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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Heather Garvie, 703-308-0034

Syngenta Crop Protection, LLC PP #6F8455

EPA has received a pesticide petition (PP #6F8455) from Syngenta Crop 

Protection, LLC, P.O. Box 18300, Greensboro, NC 27419 requesting, pursuant to 

section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 

346a(d), to amend 40 CFR part 180

1. by establishing a tolerance for residues of

Prosulfuron, (N-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]-2-

(3,3,3-trifluoropropyl)benzenesulfonamide) in or on the raw agricultural commodity at 

[Grain, cereal, forage, fodder, and straw, group 16, fodder at 0.01 parts per million 

(ppm); Grain, cereal, forage, fodder, and straw, group 16, forage at 0.1 parts per 

million (ppm); Grain, cereal, forage, fodder, and straw, group 16, hay at 0.2 parts 

per million (ppm); Grain, cereal, forage, fodder, and straw, group 16, straw at 0.02 

parts per million (ppm); and Grain, cereal, group 15 at 0.01 parts per million ppm. 

EPA has determined that the petition contains data or information regarding the elements 

set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the 

sufficiency of the submitted data at this time or whether the data supports granting of the 

petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The nature of residue of prosulfuron is adequately 

understood for the purpose of the proposed tolerances. The metabolism of 

prosulfuron has been characterized on corn and in rotational crop studies on radish, 

lettuce, wheat and spinach.

2. Analytical method i plants. Analytical method AG-590C has been submitted 

for the detection and measurement of residue levels of prosulfuron in or on plant 

commodities. The method is based on cleanup procedures followed by 

determination by high-performance liquid chromatography with ultraviolet (UV) 

detection. The limit of quantitation (LOQ) is 0.01 ppm. A more recent analytical 

method, Syngenta Crop Protection Analytical Method REM 137.14, is being 

submitted for the determination of prosulfuron residues in crops based on cleanup 

procedures followed by analysis via LC-MS/MS. The LOQ is 0.01 ppm.
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ii livestock. Analytical method AG-592A has been submitted for the detection and 

measurement of residue levels of prosulfuron in livestock commodities. The method 

is based on cleanup procedures followed by determination by high-performance 

liquid chromatography with UV detection. The LOQ is 0.05 ppm for meat, eggs and

blood; and 0.01 for milk. 

Analytical method AG-642 was submitted as a confirmatory method for detection of 

residues of prosulfuron in crop and animal tissues on an HPLC system with an 

alternative mode of separation. The LOQ is 0.01 ppm for crops and milk and 0.05 

ppm for meat, eggs and blood.

3. Magnitude of residues. Complete, full geography residue programs, 

including processing, have been conducted on corn, wheat, grain sorghum and rice 

to determine the magnitude of residue of prosulfuron in or on these crop 

commodities. These residue trials support the requested tolerances for the cereal 

grains crop commodities.

B. Toxicological Profile

1. Acute toxicity. Prosulfuron has minimal toxicity under

acute exposure conditions. The oral rat LD50 is 986 milligram/kilogram (mg/kg). 

The dermal rabbit LD50 is >2,000 mg/kg. The rat inhalation LC50 is 5.467

milligrams per liter (mg/L). Prosulfuron is a minimal irritant for primary eye 

irritation and a non-irritant for primary dermal irritation in the rabbit. 

Prosulfuron is not a dermal sensitizer.

The NOAEL from a rat acute neurotoxicity study was 10 mg/kg/day based on

reduced motor activity and body temperature in males and abnormal gait in

females.

2. Genotoxicity. Prosulfuron was negative for mutagenic/genotoxic effects 

when tested in a bacterial reverse gene mutation assay using different S. 

typhimurium and E. coli stains; in a mammalian gene mutation study using V79 

cells; in an in vitro mammalian cytogenetic test using Chinese hamster ovary cells; 

in a micronucleus test in mice; and in a DNA- repair using rat liver hepatocytes. 

The evidence indicates that prosulfuron is not mutagenic.

3. Reproductive and developmental toxicity. The results of the reproductive and 

developmental studies indicate no evidence of increased susceptibility of fetuses or 

offspring. The reproductive and developmental toxicity profile can be summarized 

as follows:

Teratology study in rats: The maternal and developmental toxicity NOAEL was

200 mg/kg/day based on based on decreased body weight gain (maternal) and 

skeletal findings (developmental) at 400 mg/kg/day (highest dose level tested).

Teratology study in rabbits: In the developmental range-finding study in rabbits, 

signs of neurotoxicity (ataxia, hypoactivity, and neuropathology) were observed 
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starting at the lowest dose tested (150 mg/kg/day). Developmental toxicity was 

apparent (increased incidence of resorptions and abortions) starting at doses of 

300 mg/kg/day. In the first rabbit study, there were no signs of maternal or

developmental toxicity at any dose. The maternal and developmental toxicity

NOAEL was 100 mg/kg/day based on the highest dose level tested (HDT). In a 

second rabbit study conducted at doses up to 200 mg/kg/day, the maternal 

toxicity NOAEL was 20 mg/kg/day based on increases in abortion, decreases in 

food consumption, and in mean body weight gain at 100 mg/kg/day. The

developmental toxicity NOAEL was 100 mg/kg/day based on a dose-related 

increase in runts and small fetuses as well as skeletal effects at 200 mg/kg/day. 

Two-generational reproduction study in rats: The parental toxicity NOAEL was 

200 ppm (13.3 mg/kg/day for male and 15.3 mg/kg/day for female) based on 

decreased mean body weights and body weight gain observed in the P0 and P1 

generation animals at 2000 ppm (136 mg/kg/day). The reproductive toxicity 

NOAEL was 200 ppm (13.3 mg/kg/day for male and 15.3 mg/kg/day for female) 

based on decreased pup weights observed in both the Fl and F2 offspring at 2000 

ppm (136 mg/kg/day). 

4. Subchronic toxicity. The subchronic toxicity profile is summarized as 

follows:

90-day subchronic dietary toxicity study in rats: The NOAEL was 50 ppm (3.1 

mg/kg/day) for males based on reduced body weight and body weight gain at 500 

ppm (31 mg/kg/day) and 500 ppm (35 mg/kg/day) for females based on reduced 

body weight, body weight gain, food consumption, and food efficiency at 4,000 

ppm (268 mg/kg/day).

90-day subchronic dietary toxicity study in mice: The NOAEL was 15 ppm (2.0 

mg/kg/day) for males based on statistically significant decreased albumin and 

total bilirubin and statistically significant increased absolute and relative liver 

(to brain and/or body) weights at 500 ppm (69.3mg/kg/day) and 500 ppm (91.3 

mg/kg/day) for females based on statistically significant increased relative liver 

(to brain and body) weights, statistically significant increased hematocrit and 

mean corpuscular volume, and decreased mean corpuscular hemoglobin 

concentration at 1750 ppm (293 mg/kg/day).

90-day subchronic dietary toxicity study in dogs: The NOAEL was 150 ppm (5.3 

mg/kg/day) for males and females based on decreased bodyweight gain and feed 

efficiency as well as hematological and hepatic toxicity at 1500 ppm (54 

mg/kg/day).

21-day dermal toxicity study in rabbits: The systemic and dermal NOAEL was

1000 mg/kg/day based on the absence of any significant dermal or systemic 

effects at the HDT.

90-day subchronic neurotoxicity study in rats: The neurotoxicity NOAEL was

10,000 ppm for males and 5000 ppm for females and the systemic NOAEL was

200 ppm based on slightly reduced body weight gain in males at 2500 ppm.]

5. Chronic toxicity. [The chronic toxicity profile is summarized as follows:
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1-year chronic dosing study conducted in dogs: The NOAEL was 60 ppm (1.8 

mg/kg/day, females) based on hematologic and clinical chemistry effects 

(females) and incidence of lipofuscin accumulation in liver (both sexes) at 600 

ppm (18.6 mg/kg/day). 

18-month carcinogenicity study in mice: The systemic toxicity NOAEL was 700 

ppm (81.4 mg/kg/day in males and 100 mg/kg/day in females) based on slightly 

decreased body weight gain in females at 3500 ppm (410 mg/kg/day in males and 

508 mg/kg/day in females).

2-year combined chronic feeding/carcinogenicity study in rats: The systemic 

NOAEL was 200 ppm (7.9 mg/kg/day, males and 9.2 mg/kg/day, females) based 

on decreased body weight and body weight gain, decreased food consumption 

(females), hematopoietic system effects (males), and possibly increased GGT 

with decreases in liver, kidney and adrenal weight (females) at 2000 ppm (79.9 

mg/kg/day, males and 95.7 mg/kg/day, females).

6. Animal metabolism. The qualitative nature of the residue(s) of prosulfuron 

in animals is adequately understood based on the metabolism studies in rats, 

ruminants and poultry. In the rat studies, prosulfuron is rapidly absorbed from the 

gastrointestinal tract and is rapidly excreted. Approximately 90% of the 

administered dose was excreted during the first 48 hours. At higher doses a greater 

proportion of the administered dose was excreted in the feces compared to urine. 

Females usually excreted more of the dose in the urine than males in both instances. 

Prosulfuron is metabolized primarily via hydroxylation at side chains and phenyl 

ring positions, and O-demethylation of the triazyl methoxy group or Odemethylation of the methoxy group, and hydroxylation of the triazinyl methyl 

group. Minor pathways include unsaturation of the trifluoropropyl side chain,

hydrolysis of the phenyl-sulfonylurea link, and oxidative/hydrolytic cleavage of the

triazine ring system. In the goat, prosulfuron is quickly eliminated primarily via the 

urine. The metabolism in the goat follows a similar pathway as observed in the rat 

although not as extensive. The majority of the residues were accounted for as 

prosulfuron, the triazine amine, which results from bridge hydrolysis (CGA-150829) 

and the triazinyl hydroxymethyl metabolite (CGA-273437). In the hen, metabolism 

is similar to that observed in the rat and goat. The major residues found in edible 

tissues and eggs were prosulfuron, and CGA-150829 and the sulfonamide (CGA159902) which results from hydrolysis of the sulfonyurea bridge.

7. Metabolite toxicology. Prosulfuron is considered to be the only molecule of 

toxicological relevance. Metabolic pathways of prosulfuron in plants and animals 

are comparable and no detectable residues are found in or on crops. All relevant 

plant metabolites are observed in the animals and are thus toxicologically covered. 

The remaining plant metabolites are toxicologically insignificant.

8. Endocrine disruption. Prosulfuron does not belong to a class of chemicals 

known for having significant adverse effects on the endocrine system. Development 

toxicity studies in rats and rabbits and reproduction study in rats gave no indication 

that prosulfuron might have any effects on endocrine function related to 

development and reproduction. The subchronic and chronic studies also showed no 
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evidence of a long-term effect related to the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. Tier I acute and chronic aggregate risk assessments were 

performed for prosulfuron using the Dietary Exposure Evaluation Model (DEEMFCIDTM Version 4.02, Evaluation Copy); consumption data was from the USDA 

NHANES “What We Eat in America” survey, 2005-2010. These assessments 

included all current and proposed use patterns on rice to complete the registration 

on Crop Group 15 and Crop Group 16. The Tier I assessments incorporated 

tolerance values for all crops and field trial residue data for rice where prosulfuron 

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. 

Percent of crop treated values were conservatively estimated to be 100% for all uses 

in the assessments. Drinking water estimates were incorporated directly into the 

acute and chronic dietary exposure assessments using the highest estimated 

drinking water concentrations (EDWCs) for surface and ground water.

i. Food. Acute Exposure. The prosulfuron acute food risk assessments were 

performed for all population subgroups using an acute reference dose of 0.1 mg/kgbw/day based upon an acute neurotoxicity study in rats with a no observed adverse 

effect level (NOAEL) of 10 mg/kg/day and an uncertainty factor of 100X to account 

for intra- and inter-species variations. No additional FQPA safety factor was 

applied. For the purpose of the acute aggregate risk assessments, 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 26,512 (0.4% of the aRfD of 0.1 mg/kg-bw/day). The most exposed subpopulation was children (1-2 years old) with a MOE of 8,917 (1.1% of the aRfD of 

0.1 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100 and 

since the EPA generally has no concern for exposures above the Benchmark MOE 

or 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 prosulfuron.

Chronic Exposure: The prosulfuron chronic dietary food risk assessments were 

performed for all population subgroups using a chronic reference dose of 0.053 

mg/kg-bw/day based upon an oral toxicity study in dogs with a no observed adverse 

effect level (NOAEL) of 5.3 mg/kg/day and an uncertainty factor of 100X to account 

for 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 (%cRfD). Chronic (food 

only) exposure to the U.S. population resulted in a MOE of 42,159 (0.2% of the 

cRfD of 0.053 mg/kg-bw/day). The most exposed sub-population was children (1-2 
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years old) with a MOE of 9,303 (1.1% of the cRfD of 0.053 mg/kg-bw/day). Since 

the Benchmark MOE for this assessment was 100 and since the EPA generally has 

no concern for exposures above the Benchmark MOE or below 100% of the cRfD, 

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 prosulfuron.

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

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) 

of prosulfuron were determined using the Tier I PRZM-GW (v. 1.07) and Tier 1 

SCI-GROW (v. 2.3) models to estimate concentrations in ground water. For surface 

water EDWCs, the Tier II Surface Water Concentration Calculator (SWCC v. 

1.106) was used to assess terrestrial uses, and the Modified Tier-I Rice Model was 

used to assess a rice use. The proposed rice use and all registered uses were 

assessed. Based on PRZM-GW, the currently registered use on corn and sorghum 

provided the highest ground water acute EDWC of 10.3 ppb and the highest chronic 

EDWC of 8.7 ppb. The proposed rice use provided a surface water acute EDWC of 

33.2 ppb and a chronic EDWC of 16.5 ppb based on the Modified Tier-I Rice 

Model, which are higher than the respective surface water EDWCs for terrestrial 

uses. Because surface water EDWCs exceed ground water EDWCs, the surface 

water EDWCs were used for risk assessment purposes and will be considered 

protective for any ground water exposure concerns.

Acute Exposure from Drinking Water. The acute surface water EDWC of 33.2 ppb 

was input directly into the DEEM-FCIDTM software as “water, direct and indirect, 

all sources” to model the acute drinking water exposures. Exposure contributions 

at the 95th percentile of exposures were determined by taking the difference 

between the aggregate (food + drinking water) exposures and the food (alone) 

exposures for each population subgroup. Acute drinking water exposure U.S. 

population resulted in a MOE of 6,321 (1.6% of the aRfD of 0.1 mg/kg-bw/day). 

The most exposed sub-population was all infants (<1 year old) with a MOE of 1,806 

(5.5% of the aRfD of 0.1 mg/kg/day). Since the benchmark MOE for this 

assessment was 100 and since 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 acute drinking water exposure to residues arising from all 

registered and proposed uses for prosulfuron. 

Chronic Exposure from Drinking Water. The chronic surface water EDWC of 16.5 

ppb was input directly into the DEEM-FCID software as “water, direct and 

indirect, all sources” to model the chronic drinking water exposures. Chronic 

drinking water exposure to the U.S. population resulted in a MOE of 15,898 (0.6% 

of the cRfD of 0.053 mg/kg-bw/day). Chronic drinking water exposure to the most 

exposed sub-population (all infants, <1 year old) resulted in a MOE of 4,256 (2.3%

of the cRfD of 0.01 mg/kg-bw/day). Since the Benchmark MOE for this assessment 

was 100 and since EPA generally has no concern for exposures below 100% of the 
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cRfD, Syngenta believes that there is a reasonable certainty that no harm will result 

from chronic drinking water exposure to residues arising from all registered and 

proposed uses for prosulfuron.

2. Non-dietary exposure. Residential exposure risk assessments were 

performed for prosulfuron for exposure due to off-site drift of agricultural 

products. Prosulfuron is not labeled for residential use; therefore no residential 

handler exposure assessments are required. Prosulfuron is not labeled for use on 

residential lawns; only post-application exposure due to spray drift was assessed. 

Incidental exposure to consumers from spray drift from non-residential uses were 

not included in the aggregate consumer risk; this approach agrees with the EPA’s 

current policy and practice.

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 the EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, the EPA has not made a common mechanism of 

toxicity finding as to prosulfuron and any other substances, and prosulfuron 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 prosulfuron 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 proposed uses of prosulfuron would result in a MOE 

of 5,104 (2.0% of the aRfD of 0.1 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 proposed uses of prosulfuron 

resulted in a MOE of 11,545 (0.8% of the cRfD of 0.053 mg/kg-bw/day) for the 

general U.S. population, which also 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 uses of 

prosulfuron, including anticipated dietary exposure from food, water, and all other 

types of non-occupational exposures.

2. Infants and children. The acute dietary exposure analysis (food plus water) 

showed that exposure from all proposed uses of prosulfuron would result in a MOE 

of 1,604 (6.2% of the aRfD of 0.1 mg/kg-bw/day) for the most sensitive population 

subgroup, all infants (<1 year old), which exceeds the Benchmark MOE of 100. The 
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chronic aggregate dietary (food plus water) exposure analysis showed that exposure 

from all proposed uses of prosulfuron would result in a MOE of 3,673 (2.7% of the 

cRfD of 0.053 mg/kg-bw/day) for the most sensitive population subgroup, all infants 

(<1 year 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 to infants and 

children from aggregate exposure to residues arising from all current and proposed 

uses of prosulfuron, including anticipated dietary exposure from food, water, and 

all other types of non-occupational exposures.

F. International Tolerances

Codex Alimentarius Commission has not yet established Maximum Residue 

Limits (MRLs) for prosulfuron. Canada has established MRLs for prosulfuron on 

proso millet, sorghum, wheat, pearl millet and corn (0.01 ppm); meat, meat 

byproducts and eggs (0.05 ppm) and milk (0.01 ppm).