Document ID: EPA-HQ-OPP-2023-0269-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2023-09-19T04:00Z

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

EPA Registration Division contact: [insert name and telephone number with area code]

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

(Options (pick one)
   
   1. by establishing a tolerance for residues of the herbicide Flazasulfuron, 1-(4,6-dimethoxypyrimidin-2-yl)-3-(3-trifluoromethyl-2-pyridylsulfonyl) urea in or on the raw agricultural commodity avocado 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 flazasulfuron as well as the nature of the residues in plants is adequately understood for the purposes of these tolerances.  Metabolism studies were conducted with three crops, grapes, sugarcane and tomatoes.  Directed application to the soil results in rapid degradation of flazasulfuron.  Uptake into plants is minimal.  Plants show the same metabolic pathways as those found in soil and animals.  Flazasulfuron is metabolized either by cleavage of the urea linkage to form 3-trifluoromethyl-2-pyridine sulfonamide (TPSA) and 2-amino-4,6-dimethoxypyridine (ADMP) or by rearrangement of the sulfonyl urea bridge to form (1-(4,6-dimethoxypyridin-2-yl)-1-(3-trifluoromethyl-2 pyridyl)urea (DTPU) followed by cleavage of the amide to form 4,6-dimethoxy-2-(3-trifluoromethyl-2 pyridylamino)pyridine (DTPP) then oxidative demethylation to form 4-hydroxy-6-methoxy-2-(3-trifluoromethyl-2-pyridylamino)pyridine (HTPP).  The terminal metabolites TPSA, ADMP and HTPP form conjugates and ultimately bound residues.  The only unconjugated metabolite found in the studies at levels above 10% of the TTR was DTPU in grapes.

      2. Analytical method. A practical analytical method for flazasulfuron and DTPU using Liquid Chromatography-MS/MS is available for enforcement purposes.  The limit of detection is 0.003 ppm.
      
      3. Magnitude of residues. Field trials were conducted to determine the magnitude of the residue on avocado. The study included five supervised residue trials conducted in California and Mexico. Each field trial had two plots and two applications were made to each treated plot. No residues of flazasulfuron or its metabolite were found in any control or treated sample at a level above the LOQ (0.01 mg/kg).

B. Toxicological Profile

 Acute toxicity.  
      Flazasulfuron exhibits low acute toxicity in rats and rabbits. The oral LD50 is greater than 5000 mg/kg and the acute inhalation LD50 is greater than 4.0 mg/L. All study results are in Toxicity Category III or IV. Flazasulfuron is not irritating to the skin or eyes and is not a sensitizer.
      
      In an acute neurotoxicity study, Flazasulfuron was administered by oral gavage to groups of Sprague-Dawley rats at doses of 0, 50, 1000, or 2000 mg/kg/bwt. The animals were observed for 14 days.  Mean motor activity measurements for mid and high dose males and females were statistically significantly different from the respective control groups at 5 hours post-dose. This possible effect was reversed by the next scheduled observation. Neurohistopathologic evaluation did not demonstrate any test material-related neurotoxic lesions. Based on the transient loss of motor activity, the NOAEL was 50 mg/kg bwt. The LOAEL was 1000 mg/kg bwt.

 Genotoxicty. 
      The genotoxic potential of flazasulfuron has been assessed as negative by several in vitro and in vivo mutagenicity studies. Flazasulfuron did not elicit a genotoxic response in any of the studies conducted.
         
 Reproductive and developmental toxicity. 
      A two-generation study was conducted in Sprague-Dawley rats at dose levels in the diet of 0, 200, 2,000 and 10,000 ppm. There were no effects on any of the endpoints used to assess reproductive capacity but kidney toxicity was observed in the parental animals. There was also a treatment-related effect on pup weight during lactation. The NOEL for reproductive performance was considered to be 10,000 ppm (473 mg/kg bwt/day for males and 613.7 mg/kg bwt/day for females), the highest dose tested. The NOEL for the offspring was 2000 ppm (87.5 mg/kg bwt/day for males and 124.5 mg/kg bwt/day for females) based on a reduction in lactational body weights of the F1 and F2 offspring at the next highest dose level.
      
      Two separate studies were conducted in two different strains of rats to test for the potential for development effects of flazasulfuron. In a study with Wistar-Imamichi rats, dose levels of 0, 100, 300 and 1000 mg/kg bwt/day were administered from days 6 to 15 of gestation. A second study was conducted with Sprague-Dawley rats at the same dose levels. The NOEL for maternal effects in the Wistar strain was 100 mg/kg bwt/day. The NOEL for maternal effects in the Sprague-Dawley was 300 mg/kg bwt/day. The NOEL for developmental effects in the Wistar strain was 100 mg/kg bwt/day based on increased incidence of visceral malformations (interventricular septal defect) observed at 300 mg/kg bwt/day.  The NOEL for developmental effects in the Sprague-Dawley was 300 mg/kg bwt/day based on reduced fetal weights and retardation in ossification. These fetal effects, in both strains of rats, were all considered to be secondary to maternal toxicity.
      
      In a developmental toxicity study with New Zealand White rabbits, flazasulfuron was administered at dose levels of 0, 50, 150 and 450 mg/kg bwt/day from days 6 to 18 of gestation. An increased incidence of abortion was observed but no evidence of developmental toxicity at 450 mg/kg bwt/day, a dosage that was maternally toxic. The NOEL for maternal and developmental effects was 150 mg/kg bwt/day.

 Subchronic toxicity. 
      A 90-day oral toxicity study was conducted in rats with dietary concentrations of 0, 40, 200 and 1,000 ppm technical flazasulfuron.  The systemic NOEL was 200 ppm (11.66 mg/kg bwt/day) for males and 1000 ppm (61.5 mg/kg bwt/day) for females based on based on depression of body weight gain (males and females) and slight anemia due to decrease in hemoglobin (females) at the next highest dose level.
      
      A 90-day oral toxicity study was conducted with dogs at dose levels of 0, 2, 10, 50, and 250 mg/kg bwt/day for males and 2, 10, 50, and 100 mg/kg bwt/day for females administered by capsule. The systemic NOEL was 2 mg/kg bwt/day for males and 10 mg/kg bwt/day for females based on changes in the liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration, microgranulomas) at the next highest dose level (10 mg/kg bwt/day for males and 50 mg/kg bwt/day for females).
       
      Dermal application of flazasulfuron for 21 to 22 consecutive days at dose levels of 0, 250, 500, and 1000 mg/kg bwt/day to the dorsal skin of New Zealand White rabbits resulted in no treatment-related findings. The systemic NOEL was considered to be 1000 mg/kg bwt/day (highest dose tested).  No dermal effects were observed.

 Chronic toxicity. 
      An 18-month oncogenicity study was conducted in mice with dietary concentrations of 0, 500, 3,500 and 7,000 ppm technical flazasulfuron.  The systemic NOEL was 500 ppm (77.3 and 93.7 mg/kg bwt/day for males and females, respectively) based on decreased body weights, body weight gains, food consumption and an increase in liver effects (liver weight and hepatocellular hypertrophy) at a dose of 3,500 ppm (552.7 and 659.8 mg/kg bwt/day for males and females, respectively). There was no evidence of carcinogenicity.
      
      A 2-year chronic toxicity/carcinogenicity study was conducted in rats with dietary concentrations of 0, 40, 400 and 2,000 ppm technical Flazasulfuron for males and 0, 40, 400, and 4,000 ppm for females.  The systemic NOEL was 40 ppm (1.3 and 1.6 mg/kg bwt/day for males and females, respectively) based on adverse changes in kidney function (chronic nephropathy) and kidney physiology (enlargement, dark color of kidney) at a dose of 400 ppm (13.3 and 16.4 mg/kg bwt/day for males and females, respectively). There was no evidence of carcinogenicity.
      
      A 52-week chronic toxicity study was conducted with beagle dogs at dose levels of 0, 0.4 (males only), 2, 10 and 50 mg/kg bwt/day administered by capsule. The systemic NOEL was 2 mg/kg bwt/day based on changes in liver (increase in: inflammatory cell infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation) at 10 mg/kg bwt/day.

 Animal metabolism. 
      The nature of residue in animals is adequately understood.  Metabolism studies in the rat indicate that flazasulfuron is rapidly distributed and excreted in the urine and feces. Excretion in urine occurred more slowly in males (73%) than females (90%). Fecal elimination was greater in males (23%) than females (10%).  The most prevalent metabolites (expressed as percent of administered dose) were HDTG+TPPG (~6.5-17.7% in urine, ~0.4-9.7% in feces, and ~6.5-14% in bile), with minor amounts (<5%) of other compounds. 
      
      The nature of the residue in ruminants is similar to that in rats but more complex.  In the liver and muscle tissues of goats, the major extractable residue was HTPP.  In kidney flazasulfuron, HTPP and DTPP were identified but the major compound identified was DTPU.  About 90% of the dose was eliminated in the urine and feces, mostly as glucuronide conjugates of the above compounds.  Levels in milk and fat were too low for identification.
         
 Metabolite toxicology. 
      Comparison of the metabolism of flazasulfuron by plants and in animals indicates that a number of the identified metabolites are common to both plants and animals.  The data indicate that the final products of the metabolism of flazasulfuron in animals and plants represent differences in the extent of metabolism.  Several of the metabolites resulting from flazasulfuron are similar in plants and animals and, therefore, have already been evaluated toxicologically. The fact that no quantifiable residues were found in treated crops further indicates that exposures to and accumulation of metabolites are unlikely.

 Endocrine disruption. 
      An evaluation of the potential effects on the endocrine systems of mammals has not been determined. There is no evidence that flazasulfuron causes endocrine effects.

C. Aggregate Exposure

 Dietary exposure. 
      Exposure assessments were conducted to evaluate the potential risk due to dietary exposure of the U.S. population to residues of Flazasulfuron. 
      
      For chronic dietary exposure, the chronic reference dose (RfD) of 0.013 mg/kg bwt/day was proposed by EPA for humans, based on the NOAEL from the rat combined chronic toxicity/carcinogenicity study (1.3 mg/kg bwt/day) and dividing by an uncertainty factor of 100.  The chronic population adjusted dose (cPAD) is also 0.013 mg/kg bwt/day since the FQPA safety factor is anticipated to be 1 for flazasulfuron.
      
      For acute dietary exposure, the acute RfD of 0.5 mg/kg/day was based on the NOAEL of 50 mg/kg bwt/day from the acute neurotoxicity study adjusted by the uncertainty factor of 100.  The acute population adjusted dose (aPAD) is also 0.5 mg/kg bwt/day since the flazasulfuron FQPA safety factor is anticipated to be 1.

	i. Food. 
      
      Dietary (food + drinking water) exposure and risk assessments were conducted for Flazasulfuron using the 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).

      Tier 1 chronic and acute dietary exposure analyses were conducted for flazasulfuron in/on avocado, citrus, grapes, olives, sugarcane, and treenuts to determine the exposure contribution of these commodities to the diet and to ascertain the chronic and acute risk potential.  The estimates were based on the proposed tolerance level residues, conservative market share assumptions of 100% crop treated, and consumption data from the USDA.
      
      Using all of the worst-case exposure scenarios listed above, the chronic dietary (food + drinking water) exposure estimates resulted in an estimated exposure for the general U.S. population of 0.002083 mg/kg bwt/day.  This exposure corresponds to 16% of the cPAD of 0.013 mg/kg bwt/day.  The highest exposure estimate calculated was for the subgroup non-nursing infants.  This exposure was determined to be 0.0.1.188 mg/kg bwt/day (78.4% of the cPAD).
      
      A Tier 1 acute dietary exposure assessment was performed for the general U.S. population and all population subgroups. The acute RfD of 0.5 mg/kg/day was derived from an acute neurotoxicity study with a NOAEL of 50 mg/kg/day. The acute dietary exposure estimate for the total U.S. population is 0.005466 mg/kg bwt/day, below HED's level of concern at the 95[th] percentile. 
      
      It can be concluded that acute or long-term dietary exposure to flazasulfuron through residues on treated avocado, citrus, grapes, olive, sugarcane and tree nuts should not be of cause for concern.

	ii. Drinking water. 
      Since flazasulfuron is intended for application outdoors to field grown crops, the potential exists for parent and/or metabolites to reach ground or surface water that may be used for drinking water.  Exposure models used by EPA in the 2012 tolerance assessment for grapes and citrus to estimate residues in surface and ground water provided the most conservative drinking water concentrations. The highest estimated residues were obtained from PRZM-EXAMS which predicted the ground water concentration to be 102 ppb; this was used in both the acute and chronic DEEM dietary assessments.

 Non-dietary exposure. 
      Flazasulfuron is registered for use on golf courses and athletic fields. Applications are to be made by professional turf applicators only, thus there is no residential handler exposure. However, post-application dermal exposure from recreational contact with the treated turf may occur. In the 2005 EPA risk assessment, post-application dermal exposure was calculated for adults playing golf and adults playing sports on athletic fields. To calculate post-application dermal exposure to a treated athletic field, the agency applied the same calculation used to assess high contact adult re-entry to treated residential turf (Burke, 2005; US EPA, 2001). However, instead of utilizing the updated adult transfer coefficient (TC) of 14,500 cm2/hour, the agency used the older TC of 43,000 cm2/hour (US EPA, 2001). The use of the revised transfer coefficient results in a higher MOE (10,416) for adult post-application dermal exposure to treated turf compared to the MOE of 3,400 calculated in the 2005 risk assessment.

D. Cumulative Effects

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

E. Safety Determination

 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 to infants and children from the aggregate exposure of residues of Flazasulfuron.

 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 Flazasulfuron.

F. International Tolerances

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