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# 1F 7873) 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-[[(me thoxycarbonyl)[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-(trifl uoromethoxy)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-di hydro-2-hydroxy-1-[[[[4-(t riflurormethoxy)- 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]-hydr azono]-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) combinedwith 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 an alyte 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 classifiedas 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 obser vations 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 base d on the reduced mean pup weights noted for the F1 litters of the higher concentration groups. The effects on pup weights occurred only at amaternal 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 ba sed 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 a ddition, beginning on lactation day 11, offspring were directly administered the test substan ce 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 admi nistered dosages of 1.5, 1, or 0.5 mg/kg/day.

4. Subchronic toxicity. Subchronic (90 da y) 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 c onsumption, 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 nutritiona l 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 evaluati ons. In mice, the chronic NOAEL of 2.6 mg/kg/day for males was based on deceased body weight and we ight gain effects and food efficiency at 13.8 mg/kg/day and above. The NOAEL for female s 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 eliminationof 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 a nd 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 orga nisms 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, leaf y 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 theDietary Exposure Evaluation Model with Food Commodity Intake Database (DEEMFCID TM , 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 exposureto 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 exposur e 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-FCID TM , 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 adju sted 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

22ii. 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 99.9 th 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 re gistrations 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 con cern, 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 theaggregate 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.