[Federal Register Volume 81, Number 164 (Wednesday, August 24, 2016)]
[Rules and Regulations]
[Pages 57758-57761]
[FR Doc No: 2016-19991]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 25

[Docket No. FAA-2015-5391; Special Conditions No. 25-630-SC]

Special Conditions: The Boeing Company, Boeing Model 767-2C
Airplane; Non-Rechargeable Lithium Battery Installations

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Final special conditions.

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SUMMARY: These special conditions are issued for the Boeing Model 767-
2C airplane. This airplane will have a novel or unusual design feature
when compared to the state of technology envisioned in the
airworthiness standards for transport-category airplanes. This design
feature is associated with non-rechargeable lithium battery
installations. The applicable airworthiness regulations do not contain
adequate or appropriate safety standards for this design feature. These
special conditions contain the additional safety standards that the
Administrator considers necessary to establish a level of safety
equivalent to that established by the existing airworthiness standards.

DATES: Effective April 22, 2017.

FOR FURTHER INFORMATION CONTACT: Nazih Khaouly, Airplane and Flight
Crew Interface Branch, ANM-111, Transport Airplane Directorate,
Aircraft Certification Service, 1601 Lind Avenue SW., Renton,
Washington 98057-3356; telephone<PHONE_NUMBER>; facsimile<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Future Requests for Installation of Non-Rechargeable Lithium Batteries

    The FAA anticipates that non-rechargeable lithium batteries will be
installed in other makes and models of airplanes. We have determined to
require special conditions for all applications requesting non-
rechargeable lithium battery installations, except the installations
excluded in the Applicability section, until the airworthiness
requirements can be revised to address this issue. Applying special
conditions to these installations across the range of all transport-
airplane makes and models ensures regulatory consistency among
applicants.
    The FAA issued special conditions no. 25-612-SC to Gulfstream
Aerospace Corporation for their GVI airplane. Those are the first
special conditions the FAA issued for non-rechargeable lithium battery
installations. We explained in that document our determination to make
those special conditions effective one year after publication of those
special conditions in the Federal Register, and our intention for other
special conditions for other makes and models to be effective on this
same date or 30 days after their publication, whichever is later.

Background

    On January 18, 2010, The Boeing Company (Boeing) applied for an
amendment to type certificate no. A1NM to include a new Model 767-2C
airplane. The Model 767-2C airplane is a twin-engine, transport-
category freighter derivative of the Model 767-200 airplane currently
approved under type certificate no. A1NM. This freighter has a maximum
takeoff weight of 415,000 pounds and can be configured to carry up to
11 supernumeraries.
    The Model 767-2C airplane incorporates provisions to support
subsequent supplemental type

certificate (STC) modifications, which are intended to provide
additional mission capabilities, including provisions to support
conversion into an aerial refueling platform (i.e., tanker)
configuration.

Type Certification Basis

    Under the provisions of Title 14, Code of Federal Regulations, (14
CFR) 21.101, Boeing must show that the Model 767-2C airplane meets the
applicable provisions of the regulations listed in type certificate no.
A1NM or the applicable regulations in effect on the date of application
for the change, except for earlier amendments as agreed upon by the
FAA. The regulations listed in the type certificate are commonly
referred to as the ``original type certification basis.'' The
regulations listed in type certificate no. A1NM are 14 CFR part 25,
effective February 1, 1965, including Amendments 25-1 through 25-37,
with exceptions listed in the type certificate. In addition, the
certification basis includes other regulations, special conditions, and
exemptions that are not relevant to these special conditions. Type
certificate no. A1NM will be updated to include a complete description
of the certification basis for this airplane model.
    If the Administrator finds that the applicable airworthiness
regulations (i.e., 14 CFR part 25) do not contain adequate or
appropriate safety standards for the Model 767-2C airplane because of a
novel or unusual design feature, special conditions are prescribed
under the provisions of Sec.  21.16.
    Special conditions are initially applicable to the airplane model
for which they are issued. Should the type certificate for that model
be amended later to include any other model that incorporates the same
novel or unusual design feature, or should any other model already
included on the same type certificate be modified to incorporate the
same novel or unusual design feature, these special conditions would
also apply to the other model under Sec.  21.101.
    In addition to the applicable airworthiness regulations and special
conditions, the Model 767-2C airplane must comply with the fuel-vent
and exhaust-emission requirements of 14 CFR part 34, and the noise-
certification requirements of 14 CFR part 36.
    The FAA issues special conditions, as defined in 14 CFR 11.19, in
accordance with Sec.  11.38, and they become part of the type-
certification basis under Sec.  21.101.

Novel or Unusual Design Features

    The Boeing Model 767-2C airplane will incorporate non-rechargeable
lithium batteries.
    A battery system consists of the battery and any protective,
monitoring, and alerting circuitry or hardware inside or outside of the
battery. It also includes vents (where necessary) and packaging. For
the purpose of these special conditions, a ``battery'' and ``battery
system'' are referred to as a battery.

Discussion

    The FAA derived the current regulations governing installation of
batteries in transport-category airplanes from Civil Air Regulations
(CAR) 4b.625(d) as part of the re-codification of CAR 4b that
established 14 CFR part 25 in February 1965. We basically reworded the
battery requirements, which are currently in Sec.  25.1353(b)(1)
through (b)(4), from the CAR requirements. Non-rechargeable lithium
batteries are novel and unusual with respect to the state of technology
considered when these requirements were codified. These batteries
introduce higher energy levels into airplane systems through new
chemical compositions in various battery-cell sizes and construction.
Interconnection of these cells in battery packs introduces failure
modes that require unique design considerations, such as provisions for
thermal management.
    Recent events involving rechargeable and non-rechargeable lithium
batteries prompted the FAA to initiate a broad evaluation of these
energy-storage technologies. In January 2013, two independent events
involving rechargeable lithium-ion batteries demonstrated unanticipated
failure modes. A National Transportation Safety Board (NTSB) letter to
the FAA, dated May 22, 2014, which is available at http://www.ntsb.gov,
filename A-14-032-036.pdf, describes these events.
    On July 12, 2013, an event involving a non-rechargeable lithium
battery in an emergency-locator-transmitter installation demonstrated
unanticipated failure modes. The United Kingdom's Air Accidents
Investigation Branch Bulletin S5/2013 describes this event.
    Some known uses of rechargeable and non-rechargeable lithium
batteries on airplanes include:
     Flight deck and avionics systems such as displays, global
positioning systems, cockpit voice recorders, flight data recorders,
underwater locator beacons, navigation computers, integrated avionics
computers, satellite network and communication systems, communication-
management units, and remote-monitor electronic line-replaceable units;
     Cabin safety, entertainment, and communications equipment,
including emergency-locator transmitters, life rafts, escape slides,
seatbelt air bags, cabin management systems, Ethernet switches, routers
and media servers, wireless systems, internet and in-flight
entertainment systems, satellite televisions, remotes, and handsets;
     Systems in cargo areas including door controls, sensors,
video surveillance equipment, and security systems.
    Some known potential hazards and failure modes associated with non-
rechargeable lithium batteries are:
     Internal failures: In general, these batteries are
significantly more susceptible to internal failures that can result in
self-sustaining increases in temperature and pressure (i.e., thermal
runaway) than their nickel-cadmium or lead-acid counterparts. The
metallic lithium can ignite, resulting in a self-sustaining fire or
explosion.
     Fast or imbalanced discharging: Fast discharging or an
imbalanced discharge of one cell of a multi-cell battery may create an
overheating condition that results in an uncontrollable venting
condition, which in turn leads to a thermal event or an explosion.
     Flammability: Unlike nickel-cadmium and lead-acid
batteries, lithium batteries use higher energy and current in an
electrochemical system that can be configured to maximize energy
storage of lithium. They also use liquid electrolytes that can be
extremely flammable. The electrolyte, as well as the electrodes, can
serve as a source of fuel for an external fire if the battery casing is
breached.
    Special condition no. 1 requires that each individual cell within a
non-rechargeable lithium battery be designed to maintain safe
temperatures and pressures. Special condition no. 2 addresses these
same issues but for the entire battery. Special condition no. 2
requires that the battery be designed to prevent propagation of a
thermal event, such as self-sustained, uncontrolled increases in
temperature or pressure from one cell to adjacent cells.
    Special condition nos. 1 and 2 are intended to ensure that the non-
rechargeable lithium battery and its cells are designed to eliminate
the potential for uncontrolled failures. However, a certain number of
failures will occur due to various factors beyond the control of the
designer. Therefore, other special conditions are intended to protect
the airplane and its occupants if failure occurs.

    Special condition nos. 3, 7, and 8 are self-explanatory, and the
FAA does not provide further explanation for them at this time.
    Special condition no. 4 makes it clear that the flammable-fluid
fire-protection requirements of Sec.  25.863 apply to non-rechargeable
lithium battery installations. Section 25.863 is applicable to areas of
the airplane that could be exposed to flammable fluid leakage from
airplane systems. Non-rechargeable lithium batteries contain
electrolyte that is a flammable fluid.
    Special condition no. 5 requires each non-rechargeable lithium
battery installation to not damage surrounding structure or adjacent
systems, equipment, or electrical wiring from corrosive fluids or gases
that may escape. Special condition no. 6 requires each non-rechargeable
lithium battery installation to have provisions to prevent any
hazardous effect on airplane structure or systems caused by the maximum
amount of heat it can generate due to any failure of it or its
individual cells. The means of meeting these special conditions may be
the same, but they are independent requirements addressing different
hazards. Special condition no. 5 addresses corrosive fluids and gases,
whereas special condition no. 6 addresses heat.
    These special conditions will apply to all non-rechargeable lithium
battery installations in lieu of Sec.  25.1353(b)(1) through (b)(4) at
Amendment 25-123. Sections 25.1353(b)(1) through (b)(4) at Amendment
25-123 will remain in effect for other battery installations.
    These special conditions contain the additional safety standards
that the Administrator considers necessary to establish a level of
safety equivalent to that established by the existing airworthiness
standards.

Discussion of Comments

    Notice of proposed special conditions no. 25-16-01-SC, for the
Boeing 767-2C airplane, was published in the Federal Register on
January 27, 2016 [81 FR 4596]. We received four substantive comments.
    The Aerospace Industries Association (AIA) provided several
comments that were identical to their comments for special conditions
no. 25-612-SC, which we issued to Gulfstream Aerospace Corporation for
non-rechargeable lithium battery installations on Gulfstream GVI
airplanes. The FAA responded to each of these comments in that final
special conditions document. We incorporated the same revisions into
these Boeing 767-2C special conditions that we incorporated into the
Gulfstream GVI special conditions as a result of AIA's comments.
    Boeing commented that they fully support AIA's comments.
    Boeing requested that the FAA provide adequate time before non-
rechargeable lithium battery special conditions become effective to
support validation activities by foreign civil airworthiness
authorities (FCAA) and to not adversely impact future airplane
deliveries by all applicants. The FAA considered this same comment from
Boeing for special conditions no. 25-612-SC and provided a detailed
response in that document. We determined the effective date for these
Boeing 767-2C special conditions based on Boeing's comment and other
factors stated in special conditions no. 25-612-SC.
    Boeing commented that the FAA needs to clearly define the
applicability of these special conditions. Boeing's comment is similar
to their comment on special conditions no. 25-612-SC. We provided a
detailed response in special conditions no. 25-612-SC and have clearly
defined the applicability for these Boeing 767-2C special conditions.
One aspect of Boeing's comment that we did not address in special
conditions no. 25-612-SC is that some design changes may not change a
lithium battery installation but affect it, which results in these
special conditions being applicable. For example, adding a heat source
next to a lithium battery can increase its possibility of entering into
thermal runaway. Lithium battery installations affected by design
changes must meet these special conditions. Some examples of changes
that affect lithium battery installations are those that:
     Increase the temperatures or pressures in a battery,
     Increase the electrical load on a battery,
     Increase potential for imbalance between battery cells,
     Modify protective circuitry for a lithium battery,
     Increase the airplane level risk due to the location of an
existing lithium battery. An example is installation of a new oxygen
line next to an existing part that has a lithium battery. The airplane
level risk may increase due to the potential hazard of a lithium
battery fire in the proximity of oxygen.
    Gulfstream Aerospace Corporation commented that they agree with
Boeing's comments and requested that the FAA consider incorporating
their proposed changes into this document.
    AmSafe recommended that the FAA state in the preamble that design
mitigation or analysis at the airplane level may be applied to show
that designs meet these special conditions. The FAA has determined that
these special conditions are to require the battery to be designed to
minimize the potential of uncontrollable failure, and to not only rely
on mitigation of a battery failure at the airplane level. Therefore, we
have not incorporated the proposed revision into the preamble of these
special conditions.
    AmSafe commented that they concur with proposed special condition
no. 1 with an understanding that ``foreseeable operating conditions''
equates to the full normal operating envelope of the airplane. However,
this is not a correct understanding of proposed special condition no.
1. The FAA intends for the term ``foreseeable operating conditions,''
in these special conditions, to apply at the cell level and not only at
the airplane level. In addition, ``foreseeable'' includes anticipated
abnormal operating conditions.
    AmSafe recommended revising proposed special condition no. 2 to
read, ``Battery installation and/or equipment containing any non-
rechargeable lithium battery must preclude the occurrence of, or
mitigate the effect of self-sustaining, uncontrolled increases in
temperature or pressure.'' Amsafe's rationale was based on their
recommendation that design mitigation or analysis at the airplane level
be acceptable. As explained above, the FAA has determined that these
special conditions are to require the battery to be designed to
minimize the potential of uncontrollable failure, and to not only rely
on mitigation of a battery failure at the airplane level. The FAA has
not incorporated the proposed revision into special condition no. 2.
    AmSafe recommended adding the phrase ``. . . failure which is not
shown to be extremely remote . . .'' to proposed special condition no.
3. The FAA responds that service history shows that battery failure is
not extremely remote. Therefore, to ensure that failures are properly
anticipated and accounted for, we have not revised proposed special
condition no. 3 to include these words.
    AmSafe recommended deleting Sec.  25.863(c)(d) from proposed
special condition no 4. The FAA does not concur. Section 25.863 already
applies to non-rechargeable lithium batteries since they contain
electrolyte that is a flammable fluid. Since Sec.  25.863 has
historically been applied to flammable fluids related to propulsion and
hydraulic systems, the FAA is including special condition no. 4 to
ensure that

there is no misunderstanding that Sec.  25.863 also applies to these
batteries.
    AmSafe recommended revising proposed special condition no. 5 to
prohibit damage to surrounding structure or adjacent systems,
equipment, or electrical wiring from corrosive fluids or gases that may
escape ``in such a way as to cause a hazardous or catastrophic failure
condition.'' AIA also recommended this revision. The FAA intends for
special condition no. 5 to be consistent with Sec.  25.1309. So, we
added the words ``. . . in such a way as to cause a major or more-
severe failure condition.'' The revised special condition now reads,
``. . . each non-rechargeable lithium battery installation must not
damage surrounding structure or adjacent systems, equipment, or
electrical wiring from corrosive fluids or gases that may escape in
such a way as to cause a major or more-severe failure condition.'' The
FAA does not concur with excluding major failure conditions.
    AmSafe concurred with proposed special condition no. 6.
    AmSafe concurred with proposed special condition no. 7 and
recommended revising proposed special condition no. 8. However, the FAA
deleted these proposed special conditions as explained in our response
to AIA's comments in special conditions no. 25-612-SC.
    AmSafe recommended revising ``safe operation of the airplane'' in
proposed special condition nos. 9 and 10 to ``continued safe operation
of the airplane.'' The phrase ``continued safe operation of the
airplane'' is used to refer to safe operation of the airplane after a
failure has occurred. The phrase ``safe operation of the airplane'' is
more general and appropriate for these special conditions. We did not
incorporate AmSafe's proposed revision into these special conditions.
    The FAA has determined that ``uncontrolled'' in special condition
no. 2 should be ``uncontrollable'' to more accurately describe the
concern. This revision does not change the intended meaning of this
special condition.
    Except as discussed above, the special conditions are adopted as
proposed.

Applicability

    As discussed above, these special conditions are applicable to the
Model 767-2C airplane. Should the applicant apply at a later date for a
change to the type certificate to include another model incorporating
the same novel or unusual design feature, or should any other model
already included on the same type certificate be modified to
incorporate the same novel or unusual design feature, these special
conditions would apply to that model as well.
    These special conditions are only applicable to design changes
applied for after their effective date. The existing airplane fleet and
follow-on deliveries of airplanes with previously certified non-
rechargeable lithium battery installations are not affected.
    These special conditions are not applicable to previously certified
non-rechargeable lithium battery installations where the only change is
either cosmetic or relocating the installation to improve the safety of
the airplane and occupants. The FAA determined that this exclusion is
in the public interest because the need to meet all of the special
conditions might otherwise deter such design changes that involve
relocating batteries. A cosmetic change is a change in appearance only,
and does not change any function or safety characteristic of the
battery installation.

Conclusion

    This action affects only certain novel or unusual design features
on one model of airplane. It is not a rule of general applicability.

List of Subjects in 14 CFR Part 25

    Aircraft, Aviation safety, Reporting and record keeping
requirements.

    The authority citation for these special conditions is as follows:

    Authority: 49 U.S.C. 106(g), 40113, 44701, 44702, 44704.

The Special Conditions

    Accordingly, the following special conditions are part of the type
certification basis for the Boeing Model 767-2C airplane.

Non-Rechargeable Lithium Battery Installations

    In lieu of Sec.  25.1353(b)(1) through (b)(4) at Amendment 25-123,
each non-rechargeable lithium battery installation must:
    1. Maintain safe cell temperatures and pressures under all
foreseeable operating conditions to prevent fire and explosion.
    2. Prevent the occurrence of self-sustaining, uncontrollable
increases in temperature or pressure.
    3. Not emit explosive or toxic gases, either in normal operation or
as a result of its failure, that may accumulate in hazardous quantities
within the airplane.
    4. Meet the requirements of Sec.  25.863.
    5. Not damage surrounding structure or adjacent systems, equipment,
or electrical wiring from corrosive fluids or gases that may escape in
such a way as to cause a major or more-severe failure condition.
    6. Have provisions to prevent any hazardous effect on airplane
structure or systems caused by the maximum amount of heat it can
generate due to any failure of it or its individual cells.
    7. Have a failure sensing and warning system to alert the
flightcrew if its failure affects safe operation of the airplane.
    8. Have a means for the flightcrew or maintenance personnel to
determine the battery charge state if the battery's function is
required for safe operation of the airplane.
    Note: A battery system consists of the battery and any protective,
monitoring, and alerting circuitry or hardware inside or outside of the
battery. It also includes vents (where necessary) and packaging. For
the purpose of these special conditions, a ``battery'' and ``battery
system'' are referred to as a battery.

    Issued in Renton, Washington, on August 11, 2016.
Paul Bernado,
Acting Manager, Transport Airplane Directorate, Aircraft Certification
Service.
[FR Doc. 2016-19991 Filed 8-23-16; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register Volume 83, Number 195 (Tuesday, October 9, 2018)]
[Notices]
[Pages 50658-50659]
[FR Doc No: 2018-21775]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 2837-033]

Erie Boulevard Hydropower, L.P.; Notice of Application Accepted
for Filing and Soliciting Motions To Intervene and Protests

    Take notice that the following hydroelectric application has been
filed with the Commission and is available for public inspection.
    a. Type of Application: New Major License.
    b. Project No.: 2837-033.
    c. Date filed: March 29, 2018.
    d. Applicant: Erie Boulevard Hydropower, L.P. (Erie).
    e. Name of Project: Granby Hydroelectric Project.
    f. Location: On the Oswego River in the town of Fulton in Oswego
County, New York. The project does not affect federal lands.
    g. Filed Pursuant to: Federal Power Act, 16 U.S.C. 791(a)-825(r).
    h. Applicant Contact: Steven P. Murphy, Director, U.S. Licensing,
Erie Boulevard Hydropower, L.P., 33 West 1st Street South, Fulton, NY
13069;<PHONE_NUMBER>.
    i. FERC Contact: Allyson Conner,<PHONE_NUMBER> or
[email protected].
    j. Deadline for filing motions to intervene and protests: 60 days
from the issuance date of this notice.
    The Commission strongly encourages electronic filing. Please file
motions to intervene and protests using the Commission's eFiling system
at http://www.ferc.gov/docs-filing/efiling.asp. For assistance, please
contact FERC Online Support at [email protected], (866) 208-
3676 (toll free), or<PHONE_NUMBER> (TTY). In lieu of electronic
filing, please send a paper copy to: Secretary, Federal Energy
Regulatory Commission, 888 First Street NE, Washington, DC 20426. The
first page of any filing should include docket number P-2837-033.
    The Commission's Rules of Practice require all intervenors filing
documents with the Commission to serve a copy of that document on each
person on the official service list for the project. Further, if an
intervenor files comments or documents with the Commission relating to
the merits of an issue that may affect the responsibilities of a
particular resource agency, they must also serve a copy of the document
on that resource agency.
    k. This application has been accepted, but is not ready for
environmental analysis at this time.
    l. The existing Granby Hydroelectric Project (Granby Project)
consists of: (1) An 88-foot-wide reinforced concrete intake structure
that includes two bays containing trashracks and fixed-roller,
vertical-lift type gates; (2) a 17-foot-wide sluice opening adjacent to
the intake structure; (3) a 112-foot-long, 88-foot-wide powerhouse
containing two 5.04-megawatt (MW) turbine-generator units, with a total
capacity of 10.08 MW; (4) a 3,000-foot-long, 100-foot-wide tailrace;
(5) two 4.16-kilovolt, 120-foot-long underground generator leads; (6) a
60-foot-long by 48-foot-wide electrical switchyard; and (7) appurtenant
facilities.
    The Granby Project is operated in a modified run-of-river mode. The
Granby Project and the Fulton Development at Erie's Oswego River
Hydroelectric Project (FERC Project No. 2474) are located at opposite
ends of the same dam and share a single bypassed reach and reservoir.
The flow and impoundment elevation requirements in the Oswego Project
license,\1\ which were based on a 2004 Offer of Settlement, affect the
Granby Project. The average annual generation at the Granby Project is
estimated to be 44,181 megawatt-hours.
---------------------------------------------------------------------------

    \1\ 109 FERC ] 62, 141 (2004).
---------------------------------------------------------------------------

    m. A copy of the application is available for review at the
Commission in the Public Reference Room or may be viewed on the
Commission's website at http://www.ferc.gov using the ``eLibrary''
link. Enter the docket number excluding the last three digits in the
docket number field to access the document. For assistance, contact
FERC Online Support. A copy is also available for inspection and
reproduction at the address in item h above.
    n. You may also register online at http://www.ferc.gov/docs-filing/esubscription.asp to be notified via email of new filings and issuances
related to this or other pending projects. For assistance, contact FERC
Online Support.
    o. Anyone may submit a protest or a motion to intervene in
accordance with the requirements of Rules of Practice and Procedure, 18
CFR 385.210, 385.211, and 385.214. In determining the appropriate
action to take, the Commission will consider all protests filed, but
only those who file a motion to intervene in accordance with the
Commission's Rules may become a party to the proceeding. Any protests
or motions to intervene must be received on or before the specified
deadline date for the particular application.
    All filings must (1) bear in all capital letters the title
``PROTEST'' or ``MOTION TO INTERVENE;'' (2) set forth in the heading
the name of the applicant and the project number of the application to
which the filing responds; (3) furnish the name, address, and telephone
number of the person protesting or intervening; and (4) otherwise
comply with the requirements of 18 CFR 385.2001 through 385.2005.
Agencies may obtain copies of the application directly from the
applicant. A copy of any protest or motion to intervene must be served
upon each representative of the applicant specified in the particular
application.
    p. Updated procedural schedule and final amendments: The
application will be processed according to the following preliminary
Hydro Licensing Schedule. Revisions to the schedule will be made as
appropriate.

Issue Scoping Document 1--September 2018
Comments on Scoping Document 1 due--October 2018
Issue Scoping Document 2 (if necessary)--December 2018
Issue Notice of Ready for Environmental Analysis--February 2019
Deadline for Filing Comments, Recommendations and Agency Terms and
Conditions/Prescriptions--April 2019
Commission issues EA--October 2019
Comments on EA--November 2019

    Final amendments to the application must be filed with the
Commission no later than 30 days from the issuance

date of the notice of ready for environmental analysis.

    Dated: September 28, 2018.
Kimberly D. Bose,
Secretary.
[FR Doc. 2018-21775 Filed 10-5-18; 8:45 am]
BILLING CODE 6717-01-P


[Federal Register Volume 87, Number 203 (Friday, October 21, 2022)]
[Notices]
[Pages 64055-64057]
[FR Doc No: 2022-22882]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA 2016-D-4460]

Multiple Endpoints in Clinical Trials; Guidance for Industry;
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the availability of a final guidance for industry entitled ``Multiple
Endpoints in Clinical Trials.'' This guidance provides sponsors and
review staff with the Agency's thinking about the problems posed by
multiple endpoints in the analysis and interpretation of study results
and how these problems can be managed in clinical trials for human
drugs, including drugs subject to licensing as biological products.
This guidance finalizes the draft guidance of the same title issued on
January 13, 2017.

DATES: The announcement of the guidance is published in the Federal
Register on October 21, 2022.

ADDRESSES: You may submit comments on any guidance at any time as
follows:

Electronic Submissions

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

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

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA 2016-D-4460 for ``Multiple Endpoints in Clinical Trials.'' Received
comments will be placed in the docket and, except for those submitted
as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' 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.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.
    You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
    Submit written requests for single copies of this guidance to the
Division of Drug Information, Center for Drug Evaluation and Research,
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale
Building, 4th Floor, Silver Spring, MD 20993-0002 or to the Office of
Communication, Outreach and Development, Center for Biologics
Evaluation and Research (CBER), Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. Send
one self-addressed adhesive label to assist that office in processing
your requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Scott N. Goldie, Center for Drug
Evaluation and Research, Office of Biostatistics, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 21, Rm. 3557, Silver
Spring, MD 20993-0002,<PHONE_NUMBER>, or Stephen Ripley, Center for
Biologics Evaluation and Research, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002,
240-402-7911.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry
entitled ``Multiple Endpoints in Clinical Trials.'' This guidance
describes various strategies for grouping and ordering endpoints for
analysis of a drug's effects and applying some well-recognized
statistical methods for managing multiplicity within a clinical trial
to control the chance of making erroneous conclusions about a drug's
effects. FDA's International Conference on Harmonization (ICH) guidance
for industry ``E9 Statistical Principles for Clinical Trials'' is a
broad-ranging guidance that includes discussion of multiple endpoints.
This guidance provides greater detail on the topic of multiple
endpoints.
    Failure to account for multiplicity when there are several clinical
endpoints evaluated in a clinical trial can lead to false positive
conclusions regarding the effects of the drug. The regulatory concern
regarding multiplicity arises principally in the evaluation of clinical
trials intended to demonstrate effectiveness and support drug approval;
however, this issue is important throughout the drug development
process.
    The focus of this guidance is control of the Type 1 error rate for
the planned primary and secondary endpoints of a clinical trial so that
the major findings are well supported. Multiplicity adjustments provide
a means for controlling the Type 1 error rate when there are multiple
analyses of the drug's effects. The issues of multiplicity and methods
to address them are illustrated in the guidance with examples of
different study endpoints. Both the issues and methods that apply to
multiple endpoints also apply to other sources of multiplicity,
including multiple doses, time points, or study population subgroups.
    This guidance finalizes the draft guidance of the same title that
published January 13, 2017 (82 FR 4353). FDA considered comments
received on the draft guidance as the guidance was finalized. Changes
from the draft to the final guidance include clarifications for some of
the potential issues caused by including multiple endpoints in clinical
trials and clarifications for some of the strategies for handling these
issues. In addition, editorial changes were made to improve clarity by
reducing redundancies in the text.
    This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
current thinking of FDA on ``Multiple Endpoints in Clinical Trials.''
It does not establish any rights for any person and is not binding on
FDA or the public. You can use an alternative approach if it satisfies
the requirements of the applicable statutes and regulations.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. Therefore,
clearance by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not
required for this guidance. The previously approved collections of

information are subject to review by OMB under the PRA. The collections
of information in 21 CFR 312.23 for the content and format of
investigational new drug applications have been approved under OMB
control number 0910-0014. The collections of information in 21 CFR part
314 for submitting applications for FDA approval to market a new drug
have been approved under OMB control number 0910-0001. The collections
of information in 21 CFR 201.56 and 201.57 for preparing and submitting
labeling have been approved under OMB control number 0910-0572.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: October 17, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-22882 Filed 10-20-22; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register: July 14, 2010 (Volume 75, Number 134)]
[Notices]
[Page 40821-40823]
[DOCID:fr14jy10-67]

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ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OPP-2010-0398; FRL-8832-1]

Methyl Soyate; Receipt of Application for Emergency Exemption,
Solicitation of Public Comment

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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

SUMMARY: EPA has received a specific exemption request from the Wyoming
Department of Agriculture to use the pesticide methyl soyate (BIO-LARV)
(CAS Reg. No. 67762-38-3) to treat aquatic vegetation to control
mosquito larvae. The applicant proposes the use of a new chemical which
has not been registered by EPA. EPA is soliciting public comment before
making the decision whether or not to grant the exemption.

DATES: Comments must be received on or before July 29, 2010.

ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2010-0398, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the on-line instructions for submitting comments.
     Mail: Office of Pesticide Programs (OPP) Regulatory Public
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460-0001.
     Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only
accepted during the Docket Facility's normal hours of operation (8:30
a.m. to 4 p.m., Monday through

Friday, excluding legal holidays). Special arrangements should be made
for deliveries of boxed information. The Docket Facility's telephone
number is<PHONE_NUMBER>.
    Instructions: Direct your comments to docket ID number EPA-HQ-OPP-
2010-0398. EPA's policy is that all comments received will be included
in the docket without change and may be made available on-line 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 regulations.gov or e-
mail. The regulations.gov website 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 regulations.gov,
your e-mail address will be automatically captured and included as part
of the comment that is placed in the 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 docket are listed in the docket index
available at http://www.regulations.gov. Although listed in the index,
some information is not publicly available, e.g., 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 in the electronic
docket at http://www.regulations.gov, or, if only available in hard
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac
Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The hours of
operation of this Docket Facility are from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays. The Docket Facility's
telephone number is<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Princess Campbell, Registration
Division (7505P), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number:<PHONE_NUMBER>; fax number:<PHONE_NUMBER>; e-
mail address: campbell.princess @epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).
    This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.

B. What Should I Consider as I Prepare My Comments for EPA?

    1.  Submitting CBI. Do not submit this information to EPA through
www.regulations.gov or e-mail. Clearly mark the part or all of the
information that you claim to be CBI. For CBI information in a disk or
CD-ROM that you mail to EPA, mark the outside of the disk or CD-ROM as
CBI and then identify electronically within the disk or CD-ROM the
specific information that is claimed as CBI. In addition to one
complete version of the comment that includes information claimed as
CBI, a copy of the comment that does not contain the information
claimed as CBI must be submitted for inclusion in the public docket.
Information so marked will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2.
    2.  Tips for preparing your comments. When submitting comments,
remember to:
    i. Identify the document by docket ID number and other identifying
information (subject heading, Federal Register date and page number).
    ii. Follow directions. The Agency may ask you to respond to
specific questions or organize comments by referencing a Code of
Federal Regulations (CFR) part or section number.
    iii. Explain why you agree or disagree; suggest alternatives and
substitute language for your requested changes.
    iv. Describe any assumptions and provide any technical information
and/or data that you used.
    v. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
    vi. Provide specific examples to illustrate your concerns and
suggest alternatives.
    vii. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
     viii. Make sure to submit your comments by the comment period
deadline identified.
    3. Environmental justice. EPA seeks to achieve environmental
justice, the fair treatment and meaningful involvement of any group,
including minority and/or low income populations, in the development,
implementation, and enforcement of environmental laws, regulations, and
policies. To help address potential environmental justice issues, the
Agency seeks information on any groups or segments of the population
who, as a result of their location, cultural practices, or other
factors, may have atypical or disproportionately high and adverse human
health impacts or environmental effects from exposure to the pesticide
discussed in this document, compared to the general population.

II. What Action is the Agency Taking?

    Under section 18 of the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) (7 U.S.C. 136p), at the discretion of the
Administrator, a Federal or State agency may be exempted from any
provision of FIFRA if the Administrator determines that emergency
conditions exist which require the exemption. The Wyoming Department of
Agriculture has requested the Administrator to issue a specific
exemption for the use of methyl soyate on aquatic vegetation to control
mosquito larvae. Information in accordance with 40 CFR part 166 was
submitted as part of this request.
    As part of this request, the applicant asserts that the use of
methyl soyate on aquatic vegetation will control mosquito larvae,
including those that transmit the West Nile virus, in ponds within the
State of Wyoming. The applicant asserts

that other products can be harmful to the environment, but methyl
soyate (BIO-LARV) has been shown to have little or no side effects on
other aquatic species or mammal life in or near ponds. The applicant
also cites statistics detailing the number of cases of West Nile virus
infections during the period 2003-2008, and reports 14 deaths over the
period.
    Methyl soyate (BIO-LARV) will be applied at the rate of 3-5 gallons
per acre depending on the density of the vegetation. Per the label the
mixture will consist of 3-5 gallons of BIO-LARV to 100 gallons of
water.
    This notice does not constitute a decision by EPA on the
application itself. The regulations governing section 18 of FIFRA
require publication of a notice of receipt of an application for a
specific exemption proposing use of a new chemical (i.e., an active
ingredient) which has not been registered by EPA. This notice provides
an opportunity for public comment on the application.
    The Agency will review and consider all comments received during
the comment period in determining whether to issue the specific
exemption requested by the Wyoming Departmrnt of Agriculture.

List of Subjects

    Environmental protection, Pesticides and pests.

    Dated: June 30, 2010.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 2010-16923 Filed 7-13-10; 8:45 am]
BILLING CODE 6560-50-S


[Federal Register Volume 78, Number 20 (Wednesday, January 30, 2013)]
[Notices]
[Page 6316]
[FR Doc No: 2013-01920]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. EG13-1-000, et al.]

 Big Blue Wind Farm, LLC, et al.; Notice of Effectiveness of
Exempt Wholesale Generator Status

------------------------------------------------------------------------
                                                           Docket  Nos.
------------------------------------------------------------------------
Big Blue Wind Farm, LLC................................       EG13-1-000
Calpine Bosque Energy Center, LLC......................       EG13-2-000
Homer City Generation, L.P.............................       EG13-3-000
Texas Dispatchable Wind 1, LLC.........................       EG13-4-000
Blue Creek Wind Farm LLC...............................       EG13-5-000
------------------------------------------------------------------------

    Take notice that during the month of December 2012, the status of
the above-captioned entities as Exempt Wholesale Generators Companies
became effective by operation of the Commission's regulations. 18 CFR
366.7(a).

    Dated: January 17, 2013.
Kimberly D. Bose,
Secretary.
[FR Doc. 2013-01920 Filed 1-29-13; 8:45 am]
BILLING CODE 6717-01-P


Peter Voytek To: John Schaoffer/ DC/ USEPA/ US © EPA < pvoytek@ crosshnk. n cc: et> Subject: appendix C with updated changes 02/ 12/ 2003 02: 40 PM John. The attached file contains the EDC appendix C with updated changes that were not included in the original version mailed to you by Caffey Norman. If you have any questions let me know.

Peter edc appCrevwpd RECEIVED OPPT NCIC 2003 MAR11 5: 03PM OPPT 2003 0010 0019 APPENDIX C PK/ MECH PROCEDURES AND ROUTE TO ROUTE EXTRAPOLATION REPORTING FOR ETHYLENE DICHLORIDE This Appendix contains detailed procedures for the kinetic studies and route to route extrapolations to be conducted for ethylene dichloride, and is organized into the following sections:

C. 1 Pharmacokinetic Studies for F344 Rats C. 2 Subchronic Toxicity C. 3 Subchronic Neurotoxicity C. 4 Reproductive Toxicity C. 5 PBPK Model Description and Coding C. 6 General Outline for Route to Route Extrapolation Reports C. 7 References 1 C. 1. Pharmacokinetic Studies for F344 Rats A total of 4 pharmacokinetic studies ( designated Study 1, Study 2, Study 3 and Study 4) will be conducted to support PBPK modeling activities for ethylene dichioride, as described in this section ( C. 1.). It is anticipated that the pharmacokinetic studies will start one year after the ECA is signed, with an interim report generated six months later, and the final report submitted three months later ( see Appendix A for complete schedule).

Study 1: Demonstration of Periodicity Following Repeated Inhalation Exposures __________________ Proposed Rat F344 Young adult 132 animals ( 3 controls at beginning ( t =

0) and 3 at end of exposure ( t = 6 hr) on days 1, 3, and 5; 3 exposed animals at the beginning of exposure ( t = 0) on days 3 and 5, 3 exposed animals/ time point at t = 0.25, 0.5, 6.25 and 16 hr during and after exposure on days 1, 3, and 5, and 6 exposed animals/ time point at t = 1, 3, 6, and 8 hr during and after exposure on days 1, 3, 5) To be determined Inhalation 6 hrs/ day, 5 consecutive days Liver and lung GSH in controls ( n = 3) at beginning and end of exposure ( 0 and 6 hrs) on days 1 ,3 and 5. Lung and liver GSH in exposed animals ( n = 3) at beginning of exposure on days 3 and 5. Venous blood concentrations of EDC ( n = 3) at 0.25, 0.5, 6.25, and 16 hrs after exposure starts on days 1, 3, and 5. Venous blood concentrations of EDC ( n = 6) and lung and liver GSH concentrations ( n = 3) at 1, 3, 6, and 8 hours after exposure starts on days 1, 3, and 5. Parameter Species Strain Age Number of animals Dose( s) Route Exposure Frequency Observations Kinetic studies will be conducted for demonstrating periodicity in the rat following inhalation exposures with EDC. Measurements of EDC in blood and tissue: blood partition coefficients are anticipated to be sufficient to describe tissue concentration time courses ofEDC based on the results of Spreafico et al. ( 1980) where concentrations in brain, kidney, spleen, liver, lung, and adipose tissue were found to parallel the concentrations in blood of rats exposed to EDC by iv, oral, and inhalation routes. Measurements oflung and liverGSH will be used to further calibrate and validate theGSH depletion portion ofthe PBPK model. These data will allow the model to compute the flux through both metabolism pathways that are dependent on GSH conjugation ( see section C. 5). The depletion of GSH in various tissues has been used to determine and validate the kinetic constants for GSH conjugation reactions for a number of chemicals and their metabolites. These include vinylidene chloride ( D'Souza and Andersen, 1988), EDC ( D'Souza et al., 1988), ethyl acrylate ( Frederick et al., 1992), ethylene oxide ( Krishnan et al., 1992), and allyl chloride ( Clewell and Andersen, 1994). In contrast, elimination of EDC metabolites via the GSH pathway, measured as urinary thiodiglycolic acid ( TDGA) is not an optimal biomarker of GSH metabolism. Departures from a linear relationship between dose and 24 hour TDGA may be observed as dose increases ( Payan et al., 1993) in the range of doses used in existing toxicity studies ( e. g., NCI, 1978). A possible lag in urinary elimination as TDGA, extending > 24 hours after dosing, would compromise use ofthis biomarker as validation for GSH metabolism during a repeated dosing study.

Air concentrations should be measured hourly. Blood samples will be drawn on days 1, 3, and 5. Blood samples ( from 3 or 6 animals) and liver and lung of3 animals ( forglutathione determination) will be collected immediately following sacrifice. Blood samples willbe drawn from 6 animals only at sampling times where lung and liverGSH are also being measured ( 3 animals' lungs and livers for GSH, 3 for freezing). Lung, liver, kidney, brain, adrenal gland, and thyroid will be frozen for possible further analysis. Apositive control ( spiked storage sample) will be required to demonstrate the recovery of EDC in tissues following freezing. Tissues will be stored until after the Tier I Program Review.

3 Study 2: Demonstration of Periodicity Following Repeated Oral Exposures to Ethylene Dichloride by Corn Oil Gavage Dose( s) Route Exposure Frequency Observations Pronosed Rat F344 Young adult 132 animals ( 3 controls at dosing ( t = 0) and 3 after dosing ( t = 2 6 hr) on days 1, 3, and 5; 3 exposed animals prior to dosing ( t = 0) on days 3 and 5; 3 exposed animals at t = 0.25, 4, 16, and 24 hrs after dosing on days 1, 3, and 5; and 6 exposed animals/ time point 0.5, 1, 2, and 8 hrs after dosing on days 1, 3, 5) 150 mg/ kg Corn oil gavage ix/ day, 5 consecutive days Liver and lung GSH in controls ( n = 3) prior to dosing ( at 0 hrs) and at 8 hrs after dosing. Liver and lung GSH in previously dosed animals ( n = 3) prior to dosing ofremaining animals ( t = 0) on days 3 and 5. Venous blood concentrations of EDC ( n= 3) at 0.25, 4, 16, and 24 hrs after dosing on days 1, 3, and 5. Venous blood concentrations of EDC ( n = 6) and lung and liver GSH concentrations ( n = 3) at 0.5, 1, 2, and 8 hours after exposure starts on days 1, 3, and 5 Kinetic studies will be conducted for demonstrating periodicity in the rat following corn oil gavage with EDC. Measurements of EDC in blood and tissue: blood partition coefficients are anticipated to be sufficient to describe tissue concentration time courses of EDC based on the results of Spreafico et al. ( 1980) where concentrations in brain, kidney, spleen, liver, lung, and adipose tissue were found to parallel the concentrations in blood ofrats exposed to EDC by iv, oral, and inhalation routes. Measurements of lung and liver GSH will be used to further calibrate and validate the GSHdepletion portion of the PBPK model. These data will allow the model to compute the flux through both metabolism pathways that are dependent on GSH conjugation ( see section C. 5). The depletion of GSH in various tissues has been used to determine and validate the kinetic constants for GSH Parameter Species Strain Age Number of animals 4 conjugation reactions for a number of chemicals and their metabolites. These include vinylidene chloride ( D'Souza and Andersen, 1988), EDC ( D'Souza et al., 1988), ethyl acrylate ( Frederick et al., 1992), ethylene oxide ( Krishnan et al., 1992) and allyl chloride ( Clewell and Andersen, 1994). In contrast, elimination ofEDC metabolites via the GSH pathway, measured as urinary thiodiglycolic acid ( TDGA) is not an optimalbiomarker ofGSH metabolism. Departuresfrom a linear relationship between dose and 24 hourTDGAmaybe observed as dose increases ( Payan et al., 1993) in the range ofdoses used in existing toxicity studies ( e. g., NCI, 1978). A possible lag in urinary elimination as TDGA, extending > 24 hours afterdosing, would compromise use ofthis biomarker as validation for GSH metabolism during a repeated dosing study.

The testdose was selected based on the doses administeredto ratsin the high dose group for the 90 day study conducted by Daniel et al. ( 1994). Blood samples will be drawn on days 1, 3, and 5. Blood samples ( from 3 or 6 animals) and liver and lung of 3 animals ( for glutathione determination) will be collected immediately following sacrifice. Lung, liver, kidney, brain, adrenal gland, and thyroid will be frozen for possible further analysis. A positive control ( spiked storage sample) will be required to demonstrate the recoveryofEDC in tissues following freezing. Tissues willbe stored until after the Tier I Program Review.

5 Study 3: Demonstration of Periodicity Following Repeated Oral Exposures to Ethylene Dichloride by Agueous Gavage Parameter Proposed Species Rat Strain F344 Age Young adult Number of animals 132 animals ( 3 controls at dosing ( t = 0) and 3 after dosing ( t = 2 6 hr) on days 1, 3, and 5; 3 exposed animals prior to dosing ( t = 0) on days 3 and 5; 3 exposed animals at t= 0.25, 4, 16, and 24 hrs after dosing on days 1, 3, and 5; and 6 exposed animals/ time point 0.5, 1, 2, and 8 hrs after dosing on days 1, 3, 5) Doses < 43 mg/ kg day Route Aqueous gavage Exposure Frequency 1 x/ day, 5 consecutive days Observations Liver and lung GSH in controls ( n = 3) prior to dosing ( at 0 hrs) and at 8 hrs after dosing. Liver and lung GSH in previously dosed animals ( n = 3) prior to dosing ofremaining animals ( t = 0) on days 3 and 5. Venous blood concentrations of EDC ( n= 3) at 0.25, 4, 16, and 24 hrs after dosing on days 1, 3, and 5. Venous blood concentrations of EDC ( n = 6) and lung and liver GSH concentrations ( n = 3) at 0.5, 1, 2, and 8 hours after exposure starts on days 1, 3, and 5 Kinetic studies will be conducted for demonstrating periodicity in the rat following aqueous gavage with EDC. Measurements of EDC in blood and tissue: blood partition coefficients are anticipated to be sufficient to describe tissue concentration time courses of EDC based on the results of Spreafico et al. ( 1980) where concentrations in brain, kidney, spleen, liver, lung, and adipose tissue were found to parallel the concentrations in blood ofrats exposed to EDC by iv, oral, and inhalation routes. Measurements of lung and liverGSH willbe used to further calibrate and validate the GSHdepletion portion of the PBPK model. These data will allow the model to compute the flux through both metabolism pathways that are dependent on GSH conjugation ( see section C. 5). The depletion of GSH in various tissues has been used to determine and validate the kinetic constants for GSH conjugation reactions for a number of chemicals and their metabolites. These include vinylidene 6 chloride ( D'Souza and Andersen, 1988), EDC ( D'Souza et al., 1988), ethyl acrylate ( Frederick et al., 1992), ethylene oxide ( Krishnan et al., 1992) and allyl chloride ( Clewell and Andersen, 1994). In contrast, elimination ofEDC metabolites via the GSH pathway, measured as urinary thiodiglycolic acid ( TDGA) is not an optimal biomarker ofGSH metabolism. Departures from a linear relationship between dose and 24 hourTDGAmaybe observed as dose increases ( Payan et al., 1993) in the range ofdoses used in existing toxicity studies ( e. g., NCI, 1978). A possible lag in urinary elimination as TDGA, extending > 24 hours afterdosing, would compromise use ofthis biomarker as validation for GSH metabolism during a repeated dosing study. Therateconstant for oral absorption from a gavage dose of EDC in water ( to be determined via PBPK modeling) will be considered appropriate for modeling oftoxicity studies in whichEDC was ingestedviaad libitum access to drinkingwater ( e. g., O'Flaherty, 1996).

The test dose will be selected based on the water solubility and dosing volume. Thewater solubility of EDC is 8.7 mg/ mL, and the dosing volume for a rat should be no more than 5 ml/ kg, for a maximum dose of 43 mg/ kg/ d. The actual dose will be set based on the ability of the lab to consistently, homogeneously solubilize the test article. Blood samples will be drawn on days 1, 3, and 5. Blood samples ( from 3 or 6 animals) and liver and lung of 3 animals ( for glutathione determination) will be collected immediately following sacrifice. Lung, liver, kidney, brain, adrenal gland, and thyroid will be frozen for possible further analysis. A positive control ( spiked storage sample) will be requiredto demonstrate the recoveryof EDC in tissues following freezing. Tissues will be stored until after the Tier I Program Review.

7 Study 4: Determination of Partition Coefficients The rat brain: air, kidney: air, testes: air, and ovary: air partition coefficients will be determined using the vial equilibration technique described by Gargas etal. ( 1989, Toxicol. AppI. Pharmacol. 98, 87 99).

A total of5 rats will be used, if partition coefficients are determined individually. A higher number of animals may be required if composite samples are used. It is preferred that partition coefficients be determined for individual animals, however if tissue volumes are insufficient to measure individually a composite sample may be used.

8 C. 2 Subchronic Toxicity Route To Route Extrapolation The NOAEL/ LOAEL values obtained from the existing subchronic study ofDaniel et al. ( 1994) will be extrapolated from the oral route to the inhalation routeusingaPBPK model ( Appendix C. 5). The internal dose metric ( e. g., peak concentration or average concentration ofEDC, or amount ofEDC metabolized) used to perform this extrapolation will be determined based on a consideration ofthe effects observed and a plausible mechanism of action.

9 C. 3 Subchronic Neurotoxicity Route To Route Extrapolation The NOAEL/ LOAELvalues obtained from the subchronic neurotoxicity testing willbe extrapolated from the oral route to the inhalation route using a PBPK model ( Appendix C. 5). The internal dose metric ( e. g., peak concentration or average concentration ofEDC, or amount ofEDC metabolized) used to perform this extrapolation will be determined based on a consideration of any neurological effects observed and a plausible mechanism ofaction.

10 C. 4 Reproductive Toxicity Route To Route Extrapolation The NOAEL/ LOAEL values obtained from the reproductive toxicity testing will be extrapolated from the oral route to the inhalation route using a PBPK model ( Appendix C. 5). The results Of Alumot et al. ( 1976), Rao et al. ( 1980) and Lane et al. ( 1982) will also be compared to the current reproductive toxicity testing. The internal dose metric ( e. g., peak concentration or average concentration of EDC, or amount ofEDC metabolized) used to perform this extrapolation will be determined based on a consideration ofany reproductive effectsobserved and a piausibiemechan~ sm of action.

11 C. 5 PBPK Model Description and Coding The preliminary PBPK model ( to be refined as part of this ECA) is a modification of D'Souzaet al. ( 1987, 1988) to include periodic consumption of drinking water. Rat physiology is represented by five tissue groups ( lung, liver, richly perfused tissues, slowly perfused tissues, and adipose tissues). Because conjugation of EDC with glutathione in the lung and liver is an important pathway of elimination, the model includes normal synthesis and breakdown of glutathione in the lung and liver and a time delayed compensatory increase in glutathione synthesis when glutathione concentrations are less than steady state values. The oxidative metabolite of EDC is assumed to stay within the tissue in which it was produced ( lung or liver) and its production ( from EDC) and further reactions ( GSH conjugation and other reactions) are described. The metabolic scheme is depicted below.

Ethylene dichloride Oxidative metabolism GSH cl~~ Cl~ c1~~ ° ( VmaxL, Km) ( KOSM)

+ OSH ( KGS) OH I' ( KFEE)

Cl~ S G Cl Macromolecules,

 other reactions The PBPK model for repeated exposure to EDC, to be refinedbased on the studies described in C. 1, will also be validated against other relevant, existing pharmacokinetic data for single exposures to EDC ( e. g., Reitz et al., 1982, Spreafico et al., 1980, D'Souza et al., 1987, 1988).

The model code is provided below.

PROGRAM: GLUTATHIONE DEPLETION MODEL FOR EDC ( EDC GSH. CSL) ` Initial parameter values for the rat ( DSouza et al. 1987, 1988)' ` Retyped, documentation modified by LMS 7/ 19/ 01'

INITIAL 12 ` SPECIAL FLOW RATES' CONSTANT QPC= 15 $` alveolar ventilation rate L/ hr/ kgAO. 74' CONSTANT QCC= 15 $` Cardiac output L/ hr/ kg" 0.74'

` FRACTIONAL BLOOD FLOW TO TISSUES' CONSTANT QLC = 0.07 $` Fractional blood flow to liver' CONSTANT QFC = 0.05 $` Fractional blood flow to fat' CONSTANT QRC = 0.64 $` Fractional blood flow to rapid' CONSTANT QSC = 0.24 $` Fractional blood flow to slow'

` BODY WEIGHT' CONSTANT BW = 0.22 $` Body weight ( kg)'

` FRACTIONAL TISSUE VOLUMES' CONSTANT VPC = 0.004 $` Fraction lung tissue' CONSTANT VLC = 0.04 $` Fraction liver tissue' CONSTANT VFC = 0.07 $` Fraction fat tissue' CONSTANT VRC = 0.3 16 $` Fraction rapid tissue' CONSTANT VSC = 0.48 $` Fraction slow tissue'

` PARTITION COEFFICIENTS' CONSTANT PP = 1.1 $` Lung/ blood partition coefficient' CONSTANT PL = 1.1 $` Liver/ blood partition coefficient' CONSTANT PF = 12.2 $ Fatlblood partition coefficient' CONSTANT PS = 0.8 $` Slowly perfused tissue/ blood partition coefficient' CONSTANT PR = 1.1 $` Richly perfused tissue/ blood partition coefficient' CONSTANT PB = 27.6 $` Blood/ air partition coefficient'

CONSTANTMW = 98.96 $` Molecular weight ( g/ mol)'

` KINETIC CONSTANTS' CONSTANT VMAX1C = 3.15 $` Maximum velocity of metabolism ( mg/ hr kg'~ 0.7) CONSTANT VMAXpC = 3.15 $` Maximum velocity ofmetabolism ( mg/ hr kgt' 0.7)' CONSTANT KM = 0.25 $` Michaelis Menten constant ( mg/ L)'

CONSTANT KGSC= 0.0012 S'conj rate const w parent( l/( uM hr kg'~ 0.7))' CONSTANT KGSMC = 0.15 $` conj rate const w metab ( l/( uM hr kgt' 0.7))' CONSTANT KFEEC= 4500 $` conj rate const w non gsh ( 1/( hr kg'~ 0.7))' CONSTANT KOa1C = 3.8 $` GSH synthase synthesis liv( umol/ hr/ hr/ kgt' 0.7)' CONSTANT KOapC = 0.22 $` GSH synthase synthesis lu( umol/ hr/ hr/ kg" 0.7)' CONSTANT KIC= 0. l 16 $` GSH breakdown ( l/ hr/ kg'~ 0.7)' CONSTANT K1 aC= 0.095 $` GSH synthase breakdown( 1 / hr/ kg'~' 0.7)'

13 CONSTANT KS = 1000 $` Maximum GSH induction ( uM)' CONSTANT TD = 1.5 $` Time delay ( hr)' CONSTANT GSO1 = 7000 $` Initial GSH concentration ( uM)' CONSTANT GSOp = 1200 $` Initial GSH concentration ( uM)' CONSTANT PLRATIO= 0. 14 $` MFO ratio lung/ liver' CONSTANT KOOl = 11.254 $ liver ( umol/ hr)' CONSTANT KOOp = 11.254 $` liver ( umol/ hr)'

` DOSING INFO' CONSTANT CONC = 10 $` Inhaled concentration ( ppm)'

` Periodic drinking water exposure section' ` assume t= 0 is 7 am for reference' INTEGER I $ I= 1 $` Counter for drinking arrays' CONSTANT DRCONC= 0.0 $` Conc of EDC in water ( mg/ L)' CONSTANTKA = 5 $ rate const absorp EDC from stomach' ARRAY DRTIME( 6) $` store drinking times in array ARRAY DRPCT( 6) $` store drinking percentages' CONSTANT DRTIME= 1.0,5.0,9.0,13.0,17.0,21.0 CONSTANT DRPCT= 0.233,0. 1,0.1,0.1,0.233,0.234 ` Assume 70 kg man drinks 2 liters/ day, calc rodent allometrically' DRVOL = 0. 102* BW** 0.7 $` calc vol water drunk from BW' DRDOSE = DRVOL* DRCONC $` total dose from water each day ( mg)' ODOSE = 0.0 $` to calculate input to stom ( mg)' NEWDAY = 0.0 $` to reset arrays each 24 hrs'

` TIMING PARAMETERS' CONSTANT TSTART = 48. $ Start of exposure ( hrs)' CONSTANT TPER= 24 CONSTANT TSTOP= 120 CONSTANT POINTS= 1200 $` Number of points in plot' CINT = TSTOP/ POINTS $` Communication interval' TCHNG= 6 ` SCALED PARAMETERS' QC = QCC* BW** 0.74 QP = QPC* BW** 0.74 QL = QLC* QC QF = QFC* QC QS = QSC* QC QR = QRC* QC 14 VP = VPC* BW VL = VLC* BW VF = VFC* BW VS = 0.82* BWVF VR = 0.09* BW~ VL ` Liver metabolism' VMAX1= VMAXIC* BW** 0.7 KOal = KOaIC* BW** 0.7 Kgs = KgsC* bw**(~ 0.3) Kgsm = KgsmC* bw**(~ 0.3) Kfee = KfeeC* BW**(~ 0.3) Kl = K1C* BW**(~ 0.3) Kia = KlaC* BW**(~ 0.3) AGSOl= GS01 * VL ` Lung metabolism' VMAXp= PLRATIO* VMAXpC* BW* * 0.7 KOap = KOapC* BW** 0.7 AGSOp= GSOp* VP P1= 0 P1R= 0 P2= 0 P2R= 0 P3= 100 P3R= 100 END $` End of initial'

DYNAMIC ALGORITHM IALG= 2 $` Gear method for stiff systems DERIVATIVE ` CI= Concentration in inhaled air ( mg/ I)' CI= MW/ 24450* CONC * pulse( tstart, tper, tchng)

` Algebraic solution for CAl after gas exchange' CA1= ( QC* CV + QP* CI)/( QC + QP/ PB) CX = CAl/ PB ` Mass balance for the lung tissue compartment' RAP = QC'~( CA1 CA)  RAMp 15 AP = INTEG( RAP, 0.0) CP = AP/ VP AUCP= INTEG( CP, 0.0) CA= CP/ PP AUCB= INTEG( CA, 0.0)

` UPTAKE BY ORAL ROUTE' RSTOM = ~ KA* STOM $` dSTOM/ dT' STOM = INTEG( RSTOM, 0.0) + ODOSE $` amount in stomach ( mg)'

` AS = Amount in slowly perfused tissues ( mg)' RAS = QS*( CACVS) AS = INTEG( RAS, 0.0) CVS = AS/( VS* PS) CS = AS/ VS ` AR = Amount in richly perfused tissues ( mg)' RAR QR*( CA~ CVR) AR = INTEG( RAR, 0.0) CVR = AR/( VR* PR) CR = AR/ VR ` AF = Amount in fat tissues ( mg)' RAF = QF*( CA~ CVF) AF = INTEG( RAF, 0.0) CVF = AF/( VF* PF) CF = AF/ VF ` CV = Mixed venous blood concentration ( mg/ l)' CV = ( QF* CVF + QL* CVL + QS* CVS + QR* CVR)/ QC ` LIVER METABOLISM' ` AL = Amount in liver tissue ( mg)' RAL = QL*( CA~ CVL)~ RAMl + KA* STOM AL = INTEG( RAL, 0.0) CVL = AL/( VL* PL) CL = AL/ VL AUCL = INTEG( CL, 0.)

` AM = Amount metabolized liver ( mg)' RAM1=( VMAX1* CVL)/( KM+ CVL)+ RACPG1 * MW! 1000 AM1= INTEG( RAMI, 0.)

16 AMPI= AM1* 1000/ MW RAMP1= RAML* 1 000/ MW ` CMI= OXIDATIVE METABOLITE LIVER mg/ L)' RAMMI=( VMAXI* C VL)/( KM 1 CVL) RACMGI* MW/ 1 000 RACMEE1* MW/ 1000 AMM1= INTEG( RAMM1,0.) CML= AMM1/ VL ` GSI = GLUTAHIONE LIVER ( uM)' GSHtd1 = DELAY( GS1* 1, GS1, TD, 10000) $` Time delayed GSH levels' RKO1= KOal*( GSO1+ KS)/( GSHtd1 ~ i~ KS)~ K1A* K01 K0l= INTEG( RKOL, K00l) RAMGS1= KOl K1 * GS1* VLRACMGI.. RACPG1 AMGS1= INTEG( RAMGS1, AGSO1) GS1= AMGSI/ VL ` ACMGl= AMT METABOLITE CONJUGATED WITH GSH LIVER ( uMOLES)' RACMG1= KGSM* GS1* CM1* 1000/ MW ACMGI= INTEG( RACMG1,0.0)

` ACMEEl= AMT METABOLITE CONJUGATED WITH EVERYTHING ELSE LIVER' ` uMOLES' RACMEE1= KFEE* VL* CM1* 1000/ MW ACMEE1= INTEG( RACMEE1,0.)

` ACPGl = AMT PARENT CONJUGATED WITH GSH LIVER ( uMOLES)' RACPGI= KGS* GS1* CVL* VL* 1000/ MW ACPG1= INTEG( RACPG1,0.)

` LUNG METABOLISM' ` AMp= Amount metabolized lung ( mg) RAMp=( VMAXp* CA)/( KM+ CA)+ RACPGp* MW/ 1000 AMp= INTEG( RAMp, 0.) AMPp= AMp* 1000./ MW RAMPp= RAMp* 1000./ MW ` CMp= OXIDATIVE METABOLITE ( mg/ L)' RAMMp=( VMAXp* CA)/( KM~ l~ CA)~ RACMGp* MW/ 1 000rnRACMEEp* MW/ 1000 AMMp= INTEG( RAMMp, 0.) CMp= AMMp/ VP ` GSp= GLUTAHIONE LUNG ( uM)'

17 GSHtdp= DELAY( GSp* 1 , GSp, TD, 1 0000)$' Time delayed GSH levels' RKOp= KOAP*( GS Op+ KS)/( GSHtdp+ KS ) K 1 A* KOp KOp= INTEG( RKOp, KOOp) RAMGSp= KOp K1 * GSp* VPRACMGpRACPGp AMGSp= INTEG( RAMGSp, AGSOp) GSp= AMGSp/ VP ` ACMGp= AMT METABOLITE CONJUGATED WITH GSH LUNG ( uMOLES)' RACMGp= KGSM* GSp* CMp* VP* 1000/ MW ACMGp= INTEG( RACMGp, 0.)

` ACMEEp= AMT METABOLITE CONJUGATED WITHEVERYTHING ELSE LUNG( uMOLES)' RACMEEp= KFEE* VP* CMp* 1000/ MW ACMEEp= 1NTEG( RACMEEp, 0.)

` ACPGp= AMT PARENT CONJUGATED WITH GSH LUNG ( uMOLES)' RACPGp= KGS * GSp* Cp* Vp* 1000/ MW ACPGPp= INTEG( RACPGp, 0.)

` PCTGSH PERCENT GSH COMPARED TO CONTROL' PCTGSHP= GSp/ GSOp* 100 TERMT( T. GE. TSTOP)

PROCEDURAL ( P1 , P 1 R= AMP, RAMP)

IF( T. LT.( DRTIME( I) l NEWDAY)) GO TO SKIP2 ODOSE=( ODOSE+ DRPCT( I)* DRDOSE)* PULSE( TSTART, TPER, TPER) 1= 1+ 1 IF( I. LT. 7) GO TO SKIP2 1= 1 6 NEWDAY= NEWDAY+ 24.0 SKIP2.. CONTINUE IF ( AMIN1( AMPI, RAMP1, ACMG1, RACMGI, ACMEE1, RACMEEI). LT. lE 9) GOTO OUT ` Pl= PERCENT PARENT METABOLISM THROUGH GSH' P1= ACPG1/ AMP1* 100 P1 R= RACPGI/ RAMPI* 100 ` P2= PERCENT METABOLITE CONJUGATED WITH GSH' P2= ACMGI/( ACMG1+ ACMEEI)* 100 18 P2R= RACMG1/( RACMGI+ RACMEE1)* 100 P3= 100 P2 P3R= 100 P2R OUT.. CONTINUE END $` End of procedural' END $` End of derivative' END $` End of dynamic' END $` End of program'

19 C. 6 General Outline for Route to Route Extrapolation Reports A total of three route to route extrapolation reports will be generated for EDC, one for each of the following endpoints: subchronic toxicity, subchronic neurotoxicity, and reproductive toxicity. At a minimum, each of these reports will follow the general outline presented below.

1.0 Introduction Statement of objectives for a specific endpoint route to route extrapolation relevant to the HAPs testing for EDC Application of the PBPK Model for EDC relevant to specific endpoint 2.0 Summary of Key Study ( ies)

For subchronic toxicity, the design and results of ( Daniel et al., 1994) will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

For subchronic neurotoxicity, the design and results of the TierII testing will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

For reproductive toxicity, the design and results ofthe TierII testing will be summarized and the results of Alumot et al. ( 1976), Rao et al. ( 1980) and Lane et al. ( 1982) will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

3.0 Selection of Critical Endpoints and Dose Measure( s)

For subchronic toxicity, subchronic neurotoxicity and reproductive toxicity, the endpoints and dose measures will be determined from the Tier II testing.

4.0 Route to Route Extrapolation Results Quantitative calculation ofinhalation NOAEL/ LOAELvalues forcorresponding oral values.

5.0 Sensitivity Analysis Assessment ofthe contribution ofvariability/ uncertainty in each parameter to PK modeling results.

6.0 Conclusions 7.0 References 20 C. 7 References Alumot E, Nachtomi E, Mandel E, Holstein P. Tolerance and acceptable daily intake of chlorinated fumigants in the rat diet. Food Cosmet. Toxicol. 14( 2): 105 110; 1976.

Clewell HJ 3rd, Andersen ME. Physiologically based pharmacokinetic modeling and bioactivation of xenobiotics. Toxicol Ind Health. 1994; 10: 1 24 D'Souza RW, Andersen ME. Physiologically based pharmacokinetic model for vinylidene chloride. Toxicol AppI Pharmacol. 1988; 95( 2): 230 40.

D'Souza RW, Francis WR, Bruce RD, Andersen ME. Physiologically based pharmacokinetic model for ethylene dichloride and its application in risk assessment. [ 8], 286 301. 1987. Washington, D. C., National Academy Press. Pharmacokinetics in Risk Assessment. Drinking water and health.

D'Souza RW, Francis WR, Andersen ME. Physiological model for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure. J Pharmacol Exp Ther 1988; 245( 2): 563 568.

Daniel FB, Robinson M, Olson GR, York RG, Condie LW, Lane RW, Riddle BL, Borzelleca JF. Ten and ninety day toxicity studies of 1 ,2 dichloroethane in Sprague Dawley rats. Drug Chem Toxicol 1994; 17( 4): 463 477.

Frederick CB, Potter DW, Chang Mateu MI, Andersen ME. A physiologically based pharmacokinetic and pharmacodynamic model to describe the oral dosing of rats with ethyl acrylate and its implications for risk assessment. Toxicol AppI Pharmacol 1992; 114: 246 260.

Gargas ML, Burgess RJ, Voisard DE, Cason GH, Andersen ME. Partition coefficients of low molecular weight volatile chemicals in various liquids and tissues. Toxicol Appl Pharmacol 1989; 98: 87 99.

Krishnan K, Gargas ML, Fennell TR, Andersen ME. A physiologically based description of ethylene oxide dosimetry in the rat. Toxicol Ind Health. 1992; 8: 12 1 40.

Lane RW, Riddle BL, Borzelleca JF. Effects of 1,2 dichioroethane and 1,1,1 thichioroethane in drinking water on reproduction and development in mice. Toxicol Appl Pharmacol 1982; 63( 3): 409 42 1.

National Cancer Institute. Bioassay of 1 ,2 dichloroethane for 21 possible carcinogenicity, NCI Carcinogenesis Technical Report, Series No. 55; DHEWPublication No. ( NIH) 1978; 78 1361. Washington, D. C.

O'Flaherty EJ. A physiologically based model of chromium kinetics in the rat. Toxicol AppI Pharmacol 1996; 138: 54 64.

Payan JP, Beydon D, Fabry J, Brondeau MT, Ban M, de Ceaurriz J. Urinary thiodiglycolic acid and thioether excretion in male rats dosed with 1 ,2 dichloroethane. J Appl Toxicol 1993; 13( 6): 417 422.

Rao KS, Murray JS, Deacon MM, John JA, Calhoun LL, Young JT Teratogenicity and reproduction studies in animals inhaling ethylene dichloride. Banbury Report 5: 149 166 1980 Reitz RH, Fox TR, Ramsey JC, Quast JF, Langvardt PW, Watanabe PG. Pharmacokinetics and macromolecular interactions of ethylene dichloride in rats after inhalation or gavage. Toxicol AppI Pharmacol 1982; 62: 190 204.

Spreafico F, Zuccato E, Marcucci F, Sironi M, Paglialunga S, Madonna M, Mussini E. Pharmacokinetics of ethylene dichloride in rats treated by different routes and its longterm inhalatory toxicity. In: Ames B, Infante P, Reitz RH, editors. Ethylene dichloride: A potential health risk? Banbury Report 5. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 1980: 107 133.

22


UNITED STATES OF AMERICA

DEPARTMENT OF TRANSPORTATION

OFFICE OF THE SECRETARY

WASHINGTON, DC

Issued by the Department of Transportation on January 26, 2006

NOTICE OF ACTION TAKEN -- DOCKET OST-2004-16899

This serves as notice to the public of the action described below, taken
by the Department official indicated (no additional confirming order
will be issued in this matter).

Application of US AIRWAYS, INC., filed 12/16/05, for:

XX	Renewal of exemption for two years under 49 U.S.C. 40109 to provide
the following service:

Scheduled foreign air transportation of persons, property, and mail
between Orlando, Florida, and Hamilton, Bermuda.

Applicant rep:	Howard Kass<PHONE_NUMBER>	DOT Analyst: Tretha Chromey
(202) 366-2367

D I S P O S I T I O N

XX	Granted (subject to conditions, see below)

The above action was effective when taken: January 26, 2006 through
January 26, 2008.

Action taken by:	Paul L. Gretch, Director

Office of International Aviation

XX	Grant of authority is based on comity and reciprocity with the United
Kingdom.

Except to the extent exempted or waived, this authority is subject to
the terms, conditions, and limitations indicated:	XX Holder’s
certificates of public convenience and necessity

XX Standard exemption conditions (attached)

On the basis of data officially noticeable under Rule 24(g) of the
Department’s regulations, we found the applicant qualified to provide
the services authorized.

Under authority assigned by the Department in its regulations, 14 CFR
Part 385, we found that (1) our action was consistent with Department
policy; (2) grant of the authority was consistent with the public
interest; and (3) grant of the authority would not constitute a major
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To the extent not granted, we denied all requests in the referenced
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Persons entitled to petition the Department for review of the action set
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§385.30, may file their petitions within seven (7) days after the date
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the filing of a petition for review will not alter such effectiveness.

An electronic version of this document is available on the World Wide
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U.S. Carrier Exemption Conditions

In the conduct of the operations authorized, the U.S. carrier
applicant(s) shall:

(1)  Hold at all times effective operating authority from the government
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in 14 CFR 250 (for scheduled operations, if authorized);

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241;

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certifying that coverage to the Department, contained in 14 CFR 205;

(5)  Except as specifically exempted or otherwise provided for in a
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waiver of Warsaw Convention liability limits and defenses;

(6)  Comply with all applicable requirements of the Federal Aviation
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To assure compliance with all applicable U.S. Government requirements
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(7)  Comply with such other reasonable terms, conditions, and
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05/2004

 See Notice of Action Taken in this docket of February 20, 2004, at 2
(Remarks).