FOR
FURTHER
INFORMATION
CONTACT:
AKIVA
ABRAMOVITCH
at
703
308­
8328
PP#
4F6833
SUPPLEMENTARY
INFORMATION­
EPA
has
received
a
request
to
amend
pesticide
petition
(
PP
4F6833)
from
Nippon
Soda
Co.,
Ltd.
c/
o
Nisso
America
Inc.,
45
Broadway,
Suite
2120,
New
York,
NY,
10006.
This
amendment
to
the
petition
proposes,
pursuant
to
Section
408(
d)
of
the
Federal
Food,
Drug
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
section
346a(
d),
to
amend
40
CFR
part
180
by
establishing
tolerances
for
the
residues
of
acetamiprid
in/
on
cucurbits,
stone
fruit,
tree
nuts,
and
pistachios
as
given
below.
The
proposed
analytical
method
is
by
LC/
MS/
MS.

Pursuant
to
section
408(
d)(
2)
of
the
FFDCA,
as
amended
by
the
Food
Quality
Protection
Act
(
FQPA),
Nippon
Soda
Co.,
Ltd.
has
submitted
the
following
amended
summary
of
information,
data
and
rationales
in
support
of
their
pesticide
petition
and
authorization
for
the
summary
to
be
published
in
the
Federal
Register
in
a
notice
of
receipt
of
the
petition.
This
amended
summary
was
prepared
by
Nippon
Soda
Co.,
Ltd.;
EPA
is
in
the
process
of
evaluating
the
amended
petition
and
has
not
determined
whether
the
data
supports
granting
of
the
petition.
EPA
may
have
made
minor
edits
to
the
summary
for
the
purpose
of
clarity.

A.
Residue
Chemistry­

1.
Plant
Metabolism­
The
metabolism
of
acetamiprid
in
plants
is
well
understood,
having
been
investigated
in
eggplant,
apples,
cabbage,
carrots,
and
cotton.
Metabolism
in
plants
primarily
involves
demethylation
of
the
N­
methyl
group
with
subsequent
hydrolysis
of
the
acetamidine
function
to
give
the
N­
acetyl
compound.
This
compound
is
then
hydrolyzed
to
the
corresponding
amine
followed
by
oxidation
to
the
alcohol
and
acid.
Conjugation
of
the
alcohol
with
glucose
is
also
significant.
Degradation
of
the
side
chain
without
loss
of
the
Nmethyl
group
is
seen
in
carrots
since
this
is
the
major
metabolic
route
in
soil.

2.
Analytical
Method­
Based
upon
the
metabolism
of
acetamiprid
in
plants
and
the
toxicology
of
the
parent
and
metabolites,
quantification
of
the
parent
acetamiprid
is
sufficient
to
determine
toxic
residues.
As
a
result
a
method
has
been
developed
which
involves
extraction
of
acetamiprid
from
crops
with
methanol,
filtration,
partitioning
and
cleanup,
and
analysis
by
LC/
MS/
MS
methods.
The
limit
of
quantification
(
LOQ)
for
the
method
is
0.01
ppm
and
the
method
limit
of
detection
(
LOD)
is
0.003­
0.004
ppm
for
cucurbits,
stone
fruit,
almond,
pecan
nutmeat
and
pistachio.
The
LOQ
and
LOD
for
almond
hulls
is
0.02
ppm
and
0.006
ppm,
respectively.

3.
Magnitude
of
Residues­
Magnitude
of
residue
studies
were
conducted
in
cucumber,
cantaloupe,
and
squash
as
the
representative
commodities
for
the
cucurbit
crop
grouping.
Trials
were
conducted
in
all
of
the
major
use
areas
for
each
of
the
crops
as
specified
in
the
Residue
Chemistry
Guidelines
OPPTS
860.1500
with
applications
at
the
maximum
label
use
rate
for
each
crop.
As
a
result
of
the
field
trials
the
following
tolerance
is
proposed
for
the
commodities
in
the
cucurbit
crop
group:
0.5
ppm.
Magnitude
of
residue
studies
were
conducted
in
peach,
plum
(
fresh
and
dried),
sweet
cherry,
and
tart
cherry
as
the
representative
commodities
for
the
stone
fruit
crop
grouping.
Trials
were
conducted
in
all
of
the
major
use
areas
for
each
of
the
crops
as
specified
in
the
Residue
Chemistry
Guidelines
OPPTS
860.1500
with
applications
at
the
maximum
label
use
rate
for
each
crop.
As
a
result
of
the
field
trials,
the
following
tolerance
is
proposed
for
the
commodities
in
the
stone
fruit
crop
group
except
plum,
prune,
fresh
and
dried:
1.2
ppm.
The
proposed
tolerance
for
plum,
prune,
fresh
and
dried
is
0.3
ppm.

Magnitude
of
residue
studies
were
conducted
in
almonds
and
pecans
as
the
representative
commodities
for
the
tree
nut
crop
grouping.
Almond
residue
data
is
translatable
to
pistachio.
Trials
were
conducted
in
all
of
the
major
use
areas
for
each
of
the
crops
as
specified
in
the
Residue
Chemistry
Guidelines
OPPTS
860.1500
with
applications
at
the
maximum
label
use
rate
for
each
crop.
As
a
result
of
the
field
trials,
the
following
tolerance
is
proposed
for
the
commodities
in
the
tree
nut
crop
group
except
almond
hulls:
0.1
ppm.
The
proposed
tolerance
for
almond
hulls
is
5.0
ppm.
The
proposed
tolerance
for
pistachio
is
0.1
ppm.

B.
Toxicological
Profile­

1.
Acute
Toxicity
for
Technical
Acetamiprid­
The
acute
oral
LD­
50
for
acetamiprid
was
146
mg/
kg
for
female
Sprague­
Dawley
rats
and
217
for
male
rats.
The
acute
dermal
LD­
50
for
acetamiprid
was
greater
than
2000
mg/
kg
in
rats.
The
acute
4
hour
inhalation
LC­
50
for
acetamiprid
was
greater
than
1.15
mg/
L,
the
highest
attainable
concentration.
Acetamiprid
was
not
irritating
to
the
eyes
or
skin
and
was
not
considered
to
be
a
sensitizing
agent.
The
NOEL
for
acute
neurotoxicity
was
10mg/
kg
and
no
evidence
of
neuropathy
was
noted.

Acute
Toxicity
for
Formulated
Acetamiprid
70WP­
The
acute
oral
LD­
50
for
Acetamiprid
70WP
was
944
mg/
kg
for
female
Sprague­
Dawley
rats
and
1107mg/
kg
for
male
rats.
The
acute
dermal
LD­
50
for
formulated
acetamiprid
was
greater
than
2000mg/
kg
in
rats.
The
acute
inhalation
LC­
50
(
four
hour)
for
Acetamiprid
70WP
was
determined
to
be
greater
than
2.88
mg/
L,
the
highest
attainable
concentration.
Acetamiprid
70WP
was
concluded
to
be
a
mild
eye
irritant
and
slight
skin
irritant.
There
were
no
indications
of
skin
sensitization
for
the
formulated
product.

2.
Genetic
Toxicity
for
Technical
Acetamiprid­
Based
on
the
weight
of
the
evidence
provided
by
a
complete
test
battery,
acetamiprid
is
neither
mutagenic
nor
genotoxic.
The
compound
was
found
to
be
devoid
of
mutagenic
activity
(
with
and
without
metabolic
activation)
in
Salmonella
typhimurium
and
Escherichia
coli
(
Ames
assay).
Acetamiprid
was
also
not
mutagenic
in
an
in
vitro
mammalian
cell
gene
mutation
assay
on
Chinese
hamster
ovary
(
CHO)
cells
(
HPRT
locus,
with
and
without
metabolic
activation).
Acetamiprid
did
not
induce
unscheduled
DNA
synthesis
(
UDS)
in
either
rat
liver
primary
cell
cultures
or
in
mammalian
liver
cells
in
vivo.
In
an
in
vitro
chromosomal
aberration
study
using
CHO
cells,
acetamiprid
was
positive
when
tested
under
metabolic
activation
at
cytotoxic
dose
levels;
no
effect
was
detected
without
metabolic
activation.
Acetamiprid
was
non­
clastogenic
in
an
in
vivo
chromosomal
aberration
study
in
rat
bone
marrow.
It
also
was
negative
in
an
in
vivo
mouse
bone
marrow
micronucleus
assay.
3.
Reproductive
and
Developmental
Toxicity­
In
the
multi­
generation
rat
reproduction
study
a
NOEL
of
100
ppm
was
established
based
on
decreased
body
weight
gains
and
a
reproduction
NOEL
of
800
ppm
(
highest
dose
tested)
was
established
for
reproductive
performance
and
fertility.
In
the
rat
teratology
study
the
developmental
NOEL
was
50
mg/
kg/
day
(
maternal
NOEL
of
16
mg/
kg/
day
based
on
decreased
body
weight
and
food
consumption)
and
in
the
rabbit
teratology
study
the
developmental
NOEL
was
30
mg/
kg/
day
(
maternal
NOEL
of
15
mg/
kg/
day
based
on
decreased
body
weight
and
food
consumption).
In
both
the
rat
and
rabbit
studies
there
were
no
fetotoxic
or
teratogenic
findings.

A
developmental
neurotoxicity
study
in
rats
with
acetamiprid
was
conducted.
The
test
article
was
administered
orally
by
gavage
to
Crl:
CD(
SD)
IGS
BR
rats
once
daily
from
gestation
day
6
through
lactation
day
21
inclusive
at
dosage
levels
of
2.5,
10,
and
45
mg/
kg/
day.
One
female
in
the
45
mg/
kg/
day
group
died
during
parturition
on
gestation
day
23,
following
delivery
of
one
pup.
All
other
females
survived
to
the
scheduled
necropsies.
No
adverse
clinical
signs
were
noted.
F0
maternal
toxicity
was
expressed
at
a
dose
level
of
45
mg/
kg/
day
by
a
single
mortality
and
reductions
in
body
weight
gain
and
food
consumption.
No
maternal
toxicity
was
exhibited
at
dose
levels
of
2.5
and
10
mg/
kg/
day.
F1
developmental
toxicity
was
expressed
at
a
dose
level
of
45
mg/
kg/
day
by
early
postnatal
mortality
and
reduced
postweaning
body
weights.
No
developmental
toxicity
was
exhibited
at
dose
levels
of
2.5
and
10
mg/
kg/
day.
Deficits
in
auditory
startle
response
occurred
in
the
45
mg/
kg/
day
group
F1
males
and
females
without
concomitant
effects
in
other
functional
endpoints
(
FOB),
neuropathology
or
brain
morphometry.
Based
on
the
results
of
this
study,
the
NOAEL
for
maternal
toxicity,
developmental
toxicity
and
developmental
neurotoxicity
is
considered
to
be
10
mg/
kg/
day.

4.
Subchronic
Toxicity­
In
the
3­
month
dog
feeding
study
a
NOEL
of
800
ppm
(
32
mg/
kg/
day
for
both
males
and
females)
was
established
based
on
growth
retardation
and
decreased
food
consumption.

In
the
3­
month
rat
feeding
study
a
NOEL
of
200
ppm
(
12.4
and
14.6
mg/
kg/
day
respectively
for
male
and
female
rats)
was
established
based
on
liver
cell
hypertrophy
at
a
dose
of
800
ppm.

In
the
3­
month
mouse
feeding
study
a
NOEL
of
400
ppm
(
53.2
and
64.6
mg/
kg/
day
respectively
for
male
and
female
mice)
was
established
based
on
increased
liver/
body
weight
ratio
and
decreased
cholesterol
in
females
at
800
ppm.

A
13
week
dietary
neurotoxicity
study
for
acetamiprid
established
a
NOEL
of
200
ppm
(
14.8
and
16.3
mg/
kg
for
male
and
female
rats)
based
on
reduced
body
weight
and
food
consumption
decreases
at
800
ppm.
There
was
no
evidence
of
neurotoxicity.

A
21
day
dermal
study
in
rabbits
at
dose
levels
up
to
1000
mg/
kg/
day
caused
no
systemic
toxicity,
dermal
irritation
or
histomorphological
lesions
in
either
sex
tested.

5.
Chronic
Toxicity­
In
the
1­
year
dog
study,
the
NOEL
was
established
at
600
ppm
(
20
and
21
mg/
kg/
day
for
male
and
female
dogs,
respectively)
based
on
growth
retardation
and
decreased
food
consumption
at
a
dose
of
1500
ppm.

In
the
18­
month
mouse
study
the
NOEL
was
established
at
130
ppm
(
20.3
and
25.2
mg/
kg/
day
for
male
and
female
mice)
based
on
growth
retardation
and
hepatic
toxicity
at
400
ppm.
In
the
2­
year
rat
study
the
NOEL
was
160
ppm
(
7.1
and
8.8
mg/
kg/
day
for
male
and
female
rats)
based
on
growth
retardation
and
hepatic
toxicity.
There
were
no
indications
of
carcinogenicity
in
either
the
rat
or
mouse
chronic
studies.

6.
Animal
metabolism­
The
metabolism
of
acetamiprid
is
well
understood
and
the
primary
animal
metabolite
is
IM­
2­
1.

7.
Metabolite
Toxicology­
Testing
of
IM­
2­
1
demonstrated
that
it
is
significantly
less
toxic
than
the
parent
acetamiprid
and
it
is
not
being
considered
as
part
of
the
total
toxic
residue
in
plants,
therefore
no
tolerance
is
being
requested
by
the
registrant.
The
acute
oral
LD50
of
IM­
2­
1
is
2543
mg/
kg
for
male
rats
and
1762
mg/
kg
for
female
rats.

8.
Endocrine
disruption­
Acetamiprid
does
not
belong
to
a
class
of
chemicals
known
or
suspected
of
having
adverse
effects
on
the
endocrine
system.
Developmental
toxicity
studies
in
rats
and
rabbits
and
a
reproductive
study
in
rats
gave
no
indication
that
acetamiprid
has
any
effects
on
endocrine
function.
The
chronic
feeding
studies
also
did
not
show
any
longterm
effects
related
to
endocrine
systems.

C.
Aggregate
Exposure
1.
Dietary­
Acute
and
chronic
dietary
analyses
were
conducted
to
estimate
exposure
to
potential
acetamiprid
residues
in/
on
the
following
crops:
cole
crop
group,
citrus
crop
group,
fruiting
vegetable
crop
group,
pome
fruit
crop
group,
grapes,
leafy
vegetables,
canola
oil,
mustard
seed,
cotton,
tuberous
and
corm
vegetable
crop
group,
cucurbit
crop
group,
stone
fruit
crop
group,
tree
nut
crop
group
and
pistachio
using
the
DEEM
 
FCID
software.
Exposure
estimates
to
drinking
water
were
made
based
on
conservative
tier
1
FIRST
and
SCIGROW
modeling.

2.
Food­
The
acute
dietary
exposure
estimates
at
the
99.9th
percentile
for
the
US
Population
was
calculated
to
be
6.2%
of
the
acute
Reference
Dose
(
aRfD).
The
population
subgroup
with
the
highest
exposure
was
children,
1­
2
years
old
at
19.6%
of
the
aRfD.
The
acute
RfD
was
based
on
the
NOEL
of
10
mg/
kg/
day
in
the
acute
neurotoxicity
study
in
rats.
Chronic
dietary
exposure
estimates
from
residues
of
acetamiprid
and
the
animal
metabolite
for
the
US
Population
was
0.1%
of
the
chronic
Population
Adjusted
Dose
(
cPAD).
The
subpopulation
with
the
highest
exposure
was
children
1­
2
with
0.6%
of
the
cPAD
used.
These
values
are
based
on
projected
percentages
for
percent
of
crop
treated
and
field
trial
residues
at
maximum
label
rates
and
minimum
PHI's
with
no
reduction
factors
for
common
washing,
cooking,
or
preparation
practices.
These
can
be
considered
conservative
values.
The
cPAD
was
based
on
the
NOEL
of
7.1
mg/
kg/
day
in
the
chronic
rat
study
and
an
uncertainty
factor
of
100
to
account
for
inter­
and
intra­
species
variations.
In
the
Final
Rule
establishing
tolerances
for
acetamiprid
on
canola
and
mustard
(
Federal
Register,
Vol.
68,
No.
170
/
Wednesday
,
September
3,
2003
/
Page
52343),
EPA
concluded
that
a
data
base
uncertainty
factor
(
e.
g.,
FQPA
factor)
was
not
needed
to
account
for
the
lack
of
a
developmental
neurotoxicity
study
with
acetamiprid
and
that
reliable
data
supported
removing
the
additional
safety
factor
(
e.
g.,
additional
3­
fold
or
3X)
for
the
protection
of
infants
and
children.
Since
that
time,
an
oral
exposure
developmental
neurotoxicity
study
in
the
rat
was
conducted
with
acetamiprid
and
submitted
to
EPA.
Based
on
the
results
of
this
and
other
developmental
toxicology
studies,
the
inclusion
of
an
additional
FQPA
uncertainty
factor
is
unwarranted.

3.
Drinking
Water­
US
EPA's
draft
Standard
Operating
Procedure
(
SOP)
for
Incorporating
Estimates
of
Drinking
Water
Exposure
Into
Aggregate
Risk
Assessments
was
used
to
perform
the
drinking
water
analysis
for
acetamiprid.
This
SOP
utilizes
a
variety
of
tools
to
conduct
drinking
water
assessments.
These
tools
include
water
models
such
as
SCI­
GROW,
FIRST,
PRZM/
EXAMS,
and
monitoring
data.
If
monitoring
data
are
not
available
then
the
models
are
used
to
predict
potential
residues
in
surface
water
and
ground
water.
In
the
case
of
acetamiprid,
monitoring
data
do
not
exist,
therefore,
FIRST
and
SCIGROW
models
were
used
to
estimate
acetamiprid
residues
in
surface
and
ground
water,
respectively.
The
shortterm
drinking
water
levels
of
comparison
(
DWLOC)
were
greater
than
2000
ppb
while
the
modeled
drinking
water
estimated
concentration
(
DWEC)
was
17
ppb
for
surface
water
and
0.0008
ppb
for
ground
water.
The
intermediate­
term
DWLOCs
were
also
greater
than
2000
ppb
while
the
modeled
DWEC
was
4
ppb
for
surface
water
and
0.0008
ppb
for
ground
water.
The
modeled
DWEC
surface
and
ground
water
residues
were
less
than
the
calculated
DWLOCs
for
short­
and
intermediate­
term
exposures
for
all
adults
and
toddlers
(
1­
2
years
old).

4.
Non­
dietary
exposure­
A
Ready
to
Use,
dilute
formulation
of
acetamiprid
is
registered
for
insect
control
on
outdoor
ornamentals,
vegetables
and
fruit
trees.
Based
on
surrogate
exposure
data
obtained
from
a
carbaryl
study,
the
homeowner
MOE
was
calculated
to
exceed
ten
million.
Postapplication
exposure
resulting
from
contact
with
acetamiprid
treated
foliage
resulted
in
an
MOE
in
excess
of
500,000.
Additionally
a
pending
use
allowing
residential
applications
of
formulated
acetamiprid
both
indoors
and
outdoors
resulted
in
short­
term
applicator
exposure
MOEs
of
greater
than
1,500
and
short­
term
post­
application
exposure
MOEs
of
greater
than
2,000
for
adult
and
toddler
exposure
scenarios.
For
intermediate­
term
post­
application
exposure
following
indoor
applications,
the
MOEs
for
toddlers
and
adults
were
greater
than
2,500.

Short­
and
intermediate­
term
aggregate
exposure
assessments
were
conducted
using
EPA's
Draft
Guidance
for
Performing
Aggregate
Exposure
and
Risk
Assessments
which
suggests
using
the
Total
MOE
method
for
aggregating
exposures.
In
the
case
of
acetamiprid,
an
MOE
greater
than
100
provides
a
reasonable
certainty
that
no
harm
will
occur
from
the
assessed
uses.
Using
the
Total
MOE
method
for
aggregating
exposures,
adults
had
the
lowest
MOE
estimates
in
the
short­
term
aggregate
assessment
while
toddlers
had
the
lowest
MOE
estimates
in
the
intermediate­
term
aggregate
assessment.
All
short­
term
aggregate
MOEs
were
greater
than
900
and
all
intermediate­
term
aggregate
MOEs
were
greater
than
2000.
Therefore,
there
is
reasonable
certainty
that
no
harm
will
result
from
aggregate
(
food,
drinking
water,
and
residential)
exposure
to
acetamiprid
residues.
D.
Cumulative
Effects­
A
determination
has
not
been
made
that
acetamiprid
has
a
common
mechanism
of
toxicity
with
other
substances.
Acetamiprid
does
not
appear
to
produce
a
common
toxic
metabolite
with
other
substances.
A
cumulative
risk
assessment
was
therefore
not
performed
for
this
analysis.

E.
Safety
Determination
1.
U.
S.
Population­
Using
the
conservative
assumptions
described
above
and
based
on
the
completeness
and
reliability
of
the
toxicity
data,
it
is
concluded
that
aggregate
exposure
from
the
existing
and
proposed
uses
of
acetamiprid
will
utilize
at
most
6.2%
of
the
acute
reference
dose
(
aRfD)
at
the
99.9
percentile
of
exposure
and
0.1%
of
the
chronic
Population
Adjusted
Dose
(
cPAD)
for
the
U.
S.
Population.
These
percentages
are
likely
to
be
much
less
as
more
realistic
exposure
data
and
models
are
developed.
EPA
generally
has
no
concern
for
exposures
below
100%
of
the
aRfD
and
cPAD.
Drinking
water
levels
of
comparison
(
DWLOCs)
based
on
these
exposure
estimates
are
much
greater
than
conservative
estimated
concentrations,
and
would
be
expected
to
be
well
below
the
100%
level,
if
they
occur
at
all.
Existing
and
pending
uses
allowing
residential
applications
of
acetamiprid
both
indoors
and
outdoors
resulted
in
short­
term
applicator
exposure
MOEs
of
greater
than
1,500
and
shortterm
post­
application
exposure
MOEs
of
greater
than
2,000
for
adult
and
toddler
exposure
scenarios.
For
intermediate­
term
post­
application
exposure
following
indoor
applications,
the
MOEs
for
adults
and
toddlers
were
greater
than
2,500.
Therefore,
there
is
a
reasonable
certainty
that
no
harm
will
occur
to
the
US
Population
from
aggregate
exposure
to
acetamiprid.

2.
Infants
and
Children­.
In
multi­
generation
reproduction
and
teratology
studies,
no
adverse
effects
on
reproduction
were
observed
in
either
rats
or
rabbits.
In
the
long
term
feeding
studies
in
rats
and
mice
there
was
no
evidence
of
carcinogenicity.
Acetamiprid
was
not
mutagenic
under
the
conditions
of
testing.
There
is
no
indication
of
developmental
neurotoxicity
associated
with
acetamiprid.
Using
the
conservative
assumptions
described
in
the
exposure
section
above,
the
percent
of
the
acute
reference
dose
(
aRfD)
that
will
be
used
is
19.6%
for
children
1­
2
years
old
(
the
most
highly
exposed
sub­
group)
at
the
99.9
percentile
of
exposure
and
0.6%
of
the
chronic
Population
Adjusted
Dose
(
cPAD).
As
in
the
adult
situation,
drinking
water
levels
of
comparison
are
much
higher
than
the
worst
case
drinking
water
estimated
concentrations
and
would
be
expected
to
use
well
below
100%
of
the
RfD,
if
they
occur
at
all.
MOEs
resulting
from
post­
application
exposure
to
acetamiprid
in
residential
areas
are
greater
than
2,000.
Therefore,
there
is
a
reasonable
certainty
that
no
harm
will
occur
to
infants
and
children
from
aggregate
exposure
to
residues
of
acetamiprid.

F.
International
Tolerances­

Acetamiprid
is
registered
for
use
on
food
crops
in
several
countries
outside
the
United
States.
