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, 500 College 

Road East, Suite 201 W, Princeton, NJ 08540

PP# 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. establishing 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 kiwifruit, subgroup 13-07F at 0.01 ppm, Hop, dried cones at 0.03

ppm, Fruit, stone, group 12-12 at 0.01 ppm and Nut, tree, group 14-12 at 0.01

ppm. Additionally tolerances are proposed for the crops in the proposed Crop 

Subgroup 23A. Small fruit, edible peel subgroup 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; chiraulinut; 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 aspen; 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 indaziflam, N-[(1R,2S)-2,3-dihydro2,6-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, Grape at 0.01

ppm and Pistachio at 0.01) 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 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]-

6-(1-fluoroethyl)-1,3,5-triazine-2,4-diamine, 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 quantification (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-triazine-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 

target retreatment interval of 30 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 for 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 triazinediamine) 

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 rate of 0.065 lb ai/A/application (72.9 g ai/ha/application). In dried 

hop cones, the HAFT and maximum for total indaziflam residues (including its 

metabolites and degradates) at a PHI of 127 to 188 days were 0.02 ppm.

B. Toxicological Profile
1. 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 (both 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. Immunotoxicity 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 ppm 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 indaziflam, 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 food 

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 presence 

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. Neurotoxicity. 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 resolved 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 motor 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, respectively). These results 
establish 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), 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 

developmental neurotoxicity study. The neurotoxic effects of indaziflam in dogs, which 

were more sensitive than rats, are described further in subsequent sections describing 

subchronic 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 only 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 weight, 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 exposures 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 breathing, 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 female dogs in the 90-day oral gavage 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 or 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 system 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 changes 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 of 
treatment-related clinical signs in females decreased significantly after the top dose level 

was decreased from 10,000 to 6000 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 in 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-

14C]- or [triazine-2,4-14C]-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 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 

approximately 10:1 for the high dose experiments. No volatile residues were detected, 

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 indaziflam 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 rapid, 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 with indaziflam are adequate to 

assess any potential toxicity from these metabolites. Primary mutagenicity screening tests 

were negative for these indaziflam metabolites, and therefore these metabolites are not

genotoxic.

10. 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. 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 Disruptor 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 registered 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. population 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 with an uncertainty factor of 100.

i. Food. 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 including all registered crops and proposed crops. This 

conservative, unrefined assessment assumed recommended tolerance levels for all 

commodities, 100% Percent Crop Treated (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 exposure 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 calculated 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 maximum 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 risk 
assessment. 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 chronic 

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 water) 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. Residential 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 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 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 subpopulations 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, 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 postnatal 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 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 postnatal 

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 uses of indaziflam consumes 21% of the aPAD at the 95th 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 calculated 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 residues.

F. International Tolerances

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