Document ID: EPA-HQ-OPP-2013-0035-0002
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

2F8131

EPA has received a pesticide petition (2F8131) 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, 21 U.S.C. 346a (d), to amend 40 CFR Part 180.478 by establishing a tolerance for residues of the herbicide rimsulfuron: N-((4,6-dimethoxypyrimidin-2-yl) aminocarbonyl)-3-(ethylsulfonyl)-2-pyridinesulfonamide in or on the raw agricultural commodities sorghum grain, forage and stover at 0.01 ppm.

This summary was prepared by the petitioner. 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 the petition. Additional data may be needed before EPA rules in the petition.

A. Residue Chemistry                                        

1. Plant metabolism.    

The qualitative nature of the residues of rimsulfuron in plants is adequately understood; therefore no additional metabolism data are 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 Grain, Forage and Stover:

The results from 13 trials show that all samples of sorghum grain, forage and stover were <0.01 ppm for rimsulfuron after a single application of 0.5 oz rimsulfuron a.i./A. 

B. Toxicological Profile 

1. Acute toxicity. 

Technical rimsulfuron is considered acute toxicology category III based on overall results from several studies. This compound is considered acute toxicology category III for acute dermal toxicity and eye irritation and acute toxicity category IV for acute oral and inhalation toxicity and skin irritation. Technical rimsulfuron is not a dermal sensitizer.

2. Genotoxicty. 

Technical rimsulfuron was negative for genotoxicity in batteries of in vitro and in vivo tests. These tests included the following: mutagenicity in bacterial (Ames test) and mammalian (CHO/HGPRT assay) cells; in vitro cytogenetics (chromosomal aberration in human lymphocytes); in vivo cytogenetics (bone marrow micronucleus assay in mice); and unscheduled DNA synthesis in rat primary hepatocytes.

3. Reproductive and developmental toxicity. 

A two-generation reproduction study was conducted in rats with dietary technical rimsulfuron concentrations of 0, 50, 3,000 or 15,000 ppm. The study was negative for reproductive toxicity and there was no indication that offspring were more susceptible to rimsulfuron administration than parents. The NOEL was 3,000 ppm (or 165 to 264 mg/kg/day for P1 and F1 males and females and their offspring). This was based on the following effects at 15,000 ppm (830 to 1,316 mg/kg/day): lower food consumption and/or food efficiency in P1 males and females and F1 females; decreased mean body weights and/or body weight gain by P1 and F1 males and females; lower mean body weights and increased incidence of small body size for F2 pups during lactation.

A developmental study was conducted in rats administered technical rimsulfuron by gavage at 0, 200, 700, 2,000 or 6,000 mg/kg/day. There were no systemic or developmental effects observed up to and including the highest dose tested. The NOEL was therefore > 6,000 mg/kg/day.
    
A developmental study was conducted in rabbits administered technical rimsulfuron by gavage at 0, 25, 170, 500 or 1,500 mg/kg/day. The NOELs for maternal and offspring toxicity were 170 and 500 mg/kg/day, respectively. The maternal NOEL was based on reduced body weight and mortality at higher doses. These maternal effects precluded any evaluation of adverse effects in fetuses at 1,500 mg/kg/day; however, there were no systemic or developmental effects observed among fetuses at 500 mg/kg/day and below.

4. Subchronic toxicity. 

A 90-day study in mice was conducted at dietary concentrations of 0, 50, 375, 1,500 or 7,500 ppm. The NOELs were 375 ppm (56.0 mg/kg/day) for male mice and 7,500 ppm (1,575 mg/kg/day) for female mice. The NOEL for males was based on slight reductions in mean body weight gain and food efficiency at 1,500 ppm (228 mg/kg/day).
    

Technical rimsulfuron was administered in the diets of rats at 0, 50, 1,500, 7,500 or 20,000 ppm for 90 days. The NOEL was 1,500 ppm (102 and 120 mg/kg/day for males and females, respectively) based on reduced mean body weights and body weight gains and increased relative liver weights at 7,500 ppm (495 and 615 mg/kg/day for males and females, respectively).
    
Dogs were administered technical rimsulfuron in their diets at 0, 250, 5,000 or 20,000 ppm for 90 days. The NOEL was 250 ppm (9.63 and 10.6 mg/kg/day for males and females, respectively). This was based on slight increases in liver and/or kidney weights, increased urine volume and decreased urine osmolarity at 5,000 ppm (193 and 189 mg/kg/day for males and females, respectively).

5. Chronic toxicity. 

An 18-month mouse study was conducted with dietary concentrations of 0, 25, 250, 2,500 or 7,500 ppm technical rimsulfuron. This product was not oncogenic in mice. The systemic NOEL was 2,500 ppm (351 and 488 mg/kg/day for males and females, respectively) based on decreased mean body weights in both sexes and increased incidence of spontaneous, age-related artery and tunica degeneration in the testes for this mouse strain at the highest dose tested, 7,500 ppm (1,127 and 1,505 mg/kg/day for males and females, respectively). The latter was observed in the absence of any effect on spermatogenesis. An increased incidence of dilation and cysts in the glandular stomach of males was also observed at 7,500 ppm.
    
A 2-year chronic toxicity/oncogenicity study was conducted in rats fed diets that contained 0, 25, 300, 3,000 or 10,000 ppm technical rimsulfuron. This product was not oncogenic in rats. The systemic NOELs were 300 ppm (11.8 mg/kg/day) for males and 3,000 ppm (163 mg/kg/day) for females. The NOELs were defined by decreased body weight gain and increased relative liver weights at 3,000 ppm (121 mg/kg/day) and 10,000 ppm (569 mg/kg/day) for males and females, respectively.
    
Technical rimsulfuron was administered for one year to dogs at dietary concentrations of 0, 50, 2,500 or 10,000 ppm. The NOELs were 50 ppm (1.6 mg/kg/day) for males and 2,500 ppm (86.5 mg/kg/day) for females. The NOEL for males was based on the following effects, which the Agency has previously determined were of questionable biological significance, observed at 2,500 ppm (81.8 mg/kg/day): increased absolute liver and kidney weights; and increased incidence of seminiferous tubule degeneration and increased numbers of spermatid giant cells present in the epididymides. The NOEL for females was based on the following effects observed at 10,000 ppm (358.5 mg/kg/day): decreased body weight and body weight gain; increased serum cholesterol levels and alkaline phosphatase activity, increased absolute liver weight and increased relative liver and kidney weights. 

6. Animal metabolism. 

The metabolism of rimsulfuron in animals (rat, goat and hen) is adequately understood and is similar among the species evaluated. Rimsulfuron was rapidly eliminated via urinary and fecal excretion in the rat. Approximately 60 to 70% of the administered dose to rats was excreted within 24 hours. There were no volatile metabolites detected and unmetabolised rimsulfuron was the major component in the urine (42 - 55%) and feces (5 - 16%). The major metabolic pathway in rats involved a contraction of the sulfonylurea bridge followed by dealkylation, hydroxylation and/or conjugation reactions. Cleavage of the sulfonylurea bridge was observed; however, it was considered to be a minor pathway. Elimination of administered rimsulfuron was similarly rapid for the goat and hen. Tissue residue levels were generally less than 0.3% of the administered dose for the rat, goat and hen. There was no evidence of accumulation of rimsulfuron or its metabolites in tissues of any of the species or in milk and eggs.

7. Metabolite toxicology. 

There is no evidence that the metabolites of rimsulfuron, as identified in either the plant or animal metabolism studies, are of any toxicological significance.

8. Endocrine disruption. 

No special studies investigating potential estrogenic or other endocrine effects of rimsulfuron 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 rimsulfuron has an adverse effect on the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. 

The residue of concern, as listed at 40 CFR 180.478, is parent rimsulfuron only.

No acute dietary risk assessment was needed since there is no acute tox endpoint.

The chronic reference dose (cRfD) of 0.818 mg/kg/day is based on the NOEL of 81.8 mg/kg/day from a one-year beagle dog tox study and a 100X safety factor.  

a. Food. 
   
i. Acute

For the general U.S. population, acute dietary exposure assessments were not considered relevant for rimsulfuron for the following reasons: rimsulfuron presents very low acute toxicity based on animal testing; and no detectable residues have been demonstrated in edible portions of treated crops.

ii. Chronic

There is no population in the chronic risk assessment for rimsulfuron, either dietary (food only) or aggregate (food and water), with an exposure greater than 0.1% of the chronic reference dose.

b. Drinking water.

Chronic drinking water exposure analyses were calculated for rimsulfuron using EPA screening concentration models for ground water SCI-GROW and surface water FIRST.  Results indicate that a reasonable certainty exists that rimsulfuron residues in drinking water will not contribute significantly to the aggregate human risk.

The predicted chronic concentration for rimsulfuron maximum surface water value was 0.74 ppb, and a maximum ground water value was 0.0522 ppb.  When the surface water concentration was included in the chronic dietary risk assessment, no population including the general U.S. population and all subpopulations had an exposure greater  0.1% of the chronic reference dose (cRfD), indicating a significant margin of safety.   

No acute dietary endpoint was identified. Therefore, an acute drinking water risk assessment is not considered necessary. One can conclude with reasonable certainty that residues of Rimsulfuron in drinking water do not contribute significantly to the aggregate acute human health risk.

2. Non-dietary exposure. 

Rimsulfuron is not registered for any uses that could result in non-occupational, non-dietary exposure to the general population.

D. Cumulative Effects

Rimsulfuron 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 rimsulfuron 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 toxicology database and using the conservative assumptions presented earlier, EPA has established a chronic RfD of 0.818 mg/kg/day. This RfD is based on the systemic NOEL of 81.8 mg/kg/day for males in a 1-year toxicity study in beagle dogs. It has been concluded that the aggregate exposure for existing crops plus the tolerances being proposed would utilize less than 0.1% of the RfD. Generally, exposures below 100% of the RfD are of no concern because it represents the level at or below which daily aggregate dietary exposure over a lifetime will not pose appreciable risk to human health. Thus, there is reasonable certainty that no harm will result from aggregate exposures to rimsulfuron residues. 

2. Infants and children. 

In assessing the potential for additional sensitivity of infants and children to residues of rimsulfuron, data from the previously discussed developmental and multigeneration reproductive toxicity studies were considered.

Developmental studies are designed to evaluate adverse effects on the developing organism resulting from pesticide exposure during pre-natal development. Reproduction studies provide information relating to reproductive and other effects on adults and offspring from pre-natal and post-natal exposures to the pesticide. The studies with rimsulfuron demonstrated no evidence of developmental toxicity at exposures below those causing maternal toxicity. This indicates that developing animals are not more sensitive to the effects of rimsulfuron administration than adults.
    
FFDCA section 408 provides that EPA may apply an additional uncertainty factor for infants and children in the case of threshold effects to account for pre- and post-natal toxicity and the completeness of the database. Based on current toxicological data requirements, the database for rimsulfuron relative to pre- and post-natal effects for children is complete. In addition, the NOEL upon which the RfD is based is much lower than the NOELs defined in the reproduction and developmental toxicology studies. 

Conservative assumptions utilized to estimate aggregate dietary exposures of infants and children to rimsulfuron demonstrated that less than 0.1% of the RfD would be utilized for the highest exposed group, Children 1-2 years old. 

Based on these conservative analyses, there is reasonable certainty that no harm will result to infants and children from aggregate exposures to rimsulfuron.

F. International Tolerances

A number of international tolerances (or Maximum Residue Levels, MRL's) have been established for rimsulfuron including the following:

                                   Countries
                                     Crop
                                 Tolerance/MRL
Austria, Italy
                                     Corn
                                    0.1 ppm
Austria, Italy, Canada
                                   Potatoes
                                    0.1 ppm
Belgium, Denmark, Germany, Spain
                                   Potatoes
                                   0.05 ppm
Germany, Spain, Portugal, Canada
                                   Tomatoes
                                   0.05 ppm