Document ID: EPA-HQ-OPP-2019-0346-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2020-06-29T04:00Z

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

EPA Registration Division contact: [Lindsay Roe, (703-347-0506)]

[Syngenta Crop Protection, LLC]

[9F8759]

	EPA has received a pesticide petition [9F8759] from [Syngenta Crop Protection, LLC], [410 Swing Road, Greensboro, NC 27409] 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

   	1. by establishing a tolerance for residues of

	[Mefenoxam: methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate] in or on the raw agricultural commodity [Tree Nut Group 14-12] at [0.3] 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 mefenoxam is adequately understood for the purpose of the proposed tolerance.]

	2. Analytical method. [Pecan nut: The analytical method used was Syngenta Crop Protection Analytical Method "Link K (2016) Metalaxyl - Analytical Method GRM075.01A for the Determination of Residues of Metalaxyl and Structurally Related Metabolites as Common Moiety 2,6-Dimethylaniline (CGA72649) in Crops" with EAG method modifications dated August 14, 2017.]

	3. Magnitude of residues. [Complete residue data to support the requested tolerances have been submitted. The requested tolerances are adequately supported by previously submitted studies. In support of the requested tolerances, Syngenta has conducted the necessary trials in accordance with the requirements of the EPA Residue Chemistry Guidelines 860.1500 to determine the magnitude of residue of mefenoxam in or on requested commodities.]

 B. Toxicological Profile

 1. Acute toxicity. [The toxicological endpoints for mefenoxam are discussed in EPA 2018 Metalaxyl, Mefenoxam (Metalaxyl-M): Human Health Draft Risk Assessment for Registration Review, Jun 5, 2018, Decision Number 532065. The acute toxicity profile can be summarized as follows:
 Mefenoxam has a low to moderate acute toxicity. The combined acute oral rat LD50 is 1269 mg/kg. The acute dermal rat LD50 is >2,000 mg/kg and the acute inhalation rat LC50 is >2.29 mg/L. Mefenoxam is a corrosive acute eye irritant in the rabbit and a mild acute dermal irritant in the rabbit. Mefenoxam is not a dermal sensitizer in the guinea pig.]

 2. Genotoxicty. [The toxicological endpoints for mefenoxam are discussed in EPA 2018 Metalaxyl, Mefenoxam (Metalaxyl-M): Human Health Draft Risk Assessment for Registration Review, Jun 5, 2018, Decision Number 532065. A battery of mutagenicity and genotoxicity studies is available to summarize the genotoxicity profile of metalaxyl and mefenoxam as follows:
    In vitro gene mutation test: Ames test-negative.
    In vitro chromosomal aberration test: Chinese hamster ovary (CH0)-negative.
    In vitro gene mutation tests: Ames tests (3 independent studies)- negative;
       gene mutation in mouse lymphoma cells-negative; reverse mutation in saccharomyces cerevisiae-negative.
       In vitro chromosomal aberration tests: Chinese hamster bone marrow cytogenetic test-negative. DNA repair study in rat hepatocytes-negative.]

 3. Reproductive and developmental toxicity. [The toxicological endpoints for mefenoxam are summarised in EPA 2018 Metalaxyl, Mefenoxam (Metalaxyl-M): Human Health Draft Risk Assessment for Registration Review, Jun 5, 2018, Decision Number 532065. The reproductive and developmental toxicity profile can be summarized as follows:
    Metalaxyl:
    The studies available for risk assessment include an acute toxicity battery; 28-day oral toxicity studies in rats and mice; subchronic oral toxicity studies in rats, mice, and dogs; subchronic dermal toxicity studies in rabbits; chronic toxicity studies in rats and dogs; carcinogenicity studies in rats and mice; prenatal developmental toxicity studies in rats and rabbits; a reproduction and fertility effects study in rats; a battery of mutagenicity and genotoxicity studies; and metabolism and pharmacokinetic studies in rats.
    Mefenoxam:
    The studies available for risk assessment include an acute toxicity battery; 28-day oral toxicity studies in rats; subchronic oral toxicity studies in rats and dogs; a prenatal developmental toxicity study in rats; a battery of mutagenicity and genotoxicity studies; a range-finding acute neurotoxicity study in rats; a subchronic neurotoxicity study in rats; and an immunotoxicity study in rats.
 The database is considered adequate since the mefenoxam studies that were not submitted are addressed by their respective metalaxyl studies (e.g., prenatal developmental toxicity study in rabbits, cancer studies, etc.)]

 4. Subchronic toxicity. [The toxicological endpoints for mefenoxam are discussed in EPA 2018 Metalaxyl, Mefenoxam (Metalaxyl-M): Human Health Draft Risk Assessment for Registration Review, Jun 5, 2018, Decision Number 532065. The subchronic toxicity profile can be summarized as follows:
          In rat and dog repeat dose (i.e., subchronic) oral toxicity studies, there were no indications of adverse effects up to the highest dose tested (HDT). There was no evidence of increased susceptibility in the available rat prenatal developmental toxicity study for mefenoxam. There was no indication of maternal or developmental toxicity in the study.]

 5. Chronic toxicity. [The toxicological endpoints for mefenoxam are discussed in EPA 2018 Metalaxyl, Mefenoxam (Metalaxyl-M): Human Health Draft Risk Assessment for Registration Review, Jun 5, 2018, Decision Number 532065. The chronic toxicity profile can be summarized as follows:
          A 24-month combined chronic toxicity/carcinogenicity study conducted in rats with a NOAEL of 250 ppm based on liver changes. No evidence of oncogenicity was seen.
          A 24-month oncogenicity study conducted in mice with a NOAEL of 250 ppm based on liver changes. No evidence of oncogenicity was seen.]

 6. Animal metabolism. [The rat and goat rapidly metabolize and excrete via the same metabolic pathways as plants. Urinary metabolites are polar, primarily gucuronide and other conjugates. The parent compound is not retained in animal tissues nor secreted in milk.]

 7. Metabolite toxicology. [Metabolites are considered to be of equal or less toxicity than the parent material]

 8. Endocrine disruption. [Mefenoxam does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system. Furthermore, supporting developmental toxicity studies in rats and rabbits, and a reproduction study in rats gave no indication of any effects on endocrine function related to development and reproduction. Subchronic and chronic treatment did not induce any morphological changes in endocrine organs and tissues.]

 C. Aggregate Exposure

 1. Dietary exposure. [Tier I acute and short-term aggregate exposure evaluations were made for mefenoxam using the Dietary Exposure Evaluation Model (DEEM-FCID(TM) Version 4.02) from Exponent, which utilizes consumption data from the USDA NHANES "What We Eat in America" survey, 2005-2010.  Established tolerances for mefenoxam and/or metalaxyl were used for all existing uses, as well as proposed uses for tree nuts.  Percent of crop treated values were conservatively incorporated as 100%.  Drinking water estimates were selected using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water.]
 
 i. Food. [Acute Exposure. The mefenoxam acute dietary (food only) risk assessment was performed for all population subgroups with an acute reference dose (aRfD) of 0.5 mg/kg-bw/day based on a prenatal development study in dogs with a no observed adverse effect level (NOAEL) of 50 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.  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 reference dose (%RfD).  Acute (food only) exposure to the U.S. population resulted in a MOE of 530 (18.9% of the aRfD of 0.05 mg/kg-bw/day).  The most exposed sub-population was children (1-2 years old) with a MOE of 238 (42.0% of the aRfD).  Since the benchmark MOE for these assessments was 100 and since EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from all current and proposed uses for mefenoxam.
 
 Chronic Exposure.  Chronic dietary exposure assessments were not performed since the EPA was has not established a chronic endpoint of concern for mefenoxam.
 
 Cancer.  Based on the classification of metalaxyl, mefenoxam is also considered "not likely to be a human carcinogen".  Therefore, no cancer risk assessment was performed for mefenoxam.]

 ii. Drinking water. [The estimated drinking water concentrations (EDWCs) of parent mefenoxam were derived from the Pesticide Water Calculator (PWC, v1.52) graphical user interface which incorporates the Pesticide Root Zone Model/Variable Volume Water Model (PRZM/VVWM) Tier II surface water and Tier I PRZM ground water models. Model simulations included currently registered uses, pending uses on wasabi and cacao and proposed use on pecans. The highest ground water EDWCs for acute and chronic exposure durations were 77.6 ppb and 68.7 ppb, respectively, based on proposed mefenoxam use on pecans.  For surface water, the maximum EDWCs were 168 ppb and 34.2 ppb for acute and chronic exposure durations, respectively, based on current registered mefenoxam use on citrus.  No percent cropped area adjustment was applied to the surface water estimates. 
 
 Acute Exposure from Drinking Water. The acute surface water EDWC of 168 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%-ile 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 U.S. population resulted in a MOE of 11,279 (0.9% of the acute RfD of 0.5 mg/kg-bw/day).  The most exposed sub-population was all infants (<1 year old) with a MOE of 3,560 (2.8% of the acute RfD of 0.5 mg/kg/day).  Since the benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures below 100% of the acute RfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute drinking water exposure to residues arising from the current and proposed uses for mefenoxam.
 
 Chronic Exposure from Drinking Water. Chronic dietary exposure assessments from drinking water were not performed since the EPA was has not established a chronic endpoint of concern for mefenoxam.]

 2. Non-dietary exposure. [The use of mefenoxam on residential turf may result in short- or intermediate-term exposures to selected subgroups.  A short and intermediate-term inhalation toxicological endpoint of 50 mg/kg-bw/day was selected based upon the no observed adverse effect level (NOAEL) from a developmental tox study is rats, with an uncertainty factor of 100X, which includes intra- and inter-species variations; no additional FQPA safety factor was applied.  An incidental oral short-term toxicological endpoint of 50 mg/kg-bw/day was selected based upon the no observed adverse effect level (NOAEL) from a developmental tox study in rats, with an uncertainty factor of 100X, which included intra-and inter- species variations; no additional FQPA safety factor was applied.  Exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each subgroup.  Residential exposure risk assessments were performed for use of mefenoxam formulated as Subdue GR, Subdue WSP, and Subdue MAXX for residential turf).  Assessments were also performed for exposure due to off-site drift of agricultural products.  Application of mefenoxam by residents is allowed; therefore residential handler exposure assessments are required.  Adults 13+ years old had a short-term residential MOE of 501,974 (hose-end sprayer; liquid concentrate); children 1-6 years old had MOEs of 4,786 (hand-to-mouth; liquid concentrate).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the Benchmark MOE, Syngenta believes that there is a reasonable certainty that no harm will result from short- and intermediate-term residential exposure to residues arising from all current and proposed uses of mefenoxam.]

 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."  The EPA does not have, at this time, available data to determine whether mefenoxam has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment.  For the purposes of this tolerance action, the EPA has not assumed that mefenoxam has a common mechanism of toxicity with other substances.]

 E. Safety Determination

 1. U.S. population. [Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the short- and intermediate-term aggregate exposure calculations for all current and proposed uses of mefenoxam provided an MOE of 1,361 for the U.S. population.  The acute aggregate exposure calculation for all current and proposed uses of mefenoxam provided a MOE of 506 (19.7% of the aRfD 0f 0.5 mg/kg-bw/day) for the U.S. population.  Since the aggregate MOEs exceed the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure to residues arising from all current and proposed uses of mefenoxam, including anticipated dietary exposure from food, water, and all other types of non-occupational residential exposures.]

 2. Infants and children. [Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the short- and intermediate-term aggregate exposure calculations for all current and proposed uses of mefenoxam provided an MOE of 475 for children 1-2 years old.  The acute aggregate exposure calculation for all current and proposed uses of mefenoxam provided a MOE of 229 (43.6% of the aRfD 0f 0.5 mg/kg-bw/day) for children 1-2 years old.  Since the aggregate MOEs exceed the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure to residues arising from all current and proposed uses of mefenoxam, including anticipated dietary exposure from food, water, and all other types of non-occupational residential exposures.]

 F. International Tolerances

 [There are no Codex MRLs established for residues of mefenoxam in any plant or animal commodity.  Codex MRLs have been established for metalaxyl, the racemic fungicide mixture containing the active isomer mefenoxam, in a number of commodities including asparagus, avocado, broccoli, Brussels sprouts, cabbage, cacao, carrot, cauliflower, cereal grains, citrus, cotton seed, cucumbers, grapes, hops, lettuce, melons, onions, peanuts, peas (succulent), peppers, pome fruits, potatoes, raspberries, soybeans, spices, spinach, squash, sugar beet, sunflower seed, and tomatoes.]