[Federal Register Volume 83, Number 33 (Friday, February 16, 2018)]
[Notices]
[Pages 7052-7054]
[FR Doc No: 2018-03215]

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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-0404]

Pediatric Medical Device Development; Public Meeting; Request for
Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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

SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
announcing the following public meeting entitled ``Pediatric Medical
Device Development.'' The purpose of the public meeting is to identify
strategies to enhance the medical device ecosystem to cultivate
development and innovation of devices that serve the unique needs of
pediatric populations. (The Federal Food, Drug, and Cosmetic Act (FD&C
Act) defines pediatric patients, for medical device purposes, as age 21
years or younger at the time of diagnosis or treatment and specifies
categories of pediatric subpopulations.) Topics for discussion will
include ways to improve research infrastructure and research networks
to facilitate the conduct of clinical studies of pediatric devices,
extrapolation, use of postmarket registries and data to increase
pediatric medical device

labeling, assistance to medical device manufacturers in developing
devices for pediatric populations, and identifying barriers to
pediatric device development and incentives to address such barriers.

DATES: The public meeting will be held on August 13 and August 14,
2018, from 9 a.m. to 5 p.m. Submit either electronic or written
comments on this public meeting by September 14, 2018. See the
SUPPLEMENTARY INFORMATION section for registration information.

ADDRESSES: The public meeting will be held at FDA's White Oak Campus,
10903 New Hampshire Ave., Bldg. 31 Conference Center, Rm. 1503 (the
Great Room), Silver Spring, MD 20993-0002. Entrance for the public
meeting participants (non-FDA employees) is through Building 1 where
routine security check procedures will be performed. For parking and
security information, please refer to https://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.
    You may submit comments as follows. Please note that late, untimely
filed comments will not be considered. Electronic comments must be
submitted on or before September 14, 2018. The https://www.regulations.gov electronic filing system will accept comments until
midnight Eastern Time at the end of September 14, 2018. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2018-N-0404 for ``Pediatric Medical Device Development; Public
Meeting; Request for Comments.'' Received comments, those filed in a
timely manner (see ADDRESSES), will be placed in the docket and, except
for those submitted as ``Confidential Submissions,'' publicly viewable
at https://www.regulations.gov or at the Dockets Management Staff
between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Victoria Wagman, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 5562, Silver Spring, MD 20993, 301-796-
6581, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    For more than a decade, legislative changes and regulatory process
improvements have been implemented to facilitate development of medical
devices that serve the unique needs of pediatric populations. The FD&C
Act defines pediatric patients, for medical device purposes, as age 21
years or younger at the time of diagnosis or treatment and specifies
categories of pediatric subpopulations (see section 520(m)(6)(E) of the
FD&C Act (21 U.S.C. 360j(m)(6)(E))). Nevertheless, children and those
who care for them continue to have limited medical device options. FDA
seeks to identify opportunities to support development and innovation
of medical devices designed and labeled for children. Engaging in such
opportunities will not only serve children and their families but
optimize the medical device ecosystem for all. The Agency invites all
stakeholders, including representatives from the medical device
industry, academia, recipients of funding under section 305 of the
Pediatric Medical Device Safety and Improvement Act of 2007, medical
provider organizations, and organizations and individuals representing
patients and consumers to collaborate with us in addressing this
important public health issue (See Pub. L. 110-85; 42 U.S.C. 282 note).
    FDA guidance documents entitled ``Premarket Assessment of Pediatric
Medical Devices,'' ``Providing Information about Pediatric Uses of
Medical Devices,'' and ``Leveraging Existing Clinical Data for
Extrapolation to Pediatric Uses of Medical Devices,'' provide
background information regarding pediatric medical device development
(Refs. 1 to 3).

II. Topics for Discussion at the Public Meeting

    As mandated by section 502(d) of the FDA Reauthorization Act of
2017 (FDARA), this FDA meeting on the development and labeling of
pediatric medical devices is being convened with representatives from
the medical device industry, academia, recipients of funding under
section 305 of the Pediatric Medical Device Safety and Improvement Act
of 2007, medical provider organizations, and organizations representing
patients and consumers (see Pub. L. 110-85; 42 U.S.C. 282 note).
    As directly outlined in FDARA, the meeting shall include
consideration of ways to: (1) Improve research infrastructure and
research networks to facilitate the conduct of clinical studies of
devices for pediatric populations that would result in the approval or
clearance, and labeling of medical devices for such populations; (2)
appropriately use extrapolation under section 515A(b) of the FD&C Act
(21 U.S.C. 360e-1(b)); (3) enhance the appropriate use of postmarket
registries and data to increase pediatric medical device labeling; (4)
increase FDA assistance to medical device manufacturers in developing
devices for pediatric populations that are approved or cleared, and
labeled, for their use; and (5) identify current barriers to pediatric
device development and incentives to address such barriers.
    A detailed agenda will be posted on the following website in
advance of the workshop at https://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm. Select this event from the
list of items provided.

III. Participating in the Public Meeting

    Registration: To register for the public meeting, please visit
FDA's Medical Devices News & Events--Workshops & Conferences calendar
at https://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm. (Select this public workshop from the posted events list.)
Please provide complete contact information for each attendee,
including name, title, affiliation, address, email, and telephone
number.
    Registration is free, and in-person attendance is based on space
availability, with priority given to early registrants. Persons
interested in attending this public meeting must register by August 6,
2018, 3 p.m. Eastern Time. Early registration is recommended because
seating is limited; therefore, FDA may limit the number of participants
from each organization. Registrants will receive confirmation when they
have been accepted. If time and space permit, onsite registration on
the day of the public workshop will be provided beginning at 7:30 a.m.
We will let registrants know if registration closes before the day of
the public meeting.
    If you need special accommodations due to a disability, please
contact Peggy Roney at the Center for Devices and Radiological Health,
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 32, Rm.
5231, Silver Spring, MD 20993-0002,<PHONE_NUMBER>,
[email protected], no later than June 1, 2018.
    Requests for Oral Presentations: During online registration, you
may indicate if you wish to present during a public comment session and
which topic(s) you wish to address. FDA will do its best to accommodate
requests to make public comments. Individuals and organizations with
common interests are urged to consolidate or coordinate their
presentations, and request time for a joint presentation, or submit
requests for designated representatives to participate in the focused
sessions. We encourage persons who are interested in making an oral
presentation during a public comment session to indicate their intent
on the registration form by 3 p.m. Eastern Time on June 29, 2018. Based
on the number of applicants for oral presentations, FDA will distribute
the available time equally among all presenters and inform selected
presenters of the public presentation agenda by July 6, 2018. If
selected for presentation, any presentation materials must be emailed
to Victoria Wagman at [email protected] no later than July
13, 2018. No commercial or promotional material will be permitted to be
presented or distributed at the public meeting.
    Streaming Webcast of the public meeting: This public meeting will
also be webcast. The webcast link will be available on the registration
web page after August 6, 2018. Please visit FDA's Medical Devices News
& Events--Workshops & Conferences calendar (https://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm) and select
this event from the list of items provided. Organizations are requested
to register all participants but view using one connection per
location.
    If you have never attended a Connect Pro event before, test your
connection at https://collaboration.fda.gov/common/help/en/support/meeting_test.htm. To get a quick overview of the Connect Pro program,
visit https://www.adobe.com/go/connectpro_overview. FDA has verified
the website addresses in this document as of the date this document
publishes in the Federal Register, but websites are subject to change
over time.
    Transcripts: Please be advised that as soon as a transcript of the
public meeting is available, it will be accessible at https://www.regulations.gov. It may be viewed at the Dockets Management Staff
(see ADDRESSES). A link to the transcript will also be available on the
internet at https://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm. (Select this public workshop from the
posted events list.)

IV. References

    The following references are on display at the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov.

    1. FDA's guidance for Industry and FDA Staff: ``Premarket
Assessment of Pediatric Medical Devices,'' available at https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089742.pdf.
    2. FDA's guidance for Industry and FDA Staff: ``Providing
Information about Pediatric Uses of Medical Devices,'' available at
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM339465.pdf.
    3. FDA's guidance for Industry and FDA Staff: ``Leveraging
Existing Clinical Data for Extrapolation to Pediatric Uses of
Medical Devices,'' available at<EMAIL_ADDRESS>

    Dated: February 12, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-03215 Filed 2-15-18; 8:45 am]
BILLING CODE 4164-01-P


APPENDIX C PK/ MECH PROCEDURES AND ROUTE TO ROUTE EXTRAPOLATION REPORTING FOR ETHYLENE BICHLORIDE This Appendix contains detailed procedures for the kinetic studies and route to route extrapolation to be conducted for ethylene dichioride, 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 1 OPPT 2003 0010 0009 RECEIVED OPPT NCIC 2003 MAR11 5: 03PM CA. Pharmacokinetic Studies for F344 Rats A total of 4 pharmacokinetic studies will be conducted to support PBPK modeling activities for ethylene dichloride, as described below. It is anticipated that the pharmacokinetic studies will start one year after the ECA is signed ( during the 1St quarter of 2003), with an interim report generated six months later ( 3 rd quarter of 2003), with the final report submitted three months later ( during the 4th quarter of2003) ( see Appendix A for complete schedule).

Study 1: Demonstration ofPeriodicity Following Repeated Inhalation Exoosures Parameter Proposed Species Rat Strain F344 Age Young adult Number ofanimals 132 animals ( 3 controls at beginning ( t =

0) and 3 at end ofexposure ( t = 6 hr) on days 1, 3, and 5; 3 exposed animals at the beginning ofexposure ( 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) Dose( s) To be determined Route Inhalation Exposure Frequency 6 hrs/ day, 5 consecutive days Observations Liver and lung GSH in controls ( n = 3) at beginning and end ofexposure ( 0 and 6 hrs) on days 1 ,3 and 5. Lung and liver GSH in exposed animals ( n = 3) at beginning ofexposure on days 3 and 5. Venous blood concentrations ofEDC ( n = 3) at 0.25, 0.5, 6.25, and 16 hrs after exposure starts on days 1, 3, and 5. Venous blood concentrations ofEDC ( 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.

Kinetic studies will be conducted for demonstrating periodicity in the rat. 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 of 3 animals ( for glutathione determination) will be collected immediately following sacrifice. Lung, liver, kidney, brain, adrenal gland, and thyroid will be frozen pending further analysis following the completion of the toxicity testing. A 2 positive control will be required to demonstrate the recovery of ethylene dichloride in tissues following freezing.

3 Study 2: Demonstration of Periodicity Following Repeated Oral Exposures to Ethylene Dichloride by Corn Oil 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) Dose( s) 150 mg/ kg Route Corn oil gavage Exposure Frequency ix/ 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 liverGSH concentrations ( n = 3) at 0.5, 1, 2, and 8 hours after exposure starts on days 1, 3, and 5.

The test dose was selected based on the doses administered to rats in 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 pending further analysis following the completion of the toxicity testing. A positive control will be required to demonstrate the recovery of ethylene dichioride in tissues following freezing.

4 Study 3: Demonstration of Periodicity Following Repeated Oral Exposures to Ethylene Dichloride by Aqueous Gavage Parameter Proposed Species Rat Strain F344 Age Young adult Number ofanimals 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 150 mg/ kg day Route Aqueous gavage Exposure Frequency ix/ 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 of remaining 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, and5. 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 The test dose was selected based on the doses administered to rats in 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 pending further analysis following the completion of the toxicity testing. A positive control will be required to demonstrate the recovery ofethylene dichloride in tissues following freezing.

5 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 et a!. ( 1989, Toxicol. Appi. Pharmacol. 98, 87 99).

A total of 5 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.

6 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 route using a PBPK model ( Appendix C. 5). The internal dose ( parent chemical, amount metabolized) and metric ( peak concentration, average concentration, AUC) used to perform this extrapolation will be determined based on a consideration of the effects observed and a plausible mechanism of action.

7 C. 3 Subchronic Neurotoxicity Route To Route Extrapolation The NOAEL/ LOAEL values obtained from the subchronic neurotoxicity testing will be extrapolated from the oral route to the inhalation route using a PBPK model ( Appendix C. 5). The internal dose ( parent chemical, amount metabolized in brain) and metric ( peak concentration, average concentration, AUC) used to perform this extrapolation will be determined based on a consideration ofany neurological effects observed and a plausible mechanism of action.

8 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. 6). 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 ( parent chemical, amount metabolized) and metric ( peak concentration, average concentration, AUC) used to perform this extrapolation will be determined based on a consideration of any reproductive effects observed and a plausible mechanism of action.

9 C. 5 PBPK Model Description and Coding The preliminary PBPK model ( to be refined as part ofthis ECA) is a modification ofD'Souza et 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 model code is provided below.

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

INITIAL ` SPECIAL FLOW RATES' CONSTANT QPC= 1 5 $` alveolar ventilatioh rate L/ hr/ kgt' 0.74' CONSTANT QCC= 1 5 $` 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 S'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 = 0.316 $` 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 $` Fat/ blood 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'

10 CONSTANT MW = 98.96 S'Molecular weight ( g/ mol)'

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

CONSTANT KGSC= 0.0012 $` conj rate const w parent( 1/( uM hr kg1" 0.7))' CONSTANT KGSMC = 0.15 $` conj rate const w metab ( 1/( uM hr kg'~' 0.7))' CONSTANT KFEEC= 4500 S'conj rate const w non gsh ( 1/( hr kg" 0.7))' CONSTANT KOalC = 3.8 $` GSH synthase synthesis liv( umol/ hr/ hr/ kg/' 0.7)' CONSTANT KOapC = 0.22 $` GSH synthase synthesis lu( umol/ hr/ hr/ kgt' 0.7)' CONSTANT K1C= 0.1 16 $` GSH breakdown ( 1/ hr/ kg'~ 0.7)' CONSTANT K1 aC= 0.095 $` GSH synthase breakdown( 1 / hr/ kg'~ 0. 7)' 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 ( umollhr)'

` 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)' CONSTANT KA = 5 $` rate const absorp EDC from stomach' ARRAY DRTIME( 6) $` store drinking times in array' ARRAY DRPCT( 6) $` store drinking percentages' CONSTANT DRTIIME= 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 ofpoints in plot' CINT = TSTOP/ POINTS $` Communication interval'

11 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 VP = VPC* BW VL = VLC* BW VF= VFC* BW VS = 0.82* BWVF VR = 0.09* BW~ VL ` Liver metabolism' VMAX1= VMAX1C* BW** 0.7 KOal KOalC* BW** 0.7 Kgs = KgsC* bw**(~ 0.3) Kgsm = KgsmC* bw**(~ 0.3) Kfee KfeeC* BW**(~ 0.3) Ki = K1C* BW**(~ 0.3) Kia = K1aC* BW**(~ 0.3) AGSO1= GSO1* VL ` Lung metabolism' VMAXp= PLRATIO* VMAXpC* BW** 0.7 KOap = KOapC* BW** 0.7 AGSOp= GSOp* VP P1= 0 P1 R= 0 P2= 0 P2R= 0 P3= 100 P3R= 100 END $` End ofinitial'

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* CJ)/( QC + QP/ PB)

12 CX = CAl/ PB ` Mass balance for the lung tissue compartment' RAP = QC*( CAl~ CA) RAMp AP = INTEG( RAP, 0.0) CP = AP/ VP AUCP= 1NTEG( CP, 0.0) CA= CP/ PP AUCB= INTEG( CA, 0.0)

` UPTAKE BY ORAL ROUTE' RSTOM = ~ KA* STOM $` dSTOM/ dT' STOM 1NTEG( RSTOM, 0.0) + ODOSE $` amount in stomach ( mg)'

` AS = Amount in slowly perfused tissues ( mg)' RAS = QS*( CACVS) AS = 1NTEG( 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/ i)' CV = ( QF* CVF + QL* CVL + QS* CVS + QR* CVR)/ QC ` LIVER METABOLISM' ` AL = Amount in liver tissue ( mg)' RAL = QL*( CA~ CVL)~ RAMi + ~ 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( RAM1,0.) AMPl= AM1* 1 000/ MW 13 RAMPl= RAML* 1000/ MW ` CMlOXIDATIVE METABOLITE LIVER mg/ L)' RAMMl=( VMAXl* CVL)/( KM+ CVL)~ RACMGl* MW/ 1000~ RACMEEl* MW/ 1000 AMM1= INTEG( RAMM1,0.) CML= AMM1/ VL ` GSl = GLUTAHIONE LIVER ( uM)' GSHtd1 = DELAY( GS1* 1, GSi, TD, 10000) $` Time delayed GSH levels' RKO1= KOal*( GSO1+ KS)/( GSHtd1 + KS) K1 A* KOl KOl= INTEG( RKOL, KOOl) RAMGS1= KOl K1* GS1* VLRACMG1RACPGI AMGS1= INTEG( RAMGSi, AGSO1) GS1= AMGS1/ VL ` ACMGi= AMT METABOLITE CONJUGATED WITH GSH LIVER ( uMOLES)' RACMG1= KGSM* GS1* CM1* 1000/ MW ACMG1= INTEG( RACMGi, 0.0)

` ACMEEl= AMT METABOLITE CONJUGATED WITH EVERYTHING ELSE LIVER' ` uMOLES' RACMEE1= KFEE* VL* CM1* 1000/ MW ACMEEi= INTEG( RACMEEI, 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/ 1 000 AMp= INTEG( RAMp, 0.) AMPp= AMp* 1000./ MW RAMPp= RAMp* 1000./ MW ` CMp= OXIDATIVE METABOLITE ( mg! L)' RAMMp=( VMAXp* CA)/( KM+ CA)~ RACMGp* MW/ 1000~ RACMEEp* MW/ 1000 AMMp= INTEG( RAMMp, 0.) CMpAMMp/ VP ` GSp= GLUTAHIONE LUNG ( uM)' GSHtdpDELAY( GSp* 1 , GSp, TD, 1 0000)$' Time delayed GSH levels' RK0pK0AP*( GSOp+ KS)/( GSHtdp+ KS)~ K1A* KOp KOp= INTEG( RKOp, KOOp) RAMGSp= KOp K1 * GSp* Vp.. RACMGpRACpGp AMGSp= INTEG( RAMGSp, AGSOp) GSp= AMGSp/ VP 14 ` ACMGp= AMT METABOLITE CONJUGATED WITH GSH LUNG ( uMOLES)' RACMGp= KGSM* GSp* CMp* VP* 1000/ MW ACMGp= INTEG( RACMGp, 0.)

` ACMEEp= AMT METABOLITE CONJUGATED WITH EVERYTHING ELSE LUNG ( uMOLES)' RACMEEp= KFEE* VP* CMp* 1000/ MW ACMEEp= INTEG( 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 1R= AMP, RAMP)

IF( T. LT.( DRTIME( I)+ NEWDAY)) GO TO SKIP2 ODOSE=( ODOSE+ DRPCT( I)* DRDOSE)* PULSE( TSTART, TPER, TPER) 1= 1+ 1 IF( I. LT. 7) GO TO SKJP2 1= 1 6 NEWDAY= NEWDAY+ 24.0 SKJIP2.. CONTINUE IF ( AMIN1( AMP1, RAMP1, ACMGI, RACMG1, ACMEE1, RACMEE1). LT. 1E 9) GOTO OUT ` Pl= PERCENT PARENT METABOLISM THROUGH GSH' P1 = ACPG1/ AMP1* 100 P1R= RACPG1/ RAMP1* 100 ` P2= PERCENT METABOLITE CONJUGATED WITH GSH' P2= ACMG1/( ACMG1+ ACMEE1)* 100 P2R= RACMG1/( RACMG1+ RACMEE1)* 100 P3= 1 00 P2 P3R= 1 00 P2R OUT.. CONTINUE END $` End ofprocedural' END $` End ofderivative' END $` End ofdynamic' END $` End ofprogram'

15 16 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 ofthese 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 testing for EDC Application ofthe PBPK Model for EDC relevant to specific endpoint 2.0 Summary of Key Study ( ies)

For subchronic toxicity, the design and results ofDaniel 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 Tier II 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 Tier II 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 of inhalation NOAEL/ LOAEL values for corresponding oral values.

5.0 Sensitivity Analysis Assessment of the contribution of variability/ uncertainty in each parameter to PK modeling results.

6.0 Conclusions 7.0 References 17


[Federal Register: May 31, 2006 (Volume 71, Number 104)]
[Notices]
[Page 30917-30918]
[DOCID:fr31my06-88]

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

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Notice of Application Accepted for Filing and Soliciting
Comments, Protests, and Motions to Intervene

May 24, 2006.
    Take notice that the following hydroelectric application has been
filed with the Commission and is available for public inspection:
    a. Type of Application: Preliminary Permit.
    b. Project No.: 12634-000.
    c. Date Filed: January 3, 2006.
    d. Applicant: Alaska Power & Telephone Company.
    e. Name and Location of Project: The proposed Connelly Lake
Hydroelectric Project would be located at the existing Connelly Lake on
an unnamed tributary of the Chilkoot River in Haines Borough, Alaska,
partially on Federal lands administered by the Bureau of Land
Management.
    f. Filed Pursuant to: Federal Power Act, 16 U.S.C. 791(a)-825(r).
    g. Applicant contact: Robert S. Grimm, President, Alaska Power &
Telephone Co., P.O. Box 3222, Port Townsend, WA 98368,<PHONE_NUMBER>
x120.
    h. FERC Contact: Tom Papsidero,<PHONE_NUMBER>.
    i. Deadline for filing comments, protests, and motions to
intervene: 60 days from the issuance date of this notice.
    All documents (original and eight copies) should be filed with
Magalie R. Salas, Secretary, Federal Energy Regulatory Commission, 888
First Street, NE., Washington, DC 20426. Comments, protests and
interventions may be filed electronically via the Internet in lieu of
paper; see 18 CFR 385.2001(a)(1)(iii) and the instructions on the
Commission's Web site under the ``e-Filing'' link. The Commission
strongly encourages electronic filings. Please include the project
number (P-12634-000) on any comments or motions filed.
    The Commission's Rules of Practice and Procedure require all
intervenors filing documents with the Commission to serve a copy of
that document on each person in 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.
    j. Description of Proposed Project: The proposed project would
operate as a storage project and would consist of the following new
facilities: (1) A proposed 48-foot-high, 575-foot-long rockfill dam at
the Lake outlet, (2) Connelly Lake, which would have a minimum water
surface elevation of 2,280 feet above mean sea level (msl), its current
level, and a maximum water surface elevation of 2,312 feet msl, (3) a
screened intake structure at elevation 2,270 feet msl, (4) a 6,188-
foot-long, 48-inch-diameter penstock, which connects to a valve house
with an auxiliary release adjacent to the dam, then decreases to a 30-
inch-diameter penstock, (5) a powerhouse containing one generating unit
with an installed capacity of 6.2 megawatts, (6) a 14-mile-long, 34.5-
kilovolt underground transmission line connecting to an existing power
line; and (7) appurtenant facilities. The project would have an annual
generation of 23 GWh.
    k. Location of Applications: A copy of the application is available
for inspection and reproduction at the Commission in the Public
Reference Room or may be viewed on the Commission's Web site 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, call toll-free 1-866-208-3676 or e-mail
<EMAIL_ADDRESS>For TTY, call<PHONE_NUMBER>. A copy is

also available for inspection and reproduction at the address in item g
above.
    l. Individuals desiring to be included on the Commission's mailing
list should so indicate by writing to the Secretary of the Commission.
    m. Competing Preliminary Permit: Anyone desiring to file a
competing application for preliminary permit for a proposed project
must submit the competing application itself, or a notice of intent to
file such an application, to the Commission on or before the specified
comment date for the particular application (see 18 CFR 4.36).
Submission of a timely notice of intent allows an interested person to
file the competing preliminary permit application no later than 30 days
after the specified comment date for the particular application. A
competing preliminary permit application must conform with 18 CFR
4.30(b) and 4.36.
    n. Competing Development Application: Any qualified development
applicant desiring to file a competing development application must
submit to the Commission, on or before a specified comment date for the
particular application, either a competing development application or a
notice of intent to file such an application. Submission of a timely
notice of intent to file a development application allows an interested
person to file the competing application no later than 120 days after
the specified comment date for the particular application. A competing
license application must conform with 18 CFR 4.30(b) and 4.36.
    o. Notice of Intent: A notice of intent must specify the exact
name, business address, and telephone number of the prospective
applicant, and must include an unequivocal statement of intent to
submit, if such an application may be filed, either a preliminary
permit application or a development application (specify which type of
application). A notice of intent must be served on the applicant(s)
named in this public notice.
    p. Proposed Scope of Studies under Permit: A preliminary permit, if
issued, does not authorize construction. The term of the proposed
preliminary permit would be 36 months. The work proposed under the
preliminary permit would include economic analysis, preparation of
preliminary engineering plans, and a study of environmental impacts.
Based on the results of these studies, the Applicant would decide
whether to proceed with the preparation of a development application to
construct and operate the project.
    q. Comments, Protests, or Motions to Intervene: Anyone may submit
comments, a protest, or a motion to intervene in accordance with the
requirements of Rules of Practice and Procedure, 18 CFR 385.210, .211,
.214. In determining the appropriate action to take, the Commission
will consider all protests or other comments filed, but only those who
file a motion to intervene in accordance with the Commission's Rules
may become a party to the proceeding. Any comments, protests, or
motions to intervene must be received on or before the specified
comment date for the particular application.
    Comments, protests and interventions may be filed electronically
via the Internet in lieu of paper; See 18 CFR 385.2001(a)(1)(iii) and
the instructions on the Commission's Web site under ``e-

filing'' link. The Commission strongly encourages electronic filing.
    r. Filing and Service of Responsive Documents: Any filings must
bear in all capital letters the title ``COMMENTS'', ``NOTICE OF INTENT
TO FILE COMPETING APPLICATION'', ``COMPETING APPLICATION'',
``PROTEST'', or ``MOTION TO INTERVENE'', as applicable, and the Project
Number of the particular application to which the filing refers. Any of
the above-named documents must be filed by providing the original and
the number of copies provided by the Commission's regulations to: The
Secretary, Federal Energy Regulatory Commission, 888 First Street, NE.,
Washington, DC 20426. An additional copy must be sent to Director,
Division of Hydropower Administration and Compliance, Federal Energy
Regulatory Commission, at the above-mentioned address. A copy of any
notice of intent, competing application or motion to intervene must
also be served upon each representative of the Applicant specified in
the particular application.
    s. Agency Comments: Federal, state, and local agencies are invited
to file comments on the described application. A copy of the
application may be obtained by agencies directly from the Applicant. If
an agency does not file comments within the time specified for filing
comments, it will be presumed to have no comments. One copy of an
agency's comments must also be sent to the Applicant's representatives.

Magalie R. Salas,
Secretary.
[FR Doc. E6-8336 Filed 5-30-06; 8:45 am]

BILLING CODE 6717-01-P