EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGIST ER

EPA Registration Division contact: [insert name and telephone number with area code]

INSTRUCTIONS: Please utilize this outline in preparing the pest icide petition. In cases where the outline element does not apply, ple ase insert “NA-Remove” and maintain the outline. Please do not change the marg ins, 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:

[Bayer CropScience]

[Insert petition number]

EPA has received a pesticide petition ([5F8404]) from [Bayer CropScience], [2 T.W. Alexander Drive, Research Triangle Park, NC 27 709] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosme tic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of [flupyradifurone, 2(5H)-furanone,4-[[(6-chloro-3-py ridinyl)methyl](2,2- difluoroethyl)amino] in or on the raw agricultural commodities [Kava, Roots] at [0.9]

ppm, [Cilantro, Fresh Leaves] at [30] ppm, [Kava, Fresh Leaves] at [40] ppm, [Stone Fruits (Crop Group 12-12), Fruit] at [1.5] ppm, [Caneberry (Crop Subgroup 13-07A), Fruit] at [5] ppm, [Quinoa] at [3] ppm, [Abiu, Fruit] at [0.6] ppm, [Akee Apple, Fruit] at [0.6] ppm, [Avocado, Fruit] at [0.6] ppm, [Bacury, Fruit] at [0.6] ppm, [Banana, Fruit] at [0.6] ppm, [Binjai, Fruit] at [0.6] ppm, [Canistel, Fruit] at [0.6] ppm, [Cupuacú, Fruit] at [0.6] ppm, [Etambe, Fruit] at [0.6] ppm, [Jatobá, Fruit] at [0.6] ppm, [Kei Apple, Fruit] at [0.6] ppm, [Langstat, Fruit] at [0.6] ppm, [Lanjut, Fruit] at [0.6] ppm, [Lucuma, Fruit] at [0.6] ppm, [Mabolo, Fruit] at [0.6] ppm, [Mango, Fruit] at [0.6] ppm, [Mangosteen, Fruit]

at [0.6] ppm, [Paho, Fruit] at [0.6] ppm, [Papaya, Fruit] at [0.6] ppm, [Pawpaw, Common, Fruit] at [0.6] ppm, [Pelipisan, Fruit] at [0.6] ppm, [Pequi, Fruit] at [0.6] ppm, [Pequia, Fruit] at [0.6] ppm, [Persimmon, American, Fruit] at [0.6] ppm, [Plantain, Fruit]

at [0.6] ppm, [Pomegranate, Fruit] at [0.6] ppm, [Poshte, Fruit] at [0.6] ppm, [Quandong, Fruit] at [0.6] ppm, [Sapote, Fruit] at [0.6] ppm, [Sataw, Fruit] at [0.6] ppm, [Screw-pine, Fruit] at [0.6] ppm, [Star apple, Fruit] at [0.6] ppm, [Tamarind-of-the-Indies, Fruit] at [0.6] ppm, [Wild Loquat, Fruit] at [0.6] 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 suf ficiency of the submitted data at2

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. [Primary crop metabolism studies have been perform ed on apple, tomato, potato, cotton, and rice (represe nting five diverse crops) using foliar, soil, or seed treatment application with [ 14 C]flupyradifurone.

The flupyradifurone plant metabolism studies have s hown a reasonably consistent metabolic profile across both foliar and soil appli cation. The major metabolic pathways involved cleavage of the difluoroethylamin e and pyridinylmethylamine bonds leading to the formation of difluoroacetic ac id (DFA) and difluoroethylaminofuranone and its corresponding counterpart flupyrad ifurone-CHMP, which was either conjugated with carbohydrates or oxidized to 6-chloronicotinic acid (6-CNA). Hydroxylation of the furanone moiety followed by co njugation or complete degradation of the furanone moiety and incorporatio n of carbon atoms into the natural compound pool, e.g. into glucose/carbohydra tes were also observed.

Flupyradifurone parent compound and difluoroacetic acid (DFA) were consistently observed at significant levels across all primary c rop matrices. Thus, the EPA has

determined the residue definition for enforcement o f flupyradifurone residues in primary crops as parent flupyradifurone.

The uptake and metabolism of flupyradifurone was in vestigated in the rotational crops wheat, Swiss chard and turnips from three con secutive rotations in two separate experiments with [furanone-4- 14 C]flupyradifurone or [pyridinylmethyl14 C]flupyradifurone. Additionally, all crop matrice s were analyzed for difluoroacetic acid (DFA) residues using LC/MS/MS. Overall the metabolism was very similar to primary crops and therefore the res idue definition for enforcement is the same as primary crops.]

2. Analytical method. [Tolerances are being proposed in primary crops and rotational crops and animal tissues and milk for fl upyradifurone. The analytical method involves, solvent extraction, purification t hrough a C-18 solid-phase extraction column, and addition of a mixture of sta ble, isotopically labelled internal

standards. Quantitation is by high performance liquid chromato graphyelectrospray ionization/tandem mass spectrometry (H PLC/MS/MS).]

3. Magnitude of residues. [A full program of magnitude of the residue trials was conducted in the various required regions acros s the United States and Canada in accordance with guidance for crop field trials f rom the US EPA and PMRA to support the requested tolerances.

A processing study was also conducted on plum.]3

B. Toxicological Profile

1. Acute toxicity. [Technical flupyradifurone (Toxicity Category II to IV) shows low acute toxicity via the oral, dermal and i nhalation routes of exposure. Technical flupyradifurone is a slight eye irritant, but is not irritating to the skin (Toxicity Categories III and IV, respectively). Th e technical material is not a skin sensitizer. Acute neurotoxicity of flupyradifurone was assessed in the rat. Compound-related effects following a single oral do se of the test substance were

observed in both sexes at the low dose tested of 50 mg/kg body weight, but were limited to clinical signs (i.e. dilated pupils, pil oerection) in the initial acute neurotoxicity study. A follow-up study showed no i ncidences of these clinical signs at the highest tolerated dose of 35 mg/kg body weig ht, which was established as a clear NOAEL for acute neurotoxicity in the rat.]

2. Genotoxicty. [Genotoxicity potential was evaluated in a series o f tests including in vitro and in vivo tests. There was no indication of gene mutation e ither in the presence or absence of metabolic activation in both the bacterial reverse mutation and mammalian gene mutation tests. The in vitro chromosome aberration

test and the in vivo mouse micronucleus test were also both negative. These studies demonstrate that flupyradifurone has no genotoxic p otential.]

3. Immunotoxicity. [ The immunotoxicity potential of flupyradifurone was assessed in a 28-day immunotoxicity study in the fe male adult rat, using the Sheep Red Blood Cell Enzyme-Linked Immunosorbent Assay (S RBC ELISA). Flupyradifurone demonstrated no effect on anti-SRBC IgM concentrations in plasma or on spleen and thymus organ weights. Ther efore, the NOAEL for immunotoxicity is the highest dose tested (230 mg a .i./kg body weight in females). Flupyradifurone is therefore not considered to be i mmunotoxic.]

4. Reproductive and developmental toxicity. [In both the reproductive and prenatal developmental toxicity studies in rats and /or rabbits, non-maternal toxicity was identified at equivalent or higher doses than m aternal toxicity in both species. In the rat two-generation reproduction study, decre ases in body weight and body weight gain were observed in females (P and F 1 ), and decreased body weight (F 1 ), increased liver weight (absolute and relative to bo dy weight) associated with minimal hepatocellular hypertrophy, and increased a bsolute thyroid weights in males. Decreases in cycle number, litter size, and the number of implants were

observed in the F 1 -generation only at the HDT. Decreases in pup weig ht and pup weight gain were due to maternal effects leading to secondarily-mediated changes, and organ weight changes (brain, thymus, spleen) we re considered secondary to decreases in pup weight. The findings observed in rat fetuses at the highest dose tested (slight decrease in fetal weight and increas ed incidence of skeletal variations – incomplete skull bone ossification) were minor and secondary to maternal toxicity. There was no indication of a teratogenic effect of flupyradifurone in either the rat or

the rabbit.

In the developmental neurotoxicity study, treatment -related findings in offspring4

were limited to decreased body weight and body weig ht gain during lactation, increased startle amplitude in females (PND 60), an d increased motor and locomotor activity in males on PND 13 observed only at the highest dietary level tested of 1,200 ppm. Decreased body weight and bod y weight gain were also observed in maternal animals at the same dietary le vel.]

The reproduction and developmental toxicity studies with flupyradifurone do not indicate any pre- or postnatal susceptibility of of fspring.

5. Subchronic toxicity. [The common target organ in rats, mice, and dogs wa s the liver. Liver findings seen in these species we re increased liver weights in both sexes associated with centrilobular hepatocellular hypertrophy (rat), hepatocellular vacuolation (mouse), and brown pigments in Kupffer cells (dog). In addition to the liver, the thyroid, kidney, and skeletal muscle wer e also target organs in rats, mice, and dogs, respectively. In the male rat, increased relative thyroid weights were

associated with dark coloration and follicular cell hypertrophy, but these effects were observed only at the highest dietary level tes ted and shown to be reversible. In the male mouse, decreased absolute and brain weight -relative kidney weights were associated with a loss of corticoepithelial vacuola tion at the highest dietary level tested. Myofiber atrophy/degeneration was observed in skeletal muscle of both sexes in the subchronic dog study. The dog was the most sensitive species, followed by the rat, with the mouse being the least sensitiv e.

In the subchronic neurotoxicity study, there were n o treatment-related effects observed in either sex up to and including the high est dietary level tested of 2,500

ppm.

In a 28-day dermal toxicity study in rats, decrease d absolute and relative liver weights were observed in males at 500 mg/kg/day, th e highest dose tested.]

6. Chronic toxicity. [Chronic toxicity and carcinogenicity of flupyradif urone was evaluated in the rat and mouse, and chronic tox icity in the dog. In the rat,

treatment-related effects seen in the liver were hi gher mean liver to body weight ratios associated with centrilobular hypertrophy, c entrilobular hepatocellular macrovacuolation, lower incidences of periportal he patocellular vacuolation, and eosinophilic, mixed, and tigroid foci of altered he patocytes. In addition, higher incidences of brown pigments in Kupffer cells, inte rstitial mononuclear cell infiltrate and periportal hepatocellular macrovacuo lation were observed in females. Higher incidences of follicular cell hypertrophy an d of follicular cell pigment in both

sexes at the final sacrifice and increased incidenc es of colloid alteration at the interim (both sexes) and final sacrifice (males onl y) were observed in the thyroid.

There was no evidence of a treatment-related increa sed incidence of tumors of any type in any organ. In the mouse, effects noted in the liver were increased liver weights associated with higher incidence and severi ty of diffuse hepatocellular vacuolation (mainly centrilobular) in males, while a decreased incidence of diffuse hepatocellular macrovacuolation (mainly periportal) was noted in females. In the kidney, lower weight, decreased incidence and sever ity of bilateral basophilic5

tubules, focal cortical mineralization, and cortico epithelial vacuolation were noted in males. No treatment-related neoplastic changes were observed at any dose level tested in either sex. In the chronic dog study, tr eatment-related findings were limited to minimal to slight myofiber atrophy and/o r degeneration in skeletal muscle (gastrocnemius, biceps femoris) observed in both se xes. ]

7. Animal metabolism. [Metabolism studies conducted in the rat show that although >90% of the orally administered dose was a bsorbed following single oral administration of [pyridinylmethyl- 14 C]- or [furanone-4- 14 C]-flupyradifurone, excretion of radioactivity was very fast and nearly complete at 48 hours after

administration.

The main route of excretion was renal, ranging from 75% to 90% of the administered dose. Female rats had slightly higher renal excretion rate than male rats. Only 0.02% to 2% of the administered dose wa s recovered in the expired air.

The parent compound flupyradifurone was found as a significant, if not the dominant constituent of the residue in milk, eggs, and edible tissues of both tested species in the livestock metabolism studies. Other metabolites determined in comparable concentrations were the natural compound lactose in goat's milk after administration of [furanone-4- 14 C]flupyradifurone, flupyradifurone-acetyl-AMCP in eggs and tissues of laying hens after administra tion of [pyridinylmethyl14 C]flupyradifurone, and flupyradifurone-OH in eggs.

DFA (difluoroacetic acid) was determined in selecte d livestock samples by highresolution LC-MS subsequent to the metabolism studi es, since rat studies conducted with [ethyl-1- 14 C]flupyradifurone showed major amounts of this meta bolite in organs and tissues. Extrapolation of rat data sugg ested high DFA levels in livestock tissues as well, which was confirmed by the non-rad ioactive LC/MS analyses. Based on these findings, it was concluded that difluoroac etic acid is a major livestock

metabolite and should be a constituent of the resid ue definition for data collection.

Based on these findings, flupyradifurone, DFA, flup yradifurone-OH, and flupyradifurone-acetyl-AMCP, expressed as flupyradi furone equivalents, were

included in the residue definition for data collect ion.

Based on the results from the livestock feeding stu dies, the EPA has determined that compliance with the tolerance levels in milk, meat and meat by-products, and eggs should be determined by measuring the parent flupyr adifurone only.]

8. Metabolite toxicology

. [The toxicological properties of two plant metaboli tes of flupyradifurone found at low levels in urine in the rat metabolism study, difluoroacetic acid (DFA) and flupyradifurone-diflu oroethyl-amino-furanone ( flupyradifurone-DFEAF), and two additional plant me tabolites common to other pesticides, flupyradifurone-CHMP (6-chloropyridin-3 -ylmethanol) and6

flupyradifurone-6-CNA (6-chloronicotinic acid), wer e investigated. Study results on

the metabolites indicate that all metabolites are l ess toxic than parent and that the parent flupyradifurone endpoints are sufficient to cover the residues of the metabolites in risk assessment.]

9. Endocrine disruption

. [There is no evidence to suggest that flupyradifuro ne has any primary endocrine disruptive potential. Th yroid changes observed in male rats were observed at high dietary levels of flupyr adifurone and were reversible in the subchronic rat study. Delays in sexual develop ment in rat pups in the twogeneration reproduction study were observed only in the F 1 generation and the HDT. Reproductive and developmental findings provi ded no evidence of an enhanced sensitivity of the young.]

C. Aggregate Exposure

1. Dietary exposure. [The toxicological and exposure database for flupyradifurone is considered complete. There was no indication of an increased sensitivity of the young in any studies including t he reproductive and developmental studies in rats and rabbits. Therefore, the specia l FQPA safety factor can be reduced to 1X and an uncertainty factor of 100 is a dequate to account for inter- and intra- species variability. Acute and chronic Popu lation Adjusted Doses (aPAD and cPAD) are, therefore, the same as the reference dos es for the populations and subpopulations of interest. Acute dietary exposure was expressed as a percentage of the aPAD of 0.35 mg/kg bw/day from a NOAEL of 35 mg /kg bw/day based on the acute neurotoxicity screening battery, with an unce rtainty factor of 100. Chronic dietary exposure was expressed as a percentage of t he chronic Population Adjusted Dose (cPAD) of 0.078 mg/kg bw/day based on a NOAEL of 7.8 mg/kg bw/day based on two co-critical studies, the two generation repr oduction study in rats and a chronic toxicity study in dogs, with an uncertainty factor of 100.]

i. Food. [Unrefined acute and chronic dietary risk assessmen ts were conducted to evaluate the dietary exposure of the U .S. population and selected subpopulations to flupyradifurone residues. This a ssessment includes all registered and proposed potential primary crop residues and in advertent or rotational crop residues and secondary residues in animal tissues a nd milk. The assessments conservatively assumed 100% of all crops were treat ed. The unrefined acute and chronic assessments were conducted using DEEM-FCID Version 4.02 software. Consumption data used in this program were from the NHANES/WWEIA 2005- 2010 surveys. With these conservative assumptions, acute exposure (95th percentile) for food utilizes 20.9% of the aPAD for the US Popu lation and 36.7% for Children 1-2 years, the most highly exposed subpopulation. Chronic exposure for food only utilizes 31.6% of the cPAD for the US Population an d 75.2% of the cPAD for Children 1-2 yrs. old, the most highly exposed subp opulation.]

ii. Drinking water. [Estimated Drinking Water Concentrations (EDWCs)7

from ground water and surface water sources were ca lculated. The total toxic residues are defined by EPA as parent plus two phot o-degradates (flupyradifuronesuccinamide and flupyradifurone-azabicyclosuccinami de) plus unextracted residues. The modeling approach approved by the Off ice of Pesticide Programs of EPA, the standard crop scenarios developed by the E PA and the surface water model PRZM/EXAMS and the ground water model PRZM-GW were used to estimate the values. The highest ground water conc entration was 352 μg/L (acute) and 307 μg/L (chronic) from all proposed uses. The 90 th percentile time-dependent Estimated Drinking Water Concentrations (EDWCs) fro m surface water sources were calculated for the proposed representative flu pyradifurone crop uses. Overall, the highest potential acute EDWC value was 52.5 μg/L and the highest chronic EDWC was 22.3 μg/L. The PRZM-GW ground wate r EDWCs were used in the dietary assessments.

Drinking water did not significantly increase dieta ry exposure. The incorporation of the EDWC of 352 μg/L into the acute exposure ass essment resulted in the U.S. adult population utilizing 24.1% of the aPAD (vs. 2 0.9% for food only), and Children 1-2, the most highly exposed subpopulation , utilizing 40.7% of the aPAD (vs. 36.7% for food only). The addition of the chr onic EDWC of 307 μg/L resulted in the U.S. adult population utilizing 39.6% of the cPAD (vs. 31.6% for food only) and Children 1-2, the most highly exposed subpopula tion, utilizing 86.1% (vs. 75.2% for food only). In conclusion, the results o f the very conservative acute and chronic dietary exposure analyses (including food a nd drinking water) demonstrates that flupyradifurone drinking water exposure consum es a small percentage of the risk cup for all scenarios and population subgroups examined. Therefore, there is a reasonable certainty that no harm will result from exposure to potential residues of flupyradifurone in food and water.]

2. Non-dietary exposure

. [Bayer CropScience is proposing to register flupyradifurone for professional use for foliar or soil application to landscape and production ornamental plants, greenhouse vegetables and transplants, fruits, and nut trees. Consumer uses proposed are homeowner app lication to garden vegetables, fruits, ornamental flowers, ornamentals , shrubs and outdoor houseplants. Risk assessments, as required by EPA f or all appropriate scenarios and populations (Adults 20-49 and Children 6-12), were conducted. Professional application, homeowner application and post applica tion to adults and children exposure scenarios are above the level of concern f or flupyradifurone (MOE>100).]

D. Cumulative Effects

[At this time, there is no available information t o indicate that flupyradifurone or its metabolites have a common me chanism of human toxicity with other substances. Flupyradifurone is a member of the butenolide class of8

chemistry. For this class of chemistry, EPA has no t yet conducted a detailed review of common mechanisms to determine whether it is app ropriate, or how to include

these chemicals in a cumulative risk assessment. F lupyradifurone does not appear to produce a toxic metabolite produced by other sub stances. For the purposes of this assessment, therefore, no common mechanism of toxicity has been considered.]

E. Safety Determination

1. U.S. population. [Risk assessments for flupyradifurone are based on a complete and reliable toxicity data package and con servative assumptions. Chronic dietary exposure (food and water) utilizes 39.6% of the cPAD for the US Population. Acute dietary exposure (food and water) for the U.S . population utilizes 24.1% of the aPAD. Potential residential exposure of the U. S. population to flupyradifurone (from professional and homeowner applications) is a bove levels of concern (MOE>100). FQPA requires aggregation of all potent ial sources of exposure from food, drinking water and residential exposures. An aggregate assessment including these sources for Adults (20-49) results in a combi ned MOE of 330, well above the level of concern. Therefore, there is a reasonable certainty that no harm will occur to the US Population from aggregate exposure (food, drinking water and residential sources) to residues of flupyradifurone.]

2. Infants and children

. [The toxicological and exposure database for flupyradifurone is considered complete. There was no indication of an increased sensitivity of the young in any studies including t he reproductive and developmental studies in rats and rabbits. Therefore, the specia l FQPA factor can be reduced to 1X and an uncertainty factor of 100 is adequate. B ased on conservative assumptions, chronic aggregate dietary exposure (fo od and water) utilizes 86.1% of the cPAD for Children 1-2 yrs. old, the most highly exposed subpopulation. Acute aggregate dietary exposure (food and water) utilize s 40.7% of the aPAD for Children 1-2, the most highly exposed subpopulation . A non-dietary assessment was conducted for Children 6-12, the appropriate popula tion of concern for the proposed residential uses (resulting in potential p ost application exposure). The aggregate assessment including food, drinking water and non-dietary exposure for this population resulted in an MOE of 290 (LOC=100) . Therefore, there is a reasonable certainty that no harm will occur to inf ants and children from aggregate exposure to residues of flupyradifurone.]

F. International Tolerances

[No international tolerances have been established for flupyradifurone. The initial registration application dossier for flupyr adifurone was evaluated under global joint review among Australia, Brazil, Canada , Mexico and the United States. Flupyradifurone is currently under review for propo sed domestic uses and import MRLs in the EU, Japan, Korea and Taiwan. It is als o being reviewed by JMPR for Codex MRLs. Harmonized tolerances are being propos ed to minimize trade barriers between the participating regions.]9