Document ID: EPA-HQ-OPP-2010-0425-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-09-08T04:00Z

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

<EPA Registration Division contact: [insert name and telephone number
with area code]>

 

<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:>

<[ Bayer CropScience]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Bayer CropScience], [2 T.W. Alexander Drive, Research Triangle Park, NC
27709] 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 [penflufen,
(1H-Pyrazole-4-carboxamide,
N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-)] in or on the
raw agricultural commodities [alfalfa, forage and hay ] at [0.01] parts
per million (ppm), [cotton, gin byproducts] at [0.01] ppm, [canola,
borage, crambe, cuphea, echium, flax seed, gold of pleasure, hare’s
ear mustard, lesquerella, lunaria. meadowfoam, milkweed, mustard seed,
oil radish, poppy seed, rapeseed, sesame, sweet rocket, calendula,
castor oil plant, Chinese tallowtree, euphorbia, evening primrose,
jojoba, niger seed, rose hip, safflower, stokes aster, sunflower,
tallowwood, tea oil plant, vernonia, cottonseed] at [0.01] ppm, [grain,
cereal, group 15] at [0.01] ppm, [grain, cereal, forage, fodder and
straw, group 16] at [0.01] ppm, [vegetable, legume, group 06] at [0.01]
ppm, [vegetable, foliage of legume, group 07] at [0.01] ppm, and
[vegetable, tuberous and corm, subgroup 01C] at [0.01] 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. [Plant metabolism studies with penflufen were
performed in wheat, soybeans and potatoes after seed treatments and on
rice after soil treatment in the planting hole.  In addition, metabolism
studies were performed on corn, canola, cotton, sunflowers, succulent
peas and beans, and alfalfa to determine the total radioactive residue
(TRR) uptake of penflufen.  Metabolism studies with penflufen in
rotational crops were performed in wheat, soybeans, turnips and Swiss
chard.  The metabolism in all plants was very similar.  The main
reactions involved were hydroxylation at the 3-position and conjugation
of the hydroxyl group with glucose and malonic acid; conjugation with
homoglutathione or glutathione via substitution of the fluorine atom
followed by metabolic degradation of the glutathione moiety; cleavage of
the N-phenyl bond and of the carboxamide bond; and N-demethylation and
oxidation of the methyl group in the pyrazole moiety.]

>

<	2. Analytical method. [Tolerances are being proposed in primary crops
solely for penflufen.  The analytical method involves solvent
extraction, filtration, and addition of an isotopically labeled internal
standard followed by acid hydrolysis.  Quantitation is by high
performance liquid chromatography-electrospray ionization/tandem mass
spectrometry (LC/MS/MS).]>

<	3. Magnitude of residues. [Based on the results from the TRR studies,
a reduced program of magnitude of the residue trials were conducted in
the various required regions across the United States and Canada in
accordance with guidance for crop field trials under OPPTS 860.1500 and
DIR2003-02 (Harmonization of Regulation of Pesticide Seed Treatment in
Canada and the United States) to support the requested tolerances.]>

<B. Toxicological Profile>

<	1. Acute toxicity.  [Penflufen has very low acute toxicity to mammals
irrespective of the route of exposure (oral, percutaneous or inhalation
exposure).  It is not a skin sensitizer, it is non-irritating to skin
(Magnusson and Kligmann assay) and causes only a minimal reversible
redness of the conjunctivae in the rabbit eye.  Overall, it is
classified as Toxicity Classification III.  The oral LD50 in rats is
greater than 2000 mg/kg.  The dermal LD50 value in rats is greater than
2000 mg/kg.  The inhalation LC50 for a four-hour exposure (nose only) is
greater than 2022.5 g/m3.  No clinical signs nor body weight changes or
necropsy findings were observed in the acute oral and dermal toxicity
studies conducted in rats.  In the acute inhalation toxicity study,
clinical signs were occasionally observed with recovery within four days
after exposure.  In acute neurotoxicity studies, a NOAEL of 100 mg/kg
and 50 mg/kg was established for males and females, respectively based
on slight effects in measures of motor and locomotor activity.]>

	2. Genotoxicty. [Genotoxicity potential was evaluated in a series of
tests including in vitro and in vivo tests.  There was no indication of
gene mutation either in the presence or absence of metabolic activation
in both the bacterial reverse mutation and mammalian gene mutation
tests.  The in vitro chromosome aberration test and the in vivo mouse
micronucleus test were also both negative.  These studies demonstrate
that penflufen has no genotoxic potential.]

3. Immunotoxicity. [Immunotoxicity potential was evaluated in a four
week study in rats.  Determination of cell counts in the spleen and
performance of the plaque forming assay showed no evidence for
treatment-related effects at any dose. The high dose of 7000 ppm (755.6
mg /kg bw/day in males and of 960.5 mg /kg bw/day in females) was
determined to be the NOEL for immunotoxicity for both males and females.
 Penflufen is therefore, not considered to be immunotoxic]

<	4. Reproductive and developmental toxicity. [In the rat two-generation
reproduction study,   SEQ CHAPTER \h \r 1 the parental systemic NOAEL
was 1000 ppm (64.1 mg/kg/day in males, 75.9 mg/kg/day in females) based
on decreased body weight, decreased body weight gain, alterations in
food consumption, increased liver weight with associated hepatocellular
hypertrophy, and decreased thymus weight in both genders, as well as,
decreased terminal body weight and spleen weights in females. The
reproductive NOAEL was 1000 ppm for the females (73.4 mg /kg bw/day)
based on a slight decrease in litter size in both the P and
F1-generations.  For males the NOAEL was greater than 4000 ppm in males
(>338.6 mg /kg bw/day) based on no reproductive findings observed at the
highest dose tested.  The offspring NOAEL was 1000 ppm (72.5 mg /kg
bw/day) based on maternal effects leading to secondarily-mediated
effects on pup weight, pup weight gain, delayed vaginal patency and
balanopreputial separation and organ weight changes (brain and spleen). 
In a rat developmental toxicity study, the maternal NOAEL was 30
mg/kg/day, based on reduced body weight gain, and liver changes.  The
fetal NOAEL was 300 mg/kg/day based on no findings observed at the
highest dose tested.  In a rabbit developmental toxicity study, the
NOAEL was 100 mg/kg/day both in the dam (decreased body weight gain and
reduced food consumption) and in terms of fetal development (decreased
fetal body weight) in the New Zealand White rabbit.>]

<	5. Subchronic toxicity. [Subchronic studies showed that the liver is
the major target organ in rats and dogs.  In addition to the liver, the
kidney (males) was also a target organ in rats.  In the male rat,
specific nephropathy (hyaline droplet nephropathy) was observed.  In
mice, no effects were observed at the highest dose tested.  The dog was
the most sensitive species followed by the rat with the mouse being the
least sensitive.  Overall, the lowest NOAEL was observed in the
subchronic dog study.  In this study, the NOAEL for the dog was
established at 5.6 and 6.1 mg/kg bw/day in males and females,
respectively.  However, the NOAEL in the dog was based on doses which
each varied by an order of magnitude.  The LOAELs established in the
subchronic dog and chronic dog studies were both based on the same
endpoints of increased liver weights and hepatocellular hypertrophy and
the NOAEL of 1000 ppm established in the chronic dog toxicity study was
between the doses for establishing the NOAEL of  180 ppm and the LOAEL
of  1800 ppm in the subchronic dog study.  Therefore, relevant
subchronic NOAEL of 32 mg/kg/day was established from the chronic dog
toxicity study.  This NOAEL is also comparable with the maternal NOAEL
of 30 mg/kg/day in the rat developmental toxicity study.

In a 90-day neurotoxicity study at 0, 250, 2000 and 8000 ppm, no
evidence of neurotoxicity was observed at any treatment level. 
Treatment-related findings of general toxicity at the high-dose
consisted of decreased body weight, total body weight gain and food
consumption in males and females and decreased terminal body weight in
females.  Also, liver weights were increased in high-dose males and
females.  Treatment-related findings in mid-dose males and females
included increases in liver weights (absolute and/or relative) and
decreased food consumption in females, with no corresponding effect on
body weight.  Based on neurotoxicology endpoints, a NOAEL of 8000 ppm
was established for males and females (516.0 and 608.8 mg/kg for male
and female rats, respectively).

In a four week dermal toxicity study in rats, a NOAEL of 300 mg/kg/day
was established based on increased lymphocyte debris within the thymic
cortices of the 1000 mg/kg males and females.]

>

<	6. Chronic toxicity. [In the rat, at the end of the combined chronic
toxicity and carcinogenicity study, treatment-related macroscopic
findings consisted of enlarged liver and white focus in the liver in
females only.  At the microscopic examination, in the liver, a higher
incidence of centrilobular to panlobular hepatocellular hypertrophy and
of centrilobular hepatocellular macrovacuolation was observed in both
sexes.  In females, a higher incidence of hepatocellular brown pigments
was also noted.  A higher incidence of colloid alteration in the thyroid
gland was observed in females only.  There was no evidence of a
treatment-related increased incidence of tumors of any type in any
organ.  Penflufen is thus considered not to be carcinogenic in the rat
after a 104 week treatment period.  The NOAEL over a carcinogenic (24
month) period of dietary administration of penflufen to the rat was 100
ppm in both sexes (equivalent to 4.0 mg/kg/day weight/day in males and
5.6 mg/kg body weight/day in females).

In a mouse carcinogenicity study, the target organs were the liver and
thyroid gland.  The principal changes noted in the liver were increased
liver weights associated with higher incidence and/or severity of
diffuse centrilobular hepatocellular hypertrophy in both sexes.  In
females a higher severity of hepatocellular vacuolation and higher
incidence and severity of diffuse mainly periportal hepatocellular
macrovacuolation was also observed.  In addition, a higher incidence and
severity of follicular cell hyperplasia in the thyroid gland was noted
in 38/50 females compared to 23/50 females in the control group.  No
treatment-related neoplastic changes were observed at any dose level
tested in either sex.  The NOAEL in the mouse was established at
1000 ppm in both sexes (equating approximately to 146 mg/kg body
weight/day for males and 182 mg/kg body weight/day).]

>

<	7. Animal metabolism. [In the rat, penflufen is rapidly and almost
completely absorbed (>96% of the dose in a bile fistulation experiment)
following oral administration by gavage.  Penflufen was extensively
metabolized with unchanged parent compound found only in low percentages
of the recovered dose.  The metabolism of penflufen in male and female
rats was similar and included N-demethylation in the pyrazole ring,
hydroxylation and extensive oxidation.  Some cleavage of the rings was
observed as was conjugation of several hydroxylated metabolites with
glucuronic acid and cysteine.  In ruminants and poultry, penflufen was
also extensively metabolized.  Penflufen residues do not accumulate in
animal tissues, milk or eggs. ]>

<	8. Metabolite toxicology. [Not applicable as parent is the compound of
concern.]

>

<	9. Endocrine disruption. [There is no evidence to suggest that
penflufen has any primary endocrine disruptive potential.  Reproductive
and developmental findings provided no evidence of an enhanced
sensitivity of the young.  Bayer CropScience will conduct any studies
that may be required under EPA’s Endocrine Disrupter Screening
Program.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [The toxicological and exposure database for
penflufen is considered complete.  There was no indication of an
increased sensitivity of the young in any studies including the
reproductive and developmental studies in rats and rabbits.  Therefore,
the special FQPA can be reduced to 1X and an uncertainty factor of 100
is adequate to account for inter- and intra- species variability.  Acute
and chronic Population Adjusted Doses (aPAD and cPAD) are, therefore,
the same as the reference doses for the populations and subpopulations
of interest.  Acute dietary exposure was expressed as a percentage of
the aPAD of 0.5 mg/kg bw/day from a NOAEL of 50 mg/kg bw/day established
for females, based on slight effects on measures of motor and locomotor
activity in the acute neurotoxicity study in rats, with an uncertainty
factor of 100.  Chronic dietary exposure was expressed as a percentage
of the chronic Population Adjusted Dose (cPAD) of 0.04 mg/kg bw/day
based on a NOAEL of 4 mg/kg bw/day in the rat chronic/oncogenicity study
in rats with an uncertainty factor of 100.]>

DEEM-FCID™, Version 2.14 software.  Consumption data used in this
program were taken from USDA’s CSFII, 1994-1996, 1998.  With these
conservative assumptions, acute exposure (95th percentile) for food only
utilizes 0.1% of the aPAD for the US Population and 0.2% for Children
1-2, the most highly exposed subpopulation.  Chronic exposure for food
only utilizes 0.4% of the cPAD for the US Population and 0.7% of the
cPAD for Children 1-2, the most highly exposed subpopulation.]>

<	ii. Drinking water. [Estimated Drinking Water Concentrations (EDWCs)
from ground water and surface water sources were calculated for the
residues of penflufen and the major environmental metabolites BYF
14182-3-hydroxybutyl and BYF 14182-pyrazolyl-AAP, resulting from
penflufen use on potatoes, wheat, corn, beans, soybeans, canola,
sunflowers, cotton, alfalfa, and rice.  Except for rice, PRZM (Version
3.12.2; May 2005)/EXAMS (Version 2.98.04.06; April 2005) and SCI-GROW
(Version 2.3, July 28, 2003) were used to calculate surface water and
ground water concentrations, respectively.  For rice, the RICE Water
Quality (RICEWQ Version 1.7.3; 2010) model was used to refine Tier I
rice model estimate which significantly overestimates water exposure,
especially for seed treatment.  The highest ground water concentration
was 0.23 µg/L from the potato use (160 g a.i./ha).  Concentrations
resulting from seed treatment uses (< 10 g a.i./ha) were significantly
lower.  Overall, the highest potential drinking water concentrations
were estimated from surface water with an acute concentration of 0.95
µg/L and a chronic concentration of 0.34 µg/L from the Maine potato
scenario.

Drinking water did not significantly increase dietary exposure.  The
incorporation of the EDWC of 0.95 µg/L into an acute exposure
assessment resulted in the U.S. adult population utilizing 0.1% of the
aPAD and Children 1-2, the most highly exposed subpopulation, utilizing
0.2% of the aPAD.  The addition of the chronic EDWC of 0.34 µg/L
resulted in the U.S. adult population utilizing 0.5% of the cPAD and
Children 1-2, the most highly exposed subpopulation, utilizing 0.7%.  In
conclusion, the results of the very conservative acute and chronic
dietary exposure analyses (including food and drinking water)
demonstrates that penflufen exposure consumes a very small percentage of
the risk cup for all scenarios and population subgroups examined. 
Therefore, there is a reasonable certainty that no harm will result from
exposure to potential residues of penflufen in food and water.]

>

<	2. Non-dietary exposure. [Based on the use patterns non-dietary
exposure to penflufen is not anticipated.>

<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.”   Penflufen is a novel
succinate-dehydrogenase inhibitor (SDHI).  EPA has not made a common
mechanism of toxicity finding as to penflufen and any other substances
and penflufen does not appear to produce a toxic metabolite produced by
other substances.]>

<E. Safety Determination>

<	1. U.S. population. [Risk assessments for penflufen are based on a
complete and reliable toxicity data package and highly conservative
assumptions.  Chronic aggregate dietary exposure (food and water)
utilizes 0.5% of the cPAD for the US Population.  Acute aggregate
dietary exposure (food and water) for the U.S. adult population utilizes
0.1% of the aPAD.  Non-dietary exposure of the U.S. population to
penflufen is not anticipated.  Therefore, there is a reasonable
certainty that no harm will occur to the US Population from aggregate
exposure (food and drinking water) to residues of penflufen.]>

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摧所/Ѐ1摧季fᘀNo tolerances have been established for penflufen. 
Penflufen is being reviewed as an OECD Joint Review among the U.S.,
Canada and Australia.  In the EU, tolerances are also being applied for
in potatoes.  Harmonized tolerances are being proposed to minimize trade
barriers between the participating regions.]>

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