[Federal Register: October 16, 2009 (Volume 74, Number 199)]
[Rules and Regulations]
[Page 53165-53167]
[DOCID:fr16oc09-12]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 878

[Docket No. FDA-2009-N-0333]

Medical Devices; Plastic Surgery Devices; Classification of Wound
Dressing With Poly (Diallyl Dimethyl Ammonium Chloride) Additive

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is classifying the
wound dressing with pDADMAC additive into class II (special controls).
Elsewhere in this issue of the Federal Register, FDA is announcing the
availability of a guidance document entitled ``Class II Special
Controls Guidance Document: Wound Dressing With Poly (Diallyl Dimethyl
Ammonium Chloride) (pDADMAC) Additive,'' which will serve as the
special control for this device type. The agency is classifying this
device type into class II (special controls) in order to provide a
reasonable assurance of safety and effectiveness of these devices.

DATES: This final rule is effective November 16, 2009.

FOR FURTHER INFORMATION CONTACT: Sam Arepalli, Center for Devices and
Radiological Health (HFZ-410), Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, rm. 3612, Silver Spring, MD 20993, 301-796-
6434.

SUPPLEMENTARY INFORMATION:

I. What Is the Background of This Rulemaking?

    In accordance with section 513(f)(1) of the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 360c(f)(1)), devices that were not in
commercial distribution before May 28, 1976, the date of enactment of
the Medical Device Amendments of 1976 (the amendments), generally
referred to as postamendments devices, are classified automatically by
statute into class III without any FDA rulemaking process. These
devices remain in class III and require premarket approval, unless the
device is classified or reclassified into class I or class II, or FDA
issues an order finding the device to be substantially equivalent, in
accordance with section 513(i) of the act, to a predicate device that
does not require premarket approval. The agency determines whether new
devices are substantially

equivalent to predicate devices by means of premarket notification
procedures in section 510(k) of the act (21 U.S.C. 360(k)) and part 807
of FDA's regulations (21 CFR part 807).
    Section 513(f)(2) of the act provides that any person who submits a
premarket notification under section 510(k) of the act for a device
that has not previously been classified may, within 30 days after
receiving an order classifying the device in class III under section
513(f)(1) of the act, request FDA to classify the device under the
criteria set forth in section 513(a)(1) of the act. FDA shall, within
60 days of receiving such a request, classify the device by written
order. This classification shall be the initial classification of the
device type. Within 30 days after the issuance of an order classifying
the device, FDA must publish a notice in the Federal Register
announcing such classification (section 513(f)(2) of the act).
    In accordance with section 513(f)(1) of the act, FDA issued a
written notice of classification on June 23, 2006, classifying the QMT
NIMBUS Barrier Gauze Dressing intended for use as a primary dressing
for exuding wounds, 1st and 2d degree burns, and surgical wounds, to
secure and prevent movement of a primary dressing, and as a wound
packing in class III, because it was not substantially equivalent to a
device that was introduced or delivered for introduction into
interstate commerce for commercial distribution before May 28, 1976, or
a device that was subsequently reclassified into class I or class II.
On May 10, 2007, Quick-Med Technologies, Inc., submitted a petition
requesting classification of the QMT NIMBUS Barrier Gauze Dressing
intended for use as a primary dressing for exuding wounds, 1st and 2d
degree burns, and surgical wounds, to secure and prevent movement of a
primary dressing, and as a wound packing under section 513(f)(2) of the
act. The manufacturer recommended that the device be classified into
class II (Ref. 1).
    In accordance with section 513(f)(2) of the act, FDA reviewed the
petition in order to classify the device under the criteria for
classification set forth in 513(a)(1) of the act. Devices are to be
classified into class II if general controls, by themselves, are
insufficient to provide reasonable assurance of safety and
effectiveness, but there is sufficient information to establish special
controls to provide reasonable assurance of the safety and
effectiveness of the device for its intended use. After review of the
information submitted in the petition, FDA determined that the wound
dressing with pDADMAC additive can be classified into class II with the
establishment of special controls. FDA believes that these special
controls, in addition to general controls, are adequate to provide
reasonable assurance of the safety and effectiveness of the device. The
device is assigned the generic name ``Wound Dressing with pDADMAC
Additive.'' A wound dressing with pDADMAC additive is a medical device
that is used as a primary dressing for exuding wounds, 1st and 2d
degree burns, and surgical wounds, to secure and prevent movement of a
primary dressing, and as a wound packing.
    FDA has identified the following risks to health associated with
this type of device as:
    1. Infection,
    2. Adverse tissue reactions,
    3. Leaching (of the pDADMAC into the wound),
    4. Degradation (of materials leading to device failure), and
    5. Necrosis and pain.
    FDA believes that the class II special controls guidance document
will aid in mitigating the potential risks to health as described in
Table 1 of this document.

            Table 1.--Risks to Health and Mitigation Measures
------------------------------------------------------------------------
          Identified Risk              Recommended Mitigation Measures
------------------------------------------------------------------------
Infection                            Sterility
                                     Biochemical testing
------------------------------------------------------------------------
Adverse tissue reaction              Biocompatibility
------------------------------------------------------------------------
Leaching (of the additive pDADMAC    Non-leachability
 into the wound)
------------------------------------------------------------------------
Degradation (of materials leading    Shelf life testing
 to device failure)
------------------------------------------------------------------------
Necrosis or pain                     Labeling
------------------------------------------------------------------------

    FDA believes that the special controls, in addition to general
controls, address the risks to health identified previously and provide
reasonable assurances of the safety and effectiveness of the device
type. Thus, on February 25, 2009, FDA issued an order to the petitioner
classifying the device into class II. FDA is codifying this
classification at 21 CFR 878.4015.
    Following the effective date of the final classification rule,
manufacturers will need to address the issues covered in the special
controls guidance. However, the manufacturer need only show that its
device meets the recommendations of the guidance or in some other way
provides equivalent assurance of safety and effectiveness.
    Section 510(m) of the act provides that FDA may exempt a class II
device from the premarket notification requirement under section 510(k)
of the act, if FDA determines that premarket notification is not
necessary to provide reasonable assurance of the safety and
effectiveness of the device. There is no such exemption for this type
of device. Persons who intend to market this type of device must submit
to FDA a premarket notification, prior to marketing the device, which
contains information about the wound dressing with pDADMAC additive
they intend to market.

II. What Is the Environmental Impact of This Rule?

    The agency has determined under 21 CFR 25.34(b) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Thus, neither an environmental
assessment nor an environmental impact statement is required.

III. What Is the Economic Impact of This Rule?

    FDA has examined the impacts of the final rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies

to assess all costs and benefits of available regulatory alternatives
and, when regulation is necessary, to select regulatory approaches that
maximize net benefits (including potential economic, environmental,
public health and safety, and other advantages; distributive impacts;
and equity). The agency believes that this final rule is not a
significant regulatory action under the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because classification of this device into class II
will relieve manufacturers of the cost of complying with the premarket
approval requirements of section 515 of the act (21 U.S.C. 360e), and
may permit small potential competitors to enter the marketplace by
lowering their costs, the agency certifies that the final rule will not
have a significant economic impact on a substantial number of small
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.''
    The current threshold after adjustment for inflation is $133
million, using the most current (2008) Implicit Price Deflator for the
Gross Domestic Product. FDA does not expect this final rule to result
in any 1-year expenditure that would meet or exceed this amount.

IV. Does This Final Rule Have Federalism Implications?

    FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. Section 4(a) of the Executive order
requires agencies to ``construe * * * a Federal statute to preempt
State law only where the statute contains an express preemption
provision or there is some other clear evidence that the Congress
intended preemption of State law, or where the exercise of State
authority conflicts with the exercise of Federal authority under the
Federal statute.'' Federal law includes an express preemption provision
that preempts certain State requirements ``different from or in
addition to'' certain federal requirements applicable to devices (21
U.S.C. 360k; Medtronic v. Lohr, 518 U.S. 470 (1996); Riegel v.
Medtronic, 128 S. Ct. 999 (2008)).
    The special controls established by this final rule create
``requirements'' for specific medical devices under 21 U.S.C. 360k,
even though product sponsors have some flexibility in how they meet
those requirements (Papike v. Tambrands, Inc., 107 F.3d 737, 740-42
(9th Cir. 1997)).

V. How Does This Rule Comply With the Paperwork Reduction Act of 1995?

    This final rule contains no collections of information. Therefore,
clearance by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 is not required. Elsewhere in this
issue of the Federal Register, FDA is issuing a notice announcing the
guidance for the final rule. This guidance, ``Class II Special Controls
Guidance Document: Wound Dressing With Poly (Diallyl Dimethyl Ammonium
Chloride) (pDADMAC) Additive,'' references previously approved
collections of information found in FDA regulations.

VI. What References Are on Display?

    The following reference has been placed on display in the Division
of Dockets Management (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852, and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Petition from Quick-Med Technologies, Inc., May 10, 2007.

List of Subjects in 21 CFR Part 878

    Medical devices.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
878 is amended as follows:

PART 878--GENERAL AND PLASTIC SURGERY DEVICES

0
1. The authority citation for 21 CFR part 878 continues to read as
follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

0
2. Section 878.4015 is added to subpart E to read as follows:

Sec.  878.4015  Wound dressing with poly (diallyl dimethyl ammonium
chloride) (pDADMAC) additive.

    (a) Identification. A wound dressing with pDADMAC additive is
intended for use as a primary dressing for exuding wounds, 1st and 2d
degree burns, and surgical wounds, to secure and prevent movement of a
primary dressing, and as a wound packing.
    (b) Classification. Class II (special controls). The special
control is: the FDA guidance document entitled ``Class II Special
Controls Guidance Document: Wound Dressing With Poly (Diallyl Dimethyl
Ammonium Chloride) (pDADMAC) Additive.'' See Sec.  878.1(e) for
availability of this guidance document.

    Dated: October 2, 2009.
Jeffrey Shuren,
Acting Director, Center for Devices and Radiological Health.
[FR Doc. E9-24963 Filed 10-15-09; 8:45 am]

BILLING CODE 4160-01-S


[Federal Register Volume 80, Number 160 (Wednesday, August 19, 2015)]
[Proposed Rules]
[Pages 50235-50237]
[FR Doc No: 2015-20295]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 71

[Docket No. FAA-2015-1138; Airspace Docket No. 15-AWP-3]

Proposed Amendment of Class D Airspace; Van Nuys, CA

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice of proposed rulemaking (NPRM).

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SUMMARY: This action proposes to amend Class D airspace and Class E
surface area airspace at Van Nuys Airport, Van Nuys, CA. After
reviewing the airspace, the FAA found the need to increase the Class D
airspace and Class E surface areas for the safety and management of
Instrument Flight Rules (IFR) operations for arriving and departing
aircraft at the airport. The geographic coordinates of the satellite
airports also would be adjusted for Class D airspace and Class E
surface area airspace as well as noting a name change for Burbank-
Glendale-Pasadena Airport.

DATES: Comments must be received on or before October 5, 2015.

ADDRESSES: Send comments on this proposal to the U.S. Department of
Transportation, Docket Operations, M-30, West Building Ground Floor,
Room W12-140, 1200 New Jersey Avenue SE., Washington, DC 20590;
telephone<PHONE_NUMBER>. You must identify FAA Docket No. FAA-2015-
1138; Airspace Docket No. 15-AWP-3, at the beginning of your comments.
You may also submit comments through the Internet at http://www.regulations.gov. You may review the public docket containing the
proposal, any comments received, and any final disposition in person in
the Dockets Office between 9:00 a.m. and 5:00 p.m., Monday through
Friday, except Federal holidays. The Docket Office (telephone 1-800-
647-5527), is on the ground floor of the building at the above address.
    FAA Order 7400.9Y, Airspace Designations and Reporting Points, and
subsequent amendments can be viewed online at http://www.faa.gov/air_traffic/publications/. The Order is also available for inspection
at the National Archives and Records Administration (NARA). For
information on the availability of this material at NARA, call 202-741-
6030, or go to http://www.archives.gov/federal_register/code_of_federal-regulations/ibr_locations.html.

    FAA Order 7400.9, Airspace Designations and Reporting Points, is
published yearly and effective on September 15. For further
information, you can contact the Airspace Policy and Regulations Group,
Federal Aviation Administration, 800 Independence Avenue SW.,
Washington, DC 20591; telephone:<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Steve Haga, Federal Aviation
Administration, Operations Support Group, Western Service Center, 1601
Lind Avenue SW., Renton, WA 98057; telephone<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Authority for This Rulemaking

    The FAA's authority to issue rules regarding aviation safety is
found in Title 49 of the United States Code. Subtitle I, Section 106
describes the authority of the FAA Administrator. Subtitle VII,
Aviation Programs, describes in more detail the scope of the agency's
authority. This rulemaking is promulgated under the authority described
in Subtitle VII, Part, A, Subpart I, Section 40103. Under that section,
the FAA is charged with prescribing regulations to assign the use of
airspace necessary to ensure the safety of aircraft and the efficient
use of airspace. This regulation is within the scope of that authority
as it would amend Class D and Class E airspace at Van Nuys Airport, Van
Nuys, CA.

Comments Invited

    Interested parties are invited to participate in this proposed
rulemaking by submitting such written data, views, or arguments, as
they may desire. Comments that provide the factual basis supporting the
views and suggestions presented are particularly helpful in developing
reasoned regulatory decisions on the proposal. Comments are
specifically invited on the overall regulatory, aeronautical, economic,
environmental, and energy-related aspects of the proposal.
Communications should identify both docket numbers and be submitted in
triplicate to the address listed above. Commenters wishing the FAA to
acknowledge receipt of their comments on this notice must submit with
those comments a self-addressed, stamped postcard on which the
following statement is made: ``Comments to Docket No. FAA-2015-1138;
Airspace Docket No. 15-AWP-3.'' The postcard will be date/time stamped
and returned to the commenter.

Availability of NPRMs

    An electronic copy of this document may be downloaded through the
Internet at http://www.regulations.gov. Recently published rulemaking
documents can also be accessed through the FAA's Web page at http://www.faa.gov/airports_airtraffic/air_traffic/publications/airspace_amendments/.
    You may review the public docket containing the proposal, any
comments received, and any final disposition in person in the Dockets
Office (see the ``ADDRESSES'' section for the address and phone number)
between 9:00 a.m. and 5:00 p.m., Monday through Friday, except federal
holidays. An informal docket may also be examined during normal
business hours at the Northwest Mountain Regional Office of the Federal
Aviation Administration, Air Traffic Organization, Western Service
Center, Operations Support Group, 1601 Lind Avenue SW., Renton, WA
98057.
    Persons interested in being placed on a mailing list for future
NPRMs should contact the FAA's Office of Rulemaking,<PHONE_NUMBER>,
for a copy of Advisory Circular No. 11-2A, Notice of Proposed
Rulemaking Distribution System, which describes the application
procedure.

Availability and Summary of Documents Proposed for Incorporation by
Reference

    This document proposes to amend FAA Order 7400.9Y, Airspace
Designations and Reporting Points, dated August 6, 2014, and effective
September 15, 2014. FAA Order 7400.9Y is publicly available as listed
in the ADDRESSES section of this proposed rule. FAA Order 7400.9Y lists
Class A, B, C, D, and E airspace areas, air traffic service routes, and
reporting points.

The Proposal

    The FAA is proposing an amendment to Title 14 Code of Federal
Regulations (14 CFR) Part 71 by modifying Class D airspace and Class E
surface area airspace at Van Nuys Airport, Van Nuys, CA. A review of
the airspace revealed additional Class D airspace and Class E surface
area airspace necessary to support instrument arrival procedures at the
airport. Class D airspace would extend upward from the surface to but
not including 3,000 feet within a 4.3-mile radius of Van Nuys Airport
excluding that airspace within the Bob Hope Airport, Burbank, CA,
formerly Burbank-Glendale-Pasadena Airport, CA, Class C airspace area,
and excluding that airspace within a 1.8-mile radius of Whiteman
Airport, Los Angeles, CA. Class E surface area airspace would extend
upward from the surface within a 4.3-mile radius of Van Nuys Airport
excluding that airspace within the Bob Hope Airport, Burbank, CA,
formerly Burbank-Glendale-Pasadena Airport, CA, Class C airspace area,
and excluding that airspace within a 1.8-mile radius of Whiteman
Airport, Los Angeles, CA. The geographic coordinates for both airports
would be adjusted to be in concert with the FAAs aeronautical data
base.
    Class D and Class E airspace designations are published in
paragraph 5000 and 6002, respectively, of FAA Order 7400.9Y, dated
August 6, 2014, and effective September 15, 2014, which is incorporated
by reference in 14 CFR 71.1. The Class D and Class E airspace
designations listed in this document will be published subsequently in
the Order.

Regulatory Notices and Analyses

    The FAA has determined this proposed regulation only involves an
established body of technical regulations for which frequent and
routine amendments are necessary to keep them operationally current.
Therefore, this proposed regulation; (1) is not a ``significant
regulatory action'' under Executive Order 12866; (2) is not a
``significant rule'' under DOT Regulatory Policies and Procedures (44
FR 11034; February 26, 1979); and (3) does not warrant preparation of a
regulatory evaluation as the anticipated impact is so minimal. Since
this is a routine matter that will only affect air traffic procedures
and air navigation, it is certified this proposed rule, when
promulgated, would not have a significant economic impact on a
substantial number of small entities under the criteria of the
Regulatory Flexibility Act.

Environmental Review

    This proposal will be subject to an environmental analysis in
accordance with FAA Order 1050.1E, ``Environmental Impacts: Policies
and Procedures'' prior to any FAA final regulatory action.

List of Subjects in 14 CFR Part 71

    Airspace, Incorporation by reference, Navigation (air).

The Proposed Amendment

    Accordingly, pursuant to the authority delegated to me, the Federal
Aviation Administration proposes to amend 14 CFR part 71 as follows:

PART 71--DESIGNATION OF CLASS A, B, C, D, AND E AIRSPACE AREAS; AIR
TRAFFIC SERVICE ROUTES; AND REPORTING POINTS

0
1. The authority citation for 14 CFR part 71 continues to read as
follows:

    Authority:  49 U.S.C. 106(f), 106(g); 40103, 40113, 40120; E.O.
10854, 24 FR 9565, 3 CFR, 1959-1963 Comp., p. 389.

Sec.  71.1  [Amended]

0
2. The incorporation by reference in 14 CFR 71.1 of FAA Order 7400.9Y,
Airspace Designations and Reporting Points, dated August 6, 2014, and
effective September 15, 2014, is amended as follows:

    Paragraph 5000: Class D Airspace.
* * * * *

AWP CA D Van Nuys, CA [Modified]

Van Nuys, Van Nuys Airport, CA
    (lat. 34[deg]12'35'' N., long. 118[deg]29'24'' W.)
Burbank, Bob Hope Airport, CA
    (lat. 34[deg]12'03'' N., long. 118[deg]21'31'' W.)
Los Angeles, Whiteman Airport, CA
    (lat. 34[deg]15'34'' N., long. 118[deg]24'48'' W.)

    That airspace extending upward from the surface to but not
including 3,000 feet MSL within a 4.3-mile radius of Van Nuys
Airport, excluding that airspace within the Bob Hope Airport, CA,
Class C airspace area, and excluding that airspace within a 1.8-mile
radius of Whiteman Airport, CA. This Class D airspace area is
effective during the specific dates and times established in advance
by a Notice to Airmen. The effective date and time will thereafter
be continuously published in the Airport/Facility Directory.

Paragraph 6002: Class E Airspace Designated as Surface Areas.

* * * * *

AWP CA E2 Van Nuys, CA [Modified]

Van Nuys, Van Nuys Airport, CA
    (lat. 34[deg]12'35'' N., long. 118[deg]29'24'' W.)
Burbank, Bob Hope Airport, CA
    (lat. 34[deg]12'03'' N., long. 118[deg]21'31'' W.)
Los Angeles, Whiteman Airport, CA
    (lat. 34[deg]15'34'' N., long. 118[deg]24'48'' W.)

    That airspace extending upward from the surface within a 4.3-
mile radius of Van Nuys Airport, excluding that airspace within the
Bob Hope Airport, CA, Class C airspace area, and excluding that
airspace within a 1.8-mile radius of Whiteman Airport, CA.

    Issued in Seattle, Washington, on August 6, 2015
Christopher Ramirez,
Manager, Operations Support Group, Western Service Center.
[FR Doc. 2015-20295 Filed 8-18-15; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register: July 3, 2008 (Volume 73, Number 129)]
[Notices]
[Page 38197]
[DOCID:fr03jy08-47]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. CP08-31-000]

Transcontinental Gas Pipe Line Corporation; Notice of Site Visit

June 25, 2008.
    On July 9, 2008, staff of the Federal Energy Regulatory Commission
will conduct a site visit of the Transcontinental Gas Pipe Line
Corporation's proposed Sentinel Expansion Project--Downingtown Mainline
``A'' Replacement. The purpose of this site visit is to review the
residential areas potentially affected by the proposed replacement of
mainline ``A'' and to look at potential alternatives.
    Interested parties may accompany staff during its visit and should
meet at 10 a.m. (EDT) at: Target, Western Parking Lot closest to North
Pottstown Pike, 201 Sunrise Boulevard, Exton, PA 19341, FERC Contact
Phone Number (day of the site visit):<PHONE_NUMBER>.
    Those planning to accompany staff during its visit must provide
their own transportation.
    For additional information, please contact the Commission's Office
of External Affairs at 1-866-208-FERC.

Kimberly D. Bose,
Secretary.
[FR Doc. E8-15089 Filed 7-2-08; 8:45 am]

BILLING CODE 6717-01-P


[Federal Register Volume 77, Number 95 (Wednesday, May 16, 2012)]
[Notices]
[Page 28872]
[FR Doc No: 2012-11827]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Notice of FERC Staff Attendance at the SPP-ITO Louisville Gas &
Electric/Kentucky Utilities Stakeholder Meeting

    The Federal Energy Regulatory Commission hereby gives notice that
members of its staff may attend the meeting noted below. Their
attendance is part of the Commission's ongoing outreach efforts.

SPP-ITO Louisville Gas & Electric/Kentucky Utilities Stakeholder
Meeting

May 15, 2012 (8:30 a.m.-6 p.m.)

    This meeting will be held at the Hyatt Regency Louisville, 320 W.
Jefferson, Louisville, KY 40202.
    The discussions may address matters at issue in the following
proceedings:

Docket No. ER12-1357-000--Louisville Gas & Electric Company
Docket No. ER12-1697-000--Louisville Gas & Electric Company
Docket No. ER12-1732-000--Louisville Gas & Electric Company

    These meetings are open to the public.
    For more information, contact Peter Nagler, Office of Energy Market
Regulation, Federal Energy Regulatory Commission at<PHONE_NUMBER> or
<EMAIL_ADDRESS>
    Dated: May 10, 2012.
Kimberly D. Bose,
Secretary.
[FR Doc. 2012-11827 Filed 5-15-12; 8:45 am]
BILLING CODE 6717-01-P


triglycerides, phospholipids and free fatty acids in the liver and
testes and lower serum testosterone and estradiol levels suggesting
gonadotoxic effects.  Body weight gain at sacrifice time in the nicotine
treated rats was less than the control rats (22.14 ± 0.86 g vs 34.28 ±
1.61 g in the controls). The activity of the lipogenic enzymes (NADPH
generating enzymes) was higher in the liver, but not altered in the
testes.  Mecamylamine (a known inhibitor of nicotine) counteracted the
effects seen in rats treated with nicotine only.

Non-guideline	Subchronic

Adult Female Rats	Fung et al, 1999

nicotine 3.0 or 4.5 mg/kg/day (9-10 rats/group) by subcutaneous osmotic
minipumps	had significantly lower levels of 25-hydroxyvitamin D than
controls. The high dose nicotine group had smaller vertebral areas and a
lower bone mineral content and significantly lower tibial endocortical
mineral apposition rate than the controls.  Nicotine serum levels at
sacrifice time were 60 ± 6 and 85 ± 5 ng/mL at the low and high dose,
respectively.

Non-guideline	Subchronic

Male New Zealand white rabbits

	Booyse et al, 1981

Nicotine tartrate, administered orally (2.4 mg/kg/day) in drinking water
for 25 weeks to 10 rabbits	produced in vivo morphologic effect on
endothelial cells in the aortic arch.  Fasting serum levels of glucose,
triglycerides, total cholesterol, and LDL-cholesterol were significantly
(<0.001) elevated in nicotine-treated rabbits.   Endothelial cells from
nicotine-treated arched areas (Evans-blue-stained) showed extensive
changes such as increased cytoplasmic silver disposition, increased
formation of microvilli, and numerous focal areas of

 “ruffled” endothelium (projections on cell surfaces).

Non-guideline	Subchronic

Sprague Dawley Male Rats	Chowdhury et al, 1990

nicotine ingested for 16 weeks at 50 and 200 mg/l in drinking water
equivalent to 7  and 28 mg/kg/day	alters metabolic, endocrine, and
pathologic factors that may be responsible, at least in part, for the
development of gastrointestinal ulcers and pancreatitis.
Endocrinological studies showed that the plasma levels of CCK were
significantly increased with nicotine but the amylase secretory response
of pancreatic acinar cells was inhibited in response to CCK-8 and
carbachol.  Prominent loss of gastric mucosal surface was found in
nicotine-treated animals with gross microscopic evidence of bleeding
ulcers.  All of the metabolic parameters except body weight gain were
reversed upon nicotine withdrawal. Histopathologic data showed a partial
but not a complete recovery of the pancreatic acinar cell morphology and
gastric mucosal surface following 4 weeks of nicotine withdrawal.

870.3200

	21/28-Day dermal toxicity (species)	NR

	870.3250

	90-Day dermal toxicity (species)	NR

	Non-Guideline

	Chronic, Inhalation

Female rats	Waldum et al, 1996

inhalation to 501±151 µg/m3 , 20 h/day, 5 days/week for 2 years
(equivalent to 0.3 ± 0.09 mg/kg/day)	resulted in slightly depressed
weight (Waldum et al, 1996).  Nicotine plasma concentration after 5 days
was 108.4 ± 55.1 ng/mL and remained fairly constant and after 24 months
it was 129.8±43.0 ng/mL.  All parameters measured were comparable to
the controls except for elevated adenomas of pituitary gland (4/59)
which was attributed to the neuroendocrine action of nicotine.  There
was no increase in mortality, in atherosclerosis or frequency of tumors
in these rats compared with controls. Particularly, there were no
microscopic or macroscopic lung tumors or any increase in pulmonary
neuroendocrine cells. Throughout the study, however, the body weight of
the nicotine exposed rats was reduced as compared with controls.

Non-Guideline

	Developmental

Mouse	Saad et al, 1990, 1991

Pregnant CD-1 mice, exposed to ip injection of 0.1% nicotine sulfate at
a dose of 1.67 mg/kg body weight/day on gestational days 6-15	Depressed
maternal weight gain and fetal weight. Fetal crown-rump length fetal
head dimensions were significantly reduced.  Histological examination
revealed that 9.6% of fetuses of nicotine injected mothers presented
clefts of the palate (none in the control). Nicotine treatment also had
teratogenic effects on first molar odontogenesis in the mouse. The
mesiodistal diameter of molar tooth germs of nicotine treated fetuses
without cleft palate was significantly less than those of controls.

Non-Guideline	Developmental

Rat	Chowdhury & Bromage 2000

experimental details of nicotine treatment were not presented	dental
asymmetries (calculated as a size difference between a tooth and its
antimere) were significantly increased while occlusal areas were
significantly decreased in nicotine-exposed rats compared to control
rats. Females tending to exhibit the deleterious effects of nicotine
more so than males

Non-Guideline	Developmental

Mouse	Nasrat et al, 1986

Nicotine administered subcutaneously to mice during gestation at ≥ 450
μg/kg/day dose	Nicotine increased the perinatal mortality.  The male to
female ratio was in favor of females in the nicotine treated mice during
the 2nd and 3rd trimester. When large doses of the drug were given
especially in the second and third trimesters of gestation, there was a
significant shortening of the gestation period.

Non-Guideline	Developmental

Mouse	Leblebicioglu-Bekcioglu et al, 1995

Nicotine (12 mkg or nicotine plus caffeine (125 mkg) by intubation
GD6-18. (7/group)	Nicotine had minimal ossification effects on the
fetuses as measured by staging and measuring craniofacial bones, and
counting ossification centra in sternbrae and in cervical and
sacrococcygeal vertebrae.  Caffeine had greater effect.

Non-Guideline	Developmental

Rat	Williams & Kanagasabai, 1984.

2.46 ± 0.18 mg/kg/day in drinking water. GD 0-20

	Mean fetal body fat was significantly increased in fetuses of rats
administered nicotine during pregnancy.  Rate for maternal lypolysis
were higher in the nicotine treated animals.  Maternal body weights
gains were significantly lower (77.2% of controls, p < 0.001).

Non-Guideline

	Developmental

Rat	(Witschi et al, 1994)

Nicotine - delivering transdermal patches applied on the back of
pregnant female rats

3.5mg/day (2 rats GD 2-19; 8 rats GD 2-7; 3 rats GD 2-5)

1.75 mg/day patch (13 rats GD 2-19; 4 rats GD 2-7)	Nicotine –caused
100% pregnancy failure in animals treated GD2-19 with 3.5 mg/day and 50%
in animals treated GD 2-7, and 55% in animals exposed GD2-19 to 1.75
mg/day.  Litter size and pup weights were not affected. Nicotine and
cotinine not detected in animals exposed the first trimester of
pregnancy. In animals exposed the entire pregnancy at 1.75 mg/day
patches, 3 pregnant animals out of six had measurable nicotine levels
(43 ± 22 ng/mL) and all had cotinine levels (100 ± 48 ng/mL). The non
pregnant females of the 1.75 mg/day patches had 70 ± 57 ng/mL of plasma
nicotine and 231 ± 84 ng/mL of plasma cotinine. In the two animals
exposed to 3.5 mg/day patches and became nonpregnant, nicotine plasma
levels were 241 ± 51 ng/mL and cotinine levels of 302 ± 94 ng/mL.

Non-Guideline

	Developmental

Rat (Sprague Dawley	Slotkin et al, 1986

Subcutaneous injection of nicotine (3 mg/kg/day from gestation day 4
-20) to timed pregnant Sprague Dawley rats (41 control and 57 nicotine
treated)	significant reduced maternal weight gain and increased maternal
mortality (14%) and fetal resorptions (13%).  Litter size was not
affected. Biochemical changes in the fetal brain (elevation of fetal
ornithine decarboxylase activity, suppression of DNA synthesis (most
profound in cerebellum), desynchronization of the ontogenctic patterns
of DNA, RNA and proteins in every brain region)

Non-Guideline

	Developmental

Rat (Sprague Dawley)	Muneoka et al, 1999

Subcutaneous injections of nicotine (3 or 6 mg/kg/day, divided into two
doses) on GD 7-20 to pregnant rats (10/group)	Abnormal behavior such as
ataxic gate, decrease in spontaneous activity, creeping, or salivation
in pregnant rats (3 or 6 mg/kg/day) and convulsion and ptosis (6 mg/kg),
decreased maternal body weight at GD 14 (both groups) and reduced
offspring body weight.   Significant decreases in dihydroxyphenylacetic
acid (DOPAC) content in the neocortex and in both the neocortex and in
the midbrain plus pons medulla, respectively.

Non-Guideline

	Developmental

Rat	Hussein et al, 2007

nicotine dose of 6 mg/kg/day administered to Sprague Dawley time-mated
rats from gestation day 3 through 21 by osmotic mini pump	resulted in
nicotine plasma concentrations of 115-174 ng/mL.  Maternal hematocrit
was not affected by nicotine administration, or the number of pups per
litter, pup weight, placental weight or the weight of various pups'
organs. Maternal weight changes were comparable in the nicotine treated
and control groups. Maternal plasma coticosterone concentrations were
not affected by the nicotine infusion versus the control rats.

Non-Guideline	Developmental

Rat	Zahalka et al 1993

Nicotine's effects on ontogeny of postsynaptic muscarinic M1-receptors
in rat striatum and hippocampus were investigated after continuous
maternal infusions (15-21 rats/treatment) of 2 mg/kg/day or 6 mg/kg/day
from GD 4 through 20. 	Brain region weights were unaffected. Postnatal
development of striatal M1-receptor binding, as identified with
[3H]pirenzepine, was significantly impaired with either of the fetal
nicotine regimens. Treatment with 2 mkg also produced alterations in
striatal receptor affinity state, characterized by enhanced ability of
an agonist (oxotremorine-M) to displace [3H]pirenzepine; raising the
dose to 6  mkg masked the affinity shift by affecting G-protein
regulatory mechanisms, such that addition of the GTP analog, GppNHp,
produced a larger decrease in agonist affinity. In the hippocampus, no
such effects on receptor binding, affinity state, or G-protein
regulation were seen with either regimen.

870.3800

	Reproduction and fertility effects

(species)	NA

	870.4100a

	Chronic toxicity

(species)	NA

	870.4100b

	Chronic toxicity (dog)	NA

	870.4200

	Carcinogenicity

(rat)	NA

	870.4300

	Carcinogenicity

(mouse)	NA

	Gene Mutation

Non-Guideline

Tests by the R. J. Reynolds Tobacco Co. (Doolittle et al, 1995)	Nicotine
and its major metabolites: cotinine, nicotine-N'-oxide,
cotinine-N-oxide, and trans-3'-hydroxycotinine in the Salmonella
mutagenicity assay (strains TA98, TA100, TA1535, TA1537, and TA1538) at
0 to 1000 µg/plate and in the Chinese hamster ovary sister-chromatid
exchange (SCE) assay at 0 to 1000 µg /mL,  with and without S9
metabolic activation did not increase the frequency of mutations or the
frequency of SCEs.

Cytogenetics

Non-Guideline	Bacterial luminescence genotoxicity test	Yim & Hee 1995
Cotinine  was positive in the presence or absence of S9 at 1.25 - 2.5
mg/mL (9- 30 h incubation).   Nicotine was not positive to 20 mg/mL
concentrations for up to 40 hours of incubation. Nicotine/cotinine
mixtures were still positive at physiological concentrations, with
potentiation relative to cotinine alone with and without S9

Other Effects

Non-Guideline	Chromsomal aberration (CA) and sister chromatid exchange
(SCE)	Trivedi et al, 1990	Nicotine induced chromsomal aberration (CA)
and sister chromatid exchange (SCE) frequency in a dose and duration
dependent manner and at concentrations comparable to the saliva levels
of nicotine achieved during tobacco chewing.  Statistically significant
elevations in CA frequency were observed with nicotine concentrations >
375 (g/mL; SCE frequencies were increased significantly > 150 µg/mL.
Nicotine (150 µg/mL) and in combination with arecoline (an areca nut
alkaloid) incubated in Chinese hamster ovary (CHO) cell line (-S9)
increased the SCE frequency/cell.  Nicotine alone at 300 (g/mL did not
increase the frequency of CHE/cell, but in combination with arecoline it
did at ≥90 µg/mL.

Genotoxicity Non-Guideline 	Chromosomal aberrations	Bishun et al, 1972
Nicotine was cytotoxic at 1.5 - 2.0 µg/mL to human leucocytes in
culture in vitro without producing any chromosome damage.  However,
gross chromosomal aberrations including fuzzy chromosomes (stickiness),
aneuploidy and translocations were observed in the mice receiving low
tolerable doses of the drug (0.07 -0.09 µg/total body weight injected
to 5 weeks-4 month old mice in saline , two weekly injections for 3
weeks before sacrifice and preparing  the bone marrow from the femora.

Genotoxicity Non-Guideline	DNA damage	Kleinsasser et al, 2005

The genotoxicity of nicotine was tested with the alkaline single-cell
microgel electrophoresis (Comet) assay using human lymphocytes and
target cells from lymphatic tissue of the palatine tonsils from healthy
patients.	Nicotine exerted significant direct genotoxic effects in human
target cells in vitro.  One hour exposure to nicotine at 0.125, 0.25,
0.5, 1, 2, and 4 mM induced a statistically significant dose-dependent
increase of DNA migration up to 3.8-fold and 3.2-fold in tonsillar cells
and lymphocytes, respectively. The minimum concentration eliciting
significant DNA damage was 0.5 mM nicotine. The genotoxic effect was
confirmed in a second series of experiments using nicotine of high
purity from two different suppliers.  Finally, DNA damage by nicotine
was compared in cells incubated in medium strictly adjusted to neutral
pH, with nonadjusted medium becoming alkaline with increasing nicotine
concentrations. Again no differences in DNA migration were observed.
However, no differences in DNA damage were observed in cells from
smokers and nonsmokers incubated without nicotine. The lack of higher
DNA damage in smokers compared to nonsmokers could be a question of
nicotine dose, rapid DNA repair, or interactions with other smoke
constituents.

Genotoxicity Non-Guideline	Human nasal epithelia.	Sassen et al 2005
Nicotine produced genotoxic effects in human nasal epithelia.

Genotoxicity Non-Guideline	Human gingival fibroblasts (HGFs)	Argentin
and Cicchetti, 2004	Nicotine caused concomitant genotoxic and
antiapoptotic effect in human gingival fibroblasts (HGFs) in the
cytokinesis-block micronucleus (CBMN) test.   Treatment of HGFs with
nicotine, at a concentration of 1 uM, caused a statistically significant
increase of micronucleus (MN) frequency at the tested time intervals,
while no change was detected in cell growth under the same conditions.
Preincubation of HGFs with 1 uM nicotine strongly attenuated
staurosporine (STP)-induced apoptosis. Cultures exposed to nicotine
showed an increase of reactive oxygen species, as determined by
increased levels of 2,7-dichlorofluorescein (DCF). When cells were
prelabeled with N-acetyl-cysteine (NAC), a substrate for glutathione
synthesis, and catalase (CAT), the oxygen free radical scavenger, a
significant reduction in cytogenetic damage was observed.

870.6200a

	Acute neurotoxicity screening battery	NA

	870.6200b

	Subchronic neurotoxicity screening battery	NA

	870.6300

Non-Guideline

	Developmental neurotoxicity	Temocin et al, 1993

subcutaneous injection of nicotine (0.125 - 0.375 mg/kg)	Decreased the
endurance time in swimming exercise significantly (10 minute after the
injection). At 0.125 mg/kg nicotine, the endurance time remained
unchanged, while at the doses of 0.25 and 0.375 mg/kg, it decreased
significantly (p < 0.05 and p < 0.01, respectively). This effect was
antagonized by pretreatment with hexamethonium 5 mg/kg s.c.

Non-Guideline

	Developmental neurotoxicity	Johns et al (1992)

0, 0.5, 1.5, or 2.5 mg/kg of nicotine hydrogen tartrate, injected 2X
daily throughout gestation period (15/dose).	Offspring exhibited
performance deficits in both learned and innate behavioral measures
throughout development and adulthood.  Offspring birth weight was not
affected by treatment nor the 32 day weight gain. Initial weight, weight
gain, gestation length, number of live or dead offspring, or mean food
consumption during pregnancy did not differ significantly in the treated
groups versus the controls. Dams receiving the nicotine injections
reacted with aversion.

Non-Guideline

	Developmental neurotoxicity	Navarro et al, 1989

2 mg/kg of nicotine infused per day from gestational days 4 through 20
Infusing pregnant rats with a nicotine dose that did not interfere with
maternal weight gain or resorption rate resulted in sufficient nicotine
penetrating the fetal brain to cause persistent alterations in [3H]
nicotine binding sites, abnormalities of cellular development [assessed
by measurements of ornithine decarboxylase (ODC) activity and
deoxyribonucleic acid (DNA)], and impairment of development of
peripheral noradrenergic projections (assessed by kidney norepinephrine
levels).

Non-Guideline

	Developmental neurotoxicity	Levin et al, 1993

2 mg/kg of nicotine subcutaneous injection per day from gestational days
4 through 21	Prenatal nicotine exposure caused subtle alterations in
cognitive performance of the offspring which were magnified by
challenges of nicotinic and adrenergic systems.

Non-Guideline

	Developmental neurotoxicity	Fung, 1988

1.5 mg/kg/day, nicotine tartrate subcutaneous implanting of pregnant
rats) during gestation	14 – day old male and female offspring of rats
exposed to nicotinedemonstrated an increase in spontaneous locomotor
activity compared with controls.  The total number of pups born to the
treated group was significantly less than the controls.

Non-Guideline

	Developmental neurotoxicity	Peters et al, 1979

60 - 80 days old offspring of rats treated with nicotine in drinking
water (6 mg/kg/day intake) four weeks before mating and during pregnancy
and throughout nursing and 6 weeks after weaning	Increased spontaneous
motor activity in the light which was not prevented by cross-fostering
to control dams at birth. The paternal rats had a marked reduction in
body weight gain (55% of controls for males and 63% of controls for
females after 4 month of nicotine treatment).  The dams were more active
during the day and exhibited a reduced plasma corticosterone response to
stress.  Male but not female offspring of nicotine treated rats were
significantly lighter at birth than control males.

Non-Guideline

	Developmental neurotoxicity	Peters & Ngan, 1982

Nicotine at 0, 1.5,  3 or 6.0 mg/kg per day; subcutaneously one week
prior to mating and throughout gestation	subtle neurological changes
which are manifested as behavioral alterations in the newborn (the
righting reflex, temperature  regulation, adherence to the inclined
screen, and in organ/body weight ratios for brain, heart,  lung, liver,
and kidney)  and adult offspring (prolonged time required and an
increase in number of mistakes made, during food maze testing and an
increased brain protein content).

Non-Guideline

	Developmental neurotoxicity	Roy & Sabherwal, 1998

pregnant rats were injected ip with  nicotine (2.5 mg/kg/ day, given in
two divided doses) from GD 6 to term and pups were delivered  at term
normally	Reduction in cortical thickness and decreased cell size,
decreased dendritic branching and increased dendritic spine density,
irregular arrangement of cisternae of rough endoplasmic reticulum,
paucity of free ribosomes, and frequent cytoplasmic vacuoles of the
somatosensory cortex were observed in the pup up to postnatal day 40.
Morphological changes in the hippocampus (significant reduction in the
neuronal area of nicotine-exposed brains in the dentate gyrus, CA3, and
CA1 regions) also resulted from the prental nicotine treatment, which
may contribute to the behavioral abnormalities.

Non-Guideline

	Developmental neurotoxicity	Ajarem & Ahmad, 1998

daily subcutaneous injections of nicotine  (0.5mg/kg) into the nape of
the neck during pregnancy	significant reduced postnatal body weight
gain, as well as significant delay in eye opening, in the appearance of
body hairs, and in sensory motor reflexes.  Motor activity was
significantly stimulated in early adulthood of mouse pups prenatally
exposed to nicotine, and had long-lasting hyperactive effects on mice.

Non-Guideline

	Developmental neurotoxicity	Marks et al, 1985

four inbred strains of mice (BALB, C57BL, DBA, C3H),  nicotine
administered ip at a single dose of 0, 0.5, 1.0 or 2.0 mg/kg 	Generally
nicotine administration increased the respiration rate, decreased the
body temperature and the heart rate, and a decline in the Y-maze crosses
and rears at different rates in the various strains. The startle
response was increased in the C3H strain only.

Non-Guideline

	Developmental neurotoxicity	McFarland et al, 1991

Nicotine given at an acute subcutaneous injection to neonatal rats as
nicotine dibitartrate (3 mg/kg of nicotine base) at 1, 3, 8, 10 or 15
days of age	Nicotine inhibited DNA synthesis in neonatal rat brain
regions as assessed by the incorporation of [3H]thymidine into DNA of
the brain tissues.  The inhibition potency correlated to the
concentration of nicotinic receptors: midbrain + brainstem (cerebral
cortex > cerebellum. The inhibitory effect of nicotine was also seen in
fetal brain on gestational day 20 after injection of nicotine (3 mg/kg)
to pregnant rats.

Non-Guideline

	neurobehavioral teratology	Seidler et al, 1996

developing rats (1, 7, 14 and 21 days old) challenged acutely with
nicotine (0.3 mg/kg, i.p.) and the release of catecholamines was
evaluated in vivo in three brain regions that differ in nicotinic
receptor concentrations.	Nicotine did not stimulate catecholamine
release at birth, but developed the capacity to do so in parallel with
the ontogeny of nicotinic cholinergic receptors in the
midbrain+brainstem and in the forebrain. In the cerebellum, no response
was obtained at any age. Changes in sensitivity to nicotine were also
seen that corresponded to ontogenetic changes in endogenous cholinergic
tone, suggesting that receptor desensitization occurs normally during
developmental stages in which neuronal activity is high. The absence of
a catecholamine response to nicotine at birth in the rat indicates that
neurobehavioral teratology associated with fetal nicotine exposure does
not reflect secondary actions mediated through catecholamines. However,
because brain development in the neonatal rat corresponds to fetal
stages in man, the onset of these mechanisms may be relevant to human
fetal exposure.

Non-Guideline

	Endocrine effects

in vivo and in vitro  rat models	Blackburn et al, 1994

pregnant mare’s serum gonadotropin (PMSG) - primed and human chorionic
gonadotropin (hCG) - triggered rat ovaries exposed to nicotine  (ip 6.25
ng/g animal weight)	Nicotine inhibited ovulation, estradiol production,
and fertilization both in vivo and in vitro in rat models.  A dose
dependent reduction in oocytes within the fallopian tube was noted in
nicotine treated rats (p<0.001).  On the other hand cotinine did not
affect ovulation, estradiol production or fertilization in those tests.

Non-Guideline

	Endocrine effects

rats	Slotkin and Seidler, 1975

Nicotine at1 mg/kg or 10 mg/kg, subcutaneously twice daily for 1 or 2
weeks)	Nicotine produced alterations in catecholamines (CA) release,
tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), and the
ability of isolated storage vesicles to incorporate 3H-epinephrine in
the adrenal glands and these alterations persisted when nicotine
administration was discontinued.

Non-Guideline

	Endocrine effects

Time-pregnant Sprague Dawley rats

	Lichtensteiger and Schlumpf 1985

Nicotine tartrate delivered in an osmotic minipump at a rate of 25
ug/100 g/ hr	Male fetuses of all control groups displayed the
characteristic rise in plasma testosterone at GD 18 (as compared to GD
17 and 19); this was abolished by nicotine. Adult offspring of untreated
or tartaric acid-treated dams exhibited a marked sexual dimorphism in
their preference for saccharin-containing drinking water at 0.06-0.25%.
No such sex difference was seen in offspring of nicotine-treated rats.

Non-Guideline

	Endocrine effects

	Ehlers et al, 1997

Nicotine hydrogen-

tartrate (Sigma) dissolved in distilled water and added to the milk diet
(0 mg, 1 or 4mg/kg/day) administered to neonatal rat pups from PN4
through PN12 with an artificial rearing paradigm; Nicotine. All rats
were weaned at PN21 and housed in pairs.  Thirty one suckle controls (17
males, 14 females), 23 artificially reared rats (14 males, 9 females),
22 1 mg/kg/day rats (12 males, 10 females), and 23 4 mg/kg/day animals
(16 males, 7 females) were used in this study.	Nicotine exposure altered
responses of the P3 component of the event-related potential (ERP),
recorded in dorsal hippocampus, to changes in stimulus parameters. A
significant reduction in the response to the noise tone as compared with
the level of the infrequently presented tone also was seen in the P3B
component. No effects of drug exposure were found on the N1 component in
any lead, although artificial rearing produced specific effects on the
latency of the N1 component in cortex. No significant differences among
treatment groups were found on any of the EEG-dependent variables.
Female rats overall were found to have significantly higher
electroencephalography (EEG) amplitudes than the males. However, no
overall effects of gender were found on any ERP component. These studies
suggest that neonatal nicotine exposure specifically reduces the
electrophysiological response of the hippocampus to changes in auditory
stimuli

Non-Guideline

	Endocrine effects

Sprague Dawley rats

	Slawecki et al, 2000

Male rats were exposed to 6.0 mg/kg/day nicotine via gastric infusion
using an artificial rearing, “pup-in-the-cup,” technique for 6
consecutive days PND 4–9.  At adulthood, EEG and auditory ERPs were
recorded from the cortex and hippocampus	Examination of the hippocampal
EEG revealed significantly decreased power in the 1–2-Hz frequency
band of nicotine-treated rats. In addition, there was a significantly
attenuated P300 ERP response to a noise tone in the nicotine-treated
rats compared to controls. These data indicate that neonatal nicotine
exposure alters functional activity in the hippocampus of adult rats.
These effects are likely to be the result of synaptic disorganization in
the hippocampus, and indicate that neonatal nicotine exposure exerts
teratogenic effects on the developing central nervous system,
particularly the hippocampus, which persist into adulthood.

Non-Guideline

	Immune system	Maritz & Woolward, 1992

nicotine at1 mg/kg bw/d from GD 7 until weaning three weeks after birth)
resulted in a very low elastic tissue content in the lungs of 1- and
7-day old rat pups compared with those of the controls.  This may
interfere with normal lung development since elastic tissue is part of
the lung connective tissue structure and is involved in the formation of
alveoli.  Impaired elastic synthesis may thus make the rat pups more
susceptible to lung diseases such as emphysema

Non-Guideline

	Immune system	Geng et al, 1995

Nicotine at 1 mg/kg to young adult rats by intradermal implantation for
3-4 weeks	Nicotine inhibited both the T-dependent and T-independent AFC
responses and proliferation to anti-CD3.  Significantly fewer NT T cells
entered the S and G2/M phases than CON T cells, indicating an arrest in
the GO/G1 phase.  B and T cells were unable to elevate the intracellular
calcium levels normally in response to ligation of antigen receptors,
although Ca2+ responses of salivary gland cells to acetylcholine were
normal.  Serum cotinine levels of 219  ±  40 ng/mL were comparable to
average human smokers.

Non-Guideline

	Immune system	Basta et al, 2000

pregnant rats treated with nicotine (6 mg/kg/day) from GD 4-20
subcutaneously	Nicotine suppressed splenocyte responsiveness to
Concanavalin A or lipopolysaccharide in offspring and remained
subresponsive to stimulation well into adulthood.  Nicotine treatment
also resulted in reduced maternal weight gain during early gestation,
increased resorptions, increased offspring body weight and significantly
elevated offspring spleen weights.  In combination with ethanol, the
observed effects were more severe.

Non-Guideline

	Immune system

In vitro T-cells from female mice	Zhang & Petro, 1996

T-cells (splenic mononuclear cells) exposed to nicotine at 1-100 μg/100
mL)	Exposure of T-cells (splenic mononuclear cells from female mice) to
physiological concentration of nicotine (1-100 μg/100 mL) can alter T
cell expression of CD28 and CTLA-4 and the CD4 T cell cytokine
expression pattern

Non-Guideline

	Metabolism and pharmacokineti	Hukkanen et al, 2005 	Review article.
Rapid absorption of nicotine from the inhaled cigarette smoke and rapid
distribution via the blood stream to various tissues including the brain
within 10 to 20 seconds, faster than iv.  Poorly absorbed from stomach -
protonated in the acidic gastric fluid, but well absorbed in the small
intestine - more alkaline pH and a large surface area.  Oral ingestion
of nicotine capsules or nicotine in solution, peak concentrations in the
blood are reached in about 1 hour. Nicotine crosses the placental
barrier easily, and there is evidence for the accumulation of nicotine
in fetal serum and amnionic fluid in slightly higher concentrations than
in maternal serum. The plasma half-life of nicotine after iv infusion or
cigarette smoking averages about 2 h.  However, when half-life is
determined using the time course of urinary excretion of nicotine, which
is more sensitive in detecting lower levels of nicotine in the body, the
terminal half-life averages 11 h.

Nicotine is extensively metabolized – cotinine.

Non-Guideline	Dermal penetration

(species)	Zorin et al, 1999	In vitro tests of nicotine’s permeability
through human skin using Franz’ diffusion cells demonstrated the
dermal penetration of nicotine. Flux depended on the nicotine
concentration in a non-linear fashion, with the highest flux at 50% w/w
nicotine-water solution.  The lowest flux was in the acidic nicotine
solution and ethanol solution. Penetration continued after rinsing the
nicotine from the donor compartment, indicating that the skin acts as
reservoir for continued absorption.

Non-Guideline

	Special studies:

Daily intake of nicotine from cigarette smoke	Benowitz znd Jacob III,
1984	Daily intake of nicotine in a group of 22 smokers averaged 37.6 (
17.7 mg (10.5 – 78.6 mg).  Nicotine intake per cigarette averaged
1.04( 0.36 mg.  Among several markers measured (carboxyhemoglobin level,
blood cotinine concentration), afternoon (4:00 pm) blood nicotine level
was the best marker for measuring nicotine intake in this group of
smokers.

A.3	Supplementary Toxicity Studies

	Subchronic Toxicity

Experimental data in male rats suggest that nicotine (free base)
ingested for 16 weeks at 50 or 200 mg/L in drinking water (3 and 14
mg/kg/day calculated on water intake) alters metabolic and  endocrine
factors that may be responsible, at least in part, for the development
of gastrointestinal ulcers and pancreatitis (Chowdhury et al, 1990).
The plasma levels of CCK (cholecystokinin) were significantly increased
with nicotine intake but the amylase secretory response of pancreatic
acinar cells was inhibited in response to CCK-8
(cholecystokinin–octapeptide) and carbachol.  Prominent loss of
gastric mucosal surface was found in nicotine-treated animals with gross
microscopic evidence of bleeding ulcers.  Body weight gain in the
nicotine treated groups was significantly lower than in the controls at
every measurement point.  At the end of treatment period, body weight
gain in the low and high dose groups was approximately 74% and 53% of
the controls, respectively. Nicotine treatment was accompanied by
significantly lower food and water intake.  All of the metabolic
parameters except body weight gain were reversed upon nicotine
withdrawal. Histopathologic data showed a partial but not a complete
recovery of the pancreatic acinar cell morphology and gastric mucosal
surface following 4 weeks of nicotine withdrawal.

When adult male rats (185-225 g weight) were implanted subcutaneously
with nicotine pellets containing 0, 5, 15 or 50 mg nicotine (delivering
0, 9.9, 29.8, and 99.2 ug/hr, respectively; equivalent to 0.0, 1.2, 3.6,
12.0 mg/kg/day) for up to 12 weeks, increased pancreatic enzyme
biosynthesis and accumulation of digestive enzymes within the pancreas
were reported (Lau et al.  1990). Plasma nicotine concentrations at the
50 mg dose reached a steady state level of 76±19 ng/mL and cotinine
exceeded 300 ng/mL.  No effect on enzyme secretion was observed in rats
treated with 15 mg nicotine pellets, in rats treated with 15 mg pellets,
CCK-8-mediated amylase, trypsinogen, and chymotrypsinogen secretion was
maximally stimulated at 1.5 weeks and then decreased to near control
levels.  In rats treated with 50 mg nicotine pellets, enzyme release in
response to CCK-8 was also higher at 1.5 weeks, peaked at 3 weeks and
then decreased, such that at 12 weeks, enzyme release was at or below
control levels. Electron microscopy of pancreas from rats treated with
the 50 mg nicotine pellets revealed intracytoplasmic vacuoles appearing
after 3 weeks of treatment, and persisting throughout the remaining
experimental period (evidence of morphological damage).   Nicotine
treatment and durations did not have an effect on body weight,
pancreatic weight, DNA, RNA or protein concentrations.  From this study,
a LOAEL based on pancreatic morphogic damage is the 50 mg nicotine
pellet corresponding to a daily dose of 12 mg/kg and a NOAEL is 3.6
mg/kg/day.  Earlier work from the same laboratory (Dubick et al, 1988)
showed that adult male rats receiving nicotine via a time–release
pellet at a rate of 1.65 ug/min for 3 weeks, increases in digestive
pancreatic enzymes (amylase, trypsin and chymotrypsin) were noted
compared to controls. Final body weight or pancreatic weight was not
affected.

 hepatotoxin) or the less potent hepatotoxins chloroform or
1,1,1-trichloroethane nor the cholestatic effect of
α-naphthylisothiocyanate was modified.

Nicotine administration may adversely affect bone formation and decrease
body storage of vitamin D (Fung et al, 1999). Female rats (7-month old;
9-10/group) administered nicotine (nicotine hydrogen tartrate) at 0, 3.0
or 4.5 mg/kg/day dissolved in saline solution by subcutaneous osmotic
minipumps with a delivery rate of 0.25 ul/hr for three months had
significantly lower levels of 25-hydroxyvitamin D in the two nicotine
groups than controls. The high dose nicotine group had smaller vertebral
areas and a lower bone mineral content than the controls.  Tibial
endocortical mineral apposition rate was also significantly lower in the
high dose nicotine group than in the control group. Nicotine serum
levels at sacrifice time were 60 ± 6 ng/mL, and 85 ± 5 ng/mL at the
low and high dose, respectively.

Nicotine tartrate, administered orally to 10 New Zealand white male
rabbits (2.4 mg/kg/day) in their drinking water for 25 weeks produced in
vivo morphologic effect on endothelial cells in the aortic arch (Booyse
et al, 1981).  It was estimated that each rabbit consumed about as much
as nicotine per day (2.4 mg/kg/day) as a person smoking 1- 2 packs of
cigarettes per day.  Fasting serum levels of glucose, triglycerides,
total cholesterol, and LDL-cholesterol were significantly (<0.001)
elevated in nicotine-treated rabbits.   Endothelial cells from
nicotine-treated arched areas (Evans-blue-stained) showed extensive
changes such as increased cytoplasmic silver disposition, increased
formation of microvilli, and numerous focal areas of  “ruffled”
endothelium (projections on cell surfaces).  Serum blood levels of
nicotine were not measured in this study.

	Chronic Toxicity

Dietary feeding of nicotine sulfate (0.0%, 0.00625%, 0.01255%, 0.025%,
0.05%, 0.1%, or 0.2% as nicotine base of the diet), nicotine tannate
(0.0%, 0.1%, 0.2%, or 0.4% of the diet) and nicotine bentonite (0.0%,
0.0625%, 0.1255%, 0.25%, 0.5%, 1.0%, or 2.0% of the diet) to rats
(initial weight 50-60 g) for 300 days resulted in retarded growth due to
nicotine toxicity and lower food consumption (Wilson & DeEds, 1936) with
a NOAEL of 0.006% nicotine base (4 mg/kg/day).  Retarded growth in rats
was reversed upon discontinuing the nicotine diets and rats resumed
normal growth.  Rats receiving the nicotine sulfate as 0.1% base and
above died within few days.  It was also demonstrated that “the
toxicity in terms of nicotine base was about the same for two nicotine
salts and the bentonite clay formulation” tested. Nicotine bentonite
for this study was prepared by mixing one part of nicotine base with
nine parts of finely powdered Wyoming bentonite and mixing thoroughly.
The bentonite nicotine complex was not merely an adsorption complex, but
rather some chemical bonding.  The nicotine was not removed by
extraction with alkali and only small amounts were removed by water, but
was readily extracted with dilute acid.

Developmental Toxicity

Pregnant CD-1 mice (N=19), exposed to ip injection of 0.1% nicotine
sulfate at a dose of 1.67 mg/kg body weight/day on gestational days 6-15
had significantly depressed maternal weight gain (37% decrease on GD18)
and fetal weight (64% decrease) compared to the controls. Fetal
crown-rump length fetal head dimensions (width, height and
circumference) were significantly reduced.  Histological examination
revealed that 9.6% of fetuses of nicotine injected mothers presented
clefts of the palate, whereas none of the control fetuses had that
anomaly. Nicotine treatment also had teratogenic effects on first molar
odontogenesis in the mouse. The mesiodistal diameter of molar tooth
germs of nicotine treated fetuses without cleft palate was significantly
less than those of controls (Saad et al, 1990 & 1991).  It was suggested
that nicotine, or its metabolic byproducts, interfere with normal
interaction between the epithelial and mesenchymal components of the
developing tooth.

Subcutaneous injection of nicotine to timed pregnant Sprague Dawley rats
(41 control and 57 nicotine treated) (3 mg/kg/day from gestation day 4
-20) resulted in significant reduced maternal weight gain and increased
maternal mortality (14%) and fetal resorptions (13%).  Litter size was
not affected. Nicotine exposure produced biochemical changes in the
fetal brain (elevation of fetal ornithine decarboxylase activity,
suppression of DNA synthesis (most profound in cerebellum),
desynchronization of the ontogenctic patterns of DNA, RNA and proteins
in every brain region) (Slotkin et al, 1986).

Subcutaneous injections of nicotine (3 or 6 mg/kg/day, divided into two
doses) on GD 7-20 to pregnant rats (10/group) resulted in abnormal
behavior such as ataxic gate, decrease in spontaneous activity,
creeping, or salivation in pregnant rats (3 or 6 mg/kg/day) and
convulsion and ptosis (6 mg/kg), decreased maternal body weight at GD 14
(both groups) and reduced offspring body weight. These nicotine
exposures also resulted in significant decreases in
dihydroxyphenylacetic acid (DOPAC) content in the neocortex and in both
the neocortex and in the midbrain plus pons medulla, respectively,
without any effects on the other brain regions such as the hypothalamus
or striatum.  Norepinephrine, serotonin, or 5-hydroxy-3-indolacetic acid
levels were not affected.  These data demonstrated that prenatal
nicotine exposure induced disturbances in the dopaminergic system in the
young adult period.  Furthermore, the region-specific reductions in the
DOPAC content suggests that the exposure to a high dose of nicotine in
utero might cause a predisposition to diseases related to a dopaminergic
dysfunction in the frontal cortex (Muneoka et al, 1999).

A recent study questioned developmental effects of nicotine reported in
the scientific literature (Hussein et al, 2007).  They found that a
nicotine dose of 6 mg/kg/day administered to Sprague Dawley time-mated
rats from gestation day 3 through 21 by osmotic mini pump resulted in
nicotine plasma concentrations of 115-174 ng/mL.  This is 3-10X higher
than published values observed in heavy smokers (10-50 ng/mL) and
pregnant mothers (2-10 ng/mL).  The total nicotine dose of 6 mg/kg/day
in the rat was considered to be equivalent to smoking 480 and 560
cigarettes per day (1 mg NIC per cigarette) by pregnant women weighing
60 and 70 kg, respectively, which is unrealistic. Maternal hematocrit
was not affected by nicotine administration, or the number of pups per
litter, pup weight, placental weight or the weight of various pups'
organs. Maternal weight changes were comparable in the nicotine treated
and control groups. Maternal plasma coticosterone concentrations were
not affected by the nicotine infusion versus the control rats.
Measurements of plasma nicotine concentration in this study demonstrated
that total nicotine clearance increases towards the second trimester but
remains unchanged thereafter, whereas the plasma concentrations
decrease. Thus plasma nicotine concentrations are maintained for at
least two thirds of the gestation period and only a marginal decrease is
observed during the third trimester. In earlier studies in CD-1 mice by
Paulson et al (1989), fetal retardation was observed at plasma nicotine
concentrations of 218-1284 ng/mL corresponding to 60 mg/kg/day, but not
at lower doses of 12 or 36 mg/kg/day corresponding to 100 and 400 ng/mL.

Genotoxicity

g/mL, whereas, SCE frequencies were increased significantly (150
g/mL concentrations (Trivedi et al, 1990). Nicotine (150 µg/mL) and
in combination with arecoline (an areca nut alkaloid) incubated in
Chinese hamster ovary (CHO) cell line (without S9 metabolic activation)
increased the SCE frequency/cell.  Nicotine alone at 300 µg/mL did not
increase the frequency of chromosomal aberrations/cell, but in
combination with arecoline it did at ≥90 µg/mL (Trivedi et al, 1993).

Nicotine was cytotoxic at 1.5 - 2.0 g/mL to human leucocytes in
culture in vitro without producing any chromosome damage.  However,
gross chromosomal aberrations including fuzzy chromosomes (stickiness),
aneuploidy and translocations were observed in mice receiving low
tolerable doses of the drug ( 0.07 -0.09 g/total body weight injected
to 5 weeks-4 month old mice in saline, two weekly injections for 3 weeks
before sacrifice and preparing  the bone marrow from the femora (Bishun
et al, 1972).

Nicotine has been shown to cause concomitant genotoxic and antiapoptotic
effect in human gingival fibroblasts (HGFs) in the cytokinesis-block
micronucleus (CBMN) test (Argentin and Cicchetti, 2004).   Treatment of
HGFs with nicotine, at a concentration of 1 uM, caused a statistically
significant increase of micronucleus (MN) frequency at the tested time
intervals, while no change was detected in cell growth under the same
conditions.  Preincubation of HGFs with 1 uM nicotine strongly
attenuated staurosporine (STP)-induced apoptosis. Cultures exposed to
nicotine showed an increase of reactive oxygen species, as determined by
increased levels of 2,7-dichlorofluorescein (DCF). When cells were
prelabeled with N-acetyl-cysteine (NAC), a substrate for glutathione
synthesis, and catalase (CAT), the oxygen free radical scavenger, a
significant reduction in cytogenetic damage was observed.

Cotinine (a metabolite of nicotine and a biological monitoring marker of
nicotine absorption in humans) was positive in the presence or absence
of S9 in the bacterial luminescence genotoxicity test at 1.25 - 2.5
mg/mL (9- 30 h incubation).   In contrast, nicotine was not positive to
20 mg/mL concentrations for up to 40 hours of incubation.
Nicotine/cotinine mixtures were still positive at physiological
concentrations, with potentiation relative to cotinine alone with and
without S9 (Yim & Hee 1995).

Tests by the R. J. Reynolds Tobacco Co. (Doolittle et al, 1995) on
nicotine and four of its major metabolites: cotinine, nicotine-N'-oxide,
cotinine-N-oxide, and trans-3'-hydroxycotinine in the Salmonella
mutagenicity assay (strains TA98, TA100, TA1535, TA1537, and TA1538) at
concentrations ranging from 0 to 1000 micrograms/plate and in the
Chinese hamster ovary sister-chromatid exchange (SCE) assay at
concentrations ranging from 0 to 1000 micrograms/mL,  with and without
S9 metabolic activation showed that none of the five compounds increased
the frequency of mutations or the frequency of SCEs.

Recent data indicate that nicotine exerts significant direct genotoxic
effects in human target cells in vitro (Kleinsasser et al, 2005).  The
genotoxicity of nicotine was tested with the alkaline single-cell
microgel electrophoresis (Comet) assay using human lymphocytes and
target cells from lymphatic tissue of the palatine tonsils from healthy
patients.  One hour exposure to nicotine at 0.125, 0.25, 0.5, 1, 2, and
4 mM induced a statistically significant dose-dependent increase of DNA
migration up to 3.8-fold and 3.2-fold in tonsillar cells and
lymphocytes, respectively. The minimum concentration eliciting
significant DNA damage was 0.5 mM nicotine. The genotoxic effect was
confirmed in a second series of experiments using nicotine of high
purity from two different suppliers.  Finally, DNA damage by nicotine
was compared in cells incubated in medium strictly adjusted to neutral
pH, with nonadjusted medium becoming alkaline with increasing nicotine
concentrations. Again no differences in DNA migration were observed.
However, no differences in DNA damage were observed in cells from
smokers and nonsmokers incubated without nicotine. The lack of higher
DNA damage in smokers compared to nonsmokers could be a question of
nicotine dose, rapid DNA repair, or interactions with other smoke
constituents.  Further work by Sassen et al (2005) confirmed the
genotoxic effects of nicotine on human nasal epithelia.

Many studies have demonstrated that nicotine penetrates the fetal brain
to cause various biochemical changes with behavioral consequences on the
offspring.   These studies are listed in the tox profile in Appendix
A.2.  In all of these studies, nicotine was administered subcutaneously
or intraperitonealy.  Performance deficits in both learned and innate
behavioral measures throughout development and adulthood in offspring of
animals exposed to nicotine during gestation have been reported.  Doses
as low as 0.25 mg/kg/day produced behavioral changes.

Immune System Toxicity

There is considerable evidence suggesting immune toxicity by nicotine.
Few of these studies are discussed below. Other studies are listed in
the tox profile in Appendix A.2.

Maternal nicotine exposure (1 mg/kg body mass/d from GD 7 until weaning
three weeks after birth) resulted in a very low elastic tissue content
in the lungs of 1- and 7-day old rat pups compared with those of the
controls.  This may interfere with normal lung development since elastic
tissue is part of the lung connective tissue structure and is involved
in the formation of alveoli.  Impaired elastic synthesis may thus make
the rat pups more susceptible to lung diseases such as emphysema (Maritz
& Woolward, 1992).

Nicotine at 1 mg/kg (administered to young adult rats by intradermal
implantation for 3-4 weeks), inhibited both the T-dependent and
T-independent AFC responses and proliferation to anti-CD3.
Significantly fewer NT T cells entered the S and G2/M phases than CON T
cells, indicating an arrest in the GO/G1 phase.  B and T cells were
unable to elevate the intracellular calcium levels normally in response
to ligation of antigen receptors, although Ca2+ responses of salivary
gland cells to acetylcholine were normal.  Serum cotinine levels of 219
± 40 ng/mL were comparable to average human smokers (Geng et al, 1995).

Prenatal nicotine exposure can cause long-term suppression of the
proliferative response of offspring immune cells (Basta et al, 2000).
Thus in offspring of pregnant rats treated with nicotine (6 mg/kg/day)
from GD 4-20 subcutaneously, nicotine suppressed splenocyte
responsiveness to Concanavalin A or lipopolysaccharide and remained
subresponsive to stimulation well into adulthood.  Nicotine treatment
also resulted in reduced maternal weight gain during early gestation,
increased resorptions, increased offspring body weight and significantly
elevated offspring spleen weights.  In combination with ethanol, the
observed effects were more severe.

Exposure of T-cells (splenic mononuclear cells) from female mice to
physiological concentration of nicotine (1-100 μg/100 mL) can alter T
cell expression of CD28 and CTLA-4 and the CD4 T cell cytokine
expression pattern (Zhang & Petro, 1996).

A.4	References

Registrant References:

MRID 41521101. Naas, D. (1990) Primary Dermal Irritation Study in Albino
Rabbits with Nicotine, Black Leaf 40: Lab Project Number: WIL-149014.
Unpublished study prepared by WIL Research Laboratories, Inc. April 2,
1990. 19 p.

MRID 41521102.  Naas, D. (1990) Skin Sensitization Study in Albino
Guinea Pigs with               Nicotine, Black Leaf 40: Lab Project
Number: WIL-149015, unpublished study prepared by WIL Research
Laboratories, Inc., April 2, 1990..   38 p.   30 pages.

MRID 42631101. Kuhn, J. (1992) Acute Dermal Toxicity Study in Rabbits:
F&B Rabbit & Dog Chaser: Lab Project Number: 9643-92.  Stillmeadow, Inc.
 Unpublished. 11 p.

MRID 42631102.  Holbert, M. (1992) Acute Inhalation Toxicity Study in
Rats: F&B Rabbit & Dog Chaser: Lab Project Number: 9644-92.
Stillmeadow, Inc. Unpublished.  17 pages.

MRID 42631103.  Kuhn, J. (1992) Primary Eye Irritation Study in Rabbits:
F&B Rabbit & Dog Chaser: Lab Project Number: 9645-92.  Stillmeadow, Inc.
 Unpublished. 17 p.

MRID 42631104.  Kuhn, J. (1992) Primary Dermal Irritation Study in
Rabbits: F&B Rabbit & Dog Chaser: Lab Project Number: 9646-92.
Stillmeadow, Inc. Report no. 9646-92.  Unpublished.  12 pages.

MRID 42640001.  Kuhn, J. (1993) Dermal Sensitization Study in Guinea
Pigs: F&B Rabbit & Dog Chaser: Lab Project Number: 9647-92.
Stillmeadow, Inc.  Unpublished.  17p.

MRID 43375601.  Kuhn, J. (1994) Dermal Sensitization study in Guinea
Pigs: F&B Rabbit & Dog Chaser: Amendment: Lab Project Number: 9647-92.
Stillmeadow, Inc. Unpublished. 10 p.

MRID 43523301.  Kuhn, J. (1994) Acute Oral Toxicity Study in Rats: (F &
B Rabbit and Dog Chaser): Final Report: Lab Project Number:1607-94.
Stillmeadow, Inc. MRID 43523301.  Unpublished.  11 pages.

MRID 43874001.  Bennick, J. (1995) F & B Rabbit and Dog Chaser: Acute
Inhalation Toxicity Study in Rats: Final Report: Lab Project Number:
2376-95: S9-FF81-3.  Stillmeadow, Inc. Unpublished. 10 P.

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DRAFT

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                           Body Weight (kg)


[Federal Register: October 26, 2007 (Volume 72, Number 207)]
[Notices]
[Page 60834]
[DOCID:fr26oc07-49]

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

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. EF07-3011-000]

Southeastern Power Administration; Notice of Filing

October 18, 2007.
    Take notice that on September 13, 2007, the Deputy Secretary, U.S.
Department of Energy, pursuant to the authority vested in the Deputy
Secretary by the Department of Energy's Delegation Order Nos. 00-
001.00C and 00-037.00, and by sections 302(a) and 301(b) of the
Department of Energy Organization Act (Pub. L. 95091), submitted for
confirmation and approval on a final basis, Rate Schedules SOCO-1-C,
SOCO-2-C, SOCO-3-C, SOCO-4-C, ALA-1-L, MISS-1-L, Duke-1-C, Duke-2-C,
Duke-3-C, Duke-4-C, Santee-1-C, Santee-2-C, Santee-3-C, Santee-4-C,
SCE&G-1-C, SCE&G-2-C, SCE&G-3-C, SCE&G-4-C, Pump-1-A, Pump-2,
Replacement-1, and Regulation-1, effective October 1, 2007 and ending
September 30, 2012.
    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. Such notices,
motions, or protests must be filed on or before the comment date. On or
before the comment date, it is not necessary to serve motions to
intervene or protests on persons other than the Applicant.
    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 14 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 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 e-mail
notification when a document is added to a subscribed docket(s). For
assistance with any FERC Online service, please e-mail
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For

TTY, call<PHONE_NUMBER>.
    Comment Date: 5 p.m. Eastern Time on November 19, 2007.

Kimberly D. Bose,
Secretary.
 [FR Doc. E7-21158 Filed 10-25-07; 8:45 am]

BILLING CODE 6717-01-P


[Federal Register Volume 81, Number 180 (Friday, September 16, 2016)]
[Rules and Regulations]
[Page 63700]
[FR Doc No: 2016-22320]

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DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 117

[Docket No. USCG-2016-0674]

Drawbridge Operation Regulation; South Branch of the Elizabeth
River, Atlantic Intracoastal Waterway, Chesapeake, VA

AGENCY: Coast Guard, DHS.

ACTION: Notice of deviation from drawbridge regulation.

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

SUMMARY: The Coast Guard has issued a temporary deviation from the
operating schedule that governs the Gilmerton (US13/460) Bridge across
the South Branch of the Elizabeth River, mile 5.8, on the Atlantic
Intracoastal Waterway, at Chesapeake, VA. This deviation is necessary
to avoid bridge failure and perform emergency bridge repairs. This
deviation allows the bridge to remain in the closed-to-navigation
position.

DATES: This deviation is effective without actual notice from September
16, 2016 through 5 a.m. on September 19, 2016. For the purposes of
enforcement, actual notice will be used from September 13, 2016 at 9
a.m., until September 16, 2016.

ADDRESSES: The docket for this deviation, [USCG-2016-0674] is available
at http://www.regulations.gov. Type the docket number in the ``SEARCH''
box and click ``SEARCH''. Click on Open Docket Folder on the line
associated with this deviation.

FOR FURTHER INFORMATION CONTACT: If you have questions on this
temporary deviation, call or email Mr. Hal R. Pitts, Bridge
Administration Branch Fifth District, Coast Guard, telephone 757-398-
6222, email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: The City of Chesapeake, that owns and
operates the Gilmerton (US13/460) Bridge, across the South Branch of
the Elizabeth River, mile 5.8, on the Atlantic Intracoastal Waterway,
at Chesapeake, VA, has requested a temporary deviation from the current
operating regulations to avoid bridge failure and perform emergency
repairs to the bridge due to failure of operating mechanism components,
requiring non-standard manual operation of the bridge until repair is
completed. The bridge is a vertical lift draw bridge and has a vertical
clearance in the closed position of 36 feet above mean high water. The
vertical clearance of the bridge in the open-to-navigation position of
136 feet above mean high water will be reduced to approximately 110
feet above mean high water from 9 p.m. on September 16, 2016, through 5
a.m. on September 19, 2016.
    The current operating schedule is set out in 33 CFR 117.997(c).
Under this temporary deviation, the bridge will remain in the closed-
to-navigation position, except for scheduled openings at 9 a.m., noon,
3 p.m. and 7 p.m., Monday through Friday; and 9 a.m. and 3 p.m. on
Saturday and Sunday. The scheduled openings at 9 a.m. and 3 p.m. on
Saturday and Sunday, September 17, 2016, and September 18, 2016; and
emergency openings from 9 p.m. on September 16, 2016, through 5 a.m. on
September 19, 2016, will provide a reduced vertical clearance of
approximately 110 feet above mean high water.
    The South Branch of the Elizabeth River is used by a variety of
vessels including U.S. government and public vessels, commercial
vessels, tug and barge traffic, and recreational vessels. The Coast
Guard has carefully coordinated the restrictions with waterway users in
publishing this temporary deviation.
    Vessels able to safely pass through the bridge in the closed
position may do so at any time. On Saturday and Sunday, September 17,
2016, and September 18, 2016, vessels able to safely pass through the
bridge in the closed position should contact the bridge tender to
ensure safe passage through the bridge. There is no immediate alternate
route for vessels unable to pass through the bridge in the closed
position. The bridge will open on signal for emergency vessels, if at
least one hour notice is given. The Coast Guard will also inform the
users of the waterways through our Local and Broadcast Notices to
Mariners of the change in operating schedule for the bridge so that
vessel operators can arrange their transit to minimize any impact
caused by the temporary deviation.
    In accordance with 33 CFR 117.35(e), the drawbridge must return to
its regular operating schedule immediately at the end of the effective
period of this temporary deviation. This deviation from the operating
regulations is authorized under 33 CFR 117.35.

    Dated: September 13, 2016.
Hal R. Pitts,
Bridge Program Manager, Fifth Coast Guard District.
[FR Doc. 2016-22320 Filed 9-15-16; 8:45 am]
BILLING CODE 9110-04-P