# Labeling and Effectiveness Testing; Sunscreen Drug Products for Over-the-Counter Human Use > Briefs, arguments, decisions, and more. URL: https://www.frixlaw.com/law-library/documents/fr%3A2011-14766 ## Record - **Collection:** Federal Register - **Document type:** Rule - **Published:** June 17, 2011 - **Citation:** 76 FR 35620 ## Text DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 201 and 310 [Docket No. FDA-1978-N-0018] (Formerly Docket No. 1978N-0038) RIN 0910-AF43 Labeling and Effectiveness Testing; Sunscreen Drug Products for Over-the-Counter Human Use AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is issuing this document to address labeling and effectiveness testing for certain over-the counter (OTC) sunscreen products containing specified active ingredients and marketed without approved applications. This document addresses labeling and effectiveness testing issues raised by the nearly 2,900 submissions that we received in response to the sunscreen proposed rule of August 27, 2007 (2007 proposed rule). The document also identifies specific claims that render a product that is subject to this rule misbranded or would not be allowed on any OTC sunscreen product marketed without an approved application. The document does not address issues related to sunscreen active ingredients or certain other issues regarding the GRASE determination for sunscreen products. The document requires OTC sunscreen products to comply with the content and format requirements for OTC drug labeling contained in the 1999 Drug Facts final rule (published in the Federal Register of March 17, 1999, by lifting the delay of implementation date for that rule that we published on September 3, 2004). DATES: Effective Date: This final rule is effective June 18, 2012. For additional information concerning this effective date, see section X in the preamble of this document. The incorporation by reference of a certain publication listed in this rule is approved by the Director of the Federal Register as of June 18, 2012. Compliance Date: The compliance date for all products subject to this final rule with annual sales less than $25,000 is June 17, 2013. The compliance date for all other products subject to this final rule is June 18, 2012. Implementation date: FDA is lifting the delay of implementation date for § 201.66 as published at 69 FR 53801, September 3, 2004. FOR FURTHER INFORMATION CONTACT: Reynold Tan, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 5411, Silver Spring, MD 20993, 301-796-2090. SUPPLEMENTARY INFORMATION: Table of Contents I. Overview of Document A. Rulemaking History B. Scope of This Document C. Issues Outside the Scope of This Document D. Enforcement Policy E. Summary of Major Revisions to the Labeling and Testing Requirements Included in the 2007 Proposed Rule II. Administrative and Other Issues III. Principal Display Panel (PDP) Labeling A. SPF Statement B. Broad Spectrum Statement C. Water Resistance Statement D. UVB and UVA Educational Statement IV. Drug Facts Labeling A. Active Ingredients/Purpose B. Uses C. Warnings D. Directions E. Constitutionality of Labeling Statements Regarding Skin Cancer and Skin Aging F. Other Information G. Reduced Labeling V. Miscellaneous Labeling Outside Drug Facts VI. SPF Test Parameters A. Solar Simulator B. Sunscreen Standards C. Test Subjects D. Test Sites and Subsites E. Finger Cot F. Application Amount G. Water Resistance VII. SPF Test Issues (Other Than Test Parameters) A. Pass/Fail (Binomial) SPF Test B. Photostability C. In Vitro SPF Test D. Anti-Inflammatory Ingredients VIII. Broad Spectrum Test A. In Vivo Test Method: Not Required B. In Vitro Test Method: Critical Wavelength C. Critical Wavelength Test Parameters IX. Analysis of Impacts A. Final Regulatory Impact Analysis B. Small Business Impact (Final Regulatory Flexibility Analysis) X. Paperwork Reduction Act of 1995 XI. Environmental Impact XII. Federalism XIII. References I. Overview of Document A. Rulemaking History This section of the document does not discuss every regulatory action associated with OTC sunscreen products. It highlights the major regulatory actions that are related to the regulatory actions being taken in this document. For a complete list of all regulatory actions associated with OTC sunscreen products, please refer to our Web site: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm072134.htm. In the Federal Register of May 12, 1993 (58 FR 28194), we published a proposed rule for OTC sunscreen products that identified active ingredients we tentatively considered to be generally recognized as safe and effective (GRASE), as well as associated labeling and sun protection factor (SPF) testing to be required for these OTC sunscreen products (the 1993 proposed rule). The SPF test and corresponding labeling reflect the level of protection against sunburn, which is caused primarily by UVB radiation. The 1993 proposed rule also explained the importance of protection against UVA radiation (58 FR 28194 at 28232 and 28233). The proposed rule referenced published UVA test methods but did not propose a specific method (58 FR 28194 at 28248 to 28250). Rather, the proposed rule stated that a sunscreen product could be labeled as “broad spectrum,” or labeled with a similar statement, if it protected against UVA radiation as demonstrated by one of the published UVA tests or a similar test. In April 1994, we reopened the administrative record to allow additional submissions concerning UVA-related issues. We also announced a public meeting to be held in May 1994 to discuss UVA testing procedures (59 FR 16042, April 5, 1994). We held the public meeting to gather more information to help us determine the most appropriate UVA test method and labeling. In November 1997, Congress enacted the Food and Drug Administration Modernization Act of 1997 (FDAMA), which addressed OTC sunscreen products among other FDA issues. Section 129 of FDAMA stated that “not later than 18 months after the date of enactment of this Act, the Secretary of Health and Human Services shall issue regulations for over-the-counter sunscreen products for the prevention or treatment of sunburn.” We then determined that the GRASE active ingredients, SPF testing requirements, and related labeling were issues that we could finalize within the timeframe set by FDAMA. Because we had not previously proposed specific UVA testing and labeling requirements, we did not have sufficient time to finalize these UVA requirements within the FDAMA timeframe. In the Federal Register of May 21, 1999, we published a final rule for OTC sunscreen products (64 FR 27666). The 1999 sunscreen final rule added the sunscreen monograph (regulations) in part 352 (21 CFR part 352) and included an effective date of May 2001. The 1999 sunscreen final rule stated that we would publish a proposed rule outlining UVA testing and labeling requirements at a future date. In 2000, we extended the effective date for the 1999 sunscreen final rule to December 2002 (65 FR 36319, June 8, 2000). In December 2001, we stayed the December 2002 effective date of the 1999 sunscreen final rule indefinitely. We took this action because we planned to revise part 352 to add UVA testing and labeling requirements so that OTC sunscreen products would be tested and labeled for both UVB and UVA radiation protection. We included these revisions in a proposed rule that published in the Federal Register of August 27, 2007 (72 FR 49070). The 2007 proposed rule identified UVA testing and labeling that we proposed should be required for all OTC sunscreen products. The proposed rule also revised SPF testing and corresponding labeling from the 1999 final rule. The proposed rule did not lift the existing stay of the effective date for part 352. On September 3, 2004 (69 FR 53801), we delayed until further notice the implementation date for the Drug Facts final rule (64 FR 13254, March 17, 1999) (21 CFR 201.66) for OTC sunscreen products. The Drug Facts final rule (21 CFR 201.66) establishes general labeling format and content requirements for all OTC drugs. We explained that we postponed the implementation date for general Drug Facts labeling requirements for sunscreens because we did not expect to issue the sunscreen final rule containing UVA testing and product-specific labeling requirements ( i.e., this document) by the Drug Facts implementation date of May 2005. Therefore, we delayed the implementation date until further notice to prevent sunscreen product manufacturers from having to relabel their products at two closely related time intervals, as initially required by the 1999 Drug Facts final rule and the 1999 sunscreen final rule. B. Scope of This Document This final rule establishes the labeling and testing requirements for OTC sunscreen products containing specific ingredients or combinations of ingredients and marketed without an approved application under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) (the FD&C Act). The requirements in this final rule will help ensure that these currently marketed sunscreen products are appropriately labeled and tested for both UVA and UVB protection. In addition, the requirements in this final rule will help ensure the proper use of these sunscreens and greater consumer protection from the damaging effects of UV radiation. This final rule also identifies claims that render a product that is subject to this rule misbranded or are not allowed on any OTC sunscreen drug product marketed without an approved application. As described in the previous section of this document, we issued the 2007 proposed rule as a proposed amendment to the sunscreen monograph requirements in 21 CFR part 352 primarily to establish UVA testing and labeling requirements so that all OTC sunscreen products marketed under the sunscreen monograph would be tested and labeled for both UVB and UVA radiation protection. Sunscreen active ingredients, UVB testing, UVB labeling, and other conditions under which sunscreens would be considered GRASE and not misbranded had been addressed in the 1999 (stayed) final rule. In response to the 2007 proposed rule, however, we received submissions from the public concerning all aspects of the sunscreen monograph ( i.e., the conditions specified in the 1999 final rule and the 2007 proposed rule). As discussed further in this section, some of the issues regarding the monograph conditions raised in the public submissions will require further evaluation by us. Therefore, we are not issuing a final monograph with GRASE conditions for sunscreens in this document. Instead, we are publishing this final rule establishing labeling and the effectiveness testing upon which it relies, which applies to the same sunscreens that were the subject of the 2007 proposed rule to amend the monograph, because it is in the best interest of public health to publish this final rule while we work on remaining issues that need to be addressed in order to publish a final monograph. This labeling will help ensure that these products are not misbranded by providing specific indications, directions, warnings, and other important information to help consumers select and use them appropriately. In this final rule, then, we are codifying in 21 CFR part 201 requirements for OTC sunscreen products containing specified active ingredients and marketed without approved applications under section 505 of the FD&C Act (21 U.S.C. 355) (hereafter referred to as “covered” products). With respect to these covered products, this new section 21 CFR 201.327 includes requirements for labeling and the effectiveness testing upon which it relies. Because we have not yet resolved all of the issues regarding conditions under which sunscreens are GRASE and not misbranded, the stay of 21 CFR part 352 remains in effect. Although we are not yet codifying these labeling and related effectiveness testing provisions in the monograph regulation, they do embody the agency's current determination on appropriate regulation of these aspects of sunscreens that were previously identified as falling within the monograph in part 352, and supersede the prior approach embodied in the never-effective provisions of 21 CFR part 352 subparts C and D. While this rule does not lift the stay of part 352, we are lifting the delay of implementation date for the Drug Facts labeling requirements of 21 CFR 201.66. In addition, this rule codifies certain specific claims that render a covered product misbranded or are not allowed on any OTC sunscreen drug product marketed in the United States without an approved application. We note that all provisions of new 21 CFR 201.327 and the amendments to 310.545 included in this rule apply only to the aforementioned covered products, and references in this document to “covered” products recognize this limitation. Manufacturers of sunscreen products that are already being marketed pursuant to an approved application can contact FDA's Center for Drug Evaluation and Research to discuss supplemental submissions that would enable them to include labeling on their products like that specified in this final rule. C. Issues Outside the Scope of This Document There are a number of issues that were raised in public submissions responding to the 2007 proposed rule that are outside the scope of this document. The issues fall into two categories: • GRASE determination for sunscreen products and active ingredients • Issues affecting multiple OTC drug monographs As explained below, in this document, we are not addressing these issues related to determining the GRASE status of sunscreen products or sunscreen active ingredients and are not addressing the issues described below affecting multiple OTC drug monographs. 1. Issues Regarding GRASE Determination for Sunscreen Products and Active Ingredients A large number of submissions on the 2007 proposed rule raised issues related to the conditions that define what constitutes a GRASE finished OTC sunscreen product, irrespective of its active ingredients. These included over 1000 submissions requesting that we limit the monograph to sunscreens that offer broad spectrum protection and have SPF values of 15 or higher. Because this final rule is a labeling rule, and not a monograph, we do not address these issues here but plan to address them in future rulemakings regarding the monograph and conditions for general recognition of safety and effectiveness. This rule also does not address issues related to the GRASE status of sunscreen active ingredients that are included in the 2007 proposed rule (proposed 21 CFR 352.10 and 352.20). We received 20 submissions raising questions about the safety of ingredients in sunscreens (Ref. 1). Ten of the submissions specifically asked that we ensure that none of the ingredients are carcinogenic. Others asked that we ensure that all ingredients in sunscreens are safe without citing a specific concern. We intend to address carcinogenicity and other safety considerations related to sunscreen active ingredients in a future rulemaking. We also received submissions requesting that we increase the GRASE concentration of avobenzone from 3 percent to 5 percent (Ref. 1). Another submission points out that there are two USP 1 monographs for zinc oxide: 1 United States Pharmacopeia. • Zinc oxide (Ref. 2) • Zinc oxide neutral (Ref. 3) The submission would like us to clarify that zinc oxide in OTC sunscreen products can meet the specifications of either USP monograph (Ref. 1). We intend to address all of these issues regarding GRASE determination for sunscreen active ingredients in future rulemakings. In addition, we received two submissions requesting that we classify three new ingredients not previously marketed in the United States as GRASE: bemotrizinol, bisoctrizole, and octyl triazone (Ref. 1). We found these active ingredients eligible for review under the OTC drug monograph system in 2003 (octyl triazone) and 2005 (bemotrizinol and bisoctrizole) (68 FR 41386, July 11, 2003, and 70 FR 72449, December 5, 2005). We are currently reviewing the safety and effectiveness data submitted for these and other sunscreen active ingredients found eligible for potential addition to the monograph. When we complete our review, we will issue proposed rules stating our tentative conclusions on the safety and effectiveness of all of these ingredients. 2. Issues Affecting Multiple OTC Drug Monographs This final rule also does not address three issues raised in response to the 2007 sunscreen proposed rule that are not specific to sunscreen products. Because these issues apply more generally to multiple categories of OTC drug products, we are not addressing these issues in this final rule, which is limited to OTC sunscreen products. The first issue concerns the inclusion of expiration dates on sunscreen labels. We received 12 submissions requesting that we require OTC sunscreen products to be labeled with an expiration date (Ref. 1). Currently, regulations in 21 CFR 211.137(h) do not require that an expiration date be included in labeling if an OTC drug product does not have any dosage limitations and is stable for at least 3 years. This regulation applies to many OTC drug products, including sunscreen products. Any modification of the existing regulations would require publication of a proposed rule addressing all OTC drug products affected by the expiration date regulations. The second issue concerns the term “final monograph.” One submission argued that we should not use this term because it is inaccurate (Ref. 1). As the submission states, “FDA is to continually evaluate products, so nothing is ever finalized.” This issue applies to monographs representing all categories of OTC drug products. Therefore, we are not addressing the issue in this document. The third issue concerns the country of origin listing for all ingredients ( i.e., both active and inactive ingredients) on a sunscreen drug product. We received a submission requesting that we provide the country of origin for each ingredient. The submission also requested that manufacturers be required to provide specific details about what each ingredient does in the product. This issue applies to all OTC drug products and, therefore, we are not addressing it in this document. D. Enforcement Policy As noted, no final monograph is currently in effect for OTC sunscreen drug products, and in its absence, questions may arise regarding FDA's enforcement policy for OTC sunscreen products marketed without approved applications. To clarify expectations for industry, elsewhere in this issue of the Federal Register , we are announcing the availability of a draft guidance document, explaining the agency's intended enforcement policy for these products until a final sunscreen monograph becomes effective. E. Summary of Major Revisions to the Labeling and Effectiveness Testing Included in the 2007 Proposed Rule In response to the 2007 proposed rule, we received almost 2,900 submissions from the public. Of these submissions, over 2,500 expressed general support for the proposed rule and urged us to finalize and implement the new rule quickly. Three hundred twenty-five of the submissions raised approximately 90 specific issues related to the proposed rule. We have addressed the issues specifically relating to labeling and effectiveness testing in this final rule. Based on the submissions received, and the information and data included in those submissions or otherwise available to us, we have re-evaluated our position on several issues in the 2007 proposed rule and made several changes to our proposed labeling and testing requirements. Tables 1, 2, 4, and 5 in this document summarize the labeling and effectiveness testing requirements included in the 2007 proposed rule as well as the labeling and effectiveness testing required by this final rule: • Table 1: PDP Labeling (discussed in section III) • Table 2: Drug Facts Labeling (discussed in section IV) • Table 4: SPF Test (discussed in section VI) • Table 5: Broad Spectrum Test (discussed in section VIII) Rather than summarizing all of the revisions to the labeling and testing included in the 2007 proposed rule, we are highlighting what we consider to be the most important revisions in this section of the document. We made the following changes to the proposed labeling: 1. The proposed UVA “star rating” is not required on the PDP. 2. A combined “Broad Spectrum SPF” statement is required on the PDP for sunscreen products that pass the broad spectrum test established in new 21 CFR 201.327(j). To pass the broad spectrum test, the amount of UVA protection must increase as the SPF value increases. 3. For sunscreen products that pass the broad spectrum test established in new 21 CFR 201.327(j) and have SPF values of 15 or higher in accordance with the SPF test in 21 CFR 201.327(i): a. The “Sun Alert” warning proposed as the first warning in 2007 is not required (Warning proposed located in 21 CFR 352.52(c)(1)). b. A new indication statement may be included to inform consumers that using the product “as directed with other sun protection measures (see Directions [in bold italic font]) decreases the risk of skin cancer and early skin aging caused by the sun.” c. A new direction statement has been added informing consumers that exposure to the sun increases the risk of skin cancer and early skin aging and providing a list of specific sun protection measures that can decrease this risk. 4. For any OTC sunscreen product that does not pass the broad spectrum test in 21 CFR 201.327(j), or that are broad spectrum with an SPF value less than 15, this final rule, like the 2007 proposed rule, requires that the first warning indicate the adverse consequences of spending time in the sun. The wording of this warning has been revised to state, “Skin Cancer/Skin Aging Alert [in bold font]: Spending time in the sun increases your risk of skin cancer and early skin aging. This product has been shown only to help prevent sunburn, not [in bold font] skin cancer or early skin aging.” We also made the following changes to the effectiveness testing proposed in 2007: 1. The number of subjects required in the SPF test has been reduced from 20 subjects to 10 subjects. 2. One in vitro test is required to demonstrate broad spectrum protection rather than the two previously proposed tests (an in vitro test and an in vivo test). 3. The broad spectrum test is a pass/fail test based on the critical wavelength value of 370 nm 2 . 2 Nanometers. II. Administrative and Other Issues Some of the submissions that we received following publication of the 2007 proposed rule made the following requests involving administrative issues (Ref. 1): • Extend the comment period of the 2007 proposed rule. • Lift the stay on 21 CFR part 352, imposed in 2001 (66 FR 67485). • Allow interim marketing of products containing avobenzone with ensulizole and avobenzone with zinc oxide. • Set an effective date for this final rule other than the 18 months proposed in the 2007 proposed rule. • Revise the preemption language included in the 2007 proposed rule by deleting any references regarding the rule's potential preemption of State tort law. Our positions on these issues are discussed in the remainder of this section of the document. All of the requests to extend the comment period were submitted before the November 28, 2007 Federal Register notice in which we extended the comment period of the 2007 proposed rule (72 FR 67264). In that notice, we extended the close of the comment period from November 26, 2007, to December 26, 2007. We have not received any more requests to extend the comment period since December 2007. With regard to requests to lift the stay of 21 CFR part 352 (the OTC sunscreen monograph), as already discussed, our 2007 proposed rule anticipated amending the testing and labeling provisions of that monograph and subsequently lifting the stay. However, comments received on the 2007 proposed rule not only addressed labeling and effectiveness testing for final sunscreen formulations, but also raised other issues about the monograph conditions for OTC sunscreen products that require further consideration. As a result, we are not finalizing amendments to part 352 at this time nor lifting the stay placed on that section as enacted in 1999 (66 FR 67485). Rather, this final rule establishes in 21 CFR 201.327 labeling requirements and the effectiveness testing upon which it relies for covered OTC sunscreen drug products. We intend to lift the stay on part 352 when we reach our final conclusions on the conditions under which sunscreen products are GRASE and not misbranded, including a determination regarding sunscreen active ingredients, and publish a revised final monograph. In the interim, the labeling and effectiveness testing provisions of this rule apply to covered OTC sunscreen products. We received a request that we allow interim marketing of avobenzone combinations in proposed § 352.20(a)(2) prior to issuing a final rule for part 352. Subject to our enforcement discretion, we will continue to allow the marketing of avobenzone combinations provided for in the 1999 sunscreen final rule. However, we are not allowing marketing of the additional avobenzone combinations discussed in the 2007 proposed rule until we reach a final conclusion on the GRASE determination for sunscreen active ingredients and combinations of those ingredients. We are requiring that this final rule become effective in 1 year, even though we considered 18 months in the 2007 proposed rule (72 FR 49070 at 49110). We are allowing products with annual sales less than $25,000 to comply with this rule in 2 years, as stated in the 2007 proposed rule. In response to the proposed rule, we received one submission arguing that we should require this final rule to become effective in 1 year (Ref. 1). The submission stated that a later effective date would have a negative public health impact. We received eight submissions arguing that we should extend the effective date from the proposed 18 months to 3 years (Ref. 1). The submissions listed the following reasons for allowing more than 18 months: • Repackaging • Relabeling • Testing/retesting • Removing products from market • Impact on small businesses The most common argument was that more time would be needed to test/retest OTC sunscreen products for broad spectrum protection in accordance with both the in vitro and in vivo UVA test methods included in the proposed rule. We agree with the submission which stated that it would be beneficial for consumers to have this rule become effective within 1 year. As explained in section VIII.A of this document, we are not requiring manufacturers to demonstrate broad spectrum protection by conducting in vivo and in vitro tests. This final rule requires that manufacturers conduct only the simpler and less expensive nonclinical in vitro test to demonstrate broad spectrum protection. In vitro tests are substantially shorter than in vivo tests. Therefore, we are setting an effective date for this rule 1 year from the date of publication in the Federal Register . However, we are providing two years for all products with annual sales less than $25,000 to comply with this rule. In addition, in order to ensure that limited testing laboratory capacity does not result in sunscreen shortages during the transition to the new rule, we intend to exercise enforcement discretion for a period of time with regard to the SPF test for certain OTC sunscreen products on the market by June 17, 2011 (see our draft guidance entitled “Guidance for Industry: Enforcement Policy—OTC Sunscreen Drug Products Marketed Without An Approved Application” announced elsewhere in this issue of the Federal Register ). The submissions stating that additional time is necessary for repackaging and relabeling did not submit any information or data to support these arguments (Ref. 1). The argument that more than 18 months is needed to remove non-compliant products from the market is not valid. In the 2007 proposed rule, we indicated that sunscreen products which are already distributed by the effective date of the final rule would not be expected to be relabeled or retested in conformity with the final rule conditions unless these products were subsequently relabeled or repackaged after the effective date (72 FR 49070 at 49109). Consistent with this statement, we do not expect non-compliant products introduced or delivered for introduction into interstate commerce prior to the compliance dates specified for this final rule to be removed from the market. We received a submission that expressed concern about the agency's preemption discussion in the 2007 proposed rule (72 FR 49070 at 49109 and 49110) and requested that we delete any discussion regarding the rule's potential preemption of State tort law (Ref. 1). The submission claimed that we exceeded our authority when we stated that section 751(a) of the FD&C Act displaces both State legislative requirements and State common law duties. The submission argued that Congress intended to preserve State common law claims by including section 51(e), which exempts State product liability claims from express preemption under section 751(a) of the FD&C Act. The commenter appears to have construed our statement in a way that would nullify section 751(e) of the FD&C Act. We did not intend to suggest that section 751(a) of the FD&C Act preempts State product liability claims, whether based on State legislative enactments or common law, because section 751(e) exempts such actions from the express preemption provision in section 751(a). However, it is important to note that section 751(e) of the FD&C Act exempts only those common law claims that are based on State product liability law. Our revised preemption discussion in section XII remains consistent with applicable law. The submission also requested that we delete any references to implied preemption. In this final rule, we have omitted any statement regarding implied preemption because, although implied preemption may arise, such scenarios are necessarily case-specific. Section XII of this document makes clear that the sole statutory provision giving preemptive effect to the final rule is section 751 of the FD&C Act. III. Principal Display Panel (PDP) Labeling In response to the 2007 sunscreen proposed rule, we received 45 submissions requesting that we revise the proposed principal display panel (PDP) labeling (Ref. 1). We are revising the PDP labeling based, in part, on these submissions (see table 1 of this document). We have decided that the PDP labeling included in this document will simplify the purchase decision for consumers by allowing them to more easily find important information included on the PDP. Table 1—Summary of PDP Labeling in the 2007 Proposed Rule and This Final Rule Using a Broad Spectrum SPF 30 Water Resistant Sunscreen Product as Example A and an SPF 6 Sunscreen That Is Not Broad Spectrum and Not Water Resistant as Example B Labeled information 2007 Proposed rule This final rule Effectiveness Rating 1 Example A: “UVB SPF 30 High” “UVA ★★★ High” Example A: “Broad Spectrum SPF 30” Example B: “UVB SPF 6 Low” “No UVA Protection” Example B: “SPF 6” Water Resistance Example A: “Water Resistant” Example A: “Water Resistant (40 minutes)” Example B: No statement on water resistance Example B: No statement on water resistance Educational Statement Examples A & B: “UV rays from the sun are made of UVB and UVA. It is important to protect against both UVA and UVB rays.” Examples A & B: No educational statement 1 The UVA rating in the 2007 proposed rule is a four-tier rating (low, medium, high, highest). The UVA testing in this final rule is pass/fail—a product is either allowed or not allowed to include a broad spectrum statement depending on results of the test described in new 21 CFR 201.327(j) (see section VIII of this document). A. SPF Statement In the 2007 sunscreen proposed rule, we proposed redefining the acronym “SPF” as the “sunburn protection factor.” We also proposed that the term “UVB SPF” would be required on the PDP of all OTC sunscreen products (proposed 21 CFR 352.50(a)). This term would be followed by the numerical value determined from SPF testing and one of the following descriptors: “low,” “medium,” “high,” or “highest.” For example, a sunscreen product could have contained the statement “UVB SPF 40 High” on the PDP. We received 12 submissions regarding the SPF statement in response to the 2007 sunscreen proposed rule (Ref. 1). Collectively, the submissions made the following requests: 1. Do not change the definition of SPF to “sunburn protection factor” 2. Remove UVB from “UVB SPF” 3. Redefine the “highest” product category descriptor to include SPF 50 4. Require SPF values expressed in multiples of 5 5. Label SPF as the percent of UVB radiation screened As discussed in the remainder of this section, we agree with the first and second requests, but are not granting the other three requests. In this final rule, unlike the 2007 proposed rule, we have no express definitional section. However, we identify “SPF” as an abbreviation for “sun protection factor” in new 21 CFR 201.327(a)(1), and use it consistently in this way throughout the rule. This use of the term SPF is identical to the definition in the 1999 stayed sunscreen final rule (64 FR 27666). For products that are not broad spectrum, the term “SPF” will appear on the PDP with the numerical SPF value calculated according to the test method in new 21 CFR 201.327(i). For broad spectrum sunscreen products, the term “Broad Spectrum SPF” will appear on the PDP along with the numerical SPF value calculated according to the test method in new 21 CFR 201.327(i). The term “UVB” will not be required as part of the SPF statement. We are also not requiring the descriptor ( e.g., “high” or “low”). We included these two requirements in the 2007 proposed rule because we had concluded that the requirements would help consumers understand the side-by-side SPF numerical rating in conjunction with the UVA star rating, which included the term “UVA” and the same descriptors (72 FR 49070 at 49084). As discussed in section III.B of this document, the UVA star rating is not being included in this final rule, and as discussed below, we have concluded that neither the term “UVB” nor the descriptor is necessary for consumers to understand the effectiveness statement. Neither the term “UVB” nor a descriptor ( e.g. “low” or “high”) had been included on sunscreen labels prior to our 2007 proposal, and consumers had been able to make purchase and use decisions based on SPF values alone. Under this final rule, the SPF value will be expressed on the PDP by including the term “SPF,” followed by the numerical value determined from the SPF test, similar to how it has appeared on the labels of OTC sunscreen products for more than 30 years. As described in section III.B of this document, for products passing the critical wavelength test in new 21 CFR 201.327(j), the SPF value statement will be expressed as “Broad Spectrum SPF” followed by the numerical SPF value calculated according to the test method in 21 CFR 201.327(i). We received five submissions objecting to the definition of SPF as “sunburn protection factor” and only one submission supporting the definition (Ref. 1). The submissions objecting to the definition argued that, if the term “sunburn protection factor” is used, consumers may mistakenly assume that a higher SPF value means a higher probability of sunburn. Additionally, they argued that sunscreen products protect against various harmful effects of sun exposure, such as early skin aging and skin cancer, in addition to protecting against sunburn. Some submissions suggested that the term “sunburn protection factor” will lead consumers with darker skin to assume that they do not need sunscreen products because they do not burn easily (Ref. 1). We agree with the arguments provided by the submissions suggesting that the term “sunburn protection factor” may be misleading. In the 2007 sunscreen proposed rule, we revised the definition of SPF from “sun protection factor” to “sunburn protection factor” because we thought that the new definition was more descriptive of what an SPF value represents (72 FR 49070 at 49077). The SPF value is determined from a clinical test with sunburn as the endpoint. However, for broad spectrum sunscreen products, the SPF statement also serves as a relative measure of the magnitude of broad spectrum protection (Ref. 4). In this final rule, while we do not codify a separate definitional section, we continue to use the term “SPF” to mean “sun protection factor,” as we had done in the 1999 final rule (21 CFR 201.327(a)(1)). In this final rule, we are also revising the effectiveness statement so that the term “UVB” is not required before the term “SPF,” as proposed in the 2007 proposed rule (proposed 21 CFR 352.50(a)). We received six submissions requesting this revision (Ref. 1). These submissions argued that “UVB SPF” is an incorrect representation of the SPF value determined from a test using a solar stimulator that emits both UVA and UVB radiation. The submissions point out that sunburn is not caused solely by UVB radiation. It is well known that UVA radiation contributes up to 20 percent of the skin's sunburn response (Refs. 5 and 6). One submission points out that if a sunscreen product blocked 100 percent of the incident UVB radiation and none of the erythemally effective UVA radiation, the sunscreen product would have SPF values no higher than 11 (if only 9 percent or 1/11 of UV radiation reaches the skin) (Ref. 4). We agree that UVA radiation contributes to the development of sunburn. Although the contribution of UVA to sunburn is less than UVB, it is still significant (Ref. 5). Further, as stated in the submissions, protection against UVA radiation is necessary to achieve higher SPF values (Ref. 5). We proposed including the term “UVB” in the SPF statement in the 2007 proposed rule to help consumers understand that the SPF effectiveness rating is different from the UVA effectiveness (star) rating being proposed (72 FR 49070 at 49084). However, as discussed elsewhere in this final rule we are not requiring a UVA effectiveness rating on the PDP (see section III.B.). Therefore, the term “UVB” is not necessary as part of the SPF statement. In this final rule, we are not requiring the term “UVB” be placed before the term “SPF.” In the 2007 sunscreen proposed rule, we stated that the SPF value should be followed by one of the descriptors “low,” “medium,” “high,” or “highest” (proposed 21 CFR 352.50(a)). The proposed descriptors were included to help consumers understand the SPF value because the label would have included identical descriptors for the UVA star rating. As discussed in section III.B. of this document, we are not requiring a UVA effectiveness rating on the PDP. Therefore, descriptors are no longer required to distinguish the SPF value from the UVA rating on a sunscreen label. Because we are not requiring a descriptor after the SPF value on the PDP in this document, the request to include SPF 50 sunscreen products in the “highest” category is no longer relevant. We received two other requests for revision to the SPF statement with which we do not agree. First, a submission stated that SPF values should only be labeled in multiples of five to be consistent with SPF labeling recommendations by the European Commission (Ref. 7). Second, one request from a submission suggested that SPF values should be expressed as the percent of UV absorption. The submission argued that the current SPF values are misleading because consumers believe an SPF 15 sunscreen product is not very protective even though it screens 93 percent of UV radiation. We do not agree with either submission. Based on SPF test data we have reviewed, we find that SPF values for sunscreen products generally can be determined with a precision that allows the products to be labeled with SPF values in intervals of less than 5 units (Ref. 1). Therefore, there is no mathematical or statistical basis for restricting SPF values to multiples of five. Contrary to the second request, consumers have relied on SPF values for over 30 years and are familiar with this format. Therefore, expressing SPF values as percentages may be confusing. It would imply that the stated percentage of the entire UV spectrum is absorbed by a sunscreen. However, the SPF values only reflect protection against the portion of the UV spectrum that causes sunburn. Additionally, the percentages of UV radiation screened that the submission notes are theoretical. The percentages are determined in a laboratory setting and not under actual use conditions. For example, laboratory tests may show that an SPF 15 sunscreen absorbs 93 percent of UV rays, but, under actual use conditions, the level of protection provided by an SPF 15 sunscreen product may be significantly below 93 percent. There are a number of factors that lead to this decreased protection, the most important being under-application of the sunscreen product (72 FR 49070 at 49092). Therefore, if SPF values were expressed as percentages, consumers might mistakenly believe that the sunscreen products they are using provide more protection than they really do provide under actual use conditions. B. Broad Spectrum Statement In response to the 2007 proposed rule, we received over 50 submissions collectively making the following four requests regarding the UVA effectiveness rating (Ref. 1): 1. Do not require UVA 4-star rating system. 2. Do not require “no UVA protection” statement if a product does not protect against UVA radiation. 3. Do not require the UVA statement to be the same size as the SPF statement. 4. Perform label comprehension studies prior to implementing proposed PDP labeling. The submissions included arguments, but no data, to support these requests. We agree with the first and second requests. However, we are not granting the third and fourth requests. Our reasons for these decisions are explained below, but we first summarize the related provisions of this final rule. We are not requiring a star rating or descriptors to indicate the level of UVA protection as proposed. Instead, to indicate the level of UVA and UVB protection, we are establishing a pass/fail broad spectrum test and a broad spectrum labeling statement. If a sunscreen product passes the broad spectrum test (see section VIII.B. of this document), under this final rule, the PDP of the product must include the statement “Broad Spectrum SPF [insert numerical SPF value resulting from testing under paragraph (i) of this section],” without any “UVA” reference (§ 201.327(a)(1)(i)). We are requiring the Broad Spectrum SPF statement to appear as continuous text with no intervening text or graphics. We are also requiring that the entire text be the same font style, size and color on the same background color. (§ 201.327(a)(1)(ii)). With regard to the submissions received, nearly all of the 50+ submissions argued against requiring the 4-star rating system to display the level of UVA protection on the PDP of OTC sunscreen products (Ref. 1). Many submissions stated that the presence of stars and a number (SPF) on the PDP will lead to consumer confusion. Some submissions argued that consumers may be confused when determining whether a star is filled or empty, thereby not knowing the UVA protection level. Other submissions argued that consumers are familiar with star ratings, but that the star rating for items such as movies and hotels are based on recommendations and not rigorous data. They suggested several options for labeling UVA protection, such as a numerical rating or another symbol other than stars. Some submissions suggested that the UVA rating should be proportional to the SPF value but requested that there not be two ratings on the PDP. The submissions cited the European Commission's recommendation that UVA protection increase as the SPF value increases (Ref. 7). The European Commission recommends a minimum UVA protection factor equal to at least one-third of the labeled SPF or a critical wavelength of at least 370 nm, but does not recommend that the actual value of the UVA protection factor or critical wavelength be displayed. The European Commission recommends that the main indicator of sun protection be the SPF value. Broad spectrum protection is indicated by a symbol on sunscreen labels—the acronym “UVA” enclosed within a circle the diameter of which should not exceed the height of the SPF value. We agree with the submissions that the UVA star rating would likely be confusing in conjunction with the numerical SPF rating. We also agree with the submissions requesting that UVA protection should be proportional to the SPF value. We are requiring such proportionality in the broad spectrum test described in this document. Because of this proportionality, there is no longer a need for a separate UVA rating. Instead of a rating, we are requiring a “broad spectrum” statement on the PDP if a product has a critical wavelength equal to or greater than 370 nm. This pass/fail “broad spectrum” statement is consistent with the recommendations in the submissions citing the recommendations of the European Commission. As noted, several submissions responding to our proposal for a separate UVA rating with stars suggested that consumer comprehension testing should be performed before the proposed labeling is implemented. We agree with the submissions that consumer comprehension data can be very helpful in formulating labeling changes. In fact, in conjunction with our 1993 proposal to allow products to be labeled as “broad spectrum” if they contained sunscreen active ingredients that absorbed UVA radiation (58 FR 28194 at 28233), we requested label comprehension study data to allow us to determine consumer understanding of the terms “broad spectrum,” “UVA,” and “UVB” (58 FR 28194 at 28243). Unfortunately, the data we received were not sufficient to allow us to determine the level of consumer understanding of these terms (72 FR 49070 at 49081 through 49085), and we received no further consumer comprehension data in response to the 2007 proposal to require the UVA star rating. While we acknowledge the value of consumer comprehension data, for reasons explained below, we conclude that conducting consumer comprehension testing is not necessary in this case in light of the labeling we have selected for the final rule. First, submissions suggesting consumer testing were responding to the UVA star rating in the proposed rule, the value of which would have been based on the results of two tests (72 FR 49070 at 49081 through 49085). As noted, we agree with the submissions suggesting that the 2007 UVA labeling proposal was likely to be confusing. Elsewhere in the document, we also discuss our final choice of a pass-fail test for establishing UV protection (section VIII.B). As a result of these changes in the underlying test method and the submissions on the proposed labeling, we have incorporated a much simpler labeling statement in this final rule. This statement designates as “broad spectrum” those products that are demonstrated to have a critical wavelength of at least 370 nm, using the test in new 21 CFR 201.327(j). Second, unlike in 1993 when we first sought consumer data on the term “broad spectrum”, and unlike the UVA star rating that we proposed in 2007, consumers are now likely to be familiar with the term “broad spectrum” as included in this document because some sunscreen manufacturers have labeled sunscreen products as “broad spectrum” for over 20 years. For example, the Johnson and Johnson “Sundown Broad Spectrum” line of sunscreens was on the market in 1988 (Ref. 8). As already noted, in our 1993 proposed rule, we not only sought consumer data, but in fact proposed that products be permitted to be labeled as “broad spectrum” if they contained sunscreen active ingredients that absorbed UVA radiation, although we did not at that time propose to require a specific test to demonstrate UVA protection (58 FR 28194 at 28233). We continued to allow this statement in the 1999 sunscreen final rule (64 FR 27666 at 27666 through 27667). Many consumers may also be familiar with the term “broad spectrum” because of public health campaigns and news articles about the importance of broad spectrum UV protection over the last two decades. For example, an article appearing in Working Woman magazine in 1990 urged women to “make sure to look for the term ‘broad spectrum’ on the label of a sunscreen” because “it means you're getting protection from both types of radiation” (Ref. 9). For consumers not already familiar with the term “broad spectrum,” the additional indication statement allowed in this document for certain broad spectrum sunscreen products should help consumers recognize the benefit of these products. Under “Uses” in Drug Facts, broad spectrum sunscreen products with an SPF value of 15 or higher are allowed the following indication statement: “if used as directed with other sun protection measures (see Directions [in bold italic font]), decreases the risk of skin cancer and early skin aging caused by the sun” (new 21 CFR 201.327(c)(2)). In addition, educational campaigns about sun protection will further inform consumers about the benefits of using sunscreens that include the term “broad spectrum” on their labels and have an SPF value of 15 or higher. We expect consumers to learn that a sunscreen labeled with the statement “Broad Spectrum SPF” 15 or higher, when used as directed with other sun protection measures, offers more comprehensive protection against sun-induced skin damage than that provided by a sunscreen that is not broad spectrum or that are broad spectrum with an SPF value less than 15. It is important to note that the broad spectrum test required in this document captures both UVB and UVA protection for the effectiveness of a sunscreen product. The broad spectrum test is not limited to UVA wavelengths as was the case with the proposed test (see section VIII.B of this document). By requiring that a broad spectrum sunscreen provide both UVB and UVA protection in a pass/fail test, the amount of UVA protection for a sunscreen product that passes the test must increase as the SPF increases. For example, a Broad Spectrum SPF 40 sunscreen product provides greater protection against both UVB and UVA than a Broad Spectrum SPF 20 sunscreen product. In contrast, an SPF 40 sunscreen product that is not broad spectrum provides more UVB protection than a SPF 20 sunscreen product that is not broad spectrum, but may not provide more UVA protection. This proportionality between UVB and UVA protection is important because consumers have been accustomed to basing their purchase decision concerning protection level primarily on the SPF value, and only secondarily on indications of whether or not the sunscreen provides broad spectrum protection. For example, a consumer seeking lower protection may have chosen an SPF 15 sunscreen product, whereas a consumer seeking higher protection may have chosen an SPF 40 sunscreen product. By creating a clear and standardized “yes/no” indicator regarding broad spectrum protection, these final labeling requirements will enable consumers to make better and more informed purchase decisions by looking to see if a product has a “Broad Spectrum SPF” value on the label. Thus, the ultimate purchase decision would be based on the numerical value associated with the Broad Spectrum SPF statement. For products offering broad spectrum protection, the Broad Spectrum SPF value on the PDP will not only indicate the relative level of protection against UVB radiation but will also reflect the level of UVA protection, with increasing SPF values indicating greater protection against both UVA and UVB radiation. For broad spectrum products, linking the amount of UVA protection to the SPF value, is consistent with the approach taken in Europe (Ref. 7). For broad spectrum products, we are requiring the broad spectrum statement on the PDP to appear in combination with the SPF statement. For example, an SPF 40 sunscreen product which passes the broad spectrum test will be labeled “Broad Spectrum SPF 40” in a uniform font style, size, and color and with the same background color. This placement will help consumers recognize that the particular sunscreen product is broad spectrum in conjunction with the SPF value. As previously explained, the broad spectrum statement and SPF value together will provide a relative measure of both UVB and UVA protection. Combining the broad spectrum and SPF statements will help consumers become more aware of the importance of broad spectrum protection. Under the 2007 proposed rule, if an OTC sunscreen product was not tested for or did not protect against UVA radiation, the statement “No UVA protection” would have been required on the PDP (proposed 21 CFR 352.50(b)(1)). Ten submissions argued against requiring this statement (Ref. 1). Some submissions argued that this statement is misleading because all sunscreen products provide some UVA protection. Submissions also stated that a negative statement is inconsistent with the OTC Drug Review because a drug should only describe the indications for which it is effective. Other submissions suggested that we should require all sunscreen products to provide UVA and UVB protection, making this statement unnecessary. We have concluded that the “No UVA Protection” statement is not necessary and could be misleading. Under this final rule, the labeling on the PDP of sunscreens no longer refers the type of UV radiation (UVA or UVB) protection offered; rather, products that pass the critical wavelength test in 201.327(j) are labeled with “Broad Spectrum SPF” values. Under this labeling, consumers who see “UVA” on the PDP, even if it is part of the statement “No UVA Protection,” may mistakenly believe that the product offers UVA protection. To eliminate this potential misunderstanding, we are not including the “No UVA Protection” statement on the PDP. In contrast to four submissions requesting that we make the UVA statement less prominent than the SPF statement, we are requiring the SPF and broad spectrum statements to be equally prominent on the PDP by appearing as a combined statement. The four submissions stated that they believe UVB radiation contributes more to skin cancer and photodamage than UVA radiation and argued that more prominence should be given to the SPF statement. However, none of the submissions included data to support this argument. Some submissions suggested that consumers are familiar with SPF ratings and that providing another rating with similar prominence may mislead and confuse consumers. It is well known that both UVA and UVB radiation contribute to photodamage and skin cancer (Refs. 6-7 and 10-12). Therefore, in our view, providing consumers with information about the effectiveness of a sunscreen product for UVA and UVB radiation protection is equally important. We are requiring that the broad spectrum statement be displayed in combination with the SPF statement. The two statements must not be interrupted with any graphics or text. In addition, the broad spectrum statement must be the same font style, size, and color as the SPF statement with the same background color. It is important for consumers to evaluate both statements when making a purchase decision. By requiring this information to be presented with identical prominence on the PDP, consumers should be able to quickly and easily identify sunscreen products that provide broad spectrum protection, as well as the SPF of all sunscreen products. While we are not requiring a negative statement on the PDP of products that do not pass the critical wavelength test in new 301.327(j), we caution that such products may be misbranded if they include statements regarding UVA protection; such statements may misleadingly imply that the product provides benefits that are similar or superior to those of products labeled with Broad Spectrum SPF values. C. Water Resistance Statement In the 2007 sunscreen proposed rule (proposed 21 CFR 352.52), we allowed the PDP of OTC sunscreen products to contain the statement “water resistant” if a sunscreen product was shown to retain the labeled SPF value after 40 minutes of water immersion, or “very water resistant” if a sunscreen product was shown to retain the labeled SPF value after 80 minutes of water immersion, according to the test in proposed 21 CFR 352.76. We simultaneously proposed that the “Uses” section of labeling (not the PDP) indicate specifically whether the product had been established to be water resistant for 40 minutes or 80 minutes, and included specific directions addressing times for reapplication of each product, dependent on its level of water resistance (proposed 21 CFR 352.52(b)(1)(vii), (b)(1)(viii), (d)(2), and (d)(3); 72 FR 49070 at 49113). In this document, we are revising the PDP to contain the statement “water resistant (40 minutes)” or “water resistant (80 minutes)” as determined by the water resistance test in new 21 CFR 201.327(i)(7). We are removing this information from the indications section of Drug Facts (section IV.B of this document). We continue to include directions based on the duration of water resistance established under the new water resistance test (section IV.D of this document). One submission stated that including information about water resistance in the indications section as well as in the directions section is “redundant and confusing” (Ref. 1). The submission recommended that we delete the indications statement. We agree with the submission. To eliminate redundancy and simplify the labeling for consumers, we are relocating the information formerly contained within the indication statement to the PDP. The content of the labeling as a whole is the same as that included in the 2007 proposed rule. However the proposed statement on the PDP did not clearly and accurately convey to consumers the difference between “water resistant” and “very water resistant” sunscreen products. For example, knowing that a sunscreen product is “very water resistant” does not give any indication of how much time a consumer can safely spend in the water. Under the 2007 proposed rule, a consumer would have had to read either the “Uses” or the “Directions” section of the Drug Facts label to determine the duration of water resistance for a sunscreen product (proposed 21 CFR 352.52(b)(1)(vii) and (b)(1)(viii) and proposed 21 CFR 352.52(d)(2) and (d)(3), respectively; 72 FR 49070 at 49113). Providing, on the PDP, specific information about the actual time (40 or 80 minutes) a consumer can expect a sunscreen product to retain its labeled SPF value is likely to be more helpful to consumers because the information is displayed in one place—on the PDP and not on different parts of the labeling. The revised statements “water resistant (40 minutes)” or “water resistant (80 minutes)” should make it clearer and easier for consumers to understand water resistance as part of their purchase decision. This water resistance information continues to be reinforced by information in the directions regarding reapplication. D. UVB and UVA Educational Statement In the 2007 sunscreen proposed rule, we proposed that the following educational statement be included on the PDP of all OTC sunscreen products (proposed 21 CFR 352.50(c)): “UV rays from the sun are made of UVB and UVA. It is important to protect against both UVB and UVA rays to prevent sunburn and other skin damage.” We received four submissions regarding the UVB and UVA educational statement in response to the 2007 sunscreen proposed rule (Ref. 1). The submissions made the following requests: • Do not require the educational statement on the PDP or • Combine the educational statement with the sun alert statement and include the combined statement in the “Other Information” section of the Drug Facts label. We considered including the proposed educational statement on the PDP. We concluded that this information is not critical for effective use of sunscreen products, particularly since we are no longer requiring other PDP statements to refer separately to UVA and UVB protection. An understanding that the sun produces ultraviolet (UV) rays or that there are two types of UV rays that reach the earth's surface is not necessary to ensure the safe and effective use of sunscreen products. The explanation of these concepts on sunscreen labeling is potentially confusing and could raise additional questions about their meaning. We could not determine a succinct educational statement that would not also be potentially misleading. Therefore, we have concluded that an educational statement should not be required on the PDP. As noted, submissions also requested that the proposed educational statement be combined with proposed sun alert, included in the proposed rule as a warning. In section IV.C of this document, we address submissions on the sun alert warning, and explain our decision to incorporate the information regarding the role of certain sunscreens in reducing the risk of skin cancer and early skin aging into a new indication and accompanying directions for sunscreens with Broad Spectrum SPF values of 15 or higher. We are retaining a modified warning to be included as the first warning on sunscreen products that are either not broad spectrum or that are broad spectrum with an SPF value less than 15. Because we are not requiring an educational statement on the PDP and are either eliminating or modifying the proposed sun alert warning, the request to combine these two statements is no longer relevant. IV. Drug Facts Labeling In September 2004 (69 FR 53801), we delayed the May 16, 2005, implementation date for the Drug Facts final rule (21 CFR 201.66) for OTC sunscreen products until further notice). The Drug Facts final rule (21 CFR 201.66) establishes general labeling format and content requirements for all OTC drugs. With the additional exception of certain OTC drug products in “convenience size” packages (see 67 FR 16304 at 16306 (April 5, 2002), other OTC drug products are already required to comply with 201.66. We delayed implementation of 201.66 for sunscreens so as to avoid the potential that sunscreen manufacturers would have to relabel their products twice within a short time period if a final rule specifying labeling for sunscreens published shortly after the original May 2005 implementation date for the general content and format requirements of the Drug Facts final rule. We published the notice of delay for OTC sunscreens' implementation of the Drug Facts final rule so that such products could simultaneously implement both the general labeling provisions of that rule and the specific labeling provisions for sunscreens when we published a sunscreen labeling final rule. We are now lifting the stay on the implementation of the Drug Facts final rule for OTC sunscreen products. In this document, we are requiring the same implementation date for the regulations set forth in this labeling and testing final rule (21 CFR 201.327) and in the Drug Facts final rule (21 CFR 201.66) as applied to these sunscreen products. This action will benefit both consumers and manufacturers. Consumers will benefit by having sunscreen labeling presented in the Drug Facts format that they are familiar with. Manufacturers benefit because they will achieve compliance with two rules through one labeling revision (rather than following the more expensive course of making two labeling changes at two different times). In 2003 (68 FR 33362, June 4, 2003), we also stayed the part of the skin protectant monograph that describes GRASE combinations of skin protectant and sunscreen active ingredients (21 CFR 347.20(d)). Because this document addresses the labeling and testing of sunscreen products and not the GRASE status of individual sunscreen active ingredients, we are not lifting the stay of 21 CFR 347.20(d). This document requires much of the Drug Facts labeling included in the 2007 proposed rule. However, we have made several revisions to the proposed labeling. These revisions are discussed in detail throughout the remainder of this section. In addition, table 2 of this document summarizes these revisions as follows: Table 2—Summary of Drug Facts Labeling Included in the 2007 Proposed Rule and This Final Rule Drug facts section 2007 Proposed rule This final rule Active Ingredients/Purpose Name and amount of ingredient(s) followed by “sunscreen” Name and amount of ingredient(s) followed by “sunscreen.” Uses • [low, medium, high, or highest] UVB sunburn protection • for all sunscreen products: “helps prevent sunburn.” • [low, medium, high, or highest] UVA protection • retains SPF after 80 minutes of activity in the water • Optional, for sunscreen products with Broad Spectrum SPF values of 15 or higher, “if used as directed with other sun protection measures (see Directions), decreases the risk of skin cancer and early skin aging caused by the sun.” Warnings UV exposure from the sun increases the risk of skin cancer, premature skin aging, and other skin damage. It is important to decrease UV exposure by limiting time in the sun, wearing protective clothing, and using a sunscreen. For sunscreen products that are not broad spectrum or for products that are broad spectrum with an SPF value less than 15, Skin Cancer/Skin Aging Alert [in bold font]: Spending time in the sun increases your risk of skin cancer and early skin aging. This product has been shown only to help prevent sunburn, not [in bold font] skin cancer or early skin aging. For all sunscreens: For external use only For external use only Do not use on damaged or broken skin Stop use and ask a doctor if skin rash occurs Stop use and ask a doctor if rash occurs When using this product keep out of eyes. Rinse with water to remove. When using this product keep out of eyes. Rinse with water to remove. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions Non-Water Resistant Product • apply liberally [# minutes] before sun exposure • reapply at least every 2 hours and after towel drying, swimming, or sweating • apply and reapply as directed to avoid lowering protection • children under 6 months: Ask a doctor Non-Water Resistant Product • apply liberally 15 minutes before sun exposure • use a water resistant sunscreen if swimming or sweating • reapply at least every 2 hours • children under 6 months: Ask a doctor Water Resistant Product • apply liberally [# minutes] before sun exposure Water Resistant Product • apply liberally 15 minutes before sun exposure • reapply after 40 [or 80] minutes of swimming or sweating and after towel drying. Otherwise, reapply at least every 2 hours. • apply and reapply as directed to avoid lowering protection • children under 6 months: Ask a doctor • reapply: • after 40 [or 80] minutes of swimming or sweating • immediately after towel drying • at least every 2 hours • children under 6 months: Ask a doctor Water Resistant and Non-Water Resistant Products Water Resistant and Non-Water Resistant Products No statement For sunscreens with Broad Spectrum SPF values of 15 or higher: • Sun Protection Measures [in bold font]. Spending time in the sun increases your risk of skin cancer and early skin aging. To decrease this risk, regularly use a sunscreen with a Broad Spectrum SPF value of 15 or higher and other sun protection measures including: • limit time in the sun, especially from 10 a.m.-2 p.m. • wear long-sleeved shirts, pants, hats, and sunglasses. Inactive Ingredients List inactive ingredients in alphabetical order List inactive ingredients in alphabetical order. Other Information No required statements • protect this product from excessive heat and direct sun. Questions? No required statements No required statements. A. Active Ingredients/Purpose We received one submission regarding the listing of active ingredients and one submission requesting that we provide specific details about what each ingredient does in the product (Ref. 1). One of these submission also requested that we require listing of the percentage of each active ingredient next to the ingredient name. We are not making any changes to the “Active ingredients/Purpose” section of the Drug Facts label. The general OTC labeling regulations specify that the “quantity of each active ingredient per dosage unit” be listed with the established name of each active ingredient (21 CFR 201.66(c)(2)). Therefore, every sunscreen product is already required to include the active ingredient names followed by the percentage (weight per volume) in the “Active ingredients/Purpose” section, as requested by the first submission. We are not requiring specific details about what each ingredient does in the product. The function of each active ingredient in an OTC drug product is already required to be listed by 21 CFR 201.66(c)(3), which specifies that the “Active ingredients/Purpose” section of the label list the “general pharmacologic categories or principal intended actions of each active ingredient.” There is not currently a requirement to list the purpose of inactive ingredients on OTC drug labels. This information is not needed to safely and effectively use sunscreen products. Therefore, in this document, we are not requiring the purpose of inactive ingredients to be listed on sunscreen labels. B. Uses 1. Indications Statements Proposed in the 2007 Proposed Rule The 2007 proposed rule included three indication statements under “Uses” in Drug Facts: 1. Level of UVB sunburn protection (proposed 21 CFR 352.52(b)(1)(i)-(b)(1)(iv)) 2. Level of UVA protection (proposed 21 CFR 352.52(b)(1)(v) and (b)(1)(vi)) 3. Extent of water resistance (proposed 21 CFR 352.52(b)(1)(vii) and (b)(1)(viii)) The first statement would have appeared on all monograph sunscreen products. The second statement would only have appeared on monograph sunscreen products providing UVA protection. The third statement would only have appeared on monograph sunscreen products that are water resistant for either 40 or 80 minutes. We received numerous submissions from the public concerning these statements following publication of the 2007 proposed rule (Ref. 1). We are not requiring these indication statements in this final rule. Instead, all sunscreen products covered by this rule will be required to include the indication statement “helps prevent sunburn,” as required in the 1999 sunscreen final rule (64 FR 27666; new 21 CFR 201.327(c)(1)). We are requiring this statement instead of the first proposed statement (level of UVB sunburn protection) because we agree with submissions arguing that sunburn is not caused solely by UVB radiation (Ref. 1). We also agree with submissions arguing that the SPF value by itself on the PDP informs consumers of the level of sunburn protection, so a separate description of the level of sunburn protection does not need to be included as an indication. In addition, sunscreen products covered by this rule that provide broad spectrum protection according to the test in new 21 CFR 201.327(j) and have SPF values of 15 or higher, may include the following indication statement (new 21 CFR 201.327(c)(2)(i)): “if used as directed with other sun protection measures (see Directions), decreases the risk of skin cancer and early skin aging caused by the sun.” This statement replaces the second proposed indication statement. We are allowing this statement for certain sunscreens covered by this rule based on available clinical studies, the fact that UV radiation from the sun is harmful, and the scientific understanding that substantially limiting overall UVB and UVA exposure reduces the risk of skin cancer and early skin aging. As discussed in the remainder of this section of the document, it is critical that the indication statement regarding skin cancer and early skin aging includes information about using the products as directed and following other sun protection measures (listed under the heading Directions). We have concluded that the reference to other sun protection measures is necessary to ensure that the consumer's overall UV exposure is substantially decreased. A consumer who relies on the use of a sunscreen with Broad Spectrum SPF value of 15 or higher alone may not obtain a meaningful net decrease from the risk of skin cancer or early skin aging if, because he or she is wearing the sunscreen, the consumer spends more time in the sun and/or wears less protective clothing. In fact, reliance on sunscreen use alone, without also employing other sun protection measures, could actually result in an increase in the consumer's overall UV exposure. Therefore, if the indication statement regarding decreasing risk of skin cancer and early skin aging does not include the information about using the product as directed, which includes following other sun protection measures, the statement will be considered misleading (and thus make a sunscreen product misbranded) (new 21 CFR 201.327(c)(3)). Similarly, sunscreen products covered by the rule that provide broad spectrum with SPF values between 2 and 15 or do not provide broad spectrum protection should not state or imply that the use of a sunscreen product alone will reduce the risk of skin cancer or early skin aging. Doing so would cause the product to be misbranded. We are not including the third proposed indication statement (regarding water resistance) in this document. As already discussed, under this final rule, information about water resistance is included on the PDP, as well as under “Directions” in Drug Facts (see sections III.C and IV.D of this document). We conclude that information about the water resistance of a sunscreen product is more effectively and accurately presented on the PDP and as a direction than as an indication statement. The extent of water resistance informs a consumer about how long the SPF value is retained following water exposure and, therefore, how long an interval can elapse before reapplying the sunscreen product (40 or 80 minutes). In addition, the PDP requirements in this document include the time interval as part of the water resistance statement, so that consumers can readily distinguish between products on this basis when making purchasing decisions. Because we include water resistance on the PDP and under “Directions,” we are not including a separate indication statement about water resistance in this document. 2. Statement Regarding Skin Cancer and Early Skin Aging a. Submissions Arguing For a Skin Cancer and Early Skin Aging Indication As already stated, in this final rule we have adopted, for the first time, an indication for skin cancer and early skin aging for sunscreen products covered by the rule that have Broad Spectrum SPF values of 15 or higher. In our 2007 proposed rule, we had included indication statements that indicated the degree of protection against both UVB and UVA radiation but that linked UVB protection only to sunburn prevention and did not expressly link UVA protection to any specific health benefit (proposed 21 CFR 352.52(a)). At the same time, however, we had proposed both an educational statement on the PDP stating that UV rays from the sun are made of both UVB and UVA and that it is important to protect against both types of radiation to prevent sunburn and other skin damage (proposed 21 CFR 352.50 (c)). We also proposed a “sun alert” statement as the first warning. This first warning read, “UV exposure from the sun increases the risk of skin cancer, premature skin aging, and other skin damage. It is important to decrease UV exposure by limiting time in the sun, wearing protective clothing, and using a sunscreen.” (proposed 21 CFR 352.52(c)(1)). In response to our proposed rule, we received a total of 12 submissions asking that we include a specific statement regarding reduction in risk of skin cancer and early skin aging as an indication for covered sunscreens (Ref. 1). The submissions asked that we allow an indication statement informing consumers that the regular, consistent, or continued use of a sunscreen product reduces or helps reduce the risk or chance of developing skin damage, early skin aging, and some types of skin cancer (Ref. 1). These submissions also supported our proposed requirement of a “sun alert” on the labeling to inform consumers of the need to limit time in the sun and wear protective clothing. The submissions came from sunscreen manufacturers and public health organizations including the American Academy of Dermatology, the American Cancer Society, and the Skin Cancer Foundation. Many of the submissions provided references to studies that they argued support the inclusion of this indication statement. One submission specifically requested that we allow an anti-aging claim (without mention of skin cancer), and one other submission argued that no sunscreen can claim to prevent cancer (Ref. 1). We received no new data to accompany these requests for a separate indication that the regular use of sunscreen decreases the risk of skin cancer and early skin aging. However, on reconsideration of the data reviewed prior to the 2007 proposed rule, we agree with the argument that the data underpinning our proposed education statement and warning are sufficient to support an appropriately qualified skin cancer and premature skin aging indication for one subset of sunscreens covered by this rule—those that have Broad Spectrum SPF values of 15 or higher. As a result, our final rule provides different labeling for these sunscreens than for sunscreens covered by the rule that are not broad spectrum or that provide broad spectrum with SPF values less than 15. In addition, we conclude that such an indication should not be included in the Warnings section of Drug Facts. We have concluded that, as proposed in 2007, the second sentence of the first warning ( i.e., the “Sun Alert” warning) is an implied indication: “It is important to decrease UV exposure by limiting time in the sun, wearing protective clothing, and using a sunscreen.” Because it follows a warning that “UV exposure from the sun increases the risk of skin cancer, premature skin aging, and other forms of skin damage,” the second sentence implies that using any sunscreen, regardless of SPF value or broad spectrum protection, and following other sun protection measures will decrease the risks of skin cancer, early skin aging, and other consequences of UV exposure to the sun. We have concluded, based on a reconsideration of data previously reviewed in the 2007 proposed rule, that, if consumers use broad spectrum sunscreens with SPF values of 15 or higher and follow other sun protection measures, they can reduce their risk of skin cancer and early skin aging. For these products, we agree with the public submissions that this information is most appropriately placed as an indication ( i.e., under Uses) with a reference to the need to use the product as directed with other sun protection measures. For these products, we include under the heading Directions, specific reference not only to regularly use sunscreens with Broad Spectrum SPF values of 15 or higher (the subset of sunscreens for which the indication is allowed) but also to employ the other listed sun protection measures listed under Directions. For sunscreen products covered by this rule that are not Broad Spectrum or that are broad spectrum with an SPF value less than 15, however, we conclude that existing data are insufficient to support an indication for reducing risk of skin cancer or early skin aging. In the sections that follow, we explain the specific scientific basis for our conclusion, as well as explain our rationale for the specific framing of the labeling, as included in the final rule, for both subsets of the sunscreens covered by the final rule—those that have Broad Spectrum SPF values of 15 or higher and those that do not have Broad Spectrum or that are Broad spectrum with SPF values less than 15. b. Limiting Overall UV Exposure Reduces Risk of Skin Cancer and Early Skin Aging For drugs subject to OTC monographs, like sunscreen products, indication statements about the effectiveness of the drug products must be supported with scientific data (21 CFR 330.10(a)(4)(ii)). In order for an OTC drug to be considered generally recognized as effective (GRAE), there must be a reasonable expectation that, in a given proportion of the target population, the drug will provide clinically significant relief of the type claimed (21 CFR 330.14(a)(4)(ii)). Based on the available data concerning the harmful effects of UV radiation and sunscreen UV protection, we have concluded that sunscreens, in conjunction with the critical behavioral steps of limiting time in the sun particularly during the midday hours and wearing protective clothing (long sleeve shirt, pants, hat, and sunglasses), provide “clinically significant relief” in reducing the risk of skin cancer and early skin aging. Based on the available data, we have limited this claim to broad spectrum sunscreen products with an SPF value of 15 or higher. UV radiation from the sun has been associated with nonmelanoma skin cancers since 1927 and with melanomas since 1952 (Ref. 13). It is estimated that as much as 90 percent of melanomas and nonmelanomas are caused by sun exposure (Ref. 5). In 1992, the International Agency for Research on Cancer (IARC), under the auspices of the World Health Organization, identified UV radiation as a human carcinogen 3 (Ref. 14). More recently, broad spectrum UV radiation was listed as a human carcinogen in the National Toxicology Program's 11th Report on Carcinogens issued in 2005 (Ref. 15). It is important to note that this report indicates that UVB and UVA radiation across the spectrum are known human carcinogens, but that either UVB radiation alone or UVA radiation alone is “reasonably anticipated to be a human carcinogen.” This classification is due to the fact that the exact wavelengths of UV radiation that cause different harmful effects ( e.g., DNA damage or loss of skin elasticity) have not yet been identified. It is clear, though, that broad spectrum UV radiation causes skin cancer. Broad spectrum UV radiation has also been shown to cause other types of skin damage, including early skin aging (Refs. 6 and 16). Therefore, we agree with the principle that a reduction, of sufficient magnitude, in broad spectrum UV exposure should reduce the risk of harmful effects to the skin, including skin cancer and early skin aging. 3 A carcinogen is anything that is known to cause the development of cancer. UV radiation is known to cause skin cancer. Broad spectrum sunscreens, by absorbing UVA and UVB radiation, decrease consumer exposure to both types of UV radiation from the sun that reach the earth's surface. Other critical behavioral steps, such as limiting time in the sun and wearing protective clothing, also decrease consumer exposure to UVA and UVB radiation. After considering the submissions and other available data, we have concluded that a claim for the reduction in risk of skin cancer and early skin aging is appropriate for certain sunscreen products, when the claim also includes the requirement that consumers use the product as directed and the Directions specify other sun protection measures be followed (see section IV.D of this document). We are basing this claim on the scientific understanding of the harm from UVA and UVB radiation and the absorption and/or reflection of that UV radiation by broad spectrum sunscreens, as well as data from studies concerning sunscreen use and the development of skin cancer or precursors of skin cancer (section IV.B.2.c of this document). For a sunscreen to be effective ( i.e., provide “clinically significant relief”) in reducing the risk of skin cancer and early skin aging, consumers must not increase their overall exposure to UV radiation by overreliance on sunscreen use. Other behavioral factors could account for such an increase, such as the amount of time spent in the sun and the use of protective clothing. If consumers rely on sunscreen use to spend more time in the sun and/or to wear less protective clothing, then consumers could actually increase their overall UV exposure, which would eliminate the effectiveness of sunscreen use in reducing the risk of skin cancer and early skin aging. To illustrate this point, it is helpful to consider what has been termed the “compensation hypothesis.” As we noted in the 2007 proposed rule, the compensation hypothesis states that consumers who wear high SPF sunscreens generally spend more time in the sun and/or wear less protective clothing (72 FR 49070 at 49086). If the hypothesis is true, consumers would not reduce their risk of skin cancer or early skin aging because their overall UV exposure increases, even though a properly applied (and reapplied) sunscreen absorbs UV radiation and helps prevent sunburn. We cited two retrospective studies which support the compensation hypothesis in the 2007 proposed rule (72 FR 49070 at 49086). Reynolds et al. published a study in 1996 finding, in a study of 509 sixth-graders, that adolescents who used sunscreen on both Saturday and Sunday of a Labor Day weekend spent significantly more time in the sun than those who used sunscreen only one day or not at all (Ref. 17). In the second study, parents of 503 children, aged less than 2 to 12 years, were surveyed as to parental attitudes about their children's sun exposure (Ref. 18). The authors reported that “sunscreen use in children was significantly associated with longer duration of sun exposure” (Ref. 18). Increased overall UV exposure might, in fact, increase the risk of skin cancer and early skin aging, despite the proper use of sunscreens. Likewise, if consumers limit time in the sun, especially during midday, and wear more protective clothing (such as broad brimmed hats, long pants, and long sleeve shirts) while outside, but do not use sunscreens for areas of the skin exposed to the sun (such as parts of face and neck), then the consumer may not decrease the risk of skin cancer and early skin aging for sun-exposed areas. For these reasons, for products that are entitled to include an indication for reducing the risk of skin cancer and early skin aging, we continue to direct consumers to follow a comprehensive sun protection program that includes use of sunscreens with Broad Spectrum SPF values of 15 or higher, limiting time in the sun, and wearing protective clothing, similar to the sun protection measures discussed in the 2007 proposed rule (72 FR 49070 at 49089). Nearly identical multi-step behavioral sun protection programs are advocated by a number of medical and public health organizations, including the American Academy of Dermatology, the Skin Cancer Foundation, and the American Cancer Society. We have concluded that a comprehensive sun protection approach is critical to ensure that consumers who are seeking to obtain a reduction in the risk of skin cancer and early skin aging limit their overall sun exposure. Without the reduction in consumers' overall UV exposure, even a sunscreen with Broad Spectrum SPF value of 15 or higher may not be effective in decreasing the risk of skin cancer and early skin aging. As discussed below, the available clinical studies do not control for these behavioral factors and, therefore, do not demonstrate that even this subset of sunscreens alone reduce the risk of skin cancer and early skin aging. However, based on the scientific understanding of the harm from UV exposure and our assessment of the study data, we have concluded that if consumers use sunscreens with Broad Spectrum SPF values of 15 or higher, limit time in the sun especially during the midday hours, and wear protective clothing when exposed to the sun, the resulting reduction in overall UV exposure will reduce the risk of skin cancer and early skin aging. Therefore, there is sufficient evidence of “clinically significant relief” to justify the indication and related directions for this subset of products, as set forth in the rule. However, we conclude that the omission of prominent information in the indication regarding the need for other sun protection measures would misbrand the product, as would the omission of the associated direction specifying these measures. Indeed, it would suggest a different indication than that which available evidence supports. Consequently, we have included in this final rule a new provision indicating that “Any labeling or promotional materials that suggest or imply that the use, alone, of any sunscreen reduces the risk of or prevents skin cancer or early skin aging will cause the product to be misbranded under section 502 of the FD&C Act (21 U.S.C. 352).” (new 21 CFR 201.327(c)(3)). c. Available Scientific Data We are not aware of any data other than what we reviewed in the 2007 proposed rule that evaluate the effectiveness of sunscreens in reducing the risk of skin cancer or early skin aging for healthy subjects. One more recent study, published in 2009, found that regular use of Broad Spectrum SPF 50+ sunscreen “may prevent” the development of actinic keratoses and non-melanoma skin cancer in immune-compromised organ transplant recipients (Ref. 19). We have not relied on this study in reaching our conclusions regarding OTC sunscreens, because we do not consider the immune-compromised study population to be representative of the general population. We have re-evaluated the data originally reviewed in preparing the 2007 proposed rule to determine whether those data support allowing the indication for all sunscreen products or only for certain sunscreen products. Based on our re-evaluation, we have concluded that the data is supportive of an indication for broad spectrum sunscreens having SPF values of at least 15. Further, we have determined that, while the existing evidence does not support a claim for the use of any sunscreen alone, it does support an indication that the combination of using a sunscreen with Broad Spectrum SPF value of 15 or higher along with other sun protection measures, reduces the risk of skin cancer and early skin aging, consistent with other positions in the 2007 proposed rule (72 FR 49070 at 49087 through 49090). To date, there are no clinical studies demonstrating that use of any sunscreen alone can prevent skin cancer. There are two prospective 4 studies that directly examine the role of sunscreen products in preventing skin cancer. Although it did not show any difference in primary endpoints, a large 1999 study conducted in Australia demonstrated that people who applied a Broad Spectrum SPF 15 sunscreen product on a daily basis over a 4.5 year period had a lower overall incidence of one type of skin cancer, squamous cell carcinoma, on the head, neck, arms, and forearms than study participants who did not apply sunscreen (28 cases in the broad spectrum sunscreen group vs. 46 cases in the group not using broad spectrum sunscreen) (Ref. 20). In an extension of that study, van der Pols et al. evaluated the same population of subjects over an additional 8 years, and found that the sunscreen users continued to have a statistically significant lower incidence of squamous cell carcinoma over the entire 12.5 year period (Ref. 21). Neither study found that daily sunscreen use had any measurable effect on the most common form of skin cancer, basal cell carcinoma. Further, we are not aware of any studies examining the effect of sunscreen use on the development of melanoma, which is the deadliest form of skin cancer. 4 A prospective study is designed to study subjects under pre-specified conditions. These studies differ from retrospective studies that try to prove hypotheses by assessing past experiences. Generally, prospective studies are superior to retrospective studies in demonstrating drug effectiveness. Although data from clinical studies addressing the specific end points of cancer is limited, some prospective studies have evaluated the effects of regular sunscreen use on the development of surrogate skin lesions that can be precursors to cancer: actinic keratoses and melanocytic nevi. A small percentage of actinic keratoses progress to squamous cell carcinomas (Ref. 22). At least four studies have demonstrated that the number of actinic keratoses is lower for individuals regularly using sunscreens with Broad Spectrum SPF values of 15 or higher (Refs. 23 through 26). We are not aware of any studies examining the potential effects on surrogate skin lesions of sunscreens that either are not broad spectrum or are broad spectrum with SPF values less than 15. Two prospective studies have shown that regular use of a Broad Spectrum SPF 30 sunscreen reduces the risk of developing melanocytic nevi, which can progress into melanomas (Ref. 22). In a 2000 study, Gallagher et al. examined the formation of new melanocytic nevi in 393 Canadian school children. The group of children given Broad Spectrum SPF 30 sunscreen product had fewer new nevi over the course of the three year study than did children not given sunscreen products or advice on sunscreen use (Ref. 27). The difference was small (24 v. 28 nevi, respectively), but statistically significant (p = 0.048). In a follow-up study published in 2005, Lee et al. evaluated the same group of children for differences in melanocytic nevi by location on the body and demographic factors (Ref. 28). These investigators found that the sunscreen group had significantly fewer new nevi on the trunk than the control group (p = 0.05). With respect to the role of sunscreen products in decreasing the risk of early skin aging, we are aware of only indirect evidence that sunscreen use decreases early skin aging. One recent study demonstrated that a broad spectrum sunscreen product can reduce the extent of solar UV-induced damage to factors associated with early skin aging even when the SPF value is less than 10 (Ref. 29). Although this study was small, evaluating only 12 Caucasian subjects, it shows the importance of broad spectrum protection. These findings have been corroborated in a large number of studies using broad spectrum sunscreens with SPF values ranging from 19 to 50, as reported by Fourtanier et al. in two recent reviews (Refs. 10 and 30). Neither those studies evaluating the long term effect of regular sunscreen use on the development of skin cancer and early skin aging nor those evaluating the long term effect of sunscreen use on surrogate markers for these conditions were adequately controlled. Such studies, which must take place over many years, make adequate controls extremely difficult, if not impossible to implement. For example, one cannot control for time and duration of exposure, application and re-application amounts, or use of supplemental behavioral measures such as wearing protective clothing for a study which takes place over several years. Despite their limitation, the results of the short-term effectiveness studies are consistent with our understanding that measures which significantly reduce UV exposure decrease the risk of skin cancer and early skin aging. UVA and UVB radiation is the only known external risk factor for skin cancer and early skin aging. Therefore, measures that significantly reduce both UVA and UVB exposure should decrease the risk of skin cancer and early skin aging. Based on this understanding, limiting time in the sun, wearing protective clothing and using a broad spectrum sunscreen with an SPF value of 15 or higher should decrease the risk of skin cancer and early skin aging. Using a broad spectrum sunscreen with an SPF value of 15 or higher ensures adequate breadth and magnitude of UVA and UVB protection. For these products, the broad spectrum test measures breadth and SPF test measures magnitude of UV protection. Consistent with this scientific principle, the short-term effectiveness studies demonstrate a decrease in the development of surrogates for skin cancer and early skin aging. Thus, we have concluded that the available evidence supports our finding that sunscreen products, in conjunction with limiting time in the sun and wearing protective clothing, reduce the risk of developing skin cancer or early skin aging. d. Indication Limited to Covered Sunscreens With Broad Spectrum SPF Values of 15 or Higher In light of the submissions requesting that we reframe our labeling information regarding sunscreen use and reduced risk of skin cancer and premature skin aging as an indication, we re-evaluated skin cancer and aging studies discussed in the 2007 proposed rule to determine whether the skin cancer and early skin aging indication should apply to all sunscreen products or be limited to certain sunscreen products. Available data support this indication only for broad spectrum sunscreens with SPF values of 15 or higher. Several reports have indicated that UV-induced skin damage associated with both skin cancer and early skin aging can be reduced by the use of broad spectrum sunscreens (Refs. 10 and 29 through 31). In a direct comparison of a broad spectrum sunscreen and a non-broad spectrum sunscreen with the same SPF, Moyal and Fourtanier found that the broad spectrum sunscreen provided significantly better protection from UV radiation-induced immunosuppression, a factor associated with both skin cancer and early skin aging (Ref. 32). Furthermore, the National Toxicology Program classified broad spectrum UV radiation as a known human carcinogen because it is not clear which UVB and/or UVA wavelengths contribute to the development of cancer (Ref. 15). Therefore, available data indicate that a broad spectrum sunscreen is necessary to reduce the risk of skin cancer. Likewise, we do not know which UVB and/or UVA wavelengths contribute to early skin aging. Therefore, it is reasonable to conclude that reducing the risk of early skin aging also requires a broad spectrum sunscreen (in conjunction with limiting time in the sun and wearing protective clothing). With regard to SPF value, the available study data concerning the use of sunscreens in reducing the risk of skin cancer is based on products with SPF values of 15 or higher. The sunscreen product used in the 1999 Australian study on skin cancer (squamous cell and basal cell carcinomas) had a Broad Spectrum SPF value of 16, and those that were found to reduce actinic keratoses and nevi had SPF values ranging from 16 to 46. The studies on early skin aging make it difficult to know for certain whether Broad Spectrum SPF values of 15 or higher are necessary to reduce the risk of early skin aging. However, we conclude that the data regarding the minimum sunscreen protection necessary to reduce the risk of skin cancer can be extrapolated to early skin aging. In many ways, the biological processes that take place in response to UV radiation are similar for both conditions. For both skin cancer and early skin aging, UV radiation causes damage in the skin that is not completely repaired and leads to cancer, fine lines, wrinkles, etc. Because the supporting data for a skin cancer claim are based on products with SPF values of 15 or higher, we are only allowing the skin cancer and early skin aging claim for covered sunscreen products that are broad spectrum and have SPF values of at least 15. This rule does not preclude approval of a new drug application including an indication for reduction in risk of skin cancer and early skin aging for any sunscreen product. To be approved, such an application must be supported by the submission of adequate data. This rule also does not preclude future amendment of the sunscreen monograph in 21 CFR part 352, if additional data are provided to support a similar indication for other types of sunscreens. e. Precedent for an Indication Statement That Includes Behavior Modification There is at least one other OTC drug product with an indication statement that describes not only the drug's intended effect but also one or more behavioral measures to ensure the effect. The indication statement on the weight loss aid orlistat states that the product is to be used “for weight loss in overweight adults, 18 years and older, when used along with a reduced-calorie and low-fat diet” (Ref. 33). The behavioral measure of reduced caloric intake is necessary for consumers to experience weight loss. A low-fat diet is necessary for consumers to avoid the undesirable side effect of diarrhea caused by consuming a high-fat diet while taking orlistat. The need to include reduced caloric intake as part of the indication statement for orlistat is similar to the need for including the use of other sun protection measures as part of the indication statement for sunscreens. Orlistat increases the likelihood of weight loss by preventing fat from being absorbed as food is digested in the stomach and intestines. If consumers take orlistat and decrease their caloric intake, they increase the likelihood of losing weight. However, if consumers increase their caloric intake while taking orlistat, they are less likely to lose weight. Orlistat's effect of preventing fat absorption could be offset by the high number of calories being eaten. Similarly, the reduction in UV exposure afforded by use of broad spectrum sunscreens with SPF values of 15 or higher can be offset if consumers increase their UV exposure by spending more time in the sun and/or wearing less protective clothing. This increased overall exposure could eliminate the effectiveness of sunscreen use in reducing the risk of skin cancer and early skin aging. The labeling of prescription cholesterol-lowering drug products ( i.e., statins) follows a similar principle by emphasizing that reduction of cholesterol levels requires not only use of the drug product but also a healthy diet. The National Institutes of Health (NIH) specifies therapeutic lifestyle changes that can be followed to lower levels of cholesterol in the blood (Ref. 34). These changes include following a diet restricted in saturated fat and cholesterol, exercising regularly, and managing weight. Used in conjunction with cholesterol reducing drugs (currently available only by prescription), these lifestyle changes improve the chance of effectively treating high cholesterol levels. Prescription cholesterol-lowering drug products include the behavioral step of following a low fat diet in the indication statement (Ref. 35). The body produces cholesterol, which the drug product inhibits to produce the desired drug effect of lowering cholesterol being made by the body. However, the total cholesterol circulating in the blood reflects cholesterol made by the body plus cholesterol absorbed from foods containing fats. Therefore, if consumers use a statin and minimize the amounts of food containing fats in their diet, then they will reduce the total cholesterol level in the blood. However, if consumers do not minimize the amounts of food containing fats in their diet, they may not reduce the total cholesterol in the blood. The decreased cholesterol production in the body caused by the statin may not be significant compared to the high amount of cholesterol derived from food eaten by consumers. In the same way that regularly taking an OTC weight loss aid or a prescription cholesterol-lowering drug product without also following a healthy diet may not result in the intended health effect, use of a sunscreen with Broad Spectrum SPF value of 15 or higher without also limiting time in the sun and covering sun-exposed areas may not result in a net reduction in the risk of developing skin cancer or early skin aging. For this reason, we are requiring that the indication statement allowed on sunscreens with Broad Spectrum SPF values of 15 or higher include all parts of the sun protection program and not suggest or imply that use of a sunscreen alone reduces the risk of skin cancer or early skin aging. C. Warnings We received submissions requesting that we revise warnings included in the 2007 proposed rule and that we add new warnings not included in the 2007 proposed rule (Ref. 1). In section IV.C.1 of this document, we discuss one new and one revised warning included in this final rule. We are adding the new warning “Do not use on damaged or broken skin” (new 21 CFR 201.327(d)(1)). We are revising the warning about skin rash (proposed 21 CFR 352.52(c)(3)): “Stop use and ask a doctor if skin rash occurs” to read “Stop use and ask a doctor if rash occurs.” In section IV.C.2 of this document, we discuss our revision to the proposed “Sun Alert” warning. Under this final rule, the warning proposed for all monograph sunscreens is replaced with an optional indication and required direction on covered sunscreens with Broad Spectrum SPF values of 15 or higher, while covered sunscreens that are broad spectrum with SPF values less than 15 or that do not provide broad spectrum protection will bear a revised warning, called the “Skin Cancer/Skin Aging Alert.” (new 21 CFR 201.327(d)(2)). In section IV.C.3 of this document, we discuss three new warnings that were requested in submissions, but are not being included in this document. Submissions argued that we should add warnings that the regular use of sunscreen products may cause vitamin D deficiency and may reduce the photoprotective effects of tanning. We also considered adding a warning concerning sunscreen products containing alpha hydroxy acids (AHAs). We are not adding any of these warnings because the available data do not support the need for these warnings. In summary, this document requires the following warnings on all covered OTC sunscreen products (new 21 CFR 201.327(d)): • “Do not use on damaged or broken skin” • “Stop use and ask a doctor if rash occurs” • “When using this product keep out of eyes. Rinse with water to remove.” For all covered sunscreen products that either are not broad spectrum or are broad spectrum with SPF values less than 15, this final rule also requires a “Skin Cancer/Skin Aging Alert” as the first statement under the heading Warnings. In addition to these warnings, all sunscreen products are required to include the “external use” and “keep out of reach of children” warning statements required on all topical OTC drug products (21 CFR 201.66(c)(5)(i) and (c)(5)(x)). 1. New and Revised Warnings for Damaged or Broken Skin and Rash The new warning that we are requiring on all covered sunscreen drug products reads, “do not use on damaged or broken skin.” We require this warning or a similar warning for other topical OTC drug products: • Acne treatments (21 CFR 333.350(c)(3)) • Skin protectants (21 CFR 347.50(c)(6)) • Antiperspirants (21 CFR 350.50(c)(1)) The safety data for these ingredients are based on application to intact ( i.e., unbroken or undamaged) skin. We do not have data of the safe use of these ingredients if the skin is not intact. For the same reason, the warning appears on sunscreen products marketed under new drug applications (NDAs). 5 Therefore, in this document, we are requiring this warning for all covered OTC sunscreen products, which are marketed without approved applications (new 21 CFR 201.327(d)(1)(i)). 5 NDAs 21-501, 21-502, 21-471, and 22-009. In addition to the new warning, we are revising the warning in proposed 21 CFR 352.52(c)(3): “Stop use and ask a doctor if skin rash occurs.” We are deleting the word “skin” so that the new warning reads: “Stop use and ask a doctor if rash occurs” (new 21 CFR 201.327(d)(1)(iii)). We received two submissions arguing that the word ”skin” is unnecessary in this warning because every rash is a skin rash (Ref. 1). We agree and are removing the word to make the warning more concise. Consumers will likely understand the warning without the word “skin.” 2. Revision of the Proposed “Sun Alert” Warning In 2007, we proposed a warning, based on the “Sun Alert” statement cited in the 1999 stayed sunscreen final rule (64 FR 27666 at 27679), as the first statement under the heading Warnings for all monograph sunscreen products regardless of SPF value or broad spectrum protection (proposed 21 CFR 352.52(c)(1)). As proposed, this warning would have stated, “UV exposure from the sun increases the risk of skin cancer, premature skin aging, and other skin damage. It is important to decrease UV exposure by limiting time in the sun, wearing protective clothing, and using a sunscreen.” Submissions regarding this proposed warning are discussed in section IV.B.2 of this document. As noted there, we agree that, as proposed, this warning included an implied indication that all sunscreens reduce the risk of skin cancer and skin aging. Under this final rule, we are no longer requiring a “Sun Alert” or similar warning on broad spectrum sunscreens with SPF values of 15 or higher covered by the rule. This decision is based on our re-evaluation of the available scientific data. We are now permitting an indication stating that, used as directed with other sun protection measures, these sunscreens reduce the risk of skin cancer and premature skin aging (new 21 CFR 201.327 (c)(2)). For these products we are also requiring a new direction statement (new 21 CFR 201.327(e)(1)(iv)). The direction states: Sun Protection Measures. [in bold font] Spending time in the sun increases your risk of skin cancer and early skin aging. To decrease this risk, regularly use a sunscreen with a Broad Spectrum SPF of 15 or higher and other sun protection measures including: [bullet] limit time in the sun, especially from 10 a.m.-2 p.m. [bullet] wear long-sleeved shirts, pants, hats, and sunglasses We have concluded that information about decreasing sun exposure and wearing protective clothing is more appropriate in “Directions” than in “Warnings.” These measures, in addition to use of a sunscreen with Broad Spectrum SPF value of 15 or higher, are necessary for the consumers' sun protection as part of a comprehensive program. For covered sunscreen products that do not provide broad spectrum protection or those that do provide broad spectrum protection with SPF values less than 15, we conclude that a warning regarding the risks of skin cancer and skin aging remains necessary. In light of comments received on the “Sun Alert” warning proposed in 2007, however, we are revising the text to read as follows: “Skin Cancer/Skin Aging Alert [in bold font]: Spending time in the sun increases your risk of skin cancer and early skin aging. This product has been shown only to help prevent sunburn, not [in bold font] skin cancer or early skin aging.” (new 21 CFR 201.327(d)(2). The title “Skin Cancer/Skin Aging Alert” more accurately and specifically conveys the nature of the warning that follows than the proposed “Sun Alert” warning, particularly since the products that will bear this statement are indicated to help prevent sunburn, one consequence of sun exposure. The first sentence of this warning is a factual statement similar in content to the opening statement of the warning proposed in 2007. Like the proposed “Sun Alert” warning, this statement alerts consumers to risks they continue to incur from sun exposure, the conditions under which they will make use of the product. The second sentence clarifies for users the limits on the benefits that the product in hand has been established to provide, specifying that these products have been shown to help prevent sunburn but have not been shown to reduce the risk of skin cancer or early skin aging. Inclusion of this warning is critical to help ensure that consumers do not mistakenly conclude that all sunscreens have been demonstrated to provide the same benefits. It will reinforce the distinction between sunscreens indicated only for preventing sunburn (those that have broad spectrum with SPF values below 15 or that are not broad spectrum) and sunscreens that have also been shown to reduce the risk of skin cancer and early skin aging when used as directed with other sun protection measures (those with Broad Spectrum SPF values of 15 or higher). This warning serves a similar purpose to one required on cosmetic suntanning preparations that do not contain a sunscreen ingredient, which likewise is intended to assist consumers in distinguishing among products that they might otherwise confuse. (See 21 CFR 740.19). 3. Warnings Requested in Submissions But Not Included in This Final Rule We considered adding the following three warnings: • Sunscreens may reduce the photoprotective effects of tanning • Increased sun sensitivity caused by alpha hydroxy acids (AHAs) in sunscreen products • Regular use of sunscreen products may cause vitamin D deficiency However, as discussed in this section of the document, we conclude that these warnings are not needed for the safe and effective use of sunscreen products. We received a submission arguing that we should require the following warning on all OTC sunscreen products containing UVA-protective active ingredients (Ref. 1): “The use of this product will prevent the development of photo-protective facultative pigmentation, a.k.a., a tan.” The submission implies that UVA protection is not only unnecessary but harmful to consumers. No data were included in the submission. We agree that tanning caused by UVA radiation offers some protection against sunburn. However, tanning, particularly when attributable to prolonged exposure to UVA radiation in tanning beds or booths, may also have harmful effects on the skin (Refs. 36 and 37). In addition, one study suggests that the protective effects of tanning are small, as a tan only appears to provide an SPF value of approximately 4 (Ref. 36). As stated in the 2007 proposed rule (72 FR 49070 at 49083), we do not know which UVA wavelengths cause specific types of damage ( e.g., skin cancer or early skin aging). We continue to assert, however, that protection against UVA radiation is important for consumers' health (72 FR 49070 at 49083). We have concluded that the warning suggested in the submission is not in the best interest of public health because the warning discourages consumers from using broad spectrum sunscreen products. Therefore, we are not requiring any warning related to tanning. We are not adding any additional warnings to sunscreen products containing AHAs. In the 2007 proposed rule, we requested comment on the need for additional warnings or directions on sunscreen products combined with AHAs (72 FR 49070 at 49110). We made this request in response to a 2005 guidance that we issued for cosmetic products containing alpha hydroxy acids (70 FR 1721, January 10, 2005). The guidance recommends the following warning be included on cosmetic products containing alpha hydroxy acids: “Sunburn Alert: This product contains an alpha hydroxy acid (AHA) that may increase your skin's sensitivity to the sun and particularly the possibility of sunburn. Use a sunscreen and limit sun exposure while using this product and for a week afterwards.” Many cosmetic products containing alpha hydroxy acids also contain sunscreens because the sunscreen helps protect the skin made sensitive to the sun by the alpha hydroxy acids. The guidance does not address products combining alpha hydroxy acids and sunscreens. Two submissions stated that additional warnings are not necessary on these products (Ref. 1). We agree with these submissions. We considered added a warning or other labeling to inform consumers that AHAs contained in some sunscreen products may make the consumer more likely to sunburn. However, the sunscreen component of such products would, in fact, protect consumers from sunburn. Furthermore, we have concluded that the addition of sunscreen active ingredients to AHA-containing cosmetic products provides valuable UV protection for consumers. Therefore, at this time, we have concluded that a warning about AHA is not necessary on OTC sunscreen products. The other new warning requested in submissions relates to vitamin D deficiency. We received six submissions arguing that consumers should be warned that frequent sunscreen use may result in vitamin D deficiency (Ref. 1). The submissions cite articles discussing the negative effects of vitamin D deficiency, such as growth retardation, rickets, and osteoporosis (Ref. 38). The submissions include numerous published articles concerning vitamin D, but only four clinical studies that directly examine the effect of sunscreen use on vitamin D levels. In the remainder of this section, we discuss the four studies included in submissions, as well as three additional studies that we located through a literature search. Collectively, the studies do not demonstrate that the use of sunscreen causes vitamin D deficiency. The term “vitamin D” refers to several forms of the vitamin, but the two forms important to humans are vitamin D 2 (ergocalciferol) and vitamin D 3 (cholecalciferol) (Ref. 39). Vitamin D 2 is obtained by eating vitamin D-rich foods such as fish or food fortified with vitamin D. The skin makes vitamin D 3 when it is exposed to sunlight (Ref. 40) and, therefore, vitamin D production may vary depending on the following factors: (1) Skin pigmentation, (2) age, (3) clothing, (4) season, (5) latitude, (6) time of day, (7) weather conditions, and (8) sunscreen application (Refs. 40-43). Vitamin D deficiency has long been associated with Ricketts, but recent research suggests that vitamin D deficiency may also be associated with other diseases (Ref. 38). However, the threshold of vitamin D blood levels that constitutes a deficiency is currently being re-evaluated by scientific experts (Refs. 40, 44, and 45). To determine whether sunscreen use causes vitamin D deficiency, we reviewed four clinical studies included in the submissions that explored the effect of sunscreen use on vitamin D levels as well as three studies that we identified in a literature search: • Matsuoka et al 1987 (Ref. 46) • Matsuoka et al 1988 (Ref. 47) • Marks et al. 1995 (Ref. 48) • Farrerons et al. 1998 (Ref. 49) • Kimlin et al., 2007 (Ref. 50) • Cusack et al., 2008 (ref. 51) • Hoesl et al., 2010 (Ref. 52). All but one of these studies assessed 25-hydroxyvitamin D levels because 25-hydroxyvitamin D is typically used as the biological marker for vitamin D (in the D 2 or D 3 form) (Ref. 53). Much of the data available in the literature involves nonclinical studies, which can be difficult to extrapolate to consumer (human) actual use conditions. Studies with clinical data provide more meaningful results because, if adequately designed, they can be more easily extrapolated to consumer actual use conditions. Therefore, we are focusing discussion in this document on the clinical studies. In the 1987 study by Matsuoka et al., four subjects applied a sunscreen product with an unknown SPF to the entire body, while four control subjects did not apply any topical product (Ref. 46). All of the subjects were exposed to 1 MED 6 of UV radiation (260-330 nm 7 ) and then vitamin D 3 levels were monitored for 15 days. The subjects using sunscreen product applied the sunscreen product [Text truncated at 120,000 characters. The full text is on the page linked above.] --- Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A2011-14766. Public record. Not legal advice.