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TABLE 11a—UNIQUE PERSONS OVER PERCENTAGES OF PROPOSED POSITION LIMIT LEVELS, JANUARY 1, 2013, TO DECEMBER 31, 2014—Continued

Unique persons over level Commodity type/core referenced futures contract Percent of Spot month level (physical- Spot month Single month All months delivery) (cash-settled)

80 49 63 7 9 100 31 44 (*) 6 500 — 5 — — NYMEX RBOB Gasoline (RB) ...... 60 97 57 26 30 80 67 52 15 17 100 36 37 11 12 500 — (*) — —

Metals

COMEX Copper (HG) ...... 60 12 — 61 62 80 9 — 37 40 100 4 — 29 30 COMEX Gold (GC) ...... 60 13 — 22 24 80 9 — 14 14 100 5 — 10 11 COMEX Silver (SI) ...... 60 9 — 34 32 80 4 — 20 21 100 (*) — 16 16 NYMEX Palladium (PA) ...... 60 9 — 12 13 80 5 — 9 5 100 (*) — 4 4 NYMEX Platinum (PL) ...... 60 11 — 29 29 80 7 — 18 18 100 (*) — 9 9 Legend: * means fewer than 4 unique owners exceeded the level. — means no unique owner exceeded the level. NA means not applicable.14

Both comment periods will reopen on DEPARTMENT OF HEALTH AND because the currently available data are February 26, 2015, and will close on HUMAN SERVICES insufficient to classify it as GRASE and March 28, 2015. not misbranded, and additional Food and Drug Administration information is needed to allow us to Issued in Washington, DC, on February 19, determine otherwise. 2015, by the Commission. 21 CFR Part 310 Christopher J. Kirkpatrick, DATES: Submit either electronic or [Docket Nos. FDA–2003–N–0196 (Formerly written comments on this proposed Secretary of the Commission. 2003N–0233), FDA–1978–N–0018 (Formerly order by April 13, 2015. Sponsors may Note: The following appendix will not 1978N–0038 and 78N–0038), and FDA–1996– submit written requests for a meeting N–0006 (Formerly 96N–0277)] appear in the Code of Federal Regulations. with FDA to discuss this proposed order Over-the-Counter Sunscreen Drug by March 27, 2015. See section VI for Appendix to Position Limits for Products—Regulatory Status of the proposed effective date of a final Derivatives and Aggregation of Enzacamene order based on this proposed order. Positions Reopening of Comment ADDRESSES: You may submit comments Periods—Commission Voting Summary AGENCY: Food and Drug Administration, by any of the following methods: HHS. On this matter, Chairman Massad and ACTION: Proposed order; request for Electronic Submissions Commissioners Wetjen, Bowen, and comments. Submit electronic comments in the Giancarlo voted in the affirmative. No following way: Commissioner voted in the negative. SUMMARY: The Food and Drug Administration (FDA or the Agency) is • Federal eRulemaking Portal: http:// [FR Doc. 2015–03834 Filed 2–24–15; 8:45 am] issuing a proposed sunscreen order www.regulations.gov. Follow the BILLING CODE 6351–01–P (proposed order) under the Federal instructions for submitting comments. Food, Drug, and Cosmetic Act (the Written Submissions FD&C Act), as amended by the Sunscreen Innovation Act (SIA). The Submit written submissions in the proposed order announces FDA’s following ways: tentative determination that • Mail/Hand delivery/Courier (for 14 Table notes: (1) Aggregation exemptions were not used in computing the counts of unique enzacamene is not generally recognized paper submissions): Division of Dockets persons; (2) the position data was for futures, as safe and effective (GRASE) and is Management (HFA–305), Food and Drug futures options and swaps that are significant price misbranded when used in over-the- Administration, 5630 Fishers Lane, Rm. discovery contracts (SPDCs). counter (OTC) sunscreen products 1061, Rockville, MD 20852.

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Instructions: All submissions received to be marketed in the United States received, and for which a TEA feedback must clearly identify the specific active without an approved new drug letter had not yet been issued (section ingredient (enzacamene) and the Docket application (NDA) or abbreviated new 586C(b)(4) of the FD&C Act (21 U.S.C. Nos. FDA–2003–N–0196, FDA–1978–N– drug application (ANDA). Because this 360fff–3(b)(4)), as amended by the SIA). 0018, and FDA–1996–N–0006 for this proposed order specifically addresses an Other provisions of the SIA that are not rulemaking. All comments received may OTC sunscreen active ingredient discussed in this proposed order be posted without change to http:// (enzacamene), the remainder of this address procedures applicable to other www.regulations.gov, including any discussion will refer only to ‘‘active pending and future sunscreen active personal information provided. For ingredients.’’ ingredient GRASE determinations, additional information on submitting Critical steps in a proceeding under pending and future GRASE comments, see the ‘‘Comments’’ heading the TEA regulation include the determinations for OTC products other of the SUPPLEMENTARY INFORMATION following: (1) FDA’s determination that than sunscreens, issuance of specified section of this document. an active ingredient had been marketed guidances and reports, and completion Docket: For access to the docket to for the proposed OTC use for a material of pending sunscreen rulemakings, read background documents or time and to a material extent (eligibility among others. comments received, go to http:// determination), and public call for A proposed sunscreen order under the www.regulations.gov and insert the submission of safety and efficacy data, SIA is an order containing FDA’s docket numbers, found in brackets in followed by; (2) review of safety and tentative determination proposing that a the heading of this document, into the efficacy data submitted by the sponsor nonprescription sunscreen active ‘‘Search’’ box and follow the prompts or other interested parties; and (3) ingredient or combination of and/or go to the Division of Dockets FDA’s initial determination that the data ingredients: (1) Is GRASE and is not Management, 5630 Fishers Lane, Rm. show the active ingredient to be either misbranded when marketed in 1061, Rockville, MD 20852. GRASE or not GRASE for OTC use accordance with the proposed order; (2) Submit requests for a meeting with under the applicable monograph is not GRASE and is misbranded; or (3) FDA to discuss this proposed order to conditions (including any new is not GRASE and is misbranded Kristen Hardin (see FOR FURTHER conditions rising from FDA’s review) because the data are insufficient to INFORMATION CONTACT). (GRASE determination). Under the TEA classify the active ingredient or FOR FURTHER INFORMATION CONTACT: regulation, FDA’s GRASE combination of ingredients as GRASE Kristen Hardin, Division of determinations are effectuated through and not misbranded, and additional Nonprescription Drug Products, Center notice and comment rulemaking to information is necessary to allow FDA for Drug Evaluation and Research, Food amend or establish the appropriate to determine otherwise (section 586(7) and Drug Administration, 10903 New monograph. of the FD&C Act, as amended by the Hampshire Ave., Bldg. 22, Rm. 5491, The TEA process in FDA regulations SIA). Publication of a proposed Silver Spring, MD 20993–0002, 240– was supplemented by Congress’s sunscreen order triggers several 402–4246. enactment of the SIA. Among other timelines under the SIA, including a 45- SUPPLEMENTARY INFORMATION: amendments it makes to the FD&C Act, day public comment period, and a 30- the SIA creates new procedures I. Regulatory Background day period in which a sponsor may specifically for reviewing the safety and request a meeting with FDA to discuss A. Regulatory and Statutory Framework effectiveness of nonprescription the proposed order. sunscreen active ingredients, including The data and information addressed those, such as enzacamene, that were B. FDA’s Review of Enzacamene in this proposed order were originally the subject of pending TEA proceedings Buchanan Ingersoll submitted a TEA submitted for review under FDA’s Time at the time the SIA was enacted. Like and Extent Application (TEA) in 2002 on behalf of Merck KGaA under the TEA regulation, the SIA calls for an § 330.14(c) seeking OTC monograph regulation, § 330.14 (21 CFR 330.14), a initial eligibility determination phase process that has since been status for the sunscreen active for nonprescription sunscreen active ingredient enzacamene (also known as supplemented with new statutory ingredients, followed by submissions of procedures established in the SIA (Pub. 4-Methylbenzylidene Camphor (4-MBC) safety and efficacy data and a GRASE or Eusolex 6300) at concentrations up to L. 113–195), enacted November 26, determination phase. However, the SIA 2014. The discussion that follows 4 percent for use in OTC sunscreen requires FDA to make proposed and products (enzacamene TEA) (Note 1). briefly describes and compares the pre- final GRASE determinations for and post-SIA processes as they apply to FDA issued a TEA notice of eligibility nonprescription sunscreen active for enzacamene on July 11, 2003 (68 FR the regulatory status of enzacamene. ingredients in the form of administrative The TEA regulation established a 41386), stating that enzacamene at orders rather than the multistep public process through which a sponsor could concentrations of up to 4 percent is rulemaking required by the TEA request that an active ingredient or other eligible to be considered for inclusion in regulation, and establishes strict OTC condition,1 the OTC sunscreen monograph (21 CFR particularly one not timelines for the necessary previously marketed in the United part 352, currently stayed) and calling administrative actions. for submission of safety and States, be added to an OTC drug Among other requirements, no later effectiveness data for enzacamene. In monograph to enable compliant OTC than 90 days after the SIA was enacted response, a submission of data dated drug products containing the condition (i.e., no later than February 24, 2015), October 9, 2003, was made to the docket FDA must publish a proposed sunscreen 1 on behalf of Merck KGaA (enzacamene For purposes of OTC drug regulation, a order in the Federal Register for any ‘‘condition’’ is defined as an active ingredient or data submission) (Note 2), which nonprescription sunscreen active botanical drug substance (or a combination of active referred to materials previously ingredients or botanical drug substances), dosage ingredient, including enzacamene, for submitted to other dockets.2 At the time form, dosage strength, or route of administration which, on the date of enactment, an marketed for a specific OTC use, with specific exclusions (see § 330.14(a)(2)). This document will eligibility determination had been 2 These include FDA–1978–N–0018–0744–0756 refer simply to new ‘‘active ingredients,’’ since that issued under the TEA regulation and (Sup 24, 25, 26, 27 and 28), Request to Reopen is the condition under consideration. submissions of safety and efficacy data Continued

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the SIA was enacted, FDA had not corroborated by unpublished studies all requirements applicable to issued a TEA feedback letter or and other data (§ 330.10(a)(4)(i) (21 CFR nonprescription drugs would be GRAS otherwise responded to that submission. 330.10(a)(4)(i))). for use as labeled. To demonstrate that In accordance with new section FDA’s OTC drug regulations generally these requirements are met for 586C(b)(4) of the FD&C Act as amended identify the types of information that enzacamene, initial safety testing should by the SIA, we are issuing this notice as may be submitted as evidence that an be performed using enzacamene as the a proposed order for enzacamene. Based active ingredient or other OTC drug sole active ingredient up to the highest on our review of the available safety and condition is safe, as part of the concentration for which marketing efficacy data, we have made a tentative consideration of whether an active status is sought and eligibility has been determination that enzacamene is not ingredient or other condition is GRASE established: 4 percent. If initial testing GRASE and is misbranded because the (§ 330.10(a)(2)). For convenience, this suggests a particular safety concern data are insufficient to classify it as order uses the term ‘‘generally associated with enzacamene (e.g., a GRASE and not misbranded for use in recognized as safe (GRAS)’’ to refer to hormonal activity), FDA may request OTC sunscreens, and additional that aspect of the GRASE determination. additional studies to address that information is necessary to allow us to To apply the general OTC safety concern. determine otherwise. The remainder of standard to each potential new this proposed sunscreen order describes condition, FDA uses its scientific A. Human Safety Data our review of the available safety and expertise to determine what constitutes 1. Human Irritation, Sensitization, and efficacy data, identifies additional data ‘‘adequate tests by methods reasonably Photosafety Studies needed to demonstrate that enzacamene applicable to show the drug is safe under the prescribed, recommended, or Studies of skin irritation, is GRASE for the requested use, and sensitization, and photosafety are explains our rationale for specific suggested conditions of use.’’ In assessing what specific testing or other standard elements in the safety conclusions and data requirements. evaluation of topical drug products that, This proposed order will be open for data are needed to adequately like enzacamene-containing sunscreens, public comment (see DATES). The demonstrate the safety of enzacamene are applied to the skin repeatedly over sponsor may request a meeting with for use in sunscreen, FDA considers the long periods of time. FDA recommends FDA to discuss this proposed order (see circumstances under which OTC separate studies for skin irritation and DATES). We also invite the sponsor to sunscreen products that could contain sensitization. Skin irritation studies submit additional safety and/or efficacy enzacamene would be used by should generally include at least 30 data to inform our further consideration, consumers. evaluable subjects and should evaluate as publication of a final sunscreen order When used as directed with other sun the test formulation (i.e., enzacamene in under the SIA for enzacamene will be protection measures, broad spectrum an appropriate test vehicle), the vehicle contingent on receipt of such OTC sunscreen products with a sun alone, and both negative and positive information. (See section 586C(b)(9)(ii) protection factor (SPF) value of 15 or controls. Skin sensitization studies of the FD&C Act.) We specifically higher strongly benefit the public health generally should include at least 200 encourage the sponsor to discuss any by decreasing the risk of skin cancer and subjects and should evaluate the test proposed study protocols with us before premature skin aging associated with formulation containing enzacamene, the performing the studies. solar ultraviolet (UV) radiation, as well as by helping to prevent sunburn. vehicle, and a negative control. For both II. Safety Data Considerations for OTC (Sunscreens with lower SPF values, or irritation and sensitization studies, test Sunscreen Products Containing without broad spectrum protection, also site applications should be randomized Enzacamene help prevent sunburn.) When used as and the test observer blinded to the In evaluating the safety of a proposed directed by the required labeling, all identities of the test formulations. monograph active ingredient, FDA OTC sunscreen products are applied FDA recommends that photosafety applies the following regulatory liberally to the skin and reapplied evaluation generally involve studies of standard: Safety means a low incidence frequently throughout the day skin photoirritation (phototoxicity) and of adverse reactions or significant side (§ 201.327(e) (21 CFR 201.327(e))). skin photosensitization effects under adequate directions for use Because the effects of UV exposure are (photoallergenicity). General principles and warnings against unsafe use as well cumulative, to obtain the maximum for designing and conducting as low potential for harm which may benefit, users of broad spectrum photosafety studies are described in result from abuse under conditions of sunscreens with an SPF value of 15 or FDA guidance (Ref. 1). Photosafety widespread availability. Proof of safety higher are directed to use such products studies, like sensitization and irritation shall consist of adequate tests by regularly—on a routine basis (id.). Given studies, should be conducted using methods reasonably applicable to show these conditions of use, our safety enzacamene 4 percent in an appropriate the drug is safe under the prescribed, evaluation of an OTC sunscreen active test vehicle, the vehicle alone, and a recommended, or suggested conditions ingredient such as enzacamene must negative control. In addition, of use. This proof shall include results consider both short-term safety concerns phototoxicity studies should include at of significant human experience during (such as skin sensitization/irritation and least 30 evaluable subjects and marketing. General recognition of safety photosafety) and potential concerns photoallerginicity studies should shall ordinarily be based upon related to long-term sunscreen use, include at least 45 evaluable subjects. including potential systemic exposure published studies which may be Data Available for Enzacamene: Human via dermal absorption. The purpose of the safety testing Irritation, Sensitization, and Photosafety Rulemaking Record Respect Sunscreen Drug Studies Products for OTC, submitted on April 12, 1999 described in this section II is to (1999 enzacamene submission); FDA–1978–N– establish whether an OTC sunscreen We reviewed the submitted study 0018–0766, Citizen Petition (CP1), submitted on product containing enzacamene and reports for human safety studies, December 17, 1980; and Tracking number: 805596eb Legacy Doc. ID, SUP 5, ‘‘Supplement otherwise marketed under the including a skin irritation and from Rona Pearle’’ SUP5, submitted on August 15, conditions described in a final sensitization study of enzacamene 5 1985. sunscreen order and in accordance with percent in 30 subjects (Note 3); skin

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irritation and sensitization study of potential safety signals. To ensure that that these studies were conducted in the enzacamene 5 percent in 10 subjects maximum penetration of enzacamene 1980s and the limit of analytical (Note 4); a photoirritation study of 4 has taken place and chances of it being detection for enzacamene was much percent enzacamene in 5 subjects (Note detected are optimal, studies should higher than it is today. 5); and two photosensitization studies, continue until steady state is reached. A review of the published literature one using 4 percent enzacamene in 5 General information and identified more recent studies related to subjects and the other using an recommendations on the design and the extent of absorption of enzacamene unknown concentration in 25 subjects conduct of human pharmacokinetic in humans after dermal application. A (Notes 6 and 7). Although these studies studies can be found in FDA guidance 2004 article from Janjua et al. (Ref. 3) suggest that enzacamene may not be a (Ref. 2). To support a GRAS reports on the absorption from a primary irritant, sensitizer, determination for enzacamene (up to 4 formulation containing 10 percent photosensitizer, or photoirritant, each of percent), such a study should be enzacamene and 2 other active the submitted studies has limitations, conducted under maximal use sunscreen ingredients after whole body such as inadequate sample size, lack of conditions using enzacamene 4 percent application for 4 days in 15 healthy blinding, and lack of positive and in various vehicles, including vehicles males and 17 postmenopausal females. negative controls, that prevent us from that would be expected to enhance The article provides only summary making definitive conclusions. In absorption. We encourage study bioavailability information but claims addition, protocol information, such as sponsors to consult with us before that the maximum plasma the inclusion and exclusion criteria conducting pharmacokinetic studies, concentrations were 20 milligrams (mg)/ used in subject selection, was not because the properties of enzacamene milliliter (mL) in both men and women consistently provided. bear on the optimal design. and that increasing plasma levels of FDA concludes that the data enzacamene and metabolites were seen, Data Available for Enzacamene: Human submitted are not sufficient to assess the suggesting the presence of Dermal Pharmacokinetic dermal safety of enzacamene and accumulation. It is noted that thyroid (Bioavailability) and Clinical specifically its potential to cause function was also assessed during this Pharmacology Studies irritation, sensitization, photoirritation, study, but results are confounded by the or photoallergenicity. We recommend We reviewed three submitted reports simultaneous application of three active submission of additional data from of dermal absorption studies in humans sunscreen ingredients. A 2006 article human irritation, sensitization, and in which percutaneous absorption was from Shauer et al. (Ref. 4) includes in photosafety studies to demonstrate that estimated using radiolabeled (14C) vivo pharmacokinetic data from six an OTC sunscreen containing up to 4 formulations of enzacamene. In one healthy volunteers exposed to 4 percent percent enzacamene is not an irritant, study (Note 8) a 14C-labeled 5 percent enzacamene applied over 90 percent sensitizer, photosensitizer, or formulation of enzacamene was applied body surface area for a 12-hour period. photoirritant. to the lower arms of six volunteers for The data are limited by the small 6 hours, followed by a 3-day collection number of subjects included; however, 2. Human Dermal Pharmacokinetic of urine and feces. Investigators there was gender-related difference (Bioavailability) Studies reported that approximately 54.6 observed in those males who had blood Because sunscreens are topically percent of the 14C-activity applied to the levels that were approximately twice applied, another important safety skin was recovered. An average of 0.76 that of females. A 2008 article by Janjua consideration for enzacamene for use in percent enzacamene was recovered in et al. contains a more complete analysis sunscreens is whether dermal urine and 0.14 percent in the feces. In of in vivo absorption for enzacamene in application may result in skin a second study (Note 9), investigators a 10 percent enzacamene formulation penetration and systemic exposure to reported a total recovery of 98.2 percent (Ref. 5). The levels of absorption were enzacamene, and if so, to what extent. and 90.7 percent overall recovery of the generally low but accumulation was A well-designed and -conducted human 14C-activity applied to the skin from two observed. However, the age of the dermal pharmacokinetic study can be volunteers, respectively. The third study females enrolled in the study was 2 to expected to detect and quantify the report (Note 10) was similar to the 3 times that of the males, confounding presence of enzacamene and/or any previous two studies in terms of the the interpretation of age or gender metabolites in blood or other bodily general design. Following the analysis effects. fluids that may have a bearing on safety, of the data from the planned six Overall, the data available are using recognized parameters such as volunteers, two more volunteers were incomplete for the assessment of human bioavailability percentage, maximum enrolled to evaluate the low observed bioavailability (dermal absorption) of plasma concentration (Cmax), time to recovery (54 to 69 percent) of the enzacamene. Accordingly, we request maximum plasma concentration (Tmax), radiolabeled enzacamene. A different data from human pharmacokinetic total area under the plasma recovery schema was applied to these studies to assess potential for and extent concentration versus time curve (AUC), last two patients with satisfactory of systemic absorption. These studies half-life, clearance, and volume of results in line with the previous studies. should be performed under expected distribution. This information can help As to the utility of the aggregate data, maximal-use conditions with the identify potential safety concerns and we cannot draw definitive conclusions proposed maximum concentration as help determine whether an adequate regarding the dermal absorption of discussed previously. safety margin for sunscreens containing enzacamene based on these studies. The In addition to the bioavailability data enzacamene exists. FDA recommends overall number of subjects was low, the described previously, three reports of that the pharmacokinetic studies studies were single-dose studies, a clinical pharmacology studies were performed on enzacamene also collect limited surface area was exposed to the submitted that evaluate the potential additional safety-related data from formulation, the recovery of effect of enzacamene on thyroid regularly scheduled physical radioactivity was variable, and finally function. The first was a pilot study in examinations, collection of vital signs, no blood or other body fluids were which a 5 percent enzacamene and other measures, which may help sampled to provide direct information formulation was applied twice, at 3- capture adverse skin events or other about systemic exposure. We also note hour intervals, to the abdomen and back

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of four adult subjects (two males and concentration up to 4 percent is safe for and regulatory reporting requirements two females) (Note 11). Subsequent use in finished cosmetic products for that differ from those in the United increases in the thyroid analytes whole body application (Ref. 6). If, after States, we nonetheless consider such thyroid-stimulating hormone (TSH), T3, full review of nonclinical toxicology information to be strongly relevant both and T4 were observed in some subjects. data (discussed in section I.B of this to our overall GRASE assessment of Blood and urine levels of enzacamene proposed order) and any additional enzacamene for use in sunscreens and were reported to have been measured clinical data, concerns exist regarding to our consideration of potential but no data were reported. We consider enzacamene’s thyroid safety, we will product labeling. FDA recognizes that the number of subjects in this study too recommend that additional clinical such information may not be available small to draw conclusions about the study be carried out. It is recommended from all countries; where that is the safety of enzacamene. In addition, there that we be consulted regarding the study case, please provide a written were missing data and the report lacked protocols prior to commencement of explanation for the lack of data. Overall, information about whether subjects’ such investigations. we seek sufficient data to characterize thyroid analyte levels exceeded normal 3 3. Human Safety Data To Establish enzacamene’s adverse event profile. levels. A second study evaluated the effect Adverse Event Profile Data Available for Enzacamene: Human on thyroid function of topical An evaluation of safety information Safety Data To Establish Adverse Event application of 5 percent enzacamene (6 from adverse event reports and other Profile grams (g) applied twice, at 3-hour safety-related information derived from The 1999 enzacamene submission intervals) in nine healthy volunteers commercial marketing experience of states that no complaints from (Note 12). This was a double-blind, sunscreen products containing customers concerning tolerance or placebo-controlled, crossover design enzacamene, as well as from other adverse reactions had been reported for study, and investigators reported that sources, is a critical aspect of FDA’s enzacamene by the cosmetic industry there was a statistically significant safety review for enzacamene. The TEA during the prior 10 years (Note 14). This lowering of mean T3 and T4 values in regulation under which the original information was referred to in the 2002 the active treatment group at 24 hours request for enzacamene was submitted TEA submission and the 2003 after application. Although larger than specifically calls for submission of enzacamene data submission. The 1999 the pilot study, this is a small single- information on all serious adverse drug enzacamene submission also included a dose study and the changes reported experiences, as defined in 21 CFR literature search for adverse reactions to were small relative to placebo and were 310.305(a) and 314.80(a), from each enzacamene from the following of questionable clinical significance. country where the active ingredient or databases: Medline (1966–1998), Interpretation of the results is also other condition has been or is currently Derwent Drug File (1983–1998), and hampered by the fact that some analytes marketed as either a prescription or CCSearch (week 3 1998–week 48 1998) (TSH and free T4) were below normal OTC drug; in addition, it calls for (Note 15). There were 17 articles levels at baseline. submission of all data generally reviewed which had been published or A third study was a parallel-group, specified in § 330.10(a)(2), which translated into English. Of these, 10 placebo-controlled design in which 48 includes documented case reports and articles describe contact dermatitis and subjects received treatment with either identification of expected or frequently resultant positive photopatch testing in enzacamene (5 g of a 6 percent reported side effects (§ 330.14(f)(1) and one or two patients. The 7 other articles enzacamene formulation per dose) or (f)(2)). To evaluate enzacamene, FDA are literature or case series reviews of placebo twice daily for 14 days (Note continues to seek individual adverse up to 400 patients, describing 13). According to the investigators, the drug experience reports, a summary of dermatologic adverse reactions to results of the study did not reveal any all serious adverse drug experiences, sunscreen use and subsequent significant differences in thyroid and expected or frequently reported side photopatch testing. On the whole, these function tests between enzacamene and effects of the condition (id.). To assist in reports suggest that enzacamene has the placebo, although there was a small the Agency’s safety evaluation of potential to cause contact allergy and between-group difference in thyroid enzacamene, FDA emphasizes our need photocontact allergy. However, data volume gland decrease (a 1.7 percent for the following data: from this literature have limitations. In reduction in the enzacamene arm and • A summary of all available reported some cases, the testing methodology an increase of 3.1 percent in the placebo adverse events potentially associated used to determine that enzacamene is an group). The quality of the study report with enzacamene; allergen is not described. Also, some of • submitted is inadequate to be used to All available documented case the test formulations used are not verify the analyses, but no adverse reports of serious side effects • described. It is conceivable that the events of hypothyroidism or Any available safety information observed reactions may have been hyperthyroidism or abnormal thyroid from studies of the safety and specific to particular test formulations, function tests were reported. effectiveness of enzacamene in humans; including formulations containing other The three clinical pharmacology and • active ingredients. studies submitted are insufficient either Relevant medical literature The submitted information and to substantiate or dismiss clinical describing adverse events associated literature do not fulfill the criteria concerns related to potential thyroid with enzacamene. Submissions of described previously. To support the effects from enzacamene. We request adverse event data should also include evaluation of safety of enzacamene for submission of any additional clinical a description of how each country’s thyroid function data or analyses that system identifies and collects adverse 3 See 67 FR 3060 at 3069 (January 23, 2002) have not yet been submitted to us, events, unless this information has been (agreeing that the absence of an adverse experience including any provided to the European previously submitted as part of reporting system in a foreign country for drugs or Scientific Committee on Cosmetic enzacamene’s TEA package. cosmetics does not necessarily mean that a condition cannot be GRAS/E. The GRAS/E Products and Nonfood Products Although we recognize that adverse determination will be based on the overall quality (SCCNFP) to support its 2008 event data from foreign marketing of the data and information presented to conclusion that enzacamene at a experience may reflect patterns of use substantiate safety and effectiveness).

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use in OTC sunscreens, we request that 21) weight in males; and increased uterine the sponsor either supplement the data Æ Photosensitization (guinea pig) weight, decreased ovarian weight, and already submitted, including more (Note 22) altered sexual behavior in females. recent adverse drug experience data, or • Repeat-dose toxicity studies Overall, we cannot arrive at a final explain why such data cannot be Æ 17 days oral (rat) (Note 23) determination about the findings provided. Æ 4 weeks oral (rat) (Note 24) described in the literature until we Æ 13 weeks oral (rat) (Note 25) receive a complete nonclinical B. Nonclinical (Animal) Studies Æ Liver enzyme induction study (rat) assessment as described in sections Another important element of FDA’s (Note 26) II.B.1 through II.B.3. GRAS review of enzacamene for use in • Genotoxicity and mutagenicity assays We did not receive data from sunscreens is an assessment of data Æ Chromosome aberration assay toxicokinetic or dermal or systemic from nonclinical (animal) studies that (Chinese hamster V79 cells) (Note carcinogenicity studies. Upon characterize the potential long-term 27) assessment of all available information dermal and systemic effects of exposure Æ Mutagenicity (Salmonella for enzacamene and based on the to enzacamene. Even if the typhimurium) (Note 28) nonclinical studies currently bioavailability data discussed in section Æ Photomutagenicity (S. recommended to support sunscreen II.A.2 suggest that dermal application is typhimurium, Escherichia coli) development, the following nonclinical unlikely to result in skin penetration (Note 29) studies are recommended to support the and systemic exposure to enzacamene, • Reproductive and developmental safety of enzacamene: FDA still considers data on the effects toxicity studies • Dermal and systemic of systemic exposure to be an important Æ Orienting tests for embryotoxicity carcinogenicity aspect of our safety evaluation of (rabbit) (Note 30) • Fertility enzacamene. A determination that Æ Toxicological investigation • Prenatal/postnatal toxicity enzacamene up to 4 percent is GRASE (incubated hen’s egg) (Note 31) • Toxicokinetics for use in sunscreens would permit its Æ Teratogenicity (rat) (Note 32) Additional discussion of study use in as-yet-unknown product Based on the submitted studies, acute formulations, which might in turn alter findings and data gaps are provided in toxicity was low. However, the standard the following subsections. the skin penetration of the active battery of tests detected findings that we ingredient. Therefore, an understanding will consider further as additional data 1. Carcinogenicity Studies: Dermal and of the effects of enzacamene, were become available to inform our GRAS Systemic systemic exposure to occur, is critical to assessment. Studies submitted by the FDA guidance recommends that determine whether and how regulatory sponsor showed an increase in thyroid carcinogenicity studies be performed for parameters can be defined to assure that weight and changes in thyroid function any pharmaceutical that is expected to all conforming enzacamene-containing that included an increase in T3 and be clinically used continuously for at sunscreens would be GRASE as labeled. TSH, along with a decrease in T4. Other least 6 months or ‘‘repeatedly in an FDA recommends animal testing of thyroid findings included follicular intermittent manner’’ (Refs. 26, 27, and the potential long-term dermal and epithelium hypertrophy and 28). Because the proposed use of systemic effects of exposure to hyperplasia. A decrease in adrenal and enzacamene in OTC sunscreens falls enzacamene because these effects prostate weights, and alterations in within this category, these studies cannot be easily assessed from previous ovarian weights (an increase was seen in should be conducted to help establish human use. Taken together, the some studies while decreased weight that enzacamene is GRAS for its carcinogenicity studies, developmental was noted in others), was documented proposed use. Carcinogenicity studies and reproductive toxicity studies, and with a no observed adverse effect level assist in characterizing potential dermal toxicokinetic studies described in (NOAEL) of 25–30 mg/kilograms (kg)/ and systemic risks by identifying the sections II.B.1 through II.B.3 should day (Note 33). type of toxicity observed, the level of provide the information needed to To followup on these findings, we exposure at which toxicity occurs, and characterize both the potential dermal identified published literature that the highest level of exposure at which and systemic toxic effects and the levels describes related enzacamene activity. A no adverse effects occur (i.e., NOAEL). of exposure at which they occur. These number of these articles indicate that The NOAEL would then be used in data, when viewed in the context of exposure to enzacamene at high doses determining the safety margin for human exposure data, can be used to has been associated with hormonal human exposure to sunscreens determine a margin of safety for use of changes. Among the in vitro findings containing enzacamene. enzacamene in OTC sunscreens. (Refs. 7 through 16), a number of articles Systemic carcinogenicity studies can Data Available for Enzacamene: described the in vitro binding activity of also help to identify other systemic or Nonclinical (Animal) Studies Generally enzacamene to estrogen (ER) and organ toxicities that may be associated The enzacamene submissions androgen (AR) receptors where it was with enzacamene, such as hormonal + included data from the following types able to bind to ER but showed effects. For example, the effect of of nonclinical safety studies: inconsistent binding activity at ERa persistent disruption of particular receptors. No androgenic activity and • Acute-dose toxicity studies endocrine gland systems (e.g., Æ Oral toxicity (rats, dogs) (Note 16) mixed results for antiandrogenic activity hypothalamic-pituitary-adrenal axis), if Æ Dermal toxicity (rats) (Note 17) were also documented. any, can be captured by these assays. Æ Intraperitoneal toxicity (rats) (Note Other effects of enzacamene included in vivo alterations of reproductive Data Available for Enzacamene: 18) Genotoxicity Studies Æ Mucosal irritation (rabbits) (Note tissues and behavior in rats (Refs. 17 19) through 25). Findings include decreased Enzacamene showed no evidence of Æ Skin irritation and sensitization testis weight; increased prostate volume DNA mutations in one standard Ames (guinea pigs) (Note 20) and altered duct development; delayed test. A chromosomal aberration assay Æ Phototoxicity potential (mice) (Note preputial separation; decreased prostate using a Chinese hamster V79 cell line

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and a photomutagenicity assay were not found to be teratogenic in any of the clinical studies by qualified experts, and negative. Although these studies treated groups. Additional DART testing reports of significant human experience somewhat ease concerns about potential is recommended to assess fertility and during marketing. Isolated case reports, genotoxicity and mutagenicity, they prenatal and postnatal development in a random experience, and reports lacking were not definitive evaluations of rodent model. the details that permit scientific potential toxic effects from long-term 3. Toxicokinetics (Ref. 30) evaluation will not be considered. systemic or dermal exposure. General recognition of effectiveness We recommend conducting animal shall ordinarily be based upon Data Available for Enzacamene: toxicokinetic studies because they Carcinogenicity Studies published studies which may be provide an important bridge between corroborated by unpublished studies We did not receive dermal or systemic toxic levels seen in animal studies and and other data (§ 330.10(a)(4)(ii)). For carcinogenicity studies. Assessments of potential human exposure. Data from convenience, this order uses the term both dermal and systemic these studies can be correlated to ‘‘generally recognized as effective’’ carcinogenicity are recommended potential human exposure via clinical (GRAE) when referring to this aspect of because sunscreen products containing dermal pharmacokinetic study findings. the GRASE determination. enzacamene are expected to be applied Toxicokinetic data could be collected as To evaluate the efficacy of over large portions of the body with part of animal studies being conducted enzacamene for use in OTC sunscreen multiple daily applications. In addition, to assess one or more of the safety products, FDA requests evidence from as discussed previously, marketing of parameters described previously. at least two adequate and well- this product according to a final Data Available for Enzacamene: controlled SPF studies showing that sunscreen order might permit its Toxicokinetics enzacamene effectively prevents formulation in a variety of as-yet- sunburn. To determine that enzacamene No toxicokinetic data were submitted unknown vehicles that might have an is GRAE for use in OTC sunscreens at as part of any of the nonclinical studies, impact on systemic absorption. concentrations in a range with the thus it is difficult to bridge from animal Consequently, FDA seeks information proposed maximum strength of 4 findings to potential human exposure. on dermal and system carcinogenicity, percent as requested, two adequate and Toxicokinetic data should be collected in case of the possibility that systemic well-controlled SPF studies of as part of the animal studies to allow absorption could occur. enzacamene at a lower concentration exposure comparisons between animals 2. Developmental and Reproductive should be conducted according to and humans. 4 Toxicity (DART) Studies (Ref. 29) Toxicokinetic data are particularly established standards. These SPF FDA recommends conducting DART important to the evaluation of studies should demonstrate that the studies to evaluate the potential effects enzacamene’s safety for use in selected concentration (below 4 percent) that exposure to enzacamene may have sunscreens because enzacamene appears provides an SPF of 2 or more. on developing offspring throughout to have the potential to affect some The current standard procedure for endocrine-responsive endpoints. We SPF testing is described in FDA’s gestation and postnatally until sexual 5 maturation, as well as on the need toxicokinetic data to develop more regulations in § 201.327(i). Further SPF reproductive competence of sexually information about exposure parameters, tests for enzacamene should be mature male and female animals. in order to understand whether a margin performed as described in these Gestational and neonatal stages of of safety exists between the exposures regulations, using a test formulation development may also be particularly that cause the effects in animals and containing enzacamene as the only sensitive to active ingredients with estimated human exposures. Should we active ingredient to identify its hormonal activity. For this reason, we find, after review of a more complete contribution to the overall SPF test recommend that these studies include nonclinical program, that additional results. (See the following subsection assessments of endpoints such as clinical studies are warranted, we will Data Available for Enzacamene: vaginal patency, preputial separation, provide additional recommendations Effectiveness for further discussion of anogenital distance, and nipple regarding the design of the studies. submitted SPF tests.) The study should retention, which can be incorporated also include a vehicle control arm in III. Effectiveness Data Considerations into traditional DART study designs to order to rule out any contribution the for OTC Sunscreen Products Containing assess potential hormonal effects of vehicle may have on the SPF test Enzacamene enzacamene on the developing results. Finally, as described in offspring. We also recommend FDA’s evaluation of the effectiveness § 201.327(i), an SPF standard conducting behavioral assessments (e.g., of active ingredients under formulation comparator arm should be mating behavior) of offspring, which consideration for inclusion in an OTC another component of the study design. may also detect neuroendocrine effects. drug monograph is governed by the Although current sunscreen testing following regulatory standard: and labeling regulations also specify a Data Available for Enzacamene: DART Effectiveness means a reasonable ‘‘broad spectrum’’ testing procedure to Studies expectation that, in a significant support related labeling claims for Potential reproductive and proportion of the target population, the certain OTC sunscreen products developmental effects from enzacamene pharmacological effect of the drug, marketed without approved new drug were evaluated in two embryotoxicity when used under adequate directions studies and one teratogenicity study. for use and warnings against unsafe use, 4 The upper bound of any concentration of enzacamene ultimately established in the OTC Enzacamene did not show evidence of will provide clinically significant relief sunscreen monograph will be governed by the embryotoxicity in a pilot rabbit test and of the type claimed. Proof of efficacy safety data, as well as by efficacy. hen’s egg assay. In a teratogenicity study shall consist of controlled clinical 5 Although the SPF testing procedure is used in rats with oral administration of single investigations as defined in 21 CFR primarily for final formulation testing of finished products marketed without approved NDAs, under daily doses of 10, 30, and 100 mg/kg of 314.126(b). Investigations may be the sunscreen monograph, it is equally applicable enzacamene administered on days 6 to corroborated by partially controlled or for determining whether or not a sunscreen active 15 after conception, enzacamene was uncontrolled studies, documented ingredient is GRAE.

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applications that contain specified established at any of the concentrations effectiveness of sunscreen products active ingredients included in the tested. In addition, none of these study containing enzacamene in humans stayed sunscreen monograph, those reports specified the use of appropriate 4. Relevant medical literature describing additional claims are permitted, but not standard controls to validate the test adverse events associated with required (§ 201.327(c)(2) and (j)). Under results. Currently, there are insufficient enzacamene current regulations, sunscreen active data to support a finding that Alternatively, the results of a ingredients need only be effective for enzacamene is GRAE at concentrations literature search that found no reports of the labeled indication of sunburn up to 4 percent. adverse events may be provided. In that prevention, for which the SPF test can To support a finding that enzacamene case, detailed information on how the provide sufficient evidence. Consistent is GRAE at concentrations up to 4 search was conducted should be with this approach, we here do not percent, we request data from two provided. request broad spectrum testing data for adequate and well-controlled SPF C. Nonclinical (Animal) Studies enzacamene. Broad spectrum protection studies conducted according to is often, although not always, the result established standards to demonstrate 1. Dermal and systemic carcinogenicity of the combined contribution of that the lowest selected concentration (see section II.B.1) multiple active ingredients in a final provides an SPF of 2 or more. Because 2. Fertility (see section II.B.2) 3. Prenatal/postnatal development (see sunscreen formulation. Thus, under the no study has been identified that section II.B.2) current regulations applicable to other establishes that enzacamene is effective sunscreens, the determination of 4. Toxicokinetics (see section II.B.3) at a concentration of 4 percent, we also • whether an individual sunscreen Effectiveness Data (see section III) recommend that such a study be In order for concentrations of product may be labeled as broad conducted and submitted. spectrum and bear the related additional enzacamene up to 4 percent to be found claims is made on a product-specific IV. Summary of Current Data Gaps for to be GRASE for use in nonprescription basis, applying standard testing Enzacamene sunscreen products as requested, at least two SPF studies showing effectiveness methods set forth in those regulations. Based on our review of the available of a selected concentration lower than 4 If enzacamene is established to be safety and efficacy data as discussed percent should be conducted. An GRASE for use in nonprescription previously, we request the types of data efficacy study of enzacamene at 4 sunscreens (based in part on the efficacy listed in this section of the proposed percent is also recommended. data requested here), the final order can order, at minimum, for us to reverse our likewise address broad-spectrum testing tentative determination that V. Administrative Procedures and related labeling conditions for final enzacamene is not GRASE and is A copy of this proposed order will be sunscreen formulations containing misbranded because the data are enzacamene. filed in the Division of Dockets insufficient to classify enzacamene as Management in Docket Numbers FDA– Data Available for Enzacamene: GRASE and not misbranded, and 2003–N–0196, FDA–1978–N–0018, and Effectiveness additional data are necessary to allow us FDA–1996–N–0006. To inform FDA’s to determine otherwise. For additional A total of 11 efficacy studies were evaluation of whether this ingredient is information about the purpose and submitted. Two studies, an in vitro GRASE and not misbranded for use in design of studies recommended to assessment and a field study, both dated sunscreen products, we encourage the address these data gaps, please refer to from the 1970s, did not use study sponsor and other interested parties to the earlier sections of this proposed designs that we consider valid for SPF submit additional data regarding the order referenced in parentheses. We assessment for a GRASE determination safety and effectiveness of this welcome discussions on design of any (Docket No. 78N–0038, OTC Volume ingredient for use as an OTC sunscreen of the studies prior to their 060083, submitted December 18, 1973; product. We also encourage the sponsor commencement. We request the Docket No. 78N–0038, OTC Volume and other interested parties to notify us following types of data: 060130, submitted November 1974). The in writing of their intent to submit • other nine studies all tested enzacamene Safety Data (see section II) additional data. However, as noted as the only active ingredient. These A. Human Clinical Studies previously, because the data submitted included two studies of 1.25 percent to date are not sufficient to support a enzacamene and three studies of 2.5 1. Skin irritation/sensitization and determination that enzacamene is percent enzacamene, concentrations photosafety (see section II.A.1) GRASE for use as an active ingredient within the range found eligible for 2. Human dermal pharmacokinetic in OTC sunscreen drug products, at consideration of GRASE status in the (bioavailability) studies (see section present, OTC sunscreen products Agency’s 2003 eligibility determination, II.A.2) containing enzacamene may not be and three studies of 5 percent The need for additional human safety marketed without approval of an NDA enzacamene and one study of 10 percent studies (e.g., for evaluation of hormonal (see section 586C(e)(1)(A) of the FD&C enzacamene, concentrations above the disruption) will be based on review of Act, as amended by the SIA). Data maximum established to be eligible for the completed nonclinical studies, as submissions relating to this proposed consideration, which studies we do not recommended in section IV.C. order should be submitted to Docket further address in this proposed order. Numbers FDA–2003–N–0196, FDA– B. Human Safety Data To Establish (FDA–1978–N–0018–0766, Citizen 1978–N–0018, and FDA–1996–N–0006 Adverse Event Profile (II.A.3) Petition (CP1), submitted December 17, at the Division of Dockets Management 1980.) In each of the five studies 1. A summary of all available reported (see ADDRESSES). In addition, you can addressing enzacamene at adverse events potentially submit the data through the Federal concentrations of 1.25 percent and 2.5 associated with enzacamene eRulemaking Portal at: http:// percent, enzacamene achieved a mean 2. All available documented case reports www.regulations.gov. Follow the SPF of 2, but there is substantial of serious side effects instructions for submitting comments. variability in the data and it cannot be 3. Any available safety information from Section 586C(b)(7) of the FD&C Act, confirmed that that efficacy was studies of the safety and as amended by the SIA, provides that

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the sponsor may, within 30 days of 8. FDA–1978–N–0018–0759 (Sup 25), IX. References publication of a proposed order (see Volume 2, Report 14, dated November DATES), submit a request to FDA for a 29, 1982. The following references have been meeting to discuss the proposed order. 9. FDA–1978–N–0018–0759 (Sup 25), placed on display in the Division of Submit meeting requests electronically Volume 2, Report 15, dated July 17, Dockets Management (see ADDRESSES) to http://www.regulations.gov or in 1984. and may be seen by interested persons writing to the Division of Dockets 10. FDA–1978–N–0018–0760 (Sup between 9 a.m. and 4 p.m., Monday Management (see ADDRESSES), identified 26), Volume 3, Report 16, dated July 8, through Friday, and are available with the active ingredient name 1984. electronically at http:// enzacamene, the docket numbers found 11. FDA–1978–N–0018–0760 (Sup www.regulations.gov. (FDA has verified in brackets in the heading of this 26), Volume 3, Report 19, dated August the Web site addresses in this reference proposed order, and the heading 1, 1981. section, but FDA is not responsible for ‘‘Sponsor Meeting Request.’’ To 12. FDA–1978–N–0018–0760 (Sup any subsequent changes to the Web sites facilitate your request, please also send 26), Volume 3, Report 18, dated July 2, after this document publishes in the a copy to Kristen Hardin (see FOR 1982. Federal Register.) FURTHER INFORMATION CONTACT). 13. FDA–1978–N–0018–0762 (Sup 1. FDA, Guidance for industry, ‘‘Photosafety 28), Volume 5, Report 29, Study no. 43/ Testing,’’ May 2003 (available at http:// VI. Proposed Effective Date 20792, dated October 18, 1995. www.fda.gov/downloads/Drugs/ FDA proposes that any final 14. FDA–1978–N–0018–0754 (Sup GuidanceComplianceRegulatory administrative order based on this 24), dated April 12, 1999. Information/Guidances/ucm079252.pdf). proposal become effective on the date of 15. FDA–1978–N–0018–0755 (Sup 2. FDA, Guidance for Industry, ‘‘Guideline publication of the final order in the 24), Attachment 1, dated April 12, 1999. for the Format and Content of the Human 16. FDA–1978–N–0018–0758 (Sup Pharmacokinetics and Bioavailability Federal Register. 24), Volume 1, Reports 1, 2, 3 and 4, Section of an Application,’’ February VII. Comments Study no. 4/83/71, 4/130/73, 4/131/73, 1987 (available at http://www.fda.gov/ downloads/drugs/GuidanceCompliance Similarly, section 586C(b)(6) of the 4/52/80. 17. FDA–1978–N–0018–0758 (Sup RegulatoryInformation/Guidances/ FD&C Act, as amended by the SIA, ucm072112.pdf). establishes that a proposed sunscreen 24), Volume 1, Reports 2 and 3, Study 3. Janjua, N.R., et al., ‘‘Systemic Absorption order shall provide 45 days for public no. 4/130/73 and 4/131/73. of the Sunscreens Benzophenone-3, comment. Interested persons wishing to 18. Id. Octyl-Methoxycinnamate, and 3-(4- 19. Id. Methyl-Benzylidene) Camphor After comment on this proposed order may 20. Id. submit either electronic comments to Whole Body Topical Application and 21. FDA–1978–N–0018–0759 (Sup Reproductive Hormone Levels in http://www.regulations.gov or written 25), Volume 2, Report 8, dated October Humans.’’ Journal of Investigative comments to the Division of Dockets 16, 1978. Dermatology, vol. 123, pp. 57–61, 2004. Management (see ADDRESSES). It is only 22. FDA–1978–N–0018–0759 (Sup 4. Schauer, U.M., et al., ‘‘Kinetics of 3- necessary to send one set of comments. 25), Volume 2, Report 9, dated October (methylbenzlidene) Camphor in Rats and Identify comments with the active 16, 1978. Humans After Dermal Application.’’ ingredient name (enzacamene) and the 23. FDA–1978–N–0018–0758 (Sup Toxicology and Applied Pharmacology, docket numbers found in brackets in the 24), Volume 1, Report 5, dated May 5, vol. 216(2), pp. 339–346, 2006. 5. Janjua, N.R., et al., ‘‘Sunscreens in Human heading of this proposed order. 1983. Received comments on this proposed Plasma and Urine After Repeated Whole- 24. Id. Body Topical Application.’’ Journal of order may be seen in the Division of 25. FDA–1978–N–0018–0759 (Sup the European Academy of Dermatology Dockets Management between 9 a.m. 25), Volume 2, Report 7, dated April 26, and Venereology, vol. 22, pp. 456–461, and 4 p.m., Monday through Friday, and 1984. 2008. will be posted to the docket at http:// 26. FDA–1978–N–0018–0760 (Sup 6. Scientific Committee on Consumer www.regulations.gov. 26), Volume 3, Report 17, dated May 1, Products (SCCP)/1184/08—SCCNFP 1984. opinion on 4-Methylbenzylidene VIII. Notes 27. FDA–1978–N–0018–0760 (Sup camphor (4–MBC) Colipa n° S60 adopted 1. FDA–2003–N–0196–0056, Time 26), Volume 3, Report 22, Study no. during the 16th plenary meeting of June and Extent Application (TEA) Request LMP166, dated April 25, 1986. 24, 2008 (available at http:// ec.europa.eu/health/ph_risk/ to Reopen the Rulemaking Record; 28. FDA–1978–N–0018–0759 (Sup _ _ _ submitted August 21, 2002. 25), Volume 2, Report 13, Study no. 4/ committees/04 sccp/docs/sccp o 2. FDA–2003–N–0196–0028, C1, 141.pdf). 56/80, dated June 2, 1980. 7. Jime´nez-Dı´az, I., et al., ‘‘Simultaneous dated October 9, 2003. 29. FDA–1978–N–0018–0761 (Sup Determination of the UV-Filters Benzyl 3. FDA–1978–N–0018–0759 (Sup 25), 27), Volume 4, Report 28, Study no. 40/ Salicylate, Phenyl Salicylate, Octyl Volume 2, Report 10, dated November 13/93, dated April 14, 1993. Salicylate, Homosalate, 3-(4- 27, 1972. 30. FDA–1978–N–0018–0760 (Sup Methylbenzylidene) Camphor and 3- 4. FDA–1978–N–0018–0760 (Sup 26), 26), Volume 3, Report 23, Study no. 4/ Benzylidene Camphor in Human Volume 3, Report 20, dated September 20/84, Experiment No. T9207. Placental Tissue by LC–MS/MS. 8, 1982. 31. FDA–1978–N–0018–0761 (Sup Assessment of Their In Vitro Endocrine 5. FDA–1978–N–0018–0759 (Sup 25), 27), Volume 4, Report 24 and 25, dated Activity.’’ Journal of Chromatography. B, Volume 2, Report 11, dated February 20, October 23, 1987, and October 26, 1987. Analytical Technologies in the 1980. 32. FDA–1978–N–0018–0761 (Sup Biomedical and Life Sciences, vol. 936, 6. FDA–1978–N–0018–0759 (Sup 25), 27), Volume 4, Report 26, Study no. 4/ pp. 80–87, 2013. 8. Gomez, E., et al., ‘‘Estrogenic Activity of Volume 2, Report 12, dated February 20, 43/88, Experiment No. T9305, dated Cosmetic Components in Reporter Cell 1980. September 14, 1983. Lines: Parabens, UV Screens and 7. FDA–1978–N–0018–0760 (Sup 26), 33. FDA–1978–N–0018–0759 (Sup Musks.’’ Journal of Toxicology and Volume 3, Report 21, dated June 5, 25), Volume 2, Report 7, dated April 26, Environmental Health, Part A, vol. 68, 1985. 1984. pp. 239–251, 2005.

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9. Ma, R., et al., ‘‘UV Filters With Endocrine Disrupters: Developmental DEPARTMENT OF HEALTH AND Antagonistic Action at Androgen Exposure of Rats to 4-Methylbenzylidene HUMAN SERVICES Receptors in the MDA–kb2 Cell Camphor.’’ Toxicology and Applied Transcriptional-Activation Assay.’’ Pharmacology, vol. 218(2), pp. 152–165, Food and Drug Administration Toxicological Sciences, vol. 74(1), pp. 2007. 43–50, 2003. 22. Maerkel, K., et al., ‘‘Sex- and Region- 10. Mueller, S.O., et al., ‘‘Activation of Specific Alterations of Progesterone 21 CFR Part 310 Estrogen Receptor Alpha and ERbeta by Receptor mRNA Levels and Estrogen [Docket No. FDA–2008–N–0474] 4-Methylbenzylidene-Camphor in Sensitivity in Rat Brain Following Human and Rat Cells: Comparison With Developmental Exposure to the Over-the-Counter Sunscreen Drug Estrogenic UV Filter 4- Phyto- and Xenoestrogens.’’ Toxicology Products—Regulatory Status of Letters, vol. 142(1–2), pp. 89–101, 2003. Methylbenzylidene Camphor.’’ 11. Schlumpf, M., et al., ‘‘Estrogenic Activity Environmental Toxicology and Ecamsule and Estrogen Receptor Beta Binding of Pharmacology, vol. 19(3), pp. 761–765, AGENCY: Food and Drug Administration, the UV Filter 3-Benzylidene Camphor. 2005. Comparison With 4-Methylbenzylidene 23. Schlumpf, M., et al., ‘‘In Vitro and In HHS. Camphor.’’ Toxicology, vol. 199(2–3), pp. Vivo Estrogenicity of UV Screens.’’ ACTION: Proposed order; request for 109–120, 2004. Environmental Health Perspectives, vol. comments. 12. Schmutzler, C., et al., ‘‘Endocrine 109(3), pp. 239–244, 2001. Erratum in: Disruptors and the Thyroid Gland—A Environmental Health Perspectives, vol. SUMMARY: The Food and Drug Combined In Vitro and In Vivo Analysis 109(11), p. A517, 2001. Administration (FDA or the Agency) is of Potential New Biomarkers.’’ 24. Schlumpf, M., et al., ‘‘Estrogenic Activity issuing a proposed sunscreen order Environmental Health Perspectives, vol. and Estrogen Receptor Beta Binding of the UV Filter 3-Benzylidene Camphor. (proposed order) under the Federal 115 (Supplement 1), pp. 77–83, 2007. Food, Drug, and Cosmetic Act (the 13. Schreurs, R., et al., ‘‘Estrogenic Activity Comparison With 4-Methylbenzylidene of UV Filters Determined by an In Vitro Camphor.’’ Toxicology, vol. 199(2–3), pp. FD&C Act), as amended by the Reporter Gene Assay and an In Vivo 109–120, 2004. Sunscreen Innovation Act (SIA). The Transgenic Zebrafish Assay.’’ Archives of 25. Schlumpf, M., et al. ‘‘Endocrine Activity proposed order announces FDA’s Toxicology, vol. 76, pp. 257–261, 2002. and Developmental Toxicity of Cosmetic tentative determination that ecamsule 14. Seidlova´-Wuttke, D., et al., ‘‘Comparison UV Filters—An Update.’’ Toxicology, (also known as terephthalylidene of Effects of Estradiol With Those of vol. 205(1–2), pp. 113–122, 2004. 26. International Conference on dicamphor sulfonic acid) at Octylmethoxycinnamate and 4- Harmonization (ICH), Guidance for concentrations up to 10 percent is not Methylbenzylidene Camphor on Fat Industry, ‘‘The Need for Long Term generally recognized as safe and Tissue, Lipids and Pituitary Hormones.’’ Rodent Carcinogenicity Studies of effective (GRASE) and is misbranded Toxicology and Applied Pharmacology, Pharmaceuticals S1A,’’ March 1996 when used in over-the-counter (OTC) vol. 214(1), pp. 1–7, 2006. (available at http://www.fda.gov/ 15. S

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