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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 outli ne in preparing the pesticide petition. In cases where the outline element does not apply, please insert “NA - Rem ove” and m aintain the outline. Please do not change the m argins, font, or form at in your pesticide petition. Simply replace the instructions th at appear in green , i.e., “ [ insert company name ] ,” with the inform ation specific to your action. TEMPLATE: [ Nichino America, Inc. ] [ PP #0F7791 ] EPA has received a pesticide petition [ #0F7791 ] from [ Nichino America, Inc ] , [455 0 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 - carboxam

ide ) ] 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 hea d 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, pom e 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 pom ace, wet, at 5.0 ppm , c ottonseed, undelinted, at 0.6 ppm, tea at 20 ppm , milk at 0.03 ppm, fat, cattle, goat, horse, sheep at 0.01 ppm , kidney, ca ttle, goat, horse, sheep at 0.3 ppm, liver, cattle, goat, horse, sheep at 0.7 ppm , m eat, cattle, goat, horse, sheep at 0.02 ppm , almo nd 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 submitte d 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 s tudies have been conducted with tolfenpyrad labe led 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 rem ained 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 comm on 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

2. Analytical method. [ An a nalytical m ethod was developed for determination of Tolfenpyrad residues in crops. This method involves extraction of Tolfenpyrad residues fromcrop s amples with methanol , then e xtracts are vac uumfiltered, for all m atrices, 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 chromatogra phy with tandem mass spectrom etric 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 enforcem ent method for the det ermination of residues of tolfenpyrad in crops.] 3. Magnitude of residues. [ The ma gnitude of the residue studies are submitted with this petition for apple, pear, cucumber, squash, tomatoes, peppers, potato, head and leaf lettuce, mustard greens, orange s, grapefruit, lem on, grapes, cotton, cauliflower, cabbage, alm onds, 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 indivi du al crop. Residues between 0.01 and 9.0 ppmwere detected in certain anim al 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 derm al, 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: i n vitro bacterial mutation, in vitro ma mmalian cell gene mutation (m ouse lymphoma), i n vitro cytogenetics in Chinese Hamster Lung (CHL) cells and an in vivo mo use micronucleus (cytogenetics) assay . A weight of evidence evaluation dem onstrates that tolfenpyrad is not genotoxic in m am malian syste ms.] 3. Reproductive and developmental toxicity

. [ Neither developm ental n or reproductive endpoints were of concern. No d evelopm ental toxicity was observed in the rat and rabbit below maternally toxic doses . In the rat the m aternal NOAEL was 1 m g/ kg/day and the developm ental NOAEL was 3 m g/kg/day. In the rabbit, the m aternal NOAEL was 6 m g/kg/day and the developmental NOAEL was 6 m g/kg/day . In the 2 - generation reproduction study in rats, tolfenpyrad was tested at 0.75, 1.5, and 3.0 m g/kg/day. Th e p arental NOAEL was 1.5 mg/kg, based on decreased body weight, body weight gains, and decreased m otor activity. The NOAEL for offspring was 1.5 m g/kg, based on decreased pup viability and pup weights. No reproduction effects of concern were observed bel ow m aternally toxic levels . ] 4

. Neuro toxicity

. [I n 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 m g/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 m g/kg in males and 40 m g/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 p pm (equivalent to 5.4/6.0 m g/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(equival ent to 0/0, 0.9/1.0, 4.8/5.2, and 9.3/9.3 m g/kg/day for m ales/fem ales) for 13 weeks. Additionally 6 rats/sex were similarly treated for 13 weeks at 0 or 160 ppmand then subsequently allowed 4 weeks of control diet (recovery period). The NOAEL was 15 ppm (0.9/1.0 m g/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, b rown color change in the liver; h yaline droplets in the kidney; brown color change in the H arderian gland along with hypersecretion3

at 80 ppm . A sub - chronic capsule study in dogs conducted for thirteen weeks had a NOAEL of 10 mg/kg/day in m ale/females , based on effects observed at 30 m g/ kg/day of mo rtality, 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 m g/kg/day , the highest dose tested . In a rat 28 - day inhalation study , the NOAEL was 10 m g/m 3 calculated to be 2.6 m g/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 m g/kg/day for at least 12 m onths. However, the high dose was reduced to 10 m g/kg/day on Week 5 for the rem ainder of the study because of excessive toxicity. The LOAEL wa s 10 m g/kg/day, based on m ortality, vomiting, decreased body weights, body weight gains, food consumption, increased serum alanine aminotransferase in the m ales, and microscopic liver findings in ma les and females. The NOAEL was 5 m g/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 m g/kg/day in males/fem ales), based on dec reased body weight, body weight gain, and food consumption of fem ales, gross changes in the Harderian glands of m ales, and histopathological changes in the liver, kidney and mesenteric lymph nodes of females and the kidney of m ales. The NOAEL was 15 ppm (equivalent to 0.561/0.686 m g/kg/day in males/fem ales). In a carcinogenicity study Tolfenpyrad was administered in the diet to CD1 mice (50/sex/dose) for up to 18 m onths at doses of 0, 15 or 150 ppm(equivalent to 0, 2.2/2.8, and 20.8/27.1 m g/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 ppmfor Wee ks 13 - 19, and 300 ppmfor Weeks 20 - 79 (60.9/75.9 mg/kg bw/day in males/females). T he dose for the high group was adjusted twice due to observed toxicity. The LOAEL is 150 ppm (equivalent to 21/27 m g/kg bw/day in m ales/females), based on decreased body weights, body weight gains, food consumption in both sexes, and clinical signs (increased incidence of mi ssing ears in males a nd ear sores and scabs in fem ales). The NOAEL is 15 ppm (equivalent to 2.2/2.8 m g/kg/day in males/fem ales). Tolfenpyrad was not tum orogenic in any of the long - term studies. 7

. Animal metabolism. [ In a series of oral me tabolism studies in the rat, T olfe npyrad showed rapid absorption with m aximum 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 T olfenpyrad. Tolfenpyrad was rapidly excreted with over half of the m ateri al eliminated in 24 hours and with m ost eliminated in 48 hours. The maj ority of T olfenpyrad was excreted in the feces, with m ost 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 from12 to 168 hours post - dosing. Tolfenpyrad was m etabolized 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

. En docrine 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 st udies that m ay 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: p otatoes, head and leaf lettuce, spinach,4

leaf y 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, pom e 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 LifeLine TM version 5.0.0 . Residue estim ates for water consumption were based on PRZM3/EXAMS . ] i. Food. [ The acute exposure was based on th e following assumptions: residues at tolerance levels, 100% crop treated and default proce ssing factors for all proposed commodities. The chronic exposure was based on the following assumptions: 100% crop treated, average crop residue as determined by fi eld trial residue studies, processing factors as determined by processing studies. Processing default factors were used for comm odities without processing studies. Potential water and drinking water values fromacute surface water estimates from PRZM3/EXAMS were used for both acute and chronic a s sessments 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 m g/kg/day based on the NOEL from the rat chronic/oncogeni city 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 perform ed since Tolfenpyrad had no carcinogenic potential. The resulting ex posure modeling estim ated 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 derm al and inhalation exposures and risks was m ade. Based on mi xing/loading application and re - entry MOEs for occupational exposure that represent exposure over an 8 hour time fram e and exposure tasks that are unlikely to be duplicated in a residential setting, it was determined that the non - dietary exposure ris k was minimal and of no concern. Exposure to children is not expected. ] D. Cumulative Effects [ A determination has not been m ade that Tolfenpyrad has a common mechanismof toxicity with other substances. Tolfenpyrad does not appear to produce a comm on toxic metabolite with other substances. A cumulative risk assessment was, therefore, not perform ed 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 inform ation” concerning the cumulative effects of a particular pesticide's residues and “ other substances that have a co mmon mechanism of toxicity.” Unlike other pesticides for which EPA has followed a cumulative risk approach based on a commo n mechanism of toxicity, EPA has not m ade a common mechanism of toxicity finding as to Tolfenpyrad and any other substances and Tolfenpyrad does not appear to produce a toxic m etabolite produced by other substances. For the purposes of this tolerance acti on, therefore, EPA has not assumed that Tolfenpyrad has a comm on m echanism 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 statem ents released by EPA's OPP concerning comm on m echanism determinations and procedures for cumulating effects fromsubstances found to have a comm on m echanism on EPA's web site at http://www.epa.gov/pesticides/cumulative/. ] E. Safety Determination5

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 Tolfenp yrad are estim ated at 0. 0361 mg/kg/day and will utilize 35.7 % of the acute reference dose for the general US population . This estimate is extre mely conservative as it is based on all default assumptions . Drinking water and other water consumption scenari os were included in the dietary risk assessment modeling. ii. Chronic Risk. [ Based on the toxicology data base and available inform ation on anticipated residues, the chronic dietary exposure to the U.S. Population (total) was estim ated at 0.00132 mg/kg/day and was 21.9 % of the estim ated chroni c population adjusted dose (cPAD). Drinking water and other potential water consumption were included in the dietary risk assessment m odeling. Based on these assessments , it can be concluded that there is reason able certainty of no harmto the U.S. Population or any population subgroup fromexposure 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 extr em ely conservative as it is based on all default assumptions. Children aged 1 to 2 were the m ost highly exposed subpopulation and utilized 45.7% of the cPAD . Drinking water and other potential water consumption were included in all dietary risk assessmen t modeling. Based on these assessments , it can be concluded that there is reasonable certainty of no harmto 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, tom ato at 2 ppm , sweet pepper at 3 ppm , eggpl ant at 2 ppm , cucuc mber at 1 pm, waterm elon at 0.05 ppm , oranges , lem ons, grapefruit at 3 ppm , pear at 2 ppm , peaches at 0. 2 ppm , nectarine at 5 ppm, tea at 20 ppm .]