Document ID: EPA-HQ-OPP-2015-0031-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-03-04T05:00Z

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

EPA Registration Division contact: 
Tony Kish, (703) 308-9443

Syngenta Crop Protection, LLC

4F8329

	EPA has received a pesticide petition from Syngenta Crop Protection, LLC, 410 Swing Road, Greensboro, NC 27419, 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 commodity, potato, at 0.08 ppm, and amending a tolerance for Mandipropamid in or on the raw agricultural commodity potato, wet peel at 0.12 ppm, and revising the tolerance expression for mandipropamid to read "vegetable, tuberous and corm, subgroup 1C (except potato)"  
	
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 415-02 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. 

Potato Sixteen potato crop-field trials were conducted in the United States to support the registration of a suspension concentrate (SC) formulation containing 2.08 lb ai/gallon of the active ingredient mandipropamid as a seed treatment followed by foliar use. At each trial site potato tuber samples were harvested 14 days after the last application (DALA).  At two trial sites, potato tuber samples were collected to determine the pattern of residue decline by collecting at 7, 10, 14, 17 and 21 days after the last application.  At two trial sites, bulk samples of potato tubers were collected from the non-treated control plot and from a plot where the application rate was 5X. Residues of mandipropamid and SYN500003 greater than LOQ were not found in the non-treated control samples of any potato matrix.  Mandipropamid and SYN500003 residues found in potato tubers after seed treatment followed by three foliar applications at a total nominal application rate of 0.54 lb ai/A did not exceed 0.0655 ppm and 0.0128 ppm respectively.
For processing, potato seed pieces were treated followed by three foliar applications at a total nominal exaggerated rate of 2.7 lb ai/A.  Mandipropamid residues were higher in the wet peel fraction than in the pre-processing tuber, with a mean residue concentration factor of 2.0X. Mandipropamid mean residue concentration factors for flakes, chips (crisps), and fries (chips) were <1. SYN500003 residues were higher in the flakes and chips (crisps) fractions than in the pre-processing tuber, with mean residue concentration factors of 1.7X and 1.4X respectively.  SYN500003 mean residue concentration factors for wet peel and fries (chips) were <1.
Data from this study may be used to support a tolerance proposal for mandipropamid on potato and potato, wet peel. 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.

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 software with the Food Commodity Intake Database (DEEM-FCID[TM], version 3.14).  DEEM-FCID software incorporates food consumption data from the National Health and Nutrition Examination Survey)/"What We Eat in America" (NHANES/WWEIA) dietary survey conducted in 2003-2008.  The exposure assessment included all approved uses of mandipropamid as follows: basil, dried and fresh; bean, snap; Brassica, head and stem, Subgroup 5A; Brassica, leafy greens, Subgroup 5B; fruit, small vine climbing, except fuzzy kiwifruit, Subgroup 13-07F; ginseng; grape, raisin; hop, dried cones; onion, bulb, Subgroup 3-07A; onion, green, Subgroup 3-07B; potato, wet peel; vegetable, cucurbit, Group 9; vegetable, fruiting, Group 8-10; vegetable, leafy except brassica, Group 4; vegetable, tuberous and corm, Subgroup 1C, plus a proposed use on treated potato seed pieces at a rate of 0.01 lb a.i./100 lb seed followed by up to three foliar applications at 0.114 lb a.i./A.  Processing factors were taken from the DEEM[TM] (version 7.87) default values, which were input manually into the DEEM-FCID(TM) software.  Percent of crop treated values were assumed to be 100% for all crop uses.  Drinking water estimates were incorporated directly into the dietary exposure assessments using the highest estimated drinking water concentrations (EDWCs) for surface and ground water.  

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-bw/day based upon a chronic toxicity study in rats with a no observed adverse effect level (NOAEL) of 5.0 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 chronic reference dose (% cRfD).  Chronic (food only) exposure to the U.S. population resulted in an MOE of 427 (23.4% of the cRfD of 0.05 mg/kg-bw/day).  The most exposed sub-population was children (1-2 years old) with an MOE of 243 (41.2% of the cRfD of 0.05 mg/kg-bw/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 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) for mandipropamid (determined as combined residues of mandipropamid, SYN500003, and SYN504851) were determined for surface water using the FIRST model (v 1.1.1) and for groundwater using SCI-GROW (v 2.3).  EDWCs from currently registered uses and the proposed seed treatment use on potato in conjunction with three foliar applications (a currently registered use) were assessed.  The currently registered foliar use on tomato and basil produced the highest chronic EDWCs of 2.15 ppb for surface water (adjusted for a 0.91 Percent Cropped Area), and 0.44 ppb for ground water. Because the chronic surface water EDWC (2.15 ppb) exceeds the chronic groundwater EDWC (0.44 ppb), the surface water value is used for risk assessment purposes and will be considered protective for any groundwater concentration concerns.  

Chronic Exposure from Drinking Water.  The chronic ground water EDWC of 2.15 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 an MOE of 111,064 (0.1% 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 an MOE of 43,073 (0.2% 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 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 and proposed uses for mandipropamid.

2.  Non-Dietary Exposure:  There are currently no registered residential uses associated with mandipropamid; therefore, a residential/non-occupational exposure assessment is not required. Due to potential exposures resulting from off-site drift of agricultural products into residential areas, residential post-application exposure assessments were performed.  However, these exposures are not included as a component of aggregate consumer risk (food + water + residential).  Since the EPA has not defined a short-term incidental oral endpoint, the chronic dietary endpoint (5 mg/kg-bw/day) was used.   In these assessments, children 1-6 years old were the most-exposed subgroup, with a post-application hand-to-mouth MOE of 9,828.  Since the Benchmark Level of Concern (LOC) for this assessment was 100 and since EPA generally has no concern for exposures above the Benchmark, Syngenta believes that there is a reasonable certainty that no harm will result from exposures resulting from off-site drift of agricultural products into residential areas.

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.  No appropriate endpoints were identified for acute dietary exposure; therefore no acute risk assessments were performed.  The chronic dietary exposure analysis (food plus drinking water) showed that exposure from all mandipropamid uses resulted in an MOE of 425 (23.5% of the cRfD of 0.05 mg/kg-bw/day) for the general U.S. population, which is above 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 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 assessments were performed.  The chronic aggregate dietary (food plus drinking water) exposure analysis showed that exposure from all pending and proposed mandipropamid uses would result in an MOE of 242 (41.3% of the cRfD of 0.05 mg/kg-bw/day) for the most sensitive population subgroup, children 1-2 years old, which is above 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 and proposed mandipropamid uses, including anticipated dietary exposure from food, water and all other types of non-occupational exposures.

F.  International Tolerances

There are currently no Maximum Residue Limits (MRLs) set for mandipropamid for crops by the Codex Alimentarius Commission.  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.