Document ID: FDA-2015-N-0101-0001
Agency: fda
Document Type: Proposed Rule
Title: Safety and Effectiveness of Health Care Antiseptics; Topical Antimicrobial
Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record
Posted Date: 2015-05-01T04:00Z

[Federal Register Volume 80, Number 84 (Friday, May 1, 2015)]
[Proposed Rules]
[Pages 25165-25205]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-10174]

[[Page 25165]]

Vol. 80

Friday,

No. 84

May 1, 2015

Part V

 Department of Health and Human Services

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Food and Drug Administration

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21 CFR Part 310

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

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

[[Page 25166]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

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

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

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

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

Electronic Submissions

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

Written Submissions

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

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

SUPPLEMENTARY INFORMATION:

Executive Summary

Purpose of the Regulatory Action

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

Summary of the Major Provisions of the Regulatory Action in Question

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

Effectiveness

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

Safety

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

[[Page 25167]]

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

Active Ingredients

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

Costs and Benefits

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

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

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

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

I. Introduction

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

A. Terminology Used in the OTC Drug Review Regulations

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

B. Topical Antiseptics

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

[[Page 25169]]

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

C. This Proposed Rule Covers Only Health Care Antiseptics

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

D. Comment Period

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

II. Background

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

A. Significant Rulemakings Relevant to This Proposed Rule

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

[[Page 25170]]

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

B. Public Meetings Relevant to This Proposed Rule

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

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

C. Comments Received by FDA

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

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

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

[[Page 25171]]

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

A. Eligibility for the OTC Drug Review

    An OTC drug is covered by the OTC Drug Review if its conditions of 
use existed in the OTC drug marketplace on or before May 11, 1972 (37 
FR 9464).\1\ Conditions of use include, among other things, active 
ingredient, dosage form and strength, route of administration, and 
specific OTC use or indication of the product (see Sec.  330.14(a)). To 
determine eligibility for the OTC Drug Review, FDA typically must have 
actual product labeling or a facsimile of labeling that documents the 
conditions of marketing of a product prior to May 1972 (see Sec.  
330.10(a)(2)). FDA considers a drug that is ineligible for inclusion in 
the OTC monograph system to be a new drug that will require FDA 
approval through the NDA process. Ineligibility for use as a specific 
type of health care antiseptic (e.g., health care personnel hand wash 
or surgical hand scrub) does not affect eligibility for other 
indications under the health care antiseptic monograph (e.g., patient 
preoperative skin preparations) or under any other OTC drug monograph.
---------------------------------------------------------------------------

    \1\ Also, note that drugs initially marketed in the United 
States after the OTC Drug Review began in 1972 and drugs without any 
U.S. marketing experience can be considered in the OTC monograph 
system based on submission of a time and extent application. (See 
Sec.  330.14(c).)
---------------------------------------------------------------------------

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

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

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

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

[[Page 25172]]

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

[[Page 25173]]

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

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

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

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

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

[[Page 25174]]

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

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

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

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

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

[[Page 25175]]

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

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

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

VI. Effectiveness (Generally Recognized as Effective) Determination

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

[[Page 25176]]

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

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

A. Evaluation of Effectiveness Data

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

[[Page 25177]]

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

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

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

[[Page 25178]]

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

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

[[Page 25179]]

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

VII. Safety (Generally Recognized as Safe) Determination

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

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

A. New Issues

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

[[Page 25180]]

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

B. Antimicrobial Resistance

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

C. Studies To Support a Generally Recognized as Safe Determination

    A GRAS determination for health care antiseptic active ingredients 
must be

[[Page 25181]]

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

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

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

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

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

[[Page 25182]]

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

[[Page 25183]]

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

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

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

[[Page 25184]]

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

D. Review of Available Data for Each Antiseptic Active Ingredient

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

                                  Table 10--Safety Studies Available for Health Care Antiseptic Active Ingredients \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 Human        Animal
                                                               pharmaco-    pharmaco-       Oral        Dermal    Reproductive   Potential    Resistance
                    Active ingredient \2\                       kinetic      kinetic      carcino-     carcino-     toxicity      hormonal    potential
                                                                 (MUsT)       (ADME)      genicity     genicity      (DART)       effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
Alcohol.....................................................        [cir]                               
Benzalkonium chloride.......................................                                  [cir]                                                [cir]
Benzethonium chloride.......................................                     [cir]                           [cir]                     [cir]
Chloroxylenol...............................................        [cir]        [cir]                                   [cir]                     [cir]
Hexylresorcinol.............................................                     [cir]     
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 Simple iodine solutions
--------------------------------------------------------------------------------------------------------------------------------------------------------
Iodine tincture USP.........................................        [cir]               \3\               \3\      
                                                                                           
Iodine topical solution USP.................................        [cir]               \3\               \3\      
                                                                                           
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                    Iodine complexes
--------------------------------------------------------------------------------------------------------------------------------------------------------
Povidone-iodine.............................................    \4\ [cir]          \5\          \3\               \3\      
                                                                                   
Isopropyl alcohol...........................................        [cir]        [cir]                     [cir]              [cir]     
Triclocarban................................................        [cir]        [cir]                           [cir]        [cir]
Triclosan...................................................    \4\ [cir]        [cir]                                [cir]        [cir]
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Empty cell indicates no data available; ``[cir]'' indicates incomplete data available; ``'' indicates available data are sufficient to make
  a GRAS/GRAE determination.
\2\ The following active ingredients are not included in the table because no safety data were submitted or identified since the 1994 TFM: Cloflucarban;
  combination of calomel, oxyquinoline benzoate, triethanolamine, and phenol derivative; combination of mercufenol chloride and secondary amyltricresols
  in 50 percent alcohol; fluorosalan; iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate); iodine complex (phosphate ester
  of alkylaryloxy polyethylene glycol); mercufenol chloride; methylbenzethonium chloride; nonylphenoxypoly (ethyleneoxy) ethanoliodine; phenol (less
  than 1.5 percent); phenol (greater than 1.5 percent); poloxamer-iodine complex; secondary amyltricresols; sodium oxychlorosene; triple dye; and
  undecoylium chloride iodine complex.
\3\ Based on studies of potassium iodide.
\4\ The change in classification from sufficient data to incomplete data compared to the Consumer Wash PR (78 FR 76444 at 76458) is a reflection of the
  higher frequency of use in the health care setting.
\5\ Applies to povidone molecules greater than 35,000 daltons.

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

[[Page 25185]]

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

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

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

 Benzalkonium chloride
 Benzethonium chloride
 Chloroxylenol
 Triclosan

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

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

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

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

[[Page 25186]]

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

[[Page 25187]]

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

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

[[Page 25188]]

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

[[Page 25189]]

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

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

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

[[Page 25190]]

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

[[Page 25191]]

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

[[Page 25192]]

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

[[Page 25193]]

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

[[Page 25194]]

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

[[Page 25195]]

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

VIII. Proposed Effective Date

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

IX. Summary of Preliminary Regulatory Impact Analysis

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

A. Introduction

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

[[Page 25196]]

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

B. Summary of Costs and Benefits

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

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

[[Page 25197]]

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

X. Paperwork Reduction Act of 1995

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

XI. Environmental Impact

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

XII. Federalism

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

XIII. References

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

1. Brown, T. L., et al., ``Can Alcohol-Based Hand-Rub Solutions 
Cause You to Lose Your Driver's License? Comparative Cutaneous 
Absorption of Various Alcohols,'' Antimicrobial Agents and 
Chemotherapy, 51:1107-1108, 2007.
2. Calafat, A. M., et al., ``Urinary Concentrations of Triclosan in 
the U.S. Population: 2003-2004,'' Environmental Health Perspectives, 
116:303-307, 2008.
3. Centers for Disease Control and Prevention, ``Fourth National 
Report on Human Exposure to Environmental Chemicals, Updated Tables, 
July 2010,'' 2010.
4. Kramer, A., et al., ``Quantity of Ethanol Absorption After 
Excessive Hand Disinfection Using Three Commercially Available Hand 
Rubs Is Minimal and Below Toxic Levels for Humans,'' BMC Infectious 
Diseases, 7:117, 2007.
5. Miller, M. A., et al., ``Does the Clinical Use of Ethanol-Based 
Hand Sanitizer Elevate

[[Page 25198]]

Blood Alcohol Levels? A Prospective Study,'' American Journal of 
Emergency Medicine, 24:815-817, 2006.
6. Transcript of the January 22, 1997, Meeting of the Joint 
Nonprescription Drugs and Anti-Infective Drugs Advisory Committees 
in OTC Vol. 230002.
7. Comment No. FDA-1975-N-0012-0081.
8. Transcript of the March 23, 2005, Meeting of the Nonprescription 
Drugs Advisory Committee, 2005, available at http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4184T1.pdf.
9. Summary Minutes of the November 14, 2008, Feedback Meeting with 
Personal Care Products Council and Soap and Detergent Association in 
OTC Vol. 230002.
10. Transcript of the September 3, 2014, Meeting of the 
Nonprescription Drugs Advisory Committee, 2014, available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM421121.pdf.
11. Comment Nos. FDA-1975-N-0012-0004, -0062, -0064, -0068, -0073, -
0069, -0079, -0071, -0075, -0081, -0082, -0085, -0087, -0132, -0088, 
-0089, -0090, -0091, -0092, -0093, -0094,-0095, -0096, -0097, -0098, 
-0100, -0102, -0105, -0107, -0111, -0108, -0109, -0110, -0134, -
0112, -0113, -0115, -0116, -0117, -0119, -0123, -0128, -0127, -0135, 
-0148, -0153, -0154, -0155, -0158, -0157, -0159, -0163, -0176, -
0177, -0199, -0200, -0201, -0202, -0215, -0216, -0217, -0218, -0219, 
-0005, -0223, -0284, -0281, -0282, -0283, -0224, -0275, -0285, -
0286, -0276, -0275, -0288, -0277, -0287, -0266, -0268, -0065, -0130, 
-0164, -0166, -0184, -0227, -0187, -0192, -0194, -0196, -0237, -
0238, -0037, -0038, -0245, -0258, -0273, -0204, -0206, -0207, -0208, 
-0209, -0212, -0213, -0214, -0269, -0053, -0122, -0124, -0160, -
0172, -0180, -0181, -0229, -0230, -0231, -0232, -0234, -0247, -0249, 
-0250, -253, -0255, -0264, -0010, -0129, -0138, -0066, -0126, -0140, 
-0178, -0191, -0118, -0121, -0161, -0179, -0198, -0241, -0243, -
0010, -0015, -0016, -0017, and -0018.
12. Comment Nos. FDA-1975-N-0012-0003, -0063, -0062, -0069, -0070, -
0071, -0075, -0085, -0088, -0089, -0090, -0091, -0092, -0094, -0095, 
-0096, -0102, -0105, -0107, -0111, -0108, -0109, -0134, -0112, -
0115, -0116, -0119, -0127, -0148, -0149, -0151, -0159, -0176, -0177, 
-0200, -0201, -0202, -0219, -0220, -0223, -0281, -0282, -0283, -
0224, -0286, -0276, -0275, -0288, -0266, -0289, -0065, -0130, -0164, 
-0166, -0184, -0227, -0187, -0189, -0196, -0015, -0237, -0238, -
0274, -0238, -0214, -0053, -0122, -0137, -0143, -0146, -0160, -0162, 
-0186, -0180, -0181, -0183, -0229, -0230, -0231, -0232, -0235, -
0248, -0255, -0256, -02643, -0010, -0139, -0150, -0106, -0136, -
0141, -0142, -0152, -0168, -0169, -0170, -0242, -0066, -0171, -0161, 
-0179, -0241, -0243, -0221, -0265, -0271, -0010, -0050, -0052, -
0077, -0078, -0083, -0084, -0050, -0051, and -0052.
13. Product labels in OTC Vol. 03HCATFM.
14. Comment No. FDA-1975-N-0012-0062.
15. Comment No. FDA-1975-N-0012-0115.
16. Comment No. FDA-1975-N-0012-0091.
17. Comment No. FDA-1975-N-0012-0187.
18. Comment No. FDA-1975-N-0012-0065.
19. Comment No. FDA-1975-N-0012-0102.
20. Comment No. FDA-1975-N-0012-0229.
21. Centers for Disease Control and Prevention, ``Guideline for Hand 
Hygiene in Health-Care Settings: Recommendations of the Healthcare 
Infection Control Practices Advisory Committee and the HICPAC/SHEA/
APIC/IDSA Hand Hygiene Task Force,'' Morbidity and Mortality Weekly 
Report, 51:1-45, 2002.
22. Mangram, A. J., et al., ``Guideline for Prevention of Surgical 
Site Infection, 1999. Centers for Disease Control and Prevention 
(CDC) Hospital Infection Control Practices Advisory Committee,'' 
American Journal of Infection Control, 27:97-132, 1999.
23. WHO, ``WHO Guidelines on Hand Hygiene in Health Care: First 
Global Patient Safety Challenge Clean Care Is Safer Care,'' WHO 
Guidelines on Hand Hygiene in Health Care: First Global Patient 
Safety Challenge Clean Care Is Safer Care, Geneva, 2009.
24. van Kleef, E., et al., ``Excess Length of Stay and Mortality Due 
to Clostridium difficile Infection: A Multi-State Modelling 
Approach,'' Journal of Hospital Infection, available at http://dx.doi.org/10.1016/j.jhin.2014.08.008, 2014.
25. Scott, R. D., ``The Direct Medical Costs of Healthcare-
Associated Infections in U.S. Hospitals and the Benefits of 
Prevention,'' 2009, available at http://www.cdc.gov/HAI/pdfs/hai/Scott_CostPaper.pdf.
26. Goudie, A., et al., ``Attributable Cost and Length of Stay for 
Central Line-Associated Bloodstream Infections,'' Pediatrics, 
133:e1525-e1532, 2014.
27. Zimlichman, E., et al., ``Health Care-Associated Infections: A 
Meta-Analysis of Costs and Financial Impact on the US Health Care 
System,'' JAMA Internal Medicine, 173:2039-2046, 2013.
28. Larson, E., ``Innovations in Health Care: Antisepsis as a Case 
Study,'' American Journal of Public Health, 79:92-99, 1989.
29. Malik, V. K. and A. Dey, ``Surgical Site Infection: Preventive 
Strategies,'' Principles and Practice of Wound Care, Jaypee Brothers 
Medical Publishers Ltd., New Delhi, 98-101, 2012.
30. The Joint Commission, ``2015 National Patient Safety Goals: 
Hospital,'' 2015, available at http://www.jointcommission.org/assets/1/6/2015_NPSG_HAP.pdf.
31. Fierer, N., et al., ``The Influence of Sex, Handedness, and 
Washing on the Diversity of Hand Surface Bacteria,'' Proceedings of 
the National Academy of Sciences of the USA, 105:17994-17999, 2008.
32. Aiello, A. E., et al., ``A Comparison of the Bacteria Found on 
the Hands of `Homemakers' and Neonatal Intensive Care Unit Nurses,'' 
Journal of Hospital Infection, 54:310-315, 2003.
33. Briefing Material for the March 23, 2005, Meeting of the 
Nonprescription Drugs Advisory Committee, available at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4098B1_02_01-FDA-TOC.htm.
34. FDA Review of Health Care Personnel Hand Wash Effectiveness Data 
in OTC Vol. 03HCATFM.
35. FDA Review of Surgical Hand Scrub Effectiveness Data in OTC Vol. 
03HCATFM.
36. FDA Review of Patient Preoperative Skin Preparation 
Effectiveness Data in OTC Vol. 03HCATFM.
37. FDA Review of Health Care Antiseptic Clinical Outcome 
Effectiveness Data in OTC Vol. 03HCATFM.
38. Comment Nos. FDA-1975-N-0012-0064, -0071, 0081, -0082, -0087, -
0088, and -0096.
39. Comment Nos. FDA-1975-N-0012-0073, -0071, -0075, -0081, -0085, -
0089, -0093, -0096, -0105, -0111, -0108, -0109, -0113, -0116, -0117, 
-0119, -0128, -0127, -0153, -0154, -0155, -0158, -0157, -0176, -
0177, -0200, -0201, -0282, -0275, -0285, -0286, -0276, -0288, -0266, 
-0164, -0166, -0184, -0227, -0194, -0238, -0037, -0258, -0124, -
0143, -0160, -0172, -0264, -0178, -0191, -0118, -0121, -0161, -0198, 
-0241, and -0243.
40. ICH guideline, ``Guideline on the Need for Carcinogenicity 
Studies of Pharmaceuticals S1A,'' November 1995, available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S1A/Step4/S1A_Guideline.pdf.
41. American Diabetes Association, ``Standards of Medical Care in 
Diabetes--2013,'' Diabetes Care, 36:S11-S66, 2013.
42. Ahn, K. C., et al., ``In Vitro Biologic Activities of the 
Antimicrobials Triclocarban, Its Analogs, and Triclosan in Bioassay 
Screens: Receptor-Based Bioassay Screens,'' Environmental Health 
Perspectives, 116:1203-1210, 2008.
43. Chen, J., et al., ``Triclocarban Enhances Testosterone Action: A 
New Type of Endocrine Disruptor?,'' Endocrinology, 149:1173-1179, 
2008.
44. Crofton, K. M., et al., ``Short-Term In Vivo Exposure to the 
Water Contaminant Triclosan: Evidence for Disruption of Thyroxine,'' 
Environmental Toxicology and Pharmacology, 24:194-197, 2007.
45. Gee, R. H., et al., ``Oestrogenic and Androgenic Activity of 
Triclosan in Breast Cancer Cells,'' Journal of Applied Toxicology, 
28:78-91, 2008.
46. Jacobs, M. N., G. T. Nolan, and S. R. Hood, ``Lignans, 
Bacteriocides and Organochlorine Compounds Activate the Human 
Pregnane X Receptor (PXR),'' Toxicology and Applied Pharmacology, 
209:123-133, 2005.
47. Kumar, V., C. Balomajumder, and P. Roy, ``Disruption of LH-
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List of Subjects in 21 CFR Part 310

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

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

PART 310--NEW DRUGS

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

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

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

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

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

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

[[Page 25205]]

Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Undecoylium chloride iodine complex

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

Alcohol (ethanol and ethyl alcohol)
Benzalkonium chloride
Isopropyl alcohol

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

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

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

Alcohol (ethanol and ethyl alcohol)
Isopropyl alcohol

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

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

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