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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

[BASF Corporation]

[1F7967]

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

Corporation], [c/o Landis International, Inc. P.O. Box 5126 3185 Madison Highway 

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 

in or on [all food/feed items (other than those already covered by a higher tolerance 

as a result of use on growing crops) in food/feed handling establishments where food 

products are held, processed or prepared] at [0.01] 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 the 

magnitude of residues that accumulate in /on perishable food matrices (butter, 

processed meat, lettuce, bread, milk, peaches and pie), on non-perishable food 

matrices (candy M&Ms), rice, crackers, potatoes and flour) and on bare surfaces 

(dinner plates, aluminum foil and table knives) following a spot and crack and 

crevice treatment of dinotefuran in a simulated food handling establishment has 

been conducted. The analytical method included sample extraction with acetonitrile 

or acetonitrile/water in conjunction with a solid-phase extract ion/clean-up of 
2

extracts prior to analysis. Quantitation of dinotefuran in extracts was performed 

using LC/MS/MS. The Limit of Quantitations (LOQs) were established at 

concentrations of 0.01 mg/kg or 0.01 mg/L, as appropriate for food matrices. 

 3. Magnitude of residues. A residue study was conducted in a simulated food 

handling establishment using a pressurized liquid aerosol formulation of 

dinotefuran 0.5% to make multiple general, crack and crevice and spot treatments 

at exaggerated label rates. Testing matrix consisted of perishable, non-perishable 

and inert food service items. Quantitation of dinotefuran was performed using LCMS/MS. Mean recoveries ranged from 90.5% to 107% of expected values. Potential 

residue-transfer routes were adequately addressed and results show that residues 

may occur in/on food from treatment in food handling establishments via direct 

deposit resulting from general treatment, but crack and crevice and spot treatment 

did not result in quantifiable dinotefuran residues in any food matrix or on any 

inert surfaces. Residues are summarized in the following tables: 

Residues of Perishable Food Items 

Matrix 

Estimated 

Surface 

Area 

Mean Residue 

Following CC 

and ST 

Treatments 1

Mean Residue 

Following a 

General 

Treatment 

Maximum 

Observed Residue 

Butter 280 cm2 <LOQ 0.0189 mg/kg 0.0194 mg/kg 

Meat 254 cm2 <LOQ 0.0549 mg/kg 0.0571 mg/kg 

Milk 50 cm2 <LOQ 0.01 mg/L 0.0128 mg/L 

Bread 314 cm2 <LOQ 0.165 mg/kg 0.170 mg/kg 

Lettuce 201 cm2 <LOQ 0.0305 mg/kg 0.0351 mg/kg 

Sliced 

peaches 

133 cm2 <LOQ 0.0285 mg/kg 0.0307 mg/kg 

Sliced Pie 201 cm2 <LOQ 0.0310 mg/kg 0.0363 mg/kg 

1

 CC = crack & crevice, ST = spot treatment. The LOQ was 0.01 mg/kg (or 0.01 

mg/L, for milk). 

Residues of Non-Perishable Food Items 

Matrix 

Estimated 

Surface 

Area 

Mean Residue 

Following CC 

and ST 

treatments 1

Mean Residue 

Following a 

General 

Treatment 

Maximum 

Observed 

Residue 

Flour 133 cm2 <LOQ 0.0353 mg/kg 0.0673 mg/kg 

Candy 133 cm2 <LOQ 0.0319 mg/kg 0.0557 mg/kg 

Potatoes 133 cm2 <LOQ 0.0306 mg/kg 0.0417 mg/kg 

Rice (in bag) 211 cm2 Not Detected Not Detected Not Detected 

Crackers (in 

box) 

286 cm2 <LOQ <LOQ <LOQ 

Knife 36 cm2 <LOQ <LOQ 3.3 mg/m2

Plate 314 cm2 <LOQ 0.938 mg /m2 1.76 mg/m2

Aluminum 621 cm2 <LOQ 0.678 mg/m2 1.44 mg/m2
3

foil 

1

 CC = crack & crevice, ST = spot treatment. The LOQ was 0.01 mg/kg for food 

and 10.0 μg for inert surfaces. 

4. Crop Rotation Studies. A crop rotational study has been reviewed and 

accepted by the Agency for dinotefuran. In this study, an application formulation 

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

dinotefuran and blank formulation and 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 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. 

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 
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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.

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

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 dintoefuran 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 
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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. 

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 1552). 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. 
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 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. 

MOEs for non-dietary exposure assessments do not exceed the Agency's level of 

concern for all exposure scenarios analyzed (applicator, aerosol can; 

loader/applicator, bulb duster; applicator, trigger-spray bottle). 

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.