Document ID: EPA-HQ-OPP-2017-0417-0016
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2018-03-06T05:00Z

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

EPA Registration Division contact: [Shaja Joyner, PM 20 (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, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[FMC Corporation]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from [FMC Corporation], [1735 Market St., 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

	[valifenalate (Methyl N-(isopropoxycarbonyl)-L-valyl-(3RS)-3-(4-chlorophenyl)- β  - alaninate)] in or on the raw agricultural commodity potato at 0.01; fruiting vegetable crop group 8-10 at 0.50; tomato-wet peel at 0.9; bulb vegetable crop group 3-07 at 0.40; cucurbit crop group 9 at 0.30; celery at 5.0; and grape import tolerance at 5.0 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. Valifenalate metabolism in plants was studied in grapes, potato, tomato and lettuce covering fruits, root and tuber vegetables and leafy crop groups. Valifenalate was not extensively metabolized in the crop matrices (RACs) analyzed. Majority of the parent compound remained unchanged with formation of a few minor non-significant metabolites. In addition, there was no change in the ratio of isomers (S,R/S,S). 

	A confined rotational crop (CRC) study with Valifenalate in leafy crop (lettuce), root crop (carrot) and cereal crop (wheat) was conducted at an exaggerated application rate of 1.4 kg a.i./ha. The total radioactive residue (TRR) in the crops was less than 0.03 mg/kg in all RACs of human consumption, and valifenalate was found at low levels only in carrot leaves and wheat straw matrices. Valifenalate metabolic pathway in rotational crops was similar to that of primary crops. 
	
	2. Analytical method. There is a practical analytical method for detecting and measuring levels of valifenalate and its metabolite in or on crop matrices and processed commodities.  The analytical method has a limit of quantitation that allows monitoring of food with residues at or above the levels set in the tolerances.  The analytical enforcement method for valifenalate was used with minor modifications to match the analytical laboratory equipment parameters and to optimize chromatography.  The analytical method for valifenalate involves sequential solvent extractions followed by dilution and analysis by LC/MS/MS.  Valifenalate and the metabolite valifenalate acid are separated by the same analytical method and quantitated using matrix matched standards.   

	3. Magnitude of residues. Field residue trials were conducted on potatoes.  Three (3) applications of valifenalate formulated as a WG were applied at a nominal rate of 150 g/ha.  The test substance was applied at 5 day intervals with the last application 7 days prior to potato harvest.  Twenty six (26) field residue trials were performed on potatoes in NAFTA regions 1, 2, 3, 5, 7, 9, 10, 11, and 14.  Residues in harvested potatoes ranged from below the limit of detection (ND) to 0.009 ppm.  An exaggerated rate (5X) trial was conducted to determine residues in processed commodities wet peel, peeled potatoes, dried pulp, granules/flakes, and chips.  Valifenalate residues were less than the LOQ in all processed commodities.

Field residue trials were conducted on grapes.  Fifteen trials were conducted in the United States and Canada.  Three (3) applications of valifenalate formulated as a WG were applied at a nominal rate of 150 g/ha.  The test substance was applied at 10 day intervals with the last application 14 days prior to fruit harvest.  Fifteen (15) field residue trials were performed on grapes in NAFTA regions 1, 5, 10, and 11.  Residues in harvested grapes ranged from 0.031  -  1.77 ppm.  Six trials were previously conducted in Argentina in 2008 and 2011.  Three to four (3-4) applications of valifenalate formulated as a WG were applied at a nominal rate of 180 g/ha.  The test substance was applied at 7-14 day intervals with the last application 21 days prior to fruit harvest.  Valifenalate residues in harvested grapes ranged from 0.64  -  2.92 ppm.  Fourteen trials were previously conducted in Europe (France, Italy, and Germany) from 2003  -  2005.  Three applications of valifenalate formulated as a WG were applied at a nominal rate of 120 g/ha.  The test substance was applied at a 12-14 day interval with the last application 28 days prior to fruit harvest.  Valifenalate residues in harvested grapes ranged from <0.010  -  0.121 ppm. 

Field residue trials were conducted on the representative crops of the bulb vegetable crop group 3-07 (green onion and bulb onion).  Three (3) applications of valifenalate formulated as a WG were applied at a nominal rate of 150 g/ha.  The test substance was applied at 7 day intervals with the last application 7 days prior to onion harvest.  Five (5) field residue trials were performed on green onions in NAFTA regions 5, 6, and 10.    Valifenalate residues in harvested green onions ranged from 0.038  -  0.340 ppm.  Nine (9) field residue trials were performed on bulb onions in NAFTA regions 1, 5, 6, 8, 10, and 11.  Valifenalate residues in harvested bulb onions ranged from 0.011  -  0.117 ppm.  

Field residue trials were conducted on celery.  Three (3) applications of valifenalate formulated as a WG were applied at a nominal rate of 150 g/ha.  The test substance was applied at 7 day intervals with the last application 1 day prior to vegetable harvest. Ten (10) field residue trials were performed on celery in NAFTA regions 3, 5, and 10.  Valifenalate residues in harvested celery ranged from 0.054  -  3.47 ppm.  

Field residue trials were conducted on the representative crops of the fruiting vegetable crop group 8-10 (tomatoes, bell peppers, non-bell peppers).  Three (3) applications of valifenalate formulated as a WG were applied at a nominal rate of 150 g/ha.  The test substance was applied at 7 day intervals with the last application 1 day prior to vegetable harvest.  Nineteen (19) field residue trials were performed on tomatoes in NAFTA regions 1, 2, 3, 5, and 10.  Valifenalate residues in harvested tomatoes ranged from ND  -  0.161 ppm.    An exaggerated rate (5X) trial was conducted to determine residues in processed commodities paste, puree, washed tomatoes, and wet peel.  Valifenalate residues concentrated 5.8X in wet peel.  Valifenalate did not concentrate significantly in the other tomato processed commodities.  Ten (10) field trials were performed on bell peppers in NAFTA regions 2, 3, 5, 6, and 10.  Valifenalate residues in harvested bell peppers ranged from 0.0089  -  0.300 ppm.  Three (3) field trials were performed on non-bell peppers in NAFTA regions 8, 9, and 10.  Valifenalate residues in harvested non-bell peppers ranged from <LOQ  -  0.470 ppm.

Field residue trials were conducted on the representative crops of the cucurbit vegetable crop group 9 (cucumbers, muskmelon, summer squash).  Three (3) applications of valifenalate formulated as a WG were applied at a nominal rate of 150 g/ha.  The test substance was applied at 7 day intervals with the last application 1 day prior to vegetable harvest.  Nine (9) field residue trials were performed on cucumbers in NAFTA regions 2, 3, 5, and 6.  Valifenalate residues in harvested cucumbers ranged from 0.010  -  0.090 ppm.  Ten (10) field residue trials were performed on muskmelon in NAFTA regions 2, 5, 6, and 10.  Valifenalate residues in harvested muskmelon ranged from 0.018  -  0.193 ppm.  Nine (9) field residue trials were performed on summer squash in NAFTA regions 1, 2, 3, 5, and 10.  Valifenalate residues in harvested summer squash ranged from ND  -  0.126 ppm. 

B. Toxicological Profile

	1. Acute toxicity.  Valifenalate demonstrates low oral, dermal and inhalation toxicity.  The acute oral LD50 value in the rat was greater than 5000 mg/kg, the acute dermal LD50 value in the rat was greater than 2000 mg/kg and the acute inhalation LC50 value in the rat was greater than 3.118 mg/L/4h.  Valifenalate is non-irritating to rabbit skin and to rabbit eyes.  It did not cause skin sensitization in guinea pigs.  An acute neurotoxicity study in the rat had a NOAEL for neurotoxicity greater than 2000 mg/kg (highest dose tested) based on the lack of neurotoxic clinical signs or effects on neuropathology. 

	2. Genotoxicty. Valifenalate did not cause mutations in the Ames assay with or without metabolic activation.  The Chromosome Aberration and Mouse Lymphoma (forward gene mutation) Assays were negative with and without S9 activation.  The Mouse Micronucleus assay in bone marrow cells (an in vivo test which also measures chromosome damage), was negative.  

	3. Reproductive and developmental toxicity. Valifenalate is not considered to be a reproductive or a developmental toxicant.  In the 2-generation reproduction study, the NOAEL for parental, reproductive, and developmental toxicity was greater than 1250/850 ppm (greater than 80-100 mg/kg/day).  In the developmental toxicity studies, the rat and rabbit maternal and fetal NOAELs were greater than 1000 mg/kg/day (highest dose tested).  

	4. Subchronic toxicity. Ninety-day feeding studies were conducted in mice, rats and dogs with valifenalate.  The NOAEL for the mouse study was 110 ppm (15.3 mg/kg/day) based on decreased body weight gain; for the rat study the NOAEL was 150 mg/kg/day based on distended caecum, and adaptive changes in liver and kidney; and for the dog study the NOAEL was < 50 mg/kg/day (no NOAEL could be established) based on liver and thyroid alterations.  A 90-day subchronic neurotoxicity study was not conducted in the rat. 

	5. Chronic toxicity. A 2-Year Combined Chronic Toxicity/Oncogenicity study in the rat was negative for carcinogenicity and had a chronic toxicity NOAEL of 150 mg/kg/day in males and females based on slight anemia in males and pelvic epitheliar hyperplasia in females. There is no carcinogenic potential in rat.  An 18 Month Oncogenicity study in the mouse had a NOAEL greater than 150 ppm (>16.8 mg/kg/day for males; >21.6 mg/kg/day for females) based on increased incidence of hepatocellular tumors evident in both males and females. Additional mode of action studies support rodent specific tumors. The increased incidence of hepatocellular tumors was secondary to adaptive metabolic changes. Such findings are observed commonly in mice and are generally considered of no significance for man.  A 1-Year Oral Toxicity study in the dog had a NOEL of 7 mg/kg/day based on changes in clinical chemistry, and liver and thyroid alterations.

Using the Guidelines for Carcinogen Risk Assessment, valifenalate should be classified as "not likely to be carcinogenic". 

	6. Animal metabolism. In rat ADME studies, valifenalate absorption was about 80%. Excretion was rapid (>99%, within 48 hrs) and it was mainly via bile. There was no evidence for accumulation in tissues. Liver and kidneys had higher concentrations of radioactivity compared to rest of the tissues. Valifenalate was extensively metabolized (> 90%) through ester hydrolysis, hydroxylation and side-chain cleavage. Valifenalate acid and 3-amino-3-(4-chlorophenyl)propionic acid) were the main metabolites. 

In a metabolism study with lactating goat, valifenalate reached plateau concentrations within 8 hrs in milk. The concentrations of radioactivity in milk were low. Valifenalate excreted primarily via feces (~ 68%). Liver and kidneys were found to have the highest residues with very low concentrations in muscle. The compound was not fat soluble. Metabolism in rat and live-stock was similar. 

	7. Metabolite toxicology. Two relevant metabolites have been identified: IR5839 (valifenalate acid) and PCBA. For IR5839, the acute oral LD - 50 > 2000 mg/kg bw and had no genotoxic potential (3 in vitro and 1 in vivo studies). For PCBA, the acute oral LD - 50 > 1170 mg/kg bw and had no genotoxic potential (3 in vitro and 1 in vivo studies).

	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.  There is no evidence at this time that valifenalate causes an endocrine effect.

C. Aggregate Exposure

	1. Dietary exposure. Acute and chronic dietary exposure assessments were performed for valifenalate using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02), which incorporates food consumption data from the National Health and Nutrition Examination Survey)/"What We Eat in America" (NHANES/WWEIA) dietary survey for the years 2005-2010. The residues of concern for risk assessment in plant commodities are parent valifenalate and valifenalate acid. The residues of concern for risk assessment in drinking water are parent valifenalate, valifenalate acid and PCBA (p-Chlorobenzoic acid). The acute and chronic analyses were based on tolerance-level residues and 100% crop treated assumptions for all commodities. Default DEEM processing factors were used for all processed commodities. Drinking water estimates were incorporated directly into the acute and chronic dietary exposure assessments using the highest estimated drinking water concentrations (EDWCs) from surface and ground water.

	i. Food. The acute dietary (food only) risk assessment for valifenalate was performed for all population subgroups using an acute reference dose (aRfD) of 10 mg/kg/day based upon a developmental toxicity study in rats with a no observed adverse effect level (NOAEL) of 1000 mg/kg/day and an uncertainty factor of 100X to account for intra- and inter-species variations. No additional FQPA safety factor was applied. The acute population adjusted dose (aPAD) is equivalent to the aRfD of 10 mg/kg/day. At the 95[th] percentile, the acute (food only) exposure for total U.S. population was estimated to be 0.15% of the aPAD. The population subgroup with the highest acute dietary (food only) exposure was children 1-2 years old, estimated to be 0.67% of the aPAD. Since the EPA generally has no concern for exposures < 100% of the aPAD, there is reasonable certainty that no harm will result from acute dietary (food only) exposure to residues arising from all proposed uses of valifenalate.

The chronic dietary (food only) risk assessment for valifenalate was performed for all population subgroups using a chronic reference dose (cRfD) of 0.07 mg/kg/day based upon a 1-year oral toxicity study in dogs with a no observed adverse effect level (NOAEL) of 7 mg/kg/day and an uncertainty factor of 100X to account for intra- and inter-species variations. No additional FQPA safety factor was applied. The chronic population adjusted dose (cPAD) is equivalent to the cRfD of 0.07 mg/kg/day. The chronic (food only) exposure for total US population was estimated to be 5.3% of the cPAD. The population subgroup with the highest acute dietary (food only) exposure was children 1-2 years old, estimated to be 22.4% of the cPAD. Since the EPA generally has no concern for exposures < 100% of the cPAD, there is a reasonable certainty that no harm will result from chronic dietary (food only) exposure to residues arising from all proposed uses of valifenalate.

	ii. Drinking water. The estimated drinking water concentrations (EDWCs) of valifenalate and its degradates valifenalate acid and PCBA, reported as combined total residues of valifenalate, were determined for currently proposed uses. The Tier I FQPA Index Reservoir Screening Tool (FIRST) was used to estimate surface water EDWCs, and the Tier 1 Pesticide Root Zone Model for Ground Water (PRZM-GW) was used to estimate ground water EDWCs. For surface water, the proposed use on potatoes (3 applications x 0.133 lb ai/A with 5-day spray interval) provided a combined acute EDWC of 30.489 ppb and a combined chronic EDWC of 7.246 ppb. For ground water, the maximum proposed use rate of 0.4 lb ai/A/season (3 applications x 0.133 lb ai/A) was used for the six standard EFED vulnerable groundwater scenarios in PRZM-GW. The highest ground water EDWCs were estimated to be 6.96 ppb (acute) and 2.04 ppb (chronic). Since the surface water EDWCs exceeded the ground water EDWCs, surface water EDWCs were used for risk assessment purposes and considered protective for ground water exposure concerns. The acute EDWC (30.489 ppb) and chronic EDWC (7.246 ppb) in surface water were incorporated directly into this dietary assessment in the DEEM-FCID into the food categories "water, direct, all sources" and "water, indirect, all sources".

	2. Non-dietary exposure. There is no residential use proposed for valifenalate. Therefore, a non-dietary exposure assessment was not performed.

D. Cumulative Effects

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

E. Safety Determination

	1. U.S. population. The acute aggregate dietary exposure (food and drinking water) was estimated to be 0.16% of the aPAD for total U.S. population. The chronic aggregate dietary exposure (food and drinking water) was estimated to be 5.5% of the cPAD for total U.S. population. The EPA generally has no concern for exposures below 100% 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 dietary exposure to residues of valifenalate from food and water.

	2. Infants and children. The acute aggregate dietary exposure (food and drinking water) was estimated to be 0.67% of the aPAD for children 1-2 years old, the most sensitive population subgroup. The chronic aggregate dietary exposure (food and drinking water) was estimated to be 22.7% of the cPAD for the most sensitive population subgroup of children 1-2 years old. The EPA generally has no concern for exposures below 100% 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 to infants and children from aggregate dietary exposure to residues of valifenalate from food and water.

F. International Tolerances 
No Codex MRLs have been established for valifenalate.  European Union MRLs have been set on grapes, tomatoes and eggplant.  No Canadian MRLs exist at this time.