**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE**

**PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact:**  **Richard Gebken, (703) 305 -** **6701**

**INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In cases**  **where the outline element does not apply, please insert “NA -** **Remove” and maintain the outline. Please do not change the margins, 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: ISK Biosciences Corporation**  **[Insert petition number]** EPA has received a pesticide petition **( [insert**  **petition number] )**  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 amending the existing tolerance for **the combined residues of the**  **insecticide flonicamid [N -**  **(cyanomethyl) -** **4 -** **trifluoromethyl) -** **3 -** **p y** **ridinecarboxamide (CA) or N** **- cyanomethyl** **- 4**  **- trifluoromethylnicotinamide (IUPAC)] and its metabolites, TFNA [4**  **- trifluoromethylnicotinic**  **acid], TFNA -** **AM [4 -** **trifluoromethylnicotinamide] and TFNG [N -**  **(4 -** **trifluoromethylnicotinoyl) -**  **glycine] in or on the raw agricult ural commodity**  **Crop Group 14**  **- 12,**  **Tree Nut s**  **from 0.15 parts per million (ppm)**  **to 0.3**  **ppm and**  **the existing tolerance**  **in or on the raw a gricultural commodity**  **hops from 7 ppm to 30 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 .**  **Wheat, potato**  **and peach**  **metabolism studi** **es were**  **conducted using**  **[14C] -** **pyridyl -** **flonicamid. T**  **he metabolic**  **profile was**  **similar for**  **all three**  **matrices. The**  **major metabolites**  **for the**  **various crops**  **were: T**  **FNA in**  **peach, TFNA**  **and TFNG**  **in potato**  **and TFNG**  **in wheat.**  **The metabolism**  **of flonicamid**  **in plant** **s shows**  **the main**  **pathway of**  **metabolism involves**  **hydrolysis 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.**  **T he**  **residue analytical**  **method for**  **the ma** **jority of**  **crops includes**  **an initial**  **extraction with**  **acetonitrile (ACN)/deionized**  **(DI) water,**  **fol lowed**  **by a**  **liquid -** **liquid partition**  **with ethyl**  **acetate. T**  **he residue**  **meth od**  **for wheat**  **straw is**  **similar, except**  **that a**  **C18 solid**  **phase extraction**  **(SPE) is**  **added prior**  **to the**  **liquid -** **liquid partition.**  **T he**  **final sample**  **solution is**  **quantitated using**  **a liquid**  **ch romatograph**  **(LC) equipped**  **with a**  **reverse phase column and a triple quadruple mass spectrometer (MS/MS).** 

**3. Magnitude of residues**  **. Residue data were collected on**  **almonds and pecans during**  **field trials.**  **M aximum**  **total residues**  **in/on almond**  **nutmeats (total**  **of 5**  **field trials)**  **ranged from**  **non -**  **detect to**  **0. 047**  **parts per**  **million (ppm)**  **and from**  **0.858 to**  **4.911 ppm**  **in/on almond**  **hulls. M** **aximum total**  **residues in/on**  **pecan nutmeats**  **(total of**  **5 field**  **trials) ranged**  **from non** **- detect**  **to 0.**  **018 ppm.**  **Maximum total**  **resi dues**  **in/on pistachios**  **(total of**  **2 trials)**  **ranged from**  **0.120 to**  **0.190 ppm.**  **One additional**  **trial for**  **hops was**  **conducted and**  **maximum total residues in/on hops was 9.11 to 11.6 ppm. Maximum total residues from the previous 3 hops trials ranged from 1.09 to 3.4**  **5 ppm. B. Toxicological Profile** 

**1. Acute**  **toxicity .**  **A battery**  **of acute**  **toxicity studies**  **was conducted**  **which placed**  **flonicamid technical in Toxicity Category III for oral LD50, Category IV for dermal LD50,**  **inhalation LC50, dermal**  **irritation, and**  **eye ir** **ritation. Flonicamid**  **technical is**  **not a**  **dermal sensitizer.**  **In an acute neurotoxicity study, the 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.**  **Genotoxic i** **ty .**  **Flonicamid technical**  **did not**  **cause mutations**  **in the**  **bacterial reverse**  **mu tation**  **or mouse**  **lymphoma tests**  **with or**  **without metabolic**  **activation, chromosome**  **damage in**  **the mouse**  **mi cronucleus**  **or cytogenetics**  **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.**  **B ased**  **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 effect level (LOEL) was 500 mg/kg/day based on the**  **treatment -** **related effects**  **observed on**  **t he**  **liver and**  **kidney of**  **the dams**  **in the**  **highest dose**  **group. T**  **he developmental**  **lowest observed**  **effect level**  **(LOEL) was**  **500 mg/kg/day**  **based on**  **incidences of**  **fetal skeletal**  **variations seen**  **only at**  **maternally toxic**  **doses of**  **500 mg/kg/day.** 3

**In the**  **rabbit deve** **lopmental toxicity**  **study, the**  **ma ternal**  **and developmental**  **NOELs were**  **7.5 mg/kg/day**  **and >**  **25 mg/kg/day**  **(HDT), respectively.**  **T he**  **ma ternal**  **LOEL was**  **25 mg/kg/day**  **based on decreased body weights, body weight gains and food consumption. No adverse effects on th**  **e fetuses were observed 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, respectively,**  **for males**  **and females)**  **and 300**  **ppm for**  **their offspring**  **(22.3 and**  **26.5 mg/kg/day,**  **r espectively,**  **for males**  **and females).**  **T he**  **effects at**  **the highest**  **dose of**  **1800 ppm**  **included the**  **following: increased**  **kidney weights**  **and gross**  **and histopathological alterations in the kidney. Findings noted in the top dose females included**  **delayed vaginal**  **o pening**  **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.**  **T here**  **was an**  **increase in**  **the FSH**  **and LH**  **levels in**  **F1 fema** **les tested**  **for these**  **endpoints. T**  **hese findings**  **did not**  **affect the**  **reproductive performance or survival of offspring in the study. 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 was 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 females based on effects on hematology, triglycerides, and pathology in the liver and kidney.**  **In a 13 -** **week mouse study, the NOAEL was 100 ppm (15.25 mg/kg/day in males and 20.1 mg/kg/day in females). The LOAEL is 10**  **00 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 levels, increased liver and spleen weights and histopathology findings in the bone ma** **rrow, spleen and kidney. In a subchronic toxicity study in dogs with capsule administration, the NOAEL was 8**  **mg/kg/day in males and 20 mg/kg/day in females based on findings of severe toxicity at a dose exceeding the maximum tolerated dose; symptoms inc** **luded collapse, prostration and convulsions leading to early sacrifice 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 an**  **d 81 mg/kg/day i n**  **females). The LOAEL was 1000 and 10,000 ppm (67 and 722 mg/kg/day) in males and**  **females, respectively (highest dose tested) based on decreased motor activity, body weight**  **and food consumption effects. 5.**  **Chronic toxicity** **. In**  **the chronic**  **dog study**  **with administration**  **via using**  **capsules, the**  **NOEL was**  **8 mg/kg/day.**  **T he**  **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**  **oncog enicity**  **study, flonicamid**  **technical was** 4

**not carcinogenic**  **in rats.**  **T he**  **NOAEL was**  **200 ppm**  **(7.32 mg/kg/day)**  **for males**  **and 1000**  **ppm (44.1**  **mg/kg/day) for females. The LOAEL was 1000 ppm for**  **ma les**  **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. A** **trophy of**  **striated muscle**  **fibers, cataract**  **and retinal**  **atrophy observed**  **in the**  **high dose**  **females were**  **considered to**  **b e**  **due to**  **acceleration of**  **spontaneous age** **- related**  **lesions. In**  **the 18** **- month**  **mouse study,**  **effects were**  **observed in**  **the lung,**  **liver, spleen**  **and bone**  **ma rrow**  **at 250**  **ppm or**  **higher. F** **indings included**  **centrilobular hepatocellular**  **hypertrophy, extramedullary**  **hemat opoiesis**  **and pigment**  **deposition in**  **the spleen**  **and decreased**  **cellularity (hypocellularity)**  **in the**  **bone marrow.**  **T here**  **were statistically**  **significant increases**  **in the**  **incidence of**  **alveolar/bronchiolar adenomas**  **in both**  **sexes of**  **treated groups**  **with hyperplasia** **/hypertrophy of**  **epithelial cells**  **in terminal**  **bronchioles. There**  **was a**  **statistically significant**  **increase in**  **the incidence**  **of alveolar/bronchiolar**  **carcinomas in**  **males at**  **750 ppm**  **and 2250**  **ppm and**  **in females**  **at 2250**  **ppm only.**  **T hese**  **effects in**  **the lungs**  **of m** **ice were**  **not life**  **threatening as**  **most of**  **effects were**  **observed at**  **the terminal**  **sacrifice and**  **there was**  **no effect**  **of treatment**  **on mortality**  **in the**  **study. A** **n o**  **observed adverse**  **effect level**  **(NOAEL) could**  **not be**  **determined from**  **the dose**  **levels administered.**  **Mechanism -** **of -**  **action studies**  **have indicated**  **that the**  **lung effects**  **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 m** **ice at dose levels ranging from 10 to 250 pp m**  **to establish**  **a NOAEL**  **for hyperplasia/hypertrophy**  **of epithelial**  **cells in**  **terminal bronchioles**  **and for**  **the incidence**  **of alveolar/bronchiolar**  **adenomas and**  **carcinomas in**  **both sexes.**  **T here**  **was a**  **statistically significant**  **increase in**  **the incidence**  **of alveolar** **/bronchiolar adenomas**  **in males**  **at 250**  **ppm. I** **n females,**  **there was**  **no statistically**  **significant increase**  **in the**  **incidence of**  **pulmonary neoplastic**  **lesions at**  **any dose**  **level. T**  **he incidence**  **of hyperplasia/hypertrophy**  **of epithelial**  **cells lining**  **the terminal**  **b ronchioles**  **of the**  **lungs was**  **statistically increase**  **at 250**  **ppm in**  **both sexes.**  **T here**  **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 weigh t/day for males and females,**  **respectively. T**  **his study**  **confirmed a**  **threshold for**  **these effects**  **at 80**  **ppm. F** **lonicamid technical was not carcinogenic in the rat.**  **6. Animal**  **metabolism .**  **Rat, goat**  **and poultry**  **metabolism studies**  **were conducted**  **usin g [**  **14 C]**  **- pyridyl** **- flonicamid.**  **The majority**  **of the dose was rapidly excreted. Flonicamid was**  **a ma** 

**jor component**  **of rat**  **urine 48**  **hours after**  **dosing. T**  **FNA -** **AM was**  **the ma** **jor metabolite**  **found in**  **rats (urine),**  **goats (milk**  **and tissues)**  **and in**  **laying hens**  **(tissues and**  **eggs). T**  **FNG was**  **found between**  **8 -**  **24% of**  **the total**  **radioactive residue**  **(TRR) in**  **the livers**  **of rats sacrificed at intervals between 0.5 -**  **6 hours after 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. T**  **he metabolism**  **of flonicamid**  **in animals**  **shows the**  **main pathway**  **of metabolism**  **involves hydrolysis**  **of -**  **CN and**  **- CONH** **2 functional**  **groups in**  **the molecule,**  **identical to**  **plant metabolism.**  **T he**  **main metabolic**  **reac tions**  **were hydrolysis**  **of cyano**  **to the**  **am ide**  **function and**  **ring hydroxylation.**  **I n**  **rats flonicamid**  **was further** 5

**metabolized by**  **several routes,**  **including nitrile**  **hydrolysis, amide**  **hydrolysis, N** **- oxidation,**  **and hydroxylation**  **of the**  **pyridine ring,**  **leading to**  **mult iple**  **metabolites. The**  **metabolism of**  **flonicamid in animals is well understood. 7.**  **Metabolite toxicology .**  **The main**  **metabolites of flonicamid were**  **examined in acute**  **oral toxicity**  **studies in**  **rats and**  **bacterial reverse**  **mutation tests.**  **A ll**  **the metabolites**  **were less toxic than flonicamid and not mutagenic**  **. 8.**  **Endocrine disruption**  **. No**  **special studies**  **investigating potential**  **estrogenic or**  **other endocrine**  **effects of**  **flonicamid have**  **been conducted.**  **S om** **e suggestions**  **of possible**  **endocrine effects**  **were reported**  **at the**  **highest dose**  **tested (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. H** **owe ver,**  **there were**  **no effects**  **on reproductive**  **performance or**  **survival of**  **the offspring**  **in the**  **study. A** **t levels**  **that are**  **expected to**  **be found**  **in the**  **environment, flonicamid 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 with the Food Commodity Intake Database**  **(DEEM -** **FCID TM, Version 4.02**  **), which uses food consumption data from 2**  **005 -** **2010 of the**  **NHANES/WWEIA survey . Overall dietary exposure to flonicamid was expressed in**  **mg/kg/day and was calculated as a percent of Chronic Population Adjusted Dose (cPAD). Revision of the**  **tolerance for residues of flonicamid representing Crop Grou p 14** 

**– Tree**  **Nuts were all set to 0.3 ppm for the crop group and () were incorporated into the DEEM** **** **FCID residue file for dietary exposure assessment. Revision of the**  **tolerance for residues of flonicamid for hops was set at 30 ppm.**  **The Chronic Reference D ose (cRfD) was established 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/k g/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 Environmental 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 for proposed uses on root vegetables (except** 6

**sugarbeet; Subgroup 1B), tuberous 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 water (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 professional pest control operators. Therefore, residential handler scenarios are not expected a** **nd need not be assessed. Flonicamid label language should preclude use by non**  **- professionals (e.g., homeowners), particularly**  **regarding landscape ornamentals. D.**  **Cumulative Effects .**  **The 2007 EPA assessment (refer to Section C) was conducted fo r food and water**  **exposure only. There are no expected long -** **term residential exposures. Because drinking water estimates have been combined with dietary exposures, the dietary assessment serves**  **as the aggregate exposure and risk assessment for flonicamid. The**  **revision of the tolerance to**  **Crop Group 14 and to hops**  **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 popula tion subgroup (Children 1**  **- 2 years old)**  **only amount to 23.2**  **% of the cPAD, exposure to flonicamid 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. These cons ervative estimates include exposure**  **to flonicamid from tolerance -** **level residues representing Crop Group 14 and hops**  **. The EPA generally has no concern for exposures below 100% of the Population Adjusted Dose**  **(aPAD/cPAD) because it represents the level at o r 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 aggregate**  **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 assessment to infants and children as well as adults. Using the conservative Tier 1 assumpt** **ions described in Section C and 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 for the most sensitive sub -** 7

**population (Children 1 -** **2 years old) comprises**  **23.2 % of the cPAD. The risk from**  **revising the tolerance to**  **Crop Group 14 into the dietary 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 reasonable**  **certainty that**  **no harm**  **will result**  **to infants,**  **children, or**  **adults from**  **dietary (food**  **plus drinking**  **water) exposure**  **to flonicamid**  **residues from**  **tree nuts**  **uses (Crop**  **Group 14)**  **and hops**  **, as**  **well as**  **all other**  **existing flonicamid** **- treated hu**  **man dietary food sources.**

**F. International Tolerances Canad**  **a has**  **established MRLs**  **for flonicamid**  **and its**  **metabolites on**  **head and**  **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 resu** **lting secondary**  **residues in**  **meat, milk, poultry and eggs. There**  **are no**  **Mexican residue**  **limits or**  **Codex MRLs**  **for the**  **insecticide flonicamid**  **and its**  **metabolites TFNA, TFNA -** **AM and TFNG.**