboratory controls be established andperformed. Although the agency wouldnot require SPF testing on humansubjects for every batch produced,manufacturers need to assureconformance to their finished productspecifications. Further, any changes tothe batch formula would, at a minimum,require review and documentation bythe manufacturer’s quality control unitto determine if SPF retesting isnecessary. Finally, 21 CFR 211.180provides for the inspection of recordspertaining to production, control, anddistribution of batches of drug products.Thus, testing laboratories are subject tothese regulations.

B. Comments on the Drug/CosmeticStatus of Sunscreen Products

8. One comment questioned whethersunscreen products should be regulatedas drugs. The comment asserted thatsuch products are not active in themitigation or elimination of a diseasecondition, and that sunscreen productshave no more affect on the structure andfunction of the body than ‘‘being inphysical shade.’’

The basis for the agency’sdetermination that products intendedfor use as sunscreens are subject toregulation as drugs under section201(g)(1) of the Federal Food, Drug, andCosmetic Act (the act) (21 U.S.C.321(g)(1)) is set forth at length in thetentative final monograph (58 FR 28194at 28203 to 28206). Essentially,sunscreen active ingredients affect thestructure and function of the body byabsorbing, reflecting, or scattering theharmful, burning rays of the sun,thereby altering the normalphysiological response to solarradiation. Proper use of sunscreeningredients (see section II.L, comment

51 of this document) may help toprevent skin damage and may helpreduce the risk of skin lesions, skincancer, and other disease conditions.Products that are marketed to achievethese important health benefits meet thedefinition of a drug under section201(g)(1)(B) and (g)(1)(C) of the act.

9. One comment disagreed with theagency’s tentative conclusion thatproducts containing a sunscreeningredient, but labeled for the purposeof obtaining an ‘‘even tan,’’ are subjectto regulation as drugs. According to thecomment, such a product is subject toregulation as a drug only if it bears aclaim to treat or prevent sunburn. Thecomment asserts that this has been theagency’s consistent approach since1940.

Another comment stated that sunlesstanning products, used to impart colorwithout exposure to the sun, could beimproved by adding a sunscreen toprovide users protection during theirnormal outside activities. The commentrequested that such products should beregarded as cosmetics, because theywould be used primarily for a cosmeticeffect, with the sunscreen protectionserving only a secondary purpose.

The agency thoroughly discussed theregulatory status of ‘‘tanning’’ products,including the basis for withdrawing its1940 advisory opinion on sunburn andsuntan preparations, in the tentativefinal monograph (58 FR 28194 at 28203to 28207, 28293 to 28294). As discussedin the tentative final monograph, thepresence of a sunscreen activeingredient, in conjunction with labelingclaims that the product may be used,e.g., to permit tanning or to acquire aneven tan, generally establishes that theproduct’s intended use is that of a drug.Such products suggest, among otherthings, that the ingredients in theproduct will allow the consumer to stayin the sun longer without suffering skindamage (58 FR 28194 at 28204).Likewise, products that claim toaccelerate or stimulate the tanningprocess are claiming, either expressly orimpliedly, to stimulate the productionof melanin in the body. Such a claim toaffect the structure or function of thebody renders the product subject toregulation as a drug under section201(g)(1) of the act (see 58 FR 28194 at28293). Finally, a sunless tanningproduct that contains a sunscreeningredient, to provide protection to theconsumer, is subject to regulation as adrug. The idea that the sunburnprotection offered by the product mayonly be a ‘‘secondary’’ feature for theconsumer is not relevant. If an intendeduse of the product is to provide userswith sun protection when they go



outside (as the comment suggests), thenthe product is subject to regulation as adrug.

On the other hand, products that donot make express or implied sunprotection claims, and do not containsunscreen ingredients, may be regardedas cosmetics under section 201(i) of theact. If the product is intended solely toprovide cosmetic effects on the skin(e.g., to moisturize the skin whilesunbathing), or solely to impart color tothe skin without exposure to the sun orother sources of light (i.e., sunlesstanning), then the product may bemarketed as a cosmetic. Such products,however, must include a warningstatement (discussed in this section,comment 10 of this document) to informthe consumer that the product does notprovide any protection against sunburn.Products marketed to enhance or permittanning that do not contain a sunscreeningredient must be reviewed on a case-by-case basis to determine whether theproduct is intended solely to provide acosmetic benefit (such as moisturizing)or whether the product is intended toenhance or permit tanning by someother mechanism of action.

The comments offered no otherreasoning and no data to the contrary,other than to suggest that the agency’sapproach would encouragemanufacturers to remove sunscreeningredients from suntan products and,thereby, expose consumers to evenhigher levels of harmful ultraviolet rays.The agency is not persuaded that asignificant number of manufacturerswill choose to reformulate theirproducts, to make them less safe forconsumers, as a result of this final rule.Moreover, consumers will continue tohave an array of sunscreen-containingproducts from which to choose. Finally,as discussed below, certain tanningproducts (including sunless tanningproducts) that do not contain sunscreeningredients must bear a prominentwarning to the consumer. This willensure that the consumer is fullyinformed as to which products offer sunprotection and which do not.

10. One comment requested that thesignal word ‘‘Caution’’ replace thesignal word ‘‘Warning’’ preceding thefollowing statement for suntanningpreparations: ‘‘Warning—This productdoes not contain a sunscreen and doesnot protect against sunburn.’’ Thecomment stated that the word‘‘Warning’’ suggests safety hazardsassociated with these products that areunrelated to sunburn. Another commentpetitioned to add a second sentence tothe warning: ‘‘Tanning in sunlight orunder tanning lamps can cause skincancer and premature skin aging-even if

you don’t burn.’’ The commentconcluded that the availability oftanning products without a protectivesunscreen ingredient is a serious healthissue and detrimental to public health.A third comment objected to any suchwarnings on tanning products.

The agency considers it an importantpublic health issue that users ofsuntanning products be alerted whenthese products do not contain asunscreen and do not protect againstsunburn or other harmful effects to theskin. Because suntanning products areintended for repeated use under the sunor suntanning lamps while acquiring atan, the agency considers failure toprovide information on hazardsassociated with repeated, unprotectedexposure to UV radiation to be a failureto reveal material facts (see sections201(n), 502(a), and 602(a) of the act (21U.S.C. 352(a) and 362(a))), especially inlight of the representations that aremade for the product (e.g., suntanning).Therefore, the agency is requiring thelabeling of suntanning preparations thatdo not contain a sunscreen ingredient(§ 740.19 (21 CFR 740.19)) to bear thefollowing: ‘‘Warning—This productdoes not contain a sunscreen and doesnot protect against sunburn. Repeatedexposure of unprotected skin whiletanning may increase the risk of skinaging, skin cancer, and other harmfuleffects to the skin even if you do notburn.’’ The agency considers thisinformation to be sufficiently important,for safety reasons, to require a 12-montheffective date (as opposed to 24 monthsfor the balance of the rule) and torequire the strongest possible signalword, i.e., ‘‘Warning.’’

11. One comment disagreed with theproposal that hair care and nailproducts that contain a sunscreeningredient for a nontherapeutic use (e.g.,to protect the color of the product), andthat use the term ‘‘sunscreen’’ in thelabeling, must describe in the labelingthe functional role of the sunscreen.According to the comment, it is highlyunlikely that consumers would thinkthat these products are intended toprotect the skin. If this requirementwere finalized, the comment requestedthat the agency permit the term‘‘sunscreen’’ to appear once anywherein the labeling, with the purpose of thesunscreen explained elsewhere in thelabeling.

The agency disagrees with thepremise of this comment. The use of theterm ‘‘sunscreen’’ in labeling suggeststhat the product in some way willprotect the consumer from the harmfuleffects of the sun. The health risksassociated with relying on a product forprotection from the sun, when in fact

the product does not provide suchprotection, are sufficiently serious torequire the type of disclosure outlinedin the proposed rule. Information aboutthe purpose of a sunscreen ingredient ina hair care or nail product will be usefulto consumers to inform them that theingredient protects only the hair or onlythe color of the product.

This information need appear onlyonce and can appear anywhere in thelabeling, provided the qualifyingpurpose appears prominently andconspicuously and in conjunction withthe word ‘‘sunscreen.’’ The informationmay, e.g., be combined in a singlestatement, e.g., ‘‘Contains a sunscreen—to protect product color.’’ This willensure that consumers will see andreadily associate the two pieces ofinformation.

12. Two comments objected to the useof an OTC drug rulemaking process tochange cosmetic labeling requirements,i.e., the addition of a warning on certaintanning products and the labelingrequirements for hair care or nailproducts that contain a sunscreen for anontherapeutic use.

The agency addressed this proceduralconcern, which was also raised inresponse to the ANPRM, at length in thetentative final monograph (58 FR 28194at 28201 to 28202). The industry andconsumers have had ample notice of thefact that this proceeding includedseveral cosmetic labeling issues thatarise out of the same facts and findingsat issue in developing the OTC drugmonograph. It is not uncommon for theagency to address in an OTC rulemakingdocument the status of, or the regulationof, products that fall outside of themonograph. In this instance, thecosmetic labeling issues were so closelyrelated to the OTC drug issues that aseparate proceeding would have beenoverly duplicative and inefficient.

C. Comments on Specific SunscreenActive Ingredients

13. Several comments noted that FDAhad deferred a decision on the citizenpetitions requesting that sunscreenactive ingredients marketed solely inforeign countries be included in theOTC sunscreen monograph. Thecomments urged FDA answer thesepetitions and establish a policyconcerning the inclusion of OTCsunscreens based solely on foreign dataand marketing experience.

In the Federal Register of October 3,1996 (61 FR 51625), the agencypublished an ANPRM that addressedestablishing eligibility criteria forconsidering additional OTC conditions(i.e., OTC drug active ingredients,indications, dosage forms, dosage



strengths, routes of administration, andactive ingredient combinations) in theOTC drug monograph system. Theseproposed criteria would address howforeign or domestic OTC marketingexperience could be used to support theinclusion of an ingredient in an OTCdrug monograph. Specifically, thecriteria would address how OTCmarketing experience in the UnitedStates or abroad could be used to meetthe statutory requirement under section201(p) of the act of marketing ‘‘to amaterial extent’’ and ‘‘for a materialtime.’’ ‘‘Material extent’’ and ‘‘materialtime’’ are needed to qualify a specificOTC drug condition for considerationunder the OTC drug monograph system.

The decision on whether to proceedwith a final rulemaking on this subjectwill be based, in part, on theinformation and comments submitted inresponse to the notice of proposedrulemaking that the agency is preparingfor publication in a future issue of theFederal Register. Resolution of thepending sunscreen petitions must awaitthe outcome of any final rulemaking onthis subject.

14. One comment requested that theagency adopt simpler, more user-friendly, names for several sunscreeningredients: (1) Roxadimate for ethyl-[bis(hydroxypropyl)] aminobenzoate, (2)lisadimate for glyceryl aminobenzoate,and (3) diolamine methoxycinnamatefor diethanolamine methoxycinnamate.The comment claimed that these nameshad been adopted or designated by theUnited States Adopted Names (USAN)Council. The comment also requestedthat if USAN adopts a name forphenylbenzimidazole sulfonic acid,FDA adopt this name as well. Thecomment also suggested the use of theacronyms ‘‘TEA’’ and ‘‘DEA’’ fortriethanolamine and diethanolamine,respectively.

The agency is including in this finalmonograph only those activeingredients that are the subject of anofficial USP compendial monographthat sets forth its standards of identity,strength, quality, and purity (see sectionI of this document). In the FederalRegister of June 8, 1994, FDA deletedethyl-[bis(hydroxypropyl)]aminobenzoate and glycerylaminobenzoate from the tentative finalmonograph due to the lack of interest inestablishing USP monographs for theseingredients. Moreover, two sunscreeningredients (including diethanolaminemethoxycinnamate) have been deferredfrom the final monograph due to thelack of a current or proposedcompendial monograph. Therefore, theissue of whether a ‘‘user-friendly’’ namefor these ingredients should be

developed or adopted need not beresolved in this proceeding at this time.Similarly, TEA and DEA need not beaddressed in this proceeding, astriethanolamine is not a sunscreenactive ingredient, and diethanolamine isonly used in the ingredientdiethanolamine methoxycinnamatewhich, as discussed, is not a monographingredient at this time.

With respect to the comment on themonograph ingredientphenylbenzimidazole sulfonic acid, theagency agrees that if USAN or the USPwere to adopt a different or alternativename for this ingredient, such a namecould be used in the labeling of aproduct that contains this ingredient. Asdiscussed in comment 30 of thetentative final monograph (58 FR 28194at 28207 to 28209), the agency is usingthe compendial name as the establishedname for each active ingredient.

15. Two comments requested that theterm ‘‘PABA’’ continue to be allowed inlabeling. The comments stated that thename aminobenzoic acid is meaninglessto consumers and physicians, who overthe years have learned to recognize thisingredient on the label as PABA. Onecomment recommended the use ofaminobenzoic acid in the ingredient listand the use of PABA in othercommunications about the product. Thecomment added that the term ‘‘PABA-free’’ should be allowed on productsthat do not contain aminobenzoic acid.The other comment proposed either topermit the listing of the ingredient asPABA or, if that is unacceptable, asPABA (aminobenzoic acid).

In comment 30 of the tentative finalmonograph (58 FR 28194 at 28207 to28209), the agency discussed the issueof the appropriate established name forthis and other sunscreen ingredients. Asthe agency stated in that discussion, therecognized compendial name foraminobenzoic acid no longer includesthe term PABA.

The agency acknowledges, however,that the term PABA formerly was partof the established name for thisingredient and that the use of the termin consumer labeling has continueddespite the change in the compendialname. In addition, the agency agreeswith the comment that many consumershave learned to recognize thisingredient as, and only as, PABA. Theagency also recognizes that consumersseeking to avoid the use of thisingredient for health-related reasons(e.g., allergy) may, in this case, bemisled if the term PABA were no longerpermitted. Some consumers may believethat a product that lists aminobenzoicacid as an ingredient, but does not listPABA, is PABA-free. If such a consumer

has an allergy to aminobenzoic acid, theindividual may suffer adverse healthconsequences.

For these reasons, and especially inlight of the potential safety concerns forcertain consumers, the agencyconcludes that wherever the ingredientaminobenzoic acid appears in thelabeling of an OTC sunscreen drugproduct, including labeling that notesthe absence of this ingredient, thedescriptive term PABA mustimmediately follow the establishedname, i.e., ‘‘Aminobenzoic acid(PABA).’’ Thus, e.g., a product that iscurrently marketed as ‘‘PABA-free’’would now be required to state that theproduct is ‘‘Aminobenzoic acid (PABA)-free.’’ This convention will allowconsumers to begin to recognize that theingredient they may wish to avoid is‘‘aminobenzoic acid.’’ After a sufficientperiod of time, the agency will revisitthe need for consumer labeling tocontinue to bear the descriptive termPABA.

16. One comment stated that claims ofprotection by artificial melanin,melanin-containing products, andantioxidants should be enumerated,well regulated, and defined.

The agency agrees with the comment,but these claims are not covered by thisfinal monograph. Melanin and artificialmelanins are not recognized sunscreenactive ingredients. Any productcontaining melanin or artificialmelanins as active ingredients andmaking sun protection claims wouldhave to seek marketing approval undera new drug application (NDA).

The agency is aware that claims ofprotection from antioxidants are used inthe labeling of some cosmetic productswith or without a sunscreen. The agencywill ascertain the nature of any suchclaims (drug or cosmetic) on a case-by-case basis.

17. Several comments objected to theagency’s proposal that OTC sunscreendrug products must contain less than500 parts per billion (ppb) of N-methyl-N-nitrosoaminobenzoate octyl ester(NMPABAO) for several reasons: (1)Toxicological studies indicate thatNMPABAO does not have mutagenic orsuspected carcinogenic potential (Ref.8), (2) NMPABAO may be present insunscreens containing padimate O onlyin small amounts (ppb range) and therisks associated with NMPABAO arevery low, (3) NMPABAO decomposesquickly when exposed to UV radiation,and (4) industry is aware not toformulate with known nitrosating agentsin the presence of amines in order toavoid nitrosamine contamination of itsproducts. Some comments stated thatFDA’s own conclusions in the tentative



final monograph concerning the safetyof both NMPABAO and padimate O donot support the imposition ofconcentration limits for NMPABAO insunscreens nor do they justify the highcost of analyzing each batch ofsunscreen product for NMPABAO. Onecomment contended that any proposedlimit should apply to all nitrosaminesand not just NMPABAO. The commentstated that nitrosamines can be formedfrom any secondary or tertiary amine.Several sunscreen active ingredientscontain this moiety in their chemicalstructure and many inactive ingredientsare secondary or tertiary amines. Thecomment concluded that targetingNMPABAO falsely conveys thatpadimate O is a unique concern,resulting in manufacturers using otheringredients to avoid costly testing andnegative implications.

In the tentative final monograph, theagency did not propose a concentrationlimit on NMPABAO. Rather, based onconcerns that had been raised, theagency asked for comment on whetherit should consider proposing a fixedlimit. As discussed in the tentative finalmonograph (58 FR 28194 at 28288 to28293), toxicological studies support theagency’s belief that the risk associatedwith NMPABAO contamination ofsunscreen drug products is very low dueto NMPABAO’s low mutagenicity andcarcinogenicity potential and rapiddecomposition in the presence of UVradiation. The agency has not becomeaware of any new data or informationsince the publication of the tentativefinal monograph suggesting a safetyconcern with NMPABAO in sunscreendrug products. Therefore, the agencyhas decided not to propose or otherwiseinclude in this final monograph arequirement that OTC sunscreen drugproducts must contain less than 500 ppbof NMPABAO.

In the tentative final monograph (58FR 28194 at 28292), the agencydiscussed its analysis for NMPABAO in25 commercially available sunscreenproducts. Of the 11 samples found to becontaminated with NMPABAO, the fourhighest contained 2-bromo-2-nitro-1,3-propanediol, an indirect nitrosatingagent. The agency concluded that therewould be no nitrosamine contaminationif these products were formulatedwithout the nitrosating agent. As notedby several of the comments, the industryis aware not to formulate with knownnitrosating agents in the presence ofamines in order to avoid nitrosaminecontamination of its products.

18. One comment submitted areference to a subchronic oral toxicitystudy in rats conducted with padimateO which a chemical manufacturer had

submitted to the Toxic SubstanceControl Act 8(e) coordinator of theUnited States Environmental ProtectionAgency for consideration. The studywas a 4-week repeated dose study atdoses of 0, 100, 300, and 1,000milligrams (mg)/kilogram (kg)/day ofpadimate O administered by gavage ina corn oil vehicle (10 to 15 rats/group/sex). The study included a 4-weekrecovery period to assess the persistenceor reversibility of any toxic effects. Atthe end of the 4-week treatment period,toxic effects were seen in four targetorgans: Testes, epididymis, spleen, andliver. The no-observed-effect-level inthis study was 100 mg/kg/day for bothmales and females. Toxic effectsappeared reversible in the animalsnecropsied after the 4-week recoveryperiod with the exception of markedepididymal hypospermia at the 1,000mg/kg/day dose (5/5 animals).

The clinical relevance of this animaltoxicity study is difficult to assess.Padimate O was administeredchronically and at very high oral doses.Under normal use conditions, sunscreendrug products containing padimate Oare applied topically and usedintermittently. In addition,pharmacokinetic parameters were notcalculated and the different routes ofadministration (oral in this study versustopical for sunscreen products) precludecalculation of a ‘‘safety margin’’ on thebasis of dose per unit of body weight orsurface area. Similarly, kinetic data arenot available for a comparison of serumlevels of drug or metabolites. Literaturesearches indicate no publishedinformation on the kinetics of padimateO with topical application in man. Ifpercutaneous absorption of padimate Odoes occur in man, it seems likely thatthe peak and/or cumulative levelsachieved with sunscreen usage wouldbe quite low compared to the systemicexposure achieved in this animaltoxicity study. Further, it is not knownwhether the irreversible epididymalhypospermia found in the 1,000 mg/kg/day group would also be reversible withmore time.

The agency has determined that thisstudy does not present sufficient data toexclude padimate O from the finalmonograph and that an adequate safetymargin exists for its use as an OTCsunscreen ingredient.

19. Two comments submitted safetyand/or efficacy data to support CategoryI status for micronized titanium dioxide(Refs. 9 and 10). One comment statedthat micronized titanium dioxide is nota new material but is a selecteddistribution of existing material thatprovides higher SPF values while beingtransparent and esthetically pleasing on

the skin. The comments added thatmicronized titanium dioxide meets allsafety and efficacy criteria and alsomeets the USP specifications for purityexcept pure water content.

Another comment asserted for thefollowing reasons that micronizedtitanium dioxide is a new ingredientwith several unresolved safety andefficacy issues: (1) It does not meet thedefinition of a sunscreen opaquesunblock, (2) there is no control ofparticles to agglomerate, which iscritical to effectiveness, (3) no standardsexist to ensure integrity of coatings, (4)there are no performance-basedstandards of identity; micronizedtitanium dioxide is not included in theUSP, (5) its photocatalyst potential, and(6) the potential for the smaller particlesize to accumulate under the skin.

The agency finds the data with thecomments supportive of monographstatus for micronized titanium dioxide.Acute animal toxicity, irritation,sensitization, photoirritation,photosensitization, and human repeatinsult patch and skin penetrationstudies revealed no deleterious effects.SPF values for four productformulations containing from 4.4 to 10percent micronized titanium dioxidewere from 9 to 24 and supporteffectiveness as a sunscreen ingredient.

The agency is aware that sunscreenmanufacturers are using micronizedtitanium dioxide to create high SPFproducts that are transparent andesthetically pleasing on the skin. Theagency does not consider micronizedtitanium dioxide to be a new ingredientbut considers it a specific grade of thetitanium dioxide originally reviewed bythe Panel. Fairhurst and Mitchnick (Ref.11) note that ‘‘fines’’ have been part ofcommercially used titanium dioxidepowders for decades, and that amicronized product simply refers to arefinement of particle size distribution.Based on data and informationpresented at the September 19 and 20,1996, public meeting on thephotobiology and photochemistry ofsunscreens (Ref. 12), the agency is notaware of any evidence at this time thatdemonstrates a safety concern from theuse of micronized titanium dioxide insunscreen products. While micronizedtitanium dioxide does not meet theproposed definition of a sunscreenopaque sunblock, the agency has notincluded the use of this term in the finalmonograph (see section II.L, comment52 of this document). The potential fortitanium dioxide particles toagglomerate in formulation, whichcould result in lower SPF values, isaddressed by the final product SPF test.



The SPF data that the agency reviewed(Ref. 9) did not indicate such a problem.

Micronized titanium dioxide meetscurrent USP monograph specificationsfor titanium dioxide with the exceptionthat the material contains moreassociated water. In both the Julythrough August 1996 and 1998 issues ofthe Pharmacopeial Forum (Refs. 13 and14), the United States PharmacopeialConvention published in-processrevision proposals to make themonograph for titanium dioxide moreapplicable to ingredients used insunscreen drug products. The agencywill work with the USP in the future toupdate this monograph as necessary.

20. One comment stated that it isunnecessary to set the maximum limitof titanium dioxide at 25 percent.

The Panel discussed the safety andeffectiveness of 2 to 25 percent titaniumdioxide in the ANPRM (43 FR 38206 at38250) and the agency concurred withthe Panel’s findings in the tentative finalmonograph (58 FR 28194 at 28295). Thecomment submitted no data and theagency has no data to support the useof titanium dioxide in sunscreen drugproducts at concentrations higher than25 percent.

D. Comments on Dosages for SunscreenDrug Products

21. Several comments objected to theminimum concentration requirementsfor sunscreen active ingredients whenused in combination because they: (1)Are a less effective measurement ofeffectiveness than a performance basedSPF test, (2) impact on creativity andinnovation of new formulations(technological advances sincepublication of the 1978 ANPRM haveresulted in higher SPF values usinglower concentrations of activeingredients), (3) increase potential forirritation and allergic reactions due tounnecessarily high concentration levelsof active ingredients, (4) contradictFDA’s position that the lowest effectivedose of an active ingredient be used toproduce the desired treatment effect, (5)result in higher manufacturing andconsumer costs due to unnecessarylevels of active ingredients, and (6)affect international harmonizationbecause Canada, Australia, and theEuropean Union have no concentrationminimums for active ingredients whenused in combination.

One comment petitioned the agencyto amend proposed § 352.20 of thetentative final monograph to include aprovision for formulating combinationsunscreen products at lower minimumconcentrations. Two commentssubmitted efficacy data to support lowerconcentrations of sunscreen active

ingredients when used in combination.One comment (Ref. 15) submitted invitro SPF testing data for severaldifferent combinations. Although thesedata showed a statistically significantincreased efficacy for lower thanminimum concentrations, they were notpredictive of the SPF values that wouldbe obtained with human testing and,therefore, were not used to supportlower concentrations of sunscreenactive ingredients when used incombination. The other comment (Ref.16) submitted in vivo SPF testing dataconducted according to the procedureproposed in the tentative finalmonograph (58 FR 28194 at 28298 to28301) in which a selected cross sectionof active ingredients were tested in pairsby substituting water or the solventsystem for the active ingredients. Thedata were evaluated using a matchedpairs comparison statistical hypothesistest procedure and demonstrated thatconcentrations of sunscreen activeingredients lower than the minimumconcentrations proposed in§ 352.20(a)(2) for combination productscan provide a significant contribution toproduct effectiveness.

The agency recognizes thattechnological advances in sunscreenformulation technology since 1978 haveresulted in the ability to formulateproducts with lower concentrations ofactive ingredients and higher SPFvalues. The agency also recognizes thatfinal product testing, and not theconcentration of the active ingredientsin the combination, ensures producteffectiveness.

Due to the recent advances insunscreen formulation and the datareferenced previously, the agency isconcerned that setting minimumconcentration requirements for activeingredients in sunscreen combinationdrug products could subject consumersto unnecessary levels of activeingredients. Therefore, the agency isonly requiring the maximumconcentration limits in § 352.10 forsunscreen active ingredients when usedin combination with another sunscreenor when the combination is used withany other permitted active ingredient.However, any such ingredient used incombination with one or moresunscreen active ingredients must beconsistent with the regulations in§ 330.10(a)(4)(iv), i.e., each of thecombined active ingredients must makea contribution to the claimed effect, thecombining of active ingredients mustnot decrease the safety or effectivenessof any individual active ingredient, andthe combination must provide rationalconcurrent therapy for a significantproportion of the target population.

Although the agency needs assurancethat each ingredient is contributing tothe effectiveness of the product, it doesnot want to impose unnecessary testingrequirements on sunscreen productmanufacturers. Therefore, the agency isremoving the minimum concentrationrequirement for sunscreen activeingredients proposed in § 352.20 and isadding the requirement that: (1) Theconcentration of each active sunscreeningredient used in a combinationproduct must be sufficient to contributea minimum SPF of not less than 2 to thefinished product, and (2) the finishedproduct must have a minimum SPF ofnot less than the number of thesunscreen active ingredients used incombination multiplied by 2.

E. Comments on Labeling and TestingProcedures for UVA Sunscreen DrugProducts

22. In the sunscreen tentative finalmonograph (58 FR 28194 at 28232 and28233), the agency proposed to allowclaims relating to ‘‘broad spectrumprotection’’ or ‘‘UVA radiationprotection’’ for sunscreen products: (1)Containing sunscreen active ingredientswith absorption spectra extending to360 nm or above, and (2) thatdemonstrate meaningful UVA radiationprotection using appropriate testingprocedures to be developed. The agencyreceived numerous commentsconcerning such claims and currentscientific evidence implicates UVAradiation as a major cause of, amongother things, photoaging of the skin(Refs. 17 through 20).

In the Federal Register of September16, 1996, and October 22, 1998, theagency proposed a specific skin damageand premature skin aging claim forsunscreen products containing specificconcentrations of avobenzone or zincoxide based upon the submission ofdata to support claims of UVA radiationprotection in such products. The agencywill address comments pertaining tomeasurement of UVA radiationprotection in sunscreen products andrelated UVA radiation protection claimsin a future issue of the Federal Register.Until then, UVA labeling may continuein accord with the tentative finalmonograph and its amendments.

F. General Comments on the Labeling ofSunscreen Drug Products

23. Several comments requested thatproducts containing sunscreeningredients as an adjunct to their mainpurpose (e.g., a daily moisturizer or alipstick with a sunscreen) be considered‘‘secondary sunscreens’’ (intended onlyfor incidental or casual sun exposure),and should be subject to different



labeling requirements from ‘‘primary’’sunscreen products. A number ofcomments likewise contended that someof the labeling requirements for ‘‘beach’’or ‘‘primary’’ sunscreen products are notappropriate for ‘‘non-beach’’ or‘‘secondary’’ sunscreen products.

For example, the comments statedthat neither the proposed‘‘Recommended Sunscreen ProductGuide’’ nor any other references tosunburn or sunburn protection shouldbe required for secondary sunscreens.Some suggested that the warnings bereduced for secondary sunscreens to astatement such as ‘‘For external useonly, keep out of eyes. Discontinue useif signs of irritation appear.’’ Onecomment recommended that thestatement of identity for a secondarysunscreen should be its cosmeticfunction, e.g., ‘‘moisturizer.’’ Anotherrecommended stating the primary(cosmetic) function first, then thesecondary (drug) function, e.g.,‘‘moisturizing face cream withsunscreen (or with SPF llsunscreen).’’

The comments also suggested thatsecondary products be permitted to bearcertain labeling claims relating to aging,such as ‘‘Helps reduce the chance ofskin aging caused by incidental (orcasual) exposure to the sun,’’ or ‘‘Helpsreduce premature aging from incidental(or casual) exposure to the sun.’’ Somealso requested the option of beingallowed to relate skin aging claimsdirectly to sun exposure, to informconsumers more clearly that sunprotection is not the primary attribute ofthe product, e.g., ‘‘Provides moisture tofacial skin throughout the day whileprotecting facial skin from skin agingdue to exposure to sun.’’ Othercomments recommended that theproposed ‘‘Sun alert’’ statement or otherreferences to ‘‘skin cancer’’ or othercancers should not be required forsecondary products.

On the other hand, the agency alsoreceived comments opposing the idea ofrecognizing ‘‘primary’’ and ‘‘secondary’’or ‘‘beach’’ and ‘‘non-beach’’ categoriesof sunscreen products. One commentstated that any product containing asunscreen for the purpose of protectionfrom the sun’s harmful effects should beheld to the same standards as othersunscreen products. Another commentdisagreed with the idea of allowingdifferent sets of claims for ‘‘primary’’and ‘‘secondary’’ products. According tothis comment, claims such as ‘‘Helpsreduce the chance of skin aging’’ aredrug claims and should be regulated assuch. Finally, one comment stated thatany sunscreen product (primary orsecondary) must have an SPF of 15 to

30 or higher to provide adequateprotection, whether for continuousbeach exposure or everyday (incidental)sun exposure.

The agency agrees that all sunscreenproducts (whether drug only or drug-cosmetic) should be held to the samestandards (e.g., active ingredient(s),testing requirements, and labeling).Regardless of what type of product aconsumer chooses for sun protection,the essential information relevant to sunprotection is the same. Thus, to ensurethat consumers are adequately protectedfrom overexposure to the sun, allproducts intended for use as sunscreensshould have similar labelingrequirements, irrespective of theirmethod of use and irrespective ofwhether the sunscreen use is consideredprimary or secondary to the product.Consistent with this approach, theagency has developed uniform,streamlined labeling for all sunscreenproducts (see sections II.I through II.L ofthis document).

The agency also notes, however, thata number of the labeling issues raised inthese comments, including the issue ofthe ‘‘Recommended Sunscreen ProductGuide,’’ are addressed elsewhere in thisdocument. In addressing these issues,the agency gave careful consideration tothe wide variety of products marketedfor sunscreen uses.

Finally, the agency notes that underthe recently issued standardized OTCdrug product labeling format (§ 201.66(21 CFR 201.66)), manufacturers willnot be allowed to commingle drug andcosmetic claims within the ‘‘Drug Facts’’portion of the labeling.

24. One comment requestedclarification of the agency’s discussionof the term ‘‘anti-aging’’ as a claim or aspart of a trade name (58 FR 28194 at28287). The comment was concernedthat products containing no sunscreenactive ingredients and no sunscreenclaims, but which are sold under ‘‘anti-aging’’ trade names, would be subject toregulation under the OTC drugsunscreen monograph.

The use of ‘‘anti-aging’’ language in aproduct that made no sunscreen claimsand contained no sunscreen activeingredients would not, as the commentasked, cause the product to fall withinthe scope of the OTC sunscreen drugmonograph. Such a product may,however, be subject to regulation as adrug and as a new drug, under section201(g)(1) and (p) of the act, or as acosmetic under section 201(i), or as botha drug and a cosmetic, depending uponall of the circumstances surrounding itsdistribution. A product that is marketedunder the final OTC sunscreen drugmonograph, but which uses anti-aging

language in the labeling to suggest orimply an unapproved therapeutic orphysiologic effect, would likely besubject to regulatory action as anunapproved new drug (58 FR 28194 at28286 to 28287; see comments 37 and38 in section II.I of this document).

25. Three comments contended thatthe terms ‘‘natural,’’ ‘‘non-chemical,’’and ‘‘chemical free’’ are false andmisleading in the labeling of OTCsunscreen drug products. The commentsrequested the agency to restrict the useof these terms, especially for sunscreenproducts containing titanium dioxideand zinc oxide.

Generally, the appropriateness ofthese terms requires case-specificanalysis to determine whether their usewould render the product false ormisleading in any particular (seesections 502(a) and 602(a) of the act).The agency notes, however, that the useof the terms ‘‘non-chemical’’ and‘‘chemical-free’’ in the labeling of anOTC sunscreen drug product, todescribe the ingredients contained inthe product, is likely to be consideredunacceptable. Sunscreen drug productscontain active (and often inactive)ingredients that have been obtainedthrough a chemical process, or that havebeen formulated into the finishedproduct through a chemical process.The term ‘‘natural’’ is more likely torequire context-specific analysis,particularly when used in labeling todescribe certain cosmetic aspects oruses of a sunscreen product. The term‘‘natural,’’ however, would not bepermitted to appear within the requiredOTC drug labeling of a sunscreenproduct and is not considered to beinterchangeable with any of the finalsunscreen monograph language.

26. Four comments opposed anylabeling that a sunscreen product ‘‘doesnot provide UVA protection,’’contending that FDA’s policy does notrequire disclaimers of broader purposesfor which products are not useful. Onecomment added that an SPF 15 productmust block UVA radiation to beeffective in preventing sunburn.

Two comments argued that a‘‘negative warning’’ would be useful andnecessary to warn and protectconsumers and suggested ‘‘Does notprovide broad spectrum UVAprotection,’’ or ‘‘Caution: This productdoes not provide protection from therecognized dangers of UVA rays whichmay contribute to skin cancer and otherchronic skin disease.’’

Labeling should primarily directconsumers towards the purposes forwhich a product is considered useful.However, in establishing the conditionsfor the safe and effective use of an OTC



drug product, the agency also must takeinto account, among other things, thecontext in which a product iscustomarily marketed and the potentialthat consumers may use the product fora use for which it may not be beneficial(see sections 201(n) and 502(a) of theact; § 330.10(a)(3)).

With these factors in mind, the agencywill further evaluate whether ‘‘negativewarnings’’ or disclosure statements areneeded when it completes the UVAportion of the sunscreen monograph ina future issue of the Federal Register.

27. Four comments contended thatthe signal words ‘‘Indications’’ and‘‘Directions’’ are not needed, take upvaluable label space, and should eithernot be required or be optional,especially for sunscreen-containing drugproducts that have some ‘‘traditional’’cosmetic uses (e.g., lipsticks).

The agency allows the signal word‘‘Use’’ or ‘‘Uses’’ in place of‘‘Indication’’ or ‘‘Indications.’’ Thisshort signal word is useful forconsumers, appropriate for dual useproducts, and does not clutter labelspace. Likewise, the agency concludesthat the signal word ‘‘Directions’’ isuseful for consumers and does notclutter label space (64 FR 13254 at13264 to 13268, March 17, 1999). Theagency is including § 352.52(f) in thisfinal monograph to provide labelingmodifications for sunscreen productsthat meet the small packagespecifications in § 201.66(d)(10) and arelabeled for use on specific small areasof the face (e.g., lips, nose, ears, and/oraround eyes). These products includemany traditional cosmetics (e.g., lipstickor eye makeup) that may containsunscreens. These products will beallowed to present a condensed ‘‘Uses’’section and may omit directions for useif they are marketed in a lipstick form.

28. One comment requested that themonograph include professionallabeling for both UVB and UVAradiation protection to assist healthprofessionals to select appropriateproducts. The comment recommendedinclusion of the absorption spectrum ofeach sunscreen in the product andsuggested that the labeling includeinformation that the product: (1)Protects against drug-inducedphotosensitization reactions induced byUV radiation in the ranges ll nm toll nm, and (2) other truthful andnonmisleading statements describingboth UVB and UVA radiation protectionagainst photosensitization reactions.

The agency did not proposeprofessional labeling in the tentativefinal monograph, but did ask for data tobe submitted (58 FR 28194 at 28210 and28245). No data were received. The

agency will consider including this typeof professional labeling in themonograph in the future when specificsupportive data are provided.

G. Comments on Sunscreen DrugProducts With High SPF Values

29. Numerous comments objected tothe proposed maximum SPF value of 30for OTC sunscreen drug products. Thecomments requested either that theagency adopt no limit or a limit of SPF50, for the following reasons: (1) UVradiation exposure is increasing due toboth lifestyle changes and depletion ofthe atmospheric ozone layer, (2) skincancer rates are increasing and there isno safe threshold to prevent cancer, (3)people using an SPF 30 sunscreen willhave slight sunburn after receiving their30 MED and therefore should haveavailable sunscreens with higher SPFvalues, (4) high SPF sunscreens areneeded for extremely sun-sensitivepeople during periods of unavoidableintense or lengthy sun exposure, andbecause of less than ideal usage byconsumers due to misjudging of theirskin type and/or inadequate/infrequentapplication, (5) there is a significantvariation of skin types, sensitivities, andUV radiation exposures among people,(6) formulation techniques can increaseSPF values without necessarilyincreasing ingredient concentrations, (7)current information does not support anassociation between high SPF productsand safety concerns, and (8) high SPFproducts provide for greater relativeexposure times and decreased UVradiation transmission. Three comments(Refs. 21, 22, and 23) submittedsupporting data.

Some comments stated that ‘‘HighSPF’’ (i.e., above SPF 30) products areon the market and used by consumers,and that limiting SPF values wouldstifle sunscreen product developmentand preventative health benefits. Othercomments argued that sunscreens withhigh SPF values provide increasedprotection from ultraviolet radiationeffects such asphotoimmunosuppression and areneeded by those with ‘‘dermatologicalproblems.’’

In contrast, some commentssupported the agency’s proposal to limitSPF values to 30 to stop the promotional‘‘bidding war’’ or ‘‘horsepower race.’’Another comment contended that realconsumer benefit is achieved throughappropriate balance of SPF,substantivity, UVA radiation protection,irritation potential, and cost, whereasSPF values above 30 provide only‘‘incremental benefit’’ and anunnecessary increase in drug exposure.

The data provided by the commentsin support of allowing numerical valuesabove 30 were of only limited use. Datafrom a field survey of 62 sunbathers onMiami’s South Beach during July 1993(Ref. 21) did not provide any reliableconclusions on the frequency or extentof solar overexposure by light-skinnedindividuals or a benefit provided bysunscreen products with an SPF valueabove 30 as: (1) The sample size wassmall and the survey population did notrepresent a random sample, (2) the MEDwas not determined under controlledconditions or standardized procedure,and (3) full-day UVB radiation exposurewas based on crude extrapolation ofweather data.

Data from MED determinations on1,332 people with skin types I, II, andIII, and UV radiation data for the monthof June 1974 in 5 cities in the UnitedStates (Ref. 22), support the contentionthat a sizeable population may exist thatis at risk to more than 30 MED’s of UVradiation per day. However, the data areinsufficient for extrapolation to thegeneral population. The small samplesize in this study limits the sensitivityof the study and the study populationdid not represent a random sample.

Finally, data from animal studies (Ref.23) showed that: (1) Limiting sunscreenprotection to SPF 30 may not be prudentif UV radiation damage is not related toSPF; (2) a greater amount of sunscreenis needed to completely inhibit some ofthe nonerythemogenic damage causedby UV radiation, and (3)nonerythemogenic effects (e.g.,photoimmunosuppression) occur withsuberythemal doses of UV radiation (ascan be obtained with the use of low orhigh SPF sunscreens). While the agencyagrees that higher SPF values mayprovide for greater relative exposuretimes, the SPF test is not the appropriatemeasurement of protection fromnonerythemogenic damage because SPFis only a measure of erythema. Theagency finds that the data from thesestudies were not sufficient to eithersupport or dismiss limiting themaximum SPF value in this final rule.

The agency continues to agree withthe comments about overall increases inboth UV radiation exposure (58 FR28194 at 28223), skin cancer rates (58FR 28194 at 28227), and the variation ofskin types, sensitivities, and UVradiation exposures among people (58FR 28194 at 28222). The agency alsoagrees with the comment that a personusing an SPF 30 sunscreen could havea slight sunburn after being exposed totheir 30 MED (i.e., after their skinreceives a MED). However, the agencycontinues to believe that an SPF 30sunscreen product provides adequate



protection for the majority of consumerseven under extreme conditions, lessthan ideal usage, or in varying weatherconditions (58 FR 28194 at 28225).

On the other hand, the agency is alsoaware that many OTC sunscreenproducts with SPF values above 30 arecurrently marketed and are increasinglyused by consumers. Numerouscomments from health professionals,consumers, and industry provide actualuse information in support of SPFvalues above 30 for what may be asubstantial number of sun-sensitivepeople in this country. Further, asnumerous comments noted: (1) There isa lack of data to correlate higher thanSPF 30 sunscreen products withcorresponding safety problems, and (2)modern formulation techniques haveresulted in higher SPF values usinglower active ingredient concentrations.

Because of the numerous concernsfrom health professionals, new data tosupport the need for SPF values above30, and the lack of data concerningsafety problems with such SPF values,the agency concludes that OTCsunscreen drug products with SPFvalues above 30 should be available forthose sun-sensitive consumers whorequire such products based uponpersonal knowledge of their skin’ssusceptibility to sunburn, experiencewith specific products, planned sunexposure, or the recommendation of ahealth professional. The agency agreeswith the comments that higher SPFvalues generally can provide for greaterrelative exposure times and decreasedUV radiation transmission. However,the agency continues to believe that theadditional sunburn protection providedby an SPF 30 sunscreen and, e.g., anSPF 50 sunscreen (i.e., about a 1.3percent increase in absorption oferythemal UV radiation) is extremelysmall for most people. The agency isalso concerned about the ability ofcurrent testing methods to accuratelyand reproducibly determine SPF valuesfor high SPF products (see section II.M,comment 53 of this document). Inaddition, nonlinearity of the SPF ratingsystem is a concept difficult to explainin the limited space on a product label.Therefore, the agency concludes that thelabel SPF declaration for sunscreenswith SPF values above 30 should belimited to one collective term, whichappears in § 352.50(a) of this documentas follows: ‘‘For products with SPFvalues over 30. ‘‘SPF 30’’ (select one ofthe following: ‘‘plus’’ or ‘‘+’’). Anystatement accompanying the marketedproduct that states a specific SPF valueabove 30 or similar language indicatinga person can stay in the sun more than30 times longer than without sunscreen

will cause the product to be misbrandedunder section 502 of the Federal Food,Drug, and Cosmetic Act (the act).’’

Numerous comments fromdermatologists asked that a specific SPF50 product be allowed to remain on themarket because it is needed for the‘‘ultrasensitive patient’’ and for patientswith ‘‘dermatological problems.’’ Theagency has previously discussed the useof high SPF sunscreen drug products toprotect consumers with photosensitivitydiseases (58 FR 28194 28225) and theneed to provide data for such uses (seesection II.F, comment 28 of thisdocument) as the absorption spectrumof a specific product, not necessarily theSPF, may be the more clinicallysignificant factor for such people.

As discussed previously in thiscomment 29 of section II.G of thisdocument, the agency has concludedthat the use of SPF label values above30 in OTC drug products is notsupported at this time. The agency,however, invites interested persons tocontinue developing the test methodsneeded to measure high SPF values, andto submit the data in support of suchmethods to FDA. If test methods aredeveloped, the agency also invitesinterested persons to consider proposedmethods for communicating in labelingthe level of protection associated withhigh SPF values (given the nonlinearnature of the SPF rating system). Theseand other well-supported improvementsto the methodology for accurately andreproducibly measuring SPF values willbe addressed, as appropriate, in futureissues of the Federal Register. Untilthen, OTC sunscreen drug products arepermitted to be labeled with SPF valuesno higher than ‘‘30+’’ or ‘‘30 plus.’’

Finally, the agency does not agreewith the argument that limiting SPFvalues would stifle sunscreen productdevelopment and preventative healthbenefits. Undue emphasis for sunburnprotection should not be placed uponSPF value alone (i.e., ‘‘single focusproducts’’). As noted by anothercomment, consumer benefit is achievedthrough appropriate balance of severalfactors, including substantivity, UVAradiation protection, and irritationpotential.

H. Comments on Water ResistantLabeling and Testing for SunscreenDrug Products

30. One comment agreed and severaldisagreed with proposed§ 352.52(e)(2)(iii) and (e)(3)(iii)concerning sweat resistant claims basedupon water resistance testing instead ofa specific sweat resistance test. Onecomment submitted data from twosweat resistance studies and two water

resistance studies (Ref. 24) utilizingmethods proposed by the Panel in theANPRM (43 FR 38206) and involving atotal of 117 subjects. The commentconcluded that the water resistance testis less stressful than the sweat resistancetest.

The agency does not find the datasubmitted in the studies sufficient tosupport the comment’s contention. Thestudies each comprised distinct subjectpopulations and addressed a singlevariable, i.e., the effect of waterexposure or induced sweating on aproduct’s SPF. Therefore, a comparisonof mean SPF values across studies is notthe appropriate measure of relative‘‘stress’’ associated with these variables.The agency believes that a randomized,two-period crossover study design in asingle patient population would betterhave addressed the comment’scontention. Further, the Panel’s sweatand water resistance protocols providequalitative information and were notdesigned to provide comparativeassertions requiring valid statisticalinferences. Thus, the agency is allowingwater and sweat resistant claims basedupon the water resistance testprocedures in § 352.76 of thisdocument.

31. One comment contended that the‘‘water resistant’’ labeling proposed in§ 352.50(b)(1) and (c)(1) should not berequired for products labeled orpurchased for uses other thanswimming or bathing.

The agency notes that the waterresistance statements referenced by thecomment were not required unless themanufacturer wished to make waterresistant claims in the labeling of itssunscreen products. This final rule alsowill not require a manufacturer to makea water resistance claim for itssunscreen product, even if the productis determined to be water resistant.However, a manufacturer wishing tomake water resistance claims mustcomply with §§ 352.50(b) or (c) and352.52(b)(1)(ii) or (b)(1)(iii) of thisdocument, as applicable for ‘‘waterresistant’’ or ‘‘very water resistant’’products.

32. Several comments urged theagency to return to the ‘‘waterproof’’and ‘‘water resistant’’ label claimsproposed by the Panel and to limit thelabeled SPF value to only the SPF afterwater resistance testing. Anothercomment requested only generalguidelines for claims such as ‘‘waterresistant’’ or ‘‘sweat resistant’’ on thebasis that such claims reflect theinherent characteristics of specificformulations and not sunscreeningredients.



The agency thoroughly discussed useof the terms ‘‘waterproof’’ and ‘‘waterresistant’’ in the tentative finalmonograph (58 FR 28194 at 28228). Thecomments did not present anyarguments or data that the agency didnot previously consider. In addition, theagency points out that performanceclaims such as these for OTC sunscreendrug products are based on finalproduct formulation.

The agency agrees with the commentsthat the more relevant SPF value forproducts labeled ‘‘water resistant’’ or‘‘very water resistant’’ is the SPF valueof the final product formulationfollowing water resistance testing.Therefore, in this document the agencyis limiting the SPF label declaration tothe SPF after water resistance testingand is modifying the testing proceduresin § 352.76 to reflect deletion of theproposed dual SPF testing requirementfor sunscreen products with waterresistant claims.

33. Two comments suggested that‘‘water resistant’’ labeling be permittedfor drug products retaining at least 80percent of their SPF value after statictesting in pools and that any productmeeting this criterion could also belabeled ‘‘sweat proof.’’ The commentsfurther suggested that the term ‘‘verywater resistant’’ should be permitted forproducts retaining 90 to 98 percent oftheir SPF after testing.

The agency disagrees with thecomments. Simple immersion providesneither an aqueous shear stress northermal challenge, and thus is aninadequate assessment of waterresistance. In addition, no justificationwas offered for the respective thresholdvalues of 80 percent and 90 to 98percent.

34. Several comments contended thatthe water resistance testing proceduresin § 352.76 should be amended to allowfor continuation of the water exposureregimen beyond the 80 minute total andsuggested that the ‘‘very water resistant’’claim be expanded beyond 80 minutesfor products meeting such testingrequirements. One comment provideddata (Ref. 24) to support extended waterresistance claims. Another commentalso proposed a testing protocol (Ref.25) for an additional claim of‘‘rubproof’’ or ‘‘abrasion proof.’’

The agency does not concur with anexpansion of the ‘‘very water resistant’’claim. Although data submitted by thecomment (Ref. 24) show that undertesting conditions products may retaintheir SPF values for up to 270 minutesof water exposure, no usage data werepresented to refute the Panel’sdetermination of an 80 minute upperexposure limit (58 FR 28194 at 28277).

In addition, the agency believes that forconsumers to compare products withmultiple performance characteristics, alabeling claim of ‘‘very water resistant’’is best supported by a uniform testingstandard. Should the agency receivedata in the future indicating customaryusage patterns in excess of 80 minutesof water exposure, it will reconsider thislimit.

35. One comment disagreed with theagency’s proposal in the tentative finalmonograph (58 FR 28194 at 28278) thatmanufacturers determine the waitingperiods for the most effective use oftheir sunscreen products (i.e., the timebetween application and exposure to thesun or water, if applicable). Thisinformation would then be included inthe directions for the product. Thecomment asserted there is no reason torequire a ‘‘time versus efficacy’’ studyfor every sunscreen formula becausestudies show that products maintaintheir efficacy for up to 8 hours.

In the tentative final monograph, theagency did not propose a specificmethod or testing procedure for thedetermination of a proper waitingperiod because of the variation insunscreen product dosage forms andformulations. Instead, the agencyallowed manufacturers to make thisdetermination. However, the agency didpropose in § 352.52(d)(2) that a waitingperiod before sun or water exposure, ifapplicable, be included in the labelingof sunscreen products for their mosteffective use. In this final rule, theagency has included the requirement fora waiting period in the sunscreenproduct application statement inproposed § 352.52(d)(1) for the reasonsstated in the tentative final monograph(58 FR 28278). The agency continues toallow the manufacturer to determineboth the necessity for this statement(based on the product’s formulation anddosage form) and how the waitingperiod, if applicable, is determined.

I. Comments on Indications forSunscreen Drug Products

36. One comment urged the agency tomore strongly state the effectiveness ofsunscreens (a specific claim was notsuggested). The comment cited acontrolled study of a broad spectrum,SPF 17 sunscreen on 431 Caucasiansubjects over one summer in Australia(Ref. 26). The study showed that thegroup using the sunscreen hadsignificantly fewer solar keratoses andmore remissions than the control group.Another comment expressed concernthat use of the term ‘‘help prevent skindamage’’ may mislead consumers tothink that these products prevent skincancer and premature skin aging.

The agency agrees that solar keratosesare a clinical sign of skin damage.However, although sunscreens areassociated with a statistically significantdecrease in solar keratoses after 1 or 2years, the solar keratoses reduction inthis study was small and neither theclinical nor biological significance ofthis reduction has been established.Most solar keratoses never become skincancers and typically resolvespontaneously (Refs. 27 and 28).

Because of the wide variabilitypossible in the formulation of sunscreenproducts, not all sunscreen products areidentical in their UV radiationabsorption characteristics. Sunscreenproducts may contain active ingredientsthat absorb in different regions of theUVB radiation spectrum (the primarycause of sunburn) or absorb in both theUVB and different regions of the UVAradiation spectrum. Therefore, even thedegree/type of UV radiation protectionreported in one study using a specificsunscreen formulation may not berelevant to all possible sunscreenproducts within the scope of this finalmonograph. Further, the agency doesnot believe that it is prudent toextrapolate claims for skin cancer orskin aging based upon a test designed toonly measure erythema (i.e., the SPFtest).

The agency has reviewed informationconcerning the mechanisms of skincancers and photoaging. UV radiationappears to have a dual role in theinduction of skin cancers as it can causeseveral varieties of direct DNA damage(Refs. 23 and 29 through 32) plussuppress the immune response todeveloping skin cancers (Refs. 33through 37). This immune suppressionmay be a critical variable as skincancers, unlike other cancer types,evoke a strong immune response(especially by Langerhans cells and T-lymphocytes) (Ref. 38). In photoaging,there are multiple sites in the skin thatcan be damaged by UV radiation (Ref.17). For example, recent studies supportthe concept that specific UV radiation-induced enzymes (i.e., matrixmetalloproteinases) can mediateconnective tissue damage and result inthe premature aging effects seen in skinexposed to UV radiation (Refs. 19 and20). These data also suggest that thesemechanisms of carcinogenesis andphotoaging can occur from doses of UVradiation below that required to producesunburn (i.e., suberythemal doses).Thus, even if no sunburn has occurredwith the use of a sunscreen, theconsumer cannot assume that sun-induced skin damage that mightcontribute to the eventual development



1 See § 201.66(b)(4)

of skin cancer or signs of photoaging hasnot occurred.

The agency agrees with the commentthat terms such as ‘‘help prevent skindamage’’ may mislead consumers tothink that sunscreen use alone willprevent skin cancer and premature skinaging. However, the agency believes thatan appropriate statement can be used toinform consumers that sunscreens mayreduce the risks of skin aging, skincancer, and other harmful effects fromthe sun when used in a regular programthat includes limiting sun exposure andwearing protective clothing (see sectionII.L, comment 51 of this document).

37. Several comments expressedconcern that the statements ‘‘Allowsyou to stay in the sun up to (insert SPFof product up to 30) times longer thanwithout sunscreen protection’’ and‘‘Provides up to (insert SPF of productup to 30) times your natural protectionfrom sunburn’’ in proposed§ 352.52(b)(1)(iii) and (b)(1)(iv) maymislead consumers as to the amountand degree of protection sunscreenproducts provide. The comments wereconcerned that this message will conveya more expansive meaning thanintended and that consumers might bemisled about how long they can stay inthe sun without risking any sun-induced skin injury. One commentexpressed additional concern becausethe SPF value is only a laboratory testof a few minutes duration.

One comment also objected to theunqualified use of terms such as‘‘shields from,’’ ‘‘protects from,’’‘‘filters’’ or ‘‘screens out’’ the ‘‘sun’srays,’’ ‘‘sun’s harsh rays,’’ or ‘‘sun’sharmful rays’’ to ‘‘help prevent skindamage’’ proposed in § 352.52(b)(1)(v)and (b)(1)(vi). The comment expressedconcern that these unqualified termscould imply complete protection fromthe sun’s harmful rays and may misleadconsumers by inducing a false sense ofsecurity when using sunscreenproducts.

As discussed in section II.I, comment36 of this document, the agency believesthat sunscreen use alone will notprevent all of the possible harmfuleffects due to the sun. Variationbetween individuals, UV radiationabsorption and substantivity ofsunscreen products, exposureconditions, and conditions of usecannot promise a precise result for eachindividual. Thus, the agency agrees thatthese statements could provide thewrong message and a false sense ofsecurity to some consumers. The agencytherefore is not including proposed§ 352.52(b)(1)(iii) through (b)(1)(vi) inthis final rule and considers these andsimilar statements to be nonmonograph.

For the same reasons, the agency alsoconsiders extended wear claimsconcerning a specific number of hoursof ‘‘protection’’ (or similar terminology)or an absolute claim such as ‘‘all-dayprotection’’ to be nonmonograph.Instead, the agency is including anaccurate, simpler, and less confusingindication statement in this final ruleusing two bulleted statements under the‘‘Uses’’ heading, as follows: ‘‘[bullet]helps prevent sunburn’’ and ‘‘[bullet]higher SPF gives more sunburnprotection’’.1

38. Several comments contended thatterms such as ‘‘skin aging,’’‘‘wrinkling,’’ ‘‘premature skin aging,’’ or‘‘photoaging’’ should be permitted asindications for sunscreens, especially ifprotection is provided in the UVA II(320 to 340 nm) radiation region. Onecomment suggested that a label claimsuch as ‘‘Helps reduce the chance ofskin aging caused by incidental (orcasual) exposure to the sun’’ may helpto further position the product as acosmetic for consumers. The commentalso suggested an indication statement:‘‘Excessive, chronic sun exposure canlead to premature photoaging of theskin, characterized by drying, wrinklingand thinning of the skin. Regular use ofa sunscreen can help protect against thiscondition.’’

The agency discussed the use of termssuch as ‘‘skin aging,’’ ‘‘wrinkling,’’‘‘premature skin aging,’’ or‘‘photoaging’’ on sunscreen products inthe tentative final monograph (58 FR28194 at 28236 and 28287). Asdiscussed in the response to comments36 and 37, the agency has determinedthat the labeling should describe theproduct’s use in preventing sunburn. Amore expansive set of indications iscurrently unsupported. The agencynotes, however, that the final ‘‘Sunalert’’ statement (discussed in sectionII.L, comment 51 of this document) doesprovide the consumer with informationabout the role of sunscreens in reducingskin aging, in a context that ensures thatthe information will not be misleading.The agency, however, is continuing toconsider whether certain sunscreensmay provide protection againstphotoaging (58 FR at 28287) and hasdiscussed this in tentative finalmonograph amendments for certainsunscreens containing avobenzone orzinc oxide based upon specific datasubmitted to the agency (see section II.E,comment 22 of this document). Theagency will evaluate this issue furtherwhen it completes the UVA portion ofthe sunscreen monograph, in a futureissue of the Federal Register.

39. Several comments contended thatthe extensive labeling proposed in thetentative final monograph wasexcessive. For environmental concerns,the comments objected to the use ofextra packaging materials as a method ofincluding added labeling. One commentdisagreed with the need for a specificstatement of product indications onindividual units of non-beach productsproperly labeled with an SPF value, andcited limitations on labeling space. Thecomment suggested that manufacturersbe given the option to provide off-package information at the point-of-salerather than be required to place thestatement(s) on each individual unit ofthe product.

To balance the environmental andregulatory concerns, the agency hasstreamlined labeling in this finalmonograph by significantly reducing theamount of required labeling and makingoptional other labeling that wasproposed as required in the tentativefinal monograph. The agency is alsoincluding § 352.52(f) in this finalmonograph to provide for additionallabeling accommodations for sunscreenproducts that meet the small packagespecifications in § 201.66(d)(10) and arelabeled for use on specific small areasof the face (e.g., lips, nose, ears, and/oraround eyes) (see section IV, comment6 of this document).

J. Comments on Warnings for SunscreenDrug Products

40. One comment asked the agency topermit reduced warning statements forlip balm products containing sunscreensbased on their safe market history. Thecomment argued that lip balms are notapplied to the eye area, and thusextensive eye warnings are not required.Two comments cited the long history ofsafe use of lipstick products containingsunscreens and suggested the reducedwarning, ‘‘Discontinue use if signs ofirritation appear.’’

The agency discussed its rationale forproposing an eye warning for sunscreen-containing lip balms in comment 52 ofthe tentative final monograph (58 FR28194 at 28229 to 28232), noting thatsome lip balms could be used on otherareas of the face. However, the agencyhas received neither data concerningadverse reactions due to the use ofsunscreen-containing lip balms near theeyes, nor information that such productsare normally used in the eye area. Theseproducts also are consistent with thefactors described in the final OTCstandardized content and formatlabeling rule (64 FR 13254 at 13270) forconsidering additional labelingmodifications. Accordingly, this finalmonograph allows sunscreen-containing



lipsticks to omit the eye warning inproposed § 352.52(c)(1)(i). As discussedin Section II.J, comment 42 of thisdocument, the wording of this warningis modified in this final monograph. Forlip balms, the agency expects to adoptthe same modification when it issuesthe final monograph on OTC skinprotectant drug products.

The proposed warning in§ 352.52(c)(1)(iii) is now stated as abullet under the ‘‘Stop use and ask adoctor if’’ subheading as follows:‘‘[bullet] rash or irritation develops andlasts.’’ This warning appears in§ 352.52(c)(1)(ii) in this document.Finally, lipsticks (and lip balms, whichwill be addressed in the finalmonograph on OTC skin protectant drugproducts) will not be required to bearthe ‘‘For external use only’’ warning.Accordingly, in this final monograph,§ 352.52(c)(2) allows lipsticks to omitthe warning in § 201.66(c)(5)(i).

41. One comment requested that aneye irritancy warning need not berequired for products that containtitanium dioxide as the sole activeingredient. The comment stated thattitanium dioxide is an inert inorganicoxide (and thus is chemically distinctfrom all other Category I sunscreenactive ingredients, which are organiccompounds) and is an FDA approvedcolor additive for the eye area in bothdrugs and cosmetics. The commentargued that determination of eyeirritancy should be based on totalproduct formulation. A secondcomment concurred that the labeling forinorganic sunscreens, which are not eyeirritants, should be differentiated fromorganic sunscreens, which may beirritants in the eye.

The agency agrees that the eyewarning (proposed in § 352.52(c)(1)(ii))is based on total formulation, not simplypresence of an ingredient. The agency’srationale was discussed in comments 52and 62 of the tentative final monograph(58 FR 28194 at 28229 to 28232 and28241). Accordingly, this finalmonograph requires all sunscreen-containing drug products to bear the eyewarning in § 352.52(c)(1)(i). Onlyproducts formulated as a lipstick (andlip balms, which will be addressed inthe final monograph on OTC skinprotectant drug products) may omit thiswarning (see § 352.52(c)(3) of thisdocument). The agency will consideromitting the eye warning requirementfor a particular formulation if datasubmitted in an NDA deviation(§ 330.11 (21 CFR 330.11)) from thesunscreen monograph demonstrate it isnot an eye irritant.

42. One comment suggested restatingthe proposed warnings in § 352.52(c)(1)

more concisely, as follows: ‘‘Forexternal use only. Keep out of eyes. Ifcontact occurs, rinse thoroughly withwater. If irritation or rash occurs,discontinue use. Consult a doctor ifproblem persists.’’

Since the tentative final monographwas published, the agency haspublished a final rule revising theformat and content requirements forOTC drug product labeling (64 FR13254). Section 201.66(c)(5)(i) requiresthe warning ‘‘For external use only’’ forall topical drug products not intendedfor ingestion. Therefore, it is notnecessary to state that warning in thisdocument and the warning in proposed§ 352.52(c)(1)(i) is not included in thisfinal monograph. The agency isshortening the proposed warning in§ 352.52(c)(1)(ii). This warning appearsin § 352.52(c)(1)(i) in this document asa bullet under the ‘‘When using thisproduct’’ subheading as follows:‘‘[bullet] keep out of eyes. Rinse withwater to remove.’’ The agency is statingthe proposed warning in§ 352.52(c)(1)(iii) as a bullet under the‘‘Stop use and ask a doctor if’’subheading as follows: ‘‘[bullet] rash orirritation develops and lasts.’’ Thiswarning appears in § 352.52(c)(1)(ii) inthis document. Section 201.66(c)(5)(x)requires the ‘‘Keep out of reach ofchildren’’ and accidental ingestionwarning set forth in 21 CFR 330.1(g) forthese products.

43. One comment contended that theproposed warning about swallowing in§ 352.52(c)(1)(i) would not be needed forso-called secondary sunscreen productsbecause adults using these products(which, according to the comment, havetraditionally been marketed ascosmetics) would know not to ingestthem.

As discussed in section II.J, comment42 of this document, the warningproposed in § 352.52(c)(1)(i) has beensuperseded by the warning required by§ 201.66(c)(5)(i). The new requiredwarning no longer contains thestatement about not swallowing theproduct.

K. Comments on Directions forSunscreen Drug Products

44. Two comments stated that theproposed directions in § 352.53(d)(4) forlipsticks and make-up preparations areunnecessary because these products aremarketed primarily for their cosmeticuses, which are self-evident. Onecomment contended that it is unlikelythat consumers will modify their habitsof lipstick application and usage simplybecause the product contains asunscreen. The other comment arguedthat failure to follow directions for these

products is unlikely to have seriousconsequences.

The agency has determined thatdirections for use in the labeling oflipstick products containing sunscreenswould provide minimal benefit toconsumers and the omission of adirections statement is not likely to haveserious consequences (see section II.J,comment 40 of this document).However, the agency believes thatdirections would be useful for make-upproducts containing sunscreens becauseof the wide variety of make-up productsthat are available. Therefore, the agencyis revising proposed § 352.52(d)(4) toread: ‘‘For products formulated as alipstick. The directions in paragraphs(d)(1) and (d)(2) of this section are notrequired.’’ The agency expects tofinalize the same modifications for lipbalm products when it finalizes themonograph for OTC skin protectantdrug products.

45. Several comments contended thatthe proposed direction, ‘‘Children under2 years of age should use sunscreenproducts with a minimum SPF of 4,’’ ismisleading and has no scientific basis.Some comments stated that thedirection implies that an SPF 4 may beadequate for children and noted that theSkin Cancer Foundation advises use ofSPF 15 or higher for both children andadults. The American Academy ofDermatology questioned why childrenshould not have the benefit of a morehighly protective sunscreen. Othercomments suggested that this directionshould only be required for productswith an SPF lower than 4 because itwould be nonsensical and a waste oflabel space on products with higher SPFvalues.

The agency agrees with the commentsthat this direction could mislead parentsinto believing SPF 4 is adequate forchildren under 2 years of age. Therefore,the agency concludes it is notappropriate and is not including it in§ 352.52(d) in this document.

46. One comment stated that thewords, ‘‘adults and children 6 months ofage and over’’ in proposed § 352.52(d)(1)are unnecessary because there is aseparate statement, ‘‘Children under 6months of age: consult a doctor.’’Another comment suggested thatlengthy directions for use by children 6months to 2 years of age are notappropriate for many product types(e.g., a daily facial moisturizer with asunscreen) and should be revised to‘‘For adult use only.’’ Another commentadded that when ‘‘For adult use only’’is used, then warning and cautionarystatements concerning use by childrenwould not be needed.



The agency agrees with the commentthat the statement, ‘‘Children under 6months of age: consult a doctor,’’provides sufficient informationregarding the age limit for use and isretaining it under § 352.52(d) as a bulletwith a small modification as follows:‘‘[bullet] children under 6 months ofage: ask a doctor’’. Therefore, the agencyis removing the phrase, ‘‘Adults andchildren 6 months of age and over.’’ Theproposed directions for children 6months to 2 years of age referred to bythe comments in § 352.52(d)(1), (d)(2),(d)(3), and (d)(5) stated: ‘‘Childrenunder 2 years of age should usesunscreen products with a minimumSPF of 4.’’ As discussed in section II.K,comment 45 of this document, theagency concluded that this directionwas misleading and did not include itin § 352.52(d) in this document. Theagency finds it unnecessary to includethe direction ‘‘For adult use only’’ inthis document because there are onlytwo age groups in the directions:Children under 6 months of age and allother users of the product.

47. One comment argued that thedirection ‘‘apply generously’’ may beresponsible for some skin irritationcomplaints from consumers. However,the comment did not provide data tosupport its position. The commentcontended that application of smalleramounts of sunscreen may provideadequate coverage, but that in the caseof sun protection, it may be best to erron the generous side. Another commentmaintained that applying too littlesunscreen may significantly lowerprotection in a geometric rather than alinear fashion, e.g., an SPF 25 sunscreenapplied half as thick as the amountapplied for the SPF test may only havethe effect of SPF 8.

The agency agrees with the commentsthat adequate sunscreen should beapplied to achieve full labeled SPFprotection. Therefore, the agencyconcludes that the directions in§ 352.52(d)(1) of this final monograph toapply ‘‘liberally’’ or ‘‘generously’’convey the appropriate message toensure that consumers adequately applythe sunscreen.

48. One comment stated that theagency should permit firms to providereapplication instructions based onsubstantiation information the firmpossesses. The comment noted thatsome products may not need to beapplied as frequently as some selecttime period.

The agency is including a generalreapplication direction in § 352.52(d)(2).Manufacturers who have data to supportreapplication instructions based onspecific substantiation information may

submit that information for approval viaan NDA deviation as provided in§ 330.11.

L. Comments on Product PerformanceStatements for Sunscreen Drug Products

49. Several comments recommendedrevisions to proposed § 352.52(e), thestatement on product performance. Forexample, some comments suggested thatmultiple superlative categorydesignations (e.g., ‘‘high,’’ ‘‘very high,’’and ‘‘ultra high’’) may foster consumerconfusion about the level of protectioneach SPF provides. Other commentsstated that the current SPF scale doesnot encourage consumers to use higherSPF products. Other commentsdisagreed with the indication ‘‘permitsno tanning.’’

The agency has revised proposed§ 352.52(e) in this document bycondensing the five proposed productcategories to three broader ones, and hasgeneralized the category designations.The new categories are: minimalsunburn protection for products withSPF 2 to under 12; Moderate sunburnprotection for products with SPF 12 tounder 30; high sunburn protection forproducts with SPF 30 or above. Theseproduct category designations (PCD)should appear under the ‘‘Otherinformation’’ heading and may alsoappear on the PDP. Further, productsare now described as providingminimal, moderate, or high protectionagainst tanning, thus deleting thereference to tanning prevention that wasproposed in § 352.52(b)(2)(v)(B).

50. Many comments opposed the‘‘recommended sunscreen productguide’’ in proposed § 352.52(e)(4). Somecomments noted that the guide isincomplete because it only considersskin type and not duration of exposure,season, geographic location, and otherfactors that influence choice of product.Other comments stated that the guide isdeceptive and may encourageinappropriate use of lower SPF’s forprotection. Several comments statedthat labeling for many products is toosmall to accommodate the guide. Othercomments suggested that information inthe guide should be disseminated toconsumers through point of sale,television, and weather programs, ratherthan being required in product labeling.

The agency recognizes that variousfactors influence the purchase of asunscreen product, including skin type,geographic location, hours exposed tothe sun, and sun reflections. While theproduct guide was intended as a generalguidance for using these products, theagency acknowledges that the guide isincomplete and could be confusing andmisleading to consumers. Accordingly,

the agency is not including therecommended sunscreen product guidein this document.

51. Many comments requested thatthe ‘‘Sun alert’’ in proposed§ 352.52(e)(6) be voluntary instead ofrequired labeling and suggested thisinformation could better bedisseminated at the point of purchase orthrough consumer education programs.Some comments stated that the ‘‘Sunalert’’ is too weak and suggestedalternate language. One commentobserved that the ‘‘Sun alert’’ fails towarn consumers that UV radiation mayharm the immune system, impairing thebody’s ability to fight infectious disease.The comment did not provide data tosupport this claim.

The agency agrees that the ‘‘Sun alert’’should be optional on product labeling.Further, the agency has reevaluated the‘‘Sun alert’’ and concludes that itspurpose should be to describe the roleof sunscreens in a total program toreduce harmful effects from the sun.Marks (Ref. 39) has noted thatsunscreens ‘‘are normally recommendedfor use as an adjunct to otherprotection,’’ such as clothing, hats, andavoidance of the sun near midday. Theagency agrees with this concept, as domany researchers (Ref. 40), theAmerican Academy of Dermatology(Ref. 41), Centers for Disease Control(Ref. 41), and the Governments ofAustralia and New Zealand (Ref. 42).For this reason, the agency has revisedthe ‘‘Sun alert’’ to include otherprotective actions consumers can take,and has clarified possible results. Theagency is including skin cancer in the‘‘Sun alert’’ instead of the body’s abilityto fight infectious disease because, todate, skin cancer is the best documentedadverse effect of UV radiation on theimmune system (Ref. 43). Accordingly,§ 352.52(e)(2) in this document providesthe following optional ‘‘Sun alert,’’which should appear under the ‘‘Otherinformation’’ heading and may alsoappear on the PDP: ‘‘Limiting sunexposure, wearing protective clothing,and using sunscreens may reduce therisks of skin aging, skin cancer, andother harmful effects of the sun.’’ Theagency encourages sunscreenmanufacturers to voluntarily includethis ‘‘Sun alert’’ in the labeling and tootherwise make it available at point ofpurchase and through consumereducation programs.

52. Several comments suggested thatthe term ‘‘sunblock,’’ proposed in thedefinition in § 352.3(d) and as a labelingstatement for products containingtitanium dioxide that provide an SPF of12 to 30 in § 352.52(e)(5), not beincluded in the final monograph. Some



comments argued that the term isunclear and may mislead and confuseconsumers into thinking that theproduct blocks all of the sun, when infact it does not. One comment statedthat no product available totally blockssun damage. Numerous other commentscontended that the term ‘‘sunblock’’should be applied to all sunscreeningredients that provide an SPF of 12 orhigher, as such products block at least90 percent of the sun’s UV rays. One ofthe comments submitted a study (Ref.44) to show that micronized titaniumdioxide absorbs short wavelength UVradiation and reflects and scatters longwavelengths, thereby functioningsimilarly to chemical UVB radiationsunscreens. The comment contendedthat the method in which micronizedtitanium dioxide performs as asunscreen active ingredient furtherjustifies the use of the term ‘‘sunblock’’for all sunscreen products with an SPFof 12 or higher.

The agency has decided not toinclude the term ‘‘sunblock’’ in the finalmonograph and now considers this termnonmonograph. The agency’s intentionin the tentative final monograph was toprovide information to consumers onthe method of product performance, notto imply greater protection from using aproduct labeled as a ‘‘sunblock.’’ Theagency is concerned that the term‘‘sunblock’’ on the label of sunscreendrug products will be viewed as anabsolute term which may mislead orconfuse consumers into thinking thatthe product blocks all light from thesun. For example, consumers mightview an SPF 15 product labeled as asunblock as superior to a productlabeled as an SPF 30 broad spectrumsunscreen. As nonmonograph labeling,the term ‘‘sunblock’’ cannot appearanywhere in product labeling.

In addition, the proposed definition of‘‘sunscreen opaque sunblock’’ in§ 352.3(d) applied only to titaniumdioxide and is inconsistent with howmicronized titanium dioxide functionsas an sunscreen active ingredient (Ref.44). Further, it is the radiation from theUV portion (290 to 400 nm) of the sun’sspectrum that reaches the earth’s surfaceand may produce skin erythema,melanogenesis, and cancer. The agencybelieves that claims of protectionbeyond 400 nm (i.e., protection fromvisible and infra red light) arenonmonograph and not within thescope of this document. Therefore, toprovide clear and consistent labeling,the agency is not including proposed§§ 352.3(d) and 352.52(e)(5) in thisdocument.

M. Comments on Testing Procedures forSunscreen Drug Products

53. Several comments questioned theability of current testing methods toaccurately and reproducibly determineSPF values for high SPF products. Somecomments contended that the spectra ofcurrently used solar simulators(especially around 290 nm and above350 nm) could cause overestimation ofSPF for high SPF sunscreens andrecommended use of a specificationstable that provided percent of erythemalcontribution by wavelength regions.Other comments submitted data insupport of a high-SPF sunscreen controlfollowing concerns expressed by theagency in the proposed rule (58 FR28194 at 28253 and 28254) that datawere not sufficient to demonstrate thatthe testing methods used to evaluatesunscreen drug products with SPFvalues up to 15 are equally applicableto evaluating sunscreen drug productswith SPF values above 15. Severalcomments submitted data andinformation that questioned the abilityof current testing methods to accuratelyand reproducibly determine SPF valuesfor high SPF products and requestedsignificant changes to proposed subpartD of § 352.70. Other commentsrequested changes to the testingprocedures proposed in subpart D of thesunscreen monograph that wereunrelated to products with high SPFvalues.

The agency believes that the testmethod proposed in the tentative finalmonograph (TFM), for measuring SPFvalues up to 30, represents at this timea straightforward, well-understood, andsound method for measuring thesevalues. The agency therefore isfinalizing the method proposed in theTFM. The agency recognizes, however,that testing methods in this area areevolving and that a number ofcomments raised useful ideas forproposed improvements in the accuracyand reproducibility of the agency’smethodology. As discussed in responseto comment 29 of section II.G of thisdocument, the agency is also invitinginterested persons to continue workingon improving SPF testing methods,toward the development of accuratemethods for measuring high SPF values.In future issues of the Federal Register,if appropriate, the agency will considerproposed improvements to its testingmethodology.

54. One comment contended that thecalculation of erythema effectiveexposure (E) serves no practical purposein the calculation of SPF because the Econstant is common to both thenumerator and denominator of the

equation. Another comment stated thatthe definition of E is incorrect becauseit is defined as ‘‘dose’’ (Joules/squaremeter (m2)) on the left side of theequation E = Σ Vi (λ) * I (λ), whereas theright side of the equation is in terms ofirradiance (Watts/m2). The commentalso stated that the unit of timeexposure (seconds) is missing on theright side of the equation.

The agency acknowledges that thiscalculation is not technically necessaryif the solar simulator emission spectrumdoes not change between exposures toprotected and unprotected skin. Thesame result can then be obtained bymeasuring the difference (i.e., ratio) intime required to produce erythema onprotected versus unprotected skin.However, the agency finds that thecalculation of E provides valuableinformation and is necessary todemonstrate how the MED wasdetermined during SPF testing. Theagency agrees with the commentconcerning the missing variable of time(in seconds) in the calculation of E and,accordingly, has modified the equationin § 352.73 of this document to read asfollows: ‘‘ E = Σ Vi (λ) * I (λ) * texp’’

III. Recent DevelopmentsIn the Federal Register of October 22,

1998, the agency proposed to amend thetentative final monograph to includezinc oxide as a single ingredient and incombination with any proposedCategory I sunscreen active ingredientexcept avobenzone. Two commentssupported the proposal. One commentdisagreed with the agency’s exclusion ofavobenzone from combinations withzinc oxide. Two of the comments urgedthe agency to expeditiously review andapprove a citizen petition (Ref. 45) torecognize this combination.

The agency has informed thepetitioner that it is unable to approvethe combination without appropriateUVA radiation effectiveness data todemonstrate the UVA radiationprotection potential of zinc oxide incombination with avobenzone (Ref. 46).The agency will reconsider thiscombination for monograph status uponreceipt of the appropriate data.

This final rule includes monographconditions for zinc oxide as a sunscreenactive ingredient at concentrations up to25 percent when used alone or incombination with any monographsunscreen active ingredient exceptavobenzone.

IV. Additional Changes1. The agency has determined that for

an active ingredient to be included in anOTC drug final monograph it isnecessary to have publicly available



chemical information that can be usedby all manufacturers to determine thatthe ingredient is appropriate for use intheir products. Compendial monographsinclude an ingredient’s official name,chemical formula, and analyticalchemical tests to confirm the qualityand purity of the ingredient. Thesemonographs establish public standardsfor the strength, quality, purity, andpackaging of ingredients and drugproducts available in the United States.

In the Federal Register of June 8,1994, FDA deleted digalloyl trioleate,ethyl 4-[bis(hydroxypropyl)]aminobenzoate, glyceryl aminobenzoate,lawsone with dihydroxyacetone, andred petrolatum from the tentative finalmonograph due to the lack of interest inestablishing USP compendialmonographs for these ingredients.Lawsone with dihydroxyacetonesubsequently remained under agencyconsideration due to increased interestby manufacturers in establishing acompendial monograph. Of the 18remaining sunscreen active ingredientsunder consideration in the tentativefinal monograph (58 FR 28194 at 28295,amended at 61 FR 48645 and 63 FR56584), 16 (aminobenzoic acid,avobenzone, cinoxate, dioxybenzone,homosalate, menthyl anthranilate,octocrylene, octyl methoxycinnamate,octyl salicylate, oxybenzone, padimateO, phenylbenzimidazole sulfonic acid,sulisobenzone, titanium dioxide,trolamine salicylate, and zinc oxide)currently have compendial monographs.Two (diethanolaminemethoxycinnamate and lawsone withdihydroxyacetone) do not have a currentor proposed compendial monograph.

The agency is including in § 352.10 ofthis document the 16 sunscreen activeingredients that currently have acompendial monograph. The agency isreserving the appropriate paragraphs inproposed § 352.10 for the two activeingredients without compendialmonographs in case a monograph isdeveloped for either ingredient.Dihydroxyacetone has been proposedfor a compendial monograph, but nonehas been proposed for lawsone. Becausethese two active ingredients are used inconjunction, lawsone must have acompendial monograph in order forlawsone with dihydroxyacetone to beincluded in the sunscreen finalmonograph.

2. The agency has revised proposed§ 352.52(b) in response to commentsrequesting reduction, streamlining, andflexibility of sunscreen labeling and inaccordance with new data reviewed bythe agency (see section II.I of thisdocument). The agency has revisedproposed § 352.52(b)(1) by: (1) Deleting

references to any other indicationexcept that pertaining to the preventionof sunburn (see section II.I, comment 37of this document), (2) adding (in§ 352.52(b)(2) of this final rule) guidanceon SPF selection due to simplificationof the PCD in proposed § 352.52(e)(1)and deletion of the RecommendedProduct Guide in proposed§ 352.52(e)(4) (see section II.L,comments 49 and 50 of this document),and (3) deleting the quantitative claims(i.e., ‘‘up to (insert SPF of product up to30) times’’) and terms such as ‘‘screens,’’‘‘shields,’’ etc., concerning sunburnprotection throughout proposed§ 352.52(b) (see section II.I, comment 37of this document).

3. The tentative final monographallowed reduced labeling directions onsunscreen products if formulated as amake-up preparation, lipstick, lip balm,or skin preparation and labeled withclaims relating only to the prevention of‘‘lip damage,’’ ‘‘freckling,’’ or ‘‘unevencoloration.’’ Because there is noconvincing evidence that SPF testingpredicts protection from anything butsunburn (see section II.I, comment 36 ofthis document), the agency is notincluding proposed § 352.52(b)(1)(v),(b)(1)(vi), (d)(4), and (d)(5) in thisdocument. The agency will considerincluding such claims in the monographwhen specific supportive data areprovided or a specific clinically relevantfinal formulation test is developed.

4. Numerous comments requesteddeletion of the dual SPF testing of waterresistant products in proposed§ 352.50(b)(2) and (c)(2). The agencyagrees with the comments (see sectionII.H, comment 32 of this document) andhas revised proposed §§ 352.50(b)(2)and (c)(2) and 352.76 to require only theSPF value after water resistant testing.Further, the agency has modified andmade optional the reapplicationdirections in proposed §§ 352.52(d)(1)and (d)(2) (see section II.K, comment 48of this document). These changes toproposed § 352.52(d) provide flexibilityby allowing manufacturers to expand onreapplication information necessary forspecific sunscreen formulations and byequalizing requirements betweenproducts with and without waterresistance claims and betweensunscreen drug and drug-cosmeticproducts. Thus, the water resistancelabeling in § 352.52(b)(1)(ii) and(b)(1)(iii) of this document should alsoserve as a directive for reapplication ofthe product. In summary, for productsmaking water and/or sweat resistanceclaims, the agency has modified andcombined water resistance statementsformerly in proposed § 352.52(e)(2),(e)(3), (d)(1), and (d)(2) into

§ 352.52(b)(1)(ii) and (b)(1)(iii) in thisdocument.

5. The agency has modified referencesto ‘‘tanning’’ and ‘‘prolongs exposuretime’’ in proposed § 352.52(b)(2) bycombining the PCD claim in§ 352.52(e)(1) of this document witheither the phrase ‘‘protection againstsunburn’’ or ‘‘protection againstsunburn and tanning.’’ Based uponcurrent information, the agency believesthat the terms proposed in the tentativefinal monograph could send the wrongmessage relative to the dangers of evensuberythemal UV radiation exposureand give consumers a false sense ofsecurity concerning sun exposure andsunscreen use. The agency has reducedand simplified the other optional,additional indications in proposed§ 352.52(b)(2) to reflect a modified,simpler, combined version of the PCD inproposed § 352.52(e)(1) (see section II.L,comment 49 of this document) and the‘‘Recommended Product Guide’’ inproposed § 352.52(e)(4) (see section II.L,comment 50 of this document). Becausethe agency has deleted reference to useof the term ‘‘Sunblock’’ in proposedsection § 352.52(e)(5) (see section II.L,comment 52 of this document), it hasdeleted reference to ‘‘Reflects theburning rays of the sun’’ in proposed§ 352.52(b)(3) for the same reasons.

6. Several comments requestedlabeling exemptions or flexibility forpackages that are too small toaccommodate all required information.Some comments specifically requestedflexible labeling for products basedupon their intended use, such aslipsticks and lip balms.

As discussed in the final ruleestablishing standardized format andcontent requirements for the labeling ofOTC drug products (64 FR 13254 at13267 to 13268 and 13289), the agencyhas established specifications for smallpackages in § 201.66(d)(10). The agencyalso stated in the final labeling rule thatit will consider additional approachesfor accommodating certain small-package products in their respectiveOTC drug monograph proceedings.

The agency considers the requiredOTC drug labeling information essentialfor the safe and effective use of theseproducts and important to consumersfor selection of an appropriate product.Nevertheless, the agency agrees thatexcessive labeling requirements maydiscourage manufacturers frommarketing certain products, such aslipsticks or lip balms containingsunscreens, which provide significantpublic health benefit.

In this OTC drug rulemaking, theagency has included severalaccommodations for products such as



lipsticks (and lip balms, which will beaddressed in the final monograph onOTC skin protectant drug products),taking into consideration the intendeduses of these products, the limited areasto which these products are applied,and the overall safety profile of theseproducts, and other factors described inthe final OTC labeling rule (64 FR 13254at 13270). The agency is including§ 352.52(f) in this document to providefor labeling modifications for sunscreenproducts that meet the small packagespecifications in § 201.66(d)(10) and arelabeled for use on specific small areasof the face (e.g., lips, nose, ears, and/oraround eyes).

7. The agency has revised §§ 700.35and 740.19 (21 CFR 700.35 and 740.19)in response to comments requestingclarification on whether certainproducts will be subject to regulation asdrugs (see section II.B, comments 8through 11 of this document). Section700.35 has been revised to make clearthat, generally, products that make sunprotection claims, whether express orimplied, are subject to regulation asdrugs. Only those products that containa sunscreen ingredient solely for anontherapeutic, nonphysiologic use(e.g., as a color additive, or to protectthe color of the product such as in a nailpolish or hair coloring product) (see 58FR at 28205), and which include alabeling statement that accuratelydescribes that use, may be marketed ascosmetic products. Section 740.19 hasbeen revised to make clear that the term‘‘suntanning preparations’’ does notinclude products intended to providesun protection or otherwise to affect thestructure or any function of the body.Suntanning preparations include gels,creams, liquids, and other topicalproducts that are intended to providecosmetic effects on the skin whiletanning through exposure to UVradiation (e.g., moisturizing orconditioning), or that are intended togive the appearance of a tan byimparting color through the applicationof approved color additives (e.g.,dihydroxyacetone) without the need forexposure to UV radiation (i.e., sunlesstanning products).

V. ConclusionThe agency is issuing a final

monograph establishing conditionsunder which OTC sunscreen drugproducts are generally recognized assafe and effective and not misbranded;16 ingredients listed in § 352.10 arecurrently a monograph condition. Anydrug product labeled, represented, orpromoted for use as an OTC sunscreendrug that contains any of thenonmonograph ingredients listed in

§ 310.545(a)(29), or that is not inconformance with the monograph (21CFR part 352), may be considered a newdrug within the meaning of section201(p) of the act and misbranded undersection 502 of the act. Such a drugproduct cannot be marketed for OTCsunscreen use unless it is the subject ofan approved application under section505 of the act (21 U.S.C. 355) and 21CFR part 314 of the regulations. Anappropriate citizen petition to amendthe monograph may also be submittedin accord with 21 CFR 10.30 and§ 330.10(a)(12)(i). The agency willaddress sunscreen active ingredientsthat have foreign marketing experienceand data at a future time. Any OTCsunscreen drug product initiallyintroduced or initially delivered forintroduction into interstate commerceafter the effective date of the final rulefor § 310.545(a)(29) or this documentthat is not in compliance with theregulations is subject to regulatoryaction.

VI. ReferencesThe following references are on

display in the Dockets ManagementBranch (address above) and may be seenby interested persons between 9 a.m.and 4 p.m., Monday through Friday.

1. Comment No. CP1, Docket No. 78N–0038, Dockets Management Branch.




5. Comite de Liaison des AssociationsEuropeenes de L’Industrie de la Parfumerie,des Produits Cosmetiques et de Toilette(COLIPA), SPF Test Method (Draft), TheRecommendations of the COLIPA Task Force‘‘Sun Protection Measurement,’’ December1992 in Comment No. C00365, Docket No.78N–0038, Dockets Management Branch.

6. Peak, M. J., and J. C. van der Leun,‘‘Boundary Between UVA and UVB,’’ inFrontiers of Photobiology, edited by A. Shimaet al., Excerpta Medica, Amsterdam, pp. 425–427, 1993.

7. Comment No. LET 135, Docket 78N–0038, Dockets Management Branch.

8. Dunkel, V.C. et al., ‘‘Evaluation of theMutagenicity of an N-Nitroso Contaminant ofthe Sunscreen Padimate O,’’ Environmentaland Molecular Mutagenesis, 20:188–198,1992.

9. Comment No. C00364, Docket No. 78N–0038, Dockets Management Branch.

10. Comments No. C00397 and SUP21,Docket No. 78N–0038, Dockets ManagementBranch.

11. Fairhurst, D., and M. Mitchnick,‘‘Particulate Sun Blocks: General Principles,’’in Sunscreens: Development, Evaluation, andRegulatory Aspects, Marcel Dekker, Inc., NewYork, pp. 313–352, 1997.

12. Comment No. TR3, Docket No. 78N–0038, Dockets Management Branch.

13. Pharmacopeial Forum, United StatesPharmacopeial Convention, Inc., Rockville,MD, 22(4):2635–2636, July through August1996.

14. Pharmacopeial Forum, United StatesPharmacopeial Convention, Inc., Rockville,MD, 24(4):6547–6548, July through August1998.

15. Comment No. C00406, Docket No.78N–0038, Dockets Management Branch.


17. Kligman, L. H., and A. M. Kligman,‘‘Ultraviolet Radiation-Induced Skin Aging,’’in Sunscreens: Development, Evaluation, andRegulatory Aspects, Lowe, N. J., N. A.Shaath, and M. A. Pathak, eds., MarcelDekker, Inc., New York, pp. 117–137, 1997.

18. Lavker, R., and K. Kaidbey, ‘‘TheSpectral Dependence for UVA-InducedCumulative Damage in Human Skin,’’ TheJournal of Investigative Dermatology, 108:17–21, 1997.

19. Fisher, G. J. et al., ‘‘Pathophysiology ofPremature Skin Aging Induced by UltravioletLight,’’ The New England Journal ofMedicine, 337:1419–1428, 1997.

20. Lowe, N. J. et al., ‘‘Low Doses ofRepetitive Ultraviolet A Induce MorphologicChanges in Human Skin,’’ Journal of theAmerican Academy of Dermatology,105:739–743, 1995.





25. Comment No. SUP16, Docket No. 78N–0038, Dockets Management Branch.

26. Thompson, S. C., J. D. Jolley, and R.Marks, ‘‘Reduction of Solar Keratoses byRegular Sunscreen Use,’’ The New EnglandJournal of Medicine, 329:1147–1151, 1993.

27. Marks, R. et al., ‘‘SpontaneousRemission of Solar Keratoses: The Case forConservative Management,’’ British Journalof Dermatology, 115:649–654, 1986.

28. Marks, R., and G. Rennie, ‘‘MalignantTransformation of Solar Keratoses toSquamous Cell Carcinoma,’’ The Lancet,795–796, 1988.

29. Kornhauser, A., W. G. Wamer, and L.A. Lambert, ‘‘Cellular and Molecular EventsFollowing Ultraviolet Irradiation of Skin,’’ inDermatotoxicology, F. N. Marzulli and H. I.Maibach, eds., Taylor & Francis, Washington,pp. 189–220, 1996.

30. Kraemer, K. H., ‘‘Sunlight and SkinCancer: Another Link Revealed,’’ Proceeds ofthe National Academy of Sciences U. S. A.,94:11–14, 1997.

31. Hurks, H. M. H. et al., ‘‘In Situ ActionSpectra Suggest that DNA Damage Involvedin Ultraviolet Radiation-InducedImmunosuppression in Humans,’’Photochemistry and Photobiology, 66:76–81,1997.

32. Burren, R. et al., ‘‘Sunlight andCarcinogenesis: Expression of p53 andPyrimidine Dimers in Human Skin FollowingUVA I, UVA I + II and Solar SimulatingRadiation,’’ International Journal of Cancer,76:201–206, 1998.



33. Hersey, P. et al., ‘‘Analysis of the Effectof a Sunscreen Agent on the Suppression ofNatural Killer Cell Activity Induced inHuman Subjects by Radiation from SolariumLamps,’’ The Journal of InvestigativeDermatology, 88:271–276, 1987.

34. Van Prague, M. C. G. et al., ‘‘Effect ofTopical Sunscreens on the UV-Radiation-Induced Suppression of the AlloactivatingCapacity in Human Skin In Vivo,’’ TheJournal of Investigative Dermatology, 97:629–633, 1991.

35. Miyagi, T., A. M. Bhutto, and S.Nonaka, ‘‘The Effects of Sunscreens on UVBErythema and Langerhans Cell Depression,’’The Journal of Investigative Dermatology,21:645–651, 1994.

36. Seite, S. et al., ‘‘Effects of RepeatedSuberythemal Doses of UVA in HumanSkin,’’ European Journal of Dermatology,7:204–209, 1997.

37. Lavker, R. M. et al., ‘‘CumulativeEffects from Repeated Exposures toSuberythemal Doses of UVB and UVA inHuman Skin,’’ Journal of the AmericanAcademy of Dermatology, 32:53–62, 1995.

38. Baadsgaard, O., ‘‘In Vivo UltravioletIrradiation of Human Skin Results inProfound Perturbation of the ImmuneSystem,’’ Archives of Dermatology, 127:99–109, 1991.

39. Marks, R., ‘‘Reduction of ActinicKeratoses by Sunscreens,’’ in Sunscreens:Development, Evaluation, and RegulatoryAspects, Lowe, N. J., N. A. Shaath, and M.A. Pathak, eds., Marcel Dekker, Inc., NewYork, pp. 189–198, 1997.

40. Dial, W. F., ‘‘Mouse Study CreatesControversy Over the Use of Sunscreens,’’Cosmetic Dermatology, 7:47–48, 1994.

41. Goldsmith, L., et al., ‘‘Proceedings fromthe National Conference to Develop aNational Skin Cancer Agenda,’’ Journal of theAmerican Academy of Dermatology, 34:822–23, 1996.

42. Standards Australia/Standards NewZealand, ‘‘Sunscreen Products—Evaluationand Classification,’’ AS/NZS 2604, 1993.

43. Beissart, S. and R. D. Granstein, ‘‘UV-Induced Cutaneous Photobiology,’’ CriticalReviews in Biochemistry and MolecularBiology, 31:381–404, 1995.

44. Sayre, R. et al., ‘‘Physical Sunscreens,’’Journal of the Society of Cosmetic Chemists,41:103–109, 1990.


46. Comment No. LET166, Docket No.78N–0038, Dockets Management Branch.

47. Food and Drug Administration,‘‘Supplement to the Economic ImpactAnalysis of the Sunscreen Drug Products forOver-the-Counter Human Use; FinalMonograph,’’ in OTC Vol. 06FR, Docket No.78N–0038, Dockets Management Branch.

48. Eastern Research Group, Inc., ‘‘Over-the-Counter Drug Reformulation Changes,’’ inOTC Vol. 06FR, Docket No. 78N–0038,Dockets Management Branch.

VII. Analysis of ImpactsFDA has examined the impacts of this

final rule under Executive Order 12866,the Regulatory Flexibility Act (5 U.S.C.601–612), and the Unfunded MandatesReform Act (2 U.S.C. 1501 et seq.).

Executive Order 12866 directs agenciesto assess all costs and benefits ofavailable regulatory alternatives and,when regulation is necessary, to selectregulatory approaches that maximizenet benefits (including potentialeconomic, environmental, public healthand safety, and other advantages;distributive impacts; and equity). Theagency believes that this final rule isconsistent with the principles identifiedin Executive Order 12866. OMB hasdetermined that the final rule is asignificant regulatory action as definedby the Executive Order and so is subjectto review. Under the RegulatoryFlexibility Act, if a rule has a significanteconomic impact on a substantialnumber of small entities, an agencymust analyze regulatory options thatwould minimize any significant impactof the rule on small entities. Title II ofthe Unfunded Mandates Reform Actrequires that agencies prepare a writtenassessment of anticipated costs andbenefits before proposing any rule thatmay result in an expenditure in any 1year by State, local, and tribalgovernments, in the aggregate, or by theprivate sector, of $100 million (adjustedannually for inflation) (2 U.S.C. 1532).

Because the rule may have asignificant economic impact on asubstantial number of small entities,this section of the preamble constitutesthe agency’s Final Regulatory FlexibilityAnalysis. Because the rule does notimpose any mandates on State, local, ortribal governments, or the private sector,that will result in an expenditure in any1 year of $100 million or more, FDA isnot required to perform a cost-benefitanalysis according to the UnfundedMandates Reform Act.

An analysis of the costs and benefitsof this regulation, conducted underExecutive Order 12291, was discussedin the tentative final monograph forOTC sunscreen drug products (58 FR28194 at 28294). The agency receivedonly one response to the specific requestfor data and comment on the economicimpact of this rulemaking. Thiscomment discussed the costs that wouldresult from proposed changes insunscreen product labeling and testingmethods. The agency’s review of thiscomment is included as follows.

A. BackgroundThe purpose of this document is to

establish conditions under which OTCsunscreen drug products are generallyrecognized as safe, effective, and notmisbranded. The document sets specificrequirements for appropriatemonograph ingredients, labeling formatand content, and SPF value and waterresistant testing. Although the agency

cannot quantify the overall expectedbenefits, each provision of the rule willsupport the ability of consumers to takedesired protective actions. Monographingredients have been proven safe andeffective assuring the quality ofsunscreen products. This benefitsconsumers because it ensures that theproduct will provide ingredients thatsafely protect against sunburn. The newproduct labeling will better informconsumers about the sunburn protectionprovided by the products; and ifmanufacturers choose to include theoptional ‘‘Sun alert’’ labeling statement,the product labeling can reference thatthe use of sunscreens may reduce therisk of skin aging, skin cancer, and otherharmful effects of the sun. Theselabeling requirements, in conjunctionwith the format requirements of theOTC uniform labeling rule (64 FR13254) will provide clearer and moreconcise information that will benefitconsumers in at least four ways: (1)They will increase understandingregarding the selection of sunscreendrug products, (2) they will makeproduct comparison easier, (3) they willenhance the ability to make informeddecisions regarding product purchasesand proper use, and (4) they will makeit easier to distinguish betweensunscreen drug products that containsunscreens and suntanning productsthat do not. Finally, the newrequirements for product testing willassure the accuracy of the SPF value onthe product label. By improving theaccuracy of these ratings, thisrequirement will provide furtherassurance that consumers receiveadequate sunburn protection.

The rule will require allmanufacturers and distributors (or theiragents) to relabel their OTC sunscreendrug products to comply with themonograph language. The labeling ofcertain suntanning products that do notcontain sunscreens will need to includethe new required warning statement. Insome cases, the labeling of cosmeticscontaining sunscreens fornontherapeutic, nonphysiologic uses(e.g., to protect hair from sun damage)will need to describe the cosmetic roleof the sunscreen ingredient(s). The SPFof some OTC sunscreen drug productsmay need to be retested using themethod described in the finalmonograph. In addition, only productscontaining the active ingredientsincluded in this final rule will begenerally recognized as safe, effective,and not misbranded. Of the 18 activeingredients under consideration in theproposed rule, 16 currently have therequired USP/N.F. compendial



2 Mathematically the following formula was usedto calculate the incremental relabeling costs:

Costyx = Σ j NxAx(1/x), where j = 1 to (x-y)Total Costy = Costy6 + Costy3 + Costy2

where:x = life of labeling in years (2, 3, or 6)y = phase-in period in years

Nx = number of SKU’s with labeling life of xyears, and

Ax = amortized annual value of labeling with alife of x years.

monographs. The USP has not receivedapplications for the remaining twoingredients. If either of these activeingredients are not included in the USPand added to the monograph by May 21,2001, products containing theseingredients would need to bereformulated to replace thenonmonograph ingredient with amonograph ingredient, or the productmust be removed from the market.

B. Number of Products AffectedBased on data from FDA’s Drug

Listing System, the agency estimatesthat there are approximately 2,800 OTCsunscreen drug products (differentformulations, not including productsthat differ only by color) and about12,000 individual stockkeeping units(SKU’s) (individual products, packages,and sizes). All of the SKU’s will need tobe relabeled, some will require new SPFtesting, and those products lackingapproved active ingredients will need tobe reformulated to stay on the market.

In addition, certain suntanningproducts and certain cosmetic productscontaining sunscreens will have to berelabeled. As FDA’s Drug Listing Systemdoes not include suntanning products,the agency used 1995 data from A. C.Nielsen, a recognized provider of marketdata, to estimate that approximately 550suntanning SKU’s will be affected bythe labeling requirements of this rule.New labels will also be needed forcosmetic products that contain asunscreen for a nontherapeutic use andthat include the word ‘‘sunscreen’’ orsimilar terms in product labeling. Theagency is unable to identify the numberof these cosmetic products, but does notbelieve that there are a large number ofSKU’s in this category.

C. Cost to RelabelThe relabeling costs for this rule will

be moderated to the extent thatmanufacturers coordinate labelingchanges for the final sunscreenmonograph with labeling changesrequired by the recent rule establishinguniform format and content for OTCdrug product labeling (64 FR 13254).These costs are not discussed in thisanalysis, however, because they are

already accounted for in the agency’sanalysis of its OTC drug productlabeling rule. That is, the agency’seconomic analysis of that rule excludedredesign costs for all OTC drug productsnot marketed under current NDA’s orcurrent final monographs, explainingthat the agency would attribute allredesign costs associated with futurefinal monographs to each finalmonograph rule as it published. Allredesign costs for this final sunscreenmonograph therefore are attributed tothis rule alone.

Approximately 12,000 sunscreen drugSKU’s will have to be relabeled withina 2-year implementation period tocomply with the labeling requirementsof this final rule. In addition,approximately 550 suntanning SKU’swill have to be relabeled within a 12-month implementation period. (Asnoted previously, FDA could notestimate the number of cosmeticproducts that contain a sunscreen for anontherapeutic use and that include theword ‘‘sunscreen’’ or similar terms inproduct labeling. The agency believes,however, the relabeling of this group ofcosmetic products will impose aminimal economic burden becausesome of these products already includethe required labeling, and mostmanufacturers revise these labels formarketing considerations morefrequently than the allowed 2-yearphase-in period. Therefore, the agency’sestimates do not include a cost forrelabeling those products that containsunscreens for a nontherapeutic,nonphysiologic use.)

Frequent labeling redesigns are arecognized cost of doing business in theOTC drug industry, particularly fordrug-cosmetic and seasonal products.Thus, SKU’s with labels that wouldnormally be redesigned within theimplementation periods were assumedto incur no additional costs. The cost forthe remaining SKU’s was calculated asthe lost value of the remaining life-yearsof the existing label design. FDAestimates that labeling for the majority(90 percent) of the SKU’s affected bythis final rule are redesigned at leastevery 2 years. Of the remaining SKU’s,

the agency assumes that half would beredesigned every 3 years and half every6 years. Because the required labelingfor OTC sunscreen drug products nowincludes fewer words than the previouslanguage and the final rule contains anumber of labeling modifications forproducts used on small areas of the face(which are usually marketed in smallsize packages), this rule is not expectedto require manufacturers to increase thepackage size or available labeling space.(Although costs of redesigning labels forfuture final monographs were excludedfrom FDA’s analysis of its OTC drugproduct labeling rule, costs forincreased package sizes were consideredin the analysis of impacts for thatregulation (64 FR 13254 at 13283)).

FDA estimated the cost of redesign bycounting only the value of the label-years that would be lost, after adjustingfor the length of the traditional labelingcycle. The regulatory cost wascalculated as the product of the numberof SKU’s, the number of years oflabeling life lost, and the value of eachyear of labeling life lost (see 64 FR13254 at 13278 through 13284).2

Table 1 in section VIII.C of thisdocument details FDA’s estimates of thedistribution of relabeling costs resultingfrom the final rule. A weighted averagecost to redesign a label of $5,210 perSKU was used to calculate therelabeling cost of sunscreen drugproducts, whereas a weighted averagecost of $6,620 per SKU was used tocalculate the cost of relabelingsuntanning products. A detaileddescription of the cost analysis is on filewith the Docket Management Branch(Ref. 47). As shown, the totalincremental cost to relabel theapproximately 12,000 sunscreen drugSKU’s is about $1.5 million, while thecost to relabel the approximately 550suntanning SKU’s was about $1.8million. The greater per SKU cost forrelabeling suntanning products reflectsthe shorter, 12-month, phase-in period.With a shorter phase-in period,manufacturers are less able toincorporate labeling changes intovoluntary redesign cycles and, therefore,lose label inventory.

TABLE 1.—ONE-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



TABLE 1.—ONE-TIME COST TO RELABEL SUNSCREEN AND SUNTANNING SKU’S ($)—Continued

Type of Product

Size of Company Drug Suntanning Total Cost

Large 860,677 691,800 1,552,477Total Cost 1,509,960 1,820,500 3,330,460

1 See section VII.G of this document.

The one comment that raisedeconomic issues in response to thetentative final monograph expressedconcern about available labeling spaceon small packages of sunscreen drugproducts. The comment stated that alltext needs to be concise. The agencyconsidered this comment in developingthe final rule, which contains specificlabeling modifications for smallpackages and for sunscreen productsused on small areas of the face (e.g.,lips, nose, ears, and/or around the eyes).

D. Cost to Retest SPFFDA is uncertain about the number of

OTC sunscreen drug products that have

not been tested using the monographSPF test method. However, the SPF testmethod in this document is essentiallythe same as the method described in theproposed rule. If manufacturers haveadded new products, made formulationchanges, or otherwise needed to test orretest the SPF of their products since1993, they would probably have usedthe most current (i.e., the proposed) testmethod. Therefore, the agency estimatesthat from 15 to 30 percent of thesunscreen drug products will requireretesting as a result of this document.The cost of the SPF test varies,depending on the product claim (water

resistant or very water resistant) andSPF factor tested, and ranges from$2,500 to $6,500. On the assumptionthat 50 percent of the traditionalsunscreen drug products, and none ofthe make-up type sunscreen products,make water resistant claims, and 50percent of the products that make waterresistant claims make very waterresistant claims, the estimated weightedaverage cost of the SPF test is $3,514.FDA estimates the total cost of thisrequirement, therefore, to range from$3.1 million to $6.1 millions (see thefollowing Table 2).

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

Size of Company 15 Percent Non-compli-ance

30 Percent Non-compli-ance

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

E. Cost to Reformulate

Reformulation costs will depend onthe number of products, if any, that willhave no active ingredients withcompleted USP compendialmonographs by the end of theimplementation period. At the presenttime, only two of the active ingredientsbeing considered do not have a USPmonograph. According to the agency’sdrug listing system, two products,manufactured by one company containone of these ingredients. The agency isnot currently aware of other products inthe marketplace that contain these twoingredients.

The cost to reformulate a productvaries by the nature of thereformulation, the type of product, andthe size and complexity of the company.

Because OTC sunscreen drug productsare well characterized topicalformulations, FDA estimates the cost toreformulate at about $350,000 perproduct. Thus, on the assumption thatthe manufacturer reformulates ratherthan removes the products from themarket, the one-time cost ofreformulation for two products wouldbe $700,000.

F. Total Incremental Costs

The estimated total one-timeincremental cost of this rule, using themidpoint of the cost range for retestingand reformulation is $8.6 million (seeTable 3 of this document). Theseestimates are based on 16 of the 18active sunscreen ingredients underconsideration having USP compendialmonographs. If a USP monograph is

completed for the one ingredient inthese two products or if the twoproducts are removed from the market,the cost of reformulation would beeliminated.

G. Small Business Impact

Based on the analysis of FDA’s druglisting system and other data describedpreviously, there are about 180 domesticcompanies that manufacture OTCsunscreen and suntanning products.Distributors were not assigned costsbecause manufacturers of OTC drugproducts are usually responsible forproduct labeling, testing, andformulation. Approximately 78 percentof these firms meet the Small BusinessAdministration’s definition of a smallentity for this industry (less than 750employees).

TABLE 3.—TOTAL INCREMENTAL COST TO INDUSTRY ($)

Size of CompanyRelabel Products

Retest SPF1 Reformulation2 TotalDrug Suntanning

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



TABLE 3.—TOTAL INCREMENTAL COST TO INDUSTRY ($)—Continued

Size of CompanyRelabel Products

Retest SPF1 Reformulation2 TotalDrug 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 ofsunscreens to relabel their products.Some firms will need to retest the SPFof these products, and one firm mayhave to reformulate or remove twoproducts from the market. Because ofthe 2-year implementation period, mostfirms will be able to relabel during anormal relabeling cycle, at no additionalcost. FDA cannot estimate withcertainty the number of small firms thatwill need to retest or reformulate theirOTC sunscreen products, but projectsthat from 15 to 30 percent of allproducts may need to be retested andthat 2 products may need to bereformulated. Costs will vary by firm,depending on the type and number ofproducts requiring relabeling, retesting,and reformulation. The firm-specificimpact may vary inversely with thevolume of product sales, however,because per unit costs will be lower forproducts with high volume sales. Thus,the relative economic impact of productretesting or relabeling may be greater forsmall firms than for large firms.

Because of the 2-year phase-in periodallowed for sunscreen drug and drug-cosmetic products, which allowsmanufacturers the flexibility toincorporate regulatory changes withvoluntary/market-driven changes, theeconomic impact of the relabelingrequirement is relatively low(approximately $3.3 million). However,for those small companies that mayhave to relabel a substantial number ofproducts, the out-of-pocket costs couldbe significant.

Also, the cost to a small companyneeding to reformulate a product,estimated at approximately $350,000would be significant. This impact maybe moderated by other options available,which may be more cost effective thanreformulation. For example, amanufacturer may be able to substituteother formulations, shift production to acontract manufacturer with an approvedformulation, or temporarily remove theproduct from the market and await thecompletion of a USP compendialmonograph for the ingredient. Becausethe OTC drug industry is highlyregulated, all firms are expected to haveaccess to the necessary professionalskills on staff or to make contractual

arrangements to comply with thepaperwork and other requirements ofthis rule.

H. Analysis of Alternatives

The agency altered several proposedregulatory provisions to reduce theeconomic burden of this rule onindustry. For example, FDA decreasedthe amount of required labeling andprovided small packageaccommodations for certain products.The labeling required by the proposedrule would have increased the neededlabel and/or package size for as many as90 percent of the sunscreen products.Such size adjustments could haveimposed estimated additional one-timerelabeling costs of $18 million andannually recurring costs of $22 million(see Eastern Research Group, ‘‘CostImpacts of the Over-the-CounterPharmaceutical Labeling Rule’’ (Ref.48)). Also, in response to the comment(see section II.H, comment 32 of thisdocument), the agency has reconsideredits position on SPF testing of waterresistant and very water resistantproducts and eliminated the static testrequirement for these products. As theaverage cost of the static test isapproximately $2,800, the estimatedsavings to industry due to theelimination of this test is about$750,000.

The agency also considered a numberof implementation alternatives to thisfinal rule. Generally, the agency allowsonly a 1-year implementation period forfinal monographs. However, becausemost sunscreen products are producedseasonally, the 2-year period willsubstantially enhance the ability of theindustry to relabel and reformulate itsproducts, if necessary, and sell itsexisting product inventories. The 2-yearperiod will also allow sunscreenmanufacturers to coordinate therequired labeling changes with routineindustry-initiated labeling changes andchanges required by the new OTC drugproduct labeling final rule (64 FR13254).

A 3-year implementation period forsunscreen drug products wasconsidered, but the agency determinedthat a 2-year period provides sufficienttime to allow the required relabeling

and product retesting to be completed.The agency found that the savings toindustry of delayed implementation(estimated to be about $845,000) werenot great enough to justify delayingappropriate use and safety informationto consumers of OTC sunscreen drugproducts.

Finally, the agency is providing a 12-month implementation period forcertain suntanning preparations to addnew warning information. For thiscategory, consumers may believe thatthese products are providing sunprotection when, in fact, they do not.They may forego using other productsthat have been demonstrated to beeffective in providing sun protection,believing that their tanning productprovides some measure of protection.Because the new warning forsuntanning preparations presents animportant safety issue that needs to beconveyed to consumers at the earliestpossible date, the agency consideredrequiring a 6-month implementationperiod for these products. However,given the seasonal nature of theseproducts, the agency was concerned thatsome manufacturers may not havesufficient time to incorporate thelabeling change without disrupting theirproduction schedules. By providing anadditional 6 months to implement thechange, compliance costs were reducedby $1.8 million.

VIII. Paperwork Reduction Act of 1995

FDA concludes that the labelingrequirements in this document are notsubject to review by the Office ofManagement and Budget because theydo not constitute a ‘‘collection ofinformation’’ under the PaperworkReduction Act of 1995 (44 U.S.C. 3501et seq.). Rather, the labeling statementsare a ‘‘public disclosure of informationoriginally supplied by the Federalgovernment to the recipient for thepurpose of disclosure to the public’’ (5CFR 1320.3(c)(2)).

IX. Environmental Impact

The agency has determined that under21 CFR 25.31(c) this action is of a typethat does not individually orcumulatively have a significant effect onthe human environment. Therefore,



neither an environmental assessmentnor an environmental impact statementis required.

List of Subjects

21 CFR Part 310

Administrative practice andprocedure, Drugs, Labeling, Medicaldevices, Reporting and recordkeepingrequirements.

21 CFR Part 352

Labeling, Over-the-counter drugs.

21 CFR Part 700

Cosmetics, Packaging and containers.

21 CFR Part 740

Cosmetics, Labeling.Therefore, under the Federal Food,

Drug, and Cosmetic Act, and underauthority delegated to the Commissionerof Food and Drugs, 21 CFR part 352 isadded and 21 CFR parts 310, 700, and740 are amended as follows:

PART 310—NEW DRUGS

1. The authority citation for 21 CFRpart 310 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,353, 355, 360b–360f, 360j, 361(a), 371, 374,375, 379e; 42 U.S.C. 216, 241, 242(a), 262,263b–263n.

2. Section 310.545 is amended byadding paragraph (a)(29), by revisingparagraph (d) introductory text, byadding and reserving paragraph (d)(30),and by adding paragraph (d)(31) to readas follows:

§ 310.545 Drug products containingcertain active ingredients offered over-the-counter (OTC) for certain uses.

(a) * * *(29) Sunscreen drug products.

Diethanolamine methoxycinnamateDigalloyl trioleateEthyl 4-[bis(hydroxypropyl)] aminobenzoateGlyceryl aminobenzoateLawsone with dihydroxyacetoneRed petrolatum

* * * * *(d) Any OTC drug product that is not

in compliance with this section issubject to regulatory action if initiallyintroduced or initially delivered forintroduction into interstate commerceafter the dates specified in paragraphs(d)(1) through (d)(31) of this section.* * * * *

(30) [Reserved](31) May 21, 2001 for products subject

to paragraph (a)(29) of this section.3. Part 352 is added to read as follows:

PART 352—SUNSCREEN DRUGPRODUCTS FOR OVER-THE-COUNTER HUMAN USE

Subpart A—General Provisions

Sec.352.1 Scope.352.3 Definitions.

Subpart B—Active Ingredients

352.10 Sunscreen active ingredients.352.20 Permitted combinations of active

ingredients.

Subpart C—Labeling

352.50 Principal display panel of allsunscreen drug products.

352.52 Labeling of sunscreen drugproducts.

352.60 Labeling of permitted combinationsof active ingredients.

Subpart D—Testing Procedures

352.70 Standard sunscreen.352.71 Light source (solar simulator).352.72 General testing procedures.352.73 Determination of SPF value.352.76 Determination if a product is water

resistant or very water resistant.352.77 Test modifications.

Authority: 21 U.S.C. 321, 351, 352, 353,355, 360, 371.

Subpart A—General Provisions

§ 352.1 Scope.(a) An over-the-counter sunscreen

drug product in a form suitable fortopical administration is generallyrecognized as safe and effective and isnot misbranded if it meets eachcondition in this part and each generalcondition established in § 330.1 of thischapter.

(b) References in this part toregulatory sections of the Code ofFederal Regulations are to Chapter I ofTitle 21 unless otherwise noted.

§ 352.3 Definitions.As used in this part:(a) Minimal erythema dose (MED).

The quantity of erythema-effectiveenergy (expressed as Joules per squaremeter) required to produce the firstperceptible, redness reaction withclearly defined borders.

(b) Product category designation(PCD). A labeling designation forsunscreen drug products to aid inselecting the type of product best suitedto an individual’s complexion(pigmentation) and desired response toultraviolet (UV) radiation.

(1) Minimal sun protection product. Asunscreen product that provides a sunprotection factor (SPF) value of 2 tounder 12.

(2) Moderate sun protection product.A sunscreen product that provides anSPF value of 12 to under 30.

(3) High sun protection product. Asunscreen product that provides an SPFvalue of 30 or above.

(c) Sunscreen active ingredient. Anactive ingredient listed in § 352.10 thatabsorbs, reflects, or scatters radiation inthe UV range at wavelengths from 290to 400 nanometers.

(d) Sun protection factor (SPF) value.The UV energy required to produce anMED on protected skin divided by theUV energy required to produce an MEDon unprotected skin, which may also bedefined by the following ratio: SPFvalue = MED (protected skin (PS))/MED(unprotected skin (US)), where MED(PS) is the minimal erythema dose forprotected skin after application of 2milligrams per square centimeter of thefinal formulation of the sunscreenproduct, and MED (US) is the minimalerythema dose for unprotected skin, i.e.,skin to which no sunscreen product hasbeen applied. In effect, the SPF value isthe reciprocal of the effectivetransmission of the product viewed as aUV radiation filter.

Subpart B—Active Ingredients

§ 352.10 Sunscreen active ingredients.The active ingredient of the product

consists of any of the following, withinthe concentration specified for eachingredient, and the finished productprovides a minimum SPF value of notless than 2 as measured by the testingprocedures established in subpart D ofthis part:

(a) Aminobenzoic acid (PABA) up to15 percent.

(b) Avobenzone up to 3 percent.(c) Cinoxate up to 3 percent.(d) [Reserved].(e) Dioxybenzone up to 3 percent.(f) Homosalate up to 15 percent.(g) [Reserved].(h) Menthyl anthranilate up to 5

percent.(i) Octocrylene up to 10 percent.(j) Octyl methoxycinnamate up to 7.5

percent.(k) Octyl salicylate up to 5 percent.(l) Oxybenzone up to 6 percent.(m) Padimate O up to 8 percent.(n) Phenylbenzimidazole sulfonic

acid up to 4 percent.(o) Sulisobenzone up to 10 percent.(p) Titanium dioxide up to 25 percent.(q) Trolamine salicylate up to 12

percent.(r) Zinc oxide up to 25 percent.

§ 352.20 Permitted combinations of activeingredients.

The SPF of any combination productis measured by the testing proceduresestablished in subpart D of this part.



1 See § 201.66(b)(4) of this chapter.

(a) Combinations of sunscreen activeingredients. (1) Two or more sunscreenactive ingredients identified in§ 352.10(a), (c), (e), (f), and (h) through(r) may be combined with each other ina single product when used in theconcentrations established for eachingredient in § 352.10. Theconcentration of each active ingredientmust be sufficient to contribute aminimum SPF of not less than 2 to thefinished product. The finished productmust have a minimum SPF of not lessthan the number of sunscreen activeingredients used in the combinationmultiplied by 2.

(2) Two or more sunscreen activeingredients identified in § 352.10(b), (c),(e), (f), (i) through (l), (o), and (q) maybe combined with each other in a singleproduct when used in theconcentrations established for eachingredient in § 352.10. Theconcentration of each active ingredientmust be sufficient to contribute aminimum SPF of not less than 2 to thefinished product. The finished productmust have a minimum SPF of not lessthan the number of sunscreen activeingredients used in the combinationmultiplied by 2.

(b) [Reserved].(c) [Reserved].

Subpart C—Labeling

§ 352.50 Principal display panel of allsunscreen drug products.

In addition to the statement ofidentity required in § 352.52, thefollowing labeling statements shall beprominently placed on the principaldisplay panel:

(a) For products that do not satisfy thewater resistant or very water resistantsunscreen product testing procedures in§ 352.76. (1) For products with SPFvalues up to 30. ‘‘SPF (insert tested SPFvalue of the product up to 30).’’

(2) For products with SPF values over30. ‘‘SPF 30’’ (select one of thefollowing: ‘‘plus’’ or ‘‘+’’). Anystatement accompanying the marketedproduct that states a specific SPF valueabove 30 or similar language indicatinga person can stay in the sun more than30 times longer than without sunscreenwill cause the product to be misbrandedunder section 502 of the Federal Food,Drug, and Cosmetic Act (the act).

(b) For products that satisfy the waterresistant sunscreen product testingprocedures in § 352.76. (1) (Select one ofthe following: ‘‘Water,’’ ‘‘Water/Sweat,’’or ‘‘Water/Perspiration’’) ‘‘Resistant.’’

(2) ‘‘SPF (insert SPF value of theproduct, as stated in paragraph (a)(1) or(a)(2) of this section, after it has beentested using the water resistant

sunscreen product testing procedures in§ 352.76).’’

(c) For products that satisfy the verywater resistant sunscreen producttesting procedures in § 352.76. (1)‘‘Very’’ (select one of the following:‘‘Water,’’ ‘‘Water/Sweat,’’ or ‘‘Water/Perspiration’’) ‘‘Resistant.’’

(2) ‘‘SPF (insert SPF value of theproduct, as stated in paragraph (a)(1) or(a)(2) of this section, after it has beentested using the very water resistantsunscreen product testing procedures in§ 352.76).’’

§ 352.52 Labeling of sunscreen drugproducts.

(a) Statement of identity. The labelingof the product contains the establishedname of the drug, if any, and identifiesthe product as a ‘‘sunscreen.’’

(b) Indications. The labeling of theproduct states, under the heading‘‘Uses,’’ all of the phrases listed inparagraph (b)(1) of this section that areapplicable to the product and maycontain any of the additional phraseslisted in paragraph (b)(2) of this section,as appropriate. Other truthful andnonmisleading statements, describingonly the uses that have been establishedand listed in this paragraph (b), mayalso be used, as provided in § 330.1(c)(2)of this chapter, subject to the provisionsof section 502 of the act relating tomisbranding and the prohibition insection 301(d) of the act against theintroduction or delivery for introductioninto interstate commerce of unapprovednew drugs in violation of section 505(a)of the act.

(1) For products containing anyingredient in § 352.10. (i) ‘‘[bullet]1helps prevent sunburn [bullet] higherSPF gives more sunburn protection’’.

(ii) For products that satisfy the waterresistant testing procedures identified in§ 352.76. ‘‘[bullet] retains SPF after 40minutes of’’ (select one or more of thefollowing: ‘‘activity in the water,’’‘‘sweating,’’ or ‘‘perspiring’’).

(iii) For products that satisfy the verywater resistant testing proceduresidentified in § 352.76. ‘‘[bullet] retainsSPF after 80 minutes of’’ (select one ormore of the following: ‘‘activity in thewater,’’ ‘‘sweating,’’ or ‘‘perspiring’’).

(2) Additional indications. In additionto the indications provided in paragraph(b)(1) of this section, the following maybe used for products containing anyingredient in § 352.10:

(i) For products that provide an SPFof 2 to under 12. Select one or both ofthe following: [‘‘[bullet]’’ (select one ofthe following: ‘‘provides minimal,’’‘‘provides minimum,’’ ‘‘minimal,’’ or

‘‘minimum’’) ‘‘protection against’’(select one of the following: ‘‘sunburn’’or ‘‘sunburn and tanning’’)], or ‘‘[bullet]for skin that sunburns minimally’’.

(ii) For products that provide an SPFof 12 to under 30. Select one or both ofthe following: [‘‘[bullet]’’ (select one ofthe following: ‘‘provides moderate’’ or‘‘moderate’’) ‘‘protection against’’ (selectone of the following: ‘‘sunburn’’ or‘‘sunburn and tanning’’)], or ‘‘[bullet] forskin that sunburns easily’’.

(iii) For products that provide an SPFof 30 or above. Select one or both of thefollowing: [‘‘[bullet]’’ (select one of thefollowing: ‘‘provides high’’ or ‘‘high’’)‘‘protection against’’ (select one of thefollowing: ‘‘sunburn’’ or ‘‘sunburn andtanning’’)], or ‘‘[bullet] for skin highlysensitive to sunburn’’.

(c) Warnings. The labeling of theproduct contains the following warningsunder the heading ‘‘Warnings:’’

(1) For products containing anyingredient in § 352.10. (i) ‘‘When usingthis product [bullet] keep out of eyes.Rinse with water to remove.’’

(ii) ‘‘Stop use and ask a doctor if[bullet] rash or irritation develops andlasts’’.

(2) For products containing anyingredient identified in § 352.10marketed as a lipstick. The external useonly warning in § 201.66(c)(5)(i) of thischapter and the warning in paragraph(c)(1)(i) of this section are not required.

(d) Directions. The labeling of theproduct contains the followingstatements, as appropriate, under theheading ‘‘Directions.’’ More detaileddirections applicable to a particularproduct formulation (e.g., cream, gel,lotion, oil, spray, etc.) may also beincluded.

(1) For products containing anyingredient in § 352.10. (i) ‘‘[bullet]apply’’ (select one or more of thefollowing, as applicable: ‘‘liberally,’’‘‘generously,’’ ‘‘smoothly,’’ or ‘‘evenly’’)‘‘(insert appropriate time interval, if awaiting period is needed) before sunexposure and as needed’’.

(ii) ‘‘[bullet] children under 6 monthsof age: ask a doctor’’.

(2) In addition to the directionsprovided in § 352.52(d)(1), the followingmay be used for products containingany ingredient in § 352.10. ‘‘[bullet]reapply as needed or after towel drying,swimming, or’’ (select one of thefollowing: ‘‘sweating’’ or ‘‘perspiring’’).

(3) If the additional directionsprovided in § 352.52(d)(2) are used, thephrase ‘‘and as needed’’ in§ 352.52(d)(1) is not required.

(4) For products marketed as alipstick. The directions in paragraphs(d)(1) and (d)(2) of this section are notrequired.



(e) Statement on productperformance—(1) For productscontaining any ingredient identified in§ 352.10, the following PCD labelingclaims may be used under the heading‘‘Other information’’ or anywhereoutside of the ‘‘Drug Facts’’ box orenclosure.

(i) For products containing activeingredient(s) that provide an SPF valueof 2 to under 12. (Select one of thefollowing: ‘‘minimal’’ or ‘‘minimum’’)‘‘sun protection product.’’

(ii) For products containing activeingredient(s) that provide an SPF valueof 12 to under 30. ‘‘moderate sunprotection product.’’

(iii) For products containing activeingredient(s) that provide an SPF valueof 30 or above. ‘‘high sun protectionproduct.’’

(2) For products containing anyingredient identified in § 352.10, thefollowing labeling statement may beused under the heading ‘‘Otherinformation’’ or anywhere outside of the‘‘Drug Facts’’ box or enclosure. ‘‘Sunalert: Limiting sun exposure, wearingprotective clothing, and usingsunscreens may reduce the risks of skinaging, skin cancer, and other harmfuleffects of the sun.’’ Any variation of thisstatement will cause the product to bemisbranded under section 502 of theact.

(f) Products labeled for use only onspecific small areas of the face (e.g.,lips, nose, ears, and/or around eyes)and that meet the criteria established in§ 201.66(d)(10) of this chapter. The title,headings, subheadings, and informationdescribed in § 201.66(c) of this chaptershall be printed in accordance with thefollowing specifications:

(1) The labeling shall meet therequirements of § 201.66(c) of thischapter except that the title, headings,and information described in§ 201.66(c)(1), (c)(3), and (c)(7) may beomitted, and the headings, subheadings,and information described in§ 201.66(c)(2), (c)(4), (c)(5), and (c)(6)may be presented as follows:

(i) The active ingredients(§ 201.66(c)(2) of this chapter) shall belisted in alphabetical order.

(ii) The heading and the indicationrequired by § 201.66(c)(4) may belimited to: ‘‘Use [in bold type] helpsprevent sunburn.’’

(iii) The ‘‘external use only’’ warningin § 201.66(c)(5)(i) of this chapter maybe omitted.

(iv) The subheadings in§ 201.66(c)(5)(iii) through (c)(5)(vii) ofthis chapter may be omitted, providedthe information after the heading

‘‘Warnings’’ states: ‘‘Keep out of eyes.’’and ‘‘Stop use if skin rash occurs.’’

(v) The warning in § 201.66(c)(5)(x) ofthis chapter may be limited to thefollowing: ‘‘Keep out of reach ofchildren.’’

(vi) For a lipstick, the warnings ‘‘Keepout of eyes’’ in § 352.52(f)(1)(iv) and‘‘Keep out of reach of children’’ in§ 352.52(f)(1)(v) and the directions in§ 352.52(d) may be omitted.

(2) The labeling shall be printed inaccordance with the requirements of§ 201.66(d) of this chapter except thatany requirements related to§ 201.66(c)(1), (c)(3), and (c)(7), and thehorizontal barlines and hairlinesdescribed in § 201.66(d)(8), may beomitted.

§ 352.60 Labeling of permittedcombinations of active ingredients.

Statements of identity, indications,warnings, and directions for use,respectively, applicable to eachingredient in the product may becombined to eliminate duplicativewords or phrases so that the resultinginformation is clear and understandable.

(a) Statement of identity. For acombination drug product that has anestablished name, the labeling of theproduct states the established name ofthe combination drug product, followedby the statement of identity for eachingredient in the combination, asestablished in the statement of identitysections of the applicable OTC drugmonographs. For a combination drugproduct that does not have anestablished name, the labeling of theproduct states the statement of identityfor each ingredient in the combination,as established in the statement ofidentity sections of the applicable OTCdrug monographs.

(b) Indications. The labeling of theproduct states, under the heading‘‘Uses,’’ the indication(s) for eachingredient in the combination asestablished in the indications sectionsof the applicable OTC drug monographs,unless otherwise stated in thisparagraph. Other truthful andnonmisleading statements, describingonly the indications for use that havebeen established in the applicable OTCdrug monographs or listed in thisparagraph (b), may also be used, asprovided by § 330.1(c)(2) of this chapter,subject to the provisions of section 502of the Federal Food, Drug, and CosmeticAct (the act) relating to misbranding andthe prohibition in section 301(d) of theact against the introduction or deliveryfor introduction into interstatecommerce of unapproved new drugs inviolation of section 505(a) of the act.

(1) In addition, the labeling of theproduct may contain any of the ‘‘otherallowable statements’’ that are identifiedin the applicable monographs.

(2) For permitted combinationscontaining a sunscreen and a skinprotectant identified in § 352.20(b).

(c) Warnings. The labeling of theproduct states, under the heading‘‘Warnings,’’ the warning(s) for eachingredient in the combination, asestablished in the warnings section ofthe applicable OTC drug monographs.For permitted combinations containinga sunscreen and a skin protectantidentified in § 352.20(b).

(d) Directions. The labeling of theproduct states, under the heading‘‘Directions,’’ directions that conform tothe directions established for eachingredient in the directions sections ofthe applicable OTC drug monographs,unless otherwise stated in thisparagraph. When the time intervals orage limitations for administration of theindividual ingredients differ, thedirections for the combination productmay not contain any dosage thatexceeds those established for anyindividual ingredient in the applicableOTC drug monograph(s), and may notprovide for use by any age group lowerthan the highest minimum age limitestablished for any individualingredient. For permitted combinationscontaining a sunscreen and a skinprotectant identified in § 352.20(b).

Subpart D—Testing Procedures

§ 352.70 Standard sunscreen.

(a) Laboratory validation. A standardsunscreen shall be used concomitantlyin the testing procedures fordetermining the SPF value of asunscreen drug product to ensure theuniform evaluation of sunscreen drugproducts. The standard sunscreen shallbe an 8-percent homosalate preparationwith a mean SPF value of 4.47 (standarddeviation = 1.279). In order for the SPFdetermination of a test product to beconsidered valid, the SPF of thestandard sunscreen must fall within thestandard deviation range of the expectedSPF (i.e., 4.47 ± 1.279) and the 95-percent confidence interval for the meanSPF must contain the value 4.

(b) Preparation of the standardhomosalate sunscreen. (1) The standardhomosalate sunscreen is prepared fromtwo different preparations (preparationA and preparation B) with the followingcompositions:



COMPOSITION OF PREPARATION A AND PREPARATION B OF THE STANDARD SUNSCREEN

Ingredients Percent by weight

Preparation ALanolin .................................................................................................................. 5.00Homosalate .......................................................................................................... 8.00White petrolatum .................................................................................................. 2.50Stearic acid .......................................................................................................... 4.00Propylparaben ...................................................................................................... 0.05

Preparation BMethylparaben ...................................................................................................... 0.10Edetate disodium ................................................................................................. 0.05Propylene glycol ................................................................................................... 5.00Triethanolamine .................................................................................................... 1.00Purified water U.S.P ............................................................................................. 74.30

(2) Preparation A and preparation Bare heated separately to 77 to 82 °C,with constant stirring, until the contentsof each part are solubilized. Addpreparation A slowly to preparation Bwhile stirring. Continue stirring untilthe emulsion formed is cooled to roomtemperature (15 to 30 °C). Add sufficientpurified water to obtain 100 grams ofstandard sunscreen preparation.

(c) Assay of the standard homosalatesunscreen. Assay the standardhomosalate sunscreen preparation bythe following method to ensure properconcentration:

(1) Preparation of the assay solvent.The solvent consists of 1 percent glacialacetic acid (V/V) in denatured ethanol.The denatured ethanol should notcontain a UV radiation absorbingdenaturant.

(2) Preparation of a 1-percent solutionof the standard homosalate sunscreenpreparation. Accurately weigh 1 gram ofthe standard homosalate sunscreenpreparation into a 100-millilitervolumetric flask. Add 50 milliliters ofthe assay solvent. Heat on a steam bathand mix well. Cool the solution to roomtemperature (15 to 30 °C). Then dilutethe solution to volume with the assaysolvent and mix well to make a 1-percent solution.

(3) Preparation of the test solution(1:50 dilution of the 1-percent solution).Filter a portion of the 1-percent solutionthrough number 1 filter paper. Discardthe first 10 to 15 milliliters of thefiltrate. Collect the next 20 milliliters ofthe filtrate (second collection). Add 1milliliter of the second collection of thefiltrate to a 50-milliliter volumetricflask. Dilute this solution to volumewith assay solvent and mix well. Thisis the test solution (1:50 dilution of the1-percent solution).

(4) Spectrophotometric determination.The absorbance of the test solution ismeasured in a suitable double beamspectrophotometer with the assaysolvent and reference beam at awavelength near 306 nanometers.

(5) Calculation of the concentration ofhomosalate. The concentration ofhomosalate is determined by thefollowing formula which takes intoconsideration the absorbance of thesample of the test solution, the dilutionof the 1-percent solution (1:50), theweight of the sample of the standardhomosalate sunscreen preparation (1gram), and the standard absorbancevalue (172) of homosalate as determinedby averaging the absorbance of a largenumber of batches of raw homosalate:Concentration of homosalate =absorbance x 50 x 100 x 172 = percentconcentration by weight.

§ 352.71 Light source (solar simulator).

A solar simulator used fordetermining the SPF of a sunscreen drugproduct should be filtered so that itprovides a continuous emissionspectrum from 290 to 400 nanometerssimilar to sunlight at sea level from thesun at a zenith angle of 10 °; it has lessthan 1 percent of its total energy outputcontributed by nonsolar wavelengthsshorter than 290 nanometers; and it hasnot more than 5 percent of its totalenergy output contributed bywavelengths longer than 400nanometers. In addition, a solarsimulator should have no significanttime-related fluctuations in radiationemissions after an appropriate warmuptime, and it should have good beamuniformity (within 10 percent) in theexposure plane. To ensure that the solarsimulator delivers the appropriatespectrum of UV radiation, it must bemeasured periodically with anaccurately-calibrated spectroradiometersystem or equivalent instrument.

§ 352.72 General testing procedures.

(a) Selection of test subjects (male andfemale). (1) Only fair-skin subjects withskin types I, II, and III using thefollowing guidelines shall be selected:Selection of Fair-skin Subjects

Skin Type and Sunburn and Tanning History(Based on first 30 to 45 minutes sun exposureafter a winter season of no sun exposure.)I—Always burns easily; never tans(sensitive).II—Always burns easily; tans minimally(sensitive).III—Burns moderately; tans gradually (lightbrown) (normal).IV—Burns minimally; always tans well(moderate brown) (normal).V—Rarely burns; tans profusely (dark brown)(insensitive).VI—Never burns; deeply pigmented(insensitive).

(2) A medical history shall beobtained from all subjects withemphasis on the effects of sunlight ontheir skin. Ascertain the general healthof the individual, the individual’s skintype (I, II, or III), whether the individualis taking medication (topical orsystemic) that is known to produceabnormal sunlight responses, andwhether the individual is subject to anyabnormal responses to sunlight, such asa phototoxic or photoallergic response.

(b) Test site inspection. The physicalexamination shall determine thepresence of sunburn, suntan, scars,active dermal lesions, and uneven skintones on the areas of the back to betested. The presence of nevi, blemishes,or moles will be acceptable if in thephysician’s judgment they will notinterfere with the study results. Excesshair on the back is acceptable if the hairis clipped or shaved.

(c) Informed consent. Legally effectivewritten informed consent must beobtained from all individuals.

(d) Test site delineation—(1) Test sitearea. A test site area serves as an areafor determining the subject’s MED afterapplication of either the sunscreenstandard or the test sunscreen product,or for determining the subject’s MEDwhen the skin is unprotected (controlsite). The area to be tested shall be theback between the beltline and theshoulder blade (scapulae) and lateral tothe midline. Each test site area forapplying a product or the standard



sunscreen shall be a minimum of 50-square centimeters, e.g., 5 x 10centimeters. The test site areas areoutlined with ink. If the person is to betested in an upright position, the linesshall be drawn on the skin with thesubject upright. If the subject is to betested while prone, the markings shallbe made with the subject prone.

(2) Test subsite area. Each test sitearea shall be divided into at least threetest subsite areas that are at least 1square centimeter. Usually four or fivesubsites are employed. Each test subsitewithin a test site area is subjected to aspecified dosage of UV radiation, in aseries of UV radiation exposures, inwhich the test site area is exposed forthe determination of the MED.

(e) Application of test materials. Toensure standardized reporting and todefine a product’s SPF value, theapplication of the product shall beexpressed on a weight basis per unitarea which establishes a standard film.Both the test sunscreen product and thestandard sunscreen application shall be2 milligrams per square centimeter. Foroils and most lotions, the viscosity issuch that the material can be appliedwith a volumetric syringe. For creams,heavy gels, and butters, the productshall be warmed slightly so that it canbe applied volumetrically. On heating,care shall be taken not to alter theproduct’s physical characteristics,especially separation of theformulations. Pastes and ointments shallbe weighed, then applied by spreadingon the test site area. A product shall bespread by using a finger cot. If two ormore sunscreen drug products are beingevaluated at the same time, the testproducts and the standard sunscreen, asspecified in § 352.70, should be appliedin a blinded, randomized manner. Ifonly one sunscreen drug product isbeing tested, the testing subsites should

be exposed to the varying doses of UVradiation in a randomized manner.

(f) Waiting period. Before exposingthe test site areas after applying aproduct, a waiting period of at least 15minutes is required.

(g) Number of subjects. A test panelshall consist of not more than 25subjects with the number fixed inadvance by the investigator. From thispanel, at least 20 subjects must producevalid data for analysis.

(h) Response criteria. In order that theperson who evaluates the MEDresponses does not know whichsunscreen formulation was applied towhich site or what doses of UVradiation were administered, he/shemust not be the same person whoapplied the sunscreen drug product tothe test site or administered the doses ofUV radiation. After UV radiationexposure from the solar simulator iscompleted, all immediate responsesshall be recorded. These include severaltypes of typical responses such as thefollowing: An immediate darkening ortanning, typically greyish or purplish incolor, fading in 30 to 60 minutes, andattributed to photo-oxidation of existingmelanin granules; immediate reddening,fading rapidly, and viewed as a normalresponse of capillaries and venules toheat, visible and infrared radiation; andan immediate generalized heat response,resembling prickly heat rash, fading in30 to 60 minutes, and apparently causedby heat and moisture generally irritatingto the skin’s surface. After theimmediate responses are noted, eachsubject shall shield the exposed areafrom further UV radiation for theremainder of the test day. The MED isdetermined 22 to 24 hours afterexposure. The erythema responses ofthe test subject should be evaluatedunder the following conditions: Thesource of illumination should be eithera tungsten light bulb or a warm white

fluorescent light bulb that provides alevel of illumination at the test sitewithin the range of 450 to 550 lux, andthe test subject should be in the sameposition used when the test site wasirradiated. Testing depends upondetermining the smallest dose of energythat produces redness reaching theborders of the exposure site at 22 to 24hours postexposure for each series ofexposures. To determine the MED,somewhat more intense erythemas mustalso be produced. The goal is to havesome exposures that produce absolutelyno effect, and of those exposures thatproduce an effect, the maximal exposureshould be no more than twice the totalenergy of the minimal exposure.

(i) Rejection of test data. Test datashall be rejected if the exposure seriesfails to elicit an MED response on eitherthe treated or unprotected skin sites, orif the responses on the treated sites arerandomly absent (which indicates theproduct was not spread evenly), or if thesubject was noncompliant (e.g., subjectwithdraws from the test due to illnessor work conflicts, subject does notshield the exposed testing sites fromfurther UV radiation until the MED isread, etc.).

§ 352.73 Determination of SPF value.

(a)(1) The following erythema actionspectrum shall be used to calculate theerythema effective exposure of a solarsimulator:

Vi (λ) = 1.0 (250 < λ < 298 nm)Vi (λ) = 1.00.094 (298 - λ) (298 < λ < 328

nanometers)Vi (λ) = 1.00.015 (139 - λ) (328 < λ < 400

nanometers)(2) The data contained in this action

spectrum are to be used as spectralweighting factors to calculate theerythema effective exposure of a solarsimulator as follows:

BILLING CODE 4160–01–F



BILLING CODE 4160–01–C

(b) Determination of MED of theunprotected skin. A series of UVradiation exposures expressed as Joulesper square meter (adjusted to theerythema action spectrum calculatedaccording to § 352.73(a)) is administeredto the subsite areas on each subject withan accurately calibrated solar simulator.A series of five exposures shall beadministered to the untreated,unprotected skin to determine thesubject’s inherent MED. The dosesselected shall be a geometric seriesrepresented by (1.25n), wherein eachexposure time interval is 25 percentgreater than the previous time tomaintain the same relative uncertainty(expressed as a constant percentage),independent of the subject’s sensitivityto UV radiation, regardless of whetherthe subject has a high or low MED.Usually, the MED of a person’sunprotected skin is determined the dayprior to testing a product. This MED(US)shall be used in the determination of theseries of UV radiation exposures to beadministered to the protected site insubsequent testing. The MED(US)should be determined again on the sameday as the standard and test sunscreensand this MED(US) should be used incalculating the SPF.

(c) Determination of individual SPFvalues. A series of UV radiationexposures expressed as Joules persquare meter (adjusted to the erythemaaction spectrum calculated according to§ 352.73(a)) is administered to the

subsite areas on each subject with anaccurately-calibrated solar simulator. Aseries of seven exposures shall beadministered to the protected test sitesto determine the MED of the protectedskin (MED(PS)). The doses selectedshall consist of a geometric series of fiveexposures, where the middle exposureis placed to yield the expected SPF plustwo other exposures placedsymmetrically around the middleexposure. The exact series of exposuresto be given to the protected skin shallbe determined by the previouslyestablished MED(US) and the expectedSPF of the test sunscreen. For productswith an expected SPF less than 8, theexposures shall be the MED(US) times0.64X, 0.80X, 0.90X, 1.00X, 1.10X,1.25X, and 1.56X, where X equals theexpected SPF of the test product. Forproducts with an expected SPF between8 and 15, the exposures shall be theMED(US) times 0.69X, 0.83X, 0.91X,1.00X, 1.09X, 1.20X, and 1.44X, whereX equals the expected SPF of the testproduct. For products with an expectedSPF greater that 15, the exposures shallbe the MED(US) times 0.76X, 0.87X,0.93X, 1.00X, 1.07X, 1.15X, and 1.32X,where X equals the expected SPF of thetest product. The MED is the quantity oferythema-effective energy required toproduce the first perceptible,unambiguous redness reaction withclearly defined borders at 22 to 24 hourspostexposure. The SPF value of the testsunscreen is then calculated from thedose of UV radiation required to

produce the MED of the protected skinand from the dose of UV radiationrequired to produce the MED of theunprotected skin (control site) asfollows:

SPF value = the ratio of erythema effectiveexposure (Joules per square meter) (MED(PS))to the erythema effective exposure (Joules persquare meter) (MED(US)).

(d) Determination of the test product’sSPF value and PCD. Use data from atleast 20 test subjects with n representingthe number of subjects used. First, foreach subject, compute the SPF value asstated in § 352.73(b) and (c). Second,compute the mean SPF value, x̄, and thestandard deviation, s, for these subjects.Third, obtain the upper 5-percent pointfrom the t distribution table with n-1degrees of freedom. Denote this value byt. Fourth, compute ts/ √n. Denote thisquantity by A (i.e., A = ts/ √n). Fifth,calculate the SPF value to be used inlabeling as follows: the label SPF equalsthe largest whole number less than x̄ -A. Sixth and last, the drug product isclassified into a PCD as follows: if 30 +A < x̄, the PCD is High; if 12 + A < x̄< 30 + A, the PCD is Moderate; if 2 +A < x̄ < 12 + A, the PCD is Minimal;if x̄ < 2 + A, the product shall not belabeled as a sunscreen drug product andshall not display an SPF value.

§ 352.76 Determination if a product iswater resistant or very water resistant.

The general testing procedures in§ 352.72 shall be used as part of thefollowing tests, except where modifiedin this section. An indoor fresh water



pool, whirlpool, and/or jacuzzimaintained at 23 to 32 °C shall be usedin these testing procedures. Fresh wateris clean drinking water that meets thestandards in 40 CFR part 141. The pooland air temperature and the relativehumidity shall be recorded.

(a) Procedure for testing the waterresistance of a sunscreen product. Forsunscreen products making the claim of‘‘water resistant,’’ the label SPF shall bethe label SPF value determined after 40minutes of water immersion using thefollowing procedure for the waterresistance test:

(1) Apply sunscreen product(followed by the waiting period afterapplication of the sunscreen productindicated on the product labeling).

(2) 20 minutes moderate activity inwater.

(3) 20-minute rest period (do nottowel test sites).


(5) Conclude water test (air dry testsites without toweling).

(6) Begin solar simulator exposure totest site areas as described in § 352.73.

(b) Procedure for testing a very waterresistant sunscreen product. Forsunscreen products making the claim of‘‘very water resistant,’’ the label SPFshall be the label SPF value determinedafter 80 minutes of water immersionusing the following procedure for thevery water resistant test:

(1) Apply sunscreen product(followed by the waiting period afterapplication of the sunscreen productindicated on the product labeling).








(9) Conclude water test (air dry testsites without toweling).

(10) Begin solar simulator exposure totest site areas as described in § 352.73.

§ 352.77 Test modifications.The formulation or mode of

administration of certain products mayrequire modification of the testingprocedures in this subpart. In addition,alternative methods (includingautomated or in vitro procedures)employing the same basic procedures asthose described in this subpart may be

used. Any proposed modification oralternative procedure shall be submittedas a petition in accord with § 10.30 ofthis chapter. The petition shouldcontain data to support the modificationor data demonstrating that an alternativeprocedure provides results of equivalentaccuracy. All information submittedwill be subject to the disclosure rules inpart 20 of this chapter.

PART 700—GENERAL


Authority: 21 U.S.C. 321, 331, 352, 355,361, 362, 371, 374.

5. Section 700.35 is added to subpartB to read as follows:

§ 700.35 Cosmetics containing sunscreeningredients.

(a) A product that includes the term‘‘sunscreen’’ in its labeling or in anyother way represents or suggests that itis intended to prevent, cure, treat, ormitigate disease or to affect a structureor function of the body comes withinthe definition of a drug in section201(g)(1) of the act. Sunscreen activeingredients affect the structure orfunction of the body by absorbing,reflecting, or scattering the harmful,burning rays of the sun, thereby alteringthe normal physiological response tosolar radiation. These ingredients alsohelp to prevent diseases such assunburn and may reduce the chance ofpremature skin aging, skin cancer, andother harmful effects due to the sunwhen used in conjunction with limitingsun exposure and wearing protectiveclothing. When consumers see the term‘‘sunscreen’’ or similar sun protectionterminology in the labeling of a product,they expect the product to protect themin some way from the harmful effects ofthe sun, irrespective of other labelingstatements. Consequently, the use of theterm ‘‘sunscreen’’ or similar sunprotection terminology in a product’slabeling generally causes the product tobe subject to regulation as a drug.However, sunscreen ingredients mayalso be used in some products fornontherapeutic, nonphysiologic uses(e.g., as a color additive or to protect thecolor of the product). To avoidconsumer misunderstanding, if acosmetic product contains a sunscreeningredient and uses the term‘‘sunscreen’’ or similar sun protectionterminology anywhere in its labeling,the term must be qualified by describingthe cosmetic benefit provided by thesunscreen ingredient.

(b) The qualifying informationrequired under paragraph (a) of thissection shall appear prominently and

conspicuously at least once in thelabeling in conjunction with the term‘‘sunscreen’’ or other similar sunprotection terminology used in thelabeling. For example: ‘‘Contains asunscreen—to protect product color.’’

PART 740—COSMETIC PRODUCTWARNING STATEMENTS


Authority: 21 U.S.C. 321, 331, 352, 355,361, 362, 371, 374.

7. Section 740.19 is added to subpartB to read as follows:

§ 740.19 Suntanning preparations.The labeling of suntanning

preparations that do not contain asunscreen ingredient must display thefollowing warning: ‘‘Warning—Thisproduct does not contain a sunscreenand does not protect against sunburn.Repeated exposure of unprotected skinwhile tanning may increase the risk ofskin aging, skin cancer, and otherharmful effects to the skin even if youdo not burn.’’ For purposes of thissection, the term ‘‘suntanningpreparations’’ includes gels, creams,liquids, and other topical products thatare intended to provide cosmetic effectson the skin while tanning throughexposure to UV radiation (e.g.,moisturizing or conditioning products),or to give the appearance of a tan byimparting color to the skin through theapplication of approved color additives(e.g., dihydroxyacetone) without theneed for exposure to UV radiation. Theterm ‘‘suntanning preparations’’ doesnot include products intended toprovide sun protection or otherwiseintended to affect the structure or anyfunction of the body.

Dated: April 22, 1999.William K. Hubbard,Associate Commissioner for PolicyCoordination.[FR Doc. 99–12853 Filed 5–20–99; 8:45 am]BILLING CODE 4160–01–F

DEPARTMENT OF DEFENSE

Office of the Secretary

32 CFR Part 311

OSD Privacy Program; Correction

AGENCY: Department of Defense.ACTION: Final rule; correction.

SUMMARY: This rules makesadministrative corrections to the OSDPrivacy Program rule published onApril 28, 1999.


27666 federal register /vol. 64, no. 98/friday, may 21 ... · 27666 federal register/vol. 64, no....

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