# i

EPA REGISTRATION DIVISION CO MPANY 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 f ood/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 F DDCA; however, EPA has not fully evaluated the sufficiency

of the submitted data at this time or whethe r the data supports gran ting 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 le ttuce) were similar to those described for animals, with certain extensions of th e pathway in plants. Parent compound, dinotefuran, and two metabolites; 1-meth yl-3-(tetrahydro-3-furymethyl) guanidine (DN) and 1-methyl-3-(tetrahydro-3-furyme thyl)-urea (UF) were major metabolites in all crops. The metabolism of dinotefura n in plants and animals is understood for the purposes of the proposed tolerances. Parent dinotefuran and the metabolites, 1- methyl-3-(tetrahydro-3-furymethyl)guanidi ne (DN) and 1-methyl-3-(tetrahydro-3- furymethyl)-urea (UF) are the residues of concern for tolerance setting purposes.

2. Analytical method. Practical analytical meth odology for detecting the magnitude of residues that accumulate in /on perishable food matrices (butter, processed meat, lettuce, bread, milk, pe aches and pie), on non-perishable food matrices (candy M&Ms), rice, crackers, po tatoes 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 si mulated food handling establishment has been conducted. The analytical method incl uded sample extraction with acetonitrile or acetonitrile/water in conjunction with a solid-phase extract ion/clean-up of2

extracts prior to analysis. Quantitation of dinotefuran in extracts was performed using LC/MS/MS. The Limit of Quan titations (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 pressu rized 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 a ddressed 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 cm 2 <LOQ 0.0189 mg/kg 0.0194 mg/kg

Meat 254 cm 2 <LOQ 0.0549 mg/kg 0.0571 mg/kg

Milk 50 cm 2 <LOQ 0.01 mg/L 0.0128 mg/L

Bread 314 cm 2 <LOQ 0.165 mg/kg 0.170 mg/kg

Lettuce 201 cm 2 <LOQ 0.0305 mg/kg 0.0351 mg/kg

Sliced peaches 133 cm 2 <LOQ 0.0285 mg/kg 0.0307 mg/kg

Sliced Pie 201 cm 2 <LOQ 0.0310 mg/kg 0.0363 mg/kg

1 CC = crack & crevice, ST = spot trea tment. 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 cm 2 <LOQ 0.0353 mg/kg 0.0673 mg/kg Candy 133 cm 2 <LOQ 0.0319 mg/kg 0.0557 mg/kg

Potatoes 133 cm 2 <LOQ 0.0306 mg/kg 0.0417 mg/kg Rice (in bag) 211 cm 2 Not Detected Not Detected Not Detected Crackers (in box) 286 cm 2 <LOQ <LOQ <LOQ

Knife 36 cm 2 <LOQ <LOQ 3.3 mg/m 2

Plate 314 cm 2 <LOQ 0.938 mg /m 2 1.76 mg/m 2

Aluminum 621 cm 2 <LOQ 0.678 mg/m 2 1.44 mg/m 23

foil

1 CC = crack & crevice, ST = spot trea tment. 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 labe led dinotefuran as well as an unlabeled dinotefuran and blank formulation and applie d to soil to determine residue levels in rotational crops planted 30 and 120 days a fter treatment. The test substance was applied to the sandy loam soil at a rate of 243 g a.i./A in a volum e 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 scinti llation counting. After solven t 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 Derma l 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 exhibit4

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 embryot oxic 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 value s in rats and rabbits for embryonic development and teratogenicity were the hi ghest dose levels administered (1000 and 300 mg/kg /day), respectively. In a 2-gen eration study, parental animals of both sexes and both generations showed reduced body weight gain and food consumption at the highest dose level evaluated (10000 pp m), 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 an y 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 ex posure 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 clinic al chemistry profiles, organ weights, macroscopic and microscopic pathology. D ermal application to rats for 4 weeks generated a systemic NOAEL of 1000 mg/k g/day (highest dose) and a dermal NOAEL of 1000 mg/kg/day for males and le ss 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 a nd 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 esta blished. In the 104-week combined chronic toxicity/carcinogenicity st udy 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 oncogenicity5

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 in to the general circulation, and is widely distributed throughout the tissues and flui ds of the body. Elimination is rapid, predominantly by urinary excretion and almost complete within 7 days of

administration. There is no evidence for tissu e accumulation. Dinotefuran is rapidly transferred to maternal milk and widely distributed into feta l tissues but rapidly

eliminated from them. Mo re than 90% of orally and intravenously administered dinotefuran is eliminated as unchanged parent molecule, which is also the major radioactive component in plas ma, milk, bile and most tissues. The major route of metabolism is an initial enzymatic hydr oxylation of the tetrahydrofuran ring to form isomers of 6-hydroxy-5-(2-hydroxyeth yl)-1-methyl-1,3-diaz inane-2-ylidine-Nnitroamine (PHP), followed by further oxida tion, reduction and acetylation of PHP to produce possible isomers of dinote furan-CO, dinotefuran-DO, PHP-Ac and dinotefuran-OH+COOH. Several minor pa thways of metabolism of dinotefuran

were identified in animals. The abso rption, 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)guani dine (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 effect s on the endocrine system. There is no evidence that dinotefuran has any effect on endocrine function in developmental or reproduction studies. Furthermore, histolog ical 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 neurotoxi city 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 NO AEL 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 fo r both functional and histopathological developmental neurotoxicity in the F1 ge neration rats whose mothers were exposed to dintoefuran was 10000 ppm, the highest do se 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 matern al body weight gain during gestation at6

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 e ffect on water consumption, spleen and thymus weights or macroscopic pathol ogy 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 dinote furan was therefore greater than 7000 ppm, equivalent to dose levels of >1053 mg/k g/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 th e 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 registr ations currently being reviewed at the Agency and the proposed tolerance for food/feed handling

establishments.

i. Food. The acute exposure to dinotefura n 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-nursi ng 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 Ch ronic Reference Dose (cRfD = ADI = 0.02 mg/kg bw/day). The most sensitive subpo pulation 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 cr itical 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.7

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 (F IRST). 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; app licator, 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 pest icide chemical class known as the neonicotinoids and subclass nitroguanadines. There is no relia ble information to indicate that toxic effects produced by dinotefuran would be cumulative with those of any other chemical including another pesticide. Th erefore, Mitsui Chemicals Agro, Inc., the registrant of dinotefuran technical, believe s 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, neurotoxi city and immunotoxicity studies on dinotefuran and acute toxicity and mutage nicity studies on main metabolites.

2. Infants and children

. In 2004, the FQPA Safety Factor for increased susceptibility of infants a nd children was reduced to 1X for exposure to dinotefuran based on toxicological considerations, the conservative residue assumptions used in the dietary risk assessments, the complete ness 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 dinotefu ran on any crops at this time.