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Antagonistic Action at Androgen 

Receptors in the MDA–kb2 Cell 

Transcriptional-Activation Assay.’’ 

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43–50, 2003. 

10. Mueller, S.O., et al., ‘‘Activation of 

Estrogen Receptor Alpha and ERbeta by 

4-Methylbenzylidene-Camphor in 

Human and Rat Cells: Comparison With 

Phyto- and Xenoestrogens.’’ Toxicology 

Letters, vol. 142(1–2), pp. 89–101, 2003. 

11. Schlumpf, M., et al., ‘‘Estrogenic Activity 

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the UV Filter 3-Benzylidene Camphor. 

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Camphor.’’ Toxicology, vol. 199(2–3), pp. 

109–120, 2004. 

12. Schmutzler, C., et al., ‘‘Endocrine 

Disruptors and the Thyroid Gland—A 

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of Potential New Biomarkers.’’ 

Environmental Health Perspectives, vol. 

115 (Supplement 1), pp. 77–83, 2007. 

13. Schreurs, R., et al., ‘‘Estrogenic Activity 

of UV Filters Determined by an In Vitro 

Reporter Gene Assay and an In Vivo 

Transgenic Zebrafish Assay.’’ Archives of 

Toxicology, vol. 76, pp. 257–261, 2002. 

14. Seidlova ́-Wuttke, D., et al., ‘‘Comparison 

of Effects of Estradiol With Those of 

Octylmethoxycinnamate and 4- 

Methylbenzylidene Camphor on Fat 

Tissue, Lipids and Pituitary Hormones.’’ 

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vol. 214(1), pp. 1–7, 2006. 

15. S<eborg, T., et al., ‘‘Risk Assessment of 

Topically Applied Products.’’ 

Toxicology, vol. 236(1–2), pp. 140–148, 

2007. 

16. Tinwell, H., et al., ‘‘Confirmation of 

Uterotrophic Activity of 3-(4- 

Methylbenzylidine) Camphor in the 

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Perspectives, vol. 110(5), pp. 533–536, 

2002. 

17. Durrer, S., et al., ‘‘Estrogen Sensitivity of 

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Methylbenzylidene Camphor.’’ 

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2139, 2005. 

19. Faass, O., et al., ‘‘Female Sexual 

Behavior, Estrous Cycle and Gene 

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Regions After Pre- and Postnatal 

Exposure to Endocrine Active UV 

Filters.’’ Neurotoxicology, vol. 30(2), pp. 

249–260, 2009. 

20. Hofkamp, L., et al., ‘‘Region-Specific 

Growth Effects in the Developing Rat 

Prostate Following Fetal Exposure to 

Estrogenic Ultraviolet Filters.’’ 

Environmental Health Perspectives, vol. 

116(7), pp. 867–872, 2008. 

21. Maerkel, K., et al., ‘‘Sexually Dimorphic 

Gene Regulation in Brain as a Target for 

Endocrine Disrupters: Developmental 

Exposure of Rats to 4-Methylbenzylidene 

Camphor.’’ Toxicology and Applied 

Pharmacology, vol. 218(2), pp. 152–165, 

2007. 

22. Maerkel, K., et al., ‘‘Sex- and RegionSpecific Alterations of Progesterone 

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Sensitivity in Rat Brain Following 

Developmental Exposure to the 

Estrogenic UV Filter 4- 

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Pharmacology, vol. 19(3), pp. 761–765, 

2005. 

23. Schlumpf, M., et al., ‘‘In Vitro and In 

Vivo Estrogenicity of UV Screens.’’ 

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109(3), pp. 239–244, 2001. Erratum in: 

Environmental Health Perspectives, vol. 

109(11), p. A517, 2001. 

24. Schlumpf, M., et al., ‘‘Estrogenic Activity 

and Estrogen Receptor Beta Binding of 

the UV Filter 3-Benzylidene Camphor. 

Comparison With 4-Methylbenzylidene 

Camphor.’’ Toxicology, vol. 199(2–3), pp. 

109–120, 2004. 

25. Schlumpf, M., et al. ‘‘Endocrine Activity 

and Developmental Toxicity of Cosmetic 

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Industry, ‘‘The Need for Long Term 

Rodent Carcinogenicity Studies of 

Pharmaceuticals S1A,’’ March 1996 

(available at http://www.fda.gov/

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RegulatoryInformation/Guidance/

UCM074911.pdf). 

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for Carcinogenicity of Pharmaceuticals,’’ 

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GuidanceComplianceRegulatory

Information/Guidances/

UCM074916.pdf). 

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Carcinogenicity Studies of 

Pharmaceuticals SIC(R2)’’ (Revision 1), 

September 2008 (available at http://

www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/

UCM074919.pdf). 

29. ICH Harmonized Tripartite Guideline for 

Industry, ‘‘Detection of Toxicity to 

Reproduction for Medicinal Products & 

Toxicity to Male Fertility S5(R2),’’ 2005 

(available at http://www.ich.org/

fileadmin/Public_Web_Site/ICH_

Products/Guidelines/Safety/S5_R2/

Step4/S5_R2__Guideline.pdf). 

30. ICH, Guideline for Industry, 

‘‘Toxicokinetics: The Assessment of 

Systemic Exposure in Toxicity Studies 

S3A,’’ March 1995 (available at http://

www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/

UCM074937.pdf). 

Dated: February 20, 2015. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2015–03884 Filed 2–24–15; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 310 

[Docket No. FDA–2008–N–0474] 

Over-the-Counter Sunscreen Drug 

Products—Regulatory Status of 

Ecamsule 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed order; request for 

comments. 

SUMMARY: The Food and Drug 

Administration (FDA or the Agency) is 

issuing a proposed sunscreen order 

(proposed order) under the Federal 

Food, Drug, and Cosmetic Act (the 

FD&C Act), as amended by the 

Sunscreen Innovation Act (SIA). The 

proposed order announces FDA’s 

tentative determination that ecamsule 

(also known as terephthalylidene 

dicamphor sulfonic acid) at 

concentrations up to 10 percent is not 

generally recognized as safe and 

effective (GRASE) and is misbranded 

when used in over-the-counter (OTC) 

sunscreen products because the 

currently available data are insufficient 

to classify it as GRASE and not 

misbranded, and additional information 

is needed to allow us to determine 

otherwise. 

DATES: Submit either electronic or 

written comments on this proposed 

order by April 13, 2015. Sponsors may 

submit written requests for a meeting 

with FDA to discuss this proposed order 

by March 27, 2015. See section VI for 

the proposed effective date of a final 

order based on this proposed order. 

ADDRESSES: You may submit comments 

by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Written Submissions 

Submit written submissions in the 

following ways: 

• Mail/Hand delivery/Courier (for 

paper submissions): Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. 

Instructions: All submissions received 

must clearly identify the specific active 

ingredient (ecamsule) and the Docket 

No. FDA–2008–N–1474 for this 


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10036 Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 

1For purposes of OTC drug regulation, a 

‘‘condition’’ is defined as an active ingredient or 

botanical drug substance (or a combination of active 

ingredients or botanical drug substances), dosage 

form, dosage strength, or route of administration 

marketed for a specific OTC use, with specific 

exclusions (see § 330.14(a)(2)). This document will 

refer simply to new ‘‘active ingredients,’’ since that 

is the condition under consideration. 

rulemaking. All comments received may 

be posted without change to http://

www.regulations.gov, including any 

personal information provided. For 

additional information on submitting 

comments, see the ‘‘Comments’’ heading 

of the SUPPLEMENTARY INFORMATION

section of this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http://

www.regulations.gov and insert the 

docket numbers, found in brackets in 

the heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852. 

Submit requests for a meeting with 

FDA to discuss this proposed order to 

Kristen Hardin (see FOR FURTHER

INFORMATION CONTACT). 

FOR FURTHER INFORMATION CONTACT: 

Kristen Hardin, Division of 

Nonprescription Drug Products, Center 

for Drug Evaluation and Research, Food 

and Drug Administration, 10903 New 

Hampshire Ave., Bldg. 22, Rm. 5491, 

Silver Spring, MD 20993–0002, 240– 

402–4246. 

SUPPLEMENTARY INFORMATION: 

I. Regulatory Background 

A. Regulatory and Statutory Framework 

The data and information addressed 

in this proposed order were originally 

submitted for review under FDA’s Time 

and Extent Application (TEA) 

regulation, § 330.14 (21 CFR 330.14), a 

process that has since been 

supplemented with new statutory 

procedures established in the SIA (Pub. 

L. 113–195), enacted November 26, 

2014. The discussion that follows 

briefly describes and compares the TEA 

and SIA processes as they apply to the 

regulatory status of ecamsule. 

The TEA regulation established a 

process through which a sponsor could 

request that an active ingredient or other 

OTC condition,1 particularly one not 

previously marketed in the United 

States, be added to an OTC drug 

monograph to enable compliant OTC 

drug products containing the condition 

to be marketed in the United States 

without an approved new drug 

application (NDA) or abbreviated new 

drug application (ANDA). Because this 

proposed order specifically addresses an 

OTC sunscreen active ingredient 

(ecamsule), the remainder of this 

discussion will refer only to ‘‘active 

ingredients.’’ 

Critical steps in a proceeding under 

the TEA regulation include the 

following: (1) FDA’s determination that 

an active ingredient had been marketed 

for the proposed OTC use for a material 

time and to a material extent (eligibility 

determination), and public call for 

submission of safety and efficacy data, 

followed by; (2) review of safety and 

efficacy data submitted by the sponsor 

or other interested parties; and (3) 

FDA’s initial determination that the data 

show the active ingredient to be either 

GRASE or not GRASE for OTC use 

under the applicable monograph 

conditions (including any new 

conditions rising from FDA’s review) 

(GRASE determination). Under the TEA 

regulation, FDA’s GRASE 

determinations are effectuated through 

notice and comment rulemaking to 

amend or establish the appropriate 

monograph. 

The TEA process in FDA regulations 

was supplemented by Congress’s 

enactment of the SIA. Among other 

amendments it makes to the FD&C Act, 

the SIA creates new procedures 

specifically for reviewing the safety and 

effectiveness of nonprescription 

sunscreen active ingredients, including 

those, such as ecamsule, that were the 

subject of pending TEA proceedings at 

the time the SIA was enacted. Like the 

TEA regulation, the SIA calls for an 

initial eligibility determination phase 

for nonprescription sunscreen active 

ingredients, followed by submissions of 

safety and efficacy data and a GRASE 

determination phase. However, the SIA 

requires FDA to make proposed and 

final GRASE determinations for 

nonprescription sunscreen active 

ingredients in the form of administrative 

orders rather than the multistep public 

rulemaking required by the TEA 

regulation, and establishes strict 

timelines for the necessary 

administrative actions. 

Among other requirements, no later 

than 90 days after the SIA was enacted 

(i.e., no later than February 24, 2015), 

FDA must publish a proposed sunscreen 

order in the Federal Register for any 

nonprescription sunscreen active 

ingredient, including ecamsule, for 

which, on the date of enactment, an 

eligibility determination had been 

issued under the TEA regulation and 

submissions of safety and efficacy data 

received, and for which a TEA feedback 

letter had not yet been issued (section 

586C(b)(4) of the FD&C Act (21 U.S.C. 

360fff-3(b)(4)), as amended by the SIA). 

Other provisions of the SIA that are not 

discussed in this proposed order 

address procedures applicable to other 

pending and future sunscreen active 

ingredient GRASE determinations, 

pending and future GRASE 

determinations for OTC products other 

than sunscreens, issuance of specified 

guidances and reports, and completion 

of pending sunscreen rulemakings, 

among others. 

A proposed sunscreen order under the 

SIA is an order containing FDA’s 

tentative determination proposing that a 

nonprescription sunscreen active 

ingredient or combination of 

ingredients: (1) Is GRASE and is not 

misbranded when marketed in 

accordance with the proposed order; (2) 

is not GRASE and is misbranded; or (3) 

is not GRASE and is misbranded 

because the data are insufficient to 

classify the active ingredient or 

combination of ingredients as GRASE 

and not misbranded, and additional 

information is necessary to allow FDA 

to determine otherwise (section 586(7) 

of the FD&C Act, as amended by the 

SIA). Publication of a proposed 

sunscreen order triggers several 

timelines under the SIA, including a 45- 

day public comment period, and a 30- 

day period in which a sponsor may 

request a meeting with FDA to discuss 

the proposed order. 

B. FDA’s Review of Ecamsule 

L’Oreal asked FDA to include 

ecamsule in concentrations up to 10 

percent as an active ingredient in the 

OTC sunscreen monograph in a TEA 

submitted September 19, 2007. FDA 

announced on September 12, 2008, that 

ecamsule had been found eligible in 

concentrations up to 10 percent to be 

considered for inclusion in the OTC 

sunscreen monograph (21 CFR part 352, 

currently stayed), and requested 

submissions of safety and effectiveness 

data to support a GRASE determination 

for the requested OTC use (73 FR 

53029). L’Oreal submitted safety and 

efficacy data on ecamsule to the 

designated docket (FDA–2008–N–0474) 

on November 14, 2008 (ecamsule data 

submission). At the time the SIA was 

enacted, FDA had not issued a TEA 

feedback letter or otherwise responded 

to that submission. 

In accordance with new section 

586C(b)(4) of the FD&C Act as amended 

by the SIA, we are issuing this notice as 

a proposed order for ecamsule. Based on 

our review of the ecamsule data 

submission, we have made a tentative 

determination that ecamsule is not 

GRASE for OTC sunscreen use and is 

misbranded because the data are 

insufficient to classify it as GRASE and 

not misbranded, and additional 


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Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 10037 

information is necessary to allow us to 

determine otherwise. The remainder of 

this proposed sunscreen order describes 

our review of safety and efficacy data, 

identifies additional data needed to 

demonstrate that ecamsule is GRASE for 

the requested use, and explains our 

rationale for specific conclusions and 

data requirements. 

This proposed order will be open for 

public comment (see DATES). The 

sponsor may request a meeting with 

FDA to discuss this proposed order (see 

DATES). We also invite the sponsor to 

submit additional safety and/or efficacy 

data to inform our further consideration, 

as publication of a final sunscreen order 

for ecamsule under the SIA will be 

contingent on receipt of such 

information. (See section 586C(b)(9)(ii) 

of the FD&C Act.) We specifically 

encourage the sponsor to discuss any 

proposed study protocols with us before 

performing the studies. 

II. Safety Data Considerations for OTC 

Sunscreen Products Containing 

Ecamsule 

In evaluating the safety of a proposed 

monograph active ingredient, FDA 

applies the following regulatory 

standard: Safety means a low incidence 

of adverse reactions or significant side 

effects under adequate directions for use 

and warnings against unsafe use as well 

as low potential for harm which may 

result from abuse under conditions of 

widespread availability. Proof of safety 

shall consist of adequate tests by 

methods reasonably applicable to show 

the drug is safe under the prescribed, 

recommended, or suggested conditions 

of use. This proof shall include results 

of significant human experience during 

marketing. General recognition of safety 

shall ordinarily be based upon 

published studies which may be 

corroborated by unpublished studies 

and other data (§ 330.10(a)(4)(i) (21 CFR 

330.10(a)(4)(i))). 

FDA’s OTC drug regulations generally 

identify the types of information that 

may be submitted as evidence that an 

active ingredient or other OTC drug 

condition is safe, as part of the 

consideration of whether an active 

ingredient or other condition is GRASE 

(§ 330.10(a)(2)). For convenience, this 

order uses the term ‘‘generally 

recognized as safe (GRAS)’’ to refer to 

that aspect of the GRASE determination. 

To apply the general OTC safety 

standard to each potential new 

condition, FDA uses its scientific 

expertise to determine what constitutes 

‘‘adequate tests by methods reasonably 

applicable to show the drug is safe 

under the prescribed, recommended, or 

suggested conditions of use.’’ In 

assessing what specific testing or other 

data are needed to adequately 

demonstrate the safety of ecamsule for 

use in sunscreen, FDA considers the 

circumstances under which OTC 

sunscreen products that could contain 

ecamsule would be used by consumers. 

When used as directed with other sun 

protection measures, broad spectrum 

OTC sunscreen products with a sun 

protection factor (SPF) value of 15 or 

higher strongly benefit the public health 

by decreasing the risk of skin cancer and 

premature skin aging associated with 

solar ultraviolet (UV) radiation, as well 

as by helping to prevent sunburn. 

(Sunscreens with lower SPF values, or 

without broad spectrum protection, also 

help prevent sunburn.) When used as 

directed by the required labeling, all 

OTC sunscreen products are applied 

liberally to the skin and reapplied 

frequently throughout the day 

(§ 201.327(e) (21 CFR 201.327(e))). 

Because the effects of UV exposure are 

cumulative, to obtain the maximum 

benefit, users of broad spectrum 

sunscreens with an SPF value of 15 or 

higher are directed to use such products 

regularly—on a routine basis (id.). Given 

these conditions of use, our safety 

evaluation of an OTC sunscreen active 

ingredient such as ecamsule must 

consider both short-term safety concerns 

(such as skin sensitization/irritation and 

photosafety) and potential concerns 

related to long-term sunscreen use, 

including potential systemic exposure 

via dermal absorption. 

The purpose of the safety testing 

described in this section II is to 

establish whether an OTC sunscreen 

product containing ecamsule and 

otherwise marketed under the 

conditions described in a final 

sunscreen order and in accordance with 

all requirements applicable to 

nonprescription drugs would be GRAS 

for use as labeled. To demonstrate that 

these requirements are met for 

ecamsule, initial safety testing should be 

performed using ecamsule as the sole 

active ingredient up to the highest 

concentration for which marketing 

status is sought and eligibility has been 

established: 10 percent. If initial testing 

suggests a particular safety concern 

associated with ecamsule (e.g., a 

hormonal activity), FDA may request 

additional studies to address that 

concern. 

A. Human Safety Data 

1. Human Irritation, Sensitization, and 

Photosafety Studies 

Studies of skin irritation, 

sensitization, and photosafety are 

standard elements in the safety 

evaluation of topical drug products that, 

like ecamsule-containing sunscreens, 

are applied to the skin repeatedly over 

long periods of time. FDA recommends 

separate studies for skin irritation and 

sensitization. Skin irritation studies 

should generally include at least 30 

evaluable subjects and should evaluate 

the test formulation (i.e., ecamsule in an 

appropriate test vehicle), the vehicle 

alone, and both negative and positive 

controls. Skin sensitization studies 

generally should include at least 200 

subjects and should evaluate the test 

formulation containing ecamsule, the 

vehicle, and a negative control. For both 

irritation and sensitization studies, test 

site applications should be randomized 

and the test observer blinded to the 

identities of the test formulations. 

FDA recommends that photosafety 

evaluation generally involve studies of 

skin photoirritation (phototoxicity) and 

skin photosensitization 

(photoallergenicity). General principles 

for designing and conducting 

photosafety studies are described in 

FDA guidance (Ref. 1). Photosafety 

studies, like sensitization and irritation 

studies, should be conducted using 

ecamsule 10 percent in an appropriate 

test vehicle, the vehicle alone, and a 

negative control. In addition, 

phototoxicity studies should include at 

least 30 evaluable subjects and 

photoallerginicity studies should 

include at least 45 evaluable subjects. 

Data Available for Ecamsule: Human 

Irritation, Sensitization, and Photosafety 

Studies 

We received information regarding 26 

non-U.S. human dermal safety studies 

evaluating formulations containing up 

to approximately 4 percent ecamsule 

with one or more other additional active 

ingredients (Note 1). These studies 

exposed a total of approximately 1,500 

adults to formulations containing 

ecamsule. Reports of 21 of these studies 

were complete: 2 of these studies 

assessed primary cutaneous irritation, 7 

assessed cumulative irritation and 

sensitization potential, 9 assessed 

phototoxicity potential, and 3 assessed 

photosensitizing potential. However, the 

information provided in the 21 

complete study reports does not meet 

FDA’s current standards to support the 

human dermal safety of ecamsule at any 

concentration. All of these studies 

assessed formulations containing more 

than one active ingredient and therefore 

provide only limited insight into the 

safety of ecamsule. Furthermore, the 

formulations used in these studies 

included ecamsule only in 

concentrations of between 0.33 percent 

and 3.96 percent, and therefore would 


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10038 Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 

not support a determination that 

ecamsule is GRAS at concentrations 

between 3.96 percent and 10.0 percent 

as found eligible for review and 

requested for GRASE evaluation by 

L’Oreal. Other deficiencies noted 

included: 

• Failure to provide individual skin 

reaction scores to negative controls in 

all studies. 

• Failure to enroll a sufficient number 

of subjects in the sensitization, 

phototoxicity, and photoallergenicity 

studies. 

• Although the cumulative irritation 

studies enrolled an adequate number of 

evaluable subjects, there was a failure to 

indicate whether positive controls were 

used, and only three study reports 

indicated a negative control was used. 

• Failure to indicate whether or not 

investigators in the primary cutaneous 

irritation, phototoxicity, and 

photoallergenicity studies were blinded 

to patch applications. 

• Failure to indicate whether the 

phototoxicity and photoallergenicity 

studies included vehicle controls. 

The ecamsule data submission also 

included reports for 14 studies exposing 

a total of over 500 children primarily 

between 3 and 12 years of age to 

sunscreen formulations containing 

ecamsule in concentrations of 1.5 

percent to 9 percent, with 1 or more 

other additional active ingredients (Note 

2). Numerous dermatologic reactions 

were reported; however, none were 

considered serious. 

Three human safety-related literature 

citations listed in the submission were 

limited to studies describing 

photoallergic reactions to combination 

sunscreen products formulated both 

with and without ecamsule (Note 3). 

One publication described a single case 

of photoallergy to an ecamsulecontaining sunscreen product (Ref. 2). A 

second publication was a review that 

summarized published and unpublished 

data from a single center’s experience 

with patch and photopatch testing in a 

consecutive series of 402 patients who 

presented to a photobiology unit from 

1981 to 1996 with suspected clinical 

photosensitivity (Ref. 3). The authors 

did not observe allergy or photoallergy 

to 1 percent ecamsule, but experience 

with ecamsule was limited in this study 

because it was included in the 

sunscreen series beginning in 1995, 

towards the end of the 15-year study 

period. The third publication was a case 

report describing no photoallergy to an 

ecamsule-containing combination 

sunscreen drug product in a 71-year-old 

male patient with persistent 

photocontact allergy to other UV filters 

(Ref. 4). A literature search conducted 

by FDA did not identify additional 

publications regarding the human 

dermal safety of ecamsule in 

concentrations up to 10 percent for use 

as an OTC sunscreen. 

FDA concludes that the data 

submitted are not sufficient to assess the 

dermal safety of ecamsule in 

concentrations up to 10 percent and 

specifically its potential to cause 

irritation, sensitization, photoirritation, 

or photoallergenicity. Submission of 

data from human irritation, 

sensitization, and photosafety studies 

that meet FDA standards (see section 

II.A.1) is recommended to demonstrate 

that an OTC sunscreen product 

containing up to 10 percent ecamsule is 

not an irritant, sensitizer, 

photosensitizer, or photoirritant. 

2. Human Dermal Pharmacokinetic 

(Bioavailability) Studies 

Because sunscreens are topically 

applied, another important safety 

consideration for ecamsule for use in 

sunscreens is whether dermal 

application may result in skin 

penetration and systemic exposure to 

ecamsule, and if so, to what extent. A 

well-designed and -conducted human 

dermal pharmacokinetic study can be 

expected to detect and quantify the 

presence of ecamsule and/or any 

metabolites in blood or other bodily 

fluids that may have a bearing on safety, 

using recognized parameters such as 

bioavailability percentage, maximum 

plasma concentration (Cmax), time to 

maximum plasma concentration (Tmax), 

total area under the plasma 

concentration versus time curve (AUC), 

half-life, clearance, and volume of 

distribution. This information can help 

identify potential safety concerns and 

help determine whether an adequate 

safety margin for sunscreens containing 

ecamsule exists. FDA recommends that 

the pharmacokinetic studies performed 

on ecamsule also collect additional 

safety-related data from regularly 

scheduled physical examinations, 

collection of vital signs, and other 

measures, which may help capture 

adverse skin events or other potential 

safety signals. To ensure that maximum 

penetration of ecamsule has taken place 

and chances of it being detected are 

optimal, studies should continue until 

steady state is reached. 

General information and 

recommendations on the design and 

conduct of human pharmacokinetic 

studies can be found in FDA guidance 

(Ref. 5). To support a GRAS 

determination for ecamsule (up to 10 

percent), such a study should be 

conducted under maximal use 

conditions using ecamsule up to 10 

percent in various vehicles, including 

vehicles that would be expected to 

enhance absorption. We encourage 

study sponsors to consult with us before 

conducting pharmacokinetic studies, 

because the properties of ecamsule bear 

on the optimal design. 

Data Available for Ecamsule: Human 

Dermal Pharmacokinetic 

(Bioavailability) Studies 

Human dermal pharmacokinetic 

studies for ecamsule were submitted in 

response to our call for data. We 

reviewed one in vitro study that 

evaluated the potential for dermal 

penetration of topically applied 

ecamsule from human skin samples 

(Note 4). Because this study was not 

designed to detect or quantify ecamsule 

in the blood or other body fluids, it 

provides no useful information about 

systemic exposure. One urinary 

excretion study conducted with a 4.95 

percent ecamsule test formulation 

suggested minimal systemic absorption 

in seven male volunteers dosed over an 

extensive body surface area for a total of 

5 days (Note 5). A study in which 

radiolabeled 2 percent ecamsule was 

topically applied to the forearms of five 

male volunteers and retained for 4 hours 

detected a minimal level of radiation 

above background in urine after dosing 

but radiation levels above background 

were not detected in blood (Note 6). 

Although this study suggests that 

ecamsule is minimally absorbed 

following dermal application, the study 

formulation contained ecamsule at a 

concentration much lower than the 

requested 10 percent maximum and 

only a small number of subjects were 

dosed over a limited surface area. The 

last human dermal pharmacokinetic 

study assessed the absorption of 3 

percent ecamsule from a formulation 

containing a total of four active 

ingredients (Note 7). The formulation 

was applied to an extensive body 

surface area of six male subjects twice 

daily for 8 days. Results showed that 

there were quantifiable plasma 

concentrations of ecamsule at several 

time points, suggesting that ecamsule is 

absorbed via dermal application. None 

of the submitted human dermal 

pharmacokinetic studies assessed an 

adequate number of subjects, or tested 

ecamsule at the maximum requested 

concentration of 10 percent. 

Our literature search found no 

additional publications regarding 

human pharmacokinetics of ecamsule. 

Accordingly, we request data from 

human pharmacokinetic studies to 

assess the potential for and the extent of 

systemic absorption. These studies 

should be performed under expected 


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2See 67 FR 3060 at 3069 (January 23, 2002) 

(agreeing that the absence of an adverse experience 

reporting system in a foreign country for drugs or 

cosmetics does not necessarily mean that a 

condition cannot be GRAS/E. The GRAS/E 

determination will be based on the overall quality 

of the data and information presented to 

substantiate safety and effectiveness). 

maximal use conditions with the 

proposed maximum concentration, as 

discussed previously in this section, in 

a sufficiently large study population to 

control for both gender and age. 

3. Human Safety Data To Establish 

Adverse Event Profile 

An evaluation of safety information 

from adverse event reports and other 

safety-related information derived from 

commercial marketing experience of 

sunscreen products containing 

ecamsule, as well as from other sources, 

is a critical aspect of FDA’s safety 

review for ecamsule. The TEA 

regulation under which the original 

request for ecamsule was submitted 

specifically calls for submission of 

information on all serious adverse drug 

experiences, as defined in 21 CFR 

310.305(a) and 314.80(a), from each 

country where the active ingredient or 

other condition has been or is currently 

marketed as either a prescription or an 

OTC drug; in addition, it calls for 

submission of all data generally 

specified in § 330.10(a)(2), which 

includes documented case reports and 

identification of expected or frequently 

reported side effects (§ 330.14(f)(1) and 

(f)(2)). To evaluate ecamsule, FDA 

continues to seek individual adverse 

drug experience reports, a summary of 

all serious adverse drug experiences, 

and expected or frequently reported side 

effects of the condition (id.). To assist in 

the Agency’s safety evaluation of 

ecamsule, FDA emphasizes its need for 

the following data: 

• A summary of all available reported 

adverse events potentially associated 

with ecamsule; 

• All available documented case 

reports of serious side effects; 

• Any available safety information 

from studies of the safety and 

effectiveness of ecamsule in humans; 

and 

• Relevant medical literature 

describing adverse events associated 

with ecamsule. Submissions of adverse 

event data should also include a 

description of how each country’s 

system identifies and collects adverse 

events, unless this information has been 

previously submitted as part of 

ecamsule’s TEA package. 

Although we recognize that adverse 

event data from foreign marketing 

experience may reflect patterns of use 

and regulatory reporting requirements 

that differ from those in the United 

States, we nonetheless consider such 

information to be strongly relevant both 

to our overall GRASE assessment of 

ecamsule for use in sunscreens and to 

our consideration of potential product 

labeling. FDA recognizes that such 

information may not be available from 

all countries; where that is the case, 

please provide a written explanation for 

the lack of data. Overall, we seek 

sufficient data to characterize 

ecamsule’s adverse event profile.2

Ecamsule: Human Safety Data To 

Establish Adverse Event Profile 

The submission describes the 

marketing history of ecamsule and 

provides eight case report forms (Form 

FDA 3500A) that have been submitted 

to FDA’s MedWatch program in 

association with marketed sunscreen 

products containing ecamsule in 

combination with other active 

ingredients (Note 8). Our review of the 

FDA Adverse Event Reporting System 

(FAERS) identified one additional case 

report associated with such a sunscreen 

product. These case reports describe 

serious allergic reactions such as 

redness, swelling and urticaria, 

breathing difficulties, and anaphylaxis. 

The role, if any, of ecamsule in these 

cases cannot be fully assessed due in 

part to the presence of multiple active 

ingredients in the associated sunscreen 

products. To support the evaluation of 

the safety of ecamsule for use in OTC 

sunscreens, we request that the sponsor 

either supplement the information 

already submitted with adverse event or 

other safety-related data derived from 

commercial marketing experience, or 

explain why such information cannot be 

provided. 

B. Nonclinical (Animal) Studies 

Another important element of FDA’s 

GRAS review of ecamsule for use in 

sunscreens is an assessment of data 

from nonclinical (animal) studies that 

characterize the potential long-term 

dermal and systemic effects of exposure 

to ecamsule. Even if the bioavailability 

data discussed in section II.A.2 suggest 

that dermal application is unlikely to 

result in skin penetration and systemic 

exposure to ecamsule, FDA still 

considers data on the effects of systemic 

exposure to be an important aspect of 

our safety evaluation of ecamsule. A 

determination that ecamsule up to 10 

percent is GRASE for use in sunscreens 

would permit its use in as-yet-unknown 

product formulations, which might in 

turn alter the skin penetration of the 

active ingredient. Therefore, an 

understanding of the effects of 

ecamsule, were systemic exposure to 

occur, is critical to determine whether 

and how regulatory parameters can be 

defined to assure that all conforming 

ecamsule-containing sunscreens would 

be GRASE as labeled. 

FDA recommends animal testing of 

the potential long-term dermal and 

systemic effects of exposure to ecamsule 

because these effects cannot be easily 

assessed from previous human use. 

Taken together, the carcinogenicity 

studies, developmental and 

reproductive toxicity studies, and 

toxicokinetic studies described in 

sections II.B.1 through II.B.3 should 

provide the information needed to 

characterize both the potential dermal 

and systemic toxic effects and the levels 

of exposure at which they occur. These 

data, when viewed in the context of 

human exposure data, can be used to 

determine a margin of safety for use of 

ecamsule in OTC sunscreens. 

Data Available for Ecamsule: 

Nonclinical (Animal) Studies Generally 

The ecamsule submission included 

reports of the following types of 

nonclinical safety studies: 

• Single-dose toxicity studies 

Æ Oral toxicity (rat, mouse) (Note 9) 

Æ Dermal toxicity (rat, mouse) (Note 

10) 

Æ Intravenous toxicity (rat, mouse) 

(Note 11) 

Æ Mucosal and skin irritation (rabbit) 

(Note 12) 

Æ Skin irritation and sensitization 

(guinea pig) (Note 13) 

Æ Photoirritation and 

photosensitization (guinea pig) 

(Note 14) 

• Repeat-dose toxicity studies 

Æ 4-week bridging dermal (mouse) 

(Note 15) 

Æ 13-week dermal (mouse) (Note 16) 

Æ 9-month dermal (minipig) (Note 17) 

• Genotoxicity and mutagenicity assays 

Æ Ames test (Salmonella 

typhimurium, Escherichia coli) 

(Note 18) 

Æ Chromosomal aberration assay 

(Chinese hamster ovary (CHO cells)) 

(Note 19) 

Æ Micronucleus test (rat) (Note 20) 

Æ Photomutagenicity (E. coli) (Note 

21) 

Æ HPRT test (CHO cells) (Note 22) 

Æ Photochromosomal aberration assay 

(CHO cells) (Note 23) 

• Reproductive and developmental 

toxicity studies 

Æ Fertility and early embryonic 

development, oral (rat) (Note 24) 

Æ Pre/postnatal development, oral 

(rat) (Note 25) 

Æ Embryotoxicity/teratogenicity, 

dermal (rabbit) (Note 26) 


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Æ Embryofetal development/ 

teratogenicity, oral (rat) (Note 27) 

Æ Embryofetal development/ 

teratogenicity, oral (rabbit) (Note 

28) 

• Carcinogenicity and 

photocarcinogenicity 

Æ 104 weeks dermal carcinogenicity 

(mouse) (Note 29) 

Æ 12 months photocarcinogenicity 

(mouse) (Note 30) 

• Pharmacokinetics 

Æ Pharmacokinetic study, oral (rat) 

(Note 31) 

Æ Pharmacokinetic study, dermal 

(mouse, rat) (Note 32) 

Æ Microsome metabolism 

(interspecies, in vitro) (Note 33) 

Æ Excretion, oral and dermal (rat) 

(Note 34) 

The submission includes summary 

reports of nonclinical studies that are of 

the types FDA requests as a basis for 

evaluating whether ecamsule is GRAS 

for use in sunscreen (chronic toxicity, 

carcinogenicity, reproductive and 

developmental toxicity, and 

toxicokinetics). However, the 

submission did not provide the full 

reports and full comprehensive data sets 

that would be needed for an adequate 

review of the data for these studies. 

Because the summary data provided can 

support only tentative conclusions 

about these studies, full final study 

reports and data sets need to be made 

available to support a final GRASE 

determination. 

Additional discussion of study 

findings and data gaps are provided in 

the following subsections. 

1. Carcinogenicity Studies: Dermal and 

Systemic 

FDA guidance recommends that 

carcinogenicity studies be performed for 

any pharmaceutical that is expected to 

be clinically used continuously or 

‘‘repeatedly in an intermittent manner’’ 

for a total of 6 months of exposure (Refs. 

6, 7, and 8). Because the proposed use 

of ecamsule in OTC sunscreens falls 

within this category, these studies 

should be conducted to help establish 

that ecamsule is GRAS for its proposed 

use. Carcinogenicity studies assist in 

characterizing potential dermal and 

systemic risks by identifying the type of 

toxicity observed, the level of exposure 

at which toxicity occurs, and the highest 

level of exposure at which no adverse 

effects occur (i.e., NOAEL). The NOAEL 

would then be used in determining the 

safety margin for human exposure to 

sunscreens containing ecamsule. 

Systemic carcinogenicity studies can 

also help to identify other systemic or 

organ toxicities that may be associated 

with ecamsule, such as hormonal 

effects. For example, the effect of 

persistent disruption of particular 

endocrine gland systems (e.g., 

hypothalamic-pituitary-adrenal axis), if 

any, can be captured by these assays. 

Data Available for Ecamsule: 

Genotoxicity Studies 

The ecamsule submission included 

some information regarding genotoxicity 

studies. Based on the reviewable 

genotoxicity data included in the 

ecamsule data submission, ecamsule 

appears to be negative for causing 

genotoxic activity under the conditions 

studied (Notes 35 through 43). As we 

believe that data from the recommended 

systemic carcinogenicity and 

developmental and reproductive 

toxicology (DART) studies will provide 

an adequate and appropriate measure of 

potential long-term effects of systemic 

or dermal exposure to ecamsule, we do 

not request further genotoxicity studies. 

Data Available for Ecamsule: 

Carcinogenicity Studies 

We have reviewed study summaries 

for four dermal carcinogenicity and 

photocarcinogenicity studies, which 

appear to be negative (Notes 44 through 

47). However, full final study reports 

need to be made available to support a 

final GRASE determination. In addition, 

we did not receive any systemic 

carcinogenicity data, which are 

recommended to support the safety of 

long-term use of ecamsule. We request 

that the sponsor provide a systemic 

carcinogenicity study, as well as make 

available full final study reports for the 

previously conducted carcinogenicity 

studies that were submitted in a 

summarized form. 

2. DART Studies (Ref. 9) 

FDA recommends conducting DART 

studies to evaluate the potential effects 

that exposure to ecamsule may have on 

developing offspring throughout 

gestation and postnatally until sexual 

maturation, as well as on the 

reproductive competence of sexually 

mature male and female animals. 

Gestational and neonatal stages of 

development may also be particularly 

sensitive to active ingredients with 

hormonal activity. For this reason, we 

recommend that these studies include 

assessments of endpoints such as 

vaginal patency, preputial separation, 

anogenital distance, and nipple 

retention, which can be incorporated 

into traditional DART study designs to 

assess potential hormonal effects of 

ecamsule on the developing offspring. 

We also recommend conducting 

behavioral assessments (e.g., mating 

behavior) of offspring, which may also 

detect neuroendocrine effects. 

Data Available for Ecamsule: DART 

Studies 

We received study summaries for five 

developmental and reproductive 

toxicity assays (Notes 48 through 52), 

which appear to be negative for the 

potential to cause adverse 

developmental or reproductive effects. 

However, comprehensive data sets were 

not provided. 

We request that the sponsor make 

available full final study reports, 

including full comprehensive datasets, 

to support a final GRASE determination. 

3. Toxicokinetics (Ref. 10) 

We recommend conducting animal 

toxicokinetic studies because they 

provide an important bridge between 

toxic levels seen in animal studies and 

potential human exposure. Data from 

these studies can be correlated to 

potential human exposure via clinical 

dermal pharmacokinetic study findings. 

Toxicokinetic data could be collected as 

part of animal studies being conducted 

to assess one or more of the safety 

parameters described previously. 

Data Available for Ecamsule: 

Toxicokinetics 

We reviewed single-dose 

pharmacokinetic studies conducted in 

animal models which showed that 

systemic exposure was achieved under 

the conditions of the conducted studies 

(Notes 53 and 54). However, we did not 

receive any pharmacokinetic data 

reflecting drug levels following longterm exposure, which are usually 

collected from repeat toxicity studies 

such as chronic (systemic or dermal) 

studies. We recommend that a time 

course toxicokinetic study be conducted 

following repeat-dose exposure (via the 

oral and dermal routes) to evaluate the 

steady-state exposure level of ecamsule. 

Data obtained from this study could be 

used to compare drug levels in animals 

to those in humans under maximal 

exposure conditions to establish a 

margin of safety for human exposure. 

III. Effectiveness Data Considerations 

for OTC Sunscreen Products Containing 

Ecamsule 

FDA’s evaluation of the effectiveness 

of active ingredients under 

consideration for inclusion in an OTC 

drug monograph is governed by the 

following regulatory standard: 

Effectiveness means a reasonable 

expectation that, in a significant 

proportion of the target population, the 

pharmacological effect of the drug, 

when used under adequate directions 


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3The upper bound of any concentration of 

ecamsule ultimately established in the OTC 

sunscreen monograph will be governed by the 

safety data, as well as by efficacy. 

4Although the SPF testing procedure is used 

primarily for final formulation testing of finished 

products marketed without approved NDAs, under 

the sunscreen monograph, it is equally applicable 

for determining whether or not a sunscreen active 

ingredient is GRAE. 

for use and warnings against unsafe use, 

will provide clinically significant relief 

of the type claimed. Proof of efficacy 

shall consist of controlled clinical 

investigations as defined in 21 CFR 

314.126(b). Investigations may be 

corroborated by partially controlled or 

uncontrolled studies, documented 

clinical studies by qualified experts, and 

reports of significant human experience 

during marketing. Isolated case reports, 

random experience, and reports lacking 

the details that permit scientific 

evaluation will not be considered. 

General recognition of effectiveness 

shall ordinarily be based upon 

published studies which may be 

corroborated by unpublished studies 

and other data (§ 330.10(a)(4)(ii)). For 

convenience, this order uses the term 

‘‘generally recognized as effective’’ 

(GRAE) when referring to this aspect of 

the GRASE determination. 

To evaluate the efficacy of ecamsule 

for use in OTC sunscreen products, FDA 

requests evidence from at least two 

adequate and well-controlled SPF 

studies showing that ecamsule 

effectively prevents sunburn. To 

determine that ecamsule is GRAE for 

use in OTC sunscreens at concentrations 

in a range with the proposed maximum 

strength of 10 percent as requested, two 

adequate and well-controlled SPF 

studies of ecamsule at a lower 

concentration should be conducted 

according to established standards.3

These SPF studies should demonstrate 

that the selected concentration (below 

10 percent) provides an SPF of 2 or 

more. 

The current standard procedure for 

SPF testing is described in FDA’s 

regulations in § 201.327(i).4 Further SPF 

tests for ecamsule should be performed 

as described in these regulations, using 

a test formulation containing ecamsule 

as the only active ingredient to identify 

its contribution to the overall SPF test 

results. (See the following subsection 

Data Available for Ecamsule: 

Effectiveness for further discussion of 

submitted SPF tests.) The study should 

also include a vehicle control arm to 

rule out any contribution the vehicle 

may have on the SPF test results. 

Finally, as described in § 201.327(i), an 

SPF standard formulation comparator 

arm should be another component of the 

study design. 

Although current sunscreen testing 

and labeling regulations also specify a 

‘‘broad spectrum’’ testing procedure to 

support related labeling claims for 

certain OTC sunscreen products 

marketed without approved new drug 

applications that contain specific 

ingredients included in the OTC 

sunscreen monograph, those additional 

claims are permitted, but not required, 

for these products (§ 201.327(c)(2) and 

(j)). Under current regulations, 

sunscreen active ingredients need only 

be effective for the labeled indication of 

sunburn prevention, for which the SPF 

test can provide sufficient evidence. 

Consistent with this approach, we here 

do not request broad spectrum testing 

for ecamsule. Broad spectrum protection 

is often, although not always, the result 

of the combined contribution of 

multiple active ingredients in a final 

sunscreen formulation. Thus, under the 

current regulations applicable to other 

sunscreens, the determination of 

whether an individual sunscreen 

product may be labeled as broad 

spectrum and bear the related additional 

claims is made on a product-specific 

basis, applying standard testing 

methods set forth in those regulations. 

If ecamsule is established to be GRASE 

for use in nonprescription sunscreens 

(based in part on the efficacy data 

requested here), the final sunscreen 

order can likewise address broadspectrum testing and related labeling 

conditions for final sunscreen 

formulations containing ecamsule. 

Data Available for Ecamsule: 

Effectiveness 

Study reports were submitted for two 

studies that assessed SPF of 

formulations containing ecamsule, at a 

concentration of either 2 percent or 3 

percent (Notes 55 and 56, respectively), 

in combination with other active 

ingredients. Neither of these studies 

provides a direct evaluation of the 

efficacy of ecamsule alone. These 

studies were not adequately designed to 

provide evidence of efficacy on which 

to base a GRAE determination for 

ecamsule. No adequately designed 

studies of ecamsule efficacy were 

identified in our search of the published 

literature. To support the finding that 

ecamsule is GRAE when used at 

concentrations up to 10 percent, we 

request submission of data from two 

adequate and well-controlled SPF 

studies conducted according to 

established standards to demonstrate 

that the lowest selected concentration 

provides an SPF of 2 or more. Because 

no study has been identified that 

assesses the effectiveness of ecamsule at 

a concentration of 10 percent, it is 

recommended that such a study be 

conducted and submitted. 

IV. Summary of Current Data Gaps for 

Ecamsule 

Based on our review of the available 

safety and efficacy data as discussed 

previously, we request the types of data 

listed in this section of the proposed 

order, at minimum, for us to reverse our 

tentative determination that ecamsule is 

not GRASE and is misbranded because 

the data are insufficient to classify 

ecamsule as GRASE and not 

misbranded, and additional data are 

necessary to allow us to determine 

otherwise. Note that, in some cases, as 

discussed in section II of this proposed 

order, the ecamsule data submission 

provided some information from 

nonclinical studies of the type FDA 

requests as part of the basis for a GRAS 

determination, but only in summary 

form. Were complete study data 

generally available from these 

previously conducted studies, they 

might address several aspects of our 

GRASE consideration. If data from these 

previously conducted studies are not 

made available, further studies of those 

types would be needed to support a 

finding that ecamsule is GRASE for use 

in sunscreens. Further, as summarized 

in the following subsections, some 

additional studies of other types are 

needed. For additional information 

about the purpose and design of studies 

recommended to address present data 

gaps, please refer to the earlier sections 

of this proposed order referenced in 

parentheses. We welcome discussions 

on the design of any of the studies prior 

to their commencement. We request the 

following types of data: 

• Safety Data (see section II) 

A. Human Clinical Studies 

1. Skin irritation/sensitization, and 

photosafety (see section II.A.1) 

2. Human dermal pharmacokinetic 

(bioavailability) studies (see section 

II.A.2) 

B. Human Safety Data To Establish 

Adverse Event Profile (see Section 

II.A.3) 

1. A summary and analysis of all 

available reported adverse events 

potentially associated with ecamsule 

2. A summary and analysis of all 

available documented case reports of 

serious side effects 

3. A summary and analysis of any 

available safety information from 

studies of the safety and effectiveness of 

sunscreen products containing ecamsule 

in humans 


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4. A summary and analysis of relevant 

medical literature describing adverse 

events associated with ecamsule 

Alternatively, the results of a 

literature search that found no reports of 

adverse events may be provided. In that 

case, detailed information on how the 

search was conducted should be 

provided. 

C. Nonclinical (Animal) Studies 

Full study reports will be needed for 

the following studies: 

1. Systemic and dermal 

carcinogenicity (see section II.B.1) 

2. Reproductive and developmental 

toxicity studies (see section II.B.2) 

3. Toxicokinetics (see section II.B.3) 

• Effectiveness Data (see section III) 

For concentrations of ecamsule up to 

10 percent to be found to be GRASE for 

use in nonprescription sunscreen 

products as requested, at least two SPF 

studies showing effectiveness of a 

selected concentration lower than 10 

percent should be conducted. An 

efficacy study of ecamsule at 10 percent 

is also recommended. 

V. Administrative Procedures 

A copy of this proposed order will be 

filed in the Division of Dockets 

Management in Docket No. FDA–2008– 

N–0474. To inform FDA’s evaluation of 

whether this ingredient is GRASE and 

not misbranded for use in sunscreen 

products, we encourage the sponsor and 

other interested parties to submit 

additional data regarding the safety and 

effectiveness of this ingredient for use as 

an OTC sunscreen product. We also 

encourage the sponsor and other 

interested parties to notify us in writing 

of their intent to submit additional data. 

However, as noted previously, because 

the data submitted to date are not 

sufficient to support a determination 

that ecamsule is GRASE for use as an 

active ingredient in OTC sunscreen drug 

products, at present, OTC sunscreen 

products containing ecamsule may not 

be marketed without approval of an 

NDA or ANDA (see section 

586C(e)(1)(A) of the FD&C Act, as 

amended by the SIA). Data submissions 

relating to this proposed order should 

be submitted to Docket No. FDA–2008– 

N–0474 at the Division of Dockets 

Management (see ADDRESSES). In 

addition, you can submit the data 

through the Federal eRulemaking Portal 

at http://www.regulations.gov. Follow 

the instructions for submitting 

comments. 

Section 586C(b)(7) of the FD&C Act, 

as amended by the SIA, provides that 

the sponsor may, within 30 days of 

publication of a proposed order (see 

DATES), submit a request to FDA for a 

meeting to discuss the proposed order. 

Submit meeting requests electronically 

to http://www.regulations.gov or in 

writing to the Division of Dockets 

Management (see ADDRESSES), identified 

with the active ingredient name 

ecamsule, Docket No. FDA–2008–N– 

0474, and the heading ‘‘Sponsor 

Meeting Request.’’ To facilitate your 

request, please also send a copy to 

Kristen Hardin (see FOR FURTHER

INFORMATION CONTACT). 

VI. Proposed Effective Date 

FDA proposes that any final 

administrative order based on this 

proposal become effective on the date of 

publication of the final order in the 

Federal Register. 

VII. Comments 

Similarly, section 586C(b)(6) of the 

FD&C Act, as amended by the SIA, 

establishes that a proposed sunscreen 

order shall provide 45 days for public 

comment. Interested persons wishing to 

comment on this proposed order may 

submit either electronic comments to 

http://www.regulations.gov or written 

comments to the Division of Dockets 

Management (see ADDRESSES). It is only 

necessary to send one set of comments. 

Identify comments with the active 

ingredient name (ecamsule) and the 

docket number found in brackets in the 

heading of this proposed order. 

Received comments on this proposed 

order may be seen in the Division of 

Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday, and 

will be posted to the docket at http:// 

www.regulations.gov. 

VIII. Notes 

1. FDA–2008–N–0474–0012 and FDA– 

2008–N–0474–0013, Volumes 6 and 7, dated 

November 14, 2008. 

2. FDA–2008–N–0474–0015 and FDA– 

2008–N–0474–0016, Volumes 9 and 10, 

dated November 14, 2008. 

3. FDA–2008–N–0474–0007, Volume 1, 

dated November 14, 2008, FDA–2008–N– 

0474–0006, TEA submission. 

4. FDA–2008–N–0474–0008, Volume 2, 

Study no. 16039/G2347. 

5. FDA–2008–N–0474–0014, Volume 8, 

Study no. V3156. 

6. FDA–2008–N–0474–0014, Volume 8, 

Study no. V99.1203. 

7. FDA–2008–N–0474–0014, Volume 8, 

Study no. CG.03.SRE.2607. 

8. FDA–2008–N–0474–0007, Volume 1, 

dated November 14, 2008. 

9. FDA–2008–N–0474–0009, Volume 3, 

Study no. 3667–109/309, Study no. 

1.CG.03.SRE.12160. 

10. FDA–2008–N–0474–0009, Volume 3, 

Study no. 4222–109/310, Study no. 

1.CG.03.SRE.12156. 

11. FDA–2008–N–0474–0009, Volume 3, 

Study no. 1.CG.03.SRE.12158, Study no. 

1.CG.03.SRE.12157. 

12. FDA–2008–N–0474–0009, Volume 3, 

Study no. 712332, Volume 4, Study no. 

712320. 

13. FDA–2008–N–0474–0010, Volume 4, 

Study no. 802410, Study no. 3697–109/313. 

14. FDA–2008–N–0474–0010, Volume 4, 

Study no. 1.CG.03.SRE.12163, Study no. 

1.CG.03.SRE.12164. 

15. FDA–2008–N–0474–0010, Volume 4, 

Study no. RDA.03.SRE.12268. 

16. FDA–2008–N–0474–0009, Volume 3, 

Study no. 93/LOL/007/0971. 

17. FDA–2008–N–0474–0009, Volume 3, 

Study no. 1.CG.03.SRE.12183. 

18. FDA–2008–N–0474–0011, Volume 5, 

Study no. G185–109/314. 

19. FDA–2008–N–0474–0011, Volume 5, 

Study no. G220–109/381, Study no. G220– 

109/381A, Study no. 12174MIC, Study no. 

413/52–D6172. 

20. FDA–2008–N–0474–0011, Volume 5, 

Study no. 12639MAR. 

21. FDA–2008–N–0474–0011, Volume 5, 

Study no. EU1REBRP.031. 

22. FDA–2008–N–0474–0011, Volume 5, 

Study no. LRL 170/921503. 

23. FDA–2008–N–0474–0011, Volume 5, 

Study no. ICHUREBRP.031. 

24. FDA–2008–N–0474–0010, Volume 4, 

Study no. 1.CG.03.SRE.12181. 

25. FDA–2008–N–0474–0011, Volume 5, 

Study no. 1.CG.03.SRE.12182. 

26. FDA–2008–N–0474–0011, Volume 5, 

Study no. 10297 RSL. 

27. FDA–2008–N–0474–0010, Volume 4, 

Study no. 1412 RMR/064.89. 

28. FDA–2008–N–0474–0011, Volume 5, 

RCC Project 682874. 

29. FDA–2008–N–0474–0010, Volume 4, 

Study no. 95/LOL/008/1217, Study no. LOL/ 

011/980150. 

30. FDA–2008–N–0474–0010, Volume 4, 

Study no. C–1012–001, Study no. 

RDS.03.SRE.12215. 

31. FDA–2008–N–0474–0009, Volume 3, 

Study no. 10225PAR, Study no. 

1.CG.03.SRE.12269/RDS.03.SRE.12269. 

32. FDA–2008–N–0474–0009, Volume 3, 

Study no. 10507 PAS, Study no. RDS.03.SRE 

12268, Study no. RDS.03.SRE.12269/ 

1.CG.03.SRE.12269. 

33. FDA–2008–N–0474–0009, Volume 3, 

Study no. 2.CG.03.SRE.11029. 

34. FDA–2008–N–0474–0009, Volume 3, 

Study no. 1.CG.03.SRE.12270. 

35. FDA–2008–N–0474–0011, Volume 5, 

Study no. G185–109/314. 

36. FDA–2008–N–0474–0011, Volume 5, 

Study no. G220–109/381. 

37. FDA–2008–N–0474–0011, Volume 5, 

Study no. G220–109/381A. 

38. FDA–2008–N–0474–0011, Volume 5, 

Study no. 12174MIC. 

39. FDA–2008–N–0474–0011, Volume 5, 

Study no. 413/52–D6172. 

40. FDA–2008–N–0474–0011, Volume 5, 

Study no. 12639MAR. 

41. FDA–2008–N–0474–0011, Volume 5, 

Study no. EU1REBRP.031. 

42. FDA–2008–N–0474–0011, Volume 5, 

Study no. LRL 170/921503. 

43. FDA–2008–N–0474–0011, Volume 5, 

Study no. ICHUREBRP.031. 


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Federal Register / Vol. 80, No. 37 / Wednesday, February 25, 2015 / Proposed Rules 10043 

44. FDA–2008–N–0474–0010, Volume 4, 

Study no. 95/LOL/008/1217. 

45. FDA–2008–N–0474–0010, Volume 4, 

Study no. LOL/011/980150. 

46. FDA–2008–N–0474–0010, Volume 4, 

Study no. C–1012–001. 

47. FDA–2008–N–0474–0010, Volume 4, 

Study no. RDS.03.SRE.12215. 

48. FDA–2008–N–0474–1000, Volume 4, 

Study no. 1.CG.03.SRE.12181. 

49. FDA–2008–N–0474–0011, Volume 5, 

Study no. 1.CG.03.SRE.12182, Study no. 

1412 RMR/064.89. 

50. FDA–2008–N–0474–0011, Volume 5, 

RCC Project 682874. 

51. FDA–2008–N–0474–0011, Volume 5, 

RCC Project 682874. 

52. FDA–2008–N–0474–0011, Volume 5, 

Study no. 1.CG.03.SRE.12182. 

53. FDA–2008–N–0474–0009, Volume 3, 

Study no. 10225PAR. 

54. FDA–2008–N–0474–0009, Volume 3, 

Study no. 1.CG.03.SRE.12269/ 

RDS.03.SRE.12269. 

55. FDA–2008–N–0474–0017, Volume 11, 

Study no. PEN.810.02. 

56. FDA–2008–N–0474–0017, Volume 11, 

Study no. PEN.810.06. 

IX. References 

The following references have been 

placed on display in the Division of 

Dockets Management (see ADDRESSES) 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday, and are available 

electronically at http:// 

www.regulations.gov. (FDA has verified 

the Web site addresses in this reference 

section, but FDA is not responsible for 

any subsequent changes to the Web sites 

after this document publishes in the 

Federal Register.) 

1. FDA, Guidance for Industry, 

‘‘Photosafety Testing,’’ May 2003 (available at 

http://www.fda.gov/downloads/Drugs/ 

GuidanceComplianceRegulatoryInformation/ 

Guidances/ucm079252.pdf). 

2. Leonard, F., B. Kalis, H. Adamski, et al., 

‘‘The New Standard Battery of Photopatch 

Test in France.’’ Nouvelles Dermatologiques, 

vol. 15, pp. 343–348, 1996. 

3. Schauder, S., and H. Ippen, ‘‘Contact 

and Photocontact Sensitivity to Sunscreens. 

Review of a 15-Year Experience and of the 

Literature.’’ Contact Dermatitis, vol. 37(5), 

pp. 221–232, 1997. 

4. Schmidt, T., J. Ring, and D. Abeck, 

‘‘Photoallergic Contact Dermatitis Due to 

Combined UVB (4-Methylbenzylidene 

Camphor/Octyl Methoxycinnamate) and 

UVA (Benzophenone-3/Butyl 

Methoxydibenzoylmethane) Absorber 

Sensitization.’’ Dermatology, vol. 196(3), pp. 

354–357, 1998. 

5. FDA, Guidance for Industry, ‘‘Guideline 

for the Format and Content of the Human 

Pharmacokinetics and Bioavailability Section 

of an Application,’’ February 1987 (available 

at http://www.fda.gov/downloads/drugs/ 

GuidanceComplianceRegulatoryInformation/ 

Guidances/ucm072112.pdf). 

6. International Conference on 

Harmonization (ICH), Guidance for Industry, 

‘‘The Need for Long-Term Rodent 

Carcinogenicity Studies of Pharmaceuticals 

S1A,’’ March 1996 (available at http:// 

www.fda.gov/downloads/Drugs/ 

GuidanceComplianceRegulatoryInformation/ 

Guidance/UCM074911.pdf). 

7. ICH, Guidance for Industry, ‘‘S1B 

Testing for Carcinogenicity of 

Pharmaceuticals,’’ July 1997 (available at 

http://www.fda.gov/downloads/Drugs/ 

GuidanceComplianceRegulatoryInformation/ 

Guidances/UCM074916.pdf). 

8. ICH, ‘‘S1C(R2) Dose Selection for 

Carcinogenicity Studies’’ (Revision 1), 

September 2008 (available at http:// 

www.fda.gov/downloads/Drugs/ 

GuidanceComplianceRegulatoryInformation/ 

Guidances/UCM074919.pdf). 

9. ICH Harmonized Tripartite Guideline for 

Industry, ‘‘Detection of Toxicity to 

Reproduction for Medicinal Products & 

Toxicity to Male Fertility S5(R2),’’ 2005 

(available at http://www.ich.org/fileadmin/ 

Public_Web_Site/ICH_Products/Guidelines/ 

Safety/S5_R2/Step4/S5_R2__Guideline.pdf). 

10. ICH, Guideline for Industry, 

‘‘Toxicokinetics: The Assessment of Systemic 

Exposure in Toxicity Studies S3A,’’ March 

1995 (available at http://www.fda.gov/ 

downloads/Drugs/ 

GuidanceComplianceRegulatoryInformation/ 

Guidances/UCM074937.pdf). 

Dated: February 20, 2015. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2015–03883 Filed 2–24–15; 8:45 am] 

BILLING CODE 4164–01–P 


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