Page 1 of 10 **UNITED STA**

**TES ENVIRONMENTA L PROTECTION A**  **GENCY WA** **SHINGTON, D.C. 20460 OFFICE OF**  **CHEMICA L SA**  **FETY A ND**  **POLLUTION PREVENTION MEMORANDUM**  **Date :**  10/ 23 /11 **SUBJECT:** In doxacarb . Petition for the Est ablishment of Permanent Tolerances on Poultry

Commodities and Submission of Storage Stability Data for Poultry Commodities in Response to HED Memorandum D P# 297936, 9/22/04. **PC Code:** 067710 **DP Barcode:** D 391480 **Decision No.:** 448955 **Registration No. :**  NA **Petition No.:** 1F7873 **Regulatory Action:** Abbreviated Review **Risk Assessment Type:** NA **Case No.:** NA **T XR No.:**  NA **CAS No.:** 173584 - 44 - 6 **MRID No.:** 48510401 **40 CFR:** §180.564 From: Sey ed Tadayon, Chemist

Health Effects Di vision; 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 10/1 2 /11). The document has been reviewed by the Health Effects Division (HED) and revised to refle ct current Office of Pesticide Programs (OPP) policies.Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

Page 2 of 10 **Executive Summary** In doxacarb is an oxadiazine insecticide used for controlling the larval stages of lepidopteran pests on a variety

of fruit , vegetable, and field crops. Several formulations contai n DPX - MP062, which is an approximate 3:1 mixture of indoxacarb (DPX - KN128) and its stereoisomer I N 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 respon se to deficiencies cited in DP# 297936 (9/22/04, S. L evy ), 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. L evy ) , as well as a revised version of the proposed enforcement method for poultry commodities , DuPont Method AMR 12739, Revision No. 1 . The feeding study was deemed acceptable; however, the storage sta bility data were found to be inadequate because Day 0 samples were not analy

zed, and an insufficient number of time points were analy zed 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 Analy tical Chemistry

Branch ( ACB ) for a petition method validation ( PMV ; DP# 306822, 10/1/04, S. L evy ). HED concluded that the regis tration of indoxacarb for uses on B rassica 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 PM V 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 - [[(methox yc arbonyl)[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) - carb oxylate ] ; **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]carb onyl]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/o n the following commodities: Egg ................................ ................................ ........... 0.2 ppmIndoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

Page 3 of 10 Poultry , fat ................................ ................................ 0.2 ppm Poultry , meat ................................ ............................ 0. 06 ppm Poultry , meat by

products ................................ ......... 0. 06 ppm These tolerances are the same as those recommended by HED under DP# 297936. A n acceptable poultry storage stability study has been submitted which indicates that combined residues of indoxacarb , its R - enantiomer , and metabolites IN - KB687, I N - KG433, I

N - KT319, I

N JU873 and I

N - JT333 are stable in poultry eggs for 503 day s (16.5 months), liver for 507 day s (16.7 months), fat for 506 day s (16.6 mon ths) , and muscle for 504 day s (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 analy

zed 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 collec tion 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 Analy tical Chemistry

Branch (9/15/08), and has determined that a tolerance method validation ( TMV ) is not necessary . **Regulatory Recommendations and Residue Chem istry 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, I

N - KT319, I

N - JU873, I

N - KG433, and I

N - KB687 in the following commodities:

Egg ................................ ................................ ................................ . 0.20 ppm Poultry , fat ................................ ................................ ...................... 0.20 ppm Poultry , meat ................................ ................................ .................. 0.06 ppm Poultry , meat by

products ................................ ............................... 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 - ( trif luoromethoxy

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

Page 4 of 10 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] - 1 H - 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 i ndoxacarb residues of concern are presented in Table 1. The phy sicochemical properties of the technical grade of indoxacarb are presented in Table 2. **Table 1. Indoxacarb Nom**  **enclature.** Compound

O N N

O O C H 3 Cl N O O O

O C F 3 C H 3

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(3 H ) - 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 C H 3 Cl N O O O C H 3

O C F 3 Common name IN - KN127 (inactive R - enantiomer)Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

Page 5 of 10 **Table 1. Indoxacarb Nom**  **enclature.** 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 C om pound O F F F

N H O C H 3 O Common Name IN - KB687 CAS name Methyl [4 - (trifluoromethoxy)phenyl] - carbamate CAS # 177905 - 10 - 1 Compound Cl

N N H O O C

H 3

N O O F

F F

O O C H 3 O H

Common Name IN - KG433 IUPAC name ( Z ) - Methyl 5 - chloro - 2,3 - dihydro - 2 - hydroxy - 1 - [[[(methoxycarbonyl)[4 - trifluoromethoxy) phenyl]amino]carbo nyl]hydrazono] - 1 H - indene - 2 - carboxylate CAS # None Compound O F F F Cl

N

O O C H 3 O H N H N O O C H 3

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 Comp ound Cl

N N H O O C H 3

N H O O F F F O HIndoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

Page 6 of 10 **Table 1. Indoxacarb Nom**  **enclature.** 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 C H 3

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(3 H ) - carboxylate CAS # 144171 - 39 - 1 **Table 2. Physicochem**  **ical Properties of Indoxacarb 1**  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 ace tonitrile; 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, pK a Does not dissociate at pHs of 2.42 - 11.36 Octanol/water partition coefficient, Log(K OW ) 4 .65 at pH 5 UV/visible absorption spectrum Molar absorptivities at 3 maxima were affected by pH, but not over w avelengths of environmental significance. 1 From DP# 2 97936, 9/22/04, S. Levy (and DERs). **860. 1340 Residue Analytical Methods**  Residue Chem istry Memo DP# 306822, 10/1/04, S. Levy Residue Chemistry Memo DP# 297936, 9/22/04, S. Levy; PP #3F6576 Li vestock Commodities Enforcement method: HED previously concluded that LC /MS/MS m ethod Dupont - 12739, Revision No. 1 was suitable for the enforcement of poultry tolerances and forwarded the method to ACB for a PMV. I t is unclear whether a PMV has been completed ; however, e valuation of the method under the SOP for Reviewing Tolerance Enforcement Methods (9/15/08) indicates that a TMV of the method is no t required.Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

Page 7 of 10 Data collection: Samples from the poultry storage stability

study were analy

zed using procedure s based on the proposed enforcement method . The method was acceptable for data collection based on adequate method validation and concurrent rec overy data. Conclusions . The available data are adequate to fulfill residue analy tical methods data requirements. The proposed enforcement method, Dupont - 12739, Revision No. 1, is acceptable for determination of residues of indoxacarb, its R - enantiom er, and metabolites IN - JT333, I N KT319, IN - JU873, I

N - KG433, and I

N - KB687 in poultry

commodities. A TMV of the method is not needed. Samples from the submitted storage stability study were analy

zed for residues of indoxacarb, its R - enantiomer, and metab olites 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 froze n for up to 385 day s (12.6 months) for eggs and 301 day s (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 analy zed , a determination of r esidue levels present at the time samples were placed in frozen storage could not be made , and an insufficient number of time points was analy

zed to establish that residues of indoxacarb and metabolites were stable throughout the storage duration of the po ultry feeding study

(13 months) or to show how much of the residue was lost at various time points. Du Pont 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 I N - KN127) and five related metabolites, I

N - KB687, I

N - KG433, I

N - KT319, I

N - JU873 and I

N - 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 metabolite s, each at a level of 0.20 ppm . The fortified samples were stored frozen ( - 20 ° C) and analy zed at target intervals of 0, 1, 3, 7, 11 and 16 months. T he study

was performed at DuPont Crop Protection’s Stine - Haskell Research Center in Newark, DE. Sample s of poultry

matrices were analy

zed for DPX - MP062 and metabolites by L C/MS/MS using procedures based on DuPont - 12739, Revision No. 1. The analy tical method quantifies DPX - KN128 and I

N - KN127 as a single chromatographic peak. The method is acceptable for d ata collection based on adequate method validation and concurrent recovery data. The limit of quantitation (L OQ; determined as lowest level of method validation, L LM V) was 0.10 ppm for DPX - MP062 and metabolites in all tested poultry matrices. The resul ts of the storage stability study indicate that residues of indoxacarb (DPX - MP062) and its five metabolites, I

N - KB687, I

N - KG433, I

N - KT319, I

N - JU873 and I

N - JT333, are stable in poultry matrices (eggs, liver, fat and muscle) stored frozen ( - 20 °C) for 503 - 50 7 day s (16.5 - 16.7 months).Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

Page 8 of 10 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 Sam ples from**  **the Poultry Feeding Study**  **(MRID 46114302)** Matrix S torage Temp. (  C) Actual Maximum Storage Duration (days) Interval of Demonstrated Storage Stability 1 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 condi tions 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 commo dities be expressed in terms of combined residues of indoxacarb, its R - enantiomer, and metabolites I N KB687, I N - KG433, I

N - KT319, I

N - JU873 and I

N - 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]; **I N**  **- 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

Page 9 of 10 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 by

products. 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 t olerances for poultry commodities is presented in Table 4. **Table 4**  **. Tolerance Sum**  **ma ry 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 - In doxacarb (DPX - MP062) in/on Brassica, Sweet

Corn, Cotton, Fruiting Vegetables, L ettuce (Head and Leaf) and Pome Fruits. Evaluation of Residue Data and Analy tical Methods. Chemical No. 067710. Case No. 289487. From: S. L evy and S. Chun To: D. Peacock/A. Lay ne Dated: 1/19/00 MRI D: 44477101 - 44477112, 44477317, 44477318, 44477321 - 4447 7344, 44477401 -

44477417, 44583301, 44815204, 44815801 - 44815803, 44815805 - 44815808, 44491704 DP#: 297936 Subject: In doxacarb. Review of Amendment Submitted in Response to HED’s

Memorandum of 19 - JAN - 2000. From : S. L evy To : R. Kumar/D. Kenny Dated: 9/22/04 MRI D: 46114302Indoxacarb Summary of Analytical Chemistry and Residue Data DP#: 391480

Page 10 of 10 DP#: 306822 Subject: In doxacarb in/on Brassica, Sweet Corn, Cotton, Fruiting Vegetables, L ettuce

(head and leaf) and Pome Fruits. Request for Livestock Petition Method Validation (PMV). Chemical # 067710. Decision# 347540. From: S . L evy To: F. Siegelman Dated: 10/1/04 MRI D s : 46308003 and 46308004