Document ID: EPA-HQ-OPP-2016-0392-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-12-23T05:00Z

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

EPA Registration Division contact: [insert name and telephone number with area code]

TEMPLATE:

[Dow AgroSciences LLC]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN 46268 US 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 [XDE-777] in or on the raw agricultural commodity Bananas, Wheat, Rye and Meat, Fat, Kidney, Liver and Meat byproducts from Cattle, Goats and Sheep] at  in or on imported bananas at 0.1 parts per million (ppm) and in or on imported wheat and rye at 0.7 ppm, meat and fat from cattle, sheep and goats at 0.01 ppm and meat byproducts from cattle, sheep and goats at 0.02 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 XDE-777 has been studied in representative crops from three different crop groupings that include a cereal crop (wheat, (1)), a fruit crop (tomatoes, (2)) and a leafy vegetable (cabbage (3)).  Results from these three studies showed that XDE-777 is not extensively metabolized in crops following foliar applications.  Parent XDE-777 constitutes a large majority of residues in wheat, cabbage and tomato with low levels of individual metabolites observed.  A similar metabolite profile was observed across the three crop groups, regardless of the application rate, growth stages at application, different PHIs or formulation types.  In all crops, any metabolism that does occur proceeds through loss of the oxymethylisobutyrate group from the pyridine ring or through opening and cleavage of the bislactone ring to ultimately produce low levels of several possible pyridine-label or phenyl-label specific metabolites.  None of the observed residue components appeared to be present as conjugates. Tolerances should be comprised of the parent compound only as no metabolites of toxicological significance were detected in metabolism studies
2. Animal metabolism 
The metabolism of XDE-777 has been studied in both poultry and ruminants.  XDE-777 was rapidly and extensively metabolized in both laying hen and lactating goat with a similar metabolite profile.  
For poultry, extraction and analyses of the egg and tissue residues showed that once absorbed, XDE-777 was rapidly and extensively metabolized as a detectable residue of the unchanged parent test material was observed only in the skin with fat sample at a level of only about 5% of the TRR.  For all samples, the residue profile was complex and consisted of multiple low level components.  Over 18 different metabolites were isolated and identified.  All metabolites were formed as a result of O-dealkylation of one or both of the oxymethylisobutyrate side chains and opening of the bislactone ring at one of two possible positions.  Further metabolism resulted in complete cleavage of the bislactone ring to give a variety of phenyl-fragment and pyridine-fragment metabolites.  No residues of XDE-777 or any of its metabolites were observed in any of the egg or tissue samples at levels even approaching 0.010 mg/kg.
For ruminants, once absorbed, XDE-777 was rapidly and extensively metabolized.  Residues in tissues were readily extractable.  The metabolic profile was complex, with multiple low-level components that were observed in kidneys, liver, and urine, and a simplified profile was observed in feces.  There was evidence of O-dealkylation of the ester side chains, ring opening, and ring cleavage metabolites.  The ring-cleavage products resulted in differences in the metabolite profiles in the PH- and PY-labels.  Generally, 38-55% of the residues in kidneys and liver were identified.  In the edible matrices, metabolite X12326349 was observed at the highest level, 0.010 mg/kg, in the PY-labeled kidney.  
Based on the results of metabolism studies in ruminant / goat and laying hen, the residue definition for both enforcement / monitoring and risk assessment is proposed as the combined residues of XDE-777 and X12326349, expressed as XDE-777 equivalents.  

	2. Analytical method. [ 
Method S12-01537, "XDE 777 and its Metabolite X642188  -  Validation of the Method for the Determination of XDE 777 and its Metabolite X642188 in Crops by LC MS/MS.", was used for the analysis of XDE-777 and its metabolite X642188 in the plant materials. Residues of XDE-777 and its metabolite X642188 were extracted from crop samples by homogenizing and shaking with an acetonitrile/water (90:10) solution.  After extraction, a 250 uL aliquot of the extraction solution is diluted to 5.0 mL with an acetonitrile/water (90:10) solution containing 0.1% formic acid.  After filtering an aliquot of the diluted extract, the samples were analyzed by liquid chromatography using a Phenomenex Luna C18 column coupled with positive-ion electrospray tandem mass spectrometry (LC/MS/MS), monitoring two MS/MS transitions characteristic of each analyte. The method has a LOQ of 0.01 mg/kg. Method S12-01537 successfully passed an independent method validation (ILV) study. An adequate analytical method is available for enforcement of the tolerance expression in or on food. ]

	3. Magnitude of residues. 
Adequate data are available to support the tolerance of XDE-777 in or on imported bananas at 0.1 ppm based on the intended use of this compound for control of certain fungal diseases in Central and South America.  Additionally, adequate data are available to support tolerances of XDE-777 in or on imported wheat and rye at 0.7 ppm, meat and fat from cattle, sheep and goats at 0.01 ppm and meat byproducts from cattle, sheep and goats at 0.02 ppm based on the intended use of this compound for control of certain fungal diseases in wheat, triticale and rye in the European Union 

B. Toxicological Profile

	1. Acute toxicity. 
 XDE-777 exhibited low acute oral or dermal toxicity in the Fischer 344 rat with an LD50 >2000 (oral) or >5000 (dermal) mg/kg bw, respectively.  The 4-hour LC50 was >0.53 mg/L for the acute inhalation study, which was the highest attainable respirable concentration.  XDE-777 was essentially non-irritating in the skin and eye irritation studies in the New Zealand White (NZW) rabbit.  In a mouse local lymph node assay (LLNA), XDE-777 was negative for sensitization potential.

	2. Genotoxicty.. 
For the in vitro genotoxicity studies, the Bacterial Reverse Mutation Test (Ames test), and the Mammalian Cell Forward Mutation Assay (CHO/HGPRT) demonstrated that XDE-777 does not cause gene mutations in these cell cultures, in the absence or presence of a metabolic activation system (rat liver S9).  The Mammalian Chromosome Aberration Assay (rat lymphocytes) was positive for clastogenicity after 4-hour treatments in the absence or presence of a metabolic activation system (rat liver S9).  An in vivo mouse micronucleus assay demonstrated that XDE-777 does not induce micronuclei in somatic cells at a limit dose of 2000 mg/kg bw/day.  These data indicate that the in vitro clastogenicity effects were not reproducible following in vivo exposures. In an in vivo mouse UDS assay, XDE-777 did not induce any unscheduled DNA synthesis in the liver at the limit dose of 2000 mg/kg bw.

	3. Reproductive and developmental toxicity. 
There were no effects on reproduction or development following exposure to XDE-777 in a 2-generation rat reproduction study (up to the limit dose) and rat (up to the limit dose)  and rabbit (up to 495 mg/kg bw/day) developmental toxicity studies. 

	4. Subchronic toxicity.
The toxicity of XDE-777 has been evaluated extensively in rats, mice and dogs at doses up to the limit dose).  The target organ in the mouse is the liver (reversible effects of increased weights and slight hepatocellular hypertrophy, fatty change and necrosis), whereas there were no adverse findings in short-term rat or dog studies. There were no effects indicative of immunotoxicity or neurotoxicity following exposure to XDE-777.

	5. Chronic toxicity.
 There were no treatment-related neoplastic changes with dietary administration of XDE-777 for up to 18 months in CD-1 mice of either sex at the dose levels tested.  Similarly, dietary administration of XDE-777 to male and female F344/DuCrl rats for 2 years did not result in a treatment-related increase in neoplasms. 

	6. Animal metabolism. 
The absorption, distribution, metabolism and elimination of XDE-777 was assessed in rats, mice, rabbits and dogs.  Systemically available XDE-777 is highly metabolized, with very little parent found in the blood or in the urine of any species.  Parent XDE-777 is the major radiolabeled component present in the feces.  The majority of the urinary and fecal metabolites show similar distribution ratios across dose groups and with repeated exposure.  At high oral doses (300 mg [14]C-XDE-777/kg bw) the percent of the administered dose represented by the identified urinary and fecal metabolites was considerably less than at low oral doses (10 mg [14]C-XDE-777/kg bw), consistent with lower absorption seen at higher dose levels.  All of the proposed and identified urinary and fecal metabolites contain the intact phenyl and pyridine rings.  The four identified metabolites arise via hydrolysis of various ester moieties, as well as O-dealkylation of the hydroxymethoxy side chain of the pyridine ring.  

	7. Metabolite toxicology. 
Two studies, an Ames test and an acute oral toxicity study have been conducted on X642188, a plant metabolite which show there is no concern for mutagenicity or acute toxicity. 

	8. Endocrine disruption.
No specific studies have been conducted with XDE-777. There were no endocrine-mediated effects demonstrated in any species in the mammalian toxicological studies with XDE-777, including: the oral 28- and 90-day, multi-generational reproductive, developmental toxicity, and oncogenicity studies. Based on the lack of any effects on the endocrine system, XDE-777 is not considered an endocrine disrupter.

C. Aggregate Exposure

	1. Dietary exposure. 
For the US populations, the route of exposure to XDE-777 will only be through imported food. Residential use and drinking water exposure routes are not relevant.  XDE-777 does not have a proposed acute reference dose and, therefore, only chronic dietary exposures are germane.

	i. Food. 
The Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02) was used which incorporates NHANES 2-day food consumption data for 2005-2010 using food translations based on EPA/USDA FCID recipe set as of August 2014.  A conservative analysis (Tier 1) was initially conducted with the assumption that 100% of requested commodities would be treated with the XDE-777 and the residues would be present at the proposed tolerance levels.
Exposure through drinking water was not included because it is not applicable to imported foods.
The results of the dietary risk assessment are unlikely to underestimate risk.  This is in part due to the fact that, processing studies have shown that there was no concentration of residues of XDE-777 and X642188 metabolite in wheat processed fractions.  Edible processed fractions are wheat flour, bran and germ.  The proposed tolerance of 0.7 ppm for wheat, including processed commodities, was conservatively maintained in this assessment.
An acute reference dose (aRfD) is not required for XDE-777 as it is considered unlikely to present an acute hazard. There were no significant treatment-related findings in the acute, short-term, 2-generation reproduction or developmental toxicity studies to indicate a concern in acute dietary risk assessment.

	ii. Drinking water.  
For the US populations, the route of exposure to XDE-777 will only be through imported food. Residential use and drinking water exposure routes are not relevant.

	2. Non-dietary exposure. 
In general, commercial and homeowner uses of products in residential settings can lead to non-dietary exposures which are often aggregated with dietary exposure. However, given no additional routes of exposure are applicable to XDE-777 other than via the food route, no additional aggregation is required.

D. Cumulative Effects

	Currently, no methodologies are available to resolve the complex scientific issues concerning common mechanism of toxicity and cumulative exposure and risk. The U.S. EPA has begun a process to study this issue further through the examination of particular classes of pesticides. As such, Dow AgroSciences believes it is appropriate to consider only the potential risks of XDE-777 in this exposure assessment.

E. Safety Determination

	1. U.S. population. 
Based on the chronic dietary assessment, the dietary risk assessment supports a finding that there is a reasonable certainty that no harm will result to the general population from exposure to XDE-777 when exposure is due to imported cereals, bananas, meat and meat by-products.  For the chronic dietary assessment, all levels are 1% or less of the proposed reference dose and, therefore, are anticipated to be below the level of concern for the Agency.

	2. Infants and children. 
Based on the chronic dietary assessment, the dietary risk assessment supports a finding that there is a reasonable certainty that no harm will result to the general population from exposure to XDE-777 when exposure is due to imported cereals, bananas, meat and meat by-products.  For the chronic dietary assessment, all levels are 1% or less of the proposed reference dose and, therefore, are anticipated to be below the level of concern for the Agency.

F. International Tolerances

	There are no Codex maximum residue levels established for residues of XDE-777 for small grains or bananas nor are there international MRLs established for small grains or bananas.