EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Maggie Rudick 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 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, 

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

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-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 analytes as internal 

standards. The limit of quantification (LOQ) for each analyte was 0.005 ppm for all 

commodities.

 November 15, 2012

3. Magnitude 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 conducted 
evaluating 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. 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. 

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.

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 (BCSAA10717) 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 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 subpopulation. 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 

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 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 water to the risk assessment was minimal.

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 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 crops 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, 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 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 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.