Document ID: EPA-HQ-OPP-2009-0636-0022
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

Date: September 16, 2010

MEMORANDUM

SUBJECT:		Indaziflam: Human Health Risk Assessment for Use in Citrus,
Stone, and Pome Fruits; Grapes; Tree Nuts; Pistachios; Olives; and Sugar
Cane (Imported Refined Sugar).

PC Code:  080818	DP Barcode:  D367451

Decision No.:  416570	Registration No.:  432-1501

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

Assessment Type:  Single Chemical Aggregate	Case No.:  NA

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

MRID No.:  See Below	40 CFR:  None (New Active Ingredient)

FROM:	Margarita Collantes, Risk Assessor 

Elizabeth Holman, Chemist 

William Drew, Chemist

Michael Doherty, Ph.D., Chemist 

Linnea Hansen, Toxicologist

Edward Scollon, Ph.D., Toxicologist

Risk Assessment Branch 2

Health Effects Division (7509P)

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

Christina Swartz, Branch Chief

Risk Assessment Branch 2

		Health Effects Division (7509P)

					

TO:	Bethany Benbow/ James Tompkins, RM 25

		Herbicide Branch	

		Registration Division (7505P)

The Registration Division (RD) requested that the Health Effects
Division (HED) conduct a risk assessment for proposed uses of the active
ingredient indaziflam to estimate the risk to human health that will
result from the proposed use of indaziflam to control weeds in citrus,
stone, and pome fruits; grapes; tree nuts; pistachios; and olives; and
the requested tolerance without a U.S. registration on processed cane
sugar.   

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 Unpublished study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Unpublished study prepared by Bayer CropScience. 71 p.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Unpublished study prepared by Bayer CropScience. 70 p.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 	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 \f  1.0	Executive Summary	  PAGEREF _Toc267060395 \h  6 

2.0	Ingredient Profile	  PAGEREF _Toc267060396 \h  8 

2.1	Summary of Proposed Uses	  PAGEREF _Toc267060397 \h  8 

2.2	Structure and Nomenclature	  PAGEREF _Toc267060398 \h  9 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc267060399 \h  11 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc267060400 \h
 11 

3.1.1	Database Summary	  PAGEREF _Toc267060401 \h  11 

3.1.2	Toxicological Effects	  PAGEREF _Toc267060403 \h  12 

3.1.3	Dose-response	  PAGEREF _Toc267060404 \h  13 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc267060405 \h  14 

3.3	FQPA Considerations	  PAGEREF _Toc267060406 \h  14 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc267060407 \h  14 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc267060408 \h  15 

		3.3.3    Developmental Toxicity
Studies…………………………………………16

		3.3.4    Reproductive Toxicity Studies
…………………………………………..16

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc267060409 \h  16 

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc267060410 \h  16 

	3.4       FQPA Safety Factor for Infants and Children
…………………………………..17

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc267060412 \h  17 

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF
_Toc267060413 \h  17 

3.5.2	Chronic Reference Dose (cRfD)	  PAGEREF _Toc267060414 \h  18 

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc267060415 \h  18 

3.5.4	Dermal Absorption	  PAGEREF _Toc267060416 \h  18 

		3.5.5    Dermal Exposure (Short- and Intermediate-Term)
……………………   19

		3.5.6    Dermal Exposure (Long-term)
…………………………………………..19

		3.5.7    Inhalation Exposure (Short- and Intermediate-Term)
…………………...19

		3.5.8    Inhalation Exposure (Long-term)
……………………………………….20

3.5.9	Level of Concern for Margin of Exposure	  PAGEREF _Toc267060417 \h
 20 

3.5.10	Recommendation for Combining Routes of Exposure	  PAGEREF
_Toc267060418 \h  20 

3.5.11  Classification of Carcinogenic Potential	  PAGEREF _Toc267060419
\h  20 

		3.5.12  Acute Toxicity
…………………………………………………………..21

		3.5.13  Summary of Toxicological Doses and Endpoints
………………………21

3.6	Endocrine disruption	  PAGEREF _Toc267060420 \h  22 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc267060421 \h  23 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc267060422 \h 
23 

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc267060423 \h  26 3

5.2	Dietary Exposure and Risk	  PAGEREF _Toc267060425 \h  29 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc267060426 \h  30 

6.1	Residential Handler Exposure	  PAGEREF _Toc267060427 \h  30 

	6.2       Spray Drift
………………………………………………………………
………31

	6.3       Combined Residential Exposure
………………………………………………..32

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc267060428 \h  32 

7.1	Acute Aggregate Risk	  PAGEREF _Toc267060429 \h  32 

7.2	Short- and Intermediate-Term Aggregate Risk	  PAGEREF _Toc267060430
\h  32 

7.3	Long-Term Aggregate Risk	  PAGEREF _Toc267060432 \h  33 

7.4	Cancer Risk	  PAGEREF _Toc267060433 \h  33 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc267060434
\h  33 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc267060435 \h  34 

	9.1       Handler Risk
………………………………………………………………
…….35

	9.2       Occupational/Commercial Postapplication Exposure
…………………………..36

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc267060436 \h  36

10.1	Toxicology	  PAGEREF _Toc267060437 \h  36 

10.2	Residue Chemistry	  PAGEREF _Toc267060438 \h  37 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc267060439 \h 
38 

11.0     References	  PAGEREF _Toc267060440 \h  38 

Appendix A:  Toxicology Assessment	  PAGEREF _Toc267060441 \h  39 

A.1	Toxicology Data Requirements	  PAGEREF _Toc267060442 \h  39 

	A.2      Toxicity Profiles
………………………………………………………………
…40 

 Appendix B:  Table of
Structures……………………………………………………
………….481.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Indaziflam
([1,3,5-triazine-2,4-diamine,N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inde
n-1-yl]-6-(1-fluoroethyl)]) is registered as a selective, pre-emergent
and post-emergent alkylazine herbicide for control of many annual
grasses and broadleaf weeds in lawns, golf course, sod farms,
recreational turf, ornamentals, non-crop areas, Christmas tree farms and
forested areas.  It is also registered for use as a pre-emergent
herbicide for weed control in parks, railroads, utility, industrial and
municipal sites.  Bayer CropScience has submitted petitions proposing
new uses for indaziflam formulated as a 19.05% and 45.05% soluble
concentrates (Indaziflam 200 SC and  Indaziflam 500 SC) for control of
annual grasses and broadleaf weeds in citrus, stone, and pome fruits,
grapes, tree nuts, pistachios and olives.  This is the first food use
assessment for this chemical.   HED has sufficient information to
complete a human health risk assessment. 

The toxicology database is considered adequate for conducting a Food
Quality Protection Act (FQPA) risk assessment.  The scientific quality
is relatively high, and the toxicity is well-characterized for all types
of effects, including potential developmental, reproductive, immunologic
and neurologic toxicity.  The nervous system is a target for indaziflam
and neurotoxic effects are being used to assess risks from indaziflam
exposure.  Indaziflam is classified as “Not likely to be carcinogenic
to humans,” and, therefore, is not a concern for cancer effects.   HED
has evaluated the available data with respect to the Food Quality
Protection Act (FQPA) safety factor and recommends that the FQPA safety
factor be reduced to 1X.

The submitted residue chemistry data are relatively complete.  HED is
recommending for the establishment of permanent tolerances for all of
the requested crops.  The registration of indaziflam should be
conditional pending receipt of acceptable final storage stability and
citrus processing studies.  Suitable analytical methods are available to
enforce tolerances for residues of indaziflam.  

HED has assessed dietary, residential, and occupational exposures. 
Risks from these exposures, including aggregate exposures are below the
level of concern.  

Indaziflam contains a symmetrical triazine moiety.  Based on a
comparative review of its structure and toxicological profile, HED
determined that indaziflam does not belong in the triazine cumulative
assessment group.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), and the Outdoor Residential Exposure Task Force (ORETF)
Database, have been determined to require a review of their ethical
conduct, have received that review, and have been determined to be
ethically conducted.

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered for this human health risk assessment, in
accordance with US Executive Order 12898, Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf .

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by USDA under the CSFII, and are used
in pesticide risk assessments for all registered food uses of a
pesticide.  These data are analyzed and categorized by subgroups based
on age, season of the year, ethnic group, and region of the country. 
Whenever appropriate, non-dietary exposures based on home use of
pesticide products, associated risks for adult applicators, and for
toddlers, youths, and adults entering or playing on treated areas
post-application are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

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 diaminotriazine
{6-[(1R,1S)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine}, calculated in
terms of indaziflam stoichiometric equivalents, in or on the commodity. 

A summary of the petitioned-for tolerances and HED’s recommendations
is provided in Table 1 below.  With the exception of almond hulls, all
residue levels from field trials were below the Limit Of Quantitation
(LOQ) and the Tolerance/Maximum Residue Level (MRL) Harmonization
Spreadsheet was not used to obtain a recommended tolerance level.  

Table 1.  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

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

2.1	Summary of Proposed Uses  TC \l2 "2.1	Summary of Proposed Uses 

Indaziflam is a selective, pre-emergent alkylazine herbicide proposed
for control of annual grasses and broadleaf weeds in citrus, stone, and
pome fruits, grapes, tree nuts, pistachios and olives.  This assessment
includes two indaziflam end-use agricultural products; Indaziflam 200 SC
and 500 SC.  Both products are formulated as soluble concentrates and
contain 19.05 and 45.05% of the active ingredient, indaziflam,
respectively.  They may be applied, by ground equipment only, to the
soil as a uniform broadcast or band application.  Indaziflam may not be
applied by aerial equipment or chemigation.  Application may be at
anytime throughout the year when the ground is not frozen or covered
with snow.  It is most effective when adequate moisture is present and
the application is followed by rain or an irrigation event prior to weed
seed germination. Table 2.1 provides a summary of the proposed uses.

Table 2.1.  Summary of Directions for Use of Indaziflam.

Product 

EPA Reg. No.	Applications, Timing, Type, and Equip.	Application. Rate 

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Indaziflam

200 SC Herbicide

(Soluble Concentrate)

19.05% ai 

	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)a

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.

Indaziflam

500 SC Herbicide

(Soluble Concentrate)

45.05% ai 

Sugarcane (Non-Domestic - Imported)

	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 Note that Citrus field trials were conducted at 14-day PHI or longer. 
See Section 5.1.9 (Crop Field Trials and Processing) for further
discussion.  

Structure and Nomenclature

  TC \l2 "2.2	Structure and Nomenclature 

Table 2.2  Nomenclature

Compound

 

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

 

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

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 RD
(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%).  The first chemical name appearing
above in Table 2.2 (N-[(1R,2S)...]-6-[(1R) ….diamine) represents that
of the A isomer.  The second name is for isomer B and is identical to A
with the exception of the stereochemistry at the fluorine-bearing carbon
(i.e., …-6-[(1S)…diamine).  The remaining six isomers are present at
significantly lower levels and are considered to be impurities.  The
batches used for dosing in the toxicology studies had >90% isomer A,
about 1-3% isomer B, and negligible (<1%) levels of the remaining six
isomers.  These isomer contents are appropriate for the above described
composition of indaziflam

Physical and Chemical Properties

Table 2.3  Physicochemical Properties of Indaziflam (TGAI Unless
Otherwise Noted)

Parameter	

Value	

Reference

Melting point/range	183 -184 oC   indaziflam (pure substance)	Petition
Administrative Materials

pH (23 °C)	pH = 6.5     indaziflam (pure substance)

pH = 5.1     indaziflam (technical substance)

	Density 	1.23 g/cm3 at 20 °C (both pure and technical substance)

	Water solubility (g/L at 20 °C)

	pH 4:                                       0.0044 

pH 9:                                       0.0028

Distilled water (pH 6.6-6.9):  0.0028 

	Solvent solubility (g/L at 20 °C)

	Acetone:                                   55  

Acetonitrile:                            7.6 

Dichloromethane:                   150  

Dimethyl sulfoxide:              >250  

Ethanol:                                 13.0 

Ethyl acetate:                           47 

Heptane:                              0.032  

Toluene:                                  4.3 

	Vapor pressure 	2.5 x 10-8 Pa at 20 °C or 1.875 x 10-10 mm Hg

6.8 x 10-8 Pa at 25 °C or 5.1 x 10-10 mm Hg

6.9 x 10-6 Pa at 50 °C or 5.2 x 10-8 mm Hg

	Henry’s law constant 	2.69 x 10-6 [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

	

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment 

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization 

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

Studies considered for this assessment included acute lethality (oral,
dermal and inhalation routes); primary eye and dermal irritation, dermal
sensitization, subchronic oral toxicity (rat, mouse and dog), rat 28-day
dermal toxicity, rat acute and subchronic neurotoxicity, dog chronic
toxicity, rat chronic toxicity/carcinogenicity, mouse carcinogenicity,
developmental toxicity (rat and rabbit), rat two-generation reproductive
toxicity (with an additional special non-guideline study evaluating
sexual maturation in rats exposed during early development to the
triazine-ring metabolite BCS-AA10365, or FDAT), rat developmental
neurotoxicity, rat immunotoxicity, genotoxicity, rat general metabolism
(Tier 1 and Tier 2), in vivo rat dermal absorption and in vitro human
and rat dermal absorption.  

The database is considered complete with the possible exception of a 28-
or 90-day inhalation toxicity study in the rat.  The Agency is in the
process of evaluating expert advice and input on issues related to
volatilization of pesticides and route-to-route extrapolation using oral
studies for inhalation exposure assessment from its Federal Insecticide,
Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in
December, 2009 (final report of March 2, 2010;   HYPERLINK
"http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html" 
http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and
determining the appropriate toxicity data needed to assess inhalation
exposure.  The requirement of an inhalation toxicity study will be
determined once scientific guidance and policies on inhalation toxicity
have been established.  

3.1.1.1	Mode of action, metabolism, toxicokinetic data  TC \l4 "3.1.1.2
Mode of action, metabolism, toxicokinetic data 

Indaziflam is a broad-spectrum, pre- and/or post-emergent herbicide of
the fluoroalkyltriazine class.  It affects germination of seeds of
grasses and broadleaf weeds by inhibiting cell wall biosynthesis and
affecting meristematic stem growth.  The exact mode of toxicity in
mammals is unknown.  Metabolism in the rat is discussed below in Section
3.2.  

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

The nervous system is a target for toxicity in rats and dogs.  In
repeated-dose studies, the dog was the more sensitive species, showing
the lowest NOAELs among all available studies, based on neuropathology
(degenerative nerve fibers in the brain, spinal cord and sciatic nerve).
 In the rat, focal/multifocal vacuolation of the median eminence of the
brain and the pituitary pars nervosa was observed at higher doses.  
Clinical signs of neurotoxicity were observed in both species in several
studies, which included rat adult and developmental neurotoxicity
studies, including the rat acute neurotoxicity study.  Ophthalmologic
effects were also seen in the rat.  In the developmental neurotoxicity
study, decreased motor activity was observed in 21-day old male pups but
was not observed in females at later times.  Additional details on
neurotoxic effects are found in Section 3.3.2.  

In the rat and mouse, effects on the kidney were observed following
chronic exposure.  Female rats had an increased incidence of dark kidney
and basophilic renal tubules. Males in the reproductive toxicity study
showed increased kidney weights and incidence of hyaline degeneration
and tubular regeneration.  In the mouse, males showed decreased kidney
weights and increased incidences of collecting duct and pelvic
epithelial hyperplasia, papillary necrosis and intratubular yellow-brown
material.   

Liver cell hypertrophy was observed in the rat following chronic
exposure but was considered an adaptive response.  In males, white foci
were also observed.  In females, livers were enlarged and showed an
increased incidence of macrovacuolation and multinucleated hepatocytes
with anisokaryosis.  

The thyroid was affected by treatment only in male rats.  Increased
follicular cell hypertrophy and colloid alteration were observed. 
Statistically significant increases in TSH were observed at Week 3, but
not at Week 13.  There were no significant changes in levels of T3 or
T4.  Although treatment-related, the thyroid changes were not considered
of concern for development because they appeared to be secondary to
liver effects (and induction of liver metabolic enzymes), they were seen
at high doses relative to the endpoints selected for risk assessment,
and other thyroid hormone levels (T3, T4) did not show changes.  

Additional effects observed following chronic exposure included
atrophied or small seminal vesicles in male rats and glandular
erosion/necrosis in the stomach and blood-filled ovarian cysts/follicles
in female mice.  However, these effects occurred at higher doses than
those at which neurotoxicity was observed in the dog.  Decreased body
weight gain was observed in most studies following exposure to
indaziflam.  There was no evidence of immunotoxicity in the available
studies, which included a guideline immunotoxicity study in the rat.  No
systemic effects were observed in the rat following a 28-day dermal
exposure period.  

In the rat developmental toxicity study, decreased fetal weight was
observed in the presence of maternal effects that included decreased
body weight and clinical signs of toxicity.  No developmental effects
were observed in rabbits up to maternally toxic dose levels.  Decreased
pup weight and delays in sexual maturation (preputial separation in
males and vaginal patency in females) were observed in the rat
two-generation reproductive toxicity study, along with clinical signs of
toxicity, at a dose causing parental toxicity that included clinical
signs and decreased weight gain.  In the developmental neurotoxicity
study, transiently decreased motor activity (PND 21 only) in male
offspring was observed and was considered a potential neurotoxic effect.
 It was observed at a dose that also caused clinical signs of
neurotoxicity along with decreased body weight in maternal animals.

Indaziflam showed no evidence of carcinogenicity in the two-year dietary
rat and mouse bioassays.  All genotoxicity studies that were conducted
on indaziflam were negative.  

3.1.3	Dose-response  TC \l3 "3.1.3	Dose-response 

For acute dietary exposure, an acute reference dose (aRfD) of 0.50
mg/kg/day was selected for assessment of all populations, based on a
NOAEL of 50 mg/kg/day in the rat acute neurotoxicity study with
decreased motor and locomotor activities in females observed at 100
mg/kg/day.  This endpoint is a single-dose effect and is appropriate for
the populations of concern.  Although the rat developmental toxicity
study had a lower developmental NOAEL (25 mg/kg/day), the acute
neurotoxicity NOAEL of 50 mg/kg/day, with a LOAEL of 100 mg/kg/day, is
considered protective for all populations including potentially pregnant
females because of the large spread in the dose spacing in the rat
developmental study (i.e., NOAEL = 25 and the LOAEL = 200 mg/kg/day). 
Furthermore, our confidence in the use of the neurotoxicity endpoint is
supported by the observed mild effects at the rat developmental LOAEL
(200 mg/kg/day), which were limited to pup body weight decrements of
<10%. 

For chronic dietary exposure, a chronic reference dose (cRfD) of 0.02
mg/kg/day was selected for assessment of all populations, based on a
NOAEL of 2.0 mg/kg/day with evidence of nervous system microscopic
effects observed at the LOAEL of 6 and 7 mg/kg/day in males and females
respectively in the dog chronic dietary study.  This provided the most
sensitive endpoint available for chronic dietary exposure:  rat and
mouse chronic exposure NOAELs were ≥12 mg/kg/day.  

For short- and intermediate-term residential and occupational exposure
scenarios involving incidental oral and inhalation exposure, the NOAEL
of 7.5 mg/kg/day from the dog oral subchronic toxicity study was
selected.  The LOAEL of 15 mg/kg/day was based on nervous system
microscopic degenerative effects.  Developmental toxicity studies in the
rat and rabbit were also available for short-term exposure, but had
higher NOAELs (25 mg/kg/day) and, therefore were not considered
protective of potential neurotoxicity.  The rat subchronic neurotoxicity
study also had a significantly higher NOAEL (244 mg/kg/day), as did the
developmental neurotoxicity study (maternal and developmental 84
mg/kg/day).  The chronic dog study was considered for intermediate-term
exposure due to greater incidence and severity of lesions at lower doses
with continued exposure, but was not selected because, at one year, the
neuropathology at the LOAEL was minimal.  Furthermore, based on the
proposed use patterns, continuous daily exposures occurring for more
than 90 days are not expected to occur.  

Although a 28-day dermal toxicity study in the rat was available and
showed no toxicity up to the limit dose, including neuropathology or
clinical signs, it was not selected for dermal risk assessment because
the dog showed considerably greater sensitivity for neuropathology than
the rat in the oral studies.  The NOAEL from the subchronic dog study
was therefore selected to be protective of potential neurotoxicity, but
is considered a conservative endpoint due to the bolus (gavage) dosing
method employed in the dog subchronic study (similarly, in the chronic
dog study animals would consume their treated diets in a relatively
short time period).   

Long-term dermal and inhalation exposure are not expected; therefore,
endpoints were not selected.  

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

The metabolism of indaziflam has been evaluated in the rat using
indaziflam labeled with 14C at either the indane or the triazine ring. 
Indaziflam is rapidly and completely absorbed.  Radioactivity was
detected in the blood within 5 minutes of dosing.  Absorption was
estimated at 90% or greater of administered dose, based on bile
cannulation experiments.  Absorption was slightly more rapid in females
than males.  Radioactivity was rapidly excreted (approximately 90% of
dose by 24 hrs postdosing).  Excretion was predominantly fecal at the
high dose (1:10 urine:feces).  However, at the low dose, urinary
excretion was also prominent (1:1 to 1:2 urine:feces), indicating
absorption from the gastrointestinal tract was overwhelmed at the higher
oral doses.  Radioactivity was not retained at significant levels in the
tissues by 3 days’ postdosing (less than 0.2 to 0.3% of dose), with
the highest levels found in the gastrointestinal tract, liver, skin and
thyroid.  Metabolism was extensive with only 2-12% of the dose excreted
in feces as unchanged parent, and occurred primarily via oxidative
processes.  The major metabolite in the rat was the carboxylic acid
metabolite of indaziflam, which was largely excreted in the bile but
also found in urine.  Other compounds that were identified as major
metabolites in combined excreta in one or more groups were
3-hydroxyindane acid, 3-hydroxyindane acid epimer, dihydroxy, hydroxy
glucuronic acid, 3-ketoindane acid, and hydroxyethyl acid metabolites. 
The fluoroethyl diaminotriazine (FDAT) metabolite was identified at low
levels (1.18 to 1.69% of administered dose) in the triazine-labeled
groups.  Some metabolite profile differences were observed depending on
the site of the radiolabel.  For example, the dihydroxy and hydroxyethyl
acid and acid conjugate metabolites were found in the indane-labeled
group, but not the triazine-labeled group.  In the bile-duct-cannulated
group, the 3-ketohydroxymethyl metabolite was identified in feces but
was not found in the mass balance groups.   Parent compound was found at
higher levels in the triazine-labeled mass balance group than the
indane-labeled group, but was present at higher levels in the
indane-labeled group in the bile-duct-cannulation experiments. 
Metabolite profiles in males and females were comparable, with some
minor qualitative differences, but females excreted significantly less
unchanged parent compound.  

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database 

The database is considered adequate for assessment of potential
sensitivity of infants and children to the effects of indaziflam. 
Acceptable rat and rabbit developmental toxicity, rat two-generation
reproductive toxicity, rat developmental neurotoxicity, rat acute and
subchronic neurotoxicity screening and immunotoxicity studies have been
submitted.

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

Neurotoxicity was observed in the dog and the rat.  In the dog, axonal
nerve fiber degeneration was observed in the brain, spinal cord and
sciatic nerve following subchronic and chronic exposure at the LOAELs
(15 mg/kg/day in both sexes in the subchronic study and 6 and 7 in males
and females, respectively in the chronic study).  The study NOAELs were
7.5 mg/kg/day for the subchronic and 2 mg/kg/day for the chronic study. 
No clinical signs of toxicity were observed at doses up to 11 and 15
mg/kg/day (chronic/subchronic studies).  High dosed dogs in the
subchronic study (30 mg/kg/day) were prematurely terminated due to
excessive clinical signs including ataxia, tremors, decreased pupil
response, seizures and other findings.  

In the rat, a marginal decrease in motor/locomotor activity was observed
in females in the acute neurotoxicity study at 100 mg/kg (NOAEL = 50
mg/kg).  Additional findings at higher doses include tremors, increased
reactivity, decreased activity, and urine, oral or perianal staining. 
Males also showed nerve fiber degeneration of the gasserian ganglion,
sciatic nerves and tibial nerves.  Similar clinical and motor activity
changes were observed in the subchronic neurotoxicity study, although no
neuropathology was observed.  Decreased motor and locomotor activity in
females and clinical signs in both sexes (including tremors, repetitive
chewing movements and perianal/lacrimal staining) were reported in the
subchronic neurotoxicity study at a higher dose (about 580 mg/kg/day
with a NOAEL of 244 mg/kg/day) than the acute study, probably as a
result of gavage vs. dietary exposure.  The clinical signs were
consistent with neurotoxicity, but also could have been due to systemic
toxicity.  In addition, similar clinical findings were seen in P and F1
generation animals in the reproductive toxicity study, at doses ≥318
mg/kg/day.  Clinical signs of neurotoxicity following chronic dietary
exposure to the rat at dietary concentrations ≥12 mg/kg/day were
numerous and included dilated pupil, reduced motor activity, movement
and posture abnormalities, soiling and staining, tremors, reduced
alertness, labored, rapid or noisy respiration, piloerection and
ophthalmological abnormalities, including mydriasis, absent papillary
reflex and pale fundus.  At terminal sacrifice, focal/multifocal
vacuolation of the median eminence in the brain and of the pars nervosa
was seen in males and females and peripheral or bilateral retinal
atrophy in females.  Neurotoxicity was not observed in the mouse.  

In a developmental neurotoxicity study on indaziflam, pregnant rats were
administered indaziflam at dietary concentrations of 0, 150, 1000 or
7000 ppm; equivalent to average daily intakes of  0, 13, 83.8 or 432
mg/kg/day.  The high dose, originally at 7000 ppm, was reduced to 4000
ppm on LD 4.  Maternal and offspring toxicity were observed only at the
high dose of 432 mg/kg/day.  Maternal clinical signs (daily observations
and/or FOB) include coarse tremor, dilated pupils or dilated pupils that
were unresponsive to penlight, nasal staining and repetitive chewing
movements.  Maternal body weight and weight gain were decreased during
gestation and lactation.  The number of litters was reduced by 17%.  In
the offspring, body weights were also decreased in both sexes from PND 1
through lactation; postweaning males also had lower body weights.  A
statistically significant decrease in motor activity (29%) on PND 21 was
observed in males only at higher doses; although no changes were seen at
other assessment times or in females, it was considered
treatment-related because it was statistically significant and outside
the laboratory historical control range. 

Developmental Toxicity Studies

Acceptable developmental toxicity studies in the rat and rabbit are
available.  In the rat, maternal body weight gain and food consumption
were decreased at 200 mg/kg/day.  Decreased fetal body weight was
observed at 200 mg/kg/day.  The maternal and developmental NOAEL was 25
mg/kg/day.  In the rabbit, decreased maternal body weight gain and food
consumption, and macroscopic liver changes in one doe (pallor, white
foci) were observed at 60 mg/kg/day, but no developmental effects were
observed.  The maternal NOAEL was 25 mg/kg/day and the developmental
NOAEL was 60 mg/kg/day.  The developmental neurotoxicity study is
described above in Section 3.3.2.

Reproductive Toxicity Studies

In the reproductive study parental toxicity was observed only at the
high dose (≥317 mg/kg/day) and includes coarse tremors in females
during premating, gestation and lactation, decreased body weight gain
and food consumption in both sexes and kidney effects in males
(increased absolute and relative weight and hyaline
degeneration/regeneration).  Offspring toxicity was also observed only
at the high dose.  Clinical signs of toxicity in F1 pups included
perianal, urine and nasal stains, tremors, increased reactivity and
activity, myoclonus, and diarrhea but no signs were seen in F2 pups.  F1
pup weights were decreased through the postnatal period for males and
females. Reproductive toxicity was observed as delays in achieving
sexual maturation at the high dose, as measured by preputial separation
(males) and vaginal opening (females), in the F1 and F2 offspring.  The
NOAEL for parental, offspring and reproductive toxicity was 69.3
mg/kg/day.

3.3.5	Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources 

No published studies, relevant to human hazard resulting from use of
indaziflam, were identified. 

3.3.6	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity 

3.3.6.1	   Determination of Susceptibility  TC \l4 "3.3.6.1
Determination of Susceptibility 

There was no evidence of increased susceptibility (qualitative or
quantitative) for pre- and/or postnatal effects in developmental
toxicity studies in the rat and rabbit, the rat developmental
neurotoxicity study or the rat two-generation reproductive toxicity
study.  There is no concern and there are no residual uncertainties for
qualitative or quantitative pre- and/or postnatal susceptibility to
indaziflam.  This is based on the completeness of the database, lack of
evidence of increased susceptibility, and the selection of endpoints
with low NOAELs that are adequately protective of potential
developmental effects.  Delayed sexual maturation in offspring was
observed at the highest dose of the reproductive toxicity study in the
presence of maternal toxicity.  Effects in offspring in the
developmental neurotoxicity study (decreased motor activity in males on
PND 21) were well characterized and were only observed at doses that
caused maternal neurotoxicity.  Although treatment-related thyroid
histological changes (following subchronic or chronic exposure) and
transiently increased TSH (at Week 3 but not Week 14) were observed in
male rats, they are not of concern for developmental effects because
they were only observed in the males, were observed at a high dose
relative to the selected regulatory endpoints, and appear to be
secondary to liver effects.  

FQPA Safety Factor for Infants and Children

HED recommends reduction of the FQPA safety factor to 1X.  The toxicity
database for indaziflam is complete, including the required studies that
characterize potential susceptibility of infants and children. There was
no evidence of increased quantitative or qualitative pre- and/or
postnatal susceptibility; developmental effects in the rat were observed
only at high doses in the presence of maternal/parental toxicity. 
Although indaziflam causes neurotoxicity, the effects are well
characterized and served as the basis for endpoint selection. 
Therefore, the risk assessment is protective of potential neurotoxicity
and other effects which occurred at higher doses.  Conservative,
upper-bound assumptions were used to determine exposure through food,
drinking water and residential sources, such that these exposures have
not been underestimated.

Although the dog is the more sensitive species, the results of the rat
developmental neurotoxicity study, which thoroughly examined potential
effects to the developing nervous system following pre- and post-natal
exposure, showed only marginal effects in offspring (slightly decreased
motor activity, absolute brain weight) at relatively high (and
maternally toxic)  doses and indicates that increased susceptibility
does not occur.

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

3.5.1	Acute Reference Dose (aRfD) – All Populations Including Infants
and Children and Females Age 13-49   TC \l3 "3.5.1	Acute Reference Dose
(aRfD) - Females age 13-49 

Study Selected:  Acute Neurotoxicity – Rat 

MRID Nos:  47443310

Dose and Endpoint for Risk Assessment: NOAEL = 50 mg/kg, based on
decreased motor and locomotor activity in females at 100 mg/kg. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X
intraspecies variability)

  = 0.50 mg/kg

Comments about Study/Endpoint/Uncertainty Factors:   The selected NOAEL
of 50 mg/kg is from a study of the appropriate route and duration.  The
decreases in motor and locomotor activity are considered potential
single-dose effects because they were observed within the first hours
following dosing.  The endpoint is protective of the decreases in
maternal body weight gains seen within the first three days of exposure
in the developmental rat (25/200 mg/kg/day, NOAEL/LOAEL) and rabbit
(25/60 mg/kg/day, NOAEL/LOAEL) toxicity studies, but which were
considered questionable as an endpoint due to variability in the data. 
No other acute effects were observed in the database.  The endpoint is
also protective of potential developmental effects, based on the lack of
observed increased pre- and/or postnatal susceptibility and higher
LOAELs observed in developmental, reproductive, neurotoxicity,
developmental neurotoxicity and immunotoxicity studies.   Although the
rat developmental toxicity study’s developmental NOAEL was lower (25
mg/kg/day), the neurotoxicity NOAEL of 50 mg/kg/day is considered
protective because the rat developmental LOAEL (7-9% decrease in fetal
body weight) was significantly greater (200 mg/kg/day) and the effects
were relatively mild at that dose and unlikely to occur after a single
dose.   

3.5.2	Chronic Reference Dose (cRfD)

  TC \l3 "3.5.3	Chronic Reference Dose (cRfD) 

Study Selected:  Chronic Toxicity (Dietary) – Dog

MRID No:  47743294

Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/day, based on
nerve fiber degeneration in the brain, spinal cord and sciatic nerve at
6 and 7 mg/kg/day (M and F respectively). 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X
intraspecies variability)

  = 0.02 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:   The NOAEL selected
for this risk assessment represents the lowest available NOAEL for
effects of indaziflam following long-term dietary administration. The
RfD is protective of potential developmental effects, based on the lack
of observed increased pre- and/or postnatal susceptibility and
significantly higher NOAELs observed in developmental, reproductive,
neurotoxicity, developmental neurotoxicity and immunotoxicity studies.  

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term) 

  TC \l3 "3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected:  Subchronic Toxicity (Gavage) – Dog

MRID No:  47743289

Dose and Endpoint for Risk Assessment:  NOAEL = 7.5 mg/kg/day, based on
brain, spinal cord and sciatic nerve degenerative lesions at 15
mg/kg/day. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors:  The selected
endpoint is the most sensitive NOAEL available from an oral study of
appropriate exposure duration (90-days) for short-term (up to 30 days)
and intermediate-term (up to 6 months) exposure via the oral route.  The
selected endpoint is protective of potential postnatal developmental
toxicity, based on the lack of observed postnatal susceptibility and
significantly higher NOAELs for postnatal toxicity in the developmental
neurotoxicity and the two-generation reproductive toxicity studies.

3.5.4	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

In addition to a 28-day study evaluating dermal toxicity in the rat, an
in vivo dermal absorption study in the rat and in vitro dermal
absorption studies in the rat and human were submitted.   The data
demonstrated an inverse relationship between dosing concentration and
percent absorption.  Based on in vivo dermal absorption observed in the
rat and in vitro comparative rat:human absorption data, an estimated
human dermal absorption factor (DAF) of 7.3% was obtained.

The human DAF was calculated as follows (all absorption values adjusted
for recovery):  (1) in the rat in vivo dermal absorption study, 27.39%
of the applied dose was absorbed at 24 hrs postexposure (actual exposure
time 8 hrs) using an application of 0.0005 mg/cm2;  (2) in vitro
exposure of microtomed rat skin under the same exposure and assessment
conditions gave a dermal absorption of 22.40%;  (3) the ratio of the in
vitro to the in vivo absorption is 0.82 (22.4/27.39) and therefore is
close to 1, indicating that the in vitro data is predictive of in vivo
absorption; (4) based on this ratio, a DAF for humans may be calculated
using in vitro human dermal absorption (5.975%, adjusted for recovery) 
observed in vitro under the same exposure conditions.  The DAF for
humans is therefore 5.975%/0.82 = 7.3%.

Dermal Exposure (Short-Term, 1-30 days, and Intermediate-Term, 1-6
months)

Study Selected:  Subchronic Toxicity-Dog

MRID No:  47743289

Dose and Endpoint for Risk Assessment:  NOAEL = 7.5 mg/kg/day, based on
degenerative brain, spinal cord and sciatic nerve fiber lesions at 15
mg/kg/day. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors:  The selected
endpoint is the most sensitive NOAEL available from a study of
appropriate exposure duration (90 days) for short- and intermediate-term
exposure.  The subchronic oral dog study was selected over other studies
because the dog was the most sensitive species for neurotoxicity and had
the lowest overall NOAEL.  Although a 28-day dermal toxicity study in
the rat showed no effects at the limit dose (including neuropathology),
it was not selected as an endpoint for this exposure scenario due to the
significantly greater sensitivity for neurotoxicity seen in the dog
relative to the rat.  Neurotoxic effects in the dog were identified at
doses that were 10-20 times lower than in the rat.  The endpoint is
nonetheless considered conservative because the effects in the dog were
observed following gavage dosing, in contrast to a relatively slower
dermal absorption rate.  For route-to-route extrapolation, dermal
absorption of 7.3% relative to oral absorption was used, estimated from
human and rat in vitro and rat in vivo dermal absorption.

Dermal Exposure (Long-Term, >1 year)

Long-term dermal exposures are not anticipated from occupational
activities.  

Inhalation Exposure (Short-Term, 1-30 days and Intermediate-Term, 1-6
months)

Study Selected:  Subchronic Toxicity-Dog

MRID No:  47743289

Dose and Endpoint for Risk Assessment:  NOAEL = 7.5 mg/kg/day, based on
degenerative brain, spinal cord and sciatic nerve fiber lesions at 15
mg/kg/day. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors:  The selected
endpoint is the most sensitive NOAEL available from a study of
appropriate exposure duration (90-days) for short- and intermediate-term
exposure.  The subchronic oral dog study was selected over other studies
because the dog was the most sensitive species for neurotoxicity and
overall lowest NOAEL.  For route-to-route extrapolation, inhalation
absorption of 100% is assumed relative to oral absorption because there
are no data on inhalation absorption and a route-specific inhalation
study is not available.

Inhalation Exposure (Long-Term) 

Long-term inhalation exposure scenarios are not anticipated for
occupational exposures.  

3.5.9	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure 

Table 3.5.9.  Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	NA

Inhalation	100	100	NA

Residential Exposure

Dermal	100	100	NA

Inhalation	100	100	NA

Oral	100	100	NA 

    NA = not applicable 

3.5.10	Recommendation for Combining Routes of Exposure for Risk
Assessments  TC \l3 "3.5.9	Recommendation for Aggregate Exposure Risk
Assessments 

When there are potential occupational and residential exposures to the
pesticide, the risk assessment must address exposures from three major
sources: oral, dermal and inhalation exposures and determine whether the
individual exposures can be combined if they have the same toxicological
effects.  Since the dermal, inhalation and oral endpoints are based on
the same effects (neurotoxicity) these routes of exposure may be
combined for purposes of this risk assessment.  

3.5.11	Classification of Carcinogenic Potential  TC \l3 "3.5.10
Classification of Carcinogenic Potential 

There was no evidence of carcinogenicity observed in the two-year
dietary rat or mouse carcinogenicity bioassays.  Genotoxicity studies
(reverse gene mutation in bacteria, forward gene mutation in mammalian
cells and in vitro and in vivo chromosomal aberration assays) were
negative.  Based on the lack of evidence of carcinogenicity or
genotoxicity, HED classified indaziflam as “Not likely to be
carcinogenic to humans.”

3.5.12 Acute Toxicity

Indaziflam shows low acute toxicity by all routes of exposure (Toxicity
Category III, oral and dermal and Category IV, inhalation) and is not an
ocular or dermal irritant or a dermal sensitizer.  

3.5.13	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments of Indaziflam 

Table 3.5.13. Summary of Toxicological Doses and Endpoints for
Indaziflam for Use in Dietary and Non-Occupational Human Health Risk
Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (All Populations, including Infants and Children and
Females 13-49 years of age)	NOAEL = 50 mg/kg/day	UFA= 10X

UFH= 10X

FQPA SF= 1X   	Acute RfD = 0.5

mg/kg/day

aPAD = 0.5 mg/kg/day	Acute oral neurotoxicity in the rat

LOAEL = 100 mg/kg/day, based on decreased motor and locomotor activity
in females.

Chronic Dietary (All Populations)	NOAEL = 2 mg/kg/day	UFA= 10X

UFH= 10X

FQPA SF= 1X   	Chronic RfD = 0.02

mg/kg/day

cPAD = 0.02 mg/kg/day	Chronic oral (dietary) toxicity in the dog

LOAEL = 6/7 mg/kg/day M/F, based on nerve fiber degenerative lesions in
the brain, spinal cord and sciatic nerve. 

Incidental Oral, Short-term (1 to 30 days) and Intermediate-term (1 to 6
months)	NOAEL = 7.5 mg/kg/day	UFA=10X

UFH=10X

FQPA SF = 1X	Residential LOC for MOE = 100	 Subchronic oral (gavage) in
the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Dermal, Short-term (1 to 30 days) and Intermediate-term (1 to 6 months)
NOAEL = 7.5 mg/kg/day

DAF = 7.3%	UFA=10X

UFH=10X

FQPA SF = 1X	Residential LOC for MOE = 100	Subchronic oral (gavage) in
the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Dermal, Long-Term (>6 months)	Not required for this assessment (exposure
is seasonal; long-term dermal exposure scenarios are not anticipated).

Inhalation, Short-term (1 to 30 days) and Intermediate-term (1 to 6
months)	NOAEL = 7.5 mg/kg/day

Inhalation absorption assumed to be 100% (default) relative to oral.
UFA=10X

UFH=10X

FQPA SF = 1X	Residential LOC for MOE = 100	Subchronic oral (gavage) in
the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Inhalation, Long-term (>6 months)	Not required for this assessment
(exposure is seasonal; long-term inhalation exposure scenarios are not
anticipated).

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans”

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population
adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.  DAF
= dermal absorption factor

Table 3.5.13 Summary of Toxicological Doses and Endpoints for
Indaziflam for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal, Short-Term (1 to 30 days) and Intermediate-term (1 to 6 months)
NOAEL = 7.5 mg/kg/day

DAF = 7.3%	UFA=10X

UFH=10X	Occupational LOC for MOE = 100	Subchronic oral (gavage) in the
dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Dermal, Long-Term (>6 months)	Not required for this assessment (exposure
is seasonal; long-term occupational exposure scenarios are not
anticipated).

Inhalation Short-Term (1 to 30 days) and Intermediate-Term (1 to 6
months)	NOAEL= 7.5 mg/kg/day.  Inhalation absorption assumed to be 100%
(default) relative to oral.	UFA=10X

UFH=10X	Occupational LOC for MOE = 100	Subchronic oral (gavage) in the
dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Inhalation Long-Term (> 6 months)	Not required for this assessment
(exposure is seasonal; long-term occupational exposure scenarios are not
anticipated).

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” 

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable. DAF = dermal absorption factor.

3.6	Endocrine disruption  TC \l2 "3.6	Endocrine disruption 	

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including all pesticide active and other ingredients) “may
have an effect in humans or wildlife similar to an effect produced by a
naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations.  Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data.  Tier 2 testing is designed to identity any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.  

EPA is issuing test orders/data call-ins for the first group of 67
chemicals, which contains 58 pesticide active ingredients and 9 inert
ingredients.  This list of chemicals was selected based on the potential
for human exposure through pathways such as food and water, residential
activity, and certain post-application agricultural scenarios.  This
list should not be construed as a list of known or likely endocrine
disruptors.

Indaziflam is not among the group of 58 pesticide active ingredients on
the initial list to be screened under the EDSP.  Under FFDCA sec. 408
(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients.

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website: http://www.epa.gov/endo/.

4.0	Public Health and Pesticide Epidemiology Data and Incident Reports 
TC \l1 "4.0	Public Health and Pesticide Epidemiology Data 

There are no public health, pesticide epidemiology or incident data to
report at this time.

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

(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; D374105; E. Holman; September 9,
2010)

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops

Metabolism studies were performed in three primary crops, apples, grapes
and sugarcane.  In plants, the metabolism of indaziflam is relatively
uncomplicated with parent indaziflam and the fluoroethyl diaminotriazine
(FDAT) metabolite being the only indentified compounds.  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 5.1.7.  

5.1.2	Metabolism in Livestock

Metabolism data depicting the residue profile in the lactating goat were
submitted reflecting indaziflam labeled with 14C at either the indane or
the triazine ring, with separate studies being submitted for each
specific ring. Based on the available information, indaziflam appears to
undergo significant oxidative metabolism in ruminants.  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.

5.1.3	Metabolism in Rotational Crops

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.

5.1.4	Environmental Degradation

Field and laboratory data indicate that indaziflam and its degradates
have a potential to leach to ground water, particularly FDAT. 
Indaziflam is classified as moderately mobile; however, transformation
products of indaziflam are mobile to highly mobile and were detected in
field studies at depth.  Further, data show that indaziflam is
persistent in anaerobic soil and anaerobic aquatic systems.  There are
no data available on the anaerobic degradation of the transformation
products of indaziflam.  Key lines of evidence show that residues of
indaziflam, and degradate products (e.g., FDAT) are a concern for
exposure via ground water.  A prospective ground water study could help
reduce the uncertainty regarding the exposure via ground water.  

5.1.5	Comparative Metabolic Profile

The metabolism of indaziflam is complex, with a few major metabolites
(fluoroethyl diaminotriazine = FDAT, and indaziflam carboxylic acid)
found in plants, goat, rat, soil and water and numerous minor
metabolites.  Table 5.1.5 provides a profile of the major residues from
metabolism and environmental fate studies.

In determining metabolism OPP performed a preliminary review of the
available metabolism and environmental fate data for purposes of
determining the residues of concern for drinking water by the Residues
of Concern Knowledgebase Subcommittee (ROCKS) (G. Kramer, D371659,
February 18, 2010).

The metabolism of indaziflam has been evaluated in the rat using
indaziflam labeled with 14C at either the indane or the triazine ring. 
Indaziflam is rapidly and completely absorbed.  Radioactivity was
rapidly excreted (approximately 90% of dose by 24 hrs postdosing). 
Metabolism was extensive with only 2-12% of the dose excreted in feces
as unchanged parent, and occurred primarily via oxidative processes. 
The major metabolite in the rat was the carboxylic acid metabolite of
indaziflam, which was largely excreted in the bile but also found in
urine.  Other compounds that were identified as major metabolites in
combined excreta in one or more groups were 3-hydroxyindane acid,
3-hydroxyindane acid epimer, dihydroxy, hydroxy glucuronic acid,
3-ketoindane acid, and hydroxyethyl acid metabolites.  The fluoroethyl
diaminotriazine (FDAT) metabolite was identified at low levels (1.18 to
1.69% of administered dose) in the triazine-labeled groups.  

Conclusions regarding residues of concern for metabolites in proposed
crops and livestock are that while the residue profile in crops is
comprised of indaziflam and FDAT being the only indentified compounds;
however, in the goat indaziflam appears to undergo significant oxidative
metabolism.  There are a number of significant (> 10% TRR) metabolites,
depending on the commodity (i.e., milk, liver, muscle, fat) being
examined, with most consisting of some level of increased hydroxylation
relative to the parent compound.

Residues of concern for metabolites in soil consist of the parent, FDAT,
carboxylic acid, indaziflam ketone, and fluoroethyltriazinane-2,4-dione.

Several environmental degradates are of concern for drinking water risk
assessment.  Drinking water residues of concern for this purpose include
triazine indanone, indaziflam carboxylic acid, FDAT, dihydroamino
triazine, indaziflam hydroxyethyl, and indaziflam olefin.  

Table 5.1.5.  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

5.1.6	Toxicity Profile of Major Metabolites and Degradates

With the exception of FDAT and dihydroamino triazine, all of the major
metabolites are assumed to have comparable toxicity to the parent due to
structural similarity (i.e., both rings intact).  FDAT is not expected
to be more toxic than the parent indaziflam based on FDAT’s
non-neurotoxic mode of action (E. Scollon, D371661, April 21, 2010). 
Therefore, the neurotoxic endpoints selected for this risk assessment
will be protective of potential FDAT toxicity.  Dihydroamino triazine
(ROI1) is assumed to have comparable toxicity to FDAT.

5.1.7	Pesticide Metabolism and Degradates of Concern   TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation 

Based on the available metabolism studies, HED concluded that for these
uses, the nature of the residue has been adequately delineated for
tolerance enforcement and risk assessment (Table 5.1.7).  Structures of
these compounds are shown in Appendix C. 

Table 5.1.7:  Residue Definition for Indaziflam.

Matrix	Risk Assessment	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 + dihydro-
amino triazine	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).

5.1.8	Analytical Methodology

Bayer CropScience method DH-003-P07-02 was developed to determine the
residues of AE 1170437 in fruit and tree nut matrices.  Method
DH-003-P07-02 is based on high performance liquid chromatography with
tanden mass spectrometry (LC/MS/MS), 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
method’s accuracy and effectiveness.

Food Residue Profile 

Crop Field Trials and Processing Studies:	Bayer Crop Science has
conducted and submitted adequate field trial data on citrus, pome, and
stone fruits; tree nuts; grapes; and olives and processing studies 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
NAFTA-harmonized tolerance/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. 

Although citrus RACs from submitted field trials and a processing study
have total residues below the LOQ at a 5X exaggerated rate, data for
citrus oil are required due to the extremely high potential
concentration factor (1000X) for that processed commodity.  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.   

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.        

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.

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.   

Meat, Milk, Poultry and Eggs:	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 Crops:	Limited field 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.

Storage Stability:	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.  The petitioner has indicated that while the final
report has not been through quality assurance review, preliminary
findings show that the residues have remained stable over a 25-26 month
period.   Submission of the ongoing storage stability study covering the
full duration of sample storage should be made a condition of
registration.

5.1.10	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water
Residue Profile 

(Tier 2 Drinking Water Exposure Assessment for the Section 3 New
Chemical Registration of Indaziflam; R. Baris, D356141; February 2,
2010)

Based on a review of the available environmental fate data, the ROCKS
determined that the four major transformation products that maintain the
dual ring structure of indaziflam should be included in the drinking
water exposure assessment since they may be of toxicological concern
(i.e., they are assumed to be of equal or lower toxicity to the parent
in the absence of toxicological data).  These transformation products
include: triazine indanone, indaziflam-carboxylic acid,
indaziflam-olefin, and indaziflam-hydroxyethyl.  In order to account for
residues of these transformation products, the Environmental Fate and
Effects Division (EFED) calculated drinking water concentrations for
total indaziflam residues which included indaziflam and similarly
structured degradates.  EFED also calculated separate concentration
estimates for FDAT plus dihydroamino triazine (ROI1; a degradate of
FDAT). Drinking water concentrations were based on maximum seasonal
application rates for citrus (0.134 lb ai/A), which is higher than turf
application rates (0.094 lb ai./A) and thus protective of drinking water
scenarios and populations.  As noted above, HED has included the residue
estimates for FDAT and ROI1 directly in the indaziflam assessment due to
the available toxicity data indicating the neurotoxic endpoints for
indaziflam are protective of toxicity from these degradates.  The
drinking water concentrations used to estimate exposure via drinking
water are included in Table 5.1.10.  

Table 5.1.10	Summary of Estimated Surface Water and Groundwater
Concentrations for Indaziflam

Exposure Duration	Indaziflam	FDAT + ROI1	Combined*

	Surface, ppb a	Ground, ppb b	Surface, ppb a	Ground, ppb b	Surface, ppb
Ground, ppb

Acute	48	1.6	19	1.1	84	3.7

Chronic (non-cancer)	14	1.6	6	1.1	26	3.7

* Residue estimates for FDAT and ROI1 have been converted to indaziflam
equivalents (molecular weight ratio = 301÷157 = 1.92) and included
directly in the indaziflam concentration estimates.

a From the PRZM and EXAMS 

b From the SCI-GROW model assuming a maximum seasonal use rate of 0.134
lb ai/A for citrus.

5.1.11	International Residue Limits

At this time, there are no Canadian, Mexican, or Codex MRLs for
indaziflam and, therefore, there are no international harmonization
issues with this action.  

5.2	Dietary Exposure and Risk TC \l2 "5.2	Dietary Exposure and Risk 

(Indaziflam: Acute and Chronic Aggregate Dietary Exposure (Food and
Drinking Water) and Risk Assessment for the Section 3 Registration on
Pome Fruits, Stone Fruits, Citrus, Tree Nuts (including Pistachios),
Grapes, Olives, and Sugarcane; E. Holman; D376909; July 28, 2010)

 

Acute and chronic aggregate dietary risk assessments (food and drinking
water) were conducted using the Dietary Exposure Evaluation Model
(DEEM-FCID, Version 2.03), which uses food consumption data from the
U.S. Department of Agriculture (USDA’s) Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998.  The acute and
chronic analyses are based on tolerance-level residues and 100% crop
treated assumptions.  Default processing factors were used for all
commodities, with exception of the empirically derived raisin processing
factor of 2.8X.  For acute and chronic assessments, HED is concerned
when dietary risk exceeds 100% of the PAD.  The acute and chronic
dietary exposure analysis results are reported in Table 5.2 and show all
population exposures are well below HED’s level of concern.

The acute dietary risk estimate for the general U.S. population is <1%
of the aPAD.  The most highly exposed population subgroup is all infants
(<1 yr old), with a risk estimate of 3% of the aPAD.  

The chronic dietary risk estimate for the general U.S. population is 3%
of the cPAD.  The most highly exposed population subgroup is all infants
(<1 yr old), with a risk estimate of 10% of the cPAD.  



Table 5.2  Summary of Dietary Exposure and Risk for Indaziflam1

Population Subgroup*	

Acute Dietary	

Chronic Dietary	

Cancer

	

Dietary Exposure (mg/kg/day)	

% aPAD	

Dietary Exposure

(mg/kg/day)	

% cPAD	

Dietary Exposure

(mg/kg/day)	

Risk

General U.S. Population	0.00448	<1	0.000600	3	N/A	N/A

All Infants (< 1 year old)	0.016674	3	0.001922	10

Children 1-2 years old	0.007148	1	0.001061	5

Children 3-5 years old	0.006459	1	0.000929	5

Children 6-12 years old	0.004447	<1	0.000606	3

Youth 13-19 years old	0.003648	<1	0.000438	2

Adults 20-49 years old	0.004103	<1	0.000542	3

Adults 50+ years old	0.003712	<1	0.000571	3

Females 13-49 years old	0.004118	<1	0.000543	3

1The value for the highest exposed population in the acute and chronic
risk assessment is bolded.  

5.2.1	Cancer Dietary Risk

HED has classified indaziflam as “not likely to be carcinogenic to
humans.”  Based upon this classification, HED has determined there is
no cancer risk associated with the proposed uses.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization 

(Occupational and Residential Exposure Assessment for Use of the New
Active Ingredient Indaziflam on Turf, Golf Courses, Sod Farms, Christmas
Tree Farms, Non-Crop Areas and Forestry; M. Collantes: April 2010;
D372538)

  

6.1	Residential Handler Exposure TC \l2 "6.1	Residential Handler
Exposure 

A residential assessment for use of indaziflam on turf was previously
conducted in D372538 (M. Collantes; 4/21/10).  No new residential uses
are being requested at this time.  Handler MOEs were significantly
greater than 100 (ranging from 3,000 to 510,000) and are not of concern.
 

The postapplication scenarios resulting from commercial and residential
applications were assessed for adults and children using the HED Draft
Standard Operating Procedures (SOP’s) for Residential Exposure
Assessments, 2000.   All adult and children residential lawn and golf
dermal exposures and oral non-dietary ingestion exposures for children
(i.e. soil ingestion, and hand-/object-to-mouth) were assessed. 
Scenarios resulted in MOEs greater than the level of concern (ranging
from 2,800 to 2,100,000) for short-term exposure and are not of concern
to HED.   Furthermore, the episodic oral MOE for incidental ingestion of
granules among young children (3 to 6 years of age) is 5,000 and
therefore is not of concern to HED.  

The short- and intermediate-term dermal endpoints are the same, and only
short-term dermal exposures were assessed for adults and children.  HED
estimates short-term dermal postapplication exposure based on day-0
residues.  Using day-0 residues to assess intermediate-term exposure
does not take into account dissipation of residues over time and thus
results in a conservative estimation.  Therefore, the short-term dermal
postapplication exposure assessment represents the worst case scenario
and is protective of intermediate-term dermal exposure.

Based on the Agency's current practices, a quantitative postapplication
inhalation exposure assessment was not performed for indaziflam at this
time primarily because it has a very low vapor pressure (vapor pressure
5 x 10-10 mmHg at 25ºC), it is applied at low application rates
(maximum rates range from 0.089 - 0.125 lbs ai/A depending on use site),
and it is not projected to be applied via typically high inhalation
exposure application equipment (e.g., airblast and aerial equipment). 
However, volatilization of pesticides may be a potential source of
postapplication inhalation exposure to individuals nearby pesticide
applications.  The Agency sought expert advice and input on issues
related to volatilization of pesticides from its Federal Insecticide,
Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in
December 2009.  The Agency received the SAP’s final report on March 2,
2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). 
The Agency is in the process of evaluating the SAP report and may, as
appropriate, develop policies and procedures to identify the need for
and, subsequently, the way to incorporate postapplication inhalation
exposure into the Agency's risk assessments.  If new policies or
procedures are put into place, the Agency may revisit the need for a
quantitative postapplication inhalation exposure assessment for
indaziflam.

6.2	Spray Drift

Spray drift is a potential source of exposure for residents living in
close proximity to spraying operations.  This situation is particularly
the case with aerial application.  However, to a lesser extent, spray
drift resulting from the ground application of indaziflam could also be
a potential source of exposure.  The Agency has been working with the
Spray Drift Task Force (a membership of US pesticide registrants), EPA
Regional Offices, State Lead Agencies for pesticide regulation, and
other parties to develop the best spray drift management practices.  The
Agency is now requiring interim mitigation measures for aerial
applications that must be placed on product labels/labeling.  The Agency
has completed its evaluation of the new database submitted by the Spray
Drift Task Force, and is developing a policy on how to appropriately
apply the data and the AgDRIFT computer model to its risk assessments
for pesticides applied by air, orchard airblast, and ground hydraulic
methods.  After the policy is in place, the Agency may impose further
refinements in spray drift management practices to reduce off-target
drift, and risks associated with pesticide application.  

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  It is noted that the 0.094 lb ai/acre
application rate for turf was modeled to estimate postapplication
residential exposure of children (ages 1 to 6 years of age).  As this
rate is equal to or higher than many of the commercial application
rates, this scenario is protective of any exposure of children via spray
drift from commercial indaziflam applications.      

6.3	Combined Residential Exposure

HED combines risk values resulting from separate exposure scenarios when
it is likely they can occur simultaneously based on the use-pattern and
the behavior associated with the exposed population.  HED evaluated the
following combined residential exposures of indaziflam, 1.) adult dermal
and inhalation handler (lawns only) exposure, and 2.) child
postapplication dermal and oral exposures.  Since HED does not generally
combine adult handler and dermal postapplication exposure, such a
combined quantitative residential exposure estimate was not provided. 
However, combined residential scenario assessments for children which
could occur simultaneously were performed and did not result in risks of
concern.  

Table 6.3:  Combined Residential Exposure and Risk 

Product	Use Site	Handler Total

MOE 1	Post-application Dermal MOE 2	Hand-to-Mouth MOE 3	Combined MOE 4

Adult 

Lawn 3FL Concentrate /Ready to spray

72155-IO	Lawns, hardscapes and ornamentals	

3,000	

4,700	

NA

	

NA

Child

Lawn 3 FL (72155-IO)	Lawns, hardscapes and ornamentals	

NA	

2,800	

5,300

	

1,800

See Table 4.1.2: Indaziflam Residential Handler Exposure and Risk (Hand
Held Pump); M. Collantes: April 2010; D372538

See Table 4.2.2b Dermal Postapplication Exposure and Risk (DFR data) );
M. Collantes: April 2010; D372538

See Table 4.2.3 Hand-To-Mouth Exposure and Risk); M. Collantes: April
2010; D372538

Adult Combined MOE = NA = HED does not combine adult handler and
postapplication exposure

Child Combined MOE = NOAEL (7.5 mg/kg/day)/dermal postapplication dose
(0.00266) + HTM dose (0.00141)

HED did not combine risk resulting from adult homeowner handler,
postapplication, and golfer exposure to treated turf because HED
considers the probability of co-occurrence for these scenarios to be
low.

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Combined Risk Assessments and Risk Characterization 

7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk 

Other than dietary exposure, there are no other sources of exposure that
constitute an acute exposure scenario; therefore, acute aggregate
exposure and risk estimates are equivalent to the acute dietary exposure
and risk estimates summarized in Table 5.2 and are below HED’s level
of concern.

7.2	Short- and Intermediate-Term Aggregate Risk TC \l2 "7.2	Short- and
Intermediate-Term Aggregate Risk 

HED combined risk values resulting from chronic dietary (food + drinking
water) and residential scenarios.  When estimating adult residential
exposure,  TC \l2 "7.2	Short-Term Combined Risk HED does not generally
combine handler and dermal postapplication exposure as it would result
in an over estimate of exposure. All short-term combined exposures
resulted in MOEs greater than 100 for all populations and are not of
concern.  Short-term risks are summarized in Table 7.2 below. 

Table 7.2.  Summary of the Short- and Intermediate-Term Aggregate
Exposure and Risk Estimates for Indaziflam.

Population Subgroup	Total Residential Exposure, mg/kg/day	Chronic
Dietary Exposure, mg/kg/day	Aggregate Exposure1, mg/kg/day	MOE2

U.S. Population (total)	0.00254	0.000600	0.00314	2400

All infants (< 1 year)	0.00407	0.001922	0.00599	1300

Children 1-2 yrs	0.00407	0.001061	0.00514	1500

Children 3-5 yrs	0.00407	0.000929	0.00499	1500

Children 6-12 yrs	0.00407	0.000606	0.004678	1600

Youth 13-19 yrs	0.00254	0.000438	0.002979	2500

Adults 20-49 yrs	0.00254	0.000542	0.003082	2400

Adults 50+ yrs	0.00254	0.000571	0.003112	2400

Females 13-49 yrs	0.00254	0.000543	0.003084	2400

The population subgroup with the highest estimated exposure/risk is
bolded.

1 Aggregate Exposure = Residential Exposure + Chronic Dietary Exposure

2 Aggregate MOE = NOAEL (7.5 mg/kg/day) ÷ Aggregate Exposure
(mg/kg/day)

7.3	Long-Term Aggregate Risk TC \l2 "7.3	Long-Term Aggregate Risk 

Other than dietary exposure, there are no other sources of exposure that
constitute a long-term exposure scenario; therefore, long-term aggregate
exposure and risk estimates are equivalent to the chronic dietary
exposure and risk estimates summarized in Table 5.2 and are below
HED’s level of concern.

7.4	Cancer Risk TC \l2 "7.4	Cancer Risk 

Indaziflam has been classified as “not likely to be carcinogenic to
humans.”  Therefore, cancer risk is not a concern for this chemical.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	Cumulative
Risk Characterization/Assessment 

FQPA (1996) stipulates that when determining the safety of a pesticide
chemical, EPA shall base its assessment of the risk posed by the
chemical on, among other things, available information concerning the
cumulative effects to human health that may result from dietary,
residential, or other non-occupational exposure to other substances that
have a common mechanism of toxicity.  The reason for consideration of
other substances is due to the possibility that low-level exposures to
multiple chemical substances that cause a common toxic effect by a
common mechanism could lead to the same adverse health effect as would a
higher level of exposure to any of the other substances individually.  A
person exposed to a pesticide at a level that is considered safe may, in
fact, experience harm if that person is also exposed to other substances
that cause a common toxic effect by a mechanism common with that of the
subject pesticide, even if the individual exposure levels to the other
substances are also considered safe.

Several triazine herbicides were determined to have a common mechanism
of toxicity based on their ability to disrupt the
hypothalamic-pituitary-gonadal axis (US EPA, 2002).  The triazine common
mechanism group (TCMG) includes atrazine, simazine, propazine, and the
metabolites desethyl-s-atrazine (DEA), deisopropyl-s-atrazine (DIA), and
diaminochlorotriazine (DACT).  Indaziflam and its metabolite FDAT were
considered for incorporation into the TCMG by the HED ToxSAC committee
based on structure; indaziflam, FDAT, and the TCMG members contain a
common triazine moiety (E. Scollon, D371661, April 21, 2010).  However,
HED determined that it would not be appropriate to include indaziflam
and FDAT in the TCMG for the following reasons:   1) The structures of
indaziflam and FDAT are unique in that they contain a fluoroethyl group
at the 2-position of the triazine ring; whereas, the TCMG members
contain a chlorine substituent at the 2-position of the triazine ring
and; 2) Indaziflam and FDAT do not elicit the same toxicological
responses shared by the TCMG members.  The TCMG members cause an
increase in mammary gland tumors in rats and multiple developmental
effects such as attenuation of the luteinizing hormone surge, altered
pregnancy outcome, and delayed preputial separation. None of these
effects were observed in the carcinogenicity or developmental guideline
studies for indaziflam. Delayed maturation was observed in the rat
reproduction study, however, the effect occurred at the highest dose and
was attributed to significant clinical toxicity rather than a
perturbation of the hypothalamic-pituitary-gonadal axis. In a
non-guideline study, FDAT delayed vaginal potency in a dose dependent
manner.  However, none of the other characteristic developmental effects
of the TCMG members were observed.  

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding for indaziflam or its metabolite
FDAT and any other substances, and indaziflam does not appear to produce
a toxic metabolite produced by other substances.  Therefore, for the
purposes of this risk assessment, EPA has not assumed that indaziflam or
its metabolite FDAT has a common mechanism of toxicity with other
substances.

For information regarding EPA’s efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see the policy statements released by EPA’s
Office of Pesticide Programs concerning common mechanism determinations
and procedures for cumulating effects from substances found to have a
common mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

9.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0	Occupational
Exposure/Risk Pathway 

(Occupational and Residential Exposure Assessment for Use of Indaziflam
on Citrus Fruit, Stone

Fruit, Pome Fruit, Grapes, Tree Nuts, Pistachios and Olives; M.
Collantes: June 7, 2010; D376907)

The proposed domestic uses of indaziflam are for control of annual
grasses and broadleaf weeds in citrus fruit, stone fruit, pome fruit,
grapes, tree nuts, pistachios and olives. This document assesses
occupational exposures and risks from the proposed uses of Indaziflam
200 SC Herbicide (suspension concentrate, 19.05% ai) and Indaziflam 500
SC Herbicide (suspension concentrate, 45.05% ai).  Based on the proposed
uses, exposures to indaziflam are anticipated to occur for short- and
intermediate-term durations.

9.1	Handler Risk

dermal and total MOEs were greater than the level of concern (MOEs ≥
100).  Handler MOEs ranged from 370 to 43,000 and are not of concern.

Table 9.1.  Occupational Handler Exposures and Risksa

Exposure Scenario	Crop or Target	App. Rateb 

(lb ai/A)	Area Treated Dailyc (acres)	Unit Exposured	Dosee

(µg/kg/day)	MOEf,g

Dermal (mg/lb ai)	Inhalation (µg/lb ai)	Dermal 	Inhalation 	Dermal 
Inhalation 	Total 

Mixer/Loader

Groundboom Equipment (PHED data)	Citrus Fruit, Pome Fruit, Stone Fruit,
Grapes, Tree Nuts, Pistachios, Olives	0.085	80	2.9	1.2	0.021	0.000116
360	65,000	370

Applicator

Groundboom Equipment (PHED data)	Citrus Fruit, Pome Fruit, Stone Fruit,
Grapes, Tree Nuts, Pistachios, Olives	0.085	80	0.014	0.74	0.000099
0.000072	76,000	100,000	43,000

Mixer/Loader/Applicator

Handgun Sprayer (ORETF data)	Citrus Fruit, Pome Fruit, Stone Fruit,
Grapes, Tree Nuts, Pistachios, Olives	0.085	25	0.45

(with gloves)	1.8	0.001 

(with gloves)	0.000055	 7,600

(with gloves)	140,000	 7,200

(with gloves)

a	Risks represent baseline attire (long-sleeve shirt, long pants, no
respirator), except where indicated (i.e. addition of chemical-resistant
gloves for the mixer/loader/applicator handgun scenario).

b	Application rates = maximum application rates from labels.

c	Amount handled per day values are HED estimates of acres treated
applied per day based on Exposure SAC SOP #9.1 “Standard Values for
Daily Acres Treated in Agriculture” and professional judgment.

d.  	Unit Exposures based on PHED Version 1.1 or ORETF data. 

e	Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x  % Absorption (7.3% dermal and 100%
inhalation) / Body weight (70 kg).  

f	Dermal and Inhalation   SEQ CHAPTER \h \r 1 MOE = NOAEL (7.5
mg/kg/day) / Dose (mg/kg/day) 

g	Total MOE = 1 / (1/ Dermal MOE) + (1/ Inhalation MOE).

9.2	Occupational/Commercial Postapplication Exposure 

Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication
inhalation exposure assessment was not performed for indaziflam at this
time primarily because it has a very low vapor pressure (vapor pressure
5 x 10-10 mmHg at 25ºC), it is applied at low application rates
(maximum rates range from 0.089 - 0.134 lbs ai/A depending on use site),
it is not projected to be applied via typically high inhalation exposure
application equipment (e.g., airblast and aerial equipment).   However,
there are multiple potential sources of postapplication inhalation
exposure to individuals performing postapplication activities in
previously treated fields.  These potential sources include
volatilization of pesticides and resuspension of dusts and/or
particulates that contain pesticides. The Agency sought expert advice
and input on issues related to volatilization of pesticides from its
Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory
Panel (SAP) in December 2009.  The Agency received the SAP’s final
report on March 2, 2010
(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The
Agency is in the process of evaluating the SAP report as well as
available postapplication inhalation exposure data generated by the
Agricultural Reentry Task Force and may, as appropriate, develop
policies and procedures, to identify the need for and, subsequently, the
way to incorporate occupational postapplication inhalation exposure into
the Agency's risk assessments.  If new policies or procedures are put
into place, the Agency may revisit the need for a quantitative
occupational postapplication inhalation exposure assessment for
indaziflam.

 

Postapplication Dermal Exposure

The proposed uses for indaziflam are ground-directed uses where no crop
foliage is treated.  Currently, HED has no data to assess
postapplication dermal exposures to treated soil by occupational
workers.  In general, such exposures are considered to be negligible.
Therefore, for the proposed soil-directed uses, postapplication
exposures and risks to occupational workers were not quantitatively
assessed but are not considered to be of concern.  

	

Restricted Entry Interval

The restricted entry interval (REI) is based on the acute toxicity of
indaziflam technical material.  Active ingredients classified as
category III or IV for acute dermal toxicity, eye irritation potential,
and skin irritation potential are assigned a default REI of 12 hours
under the Worker Protection Standard for Agricultural Pesticides.  Based
on the acute toxicity profile for indaziflam, the 12-hour REI which
appears on the proposed labels is adequate.

10.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and
Label Recommendations 

     Toxicology  TC \l2 "10.1	Toxicology 

Based on the available toxicity database and the Agency's current
practices, the inhalation risk for indaziflam was assessed using an oral
toxicity study.  The Agency sought expert advice and input on issues
related to this route to route extrapolation approach (i.e. the use of
oral toxicity studies for inhalation risk assessment) from its Federal
Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel
(SAP) in December 2009.  The Agency received the SAP’s final report on
March 2, 2010
(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The
Agency is in the process of evaluating the SAP report and may, as
appropriate, re-examine and develop new policies and procedures for
conducting inhalation risk assessments, including route to route
extrapolation of toxicity data.  If any new policies or procedures are
developed, the Agency may revisit the need for an inhalation toxicity
study for indaziflam and/or a re-examination of the inhalation toxicity
risk assessment.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

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.  HED recommends that submission of acceptable
storage stability and processing study reports be made a condition of
registration.  In addition, analytical reference standards need to be
provided prior to registration (see item 3 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. 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 indicated that while
the final report has not been through quality assurance review,
preliminary findings show that the residue have remained stable over a
25-26 month period.  However, submission of the ongoing storage
stability study covering the full duration of sample storage should be
submitted as a condition of registration.    

3. 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.)

10.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational
and Residential Exposure 

None 

11.0	References  TC \l1 "References: 

Indaziflam:  Occupational/Residential Exposure Assessment for Use of
Indaziflam on 

Turf, Golf Courses, Sod Farms, Christmas Tree Farms, Non-Crop Areas and
Forestry (M.Collantes, D372538; April 2010)

Tier 2 Drinking Water Assessment for the Section 3 New Chemical
Registration of Indaziflam; Rueben Baris; D356141; and D367447; February
2, 2010.

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. (E. Holman et al, D374105; Sept.
9, 2010)

Indaziflam: Acute and Chronic Aggregate Dietary Exposure (Food and
Drinking Water) and Risk Assessment for the Section 3 Registration on
Pome Fruits, Stone Fruits, Citrus, Tree Nuts (including Pistachios),
Grapes, Olives, and Processed Cane Sugar (Import).  (E. Holman et al,
D376909; July 28, 2010)  

Appendix A:	Toxicology Assessment  TC \l1 "Appendix A:	Toxicology
Assessment 

 A.1	Toxicology Data Requirements TC \l2 "A.1	Toxicology Data
Requirements 

The requirements (40 CFR 158.340) for turf and food use for indaziflam
are shown below in Table 1. Use of the new guideline numbers does not
imply that the new (1998) guideline protocols were used.

Test 

	Technical Indaziflam

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21/28-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

 yes1

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5375    Mutagenicity—Structural Chromosomal Aberrations	

870.5550    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotoxicity (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotoxicity Screening Battery (rat)	

870.6200b  90-Day Neurotoxicity Screening Battery (rat)	

870.6300    Developmental Neurotoxicity		no

no

yes

yes

yes	--

--

yes

yes

yes

870.7485    General Metabolism	

870.7600    Dermal Penetration	

870.7800   
Immunotoxicity………………………………………..	yes

yes

yes	yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

 no

 no

 no	

--

--

--

1  Satisfied by 870.4300.

A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Indaziflam technical 

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral - rat	47443281	LD50 > 2000 mg/kg (both sexes)	III

870.1200	Acute dermal - rabbit	47443282	LD50 > 2000 mg/kg (both sexes)
III

870.1300	Acute inhalation - rat	47443283	LC50 > 2.3 mg/L (both sexes)	IV

870.2400	Acute eye irritation - rabbit	47443284	Non-irritant	IV

870.2500	Acute dermal irritation - rabbit	47443285	Non-irritant	IV

870.2600	Skin sensitization - guinea pig	47443286	Not a sensitizer
(Buehler method)	N/A

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile –
Indaziflam technical

Guideline No. 	Study Type	MRID No. (year)/ Classification /Doses	Results

870.3100

	90-Day oral toxicity (rat)	47443287 (2005)

Acceptable/Guideline

0, 200, 5000 or 10,000 ppm in diet for 13 weeks

M: 0, 14, 338 or 689 mg/kg/day

F: 0, 16, 410 or 806 mg/kg/day

98.7% a.i.	NOAEL =  14/410 mg/kg/day M/F

LOAEL = 338/806 mg/kg/day M/F, based on:  in males at 338 mg/kg/day,
increased TSH at Week 3 and diffuse thyroid follicular cell hypertrophy
at Week 13; in females at 806 mg/kg/day, mortality (one female,
sacrificed in extremis with clinical signs, decreased motor activity and
gastric red foci), marginally decreased body weights and decreased food
consumption. 

870.3100	90-Day oral toxicity (mouse)	47443288 (2005)

Acceptable/Guideline 

0, 100, 500 or 1200 ppm in diet for 13 weeks

M: 0, 19, 91 or 218 mg/kg/day;               

F: 0, 23, 118 or 256 mg/kg/day

96.5% a.i.	NOAEL = 91/118 mg/kg/day  M/F

LOAEL = 218/256 mg/kg/day M/F, based on increased mortality and wasted
appearance (females), hunched posture in males and females, decreased
body weight/weight gain and food consumption in males and females.

870.3150

	90-Day oral toxicity (dog)	47443289 (2008)

Acceptable/Guideline

0, 7.5, 15 or 30 mg/kg/day by gavage

94.5-99.4% a.i.	NOAEL = 7.5 mg/kg/day M/F

LOAEL = 15 mg/kg/day, based on axonal degeneration in the brain, spinal
cord and sciatic nerve in males and females.  At 30 mg/kg/day, 3 animals
were sacrificed with seizures by Day 30; all remaining group animals
were sacrificed on Day 36.  Decreased body weight gain and
neuropathology were observed.

870.3200

	28-Day dermal toxicity (rat)	47443290 (2006)

Acceptable/Guideline

0, 40, 200 or 1000 mg/kg/day applied to skin 5 days/week for 4 weeks
(22/23 total applications in M/F)

90.32% a.i.	Systemic NOAEL = 1000 mg/kg/day

LOAEL = not determined (>1000 mg/kg/day)

Local dermal NOAEL = 1000 mg/kg/day

LOAEL = not determined (>1000 mg/kg/day).  Some indication of local
dermal irritation was observed at all doses but the findings were
transient and observed only in females, and therefore were not
considered adverse.

870.3700a

	Prenatal developmental in (rat)	47443291 (2006)

Acceptable/Guideline

0, 10, 25 or 200 mg/kg/day by gavage in 0.5% aqueous methylcellulose, GD
6 through 20

94.5% a.i.	Maternal NOAEL = 25 mg/kg/day

LOAEL = 200 mg/kg/day based on decreased body weight gain and food
consumption.  

Developmental NOAEL = 25 mg/kg/day

LOAEL = 200 mg/kg/day based on decreased fetal body weights.

870.3700b

	Prenatal developmental in (rabbit)	47443292 (2008)

Acceptable/Guideline

0, 10, 25 or 60 mg/kg/day by gavage in 0.5% aqueous methylcellulose, GD
6 through 28

93.14% a.i.	Maternal NOAEL = 25 mg/kg/day

LOAEL = 60 mg/kg/day based on decreased maternal body weight gain and
food consumption and macroscopic changes in the liver in one doe.

Developmental NOAEL = 60 mg/kg/day

LOAEL = not established (>60 mg/kg/day).

870.3800

	Reproduction and fertility effects

(rat)	47443293 (2008)

Acceptable/Guideline

0, 150, 1000 or 8000 ppm in the diet; F1 high dose reduced to 4000 ppm
at 5-17 days’ postweaning

Average P/F1 consumption (note: high dose not averaged due to F1 dose
reduction)

M:  0, 10.4, 69.3 or 560.1 mg/kg/day (P males) and  317.6 mg/kg/day (F1
males, due to reduction in dietary dose)

F:  0, 12.9, 85.2 or 656.2 mg/kg/day (P females) and 355.2 mg/kg/day (F1
females, due to reduction in dietary dose)

93.14-94.5% a.i.	Parental NOAEL = 69.3/85.2 mg/kg/day M/F

LOAEL = 560.1/656.2 mg/kg/day M/F, based on coarse tremors in females
from Weeks 6-17 and in gestation and lactation, decreased body
weight/weight gain and food consumption and renal toxicity (tubular
degeneration/ regeneration and increased weight) in males.

Offspring NOAEL = 69.3/85.2 mg/kg/day M/F

LOAEL = 317.6/355.2 mg/kg/day M/F, based on clinical signs (perianal,
urine or nasal staining, diarrhea or soft stool, distended abdomen,
weakness, tremors, myoclonus, increased activity and reactivity) and
decreased pup body weights throughout postnatal period.

Reproductive NOAEL = 69.3/85.2 mg/kg/day M/F (based on F1 intakes)

LOAEL = 317.6/355.2 mg/kg/day M/F, based on delayed sexual maturation in
males and females (% pups reaching criterion unaffected).

870.4100a

	Chronic toxicity

(rat)	47443296 (2007)

Acceptable/Guideline

0, 300, 3000 or 10,000 ppm in the diet (6000 in females after Day 280)
equivalent to average daily intake of

M:  0, 14, 136 or 474 mg/kg/day;

F:  0, 19, 185 or 589 mg/kg/day

93.14% a.i.	NOAEL = 19 mg/kg/day F, 136 mg/kg/day M;

LOAEL = 185 mg/kg/day F, based on increased mortality, clinical signs of
toxicity, mydriasis and absence of papillary reflex;  474 mg/kg/day M,
based on decreased body weight/weight gain and food consumption.

870.4100b

	Chronic toxicity (dog)	47443294 (2008; main study);47443295 (2007;
dietary stability)

Acceptable/Guideline

0, 60, 225 or 450 ppm in the diet

M:  0, 2, 6 or 12 mg/kg/day;

F:  0, 2, 7 or 11 mg/kg/day

93.16% a.i.	NOAEL =  2.0 mg/kg/day

LOAEL = 6/7 mg/kg/day M/F, based on axonal degeneration of nerve fibers
in the brain, spinal cord and sciatic nerve in males and females. 
Marginal body weight decreases early in study seen at 12/11 mg/kg/day
M/F.

870.4200a

	Carcinogenicity

(rat)	

See 870.4300, below

870.4200b

	Carcinogenicity

(mouse)	47743416 (2008)

Acceptable/Guideline

0, 50, 250 or 1000 ppm in diet

M:  0, 6.8, 34 or 142 mg/kg/day;

F:  0, 8.4, 42 or 168 mg/kg/day

93.14% a.i.	NOAEL = 34/42 mg/kg/day M/F

LOAEL = 142/168 mg/kg/day M/F, based on decreased body weight/weight
gain and food consumption, M/F; renal and hepatotoxicity in males;
stomach and ovarian toxicity in females.  

No evidence of carcinogenicity

870.4300	Combined carcinogenicity/ chronic toxicity (rat)	47743417
(2009)

Acceptable/Guideline

0, 300, 3000 or 10,000 ppm in the diet

M:  0, 12, 118 or 414 mg/kg/day;

F:  0, 17, 167 or 452 mg/kg/day

93.14% a.i.	NOAEL = 12/17 mg/kg/day M/F

LOAEL = 118/167 mg/kg/day M/F, based on decreased body weight/weight
gain, signs of neurotoxicity (various symptoms, including dilated
pupils, tremors, limb/movement effects, reduced activity/alertness) and
renal toxicity in females, liver toxicity in males and females and
atrophic seminal vesicles and increased TSH (Week 3 only) and thyroid
colloid alteration in males.  Thyroid alterations in males appeared to
be secondary to liver effects.  Decreased survival was observed at 452
mg/kg/day in females and both males and females showed more pronounced
clinical signs of toxicity.

No evidence of carcinogenicity

Gene Mutation

870.5100	Bacterial reverse gene mutation assay (S. typhimurium)	47443297
(2006)

Acceptable/Guideline

0, 16, 50, 158, 500, 1581 or 5000 µg/plate in presence or absence of S9
activation.  Trial 1 – plate incorporation method and Trial 2,
pre-incubation method

90.32% a.i.	Negative +/-S9 activation in S. typhimurium strains TA98,
TA100, TA 102, TA1535, TA1537 for increased frequency of revertant
colonies up to cytotoxic (500 µg/plate) and precipitating
concentrations (5000 µg/plate).

Gene Mutation

870.5100	Bacterial reverse gene mutation assay (S. typhimurium)	47443301
(2007)

Acceptable/Guideline

Trial 1:  0, 15, 50, 158, 500, 1502 or 5000 µg/plate in the presence or
absence of S9 activation, plate-incorporation method

Trial 2:  0, 100, 200, 400, 800, 1600 or 3200 µg/plate in the presence
or absence of S9 activation, pre-incubation method

eased frequency of revertant colonies up to cytotoxic (≥800 µg/plate)
and precipitating (3200 µg/plate) concentrations.

Gene Mutation 870.5300	Mammalian cell in vitro forward gene mutation
(cultured V79 cells, HGPRT locus)	47443302 (2006)

Acceptable/Guideline 

0, 10, 100 or 1000 µg/mL in presence or absence of S9 activation

90.32% a.i.	Negative for increased frequency of mutation in CHO cells
(not cytotoxic).

Cytogenetics 

870.5375	Mammalian in vitro cytogenetic assay (Chinese hamster V79 lung
cells)	47443305 (2006)

Acceptable/Guideline

4 hr exposure, 14 hr recovery period:  0, 15, 30, 60, 90 or 120 µg/mL
in the absence of S9 activation; 0, 50, 100, 160, 200 and 240 µg/mL in
the presence of S9 activation.

4 hr exposure, 26 hr recovery period:  0, 60, 90 and 120 in the absence
of S9 activation; 0, 160, 200 and 240 µg/mL 

18 hr exposure, no recovery period in the absence of S9 activation:  0,
4, 8, 16, 20 and 24 µg/mL 

90.32% a.i.	Negative for induction of chromosomal aberrations above
background in the presence or absence of S9 metabolic activation. 
Tested up to the limit of solubility  (160 µg/mL, -S9)

Cytogenetics  870.5395	Mammalian in vivo micronucleus assay (mouse)
47443308 (2006)

Acceptable/Guideline

Two doses of 0, 10, 20 or 40 mg/kg by IP injection in 0.5% aqueous
Cremaphor vehicle administered 24 hrs apart; harvested 24 hrs after
second dose

90.32% a.i.	Negative for induction of increased frequency of
micronucleated polychromatic erythrocytes in bone marrow at any
treatment time.

870.6200a

	Acute neurotoxicity screening battery (rat)	47443310 (2008)

Acceptable/Guideline

0, 50, 100 or 2000 mg/kg by gavage in corn oil.  Time of peak effect
estimated at 50 min postdosing.

93.14% a.i.	NOAEL = 50 mg/kg

LOAEL = 100 mg/kg based on decreased motor and locomotor activity in
females (threshold effect level).  Lower NOAEL/LOAEL relative to
subchronic study likely due to gavage vs. dietary administration.

870.6200b	Subchronic neurotoxicity screening battery (rat)	47443309
(2008)

Acceptable/Guideline

0, 200, 4000 or 8000/10,000 ppm (M/F) equivalent to average daily intake
in the diet of

M:  0, 12.2, 243.6 or 585.7 mg/kg/day

F:  0, 15.1, 306.9 or 580.9 mg/kg/day 

93.14% a.i.	NOAEL = 243.6/306.9 mg/kg/day M/F

LOAEL = 585.7/580.9 mg/kg/day M/F, based on decreased total session
motor and locomotor activity in females, clinical signs/FOB effects in
males and females (tremors, repetitive chewing motion and perianal and
lacrimal staining), decreased body weights (females) and cumulative body
weight gain in males and females.

870.6300	Developmental neurotoxicity (rat)	47443311 (2008)

Acceptable/Nonguideline

0, 150, 1000 or 7000 ppm in the diet (high dose reduced to 4000 ppm on
LD4) equivalent to average daily intake in the diet of

0, 13, 83.8 or 432 mg/kg/day

93.14% a.i.	Maternal NOAEL = 83.8 mg/kg/day  

LOAEL = 432 mg/kg/day, based on clinical signs at daily observation and
FOB assessment (coarse tremors, dilated pupils and dilated pupils
unresponsive to penlight, nasal staining, repetitive chewing movements),
decreased body weights/weight gain and reduced number of litters (-17%).

Offspring NOAEL = 83.8 mg/kg/day

LOAEL = 432 mg/kg/day, based on decreased body weight through PND 21 in
males and females.  Males postweaning had slightly decreased body
weights.  Decreased motor activity (-29%) on PND 21 in males was
considered treatment-related, but was not seen at other measurement
times nor in females.  

870.7485

	Metabolism and pharmacokinetics

(rat) – tier 1	47443312 (2008)

Acceptable/Guideline

Male rats given single gavage dose of either 14C-indane labeled or
-triazine labeled indaziflam at 11.5-14.98 mg/kg.  Mass balance groups
– excreta collected for 3 days postdosing.  Bile-duct cannulated
groups – bile and excreta collected for 2 days postdosing.  

99-100% radiochemical purity	Absorption was complete (>90%
bioavailability) and rapid, with radioactivity found in bile by 1 hr
postdosing and most radioactivity (generally around 90%) excreted by 24
hrs. Tissue levels of radioactivity were low (0.2% of administered dose
by 3 days) with highest levels observed in the GIT, liver, kidney, skin
and thyroid.  In the bile duct-cannulated animals, tissue levels were
about 2-4 times greater in the triazine-labeled group than the
indane-labeled group but levels in other groups were similar.  Excretion
was largely fecal (62-70%), with significant biliary excretion observed.
 CO2 exhalation was negligible. Parent compound was identified at
between 2-16% of dose in urine and feces.   Major routes of metabolism
were oxidative pathways; glucuronide conjugation also observed.  Major
metabolite was carboxylic acid, found in urine, bile and feces. 
Numerous other metabolites identified or characterized; profile varied
among dose groups.  Other metabolites identified at low levels included
the 3-hydroxyindane acid epimer, diaminotriazine and 3-ketohydroxymethyl
metabolites.

870.7485	Metabolism and pharmacokinetics (rat) – tier 2	47743418
(2009)

Acceptable/Guideline

Single gavage doses as follows: (1) low dose mass balance studies in
females given 14C-indane-labelled indaziflam at 4.8 mg/kg or
14-triazine-labelled indaziflam at 8.8 mg/kg; (2) high dose mass balance
studies in males given 14C-indane-labelled indaziflam at 559 mg/kg or
14-triazine-labelled indaziflam at 723 mg/kg; (3) plasma pharmacokinetic
experiments with indane-label at 2.9 mg/kg (females) or 13.7 mg/kg
(males) or triazine-label at 13.2 mg/kg (females) or 16.3 mg/kg (males).

Radiochemical purity 99%	Absorption was rapid (radioactivity detected in
blood by 5 minutes and peak blood concentrations observed between
40-60-minutes postdosing; rapidly decreasing thereafter)   Females
showed slightly higher absorption than males.  Excretion was rapid (>87%
by 24 hrs) and was equally distributed between urine and feces in
females but was greater in feces in males (10:1).  CO2 excretion was
negligible. Radioactivity was not retained at significant levels in
tissues; the GIT, liver and skin showed the highest residues.  The
carboxylic acid metabolite was the major metabolite in both high dose
males and low dose females, which was found in urine and feces. 
Additional metabolites present at >5% of dose included 3-hydroxyindane
acid metabolite in low dose females, dihydroxy metabolite in low dose
females and hydroxyethyl acid metabolite in the high dose males
(indane-label).

870.7600	Dermal absorption, in vivo (rat)	47743420 (2008)

Acceptable/Guideline

0.5, 2 or 5000 µg ai/ cm2 on 12 cm2 skin for 8 hrs to male rats;
absorption evaluated after 8, 24, 72 and 168 hr postdosing

Radiochemical purity >98% 	Absorption was inversely proportional to
dose, indicating saturation of skin penetration with increasing dose. 
Between 0.4-20.4% of the applied dose was recovered in combined residual
carcass, excreta, blood and non-treated skin.  Based on decreased
radioactivity at the application site, the most conservative value for
risk assessment is a dermal absorption of 42.7% observed at 0.5 µg ai/
cm2 at 8 hr postapplication.

870.7800	Immunotoxicity - rat	47443313 (2008)

Acceptable/Guideline

0, 300, 3000 or 6000 (females) or 10,000/6000 (males) ppm in the diet
equivalent to average daily intake in the diet of

M:  0, 27.7, 258 or 528 mg/kg/day

F;  0, 31, 334.2 or 737.9 mg/kg/day

93.12% a.i.	Systemic NOAEL = 258.8/334.2 mg/kg/day M/F

LOAEL = 528/737.9 mg/kg/day M/F, based on mortality (one male sacrificed
in extremis), clinical signs of toxicity in males and females (including
tremor, abnormal gait, pallor, hunched back), decreased food and water
consumption in males and decreased body weight/weight gain in males and
females.

Immunotoxicity NOAEL = 528/737.9 mg/kg/day M/F

LOAEL = not established (>528/737.9 mg/kg/day M/F)

Non-guideline	In vitro dermal absorption – rat and human skin	47743419
(2007)

Acceptable/Nonguideline

Application of a 10µL/ volume of concentrated 500 mg/mL formulation and
representative spray dilutions of 0.5, 0.2 or 1.0 mg/mL to excised human
and rat dermatomed skin.  Exposure duration was 24 hr.

Radiochemical purity >98%	Total absorbed dose decreased with increasing
concentration, indicating saturation of skin penetration with increasing
dose.  Rat skin was 3.8 to 10.7 times more permeable than human skin
over 24 hr at the concentrations tested. 

Toxicity Profile - FDAT

Nonguideline Study	Sexual maturation supplemental study (rat)	47443314
(2008) Accetable/Nonguideline 0, 18.0, 36.5, 72.9 or 145.8 mg/kg/day by
gavage to LD21 offspring and timed-pregnant female Wistar rats:
administered daily until PND 41	NOAEL = 36.5 mg/kg/day

LOAEL = 72.9 mg/kg/day, based on delays in vaginal patency (+2.3 days,
increasing to 3.9 days at 145.8 mg/kg/day).  Also at high dose, body
weight was decreased and salivation and urine staining were observed.

  TC \l1 "Appendix A:	Toxicology Assessment 

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