Document ID: EPA-HQ-OPP-2013-0034-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-07-19T04:00Z

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 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 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 [14]C-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, N-dimethyl-2-sulfonamide pyridine-3-carboxamide or IN-V9367) was detected in the urine 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-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 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 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.