Document ID: EPA-HQ-OPP-2007-0338-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-27T04:00Z

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

Interregional Research Project Number 4 (IR-4)

613 by establishing a tolerance for combined residues of the
insecticide, flonicamid [ N
-(cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide] and its
metabolites TFNA [4-trifluoromethylnicotinic acid], TFNA-AM
[4-trifluoromethylnicotinamide] TFNG [ N
-(4-trifluoromethylnicotinoyl)glycine] in or on the raw agricultural
commodities vegetables, root, except sugarbeet, (subgroup 1B) at 0.45
parts per million (ppm), radish, tops, at 16 ppm, vegetables, tuberous
and corm, (subgroup 1C) at 0.2 ppm, brassica, leafy greens (subgroup 5B)
at 16 ppm, turnip greens at 16 ppm, hop at 7.0 ppm, and okra at 0.4 ppm.
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully 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.  This
notice includes a summary of the petitions made by ISK Biosciences
Corporation, 7470 Auburn Road, Suite A, Concord, OH 44077.

                                      

.  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 the increases in
placental weights and 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.  

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 was 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 marro, 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 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.

.  Acute dietary exposure was compared to the acute population adjusted
dose (aPAD) of 3.0 mg/kg/day based on the NOEL of 300 mg/kg from the
acute neurotoxicity study in rats and a 100-fold uncertainty factor. 
The US population exposure is 0.38% of the aPAD and the most highly
exposed subpopulation is children 1-2 years of age with 1.10% of the
aPAD (95th percentile).

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