i

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] pyrazole5-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.]
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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 postdosing. 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 
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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/m3calculated 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, 
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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 subpopulation 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
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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.]