EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

Interregional Research No. 4, Rutgers, The State University of New Jersey, 5 00 College R oad East, Suite 201 W, Princeton, NJ 08540

P P# 6E8452

EPA has received a pesticide petition (PP# 6E8452 ) from Interregional Research Number 4 (IR

- 4), Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08540 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 :

1. establ ishing a tolerance for residues of indaziflam, N

- [(1R,2S)

- 2,3

- dihydro

- 2,6

- dimethyl

- 1H

- inden

- 1

- yl]

- 6

- (1

- fluoroethyl)

- 1,3,5

- triazine

- 2,4

- diamine including its metabolites and degradates in or on the raw agricultural commodities Bushberry subgroup 13

- 07B at 0.01 parts per million (ppm); Caneberry subgroup 13

- 07A at 0.01 ppm; Coffee, green bean at 0.01 ppm, Fruit, small, vine climbing, except fuzzy k iwifruit , s ubgroup 13

- 07F at 0.01 ppm, Hop, dried cones at 0.03
ppm, Fruit, stone, group 12

- 12 at 0.01 ppm and N ut, t ree, group 14

- 12 at 0.01
pp m

. Additionally tolerances are proposed for the crops in the proposed Crop Subgroup 23A. Small fruit, edible peel subgrou p at 0.01 ppm including Acerola; African plum; agritos, almondette; appleberry; arbutus berry; bayberry, red; bignay; breadnut; cabeluda; carandas

- plum; Ceylon iron wood; Ceylon olive; cherry

- of

- the

- Rio

- Grande; Chinese olive, black; Chinese olive, white; chirauli

nut; cocoplum; desert

- date; false sandalwood; fragrant manjack; gooseberry, Abyssinian; gooseberry, Ceylon; gooseberry, otaheite; governor’s plum; grumichama; guabiroba; guava berry; guava, Brazilian; guava, Costa Rican; guayabillo; illawarra plum; Indian

- plum; Jamaica

- cherry; jambolan; kaffir

- plum; kakadu plum; kapundung; karnada; lemon asp en; mombin, yellow; monos plum; mountain cherry; olive; persimmon, black; pitomba; plum

- of

- Martinique; rukam; rumberry; sea grape; sete

- capotes; silver aspen; water apple; water pear; water berry; wax jambu.

2. remove established tolerances for residues of i ndaziflam, N

- [(1R,2S)

- 2,3

- dihydro

2,6

- dimethyl

- 1H

- inden

- 1

- yl]

- 6

- (1

- fluoroethyl)

- 1,3,5

- triazine

- 2,4

- diamine including its metabolites and degradates in or on raw agricultural commodities Fruit, stone, group 12 at 0.01 ppm, Nut, tree, group 14 at 0.01 ppm , G rape at 0.01
ppm and Pistachio at 0.01) ppm.

EPA has determined that the petition contains data or information regarding the el ements 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 Chemistry1. Plant metabolism. The nature of the indaziflam residues in plants and livestock is adequately underst ood. 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]

- 6

- (1

- fluoroethyl)

- 1,3,5

- triazine

- 2,4

- diami ne, including its metabolites and degradates

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 analytes as internal standards. The limit of quanti fication (LOQ) for each analyte was 0.005 ppm for all commodities.

3. Magnitude of residues. A total of eight field trials were conducted to measure the magnitude of indaziflam N

- [(1R,2S)

- 2,3

- dihydro

- 2,6

- dimethyl

- 1H

- inden

- 1

- yl]

- 6

- (1

- fluoroethyl)

- 1,3,5

- tri azine

- 2,4

- diamine including its metabolites and degradates residues in/on highbush blueberry following two banded ground applications of indaziflam, with a target retreatment interval of 60 days, at a target rate of 0.065 lb ai/A/application (72.9 g ai/ha/ application). In blueberry fruit, the highest average field trial (HAFT) and maximum total indaziflam residues ( including its metabolites and degradates ) at a target 14

- day post

- harvest interval (PHI) were <0.01 ppm, the limit of quantitation (LOQ) for the method.

A total of seven field trials (4 raspberry and 3 blackberry) were conducted to measure the magnitude of indaziflam residues in/on caneberry following two banded ground applications of indaziflam, with a target retreatment interval of 60 days, at a target rate of 0.065 lb ai/A/application (72.9 g ai/ha/application). In caneberry fruit, the HAFT and maximum for total indaziflam residues ( including its metabolites and degradates ) at a target 14

- day PHI were <0.01 ppm, the LOQ for the method.

A total of five field trials, in two different growing seasons, were conducted to measure the magnitude of indaziflam residues in/on green coffee beans, roasted beans, and freeze

- dried coffee following two banded ground applications of indaziflam, with a
tar get retreatment i nterval of 3 0 days, at target rates of 0.089 lb ai/A (99.8 g ai/ha) for application 1 and 0.045 lb ai/A (50.5 g ai/ha) for application 2. In green coffee beans, the HAFT and maximum fo r total indaziflam residues (including its metabolites and degradates ) at a target 14

- day were <0.01 ppm, the LOQ for the method. In the processed commodities of roasted coffee beans and freeze

- dried coffee, the HAFT and maximum for total indaziflam residues (parent plus the metabolite 1

- fluoromethyl triazined iamine) at a target 14

- day were <0.015 ppm, the LOQ for the method.

A total of five field trials were conducted to measure the magnitude of indaziflam residues in/on hops following two banded ground applications of indaziflam during dormancy at a target r ate of 0.065 lb ai/A/application (72.9 g ai/ha/application). In dried hop cones, the HAFT and maximum for tot al indaziflam residues (including its metabolites and degradates ) at a PHI of 127 to 188 days were 0.02 ppm.

B. Toxicological Profile1. Acute toxicity. Indaziflam has low acute oral (LD50 > 2,000 mg/kg bw; Category III), dermal (LD50 > 2,000 mg/kg bw; Category III), and inhalation toxicity (LC50 > 2.30 mg/L air; Category IV) in male and female rats. Indaziflam is not an eye or skin irritant (bot h Category IV) and is not a skin sensitizer.

2. Genotoxicity. Indaziflam is not genotoxic; it was negative for mutagenicity in reverse and forward gene mutation assays and negative for clastogenicity in vitro and in vivo.

3. Immunotoxicity. Immunotoxici ty potential was evaluated with a subacute oral (diet) exposure to rats. Immunotoxicity was not observed with indaziflam exposure, and as such the no observable adverse effect level for immunotoxicity was defined as the highest dose tested (10,000/6,000 pp m in diet, equivalent to 528 and 738 mg/kg

- bw/day in males and females, respectively

. 4. Reproductive and developmental toxicity. No effects on reproduction and development were observed in the reproductive and developmental studies conducted with indazif lam, demonstrating that indaziflam is not a reproductive toxicant. Offspring effects in the rat developmental toxicity study (i.e. decreased fetal weight) were observed only in the presence of maternal toxicity, including decreased body weight gain and foo d consumption. No developmental effects were observed in rabbits up to maternally toxic doses. Decreased pup weights and delays in preputial separation and vaginal opening were observed in the rat 2

- generation reproductive toxicity study, but only in the p resence of clinical signs of toxicity that caused parental toxicity, including coarse tremors, renal toxicity, and decreased weight gain. Further, there was no indication of a teratogenic effect of indaziflam in either the rat or the rabbit.

5. Neurotoxic ity

. Based on evaluations in the rat (acute, chronic, and developmental neurotoxicity studies) and in the dog (subchronic and chronic studies), the nervous system is considered the major target for indaziflam toxicity, with the dog being the more sensitive species. A single oral dose of indaziflam decreased motor and locomotor activity in male (at 500 mg/kg and 2000 mg/kg) and in female ( ≥ 100 mg/kg) rats, with recovery within seven days. Other effects included urine, oral and perianal stains (generally re solved one to five days after treatment); tremors; increased reactivity and decreased activity (generally resolved the following day after treatment); increased salivation; cool to touch; clonic convulsions; ventrum wet/staining; and death in three females (at 2000 mg/kg only). In male rats, acute indaziflam treatment (2000 mg/kg only) also corresponded to microscopic lesions described as focal to multi

- focal individual nerve fiber degeneration, observed in the Gasserian ganglion and peripheral nerves (sciatic and tibial). Based on these results, indaziflam exposures of 50 and 100 mg /kg

- bw are the acute NOAELs for neurotoxicity in female and male rats, respectively. In the subchronic rat study, there were no mortalities. However, similar effects in mot or and locomotor activity, as well as clinical signs of neurotoxicity (tremors, repetitive chewing motion, and perianal and lacrimal staining), were noted at the highest dose tested, 10,000 ppm (580.9 and 585.7 mg/kg/day for female and male rats, respectiv ely). These resultsestablish a NOAEL for subchronic neurotoxicity in rats at 8000 ppm (243.6 mg/kg/day in males and 306.9 mg/kg/day in females). In the developmental rat neurotoxicity study, the dam and offspring NOAEL was 1000 ppm (83.8 mg/kg bw/day), ba sed 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 neuropat hology in this developmental neurotoxicity study. The neurotoxic effects of indaziflam in dogs, which were more sensitive than rats, are described further in subsequent sections describing

s ubchronic and chronic toxicity.

6. Subchronic toxicity. Short

- and intermediate

- term exposures to indaziflam were assessed in the mouse, rat, and dog. 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 o nly adverse treatment related effects noted in the mouse following a 90

- day oral exposure were reduced body weights, body weight gain, and food consumption at the highest dose tested. Minimal to moderate follicular cell hypertrophy of the thyroid gland was seen in male rats with a 90

- day exposure (5000 and 10,000 ppm), and decreased body weights were seen with 10,000 ppm exposures in male and female rats. Adaptive, reversible findings were seen in the liver of rats, and were restricted to increased liver we ight, hepatocellular hypertrophy, increased cholesterol, and lower total bilirubin. Kidneys were enlarged in the rat, but without any corresponding weight change or pathology. Neurotoxicity was evident in both rats and dogs receiving subchronic oral exposu res to indaziflam. Effects observed in rats included tremors; repetitive chewing movements; perianal, lacrimal, and nasal staining; and decreased motor and locomotor activity in female rats. In dogs, effects observed included tremors, ataxia, labored breat hing, and seizures in high

- dose group male and female dogs. Neuropathological lesions including axonal swelling and degeneration, as well as individual nerve fiber degeneration, were also observed in male and female dogs. These findings were located in the brain, spinal cord, and peripheral (sciatic and tibial) nerve
tracts. The dog was the most sensitive species overall after subchronic administration of indaziflam, with the lowest NOAEL of 7.5 mg/kg

- bw/day based on neurotoxicity findings in males and fema le dogs in the 90

- day oral ga vage study.

7. Chronic toxicity. Chronic toxicity of indaziflam was evaluated in the mouse, rat, and dog, and there was no evidence of carcinogenicity in any of these species. There
were no treatment

- related neoplasms in rat o r mouse. Therefore, following chronic exposure, there is no indication of oncogenic potential relevant for the human health risk assessment of indaziflam. Target organs in mice and rats included liver and kidney, and effects on the thyroid and nervous syst em were also targets in rats. Following chronic exposure, mice demonstrated decreased body weight, body weight gain, and food consumption in both sexes; increased incidence of renal and hepatotoxicity in males; and, increased incidence of non

- neoplastic ch anges in the stomach and ovaries of females, at the highest dose tested. High dose female rats (10,000 ppm) demonstrated similar signs to those observed in the acute and subchronic neurotoxicity studies (e.g. dilated pupil, reduced motor activity, limited use of limbs, uncoordinated movements, tremors, hindlimbs splayed, low alertness) following chronic administration. The incidence oftreatment

- related clinical signs in females decreased significantly after the top dose level was decreased from 10,000 to 6 000 ppm due to manifestation of clinical signs. 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 i n the liver, tubular hyperplasia (male 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 after 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.

8 . Animal metabolism. A metabolism study for indaziflam, in which male rats were given single oral doses of [ indane

- 3

- 14 C]

- or [ triazine

- 2,4

- 14 C]

- labeled indaziflam

, demonstrated that the uptake and excretion of indaziflam was rapid. Following oral administration, greater than 87% of the administered dose was excreted within 24 ho urs. In general, the majority of the radioactivity was ex creted in the feces with 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 detect ed, and no mineralization was observed. Residue levels in tissues were highest in gastrointestinal tract and liver. Higher residue levels were found in the residual carcass of animals in the bile cannulation experiments.

Both uptake and clearance of indaz iflam from the blood was rapid. Females appeared to absorb slightly more material compared to for males. Blood residues smoothly declined in all dose groups over time, indicating an absence of reuptake.

Once absorbed, the metabolism of indaziflam was rapi d, occurring mainly through oxidative pathways. The portion of the administered dose recovered as parent in the feces, particularly in the high dose experiments, was likely not absorbed.

9

. Metabolite toxicology

. The two major metabolites of indaziflam are AE 2158969 ( BCS

- AA10717

- carboxylic acid) and BCS

- AA10365 (BCS

- AA10717

- fluoroethyldiaminotriazine, FDAT). As both major metabolites are produced in the rat, as well as the environment, toxicity studies conducted w ith indaziflam are adequate to assess any potential toxicity from these metabolites. Primary mutagenicity screening tests were negative for the se indaziflam metabolites

, and therefore these metabolites are not genotoxic.

10. Endocrine disruption

. The toxi cology 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. No effects on reproduction and development were observed in the reproductive and developmental studies conducted with indaziflam.Bayer CropScience will conduct additional testing if and when required under the US EPA’s Endocrine Disr u ptor Screening Program (EDSP).

C. Aggregate Exposure

1. Dietary exposure. The proposed new uses of indaziflam on bushberry /caneberry, coffee, and hops have minor effects on the previous dietary aggregate risk assessment conducted for all register ed uses (EPA, D408152, 2013)

. Residues for the additional crop group were based on recommended tolerances. Assessments, using the DEEM FCID Version 4.02 software, were conducted to evaluate potential risks due to chronic and acute dietary exposure of the U.S. popu lation and selected population subgroups to residues of indaziflam. Consumption data used in this program were taken from NHANES WWEIA 2005

- 2010.

The toxicological and exposure database for indaziflam is considered complete. There was no indication of an increased sensitivity of the young in any studies including the reproductive and developmental studies in rats and rabbits. Therefore, the special FQPA safety factor can be reduced to 1X and an uncertainty factor of 100 is adequate to account for inter

- and intra

- species variability. Acute and chronic Population Adjusted Doses (aPAD and cPAD) are, therefore, the same as the reference doses for the populations and subpopulations of interest. Acute dietary exposure was expressed as a percentage of the aPAD of 0.075 mg/kg bw/day from a NOAEL of 7.5 mg/kg bw/day, based on axonal degenerative findings in the dog subchronic gavage toxicity study, with an uncertainty factor of 100. Chronic dietary exposure was expressed as a percentage of the chronic Population Adjusted Dose (cPAD) of 0.02 mg/kg bw/day based on a NOAEL of 2 mg/kg bw/day in the dog chronic dietary toxicity study wit h an uncertainty factor of 100.

i. Food. Assessments were conducted to evaluate potential risks due to acute and chronic dietary expo sure of the U.S. population and selected population subgroups to residues of indaziflam includ ing all registered crops and proposed crops. This conservative, unrefined assessment assumed recommended tolerance levels for all commodities, 100% Percent Crop T reated (PCT) and default processing factors to adjustment crop residue values. Acute exposure (95th percentile) for food only utilizes <1% of the aPAD for the US Population and 1.1% for Children 1

- 2 yrs., the most highly exposed subpopulation. Chronic expo sure utilizes <1% of the cPAD for the US Population and 1.4% of the cPAD for Children 1

- 2 yrs. , the most highly exposed subpopulation.

ii. Drinking water. Estimated Drinking Water Concentrations (EDWCs) associated with indaziflam use on all crops were cal culated by EFED ( EPA , D356141, 2010) using SCI

- GROW v2.3 and PRZM

- EXAMS to calculate ground water and surface water EDWCs, respectively. EDWCs were calculated for total indaziflam based on parent and degradates FDAT and ROI1 (a degradate of FDAT). The maxi mum acute and chronic surface water concentrations estimated by SCI

- GROW were 84 ppb and 26 ppb, respectively, and were higher than the ground water estimates. The value from the highest surface water exposure scenarios were incorporated into the dietary r iskassessment. The addition of the acute estimated drinking water concentration (EDWC) of 84 ppb resulted in 6% of the aPAD utilized for the US Population and 21% utilized for Infants (< 1 yr.), the most highly exposed subpopulation. The addition of the c hronic EDWC of 26 ppb utilized 3% of the cPAD for the US Population and 11% of the cPAD for Infants (< 1 yr.), the most highly exposed subpopulation. In conclusion, the results of the acute and chronic Tier 1 dietary exposure analyses (including drinking w ater) are acceptable for all population subgroups examined. Addition of tolerance residues for the proposed crops shows a slight increase in %aPAD and %cPAD but these additions are well below the EPA level of concern of 100% of the PAD.

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. Residen tial post

- application exposure from contact with indaziflam treated turf or ornamentals on the day of application 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 mechanism of toxicity with any other compounds. Although it contains a triazine ring it does not exhibit the toxicological properties of the chlorotria zine 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 a completeness of toxicity data, it can be concluded that aggregate exposure to residues of indaziflam present a reasonable certainty of no harm. Chronic aggregate dietary exposure (food and water) will utilize less than 3% of the cPAD for the US Population. Acute aggregate dietary exposure (food and water) for the U.S. population, utilizes 6% of the aPAD. Non

- dietary and aggregate MOEs (food, drinking water, and

non

- dietary) are above the Level of Concern. 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 subpo pulations from th e 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, 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 d emonstrated 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 sensitiv ity of rats to in utero or post natal exposure. The developmenta l toxicity studies are designed to evaluate adverse effects on the developingorganism resulting from maternal pesticide exposure during gestation. Reproduction studies provide information relating to effects from exposure to the pesticide on the reproduct ive 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 effe cts to account for pre and post natal toxicity 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 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 use s of indaziflam consumes 21 % of the aPAD at the 95 th percentile and 11 % of the cPAD for the most sensitive population subgroup of infants. Short

- term aggregate risk assessment of indaziflam which includes food, drinking water and residential pathways calcu lated a MOE of 1, 400 for adults and a MOE of 540 for Children

. 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 exposure to indaziflam resi dues.

F. International Tolerances

Currently, there currently are no international (CODEX) tolerances/MRLs for indaziflam.