**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460

![](media/image1.wmf){width="0.85in" height="0.925in"}

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 3/7/2008

**[MEMORANDUM]{.underline}**

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 (DuPont^TM^ Rynaxypyr^TM^
Technical Insecticide) and two agricultural end-use products (DuPont^TM^
Coragen^TM^ SC Insecticide and DuPont^TM^ Altacor^TM^ 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 (DuPont^TM^ 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-chloro-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**

**1.0** **Executive Summary** [6](#__RefHeading___Toc192910386)

**2.0** **Ingredient Profile** [10](#__RefHeading___Toc192910387)

2.1 Summary of Proposed Uses [10](#__RefHeading___Toc192910388)

2.2 Structure and Nomenclature [15](#__RefHeading___Toc192910389)

2.3 Physical and Chemical Properties [15](#__RefHeading___Toc192910390)

**3.0** **Hazard Characterization/Assessment**
[16](#__RefHeading___Toc192910391)

3.1 Hazard and Dose-Response Characterization
[16](#__RefHeading___Toc192910392)

3.1.1 Toxicology Database Summary [16](#__RefHeading___Toc192910393)

3.1.1.2 Biochemical Mode of Action [17](#__RefHeading___Toc192910394)

3.1.2 Toxicological Effects [18](#__RefHeading___Toc192910395)

3.1.3 Dose-response [19](#__RefHeading___Toc192910396)

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)
[20](#__RefHeading___Toc192910397)

3.3 FQPA Considerations [22](#__RefHeading___Toc192910398)

3.3.1 Adequacy of the Toxicity Database
[22](#__RefHeading___Toc192910399)

3.3.2 Evidence of Neurotoxicity [22](#__RefHeading___Toc192910400)

3.3.3 Developmental Toxicity Studies [23](#__RefHeading___Toc192910401)

3.3.4 Reproductive Toxicity Study [23](#__RefHeading___Toc192910402)

3.3.5 Additional Information from Literature Sources
[24](#__RefHeading___Toc192910403)

3.3.6 Pre-and/or Postnatal Toxicity [24](#__RefHeading___Toc192910404)

3.3.6.1 Determination of Susceptibility
[24](#__RefHeading___Toc192910405)

3.4 Safety Factor for Infants and Children
[24](#__RefHeading___Toc192910406)

3.5 Hazard Identification and Toxicity Endpoint Selection
[25](#__RefHeading___Toc192910407)

3.5.1 Acute Dietary (All populations, including Females 13-49 years old)
[25](#__RefHeading___Toc192910408)

3.5.2 Chronic Dietary (All populations)
[25](#__RefHeading___Toc192910409)

3.5.3 Incidental Oral Exposure (Short- and intermediate-term)
[26](#__RefHeading___Toc192910410)

3.5.4 Dermal Exposure (Short- and intermediate-term)
[26](#__RefHeading___Toc192910411)

3.5.5 Inhalation Exposure (Short- and intermediate-term)
[26](#__RefHeading___Toc192910412)

3.5.6 Recommendation for Aggregate Exposure Risk Assessments
[26](#__RefHeading___Toc192910413)

3.5.7 Classification of Carcinogenic Potential
[26](#__RefHeading___Toc192910414)

3.5.8 Summary of Toxicological Doses and Endpoints for
Chlorantraniliprole for Use in Human Health Risk Assessment
[27](#__RefHeading___Toc192910415)

3.6 Endocrine Disruption [28](#__RefHeading___Toc192910416)

**4.0** **Public Health and Pesticide Epidemiology Data**
[28](#__RefHeading___Toc192910417)

**5.0** **Dietary Exposure/Risk Characterization**
[29](#__RefHeading___Toc192910418)

5.1 Pesticide Metabolism and Environmental Degradation
[29](#__RefHeading___Toc192910419)

5.1.1 Metabolism in Primary Crops [29](#__RefHeading___Toc192910420)

5.1.2 Metabolism in Rotational Crops [29](#__RefHeading___Toc192910421)

5.1.3 Metabolism in Livestock [30](#__RefHeading___Toc192910422)

5.1.4 Analytical Methodology [30](#__RefHeading___Toc192910423)

5.1.5 Environmental Degradation [31](#__RefHeading___Toc192910424)

5.1.6 Comparative Metabolic Profile [32](#__RefHeading___Toc192910425)

5.1.7 Toxicity Profile of Major Metabolites and Degradates
[33](#__RefHeading___Toc192910426)

5.1.8 Pesticide Metabolites and Degradates of Concern
[34](#__RefHeading___Toc192910427)

5.1.9 Drinking Water Residue Profile [36](#__RefHeading___Toc192910428)

5.1.10 Food Residue Profile [38](#__RefHeading___Toc192910429)

5.1.11 International Residue Limits [38](#__RefHeading___Toc192910430)

5.2 Dietary Exposure and Risk [38](#__RefHeading___Toc192910431)

5.2.1 Chronic Dietary Exposure/Risk [39](#__RefHeading___Toc192910432)

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information
[40](#__RefHeading___Toc192910433)

**6.0** **Residential (Non-Occupational) Exposure/Risk
Characterization** [40](#__RefHeading___Toc192910434)

**7.0** **Aggregate Risk Assessments and Risk Characterization**
[41](#__RefHeading___Toc192910435)

7.1 Long-Term Aggregate Risk [41](#__RefHeading___Toc192910436)

**8.0** **Cumulative Risk Characterization/Assessment**
[41](#__RefHeading___Toc192910437)

**9.0** **Occupational Exposure/Risk Pathway**
[42](#__RefHeading___Toc192910438)

**10.0** **Data Needs and Label Recommendations**
[43](#__RefHeading___Toc192910439)

10.1 Toxicology [43](#__RefHeading___Toc192910440)

10.2 Residue Chemistry [43](#__RefHeading___Toc192910441)

10.3 Occupational and Residential Exposure
[44](#__RefHeading___Toc192910442)

**References:** [45](#__RefHeading___Toc192910443)

**Appendix A: Toxicology Assessment** [46](#__RefHeading___Toc192910444)

A.1 Toxicology Data Requirements [46](#__RefHeading___Toc192910445)

A.2 Toxicity Profiles [47](#__RefHeading___Toc192910446)

A.3 Toxicity Summaries [49](#__RefHeading___Toc192910447)

**Appendix B: Metabolism Assessment** [60](#__RefHeading___Toc192910448)

B.1 Metabolism Guidance and Considerations
[60](#__RefHeading___Toc192910449)

**Appendix C: Review of Human Research**
[68](#__RefHeading___Toc192910450)

**1.0 Executive Summary**[]{#__RefHeading___Toc192910386 .anchor}

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 (Dupont^TM^ Coragen^TM^ SC Insecticide and
Dupont^TM^ Altacor^TM^ WG Insecticide) and 13 products for use on turf
and ornamentals (Dupont^TM^ 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 Dupont^TM^ 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-chloro-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). Dupont^TM^ 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*

Chlorantraniliprole/DPX-E2Y45 has no significant acute toxicity *via*
the oral, dermal, and inhalation routes of exposure. The LD~50~ for oral
and dermal acute exposure is ≥5000 mg/kg/day and the LC~50~ 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 LD~50~
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,"
<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**[]{#__RefHeading___Toc192910387 .anchor}

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**[]{#__RefHeading___Toc192910388 .anchor}

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
Dermacor^TM^ 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.

+------+-----+-------+-------+---------+---------+-------------------+
| Nu   |     |       |       |         |         |                   |
| mber |     |       |       |         |         |                   |
| r    |     |       |       |         |         |                   |
| ange |     |       |       |         |         |                   |
| CH   |     |       |       |         |         |                   |
| APTE |     |       |       |         |         |                   |
| R**T |     |       |       |         |         |                   |
| able |     |       |       |         |         |                   |
| 2    |     |       |       |         |         |                   |
| .1a. |     |       |       |         |         |                   |
| Chl  |     |       |       |         |         |                   |
| oran |     |       |       |         |         |                   |
| tran |     |       |       |         |         |                   |
| ilip |     |       |       |         |         |                   |
| role |     |       |       |         |         |                   |
| Prop |     |       |       |         |         |                   |
| osed |     |       |       |         |         |                   |
| End  |     |       |       |         |         |                   |
| -Use |     |       |       |         |         |                   |
| Pr   |     |       |       |         |         |                   |
| oduc |     |       |       |         |         |                   |
| ts** |     |       |       |         |         |                   |
+======+=====+=======+=======+=========+=========+===================+
| T    | EPA | ai (% | F     | Target  | Target  | Use Directions    |
| rade | R   | of    | ormul | Crops   | Pests   | and Limitations   |
| Name | eg. | fo    | ation |         |         |                   |
|      | No. | rmula | Type  |         |         |                   |
|      |     | tion) |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 18.4% | Suspe | *Br     | Broad   | Applications may  |
| Pont | 52- |       | nsion | assica* | s       | be conducted by   |
| ^TM^ | XXX | (     | c     | leafy   | pectrum | ground            |
| Cor  |     | 1.667 | oncen | vege    | s       | (chemigation,     |
| agen |     | lb    | trate | tables, | ystemic | groundboom,       |
| ^TM^ |     | ai/ga | (SC)  | C       | inse    | airblast) or      |
| SC   |     | llon) |       | ucurbit | cticide | aerial equipment. |
|      |     |       |       | vege    | (c      | All rotation      |
|      |     |       |       | tables, | ontrols | crops may be      |
|      |     |       |       | F       | many    | planted           |
|      |     |       |       | ruiting | im      | immediately       |
|      |     |       |       | vege    | portant | following the     |
|      |     |       |       | tables, | in      | last application. |
|      |     |       |       | Leafy   | sects); |                   |
|      |     |       |       | veg     | some    | REI 2 hours       |
|      |     |       |       | etables | contact |                   |
|      |     |       |       | (n      | a       |                   |
|      |     |       |       | on-*Bra | ctivity |                   |
|      |     |       |       | ssica*) |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 35%   | Water | Cotton, |         | Applications may  |
| Pont | 52- |       | d     | Grape,  |         | be conducted by   |
| ^TM^ | XXX |       | isper | Pome    |         | ground            |
| Alt  |     |       | sible | Fruits, |         | (groundboom,      |
| acor |     |       | gr    | Potato, |         | airblast) or      |
| ^TM^ |     |       | anule | Stone   |         | aerial equipment. |
| WG   |     |       | (WG)  | Fruits  |         | Do not apply      |
|      |     |       |       |         |         | ALTACOR^TM^       |
|      |     |       |       |         |         | through any type  |
|      |     |       |       |         |         | of irrigation     |
|      |     |       |       |         |         | system. All       |
|      |     |       |       |         |         | rotation crops    |
|      |     |       |       |         |         | may be planted    |
|      |     |       |       |         |         | immediately       |
|      |     |       |       |         |         | following the     |
|      |     |       |       |         |         | last application. |
|      |     |       |       |         |         |                   |
|      |     |       |       |         |         | REI 2 hours       |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 50%   | SC    | Rice    | For     | For use in        |
| Pont | 52- |       |       | seeds   | control | drill-seed rice   |
| ^TM^ |     |       |       |         | of rice | fields (not for   |
| Derm | XXX |       |       |         | water   | use in            |
| acor |     |       |       |         | weevil, | water-seeded rice |
| ^TM^ |     |       |       |         | *Lissor | fields)           |
| X    |     |       |       |         | hoptrus |                   |
| -100 |     |       |       |         | oryzo   |                   |
| Seed |     |       |       |         | philus* |                   |
| T    |     |       |       |         |         |                   |
| reat |     |       |       |         |         |                   |
| ment |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 18.4% | SC    | Turf,   | For     | For use by        |
| Pont | 52- |       |       | Orn     | control | commercial        |
| ^TM^ | XXX | (1.67 |       | amental | of      | applicators only. |
| E    |     | lb    |       | plants  | white   |                   |
| 2Y45 |     | ai/ga |       |         | grubs   | Do not apply      |
| SC   |     | llon) |       |         | and     | through any type  |
| Ins  |     |       |       |         | other   | of irrigation     |
| ecti |     |       |       |         | pests   | system, nor with  |
| cide |     |       |       |         | in      | aerial equipment. |
|      |     |       |       |         | festing |                   |
|      |     |       |       |         | la      | Do not apply in   |
|      |     |       |       |         | ndscape | commercial        |
|      |     |       |       |         | and     | nurseries and     |
|      |     |       |       |         | recre   | greenhouses.      |
|      |     |       |       |         | ational |                   |
|      |     |       |       |         | tu      | Do not apply more |
|      |     |       |       |         | rfgrass | than 38.3 fluid   |
|      |     |       |       |         | (in     | ounces (0.5 lb    |
|      |     |       |       |         | cluding | ai) of product    |
|      |     |       |       |         | golf    | per acre per year |
|      |     |       |       |         | courses | in broadcast      |
|      |     |       |       |         | and sod | applications to   |
|      |     |       |       |         | farms)  | turfgrass.        |
|      |     |       |       |         | as well |                   |
|      |     |       |       |         | as      | Minimum           |
|      |     |       |       |         | caterp  | retreatment       |
|      |     |       |       |         | illars, | interval -- 7     |
|      |     |       |       |         | cl      | days.             |
|      |     |       |       |         | earwing |                   |
|      |     |       |       |         | borers  | REI 2 hours       |
|      |     |       |       |         | and     |                   |
|      |     |       |       |         | other   |                   |
|      |     |       |       |         | pests   |                   |
|      |     |       |       |         | of      |                   |
|      |     |       |       |         | la      |                   |
|      |     |       |       |         | ndscape |                   |
|      |     |       |       |         | orna    |                   |
|      |     |       |       |         | mentals |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0.33% | Gra   | Turf,   | For     | For use by        |
| Pont | 52- |       | nular | Orn     | s       | commercial        |
| ^TM^ | XXX |       | (G)   | amental | ystemic | applicators only  |
| E    |     |       |       | plants  | control |                   |
| 2Y45 |     |       |       |         | of      | Apply via         |
| 0    |     |       |       |         | white   | drop-type,        |
| .33G |     |       |       |         | grubs   | rotary-type or    |
| Ins  |     |       |       |         | and     | hand-held         |
| ecti |     |       |       |         | other   | equipment         |
| cide |     |       |       |         | pests   |                   |
| (I)  |     |       |       |         | in      | Apply up 0.5 lb   |
|      |     |       |       |         | festing | ai/A/yr to        |
|      |     |       |       |         | la      | turfgrass.        |
|      |     |       |       |         | ndscape |                   |
|      |     |       |       |         | and     | Do not apply more |
|      |     |       |       |         | recre   | than 0.2 lb ai/A  |
|      |     |       |       |         | ational | in a single       |
|      |     |       |       |         | tu      | application on    |
|      |     |       |       |         | rfgrass | sod farms         |
|      |     |       |       |         | (in     |                   |
|      |     |       |       |         | cluding | Do not apply via  |
|      |     |       |       |         | golf    | air               |
|      |     |       |       |         | courses |                   |
|      |     |       |       |         | as well | Do not use in     |
|      |     |       |       |         | as      | commercial        |
|      |     |       |       |         | la      | nurseries and     |
|      |     |       |       |         | ndscape | greenhouses       |
|      |     |       |       |         | ornam   |                   |
|      |     |       |       |         | entals, | Not for use on    |
|      |     |       |       |         | i       | plants being      |
|      |     |       |       |         | nterior | grown for sale or |
|      |     |       |       |         | plan    | other commercial  |
|      |     |       |       |         | tscapes | use, or for       |
|      |     |       |       |         | and sod | commercial seed   |
|      |     |       |       |         | farms   | production        |
|      |     |       |       |         |         |                   |
|      |     |       |       |         |         | Minimum           |
|      |     |       |       |         |         | retreatment       |
|      |     |       |       |         |         | interval -- 7     |
|      |     |       |       |         |         | days              |
|      |     |       |       |         |         |                   |
|      |     |       |       |         |         | REI 2 hours       |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0.25% |       |         |         |                   |
| Pont | 52- |       |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0    |     |       |       |         |         |                   |
| .25G |     |       |       |         |         |                   |
| I    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0     |       |         |         |                   |
| Pont | 52- | .167% |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0.   |     |       |       |         |         |                   |
| 167G |     |       |       |         |         |                   |
| I    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0.16% |       |         |         |                   |
| Pont | 52- |       |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0    |     |       |       |         |         |                   |
| .16G |     |       |       |         |         |                   |
| I    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0     |       |         |         |                   |
| Pont | 52- | .133% |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0.   |     |       |       |         |         |                   |
| 133G |     |       |       |         |         |                   |
| I +  |     |       |       |         |         |                   |
| Fe   |     |       |       |         |         |                   |
| rtil |     |       |       |         |         |                   |
| izer |     |       |       |         |         |                   |
| (F)  |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0     |       |         |         |                   |
| Pont | 52- | .125% |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0.   |     |       |       |         |         |                   |
| 125G |     |       |       |         |         |                   |
| I    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0.12% |       |         |         |                   |
| Pont | 52- |       |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0    |     |       |       |         |         |                   |
| .12G |     |       |       |         |         |                   |
| I    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0.1%  |       |         |         |                   |
| Pont | 52- |       |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0.1G |     |       |       |         |         |                   |
| I +  |     |       |       |         |         |                   |
| F    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0     |       |         |         |                   |
| Pont | 52- | .067% |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0.   |     |       |       |         |         |                   |
| 067G |     |       |       |         |         |                   |
| I +  |     |       |       |         |         |                   |
| F    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0.08% |       |         |         |                   |
| Pont | 52- |       |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0    |     |       |       |         |         |                   |
| .08G |     |       |       |         |         |                   |
| I    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0.05% |       |         |         |                   |
| Pont | 52- |       |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0    |     |       |       |         |         |                   |
| .05G |     |       |       |         |         |                   |
| I +  |     |       |       |         |         |                   |
| F    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+
| Du   | 3   | 0.05% |       |         |         |                   |
| Pont | 52- |       |       |         |         |                   |
| ^TM^ | XXX |       |       |         |         |                   |
| E    |     |       |       |         |         |                   |
| 2Y45 |     |       |       |         |         |                   |
| 0    |     |       |       |         |         |                   |
| .05G |     |       |       |         |         |                   |
| I    |     |       |       |         |         |                   |
+------+-----+-------+-------+---------+---------+-------------------+

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      |        |      |       |         |    |                   |
| Dir     |        |      |       |         |    |                   |
| ections |        |      |       |         |    |                   |
| for Use |        |      |       |         |    |                   |
| of      |        |      |       |         |    |                   |
| C       |        |      |       |         |    |                   |
| hlorant |        |      |       |         |    |                   |
| ranilip |        |      |       |         |    |                   |
| role.** |        |      |       |         |    |                   |
+=========+========+======+=======+=========+====+===================+
| **      | **F    | *    | *     | **Max.  | *  | **Use Directions  |
| Applic. | ormula | *App | *Max. | S       | *P | and Limitations** |
| Timing, | tion** | lic. | No.   | easonal | HI |                   |
| Type,   |        | Ra   | Ap    | Applic. | ** |                   |
| and     |        | te** | plic. | Rate**  |    |                   |
| E       |        |      | per   |         | ** |                   |
| quip.** |        | *    | Sea   | **(lb   | (d |                   |
|         |        | *(lb | son** | ai/A)** | ay |                   |
|         |        | ai/  |       |         | s) |                   |
|         |        | A)** |       | **\[g   | ** |                   |
|         |        |      |       | ai      |    |                   |
|         |        |      |       | /ha\]** |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **C     |        |      |       |         |    |                   |
| otton** |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 35% WG | 0.0  | Not   | 0.2     | 21 | Minimum spray     |
| ergence |        | 44-0 | speci |         |    | volumes are 5     |
|         |        | .099 | fied\ | \[221\] |    | gal/A (ground) or |
| Br      |        |      | *\*\* |         |    | 5 gal/A (aerial); |
| oadcast |        |      |       |         |    | 5-day minimum RTI |
| by      |        |      |       |         |    |                   |
| ground  |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| ***Br   |        |      |       |         |    |                   |
| assica* |        |      |       |         |    |                   |
| Veget   |        |      |       |         |    |                   |
| ables** |        |      |       |         |    |                   |
|         |        |      |       |         |    |                   |
| \[Br    |        |      |       |         |    |                   |
| occoli, |        |      |       |         |    |                   |
| B       |        |      |       |         |    |                   |
| roccoli |        |      |       |         |    |                   |
| (Ch     |        |      |       |         |    |                   |
| inese), |        |      |       |         |    |                   |
| B       |        |      |       |         |    |                   |
| roccoli |        |      |       |         |    |                   |
| Raab,   |        |      |       |         |    |                   |
| B       |        |      |       |         |    |                   |
| russels |        |      |       |         |    |                   |
| S       |        |      |       |         |    |                   |
| prouts, |        |      |       |         |    |                   |
| C       |        |      |       |         |    |                   |
| abbage, |        |      |       |         |    |                   |
| Cabbage |        |      |       |         |    |                   |
| (C      |        |      |       |         |    |                   |
| hinese, |        |      |       |         |    |                   |
| Bok     |        |      |       |         |    |                   |
| Choy),  |        |      |       |         |    |                   |
| Cabbage |        |      |       |         |    |                   |
| (C      |        |      |       |         |    |                   |
| hinese, |        |      |       |         |    |                   |
| Napa),  |        |      |       |         |    |                   |
| Cabbage |        |      |       |         |    |                   |
| (       |        |      |       |         |    |                   |
| Chinese |        |      |       |         |    |                   |
| M       |        |      |       |         |    |                   |
| ustard, |        |      |       |         |    |                   |
| Choy),  |        |      |       |         |    |                   |
| Cauli   |        |      |       |         |    |                   |
| flower, |        |      |       |         |    |                   |
| Cavalo  |        |      |       |         |    |                   |
| Br      |        |      |       |         |    |                   |
| occolo, |        |      |       |         |    |                   |
| Co      |        |      |       |         |    |                   |
| llards, |        |      |       |         |    |                   |
| Kale,   |        |      |       |         |    |                   |
| Ko      |        |      |       |         |    |                   |
| hlrabi, |        |      |       |         |    |                   |
| Mizuna, |        |      |       |         |    |                   |
| Mustard |        |      |       |         |    |                   |
| Greens, |        |      |       |         |    |                   |
| Mustard |        |      |       |         |    |                   |
| S       |        |      |       |         |    |                   |
| pinach, |        |      |       |         |    |                   |
| and     |        |      |       |         |    |                   |
| Rape    |        |      |       |         |    |                   |
| G       |        |      |       |         |    |                   |
| reens\] |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 1.67   | 0    | 6     | 0.2     | 3  | Minimum spray     |
| ergence | lb     | .026 |       |         |    | volumes are 10    |
|         | ai/gal | 1-0. |       | \[219\] |    | gal/A (ground) or |
| Br      |        | 0976 |       |         |    | 5 gal/A (aerial); |
| oadcast | SC     |      |       |         |    | 3-day minimum RTI |
| by      |        |      |       |         |    | for foliar and    |
| ground, |        |      |       |         |    | 10-day RTI for    |
| drip    |        |      |       |         |    | drip chemigation. |
| chemi   |        |      |       |         |    |                   |
| gation, |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **C     |        |      |       |         |    |                   |
| ucurbit |        |      |       |         |    |                   |
| Veget   |        |      |       |         |    |                   |
| ables** |        |      |       |         |    |                   |
|         |        |      |       |         |    |                   |
| \[      |        |      |       |         |    |                   |
| Chayote |        |      |       |         |    |                   |
| (       |        |      |       |         |    |                   |
| Fruit), |        |      |       |         |    |                   |
| Chinese |        |      |       |         |    |                   |
| Wa      |        |      |       |         |    |                   |
| xgourd, |        |      |       |         |    |                   |
| Citron  |        |      |       |         |    |                   |
| Melon,  |        |      |       |         |    |                   |
| Cu      |        |      |       |         |    |                   |
| cumber, |        |      |       |         |    |                   |
| G       |        |      |       |         |    |                   |
| herkin, |        |      |       |         |    |                   |
| Gourd   |        |      |       |         |    |                   |
| Edible  |        |      |       |         |    |                   |
| (i      |        |      |       |         |    |                   |
| ncludes |        |      |       |         |    |                   |
| Hyotan, |        |      |       |         |    |                   |
| C       |        |      |       |         |    |                   |
| ucuzza, |        |      |       |         |    |                   |
| H       |        |      |       |         |    |                   |
| echima, |        |      |       |         |    |                   |
| Chinese |        |      |       |         |    |                   |
| Okra),  |        |      |       |         |    |                   |
| Mom     |        |      |       |         |    |                   |
| ordica, |        |      |       |         |    |                   |
| Mus     |        |      |       |         |    |                   |
| kmelon, |        |      |       |         |    |                   |
| P       |        |      |       |         |    |                   |
| umpkin, |        |      |       |         |    |                   |
| Squash, |        |      |       |         |    |                   |
| and     |        |      |       |         |    |                   |
| Water   |        |      |       |         |    |                   |
| melon\] |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 1.67   | 0    | Not   | 0.2     | 1  | Minimum spray     |
| ergence | lb     | .026 | speci |         |    | volumes are 10    |
|         | ai/gal | 1-0. | fied\ | \[219\] |    | gal/A (ground) or |
| Br      | SC     | 0976 | *\*\* |         |    | 5 gal/A (aerial); |
| oadcast |        |      |       |         |    | 5-day minimum RTI |
| by      |        |      |       |         |    | for foliar and    |
| ground, |        |      |       |         |    | 10-day RTI for    |
| drip    |        |      |       |         |    | drip chemigation  |
| chemi   |        |      |       |         |    |                   |
| gation, |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **F     |        |      |       |         |    |                   |
| ruiting |        |      |       |         |    |                   |
| Veget   |        |      |       |         |    |                   |
| ables** |        |      |       |         |    |                   |
|         |        |      |       |         |    |                   |
| \[Eg    |        |      |       |         |    |                   |
| gplant, |        |      |       |         |    |                   |
| Ground  |        |      |       |         |    |                   |
| cherry, |        |      |       |         |    |                   |
| Pepino, |        |      |       |         |    |                   |
| Pepper  |        |      |       |         |    |                   |
| (I      |        |      |       |         |    |                   |
| ncludes |        |      |       |         |    |                   |
| Bell    |        |      |       |         |    |                   |
| Pepper, |        |      |       |         |    |                   |
| Chili   |        |      |       |         |    |                   |
| Pepper, |        |      |       |         |    |                   |
| Cooking |        |      |       |         |    |                   |
| Pepper, |        |      |       |         |    |                   |
| P       |        |      |       |         |    |                   |
| imento, |        |      |       |         |    |                   |
| Sweet   |        |      |       |         |    |                   |
| P       |        |      |       |         |    |                   |
| epper), |        |      |       |         |    |                   |
| Tom     |        |      |       |         |    |                   |
| atillo, |        |      |       |         |    |                   |
| and     |        |      |       |         |    |                   |
| T       |        |      |       |         |    |                   |
| omato\] |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 1.67   | 0    | Not   | 0.2     | 1  | Minimum spray     |
| ergence | lb     | .026 | speci |         |    | volumes are 10    |
|         | ai/gal | 1-0. | fied\ | \[219\] |    | gal/A (ground) or |
| Br      | SC     | 0976 | *\*\* |         |    | 5 gal/A (aerial); |
| oadcast |        |      |       |         |    | 5-day minimum RTI |
| by      |        |      |       |         |    | for foliar and    |
| ground, |        |      |       |         |    | 10-day RTI for    |
| drip    |        |      |       |         |    | drip chemigation  |
| chemi   |        |      |       |         |    |                   |
| gation, |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **G     |        |      |       |         |    |                   |
| rapes** |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 35% WG | 0.0  | Not   | 0.2     | 14 | Minimum spray     |
| ergence |        | 44-0 | speci |         |    | volumes are 50    |
|         |        | .099 | fied\ | \[221\] |    | gal/A (ground) or |
| Br      |        |      | *\*\* |         |    | 10 gal/A          |
| oadcast |        |      |       |         |    | (aerial); 7-day   |
| by      |        |      |       |         |    | minimum RTI       |
| ground  |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **Leafy |        |      |       |         |    |                   |
| Veg     |        |      |       |         |    |                   |
| etables |        |      |       |         |    |                   |
| (Non    |        |      |       |         |    |                   |
| -*Brass |        |      |       |         |    |                   |
| ica*)** |        |      |       |         |    |                   |
|         |        |      |       |         |    |                   |
| \[A     |        |      |       |         |    |                   |
| maranth |        |      |       |         |    |                   |
| (       |        |      |       |         |    |                   |
| Leafy), |        |      |       |         |    |                   |
| A       |        |      |       |         |    |                   |
| rugula, |        |      |       |         |    |                   |
| C       |        |      |       |         |    |                   |
| ardoon, |        |      |       |         |    |                   |
| Celery, |        |      |       |         |    |                   |
| Celery  |        |      |       |         |    |                   |
| (Ch     |        |      |       |         |    |                   |
| inese), |        |      |       |         |    |                   |
| C       |        |      |       |         |    |                   |
| eltuse, |        |      |       |         |    |                   |
| C       |        |      |       |         |    |                   |
| hevril, |        |      |       |         |    |                   |
| Chrysa  |        |      |       |         |    |                   |
| nthemum |        |      |       |         |    |                   |
| (Edible |        |      |       |         |    |                   |
| L       |        |      |       |         |    |                   |
| eaved), |        |      |       |         |    |                   |
| Chrysa  |        |      |       |         |    |                   |
| nthemum |        |      |       |         |    |                   |
| (G      |        |      |       |         |    |                   |
| arland, |        |      |       |         |    |                   |
| Corn    |        |      |       |         |    |                   |
| Salad,  |        |      |       |         |    |                   |
| Cress   |        |      |       |         |    |                   |
| (Ga     |        |      |       |         |    |                   |
| rland), |        |      |       |         |    |                   |
| Cress   |        |      |       |         |    |                   |
| (U      |        |      |       |         |    |                   |
| pland), |        |      |       |         |    |                   |
| Da      |        |      |       |         |    |                   |
| ndelion |        |      |       |         |    |                   |
| Leaves, |        |      |       |         |    |                   |
| Dock,   |        |      |       |         |    |                   |
| Endive, |        |      |       |         |    |                   |
| F       |        |      |       |         |    |                   |
| lorence |        |      |       |         |    |                   |
| Fennel, |        |      |       |         |    |                   |
| Lettuce |        |      |       |         |    |                   |
| (Head & |        |      |       |         |    |                   |
| Leaf),  |        |      |       |         |    |                   |
| Orach,  |        |      |       |         |    |                   |
| Parsley |        |      |       |         |    |                   |
| Leaves, |        |      |       |         |    |                   |
| P       |        |      |       |         |    |                   |
| urslane |        |      |       |         |    |                   |
| (G      |        |      |       |         |    |                   |
| arden), |        |      |       |         |    |                   |
| P       |        |      |       |         |    |                   |
| urslane |        |      |       |         |    |                   |
| (W      |        |      |       |         |    |                   |
| inter), |        |      |       |         |    |                   |
| Rad     |        |      |       |         |    |                   |
| icchio, |        |      |       |         |    |                   |
| R       |        |      |       |         |    |                   |
| hubarb, |        |      |       |         |    |                   |
| S       |        |      |       |         |    |                   |
| pinach, |        |      |       |         |    |                   |
| Spinach |        |      |       |         |    |                   |
| (Vine), |        |      |       |         |    |                   |
| Spinach |        |      |       |         |    |                   |
| (New    |        |      |       |         |    |                   |
| Z       |        |      |       |         |    |                   |
| ealand, |        |      |       |         |    |                   |
| and     |        |      |       |         |    |                   |
| Swiss   |        |      |       |         |    |                   |
| Chard\] |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 1.67   | 0    | 6     | 0.2     | 1  | Minimum spray     |
| ergence | lb     | .026 |       |         |    | volumes are 10    |
|         | ai/gal | 1-0. |       | \[219\] |    | gal/A (ground) or |
| Br      | SC     | 0976 |       |         |    | 5 gal/A (aerial); |
| oadcast |        |      |       |         |    | 3-day minimum RTI |
| by      |        |      |       |         |    | for foliar and    |
| ground, |        |      |       |         |    | 10-day RTI for    |
| drip    |        |      |       |         |    | drip chemigation  |
| chemi   |        |      |       |         |    |                   |
| gation, |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **Pome  |        |      |       |         |    |                   |
| F       |        |      |       |         |    |                   |
| ruits** |        |      |       |         |    |                   |
|         |        |      |       |         |    |                   |
| \       |        |      |       |         |    |                   |
| [Apple, |        |      |       |         |    |                   |
| Cra     |        |      |       |         |    |                   |
| bapple, |        |      |       |         |    |                   |
| Loquat, |        |      |       |         |    |                   |
| Mayhaw, |        |      |       |         |    |                   |
| Pear,   |        |      |       |         |    |                   |
| Pear    |        |      |       |         |    |                   |
| (Ori    |        |      |       |         |    |                   |
| ental), |        |      |       |         |    |                   |
| and     |        |      |       |         |    |                   |
| Q       |        |      |       |         |    |                   |
| uince\] |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 35% WG | 0.0  | 4     | 0.2     | 21 | Minimum spray     |
| ergence |        | 44-0 |       |         | \* | volumes are 50    |
|         |        | .099 |       | \[221\] |    | gal/A (ground) or |
| Br      |        |      |       |         |    | 10 gal/A          |
| oadcast |        |      |       |         |    | (aerial); 10-day  |
| by      |        |      |       |         |    | minimum RTI.      |
| ground  |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **P     |        |      |       |         |    |                   |
| otato** |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 35% WG | 0.0  | Not   | 0.2     | 14 | Minimum spray     |
| ergence |        | 44-0 | speci |         |    | volumes are 10    |
|         |        | .066 | fied\ | \[222\] |    | gal/A (ground) or |
| Br      |        |      | *\*\* |         |    | 5 gal/A (aerial); |
| oadcast |        |      |       |         |    | 5-day minimum     |
| by      |        |      |       |         |    | RTI.              |
| ground  |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **Stone |        |      |       |         |    |                   |
| F       |        |      |       |         |    |                   |
| ruits** |        |      |       |         |    |                   |
|         |        |      |       |         |    |                   |
| \[A     |        |      |       |         |    |                   |
| pricot, |        |      |       |         |    |                   |
| Cherry  |        |      |       |         |    |                   |
| (       |        |      |       |         |    |                   |
| Sweet), |        |      |       |         |    |                   |
| Cherry  |        |      |       |         |    |                   |
| (       |        |      |       |         |    |                   |
| Tart),  |        |      |       |         |    |                   |
| Nec     |        |      |       |         |    |                   |
| tarine, |        |      |       |         |    |                   |
| Peach,  |        |      |       |         |    |                   |
| Plum,   |        |      |       |         |    |                   |
| Plum    |        |      |       |         |    |                   |
| (Ch     |        |      |       |         |    |                   |
| icksaw, |        |      |       |         |    |                   |
| Damson, |        |      |       |         |    |                   |
| Jap     |        |      |       |         |    |                   |
| anese), |        |      |       |         |    |                   |
| P       |        |      |       |         |    |                   |
| lumcot, |        |      |       |         |    |                   |
| and     |        |      |       |         |    |                   |
| Prune\] |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| Postem  | 35% WG | 0.0  | 4     | 0.2     | 10 | Minimum spray     |
| ergence |        | 44-0 |       |         |    | volumes are 50    |
|         |        | .099 |       | \[221\] |    | gal/A (ground) or |
| Br      |        |      |       |         |    | 10 gal/A          |
| oadcast |        |      |       |         |    | (aerial); 7-day   |
| by      |        |      |       |         |    | minimum RTI       |
| ground  |        |      |       |         |    |                   |
| or air  |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| **      |        |      |       |         |    |                   |
| Section |        |      |       |         |    |                   |
| 18      |        |      |       |         |    |                   |
| /Rice** |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| At      | De     | 2.5  | 1     | 0.13    | NA | Treated seed must |
| s       | rmacor | -5.0 |       |         |    | not be used for   |
| eeding: | X-100  | fl   |       | (based  |    | or mixed with     |
| drill   |        | oz   |       | on      |    | food or animal    |
| -seeded | 50% SC | per  |       | label,  |    | feed, or          |
|         |        | 100  |       | which   |    | processed for     |
|         |        | lbs  |       | p       |    | oil. All rotation |
|         |        | seed |       | rovides |    | crops may be      |
|         |        | (0.  |       | seed    |    | planted           |
|         |        | 098- |       | trea    |    | immediately       |
|         |        | 0.20 |       | tment + |    | following last    |
|         |        | lb   |       | seeding |    | application.      |
|         |        | ai   |       | rates)  |    | Treated seed not  |
|         |        | /100 |       |         |    | to exceed 120     |
|         |        | lbs  |       |         |    | lb/A seeding      |
|         |        | s    |       |         |    | rate.             |
|         |        | eed) |       |         |    |                   |
|         |        | \*\* |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| *       |        |      |       |         |    |                   |
| *Turf** |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| G       | DuPo   | 0    | Not   | 0.5     | N  | For use by        |
| formul  | nt^TM^ | .06- | speci |         | /A | commercial        |
| ations: | E2Y45  | 0.33 | fied\ |         |    | applicators only. |
| dro     | G      |      | *\*\* |         |    | No aerial, no     |
| p-type, | (0.05- |      |       |         |    | chemigation       |
| rota    | 0.33%) |      |       |         |    | application       |
| ry-type |        |      |       |         |    |                   |
| or      |        |      |       |         |    |                   |
| ha      |        |      |       |         |    |                   |
| nd-held |        |      |       |         |    |                   |
| eq      |        |      |       |         |    |                   |
| uipment |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| SC      | DuPo   | 0.0  | Not   | 0.5     | N  | For use by        |
| formu   | nt^TM^ | 13-0 | speci |         | /A | commercial        |
| lation: | E2Y45  | .313 | fied\ | (38.3   |    | applicators only. |
| br      | SC     |      | *\*\* | fl      |    | No aerial, no     |
| oadcast | Insec  | (1   |       | oz./A)  |    | chemigation       |
| appl    | ticide | to   |       |         |    | application.      |
| ication |        | 24   |       |         |    |                   |
| eq      |        | fl   |       |         |    |                   |
| uipment |        | o    |       |         |    |                   |
|         |        | z/A) |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| *       |        |      |       |         |    |                   |
| *Orname |        |      |       |         |    |                   |
| ntals** |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+
| G       | DuPo   | Hi   | Not   | 0.33    | N  | For use by        |
| formu   | nt^TM^ | ghly | speci |         | /A | commercial        |
| lations | E2Y45  | vari | fied\ |         |    | applicators only. |
|         | G      | able | *\*\* |         |    | No aerial, no     |
|         | (0.05- |      |       |         |    | chemigation       |
|         | 0.33%) |      |       |         |    | application.      |
+---------+--------+------+-------+---------+----+-------------------+
| SC      | DuPo   | Hi   | Not   | 0.5     | N  | For use by        |
| formu   | nt^TM^ | ghly | speci |         | /A | commercial        |
| lation: | E2Y45  | vari | fied\ | (38.3   |    | applicators only. |
| br      | SC     | able | *\*\* | fl      |    | No aerial, no     |
| oadcast | Insec  |      |       | oz./A)  |    | chemigation       |
| appli   | ticide |      |       |         |    | application.      |
| cation; |        |      |       |         |    |                   |
| soil    |        |      |       |         |    |                   |
| inj     |        |      |       |         |    |                   |
| ection, |        |      |       |         |    |                   |
| d       |        |      |       |         |    |                   |
| renches |        |      |       |         |    |                   |
+---------+--------+------+-------+---------+----+-------------------+

\*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**[]{#__RefHeading___Toc192910389
.anchor}

[]{.mark}

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.      |                                                  |
| Ch                |                                                  |
| lorantraniliprole |                                                  |
| Nomenclature**.   |                                                  |
+===================+==================================================+
| Chemical          | !                                                |
| structure         | [](media/image2.wmf){width="1.320138888888889in" |
|                   | height="1.43125in"}                              |
+-------------------+--------------------------------------------------+
| Common name       | Chlorantraniliprole                              |
+-------------------+--------------------------------------------------+
| Company           | DPX-E2Y45                                        |
| experimental name |                                                  |
+-------------------+--------------------------------------------------+
| IUPAC name        | 3-Bromo-*N*-\[4-chloro-2-m                       |
|                   | ethyl-6-(methylcarbamoyl)phenyl\]-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-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide |
+-------------------+--------------------------------------------------+
| CAS registry      | 500008-45-7                                      |
| number            |                                                  |
+-------------------+--------------------------------------------------+
| End-use product   | Coragen^TM^ SC (18.4% ai, 1.67 lb/gal; EPA Reg.  |
| (EP)              | No. 352-XXX)                                     |
|                   |                                                  |
|                   | Altacor^TM^ WG (35% ai; EPA Reg. No. 352-XXX)    |
|                   |                                                  |
|                   | DuPont^TM^ E2Y45 SC Insecticide (18.4% ai, 1.67  |
|                   | lb/gal; EPA Reg. No. 352-XXX)                    |
|                   |                                                  |
|                   | DuPont^TM^ 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**[]{#__RefHeading___Toc192910390
.anchor}

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                |                               |                 |
| Chlor             |                               |                 |
| antraniliprole.** |                               |                 |
+===================+===============================+=================+
| Parameter         | Value                         | Reference       |
+-------------------+-------------------------------+-----------------+
| Melting           | 200-202 (95.9%)/208 -- 210    | DuPont-13180    |
| point/range (°C)  | (99.2%)                       |                 |
|                   |                               | MRID 46889033   |
+-------------------+-------------------------------+-----------------+
| pH                | 5.77 ± 0.087 at 20°C          | DuPont-13176    |
|                   |                               |                 |
|                   |                               | MRID 46889031   |
+-------------------+-------------------------------+-----------------+
| Relative Density  | 1.5189 (95.9%)/1.507 (99.2%)  | DuPont-13180    |
|                   | at 20°C                       |                 |
|                   |                               | MRID 46889033   |
+-------------------+-------------------------------+-----------------+
| Water solubility  | Deionized Water 1.023 mg/L    | DuPont-13169    |
| (20°C)            |                               |                 |
|                   | pH 4 0.972 mg/L               | MRID 46889026   |
|                   |                               |                 |
|                   | pH 7 0.880 mg/L               |                 |
|                   |                               |                 |
|                   | pH 9 0.971 mg/L               |                 |
+-------------------+-------------------------------+-----------------+
| Solvent           | Acetone 3.446 ± 0.172 g/L     | DuPont-13173    |
| solubility (20°C) |                               |                 |
|                   | Acetonitrile 0.711 ± 0.072    | MRID 46889030   |
|                   | 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     |                 |
+-------------------+-------------------------------+-----------------+
| Vapor pressure    | 6.3 x 10^-12^ Pa @ 20°C, 2.1  | DuPont-16517    |
|                   | x 10^-11^ Pa @ 25°C           |                 |
|                   |                               | MRID 46889130   |
+-------------------+-------------------------------+-----------------+
| Dissociation      | 10.88 ± 0.71                  | DuPont-13254    |
| constant, pK~a~   |                               |                 |
|                   |                               | MRID 46889034   |
+-------------------+-------------------------------+-----------------+
| Octanol/water     | Deionized Water 589           | DuPont-13177    |
| partition         |                               |                 |
| coefficient,      | pH 4 588                      | MRID 46889032   |
| K~OW~ (20°C)      |                               |                 |
|                   | pH 7 721                      |                 |
|                   |                               |                 |
|                   | pH 9 654                      |                 |
+-------------------+-------------------------------+-----------------+
| UV/visible        | pH \<2 no absorption max      | DuPont-13167    |
| absorption (max)  | \>200 nm, at 290 ε = 3941     |                 |
|                   |                               | MRID 46991001   |
|                   | 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    |                 |
+-------------------+-------------------------------+-----------------+

**3.0 Hazard Characterization/Assessment**
[]{#__RefHeading___Toc192910391 .anchor}

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

**3.1 Hazard and Dose-Response
Characterization**[]{#__RefHeading___Toc192910392 .anchor}

**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**[]{#__RefHeading___Toc192910393
.anchor}

[]{.mark}

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.

2.  **Biochemical Mode of Action**[]{#__RefHeading___Toc192910394
    .anchor}

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**[]{#__RefHeading___Toc192910395 .anchor}

DPX-E2Y45 has no significant acute toxicity via the oral, dermal, and
inhalation routes of exposure. The LD~50~ for oral and dermal acute
exposure is ≥5000 mg/kg/day and the LC~50~ 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 LD~50~ 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**[]{#__RefHeading___Toc192910396 .anchor}

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.

1.  **Absorption, Distribution, Metabolism, Excretion
    (ADME)**[]{#__RefHeading___Toc192910397 .anchor}

The absorption of ^14^C-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 ^14^C 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 ^14^C-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 (T~max~) was 0.25, 0.42,
and 2.75 hours in the 25, 100, and 1000 mg/kg/day groups, respectively.
The maximum concentrations (C~max~) 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:]{.underline}*

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 ^14^C residues,
decreased absorption, and proposed metabolic pathway from the single and
multiple oral gavage studies with ^14^C-DPX-E2Y45 in rats.

**3.3 FQPA Considerations**[]{#__RefHeading___Toc192910398 .anchor}

**3.3.1 Adequacy of the Toxicity
Database**[]{#__RefHeading___Toc192910399 .anchor}

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.

2.  **Evidence of Neurotoxicity**[]{#__RefHeading___Toc192910400
    .anchor}

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**[]{#__RefHeading___Toc192910401
.anchor}

For both the rat and rabbit developmental studies, no adverse, test
substance-related effects on maternal clinical observations, body
weight, weight gain, food consumption, or gross post-mortem observations
were detected at any dose. The mean number of corpora lutea,
implantation sites, resorptions, live fetuses, fetal weight, and sex
ratio were comparable across all groups. There were no abortions,
premature deliveries, or complete litter resorptions and no effects of
treatment on the numbers of litters, post-implantation loss, or on
gravid uterine weights. The maternal systemic toxicity is ≥1000
mg/kg/day and the maternal systemic toxicity LOAEL is greater than 1000
mg/kg/day (the limit dose). There were no test substance-related fetal
external, visceral, skeletal malformations, variations, adverse effects
on fetal skeletal ossification observed at any dose. The developmental
toxicity is ≥1000 mg/kg/day and the developmental toxicity LOAEL is
greater than 1000 mg/kg/day (the limit dose).

**3.3.4 Reproductive Toxicity Study**[]{#__RefHeading___Toc192910402
.anchor}

There were no adverse, test substance-related effects on body weight,
body weight gain, food consumption, or food efficiency, clinical signs
of toxicity, or mortality in P and F1 males during pre-mating and in P
and F1 females during pre-mating, gestation, or lactation. An increase
in mean liver weights was observed in P and F1 females at 238/318.9
mg/kg/day, respectively and above and was attributed to a
pharmacological increase in metabolism. In addition, a slight, yet
statistically significant, increase in mean adrenal weight (absolute
and/or relative to body weight) was observed at 4000 and 20,000 ppm P
and F1 males and females. There were no adverse test substance-related
effects on any gross or microscopic pathology endpoint. The parental
systemic toxicity NOAEL is ≥ 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).

Mean body weight of the 20,000 ppm F1 pups was slightly reduced (7-8%)
when compared to controls on lactation days 7, 14, and 21. The slightly
lower 20,000 ppm pup weights were considered not adverse as they were
transient, small in magnitude, and F1 offspring weights were similar to
controls by Day 35 postweaning. In addition, there were no effects on F2
offspring weights during lactation. The offspring/developmental toxicity
NOAEL is ≥ 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**[]{#__RefHeading___Toc192910403 .anchor}

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

**3.3.6 Pre-and/or Postnatal Toxicity**[]{#__RefHeading___Toc192910404
.anchor}

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**[]{#__RefHeading___Toc192910405 .anchor}

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**[]{#__RefHeading___Toc192910406 .anchor}

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**[]{#__RefHeading___Toc192910407 .anchor}

**3.5.1 Acute Dietary (All populations, including Females 13-49 years
old)**[]{#__RefHeading___Toc192910408 .anchor}

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)**[]{#__RefHeading___Toc192910409 .anchor}

[Establishment of a Chronic Dietary Reference Dose (cRfD)]{.underline}

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[^1] of 1.58 mg/kg/day.

[158 mg/kg bw/day]{.underline} = 1.58 mg/kg bw/day (cRfD/cPAD)

100 (UF)

3.  **Incidental Oral Exposure (Short- and
    intermediate-term)**[]{#__RefHeading___Toc192910410 .anchor}

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)**[]{#__RefHeading___Toc192910411 .anchor}

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**)[]{#__RefHeading___Toc192910412 .anchor}

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 LC~50~ 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**[]{#__RefHeading___Toc192910413 .anchor}

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**[]{#__RefHeading___Toc192910414 .anchor}

> 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 ^14^C-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**[]{#__RefHeading___Toc192910415 .anchor}

+----------+--------+-----------+---------+--------------------------+
| **Table  |        |           |         |                          |
| 3.5.8a   |        |           |         |                          |
| Summary  |        |           |         |                          |
| of       |        |           |         |                          |
| Toxic    |        |           |         |                          |
| ological |        |           |         |                          |
| Doses    |        |           |         |                          |
| and      |        |           |         |                          |
| E        |        |           |         |                          |
| ndpoints |        |           |         |                          |
| for      |        |           |         |                          |
| Chl      |        |           |         |                          |
| orantran |        |           |         |                          |
| iliprole |        |           |         |                          |
| for Use  |        |           |         |                          |
| in       |        |           |         |                          |
| Dietary  |        |           |         |                          |
| and      |        |           |         |                          |
| Non-Occu |        |           |         |                          |
| pational |        |           |         |                          |
| Human    |        |           |         |                          |
| Health   |        |           |         |                          |
| Risk     |        |           |         |                          |
| Asses    |        |           |         |                          |
| sments** |        |           |         |                          |
+==========+========+===========+=========+==========================+
| E        | Point  | Uncerta   | RfD,    | Study and Toxicological  |
| xposure/ | of     | inty/FQPA | PAD,    | Effects                  |
|          | Dep    | Safety    | Level   |                          |
| Scenario | arture | Factors   | of      |                          |
|          |        |           | Concern |                          |
|          |        |           | for     |                          |
|          |        |           | Risk    |                          |
|          |        |           | Ass     |                          |
|          |        |           | essment |                          |
+----------+--------+-----------+---------+--------------------------+
| Acute    | N/A    | N/A       | N/A     | No acute hazard,         |
| Dietary  |        |           |         | attributable to a single |
| (All     |        |           |         | dose, was identified;    |
| Popu     |        |           |         | therefore, an acute      |
| lations) |        |           |         | dietary endpoint was not |
|          |        |           |         | selected for             |
|          |        |           |         | quantitative risk        |
|          |        |           |         | assessment.              |
+----------+--------+-----------+---------+--------------------------+
| Chronic  | NOAEL= | UF~A~=    | Chronic | 18-Month Oral            |
| Dietary  | 158    | 10x       | RfD =   | (feeding)/mouse          |
| (All     | mg/    |           | 1.58    |                          |
| Popu     | kg/day | UF~H~=10x | mg      | LOAEL = 935 mg/kg/day    |
| lations) |        |           | /kg/day | based on eosinophilic    |
|          |        | FQPA SF=  |         | foci accompanied by      |
|          |        | 1x        | cPAD =  | hepatocellular           |
|          |        |           | 1.58    | hypertrophy and          |
|          |        |           | mg      | increased liver weight   |
|          |        |           | /kg/day | (males only)             |
+----------+--------+-----------+---------+--------------------------+
| In       | N/A    | N/A       | N/A     | There was no hazard      |
| cidental |        |           |         | identified via the oral  |
| Oral     |        |           |         | route over the short-    |
| Short-/I |        |           |         | and intermediate-term    |
| ntermedi |        |           |         | and therefore, no        |
| ate-Term |        |           |         | endpoint was selected    |
|          |        |           |         | for quantitative risk    |
|          |        |           |         | assessment.              |
+----------+--------+-----------+---------+--------------------------+
| Dermal   | N/A    | N/A       | N/A     | There was no hazard      |
| Short-/I |        |           |         | identified via the       |
| ntermedi |        |           |         | dermal route (and no     |
| ate-Term |        |           |         | concerns for             |
|          |        |           |         | developmental,           |
|          |        |           |         | reproductive or          |
|          |        |           |         | neurotoxic effects) and  |
|          |        |           |         | therefore, no dermal     |
|          |        |           |         | endpoint was selected    |
|          |        |           |         | for quantitative risk    |
|          |        |           |         | assessment.              |
+----------+--------+-----------+---------+--------------------------+
| In       | N/A    | N/A       | N/A     | Based on the lack of     |
| halation |        |           |         | hazard identified in the |
| Short-/I |        |           |         | acute inhalation study,  |
| ntermedi |        |           |         | lack of acute            |
| ate-Term |        |           |         | irritation, and          |
|          |        |           |         | extremely low oral       |
|          |        |           |         | toxicity -- no           |
|          |        |           |         | inhalation endpoint was  |
|          |        |           |         | selected for             |
|          |        |           |         | quantitative risk        |
|          |        |           |         | assessment.              |
+----------+--------+-----------+---------+--------------------------+
| Cancer   | Cla    |           |         |                          |
| (oral,   | ssific |           |         |                          |
| dermal,  | ation: |           |         |                          |
| inh      | "Not   |           |         |                          |
| alation) | likely |           |         |                          |
|          | to be  |           |         |                          |
|          | Carcin |           |         |                          |
|          | ogenic |           |         |                          |
|          | to     |           |         |                          |
|          | H      |           |         |                          |
|          | umans" |           |         |                          |
|          | based  |           |         |                          |
|          | on     |           |         |                          |
|          | weight |           |         |                          |
|          | of     |           |         |                          |
|          | ev     |           |         |                          |
|          | idence |           |         |                          |
|          | of     |           |         |                          |
|          | data:  |           |         |                          |
|          | no     |           |         |                          |
|          | treat  |           |         |                          |
|          | ment-r |           |         |                          |
|          | elated |           |         |                          |
|          | tumors |           |         |                          |
|          | re     |           |         |                          |
|          | ported |           |         |                          |
|          | in the |           |         |                          |
|          | sub    |           |         |                          |
|          | mitted |           |         |                          |
|          | c      |           |         |                          |
|          | hronic |           |         |                          |
|          | and    |           |         |                          |
|          | oncoge |           |         |                          |
|          | nicity |           |         |                          |
|          | s      |           |         |                          |
|          | tudies |           |         |                          |
|          | in     |           |         |                          |
|          | rats   |           |         |                          |
|          | and    |           |         |                          |
|          | mice,  |           |         |                          |
|          | subc   |           |         |                          |
|          | hronic |           |         |                          |
|          | s      |           |         |                          |
|          | tudies |           |         |                          |
|          | in     |           |         |                          |
|          | mice,  |           |         |                          |
|          | dogs   |           |         |                          |
|          | and    |           |         |                          |
|          | rats   |           |         |                          |
|          | and    |           |         |                          |
|          | that   |           |         |                          |
|          | no     |           |         |                          |
|          | mut    |           |         |                          |
|          | agenic |           |         |                          |
|          | c      |           |         |                          |
|          | oncern |           |         |                          |
|          | was    |           |         |                          |
|          | re     |           |         |                          |
|          | ported |           |         |                          |
|          | in the |           |         |                          |
|          | genoto |           |         |                          |
|          | xicity |           |         |                          |
|          | st     |           |         |                          |
|          | udies. |           |         |                          |
+----------+--------+-----------+---------+--------------------------+

+----------+--------+---------+------------+--------------------------+
| **Table  |        |         |            |                          |
| 3.5.8b   |        |         |            |                          |
| Summary  |        |         |            |                          |
| of       |        |         |            |                          |
| Toxic    |        |         |            |                          |
| ological |        |         |            |                          |
| Doses    |        |         |            |                          |
| and      |        |         |            |                          |
| E        |        |         |            |                          |
| ndpoints |        |         |            |                          |
| for      |        |         |            |                          |
| Chl      |        |         |            |                          |
| orantran |        |         |            |                          |
| iliprole |        |         |            |                          |
| for Use  |        |         |            |                          |
| in       |        |         |            |                          |
| Occu     |        |         |            |                          |
| pational |        |         |            |                          |
| Human    |        |         |            |                          |
| Health   |        |         |            |                          |
| Risk     |        |         |            |                          |
| Asses    |        |         |            |                          |
| sments** |        |         |            |                          |
+==========+========+=========+============+==========================+
| E        | Point  | Unce    | Level of   | Study and Toxicological  |
| xposure/ | of     | rtainty | Concern    | Effects                  |
|          | Dep    | Factors | for Risk   |                          |
| Scenario | arture |         | Assessment |                          |
+----------+--------+---------+------------+--------------------------+
| Dermal   | N/A    | N/A     | N/A        | There was no hazard      |
| Short-/I |        |         |            | identified via the       |
| ntermedi |        |         |            | dermal route (and no     |
| ate-Term |        |         |            | concerns for             |
|          |        |         |            | developmental,           |
|          |        |         |            | reproductive or          |
|          |        |         |            | neurotoxic effects) and  |
|          |        |         |            | therefore, no dermal     |
|          |        |         |            | endpoint was selected    |
|          |        |         |            | for quantitative risk    |
|          |        |         |            | assessment.              |
+----------+--------+---------+------------+--------------------------+
| In       | N/A    | N/A     | N/A        | Based on the lack of     |
| halation |        |         |            | hazard identified in the |
| Short-/I |        |         |            | acute inhalation study,  |
| ntermedi |        |         |            | lack of acute            |
| ate-Term |        |         |            | irritation, and          |
|          |        |         |            | extremely low oral       |
|          |        |         |            | toxicity -- no           |
|          |        |         |            | inhalation endpoint was  |
|          |        |         |            | selected for             |
|          |        |         |            | quantitative risk        |
|          |        |         |            | assessment.              |
+----------+--------+---------+------------+--------------------------+
| Cancer   | Cla    |         |            |                          |
| (dermal, | ssific |         |            |                          |
| inh      | ation: |         |            |                          |
| alation) | "Not   |         |            |                          |
|          | likely |         |            |                          |
|          | to be  |         |            |                          |
|          | Carcin |         |            |                          |
|          | ogenic |         |            |                          |
|          | to     |         |            |                          |
|          | H      |         |            |                          |
|          | umans" |         |            |                          |
|          | based  |         |            |                          |
|          | on     |         |            |                          |
|          | weight |         |            |                          |
|          | of     |         |            |                          |
|          | ev     |         |            |                          |
|          | idence |         |            |                          |
|          | of     |         |            |                          |
|          | data:  |         |            |                          |
|          | no     |         |            |                          |
|          | treat  |         |            |                          |
|          | ment-r |         |            |                          |
|          | elated |         |            |                          |
|          | tumors |         |            |                          |
|          | re     |         |            |                          |
|          | ported |         |            |                          |
|          | in the |         |            |                          |
|          | sub    |         |            |                          |
|          | mitted |         |            |                          |
|          | c      |         |            |                          |
|          | hronic |         |            |                          |
|          | and    |         |            |                          |
|          | oncoge |         |            |                          |
|          | nicity |         |            |                          |
|          | s      |         |            |                          |
|          | tudies |         |            |                          |
|          | in     |         |            |                          |
|          | rats   |         |            |                          |
|          | and    |         |            |                          |
|          | mice,  |         |            |                          |
|          | subc   |         |            |                          |
|          | hronic |         |            |                          |
|          | s      |         |            |                          |
|          | tudies |         |            |                          |
|          | in     |         |            |                          |
|          | mice,  |         |            |                          |
|          | dogs   |         |            |                          |
|          | and    |         |            |                          |
|          | rats   |         |            |                          |
|          | and    |         |            |                          |
|          | that   |         |            |                          |
|          | no     |         |            |                          |
|          | mut    |         |            |                          |
|          | agenic |         |            |                          |
|          | c      |         |            |                          |
|          | oncern |         |            |                          |
|          | was    |         |            |                          |
|          | re     |         |            |                          |
|          | ported |         |            |                          |
|          | in the |         |            |                          |
|          | genoto |         |            |                          |
|          | xicity |         |            |                          |
|          | st     |         |            |                          |
|          | udies. |         |            |                          |
+----------+--------+---------+------------+--------------------------+

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.
UF~A~ = extrapolation from animal to human (interspecies). UF~H~ =
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**[]{#__RefHeading___Toc192910416 .anchor}

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**[]{#__RefHeading___Toc192910417 .anchor}

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**[]{#__RefHeading___Toc192910418 .anchor}

**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**[]{#__RefHeading___Toc192910419 .anchor}

**5.1.1 Metabolism in Primary Crops**[]{#__RefHeading___Toc192910420
.anchor}

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 CH~2~O (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**[]{#__RefHeading___Toc192910421
.anchor}

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**[]{#__RefHeading___Toc192910422
.anchor}

The nature of the residue in livestock is adequately understood based on
highly exaggerated acceptable goat and hen Number range
CHAPTERmetabolism 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**[]{#__RefHeading___Toc192910423 .anchor}

The registrant has proposed LC/MS/MS methods for enforcing residues of
the parent compound in plants and livestock commodities. The enforcement
method for plant commodities, Analytical Method for the Determination of
DPX-E2Y45 in Crops Using LC/MS/MS, DuPont-11374, and Analytical Method
for the Determination of DPX-E2Y45 and Degradation Products in Crop
Process Fractions Using LC/MS/MS, DuPont-14314, involves extracting
chlorantraniliprole in aqueous acetonitrile. The extracts are filtered
through SPE cartridges and the residue is analyzed by LC/MS/MS operating
in the positive ionization mode: 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**[]{#__RefHeading___Toc192910424
.anchor}

**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   **R^2^**   **Comments**
                            (days)**                 

  **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; R^2^ 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; R^2^ 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**[]{#__RefHeading___Toc192910425
.anchor}

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 (^14^C)
residues, decreased absorption, and the proposed metabolic pathway from
the single and multiple oral gavage studies with carbon-labeled
(^14^C)-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**[]{#__RefHeading___Toc192910426 .anchor}

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.[^2] 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          | Chemical name         | Chemical structure         |
| name/code       |                       |                            |
|                 |                       |                            |
| ID No.          |                       |                            |
+-----------------+-----------------------+----------------------------+
| Chlor           | 3-Bromo               | ![](media/image2.wmf){w    |
| antraniliprole, | -*N*-\[4-chloro-2-met | idth="1.320138888888889in" |
| DPX-E2Y45       | hyl-6-\[(methylamino) | height="1.43125in"}        |
|                 |                       |                            |
|                 | carbonyl              |                            |
|                 | \]phenyl\]-1-(3-chlor |                            |
|                 | o-2-pyridinyl)-1*H*-p |                            |
|                 | yrazole-5-carboxamide |                            |
+-----------------+-----------------------+----------------------------+
| IN-HXH44        | 3-Bromo-*N*-\[4-      | ![](media/ima              |
|                 | chloro-2-(hydroxymeth | ge3.wmf){width="1.26875in" |
|                 | yl)-6-\[(methylamino) | heig                       |
|                 |                       | ht="1.3854166666666667in"} |
|                 | carbonyl              |                            |
|                 | \]phenyl\]-1-(3-chlor |                            |
|                 | o-2-pyridinyl)-1*H*-p |                            |
|                 | yrazole-5-carboxamide |                            |
+-----------------+-----------------------+----------------------------+
| IN-K9T00        | 3-Bromo-*N*-\[4-chlo  | ![](media/image4.wmf){wi   |
|                 | ro-2-(hydroxymethyl)- | dth="1.2819444444444446in" |
|                 | 6-\[\[(hydroxymethyl) | heig                       |
|                 |                       | ht="1.3854166666666667in"} |
|                 | amino)carbonyl\]      |                            |
|                 |                       |                            |
|                 | phenyl\]-1-(3-chlor   |                            |
|                 | o-2-pyridinyl)-1*H*-p |                            |
|                 | yrazole-5-carboxamide |                            |
+-----------------+-----------------------+----------------------------+
| IN-F6L99        | 5-Bromo-N-methyl-1H-p | ![](media/image5.wmf){wi   |
|                 | yrazole-3-carboxamide | dth="1.0048611111111112in" |
|                 |                       | height="0.8125in"}         |
+-----------------+-----------------------+----------------------------+
| IN-LBA24        |                       | ![](media/image6.wmf){wi   |
|                 |                       | dth="1.4444444444444444in" |
|                 |                       | heig                       |
|                 |                       | ht="0.8645833333333334in"} |
+-----------------+-----------------------+----------------------------+
| IN-EQW78        | 2-\                   | ![](media/image7.wmf){wi   |
|                 | [3-Bromo-1-(3-chloro- | dth="1.2618055555555556in" |
|                 | 2-pyridinyl)-1H-pyraz | heig                       |
|                 | ol-5-yl\]-6-chloro-3, | ht="0.9291666666666667in"} |
|                 | 8-dimethy             |                            |
|                 | l-4(3H)-quinazolinone |                            |
+-----------------+-----------------------+----------------------------+

**5.1.8 Pesticide Metabolites and Degradates of
Concern**[]{#__RefHeading___Toc192910427 .anchor}

**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  Residues included in
                                    Risk Assessment       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:]{.underline} 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]{.underline}: 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]{.underline}: 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]{.underline}: 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**[]{#__RefHeading___Toc192910428
.anchor}

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.

*Surface Water*. A Tier 2 PRZM/EXAMS assessment based on a number of
different crops was used to estimate drinking water concentrations
derived from surface water sources. For the 1 in 10 year peak, the
highest PRZM/EXAMS estimated drinking water concentration (EDWC) for
chlorantraniliprole was 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.

*Groundwater*. In lieu of sufficient groundwater monitoring data for
chlorantraniliprole, the Tier 1 groundwater screening model SCI-GROW was
used to estimate concentration of chlorantraniliprole in shallow
groundwater sources. Ornamental plants, which represent the highest
registered annual use rate (0.4992 lbs ai/A) was used for the modeling,
and resulted in a groundwater EDWC of 1.06 μg/L.

+-------------------------------+------------------+-------------------+
| **Table 5.1.9a Summary of     |                  |                   |
| Estimated Surface Water and   |                  |                   |
| Groundwater Concentrations    |                  |                   |
| for Chlorantraniliprole.**    |                  |                   |
+===============================+==================+===================+
|                               | Surface Water    | Groundwater       |
|                               | Conc., ppb ^a^   | Conc., ppb ^b^    |
+-------------------------------+------------------+-------------------+
| Acute                         | 26.862           | 1.06              |
+-------------------------------+------------------+-------------------+
| Chronic (non-cancer, 1 in 10  | 3.650            |                   |
| year annual average)          |                  |                   |
+-------------------------------+------------------+-------------------+
| Chronic (cancer, 30-year      | 1.721            |                   |
| annual average)               |                  |                   |
+-------------------------------+------------------+-------------------+
| ^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 |                  |                   |
| K~oc~ 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**                    | **Chora         | **IN-LBA24**     |
|                                | ntraniliprole** |                  |
|                                |                 | **Estimated      |
|                                | **Estimated     | Concentration**  |
|                                | Concentration** |                  |
|                                |                 | **(µg/L)**       |
|                                | **(µg/L)**      |                  |
+--------------------------------+-----------------+------------------+
| Chlorantraniliprole (@ 0.202   | 84.495          | 61.766           |
| lbs ai/A)                      |                 |                  |
+--------------------------------+-----------------+------------------+

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 (t~1/2~=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**                    | **Chora         | **IN-LBA24**     |
|                                | ntraniliprole** |                  |
|                                |                 | **Estimated      |
|                                | **Estimated     | Concentration**  |
|                                | Concentration** |                  |
|                                |                 | **(µg/L)**       |
|                                | **(µg/L)**      |                  |
+--------------------------------+-----------------+------------------+
| Chlorantraniliprole (@ 0.202   | 0.257           | 0.188            |
| lbs ai/A)                      |                 |                  |
+--------------------------------+-----------------+------------------+

**5.1.10 Food Residue Profile**[]{#__RefHeading___Toc192910429 .anchor}

[]{.mark}

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**[]{#__RefHeading___Toc192910430
.anchor}

[]{.mark}

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**[]{#__RefHeading___Toc192910431
.anchor}

**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**[]{#__RefHeading___Toc192910432
.anchor}

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         |       |          |          |           |            |
| Chlorantra  |       |          |          |           |            |
| niliprole** |       |          |          |           |            |
+=============+=======+==========+==========+===========+============+
| Population  | cPAD, | Chronic  |          | Chronic   |            |
| Subgroup    | mg/k  | E        |          | Estimates |            |
|             | g/day | stimates |          |           |            |
|             |       |          |          | (Food and |            |
|             |       | (Food    |          | Drinking  |            |
|             |       | only)    |          | Water)    |            |
+-------------+-------+----------+----------+-----------+------------+
|             |       | E        | Risk, %  | Exposure, | Risk, %    |
|             |       | xposure, | cPAD     | mg/kg/day | cPAD       |
|             |       | m        |          |           |            |
|             |       | g/kg/day |          |           |            |
+-------------+-------+----------+----------+-----------+------------+
| U.S.        | 1.58  | 0.007679 | \<1      | 0.007756  | \<1        |
| Population  |       |          |          |           |            |
+-------------+-------+----------+----------+-----------+------------+
| All infants |       | 0.007856 | \<1      | 0.008108  | \<1        |
+-------------+-------+----------+----------+-----------+------------+
| Children    |       | **0.     | **\<1**  | 0.014969  | **\<1**    |
| 1-2 yrs     |       | 014855** |          |           |            |
+-------------+-------+----------+----------+-----------+------------+
| Children    |       | 0.012043 | \<1      | 0.012150  | \<1        |
| 3-5 yrs     |       |          |          |           |            |
+-------------+-------+----------+----------+-----------+------------+
| Children    |       | 0.007999 | \<1      | 0.008073  | \<1        |
| 6-12 yrs    |       |          |          |           |            |
+-------------+-------+----------+----------+-----------+------------+
| Youth 13-19 |       | 0.005850 | \<1      | 0.005906  | \<1        |
| yrs         |       |          |          |           |            |
+-------------+-------+----------+----------+-----------+------------+
| Adults      |       | 0.007082 | \<1      | 0.007154  | \<1        |
| 20-49 yrs   |       |          |          |           |            |
+-------------+-------+----------+----------+-----------+------------+
| Adults 50+  |       | 0.007613 | \<1      | 0.007689  | \<1        |
| yrs         |       |          |          |           |            |
+-------------+-------+----------+----------+-----------+------------+
| Females     |       | 0.007215 | \<1      | 0.007286  | \<1        |
| 13-49 yrs   |       |          |          |           |            |
+-------------+-------+----------+----------+-----------+------------+

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

**5.3 Anticipated Residue and Percent Crop Treated (%CT)
Information**[]{#__RefHeading___Toc192910433 .anchor}

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**[]{#__RefHeading___Toc192910434 .anchor}

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 DuPont^TM^ 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**[]{#__RefHeading___Toc192910435 .anchor}

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**[]{#__RefHeading___Toc192910436 .anchor}

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**[]{#__RefHeading___Toc192910437 .anchor}

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
[[http://www.epa.gov/pesticides/cumulative/.]{.underline}](http://www.epa.gov/pesticides/cumulative/.)

**9.0 Occupational Exposure/Risk
Pathway**[]{#__RefHeading___Toc192910438 .anchor}

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

1.  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.

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

3.  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.

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

5.  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**[]{#__RefHeading___Toc192910439 .anchor}

**10.1 Toxicology**[]{#__RefHeading___Toc192910440 .anchor}

There are no data gaps in the toxicology database.

**10.2 Residue Chemistry**[]{#__RefHeading___Toc192910441 .anchor}

[860.1200 Directions for Use]{.underline}

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]{.underline}

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]{.underline}

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**[]{#__RefHeading___Toc192910442 .anchor}

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:**[]{#__RefHeading___Toc192910443 .anchor}

[]{.mark}

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.

[]{.mark}

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

[]{.mark}

*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

[]{.mark}

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

[]{.mark}

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.

[]{.mark}

*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**[]{#__RefHeading___Toc192910444
.anchor}

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

**A.1 Toxicology Data Requirements**[]{#__RefHeading___Toc192910445
.anchor}

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            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | yes         | yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | yes         | yes         |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | no          | \-          |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | no          | \-          |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | yes         | yes         |
| (rodent)                                |             |             |
|                                         | yes         | yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | yes         | yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | yes         | yes         |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | yes         | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | yes         | yes         |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | yes         | yes         |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Gene Mutation - | yes         | yes         |
| bacterial                               |             |             |
|                                         | yes         | yes         |
| 870.5300 Mutagenicity---Gene Mutation - |             |             |
| mammalian                               | yes         | yes         |
|                                         |             |             |
| 870.5385 Mutagenicity---Structural      | yes         | yes         |
| Chromosomal Aberrations                 |             |             |
|                                         |             |             |
| 870.5395 Mutagenicity---Micronucleus    |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-          |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-          |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | yes         | yes         |
| Battery (rat)                           |             |             |
|                                         | yes         | yes         |
| 870.6200b 90-Day Neuro. Screening       |             |             |
| Battery (rat)                           | no          | \-          |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | no          | \-          |
+-----------------------------------------+-------------+-------------+
| Special Studies                         |             | yes         |
|                                         |             |             |
| > 28-day immunotoxicity (rat)           |             | yes         |
| >                                       |             |             |
| > 28-day immunotoxicity (mouse)         |             |             |
+-----------------------------------------+-------------+-------------+

**A.2 Toxicity Profiles**[]{#__RefHeading___Toc192910446 .anchor}

+-------+---------------+-------+-----------------------------+-------+
| Table |               |       |                             |       |
| A     |               |       |                             |       |
| .2.1. |               |       |                             |       |
| Acute |               |       |                             |       |
| Tox   |               |       |                             |       |
| icity |               |       |                             |       |
| of    |               |       |                             |       |
| Tech  |               |       |                             |       |
| nical |               |       |                             |       |
| DPX-  |               |       |                             |       |
| E2Y45 |               |       |                             |       |
| (     |               |       |                             |       |
| Chlor |               |       |                             |       |
| antra |               |       |                             |       |
| nilip |               |       |                             |       |
| role) |               |       |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| **G   | **Study       | *     | **Results**                 | **Tox |
| uidel | Type**        | *MRID |                             | icity |
| ine** |               | No.** |                             | Categ |
|       |               |       |                             | ory** |
| **    |               |       |                             |       |
| No.** |               |       |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Acute oral    | 468   | LD50 = \>5000 mg/kg bw      | IV    |
| .1100 | toxicity      | 89112 |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Acute dermal  | 468   | LD50 = \>5000 mg/kg bw      | IV    |
| .1200 | toxicity      | 89113 |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Acute         | 468   | LC50 = \>5.1 mg/L           | IV    |
| .1300 | inhalation    | 89121 |                             |       |
|       | toxicity      |       |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Acute eye     | 468   | Iritis score of 1 in 1/3    | IV    |
| .2400 | irritation    | 89115 | rabbits, conjuctival        |       |
|       |               |       | redness score of 1 in 2/3   |       |
|       |               |       | rabbits. All eyes returned  |       |
|       |               |       | to normal after 72 hours.   |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Primary skin  | 468   | No dermal irritation,       | IV    |
| .2500 | irritation    | 89114 | clinical signs or body      |       |
|       |               |       | weight loss                 |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Dermal        | 468   | Not a dermal sensitizer     | Neg   |
| .2600 | sensitization | 89221 |                             | ative |
+-------+---------------+-------+-----------------------------+-------+

+--------+-----------+--------+--------+-----------------------------+
| *      |           |        |        |                             |
| *Table |           |        |        |                             |
| A.2.2  |           |        |        |                             |
| Subch  |           |        |        |                             |
| ronic, |           |        |        |                             |
| C      |           |        |        |                             |
| hronic |           |        |        |                             |
| and    |           |        |        |                             |
| Other  |           |        |        |                             |
| To     |           |        |        |                             |
| xicity |           |        |        |                             |
| Pro    |           |        |        |                             |
| file** |           |        |        |                             |
+========+===========+========+========+=============================+
| **ST   | **DOSES   | *      | *      | **EFFECTS**                 |
| UDY/** | (mg/      | *NOAEL | *LOAEL |                             |
|        | kg/day)** | (      | (      |                             |
| **SPE  |           | mg/kg/ | mg/kg/ |                             |
| CIES** |           | day)** | day)** |                             |
+--------+-----------+--------+--------+-----------------------------+
| 14-day | 0, 25,    | 1000   | Not    | No adverse effects. Weak    |
| Oral   | 100, 1000 |        | estab  | inducer of cytochrome P450  |
| G      |           |        | lished | 3A at all dose levels, with |
| avage/ |           |        |        | statistical significance at |
| rat    |           |        |        | 100 and 1000 mg/kg/day.     |
+--------+-----------+--------+--------+-----------------------------+
| 28-Day | 0, 20.7,  | 584    | Not    | No adverse effects. Slight  |
| Oral   | 106 and   | (male) | estab  | increase in liver weight at |
| (fee   | 584       | and    | lished | 128 and 675 mg/kg/day in    |
| d)/rat | (male);   | 675    |        | females and minimal         |
|        | 0, 24,    | (f     |        | hepatocellular hypertrophy  |
|        | 128 and   | emale) |        | at 675 mg/kg that is        |
|        | 675       |        |        | attributed to enzyme        |
|        | (female)  |        |        | 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 | 0, 52,    | 1443   | Not    | No adverse effects. Slight  |
| Oral   | 182, 538  | (male) | estab  | increase in liver wt. in    |
| (feed) | and 1443  | and    | lished | 658 and 1524 mg/kg/day      |
| /mouse | (male);   | 1524   |        | females corresponded with a |
|        | 0, 64,    | (f     |        | mild increase in cytochrome |
|        | 206, 658  | emale) |        | P450 enzyme activity. No    |
|        | and 1524  |        |        | histopathological evidence  |
|        | (female)  |        |        | 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 | 0, 300,   | 1000   | Not    | No adverse effects.         |
| Oral   | 1000      |        | estab  | Induction of cytochrome     |
| (cap   |           |        | lished | P450 enzyme activity (58%)  |
| sule)/ |           |        |        | in both males and females   |
|        |           |        |        | at 1000 mg/kg/day,          |
| Dog    |           |        |        | specifically 1A1 and 2B1/2  |
|        |           |        |        | at 300 and 1000 mg/kg/day.  |
+--------+-----------+--------+--------+-----------------------------+
| 28-day | 0, 26,    | 1302   | Not    | No adverse effects. Food    |
| Oral   | 138, 266, | (male) | estab  | consumption generally       |
| (fee   | 797 and   | and    | lished | increased as the study      |
| d)/dog | 1302      | 1240   |        | progressed with males       |
| --     | (male);   | (f     |        | generally demonstrating the |
| Palata | 0, 28,    | emale) |        | highest food consumption    |
| bility | 138, 298, |        |        | when fed the HDT.           |
| study  | 888, and  |        |        |                             |
|        | 1240      |        |        |                             |
|        | (female)  |        |        |                             |
+--------+-----------+--------+--------+-----------------------------+
| 28-day | 0, 100,   | 1000   | Not    | No adverse effects.         |
| Derm   | 300 and   |        | estab  | Reductions in mean body     |
| al/rat | 1000      |        | lished | 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 | 0, 36.9,  | 1188   | Not    | No adverse effects. A       |
| Oral   | 120, 359, | (male) | estab  | slight increase in liver    |
| (fee   | 1188      | and    | lished | weight at HDT females and   |
| d)/rat | (male);   | 1526   |        | reduction in bilirubin in   |
|        | 0, 47,    | (f     |        | females at ≥157 mg/kg/day,  |
|        | 157, 460, | emale) |        | with no corresponding       |
|        | 1526      |        |        | histopathological evidence  |
|        | (female)  |        |        | of liver toxicity.          |
+--------+-----------+--------+--------+-----------------------------+
| 90-day | 0, 32.6,  | 1135   | Not    | No adverse effects.         |
| Oral   | 115, 345, | (male) | estab  | Hyperactivity and           |
| (feed) | 1135      | and    | lished | hyperreactivity in females  |
| /mouse | (male);   | 1529   |        | were observed near the end  |
|        | 0, 40.7,  | (f     |        | of the study and one male   |
|        | 158, 422, | emale) |        | in the upper mid dose had   |
|        | 1529      |        |        | convulsions, but these      |
|        | (female)  |        |        | 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 | 0, 32.2,  | 1163   | Not    | No adverse effects. A mild  |
| Oral   | 119, 303, | (male) | estab  | increase in liver weight    |
| (fee   | 1163      | and    | lished | was observed in males at    |
| d)/dog | (male);   | 1220   |        | 1163 mg/kg/day, with no     |
|        | 0, 36.5,  | (f     |        | corresponding               |
|        | 133, 318, | emale) |        | histopathological evidence  |
|        | 1220      |        |        | of liver toxicity.          |
|        | (female)  |        |        |                             |
+--------+-----------+--------+--------+-----------------------------+
| 5      | 0, 32,    | 1164   | Not    | No adverse effects. A mild  |
| 2-week | 112, 317, | (male) | estab  | increase in liver weight in |
| Oral   | 1164      | and    | lished | HDT males and females, and  |
| (fee   | (male);   | 1233   |        | increase in alkaline        |
| d)/dog | 0, 34,    | (f     |        | phosphatase in HDT males,   |
|        | 113, 278, | emale) |        | with no corresponding       |
|        | 1233      |        |        | histopathological evidence  |
|        | (female)  |        |        | 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 | 0, 7.71,  | 805    | Not    | No evidence of              |
| Oral   | 39, 156,  | (male) | estab  | carcinogenicity and no      |
| (      | 805       | and    | lished | adverse findings. Increased |
| feedin | (male);   | 1076   |        | adrenal cortical            |
| g)/rat | 0, 10.9,  | (f     |        | microvesiculation due to    |
|        | 51, 212,  | emale) |        | lipid was present in the    |
|        | 1076      |        |        | zona fasciculata region of  |
|        | (female)  |        |        | 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     | 0, 2.6,   | 158    | 935    | No evidence of              |
| -Month | 9.2,      | (male) | (      | carcinogenicity.            |
| Oral   | 26.1,     | and    | male), | Eosinophilic foci           |
| (fee   | 158, 935  | 1155   | no     | accompanied by              |
| ding)/ | (male);   | (f     | LOAEL  | hepatocellular hypertrophy  |
|        | 0, 3.34,  | emale) | estab  | and increased liver weight  |
| Mouse  | 11.6,     |        | lished | form the bases for the male |
|        | 32.9,     |        | for    | LOAEL of 935 mg/kg/day.     |
|        | 196, 1155 |        | female |                             |
|        | (female)  |        |        |                             |
+--------+-----------+--------+--------+-----------------------------+
| Tw     | 0, 200,   | 1199   | Not    | A slight increase in mean   |
| o-gene | 1000,     | (male) | estab  | liver weights in P1 and F1  |
| ration | 4000,     | and    | lished | males and females at        |
| oral   | 20000     | 1594   |        | 238/318.9 mg/kg/day and     |
| stu    | ppm,\     | (f     |        | above, slight increase in   |
| dy/rat | mg/kg     | emale) |        | mean adrenal weight at      |
|        | bw/d      |        |        | 238/318.9 mg/kg/day and     |
|        | equ       |        |        | 1199/1594 mg/kg/day P1 and  |
|        | ivalents: |        |        | F1 males and females. Mean  |
|        |           |        |        | body weight of 1199/1594    |
|        | [pre      |        |        | mg/kg/day F1 pups was       |
|        | -mating:\ |        |        | slightly reduced on         |
|        | ]{.und    |        |        | lactation days 7, 14 and    |
|        | erline}P1 |        |        | 21. No effects on F2        |
|        | m: 0, 12, |        |        | offspring weights during    |
|        | 60, 238,  |        |        | lactation.                  |
|        | 1199\     |        |        |                             |
|        | F1 m: 0,  |        |        | Minimal to mild increase in |
|        | 18, 89,   |        |        | adrenal cortical            |
|        | 370,      |        |        | microvesiculation in P1     |
|        | 1926\     |        |        | adult males and F1 adult    |
|        | P1 f: 0,  |        |        | males and females. P1 adult |
|        | 16, 78,   |        |        | at 60.4/77.8 mg/kg/day and  |
|        | 318,      |        |        | greater. F1 adult males at  |
|        | 1594\     |        |        | 12 mg/kg/day and greater.   |
|        | F1 f: 0,  |        |        | These effects were not      |
|        | 20, 104,  |        |        | observed in weanlings. No   |
|        | 406,      |        |        | cytotoxicity or abnormal    |
|        | 2178\     |        |        | cellular structures were    |
|        | [gestat   |        |        | observed under light or     |
|        | ion:]{.un |        |        | electron microscopy.        |
|        | derline}\ |        |        |                             |
|        | P1 f: 0,  |        |        |                             |
|        | 14, 68,   |        |        |                             |
|        | 278,      |        |        |                             |
|        | 1373\     |        |        |                             |
|        | F1 f: 0,  |        |        |                             |
|        | 14, 71,   |        |        |                             |
|        | 272,      |        |        |                             |
|        | 1465\     |        |        |                             |
|        | [la       |        |        |                             |
|        | ctation:\ |        |        |                             |
|        | ]{.und    |        |        |                             |
|        | erline}P1 |        |        |                             |
|        | f: 0, 32, |        |        |                             |
|        | 162, 654, |        |        |                             |
|        | 3118\     |        |        |                             |
|        | F1 f: 0,  |        |        |                             |
|        | 35, 183,  |        |        |                             |
|        | 696, 3641 |        |        |                             |
+--------+-----------+--------+--------+-----------------------------+
| D      | 0, 20,    | 1000   | Not    | No adverse effects.         |
| evelop | 100, 300, |        | estab  |                             |
|        | 1000      |        | lished |                             |
| mental |           |        |        |                             |
| stu    |           |        |        |                             |
| dy/rat |           |        |        |                             |
+--------+-----------+--------+--------+-----------------------------+
| D      | 0, 20,    | 1000   | Not    | No adverse effects.         |
| evelop | 100, 300, |        | estab  |                             |
|        | 1000      |        | lished |                             |
| mental |           |        |        |                             |
| study/ |           |        |        |                             |
| rabbit |           |        |        |                             |
+--------+-----------+--------+--------+-----------------------------+
| Acute  | 0, 200,   | 2000   | Not    | No evidence of              |
| oral   | 700, 2000 |        | estab  | neurotoxicity was observed  |
| neuro- | in 0.5%   |        | lished | at any dose                 |
| toxici | methyl    |        |        |                             |
| ty/rat | cellulose |        |        |                             |
+--------+-----------+--------+--------+-----------------------------+
| Subc   | 0, 12.7,  | 1313   | Not    | No evidence of              |
| hronic | 64.2,     | (male) | estab  | neurotoxicity was observed  |
| oral   | 255, 1313 | and    | lished | at any dose.                |
| n      | (male);   | 1586   |        |                             |
| euron- | 0, 15.1,  | (f     |        |                             |
| toxici | 77.3,     | emale) |        |                             |
| ty/rat | 304, 1586 |        |        |                             |
|        | (female)  |        |        |                             |
+--------+-----------+--------+--------+-----------------------------+
| 28-day | 0, 74,    | 1494   | Not    | No evidence of              |
| I      | 363, 1494 | (male) | estab  | treatment-related effects   |
| mmuno- | (male);   | and    | lished | on the sheep red blood      |
| toxici | 0, 82,    | 1601   |        | cells specific antibody     |
| ty/rat | 397, 1601 | (f     |        | (IgM) responses in either   |
|        | (female)  | emale) |        | male or female rats at any  |
|        |           |        |        | dietary concentration       |
|        |           |        |        | tested.                     |
+--------+-----------+--------+--------+-----------------------------+
| 28-day | 0, 48,    | 1144   | Not    | No evidence of              |
| Immu   | 264, 1144 | (male) | estab  | treatment-related effect on |
| no-tox | (male);   | and    | lished | the sheep red blood cells   |
| icity/ | 0, 64,    | 1566   |        | specific antibody (IgM)     |
|        | 362, 1566 | (f     |        | responses in either male or |
| Mouse  | (female)  | emale) |        | female mice at any dietary  |
|        |           |        |        | concentration tested.       |
+--------+-----------+--------+--------+-----------------------------+

**A.3 Toxicity Summaries**[]{#__RefHeading___Toc192910447 .anchor}

*[Acute Toxicity -- Technical Chlorantraniliprole]{.underline}*

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
Altacor^TM^ WG Insecticide (35% ai) and DuPont Coragen^TM^ 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 Altacor^TM^ WG and DuPont Coragen^TM^ 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 |               |       |                             |       |
| Tox   |               |       |                             |       |
| icity |               |       |                             |       |
| of    |               |       |                             |       |
| Tech  |               |       |                             |       |
| nical |               |       |                             |       |
| DPX-  |               |       |                             |       |
| E2Y45 |               |       |                             |       |
| (     |               |       |                             |       |
| Chlor |               |       |                             |       |
| antra |               |       |                             |       |
| nilip |               |       |                             |       |
| role) |               |       |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| **G   | **Study       | *     | **Results**                 | **Tox |
| uidel | Type**        | *MRID |                             | icity |
| ine** |               | No.** |                             | Categ |
|       |               |       |                             | ory** |
| **    |               |       |                             |       |
| No.** |               |       |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Acute oral    | 468   | LD50 = \>5000 mg/kg bw      | IV    |
| .1100 | toxicity      | 89112 |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Acute dermal  | 468   | LD50 = \>5000 mg/kg bw      | IV    |
| .1200 | toxicity      | 89113 |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Acute         | 468   | LC50 = \>5.1 mg/L           | IV    |
| .1300 | inhalation    | 89121 |                             |       |
|       | toxicity      |       |                             |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Acute eye     | 468   | Iritis score of 1 in 1/3    | IV    |
| .2400 | irritation    | 89115 | rabbits, conjuctival        |       |
|       |               |       | redness score of 1 in 2/3   |       |
|       |               |       | rabbits. All eyes returned  |       |
|       |               |       | to normal after 72 hours.   |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Primary skin  | 468   | No dermal irritation,       | IV    |
| .2500 | irritation    | 89114 | clinical signs or body      |       |
|       |               |       | weight loss                 |       |
+-------+---------------+-------+-----------------------------+-------+
| 870   | Dermal        | 468   | Not a dermal sensitizer     | Neg   |
| .2600 | sensitization | 89221 |                             | ative |
+-------+---------------+-------+-----------------------------+-------+

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
                                      ^14^C 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 ^14^C
                                      residues from plasma through 5 days
                                      after single low dose
                                      administration were shorter in male
                                      (T~1/2~ = 1.7 days) than female
                                      rats (T~1/2~ = 3.3 days), increased
                                      to T~1/2~ = 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 ^14^C-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)]{.underline}*

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 (T~max~) was 0.25, 0.42,
and 2.75 hours in the 25, 100, and 1000 mg/kg/day groups, respectively.
The maximum concentrations (C~max~) 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]{.underline}*

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]{.underline}*

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]{.underline}*

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:]{.underline}*

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 ^14^C residues,
decreased absorption, and proposed metabolic pathway from the single and
multiple oral gavage studies with ^14^C-DPX-E2Y45 in rats.

*[28-day Dermal Toxicity Study (MRID 46889128)]{.underline}*

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)]{.underline}*

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)]{.underline}*

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

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

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

A functional observational battery was included in the 18-month mouse
feeding study. 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)]{.underline}*

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)]{.underline}*

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)]{.underline}*

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)]{.underline}*

*[Developmental Rabbit Study (MRID 46889109)]{.underline}*

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)]{.underline}*

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)]{.underline}*

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)]{.underline}*

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)]{.underline}*

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 μg/mL) and did not induce a mutagenic effect at the
HGPRT locus.

CHROMOSOME ABERRATIONS

**Mammalian Cell Cytogenetic Assay:** In a cytogenetic assay (MRID
46889105), primary human lymphocyte cultures were exposed to DPX-E2Y45
Technical (chlorantraniliprole) at concentrations up to precipitating
levels (≥750 μg/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)]{.underline}*

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]{.underline}*

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

*[Corticosterone Under Simulated Physiologic Stress -- ACTH Stimulation
Test]{.underline}*

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**[]{#__RefHeading___Toc192910448
.anchor}

**B.1 Metabolism Guidance and
Considerations**[]{#__RefHeading___Toc192910449 .anchor}

+-------------+-------+----------------+--------------+--------------+
| **Table     |       |                |              |              |
| B.2.        |       |                |              |              |
| Tabular     |       |                |              |              |
| Summary of  |       |                |              |              |
| Metabolites |       |                |              |              |
| and         |       |                |              |              |
| D           |       |                |              |              |
| egradates** |       |                |              |              |
+=============+=======+================+==============+==============+
| Chemical    | M     | Percent TRR    |              | Structure    |
| Name (other | atrix | (PPM)          |              |              |
| names in    |       |                |              |              |
| p           |       |                |              |              |
| arenthesis) |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       | Matrices --    | Matrices --  |              |
|             |       |                | Minor        |              |
|             |       | Major Residue  | Residue      |              |
|             |       | (≥10%TRR)      | (\<10%TRR)   |              |
+-------------+-------+----------------+--------------+--------------+
| 3-Bro       | Apple | Fruit --       |              | !            |
| mo-*N*-\[4- |       | 83.2-83.5      |              | [](media/ima |
| chloro-2-me |       |                |              | ge2.wmf){wid |
| thyl-6-\[(m |       | (0.077-0.089)  |              | th="1.320138 |
| ethylamino) |       |                |              | 888888889in" |
|             |       |                |              | height=      |
| carbo       |       |                |              | "1.43125in"} |
| nyl\]phenyl |       |                |              |              |
| \]-1-(3-chl |       |                |              |              |
| oro-2-pyrid |       |                |              |              |
| inyl)-1*H*- |       |                |              |              |
| pyrazole-5- |       |                |              |              |
| carboxamide |       |                |              |              |
| (Chlorantr  |       |                |              |              |
| aniliprole, |       |                |              |              |
| DPX-E2Y45)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       | Leaves --      |              |              |
|             |       | 91.6-93.7      |              |              |
|             |       |                |              |              |
|             |       | (3.803-3.180)  |              |              |
+-------------+-------+----------------+--------------+--------------+
|             | C     | Foliage/hulls  |              |              |
|             | otton | -- 24.7-68.1   |              |              |
|             |       | (\<0.01-0.04)  |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       | Lint/seed --   |              |              |
|             |       | 56.9 (\<0.01)  |              |              |
+-------------+-------+----------------+--------------+--------------+
|             | Le    | Leaves -- 88.7 |              |              |
|             | ttuce | (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)   |              |              |
+-------------+-------+----------------+--------------+--------------+
|             | T     | Fruit -- 92.2  |              |              |
|             | omato | (0.012)        |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       | Leaves -- 98.1 |              |              |
|             |       | (1.340)        |              |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat | Lettuce --     | Beet tops -- |              |
|             | ional | 63.9-85.2      | 0.9-4.8      |              |
|             | Crops | (0.020-0.032)  | (\<          |              |
|             |       |                | 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)    |              |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   | Milk -- 23.6   | Liver --     |              |
|             | inant | (0.016)        | 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)  |              |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    | Egg yolk --    | Liver --     |              |
|             | ultry | 11.9-22.65     | 2.21-3.75    |              |
|             |       | (0.059-0.106)  | (            |              |
|             |       |                | 0.012-0.017) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       | Egg white --   | Muscle --    |              |
|             |       | 26.18-31.62    | 3.54         |              |
|             |       | (0.355-0409)   | (\<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-          | Rice  |                | Grain -- 1.3 | ![           |
| \[3-Bromo-1 |       |                | (0.002)      | ](media/imag |
| -(3-chloro- |       |                |              | e7.wmf){widt |
| 2-pyridinyl |       |                |              | h="1.2618055 |
| )-1*H*-pyra |       |                |              | 555555556in" |
| zol-5-yl\]- |       |                |              | height       |
| 6-chloro-3, |       |                |              | ="0.92916666 |
| 8-dimethyl  |       |                |              | 66666667in"} |
| -4(3*H*)-qu |       |                |              |              |
| inazolinone |       |                |              |              |
| (IN-EQW78)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Hulls -- 3.2 |              |
|             |       |                | (0.006)      |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Leaves --    |              |
|             |       |                | 4.2 (0.167)  |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Sheaths --   |              |
|             |       |                | 5.3 (0.007)  |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 4.3 (0.039)  |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat |                | Radish tops  |              |
|             | ional |                | -- 1.5       |              |
|             | crops |                |              |              |
|             |       |                | (\<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) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   | Fat --         | Liver -- 6.2 |              |
|             | inant | 6.35-10.99     | (0.040)      |              |
|             |       |                |              |              |
|             |       | (0.004-0.007)  |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Muscle --    |              |
|             |       |                | 2.0          |              |
|             |       |                | (\<0.001)    |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    |                | Egg white -- |              |
|             | ultry |                | 3.25-6.4     |              |
|             |       |                | (            |              |
|             |       |                | 0.042-0.087) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Muscle --    |              |
|             |       |                | 6.79 (0.002) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Skin w/fat   |              |
|             |       |                | -- 3.10      |              |
|             |       |                | (0.002)      |              |
+-------------+-------+----------------+--------------+--------------+
| 5-          | Rice  |                | Grain -- 1.5 | ![]          |
| Bromo-*N*-m |       |                | (0.002)      | (media/image |
| ethyl-1*H*- |       |                |              | 5.wmf){width |
| pyrazole-3- |       |                |              | ="1.21875in" |
| carboxamide |       |                |              | height       |
|             |       |                |              | ="0.97916666 |
| (IN-F6L99)  |       |                |              | 66666666in"} |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Leaves --    |              |
|             |       |                | 2.7 (0.107)  |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Sheaths --   |              |
|             |       |                | 1.2 (0.002)  |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 2.5 (0.023)  |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat | Beet tops --   | Lettuce --   |              |
|             | ional | 0.2-10.8       | 1.4 (0.001)  |              |
|             | crops | (              |              |              |
|             |       | \<0.001-0.013) |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat hay -- |              |
|             |       |                | 0.2-2.4      |              |
|             |       |                | (            |              |
|             |       |                | 0.001-0.038) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat straw  |              |
|             |       |                | -- 0.5-2.6   |              |
|             |       |                | (\<          |              |
|             |       |                | 0.002-0.013) |              |
+-------------+-------+----------------+--------------+--------------+
| *N*-\[2-(A  | Rice  |                | Leaves --    | !            |
| minocarbony |       |                | 3.2 (0.134)  | [](media/ima |
| l)-4-chloro |       |                |              | ge8.wmf){wid |
| -6-methylph |       |                |              | th="1.261111 |
| enyl\]-3-br |       |                |              | 111111111in" |
| omo-1-(3-ch |       |                |              | height       |
| loro-2-pyri |       |                |              | ="1.25277777 |
| dinyl)1*H*- |       |                |              | 77777778in"} |
| pyrazole-5- |       |                |              |              |
| carboxamide |       |                |              |              |
|             |       |                |              |              |
| (IN-F9N04)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 2.8 (0.025)  |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat |                | Lettuce --   |              |
|             | ional |                | 1.6-5.2      |              |
|             | crops |                | (            |              |
|             |       |                | 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) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    |                | Egg white -- |              |
|             | ultry |                | 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-\[3-Br    | Rice  |                | Leaves --    | !            |
| omo-1-(3-ch |       |                | 6.1 (0.244)  | [](media/ima |
| loro-2-pyri |       |                |              | ge9.wmf){wid |
| dinyl)-1*H* |       |                |              | th="1.261111 |
| -pyrazol-5- |       |                |              | 111111111in" |
| yl\]-6-chlo |       |                |              | heig         |
| ro-8-methyl |       |                |              | ht="0.95in"} |
| -4(3*H*)-qu |       |                |              |              |
| inazolinone |       |                |              |              |
|             |       |                |              |              |
| (IN-GAZ70)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 5.4 (0.049)  |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat |                | Lettuce --   |              |
|             | ional |                | 0.8-1.9      |              |
|             | Crops |                | (\<          |              |
|             |       |                | 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) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   |                | Liver --     |              |
|             | inant |                | 3.12 (0.020) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Fat -- 4.86  |              |
|             |       |                | (0.002)      |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    | Egg white --   | Egg yolk --  |              |
|             | ultry | 32.57-40.44    | 4.25-6.57    |              |
|             |       |                | (            |              |
|             |       | (0.421-0.548)  | 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* | Rice  |                | Leaves --    | ![]          |
| -\[4-chloro |       |                | 2.5 (0.101)  | (media/image |
| -2-\[\[(hyd |       |                |              | 10.wmf){widt |
| roxymethyl) |       |                |              | h="1.2798611 |
| amino\]car  |       |                |              | 111111111in" |
| bonyl\]-6-m |       |                |              | height       |
| ethylphenyl |       |                |              | ="1.40069444 |
| \]-1-(3-chl |       |                |              | 44444445in"} |
| oro-2-pyrid |       |                |              |              |
| inyl)-1*H*- |       |                |              |              |
| pyrazole-5- |       |                |              |              |
| carboxamide |       |                |              |              |
|             |       |                |              |              |
| (IN-H2H20)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 2.2 (0.02)   |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat |                | Beet tops -- |              |
|             | ional |                | 0.9-2.8      |              |
|             | crops |                | (            |              |
|             |       |                | 0.001-0.002) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat hay -- |              |
|             |       |                | 1.5 (0.009)  |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat straw  |              |
|             |       |                | -- 2-2.5     |              |
|             |       |                | (            |              |
|             |       |                | 0.007-0.009) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   |                | Kidney --    |              |
|             | inant |                | 2.54 (0.002) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Liver --     |              |
|             |       |                | 0.65-1.21    |              |
|             |       |                | (            |              |
|             |       |                | 0.004-0.008) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Muscle --    |              |
|             |       |                | 5.8 (0.001)  |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Fat -- 1.20  |              |
|             |       |                | (\<0.001)    |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    | Egg yolk --    | Egg white    |              |
|             | ultry | 10.76-16.58    | --3.49       |              |
|             |       | (0.054-0.078)  | (0.045)      |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rat   | In female rat  |              |              |
|             |       | feces, 15% of  |              |              |
|             |       | administered   |              |              |
|             |       | dose in        |              |              |
|             |       | repeated       |              |              |
|             |       | dosing rat     |              |              |
|             |       | metabolism     |              |              |
|             |       | study at day   |              |              |
|             |       | 14             |              |              |
+-------------+-------+----------------+--------------+--------------+
| (*N*-\[     | Rice  |                | Leaves --    | ![]          |
| 2-Aminocarb |       |                | 3.7 (0.153)  | (media/image |
| onyl\]-4-ch |       |                |              | 11.wmf){widt |
| loro-6-(hyd |       |                |              | h="1.2944444 |
| roxymethyl) |       |                |              | 444444445in" |
|             |       |                |              | height       |
| phe         |       |                |              | ="1.31041666 |
| nyl\]-3-bro |       |                |              | 66666666in"} |
| mo-1-(3-chl |       |                |              |              |
| oro-2-pyrid |       |                |              |              |
| inyl)-1*H*- |       |                |              |              |
| pyrazole-5- |       |                |              |              |
| carboxamide |       |                |              |              |
|             |       |                |              |              |
| (IN-HXH40)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 3.4 (0.031)  |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat |                | Beet tops -- |              |
|             | ional |                | 5.7-9.7      |              |
|             | crops |                | (            |              |
|             |       |                | 0.004-0.012) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat forage |              |
|             |       |                | -- ≤5.7      |              |
|             |       |                | (≤0.005)     |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat hay -- |              |
|             |       |                | 2.2 (0.009)  |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat straw  |              |
|             |       |                | -- 1.1-1.2   |              |
|             |       |                | (0.004)      |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   |                | Milk -- 5.9  |              |
|             | inant |                | (0.004)      |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Liver --     |              |
|             |       |                | 0.65-2.1     |              |
|             |       |                | (            |              |
|             |       |                | 0.004-0.014) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Fat -- 1.18  |              |
|             |       |                | (\<0.001)    |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    |                | Liver --     |              |
|             | ultry |                | 2.92-3.20    |              |
|             |       |                | (            |              |
|             |       |                | 0.015-0.016) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Muscle --    |              |
|             |       |                | 1.10         |              |
|             |       |                | (\<0.001)    |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Skin w/fat   |              |
|             |       |                | -- 1.31      |              |
|             |       |                |              |              |
|             |       |                | (0.001)      |              |
+-------------+-------+----------------+--------------+--------------+
| 3-B         | Rice  |                | Leaves --    | ![]          |
| romo-*N*-\[ |       |                | 2.3 (0.088)  | (media/image |
| 4-chloro-2- |       |                |              | 3.wmf){width |
| (hydroxymet |       |                |              | ="1.26875in" |
| hyl)-6-\[(m |       |                |              | height       |
| ethylamino) |       |                |              | ="1.38541666 |
|             |       |                |              | 66666667in"} |
| carbo       |       |                |              |              |
| nyl\]phenyl |       |                |              |              |
| \]-1-(3-chl |       |                |              |              |
| oro-2-pyrid |       |                |              |              |
| inyl)-1*H*- |       |                |              |              |
| pyrazole-5- |       |                |              |              |
| carboxamide |       |                |              |              |
|             |       |                |              |              |
| (IN-HXH44)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 2.0 (0.018)  |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat |                | Beet tops -- |              |
|             | ional |                | 2.7-7.5      |              |
|             | crops |                | (            |              |
|             |       |                | 0.003-0.008) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | 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) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   | Milk -- 26.9   | Kidney --    |              |
|             | inant | (0.018)        | 3.35 (0.003) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       | Muscle --      | Liver --     |              |
|             |       | 10.98 (0.002)  | 0.95-4.16    |              |
|             |       |                | (            |              |
|             |       |                | 0.006-0.026) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Fat --       |              |
|             |       |                | 1.40-1.75    |              |
|             |       |                | (            |              |
|             |       |                | 0.001-0.002) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    |                | Egg yolk --  |              |
|             | ultry |                | 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-\[3-      | Rice  |                | Grain -- 1   | ![]          |
| Bromo-1-(3- |       |                | (0.001)      | (media/image |
| chloro-2-py |       |                |              | 12.wmf){widt |
| ridinyl)-1* |       |                |              | h="1.2618055 |
| H*-pyrazol- |       |                |              | 555555556in" |
| 5-yl\]-6-ch |       |                |              | height       |
| loro-8-(hyd |       |                |              | ="0.95069444 |
| roxymethyl) |       |                |              | 44444444in"} |
| -4(3*H*)-qu |       |                |              |              |
| inazolinone |       |                |              |              |
|             |       |                |              |              |
| (IN-K7H29)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat |                | Wheat forage |              |
|             | ional |                | --           |              |
|             | crops |                |              |              |
|             |       |                | 0.2-2.2      |              |
|             |       |                | (\<          |              |
|             |       |                | 0.001-0.002) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat straw  |              |
|             |       |                | -- 0.6-1.8   |              |
|             |       |                | (            |              |
|             |       |                | 0.003-0.012) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   |                | Fat --       |              |
|             | inant |                | 1.52-1.75    |              |
|             |       |                | (\<          |              |
|             |       |                | 0.001-0.001) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    | Egg yolk --    | Egg white -- |              |
|             | ultry | 13.14-24       | 3.13-3.52    |              |
|             |       | (0.066-0.112)  | (            |              |
|             |       |                | 0.042-0.046) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Liver --     |              |
|             |       |                | 2.27 (0.011) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Muscle --    |              |
|             |       |                | 1.03         |              |
|             |       |                | (\<0.001)    |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Skin w/fat   |              |
|             |       |                | -- 3.19      |              |
|             |       |                | (0.002)      |              |
+-------------+-------+----------------+--------------+--------------+
| 3-Bromo     | Rum   | Milk -- 26.1   | Kidney --    | ![           |
| -*N*-\[4-ch | inant | (0.017)        | 2.85 (0.002) | ](media/imag |
| loro-2-(hyd |       |                |              | e4.wmf){widt |
| roxymethyl) |       |                |              | h="1.2819444 |
| -6-\[\[(hyd |       |                |              | 444444446in" |
| roxymethyl) |       |                |              | height       |
|             |       |                |              | ="1.38541666 |
| amino       |       |                |              | 66666667in"} |
| )carbonyl\] |       |                |              |              |
|             |       |                |              |              |
| phenyl      |       |                |              |              |
| \]-1-(3-chl |       |                |              |              |
| oro-2-pyrid |       |                |              |              |
| inyl)-1*H*- |       |                |              |              |
| pyrazole-5- |       |                |              |              |
| carboxamide |       |                |              |              |
|             |       |                |              |              |
| (IN-K9T00)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rat   | 11.28% of      |              |              |
|             |       | administered   |              |              |
|             |       | dose in        |              |              |
|             |       | repeated       |              |              |
|             |       | dosing rat     |              |              |
|             |       | metabolism     |              |              |
|             |       | study at day   |              |              |
|             |       | 14             |              |              |
+-------------+-------+----------------+--------------+--------------+
| 2-\[        | Rice  |                | Leaves --    | ![]          |
| \[\[3-Bromo |       |                | 4.3 (0.171)  | (media/image |
| -1-(3-chlor |       |                |              | 13.wmf){widt |
| o-2-pyridin |       |                |              | h="1.3180555 |
| yl)-1*H*-py |       |                |              | 555555555in" |
| razol-5-yl\ |       |                |              | height       |
| ]carbonyl\] |       |                |              | ="1.43958333 |
| amino\]-5-c |       |                |              | 33333334in"} |
| hloro-3-\[( |       |                |              |              |
| methylamino |       |                |              |              |
|             |       |                |              |              |
| carbon      |       |                |              |              |
| yl\]benzoic |       |                |              |              |
| acid        |       |                |              |              |
|             |       |                |              |              |
| (IN-KAA24)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 3.9 (0.035)  |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rotat |                | Beet tops -- |              |
|             | ional |                | 1-3.2        |              |
|             | crops |                | (            |              |
|             |       |                | 0.001-0.004) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat forage |              |
|             |       |                | --           |              |
|             |       |                |              |              |
|             |       |                | 0.1-2.1      |              |
|             |       |                | (\<          |              |
|             |       |                | 0.001-0.002) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Wheat straw  |              |
|             |       |                | -- 2.3       |              |
|             |       |                | (0.048)      |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   |                | Liver --     |              |
|             | inant |                | 0.64-2.6     |              |
|             |       |                | (            |              |
|             |       |                | 0.004-0.017) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    |                | Egg yolk --  |              |
|             | ultry |                | 1.92 (0.009) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rat   | 7.65% of       |              |              |
|             |       | administered   |              |              |
|             |       | dose in        |              |              |
|             |       | repeated       |              |              |
|             |       | dosing rat     |              |              |
|             |       | metabolism     |              |              |
|             |       | study at day   |              |              |
|             |       | 14             |              |              |
+-------------+-------+----------------+--------------+--------------+
| 2           | Rice  |                | Grain -- 1.8 | ![]          |
| -Amino-5-ch |       |                | (0.003)      | (media/image |
| loro-3-\[(m |       |                |              | 14.wmf){widt |
| ethylamino) |       |                |              | h="1.1368055 |
|             |       |                |              | 555555556in" |
| carbon      |       |                |              | height       |
| yl\]benzoic |       |                |              | ="1.02083333 |
| acid        |       |                |              | 33333333in"} |
|             |       |                |              |              |
| (IN-L8F56)  |       |                |              |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Leaves --    |              |
|             |       |                | 3.3 (0.135)  |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Straw ^1^ -- |              |
|             |       |                | 2.9 (0.026)  |              |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   |                | Liver --     |              |
|             | inant |                | 4.5-8.23     |              |
|             |       |                | (            |              |
|             |       |                | 0.028-0.052) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Kidney --    |              |
|             |       |                | 1.35 (0.001) |              |
+-------------+-------+----------------+--------------+--------------+
|             | Po    |                | Liver --     |              |
|             | ultry |                | 0.41-1.20    |              |
|             |       |                | (            |              |
|             |       |                | 0.002-0.006) |              |
+-------------+-------+----------------+--------------+--------------+
| (IN-GKQ52)  | Rum   |                | Liver -- 1.3 | ![]          |
|             | inant |                | (0.008)      | (media/image |
|             |       |                |              | 15.wmf){widt |
|             |       |                |              | h="1.2756944 |
|             |       |                |              | 444444445in" |
|             |       |                |              | height       |
|             |       |                |              | ="1.31666666 |
|             |       |                |              | 66666667in"} |
+-------------+-------+----------------+--------------+--------------+
|             | Po    |                | Egg yolk --  |              |
|             | ultry |                | 3.68 (0.019) |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Liver --     |              |
|             |       |                | 1.79-5.05    |              |
|             |       |                | (            |              |
|             |       |                | 0.009-0.026) |              |
+-------------+-------+----------------+--------------+--------------+
| (IN-K3X21)  | Po    |                | Egg white -- | ![           |
|             | ultry |                | 2.07 (0.027) | ](media/imag |
|             |       |                |              | e16.wmf){wid |
|             |       |                |              | th="1.275in" |
|             |       |                |              | height       |
|             |       |                |              | ="0.97152777 |
|             |       |                |              | 77777778in"} |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Muscle --    |              |
|             |       |                | 1.49         |              |
|             |       |                | (\<0.001)    |              |
+-------------+-------+----------------+--------------+--------------+
|             |       |                | Skin w/fat   |              |
|             |       |                | -- 5.86      |              |
|             |       |                | (0.003)      |              |
+-------------+-------+----------------+--------------+--------------+
| (IN-LEM10)  | Rotat |                | Beet tops -- | ![]          |
|             | ional |                | 1.3 (0.002)  | (media/image |
|             | crops |                |              | 17.wmf){widt |
|             |       |                |              | h="1.2743055 |
|             |       |                |              | 555555556in" |
|             |       |                |              | height       |
|             |       |                |              | ="0.97569444 |
|             |       |                |              | 44444444in"} |
+-------------+-------+----------------+--------------+--------------+
|             | Rum   |                | Kidney --    |              |
|             | inant |                | 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        |       |                |              |              |
| (fol        |       |                |              |              |
| iage/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 (t~1/2~ = 228 to 924 days) in aerobic
soils incubated at 25^0^C. It degrades faster at higher soil
temperatures of 34-35^0^C and 49^0^C. 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 (t~1/2~= 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 (K~oc~=153, 1/n=1.0028) in a loamy sand from Spain,
9.16 (K~oc~=509, 1/n=1.0434) in a silty clay loam from IA, 1.36
(K~oc~=272, 1/n=0.8485) in a sandy loam from MS, 1.59 (K~oc~= 526,
1/n=0.9370) in a loamy sand from GA, 2.34 (K~oc~=180, 1/n=0.9256) in a
loam from Italy. Because there is a positive, linear regression between
K~d~ and soil organic carbon, it is appropriate to use K~oc~ 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**[]{#__RefHeading___Toc192910450
.anchor}

No studies were relied on which involved human subjects.

[^1]: 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.

[^2]: **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)