Vol. 78 Tuesday, No. 242 December 17, 2013

Part III

Department of Health and Human Services

Food and Drug Administration 21 CFR Parts 310 and 333 Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record; Proposed Rule

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DEPARTMENT OF HEALTH AND Written Submissions Summary of the Major Provisions of the HUMAN SERVICES Regulatory Action in Question Submit written submissions in the Food and Drug Administration following ways: We are proposing that additional safety and effectiveness data are • Mail/Hand delivery/Courier (for necessary to support a GRAS/GRAE 21 CFR Parts 310 and 333 paper submissions): Division of Dockets determination for OTC antiseptic active Management (HFA–305), Food and Drug [Docket No. FDA–1975–N–0012] (Formerly ingredients intended for repeated daily Administration, 5630 Fishers Lane, Rm. Docket No. 1975N–0183H) use by consumers. The safety data, the 1061, Rockville, MD 20852. RIN 0910–AF69 effectiveness data, and the effect on the Instructions: All submissions received previously proposed classification of Safety and Effectiveness of Consumer must include the Agency name and active ingredients are described briefly Antiseptics; Topical Antimicrobial Docket No. FDA–1975–N–0012 and RIN in this summary. Drug Products for Over-the-Counter 0910–AF69 for this rulemaking. All Human Use; Proposed Amendment of comments received may be posted Effectiveness the Tentative Final Monograph; without change to http:// A determination that an active Reopening of Administrative Record www.regulations.gov, including any ingredient is GRAS/GRAE for a personal information provided. particular intended use requires AGENCY: Food and Drug Administration, Docket: For access to the docket to consideration of the benefit-to-risk ratio HHS. read background documents or for the drug for that use. If the active ACTION: Proposed rule. comments received, go to http:// ingredient in a drug product does not SUMMARY: The Food and Drug www.regulations.gov and insert the provide clinical benefit, but potentially Administration (FDA) is issuing this docket number, found in brackets in the increases the risk associated with the proposed rule to amend the 1994 heading of this document, into the drug (e.g., from reproductive toxicity or tentative final monograph or proposed ‘‘Search’’ box and follow the prompts carcinogenicity), then the benefit-risk rule (the 1994 TFM) for over-the-counter and/or go to the Division of Dockets calculation shifts, and the drug is not (OTC) antiseptic drug products. In this Management, 5630 Fishers Lane, Rm. GRAS/GRAE. New information on proposed rule, we are proposing to 1061, Rockville, MD 20852. potential risks posed by the use of certain consumer antiseptic washes has establish conditions under which OTC FOR FURTHER INFORMATION CONTACT: consumer antiseptic products intended Colleen Rogers, Center for Drug prompted us to reevaluate the data for use with water (referred to Evaluation and Research, Food and needed for classifying consumer throughout as consumer antiseptic Drug Administration, 10903 New antiseptic wash active ingredients as washes) are generally recognized as safe Hampshire Ave., Bldg. 22, Rm. 5411, generally recognized as effective and effective. In the 1994 TFM, certain Silver Spring, MD 20993, 301–796– (GRAE). As a result, the risk from the antiseptic active ingredients were 2090. use of a consumer antiseptic wash drug proposed as being safe for antiseptic product must be balanced by a handwash use by consumers based on SUPPLEMENTARY INFORMATION: demonstration that it is superior to washing with nonantibacterial soap and safety data evaluated by FDA as part of Executive Summary our ongoing review of OTC antiseptic water in reducing infection. drug products. However, in light of Purpose of the Regulatory Action We have evaluated the available more recent scientific developments and literature, and the data and other changes in the use patterns of these FDA is proposing to amend the 1994 information that were submitted to the products we are now proposing that TFM for OTC antiseptic drug products rulemaking on the effectiveness of additional safety data are necessary to that published in the Federal Register of consumer antiseptic wash active support the safety of antiseptic active June 17, 1994 (59 FR 31402). The 1994 ingredients, as well as the ingredients for this use. We also are TFM is part of FDA’s ongoing recommendations from the public proposing that all consumer antiseptic rulemaking to evaluate the safety and meetings held by the Agency on wash active ingredients have data that effectiveness of OTC drug products antiseptics. The record does not demonstrate a clinical benefit from the marketed in the United States on or currently contain sufficient data to show use of these consumer antiseptic wash before May 1972 (OTC Drug Review). that there is any additional benefit from products compared to nonantibacterial FDA is proposing to establish new the use of consumer antiseptic hand or soap and water. conditions under which OTC consumer body washes compared to DATES: Submit electronic or written antiseptic products intended for use nonantibacterial soap and water. comments by June 16, 2014. See section with water are generally recognized as Adequate and well-controlled clinical VIII of this document for the proposed safe and effective (GRAS/GRAE) based outcome studies capable of identifying effective date of a final rule based on on FDA’s reevaluation of the safety and the conditions of use that reduce the this proposed rule. effectiveness data requirements numbers of infections would ADDRESSES: You may submit comments, proposed in the 1994 TFM in light of demonstrate whether there is a benefit identified by Docket No. FDA–1975–N– comments received, input from from the use of consumer antiseptic 0012 and Regulatory Information subsequent public meetings, and our washes. Consequently, we are proposing Number (RIN) number 0910–AF69, by independent evaluation of other that data from clinical outcome studies any of the following methods: relevant scientific information it has (demonstrating a reduction in identified and placed in the docket. We infections) are necessary to support a Electronic Submissions are not, at this time, proposing GRAE determination for consumer Submit electronic comments in the conditions under which OTC consumer antiseptic wash active ingredients. following way: antiseptic hand rubs (commonly called • Federal eRulemaking Portal: http:// hand sanitizers) or antiseptics intended Safety www.regulations.gov. Follow the for use by health care professionals are Several important scientific instructions for submitting comments. GRAS/GRAE. developments that affect the safety

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evaluation of these ingredients have ingredients falls into three broad discussed separately in this proposed occurred since FDA’s 1994 evaluation of categories: (1) Safety data studies rule for each active ingredient. the safety of consumer antiseptic active described in current FDA guidance (e.g., Several consumer antiseptic wash ingredients under the OTC Drug preclinical and human pharmacokinetic active ingredients evaluated in the 1994 Review. New data suggest that the studies, developmental and TFM were proposed as GRAS, but not systemic exposure to these active reproductive toxicity studies, and GRAE, because they lack sufficient ingredients is higher than previously carcinogenicity studies); (2) data to evidence of effectiveness for consumer thought, and new information about the characterize potential hormonal effects; potential risks from systemic absorption and, (3) data to evaluate the use. We are now proposing that these and long-term exposure have become development of resistance. ingredients need additional safety data, available. New safety information also as well as effectiveness data, to be Active Ingredients suggests that widespread antiseptic use classified as GRAS/GRAE. In the 1994 TFM, 22 antiseptic active can have an impact on the development Costs and Benefits of bacterial resistance. ingredients were classified for OTC The previous GRAS determinations antiseptic handwash use (59 FR 31402 We estimate the benefits of the were based on safety principles that at 31435) (for a list of all active proposed rule in terms of the 2.2 have since evolved significantly due to ingredients covered by this proposed millions pounds reduction in annual advances in technology, development of rule, see tables 3 and 4). Among these aggregate exposure to antiseptic active new test methods, and experience with 22 active ingredients are triclosan and ingredients, including triclosan, performing test methods. The standard triclocarban, two of the most commonly chloroxylenol, and benzalkonium battery of tests that were used to used active ingredients in consumer chloride. The inadequacy of the antiseptic washes and the subject of determine the safety of drugs has available dermal exposure data prevents much scientific debate. Our detailed changed over time to incorporate us from characterizing the health effects evaluation of the effectiveness and improvements in safety testing. In order resulting from widespread long-term to ensure that consumer antiseptic wash safety of triclosan and triclocarban, as exposure to such ingredients and active ingredients are GRAS, data that well as other active ingredients for prevents us from translating the meet current safety standards are which data were submitted, can be estimated reduced exposure into needed. found in sections VI.A and VII.D of this Based on these developments, we are proposed rule. In the 1994 TFM, only monetary equivalents of health effects. now proposing that additional safety one active ingredient that is being We estimate the costs of the proposed data will need to be submitted to the evaluated for use as a consumer rule, consisting of one-time costs of administrative record for each consumer antiseptic wash, povidone-iodine (5 to relabeling and reformulation, ranging antiseptic wash active ingredient to 10 percent), was proposed to be from $112.2 to $368.8 million. support a GRAS classification. The data classified as GRAS/GRAE (59 FR 31402 Annualized over 10 years, the primary requirements proposed in this proposed at 31436). However, we now propose cost estimate is approximately $23.6 rule are the minimum data necessary to that none of the consumer antiseptic million at a 3 percent discount rate and establish the safety of long-term, daily, wash active ingredients classified in the $28.6 million at a 7 percent discount repeated exposure to antiseptic active 1994 TFM (including povidone-iodine) rate. Under the proposed rule, we ingredients used in consumer wash has the safety and effectiveness data estimate that each pound of reduced products in light of the new safety needed to support a classification of exposure to antiseptic active ingredients information. The data we propose is GRAS/GRAE for consumer antiseptic would cost $3.86 to $43.67 at a 3 needed to demonstrate safety for all hand or body washes. The data available percent discount rate and $4.69 to consumer antiseptic wash active and the data that are missing are $53.04 at a 7 percent discount rate.

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

Total ...... Reduced exposure to antiseptic active ingredients by 2.2 million $23.6 (at 3%) ...... $112.2 to $368.8 pounds annually. $28.6 (at 7%) ......

Table of Contents B. Eligibility of Certain Active Ingredients C. Studies To Support a Generally for the OTC Drug Review Recognized as Safe Determination I. Introduction IV. Ingredients Previously Proposed as Not D. Review of Available Data for Each A. Terminology Used in the OTC Drug Antiseptic Active Ingredient Review Regulations Generally Recognized as Safe and Effective (GRAS/GRAE) VIII. Proposed Effective Date B. Topical Antiseptics IX. Summary of Preliminary Regulatory V. Summary of Proposed Classifications of C. This Proposed Rule Covers Only Impact Analysis Consumer Antiseptic Washes OTC Consumer Antiseptic Wash Active A. Introduction D. Comment Period Ingredients B. Summary of Costs and Benefits II. Background VI. Effectiveness (Generally Recognized as X. Paperwork Reduction Act of 1995 A. Significant Rulemakings Relevant to Effective) Determination XI. Environmental Impact This Proposed Rule A. Evaluation of Effectiveness Data XII. Federalism B. Public Meetings Relevant to This B. In Vitro Studies To Support a Generally XIII. References Proposed Rule Recognized as Effective Determination C. Comments Received by FDA I. Introduction III. Active Ingredients With Insufficient VII. Safety (Generally Recognized as Safe) Evidence of Eligibility for the OTC Drug Determination In the following sections, we provide Review A. New Issues a brief description of terminology used A. Eligibility for the OTC Drug Review B. Antimicrobial Resistance in the OTC Drug Review regulations,

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and an overview of OTC topical antimicrobial products that the 1994 TFM, we proposed that both antiseptic drug products, and then encompassed products for both health consumer antiseptic handwashes and describe in more detail the OTC care and consumer use (39 FR 33103, health care personnel handwashes consumer antiseptics that are the subject September 13, 1974). The ANPR should have the same effectiveness of this proposed rule. covered seven different intended uses testing and performance criteria. In for these products: (1) Antimicrobial response to the TFM we received A. Terminology Used in the OTC Drug soap; (2) health care personnel submissions from the public arguing Review Regulations handwash; (3) patient preoperative skin that consumer products serve a different 1. Proposed, Tentative Final, and Final preparation; (4) skin antiseptic; (5) skin purpose and should continue to be Monographs wound cleanser; (6) skin wound distinct from health care antiseptics. We protectant; and (7) surgical hand scrub agree, and in this proposed rule we To conform to terminology used in (39 FR 33103 at 33140). FDA make a distinction between consumer the OTC Drug Review regulations subsequently identified skin antiseptics, antiseptics for use by the general (§ 330.10 (21 CFR 330.10)), the skin wound cleansers, and skin wound population and health care antiseptics September 1974 advance notice of protectants as antiseptics used primarily for use in hospitals or in other specific proposed rulemaking (ANPR) was by consumers for first aid use and health care situations. designated as a ‘‘proposed monograph.’’ referred to them collectively as ‘‘first aid We refer to the group of products Similarly, the notices of proposed antiseptics’’. We published a separate covered by this proposed rule as rulemaking, which were published in TFM covering the first aid antiseptics in ‘‘consumer antiseptics.’’ Consumer the Federal Register of January 6, 1978 the Federal Register of July 22, 1991 (56 antiseptic drug products addressed by (43 FR 1210) (the 1978 TFM), and in the FR 33644) (First Aid TNM). Thus, first this proposal include a variety of Federal Register of June 17, 1994 (59 FR aid antiseptics are not discussed further personal care products intended to be 31402) (the 1994 TFM), were each in this document. used with water, such as antibacterial designated as a ‘‘tentative final The four remaining categories of soaps, handwashes, and antibacterial monograph.’’ The present proposed topical antimicrobials were addressed in body washes. These products do not rule, which is a reproposal regarding an amended TFM, published on June include consumer antiseptic hand rubs consumer antiseptic wash drug 17, 1994 (59 FR 31402). This TFM (commonly called hand sanitizers). products, is also designated as a covered: (1) Antiseptic handwash (i.e., These products may be used by ‘‘tentative final monograph.’’ consumer handwash); (2) health care consumers for personal use in the home 2. Category I, II, and III Classifications personnel handwash; (3) patient on a frequent, even daily, basis. In the preoperative skin preparation; and (4) U.S. consumer setting, where the target The OTC drug procedural regulations surgical hand scrub (59 FR 31402 at population is composed of generally in § 330.10 use the terms ‘‘Category I’’ 31442). In the 1994 TFM, FDA also healthy individuals, the risk of infection (generally recognized as safe and identified a new category of antiseptics and the scope of the spread of infection effective and not misbranded), for use by the food industry and is relatively low compared to the health ‘‘Category II’’ (not generally recognized requested relevant data and information care setting, where patients are as safe and effective or misbranded), (59 FR 31402 at 31440). Antiseptics for generally more susceptible to infection and ‘‘Category III’’ (available data are use by the food industry are not and the potential for spread of infection insufficient to classify as safe and discussed further in this document. is high. effective, and further testing is With regard to the health care and required). Section 330.10 provides that consumer antiseptic products, we are C. This Proposed Rule Covers Only any testing necessary to resolve the now proposing that our evaluation of Consumer Antiseptic Washes safety or effectiveness issues that OTC antiseptic drug products be further In this proposed rule, FDA proposes formerly resulted in a Category III subdivided into health care antiseptics the establishment of a monograph for classification, and submission to FDA of and consumer antiseptics. We believe OTC consumer antiseptics that are the results of that testing or any other that these categories are distinct based intended for use as either a handwash data, must be done during the OTC drug on the proposed use setting, target or a body wash, but that are not rulemaking process before the population, and the fact that each identified as ‘‘first aid antiseptics’’ in establishment of a final monograph (i.e., setting presents a different risk for the 1991 First Aid TFM. When the 1994 a final rule or regulation). Therefore, infection. Therefore, the safety and TFM was published, the term for daily this proposed rule (at the tentative final effectiveness should be evaluated for consumer use antiseptics was changed monograph stage) retains the concepts each intended use separately. to ‘‘antiseptic handwash.’’ In response of Categories I, II, and III. Health care antiseptics are drug to this change, we received comments At the final monograph stage, FDA products intended for use by health care that the term ‘‘antiseptic handwash’’ did does not use the terms ‘‘Category I,’’ professionals in a hospital setting or not include all of the consumer ‘‘Category II,’’ and ‘‘Category III.’’ In other health care situations outside the products on the market, such as hand place of Category I, the term hospital, and include health care rubs and body washes. Therefore, in this ‘‘monograph conditions’’ is used; in personnel hand antiseptics, surgical proposed rule, we use the term place of Categories II and III, the term hand scrubs, and patient preoperative ‘‘consumer antiseptic,’’ which is a broad ‘‘nonmonograph conditions’’ is used. skin preparations. In 1974, when the term and meant to include all of the ANPR (39 FR 33103) to establish an types of antiseptic products used on a B. Topical Antiseptics OTC topical antimicrobial monograph frequent or daily basis by consumers. The OTC topical antimicrobial was published in the Federal Register, The proposed rule does not include rulemaking has had a broad scope, antimicrobial soaps used by consumers consumer antiseptic hand rubs encompassing drug products that may were distinct from professional use (commonly called hand sanitizers). contain the same active ingredients, but antiseptics, such as health care The distinctions between washes and that are labeled and marketed for personnel handwashes. (See section I.C rubs, and between handwashes and different intended uses. In 1974, the of this proposed rule about the term body washes are discussed in this Agency published an ANPR for topical ‘‘antimicrobial soaps’’.) In contrast, in section.

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1. Consumer Washes and Consumer include ‘‘antimicrobial soap’’ as a on any new data or information may Rubs separate product category because soap then be submitted for an additional 60 Consumer antiseptics (other than first was considered to be a dosage form and days (see § 330.10(a)(7)(iii) and aid antiseptics) fall into two categories: specific dosage forms were not being (a)(7)(iv)). In addition, FDA will also (1) Products that are rinsed off, included in the monograph unless there consider requests for an extension of the including handwashes and body was a particular safety or efficacy reason time to submit new safety and/or washes, and (2) products that are not to do so (59 FR 31402 at 31407). At that effectiveness data to the record if such rinsed off after use, including hand rubs time, we had not identified antiseptic requests are submitted to the docket and antibacterial wipes. The 1994 TFM body washes as a separate category of within the initial 180-day comment did not distinguish between products product. period. Upon the close of the comment Comments on the 1994 TFM noted that we are now calling antiseptic period, FDA will review all data and that the elimination of the category of washes and products we are now calling information submitted to the record in antimicrobial soaps in the 1994 TFM antiseptic rubs. Nor did the 1994 TFM conjunction with all timely and resulted in products that otherwise distinguish between consumer complete requests to extend. In antiseptic handwashes and rubs and would have been considered antimicrobial soaps (such as assessing whether to extend the health care antiseptic handwashes and comment period to allow for additional rubs. This proposed rule covers antimicrobial bar soaps) being placed in the category of antiseptic handwashes. time for studies to generate new data consumer antiseptic washes only and and information, FDA will consider the does not cover consumer antiseptic The comments stated that because the proposed labeling for antiseptic data already in the docket along with rubs. Completion of the monograph for any information that is provided in any Consumer Antiseptic Wash Products handwash products directs use on only requests to extend. FDA will determine and certain other monographs for the the hands and forearms, this category is whether the sum of the data, if timely active ingredient triclosan is subject to not appropriate for certain products that submitted, is likely to be adequate to a Consent Decree entered by the United were originally proposed to be called States District Court for the Southern ‘‘antimicrobial soaps’’ and that were to provide all the data that are necessary District of New York on November 21, be used on the whole body (i.e., bar to make a determination of general 2013, in Natural Resources Defense soaps). We agree with the comments to recognition of safety and effectiveness. the extent that some products Council, Inc. v. United States Food and II. Background Drug Administration, et al., 10 Civ. 5690 previously identified as antimicrobial (S.D.N.Y.). soaps had, among other intended uses, In this section we describe the the intended use of being used on the significant rulemakings and public 2. Handwashes and Body Washes entire body. In this proposed rule, we meetings relevant to this rulemaking, Consumer antiseptic hand and body are identifying products with the and how we are responding to washes were not a category of topical intended use of being used on the entire comments received in response to the antiseptic drug products specifically body as antiseptic body washes. 1994 TFM. identified by the Advisory Review Panel Consequently, the active ingredients on OTC Topical Antimicrobial I Drug reviewed by the Panel for use in A. Significant Rulemakings Relevant to Products (Antimicrobial I Panel or antimicrobial soaps have been reviewed This Proposed Rule Panel). In the ANPR and the 1978 TFM, for use in antiseptic body washes. products for daily consumer use were A summary of the significant Federal D. Comment Period called ‘‘antimicrobial soaps.’’ This Register publications relevant to this category encompassed deodorant soaps Because of the complexity of this proposed rule is provided in table 1 of and hand soaps containing proposed rule, we are providing a this proposed rule. Other Federal antimicrobial ingredients used for comment period of 180 days. Moreover, Register publications relevant to this handwashing and personal hygiene. new data or information may be proposed rule are available from the In the 1994 TFM, we concluded that submitted to the docket within 12 Division of Dockets Management (see there was no reason to continue to months of publication, and comments ADDRESSES).

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

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 topical 33103). antimicrobial drug products, together with the recommendations of the Panel, which was the advi- sory review panel responsible for evaluating data on the active ingredients in this drug class. 1978 Antimicrobial TFM (January 6, 1978, We published our tentative conclusions and proposed effectiveness testing for the drug product cat- 43 FR 1210). egories evaluated by the Panel. The 1978 TFM reflects our evaluation of the recommendations of the Panel 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 prod- 33644). ucts. 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 that were 1994, 59 FR 31402). referred to as OTC topical health care antiseptic drug products. These antiseptics are generally intended for use by health care professionals. In this proposed rule 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 handwash.

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B. Public Meetings Relevant to This proposed rule, there have been three relevant to the discussion of consumer Proposed Rule meetings of the Nonprescription Drugs antiseptic wash safety and effectiveness. In addition to the Federal Register Advisory Committee (NDAC) and one These are summarized in table 2 of this publications listed in table 1 of this public feedback meeting that are proposed rule.

TABLE 2—PUBLIC MEETINGS RELEVANT TO CONSUMER ANTISEPTICS

Date and type of meeting Topic of discussion

January 1997 NDAC Meeting (Joint meet- Antiseptic and antibiotic resistance in relation to an industry proposal for consumer and health care ing with the Anti-Infective Drugs Advi- antiseptic effectiveness testing (Health Care Continuum Model) (Refs. 1 and 2). sory Committee) (January 6, 1997, 62 FR 764). March 2005 NDAC Meeting (February 18, The use of surrogate endpoints and study design issues for the in vivo testing of health care 2005, 70 FR 8376). antiseptics (Ref. 3) October 2005 NDAC Meeting (September Benefits and risks of consumer antiseptics. NDAC expressed concern about the pervasive use of 15, 2005, 70 FR 54560). consumer antiseptic washes where there are potential risks and no demonstrable benefit. To demonstrate a clinical benefit, NDAC recommended clinical outcome studies to show that anti- septic washes are superior to nonantibacterial soap and water (Ref. 4). November 2008 Public Feedback Meeting Demonstration of the effectiveness of consumer antiseptics (Ref. 5).

C. Comments Received by FDA III. Active Ingredients With Insufficient However, if documentation of the type Evidence of Eligibility for the OTC Drug described in this section is submitted, In response to the 1994 TFM, FDA Review these active ingredients could be received approximately 160 comments In this section of the proposed rule we determined to be eligible for evaluation. from drug manufacturers, trade describe the requirements for eligibility associations, academia, testing B. Eligibility of Certain Active for the OTC Drug Review and the laboratories, consumers, health Ingredients for the OTC Drug Review ingredients submitted to the OTC Drug professionals, and law firms. Copies of Review that lack adequate evidence of 1. Chlorhexidine Gluconate the comments received are on public eligibility for evaluation as consumer Previously, chlorhexidine gluconate 4 display at http://www.regulations.gov antiseptic washes. percent aqueous solution as a health (see ADDRESSES). care antiseptic was found to be A. Eligibility for the OTC Drug Review Because only consumer antiseptic ineligible for inclusion in the washes are discussed in this proposed An OTC drug is covered by the OTC monograph and was not included in the rule, only those comments and data Drug Review if its conditions of use 1994 TFM (59 FR 31402 at 31413). We concerning the 1994 TFM that are existed in the OTC drug marketplace on have not received any new information related to consumer antiseptic wash or before May 11, 1972 (37 FR 9464). since the 1994 TFM demonstrating that active ingredients are addressed. If in Conditions of use include, among other this active ingredient is eligible for the the future we determine that there are things, active ingredient, dosage form monograph. Consequently, we are not and strength, route of administration, monograph consumer antiseptic wash proposing to change the categorization and specific OTC use or indication of active ingredients that are safe and of chlorhexidine gluconate from that of the product (see 21 CFR 330.14(a)). To effective, we will address labeling and a new drug based on the lack of determine eligibility for the OTC Drug documentation demonstrating its final formulation testing of consumer Review, FDA typically must have actual eligibility as a consumer antiseptic antiseptic washes, and the comments product labeling or a facsimile of wash, and we do not include a that were received on those subjects, in labeling that documents the conditions discussion of any safety or effectiveness a future document. Comments that were of marketing of a product prior to May data submitted for chlorhexidine received in response to the 1994 TFM 1972 (see § 330.10(a)(2)). FDA considers gluconate. regarding other intended uses of the a drug that is ineligible for the OTC active ingredients will be addressed in Drug Review to be a new drug that will 2. Polyhexamethylene Biguanide; future documents related to those other require FDA approval through the new Benzalkonium Cetyl Phosphate; uses. drug application (NDA) process. Cetylpyridinium Chloride; Salicylic Ineligibility for use as a consumer Acid; Sodium Hypochlorite; Tea Tree This proposal constitutes FDA’s Oil; Combination of Potassium evaluation of submissions made in antiseptic wash does not affect eligibility for other indications under Vegetable Oil Solution, Phosphate response to the 1994 TFM to support the Sequestering Agent, and safety and effectiveness of OTC the OTC Drug Review. Based on a review of the labeling Triethanolamine consumer antiseptic wash active submitted to the Antimicrobial I Panel, Following the publication of the 1994 ingredients (Refs. 6 through 10). We the ingredients discussed in section III.B TFM, FDA received submissions for the reviewed the available literature and of this proposed rule currently do not first time requesting that data and other comments submitted to have adequate evidence of eligibility for polyhexamethylene biguanide, the rulemaking and are proposing that evaluation under the OTC Drug Review benzalkonium cetyl phosphate, adequate data for a determination of as a consumer antiseptic wash. Due to cetylpyridinium chloride, salicylic acid, safety and effectiveness were not yet their lack of eligibility, effectiveness and sodium hypochlorite, tea tree oil, and available for any consumer antiseptic safety information that has been the combination of potassium vegetable wash active ingredient. submitted to the rulemaking for these oil solution, phosphate sequestering antiseptic active ingredients are not agent, and triethanolamine be added to discussed in this proposed rule. the monograph (Refs. 11 through 17).

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These compounds were not addressed washes and does not include consumer the description of data still lacking in in prior FDA documents related to the antiseptic hand rubs (commonly called the administrative record is described in monograph and were not evaluated for hand sanitizers). detail for each active ingredient antiseptic handwash use by the IV. Ingredients Previously Proposed as separately in section VII.D of this Antimicrobial I Panel. The submissions Not Generally Recognized as Safe and proposed rule. received by the Agency to date do not Effective (GRAS/GRAE) include documentation demonstrating TABLE 3—CLASSIFICATION OF OTC the eligibility of any of these seven FDA may determine that an active CONSUMER ANTISEPTIC ACTIVE IN- ingredient is not GRAS/GRAE (i.e., compounds for inclusion in the GREDIENTS IN THIS PROPOSED RULE monograph (Ref. 18). Therefore, nonmonograph) because of lack of AND IN THE 1994 TFM polyhexamethylene biguanide, evidence of effectiveness or lack of benzalkonium cetyl phosphate, evidence of safety or both. In the 1994 This pro- cetylpyridinium chloride, salicylic acid, TFM (59 FR 31402 at 31435), FDA Active ingredient 1994 TFM posed rule sodium hypochlorite, tea tree oil, and proposed that the active ingredients the combination of potassium vegetable fluorosalan, hexachlorophene, phenol Hexylresorcinol ..... IIIE 1 ...... IIISE. oil solution, phosphate sequestering (greater than 1.5 percent), and Iodine complex IIIE ...... IIISE. agent, and triethanolamine have not tribromsalan be found not GRAS/GRAE (ammonium been demonstrated to be eligible for the for use as an antiseptic handwash or ether sulfate and OTC Drug Review. Based on the health care personnel handwash. The polyoxyethylene information about eligibility that we Agency did not classify sorbitan have at this time, we propose to hexachlorophene or tribromsalan in the monolaurate). categorize them as new drugs, and we 1978 TFM (43 FR 1210 at 1227) because Iodine complex IIIE ...... IIISE. (phosphate ester do not include a discussion of safety or it had already taken final regulatory of alkylaryloxy effectiveness data submitted for them. action against hexachlorophene (21 CFR polyethylene gly- 250.250) and certain halogenated col). 3. Alcohol (Ethyl Alcohol) and salicylamides, particularly tribromsalan Isopropyl Alcohol Nonylphenoxypoly IIIE ...... IIISE. (21 CFR 310.502). No substantive (ethyleneoxy) In the 1994 TFM, denatured ethyl comments or new data were submitted ethanoliodine. alcohol (ethanol or alcohol) 60 to 95 to support reclassification of any of Poloxamer iodine IIIE ...... IIISE. percent by volume in an aqueous these ingredients to GRAS/GRAE status. complex. solution was one of two active Therefore, FDA is continuing to propose Povidone-iodine 5 I 2 ...... IIISE. ingredients classified as Category I for that these active ingredients be found to 10 percent. use as an antiseptic handwash or health not GRAS/GRAE for OTC consumer Secondary IIIE ...... IIISE. care personnel handwash (59 FR 31402 antiseptic hand or body washes as amyltricresols. at 31442). Isopropyl alcohol 70 to 91.3 defined in this proposed rule and that Triclocarban ...... IIIE ...... IIISE. percent was classified as Category III for any OTC consumer antiseptic hand or Undecoylium chlo- IIIE ...... IIISE. use as an antiseptic handwash or health ride iodine com- body wash drug product containing any plex. care personnel handwash. The only of these ingredients not be allowed to consumer products containing alcohol continue to be introduced or delivered 1 ‘‘III’’ denotes that additional data are need- or isopropyl alcohol that were for introduction into interstate ed. ‘‘E’’ denotes effectiveness data needed. submitted to the OTC Drug Review were commerce unless it is the subject of an ‘‘S’’ denotes safety data needed. 2 ‘‘I’’ denotes that an active ingredient has products that were intended to be used approved application effective, except been shown to be safe and effective. without water (Ref. 19). Consequently, as otherwise provided in other alcohol and isopropyl alcohol have not regulations, as of 1 year after This proposed rule does not change been demonstrated to be eligible for the publication of the final monograph in the status of a number of antiseptic OTC Drug Review for evaluation as the Federal Register. active ingredients previously proposed consumer antiseptic wash drug V. Summary of Proposed Classifications as lacking sufficient evidence of safety products, which by definition are and effectiveness or the status of several intended to be rinsed off with water. of OTC Consumer Antiseptic Wash Active Ingredients ingredients previously proposed as Based on the information we currently having been shown to be unsafe, have about eligibility of these active Tables 3 and 4 in this proposed rule ineffective, or both (see table 4 of this ingredients, we propose to categorize list the classification proposed in the proposed rule). alcohol and isopropyl alcohol intended 1994 TFM for each OTC consumer for use as an antiseptic wash as new antiseptic active ingredient and the drugs, and we do not include a classification being proposed in this discussion of safety or effectiveness of proposed rule. The specific data that has alcohol or isopropyl alcohol for such been submitted to the public docket (the use. This proposal relates to antiseptic rulemaking) and evaluated by FDA and

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TABLE 4—OTC CONSUMER ANTI- simulation standard) for establishing agree with NDAC’s recommendations on SEPTIC ACTIVE INGREDIENTS WITH effectiveness of consumer and health this issue. NO CHANGE IN CLASSIFICATION IN care antiseptics (59 FR 31402 at 31448) A coalition of trade organizations that THIS PROPOSED RULE COMPARED for the proposed intended use of represent antiseptic manufacturers decreasing bacteria on the skin. The submitted comments disagreeing with TO THE 1994 TFM 1994 TFM log reduction standard for NDAC’s conclusions. The comments No change in effectiveness is based on an unvalidated state that clinical outcome studies in the Active ingredient classification surrogate endpoint (i.e., number of consumer setting are not feasible bacteria removed from the skin), rather because of the cost and considerable Benzalkonium chloride ..... IIISE 1 than a clinical outcome (e.g., reduction number of confounding factors that Benzethonium chloride .... IIISE in the number of infections). Because of would make interpretation of the Chloroxylenol ...... IIISE new concerns about the potential risks studies difficult (Refs. 5, 20, and 21). Cloflucarban ...... IIISE (e.g., resistance and hormonal effects) Some of these confounding factors Fluorosalan ...... II 2 posed by the repeated daily use of identified in these comments included: Hexachlorophene ...... II consumer antiseptic washes (see section Methylbenzethonium chlo- IIISE • Number and length of handwashes ride. VII of this proposed rule), we are now performed Phenol (less than 1.5 per- IIISE proposing that a different type of • Amount of product used cent). effectiveness study is necessary to • Compliance with handwashing Phenol (greater than 1.5 II support the GRAE status of consumer technique and frequency percent). antiseptic wash active ingredients. We • Blinding of products Sodium oxychlorosene .... IIISE are proposing that the use of antiseptic • Use of other (non-study) products Tribromsalan ...... II active ingredients to be used in when outside the home Triclosan ...... IIISE consumer antiseptic wash products be • Triple dye 3 ...... II Type of infection supported by studies that demonstrate a • Virulence of the infecting 1 ‘‘III’’ denotes that additional data are need- direct clinical benefit (i.e., a reduction microorganism ed. ‘‘S’’ denotes safety data needed. ‘‘E’’ de- of infection). Data from these clinical • Generally low bacterial infection rate notes effectiveness data needed. 2 outcome studies will help assure that in the United States ‘‘II’’ denotes that an active ingredient has any potential risk from consumer been shown to be unsafe, ineffective, or both. NDAC found the studies by Luby et 3 antiseptic wash products is balanced by Triple dye was proposed as Category II for al. (Ref. 22) and Larson et al. (Ref. 23), antimicrobial soap due to a physical and/or a demonstrated clinical benefit. chemical incompatibility in formulation and for This effectiveness requirement is which are discussed in section VI.A of skin antiseptic (except for use in neonatal consistent with NDAC’s this proposed rule, to be evidence that ward) in the 1978 TFM (43 FR 1210 at 1227), recommendations from the October such clinical outcome studies are and was not further evaluated as an antiseptic feasible. We agree. Although there are handwash in the 1994 TFM (59 FR 31402 at 2005 meeting regarding consumer 31436). FDA has received no further informa- antiseptics (Ref. 4). NDAC unanimously many confounding factors that must be tion on triple dye for use as an antiseptic wash agreed that in order to be considered addressed when designing a clinical since the 1994 TFM. effective, a demonstration that the drug outcome study of the effectiveness of VI. Effectiveness (Generally Recognized removes bacteria is not enough and that antiseptic washes in the consumer as Effective) Determination consumer antiseptic products should setting, this is the case in any clinical provide a clinical benefit by reducing outcome study. Despite this fact, well- OTC regulations (§ 330.10(a)(4)(ii)) infections. They concluded that studies designed clinical outcome studies are define the standards for establishing an using surrogate endpoints would not be conducted for other types of drug OTC active ingredient as GRAE. These adequate to demonstrate this benefit and products, and the most important regulations require controlled clinical recommended studying the impact of factors can be addressed in an trials of the kind described in these products on infections in specific appropriately designed study. If § 314.126(b) (21 CFR 314.126(b)) as populations of consumers that use these effectiveness cannot be demonstrated in proof of the effectiveness of an active products. NDAC also did not believe a clinical outcome study for consumer ingredient unless this requirement is that it is possible to generalize from antiseptic washes, we should not rush waived. According to § 314.126(a), these effectiveness in the health care to conclude that it is the confounding clinical studies must be adequate and environment to effectiveness in the factors that limit our ability to detect a well-controlled studies that can consumer setting because of differences benefit; rather, if the study is distinguish the effect of a drug from in populations and other risk factors. appropriately designed, it is likely other influences such as a spontaneous NDAC concluded that it would be telling us that the consumer antiseptic change in the course of the disease, feasible to use clinical outcome studies wash does not provide a clinically placebo effect, or biased observation. In to show a benefit of consumer antiseptic significant benefit in a population at general, such studies include controls washes over and above washing with low risk to develop an infection, such as that are adequate to provide an nonantibacterial soap. They pointed out a healthy consumer. assessment of drug effect, adequate that there are already studies in the As discussed later in this section of measures to minimize bias, and the use community setting that have looked at this proposed rule, we evaluated all the of adequate analytical methods to clinical outcomes, such as the number available effectiveness studies for demonstrate effectiveness. For active of symptoms or infections over a given consumer antiseptic washes to ingredients being evaluated in the OTC timeframe. NDAC concluded that it determine if the data supported Drug Review, this means that a would not be unethical to run a placebo- effectiveness of consumer antiseptic demonstration of the contribution of the controlled study of consumer antiseptic active ingredients based on the 1994 active ingredient to any effectiveness washes to demonstrate clinical benefit. TFM effectiveness criteria. We found observed is required before an NDAC also stated that it is important to that the available studies are not ingredient can be GRAE. know if there is any added benefit from adequate to support a GRAE In the 1994 TFM, we proposed a log the antiseptic active ingredient in determination for any consumer reduction standard (a clinical consumer antiseptic wash products. We antiseptic wash active ingredient under

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either the 1994 TFM effectiveness valid demonstration of log reductions. based on published bacterial exposure- criteria or what we propose now. The Agency’s detailed evaluation of the response data for Shigella flexneri (S. data is on file at http:// flexneri). Here, exposure-response data A. Evaluation of Effectiveness Data www.regulations.gov (see ADDRESSES) refers to the correlation between the 1. Clinical Simulation Studies (Ref. 26). Only one submitted clinical amount of S. flexneri ingested and the Most of the data available to support simulation study was adequately severity of clinical disease (e.g., the effectiveness of consumer antiseptic designed and controlled to evaluate the diarrhea) that results from that washes are based on clinical simulation contribution of the active ingredient to ingestion. The rationale for this study studies, such as the one described in the the observed bacterial log reductions design is that if ready-to-eat food was 1994 TFM (59 FR 31402 at 31444). The (Ref. 27). This study compared a liquid contaminated with bacteria left behind premise behind these studies is that soap containing 0.7 percent triclocarban on washed hands and then eaten, those bacterial reductions achieved in this to both the formulation without any organisms would have the potential to cause illness. This scenario has the type of study translate to a reduced risk antiseptic (placebo) and a 4 percent chlorhexidine gluconate active control. potential to occur in the consumer for infection. However, there currently The triclocarban-containing soap was setting during domestic food are no clinical data that demonstrate superior to placebo and met the 1994 preparation. that the specific bacterial log reductions TFM effectiveness criteria of a 2-log The antiseptic handwash met the that we have relied upon as a 10 reduction after the first wash and a 3- 1994 TFM criteria for bacterial demonstration of effectiveness lead to a log reduction after the eleventh wash reduction after one wash; however, the specific reduction in infections. We now 10 (59 FR 31402 at 31448). The active study used a novel hand contamination believe that the appropriate control also met the 1994 TFM method (Ref. 28) that has not been demonstration of effectiveness is a effectiveness criteria when tested sufficiently validated. In addition, we clinical outcome study. Moreover, against Serratia marcescens and believe this novel hand contamination clinical outcome studies are feasible in validated the study conduct. Therefore, method does not accurately reflect an the consumer setting and may not give this was a valid, adequately controlled antiseptic handwash’s intended use rise to ethical concerns such as those study that met the effectiveness criteria because it ignores an important that could occur in studies in a hospital proposed in the 1994 TFM. reservoir of bacteria on the hands (i.e., setting. Although the 0.7 percent triclocarban the area around and under the Although we are now proposing to soap met the standard for effectiveness fingernails), which is evaluated when require clinical outcome studies, we proposed in the 1994 TFM, the log the whole hand contamination method evaluated all clinical simulation studies reduction differences compared to is used. Further, although the study that were submitted to the OTC Drug placebo were small (less than a 0.5-log authors report that the transfer of Review for evidence of antiseptic hand reduction difference compared to bacteria to melon balls decreased with and body wash effectiveness placebo after the first wash and just over use of a consumer antiseptic handwash, demonstrated under the log reduction a 1-log reduction difference after the it is not clear what factors other than the criteria proposed in the 1994 TFM (59 eleventh wash). Because we do not have antiseptic may influence bacterial FR 31402 at 31448) (Ref. 6). We also any data that correlates specific transfer from skin to ready-to-eat foods searched the published literature for bacterial log reductions with clinical such as melon. Therefore, the results of clinical simulation studies that assess outcomes, we have no basis to interpret this study do not demonstrate the antiseptic wash effectiveness also using the impact of these small log reductions effectiveness of the consumer antiseptic the log reduction criteria in the 1994 on infections in a population at low risk handwash used in this study because of TFM (Refs. 24, 25, and 26). Overall, for infection. Thus, even with an the novel and unvalidated methodology. when judged against the criteria in the adequately designed and controlled In addition, the data used by the 1994 TFM, the studies are not clinical simulation study, the data do study authors for the infection risk adequately controlled to allow an not provide sufficient evidence of a estimates have several limitations. First, accurate assessment of the effectiveness meaningful contribution of consumer the bacterial exposure-response data for of consumer antiseptic wash active antiseptic wash active ingredients S. flexneri are based on a small number ingredients for one or more reasons. relative to a placebo handwash. of control subjects in human feeding First, the majority of testing was studies (Refs. 29 through 33). Second, conducted using a formulated product 2. Exposure-Response Studies there is substantial variability in the without adequate comparison to a Although most clinical simulation exposure-response data. In cases where vehicle control, which is needed to studies submitted to the OTC Drug the same bacterial dose was fed to demonstrate the contribution of the Review only evaluated bacterial log subjects in different studies, the number antiseptic active ingredient, if any (43 reductions, one study (Ref. 21) of subjects that became ill varied greatly FR 1210 at 1240). Second, many studies attempted to correlate the reduction of (e.g., 33 to 86 percent) (Refs. 30 and 31). did not include an active control, which bacteria on the hands with a reduction Third, investigators used different is needed to validate the conduct of the in infection rate. The study was criteria to define illness in the various study (59 FR 31402 at 31450). Third, designed to compare the ability of a feeding studies (Refs. 29, 30, and 32). many studies lacked adequate nonantibacterial handwash to the ability Depending on which parameter was documentation of neutralization (43 FR of an antiseptic (triclosan) handwash to examined, the percentage of subjects 1210 at 1244). Residual antiseptic reduce bacteria on the hands after a that were defined as having illness remaining on the skin after rinsing, if single use. The study also evaluated the varied. In studies that examined both not effectively neutralized, will impact of product use on the subsequent clinical symptoms and bacterial continue its antimicrobial action and transfer of surviving bacteria from shedding or antibody response, there result in an exaggerated bacterial washed hands to a ready-to-eat food was no parameter that consistently reduction that is not reflective of item, melon balls. The observed appeared to be correlated with illness in product performance on the skin. reduction in bacterial transfer was then all subjects. Finally, much of the feeding Finally, none of the studies were of used to estimate the potential reduction data comes from high-dose exposures. adequate size to assure a statistically in infection risk from antiseptic use Consequently, the infection rates at low

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doses must be extrapolated, and there consumer antiseptic wash active infectious disease or disease may be a high degree of uncertainty for ingredients. transmission as a result of antimicrobial these values. Furthermore, the bacterial The first study compared the product use. exposure-response data from feeding household use of a 1.2 percent 4. Antiseptic Body Wash Studies studies are not linear, which means that triclocarban-containing consumer an increase in the bacterial dose does antiseptic wash (bar soap) to placebo Several studies were submitted to not necessarily correlate with an wash (nonantibacterial bar soap) or to show a clinical benefit from the use of increase in the number of subjects who standard practice in squatter consumer antiseptic body washes in the become ill. Because of this, a statistical neighborhoods in Pakistan (Ref. 22). prevention of skin infection (Ref. 25). In model must be used to create the Thirty-six neighborhoods were contrast to antiseptic handwashes, bacterial exposure-response curve (Ref. randomized to 1 of 3 groups, with at which are meant to work by removing 34). Use of different statistical models is least 300 households in each group. transiently acquired microorganisms, likely to provide different results. Fieldworkers visited households weekly antiseptic body washes are meant to for 1 year to encourage handwashing in reduce the number of resident bacteria 3. Clinical Outcome Studies the two soap groups and to record on the skin. The majority of these Unlike clinical simulation studies that symptoms in all groups. The primary studies describe the use of antiseptics evaluate effectiveness using unvalidated study outcomes were the incidence rates for nonmonograph indications, such as surrogate endpoints, adequate and well- of diarrhea, impetigo, and acute for the treatment of atopic dermatitis or controlled studies in the general respiratory tract infection. The authors erythrasma. Furthermore, in most of the population could more directly report that handwashing with either studies, the effectiveness of the demonstrate the existence of any soap significantly reduced diarrhea and antiseptic body wash was not the focus clinical benefit for consumer antiseptic acute lower respiratory tract infections, of the study. For example, often the washes. Although these studies are and handwashing in conjunction with antiseptic body wash was part of a complex because of the number of daily bathing prevented impetigo. There treatment regimen that included factors that need to be controlled for, we was no difference between antibiotics or corticosteroid creams, and believe that they are feasible and are the nonantibacterial soap and triclocarban- the effectiveness of the treatment most appropriate method of containing soap. Consequently, this regimens as a whole were the primary demonstrating the effectiveness of study does not show a clinical benefit focus of the investigation. Overall, these consumer antiseptic washes. from the use of the consumer antiseptic studies were not adequately controlled to assess the contribution of the FDA evaluated all the clinical wash over nonantibacterial soap and antiseptic active ingredient, and these outcome studies that were submitted to water, and does not support a GRAE data are not sufficient to demonstrate a the OTC Drug Review to look for finding for the active ingredient (triclocarban). clinical benefit (Ref. 25). evidence of a clinical benefit from the The second study, conducted in the use of consumer antiseptic washes (Ref. B. In Vitro Studies To Support a United States, examined the use of Generally Recognized as Effective 6). In addition, we searched the triclosan-containing hand soap in the Determination published literature for clinical outcome home (Ref. 23). This was a randomized, studies that would provide evidence of double-blind, placebo-controlled trial in In the 1994 TFM we proposed that the a clinical benefit from the use of 224 inner city households randomly effectiveness of antiseptic active consumer antiseptic washes (Refs. 25 assigned to use hand soap and ingredients could be supported by a and 26). We are defining a clinical household cleaning products with or combination of in vitro studies and in benefit here as a reduction in the without antimicrobial ingredients for 48 vivo clinical simulation testing as number of infections in the population weeks. The authors measured infections described in § 333.470 (59 FR 31402 at that uses the consumer antiseptic wash. by assessing the number of infectious 31437). Today, we continue to believe We found only a few clinical outcome disease symptoms during the course of that a GRAE determination for an studies for consumer antiseptic washes. the study (e.g., diarrhea). Test antiseptic active ingredient should be Overall, most of the studies were households received several supported by an adequate confounded, underpowered, and/or not antibacterial cleaning products: Liquid characterization of the antimicrobial properly controlled. Importantly, most triclosan hand soap, quaternary activity of the ingredient. Extensive of the studies did not include a vehicle ammonium hard surface and kitchen testing for this purpose was proposed in control and, therefore, are not able to cleaner, and oxygenated bleach laundry the 1994 TFM which included a show the contribution of the antiseptic detergent. Control households received determination of the in vitro spectrum active ingredient to the observed similar nonantibacterial hand soap, hard of antimicrobial activity, minimum clinical outcome. surface and kitchen cleaner, and inhibitory concentration (MIC) testing Only two of the clinical outcome laundry detergent. Both groups received against 25 fresh clinical isolates and 25 studies identified were randomized, nonantibacterial liquid dish soap and laboratory strains, and time-kill testing blinded, and placebo-controlled with no bar soap. Adherence to the product against 10 laboratory strains (59 FR major design flaws, and only one of regimen was assessed monthly by 31402 at 31444). Comments received in these was designed to evaluate the weighing the remainder of the products response to the 1994 TFM objected to effectiveness of a particular antiseptic and inspecting the home for the the proposed in vitro testing active ingredient. These are the best presence of other products. requirements, stating that they were available studies to evaluate the impact The participants in both groups overly burdensome (Ref. 35). of consumer antiseptic washes on experienced primarily respiratory Consequently, submissions of in vitro infections. Neither of these studies symptoms (runny nose, sore throat, or data submitted to support the demonstrates a benefit from the use of cough). The differences between the effectiveness of antiseptic active the tested antiseptic active ingredient; intervention and control groups were ingredients were far less extensive than however, their study designs can be not significant for any symptoms or for proposed in the TFM (Ref. 6). used as a guide in the development of numbers of symptoms. The study did Based on our proposal for clinical future clinical outcome studies of not show any reduction in symptoms of outcome studies to support a GRAE

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determination and in consideration of VII. Safety (Generally Recognized as of important drug use factors that can comments on our in vitro testing Safe) Determination influence systemic exposure such as proposal (Ref. 35), FDA has reevaluated In the 1994 TFM, 11 active dose, application frequency, application its proposed testing standards. Because ingredients were classified as GRAS for method, duration of exposure (e.g., of the short exposure times for antiseptic handwash use (59 FR 31402 potentially a consumer’s entire lifetime), consumer antiseptic products, we no at 31435). There have since been a product formulation, skin condition, longer believe that MICs are relevant to number of important scientific and age. The evaluation of the safety of drug the effectiveness of antiseptic active developments affecting our evaluation products involves correlating findings ingredients. We also now believe that a of the safety of these active ingredients from animal toxicity studies to the level modified time-kill assay designed to and causing us to reassess the data of exposure to the drug obtained from provide an assessment of how rapidly necessary to support a GRAS an antiseptic active ingredient produces pharmacokinetic studies in animals and determination. There is now new humans. Our administrative record a bactericidal effect is a more efficient information regarding the potential risks and less burdensome way of lacks the data necessary to determine if from systemic absorption and long-term there is an acceptable margin of safety documenting in vitro antiseptic activity. exposure to antiseptic active Further, because clinical outcome for the repeated daily use of consumer ingredients. The potential for antiseptic wash active ingredients. studies are now needed to support a widespread antiseptic use to promote GRAE determination, we no longer Thus, we are continuing to propose that the development of antibiotic-resistant this data is necessary for consumer believe that a demonstration of in vitro bacteria also needs to be evaluated. antiseptic activity against an extensive antiseptic wash active ingredients. This Further, additional experience with and information will help identify potential list of organisms is necessary. knowledge about safety testing has led Therefore, we now propose that data safety concerns and help determine if an to improved testing methods. adequate safety margin exists for OTC from a modified time-kill assay Improvements include study designs designed to provide an adequate human use. One effect of systemic that are more capable of detecting exposure to consumer antiseptic wash assessment of how rapidly an antiseptic potential safety risks. Based on our active ingredient produces a bactericidal ingredients that has come to our reassessment, we are proposing new attention since publication of the 1994 effect and to estimate the antibacterial GRAS data requirements for consumer spectrum of an antiseptic active TFM is data suggesting that triclosan antiseptic wash active ingredients. For and triclocarban can cause alterations in ingredient would be sufficient to our administrative record to be characterize the in vitro antimicrobial thyroid, reproductive, growth, and complete with regard to these new developmental systems of neonatal and activity of an antiseptic active safety concerns, additional safety data adolescent animals (Refs. 41 through ingredient. The assay should test the will be necessary to support a GRAS 50). Hormonally active compounds have following reference strains and determination for consumer antiseptic been shown to affect not only the representative clinical isolates: wash active ingredients. exposed organism, but also subsequent • Enterococcus faecalis (ATCC 19433 A. New Issues generations (Ref. 51). These effects may and ATCC 29212) not be related to direct deoxyribonucleic • Staphylococcus aureus (ATCC 6538 Since the 1994 TFM was published, acid (DNA) mutation, but rather to and ATCC 29213) and methicillin- new data have become available alterations in factors that regulate gene resistant S. aureus (MRSA) (ATCC indicating that systemic exposure to expression (Ref. 52). 33591 and ATCC 33592) topical antiseptic active ingredients may A hormonally active compound that • Streptococcus pyogenes (ATCC 14289 be more than previously thought. causes reproductive system disruption and ATCC 19615) Systemic exposure refers to the presence in the fetus or infant may have effects • Listeria monocytogenes (ATCC 7644 of antiseptic active ingredients inside that are not apparent until many years and ATCC 19115) and throughout the body. For example, after initial exposure. There are also • Campylobacter jejuni (ATCC 33291 triclosan is an antiseptic active critical times in fetal development when and ATCC 49943) ingredient commonly found in a change in hormonal balance that consumer antiseptic hand and body • Escherichia coli (ATCC 11775 and would not cause any lasting effect in an wash products. It is absorbed through ATCC 25922) adult could cause a permanent • the skin and has been found in both developmental abnormality in a child. Pseudomonas aeruginosa (ATCC human breast milk and urine (Refs. 37 15442 and ATCC 27853) For example, untreated hypothyroidism and 38). Further, triclosan has been during pregnancy has been associated • Salmonella enterica Serovar found at relatively consistent levels in with cognitive impairment in the Enteritidis (ATCC 13076) and Serovar urine samples collected from a offspring (Refs. 53, 54, and 55). Typhimurium (ATCC 14028). Serovar representative sample of the U.S. Because consumer antiseptic washes refers to the subspecies classification population since sampling began in are chronic use products and are used of a group of microorganisms based 2003 (Ref. 39). We believe that the by sensitive populations such as on cell surface antigens. consequences of this systemic exposure children and pregnant women, • Shigella sonnei (ATCC 9290 and need to be assessed. evaluation of the potential for chronic ATCC 25931) Given the prevalent use of consumer toxicity and effects on reproduction and The consumer antiseptic drug product antiseptic wash drug products, systemic development should be included in the will be considered bactericidal at the exposure may be commonplace (see Ref. safety assessment. The designs of concentration and contact time that 40 for a discussion of the consumer general toxicity and reproductive/ demonstrates a 3-log10 (99.9 percent) or antiseptic wash market). While some developmental studies are often greater reduction in bacterial viability systemic exposure data exist for sufficient to identify developmental for all of the tested strains. This is the triclosan, many of the other antiseptic effects that can be caused by hormonally same performance criterion used by the wash active ingredients have not been active compounds through the use of Clinical and Laboratory Standards evaluated in this regard. Currently there currently accepted endpoints and Institute (Ref. 36). is also a lack of data to assess the impact standard good laboratory practice

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toxicology study designs. However, could select for antiseptic or antibiotic and bacterial resistance mechanisms in additional study endpoints may be resistance in the natural setting. consumer products and will provide the needed to fully characterize the The impact on bacterial resistance in information needed to perform an potential effects of drug exposure on the the natural setting (rather than in the adequate risk assessment for these exposed individuals. In light of the laboratory) has not been extensively consumer product uses. FDA recognizes preliminary findings for triclosan and evaluated. The existing data are very that the science of evaluating the triclocarban, it is particularly important limited in scope. A few studies have not potential of compounds to cause that adequate analysis of all potential found evidence of such selective bacterial resistance is evolving, and toxic effects of antiseptic active pressures occurring in the natural acknowledges the possibility that ingredients be conducted before their setting (Refs. 78 through 81). However, alternative data different from that listed classification as GRAS. Section VII.C of these data are limited by the small in section VII.C may be identified as an this proposed rule describes the types of numbers and types of organisms, the appropriate substitute for evaluating studies that can adequately evaluate an brief time periods, and locations resistance. active ingredient’s potential to cause examined. More importantly, none of C. Studies to Support a Generally developmental or reproductive toxicity, these consumer studies address the Recognized as Safe Determination or adverse effects on the thyroid gland. level of exposure to antiseptic active The potential of hormonally active ingredients. Thus, the available data are A GRAS determination for consumer antiseptic active ingredients to cause not sufficient to support a finding that antiseptic wash active ingredients developmental or reproductive effects these mechanisms would not have should be supported by both nonclinical raises particular concerns for the safe meaningful clinical impact. Given the (animal) and clinical (human) studies. use of these ingredients on children. increasing evidence about the In order to issue a final monograph for Currently, there is a lack of data to magnitude of the antibiotic resistance these products, this safety data must be assess the systemic exposure of problem and the speed with which new in the administrative record (i.e., antiseptic active ingredients in children. antibiotic resistant organisms are rulemaking docket). In order to assist Additional data to support the safety of emerging, it is important to assess this manufacturers or others who wish to the use of consumer antiseptic active potential consequence of consumer pursue GRAS status for these active ingredients on children may be needed. antiseptic use (Ref. 82). ingredients we are including specific The need for additional data in children FDA has been evaluating the role that information based in part on existing would depend on the risks identified in consumer antiseptic products may play FDA guidance about the kinds of studies the animal safety assessment. If studies in the development of antibiotic to consider conducting and submitting. in children are needed, we recommend resistance for quite some time, and has We have published guidance documents that manufacturers discuss the types of sought the advice from expert panels on describing the nonclinical safety studies studies needed with FDA before this topic on two occasions. In 1997, a that a manufacturer should perform proceeding. joint Nonprescription Drugs and Anti- when seeking to market a drug product Infective Drugs Advisory Committee under an NDA (Refs. 86 through 91). B. Antimicrobial Resistance concluded that the data were not These guidance documents also provide Since publication of the 1994 TFM, sufficient to take any action on this suitable guidance for performing the there is new information raising issue at that time (Ref. 2). The joint studies necessary to determine GRAS concerns about the impact of Committee recommended that FDA status for a consumer antiseptic wash widespread antiseptic use on the work with industry to establish active ingredient. Because consumer development of antimicrobial resistance surveillance mechanisms to address antiseptic washes may be used (Refs. 56 through 59). Bacteria use some antiseptic and antibiotic resistance. At repeatedly over a lifetime and in of the same resistance mechanisms the October 2005 NDAC meeting on sensitive populations, we propose that against both antiseptics and antibiotics. antiseptics for consumer use, however, antiseptic active ingredients will need Thus, the use of antiseptic active some NDAC members expressed to be tested for carcinogenic potential, ingredients with resistance mechanisms concern about the societal consequences developmental and reproductive in common with antibiotics may have of the pervasive use of consumer toxicity (DART), and other potential the potential to select for bacterial antiseptic wash products, including the effects as described in more detail in strains that are also resistant to potential for antiseptic use to lead to this section. clinically important antibiotics, adding changes in bacterial susceptibilities to 1. Safety Studies Described in Existing to the problem of antibiotic resistance. clinically important antibiotics (Ref. 4). Laboratory studies of some of the Reports of the persistence of low FDA Guidances antiseptic active ingredients evaluated levels of some consumer antiseptic NDA safety studies that are described in this proposed rule demonstrate the wash active ingredients in the in the existing FDA guidances (Refs. 86 development of reduced susceptibility environment (Refs. 83, 84, and 85) through 91) provide a framework for the to antiseptic active ingredients and signal the need to better understand the types of studies that are needed for FDA some antibiotics after growth in impact of widespread use of consumer to assess the safety of each antiseptic nonlethal amounts of the antiseptic (i.e., antiseptic washes. Section VII.C of this active ingredient and make a GRAS low-to-moderate concentrations of proposed rule describes the data that determination. A description of each antiseptic) (Refs. 25 and 60 through 77). will help establish a better type of study and how we would use These studies provide ample evidence understanding of the interactions this information to determine safety is of bacterial resistance mechanisms that between antiseptic active ingredients provided in table 5.

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TABLE 5—REQUESTED SAFETY DATA AND RATIONALE FOR STUDIES

Type of study Study conditions What the data tell us How the data are used

Animal pharmaco- Both oral and dermal Allows identification of the dose at which the Used as a surrogate to identify toxic systemic kinetic absorption, administration. toxic effects of an active ingredient are ob- exposure levels that can then be correlated distribution, metabo- served due to systemic exposure of the to potential human exposure via dermal lism, and excretion drug. ADME data provide: The rate and ex- pharmacokinetic study findings. Adverse (ADME) (Refs. 88 tent an active ingredient is absorbed into event data related to particular doses and and 92). the body (e.g., AUC, Cmax, Tmax);1 where drug levels (exposure) in animals are used the active ingredient is distributed in the to help formulate a safety picture of the body; whether metabolism of the active in- possible risk to humans. gredient by the body has taken place; infor- mation on the presence of metabolites; and how the body eliminates the original active ingredient (parent) and its metabolites (e.g., T1⁄2) 2. Human pharmaco- Dermal administration Helps determine how much of the active in- Used to relate the potential human exposure kinetics (Ref. 93). using multiple for- gredient penetrates the skin, leading to to toxic drug levels identified in animal mulations under measurable systemic exposure. studies. maximum use con- ditions. Carcinogenicity (ICH Minimum of one oral Provides a direct measure of the potential for Identifies the systemic and dermal risks asso- S1A and S1B (Refs. and one dermal active ingredients to cause tumor formation ciated with drug active ingredients. Taken 86, 87, and 90)). study for topical (tumorogenesis) in the exposed animals. together, these studies are used to identify products. the type of toxicity, the level of exposure Developmental toxicity Oral administration. Evaluates the effects of a drug on the devel- that produces this toxicity, and the highest (ICH S5 (Ref. 89)). oping offspring throughout gestation and level of exposure at which no adverse ef- postnatally until sexual maturation. fects occur, referred to as the ‘‘no ob- Reproductive toxicity Oral administration. Assesses the effects of a drug on the repro- served adverse effect level’’ (NOAEL). The (ICH S5 (Ref. 89)). ductive competence of sexually mature NOAEL is used to determine a safety mar- male and female animals. gin for human exposure. 1 ‘‘AUC’’ denotes the area under the concentration-time curve, a measure of total exposure or the extent of absorption. ‘‘Cmax’’ denotes the maximum concentration, which is peak exposure. ‘‘Tmax’’ denotes the time to reach the maximum concentration, which aids in determining the rate of exposure. 2 ‘‘T1⁄2’’ denotes the half-life, which is the amount of time it takes to eliminate half the drug from the body or decrease the concentration of the drug in plasma by 50 percent.

Because the available data indicate an unchanged AUC or drug or elimination of natural hormones, that some antiseptic active ingredients concentration on 3 consecutive days which results in a deviation from are absorbed after topical application in taken at the same time of day. normal homeostasis, development, or humans and animals, it is necessary to These studies represent FDA’s current reproduction (Ref. 94). Exposure to a assess the effects of long-term dermal thinking on the data needed to support hormonally active compound early in and systemic exposure to these a GRAS determination for an OTC development can result in long-term or ingredients. It also is important that the antiseptic active ingredient and are delayed effects, including human pharmacokinetic studies reflect similar to those recommended by the neurobehavioral, reproductive, or other maximal use conditions of consumer Antimicrobial I Panel (described in the adverse effects. antiseptic washes using different ANPR (39 FR 33103 at 33135)). The There are several factors common to formulations to fully characterize the Panel’s recommendations for data to antiseptic wash products that make it active ingredient’s potential for dermal support the safety of an OTC topical necessary to assess their full safety penetration. Because consumer antimicrobial active ingredient included profile prior to classifying an antiseptic antiseptic active ingredients can be studies to characterize the following: wash active ingredient as GRAS. These formulated into either hand or body • Degree of absorption through intact are: washes and consumers may use both on and abraded skin and mucous • Evidence of systemic exposure to a daily basis, studies examining membranes several of the antiseptic active maximal use conditions must take full • Tissue distribution, metabolic rates, ingredients body exposure into account. metabolic fates, and rates and routes • Consumer exposure to multiple The duration of the studies should be of elimination sources of antiseptic active sufficient to reach steady-state levels of • Teratogenic and reproductive effects ingredients or other drugs that may be absorption (i.e., the concentration of • Mutagenic and carcinogenic effects hormonally active compounds active ingredient is unchanged by • Exposure to antiseptic active further application of the product 2. Studies To Characterize Hormonal ingredients throughout a consumer’s because the amount of active ingredient Effects lifetime starting in utero being absorbed is equal to the amount We propose that data are also needed Most antiseptic active ingredients being eliminated by the body). For a to assess whether antiseptic active have not been evaluated for these effects steady-state study, the measurement of ingredients have hormonal effects that despite the fact that several of the total exposure would be the area under could produce developmental or ingredients have evidence of systemic the concentration-time curve (AUC) for reproductive toxicity. A hormonally absorption. For antiseptic active plasma, serum, or blood over the length active compound is a substance that ingredients that have not been of the dosing interval at steady-state. interferes with the production, release, evaluated, in vitro receptor binding or Steady-state must be demonstrated by transport, metabolism, binding, activity, enzyme assays can provide a useful

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preliminary assessment of the potential hypothalamic-pituitary-adrenal axis) parturition, lactation, weaning, and hormonal activity of an ingredient. can be detected in these bioassays. growth and development of the However, such preliminary assays do Certain hormone-dependent ovarian and offspring. The multigeneration study not provide conclusive evidence that testicular tumors and parathyroid also provides information about the such an interaction will lead to a hormone-dependent osteosarcoma also effects of the test substance on neonatal significant biological change (Ref. 95). can be detected in rodent morbidity, mortality, target organs in the Conversely, lack of binding does not carcinogenicity bioassays. offspring, and data on prenatal and rule out an effect (e.g., compounds b. Supplementary studies. If no postnatal developmental toxicity. could affect synthesis or metabolism of signals are obtained in the traditional In those cases where adverse effects a hormone resulting in drug-induced RDT, DART, and carcinogenicity are noted on the developing offspring changes in hormone levels indirectly). studies, assuming the studies covered due to a disturbance of any of the organ a. Traditional studies. General all the life stages at which a consumer systems discussed previously in this toxicity and reproductive/ may be exposed to such products (e.g., proposed rule, a risk-benefit analysis developmental studies such as the ones pregnancy, infancy, adolescence), then should be conducted based on the dose- described in this section are generally no further assessment of drug-induced response observed for the findings and sufficient to identify potential hormonal hormonal effects are needed. However, the animal-to-human exposure effects on the developing offspring. if a positive response is seen in any of comparison. If such an assessment Developmental and reproductive the animal studies and this response is indicates a potentially significant risk, toxicity caused by hormonal effects will not adequately understood, then then the antiseptic active ingredient generally be identified using these additional studies, such as juvenile with such findings would not be traditional studies if the tested active animal, pubertal animal, or suitable for inclusion in an OTC ingredient induces a detectable change multigeneration studies, may be needed monograph. Consequently, such in the hormone-responsive tissues (Ref. 96). Juvenile animal, pubertal antiseptic active ingredients would typically evaluated in the traditional animal, and multigeneration studies are require an approval via the NDA toxicity study designs. designed to evaluate endocrine effects pathway prior to marketing. Repeat-dose toxicity (RDT) studies. in developmental stages that 3. Studies To Evaluate the Potential RDT studies typically include a variety supplement the information obtained Impact of Antiseptics Active Ingredient of endpoints, such as changes in body from traditional DART studies (Refs. 97, on the Development of Resistance weight gain, organ weights, gross organ 98, and 99). changes, clinical chemistry changes, or Juvenile animal studies. Young Since the 1994 TFM published, the histopathology changes, which can help animals are considered juveniles after issue of antiseptic resistance and the identify adverse hormonal effects of the they have been weaned. In traditional potential for antibiotic cross-resistance tested drug. The battery of organs DART studies, neonatal animals (pups) has been the subject of much study and typically collected for histopathological are typically dosed only until they are scrutiny. In particular, triclosan has evaluation in RDT studies includes weaned. If a drug is not secreted via the been shown to cause changes in reproductive organs and the thyroid mother’s milk, the DART study will not bacterial efflux activity at nonlethal gland, which can indicate potential be able to test the direct effect of the concentrations (Refs. 62, 64, 66, 101, adverse hormonal effects. For example, drug on the pup. Furthermore, since and 102). Efflux pumps are an important estrogenic compounds can produce pups are not dosed after weaning, they nonspecific bacterial defense effects such as increased ovarian weight are not exposed to the drug during the mechanism that can confer resistance to and stimulation, increased uterine juvenile stage of development. A a number of substances toxic to the cell, weight and endometrial stimulation, juvenile animal toxicity study in which including antibiotics. For this reason, mammary gland stimulation, decreased the young animals are dosed directly the effects of triclosan’s use as a thymus weight and involution, or can be used to evaluate potential drug- preservative in cosmetic products on the increased bone mineral density. induced effects on postnatal development of resistance have been DART studies. Some developmental development for products intended for evaluated by a number of European stages that are evaluated in DART pediatric populations. Advisory Review Committees (Refs. 103 studies, such as the gestational and Pubertal animal studies. The period through 108). In general, these Advisory neonatal stages, may be particularly between the pup phase and the adult Review Committees have concluded sensitive to hormonally active phase, referred to as the juvenile phase that the data are not sufficient to compounds. Traditional DART studies of development, includes the pubertal conclude that the use of triclosan poses capture gestational developmental time period where the animal reaches a public health risk. However, more points effectively, but are less adequate puberty and undergoes important recently, a number of data gaps have for evaluation of effects on postnatal growth landmarks. In mammals, puberty been identified that some Advisory development. Endpoints in pre/ is a period of rapid morphological Review Committees believe need to be postnatal DART studies that may be changes and endocrine activity. Studies addressed to allow for a complete risk particularly suited at detecting in pubertal animals are designed to assessment of the use of triclosan (Refs. hormonal effects include vaginal detect alterations of pubertal 107 and 108). patency, preputial separation, development, thyroid function, and Our own evaluation also found data anogenital distance, and nipple hypothalamic-pituitary-gonadal system gaps with respect to triclosan’s impact retention. Behavioral assessments (e.g., maturation (Ref. 100). on the development of resistance; mating behavior) of offspring may also Multigeneration studies. The however, based on the data available for detect neuroendocrine effects. multigeneration reproductive toxicity other active ingredients, the need to Carcinogenicity studies. A variety of studies (Ref. 98) are conducted to assess evaluate potential resistance is not tumors that result from long-term the performance and integrity of the limited to triclosan. Further, because of hormonal disturbance can be detected male and female reproductive systems the pervasive use of consumer antiseptic in carcinogenicity assays. For example, and include assessment of gonadal wash products we believe that it is the effect of a persistent disturbance of function, the estrous cycle, mating necessary to assess this safety issue particular endocrine gland systems (e.g., behavior, conception, gestation, prior to classifying an antiseptic active

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ingredient as GRAS. Therefore, in resistance are needed to support a GRAS environmental compartments that are addition to the preclinical data determination. sufficient to induce changes in bacterial requirements (as discussed in this However, for antiseptic active susceptibilities. Data on the antiseptic section of this proposed rule), data are ingredients that demonstrate an effect and antibiotic susceptibilities of bacteria also needed to clarify the effect of on antiseptic and antibiotic in areas of prevalent antiseptic use can antiseptic active ingredients on the susceptibilites, additional data will be help demonstrate whether or not emergence of bacterial resistance. necessary to help assess the likelihood changes in susceptibility are occurring Laboratory studies are a feasible first that changes in susceptibility observed with actual use. Because actual use step in evaluating the impact of in the preliminary studies would occur concentrations of consumer antiseptics exposure to nonlethal amounts of in the consumer setting. Different types are much higher than the MICs for these antiseptic active ingredients on of data could be used to assess whether active ingredients, data from antiseptic and antibiotic bacterial or not ingredients with positive compartments where sublethal susceptibilities. As discussed in section laboratory findings pose a public health concentrations of biologically active VII.D of this proposed rule, some of the risk. We do not anticipate that it will be antiseptic active ingredients may occur active ingredients evaluated in this necessary to obtain data from multiple (e.g., environmental compartments) can proposed rule have laboratory data types of studies for each active give us a sense of the potential for demonstrating the development of ingredient to adequately assess the change in antimicrobial susceptibilities reduced susceptibility to antiseptic potential to affect resistance. Such in these compartments (Refs. 83, 84, and active ingredients and antibiotics after studies include, but are not limited to 112 through 115). However, FDA exposure to nonlethal concentrations. the following: recognizes that methods of evaluating However, the testing conducted thus far • Information about the mechanism(s) this issue are an evolving science and has been limited largely to human of antiseptic action (for example, that there may be other data appropriate bacterial pathogens. Only limited data membrane destabilization or to evaluate the impact of antiseptic exist on the effects of antiseptic inhibition of fatty acid synthesis), and active ingredients on the development exposure on the bacteria that are whether there is a change in the of resistance. For this reason, FDA predominant in the oral cavity, gut, skin mechanism of action with changes in encourages interested parties to consult flora, and the environment (Ref. 109). antiseptic concentration with FDA on the specific studies These organisms represent pools of • Information clarifying the appropriate to address this issue. resistance determinants that are mechanism(s) for the development of In those cases where data of the type potentially transferable to human resistance or reduced susceptibility to described in this proposed rule shows pathogens (Refs. 110 and 111). Broader the antiseptic active ingredient (for that changes in bacterial susceptibilities laboratory testing would more clearly example, efflux mechanisms) are likely to occur in the consumer define the scope of the impact of • Data characterizing the potential for setting, an analysis of the risk in relation antiseptic active ingredients on the reduced antiseptic susceptibility to the effectiveness shown for the active development of resistance and provide caused by the antiseptic active ingredient would be conducted. Based a useful preliminary assessment of an ingredient to be transferred to other on this evaluation, a determination antiseptic active ingredient’s potential bacteria that are still sensitive to the would be made as to whether the to foster the development of resistance. antiseptic antiseptic active ingredient would be Studies evaluating the impact of • Data characterizing the concentrations suitable for inclusion in an OTC antiseptic active ingredients on the and antimicrobial activity of the monograph. antiseptic and antibiotic susceptibilities antiseptic active ingredient in of each of the following types of biological and environmental D. Review of Available Data for Each organisms could support a GRAS compartments (for example, on the Antiseptic Active Ingredient determination for antiseptic active skin, in the gut, and in environmental We have identified for each antiseptic ingredients intended for use in OTC matrices) active ingredient whether the studies consumer antiseptic wash products: • Data characterizing the antiseptic and outlined in section VII.C of this • Human bacterial pathogens antibiotic susceptibility levels of proposed rule are available. Table 6 of • Nonpathogenic organisms, environmental isolates in areas of this proposed rule lists the types of opportunistic pathogens, and obligate prevalent antiseptic use (for example, studies available for each antiseptic anaerobic bacteria that make up the in the home, health care, food active ingredient proposed as Category I resident microflora of the human skin, handler, and veterinary settings) or Category III in the 1994 TFM and gut, and oral cavity These data can help ascertain whether indicates whether the currently • Food-related bacteria such as Listeria, or not an antiseptic active ingredient is available data are adequate to serve as Lactobacillus, and Enterococcus • likely to induce nonspecific bacterial the basis of a GRAS determination. Nonpathogenic organisms and resistance mechanisms such as those Although we have data from opportunistic pathogens from that have been shown to occur with submissions to the rulemaking and from environmental compartments (e.g., triclosan exposure. These data could information we have identified in the soil) also help determine the likelihood that literature, our administrative record is If the results of these studies show no changes in susceptibility would spread incomplete for some types of safety evidence of changes in antiseptic or to other bacterial populations and studies for many of the active antibiotic susceptibility, then no further whether or not concentrations of ingredients (see table 6 of this proposed studies addressing the development of antiseptics exist in biological and rule).

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TABLE 6—SAFETY STUDIES AVAILABLE FOR CONSUMER ANTISEPTIC WASH ACTIVE INGREDIENTS 1

Animal Human pharmaco- Oral Dermal Reproductive Potential Resistance Active ingredient pharmaco- kinetic carcinogenicity carcinogenicity toxicity hormonal potential kinetic (ADME) (DART) effects

Benzalkonium chloride ...... ✓ ✓ Benzethonium chloride ...... ✓ ✓✓ ✓ ✓ Chloroxylenol ...... ✓ ✓ ✓ ✓ Hexylresorcinol ...... ✓ ✓✓ Iodophors: Iodine complex (ammonium ether sul- fate and polyoxyethylene sorbitan monolaurate) ...... ✓✓* ✓✓* ✓✓ Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) ...... ✓✓* ✓✓* ✓✓ Nonylphenoxypoly (ethyleneoxy) ethanoliodine ...... ✓✓* ✓✓* ✓✓ Poloxamer-iodine complex ...... ✓✓* ✓✓* ✓✓ Povidone-iodine ...... ✓✓ ✓✓* ✓✓* ✓✓ Undecoylium chloride iodine complex ... ✓✓* ✓✓* ✓✓ Methylbenzethonium chloride 2 ...... Phenol 2 ...... Secondary amyltricresols 2 ...... Sodium oxychlorosene 2 ...... Triclocarban ...... ✓ ✓ ✓✓ ✓ ✓ ✓ Triclosan ...... ✓✓ ✓ ✓✓ ✓✓ ✓ ✓ 1 Empty cell indicates no data available; ‘‘✓’’ indicates some data available, but inadequate; ‘‘✓✓’’ indicates available data are adequate; * indicates based on stud- ies of potassium iodide. 2 These active ingredients are not discussed further because no safety data were submitted.

In the remainder of this section, we hexylresorcinol’s long history of use as levels were undetectable 12 hours after discuss the existing data and data gaps an oral antihelmintic (a drug used in the the 1 g dose and 24–36 hours after the for each of the following antiseptic wash treatment of parasitic intestinal worms) 3 g dose. active ingredients that was proposed as in humans and the lack of allergic In the only study in humans (Ref. GRAS in the 1994 TFM and explain reactions or dermatitis associated with 118), two men received oral doses of why these active ingredients are no topical use. The Panel noted that no 1 g of 4-hexylresorcinol. An average of longer proposed as GRAS (i.e., why they information was provided regarding 18 percent of the dose was recovered in are now proposed as Category III): dermal or ophthalmic toxicity or urine within the first 12 hours; • Hexylresorcinol absorption and blood levels attained thereafter, the compound was not • Iodophors (i.e., all iodine-containing after application to intact or abraded detected in urine samples. Fecal ingredients) skin or mucous membranes, but excretion accounted for 64 percent of • Triclocarban concluded that the few animal toxicity the dose. It has been reported that We also discuss the following studies submitted as summaries hexylresorcinol is excreted via the urine antiseptic active ingredients that were indicated a ‘‘low order’’ of toxicity (Ref. mainly in the form of an ethereal sulfate conjugate (Ref. 119). proposed as Category III in the 1994 116). Overall, the animal ADME data are TFM and for which there are some new In light of the new safety information not adequate and additional data available and explain why these about the potential risks of systemic exposure to antiseptic active pharmacokinetic data (e.g., AUC, Tmax, ingredients are still Category III: and Cmax) at steady-state levels • ingredients, the data relied on by the Benzalkonium chloride continue to be necessary to bridge • Benzethonium chloride Panel no longer can be considered • animal data to humans. Chloroxylenol adequate to support a GRAS Hexylresorcinol carcinogenicity data. • Triclosan determination. Currently, there are only An adequate oral carcinogenicity study We do not discuss the following minimal data available to assess the was conducted by the National antiseptic active ingredients that were safety of the repeated, daily, long-term Toxicology Program (NTP) in which proposed as Category III in the 1994 use of hexylresorcinol. hexylresorcinol was administered orally TFM because we are not aware of any a. Summary of available to groups of rats and mice of each sex safety data for these active ingredients: hexylresorcinol safety data. 5 days per week for 2 years (Ref. 120). • Methylbenzethonium chloride Hexylresorcinol ADME data. There No evidence of carcinogenicity was • Phenol (less than 1.5 percent) currently are no well characterized found in rats. However, precancerous • Secondary amyltricresols absorption studies in either humans or cells of the adrenal gland were observed • Sodium oxychlorosene animals and only minimal ADME data at increased incidences in dosed male by the oral route available. In one study mice. A marginal upward trend in 1. Hexylresorcinol (Ref. 117) male dogs were given single tumors of the adrenal gland was also In the 1994 TFM, FDA proposed to oral doses of observed in male mice. The increase of classify hexylresorcinol as GRAS for use 1 or 3 grams (g) of 4-hexylresorcinol. these two types of cancers was not as an OTC antiseptic handwash based The majority of the administered dose statistically significant and was on the recommendations of the Panel, was detected in its free form in the feces considered equivocal by the NTP. who concluded that the topical (67 to 80 percent) with some excretion FDA agrees that the findings in male application of hexylresorcinol is safe (39 in the urine (10 to 29 percent) primarily mice should not be considered a FR 33103 at 33134). In support of its as conjugates. Urinary excretion was positive carcinogenic signal. No changes conclusion, the Panel cited rapid, mainly in the first 6 hours, and were noted in the adrenal glands in 16-

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and 30-day subgroups included in the • Poloxamer-iodine complex of topical application of povidone- study. Also, the fact that the marginal • Povidone-iodine 5 to 10 percent iodine either as a surgical scrub (Ref. increase in changes that occurred in • Undecoylium chloride iodine 124) or as an antiseptic treatment of male mice were not corroborated in complex premature babies in a neonatal intensive earlier RDT studies in female mice, or Iodine is found naturally in the care nursery (Ref. 125). Nobukuni et al. in rats of either sex, makes the weight human body and is essential for normal (Ref. 126) evaluated the effect of long- of the evidence for the male-only human body function. In the body, term topical povidone-iodine treatment findings weak. In an 18-month iodine accumulates in the thyroid gland on serum iodine levels and thyroid intravaginal study (Ref. 121), injection and is a critical component of thyroid function in bedridden inpatients. of 1 percent hexylresorcinol dissolved hormones. People obtain iodine through Inpatients treated with povidone-iodine in carbowax 1000 twice weekly in 20 their food and water, which are often had higher blood concentrations of female mice did not cause any genital supplemented with iodine to prevent organic iodine compared to the control tract tumors. iodine deficiency. Because consumers group, suggesting absorption of topically The submitted oral carcinogenicity are widely exposed to iodine, it has applied iodine. It is possible that steady- state levels may have been achieved in data are adequate and show that been the subject of comprehensive this study; however, this was not hexylresorcinol does not pose a risk of toxicological review by public health cancer after repeated oral administration directly demonstrated. organizations (Refs. 122 and 123). Although these studies provide some under the experimental conditions used; In the 1994 TFM, FDA stated that information on absorption of topically however, data from a dermal neither the medium nor large molecular applied povidone-iodine, they do not carcinogenicity study are lacking. weight size povidone molecules b. Hexylresorcinol safety data gaps. In provide sufficient information to presented a safety risk when limited to summary, our administrative record for estimate typical amounts of iodine that the topical uses described in the the safety of hexylresorcinol is could be absorbed from consumer monograph and that larger size incomplete with respect to the antiseptic wash products containing molecules would not be absorbed under following: povidone-iodine. Nor can the results of • the TFM conditions of use (59 FR 31402 these studies be extrapolated to assess Human pharmacokinetic studies at 31424). We continue to believe that under maximal use conditions when the potential dermal penetration of the larger size molecules pose no risk of iodine from other iodophor complexes. applied topically, including absorption. However, data are lacking documentation of validation of the Because the iodophor complex affects on the absorption of smaller molecular the release rate of iodine, absorption methods used to measure weight povidone molecules and for hexylresorcinol and its metabolites data are needed for each different • other carriers currently under complex. Animal ADME consideration, e.g. poloxamer. Human • Data to help define the effect of Iodophor ADME data. In addition to absorption studies following maximal formulation on dermal absorption human absorption data (described in the • Dermal carcinogenicity dermal exposure to these carriers can be previous subsection), the distribution, • DART studies used to determine the risk of systemic metabolism, and excretion of iodine • Potential hormonal effects toxicity from the carrier molecule. For have been characterized in humans for • Data from laboratory studies that carrier molecules that are absorbed oral exposures (Ref. 122). Because the assess the potential for the following dermal exposure, we propose distribution of absorbed iodine has been development of resistance to that the following data are needed: shown to be similar regardless of the hexylresorcinol and cross-resistance Systemic toxicity of the carrier in route of exposure, we can use data from to antibiotics in the types of animal studies that identify the target oral exposures in assessing distribution, organisms listed in section VII.C.3 of organ for toxicity, and characterization metabolism, and excretion of iodine this proposed rule of the metabolic fate of the carrier as from topical exposure. Most of the recommended by the Panel (39 FR iodine from orally ingested sodium 2. Iodophors (Iodine-Containing 33103 at 33130). iodide accumulates in the thyroid Ingredients) a. Summary of iodophor safety data. (approximately 20 to 30 percent) as Iodophor complexes are complexes Iodophor human pharmacokinetics iodide or is excreted in the urine (30 to formed between iodine, which is the data. Several studies demonstrated that 60 percent) within 10 hours (Refs. 122 active antimicrobial component, and a iodine applied to human skin was and 127). The elimination half-life of carrier molecule. Both surfactant and systemically absorbed to some extent absorbed iodine is approximately 31 nonsurfactant compounds have been (Ref. 122). The studies consistently days in healthy adult males (Ref. 127), complexed with iodine. The rate of the found raised blood concentrations of but has considerable variability (Ref. release of ‘‘free’’ elemental iodine from both organic (protein-bound) and 128). Overall, the distribution, the complex is a function of the inorganic (nonbound) iodine following metabolism, and excretion of iodine equilibrium constant of the complexing topical application of iodine-containing have been adequately assessed in formulation (39 FR 33103 at 33129). The antiseptics, indicating that iodine humans and no further animal ADME following surfactant and nonsurfactant permeated the skin. However, the data is needed. iodophor complexes were proposed as studies did not provide sufficient Iodophor carcinogenicity data. The GRAS in the 1994 TFM for OTC information to quantify typical amounts oral carcinogenicity data indicate that antiseptic handwash use (59 FR 31402 of iodine that can be absorbed from iodine does not pose a risk of cancer in at 31435): topically applied products containing rats after repeated oral administration to • Iodine complex (ammonium ether iodine. In addition, the studies do not rats under the experimental conditions sulfate and polyoxyethylene sorbitan provide pharmacokinetic data at used (Ref. 129). Overall, there was no monolaurate) maximal exposure and steady-state significant increase in the incidence of • Iodine complex (phosphate ester of levels. tumors from iodine exposure. Although alkylaryloxy polyethylene glycol) Most of the absorption studies there was an increased incidence of • Nonylphenoxypoly (ethyleneoxy) evaluated povidone-iodine. Significant squamous cell carcinomas in the ethanoliodine iodine absorption was seen as a result submandibular salivary gland in the

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high dose group, this increase was not necessary endpoints regarding fertility topical or vaginal iodine-containing significant. and embryo-fetal development. antiseptics during pregnancy or after The ability of iodine to function as a Shoyinka, Obidike, and Ndumnego delivery (Refs. 135, 136, and 141). Other tumor promoter (i.e., something that (Ref. 133) evaluated the effect of iodine studies have shown hypothyroidism in stimulates existing tumors to grow) also on the male reproductive system of rats. infants after topical iodine exposure has been evaluated in rats. In a study by A statistically significant (p<0.05) (Refs. 125, 134, 138, and 142). Elevated Takegawa et al. (Ref. 130), rats were increase in the average weights of the thyroid stimulating hormone (TSH) pretreated with a chemical that can testes and epididymides, and levels have been reported in full-term initiate tumors (DHPN). One group then approximately 12 percent decrease in newborns after repeated topical received a high dose of potassium epididymal sperm counts were observed application of povidone-iodine (Refs. iodide (1,000 parts per million (ppm)) in in the high dose-treated group. The 143 and 144). their water while a control group authors suggest that excess iodine may Iodine readily crosses the placenta received untreated water over 82 weeks. reduce fertility by lowering epididymal and is concentrated in the mammary The iodine-treated group had a sperm counts. gland and secreted in breast milk (Ref. significantly higher incidence of We found no information on 145). Although iodine-induced follicular thyroid cancer compared to reproductive effects in humans due to hypothyroidism is transient in the control group, suggesting that iodine dermal iodine exposure. However, newborns, even transient may be a tumor promoter for other transient hypothyroidism (diminished hypothyroidism should be avoided carcinogens in the thyroid gland. production of thyroid hormones) in during this critical phase of brain In another study (Ref. 131), rats were infants has been reported as a result of development to prevent loss of injected with either DHPN or saline and topical exposure to povidone-iodine intellectual capacity (Refs. 146, 147, and then received doses of potassium iodide (Refs. 134 through 138). Thyroid 148). in their drinking water to simulate hormone deficiency from any cause at For adults, the association between conditions of iodine deficiency to critical times of development may result topically applied iodine and iodine excess. For the two highest-dose in adverse effects, including abnormal hypothyroidism is unclear. One study in groups, 5 of 20 rats and 2 of 20 rats pubertal development (Ref. 122). 27 bedridden inpatients treated developed thyroid tumors, respectively. Although excess iodine may result in continuously with povidone-iodine for Although the authors concluded that hypothyroidism, iodine deficiency is 3 to 133 months showed changes in excess iodine can promote thyroid more likely to cause prenatal and TSH levels (Ref. 126). However, these tumor formation, these results were postnatal hypothyroidism (Ref. 122). data are difficult to extrapolate to barely significant, and higher dosing did Overall, the effect of iodine on typical consumer antiseptic hand or not correlate with increased tumor development and reproductive body wash use because povidone-iodine promotion activity. Therefore, some toxicology are well characterized and was applied to damaged skin in this evidence suggests that very high oral additional DART studies are not study. Another study in 16 nurses who doses of iodine may have tumor needed. used povidone-iodine regularly for promoter activity. However, based upon Iodophor data on hormonal effects. handwashing and gargling (Ref. 149) the available data, oral doses of iodine We found no nonclinical studies that found that thyroid hormone levels were do not significantly raise the risk of examine the effect of excess iodine or not significantly different from control cancer in animals. iodine deficiency on endocrine systems subjects who rarely used povidone- Iodophor DART data. The effects of in animal models. However, clinical iodine, which suggests topical iodine on embryo-fetal development data indicate that at high doses iodine povidone-iodine does not significantly and on fertility were studied in animals ingestion exerts a direct effect on the affect thyroid function. (Ref. 132). No fetal malformations were thyroid gland and on the regulation of Oral exposure to iodine has been reported when the fetuses were exposed thyroid hormone production and demonstrated to cause significant to iodine prenatally, nor were there any secretion (Ref. 122). The effects of thyroid effects (Refs. 122 and 123). effects on fertility in adult animals that iodine on the thyroid gland have been Several clinical studies demonstrated were exposed to iodine. The design of shown to include hypothyroidism, that high oral doses of iodine can affect these studies, however, does not fit into hyperthyroidism (excessive production blood levels of thyroid hormones, but current testing paradigms for an or secretion of thyroid hormones), and rarely did these effects seriously impair adequate evaluation of the reproductive inflammation of the thyroid. These thyroid function. Oral iodine exposure and developmental toxicity of a drug. conditions can adversely affect exceeding 200 mg/day (2.8 mg/kg/day) One series of studies (Ref. 132) reproduction, growth, and during pregnancy can result in evaluated the effects of diets developmental systems in humans. congenital hypothyroidism (Ref. 122). supplemented with high levels of iodine The data demonstrating the thyroid Generally, however, adverse effects on reproduction, lactation, and survival effects of iodine are primarily from oral were only observed following very high in rats, hamsters, rabbits, and pigs. For administration (Ref. 122). There is much oral doses that caused very high serum the rats, excess iodine in the diet (2,500 less information on thyroid effects after iodine concentrations. ppm) was associated with an increase in topical administration of iodine. The Drawing conclusions from these the incidence of death in newborns and majority of cases of thyroid hormone studies is difficult because the studies an increase in the time to give birth. In changes resulting from topical have several limitations. Many of these rabbits, a dose-dependent decrease in administration of iodine involve studies lacked control groups, used newborn survival was observed. There mothers and newborn infants. Studies small subject numbers, and/or did not were no observed effects in hamsters or have shown that topical povidone- record subjects’ iodine status at baseline pigs. The results suggest a species iodine applied to pregnant and breast- (iodine-deficient subjects may be more difference in response to similar levels feeding women causes transient susceptible to thyroid effects caused by of excess iodine; however, the daily hypothyroidism in their newborns (Refs. iodine exposure). The study results are iodine intake per kilogram (kg) of body 135, 136, 139, and 140). Iodine-induced also difficult to compare because the weight varied among species. Further, hypothyroidism has been reported in studies used different subject age these studies do not evaluate all the nursing infants whose mothers used groups, subject types, iodine

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formulations and amounts, durations steady-state levels were reached is and humans. The principal metabolites and frequency of iodine treatment, and unknown. common to all species were the sulfate methods for measuring absorbed iodine We found several studies in humans and glucuronide conjugates of 2′-, 3′-, levels or thyroid effects. Despite these that examine the absorption of and 6-hydroxy-triclocarban. However, deficiencies, we believe there are triclocarban after topical application there were differences in triclocarban adequate data regarding the potential of (Refs. 153 through 156). Most of these metabolism between rats and higher iodine to cause changes in thyroid studies evaluated absorption after a primates, and the monkey appears to be hormone levels and additional studies single topical exposure and used a small the more appropriate model for studying are not necessary. number of subjects. After a single triclocarban pharmacokinetics in b. Iodophor safety data gaps. In exposure, blood levels of triclocarban humans (Ref. 159). summary, our administrative record for ranged from below the limit of detection Elimination of triclocarban the safety of iodophor complexes is (10 ng/mL) to a Cmax of 530 nanomolar metabolites from the plasma appears to incomplete with respect to the (nM) (167 ng/mL) (Refs. 153, 154, and be biphasic. In adult rhesus monkeys, following: 155). Small amounts of triclocarban elimination from the plasma occurs in • Human studies of the absorption of were also detectable in the urine and two distinct phases: Rapid elimination iodine following maximal dermal feces of subjects. The estimated total of parent triclocarban and glucuronide exposure to the complexes average recovery ranged between 0.39 conjugates, and slower elimination of • Human absorption studies of the and 0.6 percent of the applied dose. sulfate conjugates (Ref. 160). Similarly, carrier molecule for small molecular Although small, these studies suggest in humans, the major plasma weight povidone molecules and the that very little triclocarban is absorbed metabolites are glucuronide conjugates, other carriers listed in this section after a single topical exposure; however, which were eliminated in urine with a • Dermal carcinogenicity studies for steady-state levels were not evaluated. half-life of about 2 hours (Ref. 152). each of the iodophor complexes Howes and Black (Ref. 156) examined Triclocarban sulfate conjugates are • Data from laboratory studies that absorption of triclocarban after repeated removed from plasma with a half-life of assess the potential for the daily application in a 28-day bathing about 20 hours, presumably into the development of resistance to iodine study. Twelve subjects bathed once bile. and cross-resistance to antibiotics in daily using bar soap that contained 2 The majority of triclocarban and its the types of organisms listed in percent triclocarban. Each subject was metabolites are eliminated through the section VII.C.3 of this proposed rule exposed to approximately 260 mg of feces, with smaller amounts eliminated triclocarban per day. Triclocarban was through the urine. In a human study 3. Triclocarban below the limit of detection (25 ng/mL) where six male volunteers received a In the 1994 TFM, FDA proposed to in all samples at all time points. A single oral dose of 14C-labeled classify triclocarban as GRAS for use as manufacturer of triclocarban has triclocarban in corn oil, 70 percent of an OTC antiseptic handwash. This suggested that steady-state levels were the dose was eliminated in the feces and determination was based on safety data achieved in this study (Ref. 157), but elimination was complete after 120 and information that were submitted in this was not directly demonstrated. hours (Ref. 152). Twenty-seven percent response to the 1978 TFM on In addition to systemic exposure as a of the dose was eliminated in urine, and triclocarban formulated as bar soap result of dermal absorption, consumers the urinary excretion of triclocarban and (Refs. 151 and 152). These data included may have prolonged exposure to those its metabolites was complete by 80 blood levels, target organs for toxicity, antiseptic active ingredients that remain hours after dosing. and no effect levels and were discussed bound to the skin after use (that is, Although there are some ADME data in the 1991 First Aid TFM (56 FR 33644 substantive). Triclocarban has been on triclocarban after oral exposure, there at 33664). The existing data, however, shown to be substantive. North-Root et are little data after topical exposure. are no longer sufficient to fully evaluate al. (Ref. 158) measured the amount of Gruenke et al. (Ref. 163) analyzed the safety of triclocarban. New triclocarban that remained on the skin plasma and urine samples from human information regarding potential risks after a single application of bar soap in subjects who used triclocarban- from systemic absorption and long-term 12 human subjects. An average of 1.4 containing bar soap. The major plasma exposure to antiseptic active ingredients percent of the applied triclocarban metabolite was a sulfate of hydroxy- is leading us to propose additional remained on the skin. Substantive triclocarban, with levels ranging from 0– safety testing. product remaining on the skin after 20 ng/mL. The major metabolites found a. Summary of triclocarban safety rinsing may lead to additional in the urine were triclocarban data. absorption and systemic exposure. glucuronides, with typical levels Triclocarban human pharmacokinetic Overall, the human pharmacokinetic averaging 30 ng/mL. The authors did data. Some human pharmacokinetic studies are not adequate, and we not describe the frequency or length of parameters were reported in a study propose that human pharmacokinetic time the subjects bathed with the soap; where six male subjects received a studies using dermal administration consequently, it is not known whether single oral dose of 14C-labeled under maximal use conditions are still maximal exposure or steady-state levels triclocarban: The maximum plasma needed to define the level of systemic were reached. Overall, the animal concentration (i.e., Cmax) was 3.7 exposure following repeated use. In ADME data are not adequate and nanomole (nmol)-equivalents of addition, data are needed to help define additional pharmacokinetic data (e.g., triclocarban per g of plasma the effect of formulation on dermal AUC, Tmax, and Cmax) at steady-state (approximately 1,200 nanograms per absorption. levels continue to be necessary to bridge milliliter (ng/mL)) and occurred at 2.8 Triclocarban ADME data. animal data to humans. hours (Tmax) (Ref. 152). Although Triclocarban is readily metabolized in Triclocarban carcinogenicity data. A human pharmacokinetic parameters both humans and animals (Refs. 159 manufacturer submitted a 2-year oral were reported in this study, triclocarban through 162). Birch et al. (Ref. 159) carcinogenicity study of triclocarban in was administered orally. As a result, the identified the metabolites of rats (Refs. 150 and 151). Based on this exposure when applied topically under triclocarban in plasma and urine after study, the no observed adverse effect maximal use conditions and when oral exposure in rats, rhesus monkeys, level (NOAEL) for triclocarban in the rat

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is 25 mg/kg/day. Although no address possible testicular effects have not provide the rationale for pooling carcinogenicity findings were seen in been conducted and submitted to a triclocarban and triclosan user data in this study, some noncarcinogenicity triclocarban drug master file (Ref. 164). the analysis. Currently, there is no findings were noted. Male rats treated For FDA to include these data in the evidence to suggest that bacteria would with 75 and 250 mg/kg/day doses of administrative record for this use the same mechanisms of resistance triclocarban exhibited male sex organ rulemaking, they must be submitted to against these two antiseptic active toxicity, including degeneration of the the rulemaking or otherwise publicly ingredients. When CNS susceptibility to seminiferous tubules, enlargement of available. Overall, the data submitted to antiseptics was examined, the MIC the epididymal secretory epithelium, the antiseptic rulemaking are not range for triclocarban was the same and a decrease or absence of sperm in adequate to address concerns about among all three groups (maximum MIC epididymal ducts. hormonal effects of triclocarban. We value of 0.750 (no units provided)). No No dermal carcinogenicity data have propose that additional reproductive patterns emerged when the data were been submitted for triclocarban. and developmental studies are analyzed for cross-resistance between Previously, we considered data from necessary, which should include an triclocarban or triclosan and antibiotics. systemic exposure to represent a worst assessment of any hormonal effects. The authors conclude that this study case scenario for topical products. Now, Triclocarban resistance data. We shows no increase in antibiotic however, we recognize that topical found one study that examined the resistance from the regular use of products may affect the skin or be potential for development of cross- triclocarban body wash. But, this study metabolized in the skin, which is not resistance between triclocarban and was not adequately designed to addressed in oral carcinogenicity antibiotics. Cole et al. (Ref. 78) determine whether use of antiseptic studies. described antibiotic and antiseptic body washes leads to changes in The submitted oral carcinogenicity susceptibilities of staphylococci isolated antibiotic or antiseptic susceptibilities. data are adequate and show that from the skin of consumers who used Given the limited number of isolates triclocarban does not pose a risk of nonantibacterial or antiseptic body examined, it is not clear that the study cancer after repeated oral administration washes. Subjects were considered was adequately powered to detect a under the experimental conditions used; antiseptic body wash users if they used difference in resistance patterns. however, data from a dermal either bar soaps containing triclocarban Furthermore, the amount of antiseptic carcinogenicity study are lacking. (triclocarban group) or liquid bath or exposure was not defined. The length of Triclocarban DART data. Our records shower products containing triclosan time subjects has used antiseptic body indicate that a manufacturer submitted (triclosan group) on a regular basis for washes (beyond the specified 30 days), data regarding the reproductive toxicity at least 30 days prior to study initiation. the frequency of bathing, and the of triclocarban to a triclocarban drug From a pool of 450 qualified subjects, 70 volume of antiseptic wash used per bath master file (Ref. 164). Safety data were randomly chosen for each or shower was not reported. Finally, few submitted to drug master files are not treatment arm (non-user, triclocarban bacterial isolates were examined. It is publicly available and, consequently, group, or triclosan group). cannot be used to support a GRAS Bacterial skin samples were collected reasonable to examine the classification (§ 330.10(a)(4)(i)). For FDA using a pre-validated method and were susceptibilities of Staphylococcus to include these data in the comprised of the combined samples species; however, an average of only 1.5 administrative record for this from both forearms. Staphylococcus isolates was obtained from each subject. rulemaking, they must be submitted to aureus and coagulase-negative Overall, the available data are not this rulemaking or be otherwise publicly Staphylococcus (CNS) were adequate to characterize triclocarban’s available. presumptively identified according to potential to foster the development of Triclocarban data on hormonal morphology, pigmentation, hemolysis, cross-resistance with clinically effects. Recent studies have and other characteristics from these important antibiotics and we propose demonstrated that triclocarban may samples. One representative of each that these studies are needed. have the ability to alter the activity of colony type from each sample was b. Triclocarban safety data gaps. In the androgen system (Refs. 41 and 42). selected for further testing, for a total of summary, our administrative record for Chen et al. (Ref. 42) reported that 317 isolates: 16 S. aureus and 301 CNS. the safety of triclocarban is incomplete triclocarban enhanced the testosterone- All 317 Staphylococcus isolates were with respect to the following: induced androgen receptor-mediated tested for susceptibility to 10 • Human pharmacokinetic studies response both in cell culture and in an antibiotics, including the primary and under maximal use conditions when in vivo rat model although triclocarban secondary antibiotics of choice for applied topically, including by itself had no activity. When castrated treatment of Staphylococcus infections, documentation of validation of the male rats were fed a diet containing 0.25 by a commercial lab using an automated methods used to measure triclocarban percent triclocarban and treated with procedure. In addition, all isolates were and its metabolites testosterone propionate (0.2 mg/kg) for tested for MIC of triclocarban and • Animal ADME 10 days, all male sex accessory organs triclosan using a standard broth • Data to help define the effect of were significantly increased in size microdilution method. formulation on dermal absorption compared to rats treated with either The percentage of CNS isolates • triclocarban or testosterone alone. The resistant to any of the 10 antibiotics was Dermal carcinogenicity • implications of these findings on human similar for all three groups (non-user, DART studies health, especially for children, are not triclocarban, or triclosan group). When • Potential hormonal effects well understood. data from both user groups (triclocarban • Data from laboratory studies that The testicular effects seen in the 2- and triclosan) were pooled, there was no assess the potential for the year oral carcinogenicity study (Refs. statistical difference in bacterial development of resistance to 150 and 151) also suggest a hormonal resistance patterns between users and triclocarban and cross-resistance to disturbance on the testes as a result of non-users with the exception of antibiotics in the types of organisms exposure to triclocarban. Our records tetracycline, which approached listed in section VII.C.3 of this indicate that additional studies to significance (p = 0.052). The authors did proposed rule

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4. Benzalkonium Chloride propose that both oral and dermal antibiotics but believe a larger study is In the 1994 TFM, FDA categorized carcinogenicity studies are needed for needed to confirm or change that benzalkonium chloride in Category III benzalkonium chloride. conclusion. Benzalkonium chloride resistance because of a lack of adequate safety data Similar to what has been observed data. Several gram-negative bacteria for its use as OTC antiseptic handwash with triclosan, exposure to (GNB) (Escherichia coli, Salmonella, (59 FR 31402 at 31435). Because of its benzalkonium chloride in the laboratory and Pseudomonas) have been shown to widespread use as an antimicrobial has resulted in changes to the antibiotic readily adapt when grown in the agent in cosmetics and as a disinfectant susceptibility profiles of some bacteria presence of subinhibitory levels of for hard surfaces in agriculture and (Refs. 60, 70, 72, 79, 169, and 170). benzalkonium chloride in laboratory medical settings, the safety of However, the data are limited in scope. studies (Refs. 60, 68, 70, 72, 169, and benzalkonium chloride has also been The available studies have examined 170). These bacteria also displayed reviewed by the Environmental few bacterial species, provide no reduced susceptibility to antibiotics Protection Agency and an industry information on exposure levels, and are compared to the nonadapted parental not adequate to define the potential for review panel (Cosmetic Ingredient strain (Refs. 60, 70, 72, 169, and 170). Review (CIR)) (Refs. 165 and 166) and the development of resistance or cross- Four studies showed an association resistance. Additional laboratory studies found to be safe for disinfectant and between reduced susceptibility to cosmetic uses, respectively. Both these are necessary to more clearly define the benzalkonium chloride and the potential for the development of evaluations have been cited by the antibiotic chloramphenicol (Refs. 70, 72, comments in support of the safety of resistance to benzalkonium chloride. 79, and 170). This association was Depending on the results of the benzalkonium chloride as an antiseptic shown in three different bacteria; wash active ingredient (Ref. 167). laboratory studies, additional data of the however, no common mechanism has type described in section VII.C of this Each of these evaluations cites been identified to explain this finding. findings from the type of studies proposed rule may also be needed to There are data available suggesting that assess the level of risk posed by necessary to support the safety of efflux pumps may not play a major role benzalkonium chloride for repeated benzalkonium chloride. in the reduced susceptibility of b. Benzalkonium chloride safety data daily use. However, the data that are the Salmonella to benzalkonium chloride gaps. In summary, our administrative basis of these safety assessments are (Ref. 170). record for the safety of benzalkonium proprietary and are publicly available In a study by Lambert and colleagues chloride is incomplete with respect to only in the form of summaries. (Ref. 69), human clinical and industrial the following: Consequently, these studies are not isolates and standard culture collection • available to FDA and are precluded Human pharmacokinetic studies strains of P. aeruginosa were examined under maximal use conditions when from a complete evaluation by FDA. In for reduced susceptibility to addition, the submitted safety applied topically, including benzalkonium chloride, chlorhexidine, documentation of validation of the assessments with study summaries do and eight antibiotics. No statistically not constitute an adequate record on methods used to measure significant association between benzalkonium chloride and its which to base a GRAS classification benzalkonium chloride and antibiotic metabolites (§ 330.10(a)(4)(i)). For FDA to evaluate susceptibility (i.e., cross-resistance) was • the safety of benzalkonium chloride for Animal ADME found in the industrial isolates. In • Data to help define the effect of this rulemaking, these studies must be contrast, there was a highly significant formulation on dermal absorption submitted to the rulemaking or correlation between benzalkonium • Oral carcinogenicity otherwise be publicly available. chloride and gentamycin resistance in • Dermal carcinogenicity a. Summary of benzalkonium chloride the clinical isolates. In other words, • DART studies safety data. strains that were resistant to gentamycin • Potential hormonal effects Benzalkonium chloride also tended to have reduced • Data from laboratory studies that carcinogenicity data. Currently, no oral benzalkonium chloride susceptibility. assess the potential for the or dermal carcinogenicity data are Although the authors suggest that the development of resistance to publicly available. We found one short- clinical environment is responsible for benzalkonium chloride and cross- term dermal toxicity study (Ref. 168). cross-resistance, this study is not large resistance to antibiotics in the types of Mice were treated with a single topical enough to provide sufficient support for organisms listed in section VII.C.3 of application of 0.8, 3, 13, or 50 percent this theory. this proposed rule benzalkonium chloride aqueous In a second study, Lambert and solution and monitored for 1 month. colleagues found a positive correlation 5. Benzethonium Chloride Treatment with either the 13 or 50 between benzalkonium chloride and six In the 1994 TFM, FDA classified percent solution (concentrations well antibiotics (ciprofloxacin, erythromycin, benzethonium chloride as lacking above the actual use concentrations of oxacillin, clindamycin, amoxicillin/ sufficient evidence of safety for use as 0.1 to 5 percent) caused death in 9 of 48 clavulanic acid, and sodium cefazolin) an antiseptic handwash (59 FR 31402 at and 20 of 48 mice in each group, in MRSA clinical isolates. However, 31435). Since FDA’s proposed respectively. The surviving mice most of the statistically significant classification, two industry review developed skin lesions at the correlations found in this study were panels (CIR and a second industry panel application site. The low-dose groups between two antiseptics or two identified in a comment only as an (0.8 or 3 percent solutions) showed antibiotics, rather than between an ‘‘industry expert panel’’) and a slightly lower body weights and rates of antiseptic and an antibiotic. In addition, European regulatory advisory board growth than the control group, there was also a negative correlation (Scientific Committee on Cosmetic suggesting a slight detrimental effect between benzalkonium chloride and Products and Non-food Products from dermal exposure to these low ciprofloxacin in P. aeruginosa. The Intended for Consumers) have evaluated concentrations. The available data are authors suggest that there are no the safety of benzethonium chloride not adequate to assess the carcinogenic correlations in resistance to when used as a preservative in cosmetic potential of benzalkonium chloride. We benzalkonium chloride and resistance to preparations and as an active ingredient

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in consumer hand soaps (Refs. 171, 172, following the last dose was about 25 define the level of systemic exposure and 173). These advisory bodies found percent, suggesting some accumulation following repeated use. benzethonium chloride to be safe for with repeated dermal administration. Benzethonium chloride these uses. However, all of these safety More recent data submitted to support carcinogenicity data. In 1995, the NTP determinations have largely relied on the safety of benzethonium chloride conducted dermal carcinogenicity the findings of proprietary studies that have shown a much lower level of studies of benzethonium chloride in an are not publicly available. One of these absorption. In response to the 1994 ethanol vehicle in rats and mice (Ref. evaluations, the findings of the TFM, a manufacturer provided data 175). There were no treatment-related unidentified industry expert panel, was from a preliminary rat dermal differences from control animals in submitted to the rulemaking to support absorption study and an in vitro dermal survival, clinical signs (e.g., reddening the safety of benzethonium chloride absorption study (Ref. 176). In the rat or crusting of the skin), body weights, (Ref. 174). study, an aqueous 1 percent solution of organ weights, or neoplastic lesions in Some of the safety data reviewed by 14C-benzethonium chloride was applied either rats or mice. Histological the unidentified industry expert panel to the shaved back of rats and covered evaluation revealed dose-related represent the type of data that are with a nonocclusive patch. Blood, urine, (minimal in low dose, moderate in high needed to evaluate the safety of and feces were collected for 48 hours dose) epithelial hyperplasia in both rats benzethonium chloride for use in after dosing. Little or no radioactivity and mice at doses greater than 0.15 mg/ consumer antiseptic wash products, e.g., was detected in blood or urine samples. kg/day. In rats, epidermal ulceration ADME, DART, and oral carcinogenicity Approximately 7 percent of the was frequent in high dose females and studies. The safety assessments used to administered radioactivity was detected in one high dose male. support the unidentified industry expert in the fecal samples. The remaining There was no systemic toxicity or panel’s finding of safety, however, are radioactivity was not accounted for. carcinogenicity at any dose level in either species. The no observed effect publicly available only in the form of The in vitro dermal absorption study level (NOEL) for systemic toxicity was summaries. Consequently, these studies compared the absorption of 1.5 mg/kg/day based on systemic are not available to FDA and are benzethonium chloride through rat and precluded from a complete evaluation toxicity and carcinogenicity. While we human skin (Ref. 176). Pieces of skin by FDA. Further, the submitted safety agree with NTP’s analysis of the were obtained from rats and human assessments with study summaries do systemic toxicity, we disagree with the plastic surgery patients. Total not constitute an adequate record on NOEL for dermal toxicity because absorption was higher in rat compared which to base a GRAS classification epithelial hyperplasia and reddening of to human skin. Under the conditions of (§ 330.10(a)(4)(i)). For FDA to include the skin were noted at all doses greater this study, the total amount of these studies in the administrative than 0.15 mg/kg/day. Therefore, we benzethonium chloride maximally record for this rulemaking, they must be consider the NOEL for dermal toxicity absorbed by human skin during 24 submitted to the rulemaking or to be 0.15 mg/kg/day. hours was 4.14 percent. Accumulation otherwise publicly available. The submitted dermal carcinogenicity a. Summary of benzethonium chloride of benzethonium chloride in the skin data are adequate and show that safety data. was less than 1 percent in human skin benzethonium chloride does not pose a Benzethonium chloride ADME data. but was about 5 percent in rat skin. risk of cancer after repeated dermal In 1988, NTP studied the extent of The available data demonstrate that administration under the experimental absorption following single and there is absorption of benzethonium conditions used; however, data from an repeated once-daily dermal doses of chloride following dermal exposure. oral carcinogenicity study are lacking. benzethonium chloride and determined However, the level of absorption is not Benzethonium chloride DART data. A the pattern of tissue distribution and clearly defined. These data also suggest manufacturer submitted summaries of route of elimination of 14C-labeled that the amount of dermal absorption four teratology studies (three rat and one benzethonium chloride in rats (Ref. varies by species and with formulation. rabbit) and one perinatal and postnatal 175). They also determined the kinetics The currently available animal data also study in rats (Ref. 174). In two of the rat of distribution and excretion following lack other pharmacokinetic teratology studies, the rats showed intravenous administration. Under the determinations, i.e., distribution and delayed bone tissue formation conditions of the dermal studies, metabolism. Subsequent to the 1994 (ossification) and soft tissue and skeletal benzethonium chloride was readily TFM, FDA had numerous discussions malformation at the high dose. Only absorbed following single or repeated with a manufacturer interested in delayed ossification was noted in the dermal applications. attaining a GRAS classification for third rat study and in the rabbit study. After a single application of 14C- benzethonium chloride (Refs. 174, 177, These findings suggest that labeled benzethonium chloride in and 178). Topics covered in these benzethonium chloride is a teratogen at ethanol to skin that was covered by a discussions included the need for high doses when administered orally. nonocclusive patch, total urinary pharmacokinetic studies in animals However, without the complete study excretion was 1 to 2 percent of the following dermal exposure (Refs. 177 reports, we are unable to fully assess the applied dose, and fecal excretion and 178). The available data are not significance of these findings. accounted for about 45 percent of the adequate and data from ADME studies An embryo-fetal rat study with dose. The radiolabel was below the in animals continue to be necessary sufficient detail for evaluation was detection limit in blood and most because of highly variable results in the submitted (Ref. 174). In this study, tissues during the study, but low levels submitted studies, the need to clearly pregnant female rats were administered were measured in the liver. Some define the level of dermal absorption, benzethonium chloride on gestational residual radiolabel could be accounted the effect of formulation on dermal days 6 through 15. Maternal toxicity for in the epidermis at the site of absorption, and the distribution and was noted among the high dose-treated application. When similar studies were metabolism of benzethonium chloride females. In the other dose groups, performed with repeated once-daily in animals. In addition, we lack human toxicity findings were sporadic and not dermal dosing, the total amount of pharmacokinetic studies under maximal dose-related. There were no treatment- radiolabel excreted up to 10 days use conditions, which are needed to related gross necropsy findings or

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reproductive endpoint changes caused no associations between benzethonium • Potential hormonal effects by the treatment. The incidence of chloride and antibiotic resistance in the • Data from laboratory studies that delayed sternal ossification and/or other tested organisms (methicillin- assess the potential for the nonossified sternal centrae was noted in sensitive S. aureus or P. aeruginosa). development of resistance to all treatment groups and was Overall, the available studies are benzethonium chloride and cross- statistically significant. However, this limited in scope. They examine few resistance to antibiotics in the types of finding is not considered biologically bacterial species, provide no organisms listed in section VII.C.3 of significant as the incidence was not information on the level of this proposed rule dose-related, the litter incidence values benzethonium chloride exposure, and 6. Chloroxylenol did not differ significantly, and the are not adequate to define the potential values were within the range of for the development of resistance and There are limited safety data to historical values. The maternal NOAEL cross-resistance to antibiotics. support the long-term use of is 100 mg/kg/day based on body weight Additional laboratory studies are chloroxylenol in OTC consumer changes and deaths at the dose of 170 necessary to more clearly define the antiseptic hand and body wash mg/kg/day. potential for the development of products. Chloroxylenol is absorbed Overall, the DART data are not resistance to benzethonium chloride. after topical application in both humans adequate to characterize all aspects of Depending on the results of the and animals. However, studies reproductive toxicity and we propose laboratory studies, additional data of the conducted in humans and animals are that studies are needed to assess the type described in section VII.C of this inadequate to fully characterize the effect of benzethonium chloride on male proposed rule may also be needed to extent of systemic absorption after and female fertility and on pre- and assess the level of risk posed by repeated topical use or to demonstrate postnatal endpoints (e.g., the number of benzethonium chloride. the effect of formulation on dermal live or dead offspring, body weight at b. Benzethonium chloride safety data absorption. The administrative record birth, physical growth and gaps. In summary, our administrative also lacks other important data to development, neurodevelopmental record for the safety of benzethonium support a GRAS determination for this effects, and fertility of the pups). chloride is incomplete with respect to antiseptic active ingredient. Benzethonium chloride resistance the following: a. Summary of chloroxylenol safety data. We found two studies that • Human pharmacokinetic studies data. examined bacterial susceptibility under maximal use conditions when Chloroxylenol human profiles for both benzethonium chloride applied topically, including pharmacokinetic data. The dermal and antibiotics. One study (Ref. 179) documentation of validation of the absorption of chloroxylenol has been provided the data collectively, so no methods used to measure studied in humans following single and associations between reduced benzethonium chloride and its repeated bathing (10 minutes daily for 1 susceptibility to benzethonium chloride metabolites to 10 days) and following a single 30- and specific antibiotics could be • Animal ADME minute percutaneous application to the determined. The second study (Ref. 180) • Data to help define the effect of back of one subject (Refs. 181 and 182). found a positive correlation between formulation on dermal absorption The studies were conducted with few reduced susceptibility to benzethonium • Oral carcinogenicity subjects and a single formulation, and as chloride and ciprofloxacin or oxacillin • DART studies (fertility and embryo- shown in table 7 of this proposed rule, in clinical isolates of MRSA. There were fetal testing) produced inconsistent results.

TABLE 7—RESULTS OF HUMAN ABSORPTION STUDIES OF CHLOROXYLENOL

Absorption 1 Study Number of Bath subjects Milligrams Percent

Jordan, Nichols, and Rance, Preliminary Bathing Study (Ref. 181) ...... 1 1st ...... 5.74 ...... 0.5. Jordan, B. J., et. al., Repeat Bathing Study (Ref. 182) ...... 4 1st ...... 2.4 to 4.4 ...... 0.2 to 0.37...... 10th ...... 2.4 to 6.4 ...... 0.2 to 0.5. Jordan, B. J., et. al., Dermal ADME under Occlusion Study (Ref. 182) ...... 1 N/A ...... 7.2 ...... 15.7. 1 Based on amounts in urine.

The wide variation in the study urine samples revealed that all is needed to help define the effect of findings may be due to the much lower chloroxylenol was excreted as formulation on dermal absorption. concentration of chloroxylenol used in conjugated metabolites. No unchanged Chloroxylenol animal ADME data. bathing studies (1:4,000 and 1:4,800 chloroxylenol was found in the urine at Dermal ADME studies in rats and mice dilution of a 4.8 percent product versus any time point, and most of the drug are available (Refs. 183 and 184). In a 1 mL of the same product undiluted). was excreted in the first 8 hours after study conducted by Sved (Ref. 184), However, the small sample size and application. increasing doses of 14C-labeled disparate study results make it difficult Overall, the human pharmacokinetic chloroxylenol were applied to the to draw any meaningful conclusions on shaved backs of mice as a single or the level of dermal absorption following studies are not adequate and we propose that human pharmacokinetic studies repeated dose (once daily for 14 or 28 single or repeated use. days). Absorption was apparent at all using dermal administration under The percutaneous absorption study time points and increased with maximal use conditions are still needed (Ref. 182) also provides some limited increasing length of exposure. information on the elimination of to define the level of systemic exposure Approximately 50 percent of the chloroxylenol in humans. Assays of following repeated use. In addition, data applied dose was absorbed at 24 hours

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after a single dose and approximately 65 observed in animal toxicity studies to susceptibilities that may occur after percent at 24 hours after 14 and 28 days humans. exposure to nonlethal amounts of of daily dosing. The amount of Chloroxylenol carcinogenicity data. In chloroxylenol. The few studies that are chloroxylenol absorbed was the 1994 TFM, FDA stated that a available assess antibiotic susceptibility proportional to the administered dose. lifetime dermal carcinogenicity study in chloroxylenol-tolerant bacteria. In The plasma half-life for chloroxylenol (up to 2 years) in mice was needed to one study Lambert and colleagues was 18, 22, and 12 hours for low, mid, assess the dermal toxicity of determined the MICs of 8 antiseptics and high dose males, respectively, and chloroxylenol (59 FR 31402 at 31415). and at least 7 antibiotics for 256 clinical 70, 9, and 12 hours for low to high dose In response to this request, data from a isolates of S. aureus (including MRSA) females, respectively. The half-life in 13-week dose ranging dermal toxicity and 111 clinical isolates of P. skin was longer at lower doses of study in mice were submitted (Ref. 185). aeruginosa (Ref. 180). Although most of chloroxylenol. The study results show dose-related the statistically significant correlations After dermal application dermal adverse effects that may be were between two antiseptics or chloroxylenol has been found in the indicative of dermal toxicity, such as between two antibiotics rather than following tissues: Kidney, lung, liver, erythema (skin redness), edema between an antiseptic and an antibiotic, adrenal glands, skin, heart, ovary, (swelling), and exfoliation (skin the authors found a significant positive ovarian fat, skeletal muscle, skull, peeling). Microscopic changes correlation between chloroxylenol and spinal cord, spleen, eyes, femur, and consistent with a mild dermal irritant gentamycin resistance in P. aeruginosa, brain (Refs. 183 and 184). Tissue were also noted. These changes but a negative correlation between concentrations increased with repeated included hyperplasia (abnormal chloroxylenol and ciprofloxacin dosing, up to 1.8-fold in the kidney, up multiplication of skin cells) and resistance. They found no correlations to 3.8-fold in the liver, and up to 8.9- hyperkeratosis of the epidermis between chloroxylenol and antibiotic fold in the brain (Ref. 183). (overgrowth of outermost layer of the resistance for S. aureus. Concentrations in tissue also increased skin) in all dosed animals, inflammation In a pair of studies (Refs. 79 and 80), with dose. Unlike the concentrations in of the superficial dermis (a deeper layer Lear and colleagues collected, the liver and kidney, chloroxylenol of the skin) in most treated animals, identified, and measured antimicrobial levels in the brain did not appear to crust formation, and necrosis susceptibilities of bacteria from reach steady-state concentrations after (degradation) of epidermal cells. There industrial sources. The authors saw no 28 days of dosing, particularly at the were also dose-dependent lesions that difference in the antibiotic lower chloroxylenol concentrations increased in significance with dose. susceptibility patterns of the industrial (Ref. 183). The relevance of these Hyperplasia of bone marrow and and standard strains of P. aeruginosa. findings from a chronic use perspective increased extramedullary hematopoiesis Overall, there were few changes in (formation of red blood cells outside the cannot be evaluated without long-term antibiotic resistance patterns between bone barrow) in the spleen consistent animal studies. the standard and industrial strains. The majority of chloroxylenol is with an increasing inflammatory While these studies provide little excreted in the urine, and this is largely reaction were observed in the high dose evidence of cross-resistance to as polar conjugated metabolites. Only group. The NOEL was 15 percent antibiotics, they are limited in scope. traces of unchanged chloroxylenol are chloroxylenol and the NOAEL was less They examine few bacterial species, present in urine. Havler identified a than 30 percent. provide no information on the level of minor metabolite of chloroxylenol, To adequately assess the significance chloroxylenol exposure, and are not hydroxylated chloroxylenol, which of these study findings, a long-term adequate to define the potential for the represents 10 to 15 percent of the dermal carcinogenicity study is needed. metabolites found in urine (Ref. 183). In addition, because of potential development of resistance to Both chloroxylenol and the minor systemic exposure, an oral chloroxylenol and cross-resistance to metabolite are excreted as a mixture of carcinogenicity study is also necessary antibiotics. If the data from initial glucuronide and sulfate conjugates (Ref. to characterize the systemic effects from laboratory studies indicate a potential 183). Excretion is largely complete 24 long-term exposure. for the development of chloroxylenol hours after a single dermal application. Chloroxylenol DART data. Data are resistance and antibiotic cross- Overall, these data demonstrate that available from a teratology study in rats resistance, additional data such as the absorption of chloroxylenol occurs after that adequately characterizes type described in section VII.C of this dermal application in humans and chloroxylenol’s potential effects on proposed rule will be necessary to animals. However, the extent of this embryo and fetal development (Ref. assess the level of risk posed by absorption and the resulting systemic 186). The maternal NOEL in this study chloroxylenol. exposure has not been adequately was 100 mg/kg/day. The maternal b. Chloroxylenol safety data gaps. In characterized. In the 1994 TFM, FDA lowest observed effect level was 500 summary, our administrative record for stated that data from human studies mg/kg/day based on decreased food the safety of chloroxylenol is characterizing the absorption, consumption and decreased body incomplete with respect to the distribution, and metabolism of weight gain. The NOEL for following: chloroxylenol conducted under developmental toxicity was 1,000 mg/ • Human pharmacokinetic studies maximal exposure conditions were kg/day. However, this study is not under maximal use conditions when needed (59 FR 31402 at 31415). The sufficient to characterize effects on other applied topically that includes administrative record for this active aspects of reproduction. Additional documentation of validation of the ingredient still lacks data to characterize studies are necessary to assess the effect methods used to measure the rate and extent of systemic of chloroxylenol on fertility and early chloroxylenol and its metabolites absorption, the similarities and embryonic development and on pre- • Animal ADME at toxic exposure differences between animal and human and postnatal development. levels metabolism of chloroxylenol under Chloroxylenol resistance data. We • Data to help define the effect of maximal use conditions, and data to found no published studies that formulation on dermal absorption help establish the relevance of findings examine the changes in bacterial • Dermal carcinogenicity

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• Oral carcinogenicity the mean steady-state concentrations due to the use of the triclosan- • DART studies defining the effects of that would result if a multiple- containing toothpaste. chloroxylenol on fertility and pre- and application body wash study were to be There have been several studies that postnatal development conducted. From the reported study attempted to estimate the absorption of • Potential hormonal effects results, it is possible to calculate the triclosan following topical application • Data from laboratory studies that cumulative amount of product used by in a variety of different formulations assess the potential for the each subject, and to relate this amount (Refs. 189, 191, 192, and 193). In theses development of resistance to to the amount that would be used as a studies triclosan was delivered as a chloroxylenol and cross-resistance to body wash. Assuming a concentration of solution, in toothpaste, as a mouthwash, antibiotics in the types of organisms 1 g triclosan/mL of soap, the mean of all or in a cream. Despite the different listed in section VII.C.3 of this subjects in the handwash study was 3.6 properties of the dosage forms and proposed rule. mL/wash. Multiplying this value by six vehicles used, the estimated absorption 7. Triclosan washes per day gives a total mean was approximately in the range of 5 to volume of 21.6 mL/day. 15 percent of the applied dose. Based on A large number of studies have been Using a reported industry estimate these data, the impact of different conducted to characterize the (Ref. 190) that a 10 ounce (295.5 mL) formulations on the dermal absorption toxicological and metabolic profile of bottle contains enough body wash for 29 of triclosan appears to be minimal. triclosan using animal models. Most of washes, the estimated amount of body In summary, human absorption of these studies have focused on wash per use would be 10.2 mL (295.5 triclosan has been adequately understanding the fate of triclosan mL/29 washes = 10.2 mL/wash). characterized and no further human following exposure to a single source of Assuming that an individual bathes pharmacokinetic studies are needed. triclosan via the oral route of twice a day with a 1 percent triclosan- Triclosan ADME data. Triclosan is administration. However, dermal containing body wash, the total mean readily metabolized in both humans and studies in both humans and animals are volume estimate would be animals to two main parent conjugates, also available. These studies show that approximately 20.4 mL. This is less than triclosan glucuronide and triclosan triclosan is absorbed through the skin, the mean amount used in the handwash sulfate. Several other minor metabolites but to a lesser extent than oral study (21.6 mL/day). Based on the have been detected in animal studies absorption. pharmacokinetic data provided, steady- (Refs. 194 through 197); however, the a. Summary of triclosan safety data. state was achieved during the study, relevance of these minor metabolites to Triclosan human pharmacokinetics indicating that the study was of humans is unknown. In humans after data. Although much of the human data sufficient length to evaluate the oral or oral plus dermal triclosan relates to oral exposure, there are some pharmacokinetics of chronically exposure, triclosan glucuronide is the human studies that examine triclosan administered triclosan. primary circulating metabolite in pharmacokinetics after dermal exposure Another of the available studies (Ref. plasma (Ref. 188). After a single oral on the hands or body (Refs. 187, 188, 188) addresses triclosan exposure as a exposure to 4 mg of triclosan, the and 189). The dermal absorption of result of multiple product use. Two triclosan levels in human plasma triclosan has been estimated or groups of 84 subjects were enrolled in increased rapidly and reached characterized using a variety of this 13-week study. One group used maximum concentration within 1 to 3 formulations and techniques, as triclosan toothpaste twice a day plus hours (Ref. 198). In this study, the described in this subsection. The triclosan bar soap for face and majority of the triclosan in plasma was available data show that dermal handwashing twice a day plus triclosan conjugated; the unconjugated fraction of absorption of triclosan is low. deodorant once a day. The other group triclosan in plasma was 30 to 35 Consequently, additional human used triclosan toothpaste twice a day percent. Triclosan was cleared from the pharmacokinetic studies are not plus placebo soap and deodorant. Blood plasma at a rate of 2.9 L/hour. necessary. was drawn before product usage and at There also are some data to suggest In one multiple exposure handwash 3, 6, and 13 weeks. that triclosan is metabolized during study (Ref. 187), 13 human subjects At baseline, there was no significant passage through the skin. Moss, Howes, washed their hands 6 times a day with difference in the mean triclosan plasma and Williams (Ref. 191) examined 1 percent triclosan liquid soap for 20 concentrations between groups. After dermal metabolism of triclosan in vivo days. Dermal absorption of triclosan was product use, however, the mean in the rat and in vitro using rat or demonstrated by an increase in the triclosan plasma concentrations were human skin in flow-through diffusion levels of triclosan in plasma after significantly higher in the multiple cells. In both species, triclosan was handwash use; however, the percentage triclosan-containing product group metabolized during passage through the of the applied dose that was absorbed (highest achieved concentration: 31.04 skin to triclosan glucuronide and through the skin was not provided or ng/mL) than in the toothpaste only triclosan sulfate. Triclosan was more estimated. Steady-state levels of free and group (highest achieved concentration: readily metabolized to the glucuronide total triclosan were achieved within 22.47 ng/mL) for all three time points. conjugate, which was also more readily approximately 1 week (days 6–8). The This suggests that the use of multiple removed from the skin than the sulfate highest plasma concentrations achieved triclosan-containing products can lead conjugate. by any subject during the study were to higher triclosan exposure than from The elimination pattern of triclosan 69.9 ng/mL for free triclosan and 229 use of a single product. The varies depending on the species. ng/mL for total triclosan. Although this concentrations observed in this study Triclosan is excreted mainly via urine in study provides a picture of the steady- are substantially lower than the range of humans (Ref. 198) and hamsters (Ref. state levels of triclosan from repeated concentrations at steady-state that were 195), while it is eliminated mainly handwash use, it does not provide observed in the handwashing study through feces in mice (Ref. 196) and rats Cmax, Tmax or AUC values for humans. (Ref. 187). The substantial increase in (Ref. 199). After a single oral Despite the lack of individual triclosan concentration from baseline to administration of 4 mg of triclosan to concentration-time data, this study 3 weeks indicates that the majority of human subjects, the majority of the provides a basis on which to estimate the absorbed triclosan in this study was triclosan was excreted in urine within

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the first 24 hours (Ref. 198). There was rather than through a more relevant Triclosan DART data. In the 1994 considerable variability among subjects; route of administration, such as the oral TFM, we stated that we were evaluating between 24 and 83 percent of the dose or dermal route. We invite comment on the data from a two-generation study of was excreted within 4 days after what these findings tell us about the reproductive toxicity of triclosan in exposure. The urinary excretion half-life triclosan’s potential impact on human rats (Ref. 217). In this study, rats that ranged from 7 to 17 hours, and excretion health and the submission of additional were exposed to a high dose (3,000 approached baseline levels by 8 days data on this subject. ppm) of triclosan in utero showed lower after exposure. Triclosan carcinogenicity data. A 2- neonatal survival and lower mean body In the multiple exposure handwash year oral carcinogenicity study in weights compared to untreated controls. study (previously described in this hamsters was submitted to the The offspring of these rats (i.e., F2 pups) section (Ref. 187)), the mean elimination rulemaking (Ref. 208). The study was had a lower rate of survival to weaning half-life for total triclosan after multiple conducted in Syrian hamsters because compared to untreated controls. Based dermal exposures was 33 hours. This is the elimination pattern of triclosan is on the findings from this two-generation longer than the elimination half-life similar in hamsters and humans. study, we recommended that a segment calculated after a single oral exposure Although some treatment-related II study should be conducted to address (12 hours). The authors suggest the noncancerous lesions were seen in the the decreased survival among the high reason for this difference is that kidneys, epididymides, testes, and dose-treated litters. absorption through the skin takes longer stomach, there were no tumor findings Since that time, additional segment II than absorption from the in any of the organs examined. The reproductive toxicity studies have been gastrointestinal tract. NOAEL for triclosan in this hamster submitted showing that triclosan is not It is well documented that triclosan in study is 75 mg/kg/day. The study teratogenic in mice, rats, or rabbits (Ref. aqueous solution can be degraded into included additional (satellite) groups to 218). No treatment-related mortality was 2,8-dichlorodibenzo-p-dioxin and other assess triclosan plasma levels at week observed, and pregnancy rates and the degradation products by heat or 53 and at study termination (Ref. 209). number of litters for treated animals ultraviolet irradiation (i.e., At both time points, plasma levels were comparable to controls. The oral photodegradation) (Refs. 200 through increased with increasing doses and NOAELs from these studies are listed in 206). Although the data support significantly higher triclosan plasma table 8 of this proposed rule. photodegradation in aqueous solution, levels were seen in males compared to we found no data regarding whether females (p < 0.001). This increase over TABLE 8—ORAL NO OBSERVED AD- photodegradation of triclosan can occur time suggests that triclosan is VERSE EFFECT LEVELS (NOAEL) on human skin. It is not known whether accumulating in the animals; however, FROM REPRODUCTIVE TOXICITY photodegradation products would be the effect of this accumulation is STUDIES OF TRICLOSAN formed on human skin after topical unknown. application of triclosan-containing In contrast to the oral data, there are Oral NOAEL antiseptics and, if so, whether they little data regarding dermal toxicity of (mg/kg/day) would be absorbed or affect the skin. triclosan. Short-term dermal toxicity Species Because of this new information studies in rats (Ref. 210) and mice (Refs. Maternal Developmental toxicity toxicity regarding photodegradation of triclosan, 211 and 212) show dose-related dermal we propose that data are needed adverse effects following a 14-day Mouse ...... 25 25 regarding the potential for formation of treatment period. Similar dermal effects Rat ...... 50 50 triclosan photodegradation products on were seen in a 90-day subchronic Rabbit ...... 50 150 human skin as a result of consumer dermal toxicity study in rats (Ref. 213). antiseptic use and, if present, their A long-term dermal carcinogenicity Overall, the triclosan DART data are effects on the skin. study could be used to assess the adequate and additional traditional Overall, the animal ADME data are relevance of the short-term dermal DART studies are not necessary. not adequate and additional toxicity findings to a chronic use However, as discussed in the subsection pharmacokinetic data (e.g., AUC, Tmax, situation; however, currently no long- of this proposed rule on drug-induced and Cmax) at steady-state levels term dermal carcinogenicity data are hormonal effects, we propose that continue to be necessary to bridge available. Because these data are not additional reproductive and animal data to humans. In addition, data available but are needed to fully developmental testing will be needed to regarding the potential for formation of evaluate the safety of triclosan, FDA address concerns about these effects. photodegradation products on human nominated triclosan to NTP for Triclosan data on hormonal effects. skin and their effects on the skin are toxicological evaluation (Ref. 214). The Recent studies have demonstrated that needed. NTP studies will evaluate the dermal triclosan has effects on the thyroid, New triclosan findings. A recent study carcinogenicity potential following estrogen, and testosterone systems in evaluated the physiological effects of chronic dermal exposure to triclosan several animal species, including triclosan treatment on muscle function (Refs. 215 and 216). These studies are mammals (Refs. 41, 43 through 47, 50, in mice and fish (Ref. 207). The authors ongoing; however, results of these and 219). In addition, effects were also observed a negative effect on both studies are not expected to be available seen in the hamster carcinogenicity cardiac and skeletal muscle function as for several years, and we do not intend study (e.g., a reduction or absence of a result of a single triclosan treatment to delay the antiseptic rulemaking to spermatozoa, abnormal spermatogenic and identified a mechanism to explain wait for these study results. cells, and partial depletion of one or the observed effect. While this finding The submitted oral carcinogenicity more generations of germ cells in male suggests a previously unidentified data are adequate and show that testes in the high dose-treated group) toxicity of triclosan, it is a preliminary triclosan does not pose a risk of cancer (Ref. 220). The implications of these finding that has not been duplicated. after repeated oral administration under findings on human health, especially for Further, the mice were treated by the experimental conditions used; children, are still not well understood. injecting triclosan into the abdomen however, data from a dermal At this time, no adequate long-term (i.e., intraperitoneal administration), carcinogenicity study are still needed. (i.e., more than 30 days) in vivo animal

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studies have been conducted to address Although numerous studies have The authors conclude that this study the consequences of these hormonal evaluated the antiseptic and antibiotic shows no increase in antibiotic effects on functional endpoints of susceptibility profiles of clinical or resistance from the regular use of growth and development (e.g., link of culture collection strains, there are few antiseptic body washes. But, this study preputial separation to sexual studies that evaluate the susceptibility was not adequately designed to differentiation and fertility, link of profiles of bacterial isolates from determine whether use of antiseptic decreased thyroxine/triiodothyronine to nonhospital or consumer settings. In a body washes leads to changes in growth and neurobehavioral pair of studies (Refs. 79 and 80), Lear antibiotic or antiseptic susceptibilities. development) in exposed fetuses or and colleagues collected, identified, and Given the limited number of isolates pups. Studies in juvenile animals (of the measured antimicrobial susceptibilities examined, it is not clear that the study type described in section VII.C.2 of this of bacteria from industrial sources. was adequately powered to detect a proposed rule) could address the Samples were taken from a factory and difference in resistance patterns. consequences of short-term thyroid and laboratories of companies that Furthermore, the amount of antiseptic reproductive findings on the fertility, manufacture products containing exposure was not defined. The length of growth, and development of triclosan- triclosan, where it was likely that the time subjects had used antiseptic body exposed litters. organisms were exposed to this washes (beyond the specified 30 days), Triclosan resistance data. Much of the ingredient. Of approximately 100 the frequency of bathing, and the recent data looking at cross-resistance industrial isolates, two triclosan-tolerant volume of antiseptic wash used per bath between antiseptic active ingredients isolates were chosen for further study or shower was not reported. Finally, few and antibiotics involve an evaluation of (Acinetobacter johnsonii and bacterial isolates were examined. It is triclosan. Several bacterial species that Citrobacter freundii). reasonable to examine the showed reduced susceptibility to The authors then determined the susceptibilities of Staphylococcus triclosan were also resistant to one or antibiotic susceptibility profiles of the species; however, an average of only 1.5 more of the tested antibiotics (Refs. 60 two industrial isolates compared to isolates was obtained from each subject. through 66, 71, and 73 through 77). This standard culture collection strains (Ref. Aiello et al. (Ref. 81) looked for a trend was seen for both gram-negative 79). The authors saw no difference in possible association between antibiotic (E. coli, Pseudomonas aeruginosa, the antibiotic susceptibility patterns of and triclosan susceptibilities among Salmonella enterica, Stenotrophomonas the industrial and standard strains of A. staphylococci and GNB isolated from maltophilia, Acinetobacter, and johnsonii. In contrast, the C. freundii the hands of consumers who used Campylobacter) and gram-positive industrial isolate was more resistant to nonantibacterial or 0.2 percent (Staphylococcus aureus, including 12 of 14 antibiotics tested. These triclosan-containing antiseptic MRSA) organisms. Although the clinical changes in antibiotic susceptibility were handwashes for 1 year. Two hundred relevance of these studies is not clear, quite modest, however. While this twenty-four inner city households were the possibility that triclosan contributes industrial isolate showed only modest randomized to use soap and cleaning to changes in antibiotic susceptibility changes in susceptibility for most of the products with or without antibacterial warrants further evaluation. tested antibiotics, it still demonstrates a ingredients. The products were blinded One of our concerns stems from the change in the antibiotic susceptibility and were delivered to each household observation that triclosan exposure can pattern after triclosan exposure. monthly. During the study period, the lead to changes in bacterial efflux pump Unfortunately, the number of sites that activity. Several studies (Refs. 62, 64, were sampled was low (50 total sites), households were required to use only 66, and 102) suggest that an efflux only two isolates were studied, and the the assigned home hygiene products mechanism is responsible for the time and extent of triclosan exposure is and were asked not to change any of observed reduced triclosan unknown. their other normal hygiene practices. To susceptibility. In addition, In addition to laboratory data, there assess prior exposure to antimicrobials, overexpression of efflux pump are also a few studies that examined the including antiseptics, a survey of the regulatory genes also leads to reduced potential for development of cross- antibacterial cleaning and hygiene triclosan susceptibility in E. coli (Ref. resistance in bacterial isolates taken products used within the home was 101). from the skin of consumer antiseptic conducted at baseline. In addition to bacterial efflux activity, users. Cole et al. (Ref. 78) described The hands of the primary caregiver in other mechanisms have been antibiotic and antiseptic susceptibilities the home were sampled for bacteria at documented that may also contribute to of staphylococci isolated from the skin baseline and 1 year later. Only the most reduced antiseptic susceptibility and of consumers who used antiseptic or commonly isolated bacterial species, cross-resistance, e.g., changes in nonantibacterial body washes. This defined as at least 38 isolates of a single bacterial membrane (Ref. 67). This type study also evaluated triclocarban and is species from all samples, were analyzed of nonspecific mechanism, in theory, described in detail in section VII.D.3.a further. A total of 628 isolates were could work against multiple antibiotics of this proposed rule. examined for their triclosan MICs and or antiseptics. When CNS susceptibility to susceptibilities to selected antibiotics. Other data suggest that different antiseptics was examined, the Staphylococci were tested against mechanisms of action may occur at maximum MIC value was the same for oxacillin to determine methicillin different triclosan concentrations. In the all three groups (2.020 (no units resistance. The GNB were tested against laboratory, at low concentrations provided)); however, the minimum MIC three to six antibiotics, based on clinical triclosan has a specific action against a value differed between triclosan users relevance. There were no significant bacterial enzyme (FabI), while high (0.008) and non-users (0.120). Because differences in the observed proportions concentrations act against less specific antiseptic MICs do not correlate with of isolates that were antibiotic resistant targets, such as the cell membrane (Ref. clinical endpoints, it is not clear what at baseline versus the end of the year 109). Currently, there is not enough this difference in MIC means. No except for Enterobacter cloacae, which information to know which scenarios, if patterns emerged when the data were was significantly higher at baseline (36 any, could occur under actual use analyzed for cross-resistance between percent) than at the end of the year (0 conditions. triclosan or triclocarban and antibiotics. percent) (p = 0.016).

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The MICs of triclosan ranged from However, the administrative record is i.e., a condition that would cause the 0.03 to 4.00 mg/mL; however, two thirds not complete with respect to data that drug to be not GRAS/GRAE or to be of the isolates had triclosan MICs over would clarify the potential public health misbranded, could not be initially 1 mg/mL. The median triclosan MICs for impact of the currently available data. introduced or initially delivered for the gram negative species varied widely. Examples of the type of information that introduction into interstate commerce In contrast, the staphylococcus median could be submitted to complete the unless it is the subject of an approved values were very similar, except for S. record include the following: new drug application or abbreviated aureus, which was 2 mg/mL at baseline • Data to characterize the new drug application. Any OTC and 0.03 mg/mL at the end of the year. concentrations and antimicrobial consumer antiseptic wash drug product There was no statistically significant activity of triclosan in various subject to the final rule that is association between triclosan MICs and biological and environmental repackaged or relabeled after the susceptibility to antibiotics. compartments (e.g., on the skin, in the effective date of the final rule would be A randomly chosen subset of seven gut, and in environmental matrices) required to be in compliance with the GNB organisms with triclosan MICs of • Data to characterize the antiseptic and final rule, regardless of the date the at least 32 mg/mL was retested with agar antibiotic susceptibility levels of product was initially introduced or containing triclosan concentrations in environmental isolates in areas of initially delivered for introduction into the range of 64 to 1,024 mg/mL. The prevalent antiseptic use, e.g., in the interstate commerce. subset contained Klebsiella home, health care, food handler, and pneumoniae, Acinetobacter baumannii, IX. Summary of Preliminary Regulatory veterinary settings and Impact Analysis Enterobacter cloacae, and P. fluorescens • Data to characterize the potential for The summary analysis of benefits and isolates. All of the isolates grew on agar the reduced antiseptic susceptibility costs included in this proposed rule is containing 1,024 mg/mL triclosan, caused by triclosan to be transferred drawn from the detailed Preliminary suggesting that they may survive the to other bacteria that are still sensitive Regulatory Impact Analysis (PRIA) that triclosan concentrations used in some to triclosan consumer products. is available at http:// This study did not show an b. Triclosan safety data gaps. In www.regulations.gov, Docket No. FDA– association between high triclosan MICs summary, our administrative record for 1975–N–0012 (formerly Docket No. and antibiotic resistance after 1 year of the safety of triclosan is incomplete 1975N–0183H). triclosan handwash use. However, the with respect to the following: A. Introduction authors note that the triclosan MICs • Animal ADME seen for many of the isolates in this • Dermal carcinogenicity FDA has examined the impacts of the study are higher than those reported • Data regarding the potential for proposed rule under Executive Order previously. They suggest that general formation of photodegradation 12866, Executive Order 13563, the levels of decreased susceptibility to products on human skin and their Regulatory Flexibility Act (5 U.S.C. triclosan seem to be increasing in the effects on the skin 601–612), and the Unfunded Mandates community, regardless of whether • Potential hormonal effects Reform Act of 1995 (Pub. L. 104–4). triclosan-containing products are used • Data to clarify the relevance of Executive Orders 12866 and 13563 in the home or not. The authors also antimicrobial resistance laboratory direct Agencies to assess all costs and concluded that the absence of a findings to the consumer setting benefits of available regulatory alternatives and, when regulation is statistically significant association VIII. Proposed Effective Date between elevated triclosan MICs and necessary, to select regulatory reduced antibiotic susceptibility may Based on the currently available data, approaches that maximize net benefits indicate that such a correlation does not this proposed rule finds that consumer (including potential economic, exist or that it is relatively small among antiseptic wash active ingredients can environmental, public health and safety, the isolates that were studied. Still, they be considered neither safe nor effective and other advantages; distributive theorized that a relationship may for use in OTC consumer antiseptic impacts; and equity). This proposed rule emerge after longer term or higher dose wash drug products. Accordingly, would be an economically significant exposure of bacteria to triclosan in the consumer antiseptic wash active regulatory action as defined by community setting. ingredients would be nonmonograph in Executive Order 12866. Overall, the administrative record for any final rule based on this proposed The Regulatory Flexibility Act triclosan is complete on the following rule. We recognize, based on the scope requires Agencies to analyze regulatory aspects of the resistance issue: of products subject to this monograph, options that would minimize any • Laboratory studies demonstrate that manufacturers will need time to significant impact of a rule on small triclosan’s ability to alter antibiotic comply with a final rule based on this entities. This proposed rule would have susceptibilities (Refs. 60 through 66, proposed rule. However, because of the a significant economic impact on a 71, and 73 through 77) potential safety considerations raised by substantial number of small entities. • Data define triclosan’s mechanisms of the data for some antiseptic active Section 202(a) of the Unfunded action and demonstrate that these ingredients evaluated, we believe that Mandates Reform Act of 1995 requires mechanisms are dose dependent (Ref. an effective date later than 1 year after that Agencies prepare a written 109) publication of the final rule would not statement, which includes an • Data demonstrate that exposure to be appropriate or necessary. assessment of anticipated costs and triclosan changes efflux pump Consequently, any final rule that results benefits, before proposing ‘‘any rule that activity, a common nonspecific from this proposed rule will be effective includes any Federal mandate that may bacterial resistance mechanism (Refs. 1 year after the date of the final rule’s result in the expenditure by State, local, 62, 64, 66, and 102) publication in the Federal Register. On and tribal governments, in the aggregate, • Data show that low levels of triclosan or after that date, any OTC consumer or by the private sector, of $100,000,000 may persist in the environment (Refs. antiseptic wash drug product that is or more (adjusted annually for inflation) 85, 113, 114, 115, and 221 through subject to the monograph and that in any one year.’’ The current threshold 224) contains a nonmonograph condition, after adjustment for inflation is $141

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million, using the most current (2012) resulting from widespread long-term at a 3 percent discount rate and $4.69 Implicit Price Deflator for the Gross exposure to such ingredients prevent us to $53.04 at a 7 percent discount rate. Domestic Product. FDA expects this from translating the estimated reduced Manufacturers are expected to incur proposed rule to result in a 1-year exposure into monetary equivalents of most product reformulation and expenditure that would meet or exceed health effects. relabeling costs with the impact to this amount. relabelers, repackers, and distributors The primary estimate of costs being considerably less. The impact on B. Summary of Costs and Benefits annualized over 10 years is a manufacturer can vary considerably approximately $23.6 million at a 3 The costs and benefits of the proposed depending on the number and type of percent discount rate and $28.6 million rule are summarized in table 9 of this products it produces. For the estimated proposed rule entitled ‘‘Economic Data: at a 7 percent discount rate. These costs 707 affected establishments that would Costs and Benefits Statement.’’ As table consist of total one-time costs of qualify as small,1 our estimate of the 9 shows, the primary estimated benefits relabeling and reformulation ranging average one-time cost of compliance come from reduced exposure to from $112.2 to $368.8 million. Estimates ranges from $0.10 million to $0.33 antiseptic active ingredients by 2.2 of the cost of relabeling and million, which would be approximately million pounds per year. Using the reformulating may be overstated if 0.33 percent to 1.10 percent of the primary estimates, the combined total manufacturers produce data consistent average annual value of shipments for a consists of a reduction in triclosan with the monograph changes in this small business. In its Initial Regulatory exposure by 799,426 pounds per year, proposed rule and do not need to relabel Flexibility Analysis, the Agency triclocarban exposure by 1.4 million or reformulate. In such a scenario, the assesses a pair of regulatory options that pounds per year, chloroxylenol costs of producing the data would be would reduce the proposed rule’s exposure by 231.9 pounds per year, and incurred instead. Under the proposed burden on small entities: (1) Exempting benzalkonium chloride by 63.8 pounds rule, we estimate that each pound of small businesses from the rule and (2) per year. Limitations in the available reduced exposure to antiseptic active longer compliance period, allowing 18 data characterizing the health effects ingredients would cost $3.86 to $43.67 months (rather than 12 months). TABLE 9—ECONOMIC DATA: COSTS AND BENEFITS STATEMENT

Units Primary Low High Category estimate estimate estimate Year Discount Period Notes dollars rate covered

Benefits

Annualized Monetized $millions/year ...... 7% Annual. 3% Annual. Annualized Quantified ...... 2,198,033 989,922 3,406,145 ...... 7% Annual. Reduced antiseptic active ingredient ex- 2,198,033 989,922 3,406,145 3% Annual. posure (in pounds).

Qualitative

Costs

Annualized Monetized $millions/year $28.6 $16.0 $52.5 2010 7% Annual. Annualized costs of relabeling and refor- $23.6 $13.2 $43.2 2010 3% Annual. mulation. Range of estimates cap- tures uncertainty. Annualized Quantified ...... 7% 3%

Qualitative

Transfers

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

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

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

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

Effects State, Local, or Tribal Government: Not applicable.

Small Business Annual cost per affected small entity estimated as $0.01–$0.04 million, which would represent 0.04–0.13 percent of annual shipments.

Wages: No estimated effect.

Growth: No estimated effect.

1 FDA notes that the analysis was conducted roughly equivalent to the typical small small entities, may be an overestimate of the actual using data at the establishment level rather than at manufacturing firm. However, if market is number of businesses with fewer than 750 the firm level. This makes the implicit assumption dominated by a few large firms with a large number employees. that the typical manufacturing establishment is of small establishments, our estimated number of

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X. Paperwork Reduction Act of 1995 antiseptics that are different from, in LET13, LET15, LET18, LET43, RPT3, RPT5, SUP1, SUP2, SUP3, SUP5, SUP6, This proposed rule contains no addition to, or not otherwise identical with a requirement in the final rule. and SUP7 in Docket No. 1975N–0183H. collections of information. Therefore, 7. Comment Nos. C1, C8, C11, C14, C18, C19, clearance by the Office of Management This preemptive effect is consistent C20, C23, C32, C34, C35, C36, C38, C42, and Budget under the Paperwork with what Congress set forth in section C43, C45, C48, C50, C51, C52, C58, C60, Reduction Act of 1995 is not required. 751 of the FD&C Act. Section 751(a) of C61, C70, C76, C79, C82, C84, C85, C89, the FD&C Act displaces both State C93, CP1, CP3, CP4, CP7, CP9, CP12, XI. Environmental Impact legislative requirements and State CP14, CP17, LET1, LET12, LET13, common law duties. We also note that LET16, LET17, LET43, PR1, PR3, PR4, We have determined under 21 CFR PR5, PR6, PR7, PR9, RPT4, SUP3, SUP4, 25.31(a) that this action is of a type that even where the express preemption provision is not applicable, implied SUP5, SUP7, SUP12, and SUP13 in does not individually or cumulatively Docket No. 1975N–0183H. have a significant effect on the human preemption may arise (see Geier v. 8. Comment Nos. C171, C172, C173, LET98, environment. Therefore, neither an American Honda Co., 529 U.S. 861 LET99, PR2, and SUP47 in Docket No. environmental assessment nor an (2000)). 1975N–0183H. environmental impact statement is FDA believes that the preemptive 9. Comment Nos. DRAFT–1044, DRAFT– required. effect of the proposed rule, if finalized, 1045, DRAFT–1046, DRAFT–1047, would be consistent with Executive DRAFT–1048 in Docket No. FDA–1975– XII. Federalism Order 13132. Section 4(e) of the N–0012. Executive order provides that ‘‘when an 10. Comment No. CP1 in Docket No. 2005P– FDA has analyzed this proposed rule 0432. in accordance with the principles set agency proposed to act through 11. Comment No. C4 in Docket No. 1975N– forth in Executive Order 13132. FDA adjudication or rulemaking to preempt 0183H. has determined that the proposed rule, State law, the agency shall provide all 12. Comment No. C42 in Docket No. 1975N– if finalized, would have a preemptive affected State and local officials notice 0183H. effect on State law. Section 4(a) of the and an opportunity for appropriate 13. Comment No. C20 in Docket No. 1975N– 0183H. Executive order requires Agencies to participation in the proceedings.’’ FDA is providing an opportunity for State 14. Comment No. CP8 in Docket No. 1975N– ‘‘construe * * * a Federal statute to 0183H. preempt State law only where the and local officials to comment on this 15. Comment No. CP1 in Docket No. 1996P– statute contains an express preemption rulemaking. 0312. provision or there is some other clear XIII. References 16. Comment No. CP1 in Docket No. 1975N– evidence that the Congress intended 0183H. The following references are on preemption of State law, or where the 17. Comment No. C30 in Docket No. 1975N– display in the Division of Dockets 0183H. exercise of State authority conflicts with Management (see ADDRESSES) under 18. Comment No. LET23 in Docket No. the exercise of Federal authority under Docket No. FDA–1975–N–0012 1975N–0183H. the Federal statute.’’ Section 751 of the (formerly 1975N–0183H) and may be 19. Product labels in OTC Vol. Federal Food, Drug and Cosmetic Act seen by interested persons between 9 02CAWASHTFM. (the FD&C Act) (21 U.S.C. 379r) is an 20. Briefing Material for the November 14, a.m. and 4 p.m., Monday through express preemption provision. Section 2008, Feedback Meeting with Personal Friday, and are available electronically 751(a) of the FD&C Act (21 U.S.C. Care Products Council and Soap and at http://www.regulations.gov. (FDA has 379r(a)) provides that ‘‘no State or Detergent Association, OTC Vol. verified all Web site addresses in this 02CAWASHTFM. political subdivision of a State may reference section, but we are not 21. Fischler, G. E. et al., ‘‘Effect of Handwash establish or continue in effect any responsible for any subsequent changes Agents on Controlling the Transmission requirement—(1) that relates to the to the Web sites after this proposed rule of Pathogenic Bacteria From Hands to regulation of a drug that is not subject publishes in the Federal Register.) Food,’’ Journal of Food Protection, to the requirements of section 503(b)(1) 70:2873–2877, 2007. or 503(f)(1)(A); and (2) that is different 1. Comment No. C12 in Docket No. 1975N– 22. Luby, S. P. et al., ‘‘Effect of Handwashing from or in addition to, or that is 0183H. on Child Health: A Randomised otherwise not identical with, a 2. Transcript of the January 22, 1997, Meeting Controlled Trial,’’ Lancet, 366:225–233, of the Joint Nonprescription Drugs and 2005. requirement under this Act, the Poison Anti-Infective Drugs Advisory 23. Larson, E. L. et al., ‘‘Effect of Prevention Packaging Act of 1970 (15 Committees, OTC Vol. 02CAWASHTFM. Antibacterial Home Cleaning and U.S.C. 1471 et seq.), or the Fair 3. Transcript of the March 23, 2005, Meeting Handwashing Products on Infectious Packaging and Labeling Act (15 U.S.C. of the Nonprescription Drugs Advisory Disease Symptoms: A Randomized, 1451 et seq.).’’ Currently, this provision Committee, http://www.fda.gov/ohrms/ Double-Blind Trial,’’ Annals of Internal operates to preempt States from dockets/ac/05/transcripts/2005- Medicine, 140:321–329, 2004. imposing requirements related to the 4098T1.pdf, 2005. 24. Briefing Material for the March 23, 2005, regulation of nonprescription drug 4. Transcript of the October 20, 2005, Meeting of the Nonprescription Drugs Meeting of the Nonprescription Drugs Advisory Committee, http:// products. (See section 751(b) through (e) Advisory Committee, http:// www.fda.gov/ohrms/dockets/ac/05/ of the FD&C Act for the scope of the www.fda.gov/ohrms/dockets/ac/05/ briefing/2005-4098B1_02_01-FDA- express preemption provision, the transcripts/2005-4184T1.pdf, 2005. TOC.htm. exemption procedures, and the 5. Summary Minutes of the November 14, 25. Briefing Material for the October 20, exceptions to the provision.) 2008, Feedback Meeting with Personal 2005, Meeting of the Nonprescription This proposed rule, if finalized as Care Products Council and Soap and Drugs Advisory Committee, http:// proposed, would require data from Detergent Association, OTC Vol. www.fda.gov/ohrms/dockets/ac/05/ _ _ clinical outcome studies to demonstrate 02CAWASHTFM. briefing/2005-4184B1 01 00-FDA- 6. Comment Nos. C7, C10, C11, C12, C14, TOC.htm. the effectiveness of consumer antiseptic C18, C22, C25, C32, C34, C35, C36, C40, 26. FDA Review of Consumer Antiseptic active ingredients. Any final rule would C43, C44, C45, C47, C48, C53, C54, C55, Effectiveness Data, OTC Vol. have a preemptive effect in that it would C56, C57, C60, C61, C63, C64, C77, C80, 02CAWASHTFM. preclude States from issuing C81, C82, C83, C85, C89, CP3, CP4, CP6, 27. Hill Top Research, ‘‘Efficacy Evaluation requirements related to OTC consumer CP7, CP11, CP14, CP15, CP16, LET11, of Health Care Personnel Handwash

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Solution,’’ Journal of Photochemistry htdocs/Chem_Background/ExSumPdf/ PART 310—NEW DRUGS and Photobiology A, 158:63–66, 2003. triclosan_508.pdf. 201. Latch, D. E. et al., ‘‘Aqueous 215. ‘‘Testing Status of Agents at NTP. ■ 1. The authority citation for 21 CFR Photochemistry of Triclosan: Formation Testing Status: Triclosan M030039,’’ part 310 continues to read as follows: of 2,4-dichlorophenol, 2,8- http://ntp.niehs.nih.gov/go/TS-M030039. dichlorodibenzo-p-dioxin, and 216. Fang, J.-L., et al., ‘‘Occurrence, Efficacy, Authority: 21 U.S.C. 321, 331, 351, 352, Oligomerization Products,’’ Metabolism, and Toxicity of Triclosan,’’ 353, 355, 360b–360f, 360j, 361(a), 371, 374, Environmental Toxicology and Journal of Environmental Science and 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, Chemistry, 24:517–525, 2005. Health Part C, 28:147–171, 2010. 263b–263n. 202. Lindstro¨m, A. et al., ‘‘Occurrence and 217. Morseth, S. L., ‘‘Two-Generation ■ 2. Amend § 310.545 by removing from Environmental Behavior of the Reproduction Study in Rats FAT 80’023 paragraph (d) introductory text the Bactericide Triclosan and Its Methyl (HLA Study No. 2386–100),’’ Comment Derivative in Surface Waters and in number ‘‘(d)(39)’’ and adding in its No. RPT7 in Docket No. 1975N–0183, place the number ‘‘(d)(40)’’; and by Wastewater,’’ Environmental Science 1988. and Technology, 36:2322–2329, 2002. adding paragraphs (a)(27)(iii), 218. Comment No. C85 in Docket No. 1975N– 203. Mezcua, M. et al., ‘‘Evidence of 2,7/2,8- 0183H. (a)(27)(iv), and (d)(41) to read as dibenzodichloro-p-dioxin as a 219. James, M. O. et al., ‘‘Triclosan Is a Potent follows: Photodegradation Product of Triclosan in Water and Wastewater Samples,’’ Inhibitor of Estradiol and Estrone § 310.545 Drug products containing Analytica Chimica Acta, 524:241–247, Sulfonation in Sheep Placenta,’’ certain active ingredients offered over-the- 2004. Environment International, 36:942–949, counter (OTC) for certain uses. 2009. 204. Sanchez-Prado, L. et al., ‘‘Monitoring the (a) * * * Photochemical Degradation of Triclosan 220. Rodricks, J. V. et al., ‘‘Triclosan: A Critical Review of the Experimental Data (27) * * * in Wastewater by UV Light and Sunlight (iii) Consumer antiseptic handwash Using Solid-Phase Microextraction,’’ and Development of Margins of Safety Chemosphere, 65:1338–1347, 2006. for Consumer Products,’’ Critical drug products. Approved as of [DATE 1 205. Son, H. S., G. Ko, and K. D. Zoh, Reviews in Toxicology, 40:422–484, YEAR AFTER DATE OF PUBLICATION ‘‘Kinetics and Mechanism of Photolysis 2010. OF THE FINAL RULE IN THE Federal and TiO2 Photocatalysis of Triclosan,’’ 221. Boyd, G. R. et al., ‘‘Pharmaceuticals and Register]. Personal Care Products (PPCPs) in Journal of Hazardous Materials, Benzalkonium chloride 166:954–960, 2009. Surface and Treated Waters of Louisiana, USA and Ontario, Canada,’’ The Science Benzethonium chloride 206. Tixier, C. et al., ‘‘Phototransfomation of Chloroxylenol Triclosan in Surface Waters: A Relevant of the Total Environment, 311:135–149, Elimination Process for This Widely 2003. Cloflucarban Used Biocide—Laboratory Studies, Field 222. Kinney, C. A. et al., ‘‘Bioaccumulation Fluorosalan Measurements, and Modeling,’’ of Pharmaceuticals and Other Hexachlorophene Environmental Science and Technology, Anthropogenic Waste Indicators in Hexylresorcinol 36:3482–3489, 2002. Earthworms From Agricultural Soil Iodine complex (ammonium ether 207. Cherednichenko, G. et al., ‘‘Triclosan Amended With Biosolid or Swine sulfate and polyoxyethylene sorbitan Impairs Excitation-Contraction Coupling Manure,’’ Environmental Science and monolaurate) ∂ and Ca2 Dynamics in Striated Muscle,’’ Technology, 42:1863–1870, 2008. Iodine complex (phosphate ester of Proceedings of the National Academy of 223. Singer, H. et al., ‘‘Triclosan: Occurrence and Fate of a Widely Used Biocide in the alkylaryloxy polyethylene glycol) Sciences of the USA, 109:14158–14163, Methylbenzethonium chloride 2012. Aquatic Environment: Field 208. Chambers, P. R., ‘‘FAT 80’023/S Measurements in Wastewater Treatment Nonylphenoxypoly (ethyleneoxy) Potential Tumorigenic and Chronic Plants, Surface Waters, and Lake ethanoliodine Toxicity Effects in Prolonged Dietary Sediments,’’ Environmental Science and Phenol Administration to Hamsters,’’ Comment Technology, 36:4998–5004, 2002. Poloxamer iodine complex No. PR5 in Docket No. 1975N–0183H, 224. Ying, G. G., X. Y. Yu, and R. S. Kookana, Povidone-iodine 1999. ‘‘Biological Degradation of Triclocarban Secondary amyltricresols 209. Chasseaud, L. F. et al., ‘‘Toxicokinetics and Triclosan in a Soil Under Aerobic Sodium oxychlorosene of FAT 80’023/S After Prolonged Dietary and Anaerobic Conditions and Tribromsalan Administration to Hamsters,’’ Comment Comparison With Environmental Fate Triclocarban No. PR5 in Docket No. 1975N–0183H, Modelling,’’ Environmental Pollution, Triclosan 1999. 150:300–305, 2007. 210. Burns, J. M., et. al., ‘‘14-Day Repeated Undecoylium chloride iodine complex Dose Dermal Study of Triclosan in Rats List of Subjects (iv) Consumer antiseptic body wash (CHV 6718–102),’’ Comment No. CP9 in drug products. Approved as of [DATE 1 Docket No. 1975N–0183H, 1997. 21 CFR Part 310 YEAR AFTER DATE OF PUBLICATION 211. Burns, J. M., et. al., ‘‘14-Day Repeated Federal Administrative practice and OF THE FINAL RULE IN THE Dose Dermal Study of Triclosan in Mice Register]. (CHV 6718–101),’’ Comment No. CP9 in procedure, Drugs, Labeling, Medical Docket No. 1975N–0183H, 1997. devices, Reporting and recordkeeping Benzalkonium chloride 212. Burns, J. M., et. al., ‘‘14-Day Repeated requirements. Benzethonium chloride Dose Dermal Study of Triclosan in CD– Cloflucarban 1 Mice (CHV 2763–100),’’ Comment No. 21 CFR Part 333 Fluorosalan CP9 in Docket No. 1975N–0183H, 1997. Hexachlorophene Labeling, Over-the-counter drugs, 213. Trimmer, G. W., ‘‘90-Day Subchronic Hexylresorcinol Incorporation by reference. Dermal Toxicity Study in the Rat With Iodine complex (phosphate ester of Satellite Group With Irgasan DP 300 Therefore, under the Federal Food, alkylaryloxy polyethylene glycol) (MRD–92–399),’’ Comment No. C1 in Docket No. 1975N–0183H, 1994. Drug, and Cosmetic Act and under Iodine tincture 214. ‘‘Nomination Profile: Triclosan. authority delegated to the Commissioner Methylbenzethonium chloride Supporting Information for Toxicological of Food and Drugs, it is proposed that Nonylphenoxypoly (ethyleneoxy) Evaluation by the National Toxicology 21 CFR parts 310 and 333 be amended ethanoliodine Program,’’ http://ntp.niehs.nih.gov/ntp/ as follows: Parachlorometaxylenol (chloroxylenol)

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Phenol removing the phrase ‘‘Antiseptic ■ e. Removing from paragraph (c)(1) the Poloxamer iodine complex handwash or health-care’’ from the paragraph designation and paragraph Povidone-iodine paragraph heading and adding in its heading; and Tribromsalan place ‘‘Health-care’’. ■ Triclocarban f. Removing paragraph (c)(2). Triclosan § 333.410 [Amended] § 333.470 [Amended] Undecoylium chloride iodine complex ■ 5. As proposed to be added June 17, ■ 7. As proposed to be added June 17, * * * * * 1994 (59 FR 31442), § 333.410 is further 1994 (59 FR 31444), § 333.470 is further (d) * * * amended by removing the phrase amended in paragraph (a) introductory (41) [DATE 1 YEAR AFTER DATE OF ‘‘Antiseptic handwash or health-care’’ text and paragraph (b)(2) heading and PUBLICATION OF THE FINAL RULE IN from the section heading and adding in introductory text by removing the THE Federal Register], for products its place ‘‘Health-care’’. subject to paragraph (a)(27)(iii) or phrase ‘‘an antiseptic handwash or’’ and (a)(27)(iv) of this section. § 333.455 [Amended] adding in its place the word ‘‘a’’; and in ■ 6. As proposed to be added June 17, paragraph (b)(2)(iii) introductory text by PART 333—TOPICAL ANTIMICROBIAL 1994 (59 FR 31443), § 333.455 is further removing the phrase ‘‘antiseptic or’’. DRUG PRODUCTS FOR OVER-THE- amended by: ■ 8. Add and reserve subpart F to read COUNTER HUMAN USE ■ a. Removing from the section heading as follows: ■ 3. The authority citation for 21 CFR the phrase ‘‘antiseptic handwash or’’; Subpart F—Consumer Antiseptic Drug part 333 continues to read as follows: ■ b. Removing from paragraph (a) the phrase ‘‘ ‘antiseptic handwash,’ or’’; Products [Reserved] Authority: 21 U.S.C. 321, 351, 352, 353, ■ 355, 360, 371. c. Removing and reserving paragraph (b)(2); Dated: December 11, 2013. § 333.403 [Amended] ■ d. Removing from the paragraph (b)(3) Leslie Kux, ■ 4. As proposed to be added June 17, paragraph heading the phrase ‘‘either Assistant Commissioner for Policy. 1994 (59 FR 31442), § 333.403 is further antiseptic or’’ and adding in its place [FR Doc. 2013–29814 Filed 12–16–13; 8:45 am] amended in paragraph (c)(1) by the word ‘‘a’’; BILLING CODE 4160–01–P

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