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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: 10/23/11

SUBJECT: Indoxacarb. Petition for the Establishment of Permanent Tolerances on Poultry

Commodities and Submission of Storage Stability Data for Poultry Commodities

in Response to HED Memorandum DP# 297936, 9/22/04.

PC Code: 067710 DP Barcode: D391480

Decision No.: 448955 Registration No.: NA

Petition No.: 1F7873 Regulatory Action: Abbreviated Review

Risk Assessment Type: NA Case No.: NA

TXR No.: NA CAS No.: 173584-44-6

MRID No.: 48510401 40 CFR: §180.564

 

From: Seyed Tadayon, Chemist

Health Effects Division; 

Risk Assessment Branch V (7509P)

Through: William H. Donovan, Ph.D., Chemist

Health Effects Division; 

Risk Assessment Branch V (7509P)

To: John Hebert, RM 07

Registration Division (RD; 7505P)

Note: This DER was originally prepared under contract by Versar, Inc. (6850 Versar Center, Springfield, VA 22151; submitted 

10/12/11). The document has been reviewed by the Health Effects Division (HED) and revised to reflect current Office of

Pesticide Programs (OPP) policies.
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

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Executive Summary

Indoxacarb is an oxadiazine insecticide used for controlling the larval stages of lepidopteran 

pests on a variety of fruit, vegetable, and field crops. Several formulations contain DPX-MP062, 

which is an approximate 3:1 mixture of indoxacarb (DPX-KN128) and its stereoisomer INKN127 (inactive R-enantiomer). Permanent tolerances are established under 40 CFR 

§180.564(a) for the combined residues of indoxacarb and its R-enantiomer on a number of plant 

and livestock commodities. 

In response to deficiencies cited in DP# 297936 (9/22/04, S. Levy), E.I. du Pont de Nemours and 

Company has submitted a petition for the establishment of permanent tolerances for residues of 

indoxacarb, its R-enantiomer, and five metabolites in poultry commodities, as well as a storage 

stability study for poultry commodities.

Under DP #297936, HED reviewed a poultry feeding study and supporting storage stability data,

which had been submitted in response to DP#s 244253, 244460, 245424, and 248057 (1/19/00, 

S. Levy), as well as a revised version of the proposed enforcement method for poultry

commodities, DuPont Method AMR12739, Revision No. 1. The feeding study was deemed 

acceptable; however, the storage stability data were found to be inadequate because Day 0 

samples were not analyzed, and an insufficient number of time points were analyzed to establish 

that residues of indoxacarb and metabolites were stable throughout the duration of the study (13 

months), or to show how much of the residue was lost at various time points. The proposed 

enforcement method was forwarded to the Analytical Chemistry Branch (ACB) for a petition 

method validation (PMV; DP# 306822, 10/1/04, S. Levy).

HED concluded that the registration of indoxacarb for uses on Brassica vegetables, sweet corn, 

cotton, fruiting vegetables, lettuce, and pome fruits should remain conditional pending 

submission of an acceptable poultry storage stability study, a revised Section F, and a successful 

PMV of the tolerance enforcement method. Further, the recommended poultry tolerance levels 

would be re-evaluated when an acceptable storage stability study had been submitted.

Under PP#1F7873, DuPont has now requested the establishment of tolerances for combined 

residues of the insecticide 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-(trifluoromethoxy)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/on the following commodities: 

Egg ...........................................................................0.2 ppm
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

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Poultry, fat................................................................0.2 ppm

Poultry, meat ............................................................0.06 ppm

Poultry, meat byproducts .........................................0.06 ppm

These tolerances are the same as those recommended by HED under DP# 297936.

An acceptable poultry storage stability study has been submitted which indicates that combined 

residues of indoxacarb, its R-enantiomer, and metabolites IN-KB687, IN-KG433, IN-KT319, INJU873 and IN-JT333 are stable in poultry eggs for 503 days (16.5 months), liver for 507 days 

(16.7 months), fat for 506 days (16.6 months), and muscle for 504 days (16.6 months). These 

data are acceptable to support the storage conditions and durations of samples from the poultry

feeding study.

Samples from the storage stability study were analyzed for residues of indoxacarb, its Renantiomer, and metabolites using procedures based on the proposed enforcement method, 

DuPont-12739, Revision No. 1, a high performance liquid chromatography method with tandem 

mass spectrometry (LC/MS/MS). The method was acceptable for data collection based on 

adequate method validation and concurrent recovery data. Although Dupont method AMR 

12739, Revision No. 1, was forwarded to ACB for a PMV, it is unclear whether a PMV has been 

completed. HED has evaluated the method under the Standard Operating Procedure (SOP) for 

Reviewing Tolerance Enforcement Methods at the Analytical Chemistry Branch (9/15/08), and 

has determined that a tolerance method validation (TMV) is not necessary.

Regulatory Recommendations and Residue Chemistry Deficiencies

HED has examined the residue chemistry database for indoxacarb. There are no remaining 

residue chemistry issues that would preclude granting full registration for the requested uses of 

indoxacarb on Brassica vegetables, sweet corn, cotton, fruiting vegetables, lettuce, and pome 

fruits, or establishment of tolerances for combined residues of indoxacarb, its R-enantiomer, and 

metabolites IN-JT333, IN-KT319, IN-JU873, IN-KG433, and IN-KB687 in the following 

commodities:

Egg ................................................................................................. 0.20 ppm

Poultry, fat...................................................................................... 0.20 ppm

Poultry, meat .................................................................................. 0.06 ppm

Poultry, meat byproducts ............................................................... 0.06 ppm

Note to PM: According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. 

Knizner), the tolerance expression for indoxacarb on poultry commodities should be added 

under 180.564(a)(2) and state:

Tolerances are established for residues of indoxacarb, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only the sum 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)-
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

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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-(trifluoromethoxy)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], calculated as the stoichiometric equivalent of indoxacarb in the 

commodity.

Background

The chemical structure and nomenclature of indoxacarb residues of concern are presented in 

Table 1. The physicochemical properties of the technical grade of indoxacarb are presented in

Table 2.

Table 1.Indoxacarb Nomenclature.

Compound

O

N

N

O O

CH3

Cl N

O

O

O

O

CF3

CH3

Common name Indoxacarb

Company experimental name DPX-KN128

IUPAC name (S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-

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

carboxylate

CAS name methyl (4aS)-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-

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

carboxylate

CAS registry number 173584-44-6

End-use product (EP) Not applicable

Compound

O

N

N

O O

CH3

Cl N

O

O

O

CH3

O

CF3

Common name IN-KN127 (inactive R-enantiomer)
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

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Table 1.Indoxacarb Nomenclature.

IUPAC name (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

Compound

O

F

F

F

HN

O

CH3

O

Common Name IN-KB687

CAS name Methyl [4-(trifluoromethoxy)phenyl]-carbamate

CAS # 177905-10-1

Compound

Cl

N N

H

O

O

CH3

N

O

O

F

F

F

O

O

CH3

OH

Common Name IN-KG433

IUPAC name (Z)-Methyl 5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-

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

CAS # None

Compound

O

F

F

F

Cl

N

O

O

CH3

OH

HN N

O O

CH3

O

Common Name IN-KT319

IUPAC name (E)-methyl 5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-

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

CAS # None

Compound

Cl

N N

H

O

O

CH3

N

H

O

O

F

F

F

OH
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

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Table 1.Indoxacarb Nomenclature.

Common Name IN-JU873

IUPAC name Methyl 5-chloro-2,3-dihydro-2-hydroxy-1-[[[[4-(trifluoromethoxy)phenyl]amino]-

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

CAS # 144172-25-8

Compound

O

F

F

F

Cl

N N

O

O

O

CH3

N

H O

Common Name IN-JT333

IUPAC name Methyl 7-chloro-2,5-dihydro-2-[[[4-(trifluoromethoxy)-

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

CAS # 144171-39-1

Table 2. Physicochemical Properties of Indoxacarb1

Parameter Value Reference

Melting point/range 140-141 oC DP#s 244253, 244460, 

245424, 248057, S. Levy

and S. Chun, 1/19/2000

pH 5.32 at 25 oC

Density 1.34 at 20 oC

Water solubility 15.4 ± 2.3 ppb in pH 5 buffer

Solvent solubility 1.72 g/L in n-heptane; 14.5 g/L in 1-octanol; 

103 g/L in methanol; 117 g/L in o-xylene; 139 

g/L in acetonitrile; 160 g/L in ethyl acetate; and 

>250 g/kg in methylene chloride, acetone, and 

dimethyl-formamide

Vapor pressure 2.5 x 10-8Pa

Dissociation constant, pKa Does not dissociate at pHs of 2.42-11.36

Octanol/water partition coefficient, 

Log(KOW)

4.65 at pH 5

UV/visible absorption spectrum Molar absorptivities at 3 maxima were affected 

by pH, but not over wavelengths of 

environmental significance.

1

From DP# 297936, 9/22/04, S. Levy (and DERs).

860.1340 Residue Analytical Methods

Residue Chemistry Memo DP# 306822, 10/1/04, S. Levy

Residue Chemistry Memo DP# 297936, 9/22/04, S. Levy; PP #3F6576

Livestock Commodities

Enforcement method: HED previously concluded that LC/MS/MS method Dupont-12739, 

Revision No. 1 was suitable for the enforcement of poultry tolerances and forwarded the method 

to ACB for a PMV. It is unclear whether a PMV has been completed; however, evaluation of the 

method under the SOP for Reviewing Tolerance Enforcement Methods (9/15/08) indicates that a 

TMV of the method is not required. 
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

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Data collection: Samples from the poultry storage stability study were analyzed using 

procedures based on the proposed enforcement method. The method was acceptable for data 

collection based on adequate method validation and concurrent recovery data. 

Conclusions. The available data are adequate to fulfill residue analytical methods data 

requirements. The proposed enforcement method, Dupont-12739, Revision No. 1, is acceptable 

for determination of residues of indoxacarb, its R-enantiomer, and metabolites IN-JT333, INKT319, IN-JU873, IN-KG433, and IN-KB687 in poultry commodities. A TMV of the method is 

not needed. 

Samples from the submitted storage stability study were analyzed for residues of indoxacarb, its 

R-enantiomer, and metabolites using an acceptable data collection method.

860.1380 Storage Stability

DER Reference: 48510401.der 

Residue Chemistry Memo DP# 297936, 9/22/04, S. Levy; PP #3F6576

Samples from the available poultry feeding study (46114302.der3) were stored frozen for up to 

385 days (12.6 months) for eggs and 301 days (10 months) for tissues. The storage study

(46114302.der2) submitted in conjunction with the feeding study, was deemed inadequate by

HED because Day-0 samples were not analyzed, a determination of residue levels present at the 

time samples were placed in frozen storage could not be made, and an insufficient number of 

time points was analyzed to establish that residues of indoxacarb and metabolites were stable 

throughout the storage duration of the poultry feeding study (13 months) or to show how much of 

the residue was lost at various time points. 

DuPont has now submitted the results of a storage stability study on DPX-MP062 (a 3:1 mixture 

of indoxacarb (DPX-KN128) and its inactive stereoisomer IN-KN127) and five related 

metabolites, IN-KB687, IN-KG433, IN-KT319, IN-JU873 and IN-JT333, in poultry matrices 

(eggs, muscle, fat, and liver). Samples of untreated poultry eggs, muscle, fat, and liver were 

fortified with DPX-MP062 and its five metabolites, each at a level of 0.20 ppm. The fortified 

samples were stored frozen (-20 °C) and analyzed at target intervals of 0, 1, 3, 7, 11 and 16 

months. The study was performed at DuPont Crop Protection’s Stine-Haskell Research Center in 

Newark, DE. 

Samples of poultry matrices were analyzed for DPX-MP062 and metabolites by LC/MS/MS 

using procedures based on DuPont-12739, Revision No. 1. The analytical method quantifies 

DPX-KN128 and IN-KN127 as a single chromatographic peak. The method is acceptable for 

data collection based on adequate method validation and concurrent recovery data. The limit of 

quantitation (LOQ; determined as lowest level of method validation, LLMV) was 0.10 ppm for 

DPX-MP062 and metabolites in all tested poultry matrices. 

The results of the storage stability study indicate that residues of indoxacarb (DPX-MP062) and 

its five metabolites, IN-KB687, IN-KG433, IN-KT319, IN-JU873 and IN-JT333, are stable in 

poultry matrices (eggs, liver, fat and muscle) stored frozen (-20 °C) for 503-507 days (16.5-16.7 

months). 
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

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The storage intervals and conditions of samples from the poultry feeding study are presented in 

Table 3.

TABLE 3. Summary of Storage Conditions and Durations of Samples from the Poultry Feeding Study 

(MRID 46114302)

Matrix Storage Temp. (C) Actual Maximum Storage 

Duration (days)

Interval of Demonstrated Storage Stability1

Eggs ~-20 385 (12.6 months) 503 days (16.5 months)

Liver 301 (10 months) 507 days (16.7 months)

Fat 506 days (16.6 months)

Muscle 504 days (16.6 months)

Skin None

1

For residues of indoxacarb, its R-enantiomer, and metabolites IN-KB687, IN-KG433, IN-KT319, IN-JU873, and 

IN-JT333.

Conclusions. The submitted storage stability data are adequate to support the sample storage 

durations and conditions from the poultry feeding study. No additional data are required.

860.1550 Proposed Tolerances

Residue Chemistry Memo DP# 297936, S. Levy, 9/22/04; PP #3F6576

DuPont has proposed that tolerances for indoxacarb residues of concern in poultry commodities 

be expressed in terms of combined residues of indoxacarb, its R-enantiomer, and metabolites INKB687, IN-KG433, IN-KT319, IN-JU873 and IN-JT333. 

The proposed tolerance expression is appropriate; however, the tolerance should be stated as 

follows:

Tolerances are established for residues of indoxacarb, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only the sum 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-(trifluoromethoxy)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], calculated as the stoichiometric equivalents of indoxacarb in the 

commodity.
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

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An acceptable feeding study was previously submitted and reviewed. HED concluded that, 

pending submission of an acceptable storage stability study, the data would support tolerances of 

0.20 ppm for egg and poultry fat and 0.06 ppm for poultry meat and meat byproducts. With the 

submission of acceptable storage stability data, the recommended tolerance levels have been reevaluated and confirmed. No additional data are required.

A summary of the proposed and recommended tolerances for poultry commodities is presented in 

Table 4.

Table 4. Tolerance Summary for Indoxacarb.

Crop Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

(Corrected commodity definition)

Egg 0.20 0.20

Poultry, fat 0.20 0.20

Poultry, meat 0.06 0.06

Poultry, meat byproducts 0.06 0.06

References

DP#s: 244253, 244460, 245424, 248057

Subject: PP# 8F04948. New Chemical - Indoxacarb (DPX-MP062) in/on Brassica, Sweet 

Corn, Cotton, Fruiting Vegetables, Lettuce (Head and Leaf) and Pome Fruits. 

Evaluation of Residue Data and Analytical Methods. Chemical No. 067710. 

Case No. 289487. 

From: S. Levy and S. Chun

To: D. Peacock/A. Layne

Dated: 1/19/00

MRID: 44477101-44477112, 44477317, 44477318, 44477321-44477344, 44477401-

44477417, 44583301, 44815204, 44815801-44815803, 44815805-44815808, 

44491704

DP#: 297936

Subject: Indoxacarb. Review of Amendment Submitted in Response to HED’s 

Memorandum of 19-JAN-2000.

From: S. Levy

To: R. Kumar/D. Kenny

Dated: 9/22/04

MRID: 46114302
Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

Page 10 of 10

DP#: 306822

Subject: Indoxacarb in/on Brassica, Sweet Corn, Cotton, Fruiting Vegetables, Lettuce 

(head and leaf) and Pome Fruits. Request for Livestock Petition Method 

Validation (PMV). Chemical# 067710. Decision# 347540.

From: S. Levy

To: F. Siegelman

Dated: 10/1/04

MRIDs: 46308003 and 46308004