[Federal Register Volume 88, Number 155 (Monday, August 14, 2023)]
[Notices]
[Pages 55051-55053]
[FR Doc No: 2023-17287]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-N-2483]

Microbiology Devices Panel of the Medical Devices Advisory
Committee; Notice of Meeting; Establishment of a Public Docket; Request
for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) announces a forthcoming
public advisory committee meeting of the Microbiology Devices Panel of
the Medical Devices Advisory Committee (the Committee). The general
function of the Committee as a medical device panel is to provide
advice and recommendations to FDA. In addition, the Committee will meet
to discuss and provide advice to FDA on in vitro diagnostic devices
used in pandemic preparedness and response to satisfy, in part, a
requirement under the Food and Drug Omnibus Reform Act of 2022 (FDORA).
The meeting will be open to the public. FDA is establishing a docket
for public comment on this document.

DATES: The meeting will be held virtually on September 7, 2023, from 9
a.m. to 5:15 p.m. Eastern Time and September 8, 2023, from 9:30 a.m. to
3:45 p.m. Eastern Time.

ADDRESSES: All meeting participants will be heard, viewed, captioned,
and recorded for this advisory committee meeting via an online
teleconferencing and/or video conferencing platform. Answers to
commonly asked questions about FDA advisory committee meetings may be
accessed at: https://www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/ucm408555.htm.
    FDA is establishing a docket for public comment on this meeting.
The docket number is FDA-2023-N-2483. Please note that late, untimely
filed comments will not be considered. The docket will close on October
10, 2023. The https://www.regulations.gov electronic filing system will
accept comments until 11:59 p.m. Eastern Time at the end of October 10,
2023. Comments received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are received on or
before that date.
    Comments received on or before August 30, 2023, will be provided to
the Committee. Comments received after that date will be taken into
consideration by FDA. In the event that the meeting is cancelled, FDA
will continue to evaluate any relevant applications or information, and
consider any comments submitted to the docket, as appropriate.
    You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that

identifies you in the body of your comments, that information will be
posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2023-N-2483 for ``Microbiology Devices Panel of the Medical Devices
Advisory Committee; Notice of Meeting; Establishment of a Public
Docket; Request for Comments.'' Received comments, those filed in a
timely manner (see ADDRESSES), will be placed in the docket and, except
for those submitted as ``Confidential Submissions,'' publicly viewable
at https://www.regulations.gov or at the Dockets Management Staff
between 9 a.m. and 4 p.m., Monday through Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' FDA will review
this copy, including the claimed confidential information, in its
consideration of comments. The second copy, which will have the claimed
confidential information redacted/blacked out, will be available for
public viewing and posted on https://www.regulations.gov. Submit both
copies to the Dockets Management Staff. If you do not wish your name
and contact information be made publicly available, you can provide
this information on the cover sheet and not in the body of your
comments and you must identify the information as ``confidential.'' Any
information marked as ``confidential'' will not be disclosed except in
accordance with 21 CFR 10.20 and other applicable disclosure law. For
more information about FDA's posting of comments to public dockets, see
80 FR 56469, September18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Candace Nalls, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 5216, Silver Spring, MD 20993-0002,<PHONE_NUMBER>,
[email protected], or FDA Advisory Committee Information Line,
1-800-741-8138<PHONE_NUMBER> in the Washington, DC area). A notice in
the Federal Register about last-minute modifications that impact a
previously announced advisory committee meeting cannot always be
published quickly enough to provide timely notice. Therefore, you
should always check FDA's website at https://www.fda.gov/AdvisoryCommittees/default.htm and scroll down to the appropriate
advisory committee meeting link, or call the advisory committee
information line to learn about possible modifications before the
meeting.

SUPPLEMENTARY INFORMATION:
    Agenda: All meeting presentations will be heard, viewed, captioned,
and recorded through an online teleconferencing and/or video
conferencing platform. FDA is seeking the Committee's preliminary input
on potential future reclassification of certain microbiology devices to
inform FDA's thinking regarding whether reclassification from class III
to class II may be appropriate for such devices. Specifically, on
September 7, 2023, during session I, the Committee will discuss and
make recommendations regarding a potential future reclassification from
class III to class II with special controls of nucleic acid and
serology-based in vitro diagnostic devices indicated for use to aid in
diagnosis of hepatitis B virus (HBV) infection and/or for use to aid in
the management of HBV infected patients. The Committee, during session
II, will discuss and make recommendations regarding a potential future
reclassification from class III to class II with special controls of
serology-based in vitro diagnostic devices indicated for use to aid in
the detection of past, recent, or current infection with human
parvovirus B19. The Committee, during session III, will discuss and
make recommendations regarding a potential future reclassification from
class III to class II with special controls of cell-mediated immune
reactivity in vitro diagnostic devices indicated for use to aid in
identification of in vitro responses to peptide antigens that are
associated with Mycobacterium tuberculosis infection and/or for use as
detection of effector T cells that respond to stimulation by M.
tuberculosis agents.
    All devices to be discussed by the Committee on September 7, 2023,
are postamendments devices that currently are classified into class III
under section 513(f)(1) of the Federal Food, Drug, and Cosmetic (FD&C)
Act (21 U.S.C. 360c(f)(1)). For these devices, the Committee will
discuss: (1) if there is sufficient information for FDA to consider
reclassifying them from class III to class II and (2) what special
controls, in addition to general controls, may be appropriate and
necessary to provide reasonable assurance of safety and effectiveness
for these devices, if FDA were to take action to reclassify them into
class II devices. FDA intends to follow the procedures outlined in
section 513 of the FD&C Act related to the reclassification of
postamendments devices after considering the Committee's input.
    On September 8, 2023, the Committee will discuss and provide
recommendations to FDA regarding topics related to in vitro diagnostic
devices used in pandemic preparedness and response, consistent with the
requirements under section 3302 of FDORA.
    FDA intends to make background material available to the public no
later than 2 business days before the meeting. If FDA is unable to post
the background material on its website prior to the meeting, the
background material will be made publicly available on FDA's website at
the time of the advisory committee meeting. Background material and the
link to the online teleconference and/or video conference meeting will
be available at https://www.fda.gov/AdvisoryCommittees/Calendar/default.htm. Scroll down to the appropriate advisory committee meeting
link.
    The meeting will include slide presentations with audio and video
components to allow the presentation of materials in a manner that most
closely

resembles an in-person advisory committee meeting.
    Procedure: Interested persons may present data, information, or
views, orally or in writing, on issues pending before the Committee.
All electronic and written submissions to the Docket (see ADDRESSES) on
or before August 18, 2023, will be provided to the Committee. Oral
presentations from the public will be scheduled on September 7, 2023,
between approximately 10:05 a.m. and 10:35 a.m., 1:15 p.m. and 1:45
p.m., and 3:30 p.m. and 4 p.m. Eastern Time; and on September 8, 2023,
between approximately 10:30 a.m. and 11:30 a.m. Eastern Time. Those
individuals interested in making formal oral presentations should
notify the contact person and submit a brief statement of the general
nature of the evidence or arguments they wish to present, the names and
addresses of proposed participants, and an indication of the
approximate time requested to make their presentation on or before
August 10, 2023. Time allotted for each presentation may be limited. If
the number of registrants requesting to speak is greater than can be
reasonably accommodated during the scheduled open public hearing
session, FDA may conduct a lottery to determine the speakers for the
scheduled open public hearing session. The contact person will notify
interested persons regarding their request to speak by August 11, 2023.
    For press inquiries, please contact the Office of Media Affairs at
[email protected] or<PHONE_NUMBER>.
    FDA welcomes the attendance of the public at its advisory committee
meetings and will make every effort to accommodate persons with
disabilities. If you require accommodations due to a disability, please
contact Artair Mallett, at [email protected] or<PHONE_NUMBER>
at least 7 days in advance of the meeting.
    FDA is committed to the orderly conduct of its advisory committee
meetings. Please visit our website at https://www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/ucm111462.htm for procedures
on public conduct during advisory committee meetings.
    Notice of this meeting is given under the Federal Advisory
Committee Act (5 U.S.C. 1001 et seq.). This meeting notice also serves
as notice that, pursuant to 21 CFR 10.19, the requirements in 21 CFR
14.22(b), (f), and (g) relating to the location of advisory committee
meetings are hereby waived to allow for this meeting to take place
using an online meeting platform. This waiver is in the interest of
allowing greater transparency and opportunities for public
participation, in addition to convenience for advisory committee
members, speakers, and guest speakers. No participant will be
prejudiced by this waiver, and that the ends of justice will be served
by allowing for this modification to FDA's advisory committee meeting
procedures.

    Dated: August 8, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-17287 Filed 8-11-23; 8:45 am]
BILLING CODE 4164-01-P


Table 1 Annual Respondent Burden and Cost  Non Road Engine Certification Application Hours and cost per application Information Collection Activity Mgr./ Engr/

Tech @$ 75/ hr Cler. @

$ 38/ hr Respon.

hr/ yr Labor Cost/ yr Capital Startup Cost O & M Cost ( annualized) ( 1) Number of Respondents Frequency ( 2) Total hr/ yr Total Cost/ yr Review of regs and guidance document 341 0 341.0 25,575 0 0 54 1.0 18,414 1,381,050 Developing engine family groups 34 0 34.0 2,550 0 0 54 1.0 1,836 137,700 Gathering emission data on test engines 1 9 10.0 417 0 60,000 54 1.5 810 3,273,777 gather durability data on test engines 2 18 20.0 834 0 0 54 1.5 1,620 67,554 Preparing and submitting certification application 2 0 2.0 150 0 0 54 1.5 162 12,150 Preparing " carry over" applications( 3) 2 0 2.0 150 0 0 54 7.0 756 56,700 Preparing and supporting running changes 1 0 1.0 75 0 2 54 3.5 189 14,283 Store, file and maintain records 10 10 20.0 1,130 0 1 54 12.0 12,960 732,294 Total per manufacturer 393 37 430.0 30,881 0 60,003 1 varies N/ A N/ A Total for the industry N/ A N/ A N/ A 2,435,346 0 3,240,162 54 varies 36,747 5,675,508 ( 1) Includes costs incurred in keeping emissions laboratories operational such as test fuel and calibration gases.

Other expenses include the cost of making copies, and paying for diskettes and postage. Frequency is one.

( 2) Number of times one manufacturer performs each task in a year, in average.

( 3) Carry over applications use certication data from the previous model year. No new certification testing is required.


[Federal Register Volume 81, Number 160 (Thursday, August 18, 2016)]
[Notices]
[Pages 55195-55196]
[FR Doc No: 2016-19759]

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ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OPP-2015-0022; FRL-9949-74]

Pesticide Product Registrations; Receipt of Applications for New
Uses

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: EPA has received applications to register new uses for
pesticide products containing currently registered active ingredients.
Pursuant to the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA), EPA is hereby providing notice of receipt and opportunity to
comment on these applications.

DATES: Comments must be received on or before September 19, 2016.

ADDRESSES: Submit your comments, identified by the docket
identification (ID) number and the File Symbol or Registration Number
of interest as shown in the body of this document by one of the
following methods:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the online instructions for submitting comments.

Do not submit electronically any information you consider to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute.
     Mail: OPP Docket, Environmental Protection Agency Docket
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC
20460-0001.
     Hand Delivery: To make special arrangements for hand
delivery or delivery of boxed information, please follow the
instructions at http://www.epa.gov/dockets/contacts.html. Additional
instructions on commenting or visiting the docket, along with more
information about dockets generally, is available at http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Robert McNally, Biopesticides and
Pollution Prevention Division (BPPD) (7511P), main telephone number:
(703) 305-7090, email address<EMAIL_ADDRESS>or Michael
Goodis, Registration Division (RD) (7505P), main telephone number:
(703) 305-7090, email address<EMAIL_ADDRESS>The mailing address
for each contact person is: Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-
0001. As part of the mailing address, include the contact person's
name, division, and mail code. The division to contact is listed at the
end of each application summary.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
The following list of North American Industrial Classification System
(NAICS) codes is not intended to be exhaustive, but rather provides a
guide to help readers determine whether this document applies to them.
Potentially affected entities may include:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).

B. What should I consider as I prepare my comments for EPA?

    1. Submitting CBI. Do not submit this information to EPA through
regulations.gov or email. Clearly mark the part or all of the
information that you claim to be CBI. For CBI information in a disk or
CD-ROM that you mail to EPA, mark the outside of the disk or CD-ROM as
CBI and then identify electronically within the disk or CD-ROM the
specific information that is claimed as CBI. In addition to one
complete version of the comment that includes information claimed as
CBI, a copy of the comment that does not contain the information
claimed as CBI must be submitted for inclusion in the public docket.
Information so marked will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2.
    2. Tips for preparing your comments. When preparing and submitting
your comments, see the commenting tips at http://www.epa.gov/dockets/comments.html.

II. Registration Applications

    EPA has received applications to register new uses for pesticide
products containing currently registered active ingredients. Pursuant
to the provisions of FIFRA section 3(c)(4) (7 U.S.C. 136a(c)(4)), EPA
is hereby providing notice of receipt and opportunity to comment on
these applications. Notice of receipt of these applications does not
imply a decision by the Agency on these applications.
    1. EPA Registration Numbers: 264-1049, 264-1050, 264-1065. Docket
ID number: EPA-HQ-OPP-OPP-2016-0255. Applicant: Bayer CropScience, P.O.
Box 12014, Research Triangle Park, North Carolina 27709. Active
ingredient: Spirotetramat. Product type: Insecticide. Proposed use:
Carrot. Contact: RD.
    2. EPA Registration Numbers: 264-1049, 264-1050, 264-1051, 264-
1065. Docket ID number: EPA-HQ-OPP-OPP-2016-0255. Applicant: Bayer
CropScience, P.O. Box 12014, Research Triangle Park, North Carolina
27709. Active ingredient: Spirotetramat. Product type: Insecticide.
Proposed uses: Sugar beet, bushberry subgroup low growing berry (crop
subgroups 13-07B and 13-07H). Contact: RD.
    3. EPA Registration Number: 2724-804. Docket ID number: EPA-HQ-OPP-
2016-0342. Applicant: Wellmark International; 1501 E. Woodfield Road,
Suite 200 West; Schaumburg, IL 60173. Active ingredient: Piperonyl
butoxide. Product type: Insecticide. Proposed use: Fungi, edible, group
21. Contact: RD.
    4. EPA Registration Numbers: 42750-85 and 42750-169. Docket ID
number: EPA-HQ-OPP-2016-0384. Applicant: Albaugh, LLC, P.O. Box 2127,
Valdosta, GA 31604. Active ingredient: Quinclorac. Product type:
Herbicide. Proposed uses: Bushberries, caneberries, and asparagus.
Contact: RD.
    5. EPA Registration Number: 89459-19. Docket ID number: EPA-HQ-OPP-
2016-0342. Applicant: Central Garden and Pet Company; 1501 East
Woodfield Road, Suite 200W; Schaumburg, IL 60173. Active ingredient:
Piperonyl butoxide. Product type: Insecticide. Proposed use: Fungi,
edible, group 21. Contact: RD.
    6. File Symbol: 6218-IT. Docket ID number: EPA-HQ-OPP-2016-0165.
Applicant: Summit Chemical Co., 235 S. Kresson St., Baltimore, MD
21224-2616. Active ingredient: Bacillus thuringiensis subspecies
israelensis strain SUM-6218. Product type: Insecticide. Proposed use:
To control mosquito larvae outdoors, indoors, and in residential areas
and psychodid fly larvae in wastewater treatment plants. Contact: BPPD.
    7. File Symbol: 7173-GNL. Docket ID number: EPA-HQ-OPP-2016-0420.
Applicant: Liphatech, 3600 West Elm St., Milwaukee, WI 53209. Active
ingredient: Chlorophacinone. Product type: Rodenticide. Proposed use:
California ground squirrels. Contact: RD.
    8. File Symbol: 42750-GRG. Docket ID number: EPA-HQ-OPP-2016-0360.
Applicant: Albaugh, LLC, P.O. Box 2127, Valdosta, GA 31604. Active
ingredient: quizalofop-P-ethyl. Product type: Herbicide. Proposed use:
Herbicide-tolerant wheat. Contact: RD.

    Authority: 7 U.S.C. 136 et seq.

    Dated: August 10, 2016.
Michael Goodis,
Acting Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 2016-19759 Filed 8-17-16; 8:45 am]
BILLING CODE 6560-50-P


[Federal Register: March 10, 2006 (Volume 71, Number 47)]
[Notices]
[Page 12412]
[DOCID:fr10mr06-148]

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SECURITIES AND EXCHANGE COMMISSION

[File No. 1-00043]

Issuer Delisting; Notice of Application of General Motors
Corporation To Withdraw Its Common Stock, $1\2/3\ Par Value, From
Listing and Registration on the Pacific Exchange, Inc.

March 6, 2006.
    On February 23, 2006, General Motors Corporation, a Delaware
corporation (``Issuer''), filed an application with the Securities and
Exchange Commission (``Commission''), pursuant to Section 12(d) of the
Securities Exchange Act of 1934 (``Act'') \1\ and Rule 12d2-2(d)
thereunder,\2\ to withdraw its common stock, $1\2/3\ par value
(``Security''), from listing and registration on the Pacific Exchange,
Inc. (``PCX'').
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    \1\ 15 U.S.C. 78l(d).
    \2\ 17 CFR 240.12d2-2(d).
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    The Administrative Committee of the Issuer's Board of Directors
(``Board'') approved a resolution on September 9, 2005, to delist the
Issuer's Security from listing and registration on PCX. The Issuer
stated that the purposes for seeking to delist the Security from PCX
are to avoid dual regulatory oversight and dual listing fees. The
Security is traded, and will continue to trade on the New York Stock
Exchange, Inc. (``NYSE''). In addition, the Issuer stated in its
application that PCX advised the Issuer that the Security will continue
to trade on Archipelago Exchange (``ArcaEx''), the trading facility of
PCX, under unlisted trading privileges.
    The Issuer stated in its application that it has complied with
applicable rules of PCX by providing PCX with the required documents
governing the withdrawal of securities from listing and registration on
PCX. The Issuer's application relates solely to the withdrawal of the
Security from listing on PCX and shall not affect its continued listing
on NYSE, the Chicago Stock Exchange, Inc. (``CHX''), or the
Philadelphia Stock Exchange, Inc. (``PHLX''),\3\ or its obligation to
be registered under Section 12(b) of the Act.\4\
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    \3\ The Issuer filed applications with the Commission to
withdraw the Security from listing and registration on CHX and PHLX
on March 2, 2006 and February 27, 2006, respectively. Notice of such
applications will be published separately.
    \4\ 15 U.S.C. 78l(b).
---------------------------------------------------------------------------

    Any interested person may, on or before March 29, 2006, comment on
the facts bearing upon whether the application has been made in
accordance with the rules of PCX, and what terms, if any, should be
imposed by the Commission for the protection of investors. All comment
letters may be submitted by either of the following methods:

Electronic Comments

     Send an e-mail to<EMAIL_ADDRESS>Please include
the File Number 1-00043 or;

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 1-00043. This file number
should be included on the subject line if e-mail is used. To help us
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/delist.shtml). Comments are

also available for public inspection and copying in the Commission's
Public Reference Room. All comments received will be posted without
change; we do not edit personal identifying information from
submissions. You should submit only information that you wish to make
available publicly.
    The Commission, based on the information submitted to it, will
issue an order granting the application after the date mentioned above,
unless the Commission determines to order a hearing on the matter.

    For the Commission, by the Division of Market Regulation,
pursuant to delegated authority.\5\
---------------------------------------------------------------------------

    \5\ 17 CFR 200.30-3(a)(1).
---------------------------------------------------------------------------

Nancy M. Morris,
Secretary.
[FR Doc. E6-3438 Filed 3-9-06; 8:45 am]

BILLING CODE 8010-01-P


[Federal Register: February 6, 2008 (Volume 73, Number 25)]
[Notices]
[Page 6962]
[DOCID:fr06fe08-51]

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ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OPPT-2007-1081; FRL-8351-1]

Agency Information Collection Activities; Proposed Collection;
Comment Request; Tier 1 Screening of Certain Chemicals Under the
Endocrine Disruptor Screening Program (EDSP); EPA ICR No. 2249.01, OMB
Control No. 2070-new; Extension of Comment Period

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice; extension of comment period.

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SUMMARY: EPA issued a notice in the Federal Register of December 13,
2007, announcing EPA's plan to submit a request for a new Information
Collection Request (ICR) to the Office of Management and Budget (OMB).
This ICR is entitled: ``Tier 1 Screening of Certain Chemicals Under the
Endocrine Disruptor Screening Program (EDSP)'' and identified by EPA
ICR No. 2249.01 and OMB Control No. 2070-new. The December 13, 2007
document provided for a 60 day public comment period ending February
11, 2008. EPA received several requests from the public to extend this
comment period. This document extends the comment period for 30 days,
from February 11, 2008, to March 12, 2008.

DATES: Comments, identified by docket identification (ID) number EPA-
HQ-OPPT-2007-1081, must be received on or before March 12, 2008.

ADDRESSES: Follow the detailed instructions as provided under ADDRESSES
in the Federal Register document of December 13, 2007.

FOR FURTHER INFORMATION CONTACT: William Wooge, Office of Science
Coordination and Policy (7201M), Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone number:
(202) 564-8476; e-mail address<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: This document extends the public comment
period established in the Federal Register of December 13, 2007 (72 FR
70839) (FRL-8155-8). In that document, EPA solicited comments and
information on its request for a new ICR entitled ``Tier 1 Screening of
Certain Chemicals Under the Endocrine Disruptor Screening Program
(EDSP).'' On December 17, 2007, EPA held a workshop to discuss the ICR.
EPA intends to convene a second half-day public meeting to discuss this
ICR and answer questions from the public. A separate Federal Register
document will announce the details of the meeting. EPA is hereby
extending the comment period, which was set to end on February 11,
2008, to March 12, 2008.
    To submit comments, or access the public docket, please follow the
detailed instructions as provided under ADDRESSES in the December 13,
2007 Federal Register document. If you have questions, consult the
person listed under FOR FURTHER INFORMATION CONTACT.

List of Subjects

    Environmental protection, Reporting and recordkeeping requirements.

    Dated: January 30, 2008.
James B. Gulliford,
Assistant Administrator, Office of Prevention, Pesticides and Toxic
Substances.
[FR Doc. E8-2169 Filed 2-5-08; 8:45 am]

BILLING CODE 6560-50-S


Poly( hexamethylenebiguanide) hydrochloride ( PHMB) Case 3122 PC Code: 111801 Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision Document January 18, 2005 Jonathan Chen, Ph. D. Tim McMahon, Ph. D. Antimicrobials Division Office of Pesticide Programs U. S. Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460 TABLE OF CONTENTS 1.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.0 REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3.0 DATA GAPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.0 HAZARD ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.1 Acute Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.2 Subchronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.3 Prenatal Developmental Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.4 Reproductive Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.5 Chronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.6 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 4.7 Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.8 Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.9 Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 5.0 TOXICITY ENDPOINT SELECTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 5.1 See Section 8.2 for Endpoint Selection Table. . . . . . . . . . . . . . . . . . . . . . . . . . . 17 5.2 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 5.3 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.0 FQPA CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.1 Special Sensitivity to Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.2 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 18 7.0 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 8.0 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 8.1 Toxicity Profile Summary Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 8.1.1 Acute Toxicity Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 8.1.2 Subchronic, Chronic and Other Toxicity Tables . . . . . . . . . . . . . . . . . . . 23 8.2 Summary of Toxicological Dose and Endpoints . . . . . . . . . . . . . . . . . . . . . . . . 26 1 1.0 HAZARD CHARACTERIZATION Poly( hexamethylenebiguanide) hydrochloride ( PHMB) is used as a swimming pool sanitizer and algicide. PHMB is the active ingredient in Vantocil Ib ® . PHMB is also used in several other types of applications, including as a preservative for cut flowers, materials preservative, and all purpose cleaner.

PHMB technical ( 20% aqueous solution) has low acute toxicity by the oral ( Category III) and dermal routes ( Category III IV). PHMB has severe to moderate acute eye irritation ( Category I II) and slight to moderate acute dermal irritation ( Category II & IV). It causes mild to moderate skin sensitization in guinea pigs.

The 21 day dermal study showed no systemic toxicity, but it did show severe dermal irritation in the acute assay. The 21 day dermal study did not test to the limit dose because a severe dermal irritation was found at a dose level of 300 mg/ kg in a preliminary study.

Dermal studies demonstrate that the target organ is the liver. Reduced body weight is the primary effect of concern in all animal studies.

No quantitative or qualitative susceptibility was shown in the prenatal studies or the reproductive study. The rat prenatal study showed increased incidence of extra ribs in the fetus but with no increased susceptibility. The rabbit prenatal study showed possible toxicity in the form of reduced numbers of litters and skeletal abnormalities, but no increased susceptibility. The reproductive study showed no adverse effects on reproduction.

Chronic toxicity studies showed multiple effects on the liver in both sexes of rats as well as body weight decrement. The dog study showed testes and liver changes in males and clinical signs of toxicity and clinical effects and alterations in clinical chemistry in 1 out of 4 females.

There were no neurotoxic effects seen in any subchronic or chronic toxicity studies. Due to the lack of neurotoxic affects no neurotoxicity tests were required.

The carcinogenicity studies showed an apparent increase in hemangiosarcomas in the liver of female rats, increased hemangiosarcomas in mice, and increased squamous cell carcinomas of the rectal anal junction in mice. The potential cancer causing effects are referred to the Cancer Assessment Review Committee ( CARC).

There is no evidence of a mutagenic response in a battery of mutagenicity studies, including a lack of clastogenic responses in peripheral human lymphocytes.

Rat metabolism studies showed that PHMB is metabolized in a similar fashion by male and female rats. PHMB was excreted mainly through feces. Pooled urine showed the presence of more than one metabolite. 2 2.0 TOXICOLOGY DATA REQUIREMENTS The toxicology data requirements for PHMB are shown in Table 1. Use of the new guideline numbers does not imply that the new ( 1998) guideline protocols were used.

Table 1. Toxicity Data Requirements for PHMB Test Technical Required Satisfied 870.1100 Acute Oral Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 870.1200 Acute Dermal Toxicity . . . . . . . . . . . . . . . . . . . . . . 870.1300 Acute Inhalation Toxicity . . . . . . . . . . . . . . . . . . . . 870.2400 Primary Eye Irritation . . . . . . . . . . . . . . . . . . . . . . . 870.2500 Primary Dermal Irritation . . . . . . . . . . . . . . . . . . . . 870.2600 Dermal Sensitization . . . . . . . . . . . . . . . . . . . . . . . . yes yes no yes yes yes yes yes  yes yes yes 870.3100 Oral Subchronic ( rodent) . . . . . . . . . . . . . . . . . . . . . 870.3150 Oral Subchronic ( nonrodent) . . . . . . . . . . . . . . . . . . 870.3200 21 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3250 90 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3465 90 Day Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes no yes yes yes yes*

870.3700a Developmental Toxicity ( rodent) . . . . . . . . . . . . . . . 870.3700b Developmental Toxicity ( nonrodent) . . . . . . . . . . . . 870.3800 Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes 870.4100a Chronic Toxicity ( rodent) . . . . . . . . . . . . . . . . . . . . 870.4100b Chronic Toxicity ( nonrodent) . . . . . . . . . . . . . . . . . 870.4200a Oncogenicity ( rat) . . . . . . . . . . . . . . . . . . . . . . . . . . 870.4200b Oncogenicity ( mouse) . . . . . . . . . . . . . . . . . . . . . . . 870.4300 Chronic/ Oncogenicity . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes no yes* yes yes* yes yes 870.5100 Mutagenicity  Gene Mutation  bacterial . . . . . . . . 870.5395/ Mutagenicity  Structural Chromosomal Aberrations 870.5345 870.5550 Mutagenicity  Other Genotoxic Effects . . . . . . . . . . yes yes yes yes yes yes 870.7485 General Metabolism . . . . . . . . . . . . . . . . . . . . . . . . yes yes * Satisfied by the 90 day oral study and the dermal absorption value, which will be used for dermal risk assessments * Satisfied by Chronic/ Oncogenicity test 3 3.0 DATA GAPS None 4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of database for acute toxicity: The database for acute toxicity is considered complete. No additional studies are required at this time.

The acute toxicity data on PHMB ( 20% a. i.; technical grade) is summarized below in Table 2. 4 Table 2. Acute Toxicity of PHMB Product A. I. / EPA Reg. No. Baquacil 20% PHMB / 72674 19 Baquacil Ultra 20% PHMB / 72674 22 A Breeze 96% PHMB / 72674 32 870.1100 Acute oral toxicity MRID Tox Category LD50 = 2747 mg/ kg 00030330 III LD50 = 1831mg/ kg ( M) LD50 = 1617mg/ kg ( F) 44940701 III LD50 = 1049mg/ kg ( F)

45916505 III 870.1200 Acute dermal toxicity MRID Tox Category LD50 > 2.0 ml/ kg 00065124 III LD50 > 2000mg/ kg 44940702 III LD50 > 5000mg/ kg 45916506 IV 870.1300 Acute inhalation toxicity MRID Tox Category waived LC50 = 1.76mg/ L 44970403 III waived 870.2400 Acute eye irritation MRIDs Tox Category moderate irritant 00046789; 00065120 II moderate irritant 44963902 II corrosive 45916508 I 870.2500 Acute dermal irritation MRIDs Tox Category moderate irritant 00046789; 00065120 II slight irritant 44949704 IV slight irritant 45916509 IV 870.2600 Skin sensitization MRID moderate sensitizer 42674201 Moderate Sensitization mild sensitizer 44940705 4.2 Subchronic Toxicity Adequacy of database for subchronic toxicity: The database for subchronic toxicity is considered complete. No additional studies are required at this time.

There were no systemic effects observed, however dermal irritation was caused by PHMB. 5 870.3100 90 Day Oral Toxicity  Rat Executive Summary: In a 90 day subchronic toxicity study ( MRID 00053460), young adult specific pathogen free ( S. P. F.) rats ( 25 M + 25 F) received 0, 2500, and 5000 ppm of PHMB in the diet for 90 days. Food consumption, general clinical observations, body weight, and hematological parameters were examined. At the end of the 90 day test period all animals were sacrificed with chloroform, and an immediate postmortem examination was made. Organ weights were recorded and organ/ body weight ratios calculated from a randomly selected five males and five females from each group. The following organs were included: liver, heart, lung, adrenals, kidneys, and spleen. Tissues from the remaining animals were fixed in Fenker's fluid, except brains and spinal cords, which were fixed in 10% formal saline and examined microscopically. The following were examined: liver, kidney, spleen, heart, lung, adrenals, gonads, thymus, thyroid, pancreas, stomach, duodenum, jejunum, ileum, cecum, colon, salivary gland, messenteric lymph nodes, spinal cord and brain ( cerebrum, cerebellum, and pons).

All animals survived the 90 day test period. There were no specific adverse effects of the compound. Food consumption was comparable for the test groups and controls. Body weight was moderately reduced in males ( 13.2% less than controls), and females ( 16.6% less than controls) fed the compounds at the highest dietary level ( 5000 ppm). No abnormalities in hematological parameters were observed. No gross abnormalities were observed. No remarkable change in organ/ body weight ratios was detected. Microscopic evaluation revealed that the liver of some females given the compound at a level of 5000 ppm showed an unusual degree of iron pigment both within the liver cells and kupffer cells. Although the report states that no iron pigments was seen in animals fed 2500 ppm test material in the diet, the study does not include detailed histopathological results of the 2500 ppm animals. Therefore, the NOAEL cannot be determined in this study.

870.3150 90 Day Oral Toxicity  Dog Executive Summary: In a 90 day subchronic toxicity study in the dog ( MRID 00053461), three groups of Beagle Dogs ( 4M + 4F per group), 12.4  14.6 kg initial BW, received dietary levels of 0, 5500, and 11000 ppm of PHMB ad libitum for 90 days. General observation, food consumption, body weight and the following clinical chemistry measurements were performed: hemoglobin, packed cell volume ( hematocrit), leucocyte count ( total and differential), blood urea, serum alkaline phosphatase, BSP ( liver function test) and urine analyses ( pH, specific gravity, glucose, protein, bilirubin, and microscopy of centrifuge deposit). At the end of the test period the animals were sacrificed with an overdose of pentobarbitone administered intravenously. A full post mortem examination was performed at the time of necropsy: heart, liver, kidneys, adrenals, spleen, thyroid, epididymis, brain and pituitary. Representative pieces of tissues for microscopic examination were taken from the following: brain ( cerebrum, cerebellum and pons), spinal cord, pituitary, submaxillory gland, thyroid, thymus, heart, lung, aorta, stomach, duodenum, jejunum, ileum, colon, liver, spleen, kidney, bladder, adrenal, ovary and uterus or testis and epididymides, and sciatic nerves. 6 Both treated and control animals maintained an excellent condition throughout and no adverse effects were noted. No food consumption data was submitted. Mean body weights were comparable between control and treated animals except for the 11,000 ppm female dogs which gained significantly less total weight than the female dogs. Results of the hematological parameters were unremarkable. The clinical function test showed no difference in retention of BSP attributable to test material. Urine analyses do not appear to be influenced by treatment. Organ/ body weight ratios showed no significant variation from the normal as a result of treatment. No gross pathology attributable to test material was detected. Microscopic examination revealed slight hemosiderons in 2 out of 4 males at 11,000 ppm. No other microscopic abnormalities attributable to treatment were present at either dose level.

The NOAEL for this 90 day dog feeding study appears to be 5500 ppm ( low dose). The high dose treatment caused a lower total weight gain in female dogs and slight hemosiderons in 2 out of 4 male dogs.

870.3200 21/ 28 Day Dermal Toxicity   Rat Executive Summary: In a 21 day dermal toxicity study ( MRID 43047701), PHMB was applied at dose levels of 0, 20, 60, and 200 mg/ kg to the shorn backs of 5 male and female Alpk: APfSD ( Wistar derived) rats over the course of 30 days for a total of 21 applications of 6 hours duration each.

There was no evidence of systemic toxicity at any dose level in this study. Dermal toxicity was evident at the 60 mg/ kg and 200 mg/ kg dose levels in the form of erythema, edema, scabbing, acanthosis, and inflammatory cell infiltration in both sexes. Based on the data in this study, the Systemic Toxicity NOAEL is greater than or equal to 200 mg/ kg/ day for both sexes, and the Systemic Toxicity LOAEL is greater than 200 mg/ kg/ day for both sexes. The Dermal Toxicity NOAEL is 20 mg/ kg/ day for both sexes, and the Dermal Toxicity LOAEL is 60 mg/ kg/ day for both sexes, based on the increased incidence of erythema, edema, and scabbing observed at this dose.

Although there was no evidence for systemic toxicity at any dose level tested in this study, higher dose levels were not tested due to the presence of severe dermal irritation at a dose level of 300 mg/ kg in a preliminary study. Therefore, this study is classified as core minimum data and satisfies the guideline requirement ( 870.3200 § 82 2) for a repeated dermal toxicity study in rats.

870.3250 90 Day Dermal This requirement is satisfied by the 80 week dermal carcinogenicity study in mice, which will be used for dermal risk assessments. 7 870.3465 90 Day Inhalation   Rat A 90 day inhalation toxicity study with PHMB was not available. The inhalation risk assessment was performed using the NOAEL value of 20 mg/ kg/ day from the developmental toxicity study in rabbits ( MRID 42865901).

4.3 Prenatal Developmental Toxicity Adequacy of database for prenatal developmental toxicity: The database for prenatal developmental toxicity is considered complete. No additional studies are required at this time.

There was no quantitative/ qualitative evidence of increased susceptibility of developmental effects following in utero exposure in the rat or rabbit. Maternal toxicity was reported at lower dose levels than the developmental toxicity in rats. In rabbits, developmental effects were observed at the same dose level as the maternal effects.

870.3700a Prenatal Developmental Toxicity Study  Rat Executive Summary: In the rat developmental toxicity study ( Report # CTL/ P/ 1262, 1976 cited in Report # 003810, 1978. Section C 11), groups of at least 20 pregnant Alderley Park female rats were fed diets containing 0, 200, 1000, or 2000 ppm ( 0, 17.2, 86.2, and 172.4 mg/ kg/ day) PHMB throughout gestation. On gestation day 20, animals were killed by cervical dislocation until at least 20 pregnancies in each group were established. Mean maternal body weight and food consumption were reduced significantly in animals receiving 86.2 or 172.4 mg/ kg PHMB ( 20% a. i.). Maternal microscopic findings revealed an enlarged and hemorrhagic thymus in one female that had received 100 mg/ kg/ day 20% PHMB. Based on the reduced body weight and reduced food consumption, the Maternal Toxicity LOAEL is 86.2 mg/ kg/ day. The Maternal Toxicity NOAEL is 17.2 mg/ kg/ day.

There was no increase in late resorptions in any group. The fetal weight and litter weight were not reduced in the PHMB treated groups. No adverse effects in ossification were seen in the fetuses from the PHMB treated animals. The fetus from the 100 mg/ kg/ day group showed a significant increase in extra ribs. Based on the increased incidence of ribs in the fetus, the Developmental Toxicity LOAEL is 172.4 mg/ kg/ day. The Developmental Toxicity NOAEL is 86.2 mg/ kg/ day.

870.3700b Prenatal Developmental Toxicity Study  Rabbit Executive Summary: In the rabbit developmental study ( MRID 42865901), administration of PHMB to 20 pregnant female New Zealand White rabbits per group at levels of 0, 10, 20, and 40 mg/ kg/ day on gestation days 8 through 20 resulted in maternal toxicity at 40 mg/ kg/ day in the form of increased mortality and clinical toxicity. Mortality occurred in 6 rabbits at this dose. One rabbit died probably as a result of mis dosing; one rabbit was killed in extremis on day 22 due to 8 inappetance and weight loss starting on day 11; and the remaining 4 rabbits were killed due to abortion of fetuses and thus a lack of data for analysis. There are 6 rabbits that died in the 40 mg/ kg/ day dose group; clinical signs included coldness ( 6/ 20 vs. 0/ 20 in control), few feces ( 16/ 20 vs. 7/ 20 in control), no feces ( 6/ 20 vs. 0/ 20 in control), thin appearance ( 6/ 20 vs. 0/ 20 in control) and subdued behavior ( 3/ 20 vs. 1/ 20 in control). Based on the increased mortality, reduced food consumption, and clinical toxicity, the Maternal Toxicity LOAEL is 40 mg/ kg/ day. The Maternal Toxicity NOAEL is 20 mg/ kg/ day.

There was evidence of possible developmental toxicity of PHMB at 40 mg/ kg/ day, in the form of reduced numbers of litters and skeletal abnormalities ( non ossified 5th sternebrae and fused 3rd, 4th, and 5th sternebrae). The incidence of non ossified 5th sternebrae was found in 12 ( 10.1%) of fetuses from the 40 mg/ kg/ day dose group vs. 6 ( 3.3%) in control, and a fused 4th and 5th sternebrae, found in 7 ( 5.9%) of fetuses and 6 ( 46.2%) of litters at the 40 mg/ kg/ day dose level, compared to 1 ( 0.6%) fetus and 1 ( 5.3%) litter in controls. The incidence of fetuses and litters with fused 3rd and 4th sterebrae at the 40 mg/ kg/ day dose is 5 ( 4.2%) of fetuses and 3 ( 23.1%) of litters vs. 1 fetus ( 0.6%) and 1 litter ( 5.3%) in controls. The developmental toxicity NOAEL is 20 mg/ kg/ day, based on reduced number of litters and skeletal abnormalities; the developmental toxicity LOAEL is 40 mg/ kg/ day. Developmental effects occurred at doses that also caused maternal toxicity. Therefore, the data indicate that developmental toxicity at the high dose was related to maternal toxicity ( 6 out of 20 animals died in the group, no quantitative/ qualitative evidence of increased susceptibility of developmental effects in this study). ( Note: dosing started at gestation day ( gd) 8 which is different from the guideline specifying that the study should start at gd 6)

4.4 Reproductive Toxicity Adequacy of database for reproductive toxicity: The database for reproductive toxicity is considered complete. No additional studies are required at this time.

There was no evidence of quantitative or qualitative susceptibility in the multi generation reproduction study.

870.3800 Reproduction and Fertility Effects  Rat Executive Summary: In a multi generation reproduction study ( MRID 43617401), male and female Alpk: APfSD rats ( 26 males/ dose; 26 females/ dose), obtained from the Barriered Animal Breeding Unit at Zeneca Pharmaceuticals, Alderley Park, UK, received PHMB ( 20.2% a. i.) in the diet at nominal doses of 0, 200, 600, and 2000 ppm ( 23.0, 69.6, and 238.9 mg/ kg/ day for F0 males; 25.3, 77.0 and 258.2 mg/ kg/ day for F0 females; 23.9, 71.3, and 249.3 mg/ kg/ day for F1 males; and 26.1, 79.2, 270.5 mg/ kg/ day for F0 [ note: we believe this to be a typo and should be the data for F1] females). The rats in each generation received test diets continuously until termination. Systemic toxicity was observed at the 2000 ppm dose level in the F0 generation as indicated by a decrease in group body weight ( 9 10%) and food efficiency ( 7%) for the 10 week pre mating period. The weight of the epididymides and kidneys were also significantly decreased in F0 generation males. There were no corresponding effects in the F1 parental generation except 9 for decreased food efficiency ( 15%) in females for weeks 5 7 pre mating. There were no detrimental effects of treatment with PHMB on reproduction in this study, but it is noted that there was a dose related decrease in number of pup deaths on days 1 5 post partum for both generations.

The Parental Systemic Toxicity NOAEL is 600 ppm ( 69.6 mg/ kg/ day [ F0 males]; 77.0 mg/ kg/ day [ F0 females]; 71.3 mg/ kg/ day [ F1 males]; 79.2 mg/ kg/ day [ F1 females]); The Parental Systemic Toxicity LOAEL is 2000 ppm ( 238.9 mg/ kg/ day [ F0 males]; 258.2 mg/ kg/ day [ F0 females]; 249.3 mg/ kg/ day [ F1 males]; 270.5 [ F1 females]) based on decreased body weight and food efficiency in F0 males and females, and decreased epididymis and kidney weight in F0 males.

Reproductive/ Systemic Toxicity NOAEL is 2000 ppm; Reproductive/ Systemic Toxicity LOAEL is greater than 2000 ppm.

This study is classified as acceptable and satisfies the guideline requirement ( OPPTS 870.3800; § 83 4) for a 2 generation reproduction study in rats.

4.5 Chronic Toxicity Adequacy of database for chronic toxicity: The database for chronic toxicity is considered complete. No additional studies are required at this time.

There were multiple effects on the liver of both sexes in the rat study. Body weight decrement was also noted in the rat study. The dog study showed a change in the testes and liver of male dogs and clinical signs of toxicity and clinical chemistry alterations in a female dog.

870.4100a ( 870.4300) Chronic Toxicity/ Carcinogenicity Study   Rat Executive Summary: In a rat chronic/ oncogenicity study ( MRID 44059301) male and female Alpk: APfSD Wistar rats ( 64/ sex/ dose) were fed diets containing PHMB at 0, 200, 600, or 2000 ppm ( equivalent to 0, 12.1, 36.3, and 126.1 mg/ kg/ day in males and 14.9, 45.3, and 162.3 mg/ kg/ day in females) for 2 years. An interim sacrifice of 12 rats/ sex/ dose was conducted at 52 weeks.

At the high dose ( 2000 ppm), survival was decreased in females by 25% vs. controls. Body weights were significantly ( p< 0.01 or 0.05) reduced by 5 8% in high dose females throughout the study. In high dose males, body weights were significantly ( p< 0.01 or 0.05) reduced vs. controls through week 79. Food utilization ( g growth/ 100 g feed) for the first 12 weeks decreased significantly ( p< 0.01) vs. controls, 97 8% in both sexes at 2000 ppm.

The liver was the target organ in males and females. Plasma alkaline phosphatase activity was elevated significantly ( p< 0.01) over controls 843 74% in females from the main study dosed at 2000 ppm; in 2000 ppm males, the enzyme was significantly increased by 36 and 27% at weeks 14 and 27. In females at 2000 ppm absolute liver weight was reduced significantly ( p< 0.05) by 10 11%. In 2000 ppm males, microscopic observations of liver hepatocyte fat and spongiosis were 844 and 22% over controls; corresponding increase in these lesions were not seen in females. There were no corroborating gross pathology findings of the liver abnormalities.

For chronic toxicity, the LOAEL for PHMB is 2000 ppm ( 126.1 and 162.3 mg/ kg/ day for males and females respectively) and the NOAEL is 600 ppm ( 36.3 and 45.3 mg/ kg/ day).

Under the conditions of this study, PHMB appears to have the potential to induce vascular neoplasms in female rats of this strain. The study pathologist and study peer reviewer observed hemangiosarcomas of the liver in 3/ 64 2000 ppm females; benign hemangioma was not observed. The increased incidence of hemangiosarcoma in females gave positive results in trend analyses ( p< 0.05). A single observation of benign hemangioma was made in each of the control and high dose male groups; no hemangiosarcoma was observed in males. A Pathology Working Group ( PWG) was convened to confirm the diagnoses of the vascular neoplasms ( MRID 44042801). The PWG observed hemangioma ( 2/ 64) and hemangiosarcoma ( 1/ 64) in 2000 ppm females and 2/ 64 hemangiomas in 2000 ppm males. The PWG concluded that the findings of vascular neoplasms in high dose females were incidental. However, the report of the PWG consensus indicated that no hemangiosarcoma or hemangioma had been observed in female controls in 18 studies with the same strain of rat. Furthermore, there was a significant increase ( p< 0.01 or 0.05) in hemangiosarcomas in both sexes in a mouse oncogenicity study with PHMB. Therefore it is concluded that PHMB appears to induce hemangiosarcomas of the liver in female Alpk: APfSD rats. Liver hemangiosarcomas are rare in this strain of rat.

This study is classified as acceptable ( guideline 870.4300 § 83 5) and satisfies the guideline requirements for a chronic/ oncogenicity study in rats.

870.4100b Chronic Toxicity  Dog Executive Summary: In a chronic toxicity study ( MRID 43620501), PHMB was administered to groups of 4 male and female Beagle dogs in the diet initially at dose levels of 0, 300, 1500, and 4500 ppm. Following an unexpectedly severe reaction in 3 of 4 males at 4500 ppm ( scrotal skin lesions), 3 of 4 males were killed for humane reasons. The high dose was discontinued on week 9 or 10, and then recommenced at a dose of 3000 ppm on week 11 or 12. Doses received in the study were 0, 9, 46, and 91 mg/ kg/ day for males and 9, 45, and 91 mg/ kg/ day for females for the 3000, 150 and 3000 ppm dose groups, respectively. Up to and including the 3000 ppm dose, there were no consistent effects of PHMB on body weight, weight gain, food consumption, or hematological parameters. Plasma alanine aminotransferase ( ALT) activity was significantly increased in male and female dogs at the 3000 ppm dose level beginning at week 8, but there was variability in the response, and only one male dog was available for measurement after week 10. Testes weight was decreased 29% and 32% for the left and right testis of high dose male dogs, and testicular tubular degeneration was observed in the surviving male dog as well as in one dog sacrificed intercurrently. Liver weight in high dose male dog was decreased 14% at the high dose, and microscopic changes of the liver were also observed in male dogs at the high dose. In one female dog at the high dose, significant clinical signs ( decreased activity, stiff/ splayed gait, slight 11 tremors) were observed which were not reversible. In addition, plasma alanine aminotransferase was increased almost 10 fold over the pre treatment level by week 35 of treatment. Plasma aspartate aminotransferase in this dog was almost doubled by week 35 of treatment. Marked dermatitis of the limbs was also observed in this dog. The Systemic Toxicity LOAEL is 3000 ppm ( 91 mg/ kg/ day) for male and female dogs, based on changes in testis and liver weight and microscopic observations in male dogs and based on clinical signs of toxicity and clinical chemistry alterations in the female dog. The Systemic Toxicity NOAEL is 1500 ppm ( 46/ 45 mg/ kg/ day, male/ female) for male and female dogs.

This study is acceptable and satisfies the guideline requirement [ OPPTS 870.4100; OPP § 83 1] for chronic oral toxicity in dogs.

4.6 Carcinogenicity Adequacy of database for carcinogenicity: The database for carcinogenicity is considered complete. No additional studies are required at this time.

The combined chronic/ carcinogenicity study in rats showed an apparent increase in hemangiosarcomas in the liver of female rats. The mouse study showed increased hemangiosarcomas and squamous cell carcinomas of the rectal anal junction in both sexes.

870.4200a Carcinogenicity Study  Rat See above Chronic toxicity/ Oncogenicity study rat ( MRID 44059301)

870.4200b Carcinogenicity ( feeding)  Mouse Executive Summary: In a mouse oncogenicity study ( MRID 44074201), PHMB was administered to C57B1/ 10J f CD 1/ Alpk mice ( 55/ sex/ group) at 0, 400, 1,200, or 4,000 ppm ( equivalent to 55, 167, or 715 mg/ kg/ day for males and 69, 217, or 856 mg/ kg/ day for females) for 2 years.

At the 1,200 ppm level, mice were observed with decreased overall body weight gains ( males, 97%; females 92%); increases in hematology parameters ( p< 0.05) including hemoglobin in females ( 86%), hematocrit in females ( 86%), and RBCs in females ( 85%); decreased absolute weight of the liver in males ( 915%) and in females ( 921%); increased incidences of gross pathological changes including distended caeca in females ( 4% treated vs. 0% in controls); traumatized pinnae of ears in males ( 36% treated vs. 4% controls) and females ( 44% treated vs. 4% controls); and increased incidences of non neoplastic lesions including luminal dilatation of the gall bladder in females ( 9% treated vs. 2% controls), hepatocyte hypertrophy of the liver in males ( 13% treated vs. 0% controls) and females ( 35% treated vs. 0% controls), ploidy of the liver in males ( 13% treated vs. 0% controls) and females ( 36% treated vs. 0% controls), pigmentation of the liver in females ( 11% treated vs. 0% controls), and inflammation of the rectalanal junction in males ( 44% treated vs. 2% controls) and females ( 47% treated vs. 21% controls).

At the 4,000 ppm dose level, decreased overall body weight gain was observed in males 12 ( 950%) and females ( 932%); increased food consumption ( p< 0.05 or 0.01) from approximately week 12 through termination in males ( 87 29%) and females ( 87 26%); decreased food utilization ( p< 0.01) during weeks 1 12 in males ( 940%) and females ( 920%); increased hemoglobin in males ( 87%) and females ( 817%), hematocrit in males ( 85%) and females ( 816%), and RBCs in males ( 810%) and females ( 817%); decreased weight of the liver in males ( 20%) and females ( 30%); decreased weight of the testes of males ( 915%) and in adrenals of females ( 922%); increased incidences of gross pathological changes including swollen anuses in males ( 18% treated vs. 0% controls) and females ( 7% treated vs. 0% controls), distended caeca in males ( 9% treated vs. 0% controls) and females ( 13% treated vs. 0% controls), pinnae of ears traumatized in males ( 27% treated vs. 4% controls) and females ( 22% treated vs. 4% controls), distention of the gall bladder in males ( 49% treated vs. 11% controls) and females ( 47% treated vs. 9% controls); liver mass in males ( 48% treated vs. 20% controls) and females ( 39% treated vs. 2% controls); epithelial hyperplasia of the gall bladder in males ( 25% treated vs. 0% controls) and females ( 13% treated vs. 0% controls); hepatocyte hypertrophy of the liver in males ( 53% treated vs. 0% controls) and females ( 49% treated vs. 0% controls); increased ploidy of the liver in males ( 53% treated vs. 0% controls) and females ( 38% treated vs. 0% controls); pigmentation of the liver in males ( 36% treated vs. 0% controls) and females ( 42% treated vs. 0% controls); and inflammation of the rectal anal junction in males ( 82% treated vs. 2% controls) and females ( 74% treated vs. 21% controls).

Toxicity observed common to both sexes of the 1,200 and 4,000 ppm treatment groups included decreased overall weight gains, pinnae of ears traumatized, hepatocyte hypertrophy of the liver, increased ploidy of the liver, and inflammation of the rectal anal junction. There was also epithelial hyperplasia of the gall bladder common to females of both treatment groups but occurring in males only at 4,000 ppm.

No treatment related effects were seen in mice in the 400 ppm dose group.

Based on decreased body weight gains and non neoplastic histopathological changes in the gall bladder, liver, and rectal anal junction of mice in the 1,200 ppm and 4,000 ppm treatment groups, the Systemic Toxicity LOAEL in male and female mice is 1,200 ppm ( equivalent to 55 mg/ kg/ day in males and 69 mg/ kg/ day in females). The Systemic Toxicity NOAEL is 400 ppm.

Carcinogenic potential was evidenced by increased incidence of hemangiosarcomas and hemangiomas in both sexes of mice in the 4,000 ppm treatment group. In males at this treatment level a statistically significant ( p < 0.01) increase was observed in combined incidence of hemangiosarcoma and hemangioma combined ( 20/ 53 animals [ 38%]) vs. 6/ 55 in control ( 11%). In females, a significant increase ( p < 0.05) in combined incidence of hemangioma and hemangiosarcoma was also observed at this dose ( 15/ 49 vs. 8/ 54 in control). Historical control incidence of angiosarcoma in all tissues within this strain of mouse ranged from 2 15% in males and 0 9% in females. Concurrent control incidences of hemangiosarcomas were within the historical control range. The earliest hemangiosarcomas occurred at 39 and 42 weeks in males and females, respectively. Hemangiosarcoma of the liver was a statistically significant factor contributing to the death of male and female mice at 4,000 ppm PHMB. Treatment related 13 squamous cell carcinomas of the rectal anal junction were found in 5/ 49 ( 10%) males and 8/ 39 ( 21%) females of the 4,000 ppm treatment group. Two males in the 4,000 treatment group had papillomas in the gall bladder, with none in controls or at other treatment levels. No treatmentrelated carcinogenic effects were observed at 400 or 1,200 ppm. Based on the study results, carcinogenic effects ( vascular system and anus) were observed for male and female mice at dietary levels of 4,000 ppm PHMB ( equivalent to 715 mg/ kg/ day in males and 856 mg/ kg/ day in females).

Dosing was considered to be excessive at the high dose of 4000 ppm based on decreased overall body weight gains of 50% in males and 32% in females at termination. In addition, decreased body weight gains of 33% in males and 19% in females at 13 weeks. The study indicated that the animals at the 4000 ppm dose group had increased food consumption ( p< 0.05 or 0.01) from approximately week 12 through termination in males ( 87 29%) and females ( 87 26%).

Dosing was considered to be adequate, but not excessive, in both males and females at the mid dose of 1200 ppm based on decreased overall body weight gains ( males, 7%; females, 2%), and increases in hematology parameters, and non neoplastic histopathological changes in the gall bladder, liver, and rectal anal junction.

This study is classified as acceptable and satisfies the guideline requirements for a carcinogenicity study [ OPPTS 870.4200 ( § 83 2b)] in the mouse.

870.4200b Carcinogenicity ( dermal)  Mouse Executive Summary: In an 80 week skin painting study ( MRIDs 00066475, 00104796), four groups of specific pathogen free ( 50/ dose/ sex) Alderley Park mice received dermal applications of 0.3 mL of the test material at doses of 0 ( solvent in ethanol), 0.6 mg ( 0.2% PHMB in ethanol), 6.0 mg ( 2% PHMB in ethanol) and 30.0 mg ( 10% PHMB in ethanol) per day, five days a week for a period of 80 weeks. The treatment dosages are equivalent to 0, 15, 150, and 750 mg/ kg day of 20% PHMB solutions.

Mice that received the highest dose level of PHMB ( 750 mg/ kg day) showed a poorer health status, appearing very thin throughout the experiment. Mortality in both male and female mice in the highest dose group was slightly higher than in other groups during the first year. This pattern continued throughout the remainder of the study resulting in a high mortality rate ( 75% in males and females) in the highest dose animals at termination, compared with approximately 30% in the other groups. The highest dose level of PHMB resulted in noticeable irritation to the skin of both males and females immediately after application. Erythema and some clumping of the growing fur were noticed during the first few weeks and after the 4th week, hyperkeratosis became evident especially in males. No differences were apparent between the controls and those mice receiving 0.6 or 6.0 mg PHMB per mouse per application. A significant reduction in mean body weight was observed for both male and female animals that received the highest dose level. There were no overall differences in food consumption between the control and treatment groups. 14 Therefore, the systemic toxicity NOAEL was 150 mg/ kg day and the LOAEL was 750 mg/ kg day based on increased mortality and decreased body weight in male and female mice receiving PHMB ( 20% a. i.).

There were no compound related tumors observed in male mice. Female mice had significant increasing trends in liver angiosarcomas ( p< 0.01) and vascular tumors from all sites combined ( p< 0.05). There was a significant difference in the pair wise comparison of the 30 mg dose group with the controls for liver angiosarcomas at p< 0.05. The statistical analyses of the female mice were based on Peto's prevalence test.

The HED Cancer Assessment Review Committee considered the tumor increase at the high dose to be equivocal since tumors were observed at an excessive dose. Vascular tumors were not seen at lower doses. Dosing was considered to be excessive at the high dose ( 750 mg/ kg/ day of 20% PHMB equivalent) in both sexes due to increased mortality ( 78%, high dose, versus 33% and 28% in the male and female controls, respectively) and decreased body weight gain. Overall body weight gain decreases of 45% and 17% were seen in males and females, respectively. No treatment related effects were noted at the mid dose level of 150 mg/ kg/ day of 20% PHMB equivalent.

This carcinogenicity study is classified as acceptable non guideline. Although this nonguideline ( dermal painting) study does not fulfill any toxicity guideline requirement, it does provide useful information for assessing the carcinogenic potential of PHMB and should be evaluated in conjunction with the 1996 and 2002 guideline PHMB carcinogenicity studies ( MRID 44059301, 44042801, 44074201, and 45710802).

4.7 Mutagenicity Adequacy of database for mutagenicity: The following assays used PHMB at 19.6% ( a. i.). The database for mutagenicity is considered adequate based on 1991 mutagenicity guidelines ( note: assays were conducted before 1991, but appear to meet 1991 guidelines).

There is no evidence that Vantocil IB induced any genotoxicity.

Gene Mutation Guideline OPPTS 870.5100 [ § 84 2], Microbial gene mutation assy MRID 41687004 This study is classified as acceptable and satisfies the guideline requirement for a microbial gene mutation assay ( § 84 2). In two independently performed assays, Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, and TA100 were exposed to 0.32 500 µ g/ plate Vantocil IB ( 19.6% a. i.) in the absence or presence of S9 activation. Additional testing was carried out using comparable doses with and without S9 in TA1537 and TA98. The S9 fraction was derived from Aroclor 1254 induced rat livers and the test material was delivered to the nonactivated and S9 activated positive controls. There was, however, no evidence that Vantocil IB induced a mutagenic response in any strain at any nonactivated or S9 activated dose. 15 Cytogenetics Guideline OPPTS 870.5395 [ § 84 2], Mouse micronucleus assay MRID # 41096901/ 41404503 Study is classified as acceptable and satisfies the requirements for FIFRA Test Guideline 84 2 for a micronucleus assay.

Guideline OPPTS 870.5375 [ § 84 2], In vitro cytogenetic assay with human lymphocytes MRID # 41404501/ 42149905 This study is classified as acceptable and satisfies the guideline requirement for an in vitro cytogenetic study. In a mouse micronucleus assay ( MRID # 41096901/ 41404503), groups of five male and five female C57BL/ 6JfCD 1/ Alpk mice received single oral gavage administrations of 250 or 400 mg/ kg Vantocil IB ( 19.6% a. i.) prepared in deionized water. Mice in the high dose group were sacrificed at 24, 48, and 72 hours post administration and harvested bone marrow cells were examined for the incidence of micronucleated polychromatic erythrocytes ( MPEs). Low dose animals were sacrificed at 24 hours. Two animals receiving 400 mg/ kg died prior to the scheduled sacrifice. There was also clear evidence of target cell cytotoxicity in the high dose males and females at all sacrifice intervals. The positive control induced the expected high yield of MPEs in males and females. Vantocil IB did not, however, induce a clastogenic or aneugenic effect in either sex at any dose or sacrifice time.

In an in vitro mammalian cell cytogenetic assay ( MRID # 41404501/ 42149905), human lymphocytes derived from male and female donors were exposed to Vantocil IB ( 19.6% a. i. in water) doses of 5, 25, or 50 µ g/ mL without S9 activation ( both donors) and levels of 25, 100, or 187.5 µ g/ mL ( male donor) or 25, 100, 250 µ g/ mL ( female donor) with S9 activation for approximately 2.5 3.5 hours. The S9 liver homogenate was derived from Aroclor 1254 induced Sprague Dawley rat livers, and the test material was delivered to the test system in physiological saline. A 50% reduction in the mitotic index occurred at 50 µ g/ mL  S9 ( both donors) and at 100 µ g/ mL + S9 ( male donors) or at 250 µ g/ mL ( female donors). The positive controls induced the expected high yield of chromosome aberrations in the lymphocytes derived from the male and female donors. There was, however, no evidence that Vantocil IB induced a clastogenic effect.

Other Mechanisms of Genotoxicity Guideline OPPTS 870.5550 [ § 84 2], In vivo/ In vitro unscheduled DNA synthesis assay in primary rat hepatocytes MRID # 41404502/ 42149903 This study is classified as acceptable and satisfies the guideline requirement for a UDS assay ( § 84 4). In two independently performed in vivo/ in vitro unscheduled DNA synthesis ( UDS) assays ( MRID # 41404502/ 42149903), groups of two to three male rats were administered single oral gavage doses of 750 or 1500 mg/ kg Vantocil IB ( 19.6%) prepared in deionized water. Animals were sacrificed at 4 and 12 hours post treatment and recovered hepatocytes were scored for UDS. Clinical toxicity ( i. e., excessive salivation and subdued nature) was observed at 1500 mg/ kg; higher levels were lethal. No cytotoxicity for the target organ was seen at either level. The positive control induced the expected high yield of hepatocytes with net nuclear grains. There was, however, no evidence that the Vantocil IB induced a genotoxic response at either dose or sacrifice time.

4.8 Neurotoxicity Adequacy of database for neurotoxicity: No indication of neurotoxicity, neuropathology, or histopathology of the nervous system has been reported in the available studies. No neurotoxicity data are required. 16 870.6100 Delayed Neurotoxicity Study  Hen Not required since PHMB is not an organophosphate.

870.6300 Developmental Neurotoxicity Study This study is not required because there is no evidence PHMB will induce neurotoxic effects. In addition, there is no quantitative or qualitative evidence of increased susceptibility of the fetus following in utero exposure in the prenatal developmental toxicity studies or in the offspring when exposed to adults in the two generation reproduction study. Therefore, PHMB will not cause an FQPA concern.

4.9 Metabolism Adequacy of database for metabolism: The database for metabolism is considered to be complete. No additional studies are required at this time.

870.7485 Metabolism  Rat Executive Summary: Bioavailability of PHMB was investigated in male and female Sprague Dawley rats fed diets of 200 ppm or 2000 ppm ( 10 and 100 mg/ kg nominal dose) for fourteen days followed by a single radiolabelled dose of either 0.08 mg/ kg ( MRID 43567001 and 43599901), or after a single 100 mg/ kg dose ( MRID 00077926 and 00086363). In both studies, feces represented the major route of excretion at all dose levels, comprising greater than 90% of the administered dose. A similar excretion in feces was observed in bile cannulated rats after a single radiolabelled dose of 20 mg/ kg ( MRID 43567001). Thus, fecal excretion of PHMBderived radioactivity represents unabsorbed test material. The excretion pattern of low, mid, and high molecular weight fractions of PHMB was similar. Bioavailability was 4.7% and 3.9% for males and females, respectively, at the 10 mg/ kg dose, and 3.9% and 2.6% for males and females, respectively, at the 100 mg/ kg dose. Tissue distribution in rats given 10 mg/ kg PHMB showed concentrations in the liver and kidney of male rats to be 0.568 µ g/ g and 0.499 µ g/ g, respectively. As a percentage of the dose, liver of male and female rats contained 0.18% and 0.19% of the dose, respectively, while kidneys contained 0.03% and 0.04% of the dose, respectively. Metabolite analysis of pooled urine from rats administered a low molecular weight fraction of PHMB at 20 mg/ kg ( the fraction showing the greatest absorption) revealed the presence of more than one metabolite but identification was not performed due to the small amount sample available for analysis.

The studies when taken together are acceptable, and satisfy the § 85 1 guideline [ OPPTS 870.7485] requirement. 17 5.0 TOXICITY ENDPOINT SELECTION 5.1 See Section 8.2 for Endpoint Selection Table.

5.2 Dermal Absorption A value for dermal absorption was not needed for PHMB based on the selection of dermal endpoints from a route specific ( dermal) toxicity study.

5.3 Classification of Carcinogenic Potential 5.3.1 In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment ( July 1999), the CARC classified PHMB into the category " Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential" by the oral and dermal routes. The weight of the evidence considerations for this classification are as follows:

( i) A treatment related statistically significant increase ( trend and pair wise) in vascular tumors ( mainly benign) was seen in female rats at an oral dose that was considered to be adequate, but not excessive. This was considered as the strongest evidence in the CARC's evaluation of PHMB.

( ii) Oral exposure to male and female mice also resulted in treatment related vascular tumors seen at an excessive dose. However, at the next highest dose level, which was considered adequate but not excessive, there was a slight, but not statistically significant, increase in this same tumor, which added to the CARC's concern for this tumor type.

( iii) It is noted that dermal exposure to female mice resulted in an equivocal increase in vascular tumors seen at only an excessive dose.

( iv) No treatment related increase in any tumors was seen in male rats via the oral route or in male mice via the dermal route of exposure.

Based on the above, the Agency has determined that the quantification of human cancer risk is not required.

6.0 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children There is no qualitative or quantitative evidence of increased susceptibility of rabbit, mice or rat fetuses in utero exposure in developmental studies.

There is no qualitative or quantitative evidence of increased susceptibility in multigeneration reproduction study in rats. 18 6.2 Recommendation for a Developmental Neurotoxicity Study PHMB does not raise an FQPA concern, because there is no evidence PHMB will induce neurotoxic effects. There is no quantitative or qualitative evidence of increased susceptibility to fetus following in utero exposure in the prenatal developmental toxicity studies or in the offspring when adults are exposed in the two generation reproductive study. 19 7.0 REFERENCES ( in MRID order)

MRID 00030330 Central Toxicology Laboratory. Report No. CTL/ T/ 1361. January 1, 1979. acute oral MRID 00046789/ 00065120 Imperial Chemical Industries. Report No. TR/ 558. October 26, 1966. acute eye and dermal irritant MRID 00053460 Griffiths, D., M. J. Hayes, and T. F. McElligott ( 1966). Ninety Day Oral Toxicity of Antibacterial 9073  Albino Rats. Industrial Hygiene Research Labs. Report No. IHR/ 199. August 1, 1966. Unpublished MRID 00053461 Griffiths, D., M. J. Hayes, and T. F. McElligott ( 1966). Ninety Day Oral Toxicity of Antibacterial 9073  Beagle Dogs. Industrial Hygiene Research Labs. Report No. IHR/ 202. September 1, 1966. Unpublished.

MRID 00065124 Trueman, R. W. and D. Eaton ( 1977). Baquacil SB: Acute Dermal Toxicity and Skin Irritation Effects. Central Toxicology Laboratory. Imperial Chemical Industries Ltd., England. Report No. CTL/ T/ 1057. October 6, 1977. Unpublished.

MRID00065131 Hodge, M. C. E. and S. Palmer ( 1976). Baquacil SB: A tertology Study in the Rat by Dietary Administration. ICI Central Toxicology Laboratory. Report No. CTL/ P/ 262. July 1, 1976. Unpublished MRID 00066475/ 00104796 Ishmael, J. and T. M. Weight. Polyhexamethylene Biguanide ( PHMB) 80 Week Mouse Skin Painting Study: Incidence of Tumors in the Liver. Imperial Chemical Industries Limited, Central Toxicology Laboratory.

MRID 00077926 Bratt, H. ( 1977). Vantocil IB: Absorption and Excretion Studies in the Rat. ICI Americas, Inc. Wilmington, DE. Report No. CTL/ P/ 163B. Unpublished.

MRID 00086362 Trutter, J. A. and D. R. Patterson ( 1977). 26 week Toxicity study in Dogs: 20% PHMB. Final report. Hazelton Laboratories America Inc. Report No. 458 123. June 30, 1977. Unpublished MRID 00086363 Bratt, H. ( 1975). Vantocil IB: Absorption and Excretion Studies in the Rat. ICI Americas, Inc. Wilmington, DE. Report No. CTL/ P/ 163B. March 10, 1975. Unpublished. 20 MRID 41096901/ 41404503 Randall, V. and S. L. Beck ( 1989). " Vantocil" IB: An Evaluation in the Mouse Micronucleus Test ( Original Report) MRID # 41096901; " Vantocil" IB: An Evaluation in the Mouse Micronucleus Test ( Addendum) MRID # 41404503. ICI Central Toxicology Laboratory. Alderely Park, Nr. Macclesfield, Cheshire, UK. Study No. CTL/ P/ 2436. April 14, 1989. Unpublished.

MRID 41404501/ 42149905 Howard, C. A. ( 1989). Vantocil IB: An Evaluation in the In vivo Cytogenetic Assay in Human Lymphocytes. ICI Central Toxicology Laboratory. Alderely Park, Nr. Macclesfield, Cheshire, UK. Report No. CTL/ P/ 2582. July 26, 1989. Unpublished.

MRID 41404502/ 42149903 Trueman, R. W. ( 1989). Vantocil IB: An Assessment for the Induction of Unscheduled DNA Synthesis in Rat Hepatocytes In vivo; ICI Central Toxicology Laboratory. Alderely Park, Macclesfield, Cheshire, UK. Study No. CTL/ P/ 2603. August 29, 1989. Unpublished.

MRID 41687004 Callander, R. D. ( 1989). Vantocil IB: An Evaluation in the Salmonella Mutation Assay. ICI Central Toxicology Laboratory. Alderely Park, Macclesfield, Cheshire, UK. Report No. CTL/ P/ 2406. June 7, 1989. Unpublished.

MRID 42674201 Duerden, L. ( 1993). Polyhexamethlyene Biguanide: Skin Sensitization to the Guinea Pig of a 20% Aqueous Solution. Zeneca Inc. Wilmington, DE. Study Nos. GG5741/ GG5694. February 10, 1993.

MRID 42865901 Brammer, A. ( 1993). Polyhexamethylene Biguanide: Developmental Toxicity Study in the Rabbit. Zeneca Central Toxicology Lab. Lab Project No. CTL/ P/ 3997. Study No. RB0614. July 14, 1993. Unpublished MRID 430477 01 Lees, D. and A. M. Leah ( 1993). PHMB: 21 Day Dermal Toxicity Study in the Rat. Study performed by Zeneca Central Toxicology Laboratory. Alderley Park, Macclesfield, Cheshire, UK. Study number LR0559. Completed on November 25, 1993.

MRID 43567001 Lythgoe, R. E, E. F. Howard, and E. Prescott ( 1995). PHMB: Absorption, Distribution, Metabolism, and Excretion Following Single Oral Dosing. Zeneca Central Toxicology Laboratory. Alderley Park, Macclesfield, Cheshire, UK. Lab Project No. URO 360. February 22, 1995. Unpublished.

MRID 43599901 Lythgoe, R. E and E. F. Howard ( 1995). PHMB: Bioavailability Following 21 Dietary Administration in the Rat. Zeneca Central Toxicology Laboratory. Alderley Park, Macclesfield, Chesire, UK. Lab Project No. URO 468. March 22, 1995. Unpublished.

MRID 43617401 Milburn, G. M. ( 1995). Polyhexamethylene Biguanide: Multi generation Study in the Rat. Study performed by Zeneca Central Toxicology Laboratory. Alderley Park, Macclesfield, Cheshire, UK. Study Nos. RR0621/ F0; RR0621/ F1. Study completed on March 8, 1995. Unpublished.

MRID 43620501 Horner, S. A. ( 1995). Polyhexamethylene Biguanide: 1 Year Dietary Toxicity Study in Dogs. Study performed by Zeneca Central Toxicology Laboratory. Alderley Park, Macclesfield, Cheshire, UK. Report number CTL/ P/ 4488; Study number PD0947.

MRID 44042801 Busey, W. M. ( 1996) Polyhexamethylene Biguanide ( PHMB): Two Year Feeding Study in Rats. Pathology Working Group Peer Review of Proliferative Vascular Lesions in Male and Female rats. Zeneca CTL, Alderley Park, Macclesfield, Cheshire, UK. Study No. PR0936, Report No. CTL/ C/ 3172. May 13, 1996. Unpublished.

MRID 44059301 Horner, S. A. ( 1996). Polyhexamethylene Biguanide: Two Year Feeding Study in rats. Study performed by Zeneca Central Toxicology Laboratory. Alderley Park, Macclesfield, Cheshire, UK. Laboratory Report No. CTL/ P/ 4663, Study No. PR0936. June 5, 1996. Unpublished.

MRID 44074201 Milburn, G. M. ( 1996). Polyhexamethylene Biguanide: Two Year Oncogenicity Study in Mice. Zeneca Central Toxicology Laboratory. Alderley Park, Macclesfield, Cheshire, UK. SK10 4TJ. Laboratory Study No. PM0937. June 21, 1996. Unpublished. 22 8.0 APPENDICES Tables for Use in Risk Assessment 23 8.1 Toxicity Profile Summary Tables 8.1.1 Acute Toxicity Table  See Section 4.1 8.1.2 Subchronic, Chronic, and Other Toxicity Tables Guideline No./ Study Type MRID No. ( year)/ Classification/ Doses Results 870.3100 90 Day oral toxicity rodents 00053460 ( 1966) Supplementary 0, 2500, 5000 ppm NOAEL and LOAEL were not established due to inadequate data.

870.3150 90 Day oral toxicity in nonrodents 00053461 ( 1966) Minimum 0, 5500, 11000 ppm NOAL = 5500 ppm LOAEL = 11,000 ppm based on slight hemosiderosis in males, decrease total body weight gain in females.

870.3200 21/ 28 Day dermal toxicity 430477 01 ( 1993) Core minimum/ guideline 0, 20, 60, and 200 mg/ kg/ d NOAL = 20 mg/ kg/ day LOAEL = 60 mg/ kg/ day based on the increased incidence erythema, edema, and scabbing.

870.3250 90 Day dermal toxicity This study is satisfied by the 80 week dermal carcinogenicity study in mice, which will be used for dermal non cancer risk assessment 870.3465 90 Day inhalation toxicity No appropriate route specific study was available. An older study conducted with Vantocil B contained many deficiencies.

870.3700a Prenatal developmental in rodents 00065131 ( 1979) minimum/ guideline 0, 200. 1000, 2000 ppm 0, 17.2, 86.2, 172.4 mg/ kg/ d Maternal NOAEL = 17.2 mg/ kg/ day LOAEL = 86.2 mg/ kg/ day based on reduced body weight and reduced food consumption. Developmental NOAEL = 86.2 mg/ kg/ day LOAEL = 172.4 mg/ kg/ day based on increased incidence of extra ribs in the fetuses.

870.3700b Prenatal developmental in nonrodents 42865901 ( 1993) minimum 0, 10, 20, 40 mg/ kg/ day Maternal NOAEL = 20 mg/ kg/ day LOAEL = 40 mg/ kg/ day based on increased mortality, reduced food consumption, and clinical toxicity. Developmental NOAEL = 20 mg/ kg/ day LOAEL = 40 mg/ kg/ day based on reduced number of litters and skeletal abnormalities. Guideline No./ Study Type MRID No. ( year)/ Classification/ Doses Results 24 870.3800 Reproduction and fertility effects 43617401( 1995) acceptable/ guideline 1, 200, 600, 2000 ppm F0 males 23.0, 69.6, 238.9 mg/ kg/ d F0 females 25.3, 77.0, 258.2 mg/ kg/ d F1 male 23.9, 71.3, 249.3 mg/ kg/ d F1 female 26.1, 79.2, 270.5 mg/ kg/ day Parental/ Systemic NOAEL = 600 ppm LOAEL = 2000 ppm based on decreased body weight and food efficiency in F0 males and females and decreased epididymis and kidney weight in F0 males. Reproductive NOAEL = 2000 ppm LOAEL not observed. Offspring NOAEL = 2000 mg/ kg/ day 870.4100a Chronic toxicity rodents 44059301/ 44042801 ( 1996) acceptable/ guideline 0, 200, 600, 2000 ppm male 0, 12.1, 36.3, 126.1 mg/ kg/ day female 14.9, 45.3, 162.3 mg/ kg/ day NOAEL = 600 ppm LOAEL = 2000 ppm based on decreased survival, reduced body weight, and decreased food utilization in females and decreased body weight and decreased food utilization in males.

870.4100b Chronic toxicity dogs 43620501 ( 1995) acceptable/ guideline 0, 300, 1500, 4500 ppm 0, 9, 46, 91 mg/ kg/ day for males, , 45 and 91 mg/ kg/ day for females. 4500 ppm reduced to 3000 ppm ( 91mg/ kg/ day) on week 11 12. NOAEL = 46/ 45 mg/ kg/ day for males/ females LOAEL = 91 mg/ kg/ day based on changes in testis, liver weight, and microscopic observations in males and clinical signs of toxicity and clinical chemistry alterations in females.

870.4200 Carcinogenicity rats 44059301/ 44042801 ( 1996) acceptable/ guideline 0, 200, 600, 2000 ppm male 0, 12.1, 36.3, 126.1 mg/ kg/ day female 14.9, 45.3, 162.3 mg/ kg/ day NOAEL = 600 ppm LOAEL = 2000 ppm based on decreased survival, reduced body weight, and decreased food utilization in females and decreased body weight and decreased food utilization in males. Vascular tumors at 126/ 162 mg/ kg/ day 870.4300 Carcinogenicity mice ( oral) 44074201( 1996) acceptable/ guideline 0, 400, 1,200, 4000 ppm male 55, 167, 715 mg/ kg/ d female 69, 217, 856 mg/ kg/ d NOAEL = 400 ppm LOAEL = 1,200 ppm based on decreased body weight, nonneoplastic histopathological changes in gall bladder, liver, and rectal anal junction. Vascular tumors and rectal anal tumors at 715/ 856 mg/ kg/ day Guideline No./ Study Type MRID No. ( year)/ Classification/ Doses Results 25 870.4300 Carcinogenicity mice ( dermal) 93191028, 00066475, 00104796 ( 1990) acceptable/ non guideline 0, 15, 150, and 750 mg/ kg/ day PHMB NOAEL = 150 mg/ kg/ day LOAEL = 750 mg/ kg/ day based on increased mortality and decreased body weight in male and female mice receiving PHMB. Vascular tumors at 750 mg/ kg/ day Gene Mutation 870.5265 Microbial gene mutation assay 41687004 ( 1996) acceptable 3.3, 10, 33.3, 100, 333.3 µ g/ plate No evidence of mutagenic response Cytogenetics 870.5395 Micronucleus Assay 870.5375 Cytogenetic assay with human lymphocytes 41096901/ 41404503 ( 1989) acceptable/ guideline 250, 400 mg/ kg 41404501/ 42149905 ( 1989) acceptable/ guideline 5, 25, 50 µ g/ mL  S9 male 25, 100, 187.5 µ g/ mL + S9 female 25, 100, 250 µ g/ mL + S9 No evidence of clastogenic or aneugenic effects No evidence of clastogenic effects Other Effects 870.5550 Unscheduled DNA synthesis assay in rat hepatocytes 41404502/ 42149903 ( 1989) acceptable/ guideline 750, 1500 mg/ kg No evidence of a genotoxic response 870.6300 Developmental neurotoxicity Not required; no evidence of neurotoxicity, no evidence of selective developmental or reproductive toxicity to offspring 870.7485 Metabolism and pharmaco kinetics 435999 01, 435670 01, 00077926, and 00086363 ( 1975& 1995) together they are acceptable/ guideline 200, 2000 ppm 10, 100 mg/ kg Metabolite analysis of pooled urine from rats administered a low molecular weight fraction of PHMB at 20 mg/ kg ( the fraction showing the greatest absorption) revealed the presence of more than one metabolite but identification was not performed due to the small amount of sample available for analysis. 26 8.2 Summary of Toxicological Dose and Endpoints for PHMB for Use in Human Risk Assessment1 Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( Females 13 50 years of age) NOAEL = 20 mg/ kg/ day UF = 100 Acute RfD = 0.2 mg/ kg/ day FQPA SF = 1 aPAD = acute RfD FQPA SF = 0.2 mg/ kg/ day Rabbit Developmental Study ( MRID 42865901)

LOAEL = 40 mg/ kg/ day based on reduced number of litters and skeletal abnormalities.

Acute Dietary ( General population including infants and children) No appropriate single dose effects were identified for general population Chronic Dietary ( All populations) NOAEL= 20 mg/ kg/ day UF = 100 Chronic RfD = 0.2 mg/ kg/ day FQPA SF = 1 cPAD = chronic RfD FQPA SF = 0.2 mg/ kg/ day Rabbit Developmental Study ( MRID #: 42865901) LOAEL = 40 mg/ kg/ day Based on the increased mortality, reduced food consumption, and clinical toxicity;

Mouse Developmental Study ( Report No. CTL/ P/ 335, 1977 ( cited in Report No. 003810, 1978. Section C 9)) LOAEL = 40 mg/ kg/ day; Based on reduced body weight gain; and Rat Developmental Study ( Report No. CTL/ P/ 1262, 1976 ( cited in Report No. 003810, 1978. Section C 11)) LOAEL = 50 mg/ kg/ day Based on reduced food consumption.

Short Term Incidental Oral ( 1 30 days) NOAEL= 20 mg/ kg/ day Residential LOC for MOE = 100 Occupational = NA See Chronic RfD Intermediate Term Incidental Oral ( 1 6 months) NOAEL= 20 mg/ kg/ day Residential LOC for MOE = 100 Occupational = NA See Chronic RfD Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects 27 Short Term, Intermediate Term, and Long Term Dermal Exposure Dermal ( or oral) study NOAEL= 150 mg/ kg/ day ( Relative dermal absorption rate = 100%) Residential LOC for MOE = 100 Occupational LOC for MOE = 100 80 Week Dermal Painting Study ( MRIDs 00066475 and 00104796) LOAEL = 750 mg/ kg/ day based on decreased body weight and liver tumors.

Short Term and Intermediate

Term Inhalation Exposure No appropriate route specific study was available. The oral endpoint of 20 mg/ kg with a Margin of Exposure of 100 ( 10x inter species extrapolation, 10x intra species variation) is used. An additional 10x route to route extrapolation is used to determine if a confirmatory inhalation toxicity study is warranted.

Cancer ( oral,

dermal) The HED Cancer Assessment Review Committee ( CARC) classified PHMB as " Suggestive Evidence of Carcinogenicity, but not sufficient to Assess Human Carcinogenic Potential" by the oral and dermal routes. Quantification of human cancer risk is not required.

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, LOC = level of concern, MOE = margin of exposure


[Federal Register Volume 86, Number 222 (Monday, November 22, 2021)]
[Notices]
[Page 66296]
[FR Doc No: 2021-25400]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Combined Notice of Filings

    Take notice that the Commission has received the following Natural
Gas Pipeline Rate and Refund Report filings:

Filings Instituting Proceedings

    Docket Numbers: RP22-317-000.
    Applicants: Granite State Gas Transmission, Inc.
    Description: Compliance filing: Compliance Filing for Order No.
587-Z--NAESB Update to be effective 6/1/2022.
    Filed Date: 11/15/21.
    Accession Number: 20211115-5000.
    Comment Date: 5 p.m. ET 11/29/21.

    Docket Numbers: RP22-318-000.
    Applicants: Iroquois Gas Transmission System, L.P.
    Description: Sec.  4(d) Rate Filing: 11.15.21 Negotiated Rates--
Twin Eagle Resource Management, LLC H-7300-89 to be effective 12/1/
2021.
    Filed Date: 11/15/21.
    Accession Number: 20211115-5054.
    Comment Date: 5 p.m. ET 11/29/21.

    Docket Numbers: RP22-319-000.
    Applicants: Tennessee Gas Pipeline Company, L.L.C.
    Description: Sec.  4(d) Rate Filing: Volume No. 2--Castleton
SP367814 & 367815 and Citadel SP369972 to be effective 1/1/2022.
    Filed Date: 11/15/21.
    Accession Number: 20211115-5055.
    Comment Date: 5 p.m. ET 11/29/21.

    Docket Numbers: RP22-320-000.
    Applicants: ANR Pipeline Company.
    Description: Compliance filing: CP20-8_GCXP Compliance Filing to be
effective 1/1/2022.
    Filed Date: 11/15/21.
    Accession Number: 20211115-5118.
    Comment Date: 5 p.m. ET 11/29/21.

    Docket Numbers: RP22-321-000.
    Applicants: Discovery Gas Transmission LLC.
    Description: Sec.  4(d) Rate Filing: 2022 HMRE Surcharge Filing to
be effective 1/1/2022.
    Filed Date: 11/15/21.
    Accession Number: 20211115-5128.
    Comment Date: 5 p.m. ET 11/29/21.

    Docket Numbers: RP22-322-000.
    Applicants: SWN Energy Services Company, LLC, GEP Haynesville, LLC.
    Description: Joint Petition for Temporary Waivers of Capacity
Release Regulations, and Related Interstate Pipeline Tariff Provisions
and Request for Expedited Consideration of SWN Energy Services Company,
LLC, et al.
    Filed Date: 11/15/21.
    Accession Number: 20211115-5140.
    Comment Date: 5 p.m. ET 11/29/21.

    Docket Numbers: RP22-323-000.
    Applicants: Transcontinental Gas Pipe Line Company, LLC.
    Description: Sec.  4(d) Rate Filing: 2021 GSS and LSS Fuel
Percentage Changes to be effective 11/1/2021.
    Filed Date: 11/15/21.
    Accession Number: 20211115-5201.
    Comment Date: 5 p.m. ET 11/29/21.

    Any person desiring to intervene or protest in any of the above
proceedings must file in accordance with Rules 211 and 214 of the
Commission's Regulations (18 CFR 385.211 and 385.214) on or before 5:00
p.m. Eastern time on the specified comment date. Protests may be
considered, but intervention is necessary to become a party to the
proceeding.
    The filings are accessible in the Commission's eLibrary system
(https://elibrary.ferc.gov/idmws/search/fercgensearch.asp) by querying
the docket number.
    eFiling is encouraged. More detailed information relating to filing
requirements, interventions, protests, service, and qualifying
facilities filings can be found at: http://www.ferc.gov/docs-filing/efiling/filing-req.pdf. For other information, call<PHONE_NUMBER>
(toll free). For TTY, call<PHONE_NUMBER>.

    Dated: November 16, 2021.
Debbie-Anne A. Reese,
Deputy Secretary.
[FR Doc. 2021-25400 Filed 11-19-21; 8:45 am]
BILLING CODE 6717-01-P