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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

 EPA has received a pesticide petition ([insert petition number]) from [Mitsui 

Chemicals Agro, Inc.], [c/o Landis International, Inc., P.O. Box 5126, Valdosta, GA 

31603-5126] 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.

 1. by establishing a tolerance for residues of 

[Dinotefuran, (RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine 

and its major metabolites DN, 1-methyl-3-(tetrahydro-3-furylmethyl)guanidine, and 

UF, 1-methyl-3-(tetrahydro-3-furylmethyl)-urea] in or on [rice, grain] at [10] 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 primary metabolic pathways of dinotefuran in plants 

(rice, apple, potato, oilseed rape and lettuce) were similar to those described for 

animals, with certain extensions of the pathway in plants. Parent compound, 

dinotefuran, and two metabolites; 1-methyl-3-(tetrahydro-3-furymethyl) guanidine 

(DN) and 1-methyl-3-(tetrahydro-3-furymethyl)-urea (UF) were major metabolites 

in all crops. The metabolism of dinotefuran in plants and animals is understood for 

the purposes of the proposed tolerances. Parent dinotefuran and the metabolites, 1-

methyl-3-(tetrahydro-3-furymethyl)guanidine (DN) and 1-methyl-3-(tetrahydro-3-

furymethyl)-urea (UF) are the residues of concern for tolerance setting purposes.

 2. Analytical method. Practical analytical methodology for detecting and 

measuring levels of dinotefuran and its metabolites, UF and DN, in or on raw 

agricultural commodities has been conducted. Dinotefuran and its metabolites in 

the plant matrix extracts were analyzed by HPLC and TLC chromatography to 

determine the number of metabolites and their relative distribution in the samples. 

The HPLC method was validated for determination of dinotefuran, DN and UF in 

or on tomatoes and peppers, cucurbits, brassica, grapes, potatoes, mustard greens, 

rice, and lettuce for raw agricultural commodity matrices and in or on tomato paste 

and puree, grape juice and raisins and potato chips, granules, and wet peel, rice 

grain, hulls, and bran for processed commodity matrices. After extraction with a 

water/acetonitrile mixture and clean up with hexane and extraction columns, 
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concentrations of dinotefuran and its metabolites were quantified after HPLC 

separation by MS/MS detection. The limit of quantitation was 0.01 ppm for all 

matrices. 

 3. Magnitude of residues. Crops in residue trials were treated at or above the 

maximum label rate and harvested at the specified minimum treatment to harvest 

intervals. The residue method for dinotefuran, DN and UF in rice grain, straw, 

bran and hulls utilized HPLC separation with MS/MS detection. The rice grain 

residue values for dinotefuran ranged from 0.72 to 4.24 ppm. The rice grain residue 

values for DN ranged from 0.16 ppm to 1.66 ppm. The rice grain residue values for 

UF ranged from 0.13 ppm to 1.1 ppm. The rice straw residue values for dinotefuran 

ranged from 0.24 ppm to 7.2 ppm. The rice straw residue values for DN ranged 

from <LOQ to 0.98 ppm. The rice straw residue values for UF ranged from <LOQ 

ppm to 0.59 ppm. The proposed tolerance for dinotefuran and metabolites DN and 

UF on rice grain are 10 ppm. Dinotefuran 20% water soluble granule was applied 

to rice at exaggerated rates (7.5 and 5 times the label rate) to determine if residues 

of dinotefuran, UF and DN concentrated in hulls, bran, and polished rice. Residues 

of dinotefuran, UF and DN were detected in hulls, bran and polished rice. The data 

showed 3.9- to 5.3-fold concentration factors for dinotefuran, UF and DN in hulls. 

There was no evidence of concentration of residues in bran or polished rice. 

Tolerances have been previously proposed for combined residues of Dinotefuran, 

DN and UF in or on Leafy Vegetables (Crop Group 4), Cotton Seed Undelinted and 

Cotton Gin Byproducts, Cucurbit Vegetables (Crop Group 9), Grapes, Potatoes, 

Fruiting Vegetables (Crop Group 8), Vegetables, Brassica Head and Stem crop 

subgroup (Crop Subgroup 5A), and Meat, Milk and Byproducts and Leafy Brassica 

Greens including Turnip Greens (Crop Subgroup 5B). 

4. Crop Rotation Studies. For a field rotational crop study, an application 

formulation was mixed with equal parts of F and G labeled dinotefuran as well as 

an unlabeled dinotefuran and blank formulation for a field trial conducted in 

California where dinotefuran was applied to soil to determine residue levels in 

rotational crops planted 30 and 120 days after treatment. The test substance was 

applied to the sandy loam soil at a rate of 243 g a.i./A in a volume of 113.55 GPA. At 

30 days after the application, radish, lettuce, and sorghum crops were planted. 

Each crop was harvested at maturity and sent to the laboratory for analysis. At 120 

days after the application this procedure was repeated with the exception of wheat 

rather than sorghum. To determine residues, plant tissues were analyzed first by 

combustion followed by scintillation counting. After solvent extraction on selected 

matrices, the extracts were analyzed by HPLC and TLC. The results showed 

several compounds present at above 0.01 ppm (LOQ) at the 30-day time interval, 

including the parent molecule. However, there were no individual components seen 

at concentrations above 0.006 ppm in any matrix in the 120-day samples including 

radish leaves. Therefore, neither the parent dinotefuran nor any of its metabolites 

would be expected to be taken up by crops when planted 120 days from the time of 

application. 
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B. Toxicological Profile 

 1. Acute toxicity. Dinotefuran has low acute oral, dermal and inhalation 

toxicity. The oral LD50 in rats is 2804/2000 mg/kg [M/F], the oral LD50 in mice is 

2450/2275 mg/kg [M/F], the dermal LD50 is >2000 mg/kg and the inhalation 4-hour 

LC50 is >4.09 mg/L air. Dinotefuran is not a skin sensitizer in guinea pigs but is 

slightly irritating to the skin and eyes of rabbits. End-use formulations of 

dinotefuran have similar low acute toxicity profiles. 

Acute Toxicity Profile of Dinotefuran 

Guideline No. Study Type Toxicity Category 

870.1100 Acute Oral III 

870.1200 Acute Dermal IV 

870.1300 Acute Inhalation IV 

870.2400 Acute Eye Irritation II 

870.2500 Acute Dermal Irritation IV 

870.2600 Skin Sensitization Not a Sensitizer 

 2. Genotoxicity. Dinotefuran and its metabolites do not induce gene mutations 

in bacterial and mammalian cells, chromosome aberrations in mammalian cells or 

DNA damage in bacterial cells in in vitro test systems. Similarly, it does not exhibit 

a clastogenic effect in vivo in the mouse micronucleus test. Therefore, there is no 

evidence to suggest a genotoxic hazard at any of the 3 main levels of genetic 

organization. 

 3. Reproductive and developmental toxicity.

In rat and rabbit developmental toxicity studies with dinotefuran, there was no 

evidence of teratogenicity or other embryotoxic effects at the highest dose levels. 

There were no treatment-related effects on litter parameters at any dose level in 

either species. The maternal NOAELs in rats and rabbits were 300 mg/kg/day and 

52 mg/kg/day, respectively. The NOAEL values in rats and rabbits for embryonic 

development and teratogenicity were the highest dose levels administered (1000 and 

300 mg/kg /day), respectively. In a 2-generation study, parental animals of both 

sexes and both generations showed reduced body weight gain and food consumption 

at the highest dose level evaluated (10000 ppm), but there was no effect of treatment 

at any dose level in either generation on reproductive performance indicators. There 

were no treatment-related effects at any dose level on the histopathological 

appearance of the reproductive organs of either sex. Similarly, there were no effects 

at any dose level in either generation on quantitative ovarian histopathology or on 

sperm counts, motility and morphology. F1 pup behavioral and sexual development 

was unaffected by treatment at all dose levels but pup weight gain during lactation 

was reduced at 10000 ppm in both generations. The parental (systemic), 

reproductive, and developmental NOELs in the 2-generation study were all 241/268 

[M/F] mg/kg/day.
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 4. Subchronic toxicity. Dinotefuran was evaluated in 13-week oral (diet) 

toxicity studies in rats, mice, and dogs. No specific target organs were identified in 

any species. The NOAELs were 38/384 [M/F] mg/kg/day in rats, 4442/5414 [M/F] 

mg/kg in mice, and 307 mg/kg/day in male dogs. A NOAEL was not established in 

female dogs. Dinotefuran was also evaluated for dermal and inhalation toxicity for 4 

weeks in rats. During daily inhalation exposure of rats for 6 hours/day for 4 weeks, 

a NOAEL of <0.22/0.22 [M/F] mg/L was established based upon decreased weight 

gain. Dinotefuran was well tolerated and there were no treatment related effects on 

clinical condition, hematology, and clinical chemistry profiles, organ weights, 

macroscopic and microscopic pathology. Dermal application to rats for 4 weeks 

generated a systemic NOAEL of 1000 mg/kg/day (highest dose) and a dermal 

NOAEL of 1000 mg/kg/day for males and less than or equal to 200 mg/kg/day for 

females. 

 5. Chronic toxicity and Carcinogenicity. Chronic toxicity studies with 

dinotefuran have been conducted in rats and dogs. Similar to the subchronic studies 

in these species, no specific target organs were identified. In the 52-week dog study a 

NOAEL of <20/22 [M/F] mg/kg/day was established based on decreased weight gain 

in both sexes and decreased food consumption in females. In the 104-week 

combined chronic toxicity/carcinogenicity study for rats a NOAEL of 99.7/127.3 

[M/F] mg/kg/day was established. 

The carcinogenic potential of dinotefuran also has been evaluated in a 78-week 

dietary carcinogenicity study in mice. Survival incidences in the oncogenicity 

studies were unaffected by treatment at all dose levels. The NOAEL was 25000 ppm, 

the highest concentration tested. 

 6. Animal metabolism. In the rat, dinotefuran is rapidly and almost completely 

absorbed from the gastrointestinal tract into the general circulation, and is widely 

distributed throughout the tissues and fluids of the body. Elimination is rapid, 

predominantly by urinary excretion and almost complete within 7 days of 

administration. There is no evidence for tissue accumulation. Dinotefuran is rapidly 

transferred to maternal milk and widely distributed into fetal tissues but rapidly 

eliminated from them. More than 90% of orally and intravenously administered 

dinotefuran is eliminated as unchanged parent molecule, which is also the major 

radioactive component in plasma, milk, bile and most tissues. The major route of 

metabolism is an initial enzymatic hydroxylation of the tetrahydrofuran ring to 

form isomers of 6-hydroxy-5-(2-hydroxyethyl)-1-methyl-1,3-diazinane-2-ylidine-Nnitroamine (PHP), followed by further oxidation, reduction and acetylation of PHP 

to produce possible isomers of dinotefuran-CO, dinotefuran-DO, PHP-Ac and 

dinotefuran-OH+COOH. Several minor pathways of metabolism of dinotefuran 

were identified in animals. The absorption, distribution, metabolism and 

elimination of dinotefuran is unaffected by sex and treatment regimen. In hens and 

goats, the metabolite profile was similar as in plant metabolism.

 7. Metabolite toxicology. The metabolism profile for dinotefuran supports the 

use of an analytical enforcement method that accounts for parent dinotefuran and 
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1-methyl-3-(tetrahydro-3-furymethyl)guanidine (DN) and 1-methyl-3-(tetrahydro-3-

furymethyl)-urea (UF). Other metabolites are considered of equal or lesser toxicity 

than parent compound.

 8. Endocrine disruption. Dinotefuran does not belong to a class of chemicals 

known or suspected of having adverse effects on the endocrine system. There is no 

evidence that dinotefuran has any effect on endocrine function in developmental or 

reproduction studies. Furthermore, histological investigation of endocrine organs in 

chronic dog, rat and mouse studies did not indicate that the endocrine system is 

targeted by dinotefuran. 

9. Neurotoxicity. Dinotefuran did not produce any functional or 

histomorphological evidence of neurotoxicity in acute (gavage) and 13-week 

(dietary) neurotoxicity studies in rats. The NOAEL for neurotoxicity in the acute 

study was 750/325 [M/F] mg/kg/day. The NOAEL for neurotoxicity in the 13-week 

dietary study was 500 ppm (33/40 [M/F] mg/kg/day). In a developmental 

neurotoxicity study in rats, The NOAEL for both functional and histopathological 

developmental neurotoxicity in the F1 generation rats whose mothers were exposed 

to dinotefuran was 10000 ppm, the highest dose tested. This dietary concentration 

provided an average maternal dose level of 784 mg/kg/day during the gestation and 

1643 mg/kg/day during the lactation period. A NOAEL for all toxicological effects 

was established as 3000 ppm (equivalent to an average maternal dose level of 237 

mg/kg/day during the gestation and 501 mg/kg/day during the lactation period) 

based on the occurrence of reduced maternal body weight gain during gestation at 

10000 ppm. 

10. Immunotoxicity. An assessment of the functional responsiveness of 

specified elements of the immune system using a modification of the Jerne Plaque 

Forming Cell Assay (PFC) in rats following a dietary administration of dinotefuran 

was conducted for 4 weeks. Three groups of 10 males and 10 females each received 

dinotefuran at rates of 2240, 5600 or 14000 ppm. There were no unexpected deaths, 

treatment related clinical signs or any effect on water consumption, spleen and 

thymus weights or macroscopic pathology findings. The NOEL for functional 

immunotoxicity by dinotefuran was greater than 14000 ppm (maximum dose), 

equivalent to dose levels of ≥992 mg/kg/day in males and ≥1080 mg/kg/day in 

females. 

A similar immuntoxicity study in was performed in CD-1 mice. The dietary 

administration of dinotefuran to the CD-1 mouse at 1120, 2800 or 7000 ppm for four 

weeks was well-tolerated by both sexes. The NOAEL for all effects was 7000 ppm, 

equivalent to dose levels of 1053 and 1438 mg/kg/day in males and females, 

respectively. There was no effect on immune function, as assessed by the 

measurement of antigen-specific, T-cell dependent antibody formation. The NOEL 

for functional immunotoxicity by dinotefuran was therefore greater than 7000 ppm, 

equivalent to dose levels of >1053 mg/kg/day in males and >1438 mg/kg/day in 

females. 
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C. Aggregate Exposure

 1. Dietary exposure. The acute and chronic dietary exposure assessment for 

dinotefuran was determined with the Dietary Exposure Evaluation Model software 

with Food Commodity Intake Database (DEEM-FCIDTM), version 2.16, from 

Exponent, Inc. The dietary analysis includes established tolerances, pending 

registrations currently being reviewed at the Agency and the proposed tolerance for 

food/feed handling establishments.

 i. Food. The acute exposure to dinotefuran at the 95th percentile for the 

overall U.S. population was 2.23% of the aRfD (MOE 4482). The acute exposure of 

the most highly exposed subgroup, non-nursing infants (<1 yr old), was 4.43% of the 

aRfD; therefore, there are large margins of safety for all population groups. The 

chronic exposure to dinotefuran for the overall U.S. population in this conservative 

analysis is 30.2% (MOE 3306) of the Chronic Reference Dose (cRfD = ADI = 0.02 

mg/kg bw/day). The most sensitive subpopulation in the chronic analysis was 

children (1-2 years) at 65.7% of the cRfD (MOE 1522). The chronic analysis 

includes the percent crop treated for the critical commodity rice. The predicted 

percent crop treated for rice is 30% at maturity (after 5 years). All other 

commodities assumed 100% crop treated. Thus, the aggregate acute and chronic 

dietary exposure of dinotefuran, including the contribution of drinking water, meets 

the standard of reasonable certainty of no harm. 

 ii. Drinking water. To assess the aggregate dietary exposure to food and 

drinking water, water residue values were included in the acute and chronic dietary 

assessment described above for food only. Worst-case concentrations of dinotefuran 

in groundwater were modeled using Screening Concentration in Ground Water 

(SCI-GROW, v2), and worst-case surface water concentrations were modeled using 

FQPA Index Reservoir Screening Tool (FIRST). The EDWCs were directly entered 

into the DEEM-FCID software into the food categories “water, direct, all sources” 

and “water, indirect, all sources”. For the acute assessment, the acute (peak) 

surface water concentration of 75.78 ppb (0.07578 ppm) was used. For the chronic 

assessment, the annual average water concentration of 20.97 ppb (0.02097 ppm) was 

used. 

 2. Non-dietary exposure. The EPA evaluated the occupation and residential 

exposure assessment for dinotefuran as part of the proposed new uses of 

dinotefuran on turnip greens and brassica leafy vegetables and an aggregate 

exposure was addressed in that risk assessment (D358026, B, O’Keefe, Aug 6, 2009). 

Occupational handlers may be exposed by the dermal and inhalation routes during 

mixing, loading, applying, flagging, and otherwise handling dinotefuran. All 

scenarios for the rice use pattern that would result in occupational handler exposure 

(i.e., open mixing/loading of liquids for aerial application; applicator, aerial, fixedwing; flagging for aerial application) have been previously assessed at a higher 
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application rate than that of the new rice use. All dermal and inhalation MOEs for 

these scenarios were >100 and therefore, not of concern to EPA. 

Combined risk was estimated by calculating an ARI because, while dermal and 

inhalation endpoint effects are the same, they have different associated levels of 

concern for the MOE. Calculated ARIs of > or = 1 do not cause concern to EPA. 

Occupational postapplication risk was assessed using data in the Science Advisory 

Council for Exposure (ExpoSAC) Policy 3 memorandum revised June 3, 2011. 

Intermediate-term dermal exposure was assessed for activities such as scouting and 

hand weeding. MOEs for these activities were >100 and are therefore not of 

concern.

D. Cumulative Effects The potential for cumulative effects of dinotefuran and other 

substances that have a common mechanism of toxicity has also been considered. 

Dinotefuran belongs to a pesticide chemical class known as the neonicotinoids and 

subclass nitroguanadines. There is no reliable information to indicate that toxic 

effects produced by dinotefuran would be cumulative with those of any other 

chemical including another pesticide. Therefore, Mitsui Chemicals Agro, Inc., the 

registrant of dinotefuran technical, believes it is appropriate to consider only the 

potential risks of dinotefuran in an aggregate risk assessment.

E. Safety Determination

 1. U.S. population. The toxicity database for dinotefuran is now complete. 

The database includes acute, subchronic, chronic, mutagenicity, genotoxicity, 

developmental, reproduction, neurotoxicity and immunotoxicity studies on 

dinotefuran and acute toxicity and mutagenicity studies on main metabolites. 

 2. Infants and children. In 2004, the FQPA Safety Factor for increased 

susceptibility of infants and children was reduced to 1X for exposure to dinotefuran 

based on toxicological considerations, the conservative residue assumptions used in 

the dietary risk assessments, the completeness of the residue chemistry database, 

and conservative drinking water assessment. 

F. International Tolerances No Codex Maximum Residue Levels (MRLs) have been 

established for residues of dinotefuran on any crops at this time.