Document ID: EPA-HQ-OPP-2022-0198-0001
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2022-05-20T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Heather McFarley, (703) 308-8119

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

ISK Biosciences Corporation

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from ISK Biosciences Corporation, 7470 Auburn Road, Suite A, Concord, Ohio, 44077, requesting, 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 by establishing a tolerance for residues of the herbicide Tolpyralate, 1-[[1-Ethyl-4-[3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoyl]-1H-pyrazol-5-yl]oxy]ethyl methyl carbonate (CAS), including its metabolite MT-2153, in or on the raw agricultural commodities wheat and barley 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; 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 metabolism. The metabolism of tolpyralate as well as the nature of the residues in corn (maize) is adequately understood for the purposes of this tolerance.  A metabolism study was conducted with maize.  The main metabolite of tolpyralate was MT-2153 comprising up to 8% in immature harvests and up to 4% in mature harvests and a number of minor metabolites and bound residues.  Hence, parent tolpyralate and the metabolite MT-2153 define the residue of concern.

      2. Analytical method. A practical analytical method for Tolpyralate and MT-2153 using Liquid Chromatography-MS/MS is available for analysis of all plant matrices.  This method has been confirmed through independent laboratory validation and is available for enforcement purposes.

      3. Magnitude of residues.
      Wheat: Twenty-two spring or winter wheat field trials were conducted in NAFTA Regions 2 (2 trials), 5 (5 trials), 6 (1 trial), 7 (5 trials), 8 (2 trials), 11 (2 trials), and 14 (5 trials) during the 2019-2020 growing seasons. One non-treated control and two treated plots were established at each test site.  The two treated plots received one foliar broadcast application of Tolpyralate 400 SC at a rate of 0.0357 lb ai/A +-5% (equivalent to 40 g ai/ha) at timings supporting a 21-day PHI for forage and hay and a 50-day PHI for grain and straw. Two exaggerated rate plots were also included for the collection of bulk grain samples for processing.  At the processing sites, the application was made at a 5x rate of 0.179 lb ai/A +- 5% (equivalent to 200 g ai/ha).  Spray volumes ranged from 3 to 22 gal/A (28 to 206 L/ha) across all sites.  A methylated seed oil (MSO) was added to the spray mixtures for all applications at ~1.0% v/v.

      The results from these trials show that after one foliar application of Tolpyralate 400 SC at a rate of 0.0357 lb ai/A +-5% (equivalent to 40 g ai/ha) made 7 +- 1 days before 6-8 inch to jointing stage, residues were as follows:
 maximum tolpyralate residue in forage collected 20-23 DAA was 0.0161 ppm (mean of per-trial averages = 0.0105, and maximum MT-2153 residue in forage was 0.0106 ppm (mean of per-trial averages =  <LOQ (0.0100 ppm).
 maximum tolpyralate residue in hay collected 20-23 DAA was 0.0445 ppm (mean of per-trial averages = 0.0133 ppm), and maximum MT-2153 residue in hay was 0.0374 ppm (mean of per-trial averages = 0.0126 ppm).    
      
      The results from these trials show that after one foliar application of Tolpyralate 400 SC at a rate of 0.0357 lb ai/A +-5% (equivalent to 40 g ai/ha) nominally made 50 days prior to normal crop maturity, residues were as follows:
 maximum tolpyralate residue in grain collected 47-58 DAA was <LOD (0.003 ppm) (mean of per-trial averages = <LOQ (0.0100 ppm)), and maximum MT-2153 residue in grain was <LOQ (0.0100 ppm) (mean of per-trial averages = <LOQ (0.0100 ppm)).
 maximum tolpyralate residue in straw collected 47-58 DAA was 0.0236 ppm (mean of per-trial averages = 0.0106 ppm), and maximum MT-2153 residue in straw was 0.0166 ppm (mean of per-trial averages = 0.0105 ppm). 
      
      The results from processing trials show that after one foliar application of Tolpyralate 400 SC at a 5x rate of 0.179 lb ai/A +- 5% (equivalent to 200 g ai/ha) made 50 days prior to normal crop maturity, maximum tolpyralate and MT-2153 residues in the grain were <LOD.

      Barley: Eighteen barley field trials were conducted in NAFTA Regions 5 (2 trials), 7 (3 trials), 7A (1 trial), 9 (1 trial), 11 (2 trials), and 14 (9 trials) during the 2020 growing season.  One non-treated control and two treated plots were established at each test site.  The two treated plots received one foliar broadcast application of Tolpyralate 400 SC at a rate of 0.0357 lb ai/A +-5% (equivalent to 40 g ai/ha) at timings supporting a 21-day PHI for hay and a 50-day PHI for grain and straw.  Two exaggerated rate treated plots were also included for the collection of bulk grain samples for processing.  At the processing sites, the application was made at a 5x rate of 0.179 lb ai/A +-5% (equivalent to 200 g ai/ha).  Spray volumes ranged from 2.8 to 20 gal/A (26 to 187 L/ha).  A methylated seed oil (MSO) was added to the spray mixtures for all applications at ~1.0% v/v.
      
      The results from these trials show that after one foliar broadcast application of Tolpyralate 400 SC at the maximum proposed label use rate of 0.0357 lb ai/A +-7% (equivalent to 40 g ai/ha) made 21 +- 2 days before harvest (DBH) of hay sampling at the milk to soft dough stage, residues were as follows:
 maximum tolpyralate residue in hay collected 19-23 DAA was 0.190 ppm (mean of per-trial averages = 0.0297 ppm), and maximum MT-2153 residue in hay was 0.166 ppm (mean of per-trial averages = 0.0286 ppm).  
      
      The results from these trials show that after one foliar broadcast application of Tolpyralate 400 SC at the maximum proposed label use rate of 0.0357 lb ai/A +-5% (equivalent to 40 g ai/ha) made 50 +- 6 days prior to normal crop maturity, residues were as follows:
 maximum tolpyralate residue in grain collected 47-56 DAA was <LOD (0.003 ppm) (mean of per-trial averages = 0.01 ppm), and maximum MT-2153 residue in grain was <LOQ (0.01 ppm) (mean of per-trial averages = 0.01 ppm).
 maximum tolpyralate residue in straw collected 47-56 DAA was 0.0691 ppm (mean of per-trial averages = 0.0147 ppm), and maximum MT-2153 residue in straw was  0.115 ppm (mean of per-trial averages = 0.0157 ppm). 
       
      The results from processing trials show that after one foliar application of Tolpyralate 400 SC at a 5x rate of 0.179 lb ai/A +- 5% (equivalent to 200 g ai/ha) made 50 days prior to normal crop maturity, maximum tolpyralate and MT-2153  residues in the grain were <LOQ.
      
      

B. Toxicological Profile

      1. Acute toxicity.  Results from a battery of acute toxicity studies place technical Tolpyralate in Toxicity Category III for oral LD50 and dermal LD50, and Category IV for inhalation LC50, dermal irritation, and eye irritation.  Technical Tolpyralate was not a dermal sensitizer. 
	
      
      In an acute neurotoxicity study, Tolpyralate was administered orally to groups of rats at oral doses up to 2000 mg/kg, with no evidence of neurotoxicity or neurohistopathological change.  Consequently, 2000 mg/kg was considered to be the NOEL.

      2. Genotoxicty. The genotoxic potential of Tolpyralate has been assessed as negative by several in vitro and in vivo mutagenicity studies. Tolpyralate did not elicit a genotoxic response in any of the studies conducted.

      3. Reproductive and developmental toxicity. Results from a two-generation study indicate that Tolpyralate is not a reproductive toxicant.  The NOEL for reproductive performance was >1000 ppm, the highest dose tested (equivalent to >54.9 and >81.8 mg/kg/day, respectively for P males and females and >63.3 and >90.2 mg/kg/day for F1 males and females). The no-observed-adverse-effect level (NOAEL) for systemic effects in parental rats is 5 ppm (0.270/0.410 mg/kg bw/day male/female).
      Results from developmental studies in rats and rabbits provided no indication of teratogenic effects for fetuses of either species and no evidence of developmental effects in the absence of maternal toxicity. For the rat teratology study, doses up to 500 mg/kg bwt/day were administered between Days 6 and 19 of gestation. The NOEL for maternal toxicity and developmental toxicity was 10 mg/kg bwt/day for maternal rats and their fetuses. Tolpyralate technical was not teratogenic to rats.  For the rabbit teratology study, doses up to 500 mg/kg bwt/day were administered between Days 6 and 27 of gestation. The NOEL for maternal toxicity and developmental toxicity was 5 mg/kg bwt/day and that of 500 mg/kg/day is the effect level for both of maternal rabbits and their fetuses. Tolpyralate technical was not teratogenic to rabbits.

      4. Subchronic toxicity. Subchronic (90-day) feeding studies were conducted in rats, mice and dogs. Doses evaluated in the rat (repeated dose, oral) study were 0, 5, 20, 2000 and 20000 ppm.  The NOAEL was 5 ppm in males (equivalent to 0.323 mg/kg bwt/day) and 20 ppm for females (equivalent to 1.58 mg/kg bwt/day).  Effects on the liver and eye were observed for both sexes.  Doses evaluated in mice (repeated dose, oral) study were 0, 50, 500, 2000 and 7000 ppm.  The NOAEL was 500 ppm in males (equivalent to 70.8 mg/kg/day) and 2000 ppm for females (equivalent to 331 mg/kg/day).  Centrilobular hepatocellular hypertrophy was a treatment-related change for the 2000 ppm group for males and 7000 ppm group for females.  Doses evaluated in the dog study were 0, 200, 2000 and 20000 ppm.  The NOAEL was 2000 ppm for males (64.61 mg/kg bw/day) and 2000 ppm for females (65.33 mg/kg bw/day).

      5. Chronic toxicity. An 18-month oncogenicity study was conducted in mice with dietary concentrations of 0, 70, 700 and 7000 ppm.  There was no evidence of carcinogenicity. 

      A 1-year chronic toxicity study was conducted in rats with dietary concentrations of 0, 5, 20, 2000, and 10000 (M) or 20000 (F) ppm technical Tolpyralate.  The systemic NOAEL was considered to be 20 ppm (males, 0.925 mg/kg bw/day; females, 1.18 mg/kg bw/day).

      A 2-year chronic toxicity/carcinogenicity study was conducted in rats with dietary concentrations of 0, 5, 20, 2000 and 10000 ppm technical Tolpyralate.  The no-observed-adverse-effect level (NOAEL) for toxicity was determined to be 20 ppm for males (0.765 mg/kg/day) and 20 ppm for females (1.01 mg/kg bw/day). There was no evidence of carcinogenicity.

      A 52-week chronic toxicity study was conducted in dogs with dietary concentrations of 0, 100, 1000 and 10,000 ppm.  The NOAEL was 1000 ppm (males, 28.13 mg/kg bw/day; females, 28.46 mg/kg bw/day).

      6. Animal metabolism. The metabolism of Tolpyralate in rats, goats and laying hens are adequately understood. Tolpyralate is rapidly excreted mainly via the feces. The majority of excreted material was unchanged Tolpyralate, with several minor metabolites present in feces, bile, urine and tissues.  There are no significant qualitative differences between rat and ruminant metabolic pathways.

      7. Metabolite toxicology. No toxicologically significant metabolites were detected in plant or animal metabolism studies. The residue of concern for tolerance setting purposes is the parent compound and the major plant metabolite, MT-2153. Consequently, there is no additional concern for toxicity of metabolites.

      8. Endocrine disruption. The submitted studies include evaluation of the potential effects on reproduction and development and an evaluation of the pathology of the endocrine organs following short or long-term exposure. The data demonstrate no treatment-related effects on the endocrine system.

C. Aggregate Exposure

      1. Dietary exposure. Exposure assessments were previously conducted by the EPA to evaluate the potential risk due to dietary exposure of the U.S. population to residues of Tolpyralate.

      For acute dietary exposure assessment, an endpoint was only identified for the Females 13-49 population subgroup. The FQPA Safety Factor was reduced to 1x for all population subgroups.
      
      For chronic dietary exposure, the chronic reference dose (cRfD) is 0.0093 mg/kg bwt/day, based on the NOAEL from the rat chronic oral toxicity study (0.925 mg/kg bwt/day) and dividing by an uncertainty factor of 100.  The chronic population adjusted dose (cPAD) is also 0.0093 mg/kg bwt/day since the FQPA safety factor is 1x for Tolpyralate.

      i. Food. Tier 1 chronic dietary exposure analyses were conducted for Tolpyralate in/on corn (field, sweet and popcorn), wheat, and barley to determine the exposure contribution of this commodity to the diet and to ascertain the chronic risk potential.  The exposure estimates were based on the proposed tolerance level residues, average processing factors and a market share of 100% crop treated as a conservative assumption. The consumption data were from the USDA's National Health and Nutrition Examination Survey/What We Eat in America NHANES/WWEIA dietary survey conducted in 2005-2010 (2 day food consumption data) using the Dietary Exposure Evaluation Module (DEEM-FCID) software, version 4.02/05-10-c.

      Using all of the worst case exposure scenarios listed above, the Tier 1 chronic dietary exposure estimates resulted in an estimated exposure for the general U.S. population of 0.000220 mg/kg bwt/day.  This exposure corresponds to 2.4% of the cPAD.  The highest exposure estimate calculated was for the subgroup All Infants.  This exposure was determined to be 0.000803 mg/kg bwt/day (8.6% of the cPAD).  The chronic dietary exposure analysis is summarized in the table below.
      
 Summary of Acute and Chronic Dietary Exposure Analyses for Tolpyralate.
     Population
   Subgroup* [Years of Age]
       Acute (95[th] Percentile)
                                          Chronic

                               Exposure Estimate
                                  (mg/kg/day)
                                  Risk Estimate
                                    (% aPAD)
                                Exposure Estimate
                                  (mg/kg/day)
                                  Risk Estimate
                                    (% cPAD)
 General US Population
                                             NA
                                    0.000220
                                       2.4
 All infants [<1]

                                    0.000803
                                       8.6
 Children [1-2]

                                    0.000314
                                       3.4
 Children [3-5]

                                    0.000263
                                       2.8
 Children [6-12]

                                    0.000195
                                       2.1
 Youth [13-19]

                                    0.000161
                                       1.7
 Adults [20-49]

                                    0.000216
                                       2.3
 Adults [50+]

                                    0.000207
                                       2.2
 Females [13-49]
     0.000617
                                      1.23
                                    0.000212
                                       2.3
      
      It can be concluded that long-term dietary exposure to Tolpyralate through residues on all commodities should not be of cause for concern.

      ii. Drinking water. The EPA calculated drinking water residues previously to support the initial registration of Tolpyralate on corn. The groundwater value was generated using the Pesticide Root Zone Model for Groundwater (PRZM-GW) Model, and the surface water values were generated using the Pesticide Root Zone Model (PRZM5) and the Variable Volume Water Model (VVWM). The groundwater estimates were used for both the acute and chronic assessments, because these estimates were higher than the respective surface water values. Both acute and chronic estimates included parent and the MT-2153 metabolite. For the acute assessment, a value of 11.53 ppb was used, and for the chronic assessment, a value of 10.18 ppb was used.

      2. Non-dietary exposure. Based on the proposed uses for Tolpyralate on the crops noted above, non-occupational exposure of Tolpyralate would not be expected to the general population.  The only anticipated exposure route for the US population is via the diet (food and water only). Therefore, residential risk assessments for the incidental oral, dermal, and inhalation exposure routes are not required. 

      Occupational post-application exposure is possible.  For dermal short-term exposure, no toxicity was found at 1000 mg/kg in a 28-day rat dermal toxicity study.  Therefore, in the absence of any hazard identified for dermal exposure, a dermal post-application risk assessment was not conducted.  Potential inhalation exposure was not considered since it is negligible when assessing re-entry risks.  

      Occupational exposure for mixing/loading and applying Tolpyralate was considered.  Potential exposure was considered negligible since MOEs were greater than 1,000 for all calculations.

D. Cumulative Effects

      EPA has not made a common mechanism of toxicity finding as to Tolpyralate and any other substances, and Tolpyralate does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that Tolpyralate has a common mechanism of toxicity with other substances.

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 Tolpyralate.

      2. Infants and children. 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 to infants and children from the aggregate exposure of residues of Tolpyralate.

F. International Tolerances

      Presently, there are no Codex maximum residue levels (MRLs) established for residues of Tolpyralate on any crop.