[Federal Register Volume 86, Number 121 (Monday, June 28, 2021)]
[Notices]
[Pages 34080-34084]
[FR Doc No: 2021-13660]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-92234; File No. SR-NYSE-2021-36]

Self-Regulatory Organizations; New York Stock Exchange LLC;
Notice of Filing and Immediate Effectiveness of Proposed Rule Change To
Amend Its Price List Regarding Ports

June 22, 2021.
    Pursuant to Section 19(b)(1) \1\ of the Securities Exchange Act of
1934 (the ``Act''),\2\ and Rule 19b-4 thereunder,\3\ notice is hereby
given that on June 10, 2021, New York Stock Exchange LLC (``NYSE'' or
the ``Exchange'') filed with the Securities and Exchange Commission
(the ``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\ 15 U.S.C. 78a.
    \3\ 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 its Price List to extend the end of
the Decommission Period from June 2021 to August 2021. The Exchange
proposes to implement these changes to its Price List effective June
10, 2021.\4\ The proposed rule change is available on the Exchange's
website at www.nyse.com, at the principal office of the Exchange, and
at the Commission's Public Reference Room.
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    \4\ The Exchange originally filed to amend the Price List on May
28, 2021 (SR-NYSE-2021-34). SR-NYSE-2021-34 was subsequently
withdrawn and replaced by this filing.
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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
    The purpose of this filing is to provide additional time for member
organizations to finalize their transition from older to newer and more
efficient Pillar technology. The Exchange is not proposing to adjust
the amount of the port fees or the fees charged to offset the
Exchange's continuing costs of supporting legacy ports, which will
remain at the current level for all market participants.
    Effective July 3, 2019, the Exchange introduced transition pricing
designed to provide member organizations an extended transition period
to connect to the Exchange using Pillar technology with no fee
increase. Specifically, the Exchange (1) adopted a cap on monthly fees
for the use of certain ports connecting to the Exchange for the billing
months July 2019 through March 2020 (the ``Transition Period''); (2)
adopted a Decommission Extension Fee applicable for the billing months
April 2020 through September 2020 (the ``Decommission Period'') for
legacy port connections; and (3) prorated the monthly fee for certain
ports activated after July 1, 2019, effective April 1, 2020.\5\
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    \5\ See Securities Exchange Act Release No. 86360 (July 11,
2019), 84 FR 34210 (July 17, 2019) (SR-NYSE-2019-39).
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    Effective March 2, 2020, the Exchange (1) extended the end of the
Transition Period from March 2020 to August 2020 for member
organizations to transition to the utilization of ports that connect to
the Exchange using Pillar technology; (2) shortened the Decommission
Period from six months (April 2020-September 2020) to four months
(September-December 2020); (3) extended the effective date that the
Exchange would prorate the monthly fee for certain ports activated on
or after July 1, 2019 from April 1, 2020 to September 1, 2020; and (4)
revised the fees charged for legacy port connections during the
Decommission Period.\6\
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    \6\ See Securities Exchange Act Release No. 88373 (March 12,
2020), 85 FR 15533 (March 18, 2020) (SR-NYSE-2020-14).
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    Effective August 1, 2020, the Exchange (1) extended the end of the
Transition Period from August 2020 to October 2020; (2) extended the
beginning of the Decommission Period from September 2020 to November
2020 and the end of the Decommission Period from December 2020 to
February 2021; and (3) extended the effective date that the Exchange
would prorate the monthly fee for ports activated on or after July 1,
2019 from September 1, 2020 to November 1, 2020.\7\
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    \7\ See Securities Exchange Act Release No. 89591 (August 18,
2020), 85 FR 52159 (August 24, 2020) (SR-NYSE-2020-14).
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    Effective October 1, 2020, the Exchange (1) extended the end of the
Transition Period from October 2020 to December 2020; (2) extended the
beginning of the Decommission Period from November 2020 to January 2021
and the end of the Decommission Period from February 2021 to April
2021; and (3) extended the effective date that the Exchange would
prorate the monthly fee for ports activated on or after July 1, 2019
from November 1, 2020 to January 1, 2021.\8\
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    \8\ See Securities Exchange Act Release No. 90180 (October 14,
2020), 85 FR 66612 (October 20, 2020) (SR-NYSE-2020-82).
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    Effective December 1, 2020, the Exchange (1) extended the end of
the Transition Period from December 2020 to February 2021; (2) extended
the beginning of the Decommission Period from January 2021 to March
2021 and the end of the Decommission Period from April 2021 to June
2021; and (3) extended the effective date that the Exchange would
prorate the monthly fee for ports activated on or after July 1, 2019
from January 1, 2021 to March 1, 2021.\9\
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    \9\ See Securities Exchange Act Release No. 90661 (December 14,
2020), 85 FR 82532 (December 18, 2020) (SR-NYSE-2020-99).
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    The Exchange proposes to extend the end of the Decommission Period
two months from June 2021 to August 2021 in order to allow member
organizations that did not complete the transition during the
Transition Period the ability to choose to continue using Phase I ports
until August 2021.
    The Exchange proposes to implement these changes to its Price List
effective June 1, 2021.
Competitive Environment
    The Exchange operates in a highly competitive market. The
Commission has repeatedly expressed its preference for competition over
regulatory intervention in determining prices, products, and services
in the securities markets. In Regulation NMS, the Commission
highlighted the importance of market forces in determining prices and
SRO revenues and, also, recognized that current regulation of the
market system ``has been remarkably successful in promoting market
competition in its broader forms that are most important to investors
and listed companies.'' \10\
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    \10\ See Securities Exchange Act Release No. 51808 (June 9,
2005), 70 FR 37495, 37499 (June 29, 2005) (S7-10-04) (Final Rule)
(``Regulation NMS'').
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    While Regulation NMS has enhanced competition, it has also fostered
a ``fragmented'' market structure where trading in a single stock can
occur across multiple trading centers. When multiple trading centers
compete for order flow in the same stock, the Commission has recognized
that ``such competition can lead to the fragmentation of order flow in
that stock.'' \11\ Indeed, equity trading is currently dispersed across
16 exchanges,\12\ 31 alternative trading systems,\13\ and numerous
broker-dealer internalizers and wholesalers, all competing for order
flow. Based on publicly available information, no single exchange has
more than 16% market share.\14\ The Exchange believes that the ever-
shifting market share among the exchanges from month to month
demonstrates that market participants can shift order flow, or
discontinue or reduce use of certain categories of products, including
ports, in response to fee changes. Accordingly, the Exchange's fees,
including port fees, are reasonably constrained by competitive
alternatives and market participants can readily trade on competing
venues if they deem pricing levels at those other venues to be more
favorable.
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    \11\ See Securities Exchange Act Release No. 61358, 75 FR 3594,
3597 (January 21, 2010) (File No. S7-02-10) (Concept Release on
Equity Market Structure).
    \12\ See Cboe Global Markets, U.S. Equities Market Volume
Summary, available at http://markets.cboe.com/us/equities/market_share/. See generally https://www.sec.gov/fast-answers/divisionsmarketregmrexchangesshtml.html.
    \13\ See FINRA ATS Transparency Data, available at https://otctransparency.finra.org/otctransparency/AtsIssueData. A list of
alternative trading systems registered with the Commission is
available at https://www.sec.gov/foia/docs/atslist.htm.
    \14\ See Cboe Global Markets U.S. Equities Market Volume
Summary, available at http://markets.cboe.com/us/equities/market_share/.
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    The Exchange is proposing these changes in the context of a
competitive environment in which market participants can and do shift
order flow, or discontinue or reduce use of certain categories of
products, in response to fee changes. Because ports are used by member
organizations to trade electronically on the Exchange, fees associated
with ports are subject to these same competitive forces. The Exchange
believes that the proposal represents a reasonable attempt to provide
member organizations with additional time to finalize an orderly
transition to upgraded technology.
Proposed Rule Change
    Member organizations enter orders and order instructions, and
receive information from the Exchange, by

establishing a connection to a gateway that uses communication
protocols that map to the order types and modifiers described in
Exchange rules. These gateway connections, also known as logical port
connections, are referred to as ``ports'' on the Exchange's Price List.
Legacy ports connect with the Exchange via a Common Customer Gateway
(known as ``CCG'') that accesses its equity trading systems (``Phase I
ports''). Beginning July 1, 2019, the Exchange began making available
ports using Pillar gateways to its member organizations (``Phase II
ports'').
    Currently, member organizations that have not transitioned to Phase
II ports and are still utilizing Phase I ports during the billing
months of March 2021 through June 2021 (i.e., the Decommission Period),
would, in addition to the current port fees, be charged a Decommission
Extension Fee of $1,000 per port per month, increasing by $1,000 per
port for each month for any ports that communicate using Pillar phase I
protocols. As per the Price List, ports using Pillar phase I protocols
would no longer be available beginning July 1, 2021.
    The Exchange proposes that the Decommission Period would end two
months later, in August 2021. As proposed, the Price List would also be
amended to provide that ports using Pillar phase I protocols would no
longer be available beginning September 1, 2021.
    As noted above, the Exchange believes that, to the extent that
member organizations do not complete the transition during the
Transition Period, the proposed rule change will offer member
organizations the ability to choose to continue using Phase I ports
until August 2021.
    The proposed changes are not otherwise intended to address any
other issues, and the Exchange is not aware of any problems that member
organizations would have in complying with the proposed change.
2. Statutory Basis
    The Exchange believes that the proposed rule change is consistent
with Section 6(b) of the Act,\15\ in general, and furthers the
objectives of Sections 6(b)(4) and 6(b)(5) of the Act,\16\ in
particular, because it provides for the equitable allocation of
reasonable dues, fees, and other charges among its members, issuers and
other persons using its facilities and does not unfairly discriminate
between customers, issuers, brokers or dealers.
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    \15\ 15 U.S.C. 78f(b).
    \16\ 15 U.S.C. 78f(b)(4) & (5).
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The Proposed Change Is Reasonable
    The Exchange operates in a highly competitive market. The
Commission has repeatedly expressed its preference for competition over
regulatory intervention in determining prices, products, and services
in the securities markets. In Regulation NMS, the Commission
highlighted the importance of market forces in determining prices and
SRO revenues and, also, recognized that current regulation of the
market system ``has been remarkably successful in promoting market
competition in its broader forms that are most important to investors
and listed companies.'' \17\
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    \17\ See Securities Exchange Act Release No. 51808 (June 9,
2005), 70 FR 37495, 37499 (June 29, 2005) (S7-10-04) (Final Rule)
(``Regulation NMS'').
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    While Regulation NMS has enhanced competition, it has also fostered
a ``fragmented'' market structure where trading in a single stock can
occur across multiple trading centers. When multiple trading centers
compete for order flow in the same stock, the Commission has recognized
that ``such competition can lead to the fragmentation of order flow in
that stock.'' \18\ Indeed, equity trading is currently dispersed across
16 exchanges,\19\ 31 alternative trading systems,\20\ and numerous
broker-dealer internalizers and wholesalers, all competing for order
flow. Based on publicly available information, no single exchange has
more than 16% market share.\21\ The Exchange believes that the ever-
shifting market share among the exchanges from month to month
demonstrates that market participants can shift order flow, or
discontinue or reduce use of certain categories of products, including
ports, in response to fee changes. Accordingly, the Exchange's fees,
including port fees, are reasonably constrained by competitive
alternatives and market participants can readily trade on competing
venues if they deem pricing levels at those other venues to be more
favorable.
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    \18\ See Securities Exchange Act Release No. 61358, 75 FR 3594,
3597 (January 21, 2010) (File No. S7-02-10) (Concept Release on
Equity Market Structure).
    \19\ See Cboe Global Markets, U.S. Equities Market Volume
Summary, available at http://markets.cboe.com/us/equities/market_share/. See generally https://www.sec.gov/fast-answers/divisionsmarketregmrexchangesshtml.html.
    \20\ See FINRA ATS Transparency Data, available at https://otctransparency.finra.org/otctransparency/AtsIssueData. A list of
alternative trading systems registered with the Commission is
available at https://www.sec.gov/foia/docs/atslist.htm.
    \21\ See Cboe Global Markets U.S. Equities Market Volume
Summary, available at http://markets.cboe.com/us/equities/market_share/.
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    The Exchange believes that the ever-shifting market share among the
exchanges from month to month demonstrates that market participants can
shift order flow, or discontinue or reduce use of certain categories of
products, including ports, in response to fee changes. Accordingly, the
Exchange's fees, including port fees, are reasonably constrained by
competitive alternatives and market participants can readily trade on
competing venues if they deem pricing levels at those other venues to
be more favorable.
    If a particular exchange charges excessive fees for connectivity,
impacted members and non-members may opt to terminate their
connectivity arrangements with that exchange, and adopt a possible
range of alternative strategies, including routing to the applicable
exchange through another participant or market center or taking that
exchange's data indirectly. Accordingly, if the Exchange charges
excessive fees, it would stand to lose not only connectivity revenues
but also revenues associated with the execution of orders routed to it,
and, to the extent applicable, market data revenues. The Exchange
believes that this competitive dynamic imposes powerful restraints on
the ability of any exchange to charge unreasonable fees for
connectivity.
    Given this competitive environment, the proposal represents a fair
and reasonable attempt to provide member organizations with additional
time to finalize an orderly transition to upgraded technology. As of
April 2021, 16.2% of legacy ports have not been cancelled. The pricing
is designed so that these few remaining member organizations utilizing
legacy ports would pay for the Exchange to continue to support their
Phase I ports through August 2021.
The Proposal Is an Equitable Allocation of Fees
    The Exchange believes its proposal equitably allocates its fees
among its market participants. The Exchange is not proposing to adjust
the amount of the port fees or the fees charged fees to offset the
Exchange's continuing costs of supporting legacy ports, which will
remain at the current level for all market participants. Rather, the
proposal would provide additional time for member organizations to
transition from older to newer and more efficient Pillar technology and
would charge the same fee for those few member organizations that
choose not to transition to Phase II ports during the extended
Transition Period.

    The proposal constitutes an equitable allocation of fees because
all similarly situated member organizations and other market
participants that, following the transition period, choose to connect
to the Exchange through the use of Phase I ports during the
Decommission Period would continue to be charged the same, unchanged
Decommission Extension Fee.
The Proposal Is Not Unfairly Discriminatory
    The Exchange believes that the proposal is not unfairly
discriminatory. In the prevailing competitive environment, member
organizations are free to disfavor the Exchange's pricing if they
believe that alternatives offer them better value, and are free to
discontinue to connect to the Exchange through its ports. As noted, the
Exchange is offering upgraded connections in an effort to keep pace
with changes in the industry and evolving customer needs as new
technologies emerge and products continue to develop and change.
    The proposal neither targets nor will it have a disparate impact on
any particular category of market participant. The Exchange believes
that the proposal does not permit unfair discrimination because the
proposal would be applied to all similarly situated member
organizations and other market participants would be charged the same
rates, which will remain unchanged.
    The Exchange believes that the proposal does not permit unfair
discrimination because the Decommission Extension Fee would apply
equally to all member organizations that require additional time to
complete their transition to the Phase II ports. At any point during
the Decommission Period, a member organization could cease to be
subject to the Decommission Fee by expediting its transition to the new
ports. The Decommission Fee would thus apply equally to all member
organizations during the proposed extended Decommission Period that
choose to continue to connect to the Exchange through the use of legacy
ports. As noted, to the extent a member organization continues to use
ports activated before July 1, 2019 to connect to the Exchange during
the proposed extended Decommission Period, the Exchange believes it is
fair, equitable and not unfairly discriminatory to continue to charge
flat fees for such ports until such time that connection to the
Exchange through the use of old ports is no longer available beginning,
as proposed, on September 1, 2021.
    Finally, the Exchange believes that it is subject to significant
competitive forces, as described below in the Exchange's statement
regarding the burden on competition.
    For the foregoing reasons, the Exchange believes that the proposal
is consistent with the Act.

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

    In accordance with Section 6(b)(8) of the Act,\22\ the Exchange
believes that the proposed rule change would not impose any burden on
competition that is not necessary or appropriate in furtherance of the
purposes of the Act. Instead, as discussed above, the Exchange believes
that the proposed changes would provide additional time for member
organizations to finalize the transition from older to newer and more
efficient Pillar technology with no fee increase and offset the
Exchange's continuing costs of supporting the Phase I ports for the few
firms that do not transition to the new ports during the longer
transition period without any change to the fees currently charged by
the Exchange for the use of ports to connect to the Exchange's trading
systems.
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    \22\ 15 U.S.C. 78f(b)(8).
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    Intramarket Competition. The Exchange does not believe the proposed
rule change would impose any burden on intramarket competition that is
not necessary or appropriate because it would apply to all member
organizations equally that connect to the Exchange. All member
organizations, regardless of size, that did not complete the transition
to Phase II ports by the end of February 2021 date are subject to the
Decommission Fee on an equal basis and would continue to be subject to
the fee on an equal basis for the proposed additional two months if
they do not complete the transition to Phase II ports. As noted, as of
April 2021, 16.2% of legacy ports have not been cancelled. The pricing
is designed so that these few remaining member organizations utilizing
legacy ports would pay for the Exchange to continue to support their
Phase I ports through August 2021.
    Intermarket Competition. The Exchange does not believe the proposed
rule change would impose any burden on intermarket competition that is
not necessary or appropriate because the Exchange operates in a highly
competitive market in which market participants can readily choose to
send their orders to other exchange and off-exchange venues if they
deem fee levels at those other venues to be more favorable. The
Exchange believes that fees for connectivity are constrained by the
robust competition for order flow among exchanges and non-exchange
markets.
    As noted, the no single exchange has more than 16% of the market
share of executed volume of equity trades (whether excluding or
including auction volume).\23\ The Exchange believes that the ever-
shifting market share among the exchanges from month to month
demonstrates that market participants can shift order flow, or
discontinue or reduce use of certain categories of products, including
ports, in response to fee changes. Accordingly, the Exchange's fees,
including port fees, are reasonably constrained by competitive
alternatives and market participants can readily trade on competing
venues if they deem pricing levels at those other venues to be more
favorable.
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    \23\ See Cboe Global Markets U.S. Equities Market Volume
Summary, available at http://markets.cboe.com/us/equities/market_share/.
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    The Exchange is proposing these changes in the context of a
competitive environment in which market participants can and do shift
order flow, or discontinue or reduce use of certain categories of
products, in response to fee changes. Because ports are used by member
organizations to trade electronically on the Exchange, fees associated
with ports are subject to these same competitive forces. The Exchange
therefore believes that the proposal would not impose an undue burden
on intermarket competition because the purpose of this filing is not to
change the rates charged for ports or to offset the Exchange's
continuing costs of supporting legacy ports but rather to provide
member organizations with more time to effect an orderly transition to
upgraded technology without needing to incur any additional costs.

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

    The foregoing rule change is effective upon filing pursuant to
Section 19(b)(3)(A) \24\ of the Act and subparagraph (f)(2) of Rule
19b-4 \25\ thereunder, because it establishes a due, fee, or other
charge imposed by the Exchange.
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    \24\ 15 U.S.C. 78s(b)(3)(A).
    \25\ 17 CFR 240.19b-4(f)(2).
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    At any time within 60 days of the filing of such 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 under Section
19(b)(2)(B) \26\ of the Act to determine whether the proposed rule
change should be approved or disapproved.
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    \26\ 15 U.S.C. 78s(b)(2)(B).
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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 Number SR-NYSE-2021-36 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-2021-36. 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 website (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 website 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 the filing also will be available for inspection
and copying at the principal office of the Exchange. All comments
received will be posted without change. Persons submitting comments are
cautioned that we do not redact or edit personal identifying
information from comment submissions. You should submit only
information that you wish to make available publicly. All submissions
should refer to File Number SR-NYSE-2021-36, and should be submitted on
or before July 19, 2021.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\27\
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    \27\ 17 CFR 200.30-3(a)(12), (59).
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J. Matthew DeLesDernier,
Assistant Secretary.
[FR Doc. 2021-13660 Filed 6-25-21; 8:45 am]
BILLING CODE 8011-01-P


Lethco and Brouwer, 1966. carboxy -[14]C-1- NAA as NA salt in male rats.  Within 3 days, 71-90% of the AD was excreted in the urine.  At the lower doses (0.1-100 mg/kg)  most of the radioactivity was excreted during the first 24 hours, while at the higher dose (250 mg/kg), excretion was highest on the second day.  Fecal excretion was 3-10% at the 0.1-1.0 mg/kg doses and 14-21% of the AD at the 100 and 250 mg/kg doses.  After the third day, no radioactivity was detected in the feces or urine at any dose.   70-93% of the urinary radioactivity was NAA glycine conjugate and NAA GAC.  The GAC predominated at the two high doses and the glycine conjugate predominated at the lower dose.  Minor amounts of  NAA and two other minor unidentified metabolites were detected in the urine.   Bile cannulation experiments demonstrated biliary metabolism and excretion of the test material.  At the high dose a maximum of 29% of the AD was recovered at 6 hours, while a maximum of 54% was recovered at the low dose at 2 hours.  At the low dose, the NAA glycine conjugate was the major urinary metabolite and the NAA GAC was a minor metabolite, while in the bile the preponderance of these two metabolites was reversed.  Unchanged NAA was detected in the bile but not in the urine at both doses.  At the high dose the NAA GAC was the major metabolite in both urine and bile while the glycine conjugate was a minor metabolite.

MRID 43961701.  Rats (5/sex) were given a single 1 or 100 mg/kg bw oral dose of [[14]C] ring labeled -1-naphthaleneacetic acid, ethyl ester, or a 14-day repeated dose (1 mg/kg/day) of unlabeled material followed by a single dose of the labeled material.  Overall recovery of AD was 98.6-101.8%.  NAA ethyl ester was readily absorbed and excreted within 36 - 48 hours following all exposure regimens (urinary excretion: 67.6-85.3% of the AD at the low dose and 61.8-78% of the AD at the high dose).  Fecal excretion was 12.3-35.2% of the AD.  Tissue radioactivity was very low.  The major pathway of metabolism involved ester cleavage followed by glycine and glucuronide conjugation at the low and low repeat doses.  At the high dose, glucuronide conjugation appeared to play a more important role following ester cleavage.  Parent compound was detected at low concentrations (0.5-4.7% of administered) only in feces.

MRID 43963301.  Rrats (5/sex) were given either a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day) using [[14]C] ring labeled -1-naphthaleneacetamide (NAAD).  Overall recovery of the AD was 97.2-101%.  NAAD was readily absorbed and excreted within 36 hours (urinary excretion: 70.8-74.1% of the AD at the low dose, single or multiple,  66.2-69.5% of the AD excreted in urine at the high dose).  Fecal excretion was 21.6-26.2% of the AD.  Tissue radioactivity was very low (<0,5% of the AD).   Metabolism involved amide cleavage followed by glycine conjugation (13.7-47.3% of the AD) glucuronide conjugation (4.5-7.0% of the AD at the low dose and 12.8-18.1% of the AD at the high dose inthe urine).  For feces, the major metabolite detected was the dihydrodiol of naphthaleneacetamide (3.6-11.3% of the AD).  Parent compound was detected at low concentrations (0.7-1.9% of administered) only in feces.

APPENDIX A.3	HAZARD IDENTIFICATION AND ENDPOINT SELECTION

A.3.1	Acute Population Adjusted Doses (aPAD)  -  All Populations

Selected Study: Developmental Toxicity Study in Rats
MRID 46685803

Dose and Endpoint for Establishing an aPAD: On the basis of this study, the dose selected is 50 mg/kg/day based on decreased body weight gain at 250 mg/kg/day during the gestation period.  This dose and endpoint is protective of the general population and is representative of the exposure duration of concern (effects occurred during administration of NAA during short period of exposure).  This was also the only available study on NAA with short exposure duration.

Uncertainty Factor (UF): 100 This includes 10X for interspecies extrapolation and 10x for intraspecies variation.
General Population aPAD =        (NOAEL) 25 mg/kg    =  0.25 mg/kg
                                                              (UF) 100

A.3.2	Chronic Population Adjusted Dose (cPAD)  -  All Populations

Selected Study: Chronic/Oncogenicity Study in Dogs
MRID 43744201
Dose and Endpoint for Establishing an cPAD: On the basis of this study, the dose selected is 15 mg/kg/day based on stomach lesions in 75% of the males consisting of necrosis of the fundic or pyloric epithelium and by slight sinusoidal histiocytosis in the liver of 50% of the males occurring  at 75 mg/kg/day of oral feeding of the NAA sodium salt.  The sodium salt also appeared to be the more toxic in subchronic testing among the NAA group of chemicals.  A chronic study in rats with NAA sodium salt showed a NOAEL of 44-56 mg/kg/day based on increased incidence of stomach (mucosal gland dilation) and lung lesions (focal alveolar macrophages) in both sexes, and on lowered body weight gain and food efficiency in female rats at 224 - 303 mg/kg/day.  Therefore, this dose and endpoint is appropriate for protecting the general population from dietary chronic exposure to NAA group of chemicals.

Uncertainty Factor (UF): 100 This includes 10X for interspecies extrapolation and 10x for intraspecies variation.

General Population  cPAD  =         (NOAEL) 15 mg/kg/day    = 0.15 mg/kg/day
		                                          (UF) 100

A.3.4	Dermal Absorption

	A dermal absorption factor (DAF) is applied when dermal exposure endpoints are selected from oral toxicity studies.  The dermal factor converts the oral dose to an equivalent dermal dose for the risk assessment.  A DAF of 6% was selected for use in risk assessment based on available in vivo dermal absorption studies in rat and in vitro dermal absorption studies conducted with rat and human skin.  The DAF was selected by a special working group of the  Antimicrobials Division Toxicity Endpoint Selection Committee (12/18/08 memorandum from J. Chen to M. Swindell  -  Attachment A.3).

4.3.5	Dermal Exposure (Short and Intermediate-Term)

Selected Study: 21-day dermal toxicity study
MRID 42090018

Dose and Endpoint for Establishing POD: In this study, the systemic NOAEL was 300 mg/kg/day based on reduced body weight gain and food efficiency at the LOAEL of 1000 mg/kg/day.  Therefore, the dermal dose for risk assessment is 300 mg/kg/day.  A margin of Exposure (MOE) of 100 is applied.

Uncertainty Factor (UF): An MOE 100 is required for the short- and intermediate-term scenarios for dermal exposure is based on the conventional uncertainty factor of 100.  This includes 10x for interspecies extrapolation and 10x for intraspecies variation..

A.3.6 	Inhalation Exposure (Short- and Term)

Selected Study: Developmental Toxicity Study in Rats
See Section A.3.1

A.3.6  Inhalation Exposure (Intermediate Term)

Selected Study: 90 day oral toxicity study in dogs
MRID 42983801

Dose and Endpoint for Establishing POD:  In this study, the systemic NOAEL was 25 mg/kg/day based on lesions of the GI tract and hypocellularity of the bone marrow at the LOAEL of 150 mg/kg day.  Therefore, the dose for risk assessment is 25 mg/kg/day.

Uncertainty Factor (UF): An MOE 100 is required for the intermediate-term scenarios for dermal exposure is based on the conventional uncertainty factor of 100.  This includes 10x for interspecies extrapolation and 10x for intraspecies variation..

A.4		EXECUTIVE SUMMARIES FOR SUPPORTING TOXICITY STUDIES

A.4.1	Subchronic Toxicity

870.3100: 	90-Day Oral Toxicity - Rat

In a subchronic oral toxicity study (MRID 00043624), 1-naphthaleneacetic acid, technical (Lot # not reported; purity not reported) was administered, in the diet, to Sprague Dawley rats (20/sex/dose) at dose levels of  0, 50, 150 or 300 mg/kg bw/day for 13 weeks.  Two additional group of 10 rats/sex were administered 0 or 300 mg/kg bw/day and sacrificed after 30 days and necropsied.  All rats survived except for one death in the control group.  No abnormal behavior or toxic effects were observed in the treated rats.  Fluctuations in food consumption occurred in control and treated groups.  Body weights in males and females of the high dose group were depressed particularly in the females where they gained only one third of the body weight achieved by the controls.  All hematologic values were within the reference limits.  Hematocrit, hemoglobin, and/or RBC values in the mid and high dose males and females were slightly reduced, but considered not compound related.  Alkaline phosphatase in the high dose group was elevated, probably associated with the rate of body growth.  Urinalysis values were comparable in all groups.  There were no visible macroscopic lesions in male rats except for one control male with enlarged spleen and liver and red, depressed areas in the stomach.  In the females, clear fluid in the uterus (hydrometra) was noted in 3 controls, 2 low dose, 7 mid dose and 5 high dose.  These and other lesions (ovarian cyst in one mid dose female, focal omental fat necrosis in one high dose female, one nenocortical cyst in another high dose female) observed were considered not be compound induced.  The absolute and relative liver weight in the high dose females appeared to be significantly increased with no histopathological findings. It was concluded that the LOAEL for toxic effects in this study is 300 mg/kg/day based on decreased body weight in both sexes and enlarged liver weights in females.  The NOAEL is 150 mg/kg/day.  This subchronic toxicity study in the rat was conducted prior to the current testing guidelines.

In a subchronic toxicity study (MRID 43896001), 1-Naphthaleneacetamide (Lot # I940415; 98.7% a.i.) was administered to CRL:CD BR rats (10/sex/dose) by feeding at dose levels of 0, 250, 1,000, or 4,000 ppm (mean measured concentrations of 0, 19.1, 73.8, or 292.1 mg/kg/day for males and 0, 20.4, 81.5, or 313.5 mg/kg/day for females) for 90 days.  In the 4,000 ppm treatment groups, mean body weights were lower for males (10-15%) and females (9-12%) throughout the study, compared to controls.  Final mean body weight gains were lower for males (14%) and females (20%).  In addition, food consumption was consistently reduced for males (11-28%) and females (2-20%) throughout the study.  Mean relative liver weights were significantly increased in both 4,000 ppm males (14%; p0.05) and females (32%; p0.01) with accompanying histopathological changes consisting of enlarged (hypertrophied) centrilobular hepatocytes with an abundance of fine granular eosinophilic cytoplasm.  No rats died during the study.  No treatment-related differences in clinical appearance, ophthalmology, hematology, clinical blood chemistry or urinalysis parameter or gross pathology were observed in any treatment group.  No neoplastic tissue was observed in any of the treatment groups.  The LOAEL is 4,000 ppm (292.1 mg/kg/day), based on decreased body weight, reduced body weight gain, reduced food consumption, and increased relative liver weights with histopathological changes in both sexes.  The NOAEL is 1,000 ppm (73.8 mg/kg/day).

In a 90 day oral (diet) toxicity study (MRID 42932601), male and female Crl:CDBR (Sprague-Dawley) rats (10/group/sex) received 1-Napthaleneacetic Acid Sodium Salt (Lot # 214001; 96.44% purity) either 0, 200, 2000, or 8000 ppm (equivalent to 13.9, 136.6, and 564.9 mg/kg/day for males and 15.2, 149.3, and 583.4 mg/kg/day for females, respectively) for 13 weeks.  Dose levels were based on a 14-day dietary study with 1-Na-NAA, no information was provided.  No clinical toxicity or mortality related to the treatment was reported in any of the groups.  The absolute body weights for both sexes in the high dose groups were statistically significantly different from control from day 7 for males and day 14 for females, approximately 18 to 20 % lower than control for both sexes at the end of 90 days.  Systemic toxicity was noted at 2000 ppm and above based on statistically significant (p<0.05 -p<0.01) decreased hematocrit and hemoglobin, increased liver weights and vacuolation of the periportal hepatocytes along with hypertrophy of the cells of the adrenal cortex zona glomerulosa in females and increased kidney weights in males.  Further, at the 8000 ppm dose group there were decreased body weight gains (25-30% decrease), decreased food consumption and decreased food efficiency along with decreased red blood cell parameters, platelet counts, total serum protein and albumin.  The liver and kidney weights (absolute and relative to body weight) were increased in high dose males and females along with hepatocellular hypertrophy (4/10 in high dose males and females) and vacuolation of the periportal hepatocytes (10/10 in mid and high dose females) and hypertrophy of the cells of the adrenal cortex zona glomerulosa (6/10 in the mid dose females and 7/10 in the high dose females, and 3/10 in high dose males) and urinary bladder mucosa (9/10 in high dose males and 7/10 in high dose females).  The LOAEL for systemic toxicity is 2000 ppm (136.6 mg/kg/day for males and 149.3 mg/kg/day for females) with a NOAEL for systemic toxicity of 200 ppm (13.9 mg/kg/day for males and 15.2 mg/kg/day for females) based on decreased hematocrit and hemoglobin, increased liver weights and vacuolation of the periportal hepatocytes along with hypertrophy of the cells of the adrenal cortex zona glomerulosa.

In a subchronic oral toxicity study (MRID 43896002), 1-naphthaleneacetic acid, ethyl ester (Lot # AM 315002; 100% ai) was administered, in the diet, to CRL:CD BR rats (10/sex/dose) at dose levels of 400, 2000 or 8000 ppm for 13 weeks. The actual average doses at the end of the study were 19-25 mg/kg/day for the 400 ppm group, 92-123 mg/kg/day for the 2000 ppm group, and 388 - 519 mg/kg/day for the 8000 ppm group, for males and females, respectively. Lower body weight, body weight gain, food consumption and food efficiency were observed for the 8000 ppm males and females compared to the controls.  Body weights for the males were 7-13% lower and for the females were 9-21% lower than the corresponding controls throughout the study.  Body weight gains were significantly reduced for both sexes at various weekly intervals throughout the study, and by the end of the study, were 18 and 38% lower for males and females, respectively, than the control gains.  Mean food consumption by the males and females was 5-11 and 15-22 lower, respectively, than the control values for most weekly intervals; decreased food efficiency for both sexes was observed at most weekly intervals.  Increased relative and/or absolute liver and kidney weights were observed for the 2000 and 8000 ppm treatment groups.  Relative liver weights were 21% higher for the 2000 ppm females and 20 and 58% higher for the 8000 ppm males and females, respectively, compared to the control weights.  Absolute liver weights were 13 and 24% higher for the 2000 and 8000 ppm females, respectively, compared to the controls.  Relative kidney weights were higher for both sexes from the 2000 ppm (11% higher) and 8000 ppm (17-23% higher) treatment groups.  Absolute kidney weight for the 2000 ppm males was 16% higher than the controls but was not increased for the 8000 ppm males.  No associated macroscopic or microscopic changes were observed in the livers and kidneys of rats from any treatment group.  Decreased red blood cell counts, hemoglobin, and hematocrits for both sexes from the 2000 and 8000 ppm groups were not considered clinically significant, but appeared to be treatment-related since they were dose-dependent.  The 8000 ppm males and females also exhibited increased total bilirubin (19-21% higher) in conjunction with reduced red blood cell counts, hemoglobin, and hematocrits.  No other treatment-related effects were observed during the study.  No rats died during the study.  No differences in clinical signs, ophthalmology, macroscopic or microscopic pathology were observed between any of the treatment and control groups.  Decreased urine protein in the 2000 and 8000 ppm males was not observed in the corresponding females.  The LOAEL for this study is 8000 ppm (594 mg/kg/day) for male and female rats, based on lower body weight, suppressed body weight gain, and reduced food consumption as compared to the controls.  Absolute and/or relative liver and kidney weights for both sexes were seen at this dose but were not accompanied by any macroscopic or microscopic changes, however, males and females at this dose also exhibited increased total bilirubin (19-21% higher) in conjunction with reduced red blood cell counts, hemoglobin, and hematocrits.  The NOAEL is 2000 ppm (144 mg/kg/day) for both sexes.

870.3150:	90-Day Oral Toxicity - Dog

In a subchronic oral toxicity study (MRID 00136446), 1-naphthaleneacetic acid, technical (Lot # 16388; purity not reported) was fed (gelatin capsules) to beagle dogs (4/sex/dose) at dose levels of 0, 50, 150, or 300 mg/kg/day for 180 consecutive days.  Clinical signs of toxicity were evident in the high dose group.  These included anorexia lasting several days, tenderness in the mouth while dosing, icteric and pale mucous membranes, steady loss in weight, lethargy, an uncoordinated gait, dark urine, and dark stools.  Two of four males and all the females showed some or all of these effects at the end of the study.  One dog had a great amount of edema in the hind legs progressing over 3 days until its legs were swollen to approximately the coxo femoral joint.  This dog was sacrificed on day 126 of the study.  Urine collected from this dog prior to sacrifice showed large amounts of bilirubin, urobilinogen and a small amount of RBC and blood.  These effects are considered to treatment-related.  The mean body weight and body weight gain was significantly depressed in the high dose females (p<0.01) at 2, 3, 4,5 and 6 months in comparison to the control dogs.  The male dogs had also reduced body weight and body weight gain during the last two months of the study.  Hematological parameters were within reference limits for the four groups.  The hematology of the dog that was sacrificed showed slightly increased WBC count with a relative and absolute neutrophilia and lymphopenia which may be compound related.  The clinical chemistry analysis showed that alanine amino transferase (SGPT) were elevated at 4 months (slightly) and 6 months (2x the normal value) for the high dose females.  The clinical chemistry of the male dog that was sacrificed in moribund condition showed lower protein, cholesterol and glucose and greatly elevated levels of total bilirubin, direct bilirubin, alkaline phosphatase, aspartate amino transferase (SGOT) and SGPT.  Dose-related increases in relative weights of kidneys occurred in both males and females of the high dose group.  Dose-related weight increases in liver, adrenals, brain and heart occurred in high dose females.  The low dose group males had increased relative kidney weights and the mid dose group females had an increase in relative heart weights.  Histopathologisal examination revealed very slight evidence of pericholangistis in the low dose group (2/8), very slight to moderate degree of hepatic insult in the mid dose group (7/8)and slight to severe degree of hepatic insult in the high dose group (8/8).  This hepatic insult was characterized by pericholangistis, toxic degeneration of hepatocytes and hepatocellular hypertrophy in the mid dose group and additionally centrilobular necrosis, periportal fibrosis in the high dose group and hyperplastic nodule in the male dog that was sacrificed moribund.  There was also evidence of squamoid metaplasi in the tracheal epithelium of 2/8 dogs and a slight degree of myocarditis (1/8) in the high dose group.  Hyperkeratosis of the skin at the thoroacolumbar junction was seen in 2/8 dogs of the mid dose and 4/8 dogs of the high dose groups.  It was concluded that there was no NOAEL derived from this study.  The LOAEL was 50 mg/kg/day, the lowest dose tested, based on hepatic liver changes (pericholangistis).  This subchronic toxicity study in the dog was conducted prior to the current testing guidelines.

In a subchronic toxicity study (MRID 43895901), 1-Naphthaleneacetamide (Lot/Batch #  I940415;  98.7% a.i.) was administered via capsule to four beagle dogs/sex/dose at dose levels of 0, 30, 100, or 300 mg/kg/day for 13 weeks.  In the 300 mg/kg/day treatment group, all livers contained accumulations of a hemosiderin-containing pigment in the reticuloendothelial cells and bilirubin in the intracanicular spaces.  The spleens of 3/4 males and 2/4 females also contained hemosiderin and hematopoiesis was increased in the bone marrow in 3/4 animals of both sexes.  Decreases in red blood cell counts, hematocrit, and hemoglobin occurred in both sexes.  Platelet counts and mean corpuscular volumes were increased in both sexes.  Total bilirubin was increased in 1/4 males and 3/4 females, but the increases were significant (p<0.05 or 0.01) only for females.  Body weights were reduced in males only.  Clinical signs of toxicity in both sexes were soft or liquid feces.  No treatment-related effects were observed in the 30 or 100 mg/kg/day treatment groups.  No dogs died during the study.  No treatment-related differences in clinical appearance, food consumption, ophthalmology, urinalysis parameters, organ weights, or gross pathology were observed in any treatment group.  No neoplastic tissue was observed in any of the treatment groups.  The LOAEL is 300 mg/kg/day, based on increased platelet count, decreased red cell parameters, and increased mean corpuscular volume which correlate with histopathological changes observed in the liver, spleen, and bone marrow in both sexes.

In a 13 week oral toxicity study (MRID 42983801), 6-month old beagle dogs (4/group/sex) received by capsule either 0, 25, 150, or 450 mg/kg/day 1-Naphthaleneacetic Acid Sodium Salt (Lot# 214001, Purity - 96.44% 1-NAA & 1.79% 2-NAA).  Due to inappetence at the high dose, the feeding regimen was altered for several high dose animals to reduce excessive weight loss.  Dose levels were based on a previous 6 month study with Naphthalene Acetic Acid (MRID 00136446) where male and female dogs receiving 50, 150, or 300 mg/kg/day experienced severe toxicity at the 300 mg/kg/day dose.  These included depressed body weight and body weight gain, histopathological changes and mortality.  In the current study with NAA sodium salt, none of the animals died.  Regurgitation of intact or partially digested capsules and emesis were the most common treatment- related clinical sign and was toxicologically significant at the high dose.  Body weight gain was significantly reduced in the high dose males (15% of controls, p<0.05) and females (29% of controls, p<0.05) accompanied by decreased food consumption and food efficiency.  There were statistically significant increases in relative organ weight for the liver, adrenals, thyroids/parathyroids, kidneys and brain and a decrease in gonad absolute and relative weights for the high dose males.  The high dose females only showed a statistically significant increase in relative kidney weights, although the relative weights for other organs did show a tendency towards an increase.   Gross examination of the genital tract revealed small prostates, small testes and epididymides in all high dose males.  Microscopic examination in these males revealed an increased incidence of hypospermatogenesis, characterized by less spermatogonia and spermatocytes and were associated with aspermia in the epididymides.  These may be secondary effects to the condition of the animals, but deserve further examination. Systemic toxicity was noted at 150 mg/kg/day and above based on  lesions of the gastrointestinal tract (ulcerative duodenitis and acute or erosive gastritis), hypocellularity of the bone marrow along with changes in liver enzymes (increased alkaline phosphatase in the high dose group), increased relative liver weights, histopathological changes of the liver (single cell necrosis, centrilobular necrosis, pigment accumulation, extramedullary hematopoiesis and mononuclear or mixed cell infiltration), depression in erythrocyte parameters (red blood cell count, hemoglobin and hematocrit levels in high dose females with a slight similar effect in males), decreased body weight gains, food consumption and food efficiency, inappetence and emesis in the high dose group.  The NOAEL for systemic toxicity is 25 mg/kg/day with a LOAEL for systemic toxicity of 150 mg/kg/day based on lesions of the gastrointestinal tract and hypocellularity of the bone marrow.

In a subchronic oral toxicity study (MRID 43914901), 1-naphthaleneacetic acid, ethyl ester (Lot/Batch # AM 315002; 97.75% ai) was fed (gelatin capsules) to beagle dogs (4/sex/dose) at dose levels of 0, 40, 125, or 400 mg/kg/day for 13 weeks.  All dogs survived the treatment.  Treatment-related clinical signs were limited to soft or liquid feces particularly in males and to a lesser extent in females at the high dose of 400 mg/kg/day.  Male dogs in the 40, 125, or 400 mg/kg/day treatment groups had a 4- to 5.5-fold increase in soft/liquid feces (maximum 65 instances during 13 weeks in the 400 mg/kg/day group) compared to the control group.  For females, there was one incident of soft/liquid feces in the control group, five in the 40 mg/kg/day group, eight in the 125 mg/kg/day group, and 19 in the 400 mg/kg/day group during the 13-week study.  A treatment-related lower body weight gain (20% less than the control) was seen in the males and females of the high dose group.  Males in the 40 or 125 mg/kg/day treatment group were 25-29% heavier, and males in the 400 mg/kg/day treatment group were 20% lighter than males in the control group; all three groups consumed 19% more food than the control during the study.   Female dogs in the 400 mg/kg/day treatment groups consumed 11% less food over the course of the study.  Male dogs in the 40, 125, or 400 mg/kg/day treatment groups had significantly (p <0.05 or 0.01) lower red blood cell, hemoglobin, and hematocrit levels, and lower mean platelet volumes (MPV) than the controls throughout the study.  In the high dose males at 12 weeks,  these were 18%, 17%, 17% and 22% lower than the controls for RBC, hemoglobin, hematocrit and MPV levels, respectively.  Although , these parameters were within the historical range values for this dog type, they were at the lower end of the range and may suggest anemic affects caused by the administration of this material at this dose.  Low white blood cell counts in female dogs in the 125 or 400 mg/kg/day treatment groups after 12 weeks of treatment were also within expected biological ranges.  No other treatment-related responses were observed during the study.  No differences were observed in clinical blood chemistry, ophthalmology, urine volume or chemistry, organ weights, or macroscopic or microscopic organ morphology between dogs in the treated and the control groups.  No neoplastic tissue was observed.  The LOAEL for this study is 400 mg/kg/day, based on soft/liquid feces and the depressed body weight gains of male and female dogs at this treatment level.  Additionally some blood parameters (RBC, hemoglobin, hematocrit and mean platelet volume) were all depressed in the male dogs at this level.  The NOAEL was 125 mg/kg/day.

A.4.2	Prenatal Developmental Toxicity

870.3700a:	 Prenatal Developmental Toxicity Study - Rat

In a prenatal developmental study (MRID 00042765), NAA technical (Lot # NAA 73323G; purity not reported, white powder) was administered by gastric intubation to groups (24/group) of healthy timed pregnant albino CD rats at dose levels of 0, 10, 50 or 250 mg/kg/day in 0.05% sodium carboxymethylcellulose from days 6 through 15 of gestation.  The dams were observed daily for signs of toxicity and weighed on day 1, 3, 6-15, 17 and 20 of gestation.  On day 20 of gestation the dams were euthanized with ether and the ovaries and uterine contents were immediately examined for viable and nonviable fetuses, resorptions, number of implantations, and number of corpora lutea.  Fetuses were examined for visceral and skeletal anomalies using proper techniques.   No deaths or toxic symptoms were reported at any dose level.  There was a statistically significant decrease in the mean body weight gain in the 250 mg/kg/day rats with the onset of the compound administration.  The dams in the 10 and 50 mg/kg/day groups did not show significant decrease in body weight gain during compound administration but showed a decrease compared to the controls from days 17-20.  Litter size and fetal loss were not affected by the treatment.  A slight decrease (statistically insignificant) in mean litter size (9.3, 9.3, 8.8 and 7.9 in the control, low-, mid-, and high-dose groups, respectively) was considered unrelated to treatment.  There was a statistically increased (p<0.05) mean preimplantation loss in the mid- and high dose groups (38.1-42.6%) in comparison to the control animals (20.6%).  However the means were within the range of the individual values of the control animals and were considered not treatment related. The incidence of major malformations and minor anomalies were comparable in all groups.  It was concluded that NAA is not teratogenic in pregnant rats at 250 mg/kg/day, the highest dose tested.  Therefor the developmental LOAEL is >250 mg/k/day and the NOAEL is 250 mg/kg/day.  The maternal toxicity LOAEL 250 mg/kg/day based on decreased body weight gain during the compound administration and the NOAEL for maternal toxicity is 50 mg/kg/day.

In another  developmental toxicity study (MRID 46685803), 1-Naphthaleneacetic acid sodium salt (97.4% a.i., batch/lot # 014-S0401-001) was administered to 24 female SD (Wistar-derived) rats/dose by gavage at dose levels of 0, 15, 50 or 150 mg/kg bw/day from days 5 through 21 (inclusive) of gestation.  All animals survived the duration of the study and all were pregnant with live fetuses in utero at scheduled termination on day 22 of gestation.  There were no treatment-related clinical signs.  Cesarean section data did not reveal any differences among all groups including the controls.  Maternal body weights of the 150 mg/kg/day females adjusted for initial weight were statistically significantly (p<0.01) lower than the control group from day 6 through day 17.  For the 50 mg/kg/day females body weights were lower during the first 4 days following the test material administration. Females in the low dose groups were not affected. Body weight gains were lower following the first day of treatment and recovered completely on the second day (low-dose group) and third day of treatment for the mid-and high-dose groups.  Sporadic lower food consumption occurred in the mid- and high-dose groups. Although the lower body weights seen in the high and mid dose groups were statistically significant, these are considered not to be biologically significant or adverse since these changes were only 1-4% lower than the controls. Therefore, the maternal LOAEL is >150 mg/kg bw/day, and the maternal NOAEL is 150 mg/kg bw/day.

A treatment-related effect at the high dose resulted in reduced mean fetal weights of male and female fetuses.  The only notable visceral anomaly was increased slightly dilated ureters with statistical significance in the mid (p<0.05) and the high doses (p<0.01). There were no treatment-related external malformations or variations of the fetuses.  Minor treatment-related skeletal malformations were seen at the high dose of 150 mg/kg/day.  These included an increased number of unossified centrum 5, increased number of cervical arch 7 cartilage fused to arch 6 cartilage, increased interruptions of thoracic rib 10 costal cartilage, increased number of long length cervical rib.  A treatment-related increased incidence of fetuses but not litters with a shortened 7[th] cervical rib was observed in the 50 and 150 mg/kg/day groups. The incidence of both fetuses and litters with an ossified calcaneum was lower than in the control group and indicated a reduction in ossification, in the 150 mg/kg/day group.  Reduced ossification of the mania and pes was seen at the high dose.  A statistically significant higher mean score for the pes was reported for the 50 mg/kg/day group, but the difference from the control mean was minimal. The developmental LOAEL is 150 mg/kg bw/day, based on decreased fetal weight and minor skeletal changes (centrum 5 not ossified, cervical arch 7 cartilage fused to arch 6 cartilage, shortened 7[th] cervical rib).  The developmental NOAEL is 50 mg/kg bw/day.

870.3700b:	Prenatal Developmental Toxicity Study - Rabbit

In a prenatal developmental study (MRID 00137822), NAA (Lot # RTS2846AC; 98.55% purity)  was administered by oral gavage to groups (16/group) of artificially inseminated Dutch Belted rabbits  (4 (1/2) to 5 months old) at dose levels of 0, 37.5, 75, or 150 mg/kg/day from days 6 through 27 of gestation.  These doses were selected on the basis of a range finding study (MRID  00137821) where groups (5 rabbits/group) were dosed NAA once daily by gavage at dose levels of 0, 28, 80 or 240 mg/kg/day from days 6 through 27 of gestation.  Animals were observed twice daily for mortality and once daily for toxic signs during the dosing period.  Animals that died were necropsied. Body weights were taken on days 0, 6, 12, 18, 24 and 28.  Surviving animals were sacrificed on day 28 and the uterus and ovaries were examined for viable and nonviable fetuses, resorptions, number of implantations, and number of corpora lutea.  One animal in the range finding study dosed at 240 mg/kg/day aborted on GD 28 following signs of toxicity consisting of hair loss, decreased feces and significant weight loss.  In the main study, one low dose animal died on GD 25 and three high dose gravid animals died during the study on GD 20, 22 and 27.  Only two of the high dose animals showed signs of toxicity (hair loss on the forelimbs, clear or white nasal discharge with dried material around the nose, decreased defecation and dry red material, presumably died blood, beneath the cage) prior to death.  Necropsy observations of the dead animals showed foamy fluid or congested lining in the trachea, congested lungs, fluid in the thoracic and/or abdominal cavities., reddening and/or erosions on the stomach mucosa, mucoid material or fluid in the intestines and pale liver or pitted kidneys.  Weights of the pregnant animals varied over the gestation period with some indication of treatment related loss in the high dose.  No compound-related abnormalities were observed in the pregnant animals at necropsy.  No compound-related effect was observed on implantation or fetal viability.  However, in the range finding study, an increase in the mean preimplantaion loss (23.2% at the low dose to 42.1% at the high dose compared to 11.4% in the concurrent control) occurred at all doses in the treated animals and appeared to be treatment related.  However, this increased preimplantation loss was considered problematic by the EPA reviewer since historical control data on 343 animals showed a preimplantaion loss of 30.8%.  Examination of the fetuses derived from the main study did not reveal any teratogenic effects.  It was concluded that the maternal toxicity NOAEL is 75 mg/kg/day based on lethality at the LOAEL of 150 mg/kg/day. The teratogenic and fetotoxic NOAEL was 150 mg/kg/day based on lack of developmental and fetoxic effects at the highest dose of 150 mg/kg/day tested.

In another developmental toxicity study (MRID 46685801) 1-Naphthaleneacetic acid sodium salt (97.4% a.i., batch/lot # 014-S0401-001) was administered to 24 female New Zealand White rabbits/dose in water by gavage at dose levels of 0, 30, 100 or 300 mg/kg bw/day from days 5 through 29 (inclusive) of gestation.  All animals survived the duration of the study except for one rabbit at the high dose which died on GD 22 due to a dosing error and one control rabbit was sacrificed on GD 24 following accidentally biting the dosing catheter into its esophagus.  A treatment related reduction in body weight and body weight gain was noted following the initial oral administration of 1-NAA Na salt to pregnant rabbits at the high dose of 300 mg/kg/day.  This was accompanied by initial reduction in food consumption.  Final body weights were comparable in all treatment groups.  Several dams receiving this dose were observed with few/no feces during the study.  Post mortem examination revealed red/black spots/areas in the glandular mucosa of the stomach in several of these dams indicating local irritation by the test material.  No adverse effects were noted in the dams at the lower dose of 30 and 100 mg 1-NAA Na salt /kg/day.  Cesarean section data did not reveal any statistically significant differences among all groups including the controls.  The LOAEL for maternal toxicity is 300 mg/kg/day based on reduced body weight, body weight gain and reduced food consumption, clinical signs (few/no feces) and stomach irritation (red/black spots/areas in the glandular mucosa of the stomach).  The maternal toxicity NOAEL of 1-NAA Na in pregnant rabbits derived from this study is 100 mg/kg/day.

Developmental Toxicity.   The oral administration of 1-NAA Na salt during gestation to rabbits resulted in decreased mean fetal weights (males and females) at the high dose of 300 mg/kg/day. Mean fetal weights at the low- and mid-dose were comparable to the control group.  There was no effect by l-NAA-Na salt administration on the overall incidence of major external/visceral, skeletal or Bouin's head defects or on the incidence of any specific major fetal abnormalities. The defects were considered to be spontaneous in origin. Fetuses with minor defects of the head following Bouin's fixation and sectioning, and fetuses with minor external/visceral defects were comparable in all groups including the control.  There was no indication that any of the specific effects were attributable to the test material. Fetuses with minor skeletal defects were statistically significantly higher in the 300 mg/kg/day.  However, only one specific defect (dumbbell shaped ossification of the 7[th] thoracic centrum) was statistically significantly higher (p<0.01) in the 300 mg/kg/day group in comparison with the control group.  No variants were detected in the heads of the fetuses following Bouin's fixation and serial sectioning and no external/visceral findings were detected in any fetus.  The overall proportion of fetuses with skeletal variants was statistically significantly higher in the 30, 100 and 300 mg/kg/day groups in comparison with the control group, but there was no specific increase in any specific variant and is not attributable to the test material administration.  The incidence of lengthened costal cartilage of the 10[th] thoracic rib was statistically significantly higher in all groups administered 1-NAA-Na in comparison with the control group, although there was no evidence of a dose-related trend. However, the incidences of fetuses with shortened or lengthened 13[th] thoracolumbar ribs (i.e. extra ribs) and with 27 bilateral pre-pelvic vertebrae were statistically significantly increased in the 300 mg/kg/day group in comparison with the control group and were considered to be attributable to 1-NAA-Na administration.  The LOAEL for developmental toxicity is 300 mg/kg/day based on an increase in the overall incidences of fetuses with minor skeletal defects and variants (dumbell ossification of the 7[th] thoracic centrum, extra thoracolumbar ribs and 27 pre-pelvic vertebrae) and a decrease in ossification of the manus.  The NOAEL is 100 mg/kg/day.

A.4.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects  -  Rat MRID 42090018

870.3800:	Reproduction and Fertility Effects - Rat

In a 2-generation reproduction study (MRID 43796301) 1-Na-NAA (Lot # 214001; 96.44% a.i.) was administered to 35 Crl:CD(R)BR, rats/sex/group in diet at dose levels of 0, 100, 1000 and 3000 ppm [0, 7, 69 and 210 mg/kg/day for males and 0, 8, 81 and 239 mg/kg/day for females, respectively].  The dose levels were selected on the basis of previous toxicity studies in rats.  At 3000 ppm (HDT), treatment-related decreases in body weight  gain and food consumption were observed in the P1 and P2 females during premating and gestation periods and decrease in body weight gain in P2 males during the premating period.  Reductions in P2 male and female premating body weight gain, although appearing systemic in nature, may have been secondary to developmental toxicity in these animals.  Reduced survival and growth were observed in both F1 and F2 offspring.  No adverse effects were noted at 1000 ppm.  Systemic and reproductive/developmental LOAEL = 3000 ppm (210 mg/kg/day for males, 239 mg/kg/day for females), based upon reduced body weight gain and food consumption in parental animals and reduced litter survival, and pup weight throughout lactation in both generations of offspring.  Systemic and reproductive/developmental NOAEL = 1000 ppm (69 mg/kg/day for males, 81 mg/kg/day for females).

A.4.4	Chronic Toxicity

870.4100a:	Chronic Toxicity  -  Rat

In a combined chronic toxicity/oncogenicity study (MRID 44157501), 1- Naphthaleneacetic acid sodium salt (1-Na-NAA) (96.44% 1-NAA; 1.79% 2-NAA w/w; Lot no. 214001) was administered to Crl:CD(R) BR rats (80/sex/dose) in the diet at concentrations of 0, 100, 1000, or 5000 ppm (corresponding to 0, 4.4, 43.8, and 224.5 mg/kg/day for males and 0, 5.6, 55.8, and 303.6 mg/kg/day for females).  An interim sacrifice was performed at 12 months on 20 rats/sex/dose;  terminal sacrifice (main study) was after 20.5-23 months due to the high mortality and poor health in the treated and control groups.  There were no treatment-related effects on survival or clinical observations.  High-dose females had lower mortality than the controls (p  0.05).  Weekly body weights of the high-dose males were significantly lower for days 14-119 and 238-259 ( 8.8%; p  0.05 or 0.01), but their overall weight gain was similar to that of the controls.  The low- and mid-dose females' weekly body weights and overall weight gains were within 7.4% and 14% of controls, respectively (p  0.05 or 0.01).  High-dose females, however, had lowered weekly body weights ( 35%; p  0.01), total weight gain (61% of controls), and overall food consumption and efficiency (15% and 36% lower than controls, respectively).  Serum triglyceride levels were about 50% lower than control levels at 6 and 12 months in high-dose males, and were 66-78% lower at 12 and 18 months in high-dose females (p  0.05 or 0.01).  The urine protein content of high-dose females was decreased from 12 months to terminal sacrifice to only 4.1-6.1% of control values (p  0.05 or 0.01).  These clinical chemistry changes had no histopathological correlates and their toxicological significance is unknown.  High-dose males and females had a significantly increased incidence and severity of stomach mucosal gland dilation (p  0.05).  The incidence of focal alveolar macrophages (in some cases accompanied by focal chronic inflammation) was increased in mid- and high-dose females, and was correlated at the high dose with an increased incidence of grossly observed lung nodules (p  0.05 or 0.01).  The incidence of focal alveolar macrophages was also slightly increased in high-dose males (p = 0.071).  The LOAEL is 5000 ppm (224.5 mg/kg/day for males and 303.6 mg/kg/day for females), based on an increased incidence of stomach (mucosal gland dilation) and lung lesions (focal alveolar macrophages) in both sexes of rats, and on lowered body weight gain and food efficiency in females.  The corresponding NOAEL is 1000 ppm (43.8 mg/kg/day for males and 55.8 mg/kg/day for females).  The only neoplastic finding (p  0.01) was an increased incidence of uterine endometrial stromal polyps in high-dose females (2/60, 1/60, 3/60, 13/60 at 0, 100, 1000, 5000 ppm, respectively).  The longer survival time of the high-dose females (about 88 days) did not account for the greater incidence of these benign neoplasms.  The rats were dosed adequately, judging by the toxicologic findings in both sexes of high-dose rats.

870.4100b:	Chronic Toxicity - Dog

In a chronic toxicity study (MRID 43744201), 1-napthaleneacetic acid, sodium salt (Lot # 214001; 96.44% ai) was administered (gelatin capsules) to beagle dogs (4/sex/dose) at dose levels of 0, 15, 75, or 225 mg/kg/day for 52 weeks.  At 225 mg/kg/day, Na-NAA administration resulted in gross pathological changes in the stomach of one male and one female and histopathological changes in the stomachs of four males and one female. The latter were characterized by mucosal atrophy (3) and congestion (1) in males and hemorrhaging in the female.  Slight sinusoidal histiocytosis was observed in the livers of four males and three females.  Both males and females exhibited a high incidence of emesis and capsule regurgitation at the 225 mg/kg/day dose level.  At 75 mg/kg only males exhibited dose-related toxic response to Na-NAA as characterized by stomach lesions in three animals consisting of necrosis of the fundic or pyloric epithelium and by slight sinusoidal histiocytosis in the liver of two males.  No other definitive treatment-related changes were noted in organ weights or gross pathological changes. All microscopic tissue abnormalities, other than those mentioned, occurred randomly and sporadically in all study groups.  No neoplastic tissue was observed in beagles in the treatment or control groups.  No dogs died during the study.  No treatment-related differences were observed between the clinical appearance, body weights, food consumption, biochemistry, hematology, urinalysis, or ophthalmology of the treated and control animals.  The LOAEL is 75 mg/kg/day in males and 225 mg/kg/day in females, based on emesis, capsular regurgitation incidences, gross and histopathologic changes in stomachs, and sinusoidal histiocytosis in livers. The NOAEL is 15 mg/kg/day in males and 75 mg/kg/day in females.

A.4.5	Carcinogenicity

870.4200a:	Carcinogenicity Study - Rat

This study is described above in the chronic studies section.  An increased incidence of uterine endometrial stromal polyps occurred in female rats at 303 mg/kg/day dietary feeding of Na NAA for two years.  According to HED consulting pathologist, Dr.  John Pletcher these are considered to be benign proliferative lesions of no carcinogenic concern (email to Dr.  William Burnam of HED on 04/04/2002).  Na NAA was not carcinogenic in the rat.

870.4200b:	Carcinogenicity (feeding) - Mouse

There is an NCI study published in 1969 where NAA acetamide was tested at one dose (maximum tolerated dose: according to the published article) as part of a testing program of 120 compounds.  Only the preliminary results were published (Innes et al, Innes JR, Ulland BM, Valerio MG, Petrucelli L, Fishbein L, Hart ER, Pallotta AJ, Bates RR, Falk HL, Gart JJ, Klein M, Mitchell I, Peters J. 1969.  Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: a preliminary note.  J.  Natl Cancer Inst.  42: 1101-1114).  The test materials were administered to two hybrid strains of mice : C57BL/6 x C3H/Anf and C57BL/6 x AKR (18/sex/hybrid strain).  The mice were administered NAA acetamide at one week of age by stomach intubation at 464 mg/kg/day until weaning at 4 weeks of age and administered the NAA acetamide in the diet at 1298 ppm (equivalent to 195 mg/kg/day at the conversion rate of 0.15 mg/kg for 1ppm) for approximately 18 months.  Gross and hostopathologic examination of the mice at the end of the feeding period did not reveal a significant increase in tumors over the controls.

In a carcinogenicity study (MRID # 46685802), Naphthaleneacetic Acid Sodium Salt (97.4%, batch/lot # 014-S0401-001) was administered to 50 C57BI/10JfCD-1 Alpk mice/sex/dose in the diet at dose levels of 0, 100, 500, or 2500 ppm [equivalent to 0, 10.8, 53.3, 276.0 / 0, 14.3, 70.9, 348.7 mg/kg bw/day M/F, respectively] for at least 80 weeks.  There were no statistically significant differences in survival or clinical signs between treated groups and controls in either sex. At the top dose (2500 ppm), bodyweights in males and females were statistically significantly lower than controls throughout the study with a maximum effect of 11% at week 77 in males, and 5% in females at week 41. Food consumption in males and females at this dose level was statistically significantly lower than controls at some time points throughout the study while food utilization in males was statistically significantly lower than controls in weeks 1-4 and overall in weeks 1-13. Total white blood cell, monocytes and large unstained cell counts were statistically significantly higher than controls in females at the top dose. This apparent elevation is due to higher counts in 2 individual animals and is considered to reflect animals with lymphomas in which there is also a leukaemic response. This effect was not compound-related. Also, at the top dose, liver and kidney weights in both sexes and epididymis in males were statistically higher than controls while brain weights in males were statistically lower.  Masses in the liver were identified in 3 male rats at the top dose, and in one female at 100 ppm. Pancreatic masses were also identified in 2 females at 2500 ppm and in 1 female at 500 ppm. A four-fold increase, compared to controls, in the incidence of hepato-cellular vacuolation in the liver was observed in males dosed at 2500 ppm. A slight increase in the presence of mononuclear cell infiltration in the liver was also observed in both males and females at this dose level. An increase in the incidence of intratubular microlithiasis and tubular basophilia within the kidney was observed in females and an increase in interstitial mononuclear cell infiltration in the kidney of males at 2500 ppm. There was an increase in the incidence of marked degeneration in the testes in males dosed with 2500 ppm of compound. Associated with this change, there was an increase in the incidence of decreased spermatozoa within the epididymis and dilated rete within the testis.  At 2500 ppm, adenomas of the liver were observed in one male rat, and adenomas of the lung were observed two males. Adenocarcinomas of the liver were observed in one control male and two males given 2500 ppm. None of these changes achieved statistical significance. There was a statistically significant increase in the incidence of histiocytic sarcoma in females at 2500 ppm but it was within historical control levels. There was a statistically significant increase (overall) in the incidence of multiple tumors in females given 2500 ppm. However there was no statistically significant increase in any individual tumor type, the incidence was low, and there was no dose-response relationship. Therefore this difference was considered not to be compound related.  The LOAEL is 2500 ppm [276 (M), 348.7 (F) mg/kg/day], based on lower body weight, food consumption, increased liver and kidney weights in both sexes and epididymis in males, lower brain weights in males, hepato-cellular vacuolation in males, adenomas of the liver and lung in males, increase in the incidence of multiple tumors in females.
The NOAEL is 500 ppm [53.3 (M), 70.9 (F)] mg/kg/day.  At the doses tested, there was no treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate based on the effects observed on the top dose (2500 ppm/kg/day).

A.4.6	Mutagenicity

Gene Mutation

GLN 870.5100,
MRID 43581006: NAA Acetamide
MRID 00042761: NAA
MRID 43581004: NAA Ethyl Ester

No mutagenic effect was noted with or without microsomal activation at concentrations up to the toxic range of 5000 micrograms/plate in the initial tests or in the confirmatory assay.

Chromosomal Aberrations

GLN 870.5395
MRID 43581005 NAA Acetamide
MRID 00042763 NAA
MRID 43581003 NAA Ethyl Ester

In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay in Mice.  There was no indication that NAA technical or the acetamide or the ethyl ester induced a clastogenic or aneugenic effect in either sex at any dose or sacrifice time.

GLN 870.5300
MRID 43580202: NAA Acetamide
MRID 43580201: NAA Ethyl Ester

In Vitro mammalian cell gene mutation -  L5178Y TK+/- Mouse Lymphoma Mutagenesis Assay.  NAA acetamide was tested up to cytotoxic levels (1250 μg/mL -S9 and 150 μg/mL +S9).  NAA Ethyl ester was tested up to cytotoxic levels (100 μg/mL -S9 and 300 μg/mL +S9).  Both were non mutagenic without S9 activation system, but positive with S9 activation system at or above 100 ug/mL for the acetamide and 300 ug/mL for the ethyl ester.

GLN 870.5450
MRID 00042764 NAA

Rodent Dominant Lethal Assay.  NAA did not produce dominant lethal effects in mice at oral doses of 125, 250 or 500 mg/kg/day as measured by pre implantation and post implantation losses

A.4.7	Neurotoxicity

A neurotoxicity screening battery is required.  The registrant has committed to either develop new data or submit existing data to satisfy this requirement by early 2014. AMVAC is in the process of determining the value of certain acute neurotoxicity data that have successfully supported foreign registrations. If applicable to EPA standards these data could be submitted this year.  However, HASPOC has determined that these studies are not required at the present time.

A.4.8	Metabolism

870.7485	Metabolism  -  Rat

In a study (MRID 43963301) conducted to examine the metabolism and disposition of 1-naphthaleneacetamide, five male and five female Sprague-Dawley rats were given either a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day).  Groups of male and female rats were subjected to the dosing regimens above using [[14]C] ring labeled -1-naphthaleneacetamide (Batch No. 94-516-38-10; 99.7% radiochemical purity, specific activity 55.5 mCi/mmol), and nonlabeled test article (Batch No. KP 0100487, chemical purity not available).  Excretion, tissue distribution, and metabolite profiles were determined.  There were no biologically significant treatment-related effects noted during the course of the study.  Overall recovery of administered radioactivity was an excellent 97.2-101%. 1-Naphthaleneacetamide was readily absorbed and excreted within 36 hours following a single 1 mg/kg bw, a 14-day repeat oral dose of 1 mg/kg bw, or a single 100 mg/kg bw oral dose. Following single or multiple oral low doses (1 mg/kg bw) of [C[14]]-1-naphthaleneacetamide, urinary excretion accounted for 70.8-74.1% of the administered radioactivity suggesting that a multiple exposure regimen did not affect the absorption/excretion processes.  Urinary excretion was unaffected following a single 100 mg/kg dose with 66.2-69.5% of the administered radioactivity excreted in urine.  Excretion via the feces accounted for the remainder of the administered radioactivity in all treatment groups (21.6-26.2%).  Excretory patterns did not exhibit gender-related variability but reflected delayed absorption in the high-dose group.  Because tissue burdens were very low at termination, neither 1-naphthaleneacetamide nor its metabolites appear to undergo significant sequestration.  Both  urinary and fecal metabolites were quantified by HPLC and most were identified using HPLC and HPLC/MS in conjunction with known standards.  Urinary metabolism involved amide cleavage followed by glycine conjugation with the glycine conjugate being the major metabolite of the low and repeat doses (13.7-47.3% of the administered radioactivity).  The glucuronide conjugate was also a major metabolite at the low doses (4.5-7.0% of administered).  For feces, the major metabolite detected was the dihydrodiol of naphthaleneacetamide (3.6-11.3% of administered.  Parent compound was detected at low concentrations (0.7-1.9% of administered) only in feces.  Extraction efficiencies appeared to be excellent and most components in the matrices examined (urine and feces) were adequately quantified and characterized.  The available data, based upon studies using labeled 1-naphthaleneacetamide, affirmed the metabolism pathway proposed by the investigators.

In another study (MRID 43961701) conducted to examine the metabolism and disposition of 1-naphthaleneacetic acid, ethyl ester, male and female Sprague-Dawley rats were given a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day).  Groups of male and female rats were subjected to the dosing regimens above using [[14]C] ring labeled -1-naphthaleneacetic acid, ethyl ester (Batch No. CSL-94-516-33-25, 99.3% radiochemical purity, specific acttivity 56.2 mCi/mmol), and nonlabeled test article (Batch No. GAB 69-34-02, chemical purity not available).  Excretion, tissue distribution, pharmacokinetic parameters, and metabolite profiles were determined.  There were no biologically significant treatment-related effects noted during the course of the study.  Overall recovery of administered radioactivity was an excellent 98.6-101.8%. 1-Naphthaleneacetic acid, ethyl ester was readily absorbed and excreted within 36 - 48 hours following a single 1 mg/kg bw, a 14-day repeat oral dose of 1 mg/kg bw, or a single 100 mg/kg bw oral dose.  Following single or multiple oral low doses (1 mg/kg bw) of [C[14]]-1-naphthaleneacetic acid, ethyl ester, urinary excretion accounted for 67.6-85.3% of the administered radioactivity.  Urinary excretion was unaffected following a single 100 mg/kg bw dose with 61.8-78% of the administered radioactivity excreted in urine.  Excretion via the feces accounted for the remainder of the administered radioactivity excreted by all treatment groups (12.3-35.2%).   Excretory patterns did not exhibit gender-related variability for the low dose groups although a minor difference was observed at the high dose.  Excretion patterns of the high-dose group reflected delayed absorption.  Because  - tissue burdens were very low at termination, neither 1-naphthaleneacetic acid, ethyl ester nor its metabolites appear to undergo significant sequestration.  Both  urinary and fecal metabolites were quantified by HPLC, TLC and most were identified using HPLC, GC/MS, and HPLC/MS in conjunction with known standards.  The major pathway of metabolism involved ester cleavage followed by glycine and glucuronide conjugation at the low and low repeat doses.  At the high dose, glucuronide conjugation appeared to play a more important role following ester cleavage.  Parent compound was detected at low concentrations (0.5-4.7% of administered) only in feces.  Extraction efficiencies appeared to be excellent and most components in the matrices examined (urine and feces) were adequately quantified and characterized.  The available data, based upon studies using labeled 1-naphthaleneacetic acid, ethyl ester, affirmed the metabolism pathway proposed by the investigators.

There are two published reports dealing with the metabolism of NAA in animals.  In one study (Dixon et al, 1977), carboxy -[14]C-1-naphthylacetic acid (aqueous equivalent NaOH solution) at 100 mg/kg was administered intramuscularly to 6 primate species (rhesus monkey: 1M, 1F; cynomolgus monkey: 1F; squirrel monkey: 2F; capuchin: 2F; marmoset: 1M and bushbaby: 1M, 1F), and intraperitoneally to cats (2F, 1M), rat (3F) and fruit bat (1F, 1M), orally to the rabbit (2F) and orally to 2 human males at 5 mg/individual.  Urine was collected for 24 hours and analyzed for radioactivity and metabolites, by liquid scintillation counting, chromatography,  radiochromatography scanning, and reverse isotope dilution.  In most species tested, 60-100% of the administered radioactivity was excreted in the urine by the end of 48 hours.  The glucuronic acid conjugate was the major urinary metabolite in man, rhesus monkey, marmoset, rabbit, rat, and fruit bat.  In the cat, no glucuronic acid conjugate was detected; turine and glycine conjugates were the major excretion products.  The 1-Naphthylacetyl glycine conjugate was a major urinary metabolite (>20%) in the cat, squirrel and bushbaby monkey and a minor metabolite in rabbit, rat, capuchia and marmoset monkey.  1-Naphthylacetylglutamine conjugate was formed only in the cynomolgus , squirrel and capuchin monkeys and marmoset in amounts not exceeding 3% of the administered dose.  1-Naphthylacetylturine was excreted by all species except the rabbit, rat  and the fruit bat.  It was a major excretion product (>6%) in the squirrel and capuchin monkeys, the marmoset and the cat.  In addition, when female rats were administered intraperitoneally doses of 5-500 mg/kg, bile duct cannulation showed that 10-44% of the radioactivity was present in the bile 3 hours after injection, while 0.6-32% was present in the urine.  At higher doses, urinary glucuronic acid predominated whereas at the lower doses the glycine conjugates predominated.  In the bile, the glucuronic acid conjugate was the major metabolite (>80% of the bile radioactivity), and the glycine conjugate was a minor metabolite (<4% of the bile radioactivity).  There was no analysis of the fecal radioactivity reported.

In another study (Lethco and Brouwer, 1966) carboxy -[14]C-1-naphthylacetic acid metabolism was investigated in male rats.  [14]C-NAA (neutralized with NaOH) was administered orally by stomach intubation at 0.1, 1.0, 100 and 250 mg/rat (2 rats/dose, weighing 250-280 g).  Urine and feces were collected for 3 days.  For bile cannulation study, [14]C-NAA was administered orally to 8 and 7 rats (weighing 350-435 g) at 0.1 and 100 mg/ rat, respectively, and urine and bile were collected at 2 and 6 hours after administration.  Radioactivity was analyzed by liquid scintillation counting, column and paper chromatography and enzymatic analysis.  Within 3 days, 71-90% of the administered [14]C was excreted in the urine.  At the lower doses (0.1-100 mg/kg)  most of the radioactivity was excreted during the first 24 hours, while at the higher dose (250 mg/kg), excretion was highest on the second day.  Fecal excretion accounted for 3-10% at the 0.1-1.0 mg/kg doses and 14-21% of the administered dose at the 100 and 259 mg/kg doses.  After the third day, no radioactivity was detected in the feces or urine at any dose.  Fractionation of the urinary radioactivity by column chromatography and subsequent paper chromatography, UV spectral analysis and B-glucuronidase enzyme hydrolysis, revealed that 70-93% of the urinary radioactivity was NAA glycine conjugate and NAA glucuronic acid conjugate.  The glucuronic acid conjugate predominated at the two high doses and the glycine conjugate predominated at the lower dose.  Minor amounts of unchanged NAA and two other minor unidentified metabolites were also detected in the urine.  The fecal radioactivity was not characterized.  In the bile cannulation experiment, excretion  of radioactivity into the bile and urine varied by the administered dose.  At the low dose of 0.1 mg/kg radioactivity in the urine was nearly four times the radioactivity detected in the bile after 2 hours, while at the higher dose of 100 mg/kg the ratio was reversed.  At the high dose a maximum of 29% of the administered radioactivity was recovered at 6 hours, while a maximum of 54% was recovered at the low dose at 2 hours.  At the low dose, the NAA glycine conjugate was the major metabolite and the NAA glucuronic conjugate was a minor metabolite, while in the bile the preponderance of these two metabolites was reversed.  Also unchanged NAA was detected in the bile but not in the urine at both doses.  At the high dose the NAA glucuronic conjugate was the major metabolite in both urine and bile while the glycine conjugate was a minor metabolite.

A.4.9	Immunotoxicity

	870.7800	Immunotoxicity  -  Rat

An immunotoxicity study is required.  The registrant has committed to begin this study in early 2013 and submit to EPA in early 2014.

B.  PHYSICAL/CHEMICAL PROPERTIES

Table 2.  Physicochemical Properties of NAA[1]
Parameter
Value
Reference
Active Ingredient
NAA acetamide
Melting point/range
182-184 C
Farm Chemicals Handbook
pH of 1% aqueous suspension
5.1
Product CSF
Density or specific gravity
0.221 g/cm[3]
Product CSF
Water solubility  (20̊C)
not available

Solvent solubility (20̊C)
not available

Vapor pressure at 20̊C
not available

Dissociation constant (pKa)
not available

Octanol/water partition coefficient (Kow)
not available

UV/vis  absorption spectrum
not available

Active ingredient
NAA
Melting point/range
130 C
Farm Chemicals Handbook
pH of 1% aqueous suspension
3.45
RD D265117, 5/15/00, B. Kitchens
Density or specific gravity
0.45 g/mL
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Water solubility  (26̊C)
0.042 g/100 mL
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Solvent solubility (26̊C)
xylene 5.5 g/100 mL
CCl4 1.06 g/100 mL
freely soluble in acetone, ether, and chloroform
CB Nos. 3468 and 3469, 6/3/88, F. Suhre

Farm Chemicals Handbook
Vapor pressure at 20̊C
0.3 mm Hg at 26 C
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Dissociation constant (pKa)
3.16 x 10[-4]
CB Nos. 3970 and 3971, 7/5/88, F. Suhre
Octanol/water partition coefficient (Kow)
not applicable; polar compound

UV/vis  absorption spectrum
not available

Active ingredient
NAA sodium salt
Melting point/range
>300 C
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
pH of 1% aqueous suspension
9.1
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Density or specific gravity
0.46 g/mL
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Water solubility  (26̊C)
340 g/100 mL
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Solvent solubility (26̊C)
insoluble in nonpolar solvents
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Vapor pressure at 20̊C
not available

Dissociation constant (pKa)
3.16 x 10[-4]
CB Nos. 3970 and 3971, 7/5/88, F. Suhre
Octanol/water partition coefficient (Kow)
not applicable; polar compound

UV/vis  absorption spectrum
not available

Active ingredient
NAA ethyl ester
Boiling point/range
>150 C
Old unreviewed Union Carbide data
pH of 1% aqueous suspension
not available

Density or specific gravity
1.11 at 20 C
Old unreviewed Union Carbide data
Water solubility  (26̊C)
insoluble
Old unreviewed Union Carbide data
Solvent solubility
soluble in xylene, toluene, ethanol, acetone, and methyl ethyl ketone
Old unreviewed Union Carbide data
Vapor pressure at 20̊C
not available

Dissociation constant (pKa)
not available

Octanol/water partition coefficient (Kow)
not available

UV/vis  absorption spectrum
not available

   C.  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 were determined to require a review of their ethical conduct, have received that review and have been determined to be ethical.

Klonne, D. (1999) Integrated Report for Evaluation of Potential Exposures to Homeowners and Professional Lawn Care Operators Mixing, Loading, and Applying Granular and Liquid Pesticides to Residential Lawns:  Lab Project Number:  OMA005: OMA001: OMA002.  Unpublished study prepared by Riceerca, Inc., and Morse Laboratories.  2213 p. (MRID 44972201).

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.