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DEPARTMENT OF HEALTH AND instructions for submitting comments. information that you do not wish to be HUMAN SERVICES Comments submitted electronically, made publicly available, submit your including attachments, to http:// comments only as a written/paper Food and Drug Administration www.regulations.gov will be posted to submission. You should submit two the docket unchanged. Because your copies total. One copy will include the 21 CFR Part 310 comment will be made public, you are information you claim to be confidential [Docket No. FDA–2016–N–0124 (Formerly solely responsible for ensuring that your with a heading or cover note that states Part of Docket No. FDA–1975–N–0012)] comment does not include any ‘‘THIS DOCUMENT CONTAINS confidential information that you or a CONFIDENTIAL INFORMATION.’’ The RIN 0910–AF69 third party may not wish to be posted, Agency will review this copy, including such as medical information, your or the claimed confidential information, in Safety and Effectiveness of Consumer anyone else’s Social Security number, or its consideration of comments. The ; Topical confidential business information, such second copy, which will have the Drug Products for Over-the-Counter as a manufacturing process. Please note claimed confidential information Human Use; Proposed Amendment of that if you include your name, contact redacted/blacked out, will be available the Tentative Final Monograph; information, or other information that for public viewing and posted on http:// Reopening of Administrative Record identifies you in the body of your www.regulations.gov. Submit both AGENCY: Food and Drug Administration, comments, that information will be copies to the Division of Dockets HHS. posted on http://www.regulations.gov. Management. If you do not wish your • ACTION: Proposed rule. If you want to submit a comment name and contact information to be with confidential information that you made publicly available, you can SUMMARY: The Food and Drug do not wish to be made available to the provide this information on the cover Administration (FDA or Agency) is public, submit the comment as a sheet and not in the body of your issuing this proposed rule to amend the written/paper submission and in the comments and you must identify this 1994 tentative final monograph or manner detailed (see ‘‘Written/Paper information as ‘‘confidential.’’ Any proposed rule (the 1994 TFM) for over- Submissions’’ and ‘‘Instructions’’). We information marked as ‘‘confidential’’ the-counter (OTC) drug note however, that the OTC drug will not be disclosed except in products. In this proposed rule, we are monograph process is a public process; accordance with 21 CFR 10.20 and other proposing to establish conditions under and, the Agency intends to consider applicable disclosure law. For more which OTC consumer antiseptic only non-confidential material that is information about FDA’s posting of products intended for use without water submitted to the docket for this comments to public dockets, see 80 FR (referred to throughout as consumer rulemaking or that is otherwise publicly 56469, September 18, 2015, or access antiseptic rubs or consumer rubs) are available in evaluating if a relevant the information at: http://www.fda.gov/ generally recognized as safe and ingredient is GRAS/GRAE. regulatoryinformation/dockets/ generally recognized as effective (GRAS/ default.htm. GRAE). In the 1994 TFM, certain Written/Paper Submissions Docket: For access to the docket to antiseptic active ingredients were Submit written/paper submissions as read background documents or the proposed as being GRAS for antiseptic follows: electronic and written/paper comments rub use by consumers based on safety • Mail/Hand delivery/Courier (for received, go to http:// data evaluated by FDA as part of its written/paper submissions): Division of www.regulations.gov and insert the ongoing review of OTC antiseptic drug Dockets Management (HFA–305), Food docket number, found in brackets in the products. However, in light of more and Drug Administration, 5630 Fishers heading of this document, into the recent scientific developments and Lane, Rm. 1061, Rockville, MD 20852. ‘‘Search’’ box and follow the prompts changes in the use patterns of these • For written/paper comments and/or go to the Division of Dockets products, we are now proposing that submitted to the Division of Dockets Management, 5630 Fishers Lane, Rm. additional safety data are necessary to Management, FDA will post your 1061, Rockville, MD 20852. support the safety of antiseptic active comment, as well as any attachments, FOR FURTHER INFORMATION CONTACT: ingredients for this use. We also are except for information submitted, Anita Kumar, Center for Drug proposing that all consumer antiseptic marked and identified, as confidential, Evaluation and Research, Food and rub active ingredients have in vitro data if submitted as detailed in Drug Administration, 10903 New characterizing the ingredient’s ‘‘Instructions.’’ Hampshire Ave., Bldg. 22, Rm. 5445, antimicrobial properties and in vivo Instructions: All submissions received Spring, MD 20993, 301–796– clinical simulation studies showing that must include the Docket No. FDA– 1032. specified log reductions in the amount 2016–N–0124 for ‘‘Safety and of certain bacteria are achieved using Effectiveness of Consumer Antiseptics; SUPPLEMENTARY INFORMATION: the ingredient. Topical Antimicrobial Drug Products for Table of Contents Over-the-Counter Human Use; Proposed DATES: Submit electronic or written I. Executive Summary comments by December 27, 2016. See Amendment of the Tentative Final A. Purpose of the Regulatory Action section IX of this document for the Monograph; Reopening of B. Summary of the Major Provisions of the proposed effective date of a final rule Administrative Record.’’ Received Regulatory Action in Question based on this proposed rule. comments will be placed in the docket C. Effectiveness ADDRESSES: You may submit comments and, except for those submitted as D. Safety as follows: ‘‘Confidential Submissions,’’ publicly E. Active Ingredients viewable at http://www.regulations.gov F. Costs and Benefits Electronic Submissions II. Introduction or at the Division of Dockets A. Terminology Used in the OTC Drug Submit electronic comments in the Management between 9 a.m. and 4 p.m., Review Regulations following way: Monday through Friday. B. Topical Antiseptics • Federal eRulemaking Portal: http:// • Confidential Submissions—To C. This Proposed Rule Covers Only www.regulations.gov. Follow the submit a comment with confidential Consumer Antiseptic Rubs

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D. Comment Period information we have identified and posed by the use of certain consumer III. Background placed in the docket. This proposed rule antiseptic products, as well as input A. Significant Rulemakings Relevant to applies to active ingredients used in from the Nonprescription Drugs This Proposed Rule consumer antiseptic rub products that Advisory Committee (NDAC) that met in B. Public Meetings Relevant to This Proposed Rule are sometimes referred to as rubs, leave- March 2005 (the March 2005 NDAC) C. Comments Received by FDA on products, or hand ‘‘sanitizers,’’ as and October 2005 (the October 2005 IV. Active Ingredients With Insufficient well as to consumer antiseptic wipes. NDAC), has prompted us to reevaluate Evidence of Eligibility for the OTC Drug These products are intended to be used the data needed for classifying active Review when and water are not available, ingredients used in consumer rubs as A. Eligibility for the OTC Drug Review and are left on and not rinsed off with GRAE. The reevaluation of effectiveness B. Eligibility of Certain Active Ingredients water. We will refer to them here as will help to ensure that the level of for the OTC Drug Review consumer antiseptic rubs or consumer effectiveness achieved is adequate to V. Ingredients Previously Proposed as Not Generally Recognized as Safe and rubs. In separate rulemakings (78 FR offset newly identified safety concerns Effective 76444, December 17, 2013; 80 FR 25166, (see new information described in the VI. Summary of Proposed Classifications of May 1, 2015), we proposed conditions safety section of this executive OTC Consumer Antiseptic Rub Active under which OTC consumer antiseptic summary). We continue to propose the Ingredients washes and OTC antiseptics intended use of surrogate endpoints (bacterial log VII. Effectiveness (Generally Recognized as for use by health care professionals in reductions) as a demonstration of Effective) Determination a hospital setting or other health care effectiveness for consumer antiseptic A. Evaluation of Effectiveness Data situation outside the hospital are GRAS/ rubs combined with in vitro testing to B. Current Standards: Studies Needed To Support a Generally Recognized as GRAE. Those antiseptic products are not characterize the antimicrobial activity of Effective Determination addressed in this proposed rule. the ingredient. However, the log reductions required for the C. Impact of Application Parameters on B. Summary of the Major Provisions of demonstration of effectiveness for Efficacy the Regulatory Action in Question VIII. Safety (Generally Recognized as Safe) consumer rubs have been revised based Determination We are proposing that additional on the recommendations of the March A. New Issues safety and effectiveness data are 2005 and October 2005 NDAC meetings, B. Antimicrobial Resistance necessary to support a GRAS/GRAE comments received after the 1994 TFM, C. Studies To Support a Generally determination for OTC antiseptic rub and other information we reviewed. Recognized as Safe Determination active ingredients intended for use by We have evaluated the available D. Review of Available Data for Each consumers. The effectiveness data, the Antiseptic Active Ingredient literature, the data, and other IX. Proposed Effective Date safety data, and the effect on the information that were submitted to the X. Summary of Preliminary Regulatory previously proposed classification of rulemaking on the effectiveness of Impact Analysis active ingredients are described briefly consumer rub active ingredients, as well A. Introduction in this summary. Because no ingredients as the recommendations from the public B. Summary of Costs and Benefits currently meet the criteria for a GRAS/ meetings held by the Agency on XI. Paperwork Reduction Act of 1995 GRAE determination in this proposed antiseptics. We propose that the record XII. Environmental Impact rule, this rulemaking does not contain additional log reduction data to XIII. Federalism specifically address requirements for demonstrate the effectiveness of XIV. References anticipated final formulation testing consumer rub active ingredients. We are I. Executive Summary (i.e., testing the mixture of both active also asking for data and information to and inactive ingredients proposed for A. Purpose of the Regulatory Action be submitted about the impact of marketing) or labeling. Final product use factors (such as volume of FDA is proposing to amend the 1994 formulation testing could potentially product per application) on efficacy to TFM for OTC antiseptic drug products involve both efficacy testing and safety help inform labeling and requirements that published in the Federal Register of testing to determine absorption. It is for final formulation testing. June 17, 1994 (59 FR 31402). The 1994 anticipated that if a final rule includes TFM is part of FDA’s ongoing any GRAS/GRAE ingredients, labeling D. Safety rulemaking to evaluate the safety and will be addressed as part of the final Several important scientific effectiveness of OTC drug products rule and may include elements related developments that affect the safety marketed in the United States on or to application volume and safety evaluation of consumer rub active before May 1972 (OTC Drug Review). labeling for children, including a ingredients have occurred since FDA’s FDA is proposing to establish new warning to keep out of reach of 1994 evaluation of the safety of these conditions under which active children. We anticipate that specific active ingredients under the OTC Drug ingredients used in OTC consumer effectiveness claims in labeling will Review. Improved analytical methods antiseptic products intended to be used reflect the testing performed in support now exist that can detect and more without water are GRAS/GRAE based on of these claims. Effectiveness testing accurately measure these active FDA’s reevaluation of the safety and using surrogate endpoints as described ingredients at lower levels in the effectiveness data requirements in this proposed rule is designed to bloodstream and tissue. Consequently, proposed in the 1994 TFM for what support antibacterial claims. we now know that, at least for certain were then referred to as antiseptic hand consumer antiseptic rub ingredients, washes (which included the products C. Effectiveness systemic exposure is higher than we refer to in this document as A determination that a drug product previously thought (Refs. 1 through 5), consumer antiseptic rubs or consumer containing a particular active ingredient and new information is available about rubs). We are conducting this would be GRAE for a particular the potential risks from systemic reevaluation based on the comments intended use requires consideration of absorption and long-term exposure. received, input from subsequent public the benefit-to-risk ratio for the drug These data are particularly important meetings, and our independent under the specified conditions of use. given the increased use of consumer evaluation of other relevant scientific New information on potential risks antiseptic rubs since the publication of

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the 1994 TFM. New safety information proposed to be classified as GRAS/ possible that none, one, two, or all three also suggests that widespread antiseptic GRAE (59 FR 31402 at 31435 to 31436) of the ingredients will be determined to use could have an impact on the for use as what was then called an be GRAS/GRAE. We consider two development of bacterial resistance. antiseptic hand wash (a use which extreme scenarios to capture the entire Currently, the significance of this new included both products intended to be range of total costs: (1) All three information is not known and we are rinsed off (washes) and those intended ingredients are deemed to be GRAS/ unaware of any information that would to be left on (rubs)). GRAE or (2) none of the ingredients is lead us to conclude that any consumer (70 to 91.3 percent) was proposed to be deemed to be GRAS/GRAE. antiseptic rub active ingredient is unsafe categorized in Category III in the 1994 The range of estimated costs is wide (other than those that we proposed to be TFM because of a lack of adequate because the number of products that Category II in the 1994 TFM). The effectiveness data for use as an would need to be reformulated and benefits of any active ingredient will antiseptic hand wash (59 FR 31402 at relabeled depends on whether or not an need to be weighed against its risks once 31435 to 31436). However, we now antiseptic ingredient is deemed to be both the effectiveness and safety have propose that both alcohol and isopropyl GRAS/GRAE. A small number of been better characterized to determine alcohol need additional safety and products contain active ingredients GRAS/GRAE status. effectiveness data to support a which FDA has determined are not The previously proposed GRAS classification of GRAS/GRAE for eligible for use in consumer antiseptic determinations were based on safety consumer antiseptic rub use. Our rubs and these products will need to be principles that have since evolved detailed evaluation of the effectiveness reformulated and relabeled (scenario 1). significantly because of advances in and safety of the active ingredients for However, in scenario 2 (and technology, development of new test which data were submitted can be intermediate scenarios), the resulting methods, and experience with found in sections VII.A and VIII.D. costs are higher because a greater performing test methods. The standard In the 1994 TFM, FDA categorized number of products will need to be battery of tests that were used to in Category III reformulated and relabeled as a result of determine the safety of drugs has because of a lack of adequate safety and tests failing to show GRAS/GRAE status. changed over time to incorporate effectiveness data for its use as an The total upfront costs of the improvements in safety testing. To antiseptic hand wash (59 FR 31402 at proposed regulation—which include the ensure that consumer antiseptic rub 31435). We have evaluated safety data expenditures to reformulate and relabel active ingredients are GRAS, data that received in response to the 1994 TFM products that contain nonmonograph meet current safety standards are and the consumer antiseptic wash ingredients—are estimated to range from needed. proposed rule published in the Federal $0.34 million to $1.02 million for Based on these developments, we are Register of December 17, 2013 (78 FR scenario 1 and from $15.99 million to now proposing that additional safety 76444) (2013 Consumer Wash Proposed $47.09 million for scenario 2. data are needed for each consumer Rule (PR)) (see section VIII.D). In this Annualizing upfront costs over a 10- antiseptic rub active ingredient to proposed rule, we propose that year period at a discount rate of 3% for support a GRAS classification. The data benzalkonium chloride needs additional scenario 1, the costs of the proposed described in this proposed rule are the safety and effectiveness data to support rule are estimated to be between $0.04 minimum data necessary to establish a classification of GRAS/GRAE for million and $0.12 million per year; the the safety of antiseptic active consumer antiseptic rub use. corresponding estimated cost at a ingredients used in consumer antiseptic If we do not receive sufficient data to discount rate of 7% is between $0.05 rub products in light of the new safety support monograph conditions for million and $0.14 million per year. In information. Consumers may use consumer antiseptic rub products scenario 2, none of the ingredients is containing these active ingredients, antiseptic rubs on a daily, long-term determined to be GRAS/E and we these active ingredients may not be (i.e., chronic) basis. The data we expect that manufacturers will included in the future OTC consumer propose, which are needed to reformulate their products to be free of antiseptic rub final monograph. Any demonstrate safety for all consumer antiseptics and relabel them to reflect consumer antiseptic rub product antiseptic rub active ingredients, fall the change in ingredients. Annualizing containing the active ingredients being into two broad categories: (1) Human upfront costs over a 10-year period at a considered under this rulemaking that safety studies and (2) nonclinical safety discount rate of 3% for scenario 2, the are not included in a future final studies. For one of the consumer costs of the proposed rule are estimated monograph could seek approval to antiseptic rub active ingredients to be between $1.87 million and $5.52 market by submitting new drug (benzalkonium chloride), data to million per year; the corresponding applications (NDAs) under section 505 evaluate the development of estimated cost at a discount rate of 7% of the Federal Food, Drug, and Cosmetic antimicrobial resistance also is required is between $2.28 million and $6.70 Act (the FD&C Act) (21 U.S.C. 355). to demonstrate its safety. million per year. We assume that health After a final monograph is established, risk falls with reduced exposure to E. Active Ingredients NDA deviations might be submitted for potentially unsafe or ineffective Three active ingredients are being these products in accordance with 21 antiseptic ingredients in consumer evaluated for use as a consumer CFR 330.11, limiting the scope of review antiseptic rubs. We estimate that the antiseptic rub in this proposed rule: necessary to obtain approval. Alcohol ( or ethyl alcohol), proposed rule will reduce exposure to isopropyl alcohol, and benzalkonium F. Costs and Benefits potentially unsafe or ineffective chloride (sometimes referred to as The impact of the proposed rule on antiseptic ingredients in consumer ADBAC). As part of this proposed rule, the OTC consumer antiseptic rub antiseptic rubs by between 110 and 1 FDA evaluated new data submitted after product industry will depend on the 67,272,847 pounds. publication of the 1994 TFM for each of outcome of tests to determine whether 1 As was the case with estimated costs, there is these three ingredients. three antiseptic ingredients—alcohol, a great disparity in the estimated reductions in In the 1994 TFM (59 FR 31402 at isopropyl alcohol, and benzalkonium exposure to antiseptic ingredients. The lower bound 31435), alcohol (60 to 95 percent) was chloride—are GRAS/GRAE. It is (110 pounds) represents the estimated reduction in

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

Total ...... 110 and 67,272,847 ...... $0.04 to $5.52 (3%) .. $0.34 and $47.09. $0.05 to $6.70 (7%) ..

II. Introduction monograph stage) retains the concepts as health care personnel hand washes. of Categories I, II, and III. (See section II.C about the term In the following sections, we provide At the final monograph stage, FDA ‘‘antimicrobial .’’) In contrast, in a brief description of terminology used does not use the terms ‘‘Category I,’’ the 1994 TFM, we proposed that both in the OTC Drug Review regulations and ‘‘Category II,’’ and ‘‘Category III.’’ In antiseptic hand washes (i.e., consumer an overview of OTC topical antiseptic place of Category I, the term antiseptic washes) and health care drug products, and then describe in ‘‘monograph conditions’’ is used; in personnel hand washes should have the more detail the OTC consumer place of Categories II and III, the term same effectiveness testing and antiseptic rubs that are the subject of ‘‘nonmonograph conditions’’ is used. performance criteria. In response to the this proposed rule. 1994 TFM, we received submissions B. Topical Antiseptics A. Terminology Used in the OTC Drug from the public arguing that consumer Review Regulations The OTC topical antimicrobial products serve a different purpose and rulemaking has had a broad scope, should continue to be distinct from 1. Proposed, Tentative Final, and Final encompassing drug products that may health care antiseptics. We agreed, and Monographs contain the same active ingredients, but in the 2013 Consumer Wash PR and in that are labeled and marketed for the health care antiseptic proposed rule To conform to terminology used in different intended uses. In 1974, the published in the Federal Register of the OTC Drug Review regulations Agency published an ANPR for topical May 1, 2015 (80 FR 25166) (2015 Health (§ 330.10 (21 CFR 330.10)), the antimicrobial products that Care Antiseptic PR), our evaluation of September 1974 advance notice of encompassed products for both health OTC antiseptic drug products has been proposed rulemaking (39 FR 33103, care and consumer use. The 1974 ANPR further subdivided into consumer September 13, 1974) (1974 ANPR) was covered seven different intended uses antiseptics and health care antiseptics, designated as a ‘‘proposed monograph.’’ for these products: (1) Antimicrobial which are used by health care Similarly, the notices of proposed soap; (2) health care personnel hand professionals in a hospital setting or rulemaking, which were published in wash; (3) patient preoperative skin other health care situations outside the the Federal Register of January 6, 1978 preparation; (4) skin antiseptic; (5) skin hospital. We believe that these (43 FR 1210) (the 1978 TFM), and in the wound cleanser; (6) skin wound categories are distinct based on the Federal Register of June 17, 1994 (59 FR protectant; and (7) surgical hand scrub proposed-use setting, target population, 31402) (the 1994 TFM), were each (39 FR 33103 at 33140). FDA and the fact that each setting presents a designated as a ‘‘tentative final subsequently identified skin antiseptics, different level of risk for infection. For monograph’’ (see table 1 in section skin wound cleansers, and skin wound example, in health care settings, the III.A). The present proposed rule, which protectants as antiseptics used primarily patient population is generally more is a proposal to amend the 1994 TFM by consumers for first aid use and susceptible to infection than the general with respect to consumer antiseptic rub referred to them collectively as ‘‘first aid U.S. consumer population (i.e., the drug products, is also designated as a antiseptics.’’ We published a separate population who use consumer ‘‘tentative final monograph.’’ TFM covering the first aid antiseptics in antiseptic rubs or washes). Furthermore, 2. Category I, II, and III Classifications the Federal Register of July 22, 1991 (56 the purpose of use is generally different; FR 33644) (1991 First Aid TFM). Thus, health care antiseptics are primarily The OTC drug procedural regulations first aid antiseptics are not discussed used to protect the patient (rather than in § 330.10 use the terms ‘‘Category I’’ further in this document. just the user), whereas consumer (generally recognized as safe and The four remaining categories of antiseptics are generally applied to effective and not misbranded), topical were addressed in protect the user. In the health care ‘‘Category II’’ (not generally recognized the 1994 TFM. The 1994 TFM covered: setting, the potential for spread of as safe and effective or misbranded), (1) Antiseptic hand wash (i.e., consumer infection and the potential for serious and ‘‘Category III’’ (available data are hand wash); (2) health care personnel outcomes of infection may be relatively insufficient to classify as safe and hand wash; (3) patient preoperative skin higher than in the U.S. consumer effective, and further testing is preparation; and (4) surgical hand scrub setting. Therefore, the safety and required). Section 330.10 provides that (59 FR 31402 at 31442). In the 1994 effectiveness should be evaluated any testing necessary to resolve the TFM, FDA also identified a new separately for each intended use to safety or effectiveness issues that category of antiseptics for use by the support a GRAS/GRAE determination. formerly resulted in a Category III food industry and requested relevant As we did in the 2013 Consumer classification, and submission to FDA of data and information (59 FR 31402 at Wash PR, we refer to the group of the results of that testing or any other 31440). Antiseptics for use by the food products covered by this proposed rule data, must be done during the OTC drug industry are not discussed further in as ‘‘consumer antiseptics.’’ Consumer rulemaking process before the this document. antiseptic drug products addressed by establishment of a final monograph (i.e., In the 1974 ANPR, we distinguished this proposal include consumer a final rule or regulation). Therefore, antimicrobial soaps used by consumers antiseptic hand rubs (commonly called this proposed rule (the tentative final from professional use antiseptics, such hand sanitizers) and antiseptic wipes.

exposure to ingredients which FDA has determined rubs and few products contain such GRAS/GRAE are not GRAS/GRAE for use in consumer antiseptic ingredients.

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These products may be used by used when soap and water are not complete requests to defer rulemaking. consumers for personal use on a available. Consumer antiseptic rubs In assessing whether to defer further frequent basis, even multiple times per include ‘‘hand sanitizers’’ and wipes. rulemaking for a particular active day. These products do not include The 1994 TFM also did not distinguish ingredient to allow for additional time personal care products intended to be between consumer antiseptic washes for studies to generate new data and used with water, such as antibacterial and rubs, and health care hand washes information, FDA will consider the data soaps, hand washes, and body washes. and rubs. This proposed rule covers already in the docket, along with any C. This Proposed Rule Covers Only only consumer antiseptic rubs. information that is provided in any Consumer Antiseptic Rubs Completion of the monograph for requests. FDA will determine whether consumer antiseptic rubs and certain the sum of the data, if submitted in a In this proposed rule, FDA proposes other monographs for the active timely fashion, is likely to be adequate the establishment of a monograph for ingredient are subject to a to provide all the data that are necessary OTC consumer antiseptics that are Consent Decree entered by the U.S. to make a GRAS/GRAE determination. intended for use as an antiseptic rub, District Court for the Southern District We note that the OTC Drug Review is but that are not identified as ‘‘first aid of New York on November 21, 2013, in a public process and any data submitted antiseptics’’ in the 1991 First Aid TFM. Natural Resources Defense Council, Inc. is public. There is no requirement or When the 1994 TFM was published, the v. United States Food and Drug expectation that more than one set of term for daily consumer use antiseptics Administration, et al., 10 Civ. 5690 data will be submitted to the docket for was changed to ‘‘antiseptic hand wash.’’ (S.D.N.Y.). a particular active ingredient, and it In response to this change, we received does not matter who submits the data. comments that the term ‘‘antiseptic D. Comment Period hand wash’’ did not include all of the In addition, data and other information consumer products on the market, such Because of the complexity of this for a single active ingredient may be as hand rubs and body washes. proposed rule, we are providing a submitted by any interested party and Therefore, in this proposed rule, we use comment period of 180 days. Moreover, not all data for an ingredient must be the term ‘‘consumer antiseptic,’’ which new data or information may be submitted by a single party. is a broad term and meant to include all submitted to the docket via http:// III. Background of the types of antiseptic products used www.regulations.gov (see ADDRESSES) on a frequent or daily basis by within 12 months of publication, and In this section, we describe the consumers. However, this proposed rule comments on any new data or significant rulemakings and public covers only consumer antiseptic rubs information may then be submitted to meetings relevant to this proposed rule, and does not include consumer the docket for an additional 60 days (see and how we are responding to antiseptic hand washes or body washes. § 330.10(a)(7)(iii) and (iv)). In addition, comments received in response to the The 1994 TFM did not distinguish FDA will also consider requests to defer 1994 TFM. between products that we are now further rulemaking with respect to a A. Significant Rulemakings Relevant to calling ‘‘antiseptic washes’’ and specific active ingredient for use as a This Proposed Rule products we are now calling ‘‘antiseptic consumer antiseptic rub to allow the rubs.’’ Washes are rinsed off with water, submission of new safety or A summary of the significant Federal and include consumer hand washes and effectiveness data to the record if these Register publications relevant to this body washes, and health care personnel requests are submitted to the docket proposed rule is provided in table 1. hand washes and surgical hand scrubs. within the initial 180-day comment Other publications relevant to this Rubs are sometimes referred to as period. FDA will review all data and proposed rule are available at http:// ‘‘leave-on products’’ and are not rinsed information submitted to the record in www.regulations.gov in FDA Docket No. off after use. They are intended to be conjunction with all timely and 1975–N–0012.

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

Federal Register Notice Information in notice

1974 ANPR (September 13, 1974, 39 FR We published an ANPR to establish a monograph for OTC topical antimicrobial drug products, to- 33103). gether with the recommendations of the Advisory Review 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, We published our tentative conclusions and proposed effectiveness testing for the drug product cat- 43 FR 1210). egories evaluated by the Panel. The 1978 TFM reflects our evaluation of the recommendations of the Panel and comments and data submitted in response to the Panel’s recommendations. 1982 Alcohol ANPR (May 21, 1982, 47 We published an ANPR to establish a monograph for alcohol drug products for topical antimicrobial FR 22324). use, together with the recommendations of the Advisory Review Panel on OTC Miscellaneous Ex- ternal Drug Products, which was the advisory review panel responsible for evaluating data on the active ingredients in this drug class. 1991 First Aid TFM (July 22, 1991, 56 FR We amended the 1978 TFM to establish a separate monograph for OTC first aid antiseptic prod- 33644). ucts. In the 1991 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 We amended the 1978 TFM to establish a separate monograph for the group of products that were 17, 1994, 59 FR 31402). referred to as OTC topical health care antiseptic drug products. These antiseptics are generally intended for use by health care professionals. In 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.

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

Federal Register Notice Information in notice

2013 Consumer Antiseptic Wash TFM We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining (December 17, 2013, 78 FR 76444). 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. 2015 Health Care Antiseptics TFM (May We issued a proposed rule to amend the 1994 TFM and to establish data standards for determining 1, 2015, 80 FR 25166 ). whether OTC health care antiseptics are GRAS/GRAE. In that proposed rule, we proposed that additional safety and effectiveness data are necessary to support the safety and effectiveness of health care antiseptic active ingredients. 1 The publications listed in table 1 can be found at the FDA’s ‘‘Status of OTC Rulemakings’’ Web site available at http://www.fda.gov/Drugs/De- velopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm070821.htm. The publications dated after 1993 can also be found in the Federal Register at https://www.federalregister.gov.

B. Public Meetings Relevant to This been four 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 consumer publications listed in table 1, there have antiseptic rub safety and effectiveness.

TABLE 2—RELEVANT PUBLIC MEETINGS

Date and type of meeting Topic of discussion

January 1997 NDAC Meeting (Joint meet- Antiseptic and resistance in relation to an industry proposal for consumer and health care ing with the Anti-Infective Drugs Advi- antiseptic effectiveness testing (Health Care Continuum Model) (Refs. 6, 7). sory Committee) (January 6, 1997, 62 FR 764). March 2005 NDAC Meeting (February 18, The use of surrogate endpoints and study design issues for the in vivo testing of health care 2005, 70 FR 8376). antiseptics (Ref. 8). October 2005 NDAC Meeting (September Benefits and risks of consumer antiseptics. NDAC expressed concern about the pervasive use of 15, 2005, 70 FR 54560). consumer antiseptic washes where there are potential risks and no demonstrable benefit. To demonstrate a clinical benefit, NDAC recommended clinical outcome studies to show that anti- septic washes are superior to nonantibacterial soap and water (Ref. 9). November 2008 Public Feedback Meeting Demonstration of the effectiveness of consumer antiseptics (Ref. 10). September 2014 NDAC Meeting (July 29, Safety testing framework for health care antiseptic active ingredients (Ref. 11). 2014, 79 FR 44042).

C. Comments Received by FDA formulation testing and labeling IV. Active Ingredients With Insufficient In response to the 1994 TFM, FDA conditions proposed in the 1994 TFM, Evidence of Eligibility for the OTC Drug received approximately 160 comments particularly in light of the data proposed Review from drug manufacturers, trade in this proposed rule as necessary to In this section of the proposed rule, associations, academia, testing support a GRAS/GRAE determination. we describe the requirements for laboratories, consumers, health Comments that were received in eligibility for the OTC Drug Review and professionals, and law firms. In response to the 1994 TFM regarding the ingredients submitted to the OTC response to the 2013 Consumer Wash other intended uses of the active Drug Review that lack adequate PR, we received safety data regarding ingredients are addressed in the 2013 evidence of eligibility for evaluation as benzalkonium chloride that is relevant Consumer Wash PR (78 FR 76444), or consumer antiseptic rub products. to this ingredient’s use in a consumer the 2015 Health Care Antiseptic PR (80 A. Eligibility for the OTC Drug Review rub and these data are evaluated in FR 25166), or will be addressed in section VIII.D.2. Copies of the comments future documents related to those other An OTC drug is covered by the OTC received are on public display at http:// uses. Drug Review if its conditions of use existed in the OTC drug marketplace on www.regulations.gov (see ADDRESSES). This proposed rule constitutes FDA’s or before May 11, 1972 (37 FR 9464) Because only consumer antiseptic rubs evaluation of submissions made in are discussed in this proposed rule, only (Ref. 13).2 Conditions of use include, response to the 1994 TFM to support the those comments and data received in among other things, active ingredient, safety and effectiveness of OTC response to the 1994 TFM that are dosage form and strength, route of related to consumer antiseptic rub consumer antiseptic rub active administration, and specific OTC use or active ingredients are addressed. We ingredients (Ref. 12). We reviewed the indication of the product (see also received comments related to final available literature and data and the § 330.14(a)). To determine eligibility for formulation testing and labeling comments submitted to the rulemaking the OTC Drug Review, FDA typically conditions proposed in the 1994 TFM. and are proposing that adequate data for If in the future we determine that there a determination of safety and 2 Also, note that drugs initially marketed in the are monograph consumer antiseptic rub effectiveness are not yet available for the United States after the OTC Drug Review began in consumer antiseptic rub active 1972 and drugs without any U.S. marketing active ingredients that are GRAS/GRAE, experience can be considered in the OTC we will address these comments. We ingredients. monograph system based on submission of a Time invite further comment on the final and Extent Application. (See § 330.14).

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must have actual product labeling or a • Sodium oxychlorosene given OTC use (i.e., nonmonograph) facsimile of labeling that documents the • Tribromsalan because of lack of evidence of conditions of marketing of a product • effectiveness, lack of evidence of safety, • prior to May 1972 (see § 330.10(a)(2)). Triclosan or both. In the 1994 TFM (59 FR 31402 FDA considers a drug that is ineligible • Triple dye • at 31435), FDA proposed that the active for inclusion in the OTC monograph Undecoylium chloride ingredients fluorosalan, system to be a new drug that will complex , (greater than require FDA approval through the NDA Following the publication of the 1994 1.5 percent), and tribromsalan be found process. Ineligibility for use as a TFM, FDA received submissions for the not GRAS/GRAE for the uses referred to consumer antiseptic rub does not affect first time requesting that the following in the 1994 TFM as antiseptic hand eligibility under any other OTC drug compounds be added to the monograph wash and health care personnel hand monograph. (Refs. 14 through 20): wash. None of these ingredients B. Eligibility of Certain Active • Polyhexamethylene currently have adequate evidence of • Ingredients for the OTC Drug Review Benzalkonium cetyl phosphate eligibility for use in a consumer • The following list includes those • antiseptic rub (see section IV.B). Calicylic acid, Consequently, effectiveness and safety active ingredients that were addressed • Tea tree oil information that has been submitted to in the 1994 TFM for use as an antiseptic • Combination of potassium vegetable hand wash or health care personnel oil solution, phosphate sequestering the rulemaking for these consumer hand wash, and which currently do not agent, and triethanolamine antiseptic rub active ingredients are not have adequate evidence of eligibility for discussed in this proposed rule for such These compounds were not addressed evaluation under the OTC Drug Review use. However, if documentation of the in prior FDA documents related to the for use in a consumer antiseptic rub. monograph and were not evaluated for type described in section IV.A is Our review of the labeling submitted to antiseptic hand wash use by the submitted, these active ingredients the Panel or to FDA at a later time did Antimicrobial I Panel. The submissions could be determined to be eligible for not identify evidence demonstrating received by the Agency to date do not evaluation for use as a consumer eligibility for the following active include documentation demonstrating antiseptic rub. ingredients: the eligibility of any of these • Benzethonium chloride VI. Summary of Proposed • compounds for inclusion in the topical Classifications of OTC Consumer antimicrobial monograph (Ref. 21). • 3 Antiseptic Rub Active Ingredients gluconate Because of their lack of eligibility, • Cloflucarban • Fluorosalan effectiveness and safety information that Table 3 lists the OTC consumer • Hexachlorophene has been submitted to the rulemaking antiseptic active ingredients eligible for • for these consumer antiseptic rub active evaluation under the OTC Drug Review • Iodine complex (ammonium ether ingredients are not discussed in this for use in consumer rubs, the sulfate and polyoxyethylene sorbitan proposed rule for such use. However, if classification proposed in the 1994 monolaurate) documentation of the type described in TFM, and the classification being • Iodine complex (phosphate ester of section IV.A is submitted, these active proposed in this rulemaking. For each alkylaryloxy ) ingredients could be determined to be active ingredient, data that have been • Methylbenzethonium chloride eligible for evaluation for use as a submitted to the public docket (for the • consumer antiseptic rub. Nonylphenoxypoly (ethyleneoxy) topical antimicrobial rulemaking) and ethanoliodine V. Ingredients Previously Proposed as evaluated by FDA and the description of • Phenol (less than 1.5 percent) Not Generally Recognized as Safe and data still lacking in the administrative • Phenol (greater than 1.5 percent) Effective • Poloxamer iodine complex record are described in detail in section • Povidone-iodine 5 to 10 percent FDA may determine that an active VIII. • Secondary amyltricresols ingredient is not GRAS/GRAE for a

TABLE 3—CLASSIFICATION OF OTC CONSUMER ANTISEPTIC RUB ACTIVE INGREDIENTS IN THE 1994 TFM AND IN THIS PROPOSED RULE

Active ingredient 1994 TFM This proposed proposal 1 rule

Alcohol 60 to 95 percent ...... I 2 ...... IIISE 3 Isopropyl alcohol 70 to 91.3 percent ...... IIIE ...... IIISE Benzalkonium chloride ...... IIISE ...... IIISE 1 Because the 1994 TFM did not describe antiseptic hand washes and rubs separately, the 1994 TFM classification was for use as an anti- septic hand wash or health care antiseptic hand wash. 2 ‘‘I’’ denotes a classification that an active ingredient has been shown to be safe and effective. 3 ‘‘III’’ denotes a classification that additional data are needed. ‘‘S’’ denotes safety data needed. ‘‘E’’ denotes effectiveness data needed.

In the 1994 TFM, alcohol was alcohol was classified as Category IIIE, classified as Category IIISE for use as an classified as Category I, isopropyl and benzalkonium chloride was antiseptic hand wash or health care

3 Chlorhexidine gluconate 4 percent aqueous and was not included in the 1994 TFM (59 FR this active ingredient is eligible for the topical solution was found to be ineligible for inclusion in 31402 at 31413). We have not received any new antimicrobial monograph. the monograph for any health care antiseptic use information since the 1994 TFM demonstrating that

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personnel hand wash. However, in this demonstrating the impact of consumer determination for any consumer proposed rule, we are proposing to antiseptic rubs on infection rates are not antiseptic rub active ingredient under classify all three ingredients as Category available. In contrast to consumer either the final formulation effectiveness IIISE for use as a consumer antiseptic washes, for which we are asking for testing criteria proposed in the 1994 rub because additional effectiveness and clinical outcome data to support the TFM or under the GRAE criteria safety data are needed to classify each benefit of these products, given the proposed in this proposed rule (see ingredient as GRAS/GRAE for this use. easily available alternative of washing table 4). with soap and water, there is no similar We have also evaluated all the studies VII. Effectiveness (Generally readily available alternative for that were submitted to the OTC Drug Recognized as Effective) Determination consumer antiseptic rubs. A clinical Review and have searched the OTC regulations (§§ 330.10(a)(4)(ii) outcome trial comparing the use of published literature for studies and 314.126(b) (21 CFR 330.10(a)(4)(ii) consumer antiseptic rubs to standard performed in consumer use settings that and 314.126(b))) define the standards for hand washing with soap and water has would provide the direct evidence of a establishing that an OTC drug less applicability given that consumer clinical benefit from the use of containing a particular active ingredient antiseptic rubs are not generally used in consumer antiseptic rubs (Ref. 24). We would be GRAE for its intended use. situations in which soap and water are are defining a clinical benefit here as a These regulations provide that a readily available alternative. reduction in the number of infections in supporting investigations must be Therefore, we are currently a population that uses the consumer adequate and well-controlled, and able recommending the use of clinical antiseptic rubs. Although a definitive to distinguish the effect of a drug from simulation studies because they are a link between consumer antiseptic rubs other influences such as a spontaneous practical means to assess the general and reduced infection rates has not been change in the course of the disease, effectiveness of consumer antiseptic established, some public health agencies placebo effect, or biased observation. In rubs. recommend the use of consumer general, such investigations include FDA has already relied on clinical antiseptic rubs when soap and water are controls that are adequate to provide an simulation studies as a standard for not available (Refs. 22, 23). assessment of drug effect, are adequate evaluating effectiveness of hand measures to minimize bias, and use antiseptic drug products approved A. Evaluation of Effectiveness Data adequate analytical methods to under NDAs, which are proven to be an 1. Clinical Simulation Studies demonstrate effectiveness. For active effective measure to lower the surgical ingredients being evaluated in the OTC site infection rate (Refs. 25 through 27). Most of the available data to support Drug Review, this means that a In addition, in our recently revised the effectiveness of consumer antiseptic demonstration of the contribution of the standards for evaluating the rubs are based on clinical simulation active ingredient to any effectiveness effectiveness of health care antiseptics studies, such as the ones described in observed is required before an published in May 2015 (80 FR 25166), the 1994 TFM (59 FR 31402 at 31444). ingredient can be determined to be we relied on clinical simulation studies The premise behind these studies as GRAE for OTC drug use. based on the recommendations of the described in the 1994 TFM is that In the 1994 TFM, we continued to March 2005 NDAC. In contrast, in the bacterial reductions translate to a apply a log reduction standard (a 2013 Consumer Wash PR, we proposed reduced risk for infection. However, clinical simulation standard) for an efficacy standard for consumer currently, there are no clinical data that establishing effectiveness of consumer antiseptic washes that relies on clinical demonstrate that the specific bacterial antiseptics originally proposed in the outcome trials, also based on NDAC log reductions that we have relied upon 1978 TFM (59 FR 31402 at 31412) for recommendations. As noted previously, as a demonstration of effectiveness lead the proposed intended use of decreasing consumer antiseptic rub products are to a specific reduction in infections. In bacteria on the skin. The 1994 TFM log generally used when soap and water are our view, although a lower number of reduction standard for effectiveness is not available, so consumers lack a bacteria on hands may not directly based on a surrogate endpoint (i.e., readily available alternative. As such, translate into a reduced chance of number of bacteria removed from the we continue to propose a log reduction infection, a reduced bacterial load does skin), rather than a clinical outcome standard to demonstrate the general decrease the opportunity for infection (e.g., reduction in the number of recognition of effectiveness for when used in situations with no other infections). Although the test methods consumer antiseptic rubs in accordance options for hand cleansing. In this case, proposed in the 1994 TFM are intended with our standards for health care rather than comparing using consumer to evaluate the effectiveness of antiseptics, which contain the same antiseptic rubs to hand washing with antiseptic final formulations, this type active ingredients (i.e., alcohol, soap and water, we are comparing them of clinical simulation testing, when isopropyl alcohol, and benzalkonium to the alternative of not cleaning the adequately controlled, can also be used chloride). Details of our current hands. In addition, because we believe to demonstrate that an active ingredient proposed log reduction standard are that the consumer antiseptic rubs are is GRAE for use in a consumer outlined in section VII.B. intended to provide immediate antiseptic rub product. As reflected by As discussed in section VII.A, we reduction of bacteria rather than a the recommendations of some public have evaluated the available persistent benefit, we are proposing that health agencies, FDA believes that effectiveness studies that were log reductions be measured after a consumer antiseptic rubs are generally submitted to the OTC Drug Review or single bacterial challenge (see table 4), used when hands are not visibly soiled, retrieved through the published rather than after repeated and soap and water are not readily literature to support the effectiveness for contamination. available (Refs. 22, 23), for example, in consumer antiseptic rubs using the log We have evaluated all clinical settings such as school classrooms, reduction criteria most recently simulation studies that were submitted childcare facilities, outdoors and proposed in the 1994 TFM (59 FR 31402 to the OTC Drug Review for evidence of various other public places (Ref. 24). at 31448) (Refs. 28 and 29). We found the effectiveness of consumer antiseptic However, as discussed in section VII.A, that the available studies are not rub active ingredients under the log data from adequately controlled studies adequate to support a GRAE reduction criteria proposed in the 1994

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TFM (59 FR 31402 at 31448) (Refs. 28 literature that could potentially provide written), and children and staff were through 30). We also searched the evidence of effectiveness for the use of asked to wash hands with plain soap published literature for clinical consumer antiseptic rubs (Ref. 24). In and water, then rub with a 70-percent simulation studies that assess consumer our view, clinical outcome studies alcohol-containing consumer antiseptic antiseptic rubs’ effectiveness using the evaluating the effectiveness of consumer rub. Control groups followed the same log reduction criteria in the 1994 TFM rubs should be adequately controlled hand-washing protocol without the (Refs. 28 and 29). and include a placebo or negative hand rub. The primary outcome was the Overall, the studies used a variety of control arm to show the effect of an rate of illness absenteeism. Parents were study designs, including nonstandard active ingredient. Among the reviewed asked to report every episode when the study designs. In some cases, data studies and published literature, there child was absent from childcare because submitted to the OTC Drug Review were are only a few studies that use these of illness, including the dates of in the form of technical reports or specified parameters for evaluating the absence, symptoms, and any medical published articles without any study effectiveness of consumer antiseptic treatment. There were 0.37 absences per details. There is insufficient information rubs (Ref. 25). Overall, most of the 100 child hours in the control group, to evaluate the scientific merit of studies studies were confounded, compared to 0.33 in the intervention described in abstracts and technical underpowered, and/or not properly group. The effect of the intervention was reports. Most importantly, none of the controlled. a 12-percent reduction in absenteeism. evaluated studies were adequately Our detailed review of consumer Based on the amount of hand rub used controlled to demonstrate the hand rubs studies is available in Docket during the study, the estimated contribution of the active ingredient to No. FDA–2016–N–0124 (Ref. 24). None frequency of hand rub use by each child the effectiveness observed in the studies of the alcohol-based hand rub studies was two to six times per day. Although (43 FR 1210 at 1240) and, therefore, demonstrating benefit were adequately the study is well designed, there are cannot be used to demonstrate that the controlled, thus they could not several significant limitations, such as active ingredient tested is GRAE. demonstrate the contribution of the the following: In general, the evaluated studies also antiseptic active ingredient to the • No clinical or microbiological had at least one of the following observed clinical outcome of reduced evaluation of illness. infection rates. In general, the studies • No specific infection was studied. deficiencies: • • Some studies that were described as had the following design flaws: Children kept home based on using a standardized method (American • No comparison to vehicle. parent choice not addressed in the Society for Testing and Materials • Small sample size. statistical analysis. • • (ASTM) 4 or 1994 TFM) varied from Lack of randomization, blinding, or Degree of illness and symptoms to both. keep child home varied among parents. these methods without explanation or • validation, and the majority of studies Inadequate statistical power and, in B. Current Standards: Studies Needed did not provide sufficient information some cases, a failure to analyze results To Support a Generally Recognized as about critical aspects of the study for statistical significance. Effective Determination • Inadequate description of conduct. In the 1994 TFM, we proposed that • Many studies did not include methodology and data collection the effectiveness of antiseptic active appropriate controls; for example, most methods. • ingredients could be supported by a studies did not include a vehicle control Failure to observe and document combination of in vitro studies and in or an active control (59 FR 31402 at hand rub application technique. One clinical outcome study was vivo clinical simulation testing as 31448), and some studies that included identified that was randomized, described in 21 CFR 333.470 (59 FR an active control failed to use the blinded, and placebo-controlled and 31402 at 31444). In vitro studies are control product according to its labeled was well designed to evaluate the designed to demonstrate the product’s directions (59 FR 31402 at 31448). effectiveness of a particular antiseptic spectrum and kinetics of antimicrobial • Many studies did not provide active ingredient (Ref. 31). Although it activity, as well as the potential for the sufficient detail concerning neutralizer had several significant limitations that development of resistance associated use (43 FR 1210 at 1244) or validation prevent it from being sufficient to with product use. In vivo test methods of neutralizer effectiveness. • The studies evaluated a small establish effectiveness for use of the and evaluation criteria are based on the number of subjects (59 FR 31402 at active ingredient in a consumer premise that bacterial reductions can be 31449). antiseptic rub, this study is the best adequately demonstrated using tests • Some studies did not sample all of among the available studies that that simulate conditions of actual use the time points specified by the test evaluate the impact of consumer for OTC consumer antiseptic rub method (59 FR 31402 at 31448). antiseptic rubs on infections. products and that those reductions are FDA’s detailed evaluation of the data This clinical outcome study reflective of bacterial reductions that is filed in Docket No. FDA–2016–N– performed in Sweden compared the would be achieved during use. For the 0124, available at http:// effectiveness of a 70-percent alcohol- use of antiseptic rubs, some public www.regulations.gov. containing consumer antiseptic rub as health agencies (Ref. 22) recommend an adjunct to hand washing with plain their use when soap and water are not 2. Clinical Outcome Studies soap and water in childcare centers (Ref. available, and when there is no other Although we are not currently 31). The study included 60 childcare reasonably available alternative for the proposing to require clinical outcome centers (30 matched pairs) from 10 consumer. studies to support a GRAE counties with a mean number of 50 In addition to the standards described determination in this proposed rule, children in each center. One childcare in section VII.B, the effectiveness of FDA identified and evaluated clinical center from each matched pair was consumer antiseptic rubs can be affected outcome studies from the published randomized to the intervention group, by a variety of other factors related to with the other serving as the control product formulation and use. Section 4 General information about ASTM can be found group. The intervention groups were VII.C discusses these factors, which at https://www.astm.org/. provided instructions (verbal and includes the number of times per day a

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product is used and the volume used in Æ Bacteroides fragilis. labeling, that labeling would also be each use. Æ Enterobacter species. relevant in the health care setting. Æ Burkholderia cepacia (ATCC 25416 1. In Vitro Studies and ATCC 25608). 2. In Vivo Studies The 1994 TFM proposed that the in Æ Escherichia coli (ATCC 11775 and Based on the recommendations of the vitro antimicrobial activity of an active ATCC 25922). March 2005 NDAC meeting for health ingredient could be demonstrated by a Æ Klebsiella pneumoniae (ATCC care antiseptic products, we continue to determination of the in vitro spectrum 13883 and ATCC 27736). propose the use of bacterial log of antimicrobial activity, minimum Æ Pseudomonas aeruginosa (ATCC reductions as a means of demonstrating inhibitory concentration (MIC) testing 15442 and ATCC 27853). that consumer antiseptic rubs are GRAE against 25 fresh clinical isolates and 25 Æ Serratia marcescens (ATCC 8100 (Ref. 8). The 1994 TFM also proposed laboratory strains, and time-kill testing and ATCC 14756). final formulation testing for antiseptic against 23 laboratory strains (59 FR Æ Campylobacter jejuni (ATCC 33291 hand washes (59 FR 31402 at 31448). 31402 at 31444). Comments received in and ATCC 49943). We are not discussing the final response to the 1994 TFM objected to Æ enterica Serovar formulation testing here because we are the proposed in vitro testing Enteritidis (ATCC 13076) and Serovar not proposing that any of the requirements, stating that they were Typhimurium (ATCC 14028). Serovar ingredients are GRAS/GRAE. Although, overly burdensome (Ref. 32). refers to the subspecies classification of as previously noted, these proposed test Submissions of in vitro data submitted a group of microorganisms based on cell methods are intended to evaluate the to support the effectiveness of antiseptic surface antigens. effectiveness of antiseptic final active ingredients were far less Æ Shigella sonnei (ATCC 9290 and formulations, this type of clinical extensive than what was proposed in ATCC 25931). simulation testing when adequately the 1994 TFM (Ref. 33). Although we Gram-positive organisms. controlled can also be used to agree that the in vitro testing proposed Æ Enterococcus faecalis (ATCC 19433 demonstrate that an active ingredient is in the 1994 TFM is not warranted for and ATCC 29212). GRAE for use in a consumer antiseptic testing every final formulation of an Æ Staphylococcus aureus (ATCC 6538 rub product. Based on our experience antiseptic product that contains a GRAE and ATCC 29213) and methicillin- with the approval of NDA antiseptic ingredient, we believe that a GRAE resistant Staphylococcus aureus (ATCC products, and input from the March determination for a consumer antiseptic 33591 and ATCC 33592). 2005 and October 2005 NDAC meetings, active ingredient should be supported Æ Streptococcus pyogenes (ATCC we recommend that the bacterial log by adequate in vitro characterization of 14289 and ATCC 19615). reduction studies used to demonstrate the antimicrobial activity of the Æ Listeria monocytogenes (ATCC 7644 that an active ingredient is GRAE for use ingredient. In addition, we now propose and ATCC 19115). in consumer antiseptic rub drug Æ the option of assessing the minimum Streptococcus pneumoniae (ATCC products include the following: bactericidal concentration (MBC) as an 6303 and ATCC 49619). • A vehicle control to show the alternative to testing the MIC to We propose that a consumer contribution of the active ingredient to demonstrate the broad spectrum activity antiseptic rub active ingredient be effectiveness. The test product should of the antiseptic. The ability of an considered bactericidal at the be statistically superior to the vehicle antiseptic to kill microorganisms, rather concentration and contact time that control for the clinical simulation to be than inhibit them, is more relevant for demonstrates a 3-log10 (99.9 percent) or considered successful at showing that a topical product. Because GRAE status greater reduction in bacterial viability the test product is effective for use in is a very broad determination that can for all the tested strains. This is the consumer antiseptic rub products. apply to many different formulations of same performance criterion used by the Products with vehicles that have an active ingredient, we continue to Clinical and Laboratory Standards antimicrobial activity should consider propose that an evaluation of the Institute (NCCLS, ‘‘Methods for using a negative control, such as saline, spectrum and kinetics of antimicrobial Determining Bactericidal Activity of rather than a vehicle control. activity of a consumer antiseptic rub Antimicrobial Agents; Approved • An active control to validate the active ingredient should be evaluated by Guideline,’’ NCCLS document M26–A, study conduct, to assure that the the following testing: 1999). expected results are produced. For the • A determination of the in vitro Despite the fact that the in vitro data results to be valid, the active control spectrum of antimicrobial activity submitted to support the effectiveness of should meet the appropriate log against potential pathogens (listed in antiseptic active ingredients were far reduction criteria. this section) that may be encountered in less extensive than proposed in the 1994 • A sample size large enough to show consumer use settings where soap and TFM, manufacturers may have data of statistically significant differences from water are not readily available. MIC or this type on file from their own product the results achieved using the vehicle, MBC testing of 25 representative clinical development programs that have not and meeting the threshold of at least a isolates and 25 reference (e.g., American been submitted to the rulemaking. 70-percent success rate for the test Type Culture Collection (ATCC)) strains Furthermore, published data may be product, including justification that the of each of the microorganisms listed in available that would satisfy some or all number of subjects tested is adequate for this section. these data requirement. Data from these the test. • Time-kill testing of each of the in vitro studies, as well as data from the • Use of an appropriate neutralizer in following ATCC strains to assess how literature, may be used to inform all recovery media (i.e., sampling rapidly the antiseptic active ingredient labeling, in particular, if there are solution, dilution fluid, and plating produces its effect. The dilutions and specific organisms for which an active media) and a demonstration of time points tested should be relevant to ingredient does not have significant neutralizer validation. The neutralizer is the actual use pattern of the final activity. It is anticipated that if data used to halt the antimicrobial activity of product. supporting use of a consumer antiseptic the antiseptic after product exposure so Gram-negative organisms. demonstrate lack of activity against a that a continued effect through Æ Haemophilus influenzae. particular organism that requires subsequent dilution steps and culturing

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thereby does not create inflated log in this section should be evaluated a single application of the test product reductions. The purpose of neutralizer using log reduction criteria similar to rather than multiple applications. Given validation is to show that the neutralizer those proposed in the 1994 TFM (59 FR that we are no longer requiring a used in the study is effective against the 31402 at 31448). Our current criteria are cumulative antiseptic effect, the log test and control products, and that it is laid out in table 4. We have revised the reduction criteria were revised to reflect not toxic to the test microorganisms. If log reduction criteria proposed for this single application and fall between a test product can be neutralized consumer antiseptic rubs based on the the log reductions previously proposed through dilution, this should be recommendations of the March 2005 for the first and last applications. The demonstrated in the neutralizer NDAC and comments to the 1994 TFM, GRAE criteria proposed for consumer which argued that the demonstration of validation study. antiseptic rubs are based on log • An analysis of the proportion of a cumulative antiseptic effect for these reductions achieved by antiseptics as subjects who meet the log reduction products is unnecessary. We agree that shown in the published literature (Refs. criteria based on a two-sided statistical the critical element of the effectiveness test for superiority to vehicle and a 95- is that a product must be effective after 28 and 29) as well as those evaluated percent confidence interval approach. the first application because that under the NDA process. Table 4 shows To establish that a particular active represents the way in which consumer the log reductions that we would expect ingredient is GRAE for use in consumer antiseptic rub products are used (59 FR an effective consumer antiseptic rub antiseptic rubs, clinical simulation 31402 at 31442). For these reasons, log active ingredient to meet to show that it studies using the parameters described reduction criteria are proposed only for is GRAE.

TABLE 4—CLINICAL SIMULATION TESTING BACTERIAL LOG REDUCTION EFFECTIVENESS CRITERIA IN THIS PROPOSED RULE AND IN THE 1994 TFM

Indication 1994 TFM This proposed rule

Antiseptic hand wash/Con- (1) Reduction of 2 log10 on each hand within 5 minutes (1) Reduction of 2.5 log10 on each hand within 5 min- sumer antiseptic rub. after the first wash and utes after a single rub. (2) Reduction of 3 log10 on each hand within 5 minutes after the tenth wash.

C. Impact of Application Parameters on and 70 percent ethanol foam, Kampf et product efficacy, the factors that may Efficacy al. (2013) demonstrated that the label affect application volume are of interest. recommended volume of 1.1 milliliters Variability has been demonstrated in the Establishing GRAE status of active (mL) for the 70 percent ethanol products output of both gel and foam antiseptic ingredients is one important aspect of was not sufficient to achieve efficacy in rub dispensers. Macinga et al. (2013) ensuring the efficacy of OTC consumer in vivo efficacy testing according to measured output from a single wall- antiseptic rub products. The standards ASTM methods (Ref. 35). The mounted dispenser and among wall- for a GRAE determination for consumer recommended application of 2 mL of 85 dispensers from different manufacturers antiseptic rubs have been described (see percent gel, as well as higher than (Ref. 37). In dispensing five different gel section VII.B). These standards will help recommended volumes of the 70 formulations containing varying determine final monograph active percent products, met efficacy criteria percentages of ethanol or isopropanol, ingredients, as well as their permitted under ASTM E 2755–10 and ASTM E dispensers from five different concentrations and the skin application 1174–06 methods used in this study. In manufacturers had outputs that ranged time needed for the active ingredient to the same study, insufficient skin from 0.9 to 1.3 mL per actuation. In achieve adequate bacterial reduction. coverage with lower application dispensing three different foam However, the efficacy of any particular volumes (1.1 mL) was suggested as the formulations each containing 70 percent final formulation of a consumer reason for failure to achieve efficacy. ethanol, foam dispensers from three antiseptic rub appears to be affected by Failure to achieve effectiveness with the different manufacturers ranged from 0.6 a variety of other factors related to lower volume was based on observation to 1.1 mL per actuation. Furthermore, product formulation and use. of gaps in skin coverage after volunteers the volume of product that individuals These factors include the number of applied products containing fluorescent choose to apply may be affected, times per day a product is used and the dye to their hands. In a similar study, independent of labeled instruction, by volume used in each use. The number Kampf (2008) assessed the efficacy and factors such as the time it takes hands of times per day that a consumer coverage of four hand rub products to dry after application. Kampf et al. antiseptic rub product is applied has (foam or gel formulation unspecified) (2010) assessed four foam formulations, been shown to be positively correlated containing 85 percent, 62 percent, 61 each containing 62 percent ethanol, and with a reduction in illness-related percent, or 60 percent ethanol (Ref. 36). found that the amount (weight) of foam absenteeism in a kindergarten school At an application volume of 2.4 mL, the applied was significantly correlated (Ref. 34). In addition, more specific 60 percent and 61 percent ethanol with the perceived drying time (Ref. 38). measures of application parameters formulations failed to meet in vivo There is also evidence that final have been assessed. The volume of ASTM efficacy criteria while 2.4 mL formulation affects efficacy. Different product applied and the skin coverage application volumes of 62 percent and products containing the same achieved by the applied volume appear 85 percent ethanol formulations met the concentration of active ingredient have to have an impact on efficacy of criteria. Application volumes of 3.6 mL been shown to perform differently when antiseptic rub products containing met efficacy criteria for all ethanol tested by in vivo bacterial reduction alcohol. In comparing five different concentrations tested (Ref. 36). testing (ASTM 1174) (Ref. 39). One application volumes of 70 percent Given that the applied volume of ‘‘novel’’ gel formulation and one ethanol gel with 85 percent ethanol gel product may have consequences for ‘‘novel’’ foam formulation, each

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containing 70 percent ethanol, were experience with, and knowledge about, absorption anticipated between both shown to be statistically superior safety testing has led to improved formulations, and the safety margin for after both 1 and 10 applications testing methods. Improvements include toxic effects, final formulation safety compared to two marketed study designs that are more capable of testing for particular ingredients may be formulations, one gel and one foam, detecting potential safety risks. Based needed to assure that substantially both containing 70 percent ethanol. All on our reassessment, we are proposing different absorption that might formulations were applied in equal new GRAS data standards for consumer significantly change the margin of safety volumes. The two ‘‘novel’’ formulations antiseptic rub active ingredients. To is not anticipated for a new formulation. also demonstrated some evidence of fully address these new safety concerns, FDA does not address final formulation improved performance relative to a additional safety data will be necessary testing in this rulemaking because no marketed gel containing 90 percent to support a GRAS determination for all ingredients have been proposed as ethanol. consumer antiseptic rub active GRAS/GRAE. However, FDA recently Understanding the impact of product- ingredients. described final formulation safety related parameters, such as formulation, Many of the safety considerations for testing for another class of OTC dermal dose applied, and application volume, consumer antiseptic rubs are based on products regulated under the OTC drug to be used according to the labeling is FDA’s view that the use of consumer monograph (Ref. 41). imperative. We also need to understand antiseptic rubs is a ‘‘chronic’’ use as that The evaluation of the safety of drug the extent to which variability in term is defined by the International products involves correlating findings product-related parameters must be Council on Harmonisation (ICH).5 As from animal toxicity studies to the level reduced to ensure that products achieve defined by the ICH, a use is considered of drug exposure obtained from the results expected based on their use chronic if the drug will be used for a pharmacokinetic studies in animals and of GRAE ingredients. Given the data period of at least 6 months over the humans. Our administrative record demonstrating that efficacy varies with user’s lifetime, including repeated, lacks the data necessary to define a dose, application volume, and intermittent use (Ref. 40). We believe margin of safety for the potential formulation, final formulation efficacy that consumer antiseptic rubs are often chronic use of consumer antiseptic rub testing will be necessary for consumer used on a daily basis and sometimes active ingredients. Thus, we are antiseptic rub products in order to repeatedly over the course of the day. continuing to propose that both animal confirm effectiveness and label the and human pharmacokinetic (PK) data product appropriately for use. However, A. New Issues are necessary for consumer antiseptic because no ingredient has sufficient Since the 1994 TFM was published, rub active ingredients. This information data to support GRAS/GRAE status in new data have become available will help identify any potential safety this rulemaking, we are not proposing indicating that systemic exposure to concerns and help determine the safety specific final formulation testing or topical antiseptic active ingredients may margin for OTC human use. labeling at this time. Instead, we are be greater than previously thought. One potential effect of systemic requesting data to allow the assessment Systemic exposure refers to the presence exposure to consumer antiseptic active of the impact of various application of antiseptic active ingredients inside ingredients that has come to our parameters on efficacy and the and throughout the body. Because of attention since publication of the 1994 interaction among them (e.g., how does advances in technology, our ability to TFM is data suggesting that some formulation affect application volume detect antiseptic active ingredients in antiseptic active ingredients have requirements) to inform final body fluids such as serum and urine is hormonal effects. Ingredients in topical formulation testing and labeling greater than it was in 1994. For antiseptic products can cause alterations in the thyroid of neonatal and requirements. example, studies have shown detectable adolescent animals (Refs. 42 through blood alcohol levels after use of alcohol- VIII. Safety (Generally Recognized as 51). Hormonally active compounds have containing hand rubs (Refs. 1, 4, and 5). Safe) Determination been shown to affect not only the We believe that any consequences of In the 1994 TFM, 11 active exposed organism, but also subsequent this systemic exposure should be ingredients were proposed to be generations (Ref. 52). These effects may identified and assessed to support our classified as GRAS for antiseptic hand not be related to direct deoxyribonucleic risk-benefit analysis for consumer wash use, which includes 2 active acid (DNA) mutation, but rather to antiseptic use. ingredients (alcohol and isopropyl alterations in factors that regulate gene Given the frequent repeated use of alcohol) that are eligible for consumer expression (Ref. 53). antiseptic rub use (59 FR 31402 at consumer antiseptic rubs, systemic A hormonally active compound that 31435). As described in section II.C, exposure may occur. Although some causes reproductive system disruption consumer antiseptic hand rubs were not systemic exposure data exist for all in the fetus or infant may have effects addressed separately from antiseptic three consumer antiseptic rub active that are not apparent until many years hand washes in the 1994 TFM. There ingredients, data on systemic absorption after initial exposure. There are also have since been a number of important after maximal use are lacking. Currently, critical times in fetal development when scientific developments affecting our there is also a lack of data to assess the a change in hormonal balance that evaluation of the safety of the active impact of important drug use factors would not cause any lasting effect in an ingredients in consumer antiseptic rubs, that can influence systemic exposure adult could cause a permanent causing us to reassess the data necessary such as dose, application frequency and developmental abnormality in a child. to support a GRAS determination. There method, duration of exposure, product For example, untreated hypothyroidism is now new information regarding formulation, skin condition, and age. during pregnancy has been associated systemic exposure to antiseptic active Depending on the systemic absorption with cognitive impairment in the ingredients (Refs. 1 through 5). The of the ingredient, variability in offspring (Refs. 54 through 56). potential for widespread antiseptic use Because consumer antiseptic rubs are 5 FDA is a member of the ICH Steering to promote the development of Committee, the governing body that oversees the used chronically and are likely to be antibiotic-resistant bacteria also needs harmonization activities, and contributes to the used by sensitive populations such as to be evaluated. Furthermore, additional development of ICH guidelines. children and pregnant women,

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evaluation of the potential for chronic consequence of antiseptic use and we expect will establish GRAS status for toxicity and effects on reproduction and requested data to address the concern these active ingredients, we are development should be included in the (78 FR 76444 at 76454 and 80 FR 25166 including specific information, based in safety assessment. The designs of at 25180). However, in its evaluation of part on existing FDA guidance, about general toxicity and reproductive/ the available data on the development of the other kinds of studies to consider developmental studies are often resistance to alcohol and isopropyl conducting and submitting. We have sufficient to identify developmental alcohol in the proposed rule for health published guidance documents effects that can be caused by hormonally care antiseptics, FDA cited a number of describing the nonclinical safety studies active compounds through the use of factors (speed of action, multiple that a manufacturer should perform currently accepted endpoints and nonspecific toxic effects, and lack of a when seeking to market a drug product standard good laboratory practice residue) that made the development of under an NDA (Refs. 40, 57 through 63). toxicology study designs. As followup resistance to these as a result These guidance documents also provide in some cases, additional study of health care antiseptic use unlikely. relevant guidance for performing the endpoints may be needed to fully Based on these factors, FDA concluded nonclinical studies necessary to characterize the potential effects of drug that no additional data relevant to this determine GRAS status for a consumer exposure on the exposed individuals. issue were necessary to support a GRAS antiseptic rub active ingredient. Because determination for these ingredients for B. Antimicrobial Resistance consumer antiseptic rubs may be used health care antiseptics (80 FR 25166 at repeatedly and in sensitive populations, In the 2013 Consumer Wash PR and 25184, 25187, and 25192). Consistent we propose that consumer antiseptic 2015 Health Care Antiseptic PR, FDA with FDA’s findings for alcohol and raised the concern of the development rub active ingredients will need to be isopropyl alcohol in its proposed rule tested for carcinogenic potential, of antiseptic resistance and its potential for health care antiseptic, we have also impact on the development of antibiotic developmental and reproductive tentatively concluded that no further toxicity (DART), and other potential resistance (78 FR 76444 at 76454 and 80 data on the development of resistance to FR 25166 at 25180). This concern was effects as described in more detail in alcohol and isopropyl alcohol as a result this section. based on numerous reports of laboratory of their use in consumer antiseptic rub studies demonstrating the development products are needed. This is not the 1. FDA Guidances Describing Safety of reduced susceptibility to certain case for benzalkonium chloride for Studies antiseptic active ingredients and which additional laboratory studies will after growth in nonlethal assist in more clearly defining the The safety studies that are described amounts of the antiseptic (i.e., low-to- potential for the development of in the existing FDA guidances (Refs. 40, moderate concentrations of antiseptic) resistance. (See section VIII.D.2). 57 through 63) provide a framework for and reports of the persistence of low the types of studies that are needed for levels of some antiseptic active C. Studies To Support a Generally FDA to assess the safety of each ingredients in the environment (78 FR Recognized as Safe Determination consumer rub active ingredient 76444 at 76454 and 80 FR 25166 at A GRAS determination for consumer according to modern scientific 25180). FDA concluded in both of these antiseptic rub active ingredients must be standards and make a GRAS proposed rules that, given the increasing supported by both nonclinical (animal) determination. A description of each evidence of the magnitude of the and clinical (human) studies.6 To issue type of study and how we would use antibiotic resistance problem and the a final monograph for these products, this information to improve our speed with which new antibiotic this safety data must be in the docket.7 understanding of the safety of consumer resistant organisms are emerging, it is To assist manufacturers or others who antiseptic rub active ingredients is important to assess this potential wish to provide us with the information provided in table 5.

TABLE 5—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 pharmaco- Both oral and dermal Allows identification of the dose at which the Used as a surrogate to identify toxic systemic kinetic absorption, administration. toxic effects of an active ingredient are ob- exposure levels that can then be correlated distribution, metabo- served as a result of systemic exposure of to potential human exposure via dermal lism, and excretion the drug. ADME data provide: The rate and pharmacokinetic study findings. Adverse (ADME) (Refs. 58 extent an active ingredient is absorbed into event data related to particular doses and and 64). the body (e.g., AUC, Cmax, Tmax) 1; where drug levels (exposure) in animals are used the active ingredient is distributed in the to help formulate a safety picture of the body; whether metabolism of the active in- possible risk to humans. gredient by the body has taken place; infor- mation on the presence of metabolites; and how the body eliminates the original active ingredient (parent) and its metabolites (e.g., T1⁄2)2.

6 We encourage sponsors to consult with us on 7 The Agency intends to consider only non- submit this data or information to the docket is set non-animal testing methods they believe may be confidential material that is submitted to the docket forth in this document in the ADDRESSES section. suitable, adequate, validated, and feasible. We are for this rulemaking or that is otherwise publicly willing to consider if alternative methods could be available in its evaluation of the GRAS/GRAE status assessed for equivalency to an animal test method. of a relevant ingredient. Information about how to

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TABLE 5—FDA GUIDANCE DOCUMENTS RELATED TO REQUESTED SAFETY DATA AND RATIONALE FOR STUDIES— Continued

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

Human pharmaco- Dermal administration Helps determine how much of the active in- Used to relate the potential human exposure kinetics (MUsT) (Ref. using multiple for- gredient penetrates the skin, leading to to toxic drug levels identified in animal 62). mulations under measurable systemic exposure. studies. maximum use con- ditions. Carcinogenicity (ICH Minimum of one oral Provides a direct measure of the potential for Identifies the systemic and dermal risks asso- S1A, S1B, and S1C) and one dermal active ingredients to cause tumor formation ciated with drug active ingredients. Taken (Refs. 40, 57, and study for topical (tumorogenesis) in the exposed animals. together, these studies are used to identify 60). products 3. the type(s) of toxicity, the level of exposure that produces these toxicities, and the highest level of exposure at which no ad- verse 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 devel- (ICH S5) (Ref. 59). oping offspring throughout gestation and postnatally until sexual maturation. Reproductive toxicity Oral administration ..... Assesses the effects of a drug on the repro- (ICH S5) (Ref. 59). ductive competence of sexually mature male and female animals. Hormonal effects (Ref. Oral administration ..... Assesses the drug’s potential to interfere with Used in hazard assessment to determine 63). the endocrine system. whether the drug has the capacity to in- duce 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. 3 Assessment of dermal carcinogenicity is considered important because the intended clinical route of administration of dermal, and skin expo- sure could be high. In addition, dermal exposure can result in systemic exposure to parent and metabolites that may differ from other routes. When substantial nonclinical information is already available for an active ingredient, the need for a dermal carcinogenicity study could be recon- sidered based on available information such as negative systemic carcinogenicity information and lack of preneoplastic effects in chronic non- rodent dermal toxicity studies.

These studies represent FDA’s current assess the effects of long-term dermal are analyzed, and the resulting in vivo thinking on the data needed to support and systemic exposure to these data could be used to estimate a safety a GRAS determination for an OTC ingredients. This is particularly margin based on animal toxicity studies. antiseptic active ingredient and are important for populations, such as A MUsT to support a determination similar to those recommended by the pregnant women (and fetuses), lactating that an active ingredient is GRAS for use Antimicrobial I Panel (described in the women, and children, who may have in consumer antiseptics is conducted by ANPR (39 FR 33103 at 33135)) as greater potential to experience obtaining an adequate number of PK updated by the recommendations of the deleterious developmental effects from samples following administration of the 2014 NDAC. However, even before the drug exposure. Human exposure data active ingredient. For studies of active September 2014 NDAC meeting, the can then be compared to drug levels in ingredients to be used in topically Panel’s recommendations for data to animals known to produce adverse applied products like these, for which support the safety of an OTC topical effects in order to calculate a safety there is less information available and antimicrobial active ingredient included margin. for which crossover designs are not studies to characterize the following: feasible, a larger number of subjects are • Degree of absorption through intact Based on input from the September required compared to studies of orally and abraded skin and mucous 2014 NDAC meeting, the Agency has administered drug products. A MUsT membranes. also determined that results from a using 50 to 75 subjects per cohort • Tissue distribution, metabolic rates, human PK maximal usage trial (MUsT) should be sufficient to get estimates of metabolic fates, and rates and routes of are needed to support a GRAS the PK parameters from a topically elimination. determination. This trial design is also applied consumer antiseptic. • Teratogenic and reproductive referred to as a maximal use PK trial and The MUsT should attempt to effects. is described in FDA’s 2005 draft maximize the potential for drug • Mutagenic and carcinogenic effects. guidance for industry on developing absorption to occur by considering the drugs for treatment of acne vulgaris (Ref. 2. Studies To Characterize Maximal following design elements (Ref. 65): 62). The purpose of the MUsT is to • Adequate number of subjects (steps Human Exposure evaluate systemic exposure under should be taken to ensure that the target Because the available data indicate conditions that would maximize the population (for example, age, gender, that some dermal products, including at potential for drug absorption in a race) is properly represented). least some antiseptic active ingredients, manner consistent with possible ‘‘worst- • Frequency of dosing (e.g., number are absorbed after topical application in case’’ real world use of the product. In of rub applications during the study). humans and animals, it is necessary to a MUsT, the collected plasma samples • Duration of dosing.

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• Use of highest proposed strength standards using the highest antibiotics (Refs. 74 and 75). The (e.g., 95 percent alcohol). concentration sought under this development of bacteria that are • Total involved surface area to be proposed rule in formulations expected resistant to antibiotics is an important treated at one time (e.g., hands). to produce the highest in vivo public health issue, and additional data • Amount applied per square absorption. The assay used in the MUsT may tell us whether use of antiseptics in centimeter. should be properly validated according consumer settings may contribute to the • Method of application (e.g., rub). • to current Good Laboratory Practices selection of bacteria that are less Sensitive and validated analytical and consistent with FDA guidance for susceptible to both antiseptics and methods. industry: ‘‘Bioanalytical Method antibiotics. Therefore, we are requesting It also is important that the MUsT Validation’’ (Ref. 67). additional data and information to reflect maximal use conditions of We expect that the 0.5 ng/mL address this issue for ingredients other consumer antiseptic rubs using different concentration will be sufficiently above than alcohol or isopropyl alcohol (see formulations to fully characterize the the assay’s limit of quantitation-limit of section VIII.D). active ingredient’s potential for dermal detection to allow a signal: Noise ratio FDA believes that a tiered approach is penetration. There are very limited data that assures confidence in the derived an efficient means of developing data to on the maximal number of uses of concentrations (in the case of address this issue. Laboratory studies in antiseptic rubs in consumer settings. ‘‘exaggerated’’ values) or lack of conjunction with a literature review are Consumer antiseptic rubs used in concentrations. a feasible first step in evaluating the institutional settings, such as daycare impact of exposure to nonlethal centers, schools, and office buildings, 3. Studies To Characterize Hormonal amounts of antiseptic active ingredients would be used (as per label directions) Effects on antiseptic and antibiotic bacterial at higher rates than in domestic We propose that data are also needed susceptibilities. However, only limited households, and thus would represent to assess whether consumer antiseptic data exist on the effects of antiseptic maximal use. Kinnula et al. (2009) rub active ingredients have hormonal exposure on the bacteria that are surveyed workers in child daycare effects that could produce predominant in the oral cavity, gut, skin centers in Finland to determine how developmental or reproductive toxicity. flora, and the environment (Ref. 76). commonly alcohol-containing hand rub There are several factors common to These organisms represent pools of gels were applied daily (Ref. 66). The antiseptic products that make it resistance determinants that are respondents (n = 128) reported applying necessary to assess their full safety potentially transferable to human the alcohol hand rub gels up to 50 times profile prior to classifying an antiseptic pathogens (Refs. 77 and 78). Thus, per day. Using the upper limit of active ingredient as GRAS for use in broader laboratory testing of consumer applications per day of antiseptic hand consumer antiseptic rub products. antiseptic active ingredients would rubs from this study, FDA is considering These factors are as follows: more clearly define the scope of the 50 times per day as the maximal use of • Evidence of systemic exposure to impact of antiseptic active ingredients consumer hand rubs in a consumer several of the antiseptic active on the development of antibiotic setting. ingredients. It should be noted that a systemic • resistance and may be able to identify Exposure to multiple sources of those antiseptic active ingredients for carcinogenicity study will not be antiseptic active ingredients that may be required for an ingredient if a MUsT which the development of resistance is hormonally active compounds. not a concern. Laboratory studies results in a steady state blood level less • Exposure to antiseptic active evaluating the antiseptic and antibiotic than 0.5 nanograms (ng)/mL, and an ingredients may be long term for some susceptibilities of bacteria grown in the adequately conducted toxicology users. program demonstrates that there are no According to FDA’s 2015 guidance on presence of sublethal concentrations of other signals for the ingredient or any nonclinical evaluation of endocrine- antiseptic active ingredients could help known structurally similar compound related drug toxicity (Ref. 63), endocrine support a GRAS determination for indicating the potential for adverse effects may be identified from the antiseptic active ingredients intended effects at lower levels. The threshold standard battery of toxicity tests for use in OTC consumer antiseptic drug value of 0.5 ng/mL is based on the conducted during drug development products. The following types of principle that the level would and may not require additional separate organisms should be evaluated: • Human bacterial pathogens. approximate the highest plasma level studies. • below which the carcinogenic risk of Nonpathogenic organisms, 4. Studies To Evaluate the Potential any unknown compound would be less opportunistic pathogens, and obligate Impact of Antiseptic Active Ingredients than 1 in 100,000 after a single dose. anaerobic bacteria that make up the The lack of absorption in a MuST on the Development of Resistance resident microflora of the human skin, does not alleviate the need to assess Since the 1994 TFM published, the gut, and oral cavity. • dermal carcinogenicity because the issue of antiseptic resistance and Food-related bacteria such as magnitude of exposure to the skin can whether bacteria that exhibit antiseptic Listeria, Lactobacillus, and be much higher than would be covered resistance have the potential for Enterococcus. • by systemic studies. In addition, antibiotic cross-resistance has been the Nonpathogenic organisms and systemic exposure to the parent subject of much study and scrutiny. One opportunistic pathogens from relevant compound and metabolites can differ of the major mechanisms of antiseptic environmental sources (e.g., soil). significantly for a dermally applied and antibiotic cross-resistance is If the results of these studies show no product because the skin has metabolic changes in bacterial efflux activity at evidence of changes in antiseptic or capability and first-pass metabolism is nonlethal concentrations of the antibiotic susceptibility, no further bypassed via this route of antiseptic (Refs. 68 through 73). Efflux studies addressing the development of administration. pumps are an important nonspecific resistance would be needed to support To fulfill the maximum human bacterial defense mechanism that can a GRAS determination. exposure requirement, the MUsT study confer resistance to a number of For antiseptic active ingredients that should meet appropriate design substances toxic to the cell, including demonstrate an effect on antiseptic and

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antibiotic susceptibilities, additional environmental compartments (for D. Review of Available Data for Each data will be necessary to help assess the example, bacteria found on human skin, Antiseptic Active Ingredient likelihood that similar effects would in the gut, and in environmental occur in the consumer setting. Several matrices). We have identified for each consumer antiseptic rub active ingredient whether types of data could be used to assess • Data characterizing the antiseptic whether or not ingredients with positive the studies outlined in section VIII.C are and antibiotic susceptibility levels of publicly available. Table 6 lists the laboratory findings pose a public health environmental isolates of bacteria in risk, and the type of data needed would types of studies available for each areas of prevalent antiseptic use, such as antiseptic active ingredient eligible for depend on what is already known about in the home or in schools. the antiseptic active ingredient’s use as a consumer rub proposed as mechanism of action and persistence in Data from the types of testing described Category I or Category III in the 1994 the environment. We do not anticipate previously, as well as from testing of TFM and indicates whether the that it will be necessary to obtain data antiseptic and antibiotic susceptibilities currently available data are adequate to from multiple types of studies for each of bacteria in settings where consumer serve as the basis of a GRAS active ingredient to adequately assess its topical antiseptic rub use is prevalent determination. Although we have some potential to affect resistance. Such types can help demonstrate whether or not data from submissions to the of data could include, but are not changes in susceptibility are occurring rulemaking and from information we limited to, the following: with actual use. Because actual use have identified in the literature, our • Information about the mechanism(s) concentrations of consumer antiseptics administrative record is incomplete for of antiseptic action (for example, are much higher than the MICs for these at least some types of safety studies for membrane destabilization or inhibition active ingredients, data from each of the active ingredients (see table of fatty acid synthesis), and whether compartments where sublethal 6). As noted previously, only there is a change in the mechanism of concentrations of biologically active information that is part of the action with changes in antiseptic antiseptic active ingredients may occur administrative record for this concentration. (e.g., environmental compartments) can rulemaking can form the basis of a • Information clarifying the bacteria’s give us a sense of the potential for GRAS/GRAE determination. mechanism(s) for the development of change in antimicrobial susceptibilities We recognize that data and resistance or reduced susceptibility to in these compartments (Refs. 79 through information submitted in response to the antiseptic active ingredient (for 81). FDA recognizes, however, that the 2013 Consumer Wash PR or 2015 example, efflux mechanisms). methods of evaluating this issue are an Health Care Antiseptic PR may be • Data characterizing the potential for evolving science and that there may be relevant to this proposed rule. At the reduced antiseptic susceptibility caused other data appropriate to evaluate the time of publication of this proposed by the antiseptic active ingredient to be impact of consumer antiseptic active rule, FDA’s review of all submissions transferred to other bacteria that are still ingredients on the development of made to the 2015 Health Care Antiseptic sensitive to the antiseptic. resistance. For this reason, FDA PR has not been completed. FDA • Data characterizing the encourages interested parties to consult requests that any information relevant to concentrations and antimicrobial with the Agency on the specific studies consumer antiseptic rub active activity of the antiseptic active appropriate to address this issue for a ingredients be resubmitted under this ingredient in biological and particular active ingredient. docket (FDA–2016–N–0124). TABLE 6—SAFETY STUDIES AVAILABLE FOR CONSUMER ANTISEPTIC HAND RUB ACTIVE INGREDIENTS 1

Human Animal Pharmaco- Pharmaco- Oral Dermal Reproductive Potential Resistance Active Ingredient kinetic kinetic Carcino- Carcino- Toxicity Hormonal Potential (MUsT) (ADME) genicity genicity (DART) Effects

Alcohol ...... Æ • • • • • • Benzalkonium chloride ...... Æ • ...... • • Æ Isopropyl alcohol ...... 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.

In the remainder of this section, we data gaps identified in the 2015 Health 1. Alcohol discuss the existing data and data gaps Care Antiseptic PR are similar to those for alcohol, benzalkonium chloride and discussed in this proposed rule for each In the 1994 TFM, FDA proposed to isopropyl alcohol, the consumer ingredient. The requirements for a classify alcohol as GRAS for all health antiseptic rub active ingredients that GRAS determination for an ingredient care antiseptic uses based on the were proposed as GRAS in the 1994 are generally the same for either a health recommendation of the Advisory Review Panel on OTC Miscellaneous TFM, and explain why these active care or consumer antiseptic product, External Drug Products (Miscellaneous ingredients are no longer proposed as with the exception of higher maximal External Panel), which concluded that GRAS for use in consumer antiseptic use for health care antiseptic products. hand rubs (i.e., why they are now the topical application of alcohol is safe Therefore, it is anticipated that proposed as Category III). We also (59 FR 31402 at 31412). In the 2013 ingredients fulfilling the requirements discuss benzalkonium chloride, which Consumer Wash PR, FDA proposed to was proposed as Category III in the 1994 for a health care antiseptic GRAS separately evaluate the safety and TFM and for which there are some new determination would also meet the effectiveness of the OTC antiseptic drug data available and explain why this criteria for GRAS as a consumer products by use setting, specifically ingredient is still Category III. These antiseptic, if eligible for that indication. health care and consumer antiseptic three ingredients are also used in health products. As defined in the 2013 care antiseptic products, and the safety Consumer Wash PR, consumer

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antiseptic products that are not rinsed which is the equivalent of 10 percent of and 109). The data cited in both of these off after use include hand rubs and an alcohol-containing drink. See also evaluations are proprietary and only antiseptic wipes. FDA is proposing to the discussion of occupational exposure summaries of the data are publicly classify alcohol as Category III for use in to alcohol via the dermal route (Ref. available. Consequently, these studies consumer antiseptic rubs. Extensive 107) in the alcohol carcinogenicity are not available to FDA and FDA studies have been conducted to section of the 2015 Health Care cannot conduct a complete evaluation of characterize the metabolic and toxic Antiseptic PR (80 FR 25166 at 25186). them. Safety assessments with study effects of alcohol in animal models. Although these data do indicate summaries do not constitute an Although the impetus for most of the absorption of alcohol does occur after adequate record on which to base a studies has been to study the effects of topical administration of alcohol- GRAS classification (§ 330.10(a)(4)(i)). alcohol exposure via the oral route of containing antiseptic rubs, we did not For FDA to evaluate this data with administration, some dermal toxicity find the exposure conditions of these respect to the safety of benzalkonium studies are available and have shown studies comparable to exposure that are chloride for this rulemaking, the full that, although there is alcohol required by our current MUsT standards study reports and data sets must be absorption through human skin, it is specified in section VIII.C.2. submitted to the rulemaking docket or much lower than absorption via the oral Consequently, human pharmacokinetic otherwise be publicly available. route. Overall, there are adequate safety data under maximal use conditions as In response to the call for data in the data to make a GRAS determination for determined by a MUsT are needed to 2013 Consumer Wash PR, a alcohol, with the exception of human make a GRAS determination for the manufacturing consortium submitted pharmacokinetic data under maximal alcohol-containing consumer antiseptic the following studies to the 2013 use conditions. rubs. Consumer Wash PR docket (Refs. 110 a. Summary of alcohol safety data. b. Alcohol safety data gap. through 121): As discussed in more detail in the In summary, our administrative • An embryofetal toxicity study in the 2015 Health Care Antiseptic PR (80 FR record for the safety of alcohol is rabbit; 25166 at 25185 to 25187), FDA has incomplete with respect to the • an embryofetal toxicity study in the reviewed the following and found them following: rat; • to be sufficient to characterize the safety Human pharmacokinetic studies • a 2-generation study in the rat; of alcohol for use in consumer under maximal use conditions when • a 90 day subchronic dietary study antiseptic rubs: applied topically (MUsT), including in rats; • Animal ADME data demonstrating documentation of validation of the • a 90 day subchronic dermal toxicity absorption of alcohol both in vitro and methods used to measure alcohol and study in rats; in vivo (Refs. 82 through 86). its metabolites. • a 1-year chronic dietary toxicity • Dermal and oral carcinogenicity 2. Benzalkonium Chloride study in dogs; data in animals and oral carcinogenicity • an ADME study in rats; data in humans (Refs. 87 through 93). In the 1994 TFM, FDA categorized • a rat oral carcinogenicity study; and • DART human data (Refs. 94 and benzalkonium chloride as Category III • a mouse oral carcinogenicity study. 95). because of a lack of adequate safety data All of these studies have been • Data on the hormonal effects of for its use as both a health care reviewed by FDA. Some of the data alcohol in animals and humans (Refs. 96 antiseptic and consumer antiseptic were found to be adequate to fill some through 102). product (59 FR 31402 at 31435). FDA of the safety data gaps for a GRAS • Data on the antimicrobial also is proposing to classify determination for benzalkonium mechanism of alcohol (Refs. 103 benzalkonium chloride as Category III chloride. Data gaps remain for the through 106). Alcohol readily for the indication of consumer following endpoints: Human evaporates from the skin after topical antiseptic rubs. Thus, additional safety pharmacokinetic data under maximal application, and the resulting lack of data are still needed to make a GRAS use condition, animal dermal antiseptic residue on the skin suggests determination for benzalkonium carcinogenicity and animal ADME data, that the topical application of alcohol is chloride for use as a consumer and data on antimicrobial resistance to not likely to contribute to the antiseptic rub. benzalkonium chloride. development of antimicrobial resistance In the 2013 Consumer Wash PR, FDA a. Summary of benzalkonium chloride (Refs. 103, 105). identified the safety data needed to safety data. Alcohol human pharmacokinetic make a GRAS determination for Benzalkonium chloride ADME data. data. The 2015 Health Care Antiseptic benzalkonium chloride as an ingredient ADME studies of ADBAC in rats of both PR described data that characterize the in consumer antiseptic wash products. sexes were conducted using the oral and level of dermal absorption and expected The safety gaps listed were human and the intravenous (IV) routes of systemic exposure in adults as a result animal pharmacokinetic data, administration. In the oral studies, rats of topical use of alcohol-containing reproductive toxicity studies, potential were administered radiolabeled antiseptics (80 FR 25166 at 25185– hormonal effects, carcinogenicity (oral benzalkonium chloride using the 25186). These data do not cover and dermal) studies, and potential of the following cohorts: A low-dose single maximal use of these products as development of antimicrobial resistance oral administration study (10 mg/ detailed in section VIII.D.1.a. to benzalkonium chloride. As was kilogram (kg)), a low-dose repeated oral A variety of alcohol-based hand rub summarized in the 2015 Health Care administration study (10 mg/kg) and a product formulations and alcohol Antiseptic PR, the safety of high-dose single oral administration concentrations have been used in these benzalkonium chloride has been study (50 mg/kg) (Ref. 115). For the low- studies. Based on the available data, reviewed and was determined to be safe dose repeated oral administration study, which represents moderate hand rub for use in and cosmetic rats were treated via freely available use (7.5 to 40 hand rub applications per products by the Environmental feed containing 100 parts per million hour, studied for 30 to 240 minutes), the Protection Agency (EPA) and the (ppm) of non-radiolabeled highest observed exposure was 1,500 Cosmetic Ingredient Review (an benzalkonium chloride for 14 days, milligrams (mg) of alcohol (Ref. 4), industry panel), respectively (Refs. 108 followed by administration of 10 mg/kg

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benzalkonium chloride by oral gavage. NOAEL of 400 ppm was determined, incidence of neoplasms were observed Benzalkonium chloride was found to be which corresponds to 13.1 and 14.6 mg/ at any of the tested doses. excreted mainly via the feces in rats kg/day in males and females, There were no treatment-related after oral administration. In all of the respectively. neoplasms in either oral carcinogenicity treated groups, the average amount of In the dermal toxicity study, rats were study. Though the mouse study is radioactivity recovered was 87 to 99 topically exposed to benzalkonium suboptimal because of its relatively percent in the feces and 5 to 8 percent chloride in concentrations ranging from short duration (78 weeks), we believe in the urine. 0 (water) to 1.0 percent (which these two studies are adequate to fill the In a separate group of animals tested correspond to 0 to 20 mg/kg/day) over oral carcinogenicity data gap for in the same study, a single low-dose of a 13-week treatment period (Ref. 113). benzalkonium chloride. 10 mg/kg benzalkonium chloride was Slight local irritation and hyperkeratosis No dermal carcinogenicity studies of administered to rats of both sexes. The (thickening of the epidermis) were benzalkonium chloride have been average amount of radioactivity observed in all treatment groups submitted to FDA. The available data recovered following IV dosing was 45 to (including control) in both sexes. All are not adequate to assess the 55 percent in the feces and 20 to 30 findings were limited to the treatment carcinogenic potential of benzalkonium percent in the urine. Tissue residues of site. Under the conditions of this study, chloride. We propose that dermal radioactivity were less than 1 percent of the NOAEL was 20 mg/kg (1.0 percent). carcinogenicity studies are still needed the orally administered dose in all Toxicokinetic data were not collected; to complete a GRAS determination for benzalkonium chloride. groups and 30 to 35 percent of the IV therefore, systemic exposure to Benzalkonium chloride DART data. A dose. No significant changes were noted benzalkonium chloride was not when comparing the ADME profile of developmental toxicity study conducted characterized. Consequently, dermal in rabbits showed some increase (not high dose versus low dose-treated rats. ADME (toxicokinetic) data is still Although the available ADME data from dose-related) in the incidence of certain needed to characterize benzalkonium visceral and skeletal malformations nondermal routes of exposure are chloride. sufficient to characterize the ADME among benzalkonium chloride-treated profile of benzalkonium chloride Benzalkonium chloride rabbits relative to concurrent controls following nondermal exposure, they are carcinogenicity data. Two oral (Ref. 110). None of the findings were not sufficient to characterize the ADME carcinogenicity studies, one in the rat considered significant. Some of the profile after dermal exposure. Studies and another in the mouse, were mated dams proved to be not pregnant; on animal ADME after dermal exposure submitted (Refs. 117 through 121). Both therefore, the total number of litters (13 to benzalkonium chloride will need to studies were conducted in the 1980’s to 15) is slightly less than the 16 to 20 be submitted to FDA for review, in order prior to the current ICH guidelines. recommended in the ICH S5 guideline, to complete a GRAS determination for They were conducted according to the but further benzalkonium chloride benzalkonium chloride. OECD (Organisation for Economic Co- DART data are not necessary to make a Benzalkonium general toxicity data. operation and Development) GRAS determination. Two subchronic 90-day toxicity studies guidelines 8 and designed to meet the In a developmental toxicity study in in rats were submitted, one dermal and requirements of EPA’s regulations, rats, the animals were administered the other dietary (oral). A 1-year chronic which use a different type of exposure benzalkonium chloride (10, 30, and 100 oral toxicity study in dogs was also risk assessment analysis than is used by mg/kg/day) (Ref. 112). There were no submitted. In the oral rat study, FDA for drug products. treatment-related differences in benzalkonium chloride was A 78-week dietary carcinogenicity gestational parameters, including total administered via feeding with study was conducted in mice with number of embryonic implantations, concentrations ranging from 0 to 8,000 benzalkonium chloride concentrations number of viable and nonviable ppm (Ref. 111) for 13 weeks. Among rats of 500, 1,000, and 1,500 ppm, implants. There were also no treatment- treated with 4,000 and 8,000 ppm corresponding to approximately 15, 73, related effects on fetal body weights per benzalkonium chloride, an increased and 229 mg/kg/day in males and 18, 92, litter, or on the incidences of external, incidence in mortality and overt toxicity 289 mg/kg/day in females (Refs. 120 and visceral, or skeletal malformations/ was seen. A no adverse effect level 121). Findings were limited to variations. Based on these findings, a (NOAEL) of 500 ppm was noted, which decreased body weight in both males NOAEL for maternal toxicity was correlated with a mean daily dose of and females treated with the highest considered to be 10 mg/kg/day and for 31.2 mg/kg in males and 38.3 mg/kg in dose compared to controls (7 percent developmental toxicity 100 mg/kg/day. females. and 5 percent at week 78 in males and A two-generation reproduction and A 1-year chronic oral toxicity study in females, respectively). There were no development study in rats was dogs was also submitted. Dogs were treatment-related increases in the submitted for review. Rats were exposed chronically administered benzalkonium incidence of neoplasms at any of the to benzalkonium chloride in the feed chloride via feeding in concentrations doses tested. (Ref. 116). The exposure to ranging from 0 to 1,200 ppm for 1 year A 2-year oral carcinogenicity study benzalkonium chloride up to the highest (Ref. 114). Changes in body weight was conducted in rats with dose tested of 2,000 mg/kg did not result included reduced absolute body weight benzalkonium chloride concentrations in parental toxicity. No treatment- and reduced body weight gain in males of 300, 1,000, and 2,000 ppm, related reproductive effects were and females in the highest group tested corresponding to 13, 44, and 88 mg/kg/ observed in any of the treatment groups. (1,200 ppm), which correlated with a day, respectively, in males, and to 17, Findings were limited to decreases in reduction in food consumption. At 57, and 116 mg/kg/day, respectively, in body weight accompanied by a decrease 1,200 ppm, cholesterol levels were females (Refs. 117 through 119). No in food consumption among treated reduced by about 10 percent in both treatment-related increases in the females at 2,000 mg/kg/day and a males and females (p ≤ 0.01). No decrease in pup body weight. Based on specific organ toxicity was identified. 8 http://www.oecd-ilibrary.org/environment/oecd- these findings, a NOAEL for adults and Based on the changes in body weight guidelines-for-the-testing-of-chemicals-section-4- offspring was considered to be 1000 and food consumption at 1,200 ppm, a health-effects_20745788. ppm (62.5 mg/kg/day).

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The submitted DART studies are a. Summary of isopropyl alcohol potential for hormonal effects of adequate and no additional DART safety data. isopropyl alcohol. However, additional studies are needed for benzalkonium As discussed in more detail in the studies may not be needed to assess the chloride. 2015 Health Care Antiseptic PR (80 FR potential hormonal effects of isopropyl Hormonal effects. Based on the 25166 at 25190–25193), FDA has alcohol if assessment of potential negative findings in the carcinogenicity reviewed the following data and found hormonal activity can be derived from studies and the two-generation DART the data to be sufficient to characterize existing (reproductive and studies, no signal for hormonal effects the safety of isopropyl alcohol: developmental studies; chronic general • DART data (Refs. 130 through 135). toxicity data) and additional pending was detected and no further testing on • hormonal effects will be required for Data on the antimicrobial isopropyl alcohol (systemic and dermal benzalkonium chloride. mechanism of isopropyl alcohol (Refs. carcinogenicity and ADME data) Antimicrobial resistance. In addition 103 through 106, 136 through 138). nonclinical studies, provided the to the summaries, as discussed in the Isopropyl alcohol readily evaporates appropriate endpoints are assessed. 2013 Consumer Wash PR (78 FR 76444 from the skin after topical application. Thus, we believe the existing at 76463), FDA has reviewed studies on The lack of antiseptic residue on the evaluations need to be supplemented to resistance data and antibiotic skin indicates that the topical fully evaluate the safety of isopropyl application of isopropyl alcohol is not susceptibility of certain bacteria related alcohol. As described in more detail in likely to contribute to the development to the development of resistance to the 2015 Health Care Antiseptic PR (80 of antimicrobial resistance (Refs. 103, benzalkonium chloride (Refs. 122 FR 25166 at 25190–25193), we propose 105). Additional data on the through 129), and determined that the that human pharmacokinetic studies development of antimicrobial resistance available studies have examined few under maximal use conditions when are not needed to make a GRAS bacterial species, provide no applied topically (MUsT), animal ADME determination. studies (dermal absorption), systemic information on exposure levels, and are No new data has been made available not adequate to define the potential for and dermal carcinogenicity studies, and to FDA since publication of the 1994 data on hormonal effects are still needed the development of resistance or cross TFM that can fill any of the remaining resistance. Additional data are needed to complete a GRAS determination for safety data gaps for isopropyl alcohol. isopropyl alcohol. to more clearly define the potential for The following areas of safety the development of resistance to b. Isopropyl alcohol safety data gaps. assessment, which were identified in In summary, our administrative benzalkonium chloride. the 1994 TFM and discussed in detail in b. Benzalkonium chloride safety data record for the safety of isopropyl alcohol the 2015 Health Care Antiseptic PR (80 is incomplete with respect to the gaps. FR 25166 at 25190–25193), are being In summary, our administrative following: updated in this document: • Human pharmacokinetic studies record for the safety of benzalkonium • Human absorption data (Refs. 1, 139 under maximal use conditions when chloride is incomplete with respect to through 142). However, the data applied topically (MUsT), including the following: submitted and found in the literature to documentation of validation of the • Human pharmacokinetic studies date do not cover maximal use of these methods used to measure isopropyl under maximal use conditions when products in an institutional setting as alcohol and its metabolites; applied topically (MUsT), including detailed in section VIII.C.2. • animal ADME (dermal absorption); documentation of validation of the • Animal ADME data following • dermal carcinogenicity; methods used to measure benzalkonium dermal and systemic exposure to • systemic carcinogenicity (may be chloride and its metabolites; isopropyl alcohol (Refs. 143 through waived if the MUsT data do not show • Animal dermal ADME; 149). The available dermal exposure absorption); and • Dermal carcinogenicity; and studies have demonstrated that there is • hormonal effects (could be derived • Data from laboratory studies that some systemic exposure to isopropyl from other endpoints). assess the potential for the development alcohol following dermal application. IX. Proposed Effective Date of resistance to benzalkonium chloride However, the extent of that exposure and cross-resistance to antibiotics as has not been fully characterized. Based on the currently available data, discussed in section VIII.C. Moreover, absorption data following this proposed rule finds that additional data are necessary to establish the safety 3. Isopropyl Alcohol dermal absorption in animals are still needed to determine the extent of and effectiveness of consumer antiseptic In the 1994 TFM, FDA proposed to systemic exposure following maximal rub active ingredients for use in OTC classify isopropyl alcohol (70 to 91.3 dermal exposure to isopropyl alcohol- consumer antiseptic rub drug products. percent) as GRAS for all consumer containing consumer antiseptic rub Accordingly, consumer antiseptic rub antiseptic washes (59 FR 31402 at products. active ingredients would be 31435). FDA is now proposing to • Systemic and dermal nonmonograph in any final rule based classify isopropyl alcohol as Category III carcinogenicity data in animal models. on this proposed rule. We recognize, for use in consumer antiseptic rubs. The Available data for chronic exposure to based on the scope of products subject GRAS determination in the 1994 TFM isopropyl alcohol include inhalation to this monograph, that manufacturers was based on the recommendations of carcinogenicity data in rodents (Refs. will need time to comply with a final the Miscellaneous External Panel, 150 and 151) and a chronic 1-year rule based on this proposed rule. which based its recommendations on dermal toxicity study in mice (Ref. 149). However, because of the potential human absorption data and blood However, these data are not adequate to effectiveness and safety considerations isopropyl alcohol levels (47 FR 22324 at assess the systemic or dermal raised by the data for some antiseptic 22329). There was no comprehensive carcinogenic potential of isopropyl active ingredients evaluated, we believe nonclinical review of the toxicity profile alcohol. that an effective date later than 1 year of isopropyl alcohol, nor was there a • Data on the hormonal effects of after publication of the final rule would nonclinical safety evaluation of the isopropyl alcohol. The existing data are not be appropriate or necessary. topical use of isopropyl alcohol. not adequate to characterize the Consequently, any final rule that results

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from this proposed rule will be effective product industry is mainly composed of costs associated with safety and 1 year after the date of the final rule’s establishments with 500 or fewer effectiveness testing. We note that the publication in the Federal Register. On employees, we tentatively conclude that testing costs for this proposed rule are or after that date, any OTC consumer the proposed rule may have a significant not attributed here because these costs antiseptic rub drug product that is economic impact on a substantial will be realized if manufacturers subject to the monograph and that number of small entities. conduct the testing discussed in the contains a nonmonograph condition, The Unfunded Mandates Reform Act proposed rule for health care antiseptics i.e., a condition that would cause the of 1995 (section 202(a)) requires us to (80 FR 25166) and we do not count costs drug to be not GRAS/GRAE or to be prepare a written statement, which twice. However, we estimate these costs misbranded, could not be introduced or includes an assessment of anticipated in this analysis to promote transparency delivered for introduction into interstate costs and benefits, before proposing in the event that this rule is finalized commerce unless it is the subject of an ‘‘any rule that includes any Federal before the health care antiseptics approved new drug application or mandate that may result in the proposed rule or manufacturers conduct abbreviated new drug application. Any expenditure by State, local, and tribal the testing for the three ingredients OTC consumer antiseptic rub drug governments, in the aggregate, or by the discussed in this rule but do not product subject to the final rule that is private sector, of $100,000,000 or more conduct the testing for these ingredients repackaged or relabeled after the (adjusted annually for inflation) in any for the health care antiseptic proposed effective date of the final rule would be 1 year.’’ The current threshold after rule or this rule is finalized but the health required to be in compliance with the adjustment for inflation is $146 million, care antiseptics proposed rule is not. using the most current (2015) Implicit final rule, regardless of the date the In scenario 1, all three ingredients are product was initially introduced or Price Deflator for the Gross Domestic Product. This proposed rule would not determined to be GRAS/E and initially delivered for introduction into manufacturers of products containing interstate commerce. result in an expenditure in any year that meets or exceeds this amount. other ingredients will no longer be able X. Economic Analysis of Impacts to market these products under B. Summary of Costs and Benefits consumer antiseptic rub labels pursuant A. Introduction There are three active ingredients to the topical antimicrobial monograph. We have examined the impacts of the being evaluated for use as a consumer We expect that these manufacturers will proposed rule under Executive Order antiseptic rub in this proposed rule: reformulate their products to contain 12866, Executive Order 13563, the Alcohol (ethanol or ethyl alcohol), one of the monograph ingredients and Regulatory Flexibility Act (5 U.S.C. isopropyl alcohol, and benzalkonium relabel their products to reflect the 601–612), and the Unfunded Mandates chloride. The impact of the proposed change in ingredients. Annualizing Reform Act of 1995 (Pub. L. 104–4). rule on OTC consumer antiseptic rub upfront costs over a 10-year period at a Executive Orders 12866 and 13563 product industry will depend on the discount rate of 3% for scenario 1, the direct Agencies to assess all costs and outcome of tests to determine whether costs of the proposed rule are estimated benefits of available regulatory these three active antiseptic ingredients to be between $0.04 million and $0.12 alternatives and, when regulation is are GRAS/GRAE. It is possible that million per year; the corresponding necessary, to select regulatory none, one, two, or all three of the estimated cost at a discount rate of 7% approaches that maximize net benefits ingredients will be determined to be is between $0.05 million and $0.14 (including potential economic, GRAS/GRAE. We consider two extreme million per year. In scenario 2, none of environmental, public health and safety, scenarios to capture the entire range of the ingredients is determined to be and other advantages; distributive total costs: (1) All three ingredients are GRAS/E and we expect that impacts; and equity). We have deemed to be GRAS/GRAE or (2) none manufacturers will reformulate their developed a comprehensive Economic of the ingredients is deemed to be products to be free of antiseptics and Analysis of Impacts that assesses the GRAS/GRAE. relabel them to reflect the change in impacts of the proposed rule. We In table 7, we provide a summary of ingredients. Annualizing upfront costs believe that this proposed rule is a the estimated costs of the proposed rule over a 10-year period at a discount rate significant regulatory action as defined for the two scenarios. The costs of the of 3% for scenario 2, the costs of the by Executive Order 12866. proposed rule involve product proposed rule are estimated to be The Regulatory Flexibility Act reformulation and relabeling of between $1.87 million and $5.52 requires us to analyze regulatory options products. It is important to note that, to million per year; the corresponding that would minimize any significant demonstrate that an antiseptic active estimated cost at a discount rate of 7% impact of a rule on small entities. ingredient is GRAS/E, some is between $2.28 million and $6.70 Because the consumer antiseptic rub manufacturers will also incur additional million per year.

TABLE 7—SUMMARY OF QUANTIFIED TOTAL COSTS (IN MILLIONS), BY SCENARIO

One-time costs Annualized costs over a 10-year period Cost category 3% Discount rate 7% Discount rate Low Med. High Low Med. High Low Med. High

Scenario 1: Assuming All Ingredients are Determined to be GRAS/E

Relabeling Costs...... $0.11 $0.19 $0.32 $0.01 $0.02 $0.04 $0.02 $0.03 $0.05 Reformulation Costs...... 0.23 0.46 0.70 0.03 0.05 0.08 0.03 0.07 0.10

Total Costs...... 0.34 0.66 1.02 0.04 0.08 0.12 0.05 0.09 0.14

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TABLE 7—SUMMARY OF QUANTIFIED TOTAL COSTS (IN MILLIONS), BY SCENARIO—Continued

One-time costs Annualized costs over a 10-year period Cost category 3% Discount rate 7% Discount rate Low Med. High Low Med. High Low Med. High

Scenario 2: Assuming None of the Ingredients is Determined to be GRAS/E

Relabeling Costs...... 6.55 11.36 18.76 0.77 1.33 2.20 0.93 1.62 2.67 Reformulation Costs...... 9.44 18.89 28.33 1.11 2.21 3.32 1.34 2.69 4.03

Total Costs...... 15.99 30.25 47.09 1.87 3.55 5.52 2.28 4.31 6.70

A potential benefit of the proposed the proposed rule’s burden on small and an opportunity for State and local rule is that the removal of potentially entities, such as extending relabeling officials to comment on this rulemaking. harmful antiseptic active ingredients in compliance times to 18 months (rather XIV. References consumer antiseptic rub products will than 12 months). prevent health consequences associated The full analysis of economic impacts The following references are on with exposure to such ingredients. FDA is available in the docket for this display in the Division of Dockets lacks the necessary information to proposed rule (Docket No. FDA–2016– Management (see ADDRESSES) and are estimate the impact of exposure to N–0124) and at http://www.fda.gov/ available for viewing by interested antiseptic active ingredients in AboutFDA/ReportsManualsForms/ persons between 9 a.m. and 4 p.m. consumer antiseptic rub products on Reports/EconomicAnalyses/default.htm. Monday through Friday; they are also human health outcomes. We are, available electronically at http:// however, able to estimate the reduction XI. Paperwork Reduction Act of 1995 www.regulations.gov. FDA has verified in the aggregate exposure to antiseptic the Web site addresses, as of the date This proposed rule contains no active ingredients found in currently this document publishes in the Federal collections of information. Therefore, marketed consumer antiseptic rub Register, but Web sites are subject to clearance by the Office of Management products. As with the total costs, the change over time. and Budget under the Paperwork reduction in aggregate exposure to Reduction Act of 1995 is not required. 1. Brown, T.L. et al., ‘‘Can Alcohol-Based antiseptic active ingredients in Hand-Rub Solutions Cause You to Lose consumer rub products depends on the XII. Analysis of Environmental Impact Your Driver’s License? Comparative outcome of testing and the Cutaneous Absorption of Various determination of GRAS/E status of the We have determined under 21 CFR Alcohols,’’ Antimicrobial Agents and three ingredients that require testing. 25.31(a) that this action is of a type that Chemotherapy, 51:1107–1108, 2007. The proposed rule will lead to an does not individually or cumulatively Available at http:// estimated reduction that ranges from have a significant effect on the human www.ncbi.nlm.nih.gov/pmc/articles/ PMC1803104/. 110 pounds to 254 pounds per year in environment. Therefore, neither an environmental assessment nor an 2. Calafat, A.M. et al., ‘‘Urinary scenario 1 and from 13,080,963 and Concentrations of Triclosan in the U.S. 67,272,847 pounds per year in scenario environmental impact statement is Population: 2003–2004,’’ Environmental 2. Absent information on the change in required. Health Perspective, 116:303–307, 2008. the short- and long-term health risks XIII. Federalism Available at http:// associated with a one pound increase in www.ncbi.nlm.nih.gov/pmc/articles/ exposure to each antiseptic active We have analyzed this proposed rule PMC2265044/. ingredient in consumer antiseptic rub in accordance with the principles set 3. Centers for Disease Control and forth in Executive Order 13132. Section Prevention, ‘‘Fourth National Report on products, we are unable to translate the Human Exposure to Environmental aggregate exposure figures into 4(a) of the Executive order requires Chemicals, Updated Tables, July 2010,’’ monetized benefits. agencies to ‘‘construe . . . a Federal 2010. Available at http://www.cdc.gov/ FDA also examined the economic statute to preempt State law only where exposurereport/. implications of the rule as required by the statute contains an express 4. Kramer, A. et al., ‘‘Quantity of Ethanol the Regulatory Flexibility Act. If a rule preemption provision or there is some Absorption After Excessive Hand will have a significant economic impact other clear evidence that the Congress Disinfection Using Three Commercially on a substantial number of small intended preemption of State law, or Available Hand Rubs Is Minimal and entities, the Regulatory Flexibility Act where the exercise of State authority Below Toxic Levels for Humans,’’ BioMed Central Infectious Diseases, requires agencies to analyze regulatory conflicts with the exercise of Federal 7:117, 2007. Available at http:// options that would lessen the economic authority under the Federal statute.’’ www.pubfacts.com/detail/17927841/ effect of the rule on small entities. This The sole statutory provision giving Quantity-of-ethanol-absorption-after- proposed rule could impose a preemptive effect to this proposed rule excessive-hand-disinfection-using-three- significant economic impact on a is section 751 of the FD&C Act (21 commercially-available-. substantial number of small entities. For U.S.C. 379r). We have complied with all 5. Miller, M.A. et al., ‘‘Does the Clinical Use small entities, we estimate the rule’s of the applicable requirements under of Ethanol-Based Hand Sanitizer Elevate one-time costs to roughly range between the Executive order and have Blood Alcohol Levels? A Prospective 0.001 and 0.16 percent of average determined that the preemptive effect of Study,’’ American Journal of Emergency Medicine, 24:815–817, 2006. Available at annual value of shipments for a small this proposed rule, if finalized, would http://www.ajemjournal.com/article/ business. In the Initial Regulatory be consistent with Executive Order S0735-6757(06)00131-8/pdf. Flexibility Analysis, we assess 13132. Through publication of this 6. Transcript of the January 22, 1997, Meeting regulatory options that would reduce proposed rule, we are providing notice of the Joint Nonprescription Drugs and

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World Health Organization International (43) [DATE 1 YEAR AFTER DATE OF Langenbeck’s Archives of Surgery., Agency for Research on Cancer, ‘‘IARC PUBLICATION OF THE FINAL RULE 394:151–157, 2009. Available at http:// Monographs on the Evaluation of IN THE Federal Register], for products www.springer.com/medicine/surgery/ Carcinogenic Risks to Humans: Re- journal/423. evaluation of Some Organic Chemicals, subject to paragraph (a)(27)(v) of this 140. Turner, P., B. Saeed, and M.C. Kelsey, Hydrazine and ,’’ 71 section. ‘‘Dermal Absorption of Isopropyl (part 3):1027–1036, 1999, available at Dated: June 24, 2016. Alcohol From a Commercial Hand Rub: http://monographs.iarc.fr/ENG/ Leslie Kux, Implications for its Use in Hand Monographs/vol71/mono71.pdf. Decontamination,’’ The Journal of 151. Burleigh-Flayer, H. et al., ‘‘Isopropanol Associate Commissioner for Policy. Hospital Infection, 56:287–290, 2004. 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