


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

EPA Registration Division contact: Reuben Baris, (703) 7356


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 ([8F8676]) from ISK Biosciences Corporation, 7470 Auburn Road, Suite A, Concord, Ohio, 44077, 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 by establishing a tolerance for combined residues of the herbicide Tiafenacil, methyl N-[2-[[2-chloro-5-[3,6-dihydro-
3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl]thio]-1-oxopropyl]-β-alaninate (CAS), including its metabolite 3-(2-((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)phenyl)thio) propanamido)propanoic acid, calculated as the stoichiometric equivalent of Saflufenacil, in or on the raw agricultural commodities corn which includes, field corn and popcorn, at 0.01 parts per million (ppm), soybean seed at 0.01 parts per million (ppm), wheat grain at 0.01 parts per million (ppm), grape at 0.01 parts per million (ppm), grape, raisin at 0.01 parts per million (ppm), cottonseed subgroup 20C, undelinted seed at 0.5 parts per million (ppm) cottonseed subgroup 20C, gin byproducts at 3.0 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

 Plant metabolism. The metabolism of Tiafenacil as well as the nature of the residues in plants is adequately understood for the purposes of this tolerance.  Metabolism studies were conducted in a diverse set of crops including corn, cotton, soybeans, potato, and mandarin trees. Residues of parent were predominant in studies following desiccation treatments.  There were no residues of parent tiafenacil in studies following pre-plant treatments. The residues of concern for the tolerance expression consist of Tiafenacil and M-01. 

 Analytical method. A practical analytical method for Tiafenacil and M-01 using Liquid Chromatography-MS/MS is available tolerance enforcement purpose.  This method has been confirmed through independent laboratory validation.

 Magnitude of residues. Field trials were conducted to determine the magnitude
      of the residue following a following one pre-plant or pre-emergence application of Tiafenacil on corn, wheat, and soybean and following a single directed application on grapes.  Field trials were also conducted on cotton to determine the magnitude of residue following a single pre-plant application followed by a second application occurring at 10 days prior to normal maturity as a dessicant for harvest aid. The number and locations of the field trials were in accordance with EPA guidelines for conducted crop residue trials. The trials support the proposed label rates, number of applications and pre-harvest intervals (PHI) for all crops. The combined residues detected support the proposed tolerances.
      
B. Toxicological Profile

   1. 	Acute toxicity.  Results from a battery of acute toxicity studies place technical Tiafenacil in Toxicity Category III for oral LD50, dermal LD50, and eye irritation and Category IV for inhalation LC50.  Technical Tiafenacil was not a dermal sensitizer. 
   	
      In an acute neurotoxicity study, Tiafenacil 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.  Genotoxicity. The genotoxic potential of Tiafenacil has been assessed as negative by several in vitro and in vivo mutagenicity studies. Tiafenacil did not elicit a genotoxic response in any of the studies conducted. 
         
   3.  Reproductive and developmental toxicity. Tiafenacil was assessed for effects on reproduction in a rat two-generation reproduction toxicity study.  Its ability to affect embryo-fetal development was assessed in rat and rabbit developmental toxicity studies. Tiafenacil had no effects on reproductive toxicity up to 150 ppm (8.01 and 12.7 mg/kg bw/day in males and females), the highest dose tested.  The findings observed in the rat two-generation study were related to the specific toxicity of the substance to disrupt hepatic heme synthesis, such as the increased liver porphyrin levels which were observed in parent and offspring treated with 150 ppm Tiafenacil. Developmental toxicity studies in the rat and rabbit showed no evidence of a selective effect on fetal development in the absence of maternal toxicity.  In rats, a slight increase in the incidence of rib abnormalities (kinked, minimally kinked and costal cartilage(s) not attached to sternum) and lower group mean fetal weights were observed at 50 mg/kg/day.  The rib abnormality incidences were within the current historical data incidence at the testing facility concerned.  These fetal findings were identified in the higher dose group where maternal toxic effects such as lower maternal body weight and decrease of the mean red blood cell volume are apparent.  This maternal toxicity, specific to Tiafenacil, was observed in the 90-day rat study at 330 ppm (28 mg/kg/day, F).  In that study, histological changes were suggestive of anemia.  Therefore, the rib abnormalities and lower fetal weights seen in rat fetuses at 50 mg/kg/day may be secondary to maternal toxicity.  In the rabbit, doses of 30 mg/kg bw/day had no effect on rabbit does.  At 100 mg/kg bw/day, decreased red cell parameters, reticulocyte increase and increase in green discoloration of the amniotic sac were noted. At doses up to 300 mg/kg bw/day, pregnancy performance and fetal weights in the rabbits were similar between all groups and the type and distribution of fetal abnormalities and skeletal ossification parameters did not indicate an association with treatment. The critical NOAEL is 50 ppm (2.60/4.26 mg/kg bw/day in males and females) set for parental general toxicity in the two-generation reproductive toxicity study based on increased total porphyrin content in liver and decreased body weight gain of parental females. The NOAEL of 50 ppm (2.97 and 4.41 mg/kg bw/day in males and females) for the offspring was also due to an increase of total porphyrin content in the liver. There was no effect of treatment on reproductive performance in rats given doses up to 150 ppm (8.99/13.2 mg/kg bw/day (males/females)).
 Subchronic toxicity. The short-term toxicity of Tiafenacil has been evaluated in rats, mice and dogs in studies up to 90 days in duration in rodents and 1 year in dogs. The rat, mouse and dog are similarly sensitive. The primary target organ is the hematopoietic system. In the submitted studies, the target organs were the liver, bone marrow and spleen.  The effect is due to the known mechanism of action of the substance which is a protoporphyrinogen oxidase inhibiting herbicide. This type of herbicide generally induces microcytic hypochromic anemia in experimental animals resulting from hepatic heme synthesis disruption, and increased liver porphyrins are defined as a toxicological endpoint. The lowest short term toxicity NOAEL was 110 ppm (corresponding to an achieved average daily dose of 9 mg/kg bw/day in males and 10 mg/kg/day in females) from the rat 90-day dietary toxicity study. This NOAEL was based on lower body weight gains, decreased red cell mass parameters and increased reticulocyte count, increased cellularity of the erythroid lineage in the sternum and femur (males only), increased hematopoiesis in the spleen (males only) and histopathological changes in the liver.  The findings in the liver and spleen suggest extramedullary hematopoiesis, an adaptive response to the reduced circulating red cells. Similar to the rat, the dog oral 90-day NOAEL was set at 10 mg/kg bw/day based on related findings. The effects on erythrocytes and the associated adaptive response from the bone marrow, spleen and liver were observed at the next higher dose levels of 50 mg/kg bw/day in the dog study and 330 ppm in the rat study (25/28 mg/kg bw/day males/females).   These effects were also observed in the 1-year dog oral toxicity study at the highest dose tested, 120 mg/kg bw/day.  A higher NOAEL of 20 mg/kg bw/day was set for this study due to a different choice of doses.  In a mouse 90-day dietary study, the NOAEL of 75 ppm (12.9 mg/kg/day) in males and 250 ppm (46.5 mg/kg bw/day) in females was based on minimal microscopic changes in the liver (centrilobular hypertrophy  -  an adaptive response) with no effects on hematology parameters. However, in a previous mouse 90-day dietary study where only a NOAEL for the females (75 ppm; 13 mg/kg bw/day) could be established, increased incidence of hepatocyte necrosis (minimal to mild adaptive response to fatty change) was accompanied by a decrease in red cell mass parameters and increase reticulocyte count, however there were no findings in the liver and spleen suggesting extramedullary hematopoiesis.  The exposure of Tiafenacil to rats via the dermal route for 28 days did not result in any toxicologically significant findings. The NOAEL was 1000 mg/kg bw/day, the highest dose tested.
      Therefore the short term critical NOAEL was selected as 110 ppm corresponding to an achieved average daily dose of 9 mg/kg bw/day in males and 10 mg/kg/day in females set in the rat 90-day dietary toxicity study.
   5.  Chronic toxicity. Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumors at the tested doses.  The long-term toxicity and carcinogenic potential of Tiafenacil was evaluated in dietary feeding studies with rats (1 and 2 years) and mice (78 weeks).  The effects observed from short-term exposure occurred at approximately the same dose level from long-term exposures, without increasing in severity. A chronic NOAEL of 50 ppm was set in a 104-week (two-year) study in female rats corresponding to an achieved average daily dose of 4 mg/kg bw/day based on lower body weight gains and changes in red blood cell parameters observed at 250 ppm (20 mg/kg/day).  A higher NOAEL (150 ppm; 8 mg/kg bw/day) was set for males in the same study based on lower body weight gains, changes in red blood cell parameters and increased spleen weight at the next higher dose level (500 ppm) corresponding to an achieved average daily dose of 32 mg/kg bw/day. Increased hematopoiesis of the spleen and in bone, increased spleen weight and retinal atrophy were also findings in females at the top dose level (1000 ppm; 80 mg/kg bw/day achieved average daily dose). In the 52-week study, at 250 ppm and above, the target organ was the spleen.  Similarly to the 2-year study, the NOAELs set for females and males were 50 and 150 ppm, respectively, corresponding to achieved average daily doses of 4 and 8 mg/kg bw/day, respectively, based on lower body weight gains, increased spleen weight, changes in red blood cell parameters and white blood cell counts observed at the next higher doses 250/500 ppm (20/32 mg/kg bw/day (female/male) achieved average daily doses) and above. 
   
      The long term critical NOAEL was 10 ppm set in the mouse 78-week carcinogenicity study, corresponding to an achieved average daily dose of 1.11 mg/kg in males and 1.30 mg/kg/day in females, based on the centrilobular vacuolation in males and females and single cell necrosis and foci of clear cell cellular alteration in males observed at the next higher dose level (75 ppm) corresponding to an achieved average daily dose of 8.0/9.7 mg/kg bw/day (male/female). 

   6.  Animal metabolism. The metabolism of Tiafenacil in rats, goats and laying hens are adequately understood. In rats, Tiafenacil is rapidly excreted mainly via the feces. In goats, Tiafenacil is excreted mainly via the feces and urine. In chickens, Tiafenacil is excreted mainly via excreta. There are some common pathways among species and some differences.
         
   7. 	Metabolite toxicology. No toxicologically significant metabolites were detected in plant or animal metabolism studies. 

   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.
       
   9. 	Immunotoxicity. There was no evidence of an immunotoxic effect after oral (dietary) administration of Tiafenacil at dose levels up to 2000 ppm. 
   
   C. Aggregate Exposure
      
   1. Dietary exposure. Exposure assessments were conducted to evaluate the potential risk due to dietary exposure of the U.S. population to residues of Tiafenacil.

      For acute dietary exposure, an Acute Reference Dose (aRfD) is not identified for Tiafenacil since there was no evidence of initial acute effects in the acute oral or short-term toxicity studies, or the developmental toxicity studies in rats and rabbits.  There were no effects seen in the acute neurotoxicity study at the limit dose level of 2000 mg/kg/day.  No initial acute effects were seen in the 90-day neurotoxicity study.
      For chronic dietary exposure, the chronic reference dose (cRfD) is 0.011 mg/kg bwt/day, based on the NOAEL for males from the mouse carcinogenicity study (1.11 mg/kg bwt/day) and dividing by an uncertainty factor of 100.  The chronic population adjusted dose (cPAD) is also 0.011 mg/kg bwt/day since the FQPA safety factor is anticipated to be 1 for Tiafenacil.

      i. Food. Tier I dietary (food + drinking water) exposure and risk assessments were conducted for tiafenacil using Dietary Exposure Evaluation Model - FCID (DEEM-FCID or DEEM), version 4.02, 05-10-c that incorporates data from USDA NHANES 2-day food consumption data for 2005-2010 (USEPA, 2014).

      For chronic risk assessment, the toxicity effects endpoint of 0.011 mg/kg was used based on liver effects observed in male mice from a carcinogenicity study; no developmental or reproductive effects were observed; therefore, sensitive subpopulations are protected with this most sensitive point of departure. If calculated tolerances of are considered, the most highly exposed population was non-nursing infants with a risk estimate of 3.5% of the chronic PAD (cPAD) (crop+water). A critical commodity analysis of risk cup contributions greater than 5% indicate that corn syrup in baby food and water are the 9% and 72% of the cPAD, respectively. 
      
      A cancer dietary (food + drinking water) exposure and risk assessment was not performed because tiafenacil is not carcinogenic. The chronic dietary exposure assessments assumed 100% crop treated for registered and proposed uses, meaning that the product is used on 100% of a given labeled crop in any given watershed. This is a standard Tier I assumption and represents an unrefined dietary risk assessment. The chronic dietary exposure analysis is summarized in the table below.
      
                                  Population
                               Exposure Estimate
                                   % of cPAD
                                   Subgroup
                              (mg/kg body wt/day)
                                       
                                U.S. Population
                                   0.000100
                                      0.9
                              Non-Nursing Infants
                                   0.000384
                                      3.5
                           Children (1-2 years old)
                                   0.000204
                                      1.9
                           Children (3-5 years old)
                                   0.000169
                                      1.5
                           Children (6-12 years old)
                                   0.000116
                                      1.1
                            Youth (13-19 years old)
                                   0.000083
                                      0.8
                           Females (13-49 years old)
                                   0.000091
                                      0.8
                           Adults (20-49 years old)
                                   0.000092
                                      0.8
                            Adults (50+ years old)
                                   0.000084
                                      0.8

      It can be concluded that long-term dietary exposure to Tiafenacil through residues on all commodities should not be of cause for concern.

      ii. Drinking water. Exposure estimates from drinking water sources was included in the dietary chronic exposure risk assessments. The chronic (annual average) TTR concentrations (surface water sources) for tiafenacil were used to represent the maximum, most conservative exposure scenario from a drinking water perspective ("water, direct, all sources" and "water, indirect, all sources"). The chronic water concentration was 3.02 ppb (TTR environmental fate surface water). This concentration is based on an extremely conservative representation of anticipated exposure and overestimates parent tiafenacil and metabolite M-01 by including additional metabolites.  The groundwater prediction for parent and M-01 is significantly less than the surface water value.

   2. Non-dietary exposure. Based on the proposed uses for Tiafenacil on the crops noted above, non-occupational exposure of Tiafenacil 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 Tiafenacil was considered.  Potential exposure was considered negligible since MOEs were considerably greater than 100 for all calculations.

D. Cumulative Effects  

EPA has not made a common mechanism of toxicity finding as to Tiafenacil and any other substances, and Tiafenacil 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 Tiafenacil 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 Tiafenacil.

   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 Tiafenacil.

F. International Tolerances

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


