EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Jim Tompkins, 703 - 305 - 5697 and Beth Benbow, 703 - 347 - 8072 Baye r CropScience LP PP#: 9F7589 EPA has rece ived a pesticide petition ( 9F7589 ) from Baye r CropScience LP , [ 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 indaziflam N - [(1R, 2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl - 1,3,5 - triazine - 2,4 - diamine] - 6 - (1 - fluoroeth yl ) ] and its fluoroethyl - indaziflam metabolite in or on raw agricultural commodities fruit, pome, group, f ruit, citrus, group, fruit, stone, group, nut, tree, group , pistachios , grapes, olives all at [0.01] parts per million (ppm), and almond, hulls at [0.2] ppm , and the import tolerance for refined sugar at [0.01] ppm . EPA has determined that the petition co ntains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not full y 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. The nature of the indaziflam residues in plants and livestock is adequatel y understood. The plant residues of concern for tolerance enforcement are the combined residue s of indaziflam (N - [(1R, 2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl 1,3,5 - triazine - 2,4 - diamine] - 6 - (1 - fluoroethyl) - ] and its fluoroethyl - indaziflam metabolite [ 1,3,5 - triazine - 2,4 - diamine] - 6 - (1 - fluoroethyl) - ]. 2. Analytical method

. Indaziflam residues are quantified in raw agricultural commodities by

high pressure liquid chromatography /triple stage quadrupole mass spectrometry

(LC/MS/MS) using the stable isotopically labeled analy

tes as internal standards. The limit of quantification (LOQ) for each analy te was 0.005 ppm for all commodities. 3. Magnitude of residues. Residue trials were conducted to support the tolerances requested above including the following:

- Citrus: A total of 23 field trials were conducted evaluating residues at target harvest interv als of 14, 45 and 240 day s after application.

- Pome Fruit: A total of 18 field trials were conducted evaluating residues at target2 harvest intervals of 14, 45 and 2 1 0 target day s after application.

- Stone Fruit: A total of 21 field trials were conducted ev aluating residues at target harvest intervals of 14, 45 and 150/210 day s after application.

- Tree Nuts: A total of 10 field trials were conducted evaluating residues at target harvest intervals of 14 day s after application.

- Grapes: A total of 12 field trial s were conducted evaluating residues at target harvest intervals of 14, 45 and 140 - 240 day s after application.

- Olives: A total of 6 field trials were conducted evaluating residues at target harvest intervals of 14, 45 and 300 day s after application.

- Sugarc ane: A sugarcane processing trial was conducted to measure the magnitude of total indaziflam residues in sugarcane and sugarcane processed commodities following an exaggerated rate application to ratooned sugarcane. B. Toxicological Profile 1. Acute toxi city . Indaziflam has a low acute oral (LD 50 > 2,000 mg/kg bw; Category III), dermal (LD 50 : > 2,000 mg/kg bw; Category III) and inhalative toxicity (L C 50 : > 2.30 mg/L air; Category IV) in male and female rats. It is not an eye or skin irritant (both Categ ory

IV) nor is it a skin sensitizer. 2. Genotoxicty. Indaziflam was negative for mutagenicity and clastogenicity

in all the standard in vivo and in vitro a ssay s. 3. Reproductive and developmental toxicity. The reproductive and developmental studies con ducted with indaziflam showed that the test substance was not a reproductive toxicant. Parental and offspring body weight and/or body weight change were decreased at high concentrations, however there was no effect on reproductive ability of adults. The findings observed in rat fetuses (decreased body weights) were minor and were secondary to maternal toxicity . There was no indication of a teratogenic effect of indaziflam in either the rat or the rabbit. 4. Neurotoxicity. Acute, subchronic and developme ntal neurotoxicity of indaziflam was assessed in the rat. Compound - related effects following a single oral dose of the test substance were limited to 500 mg/kg and 2000 mg/kg in males and 100 mg/kg and up in females. Effects in male s and/or females consisted of decreased motor and locomotor activity

on the day

of treatment (with recovery by the next test occasion), urine, oral and perianal stains (generally resolved one to five day s after treatment), tremors, increased reactivity and decreased activity

(generally

resolved the following day after treatment), salivation, cool to touch, clonic convulsions, ventrum wet/staining and death in three females (2000 mg/kg only). Lastl y, compound - related microscopic lesions in high - dose males described as focal to multi - focal individual nerve fiber degeneration observed in the gasserian ganglion and peripheral nerves (sciatic and tibial) were evident. Slight decreases in measures of motor and locomotor activity were evident in females treated at 100 mg/kg, with no effect at the next lower dose of 50 mg/kg. Based on these results, doses of 100 and 50 mg BCS - AA10717/kg body weight are the overall NOAELs for males and females, respectively . In the subchronic study , there were no mortalities.3

Ho wever, similar effects in motor and locomotor activity , as well as clinical signs of neurotoxicity

were only

noted at the top dose, 10000 ppm (580.9 and 585.7 mg/kg/day for males and females, respectively). These results establish a NOAEL for neurotoxicity endpoints of 8000 ppm (243.6 mg/kg/day in males and 306.9 mg/kg/day in females). In the developmental neurotoxicity study , the dam and offspring NOAEL was 1000 ppm (83.8 mg/kg bw/day), based on clinical signs of toxicity in dams (tremor, dilated pupils, nasal stains, and repetitive chewing movements), marked decrease in body weight and body weight gain, and decreased food consumption in dams and offspring. There were no effects on neuropathology in this study . 5 . Subchronic toxicity. Short and Intermediate - term exposures to indaziflam were assessed in the mouse, rat and dog. The only treatment related effect noted in the mouse, following a 90 - day

exposure, was reduced body weights at the highest dose tested. The common target organs in rats and dogs were the liver, thy roid, and nervous s ys tem. Liver findings seen in rats and dogs were restricted to increased liver weight, hepatocellular hyp ertrophy , and increased cholesterol. Kidney s were enlarged in the rat, but without corresponding weight change or pathology . Neurobehavioral and neuropathological changes were noted in both rats and dogs following acute, short - term and chronic exposure to indaziflam . Effects noted included tremors, salivation and decreased motor activity in rats, and uncoordinated gait and convulsions in dogs. Neuropathological lesions included axonal swelling and degeneration, as well as individual nerve fiber degeneration. These findings were found in the brain, spinal cord and peripheral (sciatic and tibial) nerve tracts. Indaziflam is not toxic by the dermal route, as there was no toxicity noted at the highest dose tested (1000 mg/kg/day) in a 28 - day dermal toxicity

study in rats. The dog was the most sensitive species overall after sub - acute to sub - chronic administration of indaziflam with the lowest NOAEL at 7.5 mg/kg bw/day in males and females in the 90 - day oral gavage study. 6 . Chronic toxicity. Chronic toxicity of indaziflam was evaluated in the rat, mouse and dog. Target organs were liver, kidney , thy roid and nervous sy stem. In the chronic rat, top dose females (10000 ppm) demonstrated similar signs as that seen in the acute and subchronic neurotoxicity studies (e.g. dilated pupil, reduced motor activity , limited use of limbs, uncoordinated movements, tremors, hindli mbs splayed, low alertness). The incidence of treatment - related clinical signs in females decreased significantly after the change of dose level from 10000 to 6000 ppm. Clinical signs were not evident in the chronic dog at any dose level. Organ effects n oted in these studies included increased liver, kidney

and thy roid weights, with centrilobular hepatocellular hy pertrophy in the liver, tubular h yperplasia (male mouse onl y) and brown pigment in the kidney, and follicular cell hypertrophy in the th yroid (m ale rat only), histopathological changes to the central and peripheral nerve tracts were noted only in the dog. The dog was the most sensitive species overall after chronic administration of indaziflam with the lowest NOAEL at 2.0 mg/kg bw/day in males and females i n the 1 - ye ar oral feeding study . There were no treatment - related neoplasms in the rat or mouse. Therefore, following chronic exposure, there is no indication of oncogenic potential relevant for the human health risk assessment of indaziflam.4 7 . Animal metabolism. A metabolism study for indaziflam, in which male rats were given single oral doses of [indane - 3 - 14 C] AE 1170437 or [triazine - 2,4 - 14 C] AE 1170437, showed that the uptake and excretion of AE 1170437 was rapid. Following oral administration, greater than 87% of the administered dose was excreted within 24 hours. In general, the majority of the radioactivity was excreted in the feces with fecal: renal excretion ratios ranging from approximately 1:1 for the low dose experiments to appro ximately

10:1 for the high dose experiments. No volatile residues were detected, and no mineralization was observed. Residue levels in tissues were highest in GIT and liver. Higher residue levels were found in the residual carcass of animals in the bile cannulation experiments. Both uptake and clearance of indaziflam from the blood was rapid. Females appeared to absorb slightl y more material compared to for males. Blood residues smoothly fell off in all dose groups indicating an absence of reuptake. Once absorbed, the metabolism of AE 1170437 was rapid, occurring mainly through oxidative pathway s. That portion of the administered dose recovered as unmetabolized parent in the feces, particularly in the high dose experiments, was likel y not absorbed. 8 . Metabolite toxicology . The two major metabolites of indaziflam are AE 2158969 ( BCS - AA10717 - carbox yl ic acid) and BCS - AA10365 (BCS - AA10717 - fluoroeth yl diaminotriazine, FDAT). As both major metabolites are common in the rat, as well as the environment, to xicity studies conducted with the TGAS are adequate to assess any potential toxicity

from these metabolites. Primary mutagenicity screening tests which were conducted on the metabolites of indaziflam showed them not to be genotoxic. 9 . Endocrine disruption . The toxicology database for Indaziflam (BCS - AA10717) is current and complete. Studies in this database include evaluation of the potential effects on reproduction and development and an evaluation of the pathology of the endocrine organs following sh ort - or long - term exposure. Baye r CropScience will conduct additional testing if and when required under the Agency ’s Endocrine Disruptor Screening Program (EDSP). C. Aggregate Exposure Aggregate risk assessments were conducted for indaziflam including an acute aggregate for food and drinking water exposure, a chronic aggregate for food and drinking water exposure and a short term aggregate assessment which includes food, drinking water and residential exposure. The assessments were conducted using the CARES® Version 3.0 software. Results of the short term aggregate assessment gave an MOE of 8700 for Children 1 - 2, the most sensitive subpopulation. The Level of Concern for aggregate assessment of indaziflam is 100.5 1. Dietary exposure. i. Food and W

a ter. Assessments were conducted to evaluate potential risks due to acute and chronic dietary exposure of the U.S. population and selected population subgroups to residues of indaziflam. The dietary (food onl y) assessment includes all proposed crops: Crop Group 10 Citrus Fruit; Crop Group 11 Pome Fruit; Crop Group 12 Stone Fruit; Crop Subgroup 13 - 07 - F Small Fruit Vine Climbing (except Kiwi); Crop Group 14 Tree Nuts; and olives. The drinking water assessment is based on conservative modeled acute and chronic estimated drinking water concentrations for the US . Exposure from food and water together based on all the proposed uses of indaziflam consumed only 1.9% of the acute RfD/PAD and 2.4% of the chronic RfD/PAD for the most sensitive subpopulation of infants. 2. Non - dietary exposure . The short term residential assessment includes application exposure by homeowners applying indaziflam on lawns or ornamental plants, as well as post application exposure estimates for adults and children playing on lawns and golf courses . Residential post - application exposure from contact with indaziflam treated turf or ornamentals on the day o f application resulted in MOEs in excess of 600 for toddlers, and in excess of 1,000 for adults, well above the Level of Concern of 10 0 for indaziflam. D. Cumulative Effects The toxicological properties of indaziflam indicate that it does not have a common mechanism of toxicity with any other compounds. Although it contains a triazine ring it does not exhibit the toxicological prop erties of the chlorotriazine common mechanism group. Therefore it is not necessary to cumulate its exposure with any other compounds. E. Safety Determination 1. U.S. population Using the conservative exposure assumptions described above and based on th e completeness of the toxicity data, it can be concluded that aggregate exposure to residues of indaziflam present a reasonable certainty of no harm. Exposure from residues in crops and drinking water utilizes 1.9% of the aPAD and 2.4% of the cPAD for the most sensitive population of infants. EPA generall y has no concerns for exposures below 100% of the Population Adjusted Doses. Therefore, the aggregate assessment for all proposed uses for indaziflam demonstrates that there is a reasonable certainty that no harm will result to the US Population and subpoppulations from th e use of indaziflam noted here.6 2. Infants and children . The developmental and reproductive toxicity of indaziflam were evaluated in developmental toxicity studies in the rat and rabb it, a 2 - generation reproduction study in the rat and a developmental neurotoxicity study in the rat. These studies are discussed under Section B (Toxicology Profile) above. The developmental toxicity

data demonstrated no increased sensitivity of rats or rabbits to in utero exposure to indaziflam. In addition, the multi - generation reproductive toxicity study did not identify

any increased sensitivity of rats to in utero or post - natal exposure. The developmental toxicity

studies are designed to evaluate adverse effects on the developing organism resulting from maternal pesticide exposure during gestation. Reproduction studies provide information relating to effects from exposure to the pesticide on the reproductive capability

of mating animals and data on sy s temic toxicity . FFDCA section 408 provides that EPA shall apply an additional tenfold margin of safety for infants and children in the case of threshold effects to account for pre - and post - natal toxicity and the completeness of the data base unless EPA de termines that a different margin of safety

will be safe for infants and children. The indaziflam database is complete for FQPA purposes and there are no residual uncertainties for pre - /post - natal toxicity for indaziflam. Therefore, the Special FQPA Safety Factor can be reduced to 1x. Based on the exposure assessments described above and on the completeness and reliability of the toxicity

data, it can be concluded that the dietary exposure from all proposed uses of indaziflam consumes 1.9% of the aRfD/aP AD at the 99.9 th percentile and 2.4% of the cRfD/cPAD for the most sensitive population subgroup of infants . Short term aggregate risk assessment of indaziflam which includes food, drinking water and residential pathway s gives an MOE of 8,700 for Children 1 - 2, the most sensitive subpopulation for this scenario. This is well above the Level of Concern of 100 for indaziflam. Thus, it can be concluded that there is a reasonable certainty that no harm will result from aggregate e xposure to indaziflam residue s. F. International Tolerances There currently

are no international (CODEX) tolerances/MRLs for indaziflam.