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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: [ Shaunta Hill, 703/347 - 8961 ] 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 app ear in green , i.e., “ [ insert company name ] ,” with the information specific to your action. TEMPLATE: [ BASF Corporation ] [ 0F7695 ] EPA has received a pesticide petition ( [ 0F 7695 ] ) from [ BASF Corporation ] , [ P.O Box 13528, 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 [ ametoctradin , 5 - ethyl- 6 - octyl[1,2,4]triazolo[1,5 - a]pyrimidin - 7 - amine ] in or on the raw agricultural commodities [ brassica, head and stem, subgroup, at 12 parts per million (ppm); b rassica, leafy greens, subgroup, at 50 ppm; grape at 5 ppm; hop, dried cones, at 9 ppm; onion, bulb, subgroup, at 1 . 2 ppm; onion, green, subg roup, at 16 ppm; raisin at 8 ppm; vegetable, fruiting, group, at 2 ppm; vegetable, leafy, except brassica, group , at 70 ppm; vegetable, cucurbit, group, at 4.5 ppm; vegetable, tuberous and corm, subgroup, at 0.05 ppm ] and b y establishing an exemption from the requirement of a tolerance [ for the metabolites M650F03, (7 - amino - 5 - ethyl[1,2,4]triazolo[1,5 - a]pyrimidine- 6 -y-l)acetic acid , and M650F04, 7 - amino - 5 - ethyl[1,2,4]triazolo[1,5 - a]pyrimidine- 6 - carboxylic acid in all food crops. ] 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

. [Ametoctradin plant metabolism studies were performed in lettuce, tomato and potato. In all three plant metabolism studies, the metabolic pathways we re comparable. Consequently, sufficient data are available to extrapolate the nature of the residue to other crops. In all three crops, unchanged parent compound ametoctradin was identified as the most prominent residue. In the2

potato metabolism study with an exaggerated application rate of 1.5x, the two soil metabolites M650F03 , (7 - amino - 5 - ethyl[1,2,4]triazolo[1,5 - a]pyrimidine - 6 -y-l)acetic acid , and M650F04 , 7 - amino - 5 - ethyl[1,2,4]triazolo[1,5 - a]pyrimidine- 6 - carboxylic acid , in all food crops were fo und in small amounts in tubers. ] 2. Analytical method. [ The proposed enforcement method for ametoctradin was fully validated. Ametoctradin is extracted with a mixture of methanol/water. An aliquot of the extract is centrifuged and partitioned against dichl oromethane. The final determination of ametoctradin is performed by HPLC - MS/MS. This method has a limit of quantitation of 0.01 mg/kg and is suitable for enforcement purposes. ] 3. Magnitude of residues. [ Supervised field trials were carried out to determine the magnitude of the residue in/on brassica, head and stem, subgroup ; brassica, leafy greens, subgroup ; grape; hop ; dried cones ; onion, bulb, subgroup ; onion, green, subgroup; raisin; vegetable, fruiting, group ; vegetable, leafy, except brassica; v egetable, cucurbit, group; and vegetable, tuberous and corm, subgroup . The number and locations of field trials are in accordance with OPPTS Guideline 860.1500. Field trials were carried out using the maximum label rates, the maximum number of application s, and the minimum pre- harvest interval (PHI) for all the crops. Detected residues of BAS 650 F in all crops support the proposed tolerances.] B. Toxicological Profile 1. Acute toxicity. [BAS 650 F and its formulated products have a favorable acute toxicity profile. The acute toxicity studies place technical BAS 650 F in the toxicity category III for the acute oral and the acute dermal category and category IV for the acute inhalation. BAS 650 F is category IV for both eye and skin irritation and is not a dermal sensitizer. ] 2. Genotoxicty. [ BAS 650 F was tested for its genotoxic potential in a battery of six in vitro or in vivo studies covering the required endpoints of point mutations, chromosomal damage and DNA damage and repair. BAS 650 F did not demonstrate any genotoxic effects. BAS 650 F was negative for inducing mutations in both an in vitro Ames test and an in vitro forward mutation assay in mammalian cells (HPRT test with and without metabolic activation). Both an in vitro and an in vivo chromosome aberration assay (with and without metabolic activation) showed no evidence of a clastogenic effect. An in vivo micronucleus test and an in vivo unscheduled DNA synthesis (UDS) test were also negative. These studies demonstrate that BA S 650 F is not genotoxic. ] 3. Reproductive and developmental toxicity. [ The reproductive and developmental toxicity of ametoctradin was investigated in a 2 - generation rat reproduction study as well as in rat and rabbit developmental toxicity studies. In the reproduction study, there were no effects on fertility. There were no parental toxicity or pup effects at any of the tested doses (up to and including the limit dose).3

The resulting parental systemic and developmental toxicity NOAEL’s are 1000 mg/kg bw. In the rat developmental toxicity study, the administration of ametoctradin elicited no signs of maternal toxicity, had no influence on gestational parameters and induced no signs of developmental toxicity at the dose levels tested (up to and including the limit dose). Based on these results, the no observed adverse effect level (NOAEL) in rat for maternal and prenatal developmental toxicity is the limit dose level of 1000 mg/kg bw/d. The administration of ametoctradin to rabbits elicited no signs of maternal toxicity, had no influence on gestational parameters and induced no signs of developmental toxicity at the dose levels tested (up to and including the limit dose). Based on these results, the no observed adverse effect level (NOAEL) in rabbit for maternal and prenatal developmental toxicity is the limit dose level of 1000 mg/kg bw/d.] 4. Subchronic toxicity. [ The subchronic toxicity of ametoctradin was investigated in 90 - day feeding studies with rats, mice and dogs as well as a dermal 28 - day repeat dose study with rats. Dosing at limit doses (about 1000 mg/kg bw) in these studies caused no substance - related adverse findings. Due to the lack of adverse findings, target organs were not identified. The lowest NOAEL in subchronic oral toxicity stu dies was 912 mg/kg bw/day in the dog 90 - day study. The neurotoxic potential of ametoctradin was studied following both acute and subchronic oral administration in the rat. In the acute neurotoxicity study there were no test-item related findings in the clinical examinations, functional observational battery or the measurement of motor activity at doses up to and including the limit dose (2000 mg/kg bw). Nor did n europathology reveal any indications for neurotoxicity at the limit dose. Therefore, am etoctr adin did not cause neurotoxicity up to the limit dose of 2000 mg/kg body weight in animals of both sexes. Am etoctradin was also tested in rats in a subchronic neurotoxicity study at doses up to 15000 ppm in the diet (921.2 mg/kg bw, male and 1077.2 mg/kg bw, female) over a period of three months. There were no test-item related findings in the clinical examinations, functional observational battery or the measurement of motor activity. The neuropathological treatment- related findings (included brain weigh t determination, necropsy and neuropathological examinations by light microscopy) also showed no treatment- related findings. In summary, am etoctradin did not show any neurotoxic potential up to the limit dose of 15000 ppm (921.2 mg/kg bw, male and 1077.2 m g/kg bw, female).] 5. Chronic toxicity. [ The results of long-term oral exposure studies indicate that am etoctradin is not carcinogenic in mice or rats. The chronic toxicity/oncogenicity studies with ametoctradin included a 12 - month feeding study with Beagle dogs, an 18 - month C57BL/6 J Rj mouse feeding study and a 24 - month4

Wistar rat chronic/oncogenicity study. At the limit dose in Beagle dogs, Wistar rats and C57BL/6 J Rj mice there was no test substance- related adverse findings or evidence of carcino genicity. The resulting NOAEL’s in the mouse oncogenicity study were 6000 ppm for both sexes (1099 mg/kg bw for the male and 1543 mg/kg bw for the female). In the rat chronic/oncogenicity study the NOAEL’s were 15000 ppm for both sexes (870.7 mg/kg bw fo r the male and 979.3 mg/kg bw for the female). In the chronic dog study, the NOAEL’s were 30000 ppm for both sexes (848 mg/kg bw for the male and 936 mg/kg bw for the female).] 6. Animal metabolism. [ Rat, goat and hen metabolism studies were conducted to determine the nature of ametoctradin residues in animals. All studies were conducted with radio labeled ametoctradin

. In ruminants and poultry ametoctradin is rapidly absorbed and excreted. Ametoctradin is metabolized in goats and hens by oxidation of the aliphatic side chain to the respective terminal carboxylic acid and subsequent stepwise oxidative cleavage of the side chain (loss of C 2 -units) analogous to the  - oxidation of fatty acids . The metabolic pathways in rats, goats and hens were qualitativ ely similar. ] 7. Metabolite toxicology

. [No metabolites of toxicological concern were identified . M650F03 and M650F04, soil metabolites of BAS 650 F, were evaluated for toxicological relevance. These metabolites are structurally similar to each other and to the parent ametoctradin . To further investigate the metabolites’ properties, genotoxicity studies and sub - chronic dietary studies in the rat were conducted. M650F03 was not genotoxic in an Ames test (with and without S - 9 activation) or in an HPRT test in CHO cells (with and without S - 9 activation). No sign of chromosomal aberrations was present in vitro (V79 cells, with and without S - 9 activation) or in vivo (NMRI mice, micronucleus test). The 90 - day dietary study demonstrated that as with the pare nt, administration of M650F03 at dose levels up to and including the limit dose resulted in no adverse substance- related findings. M650F04 was not genotoxic in an Ames test (with and without S - 9 activation) or in an HPRT test in CHO cells (with and withou t S - 9 activation). M650F04 caused no clastogenic effects in vitro (V79 cells, with and without S - 9 activation). The 90 - day dietary study demonstrated that as with the parent, administration of M650F04 at dose levels up to and including the limit dose resulted in no adverse substance - related findings. Studies with the M650F03 and M650F04 metabolites confirmed that they are not toxicologically relevant. ] 8. Endocrine disruption

. [No specific tests have been conducted with ametoctradin to determine whether the chemical may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen or other endocrine effects. However, there were no significant findings in other relevant toxicity studies (e.g., sub - chronic and chronic to xicity, developmental toxicity and multi- generation reproductive studies) which would suggest that ametoctradin produces any endocrine disruption. ]5

C. Aggregate Exposure 1. Dietary exposure. [ The dietary exposure assessment for am etoctradin was co nducted using tolerance level residues, 100% crop treated factors, and default processing factors. The crops and residue values used in the assessment were: brassica, head and stem, subgroup, = 12 parts per million (ppm); brassica, leafy greens, subgroup = 50 ppm; grape = 5 ppm; hop, dried cones = 9 ppm; onion, bulb, subgroup = 1.2 ppm; onion, green, subgroup = 16 ppm; raisin = 8 ppm; vegetable, fruiting, group = 2 ppm; vegetable, leafy, except brassica, group = 70 ppm; vegetable, cucurbit, group = 4.5 ppm ; vegetable, tuberous and corm, subgroup = 0.05 ppm . An acute dietary endpoint was not determine d because there was no toxicological effect from a single exposure to ametoctradin . The chronic dietary endpoint is based on a NOAEL of 871 mg/kg bw

– day with a safety factor of 100 which resulted in a cPAD = 8.71 mg/kg bw

–day. ] i. Food. [ Acute Dietary Exposure Assessment An acute assessment was not needed since there were no toxic effects attributable to a single dose. Therefore, a quantitative acute dietary exposure and risk assessment were not required . Acute Dietary Exposure Assessment T he chronic dietary exposure is shown in the table below . The exposure includes all food commodities and drinking water. The dietary (food + drinking water) utiliz ed less than 1% of the cPAD for all populations. Table 1. Summary of Chronic Dietary Exposure Assessment Considering All Proposed Tolerances for am etoctradin . The assessment includes food + drinking water.

Population Subgroups Exposure Estimate (mg/kg b.w./day) %cPAD U.S. Population 0.037532 0.4 All Infants 0.022184 0.3 Children 1 - 2 years 0.054469 0.6 Children 3 - 5 years 0.050184 0.6 Children 6 - 12 years 0.037335 0.4 Youth 13 - 19 years 0.030329 0.3 Adults 20 - 49 years 0.036924 0.4 Adults 50+ year s 0.037945 0.4 Females 13 - 49 0.037273 0. 4 %cPAD = percent of chronic population adjusted dose Exposure estimates based on tolerance values, default processing factors, and 100% CT for all crops/commodities6

The results indicate that the exposure f or am etoctradin is well below the EPA level of concern. The risk assessment was repeated with contribution from the metabolite residues in rotational crops. The highest total residue value of 0.8 ppm was observed in the field rotational crop study, deriv ed from the sum of the M650F03 and M650F04 residues in parent equivalents from a 118 - day wheat straw sample. For this assessment, this value of 0.8 ppm was applied to all crops in the DEEM database that could possibly be considered for crop rotation. 315 commodities were included. In addition, this value was also applied to potato commodities, since it is higher than the proposed tolerance in potatoes. The result of this assessment is shown in Table 2 . Table 2 . Chronic Dietary Risk Assessment consid ering parent residue on target crops and 0.8 ppm metabolite residue in rotational crops (315 commodities included) Consumer Group %ADI US Population (total) 0.4 All infants (<1 yr) 0.4 Children 1 - 2 yrs 0.8 Children 3 - 5 yrs 0.7 Children 6 - 12 yrs 0.5 Youth 13 - 19 yrs 0.4 Adults 20 - 49 yrs 0.5 Adults 50+ 0.5 Females 13 - 49 yrs 0.5 This assessment is overly conservative, especially considering the fact that metabolite residues in rotational crops were relatively low in consumer food items, compared to feed items. When the results from the two risk assessments are compared, it can be seen that there is no significant difference in the consumer risk assessment when the two soil metabolites are included. All consumer groups are below 1% of the ADI for b oth assessments.] ii. Drinking water

. [ The drinking water exposure was modeled for all proposed uses using the proposed label directions and the appropriate environmental fate data for ametoctradin . The highest drinking water values were obtained fro m the PA tomato scenario. Based on the PRZM/EXAMS model, the peak EDWCs for chronic exposure are estimated to be 0.206 ug/L in surface water .7

Acute Aggregate Exposure and Risk (Food and water) Toxicology studies have shown that ametoctradin poses no acu te dietary risk. Therefore an acute aggregate exposure assessment was not required.

Short- and Intermediate Term Aggregate Exposure and Risk (food, water, and residential) Residential uses for ametoctradin are not being pursued, therefore a short and in termediate term aggregate exposure and risk assessment was not required . Chronic Aggregate Exposure and Risk (food and water) The aggregate chronic risk includes residues of ametoctradin from food and water (Table 1 ). The results demonstrate there are no safety concerns for any subpopulation based on the proposed new uses, and that the results clearly meet the FQ PA standard of reasonable certainty of no harm . ] 2. Non

- dietary exposure

. [ Residential uses for ametoctradin are not being pursued, therefor e, a non - dietary exposure and risk assessment was not required . ] 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'' conce rning 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 ha s not made a common mechanism of toxicity finding as to ametoctradin . In addition, ametoctradin does not produce a toxic metabolite produced by other substances. Therefore, for the purposes of this tolerance action, BASF assumes that ametoctradin does not have a common mechanism of toxicity with other substances.] E. Safety Determination 1. U.S. population. [ Based on this risk assessment, BASF concludes that there is a reasonable certainty that no harm will result to the general population from the a ggregate exposure to ametoctradin .] 2. Infants and children

. [ Based on this risk assessment, BASF concludes that there is a reasonable certainty that no harm will result to infants or children from the aggregate exposure to am etoctradin .] F. Interna tional Tolerances [A maximum residue level (MRL) has not been established for ametoctradin in any crop by the Codex Alimentarius Commission .]