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EPA REGISTRATION DIVISION CO MPANY 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 Intern ational, 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-(t etrahydro-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 fo rth 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 da ta 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 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 th eir relative distribution in the samples. The HPLC method was validated for determination of dinotefuran, DN and UF in or on tomatoes and peppers, cucurbits, br assica, grapes, potatoes, mustard greens, rice, and lettuce for raw agricultural commod ity matrices and in or on tomato paste and puree, grape juice and raisins and pota to chips, granules, and wet peel, rice grain, hulls, and bran for processed commodi ty matrices. After extraction with a water/acetonitrile mixture and clean up with hexane and extraction columns,2

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 dinote furan, 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 ri ce 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. Dinotefura n 20% water soluble granule was applied to rice at exaggerated rates (7.5 and 5 time s 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 w ere detected in hulls, bran and polished rice. The data

showed 3.9- to 5.3-fold concentration factor s 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 (C rop Group 4), Cotton Seed Undelinted and Cotton Gin Byproducts, Cucurbit Vegetabl es (Crop Group 9), Grapes, Potatoes, Fruiting Vegetables (Crop Group 8), Ve getables, Brassica Head and Stem crop subgroup (Crop Subgroup 5A), and Meat, Milkand 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 form ulation 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 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 the paren t dinotefuran nor any of its metabolites would be expected to be taken up by crops when planted 120 days from the time of application.3

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 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 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

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 [M/F] mg/kg/day was esta blished based on decreased weight gain

in both sexes and decreased food consum ption in females. In the 104-week combined chronic toxicity/carcinogeni city 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 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 and5

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 effe cts 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 dinotefuran 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 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 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.6

C. Aggregate Exposure

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

dinotefuran was determined with the Di etary Exposure Evaluation Model software with Food Commodity Intake Databa se (DEEM-FCIDTM), version 2.16, from Exponent, Inc. The dietary analysis includes established tolerances, pending registrations currently being reviewed at th e 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 aR fD (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 1522). 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.

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

. 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 woul d result in occupational handler exposure (i.e., open mixing/loading of liquids for aeri al application; applicator, aerial, fixedwing; flagging for aerial application) have been previously assessed at a higher7

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 calculat ing an ARI because, while dermal and inhalation endpoint effects ar e the same, they have diffe rent 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 assesse d for activities such as scouting and hand weeding. MOEs for these activiti es 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 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.