Federal Register/Vol. 80, No. 84/Friday, May 1, 2015/Proposed

Home , Hexachlorophene, Potassium iodide, Triclocarban, Triclosan

25166 Federal Register / Vol. 80, No. 84 / Friday, May 1, 2015 / Proposed Rules

DEPARTMENT OF HEALTH AND Written Submissions personnel hand washes, health care HUMAN SERVICES Submit written submissions in the personnel hand rubs, surgical hand following ways: scrubs, surgical hand rubs, and patient Food and Drug Administration • Mail/Hand delivery/Courier (for preoperative skin preparations. paper submissions): Division of Dockets 21 CFR Part 310 Summary of the Major Provisions of the Management (HFA–305), Food and Drug Regulatory Action in Question Administration, 5630 Fishers Lane, Rm. [Docket No. FDA–2015–N–0101] (Formerly We are proposing that additional Docket No. FDA–1975–N–0012) 1061, Rockville, MD 20852. safety and effectiveness data are Instructions: All submissions received necessary to support a GRAS/GRAE RIN 0910–AF69 must include the Docket No. FDA– determination for OTC antiseptic active 2015–N–0101 (formerly Docket No. ingredients intended for use by health Safety and Effectiveness of Health FDA–1975–N–0012) and RIN 0910– care professionals. The effectiveness Care Antiseptics; Topical Antimicrobial AF69 for this rulemaking. All comments data, the safety data, and the effect on Drug Products for Over-the-Counter received may be posted without change the previously proposed classification of Human Use; Proposed Amendment of to http://www.regulations.gov, including active ingredients are described briefly the Tentative Final Monograph; any personal information provided. in this summary. Reopening of Administrative Record Docket: For access to the docket to read background documents or Effectiveness AGENCY: Food and Drug Administration, comments received, go to http:// A determination that a drug product HHS. www.regulations.gov and insert the containing a particular active ingredient ACTION: Proposed rule. docket number, found in brackets in the would be generally recognized as heading of this document, into the effective (GRAE) for a particular SUMMARY: The Food and Drug ‘‘Search’’ box and follow the prompts intended use requires consideration of Administration (FDA) is issuing this and/or go to the Division of Dockets proposed rule to amend the 1994 the benefit-to-risk ratio for the drug for Management, 5630 Fishers Lane, Rm. that use. New information on potential tentative final monograph or proposed 1061, Rockville, MD 20852. Earlier FDA rule (the 1994 TFM) for over-the-counter risks posed by the use of certain health publications, public submissions, and care antiseptic products, as well as (OTC) antiseptic drug products. In this other materials relevant to this proposed rule, we are proposing to input from the Nonprescription Drugs rulemaking may also be found under Advisory Committee (NDAC) that met in establish conditions under which OTC Docket No. FDA–1975–N–0012 antiseptic products intended for use by March 2005 (the March 2005 NDAC), (formerly Docket No. 1975N–0183H) has prompted us to reevaluate the data health care professionals in a hospital using the same procedures. setting or other health care situations needed for classifying health care FOR FURTHER INFORMATION CONTACT: outside the hospital are generally antiseptic active ingredients as GRAE recognized as safe and effective. In the Michelle M. Jackson, Center for Drug (see new information described in the 1994 TFM, certain antiseptic active Evaluation and Research, Food and Safety section of this summary). We ingredients were proposed as being Drug Administration, 10903 New continue to propose the use of surrogate generally recognized as safe for use in Hampshire Ave., Bldg. 22, Rm. 5411, endpoints (bacterial log reductions) as a health care settings based on safety data Silver Spring, MD 20993, 301–796– demonstration of effectiveness for evaluated by FDA as part of its ongoing 2090. health care antiseptics combined with review of OTC antiseptic drug products. SUPPLEMENTARY INFORMATION: in vitro testing to characterize the antimicrobial activity of the ingredient. However, in light of more recent Executive Summary scientific developments, we are now However, the log reductions required for proposing that additional safety data are Purpose of the Regulatory Action the demonstration of effectiveness for necessary to support the safety of health care antiseptics have been FDA is proposing to amend the 1994 revised based on the recommendations antiseptic active ingredients for these TFM for OTC antiseptic drug products uses. We also are proposing that all of the March 2005 NDAC, comments that published in the Federal Register of received after the 1994 TFM, and other health care antiseptic active ingredients June 17, 1994 (59 FR 31402). The 1994 have in vitro data characterizing the information that FDA reviewed. TFM is part of FDA’s ongoing We have evaluated the available ingredient’s antimicrobial properties rulemaking to evaluate the safety and literature and the data and other and in vivo clinical simulation studies effectiveness of OTC drug products information that were submitted to the showing that specified log reductions in marketed in the United States on or rulemaking on the effectiveness of the amount of certain bacteria are before May 1972 (OTC Drug Review). health care antiseptic active ingredients, achieved using the ingredient. FDA is proposing to establish new as well as the recommendations from DATES: Submit electronic or written conditions under which OTC health the public meetings held by the Agency comments by October 28, 2015. See care antiseptic active ingredients are on antiseptics. We propose that the section VIII of this document for the generally recognized as safe and record should contain additional log proposed effective date of a final rule effective (GRAS/GRAE) based on FDA’s reduction data to demonstrate the based on this proposed rule. reevaluation of the safety and effectiveness of health care antiseptic ADDRESSES: You may submit comments effectiveness data requirements active ingredients. by any of the following methods: proposed in the 1994 TFM in light of comments received, input from Safety Electronic Submissions subsequent public meetings, and our Several important scientific Submit electronic comments in the independent evaluation of other developments that affect the safety following way: relevant scientific information we have evaluation of these ingredients have • Federal eRulemaking Portal: http:// identified and placed in the occurred since FDA’s 1994 evaluation of www.regulations.gov. Follow the administrative file. These health care the safety of health care antiseptic active instructions for submitting comments. antiseptic products include health care ingredients under the OTC Drug

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Review. Improved analytical methods maximal use trials or MUsT), (2) active ingredients classified as GRAS/ now exist that can detect and more nonclinical safety studies described in GRAE for use in health care antiseptics accurately measure these active current FDA guidance (e.g., in the 1994 TFM need additional safety ingredients at lower levels in the developmental and reproductive and effectiveness data to support a bloodstream and tissue. Consequently, toxicity studies and carcinogenicity classification of GRAS/GRAE for health we now know that, at least for certain studies), (3) data to characterize care antiseptic use. health care antiseptic ingredients, potential hormonal effects, and (4) data Several health care antiseptic active systemic exposure is higher than to evaluate the development of ingredients evaluated in the 1994 TFM previously thought (Refs. 1 through 5), antimicrobial resistance. were proposed as GRAS, but not GRAE, and new information is available about We emphasize that our proposal for for use in health care antiseptics the potential risks from systemic more safety and effectiveness data for because they lacked sufficient evidence absorption and long-term exposure. health care antiseptic active ingredients of effectiveness for health care use (see New safety information also suggests does not mean that we believe that tables 4 and 5). We are now proposing that widespread antiseptic use could health care antiseptic products that these ingredients need additional have an impact on the development of containing these ingredients are safety data, as well as effectiveness data, bacterial resistance. Currently, the ineffective or unsafe, or that their use to be classified as GRAS/GRAE. significance of this new information is should be discontinued. However, now The data available and the data that not known and we are unaware of any that we have enhanced abilities to are missing are discussed separately for information that would lead us to measure and evaluate the safety and each active ingredient in this proposed conclude that any health care antiseptic effectiveness of these ingredients, we rule. For those ingredients for which no active ingredient is unsafe (other than believe we should obtain relevant data data have been submitted since the 1994 those that we proposed to be Category to support a GRAS/GRAE TFM, we have not included a separate II in the 1994 TFM). The benefits of any determination. Consequently, based on discussion section, but have indicated active ingredient will need to be new information and improvements in in table 10 that no additional data were weighed against its risks once both the safety testing and in our understanding submitted or identified. effectiveness and safety have been better of log reduction testing and the use of In certain cases, manufacturers may characterized to determine GRAS/GRAE surrogate endpoints since our 1994 have the data we propose as necessary status. evaluation, we are requesting more in this proposed rule, but to date these The previously proposed generally safety and effectiveness data to ensure data have not been submitted to the recognized as safe (GRAS) that these health care antiseptic active OTC Drug Review. Although currently determinations were based on safety ingredients meet the updated standards we expect to receive the necessary data, principles that have since evolved to support a GRAS/GRAE classification. if we do not obtain sufficient data to significantly because of advances in Considering the prevalent use of health support monograph conditions for technology, development of new test care antiseptic products in health care health care antiseptic products methods, and experience with settings, it is critical that the safety and containing these active ingredients, performing test methods. The standard effectiveness of these ingredients be these products may not be included in battery of tests that were used to supported by data that meet the most the future OTC health care antiseptic determine the safety of drugs has current standards. final monograph. Any health care changed over time to incorporate antiseptic product containing the active Active Ingredients improvements in safety testing. To ingredients being considered under this ensure that health care antiseptic active In the 1994 TFM, 27 antiseptic active rulemaking that are not included in a ingredients are GRAS, data that meet ingredients were classified for three future final monograph could obtain current safety standards are needed. OTC health care antiseptic uses: (1) approval to market by submitting new Based on these developments, we are Patient preoperative skin preparation, drug applications (NDAs) under section now proposing that additional safety (2) health care personnel hand wash, 505 of the Federal Food, Drug, and data are needed for each health care and (3) surgical hand scrub (59 FR Cosmetic Act (the FD&C Act) (21 U.S.C. antiseptic active ingredient to support a 31402 at 31435) (for a list of all active 355). After a final monograph is GRAS classification. The data described ingredients covered by this proposed established, these products might be in this proposed rule are the minimum rule, see tables 4 through 7). Our able to submit NDA deviations in data necessary to establish the safety of detailed evaluation of the effectiveness accordance with § 330.11 (21 CFR antiseptic active ingredients used in and safety of the active ingredients for 330.11), limiting the scope of review health care antiseptic products in light which data were submitted can be necessary to obtain approval. of the new safety information. Health found in sections VI.A and VII.D. In the Costs and Benefits care practitioners may use health care 1994 TFM, alcohol (60 to 95 percent) antiseptics on a daily, long-term (i.e., and povidone-iodine (5 to 10 percent), Benefits represent the monetary chronic) basis. Patient preoperative skin which are active ingredients that are values associated with reducing the preparations, on the other hand, are not being evaluated for use as a health care potential adverse health effects usually used on any single patient on a antiseptic in this proposed rule, were associated with the use of health care daily basis. Nevertheless, an individual proposed to be classified as GRAS/ antiseptic products containing active may be exposed to patient preoperative GRAE (59 FR 31402 at 31435–31436) for ingredients that could potentially be skin preparations (particularly those patient preoperative skin preparation, shown to be unsafe or ineffective for used for preinjection skin preparation) health care personnel hand wash, and their intended use. We estimate annual enough times over a lifetime to be surgical hand scrub. Iodine tincture, benefits to roughly range between $0 considered a chronic use. The data we iodine topical solution, and isopropyl and $0.16 million. Total upfront costs propose are needed to demonstrate alcohol were proposed to be classified are estimated to range between $64 and safety for all health care antiseptic as GRAS/GRAE for patient preoperative $90.8 million. Annualizing these costs active ingredients fall into four broad skin preparations (59 FR 31402 at over a 10-year period, we estimate total categories: (1) Human safety studies 31435–31436). However, we now annualized costs to range from $7.3 and described in current FDA guidance (e.g., propose that the health care antiseptic $10.4 million at a 3 percent discount

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rate to $8.5 and $12.1 million at a 7 conduct various safety and effectiveness products that contain nonmonograph percent discount rate. Potential one- tests, and to reformulate and relabel ingredients. time costs include the expenditures to

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

Total ...... $0.0 to $0.16 ...... $7.3 to $10.4 at (3%) ...... $64.0 to $90.8 $8.5 to $12.1 at (7%) ......

Table of Contents A. Terminology Used in the OTC Drug B. Topical Antiseptics I. Introduction Review Regulations The OTC topical antimicrobial A. Terminology Used in the OTC Drug 1. Proposed, Tentative Final, and Final rulemaking has had a broad scope, Review Regulations Monographs encompassing drug products that may B. Topical Antiseptics contain the same active ingredients, but C. This Proposed Rule Covers Only Health To conform to terminology used in that are labeled and marketed for Care Antiseptics the OTC Drug Review regulations different intended uses. In 1974, the D. Comment Period (§ 330.10), the September 1974 advance Agency published an ANPR for topical II. Background antimicrobial products that A. Significant Rulemakings Relevant to notice of proposed rulemaking (ANPR) encompassed products for both health This Proposed Rule was designated as a ‘‘proposed B. Public Meetings Relevant to This monograph.’’ Similarly, the notices of care and consumer use (39 FR 33103, Proposed Rule proposed rulemaking, which were September 13, 1974). The ANPR C. Comments Received by FDA published in the Federal Register of covered seven different intended uses for these products: (1) Antimicrobial III. Active Ingredients With Insufficient January 6, 1978 (43 FR 1210) (the 1978 soap, (2) health care personnel hand Evidence of Eligibility for the OTC Drug TFM), and in the Federal Register of Review wash, (3) patient preoperative skin A. Eligibility for the OTC Drug Review June 17, 1994 (59 FR 31402) (the 1994 preparation, (4) skin antiseptic, (5) skin B. Eligibility of Certain Active Ingredients TFM), were each designated as a wound cleanser, (6) skin wound for Certain Health Care Antiseptic Uses ‘‘tentative final monograph.’’ The protectant, and (7) surgical hand scrub Under the OTC Drug Review present proposed rule, which is a (39 FR 33103 at 33140). FDA IV. Ingredients Previously Proposed as Not reproposal regarding health care subsequently identified skin antiseptics, Generally Recognized as Safe and antiseptic drug products, is also skin wound cleansers, and skin wound Effective designated as a ‘‘tentative final protectants as antiseptics used primarily V. Summary of Proposed Classifications of monograph.’’ OTC Health Care Antiseptic Active by consumers for first aid use and referred to them collectively as ‘‘first aid Ingredients 2. Category I, II, and III Classifications VI. Effectiveness (Generally Recognized as antiseptics.’’ We published a separate Effective) Determination The OTC drug procedural regulations TFM covering the first aid antiseptics in A. Evaluation of Effectiveness Data in § 330.10 use the terms ‘‘Category I’’ the Federal Register of July 22, 1991 (56 B. Current Standards: Studies Needed to (generally recognized as safe and FR 33644) (1991 First Aid TFM). Thus, Support a Generally Recognized as effective and not misbranded), first aid antiseptics are not discussed Effective Determination further in this document. VII. Safety (Generally Recognized as Safe) ‘‘Category II’’ (not generally recognized The four remaining categories of Determination as safe and effective or misbranded), topical antimicrobials were addressed in A. New Issues and ‘‘Category III’’ (available data are the 1994 TFM. The 1994 TFM covered: B. Antimicrobial Resistance insufficient to classify as safe and (1) Antiseptic hand wash (i.e., consumer C. Studies to Support a Generally effective, and further testing is hand wash), (2) health care personnel Recognized as Safe Determination required). Section 330.10 provides that hand wash, (3) patient preoperative skin D. Review of Available Data for Each any testing necessary to resolve the Antiseptic Active Ingredient preparation, and (4) surgical hand scrub VIII. Proposed Effective Date safety or effectiveness issues that (59 FR 31402 at 31442). In the 1994 IX. Summary of Preliminary Regulatory formerly resulted in a Category III TFM, FDA also identified a new Impact Analysis classification, and submission to FDA of category of antiseptics for use by the A. Introduction the results of that testing or any other food industry and requested relevant B. Summary of Costs and Benefits data, must be done during the OTC drug data and information (59 FR 31402 at X. Paperwork Reduction Act of 1995 rulemaking process before the 31440). Antiseptics for use by the food XI. Environmental Impact establishment of a final monograph (i.e., industry are not discussed further in XII. Federalism a final rule or regulation). Therefore, this document. XIII. References this proposed rule (at the tentative final As we proposed in the consumer I. Introduction monograph stage) retains the concepts antiseptic wash proposed rule of Categories I, II, and III. published in the Federal Register of In the following sections, we provide December 17, 2013 (78 FR 76444) (the a brief description of terminology used At the final monograph stage, FDA Consumer Wash PR), our evaluation of in the OTC Drug Review regulations and does not use the terms ‘‘Category I,’’ OTC antiseptic drug products is being an overview of OTC topical antiseptic ‘‘Category II,’’ and ‘‘Category III.’’ In further subdivided into health care drug products, and then describe in place of Category I, the term antiseptics and consumer antiseptics. more detail the OTC health care ‘‘monograph conditions’’ is used; in We believe that these categories are antiseptics that are the subject of this place of Categories II and III, the term distinct based on the proposed use proposed rule. ‘‘nonmonograph conditions’’ is used. setting, target population, and the fact

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that each setting presents a different population in a hospital or health care D. Comment Period level of risk for infection. For example, facility also is different from the general in health care settings, the patient consumer population. In addition, the Because of the complexity of this population is generally more susceptible microorganisms of concern are different proposed rule, we are providing a to infection than the general U.S. in the health care and consumer comment period of 180 days. Moreover, consumer population (i.e., the settings. These differences have resulted new data or information may be population who use consumer in our proposing different effectiveness submitted to the docket via http:// antiseptic washes). Consequently, in the data requirements. (See section VI.B. www.regulations.gov within 12 months health care setting, the potential for about the different effectiveness data of publication, and comments on any spread of infection and the potential for requirements.) new data or information may then be serious outcomes of infection may be submitted for an additional 60 days (see relatively higher than in the U.S. C. This Proposed Rule Covers Only § 330.10(a)(7)(iii) and (a)(7)(iv)). In consumer setting. Therefore, the safety Health Care Antiseptics addition, FDA will also consider and effectiveness should be evaluated We refer to the group of products requests to defer further rulemaking separately for each intended use to covered by this proposed rule as ‘‘health with respect to a specific active support a GRAS/GRAE determination. care antiseptics.’’ In this proposed rule, ingredient to allow the submission of Health care antiseptics are drug FDA proposes the establishment of a new safety or effectiveness data to the products intended for use by health care monograph for OTC health care record if such requests are submitted to professionals in a hospital setting or antiseptics that are intended for use by the docket within the initial 180-day other health care situations outside the health care professionals in a hospital comment period. Upon the close of the hospital. Patient preoperative skin setting or other health care situations comment period, FDA will review all preparations, which include products outside the hospital, but that are not data and information submitted to the that are used for preparation of the skin identified as ‘‘first aid antiseptics’’ in record in conjunction with all timely prior to an injection (i.e., preinjection), the 1991 First Aid TFM. In this and complete requests to defer may be used by patients outside the proposed rule, we use the term ‘‘health rulemaking. In assessing whether to traditional health care setting. Some care antiseptics’’ to include the defer further rulemaking for a particular patients (e.g., diabetics who manage following products: active ingredient to allow for additional their disease with insulin injections) • Health care personnel hand washes time for studies to generate new data self-inject medications that have been • health care personnel hand rubs and information, FDA will consider the prescribed by a health care professional • surgical hand scrubs data already in the docket along with at home or at other locations and use • surgical hand rubs any information that is provided in any patient preoperative skin preparations • patient preoperative skin requests. FDA will determine whether prior to injection. In 1974, when the preparations the sum of the data, if submitted in a ANPR (39 FR 33103) to establish an This proposed rule covers products timely fashion, is likely to be adequate OTC topical antimicrobial monograph that are rubs and others that are washes. to provide all the data that are necessary was published in the Federal Register, The 1994 TFM did not distinguish to make a determination of general antimicrobial soaps used by consumers between products that we are now recognition of safety and effectiveness. calling ‘‘antiseptic washes’’ and were distinct from professional use We note that the OTC Drug Review is products we are now calling ‘‘antiseptic antiseptics, such as health care a public process and any data submitted rubs.’’ Washes are rinsed off with water, personnel hand washes. (See 78 FR is public. There is no requirement or and include health care personnel hand 76444 for further discussion of the term expectation that more than one set of washes and surgical hand scrubs. Rubs ‘‘antimicrobial soaps.’’) In contrast, in data will be submitted to the docket for the 1994 TFM, we proposed that both are sometimes referred to as ‘‘leave-on a particular active ingredient, and it consumer antiseptic hand washes and products’’ and are not rinsed off after does not matter who submits the data. health care personnel hand washes use. Rubs include health care personnel Additionally, data and other should have the same effectiveness hand rubs, surgical hand rubs, and information for a single active testing and performance criteria. In patient preoperative skin preparations. ingredient may be submitted by any response to the 1994 TFM, we received The 1994 TFM did not distinguish interested party and not all data for an submissions from the public arguing between consumer antiseptic washes ingredient must be submitted by a single that consumer products serve a different and rubs, and health care hand washes party. purpose and should continue to be and rubs. This proposed rule covers distinct from health care antiseptics. We health care personnel hand washes and II. Background agree, and in this proposed rule, we health care personnel hand rubs, as well make a distinction between consumer as the other health care antiseptic In this section, we describe the antiseptics for use by the general categories previously listed in this significant rulemakings and public population and health care antiseptics section. This proposed rule does not meetings relevant to this proposed rule, for use in hospitals or in other specific cover consumer antiseptic washes or and how we are responding to health care situations outside the consumer antiseptic hand rubs. comments received in response to the hospital. Completion of the monograph for 1994 TFM. The health care setting is different Health Care Antiseptic Products and A. Significant Rulemakings Relevant to from the consumer setting in many certain other monographs for the active This Proposed Rule ways. Among other things, health care ingredient triclosan are subject to a facilities employ frequent, standardized Consent Decree entered by the United A summary of the significant Federal disinfection procedures and stringent States District Court for the Southern Register publications relevant to this infection control measures that include District of New York on November 21, proposed rule is provided in table 1. the use of health care antiseptics. The 2013, in Natural Resources Defense Other Federal Register publications use of these measures is critical to Council, Inc. v. United States Food and relevant to this proposed rule are preventing the spread of infection Drug Administration, et al., 10 Civ. 5690 available from the Division of Dockets within health care facilities. The (S.D.N.Y.). Management (see ADDRESSES).

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TABLE 1—SIGNIFICANT RULEMAKING PUBLICATIONS RELATED TO HEALTH CARE 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 33103). topical antimicrobial drug products, together with the recommendations of the Advisory Re- view Panel on OTC Topical Antimicrobial I Drug Products (Antimicrobial I Panel or Panel), which was the advisory review panel responsible for evaluating data on the active ingredients in this drug class. 1978 Antimicrobial TFM (January 6, 1978, 43 We published our tentative conclusions and proposed effectiveness testing for the drug prod- FR 1210). uct categories evaluated by the Panel. The 1978 TFM reflects our evaluation of the recommendations of the Panel and comments and data submitted in response to the Panel’s recommendations. 1982 Alcohol ANPR (May 21, 1982, 47 FR We published an advance notice of proposed rulemaking to establish a monograph for alcohol 22324). drug products for topical antimicrobial use, together with the recommendations of the Advi- sory Review Panel on OTC Miscellaneous External Drug Products, which was the advisory review panel responsible for evaluating data on the active ingredients in this drug class (Miscellaneous External Panel). 1991 First Aid TFM (July 22, 1991, 56 FR We amended the 1978 TFM to establish a separate monograph for OTC first aid antiseptic 33644). products. In the 1991 First Aid TFM, we proposed that first aid antiseptic drug products be indicated for the prevention of skin infections in minor cuts, scrapes, and burns. 1994 Health-Care Antiseptic TFM (June 17, We amended the 1978 TFM to establish a separate monograph for the group of products that 1994, 59 FR 31402). were referred to as OTC topical health care antiseptic drug products. These antiseptics are generally intended for use by health care professionals. In that 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 hand wash. 2013 Consumer Antiseptic Wash TFM (Decem- We issued a proposed rule to amend the 1994 TFM and to establish data standards for deter- ber 17, 2013, 78 FR 76444). mining whether OTC consumer antiseptic washes are GRAS/GRAE. In that proposed rule, we proposed that additional safety and effectiveness data are necessary to support the safety and effectiveness of consumer antiseptic wash active ingredients.

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

TABLE 2—PUBLIC MEETINGS RELEVANT TO HEALTH CARE ANTISEPTICS

Date and type of meeting Topic of discussion

January 1997 NDAC Meeting (Joint meeting Antiseptic and antibiotic resistance in relation to an industry proposal for consumer and health with the Anti-Infective Drugs Advisory Com- care antiseptic effectiveness testing (Health Care Continuum Model) (Refs. 6 and 7). mittee) (January 6, 1997, 62 FR 764). March 2005 NDAC Meeting (February 18, 2005, The use of surrogate endpoints and study design issues for the in vivo testing of health care 70 FR 8376). antiseptics (Ref. 8). November 2008 Public Feedback Meeting ...... Demonstration of the effectiveness of consumer antiseptics (Ref. 9). September 2014 NDAC Meeting (July 29, 2014, Safety testing framework for health care antiseptic active ingredients (Ref. 10). 79 FR 44042).

C. Comments Received by FDA conditions proposed in the 1994 TFM. This proposed rule constitutes FDA’s In response to the 1994 TFM, FDA If in the future we determine that there evaluation of submissions made in received approximately 160 comments are monograph health care antiseptic response to the 1994 TFM to support the from drug manufacturers, trade active ingredients that are GRAS/GRAE, safety and effectiveness of OTC health associations, academia, testing we will address these comments. We care antiseptic active ingredients (Refs. laboratories, consumers, health invite further comment on the final 11 and 12). We reviewed the available professionals, and law firms. Copies of formulation testing and labeling literature and data and other comments the comments received are on public conditions proposed in the 1994 TFM, submitted to the rulemaking and are display at http://www.regulations.gov particularly in light of the conditions proposing that adequate data for a (see ADDRESSES). proposed in this proposed rule. determination of safety and Because only health care antiseptics Comments that were received in effectiveness are not yet available for the are discussed in this proposed rule, only response to the 1994 TFM regarding health care antiseptic active ingredients. those comments and data received in other intended uses of the active III. Active Ingredients With Insufficient response to the 1994 TFM that are ingredients are addressed in the Evidence of Eligibility for the OTC Drug related to health care antiseptic active Consumer Antiseptic Wash TFM (78 FR Review ingredients are addressed. We also 76444), or will be addressed in future received comments related to final documents related to those other uses. In this section of the proposed rule, formulation testing and labeling we describe the requirements for

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eligibility for the OTC Drug Review and drug that will require FDA approval discussed in this proposed rule for such the ingredients submitted to the OTC through the NDA process. Ineligibility use(s). However, if documentation of the Drug Review that lack adequate for use as a specific type of health care type described in this section is evidence of eligibility for evaluation as antiseptic (e.g., health care personnel submitted, these active ingredients health care antiseptic products. hand wash or surgical hand scrub) does could be determined to be eligible for not affect eligibility for other indications evaluation for such use(s). A. Eligibility for the OTC Drug Review under the health care antiseptic B. Eligibility of Certain Active An OTC drug is covered by the OTC monograph (e.g., patient preoperative Ingredients for Certain Health Care Drug Review if its conditions of use skin preparations) or under any other Antiseptic Uses Under the OTC Drug existed in the OTC drug marketplace on OTC drug monograph. Review or before May 11, 1972 (37 FR 9464).1 Section III.B discusses those Conditions of use include, among other ingredients that currently do not have Table 3 lists the health care antiseptic things, active ingredient, dosage form adequate evidence of eligibility for active ingredients that have been and strength, route of administration, evaluation under the OTC Drug Review considered under this rulemaking and and specific OTC use or indication of based on a review of the labeling shows whether each ingredient is the product (see § 330.14(a)). To submitted to the Panel. Some eligible or ineligible for each of the five determine eligibility for the OTC Drug ingredients are ineligible for any of the health care antiseptic uses: Patient Review, FDA typically must have actual categories of health care antiseptics. preoperative skin preparation, health product labeling or a facsimile of Others are eligible for some, but not care personnel hand wash, health care labeling that documents the conditions others. Because of their lack of personnel hand rub, surgical hand of marketing of a product prior to May eligibility, effectiveness and safety scrub, and surgical hand rub. After the 1972 (see § 330.10(a)(2)). FDA considers information that has been submitted to table, we discuss the ineligibility of a drug that is ineligible for inclusion in the rulemaking for these health care ingredients in this section of the the OTC monograph system to be a new antiseptic active ingredients are not proposed rule.

TABLE 3—ELIGIBILITY OF ANTISEPTIC ACTIVE INGREDIENTS FOR HEALTH CARE ANTISEPTIC USES 1

Patient preoperative Health care Health care Surgical Surgical Active ingredient skin personnel personnel hand scrub hand rub preparation hand wash hand rub

Alcohol 60 to 95 percent ...... 2 Y 3 N Y N Y Benzalkonium chloride ...... Y Y Y Y N Benzethonium chloride ...... Y Y N Y N Chlorhexidine gluconate ...... N N N N N Chloroxylenol ...... Y Y N Y N Cloflucarban ...... Y Y N Y N Fluorosalan ...... Y Y N Y N Hexylresorcinol ...... Y Y N Y N Iodine Active Ingredients: Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate) ...... N Y N Y N Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) ...... Y Y N Y N Iodine tincture USP ...... Y N N N N Iodine topical solution USP ...... Y N N N N Nonylphenoxypoly (ethyleneoxy) ethanoliodine ...... Y Y N Y N Poloxamer-iodine complex ...... Y Y N Y N Povidone-iodine 5 to 10 percent ...... Y Y N Y N Undecoylium chloride iodine complex ...... Y Y N Y N Isopropyl alcohol 70–91.3 percent ...... Y N Y N Y Mercufenol chloride ...... Y N N N N Methylbenzethonium chloride ...... Y Y N Y N Phenol (less than 1.5 percent) ...... Y Y N Y N Phenol (greater than 1.5 percent) ...... Y Y N Y N Secondary amyltricresols ...... Y Y N Y N Sodium oxychlorosene ...... Y Y N Y N Triclocarban ...... Y Y N Y N Triclosan ...... Y Y N Y N Combinations: Calomel, oxyquinoline benzoate, triethanolamine, and phenol derivative ...... Y N N N N Mercufenol chloride and secondary amyltricresols in 50 percent alcohol ...... Y N N N N Triple dye ...... Y N N N N 1 Hexachlorophene and tribromsalan are not included in this table because they are the subject of final regulatory action (see section IV). 2 Y = Eligible for specified use. 3 N = Ineligible for specified use.

1 Also, note that drugs initially marketed in the 1972 and drugs without any U.S. marketing monograph system based on submission of a time United States after the OTC Drug Review began in experience can be considered in the OTC and extent application. (See § 330.14(c).)

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1. Alcohols and patient preoperative skin intended for use as a health care a. Alcohol (ethanol or ethyl alcohol). preparation (59 FR 31402 at 31435– personnel hand wash or rub or as a In the 1994 TFM, alcohol (ethanol or 31436). Thus, we include a discussion surgical hand scrub or rub, and we do ethyl alcohol) 60 to 95 percent by of the safety and effectiveness data for not include a discussion of safety or volume in an aqueous solution was isopropyl alcohol in this proposed rule effectiveness of iodine solution or evaluated for use as a health care for such uses. tincture for such uses in this proposed personnel hand wash, surgical hand rule. 2. Benzalkonium Chloride However, both iodine topical solution scrub, and patient preoperative skin Benzalkonium chloride has not been and iodine tincture have been preparation (59 FR 31402 at 31442). The demonstrated to be eligible for the OTC demonstrated to be eligible for the OTC only health care antiseptic products Drug Review for use as a surgical hand Drug Review for use as a patient containing alcohol that were submitted rub. Based on the information we preoperative skin preparation (59 FR to the OTC Drug Review were products currently have about eligibility, we 31402 at 31435–31436). Thus, we that were intended to be used without propose to categorize as a new drug include a discussion of the safety and water (i.e., rubs and skin preparations) benzalkonium chloride for use as a effectiveness of these iodines for this (Ref. 13). Consequently, based on the surgical hand rub. Benzalkonium use in this proposed rule. information we currently have about chloride, however, has been b. Iodine complex (ammonium ether eligibility, we propose to categorize as demonstrated to be eligible for the OTC sulfate and polyoxyethylene sorbitan new drugs these health care antiseptic Drug Review for use as a health care monolaurate). The only health care washes and surgical scrubs (both of personnel hand wash, health care antiseptic products containing this which are washes and are by definition personnel hand rub, surgical hand iodine complex submitted to the OTC intended to be rinsed off with water) scrub, and patient preoperative skin Drug Review were health care personnel that contain alcohol as the active preparation (59 FR 31402 at 31435– hand washes and surgical hand scrubs ingredient, and we do not include a 31436). Thus, we include a discussion intended to be used with water (Ref. 13). discussion of safety or effectiveness of of the safety and effectiveness data for Consequently, iodine complex alcohol for such rinse-off uses in this benzalkonium chloride in this proposed (ammonium ether sulfate and proposed rule. rule for such uses. polyoxyethylene sorbitan monolaurate) Alcohol, however, has been has not been demonstrated to be eligible 3. Chlorhexidine Gluconate demonstrated to be eligible for the OTC for the OTC Drug Review for evaluation Drug Review for use as a health care Previously, chlorhexidine gluconate 4 as a health care personnel hand rub or personnel hand rub, surgical hand rub, percent aqueous solution (chlorhexidine a surgical hand rub, both of which are and patient preoperative skin gluconate) was found to be ineligible for intended to be leave-on products used preparation (59 FR 31402 at 31435– inclusion in the monograph for any without water. This iodine complex also 31436). Thus, we include a discussion health care antiseptic use and was not has not been demonstrated to be eligible of the safety and effectiveness data for included in the 1994 TFM (59 FR 31402 for the OTC Drug Review for use as a alcohol in this proposed rule for such at 31413). We have not received any patient preoperative skin preparation. It uses. new information since the 1994 TFM was not evaluated for use as a patient b. Isopropyl alcohol. In the 1994 TFM, demonstrating that this active ingredient preoperative skin preparation in the isopropyl alcohol 70 to 91.3 percent by is eligible for the monograph. 1994 TFM (59 FR 31402 at 31435– volume in an aqueous solution Consequently, we are not proposing to 31436) and we have not received any (isopropyl alcohol) was classified for change the categorization of new information to demonstrate use as a health care personnel hand chlorhexidine gluconate from that of a eligibility for this use since publication wash and surgical hand scrub (59 FR new drug based on the lack of of the 1994 TFM. Based on the 31402 at 31435–31436). Isopropyl documentation demonstrating its information we currently have about alcohol also was evaluated as a patient eligibility as a health care antiseptic, eligibility of this active ingredient, we preoperative skin preparation (59 FR and we do not include a discussion of propose to categorize as a new drug 31402 at 31442–31443). The only health any safety or effectiveness data iodine complex (ammonium ether care antiseptic products containing submitted for chlorhexidine gluconate sulfate and polyoxyethylene sorbitan isopropyl alcohol that were submitted to in this proposed rule. monolaurate) intended for use as patient the OTC Drug Review were products preoperative skin preparation as well. 4. Iodine and Iodine Complexes that were intended to be used without This iodine complex, however, has been water (i.e., rubs and skin preparations) a. Iodine topical solution USP and demonstrated to be eligible for the OTC (Ref. 13). Consequently, isopropyl iodine tincture USP. Iodine topical Drug Review for use as a health care alcohol has not been demonstrated to be solution and iodine tincture have not personnel hand wash and surgical hand eligible for the OTC Drug Review for use been demonstrated to be eligible for the scrub (59 FR 31402 at 31435–31436). as a health care personnel hand wash or OTC Drug Review for use as a health c. Iodine complex (phosphate ester of a surgical hand scrub drug product, both care personnel hand wash or rub or as alkylaryloxy polyethylene glycol), of which are washes and by definition a surgical hand scrub or rub. Neither nonylphenoxypoly (ethyleneoxy) are intended to be rinsed off with water. iodine topical solution nor iodine ethanoliodine, poloxamer-iodine Thus, we propose to categorize tincture was evaluated for these uses in complex, and undecoylium chloride isopropyl alcohol for these uses as a the1994 TFM (59 FR 31402 at 31435– iodine complex. The only health care new drug and do not include a 31436), and we have not received any antiseptic products containing these discussion of safety or effectiveness of new information to demonstrate iodine complexes that were submitted isopropyl alcohol for such rinse-off uses eligibility for these uses since to the OTC Drug Review were health in this proposed rule. publication of the 1994 TFM. Based on care personnel hand washes and Isopropyl alcohol, however, has been the information we currently have about surgical hand scrubs intended to be demonstrated to be eligible for the OTC eligibility of iodine topical solution and used with water, and patient Drug Review for use as a health care iodine tincture, we propose to preoperative skin preparations (Ref. 13). personnel hand rub, surgical hand rub, categorize as new drugs these iodines Consequently, iodine complex

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(phosphate ester of alkylaryloxy 6. Polyhexamethylene Biguanide; used with water (i.e., rinse-off products) polyethylene glycol), nonylphenoxypoly Benzalkonium Cetyl Phosphate; (Ref. 13). Consequently, based on the (ethyleneoxy) ethanoliodine, Cetylpyridinium Chloride; Salicylic information we currently have about poloxamer-iodine complex, and Acid; Sodium Hypochlorite; Tea Tree eligibility, we propose to categorize as a undecoylium chloride iodine complex Oil; Combination of Potassium new drug each of these ingredients for have not been demonstrated to be Vegetable Oil Solution, Phosphate use as a health care personnel hand rub eligible for the OTC Drug Review for Sequestering Agent, and or a surgical hand rub, and we do not evaluation as health care personnel Triethanolamine include a discussion of safety or hand rubs or surgical hand rubs (59 FR Following the publication of the 1994 effectiveness of these ingredients for these uses in this proposed rule. 31402 at 31418 and 31435–31436). TFM, FDA received submissions for the Each of the listed ingredients, first time requesting that Thus, we do not include a discussion of however, has been demonstrated to be safety or effectiveness of these iodine polyhexamethylene biguanide; eligible for the OTC Drug Review for use complexes for these uses in this benzalkonium cetyl phosphate; as a health care personnel hand wash, proposed rule. cetylpyridinium chloride; salicylic acid; surgical hand scrub, and patient sodium hypochlorite; tea tree oil; and These active ingredients, however, preoperative skin preparation. the combination of potassium vegetable have been demonstrated to be eligible oil solution, phosphate sequestering 8. Combination Active Ingredients for the OTC Drug Review for use as a agent, and triethanolamine be added to The combination active ingredients health care personnel hand wash, a the monograph (Refs. 14 through 19). surgical hand scrub, and a patient (1) calomel, oxyquinoline benzoate, These compounds were not addressed triethanolamine, and phenol derivative; preoperative skin preparation (59 FR in prior FDA documents related to the (2) mercufenol chloride and secondary 31402 at 31435–31436). Thus, we monograph and were not evaluated for amyltricresols in 50 percent alcohol; include a discussion of the safety and any health care antiseptic use by the and (3) triple dye have not been effectiveness of these ingredients for Antimicrobial I Panel. The submissions demonstrated to be eligible for the OTC these uses in this proposed rule. received by FDA to date do not include Drug Review for use as a health care d. Povidone-iodine 5 to 10 percent. documentation demonstrating the personnel hand wash or rub or as a The only health care antiseptic products eligibility of any of these seven surgical hand scrub or rub (59 FR 31402 containing povidone-iodine 5 to 10 compounds for inclusion in the at 31435–31436). Consequently, based percent submitted to the OTC Drug monograph (Ref. 20). Therefore, on the information we currently have Review were health care personnel hand polyhexamethylene biguanide, about eligibility, we propose to washes and surgical hand scrubs benzalkonium cetyl phosphate, categorize as a new drug each of these intended to be used with water (Ref. 13). cetylpyridinium chloride, salicylic acid, ingredients for use as a health care Povidone-iodine 5 to 10 percent has not sodium hypochlorite, tea tree oil, and personnel hand wash, health care the combination of potassium vegetable been demonstrated to be eligible for the personnel hand rub, surgical hand oil solution, phosphate sequestering scrub, or a surgical hand rub, and we do OTC Drug Review for evaluation as a agent, and triethanolamine have not not include a discussion of safety or health care personnel hand rub or been demonstrated to be eligible for the effectiveness of these ingredients for surgical hand rub, and we propose to OTC Drug Review. Based on the these uses in this proposed rule. categorize povidone-iodine for these information we currently have about However, each of the previously uses as a new drug. However, povidone- eligibility, we propose to categorize discussed active ingredients has been iodine has been demonstrated to be these compounds as new drugs and we demonstrated to be eligible for the OTC eligible for the OTC Drug Review for use do not include a discussion of safety or Drug Review for use as a patient as a health care personnel hand wash, effectiveness data submitted for them in preoperative skin preparation. surgical hand scrub, and patient this proposed rule. preoperative skin preparation (59 FR IV. Ingredients Previously Proposed as 31402 at 31423 and 31435–31436). 7. Other Individual Active Ingredients Not Generally Recognized as Safe and Thus, we include a discussion of the In the 1994 TFM, each of the Effective safety and effectiveness of povidone following ingredients was evaluated for FDA may determine that an active iodine for these uses in this proposed use as a patient preoperative skin ingredient is not GRAS/GRAE for a rule. preparation, a health care personnel given OTC use (i.e., nonmonograph) hand wash, and a surgical hand scrub because of lack of evidence of 5. Mercufenol Chloride (59 FR 31402 at 31435–31436): effectiveness, lack of evidence of safety, • or both. In the 1994 TFM (59 FR 31402 Mercufenol chloride was evaluated Benzethonium chloride • at 31435–31436), FDA proposed that the for use only as a patient preoperative Chloroxylenol • Cloflucarban active ingredients fluorosalan, skin preparation in the 1994 TFM (59 • Fluorosalan hexachlorophene, phenol (greater than FR 31402 at 31428–31429 and 31435– • Hexylresorcinol 1.5 percent), and tribromsalan be found 31436). Based on the information we • Methylbenzethonium chloride not GRAS/GRAE for the uses referred to currently have about eligibility, we • Phenol (less than 1.5 percent) in the 1994 TFM as antiseptic hand propose to categorize as a new drug • Secondary amyltricresols wash and health care personnel hand mercufenol chloride for use as a health • Sodium oxychlorosene wash. FDA did not classify care personnel hand wash or rub or as • Triclocarban hexachlorophene or tribromsalan in the a surgical hand scrub or rub. Mercufenol • Triclosan 1978 TFM (43 FR 1210 at 1227) because chloride, however, has been The only health care personnel hand it had already taken final regulatory demonstrated to be eligible for the OTC wash or surgical hand scrub products action against hexachlorophene (21 CFR Drug Review for use as a patient containing any of these ingredients that 250.250) and certain halogenated preoperative skin preparation. were submitted to the OTC Drug Review salicylamides, notably tribromsalan (21 were products that were intended to be CFR 310.502). No substantive comments

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or new data were submitted to the unless it is the subject of an approved being proposed in this proposed rule. record of the 1994 TFM to support application, effective, except as The specific data that has been reclassification of any of these otherwise provided in other regulations, submitted to the public docket (the ingredients to GRAS/GRAE status. as of 1 year after publication of the final rulemaking) and evaluated by FDA and Therefore, FDA is continuing to propose monograph in the Federal Register. the description of data still lacking in that these active ingredients be found V. Summary of Proposed Classifications the administrative record is later not GRAS/GRAE for OTC health care of OTC Health Care Antiseptic Active described in detail for each active antiseptic products as defined in this Ingredients ingredient for which we have some data proposed rule and that any OTC health Tables 4 through 7 in this proposed in section VII.D. care antiseptic drug product containing rule list the classification proposed in Tables 4 and 5 list ingredients for any of these ingredients not be allowed the 1994 TFM for each OTC health care which a different status is being to be introduced or delivered for antiseptic active ingredient according to proposed in this proposed rule than was introduction into interstate commerce intended use and the classification proposed in the 1994 TFM.

TABLE 4—CLASSIFICATION OF OTC HEALTH CARE PERSONNEL HAND WASH AND SURGICAL HAND SCRUB ANTISEPTIC ACTIVE INGREDIENTS IN THIS PROPOSED RULE AND IN THE 1994 TFM

This Active ingredient 1994 proposed TFM rule

Alcohol 60 to 95 percent ...... I 1 IIISE 2 Hexylresorcinol ...... IIIE IIISE Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate) ...... IIIE IIISE Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) ...... IIIE IIISE Isopropyl alcohol 70 to 91.3 percent ...... IIIE IIISE Nonylphenoxypoly (ethyleneoxy) ethanoliodine ...... IIIE IIISE Poloxamer iodine complex ...... IIIE IIISE Povidone-iodine 5 to 10 percent ...... I IIISE Secondary amyltricresols ...... IIIE IIISE Triclocarban ...... IIIE IIISE Undecoylium chloride iodine complex ...... IIIE IIISE 1 ‘‘I’’ denotes a classification that an active ingredient has been shown to be safe and effective. 2 ‘‘III’’ denotes a classification that additional data are needed. ‘‘S’’ denotes safety data needed. ‘‘E’’ denotes effectiveness data needed.

TABLE 5—CLASSIFICATION OF OTC PATIENT PREOPERATIVE SKIN PREPARATION ANTISEPTIC ACTIVE INGREDIENTS IN THIS PROPOSED RULE AND IN THE 1994 TFM

This Active ingredient 1994 proposed TFM rule

Alcohol 60 to 95 percent ...... I 1 IIISE 2 Benzalkonium chloride ...... IIIE IIISE Benzethonium chloride ...... IIIE IIISE Chloroxylenol ...... IIIE IIISE Hexylresorcinol ...... IIIE IIISE Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) ...... IIIE IIISE Iodine tincture USP ...... I IIISE Iodine topical solution USP ...... I IIISE Isopropyl alcohol 70 to 91.3 percent ...... I IIISE Mercufenol chloride ...... IIIE IIISE Methylbenzethonium chloride ...... IIIE IIISE Nonylphenoxypoly (ethyleneoxy) ethanoliodine ...... IIIE IIISE Phenol (less than 1.5 percent) ...... IIIE IIISE Poloxamer iodine complex ...... IIIE IIISE Povidone-iodine 5 to 10 percent ...... I IIISE Triclocarban ...... IIIE IIISE Triclosan ...... IIIE IIISE Undecoylium chloride iodine complex ...... IIIE IIISE 1 ‘‘I’’ denotes a classification that an active ingredient has been shown to be safe and effective. 2 ‘‘III’’ denotes a classification that additional data are needed. ‘‘S’’ denotes safety data needed. ‘‘E’’ denotes effectiveness data needed.

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This proposed rule does not change 2 ‘‘III’’ denotes a classification that additional be reduced by disinfection of the status of a number of antiseptic data are needed. ‘‘S’’ denotes safety data physicians’ hands with chlorine prior to needed. ‘‘E’’ denotes effectiveness data active ingredients previously proposed needed. patient care (Ref. 28). Around the same as lacking sufficient evidence of safety time, Lister demonstrated the effect of or effectiveness or the status of several VI. Effectiveness (Generally Recognized skin disinfection on surgical site ingredients previously proposed as as Effective) Determination infection rates (Ref. 28). This having been shown to be unsafe, OTC regulations (§§ 330.10(a)(4)(ii) observational evidence of the effect of ineffective, or both (see tables 6 and 7). and 314.126(b)) define the standards for antiseptics on infection by Semmelweis establishing that an OTC drug and Lister form the basis for the current TABLE 6—OTC HEALTH CARE PER- containing a particular active ingredient role of antiseptics as a critical SONNEL HAND WASH AND SURGICAL would be GRAE for its intended use. component of hospital infection control HAND SCRUB ANTISEPTIC ACTIVE IN- These regulations provide that procedures. Adequate and well- GREDIENTS WITH NO CHANGE IN supporting investigations must be controlled clinical trials demonstrating a definitive link between antiseptic use CLASSIFICATION IN THIS PROPOSED adequate and well-controlled, and able and a reduction in infection rates are RULE COMPARED TO THE 1994 TFM to distinguish the effect of a drug from other influences such as a spontaneous lacking, however. change in the course of the disease, The March 2005 NDAC acknowledged No the difficulty in designing clinical trials change in placebo effect, or biased observation. In Active ingredient to demonstrate the impact of health care classifica- general, such investigations include antiseptics on infection rates. This tion controls that are adequate to provide an difficulty was one reason the committee assessment of drug effect, are adequate Benzalkonium chloride ...... IIISE 1 advised against clinical outcome trials measures to minimize bias, and use Benzethonium chloride ...... IIISE to demonstrate the effectiveness of adequate analytical methods to Chloroxylenol ...... IIISE health care antiseptics. Numerous 2 demonstrate effectiveness. For active Cloflucarban ...... IIISE/II factors contribute to hospital-acquired 3 ingredients being evaluated in the OTC Fluorosalan ...... II infections and, therefore, would need to Hexachlorophene ...... II Drug Review, this means that a be controlled for in the design of these Methylbenzethonium chloride ...... IIISE demonstration of the contribution of the Phenol (less than 1.5 percent) ..... IIISE types of studies. For example, some of active ingredient to any effectiveness the known risk factors for surgical site Phenol (greater than 1.5 percent) II observed is required before an Sodium oxychlorosene ...... IIISE infection that must be controlled for ingredient can be determined to be include the following: Patient age, Tribromsalan ...... II GRAE for OTC drug use. Triclosan ...... IIISE nutritional status, diabetes, smoking, In the 1994 TFM, we proposed a log obesity, coexistent infections at a remote 1 ‘‘III’’ denotes a classification that additional reduction standard (a clinical body site, colonization with data are needed. ‘‘S’’ denotes safety data simulation standard) for establishing needed. ‘‘E’’ denotes effectiveness data need- microorganisms, altered immune ed. effectiveness of consumer and health response, length of preoperative stay, 2 Health care personnel hand wash pro- care antiseptics (59 FR 31402 at 31448) duration of surgical scrub, preoperative posed as IIISE and surgical hand scrub pro- for the proposed intended use of shaving, preoperative skin prep, posed as II. decreasing bacteria on the skin. The 3 ‘‘II’’ denotes a classification that an active duration of the operation, inadequate ingredient has been shown to be unsafe, inef- 1994 TFM log reduction standard for sterilization of instruments, foreign fective, or both. effectiveness is based on a surrogate material in the surgical site, surgical endpoint (i.e., number of bacteria drain, and surgical technique (Ref. 22). TABLE 7—OTC PATIENT PRE- removed from the skin), rather than a There are also standard infection control OPERATIVE SKIN PREPARATION ANTI- clinical outcome (e.g., reduction in the measures such as gloving, isolation number of infections). In accordance SEPTIC ACTIVE INGREDIENTS WITH procedures, sterilization of instruments, with recommendations made by NDAC NO CHANGE IN CLASSIFICATION IN and waste disposal that make it difficult at its March 2005 meeting, we continue THIS PROPOSED RULE COMPARED to demonstrate the independent to propose a log reduction standard to contribution of antiseptics to the TO THE 1994 TFM demonstrate the general recognition of reduction of the risk of hospital effectiveness of health care antiseptic infection (Ref. 28). No active ingredients. See section VI.B for change in Although we found a few studies that Active ingredient classifica- our current proposed log reduction could serve as a basis for designing a tion standard. clinical outcome study in the consumer Unlike the use of antiseptics in the setting (78 FR 76444 at 76450), we have Cloflucarban ...... II 1 consumer setting, the use of antiseptics not found any acceptable clinical Fluorosalan ...... II by health care providers in the hospital outcome study designs for health care Hexachlorophene ...... II setting is considered an essential antiseptics. The March 2005 NDAC Phenol (greater than 1.5 percent) II component of hospital infection control Secondary amyltricresols ...... IIISE 2 recommended that sponsors perform an Sodium oxychlorosene ...... IIISE measures (Refs. 21, 22, and 23). array of trials to look simultaneously at Tribromsalan ...... II Hospital-acquired infections can result the effect on the surrogate endpoint and Calomel, oxyquinoline benzoate, II in prolonged hospital stays, additional the clinical endpoint to try to establish triethanolamine, and phenol de- medical treatment, adverse clinical a link between the surrogate and clinical rivative. outcomes, and increased health care endpoints, but provided no guidance on Mercufenol chloride and sec- IIISE costs (Refs. 24 through 27). The reliance possible study designs. We have not ondary amyltricresols in 50 per- on antiseptics in the clinical setting goes seen any studies of this type. The March cent alcohol. back over 150 years when, in the mid- 2005 NDAC also believed that it would Triple dye ...... II 1800s, Semmelweis observed that the be unethical to perform a hospital trial 1 ‘‘II’’ denotes that an active ingredient has mortality associated with childbed fever using a vehicle control instead of an been shown to be unsafe, ineffective, or both. at the General Hospital in Vienna could antiseptic. Although the NDAC thought

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that performing a placebo-controlled control strategies (Refs. 21, 23, and 30). determined after use of the test product. study for routine patients on the ward As is the case for consumer antiseptics, This contamination and hand wash might be feasible, it stated that the we lack clinical outcome data from procedure is repeated several times, and Centers for Disease Control and adequate studies demonstrating the bacterial reductions are measured at Prevention hand hygiene guidelines and impact of health care antiseptics on various time points. This aspect of the hospital accreditation requirements infection rates. Given this, FDA faces study design is intended to mimic the would prohibit such a practice. The the challenge of regulating this repeated use of the product (59 FR NDAC also believed that an institutional important component of current 31402 at 31448). review board would not approve a hospital infection control measures The testing proposed in the 1994 TFM hospital trial that did not involve an without methods to directly assess their for surgical hand scrubs and patient antiseptic. clinical effect. We nonetheless need a preoperative skin preparations involves We agree that a clinical outcome practical means to assess the general testing against resident skin microflora study in the health care setting raises recognition of effectiveness of health (bacteria that normally colonize the ethical concerns. For a clinical outcome care products, such as the clinical skin), and there is no artificial study to be adequately controlled the simulation studies. contamination of the skin in these study design would need to include a As discussed in section VI.A, we studies. Testing demonstrates that the vehicle or negative control arm. evaluated all the available effectiveness resident bacterial load is highly variable However, the inclusion of such control studies for health care antiseptics (i.e., among individuals within the general arms in a clinical outcome study health care personnel hand washes and population (Refs. 31 and 32). Although conducted in a hospital setting could rubs, surgical hand scrubs and rubs, and the 1994 TFM methods specify a pose an unacceptable health risk to patient preoperative skin preparations) minimum bacterial count for study subjects (hospitalized patients to determine whether the data individuals to be included in the and health care providers). In such supported finding the health care assessment of surgical hand scrubs and studies a vehicle or negative control antiseptic active ingredient to be GRAE patient preoperative skin preparations, would be a product with no based on the 1994 TFM effectiveness there can be considerable intersubject antimicrobial activity. The use of a criteria (which we are now proposing to variability. Similar to the health care nonantimicrobial product in a hospital update). We found that the available personnel hand washes, the testing of a setting (a setting with an already studies are not adequate to support a surgical hand scrub proposed in the elevated risk of infections) could GRAE determination for any health care 1994 TFM involves multiple test increase the risk of infection for both antiseptic active ingredient under the product uses and the repeated health care providers and their patients. 1994 TFM effectiveness criteria (59 FR measurement of bacterial reductions to Thus, it is generally considered 31402 at 31445, 31448, and 31450).2 determine both immediate and unethical to perform placebo-controlled persistent antimicrobial activity (59 FR clinical studies to show the value of A. Evaluation of Effectiveness Data 31402 at 31445). The patient health care antiseptics (Ref. 8). Based on 1. Clinical Simulation Studies preoperative skin preparation test these considerations NDAC evaluates a single application of the recommended the continued use of Most of the data available to support product on a dry skin site (abdomen or clinical simulation studies to validate the effectiveness of health care back) and a moist skin site (groin or the effectiveness of health care antiseptics are based on clinical axilla) with higher numbers of resident antiseptics. simulation studies, such as the ones bacteria (59 FR 31402 at 31450). The FDA has relied upon clinical described in the 1994 TFM (59 FR effectiveness criteria for patient simulation studies to support the 31402 at 31444). In vivo test methods, preoperative skin preparations and approval of health care antiseptics such as clinical simulation studies, and surgical hand scrubs proposed in the through the NDA process. Although it is evaluation criteria proposed in the 1994 1994 TFM also require that bacterial not possible to quantify the contribution TFM are based on the premise that growth be suppressed for 6 hours (59 FR of NDA health care antiseptics to bacterial reductions achieved using tests 31402 at 31445 and 31450). reduced hospital infection rates, in that simulate conditions of actual use We evaluated all clinical simulation general, infection rates in the United for each OTC health care antiseptic studies that were submitted to the OTC States are low. For example, only 2 to product category reflect the bacterial Drug Review for evidence of health care 5 percent of over 40 million inpatient reductions that would be achieved personnel hand antiseptic, surgical surgical procedures each year are under conditions of such use. For hand antiseptic, and patient complicated by surgical site infections example, one of the intended purposes preoperative skin preparation (Ref. 29). We acknowledge that the use of a health care personnel hand wash is effectiveness demonstrated under the of surrogate endpoints to assess the to reduce the risk of patient-to-patient log reduction criteria proposed in the effectiveness of these products is not cross contamination. Thus, the clinical 1994 TFM (59 FR 31402 at 31445, optimal, but we believe it is the best simulation studies proposed in the 1994 31448, and 31450) (Ref. 33). We also means available of assessing the TFM are designed to demonstrate searched the published literature for effectiveness of health care antiseptic effectiveness of a product in the clinical simulation studies that assess products. presence of repeated bacterial challenge. health care personnel hand antiseptic, Thus, we are continuing to rely on The hands are artificially contaminated surgical hand antiseptic, and patient surrogate endpoints to evaluate the with a marker organism (bacteria), and preoperative skin preparation effectiveness of health care antiseptics the reduction from the baseline numbers effectiveness using the log reduction while requiring data from clinical of the contaminating organism is criteria in the 1994 TFM (Refs. 33 outcome studies to support the through 36). effectiveness of consumer antiseptics 2 We note that alcohol, isopropyl alcohol, and Overall, the studies used a variety of (78 FR 76444 at 76450). Unlike some iodine-containing active ingredients were study designs, including nonstandard proposed as GRAE in the 1994 TFM; however, the consumer antiseptics, however, health studies that supported that proposal do not meet study designs. In some cases, such as for care antiseptics are considered an our current standards for adequate and well- surgical hand antiseptics, data integral part of hospital infection controlled studies. See discussion in section VI.A.1. submitted to the OTC Drug Review was

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in the form of abstracts and technical evaluated all the clinical outcome premise that bacterial reductions can be reports. There is insufficient studies that were submitted to the OTC adequately demonstrated using tests information to evaluate the scientific Drug Review to look for evidence of a that simulate conditions of actual use merit of studies described in abstracts clinical benefit from the use of health for each OTC health care antiseptic and technical reports. Most importantly, care antiseptics (Ref. 33). In addition, product category and that those none of the evaluated studies were we searched the published literature for reductions are reflective of bacterial adequately controlled to demonstrate clinical outcome studies that would reductions that would be achieved the contribution of the active ingredient provide evidence of a clinical benefit during use. (See discussion in section to the effectiveness observed in the from the use of a health care antiseptic B.2.) Given the limitations of our ability studies (43 FR 1210 at 1240) and, (Ref. 37). Most of these studies were to study these active ingredients in a therefore, cannot be used to demonstrate designed to evaluate health care worker clinical outcome study in a health care that the active ingredient tested is compliance with hand hygiene setting, a GRAE determination for a GRAE. protocols, and thus, were not adequately health care antiseptic active ingredient In general, the evaluated studies also controlled to demonstrate a reduction of should be supported by an adequate had other deficiencies. Each study had infection rates. Most importantly, none characterization of the antimicrobial at least one of the following of the studies used a vehicle control. In activity of the ingredient through both deficiencies: general, the studies had additional in vitro testing and in vivo clinical • Some studies that were described as design flaws such as the following: simulation testing. using a standardized method (American • A small sample size. 1. In Vitro Studies Society for Testing and Materials • A lack of randomization, blinding, (ASTM) or 1994 TFM) varied from these or both. The 1994 TFM proposed that the methods without explanation or • Inadequate statistical power and, in antimicrobial activity of an active validation, and the majority of studies some cases, a failure to analyze results ingredient could be demonstrated in did not provide sufficient information for statistical significance. vitro by a determination of the in vitro about critical aspects of the study • Inadequate description of spectrum of antimicrobial activity, conduct. methodology and data collection minimum inhibitory concentration • Many studies did not include methods. (MIC) testing against 25 fresh clinical appropriate controls; for example, some • Inadequate documentation of isolates and 25 laboratory strains, and studies did not include a vehicle control proper training in hand wash or rub, time-kill testing against 23 laboratory or an active control (59 FR 31402 at surgical hand scrub or rub, or patient strains (59 FR 31402 at 31444). 31446, 31448, and 31450), and some preoperative skin preparation Comments received in response to the studies that included an active control technique. 1994 TFM objected to the proposed in failed to use the control product • Failure to observe and document vitro testing requirements, stating that according to its labeled directions (59 hand washing technique. they were overly burdensome (Ref. 38). • FR 31402 at 31446, 31448, and 31450). Inadequate controls to address the Consequently, submissions of in vitro • Many studies did not provide multifactorial nature of surgical site data submitted to support the sufficient detail concerning neutralizer infection. effectiveness of antiseptic active use (43 FR 1210 at 1244) or validation • Some patients received antibiotic ingredients were far less extensive than of neutralizer effectiveness. treatment and others did not. what was proposed in the 1994 TFM • The studies evaluated a small • Some studies addressed (Ref. 39). Although we agree that the in number of subjects (59 FR 31402 at nonmonograph indications. vitro testing proposed in the 1994 TFM 31446, 31449, and 31451). As discussed in section VI, the March is overly burdensome for testing every • Some studies did not sample at all 2005 NDAC agreed that there are final formulation of an antiseptic of the time points specified by the test currently no clinical trials presented product that contains a GRAE method (59 FR 31402 at 31446, 31448, that showed any clinical benefit. The ingredient, we continue to believe that and 31450). committee stated that conducting such a a GRAE determination for a health care • In the case of patient preoperative study in the hospital setting would be antiseptic active ingredient should be skin preparation studies, some studies unethical, especially considering the supported by adequate in vitro used subjects with baseline values that need to introduce a placebo or vehicle characterization of the antimicrobial were too low and other studies did not control to show contribution of an activity of the ingredient. In addition, provide baseline values at all (59 FR antiseptic drug product. This would put we now propose the option of assessing 31402 at 31451). Many of the studies the subjects’ health at risk. the minimum bactericidal concentration (MBC) as an alternative to testing the only tested one type of test site (dry or B. Current Standards: Studies Needed moist), but the 1994 TFM (as well as the MIC to demonstrate the broad spectrum To Support a Generally Recognized as activity of the antiseptic. The ability of testing proposed here) requires testing Effective Determination of both dry and moist test sites to an antiseptic to kill microorganisms, demonstrate effectiveness (59 FR 31402 In the 1994 TFM, we proposed that rather than inhibit them, is more at 31450). the effectiveness of antiseptic active relevant for a topical product. Because FDA’s detailed evaluation of the data ingredients could be supported by a the determination of GRAE status is a is filed in Docket No. FDA–2015–N– combination of in vitro studies and in very broad statement that can apply to 0101, available at http:// vivo clinical simulation testing as many different formulations of an active www.regulations.gov (Refs. 33 through described in 21 CFR 333.470 (59 FR ingredient, we continue to propose that 36). 31402 at 31444). In vitro studies are an evaluation of the spectrum and designed to demonstrate the product’s kinetics of antimicrobial activity of a 2. Clinical Outcome Studies spectrum and kinetics of antimicrobial health care antiseptic active ingredient Although we are not currently activity, as well as the potential for the should include the following: proposing to require clinical outcome development of resistance associated • A determination of the in vitro studies to support a GRAE with product use. In vivo test methods spectrum of antimicrobial activity determination in this proposal, FDA has and evaluation criteria are based on the against recently isolated normal flora

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and cutaneous pathogens (59 FR 31402 the approval of NDA antiseptic products To establish that a particular active at 31444). and input from the March 2005 NDAC, ingredient is GRAE for use in health • MIC or MBC testing of 25 we recommend that the bacterial log care antiseptics, clinical simulation representative clinical isolates and 25 reduction studies used to demonstrate studies using the parameters described reference (e.g., American Type Culture that an active ingredient is GRAE for use in this section should be evaluated Collection) strains of each of the in health care antiseptic drug products using log reduction criteria similar to microorganisms listed in the 1994 TFM include the following: those proposed in the 1994 TFM (59 FR (59 FR 31402 at 31444). • A vehicle control to show the 31402 at 31445, 31448, and 31450). Our • Time-kill testing of each of the contribution of the active ingredient to current criteria are laid out in table 8. microorganisms listed in the 1994 TFM effectiveness. The test product should We have revised the log reduction (59 FR 31402 at 31444) to assess how be statistically superior to the vehicle criteria proposed for health care rapidly the antiseptic active ingredient control for the clinical simulation to be personnel hand washes and rubs, and produces its effect. The dilutions and considered successful at showing that surgical hand scrubs and rubs based on time points tested should be relevant to the test product is effective for use in the recommendations of the March 2005 the actual use pattern of the final health care antiseptic products. NDAC and comments to the 1994 TFM product. Products with vehicles that have that argued that the demonstration of a Despite the fact that the in vitro data antimicrobial activity should consider cumulative antiseptic effect for these submitted to support the effectiveness of using a negative control, such as products is unnecessary. We agree that antiseptic active ingredients were far nonantimicrobial soap or saline, rather the critical element of effectiveness is less extensive than proposed in the 1994 than a vehicle control. that a product must be effective after the TFM, manufacturers may have data of • An active control to validate the first application because that represents this type on file from their own product study conduct to assure that the the way in which health care personnel development programs that has not been expected results are produced. For the hand washes and rubs and surgical submitted to the rulemaking. results to be valid, the active control hand scrubs and rubs are used. For Furthermore, published data may be should meet the appropriate log these indications, log reduction criteria available that would satisfy some or all reduction criteria. are proposed only for a single-product of this data requirement. • application rather than multiple- A sample size large enough to show product applications. Given that we are 2. In Vivo Studies statistically significant differences from no longer requiring a cumulative Based on the recommendations of the results achieved using the vehicle, antiseptic effect, the log reduction NDAC at its March 23, 2005, meeting, and meeting the threshold of at least a criteria were revised to reflect this we are continuing to propose the use of 70 percent success rate for the health single product application and fall bacterial log reductions as a means of care antiseptic, including justification between the log reductions previously demonstrating that health care that the number of subjects tested is proposed for the first and last antiseptics are GRAE (Ref. 8). The 1994 adequate for the test. applications. The GRAE criteria TFM also proposed final formulation • Use of an appropriate neutralizer in proposed for all the health care testing for health care personnel hand all recovery media (i.e., sampling antiseptic indications are based on log washes (59 FR 31402 at 31448), surgical solution, dilution fluid, and plating reductions achieved by antiseptics as hand scrubs (59 FR 31402 at 31445), and media) and a demonstration of shown in the published literature and patient preoperative skin preparations neutralizer validation. The purpose of evaluated under the NDA process. In (59 FR 31402 at 31450). We do not neutralizer validation is to show that the addition, based on the timeframes discuss final formulation testing here neutralizer used in the study is effective within which patient preoperative skin because we are not proposing that any against the test and control products, preparations are commonly used, we are of the active ingredients are GRAS/ and that it is not toxic to the test recommending that these products also GRAE. Although these proposed test microorganisms. If a test product can be be able to demonstrate effectiveness at methods are intended to evaluate the neutralized through dilution, this 30 seconds because we believe that effectiveness of antiseptic final should be demonstrated in the injections and some incisions might be formulations, this type of clinical neutralizer validation study. made as soon as 30 seconds after skin simulation testing when adequately • An analysis of the proportion of preparation. The log reductions that we controlled also can be used to subjects who meet the log reduction would expect an effective health care demonstrate that an active ingredient is criteria based on a two-sided statistical antiseptic active ingredient to meet to GRAE for use in a health care antiseptic test for superiority to vehicle and a 95 show that it is GRAE are shown in table product. Based on our experience with percent confidence interval approach. 8.

TABLE 8—CLINICAL SIMULATION TESTING BACTERIAL LOG REDUCTION EFFECTIVENESS CRITERIA IN THIS PROPOSED RULE AND IN THE 1994 TFM

Indication 1994 TFM This proposed rule

Health care personnel hand wash or health • reduction of 2 log10 on each hand within 5 reduction of 2.5 log10 on each hand within 5 care personnel hand rub. minutes after the first wash, and minutes after a single wash or rub. • reduction of 3 log10 on each hand within 5 minutes after the tenth wash.

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TABLE 8—CLINICAL SIMULATION TESTING BACTERIAL LOG REDUCTION EFFECTIVENESS CRITERIA IN THIS PROPOSED RULE AND IN THE 1994 TFM—Continued

Indication 1994 TFM This proposed rule

Surgical hand scrub or surgical hand rub ...... • reduction of 1 log10 on each hand within 1 • reduction of 2 log10 on each hand within 1 minute after the first wash on day 1, and minute after a single wash or rub, and • does not exceed baseline at 6 hours on day • does not exceed baseline at 6 hours. 1, and. • reduction of 2 log10 on each hand within 1 minute after the last wash on day 2, and • reduction of 3 log10 on each hand within 1 minute after the last wash on day 5. Patient preoperative skin preparation ...... • reduction of 2 log10 per square centimeter • reduction of 2 log10 per square centimeter on abdominal site within 10 minutes after on abdominal site within 30 seconds after use, and use, and • reduction of 3 log10 per square centimeter • reduction of 3 log10 per square centimeter on groin site within 10 minutes after use, on groin site within 30 seconds after use, and and • does not exceed baseline at 6 hours ...... • does not exceed baseline at 6 hours.

VII. Safety (Generally Recognized as Pharmaceuticals for Human Use (ICH).3 rubs or surgical hand rubs (Refs. 1, 4, Safe) Determination A use is considered chronic if the drug and 5). We believe that any will be used for a period of at least 6 consequences of this systemic exposure In the 1994 TFM, 11 active months over the user’s lifetime, should be identified and assessed to ingredients were classified as GRAS for including repeated, intermittent use support our risk-benefit analysis for both health care personnel hand wash (Ref. 40). Health care personnel washes health care antiseptic use. and surgical hand scrub use, and 18 and rubs are used on a frequent daily Given the frequent repeated use of active ingredients were classified as basis, as are surgical hand scrubs and both health care personnel hand washes GRAS for patient preoperative skin rubs. Health care authorities list a and rubs and surgical hand scrubs and preparation use (59 FR 31402 at 31435). variety of situations in which health rubs, systemic exposure may occur. For As described in section I.C., health care care workers should perform hand some patients, the same may be true for personnel hand rubs and surgical hand hygiene, such as before and after patient preoperative skin preparations. rubs were not separately addressed in touching a patient, after contact with Although some systemic exposure data the 1994 TFM. There have since been a body fluids, and after removing gloves exist for alcohol and triclosan, many of number of important scientific (Refs. 21 and 23). Patient preoperative the other health care antiseptic active developments affecting our evaluation skin preparations also are used daily by ingredients have not been evaluated in of the safety of these active ingredients many users. For example, many people this regard. Currently, there is also a and causing us to reassess the data with type I diabetes require three to four lack of data to assess the impact of necessary to support a GRAS insulin injections a day (Ref. 41) and important drug use factors that can influence systemic exposure such as determination. There is now new use these products prior to each dose, application frequency, application information regarding systemic injection. Accordingly, we are proposing the same safety testing for method, duration of exposure, product exposure to antiseptic active ingredients formulation, skin condition, and age. (Refs. 1 through 5). The potential for each active ingredient be done to support a GRAS determination, The evaluation of the safety of drug widespread antiseptic use to promote products involves correlating findings the development of antibiotic-resistant regardless of the proposed health care antiseptic use. from animal toxicity studies to the level bacteria also needs to be evaluated. of drug exposure obtained from Further, additional experience with and A. New Issues pharmacokinetic studies in animals and knowledge about safety testing has led Since the 1994 TFM was published, humans. Our administrative record to improved testing methods. new data have become available lacks the data necessary to define a Improvements include study designs indicating that systemic exposure to margin of safety for the potential that are more capable of detecting topical antiseptic active ingredients may chronic use of health care antiseptic potential safety risks. Based on our be greater than previously thought. active ingredients. Thus, we are reassessment, we are proposing new Systemic exposure refers to the presence continuing to propose that both animal GRAS data standards for health care of antiseptic active ingredients inside and human pharmacokinetic data are antiseptic active ingredients. In order to and throughout the body. Because of necessary for health care antiseptic fully address these new safety concerns, advances in technology, our ability to active ingredients. This information will additional safety data will be necessary detect antiseptic active ingredients in help identify any potential safety to support a GRAS determination for all body fluids such as serum and urine is concerns and help determine the safety health care antiseptic active ingredients. greater than it was in 1994. For margin for OTC human use. One potential effect of systemic example, studies have shown detectable Many of the safety considerations for exposure to health care antiseptic active blood alcohol levels after use of alcohol- the five health care antiseptic uses are ingredients that has come to our containing health care personnel hand the same because each use is considered attention since publication of the 1994 a ‘‘chronic’’ use as that term is defined TFM is data suggesting that some health 3 by the International Conference on FDA is a member of the ICH Steering care antiseptic active ingredients have Harmonisation of Technical Committee, the governing body that oversees the harmonization activities, and contributed to the hormonal effects. Triclosan and Requirements for Registration of development of ICH guidelines. triclocarban can cause alterations in

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thyroid and reproductive systems of disinfection, it is difficult to identify the surveillance mechanisms to address neonatal and adolescent animals (Refs. source of antimicrobial resistance or to antiseptic and antibiotic resistance. FDA 42 through 51). Hormonally active quantify the impact of antiseptics on the also plays a major role on the compounds have been shown to affect selection, survival, and spread of Interagency Task Force on not only the exposed organism, but also antimicrobial resistant bacterial strains. Antimicrobial Resistance and helped subsequent generations (Ref. 52). These Laboratory studies of some of the draft the Public Health Action Plan to effects may not be related to direct antiseptic active ingredients evaluated Combat Antimicrobial Resistance (Ref. deoxyribonucleic acid (DNA) mutation, in this proposed rule demonstrate that 88). The Action Plan discusses how to but rather to alterations in factors that bacteria can develop reduced sufficiently implement the surveillance, regulate gene expression (Ref. 53). susceptibility to antiseptic active prevention and control, and research A hormonally active compound that ingredients and some antibiotics after elements of the Action Plan. causes reproductive system disruption growth in nonlethal amounts of the Reports of the persistence of low in the fetus or infant may have effects antiseptic (i.e., low-to-moderate levels of some antiseptic active that are not apparent until many years concentrations of antiseptic) (Refs. 61 ingredients in the environment (Refs. after initial exposure. There are also through 78). These studies indicate that 89, 90, and 91) signal the need to better critical times in fetal development when further data needs to be gathered understand the impact of all antiseptics, a change in hormonal balance that regarding whether bacterial resistance including health care antiseptic drug would not cause any lasting effect in an mechanisms exist that could select for products. Although it is important to adult could cause a permanent cross-resistance in the health care consider the relative contribution of the developmental abnormality in a child. setting. use of health care antiseptic products to For example, untreated hypothyroidism Laboratory studies examining the any possible environmental impact, it is during pregnancy has been associated antiseptic and antibiotic susceptibilities also important to consider the benefits with cognitive impairment in the of clinical isolates of Staphylococcus of these products. Hospital-acquired offspring (Refs. 54, 55, and 56). aureus and methicillin-resistant S. infections can result in prolonged Because health care antiseptics are aureus (MRSA) have found strains of hospital stays, additional medical chronic use products and are used by these organisms with reduced treatment, adverse clinical outcomes, sensitive populations such as pregnant susceptibilities to both antiseptics and and increased health care costs. The use women, evaluation of the potential for antibiotics (Refs. 67 and 79 through 83). of health care antiseptics is considered chronic toxicity and effects on However, the impact of such dual an important component of the reproduction and development should tolerances in the clinical setting is multifaceted approach that hospitals use be included in the safety assessment. unclear. Studies of the impact of such to keep hospital acquired infection rates The designs of general toxicity and tolerance in S. aureus and Escherichia low (Refs. 21 and 23). Furthermore, in reproductive/developmental studies are coli in the clinical setting have yielded situations where there is extensive use often sufficient to identify mixed results (Refs. 84 through 87). of antibiotics, exposure to antibiotics, developmental effects that can be Interpretation of these data is further rather than exposure to antiseptics, caused by hormonally active limited by the fact that only S. aureus plays a dominant role in emerging compounds through the use of currently and E. coli have been studied. All of the antibiotic resistance. This makes it accepted endpoints and standard good organisms studied constitute a very difficult to determine whether laboratory practice toxicology study small subset of the organisms of antiseptics play a significant role in the designs. As followup in some cases, concern, and one of these organisms development of antimicrobial resistance additional study endpoints may be (MRSA) is already resistant to some in the hospital setting. Despite this, the needed to fully characterize the antimicrobials. Thus, the available data use of antiseptics in health care settings potential effects of drug exposure on the are not sufficient to support a finding may also contribute to the selection of exposed individuals. Section VII.C that these mechanisms of reduced bacterial genera and species that are less describes the types of studies that can susceptibility would have meaningful susceptible to both antiseptics and adequately evaluate an active clinical impact in a setting where antibiotics. We are requesting additional ingredient’s potential to cause extensive infection control measures data and information to address this developmental or reproductive toxicity, that include antibiotic use and frequent issue. Section VII.C describes the data or adverse effects on the thyroid gland. disinfection are the norm. In other that will help establish a better words, bacteria in the health care setting B. Antimicrobial Resistance understanding of the interactions will be exposed to multiple sources of between antiseptic active ingredients Since publication of the 1994 TFM, antimicrobials—regardless of the use of and bacterial resistance mechanisms in there is new information available health care antiseptics—which may health care antiseptic products and will concerning the impact of widespread lessen the impact of the role of health provide the information needed to antiseptic use on the development of care antiseptics in the development of perform an adequate risk assessment for antimicrobial resistance (Refs. 57 bacterial resistance. these health care product uses. FDA through 60). Bacteria use some of the FDA has been evaluating the role that recognizes that the science of evaluating same resistance mechanisms against all antiseptic products, including health the potential of compounds to cause both antiseptics and antibiotics. Thus, care antiseptic products, may play in bacterial resistance is evolving and the use of antiseptic active ingredients the development of antibiotic resistance acknowledges the possibility that with resistance mechanisms in common for quite some time, and has sought the alternative data different from that listed with antibiotics may have the potential advice from expert panels on this topic. in section VII.C may be identified as an to select for bacterial strains that are In 1997, a joint Nonprescription Drugs appropriate substitute for evaluating also resistant to clinically important and Anti-Infective Drugs Advisory resistance. antibiotics, adding to the problem of Committee concluded that the data were antibiotic resistance. In the health care not sufficient to take any action on this C. Studies To Support a Generally setting where infection-control practices issue at that time (Ref. 6). The joint Recognized as Safe Determination are multifaceted and include the use of Committee recommended that FDA A GRAS determination for health care antiseptics, antibiotics, and frequent work with industry to establish antiseptic active ingredients must be

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supported by both nonclinical (animal) when seeking to market a drug product 1. FDA Guidances Describing Safety and clinical (human) studies. To issue a under an NDA (Refs. 40 and 92 through Studies final monograph for these products, this 98). These guidance documents also safety data must be in the administrative provide relevant guidance for The safety studies that are described record (i.e., rulemaking docket).4 performing the nonclinical studies in the existing FDA guidances (Refs. 40 To assist manufacturers or others who necessary to determine GRAS status for and 92 through 98) provide a framework wish to provide us with the information a health care antiseptic active for the types of studies that are needed we expect will establish GRAS status for ingredient. Because health care for FDA to assess the safety of each these active ingredients, we are antiseptics may be used repeatedly and antiseptic active ingredient according to including specific information, based in in sensitive populations, we propose modern scientific standards and make a part on existing FDA guidance, about that health care antiseptic active GRAS determination. A description of the other kinds of studies to consider ingredients will need to be tested for each type of study and how we would conducting and submitting. We have carcinogenic potential, developmental use this information to improve our published guidance documents and reproductive toxicity (DART), and understanding of the safety of health describing the nonclinical safety studies other potential effects as described in care antiseptic active ingredients is that a manufacturer should perform more detail in this section. provided in table 9.

TABLE 9—FDA GUIDANCE DOCUMENTS RELATED TO REQUESTED SAFETY DATA AND RATIONALE FOR STUDIES

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

Animal pharmacokinetic Both oral and dermal ad- Allows identification of the dose at which Used as a surrogate to identify toxic sys- absorption, distribution, ministration. the toxic effects of an active ingredient temic exposure levels that can then be metabolism, and excre- are observed as a result of systemic ex- correlated to potential human exposure tion (ADME) (Refs. 93 posure of the drug. ADME data provide: via dermal pharmacokinetic study find- and 99). The rate and extent an active ingredient ings. Adverse event data related to par- is absorbed into the body (e.g., AUC, ticular doses and drug levels (exposure) Cmax, Tmax); 1 where the active ingre- in animals are used to help formulate a dient is distributed in the body; whether safety picture of the possible risk to hu- metabolism of the active ingredient by mans. the body has taken place; information on the presence of metabolites; and how the body eliminates the original active ingredient (parent) and its metabolites (e.g., T1⁄2). 2. Human pharmacokinetics Dermal administration Helps determine how much of the active Used to relate the potential human expo- (MUsT) (Ref. 97). using multiple formula- ingredient penetrates the skin, leading to sure to toxic drug levels identified in ani- tions under maximum measurable systemic exposure. mal studies. use conditions. Carcinogenicity (ICH S1A, Minimum of one oral and Provides a direct measure of the potential Identifies the systemic and dermal risks S1B, and S1C (Refs. one dermal study for for active ingredients to cause tumor for- associated with drug active ingredients. 40, 92, and 95)). topical products. mation (tumorogenesis) in the exposed Taken together, these studies are used animals. to identify the type(s) of toxicity, the level of exposure that produces these toxicities, and the highest level of exposure at which no adverse effects occur, referred to as the ‘‘no observed adverse effect level’’ (NOAEL). The NOAEL is used to determine a safety margin for human exposure. Developmental toxicity Oral administration ...... Evaluates the effects of a drug on the de- (ICH S5 (Ref. 94)). veloping offspring throughout gestation and postnatally until sexual maturation. Reproductive toxicity (ICH Oral administration ...... Assesses the effects of a drug on the re- S5 (Ref. 94)). productive competence of sexually ma- ture male and female animals. Hormonal effects (Ref. Oral administration ...... Assesses the drug’s potential to interfere Used in hazard assessment to determine 98). with the endocrine system. whether the drug has the capacity to induce a harmful effect at any exposure level without regard to actual human exposures. 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.

These studies represent FDA’s current similar to those recommended by the 2014 NDAC. However, even before the thinking on the data needed to support Antimicrobial I Panel (described in the 2014 NDAC meeting, the Panel’s a GRAS determination for an OTC ANPR (39 FR 33103 at 33135)) as recommendations for data to support antiseptic active ingredient and are updated by the recommendations of the the safety of an OTC topical

4 At the 2014 NDAC meeting, FDA received to the docket for this rulemaking and we are not the GRAS/GRAE status of a relevant ingredient. comments referencing data or other information aware that it is otherwise publicly available. The Information about how to submit such data or that appears to be relevant to the safety assessment Agency will consider only material that is information to the docket is set forth in this of health care antiseptic active ingredients, but the submitted to the docket for this rulemaking or that document in the ADDRESSES section. referenced data and information were not submitted is otherwise publicly available in its evaluation of

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antimicrobial active ingredient included • duration of dosing (e.g., dosing to Most antiseptic active ingredients studies to characterize the following: represent an 8- to 12-hour health care have not been evaluated for hormonal • Degree of absorption through intact worker shift); effects despite the fact that several of the and abraded skin and mucous • use of highest proposed strength ingredients have evidence of systemic membranes (e.g., 95 percent alcohol); absorption. For antiseptic active • Tissue distribution, metabolic rates, • total involved surface area to be ingredients that have not been metabolic fates, and rates and routes treated at one time (e.g., hands and arms evaluated, in vitro receptor binding or of elimination up to the elbow for surgical hand scrubs enzyme assays can provide a useful • Teratogenic and reproductive effects and rubs); preliminary assessment of the potential • Mutagenic and carcinogenic effects • amount applied per square hormonal activity of an ingredient. centimeter However, these preliminary assays do 2. Studies To Characterize Maximal • Human Exposure method of application (e.g., hand not provide conclusive evidence that rub or hand wash); and such an interaction will lead to a Because the available data indicate • sensitive and validated analytical significant biological change (Ref. 103). that some dermal products, including at methods. Conversely, lack of binding does not least some antiseptic active ingredients, It also is important that the MUsT rule out an effect (e.g., compounds are absorbed after topical application in reflect maximal use conditions of health could affect synthesis or metabolism of humans and animals, it is necessary to care antiseptics (Ref. 101) using a hormone, resulting in drug-induced assess the effects of long-term dermal different formulations to fully changes in hormone levels indirectly). and systemic exposure to these characterize the active ingredient’s a. Traditional studies. General ingredients. Based on input from the potential for dermal penetration. Since nonclinical toxicity and reproductive/ 2014 NDAC meeting, the Agency has real-world exposure from health care developmental studies such as the ones also determined that results from a personnel hand wash and rub and described in this section are generally human pharmacokinetic (PK) maximal surgical hand scrub and rub use is likely sufficient to identify potential hormonal usage trial (MUsT) are needed to to be greater than from patient effects on the developing offspring. support a GRAS determination. This preoperative skin preparation use, Developmental and reproductive trial design is also referred to as a MUsT data on an active ingredient for toxicity caused by hormonal effects will maximal use PK trial and is described either of these indications also would be generally be identified using these in FDA’s 2005 draft guidance for sufficient to fulfill the MUsT traditional studies if the tested active industry on developing drugs for requirement for a patient preoperative ingredient induces a detectable change treatment of acne vulgaris (Ref. 97). The skin preparation. in the hormone-responsive tissues purpose of the MUsT is to evaluate typically evaluated in the traditional 3. Studies To Characterize Hormonal systemic exposure under conditions that toxicity study designs. would maximize the potential for drug Effects Repeat-dose toxicity (RDT) studies. absorption in a manner consistent with We propose that data are also needed RDT studies typically include a variety possible ‘‘worst-case’’ real world use of to assess whether health care antiseptic of endpoints, such as changes in body the product. In a MUsT, the collected active ingredients have hormonal effects weight gain, changes in organ weights, plasma samples are analyzed, and the that could produce developmental or gross organ changes, clinical chemistry resulting in vivo data could be used to reproductive toxicity. A hormonally changes, or histopathology changes, estimate a safety margin based on active compound is a substance that which can help identify adverse animal toxicity studies. interferes with the production, release, hormonal effects of the tested drug. A MUsT to support a determination transport, metabolism, binding, activity, Also, the battery of organs typically that an active ingredient is GRAS for use or elimination of natural hormones, collected for histopathological in health care antiseptics is conducted which results in a deviation from evaluation in RDT studies includes by obtaining an adequate number of PK normal homeostasis, development, or reproductive organs and the thyroid samples following administration of the reproduction (Ref. 102). Exposure to a gland, which can indicate potential active ingredient. For studies of active hormonally active compound early in adverse hormonal effects. For example, ingredients to be used in topically development can result in long-term or estrogenic compounds can produce applied products like these that are used delayed effects, including effects such as increased ovarian weight primarily on adults, for which there is neurobehavioral, reproductive, or other and stimulation, increased uterine less information available and for which adverse effects. weight and endometrial stimulation, crossover designs are not feasible, a There are several factors common to mammary gland stimulation, decreased larger number of subjects are required antiseptic products that make it thymus weight and involution, or compared to studies of orally necessary to assess their full safety increased bone mineral density. administered drug products. A MUsT profile prior to classifying an antiseptic DART studies. Some developmental using 50 to 75 subjects should be active ingredient as GRAS for use in stages that are evaluated in DART sufficient to get estimates of the PK health care antiseptic products. These studies, such as the gestational and parameters from a topically applied factors are as follows: neonatal stages, may be particularly health care antiseptic. The MUsT • Evidence of systemic exposure to sensitive to hormonally active should attempt to maximize the several of the antiseptic active compounds. Note, however, that potential for drug absorption to occur by ingredients. traditional DART studies capture considering the following design • Exposure to multiple sources of gestational developmental time points elements (Ref. 100): antiseptic active ingredients that may be effectively, but are less adequate for • Adequate number of subjects (steps hormonally active compounds, in evaluation of effects on postnatal should be taken to ensure that the target addition to exposure to health care development. Endpoints in pre/ population (for example, age, gender, antiseptic products. postnatal DART studies that may be race) is properly represented); • Exposure to antiseptic active particularly suited for detecting • frequency of dosing (e.g., number of ingredients may be long-term for some hormonal effects include vaginal hand rub applications during the study); health care professionals. patency, preputial separation,

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anogenital distance, and nipple of development, includes the pubertal effects of antiseptic exposure on the retention. Behavioral assessments (e.g., period in which the animal reaches bacteria that are predominant in the oral mating behavior) of offspring may also puberty and undergoes important cavity, gut, skin flora, and the detect neuroendocrine effects. growth landmarks. In mammals, puberty environment (Ref. 113). These Carcinogenicity studies. A variety of is a period of rapid morphological organisms represent pools of resistance tumors that result from long-term changes and endocrine activity. Studies determinants that are potentially hormonal disturbance can be detected in pubertal animals are designed to transferable to human pathogens (Refs. in carcinogenicity assays. For example, detect alterations of pubertal 114 and 115). Broader laboratory testing the effect of a persistent disturbance of development, thyroid function, and of each health care antiseptic active particular endocrine gland systems (e.g., hypothalamic-pituitary-gonadal system ingredient would more clearly define hypothalamic-pituitary-adrenal axis) maturation (Ref. 107). the scope of the impact of antiseptic can be detected in these bioassays. In those cases where adverse effects active ingredients on the development Certain hormone-dependent ovarian and are noted on the developing offspring, of antibiotic resistance and provide a testicular tumors and parathyroid FDA intends to conduct a risk-benefit useful preliminary assessment of an hormone-dependent osteosarcoma also analysis based on the dose-response antiseptic active ingredient’s potential can be detected in rodent observed for the findings and the to foster the development of resistance. carcinogenicity bioassays. animal-to-human exposure comparison. Studies evaluating the impact of b. Supplementary studies. If no If such an assessment indicates a antiseptic active ingredients on the signals are obtained in the traditional potential risk to humans, then we will antiseptic and antibiotic susceptibilities RDT, DART, and carcinogenicity include that risk in our risk-benefit of each of the following types of studies, assuming the studies covered analysis in order to determine whether organisms could help support a GRAS all the life stages at which a health care the antiseptic active ingredient at issue determination for antiseptic active antiseptic user may be exposed to such is suitable for inclusion in an OTC ingredients intended for use in OTC products (e.g., pregnancy, infancy, monograph. health care antiseptic drug products: adolescence), then no further • 4. Studies To Evaluate the Potential Human bacterial pathogens; assessment of drug-induced hormonal • nonpathogenic organisms, effects are needed. However, if a Impact of Antiseptic Active Ingredients on the Development of Resistance opportunistic pathogens, and obligate positive response is seen in any of these anaerobic bacteria that make up the animal studies and this response is not Since the 1994 TFM published, the resident microflora of the human skin, adequately understood, then additional issue of antiseptic resistance and gut, and oral cavity; and studies, such as mechanistic studies whether bacteria that exhibit antiseptic • nonpathogenic organisms and involving alternative animal models, resistance have the potential for opportunistic pathogens from relevant may be needed (Refs. 98, 104, 105, and antibiotic cross-resistance has been the environmental sources (e.g., patient 106). For example, juvenile animal subject of much study and scrutiny. One rooms, surgical suites). studies can help address the long-term of the major mechanisms of antiseptic If the results of these studies show no hormonal effects from acute or and antibiotic cross-resistance is continuous exposure to drugs that are changes in bacterial efflux activity at evidence of changes in antiseptic or administered to neonates and children, nonlethal concentrations of the antibiotic susceptibility, then we when these effects cannot be adequately antiseptic (Refs. 66, 69, 76, 108, 109, propose that no further studies predicted from existing data. As an and 110). Efflux pumps are an important addressing the development of alternative to, or in addition to, nonspecific bacterial defense resistance are needed to support a GRAS supplemental nonclinical assessment of mechanism that can confer resistance to determination. hormonal effects, inclusion of endocrine a number of substances toxic to the cell, However, for antiseptic active endpoints (e.g., hormone levels) in including antibiotics (Refs. 111 and ingredients that demonstrate an effect clinical studies can be important to 112). The development of bacteria that on antiseptic and antibiotic clarify the relevance of adverse are resistant to antibiotics is an susceptibilities, additional data will be hormonal effects identified in important public health issue, and necessary to help assess the likelihood nonclinical studies. additional data may tell us whether use that changes in susceptibility observed Juvenile animal studies. Young of antiseptics in health care settings may in the preliminary studies would occur animals are considered juveniles after contribute to the selection of bacteria in the health care setting. Different types they have been weaned. In traditional that are less susceptible to both of data could be used to assess whether DART studies, neonatal animals (pups) antiseptics and antibiotics. Therefore, or not ingredients with positive are typically dosed only until they are we are requesting additional data and laboratory findings pose a public health weaned. If a drug is not secreted via the information to address this issue. risk (Ref. 291). We do not anticipate that mother’s milk, the DART study will not Laboratory studies are a feasible first it will be necessary to obtain data from be able to test the direct effect of the step in evaluating the impact of multiple types of studies for each active drug on the pup. Furthermore, since exposure to nonlethal amounts of ingredient to adequately assess its pups are not dosed after weaning, they antiseptic active ingredients on potential to affect resistance. Such types are not exposed to the drug during the antiseptic and antibiotic bacterial of data could include, but are not juvenile stage of development. A susceptibilities. As discussed in section limited to, the following: juvenile animal toxicity study in which VII.D, some of the active ingredients • Information about the mechanism(s) the young animals are dosed directly evaluated in this proposed rule have of antiseptic action (for example, can be used to evaluate potential drug- laboratory data demonstrating that membrane destabilization or inhibition induced effects on postnatal bacteria have developed reduced of fatty acid synthesis), and whether development for products intended for susceptibility to antiseptic active there is a change in the mechanism of pediatric populations. ingredients and antibiotics after action with changes in antiseptic Pubertal animal studies. The period exposure to nonlethal concentrations of concentration; between the pup phase and the adult the antiseptic active ingredient. • information clarifying the bacteria’s phase, referred to as the juvenile phase However, only limited data exist on the mechanism(s) for the development of

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resistance or reduced susceptibility to antiseptic and antibiotic susceptibilities lists the types of studies available for the antiseptic active ingredient (for of bacteria in areas of prevalent health each antiseptic active ingredient example, efflux mechanisms); care antiseptic use can help demonstrate proposed as Category I or Category III in • data characterizing the potential for whether or not changes in susceptibility the 1994 TFM and indicates whether the reduced antiseptic susceptibility caused are occurring with actual use. Because currently available data are adequate to by the antiseptic active ingredient to be actual use concentrations of health care serve as the basis of a GRAS transferred to other bacteria that are still antiseptics are much higher than the determination. Although we have some sensitive to the antiseptic; MICs for these active ingredients, data data from submissions to the • data characterizing the from compartments where sublethal rulemaking and from information we concentrations and antimicrobial concentrations of biologically active have identified in the literature, our activity of the antiseptic active antiseptic active ingredients may occur administrative record is incomplete for ingredient in biological and (e.g., environmental compartments) can at least some types of safety studies for environmental compartments (for give us a sense of the potential for each of the active ingredients (see table example, on the skin, in the gut, and in change in antimicrobial susceptibilities 10). As noted previously in this environmental matrices); and in these compartments (Refs. 116, 117, document, only information that is part • data characterizing the antiseptic and 118). FDA recognizes, however, that of the administrative record for this and antibiotic susceptibility levels of methods of evaluating this issue are an rulemaking can form the basis of a environmental isolates of bacteria in evolving science and that there may be GRAS/GRAE determination. areas of prevalent health care antiseptic other data appropriate to evaluate the use (for example, patient rooms and We recognize that data and impact of health care antiseptic active surgical suites). information submitted in response to These data can help ascertain whether ingredients on the development of the 2013 Consumer Wash PR may be or not a health care antiseptic active resistance. For this reason, FDA relevant to this proposed rule for those ingredient is likely to induce encourages interested parties to consult active ingredients eligible for use as nonspecific bacterial resistance with the Agency on the specific studies both consumer and health care mechanisms. These data could also help appropriate to address this issue for a antiseptics. At the time of publication of determine the likelihood that changes in particular active ingredient. this proposed rule, FDA’s review of all susceptibility would spread to other D. Review of Available Data for Each submissions made to the 2013 bacterial populations and whether or Antiseptic Active Ingredient Consumer Wash PR had not been not concentrations of health care completed. To be considered in this antiseptics exist in relevant biological We have identified for each health rulemaking, any information relevant to and environmental compartments that care antiseptic active ingredient health care antiseptic active ingredients are sufficient to induce changes in whether the studies outlined in section must be resubmitted under this docket bacterial susceptibilities. Data on the VII.C are publicly available. Table 10 (FDA–2015–N–0101) for consideration.

TABLE 10—SAFETY STUDIES AVAILABLE FOR HEALTH CARE ANTISEPTIC ACTIVE INGREDIENTS 1

Human Animal Oral Dermal Reproduc- Potential 2 pharmaco- pharmaco- Resistance Active ingredient kinetic kinetic carcino- carcino- tive toxicity hormonal potential (MUsT) (ADME) genicity genicity (DART) effects

Alcohol ...... Æ • • • • • • Benzalkonium chloride ...... Æ Æ Benzethonium chloride ...... Æ • Æ Æ Chloroxylenol ...... Æ Æ Æ Æ Hexylresorcinol ...... Æ • Simple iodine solutions Iodine tincture USP ...... Æ • 3 • 3 • • Iodine topical solution USP ...... Æ • 3 • 3 • • Iodine complexes Povidone-iodine ...... 4 Æ 5 • 3 • 3 • • Isopropyl alcohol ...... Æ Æ Æ • Æ • Triclocarban ...... Æ Æ • Æ Æ Triclosan ...... 4 Æ Æ • • Æ Æ 1 Empty cell indicates no data available; ‘‘Æ’’ indicates incomplete data available; ‘‘•’’ indicates available data are sufficient to make a GRAS/ GRAE determination. 2 The following active ingredients are not included in the table because no safety data were submitted or identified since the 1994 TFM: Cloflucarban; combination of calomel, oxyquinoline benzoate, triethanolamine, and phenol derivative; combination of mercufenol chloride and secondary amyltricresols in 50 percent alcohol; fluorosalan; iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate); iodine complex (phosphate ester of alkylaryloxy polyethylene glycol); mercufenol chloride; methylbenzethonium chloride; nonylphenoxypoly (ethyleneoxy) ethanoliodine; phenol (less than 1.5 percent); phenol (greater than 1.5 percent); poloxamer-iodine complex; secondary amyltricresols; sodium oxychlorosene; triple dye; and undecoylium chloride iodine complex. 3 Based on studies of potassium iodide. 4 The change in classification from sufficient data to incomplete data compared to the Consumer Wash PR (78 FR 76444 at 76458) is a reflec- tion of the higher frequency of use in the health care setting. 5 Applies to povidone molecules greater than 35,000 daltons.

In the remainder of this section, we for each of the following health care proposed as GRAS in the 1994 TFM and discuss the existing data and data gaps antiseptic active ingredients that was explain why these active ingredients are

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no longer proposed as GRAS for use in • Methylbenzethonium chloride a. Summary of Alcohol Safety Data health care antiseptics (i.e., why they • Nonylphenoxypoly (ethyleneoxy) are now proposed as Category III): ethanoliodine Alcohol human pharmacokinetic • • Alcohol Phenol (less than 1.5 percent) data. Some published data are available • • Hexylresorcinol Poloxamer-iodine complex to characterize the level of dermal • • Iodine tincture USP Secondary amyltricresols absorption and expected systemic • • Sodium oxychlorosene exposure in adults as a result of topical Iodine topical solution USP • • Isopropyl alcohol Undecoylium chloride iodine use of alcohol-containing health care • Povidone-iodine complex antiseptics. As shown in table 11, a • Triclocarban 1. Alcohol variety of alcohol-based hand rub product formulations and alcohol We also discuss the following In the 1994 TFM, FDA proposed to antiseptic active ingredients that were concentrations have been used in these classify alcohol as GRAS for all health studies. Based on the available data, proposed as Category III in the 1994 care antiseptic uses based on the TFM and for which there are some new which represents moderate hand rub recommendation of the Miscellaneous use (7.5 to 40 hand rub applications per data available and explain why these External Panel, which concluded that hour, studied for 30 to 240 minutes), the ingredients are still Category III: the topical application of alcohol is safe highest observed exposure was 1,500 • Benzalkonium chloride (47 FR 22324 at 22329 and 59 FR 31402 • milligrams (mg) of alcohol (Ref. 4), Benzethonium chloride at 31412). FDA is now proposing to • Chloroxylenol classify alcohol as Category III. which is the equivalent of 10 percent of • 5 Triclosan Extensive studies have been conducted an alcohol-containing drink. (See also We do not discuss the following to characterize the metabolic and toxic the discussion of occupational exposure antiseptic active ingredients that were effect of alcohol in animal models. to alcohol via the dermal route (Ref. proposed as Category III in the 1994 Although the impetus for most of the 119) in the alcohol carcinogenicity TFM because we are not aware of any studies has been to study the effects of section of this proposed rule.) Although new safety data for these active alcohol exposure via the oral route of the available data suggest that dermal ingredients: administration, some dermal toxicity absorption of alcohol as a result of • Cloflucarban studies are available and have shown health care antiseptic use is relatively • Iodine complex (ammonium ether that, although there is alcohol low, these studies do not reflect the sulfate and polyoxyethylene sorbitan absorption through human skin, it is amount of exposure that may occur monolaurate) much lower than absorption via the oral during a regular 8- to 12-hour work shift • Iodine complex (phosphate ester of route. Overall, there are adequate safety in a health care facility. Consequently, alkylaryloxy polyethylene glycol) data to make a GRAS determination for human pharmacokinetics data under • Mercufenol chloride alcohol, with the exception of human maximal use conditions as determined • Mercufenol chloride and secondary pharmacokinetic data under maximal by a MUsT are still needed to make a amyltricresols in 50 percent alcohol use conditions. GRAS determination.

TABLE 11—RESULTS OF ALCOHOL HAND RUB ABSORPTION STUDIES IN HUMANS

Number of Highest blood Amount of alcohol Volume of hand hand rub Total length alcohol level Study Number of in hand rub rub used applications of detected subjects (percent) (milliliter (mL)) during the assessment (Milligram/Deciliter study (mg/dL))

Kramer, et al. (Ref. 4) ...... 12 95 4 20 ...... 30 minutes ... 2.10 Kramer, et al. (Ref. 4) ...... 12 95 1 4 10 ...... 80 minutes... 1.75 Kramer, et al. (Ref. 4) ...... 12 85 4 20 ...... 30 minutes ... 1.15 Kramer, et al. (Ref. 4) ...... 12 85 1 4 10 ...... 80 minutes... 3.01 Kirschner, et al. (Ref. 120) ...... 14 74.1 2 20 One 10- 10 minutes ... ∼0.175 minute application. Brown, et al. (Ref. 121) ...... 20 70 1.2–1.5 30 ...... 1 hour ...... 1.2 Ahmed-Lecheheb, et al. (Ref. 122) 86 70 3 Average of 4 hours ...... 0.022 9 3. Miller, et al. (Ref. 5) ...... 5 62 5 50 ...... 4 hours ...... < 5 Miller, et al. (Ref. 123) ...... 1 62 5 25 ...... 2 hours ...... < 5 Kramer, et al. (Ref. 4) ...... 12 55 4 20 ...... 30 minutes ... 0.69 Kramer, et al. (Ref. 4) ...... 12 55 1 4 10 ...... 80 minutes... 0.88 Bessonneau, V. and O. Thomas 1 70 3 5...... NA 4 ...... 1.43 5 (Ref. 124). Bessonneau, V. and O. Thomas 1 70 1 3 mL x 2 5 ...... NA ...... 2.02 5 (Ref. 124). 1 Product applied using a surgical scrub procedure. 2 Product applied to the subject’s back rather than to the hands to exclude any significant interference of inhaled uptake of evaporated alcohol. 3 Assessed under actual use conditions in a hospital. 4 Not available because of different study design. 5 Alcohol concentration measured in air collected from the subject’s breathing zone.

5 One alcohol-containing drink is equivalent to approximately 14 grams of alcohol (Ref. 290).

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Alcohol ADME data. Animal percent alcohol only. The rats and mice malformations of the fetus. In humans, absorption studies have been conducted were treated for 5 days per week for 103 consumption of even small amounts of both in vitro (Ref. 125) and in vivo in weeks. There was no evidence of an alcohol in pregnant women may result several species (Refs. 126 through 129). increased incidence of skin tumors in in fetal alcohol spectrum disorders After absorption, alcohol is metabolized the alcohol-treated rats or mice. (FASD) and other major structural primarily in the liver by alcohol In another study, alcohol was used as malformations; therefore, according to dehydrogenase to acetaldehyde. a vehicle control in the dermal the Centers for Disease Control and Acetaldehyde, in turn, is rapidly administration of 9,10-dimethyl-1,2- Prevention, there is no known level of metabolized to acetic acid by aldehyde benzanthracene (DMBA), a known safe alcohol consumption during dehydrogenase. These data are sufficient carcinogen (Ref. 132). Application of pregnancy (Ref. 138). The most severe to show that about 5 percent of 0.02 mL alcohol alone on the skin of form of FASD, fetal alcohol syndrome, consumed alcohol is excreted in breath mice 3 times per week for 20 weeks did has been documented in infants of and another 5 percent in urine, with not cause any tumors. Despite the fact mothers who consumed large amounts negligible amounts excreted in sweat that this study did not cover the entire of alcohol throughout pregnancy (Ref. and feces. Overall, the available animal lifespan of the mice, it provides 292). Based on available absorption ADME data are adequate to make a additional support that alcohol is not data, however, it is highly unlikely that GRAS determination. tumorigenic to skin after prolonged the levels of alcohol absorbed as a result Alcohol carcinogenicity data. The dermal administration. of health care antiseptic use would carcinogenicity of alcohol has been In contrast, chronic administration of approach the levels that cause fetal studied by both the dermal and oral orally ingested alcohol has been alcohol syndrome. routes of administration in animals and associated with carcinogenicity in both Alcohol data on hormonal effects in by the oral route of administration in animals and humans (Ref. 133). In animals. Alcohol exposure affects the humans. These studies are sufficient to animals, alcohol treatment increased level of a number of different hormones characterize the risk of carcinogenesis tumor incidences in multiple organs in animals. In vitro studies have shown from the use of alcohol-containing (Refs. 134, 135, and 136). In humans, that alcohol at a concentration of 280 to health care antiseptics. Based on two drinking around 50,000 mg of alcohol 300 mg/dL increased production of adequate and well-controlled trials, per day increases the risk for cancers of human chorionic gonadotropin and chronic dermal application of alcohol the oral cavity, pharynx, larynx, progesterone by cultured trophoblasts does not appear to be carcinogenic in esophagus, liver, colon, and rectum in animals and no further dermal both men and women, and breast cancer (Ref. 139), and at concentrations of at carcinogenicity data are needed to make in women (Refs. 119 and 137). However, least 2,500 mg/dL, decreased the ability a GRAS determination (Refs. 130 and no significant increases in cancer risk of rat Leydig cells to secrete testosterone 131). for any of these types of cancer appear by up to 44 percent (Ref. 140). There are Dermal carcinogenicity data have to be associated with less than one also many in vivo studies of the effects been obtained from studies where alcoholic drink (about 14,000 mg of of alcohol on hormone levels in animals alcohol was used as a vehicle control in alcohol) per day. Based on currently after oral administration. Alcohol 2-year studies. For example, a study available human absorption data, the exposures are associated with performed by the National Toxicology highest observed alcohol exposure was suppression of the hypothalamic Program (NTP) evaluated the 1,500 mg after use equivalent to 40 rubs pituitary gonadal (HPA) axis in male carcinogenic potential of per hour (Ref. 4), which is far below the rats. For example, in an alcohol feeding diethanolamine by the dermal route of alcohol levels that have been shown to study where adult rats were treated for administration in rats and mice (Ref. be associated with cancer. 5 weeks with 6 percent alcohol, 130). Each species had a vehicle control Bevan and colleagues evaluated the resulting in blood alcohol levels of 110 group that was treated with alcohol potential cancer risk from occupational to 160 mg/dL, the serum and testicular only. The skin of F334/N rats (50/sex/ exposures to alcohol via the inhalation testosterone concentrations of the group) and B6C3F1 mice (50/sex/group) and dermal routes, including the risk to alcohol group were significantly lower was treated with 95 percent alcohol for health care workers (Ref. 119). They than in untreated controls (P < 0.01) 5 days per week for 103 weeks. The estimated that under a ‘‘worst-case (Ref. 141). The serum luteinizing amount of alcohol administered scenario’’ of a hospital worker hormone concentration of alcohol- corresponds to a daily dose of 442 mg/ disinfecting both hands and lower arms treated rats was significantly higher kilogram(kg)/day and 1,351 mg/kg/day with alcohol 20 times per day, dermal than that of diet controls (P < 0.01), but in rats and mice, respectively. None of uptake would be approximately 600 mg the pituitary luteinizing hormone, the the alcohol-treated rats or mice showed alcohol/day. When a more realistic serum and pituitary follicle-stimulating any skin tumors; however, every mouse worst-case estimate of 100 hand rubs hormone, and the prolactin group, including the alcohol-alone per day is used (Ref. 101), systemic concentrations did not differ. When the treatment, showed high incidences of alcohol exposure may be as high as effect of alcohol exposure was compared liver tumors. It is unclear whether the 6,825 mg/day, assuming bioavailability in prepubescent and adult rats, high liver tumor incidence was caused remains at 2.3 percent for 95 percent treatment with 500 to 4,000 mg alcohol/ by background incidence or by the alcohol (Ref. 4). Ultimately, systemic kg decreased serum testosterone levels chronic topical application of alcohol. exposure data from a human MUsT are in adult rats as expected (Ref. 293). In Dermal administration of alcohol to the needed to fully assess the risk to health contrast, the opposite effect was skin did not result in skin tumors under care workers. observed in prepubescent male rats (25– the conditions of this study. Alcohol DART data. The 30 days old) where alcohol treatment Another study performed by the NTP developmental and reproductive produced dose-dependent increases in evaluated the carcinogenic potential of toxicity profile of orally administered serum testosterone levels. Serum benzethonium chloride by the dermal alcohol is well characterized. In many luteinizing hormone levels in alcohol- route of administration in rats and mice animal species, exposure to alcohol treated rats were either unchanged or (Ref. 131). Each species had a vehicle during pregnancy can result in retarded only modestly decreased in all ages control group that was treated with 95 development and structural tested. Results of this study suggest that

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alcohol at serum levels of greater than rub use (e.g., evaluations of the amount not needed to support a GRAS 200 mg/dL exerts age-dependent effects of alcohol in the blood at up to 4 hours determination. on the synthesis and secretion of of use), systemic alcohol exposure is b. Alcohol safety data gaps. In testosterone throughout sexual relatively low, but may be as high as 10 summary, our administrative record for maturation in rats. Overall, the effects of percent of an alcohol-containing drink. the safety of alcohol is incomplete with alcohol on hormones in animals have However, health care workers who use respect to the following: been well characterized and no these products chronically and • Human pharmacokinetic studies additional data are needed to make a repetitively may be required to use under maximal use conditions when GRAS determination. alcohol-containing hand rubs in applied topically (MUsT), including Alcohol data on hormonal effects in situations such as prior to and following documentation of validation of the humans. The effects of alcohol on contact with patients or contact with methods used to measure alcohol and human hormones are multiple and its metabolites and body fluids, and therefore may be • complex. Several variables, including exposed to these products a hundred data to help define the effect of the type, length, and pattern of alcohol times or more per day (Ref. 101). formulation on dermal absorption. exposure, and coexisting medical Consequently, additional human 2. Benzalkonium Chloride problems, such as malnutrition and pharmacokinetic data are needed to liver dysfunction, must be considered In the 1994 TFM, FDA categorized when assessing the impact of alcohol on determine the level of alcohol exposure benzalkonium chloride in Category III hormonal status (Ref. 142). Pregnant following maximal use of health care because of a lack of adequate safety data health care workers are a potentially antiseptics (i.e., MUsT) to determine the for its use as both a health care vulnerable population given that level of risk from the use of these personnel hand wash and surgical hand alcohol is a teratogen, and alcohol- products. scrub (59 FR 31402 at 31435). FDA containing antiseptic hand rubs are used Alcohol resistance data. The continues to propose benzalkonium frequently in health care settings. antimicrobial mechanism of action of chloride as Category III. Because of its Alcohol in the maternal bloodstream alcohol is considered nonspecific. It is widespread use as an antimicrobial crosses readily into the placenta and the believed that alcohol has multiple toxic agent in cosmetics and as a disinfectant fetal compartment (Ref. 143). This effects on the structure and metabolism for hard surfaces in agriculture and results in similar blood alcohol of microorganisms, primarily caused by medical settings, the safety of concentrations in the mother, the fetus, denaturation and coagulation of benzalkonium chloride has also been and the amniotic fluid (Ref. 143). The proteins (Refs. 146 through 149). reviewed by the Environmental fetus has very limited metabolic Alcohol’s reactive hydroxyl (-OH) group Protection Agency and an industry capacity for alcohol primarily because readily forms hydrogen bonds with review panel (Cosmetic Ingredient of low to absent hepatic activity for the proteins, which leads to loss of structure Review (CIR)) (Refs. 151 and 152) and metabolism of alcohol (Ref. 144). and function, causing protein and other found to be safe for disinfectant and Although both the placenta and fetus macromolecules to precipitate (Ref. cosmetic uses, respectively. Both these have some capacity to metabolize 148). Alcohol also lyses the bacterial evaluations have been cited by the alcohol, the majority of alcohol cytoplasmic membrane, which releases comments in support of the safety of benzalkonium chloride as a health care metabolism occurs in maternal the cellular contents and leads to antiseptic wash active ingredient (Ref. metabolic systems outside of the fetal bacterial inactivation (Ref. 146). Because 153). compartment (Ref. 143). of alcohol’s speed of action and Maternal alcohol use (by ingestion) is Each of these evaluations cites multiple, nonspecific toxic effects, the leading known cause of findings from the type of studies microorganisms have a difficult time developmental and cognitive disabilities necessary to support the safety of developing resistance to alcohol. Of in the offspring, and is a preventable benzalkonium chloride for repeated note, researchers have been attempting cause of birth defects (Ref. 145). daily use. However, the data that are the to develop alcohol-tolerant bacteria for However, based on available absorption basis of these safety assessments are data, it is highly unlikely that the levels use in biofuel production and beverage proprietary and are publicly available of alcohol absorbed as a result of health biotechnology applications. One of the only in the form of summaries. care antiseptic use would approach the most alcohol-tolerant bacteria, Consequently, these studies are not levels that cause fetal alcohol syndrome. Lactobacillus, has been shown to grow available to FDA and are precluded Nonetheless, children exposed to lower in the presence of up to 13 percent from a complete evaluation by FDA. In levels of alcohol in utero may be alcohol, which is far lower than the addition, the submitted safety vulnerable to more subtle effects. alcohol concentrations present in health assessments with study summaries do Currently, the levels of alcohol exposure care antiseptic products (Ref. 150). not constitute an adequate record on that cause more subtle effects are Health care antiseptic products contain which to base a GRAS classification (see unknown. at least 60 percent alcohol (59 FR 31402 generally § 330.10(a)(4)(i)). For FDA to Unlike the abundance of data from at 31442), and bacteria are unable to evaluate the safety of benzalkonium oral exposure, there are no data on the grow in this relatively high chloride for this rulemaking, these effects of systemic exposure to alcohol concentration of alcohol. Furthermore, studies must be submitted to the during pregnancy from the use of alcohol evaporates readily after topical rulemaking or otherwise be made alcohol-containing hand rubs. There are, application, so no significant antiseptic publicly available. however, some pharmacokinetic data on residue is left on the skin that could In addition to these summaries, as alcohol absorption after hand rub use in contribute to the development of discussed in the 2013 Consumer Wash the nonpregnant population (described resistance (Refs. 146 and 148). PR (78 FR 76444 at 76463), FDA has in the human pharmacokinetic Consequently, the development of reviewed studies on resistance data and subsection of this section of the resistance as a result of health care antibiotic susceptibility of certain proposed rule). As noted previously, the antiseptic use is unlikely, and bacteria (Refs. 62, 68, 70, 71, 73, 154, available data suggest that with additional data on the development of 155, and 156), and determined that the moderate health care antiseptic hand antimicrobial resistance to alcohol are available studies have examined few

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bacterial species, provide no the rulemaking to support the safety of Additional laboratory studies are information on exposure levels, and are benzethonium chloride (Ref. 160). necessary to more clearly define the not adequate to define the potential for Some of the safety data reviewed by potential for the development of the development of resistance or cross- the unidentified industry expert panel resistance to benzethonium chloride. In resistance. Additional data are needed represent the type of data that are addition, we lack human to more clearly define the potential for needed to evaluate the safety of pharmacokinetic studies under maximal the development of resistance to benzethonium chloride for use in use conditions, which are needed to benzalkonium chloride. Also, currently, consumer antiseptic wash products, e.g., define the level of systemic exposure no oral or dermal carcinogenicity data ADME, DART, and oral carcinogenicity following repeated use. Thus, additional are publicly available. Thus, additional studies. The safety assessments used to safety data are needed before safety data are needed before support the unidentified industry expert benzethonium chloride can be benzalkonium chloride can be panel’s finding of safety, however, are confirmed to be GRAS for use in health confirmed to be GRAS for use in health publicly available only in the form of care antiseptic products. care antiseptic products. summaries. Consequently, these studies Benzethonium chloride safety data Benzalkonium chloride safety data are not available to FDA for a complete gaps. In summary, our administrative gaps. In summary, our administrative evaluation. Furthermore, the submitted record for the safety of benzethonium record for the safety of benzalkonium safety assessments with study chloride is incomplete with respect to chloride is incomplete with respect to summaries do not constitute an the following: the following: adequate record on which to base a • Human pharmacokinetic studies • Human pharmacokinetic studies GRAS classification (see generally under maximal use conditions when under maximal use conditions when § 330.10(a)(4)(i)). For FDA to include applied topically (MUsT), including applied topically (MUsT), including these studies in the administrative documentation of validation of the documentation of validation of the record for this rulemaking, the studies methods used to measure benzethonium methods used to measure benzalkonium must be submitted to the rulemaking or chloride and its metabolites; chloride and its metabolites; otherwise made publicly available. • data to help define the effect of • aata to help define the effect of In addition to these summaries, as formulation on dermal absorption; formulation on dermal absorption; discussed in the 2013 Consumer Wash • animal ADME; • animal ADME; PR (78 FR 76444 at 76464–76465), FDA • oral carcinogenicity; • oral carcinogenicity; has reviewed the following: (1) ADME • DART studies (fertility and embryo- • dermal carcinogenicity; studies providing data from dermal and fetal testing); • DART studies; intravenous administration to rats and a • potential hormonal effects; and • potential hormonal effects; and rat in vitro dermal absorption study • data from laboratory studies that • data from laboratory studies that (Refs. 131 and 160 through 163). FDA assess the potential for the development assess the potential for the development determined that additional data from of resistance to benzethonium chloride of resistance to benzalkonium chloride ADME studies in animals are necessary and cross-resistance to antibiotics as and cross-resistance to antibiotics as to support a GRAS determination discussed in section VII.C.4. discussed in section VII.C.4. because of highly variable results in the 4. Chloroxylenol submitted studies, the need to clearly 3. Benzethonium Chloride define the level of dermal absorption, In the 1994 TFM, FDA classified In the 1994 TFM, FDA classified the effect of formulation on dermal chloroxylenol as lacking sufficient benzethonium chloride as lacking absorption, and the distribution and evidence of safety for use as a health sufficient evidence of safety for use as metabolism of benzethonium chloride care personnel hand wash and surgical a health care personnel hand wash and in animals; (2) A dermal carcinogenicity hand scrub for FDA to determine surgical hand scrub (59 FR 31402 at study (Ref. 131), which is adequate to whether chloroxylenol is GRAS for use 31435). FDA is now proposing to show that benzethonium chloride does in health care antiseptic products (59 FR classify benzethonium chloride as not pose a risk of cancer after repeated 31402 at 31435). FDA is now proposing Category III for both safety and dermal administration; however, oral to classify chloroxylenol as Category III effectiveness. Since publication of the carcinogenicity data are still lacking; (3) for both safety and effectiveness. 1994 TFM, two industry review panels DART data from teratology studies on Additional safety data continue to be (CIR and a second industry panel rats and rabbits, as well as an embryo- needed to support the long-term use of identified in a comment only as an fetal rat study (Ref. 160) and determined chloroxylenol in OTC health care ‘‘industry expert panel’’) and a that the DART data are not adequate to antiseptic products. As discussed in the European regulatory advisory board characterize all aspects of reproductive 2013 Consumer Wash PR, chloroxylenol (Scientific Committee on Cosmetic toxicity and that studies are needed to is absorbed after topical application in Products and Non-food Products assess the effect of benzethonium both humans and animals. However, Intended for Consumers) have evaluated chloride on male and female fertility studies conducted in humans and the safety of benzethonium chloride and on prenatal and postnatal animals are inadequate to fully when used as a preservative in cosmetic endpoints; and (4) Resistance data from characterize the extent of systemic preparations and as an active ingredient studies on bacterial susceptibility for absorption after repeated topical use or in consumer hand soaps (Refs. 157, 158, benzethonium chloride and antibiotics to demonstrate the effect of formulation and 159). These advisory bodies found (Refs. 164 and 165) and determined that on dermal absorption. The benzethonium chloride to be safe for the available studies examine few administrative record also lacks other these uses. However, all these safety bacterial species, provide no important data to support a GRAS determinations have largely relied on information on the level of determination for this antiseptic active the findings of proprietary studies that benzethonium chloride exposure, and ingredient. are not publicly available. One of these are not adequate to define the potential As discussed in the 2013 Consumer evaluations, by the unidentified for the development of resistance and Wash PR (78 FR 76444 at 76465–76467), industry expert panel, was submitted to cross-resistance to antibiotics. FDA reviewed the following:

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• Human pharmacokinetic data from • animal ADME at toxic exposure incomplete with respect to the dermal and percutaneous absorption levels; following: studies (Refs. 166 and 167) and • dermal carcinogenicity; • Human pharmacokinetic studies determined that the human • oral carcinogenicity; under maximal use conditions when pharmacokinetic studies are inadequate • DART studies defining the effects of applied topically (i.e., MUsT), including and studies using dermal administration chloroxylenol on fertility and prenatal documentation of validation of the under maximal use conditions are and postnatal development; methods used to measure needed to define the level of systemic • hexylresorcinol and its metabolites; potential hormonal effects; and • exposure following repeated use and the • data from laboratory studies that data to help define the effect of effect of formulation on dermal assess the potential for the development formulation on dermal absorption; • animal ADME; absorption; of resistance to chloroxylenol and cross- • dermal ADME studies (Refs. 168 • dermal carcinogenicity; resistance to antibiotics as discussed in • and 169) that demonstrated that DART studies; section VII.C.4. • potential hormonal effects; and absorption of chloroxylenol occurs after • dermal application in humans and 5. Hexylresorcinol data from laboratory studies that animals, but that the administrative assess the potential for the development In the 1994 TFM, FDA proposed to of resistance to hexylresorcinol and record for chloroxylenol still lacks data classify hexylresorcinol as GRAS for all to fully characterize the rate and extent cross-resistance to antibiotics as antiseptic uses covered by that TFM, discussed in section VII.C.4. of systemic absorption, the similarities including health care antiseptic uses, and differences between animal and based on the recommendations of the 6. Iodine-Containing Ingredients human metabolism of chloroxylenol Panel, who concluded that the topical Elemental iodine, which is the active under maximal use conditions, and data application of hexylresorcinol is safe (39 antimicrobial component of iodine- to help establish the relevance of FR 33103 at 33134). FDA is now containing antiseptics, is only slightly findings observed in animal toxicity proposing to classify hexylresorcinol as soluble in water (Ref. 177). studies to humans; Category III. In support of its GRAS Consequently, iodine is frequently • carcinogenicity data from a dermal conclusion, the Panel cited dissolved in an organic solvent (such as toxicity study in mice (Ref. 170) and hexylresorcinol’s long history of use as a tincture) or complexed with a carrier determined that a long-term dermal an oral antihelmintic (a drug used in the molecule. Both surfactant (e.g., carcinogenicity study and an oral treatment of parasitic intestinal worms) poloxamer) and nonsurfactant (e.g., carcinogenicity study are needed to in humans and the lack of allergic povidone) compounds have been characterize the systemic effects from reactions or dermatitis associated with complexed with iodine. The carrier long-term exposure; topical use. The Panel noted that no • DART data from a teratolotgy study molecules increase the solubility and information was provided regarding in rats (Ref. 171) and determined that stability of iodine by allowing the active dermal or ophthalmic toxicity or additional studies are necessary to form of iodine to be slowly released absorption and blood levels attained assess the effect of chloroxylenol on over time (Ref. 177). The rate of the after application to intact or abraded fertility and early embryonic release of ‘‘free’’ elemental iodine from skin or mucous membranes, but development and on prenatal and the complex is a function of the concluded that the few animal toxicity postnatal development; and equilibrium constant of the complexing • resistance data from studies on studies submitted as summaries formulation (39 FR 33103 at 33129). In antibiotic susceptibility in indicated a ‘‘low order’’ of toxicity (Ref. the 1994 TFM, all the iodine-containing chloroxylenol-tolerant bacteria and 173). active ingredients were proposed as antimicrobial susceptibilities of bacteria In light of the new safety information GRAS for OTC health care antiseptic use from industrial sources (Refs. 156, 164, about systemic exposure to antiseptic (59 FR 31402 at 31435). FDA is now 171, and 172) and determined that these active ingredients, the data relied on by proposing to classify all iodine- studies examine few bacterial species, the Panel should be supplemented to containing active ingredients as provide no information on the level of support a GRAS determination. Category III for both safety and chloroxylenol exposure, and are not Currently, there are only minimal data effectiveness. Since the publication of adequate to define the potential for the available to assess the safety of the the 1994 TFM, we have identified new development of resistance to repeated, daily, long-term use of safety data for the following active chloroxylenol and cross-resistance to hexylresorcinol. As discussed in the ingredients: antibiotics. proposed rule covering consumer • Iodine tincture USP Thus, additional safety data are antiseptic washes (78 FR 76444 at • Iodine topical solution USP • needed before chloroxylenol can be 76458), FDA has reviewed an adequate Povidone-iodine 5 to 10 percent confirmed to be GRAS for use in health oral carcinogenicity study with results it Iodine is found naturally in the care antiseptic products. considers negative (Ref. 174), an ADME human body and is essential for normal Chloroxylenol safety data gaps. In study providing data from oral human body function. In the body, summary, our administrative record for administration to dogs (Ref. 175) and iodine accumulates in the thyroid gland the safety of chloroxylenol is humans (Ref. 176), and other and is a critical component of thyroid incomplete with respect to the information, and determined that hormones. People obtain iodine through following: additional safety data are needed before their food and water, which are often • Human pharmacokinetic studies hexylresorcinol can be considered supplemented with iodine to prevent under maximal use conditions when GRAS for use in OTC antiseptic iodine deficiency. Because people are applied topically (MUsT), including products. We conclude that these data widely exposed to iodine, it has been documentation of validation of the gaps also exist for use as a health care the subject of comprehensive methods used to measure chloroxylenol antiseptic. toxicological review by public health and its metabolites; Hexylresorcinol safety data gaps. In organizations (Refs. 178 and 179). • data to help define the effect of summary, our administrative record for Much of the safety data we reviewed formulation on dermal absorption; the safety of hexylresorcinol is pertained to elemental iodine alone.

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Consequently, additional data on some characterized and additional DART 7. Isopropyl Alcohol of the carrier molecules are needed. In studies are not needed to make a GRAS In the 1994 TFM, FDA proposed to the 1994 TFM, FDA stated that neither determination; and classify isopropyl alcohol (70 to 91.3 • the medium nor large molecular weight Iodine data on hormonal effects, percent) as GRAS for all health care size povidone molecules (35,000 daltons including studies of the effect of iodine antiseptic uses (59 FR 31402 at 31436). or greater) presented a safety risk when on the thyroid gland (Refs. 178, 179, FDA is now proposing to classify limited to the topical uses described in 181, 183, 190, 191, 192, and 196 through isopropyl alcohol as Category III. The the monograph and that larger size 206), and determined that, despite GRAS determination in the 1994 TFM povidone-iodine molecules would not limitations in some of the studies, FDA was based on the recommendations of be absorbed under the 1994 TFM believes there are adequate data the Miscellaneous External Panel, conditions of use (59 FR 31402 at regarding the potential of iodine to which based its recommendations on 31424). We continue to think that data cause changes in thyroid hormone human absorption data and blood on the larger size molecules are not levels and additional studies are not isopropyl alcohol levels (47 FR 22324 at necessary to support a GRAS necessary to make a GRAS 22329). There was no comprehensive determination for iodine-containing determination. nonclinical review of the toxicity profile ingredients. However, data are lacking In addition, based on the available of isopropyl alcohol, nor was there a on the absorption of smaller molecular data, more information is needed to nonclinical safety evaluation of the weight povidone molecules and for support the frequent, topical use of topical use of isopropyl alcohol. We other small molecular weight carriers iodine-containing health care believe the existing evaluations need to (less than 500 daltons (Ref. 180)). antiseptics by pregnant and be supplemented to fully evaluate the Human absorption studies following breastfeeding health care personnel. safety of isopropyl alcohol. maximal dermal exposure to these Iodine-containing health care carriers can be used to determine the antiseptics, particularly povidone- a. Summary of Isopropyl Alcohol Safety potential for systemic toxicity from the iodine, are used frequently as surgical Data carrier molecule. For carrier molecules hand scrubs. Although the daily Isopropyl alcohol human that are absorbed following dermal exposure from surgical hand scrubs pharmacokinetic data. Based on a exposure, we propose that the following would be much lower than from health review of published literature, there are data are needed to support a GRAS care personnel hand washes, because of some data to characterize the level of determination: Systemic toxicity of the the potential for absorption of iodine dermal absorption and expected carrier in animal studies that identify and transient hypothyroidism in systemic exposure in adults following the target organ for toxicity, and newborns (Refs. 191, 192, 199, and 203), topical use of isopropyl alcohol- characterization of the metabolic fate of chronic use of iodine-containing health containing products. However, these the carrier as recommended by the care antiseptics by pregnant and data do not cover maximal use in the Panel (39 FR 33103 at 33130). breastfeeding health care personnel As discussed in the 2013 Consumer health care setting. In a study by Brown, needs to be evaluated. Consequently, Wash PR (78 FR 76444 at 76459–76461), et al., the cutaneous absorption of additional human pharmacokinetic data FDA has reviewed the following: isopropyl alcohol from a commonly • Human pharmacokinetic data from are needed to determine the level of used hand rub solution containing 70 absorption studies (Refs. 178, 181, 182, iodine exposure following maximal percent isopropyl alcohol was assessed and 183) and determined that they do health care antiseptic use (i.e., MUsT) to in 19 health care workers ranging in age not provide sufficient information to determine the potential effects from from 22 to 67 years (Ref. 121). The hand estimate typical amounts of iodine that chronic use of these products. rub solution was administered under could be absorbed from health care Iodine safety data gaps. In summary, ‘‘intensive clinical conditions’’ by antiseptic products containing iodine our administrative record for the safety application of 1.2 to 1.5 mL of the and iodine complexes; of iodine-containing active ingredients isopropyl alcohol-containing hand rub • Iodine ADME data (Refs. 178, 184, is incomplete with respect to the 30 times during a 1-hour period on 2 and 185), and determined that the following: separate days separated by a 1-day • distribution, metabolism, and excretion Human pharmacokinetic studies of washout. Serum isopropyl alcohol of iodine have been adequately assessed the absorption of iodine under maximal concentrations at 5 to 7 minutes post- in humans and no further animal ADME use conditions when applied topically exposure as assessed by gas data are needed to support a GRAS (MUsT) for each of the iodine- chromatography (lower limit of determination; containing active ingredients, including quantitation of 2 mg/dL) were not • Oral carcinogenicity studies documentation of validation of the detectable in these subjects following providing data from oral administration methods used to measure iodine and its the simulated ‘‘intense clinical to rats and tumor promotion in rats metabolites; conditions.’’ (Refs. 186, 187, and 188) and • Human absorption studies of the Another study examined the determined that based upon the carrier molecule for small molecular pharmacokinetics of alcohol and available data, oral doses of iodine do weight povidone molecules (less than isopropyl alcohol after separate and not significantly raise the risk of cancer 35,000 daltons) and the other small combined application in a double-blind, in animals and no further oral molecular weight carriers (less than 500 randomized, three-way crossover study carcinogenicity data are needed to make daltons); (Ref. 120). Results show that all a GRAS determination; • Dermal carcinogenicity studies for isopropyl alcohol concentrations • DART data from studies assessing each of the iodine-containing active measured in volunteers treated with 10 the effects of iodine on reproduction, ingredients; and percent isopropyl alcohol in aqueous embryo-fetal development, lactation, • Data from laboratory studies that solution and the commercial and survival in animals (Refs. 178 and assess the potential for the development combination product were below the 189 through 195) and determined that of resistance to iodine and cross- detection limit of 0.5 mg/L. Another the effect of iodine on development and resistance to antibiotics as discussed in study by Turner and colleagues reproductive toxicology are well section VII.C.4. investigated the amount of isopropyl

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alcohol absorbed through the skin in 10 absorption of isopropyl alcohol ingestion and inhalation (Ref. 214). healthy male and female adults following dermal exposure. The Isopropyl alcohol is metabolized to following application of 3 mL of an majority of studies used non-dermal acetone in both animals and man by the isopropyl alcohol-containing hand rub routes of exposure (i.e., oral or hepatic enzyme alcohol dehydrogenase (56 percent w/w isopropyl alcohol) inhalation) (Refs. 210 and 211). The and is then metabolized further to applied to the hands every 10 minutes available dermal exposure studies have carbon dioxide through a variety of over a 4-hour period (Ref. 207). Nine of demonstrated that there is some metabolic pathways (Refs. 215 and 216). the 10 subjects exhibited measurable systemic exposure to isopropyl alcohol In animals, the excretion of isopropyl blood isopropyl alcohol concentrations following dermal application. However, alcohol is pulmonary with at 5 minutes following final application the extent of that exposure has not been approximately 3 to 8 percent excreted in of the hand rub (limit of detection, 0.5 fully characterized. the urine (Ref. 214). In humans, mg/L). The range of isopropyl alcohol In a dermal exposure study in rats, 70 isopropyl alcohol is predominantly concentrations observed in this study percent aqueous isopropyl alcohol eliminated in the urine with a small was less than 0.5 mg/L to 1.8 mg/L. solution was applied to a 4.5 square amount being excreted through A recent report assessed systemic centimeter area of skin on the shaved expiration (Ref. 217). absorption following the use of a hand backs of male and female Fischer F–344 Slauter, et al. characterized the rub containing 63.14 percent w/w rats and maintained under a sealed disposition and pharmacokinetics of isopropyl alcohol, using a surgical scrub chamber for a period of 4 hours (Ref. isopropyl alcohol following intravenous method on 10 adults (Ref. 208). First, a 212). Most of the drug (approximately (IV), oral (single and multiple doses), hygienic hand rub was performed for 30 85 percent of the dose) was recovered and inhalation exposure in male and seconds. Ten minutes later, a 1.5-minute from the application site (i.e, was not female F–344 rats and B6C3F1mice (Ref. surgical hand rub procedure was absorbed). The remainder of the dose 214). Animals were exposed to either an performed before each of the three (approximately 15 percent) was detected IV dose of 300 mg/kg, inhalation of 500 consecutive 90-minute surgical in the blood within 1 hour after or 5,000 parts per million isopropyl interventions. After application of the application, indicating that dermal alcohol for 6 hours, single oral doses of hand rub and air-drying, surgical gloves exposure resulted in some systemic 300 mg/kg or 3,000 mg/kg, or multiple were donned. Samples were collected exposure. Maximum blood doses of 300 mg/kg for 8 days. AUC and three times at 90-minute intervals after concentrations of isopropyl alcohol T1⁄2 were calculated based on the study each surgical procedure and at 60 and were attained at 4 hours and decreased data. No major differences in the rate or 90 minutes after the third surgical steadily following removal of the test route of elimination between sexes or procedure. The authors report that the material. The half-life of elimination routes of exposure were demonstrated, highest median blood level was 2.56 (T1⁄2) of isopropyl alcohol from blood and repeated exposure had no effect on mg/L for isopropyl alcohol. was 0.77 and 0.94 hours for male and excretion. However, the rate of In summary, dermal absorption of female rats, respectively. AUC was not elimination was shown to be dose- isopropyl alcohol following topical determined. dependent, with higher doses increasing application of antiseptic hand rubs Martinez, et al. compared isopropyl the T1⁄2. Isopropyl alcohol and its under simulated clinical conditions in alcohol blood levels in rabbits after oral, metabolites were distributed to all adults suggests the systemic exposure to dermal, and inhalation exposure (Ref. tissues without accumulation in any isopropyl alcohol when used as an 213). Male rabbits (unidentified strain, particular organ. While these data are active ingredient in health care three animals per group) were given 2 adequate to define the ADME profile of antiseptic products is expected to be or 4 g/kg isopropyl alcohol via oral isopropyl alcohol following non-dermal low. Clinical effects (mild intoxication) gavage, or unknown doses of isopropyl exposure, they are not sufficient to of elevated blood isopropyl alcohol alcohol via inhalation exposure with or characterize what would occur levels occur at concentrations exceeding without concomitant dermal exposure. following dermal exposure. Absorption approximately 50 mg/dL (Ref. 209). The Isopropyl alcohol blood levels were data following dermal absorption in highest blood concentration of isopropyl measured for up to 4 hours after the animals are still needed in order to alcohol observed across studies initiation of treatment. The highest determine the extent of systemic following various application scenarios blood isopropyl alcohol concentrations exposure following maximal dermal with isopropyl alcohol-containing were observed from the oral route of exposure to isopropanol-containing products was less than 2 mg/dL, or 4 administration (262 and 278 mg/dL in health care antiseptic products. percent of the systemic levels associated the 2 and 4 g/kg groups, respectively). Information on the distribution, with acute clinical effects. However, the The dermal and inhalation groups metabolism, and excretion of isopropyl available studies did not assess the produced a mean blood isopropyl alcohol can be extrapolated from highest potential concentration of alcohol concentration of 112 mg/dL. published data on the other routes of isopropyl alcohol (91.3 percent) that The inhalation-only group had a mean exposure. may be used in a health care antiseptic blood concentration of 6 to 8 mg/dL. Isopropyl alcohol carcinogenicity (59 FR 31402 at 31436), and these However, the study provides little data. No data exist for the studies do not reflect the amount of information regarding the bioavailability carcinogenicity potential of isopropyl exposure that may occur during a of dermally applied isopropyl alcohol alcohol following oral or dermal regular 8- to 12-hour work shift in a because of the unknown dosing for the exposure in humans. The International health care facility. Consequently, group given isopropyl alcohol via the Agency for Research on Cancer (IARC) human pharmacokinetic data under combination of inhalation and dermal monograph states that there is maximal use conditions as determined exposures. inadequate evidence of carcinogenicity by a MUsT are still needed to support The available animal ADME data from of isopropyl alcohol in humans (Ref. a GRAS determination for isopropyl non-dermal routes of exposure are 218). The IARC monograph indicates alcohol for use in health care antiseptic sufficient to characterize the absorption, that an increased incidence of cancer of products. distribution, metabolism, and excretion the paranasal sinuses was observed in Isopropyl alcohol ADME data. There of isopropyl alcohol. Isopropyl alcohol workers at factories where isopropyl are few animal studies that examine the is rapidly absorbed following oral alcohol was manufactured by the strong-

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acid process. In this instance, the among aged rats and was not considered hormone levels on the long-term primary route of exposure was through to be treatment related. No increased development of the treated pups has not inhalation, rather than topical. The risk incidence of other neoplastic lesions been evaluated. Overall, this study is for laryngeal cancer may also have been was observed in male rats, and no not adequate to characterize the elevated in these workers. However, it is increased incidence of neoplastic potential for hormonal effects of unclear whether the cancer risk was lesions was observed for female rats isopropyl alcohol. The existing data caused by the presence of isopropyl from any exposure group. come from a single study, using a route alcohol itself or one of its by-products No dermal carcinogenicity studies of of exposure that is not relevant to health (diisopropyl sulfate, which is an isopropyl alcohol have been completed care antiseptics, and the study did not intermediate in the process; or isopropyl in animals, and little dermal data from evaluate other important types of oils, which are formed as by-products; other sources are available. In a hormones (e.g., thyroid, sex hormones). or to other chemicals, such as sulfuric subchronic 1-year dermal toxicity study, Additional data to characterize the acid). Rockland mice (30 per group) were potential for hormonal effects of Inhalation carcinogenicity studies treated three times weekly for 1 year isopropyl alcohol are still needed to have been performed in animals to with isopropyl alcohol (Ref. 216). No make a GRAS determination. assess the potential carcinogenicity of skin tumors were observed, but the sex, Isopropyl alcohol resistance data. We isopropyl alcohol for industrial workers dose, and observation period were not found no reports of bacterial resistance under occupational exposure conditions specified. Although no evidence of to isopropyl alcohol. Like alcohol, the (Ref. 219). In a study in Fisher 344 rats carcinogenic potential was seen in this antimicrobial mechanism of action of and CD–1 mice by Burleigh-Flayer, et study, it was not long enough to be isopropyl alcohol is nonspecific, al., high-dose treated rats had higher considered adequate for the assessment primarily caused by denaturation and mortality rates and shorter survival of the carcinogenicity potential of coagulation of proteins (Refs. 146 times compared to controls. However, isopropyl alcohol via the dermal route. through 149). High concentrations of lower exposure groups of rats and mice Isopropyl alcohol DART data. A isopropyl alcohol are toxic to most did not experience significant increases number of fertility and microorganisms due to its high oxygen in any tumors following exposure to multigenerational studies were demand and membrane-disruptive isopropyl alcohol via the inhalation conducted for isopropyl alcohol characteristics (Ref. 228). Because of route for up to 2 years (Ref. 219). Groups administered via the oral route of isopropyl alcohol’s speed of action and of animals were exposed via whole- exposure (Refs. 220 through 225). multiple, nonspecific toxic effects, body exposure chambers to 0 (control), Isopropyl alcohol was associated with microorganisms have a difficult time 500 (low-dose), 2,500 (mid-dose) or maternal toxicity when pregnant developing resistance to it. 5,000 (high-dose) parts per million of animals were exposed to high doses Isopropyl alcohol is a common, cheap isopropyl alcohol vapor 6 hours per day, during pregnancy, but no teratogenic industrial solvent and researchers have 5 days per week for up to 78 weeks in effects were noted on the pups. been attempting to develop isopropyl CD–1 mice (55/sex/dose) and 104 weeks Isopropyl alcohol was not found to be alcohol-tolerant bacteria for use in in Fischer 344 rats (65/sex/dose). These teratogenic in rats in a number of biological treatment of isopropyl respective isopropyl alcohol exposure studies using the oral exposure route alcohol-containing industrial waste. A levels in the low-dose, mid-dose, and using a 2-generation study design. recent study identified an isopropyl high-dose groups correspond to doses of Adverse effects noted for postnatal pups alcohol-tolerant strain of Paracoccus approximately 570, 2,900, and 5,730 treated at high doses of isopropyl denitrificans that could grow in mg/kg/day in mice, and 350, 1,790, and alcohol were limited to decreased pup isopropyl alcohol at a concentration of 3,530 mg/kg/day in rats. At the end of body weights and increased liver 1.6 percent (Ref. 229), and a strain of treatment, a large panel of organs was weights (Ref. 221). Based on the weight Bacillus pallidus has been shown to collected from control and high-dose of evidence from several studies, Faber grow in isopropyl alcohol up to 2.4 treated groups for histopathological and colleagues calculated the no percent (Ref. 230). Thus, even isopropyl examination. In the mid- and low-dose observed adverse effect level (NOAEL) alcohol-tolerant strains could not groups, only kidneys and testes were for pup postnatal survivability as 700 survive in health care antiseptic examined. mg/kg/day in rats (Ref. 221). However, products, which would contain at least No increases in the incidence of using an alternative, quantitative 70 percent isopropyl alcohol (59 FR neoplastic lesions were observed in approach that takes dose-response 31402 at 31442). Furthermore, isopropyl either mice or rats. In mice, no information into account (i.e., alcohol evaporates readily after topical differences in the mean survival time benchmark dose approach), other application, so no antiseptic residue is were noted for any of the exposure researchers have estimated a benchmark left on the skin that could contribute to groups. No increases in the incidence of dose of 420 mg/kg/day (Ref. 226). In the development of resistance (Refs. 146 neoplastic lesions were noted from conclusion, additional DART data are and 148). Consequently, the treatment groups in either sex. In rats, not needed to support a GRAS development of resistance as a result of survival was poor in males but adequate determination for health care antiseptic health care antiseptic use is unlikely in females; none of the high-dose males products containing isopropyl alcohol. and additional data on the development survived beyond 100 weeks of dosing. Isopropyl alcohol data on hormonal of antimicrobial resistance to isopropyl The mean survival time was 631 and effects. Studies evaluating hormonal alcohol are not needed to make a GRAS 577 days (p < 0.01) for the control and effects of isopropyl alcohol are limited. determination. high-dose groups, respectively. No We found only one study in the b. Isopropyl alcohol safety data gaps. difference in mean survival time was literature, which showed that exposure In summary, our administrative record noted for female rats. The main cause of to high levels of isopropyl alcohol via for the safety of isopropyl alcohol is death was chronic renal disease. the intraperitoneal route was associated incomplete with respect to the Concentration-related increases in the with some perturbations in brain following: incidence of interstitial cell adenoma of hormones (e.g., dopamine, • Human pharmacokinetic studies the testes were observed in male rats; noradrenaline, and serotonin) (Ref. 227). under maximal use conditions when however, this type of tumor is common The significance of these changes in applied topically (MUsT), including

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documentation of validation of the 9. Triclosan antibiotic susceptibilities, but data are methods used to measure isopropyl In the 1994 TFM, FDA classified still needed that would clarify the alcohol and its metabolites; potential public health impact of the • triclosan as lacking sufficient evidence animal ADME (dermal absorption); of safety for use as a health care currently available data. • In addition to the data already oral carcinogenicity; personnel hand wash and surgical hand • reviewed in the 2013 Consumer Wash dermal carcinogenicity; and scrub (59 FR 31402 at 31436). FDA is • PR (78 FR 76444 at 76467), new data for potential hormonal effects. now proposing to classify triclosan as some of the safety categories has also Category III for all health care uses. 8. Triclocarban become available. Since the 1994 TFM, a large number of In the 1994 TFM, FDA proposed to studies have been conducted to a. Summary of New Triclosan Safety classify triclocarban as GRAS for all characterize the toxicological and Data health care antiseptic uses. FDA is now metabolic profile of triclosan using New triclosan human proposing to classify triclocarban as animal models. Most of these studies Category III. The GRAS determination in pharmacokinetics data. A recent have focused on understanding the fate biomonitoring study compared urine the 1994 TFM was based on safety data of triclosan following exposure to a and information that were submitted in triclosan levels in a convenience sample single source of triclosan via the oral of 76 health care workers in two response to the 1978 TFM on route of administration. However, triclocarban formulated as bar soap (Ref. hospitals (Ref. 264). One hospital used dermal studies in both humans and a 0.3 percent triclosan-containing soap 231). These data included blood levels, animals are also available. These studies target organs for toxicity, and no effect in all patient care areas and restrooms. show that triclosan is absorbed through The second hospital used plain soap levels and were discussed in the 1991 the skin, but to a lesser extent than oral and water, having previously phased First Aid TFM (56 FR 33644 at 33664). absorption. out triclosan-containing soaps. Both The existing data, however, need to be As discussed in the 2013 Consumer hospitals also had alcohol-based hand supplemented to fully evaluate the Wash PR (78 FR 76444 at 76467–76469), rub available. The use of triclosan- safety of triclocarban according to FDA has reviewed the following: containing toothpaste and other current scientific standards. New • Human absorption data (Refs. 243 personal care products was assessed information regarding potential risks through 248) in the consumer setting; through a questionnaire. Although the from systemic absorption and long-term • animal ADME data (Refs. 243, 244, urinary concentrations of total exposure to antiseptic active ingredients and 248 through 253) and determined (nonconjugated plus conjugated) is leading us to propose additional that the data are not adequate and triclosan were higher in health care safety testing. additional pharmacokinetic data (e.g., workers that worked at the hospital As discussed in the 2013 Consumer AUC, Tmax, and Cmax) at steady-state using triclosan-containing soap, the use Wash PR (78 FR 76444 at 76461–76462), levels continue to be necessary to bridge of triclosan-containing toothpaste was FDA has reviewed the following: animal data to humans; • correlated with the highest urinary Human absorption data (Refs. 231 • short-term dermal toxicity studies triclosan levels. through 235); in animals (Refs. 254 through 257) and This study provides some information • animal ADME data (Refs. 231 and determined that a long-term dermal about health care worker exposure to 236 through 240); carcinogenicity study is needed to triclosan, but it does not attempt to • a 2-year oral carcinogenicity study assess the relevance of the short-term measure triclosan exposure under of triclocarban in rats (Refs. 241 and dermal toxicity findings to a chronic use maximal use conditions. In summary, 242); and situation; although human absorption of triclosan • data on hormonal effects (Refs. 42 • a 2-year oral carcinogenicity study has been adequately characterized for and 43). of triclosan in hamsters (Refs. 258 and moderate daily use, such as in the Based on our evaluation of these data, 259) and determined the data are consumer setting, studies to evaluate additional safety data are needed before adequate to show that triclosan does not maximal use in the health care setting triclocarban can be considered GRAS for pose a risk of cancer after repeated oral are not available and MUsT data are use in a health care antiseptic. administration under the experimental needed to make a GRAS determination. Triclocarban safety data gaps. In conditions used; New triclosan carcinogenesis data. A summary, our administrative record for • DART data (Refs. 260 and 261) and recent study examined the effect of the safety of triclocarban is incomplete determined that the triclosan DART data triclosan treatment on the development with respect to the following: are adequate and additional traditional of liver cancer in mice (Ref. 265). Oral • Human pharmacokinetic studies DART studies are not necessary to make exposure to triclosan at a daily dose of under maximal use conditions when a GRAS determination; approximately 68.6 mg/kg for 8 months applied topically (MUsT), including • data on hormonal effects (Refs. 42, resulted in the proliferation of liver cells documentation of validation of the 44 through 48, 51, and 262) and (hepatocytes); elevated accumulation of methods used to measure triclocarban determined that the consequences of collagen in the liver, which is an and its metabolites; short-term thyroid and reproductive indicator of fibrosis of the liver; and • data to help define the effect of findings on the fertility, growth, and oxidative stress. Collectively, these formulation on dermal absorption; development of triclosan-exposed litters findings suggest that long-term triclosan • animal ADME; could be addressed by studies in treatment in mice can lead to the type • dermal carcinogenicity; juvenile animals; and of liver injury that is a risk factor for the • DART studies; • data on the potential for development of liver cancer • potential hormonal effects; and development of antimicrobial resistance (hepatocellular carcinoma). • data from laboratory studies that and cross-resistance between triclosan The ability of triclosan to function as assess the potential for the development and antibiotics (Refs. 61, 62 through 66, a tumor promoter (i.e., something that of resistance to triclocarban and cross- 69, 72, 74 through 77, and 263) and stimulates existing tumors to grow) also resistance to antibiotics as discussed in determined that triclosan exposure can was evaluated. Male mice were section VII.C.4. change efflux pump activity and alter pretreated with a single injection of a

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chemical that can initiate tumors triclosan significantly lowered T4 levels concentrations, triclosan can inhibit an (diethylnitrosamine (DEN)). Test mice in dams, but no significant effects on T4 essential bacterial enzyme (enoyl-acyl then received triclosan at approximately levels were seen in the offspring at the carrier protein reductase) involved in 28.6 mg/kg in their drinking water while end of the lactation period. In the fatty acid synthesis (Refs. 275 and 276). control mice received untreated water second study, pups were dosed directly In bacteria, four enoyl-acyl carrier for 6 months. Triclosan-treated mice (gavaged) with 50 or 150 mg triclosan/ protein reductases have been identified: had a higher number of liver tumors, kg bw/day from postnatal day 3 to 16. FabI, FabK, FabL, and FabV (Refs. 276 larger tumor size, and greater tumor Significant reductions in the T4 levels of and 277). Several recent studies have incidence than mice given DEN alone, 16-day-old offspring in both dose groups further characterized the effect of suggesting that triclosan may be a tumor were noted. This study corroborates the triclosan on enoyl-acyl carrier protein promoter for other carcinogens in the effects on the thyroid seen in previous reductases in different bacterial species, liver. The authors conclude that long- animal studies, but does not provide which confirmed that over-expression of term triclosan treatment substantially long-term data on the hormonal effects the fabI gene results in reduced accelerates the development of of triclosan exposure. Another new triclosan susceptibility in S. aureus (Ref. hepatocellular carcinoma in mice. The study showed that when triclosan was 278), demonstrated that FabV can confer relevance of this study to humans, administered directly into the stomach resistance to triclosan in Pseudomonas however, is not clear. The (i.e., intragastrically) of adult rats at aeruginosa (Ref. 279), and refuted the concentrations of triclosan used in this doses of 10, 50, and 200 mg/kg for 8 theory that FabK from Enterococcus study are likely much higher than the weeks, it resulted in a significant faecalis is responsible for the inherent concentrations that health care workers decrease in daily sperm production, triclosan resistance of this organism would be exposed to during antiseptic changes in sperm morphology, and (Ref. 280). Taken together, these studies use. We invite comment on what these epididymal histopathology in rats suggest that some bacteria have multiple findings tell us about triclosan’s treated with the highest dose of mechanisms that can be used to survive potential impact on human health and triclosan (Ref. 269). in the presence of triclosan. the submission of additional data on The information in these studies has A recent study analyzed 1,388 clinical this subject. not changed our assessment of the need isolates of S. aureus to determine their New triclosan findings on muscle for additional data on hormonal effects. triclosan susceptibilities (Ref. 79). Sixty- function. In the 2013 Consumer Wash At this time, no adequate long-term (i.e., eight strains that exhibited reduced PR, we described a study on the more than 30 days) in vivo animal susceptibility to triclosan, defined as a physiological effects of triclosan studies have been conducted to address minimum bactericidal concentration treatment on muscle function in mice the consequences of these hormonal greater than 4 mg/L, were chosen for and fish (Ref. 266). A newer study effects on functional endpoints of further characterization, including further examined the physiological growth and development (e.g., link of sequencing of the fabI gene. Previous effects of triclosan treatment on muscle preputial separation to sexual studies have shown that mutations in, function in fish (Ref. 267). This study differentiation and fertility, link of or overexpression of, the fabI gene can examined whether triclosan’s effect on decreased thyroxine/triiodothyronine to result in reduced susceptibility to fish swimming performance correlates growth and neurobehavioral triclosan (Ref. 275). Among the 68 with altered messenger ribonucleic acid development) in exposed fetuses or clinical isolates with reduced (mRNA) and protein expression of genes pups. Studies in juvenile animals (of the susceptibility to triclosan, only 30 had known to be critical for muscle type described in section VII.C.3) could a mutation in the fabI gene, while 38 function, and supports the negative address the consequences of short-term strains had a normal (wild-type) fabI effects on muscle function seen in the thyroid and reproductive findings on gene. Further molecular analysis previous study. We invite comment on the fertility, growth, and development of identified novel resistance mechanisms what these findings tell us about triclosan-exposed litters. linked to the presence of an additional, triclosan’s potential impact on human New triclosan resistance data. The alternative fabI gene derived from health and the submission of additional studies reviewed in the 2013 Consumer another species of Staphylococcus in data on this subject. Wash PR showed that bacterial species some of the strains, which was most New triclosan data on hormonal with reduced susceptibility to triclosan likely acquired by horizontal transfer effects. The studies reviewed in the were also resistant to one or more of the (the transmission of DNA between 2013 Consumer Wash PR have tested antibiotics (Refs. 61 through 66, different organisms, rather than from demonstrated that triclosan has effects 69, 72, 74 through 77, and 263). Several parent to offspring). Clinical S. aureus on the thyroid, estrogen, and studies suggested that an efflux strains with decreased susceptibility to testosterone systems in several animal mechanism is responsible for the triclosan had a strong association with species, including mammalian species observed reduced triclosan the presence of a mutated fabI gene or (Refs. 42, 44 through 48, 51, and 262). susceptibility in some of the bacteria the alternative fabI gene (P <0.001). The A recent report describes two studies of exhibiting resistance (Refs. 66, 69, 76, authors suggest that this finding is the the effect of triclosan exposure on and 109). Newer studies have further first clear evidence that utilization of thyroid hormone levels in pregnant and characterized efflux pump activity in antiseptics can drive development of lactating rats, and in directly exposed response to triclosan in a variety of antiseptic resistance in clinical isolates. offspring (Ref. 268). Pregnant rats these bacterial species (Refs. 110 and The possibility that an antiseptic may (dams) were treated with 75, 150, or 300 270 through 274). Although the clinical drive the development of resistance and mg triclosan per kilogram of body relevance of these studies is not clear, the possibility of horizontal transfer of weight per day (mg/kg bw/day) the possibility that triclosan contributes resistance determinants to clinical throughout gestation and the lactation to changes in antibiotic susceptibility isolates warrant further evaluation. period by gavage. Total thyroxine (T4) warrants further evaluation. Other studies have evaluated the serum levels were measured in both the In addition to bacterial efflux activity, antiseptic and antibiotic susceptibility dams and offspring, which had indirect other mechanisms have been described profiles of clinical isolates or isolates of exposure to triclosan through the that may also contribute to reduced bacteria associated with specific placenta and maternal milk. All doses of triclosan susceptibility. At low hospital outbreaks. In one study, the

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triclosan susceptibility of clinical • Laboratory studies demonstrate nonmonograph in any final rule based isolates of S. epidermidis isolated from triclosan’s ability to alter antibiotic on this proposed rule. We recognize, blood cultures of patients that were susceptibilities (Refs. 61 through 66, 69, based on the scope of products subject collected prior to the introduction of 72, 74 through 77, and 263). to this monograph, that manufacturers triclosan (during 1965–1966, ‘‘old’’ • Data define triclosan’s mechanisms will need time to comply with a final isolates) was compared to modern of action and demonstrate that these rule based on this proposed rule. isolates, collected in 2010–2011 (Ref. mechanisms are dose dependent (Ref. However, because of the potential 281). None of the isolates from 1965– 113). effectiveness and safety considerations 1966 were tolerant to triclosan; • Data demonstrate that exposure to raised by the data for some antiseptic however, 12.5 percent of the modern triclosan changes efflux pump activity, active ingredients evaluated, we believe isolates had decreased triclosan a common nonspecific bacterial that an effective date later than 1 year susceptibility, with MIC values that resistance mechanism (Refs. 66, 69, 76, after publication of the final rule would were up to 32-fold higher than the and 109). not be appropriate or necessary. highest value found in the old isolates. • Data show that low levels of Consequently, any final rule that results When triclosan-susceptible strains were triclosan may persist in the environment from this proposed rule will be effective grown in increasing concentrations of (Refs. 91, 116, 117, and 284 through 1 year after the date of the final rule’s triclosan, both old and modern isolates 289). publication in the Federal Register. On could be adapted to the same triclosan However, the administrative record is or after that date, any OTC health care MIC level as found in modern tolerant not complete with respect to data that antiseptic drug product that is subject to isolates. Although this study suggests would clarify the potential public health the monograph and that contains a that decreased susceptibility to triclosan impact of the currently available data. nonmonograph condition, i.e., a can occur in relevant organisms as a Examples of the type of information that condition that would cause the drug to result of triclosan exposure, the could be submitted to complete the be not GRAS/GRAE or to be source(s) and extent of triclosan record include the following: misbranded, could not be introduced or exposure for the modern isolates are • Data to characterize the delivered for introduction into interstate unknown, which makes the relevance of concentrations and antimicrobial commerce unless it is the subject of an these data to the clinical setting unclear. activity of triclosan in various biological approved new drug application or In another recent study (Ref. 282), the and environmental compartments (e.g., abbreviated new drug application. Any antimicrobial activity of triclosan was on the skin, in the gut, and in OTC health care antiseptic drug product evaluated for a multidrug-resistant environmental matrices); subject to the final rule that is strain of P. aeruginosa that had caused • data to characterize the antiseptic repackaged or relabeled after the an outbreak in an oncohematology unit and antibiotic susceptibility levels of effective date of the final rule would be in Italy (Ref. 283). Experimental environmental isolates in areas of required to be in compliance with the exposure to triclosan has been shown to prevalent antiseptic use, e.g., in health final rule, regardless of the date the lead to changes in bacterial efflux pump care, food handler, and veterinary product was initially introduced or activity, which can result in antibiotics settings; and initially delivered for introduction into being removed from the bacterial cell • data to characterize the potential for interstate commerce. and bacterial resistance (Ref. 66). The the reduced antiseptic susceptibility authors of this study examined whether IX. Summary of Preliminary Regulatory caused by triclosan to be transferred to Impact Analysis triclosan exposure increased the level of other bacteria that are still sensitive to antibiotic resistance in the outbreak triclosan. The summary analysis of benefits and strain. The outbreak strain was adapted costs included in this proposed rule is to grow in the presence of triclosan by b. Triclosan Safety Data Gaps. drawn from the detailed Preliminary serial passage in gradually increasing In summary, our administrative Regulatory Impact Analysis (PRIA) that triclosan concentrations, up to 3,400 record for the safety of triclosan is is available at http:// mg/L triclosan. Then, the susceptibility incomplete with respect to the www.regulations.gov, Docket No. FDA– of triclosan-adapted and unadapted P. following: 2015–N–0101 (formerly Docket No. aeruginosa to a panel of antibiotics that • Human pharmacokinetic studies FDA–1975–N–0012). are typically exported by efflux pumps, under maximal use conditions when A. Introduction namely tetracycline, ciprofloxacin, applied topically (MUsT), including amikacin, levofloxacin, carbenicillin, documentation of validation of the FDA has examined the impacts of the and chloramphenicol, was determined. methods used to measure triclosan and proposed rule under Executive Order For all antibiotics examined, the MIC of its metabolites; 12866, Executive Order 13563, the the triclosan-adapted strain was 2-fold • animal ADME; Regulatory Flexibility Act (5 U.S.C. higher than the unadapted strain. The • dermal carcinogenicity; 601–612), and the Unfunded Mandates addition of efflux pump inhibitors • potential hormonal effects; and Reform Act of 1995 (Pub. L. 104–4). reduced the MICs 2- to 4-fold for both • data to clarify the relevance of Executive Orders 12866 and 13563 strains and all antibiotics examined, antimicrobial resistance laboratory direct Agencies to assess all costs and suggesting that an efflux pump findings to the health care setting. benefits of available regulatory mechanism is involved in the reduced alternatives and, when regulation is VIII. Proposed Effective Date susceptibility. Despite the trend for the necessary, to select regulatory triclosan-adapted strain to be less Based on the currently available data, approaches that maximize net benefits susceptible to the tested antibiotics, the this proposed rule finds that additional (including potential economic, differences were very modest and the data are necessary to establish the safety environmental, public health and safety, clinical relevance of these small changes and effectiveness of health care and other advantages; distributive in MIC, if any, are not known. antiseptic active ingredients for use in impacts; and equity). The Agency Overall, the administrative record for OTC health care antiseptic drug believes that this proposed rule is a triclosan is complete on the following products. Accordingly, health care significant regulatory action as defined aspects of the resistance issue: antiseptic active ingredients would be by Executive Order 12866.

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The Regulatory Flexibility Act ‘‘Economic Data: Costs and Benefits FDA also examined the economic requires Agencies to analyze regulatory Statement.’’ Benefits are attributed to implications of the rule as required by options that would minimize any reducing the potential adverse health the Regulatory Flexibility Act. If a rule significant impact of a rule on small effects associated with exposure to will have a significant economic impact entities. The proposed rule could antiseptic active ingredients in the event on a substantial number of small impose significant economic burdens on that any active ingredient is shown to be entities, the Regulatory Flexibility Act a substantial number of small entities. unsafe or ineffective for chronic use. requires Agencies to analyze regulatory Section 202(a) of the Unfunded Annual benefits are estimated to range options that would lessen the economic Mandates Reform Act of 1995 requires between $0 and $0.16 million. We effect of the rule on small entities. The that Agencies prepare a written estimate the present value associated rule could impose a significant statement, which includes an with $0.16 million of annual benefits, economic impact on a substantial assessment of anticipated costs and number of small entities. For small benefits, before proposing ‘‘any rule that over a 10-year period, to approximately equal $1.4 million at a 3 percent entities, we estimate the rule’s costs to includes any Federal mandate that may roughly range between 0.01 and 82.18 result in the expenditure by State, local, discount rate and $1.1 million at a 7 percent discount rate. percent of average annual revenues. In and tribal governments, in the aggregate, the Initial Regulatory Analysis, we or by the private sector, of $100,000,000 Costs include the one-time costs assess several regulatory options that or more (adjusted annually for inflation) associated with reformulating products, would reduce the proposed rule’s in any one year.’’ The current threshold relabeling reformulated products, and burden on small entities. These options after adjustment for inflation is $141 conducting both safety and efficacy include extending testing compliance million, using the most current (2013) tests. We estimate one-time upfront time to 24 months (rather than 12 Implicit Price Deflator for the Gross costs to approximately range between months), and extending relabeling Domestic Product. FDA expects that this $64.0 million and $90.8 million. compliance times to 18 months (rather proposed rule could result in a 1-year Annualizing these costs over a 10-year than 12 months). expenditure that would meet or exceed period, we estimate total annualized this amount. The full discussion of economic costs to range from $7.3 and $10.4 impacts is available in Docket No. FDA– B. Summary of Costs and Benefits million at a 3 percent discount rate to 2015–N–0101 http://www.fda.gov/ The proposed rule’s costs and benefits $8.5 and $12.1 million at a 7 percent AboutFDA/ReportsManualsForms/ are summarized in table 12 entitled discount rate. Reports/EconomicAnalyses/default.htm.

TABLE 12—ECONOMIC DATA: COSTS AND BENEFITS STATEMENT

Units Category Low Median High Discount Period Notes estimate estimate estimate Year dollars rate covered (percent) (years)

Benefits: Annualized Monetized 0.0 $0.08 $0.16 2013 7 10 Value of reduced number $millions/year. 0.0 0.08 0.16 2013 3 10 of adverse events asso- Annualized Monetized ciated with using non- $millions/year. GRAS/GRAE antiseptic active ingredients. Range of estimates captures uncertainty.

Annualized Quantified 0 10.3 20.6 ...... 7 10 Reduced antiseptic active billion/year. 0 10.3 20.6 ...... 3 10 ingredient exposure (in Annualized Quantified milliliters). Range of es- billion/year. timates captures uncertainty.

Qualitative ...... Value of infection avoidance associated with switching from non-GRAS/GRAE antiseptic active ingredients to NDA or ANDA antiseptics.

Costs: Annualized Monetized 8.5 10.3 12.1 2013 7 10 Annualized costs of refor- $millions/year. 7.3 8.9 10.4 2013 3 10 mulating and testing an- Annualized Monetized tiseptic products. Range $millions/year. of estimates capture uncertainty.

Annualized Quantified ...... 7 billion/year. Annualized Quantified ...... 3 billion/year.

Qualitative ...... Where the products affected by this proposed rule are currently chosen over NDA and ANDA alternatives (such as chlorhexidine products), a switch brought on by the rule may lead to search costs or other types of transactions costs. In this scenario, there are also the potential costs associated with adverse reactions if patients are allergic to substitute products.

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TABLE 12—ECONOMIC DATA: COSTS AND BENEFITS STATEMENT—Continued

Units Category Low Median High Discount Period Notes estimate estimate estimate Year dollars rate covered (percent) (years)

Transfers: Federal Annualized ...... 7 Monetized $millions/ ...... 3 year. From/To. Other Annualized ...... 7 Monetized $millions/ ...... 3 year. From/To.

Effects: State, Local, or Tribal Government: Not applicable. Small Business: The costs associated with potentially affected small entities range between 0.01 and 82.18 percent of their average annual revenues. Wages: No estimated effect. Growth: No estimated effect.

X. Paperwork Reduction Act of 1995 that is otherwise not identical with, a agency proposed to act through requirement under the FD&C Act, the adjudication or rulemaking to preempt This proposed rule contains no Poison Prevention Packaging Act of State law, the agency shall provide all collections of information. Therefore, 1970 (15 U.S.C. 1471 et seq.), or the Fair affected State and local officials notice clearance by the Office of Management Packaging and Labeling Act (15 U.S.C. and an opportunity for appropriate and Budget under the Paperwork 1451 et seq.). Currently, this provision participation in the proceedings.’’ FDA Reduction Act of 1995 is not required. operates to preempt States from is providing an opportunity for State XI. Environmental Impact imposing requirements related to the and local officials to comment on this regulation of nonprescription drug rulemaking. We have determined under 21 CFR products. (See section 751(b) through (e) 25.31(a) that this action is of a type that of the FD&C Act for the scope of the XIII. References does not individually or cumulatively express preemption provision, the The following references have been have a significant effect on the human exemption procedures, and the placed on display in the Division of environment. Therefore, neither an exceptions to the provision.) Dockets Management (see ADDRESSES) environmental assessment nor an This proposed rule, if finalized as and may be seen by interested persons environmental impact statement is proposed, would remove from the between 9 a.m. and 4 p.m., Monday required. health care antiseptic monograph any through Friday, and are available XII. Federalism active ingredient for which the electronically at http:// additional safety and effectiveness data www.regulations.gov. (FDA has verified FDA has analyzed this proposed rule required to show that a health care all Web site addresses in this reference in accordance with the principles set antiseptic product containing that section, but we are not responsible for forth in Executive Order 13132. FDA ingredient would be GRAS/GRAE have any subsequent changes to the Web sites has determined that the proposed rule, not become available. Any final rule after this proposed rule publishes in the if finalized, would have a preemptive would have a preemptive effect in that Federal Register.) effect on State law. Section 4(a) of the it would preclude States from issuing 1. Brown, T. L., et al., ‘‘Can Alcohol-Based Executive order requires Agencies to requirements related to OTC health care Hand-Rub Solutions Cause You to Lose ‘‘construe . . . a Federal statute to antiseptics that are different from, in Your Driver’s License? Comparative preempt State law only where the addition to, or not otherwise identical Cutaneous Absorption of Various statute contains an express preemption with a requirement in the final rule. Alcohols,’’ Antimicrobial Agents and provision or there is some other clear This preemptive effect is consistent Chemotherapy, 51:1107–1108, 2007. evidence that the Congress intended with what Congress set forth in section 2. Calafat, A. M., et al., ‘‘Urinary preemption of State law, or where the 751 of the FD&C Act. Section 751(a) of Concentrations of Triclosan in the U.S. exercise of State authority conflicts with Population: 2003–2004,’’ Environmental the FD&C Act displaces both State Health Perspectives, 116:303–307, 2008. the exercise of Federal authority under legislative requirements and State 3. Centers for Disease Control and the Federal statute.’’ Section 751 of the common law duties. We also note that Prevention, ‘‘Fourth National Report on FD&C Act (21 U.S.C. 379r) is an express even where the express preemption Human Exposure to Environmental preemption provision. Section 751(a) of provision is not applicable, implied Chemicals, Updated Tables, July 2010,’’ the FD&C Act provides that no State or preemption may arise (see Geier v. 2010. political subdivision of a State may American Honda Co., 529 U.S. 861 4. Kramer, A., et al., ‘‘Quantity of Ethanol establish or continue in effect any (2000)). Absorption After Excessive Hand requirement that: (1) Relates to the FDA believes that the preemptive Disinfection Using Three Commercially Available Hand Rubs Is Minimal and regulation of a drug that is not subject effect of the proposed rule, if finalized, Below Toxic Levels for Humans,’’ BMC to the requirements of section 503(b)(1) would be consistent with Executive Infectious Diseases, 7:117, 2007. or 503(f)(1)(A) of the FD&C Act and (2) Order 13132. Section 4(e) of the 5. Miller, M. A., et al., ‘‘Does the Clinical Use is different from or in addition to, or Executive order provides that ‘‘when an of Ethanol-Based Hand Sanitizer Elevate

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Blood Alcohol Levels? A Prospective –0242, –0066, –0171, –0161, –0179, 32. Aiello, A. E., et al., ‘‘A Comparison of the Study,’’ American Journal of Emergency –0241, –0243, –0221, –0265, –0271, Bacteria Found on the Hands of Medicine, 24:815–817, 2006. –0010, –0050, –0052, –0077, –0078, ‘Homemakers’ and Neonatal Intensive 6. Transcript of the January 22, 1997, Meeting –0083, –0084, –0050, –0051, and –0052. Care Unit Nurses,’’ Journal of Hospital of the Joint Nonprescription Drugs and 13. Product labels in OTC Vol. 03HCATFM. Infection, 54:310–315, 2003. Anti-Infective Drugs Advisory 14. Comment No. FDA–1975–N–0012–0062. 33. Briefing Material for the March 23, 2005, Committees in OTC Vol. 230002. 15. Comment No. FDA–1975–N–0012–0115. Meeting of the Nonprescription Drugs 7. Comment No. FDA–1975–N–0012–0081. 16. Comment No. FDA–1975–N–0012–0091. Advisory Committee, available at http:// 8. Transcript of the March 23, 2005, Meeting 17. Comment No. FDA–1975–N–0012–0187. www.fda.gov/ohrms/dockets/ac/05/ of the Nonprescription Drugs Advisory 18. Comment No. FDA–1975–N–0012–0065. briefing/2005-4098B1_02_01-FDA- Committee, 2005, available at http:// 19. Comment No. FDA–1975–N–0012–0102. TOC.htm. www.fda.gov/ohrms/dockets/ac/05/ 20. Comment No. FDA–1975–N–0012–0229. 34. FDA Review of Health Care Personnel transcripts/2005-4184T1.pdf. 21. Centers for Disease Control and Hand Wash Effectiveness Data in OTC 9. Summary Minutes of the November 14, Prevention, ‘‘Guideline for Hand Vol. 03HCATFM. 2008, Feedback Meeting with Personal Hygiene in Health-Care Settings: 35. FDA Review of Surgical Hand Scrub Care Products Council and Soap and Recommendations of the Healthcare Effectiveness Data in OTC Vol. Detergent Association in OTC Vol. Infection Control Practices Advisory 03HCATFM. 230002. Committee and the HICPAC/SHEA/ 36. FDA Review of Patient Preoperative Skin 10. Transcript of the September 3, 2014, APIC/IDSA Hand Hygiene Task Force,’’ Preparation Effectiveness Data in OTC Meeting of the Nonprescription Drugs Morbidity and Mortality Weekly Report, Vol. 03HCATFM. Advisory Committee, 2014, available at 51:1–45, 2002. 37. FDA Review of Health Care Antiseptic http://www.fda.gov/downloads/ 22. Mangram, A. J., et al., ‘‘Guideline for Clinical Outcome Effectiveness Data in AdvisoryCommittees/CommitteesMeeting Prevention of Surgical Site Infection, OTC Vol. 03HCATFM. Materials/Drugs/Nonprescription 1999. Centers for Disease Control and 38. Comment Nos. FDA–1975–N–0012–0064, DrugsAdvisoryCommittee/ Prevention (CDC) Hospital Infection –0071, 0081, –0082, –0087, –0088, and UCM421121.pdf. Control Practices Advisory Committee,’’ –0096. 11. Comment Nos. FDA–1975–N–0012–0004, American Journal of Infection Control, 39. Comment Nos. FDA–1975–N–0012–0073, –0062, –0064, –0068, –0073, –0069, 27:97–132, 1999. –0071, –0075, –0081, –0085, –0089, –0079, –0071, –0075, –0081, –0082, 23. WHO, ‘‘WHO Guidelines on Hand –0093, –0096, –0105, –0111, –0108, –0085, –0087, –0132, –0088, –0089, Hygiene in Health Care: First Global –0109, –0113, –0116, –0117, –0119, –0128, –0127, –0153, –0154, –0155, –0090, –0091, –0092, –0093, –0094,– Patient Safety Challenge Clean Care Is –0158, –0157, –0176, –0177, –0200, 0095, –0096, –0097, –0098, –0100, Safer Care,’’ WHO Guidelines on Hand –0201, –0282, –0275, –0285, –0286, –0102, –0105, –0107, –0111, –0108, Hygiene in Health Care: First Global –0276, –0288, –0266, –0164, –0166, –0109, –0110, –0134, –0112, –0113, Patient Safety Challenge Clean Care Is –0184, –0227, –0194, –0238, –0037, –0115, –0116, –0117, –0119, –0123, Safer Care, Geneva, 2009. –0258, –0124, –0143, –0160, –0172, –0128, –0127, –0135, –0148, –0153, 24. van Kleef, E., et al., ‘‘Excess Length of –0264, –0178, –0191, –0118, –0121, –0154, –0155, –0158, –0157, –0159, Stay and Mortality Due to Clostridium –0161, –0198, –0241, and –0243. –0163, –0176, –0177, –0199, –0200, difficile Infection: A Multi-State 40. ICH guideline, ‘‘Guideline on the Need –0201, –0202, –0215, –0216, –0217, Modelling Approach,’’ Journal of for Carcinogenicity Studies of –0218, –0219, –0005, –0223, –0284, Hospital Infection, available at http:// Pharmaceuticals S1A,’’ November 1995, –0281, –0282, –0283, –0224, –0275, dx.doi.org/10.1016/j.jhin.2014.08.008, available at http://www.ich.org/ –0285, –0286, –0276, –0275, –0288, 2014. fileadmin/Public_Web_Site/ICH_ –0277, –0287, –0266, –0268, –0065, 25. Scott, R. D., ‘‘The Direct Medical Costs of Products/Guidelines/Safety/S1A/Step4/ –0130, –0164, –0166, –0184, –0227, Healthcare-Associated Infections in U.S. S1A_Guideline.pdf. –0187, –0192, –0194, –0196, –0237, Hospitals and the Benefits of 41. American Diabetes Association, –0238, –0037, –0038, –0245, –0258, Prevention,’’ 2009, available at http:// ‘‘Standards of Medical Care in _ –0273, –0204, –0206, –0207, –0208, www.cdc.gov/HAI/pdfs/hai/Scott Diabetes—2013,’’ Diabetes Care, 36:S11– –0209, –0212, –0213, –0214, –0269, CostPaper.pdf. S66, 2013. –0053, –0122, –0124, –0160, –0172, 26. Goudie, A., et al., ‘‘Attributable Cost and 42. Ahn, K. C., et al., ‘‘In Vitro Biologic –0180, –0181, –0229, –0230, –0231, Length of Stay for Central Line- Activities of the Antimicrobials –0232, –0234, –0247, –0249, –0250, Associated Bloodstream Infections,’’ Triclocarban, Its Analogs, and Triclosan –253, –0255, –0264, –0010, –0129, Pediatrics, 133:e1525–e1532, 2014. in Bioassay Screens: Receptor-Based –0138, –0066, –0126, –0140, –0178, 27. Zimlichman, E., et al., ‘‘Health Care- Bioassay Screens,’’ Environmental –0191, –0118, –0121, –0161, –0179, Associated Infections: A Meta-Analysis Health Perspectives, 116:1203–1210, –0198, –0241, –0243, –0010, –0015, of Costs and Financial Impact on the US 2008. –0016, –0017, and –0018. Health Care System,’’ JAMA Internal 43. Chen, J., et al., ‘‘Triclocarban Enhances 12. Comment Nos. FDA–1975–N–0012–0003, Medicine, 173:2039–2046, 2013. Testosterone Action: A New Type of –0063, –0062, –0069, –0070, –0071, 28. Larson, E., ‘‘Innovations in Health Care: Endocrine Disruptor?,’’ Endocrinology, –0075, –0085, –0088, –0089, –0090, Antisepsis as a Case Study,’’ American 149:1173–1179, 2008. –0091, –0092, –0094, –0095, –0096, Journal of Public Health, 79:92–99, 1989. 44. Crofton, K. M., et al., ‘‘Short-Term In Vivo –0102, –0105, –0107, –0111, –0108, 29. Malik, V. K. and A. Dey, ‘‘Surgical Site Exposure to the Water Contaminant –0109, –0134, –0112, –0115, –0116, Infection: Preventive Strategies,’’ Triclosan: Evidence for Disruption of –0119, –0127, –0148, –0149, –0151, Principles and Practice of Wound Care, Thyroxine,’’ Environmental Toxicology –0159, –0176, –0177, –0200, –0201, Jaypee Brothers Medical Publishers Ltd., and Pharmacology, 24:194–197, 2007. –0202, –0219, –0220, –0223, –0281, New Delhi, 98–101, 2012. 45. Gee, R. H., et al., ‘‘Oestrogenic and –0282, –0283, –0224, –0286, –0276, 30. The Joint Commission, ‘‘2015 National Androgenic Activity of Triclosan in –0275, –0288, –0266, –0289, –0065, Patient Safety Goals: Hospital,’’ 2015, Breast Cancer Cells,’’ Journal of Applied –0130, –0164, –0166, –0184, –0227, available at http:// Toxicology, 28:78–91, 2008. –0187, –0189, –0196, –0015, –0237, www.jointcommission.org/assets/1/6/ 46. Jacobs, M. N., G. T. Nolan, and S. R. –0238, –0274, –0238, –0214, –0053, 2015_NPSG_HAP.pdf. Hood, ‘‘Lignans, Bacteriocides and –0122, –0137, –0143, –0146, –0160, 31. Fierer, N., et al., ‘‘The Influence of Sex, Organochlorine Compounds Activate the –0162, –0186, –0180, –0181, –0183, Handedness, and Washing on the Human Pregnane X Receptor (PXR),’’ –0229, –0230, –0231, –0232, –0235, Diversity of Hand Surface Bacteria,’’ Toxicology and Applied Pharmacology, –0248, –0255, –0256, –02643, –0010, Proceedings of the National Academy of 209:123–133, 2005. –0139, –0150, –0106, –0136, –0141, Sciences of the USA, 105:17994–17999, 47. Kumar, V., C. Balomajumder, and P. Roy, –0142, –0152, –0168, –0169, –0170, 2008. ‘‘Disruption of LH-Induced Testosterone

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Biosynthesis in Testicular Leydig Cells Antimicrobial Agents,’’ Journal of Campylobacter spp. Isolated From by Triclosan: Probable Mechanism of Clinical Microbiology, 42:73–78, 2004. Humans and Animals,’’ Journal of Action,’’ Toxicology, 250:124–131, 2008. 63. Braoudaki, M. and A. C. Hilton, ‘‘Low Antimicrobial Chemotherapy, 52:507– 48. Kumar, V., et al., ‘‘Alteration of Testicular Level of Cross-Resistance Between 510, 2003. Steroidogenesis and Histopathology of Triclosan and Antibiotics in Escherichia 76. Sanchez, P., E. Moreno, and J. L. Reproductive System in Male Rats coli K–12 and E. coli O55 Compared to Martinez, ‘‘The Biocide Triclosan Selects Treated With Triclosan,’’ Reproductive E. coli O157,’’ FEMS Microbiology Stenotrophomonas maltophilia Mutants Toxicology, 27:177–185, 2009. Letters, 235:305–309, 2004. That Overproduce the SmeDEF 49. Paul, K. B., et al., ‘‘Short-Term Exposure 64. Brenwald, N. P. and A. P. Fraise, Multidrug Efflux Pump,’’ Antimicrobial to Triclosan Decreases Thyroxine In Vivo ‘‘Triclosan Resistance in Methicillin- Agents and Chemotherapy, 49:781–782, via Upregulation of Hepatic Catabolism Resistant Staphylococcus aureus 2005. in Young Long-Evans Rats,’’ (MRSA),’’ Journal of Hospital Infection, 77. Seaman, P. F., D. Ochs, and M. J. Day, Toxicological Sciences, 113:367–379, 55:141–144, 2003. ‘‘Small-Colony Variants: A Novel 2010. 65. Chen, Y., et al., ‘‘Triclosan Resistance in Mechanism for Triclosan Resistance in 50. Stoker, T. E., E. K. Gibson, and L. M. Clinical Isolates of Acinetobacter Methicillin-Resistant Staphylococcus Zorrilla, ‘‘Triclosan Exposure Modulates baumannii,’’ Journal of Medical aureus,’’ Journal of Antimicrobial Estrogen-Dependent Responses in the Microbiology, 58:1086–1091, 2009. Chemotherapy, 59:43–50, 2007. Female Wistar Rat,’’ Toxicological 66. Chuanchuen, R., et al., ‘‘Cross-Resistance 78. Tkachenko, O., et al., ‘‘A Triclosan- Sciences, 117:45–53, 2010. Between Triclosan and Antibiotics in Ciprofloxacin Cross-Resistant Mutant 51. Zorrilla, L. M., et al., ‘‘The Effects of Pseudomonas aeruginosa Is Mediated by Strain of Staphylococcus aureus Triclosan on Puberty and Thyroid Multidrug Efflux Pumps: Exposure of a Displays an Alteration in the Expression Hormones in Male Wistar Rats,’’ Susceptible Mutant Strain to Triclosan of Several Cell Membrane Structural and Toxicological Sciences, 107:56–64, 2009. Selects nfxB Mutants Overexpressing Functional Genes,’’ Research in 52. Anway, M. D. and M. K. Skinner, MexCD-OprJ,’’ Antimicrobial Agents and Microbiology, 158:651–658, 2007. ‘‘Epigenetic Transgenerational Actions of Chemotherapy, 45:428–432, 2001. 79. Ciusa, M. L., et al., ‘‘A Novel Resistance Endocrine Disruptors,’’ Endocrinology, 67. Cookson, B. D., et al., ‘‘Transferable Mechanism to Triclosan That Suggests 147:S43–49, 2006. Resistance to Triclosan in MRSA,’’ Horizontal Gene Transfer and 53. Bernal, A. J. and R. L. Jirtle, ‘‘Epigenomic Lancet, 337:1548–1549, 1991. Demonstrates a Potential Selective Disruption: The Effects of Early 68. Joynson, J. A., B. Forbes, and R. J. Pressure for Reduced Biocide Developmental Exposures,’’ Birth Defects Lambert, ‘‘Adaptive Resistance to Susceptibility in Clinical Strains of Research (Part A), 88:938–944, 2010. Benzalkonium Chloride, Amikacin and Staphylococcus aureus,’’ International Tobramycin: The Effect on Susceptibility 54. Alexander, E. K., et al., ‘‘Timing and Journal of Antimicrobial Agents, 40:210– to Other Antimicrobials,’’ Journal of Magnitude of Increases in Levothyroxine 220, 2012. Applied Microbiology, 93:96–107, 2002. Requirements During Pregnancy in 80. Tandukar, M., et al., ‘‘Long-Term 69. Karatzas, K. A., et al., ‘‘Prolonged Women With Hypothyroidism,’’ New Exposure to Benzalkonium Chloride Treatment of Salmonella enterica serovar Disinfectants Results in Change of England Journal of Medicine, 351:241– Typhimurium With Commercial Microbial Community Structure and 249, 2004. Disinfectants Selects for Multiple Increased Antimicrobial Resistance,’’ 55. Mitchell, M. L. and R. Z. Klein, ‘‘The Antibiotic Resistance, Increased Efflux Sequelae of Untreated Maternal and Reduced Invasiveness,’’ Journal of Environmental Science and Technology, Hypothyroidism,’’ European Journal of Antimicrobial Chemotherapy, 60:947– 47:9730–9738, 2013. Endocrinology, 151 U45–48, 2004. 955, 2007. 81. Zmantar, T., et al., ‘‘Detection of 56. Pop, V. J., et al., ‘‘Low Maternal Free 70. Lambert, R. J., J. Joynson, and B. Forbes, Macrolide and Disinfectant Resistance Thyroxine Concentrations During Early ‘‘The Relationships and Susceptibilities Genes in Clinical Staphylococcus aureus Pregnancy Are Associated With Impaired of Some Industrial, Laboratory and and Coagulase-Negative staphylococci,’’ Psychomotor Development in Infancy,’’ Clinical Isolates of Pseudomonas BMC Research Notes, 4:453, 2011. Clinical Endocrinology, 50:149–155, aeruginosa to Some Antibiotics and 82. Ho, J. and J. Branley, ‘‘Prevalence of 1999. Biocides,’’ Journal of Applied Antiseptic Resistance Genes qacA/B and 57. Fraise, A. P., ‘‘Biocide Abuse and Microbiology, 91:972–984, 2001. Specific Sequence Types of Methicillin- Antimicrobial Resistance—A Cause for 71. Langsrud, S., G. Sundheim, and A. L. Resistant Staphylococcus aureus in the Concern?,’’ Journal of Antimicrobial Holck, ‘‘Cross-Resistance to Antibiotics Era of Hand Hygiene,’’ Journal of Chemotherapy, 49:11–12, 2002. of Escherichia coli Adapted to Antimicrobial Chemotherapy, 67:1549– 58. Gilbert, P. and A. J. McBain, ‘‘Potential Benzalkonium Chloride or Exposed to 1550, 2012. Impact of Increased Use of Biocides in Stress-Inducers,’’ Journal of Applied 83. Johnson, J. G., et al., ‘‘Frequency of Consumer Products on Prevalence of Microbiology, 96:201–208, 2004. Disinfectant Resistance Genes in Antibiotic Resistance,’’ Clinical 72. Ledder, R. G., et al., ‘‘Effects of Chronic Pediatric Strains of Methicillin-Resistant Microbiology Reviews, 16:189–208, 2003. Triclosan Exposure Upon the Staphylococcus aureus,’’ Infection 59. Levy, S. B., ‘‘Antimicrobial Consumer Antimicrobial Susceptibility of 40 Ex- Control and Hospital Epidemiology, Products: Where’s the Benefit? What’s Situ Environmental and Human 34:1326–1327, 2013. the Risk?,’’ Archives of Dermatology, Isolates,’’ Journal of Applied 84. Batra, R., et al., ‘‘Efficacy and Limitation 138:1087–1088, 2002. Microbiology, 100:1132–1140, 2006. of a Chlorhexidine-Based Decolonization 60. Russell, A. D., ‘‘Biocides and 73. Loughlin, M. F., M. V. Jones, and P. A. Strategy in Preventing Transmission of Pharmacologically Active Drugs as Lambert, ‘‘Pseudomonas aeruginosa Methicillin-Resistant Staphylococcus Residues and in the Environment: Is Cells Adapted to Benzalkonium Chloride aureus in an Intensive Care Unit,’’ There a Correlation With Antibiotic Show Resistance to Other Membrane- Clinical Infectious Diseases, 50:210–217, Resistance?,’’ American Journal of Active Agents But Not to Clinically 2010. Infection Control, 30:495–498, 2002. Relevant Antibiotics,’’ Journal of 85. Buffet-Bataillon, S., et al., ‘‘Effect of 61. Birosova, L. and M. Mikulasova, Antimicrobial Chemotherapy, 49:631– Higher Minimum Inhibitory ‘‘Development of Triclosan and 639, 2002. Concentrations of Quaternary Antibiotic Resistance in Salmonella 74. Randall, L. P., et al., ‘‘Effect of Triclosan Ammonium Compounds in Clinical E. enterica serovar Typhimurium,’’ Journal or a Phenolic Farm Disinfectant on the coli Isolates on Antibiotic of Medical Microbiology, 58:436–441, Selection of Antibiotic-Resistant Susceptibilities and Clinical Outcomes,’’ 2009. Salmonella enterica,’’ Journal of Journal of Hospital Infection, 79:141– 62. Braoudaki, M. and A. C. Hilton, Antimicrobial Chemotherapy, 54:621– 146, 2011. ‘‘Adaptive Resistance to Biocides in 627, 2004. 86. Otter, J.A., et al., ‘‘Selection for qacA Salmonella enterica and Escherichia coli 75. Randall, L. P., et al., ‘‘Prevalence of Carriage in CC22, But Not CC30, O157 and Cross-Resistance to Multiple Antibiotic Resistance in 443 Methicillin-Resistant Staphylococcus

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aureus Bloodstream Infection Isolates 98. FDA draft guidance for industry, Microbiology Symposium Supplement, During a Successful Institutional ‘‘Endocrine Disruption Potential of 92:65S–71S, 2002. Infection Control Programme,’’ Journal of Drugs: Nonclinical Evaluation,’’ 112. Russell, A.D., ‘‘Do Biocides Select for Antimicrobial Chemotherapy, 68:992– September 2013, available at http:// Antibiotic Resistance?,’’ Journal of 999, 2013. www.fda.gov/Drugs/Guidance Pharmacy and Pharmacology, 52:227– 87. Sangal, V., et al., ‘‘Impacts of a Long- ComplianceRegulatoryInformation/ 233, 2000. Term Programme of Active Surveillance Guidances/default.htm. 113. Yazdankhah, S.P., et al., ‘‘Triclosan and and Chlorhexidine Baths on the Clinical 99. FDA, ‘‘Guideline for the Format and Antimicrobial Resistance in Bacteria: An and Molecular Epidemiology of Content of the Human Pharmacokinetics Overview,’’ Microbial Drug Resistance, Methicillin-Resistant Staphylococcus and Bioavailability Section of an 12:83–90, 2006. aureus (MRSA) in an Intensive Care Unit Application,’’ 1987, available at http:// 114. Martinez, J.L., ‘‘The Role of Natural in Scotland,’’ International Journal of www.fda.gov/downloads/Drugs/ Environments in the Evolution of Antimicrobial Agents, 40:323–331, 2012. GuidanceComplianceRegulatory Resistance Traits in Pathogenic 88. Interagency Task Force on Antimicrobial Information/Guidances/UCM072112.pdf. Bacteria,’’ Proceedings in Biological Resistance, ‘‘A Public Health Action Plan 100. Bashaw, E.D., et al., ‘‘Maximal Usage Science, 276:2521–2530, 2009. to Combat Antimicrobial Resistance. Trial: An Overview of the Design of 115. Nguyen, M. and G. Vedantam, ‘‘Mobile 2012 Update,’’ 2012, available at http:// Systemic Bioavailability Trial for Topical Genetic Elements in the Genus www.cdc.gov/drugresistance/itfar/ Dermatological Products,’’ Therapeutic Bacteroides, and Their Mechanism(s) of introduction_overview.html. Innovation and Regulatory Science, Dissemination,’’ Mobile Genetic 89. Ferrer, I. and E.T. Furlong, ‘‘Identification 2014. Elements, 1:187–196, 2011. of Alkyl Dimethylbenzylammonium 101. Evans, V.A. and P. Orris, ‘‘The Use of 116. Cha, J. and A.M. Cupples, ‘‘Detection of Surfactants in Water Samples by Solid- Alcohol-Based Hand Sanitizers by the Antimicrobials Triclocarban and Phase Extraction Followed by Ion Trap Pregnant Health Care Workers,’’ Journal Triclosan in Agricultural Soils Following LC/MS and LC/MS/MS,’’ Environmental of Occupational and Environmental Land Application of Municipal Science and Technology, 35:2583–2588, Medicine, 54:3, 2012. Biosolids,’’ Water Research, 43:2522– 2001. 102. Diamanti-Kandarakis, E., et al., 2530, 2009. 90. Ferrer, I. and E.T. Furlong, ‘‘Accelerated ‘‘Endocrine-Disrupting Chemicals: An 117. Kolpin, D.W., et al., ‘‘Pharmaceuticals, Solvent Extraction Followed by On-Line Endocrine Society Scientific Statement,’’ Hormones, and Other Organic Solid-Phase Extraction Coupled to Ion Endocrine Reviews, 30:293–342, 2009. Wastewater Contaminants in U.S. Trap LC/MS/MS for Analysis of 103. Sweetnam, P.M., et al., ‘‘The Role of Streams, 1999–2000: A National Benzalkonium Chlorides in Sediment Receptor Binding in Drug Discovery,’’ Reconnaissance,’’ Environmental Samples,’’ Analytical Chemistry, Journal of Natural Products, 56:441–455, Science and Technology, 36:1202–1211, 74:1275–1280, 2002. 1993. 2002. 91. Miller, T.R., et al., ‘‘Fate of Triclosan and 104. ‘‘Redbook 2000: IV.C.9.a: Guidelines for 118. Russell, A.D. and G. McDonnell, Evidence for Reductive Dechlorination of Reproduction Studies,’’ 2000, available ‘‘Concentration: A Major Factor in Triclocarban in Estuarine Sediments,’’ at http://www.fda.gov/Food/Guidance Studying Biocidal Action,’’ Journal of Environmental Science and Technology, Regulation/GuidanceDocuments Hospital Infection, 44:1–3, 2000. 42:4570–4576, 2008. RegulatoryInformation/Ingredients 119. Bevan, R.J., et al., ‘‘An Assessment of 92. ICH guidance for industry, ‘‘S1B Testing Potential Cancer Risk Following for Carcinogenicity of Pharmaceuticals,’’ AdditivesGRASPackaging/ July 1997, available at http:// ucm2006826.htm. Occupational Exposure to Ethanol,’’ www.fda.gov/Drugs/Guidance 105. EPA, ‘‘Guidelines for Reproductive Journal of Toxicology and Environmental ComplianceRegulatoryInformation/ Toxicity Risk Assessment,’’ October Health, Part B, 12:188–205, 2009. Guidances/default.htm. 1996, available at http://www2.epa.gov/ 120. Kirschner, M.H., et al., ‘‘Transdermal sites/production/files/2014-11/ Resorption of an Ethanol- and 2- 93. ICH guidance for industry, ‘‘S7A Safety _ _ Pharmacology Studies for Human documents/guidelines repro Propanol-Containing Skin Disinfectant,’’ Pharmaceuticals,’’ July 2001, available at toxicity.pdf. Langenbecks Archives of Surgery, http://www.fda.gov/Drugs/Guidance 106. FDA guidance for industry, ‘‘Nonclinical 394:151–157, 2009. ComplianceRegulatoryInformation/ Safety Evaluation of Pediatric Drug 121. Brown, T.L., et al., ‘‘Can Alcohol-Based Guidances/default.htm. Products,’’ available at http:// Hand-Rub Solutions Cause You to Lose 94. ICH guideline, ‘‘Detection of Toxicity to www.fda.gov/downloads/Drugs/ Your Driver’s License? Comparative Reproduction for Medicinal Products & GuidanceComplianceRegulatory Cutaneous Absorption of Various Toxicity to Male Fertility S5(R2),’’ Information/Guidances/ucm079247.pdf. Alcohols,’’ Antimicrobial Agents and November 2005, available at http:// 107. Stoker, T.E., et al., ‘‘Endocrine- Chemotherapy, 51:1107–1108, 2007. www.ich.org/fileadmin/Public_Web_Site/ Disrupting Chemicals: Prepubertal 122. Ahmed-Lecheheb, D., et al., ‘‘Dermal ICH_Products/Guidelines/Safety/S5_R2/ Exposures and Effects on Sexual and Pulmonary Absorption of Ethanol Step4/S5_R2__Guideline.pdf. Maturation and Thyroid Function in the From Alcohol-Based Hand Rub,’’ Journal 95. ICH guidance for industry, ‘‘S1C(R2) Dose Male Rat. A Focus on the EDSTAC of Hospital Infection, 81:31–35, 2012. Selection for Carcinogenicity Studies,’’ Recommendations,’’ Critical Reviews in 123. Miller, M.A., A. Rosin, and C.S. Crystal, (Revision 1), September 2008, available Toxicology, 30:197–252, 2000. ‘‘Alcohol-Based Hand Sanitizer: Can at http://www.fda.gov/Drugs/Guidance 108. McMurry, L.M., M. Oethinger, and S.B. Frequent Use Cause an Elevated Blood ComplianceRegulatoryInformation/ Levy, ‘‘Overexpression of marA, soxS, or Alcohol Level?,’’ American Journal of Guidances/default.htm. acrAB Produces Resistance to Triclosan Infection Control, 34:150–151, 2006. 96. ICH guidance for industry, ‘‘M3(R2) in Laboratory and Clinical Strains of 124. Bessonneau, V. and O. Thomas, Nonclinical Safety Studies for the Escherichia coli,’’ FEMS Microbiology ‘‘Assessment of Exposure to Alcohol Conduct of Human Clinical Trials and Letters, 166:305–309, 1998. Vapor From Alcohol-Based Hand Rubs,’’ Marketing Authorization for 109. Tabak, M., et al., ‘‘Effect of Triclosan on International Journal of Environmental Pharmaceuticals,’’ (Revision 1), January Salmonella typhimurium at Different Research and Public Health, 9:868–879, 2010, available at http://www.fda.gov/ Growth Stages and in Biofilms,’’ FEMS 2012. Drugs/GuidanceComplianceRegulatory Microbiology Letters, 267:200–206, 2007. 125. Beskitt, J.L. and J.D. Sun, ‘‘In Vitro Skin Information/Guidances/default.htm. 110. Srinivasan, V.B., et al., ‘‘Role of Novel Penetration Characteristics of Ethanol in 97. FDA draft guidance for industry, ‘‘Acne Multidrug Efflux Pump Involved in Drug the Rabbit, Mouse, Rat, and Human,’’ Vulgaris: Developing Drugs for Resistance in Klebsiella pneumoniae,’’ Journal of Toxicology—Cutaneous and Treatment,’’ September 2005, available at PLoS One, 9:e96288, 2014. Ocular Toxicology, 16:61–75, 1997. http://www.fda.gov/Drugs/Guidance 111. Levy, S.B., ‘‘Active Efflux, A Common 126. Behl, C.R., et al., ‘‘Hydration and ComplianceRegulatoryInformation/ Mechanism for Biocide and Antibiotic Percutaneous Absorption: I. Influence of Guidances/default.htm. Resistance,’’ Journal of Applied Hydration on Alkanol Permeation

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Through Hairless Mouse Skin,’’ Journal Production by Rat Leydig Cells With coli K–12 Studied by Transcriptome and of Investigative Dermatology, 75:346– Ethanol and Acetaldehyde: Prevention of Proteome Analyses,’’ Microbiology, 352, 1980. Ethanol Toxicity With 4- 153:935–946, 2007. 127. Durrheim, H., et al., ‘‘Permeation of methylpyrazole,’’ Alcoholism, Clinical 155. Chuanchuen, R., et al., ‘‘Susceptibilities Hairless Mouse Skin I: Experimental and Experimental Research, 7:135–139, to Antimicrobials and Disinfectants in Methods and Comparison With Human 1983. Salmonella Isolates Obtained From Epidermal Permeation by Alkanols,’’ 141. Salonen, I., P. Pakarinen, and I. Poultry and Swine in Thailand,’’ Journal Journal of Pharmaceutical Sciences, Huhtaniemi, ‘‘Effect of Chronic Ethanol of Veterinary Medical Science, 70:595– 69:781–786, 1980. Diet on Expression of Gonadotropin 601, 2008. 128. Behl, C.R., et al., ‘‘Hydration and Genes in the Male Rat,’’ Journal of 156. Lear, J.C., et al., ‘‘Chloroxylenol- and Percutaneous Absorption III: Influences Pharmacology and Experimental Triclosan-Tolerant Bacteria From of Stripping and Scalding on Hydration Therapeutics, 260:463–467, 1992. Industrial Sources—Susceptibility to Alteration of the Permeability of Hairless 142. Emanuele, N. and M.A. Emanuele, ‘‘The Antibiotics and Other Biocides,’’ Mouse Skin to Water and n-Alkanols,’’ Endocrine System: Alcohol Alters International Biodeterioration and Journal of Pharmaceutical Sciences, Critical Hormonal Balance,’’ Alcohol Biodegradation, 57:51–56, 2006. 71:229–234, 1982. Health and Research World, 21:53–64, 157. ‘‘Annual Review of Cosmetic Ingredient 129. Flynn, G.L., H. Durrheim, and W.I. 1997. Safety Assessments-2004/2005,’’ Higuchi, ‘‘Permeation of Hairless Mouse 143. Heller, M. and L. Burd, ‘‘Review of International Journal of Toxicology, 25 Skin II: Membrane Sectioning Ethanol Dispersion, Distribution, and Suppl 2:1–89, 2006. Techniques and Influence on Alkanol Elimination From the Fetal 158. Scientific Committee on Cosmetic Permeabilities,’’ Journal of Compartment,’’ Birth Defects Research Products and Non-Food Products, Pharmaceutical Sciences, 70:52–56, (Part A), 100:277–283, 2014. ‘‘Opinion of the Scientific Committee on 1981. 144. Paintner, A., A.D. Williams, and L. Cosmetic Products and Non-Food 130. National Toxicology Program, ‘‘TR 478: Burd, ‘‘Fetal Alcohol Spectrum Products (SCCNFP) Intended for Toxicology and Carcinogenesis Studies Disorders—Implications for Child Consumers Concerning Benzethonium of Diethanolamine in F344/N Rats and Neurology, Part 1: Prenatal Exposure and Chloride,’’ 2002. B6C3F1 Mice,’’ 1999. Dosimetry,’’ Journal of Child Neurology, 159. Scientific Committee on Cosmetic 131. National Toxicology Program, ‘‘NTP 27:258–263, 2012. Products and Non-Food Products, Toxicology and Carcinogenesis Studies 145. American College of Obstetricians and ‘‘Opinion of the Scientific Committee on of Benzethonium Chloride (CAS No. Gynecologists, ‘‘Alcohol and Pregnancy: Cosmetic Products and Non-Food 121–54–0) in F344/N Rats and B6C3F1 Know the Facts,’’ 2008, available at _ Products (SCCNFP) Intended for Mice (Dermal Studies),’’ National http://www.acog.org/About ACOG/ Consumers Concerning Benzethonium News_Room/News_Releases/2008/ Toxicology Program Technical Report Chloride,’’ 2003. Series, 438:1–220, 1995. Alcohol_and_Pregnancy_Know_the_ 160. Comment No. FDA–1975–N–0012–0134. 132. Stenback, F., ‘‘The Tumorigenic Effect of Facts. 161. Comment No. FDA–1975–N–0012–0171. Ethanol,’’ Acta Pathologica, 146. Ali, Y., et al., ‘‘Alcohols,’’ Disinfection, 162. Comment No. FDA–1975–N–0012–0150. Microbiologica, et Immunologica Sterilization, and Preservation, 5th ed., 163. Comment No. FDA–1975–N–0012–0186. Scandinavica, 77:325–326, 1969. Philadelphia, PA: Lippincott Williams 164. Lambert, R.J., ‘‘Comparative Analysis of 133. International Agency for Research on and Wilkins, 229–254, 2001. Antibiotic and Antimicrobial Biocide Cancer, ‘‘IARC Monographs on the 147. Kampf, G. and A. Kramer, Evaluation of Carcinogenic Risks to ‘‘Epidemiologic Background of Hand Susceptibility Data in Clinical Isolates of Humans. Volume 96, Alcohol Hygiene and Evaluation of the Most Methicillin-Sensitive Staphylococcus Consumption and Ethyl Carbamate,’’ Important Agents for Scrubs and Rubs,’’ aureus, Methicillin-Resistant 2010, available at http:// Clinical Microbiology Reviews, 17:863– Staphylococcus aureus and monographs.iarc.fr/ENG/Monographs/ 893, 2004. Pseudomonas aeruginosa Between 1989 vol96/mono96.pdf. 148. McDonnell, G.E., ‘‘Alcohols,’’ and 2000,’’ Journal of Applied 134. National Toxicology Program, ‘‘TR 510: Antisepsis, Disinfection, and Microbiology, 97:699–711, 2004. Toxicology and Carcinogenesis Studies Sterilization—Types, Action, and 165. Nakahara, H., et al., ‘‘Benzethonium of Urethane, Ethanol, and Urethane/ Resistance, ASM Press, Washington, DC, Chloride Resistance in Pseudomonas Ethanol in B6C3F1 Mice,’’ 2004. 90–92, 2007. aeruginosa Isolated From Clinical 135. Watabiki, T., et al., ‘‘Long-Term Ethanol 149. Rutala, W.A., D.J. Weber, and Healthcare Lesions,’’ Zentralblatt fur Bakteriologie, Consumption in ICR Mice Causes Infection Control Practices Advisory Mikrobiologie und Hygiene A, 257:409– Mammary Tumor in Females and Liver Committee (HICPAC), ‘‘Guideline for 413, 1984. Fibrosis in Males,’’ Alcoholism, Clinical Disinfection and Sterilization in 166. Jordan, B.J., et al., ‘‘Human Volunteer and Experimental Research, 24:117S– Healthcare Facilities, 2008,’’ 2008, Studies on Dettol Bathing Product,’’ 122S, 2000. available at http://www.cdc.gov/hicpac/ Docket No. 1975N–0183H, 1973. 136. Soffritti, M.F., et al., ‘‘Results of Long- pdf/guidelines/disinfection_nov_ 167. Jordan, B.J., J.D. Nichols, and M.J. Term Experimental Studies on the 2008.pdf. Rance, ‘‘Dettol Bathing Product- Carcinogenicity of Methyl Alcohol and 150. G-Alegria, E., et al., ‘‘High Tolerance of Preliminary Volunteer Study,’’ Docket Ethyl Alcohol in Rats,’’ Annals of the Wild Lactobacillus plantarum and No. 1975N–0183H, 1973. New York Academy of Science, 982:46– Oenococcus oeni Strains to 168. Havler, M.E. and M.J. Rance, ‘‘The 69, 2003. Lyophilisation and Stress Environmental Metabolism of p-Chloro-m-xylenol 137. Baan, R., et al., ‘‘Carcinogenicity of Conditions of Acid pH and Ethanol,’’ (PCMX) in Sprague Dawley and Gunn Alcoholic Beverages,’’ Lancet, 8:292– FEMS Microbiology Letters, 230:53–61, Wistar Rats,’’ Docket No. 1975N–0183H. 293, 2007. 2004. 169. Sved, D.W., ‘‘A Dermal Absorption 138. Centers for Disease Control and 151. Cosmetic Ingredient Review, ‘‘Final Study With [14C]-Labeled PCMX in Prevention, ‘‘Alcohol Use in Pregnancy,’’ Report on the Safety Assessment of Mice,’’ Docket No. 1975N–0183H. Updated April 17, 2014, available at Benzalkonium Chloride,’’ Journal of the 170. ‘‘A 13-Week Dermal Toxicity Study in http://www.cdc.gov/ncbddd/fasd/ American College of Toxicology, 8:589– Mice,’’ Comment No. FDA–1975–N– alcohol-use.html. 625, 1989. 0012–0242. 139. Karl, P.I. and S.E. Fisher, ‘‘Ethanol 152. U.S. Environmental Protection Agency, 171. ‘‘Teratology Study in Rats,’’ Docket No. Alters Hormone Production in Cultured ‘‘Reregistration Eligibility Decision for 1975N–0183. Human Placental Trophoblasts,’’ Alkyl Dimethyl Benzyl Ammonium 172. Lear, J.C., et al., ‘‘Chloroxylenol- and Alcoholism, Clinical and Experimental Chloride (ADBAC),’’ 2006. Triclosan-Tolerant Bacteria From Research, 17:816–821, 1993. 153. Comment No. FDA–1975–N–0012–0166. Industrial Sources,’’ Journal of Industrial 140. Santucci, L., T.J. Graham, and D.H. Van 154. Bore, E., et al., ‘‘Adapted Tolerance to Microbiology and Biotechnology, 29:238– Thiel, ‘‘Inhibition of Testosterone Benzalkonium Chloride in Escherichia 242, 2002.

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173. OTC Volume No. 020080. hydroxypropyl)nitrosamine and 204. Lyen, K.R., et al., ‘‘Transient Thyroid 174. National Toxicology Program, ‘‘NTP: Thiourea,’’ Journal of Toxicological Suppression Associated With Topically Toxicology and Carcinogenesis Studies Sciences, 25:67–75, 2000. Applied Povidone-Iodine,’’ American of 4-Hexylresorcinol in F3441N Rats and 189. Arrington, L.R., et al., ‘‘Effects of Excess Journal of Diseases of Children, 136:369– B6C3F1 Mice, Technical Report Series, Dietary Iodine Upon Rabbits, Hamsters, 370, 1982. No. 330,’’ 1988. Rats and Swine,’’ Journal of Nutrition, 205. Nobukuni, K. and S. Kawahara, 175. Robbin, B.H., ‘‘Quantitative Studies on 87:394–398, 1965. ‘‘Thyroid Function in Nurses: The the Absorption and Excretion of 190. Coakley, J.C., et al., ‘‘Transient Primary Influence of Povidone-Iodine Hand Hexylresorcinol and Heptylresorcinol Hypothyroidism in the Newborn: Washing and Gargling,’’ Dermatology, Under Different Conditions,’’ Journal of Experience of the Victorian Neonatal 204 Suppl 1:99–102, 2002. Pharmacology and Experimental Thyroid Screening Programme,’’ 206. Perez-Lopez, F.R., ‘‘Iodine and Thyroid Therapy, 43:325–333, 1931. Australian Paediatric Journal, 25:25–30, Hormones During Pregnancy and 176. Robbin, B.H., ‘‘Quantitative Studies on 1989. Postpartum,’’ Gynecological the Absorption and Excretion of Certain 191. Danziger, Y., A. Pertzelan, and M. Endocrinology, 23:414–428, 2007. Resorcinols and Cresols in Dogs and Mimouni, ‘‘Transient Congenital 207. Turner, P., B. Saeed, and M.C. Kelsey, Man,’’ Journal of Pharmacology, 52:54– Hypothyroidism After Topical Iodine in ‘‘Dermal Absorption of Isopropyl 60, 1934. Pregnancy and Lactation,’’ Archives of Alcohol From a Commercial Hand Rub: 177. McDonnell, G.E., ‘‘Halogens and Disease in Childhood, 62:295–296, 1987. Implications for Its Use in Hand Halogen-Releasing Agents’’ in 192. Delange, F., et al., ‘‘Topical Iodine, Decontamination,’’ Journal of Hospital Antisepsis, Disinfection, and Breastfeeding, and Neonatal Infection, 56:287–290, 2004. Sterilization—Types, Action, and Hypothyroidism,’’ Archives of Disease in 208. Below, H., et al., ‘‘Dermal and Resistance, ASM Press, Washington, DC, Childhood, 63:106–107, 1988. Pulmonary Absorption of Propan-1-ol 102–111, 2007. 193. Linder, N., et al., ‘‘Topical Iodine- and Propan-2-ol From Hand Rubs,’’ 178. Agency for Toxic Substances and Containing Antiseptics and Subclinical American Journal of Infection Control, Disease Registry, ‘‘Toxicological Profile Hypothyroidism in Preterm Infants,’’ 40:250–257, 2012. for Iodine,’’ April 2004, available at Journal of Pediatrics, 131:434–439, 1997. 209. Puschel, K., ‘‘Percutaneous Alcohol http://www.atsdr.cdc.gov/toxprofiles/ 194. Shoyinka, S.V., I.R. Obidike, and C.O. Intoxication,’’ European Journal of tp158.pdf. Ndumnego, ‘‘Effect of Iodine Pediatrics, 136:317–318, 1981. 179. International Programme on Chemical Supplementation on Thyroid and 210. Dhillon, S., ‘‘Toxicology Updates- Safety, ‘‘Iodine and Inorganic Iodides: Testicular Morphology and Function in Isopropanol,’’ Journal of Applied Toxicology, 15:501–506, 1995. Human Health Aspects,’’ Concise Euthyroid Rats,’’ Veterinary Research Communications, 32:635–645, 2008. 211. International Programme on Chemical International Chemical Assessment 195. Smerdely, P., et al., ‘‘Topical Iodine- Safety, ‘‘2-Propanol,’’ 1990, available at Document 72, 2009. Containing Antiseptics and Neonatal http://www.inchem.org/documents/ehc/ 180. Bos, J.D. and M.M.H.M. Meinardi, ‘‘The Hypothyroidism in Very-Low- ehc/ehc103.htm. 500 Dalton Rule for the Skin Penetration Birthweight Infants,’’ Lancet, 2:661–664, 212. Boatman, R.J., et al., ‘‘Dermal of Chemical Compounds and Drugs,’’ 1989. Absorption and Pharmacokinetics of Experimental Dermatology, 9:165–169, 196. Bongers-Schokking, J.J., et al., Isopropanol in the Male and Female F– 2000. ‘‘Influence of Timing and Dose of 344 Rat,’’ Drug Metabolism and 181. Brown, R.S., et al., ‘‘Routine Skin Thyroid Hormone Replacement on Disposition, 26:197–202, 1998. Cleansing With Povidone-Iodine Is Not a Development in Infants With Congenital 213. Martinez, T.T., et al., ‘‘A Comparison of Common Cause of Transient Neonatal Hypothyroidism,’’ Journal of Pediatrics, the Absorption and Metabolism of Hypothyroidism in North America: A 136:292–297, 2000. Isopropyl Alcohol by Oral, Dermal and Prospective Controlled Study,’’ Thyroid, 197. Calaciura, F., et al., ‘‘Childhood IQ Inhalation Routes,’’ Veterinary and 7:395–400, 1997. Measurements in Infants With Transient Human Toxicology, 28:233–236, 1986. 182. Connolly, R.J. and J.J. Shepherd, ‘‘The Congenital Hypothyroidism,’’ Clinical 214. Slauter, R.W., et al., ‘‘Disposition and Effect of Preoperative Surgical Scrubbing Endocrinology, 43:473–477, 1995. Pharmacokinetics of Isopropanol in F– With Povidone Iodine on Urinary Iodine 198. Casteels, K., S. Punt, and J. Bramswig, 344 Rats and B6C3F1 Mice,’’ Levels,’’ Australian and New Zealand ‘‘Transient Neonatal Hypothyroidism Fundamental and Applied Toxicology, Journal of Surgery, 42:94–95, 1972. During Breastfeeding After Post-Natal 23:407–420, 1994. 183. Nobukuni, K., et al., ‘‘The Influence of Maternal Topical Iodine Treatment,’’ 215. Kapp, R.W., Jr., et al., ‘‘Isopropanol: Long-Term Treatment With Povidone- European Journal of Pediatrics, 159:716– Summary of TSCA Test Rule Studies and Iodine on Thyroid Function,’’ 717, 2000. Relevance to Hazard Identification,’’ Dermatology, 195 Suppl 2:69–72, 1997. 199. Chanoine, J.P., et al., ‘‘Increased Recall Regulatory Toxicology and 184. Hays, M.T., ‘‘Estimation of Total Body Rate at Screening for Congenital Pharmacology, 23:183–192, 1996. Iodine Content in Normal Young Men,’’ Hypothyroidism in Breast Fed Infants 216. WHO International Program on Thyroid, 11:671–675, 2001. Born to Iodine Overloaded Mothers,’’ Chemical Safety Working Group, ‘‘2- 185. Vandilla, M.A. and M.J. Fulwyler, Archives of Disease in Childhood, Propanol,’’ Environmental Health ‘‘Thyroid Metabolism in Children and 63:1207–1210, 1988. Criteria, 103:132, 1990. Adults Using Very Small (Nanocurie) 200. Fisher, D.A., ‘‘The Importance of Early 217. Slaughter, R.J., et al., ‘‘Isopropanol Doses of Iodine and Iodine-131,’’ Health Management in Optimizing IQ in Infants Poisoning,’’ Clinical Toxicology, 52:470– Physics, 9:1325–1331, 1963. With Congenital Hypothyroidism,’’ 478, 2014. 186. Kanno, J., et al., ‘‘Tumor-Promoting Journal of Pediatrics, 136:273–274, 2000. 218. WHO International Agency for Research Effects of Both Iodine Deficiency and 201. Jackson, H.J. and R.M. Sutherland, on Cancer, ‘‘IARC Monographs on the Iodine Excess in the Rat Thyroid,’’ ‘‘Effect of Povidone-Iodine on Neonatal Evaluation of Carcinogenic Risks to Toxicologic Pathology, 20:226–235, Thyroid Function,’’ Lancet, 2:992, 1981. Humans: Re-Evaluation of Some Organic 1992. 202. Jeng, M.J., et al., ‘‘The Effect of Chemicals, Hydrazine and Hydrogen 187. Takegawa, K., et al., ‘‘Induction of Povidone-Iodine on Thyroid Function of Peroxide,’’ 71 (part 3):1027–1036, 1999, Squamous Cell Carcinomas in the Neonates With Different Birth Sizes,’’ available at http://monographs.iarc.fr/ Salivary Glands of Rats by Potassium Zhonghua Min Guo Xiao Er Ke Yi Xue ENG/Monographs/vol71/mono71.pdf. Iodide,’’ Japanese Journal of Cancer Hui Za Zhi, 39:371–375, 1998. 219. Burleigh-Flayer, H., et al., ‘‘Isopropanol Research, 89:105–109, 1998. 203. Koga, Y., et al., ‘‘Effect on Neonatal Vapor Inhalation Oncogenicity Study in 188. Takegawa, K., et al., ‘‘Large Amount of Thyroid Function of Povidone-Iodine Fischer 344 Rats and CD–1 Mice,’’ Vitamin A Has No Major Effects on Used on Mothers During Perinatal Fundamental and Applied Toxicology, Thyroidal Hormone Synthesis in Two- Period,’’ Journal of Obstetrics and 36:95–111, 1997. Stage Rat Thyroid Carcinogenesis Model Gynaecology (Tokyo, Japan), 21:581–585, 220. Bates, H.K., et al., ‘‘Developmental Using N-bis(2- 1995. Neurotoxicity Evaluation of Orally

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Administered Isopropanol in Rats,’’ Showering and Preliminary Evaluation 251. Van Dijk, A., ‘‘14C-Triclosan: Fundamental and Applied Toxicology, of Its Biological Effects,’’ Environmental Absorption, Distribution, Metabolism, 22:152–158, 1994. Science and Technology, 45:3109–3115, and Elimination After Single/Repeated 221. Faber, W.D., K.L. Pavkov, and R. 2011. Oral and Intravenous Administration to Gingell, ‘‘Review of Reproductive and 236. Birch, C.G., et al., ‘‘Biotransformation Hamsters,’’ Comment No. FDA–1975–N– Developmental Toxicity Studies With Products of 3,4,4′-Trichlorocarbanilide 0012–0288. Isopropanol,’’ Birth Defects Research in Rat, Monkey, and Man,’’ Drug 252. Van Dijk, A., ‘‘14C-Triclosan: Part B Developmental and Reproductive Metabolism and Disposition, 6:169–176, Absorption, Distribution, Metabolism, Toxicology, 83:459–476, 2008. 1978. and Elimination After Single/Repeated 222. Lehman, A.J., H. Schwerma, and E. 237. Gruenke, L.D., et al., ‘‘A Selected Ion Oral and Intravenous Administration to Rickards, ‘‘Isopropyl Alcohol: Acquired Monitoring GC/MS Assay for 3,4,4′- Mice,’’ Comment No. FDA–1975–N– Tolerance in Dogs, Rate of Disappearance Trichlorocarbanilide and Its Metabolites 0012–0288. From the Blood Stream in Various in Biological Fluids,’’ Journal of 253. Wu, J.L., J. Liu, and Z. Cai, Species, and Effects on Successive Analytical Toxicology, 11:75–80, 1987. ‘‘Determination of Triclosan Metabolites Generation of Rats,’’ Journal of 238. Hiles, R.A. and C.G. Birch, ‘‘Nonlinear by Using In-Source Fragmentation From Pharmacology and Experimental Metabolism and Disposition of 3,4,4′- High-Performance Liquid Therapeutics, 85:61–69, 1945. Trichlorocarbanilide in the Rat,’’ Chromatography/Negative Atmospheric 223. Nelson, B.K., et al., ‘‘Teratogenicity of n- Toxicology and Applied Pharmacology, Pressure Chemical Ionization Ion Trap Propanol and Isopropanol Administered 46:323–337, 1978. Mass Spectrometry,’’ Rapid at High Inhalation Concentrations to 239. Hiles, R.A., et al., ‘‘The Metabolism and Communications in Mass Spectrometry, Rats,’’ Food and Chemical Toxicology, Disposition of 3,4,4′- 24:1828–1834, 2010. 26:247–254, 1988. Trichlorocarbanilide in the Intact and 254. Burns, J.M., et al., ‘‘14-Day Repeated 224. Tyl, R.W., et al., ‘‘Developmental Bile Duct-Cannulated Adult and in the Dose Dermal Study of Triclosan in Rats Toxicity Evaluation of Isopropanol by Newborn Rhesus Monkey (M. mulatta),’’ (CHV 6718–102),’’ Comment No. CP9, Gavage in Rats and Rabbits,’’ Toxicology and Applied Pharmacology, Docket No. 1975N–0183H, 1997. Fundamental and Applied Toxicology, 46:593–608, 1978. 255. Burns, J.M., et al., ‘‘14-Day Repeated 22:139–151, 1994. 240. Warren, J.T., R. Allen, and D.E. Carter, Dose Dermal Study of Triclosan in Mice 225. Bevan, C., et al., ‘‘Two Generation ‘‘Identification of the Metabolites of (CHV 6718–101),’’ Comment No. CP9, Reproductive Toxicity Study With Trichlorocarbanilide in the Rat,’’ Drug Docket No. 1975N–0183H, 1997. Isopropanol in Rats,’’ Journal of Applied Metabolism and Disposition, 6:38–44, 256. Burns, J.M., et al., ‘‘14-Day Repeated Toxicology, 15:117–123, 1995. 1978. Dose Dermal Study of Triclosan in CD– 226. Allen, B., et al., ‘‘Calculation of 241. Comment No. SUP41, Docket No. 1 Mice (CHV 2763–100),’’ Comment No. Benchmark Doses for Reproductive and 1975N–0183. CP9, Docket No. 1975N–0183H, 1997. Developmental Toxicity Observed After 242. Comment No. CP4, Docket No. 1975N– 257. Trimmer, G.W., ‘‘90-Day Subchronic Exposure to Isopropanol,’’ Regulatory 0183. Dermal Toxicity Study in the Rat With Toxicology and Pharmacology, 28:38–44, 243. Beiswanger, B.B. and M.A. Tuohy, Satellite Group With Irgasan DP 300 1998. ‘‘Analysis of Blood Plasma Samples for (MRD–92–399),’’ Comment No. C1, 227. Gorkal, A.R. and A. Namasivayam, Free Triclosan, Triclosan-Glucuronide, Docket No. 1975N–0183H, 1994. ‘‘Effect of Isopropanol on Rat Brain 258. Chambers, P.R., ‘‘FAT 80′023/S Monoamine Levels,’’ Pharmacology and Triclosan Sulfate and Total Triclosan Toxicology, 65:390–392, 1989. From Subjects Using a Triclosan Potential Tumorigenic and Chronic 228. McEvoy, E.M., P.C. Wright, and M.T. Dentrifice or a Dentrifice, Bar Soap and Toxicity Effects in Prolonged Dietary Bustard, ‘‘The Effect of High Deodorant,’’ Comment No. FDA–1975– Administration to Hamsters,’’ Comment Concentration Isopropanol on the N–0012–0288. No. PR5, Docket No. 1975N–0183H, Growth of a Solvent-Tolerant Strain of 244. Plezia, P., ‘‘A Pilot Study for In Vivo 1999. Evaluation of the Percutaneous 259. Chasseaud, L.F., et al., ‘‘Toxicokinetics Chlorella vulgaris,’’ Enzyme and ′ Microbial Technology, 35:140–146, 2004. Absorption of Triclosan,’’ Comment No. of FAT 80 023/S After Prolonged Dietary 229. Geng, Y., et al., ‘‘Biodegradation of FDA–1975–N–0012–0196. Administration to Hamsters,’’ Comment Isopropanol by a Solvent-Tolerant 245. Queckenberg, C., et al., ‘‘Absorption, No. PR5, Docket No. 1975N–0183H, Paracoccus denitrificans Strain,’’ Pharmacokinetics, and Safety of 1999. Preparative Biochemistry and Triclosan After Dermal Administration,’’ 260. Comment No. FDA–1975–N–0012–0288. Biotechnology, 45:491–499, 2015. Antimicrobial Agents and 261. Morseth, S.L., ‘‘Two-Generation ′ 230. Bustard, M.T., et al., ‘‘Biodegradation of Chemotherapy, 54:570–572, 2010. Reproduction Study in Rats FAT 80 023 High-Concentration Isopropanol by a 246. Allmyr, M., et al., ‘‘Human Exposure to (HLA Study No. 2386–100),’’ Comment Solvent-Tolerant Thermophile, Bacillus Triclosan Via Toothpaste Does Not No. RPT7, Docket No. 1975N–0183, pallidus,’’ Extremophiles, 6:319–323, Change CYP3A4 Activity or Plasma 1988. 2002. Concentrations of Thyroid Hormones,’’ 262. James, M.O., et al., ‘‘Triclosan Is a Potent 231. Hiles, R.A. and C.G. Birch, ‘‘The Basic and Clinical Pharmacology and Inhibitor of Estradiol and Estrone Absorption, Excretion, and Toxicology, 2009. Sulfonation in Sheep Placenta,’’ Biotransformation of 3,4,4′- 247. Lin, Y.J., ‘‘Buccal Absorption of Environment International, 2009. Trichlorocarbanilide in Humans,’’ Drug Triclosan Following Topical Mouthrinse 263. Cookson, B., ‘‘Clinical Significance of Metabolism and Disposition, 6:177–183, Application,’’ American Journal of Emergence of Bacterial Antimicrobial 1978. Dentistry, 13:215–217, 2000. Resistance in the Hospital 232. Howes, D. and J.G. Black, ‘‘Percutaneous 248. Moss, T., D. Howes, and F.M. Williams, Environment,’’ Journal of Applied Absorption of Triclocarban in Rat and ‘‘Percutaneous Penetration and Dermal Microbiology, 99:989–996, 2005. Man,’’ Toxicology, 6:67–76, 1976. Metabolism of Triclosan (2,4, 4′- 264. MacIsaac, J.K., et al., ‘‘Health Care 233. Scharpf, L.G., Jr., I.D. Hill, and H.I. trichloro-2′-hydroxydiphenyl ether),’’ Worker Exposures to the Antibacterial Maibach, ‘‘Percutaneous Penetration and Food and Chemical Toxicology, 38:361– Agent Triclosan,’’ Journal of Disposition of Triclocarban in Man. 370, 2000. Occupational and Environmental Body Showering,’’ Archives of 249. Sandborgh-Englund, G., et al., Medicine, 56:834–839, 2014. Environmental Health, 30:7–14, 1975. ‘‘Pharmacokinetics of Triclosan 265. Yueh, M.F., et al., ‘‘The Commonly Used 234. Schebb, N.H., et al., ‘‘Whole Blood Is the Following Oral Ingestion in Humans,’’ Antimicrobial Additive Triclosan Is a Sample Matrix of Choice for Monitoring Journal of Toxicology and Environmental Liver Tumor Promoter,’’ Proceedings of Systemic Triclocarban Levels,’’ Health, Part A, 69:1861–1873, 2006. the National Academy of Sciences of the Chemosphere, 2012. 250. Tulp, M.T., et al., ‘‘Metabolism of USA, 111:17200–17205, 2014. 235. Schebb, N.H., et al., ‘‘Investigation of Chlorodiphenyl Ethers and Irgasan DP 266. Cherednichenko, G., et al., ‘‘Triclosan Human Exposure to Triclocarban After 300,’’ Xenobiotica, 9:65–77, 1979. Impairs Excitation-Contraction Coupling

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and Ca2+ Dynamics in Striated Muscle,’’ 280. Zhu, L., et al., ‘‘The Two Functional http://pubs.niaaa.nih.gov/publications/ Proceedings of the National Academy of Enoyl-acyl Carrier Protein Reductases of FASDFactsheet/FASDfact.htm. Sciences of the USA, 109:14158–14163, Enterococcus faecalis Do Not Mediate 293. Little, P.J., M.L. Adams, and T.J. Cicero, 2012. Triclosan Resistance,’’ MBio, 4:e00613– ‘‘Effects of Alcohol on the Hypothalamic- 267. Fritsch, E.B., et al., ‘‘Triclosan Impairs 13, 2013. Pituitary-Gonadal Axis in the Developing Swimming Behavior and Alters 281. Skovgaard, S., et al., ‘‘Staphylococcus Male Rat,’’ Journal of Pharmacology and Expression of Excitation-Contraction epidermidis Isolated in 1965 Are More Experimental Therapeutics, 263:1056– Coupling Proteins in Fathead Minnow Susceptible to Triclosan Than Current 1061, 1992. (Pimephales promelas),’’ Environmental Isolates,’’ PLoS One, 8:e62197, 2013. Science and Technology, 47:2008–2017, 282. D’Arezzo, S., et al., ‘‘High-level List of Subjects in 21 CFR Part 310 2013. Tolerance to Triclosan May Play a Role Administrative practice and 268. Axelstad, M., et al., ‘‘Triclosan Exposure in Pseudomonas aeruginosa Antibiotic procedure, Drugs, Labeling, Medical Reduces Thyroxine Levels in Pregnant Resistance in Immunocompromised and Lactating Rat Dams and in Directly Hosts: Evidence From Outbreak devices, Reporting and recordkeeping Exposed Offspring,’’ Food and Chemical Investigation,’’ BMC Research Notes, requirements. Toxicology, 59:534–540, 2013. 5:43, 2012. Therefore, under the Federal Food, 269. Lan, Z., et al., ‘‘Triclosan Exhibits a 283. Lanini, S., et al., ‘‘Molecular Drug, and Cosmetic Act and under Tendency to Accumulate in the Epidemiology of a Pseudomonas authority delegated to the Commissioner Epididymis and Shows Sperm Toxicity aeruginosa Hospital Outbreak Driven by of Food and Drugs, 21 CFR part 310, as in Male Sprague-Dawley Rats,’’ a Contaminated Disinfectant-Soap proposed to be amended December 17, Environmental Toxicology, 2013. Dispenser,’’ PLoS One, 6:e17064, 2011. 270. Fernando, D.M., et al., ‘‘Triclosan Can 284. Boyd, G.R., et al., ‘‘Pharmaceuticals and 2013, at 78 FR 76444, is proposed to be Select for an AdeIJK-Overexpressing Personal Care Products (PPCPs) in further amended as follows: Mutant of Acinetobacter baumannii Surface and Treated Waters of Louisiana, ATCC 17978 That Displays Reduced USA and Ontario, Canada,’’ Science and PART 310—NEW DRUGS Susceptibility to Multiple Antibiotics,’’ the Total Environment, 311:135–149, ■ Antimicrobial Agents and 2003. 1. The authority citation for 21 CFR Chemotherapy, 58:6424–6431, 2014. 285. Halden, R.U. and D.H. Paull, ‘‘Co- part 310 continues to read as follows: 271. Hernandez, A., et al., ‘‘The Binding of Occurrence of Triclocarban and Authority: 21 U.S.C. 321, 331, 351, 352, Triclosan to SmeT, the Repressor of the Triclosan in U.S. Water Resources,’’ 353, 355, 360b–360f, 360j, 361(a), 371, 374, Multidrug Efflux Pump SmeDEF, Environmental Science and Technology, 375, 379e, 379k–1; 42 U.S.C. 216, 241, 242(a), Induces Antibiotic Resistance in 39:1420–1426, 2005. 262, 263b–263n. Stenotrophomonas maltophilia,’’ PLoS 286. Kinney, C.A., et al., ‘‘Bioaccumulation of ■ Pathogens, 7:e1002103, 2011. Pharmaceuticals and Other 2. Amend § 310.545 as follows: ■ 272. Mavri, A. and S.S. Mozina, Anthropogenic Waste Indicators in a. Add reserved paragraph (a)(27)(v); ■ ‘‘Involvement of Efflux Mechanisms in Earthworms From Agricultural Soil b. Add paragraphs (a)(27)(vi) through Biocide Resistance of Campylobacter Amended With Biosolid or Swine (x); jejuni and Campylobacter coli,’’ Journal Manure,’’ Environmental Science and ■ c. In paragraph (d) introductory text, of Medical Microbiology, 61:800–808, Technology, 42:1863–1870, 2008. remove’’(d)(39)’’ and in its place add 2012. 287. Singer, H., et al., ‘‘Triclosan: Occurrence ‘‘(d)(42)’’; and 273. Mavri, A. and S. Smole Mozina, and Fate of a Widely Used Biocide in the ■ d. Add paragraph (d)(42). ‘‘Development of Antimicrobial Aquatic Environment: Field The additions read as follows: Resistance in Campylobacter jejuni and Measurements in Wastewater Treatment Campylobacter coli Adapted to Plants, Surface Waters, and Lake § 310.545 Drug products containing Biocides,’’ International Journal of Food Sediments,’’ Environmental Science and certain active ingredients offered over-the- Microbiology, 160:304–312, 2013. Technology, 36:4998–5004, 2002. counter (OTC) for certain uses. 274. Srinivasan, V.B. and G. Rajamohan, 288. Ying, G.G., X.Y. Yu, and R.S. Kookana, (a) * * * ‘‘KpnEF, A New Member of the ‘‘Biological Degradation of Triclocarban (27) * * * Klebsiella pneumoniae Cell Envelope and Triclosan in a Soil Under Aerobic (v) [Reserved] Stress Response Regulon, Is an SMR- and Anaerobic Conditions and Type Efflux Pump Involved in Broad- Comparison With Environmental Fate (vi) Health care personnel hand wash Spectrum Antimicrobial Resistance,’’ Modelling,’’ Environmental Pollution, drug products. Approved as of [DATE 1 Antimicrobial Agents and 150:300–305, 2007. YEAR AFTER DATE OF PUBLICATION Chemotherapy, 57:4449–4462, 2013. 289. Pycke, B.F.G., et al., ‘‘Transformation OF THE FINAL RULE IN THE FEDERAL 275. McMurry, L.M., M. Oethinger, and S.B. Products and Human Metabolites of REGISTER]. Levy, ‘‘Triclosan Targets Lipid Triclocarban and Triclosan in Sewage Benzalkonium chloride Synthesis,’’ Nature, 394:531–532, 1998. Sludge Across the United States,’’ Benzethonium chloride 276. Zhang, Y.M., Y.J. Lu, and C.O. Rock, Environmental Science and Technology, Chloroxylenol ‘‘The Reductase Steps of the Type II 48:7881–7890, 2014. Fatty Acid Synthase as Antimicrobial 290. Centers for Disease Control and Cloflucarban Targets,’’ Lipids, 39:1055–1060, 2004. Prevention, ‘‘Alcohol and Public Health. Fluorosalan 277. Saleh, S., et al., ‘‘Triclosan—An Frequently Asked Questions,’’ 2014, Hexachlorophene Update,’’ Letters in Applied available at http://www.cdc.gov/alcohol/ Hexylresorcinol Microbiology, 52:87–95, 2011. faqs.htm#standDrink. Iodine complex (ammonium ether 278. Nielsen, L.N., et al., ‘‘Staphylococcus 291. Scientific Committee on Emerging and sulfate and polyoxyethylene sorbitan aureus But Not Listeria monocytogenes Newly Identified Health Risks monolaurate) Adapt to Triclosan and Adaptation (SCENIHR), ‘‘Research Strategy to Iodine complex (phosphate ester of Correlates With Increased fabI Address the Knowledge Gaps on the alkylaryloxy polyethylene glycol) Expression and agr Deficiency,’’ BMC Antimicrobial Resistance Effects of Methylbenzethonium chloride Microbiology, 13:177, 2013. Biocides,’’ 2010, available at http:// 279. Zhu, L., et al., ‘‘Triclosan Resistance of ec.europa.eu/health/scientific_ Nonylphenoxypoly (ethyleneoxy) Pseudomonas aeruginosa PAO1 Is Due committees/emerging/docs/scenihr_o_ ethanoliodine to FabV, a Triclosan-Resistant Enoyl-acyl 028.pdf. Phenol Carrier Protein Reductase,’’ 292. National Institute on Alcohol Abuse and Poloxamer iodine complex Antimicrobial Agents and Alcoholism, ‘‘Fetal Alcohol Exposure,’’ Povidone-iodine Chemotherapy, 54:689–698, 2010. July 2013, available at Secondary amyltricresols

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Sodium oxychlorosene Poloxamer iodine complex Methylbenzethonium chloride Tribromsalan Povidone-iodine Nonylphenoxypoly (ethyleneoxy) Triclocarban Secondary amyltricresols ethanoliodine Triclosan Sodium oxychlorosene Phenol Undecoylium chloride iodine complex Tribromsalan Poloxamer iodine complex (vii) Health care personnel hand rub Triclocarban drug products. Approved as of [DATE 1 Triclosan Povidone-iodine YEAR AFTER DATE OF PUBLICATION Undecoylium chloride iodine complex Secondary amyltricresols OF THE FINAL RULE IN THE FEDERAL (ix) Surgical hand rub drug products. Sodium oxychlorosene REGISTER]. Approved as of [DATE 1 YEAR AFTER Tribromsalan Alcohol (ethanol and ethyl alcohol) DATE OF PUBLICATION OF THE Triclocarban Benzalkonium chloride FINAL RULE IN THE FEDERAL Triclosan Isopropyl alcohol REGISTER]. Triple dye (viii) Surgical hand scrub drug Alcohol (ethanol and ethyl alcohol) Undecoylium chloride iodine complex Isopropyl alcohol products. Approved as of [DATE 1 Combination of calomel, oxyquinoline YEAR AFTER DATE OF PUBLICATION (x) Patient preoperative skin benzoate, triethanolamine, and OF THE FINAL RULE IN THE FEDERAL preparation drug products. Approved as phenol derivative REGISTER]. of [DATE 1 YEAR AFTER DATE OF Combination of mercufenol chloride PUBLICATION OF THE FINAL RULE IN Benzalkonium chloride and secondary amyltricresols in 50 Benzethonium chloride THE FEDERAL REGISTER]. percent alcohol Chloroxylenol Alcohol (ethanol and ethyl alcohol) Cloflucarban Benzalkonium chloride * * * * * Fluorosalan Benzethonium chloride (d) * * * Hexachlorophene Chloroxylenol (42) [DATE 1 YEAR AFTER DATE OF Hexylresorcinol Cloflucarban PUBLICATION OF THE FINAL RULE IN Iodine complex (ammonium ether Fluorosalan THE FEDERAL REGISTER], for products sulfate and polyoxyethylene sorbitan Hexachlorophene subject to paragraphs (a)(27)(vi) through monolaurate) Hexylresorcinol (a)(27)(x) of this section. Iodine complex (phosphate ester of Iodine complex (phosphate ester of Dated: April 27, 2015. alkylaryloxy polyethylene glycol) alkylaryloxy polyethylene glycol) Methylbenzethonium chloride Iodine tincture Leslie Kux, Nonylphenoxypoly (ethyleneoxy) Iodine topical solution Associate Commissioner for Policy. ethanoliodine Isopropyl alcohol [FR Doc. 2015–10174 Filed 4–30–15; 8:45 am] Phenol Mercufenol chloride BILLING CODE 4164–01–P

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