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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: Hope Johnson, (703) 305**  **- 5410**  Sy ngenta Crop Protection, LLC Petition #4F8323 E PA has received a pesticide petition ( 4F8323 ) from Sy ngenta Crop Protection, LLC , 410 Swing Road, Greensboro, NC 27409 request ing, 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 - dimethylphen yl ) -N

- (methoxyacet yl ) -DL - alaninate in or on the raw agricultural commodity Rapeseed Crop Subgroup 20 A at 0. 05 parts per million (ppm). EPA has determined that the petiti on 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 adequatel y understood for the purpose of the proposed tolerance. ] 2. Analytical method. [ Canola: The analytical method used was Novartis Crop Protection Method 456 - 98, “Confirmatory Anal yt ical Method for the Enantioselective Determination of Residues of Parent Metalax yl(CGA - 48988) or Mefenoxam (CGA 329351) in Crop Substrates by Chiral High Performance Liquid Chromatography with Ma ss Spectrometric Detection”, March 1999 , MRID 44976201. 3. Magnitude of residues. [ Complete residue data to support the requested tolerances have been submitted. The requested tolerances are adequatel y supported b y previousl y submitted studies. In supp ort of the requested tolerances, Sy ngenta 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. Toxicologi cal Pro

file2 1. Acute toxi city. [The toxicological endpoints for mefenoxam are discussed in B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084) (FRL - 5726 - 4). The acute toxicity

profile can be summari z ed as follo w s: Rat acute oral study w i th LD50 value of 490 milligrams/kilograms (mg/kg). Rat acute dermal study w i th LD50 >2,000 mg/kg. Rat inhalation study w i th a L C50 >2.29 milligram/liter (mg/L) air. Primary eye irritation study

in rabbit sho w s mefenoxam as severel y irritating. Primary derm al irritation study

in rabbit sho w s mefenoxam as slightly irritating. Skin sensitization studies in guinea p i gs (maximi z ation and Buehler Test) show mefenoxam is not a se n siti z er.] 2. Genotoxicty. [The toxicological e n dpoints f o r mefenoxam are discussed i n B.4. of the Federal Register Notice of Ju ly 25, 1997, (62 FR 40084). The genotoxicity profile can be summarized as follo w s: In vitro ge n e mutation test: Ames test - neg ativ e . In vitro chromosomal a

berration test: Chinese hamster o v ary (CH0) - negative. In vi tro ge n e mutation tests: Ames tests (3 independent studies) - negative; gene mutation in mouse ly mphoma ce l ls - negative; rev e rse mutation in saccharomyces cerevi s iae - negati v e. In vitro chromosomal a

berration tests: Chinese hamster b o ne marrow cy togenetic tes t - negative. DNA re p air stud y in rat hepatocytes - negative.] 3. Reproductive and developmental toxicity. [The toxicological endpoints for mefenoxam are discussed in B.4. of the Federal Register N otice of July 25, 1997, (62 FR 40084). The reproductive and de velopme nt a l toxicity profile can be summarized as follo w s: Teratology

study in rats w i th a maternal no observed adverse effect level (NOAEL) of 10 mg/kg based on reduced body w eight (bwt) gain. The fetuses remained entirel y unaffected at the highest dose tested (HDT), 250 mg/kg. Teratology

study in rabbits w i th a m aternal N OAEL of 150 mg/kg based on b wt loss. The developmental NOAEL was greater than or equal to the HDT, 300 mg/kg. Three - generation reproduction study in rats w i th a NOAEL of 1,250 ppm, which w as the HDT. The treatment had no e ffect on re p roduction o r fert ility . Dominant lethal study

in mouse - n egative. ] 4. Subchronic toxicity. [The toxicological end p oints for mefenoxam are discussed in B.4. of the Federal Register Notice of July 25, 1997, ( 62 FR 40084). The subchronic toxicity

profile can be summari z ed as follo w s: A 28 - day cumulative toxicity

study in rats w i th a NOAEL of 50 mg/kg based on liver changes. A 90 - day subchronic dietary

toxicity s tudy in rats w ith a NOAEL of 250 ppm based on liv er changes. A 90 - day subchronic dietary

toxicity study in dogs w ith a NOAEL of 250 ppm based on changes in blood bio c hemistry and hematology

indicative of functio n al liver changes.3 A 21 - day dermal toxicity

study in rats w i th a NOAELequal to or higher than the limit dose of 1,000 mg/kg. No local or sy stemic signs of toxicity w ere found. A 6 - month dietary

toxicity study in d ogs w ith a NOAEL of 250 ppm based on changes in blood biochemistry in d i cative of hepatocellular damage.] 5. Chronic toxicity. [T h e toxi cological endpoints for mefe n oxam are discussed in B.4. of the Federal Register Notice o f July 25, 1997, (62 FR 40084). The chronic toxicity profile can be summari z ed as follo w s: A 24 - month combined chronic toxicity /carcinogenicity

s tudy c onducted in rats w i th a NOAEL of 250 ppm based on liver changes. No evidence of oncogenicit y w as seen. A 24 - month oncogenicity study conducted in mice w ith a NOAEL of 250 ppm based on liver changes. No evidence of oncogenicity w as seen.] 6. Animal metabolism. [The rat and goat rapidl y m etabolize and excrete via the same metabolic pathw ay s 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. Metab o lite toxicology . [Metabolites are considered to be of equal or less toxi c ity th an the parent mat e ri a l] 8. Endocrine disruption . [Mefenoxam does not belong to a class of chemicals kno wn or s uspected of having adver s e effects on the endocrine s y s t em. Furthermore, supporti ng developmental tox i city studies in rats and rabbits, and a reproduction study in rats gave no indicat i on of an y effects on endocrine function related to development and reproduction. Subchronic and chronic treatment did not induce any morphological chang es in endocri n e organs and tissues.] C. Aggregate Exposure 1. Dietary exposure. [Tier II chronic and short - term aggregate exposure evaluations were made for mefenoxam using the using the Dietary Exposure Evaluation Model (DEEM - FCIDTM Version 3.16) from Exponent, which utilizes consumption data from the USDA NHANES “What We Eat in America” survey , 2003 - 2008. Established tolerances for mefenoxam and/or metalaxyl were used for all existing uses, as well as proposed tolerances for the Oilseed Crop Group 20. Pe rcent of crop treated values were conservativel y estimated based upon economic, pest, and competitive pressures. Drinking water estimates were selected using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water.] i. Food. [Acute Exposure. Acute dietary exposure assessments were not performed since the EPA was has not established an acute endpoint of concern for mefenoxam. Chronic Exposure. The mefenoxam chronic di etary (food onl y) risk assessment w as4

performed for all population sub groups w i th a chronic reference do s e (cRfD) of 0.074 mg/kg - b w

/day based on a six - month feeding study in dogs w ith a no observed adverse effect le v el (NOAEL) of 7.4 mg/kg - b w /day and an uncertaint y factor o f 100X. The 100X safet y factor in cludes intra - and inter - species variations. No additional FQPA safet y factor w as ap p lied. For the purpose of aggregate risk assessment, the exposure values w ere expr ess ed in terms of margin o f exposure (MOE), which w as calculated b y dividing the NOAEL b y the exposure for each population subgroup. In addition, exposure was expressed as a percent of the reference dose ( % RfD). Chronic (food onl y) exposure to the U.S. population resulted in a MOE of 654 (15.3% of the cRfD of 0.074 mg/kg - b w

/day). The most expose d sub - population w as children (1 - 2 ye ars old) w i th a MOE of 267 (37.5% of the cRfD). Since the benchmark MOE for these assessments w as 100 and since EPA generall y h as no concern for exp o sures above the benchmark or below 100% of the reference dose, S yn gent a believes that there is a reasonable ce rtainty that no harm w ill result from diet ary (food only) exposure to residues arising fr o m the c urrent and proposed tolerances and label amendments for mefe n oxam. Cancer. Based on the classific ation of met a lax yl , m efenoxam is also considered “ not likely to be a human carcinogen”. Therefore, no cancer risk as s essment w as performed for mefenoxam.] ii. Drin k i ng water. [The Estimated Drinking Water Concentrations (EDWCs) of mefenoxam w ere determined using Tier l S C I - GR OW (version 2. 3 ), which estimates pesticide conce ntrations in ground w ater and Tier II PRZ M/EXAMS (PE version 5.0) which estimates pesticide conce ntrations in surface w ater. The application and use parameters for the proposed use on oilseeds, crop group 20 were modeled along with the currently

registered uses to identify the highest EDWCs. The currentl y registered use on citrus based on a treatment rate of 3.0 lbs ai/A, with 2 applications at an interval of 60 day s was de termined to be the crop driver. For ground water, the SCI - GROW model provided a chronic E DWC of 1.72 ppb for mefenoxam. For surface water, employing the FL citrus standard PRZM scenario, the PRZM/EXAMS output provided a chronic E DWC of 22.9 ppb for mefenoxam. This surface water EDWC has not been adju sted for Percent Cropped Area. Since the surface water EDWC exceeds the ground water EDWC, the surface water chronic exposure value will be used for risk assessment purposes and considered protective for any ground water concentration concerns. D rinking water estimates were incorporated directly into the dietary

exposure assessment along with the food exposure using the higher of the estimated drinking water concentrations (EDWCs) for surface water (22.9 ppb). Chronic drinking water exposure to th e U.S. population resulted in a MOE of 15,433 (0.6% of the cRfD of 0.074 mg/kg - bw/day). The most exposed sub - population was infants <1 ye ar old with a MOE of 5,985 (1.7% of the cRfD). Since the benchmark MOE for these assessments was 100 and since EPA gene rall y has no concern for exposures above the benchmark or below 100% of the reference dose, S yn genta believes that there is a reasonable certaint y that no harm will result from drinking water exposure to residues arising from all current and proposed uses for mefenoxam.]5 2. Non - dietary exposure . [The use of mefenoxam on residential turf may result in short - or intermediate - term exposures to selected subgroups. A short - term inhalation toxicological endpoint of 50 mg/kg - bw/day was selected based upon the no observed adverse effect level (NOAEL) from a dev tox study in rats, with an uncertainty factor of 100X, which includes intra - and inter - species variations; no additional FQPA safet y factor was applied. An intermediate - term inhalation toxicological endpoint of 7.41 mg/kg - bw/day

was selected based upon the no observed adverse effect level (NOAEL) from a 6 - month feeding study in the dog, with an uncertaint y factor of 100X, which includes intra - and inter - species variations; no additional FQPA safet y factor was applied. Exposure values were expressed in terms of margin of exposure (MOE), which was calculated b y dividing the NOAEL b y the exposure for each subgroup. Residential exposure risk assessments were performed for use of mefenoxam formulated as Subdue GR, Subdue WSP, and Subd ue 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 require d. Adults 13+ y ears 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, Sy ngenta 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 Eff

e cts [Cumulative Exposure to Substances w i th a Common Mechanism of Toxicity . S ection 408(b)(2)(D)(v) requires th at, when considering whether to establish, modify , or revoke a tolerance, the Agency consider “available inform atio n ” concerni n g the cumulative eff

e cts of a particular pesticide’s re s idues and “other substances that have a common mechanism of toxicity”. The EPA does not have, at this time, available data to dete rm ine whether mefenox am has a common mechanism of toxic ity w i th other substances or h ow to include this pesti c ide in a cumulati v e ri s k ass e s s ment. For the purposes of this tolerance acti o n, the EPA has not assumed that mefenoxam has a common mechanism of toxicity w i th other substances.] E. Safety Determinatio n 1. U.S. population. [Usi n g the conservative ass umptions described above, and based on the complete n ess and reliability o f th e toxicity d ata, the short - and intermediate - term aggregate exposure calculations for all current and proposed uses of mefenoxam provided MOEs of 4,238 and 628, respecti vely , for the U.S. population. The chronic aggregate exposure calculation for all current and proposed uses of mefenoxam provided a MOE of 627 (15.9% of the cRfD 0f 0.074 mg/kg - bw/day) for the U.S. population. Since the aggregate MOEs exceed the Benchmark MOE of 100, Sy ngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure to residues arising from all current and proposed uses of6

mefenoxam, including anticipated dietary e xposure from food, water, and all other ty pes 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 inte rmediate - term aggregate exposure calculations for all current and proposed uses of mefenoxam provided MOEs of 1,286 and 261, respectivel y, for children 1 - 2 years old. The chronic aggregate exposure calculation for all current and proposed uses of mefenoxam provided a MOE of 260 (38.4% of the cRfD 0f 0.074 mg/kg - bw/day) for children 1 - 2 years old. Since the aggregate MOEs exceed the Benchmark MOE of 100, Sy ngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure t o residues arising from all current and proposed uses of mefenoxam, including anticipated dietary exposure from food, water, and all other ty pes of non - occupational residential exposures.] F. Intern a ti o nal Tolera n ces [There are no Codex MRLs established for residues of mefenoxam in an y plant or animal commodity . Codex MRL s have been established for metalaxyl, the racemic fungicide mixture containing the active isomer mefenoxam, in a number of commodities including asparagus, avocado, broccoli, Brussels sp routs, cabbage, cacao, carrot, cauliflower, cereal grains, citrus, cotton seed, cucumbers, grapes, hops, lettuce, melons, onions, peanuts, peas (succulent), peppers, pome fruits, potatoes, raspberries, so ybeans, spices, spinach, squash, sugar beet, sunflow er seed, and tomatoes. ]