[Federal Register Volume 88, Number 172 (Thursday, September 7, 2023)]
[Notices]
[Pages 61652-61653]
[FR Doc No: 2023-19241]

-----------------------------------------------------------------------

SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-98267; File No. SR-NASDAQ-2023-016]

Self-Regulatory Organizations; The Nasdaq Stock Market LLC;
Notice of Designation of a Longer Period for Commission Action on a
Proposed Rule Change To List and Trade Shares of the iShares Bitcoin
Trust Under Nasdaq Rule 5711(d), Commodity-Based Trust Shares

August 31, 2023.
    On June 29, 2023, The Nasdaq Stock Market LLC (``Nasdaq'' or
``Exchange'') filed with the Securities and Exchange Commission
(``Commission''), pursuant to section 19(b)(1) of the Securities
Exchange Act of 1934 (``Act'') \1\ and Rule 19b-4 thereunder,\2\ a
proposed rule

change to list and trade shares of the iShares Bitcoin Trust under
Nasdaq Rule 5711(d), Commodity-Based Trust Shares. The proposed rule
change was published for comment in the Federal Register on July 19,
2023.\3\
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
    \3\ See Securities Exchange Act Release No. 97905 (July 13,
2023), 88 FR 46342. Comments on the proposed rule change are
available at: https://www.sec.gov/comments/sr-nasdaq-2023-016/srnasdaq2023016.htm.
---------------------------------------------------------------------------

    Section 19(b)(2) of the Act \4\ provides that within 45 days of the
publication of notice of the filing of a proposed rule change, or
within such longer period up to 90 days as the Commission may designate
if it finds such longer period to be appropriate and publishes its
reasons for so finding or as to which the self-regulatory organization
consents, the Commission shall either approve the proposed rule change,
disapprove the proposed rule change, or institute proceedings to
determine whether the proposed rule change should be disapproved. The
45th day after publication of the notice for this proposed rule change
is September 2, 2023. The Commission is extending this 45-day time
period.
---------------------------------------------------------------------------

    \4\ 15 U.S.C. 78s(b)(2).
---------------------------------------------------------------------------

    The Commission finds it appropriate to designate a longer period
within which to take action on the proposed rule change so that it has
sufficient time to consider the proposed rule change and the issues
raised therein. Accordingly, the Commission, pursuant to section
19(b)(2) of the Act,\5\ designates October 17, 2023, as the date by
which the Commission shall either approve or disapprove, or institute
proceedings to determine whether to disapprove, the proposed rule
change (File No. SR-NASDAQ-2023-016).
---------------------------------------------------------------------------

    \5\ 15 U.S.C. 78s(b)(2).

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\6\
---------------------------------------------------------------------------

    \6\ 17 CFR 200.30-3(a)(31).
---------------------------------------------------------------------------

Sherry R. Haywood,
Assistant Secretary.
[FR Doc. 2023-19241 Filed 9-6-23; 8:45 am]
BILLING CODE 8011-01-P


Meetings that should be recorded in the docket for the 2013 Categorical proposal
                         Docket: EPA-HQ-RCRA-2013-0110

Jan 25, 2013
Meeting to discuss C&D and recovered paint solids
Attendees: Susan Bodine, Barnes & Thornburg LLP
EPA Invitees: Suzanne Rudzinski, George Faison, Betsy Devlin
Issue: C&D (relates to rule), and recovered paint solids (which does not relate to proposal as it currently stands)
(no attachments in meeting invite)

Jan, 31, 2013
Treated Wood Council
TWC issue: Treated wood should be non-waste
Attendees: Jeff Miller (Treated Wood Council), Jane Luxton (Pepper Hamilton LLP), Jeff Lloyd (International Research Group on Wood Protection / TWC), Jack Hughes (Norfolk Southern Railroads)
EPA Invitees: George Faison, Betsy Devlin, Charlotte Mooney, Kenneth Dixon, Michael Svizzero, Ross Elliott, Sasha Gerhard, Tab Tesnau
Attachment:  "1-31-13 TWC mtng sign in.pdf"

March 20, 2013
Soundview
Issue: Soundview discussed their paper residuals in light of the current regulations and the statement in the Feb 7 final rule discussing a forthcoming proposal on paper recycling residuals. We discussed the applicability of the regulations (as updated Feb 7) to their situation and technical details of their specific process.
Attendees:  listed in attachment ("3-20-13 Soundview mtng attachment.pdf")
Attachment:
"3-20-13 Soundview mtng attachment.pdf"

May 14, 2013
C&D Meeting
Issue: Discussed the management of C&D and how it is processed for fuel [MORE??]
Attendees: See sign in sheet attachment ("5-14-13 CD mtng sign in.pdf")

May 23, 2013
Issue:  Site visit of a C&D processing site.  Kevin Herb gave an overview of the broad run recycling process before the tour.  Gary Sondermeyer discussed general C&D issues.  The tour took about 20 minutes. We had a general question and answer session to discuss the business operation and practices.

Location: Broad Run Recycling, LLC
9220 Developers Drive, Manassas, Va. 20109

Attendees:
Kevin Herb, Broad Run
Gary Sondermeyer, Bayshore

EPA Attendees:  Kenneth Dixon, George Faison, Tab Tesnau, Tracy Atagi, Jesse Miller, Sasha Gerhard, and Lyn Luben

This URL includes a link for a video of a tour.  It is representative of the one for RPA staff.
General site link:  http://www.broadrunrecycling.com/
Broadrun Recycling Video Tour: http://www.broadrunrecycling.com/video.html

May 30, 2013
Treated Wood Council
Issue: Discuss petition by Treated Wood Council
Attendees:
See attachment ("sign in sheet for TWC meeting 5-30-13.docx")
Attachment:
"EPA NHSM TWC petition 4 3 13.pdf"
 "EPA NHSM TWC petition attachments 4 3 13.pdf"

September 17, 2013
Portland Cement Association
Issue: Background on the cement manufacturing business and the focus on alternate fuels.
[DID THEY HAVE CBI CLAIMS ON THEIR MATERIALS?]

September 20, 2013
AF&PA and American Wood Council
Issue: Concerned with rule as it relates to the use of wood-based materials as alternate fuels [MORE????]
Attachments:
"2050AG45_2013_9_20_AFPA_Handout1.pdf"
"2050AG45_2013_9_20_AFPA_Handout2.pdf"

December 19, 2013
AF&PA and American Wood Council
Issue: [GEORGE  -  PLEASE ADD INFO HERE/EDIT MINE] AF&PA and the American Wood Council discussed the fuel properties of creosote railroad ties.  They also discussed the usage by combustors and the anticipated changes based on the waste status.
Attendees: [SEE IF GEORGE/SOMEONE CAN FIND THE SIGN IN SHEET]
Attachments:
AFPA Handout Dec 19 (2).pdf


[Federal Register: December 21, 2007 (Volume 72, Number 245)]
[Notices]
[Page 72803-72804]
[DOCID:fr21de07-134]

-----------------------------------------------------------------------

SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-56974; File No. SR-Amex-2007-132]

Self-Regulatory Organizations; American Stock Exchange LLC;
Notice of Filing of Proposed Rule Change as Modified by Amendment No. 1
Thereto To Include Volume Executed by Remote Quoting Towards the
Earning of Remote Quoting Rights

    Pursuant to section 19(b)(1) of the Securities Exchange Act of 1934
(``Act'') \1\ and Rule 19b-4 thereunder,\2\ notice is hereby given that
on November 30, 2007, the American Stock Exchange LLC (``Amex'' or the
``Exchange'') filed with the Securities and Exchange Commission
(``Commission'') the proposed rule change as described in Items I and
II below, which Items have been substantially prepared by the Exchange.
On December 13, 2007, Amex filed Amendment No. 1 to the proposed rule
change. The Commission is publishing this notice to solicit comments on
the proposed rule change, as amended, from interested persons.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
---------------------------------------------------------------------------

I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange, proposes to include the volume executed by
specialists and registered options traders (``ROTs'') as a result of
remote quoting towards the earning of remote quoting rights in the
Exchange's remote registered options trader (``RROT'') program (the
``RROT Program'').
    The text of the proposed rule change is available at http://www.amex.com
, at the Exchange's principal office, and at the

Commission's Public Reference Room.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the Exchange included statements
concerning the purpose of and basis for the proposed rule change and
discussed any comments it received on the proposed rule change. The
text of these statements may be examined at the places specified in
Item IV below. The Exchange has prepared summaries, set forth in
sections A, B, and C below, of the most significant aspects of such
statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

1. Purpose
    The Exchange is proposing to include the volume executed by
specialists and ROTs as a result of remote quoting, towards the earning
of remote quoting rights in the Exchange's RROT Program.
    The Exchange's RROT Program currently allows members or member
organizations designated by the Exchange to be awarded remote quoting
rights to enter bids and offers electronically from locations other
than the trading crowd where the applicable options class is traded on
the Exchange's physical trading floor.\3\ ROTs and specialists are
currently awarded remote quoting rights based on quantitative criteria
set forth in Amex Rule 994-ANTE. Specifically, specialists are awarded
remote quoting rights based on Exchange floor volume executed, and
their percentage of industry market share in the options which they
specialize. ROTs are awarded remote quoting rights based solely on
floor volume executed.
---------------------------------------------------------------------------

    \3\ See Securities Exchange Act Release No. 53652 (April 13,
2006), 71 FR 20422 (April 20, 2006) (approving the Exchange's RROT
Program).
---------------------------------------------------------------------------

    Currently, volume executed as a result of quoting remotely is not
included in the calculation of remote quoting rights in Rule 994-ANTE.
However, since the implementation of the RROT Program in May of 2006,
volume is increasingly executed as a result of remote quotes entered by
ROTs and specialists. The Exchange believes it is appropriate to reward
those ROTs and specialists for the volume they execute as a result of
quoting remotely, by including such volume towards the earning of
additional remote quoting rights.
2. Statutory Basis
    The Exchange believes the proposed rule change is consistent with
section 6(b) of the Act,\4\ in general, and section 6(b)(5) of the
Act,\5\ in particular, in that it is designed to prevent fraudulent and
manipulative acts and practices, to promote just and equitable
principles of trade, to remove impediments to and perfect the mechanism
of a free and open market and a national market system and, in general,
to protect investors and the public interest.
---------------------------------------------------------------------------

    \4\ 15 U.S.C. 78f(b).
    \5\ 15 U.S.C. 78f(b)(5).
---------------------------------------------------------------------------

B. Self-Regulatory Organization's Statement on Burden on Competition

    The Exchange does not believe that the proposed rule change will
result in any burden on competition that is not necessary or
appropriate in furtherance of the purpose of the Act.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants or Others

    The Exchange has neither solicited nor received written comments on
the proposed rule change.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    Within 35 days of the date of publication of this notice in the
Federal Register or within such longer period (i) as the Commission may
designate up to 90 days of such date if it finds such longer period to
be appropriate and publishes its reasons for so finding, or (ii) as to
which Amex consents, the Commission will:
    A. By order approve such proposed rule change; or
    B. Institute proceedings to determine whether the proposed rule
change should be disproved.

IV. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. Comments may be submitted by any of
the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://www.sec.gov/rules/sro.shtml.
); or     Send an e-mail to<EMAIL_ADDRESS>Please include

File Number SR-Amex-2007-132 on the subject line.

Paper Comments

     Send paper comments in triplicate to Nancy M. Morris,
Secretary, Securities and Exchange Commission, 100 F Street, NE.,
Washington, DC 20549-1090.

All submissions should refer to File Number SR-Amex-2007-132. This file
number should be included on the subject line if e-mail is used. To
help the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml
). Copies of the submission, all subsequent amendments, all

written statements with respect to the proposed rule change that are
filed with the Commission, and all written

communications relating to the proposed rule change between the
Commission and any person, other than those that may be withheld from
the public in accordance with the provisions of 5 U.S.C. 552, will be
available for inspection and copying in the Commission's Public
Reference Room, 100 F Street, NE., Washington, DC 20549, on official
business days between the hours of 10 a.m. and 3 p.m. Copies of such
filing also will be available for inspection and copying at the
principal offices of the Exchange. All comments received will be posted
without change; the Commission does not edit personal identifying
information from submissions. You should submit only information that
you wish to make available publicly. All submissions should refer to
File Number SR-Amex-2007-132 and should be submitted on or before
January 11, 2008.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\6\
---------------------------------------------------------------------------

    \6\ 17 CFR 200.30-3(a)(12).
---------------------------------------------------------------------------

Florence E. Harmon,
Deputy Secretary.
[FR Doc. E7-24801 Filed 12-20-07; 8:45 am]

BILLING CODE 8011-01-P


[Federal Register Volume 80, Number 121 (Wednesday, June 24, 2015)]
[Notices]
[Pages 36326-36327]
[FR Doc No: 2015-15429]

-----------------------------------------------------------------------

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. EL15-44-000]

Sage Grouse Energy Project, LLC (Complainant v. PacifiCorp
(Respondent); Notice of Amended Complaint

    Take notice that on June 16, 2015, Sage Grouse Energy Project LLC
(Sage Grouse) filed a second answer in response to PacifiCorp's April
22, 2015 filed answer; thereby, Sage Grouse amended its original
complaint filed on February 9, 2015, as more fully explained in its
amendment. In addition, on June 17, 2015, Sage Grouse supplemented the
June 16, 2015 filing with exhibits.
    Any person desiring to intervene or to protest this filing must
file in accordance with Rules 211 and 214 of the Commission's Rules of
Practice and Procedure (18 CFR 385.211, 385.214). Protests will be
considered by the Commission in determining the appropriate action to
be taken, but will not serve to make protestants parties to the
proceeding. Any person wishing to become a party must file a notice of
intervention or motion to intervene, as

appropriate. The Respondent's answer and all interventions, or protests
must be filed on or before the comment date. The Respondent's answer,
motions to intervene, and protests must be served on the Complainants.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper using the ``eFiling'' link at http://www.ferc.gov. Persons unable to file electronically should submit an
original and 5 copies of the protest or intervention to the Federal
Energy Regulatory Commission, 888 First Street NE., Washington, DC
20426.
    This filing is accessible on-line at http://www.ferc.gov, using the
``eLibrary'' link and is available for electronic review in the
Commission's Public Reference Room in Washington, DC. There is an
``eSubscription'' link on the Web site that enables subscribers to
receive email notification when a document is added to a subscribed
docket(s). For assistance with any FERC Online service, please email
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For
TTY, call<PHONE_NUMBER>.
    Comment Date: 5:00 p.m. Eastern Time on July 6, 2015.

    Dated: June 17, 2015.
Kimberly D. Bose,
Secretary.
[FR Doc. 2015-15429 Filed 6-23-15; 8:45 am]
 BILLING CODE 6717-01-P


[Federal Register Volume 80, Number 204 (Thursday, October 22, 2015)]
[Notices]
[Page 63992]
[FR Doc No: 2015-26836]

-----------------------------------------------------------------------

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 1962-203]

Pacific Gas and Electric Company; Notice of Application Accepted
for Filing, Soliciting Comments, Motions To Intervene, and Protests

    Take notice that the following hydroelectric application has been
filed with the Commission and is available for public inspection:
    a. Type of Application: Application for Temporary Variance of
Minimum Flow Requirement.
    b. Project No.: 1962-203.
    c. Date Filed: October 15, 2015.
    d. Applicant: Pacific Gas and Electric Company (licensee).
    e. Name of Project: Rock Creek-Cresta Project.
    f. Location: North Fork Feather River in Plumas, Butte, Yuba, and
Sutter counties, California.
    g. Filed Pursuant to: Federal Power Act, 16 U.S.C. 791(a)-825(r).
    h. Applicant Contact: Mr. Steve Bauman, License Coordinator,
Pacific Gas and Electric Company, Mail Code: N13E, P.O. Box 770000, San
Francisco, CA 94177,<PHONE_NUMBER>.
    i. FERC Contact: Mr. John Aedo,<PHONE_NUMBER>, or
<EMAIL_ADDRESS>    j. Deadline for filing comments, motions to intervene, protests,
and recommendations is October 30, 2015. The Commission strongly
encourages electronic filing. Please file motions to intervene,
protests, comments, or recommendations using the Commission's eFiling
system at http://www.ferc.gov/docs-filing/efiling.asp. Commenters can
submit brief comments up to 6,000 characters, without prior
registration, using the eComment system at http://www.ferc.gov/docs-filing/ecomment.asp. You must include your name and contact information
at the end of your comments. For assistance, please contact FERC Online
Support at<EMAIL_ADDRESS>(866) 208-3676 (toll free), or
(202) 502-8659 (TTY). In lieu of electronic filing, please send a paper
copy to: Secretary, Federal Energy Regulatory Commission, 888 First
Street, NE., Washington, DC 20426. Please include the project number
(P-1962-203) on any comments, motions to intervene, protests, or
recommendations filed.
    k. Description of Request: The licensee requests a temporary
variance of the minimum flow requirement in the Rock Creek and Cresta
reaches of the North Fork Feather River. The licensee states that it is
planning to conduct inspections of the low-level outlet conduit and
gates of the Rock Creek and Cresta dams. In addition, the licensee
plans to conduct dive inspections of the plunge pools of both dams. In
order to facilitate the inspections and allow the field crew to work
safely in the channel and plunge pools, the licensee requests a
temporary reduction in the minimum flows below both dams. Specifically,
the licensee requests Commission approval to reduce flows from the
required 110 cubic feet per second (cfs) and 100 below Rock Creek and
Crests Dams, respectively, to between 60 and 80 cfs at both dams. The
licensee requests that the flow variance occur between November 1 and
December 31, 2015.
    l. Locations of the Application: A copy of the application is
available for inspection and reproduction at the Commission's Public
Reference Room, located at 888 First Street NE., Room 2A, Washington,
DC 20426, or by calling<PHONE_NUMBER>. This filing may also be viewed
on the Commission's Web site at http://www.ferc.gov/docs-filing/elibrary.asp. Enter the docket number excluding the last three digits
in the docket number field to access the document. You may also
register online at http://www.ferc.gov/docs-filing/esubscription.asp to
be notified via email of new filings and issuances related to this or
other pending projects. For assistance, call 1-866-208-3676 or email
<EMAIL_ADDRESS>for TTY, call<PHONE_NUMBER>. A copy is
also available for inspection and reproduction at the address in item
(h) above.
    m. Individuals desiring to be included on the Commission's mailing
list should so indicate by writing to the Secretary of the Commission.
    n. Comments, Protests, or Motions to Intervene: Anyone may submit
comments, a protest, or a motion to intervene in accordance with the
requirements of Rules of Practice and Procedure, 18 CFR 385.210, .211,
.214. In determining the appropriate action to take, the Commission
will consider all protests or other comments filed, but only those who
file a motion to intervene in accordance with the Commission's Rules
may become a party to the proceeding. Any comments, protests, or
motions to intervene must be received on or before the specified
comment date for the particular application.
    o. Filing and Service of Responsive Documents: Any filing must (1)
bear in all capital letters the title ``COMMENTS'', ``PROTEST'', or
``MOTION TO INTERVENE'' as applicable; (2) set forth in the heading the
name of the applicant and the project number of the application to
which the filing responds; (3) furnish the name, address, and telephone
number of the person protesting or intervening; and (4) otherwise
comply with the requirements of 18 CFR 385.2001 through 385.2005. All
comments, motions to intervene, or protests must set forth their
evidentiary basis and otherwise comply with the requirements of 18 CFR
4.34(b). All comments, motions to intervene, or protests should relate
to project works which are the subject of the license surrender.
Agencies may obtain copies of the application directly from the
applicant. A copy of any protest or motion to intervene must be served
upon each representative of the applicant specified in the particular
application. If an intervener files comments or documents with the
Commission relating to the merits of an issue that may affect the
responsibilities of a particular resource agency, they must also serve
a copy of the document on that resource agency. A copy of all other
filings in reference to this application must be accompanied by proof
of service on all persons listed in the service list prepared by the
Commission in this proceeding, in accordance with 18 CFR 4.34(b) and
385.2010.

    Dated: October 16, 2015.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2015-26836 Filed 10-21-15; 8:45 am]
BILLING CODE 6717-01-P


when applied topically (MUsT), including documentation of validation of
the methods used to measure alcohol and its metabolites.
2. Benzalkonium Chloride
    In the 1994 TFM, FDA categorized benzalkonium chloride as Category
III because of a lack of adequate safety data for its use as both a
health care antiseptic and consumer antiseptic product (59 FR 31402 at
31435). FDA also is proposing to classify benzalkonium chloride as
Category III for the indication of consumer antiseptic rubs. Thus,
additional safety data are still needed to make a GRAS determination
for benzalkonium chloride for use as a consumer antiseptic rub.
    In the 2013 Consumer Wash PR, FDA identified the safety data needed
to make a GRAS determination for benzalkonium chloride as an ingredient
in consumer antiseptic wash products. The safety gaps listed were human
and animal pharmacokinetic data, reproductive toxicity studies,
potential hormonal effects, carcinogenicity (oral and dermal) studies,
and potential of the development of antimicrobial resistance to
benzalkonium chloride. As was summarized in the 2015 Health Care
Antiseptic PR, the safety of benzalkonium chloride has been reviewed
and was determined to be safe for use in disinfectants and cosmetic
products by the Environmental Protection Agency (EPA) and the Cosmetic
Ingredient Review (an industry panel), respectively (Refs. 108 and
109). The data cited in both of these evaluations are proprietary and
only summaries of the data are publicly available. Consequently, these
studies are not available to FDA and FDA cannot conduct a complete
evaluation of them. Safety assessments with study summaries do not
constitute an adequate record on which to base a GRAS classification
(Sec.  330.10(a)(4)(i)). For FDA to evaluate this data with respect to
the safety of benzalkonium chloride for this rulemaking, the full study
reports and data sets must be submitted to the rulemaking docket or
otherwise be publicly available.
    In response to the call for data in the 2013 Consumer Wash PR, a
manufacturing consortium submitted the following studies to the 2013
Consumer Wash PR docket (Refs. 110 through 121):
     An embryofetal toxicity study in the rabbit;
     an embryofetal toxicity study in the rat;
     a 2-generation study in the rat;
     a 90 day subchronic dietary study in rats;
     a 90 day subchronic dermal toxicity study in rats;
     a 1-year chronic dietary toxicity study in dogs;
     an ADME study in rats;
     a rat oral carcinogenicity study; and
     a mouse oral carcinogenicity study.
    All of these studies have been reviewed by FDA. Some of the data
were found to be adequate to fill some of the safety data gaps for a
GRAS determination for benzalkonium chloride. Data gaps remain for the
following endpoints: Human pharmacokinetic data under maximal use
condition, animal dermal carcinogenicity and animal ADME data, and data
on antimicrobial resistance to benzalkonium chloride.
    a. Summary of benzalkonium chloride safety data.
    Benzalkonium chloride ADME data. ADME studies of ADBAC in rats of
both sexes were conducted using the oral and the intravenous (IV)
routes of administration. In the oral studies, rats were administered
radiolabeled benzalkonium chloride using the following cohorts: A low-
dose single oral administration study (10 mg/kilogram (kg)), a low-dose
repeated oral administration study (10 mg/kg) and a high-dose single
oral administration study (50 mg/kg) (Ref. 115). For the low-dose
repeated oral administration study, rats were treated via freely
available feed containing 100 parts per million (ppm) of non-
radiolabeled benzalkonium chloride for 14 days, followed by
administration of 10 mg/kg

benzalkonium chloride by oral gavage. Benzalkonium chloride was found
to be excreted mainly via the feces in rats after oral administration.
In all of the treated groups, the average amount of radioactivity
recovered was 87 to 99 percent in the feces and 5 to 8 percent in the
urine.
    In a separate group of animals tested in the same study, a single
low-dose of 10 mg/kg benzalkonium chloride was administered to rats of
both sexes. The average amount of radioactivity recovered following IV
dosing was 45 to 55 percent in the feces and 20 to 30 percent in the
urine. Tissue residues of radioactivity were less than 1 percent of the
orally administered dose in all groups and 30 to 35 percent of the IV
dose. No significant changes were noted when comparing the ADME profile
of high dose versus low dose-treated rats. Although the available ADME
data from nondermal routes of exposure are sufficient to characterize
the ADME profile of benzalkonium chloride following nondermal exposure,
they are not sufficient to characterize the ADME profile after dermal
exposure. Studies on animal ADME after dermal exposure to benzalkonium
chloride will need to be submitted to FDA for review, in order to
complete a GRAS determination for benzalkonium chloride.
    Benzalkonium general toxicity data. Two subchronic 90-day toxicity
studies in rats were submitted, one dermal and the other dietary
(oral). A 1-year chronic oral toxicity study in dogs was also
submitted. In the oral rat study, benzalkonium chloride was
administered via feeding with concentrations ranging from 0 to 8,000
ppm (Ref. 111) for 13 weeks. Among rats treated with 4,000 and 8,000
ppm benzalkonium chloride, an increased incidence in mortality and
overt toxicity was seen. A no adverse effect level (NOAEL) of 500 ppm
was noted, which correlated with a mean daily dose of 31.2 mg/kg in
males and 38.3 mg/kg in females.
    A 1-year chronic oral toxicity study in dogs was also submitted.
Dogs were chronically administered benzalkonium chloride via feeding in
concentrations ranging from 0 to 1,200 ppm for 1 year (Ref. 114).
Changes in body weight included reduced absolute body weight and
reduced body weight gain in males and females in the highest group
tested (1,200 ppm), which correlated with a reduction in food
consumption. At 1,200 ppm, cholesterol levels were reduced by about 10
percent in both males and females (p <= 0.01). No specific organ
toxicity was identified. Based on the changes in body weight and food
consumption at 1,200 ppm, a NOAEL of 400 ppm was determined, which
corresponds to 13.1 and 14.6 mg/kg/day in males and females,
respectively.
    In the dermal toxicity study, rats were topically exposed to
benzalkonium chloride in concentrations ranging from 0 (water) to 1.0
percent (which correspond to 0 to 20 mg/kg/day) over a 13-week
treatment period (Ref. 113). Slight local irritation and hyperkeratosis
(thickening of the epidermis) were observed in all treatment groups
(including control) in both sexes. All findings were limited to the
treatment site. Under the conditions of this study, the NOAEL was 20
mg/kg (1.0 percent). Toxicokinetic data were not collected; therefore,
systemic exposure to benzalkonium chloride was not characterized.
Consequently, dermal ADME (toxicokinetic) data is still needed to
characterize benzalkonium chloride.
    Benzalkonium chloride carcinogenicity data. Two oral
carcinogenicity studies, one in the rat and another in the mouse, were
submitted (Refs. 117 through 121). Both studies were conducted in the
1980's prior to the current ICH guidelines. They were conducted
according to the OECD (Organisation for Economic Co-operation and
Development) guidelines \8\ and designed to meet the requirements of
EPA's regulations, which use a different type of exposure risk
assessment analysis than is used by FDA for drug products.
---------------------------------------------------------------------------

    \8\ http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788.
---------------------------------------------------------------------------

    A 78-week dietary carcinogenicity study was conducted in mice with
benzalkonium chloride concentrations of 500, 1,000, and 1,500 ppm,
corresponding to approximately 15, 73, and 229 mg/kg/day in males and
18, 92, 289 mg/kg/day in females (Refs. 120 and 121). Findings were
limited to decreased body weight in both males and females treated with
the highest dose compared to controls (7 percent and 5 percent at week
78 in males and females, respectively). There were no treatment-related
increases in the incidence of neoplasms at any of the doses tested.
    A 2-year oral carcinogenicity study was conducted in rats with
benzalkonium chloride concentrations of 300, 1,000, and 2,000 ppm,
corresponding to 13, 44, and 88 mg/kg/day, respectively, in males, and
to 17, 57, and 116 mg/kg/day, respectively, in females (Refs. 117
through 119). No treatment-related increases in the incidence of
neoplasms were observed at any of the tested doses.
    There were no treatment-related neoplasms in either oral
carcinogenicity study. Though the mouse study is suboptimal because of
its relatively short duration (78 weeks), we believe these two studies
are adequate to fill the oral carcinogenicity data gap for benzalkonium
chloride.
    No dermal carcinogenicity studies of benzalkonium chloride have
been submitted to FDA. The available data are not adequate to assess
the carcinogenic potential of benzalkonium chloride. We propose that
dermal carcinogenicity studies are still needed to complete a GRAS
determination for benzalkonium chloride.
    Benzalkonium chloride DART data. A developmental toxicity study
conducted in rabbits showed some increase (not dose-related) in the
incidence of certain visceral and skeletal malformations among
benzalkonium chloride-treated rabbits relative to concurrent controls
(Ref. 110). None of the findings were considered significant. Some of
the mated dams proved to be not pregnant; therefore, the total number
of litters (13 to 15) is slightly less than the 16 to 20 recommended in
the ICH S5 guideline, but further benzalkonium chloride DART data are
not necessary to make a GRAS determination.
    In a developmental toxicity study in rats, the animals were
administered benzalkonium chloride (10, 30, and 100 mg/kg/day) (Ref.
112). There were no treatment-related differences in gestational
parameters, including total number of embryonic implantations, number
of viable and nonviable implants. There were also no treatment-related
effects on fetal body weights per litter, or on the incidences of
external, visceral, or skeletal malformations/variations. Based on
these findings, a NOAEL for maternal toxicity was considered to be 10
mg/kg/day and for developmental toxicity 100 mg/kg/day.
    A two-generation reproduction and development study in rats was
submitted for review. Rats were exposed to benzalkonium chloride in the
feed (Ref. 116). The exposure to benzalkonium chloride up to the
highest dose tested of 2,000 mg/kg did not result in parental toxicity.
No treatment-related reproductive effects were observed in any of the
treatment groups. Findings were limited to decreases in body weight
accompanied by a decrease in food consumption among treated females at
2,000 mg/kg/day and a decrease in pup body weight. Based on these
findings, a NOAEL for adults and offspring was considered to be 1000
ppm (62.5 mg/kg/day).

    The submitted DART studies are adequate and no additional DART
studies are needed for benzalkonium chloride.
    Hormonal effects. Based on the negative findings in the
carcinogenicity studies and the two-generation DART studies, no signal
for hormonal effects was detected and no further testing on hormonal
effects will be required for benzalkonium chloride.
    Antimicrobial resistance. In addition to the 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 related to the development of resistance to
benzalkonium chloride (Refs. 122 through 129), and determined that the
available studies have examined few bacterial species, provide no
information on exposure levels, and are not adequate to define the
potential for the development of resistance or cross resistance.
Additional data are needed to more clearly define the potential for the
development of resistance to benzalkonium chloride.
    b. Benzalkonium chloride safety data gaps.
    In summary, our administrative record for the safety of
benzalkonium chloride is incomplete with respect to the following:
     Human pharmacokinetic studies under maximal use conditions
when applied topically (MUsT), including documentation of validation of
the methods used to measure benzalkonium chloride and its metabolites;
     Animal dermal ADME;
     Dermal carcinogenicity; 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 VIII.C.
3. Isopropyl Alcohol
    In the 1994 TFM, FDA proposed to classify isopropyl alcohol (70 to
91.3 percent) as GRAS for all consumer antiseptic washes (59 FR 31402
at 31435). FDA is now proposing to classify isopropyl alcohol as
Category III for use in consumer antiseptic rubs. 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.
    a. Summary of isopropyl alcohol safety data.
    As discussed in more detail in the 2015 Health Care Antiseptic PR
(80 FR 25166 at 25190-25193), FDA has reviewed the following data and
found the data to be sufficient to characterize the safety of isopropyl
alcohol:
     DART data (Refs. 130 through 135).
     Data on the antimicrobial mechanism of isopropyl alcohol
(Refs. 103 through 106, 136 through 138). Isopropyl alcohol readily
evaporates from the skin after topical application. The lack of
antiseptic residue on the skin indicates that the topical application
of isopropyl alcohol is not likely to contribute to the development of
antimicrobial resistance (Refs. 103, 105). Additional data on the
development of antimicrobial resistance are not needed to make a GRAS
determination.
    No new data has been made available to FDA since publication of the
1994 TFM that can fill any of the remaining safety data gaps for
isopropyl alcohol. The following areas of safety assessment, which were
identified in the 1994 TFM and discussed in detail in the 2015 Health
Care Antiseptic PR (80 FR 25166 at 25190-25193), are being updated in
this document:
     Human absorption data (Refs. 1, 139 through 142). However,
the data submitted and found in the literature to date do not cover
maximal use of these products in an institutional setting as detailed
in section VIII.C.2.
     Animal ADME data following dermal and systemic exposure to
isopropyl alcohol (Refs. 143 through 149). 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. Moreover, absorption
data following dermal absorption in animals are still needed to
determine the extent of systemic exposure following maximal dermal
exposure to isopropyl alcohol-containing consumer antiseptic rub
products.
     Systemic and dermal carcinogenicity data in animal models.
Available data for chronic exposure to isopropyl alcohol include
inhalation carcinogenicity data in rodents (Refs. 150 and 151) and a
chronic 1-year dermal toxicity study in mice (Ref. 149). However, these
data are not adequate to assess the systemic or dermal carcinogenic
potential of isopropyl alcohol.
     Data on the hormonal effects of isopropyl alcohol. The
existing data are not adequate to characterize the potential for
hormonal effects of isopropyl alcohol. However, additional studies may
not be needed to assess the potential hormonal effects of isopropyl
alcohol if assessment of potential hormonal activity can be derived
from existing (reproductive and developmental studies; chronic general
toxicity data) and additional pending isopropyl alcohol (systemic and
dermal carcinogenicity and ADME data) nonclinical studies, provided the
appropriate endpoints are assessed.
    Thus, we believe the existing evaluations need to be supplemented
to fully evaluate the safety of isopropyl alcohol. As described in more
detail in the 2015 Health Care Antiseptic PR (80 FR 25166 at 25190-
25193), we propose that human pharmacokinetic studies under maximal use
conditions when applied topically (MUsT), animal ADME studies (dermal
absorption), systemic and dermal carcinogenicity studies, and data on
hormonal effects are still needed to complete a GRAS determination for
isopropyl alcohol.
    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 documentation of validation of
the methods used to measure isopropyl alcohol and its metabolites;
     animal ADME (dermal absorption);
     dermal carcinogenicity;
     systemic carcinogenicity (may be waived if the MUsT data
do not show absorption); and
     hormonal effects (could be derived from other endpoints).

IX. 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 consumer antiseptic rub active ingredients for use in
OTC consumer antiseptic rub drug products. Accordingly, consumer
antiseptic rub 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 consumer antiseptic rub 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 consumer
antiseptic rub 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.

X. Economic Analysis of Impacts

A. Introduction

    We have 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). We have developed a comprehensive Economic Analysis of Impacts
that assesses the impacts of the proposed rule. We believe that this
proposed rule is a significant regulatory action as defined by
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because the consumer antiseptic rub product industry is
mainly composed of establishments with 500 or fewer employees, we
tentatively conclude that the proposed rule may have a significant
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to 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 1 year.'' The current threshold after adjustment for
inflation is $146 million, using the most current (2015) Implicit Price
Deflator for the Gross Domestic Product. This proposed rule would not
result in an expenditure in any year that meets or exceeds this amount.

B. Summary of Costs and Benefits

    There are three active ingredients being evaluated for use as a
consumer antiseptic rub in this proposed rule: Alcohol (ethanol or
ethyl alcohol), isopropyl alcohol, and benzalkonium chloride. The
impact of the proposed rule on OTC consumer antiseptic rub product
industry will depend on the outcome of tests to determine whether these
three active antiseptic ingredients are GRAS/GRAE. It is possible that
none, one, two, or all three of the ingredients will be determined to
be GRAS/GRAE. We consider two extreme scenarios to capture the entire
range of total costs: (1) All three ingredients are deemed to be GRAS/
GRAE or (2) none of the ingredients is deemed to be GRAS/GRAE.
    In table 7, we provide a summary of the estimated costs of the
proposed rule for the two scenarios. The costs of the proposed rule
involve product reformulation and relabeling of products. It is
important to note that, to demonstrate that an antiseptic active
ingredient is GRAS/E, some manufacturers will also incur additional
costs associated with safety and effectiveness testing. We note that
the testing costs for this proposed rule are not attributed here
because these costs will be realized if manufacturers conduct the
testing discussed in the proposed rule for health care antiseptics (80
FR 25166) and we do not count costs twice. However, we estimate these
costs in this analysis to promote transparency in the event that this
rule is finalized before the health care antiseptics proposed rule or
manufacturers conduct the testing for the three ingredients discussed
in this rule but do not conduct the testing for these ingredients for
the health care antiseptic proposed rule or this rule is finalized but
the health care antiseptics proposed rule is not.
    In scenario 1, all three ingredients are determined to be GRAS/E
and manufacturers of products containing other ingredients will no
longer be able to market these products under consumer antiseptic rub
labels pursuant to the topical antimicrobial monograph. We expect that
these manufacturers will reformulate their products to contain one of
the monograph ingredients and relabel their products to reflect the
change in ingredients. Annualizing upfront costs over a 10-year period
at a discount rate of 3% for scenario 1, the costs of the proposed rule
are estimated to be between $0.04 million and $0.12 million per year;
the corresponding estimated cost at a discount rate of 7% is between
$0.05 million and $0.14 million per year. In scenario 2, none of the
ingredients is determined to be GRAS/E and we expect that manufacturers
will reformulate their products to be free of antiseptics and relabel
them to reflect the change in ingredients. Annualizing upfront costs
over a 10-year period at a discount rate of 3% for scenario 2, the
costs of the proposed rule are estimated to be between $1.87 million
and $5.52 million per year; the corresponding estimated cost at a
discount rate of 7% is between $2.28 million and $6.70 million per
year.

                                          Table 7--Summary of Quantified Total Costs (in Millions), by Scenario
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                One-time costs                       Annualized costs over a 10-year period
                                                      --------------------------------------------------------------------------------------------------
                    Cost category                                                               3% Discount rate                 7% Discount rate
                                                          Low        Med.       High   -----------------------------------------------------------------
                                                                                Low        Med.       High       Low        Med.       High
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                            Scenario 1: Assuming All Ingredients are Determined to be GRAS/E
--------------------------------------------------------------------------------------------------------------------------------------------------------
Relabeling Costs.....................................      $0.11      $0.19      $0.32      $0.01      $0.02      $0.04      $0.02      $0.03      $0.05
Reformulation Costs..................................       0.23       0.46       0.70       0.03       0.05       0.08       0.03       0.07       0.10
                                                      --------------------------------------------------------------------------------------------------
    Total Costs......................................       0.34       0.66       1.02       0.04       0.08       0.12       0.05       0.09       0.14
--------------------------------------------------------------------------------------------------------------------------------------------------------

                                         Scenario 2: Assuming None of the Ingredients is Determined to be GRAS/E
--------------------------------------------------------------------------------------------------------------------------------------------------------
Relabeling Costs.....................................       6.55      11.36      18.76       0.77       1.33       2.20       0.93       1.62       2.67
Reformulation Costs..................................       9.44      18.89      28.33       1.11       2.21       3.32       1.34       2.69       4.03
                                                      --------------------------------------------------------------------------------------------------
    Total Costs......................................      15.99      30.25      47.09       1.87       3.55       5.52       2.28       4.31       6.70
--------------------------------------------------------------------------------------------------------------------------------------------------------

    A potential benefit of the proposed rule is that the removal of
potentially harmful antiseptic active ingredients in consumer
antiseptic rub products will prevent health consequences associated
with exposure to such ingredients. FDA lacks the necessary information
to estimate the impact of exposure to antiseptic active ingredients in
consumer antiseptic rub products on human health outcomes. We are,
however, able to estimate the reduction in the aggregate exposure to
antiseptic active ingredients found in currently marketed consumer
antiseptic rub products. As with the total costs, the reduction in
aggregate exposure to antiseptic active ingredients in consumer rub
products depends on the outcome of testing and the determination of
GRAS/E status of the three ingredients that require testing. The
proposed rule will lead to an estimated reduction that ranges from 110
pounds to 254 pounds per year in scenario 1 and from 13,080,963 and
67,272,847 pounds per year in scenario 2. Absent information on the
change in the short- and long-term health risks associated with a one
pound increase in exposure to each antiseptic active ingredient in
consumer antiseptic rub products, we are unable to translate the
aggregate exposure figures into monetized benefits.
    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. This proposed rule could impose a significant economic impact
on a substantial number of small entities. For small entities, we
estimate the rule's one-time costs to roughly range between 0.001 and
0.16 percent of average annual value of shipments for a small business.
In the Initial Regulatory Flexibility Analysis, we assess regulatory
options that would reduce the proposed rule's burden on small entities,
such as extending relabeling compliance times to 18 months (rather than
12 months).
    The full analysis of economic impacts is available in the docket
for this proposed rule (Docket No. FDA-2016-N-0124) and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

XI. 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.

XII. Analysis of 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.

XIII. Federalism

    We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. 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.'' The sole statutory provision giving preemptive
effect to this proposed rule is section 751 of the FD&C Act (21 U.S.C.
379r). We have complied with all of the applicable requirements under
the Executive order and have determined that the preemptive effect of
this proposed rule, if finalized, would be consistent with Executive
Order 13132. Through publication of this proposed rule, we are
providing notice and an opportunity for State and local officials to
comment on this rulemaking.

XIV. References

    The following references are on display in the Division of Dockets
Management (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m. Monday through Friday; they are also
available electronically at http://www.regulations.gov. FDA has
verified the Web site addresses, as of the date this document publishes
in the Federal Register, but Web sites are subject to change over time.

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. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1803104/.
2. Calafat, A.M. et al., ``Urinary Concentrations of Triclosan in
the U.S. Population: 2003-2004,'' Environmental Health Perspective,
116:303-307, 2008. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265044/.
3. Centers for Disease Control and Prevention, ``Fourth National
Report on Human Exposure to Environmental Chemicals, Updated Tables,
July 2010,'' 2010. Available at http://www.cdc.gov/exposurereport/.
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,'' BioMed Central
Infectious Diseases, 7:117, 2007. Available at http://www.pubfacts.com/detail/17927841/Quantity-of-ethanol-absorption-after-excessive-hand-disinfection-using-three-commercially-available-.
5. Miller, M.A. et al., ``Does the Clinical Use of Ethanol-Based
Hand Sanitizer Elevate Blood Alcohol Levels? A Prospective Study,''
American Journal of Emergency Medicine, 24:815-817, 2006. Available
at http://www.ajemjournal.com/article/S0735-6757(06)00131-8/pdf.
6. Transcript of the January 22, 1997, Meeting of the Joint
Nonprescription Drugs and

Anti-Infective Drugs Advisory Committees, OTC Vol. 230002. Available
in Docket No. FDA 2015-N-0101 at http://www.regulations.gov.
7. Comment submitted in Docket No. FDA-1975-N-0012 available at
http://www.regulations.gov with Comment No. FDA-1975-N-0012-0081.
8. Transcript of the March 23, 2005, Nonprescription Drugs Advisory
Committee. Available in Docket No. FDA 2015-N-0101 at http://www.regulations.gov.
9. Transcript of the October 20, 2005, Meeting of the
Nonprescription Drugs Advisory Committee, available at http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4184T1.pdf.
10. Summary Minutes of the November 14, 2008, Feedback Meeting with
Personal Care Products Council and Soap and Detergent Association,
OTC Vol. 230002. Available in Docket No. FDA 2015-N-0101 at http://www.regulations.gov.
11. Transcript of the September 3, 2014, Meeting of the
Nonprescription Drugs Advisory Committee, available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM421121.pdf, 2014.
12. Comments submitted in Docket No. FDA-1975-N-0012 available at
http://www.regulations.gov with Comment Nos. FDA-1975-N-0012-0037,
FDA-1975-N-0012-0049, FDA-1975-N-0012-0068, FDA-1975-N-0012-0071,
FDA-1975-N-0012-0073, FDA-1975-N-0012-0075, FDA-1975-N-0012-0081,
FDA-1975-N-0012-0082, FDA-1975-N-0012-0085, FDA-1975-N-0012-0087,
FDA-1975-N-0012-0088, FDA-1975-N-0012-0089, FDA-1975-N-0012-0090,
FDA-1975-N-0012-0091, FDA-1975-N-0012-0093, FDA-1975-N-0012-0094,
FDA-1975-N-0012-0095, FDA-1975-N-0012-0096, FDA-1975-N-0012-0097,
FDA-1975-N-0012-0098, FDA-1975-N-0012-0099, FDA-1975-N-0012-0101,
FDA-1975-N-0012-0105, FDA-1975-N-0012-0108, FDA-1975-N-0012-0109,
FDA-1975-N-0012-0111, FDA-1975-N-0012-0110, FDA-1975-N-0012-0113,
FDA-1975-N-0012-0116, FDA-1975-N-0012-0117, FDA-1975-N-0012-0118,
FDA-1975-N-0012-0119, FDA-1975-N-0012-0121, FDA-1975-N-0012-0124,
FDA-1975-N-0012-0126, FDA-1975-N-0012, FDA-1975-N-0012-0128, FDA-
1975-N-0012-0132, FDA-1975-N-0012-0134, FDA-1975-N-0012-0135, FDA-
1975-N-0012-0143, FDA-1975-N-0012-0148, FDA-1975-N-0012-0153, FDA-
1975-N-0012-0154, FDA-1975-N-0012-0155, FDA-1975-N-0012-0157, FDA-
1975-N-0012-0158, FDA-1975-N-0012-0161, FDA-1975-N-0012-0164, FDA-
1975-N-0012-0166, FDA-1975-N-0012-0176, FDA-1975-N-0012-0177, FDA-
1975-N-0012-0178, FDA-1975-N-0012-0184, FDA-1975-N-0012-0191, FDA-
1975-N-0012-0198, FDA-1975-N-0012-0199, FDA-1975-N-0012-0200, FDA-
1975-N-0012-0201, FDA-1975-N-0012-0202, FDA-1975-N-0012-0204, FDA-
1975-N-0012-0206, FDA-1975-N-0012-0208, FDA-1975-N-0012-0209, FDA-
1975-N-0012-0212, FDA-1975-N-0012-0213, FDA-1975-N-0012-0215, FDA-
1975-N-0012-0217, FDA-1975-N-0012-0218, FDA-1975-N-0012-0219, FDA-
1975-N-0012-0227, FDA-1975-N-0012-0233, FDA-1975-N-0012-0238, FDA-
1975-N-0012-0241, FDA-1975-N-0012-0243, FDA-1975-N-0012-0258, FDA-
1975-N-0012-0264, FDA-1975-N-0012-0266, FDA-1975-N-0012-0274, FDA-
1975-N-0012-0275, FDA-1975-N-0012-0276, FDA-1975-N-0012-0281, FDA-
1975-N-0012-0282, FDA-1975-N-0012-0284, FDA-1975-N-0012-0285, FDA-
1975-N-0012-0286, FDA-1975-N-0012-0288.
13. Part 130-New Drugs, Procedures for Classification of Over-the-
Counter Drugs, 37 FR 9464 (1972).
14. Comment No. FDA-1975-N-0012-0062 available at http://www.regulations.gov.
15. Comment No. FDA-1975-N-0012-0115 available at http://www.regulations.gov.
16. Comment No. FDA-1975-N-0012-0091 available at http://www.regulations.gov.
17. Comment No. FDA-1975-N-0012-0187 available at http://www.regulations.gov.
18. Comment No. FDA-1996-P-0205-0001 available at http://www.regulations.gov.
19. Comment No. FDA-1975-N-0012-0065 available at http://www.regulations.gov.
20. Comment No. FDA-1975-N-0012-0102 available at http://www.regulations.gov.
21. Comment No. FDA-1975-N-0012-0229 available at http://www.regulations.gov.
22. Centers for Disease Control and Prevention, ``Clean Hands Save
Lives: Emergency Situations,'' available at http://emergency.cdc.gov/disasters/handhygienefacts.asp.
23. National Institute of Allergy and Infectious Diseases, ``Common
Colds: Protect Yourself and Others,'' available at http://www.niaid.nih.gov/topics/commoncold/Pages/default.aspx.
24. ``FDA Review of Clinical Outcome Studies in Consumer Use
Settings,'' 2015, available at http://www.regulations.gov in Docket
No. FDA-2016-N-0124.
25. 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. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5116a1.htm.
26. 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. Available at
http://www.sciencedirect.com/science/article/pii/S019665539970088X.
27. Larson, E., ``Innovations in Health Care: Antisepsis as a Case
Study,'' American Journal of Public Health, 79:92-99, 1989.
available at http://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.79.1.92.
28. FDA Review of Health Care Personnel Hand Wash Effectiveness
Data, OTC Vol. 03HCATFM, available at http://www.regulations.gov in
Docket No. FDA-2016-N-0101.
29. ``Updated FDA Review of Antiseptic Hand Rubs Clinical Simulation
Data,'' 2015, available at http://www.regulations.gov in Docket No.
FDA-2016-N-0124.
30. ``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.
31. Lennell, A. et al., ``Alcohol-Based Hand-Disinfection Reduced
Children's Absence From Swedish Day Care Centers,'' Acta
Paediatrica, 97:1672-1680, 2008. Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1651-2227.2008.01057.x/epdf.
32. Comments submitted in Docket No. FDA-1975-N-0012 available at
http://www.regulations.gov with Comment Nos. FDA-1975-N-0012-0064,
FDA-1975-N-0012-0071, FDA-1975-N-0012-0081, FDA-1975-N-0012-0082,
FDA-1975-N-0012-0087, FDA-1975-N-0012-0088, and FDA-1975-N-0012-0096
in Docket No. FDA-1975-N-0012.
33. Comments submitted in Docket No. FDA-1975-N-0012 available at
http://www.regulations.gov with Comment Nos. FDA-1975-N-0012-0073,
FDA-1975-N-0012-0071, FDA-1975-N-0012-0075, FDA-1975-N-0012-0081,
FDA-1975-N-0012-0085, FDA-1975-N-0012-0089, FDA-1975-N-0012-0093,
FDA-1975-N-0012-0096, FDA-1975-N-0012-0105, FDA-1975-N-0012-0111,
FDA-1975-N-0012-0108, FDA-1975-N-0012-0109, FDA-1975-N-0012-0113,
FDA-1975-N-0012-0116, FDA-1975-N-0012-0117, FDA-1975-N-0012-0119,
FDA-1975-N-0012-0128, FDA-1975-N-0012-0127, FDA-1975-N-0012-0153,
FDA-1975-N-0012-0154, FDA-1975-N-0012-0155, FDA-1975-N-0012-0158,
FDA-1975-N-0012-0157, FDA-1975-N-0012-0176, FDA-1975-N-0012-0177,
FDA-1975-N-0012-0200, FDA-1975-N-0012-0201, FDA-1975-N-0012-0282,
FDA-1975-N-0012-0275, FDA-1975-N-0012-0285, FDA-1975-N-0012-0286,
FDA-1975-N-0012-0276, FDA-1975-N-0012-0288, FDA-1975-N-0012-0266,
FDA-1975-N-0012-0164, FDA-1975-N-0012-0166, FDA-1975-N-0012-0184,
FDA-1975-N-0012-0227, FDA-1975-N-0012-0194, FDA-1975-N-0012-0238,
FDA-1975-N-0012-0037, FDA-1975-N-0012-0258, FDA-1975-N-0012-0124,
FDA-1975-N-0012-0143, FDA-1975-N-0012-0160, FDA-1975-N-0012-0172,
FDA-1975-N-0012-0264, FDA-1975-N-0012-0178, FDA-1975-N-0012-0191,
FDA-1975-N-0012-0118, FDA-1975-N-0012-0121, FDA-1975-N-0012-0161,
FDA-1975-N-0012-0198, FDA-1975-N-0012-0241, and FDA-1975-N-0012-0243
in Docket No. FDA-1975-N-0012.
34. Pandejpong, D. et al., ``Appropriate Time-Interval Application
of Alcohol Hand

Gel on Reducing Influenza-Like Illness Among Preschool Children: A
Randomized, Controlled Trial,'' American Journal of Infection
Control, 40:507-511, 2012. Available at http://www.ajicjournal.org/article/S0196-6553(11)01137-0/pdf.
35. Kampf, G., ``Less And Less-Influence of Volume on Hand Coverage
and Bactericidal Efficacy in Hand Disinfection,'' BMC Infectious
Diseases, 13:472, 2013. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851816/pdf/1471-2334-13-472.pdf.
36. Kampf, G., ``How Effective Are Hand Antiseptics for the
Postcontamination Treatment of Hands When Used as Recommended?,''
American Journal of Infection Control, 36:356-360, 2008. Available
at http://www.ajicjournal.org/article/S0196-6553(07)00805-X/pdf.
37. Macinga, D. R. et al., ``Efficacy of Novel Alcohol-Based Hand
Rub Products at Typical In-Use Volumes,'' Infection Control Hospital
Epidemiology, 34:299-301, 2013. Available at http://www.jstor.org/stable/10.1086/669514?seq=1#page_scan_tab_contents.
38. Kampf, G. et al., ``Efficacy of Ethanol-Based Hand Foams Using
Clinically Relevant Amounts: A Cross-Over Controlled Study Among
Healthy Volunteers,'' BMC Infectious Diseases, 10:78, 2010.
Available at http://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-10-78.
39. Edmonds, S.L. et al., ``Comparative Efficacy of Commercially
Available Alcohol-Based Hand Rubs and World Health Organization-
Recommended Hand Rubs: Formulation Matters,'' American Journal of
Infection Control, 40:521-525, 2012. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180309/pdf/12879_2014_Article_3830.pdf.
40. ICH, ``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. FDA Draft Guidance for Industry, ``Over-the-Counter Sunscreens:
Safety and Effectiveness Data'' November 2015, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM473464.pdf.
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
Perspective, 116:1203-1210, 2008. Available at http://ehp.niehs.nih.gov/wp-content/uploads/116/9/ehp.11200.pdf.
43. Chen, J. et al., ``Triclocarban Enhances Testosterone Action: A
New Type of Endocrine Disruptor?,'' Endocrinology, 149:1173-1179,
2008. Available at http://press.endocrine.org/doi/pdf/10.1210/en.2007-1057.
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.
Available at http://www.sciencedirect.com/science/article/pii/S1382668907000683.
45. Gee, R.H. et al., ``Oestrogenic and Androgenic Activity of
Triclosan in Breast Cancer Cells,'' Journal of Applied Toxicology,
28:78-91, 2008. Available at http://onlinelibrary.wiley.com/doi/10.1002/jat.1316/pdf.
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, available at http://www.sciencedirect.com/science/journal/0041008X/209/2.
47. Kumar, V., C. Balomajumder, and P. Roy, ``Disruption of LH-
Induced Testosterone Biosynthesis in Testicular Leydig Cells by
Triclosan: Probable Mechanism of Action,'' Toxicology, 250:124-131,
2008. Available at http://www.sciencedirect.com/science/article/pii/S0300483X08002850.
48. Kumar, V. et al., ``Alteration of Testicular Steroidogenesis and
Histopathology of Reproductive System in Male Rats Treated With
Triclosan,'' Reproductive Toxicology, 27:177-185, 2009. Available at
http://www.sciencedirect.com/science/article/pii/S089062380800364X.
49. Paul, K.B. et al., ``Short-Term Exposure to Triclosan Decreases
Thyroxine In Vivo via Upregulation of Hepatic Catabolism in Young
Long-Evans Rats,'' Toxicological Sciences, 113:367-379, 2010.
Available at http://toxsci.oxfordjournals.org/content/113/2/367.full.pdf+html?sid=459e5732-786d-46ea-ab58-af2b9f517835.
50. Stoker, T.E., E.K. Gibson, and L.M. Zorrilla, ``Triclosan
Exposure Modulates Estrogen-Dependent Responses in the Female Wistar
Rat,'' Toxicological Sciences, 117:45-53, 2010. Available at http://toxsci.oxfordjournals.org/content/117/1/45.full.pdf+html?sid=44df51a6-52c0-43cc-a629-e609dd1f2b64.
51. Zorrilla, L.M. et al., ``The Effects of Triclosan on Puberty and
Thyroid Hormones in Male Wistar Rats,'' Toxicological Sciences,
107:56-64, 2009. Available at http://toxsci.oxfordjournals.org/content/107/1/56.full.pdf+html?sid=f797a245-5b8c-413a-a124-1274d1a0b704.
52. Anway, M.D. and M.K. Skinner, ``Epigenetic Transgenerational
Actions of Endocrine Disruptors,'' Endocrinology, 147:S43-49, 2006.
Available at http://press.endocrine.org/doi/pdf/10.1210/en.2005-1058.
53. Bernal, A.J. and R.L. Jirtle, ``Epigenomic Disruption: The
Effects of Early Developmental Exposures,'' Birth Defects Research
(Part A), 88:938-944, 2010. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945443/pdf/nihms-208619.pdf.
54. Alexander, E.K. et al., ``Timing and Magnitude of Increases in
Levothyroxine Requirements During Pregnancy in Women With
Hypothyroidism,'' New England Journal of Medicine, 351:241-249,
2004. Available at http://www.nejm.org/doi/pdf/10.1056/NEJMoa040079.
55. Mitchell, M.L. and R.Z. Klein, ``The Sequelae of Untreated
Maternal Hypothyroidism,'' European Journal of Endocrinology, 151
Suppl 3:U45-48, 2004. Available at http://www.eje-online.org/content/151/Suppl_3/U45.long.
56. Pop, V.J. et al., ``Low Maternal Free Thyroxine Concentrations
During Early Pregnancy Are Associated with Impaired Psychomotor
Development in Infancy,'' Clinical Endocrinology, 50:149-155, 1999.
Available at http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2265.1999.00639.x/abstract;jsessionid=8431812FC9630BDCE97AB0386480A87C.f03t01.
57. ICH, ``Testing for Carcinogenicity of Pharmaceuticals S1B,''
July 1997, available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S1B/Step4/S1B_Guideline.pdf.
58. FDA Guidance for Industry, ``S7A Safety Pharmacology Studies for
Human Pharmaceuticals,'' July 2001, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074959.pdf.
59. ICH, ``Detection of Toxicity to Reproduction for Medicinal
Products & Toxicity to Male Fertility S5(R2),'' November 2005,
available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S5_R2/Step4/S5_R2_Guideline.pdf.
60. FDA Guidance for Industry, ``S1C(R2) Dose Selection for
Carcinogenicity Studies (Revision 1),'' September 2008, available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
61. FDA Guidance for Industry, ``M3(R2) Nonclinical Safety Studies
for the Conduct of Human Clinical Trials and Marketing Authorization
for Pharmaceuticals (Revision 1),'' January 2010, available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
62. FDA Draft Guidance for Industry, ``Acne Vulgaris: Developing
Drugs for Treatment,'' September 2005, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071292.pdf.
63. FDA Guidance for Industry, ``Nonclinical Evaluation of
Endocrine-Related Drug Toxicity,'' September 2015, available at
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm369043.pdf.
64. FDA, ``Guideline for the Format and Content of the Human
Pharmacokinetics and Bioavailability Section of an Application,''
February 1987, available at<EMAIL_ADDRESS>65. Bashaw, E.D. et al., ``Maximal Usage Trial: An Overview of the
Design of

Systemic Bioavailability Trial for Topical Dermatological
Products,'' Therapeutic Innovation and Regulatory Science, 2014.
Available at http://dij.sagepub.com/content/49/1/108.full.pdf+html.
66. Kinnula, S. et al., ``Safety of Alcohol Hand Gel Use Among
Children and Personnel at a Child Day Care Center,'' American
Journal of Infection Control, 37:318-321, 2009. Available at http://www.ajicjournal.org/article/S0196-6553(08)00698-6/pdf.
67. FDA draft guidance for industry, ``Bioanalytical Method
Validation,'' (Revision 1), September 2013 available at<EMAIL_ADDRESS>68. Chuanchuen, R. et al., ``Cross-Resistance Between Triclosan and
Antibiotics in Pseudomonas aeruginosa Is Mediated by Multidrug
Efflux Pumps: Exposure of a Susceptible Mutant Strain to Triclosan
Selects nfxB Mutants Overexpressing MexCD-OprJ,'' Antimicrobial
Agents and Chemotherapy, 45:428-432, 2001. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC90308/.
69. Karatzas, K.A. et al., ``Prolonged Treatment of Salmonella
enterica serovar Typhimurium With Commercial Disinfectants Selects
for Multiple Antibiotic Resistance, Increased Efflux and Reduced
Invasiveness,'' Journal of Antimicrobial Chemotherapy, 60:947-955,
2007. Available at http://jac.oxfordjournals.org/content/60/5/947.full.pdf.
70. McMurry, L.M., M. Oethinger, and S.B. Levy, ``Overexpression of
marA, soxS, or acrAB Produces Resistance to Triclosan in Laboratory
and Clinical Strains of Escherichia coli,'' FEMS Microbiology
Letters, 166:305-309, 1998. Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1574-6968.1998.tb13905.x/pdf.
71. Sanchez, P., E. Moreno, and J.L. Martinez, ``The Biocide
Triclosan Selects Stenotrophomonas maltophilia Mutants That
Overproduce the SmeDEF Multidrug Efflux Pump,'' Antimicrobial Agents
and Chemotherapy, 49:781-782, 2005. Available at http://aac.asm.org/content/49/2/781.full.pdf+html.
72. Tabak, M. et al., ``Effect of Triclosan on Salmonella
typhimurium at Different Growth Stages and in Biofilms,'' FEMS
Microbiology Letters, 267:200-206, 2007. Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1574-6968.2006.00547.x/epdf.
73. Srinivasan, V.B. et al., ``Role of Novel Multidrug Efflux Pump
Involved in Drug Resistance in Klebsiella pneumoniae,'' PLoS One,
9:e96288, 2014. Available at http://journals.plos.org/plosone/article/asset?id=10.1371%2Fjournal.pone.0096288.PDF.
74. Levy, S.B., ``Active Efflux, A Common Mechanism for Biocide and
Antibiotic Resistance,'' Journal of Applied Microbiology Symposium
Supplement, 92:65S-71S, 2002. Available at http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2672.92.5s1.4.x/epdf.
75. Russell, A.D., ``Do Biocides Select for Antibiotic
Resistance?,'' Journal of Pharmacy and Pharmacology, 52:227-233,
2000. Available at http://onlinelibrary.wiley.com/doi/10.1211/0022357001773742/epdf.
76. Yazdankhah, S.P. et al., ``Triclosan and Antimicrobial
Resistance in Bacteria: An Overview,'' Microbial Drug Resistance,
12:83-90, 2006. Available at http://online.liebertpub.com/doi/pdf/10.1089/mdr.2006.12.83.
77. Martinez, J.L., ``The Role of Natural Environments in the
Evolution of Resistance Traits in Pathogenic Bacteria,'' Proceedings
in Biological Science, 276:2521-2530, 2009. Available at http://rspb.royalsocietypublishing.org/content/276/1667/2521.
78. Nguyen, M. and G. Vedantam, ``Mobile Genetic Elements in the
Genus Bacteroides, and Their Mechanism(s) of Dissemination,'' Mobile
Genetic Elements, 1:187-196, 2011. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312300/pdf/mge0103_0187.pdf.
79. Cha, J. and A.M. Cupples, ``Detection of the Antimicrobials
Triclocarban and Triclosan in Agricultural Soils Following Land
Application of Municipal Biosolids,'' Water Research, 43:2522-2530,
2009. Available at http://www.sciencedirect.com/science/article/pii/S0043135409001456.
80. Kolpin, D.W. et al., ``Pharmaceuticals, Hormones, and Other
Organic Wastewater Contaminants in U.S. Streams, 1999-2000: A
National Reconnaissance,'' Environmental Science and Technology,
36:1202-1211, 2002. Available at http://pubs.acs.org/doi/pdf/10.1021/es011055j.
81. Russell, A.D. and G. McDonnell, ``Concentration: A Major Factor
in Studying Biocidal Action,'' Journal of Hospital Infection, 44:1-
3, 2000. Available at http://www.sciencedirect.com/science/article/pii/S0195670199906540.
82. Beskitt, J.L. and J.D. Sun, ``In Vitro Skin Penetration
Characteristics of Ethanol in the Rabbit, Mouse, Rat, and Human,''
Journal of Toxicology--Cutaneous and Ocular Toxicology, 16:61-75,
1997. Available at http://www.tandfonline.com/doi/abs/10.3109/15569529709048888.
83. Behl, C.R. et al., ``Hydration and Percutaneous Absorption: I.
Influence of Hydration on Alkanol Permeation Through Hairless Mouse
Skin,'' Journal of Investigative Dermatology, 75:346-352, 1980.
Available at http://www.sciencedirect.com/science/article/pii/S0022202X15459317.
84. Durrheim, H. et al., ``Permeation of Hairless Mouse Skin I:
Experimental Methods and Comparison With Human Epidermal Permeation
by Alkanols,'' Journal of Pharmaceutical Sciences, 69:781-786, 1980.
Available at http://www.sciencedirect.com/science/article/pii/S0022354915432745.
85. Behl, C.R. et al., ``Hydration and Percutaneous Absorption III:
Influences of Stripping and Scalding on Hydration Alteration of the
Permeability of Hairless Mouse Skin to Water and n-Alkanols,''
Journal of Pharmaceutical Sciences, 71:229-234, 1982. Available at
http://www.sciencedirect.com/science/article/pii/S0022354915440456.
86. Flynn, G.L., H. Durrheim, and W.I. Higuchi, ``Permeation of
Hairless Mouse Skin II: Membrane Sectioning Techniques and Influence
on Alkanol Permeabilities,'' Journal of Pharmaceutical Sciences,
70:52-56, 1981. Available at http://www.sciencedirect.com/science/article/pii/S0022354915435336.
87. National Toxicology Program, ``TR 478: Toxicology and
Carcinogenesis Studies of Diethanolamine in F344/N Rats and B6C3F1
Mice,'' 1999 available at http://www.ncbi.nlm.nih.gov/pubmed/12571685.
88. National Toxicology Program, ``NTP Toxicology and Carcinogenesis
Studies of Benzethonium Chloride (CAS No. 121-54-0) in F344/N Rats
and B6C3F1 Mice (Dermal Studies),'' National Toxicology Program
Technical Report Series, 438:1-220, 1995 available at http://www.ncbi.nlm.nih.gov/pubmed/12595925.
89. Stenback, F., ``The Tumorigenic Effect of Ethanol,'' Acta
Pathologica, Microbiologica, et Immunologica Scandinavica, 77:325-
326, 1969. Available at http://onlinelibrary.wiley.com/doi/10.1111/apm.1969.77.issue-2/issuetoc.
90. World Health Organization International Agency for Research on
Cancer, ``IARC Monographs on the Evaluation of Carcinogenic Risks to
Humans. Volume 96, Alcohol Consumption and Ethyl Carbamate,'' 2010.
Available at http://monographs.iarc.fr/ENG/Monographs/vol96/mono96.pdf.
91. National Toxicology Program, ``NTP Technical Report on the
Toxicology and Carcinogenesis Studies of Urethane, Ethanol, and
Urethane/Ethanol in B6C3F1 Mice,'' August 2004, available
at http://www.ncbi.nlm.nih.gov/pubmed/16835633.
92. Watabiki, T. et al., ``Long-Term Ethanol Consumption in ICR Mice
Causes Mammary Tumor in Females and Liver Fibrosis in Males,''
Alcoholism, Clinical and Experimental Research, 24:117S-122S, 2000.
Available at http://europepmc.org/abstract/MED/10803793.
93. Soffritti, M.F. et al., ``Results of Long-Term Experimental
Studies on the Carcinogenicity of Methyl Alcohol and Ethyl Alcohol
in Rats,'' Annals of the New York Academy of Science, 982:46-69,
2003. Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2002.tb04924.x/epdf.
94. Centers for Disease Control and Prevention, ``Alcohol Use in
Pregnancy,'' Updated April 17, 2014, available at http://www.cdc.gov/ncbddd/fasd/alcohol-use.html.
95. National Institute on Alcohol Abuse and Alcoholism,''Fetal
Alcohol Exposure,'' 2015, available at http://

pubs.niaaa.nih.gov/publications/FASDFactsheet/FASDfact.htm.
96. Karl, P.I. and S.E. Fisher, ``Ethanol Alters Hormone Production
in Cultured Human Placental Trophoblasts,'' Alcoholism, Clinical and
Experimental Research, 17:816-821, 1993. Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.1993.tb00847.x/epdf.
97. Santucci, L., T.J. Graham, and D.H. Van Thiel, ``Inhibition of
Testosterone Production by Rat Leydig Cells With Ethanol and
Acetaldehyde: Prevention of Ethanol Toxicity with 4-
methylpyrazole,'' Alcoholism, Clinical and Experimental Research,
7:135-139, 1983. Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.1983.tb05426.x/epdf.
98. Salonen, I., P. Pakarinen, and I. Huhtaniemi, ``Effect of
Chronic Ethanol Diet on Expression of Gonadotropin Genes in the Male
Rat,'' Journal of Pharmacology and Experimental Therapeutics,
260:463-467, 1992. Available at http://jpet.aspetjournals.org/content/260/2/463.long.
99. Emanuele, N. and M.A. Emanuele, ``The Endocrine System: Alcohol
Alters Critical Hormonal Balance,'' Alcohol Health and Research
World, 21:53-64, 1997. Available at http://www.ncbi.nlm.nih.gov/pubmed/15706763?dopt=Abstract.
100. Heller, M. and L. Burd, ``Review of Ethanol Dispersion,
Distribution, and Elimination From the Fetal Compartment,'' Birth
Defects Research (Part A), 100:277-283, 2014. Available at http://onlinelibrary.wiley.com/doi/10.1002/bdra.23232/full.
101. Paintner, A., A.D. Williams, and L. Burd, ``Fetal Alcohol
Spectrum Disorders--Implications for Child Neurology, Part 1:
Prenatal Exposure and Dosimetry,'' Journal of Child Neurology,
27:258-263, 2012. Available at http://jcn.sagepub.com/content/27/2/258.full.pdf+html.
102. Little, P.J., M.L. Adams, and T.J. Cicero, ``Effects of Alcohol
on the Hypothalamic-Pituitary-Gonadal Axis in the Developing Male
Rat,'' Journal of Pharmacology and Experimental Therapeutics,
263:1056-1061, 1992. Available at http://jpet.aspetjournals.org/content/263/3/1056.long.
103. Ali, Y. et al., ``Alcohols'' in Disinfection, Sterilization,
and Preservation, Fifth ed., Lippincott Williams and Wilkins,
Philadelphia, PA, 229-254, 2001. Available at https://books.google.com/books?id=3f-kPJ17_TYC&printsec=frontcover&source=gbs_ViewAPI#v=onepage&q&f=false.

104. Kampf, G. and A. Kramer, ``Epidemiologic Background of Hand
Hygiene and Evaluation of the Most Important Agents for Scrubs and
Rubs,'' Clinical Microbiology Reviews, 17:863-893, 2004. Available
at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC523567/pdf/0085-03.pdf.
105. McDonnell, G.E., ``Alcohols'' in Antisepsis, Disinfection, and
Sterilization--Types, Action, and Resistance, ed., ASM Press,
Washington, DC, 90-92, 2007.
106. Rutala, W.A., D.J. Weber, and Healthcare Infection Control
Practices Advisory Committee (HICPAC), ``Guideline for Disinfection
and Sterilization in Healthcare Facilities,'' 2008, available at
http://www.cdc.gov/hicpac/pdf/guidelines/disinfection_nov_2008.pdf.
107. Bevan, R.J. et al., ``An Assessment of Potential Cancer Risk
Following Occupational Exposure to Ethanol,'' Journal of Toxicology
and Environmental Health, Part B, 12:188-205, 2009. Available at
http://www.tandfonline.com/doi/pdf/10.1080/10937400902894160.
108. Cosmetic Ingredient Review, ``Final Report on the Safety
Assessment of Benzalkonium Chloride,'' Journal of American College
of Toxicology, 8:589-625, 1989.
109. U.S. Environmental Protection Agency, ``Reregistration
Eligibility Decision for Alkyl Dimethyl Benzyl Ammonium Chloride
(ADBAC),'' August 2006, available at http://nepis.epa.gov/EPA/html/DLwait.htm?url=/Exe/ZyPDF.cgi/P1005J4P.PDF?Dockey=P1005J4P.PDF.
110. Comment No. FDA-1975-N-0012-0622 available at http://www.regulations.gov.
111. Comment No. FDA-1975-N-0012-0623 available at http://www.regulations.gov.
112. Comment No. FDA-1975-N-0012-0624 available at http://www.regulations.gov.
113. Comment No. FDA-1975-N-0012-0625 available at http://www.regulations.gov.
114. Comment No. FDA-1975-N-0012-0626 available at http://www.regulations.gov.
115. Comment No. FDA-1975-N-0012-0627 available at http://www.regulations.gov.
116. Comment No. FDA-1975-N-0012-0628 available at http://www.regulations.gov.
117. Comment No. FDA-1975-N-0012-0629 available at http://www.regulations.gov.
118. Comment No. FDA-1975-N-0012-0630 available at http://www.regulations.gov.
119. Comment No. FDA-1975-N-0012-0631 available at http://www.regulations.gov.
120. Comment No. FDA-1975-N-0012-0632 available at http://www.regulations.gov.
121. Comment No. FDA-1975-N-0012-0633 available at http://www.regulations.gov.
122. Braoudaki, M. and A.C. Hilton, ``Adaptive Resistance to
Biocides in Salmonella enterica and Escherichia coli O157 and Cross-
Resistance to Antimicrobial Agents,'' Journal of Clinical
Microbiology, 42:73-78, 2004. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC321691/pdf/0976.pdf.
123. Lambert, R.J., J. Joynson, and B. Forbes, ``The Relationships
and Susceptibilities of Some Industrial, Laboratory and Clinical
Isolates of Pseudomonas aeruginosa to Some Antibiotics and
Biocides,'' Journal of Applied Microbiology, 91:972-984, 2001.
Available at http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2672.2001.01460.x/epdf.
124. Langsrud, S., G. Sundheim, and A.L. Holck, ``Cross-Resistance
to Antibiotics of Escherichia coli Adapted to Benzalkonium Chloride
or Exposed to Stress-Inducers,'' Journal of Applied Microbiology,
96:201-208, 2004. Available at http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2672.2003.02140.x/epdf.
125. Bore, E. et al., ``Adapted Tolerance to Benzalkonium Chloride
in Escherichia coli K-12 Studied by Transcriptome and Proteome
Analyses,'' Microbiology, 153:935-946, 2007. Available at https://www.researchgate.net/publication/6427071_Bore_E_et_al_Adapted_tolerance_to_benzalkonium_chloride_in_Escherichia_coli_K-12_studied_by_transcriptome_and_proteome_analyses_Microbiology_153_935-946.
126. Chuanchuen, R. et al., ``Susceptibilities to Antimicrobials and
Disinfectants in Salmonella Isolates Obtained From Poultry and Swine
in Thailand,'' Journal of Veterinary Medical Science, 70:595-601,
2008. Available at https://www.jstage.jst.go.jp/article/jvms/70/6/70_6_595/_pdf.
127. Lear, J.C. et al., ``Chloroxylenol- and Triclosan-Tolerant
Bacteria From Industrial Sources--Susceptibility to Antibiotics and
Other Biocides,'' International Biodeterioration and Biodegradation,
57:51-56, 2006. Available at http://ac.els-cdn.com/S096483050500137X/1-s2.0-S096483050500137X-main.pdf?_tid=67672f92-2b57-11e6-8f11-00000aacb35e&acdnat=1465156688_42b5bfa1b42253d87614efd8e6e6f809
128. Loughlin, M.F., M.V. Jones, and P.A. Lambert, ``Pseudomonas
aeruginosa Cells Adapted to Benzalkonium Chloride Show Resistance to
Other Membrane-Active Agents But Not to Clinically Relevant
Antibiotics,'' Journal of Antimicrobial Chemotherapy, 49:631-639,
2002. Available at https://jac.oxfordjournals.org/content/49/4/631.full.pdf.
129. Joynson, J.A., B. Forbes, and R.J. Lambert, ``Adaptive
Resistance to Benzalkonium Chloride, Amikacin and Tobramycin: The
Effect on Susceptibility to Other Antimicrobials,'' Journal of
Applied Microbiology, 93:96-107, 2002. Available at http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2672.2002.01667.x/epdf.
130. Bates, H.K. et al., ``Developmental Neurotoxicity Evaluation of
Orally Administered Isopropanol in Rats,'' Fundamental and Applied
Toxicology, 22:152-158, 1994. Available at http://www.sciencedirect.com/science/article/pii/S0272059084710189.
131. Faber, W.D., K.L. Pavkov, and R. Gingell, ``Review of
Reproductive and Developmental Toxicity Studies With Isopropanol,''
Birth Defects Research Part B Developmental and Reproductive
Toxicology, 83:459-476, 2008. Available at http://onlinelibrary.wiley.com/doi/10.1002/bdrb.20167/full.
132. Lehman, A.J., H. Schwerma, and E. Rickards, ``Isopropyl
Alcohol: Acquired Tolerance in Dogs, Rate of Disappearance From the
Blood Stream in Various Species, and Effects on Successive

Generation of Rats,'' Journal of Pharmacology and Experimental
Therapeutics, 85:61-69, 1945. Available at http://jpet.aspetjournals.org/content/85/1/61.full.pdf+html.
133. Nelson, B.K. et al., ``Teratogenicity of n-Propanol and
Isopropanol Administered at High Inhalation Concentrations to
Rats,'' Food and Chemical Toxicology, 26:247-254, 1988. Available at
http://www.sciencedirect.com/science/article/pii/0278691588901263.
134. Tyl, R.W. et al., ``Developmental Toxicity Evaluation of
Isopropanol by Gavage in Rats and Rabbits,'' Fundamental and Applied
Toxicology, 22:139-151, 1994. Available at http://toxsci.oxfordjournals.org/content/22/1/139.full.pdf+html.
135. Bevan, C. et al., ``Two Generation Reproductive Toxicity Study
with Isopropanol in Rats,'' Journal of Applied Toxicology, 15:117-
123, 1995. Available at http://onlinelibrary.wiley.com/doi/10.1002/jat.2550150210/epdf.
136. McEvoy, E.M., P.C. Wright, and M.T. Bustard, ``The Effect of
High Concentration Isopropanol on the Growth of a Solvent-Tolerant
Strain of Chlorella vulgaris,'' Enzyme and Microbial Technology,
35:140-146, 2004. Available at http://ac.els-cdn.com/S0141022904001085/1-s2.0-S0141022904001085-main.pdf?_tid=b24dcd2a-2b59-11e6-9e77-00000aab0f02&acdnat=1465157672_20da9f1e4b98722e189e8520c5050c00.
137. Geng, Y. et al., ``Biodegradation of Isopropanol by a Solvent-
Tolerant Paracoccus denitrificans Strain,'' Preparative Biochemistry
and Biotechnology, 45:491-499, 2015. Available at http://www.tandfonline.com/doi/full/10.1080/10826068.2014.923452.
138. Bustard, M.T. et al., ``Biodegradation of High-Concentration
Isopropanol by a Solvent-Tolerant Thermophile, Bacillus pallidus,''
Extremophiles, 6:319-323, 2002. Available at https://www.researchgate.net/publication/11173057_Biodegradation_of_high-concentration_isopropanol_by_a_solvent-tolerant_thermophile_Bacillus_pallidus_Extremophiles.
139. Kirschner, M.H. et al., ``Transdermal Resorption of an Ethanol-
and 2-Propanol-Containing Skin Disinfectant,'' Langenbeck's Archives
of Surgery., 394:151-157, 2009. Available at http://www.springer.com/medicine/surgery/journal/423.
140. Turner, P., B. Saeed, and M.C. Kelsey, ``Dermal Absorption of
Isopropyl Alcohol From a Commercial Hand Rub: Implications for its
Use in Hand Decontamination,'' The Journal of Hospital Infection,
56:287-290, 2004. Available at http://www.sciencedirect.com/science/article/pii/S0195670104000131.
141. Below, H. et al., ``Dermal and Pulmonary Absorption of Propan-
1-ol and Propan-2-ol From Hand Rubs,'' American Journal of Infection
Control, 40:250-257, 2012. Avilable at http://www.ajicjournal.org/article/S0196-6553(11)00227-6/pdf.
142. Puschel, K., ``Percutaneous Alcohol Intoxication,'' European
Journal of Pediatrics, 136:317-318, 1981.
143. Dhillon, S., ``Toxicology Updates-Isopropanol,'' Journal of
Applied Toxicology, 15:501-506, 1995. Available at http://onlinelibrary.wiley.com/doi/10.1002/jat.2550150612/epdf.
144. International Programme on Chemical Safety, ``2-Propanol,''
1990, available at http://www.inchem.org/documents/ehc/ehc/ehc103.htm#SectionNumber%3A8.3.
145. Boatman, R.J. et al., ``Dermal Absorption and Pharmacokinetics
of Isopropanol in the Male and Female F-344 Rat,'' Drug Metabolism
and Disposition,'' Drug Metabolism and Disposition, 26:197-202,
1998. Available at http://dmd.aspetjournals.org/content/26/3/197.full.pdf+html.
146. Martinez, T.T. et al., ``A Comparison of the Absorption and
Metabolism of Isopropyl Alcohol by Oral, Dermal and Inhalation
Routes,'' Veterinary and Human Toxicology, 28:233-236, 1986.
Available at http://europepmc.org/abstract/med/3727356.
147. Slauter, R.W. et al., ``Disposition and Pharmacokinetics of
Isopropanol in F-344 Rats and B6C3F1 Mice,'' Fundamental and Applied
Toxicology, 23:407-420, 1994. Available at http://toxsci.oxfordjournals.org/content/23/3/407.full.pdf.
148. Kapp, R.W., Jr. et al., ``Isopropanol: Summary of TSCA Test
Rule Studies and Relevance to Hazard Identification,'' Regulatory
Toxicology and Pharmacology, 23:183-192, 1996. Available at http://www.sciencedirect.com/science/article/pii/S0273230096900422.
149. WHO International Program on Chemical Safety Working Group,
``2-Propanol,'' Environmental Health Criteria, 103:132, 1990.
Available at http://www.inchem.org/documents/ehc/ehc/ehc103.htm#SectionNumber:8.3.
150. World Health Organization International Agency for Research on
Cancer, ``IARC Monographs on the Evaluation of Carcinogenic Risks to
Humans: Re-evaluation of Some Organic Chemicals, Hydrazine and
Hydrogen Peroxide,'' 71 (part 3):1027-1036, 1999, available at
http://monographs.iarc.fr/ENG/Monographs/vol71/mono71.pdf.
151. Burleigh-Flayer, H. et al., ``Isopropanol Vapor Inhalation
Oncogenicity Study in Fischer 344 Rats and CD-1 Mice,'' Fundamental
and Applied Toxicology, 36:95-111, 1997. Available at http://www.sciencedirect.com/science/article/pii/S0272059096922848.

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, and
May 1, 2015, at 80 FR 25166, is proposed to be further amended as
follows:

PART 310--NEW DRUGS

0
1. The authority citation for part 310 is revised to read as follows:

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

0
2. In Sec.  310.545:
0
a. Add paragraph (a)(27)(v);
0
b. In paragraph (d) introductory text, remove ``(d)(42)'' and in its
place add ``(d)(43)''; and
0
c. Add paragraph (d)(43).
    The additions to read as follows:

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

    (a) * * *
    (27) * * *
    (v) Consumer antiseptic 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

* * * * *
    (d) * * *
    (43) [DATE 1 YEAR AFTER DATE OF PUBLICATION OF THE FINAL RULE IN
THE Federal Register], for products subject to paragraph (a)(27)(v) of
this section.

    Dated: June 24, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-15410 Filed 6-29-16; 8:45 am]
 BILLING CODE 4164-01-P