[Federal Register Volume 86, Number 239 (Thursday, December 16, 2021)]
[Rules and Regulations]
[Pages 71383-71385]
[FR Doc No: 2021-27227]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 882

[Docket No. FDA-2021-N-0896]

Medical Devices; Neurological Devices; Classification of the
Traumatic Brain Injury Eye Movement Assessment Aid

AGENCY: Food and Drug Administration, HHS.

ACTION: Final amendment; final order.

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SUMMARY: The Food and Drug Administration (FDA or we) is classifying
the traumatic brain injury eye movement assessment aid into class II
(special controls). The special controls that apply to the device type
are identified in this order and will be part of the codified language
for the traumatic brain injury eye movement assessment aid's
classification. We are taking this action because we have determined
that classifying the device into class II (special controls) will
provide a reasonable assurance of safety and effectiveness of the
device. We believe this action will also enhance patients' access to
beneficial innovative devices.

DATES: This order is effective December 16, 2021. The classification
was applicable on December 28, 2018.

FOR FURTHER INFORMATION CONTACT: Patrick Antkowiak, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 4254, Silver Spring, MD 20993-0002, 240-
402-3705, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Upon request, FDA has classified the traumatic brain injury eye
movement assessment aid as class II (special controls), which we have
determined will provide a reasonable assurance of safety and
effectiveness. In addition, we believe this action will enhance
patients' access to beneficial innovation, by placing the device into a
lower device class than the automatic class III assignment.
    The automatic assignment of class III occurs by operation of law
and without any action by FDA, regardless of the level of risk posed by
the new device. Any device that was not in commercial distribution
before May 28, 1976, is automatically classified as, and remains
within, class III and requires premarket approval unless and until FDA
takes an action to classify or reclassify the device (see 21 U.S.C.
360c(f)(1)). We refer to these devices as ``postamendments devices''
because they were not in commercial distribution prior to the date of
enactment of the Medical Device Amendments of 1976, which amended the
Federal Food, Drug, and Cosmetic Act (FD&C Act).
    FDA may take a variety of actions in appropriate circumstances to
classify or reclassify a device into class I or II. We may issue an
order finding a new device to be substantially equivalent under section
513(i) of the FD&C Act (see 21 U.S.C. 360c(i)) to a predicate device
that does not require premarket approval. We determine whether a new
device is substantially equivalent to a predicate device by means of
the procedures for premarket notification under section 510(k) of the
FD&C Act (21 U.S.C. 360(k) and part 807 (21 CFR part 807).
    FDA may also classify a device through ``De Novo'' classification,
a common name for the process authorized under section 513(f)(2) of the
FD&C Act. Section 207 of the Food and Drug Administration Modernization
Act of 1997 established the first procedure for De Novo classification
(Pub. L. 105-115). Section 607 of the Food and Drug Administration
Safety and Innovation Act modified the De Novo application process by
adding a second procedure (Pub. L. 112-144). A device sponsor may
utilize either procedure for De Novo classification.
    Under the first procedure, the person submits a 510(k) for a device
that has not previously been classified. After receiving an order from
FDA classifying the device into class III under section 513(f)(1) of
the FD&C Act, the person then requests a classification under section
513(f)(2).
    Under the second procedure, rather than first submitting a 510(k)
and then a request for classification, if the person determines that
there is no legally marketed device upon which to base a determination
of substantial equivalence, that person requests a classification under
section 513(f)(2) of the FD&C Act.
    Under either procedure for De Novo classification, FDA is required
to classify the device by written order within 120 days. The
classification will be according to the criteria under section
513(a)(1) of the FD&C Act. Although the device was automatically placed
within class III, the De Novo classification is considered to be the
initial classification of the device.
    When FDA classifies a device into class I or II via the De Novo
process, the device can serve as a predicate for future devices of that
type, including for 510(k)s (see section 513(f)(2)(B)(i) of the FD&C
Act). As a result, other device sponsors do not have to submit a De
Novo request or premarket approval application to market a
substantially equivalent device (see section 513(i) of the FD&C Act,
defining ``substantial equivalence''). Instead, sponsors can use the
less-burdensome 510(k) process, when necessary, to market their device.

II. De Novo Classification

    On December 22, 2017, FDA received Oculogica, Inc.'s request for De
Novo classification of the EyeBOX[supreg]. FDA reviewed the request in
order to classify the device under the criteria for classification set
forth in section 513(a)(1) of the FD&C Act.
    We classify devices into class II if general controls by themselves
are insufficient to provide reasonable assurance of safety and
effectiveness, but there is sufficient information to establish special
controls that, in combination with the general controls, provide
reasonable assurance of the safety and effectiveness of the device for
its intended use (see section 513(a)(1)(B) of the FD&C Act). After
review of the information submitted in the request, we determined that
the device can be classified into class II with the establishment of
special controls. FDA has determined that these special controls, in
addition to the general controls, will provide reasonable assurance of
the safety and effectiveness of the device.
    Therefore, on December 28, 2018, FDA issued an order to the
requester classifying the device into class II. In this final order,
FDA is codifying the classification of the device by adding 21 CFR
882.1455.\1\ We have named the generic type of device traumatic brain
injury eye movement assessment aid, and it is identified as a
prescription device that uses a patient's tracked eye movements to
provide an interpretation of the functional condition of the patient's
brain. This device is an assessment aid that is not intended for
standalone detection or diagnostic purposes.
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    \1\ FDA notes that the ``ACTION'' caption for this final order
is styled as ``Final amendment; final order,'' rather than ``Final
order.'' Beginning in December 2019, this editorial change was made
to indicate that the document ``amends'' the Code of Federal
Regulations. The change was made in accordance with the Office of
Federal Register's (OFR) interpretations of the Federal Register Act
(44 U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and
parts 21 and 22), and the Document Drafting Handbook.
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    FDA has identified the following risks to health associated
specifically with this type of device and the measures

required to mitigate these risks in table 1.

  Table 1--Traumatic Brain Injury Eye Movement Assessment Aid Risks and
                           Mitigation Measures
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            Identified risks                   Mitigation measures
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Incorrect or misinterpreted results,
 including:
     False positive: Brain       Clinical performance testing;
     injury when in fact none is
     present.
     False negative: No brain    Software verification,
     injury when in fact brain injury     validation, and hazard
     is present.                          analysis; and
                                         Labeling.
Interference with other devices........  Electromagnetic compatibility
                                          (EMC) testing; and
                                         Software verification,
                                          validation, and hazard
                                          analysis.
Electrical shock or burn...............  Electrical safety testing; and
                                         Software verification,
                                          validation, and hazard
                                          analysis.
Adverse tissue reaction................  Biocompatibility evaluation.
Eye hazard or injury...................  Light hazard assessment.
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    FDA has determined that special controls, in combination with the
general controls, address these risks to health and provide reasonable
assurance of safety and effectiveness. For a device to fall within this
classification, and thus avoid automatic classification in class III,
it would have to comply with the special controls named in this final
order. The necessary special controls appear in the regulation codified
by this order. This device is subject to premarket notification
requirements under section 510(k) of the FD&C Act.
    At the time of classification, traumatic brain injury eye movement
assessment aids are for prescription use only. Prescription devices are
exempt from the requirement for adequate directions for use for the
layperson under section 502(f)(1) of the FD&C Act (21 U.S.C. 352(f)(1))
and 21 CFR 801.5, as long as the conditions of 21 CFR 801.109 are met.

III. Analysis of Environmental Impact

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

IV. Paperwork Reduction Act of 1995

    While this final order contains no collection of information, it
establishes special controls that refer to previously approved FDA
collections of information found in other FDA regulations and guidance.
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 order. The previously approved collections of
information are subject to review by OMB under the PRA. The collections
of information in the guidance document ``De Novo Classification
Process (Evaluation of Automatic Class III Designation)'' have been
approved under OMB control number 0910-0844; the collections of
information in 21 CFR part 814, subparts A through E, regarding
premarket approval, have been approved under OMB control number 0910-
0231; the collections of information in part 807, subpart E, regarding
premarket notification submissions, have been approved under OMB
control number 0910-0120; the collections of information in 21 CFR part
820, regarding quality system regulation, have been approved under OMB
control number 0910-0073; and the collections of information in 21 CFR
part 801, regarding labeling, have been approved under OMB control
number 0910-0485.

List of Subjects in 21 CFR Part 882

    Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, 21 CFR
part 882 is amended as follows:

PART 882--NEUROLOGICAL DEVICES

0
1. The authority citation for part 882 continues to read as follows:

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

0
2. Add Sec.  882.1455 to subpart B to read as follows:

Sec.  882.1455  Traumatic brain injury eye movement assessment aid.

    (a) Identification. A traumatic brain injury eye movement
assessment aid is a prescription device that uses a patient's tracked
eye movements to provide an interpretation of the functional condition
of the patient's brain. This device is an assessment aid that is not
intended for standalone detection or diagnostic purposes.
    (b) Classification. Class II (special controls). The special
controls for this device are:
    (1) Clinical performance data under anticipated conditions of use
must evaluate tracked eye movement in supporting the indications for
use and include the following:
    (i) Evaluation of sensitivity, specificity, positive predictive
value, and negative predictive value using a reference method of
diagnosis;
    (ii) Evaluation of device test-retest reliability; and
    (iii) A description of the development of the reference method of
diagnosis, which may include a normative database, to include the
following:
    (A) A discussion of how the clinical work-up was completed to
establish the reference method of diagnosis, including the
establishment of inclusion and exclusion criteria; and
    (B) If using a normative database, a description of how the
``normal'' population was established, and the statistical methods and
model assumptions used.
    (2) Software verification, validation, and hazard analysis must be
performed. Software documentation must include a description of the
algorithms used to generate device output.
    (3) Performance testing must demonstrate the electrical safety and
electromagnetic compatibility (EMC) of the device.
    (4) The patient-contacting components of the device must be
demonstrated to be biocompatible.
    (5) A light hazard assessment must be performed for all eye-
tracking and visual display light sources.
    (6) Labeling must include:
    (i) A summary of clinical performance testing conducted with the
device, including sensitivity, specificity, positive predictive value,
negative predictive value, and test-retest reliability;

    (ii) A description of any normative database that includes the
following:
    (A) The clinical definition used to establish a ``normal''
population and the specific selection criteria;
    (B) The format for reporting normal values;
    (C) Examples of screen displays and reports generated to provide
the user results and normative data;
    (D) Statistical methods and model assumptions; and
    (E) Any adjustments for age and gender.
    (iii) A warning that the device should only be used by trained
healthcare professionals;
    (iv) A warning that the device does not identify the presence or
absence of traumatic brain injury or other clinical diagnoses;
    (v) A warning that the device is not a standalone diagnostic; and
    (vi) Any instructions to convey to patients regarding the
administration of the test and collection of test data.

    Dated: December 9, 2021.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2021-27227 Filed 12-15-21; 8:45 am]
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[Federal Register: December 8, 2006 (Volume 71, Number 236)]
[Rules and Regulations]
[Page 71037]
[DOCID:fr08de06-1]

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Rules and Regulations
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains regulatory documents
having general applicability and legal effect, most of which are keyed
to and codified in the Code of Federal Regulations, which is published
under 50 titles pursuant to 44 U.S.C. 1510.

The Code of Federal Regulations is sold by the Superintendent of Documents.
Prices of new books are listed in the first FEDERAL REGISTER issue of each
week.

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SECURITIES AND EXCHANGE COMMISSION

17 CFR Part 200

[Release No. 34-54867]

Delegation of Authority to Chief Administrative Law Judge

AGENCY: Securities and Exchange Commission.

ACTION: Final rule.

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SUMMARY: The Securities and Exchange Commission (``Commission'') is
amending its rules to delegate authority to the Chief Administrative
Law Judge to issue orders to discontinue administrative proceedings as
to a particular respondent who has died or cannot be found, or because
of a mistake in the identity of a respondent named in the order for
proceedings. The delegation is intended to conserve Commission
resources, as well as expedite disposition of administrative
proceedings.

EFFECTIVE DATE: January 8, 2007.

FOR FURTHER INFORMATION CONTACT: Geoffrey D. Kruczek, Office of
Administrative Law Judges,<PHONE_NUMBER>, Securities and Exchange
Commission, 100 F Street, NE., Washington, DC 20549-2557.

SUPPLEMENTARY INFORMATION: The Commission today is amending its rules
governing the delegation of authority to the Chief Administrative Law
Judge. The Commission's Office of the General Counsel has delegated
authority to grant motions of staff counsel to discontinue
administrative proceedings as to a particular respondent who has died
or cannot be found, or because of a mistake in the identity of a
respondent named in the order for proceedings.\1\ The Commission has
determined to extend this delegation to the Chief Administrative Law
Judge.\2\ The Commission believes that this delegation will conserve
Commission and staff resources, as well as expedite the disposition of
staff motions prompted by these circumstances. Nevertheless, the staff
may submit motions to the Commission for consideration, as it deems
appropriate. The amendment also deletes reference to the Public Utility
Holding Company Act of 1935, which has been repealed.
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    \1\ 17 CFR 200.30-14(g)(1)(vi).
    \2\ 17 CFR 200.30-10.
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Administrative Law Matters

    The Commission finds, in accordance with section 553(b)(A) of the
Administrative Procedure Act, 5 U.S.C. 553(b)(A), that this amendment
relates solely to agency organization, procedure or practice.
Accordingly, notice and opportunity for public comment are unnecessary.
Because notice and comment are not required for this final rule, a
regulatory flexibility analysis is not required under the Regulatory
Flexibility Act.\3\ Because the rule relates to ``agency organization,
procedure or practice that does not substantially affect the rights or
obligations of non-agency parties,'' it is not subject to the Small
Business Regulatory Enforcement Fairness Act.\4\
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    \3\ See 5 U.S.C. 603.
    \4\ See 5 U.S.C. 804(3)(C).
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    Section 23(a)(2) of the Securities Exchange Act of 1934 requires
the Commission, in adopting rules under such Act, to consider the
anticompetitive effects of any rules it adopts. The Commission does not
believe this rule will have any impact on competition because it
imposes no new burden on respondents in administrative proceedings, and
is intended to expedite disposition of those proceedings. The rule does
not contain any collection of information requirements as defined by
the Paperwork Reduction Act of 1995, as amended.\5\ The rule will not
impose any costs on the public.
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    \5\ See 44 U.S.C. 3501 et seq.
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Statutory Basis and Text of Amendment

    This amendment to the Commission's delegations is being adopted
pursuant to statutory authority granted to the Commission, including
section 3 of the Sarbanes-Oxley Act of 2002, 15 U.S.C. 7202; section 19
of the Securities Act of 1933, 15 U.S.C. 77s; sections 4A, 19, and 23
of the Securities Exchange Act of 1934, 15 U.S.C. 78d-1, 78s, 78w;
section 319 of the Trust Indenture Act of 1939, 15 U.S.C. 77sss;
sections 38 and 40 of the Investment Company Act of 1940, 15 U.S.C.
80a-37 and 80a-39; and section 211 of the Investment Advisers Act of
1940, 15 U.S.C. 80b-11.

List of Subjects in 17 CFR Part 200

    Authority delegations (Government agencies).

Text of Adopted Rule

0
For the reasons set out in the preamble, Title 17, Chapter II of the
Code of Federal Regulations is amended as follows:

PART 200--ORGANIZATION; CONDUCT AND ETHICS; AND INFORMATION AND
REQUESTS

0
1. The authority citation for part 200, subpart A, continues to read as
follows:

    Authority: 15 U.S.C. 77s, 77o, 77sss, 78d, 78d-1, 78d-2, 78w,
78ll(d), 78mm, 80a-37, 80b-11, and 7202, unless otherwise noted.

0
2. Section 200.30-10 is amended by:
0
a. Removing ``the Public Utility Holding Company Act of 1935, 15 U.S.C.
79a et seq.,'' in the introductory text to paragraph (a);
0
b. Removing the period at the end of paragraph (a)(7) and in its place
adding a semicolon; and
0
c. Adding paragraph (a)(8).
    The addition reads as follows:

Sec.  200.30-10  Delegation of authority to Chief Administrative Law
Judge.

* * * * *
    (a) * * *
    (8) To grant motions of staff counsel to discontinue administrative
proceedings as to a particular respondent who has died or cannot be
found, or because of a mistake in the identity of a respondent named in
the order for proceedings.
* * * * *

    Dated: December 4, 2006.

    By the Commission.
Florence E. Harmon,
Deputy Secretary.
[FR Doc. E6-20884 Filed 12-7-06; 8:45 am]

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[Federal Register Volume 78, Number 112 (Tuesday, June 11, 2013)]
[Proposed Rules]
[Pages 34965-34966]
[FR Doc No: 2013-13732]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 52

[EPA-R05-OAR-2012-0969 FRL-9821-2]

Approval and Promulgation of Air Quality Implementation Plans;
Ohio; 1997 8-Hour Ozone Maintenance Plan Revision; Motor Vehicle
Emissions Budgets for the Ohio Portion of the Wheeling Area

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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SUMMARY: Under the Clean Air Act, EPA is proposing to approve the
request by Ohio to revise the 1997 8-hour ozone maintenance air quality
State Implementation Plan (SIP) for the Ohio portion of the Wheeling,
West Virginia-Ohio area to replace the previously approved motor
vehicle emissions budgets with budgets developed using EPA's Motor
Vehicle Emissions Simulator (MOVES) emissions model. Ohio submitted the
SIP revision request to EPA on December 7, 2012.

DATES: Comments must be received on or before July 11, 2013.

ADDRESSES: Submit your comments, identified by Docket ID No. EPA-R05-
OAR-2012-0969, by one of the following methods:
    1. www.regulations.gov: Follow the on-line instructions for
submitting comments.
    2. Email<EMAIL_ADDRESS>    3. Fax:<PHONE_NUMBER>.
    4. Mail: Pamela Blakley, Chief, Control Strategies Section, Air
Programs Branch (AR-18J), U.S. Environmental Protection Agency, 77 West
Jackson Boulevard, Chicago, Illinois 60604.
    5. Hand Delivery: Pamela Blakley, Chief, Control Strategies
Section, Air Programs Branch (AR-18J), U.S. Environmental Protection
Agency, 77 West Jackson Boulevard, Chicago, Illinois 60604. Such
deliveries are only accepted during the Regional Office

normal hours of operation, and special arrangements should be made for
deliveries of boxed information. The Regional Office official hours of
business are Monday through Friday, 8:30 a.m. to 4:30 p.m., excluding
Federal holidays.
    Please see the direct final rule which is located in the Rules
section of this Federal Register for detailed instructions on how to
submit comments.

FOR FURTHER INFORMATION CONTACT: Anthony Maietta, Environmental
Protection Specialist, Control Strategies Section, Air Programs Branch
(AR-18J), Environmental Protection Agency, Region 5, 77 West Jackson
Boulevard, Chicago, Illinois 60604,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: In the Final Rules section of this Federal
Register, EPA is approving the State's SIP submittal as a direct final
rule without prior proposal because the Agency views this as a
noncontroversial submittal and anticipates no adverse comments. A
detailed rationale for the approval is set forth in the direct final
rule. If no adverse comments are received in response to this rule, no
further activity is contemplated. If EPA receives adverse comments, the
direct final rule will be withdrawn and all public comments received
will be addressed in a subsequent final rule based on this proposed
rule. EPA will not institute a second comment period. Any parties
interested in commenting on this action should do so at this time.
Please note that if EPA receives adverse comment on an amendment,
paragraph, or section of this rule and if that provision may be severed
from the remainder of the rule, EPA may adopt as final those provisions
of the rule that are not the subject of an adverse comment. For
additional information, see the direct final rule which is located in
the Rules section of this Federal Register.

    Dated: May 28, 2013.
Susan Hedman,
Regional Administrator, Region 5.
[FR Doc. 2013-13732 Filed 6-10-13; 8:45 am]
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Page 1 of 57 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES June 9, 2006 MEMORANDUM SUBJECT: Benchmark dose analysis of cholinesterase inhibition data in neonatal and adult rats ( MRID no. 46688914) following exposure to DDVP PC Code: 084001. DP Barcode DP 328793. TXR No. 0054223 FROM: Anna Lowit Toxicologist Toxicology Branch Health Effects Division ( 7509C)

THRU: Louis Scarano Branch Chief Toxicology Branch Health Effects Division ( 7509C)

TO: Ray Kent Branch Chief Reregistration Branch 4 Health Effects Division ( 7509C)

The purpose of the current memo is to provide BMD estimates calculated by the Health Effects Division for the acute and repeated dosing studies in adult and juvenile rats in DDVP ( MRID nos. 45805703, 45842301, 46433201, 46153304). The results of this memo are intended to inform the FQPA 10X factor for dichlorvos ( also called DDVP) in the single chemical aggregate and cumulative risk assessments. Page 2 of 57 Summary This memo describes a benchmark dose analysis for red blood cell ( RBC) and brain cholinesterase ( ChE) inhibition data in adult and juvenile rats exposed orally to DDVP ( MRID nos. 45805703, 45842301, 46433201, 46153304). This analysis was developed using the exponential model provided in EPA's OPCum Risk software. The estimated dose to result in 10% inhibition ( BMD10) and the lower 95% confidence limit on the BMD10 ( BMDL10) were calculated. For acute exposures, the calculated BMDs10 range from approximately 1.3 mg/ kg to 2.0 mg/ kg for each compartment, sex and age group ( young adult and postnatal day 8 [ PND8] rats). Regarding repeated exposures, the Agency has used both concurrent and historical controls to estimate RBC and brain BMD10. For most groups, the calculated the BMDs10 ranged from approximately 0.5 mg/ kg to 1.2 mg/ kg when using the historical or concurrent controls. Overall, for the repeated exposure, the BMDs are similar between compartments, sexes and age groups.

Background The Agency's draft BMD technical guidance indicates that the BMD approach is a preferable alternative to the NOAEL/ LOAEL approach ( USEPA, 2000). The Office of Pesticide Programs is increasing its use of BMD techniques in its hazard assessments and risk characterizations. BMDs are preferred over the NOAEL/ LOAEL as NOAELs/ LOAELs are highly dependent on dose selection in that they are limited to the doses included in a study. Moreover, the NOAEL/ LOAEL approach does not account for the uncertainty in the estimate of the dose response. Benchmark dose analysis attempts to model the doseresponse relationship with a dose response curve that can be described by a mathematical function. The dose response curve that is estimated based on the experimental observations is used to estimate the magnitude of the response for any dose within the experimental dose range. Various mathematical models can be used to model this dose response curve. Once a BMD model has been selected, the dose associated with a specified response ( i. e. benchmark response, BMR) is determined. For cholinesterase data, the BMR is typically expressed as a certain percent change in the control group response ( i. e., background). The dose resulting in the specified BMR and estimated based on the modeled dose response curve is termed the " benchmark dose." Generally, the dose resulting in a BMR of X% change in background is referred to as the BMDX. The corresponding 95% lower confidence limit on the BMDX is referred to as the BMDLX. In the case of ChE inhibition for DDVP, EPA has used a BMR of 10% for ChE inhibition. This BMR was selected based on both statistical and toxicological considerations. The reader is referred to the Revised Organophosphate ( OP) Cumulative Assessment which provides a detailed power analysis of over 1000 measurements of brain ChE inhibition which indicates that 10% is a level that can be reliably measured in the majority of rat toxicity studies. In the case of the ChE inhibiting pesticides, it is important to consider the degree to which the response level for inhibition of ChE is protective for other toxicities which may result from pesticide exposure. The Agency believes that at a BMR of 10% for brain ChE inhibition is, indeed, protective of other toxicities whereas higher BMR values may not be.

Methods Selected Model The BMD analysis of ChE data from the DDVP oral gavage acute and repeated comparative sensitivity toxicity studies was performed using EPA's OPCumRisk program. The exponential function used for modeling the effect of DDVP on ChE activity was:

y = B + ( A  B) e m x dose Where y is ChE activity, dose is the dose in mg/ kg, m is the dose scale factor, A is background ChE activity, and B is the limiting high dose ChE activity. Both y ( ChE activity) and dose were extracted from the above referenced toxicity study. The equation for the exponential model reflects the observation that Page 3 of 57 ChE activity decreases to a limiting value ( B) as dose increases. The model has three parameters to be estimated: m ( dose scale factor), A ( background), and B ( limiting high dose ChE activity).

The OPCumRisk program utilizes the same dose response model ( i. e., decreasing exponential model) as utilized in the Preliminary OP Cumulative Risk Assessment ( CRA; USEPA, 2001). The OPCumRisk program can be obtained at www. epa. gov/ pesticides/ cumulative/ EPA_ approach_ methods. htm. These dose response models and the respective computer code are publicly available for download, review, and use. This method has been previously evaluated by the FIFRA SAP ( www. epa. gov/ scipoly/ sap/ 2001/ index. htm). For the revised OP CRA ( USEPA, 2002), the exponential model was expanded to include a " low dose shoulder." The low dose shoulder corresponds to the portion of the dose response curve where the slope at the low end of the dose response curve is more flat compared to the slope at higher doses. This low dose shoulder is not modeled in the OPCumRisk program. For DDVP brain and RBC ChE data in the comparative ChE study, there is little evidence that a low dose shoulder exists and as such, the current BMD analysis is considered adequate and supportable. It is important to note that the exponential model is also being used by EPA in its cumulative risk assessment for the OP common mechanism group ( of which DDVP is a member; USEPA, 2002).

The calculated BMD values represent the dose at which a 10% reduction in background ChE activity levels is expected ( i. e. BMD10 values were calculated). For each ChE dataset, parameters were initially estimated including all dose groups. The OPCumRisk program utilizes a decision algorithm for selecting from among various options for the exponential model. Generally the model is fitted until an adequate pvalue for the  2 goodness of fit ( GoF) statistic is obtained. The decision algorithm is provided below.

1. If the p value for the GoF statistic is greater than 0.05, then the model's fit was considered adequate and the initial parameter estimates were used.

2. Otherwise ( that is, if the p value was less than 0.05, or no estimates resulted because the model did not converge), the horizontal asymptote was set to zero and the model was refit to the data.

3. If the p value was still less than 0.05, or there was no model fit at all, then the highest dose was dropped and the model was refit with the horizontal asymptote set to zero until either the pvalue exceeded 0.05, or there are only three doses remaining.

Although the user can specify options that are not consistent with the default decision algorithm utilized by OPCumRisk, all BMD values provided in these analyses are based on the default decision algorithm. The decision algorithm and technical details of the " basic" exponential model used in this BMD analysis can be obtained at www. epa. gov/ scipoly/ sap/ 2001/ september/ rpfappendix1. pdf.

Results BMD values ( both BMD10 and BMDL10) were calculated for the brain and RBC ChE data from the oral gavage acute comparative sensitivity toxicity study. These BMD values and the goodness of fit information from the OPCumRisk model runs are provided in Tables 1 and 2 for acute and repeated exposures, respectively. Details of this analysis can be found below in Appendix 1 and 2.

Based on statistical and/ or visual fit, the exponential model adequately fit the RBC and brain ChE data from the acute exposures to adult and PND8 rats. Moreover, for acute exposures, all of calculated the BMD10 range from approximately 1.3 mg/ kg to 2.0 mg/ kg. The BMDs are similar between compartments, sexes and age groups. It is also notable that there is a narrow margin between the BMD10 and BMDL10 indicating quality data and quality model fit.

Table 1. BMD Summary of OPP's Analysis of ChE Data from the DDVP Oral Acute Gavage Comparative Sensitivity Toxicity Study ( MRID no. 45805703, 45842301) Based on the Exponential Model Page 4 of 57 Compartment Sex Subpopulation BMD10 ( mg/ kg) BMDL10 ( mg/ kg) GoF p value Adult 1.46 0.76 0.53 Male Neonate 1.50 1.40 0.46 Adult 1.29 0.65 0.51 Brain Female Neonate 2.02 1.80 0.95 Adult 1.66 1.31 0.20 Male Neonate 1.63 1.41 0.95 Adult 1.55 1.26 0.65 RBC Female Neonate 1.47 0.83 0.15 Based on statistical and/ or visual fit, the exponential model adequately fit most of the sex agecompartment scenarios for the RBC and brain ChE data from the repeated exposures to DDVP ( Table 2). As described in the Data Evaluation Record ( DER), the ChE activity measurements in some control groups are unusually high for the laboratory which conducted the repeated exposure study. The registrant, AMVAC, provided historical control values for brain and RBC ChE activity. BMD estimates were developed using both the concurrent and pooled historical control values. For most groups, the calculated the BMDs10 ranged from approximately 0.5 mg/ kg to 1.2 mg/ kg when using the historical or concurrent controls. For the female brain ChE from juvenile rats, when using the concurrent controls, the statistical fit was not adequate ( p < 0.05); however, when using the historical controls, the fit was improved. For the female adult RBC ChE data, when using the concurrent controls, the BMDs were substantially lower than values calculated for the other groups; when the historical control values were considered, the BMD for this group increased to be consistent with the remaining groups. Overall, for the repeated exposure, the BMDs are similar between compartments, sexes and age groups. It is also notable that the BMD10 and BMDL10 are close together in magnitude indicating quality data for most treatment groups and quality model fit. Page 5 of 57 Table 2. BMD Summary of OPP's Analysis of ChE Data from the DDVP Oral Multi dosing Gavage Comparative Sensitivity Toxicity Study ( MRID no. 46433201, 46153304) Based on the Exponential Model Compartmen t Sex Subpopulati on BMD10 ( mg/ kg) BMDL10 ( mg/ kg) GoF p value Adult 0.72 0.55 0.71 Male Neonate 0.88 0.75 0.0081 Adult 0.88 0.71 0.84 Brain ( concurrent controls) Female Neonate 0.95 0.80 0.022 Adult 0.77 0.62 0.63 Male Neonate 0.84 0.65 0.37 Adult 0.92 0.75 0.75 Brain ( pooled historical controls) Female Neonate 0.85 0.62 0.39 Adult 0.71 0.45 0.11 Male Neonate 0.50 0.35 0.41 Adult 0.09 0.054 0.66 RBC ( concurrent controls) Female Neonate 0.57 0.43 0.69 Adult 0.75 0.50 0.30 Male Neonate 0.55 0.38 0.094 Adult 1.17 1.00 0.90 RBC ( pooled historical controls) Female Neonate 0.61 0.46 0.50 Conclusions The BMD analysis described here provides a robust consideration of the brain and RBC ChE data from the acute and repeated exposure studies in young adult and juvenile rats exposed to DDVP orally. This analysis indicates that for acute and repeated exposures that young adult and juvenile rats respond similarly to oral dosing to DDVP. Page 6 of 57 References USEPA, 2000. " Benchmark Dose Technical Guidance Document" Draft report. Risk Assessment Forum, Office of Research and Development, U. S. Environmental Protection Agency. Washington, DC. EPA/ 630/ R 00/ 001 USEPA ( 2001). Preliminary Organophosphorus Pesticide Cumulative Risk Assessment. Office of Pesticide Programs, U. S. Environmental Protection Agency. Washington, DC. http:// www. epa. gov/ pesticides/ cumulative/ pra_ op/.

USEPA, 2002. Revised Organophosphorous Pesticide Cumulative Risk Assessment; June 10, 2002. Office of Pesticide Programs, U. S. Environmental Protection Agency. Washington, D. C. Available: http:// www. epa. gov/ pesticides/ cumulative/ rra op/ Page 7 of 57 Appendix 1: Benchmark dose runs for the acute dosing ( MRID no. 45805703, 45842301) DDVP: Acute, Brain, Adult Page 8 of 57 DDVP: 1 D: BRAIN: F: MAIN Tue Apr 25 16: 46: 22 2006 MRID: ADULT Guideline: 81 1 Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 85.75863 89.74156  38.87931 Coefficients: Value Std. Error A 8.7164482 0.9536187 B 2.0810054 2.6396297 m 0.1093959 0.1071854 Correlation: A B m A 1.0000000 0.4940059 0.5941367 B 0.4940059 1.0000000 0.9731630 m 0.5941367 0.9731630 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 6.91981135 8.7164482 10.9795579 B 0.14322729 2.0810054 30.2357431 m 0.01384314 0.1093959 0.8645054 Residual standard error: lower est. upper 2.063742 2.750235 4.122999 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.4272 with 1 degrees of freedom. P = 0.513 dose n chei Expected sd Exp. SD X2 Resid. 1 0 5 9.17 8.716448 2.19 2.637271 0.38455377 2 1 5 7.48 8.028853 2.19 2.409555  0.50933622 3 5 5 6.03 5.920903 2.25 1.741651 0.14006697 DDVP: Acute, Brain, Adult Page 9 of 57 4 15 5 3.36 3.366941 1.00 1.021351  0.01519591  BMD Computation BMD = 1.287: BMDL = 0.6495  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.1094 se: 0.1072 var= se^ 2: 0.01149 Per cent. of background at unit dose: 90 Per cent. of background at the highest dose: 19 ED50 ( 95% CI): 6.336 ( 0.9286 , 43.24 )

ln( Potency)  2.213 se[ log( Potency)]: 0.9798 se[ log( Potency)]^ 2: 0.96 DDVP: Acute, Brain, Adult Page 10 of 57 DDVP: 1 D: BRAIN: M: MAIN Tue Apr 25 16: 46: 28 2006 MRID: ADULT Guideline: 81 1 Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 74.27587 78.25880  33.13793 Coefficients: Value Std. Error A 7.50616158 0.77906555 B 1.53331933 0.55183572 m 0.09231263 0.05727478 Correlation: A B m A 1.0000000 0.5155696 0.6408690 B 0.5155696 1.0000000 0.8990115 m 0.6408690 0.8990115 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 6.02999496 7.50616158 9.343700 B 0.71757370 1.53331933 3.276414 m 0.02493219 0.09231263 0.341792 Residual standard error: lower est. upper 1.628137 2.169729 3.252736 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.3867 with 1 degrees of freedom. P = 0.534 dose n chei Expected sd Exp. SD X2 Resid. 1 0 5 7.14 7.506162 2.05 2.1838492  0.374916996 2 1 5 7.42 6.979477 1.81 2.0377088 0.483405815 3 5 5 5.22 5.297988 1.01 1.5652808  0.111408487 DDVP: Acute, Brain, Adult Page 11 of 57 4 35 5 1.77 1.769368 0.74 0.5147315 0.002747467  BMD Computation BMD = 1.455: BMDL = 0.7623  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.09231 se: 0.05727 var= se^ 2: 0.00328 Per cent. of background at unit dose: 91 Per cent. of background at the highest dose: 4 ED50 ( 95% CI): 7.509 ( 2.226 , 25.33 )

ln( Potency)  2.383 se[ log( Potency)]: 0.6204 se[ log( Potency)]^ 2: 0.385 DDVP: Acute, RBC, Adult Page 12 of 57 DDVP: 1 D: RBC: F: MAIN Tue Apr 25 16: 46: 26 2006 MRID: ADULT Guideline: 81 1 Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power Highest 1 doses dropped from data set.

The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 201.74977 203.87392  97.87489 Coefficients: Value Std. Error A 2.571638e+ 03 71.521128484 m 6.799292e 02 0.009431473 Correlation: A m A 1.0000000 0.6800864 m 0.6800864 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 2.421676e+ 03 2.571638e+ 03 2.730886e+ 03 m 5.038701e 02 6.799292e 02 9.175059e 02 Residual standard error: lower est. upper 148.7009 205.1177 330.4533 Degrees of freedom: 15 total; 13 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.2042 with 1 degrees of freedom. P = 0.651 dose n chei Expected sd Exp. SD X2 Resid. 1 0 5 2597 2571.638 179 203.3146 0.27893149 2 1 5 2373 2402.597 264 189.8396  0.34861343 3 5 5 1835 1830.480 101 144.2978 0.07003547 DDVP: Acute, RBC, Adult Page 13 of 57  BMD Computation BMD = 1.55: BMDL = 1.262  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.06799 se: 0.009431 var= se^ 2: 8.895e 05 Per cent. of background at unit dose: 93 Per cent. of background at the highest dose: 71 ED50 ( 95% CI): 10.19 ( 7.768 , 13.38 )

ln( Potency)  2.688 se[ log( Potency)]: 0.1387 se[ log( Potency)]^ 2: 0.01924 DDVP: Acute, RBC, Adult Page 14 of 57 DDVP: 1 D: RBC: M: MAIN Tue Apr 25 16: 46: 32 2006 MRID: ADULT Guideline: 81 1 Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power Highest 1 doses dropped from data set.

The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 207.4049 209.5290  100.7024 Coefficients: Value Std. Error A 2.790461e+ 03 85.30415667 m 6.358638e 02 0.01043262 Correlation: A m A 1.0000000 0.6773461 m 0.6773461 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 2.612126e+ 03 2.790461e+ 03 2.980971e+ 03 m 4.460953e 02 6.358638e 02 9.063597e 02 Residual standard error: lower est. upper 171.6033 236.7092 381.3486 Degrees of freedom: 15 total; 13 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 1.633 with 1 degrees of freedom. P = 0.201 dose n chei Expected sd Exp. SD X2 Resid. 1 0 5 2705 2790.461 343 242.2597  0.7888111 2 1 5 2719 2618.549 170 227.7068 0.9864189 3 5 5 2015 2030.486 94 177.7275  0.1948314 DDVP: Acute, RBC, Adult Page 15 of 57  BMD Computation BMD = 1.657: BMDL = 1.305  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.06359 se: 0.01043 var= se^ 2: 0.0001088 Per cent. of background at unit dose: 94 Per cent. of background at the highest dose: 73 ED50 ( 95% CI): 10.9 ( 7.903 , 15.04 )

ln( Potency)  2.755 se[ log( Potency)]: 0.1641 se[ log( Potency)]^ 2: 0.02692 DDVP: Acute, Brain, Pup Page 16 of 57 DDVP: 1 PND: BRAIN: F: MAIN Tue Apr 25 16: 46: 45 2006 MRID: PND8 Guideline: 81 1 Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 4.4493049 7.4365018 0.7753475 Coefficients: Value Std. Error A 3.11393414 0.096228698 m 0.05220586 0.003914497 Correlation: A m A 1.0000000 0.6615286 m 0.6615286 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 2.91818820 3.11393414 3.32281030 m 0.04459687 0.05220586 0.06111309 Residual standard error: lower est. upper 0.2410419 0.3190020 0.4717480 Degrees of freedom: 20 total; 18 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.1003 with 2 degrees of freedom. P = 0.951 dose n chei Expected sd Exp. SD X2 Resid. 1 0 5 3.08 3.113934 0.21 0.3220624  0.2356035 2 1 5 2.98 2.955539 0.23 0.3058005 0.1788627 3 5 5 2.41 2.398534 0.23 0.2485596 0.1031516 4 15 5 1.42 1.423045 0.24 0.1480511  0.0459906  DDVP: Acute, Brain, Pup Page 17 of 57 BMD Computation BMD = 2.018: BMDL = 1.797  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.05221 se: 0.003914 var= se^ 2: 1.532e 05 Per cent. of background at unit dose: 95 Per cent. of background at the highest dose: 46 ED50 ( 95% CI): 13.28 ( 11.46 , 15.38 )

ln( Potency)  2.953 se[ log( Potency)]: 0.07498 se[ log( Potency)]^ 2: 0.005622 DDVP: Acute, Brain, Pup Page 18 of 57 DDVP: 1 PND: BRAIN: M: MAIN Tue Apr 25 16: 46: 52 2006 MRID: PND8 Guideline: 81 1 Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik  11.513330  8.526133 8.756665 Coefficients: Value Std. Error A 3.22799583 0.070577502 m 0.07048969 0.002815596 Correlation: A m A 1.0000000 0.6557125 m 0.6557125 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 3.08307201 3.22799583 3.37973197 m 0.06481574 0.07048969 0.07666033 Residual standard error: lower est. upper 0.1743612 0.2307548 0.3412458 Degrees of freedom: 20 total; 18 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 1.551 with 2 degrees of freedom. P = 0.46 dose n chei Expected sd Exp. SD X2 Resid. 1 0 5 3.14 3.227996 0.20 0.23552098  0.8354443 2 1 5 3.04 3.008290 0.10 0.21999032 0.3223142 3 5 5 2.33 2.269167 0.24 0.16745554 0.8123092 4 15 5 1.11 1.121331 0.09 0.08465241  0.2992973  DDVP: Acute, Brain, Pup Page 19 of 57 BMD Computation BMD = 1.495: BMDL = 1.403  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.07049 se: 0.002816 var= se^ 2: 7.928e 06 Per cent. of background at unit dose: 93 Per cent. of background at the highest dose: 35 ED50 ( 95% CI): 9.833 ( 9.093 , 10.63 )

ln( Potency)  2.652 se[ log( Potency)]: 0.03994 se[ log( Potency)]^ 2: 0.001595 DDVP: Acute, RBC, Pup Page 20 of 57 DDVP: 1 PND: RBC: F: MAIN Tue Apr 25 16: 46: 50 2006 MRID: PND8 Guideline: 81 1 Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 311.3597 315.3426  151.6799 Coefficients: Value Std. Error A 3565.7686985 253.06695411 B 1304.7155991 653.72006213 m 0.1170090 0.08519761 Correlation: A B m A 1.0000000 0.4552855 0.5739303 B 0.4552855 1.0000000 0.9594333 m 0.5739303 0.9594333 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 3069.8953381 3565.7686985 4141.7393788 B 453.3342457 1304.7155991 3755.0280190 m 0.0251796 0.1170090 0.5437383 Residual standard error: lower est. upper 553.7944 738.0112 1106.3850 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 2.127 with 1 degrees of freedom. P = 0.145 dose n chei Expected sd Exp. SD X2 Resid. 1 0 5 3830 3565.769 733 696.0392 0.84885899 2 1 5 2991 3316.097 662 639.2002  1.13726262 3 5 5 2636 2564.305 315 480.8800 0.33337969 DDVP: Acute, RBC, Pup Page 21 of 57 4 15 5 1689 1695.615 349 331.6280  0.04460369  BMD Computation BMD = 1.467: BMDL = 0.8317  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.117 se: 0.0852 var= se^ 2: 0.007259 Per cent. of background at unit dose: 89 Per cent. of background at the highest dose: 17 ED50 ( 95% CI): 5.924 ( 1.422 , 24.68 )

ln( Potency)  2.146 se[ log( Potency)]: 0.7281 se[ log( Potency)]^ 2: 0.5302 DDVP: Acute, RBC, Pup Page 22 of 57 DDVP: 1 PND: RBC: M: MAIN Tue Apr 25 16: 46: 56 2006 MRID: PND8 Guideline: 81 1 Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 301.8481 304.8353  147.9240 Coefficients: Value Std. Error A 3.677296e+ 03 1.737759e+ 02 m 6.483032e 02 6.020933e 03 Correlation: A m A 1.0000000 0.6594638 m 0.6594638 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 3.329745e+ 03 3.677296e+ 03 4.061124e+ 03 m 5.333839e 02 6.483032e 02 7.879824e 02 Residual standard error: lower est. upper 433.6720 573.9343 848.7482 Degrees of freedom: 20 total; 18 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.09684 with 2 degrees of freedom. P = 0.953 dose n chei Expected sd Exp. SD X2 Resid. 1 0 5 3620 3677.296 276 580.9977  0.22051497 2 1 5 3473 3446.460 411 545.1029 0.10887159 3 5 5 2693 2659.202 442 422.3719 0.17892749 4 15 5 1384 1390.583 359 223.2216  0.06594177  DDVP: Acute, RBC, Pup Page 23 of 57 BMD Computation BMD = 1.625: BMDL = 1.41  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.06483 se: 0.006021 var= se^ 2: 3.625e 05 Per cent. of background at unit dose: 94 Per cent. of background at the highest dose: 38 ED50 ( 95% CI): 10.69 ( 8.912 , 12.83 )

ln( Potency)  2.736 se[ log( Potency)]: 0.09287 se[ log( Potency)]^ 2: 0.008625 Page 24 of 57 Appendix 2: Benchmark dose runs for the repeated dosing ( MRID no. 46433201, 46153304) DDVP: Repeated, Brain, Adult, Concurrent controls Page 25 of 57 DDVP: 7 D: BRAIN: F: WHOLE Mon Apr 24 21: 43: 34 2006 MRID: MDAdconc Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 25.51746 29.50039  8.75873 Coefficients: Value Std. Error A 5.4680592 0.21623032 B 1.1331342 0.27076016 m 0.1529701 0.03053395 Correlation: A B m A 1.0000000 0.1901865 0.3377826 B 0.1901865 1.0000000 0.9369459 m 0.3377826 0.9369459 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 5.0303656 5.4680592 5.9438367 B 0.6844438 1.1331342 1.8759659 m 0.1003945 0.1529701 0.2330789 Residual standard error: lower est. upper 0.5119114 0.6821960 1.0227101 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.03915 with 1 degrees of freedom. P = 0.843 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 5 5.51 5.468059 0.34 0.6770768 0.138510867 2 0.1 5 5.36 5.402252 0.25 0.6689085  0.141243990 3 7.5 5 2.51 2.509476 0.56 0.3104510 0.003776490 DDVP: Repeated, Brain, Adult, Concurrent controls Page 26 of 57 4 15.0 5 1.57 1.570124 0.15 0.1945313  0.001419862  BMD Computation BMD = 0.8814: BMDL = 0.713  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.153 se: 0.03053 var= se^ 2: 0.0009323 Per cent. of background at unit dose: 86 Per cent. of background at the highest dose: 10 ED50 ( 95% CI): 4.531 ( 3.064 , 6.701 )

ln( Potency)  1.878 se[ log( Potency)]: 0.1996 se[ log( Potency)]^ 2: 0.03984 DDVP: Repeated, Brain, Adult, Concurrent controls Page 27 of 57 DDVP: 7 D: BRAIN: M: WHOLE Mon Apr 24 21: 43: 40 2006 MRID: MDAdconc Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 38.65735 42.64027  15.32867 Coefficients: Value Std. Error A 5.7226764 0.31678214 B 1.2589525 0.25158074 m 0.1917306 0.04343782 Correlation: A B m A 1.0000000 0.1403111 0.3067966 B 0.1403111 1.0000000 0.8887349 m 0.3067966 0.8887349 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 5.0918770 5.7226764 6.4316216 B 0.8258587 1.2589525 1.9191677 m 0.1188781 0.1917306 0.3092295 Residual standard error: lower est. upper 0.7591362 1.0116588 1.5166222 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.1429 with 1 degrees of freedom. P = 0.705 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 5 5.84 5.722676 0.40 0.9917110 0.264536182 2 0.1 5 5.52 5.637908 0.42 0.9768860  0.269889484 3 7.5 5 2.32 2.318672 0.68 0.4003437 0.007418733 DDVP: Repeated, Brain, Adult, Concurrent controls Page 28 of 57 4 15.0 5 1.51 1.510537 0.26 0.2624115  0.004578106  BMD Computation BMD = 0.7156: BMDL = 0.551  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.1917 se: 0.04344 var= se^ 2: 0.001887 Per cent. of background at unit dose: 83 Per cent. of background at the highest dose: 5.6 ED50 ( 95% CI): 3.615 ( 2.319 , 5.636 )

ln( Potency)  1.652 se[ log( Potency)]: 0.2266 se[ log( Potency)]^ 2: 0.05133 DDVP: Repeated, Brain, Adult, Historical controls Page 29 of 57 DDVP: 7 D: BRAIN: F: WHOLE Mon Apr 24 21: 43: 45 2006 MRID: MDAdhist Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 64.04178 70.79730  28.02089 Coefficients: Value Std. Error A 5.3368308 0.11905590 B 1.0997356 0.28281397 m 0.1465709 0.02915622 Correlation: A B m A 1.0000000 0.1150917 0.2036726 B 0.1150917 1.0000000 0.9481542 m 0.2036726 0.9481542 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 5.10097136 5.3368308 5.5835960 B 0.65311837 1.0997356 1.8517598 m 0.09794975 0.1465709 0.2193271 Residual standard error: lower est. upper 0.5322331 0.6528354 0.8446040 Degrees of freedom: 40 total; 37 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.104 with 1 degrees of freedom. P = 0.747 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 25 5.32 5.336831 0.60 0.6499687  0.129474129 2 0.1 5 5.36 5.275180 0.25 0.6424933 0.295197982 3 7.5 5 2.51 2.511155 0.56 0.3062988  0.008433535 DDVP: Repeated, Brain, Adult, Historical controls Page 30 of 57 4 15.0 5 1.57 1.569894 0.15 0.1909515 0.001242926  BMD Computation BMD = 0.9185: BMDL = 0.7518  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.1466 se: 0.02916 var= se^ 2: 0.0008501 Per cent. of background at unit dose: 86 Per cent. of background at the highest dose: 11 ED50 ( 95% CI): 4.729 ( 3.202 , 6.984 )

ln( Potency)  1.92 se[ log( Potency)]: 0.1989 se[ log( Potency)]^ 2: 0.03957 DDVP: Repeated, Brain, Adult, Historical controls Page 31 of 57 DDVP: 7 D: BRAIN: M: WHOLE Mon Apr 24 21: 43: 52 2006 MRID: MDAdhist Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 78.62698 85.38250  35.31349 Coefficients: Value Std. Error A 5.4406635 0.14572755 B 1.2233684 0.23205212 m 0.1793503 0.03602974 Correlation: A B m A 1.00000000 0.08852252 0.1851917 B 0.08852252 1.00000000 0.9107214 m 0.18519170 0.91072141 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 5.1532609 5.4406635 5.7440950 B 0.8329963 1.2233684 1.7966830 m 0.1193784 0.1793503 0.2694501 Residual standard error: lower est. upper 0.6580918 0.8072133 1.0443300 Degrees of freedom: 40 total; 37 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.2307 with 1 degrees of freedom. P = 0.631 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 25 5.41 5.440664 0.61 0.7954922  0.192733152 2 0.1 5 5.52 5.365700 0.42 0.7846436 0.439720961 3 7.5 5 2.32 2.322001 0.68 0.3407920  0.013132451 DDVP: Repeated, Brain, Adult, Historical controls Page 32 of 57 4 15.0 5 1.51 1.509570 0.26 0.2200316 0.004374445  BMD Computation BMD = 0.7701: BMDL = 0.6168  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.1794 se: 0.03603 var= se^ 2: 0.001298 Per cent. of background at unit dose: 84 Per cent. of background at the highest dose: 6.8 ED50 ( 95% CI): 3.865 ( 2.607 , 5.73 )

ln( Potency)  1.718 se[ log( Potency)]: 0.2009 se[ log( Potency)]^ 2: 0.04036 DDVP: Repeated, RBC, Adult, Concurrent controls Page 33 of 57 DDVP: 7 D: RBC: F: WHOLE Mon Apr 24 21: 43: 38 2006 MRID: MDAdconc Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 252.1003 256.0833  122.0502 Coefficients: Value Std. Error A 2727.000013 79.6172246 B 1258.499990 25.9812588 m 2.397083 0.8174793 Correlation: A B m A 1.000000e+ 00 1.765012e 06 0.66321810 B 1.765012e 06 1.000000e+ 00 0.05862781 m 6.632181e 01 5.862781e 02 1.00000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 2564.091283 2727.000013 2900.259098 B 1204.860966 1258.499990 1314.526963 m 1.167355 2.397083 4.922246 Residual standard error: lower est. upper 133.5911 178.0295 266.8919 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.1959 with 1 degrees of freedom. P = 0.658 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 5 2727 2727.0 150 178.02953  1.663420e 07 2 0.1 5 2414 2414.0 158 157.59563 2.423883e 07 3 7.5 5 1247 1258.5 109 82.15994  3.129848e 01 DDVP: Repeated, RBC, Adult, Concurrent controls Page 34 of 57 4 15.0 5 1270 1258.5 70 82.15994 3.129847e 01  BMD Computation BMD = 0.0857: BMDL = 0.05385  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 2.397 se: 0.8175 var= se^ 2: 0.6683 Per cent. of background at unit dose: 9.1 Per cent. of background at the highest dose: 2.4e 14 ED50 ( 95% CI): 0.2892 ( 0.1482 , 0.5642 )

ln( Potency) 0.8743 se[ log( Potency)]: 0.341 se[ log( Potency)]^ 2: 0.1163 DDVP: Repeated, RBC, Adult, Concurrent controls Page 35 of 57 DDVP: 7 D: RBC: M: WHOLE Mon Apr 24 21: 43: 43 2006 MRID: MDAdconc Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 290.6427 294.6256  141.3214 Coefficients: Value Std. Error A 2681.7192647 145.3811253 B 1135.7992785 123.8320471 m 0.2702996 0.1094602 Correlation: A B m A 1.0000000 0.0618944 0.1785788 B 0.0618944 1.0000000 0.8143054 m 0.1785788 0.8143054 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 2391.8831196 2681.7192647 3006.6762692 B 902.4076927 1135.7992785 1429.5534174 m 0.1150242 0.2702996 0.6351871 Residual standard error: lower est. upper 368.1789 490.6517 735.5575 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 2.552 with 1 degrees of freedom. P = 0.110 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 5 2908 2681.719 610 453.8838 1.11477671 2 0.1 5 2413 2640.493 111 445.6730  1.14139604 3 7.5 5 1346 1339.393 236 220.5037 0.06699746 DDVP: Repeated, RBC, Adult, Concurrent controls Page 36 of 57 4 15.0 5 1159 1162.612 155 200.3797  0.04030813  BMD Computation BMD = 0.7048: BMDL = 0.4481  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.2703 se: 0.1095 var= se^ 2: 0.01198 Per cent. of background at unit dose: 76 Per cent. of background at the highest dose: 1.7 ED50 ( 95% CI): 2.564 ( 1.16 , 5.671 )

ln( Potency)  1.308 se[ log( Potency)]: 0.405 se[ log( Potency)]^ 2: 0.164 DDVP: Repeated, RBC, Adult, Historical controls Page 37 of 57 DDVP: 7 D: RBC: F: WHOLE Mon Apr 24 21: 43: 50 2006 MRID: MDAdhist Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power Highest 1 doses dropped from data set.

The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 432.6351 436.8387  213.3175 Coefficients: Value Std. Error A 2.453625e+ 03 68.975570904 m 9.025628e 02 0.009178156 Correlation: A m A 1.0000000 0.4137541 m 0.4137541 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 2.316326e+ 03 2.453625e+ 03 2599.0618980 m 7.328462e 02 9.025628e 02 0.1111583 Residual standard error: lower est. upper 273.4370 344.5616 466.0030 Degrees of freedom: 30 total; 28 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.01654 with 1 degrees of freedom. P = 0.898 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 20 2458 2453.625 399 343.9574 0.056889167 2 0.1 5 2414 2431.579 158 340.8656  0.115315893 3 7.5 5 1247 1246.880 109 174.7398 0.001538003 DDVP: Repeated, RBC, Adult, Historical controls Page 38 of 57  BMD Computation BMD = 1.167: BMDL = 1  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.09026 se: 0.009178 var= se^ 2: 8.424e 05 Per cent. of background at unit dose: 91 Per cent. of background at the highest dose: 51 ED50 ( 95% CI): 7.68 ( 6.292 , 9.374 )

ln( Potency)  2.405 se[ log( Potency)]: 0.1017 se[ log( Potency)]^ 2: 0.01034 DDVP: Repeated, RBC, Adult, Historical controls Page 39 of 57 DDVP: 7 D: RBC: M: WHOLE Mon Apr 24 21: 43: 56 2006 MRID: MDAdhist Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 506.1301 512.3515  249.0650 Coefficients: Value Std. Error A 2610.5056190 77.5940879 B 1131.7044406 110.4118748 m 0.2605430 0.0942001 Correlation: A B m A 1.00000000 0.04048633 0.1151000 B 0.04048633 1.00000000 0.8225566 m 0.11509996 0.82255665 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 2457.1412313 2610.5056190 2773.4423646 B 927.7403439 1131.7044406 1380.5101278 m 0.1247496 0.2605430 0.5441513 Residual standard error: lower est. upper 314.8342 391.4927 517.8247 Degrees of freedom: 35 total; 32 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 1.095 with 1 degrees of freedom. P = 0.295 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 20 2650 2610.506 411 385.8967 0.45769820 2 0.1 5 2413 2572.474 111 379.8508  0.93877615 3 7.5 5 1346 1341.244 236 195.8061 0.05430863 DDVP: Repeated, RBC, Adult, Historical controls Page 40 of 57 4 15.0 5 1159 1161.395 155 173.2784  0.03091094  BMD Computation BMD = 0.7455: BMDL = 0.4982  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.2605 se: 0.0942 var= se^ 2: 0.008874 Per cent. of background at unit dose: 77 Per cent. of background at the highest dose: 2 ED50 ( 95% CI): 2.66 ( 1.31 , 5.404 )

ln( Potency)  1.345 se[ log( Potency)]: 0.3616 se[ log( Potency)]^ 2: 0.1307 DDVP: Repeated, Brain, Pup, Concurrent controls Page 41 of 57 DDVP: 7 D: BRAIN: F: WHOLE Mon Apr 24 21: 43: 59 2006 MRID: MDPupconc Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power Highest 1 doses dropped from data set.

The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 39.29316 41.41732  16.64658 Coefficients: Value Std. Error A 5.8381055 0.33369886 m 0.1111981 0.01312090 Correlation: A m A 1.0000000 0.5883474 m 0.5883474 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 5.15992657 5.8381055 6.6054187 m 0.08617663 0.1111981 0.1434846 Residual standard error: lower est. upper 0.8565106 1.1814689 1.9033966 Degrees of freedom: 15 total; 13 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 5.215 with 1 degrees of freedom. P = 0.0224 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 5 6.59 5.838105 0.59 1.0482540 1.60389304 2 0.1 5 5.02 5.773546 0.46 1.0365378  1.62558583 3 7.5 5 2.54 2.535575 0.54 0.4511931 0.02192763 DDVP: Repeated, Brain, Pup, Concurrent controls Page 42 of 57  BMD Computation BMD = 0.9475: BMDL = 0.7935  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.1112 se: 0.01312 var= se^ 2: 0.0001722 Per cent. of background at unit dose: 89 Per cent. of background at the highest dose: 43 ED50 ( 95% CI): 6.233 ( 4.946 , 7.855 )

ln( Potency)  2.196 se[ log( Potency)]: 0.118 se[ log( Potency)]^ 2: 0.01392 DDVP: Repeated, Brain, Pup, Concurrent controls Page 43 of 57 DDVP: 7 D: BRAIN: M: WHOLE Mon Apr 24 21: 44: 06 2006 MRID: MDPupconc Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power Highest 1 doses dropped from data set.

The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 38.62180 40.74595  16.31090 Coefficients: Value Std. Error A 6.2176817 0.33406064 m 0.1201434 0.01231365 Correlation: A m A 1.000000 0.589248 m 0.589248 1.000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 5.53629700 6.2176817 6.9829285 m 0.09628064 0.1201434 0.1499205 Residual standard error: lower est. upper 0.8659536 1.1944947 1.9243816 Degrees of freedom: 15 total; 13 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 7.004 with 1 degrees of freedom. P = 0.00813 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 5 7.09 6.217682 0.64 1.0494073 1.85872816 2 0.1 5 5.27 6.143427 0.44 1.0367170  1.88387271 3 7.5 5 2.53 2.525203 0.41 0.4213597 0.02545729 DDVP: Repeated, Brain, Pup, Concurrent controls Page 44 of 57  BMD Computation BMD = 0.877: BMDL = 0.7504  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.1201 se: 0.01231 var= se^ 2: 0.0001516 Per cent. of background at unit dose: 89 Per cent. of background at the highest dose: 41 ED50 ( 95% CI): 5.769 ( 4.719 , 7.053 )

ln( Potency)  2.119 se[ log( Potency)]: 0.1025 se[ log( Potency)]^ 2: 0.0105 DDVP: Repeated, Brain, Pup, Historical controls Page 45 of 57 DDVP: 7 D: BRAIN: F: WHOLE Mon Apr 24 21: 44: 12 2006 MRID: MDPuphist Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 91.73904 98.07312  41.86952 Coefficients: Value Std. Error A 5.4535860 0.20843990 B 1.3874190 0.37759636 m 0.1686908 0.05235096 Correlation: A B m A 1.0000000 0.0969725 0.1952096 B 0.0969725 1.0000000 0.9213612 m 0.1952096 0.9213612 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 5.04558081 5.4535860 5.8945841 B 0.79750815 1.3874190 2.4136825 m 0.08971903 0.1686908 0.3171746 Residual standard error: lower est. upper 0.867120 1.075062 1.415080 Degrees of freedom: 36 total; 33 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.7522 with 1 degrees of freedom. P = 0.386 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 21 5.54 5.453586 1.18 1.0587084 0.374039299 2 0.1 5 5.02 5.385569 0.46 1.0451764  0.782104088 3 7.5 5 2.54 2.534843 0.54 0.4881430 0.023622823 DDVP: Repeated, Brain, Pup, Historical controls Page 46 of 57 4 15.0 5 1.71 1.711208 0.22 0.3342521  0.008084159  BMD Computation BMD = 0.8537: BMDL = 0.6228  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.1687 se: 0.05235 var= se^ 2: 0.002741 Per cent. of background at unit dose: 84 Per cent. of background at the highest dose: 8 ED50 ( 95% CI): 4.109 ( 2.237 , 7.549 )

ln( Potency)  1.78 se[ log( Potency)]: 0.3103 se[ log( Potency)]^ 2: 0.09631 DDVP: Repeated, Brain, Pup, Historical controls Page 47 of 57 DDVP: 7 D: BRAIN: M: WHOLE Mon Apr 24 21: 44: 18 2006 MRID: MDPuphist Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 90.63050 97.28474  41.31525 Coefficients: Value Std. Error A 5.6883165 0.17732604 B 1.1782553 0.33427136 m 0.1610776 0.03905932 Correlation: A B m A 1.0000000 0.1065217 0.2028358 B 0.1065217 1.0000000 0.9324765 m 0.2028358 0.9324765 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 5.33981535 5.6883165 6.059562 B 0.66276419 1.1782553 2.094690 m 0.09850411 0.1610776 0.263400 Residual standard error: lower est. upper 0.7834716 0.9634302 1.2514578 Degrees of freedom: 39 total; 36 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.8159 with 1 degrees of freedom. P = 0.366 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 24 5.76 5.688316 1.05 0.9517421 0.36898250 2 0.1 5 5.27 5.616251 0.44 0.9394402  0.82415231 3 7.5 5 2.53 2.525726 0.41 0.4194838 0.02278489 DDVP: Repeated, Brain, Pup, Historical controls Page 48 of 57 4 15.0 5 1.58 1.580839 0.21 0.2660983  0.00704853  BMD Computation BMD = 0.837: BMDL = 0.6514  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.1611 se: 0.03906 var= se^ 2: 0.001526 Per cent. of background at unit dose: 85 Per cent. of background at the highest dose: 8.9 ED50 ( 95% CI): 4.303 ( 2.675 , 6.921 )

ln( Potency)  1.826 se[ log( Potency)]: 0.2425 se[ log( Potency)]^ 2: 0.0588 DDVP: Repeated, RBC, Pup, Concurrent controls Page 49 of 57 DDVP: 7 D: RBC: F: WHOLE Mon Apr 24 21: 44: 03 2006 MRID: MDPupconc Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 282.2902 286.2732  137.1451 Coefficients: Value Std. Error A 3367.8252655 128.82707749 B 1182.3605015 84.42210176 m 0.2942281 0.06693016 Correlation: A B m A 1.00000000 0.05726548 0.1789545 B 0.05726548 1.00000000 0.7844004 m 0.17895453 0.78440045 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 3106.7025997 3367.8252655 3650.8956538 B 1017.0123351 1182.3605015 1374.5913469 m 0.1820754 0.2942281 0.4754635 Residual standard error: lower est. upper 305.9931 407.7801 611.3211 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.1602 with 1 degrees of freedom. P = 0.689 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 5 3418 3367.825 470 401.9922 0.27909526 2 0.1 5 3254 3304.460 257 394.2670  0.28617896 3 7.5 5 1424 1422.897 201 169.0092 0.01459009 DDVP: Repeated, RBC, Pup, Concurrent controls Page 50 of 57 4 15.0 5 1208 1208.834 145 144.7334  0.01289216  BMD Computation BMD = 0.5688: BMDL = 0.427  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.2942 se: 0.06693 var= se^ 2: 0.00448 Per cent. of background at unit dose: 75 Per cent. of background at the highest dose: 1.2 ED50 ( 95% CI): 2.356 ( 1.508 , 3.679 )

ln( Potency)  1.223 se[ log( Potency)]: 0.2275 se[ log( Potency)]^ 2: 0.05175 DDVP: Repeated, RBC, Pup, Concurrent controls Page 51 of 57 DDVP: 7 D: RBC: M: WHOLE Mon Apr 24 21: 44: 10 2006 MRID: MDPupconc Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 284.3103 288.2933  138.1552 Coefficients: Value Std. Error A 3405.8244474 134.5531824 B 1265.5873297 82.6795659 m 0.3447276 0.0992573 Correlation: A B m A 1.00000000 0.05821642 0.1595949 B 0.05821642 1.00000000 0.7517474 m 0.15959491 0.75174742 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 3133.4511572 3405.8244474 3701.8736162 B 1102.6365176 1265.5873297 1452.6194839 m 0.1877810 0.3447276 0.6328497 Residual standard error: lower est. upper 317.7069 423.3904 634.7231 Degrees of freedom: 20 total; 17 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.6739 with 1 degrees of freedom. P = 0.412 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 5 3299 3405.824 353 418.5584  0.57068917 2 0.1 5 3441 3333.302 484 410.1457 0.58715849 DDVP: Repeated, RBC, Pup, Concurrent controls Page 52 of 57 3 7.5 5 1423 1426.879 186 177.3018  0.04892138 4 15.0 5 1280 1277.743 146 155.8875 0.03238133  BMD Computation BMD = 0.5028: BMDL = 0.3509  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.3447 se: 0.09926 var= se^ 2: 0.009852 Per cent. of background at unit dose: 71 Per cent. of background at the highest dose: 0.57 ED50 ( 95% CI): 2.011 ( 1.144 , 3.535 )

ln( Potency)  1.065 se[ log( Potency)]: 0.2879 se[ log( Potency)]^ 2: 0.0829 DDVP: Repeated, RBC, Pup, Historical controls Page 53 of 57 DDVP: 7 D: RBC: F: WHOLE Mon Apr 24 21: 44: 16 2006 MRID: MDPuphist Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 471.1821 477.1681  231.5910 Coefficients: Value Std. Error A 3212.0118304 78.13348301 B 1175.9601007 84.40054910 m 0.2793221 0.06360987 Correlation: A B m A 1.00000000 0.03961674 0.1212268 B 0.03961674 1.00000000 0.7972136 m 0.12122680 0.79721362 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 3056.3407841 3212.0118304 3375.6117944 B 1015.6286087 1175.9601007 1361.6022102 m 0.1754370 0.2793221 0.4447228 Residual standard error: lower est. upper 301.6668 377.5026 504.5976 Degrees of freedom: 33 total; 30 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 0.4548 with 1 degrees of freedom. P = 0.5 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 18 3185 3212.012 377 372.5099  0.30764682 2 0.1 5 3254 3155.927 257 366.1959 0.59885197 3 7.5 5 1424 1426.559 201 166.5420  0.03435202 DDVP: Repeated, RBC, Pup, Historical controls Page 54 of 57 4 15.0 5 1208 1206.804 145 139.2642 0.01920492  BMD Computation BMD = 0.6147: BMDL = 0.4647  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.2793 se: 0.06361 var= se^ 2: 0.004046 Per cent. of background at unit dose: 76 Per cent. of background at the highest dose: 1.5 ED50 ( 95% CI): 2.482 ( 1.588 , 3.878 )

ln( Potency)  1.275 se[ log( Potency)]: 0.2277 se[ log( Potency)]^ 2: 0.05186 DDVP: Repeated, RBC, Pup, Historical controls Page 55 of 57 DDVP: 7 D: RBC: M: WHOLE Mon Apr 24 21: 44: 21 2006 MRID: MDPuphist Guideline: NONGUIDELINE Continuous Exponential Model ( Decreasing) Formula: chei = B + ( A B)* exp(( m* dose)^ g)

Variance Function: power The BMD corresponds to a dose that results in a 10% reduction in the response relative to the control  Summary of Model Fitting Results AIC BIC logLik 508.6161 514.8375  250.3081 Coefficients: Value Std. Error A 3229.7438903 83.54133448 B 1259.4597968 88.49275967 m 0.3240709 0.09828153 Correlation: A B m A 1.00000000 0.03616319 0.1024154 B 0.03616319 1.00000000 0.7630263 m 0.10241540 0.76302628 1.0000000 Approximate 95% confidence intervals Coefficients: lower est. upper A 3063.9809484 3229.7438903 3404.4746923 B 1091.5109432 1259.4597968 1453.2506428 m 0.1747259 0.3240709 0.6010671 Residual standard error: lower est. upper 355.8975 442.5545 585.3637 Degrees of freedom: 35 total; 32 residual  Goodness of Fit The chi squared goodness of fit values should be taken as general indications of fit only. P values are likely to be inaccurate to some degree Pearson Chi Square Statistic: 2.812 with 1 degrees of freedom. P = 0.0936 dose n chei Expected sd Exp. SD X2 Resid. 1 0.0 20 3162 3229.744 385 415.0112  0.7300042 2 0.1 5 3441 3166.916 484 407.7138 1.5031865 3 7.5 5 1423 1432.825 186 187.6611  0.1170705 DDVP: Repeated, RBC, Pup, Historical controls Page 56 of 57 4 15.0 5 1280 1274.714 146 161.4604 0.0732030  BMD Computation BMD = 0.5525: BMDL = 0.3825  Potency Measures A unit dose ( 1 mg/ kg) would result in 100* exp( Potency)% of background activity Potency: 0.3241 se: 0.09828 var= se^ 2: 0.009659 Per cent. of background at unit dose: 72 Per cent. of background at the highest dose: 0.77 ED50 ( 95% CI): 2.139 ( 1.18 , 3.876 )

ln( Potency)  1.127 se[ log( Potency)]: 0.3033 se[ log( Potency)]^ 2: 0.09197 DDVP: Repeated, RBC, Pup, Historical controls Page 57 of 57


[Federal Register Volume 81, Number 62 (Thursday, March 31, 2016)]
[Notices]
[Page 18617]
[FR Doc No: 2016-07249]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. ER16-1132-000]

DifWind Farms Limited V; Supplemental Notice That Initial Market-
Based Rate Filing Includes Request for Blanket Section 204
Authorization

    This is a supplemental notice in the above-referenced proceeding of
DifWind Farms Limited V's application for market-based rate authority,
with an accompanying rate tariff, noting that such application includes
a request for blanket authorization, under 18 CFR part 34, of future
issuances of securities and assumptions of liability.
    Any person desiring to intervene or to protest should file with the
Federal Energy Regulatory Commission, 888 First Street NE., Washington,
DC 20426, in accordance with Rules 211 and 214 of the Commission's
Rules of Practice and Procedure (18 CFR 385.211 and 385.214). Anyone
filing a motion to intervene or protest must serve a copy of that
document on the Applicant.
    Notice is hereby given that the deadline for filing protests with
regard to the applicant's request for blanket authorization, under 18
CFR part 34, of future issuances of securities and assumptions of
liability, is April 11, 2016.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper, using the FERC Online links at http://www.ferc.gov. To facilitate electronic service, persons with Internet
access who will eFile a document and/or be listed as a contact for an
intervenor must create and validate an eRegistration account using the
eRegistration link. Select the eFiling link to log on and submit the
intervention or protests.
    Persons unable to file electronically should submit an original and
5 copies of the intervention or protest to the Federal Energy
Regulatory Commission, 888 First Street NE., Washington, DC 20426.
    The filings in the above-referenced proceeding are accessible in
the Commission's eLibrary system by clicking on the appropriate link in
the above list. They are also available for electronic review in the
Commission's Public Reference Room in Washington, DC. There is an
eSubscription link on the Web site that enables subscribers to receive
email notification when a document is added to a subscribed docket(s).
For assistance with any FERC Online service, please email
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For
TTY, call<PHONE_NUMBER>.

    Dated: March 22, 2016.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2016-07249 Filed 3-30-16; 8:45 am]
 BILLING CODE 6717-01-P


[Federal Register: January 22, 2007 (Volume 72, Number 13)]
[Notices]
[Page 2684-2685]
[DOCID:fr22ja07-63]

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ENVIRONMENTAL PROTECTION AGENCY

[FRL-8271-5; Docket ID No. EPA-HQ-ORD-2006-0812]

Child-Specific Exposure Factors Handbook

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of Re-opening of Public Comment Period.

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SUMMARY: EPA is re-opening the public comment period for the draft
document titled, ``Child-Specific Exposure Factors Handbook'' (EPA/600/
R-06/096A). The document was prepared by the National Center for
Environmental Assessment within EPA's Office of Research and
Development.
    On October 6, 2006, EPA published a Federal Register notice (71 FR
59107) announcing a 60-day public comment period that ended December 5,
2006. EPA is re-opening the public comment period for an additional 30
days in response to requests to extend the comment period.

    The Child-Specific Exposure Factors Handbook provides a summary of
statistical data on various exposure factors used in assessing
children's exposures. This Handbook serves as a resource for exposure
assessors for calculating children's exposures. These factors include:
drinking water consumption, soil ingestion and mouthing behavior,
inhalation rates, dermal factors including skin surface area and soil
adherence factors, consumption of retail and home-grown foods, breast
milk intake, and activity pattern data. An interim final version of
this handbook was published in 2002. The updated version provides
analysis of exposure factors data using the age groups for children as
recommended in the EPA document entitled, ``Guidance on Selecting Age
Groups for Monitoring and Assessing Childhood Exposures to
Environmental Contaminants'' (EPA/630/P-03/003F) (Available on line at
http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=146583).

    As previously stated in 71 FR 59107, EPA is releasing the draft
``Child-Specific Exposure Factors Handbook'' solely for the purpose of
pre-dissemination peer review under applicable information quality
guidelines. This document has not been formally disseminated by EPA. It
does not represent and should not be construed to represent any Agency
policy or determination. EPA will consider any public comments
submitted in accordance with this notice when revising the document.

DATES: The 30-day public comment period begins January 22, 2007, and
ends February 21, 2007. Technical comments should be in writing and
must be received by EPA by February 21, 2007.

ADDRESSES: The draft, ``Child-Specific Exposure Factors Handbook,'' is
available primarily via the Internet on the National Center for
Environmental Assessment's home page under the Recent Additions and the
Data and Publications menus at http://www.epa.gov/ncea. A limited

number of paper copies are available from the Technical Information
Staff, NCEA-W; telephone:<PHONE_NUMBER>; facsimile:<PHONE_NUMBER>. If you
are requesting a paper copy, please provide your name, your mailing
address, and the document title, ``Child-Specific Exposure Factors
Handbook'' (EPA/600/R-06/096A).
    Comments may be submitted electronically via http://www.regulations.gov
, by mail, by facsimile, or by hand delivery/

courier. Please follow the detailed instructions provided in the
SUPPLEMENTARY INFORMATION section of this notice.

FOR FURTHER INFORMATION CONTACT: For information on the public comment
period, contact the Office of Environmental Information Docket;
telephone:<PHONE_NUMBER>; facsimile:<PHONE_NUMBER>; or e-mail:
<EMAIL_ADDRESS>
    For technical information, contact Jacqueline Moya, NCEA;
telephone:<PHONE_NUMBER>; facsimile:<PHONE_NUMBER>; or e-mail:
<EMAIL_ADDRESS>

SUPPLEMENTARY INFORMATION:

How To Submit Technical Comments to the Docket at http://www.regulations.gov

    Submit your comments, identified by Docket ID No. EPA-HQ-ORD-2006-
0812 by one of the following methods:
     http://www.regulations.gov: Follow the on-line

instructions for submitting comments.
     E-mail<EMAIL_ADDRESS>     Fax:<PHONE_NUMBER>.
     Mail: Office of Environmental Information (OEI) Docket
(Mail Code: 2822T), U.S. Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington, DC 20460. The phone number is 202-
566-1752.
     Hand Delivery: The OEI Docket is located in the EPA
Headquarters Docket Center, Room 3334, EPA West Building, 1301
Constitution Ave., NW., Washington, DC. The EPA Docket Center Public
Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through
Friday, excluding legal holidays. The telephone number for the Public
Reading Room is<PHONE_NUMBER>. Such deliveries are only accepted during
the docket's normal hours of operation, and special arrangements should
be made for deliveries of boxed information.
    If you provide comments by mail or hand delivery, please submit one
unbound original with pages numbered consecutively, and three copies of
the comments. For attachments, provide an index, number pages
consecutively with the comments, and submit an unbound original and
three copies.
    Instructions: Direct your comments to Docket ID No. EPA-HQ-ORD-
2006-0812. Please ensure that your comments are submitted within the
specified comment period. Comments received after the closing date will
be marked ``late,'' and may only be considered if time permits. It is
EPA's policy to include all comments it receives in the public docket
without change and to make the comments available online at http://www.regulations.gov
, including any personal information provided,

unless a comment includes information claimed to be Confidential
Business Information (CBI) or other information whose disclosure is
restricted by statute. Do not submit information that you consider to
be CBI or otherwise protected through http://www.regulations.gov or e-mail.

The http://www.regulations.gov Web site is an ``anonymous access'' system,

which means EPA will not know your identity or contact information
unless you provide it in the body of your comment. If you send an e-
mail comment directly to EPA without going through http://www.regulations.gov,

your e-mail address will be automatically captured and included as part
of the comment that is placed in the public docket and made available
on the Internet. If you submit an electronic comment, EPA recommends
that you include your name and other contact information in the body of
your comment and with any disk or CD-ROM you submit. If EPA cannot read
your comment due to technical difficulties and cannot contact you for
clarification, EPA may not be able to consider your comment. Electronic
files should avoid the use of special characters, any form of
encryption, and be free of any defects or viruses.
    For additional information about EPA's public docket visit the EPA
Docket Center homepage at http://www.epa.gov/epahome/dockets.htm.

    Docket: Documents in the docket are listed in the
http://www.regulations.gov index. 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 materials,
such as copyrighted material, are publicly available only in hard copy.
Publicly available docket materials are available either electronically
in http://www.regulations.gov or in hard copy at the OEI Docket in the EPA

Headquarters Docket Center.

    Dated: January 12, 2007.
George Alapas,
Acting Director, National Center for Environmental Assessment.
[FR Doc. E7-827 Filed 1-19-07; 8:45 am]

BILLING CODE 6560-50-P