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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 request ing, 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, g roup 16, fodder at 0. 0 1 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, fodde r, and straw, group 16, straw at 0.02 parts per million (ppm); and Grain, cereal, grou p 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; h owever, 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 n ature 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 chromatogr aphy with ultraviolet (UV)
detection . The limit of quanti t ation (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.2

ii livestock. Analytical method AG

- 592A ha s been submitted for the detection and measurement of residue levels of prosulfuron in livestock commodities. The method
is based on c leanup procedures followed by determination by high

- performance liquid chromatography with UV detection. The LOQ is 0.0 5 ppm for meat
, eggs and blood; and 0.01 for milk

.

Analytical method AG

- 642 was submitted as a confirmat ory method for detection of

r esidues 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 commo dities.

B. Toxicological Profile

1. Acute toxicity. Pr osulfuron has minimal toxicity under acute exposure conditions

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

The dermal rabbit LD50 is >2,0 0 0 mg/kg . T he rat inhalation LC50 is 5.467 millig rams per liter (mg/L). Prosulfuron is a minimal irritant for primary eye irritation and a non

- irritant for primary dermal irritation in the rabbit.

P rosulfuron is not a dermal sensitizer.

The NOAEL from a rat acute neurotoxicity study was 10 mg/kg /day b ased on reduced motor activity and body temperature in males and abnormal gait in
females.

2. Genotoxic i ty. 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 indicat es that prosulfuron is not mutagenic

.

3. Reproductive and developmental toxicity. The results of the reproductive and developmental studies indicate n o evidence of increased susceptibility of fetuses or offspring

. The reproductive and developmental toxicity pro file can be summarized

as follows:

Teratology study in rats: The maternal and developmental toxicity NOAEL w as 200 mg/kg/day based on based on decreased body weight gain (maternal) and skeletal findings (developmental) at 400 mg/kg/day (highest dose leve l tested)

. Teratology study in rabbits: In the developmental range

- finding study in rabbits,

s igns of neurotoxicity (ataxia, hypoactivity, and neuropathology) were observed3

starting at the lowest dose tested (150 mg/kg/day). Developmental toxicity was

app arent (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 development al 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 development al 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 ma le 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 toxicit y 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 e fficiency at 4,000 ppm (268 mg/kg/day)

. 90

- day subchronic dietary toxicity study in m ic e : 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 absol ute and relative liver (to brain and/or body) weights at 50 0 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 hematocri t and mean corpuscular volume, and decreased mean corpuscular hemoglob in
concentration at 1 750 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
effect s at the HDT

. 90

- day subchronic neurotoxicity study in rats : The n eurotoxicity NOAEL was 10,000 ppm for males and 5000 ppm for females and the s ystemic NOAEL was 200 ppm based on slightly reduced body weight gain in males at 2500 ppm

. ]

5. Chronic toxici ty. [ The chronic toxicity profile is summarized as follows:4

1

- year chronic dosing study conducted in dogs : T he NOAEL was 60 ppm ( 1.8 mg/kg/day , females) based on hematologic and clinical chemistry effects (females) and incidence of lipofuscin accumulatio n in liver (both sexes) at 600

ppm ( 18.6 mg/kg/day )

. 18

- month carcinogenicity study in mice : The s ystemic 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 pp m (410 mg/kg/day in males and 508 mg/kg/day in females)

. 2

- year combined chronic feeding /carcinogenicity study in rats: The s ystemic
NOAEL wa s 200 ppm (7.9 mg/kg/day, males and 9.2 mg/kg/day, females) based

on decreased b ody weight and body weight gain , d ecreased 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 excr eted. A pproximately 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 O

demethylation of the methoxy group, and h ydroxylation of the triazinyl methyl

g roup. 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 triaziny l 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 (CGA

159902) which results from hydr olysis 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

. P rosulfuron does not belong to a class of chemicals

kno wn for having sign if icant 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 no5

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 prosulfuro n using the Dietary Exposure Evaluation Model (DEEM

FCIDTM 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 com plete 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 a t 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 usi ng an acute reference dose of 0.1 mg/kg

bw/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 additio nal 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 sub

popu lation 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 assessme nts 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 e xposure 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 m ost exposed sub

- population was children (1

- 26

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 b elow 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 a cute 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 exposure s. 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 the7

cRfD, Syngenta believes that there is a reasonable certainty that no harm will result
from chron ic 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 product s. 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 exp osure to consumers from spray drift from non

- residential uses were not included in the aggregate consumer risk; this approach agrees with the EP A’s current policy and practice

.

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechan ism 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 prosul furon 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 s ubstances.

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

gener al 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 expo sure 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 plu s 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. The8

ch ronic 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 no t 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).