EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Maggie R u dick 703 - 347 - 0257 ; rudick.maggie@epa.gov

TEMPLATE: Bayer CropScience 2E8125 EPA has received a pesticide petition ( 2E8125 ) from Bayer CropScience , 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 in daziflam 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 , each expressed as the parent compound in or on the raw agricultural commodities banana at 0.01 ppm, coffee at 0.01 ppm and palm oil at 0.03 parts per million (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 sufficienc y 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 adequately understood. The plant residues of concern for tolerance enforcement are the combined 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 - 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 spectr ometry (LC/MS/MS) using the stable isotopically labeled analytes as internal standards. The limit of quantification (LOQ) for each analyte was 0.005 ppm for all commodities. November 15, 2012 3. Magn itude of residues. Banana: A total of 14 field trials were conducted evaluating residues at a target harvest interval of 0 days after application. Coffee: A total of 8 field trials were conducted evaluating residues at target harvest interval of 20 days after application . Oil Palm: A total of 5 field trials were conductedevaluating residues at a target harvest intervals of 0, 7, 14 and 30 days after application . B. Toxicological Profile 1. Acute toxicity. Indaziflam has a low acute oral (LD50 > 2,000 mg/kg bw; Category III), dermal (LD50: > 2,000 mg/kg bw; Category III) and inhalative toxicity (LC50: > 2.30 mg/L air; Category IV) in male and female rats. It is not an eye or skin irritant (both Category IV) nor is it a skin sensitizer. 2. Gen otoxicty

. Indaziflam was negative for mutagenicity and clastogenicity in all the standard in vivo and in vitro assays. 3

. Reproductive and developmental toxicity. The reproductive and developmental studies conducted 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 r at 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 developmental neurotoxicity o f 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 males and/or females consisted of decreased mo tor 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 days after treatment), tremors, increased reactivity and decreased activity (generally resolved th e following day after treatment), salivation, cool to touch, clonic convulsions, ventrum wet/staining and death in three females (2000 mg/kg only). Lastly, compound - related microscopic lesions in high - dose males described as focal to multi - focal individu al 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. However, similar effects in motor and locomo tor 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 i n 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 move ments), marked decrease in body weight and body weight gain, and decreasedfood 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, thyroid, and nervou s system. Liver findings seen in rats and dogs were restricted to increased liver weight, hepatocellular hypertrophy, and increased cholesterol. Kidneys 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. Ne uropathological 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, thyroid and nervous system. In the chronic rat, top dose females (10000 ppm) demonstrated similar signs as that seen in the acute and subchronic neurotoxicity studies (e.g. dilat ed pupil, reduced motor activity, limited use of limbs, uncoordinated movements, tremors, hindlimbs splayed, low alertness). The incidence of treatment - related clinical signs in females decreased significantly after the change of dose level from 10000 to 6 000 ppm. Clinical signs were not evident in the chronic dog at any dose level. Organ effects noted in these studies included increased liver, kidney and thyroid weights, with centrilobular hepatocellular hypertrophy in the liver, tubular hyperplasia (mal e mouse only) and brown pigment in the kidney, and follicular cell hypertrophy in the thyroid (male 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 a fter chronic administration of indaziflam with the lowest NOAEL at 2.0 mg/kg bw/day in males and females in the 1 - year oral feeding study. There were no treatment - related neoplasms in the rat or mouse. Therefore, following chronic exposure, there is no i ndication of oncogenic potential relevant for the human health risk assessment of indaziflam.

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 within24 hours. In general, the majority of the radioactivity was excreted in the feces wi th fecal: renal excretion ratios ranging from approximately 1:1 for the low dose experiments to approximately 10:1 for the high dose experiments. No volatile residues were detected, and no mineralization was observed. Residue levels in tissues were highe st 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 slightly 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 pathways. That portion of the administered dose recovered as unm etabolized parent in the feces, particularly in the high dose experiments, was likely not absorbed. 8. Metabolite toxicology

. The two major metabolites of indaziflam are AE 2158969 ( BCS - AA10717 - carboxylic acid) and BCS - AA10365 (BCS - AA10717 - fluoroethyldi aminotriazine, FDAT). As both major metabolites are common in the rat, as well as the environment, toxicity studies conducted with the TGAS are adequate to assess any potential toxicity from these metabolites. Primary mutagenicity screening tests which w ere 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 short - or long - term exposure. Bayer CropScience will conduct additional testing if and when required under the Agency’s Endocrine Disruptor Screening Prog ram (EDSP). C. Aggregate Exposure Aggregate risk assessments were conducted for indaziflam including an acute and chronic aggregate for food and drinking water exposure, a chronic aggregate for food and drinking water exposure and a short

- term assessment which includes food, drinking water and residential exposure. The most recent assessments were conducted by EPA on April 6, 2011 using the CARES® Version 3.0DEEM

- FCID Version 2.03 software. Results of the short term aggregate assessment gave calculated an MOE of 1,700 for adults and a MOE of 1,100 for Children 1

- 2, the most sensitive subpopulat ion. The Level of Concern for aggregate assessment of indaziflam is 100. 1. Dietary exposure

. i. Food and Water

. Assessments were conducted to evaluate potential risks due to acute and chronic dietary exposure of the U.S. population and selected populat ion subgroups to residues of indaziflam. The dietary (food only) assessment includes all proposed crops: Crop Group 10 Citrus Fruit; Crop Group 11 PomeFruit; Crop Group 12 Stone Fruit; Crop Subgroup 13 - 07 - F Small Fruit Vine Climbing (except Kiwi); Crop G roup 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 consume d only 6.6% of the acute RfD/PAD and 9.0% of the chronic RfD/PAD for the most sensitive subpopulation of infants. Addition of tolerance residues for the proposed crops: banana, coffee, and palm oil would show slight increases in %aPAD and %cPAD but these additions would be well below the EPA level of concern of 100% of the PAD. ii. Drinking water. The drinking water assessment is based on conservative modeled acute and chronic estimated drinking water concentrations for the US. Contribution of drinking w ater to the risk assessment was minimal. 2. Non

- dietary exposure

. T he 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 of applicati on resulted in MOEs in excess of 5,000 for toddlers, and in excess of 3,000 for adults, well above the Level of Concern of 100 for indaziflam.
D. Cumulative Effects The toxicological properties of indaziflam indicate that it does not have a common mec hanism of toxicity with any other compounds. Although it contains a triazine ring it does not exhibit the toxicological properties 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 the 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 currently registered crops, proposed crops, and drinking water utilizes 6.6% of the aPAD and 9.0% of the cPAD for the most sensitive population of infants. Addition of the proposed cr ops will slightly increase the %aPAD and %cPAD, but will be well below EPA level of concern. EPA generally 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 the use of indaziflam noted here . 2. Infants and children

. The developmental and reproductive toxicity of indaziflam were evaluated in developmental toxicity studies in the rat and rabbit, a2 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 d ata 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 develo pmental 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 rep roductive capability of mating animals and data on systemic 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 toxici ty and the completeness of the data base unless EPA determines 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 toxici ty 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 pr oposed uses of indaziflam consumes slightly higher than 6.6% of the aRfD/aPAD at the 99.9th percentile and 9.0% 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 pathways calculated a MOE of 1,700 for adults and a MOE of 1,100 for Children 1 - 2 yrs. oldgives an MOE of 8,700 for Children 1 - 2, the most sensitive subpopulation for this scenario. This is well above the Level of Concern o f 100 for indaziflam. Thus, it can be concluded that there is a reasonable certainty that no harm will result from aggregate exposure to indaziflam residues. F. International Tolerances Currently, t here currently are no international (CODEX) tolerances/MRLs for indaziflam.