Federal Register, Volume 80 Issue 84 (Friday, May 1, 2015)

[Federal Register Volume 80, Number 84 (Friday, May 1, 2015)]
[Proposed Rules]
[Pages 25166-25205]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-10174]

[[Page 25165]]

Vol. 80

Friday,

No. 84

May 1, 2015

Part V

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Part 310

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

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

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2015-N-0101] (Formerly Docket No. FDA-1975-N-0012)
RIN 0910-AF69

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing this
proposed rule to amend the 1994 tentative final monograph or proposed
rule (the 1994 TFM) for over-the-counter (OTC) antiseptic drug
products. In this proposed rule, we are proposing to establish
conditions under which OTC antiseptic products intended for use by
health care professionals in a hospital setting or other health care
situations outside the hospital are generally recognized as safe and
effective. In the 1994 TFM, certain antiseptic active ingredients were
proposed as being generally recognized as safe for use in health care
settings based on safety data evaluated by FDA as part of its ongoing
review of OTC antiseptic drug products. However, in light of more
recent scientific developments, we are now proposing that additional
safety data are necessary to support the safety of antiseptic active
ingredients for these uses. We also are proposing that all health care
antiseptic active ingredients have in vitro data characterizing the
ingredient's antimicrobial properties and in vivo clinical simulation
studies showing that specified log reductions in the amount of certain
bacteria are achieved using the ingredient.

DATES: Submit electronic or written comments by October 28, 2015. See
section VIII of this document for the proposed effective date of a
final rule based on this proposed rule.

ADDRESSES: You may submit comments by any of the following methods:

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

Submit written submissions in the following ways:
Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Docket No.
FDA-2015-N-0101 (formerly Docket No. FDA-1975-N-0012) and RIN 0910-AF69
for this rulemaking. All comments received may be posted without change
to http://www.regulations.gov, including any personal information
provided.
Docket: 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 document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Earlier FDA publications, public submissions, and other materials
relevant to this rulemaking may also be found under Docket No. FDA-
1975-N-0012 (formerly Docket No. 1975N-0183H) using the same
procedures.

FOR FURTHER INFORMATION CONTACT: Michelle M. Jackson, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 5411, Silver Spring, MD 20993, 301-796-
2090.

SUPPLEMENTARY INFORMATION:

Executive Summary

Purpose of the Regulatory Action

FDA is proposing to amend the 1994 TFM for OTC antiseptic drug
products that published in the Federal Register of June 17, 1994 (59 FR
31402). The 1994 TFM is part of FDA's ongoing rulemaking to evaluate
the safety and effectiveness of OTC drug products marketed in the
United States on or before May 1972 (OTC Drug Review).
FDA is proposing to establish new conditions under which OTC health
care antiseptic active ingredients are generally recognized as safe and
effective (GRAS/GRAE) based on FDA's reevaluation of the safety and
effectiveness data requirements proposed in the 1994 TFM in light of
comments received, input from subsequent public meetings, and our
independent evaluation of other relevant scientific information we have
identified and placed in the administrative file. These health care
antiseptic products include health care personnel hand washes, health
care personnel hand rubs, surgical hand scrubs, surgical hand rubs, and
patient preoperative skin preparations.

Summary of the Major Provisions of the Regulatory Action in Question

We are proposing that additional safety and effectiveness data are
necessary to support a GRAS/GRAE determination for OTC antiseptic
active ingredients intended for use by health care professionals. The
effectiveness data, the safety data, and the effect on the previously
proposed classification of active ingredients are described briefly in
this summary.

Effectiveness

A determination that a drug product containing a particular active
ingredient would be generally recognized as effective (GRAE) for a
particular intended use requires consideration of the benefit-to-risk
ratio for the drug for that use. New information on potential risks
posed by the use of certain health care antiseptic products, as well as
input from the Nonprescription Drugs Advisory Committee (NDAC) that met
in March 2005 (the March 2005 NDAC), has prompted us to reevaluate the
data needed for classifying health care antiseptic active ingredients
as GRAE (see new information described in the Safety section of this
summary). We continue to propose the use of surrogate endpoints
(bacterial log reductions) as a demonstration of effectiveness for
health care antiseptics combined with in vitro testing to characterize
the antimicrobial activity of the ingredient. However, the log
reductions required for the demonstration of effectiveness for health
care antiseptics have been revised based on the recommendations of the
March 2005 NDAC, comments received after the 1994 TFM, and other
information that FDA reviewed.
We have evaluated the available literature and the data and other
information that were submitted to the rulemaking on the effectiveness
of health care antiseptic active ingredients, as well as the
recommendations from the public meetings held by the Agency on
antiseptics. We propose that the record should contain additional log
reduction data to demonstrate the effectiveness of health care
antiseptic active ingredients.

Safety

Several important scientific developments that affect the safety
evaluation of these ingredients have occurred since FDA's 1994
evaluation of the safety of health care antiseptic active ingredients
under the OTC Drug

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Review. Improved analytical methods now exist that can detect and more
accurately measure these active ingredients at lower levels in the
bloodstream and tissue. Consequently, we now know that, at least for
certain health care antiseptic ingredients, systemic exposure is higher
than previously thought (Refs. 1 through 5), and new information is
available about the potential risks from systemic absorption and long-
term exposure. New safety information also suggests that widespread
antiseptic use could have an impact on the development of bacterial
resistance. Currently, the significance of this new information is not
known and we are unaware of any information that would lead us to
conclude that any health care antiseptic active ingredient is unsafe
(other than those that we proposed to be Category II in the 1994 TFM).
The benefits of any active ingredient will need to be weighed against
its risks once both the effectiveness and safety have been better
characterized to determine GRAS/GRAE status.
The previously proposed generally recognized as safe (GRAS)
determinations were based on safety principles that have since evolved
significantly because of advances in technology, development of new
test methods, and experience with performing test methods. The standard
battery of tests that were used to determine the safety of drugs has
changed over time to incorporate improvements in safety testing. To
ensure that health care antiseptic active ingredients are GRAS, data
that meet current safety standards are needed.
Based on these developments, we are now proposing that additional
safety data are needed for each health care antiseptic active
ingredient to support a GRAS classification. The data described in this
proposed rule are the minimum data necessary to establish the safety of
antiseptic active ingredients used in health care antiseptic products
in light of the new safety information. Health care practitioners may
use health care antiseptics on a daily, long-term (i.e., chronic)
basis. Patient preoperative skin preparations, on the other hand, are
not usually used on any single patient on a daily basis. Nevertheless,
an individual may be exposed to patient preoperative skin preparations
(particularly those used for preinjection skin preparation) enough
times over a lifetime to be considered a chronic use. The data we
propose are needed to demonstrate safety for all health care antiseptic
active ingredients fall into four broad categories: (1) Human safety
studies described in current FDA guidance (e.g., maximal use trials or
MUsT), (2) nonclinical safety studies described in current FDA guidance
(e.g., developmental and reproductive toxicity studies and
carcinogenicity studies), (3) data to characterize potential hormonal
effects, and (4) data to evaluate the development of antimicrobial
resistance.
We emphasize that our proposal for more safety and effectiveness
data for health care antiseptic active ingredients does not mean that
we believe that health care antiseptic products containing these
ingredients are ineffective or unsafe, or that their use should be
discontinued. However, now that we have enhanced abilities to measure
and evaluate the safety and effectiveness of these ingredients, we
believe we should obtain relevant data to support a GRAS/GRAE
determination. Consequently, based on new information and improvements
in safety testing and in our understanding of log reduction testing and
the use of surrogate endpoints since our 1994 evaluation, we are
requesting more safety and effectiveness data to ensure that these
health care antiseptic active ingredients meet the updated standards to
support a GRAS/GRAE classification. Considering the prevalent use of
health care antiseptic products in health care settings, it is critical
that the safety and effectiveness of these ingredients be supported by
data that meet the most current standards.

Active Ingredients

In the 1994 TFM, 27 antiseptic active ingredients were classified
for three OTC health care antiseptic uses: (1) Patient preoperative
skin preparation, (2) health care personnel hand wash, and (3) surgical
hand scrub (59 FR 31402 at 31435) (for a list of all active ingredients
covered by this proposed rule, see tables 4 through 7). Our detailed
evaluation of the effectiveness and safety of the active ingredients
for which data were submitted can be found in sections VI.A and VII.D.
In the 1994 TFM, alcohol (60 to 95 percent) and povidone-iodine (5 to
10 percent), which are active ingredients that are being evaluated for
use as a health care antiseptic in this proposed rule, were proposed to
be classified as GRAS/GRAE (59 FR 31402 at 31435-31436) for patient
preoperative skin preparation, health care personnel hand wash, and
surgical hand scrub. Iodine tincture, iodine topical solution, and
isopropyl alcohol were proposed to be classified as GRAS/GRAE for
patient preoperative skin preparations (59 FR 31402 at 31435-31436).
However, we now propose that the health care antiseptic active
ingredients classified as GRAS/GRAE for use in health care antiseptics
in the 1994 TFM need additional safety and effectiveness data to
support a classification of GRAS/GRAE for health care antiseptic use.
Several health care antiseptic active ingredients evaluated in the
1994 TFM were proposed as GRAS, but not GRAE, for use in health care
antiseptics because they lacked sufficient evidence of effectiveness
for health care use (see tables 4 and 5). We are now proposing that
these ingredients need additional safety data, as well as effectiveness
data, to be classified as GRAS/GRAE.
The data available and the data that are missing are discussed
separately for each active ingredient in this proposed rule. For those
ingredients for which no data have been submitted since the 1994 TFM,
we have not included a separate discussion section, but have indicated
in table 10 that no additional data were submitted or identified.
In certain cases, manufacturers may have the data we propose as
necessary in this proposed rule, but to date these data have not been
submitted to the OTC Drug Review. Although currently we expect to
receive the necessary data, if we do not obtain sufficient data to
support monograph conditions for health care antiseptic products
containing these active ingredients, these products may not be included
in the future OTC health care antiseptic final monograph. Any health
care antiseptic product containing the active ingredients being
considered under this rulemaking that are not included in a future
final monograph could obtain approval to market by submitting new drug
applications (NDAs) under section 505 of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. 355). After a final monograph is
established, these products might be able to submit NDA deviations in
accordance with Sec. 330.11 (21 CFR 330.11), limiting the scope of
review necessary to obtain approval.

Costs and Benefits

Benefits represent the monetary values associated with reducing the
potential adverse health effects associated with the use of health care
antiseptic products containing active ingredients that could
potentially be shown to be unsafe or ineffective for their intended
use. We estimate annual benefits to roughly range between $0 and $0.16
million. Total upfront costs are estimated to range between $64 and
$90.8 million. Annualizing these costs over a 10-year period, we
estimate total annualized costs to range from $7.3 and $10.4 million at
a 3 percent discount

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

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Total benefits Total costs annualized
Summary of costs and benefits of the annualized over 10 over 10 years (in Total one-time costs
proposed rule years (in millions) millions) (in millions)
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Total............................ $0.0 to $0.16.......... $7.3 to $10.4 at (3%).. $64.0 to $90.8
$8.5 to $12.1 at (7%)..
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Table of Contents

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

I. Introduction

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

A. Terminology Used in the OTC Drug Review Regulations

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

B. Topical Antiseptics

The OTC topical antimicrobial rulemaking has had a broad scope,
encompassing drug products that may contain the same active
ingredients, but that are labeled and marketed for different intended
uses. In 1974, the Agency published an ANPR for topical antimicrobial
products that encompassed products for both health care and consumer
use (39 FR 33103, September 13, 1974). The ANPR covered seven different
intended uses for these products: (1) Antimicrobial soap, (2) health
care personnel hand wash, (3) patient preoperative skin preparation,
(4) skin antiseptic, (5) skin wound cleanser, (6) skin wound
protectant, and (7) surgical hand scrub (39 FR 33103 at 33140). FDA
subsequently identified skin antiseptics, skin wound cleansers, and
skin wound protectants as antiseptics used primarily by consumers for
first aid use and referred to them collectively as ``first aid
antiseptics.'' We published a separate TFM covering the first aid
antiseptics in the Federal Register of July 22, 1991 (56 FR 33644)
(1991 First Aid TFM). Thus, first aid antiseptics are not discussed
further in this document.
The four remaining categories of topical antimicrobials were
addressed in the 1994 TFM. The 1994 TFM covered: (1) Antiseptic hand
wash (i.e., consumer hand wash), (2) health care personnel hand wash,
(3) patient preoperative skin preparation, and (4) surgical hand scrub
(59 FR 31402 at 31442). In the 1994 TFM, FDA also identified a new
category of antiseptics for use by the food industry and requested
relevant data and information (59 FR 31402 at 31440). Antiseptics for
use by the food industry are not discussed further in this document.
As we proposed in the consumer antiseptic wash proposed rule
published in the Federal Register of December 17, 2013 (78 FR 76444)
(the Consumer Wash PR), our evaluation of OTC antiseptic drug products
is being further subdivided into health care antiseptics and consumer
antiseptics. We believe that these categories are distinct based on the
proposed use setting, target population, and the fact

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that each setting presents a different level of risk for infection. For
example, in health care settings, the patient population is generally
more susceptible to infection than the general U.S. consumer population
(i.e., the population who use consumer antiseptic washes).
Consequently, in the health care setting, the potential for spread of
infection and the potential for serious outcomes of infection may be
relatively higher than in the U.S. consumer setting. Therefore, the
safety and effectiveness should be evaluated separately for each
intended use to support a GRAS/GRAE determination.
Health care antiseptics are drug products intended for use by
health care professionals in a hospital setting or other health care
situations outside the hospital. Patient preoperative skin
preparations, which include products that are used for preparation of
the skin prior to an injection (i.e., preinjection), may be used by
patients outside the traditional health care setting. Some patients
(e.g., diabetics who manage their disease with insulin injections)
self-inject medications that have been prescribed by a health care
professional at home or at other locations and use patient preoperative
skin preparations prior to injection. In 1974, when the ANPR (39 FR
33103) to establish an OTC topical antimicrobial monograph was
published in the Federal Register, antimicrobial soaps used by
consumers were distinct from professional use antiseptics, such as
health care personnel hand washes. (See 78 FR 76444 for further
discussion of the term ``antimicrobial soaps.'') In contrast, in the
1994 TFM, we proposed that both consumer antiseptic hand washes and
health care personnel hand washes should have the same effectiveness
testing and performance criteria. In response to the 1994 TFM, we
received submissions from the public arguing that consumer products
serve a different purpose and should continue to be distinct from
health care antiseptics. We agree, and in this proposed rule, we make a
distinction between consumer antiseptics for use by the general
population and health care antiseptics for use in hospitals or in other
specific health care situations outside the hospital.
The health care setting is different from the consumer setting in
many ways. Among other things, health care facilities employ frequent,
standardized disinfection procedures and stringent infection control
measures that include the use of health care antiseptics. The use of
these measures is critical to preventing the spread of infection within
health care facilities. The population in a hospital or health care
facility also is different from the general consumer population. In
addition, the microorganisms of concern are different in the health
care and consumer settings. These differences have resulted in our
proposing different effectiveness data requirements. (See section VI.B.
about the different effectiveness data requirements.)

C. This Proposed Rule Covers Only Health Care Antiseptics

We refer to the group of products covered by this proposed rule as
``health care antiseptics.'' In this proposed rule, FDA proposes the
establishment of a monograph for OTC health care antiseptics that are
intended for use by health care professionals in a hospital setting or
other health care situations outside the hospital, but that are not
identified as ``first aid antiseptics'' in the 1991 First Aid TFM. In
this proposed rule, we use the term ``health care antiseptics'' to
include the following products:
Health care personnel hand washes
health care personnel hand rubs
surgical hand scrubs
surgical hand rubs
patient preoperative skin preparations
This proposed rule covers products that are rubs and others that
are washes. The 1994 TFM did not distinguish between products that we
are now calling ``antiseptic washes'' and products we are now calling
``antiseptic rubs.'' Washes are rinsed off with water, and include
health care personnel hand washes and surgical hand scrubs. Rubs are
sometimes referred to as ``leave-on products'' and are not rinsed off
after use. Rubs include health care personnel hand rubs, surgical hand
rubs, and patient preoperative skin preparations.
The 1994 TFM did not distinguish between consumer antiseptic washes
and rubs, and health care hand washes and rubs. This proposed rule
covers health care personnel hand washes and health care personnel hand
rubs, as well as the other health care antiseptic categories previously
listed in this section. This proposed rule does not cover consumer
antiseptic washes or consumer antiseptic hand rubs.
Completion of the monograph for Health Care Antiseptic Products and
certain other monographs for the active ingredient triclosan are
subject to a Consent Decree entered by the United States District Court
for the Southern District of New York on November 21, 2013, in Natural
Resources Defense Council, Inc. v. United States Food and Drug
Administration, et al., 10 Civ. 5690 (S.D.N.Y.).

D. Comment Period

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

II. Background

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

A. Significant Rulemakings Relevant to This Proposed Rule

A summary of the significant Federal Register publications relevant
to this proposed rule is provided in table 1. Other Federal Register
publications relevant to this proposed rule are available from the
Division of Dockets Management (see ADDRESSES).

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Table 1--Significant Rulemaking Publications Related to Health Care
Antiseptic Drug Products
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Federal Register notice Information in notice
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1974 ANPR (September 13, 1974, 39 We published an advance notice of
FR 33103). proposed rulemaking to establish a
monograph for OTC topical
antimicrobial drug products,
together with the recommendations
of the Advisory Review Panel on OTC
Topical Antimicrobial I Drug
Products (Antimicrobial I Panel or
Panel), which was the advisory
review panel responsible for
evaluating data on the active
ingredients in this drug class.
1978 Antimicrobial TFM (January 6, We published our tentative
1978, 43 FR 1210). conclusions and proposed
effectiveness testing for the drug
product categories evaluated by the
Panel. The 1978 TFM reflects our
evaluation of the recommendations
of the Panel and comments and data
submitted in response to the
Panel's recommendations.
1982 Alcohol ANPR (May 21, 1982, We published an advance notice of
47 FR 22324). proposed rulemaking to establish a
monograph for alcohol drug products
for topical antimicrobial use,
together with the recommendations
of the Advisory Review Panel on OTC
Miscellaneous External Drug
Products, which was the advisory
review panel responsible for
evaluating data on the active
ingredients in this drug class
(Miscellaneous External Panel).
1991 First Aid TFM (July 22, 1991, We amended the 1978 TFM to establish
56 FR 33644). a separate monograph for OTC first
aid antiseptic products. In the
1991 First Aid TFM, we proposed
that first aid antiseptic drug
products be indicated for the
prevention of skin infections in
minor cuts, scrapes, and burns.
1994 Health-Care Antiseptic TFM We amended the 1978 TFM to establish
(June 17, 1994, 59 FR 31402). a separate monograph for the group
of products that were referred to
as OTC topical health care
antiseptic drug products. These
antiseptics are generally intended
for use by health care
professionals.
In that proposed rule, we also
recognized the need for
antibacterial personal cleansing
products for consumers to help
prevent cross contamination from
one person to another and proposed
a new antiseptic category for
consumer use: Antiseptic hand wash.
2013 Consumer Antiseptic Wash TFM We issued a proposed rule to amend
(December 17, 2013, 78 FR 76444). the 1994 TFM and to establish data
standards for determining whether
OTC consumer antiseptic washes are
GRAS/GRAE.
In that proposed rule, we proposed
that additional safety and
effectiveness data are necessary to
support the safety and
effectiveness of consumer
antiseptic wash active ingredients.
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B. Public Meetings Relevant to This Proposed Rule

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

Table 2--Public Meetings Relevant to Health Care Antiseptics
------------------------------------------------------------------------
Date and type of meeting Topic of discussion
------------------------------------------------------------------------
January 1997 NDAC Meeting (Joint Antiseptic and antibiotic resistance
meeting with the Anti-Infective in relation to an industry proposal
Drugs Advisory Committee) for consumer and health care
(January 6, 1997, 62 FR 764). antiseptic effectiveness testing
(Health Care Continuum Model)
(Refs. 6 and 7).
March 2005 NDAC Meeting (February The use of surrogate endpoints and
18, 2005, 70 FR 8376). study design issues for the in vivo
testing of health care antiseptics
(Ref. 8).
November 2008 Public Feedback Demonstration of the effectiveness
Meeting. of consumer antiseptics (Ref. 9).
September 2014 NDAC Meeting (July Safety testing framework for health
29, 2014, 79 FR 44042). care antiseptic active ingredients
(Ref. 10).
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C. Comments Received by FDA

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

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

In this section of the proposed rule, we describe the requirements
for

[[Page 25171]]

eligibility for the OTC Drug Review and the ingredients submitted to
the OTC Drug Review that lack adequate evidence of eligibility for
evaluation as health care antiseptic products.

A. Eligibility for the OTC Drug Review

An OTC drug is covered by the OTC Drug Review if its conditions of
use existed in the OTC drug marketplace on or before May 11, 1972 (37
FR 9464).\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 prior to May 1972 (see Sec.
330.10(a)(2)). FDA considers a drug that is ineligible for inclusion in
the OTC monograph system to be a new drug that will require FDA
approval through the NDA process. Ineligibility for use as a specific
type of health care antiseptic (e.g., health care personnel hand wash
or surgical hand scrub) does not affect eligibility for other
indications under the health care antiseptic monograph (e.g., patient
preoperative skin preparations) or 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(c).)
---------------------------------------------------------------------------

Section III.B discusses those ingredients that currently do not
have adequate evidence of eligibility for evaluation under the OTC Drug
Review based on a review of the labeling submitted to the Panel. Some
ingredients are ineligible for any of the categories of health care
antiseptics. Others are eligible for some, but not others. Because of
their lack of eligibility, effectiveness and safety information that
has been submitted to the rulemaking for these health care antiseptic
active ingredients are not discussed in this proposed rule for such
use(s). However, if documentation of the type described in this section
is submitted, these active ingredients could be determined to be
eligible for evaluation for such use(s).

B. Eligibility of Certain Active Ingredients for Certain Health Care
Antiseptic Uses Under the OTC Drug Review

Table 3 lists the health care antiseptic active ingredients that
have been considered under this rulemaking and shows whether each
ingredient is eligible or ineligible for each of the five health care
antiseptic uses: Patient preoperative skin preparation, health care
personnel hand wash, health care personnel hand rub, surgical hand
scrub, and surgical hand rub. After the table, we discuss the
ineligibility of ingredients in this section of the proposed rule.

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

[[Page 25172]]

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

[[Page 25173]]

(phosphate ester of alkylaryloxy polyethylene glycol), nonylphenoxypoly
(ethyleneoxy) ethanoliodine, poloxamer-iodine complex, and undecoylium
chloride iodine complex have not been demonstrated to be eligible for
the OTC Drug Review for evaluation as health care personnel hand rubs
or surgical hand rubs (59 FR 31402 at 31418 and 31435-31436). Thus, we
do not include a discussion of safety or effectiveness of these iodine
complexes for these uses in this proposed rule.
These active ingredients, however, have been demonstrated to be
eligible for the OTC Drug Review for use as a health care personnel
hand wash, a surgical hand scrub, and a patient preoperative skin
preparation (59 FR 31402 at 31435-31436). Thus, we include a discussion
of the safety and effectiveness of these ingredients for these uses in
this proposed rule.
d. Povidone-iodine 5 to 10 percent. The only health care antiseptic
products containing povidone-iodine 5 to 10 percent submitted to the
OTC Drug Review were health care personnel hand washes and surgical
hand scrubs intended to be used with water (Ref. 13). Povidone-iodine 5
to 10 percent has not been demonstrated to be eligible for the OTC Drug
Review for evaluation as a health care personnel hand rub or surgical
hand rub, and we propose to categorize povidone-iodine for these uses
as a new drug. However, povidone-iodine has been demonstrated to be
eligible for the OTC Drug Review for use as a health care personnel
hand wash, surgical hand scrub, and patient preoperative skin
preparation (59 FR 31402 at 31423 and 31435-31436). Thus, we include a
discussion of the safety and effectiveness of povidone iodine for these
uses in this proposed rule.
5. Mercufenol Chloride
Mercufenol chloride was evaluated for use only as a patient
preoperative skin preparation in the 1994 TFM (59 FR 31402 at 31428-
31429 and 31435-31436). Based on the information we currently have
about eligibility, we propose to categorize as a new drug mercufenol
chloride for use as a health care personnel hand wash or rub or as a
surgical hand scrub or rub. Mercufenol chloride, however, has been
demonstrated to be eligible for the OTC Drug Review for use as a
patient preoperative skin preparation.
6. Polyhexamethylene Biguanide; Benzalkonium Cetyl Phosphate;
Cetylpyridinium Chloride; Salicylic Acid; Sodium Hypochlorite; Tea Tree
Oil; Combination of Potassium Vegetable Oil Solution, Phosphate
Sequestering Agent, and Triethanolamine
Following the publication of the 1994 TFM, FDA received submissions
for the first time requesting that polyhexamethylene biguanide;
benzalkonium cetyl phosphate; cetylpyridinium chloride; salicylic acid;
sodium hypochlorite; tea tree oil; and the combination of potassium
vegetable oil solution, phosphate sequestering agent, and
triethanolamine be added to the monograph (Refs. 14 through 19). These
compounds were not addressed in prior FDA documents related to the
monograph and were not evaluated for any health care antiseptic use by
the Antimicrobial I Panel. The submissions received by FDA to date do
not include documentation demonstrating the eligibility of any of these
seven compounds for inclusion in the monograph (Ref. 20). Therefore,
polyhexamethylene biguanide, benzalkonium cetyl phosphate,
cetylpyridinium chloride, salicylic acid, sodium hypochlorite, tea tree
oil, and the combination of potassium vegetable oil solution, phosphate
sequestering agent, and triethanolamine have not been demonstrated to
be eligible for the OTC Drug Review. Based on the information we
currently have about eligibility, we propose to categorize these
compounds as new drugs and we do not include a discussion of safety or
effectiveness data submitted for them in this proposed rule.
7. Other Individual Active Ingredients
In the 1994 TFM, each of the following ingredients was evaluated
for use as a patient preoperative skin preparation, a health care
personnel hand wash, and a surgical hand scrub (59 FR 31402 at 31435-
31436):

Benzethonium chloride
Chloroxylenol
Cloflucarban
Fluorosalan
Hexylresorcinol
Methylbenzethonium chloride
Phenol (less than 1.5 percent)
Secondary amyltricresols
Sodium oxychlorosene
Triclocarban
Triclosan

The only health care personnel hand wash or surgical hand scrub
products containing any of these ingredients that were submitted to the
OTC Drug Review were products that were intended to be used with water
(i.e., rinse-off products) (Ref. 13). Consequently, based on the
information we currently have about eligibility, we propose to
categorize as a new drug each of these ingredients for use as a health
care personnel hand rub or a surgical hand rub, and we do not include a
discussion of safety or effectiveness of these ingredients for these
uses in this proposed rule.
Each of the listed ingredients, however, has been demonstrated to
be eligible for the OTC Drug Review for use as a health care personnel
hand wash, surgical hand scrub, and patient preoperative skin
preparation.
8. Combination Active Ingredients
The combination active ingredients (1) calomel, oxyquinoline
benzoate, triethanolamine, and phenol derivative; (2) mercufenol
chloride and secondary amyltricresols in 50 percent alcohol; and (3)
triple dye have not been demonstrated to be eligible for the OTC Drug
Review for use as a health care personnel hand wash or rub or as a
surgical hand scrub or rub (59 FR 31402 at 31435-31436). Consequently,
based on the information we currently have about eligibility, we
propose to categorize as a new drug each of these ingredients for use
as a health care personnel hand wash, health care personnel hand rub,
surgical hand scrub, or a surgical hand rub, and we do not include a
discussion of safety or effectiveness of these ingredients for these
uses in this proposed rule. However, each of the previously discussed
active ingredients has been demonstrated to be eligible for the OTC
Drug Review for use as a patient preoperative skin preparation.

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

FDA may determine that an active ingredient is not GRAS/GRAE for a
given OTC use (i.e., nonmonograph) because of lack of evidence of
effectiveness, lack of evidence of safety, or both. In the 1994 TFM (59
FR 31402 at 31435-31436), FDA proposed that the active ingredients
fluorosalan, hexachlorophene, phenol (greater than 1.5 percent), and
tribromsalan be found not GRAS/GRAE for the uses referred to in the
1994 TFM as antiseptic hand wash and health care personnel hand wash.
FDA did not classify hexachlorophene or tribromsalan in the 1978 TFM
(43 FR 1210 at 1227) because it had already taken final regulatory
action against hexachlorophene (21 CFR 250.250) and certain halogenated
salicylamides, notably tribromsalan (21 CFR 310.502). No substantive
comments

[[Page 25174]]

or new data were submitted to the record of the 1994 TFM to support
reclassification of any of these ingredients to GRAS/GRAE status.
Therefore, FDA is continuing to propose that these active ingredients
be found not GRAS/GRAE for OTC health care antiseptic products as
defined in this proposed rule and that any OTC health care antiseptic
drug product containing any of these ingredients not be allowed to be
introduced or delivered for introduction into interstate commerce
unless it is the subject of an approved application, effective, except
as otherwise provided in other regulations, as of 1 year after
publication of the final monograph in the Federal Register.

V. Summary of Proposed Classifications of OTC Health Care Antiseptic
Active Ingredients

Tables 4 through 7 in this proposed rule list the classification
proposed in the 1994 TFM for each OTC health care antiseptic active
ingredient according to intended use and the classification being
proposed in this proposed rule. The specific data that has been
submitted to the public docket (the rulemaking) and evaluated by FDA
and the description of data still lacking in the administrative record
is later described in detail for each active ingredient for which we
have some data in section VII.D.
Tables 4 and 5 list ingredients for which a different status is
being proposed in this proposed rule than was proposed in the 1994 TFM.

Table 4--Classification of OTC Health Care Personnel Hand Wash and
Surgical Hand Scrub Antiseptic Active Ingredients in This Proposed Rule
and in the 1994 TFM
------------------------------------------------------------------------
This proposed
Active ingredient 1994 TFM rule
------------------------------------------------------------------------
Alcohol 60 to 95 percent.......... I \1\ IIISE \2\
Hexylresorcinol................... IIIE IIISE
Iodine complex (ammonium ether IIIE IIISE
sulfate and polyoxyethylene
sorbitan monolaurate).
Iodine complex (phosphate ester of IIIE IIISE
alkylaryloxy polyethylene glycol).
Isopropyl alcohol 70 to 91.3 IIIE IIISE
percent.
Nonylphenoxypoly (ethyleneoxy) IIIE IIISE
ethanoliodine.
Poloxamer iodine complex.......... IIIE IIISE
Povidone-iodine 5 to 10 percent... I IIISE
Secondary amyltricresols.......... IIIE IIISE
Triclocarban...................... IIIE IIISE
Undecoylium chloride iodine IIIE IIISE
complex.
------------------------------------------------------------------------
\1\ ``I'' denotes a classification that an active ingredient has been
shown to be safe and effective.
\2\ ``III'' denotes a classification that additional data are needed.
``S'' denotes safety data needed. ``E'' denotes effectiveness data
needed.

Table 5--Classification of OTC Patient Preoperative Skin Preparation
Antiseptic Active Ingredients in This Proposed Rule and in the 1994 TFM
------------------------------------------------------------------------
This proposed
Active ingredient 1994 TFM rule
------------------------------------------------------------------------
Alcohol 60 to 95 percent.......... I \1\ IIISE \2\
Benzalkonium chloride............. IIIE IIISE
Benzethonium chloride............. IIIE IIISE
Chloroxylenol..................... IIIE IIISE
Hexylresorcinol................... IIIE IIISE
Iodine complex (phosphate ester of IIIE IIISE
alkylaryloxy polyethylene glycol).
Iodine tincture USP............... I IIISE
Iodine topical solution USP....... I IIISE
Isopropyl alcohol 70 to 91.3 I IIISE
percent.
Mercufenol chloride............... IIIE IIISE
Methylbenzethonium chloride....... IIIE IIISE
Nonylphenoxypoly (ethyleneoxy) IIIE IIISE
ethanoliodine.
Phenol (less than 1.5 percent).... IIIE IIISE
Poloxamer iodine complex.......... IIIE IIISE
Povidone-iodine 5 to 10 percent... I IIISE
Triclocarban...................... IIIE IIISE
Triclosan......................... IIIE IIISE
Undecoylium chloride iodine IIIE IIISE
complex.
------------------------------------------------------------------------
\1\ ``I'' denotes a classification that an active ingredient has been
shown to be safe and effective.
\2\ ``III'' denotes a classification that additional data are needed.
``S'' denotes safety data needed. ``E'' denotes effectiveness data
needed.

[[Page 25175]]

This proposed rule does not change the status of a number of
antiseptic active ingredients previously proposed as lacking sufficient
evidence of safety or effectiveness or the status of several
ingredients previously proposed as having been shown to be unsafe,
ineffective, or both (see tables 6 and 7).

Table 6--OTC Health Care Personnel Hand Wash and Surgical Hand Scrub
Antiseptic Active Ingredients With No Change in Classification in This
Proposed Rule Compared to the 1994 TFM
------------------------------------------------------------------------
Active ingredient No change in classification
------------------------------------------------------------------------
Benzalkonium chloride..................... IIISE \1\
Benzethonium chloride..................... IIISE
Chloroxylenol............................. IIISE
Cloflucarban.............................. IIISE/II \2\
Fluorosalan............................... II \3\
Hexachlorophene........................... II
Methylbenzethonium chloride............... IIISE
Phenol (less than 1.5 percent)............ IIISE
Phenol (greater than 1.5 percent)......... II
Sodium oxychlorosene...................... IIISE
Tribromsalan.............................. II
Triclosan................................. IIISE
------------------------------------------------------------------------
\1\ ``III'' denotes a classification that additional data are needed.
``S'' denotes safety data needed. ``E'' denotes effectiveness data
needed.
\2\ Health care personnel hand wash proposed as IIISE and surgical hand
scrub proposed as II.
\3\ ``II'' denotes a classification that an active ingredient has been
shown to be unsafe, ineffective, or both.

Table 7--OTC Patient Preoperative Skin Preparation Antiseptic Active
Ingredients With No Change in Classification in This Proposed Rule
Compared to the 1994 TFM
------------------------------------------------------------------------
Active ingredient No change in classification
------------------------------------------------------------------------
Cloflucarban.............................. II \1\
Fluorosalan............................... II
Hexachlorophene........................... II
Phenol (greater than 1.5 percent)......... II
Secondary amyltricresols.................. IIISE \2\
Sodium oxychlorosene...................... IIISE
Tribromsalan.............................. II
Calomel, oxyquinoline benzoate, II
triethanolamine, and phenol derivative.
Mercufenol chloride and secondary IIISE
amyltricresols in 50 percent alcohol.
Triple dye................................ II
------------------------------------------------------------------------
\1\ ``II'' denotes that an active ingredient has been shown to be
unsafe, ineffective, or both.
\2\ ``III'' denotes a classification that additional data are needed.
``S'' denotes safety data needed. ``E'' denotes effectiveness data
needed.

VI. Effectiveness (Generally Recognized as Effective) Determination

OTC regulations (Sec. Sec. 330.10(a)(4)(ii) and 314.126(b)) define
the standards for establishing that an OTC drug containing a particular
active ingredient would be GRAE for its intended use. These regulations
provide that supporting investigations must be adequate and well-
controlled, and able to distinguish the effect of a drug from other
influences such as a spontaneous change in the course of the disease,
placebo effect, or biased observation. In general, such investigations
include controls that are adequate to provide an assessment of drug
effect, are adequate measures to minimize bias, and use adequate
analytical methods to demonstrate effectiveness. For active ingredients
being evaluated in the OTC Drug Review, this means that a demonstration
of the contribution of the active ingredient to any effectiveness
observed is required before an ingredient can be determined to be GRAE
for OTC drug use.
In the 1994 TFM, we proposed a log reduction standard (a clinical
simulation standard) for establishing effectiveness of consumer and
health care antiseptics (59 FR 31402 at 31448) for the proposed
intended use of decreasing bacteria on the skin. The 1994 TFM log
reduction standard for effectiveness is based on a surrogate endpoint
(i.e., number of bacteria removed from the skin), rather than a
clinical outcome (e.g., reduction in the number of infections). In
accordance with recommendations made by NDAC at its March 2005 meeting,
we continue to propose a log reduction standard to demonstrate the
general recognition of effectiveness of health care antiseptic active
ingredients. See section VI.B for our current proposed log reduction
standard.
Unlike the use of antiseptics in the consumer setting, the use of
antiseptics by health care providers in the hospital setting is
considered an essential component of hospital infection control
measures (Refs. 21, 22, and 23). Hospital-acquired infections can
result in prolonged hospital stays, additional medical treatment,
adverse clinical outcomes, and increased health care costs (Refs. 24
through 27). The reliance on antiseptics in the clinical setting goes
back over 150 years when, in the mid-1800s, Semmelweis observed that
the mortality associated with childbed fever at the General Hospital in
Vienna could be reduced by disinfection of physicians' hands with
chlorine prior to patient care (Ref. 28). Around the same time, Lister
demonstrated the effect of skin disinfection on surgical site infection
rates (Ref. 28). This observational evidence of the effect of
antiseptics on infection by Semmelweis and Lister form the basis for
the current role of antiseptics as a critical component of hospital
infection control procedures. Adequate and well-controlled clinical
trials demonstrating a definitive link between antiseptic use and a
reduction in infection rates are lacking, however.
The March 2005 NDAC acknowledged the difficulty in designing
clinical trials to demonstrate the impact of health care antiseptics on
infection rates. This difficulty was one reason the committee advised
against clinical outcome trials to demonstrate the effectiveness of
health care antiseptics. Numerous factors contribute to hospital-
acquired infections and, therefore, would need to be controlled for in
the design of these types of studies. For example, some of the known
risk factors for surgical site infection that must be controlled for
include the following: Patient age, nutritional status, diabetes,
smoking, obesity, coexistent infections at a remote body site,
colonization with microorganisms, altered immune response, length of
preoperative stay, duration of surgical scrub, preoperative shaving,
preoperative skin prep, duration of the operation, inadequate
sterilization of instruments, foreign material in the surgical site,
surgical drain, and surgical technique (Ref. 22). There are also
standard infection control measures such as gloving, isolation
procedures, sterilization of instruments, and waste disposal that make
it difficult to demonstrate the independent contribution of antiseptics
to the reduction of the risk of hospital infection (Ref. 28).
Although we found a few studies that could serve as a basis for
designing a clinical outcome study in the consumer setting (78 FR 76444
at 76450), we have not found any acceptable clinical outcome study
designs for health care antiseptics. The March 2005 NDAC recommended
that sponsors perform an array of trials to look simultaneously at the
effect on the surrogate endpoint and the clinical endpoint to try to
establish a link between the surrogate and clinical endpoints, but
provided no guidance on possible study designs. We have not seen any
studies of this type. The March 2005 NDAC also believed that it would
be unethical to perform a hospital trial using a vehicle control
instead of an antiseptic. Although the NDAC thought

[[Page 25176]]

that performing a placebo-controlled study for routine patients on the
ward might be feasible, it stated that the Centers for Disease Control
and Prevention hand hygiene guidelines and hospital accreditation
requirements would prohibit such a practice. The NDAC also believed
that an institutional review board would not approve a hospital trial
that did not involve an antiseptic.
We agree that a clinical outcome study in the health care setting
raises ethical concerns. For a clinical outcome study to be adequately
controlled the study design would need to include a vehicle or negative
control arm. However, the inclusion of such control arms in a clinical
outcome study conducted in a hospital setting could pose an
unacceptable health risk to study subjects (hospitalized patients and
health care providers). In such studies a vehicle or negative control
would be a product with no antimicrobial activity. The use of a
nonantimicrobial product in a hospital setting (a setting with an
already elevated risk of infections) could increase the risk of
infection for both health care providers and their patients. Thus, it
is generally considered unethical to perform placebo-controlled
clinical studies to show the value of health care antiseptics (Ref. 8).
Based on these considerations NDAC recommended the continued use of
clinical simulation studies to validate the effectiveness of health
care antiseptics.
FDA has relied upon clinical simulation studies to support the
approval of health care antiseptics through the NDA process. Although
it is not possible to quantify the contribution of NDA health care
antiseptics to reduced hospital infection rates, in general, infection
rates in the United States are low. For example, only 2 to 5 percent of
over 40 million inpatient surgical procedures each year are complicated
by surgical site infections (Ref. 29). We acknowledge that the use of
surrogate endpoints to assess the effectiveness of these products is
not optimal, but we believe it is the best means available of assessing
the effectiveness of health care antiseptic products.
Thus, we are continuing to rely on surrogate endpoints to evaluate
the effectiveness of health care antiseptics while requiring data from
clinical outcome studies to support the effectiveness of consumer
antiseptics (78 FR 76444 at 76450). Unlike consumer antiseptics,
however, health care antiseptics are considered an integral part of
hospital infection control strategies (Refs. 21, 23, and 30). As is the
case for consumer antiseptics, we lack clinical outcome data from
adequate studies demonstrating the impact of health care antiseptics on
infection rates. Given this, FDA faces the challenge of regulating this
important component of current hospital infection control measures
without methods to directly assess their clinical effect. We
nonetheless need a practical means to assess the general recognition of
effectiveness of health care products, such as the clinical simulation
studies.
As discussed in section VI.A, we evaluated all the available
effectiveness studies for health care antiseptics (i.e., health care
personnel hand washes and rubs, surgical hand scrubs and rubs, and
patient preoperative skin preparations) to determine whether the data
supported finding the health care antiseptic active ingredient to be
GRAE based on the 1994 TFM effectiveness criteria (which we are now
proposing to update). We found that the available studies are not
adequate to support a GRAE determination for any health care antiseptic
active ingredient under the 1994 TFM effectiveness criteria (59 FR
31402 at 31445, 31448, and 31450).\2\
---------------------------------------------------------------------------

\2\ We note that alcohol, isopropyl alcohol, and some iodine-
containing active ingredients were proposed as GRAE in the 1994 TFM;
however, the studies that supported that proposal do not meet our
current standards for adequate and well-controlled studies. See
discussion in section VI.A.1.
---------------------------------------------------------------------------

A. Evaluation of Effectiveness Data

1. Clinical Simulation Studies
Most of the data available to support the effectiveness of health
care antiseptics are based on clinical simulation studies, such as the
ones described in the 1994 TFM (59 FR 31402 at 31444). In vivo test
methods, such as clinical simulation studies, and evaluation criteria
proposed in the 1994 TFM are based on the premise that bacterial
reductions achieved using tests that simulate conditions of actual use
for each OTC health care antiseptic product category reflect the
bacterial reductions that would be achieved under conditions of such
use. For example, one of the intended purposes of a health care
personnel hand wash is to reduce the risk of patient-to-patient cross
contamination. Thus, the clinical simulation studies proposed in the
1994 TFM are designed to demonstrate effectiveness of a product in the
presence of repeated bacterial challenge. The hands are artificially
contaminated with a marker organism (bacteria), and the reduction from
the baseline numbers of the contaminating organism is determined after
use of the test product. This contamination and hand wash procedure is
repeated several times, and bacterial reductions are measured at
various time points. This aspect of the study design is intended to
mimic the repeated use of the product (59 FR 31402 at 31448).
The testing proposed in the 1994 TFM for surgical hand scrubs and
patient preoperative skin preparations involves testing against
resident skin microflora (bacteria that normally colonize the skin),
and there is no artificial contamination of the skin in these studies.
Testing demonstrates that the resident bacterial load is highly
variable among individuals within the general population (Refs. 31 and
32). Although the 1994 TFM methods specify a minimum bacterial count
for individuals to be included in the assessment of surgical hand
scrubs and patient preoperative skin preparations, there can be
considerable intersubject variability. Similar to the health care
personnel hand washes, the testing of a surgical hand scrub proposed in
the 1994 TFM involves multiple test product uses and the repeated
measurement of bacterial reductions to determine both immediate and
persistent antimicrobial activity (59 FR 31402 at 31445). The patient
preoperative skin preparation test evaluates a single application of
the product on a dry skin site (abdomen or back) and a moist skin site
(groin or axilla) with higher numbers of resident bacteria (59 FR 31402
at 31450). The effectiveness criteria for patient preoperative skin
preparations and surgical hand scrubs proposed in the 1994 TFM also
require that bacterial growth be suppressed for 6 hours (59 FR 31402 at
31445 and 31450).
We evaluated all clinical simulation studies that were submitted to
the OTC Drug Review for evidence of health care personnel hand
antiseptic, surgical hand antiseptic, and patient preoperative skin
preparation effectiveness demonstrated under the log reduction criteria
proposed in the 1994 TFM (59 FR 31402 at 31445, 31448, and 31450) (Ref.
33). We also searched the published literature for clinical simulation
studies that assess health care personnel hand antiseptic, surgical
hand antiseptic, and patient preoperative skin preparation
effectiveness using the log reduction criteria in the 1994 TFM (Refs.
33 through 36).
Overall, the studies used a variety of study designs, including
nonstandard study designs. In some cases, such as for surgical hand
antiseptics, data submitted to the OTC Drug Review was

[[Page 25177]]

in the form of abstracts and technical reports. There is insufficient
information to evaluate the scientific merit of studies described in
abstracts and technical reports. Most importantly, none of the
evaluated studies were adequately controlled to demonstrate the
contribution of the active ingredient to the effectiveness observed in
the studies (43 FR 1210 at 1240) and, therefore, cannot be used to
demonstrate that the active ingredient tested is GRAE.
In general, the evaluated studies also had other deficiencies. Each
study had at least one of the following deficiencies:
Some studies that were described as using a standardized
method (American Society for Testing and Materials (ASTM) or 1994 TFM)
varied from these methods without explanation or validation, and the
majority of studies did not provide sufficient information about
critical aspects of the study conduct.
Many studies did not include appropriate controls; for
example, some studies did not include a vehicle control or an active
control (59 FR 31402 at 31446, 31448, and 31450), and some studies that
included an active control failed to use the control product according
to its labeled directions (59 FR 31402 at 31446, 31448, and 31450).
Many studies did not provide sufficient detail concerning
neutralizer use (43 FR 1210 at 1244) or validation of neutralizer
effectiveness.
The studies evaluated a small number of subjects (59 FR
31402 at 31446, 31449, and 31451).
Some studies did not sample at all of the time points
specified by the test method (59 FR 31402 at 31446, 31448, and 31450).
In the case of patient preoperative skin preparation
studies, some studies used subjects with baseline values that were too
low and other studies did not provide baseline values at all (59 FR
31402 at 31451). Many of the studies only tested one type of test site
(dry or moist), but the 1994 TFM (as well as the testing proposed here)
requires testing of both dry and moist test sites to demonstrate
effectiveness (59 FR 31402 at 31450).
FDA's detailed evaluation of the data is filed in Docket No. FDA-
2015-N-0101, available at http://www.regulations.gov (Refs. 33 through
36).
2. Clinical Outcome Studies
Although we are not currently proposing to require clinical outcome
studies to support a GRAE determination in this proposal, FDA has
evaluated all the clinical outcome studies that were submitted to the
OTC Drug Review to look for evidence of a clinical benefit from the use
of health care antiseptics (Ref. 33). In addition, we searched the
published literature for clinical outcome studies that would provide
evidence of a clinical benefit from the use of a health care antiseptic
(Ref. 37). Most of these studies were designed to evaluate health care
worker compliance with hand hygiene protocols, and thus, were not
adequately controlled to demonstrate a reduction of infection rates.
Most importantly, none of the studies used a vehicle control. In
general, the studies had additional design flaws such as the following:
A small sample size.
A lack of randomization, blinding, or both.
Inadequate statistical power and, in some cases, a failure
to analyze results for statistical significance.
Inadequate description of methodology and data collection
methods.
Inadequate documentation of proper training in hand wash
or rub, surgical hand scrub or rub, or patient preoperative skin
preparation technique.
Failure to observe and document hand washing technique.
Inadequate controls to address the multifactorial nature
of surgical site infection.
Some patients received antibiotic treatment and others did
not.
Some studies addressed nonmonograph indications.
As discussed in section VI, the March 2005 NDAC agreed that there
are currently no clinical trials presented that showed any clinical
benefit. The committee stated that conducting such a study in the
hospital setting would be unethical, especially considering the need to
introduce a placebo or vehicle control to show contribution of an
antiseptic drug product. This would put the subjects' health at risk.

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

In the 1994 TFM, we proposed that the effectiveness of antiseptic
active ingredients could be supported by a combination of in vitro
studies and in vivo clinical simulation testing as described in 21 CFR
333.470 (59 FR 31402 at 31444). In vitro studies are designed to
demonstrate the product's spectrum and kinetics of antimicrobial
activity, as well as the potential for the development of resistance
associated with product use. In vivo test methods and evaluation
criteria are based on the premise that bacterial reductions can be
adequately demonstrated using tests that simulate conditions of actual
use for each OTC health care antiseptic product category and that those
reductions are reflective of bacterial reductions that would be
achieved during use. (See discussion in section B.2.) Given the
limitations of our ability to study these active ingredients in a
clinical outcome study in a health care setting, a GRAE determination
for a health care antiseptic active ingredient should be supported by
an adequate characterization of the antimicrobial activity of the
ingredient through both in vitro testing and in vivo clinical
simulation testing.
1. In Vitro Studies
The 1994 TFM proposed that the antimicrobial activity of an active
ingredient could be demonstrated in vitro by a determination of the in
vitro spectrum of antimicrobial activity, minimum inhibitory
concentration (MIC) testing against 25 fresh clinical isolates and 25
laboratory strains, and time-kill testing against 23 laboratory strains
(59 FR 31402 at 31444). Comments received in response to the 1994 TFM
objected to the proposed in vitro testing requirements, stating that
they were overly burdensome (Ref. 38). Consequently, submissions of in
vitro data submitted to support the effectiveness of antiseptic active
ingredients were far less extensive than what was proposed in the 1994
TFM (Ref. 39). Although we agree that the in vitro testing proposed in
the 1994 TFM is overly burdensome for testing every final formulation
of an antiseptic product that contains a GRAE ingredient, we continue
to believe that a GRAE determination for a health care antiseptic
active ingredient should be supported by adequate in vitro
characterization of the antimicrobial activity of the ingredient. In
addition, we now propose the option of assessing the minimum
bactericidal concentration (MBC) as an alternative to testing the MIC
to demonstrate the broad spectrum activity of the antiseptic. The
ability of an antiseptic to kill microorganisms, rather than inhibit
them, is more relevant for a topical product. Because the determination
of GRAE status is a very broad statement that can apply to many
different formulations of an active ingredient, we continue to propose
that an evaluation of the spectrum and kinetics of antimicrobial
activity of a health care antiseptic active ingredient should include
the following:
A determination of the in vitro spectrum of antimicrobial
activity against recently isolated normal flora

[[Page 25178]]

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

Table 8--Clinical Simulation Testing Bacterial Log Reduction
Effectiveness Criteria in This Proposed Rule and in the 1994 TFM
------------------------------------------------------------------------
Indication 1994 TFM This proposed rule
------------------------------------------------------------------------
Health care personnel hand wash reduction reduction of 2.5
or health care personnel hand of 2 log10 on log10 on each
rub. each hand within hand within 5
5 minutes after minutes after a
the first wash, single wash or
and rub.
reduction
of 3 log10 on
each hand within
5 minutes after
the tenth wash.

[[Page 25179]]

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

VII. Safety (Generally Recognized as Safe) Determination

In the 1994 TFM, 11 active ingredients were classified as GRAS for
both health care personnel hand wash and surgical hand scrub use, and
18 active ingredients were classified as GRAS for patient preoperative
skin preparation use (59 FR 31402 at 31435). As described in section
I.C., health care personnel hand rubs and surgical hand rubs were not
separately addressed in the 1994 TFM. There have since been a number of
important scientific developments affecting our evaluation of the
safety of these active ingredients and causing us to reassess the data
necessary to support a GRAS determination. There is now new information
regarding systemic exposure to antiseptic active ingredients (Refs. 1
through 5). The potential for widespread antiseptic use to promote the
development of antibiotic-resistant bacteria also needs to be
evaluated. Further, additional experience with and knowledge about
safety testing has led to improved testing methods. Improvements
include study designs that are more capable of detecting potential
safety risks. Based on our reassessment, we are proposing new GRAS data
standards for health care antiseptic active ingredients. In order to
fully address these new safety concerns, additional safety data will be
necessary to support a GRAS determination for all health care
antiseptic active ingredients.
Many of the safety considerations for the five health care
antiseptic uses are the same because each use is considered a
``chronic'' use as that term is defined by the International Conference
on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH).\3\ A use is considered chronic if
the drug will be used for a period of at least 6 months over the user's
lifetime, including repeated, intermittent use (Ref. 40). Health care
personnel washes and rubs are used on a frequent daily basis, as are
surgical hand scrubs and rubs. Health care authorities list a variety
of situations in which health care workers should perform hand hygiene,
such as before and after touching a patient, after contact with body
fluids, and after removing gloves (Refs. 21 and 23). Patient
preoperative skin preparations also are used daily by many users. For
example, many people with type I diabetes require three to four insulin
injections a day (Ref. 41) and use these products prior to each
injection. Accordingly, we are proposing the same safety testing for
each active ingredient be done to support a GRAS determination,
regardless of the proposed health care antiseptic use.
---------------------------------------------------------------------------

\3\ FDA is a member of the ICH Steering Committee, the governing
body that oversees the harmonization activities, and contributed to
the development of ICH guidelines.
---------------------------------------------------------------------------

A. New Issues

Since the 1994 TFM was published, new data have become available
indicating that systemic exposure to topical antiseptic active
ingredients may be greater than previously thought. Systemic exposure
refers to the presence of antiseptic active ingredients inside and
throughout the body. Because of advances in technology, our ability to
detect antiseptic active ingredients in body fluids such as serum and
urine is greater than it was in 1994. For example, studies have shown
detectable blood alcohol levels after use of alcohol-containing health
care personnel hand rubs or surgical hand rubs (Refs. 1, 4, and 5). We
believe that any consequences of this systemic exposure should be
identified and assessed to support our risk-benefit analysis for health
care antiseptic use.
Given the frequent repeated use of both health care personnel hand
washes and rubs and surgical hand scrubs and rubs, systemic exposure
may occur. For some patients, the same may be true for patient
preoperative skin preparations. Although some systemic exposure data
exist for alcohol and triclosan, many of the other health care
antiseptic active ingredients have not been evaluated in this regard.
Currently, there is also a lack of data to assess the impact of
important drug use factors that can influence systemic exposure such as
dose, application frequency, application method, duration of exposure,
product formulation, skin condition, and age.
The evaluation of the safety of drug products involves correlating
findings from animal toxicity studies to the level of drug exposure
obtained from pharmacokinetic studies in animals and humans. Our
administrative record lacks the data necessary to define a margin of
safety for the potential chronic use of health care antiseptic active
ingredients. Thus, we are continuing to propose that both animal and
human pharmacokinetic data are necessary for health care antiseptic
active ingredients. This information will help identify any potential
safety concerns and help determine the safety margin for OTC human use.
One potential effect of systemic exposure to health care antiseptic
active ingredients that has come to our attention since publication of
the 1994 TFM is data suggesting that some health care antiseptic active
ingredients have hormonal effects. Triclosan and triclocarban can cause
alterations in

[[Page 25180]]

thyroid and reproductive systems of neonatal and adolescent animals
(Refs. 42 through 51). Hormonally active compounds have been shown to
affect not only the exposed organism, but also subsequent generations
(Ref. 52). These effects may not be related to direct deoxyribonucleic
acid (DNA) mutation, but rather to alterations in factors that regulate
gene expression (Ref. 53).
A hormonally active compound that causes reproductive system
disruption in the fetus or infant may have effects that are not
apparent until many years after initial exposure. There are also
critical times in fetal development when a change in hormonal balance
that would not cause any lasting effect in an adult could cause a
permanent developmental abnormality in a child. For example, untreated
hypothyroidism during pregnancy has been associated with cognitive
impairment in the offspring (Refs. 54, 55, and 56).
Because health care antiseptics are chronic use products and are
used by sensitive populations such as pregnant women, evaluation of the
potential for chronic toxicity and effects on reproduction and
development should be included in the safety assessment. The designs of
general toxicity and reproductive/developmental studies are often
sufficient to identify developmental effects that can be caused by
hormonally active compounds through the use of currently accepted
endpoints and standard good laboratory practice toxicology study
designs. As followup in some cases, additional study endpoints may be
needed to fully characterize the potential effects of drug exposure on
the exposed individuals. Section VII.C describes the types of studies
that can adequately evaluate an active ingredient's potential to cause
developmental or reproductive toxicity, or adverse effects on the
thyroid gland.

B. Antimicrobial Resistance

Since publication of the 1994 TFM, there is new information
available concerning the impact of widespread antiseptic use on the
development of antimicrobial resistance (Refs. 57 through 60). Bacteria
use some of the same resistance mechanisms against both antiseptics and
antibiotics. Thus, the use of antiseptic active ingredients with
resistance mechanisms in common with antibiotics may have the potential
to select for bacterial strains that are also resistant to clinically
important antibiotics, adding to the problem of antibiotic resistance.
In the health care setting where infection-control practices are
multifaceted and include the use of antiseptics, antibiotics, and
frequent disinfection, it is difficult to identify the source of
antimicrobial resistance or to quantify the impact of antiseptics on
the selection, survival, and spread of antimicrobial resistant
bacterial strains.
Laboratory studies of some of the antiseptic active ingredients
evaluated in this proposed rule demonstrate that bacteria can develop
reduced susceptibility to antiseptic active ingredients and some
antibiotics after growth in nonlethal amounts of the antiseptic (i.e.,
low-to-moderate concentrations of antiseptic) (Refs. 61 through 78).
These studies indicate that further data needs to be gathered regarding
whether bacterial resistance mechanisms exist that could select for
cross-resistance in the health care setting.
Laboratory studies examining the antiseptic and antibiotic
susceptibilities of clinical isolates of Staphylococcus aureus and
methicillin-resistant S. aureus (MRSA) have found strains of these
organisms with reduced susceptibilities to both antiseptics and
antibiotics (Refs. 67 and 79 through 83). However, the impact of such
dual tolerances in the clinical setting is unclear. Studies of the
impact of such tolerance in S. aureus and Escherichia coli in the
clinical setting have yielded mixed results (Refs. 84 through 87).
Interpretation of these data is further limited by the fact that only
S. aureus and E. coli have been studied. All of the organisms studied
constitute a very small subset of the organisms of concern, and one of
these organisms (MRSA) is already resistant to some antimicrobials.
Thus, the available data are not sufficient to support a finding that
these mechanisms of reduced susceptibility would have meaningful
clinical impact in a setting where extensive infection control measures
that include antibiotic use and frequent disinfection are the norm. In
other words, bacteria in the health care setting will be exposed to
multiple sources of antimicrobials--regardless of the use of health
care antiseptics--which may lessen the impact of the role of health
care antiseptics in the development of bacterial resistance.
FDA has been evaluating the role that all antiseptic products,
including health care antiseptic products, may play in the development
of antibiotic resistance for quite some time, and has sought the advice
from expert panels on this topic. In 1997, a joint Nonprescription
Drugs and Anti-Infective Drugs Advisory Committee concluded that the
data were not sufficient to take any action on this issue at that time
(Ref. 6). The joint Committee recommended that FDA work with industry
to establish surveillance mechanisms to address antiseptic and
antibiotic resistance. FDA also plays a major role on the Interagency
Task Force on Antimicrobial Resistance and helped draft the Public
Health Action Plan to Combat Antimicrobial Resistance (Ref. 88). The
Action Plan discusses how to sufficiently implement the surveillance,
prevention and control, and research elements of the Action Plan.
Reports of the persistence of low levels of some antiseptic active
ingredients in the environment (Refs. 89, 90, and 91) signal the need
to better understand the impact of all antiseptics, including health
care antiseptic drug products. Although it is important to consider the
relative contribution of the use of health care antiseptic products to
any possible environmental impact, it is also important to consider the
benefits of these products. Hospital-acquired infections can result in
prolonged hospital stays, additional medical treatment, adverse
clinical outcomes, and increased health care costs. The use of health
care antiseptics is considered an important component of the
multifaceted approach that hospitals use to keep hospital acquired
infection rates low (Refs. 21 and 23). Furthermore, in situations where
there is extensive use of antibiotics, exposure to antibiotics, rather
than exposure to antiseptics, plays a dominant role in emerging
antibiotic resistance. This makes it difficult to determine whether
antiseptics play a significant role in the development of antimicrobial
resistance in the hospital setting. Despite this, the use of
antiseptics in health care settings may also contribute to the
selection of bacterial genera and species that are less susceptible to
both antiseptics and antibiotics. We are requesting additional data and
information to address this issue. Section VII.C describes the data
that will help establish a better understanding of the interactions
between antiseptic active ingredients and bacterial resistance
mechanisms in health care antiseptic products and will provide the
information needed to perform an adequate risk assessment for these
health care product uses. FDA recognizes that the science of evaluating
the potential of compounds to cause bacterial resistance is evolving
and acknowledges the possibility that alternative data different from
that listed in section VII.C may be identified as an appropriate
substitute for evaluating resistance.

C. Studies To Support a Generally Recognized as Safe Determination

A GRAS determination for health care antiseptic active ingredients
must be

[[Page 25181]]

supported by both nonclinical (animal) and clinical (human) studies. To
issue a final monograph for these products, this safety data must be in
the administrative record (i.e., rulemaking docket).\4\
---------------------------------------------------------------------------

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

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

Table 9--FDA Guidance Documents Related to Requested Safety Data and Rationale for Studies
----------------------------------------------------------------------------------------------------------------
Type of study Study conditions What the data tell us How the data are used
----------------------------------------------------------------------------------------------------------------
Animal pharmacokinetic absorption, Both oral and dermal Allows identification Used as a surrogate to
distribution, metabolism, and administration. of the dose at which identify toxic
excretion (ADME) (Refs. 93 and 99). the toxic effects of systemic exposure
an active ingredient levels that can then
are observed as a be correlated to
result of systemic potential human
exposure of the drug. exposure via dermal
ADME data provide: The pharmacokinetic study
rate and extent an findings. Adverse
active ingredient is event data related to
absorbed into the body particular doses and
(e.g., AUC, Cmax, drug levels (exposure)
Tmax); \1\ where the in animals are used to
active ingredient is help formulate a
distributed in the safety picture of the
body; whether possible risk to
metabolism of the humans.
active ingredient by
the body has taken
place; information on
the presence of
metabolites; and how
the body eliminates
the original active
ingredient (parent)
and its metabolites
(e.g., T\1/2\). \2\.
Human pharmacokinetics (MUsT) (Ref. Dermal administration Helps determine how Used to relate the
97). using multiple much of the active potential human
formulations under ingredient penetrates exposure to toxic drug
maximum use conditions. the skin, leading to levels identified in
measurable systemic animal studies.
exposure.
Carcinogenicity (ICH S1A, S1B, and Minimum of one oral and Provides a direct Identifies the systemic
S1C (Refs. 40, 92, and 95)). one dermal study for measure of the and dermal risks
topical products. potential for active associated with drug
ingredients to cause active ingredients.
tumor formation Taken together, these
(tumorogenesis) in the studies are used to
exposed animals. identify the type(s)
of toxicity, the level
of exposure that
produces these
toxicities, and the
highest level of
exposure at which no
adverse effects occur,
referred to as the
``no observed adverse
effect level''
(NOAEL). The NOAEL is
used to determine a
safety margin for
human exposure.
Developmental toxicity (ICH S5 (Ref. Oral administration.... Evaluates the effects
94)). of a drug on the
developing offspring
throughout gestation
and postnatally until
sexual maturation.
Reproductive toxicity (ICH S5 (Ref. Oral administration.... Assesses the effects of
94)). a drug on the
reproductive
competence of sexually
mature male and female
animals.
Hormonal effects (Ref. 98)........... Oral administration.... Assesses the drug's Used in hazard
potential to interfere assessment to
with the endocrine determine whether the
system. drug has the capacity
to induce a harmful
effect at any exposure
level without regard
to actual human
exposures.
----------------------------------------------------------------------------------------------------------------
\1\ ``AUC'' denotes the area under the concentration-time curve, a measure of total exposure or the extent of
absorption. ``Cmax'' denotes the maximum concentration, which is peak exposure. ``Tmax'' denotes the time to
reach the maximum concentration, which aids in determining the rate of exposure.
\2\ ``T\1/2\'' denotes the half-life, which is the amount of time it takes to eliminate half the drug from the
body or decrease the concentration of the drug in plasma by 50 percent.

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

[[Page 25182]]

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

[[Page 25183]]

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

If the results of these studies show no evidence of changes in
antiseptic or antibiotic susceptibility, then we propose that no
further studies addressing the development of resistance are needed to
support a GRAS determination.

However, for antiseptic active ingredients that demonstrate an
effect on antiseptic and antibiotic susceptibilities, additional data
will be necessary to help assess the likelihood that changes in
susceptibility observed in the preliminary studies would occur in the
health care setting. Different types of data could be used to assess
whether or not ingredients with positive laboratory findings pose a
public health risk (Ref. 291). We do not anticipate that it will be
necessary to obtain data from multiple types of studies for each active
ingredient to adequately assess its potential to affect resistance.
Such types of data could include, but are not limited to, the
following:
Information about the mechanism(s) of antiseptic action
(for example, membrane destabilization or inhibition of fatty acid
synthesis), and whether there is a change in the mechanism of action
with changes in antiseptic concentration;
information clarifying the bacteria's mechanism(s) for the
development of

[[Page 25184]]

resistance or reduced susceptibility to the antiseptic active
ingredient (for example, efflux mechanisms);
data characterizing the potential for reduced antiseptic
susceptibility caused by the antiseptic active ingredient to be
transferred to other bacteria that are still sensitive to the
antiseptic;
data characterizing the concentrations and antimicrobial
activity of the antiseptic active ingredient in biological and
environmental compartments (for example, on the skin, in the gut, and
in environmental matrices); and
data characterizing the antiseptic and antibiotic
susceptibility levels of environmental isolates of bacteria in areas of
prevalent health care antiseptic use (for example, patient rooms and
surgical suites).
These data can help ascertain whether or not a health care
antiseptic active ingredient is likely to induce nonspecific bacterial
resistance mechanisms. These data could also help determine the
likelihood that changes in susceptibility would spread to other
bacterial populations and whether or not concentrations of health care
antiseptics exist in relevant biological and environmental compartments
that are sufficient to induce changes in bacterial susceptibilities.
Data on the antiseptic and antibiotic susceptibilities of bacteria in
areas of prevalent health care antiseptic use can help demonstrate
whether or not changes in susceptibility are occurring with actual use.
Because actual use concentrations of health care antiseptics are much
higher than the MICs for these active ingredients, data from
compartments where sublethal concentrations of biologically active
antiseptic active ingredients may occur (e.g., environmental
compartments) can give us a sense of the potential for change in
antimicrobial susceptibilities in these compartments (Refs. 116, 117,
and 118). FDA recognizes, however, that methods of evaluating this
issue are an evolving science and that there may be other data
appropriate to evaluate the impact of health care antiseptic active
ingredients on the development of resistance. For this reason, FDA
encourages interested parties to consult with the Agency on the
specific studies appropriate to address this issue for a particular
active ingredient.

D. Review of Available Data for Each Antiseptic Active Ingredient

We have identified for each health care antiseptic active
ingredient whether the studies outlined in section VII.C are publicly
available. Table 10 lists the types of studies available for each
antiseptic active ingredient proposed as Category I or Category III in
the 1994 TFM and indicates whether the currently available data are
adequate to serve as the basis of a GRAS determination. Although we
have some data from submissions to the rulemaking and from information
we have identified in the literature, our administrative record is
incomplete for at least some types of safety studies for each of the
active ingredients (see table 10). As noted previously in this
document, only information that is part of the administrative record
for this rulemaking can form the basis of a GRAS/GRAE determination.
We recognize that data and information submitted in response to the
2013 Consumer Wash PR may be relevant to this proposed rule for those
active ingredients eligible for use as both consumer and health care
antiseptics. At the time of publication of this proposed rule, FDA's
review of all submissions made to the 2013 Consumer Wash PR had not
been completed. To be considered in this rulemaking, any information
relevant to health care antiseptic active ingredients must be
resubmitted under this docket (FDA-2015-N-0101) for consideration.

Table 10--Safety Studies Available for Health Care Antiseptic Active Ingredients \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Human Animal
pharmaco- pharmaco- Oral Dermal Reproductive Potential Resistance
Active ingredient \2\ kinetic kinetic carcino- carcino- toxicity hormonal potential
(MUsT) (ADME) genicity genicity (DART) effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
Alcohol..................................................... [cir]
Benzalkonium chloride....................................... [cir] [cir]
Benzethonium chloride....................................... [cir] [cir] [cir]
Chloroxylenol............................................... [cir] [cir] [cir] [cir]
Hexylresorcinol............................................. [cir]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Simple iodine solutions
--------------------------------------------------------------------------------------------------------------------------------------------------------
Iodine tincture USP......................................... [cir] \3\ \3\

Iodine topical solution USP................................. [cir] \3\ \3\

--------------------------------------------------------------------------------------------------------------------------------------------------------
Iodine complexes
--------------------------------------------------------------------------------------------------------------------------------------------------------
Povidone-iodine............................................. \4\ [cir] \5\ \3\ \3\

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

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

[[Page 25185]]

no longer proposed as GRAS for use in health care antiseptics (i.e.,
why they are now proposed as Category III):

Alcohol
Hexylresorcinol
Iodine tincture USP
Iodine topical solution USP
Isopropyl alcohol
Povidone-iodine
Triclocarban

We also discuss the following antiseptic active ingredients that
were proposed as Category III in the 1994 TFM and for which there are
some new data available and explain why these ingredients are still
Category III:

Benzalkonium chloride
Benzethonium chloride
Chloroxylenol
Triclosan

We do not discuss the following antiseptic active ingredients that
were proposed as Category III in the 1994 TFM because we are not aware
of any new safety data for these active ingredients:

Cloflucarban
Iodine complex (ammonium ether sulfate and polyoxyethylene
sorbitan monolaurate)
Iodine complex (phosphate ester of alkylaryloxy polyethylene
glycol)
Mercufenol chloride
Mercufenol chloride and secondary amyltricresols in 50 percent
alcohol
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol (less than 1.5 percent)
Poloxamer-iodine complex
Secondary amyltricresols
Sodium oxychlorosene
Undecoylium chloride iodine complex
1. Alcohol
In the 1994 TFM, FDA proposed to classify alcohol as GRAS for all
health care antiseptic uses based on the recommendation of the
Miscellaneous External Panel, which concluded that the topical
application of alcohol is safe (47 FR 22324 at 22329 and 59 FR 31402 at
31412). FDA is now proposing to classify alcohol as Category III.
Extensive studies have been conducted to characterize the metabolic and
toxic effect of alcohol in animal models. Although the impetus for most
of the studies has been to study the effects of alcohol exposure via
the oral route of administration, some dermal toxicity studies are
available and have shown that, although there is alcohol absorption
through human skin, it is much lower than absorption via the oral
route. Overall, there are adequate safety data to make a GRAS
determination for alcohol, with the exception of human pharmacokinetic
data under maximal use conditions.
a. Summary of Alcohol Safety Data
Alcohol human pharmacokinetic data. Some published data are
available to characterize the level of dermal absorption and expected
systemic exposure in adults as a result of topical use of alcohol-
containing health care antiseptics. As shown in table 11, a variety of
alcohol-based hand rub product formulations and alcohol concentrations
have been used in these studies. Based on the available data, which
represents moderate hand rub use (7.5 to 40 hand rub applications per
hour, studied for 30 to 240 minutes), the highest observed exposure was
1,500 milligrams (mg) of alcohol (Ref. 4), which is the equivalent of
10 percent of an alcohol-containing drink.\5\ (See also the discussion
of occupational exposure to alcohol via the dermal route (Ref. 119) in
the alcohol carcinogenicity section of this proposed rule.) Although
the available data suggest that dermal absorption of alcohol as a
result of health care antiseptic use is relatively low, these studies
do not reflect the amount of exposure that may occur during a regular
8- to 12-hour work shift in a health care facility. Consequently, human
pharmacokinetics data under maximal use conditions as determined by a
MUsT are still needed to make a GRAS determination.
---------------------------------------------------------------------------

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

Table 11--Results of Alcohol Hand Rub Absorption Studies in Humans
--------------------------------------------------------------------------------------------------------------------------------------------------------
Highest blood
alcohol level
Number of Amount of alcohol Volume of hand Number of hand rub Total length of detected
Study subjects in hand rub rub used applications during assessment (Milligram/
(percent) (milliliter (mL)) the study Deciliter (mg/
dL))
--------------------------------------------------------------------------------------------------------------------------------------------------------
Kramer, et al. (Ref. 4)............ 12 95 4 20.................... 30 minutes........... 2.10
Kramer, et al. (Ref. 4)............ 12 95 \1\ 4 10.................... 80 minutes........... 1.75
Kramer, et al. (Ref. 4)............ 12 85 4 20.................... 30 minutes........... 1.15
Kramer, et al. (Ref. 4)............ 12 85 \1\ 4 10.................... 80 minutes........... 3.01
Kirschner, et al. (Ref. 120)....... 14 74.1 \2\ 20 One 10-minute 10 minutes........... ~0.175
application.
Brown, et al. (Ref. 121)........... 20 70 1.2-1.5 30.................... 1 hour............... 1.2
Ahmed-Lecheheb, et al. (Ref. 122).. 86 70 3 Average of 9 \3\...... 4 hours.............. 0.022
Miller, et al. (Ref. 5)............ 5 62 5 50.................... 4 hours.............. < 5
Miller, et al. (Ref. 123).......... 1 62 5 25.................... 2 hours.............. < 5
Kramer, et al. (Ref. 4)............ 12 55 4 20.................... 30 minutes........... 0.69
Kramer, et al. (Ref. 4)............ 12 55 \1\ 4 10.................... 80 minutes........... 0.88
Bessonneau, V. and O. Thomas (Ref. 1 70 3 5..................... NA \4\............... 1.43 \5\
124).
Bessonneau, V. and O. Thomas (Ref. 1 70 \1\ 3 mL x 2 5..................... NA................... 2.02 \5\
124).
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Product applied using a surgical scrub procedure.
\2\ Product applied to the subject's back rather than to the hands to exclude any significant interference of inhaled uptake of evaporated alcohol.
\3\ Assessed under actual use conditions in a hospital.
\4\ Not available because of different study design.
\5\ Alcohol concentration measured in air collected from the subject's breathing zone.

[[Page 25186]]

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

[[Page 25187]]

alcohol at serum levels of greater than 200 mg/dL exerts age-dependent
effects on the synthesis and secretion of testosterone throughout
sexual maturation in rats. Overall, the effects of alcohol on hormones
in animals have been well characterized and no additional data are
needed to make a GRAS determination.
Alcohol data on hormonal effects in humans. The effects of alcohol
on human hormones are multiple and complex. Several variables,
including the type, length, and pattern of alcohol exposure, and
coexisting medical problems, such as malnutrition and liver
dysfunction, must be considered when assessing the impact of alcohol on
hormonal status (Ref. 142). Pregnant health care workers are a
potentially vulnerable population given that alcohol is a teratogen,
and alcohol-containing antiseptic hand rubs are used frequently in
health care settings. Alcohol in the maternal bloodstream crosses
readily into the placenta and the fetal compartment (Ref. 143). This
results in similar blood alcohol concentrations in the mother, the
fetus, and the amniotic fluid (Ref. 143). The fetus has very limited
metabolic capacity for alcohol primarily because of low to absent
hepatic activity for the metabolism of alcohol (Ref. 144). Although
both the placenta and fetus have some capacity to metabolize alcohol,
the majority of alcohol metabolism occurs in maternal metabolic systems
outside of the fetal compartment (Ref. 143).
Maternal alcohol use (by ingestion) is the leading known cause of
developmental and cognitive disabilities in the offspring, and is a
preventable cause of birth defects (Ref. 145). However, based on
available absorption data, it is highly unlikely that the levels of
alcohol absorbed as a result of health care antiseptic use would
approach the levels that cause fetal alcohol syndrome. Nonetheless,
children exposed to lower levels of alcohol in utero may be vulnerable
to more subtle effects. Currently, the levels of alcohol exposure that
cause more subtle effects are unknown.
Unlike the abundance of data from oral exposure, there are no data
on the effects of systemic exposure to alcohol during pregnancy from
the use of alcohol-containing hand rubs. There are, however, some
pharmacokinetic data on alcohol absorption after hand rub use in the
nonpregnant population (described in the human pharmacokinetic
subsection of this section of the proposed rule). As noted previously,
the available data suggest that with moderate health care antiseptic
hand rub use (e.g., evaluations of the amount of alcohol in the blood
at up to 4 hours of use), systemic alcohol exposure is relatively low,
but may be as high as 10 percent of an alcohol-containing drink.
However, health care workers who use these products chronically and
repetitively may be required to use alcohol-containing hand rubs in
situations such as prior to and following contact with patients or
contact with body fluids, and therefore may be exposed to these
products a hundred times or more per day (Ref. 101). Consequently,
additional human pharmacokinetic data are needed to determine the level
of alcohol exposure following maximal use of health care antiseptics
(i.e., MUsT) to determine the level of risk from the use of these
products.
Alcohol resistance data. The antimicrobial mechanism of action of
alcohol is considered nonspecific. It is believed that alcohol has
multiple toxic effects on the structure and metabolism of
microorganisms, primarily caused by denaturation and coagulation of
proteins (Refs. 146 through 149). Alcohol's reactive hydroxyl (-OH)
group readily forms hydrogen bonds with proteins, which leads to loss
of structure and function, causing protein and other macromolecules to
precipitate (Ref. 148). Alcohol also lyses the bacterial cytoplasmic
membrane, which releases the cellular contents and leads to bacterial
inactivation (Ref. 146). Because of alcohol's speed of action and
multiple, nonspecific toxic effects, microorganisms have a difficult
time developing resistance to alcohol. Of note, researchers have been
attempting to develop alcohol-tolerant bacteria for use in biofuel
production and beverage biotechnology applications. One of the most
alcohol-tolerant bacteria, Lactobacillus, has been shown to grow in the
presence of up to 13 percent alcohol, which is far lower than the
alcohol concentrations present in health care antiseptic products (Ref.
150). Health care antiseptic products contain at least 60 percent
alcohol (59 FR 31402 at 31442), and bacteria are unable to grow in this
relatively high concentration of alcohol. Furthermore, alcohol
evaporates readily after topical application, so no significant
antiseptic residue is left on the skin that could contribute to the
development of resistance (Refs. 146 and 148). Consequently, the
development of resistance as a result of health care antiseptic use is
unlikely, and additional data on the development of antimicrobial
resistance to alcohol are not needed to support a GRAS determination.
b. Alcohol safety data gaps. In summary, our administrative record
for the safety of alcohol is incomplete with respect to the following:

Human pharmacokinetic studies under maximal use conditions
when applied topically (MUsT), including documentation of validation of
the methods used to measure alcohol and its metabolites and
data to help define the effect of formulation on dermal
absorption.
2. Benzalkonium Chloride
In the 1994 TFM, FDA categorized benzalkonium chloride in Category
III because of a lack of adequate safety data for its use as both a
health care personnel hand wash and surgical hand scrub (59 FR 31402 at
31435). FDA continues to propose benzalkonium chloride as Category III.
Because of its widespread use as an antimicrobial agent in cosmetics
and as a disinfectant for hard surfaces in agriculture and medical
settings, the safety of benzalkonium chloride has also been reviewed by
the Environmental Protection Agency and an industry review panel
(Cosmetic Ingredient Review (CIR)) (Refs. 151 and 152) and found to be
safe for disinfectant and cosmetic uses, respectively. Both these
evaluations have been cited by the comments in support of the safety of
benzalkonium chloride as a health care antiseptic wash active
ingredient (Ref. 153).
Each of these evaluations cites findings from the type of studies
necessary to support the safety of benzalkonium chloride for repeated
daily use. However, the data that are the basis of these safety
assessments are proprietary and are publicly available only in the form
of summaries. Consequently, these studies are not available to FDA and
are precluded from a complete evaluation by FDA. In addition, the
submitted safety assessments with study summaries do not constitute an
adequate record on which to base a GRAS classification (see generally
Sec. 330.10(a)(4)(i)). For FDA to evaluate the safety of benzalkonium
chloride for this rulemaking, these studies must be submitted to the
rulemaking or otherwise be made publicly available.
In addition to these summaries, as discussed in the 2013 Consumer
Wash PR (78 FR 76444 at 76463), FDA has reviewed studies on resistance
data and antibiotic susceptibility of certain bacteria (Refs. 62, 68,
70, 71, 73, 154, 155, and 156), and determined that the available
studies have examined few

[[Page 25188]]

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

[[Page 25189]]

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

Iodine tincture USP
Iodine topical solution USP
Povidone-iodine 5 to 10 percent

Iodine is found naturally in the human body and is essential for
normal human body function. In the body, iodine accumulates in the
thyroid gland and is a critical component of thyroid hormones. People
obtain iodine through their food and water, which are often
supplemented with iodine to prevent iodine deficiency. Because people
are widely exposed to iodine, it has been the subject of comprehensive
toxicological review by public health organizations (Refs. 178 and
179).
Much of the safety data we reviewed pertained to elemental iodine
alone.

[[Page 25190]]

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

[[Page 25191]]

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

[[Page 25192]]

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

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

[[Page 25194]]

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

[[Page 25195]]

triclosan susceptibility of clinical isolates of S. epidermidis
isolated from blood cultures of patients that were collected prior to
the introduction of triclosan (during 1965-1966, ``old'' isolates) was
compared to modern isolates, collected in 2010-2011 (Ref. 281). None of
the isolates from 1965-1966 were tolerant to triclosan; however, 12.5
percent of the modern isolates had decreased triclosan susceptibility,
with MIC values that were up to 32-fold higher than the highest value
found in the old isolates. When triclosan-susceptible strains were
grown in increasing concentrations of triclosan, both old and modern
isolates could be adapted to the same triclosan MIC level as found in
modern tolerant isolates. Although this study suggests that decreased
susceptibility to triclosan can occur in relevant organisms as a result
of triclosan exposure, the source(s) and extent of triclosan exposure
for the modern isolates are unknown, which makes the relevance of these
data to the clinical setting unclear.
In another recent study (Ref. 282), the antimicrobial activity of
triclosan was evaluated for a multidrug-resistant strain of P.
aeruginosa that had caused an outbreak in an oncohematology unit in
Italy (Ref. 283). Experimental exposure to triclosan has been shown to
lead to changes in bacterial efflux pump activity, which can result in
antibiotics being removed from the bacterial cell and bacterial
resistance (Ref. 66). The authors of this study examined whether
triclosan exposure increased the level of antibiotic resistance in the
outbreak strain. The outbreak strain was adapted to grow in the
presence of triclosan by serial passage in gradually increasing
triclosan concentrations, up to 3,400 mg/L triclosan. Then, the
susceptibility of triclosan-adapted and unadapted P. aeruginosa to a
panel of antibiotics that are typically exported by efflux pumps,
namely tetracycline, ciprofloxacin, amikacin, levofloxacin,
carbenicillin, and chloramphenicol, was determined. For all antibiotics
examined, the MIC of the triclosan-adapted strain was 2-fold higher
than the unadapted strain. The addition of efflux pump inhibitors
reduced the MICs 2- to 4-fold for both strains and all antibiotics
examined, suggesting that an efflux pump mechanism is involved in the
reduced susceptibility. Despite the trend for the triclosan-adapted
strain to be less susceptible to the tested antibiotics, the
differences were very modest and the clinical relevance of these small
changes in MIC, if any, are not known.
Overall, the administrative record for triclosan is complete on the
following aspects of the resistance issue:
Laboratory studies demonstrate triclosan's ability to
alter antibiotic susceptibilities (Refs. 61 through 66, 69, 72, 74
through 77, and 263).
Data define triclosan's mechanisms of action and
demonstrate that these mechanisms are dose dependent (Ref. 113).
Data demonstrate that exposure to triclosan changes efflux
pump activity, a common nonspecific bacterial resistance mechanism
(Refs. 66, 69, 76, and 109).
Data show that low levels of triclosan may persist in the
environment (Refs. 91, 116, 117, and 284 through 289).
However, the administrative record is not complete with respect to
data that would clarify the potential public health impact of the
currently available data. Examples of the type of information that
could be submitted to complete the record include the following:
Data to characterize the concentrations and antimicrobial
activity of triclosan in various biological and environmental
compartments (e.g., on the skin, in the gut, and in environmental
matrices);
data to characterize the antiseptic and antibiotic
susceptibility levels of environmental isolates in areas of prevalent
antiseptic use, e.g., in health care, food handler, and veterinary
settings; and
data to characterize the potential for the reduced
antiseptic susceptibility caused by triclosan to be transferred to
other bacteria that are still sensitive to triclosan.
b. Triclosan Safety Data Gaps.
In summary, our administrative record for the safety of triclosan
is incomplete with respect to the following:
Human pharmacokinetic studies under maximal use conditions
when applied topically (MUsT), including documentation of validation of
the methods used to measure triclosan and its metabolites;
animal ADME;
dermal carcinogenicity;
potential hormonal effects; and
data to clarify the relevance of antimicrobial resistance
laboratory findings to the health care setting.

VIII. Proposed Effective Date

Based on the currently available data, this proposed rule finds
that additional data are necessary to establish the safety and
effectiveness of health care antiseptic active ingredients for use in
OTC health care antiseptic drug products. Accordingly, health care
antiseptic active ingredients would be nonmonograph in any final rule
based on this proposed rule. We recognize, based on the scope of
products subject to this monograph, that manufacturers will need time
to comply with a final rule based on this proposed rule. However,
because of the potential effectiveness and safety considerations raised
by the data for some antiseptic active ingredients evaluated, we
believe that an effective date later than 1 year after publication of
the final rule would not be appropriate or necessary. Consequently, any
final rule that results from this proposed rule will be effective 1
year after the date of the final rule's publication in the Federal
Register. On or after that date, any OTC health care antiseptic drug
product that is subject to the monograph and that contains a
nonmonograph condition, i.e., a condition that would cause the drug to
be not GRAS/GRAE or to be misbranded, could not be introduced or
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application or abbreviated new drug
application. Any OTC health care antiseptic drug product subject to the
final rule that is repackaged or relabeled after the effective date of
the final rule would be required to be in compliance with the final
rule, regardless of the date the product was initially introduced or
initially delivered for introduction into interstate commerce.

IX. Summary of Preliminary Regulatory Impact Analysis

The summary analysis of benefits and costs included in this
proposed rule is drawn from the detailed Preliminary Regulatory Impact
Analysis (PRIA) that is available at http://www.regulations.gov, Docket
No. FDA-2015-N-0101 (formerly Docket No. FDA-1975-N-0012).

A. Introduction

FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). The Agency believes that this proposed rule is a significant
regulatory action as defined by Executive Order 12866.

[[Page 25196]]

The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The proposed rule could impose significant economic
burdens on a substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141 million, using the most current (2013) Implicit
Price Deflator for the Gross Domestic Product. FDA expects that this
proposed rule could result in a 1-year expenditure that would meet or
exceed this amount.

B. Summary of Costs and Benefits

The proposed rule's costs and benefits are summarized in table 12
entitled ``Economic Data: Costs and Benefits Statement.'' Benefits are
attributed to reducing the potential adverse health effects associated
with exposure to antiseptic active ingredients in the event that any
active ingredient is shown to be unsafe or ineffective for chronic use.
Annual benefits are estimated to range between $0 and $0.16 million. We
estimate the present value associated with $0.16 million of annual
benefits, over a 10-year period, to approximately equal $1.4 million at
a 3 percent discount rate and $1.1 million at a 7 percent discount
rate.
Costs include the one-time costs associated with reformulating
products, relabeling reformulated products, and conducting both safety
and efficacy tests. We estimate one-time upfront costs to approximately
range between $64.0 million and $90.8 million. Annualizing these costs
over a 10-year period, we estimate total annualized costs to range from
$7.3 and $10.4 million at a 3 percent discount rate to $8.5 and $12.1
million at a 7 percent discount rate.
FDA also examined the economic implications of the rule as required
by the Regulatory Flexibility Act. If a rule will have a significant
economic impact on a substantial number of small entities, the
Regulatory Flexibility Act requires Agencies to analyze regulatory
options that would lessen the economic effect of the rule on small
entities. The rule could impose a significant economic impact on a
substantial number of small entities. For small entities, we estimate
the rule's costs to roughly range between 0.01 and 82.18 percent of
average annual revenues. In the Initial Regulatory Analysis, we assess
several regulatory options that would reduce the proposed rule's burden
on small entities. These options include extending testing compliance
time to 24 months (rather than 12 months), and extending relabeling
compliance times to 18 months (rather than 12 months).
The full discussion of economic impacts is available in Docket No.
FDA-2015-N-0101 http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

Table 12--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
---------------------------------------
Category Low Median High Discount Period Notes
estimate estimate estimate Year rate covered
dollars (percent) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $millions/year.... 0.0 $0.08 $0.16 2013 7 10 Value of reduced number of
Annualized Monetized $millions/year.... 0.0 0.08 0.16 2013 3 10 adverse events associated
with using non-GRAS/GRAE
antiseptic active
ingredients. Range of
estimates captures
uncertainty.
------------------------------------------------------------------------------------------------------------
Annualized Quantified billion/year..... 0 10.3 20.6 ........... 7 10 Reduced antiseptic active
Annualized Quantified billion/year..... 0 10.3 20.6 ........... 3 10 ingredient exposure (in
milliliters). Range of
estimates captures
uncertainty.
------------------------------------------------------------------------------------------------------------
Qualitative............................ Value of infection avoidance associated with switching from non-GRAS/GRAE antiseptic active ingredients to
NDA or ANDA antiseptics.
------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized $millions/year.... 8.5 10.3 12.1 2013 7 10 Annualized costs of
Annualized Monetized $millions/year.... 7.3 8.9 10.4 2013 3 10 reformulating and testing
antiseptic products. Range
of estimates capture
uncertainty.
------------------------------------------------------------------------------------------------------------
Annualized Quantified billion/year..... ........... ........... ........... ........... 7
Annualized Quantified billion/year..... ........... ........... ........... ........... 3
------------------------------------------------------------------------------------------------------------
Qualitative............................ Where the products affected by this proposed rule are currently chosen over NDA and ANDA alternatives (such
as chlorhexidine products), a switch brought on by the rule may lead to search costs or other types of
transactions costs. In this scenario, there are also the potential costs associated with adverse reactions
if patients are allergic to substitute products.
------------------------------------------------------------------------------------------------------------

[[Page 25197]]

Transfers:
Federal Annualized..................... ........... ........... ........... ........... 7
Monetized $millions/year............... ........... ........... ........... ........... 3
From/To................................
Other Annualized....................... ........... ........... ........... ........... 7
Monetized $millions/year............... ........... ........... ........... ........... 3
From/To................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
State, Local, or Tribal Government: Not applicable..................................................................................................
Small Business: The costs associated with potentially affected small entities range between 0.01 and 82.18 percent of their average annual revenues.
Wages: No estimated effect..........................................................................................................................
Growth: No estimated effect.........................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

X. Paperwork Reduction Act of 1995

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

XI. Environmental Impact

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

XII. Federalism

FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would have a preemptive effect on
State law. Section 4(a) of the Executive order requires Agencies to
``construe . . . a Federal statute to preempt State law only where the
statute contains an express preemption provision or there is some other
clear evidence that the Congress intended preemption of State law, or
where the exercise of State authority conflicts with the exercise of
Federal authority under the Federal statute.'' Section 751 of the FD&C
Act (21 U.S.C. 379r) is an express preemption provision. Section 751(a)
of the FD&C Act provides that no State or political subdivision of a
State may establish or continue in effect any requirement that: (1)
Relates to the regulation of a drug that is not subject to the
requirements of section 503(b)(1) or 503(f)(1)(A) of the FD&C Act and
(2) is different from or in addition to, or that is otherwise not
identical with, a requirement under the FD&C Act, the Poison Prevention
Packaging Act of 1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging
and Labeling Act (15 U.S.C. 1451 et seq.). Currently, this provision
operates to preempt States from imposing requirements related to the
regulation of nonprescription drug products. (See section 751(b)
through (e) of the FD&C Act for the scope of the express preemption
provision, the exemption procedures, and the exceptions to the
provision.)
This proposed rule, if finalized as proposed, would remove from the
health care antiseptic monograph any active ingredient for which the
additional safety and effectiveness data required to show that a health
care antiseptic product containing that ingredient would be GRAS/GRAE
have not become available. Any final rule would have a preemptive
effect in that it would preclude States from issuing requirements
related to OTC health care antiseptics that are different from, in
addition to, or not otherwise identical with a requirement in the final
rule. This preemptive effect is consistent with what Congress set forth
in section 751 of the FD&C Act. Section 751(a) of the FD&C Act
displaces both State legislative requirements and State common law
duties. We also note that even where the express preemption provision
is not applicable, implied preemption may arise (see Geier v. American
Honda Co., 529 U.S. 861 (2000)).
FDA believes that the preemptive effect of the proposed rule, if
finalized, would be consistent with Executive Order 13132. Section 4(e)
of the Executive order provides that ``when an agency proposed to act
through adjudication or rulemaking to preempt State law, the agency
shall provide all affected State and local officials notice and an
opportunity for appropriate participation in the proceedings.'' FDA is
providing an opportunity for State and local officials to comment on
this rulemaking.

XIII. References

The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday,
and are available electronically at http://www.regulations.gov. (FDA
has verified all Web site addresses in this reference section, but we
are not responsible for any subsequent changes to the Web sites after
this proposed rule publishes in the Federal Register.)

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[[Page 25198]]

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7. Comment No. FDA-1975-N-0012-0081.
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11. Comment Nos. FDA-1975-N-0012-0004, -0062, -0064, -0068, -0073, -
0069, -0079, -0071, -0075, -0081, -0082, -0085, -0087, -0132, -0088,
-0089, -0090, -0091, -0092, -0093, -0094,-0095, -0096, -0097, -0098,
-0100, -0102, -0105, -0107, -0111, -0108, -0109, -0110, -0134, -
0112, -0113, -0115, -0116, -0117, -0119, -0123, -0128, -0127, -0135,
-0148, -0153, -0154, -0155, -0158, -0157, -0159, -0163, -0176, -
0177, -0199, -0200, -0201, -0202, -0215, -0216, -0217, -0218, -0219,
-0005, -0223, -0284, -0281, -0282, -0283, -0224, -0275, -0285, -
0286, -0276, -0275, -0288, -0277, -0287, -0266, -0268, -0065, -0130,
-0164, -0166, -0184, -0227, -0187, -0192, -0194, -0196, -0237, -
0238, -0037, -0038, -0245, -0258, -0273, -0204, -0206, -0207, -0208,
-0209, -0212, -0213, -0214, -0269, -0053, -0122, -0124, -0160, -
0172, -0180, -0181, -0229, -0230, -0231, -0232, -0234, -0247, -0249,
-0250, -253, -0255, -0264, -0010, -0129, -0138, -0066, -0126, -0140,
-0178, -0191, -0118, -0121, -0161, -0179, -0198, -0241, -0243, -
0010, -0015, -0016, -0017, and -0018.
12. Comment Nos. FDA-1975-N-0012-0003, -0063, -0062, -0069, -0070, -
0071, -0075, -0085, -0088, -0089, -0090, -0091, -0092, -0094, -0095,
-0096, -0102, -0105, -0107, -0111, -0108, -0109, -0134, -0112, -
0115, -0116, -0119, -0127, -0148, -0149, -0151, -0159, -0176, -0177,
-0200, -0201, -0202, -0219, -0220, -0223, -0281, -0282, -0283, -
0224, -0286, -0276, -0275, -0288, -0266, -0289, -0065, -0130, -0164,
-0166, -0184, -0227, -0187, -0189, -0196, -0015, -0237, -0238, -
0274, -0238, -0214, -0053, -0122, -0137, -0143, -0146, -0160, -0162,
-0186, -0180, -0181, -0183, -0229, -0230, -0231, -0232, -0235, -
0248, -0255, -0256, -02643, -0010, -0139, -0150, -0106, -0136, -
0141, -0142, -0152, -0168, -0169, -0170, -0242, -0066, -0171, -0161,
-0179, -0241, -0243, -0221, -0265, -0271, -0010, -0050, -0052, -
0077, -0078, -0083, -0084, -0050, -0051, and -0052.
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15. Comment No. FDA-1975-N-0012-0115.
16. Comment No. FDA-1975-N-0012-0091.
17. Comment No. FDA-1975-N-0012-0187.
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19. Comment No. FDA-1975-N-0012-0102.
20. Comment No. FDA-1975-N-0012-0229.
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37. FDA Review of Health Care Antiseptic Clinical Outcome
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38. Comment Nos. FDA-1975-N-0012-0064, -0071, 0081, -0082, -0087, -
0088, and -0096.
39. Comment Nos. FDA-1975-N-0012-0073, -0071, -0075, -0081, -0085, -
0089, -0093, -0096, -0105, -0111, -0108, -0109, -0113, -0116, -0117,
-0119, -0128, -0127, -0153, -0154, -0155, -0158, -0157, -0176, -
0177, -0200, -0201, -0282, -0275, -0285, -0286, -0276, -0288, -0266,
-0164, -0166, -0184, -0227, -0194, -0238, -0037, -0258, -0124, -
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List of Subjects in 21 CFR Part 310

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

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

PART 310--NEW DRUGS

0
1. The authority citation for 21 CFR part 310 continues to read as
follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e, 379k-1; 42 U.S.C. 216, 241,
242(a), 262, 263b-263n.

0
2. Amend Sec. 310.545 as follows:
0
a. Add reserved paragraph (a)(27)(v);
0
b. Add paragraphs (a)(27)(vi) through (x);
0
c. In paragraph (d) introductory text, remove''(d)(39)'' and in its
place add ``(d)(42)''; and
0
d. Add paragraph (d)(42).
The additions read as follows:

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

(a) * * *
(27) * * *
(v) [Reserved]
(vi) Health care personnel hand wash drug products. Approved as of
[DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN THE FEDERAL
REGISTER].

Benzalkonium chloride
Benzethonium chloride
Chloroxylenol
Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan
monolaurate)
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol
Poloxamer iodine complex
Povidone-iodine
Secondary amyltricresols

[[Page 25205]]

Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Undecoylium chloride iodine complex

(vii) Health care personnel hand rub drug products. Approved as of
[DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN THE FEDERAL
REGISTER].

Alcohol (ethanol and ethyl alcohol)
Benzalkonium chloride
Isopropyl alcohol

(viii) Surgical hand scrub drug products. Approved as of [DATE 1
YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN THE FEDERAL
REGISTER].

(ix) Surgical hand rub drug products. Approved as of [DATE 1 YEAR
AFTER DATE OF PUBLICATION OF THE FINAL RULE IN THE FEDERAL REGISTER].

Alcohol (ethanol and ethyl alcohol)
Isopropyl alcohol

(x) Patient preoperative skin preparation drug products. Approved
as of [DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN THE
FEDERAL REGISTER].

Alcohol (ethanol and ethyl alcohol)
Benzalkonium chloride
Benzethonium chloride
Chloroxylenol
Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Iodine tincture
Iodine topical solution
Isopropyl alcohol
Mercufenol chloride
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol
Poloxamer iodine complex
Povidone-iodine
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Triple dye
Undecoylium chloride iodine complex
Combination of calomel, oxyquinoline benzoate, triethanolamine, and
phenol derivative
Combination of mercufenol chloride and secondary amyltricresols in 50
percent alcohol
* * * * *
(d) * * *
(42) [DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN
THE FEDERAL REGISTER], for products subject to paragraphs (a)(27)(vi)
through (a)(27)(x) of this section.

Dated: April 27, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-10174 Filed 4-30-15; 8:45 am]
BILLING CODE 4164-01-P