Document ID: EPA-HQ-OPP-2007-0275-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-07T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 3/7/2008

MEMORANDUM

SUBJECT:	Chlorantraniliprole (DPX-E2Y45): Human Health Risk Assessment
for Proposed Uses on Pome fruit, Stone fruit, Leafy vegetables, Brassica
leafy vegetables, Cucurbit vegetables, Fruiting vegetables, Cotton,
Grapes, Potatoes, Turf and Ornamentals. PC Code: 090100, Petition
#7F7181 DP Barcode: D336983, D338120, D348103, D346324, Section 18
Registration # 08LA01 (Rice), D346324.

		Regulatory Action: Section 3 and Section 18 registration actions

		Risk Assessment Type: Single Chemical Aggregate

FROM:	Sarah Winfield, Biologist

		Leung Cheng, Ph.D., Chemist

		Mary Manibusan, Toxicologist

		Jack Arthur, Industrial Hygienist 

		Registration Action Branch 3

		Health Effects Division (7509P)

			and

		James A. Hetrick, Ph.D., Senior Science Advisor

		Environmental Risk Branch III

		Environmental Fate and Effects Division (7507P)

THROUGH:	Paula Deschamp, Branch Chief 

Registration Action Branch 3

		Health Effects Division (7509P)

			AND

		Kelly O’Rourke, Biologist, Designated Reviewer

		PV Shah, Toxicologist, Designated Reviewer

Risk Assessment Review Committee

		Health Effects Division (7509P)

TO:		Meredith Laws, Branch Chief and Kable Davis, Entomologist

		Insecticide Review Branch

		Registration Division (7505P)

Introduction

This document addresses three different actions submitted to the Agency
regarding chlorantraniliprole.  The primary action (Section 3,
food-uses, Petition #7F7181) was conducted as part of a global project
with the Organization for Economic Cooperation and Development (OECD). 
The goals of the project were to work-share among participating
countries and harmonize on maximum residue levels (MRLs) to attenuate
potential trade issues.  To facilitate the project a common dossier was
submitted, and a common OECD monograph is expected as an output.  The
United States (US) was the lead country for the mammalian toxicology
database assessment.

As part of the OECD work-share project, E. I. DuPont de Nemours and
Company, DuPont Crop Protection (referred to as DuPont or the registrant
throughout the rest of the document) proposed product registrations and
exemptions for the requirement of tolerances (for the US only) for the
new active ingredient (ai) chlorantraniliprole.  The common name,
chlorantraniliprole, was officially granted following the generation and
submission of the supporting datasets.  Therefore, although
chlorantraniliprole is used on product labels and government forms, the
company name, DPX-E2Y45 is used in the technical reports (both names are
used synonymously in this document).  This action involves the
registration of one technical product (DuPontTM RynaxypyrTM Technical
Insecticide) and two agricultural end-use products (DuPontTM CoragenTM
SC Insecticide and DuPontTM AltacorTM WG Insecticide) for use on pome
fruit, stone fruit, leafy vegetables, Brassica leafy vegetables,
cucurbit vegetables, fruiting vegetables, cotton, grapes and potatoes.

Additionally, DuPont submitted 13 product registration applications to
the US EPA, to consider the use of chlorantraniliprole on terrestrial
non-food crops (i.e., landscape ornamentals and turf grass).  One is a
soluble concentrate (18.4% ai), but the remaining 12 end-use products
are formulated as granulars (all contain less than 1% ai).  Also, the
registrant has submitted a product registration for a manufacturing
concentrate (a dry powder formulation, 35% ai) used to generate the
granular formulations.  The end-use products are for use on turf grasses
and ornamental plants growing in residential, commercial, and public
landscaped areas; on golf courses and athletic fields; and to turf
grasses grown on commercial sod farms.

Lastly, the Louisiana Department of Agriculture and Forestry has
requested an exemption under Section 18 of FIFRA for the use of
chlorantraniliprole (DuPontTM Dermacor X-100 Seed Treatment, 51.85% ai)
for the purpose of controlling rice water weevils in drill-seeded rice
fields in Louisiana (treated seeds are not to be used as part of
water-seeded cultivation practices).  Associated with this action, is
another Section 18 for exemption from tolerances from inadvertent
residues on crayfish, resulting from the use on rice seed (residue data
in crayfish were not required for the Section 18 request, and therefore
are not addressed in this document).

Although maximum residue limits are proposed for food uses outside of
the US, based on toxicity considerations, DuPont requests an exemption
from the requirement of tolerances for residues resulting from the
application of chlorantraniliprole formulations to the crops or crop
groups grown in/imported to the US, as well as for residues of
chlorantraniliprole which may be found on rotational crops planted to
areas previously treated with chlorantraniliprole; and finally, for
residues of chlorantraniliprole on the meat, milk, poultry, and eggs
which are derived from animals which consume feed commodities which have
been treated with chlorantraniliprole formulations.  On the other hand,
the Louisiana Department of Agriculture and Forestry has proposed
temporary tolerances of 0.05 ppm in rice grain (kernels plus hulls) and
0.25 ppm in rice straw.

Pending submission of a revised Section B (label modifications –see
Section 10.2 and 10.3 of this document), the submission of extensive
field rotational crop data (see Section 10.2), and the submission of a
revised Section F (below), there are no residue chemistry, toxicology
and/or exposure issues that would preclude granting a conditional
registration for the requested uses of chlorantraniliprole on the crops
and/or crop groups addressed herein.  Registration should be made
conditional pending adequate resolution of the data gaps listed.

The Agency has determined that the request for exemption from tolerances
for chlorantraniliprole is not appropriate due to identified toxicity in
the submitted mammalian toxicology database and identified exposure
potential based on submitted exposure data.  The proposed uses and the
submitted data support the following 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 (i.e., chlorantraniliprole)
in/on the following raw agricultural or processed commodities or crop
groups, at the following levels:

Apple, wet pomace	0.60 ppm

Brassica, head and stem, subgroup 5A	4.0 ppm

Brassica, leafy greens, subgroup 5B 	11 ppm

Cotton, gin byproduct	30 ppm

Cotton, hulls	0.40 ppm

Cotton, undelinted seed	0.30 ppm

Fruit, pome, group 11 	0.30 ppm

Fruit, stone, group 12 	1.0 ppm

Grape	1.2 ppm

Grape, raisin	2.5 ppm

Potato	0.01 ppm

Vegetable, cucurbit, group 9	0.25 ppm

Vegetable, fruiting, group 8	0.70 ppm

Vegetable, leafy, except Brassica, group 4	13 ppm

Milk	0.01 ppm

Meat*	0.01 ppm

Meat byproducts* 	0.01 ppm

Fat*	0.01 ppm

*of cattle, goats, horses, sheep

And for the Section 18 use on rice, HED recommends the following
temporary tolerances or time-limited tolerances in/on the following
commodities:

Rice, grain	0.10 ppm

Rice, straw	0.25 ppm

This HED document provides a summary of the findings from the data
evaluation and subsequent assessment of human health risk resulting from
these requests.  The hazard assessment and characterization was
conducted by Mary Manibusan; the occupational exposure data review 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 _Toc192910386 \h  6 

2.0	Ingredient Profile	  PAGEREF _Toc192910387 \h  10 

2.1	Summary of Proposed Uses	  PAGEREF _Toc192910388 \h  10 

2.2	Structure and Nomenclature	  PAGEREF _Toc192910389 \h  15 

2.3	Physical and Chemical Properties	  PAGEREF _Toc192910390 \h  15 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc192910391 \h  16 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc192910392 \h
 16 

3.1.1	Toxicology Database Summary	  PAGEREF _Toc192910393 \h  16 

3.1.1.2	Biochemical Mode of Action	  PAGEREF _Toc192910394 \h  17 

3.1.2	Toxicological Effects	  PAGEREF _Toc192910395 \h  18 

3.1.3	Dose-response	  PAGEREF _Toc192910396 \h  19 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc192910397 \h  20 

3.3	FQPA Considerations	  PAGEREF _Toc192910398 \h  22 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc192910399 \h  22 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc192910400 \h  22 

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc192910401 \h  23 

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc192910402 \h  23 

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc192910403 \h  24 

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc192910404 \h  24 

3.3.6.1	Determination of Susceptibility	  PAGEREF _Toc192910405 \h  24 

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc192910406 \h 
24 

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc192910407 \h  25 

3.5.1	Acute Dietary (All populations, including Females 13-49 years old)
  PAGEREF _Toc192910408 \h  25 

3.5.2	Chronic Dietary (All populations)	  PAGEREF _Toc192910409 \h  25 

3.5.3	Incidental Oral Exposure (Short- and intermediate-term)	  PAGEREF
_Toc192910410 \h  26 

3.5.4	Dermal Exposure (Short- and intermediate-term)	  PAGEREF
_Toc192910411 \h  26 

3.5.5	Inhalation Exposure (Short- and intermediate-term)	  PAGEREF
_Toc192910412 \h  26 

3.5.6	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc192910413 \h  26 

3.5.7	Classification of Carcinogenic Potential	  PAGEREF _Toc192910414
\h  26 

3.5.8	Summary of Toxicological Doses and Endpoints for
Chlorantraniliprole for Use in Human Health Risk Assessment	  PAGEREF
_Toc192910415 \h  27 

3.6	Endocrine Disruption	  PAGEREF _Toc192910416 \h  28 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc192910417 \h  28 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc192910418 \h 
29 

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc192910419 \h  29 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc192910420 \h  29 

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc192910421 \h  29 

5.1.3	Metabolism in Livestock	  PAGEREF _Toc192910422 \h  30 

5.1.4	Analytical Methodology	  PAGEREF _Toc192910423 \h  30 

5.1.5	Environmental Degradation	  PAGEREF _Toc192910424 \h  31 

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc192910425 \h  32 

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc192910426 \h  33 

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc192910427 \h  34 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc192910428 \h  36 

5.1.10	Food Residue Profile	  PAGEREF _Toc192910429 \h  38 

5.1.11	International Residue Limits	  PAGEREF _Toc192910430 \h  38 

5.2	Dietary Exposure and Risk	  PAGEREF _Toc192910431 \h  38 

5.2.1	Chronic Dietary Exposure/Risk	  PAGEREF _Toc192910432 \h  39 

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc192910433 \h  40 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc192910434 \h  40 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc192910435 \h  41 

7.1	Long-Term Aggregate Risk	  PAGEREF _Toc192910436 \h  41 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc192910437
\h  41 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc192910438 \h  42 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc192910439 \h  43

10.1	Toxicology	  PAGEREF _Toc192910440 \h  43 

10.2	Residue Chemistry	  PAGEREF _Toc192910441 \h  43 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc192910442 \h 
44 

References:	  PAGEREF _Toc192910443 \h  45 

Appendix A:  Toxicology Assessment	  PAGEREF _Toc192910444 \h  46 

A.1	Toxicology Data Requirements	  PAGEREF _Toc192910445 \h  46 

A.2	Toxicity Profiles	  PAGEREF _Toc192910446 \h  47 

A.3	Toxicity Summaries	  PAGEREF _Toc192910447 \h  49 

Appendix B:  Metabolism Assessment	  PAGEREF _Toc192910448 \h  60 

B.1	Metabolism Guidance and Considerations	  PAGEREF _Toc192910449 \h 
60 

Appendix C:  Review of Human Research	  PAGEREF _Toc192910450 \h  68 

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Chlorantraniliprole, or DPX-E2Y45, is a novel anthranilic diamide
insecticide that belongs to a class of compounds that acts on the
ryanodine receptor (Group 28 based on the target site of action).  It is
an insecticide that was developed by DuPont for control of lepidopteran
pests and controls many insects primarily via interruption of normal
muscle contraction pathways, which leads to paralysis and eventual death
of the pest.  DuPont has applied for a Section 3 registration of two
agricultural end-use products (DupontTM CoragenTM SC Insecticide and
DupontTM AltacorTM WG Insecticide) and 13 products for use on turf and
ornamentals (DupontTM E2Y45 SC Insecticide, and 12 granular formulations
of varying concentrations ai).  Additionally the Louisiana Department of
Agriculture has applied for a Section 18 exemption for the use of
DupontTM Dermacor X-100 Seed Treatment on rice seeds.  These actions
require the establishment of tolerances for 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 pome fruit, stone fruit,
leafy vegetables, Brassica leafy vegetables, cucurbit vegetables,
fruiting vegetables, cotton, grapes and potatoes and rice.

Use Profile

For agricultural crops (pome fruit, stone fruit, leafy vegetables,
Brassica leafy vegetables, cucurbit vegetables, fruiting vegetables,
cotton, grapes, potatoes and rice) application rates range from about
0.03 to 0.1 lb ai/A, re-treatment intervals range from 5-10 days, and,
pre-harvest intervals (PHIs) range from 1-21 days (except for rice,
which is a seed-treatment use).  Crops can be treated from 2-6 times per
season; as the maximum seasonal application rate is 0.2 lb ai/A (except
for rice, which is 0.13 lb ai/A/yr).  Application is expected via aerial
and ground equipment, as well as chemigation.  For turf, application
rates range from 0.013 to 0.33 lb ai/A, and the maximum application rate
is 0.5 lb ai/A (if the minimum application rate is used, turf can be
treated up to 38 times per year).  DupontTM E2Y45 SC Insecticide for use
on turf can be applied by ground equipment, and the granular
formulations are applied by drop-type, rotary-type or hand-held
equipment.  Ornamental use directions are highly variable, but maximum
seasonal rates range from 0.33 to 0.5 lb ai/A (see Section 2.0 for more
specifics on use patterns for each use site).  Turf and ornamental use
sites include industrial facilities, residential dwellings, business and
office complexes/buildings/interior plantscapes, recreational areas of
all sorts (parks, playgrounds, golf courses, athletic fields) and sod
farms.  The labels associated with the Section 3 action propose a
restricted entry interval (REI) of 2 hours (agricultural crops, turf and
ornamentals).

Toxicity/Hazard Assessment

 for oral and dermal acute exposure is ≥5000 mg/kg/day and the LC50
for acute inhalation exposure is ≥5.1 mg/L.  This substance is not an
eye or skin irritant and does not cause skin sensitization.  In
short-term studies, the most consistent effects are those associated
with non adverse pharmacological response to the xenobiotic, induction
of liver enzymes and subsequent increase in liver weights.  DPX-E2Y45 is
not genotoxic, neurotoxic, immunotoxic, carcinogenic, or teratogenic. 
Furthermore, it is not uniquely toxic to the conceptus as there were no
maternal or fetal effects in studies conducted in rats and rabbits. 
Based on the results of a 28-day dermal study in rats, as well as the
dermal LD50 study, DPX-E2Y45 has relatively low dermal toxicity.

Overall, chlorantraniliprole exhibits minimal mammalian toxicity after
long-term exposure.  The only consistent observation in the mammalian
toxicology studies is an increased degree of microvesiculation of the
adrenal cortex after dermal or dietary administration of
chlorantraniliprole.  Based on the lack of adverse effect on the
function of the adrenal gland, this observation was considered treatment
related, but not “adverse.”

In addition to the adrenal effects, liver effects (e.g., increased liver
weight and induction of Cytochrome P450 enzymes) were reported in the
90-day oral subchronic studies across species and only at the highest
dose tested (>1000 mg/kg/day).  While in the subchronic studies, these
effects were considered adaptive, the liver effects were more pronounced
in the 18-month chronic mouse study at the highest dose tested. 
Increased eosinophilic foci (preneoplastic foci) were noted in male mice
at 935 mg/kg/day and liver hypertrophy and weight increase were evident
at the next lower dose (158 mg/kg/day), but progression to tumors was
not apparent for these effects.  Therefore, the eosinophilic foci appear
to be an adverse effect only seen in the highest dose tested and was
graded minimal in severity.

Dietary Exposure (food/water)

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).  If new uses
are proposed that significantly impact the dietary burden for livestock,
the residue of concern decision for livestock may need to be
reevaluated.  LC/MS/MS methods are available for measuring
chlorantraniliprole in plants, livestock (although tolerances in poultry
and eggs are not required), and processed commodities.  Adequate methods
and concurrent recovery data were provided, and the fortification levels
used in the methods and concurrent validations were adequate to bracket
the residue levels determined in the proposed crops (and secondary
‘crops’).  The validated limit of quantitation (LOQ) in plant and
livestock matrices is 0.01 ppm.  The LC/MS/MS methods have been
validated in EPA laboratories.  Although data from testing multiresidue
methods were submitted, chlorantraniliprole was not recovered by these
methods.

Crop field trials were conducted on crops or representative commodities
of crop groups.  There are adequate field residue data for these crops
based on geographic representation and number of field trials.  The
residue field trials were conducted using either the WG or SC
formulation to the proposed crops at the maximum proposed use patterns
[residues ranged from <0.01 ppm in many field trial samples to 15 ppm
(cotton gin byproducts) and 9.7 ppm (spinach)].  Acceptable processing
studies were conducted on apple, cotton, grape, plum, potato, and
tomato.  The results of these studies show that chlorantraniliprole,
upon processing, concentrates in some processed commodities, but not in
others.  Acceptable limited field rotational crop studies were
submitted.  The data suggest that rotational crop tolerances are
required, and that the petitioner needs to conduct extensive field
rotational crop trials.  Until the requested data are submitted, a
restriction should be imposed on the proposed labels to prohibit the
rotation to any crop not on the label.  The data that were submitted are
supported by adequate storage stability data which indicate that
chlorantraniliprole is stable under frozen conditions and during storage
intervals.  When applicable, the Agency’s standard operating
procedures, along with the tolerance spreadsheet, were used for
calculating recommended tolerances.

The laboratory environmental fate data indicate chlorantraniliprole is
persistent and mobile in terrestrial and aquatic environments.  Although
degradation products of chlorantraniliprole (in particular, the major
environmental degradates IN-EQW78 and IN-LBA24) 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).  The modeled EDWCs ranged
from 1 µg/L in groundwater (based on the highest use rate, for
ornamental plants) to 85 µg/L (an acute estimate based on the rice
use).

Because long-term oral exposure was the only route and duration where
chlorantraniliprole demonstrated toxicity (an adverse effect), only
chronic dietary (food and drinking water) exposure assessments were
conducted (using the dietary model DEEM-FCID).  The modeled exposure
estimates are based on tolerance level residues, assuming 100% of crops
associated with the Section 3 and 18 requests are treated, and include
the highest modeled EDWC relevant to the scenario.  Despite the
conservative assumptions on the exposure side, the resulting chronic
dietary exposures for all population subgroups were less than 1% of the
cPAD.

Residential Exposure

Residential exposure to chlorantraniliprole is expected.  The multitude
of use sites, in addition to the persistence of chlorantraniliprole,
indicate there is potential for short- and intermediate-term
postapplication dermal (adults and children) and incidental oral
(children only) exposure to chlorantraniliprole (inhalation exposure is
not expected due to low vapor pressure).  However, due to the lack of
toxicity via the dermal route, as well as the lack of toxicity over the
acute, short- and intermediate-term via the oral route – no risk is
expected from these exposures.

Aggregate Exposure

Although there is potential residential exposure, there is no
residential hazard/risk associated with the route/duration of the
proposed uses; therefore, aggregate exposure is comprised of food and
water only, and is considered in the dietary section of this document.

Occupational Exposure

There is a potential for occupational short- and intermediate-term
inhalation and dermal exposure to chlorantraniliprole during mixing,
loading, application and postapplication activities.  However, the
chlorantraniliprole toxicology database indicates there is no systemic
hazard associated with short- and intermediate-term dermal and
inhalation exposure, and therefore, no occupational exposure and risk
assessment was conducted.

In addition to systemic hazard, the Worker Protection Standard (WPS)
sets an REI based on the acute toxicity of chemicals.  Technical
chlorantraniliprole is in Category IV for acute dermal toxicity and
Category IV for primary eye and skin irritation.  Per the WPS, a 12-hr
REI is required for chemicals classified under Toxicity Category III or
IV.  However, all the labels submitted for chlorantraniliprole indicate
a proposed REI of 2 hours (except the Dermacor label associated with the
rice seed use).  According to Pesticide Registration (PR) Notice 95-3,
EPA permits registrants to reduce REIs from 12 to 4 hours for certain
low risk pesticides that meet certain criteria, but not to 2 hours. 
Chlorantraniliprole meets all of the criteria listed in PR Notice 95-3,
and therefore, is a candidate for a reduced REI of 4 hours.  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).

Environmental Justice

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.

Review of Human Research

This risk assessment does not rely on any data from studies in which
human subjects were intentionally exposed to a pesticide or other
chemical.

Recommendations for Tolerances and Registration

The residue chemistry, toxicological and exposure databases support the
establishment of tolerances outlined in the introduction of this
document.  Pending submission of a revised Section B (label
modifications –see Section 10.2 and 10.3 of this document), the
submission of extensive field rotational crop data (see Section 10.2),
and the submission of a revised Section F (described in the
introduction), there are no residue chemistry, toxicology and/or
exposure issues that would preclude granting a conditional registration
for the requested uses of chlorantraniliprole on the crops and/or crop
groups addressed herein.  The conditional registration can be converted
to unconditional registration when the remaining deficiencies cited in
Section 10.0 of this document are resolved.

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 anthranilic diamide
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.  It is a Group 28 insecticide based on the
target site of action.  Chlorantraniliprole controls many insects
(moths, beetles, worms, caterpillars, etc.) primarily via interruption
of normal muscle contraction pathways, which leads to paralysis and if
sustained, leads to the eventual death of the pest.  Chlorantraniliprole
is formulated as a suspension concentrate (SC) and a water dispersible
granule (WG) for agricultural end-use products; and as a SC and granular
formulations (G) for use on turf and ornamental plants.

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

DuPont is proposing a total of two technical grade/manufacturing
formulations and 15 end-use products for use in the US.  Two end-use
products are intended for agricultural use sites; 13 end-use products
are intended for residential and recreational use sites (for use by
commercial applicators only).  Louisiana is requesting use of DermacorTM
X-100 Seed Treatment formulation [a formulation not proposed by (but
manufactured by) DuPont] to treat rice seeds intended for drill-seeded
rice fields in Louisiana.

  SEQ CHAPTER \h \r 1 Table 2.1a.  Chlorantraniliprole Proposed End-Use
Products

Trade Name	EPA Reg. No.	ai (% of formulation)	Formulation Type	Target
Crops	Target Pests	Use Directions and Limitations

DuPontTM CoragenTM SC	352-XXX	18.4%

(1.667 lb ai/gallon)	Suspension concentrate  (SC)	Brassica leafy
vegetables, Cucurbit vegetables, Fruiting vegetables, Leafy vegetables
(non-Brassica)	Broad spectrum systemic insecticide (controls many
important insects); some contact activity	Applications may be conducted
by ground (chemigation, groundboom, airblast) or aerial equipment.  All
rotation crops may be planted immediately following the last
application. 

REI 2 hours

DuPontTM AltacorTM WG	352-XXX	35%	Water dispersible granule (WG)	Cotton,
Grape, Pome Fruits, Potato, Stone Fruits

Applications may be conducted by ground (groundboom, airblast) or aerial
equipment.  Do not apply ALTACORTM through any type of irrigation
system. All rotation crops may be planted immediately following the last
application. 

REI 2 hours

DuPontTM DermacorTM X-100 Seed Treatment 	352-

XXX	50%	SC	Rice seeds	For control of rice water weevil, Lissorhoptrus
oryzophilus	For use in drill-seed rice fields (not for use in
water-seeded rice fields)

DuPontTM E2Y45 SC Insecticide	352-XXX	18.4%

(1.67 lb ai/gallon)	SC	Turf, Ornamental plants	For control of white
grubs and other pests infesting landscape and recreational turfgrass
(including golf courses and sod farms) as well as caterpillars,
clearwing borers and other pests of landscape ornamentals	For use by
commercial applicators only.

Do not apply through any type of irrigation system, nor with aerial
equipment.

Do not apply in commercial nurseries and greenhouses.

Do not apply more than 38.3 fluid ounces (0.5 lb ai) of product per acre
per year in broadcast applications to turfgrass.

Minimum retreatment interval – 7 days.

REI 2 hours

DuPontTM E2Y45 0.33G Insecticide (I)	352-XXX	0.33%	Granular (G)	Turf,
Ornamental plants	For systemic control of white grubs and other pests
infesting landscape and recreational turfgrass (including golf courses
as well as landscape ornamentals, interior plantscapes and sod farms	For
use by commercial applicators only 

Apply via drop-type, rotary-type or hand-held equipment

Apply up 0.5 lb ai/A/yr to turfgrass.

Do not apply more than 0.2 lb ai/A in a single application on sod farms

Do not apply via air

Do not use in commercial nurseries and greenhouses

Not for use on plants being grown for sale or other commercial use, or
for commercial seed production

Minimum retreatment interval – 7 days 

REI 2 hours

DuPontTM E2Y45 0.25G I	352-XXX	0.25%

DuPontTM E2Y45 0.167G I	352-XXX	0.167%

DuPontTM E2Y45 0.16G I	352-XXX	0.16%

DuPontTM E2Y45 0.133G I + Fertilizer (F)	352-XXX	0.133%

DuPontTM E2Y45 0.125G I	352-XXX	0.125%

DuPontTM E2Y45 0.12G I	352-XXX	0.12%

DuPontTM E2Y45 0.1G I + F	352-XXX	0.1%

DuPontTM E2Y45 0.067G I + F	352-XXX	0.067%

DuPontTM E2Y45 0.08G I	352-XXX	0.08%

DuPontTM E2Y45 0.05G I + F	352-XXX	0.05%

DuPontTM E2Y45 0.05G I	352-XXX	0.05%

The summary of the proposed use patterns presented in Table 2.1b is
based on information in the labels and from in the document “Good
Agricultural Practice for DPX-E2Y45 35WG and DPX-E2Y45 20SC in the
United States” provided by the registrant.

Table 2.1b.	  Summary of Directions for Use of Chlorantraniliprole.

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

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

(lb ai/A)

[g ai/ha]	PHI

(days)	Use Directions and Limitations

Cotton

Postemergence

Broadcast by ground or air 	35% WG	0.044-0.099	Not specified***	0.2

[221]	21	Minimum spray volumes are 5 gal/A (ground) or 5 gal/A (aerial);
5-day minimum RTI 

Brassica Vegetables

[Broccoli, Broccoli (Chinese), Broccoli Raab, Brussels Sprouts, Cabbage,
Cabbage (Chinese, Bok Choy), Cabbage (Chinese, Napa), Cabbage (Chinese
Mustard, Choy), Cauliflower, Cavalo Broccolo, Collards, Kale, Kohlrabi,
Mizuna, Mustard Greens, Mustard Spinach, and Rape Greens]

Postemergence

Broadcast by ground, drip chemigation, or air	1.67 lb ai/gal

SC	0.0261-0.0976	6	0.2

[219]	3	Minimum spray volumes are 10 gal/A (ground) or 5 gal/A (aerial);
3-day minimum RTI for foliar and 10-day RTI for drip chemigation.

Cucurbit Vegetables 

[Chayote (Fruit), Chinese Waxgourd, Citron Melon, Cucumber, Gherkin,
Gourd Edible (includes Hyotan, Cucuzza, Hechima, Chinese Okra),
Momordica, Muskmelon, Pumpkin, Squash, and Watermelon]

Postemergence

Broadcast by ground, drip chemigation, or air	1.67 lb ai/gal SC
0.0261-0.0976	Not specified***	0.2

[219]	1	Minimum spray volumes are 10 gal/A (ground) or 5 gal/A (aerial);
5-day minimum RTI for foliar and 10-day RTI for drip chemigation

Fruiting Vegetables

[Eggplant, Groundcherry, Pepino, Pepper (Includes Bell Pepper, Chili
Pepper, Cooking Pepper, Pimento, Sweet Pepper), Tomatillo, and Tomato]

Postemergence

Broadcast by ground, drip chemigation, or air	1.67 lb ai/gal SC
0.0261-0.0976	Not specified***	0.2

[219]	1	Minimum spray volumes are 10 gal/A (ground) or 5 gal/A (aerial);
5-day minimum RTI for foliar and 10-day RTI for drip chemigation

Grapes

Postemergence

Broadcast by ground or air	35% WG	0.044-0.099	Not specified***	0.2

[221]	14	Minimum spray volumes are 50 gal/A (ground) or 10 gal/A
(aerial); 7-day minimum RTI 

Leafy Vegetables (Non-Brassica)

[Amaranth (Leafy), Arugula, Cardoon, Celery, Celery (Chinese), Celtuse,
Chevril, Chrysanthemum (Edible Leaved), Chrysanthemum (Garland, Corn
Salad, Cress (Garland), Cress (Upland), Dandelion Leaves, Dock, Endive,
Florence Fennel, Lettuce (Head & Leaf), Orach, Parsley Leaves, Purslane
(Garden), Purslane (Winter), Radicchio, Rhubarb, Spinach, Spinach
(Vine), Spinach (New Zealand, and Swiss Chard]

Postemergence

Broadcast by ground, drip chemigation, or air	1.67 lb ai/gal SC
0.0261-0.0976	6	0.2

[219]	1	Minimum spray volumes are 10 gal/A (ground) or 5 gal/A (aerial);
3-day minimum RTI for foliar and 10-day RTI for drip chemigation

Pome Fruits

[Apple, Crabapple, Loquat, Mayhaw, Pear, Pear (Oriental), and Quince]

Postemergence

Broadcast by ground or air	35% WG	0.044-0.099	4	0.2

[221]	21*	Minimum spray volumes are 50 gal/A (ground) or 10 gal/A
(aerial); 10-day minimum RTI. 

Potato

Postemergence

Broadcast by ground or air 	35% WG	0.044-0.066	Not specified***	0.2

[222]	14	Minimum spray volumes are 10 gal/A (ground) or 5 gal/A
(aerial); 5-day minimum RTI. 

Stone Fruits

[Apricot, Cherry (Sweet), Cherry ( Tart), Nectarine, Peach, Plum, Plum
(Chicksaw, Damson, Japanese), Plumcot, and Prune]

Postemergence

Broadcast by ground or air 	35% WG	0.044-0.099	4	0.2

[221]	10	Minimum spray volumes are 50 gal/A (ground) or 10 gal/A
(aerial); 7-day minimum RTI 

Section 18/Rice

At seeding: drill-seeded 	Dermacor X-100

50% SC	2.5-5.0 fl oz per 100 lbs seed (0.098-0.20 lb ai/100 lbs seed)**
1	0.13

(based on label, which provides seed treatment + seeding rates)	NA
Treated seed must not be used for or mixed with food or animal feed, or
processed for oil. All rotation crops may be planted immediately
following last application.  Treated seed not to exceed 120 lb/A seeding
rate.

Turf

G formulations: drop-type, rotary-type or hand-held equipment	DuPontTM
E2Y45 G (0.05-0.33%)	0.06-0.33	Not specified***	0.5	N/A	For use by
commercial applicators only.  No aerial, no chemigation application

SC formulation: broadcast application equipment 	DuPontTM E2Y45 SC
Insecticide	0.013-0.313

(1 to 24 fl oz/A)	Not specified***	0.5

(38.3 fl oz./A)	N/A	For use by commercial applicators only.  No aerial,
no chemigation application.

Ornamentals

G formulations	DuPontTM E2Y45 G (0.05-0.33%)	Highly variable	Not
specified***	0.33	N/A	For use by commercial applicators only.  No
aerial, no chemigation application.

SC formulation: broadcast application; soil injection, drenches	DuPontTM
E2Y45 SC Insecticide	Highly variable	Not specified***	0.5

(38.3 fl oz./A)	N/A	For use by commercial applicators only.  No aerial,
no chemigation application.

*Although the proposed Section 3 label states a PHI of 21 days for pome
fruits, the proposed label for the Experimental Use Permit label
proposed a PHI of 14 days, and the residue chemistry data reflect a PHI
of 13/14 days.

**Seed treatment rates in lb ai/lbs seed are calculated assuming
Dermacor X-100 contains 5 lbs ai/gal formulation – which was
back-calculated using the seed treatment rate + seeding rate table
provided in the label.

***Although the maximum number of applications is not specified for all
the agricultural crops on the DPX-E2Y45 35WG and DPX-E2Y45 20SC labels,
if the minimum application rate is 0.044 lb ai/A, to reach the maximum
seasonal application rate, about 4 applications can be made per season;
and if the minimum application rate is 0.026 lb ai/A, to reach the
maximum seasonal application rate, about 6 applications can be made per
season.  On the E2Y45 SC Insecticide label for use on turf and
ornamentals, if the minimum turf application rate of 0.013 lb ai/A is
used, the product could be applied 38 times per year (to result in a
maximum seasonal rate of 0.5 lb ai/A/yr).

HED Conclusion: Since the residue data (i.e., field studies) for pome
fruit reflect spray volumes of 100 gallons per acre, the use directions
for pome fruit should be revised to state “minimum spray volume of 100
gal/A (ground).”  Also, as there are inadequate residue data that
reflect addition of adjuvants in end-use products in the field studies,
the proposed labels should be revised to delete the use of adjuvants in
all crops except Brassica crops.  In the absence of residue data on
crops grown in greenhouses, the label should prohibit use on crops grown
in greenhouses.  Given the results of the confined accumulation and
limited field accumulation in rotational crops study, a restriction
should be imposed on the proposed labels to prohibit the rotation to any
crop not on the label.  The proposed REI of 2 hours on most labels
should be amended

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

The chemical nomenclature for chlorantraniliprole is presented in Table
2.2.  The chemical names and structures of chlorantraniliprole and its
transformation products, reported from metabolism studies, are presented
in Appendix B.

Table 2.2.	   Chlorantraniliprole Nomenclature.

Chemical structure	

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 (18.4% ai, 1.67 lb/gal; EPA Reg. No.
352-XXX)

AltacorTM WG (35% ai; EPA Reg. No. 352-XXX)

DuPontTM E2Y45 SC Insecticide (18.4% ai, 1.67 lb/gal; EPA Reg. No.
352-XXX)

DuPontTM E2Y45 G (0.05-0.33%) – 12 products of varying concentrations

Dermacor X-100 (an SC, 50% ai, Section 18)

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

The physicochemical properties of DPX-E2Y45 are reported in Table 2.3. 
The vapor pressure is low, so inhalation exposure is only expected
during application, and not via volatilization of deposited residues.

Table 2.3.	   Physicochemical Properties of Technical Grade of
Chlorantraniliprole.

Parameter	Value	Reference

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

MRID 46889033

pH	5.77 ± 0.087 at 20°C	DuPont-13176

MRID 46889031

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

MRID 46889033

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

MRID 46889026

Solvent solubility (20°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

MRID 46889030

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

MRID 46889130

Dissociation constant, pKa	10.88 ± 0.71	DuPont-13254

MRID 46889034

Octanol/water partition coefficient, KOW (20°C)	Deionized Water        
     589

pH 4                                 588

pH 7                                 721

pH 9                                 654	DuPont-13177

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

MRID 46991001

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

Reference: Chlorantraniliprole (DPX-E2Y45) Toxicology Assessment, Mary
Manibusan, TXR #0054555, D336940, D337737, D343520, D345100, 11/17/2007.

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

OECD Global Review Process

Chlorantraniliprole is the subject of a global work-share registration
with several partnering countries.  To this end, the toxicology
assessment, lead by the United States, has undergone extensive technical
external peer review.  Written comments were submitted from Ireland,
Canada, Italy, Germany, UK, Australia and the Netherlands.  A peer
review teleconference was also conducted to achieve harmonization on the
endpoint selection.  This toxicology assessment reflects the collective
views of the US and our global partners.

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.  Toxicity studies that have been submitted in
support of this registration include: 1) acute oral, dermal, inhalation,
primary eye irritation, dermal irritation and dermal sensitization
toxicity studies in rats, mice and rabbits, 2) absorption, distribution,
metabolism, and excretion in male and female rats (single and multiple
dose administration), 3) 28-day dermal study in rats, 4) 90-day
subchronic oral toxicity studies in rats, dogs, and mice 5) combined
chronic toxicity/oncogenicity study 2- year feeding study in rats, 6)
oncogenicity eighteen-month feeding study in mice, 7) developmental
toxicity studies in rats and rabbits, 8) 2-generation reproduction study
in rats, 9) 28-day immunotoxicity feeding study in rats and mice, 10)
acute oral neurotoxicity study in rats, 11) subchronic oral
neurotoxicity study in rats, 12) 2-week gavage study in rats with
metabolism and genetic toxicology, 13) a full battery of required
genetic toxicology assays, and 14) mechanistic studies designed to
evaluate the adrenal cortical function in rats.  A brief summary of the
findings and a toxicology profile table is attached in Appendix A.

Biochemical Mode of Action  TC \l4 "3.1.1.2	Biochemical Mode of Action 

Chlorantraniliprole is an anthranilic diamide insecticide that operates
via a unique biochemical mode of action.  Chlorantraniliprole binds and
activates ryanodine receptors (RyRs), located in the sarcoendoplasmic
reticulum, to release stored intracellular calcium into the cytoplasm of
the cell. Calcium is a universal intracellular second messenger, which
mediates many cellular and physiological activities; its flux is
modulated by several specific calcium channels such as voltage-gated and
the ryanodine calcium channels.  Calcium ions mediate many cellular and
physiological activities, e.g., neurotransmitter release, hormone
secretion, gene expression and for the purposes of this insecticide,
muscle contraction.  In muscle cells, chlorantraniliprole locks RyR
channels in a subconductance state without prior activation by plasma
membrane voltage-gated calcium channels.  Ryanodine channels remain
opened, internal calcium stores become depleted, triggering capacitative
calcium entry upon depletion of internal calcium stores.  Sustained
exposure to chlorantraniliprole leads to impaired regulation of the
muscle excitation, contraction and relaxation cycle; this in turn, leads
to complete muscle contraction, paralysis and the ensuing death of the
organism (Cordova et al., 2006). This mode of action has been shown to
be highly selective for insect ryanodine receptors, but not for
mammalian ryanodine receptors, typically exhibiting several hundred fold
lower potency to mammalian ryanodine receptors.  Comparative studies
with mammalian cell lines that endogenously express RyRs demonstrate
that the most potent anthranilic diamide tested exhibits greater than a
500-fold differential selectivity for insect receptors relative to
mammalian receptors (Cordova et al., 2006).  For chlorantraniliprole,
the differential selectivity is greater than approximately 350-fold
(Cordova et al., 2007).

This difference in selectivity may be explained by the considerable
variability in the amino acid sequences of specific N-terminal domains
between insect and mammalian ryanodine receptors.  Mammals express three
isoforms of ryanodine receptors: RyR1 and RyR2, distributed
predominately in skeletal and cardiac muscle, respectively, and RyR3
distributed more heterogeneously.  While these three isoforms are
reasonably similar in structure, there are known differences.  For
example, under three-dimensional cryo-microscopy, it is revealed that
RyR3 is similar in its overall three-dimensional architecture to the
other RyR isoforms but there is at least one significant difference that
is attributed provisionally to a particular region of the amino acid
sequence of the receptor.  There are also several structural differences
at diverse locations between two conformational states of RyR3 that
likely correspond to “open” and “closed” states of the receptor
(Manjuli et al., 2000).  To what extent each isoform contributes to the
overall calcium response in mammals is not yet clear.  Insects, on the
other hand, express a single form of the receptor, sharing only a 47%
amino acid sequence homology with mammalian ryanodine receptors. 
(Takeshima et al., 1994; Cordova et al., 2006).  Sequence analysis for
the amino acid region corresponding to the chlorantraniliprole binding
site has been conducted for various species.  Sequence comparisons for
the corresponding RyR isoforms in humans, rats, mice, and dogs show
similarities of 85% or greater in these mammalian species.  However, the
sequence similarity between mammals and insects for this region is no
greater than 21%.  Consequently, there is a high degree of divergence
between mammalian and insect amino acids for the region associated with
the chlorantraniliprole binding site.

The ryanodine receptor is present across species, its role is similar
across species, but primary sequence diversity indicates differences
between the isoforms within and across species.  The level of activation
of this receptor, and the subsequent release of intracellular calcium
stores via the binding of chlorantraniliprole to the cytoplasmic face of
the receptor, accounts for the difference in specificity between insect
and mammalian species.  Differences in specificity and potency of
effects distinguish the mammalian ryanodine receptor response from that
of the insect and these differences appear to be the major contributing
factors to the low mammalian toxicity exhibited for chlorantraniliprole.

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

DPX-E2Y45 has no significant acute toxicity via the oral, dermal, and
inhalation routes of exposure.  The LD50 for oral and dermal acute
exposure is ≥5000 mg/kg/day and the LC50 for acute inhalation exposure
is ≥5.1 mg/L.  This substance is not an eye or skin irritant and does
not cause skin sensitization.  The acute inhalation study did not report
any portal of entry effects or acute irritation via the inhalation route
of exposure.  In short-term studies, the most consistent effects are
those associated with non adverse pharmacological response to the
xenobiotic, induction of liver enzymes and subsequent increase in liver
weights.  DPX-E2Y45 is not genotoxic, neurotoxic, immunotoxic,
carcinogenic, or teratogenic.  Furthermore, it does not exhibit pre- or
postnatal toxicity as there were no maternal or fetal effects in studies
conducted in rats and rabbits.  Based on the results of a 28-Day dermal
study in rats, as well as the dermal LD50 study, DPX-E2Y45 has
relatively low dermal toxicity.

The only consistent effects associated with DPX-E2Y45 exposure were
those associated with the adrenal cortex (mild microvesiculation of the
zona fasciculata) and liver toxicity.  These effects were not considered
adverse because the effect in the adrenal cortex was minimal, the
adrenal cortical morphology was generally within the range of what was
observed in the control rats and there was no cytotoxicity or abnormal
cellular structures observed by light or electron microscopy. 
Furthermore, no adverse effects indicative of an adverse impact on the
function of the adrenal cortex was found in the numerous toxicological
studies available (e.g., 90-day rat, mouse, dog studies, prenatal
toxicity studies, two-generation reproductive study, dermal toxicity
study) or in special adrenal functionality studies evaluating
corticosterone concentrations in serum and urine (under both basal and
stimulated conditions).   There was also an absence of adrenal tumors or
tumors of any organ in the 18-month mouse and 2-year rat cancer
bioassay.  Therefore, the mild microvesiculation reported in the male
rat adrenal cortex is not considered of toxicological significance.

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 (MRID 46979719)

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)

While the adrenal cortex effects were considered non-adverse, the liver
effects form the bases for establishing the no observed adverse effect
level (NOAEL) of 158 mg/kg bw/day on the mean daily intake in male mice
in an eighteen month chronic toxicity/carcinogenicity study.  A lowest
observed adverse effect level (LOAEL) was established in the same study
at 935 mg/kg/day for male mice based on eosinophilic foci of cellular
alteration accompanied by hepatocellular hypertrophy and increased liver
weight.  While in the shorter-term toxicity studies, the slight liver
weight increase in the 90-day studies were considered pharmacological
effects and not adverse, the weight of evidence from the combined liver
weight increase, liver hypertrophy and eosinophilic foci in the 18-month
mice study shifts these effects to be considered adverse.

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

Overall, chlorantraniliprole exhibits minimal mammalian toxicity after
exposure.  The only consistent 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 (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. 
Based on the lack of adverse effect on the function of the adrenal
gland, this observation was considered treatment related, but not
“adverse.”

In addition to the adrenal effects, liver effects (e.g., increased liver
weight and induction of Cytochrome P450 enzymes) were reported in the
90-day oral subchronic studies across species and only at the highest
dose tested (>1000 mg/kg/day).  While in the subchronic studies, these
effects were considered adaptive, the liver effects were more pronounced
in the 18-month chronic mouse study at the highest dose tested. 
Increased eosinophilic foci (preneoplastic foci) were noted in male mice
at 935 mg/kg/day and liver hypertrophy and weight increase were evident
at the next lower dose (158 mg/kg/day), but progression to tumors was
not apparent for these effects.  Therefore, the eosinophilic foci appear
to be an adverse effect only seen in the highest dose tested and was
graded minimal in severity.

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

The absorption of 14C-DPX-E2Y45 was rapid with peak concentrations
occurring at 5-12 hours after low or high (10 or 200 mg/kg bw) oral
single dose administration.  Absorption at the low dose (10 mg/kg bw)
was determined to be 72.9-85.2% compared with 11.8-13.3% at the high
dose (200 mg/kg bw) using bile duct cannulated rats.  The plasma
elimination half-lives ranged from 38-82 hours.  Tissue distribution of
the absorbed dose was extensive and indicated low potential for
accumulation.  The tissue residues were higher in female rats than in
male rats, which is consistent with female rats having a longer
elimination half-life and higher area under the curve (AUC) in plasma. 
Excretion in both high- and low-dose groups was substantially complete
by 48-72 hours after dosing.  Fecal excretion was the primary route of
elimination followed by the urine with no significant excretion
occurring by exhalation.  Metabolism of the absorbed dose was extensive
and involved sex (greater hydroxylation in males) differences primarily
in initial tolyl methyl and N-methyl carbon hydroxylation.  Further
metabolism of the hydroxylated metabolites included N-demethylation,
nitrogen-to-carbon cyclisation with loss of a water molecule resulting
in the formation of the pyrimidone ring, oxidation of alcohols to
carboxylic acids, amide bridge cleavage, amine hydrolysis, and
O-glucuronidation.  Most of the administered dose (88-97%) was
eliminated in the excreta.  Tissue:plasma concentration ratios (<1)
indicated low potential for accumulation.  Metabolites represented in
the rat metabolism cascade were: IN-K9T00, IN-HXH44, IN-KAA24, IN-H2H20,
and IN-GAZ70.

Following 14 days of oral dose administration (10 mg/kg), steady-state
kinetic behaviour was apparent in male rats.  The slight increase in
plasma and tissue concentrations through the 14 days of oral dosing
indicated that female rats were near steady state.  After cessation of
dosing, the 14C residues were readily eliminated from the plasma and
tissues.  The overall tissue distribution in male and female rats at 1
and 7 days after dosing was similar to that found after single dose
administration and confirmed minimal potential for accumulation. 
Cumulative excretion in feces was the predominate route of elimination. 
The profile of metabolites in urine and feces indicated extensive
metabolism consistent with that observed for the single dose study.

In addition to the rat metabolism studies conducted with 14C-labelled
DPX-E2Y45, analysis of plasma for parent and primary metabolites was
conducted during the 90-day rats, mice and dogs dietary administration
studies and the rat 14-day oral gavage study.  DPX-E2Y45 and primary
metabolites observed above the limit of quantification of 0.005 ug/mL
plasma were reported.

14-day oral gavage rat

In the 14-day oral gavage study, a toxicokinetic assessment was
performed.  The area under the plasma concentration versus time curve
(AUC) was not proportional with the dose of DPX-E2Y45 indicating
decreased absorption at higher doses.  The half-lives were estimated to
be 3.4, 3.4 and 4.0 hours for 25, 100 and 1000 mg/kg/day groups,
respectively.  The time of maximum concentration (Tmax) was 0.25, 0.42,
and 2.75 hours in the 25, 100, and 1000 mg/kg/day groups, respectively. 
The maximum concentrations (Cmax) were similar at all dose levels, with
the highest concentration (0.48 ug/mL) occurring in the 25 mg/kg/day
group.  The half life for DPX-E2Y45 was sufficiently short that a
significant portion of the parent compound will be cleared from the
plasma after 24 hours, even following two weeks of repeated dosing at
1000 mg/kg/day indicating low potential for bioaccumulation.

90-day oral rat

In the 90-day oral rat study, DPX-E2Y45 and the metabolites IN-GAZ70 and
IN-H2H2O were identified quantitatively.  The concentration of IN-GAZ70
in plasma from male and female rats on Day 59 was considerably greater
than the plasma concentration of DPX-E2Y45.  In males, this difference
was approximately 10-fold, but in females, the difference was 100-fold. 
The concentration of each analyte was greater in females than in males. 
With the exception of the plasma concentration of IN-H2H2O in male rats
dosed at the highest dose being statistically different from the 2000
ppm dose, the plasma concentration of DPX-E2Y45, IN-GAZ70 and IN-H2H2O
were not statistically different from one another in the three highest
dose concentrations in either sex.  

90-day oral mouse

In the 90-day oral mouse study, DPX-E2Y45 and the metabolite IN-GAZ70
were quantified.  The concentration of the parent DPX-E2Y45 was below
the limit of quantification in all mouse samples analyzed.  The
metabolite IN-GAZ70 was the only significant analyte present in plasma
from male mice on day 92 and female mice on day 93.  The plasma
concentration of IN-GAZ70 in plasma from female mice dosed at the
highest dietary concentration was statistically different from the 700
ppm dose.  In male mice, the plasma concentration in mice dosed at the
2000 and 7000 ppm dose concentrations were both statistically different
from the 700 ppm dose concentration.

90-day oral dog 

In the 90-day dog study, DPX-E2Y45 and metabolite IN-HXH44 were
quantified.  The concentration of parent DPX-E2Y45 for both male and
female dogs in plasma was approximately five times the concentration of
the metabolite IN-HXH44.  The plasma concentration of DPX-E2Y45 in male
dogs dosed at the high dose (40,000 ppm) was not statistically different
from the 4000 ppm dose.  The plasma concentration of the IN-HXH44 was
not statistically different at any dose concentration in either sex.

Conclusions:

These results demonstrate systemic uptake and metabolism of DPX-E2Y45
during dietary and oral gavage administrations.  These results also
suggest possible species differences in the primary metabolites formed
in all three species, rats, mice and dogs.  The concentration of
DPX-E2Y45 in plasma was dog>rat>mouse.  The primary methylphenyl ring
hydroxylated metabolite (IN-HXH44) was quantified only in dog plasma,
while the N-methyl hydroxylated metabolite (IN-H2H2O) was quantified
only in rat plasma.  The cyclization product of IN-H2H20 with loss of a
water molecule or N-demethylation product of IN-EQW78 (IN-GAZ70) was
quantified in both mouse and rat, but not dog plasma.  Mouse plasma
contained more IN-GAZ70 than rat plasma in these studies.  In all three
species, the relatively constant analyte concentrations at the higher
dose levels suggested decreased absorption with increasing dose,
confirming the previously described rat metabolism studies.  The slight
decrease in the plasma DPX-E2Y45 concentrations with increasing dose in
the 14-day oral gavage rat study also provided evidence for decreased
absorption.  A significant sex difference was observed in rats with
female rats showing higher concentrations of DPX-E2Y45, IN-H2H20, and
IN-GAZ70 than male rats.  No sex difference was noted in the dog or
mouse.  Overall, the results in rats for the 90-day and 14-day studies
were consistent with the plasma concentrations of 14C residues,
decreased absorption, and proposed metabolic pathway from the single and
multiple oral gavage studies with 14C-DPX-E2Y45 in rats.

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 purposes of
this risk assessment and considered adequate for the characterization of
potential pre- and postnatal risks to infants and children.  Acceptable
developmental and 2-generation reproduction studies have been submitted
and reviewed.  

In addition, a developmental neurotoxicity is not required based on the
lack of any clinical signs indicative of potential neurotoxicity in
either acute or subchronic oral neurotoxicity studies in rats, lack of
any substance related developmental toxicity tested at 1000 mg/kg/day
(limit dose), and no indications of 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.  There is no concern for developmental neurotoxicity
associated with chlorantraniliprole exposure; therefore, a developmental
neurotoxicity study is not being requested.  The current toxicity
database is considered adequate for risk assessment.

Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity 

No evidence of neurotoxicity was observed in studies conducted with
DPX-E2Y45 in rats.  The NOAEL in an acute, oral gavage neurotoxicity
study was 2000 mg/kg bw and was the highest dose administered in the
study.  In a subchronic neurotoxicity study, the NOAEL was 1313 and 1586
mg/kg bw/day in males and females, respectively, the maximum dietary
concentration administered.  The NOAELs were based on the absence of
treatment related effects on systemic toxicity and neurotoxicity
parameters, including microscopic neuropathology.  Neurological
assessments conducted in conjunction with the 18-month oncogenicity
study in mice following 45, 60, and 90 days of dietary administration of
DPX-E2Y45 confirmed the lack of potential neurotoxicity.  Further, no
treatment related clinical signs indicative of potential neurotoxicity
were observed in short-term and long-term exposure studies in rats,
mice, or dogs.  Therefore, it is concluded that DPX-E2Y45 is not a
neurotoxicant.   

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

rtions, 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 

toxicity NOAEL is ≥ 1199/1594 mg/kg/day males/females, respectively
and the parental systemic toxicity LOAEL is greater than 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).

s ≥ 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 

No additional information relevant to the toxicity of
chlorantraniliprole was identified.

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

There were no effects on prenatal fetal growth or postnatal 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 

Based on the dataset submitted in support of this registration, there
appears to be 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 

The chlorantraniliprole risk assessment team evaluated the quality of
the toxicity and exposure data and, based on these data, recommended
that the FQPA Safety Factor be reduced to 1x.  The recommendation is
based on the following:

The toxicology database for chlorantraniliprole is complete for the
purposes of this risk assessment and the characterization of potential
pre- and postnatal risks to infants and children.

No susceptibility was identified in the toxicological database, and
there are no residual uncertainties re: pre-and/or postnatal exposure
[i.e., 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.

There are no treatment-related neurotoxic findings in the acute and
subchronic oral neurotoxicity studies in rats. 

Additionally, the exposure assessment is protective: the dietary food
exposure assessment utilizes tolerance level residues and 100% crop
treated information for all commodities; the drinking water assessment
(Tier 2 estimates) utilizes values generated by models and associated
modeling parameters which are designed to provide conservative, health
protective, high-end estimates of water concentrations.  By using these
screening-level exposure assessments, the chronic dietary (food and
drinking water) risk is not underestimated.

Although residential exposure is expected over the short- and
intermediate-term (via the dermal and/or incidental oral route), there
is no hazard expected via these routes/durations, and therefore no risk
associated with these scenarios.

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

3.5.1	Acute Dietary (All populations, including Females 13-49 years old)
 TC \l3 "3.5.1	Acute Dietary (All populations, including Females 13-49
years old) 

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) 

Establishment of a Chronic Dietary Reference Dose (cRfD)

The relevant NOAEL from chronic toxicity studies is derived from the
oncogenicity eighteen month feeding toxicity study in male Crl:CD1(ICR)
mice at 158 mg/kg/day based on the presence of eosinophilic foci
accompanied by hepatocellular hypertrophy and increased liver weight
observed at the next highest dose (935 mg/kg/day).  These liver effects
are considered minimal in severity, low in incidence and do not display
progression to tumors in the 18-month chronic mouse study.  In addition,
the 24-month rat cancer study also does not show evidence for an active
substance related increase in liver tumors.  The eosinophilic foci were
observed in one gender only (males), categorized as minimal, and there
was no increase in severity (i.e., dose response); the foci were
observed only at the highest dose tested and a monotonic dose response
was not evident.  Examination of the microscopic results presented in
the original study showed no evidence of increased degenerative changes
to hepatocytes with increasing dose.  There is no increase in necrotic
cells, fatty change, hyperplastic nodules, inflammation, mitotic
figures, or evidence of Mallory bodies relative to controls and low dose
groups.  However, despite the lack of general histopathology and
progression to tumors, these eosinophilic foci are not considered an
adaptive response because they are not reversible nor are they commonly
associated with a normal liver response to high dose xenobiotics
(historical control range 0-1.92% for Crl:CD-1(ICR) mice).  Based on
this understanding, it is considered a prudent public health protective
decision to base the chronic reference dose on the liver effects
observed at the highest dose in the 18-month chronic mouse study as
treatment related and adverse.

A composite uncertainty factor of 100 to account for interspecies
extrapolation and intraspecies variability is applied to the NOAEL to
derive a cRfD/cPAD of 1.58 mg/kg/day.

158 mg/kg bw/day  =  1.58 mg/kg bw/day (cRfD/cPAD)

           100 (UF)

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

Establishment of a short- and intermediate-term reference dose for
incidental oral exposure is not justified for chlorantraniliprole
(DPX-E2Y45) based on the lack of identified hazard over the short- and
intermediate-term: only a slight increase in liver weight at the highest
dose tested (HDT) in the 90-day rat, mouse and dog oral toxicity
studies, at doses up to 1000 mg/kg/day (limit dose) was observed.  The
liver weight increases (approximately 20%) were considered a
pharmacological response to the xenobiotic and not an adverse effect. 
Therefore, no short- and/or intermediate-term incidental oral endpoint
was 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.  Additionally, there were no identified developmental
reproductive effects in the database, nor neurotoxic effects.  Because
there was no hazard identified, 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) 

For chlorantraniliprole, the requirement for a longer term, repeat
inhalation study may be waived based on its lack of acute irritation and
extremely low oral toxicity, even at the limit dose of 1000 mg/kg/day. 
The acute 4-hour inhalation study determined an LC50 of >5.1 mg/L for
both male and female rats, and did not report any portal of entry
effects or acute irritation via the inhalation route of exposure.  Based
on this weight of evidence in support of the longer term inhalation
study waiver and the lack of hazard identified in the acute inhalation
study, no inhalation endpoint was selected for quantitative risk
assessment.

There is no short-term oral toxicity, and the chronic liver effect is
only at the limit dose in the cancer study (and late in the study),
these effects observed in oral studies are not relevant to extrapolate
to short- and intermediate-term inhalation exposure scenarios.

3.5.6	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.6	Recommendation for Aggregate Exposure Risk Assessments 

Dietary exposure via residues in/on food and drinking water are
aggregated in the chronic dietary assessment.  Aggregating routes and/or
pathways of exposure are not relevant for all other scenarios due to
lack of observed hazard for all other durations and exposure routes.

3.5.7	Classification of Carcinogenic Potential  TC \l3 "3.5.7
Classification of Carcinogenic Potential 

No treatment-related tumors have been reported in the submitted chronic
and oncogenicity studies in rats and mice, subchronic studies in mice,
dogs and rats and no mutagenic concern was reported in the genotoxicity
studies.  The most consistent effect across durations and species tested
is a slight increase in liver weight due to induction of cytochrome P450
activity that is reflective of a pharmacological response to the
xenobiotic and not considered adverse.  In the 18-month
chronic/oncogenicity oral mice study, however, the increase in liver
weight was accompanied by hepatocellular hypertrophy and a slight
increase in eosinophilic foci of cellular alteration, which in
combination formed the bases of establishing the LOAEL at the highest
dose tested (935 mg/kg/day) and the NOAEL at 158 mg/kg/day for male
mice.  Eosinophilic foci are preneoplastic lesions, but in neither the
24-month oral rat cancer bioassay nor the 18-month oral mouse study were
treatment-related rodent liver tumors reported.  In addition, the
possibility of rodent liver tumors formed via the activation of the
peroxisome proliferator-activated receptor (PPARa) was negated through
the 14-day oral gavage rat study that measured for peroxisomal
beta-oxidation activity using 14C-palmitoyl CoA as the substrate and did
not find an association.  DPX-E2Y45 did not alter beta-oxidation
activity.

Based on the weight of evidence of the available scientific data, and in
accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment
(March 2005), chlorantraniliprole is classified as “Not Likely to Be
Carcinogenic to Humans”.

3.5.8	Summary of Toxicological Doses and Endpoints for
Chlorantraniliprole for use in Human Health Risk Assessment  TC \l3
"3.5.8	Summary of Toxicological Doses and Endpoints for
Chlorantraniliprole for Use in Human Health Risk Assessment 

Table 3.5.8a Summary of Toxicological Doses and Endpoints for
Chlorantraniliprole for Use in Dietary and Non-Occupational Human Health
Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary (All Populations)	N/A	N/A	N/A	No acute hazard,
attributable to a single dose, was identified; therefore, an acute
dietary endpoint was not selected for quantitative risk assessment.

Chronic Dietary (All Populations)	NOAEL= 158 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Chronic RfD = 1.58 mg/kg/day

cPAD = 1.58 mg/kg/day	18-Month Oral (feeding)/mouse

LOAEL = 935 mg/kg/day based on eosinophilic foci accompanied by
hepatocellular hypertrophy and increased liver weight (males only)

Incidental Oral Short-/Intermediate-Term 	N/A	N/A	N/A	There was no
hazard identified via the oral route over the short- and
intermediate-term and therefore, no endpoint was selected for
quantitative risk assessment.

Dermal Short-/Intermediate-Term 	N/A	N/A	N/A	There was no hazard
identified via the dermal route (and no concerns for developmental,
reproductive or neurotoxic effects) and therefore, no dermal endpoint
was selected for quantitative risk assessment.

Inhalation Short-/Intermediate-Term 	N/A	N/A	N/A	Based on the lack of
hazard identified in the acute inhalation study, lack of acute
irritation, and extremely low oral toxicity – no inhalation endpoint
was selected for quantitative risk assessment.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on weight of evidence of data: no
treatment-related tumors reported in the submitted chronic and
oncogenicity studies in rats and mice, subchronic studies in mice, dogs
and rats and that no mutagenic concern was reported in the genotoxicity
studies. 

Table 3.5.8b  Summary of Toxicological Doses and Endpoints for
Chlorantraniliprole for Use in Occupational Human Health Risk
Assessments

Exposure/

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

Dermal Short-/Intermediate-Term 	N/A	N/A	N/A	There was no hazard
identified via the dermal route (and no concerns for developmental,
reproductive or neurotoxic effects) and therefore, no dermal endpoint
was selected for quantitative risk assessment.

Inhalation Short-/Intermediate-Term 	N/A	N/A	N/A	Based on the lack of
hazard identified in the acute inhalation study, lack of acute
irritation, and extremely low oral toxicity – no inhalation endpoint
was selected for quantitative risk assessment.

Cancer (dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on weight of evidence of data: no
treatment-related tumors reported in the submitted chronic and
oncogenicity studies in rats and mice, subchronic studies in mice, dogs
and rats and that no mutagenic concern was reported in the genotoxicity
studies. 

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

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.

The following information was provided by DuPont:  DPX-E2Y45 has been
produced on a pilot scale since 2003 at a contract facility, Albemarle
Process Development Center, in Baton Rouge, Louisiana or at the DuPont
Experimental Station (Wilmington, Delaware).  The formulated
preparations have been made at the DuPont Stine Haskell Research Center
(Newark, Delaware).   DPX-E2Y45 has not been manufactured on an
industrial scale for commercial use.  A limited number of workers have
been involved with the synthesis of this compound to date.  No illnesses
have been attributed to exposure associated with the handling, testing,
or manufacturing of DPX-E2Y45.

Additional workers have been exposed during the regulatory and field
biological testing.  No illnesses have been attributed to exposure
associated with the handling, testing, or manufacturing of DPX-E2Y45.

No specific human symptoms of DPX-E2Y45 toxicity are known.

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

Reference: The residue chemistry summary document was reviewed by the
Chemistry Science Advisory Council: Chlorantraniliprole (DPX-E2Y45). 
Section 3 Registration Request for Use on Leafy Vegetables (Except
Brassica) (Crop Group 4), Brassica (Cole) Leafy Vegetables (Crop Group
5), Fruiting Vegetables (Crop Group 8), Cucurbit Vegetables (Crop Group
9), Pome Fruits (Crop Group 11), Stone Fruits (Crop Group 12), Cotton,
Grapes, and Potatoes and Summary of Analytical Chemistry and Residue
Data, Section 18 Exemption 08LA01 for Use on Rice, D336941, Leung Cheng,
2/25/08.  Note:  Under international agreements the Australian Pesticide
and Veterinary Medicines Authority was designated as the lead for
residue chemistry data review.  The US did review North American field
trials, analytical methods, storage stability data and processing
studies.

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 nature of the residue in plants is adequately understood.  Studies
have been conducted depicting the metabolism of chlorantraniliprole in
apple, cotton, lettuce, rice, and tomato.  In the apple, cotton, lettuce
and tomato studies, the plants were treated at 3 x 100 g ai/ha by foliar
application (~ 0.5 proposed maximum application rate), and rice was
treated at 1 x 150 g ai/ha by soil drench (0.68x, based on the proposed
Section 18 use).  Total radioactive residues were measured in apples
(0.092-0.138 ppm at 15 and 30 day PHI, respectively), lettuce (0.301 and
0.372 ppm at 7 and 15 day PHI, respectively), cotton seed (<0.01 ppm at
126 day PHI), tomato (0.056 and 0.013 ppm at 7 and 15 day PHI,
respectively), and rice (0.155 ppm at 132 day PHI).  For apple, lettuce
and tomato, the majority of the residues were surface residues.  In all
these crops, unchanged chlorantraniliprole was the major residue (57-92%
TRR).

Very little degradation of chlorantraniliprole was observed in apple,
cotton, lettuce and tomato.  Many metabolites were found in rice
commodities and the metabolism in rice generally involves:  (i)
hydroxylation of the N-methyl group (to IN-H2H20) or hydroxylation of
the tolyl methyl group (to IN-HXH44); (ii) cyclization with loss of
water to a quinazolinone derivative (IN-EQW78); and similar condensation
of IN-H2H20 with an additional loss of CH2O (to IN-GAZ70); and (iii)
N-demethylation via IN-H2H20 to IN-F9N04.  HED concludes that the nature
of the residue in primary crops is parent chlorantraniliprole.  For the
chemical names and structures of identified metabolites, see Appendix B
and Table 5.1.7.

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

The submitted confined rotational crop studies have been reviewed and
deemed adequate to satisfy data requirements. Unchanged parent was the
major identified residue in all rotational crop commodities (1 x 300g
ai/ha) including lettuce (64-85% TRR), wheat grain (48% TRR from an
exaggerated rate at 120 DAT), wheat forage (54-84% TRR), wheat hay
(51-73% TRR), and wheat straw (37-69% TRR); TRR were <0.01 ppm in wheat
grain, beet root, and beet foliage.  HED concludes that the nature of
the residue in rotational crops is parent chlorantraniliprole.

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

The nature of the residue in livestock is adequately understood based on
highly exaggerated acceptable goat and hen   SEQ CHAPTER \h \r 1
metabolism studies.  The ruminant metabolism study was conducted at 10
ppm (5.6x for beef cattle and 40x for dairy cattle) in the diet; the
poultry metabolism study was conducted at 10 ppm (111x) in the diet. 

The metabolism of chlorantraniliprole in livestock was extensive and
followed the major steps similar to those observed in rice: (i)
hydroxylation of the N-methyl group (to IN-H2H20) or hydroxylation of
the tolyl methyl group (to IN-HXH44); (ii) cyclization with loss of
water to a quinazolinone derivative (IN-EQW78); and (iii)
N-demethylation via IN-H2H20 to IN-F9N04.

The residue of concern in ruminants for tolerance enforcement and for
risk assessment is the parent compound.  The residue of concern in
poultry in connection with the proposed Section 18 use on rice is the
parent compound for tolerance enforcement and risk assessment (even
though, at this time, poultry is considered a category 180.6(a)(3)
situation, based on the current dietary burden).

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

m/z 484 → 453, 484 → 286, 284 → 112, 284 → 177.  The validated
limit of quantification is 0.01 ppm.  The method has undergone a
successful independent laboratory validation and has been validated with
the analysis of numerous field trial samples.  The method is adequate
for tolerance enforcement purposes for plant commodities.

The enforcement method for livestock commodities, Analytical Method for
the Determination of DPX-E2Y45 and Metabolites in Bovine Tissues, Milk,
and Eggs Using LC/MS/MS, is described in DuPont-14314.  Milk and cream
samples and tissue and egg samples are extracted and partitioned with
hexane and water/acetonitrile. A homogenizing probe followed by
centrifugation is used with the tissue and egg samples.  Proteins are
expected to precipitate from milk during the partitioning. An aliquot of
the water/acetonitrile phase is diluted with water and purified by solid
phase extraction.  Extracts are placed on a Varian SAX SPE cartridge in
series with a Water Oasis HLB SPE cartridge. Analytes are eluted with
acetonitrile, followed by acidified (0.5% formic acid) ethyl acetate. 
The eluate separates into two layers, and the lower water layer (pH 2)
is removed (and discarded) to obtain consistent recoveries of IN-K9T00. 
The organic eluate is evaporated to dryness and reconstituted in
acetonitrile.

Reversed-phase liquid chromatography (C18 column for dairy, muscle,
liver, and fat samples; phenyl-hexyl column for kidney and whole egg
samples) is used to separate parent and metabolites.  Detection is by
Atmospheric Pressure Chemical Ionization (APCI) MS/MS operated in the
positive ion mode. The validated LOQ is 0.01 ppm chlorantraniliprole.
The method is adequate for tolerance enforcement purposes for livestock
commodities.

The proposed plant and animal methods have been reviewed by Agency
chemists in ACB/BEAD (D340358, C. Stafford, 2/6/08).

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

Reference: Drinking Water Assessment for Chlorantraniliprole, D348133,
James A. Hetrick, et.al., January 10, 2008.  Under international
agreements the Agency was not responsible for conducting environmental
fate data reviews.  Data review was conducted for use by all parties to
the international agreement by the Pesticide Control Service, Department
of Agriculture and Food, Ireland. The Agency is using the results of the
PSD review as they appear in the dossier for registration in Europe
except for the aerobic soil metabolism half-lives, which EFED
recalculated to be representative of the total extractable fraction in
soil.

Chlorantraniliprole is persistent and mobile in terrestrial and aquatic
environments.  Extended chlorantraniliprole use is expected to cause
accumulation of residues in soil from year to year.  Laboratory studies
indicate the major routes of dissipation are expected to be
alkaline-catalyzed hydrolysis (predominant degradate IN-EQW78),
photodegradation in water (predominant degradate IN-LBA24), leaching,
and runoff.  Soil metabolism is minimal, although higher temperatures
are expected to reduce half-lives.  Field studies support the findings
in the laboratory studies, where half-lives of chlorantraniliprole range
from 52 to 1130 days in both radiolabeled and non-radiolabeled studies. 
For a more detailed description of the fate studies, as well as a
summary table of structures and study results, see Appendix B.

In addition to the environmental fate and effects studies, there were
three dislodgeable foliar residue (DFR) studies submitted on cabbage
plants (in New York, Georgia and California), tomato plants (in New
York, Georgia and California), and apple trees (in New York, Minnesota
and Idaho).  These studies show similar findings as in the fate
database, indicating chlorantraniliprole is persistent.  As shown below,
the DFR studies indicate that chlorantraniliprole dissipates slowly,
however, it does not necessarily following a pattern of steady decline. 
The studies also indicate rain events aid dissipation.

Table 5.1.5 Dislodgeable Foliar Residue Studies Summary

Crop	Site	Half-life (days)	R2	Comments

Cabbage	NY	14	0.807	Residue levels declined, increased, and then
declined again

	GA	13	0.897

CA	19	0.251	Residue levels declined, increased, and then declined again;
R2 value particularly low

Tomato	NY	18	0.641

GA	15	0.798

CA	21	0.393	Residues declined until day 14, and then increased until day
35; R2 value particularly low

Apple	NY	25	0.541	Not certain that the sampling duration was sufficient
to thoroughly characterize the dissipation

	MN	5	0.947	Higher than average rainfall

	ID	30	0.573	Not certain that the sampling duration was sufficient to
thoroughly characterize the dissipation

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

In plants where DPX-E2Y45 is applied to the foliage, although
metabolites are identified, they are at such low levels, metabolism is
not considered significant.  However, in animal matrices (such as
livestock, rats, mice, dogs) and rice (where DPX-E2Y45 is in contact
with soil), DPX-E2Y45 does get metabolized and follows similar patterns.
 Either the tolyl methyl or N-methyl carbon gets hydroxylated (IN-HXH44,
IN-H2H20) – then, further metabolism results in N-demethylation
(IN-F9N04) and nitrogen to carbon cyclization with loss of a water
molecule resulting in the formation of the pyrimidone ring (IN-EQW78). 
The mammalian metabolism studies further describe oxidation of alcohols
to carboxylic acids, amide bridge cleavage, amine hydrolysis and
O-glucuronidation.  It is not clear if environmental degradation follows
the same breakdown pattern – although DPX-E2Y45 resists degradation in
environmental matrices as well.  Laboratory studies indicate degradation
is expected via alkaline-catalyzed hydrolysis (predominant degradate
IN-EQW78) and photodegradation in water (predominant degradate IN-LBA24,
which was not identified in plant or animal metabolism studies).  Also,
degradation could occur through soil metabolism (although only
minimally; degradates include IN-F6L99, IN-EVK64, IN-EQW78, IN-ECD73 and
IN-GAZ70).

Although metabolism pathways/patterns are similar across matrices, there
are differences.  Within the metabolism studies/assessments from the
toxicology database, the results suggest possible species and sex
differences in the primary metabolites formed in all three species:
rats, mice and dogs.  And even though IN-EQW78 is postulated as an
intermediary metabolite in the rat metabolism pathway, it was not
quantified in the study in urine and/or feces (tissues were not analyzed
for metabolites).  These studies discuss these differences further: the
primary methylphenyl ring hydroxylated metabolite (IN-HXH44) was
quantified only in dog plasma, while the N-methyl hydroxylated
metabolite (IN-H2H2O) was quantified only in rat plasma.  The
cyclization product of IN-H2H20 with loss of a water molecule or
N-demethylation product of IN-EQW78 (IN-GAZ70) was quantified in both
mouse and rat, but not dog plasma.  Mouse plasma contained more IN-GAZ70
than rat plasma in these studies.  A significant sex difference was
observed in rats with female rats showing higher concentrations of
DPX-E2Y45, IN-H2H20, and IN-GAZ70 than male rats.  No sex difference was
noted in the dog or mouse.  Overall, the results in rats for the 90-day
and 14-day studies were consistent with the plasma concentrations of
carbon-labeled (14C) residues, decreased absorption, and the proposed
metabolic pathway from the single and multiple oral gavage studies with
carbon-labeled (14C)-DPX-E2Y45 in rats.

However, despite the metabolic differences between species and sexes,
there is a consistent effect on the liver, indicating that the
differences in metabolism do not appear to be the primary driver of
mammalian toxicity for DPX-E2Y45.

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

Limited information is available on the toxicity of the major DPX-E2Y45
metabolites/degradates that were not tested in the mammalian toxicology
database (i.e., compounds that were not identified as metabolites in the
rat, mouse or dog, and therefore not tested).  The only major degradate
expected to be encountered via drinking water exposure is IN-LBA24 (due
to rice cultivation having the potential for degradation via aquatic
photolysis).  However, IN-LBA24 is expected to be of equivalent or
lesser toxicity than DPX-E2Y45 based on submitted acute oral and
genotoxicity studies of LBA-24.  Additionally, it is not clear whether
IN-EQW78 was tested in the mammalian toxicology database, however, again
– because it is structurally similar to parent (and metabolites that
are seen in the rat metabolism cascade), it is expected to be of
equivalent or lesser toxicity than DPX-E2Y45 (which is considered in
light of the extremely low toxicity of DPX-E2Y45).

The only other major metabolites are IN-K9T00 and IN-HXH44, bis- or
monohydroxylated on the methyl groups, identified in milk.  These
species were considered in the mammalian toxicology database.  Also,
since the hydroxylated metabolites are very similar to DPX-E2Y45 (and
expected to be readily excreted) they are not anticipated to pose
increased toxicity over the parent compound.

Table 5.1.7. Major Metabolites and Degradates

Common name/code

ID No.	Chemical name	Chemical structure

 Chlorantraniliprole, DPX-E2Y45
3-Bromo-N-[4-chloro-2-methyl-6-[(methylamino)

carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide	

 IN-HXH44

	3-Bromo-N-[4-chloro-2-(hydroxymethyl)-6-[(methylamino)

carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

	

 IN-K9T00	3-Bromo-N-[4-chloro-2-(hydroxymethyl)-6-[[(hydroxymethyl)

amino)carbonyl]

phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

	

IN-F6L99	5-Bromo-N-methyl-1H-pyrazole-3-carboxamide	

IN-LBA24

IN-EQW78
2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-3,
8-dimethyl-4(3H)-quinazolinone	

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

Reference: the risk assessment team consulted the Residues of Concern
Knowledgebase Subcommittee (ROCKS), the meeting is captured in the
following memo: Chlorantraniliprole (DPX-E2Y45).  Report of the Residues
of Concern Knowledgebase Subcommittee, D343519, Christine Olinger,
2/29/08.

HED is including the residues of only the parent compound in its risk
assessments for chlorantraniliprole as well as for tolerance-enforcement
purposes, (although drinking water is not subject to tolerance
enforcement).  See Table 5.1.8 below.

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	Chlorantraniliprole	Chlorantraniliprole

	Rotational Crop	Chlorantraniliprole	Chlorantraniliprole

Livestock	Ruminant	Chlorantraniliprole	Chlorantraniliprole

	Poultry*	N/A	N/A

Drinking Water	Chlorantraniliprole	N/A

N/A = not applicable

* At this time the risk assessment team believes that poultry can be
considered a category 180.6(a)(3) situation that based on the current
dietary burden, tolerances are not needed for poultry commodities.

Plants:  The parent compound was the major residue found in the nature
of the residue studies and the confined rotational crop studies.  One
metabolite, IN-F6L99, was found at 11% of the total radioactive residues
(TRR) in beet tops in the rotational crop studies.  Since this
metabolite was not a major residue in any other study, and there were no
specific toxicity concerns with this metabolite, it need not be included
in the risk assessment or tolerance expression.

Ruminants:  The parent compound was a major residue in the ruminant
metabolism and feeding studies, and a reliable method is available for
analysis.  Although two metabolites (IN-K9T00 and IN-HXH44, structures
in Table 5.1.7), were major residues in the milk for both the ruminant
metabolism and feeding studies (only when dosed at levels greater than
100 times the expected dietary burden) – both are hydroxylated
metabolites, and as such are likely to be more readily excreted than the
parent.  The feeding studies are considered more representative and
reliable since a large number of animals were employed in the study and
pooled samples of morning and afternoon milk were collected over a
28-day period at four different dose levels.  Generally the levels found
for the individual metabolites were comparable to, or less than, the
parent.  Toxicity data and QSAR (quantitative structure activity
relationship) information are not available for the metabolites. 
However, both metabolites are included in the rat metabolism cascade,
and therefore the in vivo rat studies provide insight on the low
relative toxicity of these metabolites.  Considering that the estimated
combined levels of the parent and metabolites would be much less than
the proposed tolerance levels in livestock commodities, only the parent
compound need be included in the risk assessment at this time.  In the
future if the anticipated dietary burden increases significantly, the
decision to exclude the hydroxylated metabolites as residues of concern
for risk assessment should be reconsidered.

Poultry:  At this time poultry can be considered a category 40 CFR
180.6(a)(3) situation – based on the current dietary burden,
tolerances are not needed for poultry commodities.  

Water:  The environmental fate data suggest that chlorantraniliprole is
persistent, and that microbial-mediated degradation is likely the major
degradation pathway for the proposed terrestrial agricultural uses. 
IN-EQW78 is the primary environmental degradation product of
chlorantraniliprole.  It is a major degradation product [>10% of (e.g.,
86.7% of applied at pH 9) applied chlorantraniliprole @ 120 days
post-treatment] in hydrolysis studies only at elevated temperatures
and/or under alkaline conditions.  IN-EQW78 was the major degradation
product (9 to 46 % of applied) in field dissipation studies in
California, Texas, New Jersey, and Georgia.  Leaching was detected as a
route of dissipation for IN-EQW78; it was found at a maximum soil depth
of 36 inches.  Degradation of IN-EQW78 was not observed in laboratory
and field studies because levels were generally still increasing or
reached a steady-state condition at the termination of the studies.  The
average half-life of IN-EQW78 is 703 days in aerobic soil metabolism
studies.  Under standard test conditions (25°C) in aerobic soils, the
90th percentile of mean half-life for total soil extractable
chlorantraniliprole is 632 days.  However, chlorantraniliprole can be as
persistent as IN-EQW78 (the aerobic soil metabolism half-life was as
long as 924 days, and in the field dissipation study in Georgia, 1130
days).

Because the parent is so persistent, modeling EDWCs based on parent and
IN-EQW78 with current aquatic models in EFED would not give estimates
substantially different than modeling parent alone.  Therefore, only the
parent need be included in the human health drinking water risk
assessment.

It is noted that a Section 18 registration has been proposed for the use
of chlorantraniliprole on rice.  Unique photochemical degradation
products (IN-LBA22, IN-LBA23, and IN-LBA24) of chlorantraniliprole were
detected in laboratory aquatic photolysis studies.  IN-LBA22 and
IN-LBA23 were sequentially and rapidly photolyzed to form IN-LBA24. 
IN-LBA24 (structurally similar to IN-EQW78, but without the
chloropyridine ring attached to the pyrazole ring at the 1-position) was
a major degradation product (>80% of applied chlorantraniliprole) in
photolysis studies in natural water and pH 7 buffer solution.  The
estimated photolytic half-life of IN-LBA24 was stable in pH 7 buffer
solution and 129 days in natural water.  IN-LBA24 has the potential to
be present in drinking water sources when chlorantraniliprole is applied
to agricultural crops that are cultivated via flooding.

Because the parent is substantially more persistent than IN-LBA24,
modeling EDWCs based on parent alone is more protective than modeling
parent and IN-LBA24 with current aquatic models in EFED.  Therefore, for
this screening level Section 18 action, only the parent need be included
in the human health drinking water risk assessment.

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

Chlorantraniliprole is persistent and mobile in terrestrial and aquatic
environments.  These fate properties suggest that it has a potential to
move into surface water and shallow groundwater.

The Environmental Fate and Effects Division (EFED) has completed a
drinking water assessment for chlorantraniliprole (James Hetrick,
D348133, 1/10/2008).  At this time, the Agency lacks sufficient
monitoring exposure data for use in risk assessments, as this is a new
ai.  Because the Agency does not have comprehensive monitoring data,
drinking water concentration estimates are made by reliance on
simulation or modeling, taking into account data on the physical
characteristics and fate characteristics of chlorantraniliprole.

26.862 μg/L based on nursery applications in Tennessee.  For the 1 in
10 year annual average, the highest PRZM/EXAMS EDWC was 3.650 μg/L,
also based on nursery applications in Tennessee.  For the 30 year annual
average, the highest EDWC was 1.721 μg/L based on nursery applications
in Florida.

 μg/L.

Table 5.1.9a	Summary of Estimated Surface Water and Groundwater
Concentrations for Chlorantraniliprole.

	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	26.862	1.06

Chronic (non-cancer, 1 in 10 year annual average)	3.650

	Chronic (cancer, 30-year annual average)	1.721

	a From the Tier II PRZM-EXAMS - Index Reservoir model.  Input
parameters are based on nursery applications in Tennessee, AR 0.4992 lb
ai/A.

b From the SCI-GROW model assuming a maximum seasonal use rate of 0.4992
lb ai/A, a Koc of 272, and a half-life of 509 days from the aerobic soil
metabolism study.

Tier 1 modeling for rice was conducted to provide EDWCs for the proposed
rice seed treatment use of chlorantraniliprole. The proposed label
(Dermacor X-100) for rice allows chlorantraniliprole treated rice seed
use with only drill seeded and broadcast rice planting techniques. Water
seeded rice is not allowed on the proposed label.  Because the Tier 1
rice model assumes a 1 cm sediment depth interaction zone, the model was
modified to account for 1 inch (2.54 cm) seed incorporation depth. 
Table 5.1.9b shows the peak concentration of chlorantraniliprole in rice
paddy water.  This concentration is expected to provide conservative
EDWC because it represents edge-of-paddy concentrations.  No dilution or
aerobic aquatic metabolism is considered in the modeling.  The maximum
application rate of chlorantraniliprole (0.202 lbs ai/A) was assumed in
the modeling.

Table 5.1.9b. Acute Chlorantraniliprole Concentrations in Rice Paddy
Water 

Residue	Chorantraniliprole

Estimated Concentration

(µg/L)	IN-LBA24

Estimated Concentration

(µg/L)

Chlorantraniliprole (@ 0.202 lbs ai/A)	84.495	  

61.766

Further refinement of the rice paddy EDWC was conducted to assess the
annual average concentration.  Although degradation routines in the Tier
1 rice model are not standard policy, photodegradation is an important
degradation pathway (t1/2=0.31 days) of chlorantraniliprole in aquatic
environments. A first-order decay model (y= 60.27*e-2.359*time) was used
to estimate the average annual concentration in the rice paddy water. 
Table 5.1.9c shows the estimated annual average concentration of
chlorantraniliprole.

Table 5.1.9c. Annual Average Chlorantraniliprole Concentrations in Rice
Paddy Water

Residue	Chorantraniliprole

Estimated Concentration

(µg/L)	IN-LBA24

Estimated Concentration

(µg/L)

Chlorantraniliprole (@ 0.202 lbs ai/A)	

0.257	 0.188

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

Most residues are found on the surface of plants.  Residues ranged from
less than the LOQ (<0.01 ppm) to up to 15 ppm (cotton gin byproducts)
and 9.7 ppm (spinach).  Residue levels varied depending on the crop. 
Residues in livestock are expected due to residues in feedstuff. 
Residues of detected metabolites seem to partition into milk fat –
which is supported by the rat metabolism study.  There is a high level
of confidence in the field trial data, from which the tolerance levels
were determined (and subsequently used in the dietary exposure
assessment) – as field trials were conducted on a wide variety of
crops, generally at maximum application rates and re-treatments, and
minimal re-treatment intervals and PHIs.

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

There are no international residue limits that affect HED’s
recommendations at this time.  There are no Canadian, CODEX or Mexican
maximum residue limits (MRLs) for chlorantraniliprole. The new
tolerances recommended by HED have been derived using the NAFTA
Tolerance Harmonization Spreadsheet.  As this is a global review,
considerable effort was devoted to harmonizing the MRLs.  Although the
tolerance expression achieved harmonization, due predominantly to
differences in crop grouping and what crops are considered
representative of a group – harmonized MRLs were only achieved for
potatoes and possibly cotton (MRL decisions still pending).

Secondary reasons that contribute to harmonization difficulties include
use pattern differences (for one crop, application rates and
formulations may be different in different countries due to different
pest pressures/conditions).

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

Reference: The dietary exposure and risk assessment was reviewed by the
Dietary Exposure Science Advisory Council.  Chlorantraniliprole Chronic
Aggregate Dietary and Drinking Water Exposure and Risk Assessments for
the Section 3 Registration Action to Support New Use on Leafy Vegetables
(Except Brassica) (Crop Group 4), Brassica (Cole) Leafy Vegetables (Crop
Group 5), Fruiting Vegetables (Crop Group 8), Cucurbit Vegetables (Crop
Group 9), Pome Fruits (Crop Group 11), Stone Fruits (Crop Group 12),
Cotton, Grapes, Potatoes, and Section 18 Exemption on Rice, D346596,
Leung Cheng, 2/19/2008

The dietary exposure assessment considers only chronic exposure, since
chlorantraniliprole was determined to be toxic only via the chronic oral
exposure duration.

5.2.1	Chronic Dietary Exposure/Risk  TC \l3 "5.2.1	Chronic Dietary
Exposure/Risk 

Chronic dietary risk assessments were conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID™, Version 2.03) which uses food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. 
The analyses were performed to evaluate Section 3 requests for new uses
of chlorantraniliprole on leafy vegetables (except Brassica), Brassica
leafy vegetables, fruiting vegetables, cucurbit vegetables, pome fruit,
stone fruit, cotton, grapes, potatoes and rice (a Section 18 request).

The chronic assessments assumed that 100% of crops with requested uses
of chlorantraniliprole are treated, and that all treated crops contain
residues at tolerance level.  In addition, the assessments include the
maximum modeled EDWC (3.650 µg/L – the maximum value relevant to
chronic exposure).

These assumptions result in conservative, health-protective estimates of
exposure (Table 5.2).  These estimates are well below HED’s level of
concern (100% of the cPAD).  The maximum estimate is less than 1% of the
cPAD for all population subgroups.  These analyses indicate that there
are no dietary exposure considerations that would preclude registration
of chlorantraniliprole for the requested uses (i.e., dietary risk is not
of concern).

Table 5.2.  Results of Chronic Dietary Exposure and Risk Estimates for
Chlorantraniliprole

Population Subgroup	cPAD, mg/kg/day	Chronic Estimates

(Food only)	Chronic Estimates

(Food and Drinking Water)

Exposure, mg/kg/day	Risk, % cPAD	Exposure, mg/kg/day	Risk, % cPAD

U.S. Population	1.58	0.007679	<1	0.007756	<1

All infants

0.007856	<1	0.008108	<1

Children 1-2 yrs

0.014855	<1	0.014969	<1

Children 3-5 yrs

0.012043	<1	0.012150	<1

Children 6-12 yrs

0.007999	<1	0.008073	<1

Youth 13-19 yrs

0.005850	<1	0.005906	<1

Adults 20-49 yrs

0.007082	<1	0.007154	<1

Adults 50+ yrs

0.007613	<1	0.007689	<1

Females 13-49 yrs

0.007215	<1	0.007286	<1

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

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

The dietary assessment is a screening-level assessment using residues at
tolerance levels and assuming that 100% of requested crops are treated.

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

DuPont is applying to register thirteen end-use products for use by
commercial applicators on turfgrass and ornamental plants.  One end-use
product is a suspension concentrate, and all others are formulated as
granulars.  Although the percent ai in each formulation varies, the
use-sites and application rates are comparable.

Although there are only two use sites (turfgrass and ornamental plants),
as indicated on the DuPontTM E2Y45 0.33G Insecticide label, these use
sites encompass a multitude of places that may be treated: home lawns,
commercial lawns, industrial facilities, residential dwellings, business
and office complexes, shopping complexes, multi-family residential
complexes, institutional buildings, airports, cemeteries, interior
plantscapes, ornamental gardens, parks, wildlife plantings, playgrounds,
schools, daycare facilities, golf courses (tee box areas, roughs,
fairways, greens, collars, etc.), athletic fields, sod farms and other
landscaped areas.  The multitude of use sites, in addition to the
persistence of chlorantraniliprole, indicates there is potential for
short- and intermediate-term postapplication dermal (adults and
children) and incidental oral (children only) exposure to
chlorantraniliprole (inhalation exposure is not expected due to low
vapor pressure).  However, due to the lack of toxicity over the acute,
short- and intermediate-term via the oral and dermal routes – no risk
is expected from these exposures.

Long-term (greater than 6 months) dermal exposure to turfgrass is not
expected because the use pattern suggests a seasonal window of
application, and DFR data indicate a maximum half-life of only 30 days
on foliage.  While chlorantraniliprole’s persistence in soil
(half-life up to 1130 days in dissipation studies on bareground plots)
increases the possibility of long-term exposure for toddlers via
incidental ingestion, the daily quantity of soil a toddler would need to
eat to reach the cPAD is not feasible (more than 4 lbs/day, even when
accounting for accumulation).

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 and
airblast application methods employed for chlorantraniliprole.  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 US 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 due to the lack of toxicity resulting
from chlorantraniliprole exposure (other than chronic oral ingestion),
spray drift is not expected to pose a risk to residents near spraying
operations.

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 action, although there is potential exposure to
chlorantraniliprole from food, drinking water and residential use sites,
the only identified hazard is via the oral route over a chronic
duration.  Residential exposures are expected to occur over a short- or
intermediate-term duration.  Therefore, the aggregate risk assessment
considers only exposures from food and drinking water consumed over a
long-term duration (greater than 6 months of daily exposure).

7.1	Long-Term Aggregate Risk TC \l2 "7.1	Long-Term Aggregate Risk 

Refer to Section 5.2, which discusses dietary exposure (food and water)
in detail.  The dietary route alone is relevant for long-term/chronic
exposure and risk assessment; and the chronic dietary exposure and risk
assessment conducted for chlorantraniliprole is screening-level (the
assessment assigns tolerance level residue values to all food
commodities proposed to be treated with chlorantraniliprole; and modeled
residue values to all 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
tolerance action, 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   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

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

As mentioned in Section 6.0, DuPont has applied to register thirteen
end-use products for use by commercial applicators on turfgrass and
ornamental plants.  There is one end-use product that is a suspension
concentrate, and all others are formulated as granulars.  Additionally,
DuPont is applying to register two chlorantraniliprole end-use products
(one suspension concentrate and one water dispersible granule) for use
on pome fruit, stone fruit, leafy vegetables, Brassica leafy vegetables,
cucurbit vegetables, fruiting vegetables, cotton, grapes and potatoes. 
The Section 18 use on rice seed involves a 50% ai SC formulation.

For agricultural crops the maximum application rate is about 0.1 lb
ai/A, re-treatment intervals range from 5-10 days, and, PHIs range from
1-21 days.  Application is expected via aerial and ground equipment, as
well as chemigation for the SC and WG formulations.  The 50% ai SC
formulation for use on rice seed is to be used with commercial seed
treaters only.  For turf and ornamentals, the maximum application rate
is 0.3 lb ai/A.  The SC formulation can be applied by ground equipment,
and the granular formulations are applied by drop-type, rotary-type or
hand-held equipment (see Section 2.0 for more specifics on use patterns
for each use site).  Subsequently, there is potential for short- and
intermediate-term occupational exposure to chlorantraniliprole during
both handler [mixing, loading and application (via the dermal and
inhalation routes)] and postapplication activities (via the dermal
route) based on the proposed uses.

However, the chlorantraniliprole toxicology database indicates there is
no systemic hazard associated with short- and intermediate-term dermal
and inhalation exposure, and therefore, no occupational exposure and
risk assessment was conducted.

In addition to systemic hazard, the Worker Protection Standard (WPS)
sets a restricted entry interval (REI) based on the acute toxicity of
chemicals.  Technical chlorantraniliprole is in Category IV for acute
dermal toxicity and Category IV for primary eye and skin irritation. 
Per the WPS, a 12-hr REI is required for chemicals classified under
Toxicity Category III or IV.  However, all the labels submitted for
chlorantraniliprole indicate a proposed REI of 2 hours.

REIs of 2 hours are not an option under the WPS.

According to Pesticide Registration (PR) Notice 95-3, EPA permits
registrants to reduce REIs from 12 to 4 hours for certain low risk
pesticides that meet certain criteria.  The criteria are

The active ingredient is in Toxicity category III or IV based upon data
for acute dermal toxicity, acute inhalation toxicity, primary skin
irritation, and primary eye irritation.

The active ingredient is not a dermal sensitizer (or in the case of
biochemical and microbial active ingredients, no known reports of
hypersensitivity exist). 

The active ingredient is not a cholinesterase inhibitor (NMethyl
carbamate and Organophosphate) as these chemicals are known to cause
large numbers of pesticide poisonings and have the potential for serious
neurological effects. 

No known reproductive, developmental, carcinogenic, or neurotoxic
effects have been associated with the active ingredient.

EPA does not possess incident information (illness or injury reports)
that are ``definitely'' or ``probably'' related to post-application
exposures to the active ingredient. 

Chlorantraniliprole meets all of the above criteria, and therefore, is a
candidate for a reduced REI of 4 hours according to PR Notice 95-3.

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).

Three dislodgeable foliar residue (DFR) studies were submitted by the
registrant.  DFR studies are generally used to refine postapplication
activity exposure estimates.  Since no risk is expected, the DFR results
are not used in that way.  Regardless, it is interesting to note that
the dissipation pattern on the surface foliage of plants (tomatoes,
cabbage and apples, in this case) do not follow a uniform pattern.  In
some cases the residues decline and then increase.  It is possible that
climate/weather plays a significant role in the dissipation pattern –
with rainfall aiding dissipation.  Although the DFR studies are quite
different from the fate studies (fate studies investigate residues
remaining within a 3-dimensional volume, rather than the residue that
can be dislodged on a 2-dimensional plant surface), they both indicate
that chlorantraniliprole is persistent.

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

10.1	Toxicology  TC \l2 "10.1	Toxicology 

There are no data gaps in the toxicology database.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

860.1200  Directions for Use

Since the residue data for pome fruit reflect spray volumes of 100
gallons per acre, the use directions for pome fruit should be revised to
state “minimum spray volume of 100 gal/A (ground).”  Also, as there
are inadequate residue data that reflect use of adjuvants in end-use
products in the residue field trials, the proposed labels should be
revised to delete the use of adjuvants on all crops except Brassica
crops.  In the absence of residue data on crops grown in greenhouses,
the label should prohibit use on crops grown in greenhouses.  Given the
results of the confined accumulation and limited field accumulation in
rotational crops study, a restriction should be imposed on the proposed
labels to prohibit the rotation to any crop not on the label. 

860.1400  Water, fish, and irrigated crops

Residue data in crayfish will not be required for the Section 18
request, but may be required for a Section 3 registration.

860.1900  Field Accumulation In Rotational Crops

The petitioner is required to conduct extensive field rotational crop
trials.  The requirement for number of trials would be the same as that
to establish primary tolerances on all crops or crop groups which the
petitioner intends to have as rotational crops on the label.  If a
registrant desires to allow the universe of crops to be rotated,
magnitude of the residue data are required on representative crops for
all crop groups which could be planted in a typical crop rotation
sequence.

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

REIs of 2 hours are not an option under the WPS, but are listed on most
of the proposed labels.  Chlorantraniliprole meets all of the criteria
listed in Section 9.0, and therefore, is a candidate for a reduced REI
of 4 hours according to PR Notice 95-3.

References:  TC \l1 "References: 

H. Takeshima, M. Nishi, N. Iwabe, T. Miyata, T. Hosoya, I. Masai, Y.
Hotta, Isolation and

characterization of a gene for a ryanodine receptor/calcium release
channel in Drosophila melanogaster.

(1994) FEBS Lett. 337, 81-87.

D. Cordova, E.A. Benner, M.D. Sacher, J.J. Rauh, J.S. Sopa, G.P. Lahm,
T.P. Selby, T.M. Stevenson, L.

Flexner, S. Gutteridge, D.F. Rhoades, L. Wu, R.M. Smith, and Y. Tao,
Anthranilic diamides: A new

class of insecticides with a novel mode of action, ryanodine receptor
activation. (2006) Pest. Biochem.

Phys. 84, 196-214.

D. Cordova, E.A. Benner, M.D. Sacher, J. J. Rauh, J. S. Sopa, G.P. Lahm,
T. P. Selby, T. M. Stevenson,

L. Flexner, T. Caspar, J. J. Ragghianti, S. Gutteridge, D. F. Rhoades,
L. Wu, R. M. Smith, and Y. Tao,

Elucidation of the mode of action of Rynaxypyr™, a selective ryanodine
receptor activator. in Pesticide

Chemistry: Crop Protection, Public Health and Environmental Safety, E.
Ohkawa, H. Miyagawa and P.

W. Lee Eds.; Wiley-VCH, 2007.

Majuli R. Sharma, Loice H. Jeyakumar, Sidney Fleischer, and Terence
Wagenknech. 2000. Three-dimensional structure of ryanodine receptor
isoform three in two conformational states as visualized by
cryo-electron microscopy. The journal of biological chemistry. 275(13),
9485-9491.

Snyder, P. W., Kazacos, E. A., Scott-Moncrieff, J. C., HogenEsch, H.,
Carlton, W. W., Glickman, L. T., Felsburg, P. J. Pathologic features of
naturally occurring juvenile polyarteritis in beagle dogs. Veterinary
Pathology, Vol 32, Issue 4 337-345, 1995.

Chlorantraniliprole (DPX-E2Y45) Toxicology Assessment, Mary Manibusan,
TXR #0054555, D336940, D337737, D343520, D345100, 11/17/2007.

Chlorantraniliprole (DPX-E2Y45).  Section 3 Registration Request for Use
on Leafy Vegetables (Except Brassica) (Crop Group 4), Brassica (Cole)
Leafy Vegetables (Crop Group 5), Fruiting Vegetables (Crop Group 8),
Cucurbit Vegetables (Crop Group 9), Pome Fruits (Crop Group 11), Stone
Fruits (Crop Group 12), Cotton, Grapes, and Potatoes and Summary of
Analytical Chemistry and Residue Data, Section 18 Exemption 08LA01 for
Use on Rice, D336941, Leung Cheng, 2/25/08

Chlorantraniliprole (DPX-E2Y45).  Report of the Residues of Concern
Knowledgebase Subcommittee, D343519, Christine Olinger, 2/29/08.

Stafford, Charles, Review of Proposed Tolerance Enforcement Methods for
Chlorantraniliprole. ACB Project # B08-08, D340358, February 6, 2008.

Hetrick, James A., et. al., Drinking Water Assessment for
Chlorantraniliprole, D348133, January 10, 2008.

Chlorantraniliprole Chronic Aggregate Dietary and Drinking Water
Exposure and Risk Assessments for the Section 3 Registration Action to
Support New Use on Leafy Vegetables (Except Brassica) (Crop Group 4),
Brassica (Cole) Leafy Vegetables (Crop Group 5), Fruiting Vegetables
(Crop Group 8), Cucurbit Vegetables (Crop Group 9), Pome Fruits (Crop
Group 11), Stone Fruits (Crop Group 12), Cotton, Grapes, Potatoes, and
Section 18 Exemption on Rice, D346596, Leung Cheng, 2/19/2008

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

Reference: Chlorantraniliprole (DPX-E2Y45) Toxicology Assessment, Mary
Manibusan, TXR #0054555, D336940, D337737, D343520, D345100, 11/17/2007.

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

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

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5385    Mutagenicity—Structural Chromosomal Aberrations	

870.5395    Mutagenicity—Micronucleus		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

yes

yes

no

	-

-

yes

yes

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

no	yes 

-

Special Studies

28-day immunotoxicity (rat)	

28-day immunotoxicity (mouse)	

yes

yes

A.2	Toxicity Profiles TC \l2 "A.2	Toxicity Profiles 

Table A.2.1. 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

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

STUDY/

SPECIES	DOSES (mg/kg/day)	NOAEL (mg/kg/day)	LOAEL (mg/kg/day)	EFFECTS

14-day Oral Gavage/ rat	0, 25, 100, 1000 	1000	Not established	No
adverse effects.  Weak inducer of cytochrome P450 3A at all dose levels,
with statistical significance at 100 and 1000 mg/kg/day.

28-Day Oral (feed)/rat	0, 20.7, 106 and 584 (male); 0, 24, 128 and 675
(female)	584 (male) and 675 (female)	Not established	No adverse effects.
 Slight increase in liver weight at 128 and 675 mg/kg/day in females and
minimal hepatocellular hypertrophy at 675 mg/kg that is attributed to
enzyme induction characterized by increased amount of eosinophilic
cytoplasm with hepatocytes but no histomorphologic evidence of
hepatocellular damage.  In 128 and 675 mg/kg females, a statistically
significant increase in UDP-GT activity was observed in HDT female rats,
with a similar increase in males.  These changes are consistent with a
pharmacological response and were not considered adverse.

28-Day Oral (feed)/mouse	0, 52, 182, 538 and 1443 (male); 0, 64, 206,
658 and 1524 (female)	1443 (male) and 1524 (female)	Not established	No
adverse effects.  Slight increase in liver wt. in 658 and 1524 mg/kg/day
females corresponded with a mild increase in cytochrome P450 enzyme
activity.  No histopathological evidence of liver toxicity was observed.

A reduction in body weight gain was observed in HDT males (52%) but not
in females.  No statistically significant decrease in absolute body
weight was observed therefore, this effect was not considered adverse.  

28-day Oral (capsule)/

Dog	0, 300, 1000 	1000	Not established	No adverse effects.  Induction of
cytochrome P450 enzyme activity (58%) in both males and females at 1000
mg/kg/day, specifically 1A1 and 2B1/2 at 300 and 1000 mg/kg/day.

28-day Oral (feed)/dog – Palatability study	0, 26, 138, 266, 797 and
1302 (male); 0, 28, 138, 298, 888, and 1240 (female)	1302 (male) and
1240 (female)	Not established	No adverse effects.  Food consumption
generally increased as the study progressed with males generally
demonstrating the highest food consumption when fed the HDT.

28-day Dermal/rat	0, 100, 300 and 1000	1000	Not established	No adverse
effects.  Reductions in mean body weight gain (22% and 19% for males and
females) and food efficiency (19% and 17% for males and females) over
the 28-day at the HDT.

Increased microvesiculation of adrenal cortex in males only, with no
light or electronic microscopic evidence of adrenal cellular
degeneration or toxicity.  No effect on the capacity of the adrenal
gland to produce corticosterone under either basal or following ACTH
stimulation.  Therefore, these effects were not considered adverse.

90-day Oral (feed)/rat	0, 36.9, 120, 359, 1188 (male); 0, 47, 157, 460,
1526 (female)	1188 (male) and 1526 (female)	Not established	No adverse
effects.  A slight increase in liver weight at HDT females and reduction
in bilirubin in females at  ≥157 mg/kg/day, with no corresponding
histopathological evidence of liver toxicity.

90-day Oral (feed)/mouse	0, 32.6, 115, 345, 1135 (male); 0, 40.7, 158,
422, 1529 (female)	1135 (male) and 1529 (female)	Not established	No
adverse effects.  Hyperactivity and hyperreactivity in females were
observed near the end of the study and one male in the upper mid dose
had convulsions, but these effects were considered spurious as they were
not reproducible in the 18-month mouse study with a FOB.

A slight increase in liver weight at the HDT males and females, with no
corresponding histopathological evidence of liver toxicity.

90-day Oral (feed)/dog	0, 32.2, 119, 303, 1163 (male); 0, 36.5, 133,
318, 1220 (female)	1163 (male) and 1220 (female)	Not established	No
adverse effects.  A mild increase in liver weight was observed in males
at 1163 mg/kg/day, with no corresponding histopathological evidence of
liver toxicity.

52-week Oral (feed)/dog	0, 32, 112, 317, 1164 (male); 0, 34, 113, 278,
1233 (female)	1164 (male) and 1233 (female)	Not established	No adverse
effects.  A mild increase in liver weight in HDT males and females, and
increase in alkaline phosphatase in HDT males, with no corresponding
histopathological evidence of liver toxicity.

Body weight gain increase in HDT males for weeks 8-9 compared to
controls, with an increase in food efficiency in week 9.

2-Year Oral (feeding)/rat	0, 7.71, 39, 156, 805 (male); 0, 10.9, 51,
212, 1076 (female)	805 (male) and 1076 (female)	Not established	No
evidence of carcinogenicity and no adverse findings. Increased adrenal
cortical microvesiculation due to lipid was present in the zona
fasciculata region of the adrenal gland of some male rats in all dose
groups in both the one-year and main studies.  This finding was
considered test substance related but was not considered adverse as the
adrenal morphology was generally in the range of what was observed in
control rats, and the finding was not associated with any indication of
cytotoxicity or other evidence of structural or functional impairment of
the adrenal gland.

18-Month Oral (feeding)/

Mouse	0, 2.6, 9.2, 26.1, 158, 935 (male); 0, 3.34, 11.6, 32.9, 196, 1155
(female)	158 (male) and 1155 (female)	935 (male), no LOAEL established
for female	No evidence of carcinogenicity.  Eosinophilic foci
accompanied by hepatocellular hypertrophy and increased liver weight
form the bases for the male LOAEL of 935 mg/kg/day.

Two-generation oral study/rat	0, 200, 1000, 4000, 20000 ppm,

mg/kg bw/d equivalents: 

pre-mating:

P1 m: 0, 12, 60, 238, 1199

F1 m: 0, 18, 89, 370, 1926

P1 f: 0, 16, 78, 318, 1594

F1 f: 0, 20, 104, 406, 2178

gestation:

P1 f: 0, 14, 68, 278, 1373

F1 f: 0, 14, 71, 272, 1465

lactation:

P1 f: 0, 32, 162, 654, 3118

F1 f: 0, 35, 183, 696, 3641	1199 (male) and 1594 (female)	Not
established	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 microvesiculation 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 cytotoxicity or
abnormal cellular structures were observed under light or electron
microscopy.

Develop

mental study/rat	0, 20, 100, 300, 1000	1000	Not established	No adverse
effects.

Develop

mental study/rabbit	0, 20, 100, 300, 1000	1000	Not established	No
adverse effects.

Acute oral neuro-toxicity/rat	0, 200, 700, 2000  in 0.5% methyl
cellulose	2000 	Not established	No evidence of neurotoxicity was
observed at any dose

Subchronic oral neuron-toxicity/rat	0, 12.7, 64.2, 255, 1313 (male); 0,
15.1, 77.3, 304, 1586 (female)	1313 (male) and 1586 (female)	Not
established	No evidence of neurotoxicity was observed at any dose.

28-day Immuno-toxicity/rat	0, 74, 363, 1494 (male); 0, 82, 397, 1601
(female)	1494 (male) and 1601 (female)	Not established	No evidence of
treatment-related effects on the sheep red blood cells specific antibody
(IgM) responses in either male or female rats at any dietary
concentration tested.

28-day Immuno-toxicity/

Mouse	0, 48, 264, 1144 (male); 0, 64, 362, 1566 (female)	1144 (male) and
1566 (female)	Not established	No evidence of treatment-related effect on
the sheep red blood cells specific antibody (IgM) responses in either
male or female mice at any dietary concentration tested.

A.3	Toxicity Summaries TC \l2 "A.3	Toxicity Summaries 

Acute Toxicity – Technical Chlorantraniliprole

DuPont has submitted three six-packs of acute toxicity studies (eighteen
studies total) in support of this registration for 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

Metabolism Studies (MRID 46979330)

Rate and extent of oral absorption	Absorption was 73-85% within 48 hours
after a single low dose (10 mg/kg/day) and 12-13% after a single high
dose (200 mg/kg/day) based on the sum in bile, urine, and carcass
(except GI contents).  Peak plasma concentrations occurred at 5-12 hours
after low and high single dose administration.  Plasma 14C residue
concentrations showed steady-state kinetics in male rats and near
steady-state kinetics in female rats after multiple low dose
administration (10 mg/kg/day x 14 days).

Distribution	Uniformly distributed with maximum concentrations observed
in plasma relative to other tissues.  Female rats had higher tissue
residues than male rats.

Potential for accumulation	Very low potential for accumulation based on
tissue to plasma ratios substantially less than one after single or
multiple oral dosing.

Rate and extent of excretion	Elimination half-lives for 14C residues
from plasma through 5 days after single low dose administration were
shorter in male (T1/2 = 1.7 days) than female rats (T1/2 = 3.3 days),
increased to T1/2 = 7.2 days through 13 days after multiple oral dosing.
 Rapid excretion observed via bile (49-53%) within 48 hours.  Extensive
excretion (98-97%) within 7 days after single or multiple dose
administration mainly via feces (62-92%) compared with urine (3.7-29%). 
Urinary excretion for the low dose at 48 hour ranged from 18-30%.

Metabolism in animals	Metabolism of the absorbed dose was fairly
extensive* and involved sex differences primarily in initial tolyl
methyl and N-methyl carbon hydroxylations.  Further metabolism of the
hydroxylated metabolites included N-demethylation, nitrogen to carbon
cyclization with loss of a water molecule resulting in the formation of
the pyrimidone ring, oxidation of alcohols to carboxylic acids, amide
bridge cleavage, amine hydrolysis, and O-glucuronidation.  Metabolism
was similar after multiple low dose (10 mg/kg/day x 14 days) or single
high dose (200 mg/kg/day) administration.

Toxicologically relevant compound	Parent compound (DPX-E2Y45)

*Note: The majority of the administered dose is excreted as the
unchanged parent molecule with little of the truncated species arising
from cleavage of the central carboximide link.

In addition to the rat metabolism studies conducted with 14C-labelled
DPX-E2Y45, analysis of plasma for parent and primary metabolites was
conducted during the 90-day rats, mice and dogs dietary administration
studies and the rat 14-day oral gavage study.  DPX-E2Y45 and primary
metabolites observed above the limit of quantification of 0.005 ug/mL
plasma were reported.

14-day oral gavage rat (MRID 46979935)

In the 14-day oral gavage study, a toxicokinetic assessment was
performed.  The area under the plasma concentration versus time curve
(AUC) was not proportional with the dose of DPX-E2Y45 indicating
decreased absorption at higher doses.  The half-lives were estimated to
be 3.4, 3.4 and 4.0 hours for 25, 100 and 1000 mg/kg/day groups,
respectively.  The time of maximum concentration (Tmax) was 0.25, 0.42,
and 2.75 hours in the 25, 100, and 1000 mg/kg/day groups, respectively. 
The maximum concentrations (Cmax) was similar at all dose levels, with
the highest concentration (0.48 ug/mL) occurring in the 25 mg/kg/day
group.  The half life for DPX-E2Y45 was sufficiently short that a
significant portion of the parent compound will be cleared from the
plasma after 24 hours, even following two weeks of repeated dosing at
1000 mg/kg/day indicating low potential for bioaccumulation.

90-day oral rat

In the 90-day oral rat study, DPX-E2Y45 and the metabolites IN-GAZ70 and
IN-H2H2O were identified quantitatively.  The concentration of IN-GAZ70
in plasma from male and female rats on Day 59 was considerably greater
than the plasma concentration of DPX-E2Y45.  In males, this difference
was approximately 10-fold, but in females, the difference was 100-fold. 
The concentration of each analyte was greater in females than in males. 
With the exception of the plasma concentration of IN-H2H2O in male rats
dosed at the highest dose being statistically different from the 2000
ppm dose, the plasma concentration of DPX-E2Y45, IN-GAZ70 and IN-H2H2O
were not statistically different from one another in the three highest
dose concentrations in either sex.  

90-day oral mouse

In the 90-day oral mouse study, DPX-E2Y45 and the metabolite IN-GAZ70
were quantified.  The concentration of the parent DPX-E2Y45 was below
the limit of quantification in all mouse samples analyzed.  The
metabolite IN-GAZ70 was the only significant analyte present in plasma
from male mice on day 92 and female mice on day 93.  The plasma
concentration of IN-GAZ70 in female mice dosed at the highest dietary
concentration was statistically different from the 700 ppm dose.  In
male mice, the plasma concentrations at the 2000 and 7000 ppm dose
concentrations were both statistically different from the 700 ppm dose
concentration.

90-day oral dog 

In the 90-day dog study, DPX-E2Y45 and metabolite IN-HXH44 were
quantified.  The concentration of parent DPX-E2Y45 for both male and
female dogs in plasma was approximately five times the concentration of
the metabolite IN-HXH44.  The plasma concentration of DPX-E2Y45 in male
dogs dosed at 40,000 ppm (high dose) was not statistically different
from the 4000 ppm dose.  The plasma concentration of the IN-HXH44 was
not statistically different at any dose concentration in either sex.

Conclusions:

These results demonstrate systemic uptake and metabolism of DPX-E2Y45
during dietary and oral gavage administrations.  These results also
suggest possible species differences in the primary metabolites formed
in all three species, rats, mice and dogs.  The concentration of
DPX-E2Y45 in plasma was dog>rat>mouse.  The primary methylphenyl ring
hydroxylated metabolite (IN-HXH44) was quantified only in dog plasma,
while the N-methyl hydroxylated metabolite (IN-H2H2O) was quantified
only in rat plasma.  The cyclization product of IN-H2H20 with loss of a
water molecule or N-demethylation product of IN-EQW78 (IN-GAZ70) was
quantified in both mouse and rat, but not dog plasma.  Mouse plasma
contained more IN-GAZ70 than rat plasma in these studies.  In all three
species, the relatively constant analyte concentrations at the higher
dose levels suggested decreased absorption with increasing dose,
confirming the previously described rat metabolism studies.  The slight
decrease in the plasma DPX-E2Y45 concentrations with increasing dose in
the 14-day oral gavage rat study also provided evidence for decreased
absorption.  A significant sex difference was observed in rats with
female rats showing higher concentrations of DPX-E2Y45, IN-H2H20, and
IN-GAZ70 than male rats.  No sex difference was noted in the dog or
mouse.  Overall, the results in rats for the 90-day and 14-day studies
were consistent with the plasma concentrations of 14C residues,
decreased absorption, and proposed metabolic pathway from the single and
multiple oral gavage studies with 14C-DPX-E2Y45 in rats.

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 fasciculata 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
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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.  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.

52-week Chronic Feeding Dog Study (MRID 46979718)

In a 1-year feeding study, DPX-E2Y45 (Batch #177; 96.45% a.i.) was
administered to male and female beagle dogs (4 dogs/sex/concentration)
at 0, 1000, 4000, 10,000, or 40,000 ppm.  The mean daily intakes for
male dogs were 0, 32, 112, 317, and 1164 mg/kg bw/day.  The mean daily
intakes for female dogs were 0, 34, 113, 278, and 1233 mg/kg bw/day. 
Parameters evaluated included body weight, body weight gain, food
consumption, food efficiency, clinical and neurobehavioral signs,
clinical pathology (hematology, clinical chemistry, urinalysis),
ophthalmology, organ weights, gross and microscopic pathology.  

No test substance-related effects were observed on survival, clinical
and neurobehavioral signs, or ophthalmology, body weight and nutritional
parameters, clinical pathology, or gross or microscopic pathology.  Test
substance-related increases in liver weight (absolute and relative) were
observed in 40,000 ppm male and female dogs, but were not associated
with any microscopic pathology changes.  These weight effects were
considered non-adverse and due to induction of liver metabolic enzymes. 
One male dog in the 40,000 ppm group demonstrated clinical signs,
clinical pathology, and anatomic pathology changes consistent with
canine juvenile polyarteritis syndrome, a naturally occurring vasculitis
and perivasculitis of unknown etiology (Snyder et. al. 1995); these
effects were not considered to be test substance related.

The no observed adverse effect level (NOAEL) was 40,000 ppm (1164 mg/kg
bw/day for males and 1233 mg/kg bw/day for females).  The NOAEL was
based on a lack of adverse effects in males or females at 40,000 ppm,
the highest concentration tested.

Combined chronic toxicity/oncogenicity study 2- year feeding study in
rats (MRID 46979719) and Eighteen month chronic feeding study in mice
(46979720)

DPX-E2Y45 was not carcinogenic in rats or mice.  The NOAEL for chronic
toxicity in rats was 20000 ppm (805/1076 mg/kg/day, M/F) and was based
on the absence of any treatment-related toxicity at any dietary
concentration evaluated in the study.  Mild increases in liver weight
occurred in the 4000 (156/212 mg/kg/day, M/F) and 20000 ppm female rats
at 1 year.  These changes were not associated with other changes
indicative of liver toxicity, but were consistent with the non-adverse
pharmacological response to metabolism that was observed in short-term
feeding studies with DPX-E2Y45.  A minimal to mild increase in the
degree of microvesiculation in the adrenal cortex was present in some
male rats at 1 and 2 years.  Based on mechanistic studies, this finding
was determined to have no toxicological impact on adrenal cortical cell
function and was not considered toxicologically relevant.

In mice, there were treatment-related effects in males at the highest
dose tested, but not females administered DPX-E2Y45 up to and including
a maximum dietary concentration of 7000 ppm (1155 mg/kg/day).  Increased
liver weights in males and females and small increases in the incidence
of hepatocellular hypertrophy in males were observed at the two highest
concentrations tested (158 mg/kg/day and 935 mg/kg/day).  The liver
changes at the mid dose (158 mg/kg/day) were consistent with the
non-adverse induction of liver enzymes observed in short-term feeding
studies with DPX-E2Y45.  However, the slight increase in the incidence
of eosinophilic foci (5/70) of cellular alteration in the livers of high
dose male mice was considered outside the historical control range
(0-1.92%) for this strain of mice and therefore, treatment related and
adverse.

The LOAEL in male mice is 935 mg/kg bw/day based on the slightly
increased, minimal eosinophilic foci of cellular alteration accompanied
by hepatocellular hypertrophy and increased liver weight in male mice. 
The NOAEL in male mice was taken as the next highest dose tested, 158
mg/kg bw/day.  The NOAEL for female mice was 1155 mg/kg bw/day due to
the lack of adverse treatment-related effects on any parameter at any
dietary level of DPX-E2Y45 evaluated.

The NOAEL in the 2-year rat study is 805 and 1076 mg/kg/day (M/F, HDT)
based on the lack of adverse treatment related findings.

Based on the results of chronic feeding studies in rats and mice,
DPX-E2Y45 is not carcinogenic at the durations and doses tested in these
animal toxicity studies.

Developmental Rat Study (MRID 46889108)

Developmental Rabbit Study (MRID 46889109)

In the rat developmental toxicity study, chlorantraniliprole was
administered by oral gavage to time mated Crl:CD(SD)IGS BR female rats
(22/dose group) on gestation days 6-20 at dose levels of 0, 20, 100, 300
or 1000 mg/kg/day (dose volume was 4 mL/kg); and in the rabbit
developmental toxicity study, chlorantraniliprole was administered by
oral gavage to time-mated Hra:(NZW)SPF female rabbits (22/dose group) on
gestation days 7-28 at dose levels of 0, 20, 100, 300, and 1000
mg/kg/day. No test substance related effects on maternal clinical
observations, body weight, weight gain, food consumption, or gross
post-mortem observations were detected at any dose.  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.  No test substance-related fetal external,
visceral, skeletal malformations, variations, and adverse effects on
fetal skeletal ossifications were observed at any dose.

Based on the absence of treatment related adverse effects the maternal
systemic toxicity and developmental toxicity NOAEL 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.  

Based on the absence of treatment related adverse effects, the parental
systemic toxicity, reproductive toxicity and offspring/developmental
toxicity NOAEL is ≥20,000 ppm (1199/1594 mg/kg/day (M/F) (above the
limit dose and HDTs).

28-day Immunotoxicity Studies in Rats and Mice (MRID 46979344 and MRID
46979343)

Exposure to DPX-E2Y45 produced no effects on thymus or spleen weights or
on the antibody response to sheep red blood cells in rat and mouse
28-day immunotoxicity studies.  No evidence of systemic toxicity was
noted during the studies.  The NOAELs in the studies were the highest
dietary concentrations evaluated, corresponding to 20000 ppm in rats and
7000 ppm in mice.  In addition, no indications of the potential of
DPX-E2Y45 to adversely affect the immune system were noted in 90-day and
chronic/oncogenicity studies conducted in rats, mice, or dogs.  Based on
these results, DPX-E2Y45 does not pose an immunotoxic hazard.  The NOAEL
is >1000 mg/kg/day (limit dose).

Acute Oral Neurotoxicity in Rats (46979312) and Subchronic Oral
Neurotoxicity in Rats (4697921)

No evidence of neurotoxicity was observed in studies conducted with
DPX-E2Y45 in rats.  The NOAEL in an acute, oral gavage neurotoxicity
study was 2000 mg/kg bw and was the highest dose administered in the
study.  In a subchronic neurotoxicity study, the NOAEL was 20000 ppm
(equivalent to 1313 and 1586 mg/kg bw/day in males and females,
respectively), the maximum dietary concentration administered.  The
NOAELs were based on the absence of treatment related effects on
systemic toxicity and neurotoxicity parameters, including microscopic
neuropathology.  Neurological assessments conducted in conjunction with
the 18-Month oncogenicity study in mice following 45, 60, and 90 days of
dietary administration of DPX-E2Y45 confirmed the lack of potential
neurotoxicity.  Further, no treatment related clinical signs indicative
of potential neurotoxicity were observed in short-term and long-term
exposure studies in rats, mice, or dogs.  Therefore, it is concluded
that DPX-E2Y45 is not a neurotoxicant.   The NOAEL is >1000 mg/kg/day
(limit dose).  

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

ions 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

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 of 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.

Appendix B:  Metabolism Assessment  TC \l1 "Appendix B:  Metabolism
Assessment 

B.1	Metabolism Guidance and Considerations TC \l2 "B.1	Metabolism
Guidance and Considerations 

Table B.2.  Tabular Summary of Metabolites and Degradates

Chemical
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 Major Residue (≥10%TRR)	Matrices – Minor Residue (<10%TRR)

	3-Bromo-N-[4-chloro-2-methyl-6-[(methylamino)

carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide
(Chlorantraniliprole, DPX-E2Y45)	Apple 	Fruit –  83.2-83.5

(0.077-0.089)

Leaves –  91.6-93.7

(3.803-3.180)

	Cotton	Foliage/hulls – 24.7-68.1 (<0.01-0.04)

Lint/seed – 56.9 (<0.01)

	Lettuce	Leaves –  88.7 (0.268)

	Rice 	Grain –  51.4 (0.08)

Hulls –  66.3 (0.117)

Leaves –  52.3 (2.118)

Sheaths –  64.9 (0.086)

Straw 1–  53.8 (0.486)

	Tomato 	Fruit –  92.2 (0.012)

Leaves – 98.1 (1.340)

	Rotational Crops	Lettuce – 63.9-85.2 (0.020-0.032)	Beet tops –
0.9-4.8 (<0.002-0.005)

	Radish tops – 53.8 (0.016)

Radish root – 68 (0.05)

Soybean fodder – 

45.4-63.6 (0.07-0.08)

Wheat forage – 53.5-84.1 (0.050-0.198)

Wheat hay – 50.6-73.1 (0.224-0.797)

Wheat grain – 85.9

(0.02)

Wheat straw – 36.6-73.2

(0.079-1.34)

Wheat chaff – 87.3 (0.39)

	Ruminant	Milk – 23.6 (0.016)	Liver – 0.72-4.45 (0.005-0.029)

	Kidney – 18.92 (0.016)

Muscle – 41.01 (0.007)

Fat – 34.72-75.29

 (0.024-0.051)

	Poultry	Egg yolk – 11.9-22.65 (0.059-0.106)	Liver – 2.21-3.75
(0.012-0.017)

	Egg white – 26.18-31.62 (0.355-0409)	Muscle – 3.54 (<0.001)

	Skin w/fat – 17.87 (0.009)

	Rat	38.6% of administered dose in repeated dosing rat metabolism study
at day 14

	2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-3,
8-dimethyl-4(3H)-quinazolinone (IN-EQW78)

	Rice

Grain – 1.3 (0.002)	

	Hulls – 3.2 (0.006)

Leaves – 4.2 (0.167)

Sheaths – 5.3 (0.007)

Straw 1 – 4.3 (0.039)

Rotational crops

Radish tops – 1.5

(<0.01)

Radish root – 1.4 (<0.01)

Soybean fodder – 

0.6-1 (<0.01)

Wheat forage – 

0.8-1.4 (0.001-0.002)

Wheat hay – 1.1-2.9 (0.005-0.022)

Wheat straw – 1-2.6 (0.005-0.054)

Ruminant	Fat – 6.35-10.99 

(0.004-0.007)	Liver – 6.2 (0.040)

Muscle – 2.0 (<0.001)

Poultry

Egg white – 3.25-6.4 (0.042-0.087)

Muscle – 6.79 (0.002)

Skin w/fat – 3.10 (0.002)

	 5-Bromo-N-methyl-1H-pyrazole-3-carboxamide

(IN-F6L99)

	Rice

Grain – 1.5 (0.002)	

	Leaves – 2.7 (0.107)

Sheaths – 1.2 (0.002)

Straw 1 – 2.5 (0.023)

Rotational crops	Beet tops – 0.2-10.8 (<0.001-0.013)	Lettuce – 1.4
(0.001)

Wheat hay – 0.2-2.4 (0.001-0.038)

Wheat straw – 0.5-2.6 (<0.002-0.013)

	
N-[2-(Aminocarbonyl)-4-chloro-6-methylphenyl]-3-bromo-1-(3-chloro-2-pyri
dinyl)1H-pyrazole-5-carboxamide

(IN-F9N04)

	Rice

Leaves – 3.2 (0.134)	

	Straw 1 – 2.8 (0.025)

Rotational crops

Lettuce – 1.6-5.2 (0.001-0.002)

Beet tops – 4.1-6.2 (0.003-0.007)

Radish tops – 1.1 (<0.01)

Radish root – 2.9 (<0.01)

Soybean fodder – 

1.8-2.0 (<0.01)

Wheat forage – 

1.4-3.2 (0.002-0.004)

Wheat hay – 0.8-2.1 (0.003-0.032)

Wheat straw – 1.2-2.0 (0.006-0.028)

Poultry

Egg white – 4.37-9.23 (0.055-0.119)

Liver – 1.17-5.37 (0.007-0.028)

Skin w/fat – 8.82 (0.005)

	
2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4
(3H)-quinazolinone

(IN-GAZ70)

	Rice

Leaves – 6.1 (0.244)	

	Straw 1 – 5.4 (0.049)

Rotational Crops

Lettuce – 0.8-1.9 (<0.001-0.001)

Beet tops – 1.6 (0.002)

Wheat hay – 0.4-2.5 (0.002-0.039)

Soybean fodder – 

3.0-6.4 (<0.01-0.01)

Ruminant

Liver – 3.12 (0.020)

Fat – 4.86 (0.002)

Poultry	Egg white – 32.57-40.44

(0.421-0.548)	Egg yolk – 4.25-6.57 (0.020-0.034)

Skin w/fat – 1.11 (0.001)

Rat	In the female rat, 1.41% of administered dose in repeated dosing rat
metabolism study at day 14

	 3-Bromo-N-[4-chloro-2-[[(hydroxymethyl)
amino]carbonyl]-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-c
arboxamide

(IN-H2H20)

	Rice

Leaves – 2.5 (0.101)	

	Straw 1 – 2.2 (0.02)

Rotational crops

Beet tops – 0.9-2.8 (0.001-0.002)

Wheat hay – 1.5 (0.009)

Wheat straw – 2-2.5 (0.007-0.009)

Ruminant

Kidney – 2.54 (0.002)

Liver – 0.65-1.21 (0.004-0.008)

Muscle – 5.8 (0.001)

Fat – 1.20 (<0.001)

Poultry	Egg yolk – 10.76-16.58 (0.054-0.078)	Egg white –3.49 (0.045)

Rat	In female rat feces, 15% of administered dose in repeated dosing rat
metabolism study at day 14

	(N-[2-Aminocarbonyl]-4-chloro-6-(hydroxymethyl)

phenyl]-3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

(IN-HXH40)	Rice

Leaves – 3.7 (0.153)	

	Straw 1 – 3.4 (0.031)

Rotational crops

Beet tops – 5.7-9.7 (0.004-0.012)

Wheat forage – ≤5.7 (≤0.005)

Wheat hay – 2.2 (0.009)

Wheat straw – 1.1-1.2 (0.004)

Ruminant

Milk – 5.9 (0.004)

Liver – 0.65-2.1 (0.004-0.014)

Fat – 1.18 (<0.001)

Poultry

Liver – 2.92-3.20 (0.015-0.016)

Muscle – 1.10 (<0.001)

Skin w/fat – 1.31

(0.001)

	3-Bromo-N-[4-chloro-2-(hydroxymethyl)-6-[(methylamino)

carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

(IN-HXH44)

Wheat forage – ≤5.7 (≤0.005)

Wheat hay – 0.5-3.1 (0.007-0.013)

Wheat straw – 0.7-2.6 (0.002-0.054)

Ruminant	Milk – 26.9 (0.018)	Kidney – 3.35 (0.003)

	Muscle – 10.98 (0.002)	Liver – 0.95-4.16 (0.006-0.026)

Fat – 1.40-1.75 (0.001-0.002)

Poultry

Egg yolk – 1.96 (0.011)

Egg white – 2.86 (0.037)

Liver – 1.65-2.03 (0.009-0.010)

Rat	10.04% of administered dose in repeated dosing rat metabolism study
at day 14

	2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-(hydrox
ymethyl)-4(3H)-quinazolinone

(IN-K7H29)	Rice

Grain – 1 (0.001)	

	Rotational crops

Wheat forage – 

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112)	Egg white – 3.13-3.52 (0.042-0.046)

Liver – 2.27 (0.011)

Muscle – 1.03 (<0.001)

Skin w/fat – 3.19 (0.002)

	3-Bromo-N-[4-chloro-2-(hydroxymethyl)-6-[[(hydroxymethyl)

amino)carbonyl]

phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

	Rat	11.28% of administered dose in repeated dosing rat metabolism study
at day 14

	2-[[[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]carbonyl]amino]-5
-chloro-3-[(methylamino

carbonyl]benzoic acid

	Straw 1 – 3.9 (0.035)

Rotational crops

Beet tops – 1-3.2 (0.001-0.004)

Wheat forage – 

0.1-2.1 (<0.001-0.002)

Wheat straw – 2.3 (0.048)

Ruminant

Liver – 0.64-2.6 (0.004-0.017)

Poultry

Egg yolk – 1.92 (0.009)

Rat	7.65% of administered dose in repeated dosing rat metabolism study
at day 14

	2-Amino-5-chloro-3-[(methylamino)

carbonyl]benzoic acid

(IN-L8F56)

	Poultry

Egg yolk – 3.68 (0.019)

Liver – 1.79-5.05 (0.009-0.026)

	Ruminant

Kidney – 5.24 (0.005)

Liver – 2.87 (0.018)

Fat – 1.16-6.94 (<0.001-0.005)

	Apple; 46889004; 0.268 lb ai/A (300 g ai/ha); 1.36x; 3 foliar apps. at
BBCH 71, 75, and 77; 30 days.

Cotton; 46979310; 0.134 lb ai/A (150 g ai/ha); 0.68x; 1 foliar app. with
0.5% surfactant to 41-day-old plants; 86 days (foliage, hulls, and
lint/seed), and 126 days (foliage/hulls, lint, and seed); or 1 foliar
app. without surfactant to 57-day-old plants; 48 days (foliage).

Lettuce; 46889005; 0.268 lb ai/A (300 g ai/ha); 1.37x; 3 foliar apps. at
BBCH 13, 19, and 19; 15 days.

Rice; 46979738; 0.268 lb ai/A (300 g ai/ha); 1 soil drench app. at BBCH
11-12; 132 days.

Tomato; 46889006; 0.268 lb ai/A (300 g ai/ha); 1.37x; 3 foliar apps. at
BBCH 19-61, 19-73, and 19-81; 15 days.

Rotational lettuce, beet, and wheat; 46895501; 0.268 lb ai/A (300 g
ai/ha); applied to bare soil; 0-, 30-, 120, and/or 365-day PBIs.

Rotational radish, soybean, and wheat; 46979311; 0.134 lb ai/A (150 g
ai/ha); applied to bare soil; 30-day PBI.

Goat; 46889116; 10 ppm; (5.6x for beef, 40x for dairy); orally for 7
days; 23-hour PSI. 

Hen; 46979424; 10 ppm; 91x; orally for 14 days; 23-hour PSI.

Environmental Fate and Effects

Laboratory Studies Summary

Hydrolysis

Chlorantraniliprole is stable to hydrolytic degradation in pH 5 and 7
buffer solutions.  It does, however, undergo rapid hydrolysis in pH 9
buffer solution.  The major hydrolysis degradation product is IN-EQW78. 

Photodegradation

Photodegradation of chlorantraniliprole is a predominant degradation
pathway.  Chlorantraniliprole has a half-life of 0.37 days in pH 7
buffer solution and 0.31 days in natural water irradiated with a Xenon
arc lamp.  In a water/sediment system, chlorantraniliprole had
photodegradation half-lives of 22 days in loamy sand sediment and 9.9
days in sandy loam sediment system.  The major photodegradation products
are IN-EQW78, IN-LBA22, IN-LBA24, and IN-LBA23.  A minor
photodegradation product was identified as IN-ECD73. 

Soil metabolism

Chlorantraniliprole is stable (t1/2 = 228 to 924 days) in aerobic soils
incubated at 250C.  It degrades faster at higher soil temperatures of
34-350C and 490C.  Major degradation products were identified as
IN-F6L99, IN-EVK64, IN-EQW78, IN-ECD73, IN-GAZ70.  Minor degradation
products were identified IF-F9N04 and IN-EVK64.  Chlorantraniliprole is
also persistent (t1/2= 231 and 125 days) under stratified redox test
conditions in a sand and loam sediment/water systems.   The major
degradation product was identified as IN-EQW78.  Minor degradations
products were identified as IN-F6L99, IN-F9N04, IN-GAZ70, and IN-ECD73.

Mobility

Chlorantraniliprole is expected to be mobile in soil and aquatic
environments.  It has soil: water Freundlich batch equilibrium
adsorption coefficients of 1.22 (Koc=153, 1/n=1.0028) in a loamy sand
from Spain, 9.16 (Koc=509, 1/n=1.0434) in a silty clay loam from IA, 
1.36 (Koc=272, 1/n=0.8485) in a sandy loam from MS, 1.59 (Koc= 526,
1/n=0.9370) in a loamy sand from GA, 2.34 (Koc=180, 1/n=0.9256) in a
loam from Italy.  Because there is a positive, linear regression between
Kd and soil organic carbon, it is appropriate to use Koc for
environmental fate modeling.

Field Studies Summary

Field studies support the findings in the laboratory.  Radiolabelled
chlorantraniliprole (applied at 0.286 lbs ai/A) had half-lives of 181 to
222 days for dissipation studies in California and Texas bareground
field dissipation studies. In the Texas study, degradation products
include IN-EQW78 (42% of applied @ Day 450), IN-GAZ70 (7% of applied
radioactivity), IN-ECD73 (9.5%@ Day 540), IN-F6L99 (5% @ Day 120). Most
of radioactivity was detected in the surface 0 to 6 inch soil layer.  In
the California study, degradation products include IN-EQW78 (29% of
applied @ Day 741), IN-ECD73 (6.8% of applied radioactivity@ Day 740),
IN-GAZ70 (5.9%@ Day 300), IN-F6L99 (2.1% @ Day 531).  The maximum depth
of radioactivity detection was 30-36 inches soil layer (2.7% of applied
radioactivity @ Day 379).

Nonradiolabelled chlorantraniliprole (formulated as 35WG at 0.286 lbs
ai/A) had half-lives of  210 days in a Minnesota study and 274 days in a
Prince Edward Island study.  In the Minnesota study, degradation
products included IN-EQW78 (3.8% of applied @ Day 0), IN-ECD73 (4.1%@
Day 0) and IN-GAZ70 (4.1% @Day 0).  Routes of dissipation for
chlorantraniliprole were identified as leaching (1% of applied @ 12 to
30 inches) and runoff (<6% of applied).  In the Prince Edward study,
IN-EQW78 (5.3% of applied @ Day 0), IN-ECD73 (1.3%@ Day 0) and IN-GAZ70
(0.4% @Day 0) were identified.  Chlorantraniliprole was detected (<0.5%
of applied) at soil depths greater than 30 cm.

Nonradiolabelled chlorantraniliprole (formulated as 20SC at 0.286 lbs
ai/A) on bareground plots had half-lives of  52 days in a California
study, 206 days in the a Texas study, 697 days in a New Jersey study,
and 1130 days in a Georgia study.  In the California study, degradation
products included IN-EQW78 (21% of applied @ Day 540) and IN-ECD73
(4.0%@ Day 540).  Chlorantraniliprole residues were detected at depth 18
inches (45 cm). In the Texas study, degradation products included
IN-EQW78 (20% of applied @ Day 540) and IN-ECD73 (2%@ Day 540). 
Chlorantraniliprole residues were detected at depths > 24 inches (<0.8%
of applied). In the New Jersey study, degradation products included
IN-EQW78 (9% of applied @ Day 475) and IN-ECD73 (4%@ Day 541). 
Chlorantraniliprole residues were detected at depths > 24 inches (1% of
applied).  In the Georgia study, degradation products included IN-EQW78
(12% of applied @ Day 540) and IN-ECD73 (6%@ Day 540). 
Chlorantraniliprole residues were detected at depths 12 to 18 inches
(~0.33 % of applied).

Appendix C:  Review of Human Research TC \l1 " Appendix C:  Review of
Human Research 

No studies were relied on which involved human subjects.

 The chronic Population Adjusted Dose (cPAD) is equivalent to the
chronic Reference Dose (cRfD) divided by the FQPA Safety Factor, which
in the case of chlorantraniliprole, is 1x.

 IN-HXH44 – in the single oral gavage rat metabolism study, only 2%
and 5% were excreted in the urine, female and male respectively; and in
3% and 7% in female and male feces, respectively.  In the repeat dose
rat metabolism study, the % excreted decreased over time.  This
particular metabolite is found mostly in dog plasma and evaluations of
the dog studies have indicated no toxicological effects associated with
short- or long-term exposures at doses that exceed the limit dose (1000
mkd)

IN-K9T00 – in the single oral gavage rat metabolism study, only 2% and
7% were excreted in the urine, female and male respectively; and in 5%
and 10% in female and male feces, respectively.  In the repeat dose rat
metabolism study, the % excreted decreased over time.  While this
metabolite is included in the rat metabolism cascade, it has not been
specifically identified in any one species tested.  Its structure is
similar to IN-H2H20 which is a single hydroxylated metabolite found only
in rat plasma.  The short-term and long-term rat studies have shown
liver induction effects, but no other frank toxicities, even at doses
that exceed the limit dose (1000 mkd)

Page   PAGE  57  of   NUMPAGES  68 

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