Document ID: EPA-HQ-OPP-2011-0985-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-03-14T04:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS 

Docket ID Number:  EPA-HQ-OPP-2011-0985

EPA Registration Division Contact: Sidney Jackson (703-305-7610)

Pesticide Petition Number: 1E7942  

	EPA has received a pesticide petition (PP) 1E7942 from the  Interregional Research Project Number 4 (IR-4), IR-4 Project Headquaters, 500 College Road East, Suite 201W, Princeton, New Jersey, 08540, 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 tolerance for residues of the combined residues of the insecticide flonicamid [N-(cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide]and its metabolites TFNA [4-trifluoromethylnicotinic acid], TFNA-AM [4-trifluoromethylnicotinamide] and TFNG [N-(4-trifluoromethylnicotinoyl)glycine] in or on the raw agricultural commodities: Berry, low growing, subgroup 13-07G at 1.4 parts per million (ppm), Cucumber at 1.3 ppm and Rapeseed subgroup 20A at 1.5 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 Berry, low growing, subgroup 13-07G; greenhouse cucumber; and Rapeseed subgroup 20A during field trials.  Maximum total residues for strawberry, representative of low growing berry crops (total of 8 field trials) ranged from 0.140 to 0.768 parts per million (ppm) strawberry samples.  Maximum total residues for greenhouse cucumber as a separate commodity (total of 4 field trials) ranged from 0.076 to 0.76 ppm.  Maximum total residues for canola, representative of rapeseed (total of 9 field trials) ranged from 0.027 to 0.855 ppm.  

In one trial, samples were processed into canola meal and oil.  Processed canola samples (meal and oil) had lower residues than the unprocessed canola seed that had been treated at the same rate, thus it is demonstrated that flonicamid does not concentrate in processed canola matrices.

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 increased 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.   Exposure assessments were conducted to evaluate the potential risk due to dietary exposure of the U.S. population to residues of flonicamid.

For acute dietary exposure, an Acute Reference Dose (aRfD) is not identified for flonicamid since there was no evidence of initial acute effects in the acute toxicity studies.  Furthermore, endpoints from the acute neurotoxicity and developmental toxicity studies, as well as from other short- and long-term studies, were not appropriate for assessing acute dietary risk. 
For chronic dietary exposure, the chronic reference dose (cRfD) is 0.04 mg/kg/day, based on the NOEL of 3.7 mg/kg/day from the 2-generation reproduction toxicity rat study
and a 100-fold uncertainty factor.  The chronic population adjusted dose (cPAD) is also 0.04 mg/kg/day since the FQPA safety factor for flonicamid is 1x.

	i. Food.  Potential dietary exposures from food were estimated using the proposed tolerances for all crops using the Dietary Exposure Evaluation Model (DEEM-FCID[TM])  and percent crop treated of 100%.  The following raw agricultural commodities were included:  head and stem brassica, leafy brassica greens, leafy vegetables (except brassica), cotton, tuberous and corm vegetables, fruiting vegetables, cucurbits, stone fruits, pome fruits, vegetable root crops except sugarbeet, radish tops, turnip greens, hops, okra, berry, low growing, greenhouse cucumber, canola seed and resulting secondary residues in meat, milk, poultry and eggs.
   
Chronic dietary exposure estimates resulted in an estimated exposure for the general U.S. population of 0.004240 mg/kg bwt/day.  This exposure corresponds to 10.6% of the cPAD of 0.04 mg/kg bwt/day.  The highest exposure estimate calculated was for the subgroup children, 1-2 years.  This exposure was determined to be 0.009081 mg/kg bwt/day (22.7% of the cPAD). 

	ii. Drinking water. Since flonicamid is intended for application outdoors to field grown crops, the potential exists for parent and/or metabolites to reach ground or surface water that may be used for drinking water.  An estimated concentration of 1.5 ppb of flonicamid in drinking water was provided by EFED for crops uses in 2007. This value was used in the chronic DEEM dietary assessment.

	2. Non-dietary exposure. There are currently no residential uses of flonicamid registered or pending action that need to be added to the total risk from exposure.

D. Cumulative Effects
      
	Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to flonicamid and any other substances, and flonicamid does not appear to produce a toxic metabolite produced by other substances.  EPA concluded that the evidence did not support a finding of common mechanism for flonicamid and other substances.  

E. Safety Determination
      
	1. U.S. population. Using conservative exposure assessment analyses, the chronic dietary exposure estimates for the various population groups are well below the cPAD of 0.04 mg/kg bw/day.  Based on this information, it can be concluded that there is reasonable certainty that no harm will result from acute or chronic exposure to flonicamid. 
      
	2. Infants and children. Based on the available developmental and reproductive data on flonicamid, it can be concluded that reliable data support use of the standard 100-fold uncertainty factor, and that an additional uncertainty factor is not needed to protect the safety of infants and children under the FQPA. Although the reproduction study indicated signs of toxicity to some reproductive organs/systems at the high dose of 1800 ppm in the diet, other signs of toxicity such as effects on the kidney accompanied these; there were no effects observed at a dose level of 300 ppm.  There were no effects on reproduction or survival at any dose level.  Since chronic aggregate exposure assessments are well below the cPAD, there is reasonable certainty that no harm will result to infants and children from aggregate exposure to flonicamid residues.

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.