[Federal Register Volume 83, Number 237 (Tuesday, December 11, 2018)]
[Notices]
[Pages 63648-63651]
[FR Doc No: 2018-26725]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-4087]

The Food and Drug Administration's Proposed Current Good
Manufacturing Practice Policies for Outsourcing Facilities:
Considerations Regarding Access to Office Stock; Public Meeting;
Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
announcing a public meeting entitled ``FDA's Proposed Current Good
Manufacturing Practice Policies for Outsourcing Facilities:
Considerations Regarding Access to Office Stock.'' Stakeholders,
including healthcare providers (HCPs) and medical specialty groups,
have expressed concerns regarding the availability of certain
compounded drug products from outsourcing facilities that they would
like to have on-hand as in-office supplies of non-patient-specific
compounded drugs (``office stock''). The purpose of the public meeting
is to provide HCPs, outsourcing facilities, entities considering
becoming outsourcing facilities, and other interested parties with an
opportunity to present to FDA their perspectives concerning access to
office stock from outsourcing facilities in light of FDA's enforcement
policies as proposed in the revised draft guidance on current good
manufacturing practice (CGMP) for human drug compounding outsourcing
facilities.

DATES: The public meeting will be held on May 21, 2019, from 9 a.m. to
5 p.m. Submit either electronic or written comments on this public
meeting by June 21, 2019. See the SUPPLEMENTARY INFORMATION section for
registration date and information.

ADDRESSES: The public meeting will be held at FDA's White Oak Campus,
10903 New Hampshire Ave., Bldg. 31 Conference Center, the Great Room
(Rm. 1503), Silver Spring, MD 20993-0002. Entrance for the public
meeting participants (non-FDA employees) is through Building 1 where
routine security check procedures will be performed. For parking and
security information, please refer to https://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.
    You may submit comments as follows. Please note that late, untimely
filed comments will not be considered. Electronic comments must be
submitted on or before June 21, 2019. The https://www.regulations.gov
electronic filing system will accept comments until 11:59 p.m. Eastern
Time at the end of June 21, 2019. Comments received by mail/hand
delivery/courier (for written/paper submissions) will be considered
timely if they are postmarked or the delivery service acceptance
receipt is on or before that date.

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 Docket No. FDA-
2018-N-4087 for ``FDA's Proposed Current Good Manufacturing Practice
Policies for Outsourcing Facilities: Considerations Regarding Access to
Office Stock.'' Received comments, those filed in a timely manner (see
ADDRESSES), will be placed in the docket and, except for those
submitted as ``Confidential Submissions,'' are publicly viewable at
https://www.regulations.gov or at the Dockets Management Staff between
9 a.m. and 4 p.m., Monday through Friday.
     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.'' The Agency 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 to 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 this 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, September 18, 2015, or access the information at: https://www.gpo.gov/fdsys/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.

FOR FURTHER INFORMATION CONTACT: Bronwen Blass, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Silver Spring, MD 20993-0002,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

A. Drug Compounding

    Drug compounding is often regarded as the process of combining,
mixing, or altering ingredients to create a medication tailored to the
needs of an individual patient. Compounded drug products serve an
important role for patients whose clinical needs cannot be met by an
FDA-approved drug product, such as for a patient who has an allergy to
a certain dye contained in an FDA-approved drug product and needs a
medication compounded without that dye, or an elderly patient or a
child who cannot swallow a pill and needs a medicine in a liquid form
that is not available in an approved product. Drug products can be
compounded consistent with section 503A of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 U.S.C. 353a) by licensed pharmacists in
State-licensed pharmacies and Federal facilities, or by licensed
physicians, or consistent with section 503B of the FD&C Act (21 U.S.C.
353b) by compounders known as outsourcing facilities.
    Sometimes, it is necessary for HCPs in hospitals, clinics, offices,
or other settings to have a certain compounded drug product on hand, so
they can administer it to a patient who presents with an immediate need
for the compounded drug product. Such drug products are often known as
``office stock,'' and outsourcing facilities are uniquely permitted to
supply these compounded products in accordance with the law.
    For example, if a patient presents at an ophthalmologist's office
with a fungal eye infection, timely administration of a compounded
antifungal medication may be critical to preventing vision loss. In
such a case, the ophthalmologist may need to inject the patient with a
compounded drug product immediately, rather than writing a prescription
and waiting for the drug product to be compounded and shipped to the
prescriber. In other cases, compounded drug products may need to be
administered by a healthcare practitioner in his or her office because
it would not be safe for the patient to take the drug home for self-
administration, and it would be preferable for the physician to have
the drug in his or her office to administer immediately upon diagnosis,
rather than asking the physician to order the drug and have the patient
return to the healthcare practitioner for administration.
    Although compounded drugs can serve an important role for certain
patients in cases such as these, they also can pose a higher risk to
patients than FDA-approved drugs. Compounded drug products are not FDA-
approved, which means they have not undergone FDA premarket review for
safety, effectiveness, and quality. Because compounded drug products
are subject to a lower regulatory standard than FDA-approved drug
products, they present a greater risk to patients and should not be
administered to patients unless their medical needs cannot be met by
FDA-approved drug products.

B. Compounding Under the FD&C Act

    Sections 503A and 503B of the FD&C Act address human drug
compounding. Section 503A, added to the FD&C Act by the Food and Drug
Administration Modernization Act of 1997 (Pub. L. 105-115), describes
the conditions that must be satisfied for human drug products
compounded by a licensed pharmacist in a State-licensed pharmacy or
Federal facility, or by a licensed physician, to be exempt from the
following three sections of the FD&C Act:
     Section 501(a)(2)(B) (21 U.S.C. 351(a)(2)(B)) (concerning
CGMP requirements);
     section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the
labeling of drugs with adequate directions for use); and
     section 505 (21 U.S.C. 355) (concerning the approval of
drugs under new drug applications or abbreviated new drug
applications).
    A compounded drug product may be eligible for the exemptions under
section 503A of the FD&C Act only if it is, among other things,
compounded for an identified individual patient based on the receipt of
a valid prescription order or a notation, approved by the prescribing
practitioner, on the prescription order that a compounded product is
necessary for the identified patient. Among other conditions, to
qualify for the exemptions under section 503A, the drug product must be
compounded by a licensed pharmacist in a State-licensed pharmacy or a
Federal facility, or by a licensed physician (section 503A(a)).
    New section 503B, added to the FD&C Act by the Drug Quality and
Security Act in 2013, created a new category of compounders called
outsourcing facilities. Section 503B defines outsourcing facility, in
part, as a facility that is engaged in the compounding of sterile drugs
(section 503B(d)(4)(A)(i)). An outsourcing facility may engage in
nonsterile compounding provided that it also engages in the compounding
of sterile drugs, and provided that it compounds all of its drugs (both
sterile and nonsterile) in accordance with the conditions of section
503B.
    Section 503B of the FD&C Act describes the conditions that must be
satisfied for human drug products compounded by or under the direct
supervision of a licensed pharmacist in an outsourcing facility to
qualify for exemptions from three sections of the FD&C Act:
     Section 502(f)(1);
     section 505; and
     section 582 (21 U.S.C. 360eee-1) (concerning drug supply
chain security requirements).
    In contrast to compounders compounding in accordance with section
503A of the FD&C Act, outsourcing facilities may, but need not, obtain
prescriptions for identified individual patients for their

compounded drug products (section 503B(d)(4)(C)). Outsourcing
facilities are subject to CGMP requirements in section 501(a)(2)(B).
They must also be inspected by FDA according to a risk-based schedule
and are subject to specific adverse event reporting requirements and
other conditions that help to mitigate the risks of the drug products
they compound.

C. CGMP Requirements for Outsourcing Facilities

    Elsewhere in this issue of the Federal Register, FDA announced the
availability of a revised draft guidance for industry entitled
``Current Good Manufacturing Practice--Guidance for Human Drug
Compounding Outsourcing Facilities Under Section 503B of the FD&C
Act.'' (revised draft guidance). FDA previously issued a draft guidance
for industry on this subject in July 2014 (79 FR 37743). This guidance,
once final, will provide for conditions under which FDA generally does
not intend to take regulatory action against an outsourcing facility
regarding certain CGMP requirements in 21 CFR parts 210 and 211 during
the interim period before FDA issues regulations specific to
outsourcing facilities. In developing policies pertaining to CGMP
requirements for outsourcing facilities, FDA seeks to recognize the
differences between outsourcing facilities and conventional drug
manufacturers and to develop policies that reflect the specific
compounding operations conducted by outsourcing facilities. The revised
draft guidance proposes a risk-based approach to enforcement of CGMP
requirements, tailored to the size and scope of outsourcing facilities'
operations. The policies are aimed at making it more feasible for
entities to register as outsourcing facilities to compound drugs for
office stock in accordance with CGMP requirements, while maintaining
the minimum standards necessary to protect patients from the risks of
contaminated or otherwise substandard drug products.
    In the revised draft guidance, FDA made a number of revisions to
address comments submitted on the 2014 draft. For example, the revised
draft guidance differentiates between CGMP requirements applicable to
sterile drug products and nonsterile drug products where appropriate.
Among other changes, FDA made revisions to address comments on (1)
stability testing, including the assignment of a beyond use date (BUD)
as an expiration date; (2) a clear definition of ``in-use time,''
distinguishing it from ``BUD'' and ``expiration date''; (3) testing
batches before release for distribution; and (4) collection and use of
samples retained from distributed batches, known as reserve samples.
For a more comprehensive discussion of the policies proposed in the
revised draft guidance, please see the revised draft guidance
(available at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or
https://www.regulations.gov) and associated notice of availability,
which FDA is publishing elsewhere in this issue of the Federal
Register. In the docket for the revised draft guidance, FDA is seeking
comment on whether the conditions outlined appropriately balance the
risks and needs associated with compounded drugs produced for office
stock.

II. Topics for Discussion at the Public Meeting

    FDA is seeking public input regarding outsourcing facilities
supplying compounded drugs for office stock in light of the CGMP
policies described in the revised draft guidance, if finalized as
written. FDA has developed a list of topics to facilitate a productive
discussion at the public meeting. This list is not intended to be
exhaustive, and FDA encourages comments on the potential implications
of the policies pertaining to compliance with CGMP requirements
described in the revised draft CGMP guidance, if finalized as written,
for outsourcing facilities supplying drugs compounded for office stock.
Policies include, but are not limited to, those related to stability
studies, beyond use dating, and release testing. Issues that are of
specific interest to the Agency include the following:
     Perspectives related to demand and supply of office stock,
including:
    [cir] Ways in which HCPs seek to identify outsourcing facilities
that compound the drugs they want for office stock, as well as issues,
if any, with this process.
    [cir] Communications between HCPs and outsourcing facilities to
address potential issues related to requested formulations, timing, and
order size.
    [cir] Coordination or consolidation of orders among providers for
same or similar compounded drug products.
    [cir] HCPs' experiences with the availability of office stock
products from outsourcing facilities.
     Perspectives related to orders for drug products that an
outsourcing facility has not made or does not routinely make.
    [cir] Factors outsourcing facilities consider before deciding
whether to fill an order for a requested compounded drug product that
it has not previously made or does not routinely make.
    [cir] The impact that FDA's policies proposed in the revised draft
guidance would have on outsourcing facilities filling orders for
requested products not previously or routinely made.
     Perspectives related to small volume orders of office
stock products, including:
    [cir] HCPs' experiences seeking small volume orders from
outsourcing facilities.
    [cir] Factors outsourcing facilities consider before determining
whether to produce small batches of compounded drug products for office
stock.
    [cir] The impact that FDA's policies proposed in the revised draft
guidance would have on outsourcing facilities' decisions regarding
filling small volume orders and/or producing small batches of
compounded drug products for office stock.
    [cir] Whether/how the revisions proposed in the revised draft
guidance would affect registration of compounders engaged in smaller-
scale production as outsourcing facilities.
     Perspectives related to beyond use dating for office stock
products, including:
    [cir] How long HCPs seek to keep office stock drug products before
use.
    [cir] The impact that FDA's policies proposed in the revised draft
guidance would have on outsourcing facilities' production of compounded
drug products for office stock with beyond use dating desired by HCPs.
    FDA will post the agenda and other meeting materials at least 5
days before the meeting on the public meeting website. More information
regarding the meeting, including the public meeting website address,
will be posted at: https://www.fda.gov/Drugs/NewsEvents/ucm132703.htm.

III. Participating in the Public Meeting

    Registration: Persons interested in attending this public meeting
must register online by May 7, 2019. Please provide complete contact
information for each attendee, including name, title, affiliation,
address, email, and telephone. More information regarding the meeting,
including the public meeting website address and registration
instructions, will be posted at: https://www.fda.gov/Drugs/NewsEvents/ucm132703.htm.
    Registration is free and in-person attendance is based on space
availability, with priority given to early registrants. Early
registration is recommended because seating is limited; therefore, FDA
may limit the number of participants from each

organization. Registrants will receive confirmation when they have been
accepted. If time and space permit, onsite registration on the day of
the public meeting will be provided beginning at 8:30 a.m. We will post
information at https://www.fda.gov/Drugs/NewsEvents/ucm132703.htm if
registration closes before the day of the public meeting.
    If you need special accommodations due to a disability, please
contact<EMAIL_ADDRESS>no later than May 14,
2019.
    Requests for Oral Presentations: During online registration you may
indicate if you wish to present during a public comment session and
which topic(s) you wish to address. All requests to make oral
presentations must be received by March 1, 2019. You will also be asked
to send<EMAIL_ADDRESS>a brief summary your
comments by March 1, 2019. Individuals and organizations with common
interests are urged to consolidate or coordinate their presentations,
and request time for a joint presentation, or submit requests for
designated representatives to present. For more information on oral
presentation requests, visit https://www.fda.gov/Drugs/NewsEvents/ucm132703.htm. Following the close of registration, we will determine
the amount of time allotted to each presenter and the approximate time
each oral presentation is to begin. We will do our best to accommodate
all stakeholders who wish to speak; however, the duration of comments
may be limited by time constraints, including time allowances for each
topic. Presenters will be notified of their selection no later than May
7, 2019. If selected for presentation, any presentation materials must
be emailed to the<EMAIL_ADDRESS>no later than
May 14, 2019. No commercial or promotional material will be permitted
to be presented or distributed at the public meeting.
    Streaming Webcast of the Public Meeting: This public meeting will
also be webcast. Further information regarding the webcast, including
the address for the webcast, will be made available at least 2 days in
advance of the meeting on the public meeting website. More information
regarding the meeting, including the public meeting website address,
will be posted at: https://www.fda.gov/Drugs/NewsEvents/ucm132703.htm.
FDA has verified the website addresses in this document, as of the date
this document publishes in the Federal Register, but websites are
subject to change over time.

    Dated: December 4, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-26725 Filed 12-10-18; 8:45 am]
 BILLING CODE 4164-01-P


[Federal Register Volume 76, Number 108 (Monday, June 6, 2011)]
[Rules and Regulations]
[Pages 32321-32323]
[FR Doc No: 2011-13878]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 52

[EPA-R03-OAR-2011-0379; FRL-9314-4]

Approval and Promulgation of Air Quality Implementation Plans;
Pennsylvania; Revision to the Inspection and Maintenance (I/M)
Program--Quality Assurance Protocol for the Safety Inspection Program
in Non-I/M Counties

AGENCY: Environmental Protection Agency (EPA).

ACTION: Direct final rule.

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SUMMARY: EPA is taking direct final action to approve revisions to the
Pennsylvania State Implementation Plan (SIP). The revision consists of
a change by the Commonwealth of Pennsylvania to the quality assurance
program for its motor vehicle inspection and maintenance program (I/M
program). Specifically, the Commonwealth is amending a provision of its
prior SIP-approved I/M program to change the duration of the timing of
quality assurance audits performed by the Pennsylvania Department of
Transportation (PENNDOT) as part of their program oversight. The
amendment allows for these audits to be conducted within five days of
vehicle inspection, instead of the two-day window allowed under the
prior approved SIP. This SIP revision affects forty-two counties in
Pennsylvania where visual emissions equipment inspections are performed
as part of the Commonwealth's annual vehicle safety inspection program
(i.e., non-I/M counties). It does not affect the twenty-five counties
where separate enhanced I/M emissions inspections are performed in
addition to the annual safety inspection program (i.e., I/M counties).
This SIP revision applies to PENNDOT staff overseeing stations that
conduct safety inspections in non-I/M program counties. It does not
impact motorists subject to the program or stations that perform
emissions inspections. EPA is approving this amendment to
Pennsylvania's approved I/M SIP in accordance with the requirements of
the Clean Air Act (CAA).

DATES: This rule is effective on August 5, 2011 without further notice,
unless EPA receives adverse written comment by July 6, 2011. If EPA
receives such comments, it will publish a timely withdrawal of the
direct final rule in the Federal Register and inform the public that
the rule will not take effect.

ADDRESSES: Submit your comments, identified by Docket ID Number EPA-
R03-OAR-2011-0379 by one of the following methods:
    A. http://www.regulations.gov. Follow the on-line instructions for
submitting comments.
    B. E-mail<EMAIL_ADDRESS>    C. Mail: EPA-R03-OAR-2011-0379, Cristina Fernandez, Associate
Director, Office of Air Program Planning, Mailcode 3AP30, U.S.
Environmental Protection Agency, Region III, 1650 Arch Street,
Philadelphia, Pennsylvania 19103.
    D. Hand Delivery: At the previously-listed EPA Region III address.
Such deliveries are only accepted during the Docket's normal hours of
operation, and special arrangements should be made for deliveries of
boxed information.
    Instructions: Direct your comments to Docket ID No. EPA-R03-OAR-
2011-0379. EPA's policy is that all comments received will be included
in the public docket without change, and may be made available online
at http://www.regulations.gov, including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through http://www.regulations.gov or e-mail. The http://www.regulations.gov Web site
is an ``anonymous access'' system, which means EPA will not know your
identity or contact information unless you provide it in the body of
your comment. If you send an e-mail comment directly to EPA without
going through http://www.regulations.gov, your e-mail address will be
automatically captured and included as part of the comment that is
placed in the public docket and made available on the Internet. If you
submit an electronic comment, EPA recommends that you include your name
and other contact information in the body of your comment and with any
disk or CD-ROM you submit. If EPA cannot read your comment due to
technical difficulties and cannot contact you for clarification, EPA
may not be able to consider your comment. Electronic files should avoid
the use of special characters, any form of encryption, and be free of
any defects or viruses.
    Docket: All documents in the electronic docket are listed in the
http://www.regulations.gov index. Although listed in the index, some
information is not publicly available, i.e., CBI or other information
whose disclosure is restricted by statute. Certain other material, such
as copyrighted material, is not placed on the Internet and will be
publicly available only in hard copy form. Publicly available docket
materials are available either electronically in http://www.regulations.gov or in hard copy during normal business hours at the
Air Protection Division, U.S. Environmental Protection Agency, Region
III, 1650 Arch Street, Philadelphia, Pennsylvania 19103.
    Copies of the State submittal are available at the Pennsylvania
Department of Environmental Protection, Bureau of Air Quality Control,
P.O. Box 8468, 400 Market Street, Harrisburg, Pennsylvania 17105.

FOR FURTHER INFORMATION CONTACT: Brian Rehn,<PHONE_NUMBER>, or by e-
mail at<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: Throughout this document, whenever ``we,''
``us,'' or ``our'' is used, we mean EPA.

I. Background

    On May 22, 2009, the Commonwealth of Pennsylvania submitted a
formal revision to its SIP. That SIP revision, which is the subject of
this action, consists of an amendment to the enhanced motor vehicle
emission inspection program SIP submitted by Pennsylvania on December
1, 2003 and approved as part of the Commonwealth's SIP on October 6,
2005 (70 FR 58313). This SIP revision amends Pennsylvania's quality
assurance program, which applies to PENNDOT staff that oversee the
anti-tampering visual inspection performed as part of the annual safety
inspection program in the forty-two Pennsylvania

counties (where separate enhanced I/M inspection is not required).

II. Summary of SIP Revision

    Pennsylvania's approved I/M SIP includes, as a SIP-strengthening
measure, a program to address emissions from in-use vehicles registered
in counties in Pennsylvania that are not mandated by the CAA to have an
emission inspection program. In these forty-two non-I/M counties,
Pennsylvania requires (as part of its annual vehicle safety inspection)
a visual check of select vehicle emission components to ensure that the
components have not been removed or disconnected, and that they are the
correctly configured components for that particular vehicle (referred
to hereafter as the anti-tampering program). This SIP-approved anti-
tampering program check applies to the following components (where
equipped on a new vehicle as part of an EPA-certified configuration):
Catalytic converter, exhaust gas recirculation (EGR) valve, positive
crankcase ventilation (PCV) valve, fuel inlet restrictor, air pump, and
evaporative control system. The non-I/M region affected by this SIP
revision is comprised of the following counties: Adams, Armstrong,
Bedford, Bradford, Butler, Cameron, Carbon, Clarion, Clearfield,
Clinton, Columbia, Crawford, Elk, Fayette, Forest, Franklin, Fulton,
Greene, Huntingdon, Indiana, Jefferson, Juniata, Lawrence, McKean,
Mifflin, Monroe, Montour, Northumberland, Perry, Pike, Potter,
Schuylkill, Snyder, Somerset, Sullivan, Susquehanna, Tioga, Union,
Venango, Warren, Wayne, and Wyoming.
    The SIP revision amends a portion of the Commonwealth's quality
assurance program for safety inspections, as it relates to
administrative audits of approximately 5,200 safety inspection stations
in the forty-two non-I/M counties. The quality assurance program
established a window during which program auditors ascertain whether
selected vehicles properly passed the required visual emissions
equipment inspection portion of the state-required, annual vehicle
safety inspection. After reviewing its procedures, PENNDOT determined
that increasing the length of time between the safety inspection and
the allowable time by when PENNDOT inspectors can perform an inspection
audit from two to five days allows for improved oversight of the visual
inspection portion of the safety inspection program. This allows the
Commonwealth to better assure that the visual inspection is being
properly performed as part of the safety inspection in non-I/M
counties, ensuring that these emission components are present and have
not been tampered with, as is required by the CAA. The visual
inspection bolsters the Commonwealth's SIP by ensuring that vehicles in
non-I/M counties in the Commonwealth are operated with the required
emissions components in place. The Commonwealth's SIP revision is
intended to improve the Commonwealth's ability to oversee the safety
inspection program in the non- I/M counties to better ensure that the
visual emissions component inspection is being properly performed by
safety inspection technicians. This SIP revision is a procedural change
that does not affect the Commonwealth's prior SIP-approved I/M
regulations, nor does it affect oversight of the I/M program in the 25
counties where I/M is performed separately from the state safety
inspection program.

III. Final Action

    EPA is approving Pennsylvania's SIP revision to amend the quality
assurance program for visual emission component inspection performed as
part of the Commonwealth's annual safety inspection program in non-I/M
counties. EPA is publishing this rule without prior proposal because
EPA views this as a noncontroversial amendment and anticipates no
adverse comment. However, in the ``Proposed Rules'' section of today's
Federal Register, EPA is publishing a separate document that will serve
as the proposal to approve the SIP revision if adverse comments are
filed. This rule will be effective on August 5, 2011 without further
notice unless EPA receives adverse comment by July 6, 2011. If EPA
receives adverse comment, EPA will publish a timely withdrawal in the
Federal Register informing the public that the rule will not take
effect. EPA will address all public comments in a subsequent final rule
based on the proposed rule. EPA will not institute a second comment
period on this action. Any parties interested in commenting must do so
at this time.

IV. Statutory and Executive Order Reviews

A. General Requirements

    Under the CAA, the Administrator is required to approve a SIP
submission that complies with the provisions of the CAA and applicable
Federal regulations. 42 U.S.C. 7410(k); 40 CFR 52.02(a). Thus, in
reviewing SIP submissions, EPA's role is to approve state choices,
provided that they meet the criteria of the CAA. Accordingly, this
action merely approves state law as meeting Federal requirements and
does not impose additional requirements beyond those imposed by state
law. For that reason, this action:
     Is not a ``significant regulatory action'' subject to
review by the Office of Management and Budget under Executive Order
12866 (58 FR 51735, October 4, 1993);
     Does not impose an information collection burden under the
provisions of the Paperwork Reduction Act (44 U.S.C. 3501 et seq.);
     Is certified as not having a significant economic impact
on a substantial number of small entities under the Regulatory
Flexibility Act (5 U.S.C. 601 et seq.);
     Does not contain any unfunded mandate or significantly or
uniquely affect small governments, as described in the Unfunded
Mandates Reform Act of 1995 (Public Law 104-4);
     Does not have Federalism implications as specified in
Executive Order 13132 (64 FR 43255, August 10, 1999);
     Is not an economically significant regulatory action based
on health or safety risks subject to Executive Order 13045 (62 FR
19885, April 23, 1997);
     Is not a significant regulatory action subject to
Executive Order 13211 (66 FR 28355, May 22, 2001);
     Is not subject to requirements of Section 12(d) of the
National Technology Transfer and Advancement Act of 1995 (15 U.S.C. 272
note) because application of those requirements would be inconsistent
with the CAA; and
     Does not provide EPA with the discretionary authority to
address, as appropriate, disproportionate human health or environmental
effects, using practicable and legally permissible methods, under
Executive Order 12898 (59 FR 7629, February 16, 1994).

In addition, this rule does not have Tribal implications as specified
by Executive Order 13175 (65 FR 67249, November 9, 2000), because the
SIP is not approved to apply in Indian country located in the state,
and EPA notes that it will not impose substantial direct costs on
Tribal governments or preempt Tribal law.

B. Submission to Congress and the Comptroller General

    The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General

of the United States. EPA will submit a report containing this action
and other required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of the rule in the Federal Register. A major rule cannot
take effect until 60 days after it is published in the Federal
Register. This action is not a ``major rule'' as defined by 5 U.S.C.
804(2).

C. Petitions for Judicial Review

    Under section 307(b)(1) of the CAA, petitions for judicial review
of this action must be filed in the United States Court of Appeals for
the appropriate circuit by August 5, 2011. Filing a petition for
reconsideration by the Administrator of this final rule does not affect
the finality of this action for the purposes of judicial review nor
does it extend the time within which a petition for judicial review may
be filed, and shall not postpone the effectiveness of such rule or
action. Parties with objections to this direct final rule are
encouraged to file a comment in response to the parallel notice of
proposed rulemaking for this action published in the proposed rules
section of today's Federal Register, rather than file an immediate
petition for judicial review of this direct final rule, so that EPA can
withdraw this direct final rule and address the comment in the proposed
rulemaking.
    This action to approve Pennsylvania's quality assurance program
changes for oversight of the safety inspection program in non-I/M
counties may not be challenged later in proceedings to enforce its
requirements. (See section 307(b)(2).)

List of Subjects in 40 CFR Part 52

    Environmental protection, Air pollution control, Carbon monoxide,
Environmental protection, Incorporation by reference, Intergovernmental
relations, Nitrogen dioxide, Ozone, Volatile organic compounds.

    Dated: May 18, 2011.
Shawn M. Garvin,
Regional Administrator, Region III.

    40 CFR part 52 is amended as follows:

PART 52--[AMENDED]

0
1. The authority citation for part 52 continues to read as follows:

    Authority: 42 U.S.C. 7401 et seq.

Subpart NN--Pennsylvania

0
2. In Sec.  52.2020, the table in paragraph (e)(1) is amended by adding
an entry for Revision of the Quality Assurance Protocol for the Safety
Inspection Program in Non-I/M Counties at the end of the table to read
as follows:

Sec.  52.2020  Identification of plan.

* * * * *
    (e) * * *
    (1) * * *

----------------------------------------------------------------------------------------------------------------
                                                                    State
  Name of non-regulatory SIP       Applicable geographic area     submittal     EPA approval       Additional
           revision                                                  date           date           explanation
----------------------------------------------------------------------------------------------------------------

                                                  * * * * * * *
Revision of the Quality         Non-I/M Program Region,              5/22/09  6/6/11 [Insert    Applicable to
 Assurance Protocol for the      Counties of: Adams, Armstrong,                page number       SIP-approved
 Safety Inspection Program in    Bedford, Bradford, Butler,                    where the         safety
 Non-I/M Counties.               Cameron, Carbon, Clarion,                     document          inspection
                                 Clearfield, Clinton, Columbia,                begins].          program
                                 Crawford, Elk, Fayette,                                         regulation for
                                 Forest, Franklin, Fulton,                                       non-I/M
                                 Greene, Huntingdon, Indiana,                                    counties at
                                 Jefferson, Juniata, Lawrence,                                   Title 67, Part
                                 McKean, Mifflin, Monroe,                                        1, Chapter 175.
                                 Montour, Northumberland,
                                 Perry, Pike, Potter,
                                 Schuylkill, Snyder, Somerset,
                                 Sullivan, Susquehanna, Tioga,
                                 Union, Venango, Warren, Wayne,
                                 and Wyoming.
----------------------------------------------------------------------------------------------------------------

* * * * *
[FR Doc. 2011-13878 Filed 6-3-11; 8:45 am]
BILLING CODE 6560-50-P


26 DATA EVALUATION REPORT 6/ 17/ 2001 Reviewed by: Chris A. Wozniak, Ph. D., Biologist, OPP / BPPD / s/ Secondary Reviewer: John L. Kough, Ph. D., Biologist, OPP / BPPD / s/ MRID No.: 452422 05 Active Ingredients: Bacillus thuringiensis strain PS149B1 ( NRRL B 21553) binary insect control proteins as expressed in maize Product Name: PS149B1 insect control proteins as expressed in maize ID No.: 068467 EUP G, 068467 EUP L, 029964 EUP R, 022964 EUP G Submission No.: S590323, S590337 Chemical No.: 006430 Bacillus thuringiensis PS149B1 proteins DP Barcode: D271578 Sponsor: Dow Agrosciences LLC Authors: S. J. Stelman Testing Facility: Dow Agrosciences LLC, 5501 Oberlin Drive, San Diego, CA 92025. Study Titles: Comparison of the amino acid sequence of the Bacillus thuringiensis strain PS149B1 13.6 kDa and 43.8 kDa insecticidal crystal proteins to known protein allergens. Study Date: October 13, 2000 Study No.: GH C 5140 Conclusion: Based upon the search requirements that at least 8 contiguous amino acids are identical to a known allergenic sequence, PS149B1 13.6 and 43.8 kDa proteins are unrelated to any known allergens in that they do not share any linear epitopes with known protein allergens.

Classification: Acceptable.

Good Laboratory Practices: This study was not conducted in compliance with the Certification of Good Laboratory Practices as outlined in 40 CFR 160.

Purpose: To assess the potential homology between the PS149B1 proteins and known allergens as present in available databases.

METHODS General  All sequence analysis programs used int his study were part of version 10.1 of the GCG ( Genetics Computer Group), Inc., Madison, WI) package run on a Silicon Graphics Origin 200 computer under the Irix ( Silicon Graphics, Inc.) 6.5 operating system.

Database construction  The GCG DATASET was used to generate four allergen databases as follows: a dataset generated by searching for ` allergen' against the PIR ( release 65, Swiss Prot ( release 39), TrEMBL ( release 14) and GenPept ( release 118) databases using GCG STRINGSEARCH and LOOKUP programs; three other databases based upon published, curated protein databases of known or putative allergens  Gendel, S., 1998. Sequence databases for assessing the potential allergenicity of proteins used in transgenic foods. Advances in Food and 27 Nutrition Research 42: 63 92 ( see also http:// www/ iit. edu/~ sgendel/ fa. htm); Metcalfe, D., et al., 1996. Assessment of the allergenic potential of foods derived from genetically engineered crop plants. Critical Reviews in Food Science and Nutrition 36( S): S165 S186; Bairoch, A., 1999. Nomenclature and index of allergen sequences. SWISS PROT Protein Sequence Databank. Release 38.0, July 1999 and updates to September 1999 ( see also http:// www. ex[ asy. ch/ cgibin lists? allergen. txt)

To test the sensitivity of the databases and search engines to detect as little as 8 contiguous amino acids, a positive control of 8 aa was hypothetically inserted in to the sequence data of the 13.6 and 43.8 kDa proteins from a randomly chosen sequence of the public database ( TrEMBL accession Q45630; Bacillus sp. bacteriolytic enzyme). These modified sequences were then run through the database screen for homology comparison for each of the databases. A sequence of 8 amino acid residues is considered the minimum for an immunological recognition.

Sequence comparison  Pattern matching  A UNIX Bourne shell script was used to parse the sequences of the 13.6 and 43.8 kDa PS149B1 proteins into all possible eight letter scripts. A data file was generated for input into the GCG FINDPATTERNS program.

GCG FINDPATTERNS was used to compare each of the four allergen databases with the generated pattern file allowing zero mismatched characters. The Swiss Prot, TrEMBL, PIR and GenPept databases were then compared with the generated pattern file, allowing for zero mismatches. Any hits containing a match to a known allergen sequence were compared back to the allergen databases, then evaluated for any obvious sequence relationship. This method would allow for matching between any new entry into the database which contained an 8 residue match, but which lacked the designation as an allergen.

Sequence comparison  Local alignments  Local amino acid alignment comparisons were performed with GCG FASTA program with the wordsize set at 2 and both the blosum50 default and the constructed identity matrices employed as recommended by Gendel, 1998a). Gap creation penalty default value of 12 and gap extension penalty of 2 were used. Each of the PS149B1 proteins was compared against all four databases.

RESULTS Pattern Matching  Analysis of the 13.6 kDa or the 43.8 kDa protein from B. thuringiensis PS149B1 failed to show any identity of 8 amino acid residues or more between these sequences and any of the known allergens in the databases. The positive control protein sequence was identified in the searches.

The full protein database search revealed 5 sequences with homology of 8 amino acids with either the 13.6 or 43.8 kDa PS149B1 proteins. However, none of these were from allergenic proteins as indicated in the database.

Local alignments  Using the constructed identity matrix or the blosum50 matrix, FASTA alignments did not find any immunologically significant sequence homology with known 28 allergens.

Conclusion Based upon the search requirements that at least 8 contiguous amino acids are identical to a known allergenic sequence, PS149B1 13.6 and 43.8 kDa proteins are unrelated to any known allergens in that they do not share any linear epitopes with known protein allergens. An attachment to this report contains the amino acid sequence.


[Federal Register Volume 80, Number 220 (Monday, November 16, 2015)]
[Notices]
[Pages 70774-70775]
[FR Doc No: 2015-29145]

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

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. EL16-10-000]

Industrial Energy Users--Ohio, Complainant, v. The Ohio Power
Company and PJM Interconnection, LLC, Respondents: Notice of Complaint

    Take notice that on November 6, 2015, pursuant to sections 206,
306, and

309 of the Federal Power Act (FPA), 16 U.S.C. 824e, 825e, and 825h,
Rule 206 of the Federal Energy Regulatory Commission's (Commission)
Rules of Practice and Procedure, 18 CFR 385.206, Industrial Energy
Users--Ohio filed a formal complaint against Ohio Power Company (AEP-
Ohio) and PJM Interconnection, LLC (PJM) alleging that AEP-Ohio has
taken, and PJM has allowed to be taken actions in contravention of the
PJM Open Access Transmission Tariff and that such actions are unjust,
unreasonable, and unduly discriminatory, in violation of the Federal
Power Act, as more fully explained in the complaint.
    The Complainant states that a copy of the complaint has been served
on the Respondents.
    Any person desiring to intervene or to protest this filing must
file in accordance with Rules 211 and 214 of the Commission's Rules of
Practice and Procedure (18 CFR 385.211, 385.214). Protests will be
considered by the Commission in determining the appropriate action to
be taken, but will not serve to make protestants parties to the
proceeding. Any person wishing to become a party must file a notice of
intervention or motion to intervene, as appropriate. The Respondent's
answer and all interventions, or protests must be filed on or before
the comment date. The Respondent's answer, motions to intervene, and
protests must be served on the Complainants.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper using the ``eFiling'' link at http://www.ferc.gov. Persons unable to file electronically should submit an
original and 5 copies of the protest or intervention to the Federal
Energy Regulatory Commission, 888 First Street NE., Washington, DC
20426.
    This filing is accessible on-line at http://www.ferc.gov, using the
``eLibrary'' link and is available for electronic review in the
Commission's Public Reference Room in Washington, DC There is an
``eSubscription'' link on the Web site that enables subscribers to
receive email notification when a document is added to a subscribed
docket(s). For assistance with any FERC Online service, please email
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For
TTY, call<PHONE_NUMBER>.
    Comment Date: 5 p.m. Eastern Time on November 25, 2015

     Dated: November 6, 2015.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2015-29145 Filed 11-13-15; 8:45 am]
BILLING CODE 6717-01-P


6.0 	Aggregate Risk Assessments and Risk Characterization

An aggregate risk assessment for all expected routes of exposure was not
performed as there is no common sensitive endpoint among all routes of
exposure. Generally, a short-term aggregate risk assessment may be
performed by combining short-term incidental oral exposure and
average/background dietary (in this case drinking water) exposures. A
short-term aggregate risk assessment was not performed for naphthalene
since the short-term incidental oral exposure risk estimate alone
exceeds the level of concern and combining with other routes of exposure
would further exceed the level of concern.

7.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to naphthalene and any other
substances and naphthalene does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this action,
therefore, EPA has not assumed that naphthalene has a common mechanism
of toxicity with other substances.  For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at
HYPERLINK http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/.

8.0	Occupational Exposure/Risk Pathway

Naphthalene pesticide products are not registered for occupational use
and, therefore, occupational exposure and risk associated with the
pesticidal uses of naphthalene is not anticipated and has not been
assessed here.

9.0        Data Needs

Residential

HED recommends that the registrant conduct an exposure study to
determine levels of naphthalene in indoor air resulting from simulated
residential mothball use over intermediate- and long-term durations.
Intermediate- and long-term residential indoor postapplication exposure
and risk was estimated using surrogate data from an exposure study which
was conducted to determine indoor ambient levels of naphthalene.  Since
the surrogate exposure study was not duration or use specific, it may
potentially underestimate naphthalene exposure and risk.  An appropriate
study is required to confirm that the estimation of residential
postapplication inhalation exposure is protective of human health.

Toxicology

No new data are currently being required. There is ongoing naphthalene
research to address toxicology issues including:

More accurate assessment of species differences in metabolism and
clearance of naphthalene.

Cell proliferation data to provide linkage to cytotoxicity.

DNA adduct and mutagenicity studies in relevant target tissues in vivo
to confirm lack of direct DNA mutagenicity.

PbPK model under development (2-3 years rough estimate) to better
support the mode of action, and to characterize species differences in
metabolism, and address involvement of multiples enzymes and clearance
in humans versus rodents.  The PBPK model may provide a more accurate
determination of a human equivalent dose to be used in inhalation risk
assessment.

Appendix A: Toxicology

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.340) for a food use for naphthalene are in
Table A.1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

TABLE A.1 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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (rodent)

870.3150	Oral Subchronic (nonrodent)

870.3200	21/28-Day Dermal

870.3250	90-Day Dermal

870.3465	90-Day Inhalation

yes

yes

yes

no

no

yes

yes

yes

---

---

870.3700a	Developmental Toxicity (rodent)

870.3700b	Developmental Toxicity (nonrodent)

870.3800	Reproduction

yes

yes

no

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

yes

yes

yes

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial

870.5300	Mutagenicity—Gene Mutation - mammalian

870.5375	Mutagenicity—Structural Chromosomal Aberrations

870.5395	Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)

870.6100b	90-Day Neurotoxicity (hen)

870.6200a	Acute Neurotox. Screening Battery (rat)

870.6200b	Chronic Neurotox. Screening Battery (rat)

870.6300	Develop. Neuro

no

no

no

no

no

---

---

yes

yes

---

870.7485	General Metabolism

870.7600	Dermal Penetration

yes

no

yes

yes

A.2  Toxicity Profiles

Table A.2.a  Acute Toxicity of Naphthalene.

GDLN

Study Type

MRID

Results	Tox

: 2649 mg/kg (♂+♀)	III

870.1200	Acute Dermal	257229	LD50 >2000  mg/kg (♂+♀)	III

870.1300	Acute Inhalation	257902	LC50 > 0.4 mg/L (77.7 ppm) (♂+♀)	II

870.2400	Primary Eye Irritation	257228	Slight-moderate irritation	III

870.2500	Primary Skin Irritation	257227	Moderate irritation	III

870.2600	Dermal Sensitization	00148173	Nonsensitizer – guinea pig	N/A

Table A.2.b  Subchronic, Chronic and Other Toxicity.

Guideline No./Study Type	Doses tested and Results

Nonguideline

90-Day oral toxicity – rat

NTP 1980a	Doses:  0, 25, 50, 100, 200, or 400 mg/kg/day

NOAEL =  100  mg/kg/day (males/females)

LOAEL =  200 mg/kg/day (males/females) based on decreased body weight
gain.  Renal lesions in males at 200 mg/kg (minimal cortical focal
lymphocytic infiltrate; focal tubular regeneration) and 400 mg/kg
(cortical diffuse tubular degeneration).  At 400 mg/kg/day, clinical
signs (lethargy, hunched posture) and roughened hair coat in both sexes.
 2/10 females at 400 mg/kg displayed moderate lymphoid depletion of
thymus.

Nonguideline

90-Day oral toxicity – B6C3F1

Mouse

NTP 1980b	Doses:  0, 12.5, 25, 50, 100 or 200 mg/kg/day

NOAEL =  100 mg/kg/day (males/females)

LOAEL =  200 mg/kg/day based on transient clinical signs (rough hair and
lethargy) at weeks 3 and 4.

Nonguideline

90-Day oral toxicity – CD1

Mouse

Shopp et al. 1984	Doses:  5.3, 53 or 133 mg/kg/day

NOAEL = 53 mg/kg/day  mg/kg/day

Possible LOAEL =  133 mg/kg/day based on  >10% decreases in absolute
weights of the brain, liver and spleen in females and decreased relative
spleen weights in females.  However, no histopathological examinations
were performed.  Decreassed absolute and relative spleen weights also
noted in females after 14 day treatment with 267 mg/kg naphthalene, but
no histological examinations were performed. Mortality observed at 267
mg/kg/day.  Immunotoxicity assays were negative.

870.3250

90-Day dermal toxicity – rat

MRID 40021801

Acceptable guideline	Doses:  0, 100, 300, or 1000 mg/kg/day

NOAEL =  300 mg/kg/day (males/females)

LOAEL =  1000 mg/kg/day based on atrophy of seminiferous tubules in
males; non-neoplastic lesions in cervical lymph node, liver, thyroid,
kidneys, urinary bladder and skin in females.  Both sexes also displayed
excoriated skin and papules.

870.3700a

Prenatal developmental – rat

NTP 1991	Doses:  0, 50, 150 or 450 mg/kg/day

Maternal NOAEL =  50 mg/kg/day

LOAEL = 150  mg/kg/day based on transient clinical signs of lethargy and
slow breathing, and significant decreases in body weights/body weight
gains and food and water consumption.

Developmental NOAEL = 450 mg/kg/day

LOAEL =   not identified

870.3700b

Prenatal developmental – rabbit

NTP 1992	Doses:  0, 20, 80, or 120 mg/kg/day

Maternal NOAEL = 120  mg/kg/day

LOAEL =   not identified

Developmental NOAEL = 120  mg/kg/day

LOAEL =   not identified

870.6200a

Acute Neurotoxicity  (Oral) Study – rat

MRID 44282801

Acceptable Guideline	Doses:  0, 400, 800, or 1200 mg/kg/day

NOAEL =   not identified

LOAEL =  400 mg/kg based on clinical signs (piloerecton, fast
respiration, hunch posture), reduced motor activity, lower body
temperature, and head shaking and increased urination and defecation in
the open field.

870.6200a

Subchronic Neurotoxicity  (inhalation) Study – rat

MRID 44856401

Acceptable Guideline	Concentrations:  0, 1, 10, or 60 ppm

NOAEL =     1ppm

LOAEL =  10  ppm (males/females) based on nasal lesions (loss of
olfactory nerve fibers, loss of bowman’s glands, olfactory epithelium
atrophy/disorganization, olfactory epithelium erosion/necrosis,
olfactory epithelium hyperplasia,  olfactory epithelium inflammatory
exudate in airway, olfactory epithelium rosettes, respiratory epithelium
hyperplasia.

Nonguideline

4-Week Inhalation  – rat

MRID 42934901

Acceptable nonguideline	Concentrations:  0, 1, 3, 10,  30 or 77 ppm.
6hrs/day; 5 d/wk.

NOAEL =    3 ppm

LOAEL =  10 ppm (males/females) based on increased incidence and
severity of nasal lesions (slight disorganization, rosette formation,
basal cell hyperplasia, erosion, atrophy, and degenerate cells in the
olfactory epithelium; loss of bowman’s glands; respiratory epithelium
hypertrophy; rosette formation in the septal organ of Masera and fusion
of the turbinates).

870.3465

90-day inhalation – rat

MRID 42835901

Acceptable guideline	0, 2, 10 or 60 ppm .  6hrs/day; 5 d/wk.

NOAEL = not identified

LOAEL = 2  ppm based on increased incidence and severity of nasal
lesions (degeneration, atrophy and hyperplasia of basal cells of the
olfactory epithelium; rosette formation of olfactory epithelium; loss of
Bowman’s glands; hypertrophy of respiratory epithelium).

Nonguideline

Chronic toxicity/carcinogenicity (chamber) Inhalation – rat

NTP 2000

Acceptable nonguideline	Concentrations:  0, 10, 30, or 60 ppm.
6hrs/day; 5 d/wk.

NOAEL = not identified.

LOAEL = 10 ppm, based on increased incidence and severity of atypical
(basal cell) hyperplasia, atrophy, chronic inflammation, and hyaline
degeneration of the olfactory epithelium; hyperplasia, squamous
metaplasia, hyaline degeneration, and goblet cell hyperplasia of the
respiratory epithelium; and glandular hyperplasia and squamous
metaplasia.

Nonguideline

Chronic toxicity/carcinogenicity (chamber) Inhalation – mouse

NTP 1992

Acceptable nonguideline	Concentrations:  0, 10,  or 30 ppm.   6hrs/day;
5 d/wk.

NOAEL = not identified.

LOAEL =  10 ppm increased incidence and severity of chronic
inflammation, metaplasia of the olfactory epithelium, and hyperplasia of
respiratory epithelium. There was also increased incidence and severity
of chronic inflammation in the lung.

870.5265

Gene mutation in S. typhimurium

MRID 42071602

r TA1538 up to cytotoxic concentrations (300 μg/plate ± S9)

870.5265

Gene mutation in S. typhimurium

NTP 2000	Naphthalene was negative in S. typhimurium strains TA98, TA100,
TA1535, TA1537 or TA1538 up to cytotoxic concentrations (100 μg/plate
± S9) in two separate trials using the pre-incubation modification to
the standard assay and S9 derived from hamster and Aroclor 1254-induced
rat livers.

870.5375

CHO  chromosome aberration

in the presence of S9 activation, over a concentration range of 30 to
67.5 μg/mL.  Based on cell cycle data from the SCE assay, the harvest
time was extended to 20.5 hours to allow accumulation of a sufficient
number of metaphases to score and to demonstrate a clastogenic effect in
the CHO chromosome aberration assay.

870.5375

CHO   Sister Chromatid Exchange

NTP 2000	Naphthalene induced significant and concentration-related
increases in SCEs in CHO cells within a concentration range of 27 to 90
μg/mL ± S9).

870.5395

In vivo mouse bone marrow micronucleus

MRID 42071603

Acceptable	Naphthalene was negative for micronuclei induction in the
bone marrow of CD-1 male and female mice up to the maximum tolerated
dose (250 mg/kg) administered by intraperitoneal injection.

870. 5550

UDS assay

MRID 42071604

Naphthalene did not induce UDS in primary rat hepatocytes up to
insoluble (≥ 166 μg/mL) and cytotoxic (≥ 50 μg/mL) concentrations.

Nonguideline

In Vitro Dermal penetration – rat

Acceptable nonguideline	Based on an exposure time of 10 minutes, the
short-term in vitro penetration rate was calculated to be 142.6 μg
equiv/cm2/h.  Based on an exposure time of  60 minutes, the short-term
penetration rate was calculated to be 25.0 μg equiv/cm2/h.

A.3  	Executive Summaries

A.3.1	Subchronic Toxicity

90-Day Oral Toxicity – Rat

EXECUTIVE SUMMARY:  Rats were administered by gavage to groups of 10
male and 10 female Fischer 344 rats at dose levels of 0, 25, 50, 100,
200, or 400 mg/kg/day, for 5 days/week for 13 weeks (NTP 1980a).  Body
weight gains decrements exceeding 10% was observed in both males and
females administered 200 or 400 mg/kg/day.  At the highest dose level,
clinical signs included lethargy, hunched posture, and roughened hair
coats.  High-dose males and females also exhibited marginal decreases in
hemoglobin and hematocrit levels.  Males in this group also displayed a
moderate increase in neutrophils and decrease in lymphocytes.  Minimal
renal cortical focal lymphocytic infiltrate (1 of 10 males) and minimal
renal focal tubular regeneration (1 of 10 males) were noted in male rats
treated with 200 mg/kg.  One male rat treated with 400 mg/kg naphthalene
exhibited moderate renal cortical diffuse tubular degeneration.  There
were no renal lesions in treated females, however, 2 of 10 females
treated with 400 mg/kg displayed moderate lymphoid depletion of the
thymus.

The LOAEL = 200 mg/kg/day based on significant body weight decrement.
The NOAEL = 100 mg/kg/day.

90-Day Oral Toxicity – Mouse

EXECUTIVE SUMMARY:  In this study, groups of 10 male and 10 female
B6C3F1 were administered 0, 12.5, 25, 50, 100 or 200 mg/kg naphthalene
by gavage 5 days/week for 13 weeks (NTP 1980b). Vehicle controls
received corn oil. Animals were observed for clinical signs of toxicity.
 Body weight and food consumption were frequently monitored.
Hematology, clinical chemistry, and complete necropsy and histology were
performed.  In the high-dose males and females, rough hair coats and
lethargy were noted at weeks 3 or 4.  There were no other effects of
biological significance.

The LOAEL is 200 mg/kg/day based on transient clinical signs of toxicity
(rough hair coat and lethary).  The NOAEL is 100 mg/kg/day.

90-Day Inhalation – Rat

EXECUTIVE SUMMARY:    In this study, Sprague-Dawley rats, 10/sex/group,
were exposed to naphthalene vapor (purity:  99.9%) for 13 consecutive
weeks( MRID 42835901).  Concentrations were 0, 2, 10 or 60 ppm.   The
parameters monitored included:  clinical observations, body weights,
food consumption, hematology, clinical chemistry, ophthalmoscopy,
necropsy, organ weights, and histology.

m), but these changes were minimal.  However, several of the low-dose
rats exhibited  some loss of Bowman’s glands.  Significant body weight
decrements (≥ 10%) were observed throughout the study in males and
females exposed to 10 or 60 ppm.

The LOAEL is 2 ppm based on nasal lesions and a NOAEL was not
identified.

90-Day Dermal Toxicity – Rat

EXECUTIVE SUMMARY:  Groups of 10 – 20 male and female Sprague-Dawley
rats were exposed to naphthalene via the dermal route at 0, 100, 300,
and 1000 mg/kg/day.   The test material was applied as a neat solid
under occlusion for 6 hours/day, 5 days/week for 13 weeks.  Rats
(10/group) were sacrificed after 13 weeks of treatment, except for
additional animals (10/group) from each of the control and high-dose
groups that were observed for 4 weeks during a recovery phase.
Following each exposure, the treatment area was wiped clean, and the
wrap and the test material discarded.  Animals were inspected for
clinical signs, mortality, changes in body weights, food consumption,
ophthalmology, hematology and clinical chemistry, organ weights,
urinalysis, gross necropsy and histopathology.

There were no effects on mortality, food consumption, body weights,
hematology, clinical chemistry, urinalysis, and organ weights.  At 1000
mg/kg/day, there was excoriated skin and papules in both sexes; atrophy
of seminiferous tubules in the males; and nonneoplastic lesions in the
cervical lymph node (hyperplasia), liver (hemosiderosis), thyroid
(thyroglossal duct cysts), kidneys (pyelonephritis), urinary bladder
(hyperplasia) and skin (acanthosis, hyperkeratosis) in females.

The LOAEL is 1000 mg/kg/day based on atrophy of seminiferous tubules in
males and various nonneoplastic lesions in females.   The NOAEL was 300
mg/kg/day.

A.3.2	Prenatal Developmental Toxicity

Prenatal Developmental Toxicity Study – Rat

EXECUTIVE SUMMARY:  In the developmental toxicity study in
Sprague-Dawley CD rats, naphthalene was administered in corn oil by
gavage to 25-26 pregnant rats/dose group during gestation days 6 – 15.
 Dose levels were 0, 50, 150 or 450 mg/kg/day.  Dams and fetuses were
examined for signs of toxicity and teratogenicity.

Clear evidence of maternal toxicity was noted in the mid- and high-dose
groups.  Maternal toxicity consisted of transient clinical signs of
lethargy and slow breathing, and significant decreases in body
weights/body weight gains and food and water consumption.  The dams
developed a tolerance to the clinical signs of lethargy and slow
breathing with duration of the study.  Rooting behavior (aversion to
treatment), a common observation in rodents following gavage
administration of a compound with noxious odor or with local irritant
action, increased with duration.  In regard to body weight decrement,
the mid-dose group exhibited a 31% reduction in weight gain compared to
controls, while the high-dose group displayed a 53% reduction. . Body
weight loss in the dams was evident during the first 3 days of dosing;
afterwards dams gained weight at nearly the same rate as controls.
Post-treatment weight gain remained below control values.  There were no
treatment-related mortalities.

There were no biologically significant effects of naphthalene on number
of corpora lutea per dam, % resorptions or fetal deaths/litter, %
litters with resorptions or deaths, number of live fetuses/litter,
average fetus body weight/litter, % malformed fetuses/litter, % litters
with malformations (external, visceral, skeletal) and % fetuses with
variations/litter.

The maternal LOAEL is 150 mg/kg/day based on transient clinical signs of
lethargy and slow breathing, and significant decreases in body
weights/body weight gains and food and water consumption. The maternal
NOAEL is 50 mg/kg/day.

The developmental NOAEL is 450 mg/kg/day (highest dose tested).

Prenatal Developmental Toxicity Study – Rabbit

EXECUTIVE SUMMARY:  In the NTP developmental rabbit study, naphthalene
was administered in corn oil by gavage at dose levels of 0, 20, 80, or
120 mg/kg/day to pregnant rabbits during gestation days 6 – 19.
Maternal clinical signs, body weights, and food consumption were
monitored on gestation days 0 – 30.  Fetuses were removed from dams on
gestation day 30, and then subjected to examination for any
treatment-related alterations on growth, viability, and morphological
development.

There were no effects of naphthalene treatment on survival, maternal
body weights (including corrected gestational weight gain), and food
consumption.

Naphthalene was not fetotoxic.  Average live litter size and average
fetal body were similar between control and treated groups.  There was
no effect of treatment on the incidence of external, visceral, or
skeletal malformations.  Similarly, the incidence of variations or
defects on a fetal or litter basis was unaffected by treatment.

The maternal and developmental NOAELs are 120 mg/kg/day (highest dose
tested).

A.3.3	Reproductive Toxicity

No reproductive toxicity studies are available.

A.3.4	Chronic Toxicity -  See A.3.5 for Combined Chronic/Carcinogenicity
NTP Inhalation Studies in the Rat and Mouse.

A.3.5	Carcinogenicity

Combined Chronic/Carcinogenicity Study – Rat

EXECUTIVE SUMMARY:  In this study,  groups of 49 male and 49 female
F344/N rats were exposed to naphthalene by inhalation at concentrations
of 0, 10, 30, or 60 ppm for 6 hours plus T90 (12 minutes) per day, 5
days per week for 105 weeks (NTP 2000).  Additional groups of nine male
and nine female rats were exposed to 10, 30, or 60 ppm for up to 18
months for evaluation of toxicokinetic parameters.

Survival in the exposed groups was similar to chamber controls.
Decreased mean body weight was observed at the highest dose level in
males throughout the study (89-91% of control).  Mean body weight gains
in the high-dose group males were decreased by 10.5% (weeks 1-13), 10.9%
(weeks 14-52) and 8.6% (weeks 53-104).

Nasal lesions were observed at all concentrations levels and included
atypical (basal cell) hyperplasia, atrophy, chronic inflammation, and
hyaline degeneration of the olfactory epithelium; hyperplasia, squamous
metaplasia, hyaline degeneration, and goblet cell hyperplasia of the
respiratory epithelium; and glandular hyperplasia and squamous
metaplasia. The severities of olfactory epithelial and glandular lesions
increased with increasing exposure concentration.

Nasal tumors included neuroblastomas of the olfactory epithelium and
adenomas of the respiratory epithelium.  Neuroblastomas of the olfactory
epithelium occurred in males exposed to 30 or 60 ppm and in all exposed
groups of females.  The incidences of neuroblastoma occurred with
positive trends in males (p<0.05) and females (p<0.01), and the
incidence in females exposed to 60 ppm was significantly greater
(p<0.01) than that in the chamber controls.  Neuroblastomas have not
been observed in male or female chamber control rats in the NTP database
for animals fed NIH-07 feed in 2-year inhalation studies or in the more
recent, smaller database for control rats fed NTP-2000 feed.

The incidences of adenoma of the respiratory epithelium occurred with a
positive trend in male rats and were significantly increased in all
exposed groups; the incidences in female rats exposed to 30 or 60 ppm
were also increased, but not significantly.  Nasal adenomas have not
been observed in male or female chamber control rats in the NTP database
for animals fed NIH-07 feed in 2-year inhalation studies or in the more
recent, smaller database for control rats fed NTP-2000 feed.

The NTP concluded that “under the conditions of this 2-year inhalation
study, there was clear evidence of carcinogenic activity of naphthalene
in male and female F344/N rats based on increased incidences of
respiratory epithelial adenoma and olfactory epithelial neuroblastoma of
the nose.  In male and female rats, exposure to naphthalene caused
significant increases in the incidences of non-neoplastic lesions of the
nose.”

The LOAEL is 10 ppm based on nasal lesions, and a NOAEL was not
identified.

Combined Chronic/Carcinogenicity Study – Mouse

EXECUTIVE SUMMARY:  In this inhalation chamber study, groups of 75 mice
per sex were allocated to dose levels of 0 and 10 ppm, and 150 mice per
sex to the 30 ppm group (NTP 1992). Nasal lesions were observed in all
concentration levels and consisted of increased incidence and severity
of chronic inflammation, metaplasia of the olfactory epithelium, and
hyperplasia of respiratory epithelium. There was also increased
incidence and severity of chronic inflammation in the lung.

Male mice had statistically significant pair-wise comparisons of the 10
ppm dose group with the controls for liver adenomas, and adenomas and
carcinomas combined, both at p < 0.01.  Only those animals with gross
lesions were examined microscopically for the liver in the 10 ppm dose
group, therefore, the statistical significance of the liver at this dose
group is skewed.  There were no statistically significant trends for
liver or lung tumors in the males and no pair-wise statistical
significance in the lung.  The statistical analyses of the tumors in
male mice were based upon Peto’s Prevalence Test since there were
statistically significant survival disparities among the dose groups.

Female mice had statistically significant trends, and statistically
significant pair-wise comparisons of the 30 ppm dose group with the
controls, for alveolar/bronchiolar adenomas, and adenomas and carcinomas
combined, all at p < 0.01.  The statistical analyses of the tumors in
female mice were based upon Peto’s Prevalence Test since there were
statistically significant survival disparities among the dose groups.

The NTP concluded that “under the conditions of this 2-year inhalation
study, there was “no evidence of carcinogenic activity” of
naphthalene in male B6C3F1 mice exposed to 10 or 30 ppm.  There was
“some evidence of carcinogenic activity” of naphthalene in female
B6C3F1 mice, based on increased incidences of pulmonary
alveolar/bronchiolar adenomas.

The LOAEL is 10 ppm, and a NOAEL was not identified.

A.3.6	Mutagenicity

Gene Mutations

s (300 μg/plate +/-S9) (MRID 42071602).

In the NTP microbial gene mutation assay, naphthalene was negative in S.
typhimurium strains TA98, TA100, TA1535 and TA1537 up to a cytotoxic
concentration (100 μg/plate +/-S9) in two separate trials using the
pre-incubation modification to the standard assay and S9 derived from
hamster and Aroclor 1254-induced rat livers.

Chromosome Aberrations

Based on the cell cycle data from the SCE assay (see below) showing cell
cycle delay (indicative of cytotoxicity), an extended harvest time of
20.5 hours was used in the NTP study to allow accumulation of a
sufficient number of metaphases to score and to demonstrate a
clastogenic effect in the CHO chromosome aberration assay.  The positive
response was observed only in the presence of S9 activation, over a
concentration range of 30 to 67.5 µg/mL.  The types of structural
aberrations were not reported.

In a mouse micronucleus assay (MRID 42071603), naphthalene (99.9%) was
negative for micronuclei induction in the bone marrow of CD-1 male and
female mice up to the maximum tolerated dose (250 mg/kg) administered by
intraperitoneal injection.  At this dose, reduced body tone, abnormal
gait and lacrimation were seen in conjunction with cytotoxic effects on
the target organ (i.e., reduced polychromatic to normochromatic
erythrocytes at all sacrifice times).

Other Genotoxic Tests

ble (≥ 166 µg/mL) and cytotoxic (≥ 50 µg/mL) concentrations.

In the NTP SCE assay, naphthalene induced significant and
concentration-related increases in SCEs in CHO cells within a
concentration range of 27 to 90 µg/mL +/-S9.

Evidence of Oxidative Stress

Several studies in the open literature show that naphthalene undergoes
extensive oxidative metabolism to form naphthoquinones, which are
thought to generate ROS (superoxide anion radical, hydrogen peroxide,
hydroxyl radical and o-semiquinone anion radicals) via redox cycling
(Bolton, 2000).  A number of investigators have reported evidence of
naphthalene-induced oxidative damage by ROS (reviewed in Stohs, et al.,
2002).

О2.-) and hydroxyl radical (OH) production.

In vivo evidence of increased superoxide anion production was also
observed in hepatic and brain tissues in mice (C57BL/6NTac) treated with
naphthalene (Bagchi et al., 2000). As previously mentioned, the
naphthalene metabolite 1,2-naphthoquinone was positive for mutation in
S. typhimurium TA104, a tester strain sensitive to oxidative damage
(Flowers-Geary, et al., 1996).  Overall, the evidence suggests that the
oxidative metabolism of naphthalene leads to the production of ROS which
may result in oxidative-stress induced cytotoxicity.

Other Published Literature

Using a modified CREST in vitro micronucleus assay, Saskai et al. (1997)
reported that naphthalene (30 µg/ml) induced chromosome breakage-type
micronuclei and naphthalene metabolite 1,4-naphthoquinone (0.10 µg/ml)
induced chromosome loss-type micronuclei in metabolically competent
human lymphoblastoid cells (MCL-5).  However, in vivo studies showed no
induction of micronuclei using either the oral or intraperitoneal (ip)
route in mouse bone marrow cells.  Similarly, naphthalene was negative
for in vivo UDS in rat hepatocytes and failed to induce morphologic cell
transformation in five different cell lines including Fischer rat
embryo, Syrian baby hamster, BALB/c, BALB/c 3T3 or human diploid WI-38
cells.

In another study, naphthalene did not induce neoplastic transformation
in partially hepectomized F344 rats receiving single oral gavage
administrations of 100 mg/kg.  However, Bagchi et al. (1998, 2000 and
2002), reported that naphthalene caused DNA fragmentation in brain and
liver tissue of C57BL/6NTac dosed once with 158 mg/kg (0.5x LD50), in
Sprague-Dawley rats administered an oral dose of 110 mg/kg/day for 120
days and in p53-deficient mice (C57BL6/6TSG-p53) after single oral doses
of 0.01x, 0.10x or 0.5x LD50.  In these assays, DNA fragmentation was
accompanied by increased lipid peroxidation in the harvested tissues.
It was, therefore, speculated that, the results were unclear as to
whether the DNA damage was “due to direct effects of naphthalene
metabolites or reactive oxygen species (ROS) or was secondary to cell
death induced at an extranuclear site.” No genetic toxicology studies
were found for sensitive target organs (lung or nasal epithelial
tissues).

A.3.7	Neurotoxicity

870.6200a   Acute Neurotoxicity Screening Battery – Oral route

EXECUTIVE SUMMARY -  In an acute neurotoxicity study (MRID 44282801),
groups of fasted, 5-7 week-old CD rats (10/sex/dose) were given a single
oral dose of naphthalene (99.9% a.i., batch/lot # 235/50320) in corn oil
at doses of 0, 400, 800, or 1200 mg/kg bw and observed for 14 days.
Neurobehavioral assessment (functional observational battery and motor
activity testing was performed on all animals pre-treatment, on Day 1 at
estimated time of peak effect (i.e. 2 hours after dosing) and Days 7 and
14 of the observation period.  Cholinesterase activity was not
determined.  Motor activity of all animals was measured for one hour, at
6-minute intervals, immediately after the completion of the Functional
Observation Battery (FOB).  At study termination, 5 animals/sex/group
were euthanized and perfused in situ for neuropathological examination.
Of the perfused animals, 5/animals/sex from the control and high dose
groups were subjected to histopathological evaluation of brain and
spinal cord.  In addition, peripheral nervous system tissues from all
animals sacrificed were examined. All animals survived to study
termination.   SEQ CHAPTER \h \r 1  Clinical signs from daily cage-side
observation were similar to findings in the FOB (see below).

Absolute body weight was slightly decreased in high dose males on Day 7
and 14 (12% and 9%, respectively) compared to controls.  A dose-related
decrease in body weight gain was noted in all treated animals compared
to controls.  The most pronounced effect on weight gain was during the
first four days of the study when the low-, mid-, and high-dose groups
gained 30%, 57%, and 80%, respectively, less than controls in males and
23%, 40%, and 57%, respectively, less in females.  Recovery was
subsequently seen in all treated groups.  Food consumption in females
was unaffected by treatment.  Food consumption among treated males was
reduced on the day of administration (37%, 52% and 67% in low-, mid- and
high-dose groups, respectively).

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'ated effects seen in the open field were gait abnormalities in
high-dose females (9/10), and head shaking behavior in males and females
from low-, mid- and high-dose groups (2/10, 4/10 and 6/10 in males and
5/10, 6/10 and 7/10 in females, respectively).  On Day 7, hunched
posture (1/10, 3/10, 5/10 and 6/10) was seen in females at all dose
levels with decreased reactivity during removal from cage in both sexes
(6/10, 9/10, 9/10 and 10/10 in males; 4/10, 8/10, 9/10 and 10/10 in
females at control, low-, mid- and high-dose groups, respectively) and
an increased incidence of piloerection in high-dose males (8/10) and all
treated females (5/10, 3/10 and 5/10 at low-, mid- and high-dose,
respectively).  Urination and defecation frequencies were higher in all
treated groups of males and females compared to those of controls.  By
Day 14 in both males and females there was increased urination in all
dose groups and defecation in mid- and high-dose groups.  Body
temperature of the treated female groups was 35.2-36.8°C compared with
38.4°C for the controls on Day 1, 38.1-38.2°C compared with 38.6°C
for controls on Day 7 and 38.0-38.2°C compared with 38.5°C for
controls on Day 14.

No treatment-related effects were seen in landing footsplay or fore- and
hind-limb grip strengths on any testing day.

On Day 1, a marked decrease in motor activity was noted in both sexes in
all treatment groups.  Low and high beam counts for the treated groups
were 63-75% and 78-88%, respectively, less than controls for males and
74-78% and 90-94%, respectively, less than controls for females.  On Day
7, motor activity was significantly reduced compared to controls in all
treatment groups with low and high beam breaks 38-62% and 49-61%,
respectively, less than controls for males and 54-60% and 58-67%,
respectively, less than control levels for females.  Motor activity on
Day 14 was lower compared to that of the controls although to a lesser
extent than on day 7 with low and high beam breaks 27-43% and 36-50%,
respectively, less than control levels for males and 23-40% and 41-42%,
respectively, less for females.

There was no difference in weight of the brain and pituitary between the
control and treated groups.  Gross and microscopic examinations of
central and peripheral nervous tissue did not reveal any
treatment-related effects.

The LOAEL for neurotoxicity of  naphthalene in rats was 400 mg/kg bw
based on clinical signs (piloerection, fast respiration, hunch posture),
reduced motor activity, lower body temperature, and head shaking and
increased urination and defecation in the open field.  The NOAEL was not
established.

870.6200b   Subchronic Neurotoxicity Screening Battery – Inhalation
route

EXECUTIVE SUMMARY -  In this subchronic inhalation neurotoxicity study
(MRID 44856401) naphthalene  was administered to 10 CD rats/sex/group as
a vapor by dynamic nose-only exposure at target concentrations of 0, 1,
10, or 60 ppm for 6 hours per day, 5 days/week for a total of 13 weeks.
Overall mean analytical concentrations were 0, 0.99, 10.0, and 62.8 ppm.
 Neurobehavioral assessment (functional observational battery and motor
activity testing) was performed on all animals pre-test and at the end
of Weeks 4, 8, and 13.  At study termination, the animals were
euthanized and perfused in situ.  The first 5 males and 5 females per
group were used for neuropathological examination (control and
high-concentration, only) and microscopic evaluation of the nasal
passages (all treatment groups).

There were no deaths during the study.  One female from each of the mid-
and high-concentration groups appeared slightly emaciated during Week
12.  Five/10 and 6/10 mid- and high-concentration females and 1/10
mid-concentration males had brown staining of the ventral surface during
Weeks 10-14 with two females from each group also showing brown staining
of the dorsal surface.  At 10 and 60 ppm, mean cumulative body weight
gain was significantly decreased in both sexes compared to controls
(males: -22% and -34%, respectively; females: -26% and -34%; p<0.01).
Absolute body weight was also decreased in these same groups compared to
their respective controls, with high-concentration males weighing 12-18%
less during Weeks 4-13, mid-concentration males weighing 9-11% less
during Weeks 8-13, high-concentration females weighing 10-14% less
during Weeks 4-13, and mid-concentration females weighing 9-12% less
during Weeks 3-13.  Mean weekly food consumption was decreased in
high-concentration males during Weeks 3-13 (12-16% less than that of
controls) and in mid- and high-concentration females during Weeks 2-13
(10-15% and 10-19% less than controls, respectively).
High-concentration females spent significantly less total time in
locomotor activity at Week 13 (-38%; p<0.01).

A number of treatment-related microscopic lesions of the nasal passages
were seen.   Minimal or slight hyperplasia of the
respiratory/transitional epithelium in the rostral region was noted in
all treated animals (vs. no controls), and atrophy/disorganization of
the olfactory epithelium was seen at all exposure levels in both sexes
(in ascending dose order, males: 0/5,1/5, 3/5, 5/5 and females 0/5, 2/5,
5/5, 5/5).  Apparent loss of Bowman’s glands and olfactory nerve
fibers was noted in all animals of both sexes at 10 and 60 ppm.  Other
lesions included erosion/necrosis of the olfactory epithelium (males:
0/5, 0/5, 0/5, 2/5; females: 0/5, 1/5, 5/5, 4/5), hyperplasia of the
olfactory epithelium (males: 0/5, 0/5, 0/5, 5/5; females; 0/5, 0/5, 5/5,
4/5), inflammatory exudate in the airway (males: 0/5, 0/5, 2/5, 3/5;
females: 0/5, 0/5, 5/5, 5/5), and rosettes of the olfactory epithelium
(males: 0/5, 0/5, 1/5, 5/5; females: 0/5, 0/5, 2/5, 3/5).  There were no
treatment related effects on brain weight or neuropathology.

The LOAEL was 10 ppm based on atrophy/disorganization of the olfactory
epithelium and hyperplasia of the respiratory and transitional
epithelium.  The NOAEL is 1 ppm.

Appendix B:	Review of Human Research

Studies reviewed for ethical conduct:

No MRID - PHED Surrogate Exposure Guide

MRID 43716501

Waggoner, T. (1994) Estimation of Homeowner Exposure to LX1298-01
(Naphthalene) Resulting from Simulated Residential Use as an Insect
Repellent.  Unpublished study prepared by Landis International, Inc. and
Pharmaco LSR Inc. under Project No. 93-9083.  100 p.

Page   PAGE  8  of   NUMPAGES  64

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[Federal Register Volume 82, Number 193 (Friday, October 6, 2017)]
[Notices]
[Page 46886]
[FR Doc No: 2017-21510]

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

 DEPARTMENT OF TRANSPORTATION

Federal Railroad Administration

[Docket Number FRA-1999-5102]

Petition for Waiver of Compliance

    Under part 211 of Title 49 of the Code of Federal Regulations
(CFR), this provides the public notice that on August 25, 2017, the
Southeastern Pennsylvania Transportation Authority (SEPTA) petitioned
the Federal Railroad Administration (FRA) for an extension of a waiver
of compliance from certain provisions of the Federal railroad safety
regulations contained at 49 CFR part 213, Track Safety Standards. The
docket number associated with this petition is FRA-1999-5102.
    SEPTA seeks to extend its existing waiver from 49 CFR 213.233(c),
relating to the frequency of the required visual track inspections for
FRA Class 3 and 4 track carrying passenger traffic. FRA issued the
initial waiver on July 24, 2000, and FRA extended the waiver on August
4, 2003, February 28, 2008, and April 25, 2013 for three 5-year
periods.
    SEPTA requests an extension of its existing waiver to conduct fewer
visual track inspections than required by Sec.  213.233(c),
specifically for tracks constructed with continuous welded rail that
carry passenger traffic. SEPTA proposes to continue conducting one
visual track inspection per week, instead of the two inspections per
week that are required, and to supplement its visual inspections with
the operation of an automated track geometry measuring vehicle over the
affected main tracks and sidings four times per year. SEPTA has owned
and operated such a measuring vehicle since 1992.
    A copy of the petition, as well as any written communications
concerning the petition, is available for review online at
www.regulations.gov and in person at the Department of Transportation's
Docket Operations Facility, 1200 New Jersey Ave. SE., W12-140,
Washington, DC 20590. The Docket Operations Facility is open from 9
a.m. to 5 p.m., Monday through Friday, except Federal Holidays.
    Interested parties are invited to participate in these proceedings
by submitting written views, data, or comments. FRA does not anticipate
scheduling a public hearing in connection with these proceedings since
the facts do not appear to warrant a hearing. If any interested parties
desire an opportunity for oral comment, they should notify FRA, in
writing, before the end of the comment period and specify the basis for
their request.
    All communications concerning these proceedings should identify the
appropriate docket number and may be submitted by any of the following
methods:
     Web site: http://www.regulations.gov. Follow the online
instructions for submitting comments.
     Fax:<PHONE_NUMBER>.
     Mail: Docket Operations Facility, U.S. Department of
Transportation, 1200 New Jersey Avenue SE., W12-140, Washington, DC
20590.
     Hand Delivery: 1200 New Jersey Avenue SE., Room W12-140,
Washington, DC 20590, between 9 a.m. and 5 p.m., Monday through Friday,
except Federal Holidays.
    Communications received by November 20, 2017 will be considered by
FRA before final action is taken. Comments received after that date
will be considered if practicable.
    Anyone can search the electronic form of any written communications
and comments received into any of our dockets by the name of the
individual submitting the comment (or signing the document, if
submitted on behalf of an association, business, labor union, etc.).
Under 5 U.S.C. 553(c), DOT solicits comments from the public to better
inform its processes. DOT posts these comments, without edit, including
any personal information the commenter provides, to
www.regulations.gov, as described in the system of records notice (DOT/
ALL-14 FDMS), which can be reviewed at https://www.transportation.gov/privacy. See also https://www.regulations.gov/privacyNotice for the
privacy notice of regulations.gov.

Robert C. Lauby,
Associate Administrator for Railroad Safety, Chief Safety Officer.
[FR Doc. 2017-21510 Filed 10-5-17; 8:45 am]
 BILLING CODE 4910-06-P


UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES PC Codes: 029801, 029802, 029806, 128931, 128944, 129043 DP Barcode: 317694 November 15, 2005 MEMORANDUM Subject: Revised EFED RED Chapter For Dicamba/ Dicamba Salts and Response to BASF's " Error Only" Comments of October 27, 2005 To: Susan Lewis, Branch Chief Kendra Tyler, RM Reviewer Reregistration Branch 1 Special Review and Reregistration Division From: William Erickson, Biologist Ibrahim Abdel Saheb, Environmental Scientist Shannon Borges, Biologist Environmental Risk Branch 2, Environmental Fate and Effects Division Through: Thomas Bailey, Branch Chief, Environmental Risk Branch 2, Environmental Fate and Effects Division EFED has completed a revision of the RED chapter for dicamba and its salts in response to BASF's errors comments submitted on October 27, 2005. The revised chapter is attached. Below is EFED's response to BASF.

BASF Comment: BASF states that a lay person reading the chapter could erroneously conclude that dicamba has an incomplete data base.

EFED Response: The data base is incomplete. In EFED's August 31, 2005 risk assessment, both the cover letter and Appendix E identify the following data gaps:

° seedling emergence and vegetative vigor studies ( 123 1a, b); dicamba acid, TEP ° seedling emergence and vegetative vigor studies ( 123 1a, b); dimethylamine salt, TEP ° seedling emergence and vegetative vigor studies ( 123 1a, b); diglycoamine salt, TEP ° seedling emergence and vegetative vigor studies ( 123 1a, b); isopropylamine salt, TEP ° seedling emergence and vegetative vigor studies ( 123 1a, b); sodium salt, TEP ° seedling emergence and vegetative vigor studies ( 123 1a, b); potassium salt, TEP"

A DCI was issued in 1992 but EFED has not received any of the plant studies cited above.

BASF Comment: BASF notes that the mammalian NOAEC reported as mg ai/ kg diet should be mg ai/ kg bw/ day and that mistake has lead to computational errors in the risk quotients for chronic risk to mammals.

EFED Response: EFED agrees that this error occurred. The change in units has been made in the revised assessment, and the chronic mammalian RQs have been recomputed. EFED notes the RQs change only slightly, and the risk conclusions do not change. Because an updated version of T REX ( version 1.2.3, August 2005) is now available, EFED has used that version to recalculate the RQs. Because the acute avian RQs also change slightly, the tables of acute avian RQs also are updated in the revised assessment, as well the T REX results presented in Appendix C for sugarcane.

BASF Comment: BASF states that they are unaware that EPA has specific data requirements for riparian habitats.

EFED Response: EFED has no specific data requirements for riparian habitats. EFED uses the terrestrial plant phytotoxicity data ( guideline studies 123 1a, b) for risk assessments to both upland and lowland plants. The difference is in the exposure scenarios ( sheet runoff onto upland habitats versus channelized runoff onto lowland ( i. e., semi aquatic) habitats).