Document ID: EPA-HQ-OPP-2019-0130-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2019-12-30T05:00Z

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

<EPA Registration Division contact: Hope Johnson, (703)305-5410

>
<Bayer CropScience >

< 8F8729 >

<	EPA has received a pesticide petition (8F8729) 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. >

   <	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 dried shelled pea and bean (except soybean) subgroup 6C at 0.06 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 residue of concern for tolerance setting purposes. >

<	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 LODs for trifloxystrobin range from 0.002 ppm to 0.01 ppm, depending on the crops, and the LOQ of each analyte is 0.01 ppm. >

<	3. Magnitude of residues.  Nine field-residue trials (eight harvest, one decline) were established across Canada (three trials in Crop Growing Region 5, three in Crop Growing Region 7, one in Crop Growing Region 7A and two in Crop Growing Region 14) where dry beans are commonly grown.

The treated plot received two foliar applications of FOX 325 SC at 0.88 L FOX 325 SC/ha/application (286 g ai/ha/application) for a total target seasonal rate of 572 g ai/ha.  Although for this study only trifloxystrobin residue data is being reported, FOX 325 SC active ingredient is comprised of 150 g trifloxystrobin/L and 175 g prothioconazole/L. The corresponding target rate for trifloxystrobin was 132 g trifloxystrobin/ha/application for a total seasonal rate of 264 g trifloxystrobin/ha.

Crop growth stages ranged from BBCH 60 (first flowers opened) to BBCH 65 (full flowering, 50% flowers open) for the first applications.  The second applications, which occurred 10 to 14 days later, were made at BBCH 65 (full flowering) to BBCH 77 (about 70% of pods have reached final length).

Mature dry bean seed was collected in the eight harvest trials at pre-harvest intervals (PHIs) of 28 to 32 days following the last application.  Seed was collected in the single decline trial at PHIs of 21, 25, 29, 36, and 40 days.  Mature dry bean seed was collected from the control plot at the same time the 30-day samples were collected from the treated plot.  Samples were placed in frozen storage within 6 hours after collection.

All samples were stored and transported under deep freeze and remained frozen until subjected to chemical extraction and analysis at the analytical facility.

The samples were analyzed for residue of total trifloxystrobin (sum of trifloxystrobin and trifloxystrobin acid).  The residue of total trifloxystrobin was quantitated by high-pressure liquid chromatography/triple stage quadrupole mass spectrometry (LC/MS/MS) using stable-labeled internal standards.  The LOQ for total trifloxystrobin residue was 0.02 ppm in dry bean seed.

Total trifloxystrobin residue ranged from <0.020 ppm to a maximum of 0.023 ppm for individual samples collected at the desired PHI of 30 days. The HAFT residue found in the nine trials comprising this study was 0.023 ppm.

Total trifloxystrobin residue in the decline trial declined slightly with time, from a maximum average residue of 0.031 ppm at 21 DAT to 0.021 ppm by 40 DAT.

An additional four field-residue trials (one harvest, three decline) were conducted in NAFTA Growing Regions 8, 9, 10 and 11 to measure the magnitude of trifloxystrobin residues in/on dry beans following two applications of Stratego YLD.  Stratego YLD is a suspension concentrate formulation containing 375 g/L trifloxystrobin and 125 g/L prothioconazole.

The treated plots received two foliar spray applications at individual application rates of 130 g trifloxystrobin/ha/application.  Total seasonal application rates ranged from 258 to 269 g trifloxystrobin/ha.  The first applications were made between BBCH growth stages 62 and 71 (BBCH 62: 20% of flowers open; BBCH 71: 10% of pods have reached typical length, beginning of pod development).  The interval between applications was 12 to 13 days.  The spray volumes ranged from 14 to 19 gal/A (131 to 177 L/ha).  All applications were made using ground-based equipment.  An adjuvant (Induce or Induce PH) was used in all applications, at a rate of 0.12 to 0.13 % v/v.

At each sampling interval, duplicate composite samples (two separate runs through the plot) of dry seed (also called dry bean) raw agricultural commodities (RACs) were harvested from treated plot TRTD (BBCH 89, dry seed was fully ripe, to BBCH 99, harvested product).  In the harvest trial, dry seed samples were collected at a 28-day PHI.  In the decline trials, dry seed samples were collected at PHIs of 21, 25, 29 to 30, 35 to 36, and 39 to 40 days.

Single composite samples of dry seed were harvested from the control plot of each trial on the same day that the 28- to 30-day PHI samples were harvested from the treated plots.

For the collection of dry seed, beans were shelled in the field at the time of bagging. In some trials, bean plants were cut and allowed to dry in the field for up to 23 days to reach commercial dryness prior to shelling and bagging.  The residues of Stratego YLD (trifloxystrobin and trifloxystrobin acid, also called CGA 321113) were quantitated by high performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) using stable, isotopically-labeled internal standards. The individual analyte residues were summed to give a total trifloxystrobin residue.

Following 2 foliar applications of Stratego YLD to dry beans at a total seasonal rate ranging from 258 to 269 g trifloxystrobin/ha, the total trifloxystrobin residues in dry bean seed collected at a 28- to 30-day PHI ranged from less than the LOQ (<0.020 ppm) to 0.025 ppm.

In the residue decline trials, mean residue levels remained below the LOQ or generally declined with time.

<B. Toxicological Profile>

<	1. Acute toxicity.  There is a full battery of acute toxicity studies for trifloxystrobin. Trifloxystrobin is of low acute toxicity by oral, dermal, or inhalation routes of exposure (Cat. IV), however it is a strong dermal sensitizer. Trifloxystrobin is a mild ocular (Cat III) and dermal irritant (Cat IV). >

<	2. Genotoxicty. Trifloxystrobin has been tested for its potential to induce gene mutation and chromosomal changes in five different test systems. The only positive finding was seen in an in vitro gene mutation assay in Chinese hamster V79 cells as a slight increase in mutant frequency at a very narrow range (250  -  278 g/mL) of cytotoxic and precipitating concentrations (compound solubility in water was reported to be 0.61 g/mL; precipitate was visually noted in culture medium at 150 g/mL).  The chemical was found to be not genotoxic in all other in vitro and in vivo assay systems. Consequently, the limited gene mutation activity in the V79 cell line is considered a nonspecific effect under non-physiological in vitro conditions and not indicative of a real mutagenic hazard. >

<	3. Reproductive and developmental toxicity. In a developmental study in rats, reductions in body weight gain and food consumption were observed in the dams at 100 mg/kg/day. No teratogenic effects or any other effects were seen on pregnancy or fetal parameters. The maternal and developmental NOAELs were 10 and 1000 mg/kg/day, respectively.

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

	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. Consequently, the reduced pup weight gain during lactation (750 ppm) and the slight delay in eye opening (1500 ppm; 110.6 mg/kg/day) were judged to be a secondary effect of maternal toxicity. No other fetal effects or any reproductive changes were noted.  Both the parental and offspring NOAELs were 50 ppm (3.8 mg/kg/day). The reproductive NOAEL was 1500 ppm (110.6 mg/kg/day). >

<	4. Subchronic toxicity. In a subchronic study in rats, a NOAEL of 500 ppm [30.6 (M) and 32.8 (F) mg/kg/day] was found based on decreased body weights (males), hypertrophy of hepatocytes (males), and pancreatic atrophy observed at the LOAEL of 2000 ppm [127 (M) and 133 (F) mg/kg/day].

In mice, a NOAEL was determined at 500 ppm [76.9 (M) and 110 (F) mg/kg/day] based on increased liver weights and necrosis of hepatocytes observed at the LOAEL of 2000 ppm [315 (M) and 425 (F) mg/kg/day].

A subchronic feeding study in dogs resulted in a NOAEL of 30 mg/kg/day. Increased liver weight and hepatocyte hypertrophy in males were observed at the LOAEL of 150 mg/kg/day. 

In a 28 - day dermal toxicity study in rats, the NOAEL was 1000 mg/kg/day, the highest dose level tested. >

<	5. Chronic toxicity. A chronic toxicity study in dogs established a NOAEL of 5 mg/kg/day. The LOAEL of 50 mg/kg/day was based on clinical signs, increased liver weight and hepatocellular hypertrophy. 

In a carcinogenicity study in mice, liver effects were observed at doses at and above the LOAEL of 1000 ppm [131.1 (M) and 124.1 (F) mg/kg/day]. The NOAEL was determined to be 300 ppm [39.4 (M) and 35.7 (F) mg/kg/day].

A chronic toxicity/carcinogenicity study in rats established a NOAEL of 250 ppm [9.81 (M) and 11.37 (F) mg/kg/day]. Decreased mean body weight and decreased mean body weight gain (compared to control) were observed at the LOAEL of 750 ppm [29.7 (M) and 34.5 (F) mg/kg/day].

Trifloxystrobin did not cause any treatment-related increase in general tumor incidence, any elevated incidence of rare tumors, or shortened time to the development of palpable or rapidly lethal tumors in the 18-month mouse and the 24-month rat studies.  EPA determined that trifloxystrobin should be classified as "Not Likely to be Carcinogenic to Humans" based on the lack of evidence for carcinogenicity in rats and mice.  >

<	6. Animal metabolism. Trifloxystrobin is moderately absorbed from the gastrointestinal tract of rats and is rapidly distributed. Subsequent to a single oral dose, the elimination half-life is about 2 days and excretion is primarily via bile. Trifloxystrobin is extensively metabolized by the rat into about 35 metabolites, but the primary actions are on the methyl ester (hydrolysis into an acid), the methoxyimino group (O-demethylation), and the methyl side chain (oxidation to a primary alcohol). Metabolism is dose dependent as it was almost complete at low doses but only about 60% complete at high doses.

In the goat, elimination of orally administered trifloxystrobin is primarily via the feces. The major residues were the parent compound and the acid metabolite (CGA-321113) plus its conjugates. In the hen, trifloxystrobin is 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, are also seen. In conclusion, the major pathways of metabolism in the rat, goat, and hen are 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 material 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), has been 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, are not mutagenic to bacteria and are 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 effects 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).  This assessment already included tolerance for dry peas, but did not include the proposed import tolerance for flax seed or current proposed tolerance on dry beans.  The addition of dry beans at 0.06 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 use on dry peas and beans.

A dietary assessment was evaluated based on established tolerances for all registered uses and 100% crop treated.  For the proposed use on dry peas and beans, the proposed tolerance of 0.06 ppm was used in this assessment.  Dry peas and beans can be used as alternative feedstuff serving as a source of roughage and protein.  The proposed uses are not feed to feedlot beef.  Addition of the proposed uses on feed items will have minimal effect on total burden for dairy cattle.  The current risk assessments are based on established livestock tolerances (milk = 0.02 ppm) which are more conservative than residues estimated from Maximum Reasonably Balanced Diets (MRBD).  

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 by the FQPA Safety Factor Committee (HED Doc. No. 013545, B. Tarplee, 01/JUL/1999), the conservative residue assumptions used in the dietary exposure risk assessments, and the completeness of the residue chemistry and environmental fate databases (DP Num: 3 17330, B. O'Keefe,1 6/AUG/2006).  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 uses on dry peas and beans. 

<	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 dry beans and peas 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. There is no potential for dermal or incidental oral exposure during or post application of trifloxystrobin when applied to dry peas and beans.   As such, non-dietary exposure from this new tolerance is covered by previous non-dietary risk assessments performed by EPA. As published in the Federal Register (FR Vol 68, no. 175, 10-Sep-03, FR Vol 73, no. 1, 02-Jan-08), the EPA considered chronic, short term and intermediate term risk from residential uses of trifloxystrobin. The EPA determined that the risk did not exceed the Agency's level of concern.

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. No indication of increased susceptibility of rat or rabbit fetuses to in utero and/or postnatal exposure was noted in the developmental and reproductive toxicity studies.  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 and CODEX tolerances (MRLs) for trifloxystrobin are established for many crops in various countries including dry peas and beans.