Pesticide Petition for Tolerances for Nicosulfuron AGRICULTURAL COMMODITIES Sorghum Grain, Forage and Stover

Page 1 of 5 EPA REGI STRATION DIVISION COMPANY NOTICE OF FILING FOR PESTI CIDE PETI TI ONS PUBLISHED IN THE FEDERAL REGI STER 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. d uPont 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 - py ridinecarboxamide, 2 - ((((4,6 - dimethoxy py rimidin - 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 adequatel y understood; therefore no additional metabolism data nicosulfuron required to support the proposed tolerances on sorghum grain, forage and stover 2. Analy tical 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 distribut ed across the U.S. The nature of nicosulfuron residue in sorghum is adequatel y understood through the corn and canola metabolism studies. These residue data were the basis for establishing tolerances for Sorghum, grain, forage and stover B. Toxicolog ical Profile 1. Acute toxicity . Technical nicosulfuron has been placed in acute toxicology category I II based on overall results from several studies. This compound was placed in toxicology category I II for acute dermal toxicity (LD 50 > 2,000 mg/kg; rabbits) and eye irritation (effects reversible within 72 hours; rabbits). Acute oral toxicity (LD 50 > 5,000 mg/kg; rats), acute inhalation toxicity (LC 50 > 5.4 mg/L, rats) and skin irritation (no observedPesticide Petition for Tolerances for Nicosulfuron AGRICULTURAL COMMODITIES Sorghum Grain, Forage and Stover

Page 2 of 5 irritation; rabbits) results were as signed 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 Sy nthesis In Primary

Rat Hepatocy

tes , In Vitro Cho Mammalian Cells Gene Mutation Assay , Mammalian Cells In Culture C yt ogenic Assay In Human Ly

mphocy tes , In Vivo Micronucleus Assay

– Mouse 3. Reproductive and developmental toxicity . i. Rat developmental study . A developmental study

w as 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 developmen tal toxicity

u p to and including the highest dose tested of 5581 mg/kg (the limit of the suspension capability ). The LOAEL for maternal and developmental toxicity c ould not be determined and the NOAEL is at least 5581 mg/kg/day for both maternal and developmental toxicity . ii. Rabbit developmental study . I n developmental study

w as 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 i s 465 mg/kg/day

a nd 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 i s 93 mg/kg/day . There were no external on visceral anomalies in the fetuses. Fetal toxicity was manifested by reduced mean fetal body w eight at 930 mg/kg/day and above. Therefore, the LOAEL for fetal toxicity i s 930 mg/kg/day

and the NOAEL is 465 mg/kg/day . iii. Two - generation rat reproduction study . A two generation reproduction study was cond ucted 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 sy stemic 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 statisticall y 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 mortal ity

werePesticide Petition for Tolerances for Nicosulfuron AGRICULTURAL COMMODITIES Sorghum Grain, Forage and Stover

Page 3 of 5 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 pp m (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, particularl y 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 500 0 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) d emonstrated that no carcinogenic effects up to the highest dose tested. The sy stemic 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 - ye ar combined rat chronic toxicity /oncogenicity

study . In a two - ye ar 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 N OAEL 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 moderatel y absorbed and is rapidly e liminated via urinary

and fecal excretion. F ollowing 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

e xcretion ranged from 89

– 95% and 5

– 11%, respectivel y. Elimination of 14 C - CO 2 was negligible. The average cumulative excretion half - lives were between 12 and 24 hours. Following intravenous administration, approximately 7 6 to 80% of the dose was eliminated in the urine and 27 to 30% in the fece s. 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, py ridine sulfonamide (N, N dimethyl - 2 - sulfonamide py ridine - 3 - carboxamide or IN - V9367) was detected in the urinePesticide Petition for Tolerances for Nicosulfuron AGRICULTURAL COMMODITIES Sorghum Grain, Forage and Stover

Page 4 of 5 and accounted for 1.1 to 5.7% of the dose. Py ridine acid sulfonamide (2 - sulfonamidepy

ridine - 3 - carbox yl ic acid, or IN - 64859) was tentativel y identified as a minor metabolite in the feces of orall y dosed rats and urine of intravenously d osed rats. These metabolites represent hydrol ytic cleavage/oxidation of the parent molecule. 7. Metabolite toxicology . Common metabolic pathway s for nicosulfuron were demonstrated in the rat, goat and in corn. The major nicosulfuron metabolites in corn and the g oat 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 unlikel y. The EPA has previously

determined that the residue to be regulated is nicosulfuron onl y. 8. Endoc rine 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 onl y chronic exposure and not acute. Chronic dietary

exposure assessment. Chronic dietary exposure resulting from the currentl y 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 - FCID TM , 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 b y respondents in the Nutritional Health and Nutrition Examination Survey (NHANES) 2003 - 4, 2005 - 6, 2007 - 8 What We Eat in America (WWEIA). The anal ys is used tolerance values in place of residue values for relevant crops and meat and mi lk 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 nicosu lfuron. 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 estimatedPesticide Petition for Tolerances for Nicosulfuron AGRICULTURAL COMMODITIES Sorghum Grain, Forage and Stover

Page 5 of 5 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 expos ure 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, clearl y 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 chem icals. Other structurally

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

of sulfonylureas is due to the inhibition of acetolactate sy nthase (AL S), an enz ym e found only in plants. This enzyme is part of the bios y nthesis pathway leading to the formation of branched chain amino acids. Animals lack ALS and this biosy nthetic pathway . This lack of ALS contributes to the relativel y 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 co nservative 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, the re 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. Accordingl y, there is no need to app ly 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.