Document ID: EPA-HQ-OPP-2009-0737-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-01-15T05:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (7/1/2007)>

<EPA Registration Division contact: Julie Chao, PM Team 1; (703)
308-8735>

<Syngenta Crop Protection, Inc., P.O. Box 18300, Greensboro, NC  27419>

<[Petition number 9F7582]>

<	EPA has received a pesticide petition ([petition number 9F7582]) from 

Syngenta Crop Protection, Inc., P.O. Box 18300, Greensboro, NC  27419

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 180.565 by
establishing a tolerance for residues of	thiamethoxam
{3-[(2-chloro-5-thiazolyl)methyl]tetrahydro-5-methyl-N-nitro-4H-1,3,5-ox
adiazin-4-imine}(CAS Reg. No. 153719-23-4) and its metabolite
[N-(2-chloro-thiazol-5-ylmethyl)-N’-methyl-N’-nitro-guanidine] in or
on onion, dry bulb (0.03 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 primary metabolic pathways of thiamethoxam
in plants (corn, rice, pears, and cucumbers) were similar to those
described for animals, with certain extensions of the pathway in plants.
 Parent compound and CGA-322704 were the major residues in all crops. 
The metabolism of thiamethoxam in plants and animals is understood for
the purposes of the proposed tolerance.  Parent thiamethoxam and the
metabolite, CGA-322704, are the residues of concern for tolerance
setting purposes.>

<	2. Analytical method. Syngenta Crop Protection, Inc. has submitted
practical analytical methodology for detecting and measuring levels of
thiamethoxam in or on raw agricultural commodities.  This method is
based on crop specific cleanup procedures and determination by liquid
chromatography with either UV or MS detections.  The limit of detection
(LOD) for each analyte of this method is 1.25 ng injected for samples
analyzed by UV and 0.25 ng injected for samples analyzed by MS, and the
limit of quantification (LOQ) is 0.005 ppm for milk and juices, and 0.01
ppm for all other substrates.>

<	3. Magnitude of residues. Syngenta Crop Protection, Inc. has submitted
complete residue data for thiamethoxam on dry bulb onions.>

<B. Toxicological Profile>

<	1. Acute toxicity.  The acute oral LD50 for thiamethoxam in the rat is
1563 mg/kg body weight.  The acute dermal LD50 of thiamethoxam is >2000
mg/kg body weight.  Thiamethoxam is non-toxic at atmospheric
concentrations of 3.72 mg/l.  Thiamthoxam is minimally irritating to the
eye, non-irritating to skin and is not a dermal sensitizer.

In an acute neurotoxicity study in rats (OPPTS 870.6200a), the NOAEL was
100 mg/kg/day with a NOAEL of 500 mg/kg/day based on drooped palpebral
closure, decrease in rectal temperature and locomotor activity and
increase in forelimb grip strenght (males only).  At higher dose levels,
mortality, abnormal body tone, ptosis, impaired respiration, tremors,
longer latency to first step in the open field, crouched over posture,
gait impairment, hypo-arousal, decreased number of rears, uncoordinated
landing during the righting reflex test, slight lacrimation (females
only) and higher mean average input stimulus value in the auditory
startle response test (males only).>

<	2. Genotoxicty. In gene mutation studies with S. typhimurium and E.
coli (OPPTS 870.5100 and 870.5265, there was no evidence of gene
mutation when tested up to 5000 g/plate and there was no evidence of
cytoxicity.

In a gene mutation study with chinese hamster V79 cells at HGPRT focus
(OPPTS 870.5300) there was no evidence of gene mutation when tested up
to the solubility limit.

In a CHO cell cytogenetics study (OPPTS 870.5375) there was no evidence
of chromosomal aberrations when tested up to cytotoxic or solubility
limit concentrations.

An in vivo mouse bonemarrow micronucleus study (OPPTS 870.5395) was
negative when tested upto levels of toxicity in whole animals; however,
no evidence of target cell cytoxicity.  A UDS assay (OPPTS 870.5550) was
negative when tested up to precipitating concentrations.>

<	3. Reproductive and developmental toxicity. A prenatal developmental
study in the rat (OPPTS 870.3700a) resulted in Maternal and
Developmental NOAELs of 30 mg/kg/day and 200 mg/kg/day, respectively. 
The maternal LOAEL is 200 mg/kg/day based on decreased body weight, body
weight gain and food consumption.  The developmental LOAEL was 750
mg/kg/day based on decreased fetal body weight and an increased
incidenceof skeletal anomalies.

A prenatal developmental study in the rabbit (OPPTS 870.3700b) resulted
in maternal and developmental NOAELs of 50 mg/kg/day.  The maternal and
develomental LOAEL is 150 mg/kg/day.  The maternal LOAEL is based on
maternal deaths, hemorrhagic discharge, decreased body weight and food
intake during the dosing period.  The developmental LOAEL is based on
decreased fetal body weights, increased incidence of post-implantation
loss and a slight increase in the incidence of skeletal
anomalies/variations.

In a reproduction and fertility effects study in rats (OPPTS 870.3800)
the Parental/sytemic NOAEL is 1.84 (males), 202.06 (females) mg/kg/day;
the reproductive NOAEL is 0.61 (males), 202.06 (females) mg/kg/day and
the offspring NOAEL is 61.25 (males), 79.20 (females) mg/kg/day.  The
parental /sytemic LOAEL is 61.25 (males), not determined (females)
mg/kg/day based on inscreased incidence of hyaline change in renal
tubules in F0 and F1 males.  The reproductive LOAEL is 1.84 (males), not
determined (females) mg/kg/day based on increased incidence and severity
of tubular atrophy observed in testes of the F1 generation males.  The
offspring LOAEL is 158.32 (males), 202.06 (females) mg/kg/day based on
reduced body weight gain during lactation period in all litters.>

<	4. Subchronic toxicity. A 90 day oral toxicity study in rats (OPPTS
870.3100) resulted in a NOAEL of 1.74 (males, 92.5 (females) mg/kg/day. 
The LOAEL is 17.4 (male), 182.1 (female) mg/kg/day based on increased
incidence of hyaline change or renal tubules epithelium (males), fatty
change in adrenal gland of females, liver changes in females, all at the
LOAEL.

A 90 day oral toxicity in mice (OPPTS 870.3100) resulted in a NOAEL of
1.41 (males, 19.2 (females) mg/kg/day.  The LOAEL was 14.3 (male) 231
(female) mg/kg/day based on increased incidence of hepatocellular
hpertrophy.  At higher dose levels: decrease in body weight and body
weight gain, necrosis of individual hepatocytes, pigmentation of Kupffer
cells, and lymphocytic infiltration of the liver in both sexes; slight
hematologic effects and decreased absolute and erlative kidney weights
in males; and ovarion atrophy, decreased ovary and spleen weights and
increased liver weights in females.

In a 90 day oral toxicity in dogs (OPPTS 870.3150), the NOAEL is 8.23
(males), 9.27 (females) mg/kg/day.  The LOAEL is 32.0 (male), 33.9
(female) mg/kg/day based on slightly prolonged prothrombin times and
decreased plasma albumin and A/G ration (both sexes; decreased calcium
levels and ovary weights and delayed maturation in the ovaries (female);
decreased cholesterol and phospholipid levels, testis weights,
spermatogenesis, and spermatic giant cells in testes (male).

In a 28 day dermal study in rats (OPPTS 870.3200) the NOAEL was 250
(male), 60 (female) mg/kg/day.  The LOAEL was 1000 (male), 250 (female)
mg/kg/day based on increased plasma glucose, triglyceride levels, and
alkaline phosphatase activity and inflammatory cell infiltration in the
liver and necrosis if single hepatocyts in females and hhaline change in
renal tubules and a very slight reduction in body weight in males.  At
higher dose levels in females, chronic tubular lesions in the kidneys
and inflammatory cell infiltration in the adrenal cortex were observed.

In a subchronic neurotoxicity screening study in rats  (OPPTS 870.6200b)
the NOAEL was 95.4 (male), 216.4 (female) mg/kg/day, both at the highest
dose tested.  The LOAEL was not determined.  No treatment related
observations at any dose level.  LOAEL was not achieved.  May not have
been tested at sufficient high dose levels; however, a new study is not
required because the weight of evidence from other toxicity studies
indicates no evidence of concern.>

<	5. Chronic toxicity.  In a chronic toxicity study in dogs (OPPTS
870.4100) the NOAEL was 4.05 (male), 4.49 (female) mg/kg/day.  The LOAEL
was 21.0 (male), 24.6 (female) mg/kg/day based on increase in creatinine
in both sexes, transient decease in food consumption in females, and
occasional increase in urea levels, decrease in ALT, and atrophy of
seminiferous tubules in males.

In a mouse carcinogenicity study (OPPTS 870.4200) the NOAEL was 2.63
(male), 3.68 (female) mg/kg/day.  The LOAEL was 63.8 (male), 87.6
(female) mg/kg/day based on hepatocyte hypertrophy, single cell
necrosis, inflammatory cell infiltration, pigment deposition, foci of
cellular alteration, hyperplasia of Kupffer cells and increased mitotic
activity, also an increase in the incidence of hepatocellular adenoma
(both sexes).  At higher doses, there was an increase in the incidence
of hepatocellular adenocarcinoma (both sexes) and the number of animals
with multiple tumors, evidence of carcinogenicity.

In a combined carcinogenicity study in rats (OPPTS 870.4300) the NOAEL
was 21.0 (male), 50.3 (female) mg/kg/day.  The LOAEL was 63.0 (male),
255 (female) mg/kg/day based on the increased incidence of lymphocytic
infiltration of the renal pelvis and chronic nephropathy in males and
decreased body weight gain, slight increase in the severity of
hemosiderosis of the spleen, foci of cellular alteration in liver and
chronic tubular lesions in kidney in females.  No evidence of
carcinogenicity.

In a hepatic cell proliferation study in mice, the NOAEL was 16 (male),
20 (female) mg/kg/day.  The LOAEL was 72 (male), 87 (female) mg/kg/day
based on proliferative activity of hepatocytes.  At higher dose levels,
increases in absolute and relative liver weights, speckled liver,
haptocellular glycogenisis/fatty change, heptocellular necrosis,
apoptosis and pigmentation were observed.

In a  28 day feeding study to assess replicative DNA synthesis in the
amle rat, the NOAEL was 711 mg/kg/day.  The LOAEL was not established. 
Immunohistochemical staining of the liver sections from control and high
dose animals for proliferating cell nuclear antigen gave no indication
for a treatment related increase in the fraction of DNA synthesizing
hepatocytes in S-phase.  CGA-293343 did not stimulate hepatocyte cell
proliferation in male rats.

-oxidation.>

<	6. Animal metabolism. The metabolism of thiamethoxam in rats and
livestock animals is adequately understood.  The residues of concern
have been determined to be parent thiamethoxam and its metabolite
[N-(2-chloro-thiazol-5-ylmethyl)-N’-methyl-N’-nitro-guanidine]
expressed as thiamethoxam.>

<	7. Metabolite toxicology. For most risk assessment purposes, residues
of the metabolite corrected for molecular weight are considered to be
toxicologically equivalent to parent thiamethoxam.  However, EPA has
determined that the metabolite should not be included in the cancer risk
assessment.>

<	8. Endocrine disruption. There are no specific studies requested by
the Endocrine Disruptor Screening Program (EDSP) at this time because
endocrine effects have been well characterized in an acceptable
2-generation reproduction study with a clear NOAEL and LOAEL, and the
chronic reference dose (cRfD) selected for thiamethoxam risk assessments
is considered protective of the observed endocrine effects.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Tier I acute, and Tier III chronic aggregate risk
assessments were performed for thiamethoxam using the Dietary Exposure
Evaluation Model (DEEM-FCIDTM, version 2.16) from Exponent.  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.  In the Tier I acute assessment, in
addition to established tolerances (40 CFR 180.565) for the combined
residues of thiamethoxam (CGA293343) and its metabolite (CGA322704) in
or on a variety of raw agricultural commodities including meat and milk.
 These exposure assessments also included the proposed crop tolerance
for seed treatment use on onions (0.03 ppm).  Percent of crop treated
values were conservatively estimated to be 100% for all registered and
proposed uses.  Field trials residue values were used in the Tier III
chronic assessments where thiamethoxam was applied at the maximum
intended use rate and samples were harvested at the minimum pre-harvest
interval (PHI) to obtain the maximum expected residues.  Calculated
percent crop treated (%CT) values were incorporated in these chronic
Tier III assessments.  Drinking water estimates were incorporated
directly into the dietary exposure assessments using the highest
estimated drinking water concentrations (EDWCs) for surface and ground
water.  >

<	i. Food. Acute Exposure: The thiamethoxam acute dietary (food only)
risk assessment was performed for all population subgroups using an
acute reference dose of 0.35 mg/kg-bw/day based upon a developmental
neurotoxicity study in rats with a no observed adverse effect level
(NOAEL) of 34.5 mg/kg/day and an uncertainty factor of 100X.  The 100X
safety factor includes intra- and inter-species variations.  No
additional FQPA safety factor was applied.  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 NOAEL by the
exposure for each population subgroup.  In addition, exposure was
expressed as a percent of the acute reference dose (%aRfD).  At the 95th
percentile, acute (food only) exposure to the U.S. population resulted
in a MOE of 2,573 (3.83% of the aRfD of 0.35 mg/kg-bw/day).  The most
exposed sub-population was children (1-2 years old) with a MOE of 1,349
(7.30% of the aRfD of 0.35 mg/kg-bw/day).  Since the Benchmark MOE for
this assessment was 100 and since the EPA generally has no concern for
exposures below 100% of the aRfD, Syngenta believes that there is a
reasonable certainty that no harm will result from dietary (food only)
exposure to residues arising from all current and proposed uses of
thiamethoxam.	

Chronic Exposure.  The thiamethoxam chronic dietary (food only) risk
assessment was performed for all population subgroups using a chronic
reference dose of 0.012 mg/kg-bw/day based upon a two generation
reproduction study in rats with a no observable adverse effect level
(NOAEL) of 1.2 mg/kg/day and an uncertainty factor of 100X.  The 100X
safety factor includes intra- and inter-species variations.  No
additional FQPA safety factor was applied.  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 NOAEL by the
exposure for each population subgroup.  In addition, exposure was
expressed as a percent of the chronic reference dose (%RfD).  Chronic
(food only) exposure to the U.S. population resulted in a MOE of 15,879
(0.6% of the RfD of 0.012 mg/kg-bw/day).  The most exposed
sub-population was children (1-2 years old) with a MOE of 4,756 (2.1% of
the RfD of 0.012 mg/kg-bw/day).  Since the Benchmark MOE for this
assessment was 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 only)
exposure to residues arising from the current and proposed uses of
thiamethoxam.

Cancer.  A quantitative risk assessment using a cancer endpoint was not
performed.>

<	ii. Drinking water. EPA uses the Tier 2 model PRZM/EXAMS to estimate
potential surface water concentrations and the screening model SCI-GROW
to estimate potential ground water concentrations.  None of these models
includes consideration of the impact that processing (mixing, dilution,
or treatment) would have on the removal of pesticides from the water
source prior to distribution as drinking water.  The primary use of
these models is to provide a conservative approximation of the Estimated
Drinking Water Concentrations (EDWCs) of specific pesticides in drinking
water.  These models were used by Syngenta to provide EDWCs of
thiamethoxam for the registered uses and the proposed use on onions as a
seed treatment.  Based on these assumptions, the highest acute surface
water EDWC (generated using the standard PRZM crop scenario for Florida
peppers) is 12.15 parts per billion (ppb) based on the existing pepper
use.  The highest chronic surface water EDWC, generated using the PRZM
crop scenario for California lettuce, is 0.764 ppb based on the existing
lettuce use.  The highest acute and chronic EDWC for ground water (based
on an application rate of 1 x 0.266 lb./acre) is 4.12 ppb.  The highest
of these values was used for the acute and chronic aggregate assessments
and will be considered to be protective for all drinking water concerns.

 

 was input directly into the DEEM-FCID™ software as “water, direct
and indirect, all sources”.  Acute exposure (water only) to the U.S.
population resulted in a MOE of 132,184 (0.07% of the aRfD of 0.35
mg/kg-bw/day).  The most exposed sub-population was children (1-2 years
old) with a MOE of 42,435 (0.23% of the aRfD of 0.35 mg/kg-bw/day). 
Since the Benchmark MOE for this assessment was 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 acute dietary (food and drinking water) exposure to residues
arising from all current and proposed uses of thiamethoxam.

Chronic Exposure from Drinking Water:  The chronic EDWC of 4.12 ppb
(ground water) was used to calculate the chronic drinking water exposure
values for the U.S. Population and population subgroups.  Chronic
drinking water estimates were incorporated directly into the
DEEM-FCID™ software as “water, direct and indirect, all sources”. 
Chronic exposure (water only) to the U.S. population resulted in a MOE
of 13,953 (0.72% of the chronic RfD of 0.012 mg/kg-bw/day).  The most
exposed sub-population was infants (<1 year old) with a MOE of 4,211
(2.38% of the chronic RfD of 0.012 mg/kg-bw/day).  Since the Benchmark
MOE for this assessment was 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 chronic
drinking water exposure to residues arising from all current and
proposed uses of thiamethoxam.>

<	2. Non-dietary exposure. A residential exposure and risk assessment
was performed for thiamethoxam using the recently revised endpoints and
uncertainty factors established by the EPA.  The residential exposure
and risk assessment was performed for thiamethoxam uses on turf and
ornamentals using the Meridian 0.33G and 25WG labels.  Based on these
Meridian labels, there is a potential for residential handler exposure
from consumers making applications to home lawns and ornamentals.  There
is also a potential for post-application residential exposure to adults
and children re-entering treated lawns and to adults playing golf on
treated turf.  The following endpoints were used for these residential
risk assessments:  NOAEL = 1.2 mg/kg/day (for adults, from a two
generation oral reproduction study in rats) and NOAEL = 60 mg/kg/day
(for children 1-6, from a short-term dermal from a 28-day dermal study
in rats).  The post-application residential MOE for children (1-6 years)
from turfgrass use of Meridian 25 WG is 1,347, which exceeds the
residential risk arising from the turfgrass use Meridian 0.33G (MOE =
1,650).  The resultant combined short-term MOEs were1,347 (total
post-application risk) and 2,111 (combined post-application and handler
risk) for children (1-6 years) and adults (20-49 years), respectively. 
Both children (1-6 years) and adults (20-49 years) MOEs are above the
Benchmark MOE of 100 and thus do not exceed the EPA’s level of
concern.>

<D. Cumulative Effects>

<	Cumulative Exposure to Substances with a Common Mechanism of Toxicity.
 Section 408(b)(2)(D)(v) of FFDCA 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”.  Unlike other pesticides for which EPA
has followed a cumulative risk approach based on a common mechanism of
toxicity, EPA has not made a common mechanism of toxicity finding as to
thiamethoxam and any other substances and thiamethoxam does not appear
to produce a toxic metabolite produced by other substances.  For the
purposes of this tolerance action, the EPA has not assumed that
thiamethoxam 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
thiamethoxam tolerances would result in a MOE of 2,523 (3.91% of the
aRfD of 0.35 mg/kg-bw/day) for the general U.S. population, which
exceeds the Benchmark MOE of 100.  The chronic dietary exposure analysis
(food plus water) showed that exposure from all registered and proposed
thiamethoxam tolerances resulted in a MOE of 7,389 (1.4% of the chronic
RfD of 0.012 mg/kg-bw/day) for the general U.S. population, which also
exceeds the Benchmark MOE of 100.  For the short-term aggregate exposure
analysis the corresponding food, water and residential MOEs were
aggregated using the inverse MOE approach.  The short-term aggregate
(food, drinking water, and residential) MOE was 2,040 for adults (20-49
years old), which exceeds the Benchmark MOE of 100.  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 thiamethoxam uses, including anticipated dietary
exposure from food, water, and all other types of non-occupational
exposures.>

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 which exceeds the Benchmark MOE of 100.  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
to infants and children from aggregate exposure to residues arising from
all current and proposed thiamethoxam tolerances, including anticipated
dietary exposure from food, water, and all other types of
non-occupational exposures.>

<F. International Tolerances>

<	There are currently no Maximum Residue Limits (MRLs) set for
thiamethoxam for crops by the Codex Alimentarius Commission. 
International MRLs for the insecticide thiamethoxam have been
established for various agricultural commodities in a number of
countries including Argentina, Australia, Belarus, Brazil, Canada, Czech
Republic, Denmark, Denmark, Estonia, Georgia, Great Britain (UK),
Greece, Hungary, India, Israel, Italy, Korea (South), Latvia, Moldova,
Netherlands, New Zealand, Russia, Serbia and Montenegro, Slovak
Republic, Slovenia, South Africa, Spain, Switzerland, Taiwan, Ukraine,
and United States.>

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