EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Richard Gebken, (703) 305-6701

ISK Biosciences Corporation

[PP#5F8416]

EPA has received a pesticide petition (PP#5F8416) from ISK Biosciences Corporation, 7470 Auburn Road, Suite A, Concord, Ohio, 44077, 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 by establishing a tole rance for residues of the combined residue s of the insecticide flonicamid [N-(cyanomethyl)-4-trifluoro methyl)-3-pyridinecarboxamide (CA) or Ncyanomethyl-4-trifluoromethylnicotinamid e (IUPAC)] and its metabolites, TFNA [4- trifluoromethylnicotinic acid], TFNA-AM [4 -trifluoromethylnicotinamide] and TFNG [N- (4-trifluoromethylnicotinoyl)-glycine] in or on dried tea leaves at 40 parts per million (ppm). EPA has determined that the petition contains data or information re garding 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 th e data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism

. Wheat, potato and peach metabolism studies were conducted using [14C]-pyridyl-flonicamid. The metabolic profile was similar for all three matrices. The major metabolites for the various crops were: TFNA in peach, TFNA and TFNG in potato and TFNG in wheat. The metabolism of flonicamid in plants shows the main pathway of metabolism involves hydrolys is of -CN and BCONH2 functional groups in the molecule. The metabolism of flonicamid in plants is well understood.

2. Analytical method

. Analytical methodology has been developed to determine the residues of flonicamid and its three major plant metabolites, TFNA, TFNG, and TFNA-AM in various crops. The residue analytical method for the majority of crops includes an initial extraction with acetonitrile ( ACN)/deionized (DI) water, follo wed by a liquid-liquid partition with ethyl acetate. The residue method for wh eat straw is similar, except that a C18 solid phase extraction (SPE) is added prior to the liqui d-liquid partition. The final sample solution is quantitated using a liquid chromatograph (L C) equipped with a reverse phase column and a triple quadruple mass spectrometer (MS/MS).

3. Magnitude of residues

. Studies were conducted on tea at two sites in the tea growing region in Japan to provide information on th e residues of Flonicamid and its metabolites2

TFNG and TFNA remaining in or on tea at harvest following treatment of the growing crop

with Flonicamid. Residues ranged from 16.7 ppm to 25.7 ppm.

B. Toxicological Profile

1. Acute toxicity

. A battery of acute toxicity st udies was conducted which placed flonicamid technical in Toxicity Category III for oral LD50, Category IV for dermal LD50, inhalation LC50, dermal irritati on, and eye irritation. Flonicam id technical is not a dermal sensitizer. In an acute neurotoxicity study, th e no observed adverse effect levels (NOAELs) for neurotoxicity were 600 mg/kg in males and 1000 mg/kg in female (highest doses tested). The systemic NOAELs were 600 mg/kg in males and 300 mg/kg in females.

2. Genotoxicity

. Flonicamid technical did not cause mutations in the bacterial reverse mutation or mouse lymphoma tests with or without metabolic activation, chromosome damage in the mouse micronucleus or cytoge netics tests with and without metabolic activation, an increase in DNA damage in the comet assay or in an in vivo rat unscheduled DNA synthesis (UDS) study. Based on the weight of evidence, it is concluded that flonicamid technical is not genotoxic.

3. Reproductive and developmental toxicity. A developmental toxicity study in rats resulted in the maternal and developmental no observed effect levels (NOELs) of 100 mg/kg/day. The maternal lowest observed eff ect level (LOEL) was 5 00 mg/kg/day based on

the treatment-related effects observed on the liv er and kidney of the dams in the highest dose group. The developmental lowest observed ef fect level (LOEL) was 500 mg/kg/day based on

incidences of fetal skeletal var iations seen only at maternally toxic doses of 500 mg/kg/day.

In the rabbit developmental toxicity study, the maternal and developmental NOELs were 7.5 mg/kg/day and > 25 mg/kg/day (HDT), respect ively. The maternal LOEL was 25 mg/kg/day based on decreased body weights, body weight gains and food consumption. No adverse

effects on the fetuses were obs erved at the highest dose. In the multigeneration rat reproduction study , the NOAEL was 50 ppm for parental animals (3.7 and 4.4 mg/kg/day, respect ively, for males and females) and 300 ppm for their offspring (22.3 and 26.5 mg/kg/day, respectively, for males a nd females). The effects at the highest dose of 1800 ppm included the following: increased kidney weights and gross and histopathological alterations in the kidney. Fi ndings noted in the top dose females included delayed vaginal opening and increased liver, kidney and spleen weights in the F1 generation and reduced ovary and adrenal weights in the parental generation and decreased uterine weights in the F1 female weanlings. There was an increase in the FSH and LH levels in F1 females tested for these endpoints. These findings did not affect the reproductive performance or survival of offspring in the study.3

4. Subchronic toxicity

. The no observed adverse effect level (NOAEL) for flonicamid technical in the rat 28-day dermal toxicity study was 1000 mg/kg/day, which was the highest

dose tested.

In a 90-day rat feeding study the NOAEL wa s established at 200 ppm (12.11 mg/kg/day) for males and 1000 ppm (72.3 mg/kg/day) for females. The LOAELs were 1000 ppm (60.0 mg/kg/day) for males and 5000 ppm (340 mg/kg/day) for fema les based on effects on hematology, triglycerides, and pa thology in the liver and kidney.

In a 13-week mouse study, the NOAEL wa s 100 ppm (15.25 mg/kg/day in males and 20.1 mg/kg/day in females). The LOAEL is 1000 ppm (153.9 mg/kg/day in males and 191.5 mg/kg/day in females) based on hematology effects and changes in glucose, creatinine, bilirubin, sodium, chloride and potassium le vels, increased liver and spleen weights and histopathology findings in the bone marrow, spleen and kidney.

In a subchronic toxicity study in dogs wi th capsule administration, the NOAEL was 8 mg/kg/day in males and 20 mg/kg/day in females based on findings of se vere toxicity at a dose exceeding the maximum tolerated dose; symptoms included collapse, prostration and convulsions leading to early sacrif ice at the LOAEL of 50 mg/kg/day.

In a subchronic neurotoxicity study in rats , the NOAEL for dietary administration was 200 ppm for males and 1000 ppm for females (13 mg/kg/day in males and 81 mg/kg/day in females). The LOAEL was 1000 and 10,000 ppm (67 and 722 mg/kg/day) in males and females, respectively (highest dose tested) ba sed on decreased motor activity, body weight and food consumption effects.

5. Chronic toxicity

. In the chronic dog study with ad ministration via using capsules, the NOEL was 8 mg/kg/day. The LOAEL was 20 mg/kg/day based on reduced body weights in females and effects on the circulating red blood cells.

In a rat 24-month combined chronic and onc ogenicity study, flonicamid technical was not carcinogenic in rats. The NOAEL was 200 ppm (7.32 mg/kg/day) for males and 1000 ppm (44.1 mg/kg/day) for females. The LO AEL was 1000 ppm for males and 5000 ppm for females based on histopathology in the kidney, hematology effects, hepatic effects including changes in biochemical parameters, increased organ weights, and histopathological changes. Atrophy of striated muscle fibers, cataract a nd retinal atrophy observed in the high dose

females were considered to be due to accelera tion of spontaneous age-related lesions.

In the 18-month mouse study, effects were obs erved in the lung, liver, spleen and bone marrow at 250 ppm or higher. Findings incl uded centrilobular hepatocellular hypertrophy, extramedullary hematopoiesis and pigment deposi tion in the spleen an d decreased cellularity (hypocellularity) in the bone marrow. There were statistically significant increases in the

incidence of alveolar/bronchi olar adenomas in both sexes of treated groups with hyperplasia/hypertrophy of epithe lial cells in terminal bronchio les. There was a statistically significant increase in the incidence of alveol ar/bronchiolar carcinomas in males at 750 ppm4

and 2250 ppm and in females at 2250 ppm only. These effects in the lungs of mice were not life threatening as most of e ffects were observed at the term inal sacrifice and there was no

effect of treatment on mortalit y in the study. A no observed adverse effect level (NOAEL)

could not be determined from the dose leve ls administered. Mechanism-of-action studies have indicated that the lung e ffects are unique to the mouse and are not likely to translate to other species including the rat. A second 18 -month mouse study was conducted in CD-1 mice at dose levels ranging from 10 to 250 ppm to establish a NOAEL for hyperplasia/hypertrophy of epithelial cells in terminal bronchioles an d for the incidence of alveolar/bronchiolar

adenomas and carcinomas in both sexes. There was a statistically significant increase in the

incidence of alveolar/bronchiolar adenomas in males at 250 ppm. In females, there was no statistically significant increase in the incidence of pulmonary ne oplastic lesions at any dose level. The incidence of hyperplasia/hypert rophy of epithelial cells lining the terminal bronchioles of the lungs was statistically incre ase at 250 ppm in both sexes. There were no treatment-related increases in neoplastic or non-neoplastic lesions at dose levels of 80 ppm

or lower in either sex. The NOAELs were 10.0 and 11.8 mg/kg body weight/day for males and females, respectively. This study confirme d a threshold for these effects at 80 ppm. Flonicamid technical was not carcinogenic in the rat.

6. Animal metabolism

. Rat, goat and poultry metabolism studies were conducted using [ 14 C]-pyridyl-flonicamid. The ma jority of the dose was rapidl y excreted. Flonicamid was a major component of rat urine 48 hours after dosing. TFNA-AM was the major metabolite found in rats (urine), goats (mil k and tissues) and in laying hens (tissues and eggs). TFNG

was found between 8 - 24% of the total radioacti ve residue (TRR) in the livers of rats

sacrificed at intervals between 0.5 - 6 hours a fter dosing. The liver samples at these time

intervals had 14 C-residues of 2.3% - 4.6% of the dose. TFNA was not a major component in

animal tissues. The metabolism of flonic amid in animals shows the main pathway of metabolism involves hydrolysis of -CN and -CONH 2 functional groups in the molecule, identical to plant metabolism. The main metabo lic reactions were hydrolysis of cyano to the amide function and ring hydroxylation. In rats flonicamid was fu rther metabolized by several routes, including nitrile hydrol ysis, amide hydrolysis, N-oxidation, and hydroxylation of the pyridine ring, leading to multiple metabolit es. The metabolism of

flonicamid in animals is well understood.

7. Metabolite toxicology

. The main metabolites of flonic amid were examined in acute oral toxicity studies in rats and bacterial rev erse mutation tests. A ll the metabolites were less toxic than flonicamid and not mutagenic.

8. Endocrine disruption

. No special studies investigat ing potential estrogenic or other

endocrine effects of flonicamid have been conduc ted. Some suggestions of possible endocrine effects were reported at the highest dose te sted (1800 ppm) in the multi-generation reproduction study which showed increased FSH and LH levels, a delay in the time to vaginal opening in the F1 generation, and reduced ovary and adrenal weights in the parental generation. However, there were no effects on reproductive performance or survival of the offspring in the study. At levels that are expected to be found in the environment, flonicamid5

will not cause any endocrine-related effects.

C. Aggregate Exposure.

1. Dietary exposure

i. Food

.

Tier 1 chronic dietary exposure assessments on flonicamid were conducted using the Dietary Exposure Evaluation Model software wi th the Food Commodity Intake Database (DEEM-FCID TM, Version 4.02), which uses food consumption data from 2005-2010 of the NHANES/WWEIA survey. Overall dietary ex posure to flonicamid was expressed in mg/kg/day and was calculated as a percent of Chronic Population Adjusted Dose (cPAD).

The Chronic Reference Dose (cRfD) was es tablished at 0.04 mg/kg/day. The cRfD was based on a 2-generation reproduction rat study with a NOAEL of 3.7 mg/kg/day. The uncertainty factor of 100 was applied to the NOAEL to derive cRfD. The cPAD is equivalent to the cRfD of 0.04 mg/kg/day (FQPA SF = 1).

ii. Drinking water

.

A Tier II drinking water assessment was conducted to represent drinking water exposure (SCI-GROW2 for groundwater and PRZM/EXAMS for surface water). The

maximum chronic Estimated Environmenta l Concentration (EEC) from PRZM/EXAMS was 1.5 ppb, derived from the ME potato and CA lettuce standard EPA scenarios ( see “Flonicamid: Human health risk assessment fo r proposed uses on root vegetables (except sugarbeet; Subgroup 1B), tubero us corm vegetables (subgroup 1C), leafy Brassica green vegetables (subgroup 5B), turnip greens, hops and okra. PC Code: 128016, Petition No: 6E7081, DP Barcode: D347805. December 21, 2007” ). Using the Tier 1 screening model SCI-GROW2, the ground water EEC for flonicamid was 0.00132 ppb, which was considered appropriate for chronic EEC. To be protective of all drinking water systems, the predicted chronic EEC for surface wat er (1.5 ppb) was incorporated in the DEEM dietary assessment modeling.

2. Non-dietary exposure

. Based upon the product label, EPA assumes that the proposed food-use sites are commercial in nature, and that the applications on landscape ornamentals would only be made by professi onal pest control operators. Therefore, residential handler scenarios are not expected a nd need not be assessed. Flonicamid label language should preclude use by non-prof essionals (e.g., homeowners), particularly regarding landscape ornamentals.

D. Cumulative Effects

.

The 2007 EPA assessment (refer to Section C) was conducted for food and water exposure only. There are no expected long-term residential exposures. Because drinking6

water estimates have been combined with dietary exposures, the dietary assessment serves as the aggregate exposure and risk assessment for flonicamid. The establishment of the

tolerance for dried tea is not expected to change the nature of the aggregate assessment. Because aggregated food and drinking water exposures from this conservative Tier I assessment for the most highly exposed populat ion subgroup (Children 1-2 years old) only amount to 23.2% of the cPAD, exposure to fl onicamid from all current uses should not

exceed HED’s level of concern.

E. Safety Determination

.

1 . U.S. population

. Using the conservative Tier 1 assumptions described in Section C., based on the completeness and reliability of the toxicology data, it is estimated that the chronic dietary exposure (food plus drinking water) at the 95 th percentile general U.S. population comprises 10.4% of the cPAD. The EPA generally has no concern for exposures below 100% of the Population Ad justed Dose (aPAD/cPAD) because it represents the level at or below which daily aggregate dietary exposure over a lifetime will not pose any unacceptable risks to human health. It is concluded that there is a reasonable certainty that no harm will result from aggreg ate exposure to residues of flonicamid, including all anticipated dietary exposure.

2. Infants and children

. The FQPA safety factor was set at 1 to derive the cPAD (i.e. 0.04 mg/kg/day) for chronic dietary risk asse ssment to infants and children as well as adults. Using the conservative Tier 1 assumpti ons described in Section C and based on the completeness and reliability of the toxicology dat a, it is estimated that the chronic dietary exposure (food plus drinking water) at the 95 th percentile for the most sensitive subpopulation (Children 1-2 years old) comprises 23.2% of the cPAD. The risk from revising the tolerance to Crop Group 14 into the diet ary risk assessment increased the cPAD by 0.5% for the most sensitive population subgroup (Children 1-2 years old). Based on the above information, there is reasona ble certainty that no harm will result to infants, children, or adults from dietary (food plus drinking water) exposure to flonicamid residues from dried tea, as well as all other existing flonicamid-treated human dietary food

sources.

F. International Tolerances

Japan has established a toleran ce for flonicamid at 40 ppm. Canada has established MRLs

for flonicamid and its metabolites on head a nd stem brassica, leafy brassica greens, leafy vegetables (except brassica), tuberous and corm vegetables, fruiting vegetables, cucurbits, stone fruits, pome fruits, vegetable root crops except sugarbeet, radish tops, turnip greens, hops, and resulting secondary residue s in meat, milk, poultry and eggs.

There are no Mexican residue limits or Codex MRLs for the insecticid e flonicamid and its metabolites TFNA, TFNA-AM and TFNG.7