Brassica (Cole) Leafy Vegetables (Crop Group 5), Fruiting Vegetables
(Crop Group 8), Cucurbit Vegetables (Crop Group 9), Pome Fruits (Crop
Group 11), Stone Fruits (Crop Group 12), Cotton, Grapes, Potatoes, and
Section 18 Exemption on Rice, D346596, Leung Cheng, 2/19/2008

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

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

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

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

Test

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (nonrodent)

870.3200    21-Day Dermal

870.3250    90-Day Dermal

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (nonrodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial

870.5300    Mutagenicity—Gene Mutation - mammalian

870.5385    Mutagenicity—Structural Chromosomal Aberrations

870.5395    Mutagenicity—Micronucleus		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotox. Screening Battery (rat)

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

870.6300    Develop. Neuro		no

no

yes

yes

no

	-

-

yes

yes

-

870.7485    General Metabolism

870.7600    Dermal Penetration		yes

no	yes

-

Special Studies

28-day immunotoxicity (rat)

28-day immunotoxicity (mouse)

yes

yes

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

Table A.2.1. Acute Toxicity of Technical DPX-E2Y45 (Chlorantraniliprole)

Guideline

No.	Study Type	MRID No.	Results	Toxicity Category

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

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

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

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

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

870.2600	Dermal sensitization	46889221	Not a dermal sensitizer	Negative

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

STUDY/

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

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

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

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

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

28-day Oral (capsule)/

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

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

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

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

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

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

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

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

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

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

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

18-Month Oral (feeding)/

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

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

mg/kg bw/d equivalents:

pre-mating:

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

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

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

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

gestation:

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

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

lactation:

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

F1 f: 0, 35, 183, 696, 3641	1199 (male) and 1594 (female)	Not
established	A slight increase in mean liver weights in P1 and F1 males
and females at 238/318.9 mg/kg/day and above, slight increase in mean
adrenal weight at 238/318.9 mg/kg/day and 1199/1594 mg/kg/day P1 and F1
males and females.  Mean body weight of 1199/1594 mg/kg/day  F1 pups was
slightly reduced on lactation days 7, 14 and 21.  No effects on F2
offspring weights during lactation.

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

Develop

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

Develop

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

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

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

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

28-day Immuno-toxicity/

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

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

Acute Toxicity – Technical Chlorantraniliprole

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

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

Guideline

No.	Study Type	MRID No.	Results	Toxicity Category

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

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

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

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

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

870.2600	Dermal sensitization	46889221	Not a dermal sensitizer	Negative

Metabolism Studies (MRID 46979330)

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

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

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

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

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

Toxicologically relevant compound	Parent compound (DPX-E2Y45)

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

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

14-day oral gavage rat (MRID 46979935)

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

90-day oral rat

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

90-day oral mouse

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

90-day oral dog

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

Conclusions:

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

28-day Dermal Toxicity Study (MRID 46889128)

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

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

90-day Subchronic Feeding Rat Study (MRID 46889010)

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

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

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

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

90-day Subchronic Feeding Mouse Study (MRID 46889013)

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

A slight increase (13% and 10% for males and females, respectively) in
liver weight at 1135 mg/kg/day males and 1539 mg/kg/day females was not
associated with any gross or microscopic liver pathology, but could be
attributed to a pharmacological response of hepatic cytochrome P450
enzyme induction.  No liver enzyme measurements were
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Increased incidences (see Table 3, section 3.3.2) of hyper-reactive
behavior in the ≥700 ppm females and hyperactive behavior in the
≥2000 ppm females were observed.  In these animals, hyperactivity and
hyper-reactivity were most commonly observed between Day 56 and 70 or
thereafter.  One 2000 ppm male had convulsions on Day 91, but no other
instance of convulsions was observed in any animal.

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

90-day Subchronic Feeding Dog Study (MRID 46889012)

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

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

52-week Chronic Feeding Dog Study (MRID 46979718)

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

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

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

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

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

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

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

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

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

Developmental Rat Study (MRID 46889108)

Developmental Rabbit Study (MRID 46889109)

In the rat developmental toxicity study, chlorantraniliprole was
administered by oral gavage to time mated Crl:CD(SD)IGS BR female rats
(22/dose group) on gestation days 6-20 at dose levels of 0, 20, 100, 300
or 1000 mg/kg/day (dose volume was 4 mL/kg); and in the rabbit
developmental toxicity study, chlorantraniliprole was administered by
oral gavage to time-mated Hra:(NZW)SPF female rabbits (22/dose group) on
gestation days 7-28 at dose levels of 0, 20, 100, 300, and 1000
mg/kg/day. No test substance related effects on maternal clinical
observations, body weight, weight gain, food consumption, or gross
post-mortem observations were detected at any dose.  The mean number of
corpora lutea, implantation sites, resorptions, live fetuses, fetal
weight, and sex ratio were comparable across all groups.  There were no
abortions, premature deliveries, or complete litter resorptions and no
effects of treatment on the numbers of litters, post-implantation loss,
or on gravid uterine weights.  No test substance-related fetal external,
visceral, skeletal malformations, variations, and adverse effects on
fetal skeletal ossifications were observed at any dose.

Based on the absence of treatment related adverse effects the maternal
systemic toxicity and developmental toxicity NOAEL is greater than 1000
mg/kg/day (limit dose and HDT).

Two Generation Reproduction Rat Study (MRID 46889107)

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

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

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

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

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

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

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

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

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

GENE MUTATION

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

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

CHROMOSOME ABERRATIONS

ions up to precipitating levels (≥750 (g/mL) and there were no
statistically significant increases in the percentages of cells with
structural aberrations or in polyploidy.

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

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

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

Corticosterone Under Basal Conditions

microvesiculation in the adrenal cortex observed in males fed ≥200
ppm.  There were no treatment related effects of chlorantraniliprole on
urine corticosterone excretion in male and female rats.
Chlorantraniliprole does not affect basal corticosterone synthesis in
rats with histologic evidence of minimal to mild increases in the degree
of microvesiculation of the adrenal cortical zona fasciculata.

Corticosterone Under Simulated Physiologic Stress – ACTH Stimulation
Test

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

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

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

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

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

Table B.2.  Tabular Summary of Metabolites and Degradates

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

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

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

(0.077-0.089)

Leaves –  91.6-93.7

(3.803-3.180)

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

Lint/seed – 56.9 (<0.01)

	Lettuce	Leaves –  88.7 (0.268)

	Rice 	Grain –  51.4 (0.08)

Hulls –  66.3 (0.117)

Leaves –  52.3 (2.118)

Sheaths –  64.9 (0.086)

Straw 1–  53.8 (0.486)

	Tomato 	Fruit –  92.2 (0.012)

Leaves – 98.1 (1.340)

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

	Radish tops – 53.8 (0.016)

Radish root – 68 (0.05)

Soybean fodder –

45.4-63.6 (0.07-0.08)

Wheat forage – 53.5-84.1 (0.050-0.198)

Wheat hay – 50.6-73.1 (0.224-0.797)

Wheat grain – 85.9

(0.02)

Wheat straw – 36.6-73.2

(0.079-1.34)

Wheat chaff – 87.3 (0.39)

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

	Kidney – 18.92 (0.016)

Muscle – 41.01 (0.007)

Fat – 34.72-75.29

 (0.024-0.051)

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

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

	Skin w/fat – 17.87 (0.009)

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

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

	Rice

Grain – 1.3 (0.002)

	Hulls – 3.2 (0.006)

Leaves – 4.2 (0.167)

Sheaths – 5.3 (0.007)

Straw 1 – 4.3 (0.039)

Rotational crops

Radish tops – 1.5

(<0.01)

Radish root – 1.4 (<0.01)

Soybean fodder –

0.6-1 (<0.01)

Wheat forage –

0.8-1.4 (0.001-0.002)

Wheat hay – 1.1-2.9 (0.005-0.022)

Wheat straw – 1-2.6 (0.005-0.054)

Ruminant	Fat – 6.35-10.99

(0.004-0.007)	Liver – 6.2 (0.040)

Muscle – 2.0 (<0.001)

Poultry

Egg white – 3.25-6.4 (0.042-0.087)

Muscle – 6.79 (0.002)

Skin w/fat – 3.10 (0.002)

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

(IN-F6L99)

	Rice

Grain – 1.5 (0.002)

	Leaves – 2.7 (0.107)

Sheaths – 1.2 (0.002)

Straw 1 – 2.5 (0.023)

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

Wheat hay – 0.2-2.4 (0.001-0.038)

Wheat straw – 0.5-2.6 (<0.002-0.013)

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

(IN-F9N04)

	Rice

Leaves – 3.2 (0.134)

	Straw 1 – 2.8 (0.025)

Rotational crops

Lettuce – 1.6-5.2 (0.001-0.002)

Beet tops – 4.1-6.2 (0.003-0.007)

Radish tops – 1.1 (<0.01)

Radish root – 2.9 (<0.01)

Soybean fodder –

1.8-2.0 (<0.01)

Wheat forage –

1.4-3.2 (0.002-0.004)

Wheat hay – 0.8-2.1 (0.003-0.032)

Wheat straw – 1.2-2.0 (0.006-0.028)

Poultry

Egg white – 4.37-9.23 (0.055-0.119)

Liver – 1.17-5.37 (0.007-0.028)

Skin w/fat – 8.82 (0.005)

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

(IN-GAZ70)

	Rice

Leaves – 6.1 (0.244)

	Straw 1 – 5.4 (0.049)

Rotational Crops

Lettuce – 0.8-1.9 (<0.001-0.001)

Beet tops – 1.6 (0.002)

Wheat hay – 0.4-2.5 (0.002-0.039)

Soybean fodder –

3.0-6.4 (<0.01-0.01)

Ruminant

Liver – 3.12 (0.020)

Fat – 4.86 (0.002)

Poultry	Egg white – 32.57-40.44

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

Skin w/fat – 1.11 (0.001)

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

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

(IN-H2H20)

	Rice

Leaves – 2.5 (0.101)

	Straw 1 – 2.2 (0.02)

Rotational crops

Beet tops – 0.9-2.8 (0.001-0.002)

Wheat hay – 1.5 (0.009)

Wheat straw – 2-2.5 (0.007-0.009)

Ruminant

Kidney – 2.54 (0.002)

Liver – 0.65-1.21 (0.004-0.008)

Muscle – 5.8 (0.001)

Fat – 1.20 (<0.001)

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

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

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

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

(IN-HXH40)	Rice

Leaves – 3.7 (0.153)

	Straw 1 – 3.4 (0.031)

Rotational crops

Beet tops – 5.7-9.7 (0.004-0.012)

Wheat forage – ≤5.7 (≤0.005)

Wheat hay – 2.2 (0.009)

Wheat straw – 1.1-1.2 (0.004)

Ruminant

Milk – 5.9 (0.004)

Liver – 0.65-2.1 (0.004-0.014)

Fat – 1.18 (<0.001)

Poultry

Liver – 2.92-3.20 (0.015-0.016)

Muscle – 1.10 (<0.001)

Skin w/fat – 1.31

(0.001)

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

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

(IN-HXH44)

Wheat forage – ≤5.7 (≤0.005)

Wheat hay – 0.5-3.1 (0.007-0.013)

Wheat straw – 0.7-2.6 (0.002-0.054)

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

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

Fat – 1.40-1.75 (0.001-0.002)

Poultry

Egg yolk – 1.96 (0.011)

Egg white – 2.86 (0.037)

Liver – 1.65-2.03 (0.009-0.010)

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

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

(IN-K7H29)	Rice

Grain – 1 (0.001)

	Rotational crops

Wheat forage –

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

Liver – 2.27 (0.011)

Muscle – 1.03 (<0.001)

Skin w/fat – 3.19 (0.002)

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

amino)carbonyl]

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

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

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

carbonyl]benzoic acid

	Straw 1 – 3.9 (0.035)

Rotational crops

Beet tops – 1-3.2 (0.001-0.004)

Wheat forage –

0.1-2.1 (<0.001-0.002)

Wheat straw – 2.3 (0.048)

Ruminant

Liver – 0.64-2.6 (0.004-0.017)

Poultry

Egg yolk – 1.92 (0.009)

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

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

carbonyl]benzoic acid

(IN-L8F56)

	Poultry

Egg yolk – 3.68 (0.019)

Liver – 1.79-5.05 (0.009-0.026)

	Ruminant

Kidney – 5.24 (0.005)

Liver – 2.87 (0.018)

Fat – 1.16-6.94 (<0.001-0.005)

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

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

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

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

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

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

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

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

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

Environmental Fate and Effects

Laboratory Studies Summary

Hydrolysis

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

Photodegradation

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

Soil metabolism

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

Mobility

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

Field Studies Summary

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

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

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

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

No studies were relied on which involved human subjects.

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

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

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

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