[Federal Register Volume 75, Number 217 (Wednesday, November 10, 2010)]
[Rules and Regulations]
[Page 68970]
[FR Doc No: 2010-28387]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 73

[Docket No. FAA-2010-1070; Airspace Docket No. 10-AEA-18]
RIN 2120-AA66

Amendment of Using Agency for Restricted Areas R-4002, R-4005, R-
4006 and R-4007; MD

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Final rule.

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SUMMARY: This action makes a minor change to the name of the using
agency for restricted areas R-4002, Bloodsworth Island, MD; and R-4005,
R-4006 and R-4007, Patuxent River, MD to ``U.S. Navy, Commanding
Officer, NAS Patuxent River, MD.'' This is an administrative change
only and there are no changes to the dimensions, time of designation or
activities conducted within the affected restricted areas.

DATES: Effective date 0901 UTC, January 13, 2011.

FOR FURTHER INFORMATION CONTACT: Paul Gallant, Airspace, Regulations
and ATC Procedures Group, Office of Airspace Services, Federal Aviation
Administration, 800 Independence Avenue, SW., Washington, DC 20591;
telephone:<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Background

    The U.S. Navy requested a minor change to the name of the using
agency for restricted areas R-4002, R-4005, R-4006 and R-4007 in
Maryland, in order to reflect the correct organization responsible for
operation of the areas and to standardize the using agency listing in
the area legal descriptions.

The Rule

    This action amends Title 14 Code of Federal Regulations (14 CFR)
part 73 by changing the using agency name from ``Commanding Officer,
Naval Amphibious School Little Creek, Norfolk, VA,'' To ``U.S. Navy,
Commanding Officer, NAS Patuxent River, MD'' for restricted area R-
4002, Bloodsworth Island, MD; and restricted areas R-4005, R-4006 and
R-4007, Naval Air Station Patuxent River, MD, from ``Commanding
Officer, NAS Patuxent River, MD,'' to ``U.S. Navy, Commanding Officer,
NAS Patuxent River, MD.'' This is an administrative change and does not
affect the boundaries, designated altitudes, or activities conducted
within the restricted area; therefore, notice and public procedures
under 5 U.S.C. 553(b) are unnecessary.
    The FAA has determined that this action only involves an
established body of technical regulations for which frequent and
routine amendments are necessary to keep them operationally current.
Therefore, this regulation: (1) Is not a ``significant regulatory
action'' under Executive Order 12866; (2) is not a ``significant rule''
under DOT Regulatory Policies and Procedures (44 FR 11034; February 26,
1979); and (3) does not warrant preparation of a regulatory evaluation
as the anticipated impact is so minimal. Since this is a routine matter
that will only affect air traffic procedures and air navigation, it is
certified that this rule, when promulgated, will not have a significant
economic impact on a substantial number of small entities under the
criteria of the Regulatory Flexibility Act.

Environmental Review

    The FAA has determined that this action qualifies for categorical
exclusion under the National Environmental Policy Act in accordance
with 311d., FAA Order 1050.1E, Environmental Impacts: Policies and
Procedures. This airspace action is an administrative change to the
descriptions of the affected restricted areas to update the using
agency name. It does not alter the dimensions, altitudes, or times of
designation of the airspace; therefore, it is not expected to cause any
potentially significant environmental impacts, and no extraordinary
circumstances exists that warrant preparation of an environmental
assessment.

List of Subjects in 14 CFR Part 73

    Airspace, Prohibited areas, Restricted areas.

Adoption of the Amendment

0
In consideration of the foregoing, the Federal Aviation Administration
amends 14 CFR part 73, as follows:

PART 73--SPECIAL USE AIRSPACE

0
1. The authority citation for part 73 continues to read as follows:

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

Sec.  73.40  [Amended]

0
2. Sec.  73.40 is amended as follows:
* * * * *

1. R-4002 Bloodsworth Island, MD [Amended]

    By removing the words ``Using agency. Commanding Officer, Naval
Amphibious School Little Creek, Norfolk, VA'' and inserting the words
``Using agency. U.S. Navy, Commanding Officer, NAS Patuxent River,
MD.''

2. R-4005 Patuxent River, MD [Amended]

    By removing the words ``Using agency. Commanding Officer, NAS
Patuxent River, MD'' and inserting the words ``Using agency. U.S. Navy,
Commanding Officer, NAS Patuxent River, MD.''

3. R-4006 Patuxent River, MD [Amended]

    By removing the words ``Using agency. Commanding Officer, NAS
Patuxent River, MD'' and inserting the words ``Using agency. U.S. Navy,
Commanding Officer, NAS Patuxent River, MD.''

4. R-4007 Patuxent River, MD [Amended]

    By removing the words ``Using agency. Commanding Officer, NAS
Patuxent River, MD'' and inserting the words ``Using agency. U.S. Navy,
Commanding Officer, NAS Patuxent River, MD.''

    Issued in Washington, DC, on November 4, 2010.
Edith V. Parish,
Manager, Airspace, Regulations and ATC Procedures Group.
[FR Doc. 2010-28387 Filed 11-9-10; 8:45 am]
BILLING CODE 4910-13-P


[Federal Register Volume 78, Number 157 (Wednesday, August 14, 2013)]
[Notices]
[Pages 49556-49561]
[FR Doc No: 2013-19650]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-70150]

Order Temporarily Exempting Certain Broker-Dealers and Certain
Transactions From the Recordkeeping and Reporting Requirements of Rule
13h-1 Under the Securities Exchange Act of 1934

August 8, 2013.
    On July 27, 2011, the Securities and Exchange Commission
(``Commission'') adopted Rule 13h-1 (the ``Rule'') under the Securities
Exchange Act of 1934 (``Exchange Act'') concerning large trader
reporting to assist the Commission in both identifying and obtaining
trade information for market participants that conduct a substantial
amount of trading activity, as measured by volume or market value, in
U.S. securities (such persons are referred to as ``large traders'').\1\
The Financial Information Forum (``FIF'') and the Securities Industry
and Financial Markets Association (``SIFMA,'' and collectively the
``Industry Organizations''), each representing a variety of broker-
dealers and other market participants, have requested that the
Commission grant certain substantive relief from the broker-dealer
recordkeeping and reporting

requirements of the Rule.\2\ Pursuant to Section 13(h)(6) of the
Exchange Act and Rule 13h-1(g) thereunder,\3\ the Commission, by order,
may exempt from the provisions of Rule 13h-1, upon specified terms and
conditions or for stated periods, any person or class of persons or any
transaction or class of transactions from the provisions of Rule 13h-1
to the extent that such exemption is consistent with the purposes of
the Exchange Act.
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    \1\ See Securities Exchange Act Release No. 64976 (July 27,
2011), 76 FR 46960 (Aug. 3, 2011) (``Large Trader Adopting
Release''). The effective date of Rule 13h-1 was October 3, 2011.
    \2\ See Letters from: Manisha Kimmel, Executive Director, FIF,
to Robert Cook, Director, and David Shillman, Associate Director,
Division of Trading and Markets, Commission, dated January 25, 2012
(``FIF Letter''); Ann L. Vlcek, Managing Director and Associate
General Counsel, SIFMA, to David S. Shillman, Associate Director,
Division of Trading and Markets, Commission, dated March 29, 2012
(``SIFMA Letter I''); and Theodore R. Lazo, Managing Director and
Associate General Counsel, SIFMA, to David S. Shillman, Associate
Director, Division of Trading and Markets, Commission, dated
February 13, 2013 (``SIFMA Letter II''). These letters are available
at: http://www.sec.gov/comments/s7-10-10/s71010.shtml.
    \3\ See 15 U.S.C. 78m and 17 CFR 240.13h-1(g), respectively.
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    In response to the Industry Organizations' requests and as further
discussed below, the Commission extended the compliance date for the
broker-dealer recordkeeping, reporting, and monitoring requirements and
took a two-phased approach to implementation of the broker-dealer
requirements under the Rule. Commencing on November 30, 2012, the first
phase of implementation required clearing broker-dealers for large
traders to keep records of and report upon Commission request data
concerning: (1) proprietary trades by large traders that are U.S.-
registered broker-dealers; and (2) transactions effected by large
traders through a sponsored access arrangement (collectively, ``Phase
One'').\4\
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    \4\ See Securities Exchange Act Release No. 66839 (April 20,
2012), 77 FR 25007, 25008 (April 26, 2012) (``Extension Order I'').
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    The second phase of implementation concerned those remaining
requirements of the Rule that were not covered in Phase One. As more
fully described below, the Commission is herein modifying this second
phase by limiting the recordkeeping and reporting requirements of the
Rule to include transactions effected by large traders through direct
market access arrangements (``Phase Two''). The compliance date for
Phase Two, as modified, will remain November 1, 2013.\5\
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    \5\ See infra note 19.
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    Finally, the Commission is herein establishing a new third phase
for which the compliance date will be November 1, 2015. As discussed
further below, this new and final phase will include all of the
remaining requirements of the Rule that have not been, or will not be,
implemented in either Phase One or Phase Two (collectively, ``Phase
Three'').

I. Background

A. The Requirements of Rule 13h-1 and Applicable Compliance Dates for
Those Requirements

    Large Trader Self-Identification. Rule 13h-1 requires that large
traders register with the Commission by electronically filing and
periodically updating Form 13H.\6\ Additionally, promptly after
receiving a large trader identification number (``LTID'') assigned by
the Commission,\7\ a large trader must disclose its LTID to registered
broker-dealers effecting transactions on its behalf and identify to
each such broker-dealer each account to which the LTID number
applies.\8\ These requirements have been in effect since December 1,
2011.\9\
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    \6\ See Rule 13h-1(b)(1)(i)-(iii).
    \7\ When a large trader files its initial Form 13H filing
through EDGAR, the system sends an automatically generated
confirmation email acknowledging acceptance of the filing. That
email also contains the unique 8-digit LTID number assigned to the
large trader.
    \8\ See Rule 13h-1(b)(2). See also Large Trader Adopting
Release, supra note 1, 76 FR at 46971 (``the requirements that a
large trader provide its LTID to all registered broker-dealers who
effect transactions on its behalf, and identify each account to
which it applies, are ongoing responsibilities that must be
discharged promptly'').
    \9\ See Large Trader Adopting Release, supra note 1, 76 FR at
46960.
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    Broker-Dealer Recordkeeping and Reporting. Rule 13h-1 also requires
that every registered broker-dealer maintain records of data specified
in paragraphs (d)(2) and (d)(3) of the Rule (``Transaction Data''),
including the applicable LTID(s) and execution time on each component
trade, for all transactions effected directly or indirectly by or
through: (1) an account such broker-dealer carries for a large trader
or an Unidentified Large Trader; \10\ or (2) if the broker-dealer is a
large trader, any proprietary or other account over which such broker-
dealer exercises investment discretion.\11\ Additionally, where a non-
broker-dealer carries an account for a large trader under the Rule, the
broker-dealer effecting transactions directly or indirectly for such
large trader must maintain records of all Transaction Data.\12\
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    \10\ The definition of ``Unidentified Large Trader'' is
discussed below. See infra note 20 and accompanying text. In the
context of the broker-dealer recordkeeping and reporting
requirements, references in this release to ``large trader'' include
Unidentified Large Traders.
    \11\ See Rule 13h-1(d)(1)(i) and (ii).
    \12\ See Rule 13h-1(d)(1)(iii).
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    Rule 13h-1 requires that, upon Commission request, every registered
broker-dealer that is itself a large trader or carries an account for a
large trader must electronically report Transaction Data to the
Commission through the Electronic Blue Sheets (``EBS'') system for all
transactions, equal to or greater than the reporting activity level,
effected directly or indirectly by or through accounts carried by such
broker-dealer for large traders.\13\ Additionally, where a non-broker-
dealer carries an account for a large trader, the broker-dealer
effecting such transactions directly or indirectly for a large trader
must electronically report Transaction Data to the Commission through
the EBS system. The Rule requires that reporting broker-dealers submit
the requested Transaction Data no later than the day and time specified
in the Commission's request.\14\
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    \13\ Rule 13h-1(a)(8) defines the reporting activity level as:
(i) Each transaction in NMS securities, effected in a single account
during a calendar day, that is equal to or greater than 100 shares;
(ii) any other transaction in NMS securities, effected in a single
account during a calendar day, that a registered broker-dealer may
deem appropriate; or (iii) such other amount that may be established
by order of the Commission from time to time.
    \14\ The Commission will not require reporting earlier than the
opening of business of the day following such request, except under
unusual circumstances. See Rule 13h-1(e). Accordingly, while
information must be available on the morning after the transaction
was effected, the reporting deadline is based upon the deadline
specified in the Commission's request for Transaction Data.
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    Initially, the compliance date for the broker-dealer requirements
was April 30, 2012.\15\ To allow additional time for the Commission to
examine implementation issues identified by the Industry Organizations
subsequent to the Commission's adoption of the Rule, the Commission
deferred the initial compliance date and established a two-phased
approach to implementation of the broker-dealer requirements.\16\
Specifically, the Commission postponed until November 30, 2012, the
obligations of clearing brokers for large traders (including the large
trader itself if it is a self-clearing broker-dealer) to keep records
and report Transaction Data for such customers' transactions that are
either (1) proprietary trades by a U.S. registered broker-dealer; or
(2) effected through a ``sponsored access'' arrangement (i.e., Phase
One).\17\ The

Commission further deferred the compliance date for the recordkeeping
and reporting of other large trader transactions until May 1, 2013 \18\
and, more recently, the Commission extended that date to November 1,
2013 while it considered the industry's experience with Phase One
implementation in further evaluating the requests for relief for the
remainder of the Rule.\19\
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    \15\ See Large Trader Adopting Release, supra note 1, 76 FR at
46960.
    \16\ See Extension Order I, supra note 4.
    \17\ See id. at 25008-9. A sponsored access arrangement is one
where a broker-dealer permits a customer to enter orders into a
trading center without using the broker-dealer's trading system
(i.e., using the customer's own technology or that of a third party
provider). FIF indicated that broker-dealer compliance would be
easier for sponsored access customers because those arrangements
typically are distinct from all other business lines of the broker-
dealer, with infrastructure that processes this order flow that is
separate from the platforms that handle other client and proprietary
flows. See id. at 25008 n.16.
    \18\ See id. at 25008.
    \19\ See Securities Exchange Act Release No. 69281 (April 3,
2013), 78 FR 20960 (April 8, 2013) (``Extension Order II'').
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    Broker-Dealer Monitoring. As mentioned above, the recordkeeping and
reporting requirements apply to customers that are large traders as
well as Unidentified Large Traders. An ``Unidentified Large Trader'' is
a person who (1) has not complied with the identification requirements
of the Rule; and (2) a registered broker-dealer knows or has reason to
know is a large trader based on transactions in NMS securities effected
by or through such broker-dealer.\20\ The Rule provides a safe harbor
for broker-dealers that establish and maintain certain customer
monitoring practices. For the purposes of the Rule, a registered
broker-dealer is deemed not to know or have reason to know that a
person is a large trader if it does not have actual knowledge that a
person is a large trader and it establishes policies and procedures
reasonably designed to (among other things): (1) identify persons who
may be large traders but have not self-identified as required; and (2)
inform those persons of the self-identification requirements of the
Rule.\21\ To take advantage of this safe harbor, broker-dealers are
required to have appropriate policies and procedures in place by the
Phase Two compliance date, which is November 1, 2013.\22\

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    \20\ See Rule 13h-1(a)(9).
    \21\ See Rule 13h-1(f).
    \22\ See Extension Order II, supra note 19.
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B. Relief Requests

    The Industry Organizations have requested that the Commission
provide certain substantive relief with respect to the recordkeeping
and reporting requirements for broker-dealers.\23\ In particular, they
highlight implementation challenges associated with the Rule's
recordkeeping and reporting requirements that have come to light as
broker-dealers focused their attention on how to comply with the Rule,
in particular with respect to obtaining and reporting the execution
time of individual transactions by certain large traders.\24\ According
to the Industry Organizations, these challenges are most pronounced
when a broker-dealer effects transactions for a large trader and
processes the activity through a multi-client average price
account.\25\ As a result of the complexity and additional cost to
capture and report disaggregated trades with execution time for large
traders whose trades are processed in this manner, the Industry
Organizations request relief from the requirement to provide execution
times on transactions processed through average price accounts.\26\
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    \23\ See generally FIF Letter, SIFMA Letter I, and SIFMA Letter
II, supra note 2.
    \24\ See SIFMA Letter II, supra note 2 at 5. See also FIF
Letter, supra note 2 at 2; and SIFMA Letter I, supra note 2 at 5.
    \25\ See FIF Letter, supra note 2 at 31-32. See also SIFMA
Letter I, supra note 2 at B-1.
    \26\ See, e.g., SIFMA Letter I, supra note 2 at 5.
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    The Industry Organizations also request relief for all broker-
dealers other than self-clearing and clearing broker-dealers from the
recordkeeping and reporting requirements of the Rule.\27\ While the
Rule focuses the reporting obligation on the universe of clearing
brokers that currently report data through the EBS system, the Rule
also authorizes the Commission to obtain this data directly from
certain non-clearing broker-dealer large traders, as well as broker-
dealers that effect transactions, directly or indirectly, for large
traders where a non-broker-dealer carries the account. The Industry
Organizations have asked the Commission to impose the recordkeeping and
reporting requirement exclusively on the clearing brokers that
currently report through the EBS system.\28\
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    \27\ See FIF Letter, supra note 2 at 25-28. See also SIFMA
Letter I, supra note 2 at B-2.
    \28\ See FIF Letter, supra note 2 at 26-27. See also SIFMA
Letter I, supra note 2 at B-3.
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    In addition, the Industry Organizations argue that the complex
structure underlying execution, clearance, and settlement flows of
large trader transactions, including the fact that information related
to the identity of the large trader and the execution fill details
often reside with different broker-dealers, presents challenges to
implementation, and that these concerns are most relevant with respect
to large trader institutional customers.\29\ The Industry Organizations
further highlight areas where the burdens as they relate to
institutional large trader customers would be most extensive and impose
the greatest potential cost for some broker-dealers, particularly for
prime brokers, routing broker-dealers, and situations where clearing
responsibility is transferred between multiple brokers, and the
Industry Organizations request that the Commission provide relief from
the recordkeeping and reporting obligations of the Rule for each of
those areas.\30\

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    \29\ See FIF Letter, supra note 2 at 25-28. See also SIFMA
Letter II, supra note 2 at 5-7.
    \30\ See FIF Letter, supra note 2 at 25-28. See also SIFMA
Letter II, supra note 2 at 5-7.
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II. Discussion

    The Commission continues to believe that implementation of the
large trader reporting requirements contemplated by Rule 13h-1 is
necessary to effectively assess the impact of large trader activity on
the securities markets in the near term and support the Commission's
investigative and enforcement activities. The Commission also believes
that it is appropriate and consistent with the Exchange Act to provide
exemptive relief limiting short-term compliance costs of the Rule to
focus near-term compliance on the large trader information that is
likely to be most useful to the Commission.
    Accordingly, and as discussed more fully below, the Commission
believes that it is appropriate and consistent with the purposes of the
Exchange Act to extend the Phase Two November 1, 2013 compliance date
for certain registered broker-dealers by temporarily exempting broker-
dealers, until November 1, 2015, from the recordkeeping and reporting
requirements of Rule 13h-1(d) and (e), except for:
    (1) The clearing broker-dealer for a large trader,\31\ with respect
to \32\
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    \31\ In its letter, FIF asked the Commission for ``relief for
broker dealers involved in Large Trader transactions that do not
have a direct relationship with the Large Trader. Only the self-
clearing and clearing broker dealers with a direct relationship with
the Large Trader would perform Large Trader Reporting.'' See FIF
Letter, supra note 2, at 2. In Appendix C of its letter, FIF
provides an example of the entities for whom it recommends imposing
a recordkeeping and reporting obligation. See id. at 25. In
addition, FIF recommends that the reporting of execution time should
rest with the clearing broker for the originating broker, and any
prime broker would be relieved from being required to report
execution times.
    \32\ Items (a) and (b) are currently included in Phase One,
which was effective beginning on November 30, 2012.
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    (a) proprietary transactions by a large trader broker-dealer;
    (b) transactions effected pursuant to a ``sponsored access''
arrangement; \33\ and
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    \33\ See infra note 39 (defining ``sponsored access''
arrangement).

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    (c) transactions effected pursuant to a ``direct market access''
arrangement \34\; and
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    \34\ See infra note 41 and text following note 41 (defining
``direct market access'' arrangement).
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    (2) a broker-dealer that carries an account for a large trader,
with respect to transactions other than those set forth above, and for
Transaction Data other than the execution time.\35\
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    \35\ Accordingly, during Phase Two, a registered broker-dealer
that is itself a large trader but does not self-clear, as well as a
broker-dealer effecting transactions directly or indirectly for a
large trader where a non-broker-dealer carries the account for the
large trader, will continue to be temporarily relieved from the
recording and reporting requirements of the Rule and therefore do
not need to record and electronically report Transaction Data to the
Commission through the EBS system for purposes of the Rule during
Phase Two.
    Neither of these temporary exemptions, however, relieves a
broker-dealer from any other recordkeeping requirement that would
otherwise apply under the federal securities laws, rules, or
regulations, including Rules 17a-3 and 17a-4 under the Exchange Act,
or any self-regulatory organization rule.
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    In accordance with Phase One, clearing broker-dealers for large
traders have been complying with the recordkeeping and reporting
requirements of Rule 13h-1, with respect to (a) proprietary
transactions by a large trader broker-dealer, and (b) transactions
effected pursuant to a ``sponsored access'' arrangement, since November
30, 2012. As part of Phase Two, in accordance with this Order, clearing
broker-dealers for large traders also will have to comply with the
recordkeeping and reporting requirements of Rule 13h-1 with respect to
transactions effected pursuant to a ``direct market access''
arrangement as of November 1, 2013. In addition, with respect to all
other types of transactions, the prime broker or other carrying broker-
dealer for a large trader will have to report the applicable LTID, but
not the execution time, as of November 1, 2013. Finally, the
recordkeeping and reporting requirements with respect to Unidentified
Large Traders, and the related monitoring safe harbor provided by Rule
13h-1(f), will apply to broker-dealers that carry an account for a
large trader as of November 1, 2013.
    The Rule as adopted requires the following broker-dealers to
obtain, keep records of, and report Transaction Data to the Commission
upon request through the EBS infrastructure: (1) The broker-dealer that
``carries'' the account for the large trader (including the clearing
broker for the large trader and the large trader's prime broker, if
applicable); (2) broker-dealer large traders, with respect to their
proprietary trades and transactions over which they exercise investment
discretion; and (3) other brokers that directly or indirectly effect
transactions for a large trader, including an executing broker, where a
non-broker-dealer carries the large trader's account.\36\ As SIFMA
notes, at present, carrying brokers-dealers are the primary parties
that report through the EBS infrastructure.\37\ Accordingly, full
compliance with the recordkeeping and reporting provisions of the Rule
would require non-carrying broker-dealers to develop connectivity to
the EBS system. In its initial exemption, the Commission temporarily
limited the broker-dealer recordkeeping and reporting requirements to
the clearing broker-dealer for a large trader.\38\
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    \36\ See Rule 13h-1(d) and (e), respectively. See also Large
Trader Adopting Release, supra note 1, 76 FR at 46996 (acknowledging
SIFMA's comment that ``some broker-dealers do not have access to
execution times in a manner that is readily reportable under the EBS
infrastructure'' and would need to update their EBS infrastructure
to gather that information).
    \37\ See SIFMA Letter I, supra note 2, at B-2.
    \38\ See Extension Order I, supra note 4, at 25008.
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    To reduce implementation burdens, the Commission believes that it
is appropriate, at this time, to continue to limit the recordkeeping
and reporting obligations of the Rule to broker-dealers that carry
accounts for large traders, as they are already connected to the EBS
system. Accordingly, the Commission is extending its temporary
exemption of non-carrying brokers from the reporting requirement of the
Rule until November 1, 2015. In other words, for Phase Two, a
registered broker-dealer that is itself a large trader but does not
self-clear, as well as a broker-dealer effecting transactions directly
or indirectly for a large trader where a non-broker-dealer carries the
account for the large trader, are both temporarily relieved from the
reporting requirements of the Rule and, therefore, they do not need to
record and electronically report Transaction Data to the Commission
through the EBS system solely for purposes of the Rule. For the types
of large traders and transactions subject to reporting in Phases One
and Two, the Commission will obtain the Transaction Data it needs from
the carrying broker for the large trader, and therefore believes that
it is reasonable, at this time, to extend the temporary exemption
provided to other types of broker-dealers from the recordkeeping and
reporting requirements of the Rule.
    With respect to the specific transactions to be recorded and
reported by carrying brokers, as part of Phase One, the Commission
required recordkeeping and reporting of Transaction Data of proprietary
trades by broker-dealer large traders and transactions effected by a
large trader through a ``sponsored access arrangement.'' \39\ FIF had
previously noted that the trading activity of large traders with
sponsored access arrangements typically is processed by clearing
brokers on infrastructure separate from that used for other customers,
so that implementation of the Rule for sponsored access customers would
require less effort than for other types of large trader customers.\40\
According to the Industry Organizations, many broker-dealers charged
with recordkeeping and reporting of Transaction Data under the Rule do
not currently have ready access to all of that data for other types of
large trader customers, particularly disaggregated trades with
execution time, when it resides at unaffiliated broker-dealers. For
example, according to the Industry Organizations, while the executing
broker knows the execution time of a large trader's transaction, it
typically does not have the means to pass that information to the
clearing broker for the large trader in a format that is readily
reportable through EBS. Accordingly, to comply with the recordkeeping
and reporting requirements of the Rule, the clearing broker for the
large trader in many cases must make new arrangements to obtain
execution time data for large trader customers for reporting through
EBS.
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    \39\ In this context, a ``sponsored access arrangement'' was
defined as an arrangement in which a broker-dealer permits a large
trader customer to enter orders directly to a trading center where
such orders are not processed through the broker-dealer's own
trading system (other than any risk management controls established
for purposes of compliance with Rule 15c3-5 under the Exchange Act)
and where the orders are routed directly to a trading center, in
some cases supported by a service bureau or other third party
technology provider. See Extension Order I, supra note 4, 77 FR at
25009 n.22 (referencing the definition of the term used in the
adopting release for Rule 15c3-5).
    \40\ See FIF Letter, supra note 2 at 5.
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    Phase Two, as modified herein, represents an important incremental
step in the implementation of the Rule that is designed to allow the
Commission to collect Transaction Data, including execution time, with
respect to an additional group of large traders that are of particular
interest to the Commission in fulfilling its regulatory
responsibilities. Specifically, Phase Two will include Transaction Data
for large trader customers that trade through a ``direct market access
arrangement,'' which means an arrangement whereby a broker-dealer
permits an institutional customer to enter orders into a trading center
but such orders flow through the broker-dealer's trading systems prior
to

reaching the trading center.\41\ Because large trader customers that
trade through this type of direct market access arrangement have chosen
to retain control over critical aspects of the handling of their
orders, including the price, size, timing, and routing of individual
orders, their order handling decisions are of particular interest to
the Commission in conducting market reconstructions and analyses as
well as investigations. Direct market access arrangements subject to
recordkeeping and reporting in Phase Two, as modified, would include,
for example, those where the large trader customer enters individual
orders manually or through an algorithm under its control, but those
orders flow through the broker-dealer's systems prior to reaching the
trading center.\42\ Phase Two would not include, for example, large
trader customers that delegate to the broker-dealer the discretion to
determine the price, size, timing, or routing of individual orders.
---------------------------------------------------------------------------

    \41\ See Securities Exchange Act Release No. 63241 (November 3,
2010), 75 FR 69792, 69793 (November 15, 2010) (File No. S7-03-10)
(``Generally, direct market access refers to an arrangement whereby
a broker-dealer permits customers to enter orders into a trading
center but such orders flow through the broker-dealer's trading
systems prior to reaching the trading center. In contrast, sponsored
access generally refers to an arrangement whereby a broker-dealer
permits customers to enter orders into a trading center that bypass
the broker-dealer's trading system and are routed directly to a
trading center, in some cases supported by a service bureau or other
third party technology provider.''). The Commission notes that
sponsored access arrangements and direct market access arrangements
typically are entered into with the executing broker-dealer, which
may or may not also be the clearing broker for the large trader.
    \42\ See id. at 69793 (discussing how a direct market access
arrangement involves a broker-dealer allowing its customer to use
its systems to electronically access an exchange or alternative
trading system).
---------------------------------------------------------------------------

    From the Commission's perspective, including large trader activity
where the large trader retains control over the material terms of the
order and uses the broker-dealer primarily as a conduit to an execution
venue will capture trading activity that is similar in kind to the
sponsored access activity currently captured in Phase One, and is the
type of activity for which the precise time and other aspects of the
large trader's execution is of substantial regulatory interest.
Accordingly, clearing broker-dealers for such large traders will be
required to keep records of, and report to the Commission upon request,
all of the Transaction Data covered by the Rule, including both LTID
number(s) and execution time, on every EBS record for the categories of
large trader covered in Phase One and Phase Two.
    The Commission believes that capturing all of the Transaction Data
for the types of large trader transactions covered by Phases One and
Two (as modified herein) is important in the near term to the
Commission's enforcement and regulatory programs, and therefore the
Commission is requiring the recordkeeping and reporting of this
information as of November 1, 2013 (the current compliance date for
Phase Two). Accordingly, as of November 1, 2013, clearing broker
dealers for a large trader will be required to keep records and report
to the Commission upon request all Transaction Data for: (1)
Proprietary transactions by a large trader broker-dealer, (2)
transactions effected pursuant to a sponsored access arrangement, and
(3) transactions effected pursuant to a direct market access
arrangement.
    With respect to transactions other than those set forth above,
broker-dealers that carry an account for a large trader must record and
report, as of November 1, 2013, Transaction Data other than execution
time (e.g., LTID). The Commission notes that the Industry Organizations
have indicated that carrying brokers can readily provide the LTID,
because that information is available to them today, and the
arrangements to report it to the Commission through the EBS system
would not require significant technological development.\43\ Given the
relatively low implementation burdens, the Commission believes that
including the LTID on EBS data for all large traders would be
beneficial to the Commission, and help support, for example, its
investigative activities and analysis of significant market events.
---------------------------------------------------------------------------

    \43\ See, e.g., SIFMA Letter II, supra note 2 at 3.
---------------------------------------------------------------------------

    Finally, the recordkeeping and reporting requirements with respect
to Unidentified Large Traders, and the related monitoring safe harbor
provided by Rule 13h-1(f), will apply to broker-dealers that carry an
account for a large trader as of November 1, 2013. The Commission
believes that it is appropriate to apply the provisions that relate to
Unidentified Large Traders to the broker-dealers that otherwise will be
required to comply with the recordkeeping and reporting requirements as
of Phase Two--namely broker-dealers that carry accounts for large
traders--and that implementation of such provisions will help foster
compliance with the large trader identification requirements.

III. Summary of Phased Implementation

    With respect to Phase One and Phase Two, as modified, clearing
broker-dealers for large traders \44\ must obtain and report
Transaction Data that includes both execution time and LTID on
disaggregated trades for the following types of transactions:
---------------------------------------------------------------------------

    \44\ See supra note 31 and text accompanying note 31.
---------------------------------------------------------------------------

    (1) For Phase One, which began on November 30, 2012:
    (a) proprietary transactions by large traders that are U.S.-
registered broker-dealers;
    (b) transactions effected by large traders through a sponsored
access arrangement; \45\ and
---------------------------------------------------------------------------

    \45\ See supra note 39 (defining sponsored access arrangements).
---------------------------------------------------------------------------

    (2) for Phase Two, which will begin on November 1, 2013:
transactions effected by large traders through a direct market access
arrangement.\46\
---------------------------------------------------------------------------

    \46\ See supra note 41 and text accompanying note 41 (defining
direct market access arrangements).
---------------------------------------------------------------------------

    Further, with respect to all other types of transactions, for Phase
Two, the prime broker or other carrying broker-dealer for a large
trader must obtain and report Transaction Data, including LTID, for all
such large traders, but is not required to report execution time.
    In addition, with respect to the requirements relating to
Unidentified Large Traders, which will apply to carrying broker-dealers
as of Phase Two, the compliance date for broker-dealers that wish to
avail themselves of the monitoring safe harbor provided by Rule 13h-
1(f) to establish appropriate policies and procedures is November 1,
2013.
    Phase Three, which will begin November 1, 2015, covers the
remaining types of large traders and transactions not covered by Phases
One and Two. Specifically, all other broker-dealers subject to the
recordkeeping and reporting requirements of the Rule (i.e., broker-
dealers that are large traders but do not self-clear, and broker-
dealers effecting transactions directly or indirectly for a large
trader where a non-broker-dealer carries the account for the large
trader) are temporarily exempted from recording and reporting
Transaction Data through the EBS system for the duration of Phase Two.
Unless the Commission otherwise provides in the future, Phase Three
will require all broker-dealers subject to the recordkeeping and
reporting requirements of Rule 13h-1 to come into full compliance with
those provisions.

IV. Conclusion

    It is hereby ordered, pursuant to Exchange Act Section 13(h)(6) and
Rule 13h-1(g) thereunder, that broker-dealers are exempted temporarily
until November 1, 2015 from the recordkeeping and reporting
requirements of Rule 13h-1(d) and (e), except for (1) the clearing
broker-dealers for large traders, with respect to (a) Proprietary
transactions by a large trader broker-dealer; (b) transactions effected
pursuant to a ``sponsored access'' arrangement; \47\ and (c)
transactions effected pursuant to a ``direct market access''
arrangement; \48\ and (2) broker-dealers that carry an account for a
large trader, with respect to transactions other than those set forth
above, and for Transaction Data other than the execution time.\49\
---------------------------------------------------------------------------

    \47\ See supra note 39 (defining sponsored access arrangements).
    \48\ See supra note 41 and text accompanying note 41 (defining
direct market access arrangements).
    \49\ See supra note 35.

By the Commission.
Elizabeth M. Murphy,
Secretary.
[FR Doc. 2013-19650 Filed 8-13-13; 8:45 am]
BILLING CODE 8011-01-P


observed in the collecting ducts and papillary/pelvic epithelium in 2/50
males. In the prostatic urethra, urothelial hyperplasia was observed in
1/50 males. All the effects seen in the urinary tract were considered to
be due to a single and chronic irritative mechanism, resulting from the
formation of stones or crystals.

There was no neoplastic change in either sex.

Analysis of urinary bladder stones taken from one male at terminal
sacrifice revealed that the composition of the stones consisted of
approximately 90 to 95% of test material.

At 350 ppm:

No treatment-related changes were observed in either sex.

In conclusion, dietary administration of AE 0001789 over an 18-month
period to the C57BL/6J mouse, at dose levels up to 3500 ppm
(corresponding to 506 mg/kg/day in males and 616 mg/kg/day in females),
produced transitional cell papilloma in the urinary bladder of females.
The incidence of these tumours was very low and was considered to be
secondary to the chronic hyperplastic changes resulting from chronic
irritation due to the presence of calculi. Thus AE 0001789 was
considered not to be directly carcinogenic in the mouse. The No Observed
Effect Level (NOEL) was 350 ppm for males (equivalent to 50 mg/kg/day)
and 2000 ppm for females (equivalent to 354 mg/kg/day).

EVALUATION, SUMMARY AND CONCLUSION BY REGULATORY AUTHORITY

Name of authority	Pesticides Safety Directorate, UK

Reviewer’s Comments	Reliability rating: Totally reliable

The study (M-281276-01-2) is fully compliant with OECD 451

There was marked toxicity at the top dose (7000 ppm) which exceeded the
MTD in both sexes, clearly demonstrated by marked individual body weight
loss and mortality in both sexes. This resulted in early termination of
this group of males on Day 320 and females on Day 40.  Due to the poor
condition of the animals at 7000 ppm, only data pertaining to mortality,
clinical signs, body weight parameters and food consumption (in-life
phase), which reflected the poor condition of the animals, were included
in the study report

There was a treatment related increase in mortality in males at 3500 ppm
was higher than controls after both 12 and 18 months of treatment (20.0%
and 58.1%, respectively). The deaths were a result of the presence of
stones within the urinary tract, causing acute or chronic renal failure
or due to secondary treatment-related nephropathy. This finding together
with the clear treatment related effects on bodyweights at 3500 ppm (by
the end of the study mean cumulative bodyweight gain in males was 12%
lower than controls) indicates this dose demonstrated sufficient
toxicity.

	Week	Survival in carcinogenicity group (50 animals/sex/group)

M	F

0	350	2000	3500	0	350	2000	3500

	54	47	48	49	39	44	47	42	48

94%	96%	98%	78%	88%	94%	84%	96%

	65	46	42	47	32	44	46	41	45

92%	84%	94%	64%	88%	92%	82%	90%

	75	40	35	41	27	42	44	39	41

80%	70%	82%	54%	84%	88%	78%	82%

	80	19	11	21	21	22	25	20	39

38%	29%	42%	42%	44%	50%	40%	78%

	At 3500 ppm at the 18-month haematology determination, a tendency
towards lower RBC count was noted in both sexes. This change was
associated with a slightly lower haemoglobin concentration, haematocrit
and mean corpuscular haemoglobin concentration and a slightly higher
mean corpuscular volume. This corresponds to similar effects seen in the
short terms studies in the rat and dog, although not in the 90 day mouse
study.

Apart from the effects on the urinary system long term dosing in the
mouse resulted in treatment-related effects in the males specifically
centrilobular to panlobular hepatocellular hypertrophy doses > 2000 pp
and an increased incidence of hepatocellular single cell necrosis was
observed at 3500 ppm. Another notable change was observed in the
lymphoid system (apoptotic bodies and/or lymphoid atrophy) at 3500 ppm
which was considered stress induced. In the heart, a higher incidence of
epicardial mixed cell infiltrate was noted in 5/50 males at 3500 ppm,
when compared to no cases in controls. This minimal change only observed
in males was considered to be an indirect response to the treatment.

Two treatment related tumours were observed in this study both in top
dose females, and both transitional cell papillomas in the urinary
bladder. These tumours were very likely to be a consequence of the
chronic irritation/hyperplasia due to the presence of calculi. Analysis
of urinary bladder stones taken from one male and one female at terminal
sacrifice revealed that the composition of the stones consisted of
approximately 90 to 95% of test material.

The only other statistically significant neoplastic change was an
increased incidence of histiocytic sarcoma was noted in females at 3500
ppm (5/50) cf. 0/50 in controls. Single histiocytic sarcomas were also
noted at 350 ppm (females) and 2000 ppm (males). The Notifier has
provided some published historical control data from the early and late
1990’s; this study was conducted 2004-6 so the relevance of these data
is questionable. The HC data indicate incidence of histiocytic sarcoma
in the C57BL/6J mouse for a 19 months study, similar in length to this
study ranged between 6-42%.

Overall the HC data do show that there is a high backgrounds incidence
of histiocytic sarcoma in the C57BL/6J mouse. The tumours seen at 3500
ppm in females have an equivocal relationship to treatment at worst.

Conclusions	Cyprosulfamide was carcinogenic in the mouse although the
occurrence of tumours (transitional cell papilloma in the urinary
bladder of females) was considered to be secondary to the chronic
hyperplastic changes resulting from chronic irritation due to the
presence of calculi.

In males a NOAEL of 350 ppm (equivalent to 50 mg/kg bw/day) was based on
the effects seen in the urinary tract (combination of hyperplastic and
inflammatory changes) resulting from the presence of stones and/or
crystals at 2000 ppm and some evidence of hepatotoxicity.

In females a NOAEL of 2000 ppm for females (equivalent to 345 mg/kg
bw/day) was based on the effects seen in the urinary tract (combination
of hyperplastic and inflammatory changes, and tumours) resulting from
the presence of stones and/or crystals at 3500 ppm.

SUMMARY OF LONG-TERMTOXICITY AND CARCINOGENICITY DATA BY REGULATORY
AUTHORITY

Name of authority: Pesticides Safety Directorate, UK

Cyprosulfamide was investigated in two guideline studies in the rat and
mouse.  Treatment related tumours were seen in both species

In the rat there was a slight treatment related increase in mortality in
top dose females where half of the unscheduled deaths were attributed to
treatment-related nephropathy.  A concerning aspect of the study was
poor survival rates in males- across all groups (survival rates at 104
weeks falling to 41.1%, 49.2%, 27.4%, and 34.4% at 0, 1000, 4000 and
8000 ppm respectively).  Survival in males at doses of 4000 ppm and 8000
ppm drop below 50% at around week 94.  It was considered that this
weakens the carcinogenicity assessment at these dose levels

Sulphonamide-like crystals were observed at 8000 and 4000 ppm in both
sexes.  This finding was dose-related in terms of incidence and/or
severity on most occasions, the effect being more pronounced in females
than in males.  Urinalysis revealed slightly lower urinary protein
levels throughout most the study in both sexes at 8000 and 4000 ppm
compared to controls.  A statistically significant increase in urinary
volume was noted at 8000 ppm in females during the toxicity phase of the
study (59% higher than controls), although this was not observed during
the second year of the study.

Gross necropsy of both premature decedents and at terminal sacrifice
revealed treatment related changes in the kidneys and urinary bladder at
doses >4000 ppm.  Findings in the kidneys included abnormal shape,
pelvic dilatation, irregular surface, gritty content and stones.  In the
urinary bladder stones were observed.

At 24 months treatment-related non-neoplastic effects were observed in
the urinary tract, i.e. kidney, urinary bladder and ureter, including a
combination of hyperplastic and inflammatory changes associated with the
presence of stones.  Treatment-induced nephropathy was observed at a
higher incidence in both sexes in the kidney at 8000 ppm, with an
increased severity in females, and at 4000 ppm in a higher incidence in
females only.  Treatment-induced nephropathy is a general term which
incorporates some or all of the following findings: stones, papillary
necrosis/loss/scarring, collecting duct hyperplasia, bilateral
cortico-medullary scarring, pelvic dilatation and bilateral
cortex/medulla tubular dilatation.  In addition, an increased incidence
of pelvic dilatation was noted at 4000 ppm in males.

A slight increase in severity of simple pelvic epithelium hyperplasia
was observed in both sexes at 8000 and 4000 ppm. Nodular pelvic
epithelium hyperplasia and a higher incidence of intrapelvic mineral
deposit was observed in females at 8000 ppm. Intraluminal stones and
multifocal/diffuse urothelial hyperplasia were observed in the urinary
bladder in both sexes at 8000 ppm and in females at 4000 ppm.
Suburothelial mononuclear cell infiltrate and mixed cell infiltrate were
considered to be associated lesions

An increased incidence of the commonly occurring lesion diffuse
bilateral tubular degeneration of the testis (associated with diffuse
interstitial oedema and/or focal/multifocal mineralization in most
cases) and bilateral oligospermia of the epididymis (associated with
epithelial degenerative change) was observed at 8000 ppm, which was
considered to be treatment-related.

Indirect systemic changes commonly associated with induced nephropathy,
including compensatory hyperplasia of the parathyroid glands associated
with mineralization, especially involving lungs and the gastric mucosa,
were observed at 8000 ppm mainly in females.

At 24 months treatment-related neoplastic changes were seen at 8000 ppm,
a transitional cell carcinoma was observed in the kidney in one male and
a transitional cell carcinoma was observed in the urinary bladder in one
female.  These two single tumours were considered to be secondary to the
combination of hyperplastic and inflammatory changes associated with the
presence of stones

In the mouse mortality was higher in males at 3500 ppm than in the
control group after 12 and 18 months of treatment, largely due to the
presence of stones within the urinary tract, causing acute or chronic
renal failure or due to secondary treatment-related nephropathy
following product administration.  At 3500 ppm at the 18-month
haematology determination, a tendency towards lower RBC count was noted
in both sexes.  This change was associated with a slightly lower
haemoglobin concentration, haematocrit and mean corpuscular haemoglobin
concentration and a slightly higher mean corpuscular volume.  This
corresponds to similar effects seen in the short terms studies in the
rat and dog, although not in the 90 day mouse study.

Histopathological treatment-related changes were mainly attributed to
the presence of urinary stones or to treatment-related nephropathy.
These changes were located in the urinary bladder and to a less extent
to the kidney at the 12-month interim sacrifice.  At the carcinogenicity
phase (18-month) sacrifice, changes due to treatment-related nephropathy
were seen in the kidney, urinary bladder, prostatic urethra and ureters.
 In the liver, minimal to slight centrilobular to panlobular
hepatocellular hypertrophy and an increased incidence of hepatocellular
single cell necrosis were observed in males.  All the effects seen in
the urinary tract were considered to be due to a single and chronic
irritative mechanism, resulting from the formation of stones or
crystals.  In addition, indirect treatment-related findings were
observed in the lymphoid system in males (apoptotic bodies in the spleen
and mesenteric lymph nodes, and lymphoid atrophy in the spleen) and were
considered to be secondary to the stress induced by the stone deposition
and/or the treatment-related nephropathy. In the heart, a higher
incidence of epicardial mixed cell infiltrate was noted in 5/50 males at
3500 ppm, when compared to no cases in controls.  This minimal change
only observed in males was considered to be an indirect and non-adverse
response to the treatment.

Neoplastic changes comprised transitional cell papilloma in the urinary
bladder of 2/49 females at 3500 ppm. This finding was considered to be
secondary to the chronic hyperplastic changes due to the presence of
calculi. Analysis of urinary bladder stones taken from one male and one
female at terminal sacrifice revealed that the composition of the stones
consisted of approximately 90 to 95% of test material.

A NOAEL of 1000 ppm for both sexes (equivalent to mean achieved dietary
intakes of 147 and 185 mg/kg bw/d in males and females respectively)
was determined for this study.

Relevance of tumours to the human risk assessment

Cyprosulfamide was shown to be carcinogenic in rats and mice.  In the
rat there was a low incidence of transitional cell carcinoma in the
kidney and transitional cell carcinoma in the urinary bladder. In the
mouse a low incidence of transitional cell papilloma in the urinary
bladder.  In both species the formation of these tumours was a result of
a non-genotoxic threshold mechanism involving chronic irritation
secondary to the formation of calculi.  The Notifier has proposed a
mechanism these tumours see IIA 5.5.4 below.  The proposed mechanism is
considered to be plausible and fulfils the critical criteria of the IPCS
conceptual framework for analysis of the relevance of a cancer mode of
action for humans (IPCS, 2001).  While there is little in the way of
mechanistic data, key aspects of the IPCS criteria including a
dose-response relationship with a clear threshold, biological
plausibility and coherence, temporal association are satisfied.
Cyprosulfamide is considered to be non-genotoxic.  The lack of relevance
of the mode of carcinogenesis for the human risk assessment means that
classification of cyprosulfamide for carcinogenicity (current EC
criteria) is not proposed.

HED Reviewer Comments:

Classification: Acceptable/Guideline.  This study satisfies the
guideline requirement for a series 870.4200 carcinogenicity study in
mice.

A.3.6	Mutagenicity

Cyprosulfamide and metabolites – mutagenicity studies.

Study

MRID

Results	Classification:

UK/HED*

Cyprosulfamide

870.5100. Bacterial – Ames test	470698219

(2006)

Parent (96.0%)	Not antibacterial, Not mutagenic at up to 5000 (g/plate.
[Reliable with restrictions]/

Acceptable/Guideline

870.5100. Bacterial – Ames test	47069820 (2004/2005)

Parent (97.4%)	Not mutagenic	[Reliable with restrictions]/

Acceptable/Guideline

870.5300. Forward mutation	47069823 (2006)

Parent	Negative in the V79/HPRT forward mutation test 	[Reliable with
restrictions]/

Acceptable/Guideline

870.5375. In vitro chromosome

aberration test in V79	47069826 (2004/2006)

Parent	No clastogenic effect at up to 1600 (g/ml.	[Totally reliable]/

Acceptable/Guideline

870.5395.

Micronucleus test in vivo	47069829 (2004/2006)

Parent	No evidence of a clastogenic effect after two doses up to 2000
mg/kg (ip)	[Totally reliable]/

Acceptable/Guideline

Metabolite: Sulfamoylbenzoic acid

870.5100.Bacterial – Ames test	47069821 (2006)

Sulfamoylbenzoic acid	Not mutagenic	[Reliable with restrictions]/

Acceptable/Guideline

870.5300. Forward mutation	47069824 (2006)

Sulfanoylbenzoic

Acid	Negative in the V79/HPRT forward mutation test	[Totally reliable]/

Acceptable/Guideline

870.5375. In vitro chromosome

aberration test in V79	47069827 (2006)

sulfamoylbenzoic acid	Negative	[Totally reliable]/

Acceptable/Guideline

Metabolite: Cyclopropyl-sulfamoylbenzamide

870.5100.Bacterial – Ames test	47069822 (2006) Cyclopropyl-
sulfamoylbenzamide	Not mutagenic	[Totally reliable]/

Acceptable/Guideline

870.5300. Forward mutation	47069825 (2006)

Cyclopropyl- sulfamoylbenzamide	Negative in the V79/HPRT forward
mutation test	[Totally reliable]/

Acceptable/Guideline

870.5375. In vitro chromosome

aberration test in V79	47069828 (2006)

Cyclopropyl-sulfamoylbenzamide	Negative	[Totally reliable]/

Acceptable/Guideline

 TC \l3 "A.3.6	Mutagenicity

A.3.7	Neurotoxicity TC \l3 "A.3.7	Neurotoxicity

	870.6100 Delayed Neurotoxicity Study - Hen

No study available and not required.

	870.6200 Acute Neurotoxicity Screening Battery - MRID No>; 47069830.

Executive summary:

Technical grade AE 0001789 (batch number 08466/0013, 97.4% purity) was
administered by gavage in a single dose to non fasted young-adult Wistar
rats. Four dose groups (12 rats/sex/dose level) were administered the
test substance at nominal doses of 0 (vehicle), 125, 500 or 2000 mg/kg
for both sexes. The test substance was administered in 0.5%
methylcellulose / 0.4% Tween 80 in deionized water, at a dosing volume
of 10 ml/kg. Dose concentrations, as well as the homogeneity and
stability of AE 0001789 in the dosing suspensions, were confirmed. All
12 rats/sex/dose level were used for neurobehavioural evaluation, with
six/sex/dose level used for micropathology. Body weight was measured
weekly as a component of the functional observational battery (FOB).
Detailed clinical observations for each animal were performed daily
throughout the study. Observations for moribundity and mortality were
performed at least once daily. Automated measurements of activity
(figure-eight maze) and a functional observational battery (FOB) were
conducted during the week prior to treatment and on days 0 (the day of
treatment, at the time of peak effect), 7 and 14. All animals placed on
study were subjected to a gross necropsy. Selected animals (six/sex/dose
level) were perfused, the brain was weighed in order to calculate the
brain/body weight ratio and skeletal muscle, peripheral nerves, eyes
(with optic nerves) and tissues from the central nervous system were
examined microscopically for lesions.

Based on analytical results, the actual doses of AE 0001789 used in the
study were 0, 126, 508 and 2060 mg/kg for males and females.

Findings attributed to exposure to AE 0001789 were as follows:

2060 mg/kg: Urine staining was evident in both sexes on day 0 and
resolved by the following day.

508 mg/kg: There were no signs related to treatment in either sex.

126 mg/kg:  There were no signs related to treatment in either sex.

In conclusion, compound-related effects following a single oral dose of
the test substance were limited to the high dose (2060 mg/kg) males and
females. Effects in high-dose males and females consisted of urine
staining, which resolved the following day after treatment. Based on
these findings, a NOEL of 508 mg AE 0001789/kg body weight was
established in both sexes. There was no evidence of neurotoxicity at any
dose level and there were no compound-related gross or microscopic
lesions at the high dose of 2060 mg/kg.

EVALUATION, SUMMARY AND CONCLUSION BY REGULATORY AUTHORITY

Name of authority	Pesticides Safety Directorate, UK

Reviewer’s comments	Reliability rating: Reliable with restrictions

	The study is compliant with OECD 424 (1997) with the exception of the
following deviations:

	The guideline states that ‘dosing should normally begin as soon as
possible after weaning, preferably not later than when the animals are
six weeks, and, in any case, before the animals are nine weeks of
age’.  The study report states that the animals in this study were
‘at least nine weeks’ old at the time of dosing.  This deviation is
not considered to affect the integrity of the study in this case.  It is
noted that there was no indication of neurotoxicity in any of the
standard toxicity studies (required under Directive 91/414/EEC),
including the neurotoxicity assessment in the 90-day toxicity study.  A
study of neurotoxicity is therefore not a specific data requirement for
this compound according to EU legislation, based on the absence of
findings in the other studies and the mode of action of the compound.

	Food consumption was not measured in this study, whereas the guideline
specifies that food consumption should be measured at least weekly.
This deviation is not considered to be critical and does not affect the
integrity of the study.  Food consumption was not affected in most of
the other studies in the rat (or other species).

Conclusions	No evidence of neurotoxicity or neuropathology was seen
following the administration of a single oral limit dose of 2060 mg/kg
bw under the conditions of this study.  A NOAEL of 508 mg/kg bw can be
determined, based on urine staining at the top dose level of 2060 mg/kg
bw

HED Reviewer Comments:

This study is classified as ACDEPTABLE/GUIDELINE and satisfies the
requirement for a series 870.6200 acute neurotoxicity screen study. HED
concurs with the NOAEL and LOAEL.

	870.6200 Subchronic Neurotoxicity Screening Battery - MRID No.:
47069831

Technical grade AE 0001789 (batch number 08466/0013, 97.4 to 97.5%
purity) was administered in the diet for 13 weeks to young-adult Wistar
rats (12/sex/dietary level), using nominal concentrations of 0, 1000,
3000 and 9000 ppm for males and females. The top dose level for this
study was chosen based on mortality observed in a 90-day toxicity study
(M-105691-01-2) at a higher dietary level (i.e., 12,000 ppm). All test
diets (including control) were provided for ad libitum consumption
throughout the study except during neurobehavioural testing. All 12
rats/sex/dietary level were used for neurobehavioural evaluation, with
micropathology performed on selected tissues from 6 rats/sex from
control and high-dose groups. Body weight and food consumption
determinations, as well as a detailed clinical observation for each
animal, were conducted weekly throughout the study. Observations for
moribundity and mortality were performed at least once daily. Automated
measurements of activity (figure-eight maze) and a functional
observational battery (FOB) were conducted the week prior to treatment
and during weeks 2, 4, 8 and 13. Ophthalmologic examinations were
conducted on all animals prior to shipment release and then again on all
study animals during week 12. All animals placed on study were subjected
to a gross necropsy. For selected animals, the brain was weighed in
order to calculate the brain:body weight ratio and skeletal muscle,
peripheral nerves, eyes (with optic nerves) and tissues from the central
nervous system were also examined microscopically for lesions.  SEQ
CHAPTER \h \r 1

The mean daily intake of the test substance (mg AE 0001789/kg body
wt/day) over approximately 13 weeks at nominal dietary concentrations of
1000, 3000 or 9000 ppm, respectively, was 65.2, 193 and 592 mg/kg/day
for males and 84.5, 251 and 748 mg/kg/day for females.

There were no treatment-related effects attributed to exposure to AE
0001789 at any dietary level in either sex.

Conclusions.  Through approximately 13 weeks of continuous dietary
exposure to the test substance, there were no treatment-related findings
apparent at any dietary level in either sex.  Based on these findings, a
NOEL of 9000 ppm was established for the rat (equating to 592 and 748 mg
AE 0001789/kg body wt/day for males and females, respectively).

EVALUATION, SUMMARY AND CONCLUSION BY REGULATORY AUTHORITY

Name of authority	Pesticides Safety Directorate, UK

Reviewer’s comments	Reliability rating: Totally reliable

The study is fully compliant with OECD 424.

The animals in this study stated in the study report to be approximately
eight weeks old on Study Day 0, and not ‘at least 9 weeks’ as stated
in the Notifier’s summary.  The age of the animals is therefore
compliant with that specified in the OECD guideline (see comments for
the acute neurotoxicity study, above).

It is noted that there was no indication of neurotoxicity in any of the
standard toxicity studies (required under Directive 91/414/EEC),
including the neurotoxicity assessment in the 90-day toxicity study or
in the acute neurotoxicity study.  A study of neurotoxicity is therefore
not a specific data requirement for this compound according to EU
legislation, based on the absence of findings in the other studies and
the mode of action of the compound..

No treatment-related findings were apparent in this study, based on the
90-day toxicity study in the rat (Mc Elligott A. 2003, SA 02352) as
higher dose could have been employed however based on the absence of any
evidence of neurotoxicity in other study this is not considered a
concern.

Conclusions	No evidence of neurotoxicity or neuropathology was seen
under the conditions of this study.

A NOAEL of 9000 ppm (equivalent to mean achieved dietary intakes of 592
and 748 mg/kg bw/d in males and females respectively) can be
determined, in the absence of any treatment-related findings at the top
dose level.

HED Reviewer Comments:

This study is classified as ACCEPTABLE/GUIDELINE and satisfies the
requirement for a series 870.6200 subchronic neurotoxicity screen study
in rats.  HED concurs with the NOAEL and LOAEL setting.

	870.6300 Developmental Neurotoxicity Study

No study available and not required.

A.3.8	Metabolism TC \l3 "A.3.8	Metabolism

	870.7485	Metabolism - Rat

Study 1. MRID No. 47069832. (sulfonylbenzamide label - pharmacokinetics)

The biokinetic behaviour and metabolism of [sulfonylbenzamide-UL-14C] AE
0001789 was investigated in the rat following a single oral dose. Groups
of four animals each received a single dose per gavage at a dose level
of 2 and 200 mg/kg b.w... The absorption kinetic of the test item was
followed by the time-dependent level of radioactivity in blood plasma.
The distribution of the radioactivity in organs and tissues was studied
after sacrifice, 96 hours of administration. The metabolism was could be
derived from the observed metabolites in urine and faeces. The
elimination of radioactive residues was determined by time-dependent
determination of the radioactivity in urine and faeces.

The gastro-intestinal absorption of the test item started immediately
after dosing. The maximum plasma levels were reached already after 10
– 60 minutes. The absorption was complete at the low dose (2 mg/kg
b.w.) in both sexes; more than 90 % of the dose recovered was renally
excreted or remained in the body at sacrifice, 96 hours after dosing
(without GIT). The excretion was fast and almost complete after 72 hours
as more than 84 % of the administered dose (corresponding to > 98 % of
the recovered radioactivity) was excreted 72 hours after administration.
The predominant route of excretion was via urine, accounting for 69 to
90 % of the dose administered.

In the high dose group, a certain saturation of the absorption process
could be observed as shown via the maximum dose-normalized plasma
levels. They were lower in the high-dose than in the low-dose animals
and the faecal excretion was increased in the high-dose animals by a
factor of 2 – 3 compared to the low-dose animals.

Insignificant of radioactive residues remained in the organs, tissue and
carcass at sacrifice, 96 hours after administration; the sum of the
total residues amounted to < 0.06 % of the administered dose in all
animals. Particular increase of radioactivity in certain organs and
tissues could not be observed. Therefore, it can be concluded that
residues of AE 0001789 did not accumulate in any of the organs, tissues
or glands.

A delayed gastric emptying was observed with some of the high-dose
animals, resulting in a double peak in the plasma concentration-time
curves and in a late excretion of significant portions of the
administered dose between 24 and 72 hours after the administration.
These double peak phenomena in plasma profiles already have been
described in the pharmacokinetic literature as effects caused by
discontinuous absorption and/or delayed gastric emptying of a portion of
the dose.

From the metabolites identified in urine and faeces three metabolic
steps can be derived.

(1) Elimination of the cyclopropylamine moiety by hydrolysis of
carboxamide bond in the sulfonylbenzamide part forming AE
0001789-descyclopropylamino.

(2) Desmethylation of the methoxybenzoyl moiety leading to AE
0001789-desmethyl

(3) Hydrolytic cleavage of carboxamide bond in the methoxybenzoyl group
of the parent molecule or of AE 0001789-desmethyl resulting in AE
0001789-cyclopropyl-sulfamoylbenzamide.

Sex-specific differences were not observed with the absorption,
distribution, metabolism and excretion of AE 0001789.

Study No.: 2 - MRID No.: 47069832 - (sulfonylbenzamide label - tissue
distribution).

The distribution of radioactive residue in organs and tissues of male
rats were investigated following oral administration of
[sulfonylbenzamide-ring-UL-14C]AE 0001789 at an actual dose rate of 4.95
mg/kg b.w in Tragacanth as vehicle. Eight animals were employed in the
test and were sacrificed at the following time intervals: 1, 4, 8, 24,
48, 72, 120 and 168 hours after administration. After sacrifice, they
were fixed in a metal template in a stretched position and immediately
shock-frozen at approximately – 70°C in a dichloromethane/dry ice
bath. After removal of the template, the animal’s body was embedded in
a slurry of carboxymethyl-cellulose (7 – 8 %) together with
radioactively spiked blood standards on the platform of a microtome. The
slurry with the rat’s body and the blood standard was deep-frozen in a
block. Sections with a thickness of 50 µm from different depths of the
body were cut from the block, attached to an adhesive tape and
freeze-dried overnight in the cooled microtome. Sections with relevant
organs and tissues were used for exposure of imaging plates to scan the
radioactivity contained in these organs and tissues.

The radioactivity contained in the sections excited sensitive material
of the imaging plates at a high spatial resolution. The excitation was
scanned as photostimulated luminescence by an image analyser providing
autoradiography pictures and digital scans. With use of the
radioactively spiked blood standards a linear correlation could be
derived between the photostimulated luminescence counts per square
millimetre and the radioactivity per mass (dpm/g) of the freeze-dried
animal matrix and square millimetre after subtraction of the background
luminescence. Self-absorbing quenching effects of the animal matrix were
compensated by measuring the transmission of 14C-radioactivity
homogenously distributed over a basis foil through sections originating
from a non-radioactive control animal overlaid over the radioactive
basis foil. For each organ and tissue the transmission ratio between
matrix and blood and its reciprocal as correction factor could be
determined according to a publication of Klein, Binder and Steinke
(2000). Integration of the unit area (square millimetre) to the total
area of the organ or tissue yielded the radioactivity concentration of
this organ or tissue. Division by the specific radioactivity of the
administered test item finally resulted in the equivalent concentration
(µg parent equivalents per gram organ or tissue).

Using this technique it was shown that radiolabeled AE 0001789 was very
quickly absorbed from the gastrointestinal tract. The maxima of the
radioactivity levels were observed already one hour after administration
in almost all organs and tissues. Normalization of the maximum residue
levels by division through the dose rate resulted in dose normalized
concentration that was generally less than unity indicating that
bioaccumulation is very unlikely. With particular reference to the
organs of the endocrine system no accumulation of AE 0001789 occurred.
Residues from glandular organs or tissues responsible for hormonal
regulation (such as adrenal, testis, or thyroid gland) were rapidly
depleted in parallel with depletion from the other organs and tissues.

The absorption process was apparently interrupted, likely due to a delay
gastric emptying occurring between 4 and 48 hours after administration.
This phenomenon could be deduced from the high amounts of radioactivity
remaining in the gastro-intestinal tract in concurrence with an inflated
stomach until 48 hours after dosing, and from the slight increase in the
radioactive residues observed in most organs and tissues 48 h after the
administration.

At all intervals of sacrifice the highest radioactivity levels were
detected in blood and the excretory organs kidney and liver. Radioactive
residues in all organs and tissues decreased rapidly between 1 and 72
hours. Between 120 and 168 hours of dosing all organ and tissue levels
were below LOQ or LOD.

From additional monitoring of the radioactivity excreted with urine and
faeces it was shown that excretion with urine was the predominant
excretion route. This excretion was very fast with high radioactivity
levels in urine already 8 hours after dosing. Excretion was complete at
the end of the test period, 168 hours after administration.

Study No.: 3 - MRID No.: 47069833 (methoxybenzoyl-ring label -
pharmacokinetics).

The biokinetic behaviour and metabolism of
[methoxybenzoyl-ring-UL-14C]AE 0001789 was investigated in four male
rats following a single oral dose of 2 mg/kg b.w. given per gavage. The
absorption kinetic of the test item was followed by the time-dependent
radioactivity level in blood plasma. The distribution of the
radioactivity in organs and tissues was studied after sacrifice, 96
hours of administration. The metabolism was could be derived from the
observed metabolites in urine and faeces. The elimination of radioactive
residues was determined by time-dependent determination of the
radioactivity in urine and faeces.

The gastro-intestinal absorption of the test item started immediately
after dosing. The maximum plasma levels were reached already after 40
minutes. The absorption was nearly complete, approximately 82 % of the
dose recovered was renally excreted or remained in the body at
sacrifice, 96 hours after administration (without GIT). Excretion via
urine (82 % or the radioactivity recovered) was determined as
predominant route of excretion. A total of 18 % were excreted with the
faeces.

Consequently, residues in tissues and organs at sacrifice were very low.
Between <0.001 % and 0.029 % of the administered radioactivity were
found in the individual organs and tissues of the rats. In total,
approximately 0.07 % of the administered dose was found in the body of
the rats (inclusive GIT).

From the metabolites identified in urine and faeces three metabolic
steps can be derived.

(1) Elimination of the cyclopropylamine moiety by hydrolysis of
carboxamide bond in the sulfonylbenzamide part forming AE
0001789-descyclopropylamino (AE 0893016).

(2) Desmethylation of the methoxybenzoyl moiety leading to AE
0001789-desmethyl (AE 01448796)

(3) Hydrolytic cleavage of carboxamide bond in the methoxybenzoyl group
of the parent substance or the primary metabolite AE
0001789-descyclopropylamino resulting in AE 0001789-anisic acid
(AE 0854787).

Study No.: 4. - MRID No.: 47069833 - (methoxybenzoyl-ring label - tissue
distribution).

The distribution of radioactive residue in organs and tissues of male
rats were investigated following oral administration of
[methoxybenzoyl-ring-UL-14C]AE 0001789 at an actual dose rate of 4.94
mg/kg b.w in Tragacanth as vehicle. Eight animals were employed in the
test and were sacrificed at the following time intervals: 1, 4, 8, 24,
48, 72, 120 and 168 hours after administration. After sacrifice, they
were fixed in a metal template in a stretched position and immediately
shock-frozen at approximately – 70°C in a dichloromethane/dry ice
bath. After removal of the template, the animal’s body was embedded in
a slurry of carboxymethyl-cellulose (7 – 8 %) together with
radioactively spiked blood standards on the platform of a microtome. The
slurry with the rat’s body and the blood standard was deep-frozen in a
block. Sections with a thickness of 50 µm from different depths of the
body were cut from the block, attached to an adhesive tape and
freeze-dried overnight in the cooled microtome. Sections with relevant
organs and tissues were used for exposure of imaging plates to scan the
radioactivity contained in these organs and tissues.

The radioactivity contained in the sections excited sensitive material
of the imaging plates at a high spatial resolution. The excitation was
scanned as photostimulated luminescence by an image analyser providing
autoradiography pictures and digital scans. With use of the
radioactively spiked blood standards a linear correlation could be
derived between the photostimulated luminescence counts per square
millimetre and the radioactivity per mass (dpm/g) of the freeze-dried
animal matrix and square millimetre after subtraction of the background
luminescence. Self-absorbing quenching effects of the animal matrix were
compensated by measuring the transmission of 14C-radioactivity
homogenously distributed over a basis foil through sections originating
from a non-radioactive control animal overlaid over the radioactive
basis foil. For each organ and tissue the transmission ratio between
matrix and blood and its reciprocal as correction factor could be
determined according to a publication of Klein, Binder and Steinke
(2000). Integration of the unit area (square millimetre) to the total
area of the organ or tissue yielded the radioactivity concentration of
this organ or tissue. Division by the specific radioactivity of the
administered test item finally resulted in the equivalent concentration
(µg parent equivalents per gram organ or tissue).

Using this technique it was shown that radiolabeled AE 0001789 was very
quickly absorbed from the gastrointestinal tract. The maxima of the
radioactivity levels were observed already one hour after administration
in almost all organs and tissues. Normalization of the maximum residue
levels by division through the dose rate resulted in dose normalized
concentration that was in almost all organs and tissues less than unity
indicating that bioaccumulation is very unlikely. Only kidney (renal
medulla) as a main excretory organ showed a higher dose normalized
radioactivity level than unity. In addition, blood was slightly above
unity.

With particular reference to the organs of the endocrine system no
accumulation of AE 0001789 occurred. Residues from glandular organs or
tissues responsible for hormonal regulation (such as adrenal, testis, or
thyroid gland) were rapidly depleted in parallel with depletion from the
other organs and tissues

The absorption process was apparently interrupted, likely due to a delay
gastric emptying occurring between 4 and 24 hours after administration.
This phenomenon could be deduced from the high amounts of radioactivity
remaining in the gastro-intestinal tract in concurrence with an inflated
stomach until 24 hours after dosing, and from the slight increase in the
radioactive residues observed in most organs and tissues 24 h after the
administration.

AE 0001789 was quickly and efficiently eliminated from the body. A fast
decline of the radioactive residues in all organs and tissues could be
observed between 1 and 48 hours after the administration, residues
dropped by two orders of magnitude in all organs and tissues. At the end
of the test period, 168 hours after administration, residues in all
organs and tissues were < LOD or < LOQ (liver).

From additional monitoring of the radioactivity excreted with urine and
faeces it was shown that excretion via urine was the predominant
excretion route. This excretion was very fast with high radioactivity
levels in urine already 4 hours after dosing. Excretion was complete at
the end of the test period, 168 hours after administration. An
insignificant amount of radioactivity was expired as radiolabeled carbon
dioxide or organic volatiles

SUMMARY OF TOXICOKINETICS STUDIES BY REGULATORY AUTHORITY

Name of authority	Pesticides Safety Directorate, UK

The toxicokinetics of cyprosulfamide following oral gavage were
investigated in four studies in the rat, with the parent substance
uniformly 14C-labelled in the sulfonylbenzamide and the methoxybenzoyl
ring.  These studies included two quantitative whole body
autoradiography studies (each label).  All the studies employed single
oral gavage doses.  The Notifier considered that a study with repeated
administration was not needed as the single-dose studies demonstrated
that accumulation does not occur in any organ or tissues based on a very
rapid excretion and extremely low organ and tissue levels 96 hours after
dosing.  In addition, no indication of enzyme induction was observed in
long-term toxicity studies.

Overall it is considered that the toxicokinetics have been adequately
characterised.

Absorption

Cyprosulfamide was found to be rapidly absorbed following administration
(plasma tmax reached ca 10-40 and 40-60 minutes at 2 and 200 mg/kg bw
doses respectively).  At the high dose the plasma decline curves were
bimodal, a discontinuous excretion pattern indicating delayed absorption
of some of the dose.  Absorption was found to be high and ranged between
70-90%.  Toxicokinetic parameters were independent of sex.

Distribution

Distribution was extensive, although overall very low dose normalised
concentrations were detected in all organs and tissues, with mean
values, ranging from <LOD to 0.004 µg parent equivalent/µg (excluding
carcass) with no clear indication of accumulation in any of the tissues,
organs or glands

Metabolism

Metabolism of [cyprosulfamide was limited, with approximately 80-90% of
the administered dose excreted as unchanged parent compound. Based on
the metabolites found the following pathway has been postulated.
Elimination of the cyclopropylamine moiety by hydrolysis of carboxamide
bond in the sulfonyl-benzamide part forming cyprosulfamide
-descyclopropylamino. Desmethylation of the methoxybenzoyl moiety
leading to cyprosulfamide -desmethyl. Hydrolytic cleavage of carboxamide
bond in the methoxybenzoyl group of the parent molecule resulting in
cyprosulfamide cyclopropyl-sulfamoylbenzamide and cyprosulfamide-anisic
acid.

The characterised metabolites were:

M04, AE 1448796 (AE 0001789-desmethyl)

M01, AE 0893016 (AE 0001789-descyclopropylamino)

M02, AE 0852999 (AE 0001789-cyclopropyl-sulfamoylbenzamide)

M07, AE 0854787 (AE 0001789-anisic acid)

M06,  AE 2300015 (cyclopropylamine (postulated))

Excretion

Excretion was rapid (79-98% of the administered dose at 24 hours) and
mostly via the urine (70-90% of the administered dose) at the low dose.
At the high dose excretion was much slower reflecting the delayed
absorption (50% and 94% of the administered dose at 48 hours in males
and females respectively). Excretion of radioactivity via exhaled air
was found to be negligible. Biliary excretion was not assessed. No sex
difference was apparent in the faecal excretion rate.

HED Comments:

These four studies when taken together are classified as
ACCEPTABLE/GUIDELINE and satisfy the requirement for a series 870.7485
metabolism and pharmacokinetics study.  HED considers that these studies
demonstrate the absorption, excretion, distribution and metabolism with
identification of metabolites.

	870.7600	Dermal Absorption - Rat

No study available and not required.

A.3.9	Special/Other Studies -

There are no special studies with cyprosulfamide.  TC \l3 "A.3.9
Special/Other Studies

Appendix B:  Metabolism Assessment  TC \l1 "Appendix B:  Metabolism
Assessment

The table below was copied, with minor formatting alterations, from
“Tier 2 Summary of the Metabolism and Residues Data for Cyprosulfamide
(AE 0001789)” prepared by Bayer CropScience (Document Number
M-286420-01-1).

Table B.1	Chemical Names and Structures of Cyprosulfamide and
Metabolites.

	Report name

Structure

IUPAC name

CAS name

[CAS number]	Molecular formula

molar mass

	C18 H18 N2 O5 S

374.4 g/mol

	Rat,

Goat,

Hen

Corn,

Soil,

Water-Sediment

	N-cyclopropyl-4-[(2-methoxybenzoyl)sulfamoyl] benzamide (IUPAC)

Benzamide, N-[[4-[(cyclopropylamino)-carbonyl]phenyl]
sulfonyl]-2-methoxy- (CAS, 9CI)

[CAS-no: 221667-31-8]

	Cyprosulfamide

	C15 H13 N O6 S

335.3 g/mol

	Rat (minor),

Soil, aerobic and anaerobic (major),

Water-Sediment (major)

	4-[(2-methoxybenzoyl)sulfamoyl]benzoic acid (IUPAC)

	C10 H12 N2 O3 S

240.3 g/mol	Rat (minor),

Goat (major in milk, liver, kidney, also present as conjugates),

Hen (major)

Corn (major in forage and stover, not present in grain)

Soil, aerobic and anaerobic (major),

Succeeding crops (major),

Water-Sediment (major)

	N-cyclopropyl-4-sulfamoylbenzamide (IUPAC)

	C7 H7 N O4 S

201.2 g/mol	Goat (minor in milk),

Soil, aerobic and anaerobic (major),

Water-Sediment (minor)

	4-sulfamoylbenzoic acid (IUPAC)

Benzoic acid, 4-(aminosulfonyl)- (CAS, 9CI)

[CAS no.: 138-41-0]

	C17 H16 N2 O5 S

360.39 g/mol	Rat (minor),

Goat (minor in milk and liver),

Soil aerobic (major),

Water-Sediment (aerobic: minor; anaerobic: major)

	N-cyclopropyl-4-[(2-hydroxybenzoyl) sulfamoyl]benzamide (IUPAC)

	C15 H14 N2 O5 S

334.35 g/mol	Soil photolysis (major),

Corn (minor in forage, stover and grain)

	N-{[4-(aminocarbonyl)phenyl]sulfonyl}-2-methoxybenzamide (IUPAC)

	C3 H7 N

57.1 g/mol	Soil and water (postulated major metabolite),

Rat (postulated minor metabolite)

	Cyclopropylamine (9Cl) (IUPAC)

Cyclopropaneamine (9Cl, CAS)

[CAS no.: 765-30-0]

	AE 2300015

	C8 H8 O3

152.2 g/mol

	Rat (minor),

Goat (major in liver),

Hen (major in eggs and liver)

Aquatic photolysis (major)

	2-methoxybenzoic acid (IUPAC)

Benzoic acid, 2-methoxy- (CAS, 9CI)

[CAS no.: 579-75-9]

	AE 0854787

O-methylsalicylic acid,

anisic acid,

	C10 H11 N O4 S

241.3 g/mol	Aquatic photolysis (major)

Corn (minor in forage,

not present in grain)

	4-[(cyclopropylamino)carbonyl]benzenesulfonic acid (IUPAC)

	C7 H6 O3

138.12 g/mol

	Soil (major in anaerobic soil metabolism)

	2-methoxybenzoic acid (IUPAC)

2-hydroxy benzoic acid (CAS, 9CI)

[CAS n.: 69-72-7]

	AE 0171385

o-hydroxybenzoic acid,

	C13 H16 N2 O6 S

328.3 g/mol

lactic acid conjugate of AE 0852999

	Corn (major in forage and stover;

not present in grain)

	3-[({4-[(cyclopropylamino)carbonyl]phenyl}
sulfonyl)amino]-2-hydroxypropanoic acid (IUPAC)

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	C13 H17 N3 O5 S

327.36 g/mol

alanine conjugate of AE 0852999

	Corn (major in forage and stover;

not present in grain)

	3-[({4-[(cyclopropylamino)carbonyl]phenyl} sulfonyl)amino]alanine
(IUPAC)

	C12 H14 N2 O4 S

282.32 g/mol

acetic acid conjugate of AE 0852999

	Corn (minor in forage and stover;

not present in grain),

Goat (major in milk)

	4-[(acetylamino)sulfonyl]-N-cyclopropylbenzamide (IUPAC)

M13

	C14 H17 N3 O6 S

355.37 g/mol

aspartic acid conjugate of AE 0852999

	Corn (major in stover, minor in forage,

not present in grain)

	N-({4-[(cyclopropylamino)carbonyl]phenyl} sulfonyl)-alpha-asparagine
(IUPAC)

M14

	C12 H12 N2 O6 S

312.30 g/mol

oxalic acid conjugate of AE 0852999

	Corn (minor in forage and stover,

not present in grain)

	[({4-[(cyclopropylamino)carbonyl]phenyl} sulfonyl)amino] (oxo)acetic
acid (IUPAC)

M15

indeterminate alanine conjugate of AE 0852999	Corn (major in forage and
stover;

not present in grain)

	3-[({4-[(cyclopropylamino)carbonyl]phenyl} sulfonyl)amino]alanine,
conjugate

	C24 H18 N2 O10 S

536.6 g/mol

glucose conjugate of AE 0001789,

linkage of glucose in 4-position of the methoxy benzoyl ring

	Corn (major in stover;

minor in grain)

	glucose conjugate of parent substance

	C13 H14 N2 O5 S

310.33 g/mol

pyruvic acid conjugate of AE 0852999

	Goat (minor in milk)

	N-cyclopropyl-4-[(pyruvoylamino)sulfonyl] benzamide (IUPAC)

	C10 H11 N O4

209.2 g/mol

glycine conjugate of AE 0854787

(AE 0001789-anisic acid)	Goat (minor in milk, liver, kidney)

Corn (minor in stover,

not present in grain)

	N-(2-methoxybenzoyl)glycine (IUPAC)

Glycine, N-(2-methoxybenzoyl)- (CAS, 9CI)

(2-methoxy-benzoylamino)-acetic acid

[CAS no.: 13443-58-8]

M19	AE 0001789-sulfonamide-glycine

[((4-[(cyclopropylamino)-carbonyl]phenyl) sulfonyl)amino] acetic acid

C12H14N2O5S

298.3 g/mol

glycine conjugate of AE 0852999

Corn (minor in stover,

not present in  grain)

Appendix C:  EPA Review of Human Research TC \l1 " Appendix C:  EPA
Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (which compose PHED, listed below) were
determined to require a review of their ethical conduct, have received
that review and have been determined to be ethical.

The PHED Task Force, 1995.  The Pesticide Handlers Exposure Database,
Version 1.1.  Task Force members Health Canada, U.S. Environmental
Protection Agency, and the National Agricultural Chemicals Association,
released February, 1995.

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