Document ID: FDA-1975-N-0012-0317
Agency: fda
Document Type: Proposed Rule
Title: 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
Posted Date: 2013-12-17T05:00Z

[Federal Register Volume 78, Number 242 (Tuesday, December 17, 2013)]
[Proposed Rules]
[Pages 76443-76478]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-29814]

[[Page 76443]]

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  

[[Page 76444]]

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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

[[Page 76445]]

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.

----------------------------------------------------------------------------------------------------------------
 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,

[[Page 76446]]

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.

[[Page 76447]]

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
----------------------------------------------------------------------------------------------------------------
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.
----------------------------------------------------------------------------------------------------------------

[[Page 76448]]

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
----------------------------------------------------------------------------------------------------------------
                     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).

[[Page 76449]]

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).

[[Page 76450]]

  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

[[Page 76451]]

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

[[Page 76452]]

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

[[Page 76453]]

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

[[Page 76454]]

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.

[[Page 76455]]

                            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

[[Page 76456]]

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

[[Page 76457]]

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).

[[Page 76458]]

                                  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-

[[Page 76459]]

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

[[Page 76460]]

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 
demonstrated that high oral doses of iodine can affect blood levels of 
thyroid hormones, but rarely did these effects seriously impair thyroid 
function. Oral iodine exposure exceeding 200 mg/day (2.8 mg/kg/day) 
during pregnancy can result in congenital hypothyroidism (Ref. 122). 
Generally, however, adverse effects were only observed following very 
high oral doses that caused very high serum iodine concentrations.
    Drawing conclusions from these studies is difficult because the 
studies have several limitations. Many of these studies lacked control 
groups, used small subject numbers, and/or did not record subjects' 
iodine status at baseline (iodine-deficient subjects may be more 
susceptible to thyroid effects caused by iodine exposure). The study 
results are also difficult to compare because the studies used 
different subject age groups, subject types, iodine

[[Page 76461]]

formulations and amounts, durations and frequency of iodine treatment, 
and methods for measuring absorbed iodine levels or thyroid effects. 
Despite these deficiencies, we believe there are adequate data 
regarding the potential of iodine to cause changes in thyroid hormone 
levels and additional studies are not necessary.
    b. Iodophor safety data gaps. In summary, our administrative record 
for the safety of iodophor complexes is incomplete with respect to the 
following:

 Human studies of the absorption of iodine following maximal 
dermal exposure to the complexes
 Human absorption studies of the carrier molecule for small 
molecular weight povidone molecules and the other carriers listed in 
this section
 Dermal carcinogenicity studies for each of the iodophor 
complexes
 Data from laboratory studies that assess the potential for the 
development of resistance to iodine and cross-resistance to antibiotics 
in the types of organisms listed in section VII.C.3 of this proposed 
rule
3. Triclocarban
    In the 1994 TFM, FDA proposed to classify triclocarban as GRAS for 
use as an OTC antiseptic handwash. This determination was based on 
safety data and information that were submitted in response to the 1978 
TFM on triclocarban formulated as bar soap (Refs. 151 and 152). These 
data included blood levels, target organs for toxicity, and no effect 
levels and were discussed in the 1991 First Aid TFM (56 FR 33644 at 
33664). The existing data, however, are no longer sufficient to fully 
evaluate the safety of triclocarban. New information regarding 
potential risks from systemic absorption and long-term exposure to 
antiseptic active ingredients is leading us to propose additional 
safety testing.
    a. Summary of triclocarban safety data.
    Triclocarban human pharmacokinetic data. Some human pharmacokinetic 
parameters were reported in a study where six male subjects received a 
single oral dose of \14\C-labeled triclocarban: The maximum plasma 
concentration (i.e., Cmax) was 3.7 nanomole (nmol)-equivalents of 
triclocarban per g of plasma (approximately 1,200 nanograms per 
milliliter (ng/mL)) and occurred at 2.8 hours (Tmax) (Ref. 152). 
Although human pharmacokinetic parameters were reported in this study, 
triclocarban was administered orally. As a result, the exposure when 
applied topically under maximal use conditions and when steady-state 
levels were reached is unknown.
    We found several studies in humans that examine the absorption of 
triclocarban after topical application (Refs. 153 through 156). Most of 
these studies evaluated absorption after a single topical exposure and 
used a small number of subjects. After a single exposure, blood levels 
of triclocarban ranged from below the limit of detection (10 ng/mL) to 
a Cmax of 530 nanomolar (nM) (167 ng/mL) (Refs. 153, 154, and 155). 
Small amounts of triclocarban were also detectable in the urine and 
feces of subjects. The estimated total average recovery ranged between 
0.39 and 0.6 percent of the applied dose. Although small, these studies 
suggest that very little triclocarban is absorbed after a single 
topical exposure; however, steady-state levels were not evaluated.
    Howes and Black (Ref. 156) examined absorption of triclocarban 
after repeated daily application in a 28-day bathing study. Twelve 
subjects bathed once daily using bar soap that contained 2 percent 
triclocarban. Each subject was exposed to approximately 260 mg of 
triclocarban per day. Triclocarban was below the limit of detection (25 
ng/mL) in all samples at all time points. A manufacturer of 
triclocarban has suggested that steady-state levels were achieved in 
this study (Ref. 157), but this was not directly demonstrated.
    In addition to systemic exposure as a result of dermal absorption, 
consumers may have prolonged exposure to those antiseptic active 
ingredients that remain bound to the skin after use (that is, 
substantive). Triclocarban has been shown to be substantive. North-Root 
et al. (Ref. 158) measured the amount of triclocarban that remained on 
the skin after a single application of bar soap in 12 human subjects. 
An average of 1.4 percent of the applied triclocarban remained on the 
skin. Substantive product remaining on the skin after rinsing may lead 
to additional absorption and systemic exposure.
    Overall, the human pharmacokinetic studies are not adequate, and we 
propose that human pharmacokinetic studies using dermal administration 
under maximal use conditions are still needed to define the level of 
systemic exposure following repeated use. In addition, data are needed 
to help define the effect of formulation on dermal absorption.
    Triclocarban ADME data. Triclocarban is readily metabolized in both 
humans and animals (Refs. 159 through 162). Birch et al. (Ref. 159) 
identified the metabolites of triclocarban in plasma and urine after 
oral exposure in rats, rhesus monkeys, and humans. The principal 
metabolites common to all species were the sulfate and glucuronide 
conjugates of 2'-, 3'-, and 6-hydroxy-triclocarban. However, there were 
differences in triclocarban metabolism between rats and higher 
primates, and the monkey appears to be the more appropriate model for 
studying triclocarban pharmacokinetics in humans (Ref. 159).
    Elimination of triclocarban metabolites from the plasma appears to 
be biphasic. In adult rhesus monkeys, elimination from the plasma 
occurs in two distinct phases: Rapid elimination of parent triclocarban 
and glucuronide conjugates, and slower elimination of sulfate 
conjugates (Ref. 160). Similarly, in humans, the major plasma 
metabolites are glucuronide conjugates, which were eliminated in urine 
with a half-life of about 2 hours (Ref. 152). Triclocarban sulfate 
conjugates are removed from plasma with a half-life of about 20 hours, 
presumably into the bile.
    The majority of triclocarban and its metabolites are eliminated 
through the feces, with smaller amounts eliminated through the urine. 
In a human study where six male volunteers received a single oral dose 
of \14\C-labeled triclocarban in corn oil, 70 percent of the dose was 
eliminated in the feces and elimination was complete after 120 hours 
(Ref. 152). Twenty-seven percent of the dose was eliminated in urine, 
and the urinary excretion of triclocarban and its metabolites was 
complete by 80 hours after dosing.
    Although there are some ADME data on triclocarban after oral 
exposure, there are little data after topical exposure. Gruenke et al. 
(Ref. 163) analyzed plasma and urine samples from human subjects who 
used triclocarban-containing bar soap. The major plasma metabolite was 
a sulfate of hydroxy-triclocarban, with levels ranging from 0-20 ng/mL. 
The major metabolites found in the urine were triclocarban 
glucuronides, with typical levels averaging 30 ng/mL. The authors did 
not describe the frequency or length of time the subjects bathed with 
the soap; consequently, it is not known whether maximal exposure or 
steady-state levels were reached. 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.
    Triclocarban carcinogenicity data. A manufacturer submitted a 2-
year oral carcinogenicity study of triclocarban in rats (Refs. 150 and 
151). Based on this study, the no observed adverse effect level (NOAEL) 
for triclocarban in the rat

[[Page 76462]]

is 25 mg/kg/day. Although no carcinogenicity findings were seen in this 
study, some noncarcinogenicity findings were noted. Male rats treated 
with 75 and 250 mg/kg/day doses of triclocarban exhibited male sex 
organ toxicity, including degeneration of the seminiferous tubules, 
enlargement of the epididymal secretory epithelium, and a decrease or 
absence of sperm in epididymal ducts.
    No dermal carcinogenicity data have been submitted for 
triclocarban. Previously, we considered data from systemic exposure to 
represent a worst case scenario for topical products. Now, however, we 
recognize that topical products may affect the skin or be metabolized 
in the skin, which is not addressed in oral carcinogenicity studies.
    The submitted oral carcinogenicity data are adequate and show that 
triclocarban 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.
    Triclocarban DART data. Our records indicate that a manufacturer 
submitted data regarding the reproductive toxicity of triclocarban to a 
triclocarban drug master file (Ref. 164). Safety data submitted to drug 
master files are not publicly available and, consequently, cannot be 
used to support a GRAS classification (Sec.  330.10(a)(4)(i)). For FDA 
to include these data in the administrative record for this rulemaking, 
they must be submitted to this rulemaking or be otherwise publicly 
available.
    Triclocarban data on hormonal effects. Recent studies have 
demonstrated that triclocarban may have the ability to alter the 
activity of the androgen system (Refs. 41 and 42). Chen et al. (Ref. 
42) reported that triclocarban enhanced the testosterone-induced 
androgen receptor-mediated response both in cell culture and in an in 
vivo rat model although triclocarban by itself had no activity. When 
castrated male rats were fed a diet containing 0.25 percent 
triclocarban and treated with testosterone propionate (0.2 mg/kg) for 
10 days, all male sex accessory organs were significantly increased in 
size compared to rats treated with either triclocarban or testosterone 
alone. The implications of these findings on human health, especially 
for children, are not well understood.
    The testicular effects seen in the 2-year oral carcinogenicity 
study (Refs. 150 and 151) also suggest a hormonal disturbance on the 
testes as a result of exposure to triclocarban. Our records indicate 
that additional studies to address possible testicular effects have 
been conducted and submitted to a triclocarban drug master file (Ref. 
164). For FDA to include these data in the administrative record for 
this rulemaking, they must be submitted to the rulemaking or otherwise 
publicly available. Overall, the data submitted to the antiseptic 
rulemaking are not adequate to address concerns about hormonal effects 
of triclocarban. We propose that additional reproductive and 
developmental studies are necessary, which should include an assessment 
of any hormonal effects.
    Triclocarban resistance data. We found one study that examined the 
potential for development of cross-resistance between triclocarban and 
antibiotics. Cole et al. (Ref. 78) described antibiotic and antiseptic 
susceptibilities of staphylococci isolated from the skin of consumers 
who used nonantibacterial or antiseptic body washes. Subjects were 
considered antiseptic body wash users if they used either bar soaps 
containing triclocarban (triclocarban group) or liquid bath or shower 
products containing triclosan (triclosan group) on a regular basis for 
at least 30 days prior to study initiation. From a pool of 450 
qualified subjects, 70 were randomly chosen for each treatment arm 
(non-user, triclocarban group, or triclosan group).
    Bacterial skin samples were collected using a pre-validated method 
and were comprised of the combined samples from both forearms. 
Staphylococcus aureus and coagulase-negative Staphylococcus (CNS) were 
presumptively identified according to morphology, pigmentation, 
hemolysis, and other characteristics from these samples. One 
representative of each colony type from each sample was selected for 
further testing, for a total of 317 isolates: 16 S. aureus and 301 CNS.
    All 317 Staphylococcus isolates were tested for susceptibility to 
10 antibiotics, including the primary and secondary antibiotics of 
choice for treatment of Staphylococcus infections, by a commercial lab 
using an automated procedure. In addition, all isolates were tested for 
MIC of triclocarban and triclosan using a standard broth microdilution 
method.
    The percentage of CNS isolates resistant to any of the 10 
antibiotics was similar for all three groups (non-user, triclocarban, 
or triclosan group). When data from both user groups (triclocarban and 
triclosan) were pooled, there was no statistical difference in 
bacterial resistance patterns between users and non-users with the 
exception of tetracycline, which approached significance (p = 0.052). 
The authors did not provide the rationale for pooling triclocarban and 
triclosan user data in the analysis. Currently, there is no evidence to 
suggest that bacteria would use the same mechanisms of resistance 
against these two antiseptic active ingredients. When CNS 
susceptibility to antiseptics was examined, the MIC range for 
triclocarban was the same among all three groups (maximum MIC value of 
0.750 (no units provided)). No patterns emerged when the data were 
analyzed for cross-resistance between triclocarban or triclosan and 
antibiotics.
    The authors conclude that this study shows no increase in 
antibiotic resistance from the regular use of triclocarban body wash. 
But, this study was not adequately designed to determine whether use of 
antiseptic body washes leads to changes in antibiotic or antiseptic 
susceptibilities. Given the limited number of isolates examined, it is 
not clear that the study was adequately powered to detect a difference 
in resistance patterns. Furthermore, the amount of antiseptic exposure 
was not defined. The length of time subjects has used antiseptic body 
washes (beyond the specified 30 days), the frequency of bathing, and 
the volume of antiseptic wash used per bath or shower was not reported. 
Finally, few bacterial isolates were examined. It is reasonable to 
examine the susceptibilities of Staphylococcus species; however, an 
average of only 1.5 isolates was obtained from each subject. Overall, 
the available data are not adequate to characterize triclocarban's 
potential to foster the development of cross-resistance with clinically 
important antibiotics and we propose that these studies are needed.
    b. Triclocarban safety data gaps. In summary, our administrative 
record for the safety of triclocarban is incomplete with respect to the 
following:

 Human pharmacokinetic studies under maximal use conditions 
when applied topically, including documentation of validation of the 
methods used to measure triclocarban 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 triclocarban and cross-resistance to 
antibiotics in the types of organisms listed in section VII.C.3 of this 
proposed rule

[[Page 76463]]

4. Benzalkonium Chloride
    In the 1994 TFM, FDA categorized benzalkonium chloride in Category 
III because of a lack of adequate safety data for its use as OTC 
antiseptic handwash (59 FR 31402 at 31435). Because of its widespread 
use as an antimicrobial agent in cosmetics and as a disinfectant for 
hard surfaces in agriculture and medical settings, the safety of 
benzalkonium chloride has also been reviewed by the Environmental 
Protection Agency and an industry review panel (Cosmetic Ingredient 
Review (CIR)) (Refs. 165 and 166) and found to be safe for disinfectant 
and cosmetic uses, respectively. Both these evaluations have been cited 
by the comments in support of the safety of benzalkonium chloride as an 
antiseptic wash active ingredient (Ref. 167).
    Each of these evaluations cites findings from the type of studies 
necessary to support the safety of benzalkonium chloride for repeated 
daily use. However, the data that are the basis of these safety 
assessments are proprietary and are publicly available only in the form 
of summaries. Consequently, these studies are not available to FDA and 
are precluded from a complete evaluation by FDA. In addition, the 
submitted safety assessments with study summaries do not constitute an 
adequate record on which to base a GRAS classification (Sec.  
330.10(a)(4)(i)). For FDA to evaluate the safety of benzalkonium 
chloride for this rulemaking, these studies must be submitted to the 
rulemaking or otherwise be publicly available.
    a. Summary of benzalkonium chloride safety data.
    Benzalkonium chloride carcinogenicity data. Currently, no oral or 
dermal carcinogenicity data are publicly available. We found one short-
term dermal toxicity study (Ref. 168). Mice were treated with a single 
topical application of 0.8, 3, 13, or 50 percent benzalkonium chloride 
aqueous solution and monitored for 1 month. Treatment with either the 
13 or 50 percent solution (concentrations well above the actual use 
concentrations of 0.1 to 5 percent) caused death in 9 of 48 and 20 of 
48 mice in each group, respectively. The surviving mice developed skin 
lesions at the application site. The low-dose groups (0.8 or 3 percent 
solutions) showed slightly lower body weights and rates of growth than 
the control group, suggesting a slight detrimental effect from dermal 
exposure to these low concentrations. The available data are not 
adequate to assess the carcinogenic potential of benzalkonium chloride. 
We propose that both oral and dermal carcinogenicity studies are needed 
for benzalkonium chloride.
    Benzalkonium chloride resistance data. Several gram-negative 
bacteria (GNB) (Escherichia coli, Salmonella, and Pseudomonas) have 
been shown to readily adapt when grown in the presence of subinhibitory 
levels of benzalkonium chloride in laboratory studies (Refs. 60, 68, 
70, 72, 169, and 170). These bacteria also displayed reduced 
susceptibility to antibiotics compared to the nonadapted parental 
strain (Refs. 60, 70, 72, 169, and 170). Four studies showed an 
association between reduced susceptibility to benzalkonium chloride and 
the antibiotic chloramphenicol (Refs. 70, 72, 79, and 170). This 
association was shown in three different bacteria; however, no common 
mechanism has been identified to explain this finding. There are data 
available suggesting that efflux pumps may not play a major role in the 
reduced susceptibility of Salmonella to benzalkonium chloride (Ref. 
170).
    In a study by Lambert and colleagues (Ref. 69), human clinical and 
industrial isolates and standard culture collection strains of P. 
aeruginosa were examined for reduced susceptibility to benzalkonium 
chloride, chlorhexidine, and eight antibiotics. No statistically 
significant association between benzalkonium chloride and antibiotic 
susceptibility (i.e., cross-resistance) was found in the industrial 
isolates. In contrast, there was a highly significant correlation 
between benzalkonium chloride and gentamycin resistance in the clinical 
isolates. In other words, strains that were resistant to gentamycin 
also tended to have reduced benzalkonium chloride susceptibility. 
Although the authors suggest that the clinical environment is 
responsible for cross-resistance, this study is not large enough to 
provide sufficient support for this theory.
    In a second study, Lambert and colleagues found a positive 
correlation between benzalkonium chloride and six antibiotics 
(ciprofloxacin, erythromycin, oxacillin, clindamycin, amoxicillin/
clavulanic acid, and sodium cefazolin) in MRSA clinical isolates. 
However, most of the statistically significant correlations found in 
this study were between two antiseptics or two antibiotics, rather than 
between an antiseptic and an antibiotic. In addition, there was also a 
negative correlation between benzalkonium chloride and ciprofloxacin in 
P. aeruginosa. The authors suggest that there are no correlations in 
resistance to benzalkonium chloride and resistance to antibiotics but 
believe a larger study is needed to confirm or change that conclusion.
    Similar to what has been observed with triclosan, exposure to 
benzalkonium chloride in the laboratory has resulted in changes to the 
antibiotic susceptibility profiles of some bacteria (Refs. 60, 70, 72, 
79, 169, and 170). However, the data are limited in scope. The 
available studies have examined few bacterial species, provide no 
information on exposure levels, and are not adequate to define the 
potential for the development of resistance or cross-resistance. 
Additional laboratory studies are necessary to more clearly define the 
potential for the development of resistance to benzalkonium chloride. 
Depending on the results of the laboratory studies, additional data of 
the type described in section VII.C of this proposed rule may also be 
needed to assess the level of risk posed by benzalkonium chloride.
    b. Benzalkonium chloride safety data gaps. In summary, our 
administrative record for the safety of benzalkonium chloride is 
incomplete with respect to the following:

 Human pharmacokinetic studies under maximal use conditions 
when applied topically, including documentation of validation of the 
methods used to measure benzalkonium chloride and its metabolites
 Animal ADME
 Data to help define the effect of formulation on dermal 
absorption
 Oral carcinogenicity
 Dermal carcinogenicity
 DART studies
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the 
development of resistance to benzalkonium chloride and cross-resistance 
to antibiotics in the types of organisms listed in section VII.C.3 of 
this proposed rule
5. Benzethonium Chloride
    In the 1994 TFM, FDA classified benzethonium chloride as lacking 
sufficient evidence of safety for use as an antiseptic handwash (59 FR 
31402 at 31435). Since FDA's proposed classification, two industry 
review panels (CIR and a second industry panel identified in a comment 
only as an ``industry expert panel'') and a European regulatory 
advisory board (Scientific Committee on Cosmetic Products and Non-food 
Products Intended for Consumers) have evaluated the safety of 
benzethonium chloride when used as a preservative in cosmetic 
preparations and as an active ingredient

[[Page 76464]]

in consumer hand soaps (Refs. 171, 172, and 173). These advisory bodies 
found benzethonium chloride to be safe for these uses. However, all of 
these safety determinations have largely relied on the findings of 
proprietary studies that are not publicly available. One of these 
evaluations, the findings of the unidentified industry expert panel, 
was submitted to the rulemaking to support the safety of benzethonium 
chloride (Ref. 174).
    Some of the safety data reviewed by the unidentified industry 
expert panel represent the type of data that are needed to evaluate the 
safety of benzethonium chloride for use in consumer antiseptic wash 
products, e.g., ADME, DART, and oral carcinogenicity studies. The 
safety assessments used to support the unidentified industry expert 
panel's finding of safety, however, are publicly available only in the 
form of summaries. Consequently, these studies are not available to FDA 
and are precluded from a complete evaluation by FDA. Further, the 
submitted safety assessments with study summaries do not constitute an 
adequate record on which to base a GRAS classification (Sec.  
330.10(a)(4)(i)). For FDA to include these studies in the 
administrative record for this rulemaking, they must be submitted to 
the rulemaking or otherwise publicly available.
    a. Summary of benzethonium chloride safety data.
    Benzethonium chloride ADME data. In 1988, NTP studied the extent of 
absorption following single and repeated once-daily dermal doses of 
benzethonium chloride and determined the pattern of tissue distribution 
and route of elimination of \14\C-labeled benzethonium chloride in rats 
(Ref. 175). They also determined the kinetics of distribution and 
excretion following intravenous administration. Under the conditions of 
the dermal studies, benzethonium chloride was readily absorbed 
following single or repeated dermal applications.
    After a single application of \14\C-labeled benzethonium chloride 
in ethanol to skin that was covered by a nonocclusive patch, total 
urinary excretion was 1 to 2 percent of the applied dose, and fecal 
excretion accounted for about 45 percent of the dose. The radiolabel 
was below the detection limit in blood and most tissues during the 
study, but low levels were measured in the liver. Some residual 
radiolabel could be accounted for in the epidermis at the site of 
application. When similar studies were performed with repeated once-
daily dermal dosing, the total amount of radiolabel excreted up to 10 
days following the last dose was about 25 percent, suggesting some 
accumulation with repeated dermal administration.
    More recent data submitted to support the safety of benzethonium 
chloride have shown a much lower level of absorption. In response to 
the 1994 TFM, a manufacturer provided data from a preliminary rat 
dermal absorption study and an in vitro dermal absorption study (Ref. 
176). In the rat study, an aqueous 1 percent solution of \14\C-
benzethonium chloride was applied to the shaved back of rats and 
covered with a nonocclusive patch. Blood, urine, and feces were 
collected for 48 hours after dosing. Little or no radioactivity was 
detected in blood or urine samples. Approximately 7 percent of the 
administered radioactivity was detected in the fecal samples. The 
remaining radioactivity was not accounted for.
    The in vitro dermal absorption study compared the absorption of 
benzethonium chloride through rat and human skin (Ref. 176). Pieces of 
skin were obtained from rats and human plastic surgery patients. Total 
absorption was higher in rat compared to human skin. Under the 
conditions of this study, the total amount of benzethonium chloride 
maximally absorbed by human skin during 24 hours was 4.14 percent. 
Accumulation of benzethonium chloride in the skin was less than 1 
percent in human skin but was about 5 percent in rat skin.
    The available data demonstrate that there is absorption of 
benzethonium chloride following dermal exposure. However, the level of 
absorption is not clearly defined. These data also suggest that the 
amount of dermal absorption varies by species and with formulation. The 
currently available animal data also lack other pharmacokinetic 
determinations, i.e., distribution and metabolism. Subsequent to the 
1994 TFM, FDA had numerous discussions with a manufacturer interested 
in attaining a GRAS classification for benzethonium chloride (Refs. 
174, 177, and 178). Topics covered in these discussions included the 
need for pharmacokinetic studies in animals following dermal exposure 
(Refs. 177 and 178). The available data are not adequate and data from 
ADME studies in animals continue to be necessary because of highly 
variable results in the submitted studies, the need to clearly define 
the level of dermal absorption, the effect of formulation on dermal 
absorption, and the distribution and metabolism of benzethonium 
chloride in animals. In addition, we lack human pharmacokinetic studies 
under maximal use conditions, which are needed to define the level of 
systemic exposure following repeated use.
    Benzethonium chloride carcinogenicity data. In 1995, the NTP 
conducted dermal carcinogenicity studies of benzethonium chloride in an 
ethanol vehicle in rats and mice (Ref. 175). There were no treatment-
related differences from control animals in survival, clinical signs 
(e.g., reddening or crusting of the skin), body weights, organ weights, 
or neoplastic lesions in either rats or mice. Histological evaluation 
revealed dose-related (minimal in low dose, moderate in high dose) 
epithelial hyperplasia in both rats and mice at doses greater than 0.15 
mg/kg/day. In rats, epidermal ulceration was frequent in high dose 
females and in one high dose male.
    There was no systemic toxicity or carcinogenicity at any dose level 
in either species. The no observed effect level (NOEL) for systemic 
toxicity was 1.5 mg/kg/day based on systemic toxicity and 
carcinogenicity. While we agree with NTP's analysis of the systemic 
toxicity, we disagree with the NOEL for dermal toxicity because 
epithelial hyperplasia and reddening of the skin were noted at all 
doses greater than 0.15 mg/kg/day. Therefore, we consider the NOEL for 
dermal toxicity to be 0.15 mg/kg/day.
    The submitted dermal carcinogenicity data are adequate and show 
that benzethonium chloride does not pose a risk of cancer after 
repeated dermal administration under the experimental conditions used; 
however, data from an oral carcinogenicity study are lacking.
    Benzethonium chloride DART data. A manufacturer submitted summaries 
of four teratology studies (three rat and one rabbit) and one perinatal 
and postnatal study in rats (Ref. 174). In two of the rat teratology 
studies, the rats showed delayed bone tissue formation (ossification) 
and soft tissue and skeletal malformation at the high dose. Only 
delayed ossification was noted in the third rat study and in the rabbit 
study. These findings suggest that benzethonium chloride is a teratogen 
at high doses when administered orally. However, without the complete 
study reports, we are unable to fully assess the significance of these 
findings.
    An embryo-fetal rat study with sufficient detail for evaluation was 
submitted (Ref. 174). In this study, pregnant female rats were 
administered benzethonium chloride on gestational days 6 through 15. 
Maternal toxicity was noted among the high dose-treated females. In the 
other dose groups, toxicity findings were sporadic and not dose-
related. There were no treatment-related gross necropsy findings or

[[Page 76465]]

reproductive endpoint changes caused by the treatment. The incidence of 
delayed sternal ossification and/or nonossified sternal centrae was 
noted in all treatment groups and was statistically significant. 
However, this finding is not considered biologically significant as the 
incidence was not dose-related, the litter incidence values did not 
differ significantly, and the values were within the range of 
historical values. The maternal NOAEL is 100 mg/kg/day based on body 
weight changes and deaths at the dose of 170 mg/kg/day.
    Overall, the DART data are not adequate to characterize all aspects 
of reproductive toxicity and we propose that studies are needed to 
assess the effect of benzethonium chloride on male and female fertility 
and on pre- and postnatal endpoints (e.g., the number of live or dead 
offspring, body weight at birth, physical growth and development, 
neurodevelopmental effects, and fertility of the pups).
    Benzethonium chloride resistance data. We found two studies that 
examined bacterial susceptibility profiles for both benzethonium 
chloride and antibiotics. One study (Ref. 179) provided the data 
collectively, so no associations between reduced susceptibility to 
benzethonium chloride and specific antibiotics could be determined. The 
second study (Ref. 180) found a positive correlation between reduced 
susceptibility to benzethonium chloride and ciprofloxacin or oxacillin 
in clinical isolates of MRSA. There were no associations between 
benzethonium chloride and antibiotic resistance in the other tested 
organisms (methicillin-sensitive S. aureus or P. aeruginosa).
    Overall, the available studies are limited in scope. They examine 
few bacterial species, provide no information on the level of 
benzethonium chloride exposure, and are not adequate to define the 
potential for the development of resistance and cross-resistance to 
antibiotics. Additional laboratory studies are necessary to more 
clearly define the potential for the development of resistance to 
benzethonium chloride. Depending on the results of the laboratory 
studies, additional data of the type described in section VII.C of this 
proposed rule may also be needed to assess the level of risk posed by 
benzethonium chloride.
    b. Benzethonium chloride safety data gaps. In summary, our 
administrative record for the safety of benzethonium chloride is 
incomplete with respect to the following:

 Human pharmacokinetic studies under maximal use conditions 
when applied topically, including documentation of validation of the 
methods used to measure benzethonium chloride and its metabolites
 Animal ADME
 Data to help define the effect of formulation on dermal 
absorption
 Oral carcinogenicity
 DART studies (fertility and embryo-fetal testing)
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the 
development of resistance to benzethonium chloride and cross-resistance 
to antibiotics in the types of organisms listed in section VII.C.3 of 
this proposed rule
6. Chloroxylenol
    There are limited safety data to support the long-term use of 
chloroxylenol in OTC consumer antiseptic hand and body wash products. 
Chloroxylenol is absorbed after topical application in both humans and 
animals. However, studies conducted in humans and animals are 
inadequate to fully characterize the extent of systemic absorption 
after repeated topical use or to demonstrate the effect of formulation 
on dermal absorption. The administrative record also lacks other 
important data to support a GRAS determination for this antiseptic 
active ingredient.
    a. Summary of chloroxylenol safety data.
    Chloroxylenol human pharmacokinetic data. The dermal absorption of 
chloroxylenol has been studied in humans following single and repeated 
bathing (10 minutes daily for 1 to 10 days) and following a single 30-
minute percutaneous application to the back of one subject (Refs. 181 
and 182). The studies were conducted with few subjects and a single 
formulation, and as shown in table 7 of this proposed rule, produced 
inconsistent results.

                          Table 7--Results of Human Absorption Studies of Chloroxylenol
----------------------------------------------------------------------------------------------------------------
                                                                                     Absorption \1\
              Study                  Number of            Bath         -----------------------------------------
                                     subjects                                Milligrams            Percent
----------------------------------------------------------------------------------------------------------------
Jordan, Nichols, and Rance,                    1  1st.................  5.74...............  0.5.
 Preliminary Bathing Study (Ref.
 181).
Jordan, B. J., et. al., Repeat                 4  1st.................  2.4 to 4.4.........  0.2 to 0.37.
 Bathing Study (Ref. 182).
                                  ..............  10th................  2.4 to 6.4.........  0.2 to 0.5.
Jordan, B. J., et. al., Dermal                 1  N/A.................  7.2................  15.7.
 ADME under Occlusion Study
 (Ref. 182).
----------------------------------------------------------------------------------------------------------------
\1\ Based on amounts in urine.

    The wide variation in the study findings may be due to the much 
lower concentration of chloroxylenol used in bathing studies (1:4,000 
and 1:4,800 dilution of a 4.8 percent product versus 1 mL of the same 
product undiluted). However, the small sample size and disparate study 
results make it difficult to draw any meaningful conclusions on the 
level of dermal absorption following single or repeated use.
    The percutaneous absorption study (Ref. 182) also provides some 
limited information on the elimination of chloroxylenol in humans. 
Assays of urine samples revealed that all chloroxylenol was excreted as 
conjugated metabolites. No unchanged chloroxylenol was found in the 
urine at any time point, and most of the drug was excreted in the first 
8 hours after application.
    Overall, the human pharmacokinetic studies are not adequate and we 
propose that human pharmacokinetic studies using dermal administration 
under maximal use conditions are still needed to define the level of 
systemic exposure following repeated use. In addition, data is needed 
to help define the effect of formulation on dermal absorption.
    Chloroxylenol animal ADME data. Dermal ADME studies in rats and 
mice are available (Refs. 183 and 184). In a study conducted by Sved 
(Ref. 184), increasing doses of \14\C-labeled chloroxylenol were 
applied to the shaved backs of mice as a single or repeated dose (once 
daily for 14 or 28 days). Absorption was apparent at all time points 
and increased with increasing length of exposure. Approximately 50 
percent of the applied dose was absorbed at 24 hours

[[Page 76466]]

after a single dose and approximately 65 percent at 24 hours after 14 
and 28 days of daily dosing. The amount of chloroxylenol absorbed was 
proportional to the administered dose. The plasma half-life for 
chloroxylenol was 18, 22, and 12 hours for low, mid, and high dose 
males, respectively, and 70, 9, and 12 hours for low to high dose 
females, respectively. The half-life in skin was longer at lower doses 
of chloroxylenol.
    After dermal application chloroxylenol has been found in the 
following tissues: Kidney, lung, liver, adrenal glands, skin, heart, 
ovary, ovarian fat, skeletal muscle, skull, spinal cord, spleen, eyes, 
femur, and brain (Refs. 183 and 184). Tissue concentrations increased 
with repeated dosing, up to 1.8-fold in the kidney, up to 3.8-fold in 
the liver, and up to 8.9-fold in the brain (Ref. 183). Concentrations 
in tissue also increased with dose. Unlike the concentrations in the 
liver and kidney, chloroxylenol levels in the brain did not appear to 
reach steady-state concentrations after 28 days of dosing, particularly 
at the lower chloroxylenol concentrations (Ref. 183). The relevance of 
these findings from a chronic use perspective cannot be evaluated 
without long-term animal studies.
    The majority of chloroxylenol is excreted in the urine, and this is 
largely as polar conjugated metabolites. Only traces of unchanged 
chloroxylenol are present in urine. Havler identified a minor 
metabolite of chloroxylenol, hydroxylated chloroxylenol, which 
represents 10 to 15 percent of the metabolites found in urine (Ref. 
183). Both chloroxylenol and the minor metabolite are excreted as a 
mixture of glucuronide and sulfate conjugates (Ref. 183). Excretion is 
largely complete 24 hours after a single dermal application.
    Overall, these data demonstrate that absorption of chloroxylenol 
occurs after dermal application in humans and animals. However, the 
extent of this absorption and the resulting systemic exposure has not 
been adequately characterized. In the 1994 TFM, FDA stated that data 
from human studies characterizing the absorption, distribution, and 
metabolism of chloroxylenol conducted under maximal exposure conditions 
were needed (59 FR 31402 at 31415). The administrative record for this 
active ingredient still lacks data to characterize the rate and extent 
of systemic absorption, the similarities and differences between animal 
and human metabolism of chloroxylenol under maximal use conditions, and 
data to help establish the relevance of findings observed in animal 
toxicity studies to humans.
    Chloroxylenol carcinogenicity data. In the 1994 TFM, FDA stated 
that a lifetime dermal carcinogenicity study (up to 2 years) in mice 
was needed to assess the dermal toxicity of chloroxylenol (59 FR 31402 
at 31415). In response to this request, data from a 13-week dose 
ranging dermal toxicity study in mice were submitted (Ref. 185).
    The study results show dose-related dermal adverse effects that may 
be indicative of dermal toxicity, such as erythema (skin redness), 
edema (swelling), and exfoliation (skin peeling). Microscopic changes 
consistent with a mild dermal irritant were also noted. These changes 
included hyperplasia (abnormal multiplication of skin cells) and 
hyperkeratosis of the epidermis (overgrowth of outermost layer of the 
skin) in all dosed animals, inflammation of the superficial dermis (a 
deeper layer of the skin) in most treated animals, crust formation, and 
necrosis (degradation) of epidermal cells. There were also dose-
dependent lesions that increased in significance with dose. Hyperplasia 
of bone marrow and increased extramedullary hematopoiesis (formation of 
red blood cells outside the bone barrow) in the spleen consistent with 
an increasing inflammatory reaction were observed in the high dose 
group. The NOEL was 15 percent chloroxylenol and the NOAEL was less 
than 30 percent.
    To adequately assess the significance of these study findings, a 
long-term dermal carcinogenicity study is needed. In addition, because 
of potential systemic exposure, an oral carcinogenicity study is also 
necessary to characterize the systemic effects from long-term exposure.
    Chloroxylenol DART data. Data are available from a teratology study 
in rats that adequately characterizes chloroxylenol's potential effects 
on embryo and fetal development (Ref. 186). The maternal NOEL in this 
study was 100 mg/kg/day. The maternal lowest observed effect level was 
500 mg/kg/day based on decreased food consumption and decreased body 
weight gain. The NOEL for developmental toxicity was 1,000 mg/kg/day. 
However, this study is not sufficient to characterize effects on other 
aspects of reproduction. Additional studies are necessary to assess the 
effect of chloroxylenol on fertility and early embryonic development 
and on pre- and postnatal development.
    Chloroxylenol resistance data. We found no published studies that 
examine the changes in bacterial susceptibilities that may occur after 
exposure to nonlethal amounts of chloroxylenol. The few studies that 
are available assess antibiotic susceptibility in chloroxylenol-
tolerant bacteria. In one study Lambert and colleagues determined the 
MICs of 8 antiseptics and at least 7 antibiotics for 256 clinical 
isolates of S. aureus (including MRSA) and 111 clinical isolates of P. 
aeruginosa (Ref. 180). Although most of the statistically significant 
correlations were between two antiseptics or between two antibiotics 
rather than between an antiseptic and an antibiotic, the authors found 
a significant positive correlation between chloroxylenol and gentamycin 
resistance in P. aeruginosa, but a negative correlation between 
chloroxylenol and ciprofloxacin resistance. They found no correlations 
between chloroxylenol and antibiotic resistance for S. aureus.
    In a pair of studies (Refs. 79 and 80), Lear and colleagues 
collected, identified, and measured antimicrobial susceptibilities of 
bacteria from industrial sources. The authors saw no difference in the 
antibiotic susceptibility patterns of the industrial and standard 
strains of P. aeruginosa. Overall, there were few changes in antibiotic 
resistance patterns between the standard and industrial strains.
    While these studies provide little evidence of cross-resistance to 
antibiotics, they are limited in scope. They examine few bacterial 
species, provide no information on the level of chloroxylenol exposure, 
and are not adequate to define the potential for the development of 
resistance to chloroxylenol and cross-resistance to antibiotics. If the 
data from initial laboratory studies indicate a potential for the 
development of chloroxylenol resistance and antibiotic cross-
resistance, additional data such as the type described in section VII.C 
of this proposed rule will be necessary to assess the level of risk 
posed by chloroxylenol.
    b. Chloroxylenol safety data gaps. In summary, our administrative 
record for the safety of chloroxylenol is incomplete with respect to 
the following:

 Human pharmacokinetic studies under maximal use conditions 
when applied topically that includes documentation of validation of the 
methods used to measure chloroxylenol and its metabolites
 Animal ADME at toxic exposure levels
 Data to help define the effect of formulation on dermal 
absorption
 Dermal carcinogenicity

[[Page 76467]]

 Oral carcinogenicity
 DART studies defining the effects of chloroxylenol on 
fertility and pre- and postnatal development
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the 
development of resistance to chloroxylenol and cross-resistance to 
antibiotics in the types of organisms listed in section VII.C.3 of this 
proposed rule.
7. Triclosan
    A large number of studies have been conducted to characterize the 
toxicological and metabolic profile of triclosan using animal models. 
Most of these studies have focused on understanding the fate of 
triclosan following exposure to a single source of triclosan via the 
oral route of administration. However, dermal studies in both humans 
and animals are also available. These studies show that triclosan is 
absorbed through the skin, but to a lesser extent than oral absorption.
    a. Summary of triclosan safety data.
    Triclosan human pharmacokinetics data. Although much of the human 
data relates to oral exposure, there are some human studies that 
examine triclosan pharmacokinetics after dermal exposure on the hands 
or body (Refs. 187, 188, and 189). The dermal absorption of triclosan 
has been estimated or characterized using a variety of formulations and 
techniques, as described in this subsection. The available data show 
that dermal absorption of triclosan is low. Consequently, additional 
human pharmacokinetic studies are not necessary.
    In one multiple exposure handwash study (Ref. 187), 13 human 
subjects washed their hands 6 times a day with 1 percent triclosan 
liquid soap for 20 days. Dermal absorption of triclosan was 
demonstrated by an increase in the levels of triclosan in plasma after 
handwash use; however, the percentage of the applied dose that was 
absorbed through the skin was not provided or estimated. Steady-state 
levels of free and total triclosan were achieved within approximately 1 
week (days 6-8). The highest plasma concentrations achieved by any 
subject during the study were 69.9 ng/mL for free triclosan and 229 ng/
mL for total triclosan. Although this study provides a picture of the 
steady-state levels of triclosan from repeated handwash use, it does 
not provide Cmax, Tmax or AUC values for humans.
    Despite the lack of individual concentration-time data, this study 
provides a basis on which to estimate the mean steady-state 
concentrations that would result if a multiple-application body wash 
study were to be conducted. From the reported study results, it is 
possible to calculate the cumulative amount of product used by each 
subject, and to relate this amount to the amount that would be used as 
a body wash. Assuming a concentration of 1 g triclosan/mL of soap, the 
mean of all subjects in the handwash study was 3.6 mL/wash. Multiplying 
this value by six washes per day gives a total mean volume of 21.6 mL/
day.
    Using a reported industry estimate (Ref. 190) that a 10 ounce 
(295.5 mL) bottle contains enough body wash for 29 washes, the 
estimated amount of body wash per use would be 10.2 mL (295.5 mL/29 
washes = 10.2 mL/wash). Assuming that an individual bathes twice a day 
with a 1 percent triclosan-containing body wash, the total mean volume 
estimate would be approximately 20.4 mL. This is less than the mean 
amount used in the handwash study (21.6 mL/day). Based on the 
pharmacokinetic data provided, steady-state was achieved during the 
study, indicating that the study was of sufficient length to evaluate 
the pharmacokinetics of chronically administered triclosan.
    Another of the available studies (Ref. 188) addresses triclosan 
exposure as a result of multiple product use. Two groups of 84 subjects 
were enrolled in this 13-week study. One group used triclosan 
toothpaste twice a day plus triclosan bar soap for face and handwashing 
twice a day plus triclosan deodorant once a day. The other group used 
triclosan toothpaste twice a day plus placebo soap and deodorant. Blood 
was drawn before product usage and at 3, 6, and 13 weeks.
    At baseline, there was no significant difference in the mean 
triclosan plasma concentrations between groups. After product use, 
however, the mean triclosan plasma concentrations were significantly 
higher in the multiple triclosan-containing product group (highest 
achieved concentration: 31.04 ng/mL) than in the toothpaste only group 
(highest achieved concentration: 22.47 ng/mL) for all three time 
points. This suggests that the use of multiple triclosan-containing 
products can lead to higher triclosan exposure than from use of a 
single product. The concentrations observed in this study are 
substantially lower than the range of concentrations at steady-state 
that were observed in the handwashing study (Ref. 187). The substantial 
increase in triclosan concentration from baseline to 3 weeks indicates 
that the majority of the absorbed triclosan in this study was due to 
the use of the triclosan-containing toothpaste.
    There have been several studies that attempted to estimate the 
absorption of triclosan following topical application in a variety of 
different formulations (Refs. 189, 191, 192, and 193). In theses 
studies triclosan was delivered as a solution, in toothpaste, as a 
mouthwash, or in a cream. Despite the different properties of the 
dosage forms and vehicles used, the estimated absorption was 
approximately in the range of 5 to 15 percent of the applied dose. 
Based on these data, the impact of different formulations on the dermal 
absorption of triclosan appears to be minimal.
    In summary, human absorption of triclosan has been adequately 
characterized and no further human pharmacokinetic studies are needed.
    Triclosan ADME data. Triclosan is readily metabolized in both 
humans and animals to two main parent conjugates, triclosan glucuronide 
and triclosan sulfate. Several other minor metabolites have been 
detected in animal studies (Refs. 194 through 197); however, the 
relevance of these minor metabolites to humans is unknown. In humans 
after oral or oral plus dermal triclosan exposure, triclosan 
glucuronide is the primary circulating metabolite in plasma (Ref. 188). 
After a single oral exposure to 4 mg of triclosan, the triclosan levels 
in human plasma increased rapidly and reached maximum concentration 
within 1 to 3 hours (Ref. 198). In this study, the majority of the 
triclosan in plasma was conjugated; the unconjugated fraction of 
triclosan in plasma was 30 to 35 percent. Triclosan was cleared from 
the plasma at a rate of 2.9 L/hour.
    There also are some data to suggest that triclosan is metabolized 
during passage through the skin. Moss, Howes, and Williams (Ref. 191) 
examined dermal metabolism of triclosan in vivo in the rat and in vitro 
using rat or human skin in flow-through diffusion cells. In both 
species, triclosan was metabolized during passage through the skin to 
triclosan glucuronide and triclosan sulfate. Triclosan was more readily 
metabolized to the glucuronide conjugate, which was also more readily 
removed from the skin than the sulfate conjugate.
    The elimination pattern of triclosan varies depending on the 
species. Triclosan is excreted mainly via urine in humans (Ref. 198) 
and hamsters (Ref. 195), while it is eliminated mainly through feces in 
mice (Ref. 196) and rats (Ref. 199). After a single oral administration 
of 4 mg of triclosan to human subjects, the majority of the triclosan 
was excreted in urine within

[[Page 76468]]

the first 24 hours (Ref. 198). There was considerable variability among 
subjects; between 24 and 83 percent of the dose was excreted within 4 
days after exposure. The urinary excretion half-life ranged from 7 to 
17 hours, and excretion approached baseline levels by 8 days after 
exposure.
    In the multiple exposure handwash study (previously described in 
this section (Ref. 187)), the mean elimination half-life for total 
triclosan after multiple dermal exposures was 33 hours. This is longer 
than the elimination half-life calculated after a single oral exposure 
(12 hours). The authors suggest the reason for this difference is that 
absorption through the skin takes longer than absorption from the 
gastrointestinal tract.
    It is well documented that triclosan in aqueous solution can be 
degraded into 2,8-dichlorodibenzo-p-dioxin and other degradation 
products by heat or ultraviolet irradiation (i.e., photodegradation) 
(Refs. 200 through 206). Although the data support photodegradation in 
aqueous solution, we found no data regarding whether photodegradation 
of triclosan can occur on human skin. It is not known whether 
photodegradation products would be formed on human skin after topical 
application of triclosan-containing antiseptics and, if so, whether 
they would be absorbed or affect the skin. Because of this new 
information regarding photodegradation of triclosan, we propose that 
data are needed regarding the potential for formation of triclosan 
photodegradation products on human skin as a result of consumer 
antiseptic use and, if present, their effects on the skin.
    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. In addition, 
data regarding the potential for formation of photodegradation products 
on human skin and their effects on the skin are needed.
    New triclosan findings. A recent study evaluated the physiological 
effects of triclosan treatment on muscle function in mice and fish 
(Ref. 207). The authors observed a negative effect on both cardiac and 
skeletal muscle function as a result of a single triclosan treatment 
and identified a mechanism to explain the observed effect. While this 
finding suggests a previously unidentified toxicity of triclosan, it is 
a preliminary finding that has not been duplicated. Further, the mice 
were treated by injecting triclosan into the abdomen (i.e., 
intraperitoneal administration), rather than through a more relevant 
route of administration, such as the oral or dermal route. We invite 
comment on what these findings tell us about triclosan's potential 
impact on human health and the submission of additional data on this 
subject.
    Triclosan carcinogenicity data. A 2-year oral carcinogenicity study 
in hamsters was submitted to the rulemaking (Ref. 208). The study was 
conducted in Syrian hamsters because the elimination pattern of 
triclosan is similar in hamsters and humans. Although some treatment-
related noncancerous lesions were seen in the kidneys, epididymides, 
testes, and stomach, there were no tumor findings in any of the organs 
examined. The NOAEL for triclosan in this hamster study is 75 mg/kg/
day. The study included additional (satellite) groups to assess 
triclosan plasma levels at week 53 and at study termination (Ref. 209). 
At both time points, plasma levels increased with increasing doses and 
significantly higher triclosan plasma levels were seen in males 
compared to females (p < 0.001). This increase over time suggests that 
triclosan is accumulating in the animals; however, the effect of this 
accumulation is unknown.
    In contrast to the oral data, there are little data regarding 
dermal toxicity of triclosan. Short-term dermal toxicity studies in 
rats (Ref. 210) and mice (Refs. 211 and 212) show dose-related dermal 
adverse effects following a 14-day treatment period. Similar dermal 
effects were seen in a 90-day subchronic dermal toxicity study in rats 
(Ref. 213). A long-term dermal carcinogenicity study could be used to 
assess the relevance of the short-term dermal toxicity findings to a 
chronic use situation; however, currently no long-term dermal 
carcinogenicity data are available. Because these data are not 
available but are needed to fully evaluate the safety of triclosan, FDA 
nominated triclosan to NTP for toxicological evaluation (Ref. 214). The 
NTP studies will evaluate the dermal carcinogenicity potential 
following chronic dermal exposure to triclosan (Refs. 215 and 216). 
These studies are ongoing; however, results of these studies are not 
expected to be available for several years, and we do not intend to 
delay the antiseptic rulemaking to wait for these study results.
    The submitted oral carcinogenicity data are adequate and show that 
triclosan does not pose a risk of cancer after repeated oral 
administration under the experimental conditions used; however, data 
from a dermal carcinogenicity study are still needed.
    Triclosan DART data. In the 1994 TFM, we stated that we were 
evaluating the data from a two-generation study of the reproductive 
toxicity of triclosan in rats (Ref. 217). In this study, rats that were 
exposed to a high dose (3,000 ppm) of triclosan in utero showed lower 
neonatal survival and lower mean body weights compared to untreated 
controls. The offspring of these rats (i.e., F2 pups) had a lower rate 
of survival to weaning compared to untreated controls. Based on the 
findings from this two-generation study, we recommended that a segment 
II study should be conducted to address the decreased survival among 
the high dose-treated litters.
    Since that time, additional segment II reproductive toxicity 
studies have been submitted showing that triclosan is not teratogenic 
in mice, rats, or rabbits (Ref. 218). No treatment-related mortality 
was observed, and pregnancy rates and the number of litters for treated 
animals were comparable to controls. The oral NOAELs from these studies 
are listed in table 8 of this proposed rule.

      Table 8--Oral No Observed Adverse Effect Levels (NOAEL) From
               Reproductive Toxicity Studies of Triclosan
------------------------------------------------------------------------
                                              Oral NOAEL (mg/kg/day)
                                         -------------------------------
                 Species                     Maternal      Developmental
                                             toxicity        toxicity
------------------------------------------------------------------------
Mouse...................................              25              25
Rat.....................................              50              50
Rabbit..................................              50             150
------------------------------------------------------------------------

    Overall, the triclosan DART data are adequate and additional 
traditional DART studies are not necessary. However, as discussed in 
the subsection of this proposed rule on drug-induced hormonal effects, 
we propose that additional reproductive and developmental testing will 
be needed to address concerns about these effects.
    Triclosan data on hormonal effects. Recent studies have 
demonstrated that triclosan has effects on the thyroid, estrogen, and 
testosterone systems in several animal species, including mammals 
(Refs. 41, 43 through 47, 50, and 219). In addition, effects were also 
seen in the hamster carcinogenicity study (e.g., a reduction or absence 
of spermatozoa, abnormal spermatogenic cells, and partial depletion of 
one or more generations of germ cells in male testes in the high dose-
treated group) (Ref. 220). The implications of these findings on human 
health, especially for children, are still not well understood.
    At this time, no adequate long-term (i.e., more than 30 days) in 
vivo animal

[[Page 76469]]

studies have been conducted to address the consequences of these 
hormonal effects on functional endpoints of growth and development 
(e.g., link of preputial separation to sexual differentiation and 
fertility, link of decreased thyroxine/triiodothyronine to growth and 
neurobehavioral development) in exposed fetuses or pups. Studies in 
juvenile animals (of the type described in section VII.C.2 of this 
proposed rule) could address the consequences of short-term thyroid and 
reproductive findings on the fertility, growth, and development of 
triclosan-exposed litters.
    Triclosan resistance data. Much of the recent data looking at 
cross-resistance between antiseptic active ingredients and antibiotics 
involve an evaluation of triclosan. Several bacterial species that 
showed reduced susceptibility to triclosan were also resistant to one 
or more of the tested antibiotics (Refs. 60 through 66, 71, and 73 
through 77). This trend was seen for both gram-negative (E. coli, 
Pseudomonas aeruginosa, Salmonella enterica, Stenotrophomonas 
maltophilia, Acinetobacter, and Campylobacter) and gram-positive 
(Staphylococcus aureus, including MRSA) organisms. Although the 
clinical relevance of these studies is not clear, the possibility that 
triclosan contributes to changes in antibiotic susceptibility warrants 
further evaluation.
    One of our concerns stems from the observation that triclosan 
exposure can lead to changes in bacterial efflux pump activity. Several 
studies (Refs. 62, 64, 66, and 102) suggest that an efflux mechanism is 
responsible for the observed reduced triclosan susceptibility. In 
addition, overexpression of efflux pump regulatory genes also leads to 
reduced triclosan susceptibility in E. coli (Ref. 101).
    In addition to bacterial efflux activity, other mechanisms have 
been documented that may also contribute to reduced antiseptic 
susceptibility and cross-resistance, e.g., changes in bacterial 
membrane (Ref. 67). This type of nonspecific mechanism, in theory, 
could work against multiple antibiotics or antiseptics.
    Other data suggest that different mechanisms of action may occur at 
different triclosan concentrations. In the laboratory, at low 
concentrations triclosan has a specific action against a bacterial 
enzyme (FabI), while high concentrations act against less specific 
targets, such as the cell membrane (Ref. 109). Currently, there is not 
enough information to know which scenarios, if any, could occur under 
actual use conditions.
    Although numerous studies have evaluated the antiseptic and 
antibiotic susceptibility profiles of clinical or culture collection 
strains, there are few studies that evaluate the susceptibility 
profiles of bacterial isolates from nonhospital or consumer settings. 
In a pair of studies (Refs. 79 and 80), Lear and colleagues collected, 
identified, and measured antimicrobial susceptibilities of bacteria 
from industrial sources. Samples were taken from a factory and 
laboratories of companies that manufacture products containing 
triclosan, where it was likely that the organisms were exposed to this 
ingredient. Of approximately 100 industrial isolates, two triclosan-
tolerant isolates were chosen for further study (Acinetobacter 
johnsonii and Citrobacter freundii).
    The authors then determined the antibiotic susceptibility profiles 
of the two industrial isolates compared to standard culture collection 
strains (Ref. 79). The authors saw no difference in the antibiotic 
susceptibility patterns of the industrial and standard strains of A. 
johnsonii. In contrast, the C. freundii industrial isolate was more 
resistant to 12 of 14 antibiotics tested. These changes in antibiotic 
susceptibility were quite modest, however. While this industrial 
isolate showed only modest changes in susceptibility for most of the 
tested antibiotics, it still demonstrates a change in the antibiotic 
susceptibility pattern after triclosan exposure. Unfortunately, the 
number of sites that were sampled was low (50 total sites), only two 
isolates were studied, and the time and extent of triclosan exposure is 
unknown.
    In addition to laboratory data, there are also a few studies that 
examined the potential for development of cross-resistance in bacterial 
isolates taken from the skin of consumer antiseptic users. Cole et al. 
(Ref. 78) described antibiotic and antiseptic susceptibilities of 
staphylococci isolated from the skin of consumers who used antiseptic 
or nonantibacterial body washes. This study also evaluated triclocarban 
and is described in detail in section VII.D.3.a of this proposed rule.
    When CNS susceptibility to antiseptics was examined, the maximum 
MIC value was the same for all three groups (2.020 (no units 
provided)); however, the minimum MIC value differed between triclosan 
users (0.008) and non-users (0.120). Because antiseptic MICs do not 
correlate with clinical endpoints, it is not clear what this difference 
in MIC means. No patterns emerged when the data were analyzed for 
cross-resistance between triclosan or triclocarban and antibiotics.
    The authors conclude that this study shows no increase in 
antibiotic resistance from the regular use of antiseptic body washes. 
But, this study was not adequately designed to determine whether use of 
antiseptic body washes leads to changes in antibiotic or antiseptic 
susceptibilities. Given the limited number of isolates examined, it is 
not clear that the study was adequately powered to detect a difference 
in resistance patterns. Furthermore, the amount of antiseptic exposure 
was not defined. The length of time subjects had used antiseptic body 
washes (beyond the specified 30 days), the frequency of bathing, and 
the volume of antiseptic wash used per bath or shower was not reported. 
Finally, few bacterial isolates were examined. It is reasonable to 
examine the susceptibilities of Staphylococcus species; however, an 
average of only 1.5 isolates was obtained from each subject.
    Aiello et al. (Ref. 81) looked for a possible association between 
antibiotic and triclosan susceptibilities among staphylococci and GNB 
isolated from the hands of consumers who used nonantibacterial or 0.2 
percent triclosan-containing antiseptic handwashes for 1 year. Two 
hundred twenty-four inner city households were randomized to use soap 
and cleaning products with or without antibacterial ingredients. The 
products were blinded and were delivered to each household monthly. 
During the study period, the households were required to use only the 
assigned home hygiene products and were asked not to change any of 
their other normal hygiene practices. To assess prior exposure to 
antimicrobials, including antiseptics, a survey of the antibacterial 
cleaning and hygiene products used within the home was conducted at 
baseline.
    The hands of the primary caregiver in the home were sampled for 
bacteria at baseline and 1 year later. Only the most commonly isolated 
bacterial species, defined as at least 38 isolates of a single species 
from all samples, were analyzed further. A total of 628 isolates were 
examined for their triclosan MICs and susceptibilities to selected 
antibiotics. Staphylococci were tested against oxacillin to determine 
methicillin resistance. The GNB were tested against three to six 
antibiotics, based on clinical relevance. There were no significant 
differences in the observed proportions of isolates that were 
antibiotic resistant at baseline versus the end of the year except for 
Enterobacter cloacae, which was significantly higher at baseline (36 
percent) than at the end of the year (0 percent) (p = 0.016).

[[Page 76470]]

    The MICs of triclosan ranged from 0.03 to 4.00 [mu]g/mL; however, 
two thirds of the isolates had triclosan MICs over 1 [mu]g/mL. The 
median triclosan MICs for the gram negative species varied widely. In 
contrast, the staphylococcus median values were very similar, except 
for S. aureus, which was 2 [mu]g/mL at baseline and 0.03 [mu]g/mL at 
the end of the year. There was no statistically significant association 
between triclosan MICs and susceptibility to antibiotics.
    A randomly chosen subset of seven GNB organisms with triclosan MICs 
of at least 32 [mu]g/mL was retested with agar containing triclosan 
concentrations in the range of 64 to 1,024 [mu]g/mL. The subset 
contained Klebsiella pneumoniae, Acinetobacter baumannii, Enterobacter 
cloacae, and P. fluorescens isolates. All of the isolates grew on agar 
containing 1,024 [mu]g/mL triclosan, suggesting that they may survive 
the triclosan concentrations used in some consumer products.
    This study did not show an association between high triclosan MICs 
and antibiotic resistance after 1 year of triclosan handwash use. 
However, the authors note that the triclosan MICs seen for many of the 
isolates in this study are higher than those reported previously. They 
suggest that general levels of decreased susceptibility to triclosan 
seem to be increasing in the community, regardless of whether 
triclosan-containing products are used in the home or not. The authors 
also concluded that the absence of a statistically significant 
association between elevated triclosan MICs and reduced antibiotic 
susceptibility may indicate that such a correlation does not exist or 
that it is relatively small among the isolates that were studied. 
Still, they theorized that a relationship may emerge after longer term 
or higher dose exposure of bacteria to triclosan in the community 
setting.
    Overall, the administrative record for triclosan is complete on the 
following aspects of the resistance issue:

 Laboratory studies demonstrate triclosan's ability to alter 
antibiotic susceptibilities (Refs. 60 through 66, 71, and 73 through 
77)
 Data define triclosan's mechanisms of action and demonstrate 
that these mechanisms are dose dependent (Ref. 109)
 Data demonstrate that exposure to triclosan changes efflux 
pump activity, a common nonspecific bacterial resistance mechanism 
(Refs. 62, 64, 66, and 102)
 Data show that low levels of triclosan may persist in the 
environment (Refs. 85, 113, 114, 115, and 221 through 224)

    However, the administrative record is not complete with respect to 
data that would clarify the potential public health impact of the 
currently available data. Examples of the type of information that 
could be submitted to complete the record include the following:

 Data to characterize the concentrations and antimicrobial 
activity of triclosan in various biological and environmental 
compartments (e.g., on the skin, in the gut, and in environmental 
matrices)
 Data to characterize the antiseptic and antibiotic 
susceptibility levels of environmental isolates in areas of prevalent 
antiseptic use, e.g., in the home, health care, food handler, and 
veterinary settings and
 Data to characterize the potential for the reduced antiseptic 
susceptibility caused by triclosan to be transferred to other bacteria 
that are still sensitive to triclosan

    b. Triclosan safety data gaps. In summary, our administrative 
record for the safety of triclosan is incomplete with respect to the 
following:

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

VIII. Proposed Effective Date

    Based on the currently available data, this proposed rule finds 
that consumer antiseptic wash active ingredients can be considered 
neither safe nor effective for use in OTC consumer antiseptic wash drug 
products. Accordingly, consumer antiseptic wash active ingredients 
would be nonmonograph in any final rule based on this proposed rule. We 
recognize, based on the scope of products subject to this monograph, 
that manufacturers will need time to comply with a final rule based on 
this proposed rule. However, because of the potential safety 
considerations raised by the data for some antiseptic active 
ingredients evaluated, we believe that an effective date later than 1 
year after publication of the final rule would not be appropriate or 
necessary. Consequently, any final rule that results from this proposed 
rule will be effective 1 year after the date of the final rule's 
publication in the Federal Register. On or after that date, any OTC 
consumer antiseptic wash drug product that is subject to the monograph 
and that contains a nonmonograph condition, i.e., a condition that 
would cause the drug to be not GRAS/GRAE or to be misbranded, could not 
be initially introduced or initially delivered for introduction into 
interstate commerce unless it is the subject of an approved new drug 
application or abbreviated new drug application. Any OTC consumer 
antiseptic wash drug product subject to the final rule that is 
repackaged or relabeled after the effective date of the final rule 
would be required to be in compliance with the final rule, regardless 
of the date the product was initially introduced or initially delivered 
for introduction into interstate commerce.

IX. Summary of Preliminary Regulatory Impact Analysis

    The summary analysis of benefits and costs included in this 
proposed rule is drawn from the detailed Preliminary Regulatory Impact 
Analysis (PRIA) that is available at http://www.regulations.gov, Docket 
No. FDA-1975-N-0012 (formerly Docket No. 1975N-0183H).

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). This proposed rule would be an economically significant 
regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. This proposed rule would have a significant economic 
impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $141

[[Page 76471]]

million, using the most current (2012) Implicit Price Deflator for the 
Gross Domestic Product. FDA expects this proposed rule to result in a 
1-year expenditure that would meet or exceed this amount.

B. Summary of Costs and Benefits

    The costs and benefits of the proposed rule are summarized in table 
9 of this proposed rule entitled ``Economic Data: Costs and Benefits 
Statement.'' As table 9 shows, the primary estimated benefits come from 
reduced exposure to antiseptic active ingredients by 2.2 million pounds 
per year. Using the primary estimates, the combined total consists of a 
reduction in triclosan exposure by 799,426 pounds per year, 
triclocarban exposure by 1.4 million pounds per year, chloroxylenol 
exposure by 231.9 pounds per year, and benzalkonium chloride by 63.8 
pounds per year. Limitations in the available data characterizing the 
health effects resulting from widespread long-term exposure to such 
ingredients prevent us from translating the estimated reduced exposure 
into monetary equivalents of health effects.
    The primary estimate of costs annualized over 10 years is 
approximately $23.6 million at a 3 percent discount rate and $28.6 
million at a 7 percent discount rate. These costs consist of total one-
time costs of relabeling and reformulation ranging from $112.2 to 
$368.8 million. Estimates of the cost of relabeling and reformulating 
may be overstated if manufacturers produce data consistent with the 
monograph changes in this proposed rule and do not need to relabel or 
reformulate. In such a scenario, the costs of producing the data would 
be incurred instead. 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.
    Manufacturers are expected to incur most product reformulation and 
relabeling costs with the impact to relabelers, repackers, and 
distributors being considerably less. The impact on a manufacturer can 
vary considerably depending on the number and type of products it 
produces. For the estimated 707 affected establishments that would 
qualify as small,\1\ our estimate of the average one-time cost of 
compliance ranges from $0.10 million to $0.33 million, which would be 
approximately 0.33 percent to 1.10 percent of the average annual value 
of shipments for a small business. In its Initial Regulatory 
Flexibility Analysis, the Agency assesses a pair of regulatory options 
that would reduce the proposed rule's burden on small entities: (1) 
Exempting small businesses from the rule and (2) longer compliance 
period, allowing 18 months (rather than 12 months).
---------------------------------------------------------------------------

    \1\ FDA notes that the analysis was conducted using data at the 
establishment level rather than at the firm level. This makes the 
implicit assumption that the typical manufacturing establishment is 
roughly equivalent to the typical small manufacturing firm. However, 
if market is dominated by a few large firms with a large number of 
small establishments, our estimated number of small entities, may be 
an overestimate of the actual number of businesses with fewer than 
750 employees.

                                                  Table 9--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                  Units
                                           Primary       Low        High    -------------------------------------------------
                Category                  estimate    estimate    estimate      Year      Discount                                       Notes
                                                                               dollars      rate         Period  covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Annualized Monetized $millions/year  ..........  ..........  ..........  ..........          7%  Annual.
                                                                                                 3%  Annual.................
    Annualized Quantified..............   2,198,033     989,922   3,406,145  ..........          7%  Annual.                  Reduced antiseptic active
                                          2,198,033     989,922   3,406,145                      3%  Annual.................   ingredient exposure (in
                                                                                                                               pounds).
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                          Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Annualized Monetized $millions/year       $28.6       $16.0       $52.5        2010          7%  Annual.                  Annualized costs of
                                              $23.6       $13.2       $43.2        2010          3%  Annual.................   relabeling and
                                                                                                                               reformulation. Range of
                                                                                                                               estimates captures
                                                                                                                               uncertainty.
    Annualized Quantified..............  ..........  ..........  ..........  ..........          7%
                                                                                                 3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Transfers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Federal Annualized Monetized $millions/  ..........  ..........  ..........  ..........          7%  .......................  None.
 year.                                                                                           3%
                                        ----------------------------------------------------------------------------------------------------------------
From/To................................  From:
                                         To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Other Annualized Monetized $millions/    ..........  ..........  ..........  ..........          7%
 year.                                                                                           3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To................................  From:
                                         To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects
    State, Local, or Tribal Government: Not applicable......................................................................
----------------------------------------             ------------------------------------------------------------------------
Small Business
    Annual cost per affected small entity estimated as $0.01-$0.04 million, which would represent 0.04-0.13 percent of
     annual shipments.
----------------------------------------             ------------------------------------------------------------------------
Wages: No estimated effect.
----------------------------------------             ------------------------------------------------------------------------
Growth: No estimated effect.
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76472]]

X. Paperwork Reduction Act of 1995

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

XI. Environmental Impact

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

XII. Federalism

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

XIII. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) under Docket No. FDA-1975-N-0012 (formerly 
1975N-0183H) and may be seen by interested persons between 9 a.m. and 4 
p.m., Monday through Friday, and are available electronically at http://www.regulations.gov. (FDA has verified all Web site addresses in this 
reference section, but we are not responsible for any subsequent 
changes to the Web sites after this proposed rule publishes in the 
Federal Register.)

1. Comment No. C12 in Docket No. 1975N-0183H.
2. Transcript of the January 22, 1997, Meeting of the Joint 
Nonprescription Drugs and Anti-Infective Drugs Advisory Committees, 
OTC Vol. 02CAWASHTFM.
3. Transcript of the March 23, 2005, Meeting of the Nonprescription 
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[[Page 76476]]

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174. Comment No. C38 in Docket No. 1975N-0183H.
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176. Comment No. RPT4 in Docket No. 1975N-0183H.
177. Comment No. MT3 in Docket No. 1975N-0183H.
178. Comment No. LET17 in Docket No. 1975N-0183H.
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182. Jordan, B. J. and et al., ``Human Volunteer Studies on Dettol 
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183. Havler, M. E. and M. J. Rance, ``The Metabolism of p-Chloro-m-
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184. Sved, D. W., ``A Dermal Absorption Study With [14C]-Labeled 
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185. ``A 13-Week Dermal Toxicity Study in Mice,'' in Docket No. 
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186. ``Teratology Study in Rats,'' in Docket No. 1975N-0183.
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188. Beiswanger, B. B. and M. A. Tuohy, ``Analysis of Blood Plasma 
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189. Queckenberg, C. et al., ``Absorption, Pharmacokinetics, and 
Safety of Triclosan after Dermal Administration,'' Antimicrobial 
Agents and Chemotherapy, 54:570-572, 2010.
190. Thau, B., ``Will Body Wash or Soap Get You Cleaner?,'' http://www.dailyfinance.com/2011/05/03/savings-experiment-will-body-wash-or-soap-get-you-cleaner/.
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Penetration and Dermal Metabolism of Triclosan (2,4, 4'-trichloro-
2'-hydroxydiphenyl ether),'' Food and Chemical Toxicology, 38:361-
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192. Allmyr, M. et al., ``Human Exposure to Triclosan Via Toothpaste 
Does Not Change CYP3A4 Activity or Plasma Concentrations of Thyroid 
Hormones,'' Basic and Clinical Pharmacology and Toxicology, 2009.
193. Lin, Y. J., ``Buccal Absorption of Triclosan Following Topical 
Mouthrinse Application,'' American Journal of Dentistry, 13:215-217, 
2000.
194. Tulp, M. T. et al., ``Metabolism of Chlorodiphenyl Ethers and 
Irgasan DP 300,'' Xenobiotica, 9:65-77, 1979.
195. Van Dijk, A., ``14C-Triclosan: Absorption, Distribution, 
Metabolism, and Elimination After Single/Repeated Oral and 
Intravenous Administration to Hamsters,'' Comment No. C85 in Docket 
No. 1975N-0183H, 1994.
196. Van Dijk, A., ``14C-Triclosan: Absorption, Distribution, 
Metabolism, and Elimination After Single/Repeated Oral and 
Intravenous Administration to Mice,'' Comment No. C85 in Docket No. 
1975N-0183H, 1995.
197. Wu, J. L., J. Liu, and Z. Cai, ``Determination of Triclosan 
Metabolites by Using In-Source Fragmentation From High-Performance 
Liquid Chromatography/Negative Atmospheric Pressure Chemical 
Ionization Ion Trap Mass Spectrometry,'' Rapid Communications in 
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198. Sandborgh-Englund, G. et al., ``Pharmacokinetics of Triclosan 
Following Oral Ingestion in Humans,'' Journal of Toxicology and 
Environmental Health, Part A, 69:1861-1873, 2006.
199. Van Dijk, A., ``14C-Triclosan: Absorption, Distribution, and 
Excretion (ADE) After Single Oral and Repeated Oral Administration 
to Male Rats,'' Comment No. C85 in Docket No. 1975N-0183H, 1996.
200. Latch, D. E. et al., ``Photochemical Conversion of Triclosan to 
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Solution,'' Journal of Photochemistry and Photobiology A, 158:63-66, 
2003.
201. Latch, D. E. et al., ``Aqueous Photochemistry of Triclosan: 
Formation of 2,4-dichlorophenol, 2,8-dichlorodibenzo-p-dioxin, and 
Oligomerization Products,'' Environmental Toxicology and Chemistry, 
24:517-525, 2005.
202. Lindstr[ouml]m, A. et al., ``Occurrence and Environmental 
Behavior of the Bactericide Triclosan and Its Methyl Derivative in 
Surface Waters and in Wastewater,'' Environmental Science and 
Technology, 36:2322-2329, 2002.
203. Mezcua, M. et al., ``Evidence of 2,7/2,8-dibenzodichloro-p-
dioxin as a Photodegradation Product of Triclosan in Water and 
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204. Sanchez-Prado, L. et al., ``Monitoring the Photochemical 
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Using Solid-Phase Microextraction,'' Chemosphere, 65:1338-1347, 
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206. Tixier, C. et al., ``Phototransfomation of Triclosan in Surface 
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List of Subjects

21 CFR Part 310

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

21 CFR Part 333

    Labeling, Over-the-counter drugs, Incorporation by reference.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 310 and 333 be amended as follows:

PART 310--NEW DRUGS

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

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

0
2. Amend Sec.  310.545 by removing from paragraph (d) introductory text 
the number ``(d)(39)'' and adding in its place the number ``(d)(40)''; 
and by adding paragraphs (a)(27)(iii), (a)(27)(iv), and (d)(41) to read 
as follows:

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

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

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

    (iv) Consumer antiseptic body wash drug products. Approved as of 
[DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN THE Federal 
Register].

Benzalkonium chloride
Benzethonium chloride
Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Iodine tincture
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Parachlorometaxylenol (chloroxylenol)

[[Page 76478]]

Phenol
Poloxamer iodine complex
Povidone-iodine
Tribromsalan
Triclocarban
Triclosan
Undecoylium chloride iodine complex
* * * * *
    (d) * * *
    (41) [DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN 
THE Federal Register], for products subject to paragraph (a)(27)(iii) 
or (a)(27)(iv) of this section.

PART 333--TOPICAL ANTIMICROBIAL DRUG PRODUCTS FOR OVER-THE-COUNTER 
HUMAN USE

0
3. The authority citation for 21 CFR part 333 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

Sec.  333.403  [Amended]

0
4. As proposed to be added June 17, 1994 (59 FR 31442), Sec.  333.403 
is further amended in paragraph (c)(1) by removing the phrase 
``Antiseptic handwash or health-care'' from the paragraph heading and 
adding in its place ``Health-care''.

Sec.  333.410  [Amended]

0
5. As proposed to be added June 17, 1994 (59 FR 31442), Sec.  333.410 
is further amended by removing the phrase ``Antiseptic handwash or 
health-care'' from the section heading and adding in its place 
``Health-care''.

Sec.  333.455  [Amended]

0
6. As proposed to be added June 17, 1994 (59 FR 31443), Sec.  333.455 
is further amended by:
0
a. Removing from the section heading the phrase ``antiseptic handwash 
or'';
0
b. Removing from paragraph (a) the phrase `` `antiseptic handwash,' 
or'';
0
c. Removing and reserving paragraph (b)(2);
0
d. Removing from the paragraph (b)(3) paragraph heading the phrase 
``either antiseptic or'' and adding in its place the word ``a'';
0
e. Removing from paragraph (c)(1) the paragraph designation and 
paragraph heading; and
0
f. Removing paragraph (c)(2).

Sec.  333.470  [Amended]

0
7. As proposed to be added June 17, 1994 (59 FR 31444), Sec.  333.470 
is further amended in paragraph (a) introductory text and paragraph 
(b)(2) heading and introductory text by removing the phrase ``an 
antiseptic handwash or'' and adding in its place the word ``a''; and in 
paragraph (b)(2)(iii) introductory text by removing the phrase 
``antiseptic or''.
0
8. Add and reserve subpart F to read as follows:

Subpart F--Consumer Antiseptic Drug Products [Reserved]

    Dated: December 11, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-29814 Filed 12-16-13; 8:45 am]
BILLING CODE 4160-01-P