Document ID: EPA-HQ-OPP-2010-0458-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-06-23T04:00Z

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<NOTICE OF FILING OF PESTICIDE PETITION TO ESTABLISH TOLERANCES FOR
RESIDUES OF PICOXYSTROBIN IN OR ON FOOD COMMODITIES  >

<EPA Registration Division contact: Susan Stanton, 703-305-5218>

<Petitioner: E. I. du Pont de Nemours and Company>

Petition Number: 0F7722

<	EPA has received a pesticide petition (PP #0F7722) from E. I. du Pont
de Nemours and Company, 1007 Market Street, Wilmington, Delaware, 19898
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 picoxystrobin in or on the raw
agricultural commodities of cereal grains except rice (Crop Group 15) at
0.2 parts per million (ppm); cereal forage and fodder except rice (Crop
Group 16) at 13.0 ppm; cereal grain aspirated grain fractions at 4.5
ppm; cereal grain oil at 1.5 ppm; dry legume vegetables except soybean
(Crop Group 6, Subgroup C) at 0.1 ppm; legume vegetable foliage (Crop
Group7) at 18.0 ppm; soybean seed at 0.05 ppm; soybean forage at 0.8
ppm; soybean hay at 2.5 ppm; soybean aspirated grain fractions at 3.2
ppm; soybean hulls at 10.0 ppm; soybean oil at 0.05 ppm; canola seed at
0.05 ppm; meat and meat byproducts except liver of cattle, goat, hog,
horse, and sheep at 0.01 ppm; fat of cattle, goat, hog, horse, and sheep
at 0.05 ppm; liver of cattle, goat, hog, horse, and sheep at 0.8 ppm;
meat, meat byproducts, fat, and eggs of poultry at 0.01 ppm; milk at
0.01 ppm, and cream, at 0.03 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. The metabolism of picoxystrobin in plants is
adequately understood. Studies have been conducted to delineate the
metabolism of radiolabeled Picoxystrobin in apples, canola, soybeans,
and winter wheat, all showing similar results.

The metabolism of picoxystrobin in wheat was complex, however parent
compound, picoxystrobin, was the only residue present at >10% TRR in the
foliage (forage and straw), accounting for approximately 20% TRR in
straw and 50% TRR in forage.  In foliage a total of up to 15 metabolites
were identified and the majority of these have also been identified as
animal metabolites.  The two most abundant metabolites were both present
at <10% TRR, are both major animal metabolites and are not fungicidally
active.  On this basis they are deemed not to be of toxicological
concern.  The residue of concern in straw and forage was therefore
established as parent picoxystrobin only.  In grain, residues were lower
than in the foliage.  Parent picoxystrobin was present at 0.01 mg/kg. 
The most abundant metabolite was present at 14.9% TRR (0.023 mg/kg
compound equivalents).  It has been identified, and is also a minor
metabolite in rat urine.  It results from extensive metabolism of
picoxystrobin and has a high level of functionalization, a high polarity
and low predicted pKa.  The structure is consistent with the known
biotransfomation pathways in both wheat and the rat.

Picoxystrobin metabolism in soybean plants was extensive.  Overall
metabolic reactions included ester hydrolysis, O-demethylation,
conjugation and ether cleavage.  Metabolism of picoxystrobin’s side
chain proceeded through a series of hydrolytic, reductive, oxidative
and/or conjugation steps yielding numerous identified metabolites or
conjugates. The metabolic pathway of picoxystrobin in soybeans is
consistent with pathways observed in other plants (wheat and canola) and
animal (rat and goat) systems.>

<	2. Analytical method. Analytical method: Adequate analytical
methodology is available for enforcement purposes.

An analytical method has been developed and independently validated for
the detection and quantification of picoxystrobin and metabolites in
various crop matrices including cereals, soybean, dried legume, canola,
lettuce, and orange matrices.  The method was validated at 0.010 and
0.10 ppm in all matrices using an LC/MS/MS system operating with an
electrospray interface (ESI) in positive ion mode.  The analytical
method is suitable for enforcement/monitoring and data generation for
regulatory studies.  

An analytical method has been developed and independently validated for
the detection, quantification and confirmation of picoxystrobin residues
in animal tissues including chicken egg, bovine whole and skim milk and
cream and bovine muscle, liver, kidney and fat.  The method quantifies
picoxystrobin in the animal matrices at levels of approximately 0.010
mg/kg using a HPLC/ESI-MS/MS system.  The analytical method is suitable
for enforcement/monitoring and data generation for regulatory studies.

	3. Magnitude of residues. Magnitude of residue and processing trials
were conducted on field corn, sweet corn, wheat, barley in lieu of
sorghum, dried peas and beans, soybean, canola, cows and poultry. The
resulting data supports the proposed tolerances.>

<

Corn, Field:  The proposed use of picoxystrobin on field corn allows for
up to three applications of 0.195 lb a.i./acre, a minimum 7-day
retreatment interval (RTI) with no more than two sequential applications
before switching to a fungicide with a different mode of action, and a
preharvest interval (PHI) of 7-days for grain and ear, and 0-days for
forage. Sixteen field trials were conducted to determine the magnitude
and decline of picoxystrobin residues when applied to field corn
consistent with the proposed use pattern.  Two additional trials were
conducted to determine the magnitude of residues of picoxystrobin in
processed fractions of field corn following application at 5X maximum
label rates. Proposed tolerances on the crop group of cereal grains
except rice, cereal forage and fodder except rice, and processed
commodities thereof are consistent with the findings of these trials.

Corn, Sweet:  The proposed use of picoxystrobin on sweet corn allows for
up to four applications of 0.195 lb a.i./acre, a minimum 7-day
retreatment interval (RTI) with no more than two sequential applications
before switching to a fungicide with a different mode of action, and a
preharvest interval (PHI) of 7-days for grain and ear, and 0-days for
forage. Eleven field trials were conducted to determine the magnitude
and decline of picoxystrobin residues when applied to sweet corn
consistent with the proposed use pattern.  Proposed tolerances on the
crop group of cereal grains except rice, cereal forage and fodder except
rice, and processed commodities thereof are consistent with the findings
of these trials.

Wheat/Barley: The proposed use of picoxystrobin on wheat, barley, and
other cereal grains except corn and sorghum allows for up to three
applications of 0.195 lb a.i./acre, a minimum 7-day retreatment interval
(RTI) with no more than two sequential applications before switching to
a fungicide with a different mode of action, and a preharvest interval
(PHI) of 45-days for grain and straw, 14-days for hay, and 0-days for
forage.  The proposed use on sorghum allows for up to three applications
of 0.195 lb a.i./acre, a minimum 7-day retreatment interval (RTI) with
no more than two sequential applications before switching to a fungicide
with a different mode of action, and no applications following
flowering.  The use of sorghum forage and hay for livestock feed is also
prohibited.  Forty seven field trials were conducted to determine the
magnitude and decline of picoxystrobin residues when applied to wheat
and barley consistent with the proposed use pattern.  Two additional
trials were conducted to determine the magnitude of residues of
picoxystrobin in processed fractions of wheat following application at
5X maximum label rates. Proposed tolerances on the crop group of cereal
grains except rice, cereal forage and fodder except rice, and processed
commodities thereof are consistent with the findings of these trials.

Dried Peas and Beans:  The proposed use of picoxystrobin on dried legume
vegetables allows for up to two sequential applications of 0.195 lb
a.i./acre, a minimum 7-day retreatment interval (RTI), and a preharvest
interval (PHI) of 14-days for seed, and 0-days for vines and hay. 
Twenty two trials were conducted to determine the magnitude and decline
of picoxystrobin residues when applied to dried legume vegetables
consistent with the proposed use pattern.   Proposed tolerances on the
crop group of legume vegetables, dry, except soybean, and the crop group
of legume vegetables, foliage, are consistent with the findings of these
trials.

Soybean: The proposed use of picoxystrobin on soybean allows for up to
three applications of 0.195 lb a.i./acre, a minimum 7-day retreatment
interval (RTI) with no more than two sequential applications before
switching to a fungicide with a different mode of action, and a
preharvest interval (PHI) of 14-days.  Twenty one field trials were
conducted to determine the magnitude and decline of picoxystrobin
residues when applied to soybean consistent with the proposed use
pattern.  Two additional trials were conducted to determine the
magnitude of residues of picoxystrobin in processed fractions of soybean
following application at 5X maximum label rates. Proposed tolerances on
soybean and processed commodities thereof are consistent with the
findings of these trials.

 

Canola:  The proposed use of picoxystrobin on canola allows for up to
two sequential applications of 0.195 lb a.i./acre, a minimum 7-day
retreatment interval (RTI), and a preharvest interval (PHI) of 28-days.
Eighteen field trials were conducted to determine the magnitude and
decline of picoxystrobin residues when applied to canola consistent with
the proposed use pattern.  Two additional trials were conducted to
determine the magnitude of residues of picoxystrobin in processed
fractions of canola following application at 5X maximum label rates.
Proposed tolerances on canola are consistent with the findings of these
trials

Meat, Milk, Poultry and Eggs: The need for tolerances in meat, milk,
poultry, and eggs must be evaluated because various commodity fractions
of cereals, legumes, soybean and canola are animal feed items.  Based on
the residue values reported from cow and poultry feeding studies
tolerances are proposed for all commodities at or above the limit of
quantitation (LOQ) of 0.01 ppm.>

<B. Toxicological Profile>

<	1. Acute toxicity.  Oral LD50 value was 5000 mg/kg bw. Dermal LD 50
value was >2000 mg/kg bw. Inhalation LC50 values were >2.12 mg/L.. 
Picoxystrobin technical was not irritating to rabbit skin, was
moderately irritating to eyes in rabbits and was non-sensitizing
dermally in the Magnusson/Kligman maximization test in guinea pigs. 
Acute toxicity studies for picoxystrobin technical support an overall
toxicity Category III.>

<2. Genotoxicty. Several genotoxicity tests were conducted to test for
point-mutagenic activity, chromosome aberration in vitro and in vivo,
and for DNA repair.  The weight of the evidence indicates that
picoxystrobin does not pose a mutagenic concern based on the results of
a battery of in vitro and in vivo genotoxicity studies.>

<	3. Reproductive and developmental toxicity. There was no evidence of
reproductive toxicity in two rat multigeneration reproduction studies
conducted with picoxystrobin.  Reduced body weight and food consumption
were noted in the parental generations at high dose levels.  Reduced pup
weight was also observed at similar doses.  The NOAEL was 50 ppm, or 5.4
mg/kg bodyweight/day for the parents and 200 ppm for the offspring. No
significant developmental effects were noted in rat and rabbit
developmental toxicity studies.  Some maternal toxicity was observed,
decreases in body weight and food consumption, in both cases. In rats, a
maternal NOAEL of 30 mg/kg bw/day and a developmental NOAEL 100 mg/kg
bw/day were demonstrated.  In rabbits, a maternal NOAEL of 25 mg/kg
bw/day and a developmental NOAEL of 100 mg/kg bw/day were demonstrated. 
There was no evidence of teratogenic potential.>

<	4. Subchronic toxicity. A subchronic toxicity feeding study with rats
over 90 days demonstrated a NOAEL of 41.7 mg/kg bw/day based on
reduction in bodyweight. A Subchronic toxicity feeding study in mice
over 90 days demonstrated a NOAEL of 33.2 and 43.8 mg/kg bw/day in males
and females, respectively, based on reductions in food consumption and
bodyweight and a treatment related increase in the incidence of minimal
hepatocyte hypertrophy in the livers of females. A Subchronic toxicity
feeding study in dogs demonstrated a NOAEL of 4.3 mg/kg bw/day based on
decreased body weights without any adverse effect on food consumption.
Two 28-day dermal toxicity studies in rats demonstrated a NOAEL of 1000
mg/kg bw/day which was the highest dose tested.>

<	5. Chronic toxicity. A 24-month chronic/oncogenicity feeding study in
rats demonstrated a NOAEL of 12.2 and 14.8 mg/kg bodyweight/day in males
and females respectively based on reduced body weight and nutritional
parameters.  A second 24-month chronic/oncogenicity feeding study in
rats demonstrated a NOAEL of 52.3 and 65.0 mg/kg bw/day for males and
females, respectively at the 1-year interim time point based on
decreased bodyweight and food consumption in both sexes and reduced food
utilization efficiency in males.  There was no indication in either rat
study, or an 80-week carcinogenicity study in the mouse of an oncogenic
effect attributable to picoxystrobin.  A one-year feeding study with
dogs demonstrated a NOAEL of 4.80 and 4.57 mg/kg bw/day for males and
females, respectively, based on decreased body weights and food
consumption.>

<	

6. Neurotoxicity. Systemic toxicity accompanied by changes in
neurobehavioral parameters and motor activity primarily on the day of
dosing was observed at all dose levels in an acute neurotoxicity study
conducted with picoxystrobin in rats.  There was no evidence of any
histopathological changes in nervous system tissues.  The
low-observed-adverse-effect level was 200 mg/kg bw.  In a 90-day
neurotoxicity study, there were no test-substance related changes in
neurobehavioral endpoints, motor activity, or nervous system
histopathology.  The no-observed-adverse-effect level in this study for
systemic toxicity was 600 ppm based on reduced body weight and
nutritional parameters at 3500 ppm.

7. Immunotoxicity. Based on the results of 28-day immunotoxicity studies
in rats and mice, picoxystrobin is not considered to be an
immunotoxicant.

	8. Animal metabolism. Metabolism and pharmacokinetic studies in the
rats, lactating goats and laying hens demonstrate that picoxystrobin
residues are rapidly absorbed, metabolized and eliminated.  There was no
evidence of accumulation of residues in any tissues or organs.  The
metabolic pattern was always complex and numerous metabolites were
identified.  The main metabolic reactions, however, are very comparable
for all tested animal species and most metabolites were present at low
levels.>

<	9. Metabolite toxicology. The residues of concern are the parent
compound only, picoxystrobin.>

<	10. Endocrine disruption. There is no evidence to suggest that
picoxystrobin has any primary endocrine disruptive potential. 
Reproductive and developmental findings provided no evidence of an
enhanced sensitivity of the young.>

<C. Aggregate Exposure>

<	1. Dietary exposure. >

<	i. Food. A chronic dietary analysis was conducted to estimate exposure
to potential picoxystrobin residues in/on cereal grains (crop croup 15)
except rice, cereal forage/fodder (crop group 16) except rice, legume
vegetables-dry, except soybean (crop group 6, subgroup C), legume
vegetables, foliage (crop group 7), soybeans, canola, livestock
commodities, and processed commodities thereof.  Acute analyses were not
conducted as there was no definitive indication of an adverse effect
attributable to a single dose and therefore an acute reference dose has
not been determined.  A chronic reference dose (cRfD) of 0.043 mg/kg/day
for all populations was derived from the chronic toxicity study in the
dog, based on reduced bodyweight, and an uncertainty factor of 100.  A
conservative chronic dietary risk assessment of the proposed
picoxystrobin uses was performed by E. I. du Pont de Nemours and Company
using field trial residue levels for crops, proposed tolerance values
for meat, milk, and poultry food items, and an assumption of 100% crop
treated. Chronic dietary exposure estimates, calculated with DEEM-FCID(
(Exponent, Inc.) software, indicated the US Population exposure was 1%
of the chronic RfD.  The sub-population with the highest exposure was
children 1-2 years with 2% of the chronic RfD. These can be considered
very conservative estimates of exposure.>

<	ii. Drinking water. The proposed use of picoxystrobin on sweet corn is
associated with the highest potential impacts to surface water using
PRZM/EXAMS, with the highest long-term average concentration in surface
water of 9.10 ppb.  Groundwater concentrations have been estimated to be
much lower.  When the 9.10 ppb surface water value was included in the
chronic dietary risk assessment, there was little change from the
food-only dietary risk assessment.  For the chronic assessment which
included food and drinking water the predicted exposure for the US
population was 1% of the cRfD; the most sensitive subpopulation,
children 1-2 years, had an estimated exposure of 2% of the cRfD.>

<	2. Non-dietary exposure. The proposed uses of picoxystrobin do not
include any sites that would result in residential exposure.  Therefore,
the aggregate risk is the sum of the risk from food and water.>

<D. Cumulative Effects>

<	Section 408(b)(2)(D)(v) of the FFDCA 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.'' Picoxystrobin is a foliar fungicide
which belongs to the class of strobilurin chemistry, and picoxystrobin
is a novel strobilurin analog.  EPA has not made a common mechanism of
toxicity finding as to picoxystrobin and any other substances, and
picoxystrobin does not appear to produce a toxic metabolite produced by
other substances.>

<E. Safety Determination>

<	1. U.S. population. Using the conservative assumptions described
above, based on the completeness and reliability of the toxicity data,
it is concluded that dietary exposure (food and water) from the proposed
and registered uses of picoxystrobin will utilize at most 1% of the
reference dose for the US Population, and is likely to be much less as
more realistic data and models are used.  EPA generally has no concern
for exposures below 100% of the RfD because the RfD represents the level
at or below which daily dietary (food plus water) exposure over a
lifetime will not pose appreciable risks to human health.  In addition,
aggregate (food and water) MOEs are much greater than 100 for adults for
both short- and intermediate-term exposure durations. Finally, all
handler exposure scenarios also have MOE greater than 100. Therefore,
there is a reasonable certainty that no harm will occur to the US
Population from aggregate exposure to picoxystrobin.>

<	2. Infants and children. Consideration of the toxicology database as
described above leads to no additional concerns for infants and
children.  Therefore the FQPA safety factor can be established at 1X. 
Using the conservative exposure assumptions described in the exposure
section above, the margins of exposure that will result for short- and
intermediate-term aggregate exposure (food plus water) to residues of
picoxystrobin are much greater than 100 for children. This value is
based on a worst-case aggregate exposure calculation of a child 1-2 who
has a background dietary exposure to potential residues.  Therefore,
there is a reasonable certainty that no harm will occur to infants and
children from aggregate exposure to residues of picoxystrobin.>

<F. International Tolerances>

<	Picoxystrobin is registered and tolerances are established in a number
of countries.  There are no Codex Alimentarius Commission (CODEX)
maximum residue levels (MRLs) established for residues of
picoxystrobin.>

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