Document ID: EPA-HQ-OPP-2011-0578-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-02-15T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

CHEMICAL SAFETY AND

 

POLLUTION PREVENTION

	

  SEQ CHAPTER \h \r 1 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)

	  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

		

Note: This DER was originally prepared under contract by Versar, Inc.
(6850 Versar Center, Springfield, VA 22151; submitted 10/12/11).    SEQ
CHAPTER \h \r 1 The document has been reviewed by the Health Effects
Division (HED) and revised to reflect current Office of Pesticide
Programs (OPP) policies.

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 IN-KN127
(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]a
mino]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]a
mino]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]ind
eno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate]; IN-KT319 [(E)-methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)phenyl]amino]-carbonyl]hydrazono]-1H-indene-2-carboxylate]; IN-JU873
[methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[[4-(trifluoromethoxy)phenyl]amino]ca
rbonyl]hydrazono]-1H-indene-2-carboxylate]; IN-KG433 [methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)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

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, IN-JU873 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 R-enantiomer, 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. 

  SEQ CHAPTER \h \r 1 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]-a
mino]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]a
mino]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]ind
eno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate]; IN-KT319 [(E)-methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)-phenyl]amino]carbonyl]hydrazono]-1H-indene-2-carboxylate]; IN-JU873
[methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[[4-(trifluoromethoxy)phenyl]amino]ca
rbonyl]-hydrazono]-1H-indene-2-carboxylate]; IN-KG433 [methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)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	

Common name	Indoxacarb

Company experimental name	DPX-KN128

IUPAC name	  SEQ CHAPTER \h \r 1 (S)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]am
ino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate

CAS name	  SEQ CHAPTER \h \r 1 methyl
(4aS)-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-

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

CAS registry number	173584-44-6

End-use product (EP)	Not applicable

Compound	

Common name	IN-KN127 (inactive R-enantiomer)

IUPAC name	(R)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)-phenyl]a
mino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate

Compound	

Common Name	IN-KB687

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

CAS #	177905-10-1

Compound	

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	

Common Name	IN-KT319

IUPAC name	(E)-methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)phenyl]amino]carbonyl]hydrazono]-IH-indene-2-carboxylate

CAS #	None

Compound	

Common Name	IN-JU873

IUPAC name	Methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[[4-(trifluoromethoxy)phenyl]amino]-c
arbonyl]hydrazono]-1H-indene-2-carboxylate

CAS #	144172-25-8

Compound	

Common Name	IN-JT333

IUPAC name	Methyl
7-chloro-2,5-dihydro-2-[[[4-(trifluoromethoxy)-phenyl]amino]carbonyl]ind
eno[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 10-8 Pa

	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.  

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,
IN-KT319, 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).  

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 IN-KB687, 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]-a
mino]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]a
mino]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]ind
eno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate]; IN-KT319 [(E)-methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)-phenyl]amino]carbonyl]hydrazono]-1H-indene-2-carboxylate]; IN-JU873
[methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[[4-(trifluoromethoxy)phenyl]amino]ca
rbonyl]-hydrazono]-1H-indene-2-carboxylate]; IN-KG433 [methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)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.

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 re-evaluated 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.    SEQ CHAPTER \h \r 1 

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.  SEQ CHAPTER \h \r 1 

From:	S. Levy

To:	R. Kumar/D. Kenny

Dated:	9/22/04

MRID:	46114302

  SEQ CHAPTER \h \r 1 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

Page   PAGE  1  of   NUMPAGES  10 

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