**FILE NAME:** **company.wpt (7/1/2005)** **(xml)**

**Template Number P25**

**ATTENTION:**

**All commodity terms must comply with the Food and Feed Commodity
Vocabulary database (http://www.epa.gov/pesticides/foodfeed**/**).**

**All text in blue font (instructions for preparing the document),
should be removed prior to sending the document to the Federal Register
Staff. Instructional text and prompts in green font should also be
removed.**

**COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE**

**(1/1/2005)**

**EPA Registration Division contact: \[**Janet Whitehurst,
703-305-6129**\]**

***INSTRUCTIONS:* Please utilize this outline in preparing tolerance
petition documents. In cases where the outline element does not apply
please insert "NA-Remove" and maintain the outline. The comment notes
that appear on the left margin represent hidden typesetting codes
designed to expedite the processing of the Federal Register document.
Please do not remove or alter these comment notes or change the margins,
font, or format in your document. Simply replace the instructions that
appear in italics and brackets, i.e., "****\[*insert company name*\],"
with the information specific to your action.**

***TEMPLATE:***

**Valent U.S.A. Company**

**5f7016**

EPA has received a pesticide petition (5f7016**\]**) from **\[Valent
U.S.A. Company\]**, **\[1600 Riviera Ave., Walnut Creek, CA
94596-8025\]** 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.

**Options (pick one)**

1\. by establishing a tolerance for residues of

**\[fluopicolide\]** in or on the raw agricultural commodity **\[Grape
at 2 parts per million (ppm), Raisin at 6 ppm, Vegetable, leafy, except
brassica, group 4 at 20 ppm, Vegetable, fruiting, group 8 at 0.8 ppm,
Vegetable, cucurbit, group 9 at 0.4 ppm, Potato at 0.02 ppm, Sweet
potato, roots at 0.02 ppm, Wheat forage at 0.2 ppm, Wheat grain at 0.02
ppm, Wheat hay at 0.5 ppm, and Wheat straw at 0.5ppm**. 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 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).

iii\. 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 water*. **\[**

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

**Chronic: A tier II PRZM/EXAMS assessment was conducted to determine
the EECs in the standard EPA pond and the EDWCs in the Standard Index
Reservoir associated with fluopicolide on crops. The EXPRESS, PRZM/EXAMS
shell was used to conduct the modeling. The worst case scenario was used
in the drinking water exposure assessment and a refined chronic drinking
water exposure risk analysis was conducted using the CARES Water Wizard.
\]**

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

*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.**

**Chronic: The aggregate risk of the US population to fluopicolide was
determine and the resultant exposure value was expressed in terms of
margin of exposure (MOE), which was calculated by dividing the no
observable adverse effect level (NOAEL) by the exposure for each
population subgroup. In addition, exposure was also expressed as a
percent of the chronic reference dose (%cRfD). The results of the
chronic dietary and drinking water exposure and risk analyses presented
here, demonstrate that there is a reasonable certainty that no harm will
result to the U.S. population or sensitive sub-populations, including
infants and children, from chronic dietary exposure resulting from the
proposed uses of fluopicolide.\]**

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 2 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*

**\[There are no CODEX tolerances for residues of fluopicolide\]**