[Federal Register Volume 78, Number 242 (Tuesday, December 17, 2013)]
[Proposed Rules]
[Pages 76443-76478]
[FR Doc No: 2013-29814]

Vol. 78

Tuesday,

No. 242

December 17, 2013

Part III

 Department of Health and Human Services

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 Food and Drug Administration

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21 CFR Parts 310 and 333

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

Federal Register / Vol. 78 , No. 242 / Tuesday, December 17, 2013 /
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 333

[Docket No. FDA-1975-N-0012] (Formerly Docket No. 1975N-0183H)
RIN 0910-AF69

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing this
proposed rule to amend the 1994 tentative final monograph or proposed
rule (the 1994 TFM) for over-the-counter (OTC) antiseptic drug
products. In this proposed rule, we are proposing to establish
conditions under which OTC consumer antiseptic products intended for
use with water (referred to throughout as consumer antiseptic washes)
are generally recognized as safe and effective. In the 1994 TFM,
certain antiseptic active ingredients were proposed as being safe for
antiseptic handwash use by consumers based on safety data evaluated by
FDA as part of our ongoing review of OTC antiseptic drug products.
However, in light of more recent scientific developments and changes in
the use patterns of these products we are now proposing that additional
safety data are necessary to support the safety of antiseptic active
ingredients for this use. We also are proposing that all consumer
antiseptic wash active ingredients have data that demonstrate a
clinical benefit from the use of these consumer antiseptic wash
products compared to nonantibacterial soap and water.

DATES: Submit electronic or written comments by June 16, 2014. 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, identified by Docket No. FDA-1975-
N-0012 and Regulatory Information Number (RIN) number 0910-AF69, 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 Agency name
and 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.

FOR FURTHER INFORMATION CONTACT: Colleen Rogers, 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
consumer antiseptic products intended for use with water 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 it has identified and placed in the docket. We
are not, at this time, proposing conditions under which OTC consumer
antiseptic hand rubs (commonly called hand sanitizers) or antiseptics
intended for use by health care professionals are GRAS/GRAE.

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 repeated daily use by consumers. The
safety data, the effectiveness data, and the effect on the previously
proposed classification of active ingredients are described briefly in
this summary.

Effectiveness

    A determination that an active ingredient is GRAS/GRAE for a
particular intended use requires consideration of the benefit-to-risk
ratio for the drug for that use. If the active ingredient in a drug
product does not provide clinical benefit, but potentially increases
the risk associated with the drug (e.g., from reproductive toxicity or
carcinogenicity), then the benefit-risk calculation shifts, and the
drug is not GRAS/GRAE. New information on potential risks posed by the
use of certain consumer antiseptic washes has prompted us to reevaluate
the data needed for classifying consumer antiseptic wash active
ingredients as generally recognized as effective (GRAE). As a result,
the risk from the use of a consumer antiseptic wash drug product must
be balanced by a demonstration that it is superior to washing with
nonantibacterial soap and water in reducing infection.
    We have evaluated the available literature, and the data and other
information that were submitted to the rulemaking on the effectiveness
of consumer antiseptic wash active ingredients, as well as the
recommendations from the public meetings held by the Agency on
antiseptics. The record does not currently contain sufficient data to
show that there is any additional benefit from the use of consumer
antiseptic hand or body washes compared to nonantibacterial soap and
water. Adequate and well-controlled clinical outcome studies capable of
identifying the conditions of use that reduce the numbers of infections
would demonstrate whether there is a benefit from the use of consumer
antiseptic washes. Consequently, we are proposing that data from
clinical outcome studies (demonstrating a reduction in infections) are
necessary to support a GRAE determination for consumer antiseptic wash
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 consumer antiseptic active ingredients
under the OTC Drug Review. New data suggest that the systemic exposure
to these active ingredients is higher than previously thought, and new
information about the potential risks from systemic absorption and
long-term exposure have become available. New safety information also
suggests that widespread antiseptic use can have an impact on the
development of bacterial resistance.
    The previous GRAS determinations were based on safety principles
that have since evolved significantly due to 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. In order to ensure that consumer antiseptic wash active
ingredients are GRAS, data that meet current safety standards are
needed.
    Based on these developments, we are now proposing that additional
safety data will need to be submitted to the administrative record for
each consumer antiseptic wash active ingredient to support a GRAS
classification. The data requirements proposed in this proposed rule
are the minimum data necessary to establish the safety of long-term,
daily, repeated exposure to antiseptic active ingredients used in
consumer wash products in light of the new safety information. The data
we propose is needed to demonstrate safety for all consumer antiseptic
wash active ingredients falls into three broad categories: (1) Safety
data studies described in current FDA guidance (e.g., preclinical and
human pharmacokinetic studies, developmental and reproductive toxicity
studies, and carcinogenicity studies); (2) data to characterize
potential hormonal effects; and, (3) data to evaluate the development
of resistance.

Active Ingredients

    In the 1994 TFM, 22 antiseptic active ingredients were classified
for OTC antiseptic handwash use (59 FR 31402 at 31435) (for a list of
all active ingredients covered by this proposed rule, see tables 3 and
4). Among these 22 active ingredients are triclosan and triclocarban,
two of the most commonly used active ingredients in consumer antiseptic
washes and the subject of much scientific debate. Our detailed
evaluation of the effectiveness and safety of triclosan and
triclocarban, as well as other active ingredients for which data were
submitted, can be found in sections VI.A and VII.D of this proposed
rule. In the 1994 TFM, only one active ingredient that is being
evaluated for use as a consumer antiseptic wash, povidone-iodine (5 to
10 percent), was proposed to be classified as GRAS/GRAE (59 FR 31402 at
31436). However, we now propose that none of the consumer antiseptic
wash active ingredients classified in the 1994 TFM (including povidone-
iodine) has the safety and effectiveness data needed to support a
classification of GRAS/GRAE for consumer antiseptic hand or body
washes. The data available and the data that are missing are discussed
separately in this proposed rule for each active ingredient.
    Several consumer antiseptic wash active ingredients evaluated in
the 1994 TFM were proposed as GRAS, but not GRAE, because they lack
sufficient evidence of effectiveness for consumer use. We are now
proposing that these ingredients need additional safety data, as well
as effectiveness data, to be classified as GRAS/GRAE.

Costs and Benefits

    We estimate the benefits of the proposed rule in terms of the 2.2
millions pounds reduction in annual aggregate exposure to antiseptic
active ingredients, including triclosan, chloroxylenol, and
benzalkonium chloride. The inadequacy of the available dermal exposure
data prevents us from characterizing the health effects resulting from
widespread long-term exposure to such ingredients and prevents us from
translating the estimated reduced exposure into monetary equivalents of
health effects. We estimate the costs of the proposed rule, consisting
of one-time costs of relabeling and reformulation, ranging from $112.2
to $368.8 million. Annualized over 10 years, the primary cost estimate
is approximately $23.6 million at a 3 percent discount rate and $28.6
million at a 7 percent discount rate. Under the proposed rule, we
estimate that each pound of reduced exposure to antiseptic active
ingredients would cost $3.86 to $43.67 at a 3 percent discount rate and
$4.69 to $53.04 at a 7 percent discount rate.

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 Summary of costs and benefits of                        Total costs annualized over   Total one-time costs (in
        the proposed rule             Total benefits        10 years (in millions)             millions)
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Total............................  Reduced exposure to   $23.6 (at 3%)..............  $112.2 to $368.8
                                    antiseptic active    $28.6 (at 7%)..............
                                    ingredients by 2.2
                                    million pounds
                                    annually.
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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 Consumer Antiseptic Washes
    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 the OTC Drug
Review
IV. Ingredients Previously Proposed as Not Generally Recognized as
Safe and Effective (GRAS/GRAE)
V. Summary of Proposed Classifications of OTC Consumer Antiseptic
Wash Active Ingredients
VI. Effectiveness (Generally Recognized as Effective) Determination
    A. Evaluation of Effectiveness Data
    B. In Vitro Studies 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 consumer 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 (21 CFR 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 consumer
antiseptic wash 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 handwash; (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) (First Aid TNM). Thus,
first aid antiseptics are not discussed further in this document.
    The four remaining categories of topical antimicrobials were
addressed in an amended TFM, published on June 17, 1994 (59 FR 31402).
This TFM covered: (1) Antiseptic handwash (i.e., consumer handwash);
(2) health care personnel handwash; (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.
    With regard to the health care and consumer antiseptic products, we
are now proposing that our evaluation of OTC antiseptic drug products
be 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 that each setting
presents a different risk for infection. Therefore, the safety and
effectiveness should be evaluated for each intended use separately.
    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, and include health care personnel hand
antiseptics, surgical hand scrubs, and patient preoperative skin
preparations. 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 handwashes. (See section
I.C of this proposed rule about the term ``antimicrobial soaps''.) In
contrast, in the 1994 TFM, we proposed that both consumer antiseptic
handwashes and health care personnel handwashes should have the same
effectiveness testing and performance criteria. In response to the 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.
    We refer to the group of products covered by this proposed rule as
``consumer antiseptics.'' Consumer antiseptic drug products addressed
by this proposal include a variety of personal care products intended
to be used with water, such as antibacterial soaps, handwashes, and
antibacterial body washes. These products do not include consumer
antiseptic hand rubs (commonly called hand sanitizers). These products
may be used by consumers for personal use in the home on a frequent,
even daily, basis. In the U.S. consumer setting, where the target
population is composed of generally healthy individuals, the risk of
infection and the scope of the spread of infection is relatively low
compared to the health care setting, where patients are generally more
susceptible to infection and the potential for spread of infection is
high.

C. This Proposed Rule Covers Only Consumer Antiseptic Washes

    In this proposed rule, FDA proposes the establishment of a
monograph for OTC consumer antiseptics that are intended for use as
either a handwash or a body wash, but that are not identified as
``first aid antiseptics'' in the 1991 First Aid TFM. When the 1994 TFM
was published, the term for daily consumer use antiseptics was changed
to ``antiseptic handwash.'' In response to this change, we received
comments that the term ``antiseptic handwash'' did not include all of
the consumer products on the market, such as hand rubs and body washes.
Therefore, in this proposed rule, we use the term ``consumer
antiseptic,'' which is a broad term and meant to include all of the
types of antiseptic products used on a frequent or daily basis by
consumers. The proposed rule does not include consumer antiseptic hand
rubs (commonly called hand sanitizers).
    The distinctions between washes and rubs, and between handwashes
and body washes are discussed in this section.

1. Consumer Washes and Consumer Rubs
    Consumer antiseptics (other than first aid antiseptics) fall into
two categories: (1) Products that are rinsed off, including handwashes
and body washes, and (2) products that are not rinsed off after use,
including hand rubs and antibacterial wipes. The 1994 TFM did not
distinguish between products that we are now calling antiseptic washes
and products we are now calling antiseptic rubs. Nor did the 1994 TFM
distinguish between consumer antiseptic handwashes and rubs and health
care antiseptic handwashes and rubs. This proposed rule covers consumer
antiseptic washes only and does not cover consumer antiseptic rubs.
Completion of the monograph for Consumer Antiseptic Wash Products and
certain other monographs for the active ingredient triclosan is subject
to a Consent Decree entered by the 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.).
2. Handwashes and Body Washes
    Consumer antiseptic hand and body washes were not a category of
topical antiseptic drug products specifically identified by the
Advisory Review Panel on OTC Topical Antimicrobial I Drug Products
(Antimicrobial I Panel or Panel). In the ANPR and the 1978 TFM,
products for daily consumer use were called ``antimicrobial soaps.''
This category encompassed deodorant soaps and hand soaps containing
antimicrobial ingredients used for handwashing and personal hygiene.
    In the 1994 TFM, we concluded that there was no reason to continue
to include ``antimicrobial soap'' as a separate product category
because soap was considered to be a dosage form and specific dosage
forms were not being included in the monograph unless there was a
particular safety or efficacy reason to do so (59 FR 31402 at 31407).
At that time, we had not identified antiseptic body washes as a
separate category of product.
    Comments on the 1994 TFM noted that the elimination of the category
of antimicrobial soaps in the 1994 TFM resulted in products that
otherwise would have been considered antimicrobial soaps (such as
antimicrobial bar soaps) being placed in the category of antiseptic
handwashes. The comments stated that because the proposed labeling for
antiseptic handwash products directs use on only the hands and
forearms, this category is not appropriate for certain products that
were originally proposed to be called ``antimicrobial soaps'' and that
were to be used on the whole body (i.e., bar soaps). We agree with the
comments to the extent that some products previously identified as
antimicrobial soaps had, among other intended uses, the intended use of
being used on the entire body. In this proposed rule, we are
identifying products with the intended use of being used on the entire
body as antiseptic body washes. Consequently, the active ingredients
reviewed by the Panel for use in antimicrobial soaps have been reviewed
for use in antiseptic body washes.

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 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 for an extension of the time to submit new
safety and/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 extend. In assessing whether to extend the comment
period 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 to extend. FDA
will determine whether the sum of the data, if timely submitted, is
likely to be adequate to provide all the data that are necessary to
make a determination of general recognition of safety and
effectiveness.

II. Background

    In this section we describe the significant rulemakings and public
meetings relevant to this rulemaking, 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 of this proposed rule.
Other Federal Register publications relevant to this proposed rule are
available from the Division of Dockets Management (see ADDRESSES).

            Table 1--Significant Rulemaking Publications Related to Consumer Antiseptic Drug Products
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                     Federal Register notice                                   Information in notice
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1974 ANPR (September 13, 1974, 39 FR 33103)......................  We published an advance notice of proposed
                                                                    rulemaking to establish a monograph for OTC
                                                                    topical antimicrobial drug products,
                                                                    together with the recommendations of the
                                                                    Panel, which was the advisory review panel
                                                                    responsible for evaluating data on the
                                                                    active ingredients in this drug class.
1978 Antimicrobial TFM (January 6, 1978, 43 FR 1210).............  We published our tentative conclusions and
                                                                    proposed effectiveness testing for the drug
                                                                    product categories evaluated by the Panel.
                                                                    The 1978 TFM reflects our evaluation of the
                                                                    recommendations of the Panel and comments
                                                                    and data submitted in response to the
                                                                    Panel's recommendations.
1991 First Aid TFM (July 22, 1991, 56 FR 33644)..................  We amended the 1978 TFM to establish a
                                                                    separate monograph for OTC first aid
                                                                    antiseptic products. In the 1991 TFM, we
                                                                    proposed that first aid antiseptic drug
                                                                    products be indicated for the prevention of
                                                                    skin infections in minor cuts, scrapes, and
                                                                    burns.
1994 Healthcare Antiseptic TFM (June 17, 1994, 59 FR 31402)......  We amended the 1978 TFM to establish a
                                                                    separate monograph for the group of products
                                                                    that were referred to as OTC topical health
                                                                    care antiseptic drug products. These
                                                                    antiseptics are generally intended for use
                                                                    by health care professionals.
                                                                   In this 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 handwash.
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B. Public Meetings Relevant to This Proposed Rule

    In addition to the Federal Register publications listed in table 1
of this proposed rule, there have been three meetings of the
Nonprescription Drugs Advisory Committee (NDAC) and one public feedback
meeting that are relevant to the discussion of consumer antiseptic wash
safety and effectiveness. These are summarized in table 2 of this
proposed rule.

                            Table 2--Public Meetings Relevant to Consumer Antiseptics
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                     Date and type of meeting                                   Topic of discussion
----------------------------------------------------------------------------------------------------------------
January 1997 NDAC Meeting (Joint meeting with the Anti-Infective   Antiseptic and antibiotic resistance in
 Drugs Advisory Committee) (January 6, 1997, 62 FR 764).            relation to an industry proposal for
                                                                    consumer and health care antiseptic
                                                                    effectiveness testing (Health Care Continuum
                                                                    Model) (Refs. 1 and 2).
March 2005 NDAC Meeting (February 18, 2005, 70 FR 8376)..........  The use of surrogate endpoints and study
                                                                    design issues for the in vivo testing of
                                                                    health care antiseptics (Ref. 3)
October 2005 NDAC Meeting (September 15, 2005, 70 FR 54560)......  Benefits and risks of consumer antiseptics.
                                                                    NDAC expressed concern about the pervasive
                                                                    use of consumer antiseptic washes where
                                                                    there are potential risks and no
                                                                    demonstrable benefit. To demonstrate a
                                                                    clinical benefit, NDAC recommended clinical
                                                                    outcome studies to show that antiseptic
                                                                    washes are superior to nonantibacterial soap
                                                                    and water (Ref. 4).
November 2008 Public Feedback Meeting............................  Demonstration of the effectiveness of
                                                                    consumer antiseptics (Ref. 5).
----------------------------------------------------------------------------------------------------------------

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 consumer antiseptic washes are discussed in this
proposed rule, only those comments and data concerning the 1994 TFM
that are related to consumer antiseptic wash active ingredients are
addressed. If in the future we determine that there are monograph
consumer antiseptic wash active ingredients that are safe and
effective, we will address labeling and final formulation testing of
consumer antiseptic washes, and the comments that were received on
those subjects, in a future document. Comments that were received in
response to the 1994 TFM regarding other intended uses of the active
ingredients will be addressed in future documents related to those
other uses.
    This proposal constitutes FDA's evaluation of submissions made in
response to the 1994 TFM to support the safety and effectiveness of OTC
consumer antiseptic wash active ingredients (Refs. 6 through 10). 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 were not yet available for
any consumer antiseptic wash active ingredient.

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 eligibility for the OTC Drug Review and the ingredients submitted
to the OTC Drug Review that lack adequate evidence of eligibility for
evaluation as consumer antiseptic washes.

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). 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 21 CFR 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 the OTC Drug
Review to be a new drug that will require FDA approval through the new
drug application (NDA) process. Ineligibility for use as a consumer
antiseptic wash does not affect eligibility for other indications under
the OTC Drug Review.
    Based on a review of the labeling submitted to the Antimicrobial I
Panel, the ingredients discussed in section III.B of this proposed rule
currently do not have adequate evidence of eligibility for evaluation
under the OTC Drug Review as a consumer antiseptic wash. Due to their
lack of eligibility, effectiveness and safety information that has been
submitted to the rulemaking for these antiseptic active ingredients are
not discussed in this proposed rule. However, if documentation of the
type described in this section is submitted, these active ingredients
could be determined to be eligible for evaluation.

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

1. Chlorhexidine Gluconate
    Previously, chlorhexidine gluconate 4 percent aqueous solution as a
health care antiseptic was found to be ineligible for inclusion in the
monograph 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
consumer antiseptic wash, and we do not include a discussion of any
safety or effectiveness data submitted for chlorhexidine gluconate.
2. 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. 11 through 17).

These compounds were not addressed in prior FDA documents related to
the monograph and were not evaluated for antiseptic handwash use by the
Antimicrobial I Panel. The submissions received by the Agency to date
do not include documentation demonstrating the eligibility of any of
these seven compounds for inclusion in the monograph (Ref. 18).
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 about
eligibility that we have at this time, we propose to categorize them as
new drugs, and we do not include a discussion of safety or
effectiveness data submitted for them.
3. Alcohol (Ethyl Alcohol) and Isopropyl Alcohol
    In the 1994 TFM, denatured ethyl alcohol (ethanol or alcohol) 60 to
95 percent by volume in an aqueous solution was one of two active
ingredients classified as Category I for use as an antiseptic handwash
or health care personnel handwash (59 FR 31402 at 31442). Isopropyl
alcohol 70 to 91.3 percent was classified as Category III for use as an
antiseptic handwash or health care personnel handwash. The only
consumer products containing alcohol or isopropyl alcohol that were
submitted to the OTC Drug Review were products that were intended to be
used without water (Ref. 19). Consequently, alcohol and isopropyl
alcohol have not been demonstrated to be eligible for the OTC Drug
Review for evaluation as consumer antiseptic wash drug products, which
by definition are intended to be rinsed off with water. Based on the
information we currently have about eligibility of these active
ingredients, we propose to categorize alcohol and isopropyl alcohol
intended for use as an antiseptic wash as new drugs, and we do not
include a discussion of safety or effectiveness of alcohol or isopropyl
alcohol for such use. This proposal relates to antiseptic washes and
does not include consumer antiseptic hand rubs (commonly called hand
sanitizers).

IV. Ingredients Previously Proposed as Not Generally Recognized as Safe
and Effective (GRAS/GRAE)

    FDA may determine that an active ingredient is not GRAS/GRAE (i.e.,
nonmonograph) because of lack of evidence of effectiveness or lack of
evidence of safety or both. In the 1994 TFM (59 FR 31402 at 31435), FDA
proposed that the active ingredients fluorosalan, hexachlorophene,
phenol (greater than 1.5 percent), and tribromsalan be found not GRAS/
GRAE for use as an antiseptic handwash or health care personnel
handwash. The Agency 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, particularly tribromsalan (21 CFR 310.502).
No substantive comments or new data were submitted 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 consumer antiseptic hand or body washes
as defined in this proposed rule and that any OTC consumer antiseptic
hand or body wash drug product containing any of these ingredients not
be allowed to continue 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 Consumer Antiseptic Wash
Active Ingredients

    Tables 3 and 4 in this proposed rule list the classification
proposed in the 1994 TFM for each OTC consumer antiseptic active
ingredient 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 described in detail for each
active ingredient separately in section VII.D of this proposed rule.

Table 3--Classification of OTC Consumer Antiseptic Active Ingredients in
                 This Proposed Rule and in the 1994 TFM
------------------------------------------------------------------------
                                                         This proposed
        Active ingredient               1994 TFM              rule
------------------------------------------------------------------------
Hexylresorcinol..................  IIIE \1\..........  IIISE.
Iodine complex (ammonium ether     IIIE..............  IIISE.
 sulfate and polyoxyethylene
 sorbitan monolaurate).
Iodine complex (phosphate ester    IIIE..............  IIISE.
 of alkylaryloxy polyethylene
 glycol).
Nonylphenoxypoly (ethyleneoxy)     IIIE..............  IIISE.
 ethanoliodine.
Poloxamer iodine complex.........  IIIE..............  IIISE.
Povidone-iodine 5 to 10 percent..  I \2\.............  IIISE.
Secondary amyltricresols.........  IIIE..............  IIISE.
Triclocarban.....................  IIIE..............  IIISE.
Undecoylium chloride iodine        IIIE..............  IIISE.
 complex.
------------------------------------------------------------------------
\1\ ``III'' denotes that additional data are needed. ``E'' denotes
  effectiveness data needed. ``S'' denotes safety data needed.
\2\ ``I'' denotes that an active ingredient has been shown to be safe
  and effective.

    This proposed rule does not change the status of a number of
antiseptic active ingredients previously proposed as lacking sufficient
evidence of safety and effectiveness or the status of several
ingredients previously proposed as having been shown to be unsafe,
ineffective, or both (see table 4 of this proposed rule).

  Table 4--OTC Consumer 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
Fluorosalan............................  II \2\
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
Triple dye \3\.........................  II
------------------------------------------------------------------------
\1\ ``III'' denotes that additional data are needed. ``S'' denotes
  safety data needed. ``E'' denotes effectiveness data needed.
\2\ ``II'' denotes that an active ingredient has been shown to be
  unsafe, ineffective, or both.
\3\ Triple dye was proposed as Category II for antimicrobial soap due to
  a physical and/or chemical incompatibility in formulation and for skin
  antiseptic (except for use in neonatal ward) in the 1978 TFM (43 FR
  1210 at 1227), and was not further evaluated as an antiseptic handwash
  in the 1994 TFM (59 FR 31402 at 31436). FDA has received no further
  information on triple dye for use as an antiseptic wash since the 1994
  TFM.

VI. Effectiveness (Generally Recognized as Effective) Determination

    OTC regulations (Sec.  330.10(a)(4)(ii)) define the standards for
establishing an OTC active ingredient as GRAE. These regulations
require controlled clinical trials of the kind described in Sec.
314.126(b) (21 CFR 314.126(b)) as proof of the effectiveness of an
active ingredient unless this requirement is waived. According to Sec.
314.126(a), these clinical studies must be adequate and well-controlled
studies that can 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 studies include
controls that are adequate to provide an assessment of drug effect,
adequate measures to minimize bias, and the use of 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 GRAE.
    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 an unvalidated
surrogate endpoint (i.e., number of bacteria removed from the skin),
rather than a clinical outcome (e.g., reduction in the number of
infections). Because of new concerns about the potential risks (e.g.,
resistance and hormonal effects) posed by the repeated daily use of
consumer antiseptic washes (see section VII of this proposed rule), we
are now proposing that a different type of effectiveness study is
necessary to support the GRAE status of consumer antiseptic wash active
ingredients. We are proposing that the use of antiseptic active
ingredients to be used in consumer antiseptic wash products be
supported by studies that demonstrate a direct clinical benefit (i.e.,
a reduction of infection). Data from these clinical outcome studies
will help assure that any potential risk from consumer antiseptic wash
products is balanced by a demonstrated clinical benefit.
    This effectiveness requirement is consistent with NDAC's
recommendations from the October 2005 meeting regarding consumer
antiseptics (Ref. 4). NDAC unanimously agreed that in order to be
considered effective, a demonstration that the drug removes bacteria is
not enough and that consumer antiseptic products should provide a
clinical benefit by reducing infections. They concluded that studies
using surrogate endpoints would not be adequate to demonstrate this
benefit and recommended studying the impact of these products on
infections in specific populations of consumers that use these
products. NDAC also did not believe that it is possible to generalize
from effectiveness in the health care environment to effectiveness in
the consumer setting because of differences in populations and other
risk factors.
    NDAC concluded that it would be feasible to use clinical outcome
studies to show a benefit of consumer antiseptic washes over and above
washing with nonantibacterial soap. They pointed out that there are
already studies in the community setting that have looked at clinical
outcomes, such as the number of symptoms or infections over a given
timeframe. NDAC concluded that it would not be unethical to run a
placebo-controlled study of consumer antiseptic washes to demonstrate
clinical benefit. NDAC also stated that it is important to know if
there is any added benefit from the antiseptic active ingredient in
consumer antiseptic wash products. We agree with NDAC's recommendations
on this issue.
    A coalition of trade organizations that represent antiseptic
manufacturers submitted comments disagreeing with NDAC's conclusions.
The comments state that clinical outcome studies in the consumer
setting are not feasible because of the cost and considerable number of
confounding factors that would make interpretation of the studies
difficult (Refs. 5, 20, and 21). Some of these confounding factors
identified in these comments included:

 Number and length of handwashes performed
 Amount of product used
 Compliance with handwashing technique and frequency
 Blinding of products
 Use of other (non-study) products when outside the home
 Type of infection
 Virulence of the infecting microorganism
 Generally low bacterial infection rate in the United States

    NDAC found the studies by Luby et al. (Ref. 22) and Larson et al.
(Ref. 23), which are discussed in section VI.A of this proposed rule,
to be evidence that such clinical outcome studies are feasible. We
agree. Although there are many confounding factors that must be
addressed when designing a clinical outcome study of the effectiveness
of antiseptic washes in the consumer setting, this is the case in any
clinical outcome study. Despite this fact, well-designed clinical
outcome studies are conducted for other types of drug products, and the
most important factors can be addressed in an appropriately designed
study. If effectiveness cannot be demonstrated in a clinical outcome
study for consumer antiseptic washes, we should not rush to conclude
that it is the confounding factors that limit our ability to detect a
benefit; rather, if the study is appropriately designed, it is likely
telling us that the consumer antiseptic wash does not provide a
clinically significant benefit in a population at low risk to develop
an infection, such as a healthy consumer.
    As discussed later in this section of this proposed rule, we
evaluated all the available effectiveness studies for consumer
antiseptic washes to determine if the data supported effectiveness of
consumer antiseptic active ingredients based on the 1994 TFM
effectiveness criteria. We found that the available studies are not
adequate to support a GRAE determination for any consumer antiseptic
wash active ingredient under

either the 1994 TFM effectiveness criteria or what we propose now.

A. Evaluation of Effectiveness Data

1. Clinical Simulation Studies
    Most of the data available to support the effectiveness of consumer
antiseptic washes are based on clinical simulation studies, such as the
one described in the 1994 TFM (59 FR 31402 at 31444). The premise
behind these studies is that bacterial reductions achieved in this type
of study translate to a reduced risk for infection. However, there
currently are no clinical data that demonstrate that the specific
bacterial log reductions that we have relied upon as a demonstration of
effectiveness lead to a specific reduction in infections. We now
believe that the appropriate demonstration of effectiveness is a
clinical outcome study. Moreover, clinical outcome studies are feasible
in the consumer setting and may not give rise to ethical concerns such
as those that could occur in studies in a hospital setting.
    Although we are now proposing to require clinical outcome studies,
we evaluated all clinical simulation studies that were submitted to the
OTC Drug Review for evidence of antiseptic hand and body wash
effectiveness demonstrated under the log reduction criteria proposed in
the 1994 TFM (59 FR 31402 at 31448) (Ref. 6). We also searched the
published literature for clinical simulation studies that assess
antiseptic wash effectiveness also using the log reduction criteria in
the 1994 TFM (Refs. 24, 25, and 26). Overall, when judged against the
criteria in the 1994 TFM, the studies are not adequately controlled to
allow an accurate assessment of the effectiveness of consumer
antiseptic wash active ingredients for one or more reasons.
    First, the majority of testing was conducted using a formulated
product without adequate comparison to a vehicle control, which is
needed to demonstrate the contribution of the antiseptic active
ingredient, if any (43 FR 1210 at 1240). Second, many studies did not
include an active control, which is needed to validate the conduct of
the study (59 FR 31402 at 31450). Third, many studies lacked adequate
documentation of neutralization (43 FR 1210 at 1244). Residual
antiseptic remaining on the skin after rinsing, if not effectively
neutralized, will continue its antimicrobial action and result in an
exaggerated bacterial reduction that is not reflective of product
performance on the skin. Finally, none of the studies were of adequate
size to assure a statistically valid demonstration of log reductions.
The Agency's detailed evaluation of the data is on file at http://www.regulations.gov (see ADDRESSES) (Ref. 26). Only one submitted
clinical simulation study was adequately designed and controlled to
evaluate the contribution of the active ingredient to the observed
bacterial log reductions (Ref. 27). This study compared a liquid soap
containing 0.7 percent triclocarban to both the formulation without any
antiseptic (placebo) and a 4 percent chlorhexidine gluconate active
control. The triclocarban-containing soap was superior to placebo and
met the 1994 TFM effectiveness criteria of a 2-log10
reduction after the first wash and a 3-log10 reduction after
the eleventh wash (59 FR 31402 at 31448). The active control also met
the 1994 TFM effectiveness criteria when tested against Serratia
marcescens and validated the study conduct. Therefore, this was a
valid, adequately controlled study that met the effectiveness criteria
proposed in the 1994 TFM.
    Although the 0.7 percent triclocarban soap met the standard for
effectiveness proposed in the 1994 TFM, the log reduction differences
compared to placebo were small (less than a 0.5-log reduction
difference compared to placebo after the first wash and just over a 1-
log reduction difference after the eleventh wash). Because we do not
have any data that correlates specific bacterial log reductions with
clinical outcomes, we have no basis to interpret the impact of these
small log reductions on infections in a population at low risk for
infection. Thus, even with an adequately designed and controlled
clinical simulation study, the data do not provide sufficient evidence
of a meaningful contribution of consumer antiseptic wash active
ingredients relative to a placebo handwash.
2. Exposure-Response Studies
    Although most clinical simulation studies submitted to the OTC Drug
Review only evaluated bacterial log reductions, one study (Ref. 21)
attempted to correlate the reduction of bacteria on the hands with a
reduction in infection rate. The study was designed to compare the
ability of a nonantibacterial handwash to the ability of an antiseptic
(triclosan) handwash to reduce bacteria on the hands after a single
use. The study also evaluated the impact of product use on the
subsequent transfer of surviving bacteria from washed hands to a ready-
to-eat food item, melon balls. The observed reduction in bacterial
transfer was then used to estimate the potential reduction in infection
risk from antiseptic use based on published bacterial exposure-response
data for Shigella flexneri (S. flexneri). Here, exposure-response data
refers to the correlation between the amount of S. flexneri ingested
and the severity of clinical disease (e.g., diarrhea) that results from
that ingestion. The rationale for this study design is that if ready-
to-eat food was contaminated with bacteria left behind on washed hands
and then eaten, those organisms would have the potential to cause
illness. This scenario has the potential to occur in the consumer
setting during domestic food preparation.
    The antiseptic handwash met the 1994 TFM criteria for bacterial
reduction after one wash; however, the study used a novel hand
contamination method (Ref. 28) that has not been sufficiently
validated. In addition, we believe this novel hand contamination method
does not accurately reflect an antiseptic handwash's intended use
because it ignores an important reservoir of bacteria on the hands
(i.e., the area around and under the fingernails), which is evaluated
when the whole hand contamination method is used. Further, although the
study authors report that the transfer of bacteria to melon balls
decreased with use of a consumer antiseptic handwash, it is not clear
what factors other than the antiseptic may influence bacterial transfer
from skin to ready-to-eat foods such as melon. Therefore, the results
of this study do not demonstrate the effectiveness of the consumer
antiseptic handwash used in this study because of the novel and
unvalidated methodology.
    In addition, the data used by the study authors for the infection
risk estimates have several limitations. First, the bacterial exposure-
response data for S. flexneri are based on a small number of control
subjects in human feeding studies (Refs. 29 through 33). Second, there
is substantial variability in the exposure-response data. In cases
where the same bacterial dose was fed to subjects in different studies,
the number of subjects that became ill varied greatly (e.g., 33 to 86
percent) (Refs. 30 and 31). Third, investigators used different
criteria to define illness in the various feeding studies (Refs. 29,
30, and 32). Depending on which parameter was examined, the percentage
of subjects that were defined as having illness varied. In studies that
examined both clinical symptoms and bacterial shedding or antibody
response, there was no parameter that consistently appeared to be
correlated with illness in all subjects. Finally, much of the feeding
data comes from high-dose exposures. Consequently, the infection rates
at low

doses must be extrapolated, and there may be a high degree of
uncertainty for these values. Furthermore, the bacterial exposure-
response data from feeding studies are not linear, which means that an
increase in the bacterial dose does not necessarily correlate with an
increase in the number of subjects who become ill. Because of this, a
statistical model must be used to create the bacterial exposure-
response curve (Ref. 34). Use of different statistical models is likely
to provide different results.
3. Clinical Outcome Studies
    Unlike clinical simulation studies that evaluate effectiveness
using unvalidated surrogate endpoints, adequate and well-controlled
studies in the general population could more directly demonstrate the
existence of any clinical benefit for consumer antiseptic washes.
Although these studies are complex because of the number of factors
that need to be controlled for, we believe that they are feasible and
are the most appropriate method of demonstrating the effectiveness of
consumer antiseptic washes.
    FDA 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 consumer antiseptic washes (Ref. 6). In addition, we
searched the published literature for clinical outcome studies that
would provide evidence of a clinical benefit from the use of consumer
antiseptic washes (Refs. 25 and 26). We are defining a clinical benefit
here as a reduction in the number of infections in the population that
uses the consumer antiseptic wash.
    We found only a few clinical outcome studies for consumer
antiseptic washes. Overall, most of the studies were confounded,
underpowered, and/or not properly controlled. Importantly, most of the
studies did not include a vehicle control and, therefore, are not able
to show the contribution of the antiseptic active ingredient to the
observed clinical outcome.
    Only two of the clinical outcome studies identified were
randomized, blinded, and placebo-controlled with no major design flaws,
and only one of these was designed to evaluate the effectiveness of a
particular antiseptic active ingredient. These are the best available
studies to evaluate the impact of consumer antiseptic washes on
infections. Neither of these studies demonstrates a benefit from the
use of the tested antiseptic active ingredient; however, their study
designs can be used as a guide in the development of future clinical
outcome studies of consumer antiseptic wash active ingredients.
    The first study compared the household use of a 1.2 percent
triclocarban-containing consumer antiseptic wash (bar soap) to placebo
wash (nonantibacterial bar soap) or to standard practice in squatter
neighborhoods in Pakistan (Ref. 22). Thirty-six neighborhoods were
randomized to 1 of 3 groups, with at least 300 households in each
group. Fieldworkers visited households weekly for 1 year to encourage
handwashing in the two soap groups and to record symptoms in all
groups. The primary study outcomes were the incidence rates of
diarrhea, impetigo, and acute respiratory tract infection. The authors
report that handwashing with either soap significantly reduced diarrhea
and acute lower respiratory tract infections, and handwashing in
conjunction with daily bathing prevented impetigo. There was no
difference between nonantibacterial soap and triclocarban-containing
soap. Consequently, this study does not show a clinical benefit from
the use of the consumer antiseptic wash over nonantibacterial soap and
water, and does not support a GRAE finding for the active ingredient
(triclocarban).
    The second study, conducted in the United States, examined the use
of triclosan-containing hand soap in the home (Ref. 23). This was a
randomized, double-blind, placebo-controlled trial in 224 inner city
households randomly assigned to use hand soap and household cleaning
products with or without antimicrobial ingredients for 48 weeks. The
authors measured infections by assessing the number of infectious
disease symptoms during the course of the study (e.g., diarrhea). Test
households received several antibacterial cleaning products: Liquid
triclosan hand soap, quaternary ammonium hard surface and kitchen
cleaner, and oxygenated bleach laundry detergent. Control households
received similar nonantibacterial hand soap, hard surface and kitchen
cleaner, and laundry detergent. Both groups received nonantibacterial
liquid dish soap and bar soap. Adherence to the product regimen was
assessed monthly by weighing the remainder of the products and
inspecting the home for the presence of other products.
    The participants in both groups experienced primarily respiratory
symptoms (runny nose, sore throat, or cough). The differences between
the intervention and control groups were not significant for any
symptoms or for numbers of symptoms. The study did not show any
reduction in symptoms of infectious disease or disease transmission as
a result of antimicrobial product use.
4. Antiseptic Body Wash Studies
    Several studies were submitted to show a clinical benefit from the
use of consumer antiseptic body washes in the prevention of skin
infection (Ref. 25). In contrast to antiseptic handwashes, which are
meant to work by removing transiently acquired microorganisms,
antiseptic body washes are meant to reduce the number of resident
bacteria on the skin. The majority of these studies describe the use of
antiseptics for nonmonograph indications, such as for the treatment of
atopic dermatitis or erythrasma. Furthermore, in most of the studies,
the effectiveness of the antiseptic body wash was not the focus of the
study. For example, often the antiseptic body wash was part of a
treatment regimen that included antibiotics or corticosteroid creams,
and the effectiveness of the treatment regimens as a whole were the
primary focus of the investigation. Overall, these studies were not
adequately controlled to assess the contribution of the antiseptic
active ingredient, and these data are not sufficient to demonstrate a
clinical benefit (Ref. 25).

B. In Vitro Studies 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 Sec.
333.470 (59 FR 31402 at 31437). Today, we continue to believe that a
GRAE determination for an antiseptic active ingredient should be
supported by an adequate characterization of the antimicrobial activity
of the ingredient. Extensive testing for this purpose was proposed in
the 1994 TFM which included 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 10 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. 35). Consequently, submissions of in vitro data submitted to
support the effectiveness of antiseptic active ingredients were far
less extensive than proposed in the TFM (Ref. 6).
    Based on our proposal for clinical outcome studies to support a
GRAE

determination and in consideration of comments on our in vitro testing
proposal (Ref. 35), FDA has reevaluated its proposed testing standards.
Because of the short exposure times for consumer antiseptic products,
we no longer believe that MICs are relevant to the effectiveness of
antiseptic active ingredients. We also now believe that a modified
time-kill assay designed to provide an assessment of how rapidly an
antiseptic active ingredient produces a bactericidal effect is a more
efficient and less burdensome way of documenting in vitro antiseptic
activity. Further, because clinical outcome studies are now needed to
support a GRAE determination, we no longer believe that a demonstration
of in vitro antiseptic activity against an extensive list of organisms
is necessary.
    Therefore, we now propose that data from a modified time-kill assay
designed to provide an adequate assessment of how rapidly an antiseptic
active ingredient produces a bactericidal effect and to estimate the
antibacterial spectrum of an antiseptic active ingredient would be
sufficient to characterize the in vitro antimicrobial activity of an
antiseptic active ingredient. The assay should test the following
reference strains and representative clinical isolates:

 Enterococcus faecalis (ATCC 19433 and ATCC 29212)
 Staphylococcus aureus (ATCC 6538 and ATCC 29213) and
methicillin-resistant S. aureus (MRSA) (ATCC 33591 and ATCC 33592)
 Streptococcus pyogenes (ATCC 14289 and ATCC 19615)
 Listeria monocytogenes (ATCC 7644 and ATCC 19115)
 Campylobacter jejuni (ATCC 33291 and ATCC 49943)
 Escherichia coli (ATCC 11775 and ATCC 25922)
 Pseudomonas aeruginosa (ATCC 15442 and ATCC 27853)
 Salmonella enterica Serovar Enteritidis (ATCC 13076) and
Serovar Typhimurium (ATCC 14028). Serovar refers to the subspecies
classification of a group of microorganisms based on cell surface
antigens.
 Shigella sonnei (ATCC 9290 and ATCC 25931)

The consumer antiseptic drug product will be considered bactericidal at
the concentration and contact time that demonstrates a 3-
log10 (99.9 percent) or greater reduction in bacterial
viability for all of the tested strains. This is the same performance
criterion used by the Clinical and Laboratory Standards Institute (Ref.
36).

VII. Safety (Generally Recognized as Safe) Determination

    In the 1994 TFM, 11 active ingredients were classified as GRAS for
antiseptic handwash use (59 FR 31402 at 31435). 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 the potential risks from systemic absorption and
long-term exposure to antiseptic active ingredients. 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 requirements for consumer antiseptic
wash active ingredients. For our administrative record to be complete
with regard to these new safety concerns, additional safety data will
be necessary to support a GRAS determination for consumer antiseptic
wash active ingredients.

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 more than previously thought. Systemic exposure
refers to the presence of antiseptic active ingredients inside and
throughout the body. For example, triclosan is an antiseptic active
ingredient commonly found in consumer antiseptic hand and body wash
products. It is absorbed through the skin and has been found in both
human breast milk and urine (Refs. 37 and 38). Further, triclosan has
been found at relatively consistent levels in urine samples collected
from a representative sample of the U.S. population since sampling
began in 2003 (Ref. 39). We believe that the consequences of this
systemic exposure need to be assessed.
    Given the prevalent use of consumer antiseptic wash drug products,
systemic exposure may be commonplace (see Ref. 40 for a discussion of
the consumer antiseptic wash market). While some systemic exposure data
exist for triclosan, many of the other antiseptic wash 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 (e.g., potentially
a consumer's entire lifetime), 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 exposure to the
drug obtained from pharmacokinetic studies in animals and humans. Our
administrative record lacks the data necessary to determine if there is
an acceptable margin of safety for the repeated daily use of consumer
antiseptic wash active ingredients. Thus, we are continuing to propose
that this data is necessary for consumer antiseptic wash active
ingredients. This information will help identify potential safety
concerns and help determine if an adequate safety margin exists for OTC
human use. One effect of systemic exposure to consumer antiseptic wash
ingredients that has come to our attention since publication of the
1994 TFM is data suggesting that triclosan and triclocarban can cause
alterations in thyroid, reproductive, growth, and developmental systems
of neonatal and adolescent animals (Refs. 41 through 50). Hormonally
active compounds have been shown to affect not only the exposed
organism, but also subsequent generations (Ref. 51). These effects may
not be related to direct deoxyribonucleic acid (DNA) mutation, but
rather to alterations in factors that regulate gene expression (Ref.
52).
    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. 53, 54, and 55).
    Because consumer antiseptic washes are chronic use products and are
used by sensitive populations such as children and 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. However, additional study endpoints may be
needed to fully characterize the potential effects of drug exposure on
the exposed individuals. In light of the preliminary findings for
triclosan and triclocarban, it is particularly important that adequate
analysis of all potential toxic effects of antiseptic active
ingredients be conducted before their classification as GRAS. Section
VII.C of this proposed rule 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.
    The potential of hormonally active antiseptic active ingredients to
cause developmental or reproductive effects raises particular concerns
for the safe use of these ingredients on children. Currently, there is
a lack of data to assess the systemic exposure of antiseptic active
ingredients in children. Additional data to support the safety of the
use of consumer antiseptic active ingredients on children may be
needed. The need for additional data in children would depend on the
risks identified in the animal safety assessment. If studies in
children are needed, we recommend that manufacturers discuss the types
of studies needed with FDA before proceeding.

B. Antimicrobial Resistance

    Since publication of the 1994 TFM, there is new information raising
concerns about the impact of widespread antiseptic use on the
development of antimicrobial resistance (Refs. 56 through 59). 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.
Laboratory studies of some of the antiseptic active ingredients
evaluated in this proposed rule demonstrate the development of 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. 25 and 60 through 77).
These studies provide ample evidence of bacterial resistance mechanisms
that could select for antiseptic or antibiotic resistance in the
natural setting.
    The impact on bacterial resistance in the natural setting (rather
than in the laboratory) has not been extensively evaluated. The
existing data are very limited in scope. A few studies have not found
evidence of such selective pressures occurring in the natural setting
(Refs. 78 through 81). However, these data are limited by the small
numbers and types of organisms, the brief time periods, and locations
examined. More importantly, none of these consumer studies address the
level of exposure to antiseptic active ingredients. Thus, the available
data are not sufficient to support a finding that these mechanisms
would not have meaningful clinical impact. Given the increasing
evidence about the magnitude of the antibiotic resistance problem and
the speed with which new antibiotic resistant organisms are emerging,
it is important to assess this potential consequence of consumer
antiseptic use (Ref. 82).
    FDA has been evaluating the role that consumer 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 on two
occasions. 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. 2). The joint
Committee recommended that FDA work with industry to establish
surveillance mechanisms to address antiseptic and antibiotic
resistance. At the October 2005 NDAC meeting on antiseptics for
consumer use, however, some NDAC members expressed concern about the
societal consequences of the pervasive use of consumer antiseptic wash
products, including the potential for antiseptic use to lead to changes
in bacterial susceptibilities to clinically important antibiotics (Ref.
4).
    Reports of the persistence of low levels of some consumer
antiseptic wash active ingredients in the environment (Refs. 83, 84,
and 85) signal the need to better understand the impact of widespread
use of consumer antiseptic washes. Section VII.C of this proposed rule
describes the data that will help establish a better understanding of
the interactions between antiseptic active ingredients and bacterial
resistance mechanisms in consumer products and will provide the
information needed to perform an adequate risk assessment for these
consumer 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 consumer antiseptic wash active
ingredients should be supported by both nonclinical (animal) and
clinical (human) studies. In order to issue a final monograph for these
products, this safety data must be in the administrative record (i.e.,
rulemaking docket). In order to assist manufacturers or others who wish
to pursue GRAS status for these active ingredients we are including
specific information based in part on existing FDA guidance about the
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. 86 through 91). These guidance documents
also provide suitable guidance for performing the studies necessary to
determine GRAS status for a consumer antiseptic wash active ingredient.
Because consumer antiseptic washes may be used repeatedly over a
lifetime and in sensitive populations, we propose that 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. Safety Studies Described in Existing FDA Guidances
    NDA safety studies that are described in the existing FDA guidances
(Refs. 86 through 91) provide a framework for the types of studies that
are needed for FDA to assess the safety of each antiseptic active
ingredient and make a GRAS determination. A description of each type of
study and how we would use this information to determine safety is
provided in table 5.

                            Table 5--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. 88 and 92).                             the toxic effects of     systemic exposure
                                                                 an active ingredient     levels that can then
                                                                 are observed due to      be correlated to
                                                                 systemic exposure of     potential human
                                                                 the drug. ADME data      exposure via dermal
                                                                 provide: The rate and    pharmacokinetic study
                                                                 extent an active         findings. Adverse
                                                                 ingredient is absorbed   event data related to
                                                                 into the body (e.g.,     particular doses and
                                                                 AUC, Cmax, Tmax);\1\     drug levels (exposure)
                                                                 where the active         in animals are used to
                                                                 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 (Ref. 93).....  Dermal administration    Helps determine how      Used to relate the
                                        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 and S1B       Minimum of one oral and  Provides a direct        Identifies the systemic
 (Refs. 86, 87, and 90)).               one dermal study for     measure of the           and dermal risks
                                        topical products.        potential for active     associated with drug
Developmental toxicity (ICH S5 (Ref.   Oral administration....   ingredients to cause     active ingredients.
 89))..                                .......................   tumor formation          Taken together, these
                                       .......................   (tumorogenesis) in the   studies are used to
Reproductive toxicity (ICH S5 (Ref.    Oral administration....   exposed animals.         identify the type of
 89))..                                                         .......................   toxicity, the level of
                                                                Evaluates the effects     exposure that produces
                                                                 of a drug on the         this toxicity, and the
                                                                 developing offspring     highest level of
                                                                 throughout gestation     exposure at which no
                                                                 and postnatally until    adverse effects occur,
                                                                 sexual maturation..      referred to as the
                                                                Assesses the effects of   ``no observed adverse
                                                                 a drug on the            effect level''
                                                                 reproductive             (NOAEL). The NOAEL is
                                                                 competence of sexually   used to determine a
                                                                 mature male and female   safety margin for
                                                                 animals..                human exposure.
----------------------------------------------------------------------------------------------------------------
\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.

    Because the available data indicate that 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. It also is important that the
human pharmacokinetic studies reflect maximal use conditions of
consumer antiseptic washes using different formulations to fully
characterize the active ingredient's potential for dermal penetration.
Because consumer antiseptic active ingredients can be formulated into
either hand or body washes and consumers may use both on a daily basis,
studies examining maximal use conditions must take full body exposure
into account.
    The duration of the studies should be sufficient to reach steady-
state levels of absorption (i.e., the concentration of active
ingredient is unchanged by further application of the product because
the amount of active ingredient being absorbed is equal to the amount
being eliminated by the body). For a steady-state study, the
measurement of total exposure would be the area under the
concentration-time curve (AUC) for plasma, serum, or blood over the
length of the dosing interval at steady-state. Steady-state must be
demonstrated by an unchanged AUC or drug concentration on 3 consecutive
days taken at the same time of day.
    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)). The Panel's
recommendations for data to support the safety of an OTC topical
antimicrobial active ingredient included studies to characterize the
following:

 Degree of absorption through intact and abraded skin and
mucous membranes
 Tissue distribution, metabolic rates, metabolic fates, and
rates and routes of elimination
 Teratogenic and reproductive effects
 Mutagenic and carcinogenic effects
2. Studies To Characterize Hormonal Effects
    We propose that data are also needed to assess whether 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. 94). 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 wash products that
make it necessary to assess their full safety profile prior to
classifying an antiseptic wash active ingredient as GRAS. These are:

 Evidence of systemic exposure to several of the antiseptic
active ingredients
 Consumer exposure to multiple sources of antiseptic active
ingredients or other drugs that may be hormonally active compounds
 Exposure to antiseptic active ingredients throughout a
consumer's lifetime starting in utero

    Most antiseptic active ingredients have not been evaluated for
these 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, such preliminary assays do not provide conclusive
evidence that such an interaction will lead to a significant biological
change (Ref. 95). 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 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, organ
weights, gross organ changes, clinical chemistry changes, or
histopathology changes, which can help identify adverse hormonal
effects of the tested drug. 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. 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
at detecting hormonal effects include vaginal patency, preputial
separation, 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 consumer 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 the animal studies
and this response is not adequately understood, then additional
studies, such as juvenile animal, pubertal animal, or multigeneration
studies, may be needed (Ref. 96). Juvenile animal, pubertal animal, and
multigeneration studies are designed to evaluate endocrine effects in
developmental stages that supplement the information obtained from
traditional DART studies (Refs. 97, 98, and 99).
    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 where 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. 100).
    Multigeneration studies. The multigeneration reproductive toxicity
studies (Ref. 98) are conducted to assess the performance and integrity
of the male and female reproductive systems and include assessment of
gonadal function, the estrous cycle, mating behavior, conception,
gestation, parturition, lactation, weaning, and growth and development
of the offspring. The multigeneration study also provides information
about the effects of the test substance on neonatal morbidity,
mortality, target organs in the offspring, and data on prenatal and
postnatal developmental toxicity.
    In those cases where adverse effects are noted on the developing
offspring due to a disturbance of any of the organ systems discussed
previously in this proposed rule, a risk-benefit analysis should be
conducted based on the dose-response observed for the findings and the
animal-to-human exposure comparison. If such an assessment indicates a
potentially significant risk, then the antiseptic active ingredient
with such findings would not be suitable for inclusion in an OTC
monograph. Consequently, such antiseptic active ingredients would
require an approval via the NDA pathway prior to marketing.
3. Studies To Evaluate the Potential Impact of Antiseptics Active
Ingredient on the Development of Resistance
    Since the 1994 TFM published, the issue of antiseptic resistance
and the potential for antibiotic cross-resistance has been the subject
of much study and scrutiny. In particular, triclosan has been shown to
cause changes in bacterial efflux activity at nonlethal concentrations
(Refs. 62, 64, 66, 101, and 102). Efflux pumps are an important
nonspecific bacterial defense mechanism that can confer resistance to a
number of substances toxic to the cell, including antibiotics. For this
reason, the effects of triclosan's use as a preservative in cosmetic
products on the development of resistance have been evaluated by a
number of European Advisory Review Committees (Refs. 103 through 108).
In general, these Advisory Review Committees have concluded that the
data are not sufficient to conclude that the use of triclosan poses a
public health risk. However, more recently, a number of data gaps have
been identified that some Advisory Review Committees believe need to be
addressed to allow for a complete risk assessment of the use of
triclosan (Refs. 107 and 108).
    Our own evaluation also found data gaps with respect to triclosan's
impact on the development of resistance; however, based on the data
available for other active ingredients, the need to evaluate potential
resistance is not limited to triclosan. Further, because of the
pervasive use of consumer antiseptic wash products we believe that it
is necessary to assess this safety issue prior to classifying an
antiseptic active

ingredient as GRAS. Therefore, in addition to the preclinical data
requirements (as discussed in this section of this proposed rule), data
are also needed to clarify the effect of antiseptic active ingredients
on the emergence of bacterial resistance.
    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 of this proposed rule, some of the active
ingredients evaluated in this proposed rule have laboratory data
demonstrating the development of reduced susceptibility to antiseptic
active ingredients and antibiotics after exposure to nonlethal
concentrations. However, the testing conducted thus far has been
limited largely to human bacterial pathogens. 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. 109). These organisms represent pools of resistance determinants
that are potentially transferable to human pathogens (Refs. 110 and
111). Broader laboratory testing would more clearly define the scope of
the impact of antiseptic active ingredients on the development of
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 support a GRAS determination for antiseptic
active ingredients intended for use in OTC consumer antiseptic wash
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
 Food-related bacteria such as Listeria, Lactobacillus, and
Enterococcus
 Nonpathogenic organisms and opportunistic pathogens from
environmental compartments (e.g., soil)

    If the results of these studies show no evidence of changes in
antiseptic or antibiotic susceptibility, then 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 susceptibilites, additional data
will be necessary to help assess the likelihood that changes in
susceptibility observed in the preliminary studies would occur in the
consumer setting. Different types of data could be used to assess
whether or not ingredients with positive laboratory findings pose a
public health risk. We do not anticipate that it will be necessary to
obtain data from multiple types of studies for each active ingredient
to adequately assess the potential to affect resistance. Such studies
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 mechanism(s) for the development of
resistance or reduced susceptibility to the antiseptic active
ingredient (for example, efflux mechanisms)
 Data characterizing the potential for reduced antiseptic
susceptibility caused by the antiseptic active ingredient to be
transferred to other bacteria that are still sensitive to the
antiseptic
 Data characterizing the concentrations and antimicrobial
activity of the antiseptic active ingredient in biological and
environmental compartments (for example, on the skin, in the gut, and
in environmental matrices)
 Data characterizing the antiseptic and antibiotic
susceptibility levels of environmental isolates in areas of prevalent
antiseptic use (for example, in the home, health care, food handler,
and veterinary settings)

    These data can help ascertain whether or not an antiseptic active
ingredient is likely to induce nonspecific bacterial resistance
mechanisms such as those that have been shown to occur with triclosan
exposure. These data could also help determine the likelihood that
changes in susceptibility would spread to other bacterial populations
and whether or not concentrations of antiseptics exist in 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 antiseptic use can
help demonstrate whether or not changes in susceptibility are occurring
with actual use. Because actual use concentrations of consumer
antiseptics are much higher than the MICs for these active ingredients,
data from compartments where sublethal concentrations of biologically
active antiseptic active ingredients may occur (e.g., environmental
compartments) can give us a sense of the potential for change in
antimicrobial susceptibilities in these compartments (Refs. 83, 84, and
112 through 115). However, FDA recognizes that methods of evaluating
this issue are an evolving science and that there may be other data
appropriate to evaluate the impact of antiseptic active ingredients on
the development of resistance. For this reason, FDA encourages
interested parties to consult with FDA on the specific studies
appropriate to address this issue.
    In those cases where data of the type described in this proposed
rule shows that changes in bacterial susceptibilities are likely to
occur in the consumer setting, an analysis of the risk in relation to
the effectiveness shown for the active ingredient would be conducted.
Based on this evaluation, a determination would be made as to whether
the antiseptic active ingredient would be suitable for inclusion in an
OTC monograph.

D. Review of Available Data for Each Antiseptic Active Ingredient

    We have identified for each antiseptic active ingredient whether
the studies outlined in section VII.C of this proposed rule are
available. Table 6 of this proposed rule 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 data from submissions to the rulemaking
and from information we have identified in the literature, our
administrative record is incomplete for some types of safety studies
for many of the active ingredients (see table 6 of this proposed rule).

                                  Table 6--Safety Studies Available for Consumer Antiseptic Wash Active Ingredients \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                         Animal                                                            Potential
        Active ingredient               Human       pharmacokinetic        Oral            Dermal        Reproductive       hormonal        Resistance
                                   pharmacokinetic       (ADME)      carcinogenicity  carcinogenicity  toxicity (DART)      effects         potential
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benzalkonium chloride............                                           [check]                                                             [check]
Benzethonium chloride............                          [check]                    [check][check]          [check]                           [check]
Chloroxylenol....................         [check]          [check]                                            [check]                           [check]
Hexylresorcinol..................                          [check]   [check][check]
Iodophors:
    Iodine complex (ammonium                                         [check][check]*                   [check][check]*  [check][check]
     ether sulfate and
     polyoxyethylene sorbitan
     monolaurate)................
    Iodine complex (phosphate                                        [check][check]*                   [check][check]*  [check][check]
     ester of alkylaryloxy
     polyethylene glycol)........
    Nonylphenoxypoly                                                 [check][check]*                   [check][check]*  [check][check]
     (ethyleneoxy) ethanoliodine.
    Poloxamer-iodine complex.....                                    [check][check]*                   [check][check]*  [check][check]
    Povidone-iodine..............  [check][check]                    [check][check]*                   [check][check]*  [check][check]
    Undecoylium chloride iodine                                      [check][check]*                   [check][check]*  [check][check]
     complex.....................
Methylbenzethonium chloride \2\..
Phenol \2\.......................
Secondary amyltricresols \2\.....
Sodium oxychlorosene \2\.........
Triclocarban.....................         [check]          [check]   [check][check]                           [check]          [check]          [check]
Triclosan........................  [check][check]          [check]   [check][check]                    [check][check]          [check]          [check]
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Empty cell indicates no data available; ``[check]'' indicates some data available, but inadequate; ``[check][check]'' indicates available data are
  adequate; * indicates based on studies of potassium iodide.
\2\ These active ingredients are not discussed further because no safety data were submitted.

    In the remainder of this section, we discuss the existing data and
data gaps for each of the following antiseptic wash active ingredients
that was proposed as GRAS in the 1994 TFM and explain why these active
ingredients are no longer proposed as GRAS (i.e., why they are now
proposed as Category III):

 Hexylresorcinol
 Iodophors (i.e., all iodine-containing ingredients)
 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 safety data for these active ingredients:

 Methylbenzethonium chloride
 Phenol (less than 1.5 percent)
 Secondary amyltricresols
 Sodium oxychlorosene
1. Hexylresorcinol
    In the 1994 TFM, FDA proposed to classify hexylresorcinol as GRAS
for use as an OTC antiseptic handwash based on the recommendations of
the Panel, who concluded that the topical application of
hexylresorcinol is safe (39 FR 33103 at 33134). In support of its
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. 116).
    In light of the new safety information about the potential risks of
systemic exposure to antiseptic active ingredients, the data relied on
by the Panel no longer can be considered adequate 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.
    a. Summary of available hexylresorcinol safety data.
    Hexylresorcinol ADME data. There currently are no well
characterized absorption studies in either humans or animals and only
minimal ADME data by the oral route available. In one study (Ref. 117)
male dogs were given single oral doses of 1 or 3 grams (g) of 4-
hexylresorcinol. The majority of the administered dose was detected in
its free form in the feces (67 to 80 percent) with some excretion in
the urine (10 to 29 percent) primarily as conjugates. Urinary excretion
was rapid, mainly in the first 6 hours, and levels were undetectable 12
hours after the 1 g dose and 24-36 hours after the 3 g dose.
    In the only study in humans (Ref. 118), two men received oral doses
of 1 g of 4-hexylresorcinol. An average of 18 percent of the dose was
recovered in urine within the first 12 hours; thereafter, the compound
was not detected in urine samples. Fecal excretion accounted for 64
percent of the dose. It has been reported that hexylresorcinol is
excreted via the urine mainly in the form of an ethereal sulfate
conjugate (Ref. 119).
    Overall, the animal ADME 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.
    Hexylresorcinol carcinogenicity data. An adequate oral
carcinogenicity study was conducted by the National Toxicology Program
(NTP) in which hexylresorcinol was administered orally to groups of
rats and mice of each sex 5 days per week for 2 years (Ref. 120). No
evidence of carcinogenicity was found in rats. However, precancerous
cells of the adrenal gland were observed at increased incidences in
dosed male mice. A marginal upward trend in tumors of the adrenal gland
was also observed in male mice. The increase of these two types of
cancers was not statistically significant and was considered equivocal
by the NTP.
    FDA agrees that the findings in male mice should not be considered
a positive carcinogenic signal. No changes were noted in the adrenal
glands in 16-

and 30-day subgroups included in the study. Also, the fact that the
marginal increase in changes that occurred in male mice were not
corroborated in earlier RDT studies in female mice, or in rats of
either sex, makes the weight of the evidence for the male-only findings
weak. In an 18-month intravaginal study (Ref. 121), injection of 1
percent hexylresorcinol dissolved in carbowax 1000 twice weekly in 20
female mice did not cause any genital tract tumors.
    The submitted oral carcinogenicity data are adequate and show that
hexylresorcinol does not pose a risk of cancer after repeated oral
administration under the experimental conditions used; however, data
from a dermal carcinogenicity study are lacking.
    b. 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, including documentation of validation of the
methods used to measure hexylresorcinol and its metabolites
 Animal ADME
 Data to help define the effect of formulation on dermal
absorption
 Dermal carcinogenicity
 DART studies
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the
development of resistance to hexylresorcinol and cross-resistance to
antibiotics in the types of organisms listed in section VII.C.3 of this
proposed rule
2. Iodophors (Iodine-Containing Ingredients)
    Iodophor complexes are complexes formed between iodine, which is
the active antimicrobial component, and a carrier molecule. Both
surfactant and nonsurfactant compounds have been complexed with iodine.
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). The following surfactant and nonsurfactant
iodophor complexes were proposed as GRAS in the 1994 TFM for OTC
antiseptic handwash use (59 FR 31402 at 31435):

 Iodine complex (ammonium ether sulfate and polyoxyethylene
sorbitan monolaurate)
 Iodine complex (phosphate ester of alkylaryloxy polyethylene
glycol)
 Nonylphenoxypoly (ethyleneoxy) ethanoliodine
 Poloxamer-iodine complex
 Povidone-iodine 5 to 10 percent
 Undecoylium chloride iodine complex

    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
consumers are widely exposed to iodine, it has been the subject of
comprehensive toxicological review by public health organizations
(Refs. 122 and 123).
    In the 1994 TFM, FDA stated that neither the medium nor large
molecular weight size povidone molecules presented a safety risk when
limited to the topical uses described in the monograph and that larger
size molecules would not be absorbed under the TFM conditions of use
(59 FR 31402 at 31424). We continue to believe that the larger size
molecules pose no risk of absorption. However, data are lacking on the
absorption of smaller molecular weight povidone molecules and for other
carriers currently under consideration, e.g. poloxamer. Human
absorption studies following maximal dermal exposure to these carriers
can be used to determine the risk of systemic toxicity from the carrier
molecule. For carrier molecules that are absorbed following dermal
exposure, we propose that the following data are needed: 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).
    a. Summary of iodophor safety data.
    Iodophor human pharmacokinetics data. Several studies demonstrated
that iodine applied to human skin was systemically absorbed to some
extent (Ref. 122). The studies consistently found raised blood
concentrations of both organic (protein-bound) and inorganic (nonbound)
iodine following topical application of iodine-containing antiseptics,
indicating that iodine permeated the skin. However, the studies did not
provide sufficient information to quantify typical amounts of iodine
that can be absorbed from topically applied products containing iodine.
In addition, the studies do not provide pharmacokinetic data at maximal
exposure and steady-state levels.
    Most of the absorption studies evaluated povidone-iodine.
Significant iodine absorption was seen as a result of topical
application of povidone-iodine either as a surgical scrub (Ref. 124) or
as an antiseptic treatment of premature babies in a neonatal intensive
care nursery (Ref. 125). Nobukuni et al. (Ref. 126) evaluated the
effect of long-term topical povidone-iodine treatment on serum iodine
levels and thyroid function in bedridden inpatients. Inpatients treated
with povidone-iodine had higher blood concentrations of organic iodine
compared to the control group, suggesting absorption of topically
applied iodine. It is possible that steady-state levels may have been
achieved in this study; however, this was not directly demonstrated.
    Although these studies provide some information on absorption of
topically applied povidone-iodine, they do not provide sufficient
information to estimate typical amounts of iodine that could be
absorbed from consumer antiseptic wash products containing povidone-
iodine. Nor can the results of these studies be extrapolated to assess
the potential dermal penetration of iodine from other iodophor
complexes. Because the iodophor complex affects the release rate of
iodine, absorption data are needed for each different complex.
    Iodophor ADME data. In addition to human absorption data (described
in the previous subsection), the distribution, metabolism, and
excretion of iodine have been characterized in humans for oral
exposures (Ref. 122). Because the distribution of absorbed iodine has
been shown to be similar regardless of the route of exposure, we can
use data from oral exposures in assessing distribution, metabolism, and
excretion of iodine from topical exposure. Most of the iodine from
orally ingested sodium iodide accumulates in the thyroid (approximately
20 to 30 percent) as iodide or is excreted in the urine (30 to 60
percent) within 10 hours (Refs. 122 and 127). The elimination half-life
of absorbed iodine is approximately 31 days in healthy adult males
(Ref. 127), but has considerable variability (Ref. 128). Overall, the
distribution, metabolism, and excretion of iodine have been adequately
assessed in humans and no further animal ADME data is needed.
    Iodophor carcinogenicity data. The oral carcinogenicity data
indicate that iodine does not pose a risk of cancer in rats after
repeated oral administration to rats under the experimental conditions
used (Ref. 129). Overall, there was no significant increase in the
incidence of tumors from iodine exposure. Although there was an
increased incidence of squamous cell carcinomas in the submandibular
salivary gland in the

high dose group, this increase was not significant.
    The ability of iodine to function as a tumor promoter (i.e.,
something that stimulates existing tumors to grow) also has been
evaluated in rats. In a study by Takegawa et al. (Ref. 130), rats were
pretreated with a chemical that can initiate tumors (DHPN). One group
then received a high dose of potassium iodide (1,000 parts per million
(ppm)) in their water while a control group received untreated water
over 82 weeks. The iodine-treated group had a significantly higher
incidence of follicular thyroid cancer compared to the control group,
suggesting that iodine may be a tumor promoter for other carcinogens in
the thyroid gland.
    In another study (Ref. 131), rats were injected with either DHPN or
saline and then received doses of potassium iodide in their drinking
water to simulate conditions of iodine deficiency to iodine excess. For
the two highest-dose groups, 5 of 20 rats and 2 of 20 rats developed
thyroid tumors, respectively. Although the authors concluded that
excess iodine can promote thyroid tumor formation, these results were
barely significant, and higher dosing did not correlate with increased
tumor promotion activity. Therefore, some evidence suggests that very
high oral doses of iodine may have tumor promoter activity. However,
based upon the available data, oral doses of iodine do not
significantly raise the risk of cancer in animals.
    Iodophor DART data. The effects of iodine on embryo-fetal
development and on fertility were studied in animals (Ref. 132). No
fetal malformations were reported when the fetuses were exposed to
iodine prenatally, nor were there any effects on fertility in adult
animals that were exposed to iodine. The design of these studies,
however, does not fit into current testing paradigms for an adequate
evaluation of the reproductive and developmental toxicity of a drug.
    One series of studies (Ref. 132) evaluated the effects of diets
supplemented with high levels of iodine on reproduction, lactation, and
survival in rats, hamsters, rabbits, and pigs. For the rats, excess
iodine in the diet (2,500 ppm) was associated with an increase in the
incidence of death in newborns and an increase in the time to give
birth. In rabbits, a dose-dependent decrease in newborn survival was
observed. There were no observed effects in hamsters or pigs. The
results suggest a species difference in response to similar levels of
excess iodine; however, the daily iodine intake per kilogram (kg) of
body weight varied among species. Further, these studies do not
evaluate all the necessary endpoints regarding fertility and embryo-
fetal development.
    Shoyinka, Obidike, and Ndumnego (Ref. 133) evaluated the effect of
iodine on the male reproductive system of rats. A statistically
significant (p<0.05) increase in the average weights of the testes and
epididymides, and approximately 12 percent decrease in epididymal sperm
counts were observed in the high dose-treated group. The authors
suggest that excess iodine may reduce fertility by lowering epididymal
sperm counts.
    We found no information on reproductive effects in humans due to
dermal iodine exposure. However, transient hypothyroidism (diminished
production of thyroid hormones) in infants has been reported as a
result of topical exposure to povidone-iodine (Refs. 134 through 138).
Thyroid hormone deficiency from any cause at critical times of
development may result in adverse effects, including abnormal pubertal
development (Ref. 122). Although excess iodine may result in
hypothyroidism, iodine deficiency is more likely to cause prenatal and
postnatal hypothyroidism (Ref. 122).
    Overall, the effect of iodine on development and reproductive
toxicology are well characterized and additional DART studies are not
needed.
    Iodophor data on hormonal effects. We found no nonclinical studies
that examine the effect of excess iodine or iodine deficiency on
endocrine systems in animal models. However, clinical data indicate
that at high doses iodine ingestion exerts a direct effect on the
thyroid gland and on the regulation of thyroid hormone production and
secretion (Ref. 122). The effects of iodine on the thyroid gland have
been shown to include hypothyroidism, hyperthyroidism (excessive
production or secretion of thyroid hormones), and inflammation of the
thyroid. These conditions can adversely affect reproduction, growth,
and developmental systems in humans.
    The data demonstrating the thyroid effects of iodine are primarily
from oral administration (Ref. 122). There is much less information on
thyroid effects after topical administration of iodine. The majority of
cases of thyroid hormone changes resulting from topical administration
of iodine involve mothers and newborn infants. Studies have shown that
topical povidone-iodine applied to pregnant and breast-feeding women
causes transient hypothyroidism in their newborns (Refs. 135, 136, 139,
and 140). Iodine-induced hypothyroidism has been reported in nursing
infants whose mothers used topical or vaginal iodine-containing
antiseptics during pregnancy or after delivery (Refs. 135, 136, and
141). Other studies have shown hypothyroidism in infants after topical
iodine exposure (Refs. 125, 134, 138, and 142). Elevated thyroid
stimulating hormone (TSH) levels have been reported in full-term
newborns after repeated topical application of povidone-iodine (Refs.
143 and 144).
    Iodine readily crosses the placenta and is concentrated in the
mammary gland and secreted in breast milk (Ref. 145). Although iodine-
induced hypothyroidism is transient in newborns, even transient
hypothyroidism should be avoided during this critical phase of brain
development to prevent loss of intellectual capacity (Refs. 146, 147,
and 148).
    For adults, the association between topically applied iodine and
hypothyroidism is unclear. One study in 27 bedridden inpatients treated
continuously with povidone-iodine for 3 to 133 months showed changes in
TSH levels (Ref. 126). However, these data are difficult to extrapolate
to typical consumer antiseptic hand or body wash use because povidone-
iodine was applied to damaged skin in this study. Another study in 16
nurses who used povidone-iodine regularly for handwashing and gargling
(Ref. 149) found that thyroid hormone levels were not significantly
different from control subjects who rarely used povidone-iodine, which
suggests topical povidone-iodine does not significantly affect thyroid
function.
    Oral exposure to iodine has been demonstrated to cause significant
thyroid effects (Refs. 122 and 123). Several clinical studies