Document ID: EPA-HQ-OPP-2007-0339-0002
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)    

PP# 7E7172

	EPA has received a pesticide petition (PP) [7E7172] from the IR-4, 500
College Road East, Suite 201 W, Princeton, NJ 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. 627 by establishing a
tolerance for residues of the fungicide, fluopicolide, 2,6-dichloro- N
-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl] benzamide, in or on
the raw agricultural commodity vegetable, root and tuber, group 1 at 0.2
parts per million (ppm); Vegetable, leaves of root and tuber, group 2 at
12 ppm; Vegetable, bulb, group 3, at 5 ppm; Chive, fresh leaves at 5
ppm; Chive, Chinese, fresh leaves at 5 ppm; Daylily, bulb at 5 ppm;
Elegans hosta at 5 ppm; Fritillaria, bulb at 5 ppm; Fritillaria, leaves
at 5 ppm; Garlic, Serpent, bulb at 5 ppm; Kurrat at 5 ppm; Lady’s leek
at 5 ppm; Leek, wild at 5 ppm; Lily, bulb at 5 ppm; Onion, Beltsville
bunching at 5 ppm; Onion, Chinese, bulb at 5 ppm; Onion, fresh at 5 ppm;
Onion, macrostem at 5 ppm; Onion, pearl at 5 ppm; Onion, potato, bulb at
5 ppm; Onion, tree, tops at 5 ppm; Shallot, bulb at 5 ppm; Shallot,
fresh leaves at 5 ppm; Brassica, head and stem, subgroup 5A at 5 ppm. 
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of the 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. The fate of fluopicolide in plants is clearly
understood.  Metabolism studies were conducted with grapes, potato, and
lettuce.  The metabolic profile of fluopicolide was similar in all three
crops and demonstrated that fluopicolide is degraded by oxidation and
hydrolysis.  The primary residue found in all crops, and the only
residue of concern, is the parent molecule fluopicolide.

	2. Analytical method. A practical analytical method utilizing liquid
chromatography and mass spectrometry detection is available and has been
validated for detecting and measuring levels of fluopicolide in and on
crops. The validated limit of quantitation is 0.01 ppm.

	3. Magnitude of residues. Residue data for the use of fluopicolide on
the commodities listed within this notice has been submitted.

B. Toxicological Profile

	1. Acute toxicity.  A battery of acute toxicity studies places
technical fluopicolide in toxicity category IV. No evidence of
sensitization was observed in guinea pigs.  In an acute neurotoxicity
study in rats, only statistically lower body temperature was observed 6
hours after dosing at the limit dose of 2000 mg/kg. No other
treatment-related changes were noted in the study, and the NOAEL was
considered to be 100 mg/kg.

	2. Genotoxicty. Fluopicolide has been evaluated for genotoxicity using
a battery of tests, including bacterial reverse mutation tests, a
mammalian cell gene mutation (HPRT) assay, an in vivo mouse micronucleus
assay, an in vitro chromosome aberration test, and an in vivo
unscheduled DNA synthesis test. The weight of evidence from all of these
assays shows that fluopicolide is not genotoxic.

	3. Reproductive and developmental toxicity.

i. In a developmental toxicity study in rats gavage dosed from gestation
days 7 to 20 at levels of 0, 5, 60 or 700 mg/kg/day, evidence of
maternal and fetal toxicity was observed at 700 mg/kg/day, the highest
dose tested. The maternal and fetal NOAEL was 60 mg/kg/day based on
statistically lower body weights in dams and fetuses, and skeletal
findings in fetuses that included delayed ossification of some bones and
slight increases in the incidence of various rib and thoracic vertebrae
anomalies.  

ii. In a developmental toxicity study with rabbits, pregnant animals
were given oral doses of 0, 5, 20 or 60 mg/kg/day on gestation days 6 to
28. At the high dose, 15 animals were sacrificed following spontaneous
abortions and 3 animals were found dead. The few surviving animals in
this group had live fetuses at cesarean sectioning but other than lower
fetal weight and crown/rump length, no treatment-related findings were
observed upon external, visceral and skeletal examinations of these
fetuses. The NOAEL for maternal and fetal toxicity was 20 mg/kg/day.  

iii. In a 2-generation reproductive toxicity study, fluopicolide was
administered to rats at dietary levels of 0, 100, 500, or 2000 ppm. The
NOAEL was 500 ppm (equivalent to 26 and 33 mg/kg/day for males and
females, respectively) for developing offspring and for
parental/systemic toxicity. The LOAEL was 2000 ppm based on decreased
body weight and organ weight changes in both F0 and F1 adults and F1 and
F2 pups. The reproductive NOAEL was 2000 ppm.

	4. Subchronic toxicity. 

Ninety-day feeding studies were conducted in dogs, mice and rats. 

i. No evidence of toxicity was observed in dogs up to the limit dose of
1000 mg/kg/day.  The NOAEL in dogs is 1000 mg/kg/day.

ii. In 90-day feeding studies in both CD-1 and C57BL/6 mice, liver was
the only target organ identified with hepatocellular hypertrophy seen at
dietary levels of 320 ppm and higher. The NOAEL in C57BL/6 mice was 200
ppm (equivalent to 37.8 and 52.8 mg/kg/day in males and females,
respectively).  

iii. In a 90-day rat study with dietary levels of 100, 1400 and 20,000
ppm, the maximum tolerated dose (MTD) was exceeded at 20,000 ppm based
on body weight gain of 30 to 40% below control. The target organs
identified in rats were the liver (centrilobular hypertrophy) in both
sexes and the kidneys in males (accumulation of hyaline droplets, single
cell death at the proximal tubule epithelium, slight foci of basophilic
tubules and granular casts) at 1400 ppm and 20000 ppm. The NOAEL was 100
ppm, equivalent to 7.4 and 8.4 mg/kg/day, in males and females,
respectively.  

iv. In a subchronic neurotoxicity study, rats were treated with 0, 200,
1400 or 10000 ppm in the diet for 13 weeks.  The NOAEL for systemic
toxicity is 1400 ppm (107 mg/kg/day in males and 125 mg/kg/day in
females) based on findings in the liver and kidney.  There were no
neurotoxicity findings.  The NOAEL for neurotoxicity is 10,000 ppm (781
mg/kg/day in males and 866 mg/kg/day in females). 

v.  In a subchronic dermal toxicity study, male and female rats were
treated with fluopicolide at dose levels of 0, 100, 250, 500 and 1000
mg/kg/day.  There were no effects at any dose level.  The NOAEL of the
study is 1000 mg/kg/day.

	5. Chronic toxicity. 

i. Lower body weight gain at the limit dose of 1000 mg/kg/day was the
only treatment-related effect noted in a 52-week dog study performed at
70, 300, and 1000 mg/kg/day by gavage. Thus, the NOAEL in dogs was
established at 300 mg/kg/day.  

ii. Chronic toxicity/carcinogenicity was assessed in rats at dietary
levels of 50, 200, 750 and 2500 ppm. The NOAEL was 200 ppm (8.4
mg/kg/day in males and 10.8 mg/kg/day in females) based on microscopic
changes in the liver and kidneys similar to those observed in the 90-day
rat study.  No evidence of carcinogencity was observed in rats up to
2500 ppm.  

iii. The oncogenic potential of fluopicolide was investigated in C57BL/6
mice at dietary levels of 0, 50, 400, or 3200 ppm. Significantly lower
body weight gain was seen at 3200 ppm in conjunction with a slight
decrease in food consumption. Increased liver weight and centrilobular
hepatocellular hypertrophy were observed at 400 and 3200 ppm in both
sexes. In addition at 3200 ppm, an increased incidence of hepatocellular
adenomas was noted in both sexes, but the incidence of hepatocellular
carcinomas was not affected. The NOAEL was 50 ppm (equivalent to 7.9 and
11.5 mg/kg/day in males and females, respectively). Subsequent
mechanistic work demonstrated a marked transient hepatocellular
proliferation, which returned to control levels after 28 days of
treatment.  This was accompanied by a clear induction of total
cytochrome P-450 and related enzymes.  These results parallel findings
with Phenobarbital, which has a well understood threshold-based
mechanism of rodent tumor formation commonly known to be of no relevance
to humans.

	6. Animal metabolism. 

The animal metabolism of fluopicolide is well understood. Fluopicolide
is rapidly absorbed and excreted when administered to rats and the
resulting tissue residues are very low. The metabolic pathway for
fluopicolide is similar in rodents, goats and hens. Metabolism in
livestock proceeded primarily via hydroxylation and hydrolysis.

	7. Metabolite toxicology. 

Four metabolites (AE C653711, AE C657188, AE C657378, and AE 1344122)
were identified as low-level plant and/or soil metabolites of
fluopicolide.  Several of the metabolites were identified at low levels
in the rat following fluopicolide or AE C653711 administration and were
therefore covered by the tox studies conducted with the parent molecule.
 All compounds were tested for acute, subchronic (28-day) and genetic
toxicity and AE C653711 and AE C657188 were additionally studied in in
vivo ADME studies.  All were found to be equally or less toxic than the
parent molecule itself.  These metabolites are therefore considered not
toxicologically relevant to the overall assessment of fluopicolide human
health.

	8. Endocrine disruption. The toxicology database for fluopicolide is
current and complete. No special studies to evaluate the potential
endocrine effects of fluopicolide have been conducted.  However, the
studies in this database include evaluation of the potential effects on
reproduction and development, and an evaluation of the pathology of the
endocrine organs following short- or long-term exposure.  These studies
revealed no endocrine-related effects.

C. Aggregate Exposure

	1. Dietary exposure. 

An assessment was conducted to evaluate potential risks due to chronic
and acute dietary exposure of the U.S. population subgroups to residues
of fluopicolide.  This analysis covers all pending crop uses.

	i. Food. 

Acute:  No appropriate toxicological endpoint attributable to a single
exposure was identified in the available toxicology studies conducted
with fluopicolide.  Since no acute toxicological endpoints could be
established, the acute aggregate risk is considered to be negligible.

Chronic: Chronic assessments were conducted to evaluate potential risks
due to chronic dietary exposure to the U.S. population and selected
population subgroups to residues of fluopicolide.  This analysis was
conducted using the Cumulative and Aggregate Risk Evaluation System
(CARES) using actual field trial residue and estimated percent crop
treated.

	ii. Drinking Food. Acute: Since no acute toxicological endpoints could
be established, the acute aggregate risk is considered to be negligible.

	2. Non-dietary exposure. 

There is a potential residential exposure to adults applying
fluopicolide, and adults and children entering residential turf areas
treated with fluopicolide. Based on the application of fluopicolide to
residential turf, conservative estimates of exposure were calculated for
both children and adults.  All estimates resulted in calculated margins
of exposure in excess of 100.

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity”.  EPA does not have, at this time,
available data to determine whether fluopicolide has a common mechanism
of toxicity with other substances or how to include this pesticide in a
cumulative risk assessment.  For the purposes of this tolerance action,
EPA has not assumed that fluopicolide has a common mechanism of toxicity
with other substances.

E. Safety Determination

	1. U.S. population. 

Acute: No appropriate toxicological endpoint attributable to a single
exposure was identified in the available toxicology studies conducted
with fluopicolide.  Since no acute toxicological endpoints could be
established, the acute aggregate risk is considered to be negligible.

	2. Infants and children. 

Acute: No appropriate toxicological endpoint attributable to a single
exposure was identified in the available toxicology studies conducted
with fluopicolide.  Since no acute toxicological endpoints could be
established, the acute aggregate risk is considered to be negligible.

Chronic: The results of the chronic dietary and drinking water exposure
and risk analysis demonstrate that there is a reasonable certainty that
no harm will result to the U.S. sub-populations of infants and children
from chronic dietary exposure resulting from the proposed uses of
fluopicolide.  The percentile of chronic dietary exposure (food) was
highest among children 1 to 5 years of age.  The percentile of chronic
drinking water exposure was highest among infants “0" years of age. 
The percentile aggregate chronic exposure from food and water was
highest among infants “0" years of age.  

The maximum chronic exposure from food and water for each population
sub-group was estimated to be less than 1 % of the c-PAD.

F. International Tolerances

	There are no CODEX tolerances for residues of fluopicolide.

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