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 Pr oject 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-pyrim idinyl)amino]carbonyl] imidazo-[1,2- a ]pyridine-3-sulfonamide in or on the raw agricultural commodities in Crop Subgroup 1C, Tuberous and Corm Vegeta bles 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 granti ng 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 orde r 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 Re sidue 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 presen t 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 sens itivity in all crop commodities for which tolerances are being requested. A revised an alytical method using more ion transitions has also been provided.

3. Magnitude of residues.

Field trials were carried out to determine the magnitude of the residu e in/on potato(representative crop of Crop Subgroup 1C) a nd potato processing fractions, and in/on cantaloupe (representative crop of Crop Subgr oup 9A). The number and locations of

field trials were in accordance with O PPTS 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 cantal oupe), 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 th e 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 pr oposed 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 cont act hypersensitivity in the guinea pig and is non-irritating to the skin and to the ey e of the rabbit.

In an acute neurotoxicity study, imazosulfur on 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 in cluding abnormal gait, decreased activity, piloerection and upward curvature of the spine were observed on day 1 for animals receiving 2000 mg/kg. No other measuremen t 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 reve rse 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. Altoge ther these findings clearly show that imazosulfuron is devoid of any genotoxic potential.

3. Reproductive and developmental toxicity.

In a rat developmental toxici ty study, imazosulfuron was admi nistered 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 firs t interval of treatment fo r the 1500 mg/kg/day group were reduced. Imazosulfuron did not produce any developmental effects up to and including1500 mg/kg/day. Therefore, the NOAEL was 10 00 mg/kg/day for mate rnal toxicity and 1500 mg/kg/day for developmental toxicity.

In a rabbit developmental toxicity stu dy, imazosulfuron was administered by oral gavage to mated female New Zealand Wh ite 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, imazo sulfuron was administered continuously in the diet to male and female Sprague-Dawle y (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 a nd clinical observations were indicative of toxicity in the high dose group. Body wei ght 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-D awley 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 female s died. Clinical findings noted in survivors indicative of

test material related effects were limited to emaciation and poor haircoat in two highdose females. Mean body weight and body we ight 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 micr ocytic anemia were observed at 45000 ppm. Clinical chemistry analysis showed that c holesterol, glucose, total protein, albumin and/or globulin values for high dose animal s were significantly lowered. Mid dose

animals showed decreased cholesterol in ma les and decreased tota l 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 male s, mean body weight was reduced (7%) and food consumption was increased. Hemoglobi n, hematocrit and erythrocyte count were lower in high dose animals suggesting test ar ticle-induced anemia. Liver weights were increased in both sexes at 45000 ppm and in males at 10000 ppm. Centrilobular hepatocellular hypertrophy was the only micros copic finding clearly re lated to treatment in all males at the high and mid dose, seve ral 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 week s. Body weight, food consumption and food efficiency were slightly reduced at th e 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 wa s considered to be 200 mg/kg/day.

In a subchronic neurotoxicity study, imazosu lfuron 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 ma les 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 dos e 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 meas urement of antigenspecific, T-cell dependent antibody forma tion. The magnitude of the effect on bodyweight gain in this study may have aff ected the assessment of immune function, therefore the highest dietary concentration in the definitive four week immunotoxicity study was below 7500 ppm. In the definitiv e four week immunotoxicity study carried

out in female Han Wistar rats at diet ary 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 adrena l weights. At 1000 or 2500 ppm there was clearly no effect on immune function. Ther efore, 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 a pproached 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 fema le 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, lacrima tion and swollen, edematous tissue around the eyes. Various hematology and clinical chem istry parameters were decreased throughout the study in high dose animals although, with the exception of cholesterol values in males which were strongly re duced, not to a great extent.

Gross postmortem examinations revealed a variety of findings. The incidence of discolored lungs and adhesions or nodules/m asses 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 b acterial 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 histopat hological 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 ma les and females, (equivalent to 106.1 mg/kg/day in males and 132.5 mg/kg/day in ma les 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 dos e group was also lower in male animals. Liver weight was increased in high dose anim als. Microscopic examination revealed centrilobular hepatocellular hypertrophy in all treated gr oups. The incidence was greatest in the high dose group, but the seve rity 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 cons idered 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 pyel onephritis, while the female dog died of acute severe bronchopneumonia. Their deat hs could not clearly be linked to theadministration of the test material. No eff ects were noted on clin ical signs, body weight or food consumption. Hematology measurem ents showed a significant decrease in hematocrit, hemoglobin and erythrocytes in males from the high dose. Decreased total protein, albumin and albumin/globulin ratio s 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 a nd increased thyroid weights were observed at doses of 150 and 300 mg/kg/day. Liver weights were also significantly in creased. The NOAEL is considered to be 75 mg/kg/day.

6. Animal metabolism.

Toxicokinetic studies on th e absorption, distribution, metabolism and excretion of imazosulfuron have been conducted in the Sp rague-Dawley CD rat. The metabolism

studies conducted with imazosulfuron show that at 5 mg/kg the compound is almost completely absorbed and subsequently elim inated from the body within 2 days after administration. Approximately 60% is eliminat ed via the urine and 40% via the feces.

No remarkable sex-related differenc es were observed in the rate of 14 C-elimination or metabolic profile. 14 C residues in the tissues were gene rally 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, respectivel y, and 7% and 6% of the dose in feces of males and females, respectively. Other meta bolites 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 character ized 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 repr oduction 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 ExposureImazosulfuron dietary and non-dietary expos ure assessments were conducted using highly conservative assumptions.

1. Dietary exposure.

i. Food. Dietary exposure (food) asse ssments were conducted using

DEEM-FCID version 2.16 to evaluate the potential risk due to chronic dietary exposure of the U.S. popul ation and various subgroups to

tolerance level residues of imazo sulfuron 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 factor s and 100% crop treated.

ii. Drinking Water. The estimated drinki ng 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 applicati on rate of 0.3 lb ai/A/year. This is clearly a conser vative 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 95 th 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. Acut e 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 ca n be concluded that potential exposures to imazosulfuron are lo wer 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 gene ral 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 chil dren aged 3-5 years old. Chronic dietary exposures below 100% of th e cPAD are reasonably anticipated to result in no harm to exposed populations. As stated previously, assumption of tolerance-level resi dues and 100% crop treated for allcommodities produces a conservative assessment, so it can be concluded that potential exposures to imazosulfuron are lower than

those estimated here.

2. Non-Dietary Exposure--Resid ential/Recreational Turf.

Imazosulfuron is registered for use on turf, and applications can be made by homeowners. Therefore, the use on turf re presents 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-ap plication exposures as sociated 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 expos ure are inhalation exposures while applying imazosulfuron to turf and dietary exposur es from eating food and drinking water containing residues. Inhala tion handler exposures were estimated by EPA to be 0.000091 mg/kg bw/d for adults. Chronic diet ary exposures (food pl us 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 charac terize short-term residential exposures, the aggregate margin of exposure (MOE) is calculated to be 38,000 for adults. MOEs greater than the ta rget of 100 are reasona bly anticipated to result in no harm to exposed populations.

For children, the relevant sources of expos ure are post-applicati on incidental oral exposures from contact with treated turf and dietary e xposures from eating food and drinking water containing resi dues. Post-application incide ntal oral exposures were estimated by EPA to be 0.014 mg/kg bw/d. Ch ronic 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 character ize short-term residential exposures, the aggregate MOE is calculated to be 7,000 for ch ildren. 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 St ates. Although imazosulfuron and other sulfonylurea herbicides may have similar mode s of action on plants, no data are available to determine if these compounds have comm on mechanisms of mammalian toxicity or on

how to include imazosulfuron in a cumulativ e 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 MO Es do not exceed EPA’s level of concern. Based on this risk assessment, Valent conclude s that there is a reasonable certainty that no harm will result to the general popul ation 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 ev idence for developmental or reproductive

effects and clear NOAELs were achieved in all re levant studies. On this basis, an FQPA

factor of 1X is recommended. The results of the aggregate ex posure 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 aggreg ate exposure to imazo sulfuron from the pending and proposed uses.

F. International Tolerances

There are no CODEX maximum residue leve ls (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 Me xico. MRLs for rice grain are 0.1 ppm in Japan, 0.1 ppm in Korea, and 0.5 ppm in Taiwan.