EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [Kathryn Montague (703) 305-1243]

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert “NA-Remove” and 

maintain the outline. Please do not change the margins, font, or format in your 

pesticide petition. Simply replace the instructions that appear in green, i.e., “[insert 

company name],” with the information specific to your action.

TEMPLATE: 

[Bayer CropScience]

[Insert petition number]

 EPA has received a pesticide petition ([insert petition number]) from 

[BayerCropScience], [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. 537(a)

(Options (pick one)

 1. by establishing a tolerance for residues of 

[the herbicide isoxaflutole [5-cyclopropyl-4-(2-methylsulfonyl-4-

trifluoromethylbenzoyl) isoxazole] and its metabolite 1-(2-methylsulphonyl-4-

trifluoromethylphenyl)-2-cyano-3-cyclopropyl propane -1,3-dione (RPA 202248), 

calculated as the parent compound, in or on the raw agricultural commodity [soybean, 

at [0.05] and soybean, aspirated grain fractions at 0.25] 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 residue in plants and animals 

following exposure to isoxaflutole is understood. In plants, the first metabolic step is 

opening of the isoxazole ring of isoxaflutole to afford RPA 202248. This metabolite 

then undergoes hydrolysis to produce RPA 203328. In animals, metabolism of 

M-385623-Ü1-1
2

isoxaflutole proceeds in a similar pathway via opening of the isoxazole ring to RPA 

202248 and RPA 205834. These metabolites undergo further hydrolysis to produce 

RPA 207048 and RPA 203328. The residues of regulatory concern in plant and 

animal tissues are the parent compound, isoxaflutole, and its metabolite, RPA 

202248.] 

2. Analytical method. [Bayer CropScience has submitted a method description 

and validation for an LC-MS/MS (CAL study # 019-03) for use in corn and 

rotational crops. This method is the proposed enforcement method for all crops. A 

modification of this method, IS-004-P10-02 was developed and validated for use in 

the soybean field trials. In method IS-004P10-02, isoxaflutole and IFT-DKN are 

extracted from plant matrices by adding an acidic methanol/water solution to an 

aliquot of plant matrix followed by blending. An isotopic internal standard is added 

to the extract and the sample is capped and mixed. The sample is then diluted 1:1 

with 0.1% formic acid in water, placed in a vial and an aliquot analyzed by tandem 

mass spectrometry (LC/MS/MS). Quantification was based on the use of internal 

standards and comparison of peak areas with those of known standards. The 

detection by MS/MS was performed on a triple-quadrupole tandem mass 

spectrometer, equipped with a Turbo IonSpray (ESI) interface operated in positive 

ion mode and multiple reaction monitoring (MRM). A confirmatory transition is 

provided for use as necessary. The initial extraction for this method is similar to the 

previously submitted GC/MSD method which has been radio-validated. The radiovalidation data demonstrated that the method adequately recovers aged residues of 

isoxaflutole and its metabolites. Average concurrent recoveries for isoxaflutole and 

IFT-DKN were within 70% to 120% in soybean seed at 0.01 (LLMV) and 0.10 ppm. 

The limit of quantitation is 0.01 ppm for both compounds and the limit of detection 

is 0.0008 ppm for IFT and 0.0017 ppm for IFT-DKN. The method has been shown 

to be specific for the target analytes and includes confirmatory ion-transitions.] 

 3. Magnitude of residues. [The soybean varieties used as described in the 

following summary are tolerant to isoxaflutole. Field residue trials (20) were 

conducted to explore 3 different application patterns in soybeans. In each trial, 

Isoxaflutole 480 SC containing 4 lb ai/gal (480 g ai/L), was applied to soybean plots 

at 0.094 lb/A (105 g/ha) pre-emergent (either pre-plant, preplant incoroporated or 

post plant prior to emergence), at the V3 growth stage (3rd trifoliate unfolded) or at 

or before the R1 growth stage (beginning flowering). Soybean seeds were analyzed 

for isoxaflutole and IFT-DKN residues. Bayer CropScience proposes to off label 

harvesting soybean forage and hay and therefore, these matrices were not analyzed. 

In all treatments, parent isoxaflutole residues were <LOQ and often <LOD. Total 

isoxaflutole resdiues (parent + IFT-DKN) were <LOQ when isoxaflutole is applied 

preplant or pre-emergent. The maximum total isoxaflutole residues were slightly 

greater than 0.01 ppm when isoxaflutole was applied at the V3 growth stage. 

Residues increased when applied at the R1 growth stage (first bloom). 
3

In a processing study conducted at 5X the maximum rate (0.468 lb ai or 525 g ai/ha) 

isoxaflutole and its metabolite did not concentrate into hulls, oil or soymilk (<1X 

processing factor). Isoxaflutole and its metabolite concentrated slightly into soybean 

meal (1.21X processing factor), but this factor is less than the theoretical factor 

(2.2X) and the apparent required tolerance is less than the proposed tolerance for 

the RAC. Therefore, no separate tolerances are proposed for soybean processed 

fractions. In the same processing study conducted at 5X the maximum rate, 

isoxaflutole and its metabolite did concentrate into soybean aspirated grain 

fractions (7.26X). A separate tolerance for aspirated grain fractions is proposed at 

0.25 ppm]

B. Toxicological Profile 

 1. Acute toxicity. [The developmental LOAEL of 5 mg/kg/day from the 

developmental toxicity study in rabbits has been identified as the acute dietary 

endpoint to be used in risk assessments for the sub-population females (13-49 years 

old). Because of the use of a LOAEL, an uncertainty factor of 3X in addition to the 

conventional safety factor of 100X to account for inter- and intra-species variations 

was applied for risk assessment. Application of these uncertainty factors to the 

LOAEL of 5 mg/kg/day was used to derive the acute reference dose (aRfD) of 0.02 

mg/kg. EPA also identified the NOAEL of 125 mg/kg/day from the acute 

neurotoxicity study as the endpoint of concern to be used in acute dietary risk 

assessment for the general population including infants and children. EPA has 

applied a uncertqainty factor of 100 (10 for interspecies extrapolation and 10x for 

intraspecies variability) to the NOAEL of 125 mg/kg/day to derive an acute 

reference dose of 1.25 mg/kg for the general population.] 

 2. Short and Intermediate Term Toxicity. [The short and intermediate – term 

dermal and inhalation risks have been addressed by using a LOAEL of 5.0 

mg/kg/day, based on increased incidence of fetuses with the 27th pre-sacral 

vertebrae. A 3.5% dermal absorption factor was applied and a 100% inhalation 

absorption factor was assumed. A body weight of 60 kg was used since the endpoints 

selected were from the developmental toxicity studies with demonstrated fetal 

effects. The level of concern (LOC) for isoxaflutole occupational dermal and 

inhalation exposures is 300 (i.e., a margin of exposure <300 represents a risk of 

concern.] 

 3. Genotoxicty. [A Salmonella sp. reverse gene mutation assay, a mouse 

lymphoma forward gene mutation assay, an in vitro cytogenetic assasy in cultured 

human lymphocytes, and a mouse micronucleus assay conducted using isoxaflutole 

were negative and provided no evidence of mutagenicity.] 

 4. Reproductive and developmental toxicity. [In a developmental toxicity study, 

technical isoxaflutole was administered to female Sprague-Dawley rats by gavage at 

dose levels of 0, 10, 100 or 500 mg/kg/day between days 6 through 15 of gestation. 

The maternal LOAEL is 500 mg/kg/day based on increased incidence of clinical 
4

signs and decreased body weights, body weight gains and food consumption. The 

maternal NOEL is 100 mg/kg/day. The developmental LOAEL is 100 mg/kg/day 

based on decreased fetal body weights and increased incidences of skeletal 

anomalies. The developmental NOEL is 10 mg/kg/day. Isoxaflutole demonstrated no 

evidence of teratogenicity in this assay. In a developmental toxicity study, technical 

isoxaflutole was administered to female New Zealand white rabbits by gavage at 

dose levels of 0, 5, 20 or 100 mg/kg/day from days 6 through 19 of gestation. The 

maternal LOAEL is 100 mg/kg/day based on increased clinical signs and decreased 

body weight gains and food consumption. The maternal NOEL is 20 mg/kg/day. The 

developmental toxicity LOAEL is considered by EPA to be 5 mg/kg/day based on 

increased incidence of fetuses with 27th pre-sacral vertebrae, a very common 

variation in rabbits. Isoxaflutole demonstrated no evidence of teratogenicity. In a 2-

generation reproduction study, technical isoxaflutole was administered to rats at 

dose levels of 0, 0.5, 2, 20 or 500 mg/kg/day (actual levels in males: 0, 0.45, 1.76, 17.4 

or 414 mg/kg/day; females: 0, 0.46, 1.79, 17.7 or 437 mg/kg/day, respectively). The 

parental systemic LOAEL is 17.4 mg/kg/day for males and females based on 

increased liver weights and hypertrophy. The parental systemic NOEL is 1.76 

mg/kg/day for males and females. The reproductive LOAEL is greater than 437 

mg/kg/day based on the lack of reproductive effects. The reproductive NOEL is 

greater than or equal to 437 mg/kg/day. Overall, developmental toxicity was 

observed in rats and rabbits primarily as growth retardations, including delays in 

skeletal ossification, effects that have been observed with other HPPD inhibitors. 

There was no evidence of reproductive toxicity in the two-generation reproductive 

toxicity study in rats; however, both adults and offspring exhibited ocular and liver 

toxicities as seen in similar long-term studies. In the acute and subchronic 

neurotoxicity studies in rats, mild changes in FOB parameters (grip strength and/or 

landing foot splay) were observed in adult animals. However, similar effects were 

not observed in either pregnant animals or in offspring in the DNT study in rats. In 

both maternal animals and offspring, changes in body weight and/or food 

consumption were the primary effects seen in the DNT study and at the same dose 

(highest dose tested only). Decreased brain weights were observed in offspring on 

PND11 at the high dose only, but not at a later time point, which is an indicator of a 

developmental delay and/or a secondary effect of the decreased body weight also 

observed in the offspring. There were no effects on pup swimming ability, learning, 

memory, motor activity, or auditory startle response at any dose, nor was there any 

evidence of neuropathology in the study at any dose.] 

 4. Subchronic toxicity. [In a 21-day dermal toxicity study, technical 

isoxaflutole was administered to male and female rats at doses of 0, 10, 100 and 1000 

mg/kg/day (8-hour exposure/day, 7 days/week). No clinical signs or effects on body 

weight, food consumption, hematology, clinincal chemistry or opthalmology were 

observed. A slight but statistically significant increase in liver weight was noted for 

females (absolute and relative) and for males (relative only) at 1000 mg/kg/day. 

This finding was considered as an adaptive response to isoxaflutole treatment. 

Therefore, the no observed adverse effect level (NOAEL) for sub-acute dermal 

exposure to isoxaflutole is 1000 mg/kg/day or greater for males and females.] 
5

In a sub-chronic neurotoxicity study, technical isoxaflutole was administered to rats 

at dietary levels of 0, 25, 250 and 750 mg/kg/day for 90 days. Treatment related 

effects observed in high-dose males were decreases in body weight and body weight 

gain. The LOEL was established at 750 mg/kg/day. The NOEL was 250 mg/kg/day.] 

 5. Chronic toxicity. [A 2-year combined chronic feeding/carcinogenicity study 

in rats in which the NOAEL was 2 mg/kg/day and the LOAEL was 20 mg/kg/day 

based on hepatoxicity, thyroid, ocular effects in males and hepatoxicity in females. 

An uncertainty factor of 100 was used to account for inter- and intra-species 

variation. Application of this uncertainty factor to NOAEL resulted in the chronic 

reference dose (cRfD) of 0.02 mg/kg/day.]

 6. Animal metabolism. [In a metabolism study, 14C-isoxaflutole was 

administered to groups of male and female rats (five/sex/dose) at a single low oral 

dose (1 mg/kg), a repeated low oral dose (1 mg/kg as a final dose in a 15 day repeat 

dose series) and a single high dose (100 mg/kg). In addition, pharmacokinetics in 

blood was evaluated using 2 groups of 10 rats each that received a single low oral 

dose of 1 or 100 mg/kg of 14C-isoxaflutole. Urine and feces were collected at 24, 48, 

96, 120, 144 and 168 hours after dosing and tissues were collected at 168 hours postdosing. Isoxaflutole was rapidly and extensively absorbed and metabolized. RPA 

202248, a major metabolite, represented 70% or more of the radioactivity excreted 

in the urine and feces from the two lowest dose groups. A minor metabolite, RPA 

203328, was more polar. Elimination was rapid and dose dependent. The mean total 

recovery of the radiolabel was 99.2%. Urinary elimination was predominant in the 

two low dose groups while the major portion of radiolabel was excreted via the feces 

in the high dose group. The higher fecal elimination possibly resulted from the 

saturation of absorption resulting in elimination of unchanged parent compound. 

The majority of the radiolabel was eliminated in the first 24 and 48 hours for the 

low and high dose groups, with an estimated mean blood half-life of 60 hours. No 

sex differences were observed in the metabolism of 14C-isoxaflutole.] 

 7. Metabolite toxicology. [RPA 202248. In acute oral toxicity study, RPA 

202248 had an oral LD50 greater than 2000 mg/kg (category III) in the rat. In an 

Ames assay, RPA 202248 was found to be devoid of mutagenic activity in the 

presence and absence of metabolic activation. 

 8. Endocrine disruption. [No special studies have been conducted to investigate 

the potential of isoxaflutole to induce estrogenic or other endocrine effects. 

However, no evidence of estrogenic or other endocrine effects have been noted in 

any of the standard toxicology studies that have been conducted with this product 

and there is no reason to suspect that any such effects would be likely.] 
6

C. Aggregate Exposure

 1. Dietary exposure. [Tolerances are currently established under 40 CFR 

Section 180.537 for combined residues of the herbicide isoxaflutole and its 

metabolite RPA 202248 calculated as the parent compound, in or on field corn 

grain, forage (stover), and fodder. Associated tolerances are also established on the 

liver of cattle, goats, horses, poultry, and sheep. Bayer CropScience is requesting to 

revise the established tolerances for isoxaflutole by adding tolerances for soybean 

raw agricultural commodities. There are no residential uses proposed for 

isoxaflutole. Potential human risk scenarios, therefore, cover aggregate exposure 

from food residues and drinking water.]

 Food & Water. Acute, chronic and cancer dietary (food plus water) risk 

assessments were conducted for the U.S. using DEEM-FCIDTM, Version 2.14, which 

uses food consumption data from USDA’s Continuing Surveys of Food Intakes by 

Individuals (CSFII) from 1994-1996 and 1998. Tier 1 acute, chronic and cancer 

dietary exposure assessments were conducted using the following data and 

assumptions: 

 Maximum residue value from field trial data (0.0055ppm for corn 

grain and 0.04 ppm for soybeans) 

 No concentration in processed fractions 

 Drinking water values from FIRST: 7.29ppb acute and 2.54ppb for 

chronic 

 Secondary residues are not required 

The estimated acute dietary (food and water) exposure calculations to isoxaflutole 

residues and associated dietary risk expressed as a percentage of the acute 

population adjusted dose (%aPAD) results in a value of 0.03 % for the US 

population, 0.12% for infants, 0.06% for children 1-2 and children 3-5 years of age 

and 1.9 % for females ages 13 to 49. The estimated chronic dietary (food and water) 

exposure to isoxaflutole residues of concern and associated dietary risk expressed as 

a percentage of the chronic population adjusted dose (%cPAD) results in a value of 

0.4 % for the US population, 1.2% for infants, 0.69% for children 1-2 years of age, 

0.67% for children 3-5 and 0.35 % for females 13 to 49 years of age. 

The cancer risk estimate for the US population is 2.99 x 10-7 and 9.09 x 10-7 for 

food and food + water respectively. The Tier One risk assessment which used 

maximum residue values, 100% crop treated and conservative modeled drinking 

water concentrations, gave acceptable risk estimates for all populations examined 

for the acute and chronic scenarios. The cancer risk for the US Population was 

below 1 x 10 -6.] 

 2. Non-dietary exposure. [Isoxaflutole products are not labeled for residential 

uses (food or non-food), thereby eliminating the potential for residential exposure or 
7

non-occupational exposure.] 

D. Cumulative Effects [Section 408(b)(2)(D)(v) requires that, when considering 

whether to establish, modify, or revoke a tolerance, the Agency consider “available 

information” concerning the cumulative effects of a particular pesticide’s residues 

and “other substances that have a common mechanism of toxicity.” There are no 

available data to determine whether isoxaflutole has a common mechanism of 

toxicity with other substances or how to include this pesticide in a cumulative risk 

assessment. For the purposes of this petition filing, therefore, it has been assumed 

that isoxaflutole does not have a common mechanism of toxicity with other 

substances.]

E. Safety Determination

 1. U.S. population. [Based on the completeness and reliability of the toxicity 

data, it is concluded that dietary risk from the proposed uses of isoxaflutole are 

acceptable for all populations. Chronic exposure (non-cancer) for the US Population 

(food and water) utilizes <0.4% (0.00008 mg/kg bw/day) of the chronic PAD. The 

cancer risk estimate for the US population is 2.99 x 10-7 and 9.09 x 10-7 for food 

and food + water respectively, which is below 1 x 10 -6. Acute exposure for the US 

Population utilizes 0.03% of the acute PAD (0.000422 mg/bw/day). The most highly 

exposed population for the acute scenarios is the Female 13 to 49 years of age 

population subgroup which utilizes 1.9% (food and water) of the acute PAD 

(0.00038 mg/bw/day).] The most highly exposed population subgroups for the 

chronic scenario (food and water) are children 1-2 (0.69% of the chronic PAD, 

0.000137 mg/bw/day), children 3-5 (0.67% of the chronic PAD, 0.000133 

mg/bw/day), and infants at 1.2% (0.000239 mg/bw/day) of the chronic PAD. EPA 

generally has no concern for exposures below 100% of the PAD (acute or chronic), 

because the PAD represents the level at or below which exposure will not pose 

appreciable risk to human health. An estimated lifetime cancer risk below 1.0x10-6 

is considered acceptable for the US Population. Therefore there is a reasonable 

certainty that no harm will occur to the US Population from aggregate exposure 

(food and drinking water) to residues of isoxaflutole.]

2. Infants and children. [The most highly exposed population subgroups for the 

chronic scenario (food and water) are children 1-2 (0.69% of the chronic PAD, 

0.000137 mg/bw/day), children 3-5 (0.67% of the chronic PAD, 0.000133 

mg/bw/day), and infants at 1.2% (0.000239 mg/bw/day) of the chronic PAD. 

Children 1-6, Children 7-12 and non-nursing infants for the chronic analysis. Less 

than 3% of the chronic PAD was utilized by all three subgroups. Acute and chronic 

exposures for infants and children are far below 100% of the PAD (acute or 

chronic). Since the PAD represents a scientifically determined level at or below 

which exposure will not pose appreciable risk to human health there is a reasonable 

certainty that no harm will occur to these sub-populations from aggregate exposure 

(food and drinking water) to residues of isoxaflutole.] 
8

F. International Tolerances. [Maximum residue limits (MRLs) for isoxaflutole and 

metabolites in or on corn commodities have not been established by the Codex 

Alimentarius Commission. Maximum residue limits have been established in 

Canada for the combined residues of isoxaflutole and its metabolites at 0.1 ppm for 

soybean and at 0.2 ppm for corn, 0.01 ppm for eggs, 0.5 ppm for liver of cattle, 0.3 

ppm for liver of poultry, 0.1 ppm for meat byproducts of cattle, horses, hogs, 

poultry and sheep, 0.2 ppm for meat of cattle, horses, hogs, poultry and sheep and 

0.02 ppm for milk. PMRA Canada has a pending proposal to revise the existing 

MRLs (i.e., removing the IFT-benzoic acid metabolite from the tolerance 

expression) to 0.02 ppm in field corn grain. Maximum residue limits have also been 

established by Japan for cereal grains (including rice) at 0.05 ppm, corn (including 

pop corn and sweet corn) at 0.1 ppm, sugarcane at 0.01 ppm, legumes/pulses at 0.03 

ppm, livestock (cattle, pig and other terrestrial mammals) meat and fat at 0.2 ppm, 

liver at 0.4 ppm, milk at 0.03 ppm, edible offal at 0.08 ppm, poultry at 0.08 ppm and 

chicken and other poultry eggs at 0.02 ppm. MRLs are also established for 

isoxaflutole in Australia for maize at 0.1 ppm, sugarcane at 0.01 ppm and in Brazil 

for maize at 0.01 ppm, sugarcane at 0.08 ppm. MRLs also are establishd in Morocco 

and Montenagro for maize at 0.05 ppm. The revised/pending MRL for parent IFT 

and the DKN metabolite in the EU for corn grain will be 0.02 ppm.]