Document ID: EPA-HQ-OPP-2008-0743-0016
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-05-02T04:00Z

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

EPA Registration Division contact: [Rosanna Louie-Juzwiak, (703)
308-0037]

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:

[Nichino America, Inc.]

[PP #0F7791]

	EPA has received a pesticide petition [#0F7791] from [Nichino America,
Inc], [4550 New Linden Hill Rd., Suite 501, Wilmington, DE 19808]
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

	[Tolfenpyrad (4-chloro-3-ethyl-1 –methyl-N-[4-(p-tolyloxy) benzyl]
pyrazole-

5-carboxamide )] in or on the following raw agricultural commodities: 
[head lettuce at 5 ppm, leaf lettuce at 30 ppm, celery subgroup 4B, leaf
petioles at 12.5 ppm, spinach at 24 ppm, brassica head and stem crop
group 5A at 3.6 ppm, brassica leafy group 5B at 44 ppm, fruiting
vegetables crop group 8 at 0.6 ppm, potatoes at 0.04 ppm, tree nut crop
group 14 at 0.04 ppm, pistachio at 0.04 ppm, pome fruit group at 0.6
ppm, cucurbit crop group 9 at 0.8 ppm, stone fruit group 12 at 3.0 ppm,
prunes at 3 ppm, pomegranates at 3.0 ppm, persimmons at 3.0 ppm, citrus
crop group at 1.0 ppm, citrus pulp dried at 2.0 ppm, citrus oil at 16.0
ppm, grapes at 2.0 ppm, raisins at 5 ppm, apple pomace, wet, at 5.0 ppm,
cottonseed, undelinted, at 0.6 ppm, tea at 20 ppm, milk at 0.03 ppm,
fat, cattle, goat, horse, sheep at 0.01 ppm, kidney, cattle, goat,
horse, sheep at 0.3 ppm, liver, cattle, goat, horse, sheep at 0.7 ppm,
meat, cattle, goat, horse, sheep at 0.02 ppm, almond hulls at 5.0 ppm,
and cotton gin trash at 9.0 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. [Nature of the Residue studies have been conducted
with tolfenpyrad labeled in both the Tolyl and Pyrazole rings in four
different crop groups (fruits - peach, fruiting vegetable - eggplant,
leafy vegetables - cabbage and root and tuber vegetables - radish).  In
all these studies unmetabolized tolfenpyrad remained as the major
residue comprising 40% to 80% of the TRR. Metabolism of tolfenpyrad in
plants is similar to animals showing the classic oxidative pathway
common to both.  When metabolism occurs, it is through systemic
oxidative hydroxylation of the exposed methyl groups followed by
conversion to the water soluble acid or by simple cleavage to the
pyrazole carboxylic acid.  Individual metabolites were detected only at
low levels and there was no evidence of accumulation of any specific
analyte.]

	2. Analytical method. [An analytical method was developed for
determination of Tolfenpyrad residues in crops.  This method involves
extraction of Tolfenpyrad residues from crop samples with methanol, then
extracts are vacuum filtered, for all matrices, except processed oils,
then combined with water prior to being cleaned-up using polymeric
solid-phase extraction cartridges. The purified extract was evaporated
to dryness and reconstituted in methanol.  Residues of tolfenpyrad are
quantified using high performance liquid chromatography with tandem mass
spectrometric detection (LC-MS/MS).  The limit of quantitation is 0.01
ppm for tolfenpyrad.  This method has been successfully validated at an
independent facility and therefore is suitable for use as the
enforcement method for the determination of residues of tolfenpyrad in
crops.] 

	3. Magnitude of residues. [The magnitude of the residue studies are
submitted with this petition for apple, pear, cucumber, squash,
tomatoes, peppers, potato, head and leaf lettuce, mustard greens,
oranges, grapefruit, lemon, grapes, cotton, cauliflower, cabbage,
almonds, pecans, cherry, peach, and plum.  All studies meet EPA Test
Guidelines 860.1000, 860.1500, and 860.1520.  Residues detected are
below the tolerance proposed for the crop group or individual crop. 
Residues between 0.01 and 9.0 ppm were detected in certain animal feed
commodities.]    

B. Toxicological Profile

1. Acute toxicity.  [Tolfenpyrad Technical is acutely toxic with a
classification of Category II for acute oral toxicity and is a less
toxic Category III for acute dermal, inhalation, and eye irritation. 
Tolfenpyrad is a Category IV for skin irritation, and is not a skin
sensitizer.]

	2. Genotoxicty. [Tolfenpyrad was non-mutagenic (negative) in: in vitro
bacterial mutation, in vitro mammalian cell gene mutation (mouse
lymphoma), in vitro cytogenetics in Chinese Hamster Lung (CHL) cells and
an in vivo mouse micronucleus (cytogenetics) assay.  A weight of
evidence evaluation demonstrates that tolfenpyrad is not genotoxic in
mammalian systems.]

	3. Reproductive and developmental toxicity.  [Neither developmental nor
reproductive endpoints were of concern.  No developmental toxicity was
observed in the rat and rabbit below maternally toxic doses.  In the rat
the maternal NOAEL was 1 mg/kg/day and the developmental NOAEL was 3
mg/kg/day.  In the rabbit, the maternal NOAEL was 6 mg/kg/day and the
developmental NOAEL was 6 mg/kg/day.  In the 2-generation reproduction
study in rats, tolfenpyrad was tested at 0.75, 1.5, and 3.0 mg/kg/day. 
The parental NOAEL was 1.5 mg/kg, based on decreased body weight, body
weight gains, and decreased motor activity.  The NOAEL for offspring was
1.5 mg/kg, based on decreased pup viability and pup weights.  No
reproduction effects of concern were observed below maternally toxic
levels.] 

	4. Neurotoxicity.  [In an acute neurotoxicity study Tolfenpyrad in corn
oil was administered once via gavage (5 mL/kg) to 10 Sprague-Dawley
rats/group at dose levels of 0, 20, 40, or 60 mg/kg in males and 0, 10,
20, or 40 mg/kg in females, and the animals were observed for up to 14
days post-dosing.  The neurotoxicity LOAEL was not observed. The
neurotoxicity NOAEL is 60 mg/kg in males and 40 mg/kg in females.  In a
subchronic neurotoxicity study Tolfenpyrad was administered in the diet
to 10 Sprague-Dawley rats/sex/group at dose levels of 0, 15, 40, or 80
ppm (equivalent to 0/0, 1.0/1.2, 2.7/3.2, and 5.4/6.0 mg/kg/day [M/F],
respectively) for 13 weeks. The neurotoxicity LOAEL was not observed. 
The neurotoxicity NOAEL is 80 ppm (equivalent to 5.4/6.0 mg/kg/day,
M/F).  Tolfenpyrad is not neurotoxic.]

	5. Subchronic toxicity. [In a subchronic oral toxicity study
Tolfenpyrad was administered in the diet to Fischer 344 rats
(10/sex/dose) at doses of 0, 15, 80, or 160 ppm (equivalent to 0/0,
0.9/1.0, 4.8/5.2, and 9.3/9.3 mg/kg/day for males/females) for 13 weeks.
Additionally 6 rats/sex were similarly treated for 13 weeks at 0 or 160
ppm and then subsequently allowed 4 weeks of control diet (recovery
period).  The NOAEL was 15 ppm (0.9/1.0 mg/kg/day in males/females)
based on based on decreased body weights, body weight gains, and food
consumption in both sexes.  Additionally, increased relative liver and
kidney weights, hepatocellular hypertrophy, brown color change in the
liver; hyaline droplets in the kidney; brown color change in the
Harderian gland along with hypersecretion at 80 ppm.  A sub-chronic
capsule study in dogs conducted for thirteen weeks had a NOAEL of 10
mg/kg/day in male/females, based on effects observed at 30 mg/kg/day of
mortality, decreased body weights and body weight gains and food
consumption with effects noted in the liver, testes and kidney.  In a
rat 21-day dermal study, the NOAEL is 200 mg/kg/day, the highest dose
tested.  In a rat 28-day inhalation study, the NOAEL was 10 mg/m3
calculated to be 2.6 mg/kg/day, the highest dose tested.] 

	6. Chronic toxicity. [In a chronic oral toxicity study Tolfenpyrad was
administered to four beagle dogs/sex/dose group daily by capsule at
doses of 0, 1, 5 or 20 mg/kg/day for at least 12 months. However, the
high dose was reduced to 10 mg/kg/day on Week 5 for the remainder of the
study because of excessive toxicity.  The LOAEL was 10 mg/kg/day, based
on mortality, vomiting, decreased body weights, body weight gains, food
consumption, increased serum alanine aminotransferase in the males, and
microscopic liver findings in males and females.  The NOAEL was 5
mg/kg/day.

In a combined chronic toxicity/carcinogenicity study 50 Fischer
(F344/DuCrj) rats/sex/dose were exposed to Tolfenpyrad over 104 weeks in
the diet at concentrations of 0, 15, 40, or 80 ppm (equivalent to 0/0,
0.561/0.686, 1.50/1.85, and 3.07/3.79 mg/kg/day in males/females). The
LOAEL was 40 ppm (equivalent to 1.50/1.85 mg/kg/day in males/females),
based on decreased body weight, body weight gain, and food consumption
of females, gross changes in the  Harderian glands of males, and
histopathological changes in the liver, kidney and mesenteric lymph
nodes of females and the kidney of males.  The NOAEL was 15 ppm
(equivalent to 0.561/0.686 mg/kg/day in males/females).  In a
carcinogenicity study Tolfenpyrad was administered in the diet to CD1
mice (50/sex/dose) for up to 18 months at doses of 0, 15 or 150 ppm
(equivalent to 0, 2.2/2.8, and 20.8/27.1 mg/kg bw/day in males/females).
 An additional group of 50 mice/sex/dose was treated similarly at a dose
of 500 ppm for Weeks 1-12, 400 ppm for Weeks 13-19, and 300 ppm for
Weeks 20-79 (60.9/75.9 mg/kg bw/day in males/females).  The dose for the
high group was adjusted twice due to observed toxicity.  The LOAEL is
150 ppm (equivalent to 21/27 mg/kg bw/day in males/females), based on
decreased body weights, body weight gains, food consumption in both
sexes, and clinical signs (increased incidence of missing ears in males
and ear sores and scabs in females).  The NOAEL is 15 ppm (equivalent to
2.2/2.8 mg/kg/day in males/females).  Tolfenpyrad was not tumorogenic in
any of the long-term studies.

	7. Animal metabolism. [In a series of oral metabolism studies in the
rat, Tolfenpyrad showed rapid absorption with maximum blood
concentrations at 2 to 6 hours post-dosing at the low dose, 4 to 12
hours at the high dose and 8 hours following multiple doses of
Tolfenpyrad.  Tolfenpyrad was rapidly excreted with over half of the
material eliminated in 24 hours and with most eliminated in 48 hours. 
The majority of Tolfenpyrad was excreted in the feces, with most of the
product showing excretion via the bile.  Generally the highest
concentrations were observed in the liver, kidney, brown fat and heart. 
Radioactivity concentrations dropped substantially from 12 to 168 hours
post-dosing.  Tolfenpyrad was metabolized by oxidation followed by
conjugation (glucuronide, sulfate, asparagines or taurine).  Parent
Tolfenpyrad represented a minor component of the excreted material. 
Dermal penetration studies showed 13% absorption at 24 hours in the
mid-dose group.]

	8. Metabolite toxicology.  [A major metabolite (OH-PT) was evaluated in
the bacterial gene mutation assay and was negative.]

	9. Endocrine disruption. [There is no evidence to suggest that
Tolfenpyrad has any primary endocrine disruptive potential. 
Reproductive and developmental findings show no evidence of enhanced
sensitivity of the young.  Nichino America, Inc. will conduct any
studies that may be required under EPA’s Endocrine Disruptor Screening
Program.]

C. Aggregate Exposure

	1. Dietary exposure. [Acute and chronic dietary risk analyses were
conducted to estimate the potential Tolfenpyrad residues in/on the
following crops: potatoes, head and leaf lettuce, spinach, leafy
petioles crop group 4B, head and stem brassica crop group 5A, leafy
brassica crop group 5B, fruiting vegetables crop group 8, cucurbit crop
group 9, citrus crop group 10,  pome fruit crop group 11, stone fruit
crop group 12, tree nut crop group 14, pistachio, cottonseed oil, milk,
and meat, grapes and cottonseed oil using LifeLineTM version 5.0.0. 
Residue estimates for water consumption were based on PRZM3/EXAMS.]

	i. Food. [The acute exposure was based on the following assumptions: 
residues at tolerance levels, 100% crop treated and default processing
factors for all proposed commodities. The chronic exposure was based on
the following assumptions:  100% crop treated, average crop residue as
determined by field trial residue studies, processing factors as
determined by processing studies.  Processing default factors were used
for commodities without processing studies.  Potential water and
drinking water values from acute surface water estimates from
PRZM3/EXAMS were used for both acute and chronic assessments and
represented the worst case analysis.  The Health Effects Division (HED
Decision No. 394868, June 3, 2010) determined there was no potential for
increased susceptibility to infants and children so the special FQPA
safety factor was set at 1X.  The acute dietary aPAD was set at 0.1
mg/kg/day based on the acute neurotoxicity study endpoint of systemic
toxicity.  The cPAD was determined to be 0.006 mg/kg/day based on the
NOEL from the rat chronic/oncogenicity study.  The database uncertainty
factor used to establish both the aPAD and cPAD was 100x to account for
interspecies and intraspecies variations.  No cancer assessments were
performed since Tolfenpyrad had no carcinogenic potential.  The
resulting exposure modeling estimated the acute food exposure estimate
at the 95th percentile all sub-populations was less than HED’s level
of concern (35.7% aPAD).  Children aged 1 to 2 were shown to be the most
exposed sub-population representing 74.1% of the aPAD. The chronic food
exposure estimates were also less than HED’s level of concern (US
population, 22% cPAD; children 1-2 years old were the most highly
exposed population at 46% cPAD).]

	ii. Drinking water. [Assessments for drinking water exposure were built
into the dietary assessment and have thus, already been included in the
exposure assessments.]

	2. Non-dietary exposure. [Because of potential residential uses on
ornamentals, an assessment of dermal and inhalation exposures and risks
was made.  Based on mixing/loading  application and re-entry MOEs for
occupational exposure that represent exposure over an 8 hour time frame
and exposure tasks that are unlikely  to be duplicated in a residential
setting,  it was determined that the non-dietary exposure risk was
minimal and of no concern.  Exposure to children is not expected.]

D. Cumulative Effects

	[A determination has not been made that Tolfenpyrad has a common
mechanism of toxicity with other substances. Tolfenpyrad does not appear
to produce a common toxic metabolite with other substances. A cumulative
risk assessment was, therefore, not performed for this analysis. 
Section 408(b)(2)(D)(v) of 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.”  Unlike other pesticides for which EPA
has followed a cumulative risk approach based on a common mechanism of
toxicity, EPA has not made a common mechanism of toxicity finding as to
Tolfenpyrad and any other substances and Tolfenpyrad 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
Tolfenpyrad has a common mechanism of toxicity with other substances.
For information regarding EPA's efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see the policy statements released by EPA's
OPP concerning common mechanism determinations and procedures for
cumulating effects from substances found to have a common mechanism on
EPA's web site at http://www.epa.gov/pesticides/cumulative/.]

E. Safety Determination

	1. U.S. population. 

[i. Acute risk.  Using the conservative assumptions discussed above,
based on the completeness and reliability of the toxicity data, it is
concluded that aggregate exposure to the proposed uses of Tolfenpyrad
are estimated at 0.0361 mg/kg/day and will utilize 35.7 % of the acute
reference dose for the general US population. This estimate is extremely
conservative as it is based on all default assumptions.  Drinking water
and other water consumption scenarios were included in the dietary risk
assessment modeling.  

ii. Chronic Risk.  [Based on the toxicology data base and available
information on anticipated residues, the chronic dietary exposure to the
U.S. Population (total) was estimated at 0.00132 mg/kg/day and was 21.9
% of the estimated chronic population adjusted dose (cPAD).  Drinking
water and other potential water consumption were included in the dietary
risk assessment modeling.  Based on these assessments, it can be
concluded that there is reasonable certainty of no harm to the U.S.
Population or any population subgroup from exposure to Tolfenpyrad.] 

 

	2. Infants and children. [Children aged 1 to 2 were the most highly
exposed subpopulation and utilized 74.1% of the aPAD.  This estimate is
extremely conservative as it is based on all default assumptions. 
Children aged 1 to 2 were the most highly exposed subpopulation and
utilized 45.7% of the cPAD.  Drinking water and other potential water
consumption were included in all dietary risk assessment modeling. 
Based on these assessments, it can be concluded that there is reasonable
certainty of no harm to infants or children from exposure to
Tolfenpyrad.]

F. International Tolerances

	[No Codex Maximum Residue Levels (MRL) have been established for
residues of tolfenpyrad in raw agricultural commodities.  Tolerances
have been established in Japan for Tolfenpyrad on the following crops: 
cabbage at 0.3 ppm, broccoli at 1 ppm, head and leaf lettuce 10 ppm,
tomato at 2 ppm, sweet pepper at 3 ppm, eggplant at 2 ppm, cucucmber at
1 pm, watermelon at 0.05 ppm, oranges, lemons, grapefruit  at 3 ppm, 
pear at 2 ppm, peaches at 0. 2 ppm, nectarine at 5 ppm, tea at 20 ppm.]

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