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

EPA Registration Division contact: Shaja B. Joyner, 202-566-2808



Syngenta Crop Protection, LLC, PO Box 18300, Greensboro, NC 27419

Petition 2F8986

	EPA has received a pesticide petition 2F8986 from Syngenta Crop Protection, LLC, PO Box 18300, Greensboro, NC 27419 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 Sedaxane in or on the raw agricultural commodity Vegetable, cucurbit, group 9 at 0.01 parts per million (ppm) and Vegetable, dry bulb, crop subgroup 3-07A 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. Plant metabolism data were studied for corn, wheat, soybean, Swiss chard, and canola to support the seed treatment uses of sedaxane. Studies for all commodities reflected labeling in both the phenyl and pyrazole rings. Application rates were equal to, or exaggerations of, the currently proposed use rates, and application techniques reflect the requested use patterns.
      The metabolic pathway in wheat, soybeans, and Swiss chard is substantially similar. Radioactivity levels were too low from corn and canola samples to elucidate the metabolic pathways in these crops. Following seed treatment use of sedaxane in wheat, soybean, and Swiss chard, sedaxane metabolism may be summarized as follows: 1) oxidative metabolism of the phenyl and cyclopropane rings, 2) N-demethylation of the pyrazole ring, and 3) cleavage between pyrazole and phenyl rings. Among the three crops studied, there is variation in the extent of the three reaction processes and the nature of the observed conjugates found.
The seed treatment data on the metabolism of sedaxane in wheat, soybean, and Swiss chard demonstrate that residues are generally low but do translocate throughout the plants. The highest residues are generally found in the foliage or forage portions of plants, and not in the seeds or grains of these commodities. Crop field trial residue data were consistent with the results of the plant metabolism studies. Specifically, the magnitude of the residue studies showed no quantifiable residues of sedaxane in any human food plant parts, but low-level residues were found in some livestock feedstuffs associated with these plants.

	2. Analytical method.  Various crops were analyzed for sedaxane (parent only) using a procedure for analysis of sedaxane (SYN524464) that can distinguish between its trans and cis isomers (SYN508210 and SYN508211). Plant matrices using method GRM023.01A or modified method GRM023.01B are taken through an extraction procedure with final determination by high-performance liquid chromatography with triple quadrupole mass spectrometric detection (LC-MS/MS).
      Method GRM023.01A (and therefore GRM023.01B, which uses the same procedure) was validated on a range of plant commodities fortified with the trans and cis isomers SYN508210 and SYN508211 at the proposed limit of quantification (LOQ) of the method (0.005 mg/kg for SYN508210 and SYN508211) and either at 10 times the LOQ or at the potential MRL.
      The plant matrices included plants from each of the crop commodities identified in OECD Guidance ENV/JM/MONO(2007)17, including wheat grain, wheat straw, wheat whole plant, lentils, and oilseed rape seed as a few of those crops tested. The mean SYN508210 and SYN508211 recoveries for both primary quantification and confirmatory transitions at each fortification level and overall, for each crop commodity tested during method validation were 76%  -  102%. The limit of quantification for SYN508210 and SYN508211 residues in crop commodities using method GRM023.01A was established at 0.005 mg/kg.

	3. Magnitude of residues. 1) Adequate plant metabolism data have previously been submitted to establish the residue definition for enforcement purposes and risk assessment for sedaxane, and 2) the proposed labelled seed-treatment rates are <=10 g ai/100 kg seed for all proposed new crop uses, so a reduction in data requirements is appropriate based on the EPA Memorandum entitled Reduced Residue Chemistry Data Requirements for Seed-Treatment Uses, dated January 26, 2018.  

B. Toxicological Profile

	1. Acute toxicity. Sedaxane has low acute toxicity by the oral, dermal and inhalation routes. It is not a dermal sensitizer, causes no skin irritation, and causes only slight eye irritation.

	2. Genotoxicity. Sedaxane was negative (non-mutagenic) in an in vitro bacterial reverse mutation assay, an in vitro gene mutation assay in mammalian cells, an in vitro cytogenetics study, an in vivo unscheduled DNA synthesis study, and an in vivo rat bone marrow micronucleus assay.

	3. Reproductive and developmental toxicity. Sedaxane was evaluated for potential to cause effects on reproductive and developmental toxicity in a multi-generation reproductive toxicity study in the rat and in pre-natal developmental toxicity studies in the rat and rabbit. There were no adverse effects on reproduction or fertility up to the top dose level of 127 mg/kg/day (1500 ppm). Therefore, this high dose represented the NOAEL for reproductive toxicity.
      There were no indications of any differences in sensitivity to sedaxane between the different generations or between parental animals and offspring. There were no adverse effects at a dose level of 42 mg/kg/day (500 ppm) in adults or pups, indicating that this was the NOAEL for parental and offspring toxicity.
      Data from both the rat and rabbit developmental toxicity studies with sedaxane showed no potential for teratogenic effects, and the fetal NOAEL values were equal to or higher than the maternal NOAEL values, indicating a lack of sensitivity of developing offspring to the effects of sedaxane.

	4. Subchronic toxicity. The short-term toxicity of sedaxane has been evaluated by the oral route of administration in rats, mice and dogs. In addition, dermal toxicity was evaluated in rats in a 28-day study.
      Sedaxane is generally of a low order of toxicity in all species tested in short-term studies. Rats were slightly more sensitive to the general systemic effects of sedaxane treatment than were dogs. Mice were relatively non-responsive except at a limit dose for studies of this type, 1268 mg/kg/day in males and 1800 mg/kg/day in females (7000 ppm). A NOAEL of 28 mg/kg/day (300 ppm) was achieved in the second 90-day rat study for female rats.
      In rats, treatment-related effects were seen consistently in the liver, indicating that this is a target organ for sedaxane. At dose levels of 2000 ppm and 1000 ppm in the 90-day rat studies, slight increases in liver weight were seen in males and females, with no micropathological findings. The increases are therefore consistent with adaptive changes and were considered non-adverse. No effects on liver weights or micropathology were seen at 250 or 300 ppm in these studies.
      In male and female rats, increased incidence of thyroid follicular cell hypertrophy was observed only at the 325 mg/kg/day in males and 350 mg/kg/day in females (4000 ppm) dose level in the second 90-day rat study. There were no effects in this organ in the first 90-day rat study. A chronic/carcinogenicity study in rats also showed similar low- level changes of follicular cell hypertrophy in male and female rats after 52 weeks of treatment at 1200 and 3600 ppm concentration levels. Overall, the response in the thyroid of rats was relatively mild and was variable between studies and laboratories.
      In mice, no adverse effects of treatment were observed in the 28-day study at concentration levels up to 7000 ppm. Decreased bodyweight gain and food utilization were observed in male mice at 1167 mg/kg/day (7000 ppm) in the 90-day study, but not in females. No micropathology changes were observed in either study and the few differences in certain hematology, clinical chemistry, or organ weight values were not considered adverse. In the 90-day study, a NOAEL of 567 mg/kg/day (3500 ppm) was achieved in male mice.
      In dogs, liver weights were higher than control values in male and female dogs after one year at 200 mg/kg/day, but, in the absence of micropathology findings, this was considered non-adverse. In the 90-day dog study, there were no effects on liver weights and no differences from control animals in liver micropathology. There were no adverse effects on the thyroid in any study in the dog, including the 1-year study. A NOAEL of 50 mg/kg/day was achieved in both the 90-day and 1-year dog studies, based on initially lower food consumption and consistently lower cumulative bodyweight gains at >=150 mg/kg/day. 
      In a 28-day dermal toxicity study in rats, no treatment-related effects were observed at any dose level up to the limit dose of 1000 mg/kg/day.
      In an acute neurotoxicity study in rats, no neuropathology was observed at any dose level, and the NOAEL for neurotoxicity was 2000 mg/kg. The NOAEL for general toxicity in this study was 30 mg/kg, based on effects on body weight, food consumption, and clinical signs at 250 mg/kg. For use in acute risk assessments, EPA derived an acute reference dose (aRfD) of 0.30 mg/kg/day based on the NOAEL of 30 mg/kg from this acute neurotoxicity study.
      In a subchronic neurotoxicity study, sedaxane did not produce any evidence of neurotoxicity in rats at concentration levels of 0, 300, 1000 and 4000 ppm for 90 days. A NOAEL for general toxicity was observed at 1000 ppm, equivalent to 66.0/79.7 mg/kg/day in male and female rats, respectively.

	5. Chronic toxicity. Sedaxane has been evaluated for chronic toxicity in the rat and for carcinogenic potential in the rat and the mouse.
      In a 2-year combined rat chronic toxicity/carcinogenicity study conducted at dietary inclusion levels of 0, 200, 1200 and 3600 ppm, there were no treatment related effects on survival. There was a marked deficit in body weight gain at 3600 ppm which was evidenced throughout the entire study. The extent of the body weight effect increased substantially during the course of the study and by the end of the study represented a 24% and 50% decrease in body weight gain in males and females, respectively. The magnitude of the effect at 3600 ppm was considered to be greater than that required for an adequate evaluation of carcinogenic potential. At 1200 ppm, body weight gain was a maximum of 11% lower than control in females, which was considered to be of sufficient magnitude to provide a robust assessment of carcinogenic potential. The NOEL was 200 ppm for both males and females, equating to 11 mg/kg/day in males and 14 mg/kg/day in females. The LOAEL was 1200 ppm.
      In a carcinogenicity study in the mouse, groups of 50 male and 50 female CD-1 mice were fed diets containing 0, 200, 1250 and 7000 ppm of sedaxane for a period of at least 80 weeks. There were no treatment related effects on survival and no treatment-related clinical signs. Effects at the LOAEL and above included decreased body weight and body weight gain and food utilization in males and females. The NOAEL for this study was 1250 ppm for both sexes, equating to achieved dose levels of 157 mg/kg/day in males and 185 mg/kg/day in females.
      For non-cancer risk assessments of chronic exposures, a chronic reference dose (cRfD) of 0.11 mg/kg/day was assigned, based on the NOAEL of 11 mg/kg/day in the 2-year rat study.

	6. Animal metabolism. In both poultry and goat, the majority of the dosed radioactivity was excreted (mainly in the feces of the goat) and residues in tissues, milk and eggs were low. In the goat study, milk residues reached a plateau very rapidly, after just 2 days (reaching a maximum of 0.045 mg/kg). Residues in eggs from the hen study reached a plateau after approximately 9 days (reaching a maximum of 0.015 mg/kg in egg white and 0.089 mg/kg in egg yolk).
	In both species, the highest tissue residues were observed in liver: 0.26 mg/kg in hen and 0.61 mg/kg in goat. Residues in muscle were <0.006 mg/kg and in fat were <0.016 mg/kg. In the goat, kidney residues represented <0.19 mg/kg.
	Metabolic profiles observed in livestock commodities and excreta arise from just a few types of biotransformation. The principal routes of metabolism are oxidation resulting in hydroxylation of the phenyl ring or at the cyclopropane moiety. Additionally, the same oxidations are observed following demethylation of sedaxane. Overall results showed that the biotransformation pathway of sedaxane in ruminants and poultry is very similar to that observed in the rat.

	7. Metabolite toxicology. CSCD465008 (formed via cleavage of the carboxamide link in the pyrazole labeled aerobic soil study) has been assessed for acute oral toxicity, in vitro genotoxicity (bacterial reverse mutation, in vitro cytogenics and mammalian gene cell mutation), and repeat oral toxicity for up to 28 days. CSCD465008 was not acutely toxic by the oral route, not genotoxic in vitro, and did not result in any toxicologically significant effects at dose levels exceeding 1000 mg/kg-bw/day, the limit dose for a 28-day toxicity study in rats. Based on the toxicity data on CSCD465008, this metabolite less toxic than parent, sedaxane. 

	8. Endocrine disruption. Sedaxane does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system. Furthermore, supporting developmental toxicity studies in rats and rabbits, and a reproduction study in rats, gave no indication of any effects on endocrine function related to development and reproduction. Subchronic and chronic treatment did not induce any morphological changes in endocrine organs and tissues.

C. Aggregate Exposure

	1. Dietary exposure. Tier I acute and Tier II chronic aggregate exposure assessments were performed for sedaxane (SYN524464), a mixture of its cis- (SYN508210) and trans- (SYN508211) isomers using the Dietary Exposure Model (DEEM-FCID(TM) Version 4.02, Evaluation Copy) and CARES NG Food Model (Creme Global, Version 1.2.0). Consumption data were from the USDA NHANES "What We Eat in America" survey; 2005-2010 was used for both models. Side-by-side comparison of the two dietary models resulted in effectively no differences for acute and chronic exposures. The definition of the residue for tolerance enforcement and risk assessment purposes for crops is parent sedaxane (SYN508210 plus SYN508211). Assessments were conducted for all current uses and proposed seed treatment uses on cucurbits (Crop Group 9) and bulb onions (Crop Subgroup 3-07A). The Tier I acute assessments incorporated established (40 CFR 180.665) or proposed tolerances values for all crops where sedaxane was applied at the maximum intended seed treatment use rate and crops harvested at the minimum pre-harvest interval (PHI) to obtain the maximum expected residues. Percent of crop treated (%CT) was conservatively assumed to be 100% for the acute assessments. The Tier II chronic assessments incorporated field trial residue values where sedaxane was applied at the maximum intended use rate and crops harvested at the minimum PHI to obtain the maximum expected residues. Percent of crop treated (%CT) was conservatively assumed to be 100% for the chronic assessments. Anticipated residues in meat, milk, and eggs were estimated based on "maximum reasonably balanced diets" and transfer information from goat and hen metabolism studies and includes parent sedaxane (SYN508210 plus SYN508211) plus the metabolite CSCD658906 for risk assessment purposes. Drinking water estimates were selected using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water.

	i. Food. Acute Exposure. Acute food-only risk assessments for parent sedaxane (SYN508210 plus SYN508211) were performed for all population sub-groups using an acute reference dose of 0.30 mg/kg-bw/day, based upon a neurotoxicity study in rats with a no observed adverse effect level (NOAEL) of 30 mg/kg-bw/day and an uncertainty factor of 100X. The 100X safety factor includes intra- and inter-species variations; no additional FQPA safety factor was applied. For aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup. In addition, exposure was expressed as a percent of the acute reference dose (%aRfD). Acute food exposure to the U.S. population resulted in a MOE of 200,711 (0.1% of the aRfD of 0.30 mg/kg-bw/day). The most exposed sub-population was children (1-2 years old) with an MOE of 89,779 (0.1% of the aRfD of 0.30 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from acute food exposures to residues arising from all current and proposed uses of sedaxane.

Chronic Exposure. Chronic food-only risk assessments for parent sedaxane (SYN508210 plus SYN508211) were performed for all population sub-groups using a chronic reference dose of 0.11 mg/kg-bw/day, based upon a chronic rat study with a no observed adverse effect level (NOAEL) of 11 mg/kg-bw/day and an uncertainty factor of 100X. The 100X safety factor includes intra- and inter-species variations; no additional FQPA safety factor was applied. For the purpose of aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup. In addition, exposure was expressed as a percent of the chronic reference dose (%cRfD). Chronic food exposure to the U.S. population resulted in a MOE of 214,754 (<0.1% of the cRfD of 0.11 mg/kg-bw/day). The most exposed sub-population was children (1-2 years old) with an MOE of 82,075 (0.1% of the cRfD of 0.11 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from chronic food exposures to residues arising from all current and proposed uses of sedaxane.

	ii. Drinking water. The drinking water concentrations (EDWCs) of sedaxane were determined as combined residues of parent sedaxane isomers, CSCD668094 and CSCD668095, using a total toxic residue (TTR) approach for a screening-level estimation. For terrestrial uses, Tier I and Tier II Pesticides in Water Calculator (PWC, v. 2.001) was used to calculate EDWCs for surface water and groundwater. For the rice use, the Pesticides in Flooded Applications Model (PFAM v. 2.0) was used to model drinking water exposure. The crop uses evaluated in this assessment include all currently registered seed treatments and the proposed seed treatments on cucurbit vegetables (crop group 9) and onion (crop subgroup 3-07A). The registered seed treatment use for potato generated the highest EDWCs in groundwater for acute and chronic exposure, which were 20.2 ppb and 19.2 ppb, respectively. These EDWCs were used for risk assessment purposes and are considered protective for any surface water exposure concerns.

Acute Exposure from Drinking Water. The acute surface water EDWC of 20.2 ppb was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources" to model the acute drinking water exposures. Exposure contributions at the 95% percentile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food (alone) exposures for each population subgroup. Acute drinking water exposure U.S. population resulted in an MOE of 29,674 (0.3% of the acute RfD of 0.30 mg/kg-bw/day). The most exposed sub-population was all infants (<1 year old) with an MOE of 8,399 (1.2% of the acute RfD of 0.30 mg/kg/day). Since the benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures below 100% of the acute RfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute drinking water exposure to residues arising from the current and proposed uses for sedaxane.

Chronic Exposure from Drinking Water. The chronic surface water EDWC of 19.2 ppb was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources" to model the chronic drinking water exposures. Chronic drinking water exposure to the U.S. population resulted in an MOE of 28,356 (0.4% of the chronic RfD of 0.11 mg/kg-bw/day). Chronic drinking water exposure to the most exposed sub-population (infants, <1 year old) resulted in an MOE of 7,591 (1.3% of the chronic RfD of 0.11 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures below 100% of the chronic RfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from the current and proposed uses for sedaxane.

	2. Non-dietary exposure. There are no currently registered residential uses for sedaxane, so a non-dietary residential exposure assessment was not conducted.

D. Cumulative Effects

	Cumulative Exposure to Substances with a Common Mechanism of Toxicity.  Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity". Syngenta did not perform a cumulative risk assessment as part of this tolerance action for sedaxane because HED has not yet determined that there are any other chemical substances that have a mechanism of toxicity common with that of sedaxane.

E. Safety Determination

	1. U.S. population. The acute aggregate exposure analysis (food plus water) for all current and proposed uses of sedaxane resulted in an MOE of 25,855 for the U.S. population (0.4% of the aRfD of 0.30 mg/kg-bw/day) which exceeds the Benchmark MOE of 100. The chronic aggregate exposure analysis (food plus water) for all current and proposed uses of sedaxane resulted in an MOE of 25,049 for the U.S. population (0.4% of the cRfD of 0.11 mg/kg-bw/day) which exceeds the Benchmark MOE of 100. Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will occur to the U.S. population from acute and chronic aggregate exposures arising from all current and proposed uses of sedaxane.

	2. Infants and children. The acute aggregate exposure analysis (food plus water) for all current and proposed uses of sedaxane resulted in an MOE of 7,883 (1.3% of the aRfD of 0.30 mg/kg-bw/day) for the most sensitive population subgroup, all infants, which exceeds the Benchmark MOE of 100. The chronic aggregate exposure analysis (food plus water) for all current and proposed uses of sedaxane resulted in an MOE of 7,219 (1.4% of the cRfD of 0.11 mg/kg-bw/day) for the most sensitive population subgroup, all infants, which exceeds the Benchmark MOE of 100. Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to residues arising from all current and proposed uses of sedaxane.

F. International Tolerances

	Codex maximum residue levels (MRLs) have been established for residues of sedaxane on cereals, potato, pulses, rape seed, sweet corn, animal feeds, and animal commodities.
