Document ID: EPA-HQ-OPP-2009-0713-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-10-07T04:00Z

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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER
EPA Registration Division contact: Laura Nollen (703) 305-7390
 Interregional Research Project Number 4 (IR-4)
 PP# 9E7591
EPA has received a pesticide petition PP# 9E7591 from Interregional Research Project Number 4 (IR-4), IR-4 Project 500 College Rd. East, Suite 201W, Princeton, NJ 08540 proposing, pursuant to section 180.546 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.546 by establishing tolerances for combined residues of mefenoxam, ( R )- and ( S )-2-[(2,6-dimethyl(phenyl)-methoxyacetylamine]-propionic acid methyl ester, and its metabolites containing the 2,6 dimethylaniline moiety, and N -(2-hydroxy methyl-6-methylphenyl)- N -(methoxyacetyl)-alanine methyl ester, in or on the following raw agricultural commodities: bean, snap, succulent at 0.35 parts per million (ppm); caneberry, subgroup 13-07A at 0.80 ppm; bushberry, subgroup 13-07B at 2.0 ppm; onion, bulb, subgroup 3-07A at 3.0 ppm; Onion, green, subgroup 3-07B at 10.0 ppm, and spinach at 8.0 ppm. This petition additionally proposes to remove the tolerance for lingonberry at 2.0 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 180.546 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. Syngenta believes the studies supporting this mefenoxam petition well characterize metabolism in plants and animals. The metabolism profile supports the use of an analytical enforcement method that accounts for combined residues of mefenoxam and its metabolites which contain the

2
2,6-dimethylaniline (DMA) moiety.
 Analytical method. Snap bean and caneberry samples were analyzed for mefenoxam (parent only) using a procedure derived from "Confirmatory Analytical Method for the Enantioselective Determination of Residues of Parent Metalaxyl (CGA-48988) or Mefenoxam (CGA-329351) in Crop Substrates by Chiral High Performance Liquid Chromatography with Mass Spectrometric Detection" (Novartis Crop Protection, Inc., Procedure 456-98, March, 1999). Minor modifications were made to improve the performance of the method. The limit of quantitation (LOQ) for the method is 0.028 ppm for snap beans and 0.059 for caneberries.
Selected samples from the snap bean and caneberry trials were also analyzed with the combined residue method that converts everything to N-(2,6-dimethylpheny1)-N - (methoxyacetyl)alanine methyl ester. This served as a bridging study for the other samples that were only analyzed for parent. The common moiety method was also used for the spinach trials. The analytical method used was Ciba-Geigy Corporation Procedure AG-395, "Improved Method for the Determination of Total Residues of Metalaxyl in Crop as 2,6-dimethylaniline," December 1982. This total residue method is used for the determination of the combined residues of metalaxyl [N-(2,6-dimethylpheny1)-N-(methoxyacetyl)alanine methyl ester] and its metabolites which contain the 2,6-dimethylaniline (2, 6-DMA) moiety in crop samples. 
 Magnitude of residues.
Bean, snap, succulent: This petition is supported by eight field trials conducted on snap beans during the 2002 growing season, one in Maryland (Region 2), one in Washington (Region 11), three in Wisconsin (Region 5), one in Florida (Region 3), and one in California (Region 10).
In the first snap bean study (PR 08371) where only parent was analyzed, the results from the trial 08371.02-CA96 showed that the maximum mefenoxam residue in snap bean following a total application of approximately 0.7 lb ai/A and a pre-harvest interval (PHI) of 6 days was 0.172 ppm. Residues declined from a maximum of 0.531 ppm at 0 day to a maximum of 0.074 ppm at 14 days. In the second s study (reanalysis of samples for both parent and metabolite), the maximum combined mefenoxam residue in snap bean from trial 08371.02-CA96 with a preharvest interval (PHI) of 6 days was 0.284 ppm. Residues declined from a maximum of 0.516 ppm at 0 days to a maximum of 0.221 ppm at 14 days. Residues (parent plus metabolites) from the samples that were reanalyzed were comparable at 0 day, and higher at 6 and 14 days in this study compared to the previous study (parent only). A tolerance of 0.35 ppm for the legume vegetable subgroup 6A (except peas) has been proposed.
Caneberrv subgroup 13-07A: This petition is supported by six field trials conducted on caneberry during the 2002 growing season, two in California (EPA Region 10), two in Washington (Regions 11 and 12), and one each in North Carolina and New Jersey (both Region 2). One of the California trials can be used to represent Region 12 and another can replace Region 5 or Region 6. In the first caneberry study (PR # A1169), where only parent was analyzed, the maximum residue in caneberry following a total application of approximately 2.0 lb ai/A and a pre-harvest interval (PHI) of 0 days was 0.555 ppm. In the second caneberry study (reanalysis of samples for both parent and metabolite), the maximum mefenoxam residue in caneberry following a total application of approximately 2.0 lb ai/A and a preharvest interval (PHI) of 0 days was 0.697 ppm. Residues (parent plus metabolites) in the samples from the three samples that were reanalyzed were higher in this study compared to the previous study (parent only). A tolerance of 0.80 ppm for the caneberry group 13-07A has been proposed.
Spinach: Copper (mefenoxam + copper), is used for control of white rust and downy mildew in spinach production. To provide the sponsor with residue chemistry data to support a new use under the present pesticide tolerance for mefenoxam in or on spinach or to increase the pesticide tolerance to cover this use, nine field trials were conducted for this study during the 2004 growing season. Two trials each were conducted in Texas (EPA region 6), California (region 10), and Maryland (region 2), and one trial each in New Jersey (region 2), New York (region 1), and Colorado (region 8). In each trial, one soil-surface application of Ridomil Gold EC at a rate of approximately 1.0 lb ai/A was followed by two foliar applications of Ridomil Gold Copper at a rate of approximately 0.125 lb ai/A each, for a total of approximately 1.250 lb ai/A. The results from the trials show that the maximum residues in spinach following a total application of approximately 1.250 lb ai/A and a pre-harvest interval (PHI) of 2-4 days were 6.19 ppm.
Bushberrv subgroup 13-07B:
IR-4 requests that the blueberry tolerance of 2.0 ppm metalaxyl be converted to a Bushberry tolerance of Crop subgroup 13-07B at 2.0 ppm mefenoxam. This tolerance supports a soil application only. The Bushberry subgroup 13-07B contains Aronia berry, highbush blueberry, lowbush blueberry, buffalo currant, Chilean guava, black currant, red currant, elderberry, European barberry, gooseberry, highbush cranberry, edible honeysuckle, huckleberry, hostaberry, Juneberry, lingonberry, native currant, salal, and sea buckthorn. The previous metalaxyl residue trials that supported the 2.0 ppm tolerance consisted of seven field trials on blueberries in New York (1), North Carolina (2), Arkansas (1), New Jersey (1), Indiana (1) and Washington (1). Ridomil 2E was applied twice at 71 to 93 day intervals in a post drench band under the canopy at a broadcast equivalent rate of 3.62 lbs. ai/treated acre. This data resulted in a metalaxyl tolerance establishment in blueberries at 2.0 ppm with zero-day PBI. Mefenoxam is used at half the rate of metalaxyl, therefore the metalaxyl tolerance would cover the lower residues expected for mefenoxam.  The mefenoxam tolerance for lingonberry will be removed as lingonberry is covered by the Bushberry subgroup tolerance.
Onion, bulb subgroup 3-07A and Onion, green subgroup 3-07B-: IR-4 requests the establishment of Onion, bulb subgroup 3-07A Onion, green subgroup 3-07B tolerances at 3.0 ppm mefenoxam and 10.0 ppm mefenoxam, respectively. These tolerances are based on metalaxyl tolerances for bulb onion and green onion, respectively. Mefenoxam is used at half the rate of

                                       
metalaxyl, therefore the metalaxyl tolerance would cover the lower residues expected for mefenoxam.
The Bulb vegetable subgroups 3-07A and 3-07B contain: Daylily bulb, Fritillaria bulb, garlic bulb, great-headed garlic, serpent garlic bulb, lily bulb onion bulb, Chinese onion bulb, pearl onion, potato onion bulb, shallot bulb, chive fresh leaves, Chinese chive fresh leaves, Hosta elegans, fritillaria leaves, kurrat lady's leek, leek wild leek, Beltsville bunching onion, fresh onion, green onion, macrostem onion, tree onion tops, Welsh onion tops, and shallot fresh leaves.
B. Toxicological Profile
 Acute toxicity. 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 summarized as follows:
   Rat acute oral study with LD50 value of 490 milligrams/kilograms (mg/kg). Rat acute dermal study with LD50 >2,000 mg/kg.
   Rat inhalation study with a LC50 >2.29 milligram/liter (mg/L) air.
Primary eye irritation study in rabbit shows mefenoxam as severely irritating. Primary dermal irritation study in rabbit shows mefenoxam as slightly irritating. Skin sensitization studies in guinea pigs (maximization and Buehler Test) show mefenoxam is not a sensitizer.
 Genotoxicty. The toxicological endpoints for mefenoxam are discussed in B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084). The genotoxicity profile can be summarized 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 discussed in B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084). The reproductive and developmental toxicity profile can be summarized as follows:
      Teratology study in rats with a maternal no observed adverse effect level (NOAEL) of 10 mg/kg based on reduced body weight (bwt) gain. The fetuses remained entirely unaffected at the highest dose tested (HDT), 250 mg/kg.
         Teratology study in rabbits with a maternal NOAEL of 150 mg/kg based on bwt loss. The developmental NOAEL was greater than or equal to the HDT, 300 mg/kg.
      Three-generation reproduction study in rats with a NOAEL of 1,250 ppm,

  1. Dietary exposure. A Tier I chronic dietary exposure evaluation was made
         which was the HDT. The treatment had no affect on reproduction or fertility.
      Dominant lethal study in mouse-negative. 
 Subchronic toxicity. The toxicological endpoints 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 summarized as follows:
A 28-day cumulative toxicity study in rats with a NOAEL of 50 mg/kg based on liver changes.
A 90-day subchronic dietary toxicity study in rats with a NOAEL of 250 ppm based on liver changes.
A 90-day subchronic dietary toxicity study in dogs with a NOAEL of 250 ppm based on changes in blood biochemistry and hematology indicative of functional liver changes.
A 21-day dermal toxicity study in rats with a NOAEL equal to or higher than the limit dose of 1,000 mg/kg. No local or systemic signs of toxicity were found.
A 6-month dietary toxicity study in dogs with a NOAEL of 250 ppm based on changes in blood biochemistry indicative of hepatocellular damage.
 Chronic toxicity. The toxicological endpoints for mefenoxam are discussed in B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084). 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.
 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.
 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

                                       
for mefenoxam using the Dietary Exposure Evaluation Model (DEEM-FCID[TA1]), version 2.16 from Exponent. In addition to current tolerances for mefenoxam and/or metalaxyl, this exposure assessment included proposed mefenoxam tolerances for Bean, snap, succulent, Caneberry subgroup 13-07A, Bushberry subgroup 13-07B, Onion, bulb subgroup 3-07A and Onion, green subgroup 3-07B, and including spinach. Percent of crop treated values were conservatively estimated to be 100% for all registered and proposed uses. Drinking water estimates were incorporated directly into the dietary exposure assessment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water. All consumption data for these assessments was taken from the USDA's Continuing Survey of Food Intake by individuals (CSFII) with the 1994-96 consumption database and the Supplemental CSFII children's survey (1998) consumption database.
 Food. Acute Exposure. Mefenoxam is not considered to be acutely toxic. An acute dietary exposure was not determined for mefenoxam since the Agency was unable to identify an endpoint of concern from the available toxicological studies.
Chronic Exposure. The mefenoxam chronic dietary (food only) risk assessment was performed for all population subgroups with a chronic reference dose (cRID) of 0.074 mg/kg-bw/day based on a six-month feeding study in dogs with a no observed adverse effect level (NOAEL) of 7.4 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 (%121D). Chronic (food only) exposure to the U.S. population resulted in a MOE of 499 (20.0% of the clUD of 0.074 mg/kg-bw/day). The most exposed sub-population was children (1-2 years old) with a MOE of 181 (55.1% of the cRfD). Since the benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures below 100% of the RfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from the current and proposed tolerances and label amendments 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.
 Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of mefenoxam were determined using Tier 1 SCI-GROW (version 2.3), which estimates pesticide concentrations in ground water and Tier II PRZM/EXAMS (PE version 5.0) which estimates pesticide concentrations in surface water. The

modeling was conducted using chosen environmental fate inputs from submitted mefenoxam data, bridging data from metalaxyl studies where mefenoxam data were unavailable and four mefenoxam studies that were considered appropriate for determining model inputs, but have been submitted to the US EPA. The application and use parameters for the proposed IR4 uses on Bean, snap, succulent, Caneberry subgroup 13-07A, Bushberry subgroup 13-07B, Onion, bulb subgroup 3-07A and Onion, green subgroup 3-07B, and spinach shorter PHI were modeled along with the currently registered uses to identify the highest EDWCs. The currently registered use on citrus based on a treatment rate of 2.0 lbs ai/A, with 4 applications at 3 months (90 days) intervals as a granular soil application was determined to be the crop driver. For ground water, the SCI-GROW model provided a chronic EDWC of 8.59 ppb for mefenoxam. For surface water, employing the FL citrus standard PRZM scenario, the PRZM/EXAMS output provided a chronic EDWC of 25.5 ppb for mefenoxam. This surface water EDWC has been corrected for a 0.87 Percent Cropped Area factor. 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.
Drinking 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 (25.5 ppb). Chronic exposure (water) to the U.S. population resulted in a MOE of 13,768 (0.7% of the cRID of 0.074 mg/kg - bw/day). The most exposed sub-population was infants (<1 year old) with a MOE of 4,199 (2.4% of the cRfD). Since the benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures below 100% of the RID, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food and drinking water) exposure to residues arising from the proposed tolerances and label amendments for mefenoxam.
2. Non-dietary exposure. Subdue(R) GR, Subdue(R) MAXX and Subdue(R) WSP are currently sold for professional use only and therefore have no expected residential (home owner) handler exposures. However, since the product labels do not restrict sales to professional applicators and the most recent EPA assessment included consumer handler exposure risks, residential handler exposures assessments were calculated and found to be well above the EPA's level of concern (MOE5>100). Since there are no dermal exposures of concern for mefenoxam; the potential dermal exposures were not assessed for adults or children. EPA algorithms and default values were used to conduct the non-professional handler inhalation and children non-dietary oral residential risk assessments for the mefenoxam turf and ornamental use products. The worst-case exposure risk (MOE = 408,511) was for a non-professional handler doing hand applied spot treatment applications of Subdue(R) WSP at the maximum application rate for turfgrass. Since the target level of concern is MOE >100, there are acceptable inhalation risks to all

                                       
non-professional applicators during the application of any mefenoxam product to residential lawns. For children (1-6 years old), the aggregate post-application non- dietary oral exposure risk resulted in a MOE of 3,874 arising from the exposures to turf treated with Subdue(R) WSP at the maximum rate of 0.686 lb a.i./A. Since this MOE exceeds the target level of concern (MOE =100) for mefenoxam, there are acceptable post-application risks to children (1-6 years old) from applications of any mefenoxam product to residential lawns. Exposure to mefenoxam treated ornamentals was not included in the residential risk assessment since exposure from this source is considered to be negligible compared to turfgrass.
 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.
 Safety Determination
 US. population. Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the chronic aggregate exposure calculation for current and proposed uses of mefenoxam provided a MOE of 481 (20.7% of the cRfD Of 0.074 mg/kg-bw/day) for the U.S. population. Since the aggregate MOE exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to the U.S. Population from chronic aggregate exposures arising from the current and proposed uses for mefenoxam.
 Infants and children. Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the chronic aggregate exposure calculation for current and proposed uses of mefenoxam provided a MOE of 178 (56.2% of the clUD Of 0.074 mg/kg-bw/day) for the children 1-2 years old (the most sensitive population subgroup for the chronic assessment). Since the aggregate MOE exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to infants and children from chronic aggregate exposures arising from the current and proposed uses for mefenoxam.
F. International Tolerances
There are no Codex, Canadian, or Mexican MRLs established for residues of mefenoxam in plant or animal commodities. Therefore, a discussion of

compatibility with U.S. tolerances is not relevant at this time.