Document ID: EPA-HQ-OPP-2009-0205-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-05-06T04:00Z

Notice of Filing

[Valent U.S.A. Corporation]

[Petition No. 9F7535]

[Contact: Bethany Dalrymple (703) 347-8072]

	EPA has received a pesticide petition (9F7535) from Valent U.S.A.
Corporation, 1600 Riviera Ave., Suite 200, Walnut Creek, CA  94596,
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 by
establishing a tolerance for residues of imazosulfuron,
(2-chloro-N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]
imidazo-[1,2-a]pyridine-3-sulfonamide in or on the raw agricultural
commodities pepper, bell and non-bell, fruit at 0.02 parts per million
(ppm);  rice, grain at 0.02 ppm; and tomato, fruit at 0.02 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. 

Nature of the residue studies (OPPTS Harmonized Guideline 860.1300) were
conducted in potato, rice, and tomato as representative crops in order
to characterize the fate of imazosulfuron in all crop matrices.  Two
radiocarbon labeling positions were studied in each crop, Imidazolyl and
Pyrimidinyl.  In all three crops, low concentrations of parent
imazosulfuron were found, and the proposed Residue of Concern is
imazosulfuron.  IPSN and UDPM were found in one or more raw agricultural
commodities at greater than 10% TRR, but IPSN was only present in one
RAC at  0.003 ppm imazosulfuron equivalents.  A confined rotational crop
study was conducted, and no imazosulfuron was found in grain sorghum,
wheat, kale or radish RACs.  Conjugates of IPSN were the principal
metabolites observed, with HMS and UDPM being found in one or more RACs
at certain plantback intervals.

	2. Analytical method. 

An independently validated analytical method has been submitted for
analyzing parent imazosulfuron residues with appropriate sensitivity in
all crop commodities for which tolerances are being requested.

	3. Magnitude of residues. 

Field trials were carried out to determine the magnitude of the residue
in/on pepper (bell and non-bell), rice, and tomato and rice and tomato
processed fractions.  The number and locations of field trials were in
accordance with OPPTS Guideline 860.1500.  Field trials were carried out
using at least the maximum label rates (3X the current label rate for
pepper and tomato, and 1.7X to 2.5X for rice), the maximum number of
applications, and the minimum pre-harvest interval (PHI) proposed for
all the crops.  Except for one rice grain sample that was suspected of
contamination, no residues of imazosulfuron or UDPM were detected in any
of the crops or processed fractions.   All tolerances were proposed at
the LOQ of the analytical method, 0.02 ppm.

Toxicological Profile

A complete, valid and reliable database of mammalian and genetic
toxicology studies has been submitted to EPA that supports the proposed
tolerances for imazosulfuron on rice, peppers (bell and non-bell) and
tomatoes. 

 

Acute Toxicity.  

The acute toxicity of imazosulfuron has been evaluated in rats, rabbits
and guinea pigs following different routes of exposure.  imazosulfuron
has a low oral, dermal and inhalation toxicity to rats. It does not
cause delayed contact hypersensitivity in the guinea pig and is
non-irritating to the skin and to the eye of the rabbit.

In an acute neurotoxicity study, imazosulfuron was administered by oral
gavage to HsdRccHan:WIST rats at single doses of 0, 80, 400 and 2000
mg/kg.  No animals died.  Treatment related clinical findings including
abnormal gait, decreased activity, piloerection and upward curvature of
the spine were observed on day 1 for animals receiving 2000 mg/kg.  No
other measurement parameters were affected.  The NOAEL is considered to
be 400 mg/kg for both males and females.

Genotoxicity.

  

The genotoxic potential of imazosulfuron was studied in bacterial and
mammalian cells using various in vitro and in vivo tests.  No positive
responses were observed in any of the tests, which include a bacterial
reverse mutation assay, a mouse lymphoma L5178Y cells tk gene locus
assay, a chromosome aberration assay in Chinese hamster lung fibroblasts
and a mouse micronucleus test in CD-1 mice. Altogether these findings
clearly show that imazosulfuron is devoid of any genotoxic potential.

Reproductive and developmental toxicity.

  

In a rat developmental toxicity study, imazosulfuron was administered by
oral gavage to mated female Sprague-Dawley rats at doses of 0, 250, 500,
1000 and 1500 mg/kg/day from day 6 to day 15 of gestation. Maternal body
weight gain during treatment and food intake calculated for the first
interval of treatment for the 1500 mg/kg/day group were reduced. 
Imazosulfuron did not produce any developmental effects up to and
including 1500 mg/kg/day.  Therefore, the NOAEL was 1000 mg/kg/day for
maternal toxicity and 1500 mg/kg/day for developmental toxicity.

In a rabbit developmental toxicity study, imazosulfuron was administered
by oral gavage to mated female New Zealand White rabbits at doses of 0,
25, 50 and 125 mg/kg/day from day 6 to day 19 of gestation. At the125
mg/kg/day dosage level, one animal was sacrificed in extremis.  This was
considered a result of treatment.  Body weight and food consumption were
not affected by administration of the test article.   Whole litter
resorptions by one animal each at the 50 and 125 mg/kg/day dosage levels
were not considered treatment related.  No developmental effects were
noted at any dose level.  Therefore, the NOAEL was 50 mg/kg/day for
maternal and 125 mg/kg/day for developmental toxicity.

In a rat 2-generation reproduction study, imazosulfuron was administered
continuously in the diet to male and female Sprague-Dawley (SD) rats and
to their offspring through 2 successive generations, at dose levels of
0, 100, 1000 and 10000 ppm. In the F0 and F1 generations, treatment
related mortality and clinical observations were indicative of toxicity
in the high dose group.  Body weight and food and water consumption were
also significantly reduced at 10000 ppm for both generations.  Offspring
viability was reduced for both high dose generations at birth through
lactation day 4 or 7.  These animals were also small in size and
numerous pups were missing and presumed cannibalized.  F1 and F2
offspring growth through weaning was also significantly reduced at 10000
ppm.  No negative effects on mating or fertility were observable in all
dose groups and generations.  Therefore, the NOAEL for parental,
offspring and reproductive parameters is considered to be 1000 ppm
(equivalent to 77.8 mg/kg/day in males and 88.4 mg/kg/day in females).

Subchronic toxicity.

In a rat subchronic toxicity study, Sprague-Dawley rats received
imazosulfuron via the diet at concentrations of 0, 2500, 10000 and 45000
ppm for 13 weeks. At the high dose level, one male and two females died.
 Clinical findings noted in survivors indicative of test material
related effects were limited to emaciation and poor hair coat in two
high-dose females.  Mean body weight and body weight gain for mid and
high dose animals were statistically significantly lower than control
values.  Food consumption was increased in high dose animals.  

Hematological parameters indicative of microcytic anemia were observed
at 45000 ppm.  Clinical chemistry analysis showed that cholesterol,
glucose, total protein, albumin and/or globulin values for high dose
animals were significantly lowered.  Mid dose animals showed decreased
cholesterol in males and decreased total protein and globulin in
females.  Histopathological findings at 45000 ppm were limited to
centrilobular hepatocellular hypertrophy, minimal to slight severity, in
nine animals of each sex.  Based on reduced body weight and altered
clinical chemistry parameters, the NOAEL is 2500 ppm (equivalent to
234.7 and 265.7 mg/kg/day in males and females, respectively).

In a mouse subchronic toxicity study, CD-1 mice were fed diet containing
0, 2500, 10000 and 45000 ppm imazosulfuron in the diet for 13 weeks. 
One mid dose female animal was emaciated.  In high dose males, mean body
weight was reduced (7%) and food consumption was increased.  Hemoglobin,
hematocrit and erythrocyte count were lower in high dose animals
suggesting test article-induced anemia.  Liver weights were increased in
both sexes at 45000 ppm and in males at 10000 ppm.  Centrilobular
hepatocellular hypertrophy was the only microscopic finding clearly
related to treatment in all males at the high and mid dose, several low
dose males and high dose females.   The NOEL is considered 2500 ppm
(456.3 mg/kg/day) in males and 10000 ppm (2726.9 mg/kg/day) in females. 

Imazosulfuron was administered by capsule to Beagle dogs, 2/sex/group,
at dose levels of 0, 50, 100, 200 and 300 mg/kg/day for 4 weeks.  Body
weight, food consumption and food efficiency were slightly reduced at
the high dose.  At necropsy, kidneys, duodenum and stomach were slightly
discolored in high dose animals, although the significance of these
findings is not known.  The NOEL was considered to be 200 mg/kg/day.  

In a subchronic neurotoxicity study, imazosulfuron was administered
continuously in the diet to HsdRccHan:WIST rats for 13 weeks at doses of
0, 800, 2500 or 8000 ppm.  Body weight, body weight gain and food
utilization was lower for animals given 8000 ppm.  No neurotoxicity was
observed at any dose level.  The NOAEL for systemic toxicity was 2500
ppm (169.2 mg/kg/day in males and 200.8 mg/kg/day in females).  

Imazosulfuron was administered dermally under a semi-occlusive covering
to Sprague Dawley rats daily for 21 days.  The dose groups were 0, 100,
300 and 1000 mg/kg/day.  There were no effects at any dose level. 
Therefore, the NOEL is 1000 mg/kg/day, the highest dose tested.  

Chronic toxicity.

Imazosulfuron was administered in the diet to Sprague-Dawley rats at
concentrations of 0, 200, 2000 or 20000 ppm for 2 years.  In high dose
females, mortality was markedly increased after month 13.  Survivorship
approached 20% at month 22 so that the remaining high dose females were
sacrificed early.  Body weights in high dose animals were also decreased
throughout the study.  The maximum body weight differences occurred at
week 11 and 60 in males and females, where mean body weights were 75%
and 58% of control, respectively.  

Ocular effects were evident in several female animals of the high-dose
group as early as week 12 and continued to be observed for the remainder
of the study.  Males did not have clinically observable ocular findings,
but high dose animals did have an increased incidence of
chromodacryorrhea, lacrimation and swollen, edematous tissue around the
eyes.  Various hematology and clinical chemistry parameters were
decreased throughout the study in high dose animals although, with the
exception of cholesterol values in males which were strongly reduced,
not to a great extent.

Gross postmortem examinations revealed a variety of findings.  The
incidence of discolored lungs and adhesions or nodules/masses on the
lung was greater in the high dose animals at 18 and 24 months. 
Microscopically, the lung lesions revealed multiple foci of purulent
bronchopneumonia, caused by bacterial infection.  In the animals that
died after 12 months this was the primary cause of death.  Adrenal and
kidney (absolute and relative to brain weight) were decreased at month
12 and termination in high dose males.  There were no corresponding
histopathological abnormalities in these tissues or in any other tissues
except the lung and eye. There was no evidence of carcinogenic
potential.  The NOAEL was 2000 ppm in both males and females,
(equivalent to 106.1 mg/kg/day in males and 132.5 mg/kg/day in males
females). Furthermore, there was no evidence of carcinogenicity.

Imazosulfuron was administered to CD-1 mice in the diet at
concentrations of 0, 450, 4500 and 45000 ppm for 18 months.  Decreased
body weight gain was noted in high dose animals.  Body weight gain in
the mid dose group was also lower in male animals.   Liver weight was
increased in high dose animals.  Microscopic examination revealed
centrilobular hepatocellular hypertrophy in all treated groups.  The
incidence was greatest in the high dose group, but the severity was
comparable among all treated groups.  The microscopic and organ weight
changes suggest this finding is treatment related and may represent a
metabolic effect of the test material.  There was no evidence of
carcinogenic potential.  The NOAEL is considered to be 450 ppm (72.7
mg/kg/day) in the males and 4500 ppm (870.0 mg/kg/day) in the females.  

In a chronic dog study, Beagle dogs received imazosulfuron by gelatin
capsule at concentrations of 0, 75, 150 and 300 mg/kg/day for 12 months.
One male and one female high dose dog were found dead on day 57 and 20,
respectively.  The death of the male dog was caused by an acute severe
pyelonephritis, while the female dog died of acute severe
bronchopneumonia.  Their deaths could not clearly be linked to the
administration of the test material.  No effects were noted on clinical
signs, body weight or food consumption.  Hematology measurements showed
a significant decrease in hematocrit, hemoglobin and erythrocytes in
males from the high dose.  Decreased total protein, albumin and
albumin/globulin ratios were observed in the mid and high dose groups. 
Albumin was decreased at all dose levels at the 6 month interval but
returned to normal in the low dose group at termination.  Phospholipid
and cholesterol values were significantly decreased at 6 months and at
termination in the high dose group.  Mild to moderate thyroid
hypertrophy and increased thyroid weights were observed at doses of 150
and 300 mg/kg/day.  Liver weights were also significantly increased. 
The NOAEL is considered to be 75 mg/kg/day.  

Animal metabolism.

Toxicokinetic studies on the absorption, distribution, metabolism and
excretion of imazosulfuron have been conducted in the Sprague-Dawley CD
rat.  The metabolism studies conducted with imazosulfuron show that at 5
mg/kg the compound is almost completely absorbed and subsequently
eliminated from the body within 2 days after administration. 
Approximately 60% is eliminated via the urine and 40% via the feces.  No
remarkable sex-related differences were observed in the rate of
14C-elimination or metabolic profile.  14C residues in the tissues were
generally low and do not indicate any potential for accumulation. 
Parent compound was detected only in feces, accounting for <1% of the
dose. Five metabolites were identified and quantified.  HMS was the
predominant metabolite in urine and feces, accounting for about 55% and
58% of the dose in urine of males and females, respectively, and 7% and
6% of the dose in feces of males and females, respectively.  Other
metabolites were present at quantities of < 5%.  

Metabolite toxicology.

Bacterial mutagenesis and rodent acute oral toxicity studies have been
conducted with several imazosulfuron plant or soil metabolites.  Most
metabolites have been either been directly measured or are presumed to
be present in the rat metabolism studies and are therefore adequately
characterized by studies with the parent molecule.  Based on the results
of these studies, the metabolites tested are considered to be either
toxicologically equivalent to the parent material or not toxicologically
significant.  

Endocrine disruption.

The toxicology database for imazosulfuron is complete.  This includes a
thorough evaluation of the potential effects on reproduction and
development, and the pathology of the endocrine organs following
short-term and long-term exposure.  The battery of tests included as
part of this petition fully examines potential endocrine-related in vivo
effects, clearly defines NOAEL/LOAEL values and indicates no increased
sensitivity to developing offspring.  Imazosulfuron is not expected to
be an endocrine disrupting agent.

Aggregate Exposure

The Cumulative and Aggregate Risk Evaluation System (CARES) Version 3.0b
was used to conduct the imazosulfuron dietary and non-dietary exposure
assessments using highly conservative assumptions.  

Dietary exposure.

Food.  Dietary exposure (food) assessments were conducted to evaluate
the potential risk due to chronic dietary exposure of the U.S.
population and various subgroups to tolerance level residues of
imazosulfuron in/on rice and fruiting vegetables (including eggplant and
okra, in order to be conservative).  Proposed tolerance-level residues,
default processing values and 100% percent crop treated were used for
the assessment.

Drinking Water.  Dietary exposure from drinking water was estimated
using a PRZM/EXAMS assessment to determine the EDWCs in the standard
Index Reservoir associated with imazosulfuron proposed uses on turf,
which has the highest yearly maximum rate of all the uses.  (Application
for registration on turf is pending.)  Two applications at 1 lb ai/A
each were assumed, although the current label maximum rate is two
applications at 0.75 lb ai/A each.  The peak acute concentration (upper
10th percentile (1 in 10 year)) from all scenarios was chosen for a
worst-case estimate and imported into CARES Water module in order to
calculate drinking water risks. 

 

Non-Dietary Exposure--Residential/Recreational Turf.  

Non-dietary exposure to imazosulfuron from residential or recreational
(turf grass) application scenarios was assessed using the CARES
Residential module.  The risk assessment was conducted using
post-applicator assumptions since imazosulfuron will only be applied by
professional applicators. 

 

Aggregate Exposure Assessment.  

The aggregate risk assessment includes food, water and residential turf
exposures.  An acute risk assessment was not conducted because there was
no acute toxicology endpoint identified.  For subchronic and chronic
risk assessment scenarios, the endpoints utilized were 235 mg/kg/day and
75 mg/kg/day based on the 90-day rat and 1-year dog study, respectively.
 For dermal exposures, the endpoint was 1000 mg/kg/day, taken from the
21-day dermal study.  No additional FQPA factor was used (1X).  

For the dietary exposure pathway, both the sub-chronic and the chronic
99.9th percentile MOEs for all sub-populations were > 1,000,000, with
occupancy of the cPAD values < 0.01%.  In the case of drinking water,
the lowest MOEs were for children 1-2 years: for sub-chronic the 99.9th
percentile MOE was 188,728 and for chronic the 99.9th percentile MOE was
87,874.  In the case of residential (dermal and hand-to-mouth)
exposures, the lowest MOEs were estimated also for children 1-2 years:
for sub-chronic the 99.9th percentile MOE was 30,889 and for chronic the
99.9th percentile MOE was 19,544.  Based on these risk assessments, the
margins of exposure (MOE) for all routes of exposure and all population
subgroups greatly exceed 100 and therefore do not exceed EPA’s level
of concern.  

Cumulative Effects.  

Imazosulfuron is a sulfonylurea herbicide.  There are several
sulfonylurea herbicides registered for use within the United States. 
Although imazosulfuron and other sulfonylurea herbicides may have
similar modes of action on plants, no data are available to determine if
these compounds have common mechanisms of mammalian toxicity or on how
to include imazosulfuron in a cumulative risk assessment.  Therefore,
for the purposes of this tolerance petition no assumption has been made
with regard to cumulative exposure with other compounds having a common
mechanism of toxicity.

Safety Determination

.  

U.S. population.  

The toxicology database for imazosulfuron is complete. The results of
the aggregate exposure risk assessment indicate that the MOEs do not
exceed EPA’s level of concern.  Based on this risk assessment, Valent
concludes that there is a reasonable certainty that no harm will result
to the general population from the aggregate exposure to imazosulfuron
from the pending and proposed uses.

Infants and children.  

The toxicology database for imazosulfuron is complete.  There is no
evidence of quantitative or qualitative increases in susceptibility of
the young from in utero prenatal exposure in the rat or rabbit
developmental studies and pre/postnatal exposure in the 2-generation
reproduction study.  There is no evidence for developmental or
reproductive effects and clear NOAELs were achieved in all relevant
studies. On this basis, an FQPA factor of 1X is recommended.  The
results of the aggregate exposure risk assessment indicate that the MOEs
do not exceed EPA’s level of concern.  Based on this risk assessment,
Valent concludes that there is a reasonable certainty that no harm will
result to the general population from the aggregate exposure to
imazosulfuron from the pending and proposed uses.

F. International Tolerances

	

There are no CODEX maximum residue levels (MRLs) established or proposed
for residues of imazosulfuron in peppers, tomatoes, or rice.  There are
currently no tolerances for residues of imazosulfuron in Canada or
Mexico.  MRLs for rice grain are 0.1 ppm in Japan, 0.1 ppm in Korea, and
0.5 ppm in Taiwan.

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