Document ID: EPA-HQ-OPP-2016-0142-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-04-25T04:00Z

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

EPA Registration Division contact: [Kable Bo Davis (302) 306-0415]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[E. I. DuPont de Nemours and Company]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from [E. I. DuPont de Nemours and Company], [Chestnut Run Plaza, 974 Centre Road, Wilmington, Delaware 19805] proposing, 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.

(Options (pick one)
   
   	1. by establishing a tolerance for residues of

	[Triflumezopyrim, 2,4-dioxo-1-(5-pyrimidinylmethyl)-3-[3-(trifluoromethyl)phenyl]-2H-pyrido[1,2-a]pyrimidinium inner salt] in or on the raw agricultural commodity [rice, grain] at [0.2] parts per million (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 three radiolabelled forms of [[14]C]triflumezopyrim was investigated in rice plants under separate soil and foliar treatment regimes. Single applications [[14]C]triflumezopyrim were made at ca. 300 g a.s./ha to soil surrounding rice seedlings and two 35 g a.s./ha foliar applications were made to immature rice plants  growing under flooded conditions. Immature rice foliage and mature crop fractions (straw, chaff and grain) were extracted and extracts analyzed to determine the nature of triflumezopyrim derived residues, and define a metabolic pathway for triflumezopyrim in rice plants. Following soil application [[14]C]triflumezopyrim uptake into rice was low in immature foliage,  in straw and  in grain. Triflumezopyrim was the principal extractable residue in immature foliage , straw and grain  samples. Crop residues were higher following foliar applications as compared to soil applications. Triflumezopyrim was again the major extractable component in immature foliage , straw  and grain . Triflumezopyrim metabolism in rice resulted in numerous low level metabolites regardless of the treatment regimen (foliar or soil application). 

Triflumezopyrim was extensively metabolised in livestock (goats and poultry) and in rice and succeeding crops. While minor differences in short-lived (transient) metabolic intermediates were observed, the overall metabolic pathway in plants and animals was consistent. The proposed metabolic pathway for triflumezopyrim in plants and livestock included (a) hydroxylation on the phenyl ring ortho to the trifluoromethyl group , (b) conjugation  to glucuronic acid and sulphate conjugates in goats (and rats), (c) oxidative defluorination  to form  hydroxy acids, (d) N-oxidation of the parent molecule , (e) oxidative or hydrolytic cleavage of parent , and (f) a series of oxidative hydrolysis, decarboxylation and rearrangement reactions of triflumezopyrim.]

	2. Analytical method. [The nature of residue of triflumezopyrim is adequately understood and an acceptable method is available for enforcement purposes.  The limit of quantitation at 0.01 mg/kg allows monitoring of triflumezopyrim residues at or above the proposed levels.]

	3. Magnitude of residues. [Field trials to meet country registration, and United States import tolerance, requirements were carried out in rice. The trials covered a wide range of locations, climates, and soil types and the data obtained reflect the commercial use of the triflumezopyrim-containing products in the major rice growing regions.  Analytes chosen for residue analysis were triflumezopyrim and one metabolite. Triflumezopyrim and the metabolite residues were measured in supervised magnitude of residue and processing trials.  The metabolite was included in the analysis of the field residue studies based on conservative assessments of the preliminary plant metabolism data. Further confirmatory analysis in the plant metabolism studies showed that the metabolite was an important plant metabolite. Further, the metabolite wasnot detected in any field trial samples. Therefore, the metabolite is considered not relevant for monitoring or dietary risk assessment.

On the basis of the data presented relating to metabolism of triflumezopyrim, it is evident that triflumezopyrim is the major residue in rice commodities following post-emergence application of triflumezopyrim and accordingly should be used for the purposes of defining the residue.

A rice processing study was also conducted at exaggerated rates to ensure quantifiable residues in the RAC.  Processing factors for brown rice, polished rice, bran and hulls were determined.

The field trials substantiated the results of the metabolism studies and support the proposed import tolerance for the United States.]

B. Toxicological Profile

	1. Acute toxicity.  [Triflumezopyrim has little to no significant acute toxicity via the oral, dermal, and inhalation routes of exposure. Triflumezopyrim is not a skin or eye irritant and does not cause skin sensitization. Based on these results, triflumezopyrim is classified for acute oral toxicity in Category III and is classified as Category IV for acute dermal and inhalation toxicity, for skin and eye irritation, and for skin sensitization according to the criteria of the U.S. EPA.

Study Type
Results
Category Determination
Acute Oral Toxicity in Rats	
Male LD50 >5000 mg/kg
Female LD50 = 4930 mg/kg
Combined LD50 >4930 mg/kg

Category III
Acute Dermal Toxicity
LD50 >5000 mg/kg bw
Category IV
Acute Inhalation Toxicity
LC50>5.04 mg/L
Category IV
Primary Eye Irritation
Slight irritation clearing by 48 hours
Category IV
Primary Dermal Irritation
Not irritating
Category IV
Primary Dermal Irritation
Not sensitizing (Guinea Pig Maximization test) 
Not a sensitizer
]

	2. Genotoxicty. [Triflumezopyrim was evaluated in a battery of in vitro and in vivo genotoxicity studies. The weight of evidence supports the conclusion that triflumezopyrim is not genotoxic.]

	3. Reproductive and developmental toxicity. [In the two-generation rat reproduction toxicity study, triflumezopyrim was administered in the diet to male and female rats at concentrations of 0, 100, 500, 1500, and 3000 ppm. The NOAEL for parental toxicity was 500 ppm based on reductions in body weight and nutritional parameters in P1 and F1 males and females at 1500 ppm and above. There were no test substance-related deaths or clinical observations, and no adverse effects on gross observations, organ weights, or microscopic alterations in P1 or F1 parental rats. The NOAEL for reproductive and fertility effects was 3000 ppm based on a lack of adverse, test substance-related effects in either the P1 or F1 generation at 3000 ppm, the highest dose tested. The data for mating, fertility, precoital interval length, gestation length, and implantation site counts were comparable across all groups for both generations. Additionally, there were no adverse, treatment-related effects noted on pup survival indices, estrous parameters, or sperm parameters at any concentration for either generation. The NOAEL for effects on pup growth and development was 1500 ppm based on a reduction in the body weight of F1 and F2 pups from birth and throughout lactation at 3000 ppm. 
      
In the developmental toxicity study in rats, the NOAEL for maternal toxicity was 100 mg/kg bw/day based on reduced body weight and food consumption parameters at 200 mg/kg bw/day. No effects on survival, clinical observations, or gross pathology were observed at any dose. The NOAEL for fetal toxicity was 200 mg/kg bw/day based on a lack of adverse effects at the highest dose tested. 
      
In the developmental toxicity study in rabbits, the NOAEL for maternal toxicity was 250 mg/kg bw/day based on reduced body weight and food consumption parameters, reduced defecation, and minimal hematology changes with associated increased spleen weights, at 500 mg/kg bw/day. No effects on survival or gross pathology were observed. The NOAEL for fetal toxicity was 500 mg/kg bw/day, the highest dose tested based on the absence of any adverse effects.]

	4. Subchronic toxicity. [The primary toxicological findings in short-term, repeated-dose oral toxicity studies in rodents included changes in body weight and nutritional parameters, increases in liver weight, and hepatocellular hypertrophy. The liver weight effects in rats and mice occurred in the absence of clinical or histopathological findings indicative of liver toxicity. Increases in cytochrome P450 liver enzyme content (total and specific isozymes), beta-oxidation activity, and mild reductions in bilirubin (rats) were noted in 28-day and/or 90-day studies in rats and mice, suggesting a non-adverse, adaptive, pharmacological response to increased metabolism due to exposure to triflumezopyrim. Hepatocellular hypertrophy accompanied the increases in liver weights in rats and mice (28 days and 90 days).  In rats, these liver effects were also associated with increased liver UDP-glucuronyltransferase activity (UDP-GT). However, the effects on UDP-GT were considered non-adverse as there were no correlative effects on thyroid hormones or thyroid pathology.

No evidence of a primary effect on the nervous system was observed in toxicity studies conducted with triflumezopyrim.  The NOAEL in an acute neurotoxicity study in rats was 100 mg/kg bw based on body weight gain reductions or body weight loss that occurred between the day of dosing and the day following dosing at dose levels of 500 and 1000 mg/kg. Accompany changes in neurobehavioral parameters and motor activity on the day of dosing occurred at the same dose levels.  There was no evidence of histopathology changes in nervous system tissues.  A subchronic neurotoxicity study was conducted during the course of the 90-day feeding study in rats.  The NOAEL for systemic toxicity was 1500 ppm (70 and 83 mg/kg bw/day for males and females respectively).  The NOAEL for neurotoxicity and neuropathology was 6000 ppm (274 and 316 mg/kg bw/day, respectively), the highest concentration tested, based on the lack of adverse, test substance-related effects on neurobehavioral and neuropathology parameters.

No adverse effects on immune system parameters were observed in a 28-day immunotoxicity study conducted in female rats.

Dogs were the most sensitive species to triflumezopyrim repeated-dose toxicity. The primary effects observed in feeding studies were reductions in body weight and nutritional parameters. At the highest dietary concentrations (10000 ppm for 28 days and 4000 ppm for 90 days), effects supported that these concentrations exceeded the maximum tolerated dose (MTD). No specific target organ was identified; most clinical and anatomic pathology effects were considered secondary to marked body weight and nutritional effects and associated non-specific stress. The NOAEL in dogs is 400 ppm, equivalent to 12.20 and 12.15 mg/kg bw/day in males and females, respectively, based on the results in the 90-day study.
      
Dermal application of triflumezopyrim to rats for 28 days did not result in any treatment-related findings up to and including a maximum dose of 1000 mg/kg bw/day.]

	5. Chronic toxicity. [The chronic toxicity and carcinogenic potential of triflumezopyrim was assessed in a 2-year feeding study in rats and an 18-month feeding study in mice. 
      
In rats, the NOAEL for chronic toxicity was 500 ppm in males and females (equivalent to 15.9 and 17.3 mg/kg bw/day, respectively). The primary findings in the study included marked reductions in body weight at dietary concentrations of 2000 and 8000 ppm; and based on the magnitude of the body weight effects at 8000 ppm (both sexes) and 2000 ppm (females), the changes were considered to have greatly exceeded the MTD. 

Triflumezopyrim was not oncogenic in male rats. In the high dose females, a small increase in squamous cell carcinoma of the uterus/cervix was observed and was statistically significant by the Cochran-Armitage trend test only. At the same dose level there were also statistically significant increases in changes typified by uterine dilatation, inflammation, and hyperplasia of the endometrial epithelium and an increase in squamous cell hyperplasia in the cervix.   However, the finding of uterine tumors is not considered relevant for humans as the tumors occurred at a dose level that caused marked reductions in body weight considered to have greatly exceeded the MTD. Therefore, the biological relevance of toxicological findings under these conditions of severe systemic toxicity is highly questionable. Further, mechanistic studies demonstrated that triflumezopyrim is not a direct estrogen agonist, but did show decreases in prolactin suggesting the underlying mode of action is specific to rodents.

In mice, there were no treatment-related effects on body weight or any other in-life parameter in males or females administered triflumezopyrim up to and including a maximum dietary concentration of 7000 ppm for 18 months. 

Hepatocellular adenomas were increased in high dose male mice, which was statistically significant by Cochran-Armitage trend test only. Mechanistic work supported the conclusion that the tumors were secondary to activation of the constitutive androstane receptor (CAR), a pronounced increase in cytochrome P450 2B gene expression, heptocelluar hypertrophy, and an increase in cell proliferation confirming a phenobarbital-like mechanism for liver tumor induction in rodents that is not relevant for humans.]

	6. Animal metabolism. [The metabolism of triflumezopyrim in animals (hens and goats) is adequately understood. [[14]C]Triflumezopyrim was rapidly absorbed, extensively metabolized, and excreted in livestock animals. Hens were dosed orally once a day for 14 consecutive days with three radiolabelled forms of [[14]C]triflumezopyrim. The recovery of the administered dose was >=89% with the majority eliminated in excreta and  in cage washes. Minimal transfer of [[14]C]triflumezopyrim equivalent residues to eggs and tissues was observed. Whole eggs and edible tissues accounted for <0.1% of the dose. Total radioactive residues (TRR) in whole eggs plateaued within 4 days.. TRR in liver were ca. 0.30 mg/kg and <=0.01 mg/kg in muscle and abdominal fat. Triflumezopyrim was the principal extractable component in Day 9-13 composite eggs and liver . Muscle and fat contained low levels of triflumezopyrim.
      
Goats were dosed orally once a day for 7 consecutive days with three radiolabelled forms of [[14]C]triflumezopyrim. . The recovery of the administered dose was >=80% with the majority eliminated in the feces , urine , and cage washes. Milk accounted for 1.2-2.3% of the dose and edible tissues accounted for <=0.4% of the dose. TRRs plateaued within 2 days in milk for the three radiolabels. The majority of radioactive residues (88-99%) was characterized or identified in tissues and milk. Triflumezopyrim was the major component in all tissues.]

	7. Metabolite toxicology. [Metabolites found in plants, in domestic animals, or those that could potentially enter the human diet via drinking water were common to those produced in the rat metabolism study. Therefore, no toxicological studies were considered warranted for metabolites of triflumezopyrim.]

	8. Endocrine disruption. [Based on the standard battery of required mammalian toxicology studies and additional work to evaluate potential estrogenicity, there is no evidence to suggest that triflumezopyrim directly affects the estrogen, androgen, or thyroid pathways.]

C. Aggregate Exposure

	1. Dietary exposure. [An import tolerance is proposed in this petition for residues of triflumezopyrim on rice grain with hulls.  This is the first proposed tolerances in the U.S. for commodities treated with triflumezopyrim.  For the purpose of assessing the potential dietary exposure, an exposure assessment was conducted using the Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02) based on the National Health and Nutrition Examination Survey (NHANES) 2-day food consumption data for 2005-2010, and residues at proposed tolerance levels.]

   	i. Food. [Acute Dietary Exposure:  A conservative acute dietary risk assessment has been calculated based on a residue value of 0.014 mg/kg for brown rice based on the proposed MRL (rice grain with hull, 0.2 mg/kg) and the processing factor (brown rice, 0.069) [0.014 mg/kg = (0.2 mg/kg x 0.069)]. The assumption of 100% crop treated was applied. Estimates of the US acute dietary exposure from food was determined with Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02) based on the National Health and Nutrition Examination Survey (NHANES) 2-day food consumption data for 2005-2010. The acute dietary exposure of the US population was conservatively determined to be 0.000019 mg/kg bw/day at the 95th percentile of exposure, <1% of the proposed acute reference dose of 1 mg/kg bw/day. The calculated acute dietary exposure of all US subpopulations was <1% of the proposed acute reference dose indicating there are no short-term consumer intake concerns.
   
   Chronic Dietary Exposure:  A conservative chronic dietary risk assessment has been calculated based on a residue value of 0.014 mg/kg for brown rice based on the proposed MRL (grain with hull, 0.2 mg/kg) and the processing factor (brown rice, 0.069) [0.014 mg/kg = (0.2 mg/kg x 0.069)]. The assumption of 100% crop treated was applied. Estimates of the US chronic dietary exposure from food was determined with Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02) based on the National Health and Nutrition Examination Survey (NHANES) 2-day food consumption data for 2005-2010. The chronic dietary exposure of the US population was determined to be 0.000004 mg/kg bw/day, <1% of the proposed chronic reference dose of 0.12 mg/kg bw/day. The calculated chronic dietary exposure of all US subpopulations was <1% of the proposed chronic reference dose indicating there are no long-term consumer intake concerns.]

   	ii. Drinking water. [Since this will be an import tolerance use only, no drinking water exposures are anticipated.]

	2. Non-dietary exposure. [Since this will be an import tolerance use only, non-dietary exposures are not anticipated]

D. Cumulative Effects

	[Triflumezopyrim is an insecticide belonging to the mesoionic class of chemistry. The mode of action classification for triflumezopyrim is a Group 4E insecticide.  This is a sub-group of Group 4  -  nicotinic acetylcholine receptor (nAChR) competitive modulators.  This new insecticide for the control of rice hoppers has been reviewed by the IRAC MoA WG and a classification to Group 4E agreed.]

E. Safety Determination

	1. U.S. population. [Using the conservative exposure assumptions described above and based on the completeness of the toxicity data, it can be concluded that total dietary exposure to triflumezopyrim from the proposed use will be <1% the acute population adjusted dose (aPAD) and <1% and the chronic population adjusted dose (cPAD) for the overall US population.  EPA generally has no concern for exposures below 100% of the PAD because the PAD represents the level at or below which daily exposures will not pose appreciable risk to human health.  Thus, it can be concluded that there is a reasonable certainty that no harm will result from aggregate exposure to residues from the proposed import tolerance discussed in this petition.]

	2. Infants and children. [Using the conservative exposure assumptions described above and based on the completeness of the toxicity data, it can be concluded that total dietary exposure to triflumezopyrim from the proposed use will be <1% the acute population adjusted dose (aPAD) and <1% and the chronic population adjusted dose (cPAD) for infants and children.  Thus, based on the completeness and reliability of the toxicity data, the lack of toxicological endpoints of special concern, the lack of any indication that children are more sensitive than adults to triflumezopyrim, and the conservative exposure assessment, there is no reasonable certainty that no harm will result to infants and children from the aggregate exposure of residues of triflumezopyrim, including all anticipated dietary exposure.]

F. International Tolerances

	[Triflumezopyrim is a new active substance and there are currently no established MRLs.   An MRL is proposed for rice where triflumezopyrim is to be applied, as well as for an import tolerance for the United States.  This MRL is calculated using OECD MRL Calculator based on relevant residue data.]