[Federal Register Volume 81, Number 126 (Thursday, June 30, 2016)]
[Proposed Rules]
[Pages 42911-42937]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-15410]



[[Page 42911]]

Vol. 81

Thursday,

No. 126

June 30, 2016

Part IV





Department of Health and Human Services





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 Food and Drug Administration





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21 CFR Part 310





Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial 
Drug Products for Over-the-Counter Human Use; Proposed Amendment of the 
Tentative Final Monograph; Reopening of Administrative Record; Proposed 
Rule

Federal Register / Vol. 81 , No. 126 / Thursday, June 30, 2016 / 
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2016-N-0124 (Formerly Part of Docket No. FDA-1975-N-
0012)]
RIN 0910-AF69


Safety and Effectiveness of Consumer Antiseptics; Topical 
Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed 
Amendment of the Tentative Final Monograph; Reopening of Administrative 
Record

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is issuing 
this proposed rule to amend the 1994 tentative final monograph or 
proposed rule (the 1994 TFM) for over-the-counter (OTC) antiseptic drug 
products. In this proposed rule, we are proposing to establish 
conditions under which OTC consumer antiseptic products intended for 
use without water (referred to throughout as consumer antiseptic rubs 
or consumer rubs) are generally recognized as safe and generally 
recognized as effective (GRAS/GRAE). In the 1994 TFM, certain 
antiseptic active ingredients were proposed as being GRAS for 
antiseptic rub use by consumers based on safety data evaluated by FDA 
as part of its ongoing review of OTC antiseptic drug products. However, 
in light of more recent scientific developments and changes in the use 
patterns of these products, we are now proposing that additional safety 
data are necessary to support the safety of antiseptic active 
ingredients for this use. We also are proposing that all consumer 
antiseptic rub active ingredients have in vitro data characterizing the 
ingredient's antimicrobial properties and in vivo clinical simulation 
studies showing that specified log reductions in the amount of certain 
bacteria are achieved using the ingredient.

DATES: Submit electronic or written comments by December 27, 2016. See 
section IX of this document for the proposed effective date of a final 
rule based on this proposed rule.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions''). We 
note however, that the OTC drug monograph process is a public process; 
and, the Agency intends to consider only non-confidential material that 
is submitted to the docket for this rulemaking or that is otherwise 
publicly available in evaluating if a relevant ingredient is GRAS/GRAE.

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-N-0124 for ``Safety and Effectiveness of Consumer Antiseptics; 
Topical Antimicrobial Drug Products for Over-the-Counter Human Use; 
Proposed Amendment of the Tentative Final Monograph; Reopening of 
Administrative Record.'' Received comments will be placed in the docket 
and, except for those submitted as ``Confidential Submissions,'' 
publicly viewable at http://www.regulations.gov or at the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Anita Kumar, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 5445, Silver Spring, MD 20993, 301-796-
1032.

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose of the Regulatory Action
    B. Summary of the Major Provisions of the Regulatory Action in 
Question
    C. Effectiveness
    D. Safety
    E. Active Ingredients
    F. Costs and Benefits
II. Introduction
    A. Terminology Used in the OTC Drug Review Regulations
    B. Topical Antiseptics
    C. This Proposed Rule Covers Only Consumer Antiseptic Rubs

[[Page 42913]]

    D. Comment Period
III. Background
    A. Significant Rulemakings Relevant to This Proposed Rule
    B. Public Meetings Relevant to This Proposed Rule
    C. Comments Received by FDA
IV. Active Ingredients With Insufficient Evidence of Eligibility for 
the OTC Drug Review
    A. Eligibility for the OTC Drug Review
    B. Eligibility of Certain Active Ingredients for the OTC Drug 
Review
V. Ingredients Previously Proposed as Not Generally Recognized as 
Safe and Effective
VI. Summary of Proposed Classifications of OTC Consumer Antiseptic 
Rub Active Ingredients
VII. Effectiveness (Generally Recognized as Effective) Determination
    A. Evaluation of Effectiveness Data
    B. Current Standards: Studies Needed To Support a Generally 
Recognized as Effective Determination
    C. Impact of Application Parameters on Efficacy
VIII. Safety (Generally Recognized as Safe) Determination
    A. New Issues
    B. Antimicrobial Resistance
    C. Studies To Support a Generally Recognized as Safe 
Determination
    D. Review of Available Data for Each Antiseptic Active 
Ingredient
IX. Proposed Effective Date
X. Summary of Preliminary Regulatory Impact Analysis
A. Introduction
    B. Summary of Costs and Benefits
    XI. Paperwork Reduction Act of 1995
XII. Environmental Impact
XIII. Federalism
XIV. References

I. Executive Summary

A. Purpose of the Regulatory Action

    FDA is proposing to amend the 1994 TFM for OTC antiseptic drug 
products that published in the Federal Register of June 17, 1994 (59 FR 
31402). The 1994 TFM is part of FDA's ongoing rulemaking to evaluate 
the safety and effectiveness of OTC drug products marketed in the 
United States on or before May 1972 (OTC Drug Review).
    FDA is proposing to establish new conditions under which active 
ingredients used in OTC consumer antiseptic products intended to be 
used without water are GRAS/GRAE based on FDA's reevaluation of the 
safety and effectiveness data requirements proposed in the 1994 TFM for 
what were then referred to as antiseptic hand washes (which included 
the products we refer to in this document as consumer antiseptic rubs 
or consumer rubs). We are conducting this reevaluation based on the 
comments received, input from subsequent public meetings, and our 
independent evaluation of other relevant scientific information we have 
identified and placed in the docket. This proposed rule applies to 
active ingredients used in consumer antiseptic rub products that are 
sometimes referred to as rubs, leave-on products, or hand 
``sanitizers,'' as well as to consumer antiseptic wipes. These products 
are intended to be used when soap and water are not available, and are 
left on and not rinsed off with water. We will refer to them here as 
consumer antiseptic rubs or consumer rubs. In separate rulemakings (78 
FR 76444, December 17, 2013; 80 FR 25166, May 1, 2015), we proposed 
conditions under which OTC consumer antiseptic washes and OTC 
antiseptics intended for use by health care professionals in a hospital 
setting or other health care situation outside the hospital are GRAS/
GRAE. Those antiseptic products are not addressed in this proposed 
rule.

B. Summary of the Major Provisions of the Regulatory Action in Question

    We are proposing that additional safety and effectiveness data are 
necessary to support a GRAS/GRAE determination for OTC antiseptic rub 
active ingredients intended for use by consumers. The effectiveness 
data, the safety data, and the effect on the previously proposed 
classification of active ingredients are described briefly in this 
summary. Because no ingredients currently meet the criteria for a GRAS/
GRAE determination in this proposed rule, this rulemaking does not 
specifically address requirements for anticipated final formulation 
testing (i.e., testing the mixture of both active and inactive 
ingredients proposed for marketing) or labeling. Final formulation 
testing could potentially involve both efficacy testing and safety 
testing to determine absorption. It is anticipated that if a final rule 
includes any GRAS/GRAE ingredients, labeling will be addressed as part 
of the final rule and may include elements related to application 
volume and safety labeling for children, including a warning to keep 
out of reach of children. We anticipate that specific effectiveness 
claims in labeling will reflect the testing performed in support of 
these claims. Effectiveness testing using surrogate endpoints as 
described in this proposed rule is designed to support antibacterial 
claims.

C. Effectiveness

    A determination that a drug product containing a particular active 
ingredient would be GRAE for a particular intended use requires 
consideration of the benefit-to-risk ratio for the drug under the 
specified conditions of use. New information on potential risks posed 
by the use of certain consumer antiseptic products, as well as input 
from the Nonprescription Drugs Advisory Committee (NDAC) that met in 
March 2005 (the March 2005 NDAC) and October 2005 (the October 2005 
NDAC), has prompted us to reevaluate the data needed for classifying 
active ingredients used in consumer rubs as GRAE. The reevaluation of 
effectiveness will help to ensure that the level of effectiveness 
achieved is adequate to offset newly identified safety concerns (see 
new information described in the safety section of this executive 
summary). We continue to propose the use of surrogate endpoints 
(bacterial log reductions) as a demonstration of effectiveness for 
consumer antiseptic rubs combined with in vitro testing to characterize 
the antimicrobial activity of the ingredient. However, the log 
reductions required for the demonstration of effectiveness for consumer 
rubs have been revised based on the recommendations of the March 2005 
and October 2005 NDAC meetings, comments received after the 1994 TFM, 
and other information we reviewed.
    We have evaluated the available literature, the data, and other 
information that were submitted to the rulemaking on the effectiveness 
of consumer rub active ingredients, as well as the recommendations from 
the public meetings held by the Agency on antiseptics. We propose that 
the record contain additional log reduction data to demonstrate the 
effectiveness of consumer rub active ingredients. We are also asking 
for data and information to be submitted about the impact of product 
use factors (such as volume of product per application) on efficacy to 
help inform labeling and requirements for final formulation testing.

D. Safety

    Several important scientific developments that affect the safety 
evaluation of consumer rub active ingredients have occurred since FDA's 
1994 evaluation of the safety of these active ingredients under the OTC 
Drug Review. Improved analytical methods now exist that can detect and 
more accurately measure these active ingredients at lower levels in the 
bloodstream and tissue. Consequently, we now know that, at least for 
certain consumer antiseptic rub ingredients, systemic exposure is 
higher than previously thought (Refs. 1 through 5), and new information 
is available about the potential risks from systemic absorption and 
long-term exposure. These data are particularly important given the 
increased use of consumer antiseptic rubs since the publication of

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the 1994 TFM. New safety information also suggests that widespread 
antiseptic use could have an impact on the development of bacterial 
resistance. Currently, the significance of this new information is not 
known and we are unaware of any information that would lead us to 
conclude that any consumer antiseptic rub active ingredient is unsafe 
(other than those that we proposed to be Category II in the 1994 TFM). 
The benefits of any active ingredient will need to be weighed against 
its risks once both the effectiveness and safety have been better 
characterized to determine GRAS/GRAE status.
    The previously proposed GRAS determinations were based on safety 
principles that have since evolved significantly because of advances in 
technology, development of new test methods, and experience with 
performing test methods. The standard battery of tests that were used 
to determine the safety of drugs has changed over time to incorporate 
improvements in safety testing. To ensure that consumer antiseptic rub 
active ingredients are GRAS, data that meet current safety standards 
are needed.
    Based on these developments, we are now proposing that additional 
safety data are needed for each consumer antiseptic rub active 
ingredient to support a GRAS classification. The data described in this 
proposed rule are the minimum data necessary to establish the safety of 
antiseptic active ingredients used in consumer antiseptic rub products 
in light of the new safety information. Consumers may use antiseptic 
rubs on a daily, long-term (i.e., chronic) basis. The data we propose, 
which are needed to demonstrate safety for all consumer antiseptic rub 
active ingredients, fall into two broad categories: (1) Human safety 
studies and (2) nonclinical safety studies. For one of the consumer 
antiseptic rub active ingredients (benzalkonium chloride), data to 
evaluate the development of antimicrobial resistance also is required 
to demonstrate its safety.

E. Active Ingredients

    Three active ingredients are being evaluated for use as a consumer 
antiseptic rub in this proposed rule: Alcohol (ethanol or ethyl 
alcohol), isopropyl alcohol, and benzalkonium chloride (sometimes 
referred to as ADBAC). As part of this proposed rule, FDA evaluated new 
data submitted after publication of the 1994 TFM for each of these 
three ingredients.
    In the 1994 TFM (59 FR 31402 at 31435), alcohol (60 to 95 percent) 
was proposed to be classified as GRAS/GRAE (59 FR 31402 at 31435 to 
31436) for use as what was then called an antiseptic hand wash (a use 
which included both products intended to be rinsed off (washes) and 
those intended to be left on (rubs)). Isopropyl alcohol (70 to 91.3 
percent) was proposed to be categorized in Category III in the 1994 TFM 
because of a lack of adequate effectiveness data for use as an 
antiseptic hand wash (59 FR 31402 at 31435 to 31436). However, we now 
propose that both alcohol and isopropyl alcohol need additional safety 
and effectiveness data to support a classification of GRAS/GRAE for 
consumer antiseptic rub use. Our detailed evaluation of the 
effectiveness and safety of the active ingredients for which data were 
submitted can be found in sections VII.A and VIII.D.
    In the 1994 TFM, FDA categorized benzalkonium chloride in Category 
III because of a lack of adequate safety and effectiveness data for its 
use as an antiseptic hand wash (59 FR 31402 at 31435). We have 
evaluated safety data received in response to the 1994 TFM and the 
consumer antiseptic wash proposed rule published in the Federal 
Register of December 17, 2013 (78 FR 76444) (2013 Consumer Wash 
Proposed Rule (PR)) (see section VIII.D). In this proposed rule, we 
propose that benzalkonium chloride needs additional safety and 
effectiveness data to support a classification of GRAS/GRAE for 
consumer antiseptic rub use.
    If we do not receive sufficient data to support monograph 
conditions for consumer antiseptic rub products containing these active 
ingredients, these active ingredients may not be included in the future 
OTC consumer antiseptic rub final monograph. Any consumer antiseptic 
rub product containing the active ingredients being considered under 
this rulemaking that are not included in a future final monograph could 
seek approval to market by submitting new drug applications (NDAs) 
under section 505 of the Federal Food, Drug, and Cosmetic Act (the FD&C 
Act) (21 U.S.C. 355). After a final monograph is established, NDA 
deviations might be submitted for these products in accordance with 21 
CFR 330.11, limiting the scope of review necessary to obtain approval.

F. Costs and Benefits

    The impact of the proposed rule on the OTC consumer antiseptic rub 
product industry will depend on the outcome of tests to determine 
whether three antiseptic ingredients--alcohol, isopropyl alcohol, and 
benzalkonium chloride--are GRAS/GRAE. It is possible that none, one, 
two, or all three of the ingredients will be determined to be GRAS/
GRAE. We consider two extreme scenarios to capture the entire range of 
total costs: (1) All three ingredients are deemed to be GRAS/GRAE or 
(2) none of the ingredients is deemed to be GRAS/GRAE.
    The range of estimated costs is wide because the number of products 
that would need to be reformulated and relabeled depends on whether or 
not an antiseptic ingredient is deemed to be GRAS/GRAE. A small number 
of products contain active ingredients which FDA has determined are not 
eligible for use in consumer antiseptic rubs and these products will 
need to be reformulated and relabeled (scenario 1). However, in 
scenario 2 (and intermediate scenarios), the resulting costs are higher 
because a greater number of products will need to be reformulated and 
relabeled as a result of tests failing to show GRAS/GRAE status.
    The total upfront costs of the proposed regulation--which include 
the expenditures to reformulate and relabel products that contain 
nonmonograph ingredients--are estimated to range from $0.34 million to 
$1.02 million for scenario 1 and from $15.99 million to $47.09 million 
for scenario 2. Annualizing upfront costs over a 10-year period at a 
discount rate of 3% for scenario 1, the costs of the proposed rule are 
estimated to be between $0.04 million and $0.12 million per year; the 
corresponding estimated cost at a discount rate of 7% is between $0.05 
million and $0.14 million per year. In scenario 2, none of the 
ingredients is determined to be GRAS/E and we expect that manufacturers 
will reformulate their products to be free of antiseptics and relabel 
them to reflect the change in ingredients. Annualizing upfront costs 
over a 10-year period at a discount rate of 3% for scenario 2, the 
costs of the proposed rule are estimated to be between $1.87 million 
and $5.52 million per year; the corresponding estimated cost at a 
discount rate of 7% is between $2.28 million and $6.70 million per 
year. We assume that health risk falls with reduced exposure to 
potentially unsafe or ineffective antiseptic ingredients in consumer 
antiseptic rubs. We estimate that the proposed rule will reduce 
exposure to potentially unsafe or ineffective antiseptic ingredients in 
consumer antiseptic rubs by between 110 and 67,272,847 pounds.\1\
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    \1\ As was the case with estimated costs, there is a great 
disparity in the estimated reductions in exposure to antiseptic 
ingredients. The lower bound (110 pounds) represents the estimated 
reduction in exposure to ingredients which FDA has determined are 
not GRAS/GRAE for use in consumer antiseptic rubs and few products 
contain such GRAS/GRAE ingredients.

[[Page 42915]]



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                                  Total reduction in
 Summary of costs and benefits   antiseptic ingredient  Total costs annualized over    Total one-time costs (in
     of the proposed rule        exposure (in pounds)      10 years (in millions)             millions)
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Total.........................  110 and 67,272,847....  $0.04 to $5.52 (3%)........  $0.34 and $47.09.
                                                        $0.05 to $6.70 (7%)........
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II. Introduction

    In the following sections, we provide a brief description of 
terminology used in the OTC Drug Review regulations and an overview of 
OTC topical antiseptic drug products, and then describe in more detail 
the OTC consumer antiseptic rubs that are the subject of this proposed 
rule.

A. Terminology Used in the OTC Drug Review Regulations

1. Proposed, Tentative Final, and Final Monographs
    To conform to terminology used in the OTC Drug Review regulations 
(Sec.  330.10 (21 CFR 330.10)), the September 1974 advance notice of 
proposed rulemaking (39 FR 33103, September 13, 1974) (1974 ANPR) was 
designated as a ``proposed monograph.'' Similarly, the notices of 
proposed rulemaking, which were published in the Federal Register of 
January 6, 1978 (43 FR 1210) (the 1978 TFM), and in the Federal 
Register of June 17, 1994 (59 FR 31402) (the 1994 TFM), were each 
designated as a ``tentative final monograph'' (see table 1 in section 
III.A). The present proposed rule, which is a proposal to amend the 
1994 TFM with respect to consumer antiseptic rub drug products, is also 
designated as a ``tentative final monograph.''
2. Category I, II, and III Classifications
    The OTC drug procedural regulations in Sec.  330.10 use the terms 
``Category I'' (generally recognized as safe and effective and not 
misbranded), ``Category II'' (not generally recognized as safe and 
effective or misbranded), and ``Category III'' (available data are 
insufficient to classify as safe and effective, and further testing is 
required). Section 330.10 provides that any testing necessary to 
resolve the safety or effectiveness issues that formerly resulted in a 
Category III classification, and submission to FDA of the results of 
that testing or any other data, must be done during the OTC drug 
rulemaking process before the establishment of a final monograph (i.e., 
a final rule or regulation). Therefore, this proposed rule (the 
tentative final monograph stage) retains the concepts of Categories I, 
II, and III.
    At the final monograph stage, FDA does not use the terms ``Category 
I,'' ``Category II,'' and ``Category III.'' In place of Category I, the 
term ``monograph conditions'' is used; in place of Categories II and 
III, the term ``nonmonograph conditions'' is used.

B. Topical Antiseptics

    The OTC topical antimicrobial rulemaking has had a broad scope, 
encompassing drug products that may contain the same active 
ingredients, but that are labeled and marketed for different intended 
uses. In 1974, the Agency published an ANPR for topical antimicrobial 
products that encompassed products for both health care and consumer 
use. The 1974 ANPR covered seven different intended uses for these 
products: (1) Antimicrobial soap; (2) health care personnel hand wash; 
(3) patient preoperative skin preparation; (4) skin antiseptic; (5) 
skin wound cleanser; (6) skin wound protectant; and (7) surgical hand 
scrub (39 FR 33103 at 33140). FDA subsequently identified skin 
antiseptics, skin wound cleansers, and skin wound protectants as 
antiseptics used primarily by consumers for first aid use and referred 
to them collectively as ``first aid antiseptics.'' We published a 
separate TFM covering the first aid antiseptics in the Federal Register 
of July 22, 1991 (56 FR 33644) (1991 First Aid TFM). Thus, first aid 
antiseptics are not discussed further in this document.
    The four remaining categories of topical antimicrobials were 
addressed in the 1994 TFM. The 1994 TFM covered: (1) Antiseptic hand 
wash (i.e., consumer hand wash); (2) health care personnel hand wash; 
(3) patient preoperative skin preparation; and (4) surgical hand scrub 
(59 FR 31402 at 31442). In the 1994 TFM, FDA also identified a new 
category of antiseptics for use by the food industry and requested 
relevant data and information (59 FR 31402 at 31440). Antiseptics for 
use by the food industry are not discussed further in this document.
    In the 1974 ANPR, we distinguished antimicrobial soaps used by 
consumers from professional use antiseptics, such as health care 
personnel hand washes. (See section II.C about the term ``antimicrobial 
soaps.'') In contrast, in the 1994 TFM, we proposed that both 
antiseptic hand washes (i.e., consumer antiseptic washes) and health 
care personnel hand washes should have the same effectiveness testing 
and performance criteria. In response to the 1994 TFM, we received 
submissions from the public arguing that consumer products serve a 
different purpose and should continue to be distinct from health care 
antiseptics. We agreed, and in the 2013 Consumer Wash PR and in the 
health care antiseptic proposed rule published in the Federal Register 
of May 1, 2015 (80 FR 25166) (2015 Health Care Antiseptic PR), our 
evaluation of OTC antiseptic drug products has been further subdivided 
into consumer antiseptics and health care antiseptics, which are used 
by health care professionals in a hospital setting or other health care 
situations outside the hospital. We believe that these categories are 
distinct based on the proposed-use setting, target population, and the 
fact that each setting presents a different level of risk for 
infection. For example, in health care settings, the patient population 
is generally more susceptible to infection than the general U.S. 
consumer population (i.e., the population who use consumer antiseptic 
rubs or washes). Furthermore, the purpose of use is generally 
different; health care antiseptics are primarily used to protect the 
patient (rather than just the user), whereas consumer antiseptics are 
generally applied to protect the user. In the health care setting, the 
potential for spread of infection and the potential for serious 
outcomes of infection may be relatively higher than in the U.S. 
consumer setting. Therefore, the safety and effectiveness should be 
evaluated separately for each intended use to support a GRAS/GRAE 
determination.
    As we did in the 2013 Consumer Wash PR, we refer to the group of 
products covered by this proposed rule as ``consumer antiseptics.'' 
Consumer antiseptic drug products addressed by this proposal include 
consumer antiseptic hand rubs (commonly called hand sanitizers) and 
antiseptic wipes.

[[Page 42916]]

These products may be used by consumers for personal use on a frequent 
basis, even multiple times per day. These products do not include 
personal care products intended to be used with water, such as 
antibacterial soaps, hand washes, and body washes.

C. This Proposed Rule Covers Only Consumer Antiseptic Rubs

    In this proposed rule, FDA proposes the establishment of a 
monograph for OTC consumer antiseptics that are intended for use as an 
antiseptic rub, but that are not identified as ``first aid 
antiseptics'' in the 1991 First Aid TFM. When the 1994 TFM was 
published, the term for daily consumer use antiseptics was changed to 
``antiseptic hand wash.'' In response to this change, we received 
comments that the term ``antiseptic hand wash'' did not include all of 
the consumer products on the market, such as hand rubs and body washes. 
Therefore, in this proposed rule, we use the term ``consumer 
antiseptic,'' which is a broad term and meant to include all of the 
types of antiseptic products used on a frequent or daily basis by 
consumers. However, this proposed rule covers only consumer antiseptic 
rubs and does not include consumer antiseptic hand washes or body 
washes.
    The 1994 TFM did not distinguish between products that we are now 
calling ``antiseptic washes'' and products we are now calling 
``antiseptic rubs.'' Washes are rinsed off with water, and include 
consumer hand washes and body washes, and health care personnel hand 
washes and surgical hand scrubs. Rubs are sometimes referred to as 
``leave-on products'' and are not rinsed off after use. They are 
intended to be used when soap and water are not available. Consumer 
antiseptic rubs include ``hand sanitizers'' and wipes. The 1994 TFM 
also did not distinguish between consumer antiseptic washes and rubs, 
and health care hand washes and rubs. This proposed rule covers only 
consumer antiseptic rubs. Completion of the monograph for consumer 
antiseptic rubs and certain other monographs for the active ingredient 
triclosan are subject to a Consent Decree entered by the U.S. District 
Court for the Southern District of New York on November 21, 2013, in 
Natural Resources Defense Council, Inc. v. United States Food and Drug 
Administration, et al., 10 Civ. 5690 (S.D.N.Y.).

D. Comment Period

    Because of the complexity of this proposed rule, we are providing a 
comment period of 180 days. Moreover, new data or information may be 
submitted to the docket via http://www.regulations.gov (see ADDRESSES) 
within 12 months of publication, and comments on any new data or 
information may then be submitted to the docket for an additional 60 
days (see Sec.  330.10(a)(7)(iii) and (iv)). In addition, FDA will also 
consider requests to defer further rulemaking with respect to a 
specific active ingredient for use as a consumer antiseptic rub to 
allow the submission of new safety or effectiveness data to the record 
if these requests are submitted to the docket within the initial 180-
day comment period. FDA will review all data and information submitted 
to the record in conjunction with all timely and complete requests to 
defer rulemaking. In assessing whether to defer further rulemaking for 
a particular active ingredient to allow for additional time for studies 
to generate new data and information, FDA will consider the data 
already in the docket, along with any information that is provided in 
any requests. FDA will determine whether the sum of the data, if 
submitted in a timely fashion, is likely to be adequate to provide all 
the data that are necessary to make a GRAS/GRAE determination.
    We note that the OTC Drug Review is a public process and any data 
submitted is public. There is no requirement or expectation that more 
than one set of data will be submitted to the docket for a particular 
active ingredient, and it does not matter who submits the data. In 
addition, data and other information for a single active ingredient may 
be submitted by any interested party and not all data for an ingredient 
must be submitted by a single party.

III. Background

    In this section, we describe the significant rulemakings and public 
meetings relevant to this proposed rule, and how we are responding to 
comments received in response to the 1994 TFM.

A. Significant Rulemakings Relevant to This Proposed Rule

    A summary of the significant Federal Register publications relevant 
to this proposed rule is provided in table 1. Other publications 
relevant to this proposed rule are available at http://www.regulations.gov in FDA Docket No. 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 33103)......................  We published an ANPR to establish a monograph
                                                                    for OTC topical antimicrobial drug products,
                                                                    together 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, 43 FR 1210).............  We published our tentative conclusions and
                                                                    proposed effectiveness testing for the drug
                                                                    product categories evaluated by the Panel.
                                                                    The 1978 TFM reflects our evaluation of the
                                                                    recommendations of the Panel and comments
                                                                    and data submitted in response to the
                                                                    Panel's recommendations.
1982 Alcohol ANPR (May 21, 1982, 47 FR 22324)....................  We published an ANPR to establish a monograph
                                                                    for alcohol drug products for topical
                                                                    antimicrobial use, together with the
                                                                    recommendations of the Advisory Review Panel
                                                                    on OTC Miscellaneous External Drug Products,
                                                                    which was the advisory review panel
                                                                    responsible for evaluating data on the
                                                                    active ingredients in this drug class.
1991 First Aid TFM (July 22, 1991, 56 FR 33644)..................  We amended the 1978 TFM to establish a
                                                                    separate monograph for OTC first aid
                                                                    antiseptic products. In the 1991 First Aid
                                                                    TFM, we proposed that first aid antiseptic
                                                                    drug products be indicated for the
                                                                    prevention of skin infections in minor cuts,
                                                                    scrapes, and burns.
1994 Health Care Antiseptic TFM (June 17, 1994, 59 FR 31402).....  We amended the 1978 TFM to establish a
                                                                    separate monograph for the group of products
                                                                    that were referred to as OTC topical health
                                                                    care antiseptic drug products. These
                                                                    antiseptics are generally intended for use
                                                                    by health care professionals.
                                                                   In that proposed rule, we also recognized the
                                                                    need for antibacterial personal cleansing
                                                                    products for consumers to help prevent cross-
                                                                    contamination from one person to another and
                                                                    proposed a new antiseptic category for
                                                                    consumer use: Antiseptic hand wash.

[[Page 42917]]

 
2013 Consumer Antiseptic Wash TFM (December 17, 2013, 78 FR        We issued a proposed rule to amend the 1994
 76444).                                                            TFM and to establish data standards for
                                                                    determining 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 1, 2015, 80 FR 25166 ).....  We issued a proposed rule to amend the 1994
                                                                    TFM and to establish data standards for
                                                                    determining 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/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm070821.htm. The publications dated after 1993 can also be found in the Federal
  Register at https://www.federalregister.gov.

B. Public Meetings Relevant to This Proposed Rule

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

                                        Table 2--Relevant Public Meetings
----------------------------------------------------------------------------------------------------------------
                     Date and type of meeting                                   Topic of discussion
----------------------------------------------------------------------------------------------------------------
January 1997 NDAC Meeting (Joint meeting with the Anti-Infective   Antiseptic and antibiotic resistance in
 Drugs Advisory Committee) (January 6, 1997, 62 FR 764).            relation to an industry proposal for
                                                                    consumer and health care antiseptic
                                                                    effectiveness testing (Health Care Continuum
                                                                    Model) (Refs. 6, 7).
March 2005 NDAC Meeting (February 18, 2005, 70 FR 8376)..........  The use of surrogate endpoints and study
                                                                    design issues for the in vivo testing of
                                                                    health care antiseptics (Ref. 8).
October 2005 NDAC Meeting (September 15, 2005, 70 FR 54560)......  Benefits and risks of consumer antiseptics.
                                                                    NDAC expressed concern about the pervasive
                                                                    use of 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 antiseptic
                                                                    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, 2014, 79 FR 44042).........  Safety testing framework for health care
                                                                    antiseptic active ingredients (Ref. 11).
----------------------------------------------------------------------------------------------------------------

C. Comments Received by FDA

    In response to the 1994 TFM, FDA received approximately 160 
comments from drug manufacturers, trade associations, academia, testing 
laboratories, consumers, health professionals, and law firms. In 
response to the 2013 Consumer Wash PR, we received safety data 
regarding benzalkonium chloride that is relevant to this ingredient's 
use in a consumer rub and these data are evaluated in section VIII.D.2. 
Copies of the comments received are on public display at http://www.regulations.gov (see ADDRESSES). Because only consumer antiseptic 
rubs are discussed in this proposed rule, only those comments and data 
received in response to the 1994 TFM that are related to consumer 
antiseptic rub active ingredients are addressed. We also received 
comments related to final formulation testing and labeling conditions 
proposed in the 1994 TFM. If in the future we determine that there are 
monograph consumer antiseptic rub active ingredients that are GRAS/
GRAE, we will address these comments. We invite further comment on the 
final formulation testing and labeling conditions proposed in the 1994 
TFM, particularly in light of the data proposed in this proposed rule 
as necessary to support a GRAS/GRAE determination. Comments that were 
received in response to the 1994 TFM regarding other intended uses of 
the active ingredients are addressed in the 2013 Consumer Wash PR (78 
FR 76444), or the 2015 Health Care Antiseptic PR (80 FR 25166), or will 
be addressed in future documents related to those other uses.
    This proposed rule constitutes FDA's evaluation of submissions made 
in response to the 1994 TFM to support the safety and effectiveness of 
OTC consumer antiseptic rub active ingredients (Ref. 12). We reviewed 
the available literature and data and the comments submitted to the 
rulemaking and are proposing that adequate data for a determination of 
safety and effectiveness are not yet available for the consumer 
antiseptic rub active ingredients.

IV. Active Ingredients With Insufficient Evidence of Eligibility for 
the OTC Drug Review

    In this section of the proposed rule, we describe the requirements 
for eligibility for the OTC Drug Review and the ingredients submitted 
to the OTC Drug Review that lack adequate evidence of eligibility for 
evaluation as consumer antiseptic rub products.

A. Eligibility for the OTC Drug Review

    An OTC drug is covered by the OTC Drug Review if its conditions of 
use existed in the OTC drug marketplace on or before May 11, 1972 (37 
FR 9464) (Ref. 13).\2\ Conditions of use include, among other things, 
active ingredient, dosage form and strength, route of administration, 
and specific OTC use or indication of the product (see Sec.  
330.14(a)). To determine eligibility for the OTC Drug Review, FDA 
typically

[[Page 42918]]

must have actual product labeling or a facsimile of labeling that 
documents the conditions of marketing of a product prior to May 1972 
(see Sec.  330.10(a)(2)). FDA considers a drug that is ineligible for 
inclusion in the OTC monograph system to be a new drug that will 
require FDA approval through the NDA process. Ineligibility for use as 
a consumer antiseptic rub does not affect eligibility under any other 
OTC drug monograph.
---------------------------------------------------------------------------

    \2\ Also, note that drugs initially marketed in the United 
States after the OTC Drug Review began in 1972 and drugs without any 
U.S. marketing experience can be considered in the OTC monograph 
system based on submission of a Time and Extent Application. (See 
Sec.  330.14).
---------------------------------------------------------------------------

B. Eligibility of Certain Active Ingredients for the OTC Drug Review

    The following list includes those active ingredients that were 
addressed in the 1994 TFM for use as an antiseptic hand wash or health 
care personnel hand wash, and which currently do not have adequate 
evidence of eligibility for evaluation under the OTC Drug Review for 
use in a consumer antiseptic rub. Our review of the labeling submitted 
to the Panel or to FDA at a later time did not identify evidence 
demonstrating eligibility for the following active ingredients:

 Benzethonium chloride
 Chloroxylenol
 Chlorhexidine gluconate \3\
---------------------------------------------------------------------------

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

 Cloflucarban
 Fluorosalan
 Hexachlorophene
 Hexylresorcinol
 Iodine complex (ammonium ether sulfate and polyoxyethylene 
sorbitan monolaurate)
 Iodine complex (phosphate ester of alkylaryloxy polyethylene 
glycol)
 Methylbenzethonium chloride
 Nonylphenoxypoly (ethyleneoxy) ethanoliodine
 Phenol (less than 1.5 percent)
 Phenol (greater than 1.5 percent)
 Poloxamer iodine complex
 Povidone-iodine 5 to 10 percent
 Secondary amyltricresols
 Sodium oxychlorosene
 Tribromsalan
 Triclocarban
 Triclosan
 Triple dye
 Undecoylium chloride iodine complex

    Following the publication of the 1994 TFM, FDA received submissions 
for the first time requesting that the following compounds be added to 
the monograph (Refs. 14 through 20):

 Polyhexamethylene biguanide
 Benzalkonium cetyl phosphate
 Cetylpyridinium chloride
 Calicylic acid, sodium hypochlorite
 Tea tree oil
 Combination of potassium vegetable oil solution, phosphate 
sequestering agent, and triethanolamine

    These compounds were not addressed in prior FDA documents related 
to the monograph and were not evaluated for antiseptic hand wash use by 
the Antimicrobial I Panel. The submissions received by the Agency to 
date do not include documentation demonstrating the eligibility of any 
of these compounds for inclusion in the topical antimicrobial monograph 
(Ref. 21). Because of their lack of eligibility, effectiveness and 
safety information that has been submitted to the rulemaking for these 
consumer antiseptic rub active ingredients are not discussed in this 
proposed rule for such use. However, if documentation of the type 
described in section IV.A is submitted, these active ingredients could 
be determined to be eligible for evaluation for use as a consumer 
antiseptic rub.

V. Ingredients Previously Proposed as Not Generally Recognized as Safe 
and Effective

    FDA may determine that an active ingredient is not GRAS/GRAE for a 
given OTC use (i.e., nonmonograph) because of lack of evidence of 
effectiveness, lack of evidence of safety, or both. In the 1994 TFM (59 
FR 31402 at 31435), FDA proposed that the active ingredients 
fluorosalan, hexachlorophene, phenol (greater than 1.5 percent), and 
tribromsalan be found not GRAS/GRAE for the uses referred to in the 
1994 TFM as antiseptic hand wash and health care personnel hand wash. 
None of these ingredients currently have adequate evidence of 
eligibility for use in a consumer antiseptic rub (see section IV.B). 
Consequently, effectiveness and safety information that has been 
submitted to the rulemaking for these consumer antiseptic rub active 
ingredients are not discussed in this proposed rule for such use. 
However, if documentation of the type described in section IV.A is 
submitted, these active ingredients could be determined to be eligible 
for evaluation for use as a consumer antiseptic rub.

VI. Summary of Proposed Classifications of OTC Consumer Antiseptic Rub 
Active Ingredients

    Table 3 lists the OTC consumer antiseptic active ingredients 
eligible for evaluation under the OTC Drug Review for use in consumer 
rubs, the classification proposed in the 1994 TFM, and the 
classification being proposed in this rulemaking. For each active 
ingredient, data that have been submitted to the public docket (for the 
topical antimicrobial rulemaking) and evaluated by FDA and the 
description of data still lacking in the administrative record are 
described in detail in section VIII.

      Table 3--Classification of OTC Consumer Antiseptic Rub Active
          Ingredients in the 1994 TFM and in This Proposed Rule
------------------------------------------------------------------------
                                 1994 TFM proposal
       Active ingredient                \1\           This proposed rule
------------------------------------------------------------------------
Alcohol 60 to 95 percent......  I \2\..............  IIISE \3\
Isopropyl alcohol 70 to 91.3    IIIE...............  IIISE
 percent.
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
  antiseptic 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 classified as Category I, isopropyl 
alcohol was classified as Category IIIE, and benzalkonium chloride was 
classified as Category IIISE for use as an antiseptic hand wash or 
health care

[[Page 42919]]

personnel hand wash. However, in this proposed rule, we are proposing 
to classify all three ingredients as Category IIISE for use as a 
consumer antiseptic rub because additional effectiveness and safety 
data are needed to classify each ingredient as GRAS/GRAE for this use.

VII. Effectiveness (Generally Recognized as Effective) Determination

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

A. Evaluation of Effectiveness Data

1. Clinical Simulation Studies
    Most of the available data to support the effectiveness of consumer 
antiseptic rubs are based on clinical simulation studies, such as the 
ones described in the 1994 TFM (59 FR 31402 at 31444). The premise 
behind these studies as described in the 1994 TFM is that bacterial 
reductions translate to a reduced risk for infection. However, 
currently, there are no clinical data that demonstrate that the 
specific bacterial log reductions that we have relied upon as a 
demonstration of effectiveness lead to a specific reduction in 
infections. In our view, although a lower number of bacteria on hands 
may not directly translate into a reduced chance of infection, a 
reduced bacterial load does decrease the opportunity for infection when 
used in situations with no other options for hand cleansing. In this 
case, rather than comparing using consumer antiseptic rubs to hand 
washing with soap and water, we are comparing them to the alternative 
of not cleaning the hands. In addition, because we believe that the 
consumer antiseptic rubs are intended to provide immediate reduction of 
bacteria rather than a persistent benefit, we are proposing that log 
reductions be measured after a single bacterial challenge (see table 
4), rather than after repeated contamination.
    We have evaluated all clinical simulation studies that were 
submitted to the OTC Drug Review for evidence of the effectiveness of 
consumer antiseptic rub active ingredients under the log reduction 
criteria proposed in the 1994

[[Page 42920]]

TFM (59 FR 31402 at 31448) (Refs. 28 through 30). We also searched the 
published literature for clinical simulation studies that assess 
consumer antiseptic rubs' effectiveness using the log reduction 
criteria in the 1994 TFM (Refs. 28 and 29).
    Overall, the studies used a variety of study designs, including 
nonstandard study designs. In some cases, data submitted to the OTC 
Drug Review were in the form of technical reports or published articles 
without any study details. There is insufficient information to 
evaluate the scientific merit of studies described in abstracts and 
technical reports. Most importantly, none of the evaluated studies were 
adequately controlled to demonstrate the contribution of the active 
ingredient to the effectiveness observed in the studies (43 FR 1210 at 
1240) and, therefore, cannot be used to demonstrate that the active 
ingredient tested is GRAE.
    In general, the evaluated studies also had at least one of the 
following deficiencies:
     Some studies that were described as using a standardized 
method (American Society for Testing and Materials (ASTM) \4\ or 1994 
TFM) varied from these methods without explanation or validation, and 
the majority of studies did not provide sufficient information about 
critical aspects of the study conduct.
---------------------------------------------------------------------------

    \4\ General information about ASTM can be found at https://www.astm.org/.
---------------------------------------------------------------------------

     Many studies did not include appropriate controls; for 
example, most studies did not include a vehicle control or an active 
control (59 FR 31402 at 31448), and some studies that included an 
active control failed to use the control product according to its 
labeled directions (59 FR 31402 at 31448).
     Many studies did not provide sufficient detail concerning 
neutralizer use (43 FR 1210 at 1244) or validation of neutralizer 
effectiveness.
     The studies evaluated a small number of subjects (59 FR 
31402 at 31449).
     Some studies did not sample all of the time points 
specified by the test method (59 FR 31402 at 31448).
    FDA's detailed evaluation of the data is filed in Docket No. FDA-
2016-N-0124, available at http://www.regulations.gov.
2. Clinical Outcome Studies
    Although we are not currently proposing to require clinical outcome 
studies to support a GRAE determination in this proposed rule, FDA 
identified and evaluated clinical outcome studies from the published 
literature that could potentially provide evidence of effectiveness for 
the use of consumer antiseptic rubs (Ref. 24). In our view, clinical 
outcome studies evaluating the effectiveness of consumer rubs should be 
adequately controlled and include a placebo or negative control arm to 
show the effect of an active ingredient. Among the reviewed studies and 
published literature, there are only a few studies that use these 
specified parameters for evaluating the effectiveness of consumer 
antiseptic rubs (Ref. 25). Overall, most of the studies were 
confounded, underpowered, and/or not properly controlled.
    Our detailed review of consumer hand rubs studies is available in 
Docket No. FDA-2016-N-0124 (Ref. 24). None of the alcohol-based hand 
rub studies demonstrating benefit were adequately controlled, thus they 
could not demonstrate the contribution of the antiseptic active 
ingredient to the observed clinical outcome of reduced infection rates. 
In general, the studies had the following design flaws:
     No comparison to vehicle.
     Small sample size.
     Lack of randomization, blinding, or both.
     Inadequate statistical power and, in some cases, a failure 
to analyze results for statistical significance.
     Inadequate description of methodology and data collection 
methods.
     Failure to observe and document hand rub application 
technique.
    One clinical outcome study was identified that was randomized, 
blinded, and placebo-controlled and was well designed to evaluate the 
effectiveness of a particular antiseptic active ingredient (Ref. 31). 
Although it had several significant limitations that prevent it from 
being sufficient to establish effectiveness for use of the active 
ingredient in a consumer antiseptic rub, this study is the best among 
the available studies that evaluate the impact of consumer antiseptic 
rubs on infections.
    This clinical outcome study performed in Sweden compared the 
effectiveness of a 70-percent alcohol-containing consumer antiseptic 
rub as an adjunct to hand washing with plain soap and water in 
childcare centers (Ref. 31). The study included 60 childcare centers 
(30 matched pairs) from 10 counties with a mean number of 50 children 
in each center. One childcare center from each matched pair was 
randomized to the intervention group, with the other serving as the 
control group. The intervention groups were provided instructions 
(verbal and written), and children and staff were asked to wash hands 
with plain soap and water, then rub with a 70-percent alcohol-
containing consumer antiseptic rub. Control groups followed the same 
hand-washing protocol without the hand rub. The primary outcome was the 
rate of illness absenteeism. Parents were asked to report every episode 
when the child was absent from childcare because of illness, including 
the dates of absence, symptoms, and any medical treatment. There were 
0.37 absences per 100 child hours in the control group, compared to 
0.33 in the intervention group. The effect of the intervention was a 
12-percent reduction in absenteeism. Based on the amount of hand rub 
used during the study, the estimated frequency of hand rub use by each 
child was two to six times per day. Although the study is well 
designed, there are several significant limitations, such as the 
following:
     No clinical or microbiological evaluation of illness.
     No specific infection was studied.
     Children kept home based on parent choice not addressed in 
the statistical analysis.
     Degree of illness and symptoms to keep child home varied 
among parents.

B. Current Standards: Studies Needed To Support a Generally Recognized 
as Effective Determination

    In the 1994 TFM, we proposed that the effectiveness of antiseptic 
active ingredients could be supported by a combination of in vitro 
studies and in vivo clinical simulation testing as described in 21 CFR 
333.470 (59 FR 31402 at 31444). In vitro studies are designed to 
demonstrate the product's spectrum and kinetics of antimicrobial 
activity, as well as the potential for the development of resistance 
associated with product use. In vivo test methods and evaluation 
criteria are based on the premise that bacterial reductions can be 
adequately demonstrated using tests that simulate conditions of actual 
use for OTC consumer antiseptic rub products and that those reductions 
are reflective of bacterial reductions that would be achieved during 
use. For the use of antiseptic rubs, some public health agencies (Ref. 
22) recommend their use when soap and water are not available, and when 
there is no other reasonably available alternative for the consumer.
    In addition to the standards described in section VII.B, the 
effectiveness of consumer antiseptic rubs can be affected by a variety 
of other factors related to product formulation and use. Section VII.C 
discusses these factors, which includes the number of times per day a

[[Page 42921]]

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

[[Page 42922]]

thereby does not create inflated log reductions. The purpose of 
neutralizer validation is to show that the neutralizer used in the 
study is effective against the test and control products, and that it 
is not toxic to the test microorganisms. If a test product can be 
neutralized through dilution, this should be demonstrated in the 
neutralizer validation study.
     An analysis of the proportion of subjects who meet the log 
reduction criteria based on a two-sided statistical test for 
superiority to vehicle and a 95-percent confidence interval approach.
    To establish that a particular active ingredient is GRAE for use in 
consumer antiseptic rubs, clinical simulation studies using the 
parameters described in this section should be evaluated using log 
reduction criteria similar to those proposed in the 1994 TFM (59 FR 
31402 at 31448). Our current criteria are laid out in table 4. We have 
revised the log reduction criteria proposed for consumer antiseptic 
rubs based on the recommendations of the March 2005 NDAC and comments 
to the 1994 TFM, which argued that the demonstration of a cumulative 
antiseptic effect for these products is unnecessary. We agree that the 
critical element of the effectiveness is that a product must be 
effective after the first application because that represents the way 
in which consumer antiseptic rub products are used (59 FR 31402 at 
31442). For these reasons, log reduction criteria are proposed only for 
a single application of the test product rather than multiple 
applications. Given that we are no longer requiring a cumulative 
antiseptic effect, the log reduction criteria were revised to reflect 
this single application and fall between the log reductions previously 
proposed for the first and last applications. The GRAE criteria 
proposed for consumer antiseptic rubs are based on log reductions 
achieved by antiseptics as shown in the published literature (Refs. 28 
and 29) as well as those evaluated under the NDA process. Table 4 shows 
the log reductions that we would expect an effective consumer 
antiseptic rub active ingredient to meet to show that it 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/         (1) Reduction of 2    (1) Reduction of 2.5
 Consumer antiseptic rub.      log10 on each hand    log10 on each hand
                               within 5 minutes      within 5 minutes
                               after the first       after a single rub.
                               wash and
                              (2) Reduction of 3
                               log10 on each hand
                               within 5 minutes
                               after the tenth
                               wash.
------------------------------------------------------------------------

C. Impact of Application Parameters on Efficacy

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

[[Page 42923]]

containing 70 percent ethanol, were both shown to be statistically 
superior after both 1 and 10 applications compared to two marketed 
formulations, one gel and one foam, both containing 70 percent ethanol. 
All formulations were applied in equal volumes. The two ``novel'' 
formulations also demonstrated some evidence of improved performance 
relative to a marketed gel containing 90 percent ethanol.
    Understanding the impact of product-related parameters, such as 
formulation, dose applied, and application volume, to be used according 
to the labeling is imperative. We also need to understand the extent to 
which variability in product-related parameters must be reduced to 
ensure that products achieve the results expected based on their use of 
GRAE ingredients. Given the data demonstrating that efficacy varies 
with dose, application volume, and formulation, final formulation 
efficacy testing will be necessary for consumer antiseptic rub products 
in order to confirm effectiveness and label the product appropriately 
for use. However, because no ingredient has sufficient data to support 
GRAS/GRAE status in this rulemaking, we are not proposing specific 
final formulation testing or labeling at this time. Instead, we are 
requesting data to allow the assessment of the impact of various 
application parameters on efficacy and the interaction among them 
(e.g., how does formulation affect application volume requirements) to 
inform final formulation testing and labeling requirements.

VIII. Safety (Generally Recognized as Safe) Determination

    In the 1994 TFM, 11 active ingredients were proposed to be 
classified as GRAS for antiseptic hand wash use, which includes 2 
active ingredients (alcohol and isopropyl alcohol) that are eligible 
for consumer antiseptic rub use (59 FR 31402 at 31435). As described in 
section II.C, consumer antiseptic hand rubs were not addressed 
separately from antiseptic hand washes in the 1994 TFM. There have 
since been a number of important scientific developments affecting our 
evaluation of the safety of the active ingredients in consumer 
antiseptic rubs, causing us to reassess the data necessary to support a 
GRAS determination. There is now new information regarding systemic 
exposure to antiseptic active ingredients (Refs. 1 through 5). The 
potential for widespread antiseptic use to promote the development of 
antibiotic-resistant bacteria also needs to be evaluated. Furthermore, 
additional experience with, and knowledge about, safety testing has led 
to improved testing methods. Improvements include study designs that 
are more capable of detecting potential safety risks. Based on our 
reassessment, we are proposing new GRAS data standards for consumer 
antiseptic rub active ingredients. To fully address these new safety 
concerns, additional safety data will be necessary to support a GRAS 
determination for all consumer antiseptic rub active ingredients.
    Many of the safety considerations for consumer antiseptic rubs are 
based on FDA's view that the use of consumer antiseptic rubs is a 
``chronic'' use as that term is defined by the International Council on 
Harmonisation (ICH).\5\ As defined by the ICH, a use is considered 
chronic if the drug will be used for a period of at least 6 months over 
the user's lifetime, including repeated, intermittent use (Ref. 40). We 
believe that consumer antiseptic rubs are often used on a daily basis 
and sometimes repeatedly over the course of the day.
---------------------------------------------------------------------------

    \5\ FDA is a member of the ICH Steering Committee, the governing 
body that oversees the harmonization activities, and contributes to 
the development of ICH guidelines.
---------------------------------------------------------------------------

A. New Issues

    Since the 1994 TFM was published, new data have become available 
indicating that systemic exposure to topical antiseptic active 
ingredients may be greater than previously thought. Systemic exposure 
refers to the presence of antiseptic active ingredients inside and 
throughout the body. Because of advances in technology, our ability to 
detect antiseptic active ingredients in body fluids such as serum and 
urine is greater than it was in 1994. For example, studies have shown 
detectable blood alcohol levels after use of alcohol-containing hand 
rubs (Refs. 1, 4, and 5). We believe that any consequences of this 
systemic exposure should be identified and assessed to support our 
risk-benefit analysis for consumer antiseptic use.
    Given the frequent repeated use of consumer antiseptic rubs, 
systemic exposure may occur. Although some systemic exposure data exist 
for all three consumer antiseptic rub active ingredients, data on 
systemic absorption after maximal use are lacking. Currently, there is 
also a lack of data to assess the impact of important drug use factors 
that can influence systemic exposure such as dose, application 
frequency and method, duration of exposure, product formulation, skin 
condition, and age. Depending on the systemic absorption of the 
ingredient, variability in absorption anticipated between formulations, 
and the safety margin for toxic effects, final formulation safety 
testing for particular ingredients may be needed to assure that 
substantially different absorption that might significantly change the 
margin of safety is not anticipated for a new formulation. FDA does not 
address final formulation testing in this rulemaking because no 
ingredients have been proposed as GRAS/GRAE. However, FDA recently 
described final formulation safety testing for another class of OTC 
dermal products regulated under the OTC drug monograph (Ref. 41).
    The evaluation of the safety of drug products involves correlating 
findings from animal toxicity studies to the level of drug exposure 
obtained from pharmacokinetic studies in animals and humans. Our 
administrative record lacks the data necessary to define a margin of 
safety for the potential chronic use of consumer antiseptic rub active 
ingredients. Thus, we are continuing to propose that both animal and 
human pharmacokinetic (PK) data are necessary for consumer antiseptic 
rub active ingredients. This information will help identify any 
potential safety concerns and help determine the safety margin for OTC 
human use.
    One potential effect of systemic exposure to consumer antiseptic 
active ingredients that has come to our attention since publication of 
the 1994 TFM is data suggesting that some antiseptic active ingredients 
have hormonal effects. Ingredients in topical antiseptic products can 
cause alterations in the thyroid of neonatal and adolescent animals 
(Refs. 42 through 51). Hormonally active compounds have been shown to 
affect not only the exposed organism, but also subsequent generations 
(Ref. 52). These effects may not be related to direct deoxyribonucleic 
acid (DNA) mutation, but rather to alterations in factors that regulate 
gene expression (Ref. 53).
    A hormonally active compound that causes reproductive system 
disruption in the fetus or infant may have effects that are not 
apparent until many years after initial exposure. There are also 
critical times in fetal development when a change in hormonal balance 
that would not cause any lasting effect in an adult could cause a 
permanent developmental abnormality in a child. For example, untreated 
hypothyroidism during pregnancy has been associated with cognitive 
impairment in the offspring (Refs. 54 through 56).
    Because consumer antiseptic rubs are used chronically and are 
likely to be used by sensitive populations such as children and 
pregnant women,

[[Page 42924]]

evaluation of the potential for chronic toxicity and effects on 
reproduction and development should be included in the safety 
assessment. The designs of general toxicity and reproductive/
developmental studies are often sufficient to identify developmental 
effects that can be caused by hormonally active compounds through the 
use of currently accepted endpoints and standard good laboratory 
practice toxicology study designs. As followup in some cases, 
additional study endpoints may be needed to fully characterize the 
potential effects of drug exposure on the exposed individuals.

B. Antimicrobial Resistance

    In the 2013 Consumer Wash PR and 2015 Health Care Antiseptic PR, 
FDA raised the concern of the development of antiseptic resistance and 
its potential impact on the development of antibiotic resistance (78 FR 
76444 at 76454 and 80 FR 25166 at 25180). This concern was based on 
numerous reports of laboratory studies demonstrating the development of 
reduced susceptibility to certain antiseptic active ingredients and 
antibiotics after growth in nonlethal amounts of the antiseptic (i.e., 
low-to-moderate concentrations of antiseptic) and reports of the 
persistence of low levels of some antiseptic active ingredients in the 
environment (78 FR 76444 at 76454 and 80 FR 25166 at 25180). FDA 
concluded in both of these proposed rules that, given the increasing 
evidence of the magnitude of the antibiotic resistance problem and the 
speed with which new antibiotic resistant organisms are emerging, it is 
important to assess this potential consequence of antiseptic use and 
requested data to address the concern (78 FR 76444 at 76454 and 80 FR 
25166 at 25180). However, in its evaluation of the available data on 
the development of resistance to alcohol and isopropyl alcohol in the 
proposed rule for health care antiseptics, FDA cited a number of 
factors (speed of action, multiple nonspecific toxic effects, and lack 
of a residue) that made the development of resistance to these alcohols 
as a result of health care antiseptic use unlikely. Based on these 
factors, FDA concluded that no additional data relevant to this issue 
were necessary to support a GRAS determination for these ingredients 
for health care antiseptics (80 FR 25166 at 25184, 25187, and 25192). 
Consistent with FDA's findings for alcohol and isopropyl alcohol in its 
proposed rule for health care antiseptic, we have also tentatively 
concluded that no further data on the development of resistance to 
alcohol and isopropyl alcohol as a result of their use in consumer 
antiseptic rub products are needed. This is not the case for 
benzalkonium chloride for which additional laboratory studies will 
assist in more clearly defining the potential for the development of 
resistance. (See section VIII.D.2).

C. Studies To Support a Generally Recognized as Safe Determination

    A GRAS determination for consumer antiseptic rub active ingredients 
must be supported by both nonclinical (animal) and clinical (human) 
studies.\6\ To issue a final monograph for these products, this safety 
data must be in the docket.\7\
---------------------------------------------------------------------------

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

    To assist manufacturers or others who wish to provide us with the 
information we expect will establish GRAS status for these active 
ingredients, we are including specific information, based in part on 
existing FDA guidance, about the other kinds of studies to consider 
conducting and submitting. We have published guidance documents 
describing the nonclinical safety studies that a manufacturer should 
perform when seeking to market a drug product under an NDA (Refs. 40, 
57 through 63). These guidance documents also provide relevant guidance 
for performing the nonclinical studies necessary to determine GRAS 
status for a consumer antiseptic rub active ingredient. Because 
consumer antiseptic rubs may be used repeatedly and in sensitive 
populations, we propose that consumer antiseptic rub active ingredients 
will need to be tested for carcinogenic potential, developmental and 
reproductive toxicity (DART), and other potential effects as described 
in more detail in this section.
1. FDA Guidances Describing Safety Studies
    The safety studies that are described in the existing FDA guidances 
(Refs. 40, 57 through 63) provide a framework for the types of studies 
that are needed for FDA to assess the safety of each consumer rub 
active ingredient according to modern scientific standards and make a 
GRAS determination. A description of each type of study and how we 
would use this information to improve our understanding of the safety 
of consumer antiseptic rub active ingredients is 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 pharmacokinetic absorption,  Both oral and dermal   Allows identification of    Used as a surrogate to
 distribution, metabolism, and       administration.        the dose at which the       identify toxic systemic
 excretion (ADME) (Refs. 58 and                             toxic effects of an         exposure levels that can
 64).                                                       active ingredient are       then be correlated to
                                                            observed as a result of     potential human exposure
                                                            systemic exposure of the    via dermal
                                                            drug. ADME data provide:    pharmacokinetic study
                                                            The rate and extent an      findings. Adverse event
                                                            active ingredient is        data related to
                                                            absorbed into the body      particular doses and
                                                            (e.g., AUC, Cmax, Tmax)     drug levels (exposure)
                                                            \1\; where the active       in animals are used to
                                                            ingredient is distributed   help formulate a safety
                                                            in the body; whether        picture of the possible
                                                            metabolism of the active    risk to humans.
                                                            ingredient by the body
                                                            has taken place;
                                                            information on the
                                                            presence of metabolites;
                                                            and how the body
                                                            eliminates the original
                                                            active ingredient
                                                            (parent) and its
                                                            metabolites (e.g., T\1/
                                                            2\)\2\.

[[Page 42925]]

 
Human pharmacokinetics (MUsT)       Dermal administration  Helps determine how much    Used to relate the
 (Ref. 62).                          using multiple         of the active ingredient    potential human exposure
                                     formulations under     penetrates the skin,        to toxic drug levels
                                     maximum use            leading to measurable       identified in animal
                                     conditions.            systemic exposure.          studies.
Carcinogenicity (ICH S1A, S1B, and  Minimum of one oral    Provides a direct measure   Identifies the systemic
 S1C) (Refs. 40, 57, and 60).        and one dermal study   of the potential for        and dermal risks
                                     for topical products   active ingredients to       associated with drug
                                     \3\.                   cause tumor formation       active ingredients.
                                                            (tumorogenesis) in the      Taken together, these
                                                            exposed animals.            studies are used to
                                                                                        identify the type(s) of
                                                                                        toxicity, the level of
                                                                                        exposure that produces
                                                                                        these toxicities, and
                                                                                        the highest level of
                                                                                        exposure at which no
                                                                                        adverse effects occur,
                                                                                        referred to as the ``no
                                                                                        observed adverse effect
                                                                                        level'' (NOAEL). The
                                                                                        NOAEL is used to
                                                                                        determine a safety
                                                                                        margin for human
                                                                                        exposure.
Developmental toxicity (ICH S5)     Oral administration..  Evaluates the effects of a
 (Ref. 59).                                                 drug on the developing
                                                            offspring throughout
                                                            gestation and postnatally
                                                            until sexual maturation.
Reproductive toxicity (ICH S5)      Oral administration..  Assesses the effects of a
 (Ref. 59).                                                 drug on the reproductive
                                                            competence of sexually
                                                            mature male and female
                                                            animals.
Hormonal effects (Ref. 63)........  Oral administration..  Assesses the drug's         Used in hazard assessment
                                                            potential to interfere      to determine whether the
                                                            with the endocrine system.  drug has the capacity to
                                                                                        induce a harmful effect
                                                                                        at any exposure level
                                                                                        without regard to actual
                                                                                        human exposures.
----------------------------------------------------------------------------------------------------------------
\1\ ``AUC'' denotes the area under the concentration-time curve, a measure of total exposure or the extent of
  absorption. ``Cmax'' denotes the maximum concentration, which is peak exposure. ``Tmax'' denotes the time to
  reach the maximum concentration, which aids in determining the rate of exposure.
\2\ ``T\1/2\'' 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 exposure 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
  reconsidered based on available information such as negative systemic carcinogenicity information and lack of
  preneoplastic effects in chronic nonrodent dermal toxicity studies.

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

[[Page 42926]]

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

If the results of these studies show no evidence of changes in 
antiseptic or antibiotic susceptibility, no further studies addressing 
the development of resistance would be needed to support a GRAS 
determination.
    For antiseptic active ingredients that demonstrate an effect on 
antiseptic and

[[Page 42927]]

antibiotic susceptibilities, additional data will be necessary to help 
assess the likelihood that similar effects would occur in the consumer 
setting. Several types of data could be used to assess whether or not 
ingredients with positive laboratory findings pose a public health 
risk, and the type of data needed would depend on what is already known 
about the antiseptic active ingredient's mechanism of action and 
persistence in the environment. We do not anticipate that it will be 
necessary to obtain data from multiple types of studies for each active 
ingredient to adequately assess its potential to affect resistance. 
Such types of data could include, but are not limited to, the 
following:
     Information about the mechanism(s) of antiseptic action 
(for example, membrane destabilization or inhibition of fatty acid 
synthesis), and whether there is a change in the mechanism of action 
with changes in antiseptic concentration.
     Information clarifying the bacteria's mechanism(s) for the 
development of resistance or reduced susceptibility to the antiseptic 
active ingredient (for example, efflux mechanisms).
     Data characterizing the potential for reduced antiseptic 
susceptibility caused by the antiseptic active ingredient to be 
transferred to other bacteria that are still sensitive to the 
antiseptic.
     Data characterizing the concentrations and antimicrobial 
activity of the antiseptic active ingredient in biological and 
environmental compartments (for example, bacteria found on human skin, 
in the gut, and in environmental matrices).
     Data characterizing the antiseptic and antibiotic 
susceptibility levels of environmental isolates of bacteria in areas of 
prevalent antiseptic use, such as in the home or in schools.

Data from the types of testing described previously, as well as from 
testing of antiseptic and antibiotic susceptibilities of bacteria in 
settings where consumer topical antiseptic rub use is prevalent can 
help demonstrate whether or not changes in susceptibility are occurring 
with actual use. Because actual use concentrations of consumer 
antiseptics are much higher than the MICs for these active ingredients, 
data from compartments where sublethal concentrations of biologically 
active antiseptic active ingredients may occur (e.g., environmental 
compartments) can give us a sense of the potential for change in 
antimicrobial susceptibilities in these compartments (Refs. 79 through 
81). FDA recognizes, however, that methods of evaluating this issue are 
an evolving science and that there may be other data appropriate to 
evaluate the impact of consumer antiseptic active ingredients on the 
development of resistance. For this reason, FDA encourages interested 
parties to consult with the Agency on the specific studies appropriate 
to address this issue for a particular active ingredient.

D. Review of Available Data for Each Antiseptic Active Ingredient

    We have identified for each consumer antiseptic rub active 
ingredient whether the studies outlined in section VIII.C are publicly 
available. Table 6 lists the types of studies available for each 
antiseptic active ingredient eligible for use as a consumer rub 
proposed as Category I or Category III in the 1994 TFM and indicates 
whether the currently available data are adequate to serve as the basis 
of a GRAS determination. Although we have some data from submissions to 
the rulemaking and from information we have identified in the 
literature, our administrative record is incomplete for at least some 
types of safety studies for each of the active ingredients (see table 
6). As noted previously, only information that is part of the 
administrative record for this rulemaking can form the basis of a GRAS/
GRAE determination.
    We recognize that data and information submitted in response to the 
2013 Consumer Wash PR or 2015 Health Care Antiseptic PR may be relevant 
to this proposed rule. At the time of publication of this proposed 
rule, FDA's review of all submissions made to the 2015 Health Care 
Antiseptic PR has not been completed. FDA requests that any information 
relevant to consumer antiseptic rub active ingredients be resubmitted 
under this docket (FDA-2016-N-0124).

                                Table 6--Safety Studies Available for Consumer Antiseptic Hand Rub Active Ingredients \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                        Human            Animal                                                            Potential
        Active Ingredient          Pharmacokinetic  Pharmacokinetic        Oral            Dermal        Reproductive       Hormonal        Resistance
                                        (MUsT)           (ADME)      Carcinogenicity  Carcinogenicity  Toxicity (DART)      Effects         Potential
--------------------------------------------------------------------------------------------------------------------------------------------------------
Alcohol..........................           [cir]                                                      
Benzalkonium chloride............  ...............           [cir]            ...............                             [cir]
Isopropyl alcohol................           [cir]            [cir]   ...............           [cir]                     [cir]         
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Empty cell indicates no data available; ``[cir]'' indicates incomplete data available; ``'' indicates available data are sufficient to make
  a GRAS/GRAE determination.

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

[[Page 42928]]

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

[[Page 42929]]

benzalkonium chloride by oral gavage. Benzalkonium chloride was found 
to be excreted mainly via the feces in rats after oral administration. 
In all of the treated groups, the average amount of radioactivity 
recovered was 87 to 99 percent in the feces and 5 to 8 percent in the 
urine.
    In a separate group of animals tested in the same study, a single 
low-dose of 10 mg/kg benzalkonium chloride was administered to rats of 
both sexes. The average amount of radioactivity recovered following IV 
dosing was 45 to 55 percent in the feces and 20 to 30 percent in the 
urine. Tissue residues of radioactivity were less than 1 percent of the 
orally administered dose in all groups and 30 to 35 percent of the IV 
dose. No significant changes were noted when comparing the ADME profile 
of high dose versus low dose-treated rats. Although the available ADME 
data from nondermal routes of exposure are sufficient to characterize 
the ADME profile of benzalkonium chloride following nondermal exposure, 
they are not sufficient to characterize the ADME profile after dermal 
exposure. Studies on animal ADME after dermal exposure to benzalkonium 
chloride will need to be submitted to FDA for review, in order to 
complete a GRAS determination for benzalkonium chloride.
    Benzalkonium general toxicity data. Two subchronic 90-day toxicity 
studies in rats were submitted, one dermal and the other dietary 
(oral). A 1-year chronic oral toxicity study in dogs was also 
submitted. In the oral rat study, benzalkonium chloride was 
administered via feeding with concentrations ranging from 0 to 8,000 
ppm (Ref. 111) for 13 weeks. Among rats treated with 4,000 and 8,000 
ppm benzalkonium chloride, an increased incidence in mortality and 
overt toxicity was seen. A no adverse effect level (NOAEL) of 500 ppm 
was noted, which correlated with a mean daily dose of 31.2 mg/kg in 
males and 38.3 mg/kg in females.
    A 1-year chronic oral toxicity study in dogs was also submitted. 
Dogs were chronically administered benzalkonium chloride via feeding in 
concentrations ranging from 0 to 1,200 ppm for 1 year (Ref. 114). 
Changes in body weight included reduced absolute body weight and 
reduced body weight gain in males and females in the highest group 
tested (1,200 ppm), which correlated with a reduction in food 
consumption. At 1,200 ppm, cholesterol levels were reduced by about 10 
percent in both males and females (p <= 0.01). No specific organ 
toxicity was identified. Based on the changes in body weight and food 
consumption at 1,200 ppm, a NOAEL of 400 ppm was determined, which 
corresponds to 13.1 and 14.6 mg/kg/day in males and females, 
respectively.
    In the dermal toxicity study, rats were topically exposed to 
benzalkonium chloride in concentrations ranging from 0 (water) to 1.0 
percent (which correspond to 0 to 20 mg/kg/day) over a 13-week 
treatment period (Ref. 113). Slight local irritation and hyperkeratosis 
(thickening of the epidermis) were observed in all treatment groups 
(including control) in both sexes. All findings were limited to the 
treatment site. Under the conditions of this study, the NOAEL was 20 
mg/kg (1.0 percent). Toxicokinetic data were not collected; therefore, 
systemic exposure to benzalkonium chloride was not characterized. 
Consequently, dermal ADME (toxicokinetic) data is still needed to 
characterize benzalkonium chloride.
    Benzalkonium chloride carcinogenicity data. Two oral 
carcinogenicity studies, one in the rat and another in the mouse, were 
submitted (Refs. 117 through 121). Both studies were conducted in the 
1980's prior to the current ICH guidelines. They were conducted 
according to the OECD (Organisation for Economic Co-operation and 
Development) guidelines \8\ and designed to meet the requirements of 
EPA's regulations, which use a different type of exposure risk 
assessment analysis than is used by FDA for drug products.
---------------------------------------------------------------------------

    \8\ http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788.
---------------------------------------------------------------------------

    A 78-week dietary carcinogenicity study was conducted in mice with 
benzalkonium chloride concentrations of 500, 1,000, and 1,500 ppm, 
corresponding to approximately 15, 73, and 229 mg/kg/day in males and 
18, 92, 289 mg/kg/day in females (Refs. 120 and 121). Findings were 
limited to decreased body weight in both males and females treated with 
the highest dose compared to controls (7 percent and 5 percent at week 
78 in males and females, respectively). There were no treatment-related 
increases in the incidence of neoplasms at any of the doses tested.
    A 2-year oral carcinogenicity study was conducted in rats with 
benzalkonium chloride concentrations of 300, 1,000, and 2,000 ppm, 
corresponding to 13, 44, and 88 mg/kg/day, respectively, in males, and 
to 17, 57, and 116 mg/kg/day, respectively, in females (Refs. 117 
through 119). No treatment-related increases in the incidence of 
neoplasms were observed at any of the tested doses.
    There were no treatment-related neoplasms in either oral 
carcinogenicity study. Though the mouse study is suboptimal because of 
its relatively short duration (78 weeks), we believe these two studies 
are adequate to fill the oral carcinogenicity data gap for benzalkonium 
chloride.
    No dermal carcinogenicity studies of benzalkonium chloride have 
been submitted to FDA. The available data are not adequate to assess 
the carcinogenic potential of benzalkonium chloride. We propose that 
dermal carcinogenicity studies are still needed to complete a GRAS 
determination for benzalkonium chloride.
    Benzalkonium chloride DART data. A developmental toxicity study 
conducted in rabbits showed some increase (not dose-related) in the 
incidence of certain visceral and skeletal malformations among 
benzalkonium chloride-treated rabbits relative to concurrent controls 
(Ref. 110). None of the findings were considered significant. Some of 
the mated dams proved to be not pregnant; therefore, the total number 
of litters (13 to 15) is slightly less than the 16 to 20 recommended in 
the ICH S5 guideline, but further benzalkonium chloride DART data are 
not necessary to make a GRAS determination.
    In a developmental toxicity study in rats, the animals were 
administered benzalkonium chloride (10, 30, and 100 mg/kg/day) (Ref. 
112). There were no treatment-related differences in gestational 
parameters, including total number of embryonic implantations, number 
of viable and nonviable implants. There were also no treatment-related 
effects on fetal body weights per litter, or on the incidences of 
external, visceral, or skeletal malformations/variations. Based on 
these findings, a NOAEL for maternal toxicity was considered to be 10 
mg/kg/day and for developmental toxicity 100 mg/kg/day.
    A two-generation reproduction and development study in rats was 
submitted for review. Rats were exposed to benzalkonium chloride in the 
feed (Ref. 116). The exposure to benzalkonium chloride up to the 
highest dose tested of 2,000 mg/kg did not result in parental toxicity. 
No treatment-related reproductive effects were observed in any of the 
treatment groups. Findings were limited to decreases in body weight 
accompanied by a decrease in food consumption among treated females at 
2,000 mg/kg/day and a decrease in pup body weight. Based on these 
findings, a NOAEL for adults and offspring was considered to be 1000 
ppm (62.5 mg/kg/day).

[[Page 42930]]

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

IX. Proposed Effective Date

    Based on the currently available data, this proposed rule finds 
that additional data are necessary to establish the safety and 
effectiveness of consumer antiseptic rub active ingredients for use in 
OTC consumer antiseptic rub drug products. Accordingly, consumer 
antiseptic rub active ingredients would be nonmonograph in any final 
rule based on this proposed rule. We recognize, based on the scope of 
products subject to this monograph, that manufacturers will need time 
to comply with a final rule based on this proposed rule. However, 
because of the potential effectiveness and safety considerations raised 
by the data for some antiseptic active ingredients evaluated, we 
believe that an effective date later than 1 year after publication of 
the final rule would not be appropriate or necessary. Consequently, any 
final rule that results

[[Page 42931]]

from this proposed rule will be effective 1 year after the date of the 
final rule's publication in the Federal Register. On or after that 
date, any OTC consumer antiseptic rub drug product that is subject to 
the monograph and that contains a nonmonograph condition, i.e., a 
condition that would cause the drug to be not GRAS/GRAE or to be 
misbranded, could not be introduced or delivered for introduction into 
interstate commerce unless it is the subject of an approved new drug 
application or abbreviated new drug application. Any OTC consumer 
antiseptic rub drug product subject to the final rule that is 
repackaged or relabeled after the effective date of the final rule 
would be required to be in compliance with the final rule, regardless 
of the date the product was initially introduced or initially delivered 
for introduction into interstate commerce.

X. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). We have developed a comprehensive Economic Analysis of Impacts 
that assesses the impacts of the proposed rule. We believe that this 
proposed rule is a significant regulatory action as defined by 
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because the consumer antiseptic rub product industry is 
mainly composed of establishments with 500 or fewer employees, we 
tentatively conclude that the proposed rule may have a significant 
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any 1 year.'' The current threshold after adjustment for 
inflation is $146 million, using the most current (2015) Implicit Price 
Deflator for the Gross Domestic Product. This proposed rule would not 
result in an expenditure in any year that meets or exceeds this amount.

B. Summary of Costs and Benefits

    There are three active ingredients being evaluated for use as a 
consumer antiseptic rub in this proposed rule: Alcohol (ethanol or 
ethyl alcohol), isopropyl alcohol, and benzalkonium chloride. The 
impact of the proposed rule on OTC consumer antiseptic rub product 
industry will depend on the outcome of tests to determine whether these 
three active antiseptic ingredients are GRAS/GRAE. It is possible that 
none, one, two, or all three of the ingredients will be determined to 
be GRAS/GRAE. We consider two extreme scenarios to capture the entire 
range of total costs: (1) All three ingredients are deemed to be GRAS/
GRAE or (2) none of the ingredients is deemed to be GRAS/GRAE.
    In table 7, we provide a summary of the estimated costs of the 
proposed rule for the two scenarios. The costs of the proposed rule 
involve product reformulation and relabeling of products. It is 
important to note that, to demonstrate that an antiseptic active 
ingredient is GRAS/E, some manufacturers will also incur additional 
costs associated with safety and effectiveness testing. We note that 
the testing costs for this proposed rule are not attributed here 
because these costs will be realized if manufacturers conduct the 
testing discussed in the proposed rule for health care antiseptics (80 
FR 25166) and we do not count costs twice. However, we estimate these 
costs in this analysis to promote transparency in the event that this 
rule is finalized before the health care antiseptics proposed rule or 
manufacturers conduct the testing for the three ingredients discussed 
in this rule but do not conduct the testing for these ingredients for 
the health care antiseptic proposed rule or this rule is finalized but 
the health care antiseptics proposed rule is not.
    In scenario 1, all three ingredients are determined to be GRAS/E 
and manufacturers of products containing other ingredients will no 
longer be able to market these products under consumer antiseptic rub 
labels pursuant to the topical antimicrobial monograph. We expect that 
these manufacturers will reformulate their products to contain one of 
the monograph ingredients and relabel their products to reflect the 
change in ingredients. Annualizing upfront costs over a 10-year period 
at a discount rate of 3% for scenario 1, the costs of the proposed rule 
are estimated to be between $0.04 million and $0.12 million per year; 
the corresponding estimated cost at a discount rate of 7% is between 
$0.05 million and $0.14 million per year. In scenario 2, none of the 
ingredients is determined to be GRAS/E and we expect that manufacturers 
will reformulate their products to be free of antiseptics and relabel 
them to reflect the change in ingredients. Annualizing upfront costs 
over a 10-year period at a discount rate of 3% for scenario 2, the 
costs of the proposed rule are estimated to be between $1.87 million 
and $5.52 million per year; the corresponding estimated cost at a 
discount rate of 7% is between $2.28 million and $6.70 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
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 42932]]

 
                                         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 rule is that the removal of 
potentially harmful antiseptic active ingredients in consumer 
antiseptic rub products will prevent health consequences associated 
with exposure to such ingredients. FDA lacks the necessary information 
to estimate the impact of exposure to antiseptic active ingredients in 
consumer antiseptic rub products on human health outcomes. We are, 
however, able to estimate the reduction in the aggregate exposure to 
antiseptic active ingredients found in currently marketed consumer 
antiseptic rub products. As with the total costs, the reduction in 
aggregate exposure to antiseptic active ingredients in consumer rub 
products depends on the outcome of testing and the determination of 
GRAS/E status of the three ingredients that require testing. The 
proposed rule will lead to an estimated reduction that ranges from 110 
pounds to 254 pounds per year in scenario 1 and from 13,080,963 and 
67,272,847 pounds per year in scenario 2. Absent information on the 
change in the short- and long-term health risks associated with a one 
pound increase in exposure to each antiseptic active ingredient in 
consumer antiseptic rub products, we are unable to translate the 
aggregate exposure figures into monetized benefits.
    FDA also examined the economic implications of the rule as required 
by the Regulatory Flexibility Act. If a rule will have a significant 
economic impact on a substantial number of small entities, the 
Regulatory Flexibility Act requires agencies to analyze regulatory 
options that would lessen the economic effect of the rule on small 
entities. This proposed rule could impose a significant economic impact 
on a substantial number of small entities. For small entities, we 
estimate the rule's one-time costs to roughly range between 0.001 and 
0.16 percent of average annual value of shipments for a small business. 
In the Initial Regulatory Flexibility Analysis, we assess regulatory 
options that would reduce the proposed rule's burden on small entities, 
such as extending relabeling compliance times to 18 months (rather than 
12 months).
    The full analysis of economic impacts is available in the docket 
for this proposed rule (Docket No. FDA-2016-N-0124) and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

XI. Paperwork Reduction Act of 1995

    This proposed rule contains no collections of information. 
Therefore, clearance by the Office of Management and Budget under the 
Paperwork Reduction Act of 1995 is not required.

XII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.31(a) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

XIII. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive order requires agencies to ``construe . . . a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' The sole statutory provision giving preemptive 
effect to this proposed rule is section 751 of the FD&C Act (21 U.S.C. 
379r). We have complied with all of the applicable requirements under 
the Executive order and have determined that the preemptive effect of 
this proposed rule, if finalized, would be consistent with Executive 
Order 13132. Through publication of this proposed rule, we are 
providing notice and an opportunity for State and local officials to 
comment on this rulemaking.

XIV. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m. Monday through Friday; they are also 
available electronically at http://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. Brown, T.L. et al., ``Can Alcohol-Based Hand-Rub Solutions Cause 
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Nonprescription Drugs and

[[Page 42933]]

Anti-Infective Drugs Advisory Committees, OTC Vol. 230002. Available 
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8. Transcript of the March 23, 2005, Nonprescription Drugs Advisory 
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10. Summary Minutes of the November 14, 2008, Feedback Meeting with 
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11. Transcript of the September 3, 2014, Meeting of the 
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FDA-1975-N-0012-0049, FDA-1975-N-0012-0068, FDA-1975-N-0012-0071, 
FDA-1975-N-0012-0073, FDA-1975-N-0012-0075, FDA-1975-N-0012-0081, 
FDA-1975-N-0012-0082, FDA-1975-N-0012-0085, FDA-1975-N-0012-0087, 
FDA-1975-N-0012-0088, FDA-1975-N-0012-0089, FDA-1975-N-0012-0090, 
FDA-1975-N-0012-0091, FDA-1975-N-0012-0093, FDA-1975-N-0012-0094, 
FDA-1975-N-0012-0095, FDA-1975-N-0012-0096, FDA-1975-N-0012-0097, 
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FDA-1975-N-0012-0111, FDA-1975-N-0012-0110, FDA-1975-N-0012-0113, 
FDA-1975-N-0012-0116, FDA-1975-N-0012-0117, FDA-1975-N-0012-0118, 
FDA-1975-N-0012-0119, FDA-1975-N-0012-0121, FDA-1975-N-0012-0124, 
FDA-1975-N-0012-0126, FDA-1975-N-0012, FDA-1975-N-0012-0128, FDA-
1975-N-0012-0132, FDA-1975-N-0012-0134, FDA-1975-N-0012-0135, FDA-
1975-N-0012-0143, FDA-1975-N-0012-0148, FDA-1975-N-0012-0153, FDA-
1975-N-0012-0154, FDA-1975-N-0012-0155, FDA-1975-N-0012-0157, FDA-
1975-N-0012-0158, FDA-1975-N-0012-0161, FDA-1975-N-0012-0164, FDA-
1975-N-0012-0166, FDA-1975-N-0012-0176, FDA-1975-N-0012-0177, FDA-
1975-N-0012-0178, FDA-1975-N-0012-0184, FDA-1975-N-0012-0191, FDA-
1975-N-0012-0198, FDA-1975-N-0012-0199, FDA-1975-N-0012-0200, FDA-
1975-N-0012-0201, FDA-1975-N-0012-0202, FDA-1975-N-0012-0204, FDA-
1975-N-0012-0206, FDA-1975-N-0012-0208, FDA-1975-N-0012-0209, FDA-
1975-N-0012-0212, FDA-1975-N-0012-0213, FDA-1975-N-0012-0215, FDA-
1975-N-0012-0217, FDA-1975-N-0012-0218, FDA-1975-N-0012-0219, FDA-
1975-N-0012-0227, FDA-1975-N-0012-0233, FDA-1975-N-0012-0238, FDA-
1975-N-0012-0241, FDA-1975-N-0012-0243, FDA-1975-N-0012-0258, FDA-
1975-N-0012-0264, FDA-1975-N-0012-0266, FDA-1975-N-0012-0274, FDA-
1975-N-0012-0275, FDA-1975-N-0012-0276, FDA-1975-N-0012-0281, FDA-
1975-N-0012-0282, FDA-1975-N-0012-0284, FDA-1975-N-0012-0285, FDA-
1975-N-0012-0286, FDA-1975-N-0012-0288.
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List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
310, as proposed to be amended December 17, 2013, at 78 FR 76444, and 
May 1, 2015, at 80 FR 25166, is proposed to be further amended as 
follows:

PART 310--NEW DRUGS

0
1. The authority citation for part 310 is revised to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 360hh-360ss, 361(a), 371, 374, 375, 379e, 379k-1; 42 U.S.C. 
216, 241, 242(a), 262.

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2. In Sec.  310.545:
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a. Add paragraph (a)(27)(v);
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b. In paragraph (d) introductory text, remove ``(d)(42)'' and in its 
place add ``(d)(43)''; and
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c. Add paragraph (d)(43).
    The additions to read as follows:


Sec.  310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (27) * * *
    (v) Consumer antiseptic rub drug products. Approved as of [DATE 1 
YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN THE Federal 
Register]:

Alcohol (ethanol and ethyl alcohol)
Benzalkonium chloride
Isopropyl alcohol

* * * * *
    (d) * * *
    (43) [DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN 
THE Federal Register], for products subject to paragraph (a)(27)(v) of 
this section.

    Dated: June 24, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-15410 Filed 6-29-16; 8:45 am]
 BILLING CODE 4164-01-P