EPA Registration Division contact: Andrew Ertman 

Interregional Research Project No. 4 (IR-4)

PP No. 2E8025 

 EPA has received a pesticide petition (2E8025) from Interregional Research 

Project No. 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of New 

Jersey, 500 College Road, East, Suite 201 W, Princeton, NJ 09540, in cooperation with 

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 in Crop 

Subgroup 1C, Tuberous and Corm Vegetables Subgroup at 0.02 ppm, and in Crop 

Subgroup 9A, Melon Subgroup 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. A revised analytical method using more ion transitions 

has also been provided.

 3. Magnitude of residues. 

Field trials were carried out to determine the magnitude of the residue in/on potato 
(representative crop of Crop Subgroup 1C) and potato processing fractions, and in/on 

cantaloupe (representative crop of Crop Subgroup 9A). 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 potato 

and 2-2.7X the current label rate for cantaloupe), the maximum number of applications, 

and the minimum pre-harvest intervals (PHI) proposed for the crops. No residues of 

imazosulfuron were detected in either of the crops or in the processed fractions. All 

tolerances are proposed at the LOQ of the analytical method, 0.02 ppm. 

B. 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. 

 

1. 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. 

2. 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. 

3. 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). 

4. 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 highdose 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. 

In the preliminary four week immunotoxicity study carried out in female Han Wistar 

rats at dietary concentrations of 7500, 12000 or 15000 ppm, a non-specific systemic 

toxic response at all dietary concentrations was observed. No statistically significant 

effect on immune function was observed, as assessed by the measurement of antigenspecific, T-cell dependent antibody formation. The magnitude of the effect on 

bodyweight gain in this study may have affected the assessment of immune function, 

therefore the highest dietary concentration in the definitive four week immunotoxicity 

study was below 7500 ppm. In the definitive four week immunotoxicity study carried 

out in female Han Wistar rats at dietary concentrations of 1000, 2500 and 7000 ppm, 

there was no effect of treatment on food or water consumption. At 7000 ppm, there was 

a marked non-specific toxic response and a suppression in immune function, as assessed 

by the measurement of antigen-specific, T-cell dependent antibody formation. This 

might be a stress-related change caused by a remarkably high non-specific toxic 

response accompanying an increase of adrenal weights. At 1000 or 2500 ppm there was 

clearly no effect on immune function. Therefore, the NOAEL for both general toxicity 

and immunotoxicity was 2500 ppm, equivalent to 222 mg/kg/day.
5. 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. 

6. 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%. 

7. 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. 

8. 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. 

C. Aggregate Exposure 
Imazosulfuron dietary and non-dietary exposure assessments were conducted using 

highly conservative assumptions. 

1. Dietary exposure. 

i. Food. Dietary exposure (food) assessments were conducted using 

DEEM-FCID version 2.16 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 grain, tomato, 

peppers (bell and non-bell), .tuberous and corm vegetables (Crop 

Subgroup 1C) and melons (Crop Subgroup 9A). Key assumptions in a 

Tier 1 assessment were residues at the proposed tolerance level, 

default processing factors and 100% crop treated. 

ii. Drinking Water. The estimated drinking water concentrations 

(EDWCs) were calculated by EPA/EFED and the results are 

summarized in the June 28, 2010 assessment. The peak and annual 

average surface water concentration of imazosulfuron was estimated to 

be 278.9 ppb using the “RICE” model to estimate concentrations 

associated with the use on rice at an annual application rate of 0.3 lb 

ai/A/year. This is clearly a conservative estimate of potential drinking 

water exposures, particularly given that the EPA estimates for surface 

water are 101.25 ppb (acute) and 33.27 (chronic) for use on tomato 

and pepper. 

iii. Acute Dietary Exposure. The total 95th percentile acute dietary (food 

plus water) exposures for select subpopulations are estimated to be 

0.37% of the aPAD (4 mg/kg body weight/d) for the general U.S. 

population, 1.37% for all infants (the most highly exposed 

subpopulation), 0.58% for children aged 1-2 years old, and 0.53% for 

children aged 3-5 years old. Acute dietary exposures below 100% of 

the aPAD are reasonably anticipated to result in no harm to exposed 

populations. As stated previously, the assumption of tolerance-level 

residues and 100% crop treated for all commodities produces a 

conservative assessment, so it can be concluded that potential 

exposures to imazosulfuron are lower than those estimated here. 

iv. Chronic Dietary Exposure. Total chronic dietary (food plus water) 

exposures for select subpopulations are estimated to be 0.8% of the 

cPAD (0.75 mg/kg/d) for the general U.S. population, 2.6% for all 

infants (the most highly exposed subpopulation), 1.2% for children 

aged 1-2 years old, and 1.1% for children aged 3-5 years old. Chronic 

dietary exposures below 100% of the cPAD are reasonably anticipated 

to result in no harm to exposed populations. As stated previously, 

assumption of tolerance-level residues and 100% crop treated for all 
commodities produces a conservative assessment, so it can be 

concluded that potential exposures to imazosulfuron are lower than 

those estimated here. 

 

2. Non-Dietary Exposure--Residential/Recreational Turf. 

Imazosulfuron is registered for use on turf, and applications can be made by 

homeowners. Therefore, the use on turf represents the opportunity for exposure while 

applications are being made as well as post-application from contract with treated turf. 

EPA has estimated both application and post-application exposures associated with turf 

uses. Dermal exposures are not of interest because no systemic toxicity was observed in 

a dermal toxicity study, so only inhalation and oral exposures are included in the 

aggregate exposure assessment. 

3. Aggregate Exposure Assessment. 

The aggregate risk assessment includes food, water and residential turf exposures. 

For adults, the relevant sources of exposure are inhalation exposures while applying 

imazosulfuron to turf and dietary exposures from eating food and drinking water 

containing residues. Inhalation handler exposures were estimated by EPA to be 

0.000091 mg/kg bw/d for adults. Chronic dietary exposures (food plus water) for the 

U.S. General population are estimated to be 0.006013 mg/kg bw/d. Using these 

exposure estimates and the NOAEL of 235 mg/kg bw/d to characterize short-term 

residential exposures, the aggregate margin of exposure (MOE) is calculated to be 

38,000 for adults. MOEs greater than the target of 100 are reasonably anticipated to 

result in no harm to exposed populations. 

For children, the relevant sources of exposure are post-application incidental oral 

exposures from contact with treated turf and dietary exposures from eating food and 

drinking water containing residues. Post-application incidental oral exposures were 

estimated by EPA to be 0.014 mg/kg bw/d. Chronic dietary exposures (food plus water) 

for all infants are estimated to be 0.0194 mg/kg bw/d. Using these exposure estimates 

and the NOAEL of 235 mg/kg bw/d to characterize short-term residential exposures, the 

aggregate MOE is calculated to be 7,000 for children. MOEs greater than the target of 

100 are reasonably anticipated to result in no harm to exposed populations. 

D. 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. 
E. Safety Determination 

. 

1. 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.

2. 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.