Document ID: EPA-HQ-OPP-2007-0555-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-22T04:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (1/1/2007)>

EPA Registration Division contact: [Tracy H Ward, 703-308-9361]

<TEMPLATE:>

<[Syngenta Crop Protection, Inc.]>

<[7E7233]>

<	EPA has received a pesticide petition [7E7233] from [Syngenta Crop
Protection, Inc.], [P.O. Box 18300, Greensboro, NC 27419-8300]
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.>

<	1. by establishing a tolerance for residues of>

	

<	[Cloquintocet-mexyl, the inert safener (acetic acid,
[(5-chloro-8-quniolinyl)oxy]-, 1-methylhexyl ester)(CAS Reg. No.
99607-70-2) and its acid metabolite (5-chloro-8-quinlinoxyacetic acid,
also known as Syngenta Code CGA-153433)] when used as an inert
ingredient (safener) in pesticide formulations containing either the
herbicide clodinafop-propargyl or pinoxaden in a 1:4  ratio of safener
to active ingredient in or on the raw agricultural commodity [wheat
forage] at [0.20] parts per million (ppm) and [wheat hay] at [0.50]
parts per million (ppm).  EPA has determined that the petition contains
data or information regarding the elements set forth in section 408
(d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency
of the submitted data at this time or whether the data supports granting
of the petition. Additional data may be needed before EPA rules on the
petition.>

<A. Residue Chemistry>

<	1. Plant metabolism. [The metabolism of cloquintocet-mexyl in wheat is
well understood, as was published previously in the Federal Register
(April 19, 2000, Volume 65, Number 76, page 20972 - 20976). Total
residues in all crop samples are low. Metabolism involves primarily
rapid hydrolysis of the parent to the resulting acid followed by
conjugation.]>

<	2. Analytical method. [Syngenta Crop Protection, Inc. has submitted
practical analytical methodology for detecting and measuring combined
levels of cloquintocet-mexyl and its acid metabolite
(5-chloro-8-quinlinoxyacetic acid). The method is based upon acid
hydrolysis extraction, which converts the parent and all conjugates to
the acid metabolite.  The acid metabolite is subject to commodity
specific cleanup procedures and High Performance Liquid Chromatography
(HPLC) determination with triple stage quadruple mass spectrometry
(LC/MS/MS). The limit of quantitation (LOQ), as demonstrated by the
lowest acceptable recovery samples, is 0.01 ppm for grain, and 0.02 ppm
for forage, hay and straw.]

>

<	3. Magnitude of residues. [In support of registration of
cloquintocet-mexyl on wheat, a total of 21 field trials were conducted
on wheat per EPA region requirements in 16 states (CO, NC, ND, NM, MT,
MO, TX, CA, KS, SD, OK, IL, WA, NE, AK, MN).  In support of registration
of pinoxaden on barley, a total of 12 field trials were conducted on
barley per EPA region requirements in 10 states (VA, SD, MN, WI, ND, CO,
CA, ID, WA, and MT). The magnitude of the residue program supports the
setting of tolerances on all types of wheat and barley crops.]

>

<B. Toxicological Profile>

<	1. Acute toxicity.  [Cloquintocet-mexyl has a low order of acute
toxicity.  The acute toxicity profile of cloquintocet-mexyl was
published previously in the Federal Register (April 19, 2000, Volume 65,
Number 76, pages 20972 - 20976).  The EPA has published the acute
toxicity endpoints in the Federal Register (June 22, 2000 (Volume 65,
Number 121), page 38757-38764).]>

<	2. Genotoxicty. [Cloquintocet-mexyl was negative in all genotoxicity
tests.  The genotoxicity of cloquintocet-mexyl was published previously
in the Federal Register (April 19, 2000, Volume 65, Number 76, page
20972 - 20976).]>

<	3. Reproductive and developmental toxicity. [Cloquintocet-mexyl is not
a reproductive or developmental toxicant.  The toxicity of
cloquintocet-mexyl was published previously in the Federal Register
(April 19, 2000, Volume 65, Number 76, page 20972 - 20976).  The EPA has
published the reproductive and developmental toxicity endpoints in the
Federal Register (June 22, 2000 (Volume 65, Number 121), page
38757-38764).]>

<	4. Subchronic toxicity.  [The subchronic toxicity profile of
cloquintocet-mexyl was published previously in the Federal Register
(April 19, 2000, Volume 65, Number 76, page 20972 - 20976).  The EPA has
previously published the subchronic toxicity endpoints in the Federal
Register (June 22, 2000 (Volume 65, Number 121), page 38757-38764).]

>

<	5. Chronic toxicity. [The chronic toxicity profile of
cloquintocet-mexyl was published previously in the Federal Register
(April 19, 2000, volume 65, number 76, page 20972 - 20976). The EPA has
published the chronic toxicity endpoints in the Federal Register (June
22, 2000 (Volume 65, Number 121), page 38757-38764). The Agency
classified cloquintocet-mexyl as “not likely to be a human
carcinogen”.]

>

<	6. Animal metabolism. [The metabolism of cloquintocet-mexyl in animals
is well understood, as was published previously in the Federal Register
(April 19, 2000, Volume 65, Number 76, page 20972 - 20976). In rats,
approximately 50% of an oral dose of cloquintocet-mexyl was rapidly
absorbed through the gastrointestinal tract and excreted via urine and
bile. The administered dose was excreted independent of sex and was
essentially complete within 48 hours. Ninety-five percent of the
excreted dose was associated with one metabolite, the acid residue of
cloquintocet-mexyl (5-chloro-8-quinlinoxyacetic acid). ]

>

<	7. Metabolite toxicology. [The main metabolite in both plants and
animals is 5-chloro-8-quinlinoxyacetic acid. As this is the main
metabolite in rats, rabbits and mice, its toxicology has been tested
throughout the toxicology database for cloquintocet-mexyl. The toxicity
of cloquintocet-mexyl metabolites was discussed previously in the
Federal Register (April 19, 2000, Volume 65, Number 76, page 20972 -
20976).]

>

<	8. Endocrine disruption. [There is no evidence that cloquintocet-mexyl
has any effect on endocrine function, as was discussed previously in the
Federal Register (April 19, 2000, Volume 65, Number 76, page 20972 -
20976).]

>

<C. Aggregate Exposure>

<	1. Dietary exposure. [Tier I acute and chronic dietary exposure
evaluations were conducted for the inert ingredient safener,
cloquintocet-mexyl, using the Dietary Exposure Evaluation Model
(DEEM-FCIDTM, version 2.14), from Exponent,  DEEMTM.   Default
processing factors were used in these assessments.  All consumption data
for these assessments was taken from the USDA’s Continuing Survey of
Food Intake by individuals (CSFII) with the 1994-96 consumption database
and the Supplemental CSFII children’s survey (1998) consumption
database.  These exposure assessments included tolerance values as
listed in 40 CFR 180.560 (a) for all registered uses on wheat and
barley.  Proposed tolerance value increases are for wheat forage (0.20
ppm) and wheat hay (0.50 ppm).  Secondary residues in animal commodities
were estimated based on theoretical worst-case diets, consisting of
nutritionally balanced mixture of feeds (typically 30% protein and 70%
carbohydrates) and transfer information from metabolism studies. 
Drinking water estimates were incorporated directly into the dietary
exposure assessment using the higher of the estimated drinking water
concentrations (EDWCs) for surface and ground water.]>

<	i. Food. [Acute Exposure (Food Only):  An acute reference dose of 1.0
mg/kg-bw/day was based on a NOAEL of 100 mg/kg-bw/day from a
developmental toxicity study in the rat and an uncertainly factor of
100X.  No additional FQPA safety factor was applied.  The
cloquintocet-mexyl Tier I acute (deterministic) dietary exposure
assessment was based upon proposed tolerance residue values.  For the
purpose of aggregate risk assessment, the exposure value was expressed
in terms of margin of exposure (MOE) which was calculated by dividing
the no observable effect level (NOAEL) by the exposure for each
population subgroup.  In addition, exposure was expressed as a percent
of the acute reference dose (%RfD).  Acute exposure to the most
sensitive subpopulation (children 1-2 years) resulted in a MOE of
105,647 (0.09% of the acute RfD of 1.0 mg/kg-bw/day).  Since the
benchmark MOE for this assessment was 100 and since EPA generally has no
concern for exposures below 100% of the RfD, Syngenta believes that
there is a reasonable certainty that no harm will result from dietary
(food) exposure to residues arising from the current and proposed uses
for cloquintocet-mexyl.  Chronic Exposure (Food Only):  The chronic
reference dose (RfD) for cloquintocet-mexyl is 0.04 mg/kg-bw/day and is
based on a combined chronic toxicity/oncogenicity study in the rat with
a NOAEL of 4.3 mg/kg-bw/day and an uncertainly factor of 100X.  No
additional FQPA safety factor was applied.  The cloquintocet-mexyl Tier
I chronic dietary exposure assessment was based upon tolerance residue
values.  For the purpose of aggregate risk assessment, the exposure
values were expressed in terms of margin of exposure (MOE) which was
calculated by dividing the no observable effect level (NOAEL) by the
exposure for each population subgroup.  In addition, exposure was
expressed as a percent of the reference dose (%RfD).  Chronic exposure
to the most exposed subpopulation (children 3-5 years) resulted in a MOE
of 10,345 (1.0% of the chronic RfD of 0.04 mg/kg-bw/day).  Since the
benchmark MOE for this assessment was 100 and since EPA generally has no
concern for exposures below 100% of the RfD, Syngenta believes that
there is a reasonable certainty that no harm will result from dietary
(food) exposure to residues arising from the current and proposed uses
for cloquintocet-mexyl.  Cancer:  In August 1999, EPA classified
cloquintocet-mexyl as not likely to be a human carcinogen.  Due to the
classification, no quantitative cancer exposure assessment was
performed.]>

<	ii. Drinking water [The EPA uses FIRST (FQPA Index Reservoir Screening
Tool) as a Tier I screening model to estimate pesticide concentrations
in surface water, and SCI-GROW (Screening Concentration In Ground Water)
as a Tier I screening model to estimate pesticide concentrations in
ground water.  Neither model includes the impact of processing raw water
(mixing, dilution, or treatment) prior to distribution as drinking
water.  The primary use of these models by the Agency is to provide a
conservative approximation of the estimated environmental concentration
of specific pesticides in drinking water.  The highest labeled use rate
for the herbicide safener, cloquintocet-mexyl, in the United States is
0.0156 lb a.i./A on wheat using a single application.  This rate was
used for modeling the expected environmental exposure concentration of
cloquintocet-mexyl in drinking water.  For ground water (SCI-GROW)
modeling, Syngenta has determined a combined Estimated Drinking Water
Concentration (EDWC) for cloquintocet-mexyl and its free acid
metabolite, CGA-153433, of 2.02E-04 ppb.  For surface water modeling
(FIRST), the combined acute EDWC was estimated to be 0.2385 ppb, and the
combined chronic (cancer and non-cancer, annual average) EDWC was
estimated to be 0.058923 ppb. Since the surface water EDWC exceeds the
ground water EDWC, the FIRST surface water values should be used for
comparison purposes and are considered protective for any ground water
concentration concerns.  Acute Exposure from Drinking Water:  The acute
EDWC of 0.2385 ppb for surface water was used directly in DEEM-FCIDTM
software as “water, direct and indirect, all sources” to model the
aggregate exposures.  The acute drinking water exposure contributions at
the 95%-ile of exposures were determined by taking the difference
between the aggregate (food + drinking water) exposures and the food
(only) exposures for each population subgroup.  Acute drinking water
exposure to the U.S. population resulted in a MOE of >1,000,000 (0% of
the acute RfD of 1 mg/kg-bw/day).  Acute drinking water exposure to the
most sensitive subpopulation infants (<1 year) resulted in a MOE of
>1,000,000 (0% of the acute RfD of 1 mg/kg-bw/day).  Since the benchmark
MOE for this assessment is 100 and since the EPA generally has no
concern for exposures below 100% of the RfD, Syngenta believes that
there is a reasonable certainty that no harm will result from dietary
(food and drinking water) exposure to residues arising from all current
and proposed uses of cloquintocet-mexyl.  Chronic Exposure from Drinking
Water:  The acute EDWC of 0.058923 ppb for surface water was used
directly in DEEM-FCIDTM software as “water, direct and indirect, all
sources” to model the aggregate exposures.  Chronic drinking water
exposure to the U.S. population resulted in a MOE of >1,000,000 (0% of
the chronic RfD of 0.04 mg/kg-bw/day).  The most exposed subpopulation
was infants (<1 year) with a MOE of >1,000,000 (0% of the chronic RfD of
0.04 mg/kg/day).  Since the benchmark MOE for this assessment is 100 and
since the EPA generally has no concern for exposures below 100% of the
RfD, Syngenta believes that there is a reasonable certainty that no harm
will result from dietary (food and drinking water) exposure to residues
arising from all current and proposed uses of cloquintocet-mexyl.]>

<	2. Non-dietary exposure [There are no residential uses registered for
products in which cloquintocet-mexyl serves as a safener, and therefore,
a residential exposure assessment is not required.] >

<D. Cumulative Effects>

<	[Cumulative Exposure to Substances with a Common Mechanism of
Toxicity:  Section 408(b)(2)(D)(v) requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity”.  The EPA does not have, at this time,
available data to determine whether cloquintocet-mexyl has a common
mechanism of toxicity with other substances or how to include this
pesticide in a cumulative risk assessment.  For the purposes of this
tolerance action, the EPA has not assumed that cloquintocet-mexyl has a
common mechanism of toxicity with other substances.]

>

<E. Safety Determination>

<	1. U.S. population. [The acute dietary exposure analysis (food plus
water) showed that exposure from all established and proposed uses of
cloquintocet-mexyl would result in a MOE of 199,081 (0.05% of the acute
RfD of 1.0 mg/kg/day) for the general US population, which exceeds the
benchmark MOE of 100.  The chronic dietary exposure analysis (food plus
water) showed that exposure from all established and proposed uses of
cloquintocet-mexyl would result in a MOE of 23,560 (0.5% of the chronic
RfD of 0.04 mg/kg/day) for the general US population, which exceeds the
benchmark MOE of 100.  A chronic cancer exposure analysis was not
performed, since there is no evidence of human carcinogenic potential
for cloquintocet-mexyl.  Short-term aggregate and intermediate-term
aggregate risk was not assessed because there are no current, pending,
or proposed residential uses for cloquintocet-mexyl.  Based on the
completeness and reliability of the toxicity data supporting these
petitions, Syngenta believes that there is a reasonable certainty that
no harm will result from aggregate exposure to residues arising from all
current and proposed cloquintocet-mexyl tolerances, including
anticipated dietary exposure from food and water exposures.]

>

<	2. Infants and children. [The acute dietary exposure analysis (food
plus water) showed that exposure from all established and proposed uses
of cloquintocet-mexyl would result in a MOE of 104,797 (0.10% of the
acute RfD of 1.0 mg/kg/day) for the most sensitive subpopulation,
children (1-2 years old), which exceeds the benchmark MOE of 100.  The
chronic dietary exposure analysis (food plus water) showed that exposure
from all established and proposed uses of cloquintocet-mexyl would
result in a MOE of 10,303 (1.0% of the chronic RfD of 0.04 mg/kg/day)
for the most sensitive subpopulation, children (3-5 years old), which
exceeds the benchmark MOE of 100.  A chronic cancer exposure analysis
was not performed, since there is no evidence of human carcinogenic
potential for cloquintocet-mexyl.  Short-term aggregate and
intermediate-term aggregate risk was not assessed because there are no
current, pending, or proposed residential uses for cloquintocet-mexyl. 
Based on the completeness and reliability of the toxicity data
supporting these petitions, Syngenta believes that there is a reasonable
certainty that no harm will result from aggregate exposure to residues
arising from all current and proposed cloquintocet-mexyl tolerances,
including anticipated dietary exposure from food and water exposures. 
Syngenta has considered the potential aggregate exposure from food and
water exposure routes and concluded that aggregate exposure is not
expected to exceed 100% of the chronic or acute reference dose and that
there is a reasonable certainty that no harm will result to infants and
children from the aggregate exposure to cloquintocet-mexyl.]

>

<F. International Tolerances>

<	[There are no Codex maximum residue levels (MRLs) established for
residues of cloquintocet-mexyl in or on wheat.]

>

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