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

**PETITION Docket ID Number: EPA** **- HQ**  **- OPP**  **- 2016**  **- 0013**  **EPA Registration Division C ontact:**  **Sidney Jackson , (703) 30**  **5 -**  **7610 Interregional Research Project Number 4 (IR** **- 4)**  **Pesticide Petition Number: 5E8428**  EPA has received a pesticide petition **( PP# 5E8428**  **)** from IR- 4 Project Headquarters , 500 College Road East, Suite 201W, Princeton, New Jersey , 08540, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFD CA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 b y establishing a tolerance for residues of the combined residues of the insecticide flonicamid [N - (cyanomethyl) - 4 - trifluoromethyl ) - 3 -p y ridinecarboxamide (CA) or N cyanomethyl - 4 - trifluoromethylnicotinamide ( IUP AC)] and its metabolites, TFNA [4 - trifluoromethylnicotinic acid], TFNA - AM [4 - trifluoromethylnicotinamide] and TFNG [N - (4 - trifluoromethylnicotinoyl) - gl yc ine] in or on the raw agricultural commodities Vegetable , legume, edible podded, subgroup 6A at 4 .0 p arts per million (ppm), Pea and bean, succulent shelled, subgroup 6B at 6. 0 parts ppm , Pea and bean, dried shelled, except soy bean, subgroup 6C at 3.0 ppm , and Vegetable , fruiting, group 8 - 10 at 1.50 ppm (revision of established tolerance of 0.40 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 full y evaluated the sufficiency of the submitted data at this time or whether the data support 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] -py ridyl - flonicamid. The 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 plants shows the main pathway o f metabolism involves hydrol ys is of - CN and BCONH2 functional groups in the molecule. The metabolism of flonicamid in plants is well understood. 2. Analytical method. Analy tical 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 anal ytical method for the majority o f crops includes an initial extraction with acetonitrile (ACN)/deionized (DI) water, followed by a l iquid - liquid partition with ethyl acetate. The residue method for wheat straw is similar, except that a C18 solid phase extraction (SPE) is added prior to the liquid- liquid partition. The final sample solution is2

quantitated using a liquid chromatograph (LC) equipped with a reverse phase column and a triple quadruple mass spectrometer (MS/MS). 3. Magnitude of residues . Residue data were collected on edible podded and succulent shelled peas and beans, and dry s helled peas and beans during field trials (total of 12 dry s helled bean field trials , 5 dry

p ea field trials, 6 lima bean field trials, 7 snap bean field trials, and 13 edible podded and succulent pea field trials) . Maximum total residues ranged from <0.08 to 1.2881 parts per million (ppm) in dry bean samples **,** 0.1208 to 0.9192 ppm in lima bean samples **,** 0.4542 to 1.3677 ppm in dry p ea samples, 0.6543 to 1.420 ppm in snap bean samples, 0.356 to 2.03 ppm in edible podded pea samples, and 0.471 to 2.96 ppm in succulent shelled pea samples **.** Residue data were collected on greenhouse peppers during field trials (total of 4 trials in Canada) . Maximum total residues ranged from 0.170 to 0.886 ppm. B. Toxicological Profile 1. Acute toxicity . A battery o f acute toxicity

s tudies was conducted which placed flonicamid technical in Toxicity Catego ry III for oral lethal dose ( LD ) 50, Category IV for dermal LD50, inhalation lethal concentration ( LC ) 50, dermal irritation, and eye irritation. Flonicamid technical is not a dermal sensitizer. In an acute neurotoxicity s tudy , the no observed adverse effect levels (NOAELs) for neurotoxicity were 600 milligram per kilogram (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 mutation or mouse ly

mphoma tests with or without metabolic activation, chromosome damage in the mouse micronucleus or cy togenetics tests with and without metabolic activation, an increase in DNA damage in the comet assay or in an in vivo rat unscheduled DNA sy nthesis (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 s tudy in rats resulted in the maternal and developmental no observed adverse effect levels (NO AELs) of 100 mg/kg/day . The maternal lowest observed adverse effect level (LO AEL) was 500 mg/kg/day based on the treatment - related effects observed on the liver and kidney of the dams in the highest dose group. The developmental LO AEL was 500 mg/kg/day b ased on incidences of fetal skeletal variations seen only at maternall y toxic doses of 500 mg/kg/day . Inthe rabbit developmental toxicity s tudy , the maternal and developmental NO AELs were 7.5 mg/kg/day

and > 25 mg/kg/day highest dose tested (HDT), respectively . The maternal LOEL was 25 mg/kg/day b ased on decreased body w eights, body

w eight gains and food consumption. No adverse effects on the fetuses were observed at the highest dose. In the multigeneration rat reproduction study , the NOAELw as 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 , respectivel y, for males and females). The effects at the highest dose of 1800 ppm included the following: increased kidney w eights and gross and3

histopathological alterations in the kidney . F indings noted in the top dose females included delayed vaginal opening and increased liver, kidney and spleen w eights 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 . 4. Subchronic toxicity . The NOAEL for flonicamid technical in the rat 28 - day d ermal 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 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 levels, increased liver and spleen weights and histopathology findings in the bone marrow, spleen and kidney . In a subchronic toxicity

study in dogs with capsule administration, the NOAELwas 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; s ymptoms included collapse, prostration and convulsions leading to early sacrifice at the LOAEL o f 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, respectivel y (highest dose tested) based on decreased motor activity , body weight and food consumption effects. 5. Chronic toxicity . Inthe chronic dog study with administration via using capsules, the NOEL was 8 mg/kg/day. The LOAEL was 20 mg/kg/day b ased on reduced body

w eights in females and effects on the circulating red blood cells. In a rat 24 - month combined chronic and oncogenicity s tudy , 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 AELw as 1000 ppm for males and 5000 ppm for females based on histopathology

in the kidney , hematology e ffects, hepatic effects including changes in biochemical parameters, increase d organ weights, and histopathological changes. Atrophy of striated muscle fibers, cataract and retinal atrophy observed in the high dose females were considered to be due to acceleration of spontaneous age - related lesions. In the 18 - month mouse study, ef fects were observed in the lung, liver, spleen and bone marrow at 250 ppm or higher. F indings included centrilobular hepatocellular hy pertrophy , extramedullary

h ematopoiesis and pigment deposition in the spleen and decreased cellularity (hy pocellularity) in the bone marrow. There were statistically s ignificant increases in the incidence of alveolar/bronchiolar adenomas in both sexes of treated groups with4

hy perplasia/hy

pertrophy o f epithelial cells in terminal bronchioles. There was a statisticall y signi ficant increase in the incidence of alveolar/bronchiolar carcinomas in males at 750 ppm and 2250 ppm and in females at 2250 ppm only . These effects in the lungs of mice 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 . Ano observed adverse effect level (NOAEL) could not be determined from the dose levels administered. M echanism - 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. As econd 18 - month mouse study w as conducted in CD - 1 mice at dose levels ranging from 10 to 250 ppm to establish a NOAEL for hy perplasia/hy

pertrophy of epithelial cells in terminal bronchi oles and for the incidence of alveolar/bronchiolar adenomas and carcinomas in both sexes. There was a statistically s ignificant increase in the incidence of alveolar/bronchiolar adenomas in males at 250 ppm. In females, there was no statistically s ignif icant increase in the incidence of pulmonary n eoplastic lesions at any dose level. The incidence of hy perplasia/hy

pertrophy of epithelial cells lining the terminal bronchioles of the lungs was statistically

increase 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 w eight/day

f or males and females, respectively . This study c onfirmed a threshold for these eff ects at 80 ppm. F lonicamid technical was not carcinogenic in the rat. 6. Animal metabolism . Rat, goat and poultry m etabolism studies were conducted using [ 14 C] -py ridyl - flonicamid. The majority o f the dose was rapidl y excreted. F lonicamid w as a major component of rat urine 48 hours after dosing. T FNA - AM was the major 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. T FNA was not a major component in animal tissues. The metabolism of flonicamid in animals s hows the main pathway o f metabolism involves hydrolysis of - CN and

- CONH 2 functional groups in the molecule, identical to plant metabolism. The main metabolic reactions were hydrol ys is of cyano to the amide function and ring hydroxylation. In rats flonic amid was further metabolized by s everal routes, including nitrile hydrol ys is, amide hydrol ys is, N - oxidation, and hydroxylation of the py ridine ring, leading to multiple metabolites. The metabolism of flonicamid in animals is well understood. 7. Metabo lite toxicology . The main metabolites of flonicamid were examined in acute oral toxicity

s tudies in rats and bacterial reverse mutation tests. All the metabolites were less toxic than flonicamid and not mutagenic. 8. Endocrine disruption . N o special studies investigating potential estrogenic or other endocrine effects of flonicamid have been conducted. S ome suggestions of possible endocrine effects were reported at the highest dose tested (1800 ppm) in the multi - generation reproduction study which show ed 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 owever,5

there were no effects on reproductive performance or survival of the offspring in the s tudy . At 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 2.14), which uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSF II) from 1994 - 1996 and 1998. Overall dietary exposure to flonicamid was expressed in mg/kg/day and was calculated as a percent of Chronic Population Adjusted Dose (cPAD). Proposed tolerances for residues of flonicamid representing Crop Subgroups 6A (4.0 ppm) , 6B (6.0 ppm), 6C, except soy beans (3.0 ppm) and Crop Group 8 - 10 (1.5 ppm) were incorporated into the DEEM - FCID residue file for dietary exposure assessment. The Chronic Reference Dose (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/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 Pesticide Root Zone Model/ Exposure Analysis Modeling System (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 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 Concentration in Ground Water ( SCI - GROW) 2 model , the ground water EEC for floni camid was 0.00132 ppb, which was considered appropriate for chronic EEC. To be protective of all drinking water s ys tems, the predicted chronic EEC for surface water (1.5 ppb) was incorporated in the DEEM dietary assessment modeling. 2. Non - dietary expos ure . 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 scenari os are not expected and need not be assessed. Flonicamid label language should preclude use by non -professionals (e.g., homeowners), particularl y regarding landscape ornamentals.6

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 drinking water estimates have been combined with dietary exposures, the dietary

assessment serves as the aggregate exposure and risk asses sment for flonicamid. The addition of the proposed uses 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 highl y exposed population subgroup (Children 1 - 2 years old) onl y amount to 23.1% of the chronic Population Adjusted Dose ( cPAD ) , exposure to flonicamid from the all current and proposed uses should not exceed E PA ’s level of concern. E. Safety Determination . 1 . U.S. popula tion . 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 15.9 % of the cPAD. These conservative estimates include exposure to flonicamid from tolerance - level residues representing the proposed uses. The EPA generall y has no concern for exposures below 100% of the acute Population Adjusted Dos e (aPAD ) /cPAD because it represents the level at or below which dail y 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 aggre gate 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 assumptions 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 -population (Children 1 - 2 years old) comprises 37.5 % of the cPAD. The risk from incorporating the proposed tolerances into the dietary

risk assessment increased the cPAD b y less than 2 % 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 the proposed uses , as well as all other existing flonicamid- treated human dietary food sources. F. International Tolerances Canada has established MRL s for flonicamid and its metabolites on head and stem brassica, leafy

b rassica greens, leafy

v egetables (except brassica), tub erous and corm vegetables,7

fruiting vegetables, cucurbits, stone fruits, pome fruits, vegetable root crops except sugarbeet, radish tops, turnip greens, hops, and resulting secondary residues in meat, milk, poultry and eggs. There are no Mexican residue limits or Codex MRL s for the insecticide flonicamid and its metabolites TFNA, TFNA - AM and TFNG.