[Federal Register Volume 81, Number 172 (Tuesday, September 6, 2016)]
[Rules and Regulations]
[Pages 61106-61130]
[FR Doc No: 2016-21337]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-1975-N-0012; Formerly Part of Docket No. 1975N-0183H]
RIN 0910-AF69

Safety and Effectiveness of Consumer Antiseptics; Topical
Antimicrobial Drug Products for Over-the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, we, or the Agency) is
issuing this final rule establishing that certain active ingredients
used in over-the-counter (OTC) consumer antiseptic products intended
for use with water (referred to throughout this document as consumer
antiseptic washes) are not generally recognized as safe and effective
(GRAS/GRAE) and are misbranded. FDA is issuing this final rule after
considering the recommendations of the Nonprescription Drugs Advisory
Committee (NDAC); public comments on the Agency's notices of proposed
rulemaking; and all data and information on OTC consumer antiseptic
wash products that have come to the Agency's attention. This final rule
amends the 1994 tentative final monograph (TFM) for OTC antiseptic drug
products that published in the Federal Register of June 17, 1994 (the
1994 TFM). The final rule is part of the ongoing review of OTC drug
products conducted by FDA.

DATES: This rule is effective September 6, 2017.

ADDRESSES: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number found in brackets in the heading of this final rule 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: Pranvera Ikonomi, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 5418, Silver Spring, MD 20993-0002, 240-
402-0272.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
    A. Terminology Used in the OTC Drug Review Regulations
    B. Topical Antiseptics
    C. This Final Rule Covers Only Consumer Antiseptic Washes
II. Background
    A. Significant Rulemakings Relevant to This Final Rule
    B. Public Meetings Relevant to This Final Rule
    C. Scope of This Final Rule
    D. Eligibility for the OTC Drug Review
III. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Description of General Comments and FDA Response
    C. Comments on Effectiveness and FDA Response
    D. Comments on Safety and FDA Response
    E. Comments on Individual Active Ingredients and FDA Response
    F. Comments on the Preliminary Regulatory Impact Analysis and
FDA Response
IV. Ingredients Not Generally Recognized as Safe and Effective
V. Effective Date
VI. Summary of Regulatory Impact Analysis
    A. Introduction
    B. Summary of Costs and Benefits
VII. Paperwork Reduction Act of 1995

VIII. Environmental Impact
IX. Federalism
X. References

Executive Summary

Purpose of the Final Rule

    This final rule finalizes the consumer antiseptic wash proposed
rule published in the Federal Register of December 17, 2013 (78 FR
76444) (2013 Consumer Wash Proposed Rule (PR)) and amends the 1994 TFM
for OTC antiseptic drug products that published in the Federal Register
of June 17, 1994 (59 FR 31402). The amendment 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). This final rule applies to consumer antiseptic wash products
that are intended for use with water and are rinsed off after use,
including hand washes and body washes.
    In response to several comments submitted to the 2013 Consumer Wash
PR, FDA has deferred further rulemaking on three specific active
ingredients used in OTC consumer antiseptic wash products to allow for
the development and submission of new safety and effectiveness data to
the record for these ingredients. The deferred active ingredients are
benzalkonium chloride, benzethonium chloride, and chloroxylenol.
Accordingly, FDA does not make a determination of general recognition
of safety and effectiveness for these three active ingredients in this
final rule. The monograph or new drug status of these three ingredients
will be addressed either after completion and analysis of ongoing
studies to address the safety and efficacy data gaps of these
ingredients or at a later date if these studies are not completed.
    With the exception of the three deferred consumer antiseptic wash
active ingredients, this rulemaking finalizes the nonmonograph status
of the remaining 19 active ingredients intended for use in consumer
antiseptic washes identified in the 2013 Consumer Wash PR. As
explained, either no additional data were submitted or the data and
information that were submitted were not sufficient to support
monograph conditions for these 19 consumer antiseptic wash ingredients.
Therefore, with the exception of the three deferred consumer antiseptic
wash active ingredients, this rule finalizes the 2013 Consumer Wash PR,
which proposed amending the 1994 TFM, with the remaining 19 consumer
antiseptic wash active ingredients found to be not GRAS/GRAE.
Accordingly, these 19 consumer antiseptic wash drug products are
misbranded under section 502 of the Federal Food, Drug, and Cosmetic
Act (the FD&C Act) (21 U.S.C. 352) and are new drugs under section
201(p) of the FD&C Act (21 U.S.C. 321(p)) for which approved
applications under section 505 of the FD&C Act (21 U.S.C. 355) and part
314 (21 CFR part 314) of the regulations are required for marketing.
    In separate rulemakings, we are proposing conditions under which
OTC consumer antiseptic rubs (products that are not rinsed off after
use, including hand rubs and antibacterial wipes) (81 FR 42912, June
30, 2016) and OTC antiseptics intended for use by health care
professionals in a hospital setting or other health care situation
outside the hospital (80 FR 25166, May 1, 2015) are GRAS/GRAE.
Accordingly, this final rule covers only OTC consumer antiseptic washes
that are intended for use as either a hand wash or a body wash, and
does not cover health care antiseptics (80 FR 25166), consumer
antiseptic rubs (81 FR 42912), antiseptics identified as ``first aid
antiseptics'' in the 1991 First Aid TFM (56 FR 33644), or antiseptics
used by the food industry. Those antiseptic products are not addressed
in this final rule.

Summary of the Major Provisions of the Final Rule

A. Effectiveness

    As explained in the 2013 Consumer Wash PR, a determination that an
active ingredient is GRAS/GRAE for a particular intended use requires a
benefit-to-risk assessment for that particular use of the ingredient.
If the active ingredient in a drug product carries the potential risk
associated with the drug (e.g., reproductive toxicity or
carcinogenicity), but does not provide a clinical benefit, then the
benefit-to-risk calculation shifts towards a not GRAS/GRAE status for
that drug. New information on potential risks posed by the use of
certain consumer antiseptic washes prompted us to reevaluate the data
needed for classifying consumer antiseptic wash active ingredients as
generally recognized as effective (GRAE). As a result, we proposed that
the risk from the use of a consumer antiseptic wash drug product must
be balanced by a demonstration--through studies that demonstrate a
direct clinical benefit (i.e., a reduction of infection)--that the
product is superior to washing with nonantibacterial soap and water in
reducing infection (78 FR 76444 at 76450).
    We have considered the recommendations from the public meetings
held by the Agency on antiseptics (see section II.B, table 2) and
evaluated the available literature, as well as the data, the comments,
and other information that were submitted to the rulemaking on the
effectiveness of the consumer antiseptic wash active ingredients
addressed in this final rule. The data and information submitted for
these active ingredients are insufficient to demonstrate that there is
any additional benefit from the use of these active ingredients in
consumer antiseptic wash products compared to nonantibacterial soap and
water. Consequently, the available data do not support a GRAE
determination for these consumer antiseptic wash active ingredients.

B. Safety

    As explained in the 2013 Consumer Wash PR, several important
scientific developments that affect the safety evaluation of consumer
antiseptic wash active ingredients have occurred since FDA's 1994
evaluation of the safety of consumer antiseptic active ingredients
under the OTC Drug Review. New data suggests that the systemic exposure
to these active ingredients is higher than previously thought, and new
information about the potential risks from systemic absorption and
long-term exposure is now available. New safety information also
suggests that widespread antiseptic use could have an impact on the
development of bacterial resistance. To support a classification of
generally recognized as safe (GRAS) for consumer antiseptic wash active
ingredients, we proposed that additional data was needed to demonstrate
that those ingredients meet current safety standards (78 FR 76444 at
76453 to 76458).
    The minimum data needed to demonstrate safety for all consumer
antiseptic wash active ingredients falls into three broad categories:
(1) Safety data studies described in current FDA guidance (e.g.,
nonclinical and human pharmacokinetic studies, developmental and
reproductive toxicity studies, and carcinogenicity studies); (2) data
to characterize potential hormonal effects; and (3) data to evaluate
the development of bacterial resistance.
    We have considered the recommendations from the public meetings
held by the Agency on antiseptics (see section II.B, table 2) and
evaluated the available literature, as well as the data, the comments,
and other information that were submitted to the rulemaking on the
safety of consumer antiseptic wash active ingredients addressed in this
final rule. The available information and published data for the 19
active

ingredients considered in this final rule are insufficient to establish
the safety of long-term, daily repeated exposure to these active
ingredients used in consumer wash products. Consequently, the available
data do not support a GRAS determination for the consumer antiseptic
wash active ingredients included in this rule.

C. Costs and Benefits

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

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                                                                  Total costs annualized
 Summary of the costs and benefits          Total benefits          over 10 years  (in     Total one-time costs
         of the final rule                                               millions)             (in millions)
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Total..............................  Reduced exposure to          $23.6 (at 3%).........  $106.3 to $402.8.
                                      antiseptic ingredients by   $27.6 (at 7%).........
                                      2.2 million pounds
                                      annually.
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I. Introduction

    In the following sections, we provide a brief description of
terminology used in the OTC Drug Review regulations, an overview of OTC
topical antiseptic drug products, and a more detailed description of
the OTC consumer antiseptic wash active ingredients that are the
subject of this final 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 advance notice of proposed
rulemaking that was published in the Federal Register of September 13,
1974 (39 FR 33103) (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) (1978
TFM), the Federal Register of June 17, 1994 (59 FR 31402) (1994 TFM),
and the Federal Register of December 17, 2013 (78 FR 76444) (2013
Consumer Wash PR) were each designated as a TFM (see table 1 in section
II.A).
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 resulted in an initial
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, the proposed rules (at the
tentative final monograph stage) used the concepts of Categories I, II,
and III.
    At this 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. The 1974 ANPR for topical antimicrobial products encompassed
products for both health care and consumer use (39 FR 33103). The ANPR
covered seven different intended uses for these products: (1)
Antimicrobial soap; (2) healthcare 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 first aid antiseptics in the Federal Register of July 22, 1991
(56 FR 33644). In section III.E, we address comments filed in this
rulemaking related to first aid antiseptics, but we do not otherwise
discuss first aid antiseptics further in this document. This final rule
does not have an impact on the monograph status of first aid
antiseptics.
    The four remaining categories of topical antimicrobials were
addressed in the 1994 TFM (59 FR 31402). 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). This final rule does not
have an impact on the monograph status of health care personnel hand
washes, patient preoperative skin preparations, or surgical hand
scrubs. 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). In section III.B.4, we address
comments filed in this rulemaking on antiseptics for use by the food
industry, but we do not otherwise further discuss these antiseptics in
this document. This final rule does not have an impact on the monograph
status of antiseptics for food industry use.
    In the 2013 Consumer Wash PR, we proposed that our evaluation of
OTC antiseptic drug products be further subdivided into health care
antiseptics and consumer antiseptics (78 FR 76444 at 76446). These
categories are distinct based on the proposed use setting, target
population, and the fact that each setting presents a different risk
for

infection. In the 2013 Consumer Wash PR (78 FR 76444 at 76446 to 76447)
and the consumer antiseptic rub proposed rule published in the Federal
Register of June 30, 2016 (81 FR 42912) (2016 Consumer Rub PR), we
proposed that our evaluation of OTC consumer antiseptic drug products
be further subdivided into consumer washes (products that are rinsed
off with water, including hand washes and body washes) and consumer
rubs (products that are not rinsed off after use, including hand rubs
and antibacterial wipes) (78 FR 764444 at 76447). Consumer antiseptic
wash products are intended to be used when soap and water are
available, whereas, consumer antiseptic rub products are intended to be
used when soap and water are unavailable, and thus, are left on and not
rinsed off. To account for the differences between consumer washes and
consumer rubs, the safety and effectiveness of the active ingredients
are being evaluated for each intended use separately. This final rule
does not have an impact on the monograph status of consumer antiseptic
rub products.

C. This Final Rule Only Covers Consumer Antiseptic Washes

    We refer to the group of products covered by this final rule as
``consumer antiseptic washes.'' Consumer antiseptic washes include a
variety of personal care products intended to be used with water, such
as antibacterial soaps, hand washes, and antibacterial body washes. As
discussed further in section III.B.3, these products may be used by
consumers for personal use in the home and public settings on a
frequent, daily basis. In the United States consumer setting, where the
target population is composed of generally healthy individuals, the
risk of infection and the scope of the spread of infection is
relatively low compared to the health care setting, where patients are
generally more susceptible to infection and the potential for spread of
infection is high.
    This final rule covers only OTC consumer antiseptic washes that are
intended for use as either a hand wash or a body wash, but that are not
identified as ``first aid antiseptics'' in the 1991 First Aid TFM (56
FR 33644), health care antiseptics (80 FR 25166), consumer antiseptic
rubs (81 FR 42912), or antiseptics used by the food industry. The
distinctions between consumer washes and rubs, and between consumer
hand washes and body washes are discussed in detail in the 2013
Consumer Wash PR (78 FR at 76446 to 76447) and the 2016 Consumer Rub PR
(81 FR 42912). Completion of the monograph for Consumer Antiseptic Wash
Products and certain other monographs for the active ingredient
triclosan is 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.).

II. Background

    In this section, we describe the significant rulemakings and public
meetings relevant to this rulemaking and discuss our response to
comments received on the 2013 Consumer Wash PR.

A. Significant Rulemakings Relevant to This Final Rule

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

B. Public Meetings Relevant to This Final 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 wash
safety and effectiveness. These meetings are summarized in table 2.

        Table 2--Public Meetings Relevant to Consumer Antiseptics
------------------------------------------------------------------------
   Date and type of meeting                Topic of discussion
------------------------------------------------------------------------
January 1997 NDAC Meeting       Antiseptic and antibiotic resistance in
 (Joint meeting with the Anti-   relation to an industry proposal for
 Infective Drugs Advisory        consumer and health care antiseptic
 Committee) (January 6, 1997,    effectiveness testing (Health Care
 62 FR 764).                     Continuum Model) (Refs. 1 and 2).
March 2005 NDAC Meeting         The use of surrogate endpoints and study
 (February 18, 2005, 70 FR       design issues for the in vivo testing
 8376).                          of health care antiseptics (Ref. 3).
October 2005 NDAC Meeting       Benefits and risks of consumer
 (September 15, 2005, 70 FR      antiseptics. NDAC expressed concern
 54560).                         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. 4).
November 2008 Public Feedback   Demonstration of the effectiveness of
 Meeting.                        consumer antiseptics (Ref. 5).
September 2014 NDAC Meeting     Safety testing framework for health care
 (July 29, 2014, 79 FR 44042).   antiseptic active ingredients (Ref. 6).
------------------------------------------------------------------------

C. Scope of This Final Rule

    This rulemaking finalizes the nonmonograph status for the 19 listed
consumer antiseptic wash active ingredients (see section II.D).
Requests were made that benzalkonium chloride, benzethonium chloride,
and chloroxylenol be deferred from inclusion in this consumer
antiseptic wash final rulemaking to allow more time for interested
parties to complete the studies necessary to fill the safety and
efficacy data gaps identified in the 2013 Consumer Wash PR for these
ingredients. In March 2016, we agreed to defer rulemaking on these
three ingredients (see Docket No. 1975-N-0012 at http://www.regulations.gov). Accordingly, in this final rulemaking we do not
discuss whether benzalkonium chloride, benzethonium chloride, and
chloroxylenol are GRAS/GRAE for use as active ingredients in consumer
antiseptic washes. The monograph or new drug status of these three
ingredients will be finalized either after completion and analysis of
ongoing studies to address the safety and efficacy data gaps of these
ingredients or at a later date if these studies are not completed.
    For the 19 active ingredients included in this final rule, either
no additional data were submitted since the 2013 Consumer Antiseptic
Wash PR, or the data and information that were submitted were
insufficient to support GRAS/GRAE findings. Therefore, these
ingredients are not included in a monograph at this time. These active
ingredients are not GRAS/GRAE for use in consumer antiseptic wash drug
products and products containing these ingredients are new drugs for
which approved new drug applications are required. Accordingly, FDA is
amending part 310 (21 CFR part 310) to add the active ingredients
covered by this final rule to the list in Sec.  310.545 (21 CFR
310.545) of OTC drug products that are not GRAS/GRAE and are misbranded
in the absence of an approved new drug application.

D. 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. 7).\1\ 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 must have actual product labeling or a facsimile of labeling
that documents the conditions of marketing of a product before 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 new drug application (NDA) process.
Ineligibility for use as a consumer antiseptic rub does not affect
eligibility under any other OTC drug monograph.
---------------------------------------------------------------------------

    \1\ 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).
---------------------------------------------------------------------------

1. Eligible Active Ingredients
    There are 19 of the antiseptic active ingredients eligible for the
OTC Drug Review for use as a consumer antiseptic wash that are
addressed in this final rule. These ingredients are:

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

    In the 2013 Consumer Wash PR, we describe the lack of adequate data
needed for a GRAS/GRAE determination for consumer antiseptic wash
active ingredients (78 FR 76444). As discussed in section II.C,
rulemaking has been deferred for three of the consumer antiseptic wash
active ingredients--benzalkonium chloride, benzethonium chloride, and
chloroxylenol. Accordingly, any references to consumer antiseptic wash
active ingredients refer only to the 19 consumer antiseptic wash active
ingredients listed in this section, unless otherwise stated.
2. Ineligible Active Ingredients
    In the 2013 Consumer Wash PR, we also identified certain active
ingredients

that were considered ineligible for evaluation under the OTC Drug
Review as a consumer antiseptic wash; but, we noted that if the
requested documentation for eligibility was submitted, these active
ingredients could be determined to be eligible for evaluation (78 FR
76444 at 76448). The active ingredients proposed to be ineligible in
the 2013 Consumer Wash PR were:

 Alcohol (ethyl alcohol)
 Benzalkonium cetyl phosphate
 Cetylpyridinium chloride
 Chlorhexidine gluconate
 Isopropyl alcohol
 Polyhexamethylene biguanide
 Salicylic acid
 Sodium hypochlorite
 Tea tree oil
 Combination of potassium vegetable oil solution, phosphate
sequestering agent, and triethanolamine

    We have not received any new information since the 2013 Consumer
Wash PR demonstrating that these active ingredients are eligible for
evaluation under the OTC Drug Review for use as a consumer antiseptic
wash. Consequently, drug products containing these active ingredients
are new drugs that will require FDA approval.

III. Comments on the Proposed Rule and FDA Response

A. Introduction

    In the 2013 Consumer Wash PR, interested parties were invited to
submit comments on the proposed rule by June 16, 2014. In addition,
interested parties had until December 16, 2014, to submit new data or
information to the docket, with 2 additional months provided to submit
comments on any new data or information submitted (78 FR 76444 at
76447).
    In response to the 2013 Consumer Wash PR, FDA received
approximately 40 comments from drug manufacturers, trade associations,
academia, testing laboratories, consumer groups, and health
professionals, as well as over 1,800 comments filed by individuals. FDA
also received additional data and information for certain consumer
antiseptic wash active ingredients.
    We describe and respond to the comments in section III.B through
III.F. We have numbered each comment to help distinguish between the
different comments. We have grouped similar comments together under the
same number, and in some cases, we have separated different issues
discussed in the same comment and designated them as distinct comments
for purposes of our responses. The number assigned to each comment or
comment topic is purely for organizational purposes and does not
signify the comment's value or importance or the order in which
comments were received.

B. Description of General Comments and FDA Response

1. Advance Notice of Proposed Rulemaking
    (Comment 1) Several comments asserted that the new efficacy testing
requirements proposed in the 2013 Consumer Wash PR were unprecedented.
They stated that given the significance of the proposed change to the
efficacy testing requirements for consumer antiseptics and the lack of
precedent for this action, FDA should withdraw the proposed rule and
reissue it as an ANPR to give industry and other stakeholders an
opportunity to engage with FDA on the GRAE testing requirements for the
active ingredients and surrogate endpoint testing of final
formulations.
    (Response 1) The purpose of an ANPR is to allow the public a period
of time to comment on regulations that the FDA may pursue as part of a
future rulemaking. As explained in section II.A, we issued an ANPR for
a monograph for OTC topical antimicrobial drug products in 1974, and a
proposed rulemaking in the form of a TFM in 1978. We have amended the
TFM for OTC topical antimicrobial drug products to address, for
example, different categories of topical antimicrobial drug products
and indications of use, as well as the need for new safety and
effectiveness data based on evolving scientific developments and new
information on risks associated with use of these drug products (59 FR
31402; 56 FR 33644; 78 FR 764444; 80 FR 25166; 81 FR 42912). For each
amendment, we have allowed interested parties to submit comments on the
proposals.
    In the 2013 Consumer Wash PR, we proposed that data from clinical
outcome studies (demonstrating a reduction in infections) are necessary
to support a GRAE determination for consumer antiseptic wash active
ingredients (78 FR 76444). We explained that, if the active ingredient
in a drug product does not provide clinical benefit but potentially
increases the risk associated with the drug (e.g., from reproductive
toxicity or carcinogenicity), then the benefit-to-risk calculation
shifts, and the drug is not GRAS/GRAE. For the consumer antiseptic wash
ingredients at issue here, because of new concerns about the potential
risks (e.g., resistance and hormonal effects), the log reduction
standard (a clinical simulation standard) proposed in the 1994 TFM,
which was based on an invalidated surrogate endpoint (i.e., number of
bacteria removed from the skin), is insufficient for establishing
effectiveness of consumer antiseptic washes. Therefore, we proposed
that clinical outcome studies were needed to demonstrate a direct
clinical benefit.
    This proposed effectiveness requirement is consistent with the
NDAC's recommendations from the October 2005 NDAC meeting regarding
consumer antiseptics (Ref. 4). The October 2005 NDAC concluded that the
existing test methods are based on the premise that bacterial
reductions translate to a reduced potential for infection, and,
although bacterial reduction can be demonstrated using tests that
simulate conditions of actual use, there are no corresponding clinical
data to demonstrate that bacterial reductions of the required magnitude
produce a corresponding reduction in infection. Accordingly, the
October 2005 NDAC recommended clinical outcome studies to demonstrate
the clinical benefit of consumer antiseptic wash active ingredients and
their superiority compared to a nonantibacterial wash, such as soap and
water. In October 2008, we also held a public feedback meeting to
discuss the demonstration of effectiveness of consumer antiseptic
active ingredients.
    At each stage of this process, interested parties have had an
opportunity to participate in these proceedings. It is not necessary
now to withdraw the 2013 Consumer Wash PR and reissue it as an ANPR.
    (Comment 2) Several comments argued that the 2013 Consumer Wash PR
should be reissued as an ANPR because the proposed rule only requests
testing on the active ingredients to demonstrate effectiveness and
fails to confirm whether the Agency will impose additional surrogate
efficacy requirements for a final formulation. The comments contended
that the Agency's approach is inconsistent with the approach taken in
the 1994 TFM and other OTC monographs.
    (Response 2) The issue of whether the 2013 Consumer Wash PR should
be reissued as an ANPR to include final product formulation testing
does not need to be addressed in this final rule because we have
determined that none of the active ingredients subject to this final
rule are GRAE for use as a consumer antiseptic wash. Final formulation
testing would be required for testing formulations containing active
ingredients that have been determined as GRAS/GRAE.

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

antiseptic hand wash products used in the food industry may, by
default, be subject to the requirements of the 2013 Consumer Wash PR.
They also requested that FDA clarify that hand wash products for use by
the food industry can continue to be marketed under the current
regulatory framework.
    (Response 6) As stated in the 2013 Consumer Wash PR and the 2015
Health Care Antiseptic PR, we continue to classify the food handler
antiseptic washes as a separate and distinct monograph category, and we
clarify that such products are not part of these rulemakings on the
consumer antiseptic monograph (78 FR 76444 at 76446; 80 FR 25166 at
25168). A separate category is warranted because of additional issues
raised by the public health consequences of foodborne illness,
differences in frequency and type of use, and contamination of the
hands by grease and other oils. We plan to address OTC antiseptic
products for use by the food handler industry in a separate
rulemaking.\2\ We plan to do a thorough evaluation of the safety and
effectiveness of antiseptic active ingredients intended for this
category of use. We also confirm that this final rule is not intended
to affect antiseptic products indicated for use by the food industry.
---------------------------------------------------------------------------

    \2\ The Personal Care Products Council and American Cleaning
Institute submitted a citizen petition in this rulemaking requesting
FDA action on issues related to food handler antiseptic wash
products. This citizen petition and other issues related to food
handler products will be addressed in future documents.
---------------------------------------------------------------------------

C. Comments on Effectiveness and FDA Response

1. Clinical Outcome Studies
    (Comment 7) Several comments challenged FDA's proposal that
clinical outcome studies be conducted to demonstrate the effectiveness
of the active ingredients for consumer antiseptic wash products, for
the following reasons: (1) Clinical outcome studies are unjustified and
not feasible; (2) the potential for antimicrobial resistance is
unfounded because there has been no demonstration of a scientifically
confirmed risk associated with the usage of consumer antiseptic
products; (3) FDA has not properly considered the potential risks
caused by lack of access to antibacterial products in consumers where
specific populations of consumers may be at increased risk of
infection; (4) the requirement for clinical outcome studies is far more
extensive than antiseptic requirements for consumer, food, or health
care antiseptics in other countries; and (5) simulation studies are a
valid and feasible way to determine efficacy because they have been
used since the publication of 1978 TFM, can be modified to include
additional controls and surrogate endpoints that would satisfy the
Agency's standards, and have been used to support approval of several
NDAs.
    (Response 7) In the 2013 Consumer Wash PR, we proposed that data
from clinical outcome studies (demonstrating a reduction in infections)
are necessary to support a GRAE determination for consumer antiseptic
wash active ingredients (78 FR 76444 at 76450). We explained that new
concerns about the potential risks (e.g., resistance and hormonal
effects) shifted the benefit-risk calculation. Therefore, the log
reduction standard (a clinical simulation standard) proposed in the
1994 TFM, which was based on an invalidated surrogate endpoint (i.e.,
number of bacteria removed from the skin), was insufficient for
establishing effectiveness of consumer antiseptic washes. The
requirement for clinical outcome studies is based on the fact that
sufficient data to clearly demonstrate the benefit from the use of
consumer antiseptic washes compared to nonantibacterial soap and water
are not available. Additionally, existing data cannot demonstrate a
correlation between log reductions of bacteria achieved by antiseptic
hand washing in surrogate testing and reduction of infection and, as
the October 2005 NDAC also concluded, the ability of consumer
antiseptic wash products to decrease bacteria on the skin is
insufficient for a GRAE finding if it is not supported by a direct
clinical benefit (Ref. 4). Hence, in general consumer settings where
soap and water are readily available the benefit of using an antiseptic
wash product must be supported by clinical outcome studies. The
efficacy requirements for consumer antiseptic washes differ from the
efficacy requirements proposed for consumer antiseptic rub products
because the wash products are intended to be used when soap and water
are not available (81 FR 42912) (2016 Consumer Rub PR). In addition,
the consumer antiseptic wash efficacy requirements differ from the
efficacy requirements for health care antiseptics used in a hospital
setting, where study design limitations and ethical concerns prevent
the use of clinical outcome studies (80 FR 25166 at 25175 to 25176).
    Moreover, as explained in the 2013 Consumer Wash PR, FDA's OTC
regulations (Sec.  330.10(a)(4)(ii)) define the standards for
establishing an OTC active ingredient as GRAE. These regulations
require the efficacy of active ingredients for OTC drug products be
demonstrated by controlled clinical trials (Sec. Sec.  330.10(a)(4)(ii)
and 314.126(b) (21 CFR 314.126(b)), unless this requirement is waived
as provided in Sec.  330.10(a)(4)(ii). These studies must be 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 (Sec.  314.126(a)).
    The requirement for controlled clinical trials also is consistent
with the recommendations of the October 2005 NDAC that clinical outcome
studies be used to demonstrate the clinical benefit of consumer
antiseptic wash products and their superiority compared to a
nonantibacterial wash, such as soap and water (Ref. 4). Although two
clinical outcome studies we identified in the 2013 Consumer Wash PR did
not demonstrate a benefit from the use of the tested antiseptic active
ingredient, these studies were randomized, blinded, and placebo-
controlled, and demonstrate that such clinical outcome studies are
feasible. For these reasons, FDA's requirement that clinical outcome
studies be conducted to demonstrate the effectiveness of the active
ingredients for consumer antiseptic wash products is warranted and
reasonable.
    (Comment 8) One comment also argued that FDA's requirement for
clinical outcome studies based on its concern about the potential for
increased antimicrobial resistance and endocrine disruption because of
use of consumer antiseptic wash active ingredients is unfounded. The
comment asserted that the requirement of clinical outcome studies is
not supported by any demonstration of a confirmed risk associated with
the use of consumer antiseptic products.
    (Response 8) We agree that the development of resistant mechanisms
in natural settings is not sufficiently studied. However, as discussed
in more detail in section III.D.2, the concerns regarding the extended
use of antiseptics, its potential consequences on the systemic
exposure, and its potential consequences on the development of
bacterial resistance, must be assessed. A GRAS/GRAE determination for
an active ingredient for a particular intended use requires a benefit-
to-risk assessment--in this case, the risk posed by use of a consumer
antiseptic wash drug product must be balanced by a demonstration that
the product is statistically significant (p-value <0.05) in reducing
infections compared to washing with nonantibacterial soap and water,
which refers to a soap formulation, solid or

liquid, that does not contain any antimicrobial ingredient.
    (Comment 9) Commenters also contend the Agency has not considered
the potential risks of an increase in infections among consumers by
their not having access to antibacterial product formulations and
commenters included publications in support of their position.
    (Response 9) Although the submitted publications demonstrate some
increase of infection in consumer settings, they do not address the
effectiveness of consumer antiseptic wash products in the prevention or
reduction of infections. The cited studies underscore the urgency of
scientifically demonstrating the contribution of consumer antiseptics
in lowering the infection rates in consumer settings. Although we
acknowledge that there may be populations with increased vulnerability
to bacterial infection, such as the elderly and persons with suppressed
immune systems, the data to support the benefit of the use of consumer
antiseptic wash products over that of nonantibacterial soap and water
in these populations is still lacking.
    (Comment 10) Several comments stated that the clinical outcome
requirements proposed in the 2013 Consumer Wash PR are more extensive
and demanding than requirements for establishing GRAE for active
ingredients in other OTC monographs, and more demanding than what is
required for antiseptics that are approved for use in other countries.
    (Response 10) Although the requirement for clinical outcome studies
for consumer antiseptic wash active ingredients may be a more stringent
requirement than is used by some other countries, FDA's proposed
effectiveness requirement is supported by FDA's regulations, the
recommendations of the October 2005 NDAC, as well as by available data
and publications studying the clinical outcome of antiseptics, all of
which support the requirement of clinical outcome studies (Refs. 8 and
9). Moreover, the existence of published studies demonstrates that
clinical outcome studies are feasible. For the reasons explained in
this section, clinical outcome studies are necessary to assure that the
potential risk from use of consumer antiseptic wash products is
balanced by a demonstrated clinical benefit.
    (Comment 11) Several comments argued that clinical simulation
studies are a valid way to demonstrate efficacy and that the log
reduction of bacteria on skin proposed to demonstrate efficacy since
the 1978 TFM, has been used to support the approval of several NDAs.
The comments also proposed that clinical simulation studies can be
modified to include additional controls and neutralizers to satisfy the
Agency's requirements. The comments stated that neutralization
solutions are already included in the American Society for Testing and
Materials (ASTM) \3\ E1174 ``Standard Test method for Evaluation of the
Effectiveness of Health Care Personnel Hand Wash Formulations,'' and a
vehicle control and an active control such as Hibiclens 4 percent could
also be included in clinical simulation studies.
---------------------------------------------------------------------------

    \3\ General information about ASTM can be found at https://www.astm.org/.
---------------------------------------------------------------------------

    (Response 11) We agree that clinical simulation studies and
surrogate endpoints have been used since the publication of the 1978
TFM (43 FR 1210) and continued to be a requirement for demonstrating
effectiveness in the 1994 TFM (59 FR 31402). As addressed in the 2015
Health Care Antiseptic PR (80 FR 25166), we will continue to evaluate
the effectiveness of health care antiseptic products based on both in
vitro testing and clinical simulation studies. However, the ethical
concerns and challenges of designing clinical trials in the hospital
setting do not apply to the consumer antiseptic wash setting, where
washing with soap and water is a readily available alternative for
consumers, and clinical trials to demonstrate clinical superiority are
ethical and feasible.
    With respect to approved marketing applications, we note that the
Agency has not approved any applications for consumer antiseptic wash
products since the publication of the 1994 TFM. The approved NDA
products for which evaluation of efficacy is based on in vitro testing
results and clinical simulation studies have been for antiseptic
products used in the health care setting.
    Moreover, although the addition of vehicle and active controls, as
well as the inclusion of neutralization solutions in the test method,
may increase the accuracy of the testing itself, it does not meet the
requirement of establishing a direct connection between the use of
consumer antiseptic wash active ingredients and infection reduction in
a general consumer setting. A surrogate study, with or without
additional controls, is founded on the premise that reduction of
bacteria on skin because of use of a consumer antiseptic active
ingredient (or product) will result in reduction of infections, but it
is not a direct proof of reduced infections. While we continue to
propose the use of surrogate endpoints as a demonstration of
effectiveness for health care antiseptics and consumer antiseptic rubs,
the reasons for those different requirements, such as the challenges of
conducting such studies in the health care setting, and the fact that
consumer rubs, which are intended for use when soap and water is
unavailable, do not apply to consumer antiseptic wash products used in
general consumer settings. In addition, the infection risk in
healthcare settings is greater than in consumer settings, and as such,
a clinical outcome study for healthcare antiseptics raises ethical
questions regarding the use of non-antimicrobial vehicle in patients.
Studying the effectiveness of consumer wash antiseptics via clinical
outcome studies in consumer settings is not unethical and, as
previously shown, it is feasible (Refs. 8 and 9).
    As stated in the 2013 Consumer Wash PR, we have evaluated all
clinical simulation studies that were submitted to the OTC Drug Review
for evidence of antiseptic consumer wash active ingredient
effectiveness demonstrated under the log reduction criteria (78 FR
76444 at 76451). We also evaluated the publications referenced in the
comments submitted in response to the 2013 Consumer Wash PR. The
studies described in the referenced publications lack the appropriate
controls of a clinical outcome study, so we cannot, without additional
evidence, attribute the reduction of infection rates to the use of
antiseptic consumer wash active ingredients (Refs. 10 and 11). In sum,
the studies we have evaluated are not adequately controlled to support
an accurate assessment of the effectiveness of consumer antiseptic wash
active ingredients.
    A demonstration of the effectiveness of the active ingredients used
in consumer antiseptic wash products should result from robust,
properly designed, randomized studies with adequate numbers of subjects
and clearly defined endpoints and analysis, using reduction in
infection rates rather than reduction in pathogen counts. For the
reasons discussed in this section and in the 2013 Consumer Wash PR,
adequate clinical outcome studies that identify the conditions of use
on which an antiseptic active ingredient can demonstrate a reduction in
the number of infections, are required to demonstrate the GRAE status
of consumer antiseptic wash active ingredients.
2. Testing of the Active Ingredient
    (Comment 12) Several comments argued that the testing of the active
ingredients rather than testing of final

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

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

adequate clinical outcome studies that identify conditions of use under
which an antiseptic wash active ingredient is capable of reducing the
number of infections. The data demonstrating the effectiveness of the
active ingredients used in consumer antiseptic wash products should
result from robust, properly designed, randomized studies with adequate
numbers of subjects and clearly defined endpoints and analysis,
assessing reduction in infection rates rather than reduction in
pathogen counts.
5. American Society for Testing and Materials Standard Methods
    (Comment 16) Several comments addressed the test methods for
demonstration of effectiveness for final product formulations and
proposed that the Agency recognize several ASTM test methods for
determination of effectiveness for final product formulations,
including the ASTM E1174 ``Standard Test Method for Evaluation of the
Effectiveness of Health Care Personnel Hand Wash Formulations,'' the
ASTM E2784 ``Standard Test Method for Evaluation of the Effectiveness
of Hand Wash Formulations Using the Paper Towel (Palmar) Method of Hand
Contamination,'' the ASTM E1874 ``Standard Test Methods for Recovery of
Microorganisms From Skin Using the Cup Scrub Technique,'' and the ASTM
E2783 method ``Standard Test Method for Assessment of Antimicrobial
Activity for Water Miscible Compounds Using a Time-Kill Procedure.''
    (Response 16) As discussed in section IV, none of the active
ingredients subject to this final rule have been found to be GRAE for
use in a consumer antiseptic wash product. We will evaluate the GRAS/
GRAE status of the three deferred active ingredients either upon
completion and analysis of all safety and effectiveness studies
required for these ingredients or at a later date if these studies are
not completed (78 FR 76444 at 76458). For these reasons, it is
premature to discuss final product formulation testing requirements
before a decision is made on the adequacy of data to provide to support
monograph status of the three deferred active ingredients.
    We note, however, that the suggestion to accept the ASTM test
methods used in clinical simulation studies for final product
formulation testing is based on the assumption that for the consumer
antiseptic wash active ingredients for which clinical outcome studies
will demonstrate effectiveness, only antibacterial claims would be
supported. The guidelines for clinical outcome study design provided by
the Agency with regard to the three deferred consumer antiseptic wash
active ingredients allow for demonstration of reduction of infections
of either bacterial or viral origin. If the clinical outcome studies
demonstrate that these active ingredients can reduce infections of
origin other than bacterial (i.e. viruses), additional testing to
further characterize the activity of these ingredients must be
determined. Therefore, testing requirements for final product
formulation cannot be finalized before we have made a determination
that a deferred active ingredient is GRAE. Depending on the
indication(s) supported by clinical outcome studies for an active
ingredient, additional final product formulation testing, other than
the ASTM methods suggested, may be required.

D. Comments on Safety and FDA Response

1. Additional Safety Testing Requirements
    (Comment 17) One comment stated that before proposing new safety
testing, FDA must consider the actual risks. The comment argued that if
current product exposures do not present risk based on the existing
data, new data should not be required. The comment further recommended
that existing data should be reviewed in relation to increased risk
rather than increased analytic sensitivity and that if FDA finds that
there is no demonstration of risk, FDA should conclude that the active
ingredients and formulations are safe.
    (Response 17) We decline to withdraw our requirement in the 2013
Consumer Wash PR for the additional safety data that we determined is
necessary to support a GRAS classification for the consumer antiseptic
wash active ingredients. As explained in the 2013 Consumer Wash PR,
several important scientific developments that affect the safety
evaluation of the consumer antiseptic wash active ingredients have
occurred since FDA's 1994 evaluation. New data and information on the
antiseptic wash active ingredients raise concerns regarding potential
risks from systemic absorption and long-term exposure, as well as
development of bacterial resistance related to use of consumer
antiseptic washes (78 FR 76444 at 76445). The data required by the 2013
Consumer Wash PR is necessary for FDA to conduct an adequate safety
evaluation. The comments do not provide sufficient data to support a
determination that these consumers antiseptic wash active ingredients
can be classified as GRAS.
2. Resistance
    (Comment 18) Numerous comments relating to the issue of bacterial
resistance were submitted in response to the 2013 Consumer Wash PR.
Some comments argued that the pervasive use of consumer antiseptics
poses an unacceptable risk for the development of resistance and that
these products should be removed from the market. Other comments
disagreed and criticized the data on which they believe FDA has based
its concerns.
    Specifically, several comments dismissed the in vitro data cited by
FDA in the 2013 Consumer Wash PR as not reflecting real-life
conditions. The comments recommended that the most useful assessment of
the risk of biocide resistance and cross-resistance to antibiotics are
in-situ studies, studies of clinical and environmental strains, or
biomonitoring studies. Some comments asserted that studies of this type
have reinforced the evidence that resistance and cross-resistance
associated with antiseptics is a laboratory phenomenon observed only
when tests are conducted under unrealistic conditions. Another comment
cited the conclusions of an International Conference on Antimicrobial
Research held in 2012 on a possible connection between biocide
(antiseptic or disinfectant) resistance and antibiotic resistance to
support the point that there is no correlation between antiseptic use
and antibiotic resistance (Ref. 16).
    (Response 18) Laboratory studies have identified and characterized
bacterial resistance mechanisms that confer a reduced susceptibility to
antiseptics and, in some cases, clinically relevant antibiotics (Refs.
17 through 27). Bacteria expressing these resistance mechanisms with a
decreased susceptibility to antiseptics have been isolated from a
variety of natural settings (Refs. 28 through 30). These studies found
that the prevalence of antiseptic tolerant subpopulations in the
natural microbial populations studied is currently low. Morrissey et
al. concluded, however, that their study findings could not rule out
the existence of other resistant isolates that could be found if more
isolates were analyzed.
    In general, studies have not clearly demonstrated an impact of
antiseptic bacterial resistance mechanisms in the natural setting.
However, the available studies have limitations. As FDA noted in the
2013 Consumer Wash PR, studies in a natural setting that it evaluated
were limited by the small numbers and types of organisms, the brief
time

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

submitted no data to support its assertion, but asserted that there is
a need for research to clarify whether the bacterial composition of
immunocompromised individuals is adequately represented by the bacteria
identified for testing in the proposed rule. The comment also suggested
that there may be an additional need to perform surveillance of the
effects seen in the immunocompromised after the use of consumer
antiseptics for increased risk of bacterial resistance, because this
has been demonstrated in clinical settings. Another comment recommended
that FDA require that manufacturers establish and maintain active
surveillance of this issue and require that this information be
submitted to FDA every year.
    (Response 20) We acknowledge that there are segments of the general
population that may be more at risk from antiseptic/antibiotic cross-
resistance and that further research is needed to address this facet of
this issue. However, because no monograph is being established for the
consumer antiseptic wash active ingredients in this final rule, the
requests for an FDA requirement for active surveillance of this issue
do not apply for purposes of this final rule.
3. Alternatives to Animal Studies
    (Comment 21) One comment requested that FDA provide guidance on how
to reduce the use of animals in testing done to assess the safety of
consumer antiseptic washes. The comment recommended that FDA require
manufacturers to conduct efficacy testing in humans before safety
testing in animals and to share the data resulting from any animal
testing they conduct. The comment also recommended that FDA accept data
from non-animal safety tests.
    In addition, the comment recommended that FDA reduce the number of
rodent cancer bioassays required, by allowing for the extrapolation of
data from the dermal route of administration to the oral route, and
from the oral route to the dermal route. The comment requested that FDA
consider whether physiologically based toxicokinetic modeling (PBTK),
along with certain non-animal in vivo and in vitro absorption,
distribution, metabolism, and excretion (ADME) data, could support
route-to-route extrapolation. The comment further recommended that FDA
adopt in vitro testing strategies to replace testing using animal
models. Lastly, the comment stated that FDA should require
manufacturers to share the data resulting from any animal testing they
conduct.
    (Response 21) The required number of rodent cancer bioassay studies
have in some cases been reduced for drug products; for instance, a
waiver of dermal carcinogenicity may be considered for a substance used
previously by another route if a chronic dermal study in an appropriate
non-rodent species shows no potential neoplastic effects and there are
no other causes for concern, such as absence of a positive genotoxicity
signal and absence of association of exposure to the drug with a
positive tumor signal in systemic carcinogenicity data (Refs. 45 and
46). However, at this point, the Agency has not adopted a policy
regarding the use of route to route extrapolation method using
alternatives to animal testing such as in vitro data, ADME and PBTK
tools.
    We understand that animal use in tests for the efficacy and safety
of human and animal products has been and continues to be a concern. 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.
    However, there are still many areas where animal testing is
considered necessary and non-animal testing is not yet a fully
available option. FDA continues to support efforts to reduce animal
testing, particularly whenever new alternative methods for safety
evaluation have been validated and accepted by International Council on
Harmonization (ICH) regulatory authorities, but these efforts have not
yet resulted in the development of alternative testing that eliminate
animal testing altogether. We will not be discussing further in this
final rule the specific issues raised in the comments on animal testing
because these issues are outside the scope of this rulemaking.
    With respect to the recommendation that FDA require manufacturers
to share the data resulting from any animal testing they conduct, FDA
regulations require that data and information relevant to the monograph
and a GRAS/GRAE determination be submitted to the docket for that
monograph and made publicly available (Sec.  330.10(a)(2)).
Accordingly, any such animal testing data should be publicly available
and can be obtained from the docket for this rulemaking. We also note
that although there is a process for submitting confidential
information, the OTC drug monograph process is generally a public
process. The Agency considers either non-confidential material that is
submitted to the docket or information that is publicly available when
making its evaluation of whether a given ingredient is GRAS/GRAE.

E. Comments on Active Ingredients and FDA Response

1. Ethanol
    (Comment 22) A comment was submitted to this docket regarding the
GRAS status of ethanol.
    (Response 22) This active ingredient is not marketed as a consumer
antiseptic wash product, and, therefore is not addressed. We will
address this comment, and any other comments regarding the GRAS status
of ethanol, to the extent that it applies to indications reviewed in
the 2015 Health Care Antiseptic PR and the 2016 Consumer Rub PR.
2. Cetylpyridinium Chloride
    (Comment 23) As noted in the 2013 Consumer Wash PR, subsequent to
the 1994 TFM we received requests that certain active ingredients be
added to the antibacterial monograph (78 FR 764444 at 76448). One of
these submissions included a citizen petition that requested that we
allow the use of cetylpyridinium chloride as an antibacterial active
ingredient for household liquid soap (Ref. 47).
    (Response 23) In the 2013 Consumer Wash PR, we identified certain
active ingredients, including cetylpyridinium chloride that we
considered ineligible for evaluation under the OTC Drug Review as a
consumer antiseptic wash. We noted that if the requested documentation
for eligibility was submitted, these active ingredients, including
cetylpyridinium chloride, could be determined to be eligible for
evaluation (78 FR 76444 at 76448). Neither the citizen petition, nor
other submissions we have received in this rulemaking, include
documentation demonstrating the eligibility of cetylpryridinium
chloride for evaluation under the OTC Drug Review for use as a consumer
antiseptic wash. Consequently, this citizen petition is denied and as
indicated in section II.D, we consider consumer antiseptic wash
products containing cetylpyridinium chloride to be new drugs that
require FDA approval through the NDA process.
3. Hexylrescorinol
    In the 2013 Consumer Wash PR, FDA proposed to classify
hexylresorcinol as Category III for both safety and efficacy (78 FR
76444 at 76458). FDA determined that the administrative record for the
safety of hexylresorcinol

was incomplete with respect to the following:

 Human pharmacokinetic studies under the maximal use conditions
when applied topically, including documentation of validation of the
methods used to measure hexylresorcinol and its metabolites
 Animal pharmacokinetic studies on ADME
 Data to help define the effect of formulation on dermal
absorption
 Dermal carcinogenicity
 Developmental and reproductive toxicity (DART) data
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the
development of resistance to hexylresorcinol and cross-resistance to
antibiotics in the types of organisms listed in section VII.C.3 of the
2013 Consumer Wash PR (78 FR 76444 at 76457)

    (Comment 24) One comment referenced a 13-week oral toxicology study
from the National Toxicology Program (NTP) conducted in rats, in which
there were reports of reduction in the size of seminal vesicles and
hypospermatogenesis (abnormally low sperm production). The comment
asserted that FDA should evaluate these effects on the male rat
reproductive organs to fill the DART data gap for hexylresorcinol.
    (Response 24) Although this technical report was cited in the 2013
Consumer Wash PR (78 FR 76444 at 76475, Ref. 120) for hexylresorcinol,
the data in this 13-week study is not sufficient to conduct an adequate
DART assessment for hexylresorcinol (Ref. 48). Specifically, the NTP
report described toxicity and carcinogenicity studies of
hexylresorcinol. The report consisted of three sets of studies, 16-day
studies, 13-week studies, and 2-year studies, all conducted in mice and
rats of both sexes. Although the findings in the 13-week studies appear
to show an effect of hexylresorcinol on the reproductive system in
high-dose male rats, according to the NTP report, there was no
difference in the reproductive findings between controls and high-dose-
treated males. No adverse findings were noted for the reproductive
organs examined in males and females treated with high doses of
hexylresorcinol in the 2-year carcinogenicity studies in rats and mice.
However, the findings from the general toxicity studies (13-week and 2-
year carcinogenicity studies) do not address all relevant reproductive
and developmental endpoints for hexylresorcinol. Accordingly, we find
that the safety data gap for DART for hexylresorcinol has not been
adequately addressed. No new data were submitted to the docket to fill
other safety data gaps identified in the 2013 Consumer Wash PR. In
addition, as discussed in section IV of this document, no new data were
submitted to the docket to demonstrate the effectiveness of the active
ingredients subject to this final rule, including hexylresorcinol, for
use as a consumer antiseptic wash product. Therefore, hexylresorcinol
is not GRAS/GRAE for use in consumer antiseptic wash products.
4. Iodophors/Povidone-Iodine
    In the 2013 Consumer Wash PR, we proposed to classify iodophor
complexes, including povidone-iodine, 5-10 percent, as Category III,
determining that the available safety and effectiveness data were
insufficient and further testing was required (78 FR 76444 at 76459).
FDA determined that the administrative record for the safety of
iodophors was incomplete with respect to the following:

 Human studies of the absorption of iodine following maximal
dermal exposure to the complexes
 Human absorption studies of the carrier molecule for small
molecular weight povidone molecules and the other carriers listed in
the 2013 Consumer Wash PR
 Dermal carcinogenicity studies for each of the iodophor
complexes
 Data from laboratory studies that assess the potential for the
development of resistance to iodine and cross-resistance to antibiotics
in the types of organisms listed in the 2013 Consumer Wash PR (78 FR
76444 at 76453)

    (Comment 25) One comment requested that the Agency clarify that
multiuse consumer antiseptic products containing the active ingredient
povidone-iodine intended for first aid use and general purpose
antiseptic cleansing and labeled for only short-term use over limited
areas of the skin are outside the scope of the 2013 Consumer Antiseptic
PR. The comment explained that the skin cleanser's primary use is as a
first aid antiseptic and it is sold in the first aid aisle of retail
stores. They also explained that although the labeling provides for
uses as a wash, it recommends only short term use over limited areas of
the skin, consistent with the 1991 First Aid TFM; and thus, the safety
studies proposed in the 2013 Consumer Wash PR should not be required
for such multiuse skin cleansing products. The comments also requested
that if FDA determines that multiuse antiseptic products are within the
scope of the 2013 Consumer Wash PR, that a category I classification be
maintained for povidone-iodine, 5-10 percent, with a molecular weight
at or above 35,000 Daltons.
    (Response 25) The testing requirements for a GRAS/GRAE finding as
proposed in the 2013 Consumer Wash PR, apply to all consumer antiseptic
wash products containing the active ingredients that are the subject of
this final rule and that are intended to be used with water, such as
antibacterial soaps and antibacterial hand washes (76 FR 76444 at
76446). If the labeling for these products contains an indication for
use as a consumer antiseptic wash, then the product is subject to the
testing requirements of the 2013 Consumer Wash PR, even if the labeling
also contains an indication for other uses, such as for a first aid
antiseptic.
    Moreover, because consumer antiseptic washes may be used on
multiple occasions throughout a person's lifetime, this use pattern is
considered to be chronic. According to the International Council for
Harmonization guideline, a use is considered chronic if a certain drug
is used for a period of at least 6 months over the user's lifetime,
including repeated, intermittent use. Thus, chronic exposure testing is
necessary for a GRAS/GRAE determination for the active ingredients used
in these consumer antiseptic wash products even if a particular
ingredient's labeling recommends that the product's use should be
limited in duration.
    In addition, we decline to classify povidone-iodine 5-10 percent
with a molecular weight at or above 35,000 Daltons as Category I (GRAS/
GRAE) for use in consumer washes. Although we stated in the 2013
Consumer Wash PR that the larger molecular weight-size povidone
molecules pose no risk of absorption, and we only requested human
absorption studies of the carrier molecule for small molecular weight
povidone molecules, there are still remaining safety data gaps for the
iodophors, including large molecule povidone-iodine (76 FR 76444 at
76459 to 76461). For example, we determined that the administrative
record for the safety of iodophors was incomplete for dermal
carcinogenicity studies. Accordingly, because the safety data gaps have
not been addressed, we cannot make a GRAS determination on the
iodophors, including the large molecule povidone-iodine.
    (Comment 26) Another comment stated that human absorption data
required for the iodophors should take precedence over the requirement
for dermal carcinogenicity studies to fill the

safety data gaps for the iodophors. The comment argued that data from
the human absorption studies may reduce the number of carcinogenicity
studies needed to fill the safety data gaps for iodophors.
    (Response 26) Antiseptic products, such as povidone-iodine, are
applied topically and require toxicological evaluation in dermal
studies to assess the potential safety signals following the exposure.
The reason for requiring dermal assessment is because the skin dose
resulting from a topically applied drug product can be much higher than
the dose detected in the skin as a result of systemic exposure. In
addition, systemic exposure to the parent drug and metabolites can
differ significantly in topically applied products compared to orally
administered products because the skin has its own metabolic
capability, and the first-pass metabolism, which is available following
oral exposure, is bypassed in the topical route of administration. In
some cases, a waiver of dermal carcinogenicity may be considered for a
substance used previously by another route if a chronic dermal study in
an appropriate non-rodent species shows no potential neoplastic effects
and there are no other causes for concern, such as absence of a
positive genotoxicity signal and absence of association of exposure to
the drug with a positive tumor signal in systemic carcinogenicity data
(Refs. 45 and 46). Furthermore, the absence of significant systemic
absorption is not a qualifying reason to waive the requirement for the
dermal carcinogenicity study.
    (Comment 27) A comment submitted on behalf of a marketer of an OTC
antiseptic product containing povidone-iodine asserted that povidone-
iodine does not pose a risk for the development of resistance (see
section III.D.2 for a more general discussion on resistance). The
comment noted that none of the studies cited in the 2013 Consumer Wash
PR concerning the development of antiseptic/antibiotic resistance
involve povidone-iodine. The comment stated that historically,
povidone-iodine has not been associated with the development of
resistance, and that it has been found to be a useful tool against
several multidrug resistant bacteria. In support of its position, the
comment submitted data on the chemistry and antimicrobial effects of
povidone-iodine and studies of povidone-iodine's in vitro and in vivo
effectiveness (Refs. 49 through 54).
    (Response 27) Elemental iodine, which is the active antimicrobial
component of iodine containing antiseptics like povidone-iodine, is
generally believed to be nonspecific in its antimicrobial action (Ref.
55). The antimicrobial activity of iodine is caused by its oxidizing
effects on amino (NH-), thiol (SH-), phenolic hydroxyl (OH-) groups of
amino acids and nucleotides. These reactions lead to a loss in protein
structure and function and an inhibition of protein synthesis. Iodine
also reacts with the double bonds of unsaturated fatty acid components
of cell wall and organelle membranes, compromising the integrity of
these structures. The effects of povidone-iodine on cell ultrastructure
have been observed at concentrations as low as 0.025 percent povidone-
iodine in Staphylococcus aureus, Esherichia coli, and Candida albicans
(Ref. 49). A decrease in enzyme ([beta]-galactosidase) activity and
nucleotide efflux was also apparent at 0.42 and 0.83 percent povidone-
iodine (Ref. 49). These concentrations are well below the
concentrations of povidone-iodine found in currently marketed products.
    A search of the published literature revealed two studies that
attempted to select for resistant bacterial strains after repeated
exposure to sublethal concentrations of povidone-iodine (Refs. 56 and
57). Houang et al. studied the potential for the development of
resistance to povidone-iodine by serial passage of two strains of each
of the following organisms: Escherichia coli, Klebsiella aerogenes, and
one strain of Serratia marcescens in sub-inhibitory concentrations
(Ref. 56). The authors reported no significant differences in MIC,
minimum bactericidal concentration, or killing time after 20 passages.
Similarly, Prince et al. reported that they had failed to detect any
changes in the MIC of six Gram-negative bacteria (Proteus mirabilis,
Serratia marcescens, Serratia rubidaea, Pseudomonas cepacia (now known
as Burkholderia cepacia), Pseudomonas aeruginosa, and Salmonella
enteritidis) after 20 serial passages in povidone-iodine (Ref. 57).
    The search also revealed some reports of Burkholderia cepacia
contamination of povidone-iodine products (Refs. 58 through 62).
However, the antiseptic susceptibilities of the organisms isolated were
never established, making it hard to determine whether the
contamination was the result of an existing intrinsic antiseptic
resistance that has been associated with Burkholderia cepacia or the
development of an increased tolerance. In addition, the literature
search revealed no reports of the development of resistance to
povidone-iodine. Consequently, given iodine's multiple nonspecific
toxic effects on bacteria at low concentrations and the lack of reports
of the development of resistance to iodine, there currently are
insufficient data on which to base a concern about the development of
resistance to povidone-iodine. Consequently, additional data on the
development of antimicrobial resistance to povidone-iodine are not
needed to make a GRAS determination.
5. Triclocarban
    In the 2013 Consumer Wash PR, FDA proposed to classify triclocarban
as Category III for safety and efficacy (78 FR 76444 at 76449). FDA
determined that the administrative record for the safety of
triclocarban was incomplete with respect to the following:

 Human pharmacokinetic studies under the maximal use conditions
when applied topically, including documentation of validation of the
methods used to measure triclocarban and its metabolites
 Animal pharmacokinetic studies on ADME
 Data to help define the effect of formulation on dermal
absorption
 Dermal carcinogenicity
 Developmental and reproductive toxicity data
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the
development of resistance to triclocarban and cross-resistance to
antibiotics in the types of organisms listed in section VII.C.3 of the
2013 Consumer Wash PR (78 FR 76444 at 76456 to 76462)

    (Comment 28) One comment referenced a DART study conducted by
Monsanto in 1979. The study was summarized in a triclocarban data set
compiled in 2002 by the Triclocarban (TCC) Consortium and the Soap and
Detergent Association. The comment requested that FDA evaluate the
results of the study to fill the DART safety gap for triclocarban.
    (Response 28) The TCC Consortium Report was retrieved from the
Environmental Protection Agency (EPA) High Production Volume
Information System Web site. We were unable to locate the 1979 Monsanto
study in the docket and it does not appear to be available in the
public domain. Thus, we cannot review this study for purposes of this
final rule. The data cited in the TCC Consortium data set are
proprietary and are publicly available only in the form of a summary
(Ref. 63). In addition, the submitted safety assessments with the 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

the safety of triclocarban for this rulemaking, there must be published
studies or publicly available data with sufficient details that enable
an independent review of such data.
    (Comment 29) One comment also stated that triclocarban was
nominated to the NTP for toxicological evaluation in 2014, and based on
this nomination, a Research Concept has been adopted by NTP (Ref. 64).
The comment asserted that the author of the Triclocarban Research
Concept only discussed FDA's proposal in regard to human absorption
studies even though it identified several data gaps that were
identified by FDA, including ADME and DART studies. The comment
concluded that FDA should coordinate its efforts with those of the NTP
to ensure that experiments on the toxicological testing of triclocarban
are not being duplicated.
    (Response 29) We concur with the comment that FDA should coordinate
efforts with NTP. NTP through collaboration with FDA regularly meets
with FDA scientists to coordinate research efforts and eliminate
duplicative work whenever possible. Although this ongoing study may
provide important information on triclocarban, there are still other
missing data gaps for triclocarban for which information has not been
submitted and no interested parties have committed to filling these
data gaps. Accordingly, deferring consideration of this active
ingredient until the study is completed is unwarranted.
    In conclusion, we find that the safety data gap for DART for
triclocarban has not been adequately addressed. No new data for
triclocarban were submitted to the docket to fill other safety data
gaps identified in the 2013 Consumer Wash PR. In addition, as discussed
in section IV, no new data were submitted to the docket to demonstrate
the effectiveness of the active ingredients subject to this final rule,
including triclocarban, for use as a consumer antiseptic wash product.
Therefore, triclocarban is not considered GRAS/GRAE for use in consumer
antiseptic wash products.
6. Triclosan
    In the 2013 Consumer Wash PR, the Agency found that the
administrative record for triclosan was incomplete with respect to
several safety data and requested that additional information be
submitted for the following safety gaps (76 FR 76444 at 76467 to
76470):

 Animal ADME
 Dermal carcinogenicity
 Data regarding the potential for formation of photodegradation
products on human skin and their effects on the skin
 Potential hormonal effects
 Data to clarify the relevance of antimicrobial resistance
laboratory findings to the consumer setting

    (Comment 30) In response to the 2013 Consumer Wash PR, several
comments were submitted regarding the safety data gaps for triclosan.
One comment argued that recent and existing studies on triclosan in
each of the safety categories prove that the existing studies,
including additional studies that were not cited in the 2013 Consumer
Wash PR, are adequate to classify triclosan as GRAS.
    (Response 30) FDA has conducted a thorough review of all existing
and new data that have been submitted to the docket for this
rulemaking, including recent studies, as well as opinion papers
published by other regulatory agencies regarding the safety of
triclosan. In some cases, we identified new data that have been
published since the 2013 Consumer Wash PR--for example, the new animal
ADME dermal data discussed in the following section. In other cases, no
new data having an impact on the safety profile of triclosan were
identified--for example, we found that certain references submitted in
one of the comments did not provide additional information that would
have an impact on the safety assessment of triclosan (Refs. 65 through
67). In sum, the total available data regarding the safety profile of
triclosan does not contain sufficient information to determine that
triclosan is GRAS for use in consumer antiseptic wash products.
    In the following sections, we discuss comments addressing the
specific safety data gaps for triclosan.
a. Absorption, Distribution, Metabolism, and Excretion (ADME) Data
    The 2013 Consumer Wash PR discussed in detail the animal ADME data
available for triclosan (78 FR 76444 at 76467) and the data that were
still lacking. FDA requested that additional ADME data be submitted to
allow bridging of animal data to human exposure.
    (Comment 31) Several comments were submitted regarding animal ADME
data for triclosan. Some of the comments asserted that oral absorption,
metabolism, and excretion are comparable between hamsters and humans,
justifying data extrapolation. They also asserted that oral absorption
data are complete in all species tested and that metabolism is similar
for both dermal and oral exposure. In addition, some of the comments
urged FDA to evaluate key toxicokinetic studies in hamsters, mice, and
rats that have been submitted as part of the European Union's
Registration, Evaluation, Authorisation, and Restriction of Chemicals
registration, as well as evaluate other referenced publications of
regulatory agencies.
    (Response 31) We agree that there are a number of similarities in
pharmacokinetic parameters between humans and hamsters; however, the
hamster data available do not include dermal ADME data that can be
compared to the metabolic profile in humans following dermal exposure
to triclosan.
    We have reviewed data that were submitted to the docket for this
rulemaking, including recent studies that were published after the 2013
Consumer Wash PR, as well as opinion papers published by other
regulatory agencies regarding the safety of triclosan (Ref. 68). With
the exception of one study that we have identified that provided new
animal dermal ADME data, there were no additional ADME data for
triclosan that were submitted to the docket. The ADME study that was
identified has been recently published by National Center for
Toxicology Research (NCTR) scientists (Ref. 68) where a 13-week dermal-
dose range-finding toxicity study was conducted to determine the ADME
profile of triclosan after dermal exposure in mice. Based on a previous
dermal toxicity study in the mouse where a no observed adverse effect
level of 12.5 milligram (mg)/kilogram (kg) of body weight (bw)/day was
shown, doses of 10 and 100 mg/kg bw triclosan were used. In this study,
mice of both sexes were exposed to topical application of
[\14\C(U)]triclosan (10 or 100 mg triclosan/kg body weight) in 95
percent ethanol up to 72 hours post exposure. Treated mice were covered
with Elizabethan collars to prevent inadvertent oral ingestion of
triclosan. As a comparator group, mice of both sexes were dosed with
100 mg/kg bw where Elizabethan collars were not placed on their necks
to determine the extent of oral ingestion because of the normal
grooming behavior in mice. The study reported a dose-dependent increase
in absorption was noted when comparing the 10 mg/kg bw to the 100 mg/kg
bw. The study also reported that distribution of radiolabeled
[\14\C(U)]triclosan was evaluated to determine distribution up to 72
hours after dosing in the plasma and liver. The earliest radioactivity
measureable was seen as early as 30 minutes post dosing, while maximum
distribution was reached at approximately 8 to 12 hours after dosing
for both plasma and liver. The major metabolite detected in the plasma
and liver was triclosan sulfate, whereas the minor metabolite was

triclosan glucuronide. Maximum levels occurred 12 to 24 hours after
dosing, and the excretion half-life (t1/2E) ranged from 9.3
to 23.1 hours. The study also reported that the majority of the
excretion monitored over 72 hours occurred via the feces in both sexes
and that fecal excretion of the absorbed triclosan was ~2.5 to 6-fold
greater than urinary excretion.
    The data obtained from this study can be used to extrapolate a
safety margin for humans following chronic dermal exposure once the
dermal carcinogenicity study in the mouse, which is currently ongoing
at the NCTR, is completed. No further data is needed for the animal
ADME for triclosan.
b. Photodegradation and Phototoxicity
    (Comment 32) Several comments were submitted regarding the
phototoxicity of triclosan. One comment explained that a study is
currently ongoing at the NTP in response to the data gap on dermal
photocarcinogenicity from dioxins formed by light-induced degradation
of triclosan. The comments urged FDA to await the results of this study
before any further studies are conducted. Two other comments argued
that concern about triclosan dermal photolysis to ``dioxins'' is
unfounded, and that the most likely photolysis product, 2, 8-
dichlorbenzodioxin is toxicologically inert based on the toxicology
equivalency factor (TEF) concept (which compares the toxicity of known
members for a given chemical family and attributes a specific TEF for
each compound compared to the most toxic chemical of that family).
    (Response 32) We note that the comments did not provide any further
justification or calculation of the TEF for the photolysis product, 2,
8-dichlorbenzodioxin, to support the claim that FDA's concern about
triclosan dermal photolysis to ``dioxins'' is unfounded. Instead, an
assumption was made that 2, 8-dichlorbenzodioxin is toxicologically
inert based on the TEF concept. The TEF concept refers only to adverse
effects (e.g., cancer) following interactions with their targets (e.g.,
cellular aryl hydrocarbon receptors). Other toxic effects of dioxins
and dioxin-like compounds are not quantified by this method. In
addition, TEF values vary for different animal species. Therefore, the
ability of triclosan degradants, which belong to the dioxin family, to
form photodegradation products on human skin cannot be assessed using
the TEF concept. Furthermore, it is currently unknown whether the
photoactivity of triclosan is caused by one of the photoproducts or
caused by the interaction of triclosan itself with ultraviolet (UV)
light.
    (Comment 33) Another comment stated that triclosan has been found
to degrade into four different byproducts under certain conditions: 2,
7-dibenzodichloro-p-dioxin; 2, 8-dibenzodichloro-p-dioxin; 2, 4-
dichlorophenol (DCP); and 2, 4, 6- trichlorophenol (TCP). In the
presence of UV light (sunlight), triclosan has been shown to degrade
into two dioxins: 2, 7-dibenzodichloro-p-dioxin; and 2, 8-
dibenzodichloro-p-dioxin. The comment suggested that although the
concentrations of the degradants are low, dioxin byproducts raise some
concern because of their potential to accumulate in the human body
because of their lipophilicity. Both 2, 4-DCP and 2, 4, 6-TCP are more
stable than triclosan, suggesting that the degradants may have longer
half-lives than the parent drug, triclosan.
    (Response 33) Regardless of the causative chemical, it is unknown
at this time whether exposure to triclosan under UV light will lead to
phototoxicity or photocarcinogenicity events. In conclusion, the
comments provided insufficient data and information for assessing the
photodegradation of triclosan on human skin. Accordingly, the safety
data gap for triclosan regarding the potential for formation of
photodegradation products on human skin and their effects on the skin
has not been filled.
c. Dermal Carcinogenicity
    (Comment 34) Several comments were received regarding the dermal
carcinogenicity of triclosan. One comment argued that, based on FDA and
EPA assessments, oral carcinogenicity studies in hamsters, rats, and
mice, supported by negative in vitro and in vivo mutagenicity studies
show that triclosan is not a carcinogen. Therefore, the comments argued
that the ongoing dermal carcinogenicity study is unnecessary. Another
comment stated that dermal carcinogenicity is not supported by existing
data, and no chemical having negative mutagenicity and oral
carcinogenicity data should be expected to demonstrate dermal
carcinogenicity potential.
    (Response 34) We disagree that no dermal carcinogenicity study is
needed for triclosan based only on the negative mutagenicity and oral
carcinogenicity studies. The requirement for dermal assessment is based