Document ID: EPA-HQ-OPP-2012-0980-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-02-27T05:00Z

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

EPA Registration Division contact: Laura Nollen, (703) 305-7390; nollen.laura@epa.gov 

IR-4, Rutgers, The State University of New Jersey, 500 College Road East Suite 201 W, Princeton, NJ 08540 supported by Syngenta Crop Protection, LLC

Pesticide Petition #2E8126

	EPA has received a pesticide petition from IR-4, which Syngenta Crop Protection, LLC supports, 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 by establishing a tolerance for residues of mandipropamid in or on the raw agricultural commodities basil, fresh at 30 parts per million (ppm); basil, dried at 200 ppm; ginseng at 0.3 ppm; bean, succulent at 0.90 ppm; cowpea, forage at 15 ppm; vegetable, fruiting, group 8-10 at 1.0 ppm; fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit at 2.0 ppm; onion, bulb, subgroup 3-07A at 0.1 ppm; and onion, green, subgroup 3-07B at 7.0 ppm. 

	Upon establishment of the tolerances above, the petition additionally requests to remove the established tolerances from 40 CFR 180.637 of mandipropamid in or on grape at 1.4 ppm; onion, dry bulb at 0.05 ppm; onion, green at 4 ppm; okra at 1.0 ppm; and vegetable, fruiting, group 8 at 1.0 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. Metabolism studies of mandipropamid in three different crop groups (fruits - grape, leafy crop - lettuce and root and tuber vegetables - potato) have demonstrated that the compound undergoes extensive metabolism to form a range of metabolites which are more polar than parent. The extent of metabolism is related to the length of time between application of mandipropamid and harvest of the crop. When this time period is short, as in lettuce, mandipropamid is the principal residue (up to 93.5% TRR), levels of metabolites are very low and are structurally similar to parent. In the case of the other two crops, grape and potato, the multiple application regimes over a relatively long time period, allowed more extensive metabolism to take place. Unchanged mandipropamid remained as the major component in all aerial crop parts (ranging from approximately 40% to 80% TRR) and metabolites structurally very similar to parent were still evident, however, it was possible to identify more of the minor metabolites and to establish further steps in the biotransformation pathway. Overall, extensive degradation of the molecule was demonstrated, although individual metabolites were detected only at low levels and there was no evidence for accumulation of any specific compound.

	2. Analytical method. Analytical method RAM 415-01 was developed for determination of mandipropamid residues in crops. This method involves extraction of mandipropamid residues from crop samples by homogenization with acetonitrile:water (80:20 v/v). Extracts are centrifuged and aliquots diluted with water prior to being cleaned-up using polymeric solid-phase extraction cartridges. Residues of mandipropamid are quantified using high performance liquid chromatography with triple quadruple mass spectrometric detection (LC-MS/MS). This method has been successfully validated at an independent facility and therefore is suitable for use as the enforcement method for the determination of residues of mandipropamid in crops.

The multi-residue method was not successful at determining residues of mandipropamid.

	3. Magnitude of residues. 
Basil, fresh; Basil, dried  Six residue trials were conducted, four field trials in Wisconsin, North Carolina, California, and British Columbia and two greenhouse trials in Maryland and Florida. A total of approximately 0.52 lb ai/A was applied to the treated plots in four foliar directed applications of Revus 2.08SC at a rate of approximately 0.13 lb ai/A each. A nonionic surfactant was included in each tank mix. Fresh basil stems and leaves and additional basil for drying were collected 1 day after the final application from each trial and at 3, 7, and 11 days from one field trial. The basil for drying was dried for up to 3 days.
Maximum residues of mandipropamid in 1-day samples were 19 ppm (fresh) and 91 ppm (dried). Residues in samples grown in the greenhouse were comparable to those in samples grown in the field. Residues declined over time. Data from this study may be used to support a tolerance proposal for mandipropamid on basil. The establishment of a tolerance would provide growers with a safe and effective fungicide, yet would not expose humans or the environment to unreasonable adverse effects.

Ginseng Four residue field trials were conducted in Wisconsin and British Columbia. A total of approximately 0.52 lb ai/A was applied to the treated plots in four foliar broadcast applications of Revus 2.08SC at a rate of approximately 0.13 lb ai/A each. A nonionic surfactant was included in each tank mix. Fresh ginseng roots were collected 2 days after the final application and at 0, 7, 15, and 21 days from one trial. The roots were dried for up to 19 days in commercial facilities simulating commercial practices.
Maximum mandipropamid residues at 2 days were 0.167 ppm. Residues did not change significantly between 0 and 21 days after the last application. No residues of SYN50003 above the LLMV were observed in any sample. Data from this study may be used to support a tolerance proposal for mandipropamid on ginseng. The establishment of a tolerance would provide growers with a safe and effective fungicide, yet would not expose humans or the environment to unreasonable adverse effects.

Bean, succulent; Cowpea, forage Ten residue trials in New York (EPA Region 1), Maryland, (EPA Region 2), Georgia (EPA Region 2), Florida (EPA Region 3), Wisconsin (EPA Region 5), Michigan (EPA Region 5), one in Ohio (EPA Region 5), two in California (EPA Region 10) and Washington (EPA Region 11). At all trials, four foliar (broadcast or directed) applications of Revus 2.08 SC at a rate of approximately 0.13 lb ai/A each were applied, for a total application of approximately 0.52 lb ai/A. A non-ionic surfactant or a crop oil concentrate type additive was added to the spray tank mix. The applications were made at 7 (+/- 1) day intervals starting at 19-22 days before harvest.
The results from the trials show that the maximum residues in snap bean RACS, pods with seeds and plants with pods following a total application of between 0.49 to 0.54 lb ai A and a pre-harvest interval (PHI) of 1 day were 0.761 and 9.84 ppm, respectively.
Data from this study along with additional data generated by the registrant may be used to support a Section 3 tolerance proposal for mandipropamid on succulent  beans. The establishment of a tolerance would provide growers with a safe and effective fungicide, yet would not expose humans or the environment to unreasonable adverse effects.

Vegetable, fruiting, group 8-10 Tolerance is requested based on expanding the current tolerance for Vegetable, fruiting, group 8 to the newly established crop group 8-10.

Fruit, small, fine climbing, subgroup 13-07F, except fuzzy kiwifruit Tolerance is requested based on expanding the current tolerance for grape to the newly established crop group 13-07F.  If the crop subgroup 13-07F is established then it is requested that the grape tolerance be deleted.

Onion, bulb, subgroup 3-07A Tolerance is requested based on expanding the current tolerance for onion, dry bulb to the newly established crop group 3-07A.  if the crop subgroup 3-07A is established the it is requested the tolerance for onion, dry bulb, be deleted.

Onion, green subgroup 3-07B Tolerance is requested based on expanding the current tolerance for onion, green to the newly established crop group 3-07B.  If the crop subgroup 3-07B is established then it is requested the tolerance for Onion, green be deleted.

B. Toxicological Profile

	1. Acute toxicity.   Mandipropamid is not acutely toxic, with Category IV toxicity for the eye, oral, dermal, and inhalation routes.  Mandipropamid is not a skin irritant (Category IV) and it is not a skin sensitizer.  

	2. Genotoxicty. Mandipropamid was negative (non-mutagenic) in:  In vitro Bacterial reverse mutation,  In vitro cytogenetics, human lymphocytes, In vitro Mammalian cell gene mutation (mouse lymphoma), In vivo Rat bone marrow micronucleus, and In vivo Unscheduled DNA synthesis  -  rat liver.  A weight of the evidence evaluation demonstrates that mandipropamid is not genotoxic in mammalian systems

	3. Reproductive and developmental toxicity.
[Developmental toxicity in the rat and rabbit were tested up to a limit dose of 1000 mg/kg/day. No adverse developmental effects were observed. There were no developmental effects of concern. The NOEL/LOEL is 1000 mg/kg/day.

Reproductive toxicity in the 2-generation reproduction study in rats, mandipropamid was tested at 1500 ppm (equivalent to 138-154mg/kg/d males: 140.4-156.0mg/kg/d females). No reproduction effects of concern were observed.  The NOEL is > 1500ppm.]

	4. Subchronic toxicity. [[i. Rat 90-day feeding study. A subchronic feeding study in rats conducted for 13 weeks had a NOAEL of (41.1 mg/kg/day males) (44.7 mg/kg/day females) and a LOAEL of (260.3 mg/kg/day males) and 260.4 mg/kg/day females based on: reduction in bodyweight and bodyweight gain, reduced food utilization in males. Reductions in red blood cell parameters increased liver weight, increased periportal hypertrophy/ eosinophilia and changes in some clinical chemistry parameters.

ii. Dog 90-day feeding study. A subchronic feeding study in dogs conducted for three months had a NOAEL of 25 mg/kg/day in males/females and a LOAEL of 100 mg/kg/day in males/females based on increased liver weight, marked elevations in liver enzymes and, pigment deposition in the liver.

iii. Rat 28-day dermal study. No toxicity was seen at the limit dose of 1000 mg/kg/day. The NOAEL is greater than 1000 mg/kg/day.
iv. Rat 90 day neuropathology study. A subchronic feeding study in rats conducted for three months had a NOAEL of >192.5 mg/kg/>206.7 mg/kg in males/females. No adverse effects of treatment and no evidence of neurotoxicity.]

	5. Chronic toxicity. 
[i. Rat. A 24-month chronic/carcinogenicity study in male and female rats was conducted at 0, 50, 250, 1,000 ppm. The NOAEL was 250 ppm (15.2/17.6 mg/kg/day in males/females) with a LOAEL of 1000 ppm (61.3/69.72 mg/kg/day in males/females) based on: reduction in bodyweight and bodyweight gain, reduced food utilization in males, reductions in red blood cell parameters, increased liver weight, increased periportal hypertrophy / eosinophilia, changes in some clinical chemistry parameters and increased incidence of chronic progressive nephropathy.

ii. Mouse. An 80-week chronic/oncogenicity study was conducted in male and female mice dosed at 0, 100, 500, 2,000 ppm. The NOAEL was 500 ppm (55.2/67.8 mg/kg/day in males/females) and the LOAEL was 2000 ppm (222.7/284.6 mg/kg/day in males/females) based on: reduction in body weight and body weight gain, reduced food utilization in males, and increased liver weight.

iii. Dog. A 1-year feeding study in dogs resulted in a NOAEL of 5 mg/kg/day. The LOAEL was 40 mg/kg/day based on increased platelet counts in males & liver toxicity characterized by increased liver weight, marked elevations in liver enzymes (ALP & ALT) and pigment deposition within liver, consistent with porphyrin. The reference dose was based on this study with an UF = 100 the RfD = 0.05 mg/ kg/day.

iv. Carcinogenicity.  Mandipropamid was not oncogenic in the rat or mouse.

	6. Animal metabolism. The absorption, distribution, excretion, and metabolism of mandipropamid in rats and goats were investigated. Mandipropamid is well absorbed and completely metabolized in the rat and goat. Excretion is rapid and there is no accumulation of mandipropamid or metabolites in tissues.

	7. Metabolite toxicology. The primary residue of concern was mandipropamid parent. 

	8. Endocrine disruption. The endocrine system includes the reproductive hormones estrogen and androgens as well as the thyroid hormone system. Mandipropamid is not known to interfere with reproductive hormones and does not have reproductive toxicity.

C. Aggregate Exposure

      1. Dietary Exposure.  A Tier I chronic aggregate risk assessment was completed for mandipropamid using the Dietary Exposure Evaluation Model (DEEM-FCID[TM], version 2.16) from Exponent.  The exposure assessment included all approved uses of mandipropamid as follows: brassica, head and stem (Crop Group 5A), brassica, leafy greens (Crop Group 5B), grape and raisin, hop (dried cones), okra, onion (green and dry bulb), potato (wet peel),  cucurbit vegetables (Crop Group 9), fruiting vegetables (Crop Group 8), leafy vegetables except Brassica (Crop Group 4), and tuberous and corm vegetables (Crop Group 1C), plus proposed IR4 use on basil, ginseng, succulent beans and greenhouse tomatoes.  Processing factors were taken from the DEEM[TM] (version 7.87) default values, which were manually input into the DEEM-FCID(TM) software.  Percent of crop treated values were conservatively estimated to be 100% for all crop uses of mandipropamid.  Drinking water estimates were incorporated directly into the dietary exposure assessments using the highest estimated drinking water concentrations (EDWCs) for surface and ground water.  All consumption data for these assessments were 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.

i. Food   Acute Exposure.  No appropriate endpoints were identified for acute dietary exposure; therefore no acute risk assessment was performed.

      Chronic Exposure.  The mandipropamid chronic food risk assessment was performed for all population subgroups using a chronic reference dose of 0.05 mg/kg/day based upon a chronic toxicity study in rats with a no observed adverse effect level (NOAEL) of 5.0 mg/kg/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 chronic reference dose (% cRfD).  Chronic (food only) exposure to the U.S. population resulted in a MOE of 458 (21.8% of the cRfD of 0.05 mg/kg/day).  The most exposed sub-population was children (1-2 years old) with a MOE of 301 (33.2% of the cRfD of 0.05 mg/kg/day).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the benchmark or 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 all current, pending, and proposed uses for mandipropamid.

      Cancer.  A quantitative risk assessment using a cancer endpoint was not performed.

      ii.  Drinking Water:  The Estimated Drinking Water Concentrations (EDWCs) of mandipropamid (determined as combined residues of mandipropamid, SYN500003, and SYN504851) were determined using Tier l screening models, SCI-GROW which estimates pesticide concentration in ground water and FIRST which estimates pesticide concentration in surface water.  EDWCs of mandipropamid from currently registered, pending, plus the proposed uses on basil, ginseng, succulent beans, and greenhouse tomatoes were determined.   For ground water, the highest currently registered use rate provided a combined EDWC of 0.11 ppb (chronic).  For surface water, the pending ornamentals use provided a combined chronic EDWC of 1.085 ppb.  Since the surface water EDWCs exceed 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.  

   Chronic Exposure from Drinking Water.  The chronic surface water EDWC of 1.085 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 a MOE of 218,635 (0.05% of the chronic RfD of 0.05 mg/kg-bw/day).  Chronic drinking water exposure to the most exposed sub-population (infants, <1 year old) resulted in a MOE of 66,687 (0.15% of the chronic RfD of 0.05 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures above the benchmark or below 100% of the chronic RfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from the current, pending, and proposed uses for mandipropamid.

   2.  Non-Dietary Exposure:  Currently, there are no registered residential uses for mandipropamid.  A pending use on ornamentals is restricted to professional applications on outdoor ornamentals, commercial nurseries and indoor greenhouses.  Therefore, there are no residential exposure contributions to the aggregate risk.

D.  Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity:  Section 408(b)(2)(D)(v) of FFDCA 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 mandipropamid 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 mandipropamid has a common mechanism of toxicity with other substances.

E.  Safety Determination

	1.  U.S. Population.  The chronic dietary exposure analysis (food plus drinking water) showed that exposure from all mandipropamid uses resulted in a MOE of 457 (21.8% of the cRfD of 0.05 mg/kg/day) for the general U.S. population, which also exceeds the benchmark MOE of 100.  Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure to residues arising from all current, pending, and proposed mandipropamid uses, including anticipated dietary exposure from food, water and all other types of non-occupational exposures.

	2. Infants and children.  No appropriate endpoints were identified for acute dietary exposure; therefore no acute risk assessment was performed.  The chronic aggregate dietary (food plus drinking water) exposure analysis showed that exposure from all pending and proposed mandipropamid uses would result in a MOE of 300 (33.3% of the cRfD of 0.05 mg/kg/day) for the most sensitive population subgroup, children 1-2 years old, which exceeds the benchmark MOE of 100.  Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to residues arising from all current, pending, and proposed mandipropamid uses, including anticipated dietary exposure from food, water and all other types of non-occupational exposures.

F.  International Tolerances
   
The current Maximum Residue Limits (MRLs) set for mandipropamid by the Codex Alimentarius Commission are Grape, table 2ppm, Grape, wine 2ppm, Onion, bulb 0.1ppm and Onion, green 7ppm.  International MRLs for the fungicide mandipropamid have been established for various agricultural commodities in a number of countries in the European Union including Austria, Belgium, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Netherlands, Norway, Poland, Portugal, Romania, Spain, Sweden, and the United Kingdom.