 

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  >

<EPA Registration Division contact: Shaja Joyner, (703) 308-3194>

 

<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:>

<  SEQ CHAPTER \h \r 1 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
establishing a tolerance for residues of the fungicide pyriofenone,
(5-chloro-2-methoxy-4-methyl-3-pyridinyl)(2,3,4-trimethoxy-6-methylpheny
l)methanone, in or on the raw agricultural commodity grape at 0.2 parts
per million (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>

<Plant metabolism. The metabolism of pyriofenone as well as the nature
of the residues in plants is adequately understood for the purposes of
this tolerance.  Metabolism studies were conducted with three diverse
crops, grapes, wheat and tomatoes.  All three crops showed a similar
pattern of metabolism with unchanged pyriofenone remaining on the plant
surfaces.  The metabolism of pyriofenone in plants results in a large
number of fragments in only trace amounts.  Hence, parent pyriofenone is
the only residue of concern. 

>

<Analytical method. A practical analytical method for Pyriofenone using
Liquid Chromatography-MS/MS is available for analysis of grapes.  This
method has been confirmed through independent laboratory validation and
is available for enforcement purposes.>

<Magnitude of residues. Seventeen grape trials were conducted in Germany
(4 trials), Northern France (4 trials), southern France (4 trials),
Spain (3 trials) and Italy (2 trials).  These studies cover a wide range
of geographies with diverse climates and growing conditions, as well as
various cultural practices.  The residue values reported gave results
which lead to a proposed tolerance of 0.20 ppm.  

In four trials, samples were processed into juice, wine and raisins. 
There was no concentration of pyriofenone in grape juice, wine, or
raisins.  Residues in raisins seen during processing trials were
considered to reflect water loss during the drying process used to
produce them and are as expected.

>

<B. Toxicological Profile

The proposed tolerance for pyriofenone is for an imported commodity
only.  The acute oral toxicity and acute neurotoxicity studies are the
only studies required to evaluate acute toxicity. Subchronic dermal and
inhalation studies are not required because residential and occupational
risk assessments are not necessary to set a tolerance on an imported
commodity.>

<1. 	Acute toxicity.  Pyriofenone exhibits low oral acute toxicity. The
oral LD50 is greater than 2000 mg/kg. Since this petition is for an
import tolerance, oral toxicity data sufficiently assesses the risk of
acute exposure for this use.

In an acute neurotoxicity study, pyriofenone was administered by oral
gavage to groups of CD rats at doses up to 2000 mg/kg. The animals were
observed for 14 days.  A single oral administration of pyriofenone at
doses up to 2000 mg/kg, the maximum dose required by the guidelines to
which the study was designed, resulted in minimal, transient change and
there was no evidence of any neurological effect.  Consequently, 2000
mg/kg was considered to be the NOEL.

>

<2. Genotoxicity. The genotoxic potential of pyriofenone has been
assessed as negative by several in vitro and in vivo mutagenicity
studies. Pyriofenone did not elicit a genotoxic response in any of the
studies conducted. 

>

<3. Reproductive and developmental toxicity. Results from a
two-generation study indicate that pyriofenone is not a reproductive
toxicant. The dietary concentrations for the study were 0, 150, 1000 and
5000 ppm. The NOEL for systemic toxicity was 1000 ppm (equivalent to
64.1 and 79.2 mg/kg/day, respectively for P males and females and 76.8
and 84.4 mg/kg/day for F1 males and females). The NOEL for reproductive
toxicity was 5000 ppm (equivalent to 334 and 395 mg/kg/day for P males
and females, respectively and 393 and 434 mg/kg/day for F1 males and
females).

Results from   SEQ CHAPTER \h \r 1 developmental studies in rats and
rabbits provided no indication of teratogenic effects for fetuses of
either species and no evidence of developmental effects in the absence
of maternal toxicity. For the rat teratology study, doses of 0, 30, 300
or 1000 mg/kg bwt/day were administered between Days 6 and 19 of
gestation. The NOEL for maternal toxicity was 30 mg/kg bwt/day.  The
NOEL for developmental toxicity was 1000 mg/kg bwt/day, the highest dose
tested. Pyriofenone technical was not teratogenic to rats.  For the
rabbit teratology study, doses of 0, 30, 100, or 300 mg/kg bwt/day were
administered between Days 6 and 27 of gestation. The NOEL for maternal
toxicity was 100 mg/kg bwt/day.  The NOEL for developmental toxicity was
300 mg/kg bwt/day, the highest dose tested. Pyriofenone technical was
not teratogenic to rabbits.

4. Subchronic toxicity. Short-term (28-day) toxicity studies were
conducted in rats and dogs.  Doses evaluated in the rat study were 0,
300, 3000, 10,000, and 20,000 ppm.  The NOEL was 300 ppm (equivalent to
24.2 and 26.1 mg/kg bwt/day, respectively for males and females).
Effects observed at 3000 ppm included hyaline droplets in the kidney
proximal tubular cells, changes in the blood plasma and increased liver
weights for males and increased liver weights, increased kidney weights
and hepatocyte hypertrophy in one animal for females.  Doses evaluated
in the dog study were 0, 500, 1500, 5000, and 15,000 ppm.  The NOEL was
5000 ppm for males (equivalent to 144 mg/kg bwt/day) and 1500 ppm
(equivalent to 47.5 mg/kg bwt/day) for females. In addition, subchronic
(90-day) feeding studies were conducted in rats, mice, and dogs. Doses
evaluated in the rat study were 0, 300, 1000, 2500, and 5000 ppm.  The
NOEL was 1000 ppm (equivalent to 60.5 and 69.0 mg/kg bwt/day,
respectively for males and females). Effects observed at 2500 ppm
included high plasma protein, albumin, calcium, low chloride, and
increased liver, kidney and cecum weights.  In females at 2500 ppm,
increased activated partial thromboplastin time and globulin, and
increased liver, kidney and cecum weights were observed. Doses evaluated
in the mouse study were 0, 300, 1000, 300, and 7000 ppm.  The NOEL was
1000 ppm (equivalent to 176 mg/kg bwt/day) for males and 300 ppm
(equivalent to 61.0 mg/kg bwt/day) for females. Effects included
increased liver weights and the presence of periportal hypertrophy in
males at 3000 ppm and and increased liver weight observed in females at
1000 ppm. Doses evaluated in the dog study were 0, 500, 3000 and 25,000
ppm in males and 0, 500, 3000 and 15,000 ppm in females.  The NOEL was
3000 ppm (equivalent to 90.3 and 89.8 mg/kg bwt/day, respectively for
males and females). At the high doses, effects included decreased weight
gain and food intake as well as increased kidney weights in males,  and
progressive increase of alkaline phosphatase in both sexes.

>

<5. Chronic toxicity. An 18-month oncogenicity study was conducted in
mice with dietary concentrations of 0, 600, 1800 and 5400 ppm for males
and 0, 300, 1000, and 3000 ppm for females.    The systemic NOEL was 600
ppm (77.6 mg/kg bwt/day) for males based on non-neoplastic changes in
the kidney and liver. The systemic NOEL was 1000 ppm (167 mg/kg bwt/day)
for females based on reduced body weights and food consumption. There
was no evidence of carcinogenicity.

A 2-year chronic toxicity/carcinogenicity study was conducted in rats
with dietary concentrations of 0, 200, 1000 and 5000 ppm technical
pyriofenone.  The systemic NOEL was 1000 ppm (36.4 mg/kg bwt/day) for
males based on reduced body weight gains and non-neoplastic changes in
the kidney, liver, and mesenteric lymph nodes. The systemic NOEL was 200
ppm (9.13 mg/kg bwt/day) for females based on reduced body weight and
non-neoplastic changes in the kidney. There was no evidence of
carcinogenicity.

A 52-week chronic toxicity study was conducted in dogs with dietary
concentrations of 0, 500, 3000 and 25,000 ppm for males and 0, 500,
3000, and 15,000 ppm for females.  The NOEL was 3000 ppm (83.5 and 86.2
mg/kg bwt/day for males and females, respectively). The LOEL was 25,000
ppm (701 mg/kg bwt/day) for males and 15,000 ppm (448 mg/kg bwt/day) for
females based decreased weight gain, decreased food intake, and
increased kidney weights observed for the males and progressive increase
of alkaline phosphatase observed in both sexes.

>

<6. Animal metabolism. The metabolism of pyriofenone in rats and goats
is adequately understood. Pyriofenone is rapidly excreted in the urine
and feces and was extensively metabolized to a number of components
through a number of metabolic pathways including glucuronidation. There
are no significant qualitative differences between rat and ruminant
metabolic pathways.>

<7. 	Metabolite toxicology. No toxicologically significant metabolites
were detected in plant or animal metabolism studies. The residue of
concern for tolerance setting purposes is the parent compound.
Consequently, there is no additional concern for toxicity of
metabolites. 

>

<8. 	Endocrine disruption. The submitted studies 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. The data demonstrate no treatment-related effects on the
endocrine system.

 

≥1690mg/kg bwt/day). Dietary doses up to 7000 ppm were evaluated in
the mouse study.  There was no effect on the immune system at any dose
tested.  The NOEL was greater than 7000 ppm (≥1270mg/kg bwt/day). >

<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 pyriofenone.

For acute dietary exposure, an Acute Reference Dose (aRfD) is not
identified for Pyriofenone since there was no evidence of initial acute
effects in the acute oral or short-term toxicity studies, or the
developmental toxicity studies in rats and rabbits.  Furthermore,
effects in the acute neurotoxicity study were seen only at the limit
dose level of 2000 mg/kg/day.  No initial acute effects were seen in
the 90-day neurotoxicity study.

For chronic dietary exposure, the chronic reference dose (cRfD) is 0.106
mg/kg bwt/day, based on the NOAEL from the rat combined chronic
toxicity/carcinogenicity study (10.6 mg/kg bwt/day) and dividing by an
uncertainty factor of 100.  The chronic population adjusted dose (cPAD)
is also 0.106 mg/kg bwt/day since the FQPA safety factor is anticipated
to be 1 for pyriofenone.

>

<	i. Food. Tier 1 chronic dietary exposure analyses were conducted for
pyriofenone in/on grapes to determine the exposure contribution of this
commodity to the diet and to ascertain the chronic risk potential.  The
exposure estimates were based on the proposed tolerance level residues,
average processing factors and a market share of 100% crop treated as a
conservative assumption. The consumption data were from the USDA’s
CSFII (1994 through 1996 and 1998) continuing survey of food intake
using Exponent's Dietary Exposure Evaluation Module (DEEM-FCID)
software, version 2.16.

Using all of the worst case exposure scenarios listed above, the Tier 1
chronic dietary exposure estimates resulted in an estimated exposure for
the general U.S. population of 0.000130 mg/kg bwt/day.  This exposure
corresponds to 0.1% of the cPAD of 0.106 mg/kg bwt/day.  The highest
exposure estimate calculated was for the subgroup children, 1-2 years. 
This exposure was determined to be 0.000753 mg/kg bwt/day (0.7% of the
cPAD).  The chronic dietary exposure analysis is summarized in the table
below.

	

Population	Exposure Estimate	% of cPAD

Subgroup	(mg/kg body wt/day)	 

U.S. Population	0.000130	0.1

All Infants (< 1 year old)	0.000209	0.2

Children (1-2 years old)	0.000753	0.7

Children (3-5 years old)	0.000456	0.4

Children (6-12 years old)	0.000171	0.2

Youth (13-19 years old)	0.000062	0.1

Females (13-49 years old)	0.000078	0.1

Adults (20-49 years old)	0.000092	0.1

Adults (50+ years old)	0.000083	0.1



It can be concluded that long-term dietary exposure to pyriofenone
through residues on treated grapes should not be of cause for concern.

>

<	ii. Drinking water. Pyriofenone is proposed for use only on an
imported commodity (grape), therefore the only anticipated exposure
route for the US population is by dietary (food) exposure.  With no
proposed US registration, there will be no pyriofenone residues in
surface or ground water that would be used for drinking water.

>

<	2. Non-dietary exposure. The proposed use for pyriofenone is for an
imported commodity (grape).  The only anticipated exposure route for the
US population is via the diet (food only). Therefore, residential and
occupational exposure risk assessments for the incidental oral, dermal,
and inhalation exposure routes are not required.

>

<D. Cumulative Effects  

>

EPA has not made a common mechanism of toxicity finding as to
pyriofenone and any other substances, and pyriofenone does not appear to
produce a toxic  metabolite produced by other substances. For the
purposes of this tolerance action, therefore, EPA has not assumed that
pyriofenone has a common mechanism of toxicity with other substances.

<E. Safety Determination>

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Based on the completeness and reliability of the toxicity data and the
conservative exposure assessments, there is a reasonable certainty that
no harm will result to infants and children from the aggregate exposure
of residues of pyriofenone.>

<F. International Tolerances>

<Presently, there are no Codex maximum residue levels (MRLs) established
for residues of pyriofenone on any crop.  >

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