Document ID: EPA-HQ-OPP-2006-0800-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-16T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 3/6/2007

MEMORANDUM

SUBJECT:	Chlorantraniliprole: Human Health Risk Assessment for Proposed
Uses on Apple, Celery, Cucumber, Head Lettuce, Leaf Lettuce, Pear,
Pepper, Spinach, Squash, Tomato, and Watermelon Crops. PC Code: 090100,
Petition No: 6G7089, DP Number: D331296, 331610

		Regulatory Action: Experimental Use Permit/Temporary Tolerance
Petition

		Risk Assessment Type: Single Chemical Aggregate

FROM:	Sarah Winfield, Biologist

		Jack Arthur, Industrial Hygienist

		Leung Cheng, Chemist

		Mary Manibusan, Toxicologist

		Registration Action Branch 3

		Health Effects Division (7509P)

			and

		James Hetrick, Drinking Water Assessment

		Environmental Risk Branch 1

		Environmental Fate and Effects Division (7507P)

THROUGH:	Paula Deschamp, Branch Chief 

Registration Action Branch 3

		Health Effects Division (7509P)

TO:		Meredith Laws, Branch Chief

		Insecticide Review Branch

		Registration Division (7505P)

Introduction

E. I. DuPont de Nemours and Company, DuPont Crop Protection (referred to
as DuPont throughout the rest of the document) has requested temporary
tolerances and an experimental use permit (EUP) for the new active
ingredient (ai) chlorantraniliprole.  The common name,
chlorantraniliprole, was officially granted following this submission. 
Therefore, although chlorantraniliprole is used on product labels and
government forms, the company name, DPX-E2Y45 is used in the technical
reports, and subsequently, in this document as well.

The proposed temporary tolerances are for residues of
3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chlor
o-2-pyridinyl)-1H-pyrazole-5-carboxamide in the following raw
agricultural commodities: apple at 0.3 ppm, celery at 7.0 ppm, cucumber
at 0.09 ppm, head lettuce at 4.0 ppm, leaf lettuce at 7.5 ppm, pear at
0.3 ppm, pepper at 0.5 ppm, spinach at 13.0 ppm, squash at 0.25 ppm,
tomato at 0.3 ppm, and watermelon at 0.2 ppm.  The proposed EUP
specifies use of chlorantraniliprole (formulated as CoragenTM SC
[suspension concentrate, 18.4% ai or 1.67 lb ai/gal, 352-EUP-XXX] and
AltacorTM WG [water dispersible granule, 35% ai, 352-EUP-XXX]) on 1,300
acres of apple, celery, cucumber, head and leaf lettuce, pear, pepper,
spinach, squash, tomato and watermelon crops, at a seasonal use rate of
0.2 lb ai/A for 2 years.

The residue chemistry and the toxicological databases support granting
the EUP, provided the specifications in Section 10.0 of this document
are addressed, and a revised Section B (labels) is submitted. 
Additionally, provided a revised Section F (see below) is submitted, the
Health Effects Division (HED) recommends in favor of granting temporary
tolerances for residues of
3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chlor
o-2-pyridinyl)-1H-pyrazole-5-carboxamide in the following raw
agricultural commodities, at the following levels:

Apple			0.25 ppm

Apple, wet pomace	0.60 ppm

Celery			7.0 ppm

Cucumber		0.10 ppm

Lettuce, head		4.0 ppm

Lettuce, leaf		8.0 ppm

Pear			0.30 ppm

Pepper			0.50 ppm

Spinach		13 ppm

Squash			0.40 ppm

Tomato		0.30 ppm

Watermelon		0.20 ppm

This HED document provides a summary of the findings from the data
evaluation and subsequent assessment of human health risk resulting from
the EUP use profile.  The hazard assessment and characterization was
conducted by Mary Manibusan; the occupational exposure assessment was
conducted by Jack Arthur; the residue chemistry data was reviewed by
Leung Cheng, and he also conducted the dietary exposure assessment; and
the human health risk assessment was conducted by Sarah Winfield (RAB3);
additionally, the drinking water assessment was conducted by James
Hetrick of OPP’s Environmental Fate and Effects Division (EFED).

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc160949342 \h  5 

2.0	Ingredient Profile	  PAGEREF _Toc160949343 \h  8 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc160949344 \h  8 

2.2	Structure and Nomenclature	  PAGEREF _Toc160949345 \h  10 

2.3	Physical and Chemical Properties	  PAGEREF _Toc160949346 \h  11 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc160949347 \h  11 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc160949348 \h
 11 

3.1.1	Toxicology Database Summary	  PAGEREF _Toc160949349 \h  11 

3.1.1.2	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc160949350 \h  17 

3.1.2	Toxicological Effects	  PAGEREF _Toc160949351 \h  18 

3.1.3	Dose-reponse	  PAGEREF _Toc160949352 \h  19 

3.1.4	FQPA	  PAGEREF _Toc160949353 \h  19 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc160949354 \h  19 

3.3	FQPA Considerations	  PAGEREF _Toc160949355 \h  20 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc160949356 \h  20 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc160949357 \h  20 

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc160949358 \h  21 

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc160949359 \h  21 

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc160949360 \h  22 

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc160949361 \h  22 

3.3.6.1	Determination of Susceptibility	  PAGEREF _Toc160949362 \h  22 

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc160949363 \h 
22 

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc160949364 \h  22 

3.5.1	Acute Dietary (All populations)	  PAGEREF _Toc160949365 \h  22 

3.5.2	Chronic Dietary (All populations)	  PAGEREF _Toc160949366 \h  23 

3.5.3	Incidental Oral Exposure (Short- and intermediate-term)	  PAGEREF
_Toc160949367 \h  23 

3.5.4	Dermal Exposure (Short- and intermediate-term)	  PAGEREF
_Toc160949368 \h  23 

3.5.5	Inhalation Exposure (Short- and intermediate-term)	  PAGEREF
_Toc160949369 \h  23 

3.5.6	Level of Concern for Margin of Exposure	  PAGEREF _Toc160949370 \h
 23 

3.5.9	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc160949371 \h  24 

3.5.8	Classification of Carcinogenic Potential	  PAGEREF _Toc160949372
\h  24 

3.6	Endocrine disruption	  PAGEREF _Toc160949373 \h  24 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc160949374 \h  25 

5.0	Dietary Exposure Characterization	  PAGEREF _Toc160949375 \h  25 

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc160949376 \h  25 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc160949377 \h  25 

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc160949378 \h  26 

5.1.3	Metabolism in Livestock	  PAGEREF _Toc160949379 \h  27 

5.1.4	Analytical Methodology	  PAGEREF _Toc160949380 \h  27 

5.1.5	Environmental Degradation	  PAGEREF _Toc160949381 \h  27 

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc160949382 \h  28 

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc160949383 \h  28 

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc160949384 \h  28 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc160949385 \h  28 

5.1.10	Food Residue Profile	  PAGEREF _Toc160949386 \h  29 

5.1.11	International Residue Limits	  PAGEREF _Toc160949387 \h  30 

5.2	Dietary Exposure	  PAGEREF _Toc160949388 \h  30 

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc160949389 \h  31 

6.0	Residential (Non-Occupational) Exposure Characterization	  PAGEREF
_Toc160949390 \h  31 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc160949391 \h  31 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc160949392
\h  31 

9.0	Occupational Exposure Pathway	  PAGEREF _Toc160949393 \h  32 

9.1	Short-/Intermediate-term Handler Exposure	  PAGEREF _Toc160949394 \h
 32 

9.2	Short-/Intermediate-Term Postapplication Exposure	  PAGEREF
_Toc160949395 \h  34 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc160949396 \h  35

10.1	Toxicology	  PAGEREF _Toc160949397 \h  35 

10.2	Residue Chemistry	  PAGEREF _Toc160949398 \h  35 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc160949399 \h 
36 

References:	  PAGEREF _Toc160949400 \h  36 

Appendix A:	Toxicology Profile Table	  PAGEREF _Toc160949401 \h  37 

Appendix B:	Tabular Summary of Metabolites and Degradates	  PAGEREF
_Toc160949402 \h  41 

Appendix C:	Review of Human Research	  PAGEREF _Toc160949403 \h  43 

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Chlorantraniliprole, or DPX-E2Y45, a novel anthranilic acid diamide
insecticide, belongs to a class of compounds that acts on the ryanodine
receptor.  DuPont has applied for an experimental use permit (EUP) for
use of chlorantraniliprole on 1300 acres for 2 years, and is proposing
the establishment of temporary tolerances for the resulting residues of
3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chlor
o-2-pyridinyl)-1H-pyrazole-5-carboxamide in/on apple, celery, cucumber,
head and leaf lettuce, pear, pepper, spinach, squash, tomato, and
watermelon crops.

Use Profile

DuPont has submitted an application for two formulations in connection
with the EUP program: a 1.67 lb ai/gallon (18.4% ai by weight)
suspension concentrate (CoragenTM SC) and a 35% ai water dispersible
granule (AltacorTM WG).  The insecticide is to be applied at planting or
as foliar broadcast spray using ground or aerial equipment.  The
proposed maximum seasonal rate is 0.2 lb ai/acre and the proposed
retreatment intervals are 3-10 days. The proposed preharvest intervals
(PHIs) range from 1 day for vegetables to 14 days for apple and pear.

Toxicity/Hazard Assessment

Chlorantraniliprole exhibits few to no acute toxicological effects
following single doses as high as 5000 mg/kg and following repeated
doses as high as the limit dose (1000 mg/kg).  The only consistent
findings in feeding studies with chlorantraniliprole has been a mild and
slight increase (approximately 20% from control) in liver weight
observed in the subchronic oral rat, mice, and dog toxicity studies and
the rat 2-generation reproduction study.  This observation is considered
a physiological response to metabolism.  Other findings include a slight
reduction in body weight gain at the high dose in a 28-day dermal
toxicity study in rats and a slight reduction in F1 pup but not F2 pup
weight during lactation at a high dose level of 20,000 ppm when the P1
females received dietary doses equivalent to 3118 mg/kg/day.  This
change in F1 pup weights was without subsequent effects post-lactation
since overall weight gains and development in the F1 rats fed 20,000 ppm
were similar to control animals.

The only other consistent, treatment related observation across the
mammalian toxicology studies (reported primarily in male rats) was an
increased degree of microvesiculation of the adrenal cortex after dermal
or dietary administration of chlorantraniliprole.  This histologic
change was observed in several rat studies including a 28-day dermal
study, a 90-day oral study, a multigeneration reproduction study and at
the 1- and 2-year intervals of a 2-year chronic study.  The histologic
grading of increased microvesiculation in affected groups was mild. 
While clearly treatment related, the slight microvesiculation of the
adrenal cortex is not considered toxicologically significant.

The effects noted in the EUP toxicology database are not toxicologically
significant adverse effects, and do not indicate a hazard concern. 
Subsequently, risk assessments have not been conducted.  However, in
order to characterize exposure in light of the information provided in
the toxicology database, exposure has been estimated and compared to the
limit doses in the mammalian toxicity studies.

Dietary Exposure (food/water)

For the purposes of the EUP, the residue of concern in drinking water,
plants and livestock for risk assessment and tolerance enforcement is
chlorantraniliprole (although drinking water is not subject to tolerance
enforcement).  LC/MS/MS methods are available for measuring
chlorantraniliprole in plants and livestock.  However, an analytical
method for enforcing tolerances in livestock commodities is not germane
to this EUP as tolerances in meat, milk, poultry and eggs are not
required.  Adequate method and concurrent recovery data were provided
for the plant LC/MS/MS method, and the fortification levels used in the
method and concurrent validation are adequate to bracket the residue
levels determined in the proposed crops.  The validated limit of
quantitation (LOQ) in plant matrices is 0.01 ppm.  The LC/MS/MS method
for plant commodities may be used for enforcing tolerances pending
adequate independent laboratory validation and its review in EPA
laboratories.  No data from testing the various multiresidue methods in
the Pesticide Analytical Methods, Volume I were submitted.

Crop field trials were conducted on apple, pear, tomato, pepper,
lettuce, celery, spinach, cucumber, cantaloupe and summer squash. For
the EUP, there are adequate field residue data for these crops based on
geographic representation and number of field trials. Following
application of either the WG or SC formulation to the proposed crops at
the maximum proposed use rates, levels of chlorantraniliprole ranged
from <0.01 ppm (in a variety of raw agricultural commodities [RACs]) to
9.7 ppm (spinach).  The field residue studies are supported by adequate
storage stability data which indicate that chlorantraniliprole is stable
under frozen conditions and during storage intervals.  Processing
studies for apple and tomato are available. Upon processing,
chlorantraniliprole did not concentrate in apple juice but concentrated
in wet apple pomace (2.6x), tomato puree (1.5x) and tomato paste (1.5x).
 These data indicate that only wet apple pomace requires a tolerance
(apple, wet pomace 0.60 ppm).  Confined rotational crop studies indicate
that the parent compound was the major residue in wheat, lettuce and red
beet.  Results also show that residues in wheat forage, hay and straw
were much higher than 0.01 ppm at the 365-day plant back interval.

The laboratory environmental fate data indicate chlorantraniliprole is
persistent and mobile in terrestrial and aquatic environments.  Although
major degradation products of chlorantraniliprole (IN-EQW78, IN-LBA22,
IN-LBA24, IN-LBA23, IN-F6L99, IN-EVK64, IN-ECD73 and IN-GAZ70) are found
in environmental fate studies, their persistence and mobility in soil
and water are not expected to be substantially different than parent
chlorantraniliprole.  Therefore, the environmental fate properties of
chlorantraniliprole were used to model protective estimated drinking
water concentrations (EDWCs) in surface water and groundwater (the
models PRZM-EXAMS and SCI-GROW, respectively).

Acute and chronic dietary (food and drinking water) exposure assessments
were conducted for chlorantraniliprole (using the dietary model
DEEM-FCID), and reflect the proposed uses on apple, celery, cucumber,
head and leaf lettuce, pear, pepper, spinach, squash, tomato and
watermelon crops.  The modeled exposure estimates are based on tolerance
level residues (calculated using the MRL Calculator) assuming 100% of
crops are treated and surface water EDWCs (because surface water EDWCs
were higher than groundwater EDWCs).  As this assessment is for an EUP,
which has proposed treating 1300 acres for 2 years, these exposure
estimates are highly conservative screening level values, and they are
at least 60,000 times lower than the highest doses tested (HDT) in the
mammalian toxicity studies (at which no toxicologically significant
adverse effects were observed).

Residential Exposure

Residential use is not being requested for this EUP, nor are there
currently registered residential uses for this insecticide.  Therefore,
non-occupational handler and postapplication exposure assessments were
not performed.

Aggregate Exposure

For this EUP, there is no residential exposure associated with the
proposed use; therefore, aggregate exposure is considered in the dietary
section of this document.

Occupational Exposure

There is a potential for occupational exposure to chlorantraniliprole
during mixing, loading,  application and postapplication activities. 
Assessments of occupational short-term dermal and inhalation exposures
were conducted.  No chemical-specific handler exposure data were
submitted in support of this Section 3 registration request.  Therefore,
data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as
presented in the PHED Surrogate Exposure Guide (8/98) were used in this
assessment.  Handler inhalation exposure estimates ranged from 0.000031
mg/kg/day for aerial applicators, to 0.00034 mg/kg/day for
mixers/loaders of AltacorTM WG to support aerial application.  Handler
dermal exposure estimates ranged from 0.0014 mg/kg/day for groundboom
applicators to 1.3 mg/kg/day for mixers/loaders of CoragenTM SC to
support aerial application.  The inhalation exposure estimates
(conservative, screening level) are at least 2,900,000 times lower, and
the dermal exposure estimates (also conservative, screening level [100%
dermal absorption assumed]) are at least 800 times lower than the
highest doses tested (HDT) in the mammalian toxicity studies (at which
no toxicologically significant adverse effects were observed).  

Additionally, dermal exposures were estimated for postapplication
workers involved in a variety of agricultural tasks related to crops
subject to this EUP application (postapplication inhalation exposure is
considered negligible).  The resulting postapplication worker exposure
estimates range from 0.011 mg/kg/day to 0.066 mg/kg/day on the day of
application.  These dermal exposure estimates are at least 15,000 times
lower than the highest doses tested (HDT) in the mammalian toxicity
studies (at which no toxicologically significant adverse effects were
observed).  Technical chlorantraniliprole is in Category IV for acute
dermal toxicity and Category IV for primary eye and skin irritation. 
Per the Worker Protection Standard (WPS), a 12-hr reentry interval (REI)
is required for chemicals classified under Toxicity Category III or IV,
and therefore, an interim REI of 12 hours should appear on the
chlorantraniliprole labels, instead of the 4-hour REI currently listed.

Provided a revised Section B (labels) is submitted as indicated in
Section 10.0, HED recommends in favor of granting an EUP for the use of
chlorantraniliprole on the proposed crops; and provided a revised
Section F is submitted as indicated in Section 10.0, HED recommends in
favor of granting temporary tolerances.

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. 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 the USDA under the Continuing
Survey of Food Intake by Individuals (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.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, nondietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication 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.

Additionally, this risk assessment relies in part on data from studies
in which adult human subjects were intentionally exposed to a pesticide
or other chemical.  This database (listed in Appendix C) has been
determined to require a review of ethical conduct.  The database has
received that review, and it was concluded the database does not violate
current ethical standards

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

Chlorantraniliprole is an insecticide that was developed by DuPont for
control of lepidopteran pests.  It belongs to the diamide or pyrazole
class of insecticides.  Despite its structural similarity to some of the
phenylpyrazole insecticides, this compound has a different pesticidal
mode of action (ryanodine receptor activator), which it shares with
phthalic acid diamides.

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

There are two end-use products (EPs) proposed by DuPont for use in the
U.S. on food crops.  These EPs are designated as CoragenTM SC, which is
a 1.67 lb ai/gal suspension concentrate, and AltacorTM WG, which is a
35% ai water dispersible granule.  Example labels for the 1.67 lb/gal SC
and 35% WG were provided and the use directions are summarized below in
Table 2.1.

 

Table 2.1. Summary of Directions for Use of Chlorantraniliprole.

Application Timing, Type and Equipment	Formulation

[EPA Reg. No.]	Max. Single rate (lb ai/A)	Max. # of Appls	Max. Rate per
Season

(lb ai/A)	PHI

(Days)	Use Directions and Limitations 1,2

Celery 1

At-planting, drip, foliar applications 

Ground, overhead sprinkler, or aerial equipment	Coragen SC

[352-EUP-XXX]	0.026-0.09	Not specified – NS	0.2	1

	Cucumber 1

At-planting, drip, foliar applications 

Ground, overhead sprinkler, or aerial equipment	Coragen SC

[352-EUP-XXX]	0.026-0.09	NS	0.2	1

	Lettuce (Head & Leaf) 1

At-planting, drip, foliar applications 

Ground, overhead sprinkler, or aerial equipment	Coragen SC

[352-EUP-XXX]	0.026-0.09	NS	0.2	1

	Pepper (Bell & Non-Bell) 1

At-planting, drip, foliar applications 

Ground, overhead sprinkler, or aerial equipment	Coragen SC

[352-EUP-XXX]	0.026-0.09	NS	0.2	1

	Spinach 1

At-planting, drip, foliar applications 

Ground, overhead sprinkler, or aerial equipment	Coragen SC

[352-EUP-XXX]	0.026-0.09	NS	0.2	1

	Squash 1

At-planting, drip, foliar applications 

Ground, overhead sprinkler, or aerial equipment	Coragen SC

[352-EUP-XXX]	0.026-0.09	NS	0.2	1

	Tomato 1

At-planting, drip, foliar applications 

Ground, overhead sprinkler, or aerial equipment	Coragen SC

[352-EUP-XXX]	0.026-0.09	NS	0.2	1

	Watermelon 1

At-planting, drip, foliar applications 

Ground, overhead sprinkler, or aerial equipment	Coragen SC

[352-EUP-XXX]	0.026-0.09	NS	0.2	1

	Apple & Pear 2

Foliar application

Ground or aerial equipment	Altacor WG [352-EUP-XXX]	0.022-0.088	4	0.2	14

	1  For celery, cucumber, lettuce, pepper, squash, tomato, watermelon -
minimum interval between treatments is 3 days (celery, lettuce) or 5
days (cucumber, pepper, squash, tomato, watermelon) for foliar and 10
days for drip chemigation. Use a minimum of 5 gallons of water per acre
for aerial applications.

2 For apples and pears - Minimum interval between treatments is 10 days.
Do not apply dilute applications of more than 200 gal water per acre.
Use a minimum of 10 gallons of water per acre for aerial applications.

Pending the revisions to the labels as specified in Section 10.0, the
proposed use directions will adequately reflect the use patterns used in
the field trials and the submitted labels will be adequate to allow
evaluation of the residue data relative to the proposed use.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature 

Table 2.2.  Test Compound Nomenclature

Chemical Structure	

Empirical Formula	C18H14BrCl2N5O2

Common Name	Chlorantraniliprole

Company experimental name	DPX-E2Y45

IUPAC name
3-Bromo-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-1-(3-chloro-2-

pyridine-2-yl)-1H-pyrazole-5-carboxamide

CAS Name
3-Bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chlor
o-2-

pyridinyl)-1H-pyrazole-5-carboxamide

CAS Registry Number	500008-45-7

End-use product/EP	CoragenTM SC (1.67 lb/gal; EPA File Symbol
352-EUP-XXX)

Altacor WGTM (35%; EPA File Symbol 352-EUP-XXX)

Chemical Class	Anthranilic acid diamide

Known Impurities of Concern	None

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties 

Table 2.3.  Physiochemical Properties

Parameter	Value	Reference

Molecular Weight (g/mole)	483.15	EFED DW memo

Melting point/range (°C)	200-202 (95.9%)/208-210 (99.2%)		DuPont-13180

pH	5.77 ± 0.087 at 20°C		DuPont-13176

Relative Density (at 20°C)	1.5189 (95.9%)/1.507 (99.2%)		DuPont-13180

Water solubility (20°C)	Deionized water	1.023 mg/L

pH 4			0.972 mg/L

pH 7			0.880 mg/L

pH 9			0.971 mg/L		DuPont-13169

Solvent solubility (20°C to 25°C)	Acetone		3.446 ± 0.172 g/L

Acetonitrile		0.711 ± 0.072 g/L

Ethyl Acetate		1.144 ± 0.046 g/L

Dichloromethane	2.476 ± 0.058 g/L

Dimethylformamide	124 ± 4 g/L

n-Octanol		0.386 ± 0.01 g/L

Methanol		1.714 ± 0.057 g/L

n-Hexane		<0.0001 g/L

o-Xylene		0.162 ± 0.01 g/L	DuPont-13173

Vapor pressure (25°C)	6.3 x 10-12 Pa (20°C), 2.1 x 10-11 Pa (25°C)
DuPont-16517

Dissociation constant, pKa	10.88 ± 0.71		DuPont-13254

Octanol/water partition coefficient, logPOW (25°C)	Deionized Water     
        589

pH 4                                 588

pH 7                                 721

pH 9                                 654		DuPont-13177

UV/visible absorption spectrum	pH <2 no absorption max >200 nm, at 290
ε = 3941

pH 7 no absorption max >200 nm, at 290 ε = 4185

pH >10 absorption max at ~320 nm which may be due to decomposition of
DPX -E2Y45, at 290 ε = 6082		DuPont-13167

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

Mary Manibusan, DP Number 331610

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

3.1.1	Toxicology Database Summary  TC \l3 "3.1.1	Toxicology Database
Summary 

The toxicology database for chlorantraniliprole is considered adequate
for risk assessment in support of the application for a 2-year EUP. 
Following this EUP is the pending application for full registration
under Section 3, at which time the chronic, neurotoxicity, metabolism
and inhalation toxicity studies will be submitted.

Toxicity studies that have been submitted in support of the EUP
application include: 1) acute oral, dermal, inhalation, primary eye
irritation, dermal irritation and dermal sensitization toxicity studies
in rats, mice and rabbits, 2) 28-day dermal study in rats, 3) 90-day
subchronic oral toxicity studies in rats, dogs, and mice, 4)
developmental toxicity studies in rats and rabbits, 5) 2-generation
reproduction study in rats, 6) a full battery of required genetic
toxicology assays, and an 7) evaluation of adrenal cortical function in
rats.  A brief summary of the findings are described below.

Acute Toxicity – Technical Chlorantraniliprole

DuPont has submitted three six-packs of acute toxicity studies (eighteen
studies total) in support of the application for a 2-year EUP for the
following three products: DPX-E2Y45 technical (Table 3.1.1), and two
formulations DuPont AltacorTM WG Insecticide (35% ai) and DuPont
CoragenTM SC Insecticide (18.4% ai).  The acute oral, acute dermal,
acute inhalation, primary eye irritation, primary dermal irritation and
dermal sensitization studies submitted for each product have been
reviewed and all are classified as acceptable.  Chlorantraniliprole
(technical) and the two formulations (DuPont AltacorTM WG and DuPont
CoragenTM SC) are in Toxicity Category IV for all routes of exposure and
are non-sensitizers.  No acute hazard has been identified.

Table 3.1.1. Acute Toxicity of Technical DPX-E2Y45 (Chlorantraniliprole)

Guideline 

No.	Study Type	MRID No.	Results	Toxicity Category

870.1100	Acute oral toxicity	46889112	LD50 = >5000 mg/kg bw	IV

870.1200	Acute dermal toxicity	46889113	LD50 = >5000 mg/kg bw	IV

870.1300	Acute inhalation toxicity	46889121	LC50 = >5.1 mg/L	IV

870.2400	Acute eye irritation	46889115	Iritis score of 1 in 1/3 rabbits,
conjuctival redness score of 1 in 2/3 rabbits.  All eyes returned to
normal after 72 hours.	IV

870.2500	Primary skin irritation	46889114	No dermal irritation, clinical
signs or body weight loss	IV

870.2600	Dermal sensitization	46889221	Not a dermal sensitizer	Negative

28-day Dermal Toxicity Study (MRID 46889128)

In the 28-day dermal toxicity study, chlorantraniliprole was applied to
shaved dorsal skin of male and female CrL:CD(SD)IGS BR rats
(10/sex/dose).  Exposure doses were 0, 100, 300, or 1000 mg/kg/day. 
Test substance related reductions in mean body weight gain ((22% and
(19% males and females, respectively) and corresponding food efficiency
values (19% and 17% for males and females, respectively) were observed
over the 28-day period in both males and females at the highest dose,
1000 mg/kg/day. No statistically significant change in absolute body
weight was reported.  Mean body weight on test day 28 in the male and
female 1000 mg/kg/day group was (6% and (5% from control for both males
and females, respectively.

A minimal increase in microvesiculation in the zona fasiculata region of
the adrenal cortex was observed in some treated males at 100 (2/10), 300
(2/10) and 1000 (5/10) mg/kg/day, with histologic grade of 1 (minimal),
but not in the control or female rats.  The increased microvesiculation
was not considered adverse because the increase was within the range of
normal adrenal morphology; and under both light and electron microscopy,
there was no evidence of adrenal cellular degeneration or toxicity, and
no effect on the adrenal gland was observed in a functionality test
(MRID 46889215).  No other effects were noted in the study.  Based on
the absence of treatment related adverse effects, the NOAEL was
established at 1000 mg/kg/day (limit dose and highest dose tested
[HDT]).

90-day Subchronic Feeding Rat Study (MRID 46889010)

In a 90-day feeding study, chlorantraniliprole was administered to male
and female Crl:CD(SD)IGS BR rats (10 rats/sex/concentration) at
concentrations of 0, 600, 2000, 6000, or 20,000 ppm, which correspond to
overall mean daily intakes of 0, 36.9, 120, 359, or 1188 mg/kg/day for
males and 0, 47, 157, 460, or 1526 mg/kg/day for females.  No test
substance related effects on mean body weight, body weight gain, food
consumption or food efficiency were observed in any male or female dose
groups.  

A slight increase in mean liver weight (18% from control) at 1526
mg/kg/day and a reduction in bilirubin ((36-43% from controls on day 49
and (25-35% on day 98) at ≥157 mg/kg/day was observed in female rats,
but not in males. The increase in liver weight and reduction in
bilirubin did not correlate with any liver microscopic changes, but
could be attributed to the induction of hepatic metabolic enzymes.

Urine volume was increased by 95-100% in the ≥460 mg/kg/day males at
test day 48 and 65-75% at test day 97.  Urine osmolality was minimally
decreased in males at 1188 mg/kg/day at test day 97, but in the absence
of corroborating gross or histologic findings in the kidneys, this
finding was not considered adverse.

A minimal increase in microvesiculation (vacuolation) in the zona
fasciculata region of the adrenal cortex was observed in some treated
males at 1188 mg/kg/day (2/10 rats) pathology grade of 2 (mild); similar
effects were not reported in other treated males and females at any
dose.  This finding in isolation, without functional impact on the
adrenal cortex (MRID 46889215) or any evidence of adrenal cellular
degeneration or toxicity is not considered adverse.  Based on the
absence of treatment related adverse effects, the NOAEL is established
at 1188 and 1526 mg/kg/day for males and females, respectively (the
highest doses tested [HDTs]).  These levels exceed the limit dose (1000
mg/kg) for subchronic studies.

90-day Subchronic Feeding Mouse Study (MRID 46889013)

In the 90-day feeding study, chlorantraniliprole was administered to
male and female Crl:CD-1(ICR)BR mice (15 mice/sex/concentration) at
concentrations of 0, 200, 700, 2000, or 7000 ppm, which correspond to
mean daily intakes of 0, 32.6, 115, 345, or 1135 mg/kg/day for males,
and 0, 40.7, 158, 422, or 1539 mg/kg/day for females.  No test substance
related effects on mean body weight, body weight gain, food consumption
or food efficiency were observed in any male or female dose groups.  

A slight increase (13% and 10% for males and females, respectively) in
liver weight at 1135 mg/kg/day males and 1539 mg/kg/day females was not
associated with any gross or microscopic liver pathology, but could be
attributed to a pharmacological response of hepatic cytochrome P450
enzyme induction.  No liver enzyme measurements were provided, but
changes are not expected due to the minor increase in liver weight and
lack of liver histopathology.

Increased incidences (see Table 3, section 3.3.2) of hyper-reactive
behavior in the ≥700 ppm females and hyperactive behavior in the
≥2000 ppm females were observed.  In these animals, hyperactivity and
hyper-reactivity were most commonly observed between Day 56 and 70 or
thereafter.  One 2000 ppm male had convulsions on Day 91, but no other
instance of convulsions was observed in any animal.

A functional observational battery was included in the 18-month mouse
feeding study (study not yet submitted).  Dietary concentrations, animal
source, and approximate age of the mice at study start were the same as
in this 90-day study, but no treatment-related effects on any
neurobehavioral parameters were reported during the first 180 days.  The
author of the study stated that over the entire 18-month mouse study,
the incidence of convulsions, hyperactivity, and hyper-reactivity did
not exhibit a dose-response.  Therefore, these findings in the 90-day
study were considered incidental and not treatment related.  Based on
the absence of treatment related adverse effects, the NOAEL is
established at 1135 and 1539 mg/kg/day for males and females,
respectively (HDTs). These levels exceed the limit dose (1000 mg/kg) for
subchronic studies.

90-day Subchronic Feeding Dog Study (MRID 46889012)

In the 90-day feeding study, chlorantraniliprole was administered to
male and female beagle dogs (4 dogs/sex/concentration) at concentrations
of 0, 1000, 4000, 10,000, and 40,000 ppm, which correspond to mean daily
intakes of  0, 32.2, 119, 303, and 1163 mg/kg/day for males and 0, 36.5,
133, 318, and 1220 mg/kg/day for females, respectively.  No test
substance related effects on mean body weight, body weight gain, food
consumption or food efficiency were observed in any male or female dose
groups.

A slight increase in absolute liver with gallbladder weight (6-23% of
control) was observed in all treated male dogs, with statistical
significance at 40,000 ppm (23% of control) (1163 mg/kg/day); this
finding was not associated with any liver histopathology, but may be due
to a pharmacologic response to metabolism of a xenobiotic.  Based on the
absence of treatment related adverse effects, the NOAEL is established
at 1163 and 1220 mg/kg/day for males and females, respectively (HDTs). 
These levels exceed the limit dose (1000 mg/kg) for subchronic studies.

Developmental Rat Study (MRID 46889108)

Developmental Rabbit Study (MRID 46889109)

is ≥1000 mg/kg/day (HDT) and the maternal and developmental toxicity
LOAEL is greater than 1000 mg/kg/day (limit dose and HDT).

Two Generation Reproduction Rat Study (MRID 46889107)

In the two-generation reproduction study,  Crl:CD(SD)IGS BR rats were
administered chlorantraniliprole in the diet at dose levels of 0, 200,
1000, 4000, or 20,000 ppm, which is equivalent to 0, 12, 60.4, 238 and
1199 mg/kg/day in males and 0, 15.5, 77.8, 318.9 and 1594 mg/kg/day for
females, respectively.  There was an increase (10-19% from controls) in
liver weights observed in P and F1 females at 4000 ppm and above, which
was attributed to a pharmacological increase in metabolism.  A
statistically significant increase in mean adrenal weight (8-22% from
controls absolute and/or relative to body weight) was observed in 4000
and 20,000 P and F1 males and females.  No adverse test substance
related effects on any gross or microscopic pathology endpoint were
observed.  Mean body weight of the 20,000 ppm F1 pups was slightly
reduced when compared to controls on lactation days 7, 14 and 21.  The
slightly lower 20,000 ppm pup weights were considered not adverse as
they were transient, small in magnitude, and F1 offspring weights were
similar to controls by Day 35 postweaning.  In addition, there were no
effects on F2 offspring weights during lactation.  

An increased incidence in microvesiculation of the adrenal cortex for P
and F1 parental rats were reported.  The minimal to mild (pathology
grade 1-2) vacuolations were treatment-related in P and F1 males for all
dose groups and F1 females treated only at the high dose.  Although
treatment related, this finding in isolation, with no functional impact
on the adrenal cortex or any evidence of adrenal cellular degeneration
or toxicity, is not considered adverse.  Electron microscopy of the
adrenal gland, conducted on two control P males and two P males in the
20,000 ppm group, did not reveal any adverse, test-substance related
effects.  

≥20,000 ppm (1199/1594 mg/kg/day (M/F) (above the limit dose and
HDTs).

Genotoxicity Summary (MRID 46889103, 46889104, 46889105, 46889106)

Chlorantraniliprole has been evaluated for mutagenicity in the standard
battery of Genetic Toxicology studies.  Results indicate that the test
material is not mutagenic in bacteria (Salmonella typhimurium or
Escherichia coli) or in mammalian cells (Chinese hamster ovary, CHO
cells).  It was also not clastogenic in vitro in human lymphocytes or in
vivo in mouse bone marrow.  The submitted studies satisfy the FIFRA test
guidelines for mutagenicity, and there is no concern for mutagenicity at
this time.  Summarized findings from these studies are presented below:

GENE MUTATION

Bacterial Reverse Gene Mutation Assay: In a S.typhimurium TA1535,
TA1537, TA98 and TA100 and E.coli WP2 uvrA reverse gene mutation assay
(MRID 46889103), DPX-E2Y45 technical (chlorantraniliprole) was not
mutagenic up to insoluble concentrations (≥ 1800 µg/plate +/-S9).

Mammalian Cell Forward Gene Mutation Assay:  In a Chinese hamster ovary
(CHO) cell forward gene mutation assay (MRID 46889106), DPX-E2Y45
Technical (Chlorantraniliprole) was tested up to and beyond the limit of
solubility (≥250 (g/mL) and did not induce a mutagenic effect at the
HGPRT locus. 

CHROMOSOME ABERRATIONS

Mammalian Cell Cytogenetic Assay:  In a cytogenetic assay (MRID
46889105), primary human lymphocyte cultures were exposed to DPX-E2Y45
Technical (chlorantraniliprole) at concentrations up to precipitating
levels (≥750 (g/mL) and there were no statistically significant
increases in the percentages of cells with structural aberrations or in
polyploidy. 

Micronucleus Assay:  In a mouse micronucleus assay (MRID 46889104),
Crl:CD-1®(ICR)BR male and female mice were treated once by oral gavage
with DPX-E2Y45 Technical (chlorantraniliprole) at levels up to the limit
dose (2000 mg/kg).  No significant increase in the frequency of
micronucleated polychromatic erythrocytes was seen in bone marrow at
either sacrifice time.

Development of Methods for the Evaluation of Adrenal Cortical Function
in Rats (MRID 46889215)

The functional impact of the increased degree of microvesiculation in
the adrenal cortex of chlorantraniliprole was evaluated by measuring
corticosterone concentrations under non-stressed (i.e., basal)
conditions and conditions of simulated physiologic stress (i.e.,
ACTH-induced).  The conduct of these tests was based on clinical tests
normally conducted in human and veterinary medicine for evaluation of
adrenal cortical function.

Corticosterone Under Basal Conditions

Basal corticosterone synthesis in rats administered chlorantraniliprole
was determined by measuring total corticosterone excreted overnight in
urine (corticosterone concentration x urine volume; DuPont 14123). 
Urine corticosterone excretion was measured approximately 1 week prior
to sacrifice for all male and female rats designated for the 1-year
interim sacrifice on the 2-year chronic study.  These rats had been fed
dietary concentrations of chlorantraniliprole at 0, 200, 1000, 4000 and
20,000 ppm (intakes up to approximately 880 mg/kg/d at 1 year), with
increased microvesiculation in the adrenal cortex observed in males fed
≥200 ppm.  There were no treatment related effects of
chlorantraniliprole on urine corticosterone excretion in male and female
rats.  Chlorantraniliprole does not affect basal corticosterone
synthesis in rats with histologic evidence of minimal to mild increases
in the degree of microvesiculation of the adrenal cortical zona
fasciculata.

Corticosterone Under Simulated Physiologic Stress – ACTH Stimulation
Test

The utility of an ACTH stimulation test is dependent on its ability to
detect suppression of serum corticosterone concentrations.  The rat ACTH
stimulation test was assessed using a known adrenal toxicant and
inhibitor of corticosterone production, aminoglutethimide. The
sensitivity o the rat ACTH stimulation test was confirmed by
demonstrating that it would detect suppression of ACTH-stimulated
corticosterone synthesis at aminoglutethimide doses that did not inhibit
basal corticosterone production.

The effect of chlorantraniliprole on corticosterone production in
ACTH-stimulated rats was evaluated in male rats dosed via the dermal
route with 1000 mg/kg/day chlorantraniliprole for 1 month. In addition
to the control group, a group of unshaved, nonwrapped and unwashed male
control rats were included in the study to account for any possible
stress due to physical manipulations during dermal dosing. The dermal
route was chosen because in short term toxicity studies, an increased
degree of microvesiculation was observed most consistently in male rats
treated via the dermal route.  ACTH (12.5 µg) was administered to all
rats on the morning following the last day of dosing with
chlorantraniliprole.  One hour after ACTH administration, blood was
collected for corticosterone measurements and adrenal glands were fixed,
processed, and underwent histologic examination.  Chlorantraniliprole
did not decrease corticosterone production under conditions of simulated
physiologic stress. 

Based on these findings, the capacity of the adrenal gland to synthesize
corticosterone (primary hormonal product of the zona fasciculata) under
either non-stimulated (basal) or ACTH-stimulated (physiologic stress)
conditions was not affected by administration of chlorantraniliprole at
doses that caused increased microvesiculation.

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

Chlorantraniliprole is a novel anthranilic diamide insecticide that
functions via activation of the insect ryanodine receptors within the
sarcoplasmic reticulum causing impaired regulation of muscle
contraction.  Ryanodine receptor channels regulate the release of
internal calcium stores and are important in muscle contraction. 
Sustained release of calcium levels within the cytosol leads to muscle
contraction, paralysis and eventual death of the organism.  While
insects possess a single form of the ryanodine receptor distributed in
muscle and neuronal tissue, mammals possess three forms which are widely
distributed in muscle and nonmuscle tissues.  

Chlorantraniliprole, along with other anthranilic diamide compounds
tested, exhibits >500-fold in vitro differential selectivity for insect
ryanodine receptors over those of the mammals. (unpublished DuPont data;
Cordova et al., 2006). It is a specific analog that was selected by
DuPont based on its low mammalian toxicity, due to its specificity to
insect ryanodine receptors, and high efficacy as an insecticide.  The
low toxicity is reflected in the mammalian toxicity data submitted in
support of this experimental use permit.

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

Chlorantraniliprole exhibits little to no acute toxicological effects
following single doses as high as 5000 mg/kg and following repeated
doses as high as the limit dose (1000 mg/kg).  The only consistent
findings in feeding studies with chlorantraniliprole has been a mild and
slight increase (approximately 20% from control) in liver weight
observed in the subchronic oral rat, mice, and dog toxicity studies and
the rat 2-generation reproduction study.  This observation is considered
a physiological response to metabolism as the increase in liver weights
were accompanied by elevated levels of P450 enzymes in all three species
and occurred in the absence of clinical chemistry or histopathologic
findings suggestive of liver toxicity.  Other findings include a slight
reduction in body weight gain at the high dose of 1000 mg/kg/day in a
28-day dermal toxicity study in rats and a slight reduction in F1 pup
but not F2 pup weight during lactation at a high dose level of 20,000
ppm when the P1 females received dietary doses equivalent to 3118
mg/kg/day.  This change in F1 pup weights was without subsequent effects
post-lactation since overall weight gains and development in the F1 rats
fed 20,000 ppm were similar to control animals.

The only other consistent, treatment related observation across the
mammalian toxicology studies has been primarily reported in male rats
(see Table 3.1.2), with an increased degree of microvesiculation of the
adrenal cortex after dermal or dietary administration of
chlorantraniliprole.  A slightly increased degree of microvesiculation
in cells of the zona fasciculata of the adrenal cortex was observed in
some rats administered chlorantraniliprole.  This histologic change was
observed in several rat studies including a 28-day dermal study (MRID
46889128), a 90-day oral study (MRID 46889010), a multigeneration
reproduction study (MRID 46889107) and at the 1-and 2-year intervals of
a 2-year chronic study.  The histologic grading of increased
microvesiculation in affected groups ranged from grade 0-2 (mild) on a
scale ranging from 0-4 (see Table 3.1.2).  Increased microvesiculation
of the zona fasciculata was considered to be treatment-related as the
incidence and histologic grade increased above that observed in controls
in a dose-related pattern.  This histologic finding of increased
microvesiculation was not associated with any other adrenal changes. 
There were no changes in gross appearance, adrenal cortical
cytotoxicity, hypertrophy, or atrophy and no effect on basal or
stimulated adrenal cortical cell function (corticosterone production)
(MRID 46889215).  In addition, no treatment-related neoplastic changes
were observed in the adrenal cortex of rats at terminal sacrifice after
2 years of dietary administration of chlorantraniliprole (not yet
submitted).  An increased degree of microvesiculation of the adrenal
cortex was most consistently observed in male rats and not in mice or
dogs administered chlorantraniliprole.  While clearly treatment related,
the slight microvesiculation of the adrenal cortex is not considered
toxicologically significant.

Table 3.1.2 Incidence of Microvesiculation of Adrenal Cortex in Rats

Parameter	0 ppm	200 ppm	1000 ppm	4000 ppm	20,000 ppm

90-day Subchronic Feeding Rat Study (MRID 46889010)

Males	0	NC	NC	NC	2/10 (2)

Two Generation Reproduction Rat Study (MRID 46889107)

P1 males	3/30 (1)	2/30 (1)	8/30 (1)	13/30 (1)	16/30 (1-2)

F1 males	2/30 (1)	7/30 (1)	12/30 (1)	16/30 (1-2)	16/30 (1-2)

F1 females	1/30 (1)	1/30 (1)	0	0	3/30 (1)

Two Year Chronic Rat Study (Not Yet Submitted)

1-year males	0	2/10 (1)	5/10 (1)	5/10 (1-2)	5/10 (1-2)

2-year males	4/20 (1)	14/23 (1-2)	17/26 (1-2)	14/21 (1-2)	19/27 (1-3)

28-day Dermal Rat Study (MRID 46889128)

	0 mg/kg	100 mg/kg	300 mg/kg	1000 mg/kg

	Males	0	2/10 (1)	2/10 (1)	5/10 (1)

	NC = microscopic evaluation not conducted at this dose

() = Grade of increased degree of microvesiculation.  Histologic grading
is based on a scale of 0-4 (0= change not present, 1=minimal, 2=mild,
3=moderate, 4=severe)

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

Chlorantraniliprole exhibits little to no acute toxicological effects
following single doses as high as 5000 mg/kg and following repeated
doses as high as the limit dose (1000 mg/kg/day).

The only observation in the mammalian toxicology studies is an increased
degree of microvesiculation of the adrenal cortex after dermal or
dietary administration of chlorantraniliprole.  This histologic change
was observed in several rat studies including a 28-day dermal, 90-day
study, a multigeneration reproduction study and at the 1-and 2-year
intervals of a 2-year chronic study.  The histologic grading of
increased microvesiculation in affected groups ranged from grade 0-2
(mild) on a scale ranging from 0-4, with one microvesiculation graded 3
(moderate) in the high dose group of the 2-year rat study.  Increased
microvesiculation of the zona fasciculata was considered to be
treatment-related as the incidence and histologic grade increased above
that observed in controls in a dose-related pattern.

3.1.4	FQPA  TC \l3 "3.1.4	FQPA 

 reproductive toxicant.  All three studies were tested at ≥1000
mg/kg/day (limit dose).  Since there is no evidence of susceptibility
following in utero and/or postnatal exposure - the FQPA Safety Factor
can be reduced to 1x.

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

Rat metabolism studies were not submitted in support of this temporary
tolerance petition and EUP application.

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 toxicity database for this chemical is complete for the
characterization of potential pre- and postnatal risks to infants and
children.  Acceptable developmental and 2-generation reproduction
studies which have been submitted for review do not suggest that pups
are more susceptible.

Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity 

Potential neurotoxic effects were reported in the 90-day mouse feeding
study (MRID 46889013). Chlorantraniliprole was administered to male and
female mice at concentrations of 0, 200, 700, 2000, or 7000 ppm.  The
mean daily intakes for male mice were 0, 32.6, 115, 345, or 1135
mg/kg/day, respectively.  The mean daily intakes for female mice were 0,
40.7, 158, 422, or 1539 mg/kg/day, respectively.  The incidence of
hyper-reactivity at ≥ 700 ppm in females only and of hyperactivity at
≥ 2000 ppm were higher than in controls. Hyperactivity was also
observed in one female mouse at 200 ppm, but not observed in the 700 ppm
group.  Most of these observations were reported near the end (day
56-70) of the 90-day exposure period.  Convulsions were observed in one
male mouse in the 2000 ppm group but not in females (see Table 3.3.2
below).  

Table 3.3.2 Hyper-reactivity and Hyperactivity in Mice (MRID 46889013)

90-Day feeding study in mice: Clinical signs

	0 ppm	200 ppm	700 ppm	2000 ppm	7000 ppm

MALES

Hyper-reactivity	0	1	0	0	0

Hyperactivity	0	0	0	2	0

Convulsions	0	0	0	1	0

FEMALES

	Hyper-reactivity	0	0	2	2	3*

Hyperactivity	0	1	0	3	2

Convulsions	0	0	0	0	0

*statistically significant (p≤0.05)

N = 15 mice/sex/concentration

As described in the 90-day subchronic feeding mouse study (MRID
46889013), a follow-up to these reported effects, a functional
observational battery (FOB) was conducted as part of the 18-month mouse
feeding study (not yet submitted) with the dietary concentrations,
animal source, and approximate age of the mice at study start being the
same in the two studies (i.e., the first 90-days of the 18-month study
is the same as the 90-day study [MRID 46889013]).  The FOBs were
conducted at approximately 45, 90 and 180 days by staff specifically
trained in neurobehavioral evaluations.  No test substance-related
effects on any neurobehavioral parameter evaluated by FOBs were
reported.  No treatment related changes relating to the nervous system
were observed.  Based on the lack of reproducibility, the incidences of
hyperactivity and hyper-reactivity in the 90-day study were considered
to be spurious and unrelated to the test substance.  No other evidence
of neurotoxicity was reported in any study.

3.3.3	Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental
Toxicity Studies 

For both the rat and rabbit developmental studies, no adverse, test
substance-related effects on maternal clinical observations, body
weight, weight gain, food consumption, or gross post-mortem observations
were detected at any dose.  Unscheduled maternal mortality did not
occur. The mean number of corpora lutea, implantation sites,
resorptions, live fetuses, fetal weight, and sex ratio were comparable
across all groups.  There were no abortions, premature deliveries, or
complete litter resorptions and no effects of treatment on the numbers
of litters, post-implantation loss, or on gravid uterine weights.  The
maternal systemic toxicity is ≥1000 mg/kg/day and the maternal
systemic toxicity LOAEL is greater than 1000 mg/kg/day (the limit dose).
 There were no test substance-related fetal external, visceral, skeletal
malformations, variations, adverse effects on fetal skeletal
ossification observed at any dose.  The developmental toxicity is
≥1000 mg/kg/day and the developmental toxicity LOAEL is greater than
1000 mg/kg/day (the limit dose).

3.3.4	Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity
Study 

There were no adverse, test substance-related effects on body weight,
body weight gain, food consumption, or food efficiency, clinical signs
of toxicity, or mortality in P and F1 males during pre-mating and in P
and F1 females during pre-mating, gestation, or lactation.  An increase
in mean liver weights was observed in P and F1 females at 4000 ppm and
above and was attributed to a pharmacological increase in metabolism. 
In addition, a slight, yet statistically significant, increase in mean
adrenal weight (absolute and/or relative to body weight) was observed at
4000 and 20,000 ppm P and F1 males and females.  There were no adverse
test substance-related effects on any gross or microscopic pathology
endpoint.  The parental systemic toxicity NOAEL is ≥ 20,000 ppm
(1199/1594 mg/kg/day males/females, respectively) and the parental
systemic toxicity LOAEL is greater than 20,000 ppm (1199/1594 mg/kg/day
males/females, respectively) based on the absence of adverse effects in
P and F1 males and females (above the limit dose).

There were no test substance-related effects on sperm motility,
morphology, epididymal sperm or testicular spermatid numbers in either
the P or F1 males at any dietary concentration.  Similarly, there were
no effects produced by chlorantraniliprole on the mean percent days in
estrus, diestrus or proestrus mean cycle length, or mean precoital
interval in either the P or F1 females.  Mating, fertility, gestation
length, number of implantation sites, and implantation efficiency in
either P or F1 generation were unaffected at any dietary concentration. 
The reproductive toxicity NOAEL is ≥ 20,000 ppm (1199/1594 mg/kg/day
males/females, respectively) based on the absence of adverse effects in
P and F1 males and females (above the limit dose).

Mean body weight of the 20,000 ppm F1 pups was slightly reduced when
compared to controls on lactation days 7, 14, and 21.  The slightly
lower 20,000 ppm pup weights were considered not adverse as they were
transient, small in magnitude, and F1 offspring weights were similar to
controls by Day 35 postweaning.  In addition, there were no effects on
F2 offspring weights during lactation.  The offspring/developmental
toxicity NOAEL is ≥ 20,000 ppm (1199/1594 mg/kg/day males/females,
respectively) based on the absence of adverse effects in F1 and F2 pups
during lactation.

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

Chlorantraniliprole is an unregistered, new ai; and therefore no
literature review was performed.

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

There were no effects on fetal growth or development up to the limit
dose of 1000 mg/kg/day in rats or rabbits.  There were no treatment
related effects on the numbers of litters, fetuses (live or dead),
resorptions, sex ratio, or post-implantation loss.  There were no
effects on fetal body weights, skeletal ossification, and external,
visceral, or skeletal malformations or variations.  

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

There is no increased quantitative or qualitative susceptibility to
fetuses and pups following pre-and/or postnatal exposure to
chlorantraniliprole as reported in the rat and rabbit developmental
toxicity studies and the rat 2-generation reproduction study.  

3.4	FQPA Safety Factor for Infants and Children  TC \l2 "3.4	Safety
Factor for Infants and Children 

Due to the following, the FQPA Safety Factor does not need to be
retained at this time:

The toxicology database is complete for the characterization of
potential pre- and postnatal risks to infants and children.

, the developmental and reproduction studies report no adverse effects
related to treatment ≥ 1000 mg/kg/day [limit dose]).  Therefore, a
degree of concern analysis for pre- and/or postnatal susceptibility is
not necessary.

No neurotoxic effects were identified in the toxicology database.

Highly conservative dietary (food and water) exposure estimates are at
least 60,000 times lower than the HDT in the mammalian toxicity studies
(at which no adverse observed effects were seen).

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

There was no evidence of toxicity of chlorantraniliprole in any of the
studies submitted in support of the EUP application.  The high dose
tested in all of the studies was the limit dose of 1000 mg/kg/day or
higher.

3.5.1	Acute Dietary (All populations)  TC \l3 "3.5.1	Acute Dietary (All
populations) 

No acute hazard, attributable to a single dose, was identified;
therefore, an acute dietary endpoint was not selected for quantitative
risk assessment.

3.5.2	Chronic Dietary (All populations)  TC \l3 "3.5.2	Chronic Dietary
(All populations) 

Chronic animal studies have not yet been formally submitted to the
Agency for review.  There was no hazard identified in the extant
database and therefore, a chronic dietary endpoint was not selected for
quantitative risk assessment.

Incidental Oral Exposure (Short- and intermediate-term)  TC \l3 "3.5.3
Incidental Oral Exposure (Short- and intermediate-term) 

There is no anticipated potential for incidental oral exposure from the
proposed EUP, therefore, an incidental oral exposure endpoint has not
been selected for quantitative risk assessment.

3.5.4	Dermal Exposure (Short- and intermediate-term)  TC \l3 "3.5.4
Dermal Exposure (Short- and intermediate-term) 

A 28-day dermal toxicity study was performed on rats at doses of 0, 100,
300, or 1000 mg/kg/day (MRID 46889128).  The NOAEL was the HDT (1000
mg/kg/day).  The only effect was a reduction in overall body weight gain
(22% and 19% males and females, respectively) with a corresponding
decrease in food efficiency (17% and 19% males and females,
respectively).  There was no effect on absolute body weights in males or
females.  There was no hazard identified and therefore, no dermal
endpoint was selected for quantitative risk assessment.

3.5.5	Inhalation Exposure (Short- and intermediate-term)  TC \l3 "3.5.5
Inhalation Exposure (Short- and intermediate-term) 

The only inhalation study performed was the LC50 acute in rats (5/sex,
nose only).  The analytically determined LC50 was >5.1 mg/L for both
males and females (MRID 46889121).  All test animals survived the study
period.  Several test animals showed a loss in body weight of 0-3% on
the day after exposure, gaining weight thereafter.  All animals exceeded
their initial body weights by study termination.  Most responded to
sound when checked 3 times during the exposure.  Clinical signs observed
immediately following exposure included ocular and/or nasal discharge in
two males and a partially closed eye in one female.  All test animals
appeared normal by study day 1.  There were no gross lesions observed in
necropsy. There was no hazard identified and therefore, no inhalation
endpoint was selected for quantitative risk assessment.

3.5.6	Level of Concern for Margin of Exposure  TC \l3 "3.5.6	Level of
Concern for Margin of Exposure 

Table 3.5.6   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

Inhalation	NA	NA	NA

Dermal	NA	NA	NA

Non-Occupational Exposure

Inhalation	NA	NA	NA

Dermal	NA	NA	NA

Incidental Oral	NA	NA	NA

Dietary (Food and Water)	NA	NA	NA

*NA = not applicable

There were no toxicologically significant adverse effects identified in
the EUP toxicology database, and therefore, there were no endpoints to
select for quantitative risk assessment.  Subsequently, levels of
concern (risk thresholds at which risk estimates may cause concern) are
not applicable to this document.  However, in order to characterize
exposure in light of the information provided in the toxicology
database, exposure assessments have been conducted and qualitatively
compared to the limit doses in the mammalian toxicity studies.

3.5.7	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.9	Recommendation for Aggregate Exposure Risk Assessments 

Aggregating routes and/or pathways of exposure is not relevant, since no
hazard was identified via any route of exposure in the EUP toxicology
database.

3.5.8	Classification of Carcinogenic Potential  TC \l3 "3.5.8
Classification of Carcinogenic Potential 

Long-term exposure to humans is not expected to result from the EUP. 
The submitted subchronic studies in mice, dog and rats, and the in vivo
and in vitro genotoxicity studies, identified no tumors or preneoplastic
foci, nor did they identify mutagenic concern.  Therefore, the expected
short/intermediate-term exposure resulting from the EUP does not
indicate a concern for carcinogenicity.

3.6	Endocrine disruption  TC \l2 "3.6	Endocrine disruption 	

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

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

Chlorantraniliprole is an unregistered, new ai, and therefore, no public
health, epidemiologic data, and/or incident reports are available.

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

Reference: Chlorantraniliprole/DPX-E2Y45. Experimental Use Permit
352-EUP-RTN on Apple, Celery, Cucumber, Head Lettuce, Leaf Lettuce,
Pear, Pepper, Spinach, Squash, Tomato, and Watermelon. Summary of
Analytical Chemistry and Residue Data. DP Number: 331568. Leung Cheng,
3/5/07.

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation 

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

The registrant submitted three plant metabolism studies to support the
proposed uses:

(1) An apple metabolism study (MRID 46889004) reflecting foliar
application of [benzamide carbonyl-14C]-DPX-E2Y45 (BC-labeled DPX-E2Y45)
and [pyrazole carbonyl-14C]-DPX-E2Y45 (PC-labeled DPX-E2Y45). Three 100g
ai/ha (0.09 lb ai/A) foliar applications per radiolabeled form were
separately applied at the following times: when fruit had reached 10% of
final size, when fruit had reached 50% of final size, and 30 days before
maturity. Samples of immature apple leaves and fruit were collected
after the first application, before and after the second application,
and 15 and 30 days after the last application. Chlorantraniliprole was
not metabolized in apple to any significant extent and dissipated mainly
by growth dilution. The parent was the only quantifiable residue in the
apple fruit and leaf samples from all intervals.

(2) A tomato metabolism study (MRID 46889006) reflecting foliar
application of BC-labeled DPX-E2Y45 and PC-labeled DPX-E2Y45 mixed
together. Three foliar applications of both radiolabels in 1:1 weight
ratio were applied at 100 g ai/ha to 9-week old tomato plants with
subsequent applications about 25 days apart. Samples of immature tomato
leaf and fruit were collected immediately after the first application,
before and after the second and last application, and 7 and 15 days
after the last application. Chlorantraniliprole was not metabolized in
either tomato leaves or fruit and was the only quantifiable residue from
all intervals.

(3) A lettuce metabolism study (MRID 46889005) reflecting foliar
application of BC-labeled DPX-E2Y45 and PC-labeled DPX-E2Y45 mixed
together. Three foliar applications of both radiolabels in 1:1 weight
ratio were applied at 100 g ai/ha to 4-5 week old lettuce plants with
subsequent applications 10 days apart.  Samples of immature lettuce
whole plants were collected immediately after the first application,
before and after the second and last applications, and 7 and 15 days
after the last application. The parent compound was not metabolized in
lettuce to any significant extent and dissipated mainly by growth
dilution.  DPX-E2Y45 was the only quantifiable residue at all intervals.

Plant metabolism studies were conducted in apple, tomato and lettuce
through multiple foliar applications of BC-labeled and PC-labeled
DPX-E2Y45. Results collected at various growth stages of these 3
different crops show that chlorantraniliprole is not metabolized to any
significant extent. For the purposes of the EUP, the parent compound is
the residue of concern for tolerance enforcement and in risk assessment.

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops 

DuPont submitted two confined rotational crop studies to support the
proposed uses, one conducted using BC-labeled DPX-E2Y45 and one
conducted using PC-labeled DPX-E2Y45 (MRID 46895501).

For the BC-labeled study, seeds of spring wheat, lettuce, and red beet
were sown into a sandy loam soil at 30 days after a 300 g ai/ha (0.27 lb
ai/A) treatment. For the PC-labeled study, the same seeds were sown at
0, 30, 120 and 365 days after a 300 g ai/ha treatment. Spring wheat was
also sown at 0 and 365 days after treatment with PC-labeled DPX-E2Y45 at
an elevated rate of 900 g ai/ha for the purpose of metabolite
identification.

Following crop harvest and sample analyses, multiple metabolites were
found to be present at low levels in wheat grain, lettuce, and red beet,
and somewhat higher in livestock feedstuffs (wheat forage, hay, straw,
and beet foliage) resulting from oxidation, demethylation, and
hydrolytic cleavage reactions. The parent was the principal residue in
rotated wheat, lettuce and red beet.

Studies conducted in spring wheat, lettuce and red beet grown in soil
treated with BC-labeled or PC-labeled DPX-E2Y45 show that multiple
metabolites were present at low levels in wheat grain, lettuce and red
beet (parts for human consumption) and somewhat higher levels in wheat
forage, hay, straw and beet forage (potential livestock feeds).
Nonetheless, similar to the primary crops, the parent compound was
identified as the principal residue in these three representative
rotational crops. 

The data indicate that at the 0 or 30 day plant back interval, levels of
DPX-E2Y45 in lettuce would be substantially below the tolerances
recommended for leafy vegetables and <0.01 ppm in root crops and wheat
grain, but much higher than 0.01 ppm in wheat forage, hay and straw.  No
field rotational crop studies were submitted.  Thus, the proposed label
for the EUP needs to impose a restriction against crop rotation to
cereal grains and to any crop not on the label.  For a future full
registration field rotational crop studies would be needed. Depending on
the results, tolerances on cereal grains and other crops may be needed.

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock 

The registrant submitted a lactating goat metabolism study (MRID
46889116) to support the proposed uses. The animal was given a single
daily oral dose of 1:1 mixture of BC-labeled and PC-labeled DPX-E2Y45 at
10 ppm for 7 consecutive days. Feces and urine were collected once daily
and milk collected twice daily.  The goat was sacrificed 23 hours after
the last dose. The major metabolites were formed by N-demethylation,
hydroxylation at the benzylic position and further oxidation to
carboxylic acid and cyclization with loss of water to yield various
cyclic metabolites.

The majority of the administered dose was eliminated through the feces
and urine. Undegraded parent was the major terminal residue identified
in kidney, muscle, and fat, and it was also a residue in liver and milk.
For the purposes of the EUP, the parent compound is the residue of
concern for tolerance enforcement and in risk assessment.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

LC/MS/MS methods are available for measuring chlorantraniliprole in
plants and livestock.  The registrant has submitted an LC/MS/MS method
(Report 13294 Revision No. 1) for the determination of
chlorantraniliprole in plants, and an LC/MS/MS method (Report 11376) for
the determination of chlorantraniliprole and its metabolites in
livestock. 

Adequate method and concurrent recovery data were provided for the plant
LC/MS/MS method, and the fortification levels used in the method and
concurrent validation are adequate to bracket the residue levels
determined in the proposed crops.  The validated limit of quantitation
(LOQ) in plant matrices is 0.01 ppm. The LC/MS/MS method for plant
commodities may be used for enforcing tolerances pending its review or
validation in EPA laboratories and analytical reference standards for
DPX-E2Y45 are currently available at the EPA National Pesticide
Standards Repository.  An analytical method for enforcing tolerances in
livestock commodities is not germane to this EUP as tolerances in meat,
milk, poultry and eggs are not required.

No data for testing the various protocols in the Pesticide Analytical
Methods (PAM), Volume I, were submitted.  Testing chlorantraniliprole
through the protocols in PAM I is a residue chemistry data requirement
and should be submitted with the Section 3 registration request.

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

The laboratory environmental fate data indicate chlorantraniliprole is
persistent and mobile in terrestrial and aquatic environments.  Major
routes of chlorantraniliprole dissipation are expected to be
alkaline-catalyzed hydrolysis, photodegradation in water, leaching, and
runoff.

The major hydrolysis degradation product is IN-EQW78.  The major
photodegradation products are IN-EQW78, IN-LBA22, IN-LBA24, IN-LBA23. 
Photodegradation of chlorantraniliprole is a predominant degradation
pathway, with half-lives ranging from 0.31 to 22 days (depending on the
photo-source, pH, and matrix).  In aerobic soils, chlorantraniliprole is
stable at 25°C (with half-lives ranging from 228 to 924 days), and
tends to degrade faster at higher soil temperatures.  The major
degradation products identified in soil are IN-F6L99, IN-EVK64,
IN-EQW78, IN-ECD73 and IN-GAZ70.

5.1.6	Comparative Metabolic Profile TC \l3 "5.1.6	Comparative Metabolic
Profile 

The results of the metabolism studies conducted in apple, tomato and
lettuce show that chlorantraniliprole is not metabolized to any
significant extent in apple fruit, apple leaf, tomato fruit, tomato
leaf, or lettuce. In the ruminant metabolism study, parent was the major
terminal residue identified in kidney, muscle, and fat, and it was also
a residue in liver and milk. Metabolites were formed by N-demethylation,
hydroxylation at the two methyl groups, and/or cyclization to yield a
pyrimidone ring.

A complete comparative metabolic profile will be conducted upon receipt
and review of the rat metabolism study, which will be submitted with the
Section 3 registration request.

5.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3 "5.1.7
Toxicity Profile of Major Metabolites and Degradates 

For this EUP, metabolites and degradates are considered of similar or
lesser toxicity than parent, based on structure.  See Table B in
Appendix B for a tabular summary of identified major metabolites and
degradates.

5.1.8	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern 

Table 5.1.8 Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Parent only	Parent only

	Rotational Crop	Parent only	Parent only

Livestock

	Ruminant	Parent only*	Parent only

	Poultry	Not applicable	Not applicable

Drinking Water

	Parent only**	Not Applicable

* Although the goat metabolism study indicated EQW78 is present at >10%
TRR in fat, based on the ruminant feeding study (where EQW78 was not
detected at exaggerated rates [33X]), detectable levels are not expected
in fat.

** Although major degradation products of chlorantraniliprole (IN-EQW78,
IN-LBA22, IN-LBA24, IN-LBA23, IN-F6L99, IN-EVK64, IN-ECD73 and IN-GAZ70)
are found in environmental fate studies, their persistence and mobility
in soil and water is not expected to be substantially different than 
parent chlorantraniliprole.  Therefore, the environmental fate
properties of parent chlorantraniliprole were used to model estimated
drinking water concentrations in surface water and groundwater.

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

Table 5.1.9	Summary of Estimated Surface Water and Groundwater
Concentrations

	Chlorantraniliprole

	Surface Water Conc., ppb [µg/L] a	Groundwater Conc., ppb [ug/L] b

Acute (1 in 10 year peak)	14	0.38

Chronic (non-cancer; 1 in 10 year annual average)	2.3

	Chronic (cancer; 30 year annual average)	1.3

	a From the Tier II PRZM-EXAMS - Index Reservoir model.  Acute is based
on Florida peppers scenario (ground spray, application rate 0.1 kg ai/ha
applied 2, 5-day application interval, total application rate 0.2 kg
ai/ha), chronic non-cancer is based on California lettuce scenario, as
is the chronic cancer estimate (in-furrow, application rate 0.1 kg ai/ha
applied once). Input parameters are based on registrant-submitted
environmental fate data.

b From the SCI-GROW 2.3 model assuming a maximum seasonal use rate of
0.2 kg ai/ha, a Koc of 272 L/g, and a half-life of 410 days (from
aerobic soil metabolism study); California lettuce scenario.

Note: This screening level assessment assumes the environmental fate
properties of chlorantraniliprole degradation products are comparable to
parent chlorantraniliprole (i.e., persistent and mobile).  Additionally,
the assessment assumes that the major degradation products have
equivalent toxicity with chlorantraniliprole.

5.1.10	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile 

Crop field trials were conducted on apple, pear, tomato, pepper,
lettuce, celery, spinach, cucumber, cantaloupe and summer squash. For
the EUP, there are adequate field residue data for these crops based on
geographic representation and number of field trials in accordance with
those specified in Guideline OPPTS 860.1500. Following application of
either the WG or SC formulation to the proposed crops at the maximum
proposed use patterns, levels of DPX-E2Y45 ranged from 0.01 ppm to 0.30
ppm in apple and from 0.01 ppm to 0.14 ppm in pear; from 0.018 ppm to
0.19 ppm in tomato, from 0.012 ppm to 0.19 ppm in bell pepper, and from
0.017 ppm to 0.43 ppm in non-bell pepper; from <0.01 ppm to 2.5 ppm in
head lettuce, from 3.0 ppm to 6.3 ppm in leaf lettuce, from 0.85 ppm to
3.8 ppm in celery, and from 3.4 ppm to 9.7 ppm in spinach; and from
<0.01 ppm to 0.083 ppm in cucumber, from <0.01 ppm to 0.12 ppm in
cantaloupe/muskmelon, and from <0.01 ppm to 0.093 ppm in summer squash.
The field residue studies are supported by adequate storage stability
data which indicate that DPX-E2Y45 is stable under frozen conditions and
during storage intervals. 

Decline data indicate that chlorantraniliprole level in tomato fruit
decreases substantially after one day after the last application;
whereas in head lettuce, spinach and cucumber, the data indicate residue
levels decrease gradually.

Upon processing DPX-E2Y45 did not concentrate in apple juice (0.13x) but
did concentrate in wet apple pomace (2.6x), and concentrated in tomato
puree and paste (both at 1.5x). The data indicate that tolerances in
apple juice, tomato puree and tomato paste are not needed (for tomato
processed products, HAFT x 1.5 would not exceed the 0.30 ppm tolerance);
a tolerance in wet apple pomace at 0.60 ppm (product of HAFT [0.23 ppm]
and average concentration [2.6x]) is needed, however.

The use of wet apple pomace as a cattle feedstuff in finishing feedlots
or for milk production is highly unlikely.  Given the results of the cow
feeding study, there is no reasonable expectation of finite residues in
cattle commodities.  Wet apple pomace is not fed to poultry or swine.

5.1.11	International Residue Limits TC \l3 "5.1.11	International Residue
Limits 

There are currently no established Codex, Canadian, or Mexican MRLs for
DPX-E2Y45.

5.2	Dietary Exposure  TC \l2 "5.2	Dietary Exposure 

Acute and chronic dietary (food and drinking water) exposure estimates
were modeled for chlorantraniliprole, and reflect the proposed uses on
apple, celery, cucumber, head and leaf lettuce, pear, pepper, spinach,
squash, tomato and watermelon crops.  The dietary model DEEM-FCID™
analyses estimate the dietary exposure of the U.S. population and
various population subgroups.  Based on analysis of consumption data,
which took into account dietary patterns and survey respondents, HED
concluded that it is most appropriate to report risk for the following
population subgroups: the general U.S. population, all infants (<1 year
old), children 1-2, children 3-5, children 6-12, youth 13-19, adults
20-49, females 13-49, and adults 50+ years old.

Table 5.2 provides dietary exposure estimates for these population
subgroups.  The modeled dietary exposure estimates are based on
tolerance level residues assuming 100% of crops are treated (for food)
and modeled surface water EDWCs (for drinking water [the highest
relevant EDWCs were used]).  As this assessment is for an EUP, which has
proposed treating 1300 acres for 2 years, these exposure estimates are
highly conservative screening level values.

Table 5.2. Result of Acute and Chronic Dietary Exposure Estimates for
Chlorantraniliprole

Population Subgroup	DEEM-FCID

	Acute Exposure Estimate (95th percentile), mg/kg/day	Chronic Exposure
Estimate, mg/kg/day 

All infants (< 1 yr)	0.014	0.0044

Children 1-2 yrs	0.017	0.0051

Children 3-5 yrs	0.014	0.0040

Children 6-12 yrs	0.010	0.0026

Youth 13-19 yrs	0.0083	0.0019

Adults 20-49 yrs	0.0099	0.0024

Adults 50+ yrs	0.0094	0.0025

Females 13-49 yrs	0.010	0.0025

U.S. Population	0.010	0.0026

* The population subgroup with the highest exposure estimate is bolded.

No hazard has been identified (including no adverse effect attributable
to a single dose) in the chlorantraniliprole toxicology database and
subsequently no endpoints were selected for any dietary exposure
duration.  However, acute and chronic dietary exposure estimates were
generated to characterize the potential range of exposure resulting from
the EUP (albeit, a conservative characterization, due to the assumptions
described above).  Therefore, although it is inappropriate to utilize
these exposure estimates to generate risk estimates, it is useful to
point out, the conservative screening level acute exposure estimates are
at least 60,000 times lower, and the chronic exposure estimates are at
least 200,000 times lower than the highest doses tested (HDTs) in the
mammalian toxicity studies (and no adverse observed effects were seen at
that level, in all the studies submitted, see Section 3.0).

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l2 "5.3	Anticipated Residue and Percent Crop Treated (%CT) Information 

No anticipated residue, or percent crop treated information were used in
the dietary exposure assessment.

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

Chlorantraniliprole is not registered for use in residential or public
sites, nor is an EUP being requested for use in these areas.  Therefore,
non-occupational handler and postapplication exposure assessments were
not performed.  

It should also be noted that spray drift is always a potential source of
exposure to residents nearby to spraying operations.  This is
particularly the case with aerial application, but, to a lesser extent,
could also be a potential source of exposure from the groundboom
application.  The Agency has been working with the Spray Drift Task
Force, EPA Regional Offices and 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, a membership of U.S. pesticide registrants, 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 aerial as well as other application types where appropriate.

Again, it should be noted that for this EUP, relatively few acres will
be subject to treatment with chlorantraniliprole, thus, relatively few
areas will be potentially subject to spray drift.

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

In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.

For this EUP, there is no residential exposure associated with the
proposed use, and no hazard has been identified; subsequently, aggregate
risk assessments are not relevant to this action.  See Section 5.2 for a
discussion of potential exposure resulting from food and drinking water.

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

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 as to chlorantraniliprole and any
other substances and chlorantraniliprole does not appear to produce a
toxic metabolite produced by other substances. For the purposes of this
temporary tolerance action and EUP application, therefore, EPA has not
assumed that chlorantraniliprole 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
http://www.epa.gov/pesticides/cumulative/.

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

Reference: Chlorantraniliprole/DPX-E2Y45. Occupational and Residential
Risk Assessment of an Experimental Use Permit 352-EUP-RTN-XXX on Apple,
Celery, Cucumber, Head Lettuce, Leaf Lettuce, Pear, Pepper, Spinach,
Squash, Tomato, and Watermelon. DP Number: 331612, Jack Arthur, 2/28/07.

9.1	Short-/Intermediate-term Handler Exposure  TC \l2 "9.1
Short-/Intermediate-term Handler Exposure 

There is a potential for exposure to chlorantraniliprole during mixing,
loading, and application.  Handler’s exposures were estimated for:

(1) mixer/loader: open mixing dry flowable for airblast sprayer; 

(2) mixer/loader: open mixing dry flowable for aerial; 

(3) mixer/loader: open mixing liquid for groundboom; 

(4) mixer/loader: open mixing liquid for aerial/chemigation;

(5) groundboom application: open cab; 

(6) airblast application: open cab; 

(7) aerial application: enclosed cockpit, and; 

(8) flagging for aerial application.

No chemical-specific handler exposure data were submitted in support of
this EUP request.  In accordance with HED’s Exposure Science Advisory
Council (SAC) policy, exposure data from the Pesticide Handlers Exposure
Database (PHED) Version 1.1 as presented in PHED Surrogate Exposure
Guide (8/98) were used with HED standard values for acres treated per
day, a body weight of 70 kg, and baseline level of personal protective
equipment to assess handler exposures. Daily dermal and inhalation
exposures were calculated separately; assuming both a dermal and
inhalation absorption factor of 100%.  Details of the handler exposures
are presented in Table 9.1.

Handler inhalation exposures ranged from 0.000031 mg/kg/day for aerial
applicators, to 0.00034 mg/kg/day for mixers/loaders of dry flowable to
support aerial application.  Handler dermal exposures ranged from 0.0014
mg/kg/day for groundboom applicators to 1.3 mg/kg/day for mixers/loaders
of liquids to support aerial application.  These exposure estimates may
be very conservative for the actual EUP use pattern, because they are
based on the standard assumption of number of acres that can be treated
in a day, rather than the likely fewer number of acres that may be
receiving treatment per day during the EUP study (additionally, assuming
a dermal absorption of 100% is conservative).

The minimum level of PPE for handlers is based on acute toxicity for the
end-use product.  The Registration Division (RD) is responsible for
ensuring that PPE listed on the label is in compliance with the Worker
Protection Standard (WPS).

Table 9.1. Short-/Intermediate-term Occupational Handler Exposure
Estimates for Chlorantraniliprole (all estimates are at baseline PPE)

Exposure Scenario	End-use Product	Route of Exposure	PHED Unit Exposure1
Data Quality	Maximum Single Application Rate	Acres Treated	Exposure
Dose2

(mg/kg/day)

(1) mixer/loader: open mixing dry flowable for airblast sprayer	Altacor
WG [352-EUP-XXX]	Dermal	0.066 mg/lb ai	Low	

0.088 lb ai/A	

40	0.0033 

Inhalation	0.00077 mg/lb ai	High

	0.000039 

(2) mixer/loader: open mixing dry flowable for aerial	Altacor WG
[352-EUP-XXX]	Dermal	0.066 mg/lb ai	Low	

0.088 lb ai/A	

350	0.029

Inhalation	0.00077 mg/lb ai	High

	0.00034

(3) mixer/loader: open mixing liquid for groundboom	Coragen SC
[352-EUP-XXX]	Dermal	2.9 mg/lb ai	High	

0.09 lb ai/A	

80	0.30

Inhalation	0.0012 mg/lb ai	High

	0.00012

(4) mixer/loader: open mixing liquid for aerial/chemigation	Coragen SC
[352-EUP-XXX]	Dermal	2.9 mg/lb ai	High	

0.09 lb ai/A	

350	1.3

Inhalation	0.0012 mg/lb ai	High

	0.00054

(5) ground-boom  application: open cab	Coragen SC [352-EUP-XXX]	Dermal
0.014 mg/lb ai	High	

0.09 lb ai/A	

80	0.0014

Inhalation	0.00074 mg/lb ai	High

	0.000076

(6) airblast application: open cab	Altacor WG [352-EUP-XXX]	Dermal	0.36
mg/lb ai	High	

0.088 lb ai/A	

40	0.018

Inhalation	0.0045 mg/lb ai	High

	0.00023

(7) aerial application: enclosed cockpit	Altacor WG [352-EUP-XXX];
Coragen SC [352-EUP-XXX]	Dermal	0.0050 mg/lb ai	Medium	

0.09 lb ai/A	

350	0.0023

Inhalation	

0.000068 mg/lb ai	

Medium

	

0.000031

(8) ) flagging for aerial application	Altacor WG [352-EUP-XXX]; Coragen
SC [352-EUP-XXX]	Dermal	0.011 mg/lb ai	High	

0.09 lb ai/A	

350	0.005

Inhalation	0.00035 mg/lb ai	High

	0.00016

Unit exposure values are for baseline PPE (long sleeved shirt, long
pants, shoes and socks).

Dose = [Unit exposure (mg/lb ai) x Application rate (lb ai/acre) x Acres
treated] ÷ [Body Weight (70 kg)]

Since no hazard has been identified, and subsequently no endpoints
selected, it is inappropriate to utilize these occupational handler
exposure estimates to generate risk estimates.  However, it is useful to
point out, the inhalation exposure estimates (conservative, screening
level) are at least 2,900,000 times lower, and the dermal exposure
estimates (also conservative, screening level) are at least 800 times
lower than the highest doses tested (HDT) in the mammalian toxicity
studies (and no adverse observed effects were seen at that level, in all
the studies submitted, see Section 3.0).

9.2	Short-/Intermediate-Term Postapplication Exposure  TC \l2 "9.2
Short-/Intermediate-Term Postapplication Exposure 

Chlorantraniliprole uses subject to this action include foliar
applications to a variety of crops.  Consequently there is potential for
postapplication dermal exposure to field workers, and dermal exposures
were estimated for postapplication workers involved in a variety of
agricultural tasks relevant to the crops subject to this EUP. 
Inhalation exposure is expected to be negligible.  The revised HED
Exposure Science Advisory Council Policy (Policy 003 - revised August 7,
2000) was used to estimate worker postapplication exposures.  Transfer
coefficients (Tc) are based primarily on data submitted to the Agency by
the Agricultural Reentry Task Force (ARTF).  Studies submitted by the
ARTF are proprietary and compensation issues with ARTF may need to be
addressed.  The resulting postapplication worker exposure estimates
range from 0.011 mg/kg/day to 0.066 mg/kg/day on the day of application.
 Again, it should be noted that these estimates are conservative given
this is an EUP (with lower acreage), and postapplication activities for
a particular crop may not necessitate an 8 hour work day (which is
assumed in the assessment).  A summary of postapplication exposures are
included as Table 9.2

Technical chlorantraniliprole is in Category IV for acute dermal
toxicity and Category IV for primary eye and skin irritation.  Per the
Worker Protection Standard (WPS), a 12-hr REI is required for chemicals
classified under Toxicity Category III or IV, and therefore, an interim
REI of 12 hours should appear on the chlorantraniliprole labels, instead
of the 4-hour REI currently listed. 

Table 9.2 Summary of Occupational Postapplication Exposure Estimates for
Chlorantraniliprole on Postapplication Day 0

Crops	

Appl. Rate

(lb ai/A)	

DFR

(ug/cm2) 1	

Dermal Transfer

Coefficient 

(cm2/hr)	

Exposure Time

(hrs/day)	

Dermal

Absorption Factor 	

Body Wt (kg)	

Daily Dose 2

(mg/kg/day)

Veg., Leafy (celery, lettuce, spinach)	

0.09	

0.196	Scout: 500	

8	

1	

70	0.011

	irrigate: 1500

0.034

	Prune, thin, harvest: 2500

0.056

Veg., Cucurbit (cucumber, squash, watermelon)	

0.09	

0.196	scout, irrigate: 500	

8	

1	

70	0.011

	hand weeding: 1500

0.034

	hand harvesting: 2500

0.056

Veg. Fruiting (pepper, tomato)	0.09	0.196	Scout: 500	8	1	70	0.011

	Prune, tying: 700

0.016

	hand harvest: 1000

0.022

Tree Fruit, Deciduous (apple, pear)	

0.088	

0.192	Scout: 1000	

8	

1	

70	0.022

	 Hand harvest: 1500

0.033

	thin, prop: 3000

0.066

1  DFR = Dislodgeable Foliar Residue on Postapplication Day 0 (ug/cm2) =
Application rate (lb ai/A) x Fraction of ai Retained on the Foliage
[0.2] x (1- Fraction of Residue that Dissipates Daily [0.1])
postapplication day x  4.54E+8 ug/lb x 2.47E-8 A/cm2; (Fraction of
Residue that dissipates daily = 0.1 and Fraction of ai retained on the
foliage = 0.2)

2  Daily Dose = (Dislodgeable Foliar Residue x  Absorption Factor  x
0.001 mg/ug  x Dermal Transfer Coefficient x Exposure Time)/Body weight

Since no hazard has been identified, and subsequently no endpoints
selected, it is inappropriate to utilize these occupational
postapplication exposure estimates to generate risk estimates.  However,
it is useful to point out, these dermal exposure estimates are at least
15,000 times lower than the highest doses tested (HDT) in the mammalian
toxicity studies (and no adverse observed effects were seen at that
level, in all the studies submitted, see Section 3.0).

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

10.1	Toxicology  TC \l2 "10.1	Toxicology 

No toxicological data needs are required for this action.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

Section B/Label

Since the residue data do not reflect the use of adjuvants in the field
studies, the proposed label should be revised to delete the use of
adjuvants. 

Given the results of the confined accumulation in rotational crops
study, a restriction should be imposed on the proposed label to prohibit
the rotation to cereal grains and any crop not on the label. 

The maximum number of applications to crops other than apple and pear
must be stated on the label.  The residue data for these crops support 2
applications.

For apples and pears, the minimum number of gallons of water per acre
for ground applications must be stated.  The residue data for pome fruit
support a minimum of 100 gallons water per acre for ground applications.

The label should prohibit use on tomatoes grown in greenhouses.

Section F/Temporary tolerances

The registrant needs to propose a tolerance in/on wet apple pomace at
0.60 ppm.

The registrant needs to submit a revised Section F with temporary
tolerances for residues of
3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chlor
o-2-pyridinyl)-1H-pyrazole-5-carboxamide in the following raw
agricultural commodities, at the following levels:

Apple			0.25 ppm

Apple, wet pomace	0.60 ppm

Celery			7.0 ppm

Cucumber		0.10 ppm

Lettuce, head		4.0 ppm

Lettuce, leaf		8.0 ppm

Pear			0.30 ppm

Pepper			0.50 ppm

Spinach		13 ppm

Squash			0.40 ppm

Tomato		0.30 ppm

Watermelon		0.20 ppm

For a future full registration, the following additional data would be
required:

Independent laboratory validation for the plant method.

Data for testing the various protocols in the Pesticide Analytical
Methods, Volume I.

Field rotational crop studies. Depending on the results, tolerances in
rotational crops may be needed.

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

Technical chlorantraniliprole is in Category IV for acute dermal
toxicity and Category IV for primary eye and skin irritation.  Per the
Worker Protection Standard (WPS), a 12-hr REI is required for chemicals
classified under Toxicity Category III or IV, and therefore, an interim
REI of 12 hours should appear on the chlorantraniliprole labels, instead
of the 4-hour REI currently listed. 

References:  TC \l1 "References: 

Chlorantraniliprole/DPX-E2Y45. Experimental Use Permit 352-EUP-RTN on
Apple, Celery, Cucumber, Head Lettuce, Leaf Lettuce, Pear, Pepper,
Spinach, Squash, Tomato, and Watermelon. Summary of Analytical Chemistry
and Residue Data. DP Number: 331568. Leung Cheng, 3/5/07.

Chlorantraniliprole/DPX-E2Y45. Occupational and Residential Risk
Assessment of an Experimental Use Permit 352-EUP-RTN-XXX on Apple,
Celery, Cucumber, Head Lettuce, Leaf Lettuce, Pear, Pepper, Spinach,
Squash, Tomato, and Watermelon. DP Number: 331612, Jack Arthur, 2/28/07.

Appendix A:	Toxicology Profile Table   TC \l1 "Appendix A:	Toxicology
Profile Table 

Table A: Toxicology Profile for Chlorantraniliprole

Study	Species	Duration	Doses	NOAEL/

category	LOAEL	Effects

Acute oral (gavage)  tox	3 SD Female rats	Single dose	5000 mg/kg	LD50 =
>5000 mg/kg bw

No mortalities, clinical signs or body weight changes

Acute dermal tox	5/sex SD rats	Single application	5000 mg/kg	LD50 =
>5000 mg/kg bw

Red ocular discharge and red nasal discharge but reversed on day 3.

Acute inhalation tox	5/sex SD rats	Single 4 hour nose only exposure	5.1
mg/L	LC50 >5.1 mg/L both female and male rats

Ocular and oral discharges immediately in some male rats, slight body
weight loss in some femaled and males then return to normal remainder of
the study

Acute dermal irritation	3 male New Zealand White rabbits	Single 4 hour
exposure 	0.5 g	Category IV toxicity

No dermal irritation, clinical signs or body weight loss

Eye irritation	3 male young adult New Zealand White rabbits	Single dose
72 mg	Category IV toxicity

Iritis score of 1 in 1/3 rabbit, conjunctival redness score 1 2/3
rabbits.  All eyes returned to normal after 72 hours.

Skin sensitization – local lymph node assay	5 groups of 5 female
CBA/JHsd mice	3 consecutive days	0, 5%, 25%, 50% and 100% DPX on both
ears.

	DPX-E2Y45 is not a dermal sensitizer

Oral subchronic feeding study 	10 rats/sex/

concentration	90 days	0, 36.9, 120, 359 or 1188 mg/kg/day for males and
0, 47, 157, 460, or 1526 mg/kg/day for females.	1188 and 1526 mg/kg/day
for males and females – lack of any adverse effects in any parameter
No LOAEL	A slight increase in liver weight in HDT in females and
reduction in bilirubin in females exposed to 2000 ppm (120/157
mg/kg/day) and above but not considered adverse.  Metabolite INGAZ70 is
at higher concentration in females than parent or other metabolite

Oral subchronic feeding study	CD mice 15 mice/sex/ concentration	90 days
0, 32.6, 115, 345 or 1135 mg/kg/day (males) and 0, 40.7, 158, 422 or
1529  mg/kg/day (females)	1135 and 1539 mg/kg/day based on lack of any
adverse effects on any parameter in mice	No LOAEL	Hyperactivity and
hyperreactivity in females observed near end of exposure period. One
male had convulsions in the upper mid dose, but these effects were not
reproducible in 18-month study with FOB and considered spurious.  

Body weight gain decrease in upper two doses , 34% and 26% from control.
 Food efficiency also decreased in all doses.  A slight increase in
liver weight at HDT in males and females, but not adverse. IN-GAZ70 was
the only significant analyte present in plasma higher in female (2X)
than males

Oral subchronic feeding study	4 beagle dogs/sex/

concentration	90 days	0, 32.2, 119, 303 and 1163 mg/kg/day (males) and
0, 36.5, 133, 318 and 1220 mg/kg/day	1163 and 1220 mg/kg/day based on
lack of adverse effects 	No LOAEL	A mild increase in liver weight was
observed in male dogs dosed at HDT group.  Parent and metabolite
IN-HXH44 were identified as having the highest concentrations in plasma
and were detected at all dietary concentrations in males and females.
Parent was 5X higher than metabolite and similar across gender at the
same dietary concentration.

28-day dermal tox study 	10 SD rats/sex/dose	29 days, 6 hrs/day	0, 100,
300 or 1000 mg/kg/day	1000 mg/kg/day for dermal effects	No LOAEL
Reductions in mean body weight gain (78% and 81% for males and females)
and food efficiency (81% and 83% for males and females) over the 28-day
interval at the highest dose tested.

Increased microvesiculation of adrenal cortex in males only, no light or
electron microscopic evidence of adrenal cellular degeneration or
toxicity.  No effect on the capacity of the adrenal gland to produce
corticosterone under either basal conditions or following ACTH
stimulation.

Bacterial reverse mutation  test	TA98, TA100, TA1535 and TA1537 and
Ecoli strain uvA with and without metabolic activation	2.5 – 5000
ug/plate

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Negative for mutagenic activity in non-activated and S9-activated test
systems.  No concentration-related increase in the mean revertants per
plate in any strain.

Mammalian chromosome aberration study 	Human peripheral blood
lymphocytes	125, 250, 500, 750 and 1000 ug/mL – visible precipitate
seen at >500

Negative for the induction of structural and numerical chromosome
aberrations in cultured human peripheral blood lymphocytes with and
without an exogenous metabolic activation system.

Mammalian cell gene mutation test (CHO/HGPRT Test)	CHO/HGPRT cells	31.3,
62.5, 125, 250, 500 ug/mL  visible precipitate in the treatment medium
at greater than or equal to 250 ug/mL.

No evidence of cytotoxicity at any of the concentrations of the test
substance evaluated.  Negative for mutagenic activity in the
non-activated and S9-activated test systems in the CHO/HGPRT mutation
assay.

Mouse bone marrow, or micronucleus test in rodents	Bone marrow of CD-1
mice 5 mice per sex/group 	500, 1000 or 2000 mg/kg bw

No statistically significant increases in MNPCE frequency in male or
female mice administered DPX. No clinical signs, bw losses.  Negative 
for in vivo genotoxicity in mouse bone marrow cell.  Did not induce an
increase in micronuclei in bone marrow cells of mice at doses up to the
limit dose of 2000 mg/kg bw oral gavage.

Multigeneration reproduction study	SD rats (30 rats/sex/

concentration for both the P1 and F1 generations)	0, 12, 60.4, 238, and
1199 mg/kg/day in males and 0, 15.5, 77.8, 318.9, and 1594 mg/kg/day for
females.

NOAEL was 20,000 ppm based on lack of any adverse effects at the highest
dietary concentration tested, which is equivalent to 1199-2178 mg/kg
bw/day

A slight increase in mean liver weights in P1 and F1 males and females
at 238/318.9 mg/kg/day and above, slight increase in mean adrenal weight
at 238/318.9 mg/kg/day and 1199/1594 mg/kg/day P1 and F1 males and
females.  Mean body weight of 1199/1594 mg/kg/day  F1 pups was slightly
reduced on lactation days 7, 14 and 21.  No effects on F2 offspring
weights during lactation.

Minimal to mild increase in adrenal cortical microvesciculation in P1
adult males and F1 adult males and females.  P1 adult at 60.4/77.8
mg/kg/day and greater.  F1 adult males at 12 mg/kg/day and greater.
These effects were not observed in weanlings.  No cytotox, or abnormal
cellular structures were observed under light or electron microscopy.

Developmental Tox	SD female rats (22/dose group)	GD 6-20	Gavage doses
0,20, 100, 300, 1000 mg/kg	NOAEL – 1000 mg/kg/day

No effects – 

Developmental Tox	New Zealand White Rabbits (22/dose group)	GD 7-28
Gavage 0, 20, 100, 300, 1000 mg/kg	NOAEL – 1000 mg/kg/day

No effects

Appendix B:	Tabular Summary of Metabolites and Degradates   TC \l1
"Appendix B:	Tabular Summary of Metabolites and Degradates  

The following table was put together using not fully reviewed residue
chemistry data, environmental fate and effects data, as well as
information from a DuPont presentation re: the pending Section 3
registration; and was used to inform the residues of concern decision. 
The residues of concern decision will be re-evaluated for the pending
Section 3 action.

Table B.  Tabular Summary of Metabolites and Degradates for
Chlorantraniliprole

Chemical Name	

Matrix	Percent TRR (PPM) 1	Structure

Matrices - Major Residue (>10%TRR)	Matrices - Minor Residue (<10%TRR)

	Chlorantraniliprole	Crop 1	Apple

	Crop 2	Lettuce

	Crop 3	Tomato

	Rotational Crops	Wheat (grain, forage, hay, straw)

Lettuce

Beet foliage

	Ruminant	Milk

Muscle

Fat

Kidney

	Rat	Present (amt. unknown)

INEQW78	Ruminant	Fat

	Rat	Not present 

	Aerobic Soil Metabolism	11.31% of applied

	Hydrolysis	86.7% of applied at pH 9

	Aerobic Aquatic Metabolism	30.02% of applied

IN-LBA22	Photodegradation in water	Major (amount not specified)

IN-LBA23	Photodegradation in water	40.1% of applied

IN-LBA24

	Photodegradation in water	88.2% of applied

IN-HXH44 

(& HXH44-O-G)	Ruminant	Milk

Muscle

	Rat	Present (unknown)

IN-H2H20 

(& H2H20-O-G)	Rat	Present (amt. unknown)

IN-KAA24	Rat	Present (amt. unknown)

IN-GAZ70	Rat	Present (amt. unknown)

IN-K9T00 

(& K9T00-O-G)	Ruminant	Milk

	Rat	Present (amt. unknown)

IN-HXH40 

(& HXH40-O-G)	Rat	Present (amt. unknown)

Note: the following were also identified as major degradation products:
IN-ECD73, IN-EVK64 and IN-F6L99 and IN-EVK64

Appendix C:	Review of Human Research TC \l1 " Appendix C:	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.  The database listed below has been determined to require a
review of its ethical conduct.  It has received the appropriate review. 
It was concluded it does not violate current ethical standards

Studies reviewed for ethical conduct:

The PHED Task Force, 1995.  The Pesticide Handlers Exposure Database,
Version 1.1.  Task Force members Health Canada, U.S. Environmental
Protection Agency, and the National Agricultural Chemicals Association,
released February, 1995.

 The study has not yet been formally submitted for the EUP, but EPA
Reviewer was provided the QA/QC’d study summary and tables of gross
and microscopic observations.

 The study has not yet been formally submitted for the EUP, but EPA
Reviewer was provided the QA/QC’d study summary and tables of gross
and microscopic observations.

 The study has not yet been formally submitted for the EUP, but EPA
Reviewer was provided the QA/QC’d study summary and tables of gross
and microscopic observations.

 A dry flowable formulation is representative of water dispersible
granules, and therefore these data from the PHED Surrogate Exposure
Guide are employed in this occupational exposure assessment to assess
potential exposure resulting from the use of AltacorTM WG.

 A liquid formulation is representative of a suspension concentrate, and
therefore these data from the PHED Surrogate Exposure Guide are employed
in this occupational exposure assessment to assess potential exposure
resulting from the use of CoragenTM SC.

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DRAFT: Internal, Confidential and Deliberative

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