Document ID: EPA-HQ-OPP-2004-0152-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-05-06T04:00Z

1
TXR
No.:
012319
DATE:
September
23,
1997
MEMORANDUM
SUBJECT:
IMIDACLOPRID
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Jess
Rowland
Branch
Senior
Scientist,
Science
Analysis
Branch,
Health
Effects
Division
(
7509C)

THROUGH:
K.
Clark
Swentzel
Chairman,
Hazard
Identification
Assessment
Review
Committee
Toxicology
Branch
II,
Health
Effects
Division
(
7509C)

TO:
Donna
Davis
Chief,
Registration
Action
Branch,
Health
Effects
Division
(
7509C)

and
Elizabeth
Haeberer
Product
Manger
Registration
Action
Branch,
Registration
Division
(
7508W)

PC
Code:
129099
On
September
11,
1997,
the
Health
Effects
Division's
Hazard
Identification
Review
committee
met
to
evaluate
the
toxicology
data
base
of
Imidacloprid
to
select
toxicological
endpoints
for
acute
dietary
as
well
as
occupational
and
residential
exposure
risk
assessments.
The
Committee
also
re­
assessed
the
Reference
Dose
established
for
chronic
dietary
risk
assessment
and
addressed
the
sensitivity
of
infants
and
children
from
exposure
to
Imidacloprid
as
required
by
the
Food
Quality
Protection
Act
of
1996.
2
Committee
Members
in
Attendance
Committee
members
in
attendance:
David
Andersen,
Karl
Baetcke,
Susan
Makris,
Nancy
McCarroll,
Kathleen
Raffeale,
John
Redden
and
Jess
Rowland.
Members
in
absentia:
William
Buram
and
Melba
Morrow
did
not
attend
the
meeting.
The
data
was
presented
by
Dr
Willimas­
Foy,
Registration
Action
Branch
2.

Data
Presentation:
Dr.
S.
Williams­
Foy
Report
Preparation:
Jess
Rowland,
M.
S
3
TABLE
OF
CONTENTS
I.
TOXICOLOGY
PROFILE
A.
Acute
Toxicity
B.
Subchronic
Toxicity
C.
Chronic
Toxicity
D.
Carcinogenicity
E.
Reproductive
Toxicity
F.
Developmental
Toxicity
G.
Mutagenicity
H.
Dermal
Absorption
I.
Recommendation
for
a
Developmental
Neurotoxicity
Study
II.
HAZARD
IDENTIFICATION
A.
Acute
Dietary
B.
Chronic
Dietary
(
Reference
Dose)

C.
Occupational/
Residential
Exposure
1.
Short­
Term
Dermal
Exposure
2.
Intermediate­
Term
Dermal
Exposure
3.
Long­
Term
Dermal
Exposure
4.
Inhalation
Exposure
(
Any
Time
Period)

III.
FQPA
CONSIDERATIONS
IV.
UNCERTAINTIES
FOR
DIETARY
RISK
ASSESSMENTS
A.
Acute
Dietary
Risk
Assessment
B.
Chronic
Dietary
Risk
Assessment
4
I.
TOXICOLOGY
PROFILE
A.
Acute
Toxicity
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
Acute
Oral
42055331
LD
50
=
424
mg/
kg
(
M)
>
450
mg/
kg
(
F)
III
81­
2
Acute
Dermal
42055332
LD
50
=
>
5000
mg/
kg
IV
81­
3
Acute
Inhalation
42256317
LC
50
=
>
5.33
mg/
L
IV
81­
4
Primary
Eye
Irritation
4205534
Non
irritant
IV
81­
5
Primary
Skin
Irritation
42055335
Non­
irritant
IV
81­
6
Dermal
Sensitization
42055336
Non­
sensitzer
NA
81­
8
Acute
Neurotoxicity
4317301
NOEL
=
Not
established
LOEL
=
42
mg/
kg/
day
NA
B.
Subchronic
Toxicity
In
a
dermal
toxicity
study,
groups
of
5
male
and
5
female
New
Zealand
White
rabbits
received
repeated
dermal
applications
of
Imidacloprid
(
95%)
at
1000
mg/
kg/
day
(
Limit
Dose),
6
hours/
day,
5
days/
week
for
three
weeks.
No
dermal
or
systemic
toxicity
was
seen.
For
systemic
and
dermal
toxicity,
the
NOEL
was
>
1000
mg/
kg/
day;
a
LOEL
was
not
established
(
MRID
No.
42256329).

In
an
oral
toxicity
study,
groups
of
Fischer
344
rats
(
12/
sex/
dose)
were
fed
diets
containing
Imidacloprid
(
98.8%)
at
0,
150,
1000,
or
3000
ppm
(
0,
9.3,
63.3,
or
196
mg/
kg/
day
in
males
and
0,
10.5,
69.3
or
213
mg/
kg/
day
in
females,
respectively)
for
90
days.
No
treatment­
related
effects
were
seen
at
150
ppm.
Treatment­
related
effects
included
decreases
in
body
weight
gain
during
the
first
four
weeks
of
the
study
at
1000
ppm
(
22%
in
males
and
18%
in
females)
and
3000
ppm
(
50%
in
males
and
25%
in
females)
with
an
associated
decrease
in
forelimb
grip
strength
especially
in
males.
The
NOEL
was
150
ppm
(
9.3
and
10.5
mg/
kg/
day
in
males
and
females,
respectively)
and
the
LOEL
was
1000
ppm
(
63.3
and
69.3
mg/
kg/
day
in
males
and
females,
respectively)
(
MRID
No.
43286401).
5
C.
Chronic
Toxicity
In
a
chronic
toxicity
study,
groups
of
beagle
dogs
(
4/
sex/
dose)
were
fed
diets
containing
Imidaclorpid
(
94.9%)
at
0,
200
or
1250/
2500
ppm
(
0,
6.1,
15
or
41/
72
mg/
kg/
day,
respectively)
for
52
weeks.
The
1250
ppm
was
increased
to
2500
ppm
from
week
17
onwards.
The
threshold
NOEL
was
1250
ppm
(
41
mg/
kg/
day).
The
LOEL
was
2500
ppm
(
72
mg/
kg/
day)
based
on
increased
cytochrome­
P­
450
levels
in
both
sexes
and
was
considered
to
be
a
threshold
dose
(
MRID
No.
42273002).

D.
Carcinogenicity
In
a
combined
chronic
toxicity/
carcinogenicity
study,
groups
of
Bor
WISW
rats
(
50/
sex/
dose)
received
Imidacloprid
(
95.3%)
at
0,
100,
300
or
900
ppm
(
0,
5.7,
16.9
or
51.3
mg/
kg/
day
in
males
and
0,
7.6,
24.9,
or
73
mg/
kg/
day
in
females,
respectively)
for
104
weeks.
In
another
study,
rats
of
the
same
strain
(
50/
sex)
received
Imidacloprid
at
0
or
1800
ppm
(
0,
102.6
and
143.7
mg/
kg/
day
in
males
and
females,
respectively)
for
104
weeks.
For
chronic
toxicity,
the
NOEL
was
100
ppm
(
5.7
mg/
kg/
day)
and
the
LOEL
was
300
ppm
(
16.9
mg/
kg/
day)
based
on
decreased
body
weight
gains
in
females
and
increased
thyroid
lesions
in
males.
There
was
no
evidence
of
carcinogenicity
in
either
sex
(
MRID
No.
42256331
and
42256332).

In
a
carcinogenicity
study
groups
of
B6C3F1
mice
(
50/
sex/
dose)
were
fed
diets
containing
Imidacloprid
(
95%)
at
0,
100,
330
or
1000
ppm
(
0,
20,
66
or
208
mg/
kg/
day
in
males
and
0,
30,
104
or
274
mg/
kg/
day
in
females,
respectively)
for
2
years.
In
a
supplementary
study
conducted
to
evaluate
the
adequacy
of
the
high
dose
tested
in
the
main
study,
the
same
strain
of
mice
(
50/
sex)
received
0
or
2000
ppm
(
414
and
424
mg/
kg/
day
in
males
and
females,
respectively)
for
the
same
time
period.
For
chronic
toxicity,
the
NOEL
was
1000
ppm
(
208
mg/
kg/
day).
The
LOEL
was
2000
ppm
(
414
mg/
kg/
day)
based
on
decreased
bodyweight
gain,
food
consumption
and
water
consumption.
There
was
no
evidence
of
carcinogenicity
in
either
sex
(
MRID
No.
42256335
and
42256336).

E.
Developmental
Toxicity
In
a
developmental
toxicity
with
Sprague­
Dawley
rats,
groups
of
pregnant
animals
(
25/
group)
received
oral
administration
of
Imidacloprid
(
94.2%)
at
0,
10,
30,
or
100
mg/
kg/
day
during
gestation
days
6
through
16.
Maternal
toxicity
was
manifested
as
decreased
body
weight
gain
at
all
dose
levels
and
reduced
food
consumption
at
100
mg/
kg/
day.
No
treatment­
related
effects
were
seen
in
any
of
the
reproductive
parameters
(
i.
e.,
cesarian
section
evaluation).
At
100
mg/
kg/
day,
developmental
toxicity
manifested
as
characterized
as
wavy
ribs
(
fetus
=
7/
149
in
treated
vs.
2/
158
in
controls
and
litters,
4/
25
vs.
1/
25).
For
maternal
toxicity,
the
LOEL
was
10
mg/
kg/
day
)
LDT)
based
on
decreased
body
weight
gain;
a
NOEL
was
not
established.
For
developmental
toxicity,
the
NOEL
was
30
mg/
kg/
day
and
the
LOEL
was
100
mg/
kg/
day
based
on
increased
wavy
ribs
(
MRID
No.
42256338).
6
In
a
developmental
toxicity
with
Chinchilla
rabbits,
groups
of
16
pregnant
does
were
given
oral
doses
of
Imidacloprid
(
94.2%)
at
0,
8,
24
or
72
mg/
kg/
day
during
gestation
days
6
through
18.
For
maternal
toxicity,
the
NOEL
was
24
mg/
kg/
day
and
the
LOEL
was
72
mg/
kg/
day
based
on
mortality,
decreased
body
weight
gain,
increased
resorption,
and
increased
abortion.
For
developmental
toxicity,
the
NOEL
was
24
mg/
kg/
day
and
the
LOEL
was
72
mg/
kg/
day
based
on
decreased
fetal
body
weight,
increased
resorptions,
and
and
increased
skeletal
abnormalities
(
MRID
No.
42256339).

E.
Reproductive
Toxicity
In
a
two­
generation
reproduction
study,
95.3%
Imidacloprid
was
administered
to
Wistar/
Han
rats
at
dietary
levels
of
100,
250,
or
700
ppm
(
7.3,
18.3,
or
52.0
mg/
kg/
day
for
males
and
8.0,
20.5,
or
57.4
mg/
kg/
day
for
females)
(
MRID
42256340,
Doc.
No.
010537).
The
study
DER
indicated
that
the
parental
NOEL
was
700
ppm
(
55
mg/
kg/
day)
and
the
parental
LOEL
was
not
determined.
The
DER
also
stated
that
the
reproductive
NOEL
was
100
ppm
(
8
mg/
kg/
day)
and
the
reproductive
LOEL
was
250
ppm
(
19
mg/
kg/
day),
based
upon
decreased
pup
body
weight
in
both
generations.
The
Committee
reviewed
the
adult
and
pup
body
weight
data
and
provided
the
following
comments:
1)
Based
upon
body
weight
data
in
parental
animals,
significant
decreases
in
premating,
gestation,
and
lactation
body
weight
were
observed
in
males
and/
or
females
of
both
generations
at
700
ppm.
2)
Overall
body
weight
gains
during
premating
were
reduced
although
they
did
not
appear
to
be
significantly
affected.
The
assertion
by
the
study
reviewer,
that
decreased
palatability
was
the
primary
cause
for
the
body
weight
decrements
was
not
supported
by
the
body
weight
data
from
the
first
week
of
dosing
(
during
which
no
body
weight
decreases
occurred).

Therefore,
the
Committee
agreed
that
the
parental
systemic
LOEL
was
700
ppm,
based
upon
decreased
mean
body
weight
in
males
and
females
of
both
generations,
and
the
parental
systemic
NOEL
was
250
ppm.
The
Committee
also
reviewed
the
body
weight
data
for
the
four
sets
of
litters
produced
during
this
study.
Although
the
study
reviewer
determined
that
the
reproductive
toxicity
LOEL
was
250
ppm,
based
upon
decreased
pup
body
weight,
the
Committee
found
that
effects
at
that
dietary
level
were
inconsistent
between
and
within
generations.
The
significant
differences
noted
for
the
F1a
and
F1b
litters
were
actually
increases
in
body
weight;
then
in
the
second
generation,
significant
decreases
were
only
observed
on
day
7
for
the
F2a
pups
and
on
day
21
for
the
F2b
pups,
although
a
dose
response
was
suggested.
The
Committee
concluded
that
the
evidence
for
a
treatment­
related
effect
on
pup
body
weight
at
250
ppm
was
equivocal.
For
parental/
systemic/
reproductive
toxicity,
the
NOEL
was
250
ppm
(
18.3
mg/
kg/
day)
and
the
LOEL
was
750
ppm
(
52
mg/
kg/
day),
based
on
decreases
in
body
weight
in
both
sexes
in
both
generations.
Based
on
these
factors,
the
Committee
recommended
that
the
Data
Evaluation
Record
should
be
revised
to
indicate
the
parental/
systemic/
reproductive
NOEL
and
LOEL
to
be
250
and
700
ppm,
respectively,
based
upon
the
body
weight
decrements
observed
in
both
sexes
in
both
generations.
7
G.
Mutagenicity
As
shown
below,
mutagenicity
studies
have
demonstrated
that
Imidacloprid
is
nonmutagenic
both
in
vivo
and
in
vitro
Assay
MRIDs
#
Results
Ames­
Salmonella
42256363
Negative
Recombination
assay
­
yeast
42256353
Negative
Chromosomal
aberration
­
in
vivo
42256344
Negative
Chromosomal
aberration
­
in
vitro
42256345
Negative
Sister
Chromatid
assay
­
in
vivo
42256346
Negative
Cytogenetics
­
CHO
cells
­
in
vitro
42256342
Negative
Micronucleus
­
mouse
42256366
Negative
DNA
repair
test
42256353
Negative
HGPRT
assay
­
CHO
42256365
Negative
H.
Dermal
Absorption
No
dermal
absorption
studies
are
available.
The
Committee
noted
the
lack
of
dermal
toxicity
via
this
route
with
the
dermal
LD50
of
>
5000
mg/
kg
in
rabbits
as
well
as
lack
of
dermal
or
systemic
toxicity
at
1000
mg/
kg/
day
(
Limit­
Dose)
in
the
21­
day
dermal
toxicity
study
in
rabbits.
8
I.
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
Committee
recommended
that
a
developmental
neurotoxicity
study
be
required
for
Imidacloprid.
The
following
information
was
considered
in
the
weight­
of­
evidence
evaluation.

1)
Evidence
that
support
requiring
a
developmental
neurotoxicity
study:

Imidacloprid
is
a
neurotoxic
chemical.
Evidence
of
functional
neurotoxicity
was
seen
in
the
acute
neurotoxicity
study
where
a
single
oral
dose
caused
a
dose­
related
decreased
motor
activity
in
all
dosed
females,
including
a
25%
decrease
at
the
lowest
dose
tested
(
42
mg/
kg/
day).

Imidacloprid
is
a
nicotine
analog
and
is
expected
to
act
as
a
nicotinic
agonist.

With
this
class
of
chemical,
there
is
no
readily
available
biomarker
(
e.
g.,
Cholinesterase
inhibition)
for
assessment
of
subtle
neurotoxic
effects.

In
the
1993
2­
year
chronic
study
in
rats,
significant
alterations
to
brain
weight
were
noted
in
males
and
females
at
900
ppm
(
51.3
and
73
mg/
kg/
day
in
males
and
females).

There
has
been
no
assessment
for
delayed
neurotoxicity
study
in
the
hen.

A
review
of
the
literature
suggests
that
nicotine
causes
developmental
toxicity,
including
functional
deficits,
in
animals
and/
or
humans
exposed
in
utero.

2)
Evidence
that
do
not
support
asking
for
a
developmental
neurotoxicity
study:

No
effects
on
histopathology
of
the
brain
were
observed
in
any
of
the
guideline
studies
in
which
these
parameters
were
measured
including
the
acute
and
subchronic
neurotoxicity
studies
in
rats.

No
evidence
of
developmental
anomalies
of
the
fetal
nervous
system
were
observed
in
the
prenatal
developmental
toxicity
studies
in
either
rats,
or
rabbits,
at
maternally
toxic
oral
doses
up
to
100
and
72
mg/
kg/
day,
respectively.
9
II.
FQPA
CONSIDERATIONS
The
prenatal
developmental
toxicity
data
demonstrated
no
indication
of
increased
sensitivity
of
rats
or
rabbits
to
in
utero
exposure
to
Imidacloprid.
In
addition,
the
multigeneration
reproduction
study
data
did
not
identify
any
increased
sensitivity
of
rats
to
in
utero
or
postnatal
exposure.
Maternal
and
parental
NOELs
were
lower
or
equivalent
to
developmental
or
offspring
NOELs.

III.
HAZARD
IDENTIFICATION
A.
Acute
Dietary
(
one­
day)

Study
Selected:
Acute
Neurotoxicity
­
Rat
§
81­
8
MRID
No
41370301
&
43285801
EXECUTIVE
SUMMARY:
In
an
acute
neurotoxicity
study,
groups
of
Sprague­
Dawley
rats
(
18/
sex/
dose)
were
given
a
single
oral
administration
of
Imidacloprid
(
97.6%)
in
0.5%
methylcellulose
with
0.4%
Tween
80
in
deionized
water
at
0,
42,
151
or
307
mg/
kg.
Parameters
evaluated
included:
clinical
pathology
(
6/
sex/
dose);
Functional
Observation
Battery
(
FOB)
measurements
(
12/
sex/
dose);
and
neuropathology
(
6/
sex/
dose).
FOB
measurements
were
made
approximately
90
minutes
post
dosing,
and
on
days
7
and
14.
Motor
activity
measurements
were
made
at
approximately
2.5
hours
post
dosing.

At
307
mg/
kg/
day,
4/
18
males
and
10/
18
females
died
and
both
sexes
of
rats
at
this
dose
exhibited
decreased
number
of
rears,
grip
strength
(
forelimb
and
hindlimb)
and
response
to
stimuli
(
auditory,
touch,
or
tail
pinch)
as
well
as
increased
gait
abnormalities
and
righting
reflex
impairments
and
body
temperatures.
These
symptoms
regressed
by
day
5.
At
151
mg/
kg/
day,
cage
side
FOB
assessments
revealed
tremors
in
one
male
and
one
female
and
and
red
nasal
staining
in
one
male.
On
the
day
of
dosing,
a
dose­
related
decrease
in
total
session
motor
activity
was
observed
in
males
at
151
mg/
kg/
day
(
25%
decrease)
and
307
mg/
kg/
day
(
73%)
and
in
females
at
all
dose
levels
with
the
decreases
(
25,
48,
and
81%,
respectively
at
42,
151
and
307
mg/
kg/
day)
reaching
statistical
significance
(
p
<
0.05)
at
151
and
307
mg/
kg/
day
dose
levels.
Decreases
in
motor
activity
was
seen
at
all
time
intervals.
Total
session
locomotor
activity
was
also
decreased
to
about
the
same
percentage
difference
but
statistical
significance
were
not
reported.
On
days
7
and
14,
decreases
(
not
statistically
significant)
were
still
observed
in
motor
and
locomotor
activity
in
surviving
high­
dose
males.
The
LOEL
was
42
mg/
kg
based
on
the
decrease
in
motor
and
locomotor
activities
observed
in
females;
a
NOEL
was
not
established
(
MRID
No.
4137031
and
43285801).

Dose/
Endpoint
for
Risk
Assessment:
LOEL=
42
mg/
kg/
day
based
on
the
dose­
related
10
decreases
in
motor
activity
in
females.
A
NOEL
was
not
established.

Comments
about
Study/
Endpoint:
An
Uncertainty
Factor
of
3
was
assessed
to
this
dose
(
LOEL)
to
account
for
the
lack
of
a
NOEL.
A
Margin
of
Exposure
of
300
is
required.

The
Committee
recommended
that
the
DER
should
be
revised
to
reflect
a
LOEL
of
42
mg/
kg/
day
based
on
the
dose­
related
decreases
in
motor
activity
in
female
rats.
This
effect
was
seen
in
this
sex
at
all
dose
levels
at
all
time
intervals.

B.
Chronic
Dietary
[
Reference
Dose
(
RfD)]

Study
Selected:
Chronic
toxicity/
Carcinogenicity
­
Rat
(
§
83­
5)

MRID
No.
42256335
&
42256336
Executive
Summary:
In
a
combined
chronic
toxicity/
carcinogenicity
study,
groups
of
Bor
WISW
rats
(
50/
sex/
dose)
received
Imidacloprid
(
95.3%)
at
0,
100,
300
or
900
ppm
(
0,
5.7,
16.9
or
51.3
mg/
kg/
day
in
males
and
0,
7.6,
24.9,
or
73
mg/
kg/
day
in
females,
respectively)
for
104
weeks.
For
chronic
toxicity,
the
NOEL
was
100
ppm
(
5.7
mg/
kg/
day
in
males
and
7.6
mg/
kg/
day
in
females
)
and
the
LOEL
was
300
ppm
(
16.9
mg/
kg/
day
in
males
and
24.9
mg/
kg/
day
in
females)
based
decreased
body
weight
gains
in
females
and
increased
thyroid
lesions
in
males.
Organ
weight
changes
were
observed
in
both
sexes
of
rats
at
doses
above
900
ppm.
There
was
no
evidence
of
carcinogenicity
in
either
sex
(
MRID
No.
42256331
and
42256332).

Dose/
Endpoint
for
establishing
the
RfD:
NOEL=
5.7
mg/
kg/
day
based
on
increased
thyroid
lesions
in
males
at
16.9
mg/
kg/
day
(
LOEL).

Uncertainty
Factor
(
UF):
An
UF
of
100
was
applied
to
account
for
both
inter­
and
intraspecies
variations.

Derivation
of
RfD:
5.7
mg/
kg/
day
(
NOEL
=
0.057
mg/
kg/
day
100
(
UF)

C.
Occupational/
Residential
Exposure
1.
Short­
Term
Dermal
(
1­
7
days)

Study
Selected:
None
Dose/
Endpoint
for
Risk
Assessment:
Not
applicable
11
Comments
about
Study/
Endpoint:
No
dermal
or
systemic
toxicity
was
seen
in
a
21­
day
dermal
toxicity
study
in
rabbits
following
repeated
dermal
applications
of
Imidacloprid
at
1000
mg/
kg/
day
(
Limit­
Dose)
for
3
weeks.
Therefore,
this
risk
assessment
is
not
required.

2.
Intermediate­
Term
Dermal
(
7
days
to
several
months)

Study
Selected:
None
Dose/
Endpoint
for
Risk
Assessment:
Not
applicable
Comments
about
Study/
Endpoint:
No
dermal
or
systemic
toxicity
was
seen
in
a
21­
day
dermal
toxicity
study
in
rabbits
following
repeated
dermal
applications
of
Imidacloprid
at
1000
mg/
kg/
day
(
Limit­
Dose)
for
3
weeks.
Therefore,
this
risk
assessment
is
not
required.

3.
Long­
Term
Dermal
(
Several
months
to
Life­
time)

Study
Selected:
None
Dose/
Endpoint
for
Risk
Assessment:
Not
applicable
Comments
about
Study/
Endpoint:
No
dermal
or
systemic
toxicity
was
seen
in
a
21­
day
dermal
toxicity
study
in
rabbits
following
repeated
dermal
applications
of
Imidacloprid
at
1000
mg/
kg/
day
(
Limit­
Dose)
for
3
weeks.
Therefore,
this
risk
assessment
is
not
required.

4.
Inhalation
Exposure
(
Any­
Time
period)

Based
on
the
LC
50
of
>
5.33
mg/
L
(
Limit­
Dose),
Imidaclorprid
is
placed
in
Toxicity
Category
IV.
Therefore,
a
separate
risk
assessment
via
this
route
is
not
required.

IV
UNCERTAINTY
FACTORS
FOR
DIETARY
RISK
ASSESSMENT
A.
Acute
Dietary
Risk
Assessment
The
endpoint
selected
for
acute
dietary
risk
assessment
is
based
on
neurotoxicity
characterized
by
decreases
in
motor
or
locomotor
activity
in
female
rats
at
42
mg/
kg/
day
(
LOEL)
in
an
acute
neurotoxicity
study.
A
NOEL
was
not
established
in
this
study.
An
additional
UF
of
3
is
applied
due
to
the
use
of
the
LOEL
for
risk
assessment.

Therefore,
for
acute
dietary
risk
assessment,
the
Committee
determined
that
the
additional
UF
of
10
to
account
for
enhanced
sensitivity
of
infants
and
children
(
as
required
by
FQPA)
is
reduced
to
3
fold
for
a
total
UF
of
300
(
10
x
each
for
inter­
and
intra­
species
variation
and
3
for
FQPA).
Thus,
a
MOE
of
300
is
required
to
ensure
protection
of
this
population
from
exposure
to
Imidaclorprid.
A
MOE
of
300
is
supported
by
the
following
factors:
12
(
i)
No
maternal
or
developmental
toxicity
attributable
to
an
acute
(
single
dose)
in
utero
exposure
of
Imidacloprid
was
seen
in
developmental
toxicity
studies.

(
ii)
The
endpoint
identified
is
neurotoxicity
in
adult
rats.

(
iii)
Lack
of
a
NOEL
in
the
study
used
for
selecting
the
dose
and
endpoint
for
this
risk
assessment.

2.
Chronic
Dietary
Risk
Assessment
The
endpoint
selected
for
chronic
risk
assessment
is
decreased
body
weight
gains
in
females
and
increased
thyroid
lesions
observed
at
7.6
mg/
kg/
day
in
male
rats
in
a
combined
chronic
toxicity/
carcinogenicity
study.
The
NOEL
was
5.7
mg/
kg/
day.
An
UF
of
100
was
applied
to
account
for
inter
(
10)­
and
intra
(
10)­
species
variation.

For
chronic
dietary
risk
assessment,
the
Committee
determined
that
an
additional
UF
of
10
to
account
for
enhanced
sensitivity
of
infants
and
children
(
as
required
by
FQPA)
is
reduced
to
a
3­
fold
for
a
total
UF
of
300
(
10
for
inter­
species
variation
x
10
for
intraspecie
variation
x
3
for
FQPA).
The
UF
of
300
is
supported
by
the
following
factors:

(
i)
Concern
for
structure
activity
relationship.
Imidacloprid,
a
chloronicotinyl
compound,
is
an
analog
to
nicotine
and
studies
in
the
published
literature
suggests
that
nicotine,
when
administered
causes
developmental
toxicity,
including
functional
deficits,
in
animals
and/
or
humans
that
are
exposed
in
utero.

(
ii)
Imidacloprid
administration
resulted
in
evidence
of
functional
neurotoxicity
in
the
acute
toxicity
study
in
rats.
Dose­
related
decreases
in
motor
activity
was
seen
in
females
given
a
single
oral
dose.
Significant
alterations
to
brain
weight
were
noted
in
the
2­
year
carcinogenicity
study
in
rats.

(
iii)
Need
of
a
developmental
neurotoxicity
study
for
assessment
of
potential
alterations
on
functional
development
(
i.
e.,
data
gap).