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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 

[

14C]triflumezopyrim was investigated in rice plants under separate soil and foliar 

treatment regimes. Single applications [14C]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 
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[

14C]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.]
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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. 
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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 
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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 treatmentrelated 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. [

14C]Triflumezopyrim was rapidly absorbed, extensively

metabolized, and excreted in livestock animals. Hens were dosed orally once a day for 14 
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consecutive days with three radiolabelled forms of [

14C]triflumezopyrim. The recovery of 

the administered dose was ≥89% with the majority eliminated in excreta and in cage 

washes. Minimal transfer of [14C]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 [

14C]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-FCIDTM, 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 × 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-FCIDTM, 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% 
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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 × 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 (DEEMFCIDTM, 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, nondietary 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 
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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.]