[Federal Register: September 4, 2008 (Volume 73, Number 172)]
[Notices]
[Page 51678-51681]
[DOCID:fr04se08-73]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-58430; File No. SR-NYSE-2008-76]

Self-Regulatory Organizations; Notice of Filing of Proposed Rule
Change by New York Stock Exchange LLC Amending NYSE Rule 2B in Order To
Establish Procedures Designed To Manage Potential Informational
Advantages Resulting From the Affiliation Between the Exchange and
Archipelago Securities L.L.C.

August 27, 2008.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(``Act'') \1\ and Rule 19b-4 thereunder,\2\ notice is hereby given that
on August 20, 2008, New York Stock Exchange LLC (``NYSE'' or the
``Exchange'') filed with the Securities and Exchange Commission
(``Commission'') the proposed rule change as described in Items I, II
and III below, which Items have been prepared by the self-regulatory
organization. The Commission is publishing this notice to solicit
comments on the proposed rule change from interested persons.
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    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
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I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange proposes to amend Exchange Rule 2B in order to
establish procedures designed to manage potential informational
advantages resulting from the affiliation between the Exchange and
Archipelago Securities L.L.C., an NYSE affiliated member. The text of
the proposed rule change is available at the Exchange, the Commission's
Public Reference Room, and http://www.nyse.com.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the self-regulatory organization
included statements concerning the purpose of,

and basis for, the proposed rule change and discussed any comments it
received on the proposed rule change. The text of those statements may
be examined at the places specified in Item IV below. The Exchange has
prepared summaries, set forth in sections A, B, and C below, of the
most significant parts of such statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

1. Purpose
    On February 13, 2008, NYSE Arca Inc. (``NYSE Arca'') filed with the
Commission a proposed rule change to amend NYSE Arca Rule 7.31(x) (the
``PO Plus Proposal'').\3\ NYSE Arca filed that rule change as a ``non-
controversial'' proposed rule change pursuant to Section 19(b)(3)(A)
\4\ of the Act and Rule 19b-4(f)(6) \5\ thereunder, which rendered it
effective upon filing with the Commission. On April 11, 2008, the
Commission issued an order abrogating NYSE Arca's PO Plus Proposal (the
``Abrogation Order'').\6\
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    \3\ See Securities Exchange Act Release No. 57377 (Feb. 25,
2008), 73 FR 11177 (February 29, 2008) (SR-NYSEArca-2008-19).
    \4\ 15 U.S.C. 78s(3)(A).
    \5\ 17 CFR 240.19b-4.
    \6\ See Securities Exchange Act Release No. 57648 (Apr. 11,
2008), 73 FR 20981 (April 17, 2008) (SR-NYSEArca-2008-19) (order
abrogating NYSE Arca Rule 7.31(x)).
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    In the Abrogation Order, the Commission noted its concern regarding
(i) the potential for conflicts of interest in instances where a member
firm is affiliated with an exchange to which it is routing orders and
(ii) the potential for informational advantages that could place an
affiliated member of an exchange at a competitive advantage vis-
[agrave]-vis other non-affiliated members.\7\
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    \7\ Id.
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    The Exchange is submitting this proposed rule change in order to
address the Commission's concerns and clarify the Exchange's procedures
regarding affiliated members.
a. NYSE Arca's Proposed PO Plus Order
    According to its recent rule filing, NYSE Arca proposes to amend
its Primary Only (``PO'') Order. The PO Order is a market or limit
order that is routed to the primary, listing market, without sweeping
the NYSE Arca book.\8\ NYSE Arca Users submit the PO Order to NYSE
Arca. In turn, NYSE Arca passes the PO Order to Archipelago Securities
L.L.C. (``Arca Securities''), its outbound order routing facility. Arca
Securities routes the PO Order to the primary, listing market. PO
Orders are thus a form of directed order, an order type that is
commonly offered by exchanges and other market centers to enable firms
to discharge their obligations under Regulation NMS and other rules.\9\
According to its filing, NYSE Arca intends to offer this order type,
modified as PO Plus, for entry and execution throughout the trading
day. Of course, by its definition, PO Orders may be routed by Arca
Securities (upon instruction from NYSE Arca) to the NYSE in those
instances where the NYSE is the primary, listing exchange.
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    \8\ See NYSE Arca Equities Rule 7.31(x).
    \9\ NYSE Arca's proposed PO Plus functionality is substantially
similar to the ``Directed Order'' type currently offered by The
NASDAQ Stock Market LLC (``Nasdaq''), which allows Nasdaq members to
enter orders to be routed to a user-designated market center other
than Nasdaq, without first interacting with the Nasdaq order book.
See Securities Exchange Act Release No. 55405 (March 6, 2007), 72 FR
11069 (March 12, 2007) (SR-NASDAQ-2007-020).
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b. Order Routing and Existing NYSE Rules
    NYSE Rule 2B provides, in pertinent part, that:

    Without prior SEC approval, the Exchange or any entity with
which it is affiliated shall not, directly or indirectly, acquire or
maintain an ownership interest in a member organization. (Emphasis
added.)

    Arca Securities is the approved outbound routing facility of NYSE
Arca. In its Order approving the merger of the Archipelago Exchange
(``ArcaEx'') with the Pacific Exchange (the ``PCX''),\10\ the
Commission permitted ArcaEx's holding company, Archipelago Holdings,
Inc. (``Archipelago''), to own and operate Arca Securities, in its
capacity as a facility of the PCX that routes orders from ArcaEx to
other market centers.\11\ This approval remains in effect insofar as
Arca Securities acts in the capacity of a facility of NYSE Arca for the
routing of orders from NYSE Arca to other market centers, including the
NYSE, subject to the applicable conditions.\12\ Although Arca
Securities was required to discontinue its operation of the DOT
function in connection with the Archipelago/NYSE merger, no
restrictions other than those previously described were requested or
imposed by the Commission with respect to Arca Securities' continuing
role as an outbound router for NYSE Arca.\13\
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    \10\ Following the ArcaEx-PCX merger, Archipelago merged with
the NYSE and the PCX was later renamed NYSE Arca.
    \11\ See Securities Exchange Act Release No. 52497 (September
22, 2005), 70 FR 56949 (September 29, 2005) (order approving SR-PCX-
2005-90). The Commission's approval was subject to several
conditions and undertakings, specifically that: (1) Arca Securities
would continue to operate and be regulated as a facility of the PCX;
(2) the scope of the exception would be limited to outbound routing;
(3) the primary regulatory responsibility for Arca Securities would
lie with an unaffiliated SRO; and (4) the continued use of Arca
Securities for outbound routing would remain optional for other PCX
members.
    \12\ Id.
    \13\ For purposes of inbound orders in general and NYSE Arca's
proposed amendment in particular, the Exchange believes that there
is no functional difference between inbound orders routed by Arca
Securities that previously scrape the NYSE Arca book and the PO
Order, which do not. Each type of order is subject to the same
principles governing NYSE Arca's authority to send, and the
Exchange's authority to receive, orders routed via Arca Securities.
As clarified herein, appropriate procedures are in place to manage
any potential conflicts of interest or potential information
advantages.
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    Arca Securities performs a similar outbound routing function on
behalf of the NYSE. On April 5, 2007, in a notice of immediate
effectiveness, the Commission published the NYSE's rule change that
established Arca Securities as a facility of the NYSE for purposes of
routing orders to away market centers for execution in compliance with
NYSE Rules and Regulation NMS.\14\ Pursuant to NYSE Rule 17, Arca
Securities receives its routing instructions from the NYSE and reports
any such executions back to the NYSE.\15\ Arca Securities has no
discretion and cannot change the terms of an order or the routing
instructions.\16\ Moreover, each type of order is subject to the same
principles governing the Exchange's authority to route orders to away
market centers, namely: Use of Arca Securities for outbound routing is
only available to--and is optional for--NYSE Members, the primary
regulatory responsibility for Arca Securities lies with an unaffiliated
SRO, and, as clarified herein, appropriate procedures are in place to
manage any conflicts of interest or potential information advantages.
In this capacity as a facility of the NYSE, Arca Securities receives
the routing instructions from the NYSE and routes the orders to various
away market centers, including NYSE Arca, for execution.
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    \14\ See Securities Exchange Act Release No. 55590 (April 5,
2007), 72 FR 18707 (April 13, 2007) (notice of immediate
effectiveness of SR-NYSE-2007-29).
    \15\ See NYSE Rule 17(b)(1).
    \16\ Id.
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c. Record Keeping
    As mentioned above, in the Abrogation Order, the Commission noted
the potential for conflicts of interest in instances where a member
firm is affiliated with an exchange to which it is routing orders.
    In order to manage these concerns, with respect to orders routed to
NYSE by Arca Securities, an NYSE member, in its capacity as a facility
of NYSE Arca,

the Exchange notes that Arca Securities is subject to independent
oversight and enforcement by the Financial Industry Regulatory
Authority (``FINRA''), an unaffiliated self-regulatory organization
(``SRO'') that is Arca Securities' designated examining authority. In
this capacity, FINRA is responsible for examining Arca Securities with
respect to its books and records and capital obligations, and shares
with NYSE Regulation, Inc. (``NYSE Regulation'') the responsibility for
reviewing Arca Securities' compliance with intermarket trading rules
such as SEC Regulation NMS. In addition, through an agreement between
FINRA and the NYSE pursuant to the provisions of Rule 17d-2 under the
Act, FINRA's staff reviews for Arca Securities' compliance with other
NYSE rules through FINRA's examination program. NYSE Regulation
monitors Arca Securities for compliance with NYSE trading rules,
subject, of course, to SEC oversight of NYSE Regulation's regulatory
program.
    In order to alleviate any residual concerns the Commission may have
regarding the potential for conflicts of interest, the Exchange notes
that NYSE Regulation has agreed with the Exchange that it will collect
and maintain the following information of which NYSE Regulation staff
becomes aware--namely, all alerts, complaints, investigations and
enforcement actions where Arca Securities (in its capacity as a
facility of NYSE Arca, routing orders to the NYSE) is identified as a
participant that has potentially violated NYSE or applicable SEC
rules--in an easily accessible manner, so as to facilitate any review
conducted by the SEC's Office of Compliance Inspections and
Examinations. NYSE Regulation has further agreed with the Exchange that
it will provide a report to the Exchange's Chief Regulatory Officer, on
at least a quarterly basis, which: (i) Quantifies all alerts (of which
NYSE Regulation is aware in its tracking system) that identify Arca
Securities as a participant that has potentially violated NYSE or SEC
rules and (ii) quantifies the number of all investigations that
identify Arca Securities as a participant that has potentially violated
NYSE or SEC rules.\17\
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    \17\ The Exchange, NYSE Regulation, and SEC staff, may agree
going forward to reduce the number of applicable or relevant
surveillances that form the scope of the agreed upon report.
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d. New Policies and Procedures.
    Finally, in the Abrogation Order, the Commission noted the
potential for informational advantages that could place an affiliated
member of an exchange at a competitive advantage vis-[agrave]-vis other
non-affiliated members.
    In response to this concern, with respect to Arca Securities being
an affiliated member of the NYSE, the Exchange is proposing to amend
Exchange Rule 2B. As amended, Exchange Rule 2B will require the
implementation of policies and procedures that are reasonably designed
to prevent Arca Securities from acting on non-public information
regarding NYSE systems prior to the time that such information is made
available generally to all NYSE members performing inbound order
routing functions. These policies and procedures would include systems
development protocols to facilitate an audit of the efficacy of these
policies and procedures.
    Specifically, Exchange Rule 2B shall provide as follows:

    The holding company owning both the Exchange and Archipelago
Securities LLC shall establish and maintain procedures and internal
controls reasonably designed to ensure that Archipelago Securities,
L.L.C. does not develop or implement changes to its system on the
basis of non-public information regarding planned changes to
Exchange systems, obtained as a result of its affiliation with the
Exchange, until such information is available generally to similarly
situated members of the Exchange in connection with the provision of
inbound order routing to the Exchange.

    The Exchange believes these measures will effectively address the
concerns identified by the Commission regarding the potential for
informational advantages favoring Arca Securities vis-[agrave]-vis
other non-affiliated NYSE members.
e. Pilot Period
    The Exchange proposes that the Commission authorize the NYSE to
receive inbound routes of PO Plus Orders from Arca Securities for a
pilot period of twelve months from the date of the approval of this
rule filing. The Exchange believes that this pilot period is of
sufficient length to permit both the Exchange and the Commission to
assess the impact of the rule change described herein.
2. Statutory Basis
    The proposed rule change is consistent with Section 6(b) \18\ of
the Act, in general, and furthers the objectives of Section
6(b)(5),\19\ in particular, in that it is designed to prevent
fraudulent and manipulative acts and practices, to promote just and
equitable principles of trade, to foster cooperation and coordination
with persons engaged in facilitating transactions in securities, and to
remove impediments to and perfect the mechanisms of a free and open
market and a national market system.
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    \18\ 15 U.S.C. 78f(b).
    \19\ 15 U.S.C. 78f(b)(5).
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B. Self-Regulatory Organization's Statement on Burden on Competition

    The Exchange does not believe that the proposed rule change will
impose any burden on competition that is not necessary or appropriate
in furtherance of the purposes of the Act.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants or Others

    No written comments were solicited or received with respect to the
proposed rule change.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    Within 35 days of the date of publication of this notice in the
Federal Register or within such longer period (i) as the Commission may
designate up to 90 days of such date if it finds such longer period to
be appropriate and publishes its reasons for so finding or (ii) as to
which the self-regulatory organization consents, the Commission will:
    (A) By order approve the proposed rule change, or
    (B) Institute proceedings to determine whether the proposed rule
change should be disapproved.

IV. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. Comments may be submitted by any of
the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://
www.sec.gov/rules/sro.shtml); or
     Send an e-mail to<EMAIL_ADDRESS>Please include
File Number SR-NYSE-2008-76 on the subject line.

Paper Comments

     Send paper comments in triplicate to Secretary, Securities
and Exchange Commission, 100 F Street, NE., Washington, DC 20549-1090.

    All submissions should refer to File Number SR-NYSE-2008-76. This
file number should be included on the subject line if e-mail is used.
To help the

Commission process and review your comments more efficiently, please
use only one method. The Commission will post all comments on the
Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml).
Copies of the submission, all subsequent amendments, all written
statements with respect to the proposed rule change that are filed with
the Commission, and all written communications relating to the proposed
rule change between the Commission and any person, other than those
that may be withheld from the public in accordance with the provisions
of 5 U.S.C. 552, will be available for inspection and copying in the
Commission's Public Reference Section, 100 F Street, NE., Washington,
DC 20549, on official business days between the hours of 10 a.m. and 3
p.m. Copies of the filing will also be available for inspection and
copying at the principal office of the self-regulatory organization.
All comments received will be posted without change; the Commission
does not edit personal identifying information from submissions. You
should submit only information that you wish to make available
publicly. All submissions should refer to File Number SR-NYSE-2008-76
and should be submitted on or before September 25, 2008.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\20\
Florence E. Harmon,
Acting Secretary.
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    \20\ 17 CFR 200.30-3(a)(12).
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 [FR Doc. E8-20466 Filed 9-3-08; 8:45 am]

BILLING CODE 8010-01-P


[Federal Register Volume 80, Number 95 (Monday, May 18, 2015)]
[Notices]
[Pages 28274-28275]
[FR Doc No: 2015-11847]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-N-0012]

Cooperative Agreement to International Council for Harmonization
of Technical Requirements for Pharmaceuticals for Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of grant funds for the support of the International
Council for Harmonization of Technical Requirements for Pharmaceuticals
for Human Use (ICH). The goal of the ICH is to bring together leading
global drug regulatory agencies and pharmaceutical manufacturer
associations to achieve greater harmonization of technical standards to
ensure that safe, effective, and high-quality medicines are developed
and registered in the most resource-efficient manner.

DATES: The application due date is September 30, 2015. The expiration
date is October 1, 2015.

ADDRESSES: Submit electronic applications to: http://www.grants.gov.
For more information, see section III of the SUPPLEMENTARY INFORMATION
section of this notice.

FOR FURTHER INFORMATION CONTACT: Tracy Porter, Office of Strategic
Programs, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
51, Rm. 1173, Silver Spring, MD 20993,<PHONE_NUMBER>,
<EMAIL_ADDRESS>or Lisa Ko, Office of Acquisitions and Grants
Services, Food and Drug Administration, 5630 Fishers Lane, Rm. 2037,
Rockville, MD 20857,<PHONE_NUMBER><EMAIL_ADDRESS>    For more information on this funding opportunity announcement (FOA)
and to obtain detailed requirements, please refer to the full FOA
located at http://www.grants.gov. Search by Funding Opportunity Number:
RFA-FD-15-014.

SUPPLEMENTARY INFORMATION:

I. Funding Opportunity Description

RFA-FD-15-014
93.103

A. Background

1. Authority
    FDA activities to increase the harmonization of regulatory
requirements to ensure that safe, effective, and high quality medicines
are developed and registered in the most resource-efficient manner are
authorized by 21 U.S.C. 383(c) and 393(b).
2. Program Background
    The ICH is a globally unique venue with the capability of bringing
together the regulatory authorities and pharmaceutical industry to
discuss scientific and technical aspects of drug registration. ICH is a
programmatic global priority for FDA to achieve its identified
strategic priority of globalization. Working through its Center for
Drug Evaluation and Research (CDER) and Center for Biologics Evaluation
and Research, FDA has played a leading role in ICH since its inception
in 1990. ICH, founded to harmonize drug regulatory standards between
three regions, the United States, the European Union, and Japan, has
gradually evolved to respond to the increasingly global face of drug
development, so that the benefits of international harmonization for
better global health can be realized worldwide. ICH's mission is to
achieve greater harmonization to ensure that safe, effective, and high-
quality medicines are developed and registered in the most resource-
efficient manner.
    Over the past 2 years, FDA played a leadership role in transforming
ICH to meet the challenges of 21st century standards development while
firmly positioning ICH future work to continue the focus on technical
standards harmonization informed by relevant expertise from regulatory
agencies and regulated industry. This effort has included: (1)
Establishing ICH as a formal legal entity in the form of a nonprofit
association under Swiss law; (2) expanding the opportunities for formal
participation of other drug regulatory authorities beyond the three
founding regions via the ICH Assembly; and (3) ensuring adequate and
predictable funding for the ICH harmonization work (which is also
critical to FDA's mission).
    FDA remains an ICH founding member and completely committed to ICH
success as a science-based standards development venue to ensure
harmonization globally for safe, effective, and high-quality medicines.
As exemplified in the past 25 years, FDA leadership and participation
is an

absolutely essential element for ICH success.

B. Research Objectives

    The program's grant funds will support the ICH to develop a series
of international guidelines for implementation according to each
region's requirements aimed at achieving the following: (1) Develop and
register safe, effective, and high quality medicines in the most
efficient and cost effective manner; (2) prevent unnecessary
duplication of clinical trials and minimize the use of animal testing
without compromising safety and effectiveness, and (3) provide public
assurance that the rights, safety, and well-being of subjects are
protected during clinical trials.
    The ICH aims to make information readily available on ICH, ICH
activities, and ICH guidelines to any country or company that requests
the information. Additionally, the organization promotes a mutual
understanding of regional initiatives in order to facilitate
harmonization processes related to ICH guidelines regionally and
globally, and to strengthen the capacity of drug regulatory authorities
and industry to utilize the guidelines. These objectives will be
accomplished by bringing together representatives from both regulatory
agencies and pharmaceutic industries from the three founding regions to
establish guidelines.

C. Eligibility Information

    The following organization is eligible to apply: ICH. Within the
ICH, the mission is to make recommendations towards achieving greater
harmonization in the interpretation and application of technical
guidelines and requirements for pharmaceutical product registration,
thereby reducing or obviating duplication of testing carried out during
the research and development of new human medicines. Leveraging its
status as a neutral nonprofit entity focused on technical standards
harmonization, the ICH aims to promote international harmonization of
drug regulatory standards by bringing together representatives from
both regulatory agencies and pharmaceutic industry to discuss and
establish common guidelines.

II. Award Information/Funds Available

A. Award Amount

    FDA intends to fund one award, corresponding to a total of up to
$500,000, for fiscal year (FY) 2016. Future year amounts will depend on
annual appropriations, availability of funding, and awardee
performance. CDER anticipates providing four additional years of
support up to the following amounts:

FY 2017: $500,000
FY 2018: $500,000
FY 2019: $500,000
FY 2020: $500,000

B. Length of Support

    The support will be 1 year with the possibility of an additional 4
years of noncompetitive support. Continuation beyond the first year
will be based on satisfactory performance during the preceding year,
receipt of a noncompeting continuation application and available
Federal FY appropriations.

III. Electronic Application, Registration, and Submission

    Only electronic applications will be accepted. To submit an
electronic application in response to this FOA, applicants should first
review the full announcement located at http://www.grants.gov. (FDA has
verified the Web site addresses throughout this document, but FDA is
not responsible for any subsequent changes to the Web sites after this
document publishes in the Federal Register.) Search by Funding
Opportunity Number: RFA-FD-15-014.
    For all electronically submitted applications, the following steps
are required.

 Step 1: Obtain a Dun and Bradstreet (DUNS) Number
 Step 2: Register With System for Award Management (SAM)
 Step 3: Obtain Username & Password
 Step 4: Authorized Organization Representative (AOR)
Authorization
 Step 5: Track AOR Status
 Step 6: Register With Electronic Research Administration (eRA)
Commons

    Steps 1 through 5, in detail, can be found at http://www07.grants.gov/applicants/organization_registration.jsp. Step 6, in
detail, can be found at https://commons.era.nih.gov/commons/registration/registrationInstructions.jsp. After you have followed
these steps, submit electronic applications to: http://www.grants.gov.

    Dated: May 11, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-11847 Filed 5-15-15; 8:45 am]
 BILLING CODE 4164-01-P


Proposed Electronic Reporting Templates for the Solvent Extraction for Vegetable Oil Production NESHAP in Support of the Risk and Technology Review, June 2018

Contains electronic reporting templates in support of the proposed Solvent Extraction for Vegetable Oil Production Residual Risk and Technology Review.


UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES TXR No. 0053055 MEMORANDUM DATE: June 23, 2005 SUBJECT: Weight of Evidence Comparison of Human and Animal Toxicology Studies and Endpoints for DDVP DP Barcode: 312212 Reregistration Case#: 0310 PC Code: 084001 MRID No.: several TO: Ray Kent, Ph. D., Chief Reregistration Branch 4 Health Effects Division ( 7509C)

FROM: William Dykstra, Ph. D., Toxicologist Reregistration Branch 4 Health Effects Division ( 7509C)

THRU: Susan Hummel, Branch Senior Scientist. Reregistration Branch 4 Health Effects Division ( 7509C)

Dichlorvos is an organophosphate insecticide that is toxic to mammals, including humans, through inhibition of the acetylcholinesterase( s) of the peripheral and/ or central nervous system. The technical registrant for dichlorvos has submitted a number of toxicity studies involving direct dosing of humans to support their contention that humans are no more or less sensitive to the effects of dichlorvos than rats, dogs or other experimental animals. OPP management has requested that, whenever human studies support a risk assessment, HED compare the strengths and weaknesses of the human and animal toxicity studies and present how the human studies " fit in" with the animal studies, i. e., are the human data consistent with animal data in terms of types of effects and effect levels or are there notable differences between animals and humans. Page 2 of 16 P O O H 3 CO OCH 3 Cl Cl This document focuses on three human studies in which humans were intentionally dosed with dichlorvos; a single dose oral study ( MRID 44248802), a repeated dose oral study ( MRID 44248801) and a chronic inhalation study ( MRIDs 45812001, 00060486). The human data are compared with animal data from similar studies, and recommendations for endpoint selection are made based on the most appropriate studies and uncertainty factors. All of the studies are discussed in summary form and then the weight of evidence discussion of endpoint selection follows.

Chemical and Hazard Characterization of Dichlorvos Dichlorvos is a phosphate triester with a molecular formula of C 4 H 7 O 4 PCl 2 and a molecular weight of 221. It is a liquid at room temperature with a relatively high vapor pressure of 0.032 mm ( 30 C).

The high vapor pressure of dichlorvos is the basis for its use as a fumigant for processed food commodities, food warehouses and food handling establishments. Because of its volatility, dichlorvos is also incorporated into resin strips for use at many sites including family homes.

Like most other cholinesterase inhibiting phosphotriesters, dichlorvos is asymmetrical with respect to the ester substituents, with two relatively difficult to hydrolyze methyl groups and a dichlorovinyl " leaving group" which is more readily hydrolyzed and is the group displaced when dichlorvos reacts at the active site of cholinesterases. Many sulfur containing organophosphate cholinesterase inhibitors require metabolic activation to convert an unsubstituted phosphoroussulfur ( P= S) group to an phosphorus oxygen oxon ( P= O) group before inhibition of cholinesterase can occur; however, dichlorvos already exists in the oxon form and needs no activation to inhibit cholinesterases.

Dichlorvos is well absorbed by all routes of exposure and extensively metabolized with excretion of metabolic products occurring mostly in the urine and through exhalation as CO 2 . Absorbed dichlorvos is initially inactivated by an esterase found in plasma and liver. The esterase catalyzes the hydrolysis of dichlorvos to dimethyl phosphate and dichlorovinyl alcohol which spontaneously rearranges to 2,2, dichloroacetaldehyde which is then metabolized further. Dichlorvos may also be inactivated by a glutathione dependent reaction to form desmethyl dichlorvos. The half life of dichlorvos in the blood is very short, 15 minutes or less.

Dichlorvos inhibits plasma, erythrocyte, and brain cholinesterase in a variety of species, but does not cause organophosphate induced delayed neurotoxicity ( OPIDN) in the hen ( MRID 43433501). In acute and 90 day neurotoxicity studies in rats ( MRIDs 42497901, 41004101, there was no neuropathology associated with changes in FOB and motor activity. Subchronic and chronic oral exposures in rats and dogs ( MRIDs 41004701, 41593101) as well as chronic Page 3 of 16 inhalation exposure in rats MRIDs 00057695, 00532569) resulted in significant decreases in plasma, red blood cell and/ or brain cholinesterase activity. Animal toxicity studies do not show evidence of gender susceptibility. Repeated, oral subchronic exposures in male humans was associated with statistically and biologically significant decreases in red blood cell cholinesterase activity ( MRID 44248801). Inhalation exposure in humans over several months was associated with a marginally increased incidence of headaches and red blood cell cholinesterase depression greater than 20% at the highest exposure conditions in the study which was during the winter when indoor exposure was highest. Both headaches and RBC cholinesterase depression occurred in children as well as adults in this study ( MRIDs 45812001, 00060486).

There was no evidence of increased susceptibility following in utero exposure to rats and rabbits as well as pre/ post natal exposure to rats in developmental and reproduction studies ( MRIDs 41802401, 41951501, 42483901). However, increased sensitivity to dichlorvos induced inhibition of brain cholinesterase activity was observed in repeated gavage studies in preweaning rats in comparison to young adult rats ( MRID 46153304). These findings necessitated that a special Food Quality Protection Act ( FQPA) 3x safety factor be retained for assessment of risks ( other than risks from acute exposure) where the endpoint is based on RBC cholinesterase inhibition as a result of repeated exposure. A factor of 3x is considered appropriate since the differences in brain cholinesterase inhibition were minimal. The factor of 3x is not needed for assessing acute risks, since there was no increased sensitivity in brain cholinesterase activity in preweaning rats in comparison to young adults following a single gavage dose of dichlorvos.

Specific Toxicity Studies Single Dose Oral Studies:

A. Human In a single dose human study with DDVP ( MRID 44248802), the NOAEL for RBC cholinesterase depression is 1.0 mg/ kg bw based on the absence of statistically significant ChE depression in 6 fasted young healthy male volunteers administered a 70 mg oral dose of DDVP. In this study, the first cholinesterase measurement was recorded 24 hours after dosing. In another study ( MRID 46153303) on the measurement of RBC and brain ChE activity in pre weaning and adult female rats treated with a single dose of 15 mg/ kg dichlorvos, time course data demonstrate that the time of peak effect for both RBC and brain ChE measurements is 1 3 hours post dosing and that by 24 hours post dosing, RBC cholinesterase activity has recovered to levels similar to the controls ( MRID 46153303). Therefore, the absence of biologically significant RBC ChE depression in the human study may be due to the absence of blood sampling at the time of peak effect ( 1 3 hours), since in the human study, the first measurement did not occur until 24 hours after dosing. Page 4 of 16 B. Animals Single dose comparative cholinesterase studies in preweaning and adult rats which measured both RBC and brain ChE depression at 1 hour following oral exposure were analyzed by a Benchmark Dose ( BMD) procedure ( MRIDs 45805703, 45842301). The BMDS ( Benchmark Dose Software version 1.3.2) model was used to derive the BMD 10 , the estimated dose that results in 10% inhibition of cholinesterase, and the BMDL, the lower 95% confidence interval on the BMD 10 , for the cholinesterase data evaluated. For this analysis, the continuous polynomial model was used with the default option of relative deviation for the benchmark response ( BMR) type. A BMR factor of 0.1 was the basis for BMD and BMDL derivation.

A BMDL of 0.8 mg/ kg based on female brain ChE depression was selected as the lowest value of all the studies available which were analyzed. BMD analysis of studies with pup and adult ChE depression results did not demonstrate any substantial age related numerical differences in BMDL values ( all values were approximately 1 mg/ kg) for either RBC or brain cholinesterase.

Repeated Dose Oral Studies A. Human In a single blind oral study ( MRID 44248801), 6 fasted male volunteers were administered 7 mg of DDVP in corn oil ( equivalent to approximately 0.1 mg/ kg/ d) via capsule daily for 21 days. Three control subjects received corn oil as a placebo. Baseline values for RBC cholinesterase activity for each study participant were determined. After dosing started, RBC cholinesterase activity was monitored on days 2, 4, 7, 9, 11, 14, 16, and 18, then on day 25 or 28 post dosing. No toxicity attributable to administration of DDVP was reported. Mean RBC cholinesterase activity was statistically significantly reduced in treated subjects on days 7, 11, 14, 16, and 18. These values were 8, 10, 14, 14, and 16 percent below the pre dose mean. Although the percent mean depression was less than 20%, the blood samples were not taken until just before the next day's dose, at the point of maximum recovery. Under the conditions of the study, a LOAEL for RBC cholinesterase inhibition was established at 0.1 mg/ kg/ d based on the consistent, statistically significant ChE depression over time, although ChE depression during the study was less than 20%. A NOAEL was not established.

The repeated dose human study has been criticized for a number of reasons including:

1) Too few subjects. There were six treated adult males and three adult males served as placebo controls. All of the treated males responded to some extent to repeated dosing of dichlorvos with a mean response of 16%. If there had been no response, then the argument that there were insufficient subjects might have more merit, however, the Agency has determined that the administered dose is a LOAEL.

2) Use of males only. All subjects were adult males. Animal toxicity studies do not show evidence of gender susceptibility. Page 5 of 16 3) Administration of only a single dose level. A single dose level of 7 mg per person per day was administered for 21 days. This dose resulted in sufficient RBC cholinesterase inhibition that we consider the response to be a LOAEL. If there had been no response, interpretation of the results would have been problematic.

4) Blood sampling did not occur until 24 hours after dosing. This is considered a critical deficiency for the single dose study; however, after 21 days there is a clear response which the Agency considers a LOAEL. If blood had been sampled at 1 3 hours after dosing, RBC cholinesterase inhibition may have been somewhat greater.

B. Animal Comparative cholinesterase ( 7 day rat). In a comparative cholinesterase inhibition study ( MRID 46153304), dichlorvos was administered by gavage in seven daily doses of 0, 0.1, 7.5, or 15 mg/ kg/ day to groups of 5 rats/ sex beginning on either PND 12 ( pre weaning rats) or 42 ( young adults) and animals were sacrificed one hour after the last dose. RBC and brain ChE activities were measured in all animals in each study. In pre weaning rats, tremors were observed in 5/ 5 males and 5/ 5 females at 15 mg/ kg/ day on 3 5 days of the dosing interval. In young adult rats at 15 mg/ kg/ day, tremors were observed in 3/ 5 males and 5/ 5 females on one to four days of the dosing interval. In addition, tremors were seen in one adult male after the last dose of 7.5 mg/ kg/ day. No clinical signs of toxicity were observed in the remaining groups. Dose related inhibition of RBC and brain ChE activities was apparent after repeated dosing in both adult and pre weaning rats. Biologically significant inhibition of RBC enzyme activity (> 50%) occurred at doses of 7.5 and 15 mg/ kg/ day in both sexes of adults and pre weaning and at the low dose for adult animals ( 11 17%). Brain enzyme activity was statistically and biologically inhibited in both sexes at doses of 7.5 and 15 mg/ kg/ day for adults (> 50%) and at all doses for pups (> 20%). The LOAEL for inhibition of RBC cholinesterase was 0.1 mg/ kg/ day and a NOAEL was not identified based on findings in young adults. The LOAEL for inhibition of brain cholinesterase was 0.1 mg/ kg/ day and a NOAEL was not identified based on findings in pre weaning pups.

Subchronic neurotoxicity ( 90 day rat). In a subchronic oral neurotoxicity study ( MRID 42958101), dichlorvos was administered in deionized water to 15 Sprague Dawley rats/ sex/ group at gavage doses of 0, 0.1, 7.5, or 15.0 mg/ kg/ day for 90 days. Within each dose group, 10 rats/ sex were allocated for brain cholinesterase determination and 5 rats/ sex were allocated for neuropathology evaluation. Additionally, blood samples were collected for cholinesterase measurements prestudy and on study weeks 3, 7, and 13 . Five rats/ sex/ dose from the cholinesterase group and 5/ sex/ dose from the neuropathology group were evaluated with the Functional Observational Battery ( FOB) and motor activity tests pretest and on study weeks 3, 7, and 12. Body weight and food consumption were measured weekly.

There was no treatment related mortality. Mean body weight in high dose females was consistently lower than the control ( 11 21%) throughout the study. No body weight effects were observed in any other animals, and there was no treatment related effect on food consumption. Tremors, salivation, exophthalmos, lacrimation, and clear material on the forelimbs were observed Page 6 of 16 in high dose males and females approximately 15 minutes post dosing. Rales, chromodacryorrhea, and red/ yellow/ orange material around the nose and mouth were also seen in high dose rats. Tremors were observed in three mid dose males and nine mid dose females. Generally, the clinical signs occurred during the third week of treatment in the mid dose animals and as early as the first week of dosing and throughout the study in the high dose rats. Cholinesterase activity was decreased in mid and high dose male and female rats as follows: plasma 30 58%; erythrocyte 8 35%; brainstem and brain cortex 10 16%. There were no treatment related effects in the FOB or motor activity tests. No treatment related neurohistopathological lesions and no apparent changes in brain weight or size were observed. Based on decreased cholinesterase activity and clinical cholinergic signs, the LOAEL for dichlorvos is 7.50 mg/ kg and the NOAEL is 0.1 mg/ kg.

Chronic ( One year dog). In a chronic feeding study ( MRID 41593101), groups of 4/ sex/ dose beagle dogs were administered dichlorvos by capsule for 52 weeks at dose levels of 0, 0.1, 1.0 and 3.0 mg/ kg/ day. The 0.1 mg/ kg/ day dose was lowered to 0.05 mg/ kg/ day on day 22 due to the inhibition of plasma cholinesterase noted after 12 days ( plasma cholinesterase was decreased in males ( 21.1%) and females ( 25.7%) at week 2 in the 0.1 mg/ kg/ day group). At time points after week 2, plasma cholinesterase activity was only significantly reduced in males ( 39.1 to 59.2%) and females ( 41.0 to 56.7%) in the mid dose group and in males ( 65.1 to 74.3%) and females ( 61.1 to 74.2%) in the high dose group. Although RBC cholinesterase activity was reduced in males ( 23.6%) and females ( 50.1%) at week 6 in the low dose group, this was believed to be residual effect on RBC cholinesterase of the higher dose of 0.1 mg/ kg/ day. RBC cholinesterase inhibition was not observed in this group after week 6. At time points after week 6, RBC cholinesterase activity was only significantly decreased in males ( 43.0 to 53.9) and females ( 38.0 to 51.9) in the mid dose group and in males ( 81.2 to 86.9%) and females ( 79.2 to 82.5%) in the high dose groups. Brain cholinesterase activity was significantly reduced in males ( 22%) in the mid dose group and in males ( 47%) and females ( 29%) in the high dose group. The NOAEL was 0.05 mg/ kg/ day and the LOAEL was 0.1 mg/ kg/ day based on plasma and RBC cholinesterase inhibition in males and females.

Other animal studies. There are several other animal studies by the oral route in which RBC and plasma cholinesterase were measured: 1) 90 day rat subchronic in rats ( MRID 41004701), LOAEL = 1.5 mg/ kg/ day based on plasma and RBC cholinesterase inhibition, NOAEL = 0.1 mg/ kg/ day; 2) Range finding study for the rabbit developmental study ( MRID 41802401), LOAEL = 1 mg/ kg/ day based on RBC cholinesterase inhibition, NOAEL = 0.1 mg/ kg/ day. Repeated dose ( 28 day) delayed neurotoxicity study in hens ( MRID 43433501), LOAEL = 0.3 mg/ kg/ day based on inhibition of brain cholinesterase, NOAEL = 0.1 mg/ kg/ day.

Long Term Inhalation Exposure Studies A. Humans In a chronic inhalation toxicity ( Arizona II) study ( MRIDs 45812001, 00060486), dichlorvos technical DDVP 20% insecticide resin strips were studied in a residential setting in Tuscon, Page 7 of 16 Arizona. There were 64 human subjects, 29 adults and 35 children, selected as participants in the study which represented 15 families divided by lot into 4 groups as shown in the Table below.

Group Number Subjects Treatment I 4 Families ( J, K, L, Q) 7 adults, 7 children ( ages 2 19) 20% DDVP by weight in 10 inch Vapona insecticide strips II 4 Families ( A, B, H, P) 8 adults, 15 children ( ages 4 17) 20% DDVP resin strips enclosed in a sealed plastic wrapper permeable to DDVP III 4 Families ( C, D, E, F) 7 adults, 10 children ( ages 5 14) 20% DDVP resin strips of reduced dimensions containing the same amount of DDVP as other groups IV 3 Families ( G, M, N) 7 adults, 3 children ( ages 9 17) Non active resin strip having the same dimensions and weight as 10 inch strips in Group I Strips were placed in the homes at the rate of one strip per 1000 cu feet ( label directions) with replacement monthly for all strips for a total duration of 6 months. The number of strips used ranged from 4 to 18 per home. Atmospheric concentrations of DDVP were measured throughout the study. All participants received thorough medical evaluations including plasma and RBC ChE determinations, clinical chemistry evaluations, and physician evaluations. All complaints and symptoms were also recorded.

The human study was not originally designed as a toxicity study, although plasma and RBC cholinesterase measurements were included in the protocol. It appears that the cholinesterase measurements were included as a precaution or perhaps to demonstrate that a labeled use rate ( although high end labeled rate) did not result in cholinesterase depression. The reanalysis of the study was commissioned by the technical registrant almost 35 years after the study took place.

From air concentration data in the published study [ Leary, J. S. et al., Arch. Environ. Health, Volume 29, Dec. 1974] and additional Shell archive records on biochemical and clinical findings, a re analysis of the study comparing DDVP exposure to reported clinical findings was undertaken. The original Leary et al., analysis failed to identify any treatment related clinical signs or ChE toxicity in any of the DDVP treated groups. In the re analysis, the DDVP exposed families were grouped on the basis of measured air concentrations of DDVP over the 6 month exposure period. The new re analysis grouping of the families consisted of Group A ( families A, B, P exposed to Group Average ( Oct Jan): 0.113 µ g/ l), Group B ( families K, L exposed to Group Average ( Oct Jan): 0.145 µ g/ l) and Group C ( families C, D, E, F, H, J, Q exposed to Group Average ( Oct Jan): 0.180 µ g/ l). Assessment of the study by EPA reviewers of the raw data present in the original 1968 EPA submission ( MRID 00060486) substantiates the values present in the Exponent ( MRID 45812001) re analysis. Since Group B had 2 families which included 7 subjects ( 4 adults and 3 children) and there are no significant differences in air concentrations between Groups A and B, Page 8 of 16 EPA reviewers combined the Groups A and B. The average air concentrations during October to January were 0.125 µ g/ L.

Review of the self reported clinical symptoms in Appendix C of the re analysis and Appendix 4 in the 1968 submission reveal that 5 subjects ( D20, E22, E23, E24, and E25) had one or more days with headaches. These same subjects were all grouped together in the re analysis under Group C ( 0.180 µ g/ L which is the highest DDVP exposure concentration). Further examination of the data indicate that the headaches occurred during August, September and October. There were no biologically significant decreases (> 20%) in RBC Cholinesterase during the 3 month period when the headaches occurred ( D20 = 123%, E22 = 100%, 95%, E23 = 95%, 99%, E24 = 106%, and E25 = 98%). Four of the 5 subjects with headaches ( family E) were in the same family and were exposed to 12 pesticide strips/ house, whereas child D20 was exposed to 10 strips/ home. An equivocal relationship may exist between the presence of self reported headaches and the highdose exposure in Group C, although this possible relationship was not substantiated by the RBC cholinesterase activity. The remaining reported symptoms in the study were randomly distributed.

Because of significant individual variability in plasma ChE, these data were not considered appropriate to measure ChE inhibition in the exposed individuals in the study. The RBC cholinesterase activity (% of baseline) for participants in Exposure Group C in the month of January showed that nine subjects out of 30 measured ( 30%) had depressions of > 20%.

The NOAEL of 0.125 µ g/ L [ Group A and B] for the study is based on the headaches and RBC depression at the LOAEL of 0.180 µ g/ L [ Group C].

Although children and adults are represented in the group with RBC cholinesterase depression and headaches, more children than adults are represented in both groups with adverse effects. The following table illustrates this point.

Children with Headaches ChE Depression D20 ( 12 years) M D19 ( 10 years) F E24 ( 8 years) M D20 ( 12 years) M E25 ( 7 years) F E24 ( 8 years) M E25 ( 7 years) F E26 ( 5 years) M H38 ( 8 years) M Adults with Page 9 of 16 Headaches ChE Depression E22 ( M) C15 ( F) E23 ( F) D18 ( M) E22 ( M)

There are some limitations of the study. Clinical signs were based on self reporting of symptoms and the subjects were members of the contractor staff conducting the study ( or their families) so there might have been incentive to under report symptoms. Nevertheless the study indicates that there was RBC cholinesterase inhibition and signs consistent with cholinergic mediated neurotoxicity at the highest concentrations in the study.

B. Animals Groups of 50/ sex/ dose Carworth rats ( MRIDs 00057695, 00632569) were exposed to atmospheres containing dichlorvos vapors for 23 hours/ day, 7 days/ week at concentrations of 0, 0.05, 0.5 and 5 mg/ m3 equivalent to 0.055, 0.5, and 5.0 mg/ kg/ day for two years. Animals were observed for clinical signs of toxicity, hematology, clinical chemistry, and plasma and RBC cholinesterase activity. Brain cholinesterase was measured at study termination.

There were no toxic signs, organ weight changes, or hematological changes attributable to DDVP. Body weights were significantly decreased in mid and high dose males up to study termination, and in high dose females throughout the study. Plasma, RBC, and brain cholinesterase activity were significantly reduced in the mid and high dose groups ( 76, 72, and 90 and 83, 68, and 90 percent of control in mid dose males and females, and to 38, 4, and 21, and 22, 5, and 16 percent of control in the high dose male and female groups, respectively). RBC cholinesterase activity was reduced to 88 percent of control in the low dose females but this was not considered to be sufficient to regard the low dose as a LOAEL. The NOAEL for cholinesterase inhibition was 0.05 mg/ m3 ( 0.055 mg/ kg/ day) and the LOAEL was 0.5 mg/ m3 ( 0.5 mg/ kg/ day). This is the same inhalation study which has been used by the Agency RfD/ RfC Work Group in deriving an RfC for DDVP. Page 10 of 16 Endpoint Selection.

Acute RfD. In the past, the acute dosing study in humans was considered suitable for use in establishing an acute RfD, but recently received time course data in rats indicate that peak inhibition of RBC cholinesterase occurs 1 3 hours after oral dosing and that by 24 hours postdosing cholinesterase activity returns to near control levels. The risk assessment team concludes that the lack of cholinesterase measurements prior to 24 hours post treatment in the acute human study is a deficiency so critical that it has opted not to rely on the acute human study for either establishing an acute RfD or to decrease the interspecies uncertainty factor.

The rat acute BMDL, 0.8 mg/ kg, was selected for assessment of acute exposure scenarios. An uncertainty factor of 100 ( 10x for interspecies differences and 10x for intraspecies variation) was applied. It was concluded that an additional special FQPA factor is not needed, since BMD analysis of studies with pup and adult ChE depression results for either RBC or brain cholinesterase inhibition did not demonstrate any substantial numerical differences in the acute BMDL values for either RBC or brain cholinesterase inhibition ( all values were approximately 1 mg/ kg). Based on this assessment, an acute RfD of 0.008 mg/ kg/ day for the general population was derived for DDVP.

Short and intermediate term residential & occupational exposure. There are a number of repeated dose studies that are under consideration, either individually or collectively, for providing appropriate endpoints for risk assessment for short and intermediate term durations.  The 21 day repeated dose study in humans with a LOAEL for RBC cholinesterase inhibition of 0.1 mg/ kg/ day is of an adequate duration for selection of endpoints.  In the 7 day repeated dose comparative cholinesterase study in rats, the LOAEL for adult rats for RBC cholinesterase inhibition was 0.1 mg/ kg/ day, whereas in pre weaning rats, 0.1 mg/ kg was a NOAEL for RBC cholinesterase inhibition.  In the 7 day repeated dose comparative cholinesterase study in rats, the NOAEL for inhibition of brain cholinesterase inhibition in adult rats was 0.1 mg/ kg/ day, whereas 0.1 mg/ kg/ day was a LOAEL in preweaning rats.  The NOAEL in a 90 day rat subchronic neurotoxicity study was 0.1 mg/ kg/ day and the LOAEL was 7.5 mg/ kg/ day based on clinical signs of neurotoxicity and inhibition of plasma, RBC and brain cholinesterase.  In a chronic feeding study in dogs, the LOAEL for plasma and RBC cholinesterase inhibition was 0.1 mg/ kg/ day and the NOAEL was 0.05 mg/ kg/ day measured at 3 and 6 weeks. The NOAEL for brain cholinesterase inhibition measured at the end of the study was 0.05 mg/ kg/ day.

The findings in the repeated dose studies are consistent across species and over study durations ranging from seven days to one year, with the LOAEL or NOAEL fluctuating around 0.1 mg/ kg/ day for RBC or brain cholinesterase inhibition. The HED dichlorvos risk assessment team is of the opinion that the endpoint of RBC cholinesterase inhibition in the human repeated dose study is well supported by several animal studies and should serve as the basis for comparison in assessing short and intermediate term risks. A MOE of 100 is recommended to account for intraspecies variability ( 10x), the lack of NOAEL in this study ( 3x) and a Special FQPA factor of Page 11 of 16 3x. The Special FQPA factor is based on residual concern for the sensitivity shown by young rats to brain cholinesterase inhibition in the repeated dose comparative cholinesterase study ( MRID 46153304). A Special Factor of 3x is considered sufficient since the percent inhibition ( 25%) in brain cholinesterase in preweaning rats at 0.1 mg/ kg/ day is not substantial. The factor should be applied in any situation where the endpoint is based on RBC cholinesterase inhibition. A factor of 3x rather than 10x was used to account for a lack of a NOAEL since the RBC cholinesterase inhibition in humans during the exposure period of 21 days was minimal.

Chronic RfD and long term residential & occupational. The same rationale described under short and intermediate term scenarios could be used for long term scenarios since study duration didn't seem to make any difference in the NOAELs and LOAELs; however, the risk assessment team concluded that it would be difficult to justify using a 21 day human study for chronic or long term scenarios. The risk assessment team recommends continuing to use the one year dog study for establishing a chronic oral RfD and to assess long term occupational or residential risk.

For the chronic dog study with a NOAEL of 0.05 mg/ kg/ day, an uncertainty factor of 300x was selected ( 10x for interspecies variation, 10x for intraspecies extrapolation, and 3x for a Special FQPA factor as described above. The risk assessment team considered reducing the interspecies factor to 3x based on the similarity of the human data to the dog data, but chose to continue with the standard 10x value based again on the difficulty in justifying use of a 21 day study ( with a LOAEL) to decrease the interspecies factor for a chronic study. Based on this information, a chronic oral RfD of 0.00017 mg/ kg/ day was established for DDVP based on the dog study.

Short, intermediate and long term inhalation scenarios. The dichlorvos risk assessment team considered two studies, one a chronic ( two year) rat inhalation study ( MRIDs 00057695, 00632569) and the other a study of human families exposed to dichlorvos vapors in the home.  The NOAEL from the rat chronic inhalation study was 0.05 mg/ m3 and the LOAEL was 0.5 mg/ m3 based on inhibition of RBC and brain cholinesterase. Because the rats were exposed 23 hours per day, seven days a week for two years, the human equivalent ( continuous) concentration is also 0.05 mg/ m3.  The NOAEL calculated for the human study was 0.125 mg/ m3 based on clinical signs ( headaches) and RBC depression at the LOAEL of 0.180 mg/ m3. The subjects were estimated to spend about 59% of their time in the house during the study so the NOAEL adjusted to a 24 hour continuous equivalent is 0.074 mg/ m3.

The NOAELs from the two studies are in good agreement. The adjusted NOAEL from the human study lies between the NOAEL and the LOAEL from the rat study. Accordingly, the HED dichlorvos risk assessment team recommends that the human study be used for assessment of risks from inhalation of vapors for all durations of exposure. A MOE of 30 ( 10x for intraspecies variations and a special FQPA factor of 3) is sufficient. The special FQPA factor of 3 is required, since the possible differences in brain ChE displayed between pup and adult rats exposed to seven oral doses is not addressed in the human inhalation study. A chronic RfC for DDVP based on the human study is 0.0025 mg/ m3. Page 12 of 16 Table I. Guideline Toxicology Studies for Dichlorvos in Experimental Animals and Humans Study Type/ Guideline No. MRID No. Results Acute Oral Cholinesterase Inhibition Study ( 1st) in Adult Rats/ 870.1100 ( modified) 45805701 Acceptable ChEI NOAEL ( RBC and Brain) = not established ChEI LOAEL ( RBC and Brain) = 2.1 mg/ kg Acute Oral Cholinesterase Inhibition Study ( 2nd) in Adult Rats/ 870.1100 ( modified) 45805702 Acceptable ChEI NOAEL ( RBC and Brain) = 1 mg/ kg ChEI LOAEL ( RBC and Brain) = not established Acute Oral Cholinesterase Inhibition Study ( 3rd) in Adult Rats/ 870.1100 ( modified) 45805703 Acceptable ChEI NOAEL ( RBC and Brain) = 1 mg/ kg ChEI LOAEL ( RBC and Brain) = 5 mg/ kg RBC ChE ( F/ M) BMD 10 = 1.4/ 1.7 mg/ kg; RBC ChE ( F/ M) BMDL 10 = 1.2/ 1.3 mg/ kg; Brain ChE ( F/ M) BMD 10 = 1.3/ 1.6 mg/ kg Brain ChE ( F/ M) BMDL 10 = 0.8/ 1.0 mg/ kg Acute Oral Cholinesterase Inhibition Study in Preweaning Rat Pups/ 870.1100 ( modified) 45842301 Acceptable ChEI NOAEL ( RBC) = not established ChEI LOAEL ( RBC) = 1 mg/ kg ChEI NOAEL ( Brain) = 1 mg/ kg ChEI LOAEL ( Brain) = 5 mg/ kg PND8 RBC ChE ( F/ M) BMD 10 = 1.5/ 1.8 mg/ kg; PND8 RBC ChE ( F/ M) BMDL 10 = 1.0/ 1.3 mg/ kg; PND8 Brain ChE ( F/ M) BMD 10 = 2.2/ 1.8 mg/ kg PND8 Brain ChE ( F/ M) BMDL 10 = 1.6./ 1.5 mg/ kg PND15 RBC ChE ( F/ M) BMD 10 = 1.3/ 1.5 mg/ kg; PND15 RBC ChE ( F/ M) BMDL 10 = 1.1/ 1.2 mg/ kg; PND15 Brain ChE ( F/ M) BMD 10 = 1.4/ 1.6 mg/ kg PND15 Brain ChE ( F/ M) BMDL 10 = 1.0./ 1.3 mg/ kg Study Type/ Guideline No. MRID No. Results Page 13 of 16 Single Dose Cholinesterase Inhibition Study Humans ( Non Guideline) 44248802 Un Acceptable NOAEL = 1.0 mg/ kg/ day LOAEL = not established 70 mg/ person, single oral ( capsule) dose to 6 male volunteers with no placebos  missed time of peak effect Time Course of Cholinesterase Inhibition in Preweaning and Adult Rats/ 870.8223 ( Non Guideline) 46153303 Acceptable Brain and RBC enzyme activities were maximally inhibited one hour after single dosing in both adult and preweaning female rats. Thereafter, ChE inhibition in both compartments decreased to approximately control levels by 8 hours post dosing.

7 Day, Repeat Dose Cholinesterase Inhibition Study in Preweaning and Adult Rats/( Non Guideline) 46153304 Acceptable PND 18 ( M/ F) ChEI NOAEL ( Brain) = not established PND 18 ( M/ F) ChEI LOAEL ( Brain) = 0.1 mg/ kg/ d PND 48 ( M/ F) ChEI NOAEL ( Brain) = 0.1 mg/ kg/ d PND 48 ( M/ F) ChEI LOAEL ( Brain) = 7.5 mg/ kg/ d PND 18 ( M/ F) ChEI NOAEL ( RBC) = 0.1 mg/ kg/ d PND 18 ( M/ F) ChEI LOAEL ( RBC) = 7.5 mg/ kg/ d PND 48 ( M/ F) ChEI NOAEL ( RBC) = not established PND 48 ( M/ F) ChEI LOAEL ( RBC) = 0.1 mg/ kg/ d 21 Day Oral ( capsule) Cholinesterase Inhibition Study Humans ( Non Guideline) 44248801 Acceptable NOAEL = not established LOAEL = 0.1 mg/ kg/ day ( RBC ChE) 7 mg/ day for 21 Days in 6 male volunteers plus 3 male volunteers as placebos Single Dose and Repeated Dose Cholinesterase Inhibition Studies Humans ( Non Guideline) 44317901 Acceptable Phase I ( Single Dose of 35 mg) NOAEL = 0.5 mg/ kg/ day ( RBC ChE)

Phase II ( Repeated Dose of 21 mg/ day for 12 or 15 Days) NOAEL = not established LOAEL = 0.3 mg/ kg/ day ( RBC ChE)

28 Day Delayed Neurotoxicity Hen/ 870.6100 43433501 Acceptable Cholinesterase inhibition ( brain ChEI) NOAEL = 0.1 mg/ kg/ day LOAEL = 0.3 mg/ kg/ day No neuropathology.

90 Day Subchronic Oral Toxicity  Rat/ 870.3100 41004701 Acceptable NOAEL = 0.1 mg/ kg/ day LOAEL = 1.5 mg/ kg/ day ( plasma and RBC ChE) Study Type/ Guideline No. MRID No. Results Page 14 of 16 90 Day Neurotoxicity  Rat/ 870.6200 42958101 Acceptable NOAEL = 0.1 mg/ day LOAEL = 7.5 mg/ kg/ day ( plasma, red blood cell ( RBC) and brain ChEI).

Chronic Feeding Dog/ 870.4100 41593101 Acceptable NOAEL = 0.05 mg/ kg/ day LOAEL = 0.1 mg/ kg/ day ( plasma and RBC ChEI in both sexes).

Chronic Inhalation Rats/ Guideline 00057695, 00632569 Acceptable NOAEL = 0.00005 mg/ L LOAEL = 0.0005 mg/ L based on plasma, RBC and brain cholinesterase inhibition.

Chronic Inhalation Human/ 870.4100 45812001, 00060486 Acceptable NOAEL = 0.125 µ g/ L ( 0.000125 mg/ L) LOAEL = 0.180 µ g/ L ( 0.000180 mg/ L) ( Headaches and RBC ChEI)

Developmental Toxicity Rat/ 870.3700 41951501 Acceptable Maternal toxicity NOAEL = 3 mg/ kg/ day LOAEL = 21 mg/ kg/ day ( clinical signs, decreased body weight gain and reductions in food consumption and efficiency) Developmental toxicity NOAEL = > 21 mg/ kg/ day ( HDT)

Developmental Toxicity Rabbit/ 870.3700 41802401 Acceptable Maternal toxicity NOAEL = 0.1 mg/ kg/ day LOAEL = 2.5 mg/ kg/ day ( mortality, decreased body weight gain at LOAEL)

Developmental toxicity NOAEL= > 7 mg/ kg/ day ( HDT) ChEI was not measured. in main study Range Finding: Doses were 0, 0.1, 1.0, 2.5, 5.0, 10 mg/ kg/ day Maternal toxicity ChE NOAEL = 0.1 mg/ kg/ day ChE LOAEL = 1.0 mg/ kg/ day Study Type/ Guideline No. MRID No. Results Page 15 of 16 Reproductive Toxicity  Rat/ 870.3800 42483901 Acceptable Parental/ Systemic NOAEL = 2.3 mg/ kg/ day LOAEL = 8.3 mg/ kg/ day ( decreased % of females with estrous cycle and increased % of females with abnormal cycling) Offspring NOAEL= 2.3 mg/ kg/ day LOAEL = 8.3 mg/ kg/ day ( reduced # dams bearing litter, fertility index, pregnancy index and pup weight).

Preliminary Developmental Neurotoxicity  Rat/( Non Guideline) 46153301 Acceptable Systemic NOAEL = 7.5 mg/ kg/ day Maternal Systemic LOAEL = not identified Maternal RBC ChEI NOAEL = 0.1 mg/ kg/ day Maternal RBC ChEI LOAEL = 1.0 mg/ kg/ day Maternal Brain ChEI NOAEL = 1.0 mg/ kg/ day Maternal Brain ChEI LOAEL = 7.5 mg/ kg/ day Maternal Systemic NOAEL = 7.5 mg/ kg/ day Offspring Systemic LOAEL = not identified Offspring RBC ChEI NOAEL = 1.0 mg/ kg/ day Fetuses ( GD 22) RBC ChEI LOAEL = 7.5 mg/ kg/ day Fetuses ( GD 22)

Brain ChEI NOAEL = 1.0 mg/ kg/ day Fetuses ( GD 22) Brain ChEI LOAEL = 7.5 mg/ kg/ day Fetuses ( GD22)

Offspring ( Pups) did not demonstrate ChEI during PND 2 22 Study Type/ Guideline No. MRID No. Results Page 16 of 16 Developmental Neurotoxicity  Rat/ 870.6300 46153302 Notacceptable Maternal LOAEL/ NOAEL could not be identified due to low viability indices Offspring LOAEL/ NOAEL could not be identified due to low viability indices Offspring Effects at 7.5 mg/ kg/ day ( HDT) included increased startle response in males on PND 23, impaired memory in males on PND 27 and 62, and alterations in brain morphometry on PND 62.

Study is unacceptable/ not upgradable Developmental Neurotoxicity  Rat/ 870.6300 46239801 Notacceptable LOAEL/ NOAEL could not be identified due to low viability index in controls.

No maternal or offspring effects in FOB, motor activity, auditory startle reflex habituation, learning and memory tests, brain weight, neuropathology and morphometry at 7.5 mg/ kg/ day ( HDT).

Study is unacceptable/ not upgradable


[Federal Register: October 19, 2006 (Volume 71, Number 202)]
[Notices]
[Page 61755-61756]
[DOCID:fr19oc06-79]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. ER06-1273-000]

Wolverine Trading, Inc.; Notice of Issuance of Order

October 13, 2006.
    Wolverine Inc. (Wolverine) filed an application for market-based
rate authority, with an accompanying rate schedule. The proposed
market-based rate schedule provides for the sale of energy, capacity
and ancillary services at market-based rates. Wolverine also requested
waivers of various Commission regulations. In particular, Wolverine
requested that the Commission grant blanket approval under 18 CFR part
34 of all future issuances of securities and assumptions of liability
by Wolverine.
    On September 1, 2006, pursuant to delegated authority, the
Director, Division of Tariffs and Market Development--West, granted the
requests for blanket approval under part 34. The Director's order also
stated that the Commission would publish a separate notice in the
Federal Register establishing a period of time for the filing of
protests. Accordingly, any person desiring to be heard or to protest
the blanket approvals of issuances of securities or assumptions of
liability by Wolverine should file a motion to intervene or protest
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, 385.214
(2004).
    Notice is hereby given that the deadline for filing motions to
intervene or protest is November 13, 2006.
    Absent a request to be heard in opposition by the deadline above,
Wolverine is authorized to issue securities and assume obligations or
liabilities as a guarantor, indorser, surety, or otherwise in respect
of any

security of another person; provided that such issuance or assumption
is for some lawful object within the corporate purposes of Wolverine,
compatible with the public interest, and is reasonably necessary or
appropriate for such purposes.
    The Commission reserves the right to require a further showing that
neither public nor private interests will be adversely affected by
continued approvals of Wolverine's issuance of securities or
assumptions of liability.
    Copies of the full text of the Director's Order are available from
the Commission's Public Reference Room, 888 First Street, NE.,
Washington, DC 20426. The Order may also be viewed on the Commission's
Web site at http://www.ferc.gov, using the eLibrary link. Enter the

docket number excluding the last three digits in the docket number
filed to access the document. Comments, protests, and interventions may
be filed electronically via the internet in lieu of paper. See 18 CFR
385.2001(a)(1)(iii) and the instructions on the Commission's Web site
under the ``e-Filing'' link. The Commission strongly encourages
electronic filings.

Magalie R. Salas,
Secretary.
 [FR Doc. E6-17489 Filed 10-18-06; 8:45 am]

BILLING CODE 6717-01-P


[Federal Register Volume 77, Number 21 (Wednesday, February 1, 2012)]
[Notices]
[Pages 5072-5073]
[FR Doc No: 2012-2172]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-66252; File No. SR-Phlx-2012-10]

Self-Regulatory Organizations; NASDAQ OMX PHLX LLC; Notice of
Filing and Immediate Effectiveness of Proposed Rule Change Amending the
Rebates and Fees for Adding and Removing Liquidity in Select Symbols

January 26, 2012.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(``Act'') \1\, and Rule 19b-4 thereunder,\2\ notice is hereby given
that on January 20, 2012, NASDAQ OMX PHLX LLC (``Phlx'' or
``Exchange'') filed with the Securities and Exchange Commission
(``SEC'' or ``Commission'') the proposed rule change as described in
Items I, II, and III below, which Items have been prepared by the
Exchange. The Commission is publishing this notice to solicit comments
on the proposed rule change from interested persons.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
---------------------------------------------------------------------------

I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange proposes to amend Section I of the Exchange's Fee
Schedule titled ``Rebates and Fees for Adding and Removing Liquidity in
Select Symbols,'' specifically to remove various Select Symbols.\3\
---------------------------------------------------------------------------

    \3\ The term ``Select Symbols'' refers to the symbols which are
subject to the Rebates and Fees for Adding and Removing Liquidity in
Section I of the Exchange's Fee Schedule.
---------------------------------------------------------------------------

    While changes to the Fee Schedule pursuant to this proposal are
effective upon filing, the Exchange has designated these changes to be
operative on February 1, 2012.
    The text of the proposed rule change is available on the Exchange's
Web site at http://nasdaqtrader.com/micro.aspx?id=PHLXfilings, at the
principal office of the Exchange, and at the Commission's Public
Reference Room.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the Exchange included statements
concerning the purpose of and basis for the proposed rule change and
discussed any comments it received on the proposed rule change. The
text of these statements may be examined at the places specified in
Item IV below. The Exchange has prepared summaries, set forth in
sections A, B, and C below, of the most significant aspects of such
statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and the
Statutory Basis for, the Proposed Rule Change

1. Purpose
    The purpose of the proposed rule change is to amend the list of
Select Symbols in Section I of the Exchange's Fee Schedule, entitled
``Rebates and Fees for Adding and Removing Liquidity in Select
Symbols'' in order to attract additional order flow to the Exchange.
    The Exchange displays a list of Select Symbols in its Fee Schedule
at Section I, ``Rebates and Fees for Adding and Removing Liquidity in
Select Symbols,'' which are subject to the rebates and fees in that
section. The Exchange is proposing to delete the following symbols from
the list of Select Symbols in Section I of the Fee Schedule: American
International Group (``AIG''); The Allstate Corporation (``ALL'');
Brocade Communication Systems

(``BRCD''); DryShips, Inc. (``DRYS''); ProShares Ultra Short Financials
(``SKF''); ProShares Ultra Financials (``UYG''); and Xerox Corporation
Common Stock (``XRX'') (collectively ``Proposed Deleted Symbols'').
These Proposed Deleted Symbols would be subject to the rebates and fees
in Section II of the Fee Schedule entitled ``Equity Options Fees.'' \4\
---------------------------------------------------------------------------

    \4\ Section II includes options overlying equities, ETFs, ETNs,
indexes and HOLDRs which are Multiply Listed.
---------------------------------------------------------------------------

    While changes to the Fee Schedule pursuant to this proposal are
effective upon filing, the Exchange has designated these changes to be
operative on February 1, 2012.
2. Statutory Basis
    The Exchange believes that its proposal to amend its Fee Schedule
is consistent with Section 6(b) of the Act \5\ in general, and furthers
the objectives of Section 6(b)(4) of the Act \6\ in particular, in that
it is an equitable allocation of reasonable fees and other charges
among Exchange members and other persons using its facilities.
---------------------------------------------------------------------------

    \5\ 15 U.S.C. 78f(b).
    \6\ 15 U.S.C. 78f(b)(4).
---------------------------------------------------------------------------

    The Exchange believes that it is reasonable to remove the Proposed
Deleted Symbols from its list of Select Symbols to attract additional
order flow to the Exchange. The Exchange believes that applying the
fees in Section II of the Fee Schedule to the Proposed Deleted Symbols,
including the opportunity to receive payment for order flow, will
attract order flow to the Exchange.
    The Exchange believes that it is equitable and not unfairly
discriminatory to amend its list of Select Symbols to remove the
Proposed Deleted Symbols because the list of Select Symbols would apply
uniformly to all categories of participants in the same manner. All
market participants who trade the Select Symbols would be subject to
the rebates and fees in Section I of the Fee Schedule, which would not
include the Proposed Deleted Symbols. Also, all market participants
would be uniformly subject to the fees in Section II, which would
include the Proposed Deleted Symbols.

B. Self-Regulatory Organization's Statement on Burden on Competition

    The Exchange does not believe that the proposed rule change will
impose any burden on competition not necessary or appropriate in
furtherance of the purposes of the Act.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants, or Others

    No written comments were either solicited or received.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    The foregoing rule change has become effective pursuant to Section
19(b)(3)(A)(ii) of the Act.\7\ At any time within 60 days of the filing
of the proposed rule change, the Commission summarily may temporarily
suspend such rule change if it appears to the Commission that such
action is necessary or appropriate in the public interest, for the
protection of investors, or otherwise in furtherance of the purposes of
the Act. If the Commission takes such action, the Commission shall
institute proceedings to determine whether the proposed rule should be
approved or disapproved.
---------------------------------------------------------------------------

    \7\ 15 U.S.C. 78s(b)(3)(A)(ii).
---------------------------------------------------------------------------

IV. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. Comments may be submitted by any of
the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://www.sec.gov/rules/sro.shtml); or
     Send an email to<EMAIL_ADDRESS>Please include
File No. SR-Phlx-2012-10 on the subject line.

Paper Comments

     Send paper comments in triplicate to Elizabeth M. Murphy,
Secretary, Securities and Exchange Commission, 100 F Street, NE.,
Washington, DC 20549-1090.

All submissions should refer to File No. SR-Phlx-2012-10. This file
number should be included on the subject line if email is used. To help
the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml). Copies of the submission, all subsequent amendments, all
written statements with respect to the proposed rule change that are
filed with the Commission, and all written communications relating to
the proposed rule change between the Commission and any person, other
than those that may be withheld from the public in accordance with the
provisions of 5 U.S.C. 552, will be available for Web site viewing and
printing in the Commission's Public Reference Room, 100 F Street, NE.,
Washington, DC 20549, on official business days between the hours of
10:00 a.m. and 3:00 p.m. Copies of such filing also will be available
for inspection and copying at the principal office of the Exchange. All
comments received will be posted without change; the Commission does
not edit personal identifying information from submissions. You should
submit only information that you wish to make available publicly. All
submissions should refer to File No. SR-Phlx-2012-10 and should be
submitted on or before February 22, 2012.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\8\
---------------------------------------------------------------------------

    \8\ 17 CFR 200.30-3(a)(12).
---------------------------------------------------------------------------

Kevin M. O'Neill,
Deputy Secretary.
[FR Doc. 2012-2172 Filed 1-31-12; 8:45 am]
BILLING CODE 8011-01-P


                    UNITED STATES OF AMERICA

            DEPARTMENT OF TRANSPORTATION

                    OFFICE OF THE SECRETARY

                             WASHINGTON, DC

Issued by the Department of Transportation on May 14, 2003

NOTICE OF ACTION TAKEN -- DOCKET OST-2003-15182

________________________________________________________________________
_____________

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

Application of   World Airways, Inc.  filed   5/14/03    for:

XX  Emergency exemption from the certificate conditions imposed by Order
90-8-16 (in re suspension of operations between the United States and
Iraq, Docket 47108) in order to:

Permit the operation of one one-way all-cargo humanitarian charter
between Atlanta, Georgia, and Baghdad, Iraq (departing Atlanta May 15,
2003, and arriving Baghdad May 16, 2003), on behalf of International
Medical Corps, transporting amoxicillin, personal/portable water
filtration units, instructional tapes on hygiene, medical test kits and
medical testing equipment, pursuant to a contract between USAID and
International Medical Corps.

Applicant rep:  Joanne W. Young<PHONE_NUMBER>  DOT Analyst:  Sylvia
Moore<PHONE_NUMBER>

D I S P O S I T I O N

XX  Granted  (subject to conditions, see below)

The above action was effective when taken:   May 14, 2003

Action taken by:   Read C. Van de Water

		    Assistant Secretary for Aviation

		        and International Affairs

________________________

Conditions:  Our approval is subject to World’s compliance with all
other applicable U.S. Government and United Nations requirements.

Remarks: Because of the emergency nature of World’s application and
taking into account the nature of the authority requested, we acted on
this application without awaiting expiration of the 15-day answer
period.

________________________________________________________________________
______

We may amend, modify, or revoke the award granted in this Notice at any
time without hearing at our discretion.

An electronic version of this order is available on the World Wide Web
at

  HYPERLINK "http://dms.dot.gov//reports/reports_ aviation.asp"
http://dms.dot.gov//reports/reports_ aviation.asp


[Federal Register Volume 83, Number 143 (Wednesday, July 25, 2018)]
[Notices]
[Page 35305]
[FR Doc No: 2018-15856]

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SECURITIES AND EXCHANGE COMMISSION

Submission for OMB Review; Comment Request

Upon Written Request, Copies Available From: Securities and Exchange
Commission, Office of FOIA Services, 100 F Street NE, Washington, DC
20549-2736

Extension:
    Interagency Statement on Sound Practices, SEC File No. 270-560,
OMB Control No. 3235-0622

    Notice is hereby given that pursuant to the Paperwork Reduction Act
of 1995 (``PRA'') (44 U.S.C. 3501 et seq.) the Securities and Exchange
Commission (``Commission'') has submitted to the Office of Management
and Budget (``OMB'') a request for approval of extension of the
previously approved collection of information provided for in the
Interagency Statement on Sound Practices Concerning Elevated Risk
Complex Structured Finance Activities (``Statement'') under the
Securities Exchange Act of 1934 (15 U.S.C. 78a et seq.) (``Exchange
Act'') and the Investment Advisers Act of 1940 (15 U.S.C. 80b et seq.)
(``Advisers Act'').
    The Statement was issued by the Commission, together with the
Office of the Comptroller of the Currency, the Board of Governors of
the Federal Reserve System, the Federal Deposit Insurance Corporation,
and the Office of Thrift Supervision (together, the ``Agencies''), in
May 2006. The Statement describes the types of internal controls and
risk management procedures that the Agencies believe are particularly
effective in assisting financial institutions to identify and address
the reputational, legal, and other risks associated with elevated risk
complex structured finance transactions.
    The primary purpose of the Statement is to ensure that these
transactions receive enhanced scrutiny by the institution and to ensure
that the institution does not participate in illegal or inappropriate
transactions.
    The Commission estimates that approximately 5 registered broker-
dealers or investment advisers will spend an average of approximately
25 hours per year complying with the Statement. Thus, the total
compliance burden is estimated to be approximately 125 burden-hours per
year.
    An agency may not conduct or sponsor, and a person is not required
to respond to, a collection of information under the PRA unless it
displays a currently valid OMB control number.
    The public may view background documentation for this information
collection at the following website, www.reginfo.gov. Comments should
be directed to: (i) Desk Officer for the Securities and Exchange
Commission, Office of Information and Regulatory Affairs, Office of
Management and Budget, Room 10102, New Executive Office Building,
Washington, DC 20503, or by sending an email to:
[email protected]; and (ii) Pamela Dyson, Director/Chief
Information Officer, Securities and Exchange Commission, c/o Candace
Kenner 100 F Street NE Washington, DC 20549, or by sending an email to:
[email protected]. Comments must be submitted to OMB within 30 days
of this notice.

    Dated: July 19, 2018.
Eduardo A. Aleman,
Assistant Secretary.
[FR Doc. 2018-15856 Filed 7-24-18; 8:45 am]
 BILLING CODE 8011-01-P


[Federal Register Volume 88, Number 197 (Friday, October 13, 2023)]
[Rules and Regulations]
[Pages 70887-70889]
[FR Doc No: 2023-22649]

=======================================================================
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 1

[Docket No. FDA-2011-N-0179]

Prior Notice of Imported Food Questions and Answers (Edition 4):
Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notification of availability.

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

SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
announcing the availability of a final guidance entitled ``Prior Notice
of Imported Food Questions and Answers (Edition 4): Guidance for
Industry.'' The guidance document updates the current version of the
guidance by including three additional questions. One question relates
to any effect systems recognition or equivalency determinations have on
prior notice requirements. The other two questions relate to FDA's
notice to a submitter or transmitter of prior notice of an FDA refusal
for inadequate prior notice or hold, if the food article is from a
foreign facility that is not registered and addresses the timeframe for
making requests for FDA review of such refusal or hold. FDA is also
making other technical editorial changes. The guidance announced in
this notice finalizes the draft guidance of the same title dated
September 13, 2022.

DATES: The announcement of the guidance is published in the Federal
Register on October 13, 2023.

ADDRESSES: You may submit either electronic or written comments on
Agency guidances at any time as follows:

Electronic Submissions

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

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2011-N-0179 for ``Prior Notice of Imported Food Questions and
Answers (Edition 4): Guidance for Industry.'' Received comments will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at https://www.regulations.gov or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit

both copies to the Dockets Management Staff. If you do not wish your
name and contact information to be made publicly available, you can
provide this information on the cover sheet and not in the body of your
comments and you must identify this information as ``confidential.''
Any information marked as ``confidential'' will not be disclosed except
in accordance with 21 CFR 10.20 and other applicable disclosure law.
For more information about FDA's posting of comments to public dockets,
see 80 FR 56469, September 18, 2015, or access the information at:
https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.
    You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
    Submit written requests for single copies of the guidance to the
Division of Operational Policy, Office of Regulatory Affairs, Food and
Drug Administration, Element Building, 12420 Parklawn Dr., Rockville,
MD 20852. Send one self-addressed adhesive label to assist that office
in processing your requests. See the SUPPLEMENTARY INFORMATION section
for electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Peter Ajuonuma, Office of Regulatory
Affairs, Food and Drug Administration, Element Building, 12420 Parklawn
Dr., Rockville, MD 20852,<PHONE_NUMBER>, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a document entitled ``Prior
Notice of Imported Food Questions and Answers (Edition 4): Guidance for
Industry.'' In the Federal Register of September 13, 2022 (87 FR
55932), FDA announced the availability of the draft guidance entitled
``Prior Notice of Imported Food Questions and Answers (Edition 4);
Draft Guidance for Industry.'' FDA received no comments on the draft
guidance. As a result, we are publishing the guidance as drafted, with
minor editorial changes to improve clarity, such as replacing the term
``animal feed'' with ``animal food.'' The guidance announced in this
notice finalizes the draft guidance dated September 13, 2022, and
replaces ``Prior Notice of Imported Food Questions and Answers (Edition
3): Guidance for Industry,'' dated June 2016.
    FDA continues to believe that it is reasonable to maintain
responses to questions concerning prior notice of imported food in a
single document that is periodically updated in response to additional
questions or regulatory or policy changes. As in the previous editions,
the following indicators are used to help users identify revisions: (1)
the guidance is identified as a revision of a previously issued
document; (2) the revision date appears on the cover of the guidance;
(3) the edition number of the guidance is included in its title; and
(4) revised or added questions and answers are identified as such in
the body of the guidance.
    On November 7, 2008, we published a final rule in the Federal
Register requiring submission to FDA of prior notice of food, including
food for animals, that is imported or offered for import into the
United States (73 FR 66294). The rule implements section 801(m) of the
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 381(m)),
which was added by section 307 of the Public Health Security and
Bioterrorism Preparedness and Response Act of 2002 (the Bioterrorism
Act) (Pub. L. 107-188) and requires that FDA receive prior notice of
food imported or offered for import into the United States.
    On December 16, 2003, FDA issued a guidance entitled ``Prior Notice
of Imported Food Questions and Answers (Edition 1).'' FDA issued a
second edition of the guidance on May 3, 2004, and a third edition on
June 16, 2016. FDA issued a draft fourth edition, which was published
for public comment from September 13, 2022, to November 14, 2022. We
are issuing this guidance entitled ``Prior Notice of Imported Food
Questions and Answers (Edition 4): Guidance for Industry'' as a level 1
guidance, finalizing the draft guidance issued on September 13, 2022.
    The fourth edition of the prior notice guidance adds three
additional questions. One question relates to any effect systems
recognition or equivalency determinations have on prior notice
requirements. The other two questions relate to FDA's notice of a
refusal under 801(m)(1) of the FD&C Act (in accordance with Sec.  1.283
(21 CFR 1.283)) for inadequate prior notice or a hold under 801(l) (in
accordance with Sec.  1.285 (21 CFR 1.285)) if the food article is from
a foreign facility that is not registered, as well as address the
timeframe for making requests for FDA review of such a refusal or hold.
The guidance is intended to help clarify whether food imported from a
country with which FDA has a Systems Recognition Arrangement or
equivalence determination is exempted from prior notice requirements.
The guidance also clarifies when FDA will provide notice of the refusal
or hold to the relevant party, and when the 5-calendar-day clock to
request a review of the refusal or hold begins.
    We are also making other technical amendments to the guidance due
to the expanded capabilities of the U.S. Customs and Border
Protection's (CBP) Automated Broker Interface of the Automated
Commercial Environment (ABI/ACE) system and FDA's 2017 technical
amendments to the prior notice rule (82 FR 15627, March 30, 2017), such
as replacing references to the Automated Commercial System (ACS) and
successor system with the ABI/ACE system, removing references to
requirements that certain prior notice submissions be submitted in
FDA's Prior Notice System Interface (FDA PNSI), and updating outdated
links and FDA contact information. The fourth edition guidance
clarifies that the existence of a Systems Recognition Arrangement with
or an equivalence determination of a foreign country does not exempt
foods imported from that country from FDA's prior notice requirements.
    FDA's policy on and practice of communicating prior notice refusals
and holds has changed over time. FDA previously stated that we intended
to provide notice regarding refusals to carriers. Those carriers could
then notify others, such as the entity that hired the carrier to
transport the article of food, of a problem with the prior notice (see
73 FR 66294 at 66365). Subsequently, FDA's Guidance for Industry
``Prior Notice of Imported Food Questions and Answers (Edition 3)'' was
published with the explanation that FDA will communicate the decision
to examine articles of food to CBP.
    The fourth edition clarifies that notification of these prior
notice refusals and holds will be communicated to CBP and provided to
the relevant party (i.e., the submitter or transmitter of prior notice)
upon arrival of the article. FDA is clarifying its policy because
providing advanced notice of a refusal or hold to a submitter or
transmitter could create incentives for bad actors, who may attempt to
reroute their entries for the purpose of evading FDA requirements and
importing unsafe food.
    The fourth edition of the guidance also clarifies the 5-calendar-
day clock to request a review of these refusals and

holds. Under Sec. Sec.  1.283(d) and 1.285(j), certain parties may, for
the enumerated reasons, request reviews of the prior notice refusals
and holds within 5 calendar days of the hold or refusal. The fourth
edition clarifies that FDA considers the 5-calendar-day clock to begin
when FDA provides notice of the refusal or hold to the submitter or
transmitter.
    Additionally, in 2016, CBP issued a notice announcing that ABI/ACE
would replace ACS as the sole electronic data interchange system
authorized by CBP for the processing of electronic entries of FDA-
regulated products (see 81 FR 30320, May 16, 2016). ABI/ACE became the
successor system to ACS. In 2017, we amended 21 CFR part 1, subpart I
to replace references to ACS and successor system with ABI/ACE (see 82
FR 15627). As part of this rulemaking, we eliminated some requirements
for submitting prior notice due to the expanded capabilities of ABI/
ACE, such as the requirement to submit articles that have been refused
under section 801(m)(1) of the FD&C Act or subpart I in FDA PNSI.
Further, ABI/ACE can now accommodate entries it previously could not,
such as articles of food arriving through international mail.
Therefore, to reflect these changes that were implemented in the
rulemaking and the expanded capabilities of ABI/ACE, we are replacing
references in the prior notice guidance to ACS with the successor
system ABI/ACE. In addition, we are providing clarification regarding
how persons may submit prior notice for articles of food imported or
offered for import by international mail.
    This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
current thinking of FDA on guidance for industry on the prior notice
requirements. It does not establish any rights for any person and is
not binding on FDA or the public. You can use an alternative approach
if it satisfies the requirements of the applicable statutes and
regulations.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. The
previously approved collections of information are subject to review by
the Office of Management and Budget (OMB) under the Paperwork Reduction
Act of 1995 (PRA) (44 U.S.C. 3501-3521). The collections of information
in 21 CFR 1.278 to 1.282 have been approved under OMB control number
0910-0520.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or
https://www.regulations.gov. Use the FDA website listed in the previous
sentence to find the most current version of the guidance.

    Dated: October 10, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-22649 Filed 10-12-23; 8:45 am]
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