Document ID: EPA-HQ-OPP-2009-0636-0024
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-01-26T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF CHEMICAL SAFETY AND

                                                                        
                      POLLUTION PREVENTION

MEMORANDUM

	Date:	9 Sept 2010

	Subject:	Indaziflam.  Petition for the Establishment of Permanent
Tolerances and Registration for Use on Pome Fruits, Stone Fruits,
Citrus, Tree Nuts (including Pistachios), Grapes, and Olives (PP
9F7589); and a Tolerance without a Domestic Registration for Sugarcane
(PP 9E7588).  Summary of Analytical Chemistry and Residue Data.

PC Code:  080818	DP Barcode:  D374105, D376908

Decision No.: 416570	Registration No.:  432-RLNR

Petition No.:  9F7589, 9E7588	Regulatory Action:  Section 3

Assessment Type:  Single Chemical	Registration Case No.:  NA

TXR No.:  None	CAS No.:  730979-19-8

MRID No.:  See Below	40 CFR 180. New Active Ingredient

	FROM:	Elizabeth Holman, Chemist

		Michael A. Doherty, Ph.D., Senior Chemist

		William T. Drew, Chemist

		Risk Assessment Branch II 

		Health Effects Division (7509P)  SEQ CHAPTER \h \r 1 

	THROUGH:	Richard A. Loranger, Ph.D., Senior Scientist

		Risk Assessment Branch II

		Health Effects Division (7509P)

	TO:	Bethany Benbow/James Tompkins (RM25)

		Herbicide Branch

		Registration Division (7505P)  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r
1 



Summary of Submitted Residue Chemistry Studies

OPPTS 860 Series Guideline	MRID Number	Title

1300 – Nature of the Residue	47743272	Krolski, M. ; Nguyen, T. (2008)
The Metabolism of [Indane-3-14C] and [Triazine-2,4-14C] AE 1170437 in
Sugarcane. Project Number: M/302672/01/1, MEDHP005. Unpublished study
prepared by Bayer CropScience. 64 p.

	47743318	Nguyen, T.; Krolski, M. (2009) The Metabolism of
[Indane-3-(Carbon 14)] and [Triazine-2,4-(Carbon 14)] AE 1170437 in
Apples. Project Number: M/344398/01/1/OCR, MEDHP008, MEDHP010.
Unpublished study prepared by Bayer CropScience. 71 p.

	47743319	Krolski, M.; Nguyen, T. (2009) The Metabolism of
[Indane-3-(Carbon 14)] and [Triazine-2,4-(Carbon 14)] AE 1170437 in
Grapes. Project Number: M/344727/01/1/OCR, MEDHP007, MEDHP009.
Unpublished study prepared by Bayer CropScience. 70 p.

	47743320	Fisher, D. (2009) The Metabolism of [Triazine-2,4-(Carbon 14)]
AE 1170437 in the Lactating Goat. Project Number: M/347312/01/1/OCR,
MEDHP027. Unpublished study prepared by Bayer CropScience. 204 p.

	47743321	Fischer, D. (2009) The Metabolism of [Indane-3-(Carbon 14)] AE
1170437 in the Lactating Goat. Project Number: M/347315/01/1/OCR,
MEDHP028. Unpublished study prepared by Bayer CropScience and Southwest
Bio-Labs, Inc. 172 p.

	47743322	Mislankar, S. (2009) Waiver of the Requirement for a Poultry
Metabolism Study for Indaziflam.  Project Number: MEDHP077.  Unpublished
study prepared by Bayer CropScience. 6 p.

1340 – Analytical Methods	47743323	Timberlake, B. (2009) Validation of
Bayer CropScienceMethod DH-003-P07-01 and DH-003-P07-02 - An Analytical
Method for the Determination of Residues of AE1170437 in Fruit and Tree
Nut Matrices Using LC/MS/MS-Revised. Project Number: M/349201/01/1/OCR,
RADHP040. Unpublished study prepared by Bayer CropScience. 297 p.

	47743324	Dallstream, K. (2009) Radiovalidation of Bayer Method
DH-003-P07-01 - An Analytical Method for the Determination of Residues
of AE 1170437 in Crop Matricies Using LC/MS/MS. Project Number:
M/347745/01/1/OCR, RADHP047. Unpublished study prepared by Bayer
CropScience. 35 p.

	47743325	Merdian, H. (2009) Independent Laboratory Validation of Bayer
Method DH-003-P07-01 for the Determination of Residues of Indaziflam (AE
1170437) and its Metabolite 1-Fluoroethyl Triazinediamine in Plant
Materials, Using LC/MS/MS. Project Number: M/342267/01/2/OCR,
P612097523, P/B/1633/G. Unpublished study prepared by PTRL Europe Gmbh.
49 p.

	47743326	Simpson, R.; Bennett, R. (2009) Independent Laboratory
Validation of Method DH-003-P07-02 for the Determination of Residues of
AE1170437 and its Diaminotriazine Metabolites in Crop Matrices Using
LC/MS/MS-Revised: Final Report. Project Number: M/349152/01/1/OCR,
RADHP079, KP/2009/32. Unpublished study prepared by JRF America. 244 p.

1360 – Multiresidue Method	47743327	Rockwell, D. (2009) PAM I
Multiresidue Protocol Testing of AE 1170437 (Indaziflam) and its
Metabolite 1-Fluoroethyl Triazinediamine. Project Number:
M/346696/01/1/OCR, RADHP072, 2008. Unpublished study prepared by Pyxant
Labs, Inc. 107 p.

1380 – Storage Stability	47443279	Netzband, D. (2008) Stability of
AE1170437 and its Metabolites (AE1170437 Acid, AE1170437 ketone,
AE1170437 Hydroxy, AE1170437 Olefin, AE1170437 Diaminotriazine) in Soil
During Frozen Storage (Reported Through a Maximum of 433 Days Storage).
Project Number: M/302527/01/1, RADHP041. Unpublished study prepared by
Bayer CropScience. 56 p.

	47743328	Netzeband, D. (2009) Stability of AE1170437 and its
Metabolites (AE1170437 Acid, AE1170437 Ketone, AE1170437 Hydroxy,
AE1170437 Olefin, AE1170437 Diaminotriazine) in Soil During Frozen
Storage (Reported Through a Maximum of 736 Days Storage). Project
Number: M/302527/02/1/OCR, RADHP041/1. Unpublished study prepared by
Bayer CropScience. 56 p.

	47743329	Timberlake, B. (2009) Storage Stability of AE 1170437 and
1-Fluoroethyl Triazinediamine in / on Fruit and Nut Matrices. Project
Number: M/348221/01/1/OCR, RADHP039. Unpublished study prepared by Bayer
CropScience. 138 p.

1480 – Meat, Milk, Poultry, and Eggs	47743401	Mislankar, S. (2009)
Waiver of the Requirement for a Livestock Feeding Study for Indaziflam.
Project Number: MEDHP074, M/347958/01/1. Unpublished study prepared by
Bayer CropScience. 9 p.

1500 – Crop Field Trials	47743402	Desmarteau, D.; Fischer, D. (2009)
AE 1170437 500 SC - Magnitude of the Residue in/on Pome Fruit (CG 11).
Project Number: M/348053/01/1, RADHP029, M/348053/01/1/OCR. Unpublished
study prepared by Bayer CropScience. 199 p.

	47743403	Krolski, M.; Brungardt, J.; Stoughton, S. (2009) AE 1170437
500 SC - Magnitude of the Residue in/on Stone Fruit (CG 12). Project
Number: M/347950/01/1, RADHP030, M/347950/01/1/OCR. Unpublished study
prepared by Bayer CropScience. 246 p.

	47743404	Brungardt, J.; Krolski, M. (2009) AE 1170437 500 SC -
Magnitude of the Residue in/on Tree Nuts (CG 14). Project Number:
M/347601/01/1, RADHP028, M/344601/01/1/OCR. Unpublished study prepared
by Bayer CropScience. 197 p.

	47743405	Fischer, D.; Harbin, A. (2009) AE 1170437 500 SC - Magnitude
of the Residue in/on Citrus (CG 10). Project Number: M/348968/01/1,
RADHP027, M/348968/01/1/OCR. Unpublished study prepared by Bayer
CropScience. 273 p.

	47743406	Sturdivant, D.; Fischeer, D. (2009) AE 1170437 500 SC -
Magnitude of the Residue in/on Grapes. Project Number: M/348344/01/1,
RADHP033, M/348344/01/1/OCR. Unpublished study prepared by Bayer
CropScience. 143 p.

	47743407	Timberlake, B.; Fischer, D. (2009) AE 1170437 500 SC -
Magnitude of the Residue in/on Olives. Project Number: M/348345/01/1,
RADHP037, M/348345/01/1/OCR. Unpublished study prepared by Bayer
CropScience. 93 p.

	47743432	Mislankar, S. (2009) Proposed Tolerance (Maximum Residue
Levels) for Indaziflam in Grapes, Citrus, Pome Fruits, Stone Fruits,
Tree Nuts, and Olives. Project Number: RADHP078, M/348689/01/1.
Unpublished study prepared by Bayer CropScience. 24 p.

1520 – Processed Food and Feed	47743408	Lenz, C. (2009) AE 1170437 500
SC - Magnitude of the Residue in/on Sugarcane Processed Commodities.
Project Number: M/348217/01/1, RADHP018, M/348217/01/1/OCR. Unpublished
study prepared by Bayer CropScience and GLP Technologies. 89 p.

	47743409	Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue
in/on Apple Processed Commodities. Project Number: M/348056/01/1,
RADHP011, M/348056/01/1/OCR. Unpublished study prepared by Bayer
CropScience and University of Idaho. 81 p.

	47743410	Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude
of the Residue in/on Plum Processed Commodities. Project Number:
M/347951/01/1, RADHP012, M/347951/01/1/OCR. Unpublished study prepared
by Bayer CropScience and GLP Technologies. 80 p.

	47743411	Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude
of the Residue in/on Orange Processed Commodities. Project Number:
M/347960/01/1, RADHP013, M/347960/01/1/OCR. Unpublished study prepared
by University of Idaho and Bayer CropScience. 85 p.

	47743412	Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude
of the Residue in/on Grape Processed Commodities. Project Number:
M/348051/01/1, RADHP014, M/348051/01/1/OCR. Unpublished study prepared
by Bayer CropScience and University of Idaho, Cooperative Extension. 118
p.

	47743413	Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude
of the Residue in/on Olive Processed Commodities. Project Number:
M/348052/01/1, RADHP015, M/348052/01/1/OCR. Unpublished study prepared
by Bayer CropScience and GLP Technologies. 78 p.

1850 – Confined Accumulation in Rotational Crops	47743431	Mislankar,
S. (2009) Waiver of the Requirement for a Confined Rotational Crop Study
for Indaziflam (MRID 47743414). Project Number: MEDHP072, M/347957/01/1.
Unpublished study prepared by Bayer CropScience. 6 p.

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc260732602"  Executive
Summary	  PAGEREF _Toc260732602 \h  6  

  HYPERLINK \l "_Toc260732603"  Residue Chemistry Deficiencies	  PAGEREF
_Toc260732603 \h  7  

  HYPERLINK \l "_Toc260732604"  Background	  PAGEREF _Toc260732604 \h  8
 

  HYPERLINK \l "_Toc260732605"  860.1200  Directions for Use	  PAGEREF
_Toc260732605 \h  11  

  HYPERLINK \l "_Toc260732606"  860.1300 Nature of the Residue - Plants	
 PAGEREF _Toc260732606 \h  12  

  HYPERLINK \l "_Toc260732607"  860.1300 Nature of the Residue -
Livestock	  PAGEREF _Toc260732607 \h  18  

  HYPERLINK \l "_Toc260732608"  860.1340 Residue Analytical Methods	 
PAGEREF _Toc260732608 \h  25  

  HYPERLINK \l "_Toc260732609"  860.1360 Multiresidue Methods	  PAGEREF
_Toc260732609 \h  26  

  HYPERLINK \l "_Toc260732610"  860.1380 Storage Stability	  PAGEREF
_Toc260732610 \h  26  

  HYPERLINK \l "_Toc260732611"  860.1400 Water, Fish, and Irrigated
Crops	  PAGEREF _Toc260732611 \h  27  

  HYPERLINK \l "_Toc260732612"  860.1460 Food Handling	  PAGEREF
_Toc260732612 \h  27  

  HYPERLINK \l "_Toc260732613"  860.1480 Meat, Milk, Poultry, and Eggs	 
PAGEREF _Toc260732613 \h  27  

  HYPERLINK \l "_Toc260732614"  860.1500 Crop Field Trials	  PAGEREF
_Toc260732614 \h  28  

  HYPERLINK \l "_Toc260732615"  860.1520 Processed Food and Feed	 
PAGEREF _Toc260732615 \h  37  

  HYPERLINK \l "_Toc260732616"  860.1850 Confined Accumulation in
Rotational Crops	  PAGEREF _Toc260732616 \h  43  

  HYPERLINK \l "_Toc260732617"  860.1900 Field Accumulation in
Rotational Crops	  PAGEREF _Toc260732617 \h  43  

  HYPERLINK \l "_Toc260732618"  860.1550 Proposed Tolerances	  PAGEREF
_Toc260732618 \h  44  

 Executive Summary

Indaziflam {1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1S,1R)-fluoroethy
l)-} is a new alkylazine herbicide being developed by Bayer for
non-selective pre-emergent and early post-emergent control of annual
grass and dicot species in trees, nuts, vines, and turf.  This herbicide
is a cellulose biosynthesis inhibitor and is active at rates of 50 to
100 g ai/ha.  The technical-grade a.i. (TGAI) is made up of at least 95%
of the 1R-fluorethyl isomer and no more than 5% of the 1S-fluoroethyl
isomer.  Although the company name AE 1170437 refers specifically to the
1R-fluoroethyl isomer, it has been used interchangeably with the TGAI
during the data review process.  Both isomers have equal herbicidal
activity.  

Indaziflam 200 SC and Indaziflam 500 SC are suspension concentrate
formulations of indaziflam, containing 200 and 500 g active ingredient
(a.i.)/L (1.67 lb a.i./gallon and 4.16 lb a.i./gallon), respectively. 
The products are intended for ground-directed application for
preemergent weed control in orchards of pome fruits, stone fruits,
citrus, tree nuts (including pistachios), grapes, and olives.  Use rates
for both formulations are dependent, to some extent, on the soil type
within the use area.  Seasonal maximum application rates are 0.089 lb
a.i./A for grapes and 0.134 lb a.i./A for all other crops.  Indaziflam
is not to be applied through any type of irrigation system or by aerial
equipment.  The pre-harvest intervals (PHIs) on the proposed labels are
7 days for citrus crops and 14 days for other crops.

The residue chemistry database is relatively complete and there are no
residue chemistry issues that would preclude conditionally granting the
requested registrations and establishing permanent tolerances.  The
petitioner has submitted data depicting the nature of the residue in
apple, grape, sugarcane, and lactating goat.  The profile of residues in
crops is relatively uncomplicated, with indaziflam and fluoroethyl
diaminotriazine (a.k.a. FDAT, AE 1170437-diaminotriazine) being the only
identified compounds.  In the goat, the residue profile is far more
complex with numerous major species [> 10% total radioactive residue
(TRR)].  Residue levels (including those of major residues) in crop and
goat commodities are in the parts-per-billion (ppb) range, even at
exaggerated application/feeding rates.  The residue definition for
tolerance enforcement and risk assessment for crops is indaziflam +
FDAT.  An analytical method using solvent extraction and High
Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry
(HPLC-MS/MS) has been developed to assay the residues of concern for
tolerance enforcement and risk assessment.  Adequate crop field trials
and processing studies have been conducted to support tolerances in
plant commodities.  With the exception of almond hulls, total residues
(indaziflam + FDAT) were below the limit of quantitation (LOQ; < 0.01
ppm) in all raw agricultural commodities (RACs), even at exaggerated
rates.  Although adjuvants were not included in the field trials, a
label restriction prohibiting their addition to spray mixtures is not
required based on the nature of this use (i.e., application targeted to
soil with very little uptake of residues into harvested crop).  Residues
in all processed commodities except grape juice and raisins were not
measured due to the lack of quantifiable residues in the RACs at
exaggerated rates.  In grapes, total residues of indaziflam concentrated
upon processing by 1.5X in juice and 2.8X in raisins.  Total residues in
almond hulls ranged from <0.01 ppm to 0.153 ppm (mean = 0.05 ppm,
standard deviation = 0.06 ppm).  Using the North American Free Trade
Agreement (NAFTA)-harmonized tolerance/Maximum Residue Limit (MRL)
calculator with maximum likelihood estimation (MLE) resulted in a
recommended tolerance of 0.15 ppm for residues in almond hulls.  With
the exception of almond hulls, which may be fed to cattle, the proposed
uses do not involve any significant livestock feed items.  Based on
residue levels observed in the goat metabolism studies and the residues
in almond hulls, finite residues are not expected in ruminant meat, meat
byproduct, fat, or milk and tolerances are not required for these
commodities.  Rotational crop studies are not needed to support the
proposed uses since the target crops are not rotated.  The proposed
label currently specifies a plant-back restriction of 2 years due to
phytotoxicity concerns.

In support of the requested tolerance without a U.S. registration for
indaziflam on refined sugar, the petitioner has submitted studies
examining the nature of the residue in sugarcane and a sugar processing
study.  The samples from the processing study showed no quantifiable
residues of indaziflam or FDAT following a 2X application rate, and the
processed commodities of molasses and refined sugar were not analyzed. 
Typically, HED requires that no residues of concern be found in a RAC
following at least a 5X exaggerated application rate to make a finding
that tolerances are not necessary in the processed commodity.  Based on
information in the metabolism study, quantifiable residues of indaziflam
or FDAT would not be expected in sugarcane even at a 5X treatment rate;
therefore, HED does not believe that a processing factor is needed to
assess residues of indaziflam and FDAT in refined sugar.  A tolerance
should be set on the latter as an imported commodity at the level of the
method’s LOQ.  HED notes that a metabolism trial at a 10X exaggerated
treatment rate was initiated and subsequently terminated due to
treatment-related phytotoxicity.

Residue Chemistry Deficiencies

The residue chemistry data set is complete with the exception of a final
storage stability report and a final analysis report for the processed
commodity of citrus oil.  This assessment will be amended appropriately
once these final reports become available and have undergone HED review.
 Despite the deficiencies denoted below, 

1. Citrus oil tolerance - Although citrus RACs from submitted field
trials and a processing study have total residues below the LOQ at a 5X
exaggerated rate, data for the processed commodity of citrus oil is
required due to the extremely high potential concentration factor
(1000X).  Citrus oil was not analyzed during the originally submitted
processing study.  The petitioner has been made aware of this issue and
provided data from a preliminary analysis of citrus oil.  Although this
interim report suggests that indaziflam residues are concentrated
approximately 11.7X compared to those observed in citrus RACs, the total
residues in citrus oil are still less than LOQ (0.01 ppm).  Therefore,
HED does not believe that a tolerance for citrus oil is required, as no
finite residues would be expected even at exaggerated rates.  However,
the final study report from this citrus oil analysis should be required
as a condition of registration.   

2. 7-day PHI for citrus - The petitioner is requesting a 7-day PHI for
citrus whereas all citrus field trials were conducted at 14 days or
longer.  All 14-day PHI citrus field trials had total indaziflam
residues that were less than both the LOQ and the LOD.  With a total
indaziflam residue LOD of 0.0011 ppm, even if the 14 day PHI total
residue was equal to the LOD and the residue assumed to be ten times
more concentrated at a 7-day PHI, then the total residue should still
not exceed the LOQ and proposed tolerance of 0.01 ppm.  The field trial
design was intended to estimate the “worst case” scenario for
long-term exposure and translocation from root uptake of the
soil-applied herbicide, with the 14-day PHI used to simulate any
possible short-term uptake.  Finally, the field trial results suggest
that the highest total residues are observed in those with the longest
PHI’s, with the FDAT metabolite being the primary residue detected
above the LOD (but still less than the LOQ).  Therefore, HED believes
that the existing data support a 7-day PHI and no additional citrus
field trials are needed.        

     

3. Storage stability studies - The storage stability study submitted to
support the petition was conducted for a duration of approximately 12
months.  All residues were shown to be stable in frozen storage during
that time frame.  Samples from various studies were stored, frozen, for
up to approximately 17 months.  The petitioner has continued the storage
stability study to encompass 24 months of frozen storage, but the final
report has not been received yet.  Submittal of a valid study depicting
storage stability for 24 months should be a condition of registration.

4. Apple metabolism study (MRID 47743318) - HED notes a concern
regarding the apple metabolism study.  At issue is the unexplained loss
of radioactivity during extraction of the apple samples.  This loss
ranges from 18 to 45%.  The petitioner attributes the loss of
radioactivity to measurement variability due to low residue levels,
noting that the highest losses were observed in samples with the lowest
TRR’s (less than 0.01 ppm).  Given that the results of this study are
supported by similar metabolic profiles in the sugarcane and grape
studies, HED will accept the apple metabolism study as acceptable
despite the apparent loss of radioactivity.

5. Standards - Prior to registration, the petitioner should ensure that
analytical standards of

indaziflam and FDAT, as well as the stable-isotope-labeled internal
standards, have been sent to

the pesticide repository at the Analytical Chemistry Branch (ACB).  It
should be emphasized

with ACL that use of the proper stable-isotope-labeled internal
standards is critical to the method

accuracy.  

The reference standards should be sent to the Analytical Chemistry
Branch, which is located at

 Fort Meade, to the attention of either Theresa Cole or Thuy Nguyen at
the following address:

 US EPA

 National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

 701 Mapes Road

 Fort George G. Meade, MD  20755-5350

(Note: mail will be returned if the extended zip code is not used.)

Background

The petitioner, Bayer Crop Science, has developed a new herbicide,
indaziflam, for control of grass and broadleaf weeds in orchard crops
and non-food sites (e.g., turfgrass, ornamentals, etc.).  Indaziflam
inhibits cellulose biosynthesis in germinating seedlings and is
efficacious at relatively low use rates.  OPP has recently assessed and
recommended for the non-food uses of this herbicide (M. Collantes, et
al., D356142, 22 April 2010).  Nomenclature and the physicochemical
properties of indaziflam are summarized in Tables 1 and 2, below.

Table 1.  Nomenclature

Compound

AE 1170437

 

Common name	Indaziflam

Company experimental name	AE 1170437

IUPAC name
N-[(1R,2S)-2,6-Dimethyl-2,3-dihydro-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl
]-1,3,5-triazine-2,4-diamine

CAS name	1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl
]-

CAS #	730979-19-8

Compound

AE 1170438

 

Common name	Indaziflam

Company experimental name	AE 1170438

IUPAC name
N-[(1R,2S)-2,6-Dimethyl-2,3-dihydro-1H-inden-1-yl]-6-[(1S)-1-fluoroethyl
]-1,3,5-triazine-2,4-diamine

CAS name	1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1S)-1-fluoroethyl
]-

CAS #	730979-32-5

Compound

 1-Fluoroethyl diaminotriazine

 

Common name	Indaziflam-diaminotriazine

Company experimental name	AE 1170437-diaminotriazine

IUPAC name	6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine

CAS name	6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine

CAS #	Unavailable

Table 2.  Physicochemical Properties of the Technical Grade AE 1170437 

Parameter	Value	Reference

Molecular weight	301.37

	Melting point/range	183 -184 oC   AE 1170437 

                      pure substance	H. Mukhoty, 1 Dec 2008, D356393.

pH (23 °C)	pH = 6.5     AE 1170437 

                    pure substance

pH = 5.1     AE 1170437

                    technical substance

	Density (g/mL at 20 (C)

(relative density compared to water at  4 (C, D420)	1.23  AE 1170437 
pure substance

1.23  AE 1170437  technical substance

	Water solubility (at 20 °C)	pH 4: 4.4 mg/L, 

pH 9: 2.8 mg/L, 

Distilled water (pH 6.6-6.9): 2.8 mg/L

	Solvent solubility (g/L at 20 °C)

	Acetone:               Acetonitrile:

Dichloromethane: Dimethyl sulfoxide: Ethanol:                Ethyl
acetate: Heptane:                 Toluene: 	55  g/L

7.6  g/L

150  g/L

>250 g/L

13.0 g/L

47  g/L

0.032  g/L

4.3  g/L

	Vapor pressure 	2.5 x 10-8 PA at 20 °C

6.8 x 10-8 PA at 25 °C

6.9 x 10-6 PA at 50 °C

	Henry’s law constant 	2.69 x 10E-6 [Pa x m³/mol] at 20 °C

	Dissociation constant (pKa)	3.5 

	Octanol/water partition coefficient  Log (KOW)	pH 2: 2.0

pH4, pH7 and pH9: 2.8

	UV/visible absorption spectrum methanol (nm)	(max1 = 213 nm / A = 1.428

(max2 = 268 nm / A = 0.197

(max3 = 291 nm / A = 0.019

	

Due to the presence of three chiral carbons in the indaziflam structure,
there are eight possible isomers for this herbicide.  Based on the
product chemistry review of the manufacturing use product (MUP) by
Registration Division (H. Mukhoty, 12/1/2008, D356393), the registrant
is declaring the active ingredient to consist of only isomers “A”
(AE 1170437) and “B” (AE 1170438) with concentrations of about 92%
and 3%, respectively.  Two later RD reviews (S. Malak, 9/22/09, D367608
and 3/18/10, D372513) report additional statements of formula with
similar levels of isomer A (92-93%) and isomer B (2.4-2.9%).  As shown
in Table 1, the names for isomer A (N-[(1R,2S)...]-6-[(1R) ….diamine)
and isomer B (…-6-[(1S)…diamine) are identical with the exception of
the stereochemistry at the fluorine-bearing carbon.  The remaining six
isomers are present at significantly lower levels and are considered to
be impurities.  

860.1200  Directions for Use

Table 3.  Summary of Directions for Use of Indaziflam.  These directions
are identical for the Indaziflam 200 SC and 500 SC formulations.a

Applic. Timing, Type, and Equip.	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Pre-emergent application on annual grasses and weeds in Citrus Fruits,
Pome Fruits, Stone Fruits, Tree Nuts (Including Pistachio), Grapes

Airblast, broadcast or Band application to soil; ground equipment only
(no chemigation)	0.065 (coarse soil)

0.085 (fine soil)	2	0.134

(0.089 Grape)	7 (Citrus)b

14 (Others)	Avoid direct or indirect spray contact with crop foliage,
green bark, roots, or fruits.

Citrus trees must be established for at least 1 year prior to use.

Trees/vines other than citrus must be established for at least 3 years
prior to use.

Do not use on soils with > 40% gravel content.

Do not use on soils with open channels or cracks.

Allow at least 30 days between applications (90 days in FL and GA).

Grapes must be planted at least 12 inches deep.

Allow at least 12 months between the last application of indaziflam and
replanting with a labeled tree or vine crop.

Allow at least 24 months between the last indaziflam application and
replanting with non-labeled crop.

Sugarcane (Non-Domestic Use)

Broadcast spray, pre- or post-crop emergence, pre-emergence for weeds;
ground or aerial equipment	0.107 lb a.i./A

(120 g a.i./ha)	1	0.107 lb a.i./A

(120 g a.i./ha)	90	None that are relevant

a Indaziflam 200 SC Herbicide (Soluble Concentrate) 19.05% ai

  Indaziflam 500 SC Herbicide (Soluble Concentrate) 45.05% ai 

b Note that Citrus field trials conducted at 14 day PHI or longer.  See
Section 860.1500 (Crop Field Trials) for further discussion. 

Conclusions.  The proposed labels are adequate to evaluate the residue
data relative to the proposed uses.  

860.1300 Nature of the Residue - Plants

47743318.der.doc – Apple metabolism

47743319.der.doc – Grape metabolism

47443272.der.doc – Sugarcane metabolism

Apple.  The metabolism of indaziflam (1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl
]-; CAS Number 730979-19-8) was studied in apples following two
applications of either [indane-3-14C] indaziflam or [triazine-2,4-14C]
indaziflam to the soil at the base of the apple trees.  Two target
application rates were used in each study, corresponding to
approximately 2X and 10X the anticipated annual maximum use rate of 150g
ai/ha.  The total target was split between a spray at flowering
comprising 67% (200 g ai/ha and 1000 g ai/ha) of the total applied
material and a second spray at a 30-day pre-harvest interval (PHI)
comprising 33% of the total applied material (100 g ai/ha and
500 g ai/ha).  

At maturity, apple fruit was harvested and radioassayed to determine the
total radioactive residues (TRRs).  TRR values in apple fruit from trees
treated with [indane-3-14C] indaziflam at approximately 2X and 10X the
maximum seasonal use rate of 150 g ai/ha were 0.004 ppm and 0.011 ppm,
respectively.  TRR values in apple fruit from trees treated with
[triazine-2,4-14C] indaziflam at approximately 2X and 10X the maximum
seasonal use rate of 150 g ai/ha were 0.011 ppm and 0.054 ppm,
respectively.  When corrected for the exaggerated application rates, all
anticipated TRR values at a 1X rate were <0.01 ppm.

Apples from the 2X and 10X [indane-3-14C] indaziflam experiments had
extractable residues of 43% and 62%, respectively.  While there were
several polar compounds formed, the only identified residue in the
[indane-3-14C] indaziflam study was unmetabolized parent accounting for
13% of the TRR (<0.001 ppm) in the 2X experiment and 8% of the TRR
(<0.001 ppm) in the 10X experiment. 

Apples from the 2X and 10X [triazine-2,4-14C] indaziflam experiments had
extractable residues of 79% and 80%, respectively.  The major residue
detected, and the only metabolite identified,  in the [triazine-2,4-14C]
indaziflam study was fluoroethyldiaminotriazine,  accounting for 72% of
the TRR (0.008 ppm) in the 2X experiment and 62% of the TRR (0.033 ppm)
in the 10X experiment.   

Grape.  The metabolism of AE 1170437 or indaziflam
(1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl
]; CAS Number 730979-19-8) was studied in grapes following two
applications of either [indane-3-14C] indaziflam or [triazine-2,4-14C]
indaziflam to the soil at the base of the grape vines.  Two target
application rates were used in each study, corresponding to 2X and 10X
the anticipated annual maximum use rate of 150 grams of active
ingredient per hectare (g ai/ha).  The total target application was
split between a spray at flowering, comprising 67% (200 g ai/ha and 1000
g ai/ha) of the total applied material, and a second spray at a 30-day
pre-harvest interval (PHI), comprising 33% of the total applied material
(100 g ai/ha and 500 g ai/ha).  The pots containing the grape vines
(eight total) were maintained in an outdoor area (patio outside of the
greenhouse) during the course of the study and were only moved into the
greenhouse for spray treatment.

Grapes were harvested and radioassayed to determine the total
radioactive residues (TRR).  Grapes were harvested at full maturity from
plants in the 2X dose groups.  However, phytotoxicity forced harvest of
immature grapes from plants in the 10X dose groups prior to the second
treatment, resulting in the plants receiving a 7X overdose with harvest
59 days ([indane-3-14C] indaziflam) or 45 days ([triazine-2,4-14C]
indaziflam) after treatment.  TRR values in fruit from plants treated
with [indane-3-14C] indaziflam at 2X and 7X the maximum seasonal use
rate of 150 g ai/ha were 0.006 ppm and 0.019 ppm, respectively.  TRR
values in grapes from plants treated with [triazine-2,4-14C] indaziflam
at 2X and 7X the maximum seasonal use rate of 150 g ai/ha were 0.015 ppm
and 0.040 ppm, respectively.  

The petitioner has not provided any specific dates for extraction and
analysis.  Petitioner materials indicate that samples were analyzed no
more than 150 days after harvest.  

Grapes from the 2X and 7X [indane-3-14C] indaziflam experiments had
extractable residues of 71% and 66%, respectively.  While there were
several polar compounds formed, the only identified residue in the
[indane-3-14C] indaziflam study was unmetabolized parent, accounting for
19% of the TRR (0.001 ppm) in the 2X experiment and 24% of the TRR
(0.005 ppm) in the 7X experiment. 

Grapes from the 2X and 7X [triazine-2,4-14C] indaziflam experiments had
extractable residues of 81% and 96%, respectively.  The major residue
detected, and the only metabolite identified, in the [triazine-2,4-14C]
indaziflam study was fluoroethyldiaminotriazine (FDAT),  accounting for
43% of the TRR (0.006 ppm) in the 2X experiment and 47% of the TRR
(0.019 ppm) in the 7X experiment.  

 

The majority of radioactivity was accounted for, with overall
accountability (based on theoretical radioactivity) ranging from 85 to
99%.  

Sugarcane.  The metabolism of indaziflam (1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl
]; CAS Number 730979-19-8) was studied in sugarcane following two
applications of either [indane-3-14C] indaziflam or [triazine-2,4-14C]
indaziflam.  Two application rates were used in each study,
corresponding to 2X and 10X the anticipated annual maximum use rate of
150 grams of active ingredient per hectare (g ai/ha).  In the 2X
experiments, the total application was split between a spray to both the
plant and the surrounding soil when the plants were 10- to 12-inches
tall, comprising 67% (200 g ai/ha) of the total applied material, and a
second spray made to the base of the stalk and soil at the base of the
mature sugarcane at a 30-day pre-harvest interval (PHI), comprising 33%
of the total applied material (100 g ai/ha).  Plants in the 10X
experiments received a single treatment to both the plant and the
surrounding soil when the plants were 10- to 12-inches tall comprising
67% (1000 g ai/ha) of the total target rate.  All experiments were
carried out in a greenhouse environment.  

Due to extreme phytotoxicity following the initial treatments to plants
at the 10X rate, those experiments were terminated without sample
collection. 

At maturity, sugarcane from the 2X experiments was harvested and
radioassayed to determine the total radioactive residues (TRR).  TRR
values in sugarcane from plants treated with [indane-3-14C] indaziflam
and [triazine-2,4-14C] indaziflam at 2X the maximum seasonal use rate of
150 g ai/ha were 0.004 ppm and 0.005 ppm, respectively.    

Sugarcane from the 2X [indane-3-14C] indaziflam experiment had
extractable residues of 65%.  While there were several polar compounds
formed, the only identified residue in the [indane-3-14C] indaziflam
study was unmetabolized parent accounting for 24% of the TRR (<0.001
ppm). 

Sugarcane from the 2X [triazine-2,4-14C] indaziflam experiment had
extractable residues of 68%.  The major residue detected, and the only
metabolite identified, in the [triazine-2,4-14C] indaziflam study was
fluoroethyldiaminotriazine (FDAT), accounting for 30% of the TRR   
(0.002 ppm).  Additionally, 17% of the TRR (<0.001 ppm) was tentatively
identified as parent indaziflam in sugarcane from the 2X
[triazine-2,4-14C] indaziflam experiment.

The majority of radioactivity was accounted for, with overall
accountability (based on theoretical radioactivity) of 91-100%.  

Conclusions.  In plants, the metabolism of indaziflam is relatively
uncomplicated.  The only identified terminal residues in any of the
plant studies were parent indaziflam and the FDAT metabolite (Tables 4a,
4b, 4c, Figure 1).  The metabolism data are sufficient to support the
requested uses; however, if uses in other crops are sought in the
future, additional studies depicting the nature of the residue may be
necessary (e.g., root/tuber vegetables, small grain).  The residue
definitions based on the available data are summarized in Table 6.  HED
does note a concern regarding the apple metabolism study.  At issue is
the unexplained loss of radioactivity during extraction of the apple
samples.  This loss ranges from 18 to 45%.  The petitioner attributes
the loss of radioactivity to measurement variability due to low residue
levels, noting that the highest losses were observed in samples with the
lowest TRR’s (less than 0.01 ppm).   Given that the results of this
study are supported by similar metabolic profiles in the sugarcane and
grape studies, HED will accept the apple metabolism study as acceptable
despite the apparent loss of radioactivity.



Table 4a.  Summary of Characterization and Identification of
Radioactive Residues in Apples Following Application of [Indane-3-14C]
or [Triazine-2,4-14C] Indaziflam Harvested 30 Days Following the Last of
Two Soil Applications at the Base of the Tree 

Compound	[Indane-3-14C] Indaziflam Treated Apples	[Triazine-2,4-14C]
Indaziflam Treated Apples

	2.2x (0.29 lb ai/A)	12.8x (1.7 lb ai/A)	2.3x (0.31 lb ai/A)	  10.5x
(1.4 lb ai/A)

	TRR = 0.004 ppm 	TRR = 0.011 ppm	TRR = 0.011 ppm	TRR = 0.054 ppm

	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm

Indaziflam	13	<0.001	8	<0.001	--	--	--	--

Fluoroethyl Diaminotriazine	--	--	--

72	0.008	62	0.033

ROI 1 (Polar)	46	0.002	76	0.008	--	--	--	--

ROI 2 (Moderately polar)	15	<0.001	--	--	--	--	--	--

ROI 3 (Polar)	--	--	--	--	25	0.003	32	0.017

Diffuse	--	--	--	--	--	--	3	0.002

Total identified	13	<0.001	8	<0.001	72	0.008	62	0.033

Total characterized	61	<0.003	76	0.008	25	0.003	35	0.019

Total uncharacterized1	4	--	1	--	0	--	0	--

Total extractable	78	0.003	85	0.009	97	0.011	97	0.052

Unextractable (PES)2	22	0.001	15	0.002	3	<0.001	3	0.002

Accountability3	~100	~100	~100	~100

1 Total uncharacterized = Total extractable – Total characterized –
Total Identified.  The Total Extractable information comes from the
reported values in the registrant study profile template.  

2Residues remaining after exhaustive extractions.

3Accountability = Total extractable + Total unextractable. 
Accountabilities were ~100% because results were normalized.



Table 4b.  Summary of Characterization and Identification of Radioactive
Residues in Grapes Treated with [Indane-3-14C] or [Triazine-2,4-14C]
Indaziflam (Spray Application to Soil at the Base of the Vine)

Compound	[Indane-3-14C] Indaziflam Treated Grapes1	[Triazine-2,4-14C]
Indaziflam Treated Grapes1

	1.8x (0.24 lb ai/A)	7.4x (0.98 lb ai/A)	2.0x (0.27 lb ai/A)	  7.2x
(0.96 lb ai/A)

	TRR = 0.006 ppm 	TRR = 0.019 ppm	TRR = 0.015 ppm	TRR = 0.040 ppm

	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm

Indaziflam	19	0.001	24	0.005	--	--	--	--

Fluoroethyl Diaminotriazine	--	--	--	--	43	0.006	47	0.019

ROI 1 (Polar)	22	0.001	5	0.001	--	--	--	--

ROI 2 (Moderately polar)	27	0.002	23	0.004	--	--	--	--

ROI 3 (Moderately polar)	--	--	--	--	9	0.001	47	0.019

ROI 4 (Non-polar)	--	--	10	0.002	28	0.004

Total identified	19	0.001	24	0.005	43	0.006	47	0.019

Total characterized	49	0.003	38	0.007	37	0.005	47	0.019

Total uncharacterized2	3	--	4	--	1	--	2	--

Total extractable	71	0.004	66	0.013	81	0.012	96	0.038

Unextractable (PES)3	29	0.002	34	0.006	19	0.003	4	0.002

Accountability4	~100	~100	~100	~100

1 In the 2x studies, there were 2 applications – the first at
flowering (67% of total application), the second at a 30 day PHI (33% of
total).  In the 10x studies, there was a single application at
flowering.  

2Total uncharacterized = Total extractable – Total characterized –
Total Identified.  The Total Extractable information comes from the
reported values in the registrant study profile template.  

3Residues remaining after exhaustive extractions.

4Accountability = Total extractable + Total unextractable. 
Accountabilities were ~100% because results were normalized.



Table 4c.  Summary of Characterization and Identification of Radioactive
Residues Sugarcane Following Application of [Indane-3-14C] or
[Triazine-2,4-14C] Indaziflam Harvested 30 Days After the Last of Two
Soil and Base of Stalk Applications at a total rate of 0.29 lb a.i./A
(2.2 times the Proposed maximum seasonal field application rate)1

Compound	[Indane-3-14C] Indaziflam Treated Sugarcane	[Triazine-2,4-14C]
Indaziflam Treated Sugarcane

	TRR = 0.004 ppm	TRR = 0.005 ppm

	% TRR	ppm	% TRR	ppm

Indaziflam	24	<0.001	17	<0.001

Fluoroethyl Diaminotriazine	--	--	30	0.001

ROI 1 (Polar)	6	<0.001	--	--

ROI 2 (Moderately Polar)	35	0.001	--	--

ROI 3 (Polar)	--	--	10	<0.001

ROI 4 (Non-Polar)	--	--	11	<0.001

Total identified	24	<0.001	47	<0.002

Total characterized	41	<0.002	21	<0.002

Total uncharacterized2 	1	--	0	--

Total extractable	66	0.003	68	0.003

Unextractable (PES)3 	34	0.001	32	0.002

Accountability4	~100	~100

1A similar study was also carried out using 10x the proposed maximum
seasonal field application rate.  However, due to phytotoxicity, no
sugarcane plants survived the experiment.  

2Total uncharacterized = Total extractable – Total characterized –
Total Identified.  The Total Extractable information comes from the
reported values in the registrant study profile template.  

3Residues remaining after exhaustive extractions.

4 Accountability = Total extractable + Total unextractable. 
Accountabilities were ~100% because results were normalized.

Figure 1.  Proposed Metabolic Profile of Indaziflam in Sugarcane,
Apples, and Grapes (Note: This figure was taken from the petitioner’s
study profile without modification.) 

 

860.1300 Nature of the Residue - Livestock

47743320.der.doc/47743321.der.doc – Goat metabolism

D371659 – Report of the Residues of Concern Knowledgebase
Subcommittee. G. Kramer. 18 February 2010

Indane Label  Two lactating goats were dosed orally, via capsule, with
[indane-3-14C]-AE 1170437 at a rate of 2.14 milligrams of active
ingredient per kilogram (mg ai/kg) of body weight (approximately 57 ppm
in feed) once daily for five consecutive days.  The dose rate was 2558X
the anticipated maximum reasonably balanced dietary burden of
AE 1170437 (indaziflam) residues in ruminant feed.  

Milk was collected twice daily during the treatment period. 
Approximately 23 hours after the last dose, the goats were sacrificed,
and edible tissues (liver, kidney, perirenal fat, omental fat, round
muscle, and loin muscle) were collected for analysis.  

The total radioactive residues (TRR) in the milk and tissues were
determined using a liquid scintillation counter.  Identification and
quantitation of the residues in the milk and tissue extracts were
accomplished by using reverse-phase high-performance liquid
chromatography (hplc), and liquid chromatography with tandem
mass-spectrometric detection (lc/ms/ms).  

Tissues and milk were extracted, and the results summarized in Table 5a
(below).  The majority of the residues (85% to 98% of the TRR) in the
milk and tissues was extractable, while only 2% to 15% of the TRR
(<0.001 to 0.023 ppm) in milk and tissues were unextractable. 

The TRR (expressed in AE 1170437 equivalents) in the milk samples ranged
from 0.011 ppm in the Day-1 morning, Day-3 morning, and Day-5 morning
milk to 0.048 ppm in the Day-2 evening milk.  The TRR found in the
tissue samples was 0.368, 0.006, 0.007, 0.013, 0.015, and 0.153 ppm in
liver, loin muscle, round muscle, perirenal fat, omental fat, and
kidney, respectively.  

Table 5a	Extractability of [indane-3-14C]-AE 1170437 Residues in Edible
Tissues and Milk.  

Matrix	Total

Residues (ppm)	Extractable Residues	Unextractable Residues

%TRR 1	ppm	% TRR	ppm

Liver	0.368	97	0.362	2	0.006

Kidney	0.153	85	0.131	15	0.023

Muscle (Loin)	0.006	NE 2	-	-	-

Muscle (Round)	0.007	NE	-	-	-

Fat (Perirenal)	0.013	98	0.013	2	<0.001

Fat (Omental)	0.015	NE

	Day-1 Milk	0.120	96	0.116	4	0.005

Day-3 Milk	0.123	92	0.113	8	0.010

Day-5 Milk	0.164	86	0.141	14	0.023 3

1 %TRR = percent Total Radioactive Residues.  

2 NE = Not Extracted.  Muscle samples were not extracted due to the low
TRR values. Results are reported from the extraction of perirenal fat,
which was used to represent the residue profile in fat.  

3 The Day-5 milk solids solublized during reflux with 1 N HCl, so there
were no solids remaining after this step.  

The major residues found in the milk and tissues were parent AE 1170437
(2% to 20% of the TRR; 0.003 to 0.011 ppm), AE
1170437-4-hydroxy-hydroxymethyl (2% to 16% of the TRR; <0.001 to 0.020
ppm), AE 1170437-dihydroxy (11% to 14% of the TRR; 0.016 to 0.020 ppm),
AE 1170437-3-ketohydroxymethyl (2% to 13% of the TRR; <0.001 to
0.017 ppm), AE 1170437-3-ketohydroxymethyl GA (2% to 28% of the TRR;
0.002 to 0.105 ppm), AE 1170437-3-hydroxyindane GA (12% to 19% of the
TRR; 0.002 to 0.017 ppm), 3-hydroxyindane (12% to 18% of the TRR; 0.018
to 0.021 ppm), and AE 1170437-carboxylic acid (6% to 26% of the TRR;
0.008 to 0.089 ppm).  The minor residues found in the milk and tissues
were AE 1170437-4-hydroxy acid (2% to 7% of the TRR; <0.001 to 0.006
ppm) and AE 1170437-3-keto-4-hydroxy (3% to 5% of the TRR; 0.004 to
0.007 ppm).  

Metabolic degradation of AE 1170437 is rapid and nearly complete, with
between 2% and 20% of the TRR being observed in the milk and tissues as
unmetabolized parent (AE 1170437).  Oxidation products, including AE
1170437-4-hydroxy-hydroxymethyl, AE 1170437-dihydroxy,
AE 1170437-3-ketohydroxymethyl, 3-hydroxyindane, and AE
1170437-carboxylic acid, were observed in milk and tissue samples,
indicating that oxidation is the main route of metabolism for the parent
compound.  Glucuronic acid (GA) conjugates AE 1170437-3-hydroxyindane GA
and AE 1170437-3-ketohydroxymethyl GA were also observed.  

	 

Triazine Label.  Two lactating goats were dosed orally, via capsule,
with [triazine-2,4-14C]-AE 1170437 at a rate of 2.24 milligrams of
active ingredient per kilogram (mg ai/kg) of body weight (approximately
47 ppm in feed) once daily for five consecutive days.  The dose rate was
2125X the anticipated maximum reasonably balanced dietary burden of
AE 1170437 residues in ruminant feed.  

Milk was collected twice daily during the treatment period. 
Approximately 23 hours after the last dose, the goats were sacrificed,
and edible tissues (liver, kidney, perirenal fat, omental fat, round
muscle, and loin muscle) were collected for analysis.  

The total radioactive residues (TRR) in the milk and tissues were
determined using a liquid scintillation counter.  Identification and
quantitation of the residues in the milk and tissue extracts were
accomplished by using reverse-phase high-performance liquid
chromatography (hplc), and liquid chromatography with tandem
mass-spectrometric detection (lc/ms/ms).  

The TRR (expressed in AE 1170437 equivalents) in the milk samples ranged
from 0.037 ppm in the Day-1 morning milk to 0.067 ppm in the Day-3
evening milk.  The TRR found in the tissue samples was 0.816, 0.022,
0.025, 0.044, 0.032, and 0.405 ppm in liver, loin muscle, round muscle,
perirenal fat, omental fat, and kidney, respectively.  The residues
extrapolated to 1X the anticipated maximum reasonably balanced dietary
burden would be <0.001 ppm in all tissues and milk.  

Tissues and milk were extracted, and the results summarized in Table 5b
(below).  The majority of the residues (95% to 100% of the TRR) in the
milk and tissues was extractable, while only <1% to 4% of the TRR
(<0.001 to 0.012 ppm) in milk and tissues were unextractable.  

Table 5b.	Extractability of  [triazine-2,4-14C]-AE 1170437 Residues in
Edible Tissues and Milk.  

Matrix	Total

Residues (ppm)	Extractable Residues	Unextractable Residues

%TRR 1	ppm	% TRR	ppm

Liver 2	0.816	99	0.812	<1	0.003

Kidney 2	0.405	97	0.392	3	0.012

Muscle (Loin) 2	0.022	95	0.021	4	<0.001

Muscle (Round)	0.025	NE 3	-	-	-

Fat (Perirenal) 2	0.044	97	0.042	3	0.001

Fat (Omental)	0.032	NE	-	-	-

Day-1 Milk	0.274	99	0.271	1	0.003

Day-3 Milk	0.400	99	0.397	<1	0.003

Day-5 Milk	0.378	100	0.377	<1	0.001

1 %TRR = percent Total Radioactive Residues.  TRR were detemined by
oxidation, unless otherwise noted.  

2 The TRR values reported for the liver, kidney, loin muscle, and
perirenal fat were calculated as the sum of the extracted radioactive
residues and the radioactive residues remaining in the extracted solids.

3 NE = Not Extracted.  Muscle samples were not extracted due to the low
TRR values. Results are reported from the extraction of perirenal fat,
which was used to represent the residue profile in fat.  

The major residues found in the milk and tissues were AE
1170437-diaminotriazine (2% to 15% of the TRR; 0.001 to 0.049 ppm), AE
1170437-4-hydroxy-hydroxymethyl (4% to 18% of the TRR; 0.003 to 0.066
ppm), AE 1170437-dihydroxy (2% to 18% of the TRR; 0.002 to 0.067 ppm),
AE 1170437-4-hydroxy acid (5% to 14% of the TRR; 0.005 to 0.058 ppm),
AE 1170437-3-ketohydroxymethyl (2% to 28% of the TRR; 0.001 to 0.089
ppm), AE 1170437-3-hydroxyindane GA (9% to 24% of the TRR; 0.004 to
0.199 ppm), 3-hydroxyindane (3% to 14% of the TRR; 0.003 to 0.022 ppm),
and AE 1170437-carboxylic acid (2% to 20% of the TRR; 0.001 to 0.130
ppm).  The minor residues found in the milk and tissues were
AE 1170437-3-hydroxyindane acid (2% to 7% of the TRR; 0.002 to
0.028 ppm), AE 1170437-3-keto-4-hydroxy (4% to 6% of the TRR; <0.001 to
0.020 ppm), and AE 1170437-3-ketohydroxymethyl GA (<1% to 4% of the
TRR; <0.001 to 0.032 ppm).  Only a minor amount of parent AE 1170437 was
identified in any of the milk and tissues (1% to 9% of the TRR; 0.004 to
0.015 ppm).  

Metabolic degradation of AE 1170437 is rapid and nearly complete, with
between 1% and 9% of the TRR being observed in the milk and tissues as
unmetabolized parent (AE 1170437).  Oxidation products, including AE
1170437-4-hydroxy-hydroxymethyl, AE 1170437-dihydroxy,
AE 1170437-4-hydroxy acid, AE 1170437-3-ketohydroxymethyl,
3-hydroxyindane, and AE 1170437-carboxylic acid were observed in milk
and tissue samples, indicating that oxidation is the main route of
metabolism for the parent compound.  Glucuronic acid (GA) conjugates AE
1170437-3-hydroxyindane GA and AE 1170437-3-ketohydroxymethyl GA were
also observed.  

Conclusions.  Based on the available information, indaziflam appears to
undergo significant oxidative metabolism in ruminants.  The metabolic
pathways observed in these studies were similar, with the exception of
the label specific diaminotriazine metabolite found in the triazine
label study.  The same was true for the [14C]-AE 1170437 rat metabolism
study (MRID 47443312, 47743418) with only minor differences (two
additional metabolites, AE 1170437-4-hydroxy-hydroxymethyl and AE
1170437-3-keto-4-hydroxy, were found in the goat metabolism studies).  

Tables 5c and 5d summarize the characterization and identification of
residues in goat matrices from the indane and triazine label studies. 
There are a number of significant (> 10% TRR) metabolites, depending on
the commodity being examined, with most consisting of some level of
increased hydroxylation relative to the parent compound (Figure 2).  The
residue definitions for tolerance enforcement and risk assessment are
summarized in Table 6.

Table 5c.  Summary of Characterization and Identification of Radioactive
Residues in Goat Matrices Following the Oral Administration of
[Indane-34-14C] AE 1170437 at a Rate of 2.14 mg ai/kg Body Weight/Day
for Five Consecutive Days.             

Compound	Milka

TRR = 0.120 to 0.164 ppm	Liver

TRR = 0.368 ppm	Fatb

TRR = 0.013 ppm	Kidney

TRR = 0.153 ppm

	%TRR	ppm	%TRR	ppm	%TRR	ppm	%TRR	ppm

AE 1170437	3 to 9	0.005 to 0.011	2	0.008	20	0.003	NDc	NDc

AE 1170437-4-hydroxy-hydroxymethyl 	11 to 16	0.013 to 0.020	2	0.006	5
<0.001	4	0.006

AE 1170437-dihydroxy	12 to 14	0.016 to 0.020	NDc	NDc	NDc	NDc	11	0.016

AE 1170437-4-hydroxy acid 	NDc	NDc	2	0.006	7	<0.001	NDc	NDc

AE 1170437-3-keto-4-hydroxy	3 to 5	0.004 to 0.006	NDc	NDc	NDc	NDc	5
0.007

AE 1170437-3-ketohydroxymethyl	11 to 13	0.014 to 0.017	2	0.008	4	<0.001
3	0.004

AE 1170437-3-ketohydroxymethyl GA 	3	0.003	28	0.105	NDc	NDc	2	0.002

AE 1170437-3-hydroxyindane GA 	NDc	NDc	NDc	NDc	19	0.002	12d	0.017d

3-hydroxyindane	12 to 18	0.018 to 0.021	NDc	NDc	NDc	NDc	NDc	NDc

AE 1170437-carboxylic acid	6 to 9	0.008 to 0.011	24	0.089	16	0.002	26
0.040

M3-2, M5-2	2	0.002 to 0.003	NDc	NDc	NDc	NDc	NDc	NDc

M5-3	2	0.003	NDc	NDc	NDc	NDc	NDc	NDc

M1-5, M3-7, M5-8, L-3, F-3, K-4	5 to 7	0.008	2	0.009	4	<0.001	7	0.010

L-4, F-4	NDc	NDc	4	0.013	7	<0.001	NDc	NDc

M1-2, M3-3, M5-4	3 to 4	0.004 to 0.006	NDc	NDc	NDc	NDc	NDc	NDc

M3-4	2	0.002	NDc	NDc	NDc	NDc	NDc	NDc

M5-5	2	0.004	NDc	NDc	NDc	NDc	NDc	NDc

M3-10, M5-11	2 to 3	0.003 to 0.004	NDc	NDc	NDc	NDc	NDc	NDc

M1-9, M3-11, M5-12, K-8	5	0.006 to 0.008	NDc	NDc	NDc	NDc	1	0.002

K-1	NDc	NDc	NDc	NDc	NDc	NDc	2	0.003

M1-1, M3-1, M5-1	2	0.002 to 0.003	NDc	NDc	NDc	NDc	NDc	NDc

K-10	NDc	NDc	NDc	NDc	NDc	NDc	2	0.003

F-7	NDc	NDc	NDc	NDc	3	<0.001	NDc	NDc

K-11	NDc	NDc	NDc	NDc	NDc	NDc	1	0.002

F-9	NDc	NDc	NDc	NDc	10	0.001	NDc	NDc

K-13	NDc	NDc	NDc	NDc	NDc	NDc	2	0.002

F-11	NDc	NDc	NDc	NDc	3	<0.001	NDc	NDc

Total Identified	60 to 81	0.083 to 0.097	60	0.222	71	0.009	63	0.092

Total Characterized	16 to 28	0.021 to 0.045	38	0.141	27	0.004	23	0.035

Total Extractable	92 to 100	0.113 to 0.164	97	0.362	98	0.013	85	0.131

Unextracted	4 to 8	0.005 to 0.010	2	0.006	2	<0.001	15	0.023

Accountability	97 to 106	103	82	121

aResults are reported as ranges of values for the composite day-1,
day-3, and day-5 milk.

bResults are reported from the extraction of perirenal fat, which was
used to represent the residue profile in fat.

cND = Not detected.

dThe amount of AE 1170437-3-hydroxyindane GA reported in kidney (12% of
the TRR and 0.017 ppm) was the sum of K-9 (4% of the TRR and 0.005 ppm)
and K-14 (8% of the TRR and 0.012 ppm).



Table 5d.  Summary of Characterization and Identification of Radioactive
Residues in Goat Matrices Following the Oral Administration of
[Triazine-2,4-14C] AE 1170437 at a Rate of 2.24 mg ai/kg Body
Weight/Day for Five Consecutive Days.

Compound	Milka

TRR = 0.274 to 0.400 ppm	Liver

TRR = 0.816 ppm	Muscleb

TRR = 0.022 ppm	Fatc

TRR = 0.044 ppm	Kidney

TRR = 0.405 ppm

	%TRR	ppm	%TRR	ppm	%TRR	ppm	%TRR	ppm	%TRR	ppm

AE 1170437	1	0.004	2	0.015	NDd	NDd	9	0.004	NDd	NDd

AE 1170437-diaminotriazine	12 to 13	0.036 to 0.049	NDd	NDd	15	0.003	3
0.001	2	0.009

AE 1170437-4-hydroxy-hydroxymethyl	15 to 18	0.042 to 0.066	4	0.036	15
0.003	7	0.003	4	0.016

AE 1170437-dihydroxy	17 to 18	0.048 to 0.067	2	0.015	18	0.040	4	0.002	6
0.026

AE 1170437-4-hydroxy acid	NDd	NDd	5	0.038	NDd	NDd	12	0.005	14	0.058

AE 1170437-3-hydroxyindane acid	2 to 3	0.005 to 0.010	NDd	NDd	NDd	NDd	5
0.002	7	0.028

AE 1170437-3-keto-4-hydroxy	5 to 6	0.017 to 0.020	NDd	NDd	4	<0.001	NDd
NDd	NDd	NDd

AE 1170437-3-ketohydroxymethyl	22 to 28	0.076 to 0.089	2	0.020	5	0.001	4
0.002	6	0.024

AE 1170437-3-ketohydroxymethyl GA	<1	0.003	4	0.032	3	<0.001	2	0.001	NDd
NDd

AE 1170437-3-hydroxyindane GA	NDd	NDd	24e	0.199e	NDd	NDd	9	0.004	17
0.068

3-hydroxyindane	3 to 6	0.012 to 0.022	NDd	NDd	14	0.003	NDd	NDd	NDd	NDd

AE 1170437-carboxylic acid	2 to 3	0.007 to 0.014	16	0.130	6	0.001	19
0.008	20	0.082

M1-4, M3-4, M5-4	<1 to 1	0.002 to 0.005	NDd	NDd	NDd	NDd	NDd	NDd	NDd	NDd

M-2, K-3	NDd	NDd	NDd	NDd	2	<0.001	NDd	NDd	1	0.005

L-4, M-6	NDd	NDd	4	0.030	2	<0.001	NDd	NDd	NDd	NDd

F-7, K-8	NDd	NDd	NDd	NDd	NDd	NDd	4	0.002	5	0.022

M1-5, M3-5, M5-5, F-2	5 to 6	0.014 to 0.022	NDd	NDd	NDd	NDd	2	<0.001	NDd
NDd

M5-6	<1	0.003	NDd	NDd	NDd	NDd	NDd	NDd	NDd	NDd

M5-12, F-9, K-10	<1	0.002	NDd	NDd	NDd	NDd	3	0.001	7	0.028

M-3	NDd	NDd	NDd	NDd	5	0.001	NDd	NDd	NDd	NDd

M1-11, M3-12, M5-13, M-10, F-11, K-11	1 to 2	0.003 to 0.008	NDd	NDd	2
<0.001	2	0.001	2	0.007

M3-13, M5-14	<1 to 3	0.003 to 0.013	NDd	NDd	NDd	NDd	NDd	NDd	NDd	NDd

M1-1, M3-1, M5-1	1	0.003 to 0.005	NDd	NDd	NDd	NDd	NDd	NDd	NDd	NDd

M1-3, M3-3, M5-3, K-2	1 to 2	0.003 to 0.006	NDd	NDd	NDd	NDd	NDd	NDd	2
0.006

F-13, M-12	NDd	NDd	NDd	NDd	4	<0.001	4	0.002	NDd	NDd

F-14	NDd	NDd	NDd	NDd	NDd	NDd	2	<0.001	NDd	NDd

M3-16, L-9, F-16, K-14	2	0.008	2	0.017	NDd	NDd	2	<0.001	3	0.011

F-18	NDd	NDd	NDd	NDd	NDd	NDd	4	0.002	NDd	NDd

Total Identified	85 to 89	0.246 to 0.345	59	0.485	80	0.051	74	0.032	76
0.311

Total Characterized	8 to 14	0.025 to 0.060	40	0.326	15	0.001	23	0.010	20
0.079

Total Extractable	99 to 100	0.271 to 0.397	99	0.800	95	0.021	97	0.042	97
0.392

Unextracted	<1 to 1	0.001 to 0.003	<1	0.003	4	<0.001	3	0.001	3	0.012

Accountability	94 to 105	99	86	105	100

aResults are reported as ranges of values for the composite day-1,
day-3, and day-5 milk.

bResults are reported from the extraction of loin muscle, which was used
to represent the residue profile in muscle.

cResults are reported from the extraction of perirenal fat, which was
used to represent the residue profile in fat.

dND = Not detected.

eThe amount of AE 1170437-3-hydroxyindane GA reported in liver (24% of
the TRR and 0.199 ppm) was the sum of L-7 (5% of the TRR and 0.042 ppm)
and L-10 (19% of the TRR and 0.157 ppm).

Table 6.  Compounds to be Included in the Risk Assessment and Tolerance
Expression.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression for Compliance Monitoring

Plants	Primary Crop	Indaziflam + Fluoroethyl Diaminotriazine (FDAT)
Indaziflam + FDAT

	Rotational Crop	Not applicable at this time (no data available)	Not
applicable at this time (no data available)

Livestock	Ruminant	Indaziflam + FDAT + Indaziflam-3-ketohydroxymethyl +
Indaziflam carboxylic acid + Indaziflam-3-hydroxyindane	Indaziflam +
FDAT + Indaziflam-3-ketohydroxymethyl + Indaziflam carboxylic acid +
Indaziflam-3-hydroxyindane*

	Poultry	Not applicable at this time (no data available)	Not applicable
at this time (no data available)

Drinking Water	Indaziflam + FDAT + Triazine indanone + Indaziflam
carboxylic acid + Indaziflam hydroxyethyl + Indaziflam olefin	Not
Applicable

Indaziflam =
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-(1-fluoroethyl)-1,3
,5-triazine-2,4-diamine (CAS)

FDAT = 6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine

Indaziflam carboxylic acid =
(2S,3R)-3-[[4-amino-6-[(1R)-1-fluoroethyl]-1,3,5-triazin-2-yl]amino)-2,3
-dihydro-2-methyl-1H-indene-5-carboxylic acid

Indaziflam-3-ketohydroxymethyl =
(2S,3R)-3-[[4-amino-6-[(1R)-1-fluoroethyl]-1,3,5-triazin-2-yl]amino)-5-h
ydroxymethyl-2-methylindane-1-one

Indaziflam-3-hydroxyindane =
(2R,3R)-3-({4-amino-6-[(1R)-1-fluoroethyl]-1,3,5-triazin-2-yl}amino)-2-m
ethylindan-1-ol-5-carboxylic acid

Triazine indanone =
N-[(1R,2S)-2,3-Dihydro-2,6-dimethyl-3-oxo-1H-inden-1-yl]-6-[(1R)-1-fluor
oethyl]-1,3,5-triazine-2,4-diamine

Indaziflam hydroxyethyl =
1-{4-Amino-6-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-ylamino]-1,3,5
-triazin-2-yl}ethanol

Indaziflam olefin =
N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-6-vinyl-1,3,5-triazin
e-2,4-diamine

* tentative, these residues should be included in the feeding study (if
required).

860.1340 Residue Analytical Methods

47743323.der.doc

Bayer CropScience method DH-003-P07-02 was developed to determine the
residues of AE 1170437 in fruit and tree nut matrices.  The method was
successfully validated in almond hulls, almonds nutmeat, apple fresh
fruit, cherries (sweet), cherries (tart), grape fresh fruit, grapefruit,
lemon, olive, orange fresh fruit, peach fresh fruit, pear fresh fruit,
pecan nutmeat, plum and sugarcane matrices.  Additional validation was
performed as part of the magnitude of the residue studies.

A 5.0-g aliquot of the crop matrix was extracted by blending with a
mixture of ACN/water, filtered and analyzed by high performance liquid
chromatography / electrospray ionization / tandem mass spectrometry
(LC/MS/MS).  

The method was validated to a limit of quantitation (LOQ) of 0.005 ppm
in crop matrices.  These data support a total method LOQ of 0.01 ppm in
all fruit and tree nut matrices [combined residues of parent (0.005 ppm)
and metabolite (0.005 ppm)].  In addition, method limits of detection
(LODs) were calculated from the data.  A previous version DH-003-P07-01
was validated to a limit of quantitation of 0.01 ppm in crops matrices. 
All analytical steps, including the extraction, are identical in
DH-003-P07-02 which effectively replaces the previous version.

 

The independent laboratory validation showed that the individual
recoveries for both analytes lie between 70% and 120%, and the
individual average recoveries had a relative standard deviation (RSD)
below 20%.

The method has been shown to be specific for the target analytes. The
method used HPLC-MS/MS for detection and quantitation of the indaziflam
and fluoroethyl diaminotriazine.  

Conclusions.  Method DH-003-P07-02 has been sufficiently validated and
is suitable as an enforcement method for crops.  The method is able to
determine, separately, residues of indaziflam and FDAT.  The method has
been adequately radiovalidated using samples from the apple and grape
metabolism studies.  The method has been sent to the Analytical
Chemistry Branch of the Biological and Economic Analysis Division
(ACB/BEAD) as well as to the Food and Drug Administration (FDA) as an
official enforcement method.  The analytical standards, including the
stable-isotope internal standard, for the method will need to be
forwarded by the petitioner to ACB prior to registration.  Use of the
proper stable- isotope-labeled internal standards is critical to the
methods accuracy and effectiveness.  

860.1360 Multiresidue Methods

47743327.der.doc

Bayer CropScience tested the suitability of the Food and Drug
Administration’s (FDA’s) multi-residue methods for regulatory
analysis of indaziflam (CAS name
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]-1,3
,5-triazine-2,4-diamine, and CAS number 950782-86-2) and its metabolite,
1-fluoroethyldiaminotriazine.  None of the method protocols were
suitable for the analysis of indaziflam or its metabolite in crop
matrices.  

Conclusions.  FDA’s multiresidue methods are not suitable for analysis
or enforcement of indaziflam residues.  This information has been
forwarded to FDA.

860.1380 Storage Stability

477433329.der.doc

This study was initiated to evaluate the freezer storage stability of
indaziflam and 

1-fluoroethyldiaminotriazine in various crop matrices.  

Samples (approximately 5.00 grams each) of almond hulls, almond nutmeat,
apples (fresh fruit), cherries (fresh fruit), and oranges (fresh fruit)
were prepared.  Samples were fortified individually at 0.100 ppm each of
indaziflam or 1-fluoroethyldiaminotriazine.  Triplicate fortified
samples of each matrix were analyzed immediately after fortification
(zero days).  Stored samples were analyzed for residues of indaziflam
and 1-fluoroethyldiaminotriazine at nominal intervals of 1, 3, 6, 9 and
12 months.  Throughout these intervals, all fortified samples were
stored at a maximum daily average temperature of <-20°C.  Sample
analyses for indaziflam and 

1-fluoroethyldiaminotriazine were performed using the analytical method
for determining the total residues of indaziflam and
1-fluoroethyldiaminotriazine in crop matrices (see References 1 and 2). 

Indaziflam and 1-flurorethyldiaminotriazine were stable in all crop
matrices studied for up to 12 months.  

Conclusions.  The available storage stability data indicate that
residues of indaziflam and FDAT are stable in frozen storage for up to
approximately 12 months.  Samples from the citrus, olive, and tree nut
crop field trials, and the grape processing study were stored for over
one year and are not fully supported by the available storage stability
data.  Since the available data demonstrate that residues have some
long-term stability, HED will use the available study to support the
tolerance petition.  However, submission of an acceptable storage
stability study covering the full duration of sample storage should be
submitted as a condition of registration.

860.1400 Water, Fish, and Irrigated Crops

There are no proposed uses for indaziflam that are germane to this
guideline.  No evaluation is necessary at this time.

860.1460 Food Handling

There are no proposed uses for indaziflam that are germane to this
guideline.  No evaluation is necessary at this time.

860.1480 Meat, Milk, Poultry, and Eggs

47743401.der.doc

Bayer CropScience has requested a waiver of the requirement for a
livestock feeding study with indaziflam.  Bayer has submitted acceptable
ruminant (goat) metabolism studies with indaziflam, performed at
exaggerated rates (>2100X) relative to the expected dietary burden. 
Section (b) of EPA’s OPPTS Residue Chemistry Guideline 860.1480
(Meat/Milk/Poultry/Eggs) states that “[w]henever pesticide residues
are detected in feed items, data on the transfer of residues to meat,
milk, poultry, and eggs are required.”  Similarly, Section 8.2 of the
PMRA Residue Chemistry Guidelines (Meat/Milk/Poultry/Eggs) states that
“[w]henever pesticide residues are detected in feed items, data on the
transfer of residues to meat, milk, poultry, and eggs are required.” 
The revised Table 1 of OPPTS Residue Chemistry Guideline 860.1000 shows
that, from the target crops for indaziflam, the only Raw Agricultural
Commodity (RAC) which is used as a feed item for ruminants is almond
hulls.  Analysis of samples from the tree nuts field trial study showed
that the highest residue in almond hulls was 0.15 ppm.  Since the target
crops for indaziflam are all orchard crops, there will be no rotation to
a crop that could be used for animal feed, and, therefore, rotational
crops are of no concern.  None of the target crop commodities are used
in poultry feeds to any significant degree.  

When the highest residues in each matrix from the goat metabolism
studies are used to

calculate anticipated maximum residues in cattle, all calculated tissue
residues are less than 0.004 ppm, and milk residues are less than 0.0003
ppm, at a 10X feeding level.  

Conclusions.  Using information in the goat metabolism studies, residues
of indaziflam (as defined by the livestock residue definition) are
expected to be below the limit of quantitation of a reasonable livestock
analytical method.  Hence a 40 CFR 180.6(a)(3) situation (no expectation
of finite residues) exists.  Neither feeding studies nor tolerances for
livestock commodities are required at this time.  Feeding studies and
analytical methods may be required to support future uses of indaziflam
that involve significant livestock feed items. 

860.1500 Crop Field Trials

47743405.der.doc (citrus)

47743402.der.doc (pome fruit)

47743403.der.doc (stone fruit)

47743404.der.doc (tree nuts)

47743406.der.doc (grapes)

47743407.der.doc (olive)

Table 7.  Summary of Residues from the Crop Field Trials with Indaziflam

Crop Matrix	Applic. Rate,

lb a.i./A

(kg a.i./ha)	PHI, days	Residues, ppm 1

	n	Min	Max	HAFT	Median 	Mean	Std. Dev

Citrus (proposed use = 0.134 lb ai/A total application rate, 7-day PHI)

Orange	0.129- 0.141

(0.145-0.159)	12-28	24	<0.01	<0.01	<0.01	0.010	0.010	0

Orange	0.129- 0.141

(0.145-0.159)	43-45	24	<0.01	<0.01	<0.01	0.010	0.010	0

Orange	0.129- 0.141

(0.145-0.159)	234-240	24	<0.01	<0.01	<0.01	0.010	0.010	0

Grapefruit	0.129- 0.139

(0.144-0.156)	13-28	12	<0.01	<0.01	<0.01	0.010	0.010	0

Grapefruit	0.129- 0.139

(0.144-0.156)	43-45	12	<0.01	<0.01	<0.01	0.010	0.010	0

Grapefruit	0.129- 0.139

(0.144-0.156)	231-240	12	<0.01	<0.01	<0.01	0.010	0.010	0

Lemon	0.133- 0.136

(0.149-0.153)	14	10	<0.01	<0.01	<0.01	0.010	0.010	0

Lemon	0.133- 0.136

(0.149-0.153)	45	10	<0.01	<0.01	<0.01	0.010	0.010	0

Lemon	0.133- 0.136

(0.149-0.153)	231-240	10	<0.01	<0.01	<0.01	0.010	0.010	0

Pome Fruit (proposed use = 0.134 lb ai/A total application rate, 14-day
PHI)

Apple	0.131- 0.138

(0.147-0.155)	13-14	24	<0.01	<0.01	<0.01	0.010	0.010	0

Apple	0.131- 0.137

(0.146-0.154)	43-46	24	<0.01	<0.01	<0.01	0.010	0.010	0

Apple	0.131- 0.140

(0.147-0.157)	157-209	24	<0.01	<0.01	<0.01	0.010	0.010	0

Pear	0.134- 0.137

(0.150-0.154)	13-14	11	<0.01	<0.01	<0.01	0.010	0.010	0

Pear	0.133- 0.144

(0.149-0.161)	39-45	11	<0.01	<0.01	<0.01	0.010	0.010	0

Pear	0.129- 0.139

(0.145-0.155)	157-184	11	<0.01	<0.01	<0.01	0.010	0.010	0

Stone Fruit (proposed use = 0.134 lb ai/A total application rate, 14-day
PHI)

Cherries	0.134- 0.141

(0.150-0.158)	14-20	12	<0.010	<0.010	<0.010	0.010	0.010	0

Cherries	0.132- 0.145

(0.148-0.162)	45	12	<0.010	<0.010	<0.010	0.010	0.010	0

Cherries	0.132- 0.142

(0.148-0.159)	83-115	12	<0.010	<0.010	<0.010	0.010	0.010	0

Peaches	0.129- 0.140

(0.145-0.157)	13-14	18	<0.010	<0.010	<0.010	0.010	0.010	0

Peaches	0.129- 0.135

(0.144-0.152)	43-45	18	<0.010	<0.010	<0.010	0.010	0.010	0

Peaches	0.133- 0.139

(0.149-0.156)	120-211	18	<0.010	<0.010	<0.010	0.010	0.010	0

Plums	0.132- 0.136

(0.148-0.152)	14	12	<0.010	<0.010	<0.010	0.010	0.010	0

Plums	0.132- 0.139

(0.148-0.156)	45	12	<0.010	<0.010	<0.010	0.010	0.010	0

Plums	0.131- 0.136

(0.146-0.153)	160-210	12	<0.010	<0.010	<0.010	0.010	0.010	0

Tree Nuts (proposed use = 0.134 lb ai/A total application rate, 14-day
PHI)

Almond nutmeat	0.132- 0.135

(0.148-0.152)	14	10	<0.010	<0.010	<0.010	0.010	0.010	0

Almond hull	0.132- 0.135

(0.148-0.152)	14	10	<0.010	<0.153	<0.149	0.023	0.050	0.059

Pecan nutmeat	0.130- 0.134

(0.146-0.150)	12-13	10	<0.010	<0.010	<0.010	0.010	0.010	0

Grape (proposed use = 0.089 lb ai/A total application rate, 14-day PHI)

Fresh Fruit	0.130 - 0.140

(0.145 - 0.157)	13-14	24	<0.01	<0.01	<0.01	0.01	0.01	0

Fresh Fruit	0.131 - 0.139

(0.147 - 0.155)	43-45	24	<0.01	<0.01	<0.01	0.01	0.01	0

Fresh Fruit	0.132 - 0.142

(0.148 - 0.159)	143-240	24	<0.01	0.0115	0.0113	0.01	0.01	0.0029

Olive (proposed use = 0.134 lb ai/A total application rate, 14-day PHI)

Fresh Fruit	0.133-0.155

(0.149-0.151)	14	6	<0.01	<0.01	<0.01	0.01	0.01	0

Fresh Fruit	0.133-0.136

(0.149-0.152)	45	6	<0.01	<0.01	<0.01	0.01	0.01	0

Fresh Fruit	0.132-0.137

(0.148-0.153)	287-300	6	<0.01	<0.01	<0.01	0.01	0.01	0

1 Total indaziflam residues (indaziflam + FDAT) are reported.  For all
samples, residues of FDAT were below the LOQ (< 0.005 ppm).  For
determination of the median, mean, and standard deviation, all residues
reported as < LOQ were assumed to be equal to the single-analyte LOQ of
0.005 ppm.

Citrus Twenty-three harvest trials (twelve orange, six grapefruit, and
five lemon trials) were conducted to measure the magnitude of indaziflam
{1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]}
residues in/on citrus fruits following a single broadcast application of
Indaziflam 500 SC to bare soil, mown or chemically burned-down ground
cover, directed to the base of trees and extending to the row centers at
a target rate of 0.134 lb ai/A (150 g ai/ha).  Indaziflam 500 SC is a
suspension concentrate formulation containing 500 g ai/L.

Application rates ranged from 0.129 to 0.141 lb ai/A (145 to
159 g ai/ha) in orange, from 0.129 to 0.139 lb ai/A (144 to
156 g ai/ha) in grapefruit, and from 0.132 to 0.137 lb ai/A (148 to
153 g ai/ha) in lemon.  Spray volumes ranged from 10 to 20 gal/A (93 to
187 L/ha) for all trials.  There were no adjuvants added to the spray
mixture.  All applications were made using ground-based equipment.  

All trials had two treated plots that received an application of
Indaziflam 500 SC; samples were collected from the TRT45 plot at target
pre-harvest-intervals (PHI’s) of 14 and 45 days (actual 12 to 14 days
and 43 to 45 days, with the exception of three trials where the 14-day
PHI samples were collected two weeks late due to field investigator
oversight) and from the TR240 plot at a target PHI of 240 days (actual
231 to 240 days).  

In orange plots, application to the TRT45 plots (sampled at target PHIs
of 14 and 45 days) was made between BBCH 81 and 85 (BBCH 81: beginning
of fruit coloring; BBCH 85: advanced ripening) and application to the
TR240 plots (target PHI of 240 days) was made between BBCH 55 and 89
(BBCH 55: flowers visible but still closed, BBCH 89: fruit ripe for
consumption).  

In grapefruit plots, application to the TRT45 plots (14- and 45-day
target PHIs) was made between BBCH 81 to 89 (BBCH 81: beginning of
fruit coloring, BBCH 89: fruit ripe for consumption) and application to
the TR240 plots (240-day target PHI) was made between BBCH 60 and 89
(BBCH 60: first flowers open, BBCH 89: fruit ripe for consumption)

In lemon plots, application to the TRT45 plots (14- and 45-day target
PHIs) was made between BBCH 79 to 89 (BBCH 79: fruits are about 90% of
final size, BBCH 89: fruit ripe for consumption) and application to the
TR240 plots (240-day target PHI) was made between BBCH 07 and 74
(BBCH 07: beginning of bud burst, BBCH 74: fruits are about 40% of
final size).

Duplicate composite samples of oranges, grapefruit, and lemons were
collected from the treated plots at target PHIs of 14, 45, and 240 days
after application, and a single composite sample was collected from the
control plot at the same time the 45-day PHI samples were collected. 

The residues of indaziflam and its metabolite fluoroethyldiaminotriazine
were quantitated by high pressure liquid chromatography/triple stage
quadrupole mass spectrometry (LC/MS/MS) using stable isotopically
labeled internal standards.  The limit of quantitation (LOQ) for total
indaziflam residue (the sum of indaziflam and
fluoroethyldiaminotriazine) was 0.01 ppm in oranges, grapefruit, and
lemons.

Freezer storage stability studies indicate that indaziflam and
fluoroethyldiaminotriazine residues would have been stable in orange,
grapefruit, and lemon raw agricultural commodities (RACs) during frozen
storage (11.5 months) prior to analysis.  The orange, grapefruit, and
lemon analyzed in this study were held in frozen storage for a maximum
of 16.6 months (497 days) prior to extraction.

In orange, grapefruit, and lemon, the HAFT (highest average field trial)
and maximum total indaziflam residues at all three PHI’s (14-day,
45-day, and 240-day) were less than the LOQ (<0.01 ppm).

Pome Fruit.  Eighteen field trials (twelve on apples, and six on pears)
were conducted to measure the magnitude of indaziflam (CAS name
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]-1,3
,5-triazine-2,4-diamine, and CAS number 950782-86-2) residues in pome
fruit following a single broadcast application of indaziflam, formulated
as the end-use product (EP), Indaziflam 500 SC.  Applications were made
to bare soil, or mown or chemically burned-down ground cover, and
directed to the base of apple and pear trees (extending to the row
centers), at a target rate of 0.134 pounds of active ingredient per
acre (lb ai/A), the equivalent of 150 grams ai per hectare (g ai/ha). 
The actual use rates were 0.131-0.140 lb ai/A (146-157 g ai/ha) on
apples, and 0.129-0.144 lb ai/A (145-161 g ai/ha) on pears.  Indaziflam
500 SC is a suspension concentrate (SC) formulation containing 500 g ai
per liter (g ai/L).  There were no adjuvants added to the spray mixture.
 All applications were made using ground-based equipment.  All trials
had three treated plots that received an application of indaziflam at
target 14-day, 45-day, or 150- to 210-day (5- to 7-month) pre-harvest
intervals (PHIs).  

In apple plots, the 14-day target PHI application was made between BBCH
78 and 87 (BBCH 78 = fruit about 80% of final size; BBCH 87 = fruit
ripe for picking).  The 45-day target PHI application was made between
BBCH 74 and 81 (BBCH 74 = fruit diameter up to 40 mm; BBCH 81 =
beginning of ripening).  The 150- to 210-day target PHI application was
made between BBCH 00 and 57 (BBCH 00 = dormancy; BBCH 57 = pink bud
stage).  Duplicate composite samples of apples were collected at target
PHIs of 14, 45 and 150-210 days after application.  A single composite
sample of apple, whole fresh fruit, was collected from the control plot
of each trial at the same time the 14-day samples were collected from
the treated plot.  

In pear plots, the 14-day target PHI application was made between BBCH
78 and 85 (BBCH 78 = fruit about 80% of final size; BBCH 85 = advanced
ripening).  The 45-day target PHI application was made between BBCH 75
and 78 (BBCH 75 = fruit about half of final size).  The 150- to 210-day
target PHI application was made between BBCH 00 and 57 (BBCH 00 =
dormancy; BBCH 57 = pink bud stage).  Duplicate composite samples of
pears were collected at target PHIs of 14, 45 and 150-210 days after
application with the exception of trial DH092-06HA, which had only
single treated samples collected.  A single composite sample of pear,
whole fresh fruit, was collected from the control plot of each trial at
the same time the 14-day samples were collected from the treated plot.  

The residues of indaziflam and its metabolite,
1-fluoroethyldiaminotriazine, were quantitated by high-pressure liquid
chromatography with triple-stage quadrupole mass spectrometric detection
(LC/MS/MS), using stable isotopically labeled internal standards.  The
limit of quantitation (LOQ) for total indaziflam residues (the sum of
indaziflam and 1-fluoroethyldiaminotriazine) was 0.010 ppm in apples and
pears.  

Freezer storage stability studies indicate that the indaziflam and
1-fluoroethyldiaminotriazine residues would be stable in apple and pear
raw agricultural commodities (RACs) during frozen storage prior to
analysis.  The apples and pears analyzed in this study were held in
frozen storage for a maximum of 6.7 months (201 days) prior to
extraction.  The storage stability studies indicate that indaziflam and
1-fluoroethyldiaminotriazine are stable for intervals of at least 12.1
months in apple fresh fruit.  

In both apples and pears, the HAFT (highest average field trial) and
maximum total indaziflam residues at all three PHIs (14-day, 45-day, and
150- to 210-day) were less than the LOQ (0.010 ppm).  

Stone Fruit.  Twenty-one field trials (three tart cherry, three sweet
cherry, nine peach, and six plum) were conducted to measure the
magnitude of indaziflam (CAS name
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]-1,3
,5-triazine-2,4-diamine, and CAS number 950782-86-2) residues in stone
fruit following a single broadcast application of indaziflam, formulated
as the end-use product (EP), Indaziflam 500 SC.  Applications were made
to bare soil, or mown or chemically burned-down ground cover, and
directed to the base of cherry, peach and plum trees (extending to the
row centers), at a target rate of 0.134 pounds of active ingredient per
acre (lb ai/A), the equivalent of 150 grams ai per hectare (g ai/ha). 
The actual use rates were 0.132 to 0.145 lb ai/A (148 to 162 g ai/ha) on
cherries, 0.129 to 0.140 lb ai/A (145 to 157 g ai/ha) on peaches, and
0.131 to 0.139 lb ai/A (146 to 156 g ai/ha) on plums.  Indaziflam 500 SC
is a suspension concentrate (SC) formulation containing 500 g ai per
liter (g ai/L).  There were no adjuvants added to the spray mixture. 
All applications were made using ground-based equipment.  All trials had
three treated plots (TRT14, TRT45, and either TR150 or TR210) that
received an application of indaziflam at target 14-day, 45-day, or 150-
to 210-day (5- to 7-month) pre-harvest intervals (PHIs), respectively.  

In cherry plots, the application was made on plot TR150 at dormancy, on
plot TRT14 at a PHI of 14 days, and on plot TRT45 at a PHI of 45 days. 
Duplicate composite samples of cherries were collected at target 14-day,
45-day, and 3-5 month (150-day) PHIs from treated plots TRT14, TRT45 and
TR150, respectively.  A single composite sample was collected from the
control plot of each trial at the same time the 14-day PHI samples were
collected from the treated plot.  

In peach plots, the application was made on plot TR210 at dormancy, on
plot TRT14 at a PHI of 14 days, and on plot TRT45 at a PHI of 45 days. 
Duplicate composite samples of peaches were collected at target 14-day,
45-day, and 5-7 month (210-day) PHIs from treated plots TRT14, TRT45 and
TR210, respectively.  A single composite sample was collected from the
control plot of each trial at the same time the 14-day PHI samples were
collected from the treated plot.  

In plum plots, the application was made on plot TR210 at dormancy, on
plot TRT14 at a PHI of 14 days, and on plot TRT45 at a PHI of 45 days. 
Duplicate composite samples of plums were collected at target 14-day,
45-day, and 5-7 month (210-day) PHIs from treated plots TRT14, TRT45 and
TR210, respectively.  A single composite sample was collected from the
control plot of each trial at the same time the 14-day PHI samples were
collected from the treated plot.  

The residues of indaziflam and its metabolite,
1-fluoroethyldiaminotriazine, were quantitated by high-pressure liquid
chromatography with triple-stage quadrupole mass spectrometric detection
(LC/MS/MS), using stable isotopically labeled internal standards.  The
limit of quantitation (LOQ) for total indaziflam residues (the sum of
indaziflam and 1-fluoroethyldiaminotriazine) was 0.010 ppm in cherries,
peaches and plums.  

Freezer storage stability studies indicate that the indaziflam and
1-fluoroethyldiaminotriazine residues would be stable in cherry, peach
and plum raw agricultural commodities (RACs) during frozen storage for
at least 11.5 months prior to analysis.  The cherry, peach and plum
fruit analyzed in this study were held in frozen storage for a maximum
duration of 9 months (269 days) prior to extraction.  The continuation
of the storage stability studies will provide more information when
additional time intervals through 24 months are analyzed.  

In cherries (sweet and tart), the highest average field trials (HAFTs),
and maximum total indaziflam residues at target 14-day, 45-day, and
150-day PHIs were all less than the LOQ (0.010 ppm).  In peaches and
plums, the HAFTs and maximum total indaziflam residues at target 14-day,
45-day, and 210-day PHIs were all less than the LOQ (0.010 ppm).  

Tree Nuts.  Ten field trials (five almond and five pecan) were conducted
to measure the magnitude of indaziflam (CAS name
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]-1,3
,5-triazine-2,4-diamine, and CAS number 950782-86-2) residues in almond
nutmeat, almond hulls, and pecan nutmeat following a single broadcast
application of indaziflam, formulated as the end-use product (EP),
Indaziflam 500 SC.  Applications were made to bare soil, or mown or
chemically burned-down ground cover, and directed to the base of almond
and pecan trees, at a target rate of 0.134 pounds of active ingredient
per acre (lb ai/A), the equivalent of 150 grams ai per hectare (g
ai/ha).  The actual use rates were 0.132 to 0.135 lb ai/A (148 to 152 g
ai/ha) on almonds, and 0.130 to 0.134 lb ai/A (146 to 150 g ai/ha) on
pecans.  Indaziflam 500 SC is a suspension concentrate (SC) formulation
containing 500 g ai per liter (g ai/L).  There were no adjuvants added
to the spray mixture.  All applications were made using ground-based
equipment.  All trials had one treated plot (TRTD) that received an
application of Indaziflam 500 SC.  

In almond plots, the application was made between BBCH 79 and 87
(BBCH 79 = fruit about 90% of final size; BBCH 87 = fruit ripe for
picking).  Duplicate composite samples of almond nutmeat and almond
hulls were collected at a target 14-day pre-harvest interval (PHI) after
application.  A single composite sample was collected from the control
plot of each trial at the same time the 14-day samples were collected
from the treated plot.  

In pecan plots, the application was made between BBCH 79 and 89
(BBCH 79 = fruit about 90% of final size; BBCH 89 = fruit ripe for
consumption).  Duplicate composite samples of pecans were collected at a
target 14-day PHI after application.  A single composite sample was
collected from the control plot of each trial at the same time the
14-day samples were collected from the treated plot.  

The residues of indaziflam and its metabolite,
1-fluoroethyldiaminotriazine, were quantitated by high-pressure liquid
chromatography with triple-stage quadrupole mass spectrometric detection
(LC/MS/MS), using stable isotopically labeled internal standards.  The
limit of quantitation (LOQ) for total indaziflam residues (the sum of
indaziflam and 1-fluoroethyldiaminotriazine) was 0.010 ppm in almond
nutmeat, almond hulls, and pecan nutmeat.  

Freezer storage stability studies indicate that the indaziflam and
1-fluoroethyldiaminotriazine residues would be stable in almond and
pecan raw agricultural commodities (RACs) during frozen storage for
intervals of at least 11.8 months prior to analysis.  The nutmeat and
hulls analyzed in this study were held in frozen storage for a maximum
of 13.8 months (414 days) prior to extraction.  The continuation of the
storage stability studies will provide more information when additional
time intervals through 24 months are analyzed.  

In almond nutmeat, the HAFT (highest average field trial) and maximum
total indaziflam residues (at a target 14-day PHI) were both <LOQ (0.010
ppm).  In pecan nutmeat, the HAFT and maximum total indaziflam residues
(at a target 14-day PHI) were both <LOQ (0.010 ppm).  In almond hulls,
the HAFT and maximum total indaziflam residues (at a target 14-day PHI)
were 0.149 ppm and 0.153 ppm, respectively.

Grape.  Field trials were conducted to measure the magnitude of
Indaziflam {1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]}
residues in/on grapes following a single broadcast spray application of
Indaziflam 500 SC.  Indaziflam 500 SC is a suspension concentrate (SC)
formulation containing 500 grams of active ingredient per liter (g ai/L)
of indaziflam.

Twelve field trials were conducted on grapes in the United States,
encompassing Zones 1, 10, and 11 (Zone 1 (PA) – 2 trials, Zone 10 (CA)
– 8 trials, Zone 11 (OR) – 2 trials) during the 2007 or 2008 growing
season.  There were three treated plots for each trial.  Each treated
plot received one broadcast application at a target rate of
0.134 lb ai/A (150 g ai/ha) to bare soil, or mown or chemically
burned-down ground cover, using backpack sprayers directed to the base
of grape vines, and extending to the row centers.  Applications were
made at target pre-harvest intervals (PHIs) of 14 days, 45 days, and
either 150 to 210 days (five to seven months) or 240 days (eight
months).  Application of Indaziflam 500 SC in this manner has been shown
to be efficacious for controlling dicot and annual grass weeds in grapes
and is representative of the proposed use pattern.  The actual rates
were 0.130 to 0.142 lb ai/A (145 to 159 g ai/ha) for all trials.  There
were no adjuvants added to the spray mixture.  All trials had three
treated plots (TRT14, TRT45, and either TR210 or TR240) that received an
application of Indaziflam 500 SC.

In grape plots treated at a target 14-day PHI, the growth stage at
application ranged from BBCH 83 to BBCH 89 (BBCH 83: fruit developing
color; BBCH 89: fruit ripe for harvest).  In plots treated at a target
45-day PHI, the growth stage at application ranged from BBCH 77 to BBCH
85 (BBCH 77: fruit beginning to touch; BBCH 85: fruit softening).  In
plots treated at a target 210- or 240-day PHI, the growth stage at
application was BBCH 00, with the exception of one target 210-day PHI
plot in which application was made at BBCH 01 and one target 240-day PHI
plot in which application was made at BBCH 11 (BBCH 00: dormancy - bud
scales more or less closed; BBCH 01: beginning of bud swelling: buds
begin to expand inside the bud scales; BBCH 11: first leaf unfolded and
spread away from shoot).  Duplicate composite samples of grapes were
collected in all trials from each treated plot (TRT14, TRT45, and either
TR210 or TR240) at the target 14-day, 45-day, and either 210-day or
240-day PHI after application.  A single composite sample was collected
from the control plot of each trial at the same time the 14-day samples
were collected from the treated plot.

The residues of indaziflam and its metabolite fluoroethyldiaminotriazine
(FDAT) were quantitated by high performance liquid
chromatography/electrospray ionization/tandem  mass spectrometry
(LC/MS/MS) using stable isotopically labeled internal standards.  The
limit of quantitation (LOQ) for total indaziflam residues (the sum of
indaziflam and fluoroethyldiaminotriazine) was 0.01 ppm in grape (fresh
fruit).

Freezer storage stability studies in representative crop matrices
indicate that the indaziflam and fluoroethyldiaminotriazine residues
would have been stable (<1% decomposition) in grape raw agricultural
commodity (RAC) during frozen storage for up to 11.5 months (345 days)
prior to analysis.  The fresh fruit analyzed in this study was held in
frozen storage for a maximum of six months (181 days) prior to
extraction.  The continuation of the storage stability studies will
provide more information when additional time intervals through 24
months are analyzed.

In grape (fresh fruit), the HAFT (highest average field trial) and
maximum total indaziflam residues at target 14-day, 45-day, and 210-day
PHIs were less than the LOQ (<0.01 ppm).  The HAFT and maximum total
indaziflam residues at a target 240-day PHI were both 0.01 ppm.

Olive.  Field trials were conducted to measure the magnitude of
indaziflam {1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]}
residues in/on olives following a single broadcast spray application of
Indaziflam 500 SC.  Indaziflam 500 SC is a suspension concentrate
formulation containing 500 g ai/L of indaziflam.

Three field trials were conducted on olives.  There were three treated
plots for each trial.  Each treated plot received one broadcast
application at a target rate of 0.134 lb ai/A (150 g ai/ha) to bare
soil, mown, or chemically burned-down ground cover using backpack
sprayers directed to the base of olive trees and extending to the row
centers.  Applications were made at target pre-harvest-intervals (PHIs)
of 14 days, 45 days, and 300 days (10 months).  Application of
Indaziflam 500 SC in this manner has been shown to be efficacious for
controlling dicot and annual grass weeds in olives and is representative
of the proposed use pattern.  The actual rates were 0.132 to 0.137 lb
ai/A (148 to 153 g ai/ha) for all trials.  There were no adjuvants added
to the spray mixture.  All trials had 3 treated plots (TRT14, TRT45, and
TR300) that received an application of Indaziflam 500 SC.

Duplicate composite samples of olives were collected in all trials from
each treated plot (TRT14, TRT45 and TR300) at the target 14-day, 45-day,
and 300-days PHI after application.  A single composite sample was
collected from the control plot of each trial at the same time the
14-day samples were collected from the treated plot.

The residues of indaziflam and its metabolite fluoroethyldiaminotriazine
were quantitated by high performance liquid chromatography/electrospray
ionization/tandem  mass spectrometry (LC/MS/MS) using a stable
isotopically labeled internal standards.  The limit of quantitation
(LOQ) for total indaziflam residue (the sum of indaziflam and
fluoroethyldiaminotriazine) was 0.01 ppm in olive (fresh fruit).

Freezer storage stability studies in representative crop matrices
indicate that the indaziflam and fluoroethyldiaminotriazine residues
would have been stable (<1% decomposition) in olive raw agricultural
commodity (RAC) during frozen storage for up to 11.7 months (351 days)
prior to analysis.  The fresh fruit analyzed in this study was held in
frozen storage for a maximum of 16 months 28 days (515 days) prior to
extraction.  The continuation of the storage stability studies will
provide more information when additional time intervals through 24
months are analyzed.

	

In olive (fresh fruit), the HAFT (highest average field trial) and
maximum total indaziflam residues at a target 14-day, 45-day, and
300-day PHI were less than the LOQ (<0.01 ppm).

Sugarcane.  No data depicting residues of indaziflam in/on sugarcane
following field application were submitted to support the requested
tolerance.

Conclusions.  The submitted crop field trials are conditionally adequate
to support the requested uses of indaziflam.  Samples from the citrus,
tree nut, and olive trials were stored longer than the duration
supported by the currently available storage stability study.  Pending
submission of an acceptable final storage stability study, the data
support the requested tolerances for all crops except almond hulls and
sugarcane (see Section 860.1550, below for a discussion of tolerance
levels).

It should also be noted that the petitioner is requesting a 7-day PHI
for citrus whereas all citrus field trials were conducted at 14 days or
longer.  All 14-day PHI citrus field trials had total indaziflam
residues that were less than both the LOQ and the LOD.  With a total
indaziflam residue LOD of 0.0011 ppm, even if the 14 day PHI total
residue was equal to the LOD and the residue assumed to be ten times
more concentrated at a 7-day PHI, then the total residue should still
not exceed the LOQ and proposed tolerance of 0.01 ppm.  The field trial
design was intended to estimate the “worst case” scenario for
long-term exposure and translocation from root uptake of the
soil-applied herbicide, with the 14-day PHI used to simulate any
possible short-term uptake.  Finally, the field trial results suggest
that the highest total residues are observed in those with the longest
PHI’s, with the FDAT metabolite being the primary residue detected
above the LOD (but still less than the LOQ).  Therefore, HED believes
that the existing data support a 7-day PHI and no additional citrus
field trials are needed.        

860.1520 Processed Food and Feed

47743411.der.doc (citrus)

47743409.der.doc (pome fruit)

47743410.der.doc (stone fruit)

47743412.der.doc (grape)

47743413.der.doc (olive)

47743408.der.doc (sugarcane)

Citrus.  An orange processing trial was conducted to measure the
magnitude of total AE 1170437, 1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]-
residue in oranges and orange processed commodities following an
exaggerated rate application of Indaziflam 500 SC to the base of orange
trees.  The test substance, Indaziflam 500 SC, is a suspension
concentrate formulation containing 500 g ai/L.

A single broadcast spray application was made to mowed ground cover,
from tree row center to tree row center in the treated plot using
ground-based equipment customarily used to apply pesticides in this
manner to orange trees. The application was made at BBCH 74, when fruits
are about 40% of the final size.  The test substance application was
made at a rate of 0.662 lb ai/A (742 g ai/ha) in a spray volume of 18.29
GPA (171 L/ha). This single application rate is equivalent to five times
(5X) the total maximum proposed label rate for a single growing season. 
A single composite sample of oranges was harvested at a 236-day PHI
(BBCH 83).

Subsamples of the oranges were removed for analysis, and the remaining
oranges were used to generate the required processed commodities of
dried pulp, oil, and juice.  Processing was performed using procedures
that simulated commercial processing practices.  The resultant orange
RAC sample was analyzed to determine total indaziflam residue.

The residues of indaziflam and its metabolite fluoroethyldiaminotriazine
were quantitated by high-pressure liquid chromatography/triple stage
quadrupole mass spectrometry (LC/MS/MS) using stable-labeled isotopes as
internal standards.  The limit of quantitation (LOQ) for total
indaziflam residue (the sum of indaziflam and
fluoroethyldiaminotriazine) was 0.01 ppm in the orange fruit raw
agricultural commodity (RAC).

Freezer storage stability studies indicate that total indaziflam residue
would have been stable in oranges during frozen storage (at least
11 months) prior to analysis.  The orange fruit analyzed in this study
was held in frozen storage for less than one month (16 days) prior to
extraction.

No total indaziflam residues were observed above the total LOQ (0.01
ppm) in the orange fruit following a 5X exaggerated rate of application
of indaziflam to oranges.  In addition no total indaziflam residue above
the total LOQ was observed in orange fruit collected from a citrus fruit
tolerance setting study.  Therefore, although oranges were processed
into dried pulp, oil, and juice, no analyses were conducted on the
processed commodities and no processing factors calculated and no
tolerances are required for processed commodities of citrus.  

Pome Fruit.  An apple processing trial was conducted to measure the
magnitude of total 

indaziflam (CAS name
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]-1,3
,5-triazine-2,4-diamine, and CAS number 950782-86-2) residues in apples
and apple processed commodities, following an exaggerated rate
application of Indaziflam 500 SC to the base of apple trees.  The test
substance, formulated as the end-use product (EP) Indaziflam 500 SC, is
a suspension concentrate (SC) formulation containing 500 grams of active
ingredient per liter (g ai/L).  

A single broadcast spray application was made to flail-mowed ground
cover, from tree row center to tree row center in the treated plot,
using ground-based equipment customarily utilized to apply pesticides in
this manner.  The test substance application was made at BBCH 0
(dormancy).  The application was made at a rate of 0.658 pounds ai per
acre (lb ai/A), the equivalent of 738 grams ai per hectare (g ai/ha),
in a spray volume of 17 gallons per acre (GPA), equivalent to 159 L/ha. 
This single application rate is equivalent to five times (5X) the total
maximum proposed label rate on apples for a single growing season.  A
single composite sample of apples was harvested at a 181-day pre-harvest
interval (PHI), corresponding to BBCH 81.  

Subsamples of the apples were removed for analysis, while the remaining
apples were used to generate the required processed commodities, juice
and wet pomace.  Processing was performed using procedures that
simulated commercial processing practices.  The apple raw agricultural
commodity (RAC) samples were analyzed to determine total indaziflam
residues.  

The residues of indaziflam and its metabolite,
1-fluoroethyldiaminotriazine, were quantitated by high-pressure liquid
chromatography with triple-stage quadrupole mass spectrometric detection
(LC/MS/MS), using stable isotopically labeled internal standards.  The
individual analyte residues were summed to give a total indaziflam
residue.  The limit of quantitation (LOQ) for total indaziflam residues
was 0.010 ppm in the apple fruit RAC.

Freezer storage stability studies indicate that total indaziflam
residues would be stable in apples during frozen storage for an interval
of at least 11 months.  The apple fruit analyzed in this study was held
in frozen storage for a maximum duration of 38 days (1.2 months) prior
to extraction.  

No total indaziflam residues were observed above the LOQ (0.010 ppm) in
the apple fruit following a 5X exaggerated rate application of
indaziflam to apples.  Therefore, although apples were processed into
juice and wet pomace, no analyses were conducted on the processed
commodities, and no processing (concentration) factors were calculated
and no tolerances are required for processed commodities of apple.  

Stone Fruit.  A plum processing trial was conducted to measure the
magnitude of total indaziflam (CAS name
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]-1,3
,5-triazine-2,4-diamine, and CAS number 950782-86-2) residues in plums
and the plum processed commodity (prunes), following an exaggerated rate
application of Indaziflam 500 SC to the base of plum trees.  The test
substance, formulated as the end-use product (EP) Indaziflam 500 SC, is
a suspension concentrate (SC) formulation containing 500 grams of active
ingredient per liter (g ai/L).  

A single broadcast spray application was made to flail-mowed ground
cover, from tree row center to tree row center in the treated plot,
using ground-based equipment customarily used to apply pesticides in
this manner.  The test substance application was made at BBCH 0
(dormancy).  The application was made at a rate of 0.668 pounds ai per
acre (lb ai/A), the equivalent of 749 grams ai per hectare (g ai/ha),
in a spray volume of 15.11 gallons per acre (GPA), equivalent to 141
L/ha.  This single application rate is equivalent to five times (5X) the
total maximum proposed label rate on plums for a single growing season. 
A single composite sample of plums was harvested at a 174-day
pre-harvest interval (PHI), corresponding to BBCH 89.  

Subsamples of the plums were removed for analysis, while the remaining
plums were used to generate the required processed commodity, prunes. 
Processing was performed using procedures that simulated commercial
processing practices.  The plum raw agricultural commodity (RAC) samples
were analyzed to determine total indaziflam residues.  

The residues of indaziflam and its metabolite,
1-fluoroethyldiaminotriazine, were quantitated by high-pressure liquid
chromatography with triple-stage quadrupole mass spectrometric detection
(LC/MS/MS), using stable isotopically labeled internal standards.  The
individual analyte residues were summed to give a total indaziflam
residue.  The limit of quantitation (LOQ) for total indaziflam residues
was 0.010 ppm in the plum fruit RAC.  

Freezer storage stability studies indicate that total indaziflam residue
would be stable in plums during frozen storage for an interval of at
least 11 months.  The plum fruit analyzed in this study was held in
frozen storage for a maximum duration of less than one month (21 days)
prior to extraction.  

No total indaziflam residues were observed above the LOQ (0.010 ppm) in
the plum fruit following a 5X exaggerated rate application of indaziflam
to plums.  Therefore, although plums were processed into prunes, no
analyses were conducted on the processed commodity, and no processing
(concentration) factors were calculated and no tolerances are required
for processed commodities of plum.  

Grape.  A grape processing trial was conducted to measure the magnitude
of total indaziflam (1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl])
residue in grapes and grape processed commodities following an
exaggerated rate application of Indaziflam 500 SC to the base of grape
vines.  The test substance, Indaziflam 500 SC, is a suspension
concentrate (SC) formulation containing 500 grams of active ingredient
per liter (g ai/L) of indaziflam.

A single broadcast spray application was made to flail mowed ground
cover, to the base of grape vines in the treated plot using ground-based
equipment customarily used to apply pesticides in this manner to grape
vines. The application was made at BBCH 0, dormancy.  The test substance
application was made at a rate of 0.67 lb ai/A (754 g ai/ha) in a spray
volume of 15.12 gallons per acre (GPA, 141 L/ha). This single
application rate is equivalent to five times (5X) the total maximum
proposed label rate for a single growing season.  A single composite
sample of grapes (growth stage BBCH 89) was harvested at a 223-day
pre-harvest interval (PHI).

Subsamples of the grapes were removed for analysis, and the remaining
grapes were used to generate the required processed commodities of juice
and raisins.  Processing was performed using procedures that simulated
commercial processing practices.  The resultant grape raw agricultural
commodity (RAC) sample and processed commodities were analyzed to
determine total indaziflam residues.

The residues of indaziflam and its metabolite fluoroethyldiaminotriazine
were quantitated by high-pressure liquid chromatography/triple stage
quadrupole mass spectrometry (LC/MS/MS) using stable-labeled isotopes as
internal standards.  The individual analyte-derived residues were summed
to give a total indaziflam residue.  The limit of quantitation (LOQ) for
total indaziflam residues (the sum of indaziflam and
fluoroethyldiaminotriazine) was 0.01 ppm in the grape fresh fruit RAC
and in the processed commodities of juice and raisins.

Total indaziflam residues were found to concentrate in juice (1.5X) and
in raisins (2.8X).  

Freezer storage stability studies indicate that total indaziflam
residues would have been stable in grapes during frozen storage (at
least 11 months) prior to analysis.  The grape fresh fruit analyzed in
this study was held in frozen storage for a maximum of 569 days (19
months) prior to extraction.  

The processing factor determined for total indaziflam residues in
raisins is less than the theoretical concentration factor based on loss
of water of 4.7X cited in Table 2 of EPA’s OPPTS Residue Chemistry
Test Guideline 860.1520.  However, the processing factor determined for
total indaziflam residues in grape juice is slightly greater than the
theoretical concentration factor based on separation into components of
1.2X cited in Table 3 of the EPA’s OPPTS Residue Test Guideline
860.1520. 

Table 8.  Residue Data from Grape Processing Study Conducted on
Indaziflam.

Matrix	Total Rate lb a.i./A

(kg a.i./ha)	PHI (days)	Indaziflam

Residue (ppm)c	FDAT Residue 

(ppm) 	Total 

Indaziflam

Residueb	Total Indaziflam Processing Factor

Grape fresh fruit	0.673

(754 )	223	<LOD

<LOD

<LOD

	0.0012

0.0014

0.0016

	0.0019

0.0020

0.0023

Avg 0.0021	NAa

Juice

	<LOD

<LOD

<LOD

	0.0023

0.0025

0.0024

	0.0030

0.0032

0.0031

Avg 0.0031	1.5X

Raisins

	<LOD

<LOD

<LOD

	0.0050

0.0056

0.0051

	0.0056

0.0062

0.0058

Avg 0.0059	2.8X

a	NA = Not applicable.

b	The average total indaziflam residue in grape fresh fruit and grape
commodites were less than the total LOQ (<0.01 ppm) however, detected
residue values below the LOQ are reported in order to calculate a
processing factor.  

c Residues below the LOD are reported as <LOD and summed into the Total
Residue value as ½ the LOD (½ LOD = 0.00065) ppm.

Olive.  An olive processing trial was conducted to measure the magnitude
of total indaziflam (1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl])
residue in olives and olive processed commodities following an
exaggerated rate application of Indaziflam 500 SC to the base of olive
trees.  The test substance, Indaziflam 500 SC, is a suspension
concentrate formulation containing 500 g ai/L.

A single broadcast spray application was made to disked soil, from tree
row center to tree row center in the treated plot using ground-based
equipment customarily used to apply pesticides in this manner to olive
trees. The application was made at BBCH 55, first individual flowers
visible (still closed).  The test substance application was made at a
rate of 0.677 lb ai/A (759 g ai/ha) in a spray volume of 15.21GPA (142
L/ha). This single application rate is equivalent to five times (5X) the
total maximum proposed label rate for a single growing season.  A single
composite sample of olives was harvested at a 287-day PHI (BBCH 89).

Subsamples of the olives were removed for analysis, and the remaining
olives were used to generate the required processed commodity of oil. 
Processing was performed using procedures that simulated commercial
processing practices.  The resultant olive RAC sample was analyzed to
determine total AE 1170437 residue.

The residues of indaziflam and its metabolite fluoroethyldiaminotriazine
were quantitated by high-pressure liquid chromatography/triple stage
quadrupole mass spectrometry (LC/MS/MS) using stable-labeled isotopes as
internal standards.  The limit of quantitation (LOQ) for total
indaziflam residue (the sum of indaziflam and
fluoroethyldiaminotriazine) was 0.01 ppm in the olive fruit raw
agricultural commodity (RAC).

Freezer storage stability studies indicate that total indaziflam residue
would have been stable in olives during frozen storage (at least
11 months) prior to analysis.  The olive fruit analyzed in this study
was held in ambient/frozen storage for a maximum of 38 days (1 month)
prior to extraction.

No total AE 1170437 residues were observed above the total LOQ (0.01
ppm) in the olive fruit following a 5X exaggerated rate of application
of indaziflam to olives.  In addition no total indaziflam residue above
the total LOQ was observed in olive fruit collected from an olive fruit
tolerance setting study.  Therefore, although olives were processed into
oil, no analyses were conducted on the processed commodities and no
processing factors calculated, and no tolerances are required for
processed commodities of olives.  

Sugarcane.  A sugarcane processing trial was conducted to measure the
magnitude of total indaziflam {1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[1-fluoroethyl]
residue in sugarcane and sugarcane processed commodities following an
exaggerated rate application of Indaziflam 500 SC to ratooned
sugarcane.  The test substance, Indaziflam 500 SC, is a suspension
concentrate formulation (SC) containing 500 grams of active ingredient
per liter (g ai/L).

A single broadcast foliar spray application was applied as an early
season pre-emergence (prior to lay-by) herbicide to a ratooned crop of
sugarcane. The application was made at pre-emergence, BBCH 8, shoot
growing toward soil surface.  The test substance application was made at
a rate of 0.18 lb ai /A (206 g ai/ha) in a spray volume of 21 gallons
per acre (GPA, 193 L/ha) to a treated plot. This single application rate
is equivalent to two times (2X) the proposed label rate for a single
growing season.  A single composite sample of sugarcane was harvested at
BBCH 39, nine or more nodes present, plant actively growing. 

Subsamples of the sugarcane were removed for analysis, and the remaining
sugarcane were used to generate the required processed commodities of
blackstrap molasses and refined sugar.  Processing was performed using
procedures that simulated commercial processing practices.  The
resultant sugarcane raw agricultural commodity (RAC) sample was analyzed
to determine total indaziflam residue.

The residues of indaziflam and its metabolite fluoroethyldiaminotriazine
were quantitated by high-pressure liquid chromatography/triple stage
quadrupole mass spectrometry (lc-ms/ms) using stable-labeled isotopes as
internal standards.  The individual analyte-derived residues were summed
to give a total indaziflam residue.  The limit of quantitation (LOQ) for
total indaziflam residues was 0.01 ppm in the sugarcane RAC.

Freezer storage stability studies indicate that total indaziflam residue
would have been stable in sugarcane during frozen storage (at least
11 months) prior to analysis.  The sugarcane analyzed in this study was
held in frozen storage for a maximum of 107 days (3.5 months) prior to
extraction.

No total indaziflam residues were observed above the LOQ (0.01 ppm) in
the sugarcane RAC following a 2X exaggerated rate of application of
indaziflam to sugarcane.  Therefore, although sugarcane was processed
into blackstrap molasses and refined sugar, no analyses were conducted
on the processed commodities and no processing factors were calculated. 

Conclusions.  Based on the available data, the only processed
commodities pertinent to the subject of the requested petition that
potentially require tolerances are grape juice and raisins.  Studies
with citrus, pome fruit, stone fruit, and olive demonstrated that
residues of concern were below the limit of quantitation at exaggerated
rates appropriate for waiving analysis of the processed foods and feeds
(i.e., residues were < LOQ at 5X exaggerated application rates).

The grape processing study relied on residue estimates between the LOD
and LOQ in order to calculate processing factors.  The calculated factor
for grape juice (1.5X) is slightly greater than the theoretical maximum
factor of 1.2X).  The calculated factor for raisins (2.8X) less than the
theoretical maximum (4.6X).  Given the high variability inherent in
quantifying residues below the LOQ and the assumptions made regarding
residues below the LOD, it is not surprising that the juice factor
slightly exceeded the theoretical maximum.  The petitioner has reduced
the maximum application rate for grapes from 0.134 lb a.i./A to 0.089 lb
a.i./A.  Based on the residue values reported in the study conducted at
ca. 0.134 lb a.i./A, the reduction in the application rate, and the
processing factors discussed above, HED does not believe that residues
in processed commodities will exceed the total indaziflam LOQ of 0.01
ppm; therefore, separate tolerances are not necessary for residues of
indaziflam in grape juice and raisins as these are covered by the
proposed tolerance for residues in/on grapes.

Although citrus RACs from submitted field trials and a processing study
have total residues below the LOQ at a 5X exaggerated rate, data for the
processed commodity of citrus oil is required due to the extremely high
potential concentration factor (1000X).  Citrus oil was not analyzed
during the originally submitted processing study.  The petitioner has
been made aware of this issue and provided data from a preliminary
analysis of citrus oil.  Although this interim report suggests that
indaziflam residues are concentrated approximately 11.7X compared to
those observed in citrus RACs, the total residues in citrus oil are
still less than LOQ (0.01 ppm).  Therefore, HED does not believe that a
tolerance for citrus oil is required, as no finite residues would be
expected even at exaggerated rates.  However, the final study report
from this citrus oil analysis should be required as a condition of
registration.   

It should be noted that all of the processing studies were conducted at
long PHI’s (174-287 days) relative to the label PHI of 7 and 14 days. 
However, based on the crop field trial results, there was a general
trend towards longer PHI having higher observed residues.  Therefore,
the use of samples with longer PHI should actually have increased the
probability of finding quantifiable residues in the RAC and processed
commodities.   

For sugarcane, samples from the processing study showed no quantifiable
residues of indaziflam or FDAT following a 2X application rate, and the
processed commodities of molasses and refined sugar were not analyzed. 
Typically, HED requires that no residues of concern be found in a RAC
following at least a 5X exaggerated application rate to make a finding
that tolerances are not necessary in the processed commodity.  Based on
information in the metabolism study, quantifiable residues of indaziflam
or FDAT would not be expected in sugarcane even at a 5X treatment rate,
with the highest observed TRR of 0.005 ppm in the 2X metabolism study.  
  Therefore, HED does not believe that residues of indaziflam and FDAT
in refined sugar will exceed those in the sugarcane RAC (i.e., <0.01
ppm).  Nevertheless, in this instance HED recommends the tolerance be
set on the refined sugar since that is the commodity to be imported. 
HED notes that a metabolism trial at a 10X exaggerated treatment rate
was initiated and subsequently terminated due to treatment-related
phytotoxicity.

860.1850 Confined Accumulation in Rotational Crops

47743414.der.doc

Bayer Crop Science has requested a waiver for the requirement of a
confined rotational crop study for indaziflam.  Given that none of the
target crops are rotated, HED waives the need for a confined rotational
crop study at this time.  Should uses for indaziflam on rotated crops be
sought in the future, a confined rotational crop study will likely be
required to support such uses.

860.1900 Field Accumulation in Rotational Crops

There are no rotational crop tolerance issues associated with this
petition.

860.1550 Proposed Tolerances

At this time, tolerances are not required for livestock commodities. 
For plant commodities, the tolerance expression for indaziflam should
read as follows:

Tolerances are established for residues of the herbicide indaziflam,
including its metabolites and degradates, in or on the commodities in
the table below as a result of application of indaziflam.  Compliance
with the tolerance levels specified below is to be determined by
measuring only indaziflam {1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R,1S)-1-fluoroet
hyl]-} and 1-fluoroethyl diaminotrizine
{6-[(1R,1S)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine}, calculated in
terms of indaziflam equivalents, in or on the commodity.

A summary of the petitioned-for tolerances and HED’s recommendations
is provided in Table 9, below.  With the exception of almond hulls, all
residue levels from field trials were below the LOQ and the
Tolerance/MRL Harmonization Spreadsheet was not used to obtain a
recommended tolerance level.  A discussion of the recommended almond
hull tolerance is provided in Attachment 3.  At this time, there are no
Canadian, Mexican, or Codex MRLs for indaziflam and, therefore, there
are no international harmonization issues with this action (Attachment
4).

Table 9.  Tolerance Summary for Indaziflam

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments
(correct commodity definition)

Fruit, citrus, Group 10	0.01	0.01	--

Fruit, pome, Group 11	0.01	0.01	--

Fruit, stone, Group 12	0.01	0.01	--

Nut, tree, Group 14	0.01	0.01	--

Pistachio	0.01	0.01	--

Almond, hulls	0.20	0.15	Spreadsheet-recommended change

Grape	0.01	0.01	--

Olive	0.01	0.01	--

Sugarcane, sugar, refined	0.01	0.01	Sugarcane, refined sugar; tolerance
without a corresponding U.S. registration

Attachment 1.  Summary of Major Residues in Metabolism and
Environmental Fate Studies.

Table A1.  Summary of Major1 Residues from Metabolism and Environmental
Fate Studies.

Compound	Sugarcane	Apples	Grapes	Goat – 

Milk	Goat -  Liver	Goat - Muscle	Goat - Fat	Goat - Kidney	Rat Excreta
Soil2	Water3

Indaziflam	24	13	24	9	2	-	20	-	38	56	21

Fluoroethyl diaminotriazine	30	72	47	13	-	15	3	2	2	39	13

Indaziflam carboxylic acid	-	-	-	9	24	6	19	20	67	22	21

Indaziflam-4-hydroxyhydroxymethyl	-	-	-	18	4	15	7	4	-	-	-

Indaziflam-dihydroxy	-	-	-	18	2	18	4	11	13	-	-

Indaziflam-4-hydroxy acid	-	-	-	-	5	-	12	14	-	-	-

Indaziflam-3-ketohydroxymethyl4	-	-	-	28	2	5	4	6	1	-	-

Indaxiflam-3-hydroxyindane4	-	-	-	18	24	14	9	17	13	-	-

Indaziflam ketone	-	-	-	-	-	-	-	-	-	16	21

Fluoroethyltriazinane-2,4-dione	-	-	-	-	-	-	-	-	-	26	-

Indaziflam hydroxyethyl	-	-	-	-	-	-	-	-	9	-	21

Indaziflam olefin	-	-	-	-	-	-	-	-	-	-	54

Yellow = greater than 10% TRR, Blue = between 1 and 10% TRR, White =
less than 1% TRR; dash (-) = not detected.

1 Only metabolites that appeared in at least one study at > 10% of the
TRR or total applied radioactivity are included in this table.  Maximum
reported values for each matrix are provided.

2 The maximum value from all soil studies is reported (i.e., aerobic and
anaerobic study results are combined).

3 The maximum value from all aquatic studies is reported, including
aquatic photolysis and aerobic aquatic metabolism.

4 Including the glucuronic acid conjugateAttachment 2.  Compounds
Identified in metabolism and environmental fate studies.

Attachment 3.  Determination of the Recommended Tolerance for Almond
Hulls.

The dataset used to obtain a tolerance recommendation for residues of
indaziflam + FDAT in almond hulls consists of field trial data depicting
residues following a single application of indaziflam to almonds per the
proposed label use pattern at rates ranging from 0.132 to 0.135 lb
a.i./A.  Total residues (indaziflam + FDAT) on almond hulls, presumably
as contamination from contact with treated ground during harvesting,
ranged from <0.01 ppm to 0.153 ppm, with five of the 10 values being
below the LOQ.  Given the left-censoring of the dataset, a maximum
likelihood estimation (MLE) algorithm was applied to the data to provide
“fill-in” values for the <LOQ data.  The data used to calculate the
recommended tolerance are summarized in Table A3.1.  Note that the
fill-in values derived by HED are different from those estimated by the
petitioner and result in a different tolerance recommendation than that
given by the petitioner.  HED surmises that the different values may be
due to the petitioner not recalculating the fill-in values provided by
the MLE spreadsheet.  The lognormal probability plot (Figure A3.1) and
the analysis summary (Table A3.2) both indicate a good log-normal fit
for the data.  The recommended tolerance level is 0.15 ppm.

Table A3.1.  Summary of Residue Values for the Determination of the
Recommended Tolerance for Residues in Almond Hulls.

Regulator:	EPA

Chemical:	Indaziflam

Crop:	Almond Hulls

PHI:	14 Days

App. Rate:

	Submitter:

Residues

< LOQ; MLE Fill-in	0.001

< LOQ; MLE Fill-in	0.002

< LOQ; MLE Fill-in	0.003

< LOQ; MLE Fill-in	0.004

< LOQ; MLE Fill-in	0.007

	0.078

	0.063

	0.145

	0.153

	0.038

Figure A3.1.  Lognormal Probability Plot for Residues in/on Almond
Hulls Following Treatment with Indaziflam.

Table A3.2.  Summary of the Tolerance/MRL Harmonization Spreadsheet
Results for Indaziflam in/on Almond Hulls.

 	Regulator:	EPA	 

 	Chemical:	Indaziflam	 

 	Crop:	Almond Hulls	 

 	PHI:	14 Days	 

 	n:	10	 

 	min:	0.001	 

 	max:	0.153	 

 	median:	0.022	 

 	average:	0.049	 

 	95th Percentile	99th Percentile	99.9th Percentile

EU Method I

Normal	0.15	0.20	0.25

	(0.25)	(0.30)	(--)

95/99 Rule	0.40	1.5	7.0

	(5.0)	(40)	(--)

EU Method II

Distribution-Free	 	0.20	 

	 	 	 

Mean+3SD	 	0.25	 

	 	 	 

UCLMedian95th

0.15

	Approximate Shapiro-Francia Normality Test Statistic	 	0.9326	 

	 	p-value > 0.05 : Do not reject lognormality assumption	 

	 	 	 

Would you like the above values rounded? (Y or N)==>	Y

Attachment 4.  International Residue Limit Summary.

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name

1,3,5-triazine-2,4-diamine,
N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl
]-	Common Name:  

Indaziflam	X  Proposed tolerance

( Reevaluated tolerance

√ No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#9F7589, 9E7588

DP Barcode:  D374105

√ No Limits

( No Limits for the crops requested	( No Limits

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	Notes/Special Instructions:  S Funk/M Negussie

Indaziflam                     Summary of Analytical Chemistry and
Residue Data                             DP Barcode D374105

  PAGE  46  of   NUMPAGES  46 

Indaziflam (080818)	Summary of Analytical Chemistry and Residue Data
Barcode:  D374105

Page   PAGE  52  of   NUMPAGES  52