EPA Registration Division contact: Rosanna Louie-Juzwiak, 703-308-0037 

E. I. du Pont de Nemours and Company 

PP# 1F7873 

EPA has received a pesticide petition (PP# 1F7873) from E. I. du Pont de Nemours and 

Company, 1007 Market Street, Wilmington, DE 19898-0001, 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 180.564 by establishing a tolerance for residues of the combined residues of 

Indoxacarb, [(S)-methyl-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)-

phenyl]amino]carbonyl]indeno[1,2e] [1,3,4]oxadiazine-4a(3H)- carboxylate] , its R-enantiomer 

[(R)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy) phenyl] 

amino]carbonyl]indeno [1,2-e] [1,3,4] oxadiazine-4a(3H)- carboxylate] and the metabolites: 

• IN-JT333: Methyl 7-chloro-2,5-dihydro-2-[[[4-(trifluoromethoxy)phenyl]-

amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate 

• IN-KT319: (E)-methyl 5-chloro-2,3,-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-

(trifluoromethoxy)phenyl]amino]-carbonyl]hydrazono]-1H-indene-2-carboxylate 

• IN-JU873: methyl 5-chloro-2,3-dihydro-2-hydroxy-1-[[[[4-(triflurormethoxy)-

phenyl]amino]carbonyl]hydrazono]-1H-indene-2-carboxylate 

• IN-KG433: methyl 5-chloro-2,3,-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-

(trifluoromethoxy)phenyl]amino]carbonyl]-hydrazono]-1H-indene-2-carboxylate, and 

• IN-KB687: methyl [4-(trifluoromethoxy)phenyl]carbamate 

in or on the raw agricultural commodities egg at 0.2 ppm, poultry fat at 0.2 ppm, poultry meat at 

0.06 ppm and poultry meat byproducts at 0.06 ppm. EPA has determined that the petition 

contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; 

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 

The active ingredient in the end-use formulations, DuPont Avaunt® Insecticide and DuPontTM 

Steward® Insecticide, is a 75:25 mixture of two isomers, indoxacarb (DPX-KN128) and 

IN-KN127. Only one of the isomers, indoxacarb (DPX-KN128), has insecticidal activity. The 

active ingredient in the end-use formulation, DuPontTM Steward® EC Insecticide is indoxacarb; 

no IN-KN127 is present. Since the insecticidal efficacy is based on the concentration of 

indoxacarb (DPX-KN128), the application rates have been normalized on an indoxacarb 

(DPX-KN128) basis. The proposed tolerance expression includes both indoxacarb 

(DPX-KN128) and IN-KN127 and the residue method does not distinguish between the 

enantiomers, therefore residues are reported as the sum of indoxacarb (DPX-KN128) combined 
with IN-KN127. Residues of indoxacarb (DPX-KN128) combined with IN-KN127 will be 

referred to as "KN128/KN127." 

 

1. Plant metabolism. The metabolism of indoxacarb in plants is adequately 

understood to support these tolerances. Plant metabolism studies in cotton, lettuce, and tomatoes 

showed no significant metabolites. The only significant residue was parent compound. 

2. Analytical method. The plant residue enforcement method detects and 

quantitates indoxacarb in various matrices including sweet corn, lettuce, tomato, broccoli, apple, 

grape, cottonseed, tomato, peanut and soybean commodity samples by HPLC UV. The limit of 

quantitation in the method allows monitoring of crops with indoxacarb residues at or above the 

levels proposed in these tolerances. 

3. Magnitude of residues: Poultry Feeding study. Four groups of laying hens (10/ 

group) were dosed orally once a day for 28 consecutive days-with capsules containing 

indoxacarb at levels equivalent to target concentrations of 1.75, 7.0, 21.0, and 70.0 ppm in the 

feed on a dry weight basis. Residues of each analyte plateaued in whole eggs within 14-21 days 

of dosing. Residues in fat, skin, and liver were dose dependent, particularly for the top three 

dose levels. 

The maximum combined residues in fat were 0.11, 0.54, 1.5, and 5.0 ppm from 

the 1.75, 7, 21, and 70 ppm dose groups, respectively; and combined residues in fat averaged 

0.10, 0.44, 1.4, and 4.13 ppm from the respective dose groups. The maximum combined residues 

inskin were <0.07,0.17,0.60, and 1.20 ppm from the 1.75,7,21, and 70 ppm dose groups, 

respectively; and combined residues in skin averaged <0.07,0.12,0.51, and 1.06 ppm from the 

respective dose groups. In liver, the maximum combined residues were <0.06, <0.09, 6.21, and 

0.67 ppm from the 1.75,7,21, and 70 ppm dose groups, respectively; and combined residues in 

liver averaged 0.03, 0.08, 0.18, and 0.52 ppm from the respective dose groups In composited 

muscle, the maximum combined residues were <0.06 ppm from the 1.75 and 7 ppm dose groups, 

<0.07 ppm from the 21 ppm dose group, and 0.15 ppm from the 70 ppm dose group. Combined 

residues in muscle averaged 0.03, 0.03, 0.06, and 0.12 ppm from the 1.75, 7, 21, and 70 ppm 

dose groups, respectively. 

Following a 28-day recovery period for hens dosed at 70 ppm, residues of each analyte 

were non-detectable «0.003 ppm) in skin, liver, and muscle. Residues of each analyte were also 

<0.003 ppm in fat with the exception of IN-JT333, which had detectable residues (0.004-0.009 

ppm) below the method LOQ. following the cessation of dosing average combined residues in 

eggs declined from 0.65 ppm at 2 days post-dose to 0.07 ppm by 9 days post-dose. By 12 days 

postdose, residues of each analyte, except IN-JT333, were <0.003 ppm in eggs, and residues of 

IN-JT333 declined to <0.003 ppm by 23 days post-dose. 

B. Toxicological Profile 

1. Acute toxicity. Based on EPA criteria, indoxacarb is classified as follows for 

Toxicity Categories 

 {<P>} 1. {<E T=’03'>} Acute toxicity{</E>} . [Based on EPA criteria, indoxacarb is classified 
as follows for Toxicity Categories 

 

Guideline Title Results Category 

870.1100 

870.1200 

870.1300 

870.2400 

870.2500 

870.2600 

Acute Oral Toxicity 

Acute Dermal Toxicity 

 Acute Inhalation Toxicity 

Primary Eye Irritation 

Primary Dermal Irritation 

Skin Sensitization 

LD50:1730 mg/kg (M Rat) 

LD50: 268 mg/kg/(F Rat) 

LD50: >5000 mg/kg (Rat) 

LC50: >5.5 mg/L (M Rat) 

(70% MUP) 

Effects reversed within 72 hours 

(Rabbit) 

No irritation (Rabbit) 

Sensitizer (Guinea Pig) 

Category II 

Category IV 

Category IV 

Category III 

Category IV 

--------------- 

Formulated products are slightly less acutely toxic than indoxacarb. 

In an acute neurotoxicity study, indoxacarb exhibited decreased forelimb grip strength, 

decreased foot splay, and some evidence of slightly reduced motor activity, but only at the 

highest doses tested. The NOAEL was 100 mg/kg for males and 12.5 mg/kg for females based 

on body weight effects in females 50 mg/kg. 

2. Genotoxicty. Indoxacarb has shown no genotoxic activity in the following 

listed in vitro and in vivo tests: 

Ames Negative 

In vitro mammalian gene mutation (CHO/HGPRT) Negative 

In vitro unscheduled DNA synthesis Negative 

In vitro chromosomal aberration Negative 

In vivo mouse micronucleus-Negative 

3. Reproductive and developmental toxicity. The results of a series of studies 

indicated that there were no reproductive, developmental or teratogenic hazards associated with 

the use of indoxacarb. In a 2 generation rat reproduction study, the parental NOAEL was 1.5 

mg/kg/day. The parental NOAEL was based on observations of reduced weight gain and food 

consumption for the higher concentration groups of the F0 generation and potential treatment 

related changes in spleen weights for the higher groups of the F1 generation. There was no effect 

on mating or fertility. The NOAEL for fertility and reproduction was 6.4 mg/kg/day. The 

offspring NOAEL was 1.5 mg/kg/day, and was based on the reduced mean pup weights noted for 

the F1 litters of the higher concentration groups. The effects on pup weights occurred only at a 
maternal effect level and may have been due to altered growth and nutrition in the dams. In 

studies conducted to evaluate developmental toxicity potential, indoxacarb was neither 

teratogenic nor uniquely toxic to the conceptus (i.e., not considered a developmental toxin). 

Developmental studies conducted in rats and rabbits demonstrated that the rat was more 

susceptible than the rabbit to the maternal and fetal effects of DPX-MP062. Developmental 

toxicity was observed only in the presence of maternal toxicity. The NOAEL for maternal and 

fetal effects in rats was 2 mg/kg/day based on body weight effects and decreased food 

consumption at 4 mg/kg/day. The NOAEL for developmental effects in fetuses was >4 

mg/kg/day. In rabbits, the maternal and fetal NOAELS were 500 mg/kg/day based on body 

weight effects, decreased food consumption in dams and decreased weight and delayed 

ossification in fetuses at 1000 mg/kg/day. 

In a developmental neurotoxicity study, dams administered 3 mg/kg/day from 

gestation day 6 through lactation day 10 had decreased body weight, weight gain, and food 

consumption; increased incidences of clinical signs of toxicity; and test substance-related 

mortality. At maternally toxic doses of 3 mg/kg/day, there was also an increase in offspring 

effects including lower body weight. In addition, beginning on lactation day 11, offspring 

were directly administered the test substance daily by oral gavage through lactation day 21. 

There were no effects in offspring on learning and memory, sexual maturation, motor activity, 

acoustic startle habituation, terminal body weights, brain weights, selected hematology 

parameters, neuromorphometric parameters, or neurohistopathology. There were no biologically 

significant effects on dams or offspring administered dosages of 1.5, 1, or 0.5 mg/kg/day. 

4. Subchronic toxicity. Subchronic (90 day) feeding studies were conducted with 

rats, mice, and dogs. In a 90 day feeding study in rats, the NOAEL was 3.1 and 2.1 mg/kg/day 

for males and females, respectively. In male rats, the NOAEL was based on decreased body 

weight and nutritional parameters, mild hemolytic anemia and decreased total protein and 

globulin concentration. In female rats, the NOAEL was based on decreased body weight and 

food efficiency. 

In a subchronic neurotoxicity study in rats, there was no evidence of neurotoxicity 

at 11.9 and 6.09 mg/kg/day, the highest dose tested for males and females, respectively. The 

subchronic NOAEL in dogs (5.0 mg/kg/day, M/F) was based on hemolytic anemia. Erythrocyte 

values for most dogs were within a range that would be considered normal for dogs in a clinical 

setting. Mice were less sensitive to indoxacarb than the rats or dogs. NOAELs (23 mg/kg/day, 

males, 16 mg/kg/day, females) were based on mortality (males only); increased reticulocytes and 

Heinz bodies and decreased body weight, weight gain, food consumption, food efficiency; and 

increased clinical signs (leaning to one side and/or with abnormal gait or mobility) (females 

only). In a 28 day repeated dose dermal study, the NOAEL was 50 mg/kg/day based on 

decreased body weights, body weight gains, food consumption, and food efficiency in females, 

and changes in hematology parameters, the spleen and clinical signs of toxicity in both sexes in 

rats. 

5. Chronic toxicity. Chronic studies with indoxacarb were conducted on rats, 

mice, and dogs to determine oncogenic potential and/or chronic toxicity of the compound. 

Effects generally similar to those observed in the 90 day studies were seen in the chronic studies. 
Indoxacarb was not oncogenic in rats or mice. The chronic NOAEL in male rats was 5 

mg/kg/day based on body weight and nutritional effects. In females, the NOAEL of 2.1 

mg/kg/day was based on body weight and nutritional changes, as well as biologically significant 

hematologic changes at 3.6 mg/kg/day and above. Hemolytic effects were present only through 

the 6 month evaluation and only in females. The regenerative nature of indoxacarb induced 

hemolytic anemia was demonstrated by the absence of significant changes in indicators of 

circulating erythrocyte mass at later evaluations. In mice, the chronic NOAEL of 2.6 mg/kg/day 

for males was based on deceased body weight and weight gain effects and food efficiency at 13.8 

mg/kg/day and above. The NOAEL for females was 4.0 mg/kg/day based on body weight 

nutritional effects, neurotoxicity, and clinical signs at 20 mg/kg/day. In dogs, the chronic 

NOAEL was about 2.3 and 2.4 mg/kg/day in males and females, respectively based on hemolytic 

effects similar to those seen in the subchronic dog study. 

6. Animal metabolism. Livestock animal metabolism. Animal metabolism has 

been studied in the rat, hen, and cow and is well understood. In contrast to crops, indoxacarb is 

extensively metabolized in animals. 

Poultry. In poultry, hens were fed at 10 ppm/day for 5 days, 87 88% of the total 

administered dose was excreted; parent comprised 51 54% of the total dose in excreta. 

Concentrations of residues in eggs were low, 0.3 0.4 of the total dose, as were the concentrations 

of residues in muscle, 0.2% of the total dose. Parent and metabolite IN-JT333 were not detected 

in egg whites; only insecticidally inactive metabolites were identified. Parent and IN-JT333 were 

found in egg yolks; however, their concentrations were very low 0.01 0.02 ppm. Concentrations 

of parent and IN-JT333 in muscle were at or below the limit of quantitation, (LOQ) (0.01 ppm). 

Cattle. For the cow study, the cattle were fed at 10 ppm/day for 5 days; 

approximately 20% of the total administered dose was excreted in urine and 53 60% was 

excreted in feces in 5 days. Four tenths to 1.2% of the total dose in urine was parent indicating 

extensive metabolism; parent represented 46 68% of the fecal activity. Thus, most residues were 

not absorbed; those residues that were absorbed were extensively metabolized. Less than 1% of 

the total administered dose was in milk, most of which was parent compound. The insecticidally 

active metabolite IN-JT333 was not found in milk. Residues in muscle represented less than 

0.01% of the total administered dose most of which was parent. IN-JT333 was not detected in 

muscle. No other metabolites were seen above 10% of the dose, thus only parent and IN-JT333 

were monitored in the cattle feeding study. 

7. Metabolite toxicology. In rats, indoxacarb was readily absorbed at low dose (5 

mg/kg), but saturated at the high dose (150 mg/kg). Indoxacarb was metabolized extensively, 

based on very low excretion of parent compound in bile and extensive excretion of metabolized 

dose in the urine and feces. Some parent compound remained unabsorbed and was excreted in 

the feces. No parent compound was excreted in the urine. The retention and elimination of the 

metabolite IN-JT333 from fat appeared to be the overall rate determining process for elimination 
of radioactive residues from the body. Metabolites in urine were cleaved products (containing 

only one radiolabel), while the major metabolites in the feces retained both radiolabels. Major 

metabolic reactions included hydroxylation of the indanone ring, hydrolysis of the 

carboxylmethyl group from the amino nitrogen and the opening of the oxadiazine ring, which 

gave rise to cleaved products. Metabolites were identified by mass spectral analysis, NMR, UV 

and/or by comparison to standards chemically synthesized or produced by microsomal enzymes. 

8. Endocrine disruption. Lifespan, and multigenerational bioassays in mammals 

and acute and subchronic studies on aquatic organisms and wildlife did not reveal endocrine 

effects. Any endocrine related effects would have been detected in this definitive array of 

required tests. The probability of any such effect due to agricultural uses of indoxacarb is 

negligible. 

C. Aggregate Exposure 

Tolerances for indoxacarb are proposed on poultry items to support agricultural 

use on crops used for poultry feed commodities. 

1. Dietary exposure. The chronic RfD of 0.02 mg/kg bw/day is based on a NOAEL of 2.0 

mg/kg bw/day from the subchronic rat feeding study, the subchronic rat neurotoxicity 

study, and the chronic/carcinogenicity study, using an uncertainty factor of 100. The 

acute RfD for the general population is 0.12 mg/kg/day, based on the NOAEL of 12.5 

mg/kg in the acute neurotoxicity study and an uncertainty factor of 100. 

i. Food. Chronic dietary exposure assessment. Chronic dietary exposure resulting from 

the currently approved use of indoxacarb on apples, Crop group 5 (brassica vegetables), 

cotton, pears, peppers, sweet corn, tomatoes, eggplant, alfalfa, head and leaf lettuce, 

peanuts, potatoes, soybeans, grapes, leafy Brassica, leafy vegetables crop group 4, 

tuberous and corm vegetables crop subgroup 1C, pome fruits crop group 11 (except 

pear), okra, pea (Southern), mint, Cucurbits (Crop Group 9), Stone Fruit (Crop Group 

12), cranberries, and the uses on garden beets and bushberries (Crop SubGroup 13-B) is 

well within acceptable limits for all sectors of the population. The chronic module of the 

Dietary Exposure Evaluation Model with Food Commodity Intake Database (DEEMFCIDTM, version 2.00, Exponent, Inc.) was used to conduct the assessment with the 

chronic reference dose (cRfD) of 0.02mg/kg/ day. This model incorporates nationwide 

food consumption data as reported by respondents in the U.S. Department of Agriculture 

(USDA) 1994-1996, 1998 Continuing Surveys of Food Intake by Individuals (CSFII). 

The analysis used overall mean field trial values, processing factors and actual and 

projected five-year average percent crop treated values. Secondary residues in milk, meat 

and poultry products were also included in the analysis. The chronic dietary exposure to 

indoxacarb is 0.000294 mg/kg/day, and utilizes 2% of the cRfD for the overall U.S. 

population. The exposure of the most highly exposed subgroup in the population, 

children age 1-2 years, is 0.000751 mg/kg/day, which is 4% of the cRfD. The table 

below lists the results of this analysis, which indicate large margins of safety for each 

population subgroup and very low probability of effects resulting from chronic exposure 
to indoxacarb. 

Subgroup Maximum Dietary 

Exposure (mg/kg/day) 

% Chronic Reference 

Dose (cRfD) 

U.S Population 

All infants 

Children 1-2 

Children 3-5 

Children 6-12 

Youth 13-19 

Adults 20-49 

Adults 50+ 

0.000294 

0.000256 

0.000751 

0.000592 

0.000343 

0.000257 

0.000229 

0.000293 

2 

1 

4 

3 

2 

1 

1 

2 

Acute dietary exposure. Acute dietary exposure resulting from the currently approved use 

of indoxacarb on apples, Crop group 5 (brassica vegetables), cotton, pears, peppers, 

sweet corn, tomatoes, eggplant, alfalfa, head and leaf lettuce, peanuts, potatoes, 

soybeans, grapes, leafy Brassica, leafy vegetables crop group 4, tuberous and corm 

vegetables crop subgroup 1C, pome fruits crop group 11 (except pear), okra, pea 

(Southern), mint, Cucurbits (Crop Group 9), Stone Fruit (Crop Group 12), cranberries, 

garden beets, and bushberries (Crop SubGroup 13-B) is well within acceptable limits for 

all sectors of the population. The acute module of the Dietary Exposure Evaluation 

Model with Food Commodity Intake Database (DEEM-FCIDTM, version 2.15, Exponent, 

Inc.) was used to conduct the assessment with the acute reference dose (aRfD) of 

0.12mg/kg/ day. This model incorporates nationwide food consumption data as reported 

by respondents in the U.S. Department of Agriculture (USDA) 1994-1996, 1998 

Continuing Surveys of Food Intake by Individuals (CSFII). The Tier 3 analysis used 

distributions of field trial residue data adjusted for actual and projected peak percent crop 

treated. Secondary residues in milk, meat and poultry products were also included in the 

analysis. The results of this analysis are given in the table below. The percent of the 

acute reference dose (aRfD) for all population subgroups shows that an adequate margin 

of safety exists in each case. Thus, the acute dietary safety of indoxacarb for established 

and proposed uses clearly meets the FQPA standard of reasonable certainty of no harm. 

 99.9th Percentile Of Exposure 

Subgroup Exposure (mg/kg/day) % Acute reference dose

(aRfD) 

U.S. Population 

All infants 

Children 1-2 

Children 3-5 

Children 6-12 

Youth 13-19 

Adults 20-49 

Adults 50+ 

0.025644 

0.067568 

0.055866 

0.048160 

0.022815 

0.025837 

0.022442 

0.026808 

21 

56 

47 

40 

19 

22 

19 

22 
ii. Drinking water. Indoxacarb is highly unlikely to contaminate groundwater resources 

due to its immobility in soil, low water solubility, high soil sorption, and moderate soil 

half life. Based on the FIRST Tier 1 surface water and SCI GROW Tier 1 groundwater 

models under worst-case conditions the acute estimated environmental concentrations 

(EECs) of indoxacarb and its R enantiomer are 15.614 parts per billion (ppb) for surface 

water and 0.02 ppb for ground water. The chronic EECs are 1.655 ppb for surface water 

and 0.02 ppb for ground water. 

When the higher surface water concentrations were included in the acute and chronic 

dietary risk assessments, there was little change from the food-only dietary risk 

assessments. For the acute assessment which included drinking water as a point estimate 

the predicted exposure at the 99.9th percentile for the general U.S. population was 

0.025710 mg/kg/day which corresponds to 21% of the aRfD; the most sensitive 

subpopulation, infants, had an estimated exposure of 0.066107 mg/kg/day, 55% of the 

aRfD. For the chronic assessment which included drinking water the predicted exposure 

for the general population was 0.000330 mg/kg/day, 2% of the cRfD; the most sensitive 

subpopulation, children 1-2 years, had an estimated exposure of 0.000804 mg/kg/day, 4% 

of the cRfD. Thus, the acute and chronic dietary exposure of indoxacarb, including the 

contribution of drinking water, clearly meets the standard of reasonable certainty of no 

harm. 

 

2. Non-dietary exposure. Indoxacarb product registrations for residential non food uses 

have been approved. Non-occupational, non-dietary exposure for indoxacarb has been 

estimated to be low. 

D. Cumulative Effects 

EPA's consideration of a common mechanism of toxicity is not necessary at this time 

because there is no indication that toxic effects of indoxacarb would be cumulative with 

those of any other chemical compounds. Indoxacarb has a novel mode of action 

compared to currently registered active ingredients. 

E. Safety Determination 

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

conservative exposure assessments, there is a reasonable certainty that no harm will 

result from the aggregate exposure of residues of indoxacarb including all anticipated 

dietary exposure and all other non occupational exposures. 

2. Infants and children. Based on the completeness and reliability of the toxicity data, the 

lack of toxicological endpoints of special concern, the lack of any indication that children 

are more sensitive than adults to indoxacarb, and the conservative exposure assessment, 

there is a reasonable certainty that no harm will result to infants and children from the 
aggregate exposure of residues of indoxacarb, including all anticipated dietary exposure 

and all other non-occupational exposures. Accordingly, there is no need to apply an 

additional safety factor for infants and children. 

F. International Tolerances 

To date, numerous tolerances exist for indoxacarb residues in various food and 

feed crops and foods of animal origin in at least 25 countries.