Document ID: EPA-HQ-OPP-2016-0538-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2018-07-05T04:00Z

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:

[FMC Corporation]

[XXXXXX]

	EPA has received a pesticide petition ([XXXXXX]) from [FMC Corporation], [1735 Market Street, Philadelphia, PA 19103] 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

	[F9650 (N-(3',4'-dichloro-5-fluorobiphenyl-2-yl)-3 (difluoromethyl)-1-methylpyrazole-4-carboxamide)] in or on the raw agricultural commodity [oilseed, rapeseed subgroup 20A at 0.15 ppm; cattle, fat at 0.5 ppm; cattle, kidney at 0.3 ppm; cattle, liver at 1.5 ppm; cattle, muscle at 0.15 ppm; grain, cereal, forage, fodder and straw, group 16 (except rice), forage at 4.0 ppm; grain, cereal, forage, fodder and straw, group 16 (except rice), hay at 5.0 ppm; grain, cereal, forage, fodder and straw, group 16 (except rice), stover at 6.0 ppm; grain, cereal, forage, fodder and straw, group 16 (except rice), straw at 7.0 ppm; grain, cereal, group 15 (except rice and sorghum) at 0.15 ppm; grain, aspirated fractions at 80 ppm; peanut, hay at 10.0 ppm; peanut, nutmeat at 0.02 ppm; peanut, refined oil at 0.04 ppm; poultry, eggs at 0.02 ppm; poultry, fat at 0.02 ppm; poultry, liver at 0.02 ppm; poultry, muscle at 0.02 ppm; sorghum, grain at 3.0 ppm; soybean, hulls at 0.15 ppm; soybean, seed at 0.06 ppm; vegetable, root subgroup 1A at 0.2 ppm; vegetable, tuberous and corm subgroup 1C at 0.02 ppm; sugar beet, dried pulp at 1.0 ppm and milk] at [0.1] 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 F9650 in plants is adequately understood.  Potato, soybean and wheat metabolism studies with F9650 have shown uptake of material into plant tissue with no significant movement into root, seed or grain.  All 3 plants extensively metabolized F9650 and exhibited a similar metabolic pathway.  The residues of concern are primarily the residue of the parent compound, F9650 and the metabolite F9650-desmethyl.]

	2. Analytical method. [Practical analytical methods have been developed for detecting and measuring levels of F9650 and F9650-desmethyl in or on food with a limit of quantitation (LOQ) that allows monitoring of food with residues at or above the levels proposed for the tolerances.  For the determination of the relevant residues of F9650 in plant matrices, two methods were developed, one for data collection purposes and the other for enforcement. For the data collection method, validation data were generated by High Performance Liquid Chromatography with tandem Mass Spectrometric detection (HPLC-MS/MS). For quantification, solvent standard with internal standard was used.  The LOQ was 0.01 ppm for both F9650 and F9650-desmethyl in all matrices. For the enforcement method, for quantification, matrix-matched standards were used.  The LOQ was 0.01 ppm for all matrices. For animal matrices 2 methods were also developed for data collection and for enforcement purposes.  Similar to the plant matrices method, the LOQ was 0.01 ppm for all matrices and analytes. All the methods for all the matrices consisted of solvent extraction, followed by filtration of the extract and dilution as necessary for quantitation by HPLC-MS/MS.  The LOQ for F9650 and F9650-desmethyl was defined as 0.01 ppm with the limit of detection (LOD) set at 0.001 ppm for all plant and animal matrices tested.]

	3. Magnitude of residues. [Field residue trials were conducted in the US and Canada in appropriate NAFTA zones. All applications were by foliar broadcast spray at rates and timings dependent on the crop being treated and target spray volumes of 5-20 GPA.  Raw agricultural commodities (RAC) were collected at normal harvest timings and analyzed.  RAC samples were analyzed by validated LC-MS/MS method for F9650 and the crop metabolite F9650-desmethyl.  An additional crop metabolite, M44 was analyzed for in oily crops (canola, soybean and peanut).  The proposed residue definition is F9650 plus F9650-desmethyl.

Field residue trials were conducted on the representative crops from the cereal grains crop group (except rice): sweet corn, field corn, sorghum, and wheat.  The magnitude of the residue of F9650 and its metabolite F9650-desmethyl in/on RACs of wheat (forage, hay, grain and straw), sorghum (forage, grain, and stover), sweet corn (forage, K+CWHR and stover) and field corn (forage, grain and stover) was determined following two foliar broadcast spray applications of F9650at 1X and 5X proposed maximum label use rates in target spray volumes of 5-20 GPA.  For corn and sorghum, the first application was made approximately 20 days before the last application.  The last application occurred approximately 30 days prior to harvest of sweet corn cobs and field corn/sorghum grain.  For wheat, the first application was made at approximate crop stage BBCH 25 and the last application made 30-35 days prior to normal grain harvest.  For field corn, sorghum, and wheat applications were also made at an exaggerated (5X) rate and harvested for processing following normal agronomic practices (composite bulk samples collected, processed and analyzed).  The analyses results indicate that the RAC and processed commodities' residues would not exceed the proposed tolerances.

Field residue trials were conducted on the representative crops of the root and tuber crop group, potato, sugar beet, carrot, and radish.  F9650was applied at the target 1X rate in target spray volumes of 5-20 GPA.  Four foliar broadcast spray applications were made at 5 (+-1) day (carrot and radish) and 7 (+-1) day (potato and sugar beet) intervals with the last application occurring approximately 7 days prior to normal harvest.  An exaggerated (5X) rate was also applied to potato and sugar beet, then harvested for processing following normal agronomic practices (composite bulk samples collected, processed and analyzed).  The analyses results indicate that the RAC and processed commodities' residues would not exceed the proposed tolerances.

The magnitude of the residue of F9650 and its metabolite F9650-desmethyl in/on raw and processed commodities of Canola was determined following a single foliar broadcast spray applications of F9650at the proposed maximum label use rates in target spray volumes of 5-20 GPA. Application was made at 30 +- 2days prior to normal harvest. An additional exaggerated (5X) rate was also made for processing.  Subsequent analyses of the raw agricultural and processed commodities determined that the residues of F9650 and F9650-desmethyl would not exceed the proposed tolerances.

The magnitude of the residue of F9650 and its metabolite F9650-desmethyl in/on raw and processed commodities of peanut was determined following four foliar broadcast spray applications of F9650at the proposed maximum label use rates in target spray volumes of 5-20 GPA. Applications were made at 14-day intervals with the last application occurring 14 +- 2 days prior to normal harvest. An additional exaggerated (5X) rate was also made for processing. Subsequent analyses of the raw agricultural and processed commodities determined that the residues of F9650 and F9650-desmethyl would not exceed the proposed tolerances.

The magnitude of the residue of F9650 and its metabolite F9650-desmethyl in/on raw and processed commodities of soybean was determined following two foliar broadcast spray applications of F9650at the proposed maximum label use rates in target spray volumes of 5-20 GPA. Applications were made at 12 +- 2 days intervals with the last application occurring 20 +- 2 days prior to normal harvest. An additional exaggerated (5X) rate was also made for processing.  Subsequent analyses of the raw agricultural and processed commodities determined that the residues of F9650 and F9650-desmethyl would not exceed the proposed tolerances.]

B. Toxicological Profile

	1. Acute toxicity.  [F9650 demonstrates low oral, dermal and inhalation toxicity.  The acute oral LD50 value in the rat was greater than 5000 mg/kg bw, the acute dermal LD50 value in the rat was greater than 2000 mg/kg bw and the acute inhalation LC50 value in the rat was greater than 5.383 mg/L (4h, nose only).  F9650 is non-irritating to rabbit skin and eyes.  It did not cause skin sensitization in guinea pigs.  For the Acute neurotoxicity study, test substance-related decreased motor activity (total and ambulatory counts) was noted for males and females in the 2000 mg/kg group on study day 0 (approximately 4 hours post-dosing corresponding to Cmax) and females in the 2000 mg/kg group to a lesser degree on study day 7.  The effects on motor activity observed in these groups on study day 0 occurred in conjunction with decreased rearing counts and decreased body temperature compared to the control group.  Test substance-related effects in the 1000 mg/kg group males and females were limited to decreased motor activity during the first interval (0-10 minutes) on study day 0, which corresponded to decreased rearing counts and/or lower mean body temperature.  There were no test substance-related effects on brain weights or brain dimensions for perfused animals.  In addition, no test substance-related neuropathological lesions were observed upon microscopic examination of 5 animals/sex in the 2000 mg/kg group.  There were no indications of neurotoxicity or systemic toxicity for males and females at 250 mg/kg.  Based on a slight decrease in motor activity approximately 4 hours (corresponding to Cmax) following a single oral dose of 1000 mg/kg F9650 Technical, the NOEL of a single oral dose of F9650 Technical to rats was 250 mg/kg for males and females.]

	2. Genotoxicity. [F9650 was tested in a standard battery of genotoxicity and mutagenicity tests in vitro and in vivo. There was no indication of gene mutation either in the presence or absence of metabolic activation in both the bacterial reverse mutation and mammalian gene mutation tests. The in vitro chromosome aberration test and the in vivo mouse micronucleus test were also both negative. These studies demonstrate that F9650 has no genotoxic potential.]

	3. Reproductive and developmental toxicity. [F9650 is not considered to be a reproductive or a developmental toxicant.  In the 2-generation reproduction study, the NOEL for reproductive toxicity was 169.2 mg/kg bw/day.  In the developmental toxicity studies, the rat and rabbit NOELs were 20 mg/kg bw/day and 25 mg/kg bw/day, respectively.  There is no significant gender sensitivity evident in any species.]

	4. Subchronic toxicity. [Ninety-day feeding studies were conducted in mice, rats and dogs with F9650.  The NOEL for the mouse study was 200 ppm (34.3 mg/kg/day for males; 42.9 mg/kg/day for females), for the rat study it was 200 ppm (12.9 mg/kg/day for males; 15.0 mg/kg/day for females) and for dogs it was 100 mg/kg/day for both male and female, based on 18-21% increase in relative liver weight.  The NOAEL for the dog 1-year study was 1000 mg/kg/day for males and 100 mg/kg/day for females, based on 17% liver weight increase as a ratio to brain weight and 27% as a ratio to body weight.]

	5. Chronic toxicity. [The oncogenic potential of F9650 was assessed in both the rat and the mouse.  In the rat combined chronic toxicity and carcinogenicity study, there was no significant increase in treatment-related mortality in either sex. The NOAEL over a 24-month period of dietary administration with F9650 to the Wistar rat was 50 ppm in both males and females (equivalent to 2.0 mg/kg/day in males and 2.8 mg/kg/day in females).  In the mouse carcinogenicity study, there were no clinical signs or statistically significant increases in treatment related mortality in either sex.  No treatment-related tumors were found in any tissue in either sex.  The NOEL was 50 ppm for both sexes (equating to 6.7 mg/kg/day in males and 8.6 mg/kg/day in females) based on liver weight increases with accompanying centrilobular hypertrophy.  

In the rat two-generation reproduction study, there were no treatment-related deaths or clinical signs in the study.  The NOAEL for parental systemic parameters was 50 ppm in rats (3.4 mg/kg bw/day in males, 4.0 mg/kg bw/day in females), based on liver weight increases with accompanying histopathology. The offspring NOAEL (=NOEL) was 400 ppm (34.6 mg/kg bw/day), based on decreased body weight and body weight gain.  There was no evidence of reproductive toxicity in the study, therefore the NOAEL for reproductive effects was 2500 ppm (173 mg/kg/day in males and 196 mg/kg/day in females), the highest dose tested.

In the rat developmental toxicity study, no treatment related findings occurred in the dams at necropsy.  The NOEL for maternal and fetal toxicity was 20 mg/kg/day, based on reduced fetal and maternal body weights.  In the rabbit developmental toxicity study, there were no treatment-related findings at the external, visceral, or skeletal examinations at 100 mg/kg.  At the low dose of 25 mg/kg, there were no treatment-related adverse effects on dams or fetuses.  Thus the NOEL in the dam and fetus was 25 mg/kg/day.]

	6. Animal metabolism. [The metabolism of F9650 in animals is adequately understood. F9650 was metabolized and readily eliminated following oral administration to rodent (rat), poultry (laying hen) and ruminant (lactating goat) via excreta.  All three animals exhibited a similar metabolic pathway.  As in plants, the parent chemical (F9650) was metabolized by desmethylation to predominantly form the metabolite F9650-desmethyl.  F9650 and F9650-desmethyl are considered as representative compounds for the development of a residue method for animals.]

	7. Metabolite toxicology. [NA - Remove.]

	8. Endocrine disruption. [An evaluation of the potential effects on the endocrine systems of mammals has not been determined; however, no evidence of such effects was reported in the subchronic, chronic or reproductive toxicology studies described above.  There was no observed pathology of the endocrine organs in these studies; therefore there is no risk of endocrine disruption in humans or wildlife.  There is no evidence at this time that F9650 causes endocrine effects.]

C. Aggregate Exposure

	1. Dietary exposure. [Tier 1 acute and chronic aggregate exposure assessments were performed for F9650 using Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID[TM], version 4.02; DEEM). Tolerances have been proposed for residues of F9650 for root and tuber vegetables Group 1, soybean, cereal grains Group 15/16 (except rice), peanut, and oilseeds Subgroup 20A. DEEM default adjustment factors were used for all processed commodities. No adjustments were made for "percent crop treated", i.e. 100% CT was assumed. Drinking water estimates were selected using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water. All consumption data for these assessments were taken from USDA NHANES 2-day Food Consumption Data for 2005-2010. Using the above assumptions, the resulting acute and chronic exposure estimates were aPAD <6.5% and cPAD <34.7% respectively for the most sensitive sub-population (children 1-2 years old).]

	i. Food. [Acute Dietary Exposure: The F9650 acute dietary (food only) risk assessment was performed using acute reference dose (aRfD) of 0.2 mg/kg-bw/day based upon a developmental toxicity study in the rat with a No Observable Adverse Effect Level (NOAEL) of 20 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.  At the 95th percentile, acute (food only) exposure to children 1-2 years old resulted in 0.0128 mg/kg/day which accounts for 6.4% of the aRfD of 0.2 mg/kg-bw/day.  Since the EPA generally has no concern for exposures below 100% of the aRfD, FMC concludes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from the proposed uses for F9650.

Chronic Dietary Exposure:  The F9650 chronic dietary (food only) risk assessment was performed for all population subgroups using a cRfD of 0.02 mg/kg-bw/day based upon a 2-year chronic feeding study in rats with a NOAEL of 2.00 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.  Chronic (food only) exposure to the U.S. population resulted in 0.001748 mg/kg/day which accounts for 8.7% of the RfD of 0.02 mg/kg-bw/day.  The most exposed sub-population was children 1-2 years old with 0.006898 mg/kg/day which accounts for 34.5% of the RfD of 0.02 mg/kg-bw/day.  Since the EPA generally has no concern for exposures below 100% of the RfD, FMC concludes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from the proposed uses for F9650.]

	ii. Drinking water. [The Estimated Drinking Water Concentrations (EDWCs) of F9650 were determined using Tier I/II PRZM-GW which estimates pesticide concentration in ground water and Tier I FIRST which estimates pesticide concentration in surface water.  EDWCs of F9650 from the proposed uses on root and tuber vegetables Group 1, soybean, cereal grains Group 15/16 (except rice), peanut, and oilseeds Subgroup 20A were determined.  Based on the proposed use on potato, FIRST modeling provided the highest surface water EDWCs of 4.399 ppb for acute and 1.297 ppb for chronic.  Since the surface water EDWCs exceeded the ground water EDWC, the surface water values were used for risk assessment purposes and will be considered protective for any ground water exposure concerns.

Acute Exposure from Drinking Water:  The acute surface water EDWC of 4.399 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 to U.S. population resulted in 0.0001 mg/kg/day which accounts for <1% of the aRfD of 0.2 mg/kg-bw/day.  The most exposed sub-population was children 1-2 years old with 0.00006 mg/kg/day which accounts for <1% of the aRfD of 0.2 mg/kg/day.  Since the EPA generally has no concern for exposures below 100% of the aRfD, FMC concludes that there is a reasonable certainty that no harm will result from acute drinking water exposure to residues arising from the proposed uses for F9650.

Chronic Exposure from Drinking Water:  The chronic surface water EDWC of 1.297 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 0.000026 mg/kg/day which accounts for <1% of the cRfD of 0.02 mg/kg-bw/day.  Chronic drinking water exposure to the most exposed sub-population was children 1-2 years old with 0.000036 mg/kg/day which accounts for <1% of the cRfD of 0.02 mg/kg-bw/day.  Since the EPA generally has no concern for exposures below 100% of the cRfD, FMC concludes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from the proposed uses for F9650.]

	2. Non-dietary exposure. [Not applicable]

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".  EPA consideration of a common mechanism of toxicity is not appropriate at this time since EPA does not have information to indicate that toxic effects produced by F9650 would be cumulative with those of any other chemical compounds; thus only the potential risks of F9650 are considered in this exposure assessment.]

E. Safety Determination

	1. U.S. population. [Using the conservative exposure assumptions described and based on the completeness and reliability of the toxicity data, the aggregate exposure to F9650 will utilize 2.6% of the aPAD and 8.9% of the cPAD for the general US population.  EPA generally has no concern for exposures below 100 percent of the aPAD or cPAD.  Therefore, based on the completeness and reliability of the toxicity data and the conservative exposure assessment, there is a reasonable certainty that no harm will result from aggregate exposure to residues of F9650, including all anticipated dietary exposure and all other occupational exposures.]

	2. Infants and children. [Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the acute aggregate (food plus water) exposure calculation for all proposed uses of F9650 provided 6.46% (aPAD) and 34.7% (cPAD) for children 1-2 years old.  Since the EPA generally has no concern for exposures below 100% of the cRfD or aRfD, FMC concludes that there is a reasonable certainty that no harm will occur to infants and children from aggregate exposures arising from all proposed uses for F9650.]

F. International Tolerances [No international tolerances have been established under Codex Alimentarius Commission (CODEX) Maximum Residue Levels (MRLs) for F9650. In this F9650 NAFTA joint registration application, the current tolerance petition includes root and tuber vegetables Group 1, soybean, cereal grains Group 15/16 (except rice), peanut, and oilseeds Subgroup 20A.]