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DEPARTMENT OF HEALTH AND the public. Similarly, if your submission 1978–N–0018 (formerly Docket No. HUMAN SERVICES includes safety and effectiveness data or FDA–1978–N–0038) for ‘‘Sunscreen information marked as confidential by a Drug Products for Over-the-Counter Food and Drug Administration third party (such as a contract research Human Use.’’ Received comments, those organization or consultant), you should filed in a timely manner (see 21 CFR Parts 201, 310, 347, and 352 either include a statement that you are ADDRESSES), will be placed in the docket [Docket No. FDA–1978–N–0018] (Formerly authorized to make the information and, except for those submitted as Docket No. FDA–1978–N–0038) publicly available or include an ‘‘Confidential Submissions,’’ publicly authorization from the third party viewable at https://www.regulations.gov RIN 0910–AF43 permitting the information to be or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday Sunscreen Drug Products for Over-the- publicly disclosed. If you submit data through Friday. Counter Human Use without confidential markings in response to this document and such • Confidential Submissions—To AGENCY: Food and Drug Administration, data includes studies or other submit a comment with confidential HHS. information that were previously information that you do not wish to be made publicly available, submit your ACTION: Proposed rule. submitted confidentially (e.g., as part of a new drug application), FDA intends to comments only as a written/paper SUMMARY: The Food and Drug presume that you intend to make such submission. You should submit two Administration (FDA or Agency) is data publicly available. copies total. One copy will include the issuing this proposed rule to put into information you claim to be confidential effect a final monograph for Electronic Submissions with a heading or cover note that states nonprescription, over-the-counter (OTC) Submit electronic comments in the ‘‘THIS DOCUMENT CONTAINS sunscreen drug products. This proposed following way: CONFIDENTIAL INFORMATION.’’ The rule describes the conditions under • Federal eRulemaking Portal: Agency will review this copy, including which FDA proposes that OTC https://www.regulations.gov. Follow the the claimed confidential information, in sunscreen monograph products are instructions for submitting comments. its consideration of comments. The generally recognized as safe and Comments submitted electronically, second copy, which will have the effective (GRASE) and not misbranded. including attachments, to https:// claimed confidential information It is being published as part of the www.regulations.gov will be posted to redacted/blacked out, will be available ongoing review of OTC drug products the docket unchanged. Because your for public viewing and posted on conducted by FDA. It is also being comment will be made public, you are https://www.regulations.gov. Submit published to comply with the Federal solely responsible for ensuring that your both copies to the Dockets Management Food, Drug, and Cosmetic Act (FD&C comment does not include any Staff. If you do not wish your name and Act), as amended by the Sunscreen confidential information that you or a contact information to be made publicly Innovation Act (SIA). third party may not wish to be posted, available, you can provide this information on the cover sheet and not DATES: Submit either electronic or such as medical information, your or in the body of your comments and you written comments. on the proposed rule anyone else’s Social Security number, or must identify this information as by May 28, 2019. Electronic comments confidential business information, such ‘‘confidential.’’ Any information marked must be submitted on or before May 28, as a manufacturing process. Please note as ‘‘confidential’’ will not be disclosed 2019. The https://www.regulations.gov that if you include your name, contact except in accordance with 21 CFR 10.20 electronic filing system will accept information, or other information that and other applicable disclosure law. For comments until 11:59 p.m. Eastern Time identifies you in the body of your comments, that information will be more information about FDA’s posting at the end of May 28, 2019. See section of comments to public dockets, see 80 XII for proposed effective and posted on https://www.regulations.gov. • If you want to submit a comment FR 56469, September 18, 2015, or access compliance dates of a final rule based the information at: https://www.gpo.gov/ on this document. with confidential information that you do not wish to be made available to the fdsys/pkg/FR-2015-09-18/pdf/2015- ADDRESSES: You may submit comments public, submit the comment as a 23389.pdf. as follows. Please note that late, written/paper submission and in the Docket: For access to the docket to untimely filed comments will not be manner detailed (see ‘‘Written/Paper read background documents or the considered. Comments received by Submissions’’ and ‘‘Instructions’’). electronic and written/paper comments mail/hand delivery/courier (for written/ received, go to https:// paper submissions) will be considered Written/Paper Submissions www.regulations.gov and insert the timely if they are postmarked or the Submit written/paper submissions as docket number, found in brackets in the delivery service acceptance receipt is on follows: heading of this document, into the or before the closing date. • Mail/Hand Delivery/Courier (for ‘‘Search’’ box and follow the prompts Please be advised that safety and written/paper submissions): Dockets and/or go to the Dockets Management effectiveness data that are not available Management Staff (HFA–305), Food and Staff, 5630 Fishers Lane, Rm. 1061, to the public cannot be relied on to Drug Administration, 5630 Fishers Rockville, MD 20852. establish conditions under which the Lane, Rm. 1061, Rockville, MD 20852. Submit comments on information OTC drugs described in this document • For written/paper comments collection issues under the Paperwork of proposed rulemaking are generally submitted to the Dockets Management Reduction Act of 1995 to the Office of recognized as safe and effective. Staff, FDA will post your comment, as Management and Budget (OMB) in the Accordingly, you should not submit, well as any attachments, except for following ways: and FDA generally does not intend to information submitted, marked and • Fax to the Office of Information and rely on, any evidence of safety and identified, as confidential, if submitted Regulatory Affairs, OMB, Attn: FDA effectiveness that bears a confidential as detailed in ‘‘Instructions.’’ Desk Officer, Fax: 202–395–7285, or mark unless you include a statement Instructions: All submissions received email to [email protected]. that the information may be released to must include the Docket No. FDA– All comments should be identified with

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the title, ‘‘Sunscreen Drug Products for B. Regulatory Status of Testing Entities changed conditions, including Over-the-Counter Human Use.’’ C. Generating and Maintaining Records of substantially increased sunscreen usage The Agency encourages commenters SPF and Broad Spectrum Testing and exposure and evolving information XVI. Federalism also to submit their comments on these XVII. Consultation and Coordination With about the potential risks associated with paperwork requirements to the Indian Tribal Governments these products since they were rulemaking docket (Docket No. FDA– XVIII. References originally evaluated. While these 1978–N–0018), along with their additional data are being developed and comments on other parts of the I. Executive Summary reviewed, FDA generally intends to proposed rule. A. Purpose and Coverage of the follow the enforcement approach FOR FURTHER INFORMATION CONTACT: Proposed Rule discussed in section III.B with regard to sunscreen products that contain those Kristen Hardin, Center for Drug The Food and Drug Administration Evaluation and Research, Food and (FDA or Agency) is publishing this sunscreen active ingredients included in Drug Administration, 10903 New proposed rule as part of the regulatory the Stayed 1999 Final Monograph. This proposed rule is also being Hampshire Ave., Bldg. 22, Rm. 5443, proceeding to put into effect a final published to comply with section 586E Silver Spring, MD 20993, 240–402– monograph 1 for nonprescription, OTC of the FD&C Act (21 U.S.C. 360fff–5), as 4246. sunscreen drug products under the OTC amended by the SIA (21 U.S.C. ch. 9, Drug Review. In 2011, FDA announced SUPPLEMENTARY INFORMATION: sub. 5, part I, enacted November 26, that ‘‘we are considering certain active Table of Contents ingredient safety issues further . . . In 2014). The SIA calls for FDA to issue a a forthcoming rulemaking, we intend to final OTC sunscreen monograph to be I. Executive Summary effective within 5 years of enactment of A. Purpose and Coverage of the Proposed request additional data regarding the Rule safety of the individual sunscreen active the SIA, or by November 26, 2019 B. Summary of the Major Provisions of the ingredients.’’ (‘‘Revised Effectiveness (section 586E(a) of the FD&C Act). If the Proposed Rule Determination; Sunscreen Drug final OTC sunscreen monograph does C. Legal Authority Products for Over-the-Counter Human not include provisions related to the D. Costs and Benefits Use’’ (Max SPF PR), 76 FR 35672 at effectiveness of various sun protection II. Table of Abbreviations/Commonly Used 35673, June 17, 2011). As described in factor (SPF) levels and address all Acronyms in This Document dosage forms known to FDA to be used III. Background further detail below, changed conditions in the nearly 20 years since publication in sunscreens marketed in the United A. FDA’s Current Regulatory Framework States without approved new drug B. History of This Rulemaking of the final rule ‘‘Sunscreen Drug IV. Scope of This Rulemaking Products for Over the Counter Human applications (NDAs), the SIA requires V. Legal Authority Use’’ (64 FR 27666, May 21, 1999) (now FDA, among other things, to submit a VI. Need for Additional Safety Information stayed) (Stayed 1999 Final Monograph) report to Congress explaining these A. Increased Consumer Exposure to have meant that additional safety data omissions (section 586E(b) of the FD&C Sunscreen Active Ingredients are now needed to establish that certain Act). As explained in section I.B, in this B. Emerging Safety Concerns of the active ingredients listed in the proposed rule, FDA is addressing VII. Framework for Evaluation of Safety Data multiple conditions of use applicable to A. General Stayed 1999 Final Monograph are GRASE for use in sunscreen products.2 sunscreen monograph products, B. Clinical Safety Testing including both the effectiveness of C. Nonclinical Safety Testing As detailed below, we emphasize that D. Postmarketing Safety Data this proposed rule does not represent a various SPF values and all marketed E. Sunscreens Containing Nanomaterials conclusion by FDA that the sunscreen sunscreen dosage forms (and intends to VIII. Existing Safety Data for Sunscreen active ingredients included in the do so in the final rule as well). Active Ingredients Stayed 1999 Final Monograph but This proposed rule does not address A. Ingredients Proposed as Category I proposed here as Category III are unsafe the sunscreen active ingredients that B. Ingredients Proposed as Category II for use in sunscreens. Rather, we are were originally submitted under the C. Ingredients Proposed as Category III requesting additional information on procedures established in FDA’s time D. Anticipated Final Formulation In Vitro these ingredients so that we can and extent application (TEA) regulation Permeation Testing evaluate their GRASE status in light of (§ 330.14 (21 CFR 330.14)) (67 FR 3074, IX. Additional Proposed Conditions of Use January 23, 2002), and are now being A. Proposed Requirements Related to Dosage Form 1 An OTC monograph establishes conditions addressed through a process set forth in B. Proposed Maximum SPF and Broad under which certain OTC drugs may be marketed the SIA. without approved new drug applications because Spectrum Requirements they are generally recognized as safe and effective B. Summary of the Major Provisions of C. Proposed PDP Labeling Requirements (GRASE) and not misbranded. The proposed rule the Proposed Rule D. Proposed Requirements Related to Final classifies active ingredients and other conditions as Formulation Testing and Recordkeeping Category I (proposed to be GRASE and not 1. Proposed GRASE Status of Active E. Proposed Status of Sunscreen-Insect misbranded), Category II (proposed to be not GRASE or to be misbranded), or Category III Ingredients Listed in the Stayed 1999 Repellent Combination Products Final Monograph X. Proposed Actions To Effectuate Lifting of (additional data needed). 2 Stay and Harmonize Impacted Unless otherwise noted, references in this a. Framework for evaluation of safety proposed rule to sunscreen active ingredients and/ Regulations or sunscreen products are to sunscreen active data. As previously noted, changed XI. Comment Period ingredients or products marketed pursuant to the conditions in the time since issuance of XII. Proposed Effective/Compliance Dates OTC monograph system and subject to 21 CFR the Stayed 1999 Final Monograph have XIII. Preliminary Economic Analysis of 201.327. Unless specifically noted, references to meant that additional safety data are sunscreen active ingredients and/or sunscreen Impacts now needed to establish that certain of A. Introduction products in this notice do not refer to those B. Summary of Costs and Benefits marketed pursuant to a new drug application (NDA) the active ingredients listed in the or an abbreviated new drug application (ANDA). XIV. Analysis of Environmental Impact Stayed 1999 Final Monograph are They also do not refer to sunscreen active GRASE for use in sunscreen products in XV. Paperwork Reduction Act of 1995 ingredients being evaluated under the new A. Labeling for Sunscreen Products and procedures set out in the SIA (21 U.S.C. 360fff et accordance with the standards Associated Clinical Testing seq). established in § 330.10(a)(4) (21 CFR

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330.10(a)(4)). FDA’s approach to the proposing that these two ingredients are 3. Proposed Maximum Sun Protection clinical safety evaluation of OTC Category II. Factor and Broad Spectrum sunscreen active ingredients is based on Because the public record does not Requirements our current scientific understanding currently contain sufficient data to In the Stayed 1999 Final Monograph, support positive GRASE determinations regarding the safety evaluation of FDA established SPF 30+ as the for cinoxate, dioxybenzone, ensulizole, topical drug products for chronic use, maximum labeled SPF value for homosalate, meradimate, octinoxate, and is therefore generally consistent sunscreen monograph products, and octisalate, octocrylene, padimate O, with the safety data needed to meet the subsequently proposed (in 2011) to raise sulisobenzone, oxybenzone, or requirements for approval of an NDA for this value to SPF 50+. Because of avobenzone, we are proposing that these a chronic-use topical drug product (e.g., evidence showing additional ingredients are Category III. For topical safety studies (irritation, meaningful clinical benefit associated sensitization, and photosafety); example, the available literature with broad spectrum sunscreen bioavailability (absorption); and includes studies indicating that products with an SPF of 60, we are now evaluation of adverse events observed in oxybenzone is absorbed through the proposing to raise the maximum labeled clinical studies). Postmarketing safety skin to a greater extent than previously SPF value to SPF 60+. Given the lack of information is also relevant to our safety understood and can lead to significant data showing that sunscreens with SPF evaluation. systemic exposure, as well as data Our current approach to the showing the presence of oxybenzone in values above 60 provide additional nonclinical safety evaluation of these human breast milk, amniotic fluid, meaningful clinical benefit, we are active ingredients takes into account urine, and blood plasma. The significant proposing not to allow labeled SPF their lengthy marketing history in the systemic availability of oxybenzone, values higher than 60+. United States. Unlike the nonclinical coupled with a lack of data evaluating While our proposed cap for SPF data required to meet the standard for the full extent of its absorption labeling is SPF 60+, we are proposing to approval of chronic-use topical NDA potential, is a concern, among other permit the marketing of sunscreen products (which include comprehensive reasons, because of questions raised in products formulated with SPF values up nonclinical pharmacology and the published literature regarding the to 80. This formulation margin is toxicology safety testing), the approach potential for endocrine activity in intended to provide manufacturers with to nonclinical safety testing reflected in connection with systemic oxybenzone formulation flexibility that we hope this proposed rule is largely focused on exposure. Nearly all of these sunscreen will: (1) Help facilitate the development potential long-term adverse effects or active ingredients also have limited or of products with greater Ultraviolet A effects not otherwise readily detected no data characterizing their absorption. (UVA) protection and (2) more fully from human use (i.e., carcinogenicity account for the range of variability in 2. Proposed Requirements Related to and reproductive toxicity). SPF test results (discussed further in b. Existing safety data for ingredients Dosage Forms sections IX.B.4.b–c) for sunscreen listed in Stayed 1999 Final Monograph. In 2011, FDA published an Advance products labeled SPF 60+. We are In section VIII, we discuss our review of Notice of Proposed Rulemaking (ANPR) proposing not to allow the marketing the scientific literature, submissions to that identified sunscreen dosage forms (without an approved NDA) of the sunscreen monograph docket, and considered either eligible or ineligible sunscreen products with SPF values adverse event reports submitted to for inclusion in the sunscreen above SPF 80. FDA’s Adverse Event Reporting System monograph, and specifically requested In addition, since publication of the (FAERS) for the ingredients listed in the comments on the safety and efficacy of 2011 ‘‘Labeling and Effectiveness Stayed 1999 Final Monograph and spray sunscreens. After considering Testing; Sunscreen Drug Products for identify any existing gaps. Because our comments received in response (and Over-the-Counter Human Use’’ (L&E review of this evidence has produced other available data), we are proposing Final Rule) (76 FR 35620, June 17, 2011) sufficient safety data on both zinc oxide the following dosage forms as Category and Max SPF PR, the body of scientific and titanium dioxide to support a I: Oils, lotions, creams, gels, butters, evidence linking UVA exposure to skin proposal that sunscreen products pastes, ointments, and sticks. We are cancers and other harms has grown containing these ingredients (at also proposing Category I status for significantly. This evidence raises concentrations of up to 25 percent) spray sunscreens, subject to testing concerns about the potential for would be GRASE, we are proposing that necessary to minimize potential risks inadequate UVA protection in marketed these ingredients are Category I. Our from unintended inhalation (particle sunscreen products—particularly in evaluation of the available safety data size restrictions) and flammability high SPF sunscreen products that either for aminobenzoic acid (PABA) and (flammability and drying time testing), do not pass the current broad spectrum trolamine salicylate, however, has together with related labeling test or (though they pass our current caused us to conclude that the risks requirements. We are proposing to add broad spectrum test) have inadequate associated with use of these active sunscreen powders to the list of those uniformity in their UVA protection. ingredients in sunscreen products eligible for inclusion in the monograph Consumers using these products may, outweigh their benefits. In the case of and proposing that this dosage form is while successfully preventing sunburn, trolamine salicylate, these risks include Category III; we expect that powders accumulate excessively large doses of the potential for serious detrimental would also be subject to particle size UVA radiation—thereby exposing health effects (including bleeding) restrictions if found to be GRASE in the themselves to additional risks related to caused by the anti-coagulation effects of final monograph. Finally, we are skin cancer and early skin aging. salicylic acid and increased risk of proposing that sunscreens in all other To address these concerns, we are salicylate toxicity when this ingredient dosage forms—including wipes, making a number of proposals designed is used in sunscreens. For PABA, the towelettes, body washes, and to couple a greater magnitude of UVA risks include significant rates of allergic shampoos—are new drugs because we protection to increases in SPF values. and photoallergic skin reactions, as well did not receive data showing that they We are proposing to require that all as cross-sensitization with structurally were marketed prior to 1972, as required sunscreen products with SPF values of similar compounds. Accordingly, we are for inclusion in the monograph. 15 and above satisfy broad spectrum

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requirements. Among other things, this labeled in increments of 5 (i.e., SPF 15, to ensure that the testing of marketed proposal eliminates the potential SPF 20, SPF 25), and that the sunscreen products is conducted in a confusion permitted by the current requirement that labeled SPF values manner that both protects human labeling regime, in which a higher correspond to ranges (rather than subjects and produces reliable results. numbered product (for example, one precise numerical values) is not 6. Proposed Status of Sunscreen-Insect labeled SPF 30) may provide inferior necessary below SPF 15. Repellent Combination Products protection against UVA radiation than a 4. Proposed PDP Labeling Requirements lower numbered product (for example, The proposed rule also addresses one labeled broad spectrum SPF 15). We We are also proposing to partially sunscreen-insect repellent products, are also proposing to add to the current revise the current requirements for which are jointly regulated by FDA as broad spectrum test a requirement that information that must appear on the sunscreen drugs and by the broad spectrum products meet a UVA I/ principal display panel (PDP) of Environmental Protection Agency (EPA) UV ratio of 0.7 or higher. Given how sunscreen products. The PDP is the part as pesticides under the Federal much of the UVA portion of the of a product label that is most likely to Insecticide, Fungicide and Rodenticide ultraviolet (UV) spectrum is composed be viewed or examined when the Act (FIFRA). In 2007, FDA and EPA of UVA I radiation, and given what we product is displayed for retail sale. A both issued ANPRs requesting comment now know about the skin cancer risks major feature of the PDP is the statement on the appropriate regulatory status of associated with UVA exposure, ensuring of identity (SOI). We are proposing that these products. We are proposing to that sunscreen products provide the SOI consist of an alphabetical listing classify these products as Category II adequate protection in the UVA I of the sunscreen active ingredients in because incompatibilities between FDA portion of the spectrum is critical.3 the product, followed by ‘‘Sunscreen’’ and EPA labeling requirements prevent Because sunscreens with SPF 2 to 14 and the product’s dosage form (such as these products from being labeled in a have not been demonstrated to help lotion or spray). This information would manner that sufficiently ensures safe reduce the risk of skin cancer and early supplement other important elements of and effective use of the sunscreen skin aging caused by the sun, whether the PDP (e.g., SPF, broad spectrum, and component and provides adequate or not they provide protection against water resistance information) to provide directions for use. In addition, there are UVA radiation as well as ultraviolet B a succinct summary of the product’s key data suggesting that combining some (UVB) radiation, we are not proposing to characteristics on the front of the sunscreen active ingredients with the require that they pass the revised broad package or container, permitting insecticide DEET may increase spectrum test. However, we seek consumers to more readily compare absorption of either or both comment on whether these low SPF products and either select or avoid a components. given product accordingly. For products should remain in the market. 7. Proposed Actions To Effectuate Finally, we are proposing to require sunscreen products that have not been Lifting of Stay and Harmonize Impacted that sunscreen products with SPF shown to help prevent skin cancer or Regulations values of 15 or above be labeled with an early skin aging caused by the sun, the SPF number corresponding to the SPF statement would be followed by an Finally, we are proposing to lift the lowest number in a range of tested SPF asterisk (*) directing consumers to see stay on the 1999 Final Monograph results. For example, sunscreens testing the ‘‘Skin Cancer/Skin Aging alert’’ (subject to the revisions to parts 201, at SPF 15–19 would be labeled ‘‘SPF elsewhere on the label. Finally, to 310, 347, and 352 (21 CFR parts 201,4 15’’; those testing at 40–49 would be prevent required information from being 310, 347, and 352) described in this labeled ‘‘SPF 40.’’ We are making this obscured or overwhelmed by other document), and have proposed revisions proposal because new evidence has labeling features, we are revising the to these regulations necessary to caused us to reexamine the variability format requirements for the SPF, broad effectuate the lifting of the stay and to inherent in the SPF test (which relies on spectrum, and water resistance harmonize any impacted regulations. statements on the PDP. visual assessments of erythema in C. Legal Authority human subjects). The data we reviewed 5. Proposed Requirements Related to suggests that the clinical evaluation We are issuing this proposed rule Final Formulation Testing Processes under sections 201, 301, 501, 502, 503, undertaken during SPF testing creates and Recordkeeping variability that justifies the use of SPF 505, 510, 586E, 701, 702, 703, 704, and To ensure that FDA can assess ranges. As explained further in sections 721 of the FD&C Act (21 U.S.C. 321, compliance with our regulations, we are IX.B.4.b–c, because this variability is 331, 351, 352, 353, 355, 360, 360fff–5, proposing to require records of required exacerbated at high SPFs, we are 371, 372, 373, 374, and 379e) and under final formulation testing of sunscreen proposing that sunscreens testing at SPF section 351 of the Public Health Service products to be maintained for 1 year 30 or more be labeled in increments of Act (42 U.S.C. 262). after the product expiration date, or, if 10 (i.e., SPF 30, SPF 40, SPF 50, with D. Costs and Benefits the product is exempt from expiration a proposed maximum of SPF 60+), that dating (as most sunscreens are), for 3 If finalized, the proposed rule would sunscreens testing at SPF 15 to 29 be years after distribution of the last lot update and make effective regulations to ensure the safety and effectiveness of 3 We note that because our proposal to raise the labeled in reliance on that testing. In maximum labeled SPF value to 60+ is based on addition, we are proposing to require sunscreen products marketed under the studies that all used broad spectrum sunscreens, the responsible persons (defined in section OTC drug monograph. The rule would additional clinical benefit we are proposing to IX.D.2.b) to keep records of sunscreen update sunscreen product labeling recognize in sunscreen products with SPF values standards, address the safety of greater than 50 cannot be decoupled from the broad formulation testing, and clarifying that spectrum protection provided by those products. As required records would be subject to sunscreen active ingredients, revise and a result, our proposal to raise the maximum labeled FDA inspection. We are also proposing SPF value to SPF 60+ is both consistent with and a number of revisions to our labeling 4 We note that, for ease of comprehension, we dependent upon our proposal to require that all have included in this document the current sunscreen monograph products with SPF values of and testing regulations designed to provisions of 21 CFR 201.327 that we are not 15 and above satisfy our broad spectrum clarify FDA expectations about clinical proposing to revise along with the provisions of that requirements. final formulation testing processes and regulation that we are proposing to revise.

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clarify our expectations for testing and Abbreviation/ What it means a period of public comment, FDA recordkeeping by entities that conduct acronym publishes a tentative final monograph sunscreen testing, and address other NTP ...... National Toxicology Program of (TFM) (in the form of a proposed rule, sunscreen safety or efficacy concerns, the National Institutes of proposing conditions under which OTC like combination sunscreen-insect Health. drugs in the therapeutic class being repellents and alternative dosage forms. OMB ...... Office of Management and Budg- considered are GRASE and not et. Consumers would benefit from less OTC ...... Over-the-counter. misbranded (see § 330.10(a)(7)). exposure to sunscreen products PABA ...... Aminobenzoic acid. Following public comment on the TFM, containing active ingredients about ROS ...... Reactive oxygen species. FDA publishes a final monograph in which safety questions remain, less SIA ...... Sunscreen Innovation Act. FDA’s regulations (see 21 CFR chapter SPF ...... Sun protection factor. exposure to sunscreen products labeled TEA ...... Time and extent application. I, subchapter D) codifying the with potentially misleading sun TFM ...... Tentative final monograph. conditions under which products in the protection information, increased U.S.C...... United States Code. OTC therapeutic drug category are USP ...... United States Pharmacopeia. consumption of products with better UVA ...... Ultraviolet A. GRASE and not misbranded (see UVA protection, less exposure to UVB ...... Ultraviolet B. § 330.10(a)(9)). An OTC drug may be flammable spray sunscreens, and less legally marketed without an approved exposure to spray and powder III. Background NDA or abbreviated new drug sunscreen products posing inhalation application (ANDA) if it meets each of risks. Consumers would also experience A. FDA’s Current Regulatory Framework the conditions contained in an transaction cost savings. The costs of the In the following sections, we provide applicable final monograph, the rule to sunscreen manufacturers include a brief description of terminology used conditions contained in part 330, and administrative costs, costs to fill data in the OTC Drug Review regulations as any other applicable regulatory and gaps for active ingredients and powder well as an overview of OTC sunscreen statutory requirements for OTC drugs, dosage forms, product formulation products, their intended uses, and including the labeling requirements in testing costs, and costs to reformulate FDA’s regulation of them. part 201. d. Category I, II, and III and relabel sunscreen products. Finally, 1. Terminology testing entities would incur classifications. In the course of recordkeeping costs if they do not a. OTC drug review. The OTC Drug establishing an OTC monograph, active already maintain adequate records of Review is the process established by ingredients and other OTC drug testing equipment, methods, and FDA to evaluate the safety and conditions are classified in one of three observations in final formulation effectiveness of OTC drug products categories: Category I (conditions under testing. marketed in the United States before which a nonprescription drug in the May 11, 1972, and to establish the therapeutic category would be GRASE II. Table of Abbreviations/Commonly conditions under which they are and not misbranded), Category II Used Acronyms in This Document considered to be GRASE and not (conditions that would result in the misbranded. As described further Abbreviation/ drug being classified as not GRASE and/ acronym What it means below, the OTC Drug Review is or misbranded) and Category III generally conducted via a multiphase (conditions proposed to be excluded ANDA ...... Abbreviated new drug applica- public rulemaking process (each phase from the final monograph because tion. ANPR ...... Advance notice of proposed rule- requiring a Federal Register available data are insufficient to classify making. publication), resulting in the them as either Category I or Category II) CFR ...... Code of Federal Regulations. establishment of a monograph for an (see § 330.10(a)(6)). DART ...... Developmental and reproductive OTC therapeutic drug category. toxicity. b. Generally recognized as safe and 2. OTC Sunscreen Products Regulated DEET ...... N,N-Diethyl-meta-toluamide. Under the OTC Drug Review and Their EPA ...... Environmental Protection Agen- effective (GRASE). An OTC drug is cy. ‘‘generally recognized as safe and Intended Uses FAERS ...... FDA’s Adverse Event Reporting effective’’ if it meets each of the OTC sunscreen drugs regulated under System. FDA or Agency .. Food and Drug Administration. conditions contained in an applicable the OTC Drug Review are topically FD&C Act ...... Federal Food, Drug, and Cos- OTC final monograph, the conditions applied products indicated to help metic Act. contained in part 330 (21 CFR part 330), prevent sunburn; some are also FIFRA ...... Federal Insecticide, Fungicide, and any other applicable regulatory and indicated to decrease the risk of skin and Rodenticide Act. FR ...... Federal Register. statutory requirements for OTC drugs, cancer and early skin aging caused by GRASE ...... Generally recognized as safe including the labeling requirements in exposure to the sun’s UV radiation and effective (or general rec- part 201. (when used as directed with other sun ognition of safety and effective- c. Proposed, tentative final, and final protection measures) (see § 201.327(c)). ness). ICH ...... International Council for monographs. The proposed monograph, The active ingredients in sunscreen Harmonisation of Technical which is typically published in the form products achieve these protective effects Requirements for Pharma- of an ANPR, is the end product of the by absorbing, reflecting, and/or ceuticals for Human Use. first phase of the rulemaking process scattering radiation in the UV range IND ...... Investigational new drug applica- tion. described above. After reviewing the (from 290 to 400 nanometers (nm)) (see IRB ...... Institutional Review Board. report and recommendations of an section 586(10) of the FD&C Act (21 mL ...... Milliliter. expert advisory review panel U.S.C. 360fff(10)); see also § 352.3(c) (21 MUsT ...... Maximal usage trial. responsible for initially reviewing the NDA ...... New drug application. CFR 352.3(c)), stayed). NDAC ...... Nonprescription Drugs Advisory safety, effectiveness, and labeling of Sunscreen products must be labeled Committee. products in a given therapeutic with an SPF value calculated using a Ng ...... Nanogram. category, FDA publishes a proposed standardized SPF testing procedure set Nm ...... Nanometer. NOAEL ...... No observed adverse effect level. monograph (together with the report forth in FDA regulations (in NPIC ...... National Pesticide Information and recommendations of the expert § 201.327(i)). As discussed in further Center. review panel) (see § 330.10(a)(6)). After detail in section IX.B.1, the SPF test

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measures the amount of UV radiation sunscreen active ingredients 6 that the TABLE 1—SUNSCREEN ACTIVE INGRE- exposure it takes to cause sunburn when panel recommended for classification as DIENTS INCLUDED IN THE STAYED a person is using a sunscreen when GRASE when used under the conditions 1999 FINAL MONOGRAPH compared with how much UV exposure described in the panel’s report (43 FR it takes to cause sunburn when the 38206 at 38219). In 1993, having Maximum person is not using a sunscreen. Because reviewed the panel’s report and related Active ingredient concentration SPF values represent a sunscreen’s level public comments, FDA published a (%) of sunburn protection, they are TFM (58 FR 28194, May 12, 1993) which (with one exception—padimate Aminobenzoic acid (PABA) .. 15 primarily (though not exclusively) an Avobenzone ...... 3 indicator of expected protection from A) proposed as GRASE all of the active Cinoxate ...... 3 UVB radiation (see section IX.B.1 for a ingredients that had been included in Dioxybenzone ...... 3 discussion of both UVB and UVA the ANPR. The TFM also included Ensulizole ...... 4 radiation). specified maximum concentrations at Homosalate ...... 15 which the proposed ingredients would Meradimate ...... 5 To pass FDA’s current test for the be considered GRASE for use in Octinoxate ...... 7.5 inclusion of the term ‘‘broad spectrum’’ sunscreens. Octisalate ...... 5 in labeling (which was established in In the years following the publication Octocrylene ...... 10 the 2011 L&E Final Rule), sunscreen of the 1993 TFM, FDA removed several Oxybenzone ...... 6 products must demonstrate that, in additional ingredients from the TFM Padimate O ...... 8 addition to UVB protection, they also (see 59 FR 29706, June 8, 1994), as Sulisobenzone ...... 10 provide UVA protection. Further, only Titanium dioxide ...... 25 described at 64 FR 27666 at 27681, and Trolamine salicylate ...... 12 products that have been demonstrated 7 proposed the inclusion of two more. In Zinc oxide ...... 25 both to provide broad spectrum 1999, FDA published a final sunscreen protection and to have a minimum SPF monograph, which included the Among other things, the Stayed 1999 value of 15 have been shown to reduce following 16 sunscreen active Final Monograph established a the risk of skin cancer and early skin ingredients along with the conditions minimum SPF value of 2, and an SPF aging caused by the sun (when used as (including maximum concentrations) of 30+ as the maximum labeled SPF directed with other sun protection under which these ingredients would be value (64 FR 27666). FDA concluded measures). By contrast, sunscreens that considered GRASE for use in that the above-listed ingredients (at the have not been demonstrated to provide 8 sunscreens: listed concentrations) could also be both broad spectrum protection and an used in combination, with limited SPF value of at least 15 have only been 6 The ingredients were: Aminobenzoic acid, exceptions, provided that each active demonstrated to help prevent sunburn.5 digalloyl trioleate, 2-ethylhexyl 2-cyano-3,3- ingredient contributed a minimum SPF Thus, under the 2011 L&E Final Rule, diphenylacrylate, glyceryl aminobenzoate, menthyl anthranilate, padimate O, sulisobenzone, cinoxate, of 2 to the finished product (64 FR passing the broad spectrum test in dioxybenzone, ethylhexyl p-methoxycinnamate, 27666).9 § 201.327(j) (21 CFR 201.327(j)) is homosalate, oxybenzone, 2-phenylbenzimidazole-5- The effective date for complying with necessary, but not itself sufficient, to sulfonic acid, titanium dioxide, diethanoloamine p- methoxycinnamate, ethyl 4-[bis (hydroxylpropyl)] the Stayed 1999 Final Monograph was support inclusion of a skin cancer aminobenzoate, 2-ethylhexyl salicylate, lawsone May 21, 2001. This deadline was indication in labeling, although any with dihydroxyacetone, padimate A, red extended (65 FR 36319, June 8, 2000) product that passes the broad spectrum petrolatum, and triethanolamine salicylate. 7 and then stayed until further notice (66 test may be labeled with the term In 61 FR 48645 (September 16, 1996) (proposing that avobenzone is GRASE up to 3 percent alone FR 67485, December 31, 2001) to ‘‘Broad Spectrum’’ in conjunction with and 2 to 3 percent when in combination with provide additional time to resolve its SPF value. cinoxate, diethanolamine methoxycinnamate, dioxybenzone, homosolate, octocrylene, octyl various outstanding issues, such as the B. History of This Rulemaking methoxycinnamate, octyl salicylate, oxybenzone, labeling and testing of finished OTC sulisobenzone, and/or trolamine salicylate) and 63 sunscreen products. As a result, the 1. The OTC Sunscreen Drug Review and FR 56584 (October 22, 1998) (proposing that zinc FDA’s Regulation of OTC Sunscreen oxide is GRASE alone or in combination with any Drug Products previously proposed GRASE active ingredient ingredients, and the current compendial names are except avobenzone). The list of active ingredients used throughout this document. Because the 2002 was (and would continue to be) modified because final rule that changed those names was published Our initial call for safety and efficacy of, among other things, a lack of interest in after part 352 was stayed, however, those data for sunscreen products was issued developing United States Pharmacopeia (USP) amendments have not yet been incorporated into in 1972 (37 FR 26456, December 12, compendial monographs for certain of the active the published monograph regulation. 1972). The resulting data submissions ingredients originally proposed (see 64 FR 27666 at 9 An exception to this rule involving avobenzone was retained from the TFM: The Stayed 1999 Final were reviewed by the Advisory Review 27681). 8 See § 352.10, now stayed; 64 FR 27666. The Monograph stated that avobenzone may not be Panel on OTC Topical Analgesic, active ingredient names used in that regulation, as combined with PABA, phenylbenzimidazole Antirheumatic, Otic, Burn, and Sunburn originally published, differ from those used in table sulfonic acid, menthyl anthranilate, padimate O, Prevention and Treatment Products, 1, which are the current established names for these titanium dioxide, or zinc oxide. In 2007, we active ingredients. We note that subsequent to the proposed to include in the monograph a condition whose panel report and recommended publication of the Stayed 1999 Final Monograph, permitting the marketing of sunscreens containing monograph were published as an ANPR we issued another final rule in 2002 amending the avobenzone in combination with either zinc oxide in 1978 (43 FR 38206, August 25, 1978). names used for four of those ingredients to make or ensulizole based on safety and effectiveness data The ANPR contained a list of the 21 them consistent with the renaming of those about these combinations provided to the docket ingredients in the corresponding USP monographs (‘‘Sunscreen Drug Products for Over-the-Counter (67 FR 41821 at 41823, June 20, 2002). Under Human Use: Proposed Amendment of Final 5 As described in further detail in section IXB.2, section 502(e) of the FD&C Act, drug labels are Monograph’’, 72 FR 49070 at 49074, August 27, in the time since the L&E Final Rule was issued in required to bear the established name of each active 2007). As described in section VII.A, we now 2011, the body of evidence about the role of UVA ingredient, and if FDA has not designated an anticipate finalizing a monograph that would radiation in the development of skin cancer has official name under section 508 of the FD&C Act (21 permit all listed active ingredients to be combined grown. As a result, FDA is making a number of U.S.C. 358), the compendial name is the established without limitation. This approach is consistent with proposals designed (among other things) to couple name. To comply with section 502(e) of the FD&C the approach to sunscreen combinations generally a greater magnitude of UVA protection to increases Act, sunscreen drug products must therefore bear taken throughout the OTC Drug Review for in SPF values. the current compendial names for their active sunscreens.

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Stayed 1999 Final Monograph has never poses a potential health hazard to the in the FD&C Act (see section 760 (21 been in effect. consumer, FDA generally does not U.S.C. 379aa)), and the provisions of the In 2011, FDA published a draft intend to object to the marketing of OTC FD&C Act addressing adulteration; and guidance for industry, ‘‘Enforcement sunscreen products that do not have an (4) follow applicable labeling and Policy—OTC Sunscreen Drug Products approved NDA or ANDA provided that testing requirements for OTC sunscreens Marketed Without an Approved they: (1) Contain as sunscreen active set forth in § 201.327. Application,’’ addressing the ingredients only the active ingredients 2. Recent Significant Rulemakings circumstances under which FDA or combinations of active ingredients Relevant to This Proposed Rule intended to exercise its enforcement listed in 21 CFR 352.10 and 352.20 discretion with respect to certain (both currently stayed); (2) do not make Since publishing the Stayed 1999 marketed OTC sunscreen products in claims addressed in §§ 201.327(c)(3) and Final Monograph, FDA has issued a the period until a final OTC sunscreen (g) and 310.545(a)(29)(ii); (3) comply number of Federal Register notices monograph becomes effective. This with the requirements for OTC drugs set relating to OTC sunscreens. Major guidance was finalized in May 2018 forth in part 201 and § 330.1 (21 CFR notices pertinent to today’s proposed (2018 Final Guidance) (Ref. 1). Unless 330.1), the requirements for adverse rule are summarized briefly in table 2 the failure to pursue regulatory action event reporting for OTC drugs set forth below: TABLE 2—RECENT SIGNIFICANT Federal Register NOTICES PERTINENT TO THIS RULE

Federal Register notice Information in notice

Insect Repellent-Sunscreen Drug Prod- We issued a notice stating that we were considering amending the Stayed 1999 Final Monograph to include conditions for ucts for Over-the-Counter Human Use: marketing insect repellent-sunscreen drug products and requested information to form a regulatory position on these Request for Information and Com- products. The Environmental Protection Agency, which regulates the insect repellent component of insect repellent-sun- ments; 72 FR 7941, February 22, 2007. screen combinations, published a similar notice concurrently with ours, also seeking information and comment on these products. Sunscreen Drug Products for Over-the- We proposed to amend the Stayed 1999 Final Monograph to address, among other things, formulation, labeling, and test- Counter Human Use: Proposed ing requirements for both UVA and UVB radiation protection. Amendment of Final Monograph; 72 FR 49070, August 27, 2007. Labeling and Effectiveness Testing: Sun- We issued a final rule establishing labeling and testing requirements for sunscreen products. Among other things, the L&E screen Drug Products for Over-the- Final Rule established optional broad spectrum labeling, created an optional indication relating to decreasing the risk of Counter Human Use (L&E Final Rule); skin cancer and early skin aging for broad spectrum products with an SPF of 15 or higher, and required a labeling 76 FR 35620, June 17, 2011. warning for sunscreens that did not both satisfy the broad spectrum test and provide an SPF of at least 15. 2011 Proposed Rule: Revised Effective- We proposed to raise the limit on the maximum permissible labeled SPF value for sunscreen products to ‘‘50+.’’ Among ness Determination (Max SPF PR); 76 other things, we sought comment on the appropriateness of a formulation cap for sunscreen products. FR 35672, June 17, 2011. 2011 ANPR and Request for Data and We issued an ANPR describing the sunscreen dosage forms that we considered to be part of the OTC Drug Review and Information on Certain Dosage Forms; thus eligible for potential inclusion in a sunscreen monograph, as well as those dosage forms that we did not consider 76 FR 35669, June 17, 2011. eligible. We requested data to enable us to ensure that the administrative record would be adequate to support GRASE determinations for the eligible sunscreen dosage forms. In particular, we emphasized that additional safety and efficacy data would be needed to support final monograph status for spray dosage forms. We also announced that we were issuing a draft guidance document (discussed above) explaining the Agency’s intended enforcement policy for sun- screens marketed pursuant to the monograph system, including with respect to dosage forms. The Agency’s approach to enforcement of spray sunscreens is now described in the 2018 Final Guidance.

IV. Scope of This Rulemaking containing active ingredients listed in suggesting that it is necessary to revisit the Stayed 1999 Final Monograph. It its prior decision about the effectiveness Eligibility for inclusion in an OTC does not address the pending sunscreen of the active ingredients at this time. monograph was originally limited to active ingredients that were originally active ingredients and other conditions submitted under the procedures V. Legal Authority that had been used in drugs marketed in established in the TEA regulation and the United States prior to the inception We are issuing this proposed rule are now being addressed through the of the OTC Drug Review in 1972. After under sections 201, 301, 501, 502, 503, SIA process.10 As discussed further in publication of the final sunscreen 505, 510, 586E, 701, 702, 703, 704, and section VII, however, the safety data we monograph in 1999, FDA published its 721 of the FD&C Act and under section described as necessary to evaluate the TEA regulation (§ 330.14), (67 FR 3060 351 of the Public Health Service Act (42 safety and effectiveness of sunscreen at 3074, January 23, 2002), which sets U.S.C. 262). forth criteria and procedures by which products containing those active OTC drugs initially marketed in the ingredients are the same as what we are VI. Need for Additional Safety United States after the OTC Drug now describing as needed to establish Information Review began and OTC drugs without that the active ingredients listed in the Stayed 1999 Final Monograph are A. Increased Consumer Exposure to any U.S. marketing experience can be Sunscreen Active Ingredients considered for inclusion in the OTC GRASE for use in sunscreen products. drug monograph system. Congress later We are not revisiting the contribution Consumer exposure to sunscreen passed the SIA, which, among other that the active ingredients listed in the active ingredients has increased Stayed 1999 Final Monograph make to things, supplements FDA’s TEA dramatically since FDA began its initial the effectiveness of sunscreens. The regulations for OTC sunscreen drug safety evaluations of the sunscreen Agency has not received information products (21 U.S.C. 360fff through active ingredients at issue in this 360fff–7) (2014). proposed rule. Many factors have 10 FDA’s proposed sunscreen orders on each of This proposed rule addresses the these ingredients can be found at https:// influenced this increase, including the GRASE status (and conditions of use www.fda.gov/drugs/guidancecompliance following: applicable to) sunscreen drug products regulatoryinformation/ucm434843.htm.

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• Significant increases in the number more active ingredients combined general recognition of safety and and types of consumers using together in higher concentrations than effectiveness as set forth in § 330.10. sunscreen products (Refs. 2 and 3) were generally combined in products VII. Framework for Evaluation of • Sunscreen products containing a when FDA’s review of OTC sunscreens Safety Data greater number of active ingredients at began. Increased knowledge about the greater concentrations (Ref. 4) role of UVA radiation in causing skin In light of these safety concerns, FDA • Increased awareness of the risks of damage has also encouraged the held a meeting of its Nonprescription sun exposure and encouragement of formulation of broad spectrum products Drugs Advisory Committee (NDAC) on routine sunscreen use by medical and with combinations of active ingredients September 4 and 5, 2014, to discuss the public health authorities (see, e.g., designed to achieve protection against scope of safety testing that should be Ref. 5) both UVA and UVB radiation. In conducted to support general • Evolving directions for use on addition, other widely used products, recognition of safety and effectiveness sunscreen products instructing such as facial makeup, moisturizing for active ingredients for use in consumers to use greater amounts of creams, and lipsticks, have had nonprescription sunscreen products. sunscreen per application and to sunscreen active ingredients added to FDA proposed the following safety reapply sunscreen products more their formulations. These trends are testing paradigm: frequently (76 FR 35672 at 35678), reflected in the evolution of the current Clinical data: codified as § 201.327) labeling provisions for sunscreen • Dermal irritation and sensitization • Expanding availability and use of products regulated under the OTC testing many different types of sunscreen monograph system. • Phototoxicity and products, including daily-use Changes in the instructions for using photoallergenicity testing products such as facial makeup, these sunscreen products have also • Human maximal use bioavailability moisturizing creams, and lipstick contributed to increased use of, and studies Relatively few sunscreen products exposure to, sunscreen active • Postmarketing adverse event reports were in use when the U.S. Army ingredients. The labeling recommended Nonclinical (toxicology) data: initially funded research into the by the advisory panel in 1978 simply • Dermal carcinogenicity development of effective sunscreen instructed consumers to apply • Systemic carcinogenicity products for use by military personnel sunscreen products liberally and to • Developmental and reproductive on aircraft carriers (and others routinely reapply after swimming or excess toxicity (DART) exposed to long periods of intense perspiration (43 FR 38206 at 38215). • Toxicokinetics sunlight) during World War II (Ref. 2). The labeling currently required, by • Additional testing when data The reach of sunscreen products began contrast, encourages consumers to suggest a concern about other long- to broaden when they were later always use a broad spectrum SPF 15 or term effects, such as endocrine marketed for use specifically by higher product, to use sunscreen effects consumers who sunburned readily (i.e., products regularly, and to apply them There was consensus among the fair-skinned individuals) in situations of generously/liberally 15 minutes before committee members that FDA’s intentional sun exposure, such as sun exposure and at least every 2 hours proposed framework was a good starting sunbathing on a beach (Ref. 6). or more frequently when swimming or point (Ref. 10). In November 2015, FDA Sunscreen products are now routinely sweating (§ 201.327(e)). published a draft guidance for industry, used by a much broader range of B. Emerging Safety Concerns ‘‘Over-the-Counter Sunscreens: Safety consumers for protection against many and Effectiveness Data’’ (Draft Safety types of sun-induced skin damage, not In recent years, a growing body of and Effectiveness Data Guidance) (see just sunburn. Accumulating data data has suggested that the transdermal 80 FR 72975, November 23, 2015), demonstrate that increased sun absorption of some sunscreen active which described and requested exposure increases the risk of ingredients is greater than previously comment on the safety and effectiveness developing skin cancers and premature thought, and thus may raise previously data necessary to determine whether an skin aging (Ref. 2). To help reduce the unevaluated safety concerns, including OTC sunscreen active ingredient or risk of these types of sun-induced skin the potential for reproductive, combination of active ingredients damage, public health organizations developmental, or carcinogenic effects. evaluated under the SIA was GRASE (including FDA) have for years urged As discussed in further detail in section when used under specified conditions. consumers to use sunscreen products VIII.C.1.a, newly available information FDA finalized this guidance in along with other sun-protective suggests, for example, that there is the November 2016, after considering behaviors like limiting time in the sun potential for toxicity associated with the public comment on its draft and wearing protective clothing (Refs. 7, transdermal absorption and systemic recommendations (Ref. 11).11 The 8, and 9). availability of oxybenzone. This new recommendations in this guidance Another factor driving increased information about absorption and reflect FDA’s scientific expertise, consumer exposure to sunscreen active potential safety risks is inadequate, by existing technical guidance, experience ingredients has been the introduction itself, to support an affirmative from reviewing safety and efficacy data and widespread adoption of sunscreen conclusion that products containing the submitted for GRASE review of products with higher labeled SPF active ingredients at issue are not safe. sunscreen active ingredients under the values. The maximum SPF value Coupled with the lack of clinical OTC Drug Review, and input from and proposed for sunscreen labeling has pharmacology and nonclinical safety progressively increased from SPF 15 in data for certain sunscreen active 11 FDA’s recommendations regarding the safety the 1978 panel report, to SPF 30+ in the ingredients, however, it leads us to and effectiveness data necessary to determine Stayed 1999 Final Monograph, to SPF conclude that, for some sunscreen active whether an OTC sunscreen active ingredient (or ingredients, the current record does not combination of ingredients) evaluated under the 50+ in the 2011 Max SPF PR. To achieve SIA was GRASE when used under specified these higher SPFs, many currently include adequate evidence of safety to conditions generally remained unchanged in the marketed products are formulated with satisfy the applicable legal standards for final guidance.

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concurrence by outside scientific important for FDA to balance the toxicity). Additional testing beyond experts. potential benefits of these sunscreen what is described below may be All sunscreens marketed without an products to consumers against their recommended for active ingredients for NDA are subject to the same standard: potential risks. Providing an adequate which data suggest a concern about General recognition of safety and safety margin for OTC sunscreen active other long-term effects, such as effectiveness. Accordingly, as noted ingredients and finished sunscreen hormonal disruption. previously, the data that we expect to be products is a key element of FDA’s risk In addition, although sunscreen necessary to evaluate the safety and assessment. A safety margin calculation products are typically formulated with effectiveness of the sunscreen takes the highest animal NOAEL and two or more active ingredients, the monograph active ingredients are the estimates a maximum safe level of framework described below same as those we recommended as exposure for humans. Because animal contemplates that testing will be necessary to evaluate the safety and studies do not always predict effects in performed using formulations that effectiveness of sunscreen active humans, the actual threshold for an include one active ingredient. ingredients previously considered under effect in humans may be different (i.e., Generally, unless data suggest that there the procedures established in the TEA higher or lower) than in the species may be a safety or efficacy concern with regulation and now being considered tested. The human sensitivity to a drug a particular combination of active pursuant to the framework established is often unknown. To account for this, ingredients, we anticipate that an active by the SIA (see Safety and Effectiveness the predicted safe exposure level in ingredient that is found to be GRASE for Data Guidance (Ref. 11)). humans that is reflected in the safety use in sunscreens could be combined The studies described in this section margin is well below where toxicities with other active ingredients that are are generally needed for FDA to were seen in animals. also GRASE for use in sunscreens. If determine that a sunscreen active In determining the specific testing data suggest that there may be a safety ingredient is GRASE for use in and other data needed to adequately or efficacy concern with a particular nonprescription sunscreens. Specific demonstrate that an OTC sunscreen combination of active ingredients (or data gaps for individual active active ingredient is safe, FDA considers active and inactive ingredients), ingredients depend on the quality and both the circumstances under which additional data may be necessary to quantity of available safety data, and are OTC sunscreen products are intended to support a positive GRASE identified in section VIII. As described be used by consumers (i.e., the determination for sunscreens containing in that section, those active ingredients conditions of use) and current scientific that combination. for which the existing public record knowledge and assessment technology. The following sections describe the contains sufficient data to support a FDA’s approach to the clinical safety specific safety data that FDA expects the positive GRASE finding are proposed as evaluation of OTC sunscreen active Agency will need to determine whether Category I. Those for which additional ingredients is based on our current an active ingredient is GRASE for use in data are necessary are proposed as scientific understanding regarding sunscreens. Category III. In addition, in evaluating safety evaluation of topical drug the existing safety data for the active products for chronic use, and thus is B. Clinical Safety Testing ingredients listed in the Stayed 1999 generally consistent with the safety data 1. Human Dermal Safety Studies Final Monograph, FDA determined that requirements that would apply to an Human dermal safety studies for the risks associated with two of these NDA for a chronic-use topical drug topical products in which exposure to ingredients outweigh their benefits. As product (i.e., topical safety studies light after application is anticipated discussed in further detail in section (irritation, sensitization, and generally consist of two sets of studies— VIII.B, FDA is therefore proposing that photosafety); bioavailability those conducted without specific these two ingredients are Category II (absorption); and evaluation of adverse exposure to light and those conducted because sunscreens containing these events observed in clinical studies).12 In to assess reactions after UV exposure ingredients would not be GRASE. addition, the evaluation of adverse (photosafety studies) (Ref. 12). The events reported during the commercial A. General studies usually consist of dermal marketing of sunscreen products FDA’s OTC drug regulations identify irritation patch testing, dermal containing the ingredient and other the general types of safety information sensitization patch testing, dermal postmarketing safety information is also that should be submitted as evidence phototoxicity testing, and dermal relevant to safety. that an OTC drug is GRASE for use as FDA’s approach to the nonclinical photoallergenicity testing. Because marketed sunscreen products labeled (§ 330.10(a)(2)) and the standard safety evaluation of these active typically contain a combination of by which safety is to be judged ingredients takes into account their active ingredients, and product (§ 330.10(a)(4)(i)). When applying these lengthy marketing history in the United formulations frequently change, it is regulations to each drug, FDA uses its States. In contrast to nonclinical data difficult to determine causal links scientific expertise to determine what requirements for a chronic-use topical between individual active ingredients constitutes ‘‘adequate tests by methods drug product NDA, which include and reported irritation and reasonably applicable to show the drug results from comprehensive nonclinical hypersensitivity adverse events is safe under the prescribed, pharmacology and toxicology safety associated with a particular product. recommended, or suggested conditions testing, the approach to nonclinical Therefore, FDA generally expects to use of use’’ (§ 330.10(a)(4)(i)). safety testing in this proposed rule is FDA recognizes the contribution that data from human dermal irritation largely focused on potential long-term broad spectrum sunscreens with an SPF studies, human dermal sensitization adverse effects or effects not otherwise value of 15 or higher can make to studies, and human dermal photosafety readily detected from human use (i.e., decreasing the risk of skin cancer and studies, in conjunction with carcinogenicity and reproductive early skin aging caused by the sun if postmarketing adverse event data, to used as directed with other sun 12 Chronic use is defined as continuous or inform GRASE determinations and protection measures. To protect the intermittent use for at least 6 months during the labeling. Nonetheless, in some cases, it public health, however, it is also course of a lifetime. may be reasonable to omit human

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dermal irritation studies, human dermal sufficient number of subjects are enhancement by solvent effects on the sensitization studies, and/or human included for sensitization evaluation. lipids in the stratum corneum. Products dermal photosafety studies, depending b. Human photosafety studies. absorbed through the skin have the on the rigor of available postmarketing Topically applied dermatologic drug potential to cause systemic adverse safety information. For example, if FDA products should be tested for effects, affecting the safety assessment. concludes that there is a positive risk- photosafety if they absorb light in the Because sunscreens are intended to benefit profile for a sunscreen active UVA, UVB, or visible spectra. work at the skin’s surface, systemic ingredient, but that it is known to be a Photosafety evaluations of sunscreen absorption may also lower efficacy, sensitizer, it may be possible to develop active ingredients that absorb light affecting the efficacy assessment. Such safety labeling to address this risk should consist of skin considerations ultimately weigh into the without data generated in the human photoallergenicity and skin risk-benefit calculus FDA uses to dermal safety studies described below phototoxicity testing. Photoallergy is an determine whether an OTC sunscreen (see, e.g., section VIII.C.1.a). immunologically mediated reaction to a containing a given active ingredient is a. Human dermal irritation and chemical, initiated by the formation of GRASE. sensitization studies. Studies of dermal photoproducts (e.g., protein adducts) Since the mid-1990s, topical product irritation and sensitization, using the following a photochemical reaction. NDAs have included a Maximal Usage repeat insult patch test or other relevant Similar to dermal sensitivity testing Trial (MUsT) as part of the clinical tests, are elements in the safety described above, photoallergy tests use pharmacology/bioavailability evaluation of topical drug products that, an induction/rest/challenge/rechallenge assessment. A MUsT is designed to like sunscreens, are applied to the skin multiphase design to assess erythema, capture the effect of maximal use on repeatedly over long periods of time. edema, and vesiculation. Phototoxicity absorption into the blood with standard Designed to detect the potential for local (or photoirritation) is an acute light- pharmacokinetic assessments (e.g., Cmax, 13 dermatologic events with fewer subjects induced tissue response to a Tmax, area under the curve, half-life, than might be observed in larger clinical photoreactive chemical. Phototoxicity clearance, and volume of distribution) trials, these tests often employ product testing typically includes a test patch, a (for further information about conduct application that is more frequent and/or vehicle patch, and a sham patch of a MUsT, see Ref. 13). For a topical for longer duration than proposed application for 24 hours, followed by product NDA, the MUsT is usually clinical dosing. In dermal irritation UV light exposure of the test area. A conducted in subjects with the disease studies, a test substance is applied to a second set of patch application areas not of interest, where disrupted skin is a small pad (patch) and affixed to the test irradiated with light serves as a control. feature. In situations where disrupted subject’s skin, usually on the back, to FDA expects that, to support a GRASE skin is not a feature of the condition determine whether the ingredient finding, photosafety studies of being treated or the topical product is causes direct skin toxicity. Dermal sunscreen active ingredients that absorb intended for prevention of disease (e.g., sensitization studies are conducted light will need to be conducted using sunscreens), the MUsT for a topical similarly but are designed to detect the active ingredient at the highest product NDA should be conducted in immunologically mediated reactions, concentration for which a GRASE subjects with healthy, intact skin. The which require prior exposure to the determination is sought in an MUsT for a topical product NDA is allergen. appropriate vehicle, using the vehicle conducted with the specific product Nonprescription sunscreens regulated alone, and with a negative control. formulation for which approval is under the OTC monograph system may sought applied at the upper limit of be used in many product formulations, 2. Human Absorption Studies/Maximal Usage Trial surface area involvement that is studied including those yet unknown. in the phase 3 clinical trials and is Therefore, cumulative irritation studies Because nonprescription sunscreens proposed for labeling. For example, if that evaluate the sunscreen active are topically applied, a critical safety the proposed labeling of an acne ingredient at the highest concentration consideration is whether dermal product permits the product to be used for which a GRASE determination is application results in skin penetration on up to 30 percent of body surface area, sought should be conducted using the and systemic exposure to their active that would be the coverage evaluated in ingredient in an appropriate vehicle, ingredients and, if so, to what extent. the MUsT. using the vehicle alone, and using both This information helps identify We expect that data from a MUsT will negative and positive controls. The potential safety concerns and helps be needed to support an adequate evaluation should include scoring of determine whether an adequate safety assessment of safety for most sunscreen erythema, edema, and a papular margin exists within which an active active ingredients (Ref. 10). Because response or skin erosion. ingredient is GRASE for use in sunscreen products regulated pursuant Dermal sensitization studies, sunscreens. to the OTC monograph system may conducted to detect immunologically The principal barrier to topical drug include active ingredients in a variety of mediated reactions, should be product penetration is the multilayered, formulations, FDA recommends that a conducted in three phases: (1) The lipid-rich stratum corneum. The passage MUsT be conducted under maximal use induction phase (3 weekly applications of any drug product through this layer conditions employing a minimum of for 3 weeks); (2) the rest phase (no is influenced by many factors, including four formulations, containing the product application for 10 to 14 days); the drug product’s physicochemical sunscreen active ingredient as the only and (3) the challenge phase (patch features, molecular weight, and vehicle/ active ingredient.14 These formulations applications to new sites for 48 hours formulation properties. Vehicle/

formulation properties are particularly 13 with a confirmatory rechallenge to Cmax is the peak plasma concentration and Tmax exclude false positives). important because the choice of vehicle is the time to peak plasma concentration. Although FDA recommends separate can markedly affect the permeation 14 We note, however, as described in section dermal irritation and sensitization potential of a drug product. Effects can VIII.C.1.b, that because of avobenzone’s potential for photodegradation, we recommend that a MUsT studies, it may be appropriate to range from simple hydration of the for avobenzone evaluate avobenzone in combine irritation and sensitization stratum corneum by occlusive vehicles/ combination with a photostabilizer. In some cases, studies in the same study as long as a formulations to direct permeation Continued

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should be prepared using vehicle/ penetration of the ingredient has taken within an acceptable range for this formulation systems that are appropriate place and to optimize the chances of the population. for sunscreen topical products (e.g., they ingredient being detected. Thus, for C. Nonclinical Safety Testing are deployable and spreadable) that sunscreen active ingredients, FDA represent real-world marketed expects that single application studies 1. Carcinogenicity Studies: Dermal and formulations, and that are expected to would be inadequate. Because the Systemic produce the highest in vivo absorption. subjects in a MUsT represent an FDA generally recommends Justification for the formulations enriched dataset in the upper range of carcinogenicity studies for any chosen, including results of in vitro exposures, safety-related data (such as pharmaceutical with an expected testing using a human cadaver skin vital signs, adverse events) from the clinical use (either intermittent or permeation system (e.g., static cell, also study’s regularly scheduled physical continuous) of at least 6 months (Ref. known as vertical diffusion cell) (Refs. examinations should also be collected. 17). The animal carcinogenicity studies 14 and 15), should be included in the We strongly encourage consultation help characterize the potential tumor study protocol. The protocol should with FDA about MUsT protocols before risks associated with use of a sunscreen contain sufficient detail for others to beginning the trial. active ingredient in human beings by Finally, as discussed further in reproduce the formulations and identifying any observed tumors by 15 section VIII.D, if the sunscreen active manufacturing process. type, the level of exposure at which FDA anticipates that the use of ingredient is determined to be GRASE tumors occur, and the highest level of multiple formulations will help identify for use in sunscreens, the sunscreen exposure at which no adverse effects the overall absorption potential of the monograph, when finalized, must set occur, referred to as the NOAEL. As sunscreen active ingredient of interest. out the conditions under which any The MUsT should be conducted in future sunscreen containing that active noted earlier, FDA intends to use the subjects with healthy, intact skin 16 at ingredient will be GRASE and not NOAEL in determining the safety the highest concentration of the misbranded. As such a condition, FDA margin for human exposure to ingredient for which a GRASE is considering certain final formulation sunscreens containing the active determination is sought. Based on testing to address the potential for ingredient. In addition to detecting recommended sunscreen use on all transdermal absorption and its impact carcinogenic potential, carcinogenicity exposed skin, the exposed area should on safety. FDA anticipates that the studies in animals can also help to include at least 75 percent of the body formulation that produces the highest in identify other systemic or organ surface area. Data from the formulation vivo absorption in the MUsT would be toxicities that may be associated with that produces the highest in vivo appropriate to designate as a standard the sunscreen active ingredient. absorption would then be used to control formulation for future in vitro FDA expects that a dermal determine the safety margin. human cadaver skin permeation system carcinogenicity study involving The assay used in the MUsT should testing (e.g., a static or vertical diffusion application of the test article to the skin be properly validated according to cell) of each final sunscreen formulation of mice or rats for 2 years will thus need current good laboratory practices (21 that includes that active ingredient. If to be conducted to support a GRASE CFR part 58). Additionally, the Agency’s such testing were included as a finding for the active ingredient unless most current guidance on bioanalytical condition in a final sunscreen the ingredient has been demonstrated method validation may be found by monograph, and if in vitro permeation not to reach the viable layers of the skin searching at https://www.fda.gov/ of the sunscreen active ingredient in the where it could impact skin tumor RegulatoryInformation/Guidances/ final product formulation were equal to development. FDA also considers it default.htm. The assay’s limit of or less than the value from in vitro important to study the effects of quantitation-limit of detection should be testing of the standard control systemic exposure if human sufficiently low to allow a signal-to- formulation (that was shown by the bioavailability data show that dermal noise ratio that ensures confidence in MUsT to have the highest degree of application of a particular formulation detection of a concentration of 0.5 systemic absorption), FDA anticipates results in skin penetration and systemic nanogram (ng)/milliliter (mL) for the that the safety margin previously exposure to the active ingredient. compound of interest in the receptor calculated would be considered Therefore, we expect that a second fluid. adequate to support the safety of the carcinogenicity study by a route that An important consideration for finished formulation. produces systemic exposure will also be designing a MUsT is that it should needed to support the safety of a include testing for a duration that 3. Pediatric Considerations sunscreen active ingredient, if systemic allows for the attainment of steady state Young children have a larger ratio of exposure is observed in the levels to ensure that maximum skin surface to body volume than adults, bioavailability data. This can be a 2-year which can increase a child’s systemic study or a shorter (usually 6 months) sunscreen active ingredients (e.g., octocrylene) can exposure to topically applied drug alternative carcinogenicity model, and it serve as photostabilizers. In such cases, we expect products. In addition, growing children should be conducted in a species that the MUsT could include such ingredients. have greater potential to experience different from that used in the dermal 15 FDA has issued draft guidance with recommendations for the conduct of MUsT studies deleterious developmental effects from carcinogenicity study. FDA notes that to support the safety of active ingredients that are drug exposure. If the calculated safety the absence of a carcinogenicity signal candidates for inclusion in a topical drug product margin for an active ingredient (based from an alternative transgenic under an OTC Drug monograph (Ref. 16). When on nonclinical results and human carcinogenicity study (e.g., TgRasH2 finalized, this guidance will represent FDA’s current thinking on this topic. FDA also encourages MUsT) is relatively small, FDA will mouse) would likely support the safety persons who are interested in conducting a MUsT exercise its scientific judgment to of a sunscreen active ingredient. If a to support the safety of an active ingredient to determine whether a sunscreen active carcinogenicity signal were observed in discuss proposed protocols with the Agency. ingredient MUsT in young children or such a study, however, the study could 16 As discussed infra, the MUsT should be conducted on healthy, intact skin because other studies are warranted to ensure not be used to support the safety of a sunscreens are intended for prevention rather than that the safety margin for marketed sunscreen active ingredient because treatment. products containing the ingredient is there would be no basis for calculating

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a safety margin with this study (Ref. 18). conducted toxicology program produces applications in a wide range of All carcinogenicity studies, regardless of no signals indicating that the ingredient products, including OTC sunscreens. route, should assess a full panel of (including its clinically relevant Such materials generally have tissues.17 metabolites) or any known structurally dimensions between approximately 1 FDA expects that a systemic similar compound interacts with related and 100 nm (Ref. 23). Materials at such carcinogenicity study would not be pathways.18 We expect that effects on small sizes can have different chemical needed to support a GRASE embryofetal development will need to or physical properties or biological determination for a sunscreen active be assessed in rats and rabbits in all effects compared to larger-scale ingredient if an adequately conducted cases. counterparts, making possible a variety human pharmacokinetic MUsT resulted Gestational and neonatal stages of of functional effects, and also in a steady state blood level less than development may be particularly potentially affecting the safety, 0.5 ng/mL, and an adequately sensitive to active ingredients with effectiveness, or regulatory status of conducted toxicology program did not hormonal activity (endocrine FDA-regulated products. reveal any other safety signals for the disruption). For this reason, these FDA has not established regulatory ingredient or any known structurally studies should include assessments of definitions of nanotechnology, similar compound indicating the endpoints such as vaginal patency, nanomaterial, nanoscale, or other potential for adverse effects at lower preputial separation, anogenital related terms. As described in FDA’s levels. The threshold value of 0.5 ng/mL distance, and nipple retention, which guidance for industry ‘‘Considering is based on the assessment that the level can be incorporated into traditional Whether an FDA-Regulated Product would approximate the highest plasma DART study designs to assess potential Involves the Application of level below which the carcinogenic risk hormonal effects on the developing Nanotechnology’’ (Nanotechnology of any unknown compound would be offspring. Behavioral assessments (e.g., Considerations Guidance) (Ref. 24), at less than 1 in 100,000 after a single mating behavior) of offspring, which this time, when considering whether an dose. This threshold value is consistent may detect neuroendocrine effects, FDA-regulated product involves the with the Threshold of Toxicological should also be performed (Ref. 21). application of nanotechnology, FDA Concern concept, which was applied to asks impurities in the ICH guidance for 3. Toxicokinetics (Ref. 22) (1) Whether a material or end product industry ‘‘M7 Assessment and Control Animal toxicokinetic data should also is engineered to have at least one of DNA Reactive (Mutagenic) Impurities be collected for sunscreen active external dimension, or an internal or in Pharmaceuticals to Limit Potential ingredients, as these data provide an surface structure, in the nanoscale range Carcinogenic Risk’’ (Ref. 19). FDA important bridge between toxic levels (approximately 1 nm to 100 nm). expects that the 0.5 ng/mL seen in animal studies and any potential In addition, because materials or end concentration will be sufficiently above human adverse events associated with products can also exhibit related the assay’s limit of quantitation—limit systemic exposure to the sunscreen’s properties or phenomena attributable to a dimension(s) outside the nanoscale of detection to allow a signal-to-noise active ingredient. Toxicokinetic range of approximately 1 nm to 100 nm ratio that ensures confidence in either measurements are usually obtained that are relevant to evaluations of safety, the derived concentrations (in the case during the course of ongoing nonclinical effectiveness, performance, quality, of ‘‘exaggerated’’ values) or lack of toxicity studies, such as carcinogenicity public health impact, or regulatory concentrations. or DART studies, rather than through status of products, we will also ask: separate studies. 2. Developmental and Reproductive (2) Whether a material or end-product Toxicity Studies D. Postmarketing Safety Data is engineered to exhibit properties or FDA expects that DART studies will In addition to the active ingredient phenomena, including physical or need to be conducted to evaluate the safety data already described, FDA’s chemical properties or biological effects, potential effects that exposure to the GRASE evaluation also takes into that are attributable to its dimension(s), sunscreen active ingredient may have consideration publicly available even if these dimensions fall outside the on developing offspring throughout information about serious adverse drug nanoscale range, up to 1 micrometer gestation and postnatally until sexual m experiences and known or expected ( m) (1,000 nm). maturation, as well as on the We will apply these considerations adverse effects associated with reproductive competence of sexually broadly to all FDA-regulated products, commercially marketed products that mature male and female animals (Ref. including sunscreen products. For the contain the active ingredient(s) under 20). As with systemic carcinogenicity purpose of this proposed rule, we use consideration. studies, we expect that studies to assess the term ‘‘nanomaterial’’ generally to fertility and early embryonic E. Sunscreens Containing refer to materials falling within either development, and pre- or postnatal Nanomaterials point 1 or 2 above. The use of this term toxicity in rats will not be needed if an We note that FDA is not proposing to in this manner is consistent with its use adequately conducted human MUsT categorically classify sunscreen in FDA’s nanotechnology-related shows a steady state blood level less products manufactured using guidances, including FDA’s than 0.5 ng/mL, and an adequately nanotechnology (or containing Nanotechnology Considerations nanomaterials) as GRASE or not GRASE Guidance. 17 FDA recommends submitting the Nanomaterial forms of the active solely based on this characteristic. carcinogenicity study protocol(s) for review by ingredients zinc oxide and titanium Nanotechnology is used to create, FDA’s Center for Drug Evaluation and Research’s dioxide have been used in marketed (CDER’s) Executive Carcinogenicity Assessment explore, or manipulate materials OTC sunscreens. In addition to Committee before initiating the studies. For further measured in nanometers (nm) guidance regarding carcinogenicity studies, see the nanomaterial forms of zinc oxide and (billionths of a meter), and has FDA guidance for industry ‘‘Carcinogenicity Study titanium dioxide, other nanomaterials Protocol Submissions,’’ May 2002 (available at https://www.fda.gov/ucm/groups/fdagov-public/ 18 Examples of such pathways could include are also reported to have been used, or @fdagov-drugs-gen/documents/document/ endocrine function and signaling pathways related promoted or studied for possible use, in ucm078924.pdf). to growth and development. sunscreen products (Ref. 25).

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As discussed in further detail in outweigh their benefits, the ingredients penetration—regardless of particle section VIII.A, having examined the are proposed as Category II. size—is primarily limited to the upper scientific information in the record, layers of the non-living stratum A. Ingredients Proposed as Category I including for nanomaterial forms of zinc corneum, with most penetration oxide and titanium dioxide, FDA is not Based on our review of the publicly occurring only into skin folds and now proposing conditions of use for available data for these ingredients, both furrows or hair follicles. These studies these two active ingredients under the zinc oxide and titanium dioxide are show that zinc oxide particles do not sunscreen monograph that distinguish proposed as Category I. penetrate down into the viable dermis to nanomaterials from other forms of these 1. Zinc Oxide any significant extent. Any de minimis ingredients. As indicated above, FDA transdermal penetration that may occur also does not propose to categorically Our review of the scientific literature, does not result in adverse health effects, submissions to the sunscreen classify sunscreen products that are because the tiny amount of zinc oxide monograph docket, and adverse event manufactured using nanotechnology or particles that achieve transdermal reports submitted to FAERS has contain nanomaterials as GRASE or not, absorption, if any, would dissociate into produced sufficient safety data on zinc solely on that basis. Manufacturers of zinc and oxygen ions, both of which are oxide to support a proposal that a products containing nanomaterials naturally occurring elements in the sunscreen containing up to 25 percent marketed under the OTC sunscreen human body (Ref. 30). Zinc is the 14th zinc oxide would be GRASE under the monograph remain responsible for most common element in the human conditions proposed in this rulemaking ensuring that the product satisfies all body and is essential for all living and the general conditions required in applicable legal requirements. FDA things; the average human body part 330. This proposal is based in encourages manufacturers of such contains about 2.0 to 2.5 grams of zinc, products to consult with FDA to significant part on the existing, substantial evidence that zinc oxide and normal dietary intake of zinc is facilitate a mutual understanding of about 15 milligram (mg) per day (Refs. specific scientific or regulatory issues (including particles on the nanoscale, i.e., approximately 1 to 100 nm) does 30 and 31). Homeostatic mechanisms in relevant to their product. the body regulate zinc’s absorption, FDA invites comment on the not penetrate into or through human skin to any great extent and, to the distribution, cellular uptake, and following topics: excretion (Ref. 31). Similarly, any • Specific nanomaterials or types of extent any de minimis penetration occurs, does not result in adverse health oxygen absorbed through the skin is nanomaterials that have been used or nonharmful, as oxygen is plentiful in proposed for use in OTC sunscreen effects, given the high levels of endogenous zinc in the human system. the human body and essential for life. products Our search of the literature on zinc • Concerns about sunscreen product a. Background. Zinc oxide is an oxide revealed four recent studies about safety, effectiveness, or quality inorganic, mineral compound. Because zinc oxide’s penetration into human associated with the use of of its ability to reflect UVA wavelengths, skin, which confirm our expectations nanomaterials in OTC sunscreen zinc oxide is frequently used in products, with supporting data sunscreens to help establish broad based on the physical properties of this • Need for, and proposals of, spectrum protection (Ref. 26). While compound. The first two studies specifications or limitations for larger particles of zinc oxide used in (conducted by Leite-Silva et al. and particular nanomaterials for use in sunscreens (greater than approximately Darvin et al.) examined the penetration OTC sunscreen products 100 nm) may impart an opaque, white of zinc oxide into the skin using • Any particular nanomaterials that you color to the product, zinc oxide is also multiphoton tomography (Refs. 32 and believe should not be permitted for manufactured in smaller particle sizes 33). Both studies showed a lack of use in OTC sunscreen products, along (less than approximately 100 nm) to overall permeation of zinc oxide beyond with supporting scientific information reduce this white/opaque appearance a few cell layers, except in the case of • FDA’s proposed regulatory approach (Refs. 27 and 28). In addition to its use furrows and wrinkles (Refs. 32 and 33). and/or alternative regulatory in sunscreens, zinc oxide is also used in The second two studies—a pilot and approaches to the use of non-sunscreen ointments, pastes, and subsequent full trial conducted by nanomaterials in OTC sunscreen lotions for various skin disorders Gulson et al.—evaluated the penetration products because of its protective, astringent, and of nanoscale zinc oxide into the skin antiseptic properties (Ref. 29). and the bloodstream using a stable VIII. Existing Safety Data for Sunscreen b. Discussion. Zinc oxide is insoluble isotope tracing method (Refs. 34 and Active Ingredients in water and largely insoluble in 35). Although the Gulson studies found In the remainder of this section, we biological fluids.19 This insolubility that a minimal amount of topically discuss the existing data and data gaps precludes the possibility of its systemic applied zinc was absorbed, the for each of the sunscreen monograph absorption from topical application of absorption observed was at levels that active ingredients and explain why we sunscreen products beyond a de are orders of magnitude less than daily propose that these active ingredients are minimis amount, even if zinc oxide is nutritional intake and well below what GRASE or not GRASE for use in included at its maximum eligible would be of concern for a naturally sunscreens. Those ingredients for which concentration of 25 percent and occurring element in the body subject to the existing data are sufficient to regardless of the formulation of the homeostatic mechanisms (Ref. 36). An support a positive GRASE product. The available studies on the additional porcine study found (as determination are proposed as Category dermal penetration of zinc oxide, discussed in our 2012 response to a I. Those ingredients for which further discussed below, confirm that its citizen petition submitted by the additional data are necessary before a International Center for Technology GRASE determination can be made are 19 We note that nanoscale zinc oxide can be Assessment and others (Docket No. proposed as Category III. In cases where solubilized to a small extent in the presence of FDA–2006–P–0213–0003) (ICTA phosphate and lecithin at pH’s that are achievable FDA’s evaluation of the existing safety on the skin. Even under these conditions, however, Petition Response)), that although data caused us to determine that the the amount potentially absorbed is de minimis and sunburn caused by UVB rays increased risks associated with the ingredients far lower than daily nutritional intake of zinc. the penetration of zinc oxide into the

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non-living stratum corneum, there more active ingredients, making it c. Conclusion. Our review of the remained minimal penetration of zinc difficult to attribute causation to a available data from both animal and oxide into the epidermal and dermal specific active ingredient. Unlike other human studies and data on physical layers of the skin (Ref. 37). Because sunscreen ingredients with a known properties such as solubility leads us to topically applied zinc oxide particles do hypersensitivity risk, we did not conclude that the transdermal not enter systemic circulation to any identify any reports in FAERS or in the absorption of zinc oxide—regardless of meaningful extent, we do not consider literature with features suggestive of a particle size—from any topically a MUsT to be necessary to support the causative link, such as skin test results applied sunscreen formulation is safety of this ingredient. positive for zinc oxide. In addition, extremely unlikely, and that any de In addition to the studies described there is an extremely large safety minimis absorption that may occur above, we also located two studies database of zinc oxide use in other would not result in adverse health evaluating the clinical safety of topically topical products, including for the effects, given the high levels of applied zinc oxide in which zinc oxide treatment of diaper rash in infants. This endogenous zinc. The very low (25 percent) was used as a medicated corroborates the negative results in likelihood of any systemic absorption of occlusive dressing on the lower arms of human studies for irritation, zinc oxide in turn indicates that the healthy volunteers (Refs. 38 and 39). In photoirritation, allergy, and safety margin for zinc oxide is large; these studies (which were designed to photoallergy that support our proposed accordingly, consistent with our maximize potential absorption and finding regarding the safety of approach to pediatric studies discussed identify any resulting adverse events), sunscreens containing this ingredient in section VII.B.5, we do not consider even with the increased dermal or under the conditions proposed. Reports pediatric studies to be needed for this epidermal zinc levels resulting from of non-hypersensitivity-related clinical ingredient. We propose to find that the occlusion, there still were no adverse safety issues with zinc oxide were currently available safety data provide skin events. Our review of the available infrequent and not serious. For these sufficient evidence to demonstrate the human dermal safety studies on zinc reasons, we do not consider additional minimal absorption, low dermal oxide 20 also identified data showing clinical studies (including photosafety, irritation, low allergenic sensitization that test material containing up to 25 irritation, or sensitization studies) to be and photoallergenicity, and low percent zinc oxide did not induce necessary for this ingredient. phototoxic potential of zinc oxide— human irritant, photoirritant, allergic, or Dermal carcinogenicity studies have regardless of particle size—up to 25 photoallergic reactions. No human not been conducted for zinc oxide. In percent, and that these data support a pathological phototoxicity or significant general, as discussed in section VII.C.1, finding that zinc oxide up to 25 percent human photosensitization reaction adequate tests for safety of an active is GRASE for use in sunscreens under indicative of skin irritation were noted ingredient for use in topical products for the proposed conditions. Accordingly, either. The literature supporting the chronic use (such as a sunscreen) would we propose that zinc oxide is a Category safety of skin protectant drug products need to include dermal carcinogenicity I active ingredient. containing zinc oxide 21 reinforce these studies if the active ingredient reaches clinical safety findings. Our review in the viable layers of skin where it could 2. Titanium Dioxide this area is also consistent with the have a biological effect. Given the For similar reasons, we propose that conclusion of the European minimal penetration of zinc oxide titanium dioxide is also a Category I Commission’s Scientific Committee on below the non-living stratum corneum, active ingredient. Our review of Consumer Safety that the use of there is no plausible mechanism by information publicly available in the nanoscale zinc oxide in sunscreens at a which zinc oxide could have an effect scientific literature, submissions to the concentration of up to 25 percent does on skin tumor development. We are sunscreen monograph docket, and not pose a risk of adverse effects in therefore proposing to find that zinc FAERS has produced sufficient humans after topical application (Ref. oxide is GRASE for use in sunscreens information to support a proposal that a 40). despite the lack of dermal sunscreen product containing up to 25 A very small number of rash and carcinogenicity studies studying this percent titanium dioxide would be hypersensitivity reports for sunscreens ingredient. GRASE under the conditions proposed containing zinc oxide were located in Based on the minimal systemic in this rulemaking and the general FAERS. With a single exception, the exposure resulting from dermally conditions required in part 330. sunscreens involved contained two or applied zinc oxide, in particular when a. Background. Titanium dioxide is compared to endogenous zinc levels, we an inorganic mineral compound 20 This literature included three clinical safety see no need for further nonclinical consisting of small, crystalline- studies conducted by Hill Top Research, Inc. for studies to support the safety of structured or amorphous particles. It is Procter & Gamble regarding (a) human sensitization widely used as an excipient and is (Study Reports 96–6635–76a and 96–6635–76b); (b) sunscreens containing zinc oxide, human photoirritation/phototoxicity (Study Report including systemic carcinogenicity currently listed as an inactive ingredient 96–6634–76); and (c) human photoallergenicity studies, developmental and in more than 60 approved drug products (Study Report 96–6633–76). See Citizen Petition reproductive toxicity studies, or (including topical, oral, and inhalation submitted by Proctor & Gamble, June 24, 1997 22 products, among others) (Ref. 46). (FDA–1978–N–0018–0639) and the ‘‘Opinion toxicokinetic studies. concerning Zinc Oxide’’ drafted by the European Titanium dioxide particles can be Commission, Scientific Committee on Cosmetic 22 Our review of the available nonclinical safety manufactured to have a variety of Products and Non-Food Products Intended for literature on zinc oxide included references for a different dimensions, shapes (such as Consumers (SCCNFP), which included five 90-day dermal toxicity study, genotoxicity, and spheres or rods), and crystal summaries of human clinical safety studies, all limited developmental and reproductive toxicity evaluating zinc oxide 25 percent (Ref. 40). information. The review of this literature suggests polymorphs (such as anatase or rutile). 21 See, e.g., Beeckman et al. (Ref. 41); 43 FR 34628 that genotoxicity, findings for zinc oxide are mixed, Titanium dioxide (typically with at 34641(August 4, 1978) (discussing use of zinc and that there is minimal dermal toxicity in rodents particle dimensions ranging from 200 to oxide 1 percent to 25 percent as a skin protectant after 90 days. (See Refs. 42 and 43.) Oral rat 300 nm) is manufactured as a white active ingredient: ‘‘Zinc oxide is widely recognized embryofetal toxicity studies showed some adverse as a skin protectant’’ and ‘‘No reports of topical maternal and fetal effects, but only at very high powder for use as a white color pigment toxicity were found in the literature’’ on zinc doses (≤200 mg/kg/day) significantly higher than in pharmaceuticals. Manufacturers have oxide). what is at issue here (Refs. 44 and 45). also introduced processes that produce

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titanium dioxide with particle toxicity, or toxicokinetic) to be Coating titanium dioxide particles has dimensions ranging from 15 to 50 nm to necessary to support the safety of this also been shown to minimize reduce its white/opaque appearance. ingredient.23 Because titanium dioxide photocatalytic activity (and to limit Titanium dioxide particles used in penetration beyond the non-living particle clumping, which can have an sunscreens are also now often treated stratum corneum and into the viable impact on how products blend).25 with chemical coatings (such as layers of the skin is also minimal, as In theory, if photocatalytic activity silicones, metal oxides, or organic acids) with zinc oxide, we do not consider occurred when sunscreen products that are bonded to the exterior surface dermal carcinogenicity studies to be containing nanoscale titanium dioxide of the particles to, among other things, needed for titanium dioxide either. were exposed to light, it could result in improve the aesthetic characteristics of The inability of more than an the breakdown of other sunscreen active the final formulation. extremely minimal amount of titanium ingredients in these products. We have b. Discussion. Titanium dioxide is dioxide to reach viable tissues that no evidence, however, that this in fact essentially insoluble in water and in could have an immunologic reaction occurs in sunscreen products containing biologic fluids (Ref. 47). As with zinc also prevents dermal irritation, titanium dioxide or that there are any oxide, this lack of solubility prevents sensitization reactions, and photosafety other negative impacts resulting from the transdermal absorption of more than issues for this ingredient. Our search of such photocatalytic activity. a de minimis amount of titanium the available literature on titanium Accordingly, its potential for dioxide, regardless of either the dioxide identified nonclinical data photocatalytic activity does not concentration of titanium dioxide or the reinforcing this, showing that dermal undermine our conclusion that titanium formulation of the product (Refs. 48 and toxicity after dermal application of dioxide is GRASE for use in sunscreen 49). Further, unlike zinc oxide, which, titanium dioxide in rodents is minimal products. Nonetheless, we invite if dissolved, would dissociate into zinc (Refs. 57 to 60). Accordingly, we do not comment (including supporting data) on and oxygen (Ref. 50), the chemical consider additional clinical photosafety, whether sunscreens containing titanium stability of titanium dioxide is such that irritation, or sensitization studies to be dioxide are negatively impacted by the it does not dissociate under the necessary to support the safety of this potential photocatalytic effects of that conditions that exist in (or on) the ingredient. We note that the available ingredient and, if so, to what extent; and human body (Ref. 51). Even if titanium studies on titanium dioxide evaluate on additional regulatory conditions, if dioxide were to dissociate into titanium products with titanium dioxide any, that are necessary to address this and oxygen, titanium is unreactive in concentrations up to 10 percent. Given potential issue. physiologic conditions, and (for this, that the physical properties of titanium We note, as well, that it is the among other, reasons) is frequently used dioxide both preclude its penetration responsibility of manufacturers to in medical devices and structures into or through the human skin ensure that any inactive ingredients implanted in the human body (Refs. 51 regardless of concentration and make it used in a drug product marketed and 52). unlikely that there would be dermal pursuant to the OTC Drug Review, The available studies on the photosafety, irritation, or sensitization including coatings used to address transdermal absorption of titanium associated with titanium dioxide photocatalytic activity or for other dioxide confirm that the skin is an exposure (and that there is no data to purposes, are safe and suitable for their effective barrier to the penetration of suggest such photosafety, irritation, or intended use (see § 330.1(e)). FDA titanium dioxide, regardless of particle sensitization would exist at higher encourages manufacturers to contact the size—including those on the nanoscale concentrations), we propose that Agency regarding any specific coatings (Refs. 53, 54, and 55). In our 2012 titanium dioxide—regardless of particle that they are considering for use in a response to the ICTA Petition size—is GRASE for use in sunscreens at topical sunscreen. mentioned earlier, we described the concentrations up to 25 percent, c. Conclusion. Given the chemical then available information about the consistent with the level set in the properties of titanium dioxide as absorption of titanium dioxide Stayed 1999 Final Monograph. insoluble and unreactive under nanomaterials and concluded that the In evaluating whether titanium physiologic conditions and the available ‘‘currently available literature indicates dioxide is GRASE for use in sunscreen studies showing that titanium dioxide that insoluble nanomaterials of titanium products, we have considered published does not penetrate into the skin or enter dioxide used in sunscreens do not literature indicating that nanoscale into systemic circulation to any penetrate into or through human skin to titanium dioxide can exhibit meaningful extent, we consider the produce adverse health effects when photocatalytic properties (Ref. 61). The available safety data adequate to support applied topically’’ (ICTA Petition literature indicates that the crystalline a proposal that titanium dioxide is Response at 26). Since that time, our structure of titanium dioxide particles GRASE for use in sunscreens. As with search of the available literature has not plays a role in this photocatalytic zinc oxide, our proposal rests in revealed anything that would change activity, and that the anatase crystalline significant part on the data showing that this conclusion. Because topically polymorph is associated with greater absorption of titanium dioxide into or applied titanium dioxide particles do photocatalytic activity than the rutile through the skin is very unlikely and not enter systemic circulation to any polymorph (Ref. 61). The European meaningful extent, we do not consider Commission has established limitations Consumer Safety gave its opinion that titanium a MUsT to be necessary for this on the percentage of anatase crystalline dioxide particles consisting, among other things, of ingredient. polymorph in titanium dioxide to up to 5 percent anatase crystal ‘‘can be considered to not pose any risk of adverse effects in humans Given the lack of transdermal 24 minimize photocatalytic activity. after application on healthy, intact or sunburnt absorption of titanium dioxide beyond a skin’’ (Ref. 62). In 2016, this physicochemical de minims amount and, as a result, the 23 We note that the available literature also parameter was incorporated by the European very low likelihood of any systemic includes data showing that oral administration of Commission into its Regulation on Cosmetic effects, we also do not consider relatively high doses of titanium dioxide did not Products (Regulation (EC) No. 1223/2009 11/30/ produce adverse fetal effects in rats. (See Ref. 56.) 2009) permitting the use of titanium dioxide as a additional nonclinical studies 24 In a July 2013 opinion addressing the safe use UV filter or as a colorant in cosmetics. See (including systemic carcinogenicity, of titanium dioxide in sunscreen products, the Regulation (EC) No 1143/2016 July 13, 2016. developmental and reproductive European Commission’s Scientific Committee on 25 Id.

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that any de minimis absorption that number one recommended treatment for salicylate would not be GRASE. We note could theoretically occur would not hypertension for certain communities), that, as with PABA, our review of more result in adverse health effects. As a certain local anesthetics (such as than 700 sunscreen brands sold in the result, the safety margin here is large, benzocaine and procaine), and dyes United States suggests that trolamine and consistent with our approach to (including para-phenylenediamine (a salicylate is no longer being marketed in pediatric studies discussed in section hair dye) and aniline dyes (used in sunscreens sold in the United States VII.B.5, we therefore consider pediatric medical products)) (Refs. 70, 71, and (Ref. 63). studies to be unnecessary for this 72). Cross-sensitization to these a. Background. Trolamine salicylate is ingredient. products is a serious concern, as comprised of trolamine and salicylic widespread PABA use could result in a acid. Salicylic acid is a non-steroidal B. Ingredients Proposed as Category II significant increase in cross-reactivity anti-inflammatory drug (NSAID); it is FDA’s review of the available safety with these agents and the incidence of the active moiety in aspirin, and has data for PABA and trolamine salicylate allergic and photoallergic dermatitis, been widely used as an analgesic (i.e., have caused us to conclude that the some of which are likely to be severe. pain relieving), anti-pyretic (i.e., fever risks associated with use of these These safety issues alone are reason reducing), and anti-inflammatory agent. ingredients in sunscreen products enough to find PABA not GRASE for use In addition to these properties, salicylic outweigh their benefits. Accordingly, in sunscreens. In addition, however, acid inhibits platelet aggregation, which we are proposing that these two data obtained from the urine samples of in turn inhibits blood coagulation. For ingredients are Category II. human subjects receiving topical PABA this reason, some salicylic acid- 1. Para-Aminobenzoic Acid application shows that PABA also containing products (such as aspirin) penetrates the skin and enters systemic are used by consumers to help reduce PABA use has decreased significantly circulation (Ref. 73). Because full MUsT cardiovascular adverse events, in recent years because of, among other studies for PABA have not been done, including myocardial infarction, stent things, its adverse effects on skin and its it is unclear to what degree such thrombosis, and transient ischemic discoloring and staining effect on transdermal absorption takes place. attacks. clothing. Our review of more than 700 However, one article in the published Trolamine salicylate was included in sunscreen brands sold in the United literature suggests that there is an the Stayed 1999 Final Monograph for States (Ref. 63) indicates that PABA is association between autoimmune sunscreens at a concentration of up to in fact no longer being marketed in the disorder and PABA use (Ref. 71), and 12 percent. It was also proposed as a United States. we found one report each of Category III active ingredient in the A search of the scientific literature, hepatotoxicity (Ref. 74) and chronic tentative final monograph for OTC submissions to the sunscreen interstitial nephritis (Ref. 75) after oral external analgesic drug products monograph docket, drug approval PABA administration. Although it is (External Analgesic TFM) (‘‘External documents from FDA and the European difficult to determine causality on the Analgesic Drug Products for Over-the- Medicines Agency, adverse event basis of such single reports, if a MUsT Counter Human Use; Tentative Final reports submitted to FAERS, and FDA were to show absorption of PABA, these Monograph,’’ 48 FR 5852 at 5855 Advisory Committee meeting reports reports could represent an additional (February 8, 1983)). The mechanisms of (among other sources) has produced safety concern. action for trolamine salicylate for these clinical safety data on PABA that In addition, genotoxicity findings two drug categories are very different; to supports a conclusion that a sunscreen with PABA use have been largely be effective as an external analgesic, containing PABA would not be GRASE. negative in the absence of UV trolamine salicylate must penetrate the The available clinical information irradiation. Adequate assessments of the skin and reach the relevant sites of includes significant numbers of reports dermal carcinogenicity potential of action. The available evidence clearly of allergic and photoallergic skin PABA are unavailable, as are DART establishes that trolamine salicylate is reactions to PABA, with rates of PABA- studies. If a MUsT were to show transdermally absorbed (Refs. 76 and induced skin reactions potentially 8 absorption of PABA, therefore, 77). To be effective as a sunscreen, percent or higher (Refs. 64 to 67). An 8 necessary studies would include dermal however, trolamine salicylate must be percent incidence is a serious concern: and systemic carcinogenicity studies, present on the surface of the skin so that By comparison, only 34 hypersensitivity DART studies, and toxicokinetic it can reflect, scatter, or absorb UV reactions associated with sunscreen studies. However, given that the above- radiation. products have been identified in FAERS described safety concerns associated The directions for use for the two 26 since 1969. with PABA are significant enough to product categories differ significantly as Further, PABA has the ability to cause place PABA in Category II, conducting well. The current requirements for cross-sensitization to structurally such testing is neither appropriate nor sunscreen labeling include directions similar aromatic amines and nitro ethical. We propose that PABA is not that the product should be applied to all compounds (i.e., it can cause GRASE for use in sunscreens. skin exposed to the sun, that it should individuals exposed to it to develop be used ‘‘regularly’’ to decrease the risk sensitivity reactions to similar 2. Trolamine Salicylate of skin cancer and early skin aging,27 compounds) (Ref. 69). The list of We also propose that trolamine and that it should be reapplied at least compounds at issue includes a variety salicylate is not GRASE for use in every 2 hours (21 CFR 201.327). In of widely used products, such as sunscreens, and is, like PABA, a contrast, currently marketed external sulfonamide antibiotics (commonly Category II active ingredient. As analgesic products containing trolamine used to treat a variety of infections, from described in further detail below, there salicylate include directions for use urinary tract infections to certain types are significant safety concerns of pneumonia), thiazide diuretics (the stating that they should be applied to associated with the use of trolamine ‘‘affected areas,’’ that they should be salicylate in sunscreen products. We reapplied no more than three to four 26 Total sunscreen sales since 1969 are not readily propose that these concerns are available. However, in 2016 a total of 161,882,779 sunscreen units were sold in the United States (Ref. sufficient to support a conclusion that a 27 This direction applies to sunscreens with an 68). sunscreen containing trolamine SPF of 15 or greater that are also broad spectrum.

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times a day, and that use should be subsequent symptoms suggesting a more (including the potential for salicylism discontinued after 7 days.28 severe intoxication include altered associated with exposure to high doses b. Significant safety concerns mental status (ranging from agitation to of trolamine salicylate) would raise associated with use of trolamine lethargy), hyperpyrexia, noncardiac significant ethical concerns about the salicylate as a sunscreen. FDA is pulmonary edema, and coma.29 conduct of a MUsT in these concerned that use of trolamine If trolamine salicylate were to be circumstances. Were it possible to salicylate as an active ingredient in applied to all skin exposed to the sun ethically conduct a MUsT for this sunscreens could cause serious and reapplied every 2 hours as directed ingredient, and if such a MUsT showed detrimental health effects due to the in sunscreen labeling, the potential for significant transdermal absorption of anti-coagulation effects of salicylic acid. transdermal absorption and systemic trolamine salicylate, this would raise FDA located two case reports of serious availability of substantial amounts of questions about whether enough of this coagulation-related adverse events salicylic acid raises significant concerns ingredient remains present on the associated with liberal dermal about the potential for increased surface of the skin for it to function application of trolamine salicylate. The occurrence of the above-described effectively as a sunscreen. As we noted first case involved a surgical patient adverse events. This is a particular in section VII.B.4, such considerations who experienced coagulopathy concern given the widespread use of ultimately weigh into the risk-benefit (impairment of the blood’s ability to other OTC NSAID products with anti- calculus FDA uses to determine whether coagulate) at surgical sites in connection inflammatory, analgesic, or anti-pyretic an active ingredient would be GRASE with use of topical trolamine salicylate effects, which, combined with the use of for use in sunscreens. (Ref. 76). Although the patient sunscreens containing trolamine Although we have data addressing the discontinued aspirin use 2 weeks before salicylate, may raise the anti-platelet toxicology profile of salicylate, surgery per her doctor’s instructions, effects experienced by consumers to adequately detailed nonclinical DART she was unaware that use of a topical problematic levels. Concerns relating to studies for trolamine and toxicokinetic cream containing trolamine salicylate transdermal absorption may be data to interpret DART studies were also should have been stopped as well, and especially acute for children, who have not found in the public record. continued liberal application of the a higher surface-area-to-body-weight Adequate DART information, if it were product to her knees for arthritis pain in ratio than adults. FDA proposes that the available, might reveal additional data the period leading up to her surgery. above-described safety concerns are needs (for example, to address any Four hours after surgery, the patient enough, by themselves, to support a potential hormonal effects that may be returned to the operating room bleeding finding that trolamine salicylate is not identified). Dermal carcinogenicity data profusely from all surfaces that had GRASE for use in sunscreens, and are available from the National been operated on and experiencing therefore, is a Category II active Toxicology Program for trolamine in massive bilateral hematomas. She lost ingredient. acetone and trolamine alone (applied more than 900 mL of blood. c. Data gaps. In addition, there are neat).30 In the absence of toxicokinetic In the second case, a patient taking several categories of data about data to interpret existing carcinogenicity warfarin (an anticoagulant) for atrial trolamine salicylate that FDA expects studies, we cannot determine how the fibrillation and stroke prevention would be necessary to support a exposure in the animal studies relates to experienced a considerable increase in positive GRASE determination for its human exposure to trolamine from the prothrombin time (i.e., the time it takes use in sunscreen products that are use of trolamine salicylate as a for blood to coagulate) after liberal currently missing from the public sunscreen active ingredient. application of trolamine salicylate to his record. For example, there is d. Conclusion. For the reasons neck and shoulders for pain relief (Ref. insufficient clinical dermal described above, FDA proposes that 78). The patient’s prothrombin time had sensitization, irritation, and photosafety trolamine salicylate is not GRASE for previously been in the therapeutic range data for trolamine salicylate. Although use in sunscreens. The safety concerns of 1.3 to 1.5 times the control, but the transdermal absorption of trolamine associated with the use of trolamine increased to 2.5 times the control during salicylate is well established, the record salicylate as an active ingredient in trolamine salicylate use. When currently lacks a MUsT that would sunscreens are significant enough to trolamine salicylate use was allow us to evaluate the extent of support classification of trolamine discontinued, the patient’s prothrombin exposure to this ingredient when it is salicylate as a Category II ingredient. In time returned to 1.3 times the control. used as a sunscreen. Such data is particular, the potential for transdermal FDA is also concerned that important because it would allow FDA absorption and systemic availability of sunscreens containing trolamine to interpret systemic toxicity findings in substantial amounts of salicylic acid in salicylate could lead to other adverse animal toxicology studies in the context connection with the exposure resulting effects associated with salicylic acid of the amount likely to be absorbed from from the use of trolamine salicylate in exposure. These include gastrointestinal sunscreen use. Given the FDA sunscreens raises concerns about distress and hemorrhage, ototoxic recommendation that a MUsT for increased occurrence of the above- effects (i.e., impacts on hearing), sunscreen use include application to a described serious adverse events hypersensitivity reactions, asthma majority (75 percent at a minimum) of (including salicylism and serious exacerbations, acid-base imbalance, salt the body surface of each test subject, the coagulation-related issues). The record and water retention, liver injury, and above described safety concerns also contains several significant data Reye’s Syndrome (in children). At high gaps that would need to be addressed to 29 doses, acute salicylate toxicity The symptoms associated with both acute and support a positive GRASE chronic salicylate toxicity are well established. determination for trolamine salicylate. (salicylism) may occur. Early symptoms Descriptions are available from many sources, of salicylism include tinnitus, vertigo, including: National Library of Medicine’s 30 nausea, vomiting, and diarrhea; Toxicology Data Network (ToxNet), ‘‘Salicylic In mice, liver tumors were identified, providing Acid,’’ September 2008, available at https:// evidence of systemic absorption of trolamine, but toxnet.nlm.nih.gov/cgi-bin/sis/search/ the suspected mechanism of action is likely not 28 Based on an evaluation of product labeling a?dbs+hsdb:@term+@DOCNO+672 (accessed March relevant to humans (Refs. 79 and 80). A causal link available at https://labels.fda.gov (accessed April 4, 27, 2018). FDA also included a comprehensive between the proposed mechanism and tumor 2018). See also External Analgesic TFM. summary of salicylism in 21 CFR 343.80. formation in mice is lacking.

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Given the safety concerns described similar to many of these 10 sunscreen positive GRASE findings for above, however, conducting the clinical active ingredients are among those oxybenzone and avobenzone, we have absorption testing recommended to successfully delivered transdermally— significantly more data for these two address these gaps for use as a and therefore available systemically ingredients than for the ingredients sunscreen raises ethical concerns. (Ref. 85). This reinforces the potential discussed in the preceding section. To for transdermal absorption of and help facilitate submission of the C. Ingredients Proposed as Category III systemic exposure to these sunscreen remaining data, we describe the data The public record does not contain ingredients. The potential for such gaps for these two ingredients in greater sufficient data to support a positive systemic exposure is a concern because detail below. GRASE determination for cinoxate, the available data are inadequate to a. Oxybenzone data. Although we dioxybenzone, ensulizole, homosalate, determine either the level of systemic located substantially more data on meradimate, octinoxate, octisalate, exposure to these active ingredients or oxybenzone than on the ingredients octocrylene, padimate O, sulisobenzone, the potential unintended consequences discussed in section VIII.C.1, our review oxybenzone or avobenzone at this time. of such exposure. Given the lack of of the scientific literature, submissions Accordingly, these ingredients are being chronic exposure toxicology data for to the sunscreen monograph docket, and proposed as Category III. In the sections these 10 ingredients—which makes an postmarket safety data publicly that follow, we discuss our review of the evaluation of the dermal and systemic available through FAERS revealed available safety evidence for these effects of chronic use impossible—this significant gaps in the data we expect to ingredients and identify the existing is especially concerning. A number of be necessary to support a positive data gaps. these active ingredients have also GRASE finding for use of oxybenzone at 1. Ingredients for Which the Record shown hormonal effects in mammalian a concentration of up to 6 percent in Contains Significant Data Gaps: assays (homosalate (Refs. 86 to 92)) and sunscreen products. The available Cinoxate, Dioxybenzone, Ensulizole, padimate O (64 FR 27666 at 27671) and literature includes studies indicating Homosalate, Meradimate, Octinoxate, in in vitro and in vivo assays that oxybenzone is absorbed through the Octisalate, Octocrylene, Padimate O, (homosalate (Refs. 86 to 92), octinoxate skin and can lead to significant systemic and Sulisobenzone (Refs. 93 and 94),and octocrylene (Ref. exposure, as well as data showing the 95). Although these findings are only presence of oxybenzone in human The most significant gaps in the preliminary, we do not have adequate breast milk, amniotic fluid, urine, and administrative record exist for the DART studies to enable us to assess the blood plasma. The significant systemic following active ingredients: Cinoxate, impact of these potential hormonal availability of oxybenzone (and, as dioxybenzone, ensulizole, homosalate, effects on development and discussed further below, the lack of data meradimate, octinoxate, octisalate, reproduction. evaluating the full extent of its octocrylene, padimate O, and In addition, several of these 10 absorption potential) is a concern, sulisobenzone. We expect that data from ingredients (homosalate (Refs. 81 and among other reasons, because of all the types of studies described in 84), octinoxate (Refs. 81 and 96 to 101), questions raised in the published section VII will need to be submitted to octisalate (Refs. 81, 84, and 101 to literature regarding the potential for support general recognition of safety 105),octocrylene (Refs. 95 and 106), endocrine activity with systemic and effectiveness for each of these padimate O (Ref. 100), and oxybenzone exposure. Accordingly, we ingredients. sulisobenzone (Refs. 107 and 108)) have expect that a positive GRASE finding for Only three of these active ingredients been studied in dermal penetration oxybenzone-containing sunscreens (homosalate (Ref. 81)), octinoxate (Refs. studies, which show (in general, with would require, among other things, both 81 to 84), and octisalate (Ref. 81), for the exception of homosalate) that these a MUsT showing the degree of example, appear to have been evaluated ingredients permeate into the epidermis oxybenzone absorption under maximal in human absorption studies, and most and/or dermis. The studies show that usage conditions and DART studies that of the available absorption studies for there are several factors (including fully investigate its potential endocrine- these three ingredients had significant vehicle composition and the presence of disrupting effects. We found neither in limitations. For example, the studies use other active ingredients) that can the existing record. a limited number of subjects or are influence, and potentially increase, the The record also lacks systemic and based on only a single application of the permeation and/or penetration of these dermal carcinogenicity studies for sunscreen active ingredient to a limited ingredients. oxybenzone; these (and toxicokinetic area of the body. Even with this limited Because the record does not currently data) should also be provided to support sunscreen exposure, some of these contain sufficient data to support their a positive GRASE finding for this studies showed systemic availability of safety, we are proposing that cinoxate, ingredient. Finally, the available the active ingredient (octinoxate (Refs. dioxybenzone, ensulizole, homosalate, literature also raises questions about the 83 and 84)). None of these 10 meradimate, octinoxate, octisalate, safety of use of oxybenzone-containing ingredients has been studied in an octocrylene, padimate O, and sunscreens in young children because of adequate and well-controlled MUsT that sulisobenzone are Category III the potential for higher absorption and would determine the amount of ingredients. As previously noted, we bioaccumulation of oxybenzone in this systemic exposure to the active expect that data from all the types of population. As discussed in further ingredients under conditions of studies described in section VII will be detail in the sections that follow, we maximal use. needed to support general recognition of invite input and comment on We note that a recent publication safety and effectiveness for these appropriate studies and/or age examining the relationship between ingredients. restrictions to address these pediatric melting point, molecular weight, and issues. the transdermal delivery rates of the 2. Ingredients for Which the Record b. Background of oxybenzone. Unlike active ingredients in approved drug Contains Fewer Data Gaps: Oxybenzone zinc oxide and titanium dioxide, both of products shows that products and Avobenzone which are inorganic (or physical) UV containing active ingredients with While the record does not currently filters consisting of metal oxides that melting points and molecular weights contain sufficient data to support primarily reflect or scatter UV radiation,

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oxybenzone is an organic (or chemical) 110). As discussed below, however, of oxybenzone is high (Refs. 82, 115, filter, which absorbs UV radiation. It evidence shows that oxybenzone also and 116). One study involving sampling belongs to a class of aromatic ketones has contact allergenic and of plasma and urine following topical known as benzophenones and has a UV photoallergenic potential (Ref. 111). In application of an oxybenzone- absorption profile covering both UVA addition to its use as a sunscreen active containing formulation showed and UVB wavelengths (Ref. 109). ingredient, oxybenzone is used in, absorption and significant systemic Because of its superior UVA coverage, among other things, perfumes, lipsticks, availability of oxybenzone (Ref. 82). In oxybenzone was increasingly used hair sprays, and conditioners as a this study, 15 men and 17 women were through the early 1990s and ultimately photostabilizer and/or fragrance dosed once daily, applying a 10 percent enhancer (Refs. 112 to 114). replaced PABA in sunscreen products oxybenzone cream formulation to (Ref. 110). Use of oxybenzone in c. Data showing transdermal approximately 90 percent of the body’s sunscreens increased when ‘‘PABA- absorption and significant systemic surface area for 4 days. The figures free’’ sunscreens were introduced into availability of oxybenzone. Data that the market because of recognition that have become available since publication below illustrate the plasma and urine PABA and its esters induced contact of the Stayed 1999 Final Monograph levels observed. and photocontact allergic reactions (Ref. suggest that the transdermal absorption BILLING CODE 4164–01–P

BILLING CODE 4164–01–C

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BILLING CODE 4164–01–C UV radiation on oxybenzone absorption, d. Inadequate data on oxybenzone’s Although this study provides the sunscreen was applied to study developmental and reproductive important information about the subjects twice daily for 5 days. toxicity. The significant systemic significant absorption potential of Although the study concluded that UV availability of oxybenzone following oxybenzone, it does not obviate the exposure did not significantly affect the topical application and the lack of data need for a MUsT. Among other things, urinary excretion of oxybenzone, it fully characterizing its absorption levels once-daily application may result in provided further evidence of the are concerns, among other reasons, substantially lower systemic exposure systemic availability of oxybenzone because of literature suggesting that than application at least every 2 hours following topical application and oxybenzone may have endocrine (as sunscreen labeling directs). This showed that renal excretion of activity (see, e.g., Refs. 88, 92, and 117). difference in application frequency is a oxybenzone continued for 5 days after Dermal exposure to oxybenzone (in particular concern given that the data the last application of the sunscreen. acetone) in rats and mice and oral show oxybenzone levels would still be Although the use of a commercial feeding of oxybenzone to rats and mice increasing at the time of reapplication if sunscreen formulation, and twice- resulted in reduced sperm density in a 2-hour application window were rather than once-daily sunscreen males in 13-week general toxicity observed. Additionally, the cream application are improvements over the studies conducted by the National formulation used in the study was not formulation and application frequency Toxicology Program (NTP) (Ref. 118). In formulated as a sunscreen product and used in the previous study, twice-daily female rats and mice, increased estrous may have contained ingredients not application remains insufficient to cycle length was observed in 13-week typically used in sunscreen approximate the recommended oral feeding studies.31 Importantly, the formulations, and/or lacked other application frequency of sunscreen actual effects of oxybenzone on female ingredients typically present. Because products in real-world use. fertility were not evaluated. In a the formulation can have an impact on Furthermore, because the study used a preliminary dose range-finding pre- and absorption, the absorption results sunscreen with 4 percent rather than the postnatal development study in rats, produced by the study may not reflect full 6 percent concentration of findings in male offspring indicated that absorption levels that would result from oxybenzone eligible for the sunscreen cells in the testes undergoing actual use of oxybenzone-containing monograph, its results may not fully programmed cell death were increased sunscreen products. reflect the absorption that would result in all oxybenzone-exposed animals and Another study, which evaluated the from use of a 6 percent oxybenzone- that numbers of spermatocytes in the transdermal absorption of a marketed containing product. To properly testes were markedly reduced after oral sunscreen containing 4 percent characterize the potential for absorption feeding at oxybenzone (Ref. 119). oxybenzone in 16 women and 9 men, of oxybenzone in sunscreen products Although these findings are notable, showed prolonged systemic availability and to determine a margin of safety for they are all derived from dermal studies of oxybenzone following topical use of oxybenzone at up to 6 percent in exposure (Ref. 116). In this study, which sunscreen products, we expect that a 31 These changes could potentially be addressed was designed to evaluate the effects of MUsT will be needed. with historical control data (Ref. 88).

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with oxybenzone in acetone and oral interest (Ref. 115) to support a positive 2010 (see, e.g., Ref. 125). From 2001 to feeding studies of oxybenzone; these GRASE finding for this ingredient. The 2008, oxybenzone was tested at 3 methods of exposure could potentially results from the metabolite study will percent; from 2009 to 2010, the lead to higher levels of systemic inform whether additional nonclinical concentration used for the test was exposure to oxybenzone than with studies assessing oxybenzone’s increased to 10 percent. Of the 23,908 sunscreen use. Accordingly, a MUsT metabolites should be conducted to patients patch tested, only 82 patients and toxicokinetic data are needed to support its safety. We note that the NTP (0.34 percent) had positive test patch determine the relevance of these is currently conducting additional results with oxybenzone. In addition, a findings to human use of oxybenzone as DART studies on oxybenzone (although search of FAERS for case reports of a sunscreen active ingredient. their embryofetal studies do not appear hypersensitivity reactions to In humans, the endocrine effects of to include an assessment in a nonrodent oxybenzone-containing sunscreen oxybenzone have been studied with species) (Ref. 122).33 products resulted in only 31 cases (4 inconclusive results (see, e.g., Refs. 83, e. Inadequate carcinogenicity and with anaphylaxis) between 1988 and 120, and 121). In biomonitoring studies toxicokinetic data for oxybenzone. High 2011. Because sufficient data exist to of pregnant and lactating women, population exposure to oxybenzone, make a determination, we do not oxybenzone has been detected in breast coupled with a lack of carcinogenicity consider additional dermal irritation or milk, amniotic fluid, and urine samples testing for this ingredient, caused the sensitization studies to be necessary to (Ref. 83, 120, and 121). High levels of National Cancer Institute to nominate support a positive GRASE finding for oxybenzone in the urine of mothers oxybenzone for toxicology testing in oxybenzone up to 6 percent. As is have been associated with: (1) 1979 (Ref. 123). The NTP reports that customary in clinical trials, however, Decreased birth weight in girls and (2) 2-year oral (dosed feed) carcinogenicity we recommend that dermal safety data increased birth weight and head studies in rats and mice are in a draft for oxybenzone be collected during circumference in boys, both of which report stage, but results are not yet MUsT studies. can be indications of endocrine effects publicly available (Ref. 122). In Nevertheless, the overwhelming (Ref. 83). This association is particularly addition, no reports of either ongoing or majority of results from available concerning given the widespread planned dermal carcinogenicity studies studies (see, e.g., Refs. 125 to 136) exposure of the U.S. population to for oxybenzone have been published. To addressing allergic contact dermatitis oxybenzone. Estimates suggest that support a positive GRASE finding for for oxybenzone show that oxybenzone is oxybenzone (from all sources) is present oxybenzone, carcinogenicity data from an allergen for persons with preexisting in the urine of 97 percent of the U.S. well-conducted dermal and systemic skin conditions. Because the evidence population, and that oxybenzone carcinogenicity studies should be establishing oxybenzone as a concentrations are higher in women provided. Toxicokinetic data in rodents photoallergen in individuals with than in men (possibly because women (oral and dermal) and rabbits (oral) are photosensitivity is clear, no further are more likely to use sunscreen and also recommended; these data could be dermal photosafety studies to other personal care products containing obtained from either stand-alone studies characterize this risk are needed. oxybenzone, leading to greater or as part of DART and dermal However, if we were to receive adequate cumulative exposure) (Ref. 83 and 115). carcinogenicity studies. data to support a positive GRASE Because current data suggest that Our search of the available literature finding for oxybenzone, we would oxybenzone may affect the human also revealed information suggesting consider requiring labeling language to endocrine system, FDA believes that a that oxybenzone may generate reactive address the risk of allergic reactions positive GRASE determination for oxygen species (ROS) 34 in the presence associated with oxybenzone use. We oxybenzone would require that its of UV light, but that this issue, and the invite comment on whether such potential toxicities have been fully harms associated with it, have not been labeling should be required for explored, including through DART fully explored (Ref. 124). We invite sunscreens containing oxybenzone and, studies (fertility and early embryonic comment and input on the extent to if so, what that labeling should entail. studies in rodents, embryofetal which ROS generation is a concern for g. Safety questions regarding use of development studies in rodent and sunscreens containing oxybenzone and oxybenzone in pediatric populations. nonrodent species, and pre- and whether additional data on this topic Sunscreens are currently labeled for use postnatal development studies in are needed. in children as young as 6 months old. rodents). In addition, as noted below, f. Dermal safety of oxybenzone. The The available literature, however, toxicokinetic data are needed to available data indicate that oxybenzone includes several publications that raise interpret these studies. We note that, if (at concentrations up to 6 percent) has concerns about the use of sunscreens the results of DART studies do not a favorable safety profile with respect to containing oxybenzone in young resolve the concerns raised in the irritation and sensitization potential. children. Among these publications is a literature relating to potential endocrine For example, the North American 2006 report from the Swedish Research disruption, it may still be possible to Contact Dermatitis Group conducted an Council noting that children under the resolve these concerns through analysis of patients who were patch age of 2 years old have not fully additional testing.32 In addition, tested for allergies between 2001 and developed the enzymes believed to because of the potential risk posed by metabolize oxybenzone (Ref. 137), metabolites of oxybenzone (existing 33 As a reminder, such data must be generally which suggests, in theory, that small reports suggest that some oxybenzone available to be considered as part of this rulemaking children may not be able to eliminate process. Once available, FDA intends to review oxybenzone as easily as adults. The metabolites are more hormonally active such data to determine whether it resolves than the parent drug (Ref. 109)), we particular data concerns we have in this area. possibility for bioaccumulation in recommend that the analytical method 34 Reactive oxygen species are ‘‘a type of unstable children, taken together with the used in the MUsT be validated for both molecule that contains oxygen and that easily reacts potential increased absorption of with other molecules in a cell. A buildup of ROS oxybenzone in young children (due to the parent and the metabolites of in cells may cause damage to DNA, RNA, and proteins, and may cause cell death.’’ https:// their greater body surface-area-to-weight 32 For examples of the type of studies that could www.cancer.gov/publications/dictionaries/cancer- ratio) and the potential harms associated be explored at that juncture see Ref. 21. terms?cdrid=687227. with absorption discussed above,

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militates in favor of caution when using h. Conclusion. Given the available bridge between animal and human data. oxybenzone products in young children. data showing significant transdermal We seek any existing data on the Accordingly, we are seeking any absorption and systemic availability of pediatric safety of oxybenzone. We also existing pediatric data on the safety of oxybenzone, as well as the potential for seek comment on whether additional oxybenzone use in children under 2 endocrine activity, we propose that safety data are needed to support the years old. We are also requesting input oxybenzone is not GRASE for use in use of sunscreens containing on: (1) Whether additional data on the sunscreens without further data. As oxybenzone on children under 2 years safety of oxybenzone use in young described above, a MUsT should be of age, as well as comment on whether children is necessary to support the use conducted to fully characterize the these sunscreens should be of oxybenzone-containing sunscreens in absorption of oxybenzone and to contraindicated for use in this children under 2 years of age (taking calculate a margin of safety for human population. We note that, because of the into consideration the practical hurdles use. As part of the MUsT, we believe risk of allergic reactions associated with that a study of oxybenzone’s metabolites oxybenzone use, if we receive adequate involved in conducting studies in in humans is also necessary; the results data to support a positive GRASE children of this age) or (2) whether of this study will inform whether finding for oxybenzone, we may require sunscreen products containing additional nonclinical studies with labeling to address this risk. We seek oxybenzone should instead be metabolites are needed to address comment on whether such labeling contraindicated for use in children potential endocrine effects. Given that should be required for sunscreens younger than 2 years (given, among oxybenzone demonstrates significant containing oxybenzone and, if so, what other things, the availability for use as systemic absorption, FDA believes that such labeling language should entail. sunscreen active ingredients of physical data on carcinogenicity (both systemic In summary, table 3 shows the UV filters like titanium dioxide and zinc and dermal) and developmental/ additional studies that FDA anticipates oxide, which do not raise the same reproductive toxicity are likely to be would be necessary to support a questions about safe use in young needed to support the safety of this positive GRASE finding for sunscreens children). ingredient, as are toxicokinetic data to containing oxybenzone.

TABLE 3—SUMMARY OF RECOMMENDATIONS: STUDIES FOR OXYBENZONE UPTO6 PERCENT

Safety studies FDA proposes are necessary to support a GRASE determination Additional studies or data necessary?

Pharmacological Studies: Human absorption (MUsT) (including metabolite study in humans) Yes. Nonclinical Safety Studies: Toxicokinetics ...... Yes. Dermal Carcinogenicity ...... Yes. Systemic Carcinogenicity ...... Yes. DART: 1 ...... Yes. Fertility and early embryonic development. Embryofetal development in two species (rodent and non-rodent). Prenatal and postnatal development. Clinical Safety Testing: Skin irritation and sensitization ...... No. Skin photoallergenicity and phototoxicity ...... No. Pediatric studies ...... Seeking input on whether additional studies or contraindication are necessary to support the safety of sunscreens containing oxybenzone for children under 2 years of age. 1 As noted above, if DART studies do not resolve the concerns raised in the literature relating to potential endocrine disruption, it may be pos- sible to resolve these concerns through additional testing.

i. Avobenzone data. Our review of the avobenzone’s chemical properties sunscreen active ingredient that available scientific literature, suggest that sunscreen products provides protection in the UVB range. submissions to the sunscreen containing avobenzone have a potential Avobenzone exhibits greater monograph docket, and publicly for absorption. There are also other gaps photoinstability than other UV available FAERS data also revealed in the record, including (as discussed absorbers; the available evidence shows significant gaps in the data we expect to below) dermal carcinogenicity data, that avobenzone degrades quickly upon be necessary to support a finding that toxicokinetic data, and—potentially, exposure to sunlight, which can cause avobenzone (at up to either 3 percent or depending on the outcome of MUsT its efficacy to be decreased by between 5 percent, as discussed below) is GRASE studies assessing the absorption of 50 and 90 percent after 60 minutes of for use in sunscreens. Most critically, avobenzone—systemic carcinogenicity exposure to sunlight (Refs. 138 and we encountered no studies examining and additional DART studies. 139).35 To address this, avobenzone is the absorption of avobenzone in vivo, Accordingly, we propose to find that typically combined with a and those in vitro studies we located avobenzone is Category III. photostabilizer to prevent rapid had several weaknesses that limit their j. Background of avobenzone. photodegradation (Refs. 138 and 139). usefulness in assessing the potential Avobenzone, like oxybenzone, is an absorption of avobenzone from organic (chemical) UV filter. Because 35 Avobenzone’s photodegradation also results in formulated sunscreen products. This is the formation of free radicals, which could, in avobenzone primarily absorbs radiation theory, create sensitization and irritation responses a concern given that, as explained in in the UVA portion of the UV spectrum, and increase long-term risk of skin cancers and further detail below, certain of it is typically combined with another photoaging (Ref. 139).

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k. Potential for absorption of adhesive tape to the skin samples. expected (Refs. 142 and 143)). In avobenzone. Although avobenzone is However, it is unclear whether the addition, the study’s use of not soluble to any great extent in water, receptor phase of the study created commercially marketed sunscreen it is soluble in organic solvents. These adequate sink conditions. In addition, formulations (which, as discussed include oils (which are present on the formulations used in the study above, typically contain multiple human skin), alcohols, and other (which, as noted previously, consisted permeation/absorption-enhancing substances regularly included in of only water, mineral oil, and the excipients) more accurately reflects the sunscreen product formulations. sunscreen ingredient) did not contain absorption potential of marketed Although this solubility is not enough, any of the other types of excipients sunscreen products. by itself, to determine whether (such as emollients, stabilizers, or Despite these improvements, the transdermal absorption will take place, solubilizers) that can also function as usefulness of the study was limited by it is a necessary precondition (Ref. 140). permeation/absorption enhancers and its use of an analytical method that In addition, like the 10 active that are typically present in sunscreen prevented the detection of any ingredients described in section product formulations. The study results avobenzone absorption below 100 ng/ VIII.C.1, avobenzone’s melting point showed that there was avobenzone mL. This level of absorption is hundreds and molecular weight are similar to present in the stratum corneum, the of times higher than what is relevant for those of active ingredients in approved epidermis, and the viable dermis of the our considerations in assessing the drug products that are successfully skin used as the membrane, but not in acceptable absorption level from a delivered transdermally and therefore the receptor fluid. Although the lack of topically applied product. The available systemically (Ref. 85). As with avobenzone in the receptor fluid is concentration of avobenzone used in the the 10 sunscreen active ingredients encouraging, the other characteristics of study (ranging from 0.2 percent to 1 previously discussed, this suggests a the study limit its value in assessing the percent) is also significantly lower than potential for transdermal absorption of actual absorption potential of what is relevant for our current avobenzone. avobenzone used in sunscreen products. consideration of maximum l. Lack of adequate data on The second in vitro study (Ref. 141) concentration of this ingredient. transdermal absorption of avobenzone. we located suffered from similar Although avobenzone was only Nevertheless, our review of the available limitations. This study assessed the absorbed to a very small extent (between literature on avobenzone failed to avobenzone permeation observed using 3 percent and 3.96 percent) under these produce any studies evaluating the in a static cell (as generally described study conditions, these weaknesses in vivo absorption of avobenzone at 3 above), and then took the skin from the the study’s design significantly limit the percent or higher under (or even static cell and subjected it to multiple conclusions that can be reached from its approaching) maximal usage conditions. rounds of tape stripping to assess the results. While we were able to locate a few presence of avobenzone at various levels Given that avobenzone’s chemical studies evaluating avobenzone’s of the skin. Following tape stripping, properties suggest that it has a potential absorption in vitro, these studies had a the skin was subjected to digestion (i.e., for transdermal absorption in sunscreen number of weaknesses that significantly the skin sample was subjected to a products, the lack of adequate data limited the conclusions that could be chemical treatment that breaks down assessing its absorption in realistic drawn from them. the cell membranes to release any sunscreen formulations is a concern. We The first in vitro study we located sunscreen that might be either bound to therefore expect that a MUsT evaluated the penetration—through proteins or bound up in the cells). demonstrating the degree of absorption excised human skin—of five sunscreen The study results showed significant of avobenzone into the human body ingredients (including avobenzone) that retention of avobenzone in the stratum under maximal use conditions will be had been diluted in mineral oil and corneum, a lesser amount in the needed to support a positive GRASE water (Ref. 100). The study used a static epidermis, and none in the dermis or determination for sunscreens containing cell technique. As discussed in section receptor fluid. Like the previous study, avobenzone. Further, in light of the VIII.D, in a static cell study, the test however, the test material used in this above-described data showing product (here, a sunscreen/mineral oil/ study did not include any of the avobenzone’s photoinstability, we also water formulation) is placed on the permeation enhancers typically expect that, if sufficient data are upper side of a membrane (here, the included in commercial sunscreen provided to support the safety of excised skin) in the open donor formulations. It is also unclear whether avobenzone, any future sunscreen chamber of a static cell, and a sampling sink conditions existed in the receptor monograph including avobenzone as an fluid is placed on the other side of the phase of the study. active ingredient will include the membrane in a receptor cell. Diffusion The final in vitro study used a static limitation that avobenzone is not of the ingredient (here the avobenzone) cell to evaluate the transdermal GRASE for use in sunscreen products from the topically applied product to penetration of six sunscreen unless it has been photostabilized (via and across the membrane is monitored formulations collected from a health spa use of a photostabilizing UV filter or by examining sequentially collected that marketed its own line of skin care other photostabilizing ingredient/ samples of the receptor fluid. To ensure products (Ref. 96). This study improved mechanism) to prevent its that all transdermal penetration of the on the design of the previous two photodegradation and (among other ingredient that takes place is fully studies in several respects. First, the concerns) the attendant reduction in reflected in the receptor fluid, the receptor fluid contained ethanol, a avobenzone efficacy. receptor fluid must be optimized for permeation enhancer often used in Because photodegradation can reduce absorption (in other words, sink sunscreen products, which produced the amount of avobenzone absorbed conditions must be created in the fluid). sink conditions in the receptor phase. transdermally, we also expect that a In this study, the use of skin as the Secondly, to create favorable conditions MUsT sufficient to support the general membrane in the system allowed for an for absorption, the products were recognition of safety of avobenzone for evaluation of the presence and depth of applied at a thickness of 20 mg/square sunscreen use would need to test permeation via skin stripping—the centimeters (cm2) on the skin’s surface formulations of avobenzone that include sequential application and removal of (i.e., 10 times the skin loading typically a photostabilizer. Including

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photostabilizers in MUsT formulations (including photosafety, irritation, or have targeted evidence to support the will allow for accurate assessment of sensitization studies) to be necessary to safety and effectiveness of avobenzone absorption levels in final formulated support the safety of this ingredient for when combined with the remaining sunscreen products containing sunscreen use at up to 5 percent. As is active ingredients. We believe this avobenzone. This proposal is consistent customary in clinical trials, however, limitation was inconsistent with the with our general recommendation that we recommend that dermal safety data approach to evaluating sunscreen materials evaluated under the MUsT for avobenzone be collected during combinations that the Agency has paradigm represent real-world MUsT studies. generally taken throughout the OTC sunscreen formulations, rather than n. Other nonclinical safety studies for Drug Review for sunscreens. For this overly simplified solutions that fail to avobenzone. Dermal carcinogenicity reason, unless evidence is submitted to replicate the absorption potential of studies have not been conducted for suggest that there is a safety or efficacy marketed formulations. As noted in avobenzone. The available data on the concern associated with the section VII.B.4, we encourage sunscreen permeation of avobenzone suggest that combination of avobenzone with manufacturers to discuss their MUsT it may permeate into at least the dermis another active ingredient, we expect to protocol with FDA before beginning the and epidermis, which means that it is conclude that a positive GRASE trial. possible for avobenzone to impact skin determination for avobenzone will m. Data supporting dermal safety of tumor development. We therefore support its use in sunscreens either avobenzone. The available clinical expect that dermal carcinogenicity alone or in combination with all other dermal studies indicate that avobenzone studies will be necessary to support a sunscreen active ingredients. at concentrations up to 5 percent have positive GRASE finding for sunscreens p. L’Oreal request to increase a favorable safety profile with respect to containing this ingredient. Available concentration of avobenzone to 5 potential irritation, sensitization, and embryofetal development studies in rats percent. Avobenzone is currently listed photosafety. In 2009, in conjunction and rabbits did not reveal any findings in the Stayed 1999 Final Monograph at with a citizen petition 36 (L’Oreal of concern. However, our review of the 38 concentrations up to 3 percent. As Petition, Docket No. FDA–1978–N– nonclinical data for avobenzone also described earlier, in 2009 FDA received 0018–0675) asking FDA to take action to revealed that toxicokinetic data a citizen petition from L’Oreal permit the marketing of sunscreen following repeat-dose exposure will be requesting, among other things, that we products containing avobenzone up to 5 needed to interpret pivotal nonclinical amend the sunscreen monograph to percent, L’Oreal USA Products, Inc. safety studies (including the increase the allowable level of (L’Oreal) submitted nine human repeat embryofetal development studies in rats avobenzone to 5 percent (L’Oreal insult patch, phototoxicity, and and rabbits) once the MUsT data Petition at 1). In the Stayed 1999 Final photoallergy studies with six different become available. (As explained in Monograph, the Agency determined that sunscreen formulations containing section VII.B.4, these data are used to avobenzone at concentrations up to 3 avobenzone (3.4 percent, 4 percent, or 5 compare drug levels achieved in animal percent is an effective sunscreen active percent). The studies showed that the studies with those observed in humans ingredient. We now likewise conclude formulations were well tolerated for under maximal exposure conditions.) In that the record contains sufficient topical use (i.e., essentially non- addition, if results of a MUsT information to satisfy the effectiveness allergenic, non-irritating, and non- demonstrate that there is significant prong of the GRASE standard for sensitizing, with mild to moderate systemic absorption of avobenzone, sunscreens containing avobenzone at reactions occurring only rarely) (L’Oreal additional fertility and early embryonic concentrations up to 5 percent. Petition).37 A separate search of the development and prenatal and postnatal available scientific literature on the development studies in rats will be As described above, data submitted clinical safety of avobenzone did not needed to support a positive GRASE with that L’Oreal Petition were reveal anything to undermine these finding. Depending on the results of the sufficient to establish that avobenzone findings. Although the available MUsT, systemic carcinogenicity studies at a concentration of up to 5 percent has literature included a small number of may also be needed. a favorable safety profile with respect to reports of contact irritation and o. Avobenzone in combination with potential irritation, sensitization, and photosensitization in connection with other sunscreen active ingredients. As photosafety. To support a finding that avobenzone-containing products, details noted in section III.B, our finding in the avobenzone at concentrations up to 5 about the composition of the Stayed 1999 Final Monograph that percent is GRASE for use in sunscreens, formulations at issue (and the avobenzone was GRASE for use in however, FDA expects that a MUsT concentrations of avobenzone) were sunscreens would have allowed its evaluating the transdermal absorption of frequently missing from the literature, combination only with certain other avobenzone up to 5 percent, as well as making it difficult to determine the sunscreen active ingredients (64 FR dermal carcinogenicity studies and cause of these responses. A small 27666 at 27688) because we did not toxicokinetic data for avobenzone at a number of serious hypersensitivity concentration of at least 5 percent, will reports for sunscreens containing 38 The available nonclinical data for avobenzone also be needed. Depending on the avobenzone were also located in include acute oral and dermal toxicity studies in outcome of the MUsT, we may also need rats; a 13-week oral toxicity study in rats; a 28-day systemic carcinogenicity data and FAERS. Because the sunscreens at issue dermal toxicity study in rats; a 21-day dermal usually contained three or more active toxicity study in rabbits; several in vitro additional DART studies, including ingredients, however, it is difficult to genotoxicity tests; an in vivo micronucleus test in fertility and early embryonic mice, as well as a sensitization test in guinea pigs; determine what caused the reaction. development, and pre- and postnatal a primary skin irritation test in rabbits; an ocular development studies in rats for Because sufficient data exist to make a irritation test in rabbits; a phototoxicity study in determination, we do not consider guinea pigs; a photoallergenicity study in guinea avobenzone at 5 percent. The record additional dermal clinical studies pigs; and embryofetal development studies in rats does not currently include any of these and rabbits (Givaudan-Roure Petition, Docket No. data. However, if FDA were to receive FDA–1978–N–0018–0751). Importantly, (except for 36 FDA–1978–N–0018–0675, two volume the embryofetal development studies) these studies sufficient data to support a positive submission (February 20, 2009) (L’Oreal Petition). are not sufficient to resolve safety concerns for a GRASE finding for avobenzone up to 5 37 Id., volume I, pp. 5–8. chronically used product. percent, we would expect to include

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avobenzone at this percentage in a final and we therefore expect that any future containing avobenzone. Depending on sunscreen monograph. sunscreen monograph including the outcome of a MUsT assessing the q. Conclusion. Given that: (1) avobenzone as an active ingredient will absorption of avobenzone, systemic Avobenzone’s organic solubility, include the limitation that avobenzone carcinogenicity testing and additional molecular weight, and melting point is not GRASE for use in sunscreen DART studies, including fertility and suggest it has a potential for transdermal products unless it has been early embryonic development and pre- absorption; (2) there is a lack of photostabilized to prevent its and postnatal development studies in available data on the transdermal photodegradation. In addition, we rats may be needed as well. We will also absorption of avobenzone in vivo believe that an adequate MUsT determine the extent to which (including under maximal use evaluating the absorption potential of additional DART studies may be needed conditions); and (3) there are limitations avobenzone will need to include a based on the results of the MUsT. in the available in vitro studies photostabilizer to ensure that the Depending on the results of the assessing avobenzone absorption, we potential transdermal absorption of expect that a properly designed MUsT avobenzone from avobenzone- nonclinical and pharmacology studies will be necessary to support a positive containing sunscreens is accurately for this ingredient and the safety margin GRASE finding for avobenzone use in assessed. that is calculated from these results, sunscreens. We expect that, to be We also expect that dermal pediatric studies for avobenzone may GRASE for sunscreen use, avobenzone carcinogenicity and toxicokinetic data also be needed to support the use of will need to be photostabilized to will be necessary to support a positive sunscreens containing avobenzone in address its potential for degradation, GRASE finding for sunscreens pediatric populations.

TABLE 4—SUMMARY OF RECOMMENDATIONS: STUDIES FOR AVOBENZONE UPTO3 (OR 5) PERCENT

Safety studies FDA proposes are necessary to support a GRASE determination Additional studies or data necessary?

Pharmacological Studies: Human absorption (MUsT) (including metabolite study in humans) Yes. Nonclinical Safety Studies: Toxicokinetics ...... Yes. Dermal Carcinogenicity ...... Yes. Systemic Carcinogenicity ...... Dependent on results of the MUsT. DART: Fertility and early embryonic development ...... Dependent on results of the MUsT. Embryofetal development in two species (rodent and non-rodent) .. No. Prenatal and postnatal development ...... Dependent on results of the MUsT. Clinical Safety Testing: Skin irritation and sensitization ...... No. Skin photoallergenicity and phototoxicity ...... No. Pediatric studies ...... Pediatric studies may be required depending on the outcome of the MUsT.

D. Anticipated Final Formulation In purposes of this proposed rule, we use final formulations, which we anticipate Vitro Permeation Testing the term final formulation testing to requiring in the future for sunscreen refer to testing conducted on the products marketed under the sunscreen As noted earlier, a final sunscreen sunscreen product formulation to be monograph (unless FDA determines that monograph will need to set out the marketed. Our expectation is that final the ingredient or ingredients contained conditions under which any product formulation testing would also generally in the product are unlikely to be marketed pursuant to it would be be necessary to ensure that the active absorbed through the skin). Because this GRASE and not misbranded. Variations ingredient in any given sunscreen testing would not be required for among individual sunscreen product formulation permitted under the sunscreens containing only those active formulations—in particular, monograph would not be systemically ingredients proposed here as Category I characteristics of the specific vehicle absorbed beyond the amount FDA (zinc oxide and titanium dioxide), FDA (e.g., the cream, lotion, or oil) in which determined to be safe. has not yet reached a final active ingredients are delivered—can The discussion that follows provides determination as to the particular affect the transdermal absorption of FDA’s thinking about such testing of parameters that might be required for sunscreens, and thus, have an impact on such final formulation testing. We their safety and effectiveness. To ingredients that are addressed in this rulemaking, anticipate that we may specify final address this, FDA currently requires for use in products marketed without approved formulation testing requirements in the NDAs. OTC sunscreens marketed under NDAs final formulation testing of OTC monograph in the future, however, as sunscreen products to support labeled provide similar information in their product- specific applications to substantiate their labeling. active ingredients that we are now claims regarding their effectiveness— For proposed changes to § 201.327, see codified proposing as Category III may be namely, testing for SPF value as well as section of this document. The Stayed 1999 Final included in the monograph in the future broad spectrum protection and water Monograph also required SPF testing of final if FDA receives data supporting their resistance where those attributes are formulations as a GRASE condition. Elsewhere in this proposed rule, we propose to establish GRASE status. Final formulation testing claimed in product labels.39 For monograph conditions in 21 CFR part 352 that requirements applicable to such ensure that all sunscreens are tested for SPF in ingredients would be established on an 39 See § 201.327 for the current labeling accordance with § 201.327(i) and achieve a requirements, and underlying testing, for OTC minimum SPF of 2, and that certain sunscreens ingredient-specific basis, taking into sunscreens containing one or more of the 16 active pass the broad spectrum test in § 201.327(j). consideration the data provided to

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support a positive GRASE diffusion cell is comprised of three conduct in vitro permeation testing to determination for the specific ingredient major units: (1) An upper chamber (into establish that the reformulated product (for example, whether any safety signals which the sunscreen formulation is satisfies the final formulation in vitro are detected in well-conducted placed); (2) the rate-limiting membrane permeation testing requirements set out nonclinical carcinogenicity and DART (the prepared human skin); (3) and the in the sunscreen monograph or (2) seek studies). We encourage interested lower chamber/fluid channel NDA approval for the new formulation. parties to provide information and (containing a receptor fluid that is comment for each sunscreen active evaluated to determine how much of the IX. Additional Proposed Conditions of ingredient that is relevant to sunscreen it ‘‘receives’’) (Refs. 145 to Use establishing this kind of final 147). The vertical diffusion cell system A. Proposed Requirements Related to formulation testing for each active has been commercialized and is Dosage Form ingredient. available as both single and multiple OTC sunscreens have been marketed FDA’s expectation is that this testing unit models that can be automated. in a variety of dosage forms over the would not generally call for an in vivo Other relevant parameters FDA study. Instead, FDA expects that the expects to consider in establishing years. Responding in part to the growing conditions of marketing specified for future requirements for in vitro market acceptance of spray sunscreens, sunscreens containing a given active permeation testing include (among other on June 17, 2011, FDA issued an ANPR ingredient would require manufacturers things) the thickness and integrity of addressing sunscreen dosage forms to perform in vitro permeation testing collected skin, storage conditions used (Dosage Forms ANPR) (76 FR 35669, before marketing each sunscreen for collected skin, receptor fluid June 17, 2011). The ANPR identified formulation containing that ingredient. composition, skin and receptor fluid dosage forms considered eligible or Consistent with the approach for SPF temperature, the number of skin ineligible for review and potential and broad spectrum final formulation samples (and donors) used, study inclusion in the OTC sunscreen testing set forth in § 201.327 (for duration, sampling period, application monograph, based on FDA’s knowledge, proposed changes to § 201.327, see method, and number of experimenters. at that time, of their history of marketing codified section of this document), FDA We note that if a final sunscreen before the OTC Drug Review began in anticipates that it would not review the formulation contains a combination of 1972. It also solicited specific results of the in vitro permeation testing sunscreen active ingredients, FDA information about the safety, before product marketing. Rather, FDA anticipates requiring that this final effectiveness, and directions for use of expects that any future conditions formulation be tested against the spray sunscreens. pertaining to final formulation in vitro standard control formulations for each 1. Summary of Eligible and Ineligible permeation testing in the sunscreen of the sunscreen active ingredients it Dosage Forms monograph would include a contains. As noted above, a standard requirement that manufacturers control formulation might not be In this proposed rule, FDA is maintain records of this testing, and that specified for (and final formulation in confirming that the following dosage those records be available for FDA vitro permeation testing might not be forms identified in the Dosage Forms inspection upon request. necessary to establish safety for) a ANPR are eligible for review and FDA anticipates establishing a sunscreen containing a particular active potential inclusion in the OTC standard control formulation for each ingredient if FDA determines that the sunscreen monograph based on their sunscreen active ingredient to be used ingredient is unlikely to be absorbed history of sunscreen marketing before in the in vitro permeation testing of through the skin. As mentioned above, 1972: Oil, lotion, cream, gel, butter, products containing that ingredient. The we therefore do not propose to require paste, ointment, stick, spray, and standard control formulation would be final formulation in vitro permeation powder. With the exception of powder, the formulation that produces the testing for sunscreen formulations FDA proposes that sunscreens in these highest in vivo absorption in the MUsT. containing only zinc oxide and/or dosage forms are GRASE subject to The results of in vitro permeation titanium dioxide. certain conditions described below and testing using this control formulation In cases in which such testing is elsewhere in this proposed rule. We would then be used as a bridge to a required, FDA anticipates that if the in note that sunscreen powders were corresponding level of in vivo vitro permeation of each sunscreen classified as ineligible for review in the absorption from the MUsT that is used active ingredient in the final formulated Dosage Forms ANPR because, at that to establish the safety margin for the product is equal to or less than the value time, we were unable to identify any ingredient. Then, FDA anticipates obtained from in vitro permeation sunscreen products in powder form that establishing conditions to ensure that testing of the standard control were marketed before the OTC Drug final formulation in vitro permeation formulation for that active ingredient, Review began. Based on marketing data testing would be conducted for each the product’s safety margin would be submitted to the ANPR docket and in a formulation intended to be marketed, considered to fall within the parameters related citizen petition (Docket No. using the specified vertical diffusion judged to be GRASE, and thus to 1978–N–0018–0741), we have cell described below. The results of the support marketing of the formulation. determined that the powder dosage form in vitro permeation testing of each final However, if the in vitro permeation of is eligible to be considered for inclusion formulation would be compared to the the active ingredient from the specific in the OTC sunscreen monograph. absorption found in the standard control final formulation is greater than the However, as described in section IX.A.4, formulation for the active ingredient it value obtained from in vitro permeation we tentatively conclude that additional contains. testing of the standard control safety and efficacy data will be In vitro permeation testing is a formulation for that active ingredient, necessary to classify sunscreens in the methodology that has been used in FDA anticipates that the drug product(s) powder dosage form as GRASE and dermal formulation development for using that formulation would not be include them in the final monograph. over 30 years and, as used here, considered GRASE. In that situation, the We are proposing that sunscreens in all specifically refers to use of the ‘‘Vertical sponsor would have the option to either: dosage forms other than those identified Diffusion Cell’’ (Ref. 144). A vertical (1) Reformulate the product and as eligible for consideration above—

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including wipes, towelettes, body fine droplets or particles. In some spray to compare directly, but—taken washes, and shampoos—are new drugs products, the sunscreen formulation is together—they suggest a high degree of because we did not receive data mixed in a canister with a liquefied gas uniformity between sprays and lotions showing that they were marketed prior propellant that supplies the force to in coverage of exposed skin, as well as to 1972. generate an aerosol containing both between different spray application dissolved sunscreen formulation and scenarios such as spraying directly on 2. Overview of Comments on the Dosage propellant upon activation of a valve skin or spraying followed by rubbing. Forms ANPR system. There are also pump spray Information submitted indicated that FDA received a total of 14 comments sunscreen products that are not the amount of spray sunscreen on the Dosage Forms ANPR. Six of the packaged under pressure but generate dispensed is higher than the amount comments provided no new data, but spray by applied mechanical force dispensed for sunscreen lotions, and generally supported the advantages of without the need for a propellant. Many that consumers are more likely to spray sunscreens, agreed with the need currently marketed spray sunscreen reapply sprays than lotions. There was to address concerns about spray products use a delivery technology no response from any stakeholder sunscreens’ performance and/or safety referred to as a bag-on-valve system, in regarding consumers’ compliance with (especially when used on children), which the sunscreen formulation is directions to rub a spray sunscreen into opined that existing SPF methods contained in a bag with an attached the skin. However, data was provided would not need to be modified for valve inside a canister filled with suggesting that rubbing spray sprays, or (in most cases) agreed with propellant, so as not to mix the sunscreens into the skin did not FDA’s suggested directions for use. sunscreen formulation and propellant enhance effectiveness. Based on these Other comments argued for the ingredients. For purposes of this comments and the available data, we are inclusion of additional dosage forms document, a spray sunscreen product is not proposing to require that labeling identified as ineligible in the Dosage one discharged from either a provide instructions to rub spray Forms ANPR, but failed to provide pressurized or nonpressurized sunscreens into the skin. supporting marketing data. One container, with the understanding that Comments on the Dosage Forms comment contained marketing the degree of atomization will likely ANPR also agreed, and we concur, that information showing that sunscreen vary according to the formulation, the the current FDA-required SPF and broad products in powder form, which we had container system used, and the design of spectrum tests are appropriate for previously identified as ineligible for the spray actuator, among other factors. evaluating the efficacy of sunscreens in the monograph, had been marketed in b. Spray sunscreen performance and spray dosage forms. SPF testing requires the United States before 1972. The effectiveness. The Dosage Form ANPR application of a set amount of sunscreen remaining comments (all from industry) asked a series of questions relating to (2 mg/cm2 on each test subject), which provided data and information that the performance and effectiveness of can readily be done for spray sunscreen directly or indirectly addressed spray sunscreens, including questions formulations. For example, comments questions raised in the Dosage Forms about the amount of spray sunscreen on the Dosage Form ANPR stated that ANPR concerning the safety, typically applied by consumers, the SPF testing of sunscreen spray effectiveness, and labeling of spray uniformity of coverage, how frequently products can be conducted following sunscreens. These comments are consumers reapply spray sunscreens, the method described in the current rule discussed in sections IX.A.3 and IX.A.4 whether consumers rub spray by weighing out the liquid form and below. sunscreens into the skin when directed applying it to the skin. This premise is 3. Safety and Effectiveness of Spray to do so and the resulting effect on supported by data from SPF testing Sunscreens effectiveness, and whether—and if so, submitted in the comments. For how—the SPF and/or broad spectrum example, one comment submitted five As we recognized in the Dosage tests need to be modified to address SPF testing reports conducted on sprays Forms ANPR, compared to traditional sunscreen sprays. The Dosage Forms using the FDA-required methods, in lotions, oils, and the like, spray ANPR also solicited studies comparing which the expected SPF values for the sunscreens raise potential concerns of spray sunscreens to other eligible test formulations were almost identical both safety and efficacy that FDA must dosage forms to see whether the dosage to the SPF testing results. The same consider in determining whether forms are comparable. logic applies to broad spectrum testing, sunscreens in the spray dosage form Four comments provided data from which also uses a defined amount of would be GRASE. With respect to multiple studies examining and sunscreen by weight. Based on this efficacy, FDA must consider factors comparing the performance of spray and information, we conclude that the such as whether spraying sunscreen lotion sunscreens on a variety of current and proposed SPF and broad rather than applying it by hand provides parameters, including amounts applied, spectrum testing methods are also effective coverage on exposed skin, how uniformity of coverage as measured appropriate for spray dosage forms. consumers use spray products, and with UV filter photography, c. Spray sunscreen safety. FDA has whether current test methods for SPF comparative SPF results, and consumer identified two primary safety concerns and broad spectrum protection can be ratings of ease and effectiveness of specific to spray sunscreen dosage relied on for adequate labeling of spray application, among others. FDA’s forms: (1) The potential risk of products. With respect to safety, spray evaluation of the information submitted respiratory harm from inhaling sunscreens raise the question of indicated that key questions asked in sunscreen ingredients and (2) the potential harm from inhalation of the Dosage Forms ANPR were directly potential flammability risk when sunscreen components as well as or indirectly addressed by these studies. consumers are exposed to flame or heat potential flammability risks. These studies indicated that consumers before spray solvents have completely a. Characteristics of sunscreen spray like the convenience of spray dried. For the reasons described below, products. Spray sunscreens use varying sunscreens and adapt their use of these we believe that both potential risks can technologies to package and deliver a products to achieve effective coverage. be acceptably mitigated by proposed sunscreen formulation as an aerosol Data provided on application uniformity formulation limitations, labeling spray, i.e., an airborne suspension of lacked study reports and were difficult requirements, and adequate testing, and

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thus propose to establish these as while only particles smaller than 4 mm information in the record to support a additional conditions in the monograph reach the unciliated airways and positive finding about their safety. We to ensure that sunscreen products in a alveolar region of the lungs (see believe that, taken together, these two spray dosage form would be GRASE. generally Refs. 148 to 153). Thus, limitations would significantly reduce d. Inhalational toxicity. Broadly although there are little or no data on inhalation risk from spray sunscreens by speaking, the human respiratory system the potential inhalation toxicity of reducing particle exposure to the larynx consists of the upper respiratory tract particular spray sunscreen ingredients, and deeper lung tissues. The particle (i.e., the airways of the nose to the we are proposing that exposure to size data submitted in response to the larynx) and lower respiratory tract (the harmful levels of such ingredients can Dosage Forms ANPR also suggest that trachea and branching airways of the effectively be minimized by imposing these limitations would be readily lung, including bronchi, bronchioles, particle size limitations on spray achievable without unduly burdening and alveoli) (see generally Refs. 148 and sunscreen products. sunscreen spray manufacturers. 149). Much of the respiratory system is Several comments on the Dosage With the establishment of these two lined with a layer consisting of mucus Forms ANPR submitted results of limits, FDA believes that the risks of cells and cilia that mechanically propel particle size distribution testing using adverse events related to unintentional inhaled particles out of the lower available methods and apparatus, with inhalation of spray sunscreens will be respiratory tract toward the mouth, the aim of showing that exposure to minimal. Stakeholders asserted that the where they may be swallowed or inhaled sunscreen products or risk of inhalation toxicity is already low, expectorated (Refs. 148 and 149). The ingredients would be minimal and thus primarily based on particle size of most significant concern associated with unlikely to cause adverse effects. The marketed sprays. Limited data on any product that may be accidentally data submitted were similar and in adverse event reports and animal inhaled is the potential risk of adverse some cases overlapping. In an analysis toxicity studies were also submitted in effects associated with deep lung of pooled particle size distribution data a few comments on the Dosage Forms deposition, which occurs when particles from all submissions, representing 50 ANPR, but were inadequate to support in an aerosol (i.e., a suspension of U.S.-marketed spray sunscreen the safety of spray sunscreens in the airborne particles such as a sunscreen products, 32 had particles smaller than absence of particle size limitations. If spray) reach the unciliated airways in 4 mm in diameter and thus within the the particle size limitations proposed the lung. Particles that can reach the respirable portion of the total particle here are adopted, however, we do not unciliated airways of the deep lung are size distribution. However, the great believe that additional animal toxicity described as respirable and may be majority of the particle sizes observed or other safety data need to be provided associated with serious adverse effects were nonrespirable. The highest to support a GRASE finding for spray such as asthma, emphysema, percentage that any product had of sunscreens. bronchospasm, or chronic obstructive particles smaller than 4 mm in diameter We are proposing that particle size pulmonary disease; particles that do not was 0.43 percent and the mean was 0.22 testing to demonstrate compliance with reach the deep lung may be associated percent, which is extremely low. the proposed limitations must be with less harmful adverse events such In addition to reviewing information conducted on spray products as they are as local irritation of the upper airway, from comments on the Dosage Forms dispensed from the consumer container coughing, or sneezing (Refs. 149 to 151). ANPR, FDA conducted its own analysis as part of the lot release testing that The potential health risk associated of particle size distribution for 14 would be routinely completed as part of with inhalation of hazardous aerosols marketed spray sunscreens. In those current good manufacturing practice depends on how much of a toxic tests, no sunscreen had more than 10 (CGMP) compliance under part 211 (21 substance is deposited in a given region percent of particles in sizes less than 10 CFR part 211). It is necessary to test the of the respiratory tract and how much mm in diameter and only three had size of particles dispensed from the remains after physiological clearance particles smaller than 5 mm (Ref. 154). consumer container to ensure that occurs through mechanisms such as To limit the risks of unintentional particle size requirements are met under coughing, sneezing, mechanical exposure and potential associated conditions of use by consumers. transport, or, in the deep lung, adverse events to respirable particles in For purposes of these proposed engulfment by specialized cells or other spray sunscreens, we are proposing particle size requirements, we are using protective action (Refs. 148 and 152). limits on the size of particles dispensed the term particle size broadly to mean The pathogenic potential of inhaled from the consumer container for the discrete unit emitted from the spray aerosols depends on where in the finished spray sunscreens in order for container that is available for inhalation respiratory tract a particle is deposited those products to be GRASE. We by a consumer when the product is (Ref. 152). Whether spray particles that propose that 90 percent of the particles applied. If the particle dispensed from enter the body through inhalation at the dispensed from the consumer container the consumer container is a droplet that nose or mouth will be deposited in the must be at least 10 mm or greater in meets the size requirements, the lung depends largely on their physical order to limit exposure beyond the consumer will not accidentally inhale it characteristics: Most notably particle larynx, and to prevent deposition in the into the deep lung. However, if that size, with the likelihood of respirability deep lung, the minimum particle size same droplet breaks apart into smaller increasing as particle size decreases dispensed from the consumer container fractions when it is dispensed from the (Refs. 148 to 153). The effects of particle must be no less than 5 mm. This limit consumer container, those fractions size on respirability of inhaled particles was chosen because it is the lowest would be the particles that must meet is well studied. There is general whole number above the generally the size requirement to ensure that agreement that particles greater than 10 accepted threshold (4 mm) at which consumers will not inadvertently inhale micrometers (mm) in diameter may enter particles enter the unciliated airway and them past the larynx. the mouth and the airway up to the because it allows for experimental error We are not proposing a specific test larynx. Approximately 50 percent of that may be inherent in particle size methodology for spray sunscreen particles up to 10 mm in diameter can measurements. Sunscreen products that particle size. Rather, sunscreen penetrate beyond the larynx to the do not meet both limitations would not manufacturers would be obligated to thoracic region of the respiratory tract, be GRASE because there is not sufficient ensure that particle size testing for their

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sunscreen sprays would be conducted e. Flammability risk. In July 2013, regulating and labeling sunscreens: (1) on each lot of the final product as FDA issued a Consumer Update Extremely flammable, (2) flammable, dispensed from the consumer container regarding persons catching on fire while and (3) combustible. These definitions in accordance with adequate written wearing spray sunscreen products near refer to flash point testing to be specifications. USP General Chapter 601 an open flame: performed using the method described part B provides methodology and The Food and Drug Administration (FDA) in 16 CFR 1500.43a. These definitions requirements for sprays, aerosols, and has become aware of five separate incidents are analogous to certain CPSC powders that include methodology to in which people wearing sunscreen spray definitions located at 16 CFR 1500.3. determine droplet/particle size near sources of flame suffered significant Given the conditions under which distribution, and we expect to consider burns that required medical treatment. The sunscreens may be used, we are testing done in accordance with the USP specific products reported to have been used proposing that spray sunscreens found as adequate to meet this proposed in these cases were voluntarily recalled from to meet the definition of extremely requirement (Ref. 155). the market, so should no longer be on store flammable in proposed § 352.3(f) are not shelves.... In the five incidents reported to We note that several comments on the GRASE and may not be marketed under FDA, however, the burns occurred after the the OTC sunscreen monograph. Dosage Forms ANPR expressed concern sunscreen spray had been applied. The about the potential inhalation risk from ignition sources were varied and involved Products found to meet the definition of exposure to spray sunscreens that lighting a cigarette, standing too close to a lit flammable or combustible in proposed contain nanomaterials (as both active citronella candle, approaching a grill, and in § 352.3(g) or (h) would be required to and inactive ingredients). One comment one case, doing some welding (Ref. 156). include the following language in the ‘‘Warnings’’ section of the drug facts also recommended that FDA require the These cases all involved a single labeling: [bullet] ‘‘Flammable’’ or presence of such ingredients to be manufacturer’s product that has since ‘‘Combustible’’ [as applicable] followed disclosed on spray sunscreen labels. been voluntarily recalled. Review of by a colon and the statement ‘‘Keep FDA’s approach to nanotechnology and adverse event reports since the away from fire or flame’’. nanomaterials in sunscreen products is voluntary recall of this product discussed in section VII.E. FDA is not A further concern related to indicates that no additional cases flammability is the time required for now proposing conditions of use, involving spray sunscreens have been including labeling, for spray sunscreens volatile solvents in a spray product to reported. However, sunscreens are often dry on the skin before a consumer can that distinguish based on the presence used in very hot outdoor environments of nanomaterials because we are safely approach a source of heat or with high ambient air temperatures. flame or can smoke without danger of proposing that any sunscreen spray that Sunscreens are also frequently used contains any particles smaller than 5 mm fire. Typical sunscreen spray around sources of flame or sparks, such formulations contain 50 to 80 percent of when it is dispensed from the consumer as grills, bonfires, smoking, or other container would not be GRASE. With a volatile carrier, most commonly ethyl ignition sources. To ensure safe use of alcohol. These volatile solvents are respect to nanomaterials in spray spray sunscreens and to better inform sunscreens, we note that the primary necessary to the formulation to allow consumers about potential flammability the product to be sprayed onto the skin. determinant of inhalation risk is the size risks, we are proposing to limit the After spraying, the solvents are intended of the particles in emitted sprays, which flammability and require flammability to rapidly evaporate leaving a film of may be larger than individual labeling of spray sunscreens under the UV filters on the skin surface as the formulation components. Nanoscale OTC sunscreen monograph. product dries. Once a spray product is ingredients would not pass the particle FDA’s general labeling regulations for dry, the solvent is no longer present so size limitations for spray sunscreens; OTC drugs provide for OTC monographs the flammability risk is low. However, therefore, if they were to be detected to require flammability labeling in prior to this point, the flammability risk when sprayed from the consumer suitable cases (§ 201.66(c)(5)(ii)(C)) (21 would be higher. container during particle size testing, CFR 201.66(c)(5)(ii)(C))), and we have We think that consumers should be the sunscreen could not be marketed done so for products such as topical warned to stay away from sources of under the OTC monograph. antitussives (21 CFR 341.74) and wart flame while a flammable or combustible In addition to the proposed removers (21 CFR 358.150). As we did sunscreen spray dries. For this reason, limitations on particle size for for those products, we are proposing to we propose to require that each batch of sunscreen sprays and related testing, we require each spray sunscreen a sunscreen spray product that meets are proposing to require that the formulation to be labeled for the definition of flammable or following labeling be included in the flammability in accordance with the combustible at § 352.3(g) or (h) be tested directions for sunscreen sprays to testing methodology described in a for drying time in accordance with minimize unintended inhalation: regulatory provision issued by the written specifications. If the drying time • Hold container 4 to 6 inches from Consumer Product Safety Commission is less than 5 minutes, we propose to skin to apply. (CPSC) (see 16 CFR 1500.43a). We have require that the labeling state, ‘‘Wait 5 • Do not spray directly into face. proposed to incorporate this flash point minutes after application before Spray on hands then apply to face. testing methodology to address our approaching a source of heat or flame, • Do not apply in windy conditions. concern regarding the flammability of or before smoking.’’ If the drying time is • Use in a well-ventilated area and sunscreen in the spray dosage form after at least 5 minutes but less than 10 avoid inhalation. it has been dispensed onto the skin. We minutes, we propose that the labeling This language is the same as that therefore propose that all batches of would state, ‘‘Wait 10 minutes after published in the Dosage Forms ANPR. sunscreen spray products be tested for application before approaching a source Its adoption was supported by flammability in accordance with 16 CFR of heat or flame, or before smoking.’’ We comments on the Dosage Forms ANPR, 1500.43a as part of batch release testing propose that a sunscreen spray that is and the language is widely used on conducted in accordance with CGMP flammable or combustible and that takes currently marketed spray sunscreens requirements. 10 minutes or more to dry would not be consistent with the 2018 Final We are also proposing to define three GRASE because of the possibility of Guidance. flammability categories for use in consumers approaching sources of fire

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during such an extended drying period. • How frequently do consumers to SPF 50+ (76 FR 35672, June 17, We invite comment on this approach. reapply the product? 2011). • Does rubbing a powder into the skin In the time since these 2011 4. Powder Dosage Forms change sunscreen effectiveness? publications, the body of evidence in Although we have found powder • Are powder dosage forms water- the published literature on UVA sunscreens to be eligible for resistant? If they are not water-resistant, radiation (particularly UVA I radiation) consideration in the OTC sunscreen is a direction to reapply every 2 hours and its role in the development of skin rulemaking, we have tentatively sufficient to assure their safe and cancer has grown. This new data about determined that additional data as effective use? the harms of UVA exposure is a outlined below will be needed to • Can the powder dosage form be significant concern given, among other support a conclusion that sunscreens in used safely and effectively over all areas things, that with currently available this dosage form are GRASE and to of skin exposed to the sun, or should sunscreens, consumers may support consideration of appropriate this dosage form be limited to the face? unknowingly accumulate excessively labeling. Also, like sprays, powder • What factors, if any, should FDA large UVA doses by using sunscreens sunscreens pose the potential for consider in connection with particle with high SPF values that either: (1) Do unintended inhalation, and for this size limitations or test methods for not pass FDA’s current critical reason, if admitted to the sunscreen sunscreen powders? wavelength-based broad spectrum test monograph, the same limitations as to • Are there important differences or (2) have inadequate uniformity in particle size here proposed for sprays among powder types (e.g., loose, their UVA protection. Because of these would be expected to apply. For powder compact) or applicators that would concerns, we are making a number of sunscreens that meet the particle size affect particle size testing? proposals designed, among other things, limitations proposed for sprays, we do to couple a greater magnitude of UVA FDA will evaluate data and information protection to increases in SPF values. not expect that additional toxicology submitted in response to these data would be needed to address the questions, as well as any other 1. Background potential health risks associated with submitted or available data, to UV radiation includes both UVA and inhalation. determine whether additional data are UVB rays. UVB rays (i.e., those with One comment on the Dosage Forms needed to support a final GRASE wavelengths from 290 to 320 nm) are ANPR provided data on SPF and broad determination for this dosage form. higher energy, are much more effective spectrum performance of five powder at producing sunburn, and produce formulations, as well as data from B. Proposed Maximum SPF and Broad Spectrum Requirements greater amounts of cellular damage repeated insult patch tests and (including DNA lesions, which can photosensitivity studies that were In the Stayed 1999 Final Monograph, result in gene mutations linked to skin asserted not to show any safety issues. FDA established SPF 30+ as the cancers) (Refs. 157 and 158). UVA rays FDA has conducted particle distribution maximum labeled SPF value for (i.e., those with wavelengths from 320 to testing on five powder sunscreens. The sunscreen monograph products, and 400 nm) are lower energy and less powder sunscreens tested had a larger required that each sunscreen effective at producing sunburn, but proportion of relatively small particles monograph active ingredient contribute make up the majority of UV radiation, compared to the sprays. Only one of the a minimum SPF of 2 to finished and penetrate much deeper into the five powder sunscreens would have sunscreen products (64 FR 27666 at skin, potentially causing oxidative complied with the requirement we are 27672, 27674 and 27675). The final damage (through formation of ROS) to considering that no more than 10 monograph did not include any broad skin pigment cells (Ref. 159). UVA rays percent of the particles could be smaller spectrum protection provisions. In its also contribute to photo-aging (Ref. 157 than 10 mm in diameter, and that 2001 decision to stay the final and 160). Although the current product was also the only one that monograph, however, FDA indicated scientific literature attributes UV- would have met the prospective that it was issuing the stay because the signature DNA lesions primarily to UVB limitation of no particles smaller than 5 Agency intended to amend the wavelengths, UVA wavelengths can also mm in diameter (Refs. 153 and 154). sunscreen monograph to address produce DNA lesions. Although UVA Based on the data submitted, we believe requirements for both UVA and UVB wavelengths produce DNA lesions to a that (current and proposed) SPF and radiation protection (66 FR 67485). FDA significantly lesser degree than UVB broad spectrum test methods are later addressed these issues in the 2011 wavelengths do, DNA lesions produced appropriate for use with powder L&E Final Rule, which, among other by UVA rays have been reported to have sunscreens, and we are not requesting things: (1) Established optional broad slower repair rates (Ref. 157). UVA rays additional respiratory safety information spectrum labeling based on satisfaction are comprised of UVA I rays (340 to 400 for powders that meet the same particle of a critical wavelength test, (2) created nm) and UVA II rays (320 to 340 nm). size limitations proposed for spray an optional indication relating to skin As discussed below, until recently, UVA sunscreens. cancer and early skin aging risk I rays were generally not considered to FDA invites comments and data on reduction for broad spectrum products contribute significantly to the harms the following topics related to powder with an SPF of 15 or higher, and (3) associated with UV exposure. sunscreens: required a labeling warning for Sunscreen products must be labeled • What amounts of powder sunscreens that did not both satisfy the with an SPF value calculated using a sunscreens do consumers typically broad spectrum test and provide an SPF standardized SPF testing procedure set dispense? of at least 15 (76 FR 35620 at 35626– forth in FDA regulations (see • What amounts of powder 35628) (L&E Final Rule). Concurrently § 201.327(i)). ISO 17166 CIE S 007/E sunscreens are effectively transferred to with publication of the L&E Final Rule, was approved for incorporation by the skin? FDA issued a proposed rule to raise the reference into § 201.327(i) as of June 18, • How uniform is the sunscreen maximum labeled SPF value for 2012 (76 FR 35619, June 17, 2011). The application across the sun-exposed area sunscreen products containing SPF test measures the amount of UV of the skin? sunscreen monograph active ingredients radiation exposure it takes to cause

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sunburn when a person is using a less efficient DNA lesion repair in the couple a greater magnitude of UVA sunscreen compared with how much basal layer (Refs. 166 and 167). protection to increases in SPF values. UV exposure it takes to cause sunburn Damage to cells in the basal layer (if As discussed in further detail below, we when the person is not using a left unrepaired or if inefficiently are also making proposals designed to sunscreen. Sunscreens with increasing repaired) can lead to mutations in address evidence of variability in SPF SPF values (up to a certain point) have critical genes that increase the values and evidence showing additional been demonstrated to provide increased possibility that normal cells will clinical benefits associated with SPF 60 sunburn protection. Because SPF values transform into cancer cells. While sunscreens. represent a sunscreen’s level of sunburn inefficient DNA repair is a concern for protection, they are primarily (though all individuals exposed to UV radiation, 3. Broad Spectrum Proposals this concern is particularly acute in not exclusively) an indicator of a. UVA I/UV ratio required to pass the those with xeroderma pigmentosum (a expected protection from UVB broad spectrum test. We are proposing disease caused by a disorder of the DNA radiation. To pass FDA’s current test for certain changes to the requirements to broad spectrum labeling (§ 201.327(j)), repair system), who have extreme sensitivity to UV radiation, and who pass the broad spectrum test. however, sunscreens must demonstrate Specifically, we are proposing to add to that, in addition to UVB protection, they develop both nonmelanoma skin cancer the current broad spectrum test a also provide some UVA protection. and melanoma with a high frequency and very early in life (Ref. 168). In requirement that products meet a UVA Only products that have been addition to the skin cancer-related risks I/UV ratio of 0.7 or higher. We note that determined to have a minimum SPF associated with UVA exposure, the current broad spectrum test value of 15 and to pass our broad 40 increasing evidence shows that UVA I procedure would remain unchanged spectrum test may include statements in radiation also produces and that this new ratio would be their labeling indicating that they immunosuppression (Refs. 169 and calculated using data from the existing decrease the risk of skin cancer and 170). This, too, is a general concern for test, which should help minimize early skin aging caused by the sun when all individuals, but is especially burden on manufacturers. used as directed with other sun dangerous for certain at-risk populations protection measures (§ 201.327(c)(2)). In The current labeling regulation (such as organ transplant recipients and contrast, sunscreens that have not been requires that sunscreens labeled as others on immunosuppressive drugs). broad spectrum achieve a critical determined to provide both broad Given the above-described evidence, spectrum protection and an SPF value wavelength of 370 nm or greater we are concerned about the existing (§ 201.327(j)). A sunscreen product’s UV of at least 15 must include a skin potential for inadequate UVA protection cancer/skin aging alert warning to protection is often displayed as a curve in marketed sunscreen products. This is on a graph showing the amount of UV consumers that ‘‘[s]pending time in the a particular concern with respect to high sun increases your risk of skin cancer absorbance the product provides at each SPF sunscreen products that do not pass wavelength in the UV spectrum (i.e., and early skin aging’’ and that ‘‘[t]his FDA’s current critical wavelength-based product has been shown only to help from 290 to 400 nm). The ‘‘critical broad spectrum test or that (though they wavelength’’ of the product is the prevent sunburn, not skin cancer or pass our current broad spectrum test) early skin aging’’ (§ 201.327(d)(2)). wavelength corresponding to 90 percent have inadequate uniformity in their of the area under this curve. Higher 2. Increased Evidence of Harms UVA protection. Consumers using these critical wavelengths, therefore, illustrate Associated With Exposure to UVA products may, while successfully greater breadths of UV protection across Radiation preventing sunburn, accumulate the 290 to 400 nm spectrum. excessively large doses of UVA Since publication of the 2011 L&E radiation, thereby exposing themselves Most sunscreen products—even if Final Rule and Max SPF PR, the to additional risks related to skin cancer they achieve a critical wavelength of strength of scientific evidence linking and early skin aging. The International 370 nm or greater and therefore meet the UVA exposure to skin cancers and other Agency for Research on Cancer has current criteria for broad spectrum harms has increased. This evidence found that high SPF sunscreen products labeling—have historically covered the suggests that UVA wavelengths are associated with longer intentional UVB and UVA II ranges preferentially. continue generating DNA lesions hours UV exposures (Ref. 171), raising the Given how much of the UVA portion of after UV exposure (Ref. 161) and that if concern that use of these products may the UV spectrum is composed of UVA left unrepaired, these DNA lesions can result in significant doses of UVA I radiation (see Figure 3 below) and form UV-induced mutations in many radiation. We note that concerns given what we now know about the genes that have been detected in both relating to inadequate UVA protection risks associated with UVA exposure, melanoma and nonmelanoma skin came up in several comments we and with UVA I exposure in particular, cancers (Refs. 162 to 165). Further, received in response to the 2011 Max ensuring that sunscreen products unlike UVB-induced DNA lesions, SPF PR, and that these comments raised provide adequate protection in the UVA which attenuate with skin depth, recent particular concerns about inadequate I portion of the spectrum is critical. evidence indicates that DNA lesions UVA protection in high SPF products. induced by UVA I exposure show the This concern has also grown over time 40 We note that, as described in section IX.D.2.i, opposite pattern, with both increased in the published literature (Refs. 172 to we are proposing a minor revision in equipment specifications for the broad spectrum test to DNA lesions in the basal layer of the 175). respond to feedback that FDA received on this issue epidermis (where melanocytes and For all of these reasons, we are and proposing some minor revisions to current proliferating keratinocytes reside) and proposing a number of steps designed to language to make clear our existing expectations.

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We are therefore proposing to require particular combination of active indicating that ‘‘[t]he proposed ratio that in order to pass the broad spectrum ingredients used in the product and places too much emphasis on the UVA test, a product must demonstrate that it which parts of the UV spectrum they I region, which is not generally provides a UVA I/UV ratio of 0.7 or absorb). For example, under the current considered to contribute significantly to higher, indicating that the product testing regime, a sunscreen that is the harmful effects of exposure to UV provides a minimum measure of UVA I labeled ‘‘broad spectrum SPF 30’’ could radiation’’ (76 FR 35620 at 35650), we radiation absorbance relative to total UV provide less UVA protection than a made a number of changes to our 2007 radiation (i.e., UVB + UVA) absorbance, sunscreen labeled ‘‘broad spectrum SPF proposal in the 2011 L&E Final Rule. in addition satisfying to the 370 nm 15.’’ Those changes included elimination of critical wavelength requirement. We note that FDA first raised the UVA I/UV ratio and adoption of the Requiring a UVA I/UV ratio of 0.7 or concerns relating to the adequacy of above-described critical wavelength test higher for broad spectrum products UVA protection in sunscreen products for establishing broad spectrum would mean that these products would in 2007 (see 72 FR 49070 at 49104 to protection instead. As we noted in the have a more uniform amount of 49107). At that time, we proposed a preamble to the L&E Final Rule, our radiation protection across the UVA I, similar ratio to the one we are proposing decision not to require the UVA I/UV UVA II, and UVB ranges. This improved today as part of a different, more ratio at that time was based, in part, on fidelity across the UV spectrum is complex proposal for testing and our agreement with comments stating especially important for high SPF labeling to address broad spectrum that the scientific evidence available at products which, as discussed above, are protection that, among other things, that time indicated that UVA I exposure associated with longer intentional sun included both in vitro did not pose sufficient risk of harm to exposure, which in turn can result in (spectrophotometric) and in vivo justify the emphasis placed on it by the significant doses of UVA radiation. This (clinical) testing for UVA radiation, as ratio, and that the critical wavelength proposed UVA I/UV ratio would also well as a four-tier UVA star rating test provided a superior measure of help eliminate the current potential for labeling system. In response to broad spectrum protection (id. at a product labeled as broad spectrum comments describing purported 35650). that has a higher SPF value to provide disadvantages of that proposal, As described above, in the time since (unbeknownst to the consumer) poorer including general comments that the issuance of the L&E Final Rule, the body broad spectrum protection than a proposal was overcomplicated, specific of evidence showing the harms of UVA product labeled as broad spectrum with comments on the proposed in vitro exposure, and of UVA I exposure, in a lower SPF value (depending on the testing method, and comments particular, has grown significantly (Refs.

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159, 161, 162, 166, 167, and 169). It is higher levels of UVA radiation than if current labeling regime, in which a now clear that in addition to producing they had not been protected from higher numbered product (for example, the immunosuppression described sunburn. Given the increasing evidence one labeled SPF 30) may provide above, UVA I exposure also results in of major health risks associated with inferior protection against UVA increasing DNA damage with increasing UVA exposure, we propose to find that radiation than a lower numbered skin depth (in contrast to UVB-induced such products (those with SPF values of product (for example, one labeled Broad DNA damage, which is reduced as skin 15 and greater that do not provide Spectrum SPF 15). depth increases). In addition, given that sufficient protection across the UV c. Sunscreen products with SPFs <15. UVA I is the predominant portion of spectrum (as demonstrated by satisfying As noted above and in section III.A.2, UVA radiation, new evidence FDA’s revised broad spectrum sunscreen products with SPF values (discussed in section IX.B.2) requirement)) are not GRASE. At the below 15 have not been shown to strengthening the link between UVA same time, we conclude that the reduce the risk of skin cancer or early radiation and skin cancer development evidence described above regarding the skin aging caused by the sun, whether raises our concerns about the potential contribution of UVA I to skin or not they provide broad spectrum for inadequate protection in the UVA I carcinogenesis, coupled with the protection. Because of this limitation, portion of the UV spectrum. evidence reviewed in the 2011 L&E we considered proposing to remove Accordingly, we no longer agree with Final Rule (see 76 FR 35620 at 35630– from the monograph sunscreen products the earlier comments suggesting that 35634), supports the proposal to include with SPF values lower than 15. UVA I does not contribute significantly sunscreen products that have an SPF of However, as the Surgeon General has to the harmful effects of exposure to UV 15 or higher and also pass the revised acknowledged (Ref. 5), some consumers radiation, or with our 2011 conclusion broad spectrum test in the sunscreen may seek intentional sun exposure that a UVA I/UV ratio requirement monograph with indications both for because (for example) they associate would therefore place too much use to help prevent sunburn and for use, tanned skin with attractiveness and emphasis on this portion of the UV as directed with other sun protection health. These consumers may seek some spectrum. measures, to reduce the risk of skin protection from sunburns and therefore, We emphasize that we are not cancer and early skin aging caused by select a low SPF product (i.e., one with proposing to replace the existing critical the sun. As we indicated in the L&E an SPF value below 15). If such wavelength test, and that the proposed Final Rule, the whole range of UV products are removed from the market, ratio would supplement (and be radiation, and not specific wavelengths, these consumers may choose not to use calculated using data from) the existing is a human carcinogen, and the exact a sunscreen product at all rather than broad spectrum test. We also note that wavelengths most responsible for these use a broad spectrum product with an the UVA I/UV ratio we are proposing harmful effects are not known (see id. at SPF of 15 or above. would result in a level of UVA 35631, 35633). To assure that a Although the benefits of sunscreen protection similar to what is achieved clinically meaningful reduction in the products with SPFs below 15 (which are via the European Union’s recommended risks of skin cancer and early skin aging not indicated to reduce the risk of skin 1 minimum UVA protection factor of ⁄3 of is achieved, then, a product must cancer or early skin aging) are limited, the labeled SPF and via the United contribute to substantially limiting FDA believes that the use of such Kingdom’s Boots 3-star rating (the overall UVB and UVA exposure (see id. products is preferable to the use of no United Kingdom has for decades used a at 35630, 35631–35632), as will be sunscreen at all. Thus, to provide sunburn protection for these consumers, tiered star rating system based on an assured by our proposal to couple the FDA is proposing that sunscreens with alternative ratio method) (Refs. 173 and enhanced breadth of protection across SPF 2 to 14 that bear prominent labeling 174). We note that data collected in the UVA spectrum provided by the regarding their limited use for sunburn 2009 about 330 sunscreen products revised pass criteria for the broad prevention and the risks associated with commercially available in the United spectrum test with the magnitude of spending time in the sun (see sections States showed that, at that time, more protection assured by requiring a IX.B.1 and IX.C) may remain on the than half of these products already minimum SPF of 15. satisfied the broad spectrum test we are By requiring that all sunscreens with market without approved NDAs. now proposing (see Comment, Docket SPF values of 15 or more satisfy the Because products with SPFs below 15 No. FDA–1978–N–0018–0690). (new) broad spectrum standard have not been demonstrated to reduce b. Broad spectrum requirement for all (including the new ratio requiring the risk of skin cancer, FDA is not products that are ≥SPF 15. We are also proportionate protection), this proposal proposing to require products with SPF proposing to require that all sunscreen will also enable consumers to select a values under 15 to pass the broad products with SPF values of 15 and product primarily by numerical (SPF) spectrum test. However, we seek above demonstrate that they provide value on the label, having assurance comment on whether the limited more uniform protection across the that, when used as directed, a product benefits such sunscreen products confer UVA I, UVA II, and UVB ranges of the labeled with a higher numerical SPF outweigh the risks of sunscreen drug UV spectrum by satisfying FDA’s value provides proportionately more exposure and the potential false sense of revised broad spectrum test. This security provided regarding UV proposal is designed to link increases in protection not only against sunburn, but also against skin cancer and skin aging protection (i.e., whether such sunburn- SPF value not only to increases in UVB only sunscreen products are GRASE and than lower numbered products 41 protection, but to increases in the should remain on the market without (provided that the product provides an magnitude of UVA protection as well. approved NDAs). We note that a consumer using a SPF of at least 15). In doing so, this sunscreen that provides robust proposal also eliminates another source 4. Maximum SPF Value Proposals protection against sunburn but that does of potential confusion permitted by the a. Maximum labeled SPF value would not pass FDA’s revised broad spectrum be SPF 60+. In conjunction with the 41 As noted in section III.A.2, only those broad test—and therefore provides inadequate spectrum sunscreen products that have an SPF of broad spectrum proposals described UVA protection—may fail to get out of 15 or higher have been shown to help prevent skin above, we are also proposing to raise the the sun, thereby exposing themselves to cancer and early skin aging. maximum labeled SPF value for

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products containing sunscreen light eruption in subjects using broad on the subject’s back. Because the monograph active ingredients to SPF spectrum SPF 60 versus SPF 50 administered UV dose series for the 60+. Under this proposal, sunscreen products (Ref. 179)). Based on the final minimal erythema dose (MED) 43 of products with SPF values of 60 or additional meaningful clinical benefit a sunscreen with an expected SPF of 60 greater would be labeled ‘‘SPF 60+.’’ provided by broad spectrum SPF 60 increases by 15 percent with each FDA has proposed to raise the sunscreens shown in these studies, we successive dose (see § 201.327(i)(5)(iii)), maximum SPF value that sunscreens are proposing to raise the maximum a difference in judgment of one site in marketed pursuant to the OTC labeled SPF value to SPF 60+. opposing directions would result in up Monograph System can display on their Because the studies demonstrating the to approximately 30 percent variability labeling several times. In the 1978 additional meaningful clinical benefit in the assessment of the amount of notice of proposed rulemaking, we provided by SPF 60 sunscreens all used exposure that resulted in the proposed that such sunscreens be sunscreens that also provided broad erythema.44 labeled with a maximum SPF value of spectrum protection, however, the Allowing the marketing of sunscreen 15 (43 FR 38206 at 38213 to 38214). In additional clinical benefit shown to monograph products with determined the 1999 final monograph, we exist at SPF 60 cannot be decoupled SPF test results up to 80 would, determined that that cap should be from the broad spectrum protection therefore, more fully account for the increased to SPF 30+ (64 FR 27666 at provided by those products. That is, the range of variability in SPF test results 27675). In 2007 (72 FR 49070 at 49085 additional meaningful clinical benefit for sunscreen products labeled SPF 60+. to 49087) and then in 2011 (Max SPF shown in these studies may have been We are also proposing this formulation PR), we tentatively concluded that data the result of the sunscreens’ protection margin to provide manufacturers with existed to show that sunscreens with against rays in the UVB range or in the additional formulation flexibility that labeled SPF values of up to 50+ provide UVA range, or both. For this reason, our we hope will help facilitate the additional clinical benefit to consumers. proposal to recognize the additional development of products with greater Our proposal today to increase the meaningful clinical benefit provided by UVA protection, given our expectation maximum labeled SPF value to 60+ is sunscreens with SPF values above 50 is that active ingredients added for the similarly based on data showing the consistent with, and dependent upon, primary purpose of increasing UVA additional clinical benefit provided by our proposal that all sunscreen products protection would contribute to a SPF 60 sunscreen products when those with SPF values of 15 and above be sunscreen’s determined SPF value as products also provide broad spectrum required to provide broad spectrum well. We seek comment on whether SPF protection. protection. 80 is the appropriate formulation cap to In the 2011 Max SPF PR proposing an Given the lack of data showing that accomplish these objectives. SPF 50+ cap, we noted that the record, sunscreens with SPF values above 60 We are proposing not to allow the at that time, lacked adequate data provide additional meaningful clinical marketing (without an approved NDA) demonstrating that sunscreen products benefit, however, we are proposing not of sunscreen products with determined with SPF values above 50 provided to allow labeled SPF values higher than SPF values above SPF 80. This proposal additional meaningful clinical benefit 60+. Labeling sunscreen products with follows from the principle that if the over and above what was provided by SPF values higher than what has been addition of ingredients to a drug does SPF 50 protection (76 FR 35672 at shown to provide additional meaningful not provide additional clinical benefit 35672 to 35674). We requested data clinical benefit could have unintended but potentially increases the risk showing that such clinical benefits negative consequences. For example, as associated with the drug, this shifts the existed (id.). In response to both the discussed above, such products may benefit-risk calculation and renders the 2007 and 2011 proposals, we received inadvertently promote extended solar drug not GRASE (see, e.g., 76 FR 35673 comments providing citations to data exposures because consumers feel at 35675). In light of this principle, we showing the additional meaningful protected and assume that the higher solicited comments in 2011 on the clinical benefit provided by sunscreen SPF value implies that greater UV appropriateness of a formulation cap for products with SPF values of 60 for exposure is safe (see, e.g., Autier, et al., sunscreen products (id.). certain at-risk populations when those 2007 (Ref. 171)). Some of the comments that we sunscreens also included broad b. Formulation cap for sunscreen received in response to the 2011 Max spectrum protection. (See, e.g., Ulrich et products of SPF 80. Although we are SPF PR expressed concerns (in general) al. (showing statistically significant proposing that the maximum labeled about the safety of unnecessary protection of organ transplant SPF value will be SPF 60+, we are exposure to sunscreen active recipients, who are highly susceptible to proposing to permit the marketing of ingredients. We received only one nonmelanoma skin cancer, from sunscreen products formulated with comment, however, directly addressing squamous cell carcinoma with use of determined 42 SPF values up to 80. We the question of an SPF formulation cap. broad spectrum SPF 60 sunscreen) (Ref. are proposing to permit this additional That comment emphasized that there 176); see also Comment FDA–1978–N– formulation margin in part because of was no formulation limit in other 0018–0710, August 31, 2011, citing the inherent variability in SPF test countries using an SPF labeling cap, and Kuhn et al. (showing statistically results. A sunscreen product’s SPF significant prevention of skin lesions in value is calculated from measurements 43 The minimal erythema dose (MED) is the topical lupus erythematosus patients that are based on an investigator’s visual smallest UV dose that produces perceptible redness with use of broad spectrum SPF 60 evaluation of an individual test subject’s of the skin (erythema) with clearly defined borders sunscreen after exposure to either UVA erythema response to a series of UV at 16 to 24 hours after UV exposure (§ 201.327(i)(5)(i)). I source or UVA II/UVB source) (Ref. doses administered in successive sites 44 The determination of SPF for each subject is 177); Faurschou et al. (showing calculated via a ratio of the MED of protected skin prevention of urticarial reaction in 42 As used in this preamble, the determined SPF over the final MED of unprotected skin. In a subjects with idiopathic solar urticaria value is the SPF value that equals the largest whole scenario in which the final MED of unprotected number less than SPF¥(t*SE), determined for a skin is underestimated by 15 percent and the MED with use of broad spectrum SPF 60 sunscreen product in accordance with § 201.327(i). of protected skin is overestimated by 15 percent, sunscreen) (Ref. 178); Fourtanier et al. See also section IX.D.2.b, where we propose to this would present approximately 30 percent (showing lower levels of polymorphous define this term in the regulation. variability for the individual subject.

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that the list of permitted active This proposal is designed to avoid lab was not told the target SPF, but was ingredients in the monograph itself misleading consumers about the relative rather given a range of SPF 20 to 100 for establishes an SPF ceiling for the efficacy of sunscreen products, given a product with an expected SPF of 100. formulation as a whole. FDA rejects the the lack of clinical data showing The results showed that it was premise that the list of permitted active meaningful efficacy differences between extremely difficult for labs to reproduce ingredients establishes an adequate SPF closely grouped SPF values. We note the labeled SPF 100, with mean SPF cap for sunscreen formulations, as this that in the 2011 L&E Final Rule, FDA values ranging from 37 to 75. In a theory does not take into account the declined a request that SPF be labeled second study with multiple panels of 25 potential addition of new GRASE in multiples of five, stating that there subjects that was controlled and ingredients to the list of active was no mathematical or statistical basis randomized, the determined SPF of two ingredients under the monograph. This for this labeling approach because SPF sunscreen formulations tested across comment also appears to imply that the values could generally be determined four labs ranged from 63 to 69 for a maximum concentration of each active with a precision that allowed for SPF target SPF 70 and from 82 to 89 for a ingredient correlates specifically to a values to be labeled in intervals of less target SPF 90 (Ref. 182). Although the particular numerical contribution to the than five units. New data showing magnitude of the differences observed total SPF value of the product. This has variability both between tested SPF in this second study were not not been established (see 64 FR 27666 values for individual study subjects and statistically significant, the fact that at 27674 and 27675 (noting that for determined SPF results achieved multiple labs determined different formulation techniques may enable across multiple labs testing the same specific numerical values for a single increases in SPF without use of higher sunscreen formulation (i.e., variability formulation suggests that the use of concentrations of active ingredients)). In inherent in a clinical test that relies on labeled values representing ranges more addition, as mentioned in 2011 in the visual assessments) (FDA–1978–N– accurately represents the sun protection Max SPF PR (76 FR 35672 at 35674), the 0018–0740, 2011; Ref. 182), however, provided by a product, and therefore is theoretical increase in protection has caused us to reexamine this issue. appropriate to avoid misleading implied by higher SPF values generated As described above, the clinical SPF consumers. in a laboratory does not necessarily test is conducted using a solar simulator We note that variability in SPF values correspond to meaningful additional to administer several specified doses of is exacerbated at high SPFs. For sunburn protection for consumers in UV radiation that increase by 15 to 25 example, individual test results with 30 actual use conditions. Given that a solar percent with each successive dose to a percent variability from a determined simulator in a lab can produce much human subject’s back in both sunscreen- SPF value of 20 would range from SPF higher UV doses than a consumer would treated and untreated areas (with the 14 to SPF 26; individual test results receive from the sun (even in the most specific UV doses being derived from with 30 percent variability from a extreme situations), it is unlikely that a the expected SPF of the product and a determined SPF value of 50 would consumer could ever actually reach the determination of the individual range from SPF 35 to SPF 65. theoretical ceiling created by the list of subject’s UV sensitivity). The clinical Accordingly, as shown in table 5, we permitted active ingredients. investigator then visually evaluates both propose that the range of tested values Given the lack of demonstrated the sunscreen-treated and untreated reflected in the labeled SPF number clinical benefit for sunscreens with areas of the subject’s back to identify the should be wider at higher SPF values determined SPF values above SPF 60, areas with perceptible skin redness and narrower at lower ones, and that the and the potential for risks—discussed (erythema) that has clearly defined requirement that labeled SPF values elsewhere in this document—associated borders. Determining which of several correspond to ranges rather than precise with exposure to sunscreen active areas on a single subject’s back should numerical values is not necessary below ingredients, we propose not to permit be considered to meet this ‘‘clearly SPF 15. the marketing (without an approved defined borders’’ criteria is an exercise NDA) of sunscreen products with of clinical judgment. Once the TABLE 5—PROPOSED SPF LABELING determined SPF values above SPF 80 investigator has made this judgment, he RANGES (which reflects a formulation margin or she then records the smallest dose of intended both to give full effect to the UV radiation it took to create an area Range of SPF 60 limit and to enable formulation with the observed skin reaction of Associated labeled SPF determined value flexibility). erythema with clearly defined borders. SPF values c. Proposal for ≥SPF 15 labeling. After assessing multiple individual test Finally, we are proposing to require that subjects this way, the resulting UV 60–80 ...... 60+. 50–59 ...... 50. sunscreen monograph products with exposure information is used in determined SPF values of 15 or above be 40–49 ...... 40. calculating the determined SPF value of 30–39 ...... 30. labeled with an SPF number the sunscreen being tested. The data we 25–29 ...... 25. corresponding to the lowest number in reviewed suggest that the clinical 20–24 ...... 20. a range of tested SPF results, as shown evaluation undertaken during this 15–19 ...... 15. in table 5.45 For example, sunscreens process creates variability that justifies 2–14 ...... Determined SPF Value. testing at SPF 15 to 19 would be labeled the use of SPF ranges. ‘‘SPF 15’’; those testing at 40 to 49 For example, in a study using panels C. Proposed PDP Labeling Requirements would be labeled ‘‘SPF 40.’’ 46 of five subjects, the mean SPF values We are also proposing some revisions observed across multiple labs ranged to the principal display panel (PDP) for 45 We note that the use of ranges to represent SPF from 54 to 82 for a target SPF 80 (FDA– sunscreen products (the PDP is the values on product labeling is already in use in 1978–N–0018–0740, 2011). This same Australia and the European Union (Refs. 180 and portion of an OTC drug product label study also evaluated a scenario where a 181). that is most evident when the product 46 The proposed labeled values are expressed in is displayed for retail sale (§ 201.60)). In increments of 5 for products with determined SPF proposed labeled values are expressed in results of 15 to 29.9 (i.e., SPF 15, SPF 20, SPF 25), increments of 10 (i.e., SPF 30, SPF 40, SPF 50, with addition to satisfying general OTC drug but for determined SPF results of 30 or more, the a proposed maximum of SPF 60+.). labeling requirements found in part 201,

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sunscreen product PDPs are currently given product accordingly. As an with no intervening text or graphic. To required to satisfy specific labeling indication that consumers value further ensure the prominence and requirements in § 201.327. We are information about a sunscreen’s active readability of information that is proposing to amend these requirements ingredients, an analysis of top-rated important for consumers to evaluate and for sunscreen PDP labeling (currently sunscreen product reviews on compare sunscreen products, we codified in § 201.327(a) and (b), and (for Amazon.com found that product propose that these statements must also the statement of identity of products ingredients were listed as a positive appear in bold typeface at least one- that also include skin protectants) in factor in 17 percent of responses, and a fourth the size of the most prominent § 201.327(h)) to help consumers better negative factor in 10 percent of printed matter on the PDP, and as text understand, evaluate, and compare responses (Ref. 183). generally parallel to the base of the sunscreen products by providing Based on a review of marketed packaging. additional information on the PDP, and sunscreen product labels, FDA is The proposed new ‘‘*See Skin by ensuring the prominence and concerned that the SOI may currently be Cancer/Skin Aging Alert’’ statement readability of information required to obscured by the inclusion and would also be required to appear in bold appear on the front of the container or prominence of other printed or graphic typeface at least one-fourth the size of package. We are also proposing to information on the PDP. For this reason, the most prominent printed matter on renumber and consolidate provisions on we also propose to require the SOI to the PDP, and as text generally parallel PDP labeling and the statement of appear in direct conjunction with the to the base of the packaging. In addition, identity (SOI) in § 201.327(b) to most prominent display of the the entire statement would appear in the incorporate new proposed provisions in proprietary name, in a boldface font at same font style, size, and color with the § 201.327(a), as described in section least one-fourth the size of the most same background color, and as IX.D.2.b of this preamble. In addition, prominent printed matter on the PDP, continuous text with no intervening text we are proposing that labeling a and displayed so that the text is or graphic. sunscreen product in accordance with generally parallel to the base of the Finally, because water resistance is proposed § 201.327(b) would be a packaging. We propose that the entire also an important characteristic for condition for marketing a sunscreen SOI appear in the same font style, size, consumers when choosing a sunscreen, under the OTC sunscreen monograph in and color with the same background we also propose to apply comparable part 352. color, and as continuous text with no format requirements to the current We are proposing to revise the current intervening text or graphic material ‘‘Water Resistant’’ statement. The SOI, which is required to appear on the other than text provided in accordance statement would also be required to PDP by both current and proposed with the requirements for the SOI for a appear in bold typeface at least one- § 201.327. Currently, the SOI for product that also includes a skin fourth the size of the most prominent sunscreens under this regulation protectant, where applicable. These printed matter on the PDP, and contains ‘‘the established name of the requirements would supplement, and displayed so that the text is generally drug, if any’’ and identifies the product not replace, the general requirements parallel to the base of the packaging. In as a ‘‘sunscreen.’’ The revised SOI regarding the PDP and SOI for all addition, the entire statement would would consist of an alphabetical listing nonprescription products in §§ 201.60 appear in the same font style, size, and of all sunscreen active ingredients in the and 201.61. color with the same background color, product using the names shown in Proposed § 201.327(b) would and as continuous text with no § 201.327, followed by ‘‘Sunscreen’’ and incorporate the ‘‘Broad Spectrum SPF,’’ intervening text or graphic. the product’s dosage form (such as ‘‘SPF,’’ and ‘‘Water Resistant’’ lotion or spray). In light of these statements that already must appear on D. Proposed Requirements Related to proposed changes to the SOI for the PDP as described in current Final Formulation Testing and sunscreens, we are also proposing § 201.327(a). Additionally, for all Recordkeeping harmonizing changes to the provisions products with SPF values below 15, we We are also proposing a number of that address the SOI for products that propose to require that the SPF revisions in § 201.327: (1) To ensure that combine sunscreen and skin protectant statement be followed by an asterisk (*) efficacy testing of the sunscreen active ingredients (proposed directing the consumer to the statement formulation to be marketed is conducted § 201.327(h) and cross-referenced in the ‘‘*See Skin Cancer/Skin Aging Alert.’’ in a way that protects human subjects sunscreen monograph in § 352.60 (21 We propose that the quoted statement and produces reliable results and (2) to CFR 352.60) and in the skin protectant must appear in the bottom 30 percent of enable FDA to assess compliance with monograph in § 347.60 (21 CFR the PDP. This statement is intended to this section’s provisions going forward. 347.60)). draw the consumer’s attention to the We also propose to make compliance The proposal to list all active Skin Cancer/Skin Aging Alert that with these requirements a monograph ingredients as part of the SOI is would continue to be required for these condition in part 352. generally consistent with SOI labeling of products as part of the ‘‘Warnings’’ in other OTC and prescription drugs. the Drug Facts portion of the label 1. General Approach to Final Providing information about a product’s (§ 301.327(d)), because there is evidence Formulation Testing active ingredients and dosage form that some sunscreen consumers are not Current § 201.327 includes technical would supplement other important reading this information in its current instructions for conducting the final elements of the PDP (SPF, broad location (Refs. 184 and 185). formulation testing required to support spectrum, and water resistance Under the current regulation, the the SPF values, water resistance information) to provide a succinct entirety of the ‘‘Broad Spectrum SPF’’ or statements, and broad spectrum summary of the product’s key ‘‘SPF’’ statement, as applicable, must statements shown in sunscreen product characteristics on the front of the appear on the sunscreen PDP in the labeling. However, the current package or container. We expect that same font style, size, and color and with regulation does not explicitly address this approach would enable consumers the same background color, and, if used, important broader considerations that to more readily compare differing the ‘‘Broad Spectrum SPF’’ statement are essential to ensure that final products and either select or avoid a must also appear as continuous text formulation testing is conducted and

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documented in a way that verifiably actions to verify the reliability of final test reports are accurate and valid. This provides for protection of human formulation testing under the current is also true with respect to subjects in SPF and water resistance provisions of § 201.327 have raised documentation of emission spectrum, testing, as well as ensuring the some questions about current practices. the percentage of erythema-effective reliability of all the testing data that For example, FDA’s observations have radiation contribution, and changes to underlies sunscreen labeling. We expect raised questions about whether and how solar simulator components and the UV that persons responsible for conducting entities conducting final formulation meter/dose controller system. Failure to final formulation testing should already testing have put in place protocols and accurately calibrate and maintain be following best practices in their IRB oversight to ensure that test subjects equipment at one testing entity may current testing programs. However, we do not repeat participation in testing affect data across multiple clinical SPF are concerned that many entities may with a frequency that could both testing studies and/or broad spectrum not uniformly observe such practices compromise the ability to distinguish testing for multiple different final and/or may not maintain the records erythemic reactions to the test article formulations that are ultimately sold needed to document compliance with and raise other questions about human under different labels. Inadequate the final formulation testing procedures subject protection. We are concerned recordkeeping may interfere with set forth in § 201.327. FDA’s experience that the lack of explicit requirements efficient enforcement. We propose to in conducting inspections and other with regard to IRB oversight, as well as address these concerns and align the actions to verify testing under the the cursory nature of the informed regulation with our existing current provisions of § 201.327 have consent requirement in the current expectations through revised regulatory suggested latent problems in these areas. sunscreen labeling regulation, may provisions that are described further in Although limited, this experience result in inconsistent practices in the the following sections. reinforces FDA’s belief that further conduct of SPF testing that would 2. Specific Regulatory Proposals clarification of regulatory expectations compromise the reliability of results. is necessary given the public health Among other things, IRB review is a. Consequences of failure to observe importance of ensuring that sunscreen critical to verify the adequacy of best practices. We propose to clarify in products are effective and accurately informed consent and to ensure that the introductory paragraph of § 201.327 labeled, and the broad range of entities study protocols incorporate appropriate that a product is deemed misbranded if that may be involved in bringing inclusion/exclusion criteria for subject its labeling relies on the results of final sunscreen products to market. Thus, we selection (both to protect test subjects formulation testing that was not are proposing to incorporate FDA’s and to ensure the accuracy of results). conducted in compliance with all of the current expectations more explicitly in b. Qualifications of study personnel. applicable provisions of § 201.327. the revised provisions. The proposed In some instances, it may not be clear Unless testing is conducted in provisions are broadly consistent with upon inspection whether all aspects of compliance with all applicable current best practices for efficacy testing a study were conducted by provisions of § 201.327, FDA does not conducted in human subjects, and are appropriately qualified personnel. For have adequate assurance that the not expected to require significant example, FDA would not consider it labeling reliably reflects the properties changes by reputable and experienced adequate for a technician, rather than an of the sunscreen product. Therefore, if testing establishments. Key areas of appropriately trained medical final formulation testing is not properly concern that are addressed by the professional (such as, for example, a conducted in accordance with this proposed revisions include the nurse or dermatologist), to perform a section, labeling a sunscreen with an following. physical examination for potential nevi, SPF value or representation of water a. Protection of human subjects and moles, or other dermal lesions. As with resistance or broad spectrum properties oversight of clinical final formulation all clinical and nonclinical testing done based on that testing is a testing. Ensuring that clinical final to support labeling, the use of properly misrepresentation to the consumer that formulation testing is both designed and trained and appropriately qualified the labeling reliably states the product’s conducted in a manner that will yield personnel is essential to ensure the properties, which should also be reliable results is critical, as is ensuring reliability and accuracy of test results. consistent with a system of standardized the protection of the human subjects on Documentation of the qualifications and sunscreen labeling that can be used to whom SPF and water resistance testing training of personnel is also necessary to make cross-product comparisons. We are conducted. Existing provisions enable FDA’s efficient enforcement of propose to incorporate the provisions of within the SPF test in § 201.327(i)(3)(iv) the FD&C Act. § 201.327(a) through (l) into part 352 as require that informed consent be c. Documentation of equipment conditions under which a sunscreen is obtained, but do not otherwise specify maintenance, study methods, and GRASE and not misbranded. If these what this should involve or how clinical observations. Failure to maintain provisions are finalized, failure to final formulation testing should be adequate records of testing equipment, comply with these conditions would overseen. Across disciplines, testing methods, and observations can raise make a drug subject to regulatory action involving human subjects is ordinarily broad questions about the reliability of as misbranded and an unapproved new conducted under institutional review final formulation testing. In FDA’s drug. board (IRB) oversight as a means of experience since the promulgation of b. General obligations of responsible ensuring that informed consent and current § 201.327, there has been a lack persons. We are aware that many other human subject protections are of uniformity in testing entities’ different business relationships provided and ensuring the integrity of approaches to recordkeeping for final involving numerous entities are study design and execution. FDA formulation testing, raising concerns commonly used in the manufacturing, likewise expects that IRB review is about the adequacy of recordkeeping testing, and labeling of nonprescription already routinely being obtained by procedures. Failure of testing entities to sunscreen drug products. To clarify the many establishments for SPF and water keep adequate records to support final locus of responsibility for ensuring that resistance testing. formulation testing may leave FDA adequate final formulation testing Nonetheless, our experience in unable to verify that the UV doses procedures are in place, and to clearly conducting inspections and other provided in SPF and water resistance delineate responsibility for

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recordkeeping related to final ensure that investigators and other matter of good clinical practice, IRB formulation testing, FDA proposes a personnel conducting investigations approval should already be routinely new defined term, responsible person. under § 201.327(i) comply with currently obtained for clinical final We propose to define the term requirements related to human subject formulation testing under current responsible person in a way that is protection and the appropriate conduct § 201.327 because it is essential to consistent with FDA’s treatment of of clinical testing. We believe that this producing results that are scientifically regulatory responsibilities for other OTC better reflects the employer/employee sound and ethically appropriate. drug products and that is in alignment relationships that are more common in Because clinical final formulation with requirements for adverse event connection with final formulation testing required to support labeling reporting for over-the-counter drug testing rather than with clinical testing under current § 201.327 is not products, in section 760(b)(1) of the conducted under an IND. These conducted under an IND or in support FD&C Act. The proposed definition for proposed provisions regarding selection of a GRASE determination in the OTC responsible person is ‘‘the manufacturer, of personnel are also consistent with the sunscreen monograph, it was not packer, or distributor whose name existing obligations of manufacturers previously included explicitly in the appears on the labeling of a sunscreen under parts 210 and 211 (21 CFR parts scope of testing covered by parts 50 and product covered by this section.’’ 210 and 211), both of which govern 56. We propose to rectify this omission Defining responsible person in this way compliance with CGMPs. by explicitly cross-referencing parts 50 will enable FDA to better assess The proposed revision of and 56 in revised § 201.327(i). This will compliance with § 201.327 because it § 201.327(a)(1) permits a responsible clarify that both of these parts apply to creates a chain of responsibility that is person to transfer some or all of its clinical final formulation testing and immediately apparent from the obligations to another entity, consistent will resolve any inconsistency in product’s labeling. The responsible with current industry practice, except current practice. person, as identified on the labeling, is for obligations with respect to The proposed reference to part 50 ultimately responsible for ensuring that recordkeeping. The recordkeeping clarifies FDA’s position that legally the product bearing its name is labeled proposal is discussed in section IX.D. effective written informed consent to in accordance with the requirements of Failure of an entity to comply with participate in clinical final formulation § 201.327. provisions of this part governing testing should share the same properties The proposed revision of § 201.327(a) responsibilities it has assumed would as informed consent required for all would broadly set forth the general subject that entity to the same regulatory other clinical testing covered by FDA’s obligations of responsible persons with action as if it were a responsible person regulations in part 50. Similarly, by respect to final formulation testing who had failed to comply with those referencing part 56, the proposal under § 201.327(i) and (j), and it would obligations. This provision is analogous ensures that final formulation testing is make clear that the responsible person to the provision in FDA’s regulations at held to the same standards for IRB is charged with ensuring that sunscreen part 312 allowing for transfer of review as other clinical testing covered products are appropriately tested. The obligations of IND sponsors. by FDA’s regulations. In reviewing obligations of responsible persons as c. Adequate clinical testing clinical protocols, IRBs have the ability enumerated in § 201.327 are modeled procedures and conditions. Although to determine whether the protocol is after those of investigational new drug current § 201.327 requires ‘‘legally adequately designed to study the application (IND) sponsors under part effective written informed consent from endpoints sought, and to ensure that 312 (21 CFR part 312), but are somewhat all test subjects’’ (§ 201.327(i)(3)(iv)), it protocol elements, such as enrollment modified to accommodate unique does not address broader underlying criteria, adequately protect both human aspects of clinical and nonclinical requirements for conducting clinical subjects and the scientific rigor of the sunscreen formulation testing. Because testing. In light of the concerns we experiment. final formulation testing under identified regarding current clinical d. Control of personnel. We propose § 201.327(i) and (j) is intended to verify testing procedures and conditions, we to place responsibility on the the claimed properties of a final propose to amend § 201.327 by adding responsible person to ensure that formulation, and because this purpose is paragraph (i)(1), ‘‘Adequate Clinical investigators and other personnel narrower in scope and duration than Testing Procedures and Conditions.’’ conducting clinical final formulation most clinical testing performed under We expect that final formulation testing testing adhere to the investigational FDA’s IND regulations in part 312, a conducted in compliance with the plan, the signed investigator statement, responsible person under proposed proposals in this paragraph will be more and all applicable regulations. We also § 201.327 would have responsibilities likely to ensure protection of human propose to place responsibility on the that incorporate some of the traditional subjects while also more reliably responsible person for ensuring human responsibilities of investigators as well determining the SPF value and water subjects’ protection, including through as those of sponsors under part 312. For resistance properties of the final appropriately reporting changes in the example, FDA proposes to clarify that formulations being tested. Unless testing to IRBs, and by appropriately responsible persons must select appropriate clinical testing procedures seeking prior IRB approval for any appropriately qualified personnel to and conditions are adhered to, FDA changes to the testing, except where conduct testing, ensure compliance with cannot have confidence in the resulting necessary to eliminate apparent the requirements for IRB review and labeled SPF and water resistance immediate hazards to human subjects. obtaining informed consent, and properties of the product. Under the proposed rule, responsible monitor the compliance of personnel Proposed § 201.327(i)1(B) and (C) persons are also expected to obtain from with investigators’ statements. have been added to make clear that each investigator, and retain for their This proposed approach accounts for FDA’s regulations governing informed records, a signed investigator statement. situations in which investigators and consent (part 50 (21 CFR part 50)) and This is similar to what is required of other personnel conducting final IRB approval of research (part 56 (21 sponsors of INDs, and it helps to ensure formulation testing are employees of the CFR part 56)) apply to clinical final that the investigator is qualified, responsible person. We also propose to formulation testing that is conducted understands his or her obligations, and clarify that the responsible person must under § 201.327(i). In our view, as a will comply with the requirements of

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this paragraph and with the protocol. It individuals who have participated in parts 210 and 211 includes compliance also enables better oversight of clinical sunbathing, tanning bed use, or another with the requirements to keep certain investigations by FDA because it creates SPF clinical study for at least the past records and to have appropriately a record of the investigator’s relevant 4 weeks or perhaps longer if UV- trained and qualified personnel. Failure experience and qualifications. induced responses remain. The to comply with CGMPs results in a e. Research monitoring. A number of proposed clarification regarding product being adulterated under section changes in § 201.327(i)(1) are being conduct of physical examinations of test 501(a)(2)(B) of the FD&C Act. proposed to ensure adequate monitoring subjects reflects this consideration, and h. Recordkeeping. To enable FDA to of clinical final formulation testing. our additional proposal for IRB review, better monitor compliance with the Revised § 201.327(i)(1) would require addressed elsewhere, will help ensure it requirements of § 201.327, we propose that responsible parties inform all is appropriately acted on. to include specific recordkeeping investigators testing a formulation if g. Applicability of registration and requirements for final formulation there are new observations about the CGMP requirements. Proposed testing. Accordingly, proposed drug, particularly with regard to adverse § 201.327(k) reflects FDA’s existing view § 201.327(l) clarifies what records of events or safe use. This is necessary to that final formulation testing conducted testing performed under this section ensure proper communication between under § 201.327 constitutes the must be kept, by whom, and for how study personnel and protection of ‘‘manufacture’’ of a drug. As such, this long. This provision also allocates human subjects. Responsible persons testing must be conducted in an responsibility for records maintenance must also monitor the conduct of establishment registered in accordance and specifies what records must be investigations to ensure that clinical with part 207 (21 CFR part 207) and made available to FDA for inspection. testing is being conducted in accordance section 510 of the FD&C Act. This Recordkeeping is essential for FDA to with the protocol and with applicable interpretation is consistent with the evaluate whether required testing of regulations. If a responsible person definition of manufacture in part 207, final formulations is being conducted in discovers noncompliance by study which includes ‘‘each step in the accordance with § 201.327(i) and (j), and personnel, then the responsible person manufacture, preparation, propagation, to enable the Agency to investigate must either secure compliance or compounding, or processing of a drug postmarketing product failures or remove the noncompliant personnel . . . .’’ (§ 207.1). The definition of adverse events. Appropriate from conducting testing. manufacture as used in part 207 also recordkeeping also enables FDA to Finally, we propose to require that ‘‘includes manipulation, sampling, conduct better and more efficient investigators report adverse events and/ testing, or control procedures applied to inspections of entities conducting final or safety concerns to the responsible the final product or to any part of the formulation testing. person, and that investigators also process, including, for example, These recordkeeping requirements are provide responsible persons with final analytical testing of drugs for another in alignment with what is required for reports at the conclusion of testing. We registered establishment’s drug’’ (id). other types of manufacturing under believe that this will ensure there is Accordingly, a sunscreen product CGMPs as set forth in parts 210 and 211. appropriate documentation and labeled in reliance on final formulation The proposed provisions are intended to communication of adverse events and/ testing done in an unregistered clarify how, and for how long, records or safety concerns that arise during establishment is misbranded under must be kept to substantiate required testing. It will also ensure there is a section 502(o) of the FD&C Act. This final formulation testing. We are record of SPF testing conducted under interpretation is also consistent with proposing that records of testing must § 201.327(i) that can be relied upon FDA’s regulations in § 330.1, which be kept by the responsible person (as should questions related to a particular require that OTC monograph drug newly defined in § 201.327(a), discussed formulation arise when the sunscreen products be manufactured in a previously), as well as by any other formulation is marketed. The proposed registered establishment in order to be entity that actually performs testing requirements are consistent with generally recognized as safe and (under a transfer of obligations per reporting required in the IND context, effective and not misbranded. The § 201.327(a)(1) or otherwise). Requiring although, because of the short duration incorporation of this provision in that records be kept by both the of the clinical final formulation testing § 201.327, therefore, is intended to responsible person and the testing entity conducted under § 201.327(i), we are clarify an existing requirement for (if different) will enable FDA to more not proposing to require annual facilities performing this type of testing. easily identify records supporting the reporting. We also propose to clarify that, as a labeling of any given final formulation f. Test subject selection. We propose manufacturing activity, final even when the product is labeled with additional language regarding the formulation testing conducted under the responsible person’s information, selection of test subjects in this paragraph is expected to be done in but testing and manufacturing was § 201.327(i)(4). This is an area in which accordance with CGMPs as set forth in completed by a third party. FDA’s inspections of testing entities parts 210 and 211 (see § 210.3(b)(12), The proposed recordkeeping have suggested a lack of consistency. indicating that for the purposes of parts requirements reflect FDA’s experience We are particularly concerned that 210 and 211, ‘‘Manufacture, processing, in interacting with regulated industry. inclusion/exclusion criteria provide for packing or holding of a drug product By requiring that records be kept by adequate time between study and includes packaging and labeling both the responsible person and any enrollment and prior UV exposure, such operations, testing, and quality control other entity that performs final as from participation in a previous SPF of drug products’’). This is consistent formulation testing, the proposed rule test, sunbathing, or sunlamp use. with FDA’s regulations in § 330.1, will enable more efficient enforcement Erythemal responses can remain for which require compliance with CGMPs of the FD&C Act by, for example, days after sunbathing, and it is known as a condition for OTC drug products to allowing FDA to identify the source of that pigmentation development takes up be GRASE and not misbranded when formulation failures or apparent to a week after initial exposure and otherwise marketed consistent with inconsistencies between the product remains for weeks to months (Ref. 186). conditions in a final monograph. labeling and consumer experience. The SPF clinical studies should not include Adherence to CGMP requirements in proposed recordkeeping requirements

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will also assist FDA when it is identity and strength, and meets the unprotected skin (initial MEDu); (2) a conducting inspections of entities that quality and purity characteristics, which final MED for unprotected skin (final perform final formulation testing for a it purports or is represented to possess. MEDu); (3) an MED for skin to which number of different responsible persons This proposal also elaborates on the SPF standard has been applied and products, as we believe is the norm recordkeeping necessary to document (ssMEDp); and (4) an MED for skin to in this industry. Having ready access to compliance with the requirements of which the sunscreen test product has records reflecting the overall conduct of proposed § 201.327 regarding conduct of been applied (tpMEDp). The initial final formulation testing during an final formulation testing. MEDu is used to set the UV exposures inspection of such an entity is important Proposed required records for SPF administered to determine final MEDu, because it will enable FDA to identify testing include records that: (1) Identify ssMEDp, and tpMEDp (see potential systemic problems in final the facility conducting the testing; (2) § 201.327(i)(5)(iii)). formulation testing that may have an identify the equipment used; (3) identify Although the regulation already impact on the reliability of results product samples and lots; (4) requires that each of the MED values be supporting the labeling of multiple characterize the SPF standard that is determined 16 to 24 hours after UV different sunscreen products marketed used; (5) document parameters for water exposure, it merely notes that the final by a variety of responsible persons. We resistance testing; and (6) demonstrate MEDu, ssMEDp, and tpMEDp are note that these recordkeeping compliance with the provisions ‘‘typically determined the day following requirements should not be understood governing adequate clinical testing determination of the initial MEDu’’ (see to mandate duplicative records within procedures and conditions. For current § 201.327(i)(5)(iv)). Because the the files of a single testing entity or example, these would include skin reactivity of a test subject changes single responsible party. For example, if documentation of IRB review, case over time, we propose to clarify that the one investigator is responsible for histories for each human subject (which initial MEDu of a person’s unprotected testing multiple final formulations, one must document protocol deviations or skin must be determined no more than copy of the signed investigator injuries), administration of the 1 day before the UV exposures for final statement and Curriculum Vitae (CV) sunscreen, and reading of test results. MEDu, ssMEDp, and tpMEDp are would be sufficient to support all These proposed recordkeeping administered. We are also clarifying that formulations tested by that investigator. obligations are consistent with those to calculate the SPF value for each test required of parties engaged in human subject, under proposed paragraph Consistent with FDA’s view that final subjects testing governed by other § 201.327(i)(6), it is the subject’s final formulation testing is manufacturing, portions of FDA’s regulations. MEDu that should be used. and thus is subject to CGMPs, Required records of broad spectrum In our review of the testing equipment maintenance records and testing conducted under proposed requirements as part of this rulemaking, other records documenting compliance § 201.327(j) would include those records we also revisited our position on the with CGMPs are expected to be necessary for identifying the facility input slit bandwidth specification in the maintained as required by parts 210 and conducting the testing, providing in vitro broad spectrum test. In the 2011 211. Accordingly, we clarify in information associated with the sample, L&E Final Rule, we modified the in vitro proposed § 201.327(l) that records identifying equipment used, and broad spectrum test that was proposed documenting proper maintenance of documenting sunscreen product in the 2007 proposed rule to change the equipment used in final formulation application. These proposed input slit spectrometer bandwidth testing must be kept, consistent with requirements provide greater specificity specification from ≤5 nm to ≤1 nm. existing obligations in 21 CFR 211.68. In than existing requirements in FDA’s After the 2011 final rule published, FDA our view, this clarification will promote CGMP regulations, and are expected to received a comment from a spectrometer uniformity in adherence to best increase uniformity in current practice. manufacturer arguing that the 1 nm practices and will help ensure more We propose to clarify FDA’s input slit bandwidth specification was accurate and reliable labeling of expectations regarding access to records unreasonable. The manufacturer argued sunscreen products based on final that responsible persons and other that common spectrometer models that formulation testing. Additional testing entities are required to keep are currently used to test sunscreens specificity has been proposed here to under this paragraph. These provisions cannot comply with the ≤1 nm input slit clarify how the more general are consistent with FDA’s inspection bandwidth specification, and those that recordkeeping provisions of part 211 authorities in section 704 of the FD&C can are more expensive, more difficult apply to final formulation testing. To Act. to use, and take more time to use. The provide assurance that the test results i. Minor proposed revisions to test manufacturer provided data that are not compromised by faulty procedures. In addition to the changes indicate that spectrometers with ≤1 nm equipment maintenance or equipment discussed in section IX.D, we are input slit bandwidths do not produce failure, FDA proposes that testing proposing several modifications to the more reliable results than spectrometers entities must keep documentation technical instructions for sunscreen with larger input slit bandwidths (see demonstrating that equipment used for final formulation testing (§ 201.327(i) Comment, Docket No. FDA–2010–D– final formulation testing has been and (j)) to clarify how the testing should 0509–0004). In light of this submission, maintained in accordance with be conducted. FDA reassessed the input slit bandwidth established written specifications. This We are concerned that manufacturers parameters and concluded that ≤5 nm requirement will enable FDA to more conducting the SPF test procedure may will be sufficient for the broad spectrum efficiently monitor compliance. Failure be relying on determinations of the procedure. Although decreasing to keep required records of final initial minimal erythema dose of bandwidth improves the ability to formulation testing will render a unprotected skin (MEDu) generated too resolve closely spaced peaks (i.e., the product whose labeling relies on that far in advance of testing the sunscreen spectral resolution), this is not a testing adulterated under section product. The current regulation in significant consideration for in vitro 501(a)(2)(B) of the FD&C Act. Without § 201.327(i)(5) addresses four different broad spectrum testing of sunscreen recordkeeping, there is no assurance determinations of MED for each test products because transmittance/ that a sunscreen drug product has the subject: (1) An initial MED for absorbance curves for sunscreen

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products are typically smooth with no solar simulator. We propose to resolve insect repellent active ingredients are individual sharp peaks. Accordingly, we this error by clarifying that the exempt from registration because EPA propose to revise § 201.327(j)(1)(iv) to handheld radiometer measures the solar has determined they present minimum require that spectrometer input slits be simulator radiation intensity rather than risk potential to humans (Ref. 189). ≤ set to provide a bandwidth that is 5 the emission spectrum. Finally, we have Sunscreen-insect repellent nm. proposed edits to certain provisions combination products have been Establishing standardized testing describing final formulation testing marketed in the United States since procedures for sunscreen products and procedures to clarify our long-standing before the OTC review began, but they basing the products’ labeling on this intention that these provisions of the have not previously been addressed in testing not only helps assure the safety test are requirements, not merely the rulemaking for the OTC sunscreen and effectiveness of each product, it also suggestions. monograph (72 FR 7941 at 7943). Both provides consumers with consistent FDA and EPA have historically declined information about the sun protection E. Proposed Status of Sunscreen-Insect Repellent Combination Products to object to the marketing of these properties of sunscreen products across products pending the issuance of a final brands, which in turn facilitates 1. Background sunscreen monograph, provided that the consumer comparisons when selecting Sunscreen-insect repellent sunscreen active ingredient(s) is listed products. Accordingly, we propose to in the stayed final monograph and the delete the provision in § 352.77 (21 CFR combination drugs are products used on human skin that contain both a insect repellent component is registered 352.77) addressing test modifications or with the EPA (79 FR 7941 at 7943). In alternative testing procedures. Section sunscreen drug component and an 2011, FDA issued a draft enforcement 352.77 indicates that such test insect repellent component. A list of guidance intended for manufacturers modifications or alternative testing insect repellent products on the EPA who market OTC sunscreen products procedures require submission of a website identified a number of such without an approved application, which petition in accordance with § 10.30 (21 products as of November 2017 recommended that manufacturers of CFR 10.30). The proposed removal of (including multiple products within a 47 sunscreen-insect repellent combination § 352.77 does not alter the existing single brand line). Among those products should comply as closely as ability of a firm or individual to petition products, the majority contained either possible with FDA’s sunscreen testing the Agency to amend the monograph N,N-Diethyl-meta-toluamide (also called and labeling requirements in § 201.327. (see §§ 330.10(a)(12) and 10.30) to DEET) or IR3535 as the insect repellant, change the conditions that apply to and a few contained oil of citronella as This guidance was finalized in May products marketed under its provisions, the insect repellent. Combination insect 2018 (Ref. 1). such as to modify testing procedures for repellent-sunscreen products have been In the Federal Register of February all products having some particular set marketed in a variety of dosage forms 22, 2007 (72 FR 7941), FDA issued a of characteristics. Rather, the proposed (see section IX.A for a discussion of notice seeking public comments on deletion will clarify that the sunscreen dosage forms), with labeled SPF levels sunscreen-insect repellent combination monograph does not permit variation for ranging from 15 to 30 (Ref. 187). Some products, and, in particular, whether individual products from the products are also labeled as water FDA should amend the OTC sunscreen standardized testing procedures that are resistant or very water resistant (Ref. monograph to add conditions for monograph conditions, because such 187). The products are generally labeled marketing insect repellent-sunscreen variation could undermine important for use without regard to age (Ref. 187). drug products (FDA Call for Data or call values supported by standardization. FDA regulates sunscreens as drug for data). The call for data summarized We are also proposing to correct a products under the FD&C Act, and EPA the regulatory status and history of both minor inaccuracy in the existing concurrently regulates insect repellents sunscreens and insect repellents, and regulatory language describing testing as pesticides under FIFRA.48 FIFRA sought public input on a number of procedures. Specifically, defines a ‘‘pesticide’’ in relevant part as issues (see table 6). On that same date § 201.327(i)(1)(ii)(C) currently states that ‘‘any substance . . . intended for (February 22, 2007, 79 FR 7979), EPA ‘‘emission spectrum must be determined repelling . . . any pest,’’ including published a similar notice announcing using a handheld radiometer.’’ As insects (7 U.S.C. 136)(u)). Before they that it was also seeking information to written, this statement is inaccurate can be marketed, most skin-applied determine how insect repellent- because a handheld radiometer cannot insect repellents must be registered by sunscreen combination products should determine the emission spectrum of a EPA, although a few plant-derived be regulated. TABLE 6—KEY ISSUES AND INFORMATION REQUESTS IN FDA’S 2007 CALL FOR DATA

General issue Key concerns and information requests

Possible manufacturing conflicts ...... Requested information about whether there are known conflicts between FDA and EPA manufacturing requirements and, if so, how to resolve them. Asked how FDA should address EPA-registered insect repellents in finalizing the OTC sunscreen monograph; which re- quirements should FDA retain, revise, or eliminate? Inquired about manufacturer testing of sunscreen-insect repellent combination products and whether any problems were encountered. Possible formulation conflicts ...... Requested comments on the significance of published research suggesting a potential formulation conflict.

47 EPA Product List (Ref. 187); a similar list of scabicides intended to control parasites on humans) Department of Health, Education and Welfare Food insecticide products on the National Pesticide or animal drugs (e.g., pesticide products for oral and Drug Administration,’’ (available at https:// Information Center (NPIC) website produced similar administration to animals) (7 U.S.C. 136 et seq.); see www.fda.gov/aboutfda/partnershipscollaborations/ results (Ref. 188). also ‘‘MOU 225–73–8010 Memorandum of memorandaofunderstandingmous/domesticmous/ 48 Some insect repellents are also regulated by Understanding Between the Environmental ucm115873.htm (accessed April 17, 2018). FDA as human drugs (e.g., pediculicides and Protection Agency and the United States

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TABLE 6—KEY ISSUES AND INFORMATION REQUESTS IN FDA’S 2007 CALL FOR DATA—Continued

General issue Key concerns and information requests

Possible labeling conflicts between OTC Labeling differences noted: sunscreen monograph and EPA reg- • FDA uses ‘‘warning’’; EPA uses ‘‘caution’’ (and only uses the word ‘‘warning’’ to indicate toxicity levels). istration requirements. • Many differences in required warning/caution section headings. Note: Since publication of the call for • Directions for sunscreen use call for liberal application and frequent reapplication; EPA directions may limit where data, FDA has established additional and how to apply product and restrict frequency of application. labeling regulations for certain OTC Asked whether different directions for use can be integrated without leading to improper application, overexposure to in- sunscreen products marketed without sect repellent, and/or underexposure to sunscreen. approved applications. However, the FDA requires the outside container or wrapper of the retail package or the immediate container label to list all active and labeling concerns expressed in the call inactive ingredients (see section 502(e)(1)(A)(iii) of the FD&C Act; § 201.66(c)). EPA requires listing of the percentage of for data remain relevant. each active ingredient, and the total percentage of all ‘‘inert’’ or ‘‘other’’ ingredients, in the pesticide. Inert ingredients are not required to be identified individually on the product except in certain cases (in which case all inert ingredients are listed). Asked whether there is a way to label combination sunscreen-insect repellent drug products in a way that satisfies both the requirements of the FD&C Act and the FIFRA, and whether ‘‘inert’’ ingredients under the FIFRA are equivalent to ‘‘inactive’’ ingredients under the FD&C Act. Safety issues ...... More safety data needed given published animal studies indicating increased absorption of DEET and various sunscreens active ingredients when the components are combined. Asked for more safety data on combined products. Requested data on whether increased absorption of a sunscreen ingredient occurs when combined with an insect repel- lent. Information needed about incidence of skin irritation from combination products. Effectiveness issues ...... Requested information on: • Possible effects of insect repellent on sunscreen SPF; possible decreased sunscreen efficacy or increased expo- sure to insect repellent without greater efficacy resulting from inconsistent reapplication intervals. • Potential chemical or physical incompatibilities between particular sunscreens and insect repellents. • Potential need to specify minimum SPF for these combinations. • Any potential performance benefits of these combination products other than convenience. • Possible adjustments to formulations to minimize application time disparities.

2. FDA’s Evaluation of Sunscreen-Insect conclusions are detailed in the than using separate products. Two Repellent Combination Products discussion that follows. comments stated that properly a. Public comments on the 2007 call formulated, tested, and labeled, FDA has reviewed the comments for data. FDA received six submissions combination products are better than submitted in response to FDA’s and in response to the 2007 call for data. the unpredictable effects that could EPA’s calls for data, as well as pertinent None of the comments included arise when consumers use two different scientific literature and publicly substantive data, although some cited products. Regarding safety, one available EPA regulatory documents. published scientific and medical comment asserted various flaws in the Based on that review, we have literature, which is addressed in the studies cited in the call for data that tentatively concluded that sunscreen- following section of this document. Five questioned the safety of these insect repellent combination products, of the six comments were from combination products. (These studies as a class, are not GRASE (i.e., are manufacturers or a trade association. are discussed in section IX.E.2.d.) Category II) and are misbranded because Industry comments generally favored In general, the comments that we conflicting labeling requirements for retaining joint regulation between EPA their sunscreen and insect repellent and FDA (perhaps with enhanced received in response to the 2007 call for components cannot be reconciled to coordination and information-sharing) data were not accompanied or create labeling that will sufficiently and amending the stayed OTC corroborated by data. Although the ensure safe and effective use of the sunscreen monograph to address comments did not identify further sunscreen component, as well as sunscreen-insect repellent concerns relating to product adequate directions for use as a combinations. Several industry manufacturing or formulation, they did sunscreen, as required by section 502(f) comments claimed there was an absence not adequately address FDA’s concerns of the FD&C Act. Also, if we did not of conflicting requirements relating to about safety, effectiveness, and labeling have this labeling concern, we would manufacturing, formulation, and/or of these products. FDA renews its still tentatively determine that available labeling. Others suggested approaches request for data to support labeling and data regarding the safety and for minimizing labeling conflicts, such safety for sunscreens with insect effectiveness of these products for their as permitting exemptions to FDA’s Drug repellent added. use as sunscreens are insufficient to Facts labeling requirements to b. Pesticide-related information. classify these sunscreen products as accommodate EPA-required Pesticides that are or have been used in GRASE for such use (i.e., Category III). information, or placing FDA- and EPA- combination products that also contain Specifically, evidence suggests that required information in separate areas of sunscreens include DEET, IR3535, and interactions between some sunscreen the label. The remaining comment was oil of citronella. In evaluating active ingredients and insect repellents submitted by a medical association that combination insect repellent-sunscreen may decrease safety by increasing opposed continued marketing of products for the purposes of this rule, systemic absorption of one or both sunscreen-insect repellent products, FDA defers to EPA’s expertise and components, and potential synergistic emphasizing concerns about children’s authority regarding insect repellent effects on the efficacy of sunscreen exposure to DEET. Industry comments ingredients. We have not independently active ingredients apparently have not favoring the continued marketing of evaluated these pesticides, but instead been studied. Although the available combination sunscreen-insect repellent have focused on potential sunscreen- data are limited and not conclusive, drug products also contended that insect repellent ingredient interactions they give rise to questions about the combining sunscreen and insect and the feasibility of effectively labeling safety and effectiveness of these repellent ingredients in a single product these combination products for their use products. Our reasons for these tentative is more convenient and cost-effective as sunscreens.

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As of June 2017, DEET was by far the DEET does not pose a significant health regulations in subpart A of part 201; the most commonly used insect repellent. risk to the U.S. population.50 ‘‘Drug Facts’’ format and other OTC According to the EPA Product list, the IR3535 is classified by EPA as a drug labeling requirements in subpart B amount of DEET in combination biopesticide because it is biochemically, of part 201; and the sunscreen-specific sunscreen-insect repellent products functionally identical to beta-alanine, a labeling requirements that apply to ranged from 10 to 20 percent. DEET naturally occurring substance that sunscreens marketed without an product labels recommend that users repels insects (Ref. 194). IR3535 is approved NDA, including those based avoid over-application, use just enough classified in Toxicity Category IV on the current requirements for SPF and repellent to cover exposed skin and/or (practically nontoxic) for acute oral, broad spectrum testing in § 201.327. The clothing, and not apply to hands or near dermal, and inhalation toxicity and labeling of registered insect repellents is Category III (slightly toxic) for eye the eyes or mouth of young children subject to EPA labeling requirements irritation (Ref. 195). Overall, EPA has (Ref. 190). DEET-containing products under FIFRA (40 CFR 156), as well as assessed IR3535 as not harmful when specific language specified in individual listed on the EPA website in 2017 had ingested, inhaled, or used on skin (Ref. product registration documents. concentrations ranging from 5 percent to 195). Eye irritation could occur if the Although the FDA and EPA labeling 98 percent and provided protection chemical enters a person’s eyes (Ref. requirements for nonprescription from mosquitos for 2 to 12 hours, with 195). IR3535 is used at concentrations of sunscreens and registered pesticides many products having protection times 7.5 percent to 20 percent in a popular cover some of the same information of 4 hours or more (Ref. 187). The line of sunscreen-insect repellent (such as ingredient lists, net quantity American Academy of Pediatrics combination products (EPA Product statements, and warnings/precautions), recommends that repellents should List) (Ref. 187). Products containing there is considerable variation in the contain no more than 30 percent DEET IR3535 identified on EPA’s website in language, format, and placement of when used on children, and that insect summer 2017 had concentrations common label elements between the repellent should not be used on ranging from 7.5 percent to two Agencies, while other elements do children younger than 2 months (Ref. approximately 20 percent and listed not overlap. 191). protection time against mosquitoes of 2 Furthermore, both Agencies limit the EPA classifies the acute toxicity of to 8 hours (EPA Product List) (Ref. 187). degree to which a drug manufacturer or insect repellents and other pesticides Oil of citronella is a plant-derived pesticide registrant may depart from the into one of four toxicity categories biochemical insect repellent (72 FR prescribed text, format, and/or location of required labeling elements. This is (ranging from Category I, highly toxic, to 7979 at 7981). Depending on its source, particularly true for the wording and Category IV, practically nontoxic) (see it may be categorized as ‘‘Ceylon’’ type or ‘‘Java’’ type. It is currently listed by format of ‘‘drug facts’’ information for 40 FR 156.62). DEET is classified in EPA as a minimum risk pesticide OTC drugs (see § 201.66). Similarly, Category III based on EPA’s review of (registration generally not required if EPA regulations state that although a available animal studies, indicating formulated only with EPA-permitted registrant may choose to place non- slight acute toxicity for acute oral, inert ingredients and not labeled as FIFRA-required information on a dermal, ocular, and inhalation tests in effective against disease-causing pests) pesticide label, it may not replace, animals, and low acute toxicity for the (40 FR 152.25(f)). Oil of citronella is also obscure, conflict with, or supersede the human health risk assessment (Ref. an approved food additive for use as a FIFRA-required text (Ref. 199). 192). Although DEET is registered for flavoring agent in foods and beverages The intended uses of sunscreens and use in humans of any age, adverse (Ref. 196). EPA has designated oil of insect repellents are quite different, as events related to DEET toxicity have citronella as Toxicity Category III are the associated labeling requirements; been documented and these events (slightly toxic) for acute oral toxicity in particular, the instructions for using primarily relate to the central nervous (Java type only), dermal toxicity, dermal the two types of products are different. system. As summarized by Katz et al., irritation, and acute eye irritation (both Required labeling for OTC sunscreens DEET has been associated with seizures types), and Category IV (practically marketed without approved NDAs calls and other central nervous system nontoxic) for acute oral toxicity (Ceylon for reapplication at least every 2 hours symptoms, cardiovascular symptoms, type) and acute inhalation (Ref. 197). (see § 201.327(e)(3) through (e)(4)). The and topical and allergic symptoms (Ref. The National Pesticide Information duration of protection for insect 193). Most reported cases of adverse or Center (NPIC) fact sheet on oil of repellents varies according to the active lethal events involved overuse or citronella states that oil of citronella ingredient and strength. Based on otherwise incorrect use of the product products should not be used on children information from the EPA product list, (Ref. 193), and EPA concluded that less than 6 months old (Ref. 198). many insect repellent-sunscreen available data were insufficient to c. Disparities in required labeling of products provide protection against identify DEET as the cause of the sunscreens and insect repellents. FDA mosquitoes and/or ticks for more than 2 reported adverse events (Ref. 192). EPA and EPA regulate the format and content hours, and some provide protection for is currently in the process of updating of the labeling of nonprescription as many as 6 to 10 hours. EPA has stated its registration of a number of older sunscreen products and pesticides, that it is ‘‘concerned about consumer pesticides, including DEET, and is respectively. FDA regulations on use of products that contain sunscreens deferring decision on the regulatory nonprescription sunscreen labeling and DEET, since directions to reapply status of combination DEET/sunscreen include the general drug labeling generally and frequently may promote products as described in the EPA Call greater use of DEET than needed for 50 pesticidal efficacy and thus pose for Data.49 However, EPA has stated that Id. In June 2014, EPA issued an interim review of DEET and did not identify any specific new unnecessary exposure to DEET.51 The concerns. The proposed interim registration review Centers for Disease Control and 49 DEET 2014 reregistration interim review final decision became final on September 24, 2014. DEET decision (EPA–HQ–OPP–2012–0162) (available at 2014 reregistration interim review final decision Prevention (CDC) advises consumers https://www3.epa.gov/pesticides/chem_search/reg_ (EPA–HQ–OPP–2012–0162) (available at https:// actions/reregistration/red_PC-080301_1-Apr-98.pdf www.regulations.gov/document?D=EPA-HQ-OPP- 51 DEET 2014 reregistration interim review final (accessed April 17, 2018). 2012-0162-0012 (accessed April 17, 2018). decision, supra note 49, v.

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that ‘‘products that combine sunscreen establishment numbers (40 CFR review raise potential safety concerns and repellent are not recommended, 156.10(a)). about products that combine sunscreen because sunscreen may need to be • FDA labeling for sunscreens uses and insect repellent active ingredients. reapplied more often and in larger the word ‘‘warning’’ (see §§ 201.66(c)(5) The available data suggest that the amounts than needed for the repellent and 201.327(d)), while the EPA dermal penetration and systemic component to provide protection from requirements specify that pesticide absorption of at least one combination biting insects.’’ (Ref. 200). Similarly, the products that, like DEET, IR3535, and of a sunscreen active ingredient and an American Academy of Pediatrics oil of citronella, meet the criteria of insect repellent is increased when both advises consumers not to use products Toxicity Category III or IV as the highest are present. that combine DEET with sunscreen, in category by any route of exposure bear There have been some studies part because ‘‘[t]hese products can on the front panel either no signal word assessing the penetration of DEET and overexpose your child to DEET because or only the signal word ‘‘CAUTION’’ (40 the effects of DEET combined with the sunscreen needs to be reapplied CFR 156.64). In EPA labeling the word sunscreen (particularly the active often’’ (Ref. 201). Additionally, DEET is ‘‘WARNING’’ is used as a signal word ingredient oxybenzone) on dermal approved for use on children with no only for toxicity category II, which is a penetration. Ross et al. tested for age restriction (Ref. 202), whereas FDA higher toxicity category than that synergistic effects between DEET and labeling states ‘‘[bullet] children under applicable to any insect repellent oxybenzone using an in vitro mouse 6 months of age, ask a doctor’’ (see ingredients used in sunscreen-insect skin diffusion model and showed § 201.327(e)(1)(iv)). repellent combination products (40 CFR substantial penetration of a 20 percent 156.64(a)(2)). DEET standard in ethanol, while The recommended manner of • application also differs for sunscreens FDA labeling uses the term penetration of sunscreen active and insect repellents. For example, the ‘‘directions’’ (see §§ 201.66(c)(6) and ingredients was not found (Ref. 205). directions on the label for all insect 201.327(e)), while EPA regulations use Despite a lower DEET content (10 repellent products containing DEET say the term ‘‘directions for use’’ (see 40 percent), a commercially marketed CFR 156.10(i)(2)). to apply just enough to cover exposed sunscreen formulation had a 6-fold • FDA calls for ingredients to be skin, and avoid over-application (Ref. more rapid detection and a 3- to 4-fold listed as ‘‘active’’ and ‘‘inactive’’ (see 190), whereas the labeling of greater penetration of DEET than the 20 § 201.66(b) through (c)), while EPA percent standard. Other diffusion tests nonprescription sunscreens marketed labeling uses the term ‘‘inert’’ or ‘‘other’’ without approved NDAs calls for liberal using pigskin or artificial membranes instead of ‘‘inactive’’ for all non- and various combinations of DEET and or generous application (see pesticide ingredients (40 CFR 156.10(g)). § 201.327(e)(1)(ii)). The EPA-mandated oxybenzone in different media Given the extent of the disparities suggested an enhancing effect on dermal directions on the labels of DEET discussed above, FDA tentatively penetration of both DEET and products also state, ‘‘Do not apply near concludes that attempting to merge the oxybenzone (Refs. 206 and 207). The eyes and mouth; apply sparingly around required labeling for monograph same investigators obtained similar ears; do not use under clothing’’ (Ref. sunscreens and insect repellents in a results in a later in vitro study using 190). Such statements are potentially way that would comply with both human skin (Ref. 207). troublesome from the standpoint of sun Agencies’ requirements and permit Kasichayanula et al. assessed the protection in light of surveillance data adequate consumer understanding and dermal absorption of DEET and from Australia, which suggest that the proper use would be impracticable. In oxybenzone using an in vivo piglet incidence of certain skin cancers is this regard, we specifically disagree model, in which samples were collected more frequent on highly exposed areas with comments made in response to the from plasma, urine, and under the skin. of the body such as ears and the backs 2007 FDA Call for Data suggesting that Their results indicated that the of hands (Refs. 203 and 204). The CDC acceptable ‘‘merged’’ labeling could be enhanced dermal penetration evidenced advises consumers who need protection crafted by varying the OTC sunscreen in the in vitro studies translated to from both sun and insects to apply drug facts to include insect-repellent- increased systemic exposure to both sunscreen product first, followed by an related information, and/or by providing oxybenzone and DEET (Refs. 208 and insect repellent (Ref. 200). EPA-required labeling outside the drug 209). Finally, a study by Yiin et al. Additional disparities in the content facts box. We are particularly concerned suggests that enhanced systemic and format of labeling elements for that consumers would be confused by absorption would also occur in humans sunscreens and registered insect the juxtaposition of two sets of different (Ref. 210). Yiin et al. used human repellents include the following: and, in some cases, contradictory urinary metabolites of DEET and • EPA pesticide labeling includes information in the labeling about these oxybenzone to evaluate the mutual required elements that generally must products’ dual intended uses. We are enhancing effect on absorption of these appear on the front panel of the label, also concerned that the sheer amount of ingredients and concluded that their such as the ingredient statement (40 required information would result in findings confirm that concurrent use of CFR 156.10(g)(2)), specified signal word crowded, difficult-to-read labels lacking DEET-containing insect repellent and such as ‘‘CAUTION’’ (40 CFR 156.64), in the clarity and prominence of oxybenzone-containing sunscreen and child hazard warning (40 CFR important safety and use information results in the enhancement of dermal 156.66), which could crowd or detract that are both required by FDA absorption of DEET when insect from drug information required to regulations and vital to consumer repellent (DEET) was applied first and appear on the principal display panel comprehension. We solicit comment then covered by sunscreen (Ref. 210). for drugs (see § 201.60 (‘‘The principal and data about how to reconcile the The study authors suggested that display panel shall be large enough to labeling of suncreens and insect placing repellent spray on top of accommodate all the mandatory label repellents such that a combined product sunscreen lotion with no mixing seems information required to be placed could meet FD&C Act requirements for to be the best approach to diminish thereon by this part.’’)). Other labeling OTC sunscreen drugs. DEET penetration through the skin. elements that only EPA requires include d. FDA’s review of published medical Although insect repellents and registration numbers and manufacturing literature. The results of FDA’s literature sunscreens are designed to exert their

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protective effects on the surface of the would affect the determined SPF value addressed by further studies on both skin, the studies described above of combination sunscreen-insect combinations of individual sunscreen suggest that combining a sunscreen and repellent products. Montemarano et al. and insect repellent ingredients and insect repellent in a single product may reported a reduction in sunscreen final formulations. result in unintended systemic exposure efficacy because of concomitant use Existing data indicates there is a risk to the sunscreen ingredient oxybenzone with insect repellent. However, in that of systemic absorption of insect and the insect repellent ingredient study, the sunscreen and insect repellent and/or a sunscreen active DEET. We acknowledge the study repellent ingredients were applied ingredient when both are present. limitations cited by comments to the separately and were not part of a Additional data would be needed to FDA Call for Data, and that in vitro combination product (Ref. 211). identify any interactions between diffusion studies have their limitations With respect to efficacy, we recognize specific sunscreen active ingredients in terms of reflecting clinical use. We that the testing required by § 201.327 and insect repellents, in particular, to also note that many of the studies tested (both the current regulation and the characterize any enhancement of skin formulated commercial products with regulation if amended as proposed penetration and/or systemic absorption multiple sunscreen ingredients and elsewhere in this proposed rule) to if the resulting data presents safety or excipients for which details were not support labeled SPF levels and other effectiveness concerns. As stated above, given, and it is unclear how this may efficacy claims that may be made for FDA would need adequate human have influenced the results. Although certain OTC sunscreen products could absorption studies, such as a MUsT, as we, therefore, do not view these data as potentially mitigate concerns about the part of the clinical safety assessment (for conclusory, we have determined that impact of insect repellent active more discussion on assessment of they raise a valid safety concern that ingredients on sunscreen effectiveness. dermal absorption of sunscreen active warrants a tentative conclusion that, However, we are not aware of any data ingredients using MUsT, see section even if one could overcome the evaluating the reliability of SPF testing VII.B.4). The effectiveness of sunscreen- misbranding and associated safety and for sunscreen formulations that contain insect repellent combination products is effectiveness concerns created by the insect repellent ingredients. There also also a continuing concern. For all of inconsistent application directions for is the possibility that increasing the those reasons, we tentatively determine sunscreens and insect repellants, there amount of the sunscreen active that these products are not GRASE for would not be sufficient evidence to ingredient to compensate for any loss in nonprescription sunscreen use. We conclude that combination sunscreen efficacy because of the presence of the solicit comment on this tentative and insect repellent products are insect repellent could result in determination. unnecessarily high exposure to the GRASE for sunscreen use without X. Proposed Actions To Effectuate sunscreen active ingredient. For these further investigation. Lifting of Stay and Harmonize Regarding future investigations that additional reasons, we tentatively Impacted Regulations could assist FDA in determining conclude that even if other concerns whether these products have sufficient could be overcome, there is not In the 2011 L&E Final Rule, FDA evidence of safety to be GRASE for use currently sufficient evidence to explained that although we were not yet as sunscreen, we are not aware of any conclude that combination sunscreen- lifting the stay on the 1999 final data that define the extent of systemic insect repellent products are GRASE for monograph, the provisions set forth in exposure to either DEET or oxybenzone use as sunscreens. We solicit comment the L&E Final Rule reflected the that would occur with maximal on the data needs identified above and Agency’s position on the appropriate exposure to a sunscreen-insect repellent tentative conclusions, including testing and labeling of sunscreen combination product. There also are few supporting data and analysis. We also products that were previously identified data from which to assess whether there solicit data and information to address as falling within the Stayed 1999 Final would be a similar enhancement of skin these data needs. Monograph (76 FR 35620 at 35621). We penetration for other combinations of explained that § 201.327 would 3. Conclusion sunscreen and insect repellent active therefore supersede the prior approach ingredients. Moreover, without adequate FDA tentatively concludes that the to labeling and effectiveness testing human absorption studies under inherent disparity in labeling described in the never-effective maximal use conditions of particular requirements that apply to sunscreens provisions of part 352, subparts C sunscreen-insect repellent combinations marketed under the OTC monograph and D. (i.e., a MUsT, as discussed in section and insect repellents prevent the We are now proposing to lift the stay VII.B.4), it is difficult to evaluate creation of labeling that will sufficiently on the 1999 final monograph (21 CFR potential risks associated with the use of ensure safe and effective use of the part 352) while making certain changes such combination products. Because of sunscreen component of sunscreen- in its provisions. To fully effectuate this the potential synergistic interaction insect repellent combination products, proposal, we are proposing several between the sunscreen active ingredient particularly in connection with duration harmonizing revisions to part 352 and and the insect repellent active of action. We also conclude that these § 201.327. These changes remove certain ingredient, human absorption data for conflicting requirements prevent these provisions from part 352 that were the individual components would not products from having adequate superseded by the 2011 L&E Final Rule provide adequate data to estimate the directions for use as a sunscreen, and and, where applicable, replace them level of systemic absorption. Likewise, thus these products would be with appropriate cross references to the in vitro data would not be able to misbranded under section 502(f) of the applicable testing and labeling provide a reliable estimate of the FD&C Act. In addition, even if these provisions in § 201.327, as we propose systemic exposure that would occur issues could be overcome, existing to amend these regulations in this with such products’ use. safety concerns about potential document. We also have made minor In terms of sunscreen active enhanced systemic absorption resulting revisions in parts 347, 352 and ingredient effectiveness, we have little from combining individual sunscreen § 201.327 to improve readability and to data from which to determine whether active ingredients and insect repellent correct certain typographical errors and the presence of an insect repellent ingredients would also need to be erroneous internal cross references.

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We are also proposing revisions to Finally, we propose to add to remaining in retail outlets. Our current certain provisions describing § 310.549 new characteristics that thinking on implementation is informed requirements for products containing would render a product a new drug. in part by our understanding there are both sunscreen active ingredients and These characteristics include: (1) no currently marketed sunscreen skin protectant active ingredients to Containing the ingredients we propose products that contain the active avoid duplication between § 201.327 to classify as categories II and III (see ingredients we propose here as Category and part 352 and to harmonize the sections VIII.B–C); (2) being labeled, II. We solicit comment on this proposed requirements set forth in those represented, or promoted for use as a approach. provisions. As in the past, the proposed combined sunscreen-insect repellant XIII. Preliminary Economic Analysis of sunscreen monograph would include (see section IX.E); (3) failing to comply Impacts conditions under which a single with provisions relating to maximum product could include certain sunscreen SPF values and broad spectrum A. Introduction active ingredients as well as certain requirements (see section IX.B); and (4) ingredients determined to be GRASE for failing to conform to certain other We have examined the impacts of the use in skin protectants under part 347 sunscreen formulation and dosage form proposed rule under Executive Order (see proposed § 352.20(b), as well as conditions (see sections IX.A and D). 12866, Executive Order 13563, Executive Order 13771, the Regulatory current § 347.20(e) (21 CFR 347.20(e)). XI. Comment Period Current § 201.327(h) allows for such Flexibility Act (5 U.S.C. 601–612), and products to combine certain labeling We are providing a comment period the Unfunded Mandates Reform Act of statements applicable to each ingredient of 90 days (see DATES). FDA will also 1995 (Pub. L. 104–4). Executive Orders in the product to eliminate duplicative consider requests to defer further 12866 and 13563 direct us to assess all words or phrases. The stayed provisions rulemaking with respect to a specific costs and benefits of available regulatory of part 352 contain similar allowances sunscreen active ingredient to allow the alternatives and, when regulation is for products that contain both sunscreen submission of new safety and/or necessary, to select regulatory and skin protectant active ingredients, effectiveness data to the record if such approaches that maximize net benefits but also outline more detailed requests are submitted to the docket (including potential economic, requirements for presenting such a within the initial 90-day comment environmental, public health and safety, product’s statement of identity, period. FDA will review all data and and other advantages; distributive indications, warnings, and directions. information submitted to the record in impacts; and equity). Executive Order conjunction with all timely and We propose to relocate the labeling 13771 requires that the costs associated complete requests to extend. In requirements for such products from with significant new regulations ‘‘shall, assessing whether to extend the § 352.60 to § 201.327(h), thereby to the extent permitted by law, be offset comment period to allow for additional consolidating labeling conditions for by the elimination of existing costs time for studies to generate new data these products in one section of the associated with at least two prior and information, FDA will consider the regulations. We also propose to retain regulations.’’ We believe that this data already in the docket along with compliance with these labeling proposed rule is a significant regulatory any information that is provided in any provisions as a monograph condition for action as defined by Executive Order requests to extend. FDA will determine sunscreen/skin protectant products 12866. whether the sum of the data, if timely The Regulatory Flexibility Act under both parts 352 (the sunscreen submitted, is likely to be adequate to requires us to analyze regulatory options monograph) and 347 (the skin provide all the data that are necessary that would minimize any significant protectant monograph) by incorporating to make a determination of general impact of a rule on small entities. cross references to § 201.327(h) in recognition of safety and effectiveness. § 352.20(b)(4), and § 352.60, and Because many sunscreen manufacturers incorporating cross references to XII. Proposed Effective/Compliance are small entities and the one-time costs §§ 352.20 and 352.60 in §§ 347.20(e), Dates of the proposed rule represent a and 347.60. The proposed effective date of final significant fraction of annual revenue to Additionally, we propose to regulations resulting from the proposals sunscreen manufacturers, we find that consolidate under new § 310.549 (21 described in this rulemaking is the proposed rule will have a significant CFR 310.549) certain properties that November 26, 2019 (see FD&C Act economic impact on a substantial render an OTC drug product offered for section 586E). We recognize that number of small entities. use as sunscreen a new drug for which industry will need time after The Unfunded Mandates Reform Act an approved NDA is required prior to publication of any final regulations to of 1995 (section 202(a)) requires us to marketing. Section 310.545 (21 CFR comply with their provisions. To allow prepare a written statement, which 310.545) currently contains several such for orderly implementation of final includes an assessment of anticipated provisions addressing specific regulations and help assure continued costs and benefits, before proposing ingredients and efficacy claims. We product availability to consumers, we ‘‘any rule that includes any Federal propose to relocate these provisions would not expect full compliance with mandate that may result in the from § 310.545 to § 310.549. In addition, such final regulations for units of expenditure by State, local, and tribal in the interest of completeness, we are sunscreen product initially introduced governments, in the aggregate, or by the clarifying in § 310.549 that labeling a or initially delivered for introduction private sector, of $100,000,000 or more product with claims that it decreases the into interstate commerce, until 1 year (adjusted annually for inflation) in any risk of skin cancer or early skin aging after the effective date of the final rule. one year.’’ The current threshold after caused by the sun if that product has an We also would not expect full adjustment for inflation is $150 million, SPF of less than 15 when tested in compliance, even after that date, for using the most current (2017) Implicit accordance with § 201.327(i) and/or units of product that were initially Price Deflator for the Gross Domestic does not pass the broad spectrum test in introduced or initially delivered for Product. This proposed rule would § 201.327(j) renders the product a new introduction into interstate commerce result in an expenditure in any year that drug. before that date, such as those meets or exceeds this amount.

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We have developed a comprehensive containing active ingredients about observations in final formulation preliminary regulatory impact analysis which safety questions remain, less testing. that assesses the impacts of the exposure to sunscreen products labeled Table 7 summarizes the costs and proposed rule. We present a summary of with potentially misleading sun benefits of the proposed rule, if this analysis below. protection information, increased finalized. The annualized benefits of the proposed rule, if finalized, would range B. Summary of Costs and Benefits consumption of products with better UVA protection, less exposure to from $0.00 million to $3.72 million at a If finalized, the proposed rule would flammable spray sunscreens, and less 7 percent discount rate and from $0.00 update and make effective regulations to exposure to spray and powder million to $3.62 million at a 3 percent ensure the safety and effectiveness of sunscreen products posing inhalation discount rate. Our primary estimate of sunscreen products marketed under the risks. Consumers would also experience annualized benefits would equal $0.91 OTC drug monograph. The rule would transaction cost savings. The costs of the million at a 7 percent discount rate and update sunscreen product labeling $0.88 million at a 3 percent discount rule to sunscreen manufacturers include standards, address the safety of rate. The annualized costs of the administrative costs, costs to fill data sunscreen active ingredients, revise and proposed rule, if finalized, would range clarify our expectations for testing and gaps for active ingredients and powder from $15.57 million to $75.84 million at recordkeeping by entities that conduct dosage forms, product formulation a 7 percent discount rate and from sunscreen testing, and address other testing costs, and costs to reformulate $12.40 million to $60.42 million at a 3 sunscreen safety or efficacy concerns, and relabel sunscreen products. Finally, percent discount rate. Our primary like combination sunscreen-insect testing entities would incur estimate of annualized costs would be repellents and alternative dosage forms. recordkeeping costs if they do not $47.55 million at a 7 percent discount Consumers would benefit from less already maintain adequate records of rate and $37.79 million at a 3 percent exposure to sunscreen products testing equipment, methods, and discount rate.52

TABLE 7—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF THE PROPOSED RULE

Units Category Primary Low High Discount Period Notes estimate estimate estimate Year rate covered dollars (%) (years)

Benefits: Annualized Monetized ($m/ $0.91 $0.00 $3.72 2017 7 20 year). 0.88 0.00 3.62 2017 3 20 Annualized Quantified (mil oz/ 201.79 98.16 286.26 Increased use of products with year) 1. improved UVA protection. Annualized Quantified (mil oz/ 51.42 19.43 83.41 Less exposure to sunscreens year) 2. containing active ingredients about which safety questions remain. Annualized Quantified (mil oz/ 161.04 159.88 162.20 Less exposure to sunscreens with year) 3. potentially misleading sun pro- tection information. Annualized Quantified (mil oz/ 386.44 384.86 388.02 Less exposure to spray and pow- year) 4. der sunscreens posing inhala- tion risks.

Qualitative ...... Quicker responses to adverse events, improved inspections, and better protection of human subjects. Potential transaction cost savings re- lated to changes in the effort required to choose a sunscreen.

Costs: Annualized Monetized ($m/ 47.55 15.57 75.84 2017 7 20 year). 37.79 12.40 60.42 2017 3 20 Annualized Quantified.

Qualitative ...... Recordkeeping costs to testing entities that do not already maintain adequate records.

Transfers: Federal Annualized Mone- tized ($m/year).

52 The primary estimate of the costs is not the average of the lower bound costs and the upper bound costs.

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TABLE 7—SUMMARY OF BENEFITS, COSTS, AND DISTRIBUTIONAL EFFECTS OF THE PROPOSED RULE—Continued

Units Category Primary Low High Discount Period Notes estimate estimate estimate Year rate covered dollars (%) (years)

From: To:

Other Annualized Monetized ($m/year).

From: To:

Effects: State, Local, or Tribal Government: None. Small Business: Some small businesses could exit the sunscreen market by discontinuing their products or going out of business. Wages: None. Growth: None. 1 Values represent the 2016 consumption of sunscreens that would provide improved UVA protection under the proposed rule. 2 Value represent the 2016 consumption of sunscreens that contain active ingredients about which safety questions remain. 3 Values represent the 2016 consumption of sunscreens with potentially misleading sun protection information. 4 Values represent the 2016 consumption of potentially inhalable spray sunscreens and powder sunscreens.

Table 8 shows the Executive Order would end after 20 years. We estimate Based on these costs, this proposed rule 13771 summary over an infinite time that this rule generates $29.85 million in would be considered a regulatory action horizon. In this analysis we assume that net annualized costs, discounted at 7 under E.O. 13771. the costs and cost savings of the rule percent, over a perpetual time horizon.

TABLE 8—E.O. 13771 SUMMARY TABLE [In $ millions 2016 dollars, over an infinite time horizon) 1

Primary Lower Upper Primary Lower Upper estimate bound bound estimate bound bound (7%) (7%) (7%) (3%) (3%) (3%)

Present Value of Costs ...... $456.33 $149.22 $730.46 $618.16 $201.53 $1,002.22 Present Value of Cost Savings ...... 0.00 0.00 0.00 0.00 0.00 0.00 Present Value of Net Costs ...... 456.33 149.22 730.46 618.16 201.53 1,002.22 Annualized Costs...... 29.85 9.76 47.79 40.44 13.18 65.57 Annualized Cost Savings ...... 0.00 0.00 0.00 0.00 0.00 0.00 Annualized Net Costs ...... 29.85 9.76 47.79 40.44 13.18 65.57 1 We assume that the benefits and costs of the proposed rule would diminish after 20 years. Negative values denoted in parentheses.

We have developed a comprehensive (44 U.S.C. 3501–3520). A description of burden of the collection of information Economic Analysis of Impacts that these provisions is given in the on respondents, including through the assesses the impacts of the proposed Description section of this document use of automated collection techniques, rule. The full preliminary analysis of with an estimate of the annual when appropriate, and other forms of economic impacts is available in the reporting, recordkeeping, and third- information technology. docket for this proposed rule (Ref. 63) party disclosure burden. Included in the Title: Sunscreen Drug Products for and at https://www.fda.gov/AboutFDA/ estimate is the time for reviewing OTC Human Use. ReportsManualsForms/Reports/ instructions, searching existing data Description: The proposed rule would EconomicAnalyses/default.htm. sources, gathering and maintaining the amend FDA’s current sunscreen labeling data needed, and completing and regulation (§ 201.327) and sunscreen XIV. Analysis of Environmental Impact reviewing each collection of products monograph (part 352) We have determined under 21 CFR information. regarding product labeling, testing, and 25.31(c) that this action is of a type that FDA invites comments on these recordkeeping requirements. We note does not individually or cumulatively topics: (1) Whether the proposed that existing regulations (e.g., current have a significant effect on the human collection of information is necessary § 201.327) already require SPF testing environment. Therefore, neither an for the proper performance of FDA’s and labeling. The information environmental assessment nor an functions, including whether the collections associated with current environmental impact statement is information will have practical utility; testing, labeling, and recordkeeping required. (2) the accuracy of FDA’s estimate of the requirements have previously been burden of the proposed collection of approved in accordance with the PRA XV. Paperwork Reduction Act of 1995 information, including the validity of under OMB control numbers 0910– This proposed rule contains the methodology and assumptions used; 0139, 0910–0717, and 0910–0755. For information collection provisions that (3) ways to enhance the quality, utility, more information about current are subject to review by OMB under the and clarity of the information to be regulations and their history, see the Paperwork Reduction Act of 1995 (PRA) collected; and (4) ways to minimize the Background and Scope sections of the

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proposed rule (sections III and IV, SPF or broad spectrum testing. Thus, we accordance with § 201.327(b)(1)(ii). respectively). The proposed rule would estimate that there are approximately 20 Proposed § 352.60(a) requires that the also amend parts 310 and 347. entities that conduct covered sunscreen product bear a statement of identity as While the proposed provisions are testing; we estimate these entities have set forth in § 201.327(h)(1). Proposed broadly consistent with current best approximately 20 lead clinical § 352.20(b)(4) requires that the product practices for testing conducted in investigators to whom certain must be labeled in accordance with human subjects and are not expected to information collection obligations (e.g., §§ 201.327(h) and 352.60. Proposed require significant changes by reputable reporting) may apply. § 347.60(a)(3) requires that the labeling and experienced testing establishments, of the product bear the statement of the proposed rule clarifies and confirms A. Labeling for Sunscreen Products and Associated Clinical Testing identity set forth in proposed the application of existing requirements § 352.60(a). to sunscreens and adds certain new The proposed rule includes third- We note that current regulations requirements, particularly for labeling party disclosure obligations for already include a requirement that OTC and recordkeeping. The purpose of responsible persons. The provisions products bear a statement of identity these changes is to help ensure that may also apply to entities to which the (see § 201.66). This proposed rule would sunscreen testing is conducted and responsible persons transfer their set forth the specific requirements just documented in a way that verifiably responsibilities under section described for sunscreen drug products provides for protection of human 201.327(a)(1) (‘‘transferees’’), depending and sunscreen drug products that also subjects and increases the reliability of on the scope of transferred obligations. contain skin protectant active the testing data that underlies sunscreen There are labeling-related information ingredients. We believe this analysis labeling, and to update the labeling collections (requirements include reflects the additional burden beyond requirements. certain information on product labels) current statement of identity and a related testing burden Description of Respondents: Affected requirements. entities include: (1) ‘‘responsible (requirements for certain clinical testing b. SPF value. Proposed § 201.327(b)(2) persons,’’ as defined in proposed to determine and support labeling requires, among other things, that the § 201.327(a); (2) entities to which the information). labeling display certain statements responsible person transfers its 1. Labeling-Related Information regarding the product’s SPF value; the obligations as permitted under proposed Collection and Burden § 201.327(a)(1) (e.g., contract statements must be supported by the manufacturers, contract testing entities, Proposed § 201.327(b) and testing required by proposed contract research organizations); and (3) § 201.327(h)(1) amend certain labeling § 201.327(i) and referenced in proposed clinical investigators conducting the requirements applicable to the PDP. § 352.70. As previously noted, certain testing (the investigator(s) required to Among other things, proposed SPF testing and labeling is already submit investigator statements and other § 201.327(b) sets forth labeling required under current regulations. This materials to the responsible person). requirements for the statement of analysis reflects the estimated FDA estimates that up to 772 entities identity and SPF value claims discussed additional burden of the proposed could meet the proposed definition of in this section. Proposed § 201.327(h)(1) changes to SPF testing and labeling responsible person (equivalent to applies to the statement of identity for requirements. ‘‘brands’’ in the economic analysis sunscreen products that also contain c. Burden for proposed statement of found in section XIII, Preliminary skin protectant active ingredients. identity and SPF value information Analysis of Economic Impacts). The Proposed § 352.50 requires that the PDP collections. The estimated burden for estimate of 772 entities also includes labeling comply with the requirements the statement of identity and SPF value nearly all entities to which a responsible of § 201.327(b). The SPF value information collections just described is person might transfer its obligations statements set forth in proposed provided in table 11 (Estimated Annual (‘‘transferees’’), such as contract § 201.327(b) and referenced in proposed Third-Party Disclosure Burden). For manufacturers, contract repackagers, § 352.50 are based on the results of the currently marketed OTC sunscreen contract distributors. For example, a testing required in proposed § 201.327(i) products, FDA believes that responsible manufacturer may be a responsible and proposed part 352 (§ 352.70). persons need only complete the testing person for one brand and a contract a. Statement of identity. Proposed (or reanalyze existing testing data) and manufacturer for another. However, in § 201.327(b)(1) requires that sunscreen relabel the product as required by the addition to the 772 entities and drug products bear a statement of rule one time, and may then continue to potential transferees already described, identity consisting of the name of each utilize the resultant labeling going we estimate that there are sunscreen active ingredient listed in forward without additional burden. We approximately 10 U.S.-based contract alphabetical order, followed by estimate that 772 respondents would testing entities used by multiple ‘‘Sunscreen’’ and ‘‘[Dosage form]’’ (e.g., need to complete this relabeling and responsible persons to conduct ‘‘Lotion’’, ‘‘Spray’’). Proposed related testing (if not already done) or sunscreen testing (e.g., contract § 352.52(a) requires the labeling to reanalysis of existing test results one laboratories and contract research contain a statement of identity in time for up to 4,078 total products. In organizations). These 10 potential accordance with § 201.327(b). addition, there may be new products transferees are not included in the 772 Proposed § 201.327(h)(1) applies to introduced each year. We estimate that figure. Thus, for certain information sunscreen drug products that also as many as 1,500 new OTC sunscreen collections, the estimated respondent contain skin protectant active product stock keeping units (SKUs) may number may be 782. We note that this ingredients; it requires that the product be introduced each year by up to 772 estimate does not include non-U.S.- bear a statement of identity consisting of respondents. These new products must based contract testing entities. the name of all sunscreen and skin be tested and labeled with the SPF value In addition to the 10 contract testing protectant active ingredients in and broad spectrum results determined entities, FDA estimates that alphabetical order, followed by in the tests. We estimate that the 1,500 approximately 10 of the estimated 772 ‘‘Sunscreen/Skin Protectant’’ and new sunscreen SKUs represent 975 new responsible persons conduct their own ‘‘[Dosage form],’’ presented in formulations.

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Table 11, row 1 provides FDA’s of the part 352 monograph), there is no reflected in the estimates regarding the estimate that 772 respondents will need additional burden. number of respondents below. to create PDP labeling for currently b. Investigator statements, CVs, and 2. Clinical Testing-Related Information marketed sunscreen formulations in related burden. Proposed Collection and Burden accordance with the statement of § 201.327(i)(1)(i) requires responsible identity and SPF value requirements of Proposed § 201.327(i) contains persons to, among other things, obtain a proposed § 201.327(b)(1), (b)(2), and requirements for clinical testing of SPF signed investigator statement from each (h)(1). This would be a one-time burden, values for inclusion on sunscreen investigator. Proposed and FDA estimates 5.2824 responses per product labeling. As previously noted, § 201.327(i)(1)(iv)(B) requires respondent for a total of 4,078 current regulations already require SPF responsible persons to obtain a signed responses. FDA estimates a burden of testing. While FDA expects that SPF investigator statement and CV. In FDA’s 0.5 hours per response. We estimate the testing and some of the proposed experience, investigators for SPF testing total burden of this recordkeeping to be recordkeeping is already being done, the are most often employed by the testing 2,039 hours. proposed changes are intended to clarify entities, and we therefore believe this is Table 11, row 2 provides FDA’s existing requirements applicable to a recordkeeping requirement rather than estimate that up to 772 respondents will sunscreen drug products and set forth a third-party reporting requirement. We need to create PDP labeling for new certain new requirements intended to request comment on this assumption. formulations each year in accordance improve the reliability of SPF testing As noted above, we estimate that with the statement of identity and SPF and ensure the protection of human responsible persons will typically value requirements of proposed subjects. Proposed § 352.70 references delegate this obligation to the § 201.327(b)(1), (b)(2), and (h)(1). FDA the § 201.327(i) testing requirements approximately 20 entities conducting estimates 1.943 responses per and makes the referenced testing final formulation testing. We estimate respondent for a total of 1,500 requirements part of the monograph that each testing entity employs one responses. FDA estimates a burden of conditions of use. clinical investigator to run the SPF 0.5 hours per response. We estimate the Across disciplines, testing involving testing they conduct. One investigator total burden of this recordkeeping to be human subjects is ordinarily conducted may run multiple SPF tests, and so long 750 hours. under IRB oversight as a means of as the responsible person (or testing Table 11, row 3 provides FDA’s ensuring that adequate human subject entity) has the investigator statement estimate that 20 respondents will protections are provided and to ensure and CV on file for each investigator, conduct SPF testing in accordance with the integrity of study design and there need not be a separate copy for § 201.327(i) (to determine the SPF value execution. Thus, in this proposed each investigation. required by § 201.327(b)(2)) for regulation, FDA is proposing to apply Table 10, row 1 provides FDA’s currently marketed sunscreen certain human subject protection estimate that approximately 20 formulations, if this has not already requirements to sunscreens, with the respondents will need to obtain and been done. This would be a one-time aim of having a framework similar to keep a signed investigator statement and burden. The estimated number of that used in the IND context, but CV in accordance with § 201.327(i)(1)(i) respondents reflects FDA’s assumption tailored to sunscreen testing. and (i)(1)(iv)(B). FDA estimates 2 based on its knowledge of the existing Information collections related to responses per respondent (1 CV and 1 market that, of the 772 responsible proposed § 201.327(i) are addressed in investigator statement) for a total of 40 persons, approximately 10 will conduct detail in the sections that follow. annual responses. FDA estimates a their own final formulation testing Regarding proposed § 352.70, as in the burden of 0.6 hours per response. We under § 201.327(i), while most will previous section, because the proposed estimate the total burden of this delegate the responsibility for change does not add any additional recordkeeping to be 24 hours. conducting final formulation testing to labeling or testing-related information c. Notifications and related burden. the approximately 10 independent collections not already addressed Proposed § 201.327(i)(1)(i) requires testing entities that FDA believes elsewhere (it cross-references the responsible persons to, among other conduct most final formulation testing. proposed § 201.327(i) testing things, ensure that FDA and all FDA estimates 111 responses per requirements as a condition of the part participating investigators are promptly respondent for a total of 2,220 352 monograph), there is no additional informed of significant new adverse responses. FDA estimates a burden of 24 burden. effects or risks with respect to the drug. hours per response. We estimate the a. Investigator statements and Proposed § 201.327(i)(1)(v) requires total burden to be 53,280 hours. notifications. Proposed § 201.327(i), responsible persons to keep each Table 11, row 4 provides FDA’s among other things, requires responsible participating investigator informed of estimate that 20 respondents will persons to obtain a signed investigator new observations about the drug, conduct SPF testing in accordance with statement and an investigator CV, and to particularly with respect to adverse § 201.327(i) (to determine the SPF value provide certain notifications (e.g., effects and safe use. As mentioned required by § 201.327(b)(2)) for new notification of adverse drug above, like other obligations associated sunscreen formulations. FDA estimates experiences). These may result in third- with testing under proposed 48.75 responses per respondent for a party disclosure or reporting § 201.327(i), we anticipate that this total of 975 responses. FDA estimates a requirements for responsible persons obligation will be delegated in most burden of 24 hours per response. We (and entities to which they have instances to the approximately 20 estimate the total burden to be 23,400 transferred relevant obligations) as well entities that currently conduct SPF hours. as for clinical investigators. As noted testing on behalf of responsible persons. Regarding proposed § 352.70, because above, our experience leads us to Table 9, row 1 provides FDA’s that section does not add any additional believe that most responsible persons estimate that approximately 20 labeling or testing-related information will transfer their obligations under respondents will need to inform FDA collections not already addressed § 201.327(i) to the approximately 20 and participating investigators of elsewhere (it incorporates the proposed entities that currently conduct clinical significant new adverse effects or risks SPF testing requirements as a condition SPF testing. This assumption is in accordance with § 201.327(i)(1)(i) and

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of new safety and other observations in responses. FDA estimates a burden of 3 publication of the final rule, FDA plans accordance with § 201.327(i)(1)(v). FDA hours per response. We estimate the to amend its approved information estimates up to 40 responses per total burden of this recordkeeping to be collection 0910–0139, if necessary, to respondent for a total of up to 800 2,925 hours. adjust the respective burden estimate(s) annual responses. FDA estimates a Proposed § 352.40(i)(1) references to account for any change. We request burden of 0.5 hours per response. We limitations on particle size for comment on the accuracy of our estimate the total burden of this sunscreens in a spray dosage form. assumptions and the resulting burden recordkeeping to be 400 hours. Proposed § 352.40(i)(2) and (3) proposes estimate. d. Informed consent, IRB review, and limitations on flammability and drying related burden. Proposed time for spray sunscreen formulations. B. Regulatory Status of Testing Entities § 201.327(i)(1)(ii) requires responsible These proposed sections (§ 352.40(i)(1) Proposed § 201.327(k) clarifies the persons to obtain informed consent, as through (3)) make the referenced regulatory status of final formulation defined in part 50, before clinical final limitations on flammability and particle testing, including that final formulation formulation testing and proposed size requirements part of the monograph testing conducted pursuant to § 201.327 § 201.327(i)(1)(iii) requires that clinical conditions of use. Proposed constitutes ‘‘manufacture’’ of a drug. As testing under § 201.327(i) be reviewed § 352.40(i)(5) states that applicable such, this testing must be conducted in and approved by an IRB meeting the requirements for particle size, an establishment registered in requirements of part 56. These two flammability, and drying time for spray accordance with part 207 and section proposed provisions make clear that sunscreens must be verified through 510 of the FD&C Act, and entities FDA’s regulations governing informed batch and lot testing as part of CGMP conducting final formulation testing consent (part 50) and IRB approval of compliance under part 211. Entities required by this section must comply research (part 56) apply to clinical final conducting testing required by these with CGMP and associated formulation testing conducted pursuant sections must also comply with recordkeeping requirements, including to § 201.327(i). associated recordkeeping requirements, those set forth in § 201.327(l) and in Regarding proposed § 201.327(i)(1)(ii) including those set forth in parts 210 parts 210 and 211. As this provision is and (iii), the information collections and 211. intended only to clarify an existing associated with FDA’s regulations The recordkeeping associated with requirement, it does not create a new governing informed consent (part 50) ensuring compliance with § 352.40(i)(5) information collection. and IRB approval of research (part 56) (batch and lot testing to ensure Entities covered by this provision are have previously been approved in compliance with particle size, already included in the burden accordance with the PRA under OMB flammability, and drying time estimates for the information collections control number 0910–0755. FDA does limitations) is considered to be part of associated with registration and listing not expect that proposed the manufacturers’ CGMP requirements requirements. Recordkeeping § 201.327(i)(1)(ii) or (iii) would affect under parts 210 and 211 (OMB control obligations related to registration and the number of recordkeepers, records, number 0910–0139). While FDA listing under part 207 and section 510 reports, or associated burdens included believes that sunscreen manufacturers of the FD&C Act are part of FDA’s in the existing approval (0910–0755), are already included among the approved information collection for part but we invite stakeholders to comment respondents counted for that collection, 207 (OMB control number 0910–0829). if they have a different view. and that many of those manufacturers CGMP recordkeeping obligations are Proposed § 201.327(i)(1)(vii) requires who have spray dosage products may part of FDA’s approved information investigators to provide safety reports already be conducting flammability and collection for part 211 (OMB control and a final study report to the drying time testing (e.g., many are number 0910–0139). responsible person. Although including flammability statements and C. Generating and Maintaining Records investigators are often employees of information about drying time in of SPF and Broad Spectrum Testing testing entities, we are basing our current product labeling), the proposed estimate on our assumption the inclusion of these requirements in the FDA is proposing specific respondents in this case are the sunscreen regulations is new. The recordkeeping requirements for SPF and investigators themselves because of the proposed rule specifies the particle size, broad spectrum testing to enable FDA to framing of the duty proposed by the flammability, and drying time better monitor responsible persons’ regulation. limitations that would be required for compliance with the requirements of Table 9, row 2 provides FDA’s sunscreens in spray dosage forms to be § 201.327. Recordkeeping is essential for estimate that up to 20 respondents will GRASE under the monograph. The FDA to evaluate whether required need to provide safety reports in proposed rule also specifies that testing of final formulations is being accordance with § 201.327(i)(1)(vii)(A). compliance with these limitations must conducted properly (both as to human FDA estimates 24.4 responses per be verified through batch and lot testing. subject protection and as to study respondent for a total of 488 annual While this greater specificity as to design) and to enable the Agency to responses. FDA estimates a burden of required testing might have a marginal investigate postmarketing product 0.5 hours per response. We estimate the effect on the burden associated with failures or adverse events. Appropriate total burden of this recordkeeping to be recordkeeping for manufacturing recordkeeping also enables FDA to 244 hours. facilities that are not already conducting conduct better and more efficient Table 9, row 3 provides FDA’s such testing, FDA believes that the total inspections of entities conducting final estimate that up to 20 respondents will change would be minimal in light of the formulation testing. The proposed need to provide a final report in total recordkeeping burden under parts recordkeeping requirements are in accordance with § 201.327(i)(1)(vii)(B). 210 and 211, which is estimated across alignment with the records required for This will occur one time per study, with thousands of manufacturers of a wide other types of manufacturing under each of the 20 investigators conducting variety of drugs. We request comment CGMPs as set forth in parts 210 and 211. multiple studies per year. FDA on these assumptions. If FDA Failure to maintain adequate records estimates 48.75 responses per determines that the assumptions are of testing equipment, methods, and respondent for a total of 975 annual incorrect, then, concurrent with observations can raise broad questions

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about the reliability of final formulation addresses maintenance records. The final formulation testing on behalf of testing. In FDA’s experience, there has proposed rule clarifies that, as multiple responsible persons, an error at been a lack of uniformity in testing manufacturing, final formulation testing one testing entity may affect data across entities’ approaches to recordkeeping must comply with CGMPs, and, multiple clinical SPF testing studies for for final formulation testing, raising accordingly, records documenting multiple different final formulations concerns about the Agency’s ability to proper maintenance of equipment used that are ultimately sold under different assess the reliability of the results of in final formulation testing must be labels. final formulation testing. The proposed generated and maintained by testing In particular, proposed § 201.327(l)(2) regulation would address these entities, consistent with existing requires that, in addition to any records concerns, clarify FDA’s expectations, obligations in part 211. required to be kept pursuant to parts and align the regulation with current Regarding proposed § 201.327(l)(1), 210 and 211, records of SPF testing best practices. the existing maintenance record must include: (1) Identification of the a. Potential transfer of obligations. obligations are part of FDA’s approved testing entity; (2) the product identifier Proposed § 201.327(a)(1) permits a information collection for part 211 and expected SPF; (3) characterization responsible person (defined in (OMB control number 0910–0139), and of the SPF standard sunscreen required § 201.327(a)) to transfer some or all of its FDA believes that most of the by proposed § 201.327(i)(3) (lot number, obligations to another entity (a respondents for this collection of manufacturing date, and results of high ‘‘transferee’’), except for obligations information (the approximately 20 performance liquid chromatography with respect to recordkeeping under entities we believe are conducting final (HPLC) SPF standard assay); (4) § 201.327(l). We note that this could formulation testing) are already documentation linking any blinded create some situations in which both the included among the recordkeepers samples with the product lot number responsible person and the transferee counted for that collection. The and formulation tested; (5) specific would be required to comply with proposed rule provides greater testing records for each human subject applicable recordkeeping requirements. specificity regarding what information (identification of the UV source used for The proposed provision would also should be included in maintenance testing and various specific test results require a written record of the transfer records maintained by facilities and the individual(s) who determined of obligations to be maintained by both conducting final formulation testing. the values); (6) the mean and standard parties to the transfer. While this greater specificity might have deviation from SPFi values, standard Regarding the record of an obligation a marginal effect on the burden error and determined SPF value derived transfer, FDA believes that it is usual associated with recordkeeping for these as set forth in proposed § 201.327(i)(7); and customary business practice for a facilities, and the number of (7) records for water resistance testing of written record of a transfer of respondents for this requirement may pool temperature, air temperature, and obligations to be maintained by both need to be increased by 10 (to reflect relative humidity as required by parties to the transfer. FDA does not contract testing entities that may not be proposed § 201.327(i)(8); and (8) records believe this requirement would incur currently registered as manufacturers), demonstrating compliance with any additional recordkeeping burden FDA believes that the total change proposed § 201.327(i)(1) requirements and believes it would meet the would be minimal in light of the total for adequate clinical testing procedures exception at 5 CFR 1320.3(b)(2). recordkeeping burden under parts 210 and conditions (e.g., individual case Regarding the potential for some and 211, which is estimated across histories and documentation of IRB recordkeeping obligations to fall on both thousands of manufacturers of a wide review). responsible persons and transferees, variety of drugs. We request comment Table 10, row 2 provides FDA’s although proposed § 201.327(a)(1) does on these assumptions. If FDA estimate that approximately 20 not itself impose a specific requirement determines that the assumptions are respondents will need to generate SPF to generate records, it does create the incorrect, then, concurrent with testing records in accordance with potential for some recordkeeping publication of the final rule, FDA plans proposed § 201.327(l)(2) for existing obligations to fall on both responsible to amend its approved information products that will be reformulated. FDA persons and transferees. In particular, if collection under OMB control number estimates 85.5 records per recordkeeper a responsible person has delegated all 0910–0139 as necessary to adjust the for a total of 1,710 records. This is a other responsibilities under § 201.327(i) respective burden estimate(s) in order to one-time burden. FDA estimates a and (j), they would nonetheless need to account for any change. burden of 24 hours per recordkeeping. maintain a copy of the records of final c. SPF testing records and related We estimate the total burden of this formulation testing required by burden. Proposed § 201.327(l)(2) recordkeeping to be 41,040 hours. § 201.327(l)(2) and (3). We have addresses SPF testing records and Table 10, row 3 provides FDA’s included the burden associated with requires that respondents keep records estimate that up to 20 respondents will keeping this copy in our assumption related to the identification of the entity need to generate SPF testing records in that there are 782 respondents for conducting the testing, the formulation accordance with proposed recordkeeping obligations as described being tested, equipment used, § 201.327(l)(2) for new formulations. below (20 entities that conduct testing, investigators, SPF standards, specific FDA estimates 48.75 records per 10 of whom are also responsible subject and test result data, and records recordkeeper for a total of 975 records. persons, plus 762 responsible persons demonstrating compliance with FDA estimates a burden of 24 hours per that delegate their responsibility for § 201.327(i)(1) governing the recordkeeping. We estimate the total conducting testing (e.g., to one of the 10 establishment of adequate clinical burden of this recordkeeping to be independent testing entities that are not testing procedures and conditions. This 23,400. themselves responsible persons)). We is important because failure of testing Table 10, row 4 provides FDA’s invite comment on whether our entities to keep adequate records to estimate that up to 782 respondents will estimates properly reflect the support final formulation testing may need to keep SPF testing records in recordkeeping obligations. leave FDA unable to verify the accordance with proposed b. Maintenance records and related reliability of the results of SPF testing. § 201.327(l)(2) for existing products that burden. Proposed § 201.327(l)(1) Because one testing entity may conduct will be reformulated. This is a one-time

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burden. FDA estimates 2.1867 records testing must include: (1) Identification Table 10, row 8 provides FDA’s per recordkeeper for a total of 1,710 of the testing entity; (2) records of estimate that up to 782 respondents will records. FDA estimates a burden of 0.33 sample information (product identifier need to keep broad spectrum testing hours per recordkeeping. We estimate and expected SPF, master key for records in accordance with proposed the total burden of this recordkeeping to blinded samples, sample number and § 201.327(l)(3) for existing products. be 564.3 hours. identifier code, polymethylmethacrylate This is a one-time burden. FDA Table 10, row 5 provides FDA’s (PMMA) plate surface topography estimates 5.215 records per estimate that up to 782 respondents will measurement, and sample holder recordkeeper for a total of 4,078 records. need to keep SPF testing records in orientation); (3) identification of each FDA estimates a burden of 0.17 hours accordance with proposed UV source used for sunscreen product per recordkeeping. We estimate the total § 201.327(l)(2) for new formulations. pre-irradiation; (4) records of sunscreen burden of this recordkeeping to be 693.3 FDA estimates 1.2468 records per product application (sample weights, hours. recordkeeper for a total of 975 records. equipment identification); (5) Table 10, row 9 provides FDA’s FDA estimates a burden of 0.33 hours measurements required by proposed estimate that up to 782 respondents will per recordkeeping. We estimate the total § 201.327(j)(4) to (6)); (6) records of need to keep broad spectrum testing burden of this recordkeeping to be critical wavelength and UVA1/UV ratio records in accordance with proposed 321.75 hours. values; (7) for each sample: The identity § 201.327(l)(3) for new formulations. With regard to the testing-related of the individual(s) conducting specific FDA estimates 1.2468 records per estimates, we note that the requirements testing steps; and (8) test dates for the recordkeeper for a total of 975 records. for obtaining certain medical history broad spectrum test conducted pursuant FDA estimates a burden of 0.17 hours information from test subjects are not to § 201.327(j), and sample report forms per recordkeeping. We estimate the total considered collections of information and supporting data. burden of this recordkeeping to be because information collected from Table 10, row 6 provides FDA’s 165.75 hours. subjects of clinical testing does not estimate that approximately 20 The recordkeeping burden is constitute information under 5 CFR respondents will need to generate broad estimated as described in the tables at 1320.3(h)(5), and that the referenced spectrum testing records in accordance the end of the PRA discussion. informed consent and IRB requirements with proposed § 201.327(l)(3) for With the exceptions noted above, we under parts 50 and 56 are covered by existing products. As with records of conclude that the other provisions of existing approvals, as previously SPF testing, this number of respondents this rule are not subject to OMB review discussed. reflects FDA’s assumption that most under the PRA. d. Broad spectrum testing records and responsible persons will delegate The proposed changes to part 310 do related burden. Proposed § 201.327(l)(3) responsibility for conducting testing not include any collections of addresses broad spectrum testing under § 201.327(j) to the approximately information subject to the PRA. records. The proposed rule requires 20 testing entities. FDA estimates 203.9 The remaining sections of part 347 do records related to the identification of records per recordkeeper for a total of not include any collections of the entity conducting the testing, the 4,078 records. This is a one-time information not already addressed in formulation being tested, equipment burden. FDA estimates a burden of 1.5 this analysis. used, investigators, UV standards, hours per recordkeeping. We estimate Section 201.327 and the remaining sunscreen application, and specific test the total burden of this recordkeeping to sections of part 352 either do not result data. This is important because be 6,117 hours. contain an information collection failure of testing entities to keep Table 10, row 7 provides FDA’s subject to PRA, or contain specific adequate records to support broad estimate that up to 20 respondents will labeling information, including spectrum testing may leave FDA unable need to generate broad spectrum testing directions and warnings, which are a to verify the reliability of testing results. records in accordance with proposed ‘‘public disclosure of information Failure at one testing entity may affect § 201.327(l)(3) for new formulations. originally supplied by the Federal data across multiple broad spectrum FDA estimates 48.75 records per Government to the recipient for the testing studies for multiple different recordkeeper for a total of 975 records. purpose of disclosure to the public’’ (5 final formulations that are ultimately FDA estimates a burden of 1.5 hours per CFR 1320.3(c)(2)) and, therefore, are not sold under different labels. recordkeeping. We estimate the total collections of information. In particular, proposed § 201.327(l)(3) burden of this recordkeeping to be FDA estimates the burden of this requires that records of broad spectrum 1,462.5 hours. information collection as follows:

TABLE 9—ESTIMATED ANNUAL REPORTING BURDEN 1

Number of Activity and 21 CFR section Number of responses per Total annual Average burden Total hours respondents respondent responses per response

Inform FDA and investigators of significant new ad- 20 40 800 0.5 (30 minutes) ..... 400 verse effects or risks (§ 201.327(i)(1)(i)) and new safety and other observations (§ 201.327(i)(1)(v)). Investigators provide safety reports in accordance 20 24.4 488 0.5 (30 minutes) ..... 244 with § 201.327(i)(1)(vii)(A). Investigators provide a final report in accordance with 20 48.75 975 3...... 2,925 § 201.327(i)(1)(vii)(B) (one time per study).

Total ...... 3,569 1 There are no capital costs or operating and maintenance costs associated with this collection of information.

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TABLE 10—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1

Number of Activity and 21 CFR section Number of records per Total annual Average burden Total hours recordkeepers recordkeeper records per recordkeeping

Obtain and keep a signed investigator statement and 20 2 40 0.6 (36 minutes) ..... 24 CV in accordance with § 201.327(i)(1)(i) and (iv)(B). Generate SPF testing records for existing products 20 85.5 1,710 24...... 41,040 (§ 201.327(l)(2)) (one-time). Generate SPF testing records for new formulations 20 48.75 975 24...... 23,400 (§ 201.327(l)(2)). Keep SPF testing records for existing products 782 2.1867 1,710 0.33 (20 minutes) ... 564.3 (§ 201.327(l)(2)) (one-time). Keep SPF testing records for new formulations 782 1.2468 975 0.33...... 321.75 (§ 201.327(l)(2)). (20 minutes) ...... Generate Broad Spectrum testing records for existing 20 203.9 4,078 1.5...... 6,117 products (§ 201.327(l)(3)). Generate Broad Spectrum testing records for new 20 48.75 975 1.5...... 1,462.5 formulations (§ 201.327(l)(3). Keep Broad Spectrum testing records for existing 782 5.215 4,078 0.17 (10 minutes) .. 693.3 products (§ 201.327(l)(3)). Keep Broad Spectrum testing records for new formu- 782 1.2468 975 0.17 (10 minutes) .. 165.75 lations (§ 201.327(l)(3)).

Total ...... 773,788.6 1 There are no capital costs or operating or maintenance costs associated with this collection of information.

TABLE 11—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1

Number of Number of disclosures Total annual Average burden Activity and 21 CFR section respondents per disclosures per disclosure Total hours respondent

Create PDP labeling in accordance with statement of 772 5.2824 4,078 0.5 (30 minutes) ..... 2,039 identity and SPF value requirements (§ 201.327(b)(1), (b)(2) and (h)(1)) for currently marketed sunscreen formulations (one-time bur- den). Create PDP labeling in accordance with statement of 772 1.943 1,500 0.5 (30 minutes) ..... 750 identity and SPF value requirements (§ 201.327(b)(1), (b)(2), and (h)(1)) for new formu- lations. Conduct SPF testing in accordance with § 201.327(i) 20 111 2,220 24...... 53,280 to determine SPF value for currently marketed sunscreen formulations (if not already done) (one- time burden). Conduct SPF testing in accordance with § 201.327(i) 20 48.75 975 24...... 23,400 to determine SPF value for new sunscreen formu- lations.

Total ...... 79,469 1 There are no capital costs or operating or maintenance costs associated with this collection of information.

In compliance with the PRA (44 the statute contains an express proposed rule, we are providing notice U.S.C. 3407(d)), the Agency has preemption provision or there is some and an opportunity for State and local submitted the information collection other clear evidence that the Congress officials to comment on this rulemaking. provisions of this proposed rule to OMB intended preemption of State law, or XVII. Consultation and Coordination for review. These requirements will not where the exercise of State authority With Indian Tribal Governments be effective until FDA obtains OMB conflicts with the exercise of Federal approval. FDA will publish a notice authority under the Federal statute.’’ We have analyzed this proposed rule concerning OMB approval of these The sole statutory provision giving in accordance with the principles set requirements in the Federal Register. preemptive effect to this proposed rule forth in Executive Order 13175. We is section 751 of the FD&C Act (21 have tentatively determined that the XVI. Federalism U.S.C. 379r). We have complied with all rule does not contain policies that We have analyzed this proposed rule of the applicable requirements under would have a substantial direct effect on in accordance with the principles set the Executive order and have one or more Indian Tribes, on the forth in Executive Order 13132. Section determined that the preemptive effect of relationship between the Federal 4(a) of the Executive order requires this proposed rule, if finalized, would Government and Indian Tribes, or on Agencies to ‘‘construe . . . a Federal be consistent with Executive Order the distribution of power and statute to preempt State law only where 13132. Through publication of this responsibilities between the Federal

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Recurrent Somatic Rac1 Mutations in Dermatology, vol. 64(1), pp. 37–48, 2011. 153. Liu, X., D. Rua, A. Wokovich, et al., Melanoma,’’ Nature Genetics, vol. 44(9), 178. Faurschou, A. and H.C. Wulf, ‘‘Particle Size Distribution Analysis of pp. 1006, 2012. ‘‘Synergistic Effect of Broad-Spectrum OTC Drug Products with Unintended 165. Ziegler, A., A.S. Jonason, D.J. Leffell, et Sunscreens and Antihistamines in the Inhalation Exposure to Consumers al., ‘‘Sunburn and P53 in the Onset of Control of Idiopathic Solar Urticaria,’’ [abstract].’’ In: American Association of Skin-Cancer,’’ Nature, vol. 372(6508), Archives of Dermatology, vol. 144(6), pp. Pharmaceutical Scientists Annual pp. 773–776, 1994. 765–769, 2008. Meeting and Exposition; November 12– 166. Tewari, A., M.M. Grage, G.I. Harrison, et 179. Fourtanier, A., D. Moyal, and S. Seite, 15, 2017; San Diego Convention Center. al., ‘‘UVA1 Is Skin Deep: Molecular and ‘‘Sunscreens Containing the Broad- Abstract number T1109, 2017. Clinical Implications,’’ Photochemical Spectrum UVA Absorber, Mexoryl SX, 154. Liu, X., D. Rua, A. Wokovich, et al., and Photobiological Sciences, vol. 12(1), Prevent the Cutaneous Detrimental ‘‘Particle Size Distribution Analysis of pp. 95–103, 2013. Effects of UV Exposure: a Review of OTC Aerosol or Powder Drug Products 167. Tewari, A., R.P. Sarkany, and A.R. Clinical Study Results,’’ with Potential for Inadvertent Inhalation Young, ‘‘UVA1 Induces Cyclobutane Photodermatology, Photoimmunology & Exposure to Consumers,’’ Journal of Pyrimidine Dimers but Not 6–4 Photomedicine, vol. 24(4), pp. 164–174, Pharmaceutical Science, doi: 10.1016/ Photoproducts in Human Skin in Vivo,’’ 2008. j.xphs.2018.10.066 (Epub ahead of print), Journal of Investigative Dermatology, vol. * 180. Therapeutic Goods Administration, 2018, (available at https:// 132(2), pp. 394–400, 2012. ‘‘Australian Regulatory Guidelines for

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Minimum Risk Pesticide Products’’ 201. American Academy of Pediatrics, ‘‘Tips (Updated December 2015) (available at for Using Repellents Safely’’ (available at 21 CFR Part 310 https://www.epa.gov/sites/production/ www.healthychildren.org/English/safety- files/2015-12/documents/minrisk-active- prevention/at-play/Pages/Insect- Administrative practice and ingredients-tolerances-2015-12-15.pdf), Repellents.aspx?rf), accessed March 27, procedure, Drugs, Labeling, Medical accessed March 27, 2018. 2018. devices, Reporting and recordkeeping * 190. EPA, ‘‘Using Insect Repellents Safely 202. EPA, ‘‘DEET’’ (available at https:// requirements. and Effectively’’ (available at https:// www.epa.gov/insect-repellents/ www.epa.gov/insect-repellents/using- deet#children), accessed November 28, 21 CFR Part 347 insect-repellents-safely-and-effectively), 2018. Labeling, Over-the-counter drugs. accessed March 27, 2018. 203. Kaldor, J., D. Shugg, B. Young, et al., 191. American Academy of Pediatrics, ‘‘Non-Melanoma Skin Cancer: Ten Years 21 CFR Part 352 ‘‘Choosing an Insect Repellent for Your of Cancer-Registry-Based Surveillance,’’ Child’’ (available at https:// International Journal of Cancer, vol. 53, Labeling, Over-the-counter drugs. www.healthychildren.org/English/safety- pp. 886–891, 1993. Therefore, under the Federal Food, prevention/at-play/Pages/Insect- 204. Girschik, J., L. Fritschi, T. Threlfall, et Drug, and Cosmetic Act and under Repellents.aspx), accessed March 27, al., ‘‘Deaths from Non-Melanoma Skin authority delegated to the Commissioner 2018. Cancer in Western Australia,’’ Cancer * 192. EPA, ‘‘Reregistration Eligibility Causes and Control, vol. 19, pp. 879– of Food and Drugs, we propose that 21 Decision (R.E.D.) Facts, DEET,’’ April 885, 2008. CFR parts 201, 310, 347, and 352 be 1998 (available at https://www3.epa.gov/ 205. Ross, E.A., K.A. Savage, L.J. Utley, et al., amended as follows: pesticides/chem_search/reg_actions/ ‘‘Insect Repellant Interactions: reregistration/fs_PC-080301_1-Apr- Sunscreens Enhance DEET (N,N-Diethyl- PART 201—LABELING 98.pdf), accessed March 27, 2018. M-Toluamide) Absorption,’’ Drug 193. Katz, T.M., J.H. Miller, and A. Hebert, Metabolism and Disposition, vol. 32, ■ 1. The authority citation for part 201 ‘‘Insect Repellents: Historical pp.783–785, 2004. continues to read as follows:

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Authority: 21 U.S.C. 321, 331, 351, 352, transfer for the time period set forth in (i) SPF Broad Spectrum Statement. 353, 355, 358, 360, 360b, 360gg–360ss, 371, paragraph (l) of this section. For a product that has been shown to 374, 379e; 42 U.S.C. 216, 241, 262, 264. (ii) An entity that assumes any pass the broad spectrum test in ■ 2. Revise § 201.327 to read as follows: obligation(s) of a responsible person paragraph (j) of this section, the labeling must comply with the provisions of this states ‘‘Broad Spectrum SPF [insert the § 201.327 Over-the-counter sunscreen section applicable to the assumed labeled SPF value associated with the drug products; required labeling based on obligation and will be subject to the range into which the determined SPF effectiveness testing. same regulatory action as a responsible value falls, as set forth in the following The following provisions apply to an person for failure to comply with any table.]’’ over-the-counter (OTC) sunscreen drug obligation assumed under this section. product that is intended for application Thus, all references to ‘‘responsible TABLE 1 TO PARAGRAPH (b)(2)(i)— to the skin of humans for purposes of person’’ in this section apply to another SPF LABELING RANGES absorbing, reflecting, or scattering entity (e.g., a contract research radiation in the ultraviolet (UV) range at organization or testing laboratory) to the Range of Associated labeled wavelengths from 290 to 400 extent that it assumes one or more determined SPF values SPF value nanometers (nm), and that contains one obligations of a responsible person. or more of the following as an active (2) Personnel. A responsible person 60–80 ...... 60+. ingredient: Avobenzone, cinoxate, must select only investigators and other 50–59 ...... 50. dioxybenzone, ensulizole, homosalate, personnel qualified by appropriate 40–49 ...... 40. meradimate, octinoxate, octisalate, training and/or experience to conduct 30–39 ...... 30. octocrylene, oxybenzone, padimate O, final formulation testing pursuant to 25–29 ...... 25. sulisobenzone, titanium dioxide, or zinc this section. Personnel engaged in 20–24 ...... 20. oxide, alone or in combination. The testing under this section must have the 15–19 ...... 15. 2–14 ...... Determined SPF Value. provisions do not apply to OTC education, training, and experience, or sunscreen drug products marketed any combination thereof, to enable that under approved new drug applications person to adequately perform their (ii) SPF Statement. For a product that or abbreviated new drug applications. assigned functions. has not been shown to pass the broad The failure of a product covered by this (b) Principal display panel. The spectrum test in paragraph (j) of this section to comply with any provision of following labeling must be prominently section, the labeling states ‘‘SPF [insert this section, including the labeling of placed on the principal display panel: labeled SPF value associated with the such a product with any effectiveness (1) Statement of identity—(i) range into which the determined SPF claim based on testing that fails to Placement. The principal display panel value falls, as set forth in the table in comply with any provision of this of an over-the-counter sunscreen drug paragraph (b)(2)(i) of this section]’’. section, renders that product product bears a statement of identity as (iii) For a product with a determined misbranded under section 502 of the one of its principal features. Except as SPF value of at least 2 but less than 15. Federal Food, Drug, and Cosmetic Act. set forth in paragraph (h) of this section, The SPF statement is immediately (a) General obligations of responsible the statement of identity consists of the followed by an asterisk (‘‘*’’), and the persons. As used in this section, a name of each sunscreen active associated statement ‘‘*See Skin Cancer/ ‘‘responsible person’’ is the ingredient in the product as identified Skin Aging Alert’’ appears in the bottom manufacturer, packer, or distributor in this section, listed in alphabetical 30 percent of the principal display whose name appears on the labeling of order and followed by ‘‘Sunscreen’’ and panel. a product covered by this section. A ‘‘[Dosage form]’’ (e.g., ‘‘Lotion’’ (iv) Prominence of required responsible person must assure that ‘‘Spray’’). statements. The SPF Broad Spectrum final formulation testing conducted on (ii) Prominence. The statement of statement, SPF statement, and ‘‘*See its product(s) pursuant to paragraphs (i) identity must appear on the principal Skin Cancer/Skin Aging Alert’’ and (j) of this section complies with all display panel in boldface type at least statement, as applicable, must appear in applicable provisions of this section. one-quarter as large as the size of the boldface type at least one-quarter as (1) Transfer of obligations. (i) A most prominent printed matter on the large as the most prominent printed responsible person may transfer principal display panel, in lines matter on the principal display panel responsibility for any or all of its generally parallel to the base on which and in lines generally parallel to the obligations set forth in this section to the package rests as it is designed to be base on which the package rests as it is another entity (e.g., a contract research displayed and in direct conjunction designed to be displayed. The entire text organization and/or testing laboratory), with the most prominent display of the of the Broad Spectrum SPF or SPF except as set forth in paragraph (l) proprietary name or designation. The statement, as applicable, must appear in (recordkeeping) of this section. Any entire text of the statement of identity the same font style, size, and color with such transfer must be described in must appear in the same font style, size, the same background color and must writing. If not all obligations are and color with the same background appear as continuous text with no transferred, the writing is required to color, and as continuous text with no intervening text or graphic. The entire describe each of the obligations being intervening text or graphic, other than text of the ‘‘See Skin Cancer/Skin Aging assumed by the transferee. If all additional text provided in accordance Alert’’ statement, as applicable, must obligations are transferred, a general with paragraph (h) of this section. appear in the same font style, size, and statement that all obligations have been (2) Effectiveness claim. For purposes color with the same background color transferred is acceptable. Any obligation of this section, the term ‘‘determined and must appear as continuous text not covered by the written description SPF value’’ refers to the SPF value that with no intervening text or graphic. will be deemed not to have been equals the largest whole number less (3) Water resistance statements—(i) transferred. A written record of the than SPF¥(t*SE), determined for a For products that provide 40 minutes of transfer of obligations must be sunscreen product in accordance with water resistance according to the test in maintained by both parties to the paragraph (i) of this section. paragraph (i)(8)(i) of this section. The

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labeling states ‘‘Water Resistant (40 (1) For all sunscreen products. (i) The have a determined SPF value of 15 or minutes).’’ labeling states ‘‘Do not use [bullet] on higher. The labeling states ‘‘[bullet] Sun (ii) For products that provide 80 damaged or broken skin.’’ Protection Measures. [in bold font] minutes of water resistance according to (ii) The labeling states ‘‘When using Spending time in the sun increases your the test in paragraph (i)(8)(ii) of this this product [bullet] keep out of eyes. risk of skin cancer and early skin aging. section. The labeling states ‘‘Water Rinse with water to remove.’’ To decrease this risk, regularly use a Resistant (80 minutes).’’ (iii) The labeling states ‘‘Stop use and sunscreen with a Broad Spectrum SPF (iii) Prominence of water resistance ask a doctor if [bullet] rash occurs.’’ value of 15 or higher and other sun statement. For all products bearing a (2) For sunscreen products that are protection measures including: [bullet] water resistance statement, the broad spectrum with determined SPF limit time in the sun, especially from 10 statement must appear in boldface type values of at least 2 but less than 15 a.m.–2 p.m. [bullet] wear long-sleeved at least one-quarter as large as the most according to the SPF test in paragraph shirts, pants, hats, and sunglasses’’. prominent printed matter on the (i) of this section or that have not been (3) For products that satisfy the water principal display panel and in lines shown to pass the broad spectrum test resistance test in paragraph (i)(8) of this generally parallel to the base on which in paragraph (j) of this section. The first section. The labeling states ‘‘[bullet] the package rests as it is designed to be statement under the heading reapply: [bullet] after [select one of the displayed. The entire text of the water ‘‘Warnings’’ states ‘‘Skin Cancer/Skin following determined by water resistance statement must appear in the Aging Alert [in bold font]: Spending resistance test: ‘40 minutes of’ or ‘80 same font style, size, and color with the time in the sun increases your risk of minutes of’] swimming or sweating same background color, and as skin cancer and early skin aging. This [bullet] immediately after towel drying continuous text with no intervening text product has been shown only to help [bullet] at least every 2 hours’’. or graphic. prevent sunburn, not [in bold font] skin (4) For products that do not satisfy the (c) Indications. The labeling of the cancer or early skin aging.’’ water resistance test in paragraph (i)(8) product states, under the heading (3) For products in a spray dosage of this section. The labeling states ‘‘Uses,’’ the phrases listed in this form that meet the definition of either ‘‘[bullet] reapply at least every 2 hours paragraph, as appropriate. Other the term ‘‘flammable’’ or the term [bullet] use a water resistant sunscreen truthful and nonmisleading statements, ‘‘combustible’’ as defined in § 352.3(g) if swimming or sweating’’. describing only the uses that have been or (h) of this chapter, as applicable, (5) For sunscreen products in a spray established and listed in this paragraph, when tested in accordance with 16 CFR dosage form. The labeling states may also be used, as provided in 1500.43a—(i) Labeling statement. The ‘‘[bullet] Hold container 4 to 6 inches § 330.1(c)(2) of this chapter, subject to labeling states [bullet] ‘‘Flammable’’ or from the skin to apply. [bullet] Do not the provisions of section 502 of the ‘‘Combustible’’ (as applicable) followed spray directly into face. Spray on hands Federal Food, Drug, and Cosmetic Act by a colon and the statement ‘‘Keep then apply to face. [bullet] Do not apply relating to misbranding and the away from fire or flame.’’ in windy conditions. [bullet] Use in a prohibition in section 301(d) of the (ii) For products that have a drying well-ventilated area and avoid Federal Food, Drug, and Cosmetic Act time of less than 5 minutes. The labeling inhalation’’. against the introduction or delivery for states [bullet] ‘‘Wait 5 minutes after (f) Other information. The labeling of introduction into interstate commerce of application before approaching a source the product contains the following unapproved new drugs in violation of of heat or flame, or before smoking.’’ statement under the heading ‘‘Other section 505(a) of the Federal Food, Drug, (iii) For products that have a drying information:’’ ‘‘[bullet] protect the and Cosmetic Act. time of at least 5 minutes but less than product in this container from excessive (1) For all sunscreen products, the 10 minutes. The labeling states [bullet] heat and direct sun’’. following indication statement must be ‘‘Wait 10 minutes after application (g) False or misleading claims. There included under the heading ‘‘Uses’’: before approaching a source of heat or are claims that would be false and/or ‘‘[bullet] helps prevent sunburn’’. See flame, or before smoking.’’ misleading on sunscreen products. § 201.66(b)(4) for definition of bullet. (e) Directions. The labeling of the These claims include but are not limited (2) For sunscreen products that have product contains the following to the following: ‘‘Sunblock,’’ been shown to pass the broad spectrum statements, as appropriate, under the ‘‘sweatproof,’’ and ‘‘waterproof.’’ These test in paragraph (j) of this section and heading ‘‘Directions.’’ More detailed or similar claims will cause the product have a determined SPF value of 15 or directions applicable to a particular to be misbranded under section 502 of higher, the labeling may include the product formulation may also be the Federal Food, Drug, and Cosmetic following statement in addition to the included. Act. indication in paragraph (c)(1) of this (1) For all sunscreen products. (i) As (h) Labeling of products containing a section: ‘‘[bullet] if used as directed an option, the labeling may state ‘‘For combination of sunscreen and skin with other sun protection measures (see sunscreen use:’’. protectant active ingredients. Directions [in bold italic font]), (ii) The labeling states ‘‘[bullet] apply Statements of identity, indications, decreases the risk of skin cancer and [select one of the following: ‘liberally’ or warnings, and directions for use, early skin aging caused by the sun’’. ‘generously’] [and, as an option: ‘and respectively, applicable to each (3) Any labeling or promotional evenly’] 15 minutes before sun ingredient in the product may be materials that suggest or imply that the exposure’’. combined to eliminate duplicative use, alone, of any sunscreen reduces the (iii) As an option, the labeling may words or phrases so that the resulting risk of or prevents skin cancer or early state ‘‘[bullet] apply to all skin exposed information is clear and understandable. skin aging will cause the product to be to the sun’’. Labeling provisions in § 347.50(e) of this misbranded under section 502 of the (iv) The labeling states ‘‘[bullet] chapter do not apply to these products. Federal Food, Drug, and Cosmetic Act children under 6 months of age: Ask a (1) Statement of identity. The (21 U.S.C. 352). doctor’’. statement of identity of a sunscreen (d) Warnings. The labeling of the (2) For sunscreen products that have product that also contains one or more product contains the following warnings been shown to pass the broad spectrum skin protectant active ingredients, under the heading ‘‘Warnings’’. test in paragraph (j) of this section and identified in §§ 347.10(a), (d), (e), (g), h),

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(i), (k), (l), (m), and (r) of this chapter, engaged in SPF testing with the responsible person and the IRB, except consists of the names of all sunscreen information they need to conduct an when necessary to protect the safety, the and skin protectant active ingredients in investigation properly; must obtain a rights, or welfare of subjects; alphabetical order followed by signed investigator statement from each (ii) Will comply with all requirements ‘‘Sunscreen/Skin Protectant’’ and investigator; must ensure proper regarding the obligations of clinical ‘‘[Dosage form].’’ The statement of monitoring of the investigation(s); must investigators and all other pertinent identity must be prominently placed on ensure that the investigation(s) is requirements in this subpart; the principal display panel and conducted in accordance with written (iii) Will personally conduct or presented in accordance with paragraph general investigational plan(s) and supervise the described investigation(s); (b)(1)(ii) of this section. protocol(s); must ensure compliance (iv) Will inform any potential subjects (2) Indications. The labeling of the with paragraphs (i)(1)(ii) and (iii) of this that the drugs are being used for product states, under the heading section; and must ensure that FDA and investigational purposes and will ‘‘Uses,’’ any or all of the applicable all participating investigators are comply with the requirements relating indication(s) included in § 347.50(b) of promptly informed of significant new to obtaining informed consent (part 50 this chapter or in paragraph (c) of this adverse effects or risks with respect to of this chapter) and institutional review section. Other truthful and the drug. board review and approval (part 56 of nonmisleading statements, describing (ii) Informed consent. Effective this chapter); only the indications for use that have informed consent, as defined in part 50 (v) Will report to the responsible been established in § 347.50(b) of this of this chapter, must be obtained from person adverse experiences that occur chapter or listed in paragraph (c) of this all human subjects before initiating during the investigation(s); section, may also be used, as provided clinical final formulation testing under (vi) Will ensure that all personnel by § 330.1(c)(2) of this chapter, subject this paragraph (i). assisting in the conduct of the testing to the provisions of section 502 of the (iii) Institutional review board (IRB) are informed about their obligations in Federal Food, Drug, and Cosmetic Act approval. Clinical testing under this meeting the above commitments. relating to misbranding and the paragraph (i), must be reviewed and (2) Curriculum vitae. A curriculum prohibition in section 301(d) of the approved by an IRB meeting the vitae or other statement of qualifications Federal Food, Drug, and Cosmetic Act requirements of FDA’s regulations in of the investigator showing the against the introduction or delivery for part 56 of this chapter. education, training, and experience that introduction into interstate commerce of (iv) Control of personnel—(A) General qualifies the investigator to conduct the unapproved new drugs in violation of obligations. A responsible person is final formulation testing pursuant to section 505(a) of the Federal Food, Drug, responsible for ensuring that this paragraph (i). and Cosmetic Act. investigators and other personnel (v) Informing investigators. The (3) Warnings. The labeling of the conducting any testing under this responsible person must, as the overall product states, under the heading paragraph (i), conduct all investigations investigation proceeds, keep each ‘‘Warnings,’’ the applicable warnings for in accordance with the signed participating investigator informed of sunscreens in paragraph (d) of this investigator statement, the new observations discovered by or section and for skin protectants in investigational plan, and applicable reported to the responsible person on § 347.50(c) of this chapter. regulations. Responsible persons must the drug, particularly with respect to (4) Directions. The labeling of the ensure the implementation of adequate adverse effects and safe use. product states, under the heading safeguards to protect the rights, safety, (vi) Review of ongoing investigations. ‘‘Directions,’’ any or all of the applicable and welfare of subjects under he (A) The responsible person must directions for sunscreens, as set forth in investigator’s care. The responsible monitor the progress of all clinical paragraph (e) of this section, and for person must also ensure that testing being conducted on its final skin protectants, as set forth in investigators or other study personnel formulation pursuant to this paragraph §§ 347.50(d) and 347.60(d) of this will promptly report to the IRB all (i). chapter, unless otherwise stated in this changes in the clinical final formulation (B) A responsible person who paragraph. When the time intervals or testing and all unanticipated problems discovers noncompliance by an age limitations for administration of the involving risk to human subjects or investigator or other personnel with the individual ingredients differ, the others, and that investigators or other signed agreement, the general directions for the product may not personnel will not make any changes in investigational plan, or the requirements contain any dosage that exceeds those the clinical final formulation testing of this paragraph (i) or other applicable established for any individual without IRB approval, except where regulations (e.g., parts 50 and 56 of this ingredient in the applicable OTC drug necessary to eliminate apparent chapter) must promptly either secure monograph(s), and may not provide for immediate hazards to human subjects. compliance or end the investigator’s or use by any age group lower than the (B) Obtaining information from the other personnel’s participation in highest minimum age limit established investigator. Before permitting an testing conducted under this for any individual ingredient. When the investigator to begin participating in paragraph (i). directions for administration of the clinical final formulation testing under (C) The responsible person must sunscreen and skin protectant differ in this paragraph (i), the responsible review and evaluate the evidence any other way, the directions for person must obtain the following: relating to the safety and effectiveness of sunscreens in paragraph (e) of this (1) Investigator statement. A signed the final formulation as it is obtained section should be used. investigator statement containing the from the investigator. (i) Sun Protection Factor (SPF) name and address of the investigator (vii) Investigator reports—(A) Safety testing—(1) Adequate clinical testing and a commitment by the investigator reports. An investigator must procedures and conditions—(i) General that he or she— immediately report to the responsible obligations of responsible persons for (i) Will conduct the testing in person any serious adverse event, testing under this paragraph. accordance with the relevant, current whether or not considered related to the Responsible persons must provide protocol(s) and will only make changes final formulation, including those listed investigators and other personnel in a protocol after notifying the in the protocol, and must include an

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assessment of whether there is a I(l) = irradiance (Watts per square meter) at radiation intensity should be monitored reasonable possibility that the final each wavelength l with a broadband radiometer with a formulation being tested caused the t = exposure time (seconds) response weighted to match the Erythema-effective dose (E) is expressed as erythema action spectrum in ISO 17166 adverse event. The investigator must effective Joules per square meter (J/m2- record nonserious adverse events and eff). CIE S 007/E entitled ‘‘Erythemal report them to the responsible person reference action spectrum and standard according to the timetable specified in (C) The solar simulator radiation erythema dose,’’ which is incorporated the protocol. intensity must be determined using a by reference in paragraph (i)(2)(ii)(C) of (B) Final report. An investigator must handheld radiometer with a response this section. If a lamp must be replaced provide the responsible person with an weighted to match the spectrum in ISO due to failure or aging during a adequate report shortly after completion 17166 CIE S 007/E entitled ‘‘Erythemal phototest, broadband device readings of each investigation conducted by that reference action spectrum and standard consistent with those obtained for the investigator for the responsible person erythema dose,’’ dated 1999 (First original calibrated lamp will suffice edition, 1999–12–15; corrected and under this paragraph (i). until measurements can be performed reprinted 2000–11–15), which is (2) UV source (solar simulator)—(i) with the spectroradiometer at the incorporated by reference in accordance Emission spectrum. Filter a single port earliest possible opportunity. with 5 U.S.C. 552(a) and 1 CFR part 51. or multiport solar simulator so that it (3) SPF standard—(i) Preparation. You may obtain a copy from the ISO provides a continuous emission The SPF standard must be a formulation Copyright Office, Case Postale 56, CH– spectrum from 290 to 400 nanometers containing 7-percent padimate O and 1211, Geneva 20, Switzerland, (nm) with a limit of 1,500 watts per 3-percent oxybenzone. telephone +41–22–749–01–11 or fax square meter (W/m2) on total irradiance +41–22–74–09–47. https://www.iso.org. TABLE 3 TO PARAGRAPH (i)(3)(i)— for all wavelengths between 250 and You may inspect a copy at the Center for COMPOSITION OF THE PADIMATE O/ 1,400 nm. Drug Evaluation and Research, 10903 (A) The solar simulator must have the New Hampshire Ave., Bldg. 22, Silver OXYBENZONE SPF STANDARD following percentage of erythema- Spring, MD 20993, call 301–796–2090, effective radiation in each specified Percent by or at the National Archives and Records Ingredients weight range of wavelengths: Administration (NARA). For information on the availability of this Part A: TABLE 2 TO PARAGRAPH (I)(2)(I)(A)— material at NARA, call 202–741–6030, Lanolin ...... 4.50 SOLAR SIMULATOR EMISSION SPEC- or go to: https://www.archives.gov/ Cocoa butter ...... 2.00 TRUM federal-register/cfr/ibr-locations.html. Glyceryl monostearate .. 3.00 The solar simulator output should be Stearic acid ...... 2.00 Percent measured before and after each Padimate O ...... 7.00 Wavelength range Oxybenzone ...... 3.00 (nm) erythemal contribution 1 phototest or, at a minimum, at the Part B: beginning and end of each test day. This Purified water USP ...... 71.60 <290 ...... <0.1 radiometer should be calibrated using Sorbitol solution ...... 5.00 290–300 ...... 1.0–8.0 side-by-side comparison with the Triethanolamine, 99 per- 290–310 ...... 49.0–65.0 spectroradiometer (using the weighting cent ...... 1.00 290–320 ...... 85.0–90.0 factors determined according to Methylparaben ...... 0.30 290–330 ...... 91.5–95.5 paragraph (i)(2)(ii)(A) of this section) at Propylparaben ...... 0.10 290–340 ...... 94.0–97.0 the time of the annual Part C: 290–400 ...... 99.9–100.0 Benzyl alcohol ...... 0.50 spectroradiometric measurement of the Part D: 1 Calculation of erythema action spectrum solar simulator as described in Purified water USP ...... QS 1 described in paragraph (i)(2)(ii) of this section. paragraph (i)(2)(iv) of this section. 1 (B) In addition, UVA II (320–340 nm) (iii) Operation. A solar simulator must Quantity sufficient to make 100 grams. irradiance must equal or exceed 20 have no significant time-related (A) Step 1. Add the ingredients of Part percent of the total UV (290–400 nm) fluctuations (within 20 percent) in A into a suitable stainless steel kettle irradiance. UVA I (340–400 nm) radiation emissions after an appropriate equipped with a propeller agitator. Mix irradiance must equal or exceed 60 warm-up time and demonstrate good at 77 to 82 °C until uniform. percent of the total UV irradiance. beam uniformity (within 20 percent) in (B) Step 2. Add the water of Part B (ii) Erythema action spectrum. (A) the exposure plane. The delivered dose into a suitable stainless steel kettle Calculate the erythema action spectrum to the UV exposure site must be within equipped with a propeller agitator and ° weighting factor (Vi) at each 10 percent of the expected dose. begin mixing at 77 to 82 C. Add the wavelength l: (iv) Periodic measurement. To ensure remaining ingredients of Part B and mix that the solar simulator delivers the until uniform. (1) Vi (l) = 1.0 (250

Vi(l) = erythema action spectrum weighting mirrors, lenses, collimating devices, or Mix until uniform. Cool batch to 27 to factor at each wavelength l focusing devices). Daily solar simulator 32 °C.

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(ii) HPLC assay. Use the following verify the concentrations of padimate O (A) Instrumentation—(1) Equilibrate a high performance liquid and oxybenzone in the SPF standard: suitable liquid chromatograph to the chromatography (HPLC) procedure to following or equivalent conditions:

(i) Column ...... C–18, 250 millimeters (mm) length, 4.6 mm inner diameter (5 microns). (ii) Mobile Phase ...... 85:15:0.5 methanol: water: acetic acid. (iii) Flow Rate ...... 1.5 milliliters (mL) per minute. (iv) Temperature ...... Ambient. (v) Detector ...... UV spectrophotometer at 308 nano- meters. (vi) Attenuation ...... As needed.

(2) Use HPLC grade reagents for this section). The relative standard standard according to the following mobile phase. deviation in peak areas should not be steps: (B) Preparation of the HPLC reference more than 2 percent for either (i) Step 1. Weigh 1 g of the SPF standard. (1) Weigh 0.5 gram (g) of oxybenzone or padimate O. standard (described in paragraph (i)(3)(i) oxybenzone USP reference standard into (2) Calculate the resolution (R) of this section) into a 50-mL volumetric a 250-mL volumetric flask. Dissolve and between the oxybenzone and padimate flask. dilute to volume with isopropanol. Mix O peaks from one chromatogram as (ii) Step 2. Add approximately 30 mL well. follows: of isopropanol and heat with swirling (2) Weigh 0.5 g of padimate O USP until contents are evenly dispersed. reference standard into a 250-mL (iii) Step 3. Cool to room temperature volumetric flask. Dissolve and dilute to (15 to 30 °C) and dilute to volume with volume with isopropanol. Mix well. Where isopropanol. Mix well.

(3) Pipet 3 mL of the oxybenzone to = retention time for oxybenzone (iv) Step 4. Pipet 5.0 mL of the solution and 7 mL of the padimate O tp = retention time for padimate O preparation into a 50-mL volumetric solution into a 100-mL volumetric flask. Wo = oxybenzone peak width at baseline flask and dilute to volume with Dilute to volume with isopropanol and Wp = padimate O peak width at baseline isopropanol. Mix well. mix well. If the resolution (R) is less than 3, adjust the (2)(i) Inject 10-microliter of diluted (C) HPLC system suitability. (1) Make mobile phase or replace the column. SPF standard from paragraph three replicate 10-microliter injections (D) SPF standard assay. (1) The SPF (i)(3)(ii)(D)(1) of this section and of the HPLC reference standard standard is diluted to the same calculate the amount of oxybenzone and (described in paragraph (i)(3)(ii)(B) of concentration as the HPLC reference padimate O as follows:

(ii) The percent of oxybenzone and (5) Rarely burns; tans profusely (dark test subject has no preexisting skin padimate O in the SPF standard must be brown) (insensitive). pigmentation at the time of enrollment. between 95 and 105. (6) Never burns; deeply pigmented A suitable source of low power UVA, (4) Test subjects—(i) Number of (insensitive). such as a Woods lamp, is helpful in this subjects. A test panel should include (B) Skin type is based on first 30 to process. If any of these conditions are enough subjects to produce a minimum 45 minutes of sun exposure after a present, the subject is not qualified to of 10 valid test results. A maximum of winter season of no sun exposure. participate in the study. The presence of three subjects may be rejected from this Determine that each subject is not taking nevi, blemishes, or moles will be panel based on paragraph (i)(6)(v) of this topical or systemic medication that is acceptable if, in the physician’s section. known to alter responses to UV judgment, they will neither compromise (ii) Medical history. (A) Obtain a radiation. Determine that each subject the study nor jeopardize a subject’s medical history from each subject with has no history of sensitivities to topical safety. Subjects with dysplastic nevi emphasis on the effects of sunlight on products and/or abnormal responses to should not be enrolled. Excess hair on the subject’s skin. Determine that each sunlight, such as a phototoxic or the back is acceptable if the hair is subject is in good general health with photoallergic response. clipped. Shaving is unacceptable skin type I, II, or III as follows: (iii) Physical examination. Conduct a because it may remove a significant (1) Always burns easily; never tans physical examination to determine the portion of the stratum corneum and (sensitive). presence of sunburn, suntan, scars, temporarily alter the skin’s response to (2) Always burns easily; tans active dermal lesions, and uneven skin UV radiation. minimally (sensitive). tones on the areas of the back to be (3) Burns moderately; tans gradually tested. Adequate time must have passed (iv) Informed consent. Obtain legally (light brown) (normal). following any previous UV exposure effective written informed consent from (4) Burns minimally; always tans well (e.g., participation in a prior SPF all test subjects as required by paragraph (moderate brown) (normal). clinical study, tanning, etc.) so that the (i)(1)(ii) of this section.

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(5) Sunscreen application—(i) Test using an accurately calibrated solar doses administered; or the subject was site. Test sites are locations on each simulator. Select doses that are a noncompliant (e.g., the subject subject’s back, between the beltline and geometric series represented by 1.25n withdraws from the test due to illness the shoulder blades (scapulae) and (i.e., each dose is 25 percent greater than or work conflicts or does not shield the lateral to the midline, where skin the previous dose). exposed testing sites from further UV responses to UV radiation are (iii) UV exposure for final MEDu, radiation until the MED is determined). determined. Responses on unprotected ssMEDp, and tpMEDp. For each subject, (7) Determination of SPF. (i) Calculate skin (no test material applied) and determine the final MEDu, ssMEDp, and an SPF value for each test subject (SPFi) protected skin (sunscreen test product(s) tpMEDp by administering a series of five as follows: or SPF standard applied) are determined UV doses to the appropriate test sites. at separate unprotected and protected The middle dose (X) in each of these test sites, respectively. Test sites should dose series (i.e., the third dose) should be randomly located in a blinded equal the initial MEDu times the (ii) Calculate the mean manner. Each test site should be a expected SPF. Note that the expected minimum of 30 square centimeters and SPF equals 1 and 16.3 for the final outlined with indelible ink. MEDu and ssMEDp, respectively. The (ii) Test subsite. Test subsites are the remaining UV doses in the series and the standard deviation(s) from the locations to which UV radiation is depend upon the expected SPF value of SPFi values. Calculate the standard error administered within a test site. the sunscreen test product(s). For (SE), which equals s/√n (where n equals Administer UV doses to at least five test products with an expected SPF less than the number of subjects who provided subsites within each test site. Test 8, administer UV doses that increase by valid test results). Obtain the t value subsites must be at least 0.5 square 25 percent with each successive dose from Student’s t distribution table centimeters (cm2) in area and must be (i.e., 0.64X, 0.80X, 1.00X, 1.25X, and corresponding to the upper 5-percent separated from each other by at least 0.8 1.56X). For products with an expected point with n ¥ 1 degrees of freedom. cm. Each test subsite must be outlined SPF from 8 to 15, administer UV doses Determine the SPF value that is equal to with indelible ink. that increase by 20 percent with each the largest whole number less than (iii) Applying test materials. Apply successive dose (i.e., 0.69X, 0.83X, the sunscreen test product and the SPF 1.00X, 1.20X, and 1.44X). For products standard at 2 milligrams per square with an expected SPF higher than 15, In order for the SPF determination of a centimeter (mg/cm2) to their respective administer UV doses that increase by 15 test product to be considered valid, the test sites. Use a finger cot compatible percent with each successive dose (i.e., SPF value of the SPF standard must fall with the sunscreen to spread the 0.76X, 0.87X, 1.00X, 1.15X, and 1.32X). within the standard deviation range of product as evenly as possible. (iv) Evaluation of test subsites. In the expected SPF (i.e., 16.3 ± 3.43). (iv) Waiting period. Wait at least 15 order that the study personnel who (8) Determination of water resistance. minutes after applying a sunscreen evaluates the test subsites is not biased, To support labeling claims of water product before exposing the test sites to he/she should not be the same study resistance in accordance with paragraph UV radiation as described in paragraph personnel who applied the sunscreen (b) of this section, the following (i)(6) of this section. For water resistant product to the test site or administered procedure must be performed in an sunscreen products, proceed with the the UV doses. After UV doses are indoor fresh water pool, whirlpool, and/ water resistance testing procedure administered, record all immediate or hot tub maintained at 23 to 32 °C. described in paragraph (i)(8) of this responses. These may include an Fresh water is clean drinking water that section after waiting at least 15 minutes. immediate darkening or tanning, meets the standards in 40 CFR part 141. (6) UV exposure and erythema typically grayish or purplish in color, The pool and air temperature and the reading—(i) Definition of minimal which fades in 30 to 60 minutes; an relative humidity must be recorded. erythema dose (MED). The minimal immediate reddening at the subsite, due (i) Water resistance (40 minutes). erythema dose (MED) is the smallest UV to heating of the skin, which fades Determine the SPF value after 40 dose (quantity of erythema-effective rapidly; and an immediate generalized minutes of water immersion using the energy expressed as Joules per square heat response, spreading beyond the following procedure: meter) that produces perceptible subsite, which fades in 30 to 60 (A) Step 1: Apply the sunscreen test redness of the skin (erythema) with minutes. After the immediate responses product as described in paragraph (i)(5) clearly defined borders at 16 to 24 hours are noted, each subject should shield of this section. after UV exposure. The MED for the exposed area from further UV (B) Step 2: Perform moderate activity unprotected skin (MEDu) is determined radiation until the MED is determined. in water for 20 minutes. on a test site that does not have Determine the final MEDu, ssMEDp, and (C) Step 3: Rest out of water for 15 sunscreen applied. The MED for tpMEDp 16 to 24 hours after UV minutes. Do not towel test site(s). protected skin (MEDp) is determined on exposure. Evaluate the erythema (D) Step 4: Perform moderate activity a test site that has sunscreen applied. responses of each test subsite using in water for 20 minutes. An MEDp is determined for the SPF either tungsten or warm white (E) Step 5: Allow test sites to dry standard (ssMEDp). An MEDp is fluorescent lighting that provides at completely without toweling. determined for the sunscreen test least 450 lux of illumination at the test (F) Step 6: Apply the SPF standard as product (tpMEDp). site. For the evaluation, the test subject described in paragraph (i)(5) of this (ii) UV exposure for initial MEDu. For should be in the same position as when section. each test subject, no more than 1 day the test site was irradiated. (G) Step 7: Expose test sites to UV before testing a product, determine the (v) Invalid test data. Reject test data doses as described in paragraph (i)(6) of initial MEDu by administering a series of for a test subject if erythema is not this section. UV radiation doses expressed as J/m2-eff present on either the unprotected or (ii) Water resistance (80 minutes). (as determined according to paragraph protected test sites; or erythema is Determine the SPF value after 80 (i)(2)(ii)(B) of this section) to the test present at all subsites; or the responses minutes of water immersion using the subsites within an unprotected test site are inconsistent with the series of UV following procedure:

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(A) Step 1: Apply the sunscreen test (v) Dynamic range of the (5) Calculation of mean absorbance product as described in paragraph (i)(5) spectrometer. The dynamic range of the values. (i) Mean transmittance values, of this section. spectrometer should be sufficient to (B) Step 2: Perform moderate activity measure transmittance accurately in water for 20 minutes. through a highly absorbing sunscreen are converted into mean absorbance (C) Step 3: Rest out of water for 15 product at all terrestrial solar UV values, minutes. Do not towel test site(s). wavelengths (290 to 400 nm). (D) Step 4: Perform moderate activity (2) Sunscreen product application to in water for 20 minutes. PMMA plate. The accuracy of the test at each wavelength by taking the (E) Step 5: Rest out of water for 15 depends upon the application of a negative logarithm of the mean minutes. Do not towel test site(s). precisely controlled amount of transmittance value as follows: (F) Step 6: Perform moderate activity sunscreen product with a uniform in water for 20 minutes. distribution over the PMMA plate. The (G) Step 7: Rest out of water for 15 product is applied at 0.75 mg per square (ii) The calculation yields 111 minutes. Do not towel test site(s). centimeter to the roughened side of the monochromatic absorbance values in 1 (H) Step 8: Perform moderate activity PMMA plate. The sunscreen product nanometer increments from 290 to 400 in water for 20 minutes. should be applied in a series of small nanometers. (I) Step 9: Allow test sites to dry amounts over the entire PMMA plate (6) Number of plates. For each completely without toweling. and then spread evenly using a gloved sunscreen product, determine mean (J) Step 10: Apply the SPF standard as finger. Spreading should be done with absorbance values from at least three described in paragraph (i)(5) of this a very light spreading action for individual PMMA plates. Because section. approximately 30 seconds followed by paragraph (j)(4) of this section requires (K) Step 11: Expose test sites to UV spreading with greater pressure for at least 5 measurements per plate, there doses as described in paragraph (i)(6) of approximately 30 seconds. The plate must be a total of at least 15 this section. should then be allowed to equilibrate measurements. (j) Broad spectrum testing—(1) UV for 15 minutes in the dark before the (7) Calculation of the critical Spectrometry—(i) Plate. Use optical- pre-irradiation described in paragraph wavelength. The critical wavelength is grade polymethylmethacrylate (PMMA) (j)(3) of this section. identified as the wavelength at which plates suitable for UV transmittance (3) Sunscreen product pre-irradiation. the integral of the spectral absorbance measurements. The plate should be To account for lack of photostability, curve reaches 90 percent of the integral roughened on one side to a three- irradiate the PMMA plate with a solar over the UV spectrum from 290 to 400 dimensional surface topography simulator described paragraph (i)(2) of nm. The following equation defines the measure (Sa) between 2 and 7 this section. The irradiation dose must critical wavelength: micrometers and must have a be 4 MEDs which is equivalent to an rectangular application area of at least erythemal effective dose of 800 J/m2 16 square centimeters (with no side (i.e., 800 J/m2-eff). shorter than 4 cm). (4) Calculation of mean transmittance (ii) Sample holder. The sample holder values. (i) After pre-irradiation, Where should hold the PMMA plate in a determine the mean transmittance lc = critical wavelength horizontal position to avoid flowing of values for each wavelength l over the A(l) = mean absorbance at each wavelength the sunscreen product from one edge of full UV spectrum (290 to 400 dl = wavelength interval between the PMMA plate to the other. Mount the nanometers). Measure the transmittance measurements PMMA plate as close as possible to the values at 1 nanometer intervals. (8) Calculation of the UVA I/UV ratio. input optics of the spectrometer to Measurements of spectral irradiance The ratio of UVA I/UV is calculated as maximize capture of forward scattered transmitted for each wavelength l the area (per unit wavelength) under the radiation. The sample holder should be through control PMMA plates coated UVA I portions of a plot of wavelength a thin, flat plate with a suitable aperture with 15 microliters of glycerin (no versus A(l), divided by the area (per through which UV radiation can pass. sunscreen product) must be obtained unit wavelength) under the total curve, Place the PMMA plate on the upper from at least five different locations on as follows: surface of the sample holder with the the PMMA plate [C1(l), C2(l), C3(l), roughened side facing up. C4(l), and C5(l)]. In addition, a (iii) Light source. The light source minimum of five measurements of must produce a continuous spectral spectral irradiance transmitted for each distribution of UV radiation from 290 to wavelength l through the PMMA plate Where 400 nanometers. covered with the sunscreen product will A(l) = effective absorbance given as -log (iv) Input optics. Unless the be similarly obtained after pre- T(l)mean absorbance at each spectrometer is equipped with an wavelength, irradiation of the sunscreen product d(l) = wavelength interval between integrating sphere, an ultraviolet [P1(l), P2(l), P3(l), P4(l), and P5(l)]. measurements radiation diffuser should be placed (ii) The mean transmittance for each B(l) = any biological action spectrum factor between the sample and the input optics wavelength is the ratio of the mean of Because no appropriate biological action of the spectrometer. The diffuser will be the C(l) values to the mean of the P(l) spectrum for UVA radiation damage has constructed from any UV radiation values, as follows: been universally accepted, no action transparent material (e.g., Teflon or spectrum is specified. The value of B(l) quartz). The diffuser ensures that the is, therefore, equal to 1.0 for all radiation received by the spectrometer wavelengths. is not collimated. Set the spectrometer (9) Determination of broad spectrum input slits to provide a bandwidth that Where protection. A product that has both a is less than or equal to 5 nanometers. n ≥5 mean critical wavelength of 370 nm or

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greater, calculated in accordance with (A) Record of emission spectrum, total (vi) Records of the mean and standard paragraph (j)(7) of this section, and a irradiance, and percent of erythema- deviation from SPFi values, standard mean UVA I/UV ratio of 0.70 or greater, effective radiation contribution required error, and determined SPF value calculated in accordance with paragraph by paragraph (i)(2)(i) of this section; derived as set forth in paragraph (i)(7) (j)(8) of this section, is determined to (B) Record of each periodic of this section. pass the broad spectrum test. measurement required by paragraph (vii) Records for water resistance (k) Regulatory status of final (i)(2)(iv) of this section for each solar testing of pool temperature, air formulation testing and related simulator; temperature, and relative humidity as requirements. Final formulation testing (C) Record of each calibration, required by paragraph (i)(8) of this required under this section is realignment, or change in components section. considered a part of the manufacture of of each solar simulator, or any changes (viii) Records demonstrating a sunscreen product. Therefore, final to the broadband radiometer (or UV compliance with paragraph (i)(1) of this formulation testing required under this meter/dose control system), required by section governing the establishment of section must be performed in an paragraph (i)(2)(iv) of this section; and adequate clinical testing procedures and establishment registered in accordance (D) Record of each solar simulator conditions, including, but not limited with part 207 of this chapter and section output measurement required by to: 510 of the Federal Food, Drug, and paragraph (i)(2)(ii)(C) of this section. (A) Case histories. Responsible (2) SPF testing records. In addition to Cosmetic Act. Entities conducting final persons are required to prepare and any records required to be kept pursuant formulation testing required by this maintain adequate and accurate case to parts 210 and 211 of this chapter, section must also comply with current histories on each individual participant records of SPF testing performed good manufacturing practices (CGMPs) enrolled in SPF testing performed under and associated recordkeeping pursuant to paragraph (i) of this section must include: paragraph (i) of this section. Case requirements including those set forth histories must record all observations in paragraph (l) of this section and in (i) Identification of the entity that conducted the final formulation testing, and other data pertinent to the parts 210 and 211 of this chapter. investigation. Case histories include the Failure to comply with CGMPs or including the name and address of the establishment(s) at which testing was case report forms and supporting data recordkeeping requirements will mean (for example, signed and dated consent that any product labeled in reliance on carried out; (ii) The sunscreen test product forms, medical records including that testing will be adulterated. progress notes of the physician, the (l) Recordkeeping. Records required to identifier and characterization of the individual’s hospital chart(s), and the be kept under this section must be formulation being tested, including lot nurses’ notes (if applicable)). The case maintained for at least 1 year after the number, manufacture date, and history for each individual participant expiration date of all products labeled expected SPF; must document that informed consent in reliance on that testing or, in the case (iii) Characterization of the SPF was obtained pursuant to part 50 before of certain OTC drug products lacking standard sunscreen required by each individual’s participation in the expiration dating because they meet the paragraph (i)(3) of this section, criteria for exemption under § 211.137 including: study. Case histories as required by this of this chapter, 3 years after distribution (A) Lot number; section must include: (B) Manufacturing date; and of the last lot of drug product bearing (1) Protocol deviations or injuries, if (C) Results of HPLC SPF standard any; and labeling that relies on the testing. assay that verify compliance with the Recordkeeping requirements under this (2) Identification, by subject, of the concentrations of padimate O and study personnel who: Examined the section may not be transferred. oxybenzone in the SPF standard. Maintenance records required to be kept potential study site areas, who weighed (iv) Documentation linking any and applied the sunscreen, and who under (l)(1) must be kept by the testing blinded samples with the product entity. Records of final formulation provided the UV irradiation. identifier. (B) IRB review. Documentation that testing as described in paragraphs (l)(2) (v) For each human subject, records and (3) of this section must be kept by clinical research conducted pursuant to of: paragraph (i) of this section was the responsible person and any entity (A) The identification of the UV reviewed and approved by a registered that is performing final formulation source used for testing on that subject, IRB as required by paragraph (i)(1)(iii) of testing required by this section on including make, model, and serial this section. behalf of a responsible person pursuant number; to a transfer of obligations. (B) Initial and final individual MED (3) Broad spectrum testing records. Records of broad spectrum testing (1) Maintenance records. Entities for unprotected skin (MEDu), and the performing final formulation testing are identity of the study personnel who conducted pursuant to paragraph (j) of expected to maintain equipment in determined that value; this section must include: accordance with paragraph (k) of this (C) Final MED for sunscreen test (i) Identification of the entity that section and, as applicable, parts 210 and product protected skin (tpMEDp), and the conducted the final formulation testing, 211 of this chapter. Maintenance identity of the study personnel who including the name and address of the records must be kept for all equipment determined that value; establishment(s) at which testing was used for final formulation testing under (D) Final MED for SPF standard carried out; this section and must include: sunscreen protected skin (ssMEDp), and (ii) Records of sample information, (i) Documentation that equipment has the identity of the study personnel who including: been maintained in accordance with determined that value; and (A) A sunscreen test product established written specifications as (E) Individual SPFi values, including identifier and expected SPF. If the required by paragraph (k) of this section all valid test data and invalid test data samples used in testing under paragraph and parts 210 and 211 of this chapter; for the test product and for the SPF (j) of this section are blinded, then and standard sunscreen, and the identity of records must include a master key that (ii) Documentation of characterization the study personnel who determined enables samples to be re-identified. In of UV sources including: that value. all other cases, records must include a

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master key that links samples used to a access to and copy and verify any (3) Ethyl 4-[bis(hydroxypropyl)] sunscreen test product identifier. records and reports relating to final aminobenzoate (B) Sample number; formulation testing conducted under (4) Glyceryl aminobenzoate (C) Identifier code; this section. Upon written request by (5) Lawsone with dihydroxyacetone (D) Measurement of PMMA plate FDA, the responsible person must (6) Red petrolatum surface topography in micrometers; and submit the records or reports (or copies (7) Trolamine salicylate (E) Sample holder orientation (vertical of them) to FDA. The responsible person (8) Aminobenzoic acid or horizontal). must discontinue from further (9) Avobenzone (iii) Identification of each UV source participation in final formulation testing (10) Cinoxate used for sunscreen product pre- required by this section any investigator (11) Dioxybenzone irradiation, including make, model, and who has failed to maintain or make (12) Ensulizole serial number. available records or reports of the (13) Homosalate (iv) Records of sunscreen product investigation as required by this (14) Meradimate application, including: paragraph (l). (15) Octinoxate (A) A record of all sample weights, (16) Octisalate including analytical balance; and PART 310—NEW DRUGS (17) Octocrylene (B) For all equipment used; make, (18) Oxybenzone model, and serial number; ■ 3. The authority citation for part 310 (19) Padimate O (v) For each sample, all measurements continues to read as follows: (20) Sulisobenzone required by paragraphs (j)(4) to (6) of Authority: 21 U.S.C. 321, 331, 351, 352, (c) A sunscreen drug product that has this section. 353, 355, 360b–360f, 360j, 360hh–360ss, a determined sun protection factor (SPF) (vi) For each sample, records of 361(a), 371, 374, 375, 379e, 379k–l; 42 U.S.C. value, as defined in § 352.3(d) of this critical wavelength and the UVA I/UV 216, 241, 242(a), 262. chapter, of at least 15 when tested in ratio values required by paragraphs (j)(7) accordance with § 201.327(i) of this and (8) of this section. § 310.545 [Amended] chapter, but that has not been shown to (vii) For each sample: The identity of ■ 4. Amend § 310.545 by removing and pass the broad spectrum test in the study personnel who weighed and reserving paragraphs (a)(29) and § 201.327(j) of this chapter. applied the sunscreen to the PMMA (d)(31),and (40). (d) A sunscreen drug product that has plates; the identity of the study ■ 5. Add § 310.549 to subpart E to read a determined sun protection factor (SPF) personnel who provided the pre- as follows: value, as defined in § 352.3(d) of this irradiation; and the identity of the study chapter, of less than 2 or greater than 80 personnel, or, if calculated by software, § 310.549 Drug products offered over-the- counter (OTC) for use as sunscreen. when tested in accordance with what software, calculated the mean § 201.327(i) of this chapter. transmittance, mean absorbance values, (a) Any drug product offered OTC for (e) A sunscreen drug product that has critical wavelength, and UVA I/UV. use as sunscreen and identified in any a determined sun protection factor (SPF) (viii) For each sample, the test dates of paragraphs (b) through (i) of this value, as defined in § 352.3(d) of this for the broad spectrum test conducted section is not generally recognized as chapter, of less than 15 when tested in pursuant to paragraph (j) of this section, safe and effective and is regarded as a accordance with § 201.327(i) of this and sample report forms and supporting new drug within the meaning of section chapter and/or that does not pass the data including, for example, spectral 201(p) of the Federal Food, Drug, and broad spectrum test in § 201.327(j) of data, Excel files containing Cosmetic Act, for which an approved this chapter, and labeled with any of the transmittance or absorbance values, or new drug application under section 505 following or similar claims: any notes from the lab investigator. of the Federal Food, Drug, and Cosmetic (1) Decreases the risk of skin cancer (4) Food and Drug Administration Act and part 314 of this chapter is caused by the sun; or (FDA) inspection of records—(i) Testing required for marketing. In the absence of (2) Decreases the risk of early skin entity. Anentity performing final an approved new drug application, such aging caused by the sun. formulation testing under this section, product is also misbranded under (f) A sunscreen drug product labeled including a responsible person or an section 502 of the Federal Food, Drug, with any of the following or similar entity that has been transferred any and Cosmetic Act. Products offered OTC claims: obligations of a responsible person for use as sunscreen include those (1) Instant protection or protection under this section, must, upon request represented, labeled, or promoted as immediately upon application; or from any properly authorized officer or sunscreen, or for use to help prevent (2) Claims for ‘‘all-day’’ protection or employee of FDA, at reasonable times, sunburn, skin cancer, and/or skin aging extended wear claims citing a specific permit such officer or employee to have caused by the sun, or with similar number of hours of protection that is access to, and copy and verify any claims or representations. Clinical inconsistent with the directions for records or reports of testing pursuant to investigations designed to obtain application in § 201.327 of this chapter. this section. The testing entity is not evidence that any sunscreen drug (g) A sunscreen drug product that is required to divulge subject names product covered by this section is safe labeled, represented, or promoted for unless the records of particular and effective for the purpose intended use as a combined sunscreen-insect individuals require a more detailed must comply with the requirements and repellant. study of the cases, or unless there is procedures governing the use of (h) A sunscreen drug product that is reason to believe that the records do not investigational new drugs set forth in in any dosage form other than the represent actual case studies, or do not part 312 of this chapter. following: Oil, lotion, cream, gel, butter, represent actual results obtained. (b) A sunscreen drug product that paste, ointment, stick, or spray. (ii) Responsible persons. A contains any of the following (i) A sunscreen drug product in a responsible person must upon request ingredients: spray dosage form that has any of the from any properly authorized officer or (1) Diethanolamine following properties: employee of FDA, at reasonable times, methoxycinnamate (1) The product meets the definition permit such officer or employee to have (2) Digalloyl trioleate of the term ‘‘extremely flammable’’ as

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defined at § 352.3(f) of this chapter (2) Except as set forth in paragraph the largest whole number less than SPF when tested in accordance with 16 CFR (a)(3) of this section, for a combination ¥ (t * SE), determined for a sunscreen 1500.43a; drug product that does not have an product in accordance with § 201.327(i) (2) More than 10 percent of the established name, the labeling of the of this chapter. particles dispensed from the consumer product states the statement of identity (e) Labeled sun protection factor (SPF) container are smaller than 10 for each ingredient in the combination, value. The SPF value associated with micrometers; as established in the statement of the range into which the determined (3) Any of the particles dispensed identity sections of the applicable OTC SPF value falls, as set forth in the table from the consumer container are smaller drug monographs. in § 201.327(b)(2)(i) of this chapter. than 5 micrometers; or (3) For a product containing a (f) Extremely flammable. The term (4) The product meets the definition combination of skin protectant and ‘‘extremely flammable’’ applies to any of either the term ‘‘flammable’’ or the sunscreen active ingredients, the product that has a flashpoint at or below term ‘‘combustible’’ as defined at labeling of the product bears the 20 °F (¥6.7 °C) as determined by the §§ 352.3(g) or (h) of this chapter, as statement of identity set forth in test method described at 16 CFR applicable, when tested in accordance § 352.60(a) of this chapter. 1500.43a, except that any product with 16 CFR 1500.43a and has a (b) * * * having one component or more with a measured drying time of 10 minutes or (3) Combinations of skin protectant flashpoint higher than 20 °F (¥6.7 °C) more. and sunscreen active ingredients in that comprises at least 99 percent of the § 347.20(e). In addition to any or all of PART 347—SKIN PROTECTANT DRUG total volume of the product is not the indications for skin protectant drug PRODUCTS FOR OVER-THE- considered to be extremely flammable. products in § 347.50(b)(2)(i) of this COUNTER HUMAN USE (g) Flammable. The term ‘‘flammable’’ chapter, the required indications for applies to any product that has a ■ 6. The authority citation for part 347 sunscreen drug products in § 352.60(b) flashpoint above 20 °F (¥6.7 °C) and continues to read as follows: of this chapter must be used and any or below 100 °F (37.8 °C) as determined by Authority: 21 U.S.C. 321, 351, 352, 353, all of the additional indications for the test method described at 16 CFR 355, 360, 371. sunscreen drug products may be used. 1500.43a, except that: (c) * * * ■ (1) Any product having one 7. Amend § 347.20 by lifting the stay (1) For combinations containing a component or more with a flashpoint at on paragraph (e) (previously paragraph skin protectant and a sunscreen or above 100 °F (37.8 °C) that comprises (d), redesignated at 74 FR 9765, March identified in §§ 347.20(e) and 352.20(b). at least 99 percent of the total volume 6, 2009) and revising paragraph (e) to The warnings in § 352.60(c) of this of the product is not considered to be read as follows: chapter are used. flammable; and § 347.20 Permitted combinations of active * * * * * (2) Any product containing 24 percent ingredients. (d) * * * or less of water miscible alcohols, by * * * * * (1) For combinations containing a volume, in aqueous solution is not (e) Combinations of skin protectant skin protectant and a sunscreen considered to be flammable if the and sunscreen active ingredients. Any identified in §§ 347.20(e) and 352.20(b). product does not present a significant one (two when required to be in The directions in § 352.60(d) of this flammability hazard when used by combination) or more of the skin chapter are used. consumers. protectant active ingredients identified * * * * * (h) Combustible. The term in § 347.10(a), (d), (e), (g), (h), (i), (k), (l), ‘‘combustible’’ applies to any product (m), and (r) of this chapter may be PART 352—SUNSCREEN DRUG having a flashpoint at or above 100 °F combined with any single sunscreen PRODUCTS FOR OVER-THE- (37.8 °C) to and including 150 °F (65.6 active ingredient identified in § 352.10 COUNTER HUMAN USE °C) as determined by the test method of this chapter, or any permitted ■ described at 16 CFR 1500.43a, except combination of these ingredients 9. The authority citation for part 352 that: identified in § 352.20 of this chapter, continues to read as follows: provided the product meets the Authority: 21 U.S.C. 321, 351, 352, 353, (1) Any product having one conditions in § 352.20(b) of this chapter 355, 360, 371. component or more with a flashpoint higher than 150 °F (65.6 °C) that and is labeled according to §§ 347.60 ■ 10. Lift the stay of 21 CFR part 352. and 352.60 of this chapter. comprises at least 99 percent of the total ■ 8. Amend § 347.60 by revising § 352.1 [Amended] volume of the product is not considered paragraphs (a), (b)(3), (c)(1), and (d)(1) to ■ 11. In paragraph (a), remove the words to be combustible; and read as follows: ‘‘in a form suitable for topical (2) Any product containing 24 percent administration’’. or less of water miscible alcohols, by § 347.60 Labeling of permitted ■ 12. Revise § 352.3 to read as follows: volume, in aqueous solution is not combinations of active ingredients. considered to be combustible if the * * * * * § 352.3 Definitions. product does not present a significant (a) Statement of identity. (1) Except as As used in this part: flammability hazard when used by set forth in paragraph (a)(3) of this (a) [Reserved] consumers. section, for a combination drug product (b) [Reserved] ■ 13. Add § 352.5 to subpart A to read that has an established name, the (c) Sunscreen active ingredient. An as follows: labeling of the product states the active ingredient listed in § 352.10 that established name of the combination absorbs, reflects, or scatters radiation in § 352.5 Sun protection factor related drug product, followed by the statement the ultraviolet (UV) range at conditions. of identity for each ingredient in the wavelengths from 290 to 400 (a) The product has a determined SPF combination, as established in the nanometers. value of at least 2 but no greater than 80. statement of identity sections of the (d) Determined sun protection factor (b) If the product has a determined applicable OTC drug monographs. (SPF) value. The SPF value that equals SPF value of at least 15, it also passes

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the broad spectrum test in § 201.327(j) (4) The product must be labeled when tested accordance with 16 CFR of this chapter. according to § 201.327(h) of this chapter 1500.43a, drying time for each lot of ■ 14. Revise § 352.10 to read as follows: and § 352.60. product must be conducted in (c) [Reserved] accordance with adequate written § 352.10 Sunscreen active ingredients. ■ 16. Add § 352.30 to subpart B to read specifications. The active ingredient of the product as follows: ■ 18. Revise § 352.50 to read as follows: consists of any of the following, under the conditions specified, including § 352.30 Route of administration. § 352.50 Principal display panel of all being within the concentration specified The product is intended for topical sunscreen drug products. for each ingredient: administration. The principal display panel labeling (a) through (o) [Reserved] ■ 17. Add § 352.40 to subpart B to read must comply with § 201.327(b) of this (p) Titanium dioxide up to 25 percent as follows: chapter. (q) [Reserved] ■ 19. Revise § 352.52 to read as follows: § 352.40 Dosage forms. (r) Zinc oxide up to 25 percent. § 352.52 Labeling of products containing ■ The product is in one of the following 15. Revise § 352.20 to read as follows: one or more sunscreen active ingredients. dosage forms and meets any additional § 352.20 Permitted combinations of active conditions specified: (a) Statement of identity. The labeling ingredients. (a) Oil. of the product contains the statement of The determined SPF of any product (b) Lotion. identity, in accordance with containing a sunscreen active ingredient (c) Cream. § 201.327(b) of this chapter. is measured by the testing procedures (d) Gel. (b) Indications. The labeling of the established in § 201.327(i) of this (e) Butter. product contains the indication chapter. (f) Paste. statements identified in § 201.327(c) of (a) Combinations of sunscreen active (g) Ointment. this chapter, as appropriate, and subject ingredients. Two or more sunscreen (h) Stick. to the conditions stated therein. active ingredients identified in § 352.10 (i) Spray, provided that all of the (c) Warnings. The labeling of the may be combined with each other in a following conditions are satisfied: product contains the warnings in single sunscreen product if all of the (1) Size of particles as dispensed from § 201.327(d) of this chapter, as following conditions are met: the consumer container: applicable, under the heading (1) Each sunscreen active ingredient (i) No more than 10 percent of the ‘‘Warnings:’’ in the product must satisfy the particles dispensed from the consumer (d) Directions. The labeling of the conditions established for its use in container are smaller than 10 product contains the statements in § 352.10. micrometers; and § 201.327(e) of this chapter, as (2) The concentration of each (ii) None of the particles dispensed applicable, under the heading sunscreen active ingredient must be from the consumer container are smaller ‘‘Directions.’’ sufficient to contribute a minimum than 5 micrometers. (e) Other information. The labeling of determined SPF of not less than 2 to the (2) The product does not meet the the product contains the statement in finished product. definition of the term ‘‘extremely § 201.327(f) of this chapter under the (3) The finished product must have a flammable’’ as defined in § 352.3(f). heading ‘‘Other information.’’ minimum determined SPF of not less (3) If the product meets the definition (f) False or misleading claims. The than the number of sunscreen active of either the term ‘‘flammable’’ or the labeling of the product must not contain ingredients used in the product term ‘‘combustible’’ as defined at any claims that would be false and/or multiplied by 2. §§ 352.3(g) or (h), as applicable, when misleading on sunscreen products, as outlined in § 201.327(g) of this chapter. (b) Combinations of sunscreen and tested in accordance with 16 CFR ■ skin protectant active ingredients. Any 1500.43a, the product also has a 20. Revise § 352.60 to read as follows: single sunscreen active ingredient measured drying time of less than 10 § 352.60 Labeling of products containing a identified in § 352.10 or any minutes. combination of sunscreen and skin combination of sunscreen active (4) The product is labeled as required protectant active ingredients. ingredients permitted under paragraph by §§ 201.327(d) and (e)(5) of this Statements of identity, indications, (a) of this section may be combined with chapter. warnings, and directions for use, one or more skin protectant active (5) Testing in accordance with part respectively, applicable to each ingredients identified in §§ 347.10(a), 211 of this chapter must confirm that ingredient in the product may be (d), (e), (g), (h), (i), (k), (l), (m), and (r) the product meets the conditions for combined to eliminate duplicative of this chapter when all of the following particle size, flammability, and drying words or phrases so that the resulting conditions are met: time as required by this section and information is clear and understandable. (1) Each sunscreen active ingredient reflected in the product labeling. Labeling provisions in § 347.50(e) of this in the product must satisfy the (i) Testing of each lot of product for chapter shall not apply to these conditions established for its use in size of particles dispensed from the products. § 352.10. consumer container must be conducted (a) Statement of identity. The labeling (2) The concentration of each in accordance with adequate written of the product bears the statement of sunscreen active ingredient must be specifications. identity, as set forth in § 201.327(h)(1) of sufficient to contribute a minimum (ii) Flammability testing for each this chapter. determined SPF of not less than 2 to the batch of product must be conducted in (b) Indications. The labeling of the finished product. accordance with the specifications set product states, under the heading (3) The finished product must have a forth in 16 CFR 1500.43a. ‘‘Uses,’’ the applicable indication minimum determined SPF of not less (iii) If the product meets the statements, as set forth in than the number of sunscreen active definition of either the term § 201.327(h)(2) of this chapter. ingredients used in the product ‘‘flammable’’ or ‘‘combustible’’ as (c) Warnings. The labeling of the multiplied by 2. defined at § 352(g) or (h), as applicable, product states, under the heading

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‘‘Warnings,’’ the applicable warning Subpart D—Final Formulation Testing § 352.80 Broad spectrum testing. statements, as set forth in Sec. If the product’s determined SPF value § 201.327(h)(3) of this chapter. 352.70 SPF testing. is at least 15, the product is tested and (d) Directions. The labeling of the 352.80 Broad spectrum testing. shown to pass the broad spectrum test product states, under the heading in § 201.327(j) of this chapter. Subpart D—Final Formulation Testing ‘‘Directions,’’ the applicable direction Dated: February 14, 2019. statements, as set forth in § 352.70 SPF testing. Scott Gottlieb, § 201.327(h)(4) of this chapter. Commissioner of Food and Drugs. The product is tested in accordance ■ [FR Doc. 2019–03019 Filed 2–21–19; 8:45 am] 21. Revise subpart D to read as with § 201.327(i) of this chapter. follows: BILLING CODE 4164–01–P

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