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Accordingly, part 748 of the EAR (15 PART 748—[AMENDED] 3 CFR, 2001 Comp., p. 783; Notice of August CFR parts 730–774) is amended as 4, 2016, 81 FR 52587 (August 8, 2016). follows: ■ 1. The authority citation for part 748 ■ 2. Amend supplement No. 7 to part continues to read as follows: 748 by revising the entry for ‘‘Boeing Authority: 50 U.S.C. 4601 et seq.; 50 U.S.C. Tianjin Composites Co. Ltd.’’ in ‘‘China 1701 et seq.; E.O. 13026, 61 FR 58767, 3 CFR, (People’s Republic of)’’ to read as 1996 Comp., p. 228; E.O. 13222, 66 FR 44025, follows:

SUPPLEMENT NO. 7 TO PART 748—AUTHORIZATION VALIDATED END-USER (VEU): LIST OF VALIDATED END-USERS, RESPECTIVE ITEMS ELIGIBLE FOR EXPORT, REEXPORT AND TRANSFER, AND ELIGIBLE DESTINATIONS

Validated Eligible items Federal Register Country end-user (by ECCN) Eligible destination citation

Nothing in this Supplement shall be deemed to supersede other provisions in the EAR, including but not limited to § 748.15(c).

******* Boeing 1B001.f, 1D001 (limited to ‘‘software’’ specially designed Boeing Tianjin Composites 72 FR 59164, 10/19/ Tianjin or modified for the ‘‘use’’ of equipment controlled by Co. Ltd., 4566 Hebei 07. Composites 1B001.f), 2B001.b.2 (limited to machine tools with ac- Road, Marine Hi-Tech 74 FR 19382, 4/29/ Co. Ltd. curacies no better than (i.e., not less than) 13 mi- Development Area, 09. crons), 2D001 (limited to ‘‘software,’’ other than that Tanggu District, Tianjin, 77 FR 10953, 2/24/ controlled by 2D002, specially designed or modified China 300451. 12. for the ‘‘use’’ of equipment controlled by 2B001.b.2), 77 FR 40258, 7/9/12. and 2D002 (limited to ‘‘software’’ for electronic de- 81 FR [INSERT vices, even when residing in an electronic device or PAGE NUMBER], system, enabling such devices or systems to function September 6, 2016. as a ‘‘numerical control’’ unit, capable of coordinating simultaneously more than 4 axes for ‘‘contouring con- trol’’ controlled by 2B001.b.2).

*******

Dated: August 30, 2016. antiseptic washes) are not generally Hampshire Ave., Bldg. 22, Rm. 5418, Kevin J. Wolf, recognized as safe and effective (GRAS/ Silver Spring, MD 20993–0002, 240– Assistant Secretary for Export GRAE) and are misbranded. FDA is 402–0272. Administration. issuing this final rule after considering SUPPLEMENTARY INFORMATION: the recommendations of the [FR Doc. 2016–21333 Filed 9–2–16; 8:45 am] Table of Contents BILLING CODE 3510–33–P Nonprescription Drugs Advisory Committee (NDAC); public comments I. Introduction on the Agency’s notices of proposed A. Terminology Used in the OTC Drug rulemaking; and all data and Review Regulations DEPARTMENT OF HEALTH AND B. Topical Antiseptics HUMAN SERVICES information on OTC consumer antiseptic wash products that have C. This Final Rule Covers Only Consumer Antiseptic Washes Food and Drug Administration come to the Agency’s attention. This II. Background final rule amends the 1994 tentative A. Significant Rulemakings Relevant to 21 CFR Part 310 final monograph (TFM) for OTC This Final Rule antiseptic drug products that published B. Public Meetings Relevant to This Final [Docket No. FDA–1975–N–0012; Formerly in the Federal Register of June 17, 1994 Rule Part of Docket No. 1975N–0183H] (the 1994 TFM). The final rule is part of C. Scope of This Final Rule RIN 0910–AF69 the ongoing review of OTC drug D. Eligibility for the OTC Drug Review products conducted by FDA. III. Comments on the Proposed Rule and FDA Safety and Effectiveness of Consumer Response DATES: This rule is effective September A. Introduction Antiseptics; Topical Antimicrobial 6, 2017. B. Description of General Comments and Drug Products for Over-the-Counter ADDRESSES: For access to the docket to FDA Response Human Use read background documents or C. Comments on Effectiveness and FDA comments received, go to http:// Response AGENCY: Food and Drug Administration, D. Comments on Safety and FDA Response HHS. www.regulations.gov and insert the E. Comments on Individual Active ACTION: Final rule. docket number found in brackets in the Ingredients and FDA Response heading of this final rule into the F. Comments on the Preliminary SUMMARY: The Food and Drug ‘‘Search’’ box and follow the prompts, Regulatory Impact Analysis and FDA Administration (FDA, we, or the and/or go to the Division of Dockets Response Agency) is issuing this final rule Management, 5630 Fishers Lane, Rm. IV. Ingredients Not Generally Recognized as establishing that certain active 1061, Rockville, MD 20852. Safe and Effective V. Effective Date ingredients used in over-the-counter FOR FURTHER INFORMATION CONTACT: VI. Summary of Regulatory Impact Analysis (OTC) consumer antiseptic products Pranvera Ikonomi, Center for Drug A. Introduction intended for use with water (referred to Evaluation and Research, Food and B. Summary of Costs and Benefits throughout this document as consumer Drug Administration, 10903 New VII. Paperwork Reduction Act of 1995

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VIII. Environmental Impact consumer antiseptic wash drug products antiseptics (see section II.B, table 2) and IX. Federalism are misbranded under section 502 of the evaluated the available literature, as X. References Federal Food, Drug, and Cosmetic Act well as the data, the comments, and Executive Summary (the FD&C Act) (21 U.S.C. 352) and are other information that were submitted new drugs under section 201(p) of the to the rulemaking on the effectiveness of Purpose of the Final Rule FD&C Act (21 U.S.C. 321(p)) for which the consumer antiseptic wash active This final rule finalizes the consumer approved applications under section ingredients addressed in this final rule. antiseptic wash proposed rule 505 of the FD&C Act (21 U.S.C. 355) and The data and information submitted for published in the Federal Register of part 314 (21 CFR part 314) of the these active ingredients are insufficient December 17, 2013 (78 FR 76444) (2013 regulations are required for marketing. to demonstrate that there is any Consumer Wash Proposed Rule (PR)) In separate rulemakings, we are additional benefit from the use of these and amends the 1994 TFM for OTC proposing conditions under which OTC active ingredients in consumer antiseptic drug products that published consumer antiseptic rubs (products that antiseptic wash products compared to in the Federal Register of June 17, 1994 are not rinsed off after use, including nonantibacterial soap and water. (59 FR 31402). The amendment is part hand rubs and antibacterial wipes) (81 Consequently, the available data do not of FDA’s ongoing rulemaking to FR 42912, June 30, 2016) and OTC support a GRAE determination for these evaluate the safety and effectiveness of antiseptics intended for use by health consumer antiseptic wash active OTC drug products marketed in the care professionals in a hospital setting ingredients. United States on or before May 1972 or other health care situation outside the B. Safety (OTC Drug Review). This final rule hospital (80 FR 25166, May 1, 2015) are applies to consumer antiseptic wash GRAS/GRAE. Accordingly, this final As explained in the 2013 Consumer products that are intended for use with rule covers only OTC consumer Wash PR, several important scientific water and are rinsed off after use, antiseptic washes that are intended for developments that affect the safety including hand washes and body use as either a hand wash or a body evaluation of consumer antiseptic wash washes. wash, and does not cover health care active ingredients have occurred since In response to several comments antiseptics (80 FR 25166), consumer FDA’s 1994 evaluation of the safety of submitted to the 2013 Consumer Wash antiseptic rubs (81 FR 42912), consumer antiseptic active ingredients PR, FDA has deferred further antiseptics identified as ‘‘first aid under the OTC Drug Review. New data rulemaking on three specific active antiseptics’’ in the 1991 First Aid TFM suggests that the systemic exposure to ingredients used in OTC consumer (56 FR 33644), or antiseptics used by the these active ingredients is higher than antiseptic wash products to allow for food industry. Those antiseptic products previously thought, and new the development and submission of new are not addressed in this final rule. information about the potential risks safety and effectiveness data to the from systemic absorption and long-term record for these ingredients. The Summary of the Major Provisions of the exposure is now available. New safety deferred active ingredients are Final Rule information also suggests that widespread antiseptic use could have an benzalkonium chloride, benzethonium A. Effectiveness chloride, and chloroxylenol. impact on the development of bacterial Accordingly, FDA does not make a As explained in the 2013 Consumer resistance. To support a classification of determination of general recognition of Wash PR, a determination that an active generally recognized as safe (GRAS) for safety and effectiveness for these three ingredient is GRAS/GRAE for a consumer antiseptic wash active active ingredients in this final rule. The particular intended use requires a ingredients, we proposed that additional monograph or new drug status of these benefit-to-risk assessment for that data was needed to demonstrate that three ingredients will be addressed particular use of the ingredient. If the those ingredients meet current safety either after completion and analysis of active ingredient in a drug product standards (78 FR 76444 at 76453 to ongoing studies to address the safety carries the potential risk associated with 76458). and efficacy data gaps of these the drug (e.g., reproductive toxicity or The minimum data needed to ingredients or at a later date if these carcinogenicity), but does not provide a demonstrate safety for all consumer studies are not completed. clinical benefit, then the benefit-to-risk antiseptic wash active ingredients falls With the exception of the three calculation shifts towards a not GRAS/ into three broad categories: (1) Safety deferred consumer antiseptic wash GRAE status for that drug. New data studies described in current FDA active ingredients, this rulemaking information on potential risks posed by guidance (e.g., nonclinical and human finalizes the nonmonograph status of the use of certain consumer antiseptic pharmacokinetic studies, developmental the remaining 19 active ingredients washes prompted us to reevaluate the and reproductive toxicity studies, and intended for use in consumer antiseptic data needed for classifying consumer carcinogenicity studies); (2) data to washes identified in the 2013 Consumer antiseptic wash active ingredients as characterize potential hormonal effects; Wash PR. As explained, either no generally recognized as effective and (3) data to evaluate the additional data were submitted or the (GRAE). As a result, we proposed that development of bacterial resistance. data and information that were the risk from the use of a consumer We have considered the submitted were not sufficient to support antiseptic wash drug product must be recommendations from the public monograph conditions for these 19 balanced by a demonstration—through meetings held by the Agency on consumer antiseptic wash ingredients. studies that demonstrate a direct antiseptics (see section II.B, table 2) and Therefore, with the exception of the clinical benefit (i.e., a reduction of evaluated the available literature, as three deferred consumer antiseptic wash infection)—that the product is superior well as the data, the comments, and active ingredients, this rule finalizes the to washing with nonantibacterial soap other information that were submitted 2013 Consumer Wash PR, which and water in reducing infection (78 FR to the rulemaking on the safety of proposed amending the 1994 TFM, with 76444 at 76450). consumer antiseptic wash active the remaining 19 consumer antiseptic We have considered the ingredients addressed in this final rule. wash active ingredients found to be not recommendations from the public The available information and GRAS/GRAE. Accordingly, these 19 meetings held by the Agency on published data for the 19 active

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ingredients considered in this final rule misbranded for use in consumer monetary equivalents of health effects. are insufficient to establish the safety of antiseptic washes. Regulatory action is The primary estimate of costs long-term, daily repeated exposure to being deferred on three active annualized over 10 years is these active ingredients used in ingredients that were included in the approximately $23.6 million at a 3 consumer wash products. Consequently, proposed rule: Benzalkonium chloride, percent discount rate and $27.6 million the available data do not support a benzethonium chloride, and at a 7 percent discount rate. These costs GRAS determination for the consumer chloroxylenol. The primary estimated consist of total one-time costs of antiseptic wash active ingredients benefits come from reduced exposure to relabeling and reformulation ranging included in this rule. antiseptic active ingredients by 2.2 from $106.3 to $402.8 million. Under C. Costs and Benefits million pounds per year. Limitations in the final rule, we estimate that each This final rule establishes that 19 the available data characterizing the pound of reduced exposure to antiseptic active ingredients, including triclosan health effects resulting from widespread active ingredients will cost $12.97 to and triclocarban, are not GRAS/GRAE long-term exposure to these ingredients $14.28 at a 3 percent discount rate and and consumer antiseptic wash products prevent us from translating the $16.36 to $18.02 at a 7 percent discount containing these ingredients are estimated reduced exposure into rate.

Total costs annualized Summary of the costs and Total benefits over 10 years Total one-time costs benefits of the final rule (in millions) (in millions)

Total ...... Reduced exposure to antiseptic ingredients by 2.2 mil- $23.6 (at 3%) ...... $106.3 to $402.8. lion pounds annually. $27.6 (at 7%)

I. Introduction any testing necessary to resolve the TFM covering first aid antiseptics in the safety or effectiveness issues that Federal Register of July 22, 1991 (56 FR In the following sections, we provide resulted in an initial Category III 33644). In section III.E, we address a brief description of terminology used classification, and submission to FDA of comments filed in this rulemaking in the OTC Drug Review regulations, an the results of that testing or any other related to first aid antiseptics, but we do overview of OTC topical antiseptic drug data, must be done during the OTC drug not otherwise discuss first aid products, and a more detailed rulemaking process before the antiseptics further in this document. description of the OTC consumer establishment of a final monograph (i.e., This final rule does not have an impact antiseptic wash active ingredients that a final rule or regulation). Therefore, the on the monograph status of first aid are the subject of this final rule. proposed rules (at the tentative final antiseptics. A. Terminology Used in the OTC Drug monograph stage) used the concepts of The four remaining categories of Review Regulations Categories I, II, and III. topical antimicrobials were addressed in At this final monograph stage, FDA the 1994 TFM (59 FR 31402). The 1994 1. Proposed, Tentative Final, and Final does not use the terms ‘‘Category I,’’ TFM covered: (1) Antiseptic hand wash Monographs ‘‘Category II,’’ and ‘‘Category III.’’ In (i.e., consumer hand wash); (2) health To conform to terminology used in place of Category I, the term care personnel hand wash; (3) patient the OTC Drug Review regulations ‘‘monograph conditions’’ is used; in preoperative skin preparation; and (4) (§ 330.10 (21 CFR 330.10)), the advance place of Categories II and III, the term surgical hand scrub (59 FR 31402 at notice of proposed rulemaking that was ‘‘nonmonograph conditions’’ is used. 31442). This final rule does not have an published in the Federal Register of impact on the monograph status of B. Topical Antiseptics September 13, 1974 (39 FR 33103) (1974 health care personnel hand washes, ANPR), was designated as a ‘‘proposed The OTC topical antimicrobial patient preoperative skin preparations, monograph.’’ Similarly, the notices of rulemaking has had a broad scope, or surgical hand scrubs. In the 1994 proposed rulemaking, which were encompassing drug products that may TFM, FDA also identified a new published in the Federal Register of contain the same active ingredients, but category of antiseptics for use by the January 6, 1978 (43 FR 1210) (1978 that are labeled and marketed for food industry and requested relevant TFM), the Federal Register of June 17, different intended uses. The 1974 ANPR data and information (59 FR 31402 at 1994 (59 FR 31402) (1994 TFM), and the for topical antimicrobial products 31440). In section III.B.4, we address Federal Register of December 17, 2013 encompassed products for both health comments filed in this rulemaking on (78 FR 76444) (2013 Consumer Wash care and consumer use (39 FR 33103). antiseptics for use by the food industry, PR) were each designated as a TFM (see The ANPR covered seven different but we do not otherwise further discuss table 1 in section II.A). intended uses for these products: (1) these antiseptics in this document. This Antimicrobial soap; (2) healthcare final rule does not have an impact on 2. Category I, II, and III Classifications personnel hand wash; (3) patient the monograph status of antiseptics for The OTC drug procedural regulations preoperative skin preparation; (4) skin food industry use. in § 330.10 use the terms ‘‘Category I’’ antiseptic; (5) skin wound cleanser; (6) In the 2013 Consumer Wash PR, we (generally recognized as safe and skin wound protectant; and (7) surgical proposed that our evaluation of OTC effective and not misbranded), hand scrub (39 FR 33103 at 33140). FDA antiseptic drug products be further ‘‘Category II’’ (not generally recognized subsequently identified skin antiseptics, subdivided into health care antiseptics as safe and effective or misbranded), skin wound cleansers, and skin wound and consumer antiseptics (78 FR 76444 and ‘‘Category III’’ (available data are protectants as antiseptics used primarily at 76446). These categories are distinct insufficient to classify as safe and by consumers for first aid use and based on the proposed use setting, target effective, and further testing is referred to them collectively as ‘‘first aid population, and the fact that each required). Section 330.10 provides that antiseptics.’’ We published a separate setting presents a different risk for

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infection. In the 2013 Consumer Wash antiseptic washes.’’ Consumer antiseptic 76446 to 76447) and the 2016 Consumer PR (78 FR 76444 at 76446 to 76447) and washes include a variety of personal Rub PR (81 FR 42912). Completion of the consumer antiseptic rub proposed care products intended to be used with the monograph for Consumer Antiseptic rule published in the Federal Register water, such as antibacterial soaps, hand Wash Products and certain other of June 30, 2016 (81 FR 42912) (2016 washes, and antibacterial body washes. monographs for the active ingredient Consumer Rub PR), we proposed that As discussed further in section III.B.3, triclosan is subject to a Consent Decree our evaluation of OTC consumer these products may be used by entered by the U.S. District Court for the antiseptic drug products be further consumers for personal use in the home Southern District of New York on subdivided into consumer washes and public settings on a frequent, daily November 21, 2013, in Natural (products that are rinsed off with water, basis. In the United States consumer Resources Defense Council, Inc. v. including hand washes and body setting, where the target population is United States Food and Drug washes) and consumer rubs (products composed of generally healthy that are not rinsed off after use, Administration, et al., 10 Civ. 5690 individuals, the risk of infection and the (S.D.N.Y.). including hand rubs and antibacterial scope of the spread of infection is wipes) (78 FR 764444 at 76447). relatively low compared to the health II. Background Consumer antiseptic wash products are care setting, where patients are intended to be used when soap and generally more susceptible to infection In this section, we describe the water are available, whereas, consumer and the potential for spread of infection significant rulemakings and public antiseptic rub products are intended to is high. meetings relevant to this rulemaking be used when soap and water are and discuss our response to comments unavailable, and thus, are left on and This final rule covers only OTC received on the 2013 Consumer Wash consumer antiseptic washes that are not rinsed off. To account for the PR. differences between consumer washes intended for use as either a hand wash and consumer rubs, the safety and or a body wash, but that are not A. Significant Rulemakings Relevant to effectiveness of the active ingredients identified as ‘‘first aid antiseptics’’ in This Final Rule are being evaluated for each intended the 1991 First Aid TFM (56 FR 33644), use separately. This final rule does not health care antiseptics (80 FR 25166), A summary of the significant Federal have an impact on the monograph status consumer antiseptic rubs (81 FR 42912), Register publications relevant to this of consumer antiseptic rub products. or antiseptics used by the food industry. final rule is provided in table 1. Other The distinctions between consumer publications relevant to this final rule C. This Final Rule Only Covers washes and rubs, and between are available at http:// Consumer Antiseptic Washes consumer hand washes and body www.regulations.gov in FDA Docket No. We refer to the group of products washes are discussed in detail in the 1975–N–0012. covered by this final rule as ‘‘consumer 2013 Consumer Wash PR (78 FR at

TABLE 1—SIGNIFICANT RULEMAKING PUBLICATIONS RELATED TO CONSUMER ANTISEPTIC DRUG PRODUCTS 1

FEDERAL REGISTER notice Information in notice

1974 ANPR (September 13, 1974, 39 FR We published an advance notice of proposed rulemaking to establish a monograph for OTC 33103). topical antimicrobial drug products, together with the recommendations of the advisory re- view panel (the Panel) responsible for evaluating data on the active ingredients in this drug class. 1978 Antimicrobial TFM (January 6, 1978, 43 We published our tentative conclusions and proposed effectiveness testing for the drug prod- FR 1210). uct categories evaluated by the Panel, reflecting our evaluation of the Panel’s recommenda- tions and comments and data submitted in response to the Panel’s recommendations. 1991 First Aid TFM (July 22, 1991, 56 FR We amended the 1978 TFM to establish a separate monograph for OTC first aid antiseptic 33644). products. In the 1991 TFM, we proposed that first aid antiseptic drug products be indicated for the prevention of skin infections in minor cuts, scrapes, and burns. 1994 Healthcare Antiseptic TFM (June 17, We amended the 1978 TFM to establish a separate monograph for the group of products re- 1994, 59 FR 31402). ferred to as OTC topical health care antiseptic drug products. These antiseptics are gen- erally intended for use by health care professionals. In the 1994 TFM we also recognized the need for antibacterial personal cleansing products for consumers to help prevent cross- contamination from one person to another and proposed a new antiseptic category for consumer use: Antiseptic hand wash. 2013 Consumer Antiseptic Wash TFM (Decem- We issued a proposed rule to amend the 1994 TFM and to establish data standards for deter- ber 17, 2013, 78 FR 76444). mining whether OTC consumer antiseptic washes are GRAS/GRAE. In the 2013 Consumer Antiseptic Wash TFM, we proposed that additional safety and effective- ness data are necessary to support the safety and effectiveness of consumer antiseptic wash active ingredients. 2015 Health Care Antiseptic TFM (May 15, We issued a proposed rule to amend the 1994 TFM and establish data standards for deter- 2015, 80 FR 25166). mining whether OTC health care antiseptics are GRAS/GRAE. In the 2015 Health Care Antiseptic TFM, we proposed that additional data are necessary to support the safety and effectiveness of health care antiseptic active ingredients. 2016 Consumer Antiseptic Rub TFM (June 30, We issued a proposed rule to amend the 1994 TFM and to establish data standards for deter- 2016, 81 FR 42912). mining whether OTC consumer antiseptic rubs are GRAS/GRAE. In the 2016 Consumer Antiseptic Rub TFM, we proposed that additional safety and effective- ness data are necessary to support the safety and effectiveness of consumer antiseptic rub active ingredients. 1 The publications listed in table 1 can be found at FDA’s ‘‘Status of OTC Rulemakings’’ Web site available at http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm070821.htm. The publications dated after 1993 can also be found in the FEDERAL REGISTER at https://www.federalregister.gov.

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B. Public Meetings Relevant to This been four meetings of the NDAC and These meetings are summarized in table Final Rule one public feedback meeting that are 2. In addition to the Federal Register relevant to the discussion of consumer publications listed in table 1, there have antiseptic wash safety and effectiveness.

TABLE 2—PUBLIC MEETINGS RELEVANT TO CONSUMER ANTISEPTICS

Date and type of meeting Topic of discussion

January 1997 NDAC Meeting (Joint meeting with the Anti-In- Antiseptic and antibiotic resistance in relation to an industry proposal for con- fective Drugs Advisory Committee) (January 6, 1997, 62 sumer and health care antiseptic effectiveness testing (Health Care Continuum FR 764). Model) (Refs. 1 and 2). March 2005 NDAC Meeting (February 18, 2005, 70 FR 8376) The use of surrogate endpoints and study design issues for the in vivo testing of health care antiseptics (Ref. 3). October 2005 NDAC Meeting (September 15, 2005, 70 FR Benefits and risks of consumer antiseptics. NDAC expressed concern about the 54560). pervasive use of consumer antiseptic washes where there are potential risks and no demonstrable benefit. To demonstrate a clinical benefit, NDAC rec- ommended clinical outcome studies to show that antiseptic washes are supe- rior to nonantibacterial soap and water (Ref. 4). November 2008 Public Feedback Meeting ...... Demonstration of the effectiveness of consumer antiseptics (Ref. 5). September 2014 NDAC Meeting (July 29, 2014, 79 FR Safety testing framework for health care antiseptic active ingredients (Ref. 6). 44042).

C. Scope of This Final Rule required. Accordingly, FDA is amending • Cloflucarban part 310 (21 CFR part 310) to add the • Fluorosalan This rulemaking finalizes the • nonmonograph status for the 19 listed active ingredients covered by this final Hexachlorophene • Hexylresorcinol consumer antiseptic wash active rule to the list in § 310.545 (21 CFR • Iodophors (Iodine-containing ingredients (see section II.D). Requests 310.545) of OTC drug products that are ingredients) were made that benzalkonium chloride, not GRAS/GRAE and are misbranded in Æ Iodine complex (ammonium ether benzethonium chloride, and the absence of an approved new drug sulfate and polyoxyethylene chloroxylenol be deferred from application. sorbitan monolaurate) inclusion in this consumer antiseptic D. Eligibility for the OTC Drug Review Æ Iodine complex (phosphate ester of wash final rulemaking to allow more An OTC drug is covered by the OTC alkylaryloxy polyethylene glycol) time for interested parties to complete Drug Review if its conditions of use Æ Nonylphenoxypoly (ethyleneoxy) the studies necessary to fill the safety existed in the OTC drug marketplace on ethanoliodine and efficacy data gaps identified in the or before May 11, 1972 (37 FR 9464) Æ Poloxamer—iodine complex 2013 Consumer Wash PR for these (Ref. 7).1 Conditions of use include, Æ Povidone-iodine 5 to 10 percent ingredients. In March 2016, we agreed among other things, active ingredient, Æ Undecoylium chloride iodine to defer rulemaking on these three dosage form and strength, route of complex ingredients (see Docket No. 1975–N– administration, and specific OTC use or • Methylbenzethonium chloride 0012 at http://www.regulations.gov). indication of the product (see • Phenol (greater than 1.5 percent) Accordingly, in this final rulemaking we § 330.14(a)). To determine eligibility for • Phenol (less than 1.5 percent) do not discuss whether benzalkonium the OTC Drug Review, FDA typically • Secondary amyltricresols chloride, benzethonium chloride, and must have actual product labeling or a • Sodium oxychlorosene • chloroxylenol are GRAS/GRAE for use facsimile of labeling that documents the Tribromsalan • as active ingredients in consumer conditions of marketing of a product Triclocarban antiseptic washes. The monograph or • Triclosan before May 1972 (see § 330.10(a)(2)). • new drug status of these three FDA considers a drug that is ineligible Triple dye ingredients will be finalized either after for inclusion in the OTC monograph In the 2013 Consumer Wash PR, we completion and analysis of ongoing system to be a new drug that will describe the lack of adequate data studies to address the safety and require FDA approval through the new needed for a GRAS/GRAE determination efficacy data gaps of these ingredients or drug application (NDA) process. for consumer antiseptic wash active at a later date if these studies are not Ineligibility for use as a consumer ingredients (78 FR 76444). As discussed completed. antiseptic rub does not affect eligibility in section II.C, rulemaking has been For the 19 active ingredients included under any other OTC drug monograph. deferred for three of the consumer in this final rule, either no additional antiseptic wash active ingredients— data were submitted since the 2013 1. Eligible Active Ingredients benzalkonium chloride, benzethonium Consumer Antiseptic Wash PR, or the There are 19 of the antiseptic active chloride, and chloroxylenol. data and information that were ingredients eligible for the OTC Drug Accordingly, any references to submitted were insufficient to support Review for use as a consumer antiseptic consumer antiseptic wash active GRAS/GRAE findings. Therefore, these wash that are addressed in this final ingredients refer only to the 19 ingredients are not included in a rule. These ingredients are: consumer antiseptic wash active monograph at this time. These active ingredients listed in this section, unless ingredients are not GRAS/GRAE for use 1 Also, note that drugs initially marketed in the otherwise stated. in consumer antiseptic wash drug United States after the OTC Drug Review began in 1972 and drugs without any U.S. marketing 2. Ineligible Active Ingredients products and products containing these experience can be considered in the OTC ingredients are new drugs for which monograph system based on submission of a time In the 2013 Consumer Wash PR, we approved new drug applications are and extent application. (See § 330.14). also identified certain active ingredients

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that were considered ineligible for purely for organizational purposes and standard (a clinical simulation standard) evaluation under the OTC Drug Review does not signify the comment’s value or proposed in the 1994 TFM, which was as a consumer antiseptic wash; but, we importance or the order in which based on an invalidated surrogate noted that if the requested comments were received. endpoint (i.e., number of bacteria documentation for eligibility was removed from the skin), is insufficient B. Description of General Comments submitted, these active ingredients for establishing effectiveness of and FDA Response could be determined to be eligible for consumer antiseptic washes. Therefore, evaluation (78 FR 76444 at 76448). The 1. Advance Notice of Proposed we proposed that clinical outcome active ingredients proposed to be Rulemaking studies were needed to demonstrate a ineligible in the 2013 Consumer Wash (Comment 1) Several comments direct clinical benefit. This proposed effectiveness PR were: asserted that the new efficacy testing requirement is consistent with the • Alcohol (ethyl alcohol) requirements proposed in the 2013 • NDAC’s recommendations from the Benzalkonium cetyl phosphate Consumer Wash PR were • October 2005 NDAC meeting regarding Cetylpyridinium chloride unprecedented. They stated that given • Chlorhexidine gluconate consumer antiseptics (Ref. 4). The • the significance of the proposed change October 2005 NDAC concluded that the Isopropyl alcohol to the efficacy testing requirements for • Polyhexamethylene biguanide existing test methods are based on the • consumer antiseptics and the lack of premise that bacterial reductions Salicylic acid precedent for this action, FDA should • Sodium hypochlorite translate to a reduced potential for withdraw the proposed rule and reissue • Tea tree oil infection, and, although bacterial • Combination of potassium vegetable it as an ANPR to give industry and other reduction can be demonstrated using oil solution, phosphate sequestering stakeholders an opportunity to engage tests that simulate conditions of actual agent, and triethanolamine with FDA on the GRAE testing use, there are no corresponding clinical requirements for the active ingredients We have not received any new data to demonstrate that bacterial and surrogate endpoint testing of final reductions of the required magnitude information since the 2013 Consumer formulations. Wash PR demonstrating that these produce a corresponding reduction in (Response 1) The purpose of an ANPR infection. Accordingly, the October active ingredients are eligible for is to allow the public a period of time evaluation under the OTC Drug Review 2005 NDAC recommended clinical to comment on regulations that the FDA outcome studies to demonstrate the for use as a consumer antiseptic wash. may pursue as part of a future Consequently, drug products containing clinical benefit of consumer antiseptic rulemaking. As explained in section wash active ingredients and their these active ingredients are new drugs II.A, we issued an ANPR for a that will require FDA approval. superiority compared to a monograph for OTC topical nonantibacterial wash, such as soap and III. Comments on the Proposed Rule antimicrobial drug products in 1974, water. In October 2008, we also held a and FDA Response and a proposed rulemaking in the form public feedback meeting to discuss the of a TFM in 1978. We have amended the A. Introduction demonstration of effectiveness of TFM for OTC topical antimicrobial drug consumer antiseptic active ingredients. In the 2013 Consumer Wash PR, products to address, for example, At each stage of this process, interested parties were invited to submit different categories of topical interested parties have had an comments on the proposed rule by June antimicrobial drug products and opportunity to participate in these 16, 2014. In addition, interested parties indications of use, as well as the need proceedings. It is not necessary now to had until December 16, 2014, to submit for new safety and effectiveness data withdraw the 2013 Consumer Wash PR new data or information to the docket, based on evolving scientific and reissue it as an ANPR. with 2 additional months provided to developments and new information on (Comment 2) Several comments submit comments on any new data or risks associated with use of these drug argued that the 2013 Consumer Wash information submitted (78 FR 76444 at products (59 FR 31402; 56 FR 33644; 78 PR should be reissued as an ANPR 76447). FR 764444; 80 FR 25166; 81 FR 42912). because the proposed rule only requests In response to the 2013 Consumer For each amendment, we have allowed testing on the active ingredients to Wash PR, FDA received approximately interested parties to submit comments demonstrate effectiveness and fails to 40 comments from drug manufacturers, on the proposals. confirm whether the Agency will trade associations, academia, testing In the 2013 Consumer Wash PR, we impose additional surrogate efficacy laboratories, consumer groups, and proposed that data from clinical requirements for a final formulation. health professionals, as well as over outcome studies (demonstrating a The comments contended that the 1,800 comments filed by individuals. reduction in infections) are necessary to Agency’s approach is inconsistent with FDA also received additional data and support a GRAE determination for the approach taken in the 1994 TFM information for certain consumer consumer antiseptic wash active and other OTC monographs. antiseptic wash active ingredients. ingredients (78 FR 76444). We (Response 2) The issue of whether the We describe and respond to the explained that, if the active ingredient 2013 Consumer Wash PR should be comments in section III.B through III.F. in a drug product does not provide reissued as an ANPR to include final We have numbered each comment to clinical benefit but potentially increases product formulation testing does not help distinguish between the different the risk associated with the drug (e.g., need to be addressed in this final rule comments. We have grouped similar from reproductive toxicity or because we have determined that none comments together under the same carcinogenicity), then the benefit-to-risk of the active ingredients subject to this number, and in some cases, we have calculation shifts, and the drug is not final rule are GRAE for use as a separated different issues discussed in GRAS/GRAE. For the consumer consumer antiseptic wash. Final the same comment and designated them antiseptic wash ingredients at issue formulation testing would be required as distinct comments for purposes of here, because of new concerns about the for testing formulations containing our responses. The number assigned to potential risks (e.g., resistance and active ingredients that have been each comment or comment topic is hormonal effects), the log reduction determined as GRAS/GRAE.

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2. Effective Date (Response 4) As discussed in section antiseptic wash drug products IV of this document, the data submitted addressed by this rulemaking include a (Comment 3) Several comments stated to the Agency for the non-deferred variety of personal care products that FDA’s timeline under the 2013 consumer antiseptic wash active intended to be used with water, such as Consumer Wash PR for new data ingredients is insufficient to fill all the antibacterial soaps, hand washes, and submission is unreasonable and that safety and effectiveness data gaps body washes, which may be used by completing clinical outcome studies identified in the 2013 Consumer Wash consumers for personal use in the home within the timeframe proposed by the PR. Thus, we find that these consumer and in certain public settings on a Agency is unrealistic. antiseptic wash active ingredients, frequent, even daily, basis (78 FR 76444 (Response 3) We understand that, in including tricoslan, are not GRAS/GRAE at 76446). We also indicate that certain circumstances, planning, for use in OTC consumer antiseptic ‘‘consumer antiseptic’’ is a broad term implementing, and analyzing the data wash drug products. Products and meant to include all the types of generated from a clinical outcome study containing those ingredients are antiseptic products used on a frequent can be a time-consuming process that therefore not eligible for inclusion in a or daily basis by consumers. This is may not be completed within the period monograph and must be removed from consistent with the October 2005 NDAC granted for submission of additional the market or must be approved through meeting, at which consumer antiseptics data in response to the 2013 Consumer an NDA or an abbreviated new drug were categorized as products used by Wash PR. Accordingly, in the 2013 application (ANDA). the general public, including the use of Consumer Wash PR, we provided a This final rule involves over 700 those products in institutional and process for seeking an extension of time consumer antiseptic wash drug public settings (Ref. 4). Therefore, we to submit the required safety and/or products, which are formulated with clarify that consumer antiseptic wash effectiveness data if needed (78 FR one or more of the 19 active ingredients products are products intended for use 76444 at 76447). As explained in the discussed in this final rule. In the 2013 with water by the general population in proposed rule, we stated that we would Consumer Wash PR, we recognized, the home or public settings on a consider all the data and information based on the scope of products subject frequent or daily basis. As such, submitted to the record in conjunction to this final rule, that manufacturers antiseptic wash products used by health with all timely and completed requests would need time to comply with the care professionals or commercial food to extend the timeline to finalize the rule (78 FR 76444 at 76470). We handlers or as first aid antiseptic monograph status for a given ingredient therefore proposed that the final rule be products are not considered consumer (78 FR 76444 at 76447). Consideration effective 1 year after the publication in antiseptic wash products. the Federal Register, finding that a for deferral for an ingredient was given 4. Food Handler Antiseptics to requests with clear statements of period later than 1 year after publication intent to conduct the necessary studies of the final rule would neither be (Comment 6) Several comments required to fill all the data gaps appropriate nor necessary (78 FR 76444 requested that FDA make a distinction between hand wash products for use by identified in the proposed rule for that at 76470). We also believe that making consumers and hand wash products for ingredient. After analyzing the data and the final rule effective immediately use by commercial food handlers. The information submitted related to the upon publication or effective 6 months comments explained that the food requests for extensions, we determined after publication does not afford industry includes commercial that deferral is warranted for three manufacturers the time necessary to enterprises involved in food processing, consumer antiseptic wash active remove from the market, or reformulate preparation, or handling, but does not ingredients—benzalkonium chloride, their products containing these active include home preparation. In addition, benzethonium chloride, and ingredients, given the broad scope of they explained that the food industry chloroxylenol—to allow more time for products that are the subject of this final provides a different environment for interested parties to complete the rule. Thus, we decline to adopt an immediate or 6-month effective date for hand washing compared to consumer studies necessary to fill the safety and this rule and, instead, as discussed in use, and as a result, a separate efficacy data gaps identified for these section V, adopt our proposal that this monograph category should be created ingredients as indicated in the 2013 final rule be effective 1 year after to define standards for food handlers. Consumer Wash PR. These three publication in the Federal Register. An opposing comment, however, ingredients are not included in this final objected to FDA creating another rule and will be addressed either after 3. Definition of Consumer Antiseptic category of antiseptics for the food completion and analysis of ongoing Washes industry, arguing that these antiseptics studies to address the safety and (Comment 5) Several comments raise the same safety concerns as efficacy data gaps of these ingredients or requested that the Agency clarify the consumer antiseptic wash products. at a later date if these studies are not definition of consumer antiseptic The comments that advocated for a completed. We decline to defer final washes, stating that the definition of separate category for antiseptics used by action on the proposed rule for the 19 consumer antiseptics in the 2013 the food industry stated that FDA remaining consumer antiseptic wash Consumer Wash PR does not include recognized the distinction between active ingredients. antiseptic products used in institutional consumer hand washes and hand (Comment 4) One comment requested settings. The commenters stated that by washes in the food industry in the 2013 that the Agency finalize the monograph not including such products in the Consumer Wash PR by stating that finding that triclosan and other definition of consumer antiseptic ‘‘antiseptics for use by the food industry antimicrobial chemicals are not GRAS/ washes, we put the general population are not discussed further in this GRAE, and, in so finding, require that at risk for increased levels of bacteria on document’’ (78 FR at 76446). The all consumer antiseptic wash active skin, which may lead to increased comments said that, despite this ingredients that are not GRAS/GRAE be infection and diseases for the general statement, the absence of further removed from the market either population. language specifically addressing hand immediately or within 6 months of the (Response 5) In the 2013 Consumer wash products for use in the food publication of the final rule. Wash PR, we explained that consumer industry creates the potential that

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antiseptic hand wash products used in a valid and feasible way to determine by controlled clinical trials the food industry may, by default, be efficacy because they have been used (§§ 330.10(a)(4)(ii) and 314.126(b) (21 subject to the requirements of the 2013 since the publication of 1978 TFM, can CFR 314.126(b)), unless this Consumer Wash PR. They also be modified to include additional requirement is waived as provided in requested that FDA clarify that hand controls and surrogate endpoints that § 330.10(a)(4)(ii). These studies must be wash products for use by the food would satisfy the Agency’s standards, well controlled and able to distinguish industry can continue to be marketed and have been used to support approval the effect of a drug from other under the current regulatory framework. of several NDAs. influences, such as a spontaneous (Response 6) As stated in the 2013 (Response 7) In the 2013 Consumer change in the course of the disease, Consumer Wash PR and the 2015 Health Wash PR, we proposed that data from placebo effect, or biased observation Care Antiseptic PR, we continue to clinical outcome studies (demonstrating (§ 314.126(a)). classify the food handler antiseptic a reduction in infections) are necessary The requirement for controlled washes as a separate and distinct to support a GRAE determination for clinical trials also is consistent with the monograph category, and we clarify that consumer antiseptic wash active recommendations of the October 2005 such products are not part of these ingredients (78 FR 76444 at 76450). We NDAC that clinical outcome studies be rulemakings on the consumer antiseptic explained that new concerns about the used to demonstrate the clinical benefit monograph (78 FR 76444 at 76446; 80 potential risks (e.g., resistance and of consumer antiseptic wash products FR 25166 at 25168). A separate category hormonal effects) shifted the benefit-risk and their superiority compared to a is warranted because of additional calculation. Therefore, the log reduction nonantibacterial wash, such as soap and issues raised by the public health standard (a clinical simulation standard) water (Ref. 4). Although two clinical consequences of foodborne illness, proposed in the 1994 TFM, which was outcome studies we identified in the differences in frequency and type of use, based on an invalidated surrogate 2013 Consumer Wash PR did not and contamination of the hands by endpoint (i.e., number of bacteria demonstrate a benefit from the use of grease and other oils. We plan to removed from the skin), was insufficient the tested antiseptic active ingredient, address OTC antiseptic products for use for establishing effectiveness of these studies were randomized, blinded, by the food handler industry in a consumer antiseptic washes. The and placebo-controlled, and separate rulemaking.2 We plan to do a requirement for clinical outcome studies demonstrate that such clinical outcome thorough evaluation of the safety and is based on the fact that sufficient data studies are feasible. For these reasons, effectiveness of antiseptic active to clearly demonstrate the benefit from FDA’s requirement that clinical ingredients intended for this category of the use of consumer antiseptic washes outcome studies be conducted to use. We also confirm that this final rule compared to nonantibacterial soap and demonstrate the effectiveness of the is not intended to affect antiseptic water are not available. Additionally, active ingredients for consumer products indicated for use by the food existing data cannot demonstrate a antiseptic wash products is warranted industry. correlation between log reductions of and reasonable. bacteria achieved by antiseptic hand (Comment 8) One comment also C. Comments on Effectiveness and FDA washing in surrogate testing and argued that FDA’s requirement for Response reduction of infection and, as the clinical outcome studies based on its 1. Clinical Outcome Studies October 2005 NDAC also concluded, the concern about the potential for (Comment 7) Several comments ability of consumer antiseptic wash increased antimicrobial resistance and challenged FDA’s proposal that clinical products to decrease bacteria on the endocrine disruption because of use of outcome studies be conducted to skin is insufficient for a GRAE finding consumer antiseptic wash active demonstrate the effectiveness of the if it is not supported by a direct clinical ingredients is unfounded. The comment active ingredients for consumer benefit (Ref. 4). Hence, in general asserted that the requirement of clinical antiseptic wash products, for the consumer settings where soap and water outcome studies is not supported by any following reasons: (1) Clinical outcome are readily available the benefit of using demonstration of a confirmed risk studies are unjustified and not feasible; an antiseptic wash product must be associated with the use of consumer (2) the potential for antimicrobial supported by clinical outcome studies. antiseptic products. (Response 8) We agree that the resistance is unfounded because there The efficacy requirements for consumer development of resistant mechanisms in has been no demonstration of a antiseptic washes differ from the natural settings is not sufficiently scientifically confirmed risk associated efficacy requirements proposed for studied. However, as discussed in more with the usage of consumer antiseptic consumer antiseptic rub products detail in section III.D.2, the concerns products; (3) FDA has not properly because the wash products are intended regarding the extended use of considered the potential risks caused by to be used when soap and water are not antiseptics, its potential consequences lack of access to antibacterial products available (81 FR 42912) (2016 Consumer on the systemic exposure, and its in consumers where specific Rub PR). In addition, the consumer potential consequences on the populations of consumers may be at antiseptic wash efficacy requirements development of bacterial resistance, increased risk of infection; (4) the differ from the efficacy requirements for must be assessed. A GRAS/GRAE requirement for clinical outcome studies health care antiseptics used in a determination for an active ingredient is far more extensive than antiseptic hospital setting, where study design for a particular intended use requires a requirements for consumer, food, or limitations and ethical concerns prevent benefit-to-risk assessment—in this case, health care antiseptics in other the use of clinical outcome studies (80 countries; and (5) simulation studies are FR 25166 at 25175 to 25176). the risk posed by use of a consumer Moreover, as explained in the 2013 antiseptic wash drug product must be 2 The Personal Care Products Council and Consumer Wash PR, FDA’s OTC balanced by a demonstration that the American Cleaning Institute submitted a citizen regulations (§ 330.10(a)(4)(ii)) define the product is statistically significant (p- petition in this rulemaking requesting FDA action standards for establishing an OTC active value <0.05) in reducing infections on issues related to food handler antiseptic wash ingredient as GRAE. These regulations compared to washing with products. This citizen petition and other issues related to food handler products will be addressed require the efficacy of active ingredients nonantibacterial soap and water, which in future documents. for OTC drug products be demonstrated refers to a soap formulation, solid or

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liquid, that does not contain any The comments also proposed that demonstration of effectiveness for antimicrobial ingredient. clinical simulation studies can be health care antiseptics and consumer (Comment 9) Commenters also modified to include additional controls antiseptic rubs, the reasons for those contend the Agency has not considered and neutralizers to satisfy the Agency’s different requirements, such as the the potential risks of an increase in requirements. The comments stated that challenges of conducting such studies in infections among consumers by their neutralization solutions are already the health care setting, and the fact that not having access to antibacterial included in the American Society for consumer rubs, which are intended for product formulations and commenters Testing and Materials (ASTM) 3 E1174 use when soap and water is unavailable, included publications in support of ‘‘Standard Test method for Evaluation of do not apply to consumer antiseptic their position. the Effectiveness of Health Care wash products used in general (Response 9) Although the submitted Personnel Hand Wash Formulations,’’ consumer settings. In addition, the publications demonstrate some increase and a vehicle control and an active infection risk in healthcare settings is of infection in consumer settings, they control such as Hibiclens 4 percent greater than in consumer settings, and do not address the effectiveness of could also be included in clinical as such, a clinical outcome study for consumer antiseptic wash products in simulation studies. healthcare antiseptics raises ethical the prevention or reduction of (Response 11) We agree that clinical questions regarding the use of non- infections. The cited studies underscore simulation studies and surrogate antimicrobial vehicle in patients. the urgency of scientifically endpoints have been used since the Studying the effectiveness of consumer demonstrating the contribution of publication of the 1978 TFM (43 FR wash antiseptics via clinical outcome consumer antiseptics in lowering the 1210) and continued to be a requirement studies in consumer settings is not infection rates in consumer settings. for demonstrating effectiveness in the unethical and, as previously shown, it is Although we acknowledge that there 1994 TFM (59 FR 31402). As addressed feasible (Refs. 8 and 9). may be populations with increased in the 2015 Health Care Antiseptic PR As stated in the 2013 Consumer Wash vulnerability to bacterial infection, such (80 FR 25166), we will continue to PR, we have evaluated all clinical as the elderly and persons with evaluate the effectiveness of health care simulation studies that were submitted suppressed immune systems, the data to antiseptic products based on both in to the OTC Drug Review for evidence of support the benefit of the use of vitro testing and clinical simulation antiseptic consumer wash active consumer antiseptic wash products over studies. However, the ethical concerns ingredient effectiveness demonstrated that of nonantibacterial soap and water and challenges of designing clinical under the log reduction criteria (78 FR in these populations is still lacking. trials in the hospital setting do not 76444 at 76451). We also evaluated the (Comment 10) Several comments apply to the consumer antiseptic wash publications referenced in the stated that the clinical outcome setting, where washing with soap and comments submitted in response to the requirements proposed in the 2013 water is a readily available alternative 2013 Consumer Wash PR. The studies Consumer Wash PR are more extensive for consumers, and clinical trials to described in the referenced publications and demanding than requirements for demonstrate clinical superiority are lack the appropriate controls of a establishing GRAE for active ingredients ethical and feasible. clinical outcome study, so we cannot, in other OTC monographs, and more With respect to approved marketing without additional evidence, attribute demanding than what is required for applications, we note that the Agency the reduction of infection rates to the antiseptics that are approved for use in has not approved any applications for use of antiseptic consumer wash active other countries. consumer antiseptic wash products ingredients (Refs. 10 and 11). In sum, (Response 10) Although the since the publication of the 1994 TFM. the studies we have evaluated are not requirement for clinical outcome studies The approved NDA products for which adequately controlled to support an for consumer antiseptic wash active evaluation of efficacy is based on in accurate assessment of the effectiveness ingredients may be a more stringent vitro testing results and clinical of consumer antiseptic wash active requirement than is used by some other simulation studies have been for ingredients. countries, FDA’s proposed effectiveness antiseptic products used in the health A demonstration of the effectiveness requirement is supported by FDA’s care setting. of the active ingredients used in regulations, the recommendations of the Moreover, although the addition of consumer antiseptic wash products October 2005 NDAC, as well as by vehicle and active controls, as well as should result from robust, properly available data and publications studying the inclusion of neutralization solutions designed, randomized studies with the clinical outcome of antiseptics, all of in the test method, may increase the adequate numbers of subjects and which support the requirement of accuracy of the testing itself, it does not clearly defined endpoints and analysis, clinical outcome studies (Refs. 8 and 9). meet the requirement of establishing a using reduction in infection rates rather Moreover, the existence of published direct connection between the use of than reduction in pathogen counts. For studies demonstrates that clinical consumer antiseptic wash active the reasons discussed in this section outcome studies are feasible. For the ingredients and infection reduction in a and in the 2013 Consumer Wash PR, reasons explained in this section, general consumer setting. A surrogate adequate clinical outcome studies that clinical outcome studies are necessary study, with or without additional identify the conditions of use on which to assure that the potential risk from use controls, is founded on the premise that an antiseptic active ingredient can of consumer antiseptic wash products is reduction of bacteria on skin because of demonstrate a reduction in the number balanced by a demonstrated clinical use of a consumer antiseptic active of infections, are required to benefit. ingredient (or product) will result in demonstrate the GRAE status of (Comment 11) Several comments reduction of infections, but it is not a consumer antiseptic wash active argued that clinical simulation studies direct proof of reduced infections. ingredients. are a valid way to demonstrate efficacy While we continue to propose the use 2. Testing of the Active Ingredient and that the log reduction of bacteria on of surrogate endpoints as a skin proposed to demonstrate efficacy (Comment 12) Several comments since the 1978 TFM, has been used to 3 General information about ASTM can be found argued that the testing of the active support the approval of several NDAs. at https://www.astm.org/. ingredients rather than testing of final

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formulation products is unnecessary vehicle in a consumer population. In the based on the indications of use for and not feasible because the delivery of 2013 Consumer Wash PR, the referenced antiseptic wash products, is much the active ingredient is heavily clinical outcome studies (Refs. 8 and 9) shorter—several minutes maximum. dependent on its vehicle and testing of are two-arm studies where the effect of Thus, information on the ability of the the active ingredient alone is not the antiseptic product in reduction of antiseptic wash active ingredient to possible. One comment stated that infections in a population is compared inhibit or eliminate bacterial growth although several consumer antiseptic to a non-antibacterial product. It is in after the prolonged exposure times used wash products may contain the same the presence of these controls (i.e., the in the MIC/MLC testing is not relevant active ingredient, they can also contain vehicle or a non-antibacterial product) to the actual use of the consumer different product formulations that that the contribution of the active antiseptic wash product. account for the effective delivery of the ingredient contained in a consumer The time-kill assay, on the other active ingredient, and, thus, test results wash antiseptic product can be hand, is designed to test shorter of one specific wash product may not determined. We note that if an exposure times against the represent the effectiveness of a variety ingredient is so highly formulation microorganisms selected for testing with of consumer antiseptic wash products dependent that the results of the the test material, and as such, it formulated with the same active efficacy testing cannot be extrapolated provides more relevant information on ingredient. to demonstrate the active ingredient’s how quickly the tested active ingredient (Response 12) The controlled clinical effectiveness, products containing such eliminates the tested microorganisms. The time-kill assay also includes strains trials required by FDA’s regulations are an ingredient may require an NDA. and clinical isolates of organisms most intended to demonstrate that the 3. In Vitro Testing/Time-Kill Assays commonly found in consumer settings pharmacological effect of the drug when (Comment 13) Several comments and provides relevant information on used under adequate directions for use urged FDA to revise its proposed in the kinetics of the antimicrobial activity will provide clinically significant relief vitro test methods for consumer wash of active ingredients with regard to the of the type claimed (§§ 330.10(a)(4)(ii) antiseptic active ingredients. They bactericidal activity of active and 314.126(b); 78 FR 76444 at 76450)), stated that for demonstrating ingredients used in consumer antiseptic i.e. efficacy for the stated indication. antibacterial activity of active wash products. GRAE determinations are made based ingredients, it is more relevant to Given that we are not requiring MIC/ on the active ingredient, not the perform a minimal inhibitory MLC tests to be performed, we do not product. We understand that testing the concentration and minimal lethal address whether specific performance effectiveness of only the active concentration (MIC/MLC) test to criteria should or should not be ingredient using clinical outcome determine the potency and spectrum of established for MIC/MLC testing of the studies may not be feasible because the the antibacterial activity of the proposed active ingredients. consumer uses the product in its final active ingredient before it is included in (Comment 14) Several comments also formulation form and not necessarily in an antibacterial product formulation. contended that the time-kill assay the form of the isolated active Several comments also recommended should be used for characterization of ingredient. We agree that a variety of that FDA not establish specific final product formulation, rather than aspects of a final product formulation performance criteria for MIC/MLC for evaluation of the effectiveness of the such as its pH, surfactancy, solubility, testing of the active ingredients because active ingredient, given that many as well as the product’s stability, the ingredients have not yet been characteristics of the formulation, such depend on the formulation of the formulated. as its stability, solubility, and pH, have vehicle and can have an impact on the (Response 13) In addition to the a significant influence on the delivery of the active ingredient, as well clinical outcome studies FDA proposed performance outcome of the antiseptic as its antibacterial activity. We agree in the 2013 Consumer Wash PR, FDA product. They urged FDA to adopt that test results of one specific wash proposed an in vitro study consisting of ASTM E2783, ‘‘Standard Test Method product may not represent the a modified time-kill assay conducted on for Assessment of Antimicrobial effectiveness of a variety of consumer selected reference organisms and their Activity for Water Miscible Compounds antiseptic wash products formulated respective clinical isolates, which are Using a Time-Kill Procedure,’’ as the with the same active ingredient. representative of bacterial strains most standard for conducting the time-kill However, the proposal for conducting commonly encountered in general assay. They also argued that the adequate and well-controlled clinical consumer settings (78 FR 76444 at performance criteria for the time-kill outcome studies to demonstrate that the 76452 to 76453). The purpose of the in assay proposed in the 2013 Consumer active ingredient of a consumer vitro study is to characterize the Wash PR are more demanding than the antiseptic wash product is GRAE was antimicrobial activity of the active performance abilities of approved health not intended to be a study conducted ingredients used in consumer antiseptic care antiseptic products. only on the active ingredient, but rather wash products. (Response 14) Testing requirements a study designed to determine the As explained in the 2013 Consumer for the final product formulations are contribution of the active ingredient to Wash PR, the requirement for clinical not addressed in this final rule because the effectiveness of the product. To outcome studies lessens the need for none of the active ingredients that are determine that the active ingredient is extensive in vitro studies, given that the the subject of this final rule are GRAE, the clinical outcome studies primary support for a GRAE considered GRAE for use in consumer should include at least two arms: The determination is the clinical outcome antiseptic wash products, given the lack final formulation of the product and the study. MIC/MLC tests assess the of sufficient effectiveness data for these vehicle. The effectiveness of the active minimal concentration of the active ingredients. The testing requirements ingredient, and hence its contribution in ingredient needed to cause inhibition of for final formulations of products the reduction of infections, will be growth and/or lethality to bacteria after containing the three deferred active determined by comparing the infection a 24-hour exposure to the active ingredients will be addressed after a rate of the active ingredient plus its ingredient. However, the exposure time decision is made regarding the vehicle to the infection rate of the of consumer wash active ingredients, monograph status of those ingredients.

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In addition, for purposes of the three consumer antiseptic hand wash used in standardized tool for bacterial transfer. deferred active ingredients, we have the study. There are other factors besides the size reviewed the ASTM E2783–11 and do (Comment 15) Several comments of the melon balls, such as the melon’s not disagree with the use of this method disagreed with the Agency’s concerns ripeness and surface texture, which may for the deferred active ingredients to and supported the use of the MBDT introduce variability to bacterial help establish GRAE status for a model for establishing a GRAE transfer. Also, bacterial transfer may be consumer antiseptic wash product with classification for relevant active affected by the amount of fat/grease a bacterial indication, as long as all the ingredients, as well as supported contained in a food item. These issues bacterial strains and the respective optional final formulation testing that is cannot be addressed by using the melon clinical isolates proposed in the 2013 intended to correlate clinical simulation ball as a standardized object to study Consumer Wash PR are included in the study results with clinical outcome. bacterial transfer (Ref. 13). The test. Published data and recent studies were comments provided no useful data to With regard to the comment that the included in the comments submitted in assess the effects of these variables on performance criteria of the time-kill response to the 2013 Consumer Wash the absolute counts of bacteria assay are more demanding than the PR to address the validity of the MBDT transferred from hands to food items performance abilities of approved health model and two other models used along and the overall study outcome. care antiseptic products, the proposed with the MBDT model: (1) The Palmar Overall, the MBDT model, including 99.9 percent elimination of bacteria hand-contamination method—the the QMRA analysis, cannot be used as describes the concentration and the time model of bacterial hand contamination a standardized method to validate the of contact at which the active ingredient and (2) a computational simulation effectiveness of consumer antiseptic would be considered bactericidal. This model known as the Quantitative wash active ingredients. Such a model criterion is based on the performance of Microbial Risk Assessment (QMRA) assesses bacterial transfer as a surrogate alcohol formulations (61 percent to 85 model. for disease and is not capable of (Response 15) We reviewed and percent) and on the expectation that an showing the direct clinical benefit of an evaluated the submitted materials, effective consumer antiseptic product antiseptic active ingredient or an including the studies previously will demonstrate a comparable antiseptic product for the general addressed in the 2013 Consumer Wash bactericidal activity. The 2013 consumer population. Instead, it PR. The studies show a reduction of Consumer Wash PR did not propose that measures the transfer of bacteria from bacteria on skin, as well as reduced contaminated hands to melon balls, a a 99.9 percent performance criterion bacterial transfer from hands to objects measurement that is then used in a risk would have to be achieved on all the or food items because of use of assessment model to provide a proposed reference strains and clinical consumer antiseptic wash products. In hypothetical infection reduction isolates to make a GRAE determination the Schaffner et al. study, statistical estimate based on infection data for the active ingredient. analysis and the QMRA model were generated from S. flexneri dose-response In summary, the clinical results used, in addition to the previously studies with limited data. The proposed necessary to support a GRAE finding for reported MBDT model, in an effort to MBDT model reflects only one facet of any of the consumer antiseptic wash establish a quantitative link between the the multiple uses of consumer antiseptic active ingredients addressed in this final effectiveness of antiseptic products and wash products. Consumers can be rule have not been demonstrated. The the reduced potential for disease such as exposed to pathogenic organisms not effectiveness of each of the three Shigellosis and other low-dose enteric only through food preparation activities, consumer wash active ingredients pathogens (Ref. 12). but also through contact with a variety deferred from this rulemaking will be After evaluation, however, we find of fomites in the domestic setting. evaluated on a case-by-case basis in the that the submitted data, which include Furthermore, the MBDT model does not future. the Palmar method and QMRA model, address the scenario where a consumer 4. Melon Ball Model To Support a do not address the deficiencies of the would transfer the disease from their GRAE Determination MBDT model previously analyzed in the contaminated hands to other parts of 2013 Consumer Wash PR for the their bodies (self-inoculate). In the 2013 Consumer Wash PR, we following reasons: Although the QMRA analysis may be evaluated a study submitted to the OTC • The Palmar method is not reflective useful for exploratory analysis for risk Drug Review involving a testing of the intended use of consumer assessment and management, it is not protocol referred to as the Melon Ball antiseptic wash products and does not used for demonstrating the efficacy of Disease Transmission (MBDT) model take into consideration the bacteria drugs for approval. The comment (78 FR 76444 at 76451 to 76452). The residing under the fingernails, which is provided references to show that QMRA MBDT model attempts to link the an important reservoir for bacteria. analyses have been adopted by many efficacy of washing with antibacterial Sufficient data to compare the Palmar agencies, including FDA. Our literature consumer wash to infection reduction method to the full-hand contamination search confirms that QMRA analyses are by correlating the reduction of bacterial method currently used are not provided. used to estimate the impact of food transfer to a food item following the use • The limitations of the dose- safety policies (Ref. 14), or to predict the of a consumer antiseptic hand wash to response model generated from S. probability of adverse effects in a reduction of infection. In the 2013 flexneri dose-response studies, vaccination (Ref. 15). However, we did Consumer Wash PR, FDA raised several including the small number of subjects, not find any evidence of QMRA analysis concerns regarding the validity of the variability in the dose-response data, employed as direct proof in determining MBDT model. We found the MBDT and lack of uniformity on criteria used the efficacy of a drug product or an model deficient and inadequate to link for the definition of illness, remains the active ingredient. reduction of bacteria to a reduction in same as previously addressed in the The MBDT model fails to prove that infection incidences (78 FR 76444 at 2013 Consumer Wash PR (78 FR 76444 reduction of the pathogen counts on 76451). Therefore, we concluded, the at 76451). hands will translate into a clinically results of the MBDT study did not • Although melon is a readily found meaningful benefit, and as such, the demonstrate the effectiveness of the food item, it cannot be used as a MBDT model cannot be a substitute for

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adequate clinical outcome studies that outcome study design provided by the antiseptic wash active ingredients can identify conditions of use under which Agency with regard to the three deferred be classified as GRAS. an antiseptic wash active ingredient is consumer antiseptic wash active 2. Resistance capable of reducing the number of ingredients allow for demonstration of infections. The data demonstrating the reduction of infections of either (Comment 18) Numerous comments effectiveness of the active ingredients bacterial or viral origin. If the clinical relating to the issue of bacterial used in consumer antiseptic wash outcome studies demonstrate that these resistance were submitted in response to products should result from robust, active ingredients can reduce infections the 2013 Consumer Wash PR. Some properly designed, randomized studies of origin other than bacterial (i.e. comments argued that the pervasive use with adequate numbers of subjects and viruses), additional testing to further of consumer antiseptics poses an clearly defined endpoints and analysis, characterize the activity of these unacceptable risk for the development assessing reduction in infection rates ingredients must be determined. of resistance and that these products rather than reduction in pathogen Therefore, testing requirements for final should be removed from the market. counts. product formulation cannot be finalized Other comments disagreed and before we have made a determination criticized the data on which they 5. American Society for Testing and believe FDA has based its concerns. Materials Standard Methods that a deferred active ingredient is GRAE. Depending on the indication(s) Specifically, several comments (Comment 16) Several comments supported by clinical outcome studies dismissed the in vitro data cited by FDA addressed the test methods for for an active ingredient, additional final in the 2013 Consumer Wash PR as not demonstration of effectiveness for final product formulation testing, other than reflecting real-life conditions. The product formulations and proposed that the ASTM methods suggested, may be comments recommended that the most useful assessment of the risk of biocide the Agency recognize several ASTM test required. methods for determination of resistance and cross-resistance to effectiveness for final product D. Comments on Safety and FDA antibiotics are in-situ studies, studies of formulations, including the ASTM Response clinical and environmental strains, or E1174 ‘‘Standard Test Method for biomonitoring studies. Some comments Evaluation of the Effectiveness of Health 1. Additional Safety Testing asserted that studies of this type have Care Personnel Hand Wash Requirements reinforced the evidence that resistance Formulations,’’ the ASTM E2784 (Comment 17) One comment stated and cross-resistance associated with ‘‘Standard Test Method for Evaluation that before proposing new safety testing, antiseptics is a laboratory phenomenon of the Effectiveness of Hand Wash FDA must consider the actual risks. The observed only when tests are conducted Formulations Using the Paper Towel comment argued that if current product under unrealistic conditions. Another (Palmar) Method of Hand exposures do not present risk based on comment cited the conclusions of an International Conference on Contamination,’’ the ASTM E1874 the existing data, new data should not Antimicrobial Research held in 2012 on ‘‘Standard Test Methods for Recovery of be required. The comment further a possible connection between biocide Microorganisms From Skin Using the recommended that existing data should (antiseptic or disinfectant) resistance Cup Scrub Technique,’’ and the ASTM be reviewed in relation to increased risk and antibiotic resistance to support the E2783 method ‘‘Standard Test Method rather than increased analytic point that there is no correlation for Assessment of Antimicrobial sensitivity and that if FDA finds that between antiseptic use and antibiotic Activity for Water Miscible Compounds there is no demonstration of risk, FDA resistance (Ref. 16). Using a Time-Kill Procedure.’’ should conclude that the active (Response 16) As discussed in section (Response 18) Laboratory studies have ingredients and formulations are safe. IV, none of the active ingredients identified and characterized bacterial subject to this final rule have been (Response 17) We decline to resistance mechanisms that confer a found to be GRAE for use in a consumer withdraw our requirement in the 2013 reduced susceptibility to antiseptics antiseptic wash product. We will Consumer Wash PR for the additional and, in some cases, clinically relevant evaluate the GRAS/GRAE status of the safety data that we determined is antibiotics (Refs. 17 through 27). three deferred active ingredients either necessary to support a GRAS Bacteria expressing these resistance upon completion and analysis of all classification for the consumer mechanisms with a decreased safety and effectiveness studies required antiseptic wash active ingredients. As susceptibility to antiseptics have been for these ingredients or at a later date if explained in the 2013 Consumer Wash isolated from a variety of natural these studies are not completed (78 FR PR, several important scientific settings (Refs. 28 through 30). These 76444 at 76458). For these reasons, it is developments that affect the safety studies found that the prevalence of premature to discuss final product evaluation of the consumer antiseptic antiseptic tolerant subpopulations in the formulation testing requirements before wash active ingredients have occurred natural microbial populations studied is a decision is made on the adequacy of since FDA’s 1994 evaluation. New data currently low. Morrissey et al. data to provide to support monograph and information on the antiseptic wash concluded, however, that their study status of the three deferred active active ingredients raise concerns findings could not rule out the existence ingredients. regarding potential risks from systemic of other resistant isolates that could be We note, however, that the suggestion absorption and long-term exposure, as found if more isolates were analyzed. to accept the ASTM test methods used well as development of bacterial In general, studies have not clearly in clinical simulation studies for final resistance related to use of consumer demonstrated an impact of antiseptic product formulation testing is based on antiseptic washes (78 FR 76444 at bacterial resistance mechanisms in the the assumption that for the consumer 76445). The data required by the 2013 natural setting. However, the available antiseptic wash active ingredients for Consumer Wash PR is necessary for studies have limitations. As FDA noted which clinical outcome studies will FDA to conduct an adequate safety in the 2013 Consumer Wash PR, studies demonstrate effectiveness, only evaluation. The comments do not in a natural setting that it evaluated antibacterial claims would be provide sufficient data to support a were limited by the small numbers and supported. The guidelines for clinical determination that these consumers types of organisms, the brief time

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periods, and the locations examined; potential to select for resistant impact of exposure to nonlethal and more importantly, none of these microorganisms. amounts of antiseptic active ingredients studies address the level of exposure to Adequate data do not currently exist on antiseptic and antibiotic bacterial the antiseptic active ingredient (Refs. 30 to determine whether the development susceptibilities. We noted that only through 33) (78 FR 76444 at 76454). of bacterial antiseptic resistance could limited data exist on the effects of These limitations were also found in the also select for antibiotic resistant antiseptic exposure on the bacteria that studies cited by the comments (Refs. 35 bacteria or how significant this selective are predominant in the oral cavity, gut, through 37). There was, however, one pressure would be relative to the skin flora, and the environment, and study that found a difference in the overuse of antibiotics, an important that these organisms represent pools of antiseptic and antibiotic susceptibilities driver for antibiotic resistance. resistance determinants that are of some of the bacteria evaluated (Ref. Moreover, the possible correlation potentially transferable to human 38). between antiseptic and antibiotic pathogens (78 FR 76444 at 76457). Thus, Carson et al. assessed the effect of resistance is not the only concern. we proposed broader laboratory testing antibacterial product use (cleaning Reduced antiseptic susceptibility may of consumer antiseptic active products containing quaternary allow the persistence of organisms in ingredients that would more clearly ammonium compounds including the presence of low-level residues and define the scope of the impact of benzalkonium chloride and hand soap contribute to the survival of antibiotic antiseptic active ingredients on the containing 0.2 percent triclosan) in the resistant organisms. Data are not development of antibiotic resistance and home environment on susceptibility to currently available to assess the may enable identification of those benzalkonium chloride, triclosan, and magnitude of this risk. antiseptic active ingredients for which antibiotics. Data were collected as part (Comment 19) Other comments the development of resistance is not a of a longitudinal double-blind, disagreed that the development of concern. We are aware that there are no randomized clinical trial that compared resistance to a particular ingredient has standard protocols for these studies. the susceptibilities of bacteria isolated been demonstrated. The comments also However, there are numerous disagreed on the type of data needed to from antibacterial user and nonuser publications in the literature of studies assess the risk of the development of households at baseline and after 1 year. of this type that could provide guidance resistance. One comment disagreed with The MICs of 645 isolates were on the study design (Refs. 40 through the proposed testing described in the evaluated. The study found that after 1 44). 2013 Consumer Wash PR, arguing that year of assigned product usage, bacterial For antiseptic active ingredients for there are no standard laboratory isolates with high benzalkonium which an effect on antiseptic and methods for evaluating the development chloride MICs were more likely to have antibiotic susceptibilities is of antimicrobial resistance. With regard demonstrated, we proposed that high triclosan MICs and be resistant to to the recommendation for mechanism additional data would be necessary to one or more antibiotics. studies, some comments asserted that it help assess the likelihood that changes Other data on a possible correlation is unlikely that this kind of information in susceptibility observed in the between antiseptic and antibiotic can be developed for all active preliminary studies would occur in the resistance are conflicting. Copitch et al. ingredients, particularly given that the consumer setting. Several different found that the majority of isolates with mechanism(s) of action may be types of data were recommended to decreased resistance to triclosan were concentration dependent and assess whether or not ingredients with also resistant to multiple antibiotics in combination/formulation effects may be positive laboratory findings pose a their series of 428 isolates screened for highly relevant. The comments also public health risk, and the type of data decreased susceptibility to triclosan and believed that data characterizing the needed would depend on what is a panel of antibiotics (Ref. 29). potential for transferring a resistance already known about the antiseptic Conversely, Skovgaard et al. found no determinant to other bacteria is an active ingredient’s mechanism of action significant association between unrealistic requirement for a GRAS and persistence in the environment. We antibiotic resistance and triclosan determination. stated that we did not anticipate that it tolerance when they compared the Conversely, one comment would be necessary to obtain data from susceptibilities of current isolates of recommended that antimicrobial multiple types of studies for each active Staphylococcus epidermidis with resistance be addressed first through in ingredient to adequately assess its isolates collected in the 1960s before vitro MIC determinations. If an potential to affect resistance. Thus, the introduction of triclosan to the market organism is shown to develop resistance types of studies that would be in Denmark (Ref. 30). An analysis of rapidly, then the comment acceptable to help address this issue are 1,600 isolates of Staphlococcus aureus recommended that FDA should consider not limited to those described in the has shown a moderate correlation this negative information in its 2013 Consumer Wash PR (78 FR 76444 between susceptibility to benzalkonium evaluation. The comment believed that at 76457). chloride and some classes of antibiotics this test of the potential for the (Comment 20) One comment noted (e.g., quinolones, beta-lactams, and development of resistance is important that the recommendations in the macrolides), but not for triclosan (Ref. because consumer compliance with proposed rule pertaining to the type of 39). recommended use of consumer data that could be used did not consider In conclusion, bacteria expressing antiseptic wash products is variable and the safety of usage of antiseptics for resistance mechanisms with a decreased products that result in rapid another sensitive population: The susceptibility to antiseptics and some antimicrobial resistance would pose a immunocompromised. The comment antibiotics have been isolated from a public health risk. stated that this growing population may variety of natural settings (Refs. 28 and (Response 19) In the 2013 Consumer be at greater risk of developing bacterial 29). Although the prevalence of Wash PR, we proposed a tiered resistance from repeated usage of antiseptic tolerant subpopulations in approach as an efficient means of antiseptics, and the comment noted the natural microbial populations is developing data to address this issue. dangers that result from associated currently low, continued overuse of Laboratory studies were proposed as a infections that are unresponsive to antiseptic active ingredients has the feasible first step in evaluating the traditional antibiotics. The comment

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submitted no data to support its resulting from any animal testing they non-confidential material that is assertion, but asserted that there is a conduct. submitted to the docket or information need for research to clarify whether the (Response 21) The required number of that is publicly available when making bacterial composition of rodent cancer bioassay studies have in its evaluation of whether a given immunocompromised individuals is some cases been reduced for drug ingredient is GRAS/GRAE. adequately represented by the bacteria products; for instance, a waiver of E. Comments on Active Ingredients and identified for testing in the proposed dermal carcinogenicity may be FDA Response rule. The comment also suggested that considered for a substance used there may be an additional need to previously by another route if a chronic 1. Ethanol dermal study in an appropriate non- perform surveillance of the effects seen (Comment 22) A comment was in the immunocompromised after the rodent species shows no potential neoplastic effects and there are no other submitted to this docket regarding the use of consumer antiseptics for GRAS status of ethanol. increased risk of bacterial resistance, causes for concern, such as absence of a positive genotoxicity signal and (Response 22) This active ingredient because this has been demonstrated in is not marketed as a consumer antiseptic clinical settings. Another comment absence of association of exposure to the drug with a positive tumor signal in wash product, and, therefore is not recommended that FDA require that addressed. We will address this manufacturers establish and maintain systemic carcinogenicity data (Refs. 45 and 46). However, at this point, the comment, and any other comments active surveillance of this issue and regarding the GRAS status of ethanol, to require that this information be Agency has not adopted a policy regarding the use of route to route the extent that it applies to indications submitted to FDA every year. reviewed in the 2015 Health Care (Response 20) We acknowledge that extrapolation method using alternatives to animal testing such as in vitro data, Antiseptic PR and the 2016 Consumer there are segments of the general Rub PR. population that may be more at risk ADME and PBTK tools. We understand that animal use in from antiseptic/antibiotic cross- 2. Cetylpyridinium Chloride tests for the efficacy and safety of resistance and that further research is human and animal products has been (Comment 23) As noted in the 2013 needed to address this facet of this and continues to be a concern. We Consumer Wash PR, subsequent to the issue. However, because no monograph encourage sponsors to consult with us 1994 TFM we received requests that is being established for the consumer on non-animal testing methods they certain active ingredients be added to antiseptic wash active ingredients in believe may be suitable, adequate, the antibacterial monograph (78 FR this final rule, the requests for an FDA validated, and feasible. We are willing 764444 at 76448). One of these requirement for active surveillance of to consider if alternative methods could submissions included a citizen petition this issue do not apply for purposes of be assessed for equivalency to an animal that requested that we allow the use of this final rule. test method. cetylpyridinium chloride as an 3. Alternatives to Animal Studies However, there are still many areas antibacterial active ingredient for where animal testing is considered household liquid soap (Ref. 47). (Comment 21) One comment necessary and non-animal testing is not (Response 23) In the 2013 Consumer requested that FDA provide guidance on yet a fully available option. FDA Wash PR, we identified certain active how to reduce the use of animals in continues to support efforts to reduce ingredients, including cetylpyridinium testing done to assess the safety of animal testing, particularly whenever chloride that we considered ineligible consumer antiseptic washes. The new alternative methods for safety for evaluation under the OTC Drug comment recommended that FDA evaluation have been validated and Review as a consumer antiseptic wash. require manufacturers to conduct accepted by International Council on We noted that if the requested efficacy testing in humans before safety Harmonization (ICH) regulatory documentation for eligibility was testing in animals and to share the data authorities, but these efforts have not submitted, these active ingredients, resulting from any animal testing they yet resulted in the development of including cetylpyridinium chloride, conduct. The comment also alternative testing that eliminate animal could be determined to be eligible for recommended that FDA accept data testing altogether. We will not be evaluation (78 FR 76444 at 76448). from non-animal safety tests. discussing further in this final rule the Neither the citizen petition, nor other In addition, the comment specific issues raised in the comments submissions we have received in this recommended that FDA reduce the on animal testing because these issues rulemaking, include documentation number of rodent cancer bioassays are outside the scope of this rulemaking. demonstrating the eligibility of required, by allowing for the With respect to the recommendation cetylpryridinium chloride for evaluation extrapolation of data from the dermal that FDA require manufacturers to share under the OTC Drug Review for use as route of administration to the oral route, the data resulting from any animal a consumer antiseptic wash. and from the oral route to the dermal testing they conduct, FDA regulations Consequently, this citizen petition is route. The comment requested that FDA require that data and information denied and as indicated in section II.D, consider whether physiologically based relevant to the monograph and a GRAS/ we consider consumer antiseptic wash toxicokinetic modeling (PBTK), along GRAE determination be submitted to the products containing cetylpyridinium with certain non-animal in vivo and in docket for that monograph and made chloride to be new drugs that require vitro absorption, distribution, publicly available (§ 330.10(a)(2)). FDA approval through the NDA process. metabolism, and excretion (ADME) data, Accordingly, any such animal testing could support route-to-route data should be publicly available and 3. Hexylrescorinol extrapolation. The comment further can be obtained from the docket for this In the 2013 Consumer Wash PR, FDA recommended that FDA adopt in vitro rulemaking. We also note that although proposed to classify hexylresorcinol as testing strategies to replace testing using there is a process for submitting Category III for both safety and efficacy animal models. Lastly, the comment confidential information, the OTC drug (78 FR 76444 at 76458). FDA stated that FDA should require monograph process is generally a public determined that the administrative manufacturers to share the data process. The Agency considers either record for the safety of hexylresorcinol

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was incomplete with respect to the hexylresorcinol has not been adequately the scope of the 2013 Consumer Wash following: addressed. No new data were submitted PR, that a category I classification be • Human pharmacokinetic studies to the docket to fill other safety data maintained for povidone-iodine, 5–10 under the maximal use conditions gaps identified in the 2013 Consumer percent, with a molecular weight at or when applied topically, including Wash PR. In addition, as discussed in above 35,000 Daltons. documentation of validation of the section IV of this document, no new (Response 25) The testing methods used to measure data were submitted to the docket to requirements for a GRAS/GRAE finding hexylresorcinol and its metabolites demonstrate the effectiveness of the as proposed in the 2013 Consumer • Animal pharmacokinetic studies on active ingredients subject to this final Wash PR, apply to all consumer ADME rule, including hexylresorcinol, for use antiseptic wash products containing the • Data to help define the effect of as a consumer antiseptic wash product. active ingredients that are the subject of formulation on dermal absorption Therefore, hexylresorcinol is not GRAS/ this final rule and that are intended to • Dermal carcinogenicity GRAE for use in consumer antiseptic be used with water, such as antibacterial • Developmental and reproductive wash products. soaps and antibacterial hand washes (76 FR 76444 at 76446). If the labeling for toxicity (DART) data 4. Iodophors/Povidone-Iodine • Potential hormonal effects these products contains an indication • Data from laboratory studies that In the 2013 Consumer Wash PR, we for use as a consumer antiseptic wash, assess the potential for the proposed to classify iodophor then the product is subject to the testing development of resistance to complexes, including povidone-iodine, requirements of the 2013 Consumer hexylresorcinol and cross-resistance 5–10 percent, as Category III, Wash PR, even if the labeling also to antibiotics in the types of determining that the available safety contains an indication for other uses, organisms listed in section VII.C.3 of and effectiveness data were insufficient such as for a first aid antiseptic. the 2013 Consumer Wash PR (78 FR and further testing was required (78 FR Moreover, because consumer 76444 at 76457) 76444 at 76459). FDA determined that antiseptic washes may be used on the administrative record for the safety multiple occasions throughout a (Comment 24) One comment person’s lifetime, this use pattern is referenced a 13-week oral toxicology of iodophors was incomplete with respect to the following: considered to be chronic. According to study from the National Toxicology the International Council for • Human studies of the absorption of Program (NTP) conducted in rats, in Harmonization guideline, a use is iodine following maximal dermal which there were reports of reduction in considered chronic if a certain drug is exposure to the complexes the size of seminal vesicles and used for a period of at least 6 months • Human absorption studies of the hypospermatogenesis (abnormally low over the user’s lifetime, including carrier molecule for small molecular sperm production). The comment repeated, intermittent use. Thus, weight povidone molecules and the asserted that FDA should evaluate these chronic exposure testing is necessary for other carriers listed in the 2013 effects on the male rat reproductive a GRAS/GRAE determination for the Consumer Wash PR organs to fill the DART data gap for active ingredients used in these • Dermal carcinogenicity studies for hexylresorcinol. consumer antiseptic wash products each of the iodophor complexes (Response 24) Although this technical even if a particular ingredient’s labeling • Data from laboratory studies that report was cited in the 2013 Consumer recommends that the product’s use assess the potential for the Wash PR (78 FR 76444 at 76475, Ref. should be limited in duration. 120) for hexylresorcinol, the data in this development of resistance to iodine In addition, we decline to classify 13-week study is not sufficient to and cross-resistance to antibiotics in povidone-iodine 5–10 percent with a conduct an adequate DART assessment the types of organisms listed in the molecular weight at or above 35,000 for hexylresorcinol (Ref. 48). 2013 Consumer Wash PR (78 FR Daltons as Category I (GRAS/GRAE) for Specifically, the NTP report described 76444 at 76453) use in consumer washes. Although we toxicity and carcinogenicity studies of (Comment 25) One comment stated in the 2013 Consumer Wash PR hexylresorcinol. The report consisted of requested that the Agency clarify that that the larger molecular weight-size three sets of studies, 16-day studies, 13- multiuse consumer antiseptic products povidone molecules pose no risk of week studies, and 2-year studies, all containing the active ingredient absorption, and we only requested conducted in mice and rats of both povidone-iodine intended for first aid human absorption studies of the carrier sexes. Although the findings in the 13- use and general purpose antiseptic molecule for small molecular weight week studies appear to show an effect cleansing and labeled for only short- povidone molecules, there are still of hexylresorcinol on the reproductive term use over limited areas of the skin remaining safety data gaps for the system in high-dose male rats, according are outside the scope of the 2013 iodophors, including large molecule to the NTP report, there was no Consumer Antiseptic PR. The comment povidone-iodine (76 FR 76444 at 76459 difference in the reproductive findings explained that the skin cleanser’s to 76461). For example, we determined between controls and high-dose-treated primary use is as a first aid antiseptic that the administrative record for the males. No adverse findings were noted and it is sold in the first aid aisle of safety of iodophors was incomplete for for the reproductive organs examined in retail stores. They also explained that dermal carcinogenicity studies. males and females treated with high although the labeling provides for uses Accordingly, because the safety data doses of hexylresorcinol in the 2-year as a wash, it recommends only short gaps have not been addressed, we carcinogenicity studies in rats and mice. term use over limited areas of the skin, cannot make a GRAS determination on However, the findings from the general consistent with the 1991 First Aid TFM; the iodophors, including the large toxicity studies (13-week and 2-year and thus, the safety studies proposed in molecule povidone-iodine. carcinogenicity studies) do not address the 2013 Consumer Wash PR should not (Comment 26) Another comment all relevant reproductive and be required for such multiuse skin stated that human absorption data developmental endpoints for cleansing products. The comments also required for the iodophors should take hexylresorcinol. Accordingly, we find requested that if FDA determines that precedence over the requirement for that the safety data gap for DART for multiuse antiseptic products are within dermal carcinogenicity studies to fill the

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safety data gaps for the iodophors. The generally believed to be nonspecific in lack of reports of the development of comment argued that data from the its antimicrobial action (Ref. 55). The resistance to iodine, there currently are human absorption studies may reduce antimicrobial activity of iodine is insufficient data on which to base a the number of carcinogenicity studies caused by its oxidizing effects on amino concern about the development of needed to fill the safety data gaps for (NH-), thiol (SH-), phenolic hydroxyl resistance to povidone-iodine. iodophors. (OH-) groups of amino acids and Consequently, additional data on the (Response 26) Antiseptic products, nucleotides. These reactions lead to a development of antimicrobial resistance such as povidone-iodine, are applied loss in protein structure and function to povidone-iodine are not needed to topically and require toxicological and an inhibition of protein synthesis. make a GRAS determination. evaluation in dermal studies to assess Iodine also reacts with the double bonds the potential safety signals following the of unsaturated fatty acid components of 5. Triclocarban exposure. The reason for requiring cell wall and organelle membranes, In the 2013 Consumer Wash PR, FDA dermal assessment is because the skin compromising the integrity of these proposed to classify triclocarban as dose resulting from a topically applied structures. The effects of povidone- Category III for safety and efficacy (78 drug product can be much higher than iodine on cell ultrastructure have been FR 76444 at 76449). FDA determined the dose detected in the skin as a result observed at concentrations as low as that the administrative record for the of systemic exposure. In addition, 0.025 percent povidone-iodine in safety of triclocarban was incomplete systemic exposure to the parent drug Staphylococcus aureus, Esherichia coli, with respect to the following: and metabolites can differ significantly and Candida albicans (Ref. 49). A • Human pharmacokinetic studies in topically applied products compared decrease in enzyme (b-galactosidase) under the maximal use conditions to orally administered products because activity and nucleotide efflux was also when applied topically, including the skin has its own metabolic apparent at 0.42 and 0.83 percent documentation of validation of the capability, and the first-pass povidone-iodine (Ref. 49). These methods used to measure triclocarban metabolism, which is available concentrations are well below the and its metabolites following oral exposure, is bypassed in concentrations of povidone-iodine • Animal pharmacokinetic studies on the topical route of administration. In found in currently marketed products. ADME some cases, a waiver of dermal A search of the published literature • Data to help define the effect of carcinogenicity may be considered for a revealed two studies that attempted to formulation on dermal absorption substance used previously by another select for resistant bacterial strains after • Dermal carcinogenicity route if a chronic dermal study in an repeated exposure to sublethal • Developmental and reproductive appropriate non-rodent species shows concentrations of povidone-iodine (Refs. toxicity data no potential neoplastic effects and there 56 and 57). Houang et al. studied the • Potential hormonal effects are no other causes for concern, such as potential for the development of • Data from laboratory studies that absence of a positive genotoxicity signal resistance to povidone-iodine by serial assess the potential for the and absence of association of exposure passage of two strains of each of the development of resistance to to the drug with a positive tumor signal following organisms: Escherichia coli, triclocarban and cross-resistance to in systemic carcinogenicity data (Refs. Klebsiella aerogenes, and one strain of antibiotics in the types of organisms 45 and 46). Furthermore, the absence of Serratia marcescens in sub-inhibitory listed in section VII.C.3 of the 2013 significant systemic absorption is not a concentrations (Ref. 56). The authors Consumer Wash PR (78 FR 76444 at qualifying reason to waive the reported no significant differences in 76456 to 76462) requirement for the dermal MIC, minimum bactericidal carcinogenicity study. concentration, or killing time after 20 (Comment 28) One comment (Comment 27) A comment submitted passages. Similarly, Prince et al. referenced a DART study conducted by on behalf of a marketer of an OTC reported that they had failed to detect Monsanto in 1979. The study was antiseptic product containing povidone- any changes in the MIC of six Gram- summarized in a triclocarban data set iodine asserted that povidone-iodine negative bacteria (Proteus mirabilis, compiled in 2002 by the Triclocarban does not pose a risk for the development Serratia marcescens, Serratia rubidaea, (TCC) Consortium and the Soap and of resistance (see section III.D.2 for a Pseudomonas cepacia (now known as Detergent Association. The comment more general discussion on resistance). Burkholderia cepacia), Pseudomonas requested that FDA evaluate the results The comment noted that none of the aeruginosa, and Salmonella enteritidis) of the study to fill the DART safety gap studies cited in the 2013 Consumer after 20 serial passages in povidone- for triclocarban. Wash PR concerning the development of iodine (Ref. 57). (Response 28) The TCC Consortium antiseptic/antibiotic resistance involve The search also revealed some reports Report was retrieved from the povidone-iodine. The comment stated of Burkholderia cepacia contamination Environmental Protection Agency (EPA) that historically, povidone-iodine has of povidone-iodine products (Refs. 58 High Production Volume Information not been associated with the through 62). However, the antiseptic System Web site. We were unable to development of resistance, and that it susceptibilities of the organisms isolated locate the 1979 Monsanto study in the has been found to be a useful tool were never established, making it hard docket and it does not appear to be against several multidrug resistant to determine whether the contamination available in the public domain. Thus, bacteria. In support of its position, the was the result of an existing intrinsic we cannot review this study for comment submitted data on the antiseptic resistance that has been purposes of this final rule. The data chemistry and antimicrobial effects of associated with Burkholderia cepacia or cited in the TCC Consortium data set are povidone-iodine and studies of the development of an increased proprietary and are publicly available povidone-iodine’s in vitro and in vivo tolerance. In addition, the literature only in the form of a summary (Ref. 63). effectiveness (Refs. 49 through 54). search revealed no reports of the In addition, the submitted safety (Response 27) Elemental iodine, development of resistance to povidone- assessments with the study summaries which is the active antimicrobial iodine. Consequently, given iodine’s do not constitute an adequate record on component of iodine containing multiple nonspecific toxic effects on which to base a GRAS classification antiseptics like povidone-iodine, is bacteria at low concentrations and the (§ 330.10(a)(4)(i)). For FDA to evaluate

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the safety of triclocarban for this • Potential hormonal effects Union’s Registration, Evaluation, rulemaking, there must be published • Data to clarify the relevance of Authorisation, and Restriction of studies or publicly available data with antimicrobial resistance laboratory Chemicals registration, as well as sufficient details that enable an findings to the consumer setting evaluate other referenced publications independent review of such data. (Comment 30) In response to the 2013 of regulatory agencies. (Comment 29) One comment also Consumer Wash PR, several comments (Response 31) We agree that there are stated that triclocarban was nominated were submitted regarding the safety data a number of similarities in to the NTP for toxicological evaluation gaps for triclosan. One comment argued pharmacokinetic parameters between in 2014, and based on this nomination, that recent and existing studies on humans and hamsters; however, the a Research Concept has been adopted by triclosan in each of the safety categories hamster data available do not include NTP (Ref. 64). The comment asserted prove that the existing studies, dermal ADME data that can be that the author of the Triclocarban including additional studies that were compared to the metabolic profile in Research Concept only discussed FDA’s not cited in the 2013 Consumer Wash humans following dermal exposure to proposal in regard to human absorption PR, are adequate to classify triclosan as triclosan. studies even though it identified several GRAS. We have reviewed data that were data gaps that were identified by FDA, (Response 30) FDA has conducted a submitted to the docket for this including ADME and DART studies. thorough review of all existing and new rulemaking, including recent studies The comment concluded that FDA data that have been submitted to the that were published after the 2013 should coordinate its efforts with those docket for this rulemaking, including Consumer Wash PR, as well as opinion of the NTP to ensure that experiments recent studies, as well as opinion papers papers published by other regulatory on the toxicological testing of published by other regulatory agencies agencies regarding the safety of triclosan triclocarban are not being duplicated. regarding the safety of triclosan. In some (Ref. 68). With the exception of one (Response 29) We concur with the cases, we identified new data that have study that we have identified that comment that FDA should coordinate been published since the 2013 provided new animal dermal ADME efforts with NTP. NTP through Consumer Wash PR—for example, the data, there were no additional ADME collaboration with FDA regularly meets new animal ADME dermal data data for triclosan that were submitted to with FDA scientists to coordinate discussed in the following section. In the docket. The ADME study that was research efforts and eliminate other cases, no new data having an identified has been recently published duplicative work whenever possible. impact on the safety profile of triclosan by National Center for Toxicology Although this ongoing study may were identified—for example, we found Research (NCTR) scientists (Ref. 68) provide important information on that certain references submitted in one where a 13-week dermal-dose range- triclocarban, there are still other missing of the comments did not provide finding toxicity study was conducted to data gaps for triclocarban for which additional information that would have determine the ADME profile of triclosan information has not been submitted and an impact on the safety assessment of after dermal exposure in mice. Based on no interested parties have committed to triclosan (Refs. 65 through 67). In sum, a previous dermal toxicity study in the filling these data gaps. Accordingly, the total available data regarding the mouse where a no observed adverse deferring consideration of this active safety profile of triclosan does not effect level of 12.5 milligram (mg)/ ingredient until the study is completed contain sufficient information to kilogram (kg) of body weight (bw)/day is unwarranted. determine that triclosan is GRAS for use was shown, doses of 10 and 100 mg/kg In conclusion, we find that the safety in consumer antiseptic wash products. bw triclosan were used. In this study, data gap for DART for triclocarban has In the following sections, we discuss mice of both sexes were exposed to not been adequately addressed. No new comments addressing the specific safety topical application of [14C(U)]triclosan data for triclocarban were submitted to data gaps for triclosan. (10 or 100 mg triclosan/kg body weight) the docket to fill other safety data gaps in 95 percent ethanol up to 72 hours a. Absorption, Distribution, Metabolism, identified in the 2013 Consumer Wash post exposure. Treated mice were and Excretion (ADME) Data PR. In addition, as discussed in section covered with Elizabethan collars to IV, no new data were submitted to the The 2013 Consumer Wash PR prevent inadvertent oral ingestion of docket to demonstrate the effectiveness discussed in detail the animal ADME triclosan. As a comparator group, mice of the active ingredients subject to this data available for triclosan (78 FR 76444 of both sexes were dosed with 100 mg/ final rule, including triclocarban, for use at 76467) and the data that were still kg bw where Elizabethan collars were as a consumer antiseptic wash product. lacking. FDA requested that additional not placed on their necks to determine Therefore, triclocarban is not considered ADME data be submitted to allow the extent of oral ingestion because of GRAS/GRAE for use in consumer bridging of animal data to human the normal grooming behavior in mice. antiseptic wash products. exposure. The study reported a dose-dependent (Comment 31) Several comments were increase in absorption was noted when 6. Triclosan submitted regarding animal ADME data comparing the 10 mg/kg bw to the 100 In the 2013 Consumer Wash PR, the for triclosan. Some of the comments mg/kg bw. The study also reported that Agency found that the administrative asserted that oral absorption, distribution of radiolabeled record for triclosan was incomplete with metabolism, and excretion are [14C(U)]triclosan was evaluated to respect to several safety data and comparable between hamsters and determine distribution up to 72 hours requested that additional information be humans, justifying data extrapolation. after dosing in the plasma and liver. The submitted for the following safety gaps They also asserted that oral absorption earliest radioactivity measureable was (76 FR 76444 at 76467 to 76470): data are complete in all species tested seen as early as 30 minutes post dosing, • Animal ADME and that metabolism is similar for both while maximum distribution was • Dermal carcinogenicity dermal and oral exposure. In addition, reached at approximately 8 to 12 hours • Data regarding the potential for some of the comments urged FDA to after dosing for both plasma and liver. formation of photodegradation evaluate key toxicokinetic studies in The major metabolite detected in the products on human skin and their hamsters, mice, and rats that have been plasma and liver was triclosan sulfate, effects on the skin submitted as part of the European whereas the minor metabolite was

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triclosan glucuronide. Maximum levels interaction of triclosan itself with exposure to the parent drug and occurred 12 to 24 hours after dosing, ultraviolet (UV) light. metabolites can differ significantly in and the excretion half-life (t1/2E) ranged (Comment 33) Another comment topically applied products compared to from 9.3 to 23.1 hours. The study also stated that triclosan has been found to orally administered products because reported that the majority of the degrade into four different byproducts the skin has its own metabolic excretion monitored over 72 hours under certain conditions: 2, 7- capability, and the first-pass occurred via the feces in both sexes and dibenzodichloro-p-dioxin; 2, 8- metabolism, which is available that fecal excretion of the absorbed dibenzodichloro-p-dioxin; 2, 4- following oral exposure, is bypassed in triclosan was ∼2.5 to 6-fold greater than dichlorophenol (DCP); and 2, 4, 6- the topical route of administration. As urinary excretion. trichlorophenol (TCP). In the presence was explained in the 2013 Consumer The data obtained from this study can of UV light (sunlight), triclosan has been Wash PR, we reiterate here that short- be used to extrapolate a safety margin shown to degrade into two dioxins: 2, 7- term dermal toxicity studies do not meet for humans following chronic dermal dibenzodichloro-p-dioxin; and 2, 8- the chronic duration requirement for a exposure once the dermal dibenzodichloro-p-dioxin. The given drug to cause an increase in the carcinogenicity study in the mouse, comment suggested that although the carcinogenic potential resulting from a which is currently ongoing at the NCTR, concentrations of the degradants are lifelong exposure to a drug, such as is completed. No further data is needed low, dioxin byproducts raise some triclosan, which is used by consumers for the animal ADME for triclosan. concern because of their potential to from various products over a lifetime. In accumulate in the human body because b. Photodegradation and Phototoxicity addition, we note that the 13-week of their lipophilicity. Both 2, 4-DCP and dermal toxicity study showed dose- (Comment 32) Several comments were 2, 4, 6-TCP are more stable than related dermal adverse effects, which submitted regarding the phototoxicity of triclosan, suggesting that the degradants further amplifies the need to evaluate triclosan. One comment explained that may have longer half-lives than the longer term toxicity studies, such as the a study is currently ongoing at the NTP parent drug, triclosan. 2-year dermal carcinogenicity bioassay. in response to the data gap on dermal (Response 33) Regardless of the A dermal carcinogenicity study is photocarcinogenicity from dioxins causative chemical, it is unknown at currently ongoing at NCTR but has not formed by light-induced degradation of this time whether exposure to triclosan been completed at this time. Although triclosan. The comments urged FDA to under UV light will lead to this ongoing study may provide await the results of this study before any phototoxicity or photocarcinogenicity important information on triclosan, further studies are conducted. Two events. In conclusion, the comments there are still other missing data gaps for other comments argued that concern provided insufficient data and triclosan for which information has not about triclosan dermal photolysis to information for assessing the been submitted and no interested ‘‘dioxins’’ is unfounded, and that the photodegradation of triclosan on human parties have committed to filling these most likely photolysis product, 2, 8- skin. Accordingly, the safety data gap data gaps. In sum, no new data or dichlorbenzodioxin is toxicologically for triclosan regarding the potential for information were submitted to the inert based on the toxicology formation of photodegradation products docket to fill the dermal carcinogenicity equivalency factor (TEF) concept (which on human skin and their effects on the safety data gap for triclosan. compares the toxicity of known skin has not been filled. members for a given chemical family d. Hormonal Effects and attributes a specific TEF for each c. Dermal Carcinogenicity compound compared to the most toxic (Comment 34) Several comments were In the 2013 Consumer Wash PR, we chemical of that family). received regarding the dermal stated that recent studies have (Response 32) We note that the carcinogenicity of triclosan. One demonstrated that triclosan showed comments did not provide any further comment argued that, based on FDA effects on the thyroid, estrogen, and justification or calculation of the TEF and EPA assessments, oral testosterone systems in several animal for the photolysis product, 2, 8- carcinogenicity studies in hamsters, species, including mammals, the dichlorbenzodioxin, to support the rats, and mice, supported by negative in implications of which on human health, claim that FDA’s concern about vitro and in vivo mutagenicity studies especially for children, are still not well triclosan dermal photolysis to ‘‘dioxins’’ show that triclosan is not a carcinogen. understood (78 FR 76444 at 76468). is unfounded. Instead, an assumption Therefore, the comments argued that the (Comment 35) One comment stated was made that 2, 8-dichlorbenzodioxin ongoing dermal carcinogenicity study is that the Organisation for Economic Co- is toxicologically inert based on the TEF unnecessary. Another comment stated operation and Development (OECD) TG concept. The TEF concept refers only to that dermal carcinogenicity is not 443 extended one-generation adverse effects (e.g., cancer) following supported by existing data, and no reproductive toxicity assay provides an interactions with their targets (e.g., chemical having negative mutagenicity alternative to animal studies and cellular aryl hydrocarbon receptors). and oral carcinogenicity data should be includes endocrine-sensitive endpoints. Other toxic effects of dioxins and expected to demonstrate dermal The comment asserted that the OECD dioxin-like compounds are not carcinogenicity potential. TG 443 study design allows for quantified by this method. In addition, (Response 34) We disagree that no investigation of developmental toxicity, TEF values vary for different animal dermal carcinogenicity study is needed developmental immunotoxicity, or species. Therefore, the ability of for triclosan based only on the negative developmental neurotoxicity in the triclosan degradants, which belong to mutagenicity and oral carcinogenicity same study, and that non-animal the dioxin family, to form studies. The requirement for dermal methods, when used in an integrated photodegradation products on human assessment is based on several factors: system, can provide embryotoxicity and skin cannot be assessed using the TEF First, the dose available to the skin teratogenicity information. The concept. Furthermore, it is currently tissue resulting from a topically applied comment also referenced several other unknown whether the photoactivity of drug product can be much higher than non-animal assays that were conducted triclosan is caused by one of the that from a dose resulting from systemic to assess the reproductive toxicity photoproducts or caused by the exposure. In addition, systemic potential for triclosan.

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(Response 35) We reviewed all effects of triclosan on the thyroid gland that there is no proof of triclosan available data on the hormonal effects of during critical windows of growth and resistance or confirmation that triclosan, including those generated development when subtle functional triclosan/antibiotic cross-resistance is from the extended one-generation and/or histopathologic changes are becoming a problem in the real world. reproductive toxicity assay mentioned taking place could result in disturbing The comment also noted that although previously in this document. We also the normal homeostasis of the organism; bacteria can develop reduced reviewed the previously conducted for example, whether long-term susceptibilities to triclosan in the studies for triclosan (general toxicity exposure to triclosan is associated with laboratory, the level of sensitivity is still and reproductive toxicity) where an adverse impact on the growth or well below the at-use concentration. reproductive toxicity endpoints were neurobehavioral aspects of animals However, other comments disagreed evaluated; however, we note that the treated during critical windows of and argued that recent studies provide previously conducted studies were not development is currently unknown. evidence of the development of designed to investigate specific We have evaluated the recently resistance to triclosan (Refs. 29 and 30). endpoints for evaluating the hormonal published articles in the literature (Response 37) We agree that currently effects of triclosan, especially with reporting on the endocrine effects of there is no evidence of bacterial respect to the thyroid findings. In terms triclosan in mammalian species. Data resistance to actual-use concentrations of the alternative animal model available to date do not provide of triclosan. However, bacterial argument, it is possible that in some conclusive evidence regarding the exposure to triclosan is not limited to instances that non-animal assays, such effects of triclosan on the levels of actual-use concentrations. In a natural as those referenced in comment 35, can estrogen, androgen, and thyroid setting, bacteria are exposed to sublethal be used to explore potential DART hormones and whether a link between concentrations of the antiseptic active findings for a new chemical entity. the hormonal effects and the ingredient that can trigger the However, in the case of triclosan, there biologically relevant outcomes on the expression of bacterial resistance are many in vivo studies that have tested animal model can be drawn. mechanisms. The European assessed DART endpoints, thus making Although no significant findings were Commission’s Subcommittee on the reliance on findings from the noted for reproductive endpoints, the Consumer Safety noted that there are referenced non-animal assays thyroid gland may be a potential target environmental concentrations of unnecessary. for triclosan in animals exposed to high triclosan in a number of geographically (Comment 36) Several other doses of triclosan. The reported findings distinct areas that were high enough to comments asserted that the existing in the thyroid included a dose suggest that this triggering of bacterial database of in vitro and in vivo animal dependent decrease in the levels of resistance could occur (Ref.70). and human studies does not support a some thyroid hormones in the rat model Furthermore, as previously discussed, conclusion that triclosan causes (T3 & T4) (Ref. 69). This observation was there are data that document the hormonal effects in humans at actual seen in pubertal males and females, in existence of numerous bacterial relevant exposure concentrations. The pregnant dams and their pre-weaned resistance mechanisms to triclosan, and comments asserted that the reports of exposed pups, as well as in young male there is some expression of these high throughput screening and animal and female rats (up to day 53 mechanisms in the natural microbial studies showing thyroid or other postpartum age). It is also important to populations. Although the available hormonal activity demonstrated note that the available rat studies for studies do not prove definitively that conflicting results for the effects of which the thyroid effects were triclosan/antibiotic resistance currently triclosan on various hormonal investigated in detail only covered a poses a public health risk, they do endpoints (androgen-, estrogen-, and short duration (up to 30 days of suggest that susceptibility to triclosan thyroid-related toxicity). One comment exposure). These changes seen in may be decreasing. Data are not also argued that additional testing for thyroid hormone levels in the rat do not currently available to assess the potential hormonal effects is not necessarily predict a similar scenario in magnitude of this risk that triclosan justified because of the existence of humans because of differences in the poses for the development of resistance. adequate reproductive toxicity data that, physiology and metabolic As we stated in the in the 2013 given the doses used, endpoints characteristics that triclosan imparts on Consumer Wash PR, data to clarify the measured and study duration, should the hormonal homeostasis in the two relevance of antimicrobial resistance have detected a potential for the species. Based on the available data, a laboratory findings to the consumer indication of biologically significant conclusion regarding the significance of setting would be necessary to determine androgen-, estrogen-, or thyroid-related the thyroid findings in the rat to that in the GRAS status of triclosan. toxicity if such toxicity occurred. The humans cannot be made. Using a f. Other Issues comment maintained that available in weight-of-evidence approach for the vitro high throughput screen thyroid findings, we find that no further (Comment 38) Several comments information on these endpoints fails to nonclinical data are recommended for expressed concern that antiseptic indicate a justifiable level of concern. the characterization of potential chemicals, including triclosan, are (Response 36) We agree that some hormonal effects of triclosan in humans. contaminating waterways and aquatic data for hormonal effects for triclosan Available in vitro and in vivo animal wildlife, and are having a negative can be gleaned from previously studies cannot be used to predict a impact on the wastewater treatment conducted studies (chronic toxicity, potential human hormonal signal. process and the environment. The DART, and multigenerational studies). Clinical studies may be better able to comments supported restrictions on the Although we concur that the previously evaluate the effects of triclosan on the use of triclosan in consumer antiseptic conducted toxicology and reproductive endocrine system in humans. washes and urged FDA and EPA to studies can be useful, we note that the coordinate their evaluation of chemicals previously conducted studies were not e. Resistance like triclosan to better protect human designed to investigate specific (Comment 37) Comments from a health and the environment, as well as endpoints for evaluating the hormonal manufacturer of consumer antiseptic protect the wastewater treatment effects of triclosan. In particular, the products containing triclosan asserted process.

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(Response 38) We do not address • Hexachlorophene costs and benefits of available regulatory these comments in this final rule • Hexylresorcinol alternatives and, when regulation is because they are outside the scope of • Iodophors (Iodine-containing necessary, to select regulatory this rulemaking. We note, however, that ingredients) approaches that maximize net benefits we have conferred with EPA, wherever Æ Iodine complex (ammonium ether (including potential economic, there were issues in common between sulfate and polyoxyethylene environmental, public health and safety, the two Agencies (e.g., some of the sorbitan monolaurate) and other advantages; distributive animal toxicology studies were Æ Iodine complex (phosphate ester of impacts; and equity). We have independently reviewed by both EPA alkylaryloxy polyethylene glycol) developed a comprehensive Economic and FDA), at various stages of the Æ Nonylphenoxypoly (ethyleneoxy) Analysis of Impacts that assesses the antiseptic proceedings on matters ethanoliodine impacts of the final rule. The Office of applicable to these rulemakings. Æ Poloxamer—iodine complex Management and Budget (OMB) has In sum, the total available data Æ Povidone-iodine 5 to 10 percent determined that this final rule is a regarding the safety profile of triclosan Æ Undecoylium chloride iodine significant regulatory action as defined do not contain sufficient information to complex by Executive Order 12866. find that triclosan is GRAS for use in • Methylbenzethonium chloride The Regulatory Flexibility Act consumer antiseptic wash products. • Phenol (greater than 1.5 percent) requires us to analyze regulatory options Moreover, we reviewed studies • Phenol (less than 1.5 percent) that would minimize any significant submitted in the comments to support • Secondary amyltricresols impact of a rule on small entities. efficacy for triclosan. These studies are • Sodium oxychlorosene Because a majority of firms that will be not designed as adequate and well- • Tribromsalan affected by this rule are defined as small • controlled clinical outcome studies and Triclocarban businesses, we find that the final rule • are not sufficient to determine the GRAE Triclosan will have a significant economic impact • status of triclosan as a topical antiseptic. Triple dye on a substantial number of small Moreover, these studies lack an Accordingly, OTC consumer entities. adequate vehicle or placebo controls, antiseptic wash drug products The Unfunded Mandates Reform Act which makes it difficult to determine containing these active ingredients are of 1995 (section 202(a)) requires us to the contribution of antiseptic hand wash misbranded, and are new drugs for prepare a written statement, which implementation to reduction of which approved new drug applications includes an assessment of anticipated methicillin-resistance Staphylococcus are required for marketing. costs and benefits, before issuing ‘‘any rule that includes any Federal mandate aureus infections. Thus, we find that V. Effective Date insufficient data were submitted to the that may result in the expenditure by docket to demonstrate the effectiveness In the 2013 Consumer Wash PR, we State, local, and tribal governments, in of triclosan for use as a consumer recognized, based on the scope of the aggregate, or by the private sector, of antiseptic wash product. Therefore, products subject to this final rule, that $100,000,000 or more (adjusted triclosan is not GRAS/GRAE for use in manufacturers would need time to annually for inflation) in any one year.’’ consumer antiseptic wash products. comply with this final rule. Thus, as The current threshold after adjustment proposed in the 2013 Consumer Wash for inflation is $146 million, using the F. Comments on the Preliminary PR (78 FR 76444 at 76470), this final most current (2015) Implicit Price Regulatory Impact Analysis and FDA rule will be effective 1 year after the Deflator for the Gross Domestic Product. Response date of the final rule’s publication in the This final rule would result in an (Comment 39) Several comments Federal Register. On or after that date, expenditure in any year that meets or raised issues concerning the preliminary any OTC consumer antiseptic wash drug exceeds this amount. regulatory impact analysis and the product containing an ingredient that B. Summary of Costs and Benefits Agency’s assessment of the net benefit we have found in this final rule to be of the rulemaking. not GRAS/GRAE or to be misbranded, As discussed in the preamble of this (Response 39) Our response is cannot be initially introduced or final rule, this rule establishes that 19 provided in the full discussion of initially delivered for introduction into active ingredients, including triclosan economic impacts, available in the interstate commerce unless it is the and triclocarban, are not generally docket for this rulemaking (Docket No. subject of an approved new drug recognized as safe and effective and are 1975–N–0012, http:// application. misbranded for use in OTC consumer www.regulations.gov) and at http:// antiseptic washes. Regulatory action is www.fda.gov/AboutFDA/ VI. Economic Analysis of Impacts being deferred on three active ReportsManualsForms/Reports/ The summary analysis of benefits and ingredients that were included in the EconomicAnalyses/default.htm. costs included in this final rule is drawn 2013 Consumer Wash PR: from the detailed Regulatory Impact Benzalkonium chloride, benzethonium IV. Ingredients Not Generally Analysis that is available at http:// chloride, and chloroxylenol. The costs Recognized as Safe and Effective www.regulations.gov, Docket No. FDA– and benefits of the final rule are In addition to the individual active 1975–N–0012 (formerly Docket No. summarized in table 3, entitled ingredients discussed in section III.E, no 1975N–0183H). Economic Data: Costs and Benefits additional safety or effectiveness data Statement. As table 3 shows, the have been submitted to support a A. Introduction primary estimated benefits come from GRAS/GRAE determination for the We have examined the impacts of the reduced exposure to antiseptic active remaining consumer antiseptic wash final rule under Executive Order 12866, ingredients by 2.2 million pounds per active ingredients. Thus, the following Executive Order 13563, the Regulatory year. We note that triclosan and active ingredients are not GRAS/GRAE Flexibility Act (5 U.S.C. 601–612), and triclocarban, are the most widely used for use as a consumer antiseptic wash: the Unfunded Mandates Reform Act of OTC consumer antiseptic wash active • Cloflucarban 1995 (Pub. L. 104–4). Executive Orders ingredients on the market, based on • Fluorosalan 12866 and 13563 direct us to assess all available data, thus, our analysis focuses

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on these two products. Using the prevent us from translating the relabeling and reformulation ranging primary estimates, the combined total estimated reduced exposure into from $106.3 to $402.8 million. Under consists of a reduction in triclosan monetary equivalents of health effects. the final rule, we estimate that each exposure by 799,426 pounds per year, The primary estimate of costs pound of reduced exposure to antiseptic and triclocarban exposure by 1.4 million annualized over 10 years is active ingredients will cost $12.97 to pounds per year. Limitations in the approximately $23.6 million at a 3 $14.28 at a 3 percent discount rate and available data characterizing the health percent discount rate and $27.6 million $16.36 to $18.02 at a 7 percent discount effects resulting from widespread long- at a 7 percent discount rate. These costs rate. term exposure to these ingredients consist of total one-time costs of

TABLE 3—ECONOMIC DATA: COSTS AND BENEFITS STATEMENT

Economic Data: Costs and Benefits Statement Units Primary Low High Year Discount rate Period Category estimate estimate estimate dollars (%) covered Notes

Benefits

Annualized Monetized ...... 7 Annual. $millions/year...... 3 Annual. Annualized Quantified 2,197,737 989,856 3,405,619 ...... 7 Annual .. Reduced antiseptic 2,197,737 989,856 3,405,619 ...... 3 Annual. active ingredient ex- posure (in pounds). Qualitative ......

Costs

Annualized Monetized 27.6 14.1 53.6 2014 7 Annual .. Annualized costs of $millions/year. 23.6 12.1 45.8 2014 3 Annual. relabeling and refor- mulation. Range of estimates captures uncertainty. Annualized Quantified ...... 7 ...... 3 Qualitative ......

Transfers

Federal Annualized ...... 7 ...... None. Monetized $millions/ ...... 3 year.

From/To ...... From: To:

Other Annualized ...... 7 Monetized $millions/ ...... 3 year.

From/To ...... From: To:

Effects

State, Local, or Tribal Government: Not applicable.

Small Business

Annual cost per affected small entity estimated as $0.11–$0.41 million, which will represent 0.28–1.10 percent of annual shipments.

Wages: No estimated effect.

Growth: No estimated effect.

The full analysis of economic impacts VII. Paperwork Reduction Act of 1995 VIII. Analysis of Environmental Impact is available in the docket for this final rule (Docket No. FDA–1975–N–0012) This final rule contains no collections We have determined under 21 CFR and at http://www.fda.gov/AboutFDA/ of information. Therefore, clearance by 25.31(a) that this action is of a type that ReportsManualsForms/Reports/ OMB under the Paperwork Reduction does not individually or cumulatively EconomicAnalyses/default.htm. Act of 1995 is not required. have a significant effect on the human environment. Therefore, neither an environmental assessment nor an

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environmental impact statement is 7. Part 130-New Drugs, Procedures for 16. Oggioni, M. R., et al., ‘‘Recent Advances required. Classification of Over-the-Counter Drugs, in the Potential Interconnection Between 37 FR 9464 (1972). Available at https:// Antimicrobial Resistance to Biocides and IX. Federalism www.federalregister.gov/agencies/ Antibiotics,’’ Expert Review of Anti- We have analyzed this final rule in library-of-congress. Infective Therapy, 11(4): p. 363–6, 2013. 8. Luby, S. P., et al., ‘‘Effect of Handwashing Available at http:// accordance with the principles set forth on Child Health: A Randomised www.ncbi.nlm.nih.gov/pubmed/ in Executive Order 13132. Section 4(a) Controlled Trial,’’ Lancet, 366(9481): p. 23566146. of the Executive order requires agencies 321–329, 2005. Available at http:// 17. Hansen, L. H., et al., ‘‘Substrate to ‘‘construe . . . a Federal statute to www.thelancet.com/pdfs/journals/ Specificity of the OqxAB Multidrug preempt State law only where the lancet/PIIS0140-6736(05)66912-7.pdf. Resistance Pump in Escherichia coli and statute contains an express preemption 9. Larson, E. L., et al., ‘‘Effect of Antibacterial Selected Enteric Bacteria,’’ Journal of provision or there is some other clear Home Cleaning and Handwashing Antimicrobial Chemotherapy, 60(1): p. evidence that the Congress intended Products on Infectious Disease 145–7, 2007. Available at http:// Symptoms: A Randomized, Double-Blind pediatrics.aappublications.org/content/ preemption of State law, or where the Trial,’’ Annals of Internal Medicine, 127/Supplement_1/S31. exercise of State authority conflicts with 140(5): p. 321–9, 2004. Available at 18. Mavri, A. and S. S. Mozina, ‘‘Involvement the exercise of Federal authority under http://annals.org/article.aspx?articleid= of Efflux Mechanisms in Biocide the Federal statute.’’ The sole statutory 717252. Resistance of Campylobacter jejuni and provision giving preemptive effect to the 10. Webster, J., J. L. Faoagali, and D. Campylobacter coli,’’ Journal of Medical final rule is section 751 of the FD&C Act Cartwright, ‘‘Elimination of Methicillin- Microbiology, 61(Pt. 6): p. 800–8, 2012. (21 U.S.C. 379r). We have complied Resistant Staphylococcus aureus from a Available at http:// Neonatal Intensive Care Unit After Hand www.ncbi.nlm.nih.gov/pubmed/?term= with all of the applicable requirements Washing with Triclosan,’’ Journal of under the Executive order and have Involvement+of+efflux+mechanisms+in+ Paediatrics and Child Health, 30(1): p. biocide+resistance+of+Campylobacter+ determined that the preemptive effects 59–64, 1994. Available at http:// jejuni+and+Campylobacter+coli8. of this rule are consistent with www.ncbi.nlm.nih.gov/pubmed/ 19. Mavri, A. and S. S. Mozina, Executive Order 13132. 8148192. ‘‘Development of Antimicrobial 11. Zafar, A. B., et al., ‘‘Use of 0.3% Triclosan X. References Resistance in Campylobacter jejuni and (Bacti-Stat) to Eradicate an Outbreak of Campylobacter coli Adapted to The following references are on Methicillin-Resistant Staphylococcus Biocides,’’ International Journal of Food display in the Division of Dockets aureus in a Neonatal Nursery,’’ Microbiology, 160(3): p. 304–12, 2013. American Journal of Infection Control, Available at http:// Management (see ADDRESSES) and are 23(3): p. 200–8, 1995. Available at http:// www.ncbi.nlm.nih.gov/pubmed/ available for viewing by interested www.ajicjournal.org/article/0196- 23290239. persons between 9 a.m. and 4 p.m., 6553(95)90042-X/pdf. 20. Curiao, T., et al., ‘‘Polymorphic Variation Monday through Friday; they are also 12. Schaffner, D. W., et al., ‘‘Quantitative in Susceptibility and Metabolism of Microbial Risk Assessment of available electronically at http:// Triclosan-Resistant Mutants of www.regulations.gov. FDA has verified Antibacterial Hand Hygiene Products on Risk of Shigellosis,’’ Journal of Food Escherichia coli and Klebsiella all Web site addresses as of the date of pneumoniae clinical Strains Obtained this document, but Web sites are subject Protection, 77(4): p. 574–82, 2014. Available at http:// After Exposure to Biocides and to change over time. www.ncbi.nlm.nih.gov/pubmed/?term= Antibiotics,’’ Antimicrobial Agents and Chemotherapy, 59(6): p. 3413–23, 2015. 1. Transcript of the January 22, 1997, Meeting Quantitative+microbial+risk+ of the Joint Nonprescription Drugs and assessment+of+antibacterial+ Available at http://aac.asm.org/content/ Anti-Infective Drugs Advisory hand+hygiene+products+on+risk+of+ 59/6/3413.full. Committees, OTC. Available at http:// shigellosis. 21. Rensch, U., et al., ‘‘Salmonella enterica www.fda.gov/ohrms/dockets/ac/05/ 13. Chen, Y., et al., ‘‘Quantification and Serovar Typhimurium Multidrug Efflux transcripts/2005-4098T1.htm. Variability Analysis of Bacterial Cross- Pumps EmrAB and AcrEF Support the 2. Comment submitted in Docket No. FDA– Contamination Rates in Common Food Major Efflux System AcrAB in Decreased 1975–N–0012, available at http:// Service Tasks,’’ Journal of Food Susceptibility to Triclosan,’’ www.regulations.gov with Comment No. Protection, 64(1): p. 72–80, 2001. International Journal of Antimicrobial FDA–1975–N–0012–0081. Available at http://citeseerx.ist.psu.edu/ Agents, 44(2): p. 179–80, 2014. Available 3. Transcript of the March 23, 2005, viewdoc/download?doi= at http://www.ncbi.nlm.nih.gov/pubmed/ Nonprescription Drugs Advisory 10.1.1.492.3167&rep=rep1&type=pdf. 25059442. Committee. Available at http:// 14. Chen, Y., et al., ‘‘FDA-iRISK—A 22. Rensch, U., G. Klein, and C. Kehrenberg, www.fda.gov/ohrms/dockets/ac/05/ Comparative Risk Assessment System for ‘‘Analysis of Triclosan-Selected transcripts/2005-4184T1.pdf. Evaluating and Ranking Food-Hazard Salmonella enterica Mutants of Eight 4. Transcript of the October 20, 2005, Pairs: Case Studies on Microbial Serovars Revealed Increased Meeting of the Nonprescription Drugs Hazards,’’ Journal of Food Protection, Aminoglycoside Susceptibility and Advisory Committee 2005. Available at 76(3): p. 376–85, 2013. Available at Reduced Growth Rates,’’ PLOS One, http://www.fda.gov/ohrms/dockets/ac/ http://www.ncbi.nlm.nih.gov/pubmed/ 8(10): p. e78310, 2013. Available at 05/transcripts/2005-4184T1.pdf. ?term=FDA-iRISK-a+comparative+risk+ http://journals.plos.org/plosone/article/ 5. Summary Minutes of the November 14, assessment+system+for+evaluating+ authors?id=10.1371%2 2008, Feedback Meeting with Personal and+ranking+food-hazard+pairs% Fjournal.pone.0078310. Care Products Council and Soap and 3A+case+studies+on+microbial+ 23. Fernando, D. M., et al., ‘‘Triclosan Can Detergent Association, OTC Vol. 230002. hazards. Select for an AdeIJK-Overexpressing Available at https:// 15. Ball, R., et al., ‘‘Statistical, Mutant of Acinetobacter baumannii www.regulations.gov/document?D=FDA- Epidemiological, and Risk-Assessment ATCC 17978 that Displays Reduced 1980-N-0006-0031. Approaches to Evaluating Safety of Susceptibility to Multiple Antibiotics,’’ 6. Transcript of the September 3, 2014, Vaccines Throughout The Life Cycle at Antimicrobial Agents and Meeting of the Nonprescription Drugs the Food and Drug Administration,’’ Chemotherapy, 58(11): p. 6424–31, 2014. Advisory Committee 2014. Available at Pediatrics, 127 Suppl 1: p. S31–8, 2011. Available at http://aac.asm.org/content/ http://www.fda.gov/downloads/Advisory Available at http:// 58/11/6424.full.pdf+html. Committees/CommitteesMeeting pediatrics.aappublications.org/content/ 24. 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Excipients%E2%80%94Volume+ 60. Prevention, CDC, ‘‘Contaminated devices, Reporting and recordkeeping 25,%E2%80%9D+Academic+ Povidone-Iodine Solution—Texas,’’ in requirements. Press,+Inc&source=bl&ots= Morbidity and Mortality Weekly Report, ba5Vqlsbem&sig=z87Vk2drikzKZ9c p. 133–4, 1989. Available at http:// Therefore, under the Federal Food, VuO4ZhAxoZYI&hl=en&sa=X&ved= www.cdc.gov/mmwr/preview/ Drug, and Cosmetic Act and under 0ahUKEwiz177BtYfOAhWCGT4 mmwrhtml/00001358.htm. authority delegated to the Commissioner KHTQ7BSoQ6AEIHjAA#v=onepage&q= 61. Berkelman, R. L., et al., of Food and Drugs, 21 CFR part 310 is Barabas%3B%20Povidone-Iodine%20in ‘‘Pseudobacteremia Attributed to amended as follows: %2025%20Analytical% Contamination of Povidone-Iodine with 20Profiles%20and%20Excipients%E2% Pseudomonas cepacia,’’ Annals of PART 310—NEW DRUGS 80%94Volume%2025%2C%E2% Internal Medicine, 95(1): p. 32–6, 1981. 80%9D%20Academic Available at http://annals.org/ ■ 1. 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Available at http:// remove from paragraph (d) introductory Detergent Association. IUCLID Data Set: www.karger.com/Article/PDF/246028. Triclocarban. December 12, 2002. text the number ‘‘(39)’’ and add in its 54. Block, C., et al., ‘‘Evaluation of Available at http://www.aciscience.org/ place the number ‘‘(41)’’ to read as Chlorhexidine and Povidone Iodine docs/Triclocarban_HPV_Robust_Study_ follows: Activity Against Methicillin-Resistant Staphylococcus aureus and Vancomycin- Summaries.pdf. 64. Sutherland, V., ‘‘NTP Research Concept: § 310.545 Drug products containing Resistant Enterococcus faecalis Using a certain active ingredients offered over-the- Surface Test,’’ Journal of Hospital Triclocarban.’’ Available at http:// ntp.niehs.nih.gov/ntp/about_ntp/bsc/ counter (OTC) for certain uses. Infections, 46(2): p. 147–52, 2000. _ _ Available at http:// 2014/june/triclocarban concept 508.pdf, (a) * * * www.ncbi.nlm.nih.gov/pubmed/?term= 2014. (27) * * * Evaluation+of+chlorhexidine+ 65. Scientific Committee on Consumer (iii) Consumer antiseptic hand wash and+povidone+iodine+activity+against+ Products (SCCP) opinion on Triclosan drug products. Approved as of ° methicillin-resistant+Staphylococcus+ COLIPA n P32. Available at http:// _ September 6, 2017. aureus+and+vancomycin-resistant ec.europa.eu/health/archive/ph risk/ _ _ _ Cloflucarban +Enterococcus+faecalis+ committees/04 sccp/docs/sccp o using+a+surface+test. 166.pdf. Fluorosalan 55. Block, S. S., ‘‘Disinfection, Sterilization, 66. Addendum to the SCCP Opinion on Hexachlorophene and Preservation,’’ Philadelphia: Triclosan. Available at http:// Hexylresorcinol Lippincott Williams & Wilkins, 2001. ec.europa.eu/health/scientific_ Iodine complex (ammonium ether Available at. Available at https:// committees/consumer_safety/docs/sccs_ sulfate and polyoxyethylene sorbitan books.google.com/books?id=3f-kPJ17_ o_054.pdf. monolaurate) TYC&printsec=frontcover&dq= 67. Registered substances. Available at http:// Iodine complex (phosphate ester of Disinfection,+Sterilization,+and+ echa.europa.eu/web/guest/information- alkylaryloxy polyethylene glycol) on-chemicals/registered-substances. Preservation&hl=en&sa=X&ved= Methylbenzethonium chloride 0ahUKEwiNxurX6JHOAhWTix 68. Fang, J. L., et al., ‘‘Absorption and 4KHVcKDKcQ6AEIHjAA#v=onepage&q= Metabolism of Triclosan After Nonylphenoxypoly (ethyleneoxy) Disinfection%2C%20Sterilization Application to the Skin of B6C3F1 ethanoliodine %2C%20and%20Preservation&f=false. Mice,’’ Environmental Toxicology, 2014. Phenol (greater than 1.5 percent) 56. Houang, E. T., et al., ‘‘Absence of Avilable at http://www.ncbi.nlm.nih.gov/ Phenol (less than 1.5 percent) Bacterial Resistance to Povidone Iodine,’’ pubmed/?term=Absorption+and+ Poloxamer iodine complex Journal of Clinical Pathology, 29(8): p. metabolism+of+triclosan+after+ Povidone-iodine (5 to 10 percent) 752–5, 1976. Available at http:// application+to+the+skin+of+B6C3F1+ Secondary amyltricresols jcp.bmj.com/content/29/8/752.long. mice. Sodium oxychlorosene 57. Prince, H. N., et al., ‘‘Drug resistance 69. Crofton, K. M., et al., ‘‘Short-Term in vivo Tribromsalan studies with topical antiseptics,’’ Journal Exposure to the Water Contaminant of Pharmaceutical Sciences, 67(11): p. Triclosan: Evidence for Disruption of Triclocarban 1629–31, 1978. Available at http:// Thyroxine, ’’ Environmental Toxicology Triclosan www.ncbi.nlm.nih.gov/pubmed/712607. and Pharmacology, 24(2): p. 194–7, Triple Dye 58. Panlilio, A. L., et al., ‘‘Infections and 2007. Available at http://www.ncbi.nlm. Undecoylium chloride iodine complex pseudoinfections due to povidone-iodine nih.gov/pubmed/?term=Short-term+in+ (iv) Consumer antiseptic body wash solution contaminated with vivo+exposure+to+the+water+ drug products. Approved as of Pseudomonas cepacia,’’ Clinical contaminant+triclosan%3A+Evidence+ September 6, 2017. Infectious Diseases, 14(5): p. 1078–83, for+disruption+of+thyroxine. 1992. Available at http://www.jstor.org/ 70. European Commission Scientific Cloflucarban stable/4456469?seq=1#page_scan_tab_ Committee on Consumer Safety, Final Fluorosalan contents. Opinion on Triclosan (Antimicrobial Hexachlorophene 59. Jarvis, W. R., ‘‘Nosocomial Outbreaks: Resistance), cited March 24, 2016, Hexylresorcinol The Centers for Disease Control’s available at http://ec.europa.eu/health/ Iodine complex (phosphate ester of Hospital Infections Program Experience, scientific_committees/consumer_safety/ alkylaryloxy polyethylene glycol) 1980–1990. Epidemiology Branch, index_en.htm. Hospital Infections Program,’’ American Iodine tincture Methylbenzethonium chloride Journal of Medicine, 91(3B): p. 101S– List of Subjects in 21 CFR Part 310 106S, 1991. 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Phenol (less than 1.5 percent) analysis, or possess), or propose to delegated scheduling authority under 21 Poloxamer iodine complex handle PB-22, 5F-PB-22, AB- U.S.C. 811 to the Administrator of the Povidone-iodine (5 to 10 percent) FUBINACA, or ADB-PINACA. DEA, 28 CFR 0.100, who in turn has Secondary amyltricresols DATES: Effective date: September 6, redelegated that authority to the Deputy Sodium oxychlorosene 2016. Administrator of the DEA, 28 CFR part Tribromsalan 0, appendix to subpart R. FOR FURTHER INFORMATION CONTACT: Triclocarban The CSA provides that proceedings Michael J. Lewis, Office of Diversion Triclosan for the issuance, amendment, or repeal Control, Drug Enforcement Triple Dye of the scheduling of any drug or other Administration; Mailing Address: 8701 Undecoylium chloride iodine complex substance may be initiated by the Morrissette Drive, Springfield, Virginia * * * * * Attorney General (1) on her own 22152; Telephone: (202) 598–6812. (d) * * * motion; (2) at the request of the SUPPLEMENTARY INFORMATION: (41) September 6, 2017, for products Secretary of the Department of Health subject to paragraph (a)(27)(iii) or (iv) of Legal Authority and Human Services (HHS); 1 or (3) on this section. The Drug Enforcement the petition of any interested party. 21 Dated: August 31, 2016. Administration (DEA) implements and U.S.C. 811(a). This action was initiated Leslie Kux, enforces titles II and III of the by the former Deputy Administrator of Associate Commissioner for Policy. Comprehensive Drug Abuse Prevention the DEA on his own motion and is and Control Act of 1970, as amended. 21 supported by a recommendation from [FR Doc. 2016–21337 Filed 9–2–16; 8:45 am] the Assistant Secretary of the HHS and BILLING CODE 4164–01–P U.S.C. 801–971. Titles II and III are referred to as the ‘‘Controlled an evaluation of all other relevant data Substances Act’’ and the ‘‘Controlled by the DEA. This action imposes the regulatory controls and administrative, DEPARTMENT OF JUSTICE Substances Import and Export Act,’’ respectively, and are collectively civil, and criminal sanctions of schedule I controlled substances on any person Drug Enforcement Administration referred to as the ‘‘Controlled Substances Act’’ or the ‘‘CSA’’ for the who handles, or proposes to handle, PB- 22, 5F-PB-22, AB-FUBINACA, or ADB- 21 CFR Part 1308 purposes of this action. 21 U.S.C. 801– 971. The DEA publishes the PINACA. [Docket No. DEA–433] implementing regulations for these Background statutes in title 21 of the Code of Federal Schedules of Controlled Substances: On January 10, 2014, the DEA Placement of PB-22, 5F-PB-22, AB- Regulations (CFR), chapter II. The CSA and its implementing published a notice of intent to FUBINACA and ADB-PINACA into temporarily place quinolin-8-yl 1- Schedule I regulations are designed to prevent, detect, and eliminate the diversion of pentyl-1H-indole-3-carboxylate (PB-22; QUPIC), quinolin-8-yl 1-(5- AGENCY: Drug Enforcement controlled substances and listed Administration, Department of Justice. chemicals into the illicit market while fluoropentyl)-1H-indole-3-carboxylate (5-fluoro-PB-22; 5F-PB-22), N-(1-amino- ACTION: Final rule. ensuring an adequate supply is available for the legitimate medical, scientific, 3-methyl-1-oxobutan-2-yl)-1-(4- SUMMARY: With the issuance of this final research, and industrial needs of the fluorobenzyl)-1H-indazole-3- rule, the Drug Enforcement United States. Controlled substances carboxamide (AB-FUBINACA) and N-(1- Administration places quinolin-8-yl 1- have the potential for abuse and amino-3,3-dimethyl-1-oxobutan-2-yl)-1- pentyl-1H-indole-3-carboxylate (PB-22; dependence and are controlled to pentyl-1H-indazole-3-carboxamide QUPIC), quinolin-8-yl 1-(5- protect the public health and safety. (ADB-PINACA) into schedule I pursuant fluoropentyl)-1H-indole-3-carboxylate Under the CSA, each controlled to the temporary scheduling provisions (5-fluoro-PB-22; 5F-PB-22), N-(1-amino- substance is classified into one of five of the CSA. 79 FR 1776. On February 10, 3-methyl-1-oxobutan-2-yl)-1-(4- schedules based upon its potential for 2014, the DEA published a final order fluorobenzyl)-1H-indazole-3- abuse, its currently accepted medical amending 21 CFR 1308.11(h) to carboxamide (AB-FUBINACA) and N-(1- use in treatment in the United States, temporarily place these four synthetic amino-3,3-dimethyl-1-oxobutan-2-yl)-1- and the degree of dependence the cannabinoids into schedule I of the pentyl-1H-indazole-3-carboxamide substance may cause. 21 U.S.C. 812. The CSA. 79 FR 7577. That final order was (ADB-PINACA), including their salts, initial schedules of controlled effective on the date of publication, and isomers, and salts of isomers whenever substances established by Congress are was based on findings by the DEA that the existence of such salts, isomers, and found at 21 U.S.C. 812(c) and the the temporary scheduling of these four salts of isomers is possible, into current list of scheduled substances is synthetic cannabinoids was necessary to schedule I of the Controlled Substances published at 21 CFR part 1308. 21 avoid an imminent hazard to the public Act. This scheduling action is pursuant U.S.C. 812(a). safety pursuant to 21 U.S.C. 811(h)(1). to the Controlled Substances Act which Pursuant to 21 U.S.C. 811(a)(1), the 1 As set forth in a memorandum of understanding requires that such actions be made on Attorney General may, by rule, ‘‘add to entered into by the Food and Drug Administration the record after opportunity for a such a schedule or transfer between (FDA) and the National Institute on Drug Abuse hearing through formal rulemaking. such schedules any drug or other (NIDA), the FDA acts as the lead agency within the This action imposes the regulatory substance if he * * * finds that such HHS in carrying out the Secretary’s scheduling responsibilities under the CSA, with the controls and administrative, civil, and drug or other substance has a potential concurrence of NIDA. 50 FR 9518, Mar. 8, 1985. criminal sanctions applicable to for abuse, and * * * makes with respect The Secretary of the HHS has delegated to the schedule I controlled substances on to such drug or other substance the Assistant Secretary for Health of the HHS the persons who handle (manufacture, findings prescribed by subsection (b) of authority to make domestic drug scheduling recommendations. 58 FR 35460, July 1, 1993. distribute, reverse distribute, import, section 812 of this title for the schedule Accordingly, all subsequent references to export, engage in research, conduct in which such drug is to be placed ‘‘Secretary’’ have been replaced with ‘‘Assistant instructional activities or chemical * * *.’’ The Attorney General has Secretary.’’

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