Document ID: EPA-HQ-OPP-2018-0206-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2019-03-20T04:00Z

July 11, 2018

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (7/1/2007) >

<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: >

<Bayer CropScience >

< [Insert petition number] >

<	EPA has received a pesticide petition ([insert petition number]) from Bayer CropScience, 2 T.W. Alexander Drive, P.O. Box 12014, Research Triangle Park, NC  27709 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. >

< (Options (pick one) >
   
   <	1. by establishing tolerances and/or changing existing tolerances for residues of>
<<trifloxystrobin (Benzeneacetic acid, (E,E)-α-(methoxyimino)-2-[[[[1-[3- (trifluoromethyl) phenyl]ethylidene]amino]oxy]methyl]-methyl ester) and the free form of its acid metabolite CGA - 321113 ((E,E)-methoxyimino-[2-[1-(3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-phenyl]acetic acid) in or on the raw agricultural commodity [tea, dried] at 5 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 trifloxystrobin in plants (cucumbers, apples, wheat, sugar beets and peanuts) is well understood. Identified metabolic pathways are substantially similar in plants and animals (goat, rat and hen). EPA has determined that trifloxystrobin parent and its metabolite CGA-321113 are the residues of concern for purposes of tolerance setting and risk assessment. >
<	2. Analytical method. A practical analytical methodology for detecting and measuring levels of trifloxystrobin in or on raw agricultural commodities has been submitted. The limit of detection (LOD) for each analyte of this method is 0.08 ng injected, and the limit of quantitation (LOQ) is 0.02 ppm. The method is based on crop specific cleanup procedures and determination by gas chromatography with nitrogen-phosphorus detection.  A newer analytical method is available employing identical solvent mixtures and solvent to matrix ratio (as the first method), deuterated internal standards, and liquid chromatography/mass spectrometry-mass spectrometry (LC/MS-MS) with an electrospray interface, operated in the positive ion mode.  The limits of detection (LOD) for total trifloxystrobin range from 0.003 ppm to 0.01 ppm, depending on the crops, and the limit of quantitation is 0.01 ppm.

The following is a summary of the analytical method used for the analysis of trifloxystrobin and its metabolite CGA-321113:

 Trifloxystrobin:
      
   Sample is extracted with water/methanol mixture and extracts are partition with n-hexane/diethyle eter mixture. Purificate with C18, diatomace, silicagel or NH2 column. Trifloxystrobin is quantified with HPLC (UV) or LC-MS or LC-MS/MS.
   
   Or, sample is extracted with acetone/water (9/1) mixture.
   
   Purificate with C18 column. Quantificate with LC-MS or LC-MS/MS. 
   
   Quantification Limit: 0.005  -  0.05 ppm
  
 CGA-321113:
   
   Sample is extracted with water/methanol mixture and extracts are partitioned with n-hexan/diethyl ether mixture. After the purification with C18 column, strong cation ion exchange/ C18/ styrene divinylbenzene co polymer (MPC) column, CGA-321113 is quantified with HPLC (UV) or HPLC-MS.
   
   Described value of CGA-321113 is multiplied by factor 1.036 to express in trifloxystrobin equivalents.
   
   Quantification limit: 0.005  -  0.04 ppm >

<	3. Magnitude of residues.   The following summary for tea was adapted from the Japanese Ministry of Health, Labor and Welfare (MHLW) review for the purpose of setting food standards (maximum residue levels for pesticides in food) for trifloxystrobin, included in the accompanying application.

Three (3) decline field trials were conducted to measure the magnitude of trifloxystrobin residues in/on dried green tea leaves following two applications of FLINT[(R)] Flowable 25.  FLINT[(R)] Flowable 25 is a suspension concentrate formulation containing 270 g/L trifloxystrobin.

For foliar spray application to tea, FLINT[(R)] Flowable 25 was mixed with water at a 2000x dilution rate (100 ml FLINT[(R)] Flowable 25/200 L water) resulting in a concentration of 0.135 g trifloxystrobin/L.  At each trial location, two broadcast foliar applications of this solution were made in a water volume of 200 L/10a (in Japan "a" is considered a basic unit of agricultural area and is equivalent to 100 m[2] (10 m x 10 m) or 1/100 of ha; thus 10a = 1/10 ha or 1000 m[2]).  Based on this, 200 L/10a is equivalent to an application rate of 200 L/1000 m[2] or 2000 L solution/ha.  With a treatment solution concentration of 0.135 g trifloxystrobin/L and a treatment rate of 2000 L/ha, the resulting application rate was 270 g trifloxystrobin/ha.

Samples were collected at preharvest intervals (PHI) of 7, 14 and 21 days.  The PHI on the FLINT[(R)] label is 14 days. 

Residues in dried green tea leafs from the 3 trials were 0.78 ppm, 1.46 ppm and 2.25 ppm. 

<B. Toxicological Profile>

<	1. Acute toxicity.  In a battery of acute toxicity studies, trifloxystrobin showed mild toxicity by oral, dermal, or inhalation routes of exposure (Cat. III and IV); however, it was a strong dermal sensitizer. Trifloxystrobin was a mild ocular (Cat III) and dermal irritant (Cat IV).

<	2. Genotoxicty. Trifloxystrobin was non-genotoxic in all related studies with one exception, an in vitro mammalian cell gene mutation assays in Chinese hamster V79 cells. In that study, an inconsistent increase in hprt mutants was observed at precipitating concentrations of the test substance. In order to clarify these results as per the guidance from European Food Safety Authority, the study was repeated using current specification trifloxystrobin sample. Results from this repeat study showed a clear negative response. Collectively, these two independent studies indicate that trifloxystrobin is non-mutagenic in the in vitro mammalian cell gene mutation assay.

In vivo, orally administered trifloxystrobin was non-genotoxic up to the limit dose in a rat liver unscheduled DNA synthesis assay as well as a mouse bone marrow micronucleus test. Given that orally administered trifloxystrobin is readily bioavailable in the rat, exposure of the target tissues (liver, blood, and bone marrow) to trifloxystrobin (and its metabolites) was assured. Furthermore, whole body autoradiography experiments in the mouse confirmed bone marrow exposure to the test substance (and/or its metabolites) following oral administration of trifloxystrobin. Overall, the weight of evidence shows that trifloxystrobin has no genotoxic potential.

<	3. Reproductive and developmental toxicity. In a developmental study in rats, reductions in body weight gain and food consumption were observed in dams at 100 mg/kg/day; resulting in a maternal LOAEL of 100 mg/kg/day and NOAEL of 10 mg/kg/day. No teratogenic effects or any other effects were seen on pregnancy or fetal parameters except for an increased incidence of enlarged thymus at 1000 mg/kg/day. The developmental NOAEL was 1000 mg/kg/day.

In the rabbit developmental study, body weight loss and reduced food consumption were observed in dams at 50 mg/kg/day. No teratogenic effects or any other effects were seen on pregnancy or fetal parameters except for an increase in fused sternebrae-3 and -4 at the top dose of 500 mg/kg/day. This finding was evaluated as a marginal effect on skeletal development that likely resulted from the significantly reduced (40-65%) food intake during treatment at this dose. The maternal LOAEL and NOAEL were 100 and 10 mg/kg/day respectively. The developmental LOAEL and NOAEL were 500 and 250 mg/kg/day respectively.

In the 2-generation rat reproduction study, body weight gain and food consumption were decreased at 750 ppm (55.3 mg/kg/day), especially in females during lactation. Reduced pup weight gain during lactation (750 ppm) and a slight delay in eye opening (1500 ppm) were evaluated as secondary effects of maternal toxicity. No other fetal effects or any reproductive changes were noted.  The parental and offspring NOAEL and LOAEL were 3.8 and 55.3 mg/kg/day respectively. The reproductive NOAEL was 1500 ppm (110.6 mg/kg/day).  

<	4. Subchronic toxicity. In rats, the 90-day NOAEL was 500 ppm (30.6 mg/kg/day) based on decreased body weights (males), hepatocyte hypertrophy (males), and pancreatic atrophy observed at the LOAEL of 2000 ppm (127 mg/kg/day).

In mice, the 90-day NOAEL was 500 ppm (76.9 mg/kg/day) based on increased liver weights and hepatocyte necrosis observed at the LOAEL of 2000 ppm (315 mg/kg/day).

In dogs, the 90-day NOAEL was 30 mg/kg/day based on increased liver weight and hepatocyte hypertrophy (males) observed at the LOAEL of 150 mg/kg/day. 

In a 28-day rat dermal toxicity study, the NOAEL was 1000 mg/kg/day as increased liver and kidney weight were not accompanied by histopathological findings and evaluated as not adverse. The LOAEL was > 1000 mg/kg/day.>

<	5. Chronic toxicity. In dogs, the chronic NOAEL was 5 mg/kg/day based on increased clinical signs, liver weight, and hepatocellular hypertrophy seen at the LOAEL of 50 mg/kg/day. 

In a mouse chronic toxicity/carcinogenicity study, the NOAEL was 300 ppm (39.4 mg/kg/day) based on liver effects observed at the LOAEL of 1000 ppm (131.1 mg/kg/day). 
In a rat chronic toxicity/carcinogenicity study, the NOAEL was 250 ppm (9.81 mg/kg/day) based on decreased mean body weight and body weight gain observed at the LOAEL of 750 ppm (29.7 mg/kg/day).

Trifloxystrobin was classified as "not likely to be a carcinogen to humans," based on the lack of evidence for carcinogenicity in mice and rats.
 
<	6. Animal metabolism. Trifloxystrobin was moderately absorbed from the gastrointestinal tract of rats and was rapidly distributed. Subsequent to a single oral dose, the half-life of elimination was about 2 days and excretion primarily via bile. Trifloxystrobin was extensively metabolized by the rat into about 35 metabolites, but the primary actions were on the methyl ester (hydrolysis into an acid), the methoxyimino group (O-demethylation), and the methyl side chain (oxidation to a primary alcohol). Metabolism was dose dependent being almost complete at low doses but only about 60% complete at high doses.

In the goat, elimination of orally administered trifloxystrobin was primarily via the feces. The major residues were the parent compound and the acid metabolite (CGA-321113) plus its conjugates. In the hen, trifloxystrobin was found as the major compound in tissues and in the excreta, but hydroxylation of the trifluormethyl-phenyl moiety and other transformations, including methyl ester hydrolysis and demethylation of the methoxyimino group, were also seen. In conclusion, the major pathways of metabolism in the rat, goat, and hen were the same.

<	7. Metabolite toxicology. Metabolism of trifloxystrobin has been well characterized in plants, soil, and animals. In plants and soil, photolytically induced isomerization results in a few minor metabolites not seen in the rat; however, most of the applied materials remained as parent compound as shown in the apple and cucumber studies. All quantitatively major plant and/or soil metabolites were also seen in the rat. The toxicity of the major acid metabolite, CGA-321113 (formed by hydrolysis of the methyl ester), was evaluated in cultured rat hepatocytes and found to be 20-times less cytotoxic than the parent compound. Additional toxicity studies were conducted for several minor metabolites seen uniquely in plants and/or soil. The studies indicate that these metabolites, including CGA-357261, CGA-373466, and NOA-414412, were not mutagenic to bacteria and were of low acute toxicity (LD50 >2000 mg/kg). In conclusion, the metabolism and toxicity profiles support the use of an analytical enforcement method that accounts for parent trifloxystrobin.>

<	8. Endocrine disruption. Trifloxystrobin does not belong to a class of chemicals known for having adverse effects on the endocrine system. Developmental toxicity studies in rats and rabbits and reproduction study in rats gave no indication that trifloxystrobin might have any effects on endocrine function related to development and reproduction. The subchronic and chronic studies also showed no evidence of a long-term effect related to the endocrine system. >

<C. Aggregate Exposure>

<	1. Dietary exposure.  The most recent EPA acute and chronic dietary assessment was conducted for Registration Review (D439350, 5/31/2017), but did not include the proposed import tolerance for flax seed or current propose import tolerance on tea.  The addition of tea, dried at 5 ppm will have negligible impact on the dietary exposure previously conducted by EPA.  Assessments, using the most recent DEEM FCID Version 4.02 software, were conducted to evaluate potential risks due to chronic and acute dietary exposure of the U.S. population and selected population subgroups to residues of trifloxystrobin.  Consumption data used in this program were taken from NHANES WWEIA 2005-2010.  These analyses cover all registered crops plus the proposed import tolerance for tea, dried.

The EPA has established an acute Population Adjusted Dose (aPAD) of 2.5 mg/kg/day for acute dietary risk assessments based on a NOAEL of 250 mg/kg bw/day from a rabbit developmental toxicity study and an uncertainty factor or 100. The FQPA safety factor was reduced to 1x based on toxicological considerations, the conservative residue assumptions used in the dietary exposure risk assessments, and the completeness of the residue chemistry and environmental fate databases.  For chronic dietary analyses, the EPA established a chronic Population Adjusted Dose (cPAD) of 0.038 mg/kg/day based on a NOAEL of 3.8 mg/kg bw/day from the rat reproduction toxicity study and an uncertainty factor of 100. 

Results from the acute and chronic dietary exposure analyses described below demonstrate a reasonable certainty that no harm to the overall U.S. population or any population subgroup will result from the use of trifloxystrobin on currently registered uses plus the proposed changes tolerances. 

<	i. Food.  The acute assessments used 100% crop treated and tolerance level residue values.  The partially refined chronic assessment used percent crop treated where available, with both tolerance residue levels and average field trial residues for selected crops.  Acute exposure for food only, expressed at the 95[th] percentile of exposure, was 2.4% of the aPAD for Females 13-49 years old (only population subgroup of concern).  The chronic exposure was 8% cPAD for the Total US Population and 16% cPAD for the most sensitive population (Children 1-2 yrs. old).
>
<	ii. Drinking water. Addition of the tea import tolerance will have no impact on the previous estimation of trifloxystrobin in drinking water.  Estimated Drinking Water Concentrations (EDWCs) associated with trifloxystrobin use on all crops were calculated using PRZM-GW (ver. 1.07) and GENEEC to calculate ground water and surface water EDWCs, respectively.  The maximum acute and chronic ground water concentrations estimated by PRZM-GW were 631 ppb and 356 ppb, respectively, and were higher than the surface water estimates.  The value from the highest PRZM-GW exposure scenarios were incorporated into the dietary risk assessment.  The addition of the acute estimated drinking water concentration (EDWC) of 631 ppb resulted in 3.2% of the aPAD utilized for females 13-49 yrs. old.  The addition of the chronic EDWC of 356 ppb utilized 27% of the cPAD for the US Population and 76% of the cPAD for Infants (< 1 years old), the most highly exposed subpopulation.  In conclusion, the results of the acute and chronic dietary exposure analyses (including drinking water) are acceptable for all population subgroups examined.  Therefore, there is a reasonable certainty that no harm will result from exposure to potential residues of trifloxystrobin in food and water.>

<	2. Non-dietary exposure.  Addition of the tea import tolerance will have no impact on the non-dietary exposure to trifloxystrobin.  As such, non-dietary exposures from this change are covered by previous non-dietary risk assessments performed by EPA. 

<D. Cumulative Effects.  >EPA has determined, as published in the Federal Register (FR Vol 73, no. 1, 02-Jan-08), that unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, trifloxystrobin does not appear to produce a toxic metabolite produced by other substances. Therefore EPA has not assumed that trifloxystrobin has a common mechanism of toxicity with other substances. 

<E. Safety Determination>

<	1. U.S. population.  Risk assessments for trifloxystrobin are based on a complete and reliable toxicity data package and highly conservative assumptions. Chronic aggregate dietary (food and water) exposure will utilize about 27% of the cPAD for the US Population.  Acute aggregate dietary exposure (food and water) for the females 13-49 yrs. old (the only population of concern) utilized 3.2% of the aPAD.  Therefore, there is a reasonable certainty that no harm will occur to the US Population from aggregate exposure (food and drinking water) to residues of trifloxystrobin. >

<	2. Infants and children. EPA has determined that the toxicology database for trifloxystrobin regarding potential pre- and post-natal effects in children is complete and does not indicate any particular developmental or reproductive concerns.  The special FQPA SF has been reduced to 1X.  Using the conservative assumptions described in the exposure section above, chronic dietary exposure to residues of trifloxystrobin in food and water for Infants (< 1 years old) (the most highly exposed sub group) is 76% of the cPAD.  There is no acute endpoint of concern for children and infants.  There are no non-dietary concerns for infants and children.>

<F. International Tolerances>

	International tolerances and CODEX tolerances for trifloxystrobin are established for many crops in various countries. No MRLs exist yet in Canada or Mexico for the new proposed tolerance.