Pesticide Petition for Tolerances for Nicosulfuron AGRICULTURALCOMMODITIES

Sorghum Grain, Forage and Stover

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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Mindy Ondish (703)605-0723

E. I. du Pont de Nemours and Company

2F8132

EPA has received a pesticide petition (2F8132) from E. I. duPont de Nemours and Company, 

DuPont Crop Protection, 1007 Market Street, Wilmington, Delaware 19898, 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 to establish tolerances for residues of nicosulfuron, [3-

pyridinecarboxamide, 2-((((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)aminosulfonyl))-

N,N-dimethyl] in or on the raw agricultural commodities sorghum, grain at 0.8 parts per 

million (ppm); sorghum, forage at 0.4 ppm; and sorghum, stover at 0.05 ppm. EPA has 

determined that the petition contains data or information regarding the elements set forth in 

section 408(d)(2) of the FFDCA; 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 and animal metabolism. The qualitative nature of the residues of nicosulfuron in 

plants is adequately understood; therefore no additional metabolism data nicosulfuron 

required to support the proposed tolerances on sorghum grain, forage and stover

2. Analytical method. Adequate analytical methodology, high-pressure liquid 

chromatography with ESI-MS/MS detection, is available for enforcement purposes. 

3. Magnitude of residues

Sorghum - Residue trials were conducted on sorghum at 13 locations distributed across 

the U.S. The nature of nicosulfuron residue in sorghum is adequately understood through 

the corn and canola metabolism studies. These residue data were the basis for 

establishing tolerances for Sorghum, grain, forage and stover

B. Toxicological Profile

1. Acute toxicity. Technical nicosulfuron has been placed in acute toxicology category III 

based on overall results from several studies. This compound was placed in toxicology

category III for acute dermal toxicity (LD50 > 2,000 mg/kg; rabbits) and eye irritation 

(effects reversible within 72 hours; rabbits). Acute oral toxicity (LD50 > 5,000 mg/kg; 

rats), acute inhalation toxicity (LC50 > 5.4 mg/L, rats) and skin irritation (no observed 
Pesticide Petition for Tolerances for Nicosulfuron AGRICULTURALCOMMODITIES

Sorghum Grain, Forage and Stover

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irritation; rabbits) results were assigned toxicology category IV. Technical nicosulfuron 

is not a dermal sensitizer.

2. Genotoxicty. Technical nicosulfuron was negative for genotoxicity in a battery of in 

vitro and in vivo tests. These tests included the following: Bacterial Reverse Mutation 

Assay, Unscheduled DNA Synthesis In Primary Rat Hepatocytes, In Vitro Cho 

Mammalian Cells Gene Mutation Assay, Mammalian Cells In Culture Cytogenic Assay

In Human Lymphocytes, In Vivo Micronucleus Assay – Mouse

3. Reproductive and developmental toxicity.

i. Rat developmental study. A developmental study was conducted in rats administered 

technical nicosulfuron by oral gavage at dose levels of 0, 186, 930, 2325 or 5581 mg/kg/day. 

No treatment-related effects were noted on maternal or developmental toxicity up to and 

including the highest dose tested of 5581 mg/kg (the limit of the suspension capability). The 

LOAEL for maternal and developmental toxicity could not be determined and the NOAEL 

is at least 5581 mg/kg/day for both maternal and developmental toxicity.

ii. Rabbit developmental study. In developmental study was conducted in rabbits 

administered technical nicosulfuron by oral gavage at dose levels of 0, 93, 465, 930 or 1860 

mg/kg/day. The LOAEL for maternal toxicity is 465 mg/kg/day and the NOAEL is 93 

mg/kg/day. The LOAEL for developmental toxicity is 465 mg/kg/day (based on an apparent 

increase in percent post implantation loss) and the NOAEL is 93 mg/kg/day. There were no 

external on visceral anomalies in the fetuses. Fetal toxicity was manifested by reduced mean 

fetal body weight at 930 mg/kg/day and above. Therefore, the LOAEL for fetal toxicity is 

930 mg/kg/day and the NOAEL is 465 mg/kg/day.

iii. Two-generation rat reproduction study. A two generation reproduction study was 

conducted in rats administered continuously with technical nicosulfuron in the diet at 

0,250, 5000 or 20000 ppm. There were no treatment related effects observed in the 

parental animals except for lower body weight gain (p<0.05) in the F1 (first mating) 

females at the high dose during the last (third) week of gestation. A lower body weight 

gain was also seen, but not statistically significant in the F0 females during the last week 

of gestation. Therefore, the LOAEL for parental systemic toxicity is 20,000 ppm (1265 

mg/kg/day) and the NOAEL is 5000 ppm (287 mg/kg/day). Reproductive parameters 

were unaffected in the low- and mid-dose groups. There was a statistically significant 

(p<0.05) decrease in litter size at birth (reproductive effects) and in pup (offspring 

effects) weights at postpartum day 14 through 21 in the F2a high dose group. The other 

litters showed a similar tendency, but not a statistically significant difference. Therefore, 

the NOAEL for both reproductive and offspring toxicity is 5000 ppm (287 mg/kg/day) 

and the LOAEL is 20,000 ppm (1265 mg/kg/day).

4. Subchronic toxicity. 

i. 90-Day rat feeding study. A 90 day study in rats was conducted at dose levels of 0, 300, 

1500, 7500 or 20,000 ppm. No treatment-related signs of toxicity or mortality were 
Pesticide Petition for Tolerances for Nicosulfuron AGRICULTURALCOMMODITIES

Sorghum Grain, Forage and Stover

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attributed to the test material. No compound effects on organ weights, gross and 

microscopic pathology were seen. A LOAEL for subchronic toxicity of this test material 

is >20,000 ppm (1495/1830 mg/kg/day for males/females) and a NOAEL is 20,000 ppm 

(1495/1830 mg/kg/day for males/females). 

ii. 90-Day mouse study. A 90 day study in mice was conducted at dose levels of 0, 300, 

1500, 7500 or 10000 ppm. No treatment-related signs of toxicity or mortality were 

attributed to the test material. The LOAEL derived from this study is 1500 ppm (234.0 / 

323.0 mg/kg/day for males/ females) based on decreased hematological parameters, 

particularly the circulating neutrophils, and the NOAEL is 300 ppm (43.9/ 62.0 

mg/kg/day for males/ females).

iii. 90-Day dog study Technical nicosulfuron was administered to dogs at dose levels of 

0, 250, 5000, or 20000 ppm. Based on hematological findings (reduction of neutrophils in 

females), the LOAEL is 20000 ppm (710/ 683 mg/kg/day in males/females) and the 

NOAEL is 5000 ppm (172/ 171 mg/kg/day in males/females).

5. Chronic toxicity and oncogenicity

i. 18-Month mouse oncogenicity study. An 18-month carcinogenicity study with mice 

fed dosages of 0, 3.3/4.4, 32.7/44.8, 327/438, and 993/1,312 mg/kg/day (males/females) 

demonstrated that no carcinogenic effects up to the highest dose tested. The systemic 

NOAEL is 993/1,312 (males/females) mg/kg/ day.

ii. 1-Year chronic dog study. A 1-year feeding study with dogs fed dosages of 0, 6.25, 125, 

and 500 mg/kg/day resulted in a systemic NOAEL of 125 mg/kg/day in males based upon a 

decrease in body weight gains and a concomitant increase in relative liver and kidney

weights in males. The NOAEL for females was 500 mg/kg/day, the highest dose tested.

iii. Two-year combined rat chronic toxicity/oncogenicity study. In a two-year combined 

chronic toxicity/oncogenicity study in rats, technical nicosulfuron was administered in 

the diet at concentrations of 0, 50, 1500, 7500 or 20000 ppm. Based on the lack of 

chronic toxic effects the NOAEL is the highest dose tested: 20,000 ppm (786 mg/kg/day

in males and 1098 mg/kg/day in females). 

6. Rat metabolism. In the rat, nicosulfuron is rapidly and moderately absorbed and is 

rapidly eliminated via urinary and fecal excretion. Following oral administration of the 

low dose (10 mg/kg bw), elimination in the feces accounted for 80 to 87% of the dose, 

and elimination in the urine accounted for 13 to 20%. At the high dose (1000 mg/kg bw) 

fecal and urinary excretion ranged from 89 – 95% and 5 – 11%, respectively. 

Elimination of 14C-CO2 was negligible. The average cumulative excretion half-lives were 

between 12 and 24 hours. Following intravenous administration, approximately 76 to 

80% of the dose was eliminated in the urine and 27 to 30% in the feces. Residues in 

tissues accounted for 0.05 to 0.5% of the dose. The major excretion product in urine and 

feces was unchanged parent compound. In addition, pyridine sulfonamide (N, Ndimethyl-2-sulfonamide pyridine-3-carboxamide or IN-V9367) was detected in the urine 
Pesticide Petition for Tolerances for Nicosulfuron AGRICULTURALCOMMODITIES

Sorghum Grain, Forage and Stover

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and accounted for 1.1 to 5.7% of the dose. Pyridine acid sulfonamide (2-

sulfonamidepyridine-3- carboxylic acid, or IN-64859) was tentatively identified as a 

minor metabolite in the feces of orally dosed rats and urine of intravenously dosed rats.

These metabolites represent hydrolytic cleavage/oxidation of the parent molecule.

7. Metabolite toxicology. Common metabolic pathways for nicosulfuron were 

demonstrated in the rat, goat and in corn. The major nicosulfuron metabolites in corn and 

the goat were the same as those in the rat. A minor metabolite in the goat and two in corn 

differed from those observed in the rat. These minor metabolites were only detectable 

following exaggerated doses to corn plants and in feed provided to goats. Neither of 

these minor metabolites were detectable in human dietary components; therefore, 

exposures to and accumulation of these minor metabolites are unlikely. The EPA has 

previously determined that the residue to be regulated is nicosulfuron only.

 

8. Endocrine disruption. No special studies investigating potential estrogenic or other 

endocrine effects of nicosulfuron have been conducted. However, the standard battery of 

required toxicology studies has been completed. These include an evaluation of the potential 

effects on reproduction and development, and an evaluation of the pathology of the 

endocrine organs following repeated or long-term exposure to doses that far exceed likely

human exposures. Based on these studies there is no evidence to suggest that nicosulfuron 

has an adverse effect on the endocrine sys

C. Aggregate Exposure

1. Dietary exposure –

i. Food. Because an endpoint attributable to a single dose was not identified, the dietary 

exposure assessment considered only chronic exposure and not acute.

Chronic dietary exposure assessment. Chronic dietary exposure resulting from the 

currently approved uses and proposed uses of nicosulfuron is well within acceptable 

limits for all sectors of the population. The chronic module of the Dietary Exposure 

Evaluation Model with Food Commodity Intake Database (DEEM-FCIDTM, version 3.14, 

Durango Software, LLC) was used to conduct the assessment with the chronic reference 

dose (cRfD) of 1.25 mg/kg/ day. This model incorporates nationwide food consumption 

data as reported by respondents in the Nutritional Health and Nutrition Examination 

Survey (NHANES) 2003-4, 2005-6, 2007-8 What We Eat in America (WWEIA). The 

analysis used tolerance values in place of residue values for relevant crops and meat and 

milk and assumed 100% crop treated for all commodities included. The chronic dietary 

exposure of the US population and each subpopulation utilizes <1% of the cRfD. There 

are large margins of safety for each population subgroup for chronic exposure to 

nicosulfuron.

ii. Drinking water. Based on the FIRST Tier 1 surface water and SCI GROW Tier 1 

groundwater models under worst-case conditions the worst-case chronic estimated 
Pesticide Petition for Tolerances for Nicosulfuron AGRICULTURALCOMMODITIES

Sorghum Grain, Forage and Stover

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environmental concentrations (EECs) of nicosulfuron is 0.685 parts per billion (ppb) in 

surface water based on application on corn. When drinking water at 0.685 ppb was 

included with food in the chronic dietary risk assessment, the predicted dietary exposure 

for the US population and each subpopulation was <1% of the cRfD. Thus, the chronic 

dietary exposure of nicosulfuron, including the contribution of drinking water, clearly 

meets the standard of reasonable certainty of no harm. 

2. Non-dietary exposure. No nicosulfuron product registrations for residential non food 

uses have been approved. Therefore, there should be no non-occupational, non-dietary

exposure.

D. Cumulative Effects

Nicosulfuron belongs to the sulfonylurea class of crop protection chemicals. Other 

structurally similar compounds in this class are registered herbicides. However, the 

herbicidal activity of sulfonylureas is due to the inhibition of acetolactate synthase 

(ALS), an enzyme found only in plants. This enzyme is part of the biosynthesis pathway

leading to the formation of branched chain amino acids. Animals lack ALS and this 

biosynthetic pathway. This lack of ALS contributes to the relatively low toxicity of 

sulfonylurea herbicides in animals. There is no reliable information that would indicate or 

suggest that nicosulfuron has any toxic effects on mammals that would be cumulative 

with those of any other chemical.

E. Safety Determination

1. U.S. population. Based on the completeness and reliability of the toxicity data and the 

conservative exposure assessments, there is a reasonable certainty that no harm will result 

from the aggregate exposure of residues of nicosulfuron including all anticipated dietary

exposure and all other non occupational exposures. 

2. Infants and children. Based on the completeness and reliability of the toxicity data, the 

lack of toxicological endpoints of special concern, the lack of any indication that children 

are more sensitive than adults to nicosulfuron, and the conservative exposure assessment, 

there is a reasonable certainty that no harm will result to infants and children from the 

aggregate exposure of residues of nicosulfuron, including all anticipated dietary exposure 

and all other non-occupational exposures. Accordingly, there is no need to apply an 

additional safety factor for infants and children.

F. International Tolerances

There is neither a Codex proposal, nor a Canadian or Mexican tolerance for sorghum 

commodities.