Document ID: EPA-HQ-OPP-2015-0561-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-10-21T04:00Z

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-pyridinecarboxamide (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 agricultural commodity Crop Group 14-12, Tree Nuts from 0.15 parts per million (ppm) to 0.3 ppm and the existing tolerance in or on the raw agricultural 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 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 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.   The residue analytical method for the majority of crops includes an initial extraction with acetonitrile (ACN)/deionized (DI) water, followed by a liquid-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 is 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 almonds and pecans during field trials.  Maximum 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.  Maximum total residues in/on pecan nutmeats (total of 5 field trials) ranged from non-detect to 0.018 ppm. Maximum total residues 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 3.45 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 irritation. 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. 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 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.  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 effect level (LOEL) 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 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.  

In the rabbit developmental toxicity study, the maternal and developmental NOELs were 7.5 mg/kg/day and > 25 mg/kg/day (HDT), respectively.  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 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, respectively, for males and females).  The 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 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. 

	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 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 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 included 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 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) 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.  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 oncogenicity 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 LOAEL 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 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, effects were observed in the lung, liver, spleen and bone marrow at 250 ppm or higher.  Findings included centrilobular hepatocellular hypertrophy, extramedullary hematopoiesis and pigment deposition in the spleen and decreased cellularity (hypocellularity) in the bone marrow.  There 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.  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.  A no 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 mice at dose levels ranging from 10 to 250 ppm 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.  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 neoplastic lesions at any dose level.  The incidence of hyperplasia/hypertrophy 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 weight/day for males and females, respectively.  This study confirmed 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 majority of the dose was rapidly excreted.  Flonicamid was a major component of rat urine 48 hours after dosing.  TFNA-AM was the major metabolite found in rats (urine), goats (milk and tissues) and in laying hens (tissues and eggs).  TFNG 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.  The metabolism of flonicamid in animals shows the main pathway of metabolism involves hydrolysis of -CN and -CONH2 functional groups in the molecule, identical to plant metabolism.  The main metabolic reactions were hydrolysis of cyano to the amide function and ring hydroxylation.  In rats flonicamid was further metabolized by several routes, including nitrile hydrolysis, amide hydrolysis, N-oxidation, and hydroxylation of the pyridine ring, leading to multiple 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.  All 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.  Some 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.  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, 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 2005-2010 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 Group 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 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 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 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 and 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 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 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 population 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 conservative 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 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 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 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 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 human dietary food sources.

F. International Tolerances

      
Canada 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 resulting 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.