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

Bayer CropScience LP

PP#: 9F7589

EPA has received a pesticide petition (9F7589) from Bayer 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-

fluoroethyl)] and its fluoroethyl-indaziflam metabolite in or on raw agricultural 

commodities fruit, pome, group, fruit, 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 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-yl1,3,5-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 analytes as internal 

standards. The limit of quantification (LOQ) for each analyte 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 intervals of 14, 45 and 240 days after application. 

- Pome Fruit: A total of 18 field trials were conducted evaluating residues at target
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harvest intervals of 14, 45 and 210 target days after application.

- Stone Fruit: A total of 21 field trials were conducted evaluating residues at target 

harvest intervals of 14, 45 and 150/210 days after application.

- Tree Nuts: A total of 10 field trials were conducted evaluating residues at target

harvest intervals of 14 days after application.

- Grapes: A total of 12 field trials were conducted evaluating residues at target

harvest intervals of 14, 45 and 140-240 days after application.

- Olives: A total of 6 field trials were conducted evaluating residues at target

harvest intervals of 14, 45 and 300 days after application.

- Sugarcane: 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 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. Genotoxicty. 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 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 developmental 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 males 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 days 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). Lastly, 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. 
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However, 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, thyroid, and nervous 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. 

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, 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. dilated 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 6000 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 (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. 

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.
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7. Animal metabolism. A metabolism study for indaziflam, in which male rats 

were given single oral doses of [indane-3-

14C] AE 1170437 or [triazine-2,4-14C] 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 

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 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 unmetabolized 

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-

fluoroethyldiaminotriazine, 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 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 short- or long-term exposure.

Bayer 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.
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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 population subgroups to 

residues of indaziflam. The dietary (food only) 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 postapplication 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 600 for toddlers, and in excess of 1,000 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 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 crops and drinking water utilizes 1.9% of the aPAD and 2.4% of the 

cPAD for the most sensitive population of infants. 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.
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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 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 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 

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 1.9% of the aRfD/aPAD at the 99.9th 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 pathways 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 exposure to indaziflam residues.

F. International Tolerances

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