


EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (9/25/2015)

EPA Registration Division contact: [Shaja Joyner, (703) 308-3194]


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 and brackets, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[Syngenta Crop Protection, LLC]

[Syngenta Crop Protection, LLC PP#1F8954]

	EPA has received a pesticide petition ([PP#1F8954]) from Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419 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 180.662.

	1. by establishing a tolerance for residues of cyclobutrifluram in or on the raw agricultural commodity soybean at 0.01 ppm, cotton at 0.01 ppm, cotton, by-products at 0.01 ppm and lettuce, romaine at 0.015 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 studies with cyclobutrifluram were performed in wheat, soybean, and potatoes as representative crops in order to characterize the fate of cyclobutrifluram in all crops.  Two radiocarbon labels were studied in each crop, with 14-C labels positioned in phenyl and pyridinyl ring structures. Cyclobutrifluram was the predominant component of residue in most crops.  The metabolism in all plants (wheat, soybean and potatoes) was very similar.  It is evident that hydroxylation of the parent molecule and cleavage of the N-cyclopropyl bond to form SYN510275 represent the principle metabolic transformations observed in all three crops. Significant conjugation, hydrolysis of the amide moiety to SYN510260 and extensive metabolism to TFA were all observed as further metabolic processes. 
      
2. Analytical method.

      i. Food  The proposed definition of residue for  target crops, and rotational crops, is parent-only (cyclobutrifluram)  for monitoring and tolerance/MRL setting. For risk assessment, the proposed residue definition for target crops, and rotational crops, is total cyclobutrifluram (Parent + SYN510275 + SYN549104 calculated as parent equivalents). Methods GRM076.07A and GRM076.11A have been developed for the determination of cyclobutrifluram and related metabolites in crops for use in pre-registration studies, with an LOQ of 0.01 mg/kg. This method has also been validated.  Additionally, QuEChERS multi-residue method (EN 15662:2009) has been validated and independently validated for post-registration monitoring of cyclobutrifluram for compliance with MRLs and import tolerances in plant commodities at an LOQ of 0.01 mg/kg. 
       ii. Livestock  A definition of residue for animal commodities is not being proposed at this time. No animal feeding studies have been conducted as residues in soybean seed, undelinted cotton seed and cotton gin by products were <0.01 mg/kg. As a result, the potential dietary burdens of cyclobutrifluram in livestock diets were calculated based on transfer factors estimated from the goat and hen metabolism studies.  The anticipated residues in all animal commodities are <0.01 mg/kg.  
      
      3. Magnitude of residues. 
      The number and locations of the field trials are in accordance with OPPTS 860.1500 and SPN2017-02.  Field trials were carried out using the maximum label rates, maximum number of applications, and the minimum pre-harvest interval (PHI) for all the crops.  Residue field trials were conducted on soybeans, cotton, and romaine lettuce. Detected residues in all crops support the proposed tolerances based on parent only  -  cyclobutrifluram.

B. Toxicological Profile 
                                                                                                           
	1. Acute toxicity. The estimated acute oral median lethal dose (MLD) for cyclobutrifluram via the oral route was greater than 5000 mg/kg bw, the MLD following acute inhalation exposure was estimated to be greater 4.08 mg/L.  The acute dermal MLD was shown to be greater than 2000 mg/kg bw. Cyclobutrifluram was minimally irritating to the eye since positive scores cleared by 24 hours and a non-irritant to the skin.  Cyclobutrifluram is not a skin sensitizer. 

	2. Genotoxicity.  Cyclobutrifluram has been tested in a range of in vitro and in vivo genotoxicity assays.  In vitro assays include in vitro Ames tests (reverse mutation assay with Salmonella typhimurium and Escherichia coli), an in vitro cell gene mutation test (in mouse lymphoma L5178Y cells) and in vitro micronucleus assays (in human lymphocytes). An in vivo mouse bone marrow micronucleus test was conducted.  The genotoxicity data generated demonstrates that cyclobutrifluram is not genotoxic.

	3. Reproductive and developmental toxicity.   In a prenatal developmental study in the rat, cyclobutrifluram was tolerated up to 250 mg/kg bw/day.  There were no effects of cyclobutrifluram on uterine, implantation or fetal data.  The incidence and intergroup distribution of major, minor and variant fetal abnormalities were not affected by the administration of cyclobutrifluram.  The NOAEL for maternal and developmental toxicity was 250 mg/kg/day, which is the highest dose tested. 

In rabbits, decreased body weight gain and food consumption were noted in dams at 125 mg/kg bw/day.  Developmental toxicity was not observed.  The parental NOAEL was 75 mg/kg and developmental was 125 mg/kg bw/day, the highest dose tested.  

Cyclobutrifluram was evaluated in a two-generation reproduction study in the rat at dietary inclusion levels of 0, 50, 150 and 700 ppm.  Dietary inclusion rates for females were halved from Day 20.   There was no effect on reproductive performance, mating behavior or conception at any dose level in either generation.  There was no effect on body weight gain in either the P or F1 generation, although pup body weight gains of the F1a generation were slightly lower at 700/350 ppm. Follicular cell hypertrophy (minimal) was found in the thyroids in P and F1 generation males given 700 ppm and in the P generation females given 700/350 ppm.  This finding correlated with the statistically significant increase in thyroid weights in these groups when compared with the controls and was considered adaptive and not adverse.

The NOAEL for both sexes for systemic and reproductive toxicity and offspring was considered to be the highest dietary concentration of 700/350 ppm, equivalent to an average daily dose of 43.1 mg/kg/day and 55.8 mg/kg/day cyclobutrifluram for the P and F1 generation males and 54.6 mg/kg/day and 62.6 mg/kg/day cyclobutrifluram for the P and F1 generation females, respectively.
 
	4. Subchronic toxicity. Cyclobutrifluram is generally of a low order of toxicity in all species tested in short-term to intermediate-term studies.  The target organ was the liver with increased liver weight and hypertrophy in the rat, mouse and dog. Thyroid hypertrophy was noted in 28- and 90-day studies in the rat.  In the 90-day rat study the NOAEL was 700 ppm, equivalent to 51.1 and 58.7 mg/kg bw/day in males and females respectively.  At the highest dietary concentration of 2500 ppm body weight gain decrement and liver weight increase accompanied by minimal centrilobular hypertrophy were observed.  

In a 90-day study in mice, liver weight and liver enzymes were increased, and hepatocellular hypertrophy observed at 700 and 1750 ppm in males and females.  Increased spleen weight and splenic extramedullary hemopoiesis were noted at 700 and 1750 ppm.  The NOAEL was considered to be 1750 in males, equating to 245.0 mg/kg bw/day.  Due to corresponding increases of liver enzymes, liver weights along with the microscopic findings of hepatocellular hypertrophy, the NOAEL was considered to be 700 ppm in females, equating to 134.4 mg/kg bw/day.  

In a 90-day oral capsule study in beagle dogs with cyclobutrifluram, liver weights were statistically significantly increased in male dogs at 100 and 300 mg/kg and in female dogs at 300 mg/kg and minimal centrilobular hypertrophy was noted at 300 mg/kg in both males and females.  While all these findings were considered adaptive and non-adverse, on the basis of the magnitude of liver weight increase at 300 mg/kg which was accompanied by minimal centrilobular hypertrophy, the NOAEL was considered to be 100 mg/kg/day.

	5. Chronic toxicity. In a 2-year combined chronic toxicity/carcinogenicity study in Wistar rats, statistically significantly lower body weight gain was observed in male rats at the highest dietary concentration of cyclobutrifluram of 500 ppm, at 52 and 104 weeks.  Liver weights were higher in females at 500 ppm at 52 weeks.  Following 104 weeks of cyclobutrifluram exposure at 500 ppm, there was a reduced incidence of mammary gland alveolar/ductular dilatation and fibroadenoma in females. There were no treatment-related increases in neoplastic findings in either sex.  A NOAEL was established at 23.0 mg/kg/day in males and 30.1 mg/kg/day in females.

In an 80-week carcinogenicity study in the mouse, liver weights were increased in males, which correlated with a higher incidence of liver masses, at the highest dietary concentration, 400 ppm, equivalent to 47.8 mg/kg bw/day. At 400 ppm a higher incidence of hepatocellular carcinomas was observed which were within historical control incidence and not statistically different from control on pairwise assessment.  Since the hepatocellular carcinomas were significantly higher than control using a trend test (Peto), a relationship to treatment could not be excluded.  There were no treatment-related neoplastic findings in females in this study.    The NOAEL for the 80-week mouse study was established at 14 and 53.7 mg/kg bw/day in males and females, respectively.


      6. Animal metabolism. 
      The metabolism and distribution of cyclobutrifluram have been investigated in poultry and ruminant species (hen and goat). There was low transfer of residues into dietary tissues, milk or eggs, following the dosing of cyclobutrifluram to the hen or the goat.  Metabolic profiles observed in livestock commodities arise from three principal biotransformation steps:

i) cleavage at the carboxamide location between the cylcobutyl and pyrinidyl rings
ii) oxidation resulting in 
 monohydroxylation of the cyclobutyl ring
 dihydroxylation of the cyclobutyl ring
 to a lesser extent formation of the tetrahydrofuran metabolite SYN552415
iii) reduction of the cyclobutyl ring

Overall, the biotransformation pathway of cyclobutrifluram in ruminants and poultry is well understood and consistent with that observed in the rat.

      7. Metabolite toxicology. SYN510260 was of low acute oral toxicity via an in vivo assay, was not irritating to the eye, or skin, or a skin sensitizer, or genotoxic when assessed in in vitro assays.  SYN510275 was not genotoxic when assessed in in vitro genotoxicity assays.    
      
      8. Endocrine disruption.  Cyclobutrifluram does not belong to a class of chemicals known as suspected of having adverse effects on the endocrine system. There is no evidence in relevant toxicity studies (e.g. sub-chronic and chronic toxicity, developmental toxicity and multi-generation reproductive studies) which would suggest that cyclobutrifluram has any endocrine disruptive potential.
      
      9. Neurotoxicity.  Cyclobutrifluram was not acutely neurotoxic and no signs of systemic or neurotoxicity were observed in an acute neurotoxicity study.  The NOEL was 2000 mg/kg bw.  Examination of the toxicity database for cyclobutrifluram demonstrates that existing studies are adequate to evaluate adverse effects of repeated dosing on neurotoxicity.  Cyclobutrifluram did not have any direct influence on nervous-system-related parameters in acute, subchronic and chronic studies in rats, mice or dogs.   
      
      10. Immunotoxicity. A thorough review of the toxicology database for cyclobutrifluram indicated there was no immunotoxic potential.  Adequate toxicological and risk evaluations can be performed with the available studies and conducting a 28-day immunotoxicity study will not provide a more conservative endpoint or otherwise significantly impact risk assessment or hazard characterization.  

C. Aggregate Exposure

 Dietary exposure. Tier II short-term, and chronic dietary exposure evaluations were performed for cyclobutrifluram using both the Dietary Exposure Evaluation Model (EPA, DEEM FCID(TM) Version 4.02) and CARES NG Food Model (Creme Global, Version 1.2.0).  Consumption data 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 chronic exposures. These assessments included all proposed uses including seed treatments on cotton and soybeans, soil treatment on lettuce, and applications to turf and ornamentals.  These assessments incorporated field trial residue values where cyclobutrifluram was applied at the maximum intended use rate and samples were harvested at the minimum pre-harvest interval (PHI) to obtain the maximum expected residues. Percent of crop treated values were estimated to be 100% for all uses in all assessments.  Secondary livestock residues in meat, milk, and egg commodities were estimated based on "maximum reasonably balanced diets" and transfer information from goat and hen metabolism studies.  Drinking water estimates were incorporated directly into the short-term and chronic dietary exposure assessments using the highest estimated drinking water concentrations (EDWCs) for surface and ground water.  
 
i. Food.  Acute exposure. Acute dietary (food only) assessments were not performed, since an endpoint of concern attributable to a single oral dose has not been identified.
 

Chronic exposure.  The cyclobutrifluram chronic dietary food risk assessments were performed for all population subgroups using a chronic reference dose of 0.14 mg/kg-bw/day based upon a mouse 80-week study with a no observed adverse effect level (NOAEL) of 14 mg/kg/day and an uncertainty factor of 100X to account for 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 only) exposure to the U.S. population resulted in a MOE of 466,667 (<0.1% of the cRfD of 0.14 mg/kg-bw/day).  The most exposed sub-population was children (1-2 years old) with a MOE of 166,667 (0.1% of the cRfD of 0.14 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 MOE or below 100% of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from all current, pending, and proposed uses of cyclobutrifluram.

Cancer.  A quantitative risk assessment using a cancer endpoint was not performed as Syngenta believes that cyclobutrifluram is not likely to be carcinogenic to humans.

ii. Drinking water.  The Estimated Drinking Water Concentrations (EDWCs) of parent cyclobutrifluram from all proposed uses were determined using the Pesticide Water Calculator (PWC, v2.001). For surface water, the highest EDWCs were 27.62 ug/L and 10.65 ug/L for acute and chronic exposure, respectively, based on proposed uses on ornamental (acute) and turf (chronic) with 2 applications/year (2 x 0.25 kg a.i./ha) at 14-day retreatment intervals. No percent cropped area (PCA) adjustments were made to the surface water EDWCs. For groundwater, the proposed uses on turf and ornamental resulted in the highest EDWCs of 103.99 ug/L and 96.31 ug/L for acute and chronic exposure, respectively. Since the groundwater acute and chronic EDWCs exceed the surface water EDWCs, the groundwater EDWCs were used in the risk assessment purposes and will be considered protective for any surface water concentration concerns.  

Acute Exposure from Drinking Water:  Acute drinking water assessments were not performed since an endpoint of concern attributable to a single oral dose has not been identified.
 
Chronic Exposure from Drinking Water: The chronic ground water exposure value of 96.31 μg/L (ppb) was used as a DEEM-FCID(TM) input to determine chronic exposure from drinking water at the 95th %ile. Chronic drinking water exposure to the U.S. population resulted in a MOE of 7,194 (1.4% of the cRfD of 0.14 mg/kg-bw/day).  The most sensitive sub-population was all infants (<1 year old), with a MOE of 1,926 (5.2% of the cRfD of 0.14 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from all proposed cyclobutrifluram uses.
 


2. Non-dietary exposure. Residential handler and post-application exposure risk assessments were performed for use of cyclobutrifluram formulated as A22011B and A23156A for use on ornamentals and turf (including a turf spot treatment).  The following endpoints were used: a 1,000 mg/kg/day NOAEL for dermal exposure, using a 100% absorption factor, from a 28-day dermal study in rats; and a 51.1 mg/kg/day NOAEL for inhalation and incidental oral exposure, from a 90-day rat study.  Adults (19+ years) were most exposed via dermal exposure from high contact lawn activities to treated turf (MOE = 2,700).  Youths (11-16 years) were most exposed via golfing on treated turf (MOE = 30,000). Youths (6-11 years) were most exposed via contact to treated gardens (MOE = 10,000).  Children 1-6 years old were the most-exposed via post-application dermal plus non-dietary oral hand-to-mouth exposure from high-contact lawn activities and hand-to-mouth exposures from treated turf (short-term MOE = 1,000).  Since the MOEs for children (1-6 years), youths (6-11 years and 11-16 years), and adults (19+ years) were above the Benchmark MOE of 100, residential exposure risks for cyclobutrifluram do not exceed the EPA's Level of Concern. 
   

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity.  Section 408(b)(2)(D)(v) of FFDCA 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".  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to cyclobutrifluram and any other substances and cyclobutrifluram does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, the EPA has not assumed that cyclobutrifluram has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. Acute dietary exposure analyses were not performed since an endpoint of concern attributable to a single oral dose has not been identified.  For the short-term aggregate exposure analysis, the corresponding food, water and residential MOEs were aggregated using the inverse MOE approach.  The short-term aggregate (food, drinking water, and residential) MOE was 963 for the general US population, which exceeds the Benchmark MOE of 100.  The chronic dietary exposure analysis (food plus water) showed that exposure from all current, pending, and proposed uses of cyclobutrifluram resulted in an MOE of 7,085 (1.4% of the cRfD of 0.14 mg/kg-bw/day) for the general U.S. population, which also 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 from aggregate exposure to residues arising from all proposed uses of cyclobutrifluram, including anticipated dietary exposure from food, water, and all other types of non-occupational exposures.


2. Infants and children. Acute dietary exposure analyses were not performed since an endpoint of concern attributable to a single oral dose has not been identified. For the short-term aggregate exposure analysis, the corresponding food, water and residential MOEs were aggregated using the inverse MOE approach.  The short-term aggregate (food, drinking water, and residential) MOE was 949 for children (1-2 years), which exceeds the Benchmark MOE of 100.  The chronic aggregate dietary (food plus water) exposure analysis showed that exposure from all current, pending, and proposed uses of cyclobutrifluram would result in a MOE of 1,911 (5.2% of the cRfD of 0.14 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 proposed uses of cyclobutrifluram, including anticipated dietary exposure from food, water, and all other types of non-occupational exposures.


F. International Tolerances

Codex Alimentarius Commission has not yet established Maximum Residue Limits (MRLs) for cyclobutrifluram.

