Document ID: EPA-HQ-OPP-2005-0149-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-12T04:00Z

EPA
Registration
Division
contact:
Barbara
Madden,
703­
305­
6463
The
Interregional
Research
Project
#
4
(
IR­
4)

PP#
5E6991
EPA
has
received
a
pesticide
petition
(
PP#
5E6991)
from
The
Interregional
Research
Project
#
4
(
IR­
4),
681
U.
S.
Highway
#
1
South,
North
Brunswick,
NJ
08902­
3390,
proposing,
pursuant
to
section
408(
d)
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
346a(
d),
to
amend
40
CFR
part
180.564
by
establishing
a
tolerance
for
residues
of
the
combined
residues
of
Indoxacarb,
[(
S)­
methyl
7­
chloro­
2,5­
dihydro­
2­[[(
methoxycarbonyl)[
4­(
trifluoromethoxy)
phenyl]
amino]
carbonyl]
indeno[
1,2e]
[
1,3,4]
oxadiazine­
4a(
3H)­
carboxylate]
and
its
R­
enantiomer
[(
R)­
methyl
7­
chloro­
2,5­
dihydro­
2­[[(
methoxycarbonyl)[
4­(
trifluoromethoxy)
phenyl]
amino]
carbonyl]
indeno
[
1,2­
e]
[
1,3,4]
oxadiazine­
4a(
3H)­
carboxylate]
in
a
75:
25
mixture
(
DPX­
MP062),
respectively,
in
or
on
the
raw
agricultural
commodities:
Vegetable,
cucurbit,
group
9
at
0.5
parts
per
million
(
ppm);
Fruit,
stone,
group
12
at
1.0
ppm;
and
Cranberry
at
1.0
ppm.
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
FFDCA;
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
supports
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

A.
Residue
Chemistry
The
active
ingredient
in
the
end­
use
formulation,
DuPont
Avaunt
®
Insecticide,
is
a
75:
25
mixture
of
two
isomers,
indoxacarb
(
DPX­
KN128)
and
IN­
KN127.
Only
one
of
the
isomers,
indoxacarb
(
DPX­
KN128),
has
insecticidal
activity.
Since
the
insecticidal
efficacy
is
based
on
the
concentration
of
indoxacarb
(
DPX­
KN128),
the
application
rates
have
been
normalized
on
an
indoxacarb
(
DPX­
KN128)
basis.
The
proposed
tolerance
expression
includes
both
indoxacarb
(
DPX­
KN128)
and
IN­
KN127
and
the
residue
method
does
not
distinguish
between
the
enantiomers,
therefore
residues
are
reported
as
the
sum
of
indoxacarb
(
DPX­
KN128)
combined
with
IN­
KN127.
Residues
of
indoxacarb
(
DPX­
KN128)
combined
with
IN­
KN127
will
be
referred
to
as
"
KN128/
KN127."

1.
Plant
metabolism.
The
metabolism
of
indoxacarb
in
plants
is
adequately
understood
to
support
these
tolerances.
Plant
metabolism
studies
in
cotton,
lettuce,
and
tomatoes
showed
no
significant
metabolites.
The
only
significant
residue
was
parent
compound.

2
Analytical
method.
The
plant
residue
enforcement
method
detects
and
quantitates
indoxacarb
in
various
matrices
including
sweet
corn,
lettuce,
tomato,
broccoli,
apple,
grape,
cottonseed,
tomato,
peanut
and
soybean
commodity
samples
by
HPLC
UV.
The
limit
of
quantitation
in
the
method
allows
monitoring
of
crops
with
indoxacarb
residues
at
or
above
the
levels
proposed
in
these
tolerances.
3.
Magnitude
of
residues.
a.
Cucurbits
Crop
Group
9:
The
average
field
residue
value
for
all
cucurbits
was
0.049
ppm
and
the
maximum
was
0.393
ppm.
i.
Ten
field
trials
were
conducted
on
cucumber.
Four
applications
were
made
at
the
maximum
use
rate
of
0.11
lb.
of
active
ingredient
per
acre
(
0.44
lb.
of
active
ingredient
maximum
seasonal
use
rate).
Harvesting
was
conducted
3
days
after
the
last
application
(
PHI­
Post
Harvest
Interval).
The
median
field
residue
value
for
cucumbers
was
0.023
ppm
and
the
maximum
at
0.069
ppm.
ii.
Twelve
field
trials
were
conducted
on
cantaloupe
(
muskmelon).
Four
applications
were
made
at
the
maximum
use
rate
of
0.11
lb.
of
active
ingredient
per
acre
(
0.44
lb.
of
active
ingredient
maximum
seasonal
use
rate).
For
the
twelve
trials,
a
median
0.103
ppm
residue
level
and
a
0.393
ppm
maximum
residue
were
recorded.
The
trials
were
harvested
at
3,
4,
and
5
days
after
the
final
application.
iii.
Eleven
field
trials
were
conducted
on
summer
squash.
Four
applications
were
made
at
the
maximum
use
rate
of
0.11
lb.
of
active
ingredient
per
acre
(
0.44
lb.
of
active
ingredient
maximum
seasonal
use
rate).
For
the
eleven
trials,
harvesting
was
conducted
giving
a
median
0.027
ppm
residue
level
and
a
0.120
ppm
maximum
residue.
The
trials
were
harvested
at
2,
3
and
4
days
after
the
final
application.
b.
Stone
Fruit
Crop
Group
12:
The
average
field
residue
value
for
all
stone
fruits
was
0.164
ppm
and
the
maximum
was
0.640
ppm.
i.
Sixteen
field
trials
were
conducted
on
cherry.
Four
applications
were
made
at
the
maximum
use
rate
of
0.11
lb.
of
active
ingredient
per
acre
(
0.44
lb.
of
active
ingredient
maximum
seasonal
use
rate).
The
trials
were
harvested
at
12,
13,
14,
and
15
days
after
the
final
application
for
sixteen
(
16)
field
trials.
The
median
field
residue
value
for
cherry
was
0.0.231
ppm
with
a
maximum
residue
level
of
0.640
ppm.
ii.
Fifteen
field
trials
were
conducted
on
peach.
Four
applications
were
made
at
the
maximum
use
rate
of
0.11
lb.
of
active
ingredient
per
acre
(
0.44
lb.
of
active
ingredient
maximum
seasonal
use
rate).
The
trials
were
harvested
13,
14,
and
15
days
after
the
final
application
for
fifteen
(
15)
field
trials.
The
median
field
residue
value
for
peach
was
0.183
ppm
with
a
maximun
residue
level
of
0.590ppm.
iii.
Twelve
field
trials
were
conducted
on
plum.
Four
applications
were
made
at
the
maximum
use
rate
of
0.11
lb.
of
active
ingredient
per
acre
(
0.44
lb.
of
active
ingredient
maximum
seasonal
use
rate).
Twelve
field
trials
were
harvested
13,
14,
15
and
16
days
after
the
final
application.
The
median
field
residue
value
for
peach
was
0.045
ppm
with
a
maximum
residue
value
of
0.190
ppm.
c.
Cranberries­
Six
trials
were
conducted
to
determine
residues
for
cranberries.
Four
applications
were
made
at
the
maximum
use
rate
of
0.11
lb.
of
active
ingredient
per
acre
(
0.44
lb.
of
active
ingredient
maximum
seasonal
use
rate).
The
trials
were
harvested
28,
29,
and
30
days
following
the
final
application.
Average
residues
for
the
six
trials
were
0.22
ppm
with
a
maximum
residue
of
0.69
ppm.
B.
Toxicological
Profile
1.
Acute
toxicity.
Based
on
EPA
criteria,
indoxacarb
is
classified
as
follows
for
Toxicity
Categories
Guideline
Title
Results
Category
870.1100
870.1200
870.1300
870.2400
870.2500
870.2600
Acute
Oral
Toxicity
Acute
Dermal
Toxicity
Acute
Inhalation
Toxicity
Primary
Eye
Irritation
Primary
Dermal
Irritation
Skin
Sensitization
LD50:
1730
mg/
kg
(
Male
Rat)
LD50:
268
mg/
kg/(
Female
Rat)

LD50:
>
5000
mg/
kg
(
Rat)

LC50:
>
5.5
mg/
L
(
Male
Rat)
(
70%
MUP)

Effects
reversed
within
72
hours
(
Rabbit)

No
irritation
(
Rabbit)

Sensitizer
(
Guinea
Pig)
Category
II
Category
IV
Category
IV
Category
III
Category
IV
­­­­­­­­­­­­­­­

Formulated
products
are
slightly
less
acutely
toxic
than
indoxacarb.

In
an
acute
neurotoxicity
study,
indoxacarb
exhibited
decreased
forelimb
grip
strength,
decreased
foot
splay,
and
some
evidence
of
slightly
reduced
motor
activity,
but
only
at
the
highest
doses
tested.
The
NOAEL
was
100
mg/
kg
for
males
and
12.5
mg/
kg
for
females
based
on
body
weight
effects
in
females
50
mg/
kg.

2.
Genotoxicty.
Indoxacarb
has
shown
no
genotoxic
activity
in
the
following
listed
in
vitro
and
in
vivo
tests:
Ames
Negative
In
vitro
mammalian
gene
mutation
(
CHO/
HGPRT)
Negative
In
vitro
unscheduled
DNA
synthesis
Negative
In
vitro
chromosomal
aberration
Negative
In
vivo
mouse
micronucleus­
Negative
3.
Reproductive
and
developmental
toxicity.
The
results
of
a
series
of
studies
indicated
that
there
were
no
reproductive,
developmental
or
teratogenic
hazards
associated
with
the
use
of
indoxacarb.
In
a
2
generation
rat
reproduction
study,
the
parental
NOAEL
was
1.5
mg/
kg/
day.
The
parental
NOAEL
was
based
on
observations
of
reduced
weight
gain
and
food
consumption
for
the
higher
concentration
groups
of
the
F0
generation
and
potential
treatment
related
changes
in
spleen
weights
for
the
higher
groups
of
the
F1
generation.
There
was
no
effect
on
mating
or
fertility.
The
NOAEL
for
fertility
and
reproduction
was
6.4
mg/
kg/
day.
The
offspring
NOAEL
was
1.5
mg/
kg/
day,
and
was
based
on
the
reduced
mean
pup
weights
noted
for
the
F1
litters
of
the
higher
concentration
groups.
The
effects
on
pup
weights
occurred
only
at
a
maternal
effect
level
and
may
have
been
due
to
altered
growth
and
nutrition
in
the
dams.
In
studies
conducted
to
evaluate
developmental
toxicity
potential,
indoxacarb
was
neither
teratogenic
nor
uniquely
toxic
to
the
conceptus
(
i.
e.,
not
considered
a
developmental
toxin).
Developmental
studies
conducted
in
rats
and
rabbits
demonstrated
that
the
rat
was
more
susceptible
than
the
rabbit
to
the
maternal
and
fetal
effects
of
DPX
MP062.
Developmental
toxicity
was
observed
only
in
the
presence
of
maternal
toxicity.
The
NOAEL
for
maternal
and
fetal
effects
in
rats
was
2
mg/
kg/
day
based
on
body
weight
effects
and
decreased
food
consumption
at
4
mg/
kg/
day.
The
NOAEL
for
developmental
effects
in
fetuses
was
>
4
mg/
kg/
day.
In
rabbits,
the
maternal
and
fetal
NOAELS
were
500
mg/
kg/
day
based
on
body
weight
effects,
decreased
food
consumption
in
dams
and
decreased
weight
and
delayed
ossification
in
fetuses
at
1000
mg/
kg/
day.
4.
Subchronic
toxicity.
Subchronic
(
90
day)
feeding
studies
were
conducted
with
rats,
mice,
and
dogs.
In
a
90
day
feeding
study
in
rats,
the
NOAEL
was
3.1
and
2.1
mg/
kg/
day
for
males
and
females,
respectively.
In
male
rats,
the
NOAEL
was
based
on
decreased
body
weight
and
nutritional
parameters,
mild
hemolytic
anemia
and
decreased
total
protein
and
globulin
concentration.
In
female
rats,
the
NOAEL
was
based
on
decreased
body
weight
and
food
efficiency.
In
a
subchronic
neurotoxicity
study
in
rats,
there
was
no
evidence
of
neurotoxicity
at
11.9
and
6.09
mg/
kg/
day,
the
highest
dose
tested
for
males
and
females,
respectively.
The
subchronic
NOAEL
in
dogs
(
5.0
mg/
kg/
day,
M/
F)
was
based
on
hemolytic
anemia.
Erythrocyte
values
for
most
dogs
were
within
a
range
that
would
be
considered
normal
for
dogs
in
a
clinical
setting.
Mice
were
less
sensitive
to
indoxacarb
than
the
rats
or
dogs.
NOAELs
(
23
mg/
kg/
day,
males,
16
mg/
kg/
day,
females)
were
based
on
mortality
(
males
only);
increased
reticulocytes
and
Heinz
bodies
and
decreased
body
weight,
weight
gain,
food
consumption,
food
efficiency;
and
increased
clinical
signs
(
leaning
to
one
side
and/
or
with
abnormal
gait
or
mobility)
(
females
only).
In
a
28
day
repeated
dose
dermal
study,
the
NOAEL
was
50
mg/
kg/
day
based
on
decreased
body
weights,
body
weight
gains,
food
consumption,
and
food
efficiency
in
females,
and
changes
in
hematology
parameters,
the
spleen
and
clinical
signs
of
toxicity
in
both
sexes
in
rats.

5.
Chronic
toxicity.
Chronic
studies
with
indoxacarb
were
conducted
on
rats,
mice,
and
dogs
to
determine
oncogenic
potential
and/
or
chronic
toxicity
of
the
compound.
Effects
generally
similar
to
those
observed
in
the
90
day
studies
were
seen
in
the
chronic
studies.
Indoxacarb
was
not
oncogenic
in
rats
or
mice.
The
chronic
NOAEL
in
male
rats
was
5
mg/
kg/
day
based
on
body
weight
and
nutritional
effects.
In
females,
the
NOAEL
of
2.1
mg/
kg/
day
was
based
on
body
weight
and
nutritional
changes,
as
well
as
biologically
significant
hematologic
changes
at
3.6
mg/
kg/
day
and
above.
Hemolytic
effects
were
present
only
through
the
6
month
evaluation
and
only
in
females.
The
regenerative
nature
of
indoxacarb
induced
hemolytic
anemia
was
demonstrated
by
the
absence
of
significant
changes
in
indicators
of
circulating
erythrocyte
mass
at
later
evaluations.
In
mice,
the
chronic
NOAEL
of
2.6
mg/
kg/
day
for
males
was
based
on
deceased
body
weight
and
weight
gain
effects
and
food
efficiency
at
13.8
mg/
kg/
day
and
above.
The
NOAEL
for
females
was
4.0
mg/
kg/
day
based
on
body
weight
nutritional
effects,
neurotoxicity,
and
clinical
signs
at
20
mg/
kg/
day.
In
dogs,
the
chronic
NOAEL
was
about
2.3
and
2.4
mg/
kg/
day
in
males
and
females,
respectively
based
on
hemolytic
effects
similar
to
those
seen
in
the
subchronic
dog
study.

6.
Animal
metabolism.
Livestock
animal
metabolism.
Animal
metabolism
has
been
studied
in
the
rat,
hen,
and
cow
and
is
well
understood.
In
contrast
to
crops,
indoxacarb
is
extensively
metabolized
in
animals.

Poultry.
In
poultry,
hens
were
fed
at
10
ppm/
day
for
5
days,
87
88%
of
the
total
administered
dose
was
excreted;
parent
comprised
51
54%
of
the
total
dose
in
excreta.
Concentrations
of
residues
in
eggs
were
low,
0.3
0.4
of
the
total
dose,
as
were
the
concentrations
of
residues
in
muscle,
0.2%
of
the
total
dose.
Parent
and
metabolite
IN
JT333
were
not
detected
in
egg
whites;
only
insecticidally
inactive
metabolites
were
identified.
Parent
and
IN
JT333
were
found
in
egg
yolks;
however,
their
concentrations
were
very
low
0.01
0.02
ppm.
Concentrations
of
parent
and
IN
JT333
in
muscle
were
at
or
below
the
limit
of
quantitation,
(
LOQ)
(
0.01
ppm).
Poultry
Feeding
study.
A
poultry
feeding
study
was
not
conducted
for
the
initial
Section
3
registration
because
finite
concentrations
of
residues
would
not
be
expected
based
on
the
low
concentration
of
residues
in
the
metabolism
study.
However,
the
Agency
has
required
a
poultry
feeding
study
as
a
condition
of
registration
for
indoxacarb.
The
study
was
submitted
on
October
31,
2003.
Once
the
Agency
has
determined
the
components
of
the
tolerance
expression,
poultry
meat,
fat,
by­
products
and
egg
tolerances
will
be
proposed.

Cattle.
For
the
cow
study,
the
cattle
were
fed
at
10
ppm/
day
for
5
days;
approximately
20%
of
the
total
administered
dose
was
excreted
in
urine
and
53
60%
was
excreted
in
feces
in
5
days.
Four
tenths
to
1.2%
of
the
total
dose
in
urine
was
parent
indicating
extensive
metabolism;
parent
represented
46
68%
of
the
fecal
activity.
Thus,
most
residues
were
not
absorbed;
those
residues
that
were
absorbed
were
extensively
metabolized.
Less
than
1%
of
the
total
administered
dose
was
in
milk,
most
of
which
was
parent
compound.
The
insecticidally
active
metabolite
IN
JT333
was
not
found
in
milk.
Residues
in
muscle
represented
less
than
0.01%
of
the
total
administered
dose
most
of
which
was
parent.
IN
JT333
was
not
detected
in
muscle.
No
other
metabolites
were
seen
above
10%
of
the
dose,
thus
only
parent
and
IN
JT333
were
monitored
in
the
cattle
feeding
study.

Cattle
feeding
study.
A
cattle
feeding
study
was
conducted
with
indoxacarb
at
doses
of
7.5
ppm,
22.5
and
75
ppm.
The
mean
KN128/
KN127
concentrations
were
proportional
to
the
dosing
level
in
whole
milk,
skim
milk,
cream,
muscle,
fat,
liver
and
kidney.
Based
on
final
residue
values
for
the
respective
commodities
contributing
to
the
cattle
diet,
the
anticipated
dietary
burden
in
dairy
cattle
is
51.7
ppm
and
the
anticipated
dietary
burden
in
beef
cattle
is
49.1
ppm.
The
proposed
grape
use
will
not
increase
the
animal
dietary
burden.
Based
on
standard
curves
constructed
from
data
in
the
cattle
feeding
study,
KN128/
KN127
concentrations
at
the
51.7­
ppm
feeding
level
are
0.123
ppm
for
whole
milk,
0.033
ppm
for
skim
milk
and
1.46
ppm
for
cream.
The
KN128/
KN127
concentrations
at
the
49.1
ppm
feeding
level
are
0.046
ppm
for
muscle,
1.37
ppm
for
fat,
0.012
ppm
for
liver
and
0.026
ppm
for
kidney.
Tolerances
have
been
established
at
1.5
ppm
in
fat
(
cattle,
goat,
horse,
sheep
and
hog),
0.05
ppm
in
meat,
0.03
ppm
in
meat
by
products,
0.15
ppm
in
milk
and
4.0
ppm
in
milk
fat.

7.
Metabolite
toxicology.
In
rats,
indoxacarb
was
readily
absorbed
at
low
dose
(
5
mg/
kg),
but
saturated
at
the
high
dose
(
150
mg/
kg).
Indoxacarb
was
metabolized
extensively,
based
on
very
low
excretion
of
parent
compound
in
bile
and
extensive
excretion
of
metabolized
dose
in
the
urine
and
feces.
Some
parent
compound
remained
unabsorbed
and
was
excreted
in
the
feces.
No
parent
compound
was
excreted
in
the
urine.
The
retention
and
elimination
of
the
metabolite
IN
JT333
from
fat
appeared
to
be
the
overall
rate
determining
process
for
elimination
of
radioactive
residues
from
the
body.
Metabolites
in
urine
were
cleaved
products
(
containing
only
one
radiolabel),
while
the
major
metabolites
in
the
feces
retained
both
radiolabels.
Major
metabolic
reactions
included
hydroxylation
of
the
indanone
ring,
hydrolysis
of
the
carboxylmethyl
group
from
the
amino
nitrogen
and
the
opening
of
the
oxadiazine
ring,
which
gave
rise
to
cleaved
products.
Metabolites
were
identified
by
mass
spectral
analysis,
NMR,
UV
and/
or
by
comparison
to
standards
chemically
synthesized
or
produced
by
microsomal
enzymes.

8.
Endocrine
disruption.
Lifespan,
and
multigenerational
bioassays
in
mammals
and
acute
and
subchronic
studies
on
aquatic
organisms
and
wildlife
did
not
reveal
endocrine
effects.
Any
endocrine
related
effects
would
have
been
detected
in
this
definitive
array
of
required
tests.
The
probability
of
any
such
effect
due
to
agricultural
uses
of
indoxacarb
is
negligible.

C.
Aggregate
Exposure
Tolerances
for
indoxacarb
are
proposed
to
support
agricultural
use
on
leafy
greens,
except
spinach,
subgroup
4A,
spinach,
leaf
petioles
subgroup
4B,
fruit,
pome,
except
pear,
group
11,
vegetables,
tuberous
and
corm,
subgroup
1C,
okra,
pea
(
southern),
and
mint.
Tolerances
for
indoxacarb
are
pending
to
support
agricultural
use
on
grapes
and
leafy
brassica.

1.
Dietary
exposure.
The
chronic
RfD
of
0.02
mg/
kg
bw/
day
is
based
on
a
NOAEL
of
2.0
mg/
kg
bw/
day
from
the
subchronic
rat
feeding
study,
the
subchronic
rat
neurotoxicity
study,
and
the
chronic/
carcinogenicity
study,
using
an
uncertainty
factor
of
100.
The
acute
RfD
for
the
general
population
is
0.12
mg/
kg/
day,
based
on
the
NOAEL
of
12.5
mg/
kg
in
the
acute
neurotoxicity
study
and
an
uncertainty
factor
of
100.
The
acute
RfD
for
females
13
50
years
of
age
is
0.02
mg/
kg/
day,
based
on
the
NOAEL
of
2
mg/
kg/
day
observed
in
the
developmental
rat
toxicity
study
and
using
an
uncertainty
factor
of
100.
i.
Food.
Chronic
dietary
exposure
assessment.
Chronic
dietary
exposure
resulting
from
the
currently
approved
use
of
indoxacarb
on
apples,
Crop
group
5
(
brassica
vegetables),
cotton,
pears,
peppers,
sweet
corn,
tomatoes,
eggplant,
alfalfa,
head
and
leaf
lettuce,
peanuts,
potatoes,
soybeans,
and
the
proposed
uses
on
grapes,
leafy
Brassica,
leafy
greens
crop
subgroup
4A
(
except
spinach),
spinach,
leaf
petioles
crop
subgroup
4B,
tuberous
and
corm
vegetables
crop
subgroup
1C,
pome
fruits
crop
group
11
(
except
pear),
okra,
pea
(
Southern),
mint,
Cucurbits
(
Crop
Group
9),
Stone
Fruit
(
Crop
Group
12),
and
Cranberries
are
well
within
acceptable
limits
for
all
sectors
of
the
population.
The
Chronic
Module
of
the
Dietary
Exposure
Evaluation
Model
(
DEEM,
Exponent,
Inc.,
formerly
Novigen
Sciences,
Inc.,
Version
7.87)
was
used
to
conduct
the
assessment
with
the
reference
dose
(
RfD)
of
0.02mg/
kg/
day.
The
analysis
used
overall
mean
field
trial
values,
processing
factors
and
projected
peak
percent
crop
treated
values.
Secondary
residues
in
milk,
meat
and
poultry
products
were
also
included
in
the
analysis.
The
chronic
dietary
exposure
to
indoxacarb
is
0.000191
mg/
kg/
day,
and
utilizes
1%
of
the
RfD
for
the
overall
U.
S.
population.
The
exposure
of
the
most
highly
exposed
subgroup
in
the
population,
children
age
1­
2
years,
is
0.000362
mg/
kg/
day,
and
utilizes
2%
of
the
RfD.
The
table
below
lists
the
results
of
this
analysis,
which
indicate
large
margins
of
safety
for
each
population
subgroup
and
very
low
probability
of
effects
resulting
from
chronic
exposure
to
indoxacarb.

SubgroupSubgroup
Maximum
Dietary
Exposure
(
mg/
kg/
day)
%
cRfD
U.
S
Population
All
infants
Children
1­
2
Children
3­
5
Children
6­
12
Youth
13­
19
Adults
20­
49
Adults
50+
0.000191
0.000133
0.000362
0.000329
0.000199
0.000176
0.000167
0.000192
1
1
2
2
1
1
1
1
Acute
dietary
exposure.
Acute
dietary
exposure
resulting
from
the
currently
approved
use
of
indoxacarb
on
apples,
Crop
group
5
(
brassica
vegetables),
cotton,
pears,
peppers,
sweet
corn,
tomatoes,
eggplant,
alfalfa,
head
and
leaf
lettuce,
peanuts,
potatoes,
soybeans,
and
the
proposed
uses
on
grapes,
leafy
Brassica,
leafy
greens
crop
subgroup
4A
(
except
spinach),
spinach,
leaf
petioles
crop
subgroup
4B,
tuberous
and
corm
vegetables
crop
subgroup
1C,
pome
fruits
crop
group
11
(
except
pear),
okra,
pea
(
Southern),
mint,
Cucurbits
(
Crop
Group
9),
Stone
Fruit
(
Crop
Group
12),
and
Cranberries
are
well
within
acceptable
limits
for
all
sectors
of
the
population.
The
Dietary
Exposure
Evaluation
Model
(
DEEM,
Exponent,
Inc.,
formerly
Novigen
Sciences,
Inc.,
Version
7.87)
was
used
to
conduct
the
assessment.
Margins
of
exposure
(
MOE)
were
calculated
based
on
a
NOAEL
of
12
mg/
kg/
day
for
children
and
the
general
population
(
Pesticide
Fact
Sheet
for
Indoxacarb).
An
endpoint
of
concern
attributable
to
a
single
dose
was
not
identified
for
women
of
childbearing
age;
therefore
an
acute
RfD
was
not
established
for
this
population.
The
Tier
3
analysis
used
distributions
of
field
trial
residue
data
adjusted
for
projected
peak
percent
crop
treated.
Secondary
residues
in
milk,
meat
and
poultry
products
were
also
included
in
the
analysis.
The
results
of
this
analysis
are
given
in
the
table
below.
The
percent
of
the
acute
population
adjusted
dose
(
a
PAD)
for
all
population
subgroups
shows
that
an
adequate
margin
of
safety
exists
in
each
case.
Thus,
the
acute
dietary
safety
of
indoxacarb
for
established
and
the
follow
on
use
clearly
meets
the
FQPA
standard
of
reasonable
certainty
of
no
harm
and
presents
acceptable
acute
dietary
risk.

Subgroup
99.9th
Percentile
Of
Exposure
Exposure
(
mg/
kg/
day)
%
Acute
population
adjusted
dose
(
aPAD)
U.
S.
Population
All
infants
Children
1­
2
Children
3­
5
Children
6­
12
Youth
13­
19
Adults
20­
49
Adults
50+
0.020408
0.018959
0.027676
0.036348
0.018096
0.022845
0.019081
0.019863
17
16
23
30
15
19
16
17
ii.
Drinking
water.
Indoxacarb
is
highly
unlikely
to
contaminate
groundwater
resources
due
to
its
immobility
in
soil,
low
water
solubility,
high
soil
sorption,
and
moderate
soil
half
life.
Based
on
the
PRZM/
EXAMS
and
SCI
GROW
models
the
estimated
environmental
concentrations
(
EECs)
of
indoxacarb
and
its
R
enantiomer
for
acute
exposures
are
estimated
to
be
6.84
parts
per
billion
(
ppb)
for
surface
water
and
0.0025
ppb
for
ground
water.
The
EECs
for
chronic
exposures
are
estimated
to
be
0.316
ppb
for
surface
water
and
0.0025
ppb
for
ground
water.
Drinking
water
levels
of
comparison
(
DWLOCs),
theoretical
upper
allowable
limits
on
the
pesticide's
concentration
in
drinking
water,
were
calculated
to
be
much
higher
than
the
EECs.
The
chronic
DWLOCs
ranged
from
198
to
697
ppb.
The
acute
DWLOCs
ranged
from
440
to
3890
ppb.
Thus,
exposure
via
drinking
water
is
acceptable.

2.
Non­
dietary
exposure.
Indoxacarb
product
registrations
for
residential
non
food
uses
have
been
approved.
Non
occupational,
non
dietary
exposure
for
DPX
MP062
has
been
estimated
to
be
extremely
small.
Therefore,
the
potential
for
non
dietary
exposure
is
insignificant.
D.
Cumulative
Effects
EPA's
consideration
of
a
common
mechanism
of
toxicity
is
not
necessary
at
this
time
because
there
is
no
indication
that
toxic
effects
of
indoxacarb
would
be
cumulative
with
those
of
any
other
chemical
compounds.
Oxadiazine
chemistry
is
new,
and
indoxacarb
has
a
novel
mode
of
action
compared
to
currently
registered
active
ingredients.

E.
Safety
Determination
1.
U.
S.
population.
Dietary
and
occupational
exposure
will
be
the
major
routes
of
exposure
to
the
U.
S.
population,
and
ample
margins
of
safety
have
been
demonstrated
for
both
situations.
The
chronic
dietary
exposure
to
indoxacarb
is
0.000191
mg/
kg/
day,
which
utilizes
1%
of
the
RfD
for
the
overall
U.
S.
population,
using
mean
field
trial
values,
processing
factors
and
projected
peak
percent
crop
treated
values.
The
percent
of
the
acute
population
adjusted
dose
(
17%
aPAD)
for
the
overall
U.
S.
population
shows
that
an
adequate
margin
of
safety
exists.
Using
only
PHED
data
levels
A
and
B
(
those
with
a
high
level
of
confidence),
MOEs
for
occupational
exposure
are
650
for
mixer/
loaders
and
1351
for
air­
blast
applicators
(
worst
case).
Based
on
the
completeness
and
reliability
of
the
toxicity
data
and
the
conservative
exposure
assessments,
there
is
a
reasonable
certainty
that
no
harm
will
result
from
the
aggregate
exposure
of
residues
of
indoxacarb
including
all
anticipated
dietary
exposure
and
all
other
non
occupational
exposures.

2.
Infants
and
children.
Chronic
dietary
exposure
of
the
most
highly
exposed
subgroup
in
the
population,
children
age
1
2
years,
is
0.000362
mg/
kg/
day
or
2%
of
the
RfD.
For
all
infants,
the
exposure
accounts
for
1%
of
the
RfD.
For
acute
exposure
at
the
99.9th
percentile
(
based
on
a
Tier
3
assessment)
the
exposure
was
0.036348
mg/
kg/
day
(
30%
aPAD)
for
children
3
5
and
0.018959
mg/
kg/
day
(
16%
aPAD)
for
all
infants.
Residential
uses
of
indoxacarb
have
been
approved
and
exposure
is
calculated
to
be
extremely
minimal.
The
estimated
levels
of
indoxacarb
in
drinking
water
are
well
below
the
below
the
DWLOC.
Based
on
the
completeness
and
reliability
of
the
toxicity
data,
the
lack
of
toxicological
endpoints
of
special
concern,
the
lack
of
any
indication
that
children
are
more
sensitive
than
adults
to
indoxacarb,
and
the
conservative
exposure
assessment,
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
and
children
from
the
aggregate
exposure
of
residues
of
indoxacarb,
including
all
anticipated
dietary
exposure
and
all
other
non
occupational
exposures.
Accordingly,
there
is
no
need
to
apply
an
additional
safety
factor
for
infants
and
children.

F.
International
Tolerances
To
date,
numerous
tolerances
exist
for
indoxacarb
residues
in
various
food
and
feed
crops
and
foods
of
animal
origin
in
at
least
25
countries.