UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
Office
of
Prevention,
Pesticides
and
Toxic
Substances
TXR
NO.
0050533
DATE:
March
5,
2002
MEMORANDUM
SUBJECT:
Carbaryl
­
5
th
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Virginia
A.
Dobozy,
VMD,
MPH
Reregistration
Branch
I,
Health
Effects
Division
(7509C)

THROUGH:
Jess
Rowland,
Co­
Chair
and
Elizabeth
Doyle,
Co­
Chair
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(7509C)

TO:
Jeff
Dawson,
Risk
Assessor
Reregistration
Branch
I,
Health
Effects
Division
(7509C)

PC
Code:
056801
On
February
19,
2002,
the
Health
Effects
Division
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
reevaluated
CARBARYL
with
regard
to
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
CARBARYL
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996.
The
toxicological
endpoints
used
for
acute
and
chronic
Reference
Doses
(RfDs)
and
occupational/
residential
risk
assessments
were
also
re­
evaluated.
New
data,
including
a
multi­
generation
reproduction
study
in
rats
and
revised
brain
morphometric
measurements
from
the
developmental
neurotoxicity
study
in
rats,
were
reviewed.
Previous
HIARC
meetings
were
on
July
7,
1998,
April
6,
1999,
November
2,
1999
and
March
1,
2001.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
present
were:
Ayaad
Assaad,
William
Burnam,
Paula
Deschamp,
Elizabeth
Doyle,
Virginia
Fornillo,
John
Liccione,
Elizabeth
Mendez,
David
Nixon,
Jess
Rowland
Member(
s)
in
absentia:
Pamela
Hurley
Data
evaluation
prepared
by:
Virginia
A.
Dobozy,
VMD,
MPH
Also
in
attendance
were:
Jeff
Dawson
(HED),
Felicia
Fort
(HED),
Michael
Metzger
(HED),
Anthony
Britten
(SRRD)

Data
Evaluation
/
Report
Presentation
Virginia
A.
Dobozy,
VMD,
MPH
Toxicologist
1
Significant
changes
in
some
of
the
brain
morphometric
measurements
were
observed
in
offspring
at
the
high
dose;
only
control
and
high
dose
groups
were
examined.
EPA
requested
that
measurements
be
done
in
the
low­
and
mid­
dose
groups.
The
registrant
responded
that
the
requested
examinations
were
not
possible
because
the
tissues
of
the
low­
and
mid­
dose
animals
had
been
stored
in
a
fixative
for
two
years,
which
caused
shrinkage.
Therefore,
comparison
to
the
control
group,
which
was
not
similarly
stored,
would
not
be
valid.
A
re­
examination
of
the
control
and
high­
dose
groups
was
conducted.
The
re­
assessment
uncovered
errors
in
some
measures
and
confirmed
some
of
the
original
findings.
The
additional
statistical
analyses,
which
attempted
to
account
for
multiple
comparisons,
rendered
far
fewer
statistically
significant
findings,
but
some
results,
including
data
on
pup
cerebellar
length,
remained
statistically
significant.
The
decrease
in
the
length
of
the
cerebellum
in
10
mg/
kg/
day
female
pups
was
still
regarded
as
a
treatment­
related
effect.
The
NOAEL/
LOAEL
for
this
study
was
originally
regarded
as
tentative,
awaiting
information
from
the
registrant.
Since
morphometric
examinations
of
the
mid­
dose
group
were
impossible,
there
remained
some
uncertainty
about
the
NOAEL/
LOAEL.

3
1.
INTRODUCTION
The
toxicology
data
base
on
carbaryl
has
been
evaluated
by
the
HIARC
on
four
occasions
as
described
below.

°.
On
July
7,
1998,
the
HIARC
evaluated
the
data
base,
reassessed
the
RfD
established
in
1994
and
selected
endpoints
for
the
acute
dietary
as
well
as
occupational/
residential
risk
assessments.
At
the
time
of
that
evaluation,
the
data
base
was
incomplete.
There
were
no
acceptable
developmental
or
reproduction
studies
(July
7,
1998
report).

°
At
the
April
6,
1999
meeting,
a
recently
submitted
rat
developmental
study
was
considered.
The
HIARC
concluded
that
there
was
no
basis
to
amend
the
10X
FQPA
Safety
Factor
as
there
were
still
critical
data
gaps,
i.
e.,
no
acceptable
rabbit
developmental
study
or
reproduction
study
(April
28,
1999
report).

°
At
the
November
2,
1999
meeting
of
the
HIARC,
the
FQPA
Safety
Factor
was
again
reconsidered
with
the
submission
of
an
acceptable
rabbit
developmental
study.
The
Committee
concluded
that,
based
on
the
satisfaction
of
the
rat
and
rabbit
developmental
study
data
requirements
in
which
there
was
no
fetal
susceptibility,
the
FQPA
Safety
Factor
recommendation
could
be
reduced
from
10X
to
3X
(November
15,
1999
report).

At
the
November
29,
1999
meeting
of
the
FQPA
Safety
Factor
Committee,
it
was
concluded
that
the
10X
safety
factor
should
be
retained
because:
1)
the
toxicology
data
base
was
incomplete,
i.
e.,
lack
of
reproduction
study;
2)
an
assessment
of
susceptibility
following
pre­/
post­
natal
exposure
to
carbaryl
could
not
be
made
due
to
the
data
gaps
for
the
reproduction
study;
3)
there
was
concern
for
the
results
of
the
developmental
neurotoxicity
study.
1
The
Committee
concluded
that
the
10X
Safety
Factor
should
be
applied
to
acute
and
chronic
dietary
exposures
and
residential
(nonoccupational)
exposures
(December
13,
1999
report).

°
On
March
1,
2001,
the
HIARC
reevaluated
carbaryl
with
regard
to
the
acute
and
chronic
Reference
Doses
(RfDs)
and
the
toxicological
endpoint
selection
for
use
in
occupational/
residential
exposure
risk
assessments
(April
5,
2001
report).
On
April
16,
2001,
the
FQPA
Safety
Factor
Committee
again
confirmed
that
the
10x
factor
should
be
retained
based
on
the
same
criteria
as
described
at
the
4
November
29,
1999
meeting
(April
30,
2001
report).

The
February
19,
2002
meeting
was
convened
to
discuss
the
following
issues:

1)
A
multi­
generation
reproduction
study
(MRID
45448101)
has
been
submitted
and
evaluated.
There
is
evidence
of
offspring
susceptibility.
The
LOAEL
for
parental
systemic
toxicity
was
1500
ppm
(92.43­
124.33
mg/
kg/
day
for
males
and
110.78­
135.54
mg/
kg/
day
for
females)
based
on
decreased
body
weight,
weight
gain,
and
feed
consumption.
The
NOAEL
was
300
ppm
(23.49­
31.34
mg/
kg/
day
for
males
and
26.91­
36.32
mg/
kg/
day
for
females).
The
LOAEL
for
offspring
toxicity
was
300
ppm
(23.49­
31.34
mg/
kg/
day
for
males
and
26.91­
36.32
mg/
kg/
day
for
females)
based
on
increased
numbers
of
F2
pups
with
no
milk
in
the
stomach
and
decreased
pup
survival.
The
NOAEL
was
75
ppm
(4.67­
5.79
mg/
kg/
day
for
males
and
5.56­
6.41
mg/
kg/
day
for
females).
The
HIARC
was
requested
to
consider
how
the
study
results
affect
the
determination
of
fetal/
offspring
susceptibility
and
the
Special
FQPA
Safety
Factor
recommendation.

2)
The
registrant
has
conducted
new
brain
morphometric
measurements
of
the
control
and
high­
dose
animals
from
the
developmental
neurotoxicity
study.
In
prior
reviews,
HED
concluded
that
there
was
a
significant
increase
in
the
thickness
of
the
right
forebrain
in
male
pups
and
a
significant
decrease
in
the
left
forebrain
of
adult
males.
The
new
submission
reanalyzed
the
combined
(left
and
right)
data
on
the
forebrain
(Line
B)
in
male
pups
and
the
forebrain
(Line
A)
in
adult
males.
Based
on
a
statistical
analysis
of
combined
(left
and
right)
forebrain
measurements,
there
was
no
difference
from
controls
in
both
pups
and
adults.
However,
HED's
statistical
analysis
found
a
decrease
in
the
size
of
the
forebrain
in
adult
males.

In
prior
reviews,
HED
concluded
that
there
was
a
statistically
significant
bilateral
decrease
in
the
length
of
the
cerebellum
(Line
F)
of
female
pups
and
a
statistically
significant
bilateral
increase
in
the
width
of
the
cerebellum
(Line
G)
of
adult
females.
The
new
submission
contains
measurements
of
different
layers
of
the
cerebellum
in
pups
and
adults.
There
were
no
statistically
significant
differences
between
treated
and
control
animals.
HED
concluded
that
these
measurements
of
individual
cell
layers
do
not
negate
the
original
findings
in
the
cerebellum
of
female
pups
and
adults.

The
HIARC
was
requested
to
consider
how
these
revisions
affect
the
determination
of
fetal/
offspring
susceptibility
and
the
Special
FQPA
Safety
Factor
recommendation.

3)
At
the
March
1,
2001
HIARC
meeting,
the
endpoint
selection
for
occupational/
residential
(ORE)
risk
assessments
was
based
on
current
duration
of
exposure
definitions,
which
have
been
changed
(June
4,
2001
Memorandum
from
HED
Division
Director).
The
registrant
has
conducted
4­
week
dermal
exposure
studies
(one
with
technical
and
two
with
formulations);
however,
they
have
not
been
submitted.
RRB1
is
proposing
to
maintain
the
endpoints
selected
for
the
ORE
exposures
at
the
March
1
meeting
until
the
dermal
studies
have
been
submitted
and
reviewed.

The
HIARC
concluded
that
the
occupational/
residential
durations
used
for
the
risk
assessment
at
the
March
1,
2001
meeting
should
be
maintained
until
the
dermal
exposure
studies
have
been
submitted
and
evaluated.
The
following
document
includes
the
endpoint
selection
and
FQPA
considerations
from
the
February
19,
2001
meeting
and
cancer
reclassification
(November
7,
2001
meeting
of
the
Cancer
Assessment
Review
Committee).

2.
HAZARD
IDENTIFICATION
5
2.1
Acute
Reference
Dose
(RfD)
­
General
Population
Study
Selected:
Developmental
Neurotoxicity
Study
in
Rats
§81­
8;
OPPTS
870.6300
MRID
Nos.:
44393701,
45456701,
45456702,
45456703
Executive
Summary:
In
a
developmental
neurotoxicity
study
(MRID
#
44393701,
45456701,
45456702,
45456703),
26
pregnant
female
Sprague­
Dawley
rats/
group
were
administered
carbaryl
(99.1%
a.
i.)
by
gavage
from
Gestation
Day
(GD)
6
through
Lactation
Day
(LD)
10
at
doses
of
either
0,
0.1,
1.0
or
10
mg/
kg/
day.
An
additional
6
pregnant
females/
group
were
dosed
at
the
same
levels
for
the
cholinesterase
(ChE)
phase
of
the
study.
ChE
measurements
were
done
pre­
dosing
(GD
6)
and
post­
dosing
at
time
of
peak
effect
(1
hour
post­
dosing)
on
GD
6,
15
and
20
and
LD
4
and
10.
Functional
Observational
Battery
(FOB)
measurements
were
performed
at
approximately
0.5
and
2
hours
post­
dosing
on
the
same
days
as
body
weight
measurements
during
the
dosing
period
(GD
0,
6,
9,
12,
15,
18
and
20
and
LD
4,
7,
11,
13
and
21).
Measures
of
reproductive
performance
were
evaluated.
Offspring
were
examined
for
body
weight,
physical
development
landmarks
(tooth
eruption
and
eye
opening),
FOB
assessments
(days
4,
7,
11,
13,
17
and
21)
and
motor
activity
(days
13,
17
and
21).
On
LD
11,
1
animal/
sex/
litter
was
sacrificed
for
brain
weights;
of
these,
six/
sex
were
randomly
selected
for
neuropathological
evaluation.
The
eyes
from
all
dose
groups
were
examined.
After
LD
21,
3
animals/
sex/
litter
were
separated
from
the
dams
and
constituted
the
F1
adult
generation.
These
animals
were
evaluated
for
body
weight,
physical
development
(vaginal
opening
and
preputial
separation),
motor
activity
(day
60),
startle
habituation
response
(days
22
and
60),
passive
avoidance
(day
23)
and
water
maze
behavior
(day
60).
After
completion
of
the
behavior
test
period
(at
approximately
10
weeks
of
age),
12
animals/
sex/
group
were
anesthetized
and
perfused
for
post­
mortem
examination.
Tissues
from
6
animals/
sex
of
the
control
and
high
dose
group
were
processed
for
neuropathological
evaluation
and
morphometric
measurements;
the
eyes
from
the
low
and
mid­
dose
group
of
all
perfused
animals
were
examined.

For
the
F0
generation
animals,
there
were
no
carbaryl­
associated
deaths.
No
treatment­
related
clinical
signs
of
toxicity
were
observed.
There
was
a
statistically
significant
decrease
(92%)
in
body
weight
gain
for
females
in
the
10
mg/
kg/
day
group
for
the
period
GD
6­
9.
Unfortunately,
food
consumption
was
not
measured
during
the
study.
During
the
FOB
measurements,
the
incidence
of
females
in
the
10
mg/
kg/
day
group
with
decreased
pupil
size
(pinpoint
pupils)
was
increased
on
all
occasions
during
the
dosing
period.
An
increased
incidence
of
dams
with
slight
tremors
affecting
the
head,
body
and/
or
limbs
was
noted
on
the
majority
of
assessment
occasions
in
the
dosing
period.
There
were
also
occasional
occurrences
of
ataxic
gait/
overall
gait
in­
capacity
which
was
considered
to
be
of
toxicological
significance
due
to
other
effects
upon
gait.

For
the
10
mg/
kg/
day
group,
RBC
and
whole
blood
ChE
levels
were
statistically
significantly
decreased
(28%
and
32­
34%,
respectively)
on
GD
20
and
LD
10.
Although
the
plasma
ChE
levels
were
not
statistically
significantly
altered,
the
percentage
decreases
on
GD
20,
LD
4
and
LD
10
were
32­
39%.
Brain
ChE
levels
were
statistically
significantly
decreased
(42%).
There
6
were
no
treatment­
related
effects
on
gross
necropsy
findings
for
the
F0
generation
animals.

There
were
no
effects
observed
on
maternal
performance
parameters
of
pregnancy
rate,
gestation
index,
length
of
gestation,
numbers
of
live
pups,
dead
or
malformed
pups,
implantation
scars,
sex
ratio
or
post­
implantation
loss.
There
was
a
slight
(P>
0.05)
increase
in
the
number
of
dead
pups
in
the
10
mg/
kg/
day
group,
however
the
value
was
within
the
historical
control
range
for
this
strain.

For
the
F1
generation
pups,
there
were
no
treatment­
related
effects
on
pup
weight,
pup
survival
indices,
developmental
landmarks
(tooth
eruption
and
eye
opening),
FOB
measurements
or
motor
activity
assessments.
At
sacrifice
on
LD
11,
there
were
no
treatmentrelated
effects
on
brain
weight
and
gross
or
microscopic
pathology.
Significant
differences
noted
in
the
morphometric
measurements
included
an
increase
in
Line
B
of
the
right
forebrain
and
Line
F
of
the
left
cerebellum
in
the
10
mg/
kg/
day
males.
In
the
10
mg/
kg/
day
females,
Line
F
through
both
the
right
and
left
cerebellum
were
significantly
decreased
(15%
and
22%,
respectively).

For
the
F1
generation
adults,
there
were
no
treatment­
related
effects
on
clinical
condition,
body
weight,
physical
development
(vaginal
opening
and
preputial
separation),
motor
activity,
auditory
startle
response,
passive
avoidance
and
water
maze
measurements.
At
sacrifice,
there
were
no
gross
or
microscopic
neuropathological
lesions
observed
for
animals
examined
in
this
study
that
were
attributable
to
treatment
with
the
test
article.
There
was
an
increased
incidence
of
retinal
fold/
rosette
in
the
10
mg/
kg/
day
group
(1/
12
for
control
vs.
4/
12
for
males;
0/
12
for
control
vs.
2/
12
for
females).
The
finding
was
not
considered
of
toxicological
significance
since
the
incidence
was
within
the
historical
control
range
for
males,
occurred
at
a
low
rate
and
was
not
dose­
dependent.
For
the
morphometric
measurements,
there
was
a
significant
bilateral
decrease
in
Line
A
through
the
forebrain
(7.7­
9.8%)
and
a
significant
increase
in
Line
F
through
the
right
cerebellum
of
the
10
mg/
kg/
day
males.
Increases
originally
noted
in
10
mg/
kg
adult
females
in
Line
G,
width
of
the
cerebellum,
were
found
to
be
based
on
erroneous
measurements,
and
additional
measures
were
submitted.
Now,
for
the
10
mg/
kg/
day
females,
there
were
significant
bilateral
increases
in
Line
F
through
the
cerebellum
(7.4­
15%).
Measurements
of
the
size
of
the
thickness
of
lobes
and
of
the
granule
cell
layers
of
the
cerebellum
in
high
dose
pups
and
adults
did
not
differ
from
those
of
controls.
While
additional
statistical
analyses
by
the
registrant
indicated
no
treatment
related
effects,
HED's
additional
statisical
analyses
did
indicate
treatment
related
effects.

The
maternal
toxicity
LOAEL
was
10
mg/
kg/
day
based
on
decreased
body
weight
gain,
alterations
in
FOB
measurements
and
RBC,
plasma,
whole
blood
and
brain
cholinesterase
inhibition.
The
maternal
NOAEL
was
1.0
mg/
kg/
day.

The
developmental
neurotoxicity
LOAEL
was
10
mg/
kg/
day
based
on
a
bilateral
decrease
in
the
size
of
the
forebrain
(Line
A)
in
adult
males
(7.7­
9.8%);
a
bilateral
decrease
in
the
length
of
the
cerebella
(Line
F)
in
female
pups
(15­
22%);
and
a
bilateral
increase
in
the
length
of
the
cerebella
(Line
F)
in
female
adults
(7.4­
15%).

The
developmental
NOAEL
was
1
mg/
kg/
day.
Morphometric
assessment
at
the
mid
and
7
low
doses
could
not
be
conducted
due
to
inadequate
tissue
storage;
however,
based
on
the
minimal
findings
at
the
LOAEL,
it
is
HED's
judgment
that
effects
would
be
unlikely
to
occur
at
1
mg/
kg/
day,
which
is
10%
of
the
LOAEL.

Co­
critical
Study:

Study
Selected:
Acute
Neurotoxicity
Study
in
Rats
§81­
8;
OPPTS
870.6200a
MRID
Nos.:
43845201­
43845204
Executive
Summary:
In
an
acute
neurotoxicity
study
(MRID
#
43845204),
groups
of
12
male
and
12
female
Sprague­
Dawley
rats
were
administered
carbaryl
technical
grade
in
0.5%
carboxymethylcellulose
/
0.1%
Tween
80
at
doses
of
10,
50,
or
125
mg/
kg/
day.
Doses
were
selected
on
the
basis
of
results
from
a
benchmark
toxicity
study
(MRID
#
43845201)
and
a
"time
of
peak
effects"
study
(MRID
#
43845202).
In
the
benchmark
study,
clinical
signs
of
toxicity
and
body
weight
loss
were
observed
at
50
mg/
kg
and
above,
and
mortality
was
observed
at
500
mg/
kg
and
above.
In
the
time
of
peak
effects
study,
peak
effect
for
cholinesterase
inhibition
and
functional
observational
battery
changes
was
determined
to
be
0.5
to
1.0
hr
post­
dose.
Body
weight
was
mildly
but
significantly
decreased
in
male
rats
at
the
125
mg/
kg
dose
level,
while
weight
gain
was
significantly
decreased
in
male
and
female
rats
for
days
0­
7
of
the
study
at
125
mg/
kg.
Food
consumption
during
week
1
was
decreased
at
the
125
mg/
kg
dose
by
18­
20%,
in
excess
of
the
decrease
in
body
weight
gain,
supporting
a
treatment­
related
effect
at
the
high
dose
for
week
1
of
the
study.
Several
measurements
from
Functional
Observational
Battery
assessment
were
significantly
altered
at
the
50
and
125
mg/
kg
dose,
including
an
increased
incidence
of
tremors,
ataxic
gait,
decreased
body
temperature,
and
decreased
arousal.
Salivation
incidence
was
increased
at
the
high
dose,
as
was
hindlimb
splay.
Forelimb
and
hindlimb
grip
strength
were
decreased
significantly
at
the
high
dose.
Significant
decreases
in
total
motor
activity
were
observed
in
male
and
female
rats
at
all
dose
levels
tested.
Significant
inhibition
of
plasma,
blood,
and
brain
cholinesterase
(30­
40%)
was
also
observed
in
both
sexes
at
the
10
mg/
kg
dose.
Peak
inhibition
of
cholinesterase
occurred
during
the
time
of
FOB
and
motor
activity
measurements.
Based
on
the
data
in
this
study,
the
systemic
LOAEL
=
10
mg/
kg
for
male
and
female
rats,
based
on
significant
inhibition
of
red
cell,
plasma,
whole
blood,
and
brain
cholinesterase
at
the
10
mg/
kg
dose
level.
The
systemic
NOAEL
<
10
mg/
kg
for
male
and
female
rats.
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
an
acute
neurotoxicity
study
(§
81­
8;
OPPTS
870.6200)
in
rats.

Dose
and
Endpoint
for
Establishing
RfD:
Maternal
NOAEL
of
1
mg/
kg
based
on
alterations
in
FOB
parameters
on
the
first
day
of
dosing
at
10
mg/
kg
Uncertainty
Factor
(UF):
100
[10
for
intraspecies
variation
and
10
for
interspecies
variation].
8
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Previously
(March
1,
2001),
the
HIARC
selected
the
acute
neurotoxicity
study
this
risk
assessment.
However,
upon
reevaluation
and
comparison
of
the
results
of
the
acute
neurotoxicity
and
the
developmental
neurotoxicity
studies,
the
HIARC
determined
that
the
maternal
effects
in
the
developmental
neurotoxicity
study
observed
after
a
single
oral
dose
were
most
appropriate
for
this
risk
assessment.
This
is
also
the
dose
at
which
effects
were
observed
in
offspring;
therefore,
use
of
the
maternal
NOAEL
is
protective
for
infants
and
children.
Additionally,
use
of
the
LOAEL
from
the
acute
neurotoxicity
study
with
a
3x
uncertainty
factor
would
result
in
a
calculated
NOAEL
of
3
mg/
kg/
day
and
an
acute
RfD
of
0.03
mg/
kg.
The
HIARC
determined
that
it
was
more
conservative
and
protective
of
all
populations
(including
females
13­
50)
to
use
the
developmental
neurotoxicity
study.

2.2
Chronic
Reference
Dose
(RfD)

Study
Selected:
Chronic
Toxicity
­
Dog
§
83­
1,
OPPTS
870.4100
MRID
Nos.:
40166701,
42022801
Executive
Summary:
In
a
chronic
toxicity
study
(MRID
No.
40166701),
carbaryl
(99%)
was
administered
in
the
diet
to
6
beagle
dogs/
sex/
group
at
doses
of
0,
125,
400
or
1250
ppm
for
one
year.
Nominal
doses
were
3.1,
10
and
31.3
mg/
kg/
day.

There
were
no
deaths
during
the
study.
With
the
1250
ppm
females,
there
was
an
increased
incidence
of
clinical
signs
of
toxicity,
including
emesis,
lacrimation,
salivation
and
tremors.
Mean
body
weight
gain
was
decreased
(50%)
in
the
1250
ppm
females
for
weeks
0­
6.
Mean
food
consumption
was
decreased
(16­
24%,
not
statistically
significant)
in
the
1250
ppm
females
at
multiple
time
periods
during
the
study.
No
treatment­
related
ophthalmoscopic
changes
were
observed.
There
was
a
statistically
significant
increase
in
white
blood
cell
and
segmented
neutrophil
counts
at
some
of
the
testing
intervals
for
the
1250
ppm
group
males.
Albumin
levels
were
significantly
decreased
(9­
11%)
at
all
of
the
testing
periods
in
the
1250
ppm
females.
Plasma
cholinesterase
(ChE)
levels
in
males
were
significantly
decreased
in
the
400
ppm
(30­
36%
9
)
and
1250
ppm
(58­
66%
9
)
groups
at
all
testing
intervals
(weeks
5,
13,
26
and
52).
Plasma
ChE
levels
in
females
were
significantly
decreased
at
most
intervals
in
the
125
ppm
group
(12­
23%
9
),
400
ppm
group
(9­
31%
9
)
and
1250
ppm
group
(47­
60
).
RBC
ChE
levels
in
males
were
significantly
decreased
in
the
400
ppm
group
(23­
28%
9
at
weeks
5
and
13)
and
1250
ppm
group
(46­
56%
9
for
all
intervals).
RBC
ChE
levels
in
females
were
significantly
decreased
in
the
400
ppm
group
(29­
34%
9
at
weeks
5,
13
and
26)
and
1250
ppm
(29­
38%
9
for
all
intervals).
Brain
ChE
in
males
was
not
statistically
significantly
decreased
but
biologically
decreased
in
the
400
ppm
group
(32%
9
)
and
1250
ppm
group
(25%
9
).
Brain
ChE
in
females
was
significantly
decreased
(20­
36%
9
)
in
all
the
groups.
No
treatment
Acute
RfD
=
1
mg/
kg
=
0.01
mg/
kg
100
9
related
effects
were
seen
in
urinalysis
parameters.

At
necropsy,
there
was
a
statistically
significant
increase
in
the
absolute
weight
of
the
liver/
gall
bladder
in
the
1250
ppm
group
males.
Relative
and
liver­
to­
brain
weights
were
also
increased
but
not
significantly.
There
was
a
dose­
related
decrease
in
the
absolute,
relative
and
organ­
to­
brain
weights
of
the
pituitary
in
males,
although
none
of
the
changes
was
statistically
significant.
There
was
also
a
significant
decrease
in
the
relative
weight
of
the
thyroid
in
this
group.
However,
since
there
were
no
accompanying
microscopic
changes
in
these
organs,
the
toxicological
significance
of
these
organ
weight
effects
is
questionable.

The
LOAEL
for
systemic
toxicity
was
1250
ppm
(31.3
mg/
kg/
day)
based
on
an
increased
incidence
of
clinical
signs
(females),
decreased
body
weight
and
food
consumption
(females)
and
alterations
in
clinical
pathology
parameters
(both
sexes);
NOAEL
was
400
ppm
(10
mg/
kg/
day).

The
LOAEL
for
plasma
cholinesterase
inhibition
was
125
ppm
(3.1
mg/
kg/
day)
for
females;
a
NOAEL
was
not
established.
The
LOAEL
for
plasma
cholinesterase
inhibition
was
400
ppm
(10
mg/
kg/
day)
for
males;
the
NOAEL
was
125
ppm
(3.1
mg/
kg/
day).

The
LOAEL
for
RBC
cholinesterase
inhibition
was
400
ppm
(10
mg/
kg/
day)
for
males
and
females;
the
NOAEL
was
125
ppm
(3.1
mg/
kg/
day).

The
LOAEL
for
brain
cholinesterase
inhibition
was
125
ppm
(3.1
mg/
kg/
day)
for
females;
a
NOAEL
was
not
established.
The
LOAEL
for
brain
cholinesterase
inhibition
was
400
ppm
(10
mg/
kg/
day)
for
males;
the
NOAEL
was
125
ppm
(3.1
mg/
kg/
day).

In
a
five­
week
study
(MRID
#
42022801)
done
to
upgrade
the
chronic
study,
carbaryl
(99.3%
a.
i.)
was
administered
in
the
diet
to
six
beagles/
sex/
group
at
doses
of
0,
20,
45
or
125
ppm.
Actual
mg/
kg/
day
doses
for
males
were
0,
0.59,
1.43
and
3.83
mg/
kg/
day,
respectively;
doses
for
females
were
0,
0.64,
1.54
and
4.11
mg/
kg/
day,
respectively.
The
following
parameters
were
measured:
clinical
observations,
body
weights,
food
consumption,
ophthalmoscopic
examinations,
plasma
and
RBC
cholinesterase
(at
days
­11,
­8
and
­5
pretest
and
then
days
14
and
32
of
the
study),
brain
cholinesterase
(at
termination)
and
gross
necropsies.
This
study
was
conducted
to
complete
the
information
needed
to
satisfy
the
chronic
toxicity
study
requirement
in
nonrodent
species.

There
were
no
deaths
or
treatment­
related
clinical
signs
of
toxicity.
There
were
no
treatmentrelated
effects
on
body
weights,
food
consumption
or
ophthalmoscopic
examinations.
In
males,
there
was
a
statistically
and
biologically
significant
decrease
in
plasma
cholinesterase
for
the
125
ppm
(22%
9
)
group.

The
LOAEL
for
systemic
toxicity
and
for
RBC
and
brain
cholinesterase
inhibition
was
>125
ppm
(males:
3.83
mg/
kg/
day;
females:
4.11
mg/
kg/
day);
the
NOAEL
was
$
125
ppm.

The
LOAEL
for
plasma
cholinesterase
inhibition
for
males
was
125
ppm;
the
NOAEL
was
45
ppm
(1.43
mg/
kg/
day).
The
LOAEL
for
cholinesterase
inhibition
for
females
was
>125
ppm;
10
the
NOAEL
was
$
125
ppm.

Dose
and
Endpoint
for
Establishing
RfD:
LOAEL
=3.1
mg/
kg/
day
based
on
plasma
and
brain
cholinesterase
inhibition
in
females.

Uncertainty
Factor(
s):
300
[10
for
intra
species
variation,
10
for
interspecies
variation
and
3
for
use
of
a
LOAEL].

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
HIARC
determined
that
the
LOAEL
from
the
1­
year
dog
study
was
appropriate
for
the
following
reasons:

1)
An
additional
uncertainty
factor
of
3X
was
applied
because
of
the
use
of
a
LOAEL
(i.
e.,
lack
of
a
NOAEL
in
a
critical
study).
Although
a
NOAEL
was
not
established
in
this
study,
the
Committee
determined
that
an
additional
factor
of
3X
(as
opposed
to
a
higher
value)
was
adequate
because:
1)
cholinesterase
inhibition
was
not
accompanied
by
clinical
signs;
2)
no
inhibition
was
seen
for
any
cholinesterase
compartment
in
males
at
this
dose;
3)
the
magnitude
of
inhibition
of
plasma
cholinesterase
inhibition
(12­
23%
decrease)
was
comparable
to
the
magnitude
of
inhibition
(22%)
seen
in
the
5­
week
study
in
dogs
indicating
no
cumulative
effects
following
long­
term
exposure;
and
4)
the
study
was
well­
conducted
and
there
are
sufficient
data
from
subchronic
and
chronic
duration
studies
in
the
other
species
which
support
cholinesterase
inhibition
as
the
critical
effect
2)
Based
on
the
cholinesterase
inhibition
data,
the
dog
appears
to
be
more
sensitive
than
the
rat
in
long­
term
studies.
Male
and
female
rats
treated
at
10
and
13
mg/
kg/
day,
respectively,
of
carbaryl
in
the
diet
for
53
weeks
demonstrated
negligible
plasma,
RBC
and
brain
cholinesterase
inhibition,
whereas
dogs
treated
at
a
comparable
dose
for
the
same
duration
had
inhibition
of
all
three
compartments.

3)
The
HIARC
determined
that
use
of
the
LOAEL
from
the
1­
year
study
(plasma
and
brain
cholinesterase
inhibition
in
females)
provided
more
convincing
evidence
of
a
toxicological
effect
than
use
of
the
NOAEL
of
1.43
mg/
kg/
day
based
on
plasma
cholinesterase
inhibition
in
males
from
the
5
week
study.

4)
Use
of
the
LOAEL
from
the
1­
year
dog
study
with
an
uncertainty
factor
of
300
results
in
a
chronic
RfD
which
would
be
identical
to
that
derived
if
the
offspring
NOAEL
(1.0
mg/
kg/
day)
from
the
developmental
neurotoxicity
study
was
used
with
an
uncertainty
factor
of
100;
therefore,
infants
and
children
will
also
be
protected
by
using
the
1­
year
dog
study.

2.3
Occupational/
Residential
Exposure
2.3.1
Short­
Term
(1­
7
days)
Incidental
Oral
Exposure
Chronic
RfD
=
3.1
mg/
kg/
day
=
.01
mg/
kg/
day
300
11
Study
Selected:
Developmental
Neurotoxicity
Study
§81­
8;
OPPTS
870.6300
MRID
No.:
44393701,
45456701,
45456702,
45456703
Executive
Summary:
See
2.1
Acute
Reference
Dose
(RfD)
­
General
Population
Dose
and
Endpoint
for
Risk
Assessment:
Maternal
NOAEL
of
1
mg/
kg
based
on
alterations
in
FOB
parameters
on
the
first
day
of
dosing
at
10
mg/
kg
Comments
about
Study/
Endpoint:
The
HIARC
determined
that
study
is
appropriate
for
the
short­
term
oral
exposure
time
period
because
effects
(FOB
alterations)
were
observed
after
a
single
dose
and
continued
after
multiple
days
of
dosing
and
are
appropriate
for
the
population
of
concern
(infants
and
children).
Although
a
maternal
NOAEL
was
used,
this
dose
would
be
protective
of
offspring
effects
since
the
NOAEL/
LOAEL
were
the
same
for
offspring
toxicity.

2.3.2
Intermediate­
Term
(7
Days
to
Several
Months)
Incidental
Oral
Exposure
Study:
Subchronic
Neurotoxicity
Study
Study
Guideline#:
§
81­
8,
OPPTS
870.6200
MRID
No.:
44122601
Executive
Summary:
In
a
subchronic
neurotoxicity
study,
12
Crl:
CD(
SD)
BR
rats/
sex/
group
were
administered
technical
carbaryl
(99.1%)
by
gavage
at
doses
of
0,
1,
10
or
30
mg/
kg/
day
for
13
weeks.
Cholinesterase
(RBC,
whole
blood,
plasma
and
brain)
determinations
were
done
on
an
additional
three
groups
of
five
rats/
sex/
group
at
Weeks
4,
8
and
13.
Neurobehavioral
screening,
consisting
of
Functional
Observational
Battery
(FOB)
and
motor
activity
evaluations,
was
performed
prior
to
treatment
and
during
Weeks
4,
8
and
13.
At
terminal
sacrifice,
six
animals/
sex/
dose
were
anesthetized
and
perfusion
fixed
in
situ
for
neuropathological
evaluation.

There
were
no
deaths
during
the
study.
There
was
an
increased
incidence
of
clinical
signs
of
toxicity,
including
slight
and
moderate
salivation
and
tremors,
in
the
30
mg/
kg/
day
males
and
females.
Body
weight
over
the
course
of
the
study
was
statistically
significantly
decreased
in
the
30
mg/
kg/
day
males
(14%)
and
females
(15%).
Body
weight
gain
for
these
groups
was
decreased
27%
in
males
and
37%
in
females,
compared
to
controls.
Food
consumption
was
decreased
during
most
of
the
study
for
the
30
mg/
kg/
day
males
and
females.
Males
and
females
in
the
30
mg/
kg/
day
group
had
a
statistically
significant
decrease
in
RBC
(M:
42­
46%;
F:
52­
55%),
whole
blood
(M:
49­
51%;
F:
59­
63%)
and
plasma
(M:
63­
69%;
F:
63­
69%)
at
most
of
the
testing
periods.
Males
and
females
in
the
10
mg/
kg/
day
group
had
a
statistically
significant
decrease
in
RBC
(M:
26­
38%;
F:
17­
24%);
whole
blood
(M:
30­
41%;
F:
21­
26%)
and
plasma
(M:
43­
48%;
F:
23­
30%).
There
was
a
statistically
significant
decrease
in
brain
cholinesterase
in
males
and
females
in
the
10
mg/
kg/
day
(M:
27­
61%;
F:
20­
58%)
and
30
mg/
kg/
day
(M:
36­
80%;
F:
50­
73%)
groups.
For
the
1
mg/
kg/
day
males,
there
were
12
statistically
significant
decreases
in
whole
blood
(13%)
at
week
13
and
for
plasma
(20%)
at
week
8.
These
changes
are
not
considered
toxicologically
significant
since
they
occurred
infrequently
and
were
relatively
minor
effects.

Multiple
qualitative
and
quantitative
FOB
parameters
were
affected
in
the
10
and
30
mg/
kg/
day
males
and
females,
including
the
following:
slight
tremors,
gait
alterations,
pinpoint
pupils,
increased
salivation,
reduced
extensor
thrust,
decreased
pinna
reflex,
reduced
number
of
rearings,
decreased
vocalizations,
decreased
body
temperature
and
decreased
forelimb
grip.
Reduced
number
of
defecations
was
observed
only
at
30
mg/
kg/
day.
There
was
an
occasional
alteration
at
the
1
mg/
kg/
day
dose.
At
week
8,
males
had
a
very
slight
increase
in
the
incidence
of
pinpoint
pupils
(incidence
in
control,
1,
10
and
30
mg/
kg/
day
groups
was
0/
12,
1/
12,
6/
12
and
10/
12,
respectively).
A
statistically
significant
decrease
in
forelimb
grip
was
observed
at
week
4
in
males
(values
for
control,
1,
10
and
30
mg/
kg/
day
groups
were
1060.8,
943.8,
943.8
and
950.0,
respectively).
The
number
of
defecations
was
statistically
reduced
in
females
at
week
13
(mean
number
of
defecations
in
control,
1,
10
and
30
mg/
kg/
day
groups
were
1.4,
0.2,
0.5
and
0.0,
respectively).
The
toxicological
significance
of
these
effects
is
questionable
since
the
incidence
was
either
low
or
there
was
no
dose­
response
relationship.

Motor
activity
was
statistically
significantly
decreased
in
the
30
mg/
kg/
day
males
at
Week
4
and
the
30
mg/
kg/
day
females
at
Weeks
4
and
8.

On
necropsy,
there
was
an
increased
incidence
of
dark
areas
in
the
meninges
of
the
30
mg/
kg/
day
males;
these
animals
had
an
increased
incidence
of
hemorrhage
on
microscopic
examination.
One
female
in
the
30
mg/
kg/
day
group
also
had
retinal
atrophy.
There
were
no
differences
in
brain
length
or
width
measurements.

The
LOAEL
for
neurotoxicity
was
10.0
mg/
kg/
day
based
on
an
increased
incidence
of
FOB
changes;
the
NOAEL
was
1.0
mg/
kg/
day.
The
LOAEL
for
cholinesterase
inhibition
was
10.0
mg/
kg/
day
based
on
statistically
significant
decreases
in
RBC,
whole
blood,
plasma
and
brain
cholinesterase;
the
NOAEL
was
1.0
mg/
kg/
day.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
1.0
mg/
kg/
day
based
on
plasma,
whole
blood,
RBC
and
brain
cholinesterase
inhibition
and
FOB
changes
at
10
mg/
kg/
day.

Comments
about
Proposed
Study/
Endpoint:
The
study
was
selected
because
the
route
of
administration
(oral)
and
the
duration
(90
days)
are
appropriate
for
this
risk
assessment.
It
is
supported
by
the
five­
week
dietary
study
in
dogs
(MRID
4202801)
done
to
upgrade
the
chronic
toxicity
study.
The
NOAEL
in
males
was
1.43
mg/
kg/
day
based
on
plasma
cholinesterase
inhibition
at
3.83
mg/
kg/
day.
This
dose
and
endpoint
are
appropriate
for
the
population
of
concern
(infants
and
children).

2.3.3
Dermal
Absorption
Dermal
Absorption
Factor:
A
dermal
absorption
factor
of
12.7%
was
selected
at
the
July
7,
1998
HIARC
meeting;
no
reevaluation
was
conducted
at
the
present
meeting.
13
2.3.4
Short­
Term
Dermal
(1­
7
days)
Exposure
Study
Selected:
Developmental
Neurotoxicity
Study
§81­
8;
OPPTS
870.6300
MRID
No.:
44393701,
45456701,
45456702,
45456703
Executive
Summary:
See
2.1
Acute
Reference
Dose
(RfD)
­
General
Population
Dose
and
Endpoint
for
Risk
Assessment:
Maternal
NOAEL
of
1
mg/
kg
based
on
alterations
in
FOB
parameters
on
the
first
day
of
dosing
at
10
mg/
kg
Comments
about
Study/
Endpoint:
No
dermal
toxicity
studies
are
available.
The
HIARC
determined
that
study
is
appropriate
for
the
short­
term
exposure
time
period
because
effects
(FOB
alterations)
were
observed
after
a
single
dose
and
continued
after
multiple
days
of
dosing.
Since
an
oral
NOAEL
was
used
for
this
endpoint,
a
dermal
absorption
factor
of
12.7%
should
be
used
in
the
risk
assessment.

2.3.5
Intermediate­
Term
Dermal
(7
Days
to
Several
Months)
Exposure
Study
Selected:
Subchronic
Neurotoxicity
Study
§
81­
8,
OPPTS
870.6200
MRID
Nos.:
44122601
Executive
Summary:
See
2.3.2
Intermediate­
Term
Incidental
Oral
Exposure
Dose/
Endpoint
for
Risk
Assessment:
NOAEL
=
1.0
mg/
kg/
day
based
on
plasma,
whole
blood,
RBC
and
brain
cholinesterase
inhibition
and
FOB
changes
at
10
mg/
kg/
day.

Comments
about
Study/
Endpoint:
No
dermal
studies
are
available.
Since
an
oral
NOAEL
was
used
for
this
endpoint,
a
dermal
absorption
factor
of
12.7%
should
be
employed
in
the
risk
assessment.

2.3.6
Long­
Term
Dermal
(Longer
than
6
months)
Exposure
Study
Selected:
Chronic
Toxicity
­
Dog
§
83­
1,
OPPTS
870.4100
MRID
Nos.:
40166701,
42022801
Executive
Summary:
See
Chronic
Dietary
section
Dose
and
Endpoint
for
Risk
Assessment:
3.1
mg/
kg/
day
(LOAEL)
based
on
plasma
and
brain
cholinesterase
inhibition
in
females
in
the
1
year
study
Comments
about
Study/
Endpoint:
No
dermal
studies
are
available.
Since
an
oral
NOAEL
was
used
for
this
endpoint,
a
dermal
absorption
factor
of
12.7%
should
be
employed
in
the
risk
14
assessment.
The
reasons
for
selecting
this
oral
study
to
assess
long­
term
exposure
are
described
under
2.2
Chronic
Reference
Dose
(RfD).

2.3.7
Inhalation
Exposure
(All
Durations)

There
are
no
studies
available
in
which
carbaryl
was
administered
via
the
inhalation
route,
except
for
the
acute
oral
study
[Toxicity
Category
IV
(LC50
>
3.4
mg/
L)].

2.3.7.1
Short­
Term
Inhalation
(1­
7
days)
Exposure
Study
Selected:
Developmental
Neurotoxicity
Study
§81­
8;
OPPTS
870.6300
MRID
No.:
44393701,
45456701,
45456702,
45456703
Executive
Summary:
See
2.1
Acute
Reference
Dose
(RfD)
­
General
Population
Dose
and
Endpoint
for
Risk
Assessment:
Maternal
NOAEL
of
1
mg/
kg
based
on
alterations
in
FOB
parameters
on
the
first
day
of
dosing
at
10
mg/
kg
Comments
about
Study/
Endpoint:
No
inhalation
toxicity
studies
are
available.
The
HIARC
determined
that
the
study
is
appropriate
for
the
short­
term
exposure
time
period
because
effects
(FOB
alterations)
were
observed
after
a
single
dose
and
continued
after
multiple
days
of
dosing.
Since
an
oral
NOAEL
was
used
for
this
endpoint,
an
inhalation
factor
of
100%
should
be
used
in
the
risk
assessment.

2.3.7.2
Intermediate­
Term
Inhalation
(7
Days
to
Several
Months)
Exposure
Study
Selected:
Subchronic
Neurotoxicity
Study
§
81­
8,
OPPTS
870.6200
MRID
Nos.:
44122601
Executive
Summary:
See
2.3.2
Intermediate­
Term
Incidental
Oral
Exposure
Dose/
Endpoint
for
Risk
Assessment:
NOAEL
=
1.0
mg/
kg/
day
based
on
plasma,
whole
blood,
RBC
and
brain
cholinesterase
inhibition
and
FOB
changes
at
10
mg/
kg/
day.

Comments
about
Study/
Endpoint:
No
inhalation
studies
are
available.
Since
an
oral
NOAEL
was
used
for
this
endpoint,
an
inhalation
absorption
factor
of
100%
should
be
employed
in
the
risk
assessment.

2.3.7.3
Long­
Term
Inhalation
(Longer
than
6
months)
Exposure
Study
Selected:
Chronic
Toxicity
­
Dog
§
83­
1,
OPPTS
870.4100
MRID
Nos.:
40166701,
42022801
15
Executive
Summary:
See
Chronic
Dietary
section
Dose
and
Endpoint
for
Risk
Assessment:
LOAEL
of
3.1
mg/
kg/
day
based
on
plasma
and
brain
cholinesterase
inhibition
in
females
in
the
1
year
study.

Comments
about
Study/
Endpoint:
No
inhalation
studies
are
available.
Since
an
oral
NOAEL
was
used
for
this
endpoint,
an
inhalation
absorption
factor
of
100%
should
be
employed
in
the
risk
assessment.
The
reasons
for
selecting
this
oral
study
to
assess
long­
term
exposure
are
described
under
2.2
Chronic
Reference
Dose
(RfD).

2.3.5
Margins
of
Exposure
for
Occupational/
Residential
Risk
Assessments
The
HIARC
determined
that
the
acceptable
MOE
for
occupational
exposures
should
be
300
for
the
following
risk
assessments:
long­
term
dermal
exposure
and
long­
term
inhalation
exposure.
The
additional
3X
is
required
since
a
LOAEL
was
used
in
these
assessments.

The
acceptable
MOEs
for
residential
exposure
will
be
determined
by
the
FQPA
SF
committee.

2.4
Recommendation
for
Aggregate
Exposure
Risk
Assessments
A
common
toxicological
endpoint
of
concern
(alterations
in
FOB
parameters)
was
identified
for
short­
term
oral,
dermal
(oral
equivalent)
and
inhalation
(oral
equivalent)
exposure
scenarios.
Therefore,
these
routes
can
be
aggregated
for
the
appropriate
populations.

A
common
toxicological
endpoint
of
concern
(cholinesterase
inhibition)
was
selected
for
intermediate­
and
long­
term
oral,
dermal
(oral
equivalent)
and
inhalation
(oral
equivalent)
exposure
scenarios.
Therefore,
these
routes
can
be
aggregated
for
these
scenarios
for
the
appropriate
populations.

3
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.:
42918801
Discussion
of
Tumor
Data:.
Male
rats
had
significant
increasing
trends,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
7500
ppm
dose
group
with
the
controls,
for
thyroid
follicular
cell
adenomas
and
combined
adenomas
and/
or
carcinomas,
and
urinary
bladder
transitional
cell
papillomas,
carcinomas,
and
combined
papillomas
and/
or
carcinomas,
all
at
p
<
0.01.

Female
rats
had
significant
increasing
trends
in
urinary
bladder
transitional
cell
papillomas,
carcinomas,
and
combined
papillomas
and/
or
carcinomas,
all
at
p
<
0.01.
There
were
significant
differences
in
the
pair­
wise
comparisons
of
the
7500
ppm
dose
group
with
the
controls
for
urinary
bladder
transitional
cell
papillomas
(p
<
0.05),
carcinomas
(p
<
0.05),
and
16
combined
carcinomas
and/
or
papillomas
(p
<
0.01).

Adequacy
of
the
Dose
Levels
Tested:
At
meetings
on
October
27
and
December
8,
1993,
the
HED
Cancer
Peer
Review
Committee
determined
that
the
7500
ppm
dose
was
excessive
based
on
the
following
findings:
1)
changes
in
body
weight
gain
during
week
13
for
males
and
females
by
40%
and
52%,
respectively,
as
compared
to
controls;
2)
decreased
food
efficiency;
3)
alterations
in
hematology
and
clinical
chemistry;
and
4)
decreases
in
plasma,
RBC
and
brain
cholinesterase
at
weeks
53
and
105.
The
CPRC
also
concluded
that
the
mid
dose
(1500
ppm)
was
not
adequate
for
carcinogenicity
testing.
The
November
7,
2001
CARC
meeting
affirmed
that
the
high
dose
was
excessive
and
the
mid
dose
was
not
sufficiently
high
enough
to
test
the
carcinogenic
potential
of
carbaryl
in
rats.

2.
Carcinogenicity
Study
in
Mice
MRID
No.:
42786901
Discussion
of
Tumor
Data:
Male
mice
had
significant
increasing
trends
in
kidney
tubule
cell
adenomas
(p
<
0.05),
carcinomas
(p
<
0.05)
and
combined
adenomas
and/
or
carcinomas
(p
<
0.01).
There
was
also
a
significant
difference
in
the
pair­
wise
comparison
of
the
8000
ppm
dose
group
with
the
controls
for
combined
kidney
tubule
cell
adenomas
and/
or
carcinomas
at
p
<
0.05.
There
were
significant
differences
in
the
pair­
wise
comparisons
of
all
dose
groups
(100,
1000
and
8000
ppm)
with
the
controls
for
hemangiosarcomas,
all
at
p
<
0.05.
There
were
significant
differences
in
the
pair­
wise
comparisons
of
1000
and
8000
ppm
dose
groups
with
the
controls
for
hemangiomas
and/
or
hemangiosarcomas
combined,
both
at
p
<
0.05.

Female
mice
had
significant
increasing
trends
in
hepatocellular
adenomas
and
adenomas,
carcinomas
and/
or
hepatoblastomas
combined,
both
at
p
<
0.01.
There
were
significant
differences
in
the
pair­
wise
comparisons
of
the
8000
ppm
dose
group
with
the
controls
for
hepatocellular
adenomas
at
p
<
0.05
and
for
hepatocellular
adenomas,
carcinomas
and/
or
hepatoblastomas
combined
at
p
<
0.01.
There
was
a
significant
increasing
trend
at
p
<
0.01,
and
a
significant
difference
in
the
pair­
wise
comparison
of
the
8000
ppm
dose
group
with
the
controls
at
p
<
0.05,
for
hemangiosarcomas.
There
was
also
a
significant
increasing
trend
for
hemangiomas
and/
or
hemangiosarcomas
combined
at
p
<
0.05.

Adequacy
of
the
Dose
Levels
Tested:
At
meetings
on
October
27
and
December
8,
1993,
the
HED
Cancer
Peer
Review
Committee
concluded
that
the
8000
ppm
dose
was
excessive
based
on
the
significantly
decreased
body
weight
gain
in
males
(33%)
and
females
(19%)
during
week
13,
a
significant
decrease
in
RBC
and
brain
cholinesterase
activity,
clinical
signs
of
toxicity
and
histopathological
changes
in
the
bladder,
kidneys
and
spleen
in
both
sexes.
The
November
7,
2001
CARC
meeting
affirmed
that
the
high
dose
was
excessive.

3.
Carcinogenicity
and
Other
Studies
in
p53
Knockout
Mice
In
a
special,
non­
guideline
study
(MRID
45281801),
heterozygous
p53­
deficient
(knockout)
male
mice
(20/
group)
were
administered
carbaryl
in
the
diet
at
concentrations
of
0,
10,
30,
17
100,
300,
1000
and
4000
ppm
(approximately
0,
1.8,
5.2,
17.5,
51.2,
164.5
and
716.6
mg/
kg/
day,
respectively)
for
six
months.
The
doses
selected
for
this
study
were
based
on
two
28­
day
studies
(MRID
45236603)
in
wild­
type
mice
in
which
body
weight
decreases
were
observed
at
4000
and
8000
ppm
concentrations
of
carbaryl
in
the
diet.
A
validation
study
(MRID
45281802)
demonstrated
that
vascular
tumors
occur
in
heterozygous
p53­
deficient
mice
within
6
months
of
administration
of
a
known
genotoxic
carcinogen
(urethane).
These
studies
were
conducted
to
demonstrate
that
carbaryl
is
a
non­
genotoxic
carcinogen.
In
the
standard
mouse
carcinogenicity
study
(MRID
42786901)
at
dietary
concentrations
of
0,
100,
1000
or
8000
ppm,
there
was
an
increased
incidence
of
vascular
neoplasms
(hemangiomas
and
hemangiosarcomas)
in
all
treated
males
and
in
the
8000
ppm
group
females.
There
was
an
increased
incidence
of
adenomas,
multiple
adenomas
and
carcinomas
of
the
kidney
in
the
8000
ppm
group
males.
The
incidence
of
hepatic
neoplasms
(adenomas,
carcinomas
and
one
hepatoblastoma)
was
increased
in
the
8000
ppm
group
females.
At
meetings
on
October
27
and
December
8,
1993,
the
HED
Cancer
Peer
Review
Committee
concluded
that
the
8000
ppm
dose
was
excessive.
Therefore,
the
relevance
of
tumors
at
this
dose
was
questionable.

In
the
p53
knockout
mouse
study
with
carbaryl,
there
was
a
slight
decrease
in
body
weight
and
food
consumption
in
the
4000
ppm
group.
No
other
treatment­
related
effects
were
observed,
except
globular
deposits
in
the
urinary
bladder
were
observed
in
a
high
proportion
of
the
mice
treated
at
100
ppm
of
carbaryl
and
above
with
a
dose­
related
increase
in
incidence
and
severity.
There
was
no
evidence
of
local
irritation
or
hypertrophy
of
the
bladder
epithelium.
There
was
no
evidence
of
neoplastic
or
preneoplastic
changes
in
the
vascular
tissue
of
any
organs
examined.

The
study
is
classified
Acceptable
(non­
guideline).
This
is
a
special
study
not
submitted
to
fulfill
a
data
requirement.

4.
Classification
of
Carcinogenic
Potential.

The
carcinogenic
potential
of
carbaryl
was
evaluated
by
the
HED
Carcinogenicity
Peer
Review
Committee
on
October
27
and
December
8,
1993
(May
12,
1994
report).
The
Committee
concluded
that
carbaryl
induced
tumors
at
multiple
sites
in
the
rat
and
mouse
at
doses
considered
to
be
excessively
toxic.
Only
hemangiosarcomas
in
the
CD­
1
male
mouse
occurred
at
a
dose
which
was
considered
adequate
and
not
excessive.
The
Committee
concluded
that
carbaryl
should
be
classified
as
a
Group
C
­
possible
human
carcinogen.
Both
the
low­
dose
extrapolation
(Q1*)
approach
and
a
margin
of
exposure
(MOE)
approach
were
suggested
as
methods
of
quantifying
the
cancer
risk
in
humans.
In
addition,
a
RfD
approach
was
suggested
to
provide
the
most
sensitive
non­
cancer
health
endpoint
for
comparison
to
the
linear
and
MOE
approaches.
The
Committee
requested
additional
metabolism
studies
and
genotoxicity
studies
to:
1)
direct
the
selection
of
the
more
appropriate
quantitative
approach;
and
2)
provide
insight
into
the
significance
of
tumors
seen
only
at
excessively
toxic
doses.

Additional
metabolism
studies
were
submitted
and
evaluated
by
a
subgroup
of
the
HED
Cancer
Assessment
Review
Committee
(CARC)
in
a
memorandum
signed
October
5,
1998.
The
subgroup
concluded
that
the
available
metabolism
studies
were
not
adequate
to
support
a
nonlinear
mode
of
action
and
recommended
that
the
default
linear
approach
be
used
for
risk
18
quantitation.

In
1996,
the
registrant
convened
a
Pathology
Working
Group
(PWG)
which
reevaluated
all
histopathology
findings
of
both
the
two­
year
rat
and
mouse
studies.
The
results
of
this
PWG
are
discussed
below
with
the
study
summaries.

At
a
November
7,
2001
meeting,
the
HED
CARC
classified
carbaryl
as
"Likely
to
be
carcinogenic
to
humans"
based
on
a
statistically
significant
increase
in
hemangiosarcomas
in
male
mice
at
all
doses
tested
(100,
1000
and
8000
ppm),
all
at
p<
0.05.
In
addition,
there
were
preneoplastic
lesions
in
the
bladders
of
male
rats
at
the
mid
dose
(1500
ppm)
which
was
not
considered
adequate
for
carcinogenicity
testing.
Bladder
tumors
were
observed
in
male
rats
at
the
high
dose
which
was
considered
excessive.

The
unit
risk,
Q1
*
(mg/
kg/
day)
­1
,
of
Carbaryl
is
8.75
x
10
­4
in
human
equivalents
based
on
the
1996
PWG
re­
read
of
the
male
mouse
hemangiosarcoma
tumor
rates.

4
MUTAGENICITY
During
the
meetings
on
October
27,
and
December
8,
1993,
the
CPRC
(1994)
recommended
that
an
in
vivo
cytogenetic
assay
in
rodents
be
conducted
to
provide
insight
into
the
structural
and/
or
numerical
aberrations,
which
were
observed
in
the
gene
mutation
assay
and
reported
in
the
open
literature.
In
response
to
CPRC's
request,
a
mouse
micronucleus
assay
(MRID
44069301)
was
submitted
to
fulfill
the
guideline
requirement
but
it
was
classified
as
unacceptable.

A
recent
review
of
the
data
from
the
submitted
studies
and
the
published
literature
were
in
general
agreement
and
show
that
carbaryl
is
clastogenic
in
vitro.
The
wide
variety
of
induced
aberrations
(both
simple
and
complex)
was
consistent
between
the
submitted
study
and
the
open
literature.
However,
there
are
inconsistencies
relative
to
the
requirement
for
S9
activation.

Nevertheless,
the
two
in
vivo
studies
for
micronuclei
induction
or
chromosome
aberrations
were
negative.
Similarly,
the
6­
month
p53
knockout
transgenic
mouse
bioassay
was
negative
up
to
a
high
level
(4000
ppm,
.
720
mg/
kg/
day)
that
approached
the
limit
dose
for
a
mouse
carcinogenicity
assay.
Carbaryl
was
also
negative
for
DNA
binding
in
the
livers
of
mice
treated
with
8000
ppm
for
2
weeks
but
the
study
was
considered
to
be
of
limited
sensitivity
by
the
CARC
Metabolism
Subgroup
(HED
Document
No.
012892).
The
same
Subgroup
identified
epoxide
intermediates
of
carbaryl
which
were
found
to
be
conjugated
to
glucuronide,
"rapidly
metabolized
and
excreted
as
any
endogenous
epoxide
would
be".

Overall,
these
findings
indicate
that
carbaryl
produces
epoxides
and
its
DNA
reactivity
is
manifested
as
chromosomal
aberrations
in
cultured
mammalian
cells.
Other
in
vitro
studies
indicate
carbaryl's
effects
on
karyokinesis
and
cytokinesis,
as
well
as
stress
genes
associated
with
oxidative
damage.
Based
on
these
considerations,
it
was
concluded
that
there
is
a
concern
for
mutagenicity,
which
is
somewhat
lessened
because
of
the
lack
of
an
effect
in
in
vivo
mutagenicity
studies.
19
GENE
MUTATIONS
Mutagenicity
­
Salmonella
typhimurium/
Mammalian
Microsome
Mutagenicity
Assay
(Ames
test)

In
a
Salmonella/
mammalian
activation
gene
mutation
assay
(MRID
41370303),
carbaryl
technical
(99.3%)
was
initially
evaluated
in
the
Salmonella
typhimurium/
microsome
mutagenicity
assay
over
a
concentration
range
of
5
to
1000
µg/
plate.
The
test
material
was
not
mutagenic,
however
the
highest
assayed
dose
was
cytotoxic
in
S.
typhimurium
strains
TA98
and
TA100,
but
not
in
strains
TA1535,
TA1537,
or
TA1538.
Accordingly,
the
assay
was
repeated
with
six
concentrations
(10
to
2000
µg/
plate
+/­
S9).
Results
from
the
repeat
assay
indicated
that
2000
µg/
plate
+/­
S9
was
cytotoxic
in
strains
TA98
and
TA100,
and
the
remaining
doses
were
not
mutagenic.
It
is
concluded,
therefore,
that
carbaryl
technical
was
assayed
to
an
appropriately
high
concentration
with
no
evidence
of
mutagenicity
in
a
wellconducted
study.
The
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirements
(§
84­
2)
of
bacterial
reverse
mutation
test.

Mutagenicity
­
Mammalian
Cells
in
Culture
Gene
Mutation
Assay
in
Chinese
Hamster
Ovary
(CHO)
Cells
In
a
mammalian
cells
in
culture
gene
mutation
assay
in
Chinese
Hamster
Ovary
(CHO)
Cells
(MRIDs
41370302,
41420201),
carbaryl
technical
(99.3%)
was
evaluated
in
two
nonactivated
and
three
S­
9
activated
Chinese
hamster
ovary
(CHO)
cell
forward
mutation
assays.
The
findings
from
both
nonactivated
assays
were
in
good
agreement
and
indicated
that
over
a
concentration
range
of
1
to
300
µg/
mL,
the
test
material
did
not
induce
a
mutagenic
response.
Doses
$
200
µg/
mL
were
severely
cytotoxic
(<
10%
cell
survival),
and
<50%
of
the
cells
survived
exposure
to
$
50
µg/
mL.
Carbaryl
was
less
cytotoxic
in
the
presence
of
S9
activation
as
indicated
by
increased
survival
at
comparable
levels
in
the
preliminary
cytotoxicity
test
(e.
g.,
29.5%
survival
at
62.5
µg/
mL
­S9
as
compared
with
95.7%
survival
at
62.5
µg/
mL
+S9)
and
the
initial
mutation
assay
(e.
g.,
18.1%
survival
at
100
µg/
mL
­S9
as
compared
with
46.8%
at
100
µg/
mL
+S9).
There
was
no
definitive
evidence
of
increased
mutation
frequencies
(MFs)
in
this
trial.
The
second
S9­
activated
trial
was
aborted
because
of
excessive
cytotoxicity
at
test
material
levels
of
$
10
µg/
mL.
Results
from
the
third
S9­
activated
trial
(dose
range:
1
to
80
µg/
mL)
showed
severe
cytotoxic
effects
at
levels
$
60
µg/
mL;
no
evidence
of
mutagenic
effect
was
seen
at
the
remaining
doses.

The
results
of
the
assays
provide
no
clear
indication
of
a
mutagenic
response,
however,
the
study
does
not
fully
support
a
negative
conclusion.
The
conflicting
cytotoxicity
data
for
the
S9­
activated
assays
provide
no
assurance
that
the
final
S9­
activated
mutation
assay
was
conducted
over
an
appropriate
dose
range.
The
study
is
classified
as
unacceptable/
guideline
and
does
not
satisfy
the
guideline
requirements
(§
84­
2)
for
an
in
vitro
mammalian
cell
gene
mutation
test.
20
CHROMOSOME
ABERRATIONS
Mutagenicity
­
Mammalian
Cells
in
Culture
Cytogenetic
Assay
Carbaryl
(technical)
was
assayed
for
clastogenic
effects
in
both
the
presence
and
absence
of
S9
activation
using
Chinese
hamster
ovary
(CHO)
cells
(MRID
41370301).
Because
of
severe
cell
cycle
delay,
which
was
more
pronounced
without
S9
activation,
a
20­
hour
cell
harvest
was
selected
to
evaluate
seven
nonactivated
doses
ranging
from
5
to
100
:
g/
mL.
In
the
presence
of
S9
activation,
cells
exposed
to
carbaryl
at
doses
of
25,
50,
75,
100,
150,
200,
250,
and
300
:
g/
mL
were
harvested
30
hours
post
treatment.
Results
indicated
that
the
nonactivated
test
material
was
more
cytotoxic
than
the
S9­
activated
test
material
(i.
e.,
few
metaphases
were
recovered
at
75
and
100
:
g/
mL
,
and
moderate
to
slight
cytotoxic
effects
were
seen
at
doses
$
10.0
:
g/
mL).
With
the
exception
of
a
single
rare
complex
aberration
(quadriradial)
scored
at
the
50.0­
:
g/
mL
dose
level,
there
was
no
evidence
of
a
clastogenic
effect.
By
contrast,
in
the
S9­
activated
assays,
all
scored
doses
(150,
200,
250,
and
300
:
g/
mL)
at
both
harvest
times
induced
significant
(p
0.01)
increases
in
the
percentage
of
cells
with
aberrations.
The
majority
of
S9­
activated
doses
(both
harvests)
also
induced
significant
(p
0.01)
increases
in
the
percentage
of
cells
with
>1
aberration.
At
both
the
20­
and
30­
hour
harvest
times,
cytotoxicity
(i.
e.,
reduced
monolayers,
dead
cells,
and/
or
reduced
mitotic
cells)
were
observed
at
levels
$
200
:
g/
mL.
Induced
structural
damage
included
simple
(i.
e.,
chromatid
and
chromosome
breaks)
and
complex
aberrations
(i.
e.,
triadials,
quadriradials,
complex
rearrangements,
dicentrics
and
rings).
The
data
show
little
or
no
dose
responsiveness
and
the
lowest
reactive
level
of
carbaryl
was
not
determined.
It
was
concluded,
however,
that
the
study
was
technically
sound
and,
therefore,
acceptable/
guideline.
The
study
satisfies
the
Guideline
requirements
(§
84­
2)
for
an
in
vitro
mammalian
cell
chromosomal
aberration
test.

Mutagenicity
­
Mouse
Micronucleus
Test
In
a
mouse
micronucleus
assay
(MRID
No:
44069301),
groups
of
five
male
and
five
female
CD­
1
mice
received
single
oral
gavage
administrations
of
50,
100
or
200
mg/
kg
carbaryl
(99.9%)
once
daily
for
2
days.
Based
on
analytical
determinations,
average
daily
doses
were
.
34,
79
or
180
mg/
kg.
Mice
were
sacrificed
at
24
and
48
hours
postadministration
of
the
second
dose
and
harvested
bone
marrow
cells
were
examined
for
the
incidence
of
micronucleated
polychromatic
erythrocytes
(MPEs).
The
test
material
was
delivered
as
suspensions
prepared
in
0.5%
carboxymethyl
cellulose.

The
minimal
toxicity
(i.
e.,
lethargy
which
lasted
for
2
hours)
in
the
absence
of
cytotoxicity
to
the
target
cells
does
not
support
the
testing
of
the
maximum
tolerated
dose
(MTD).
The
positive
control
induced
the
expected
high
yield
of
MPEs
in
males
and
females.
Carbaryl
did
not
induce
a
clastogenic
or
aneugenic
effect
in
either
sex
at
any
dose
or
sacrifice
time.
However,
there
was
no
convincing
evidence
that
the
MTD
was
achieved.
The
study
is
classified
as
unacceptable/
guideline
and
does
not
satisfy
the
guideline
requirements(§
84­
2;
OPPTS
870.5385)
for
in
vivo
cytogenetic
mutagenicity
data.
2
Onfelt,
A.,
Klasterska,
I.
(1984).
Sister
­chromatid
exchanges
and
thioguanine
resistance
in
V79
Chinese
hamster
cells
after
treatment
with
the
aneuploidy­
inducing
agent
carbaryl
+/­
S9
mix.
Mutat
Res
125(
2):
269­
274
3
Ahmed,
F.
E.,
Lewis,
N.
J.,
Hart,
R.
W.
(1977).
Pesticide
induced
ouabain
resistant
mutants
in
Chinese
hamsterV79
cells.
Chem
Biol
Interact,
19:
369­
374.

4
Onfelt,
A.,
Klasterska,
I.
(1983).
Spindle
disturbances
in
mammalian
cells
II.
Induction
of
viable
aneuploidy/
polyploidy
cells
and
multiple
chromatid
exchanges
after
treatment
of
V79
Chinese
hamster
cells
with
carbaryl,
modifying
effect
of
glutathione
and
S9.
Mutat
Res
119:
319­
330.

5
Delescluse,
C.
et
al
(2001).
Induction
of
cytochrome
P450
1A1
gene
expression,
oxidative
stress,
and
genotoxicity
by
carbaryl
and
thiabendazole
in
transfected
human
HepG2
and
lymphoblastoid
cells.
Biochem
Pharmacol.
61(
4):
399­
407.

6
Renglin,
A.,
Olsson
A.,
Wachtmeister,
C.,
Onfelt,
A.
(1998).
Mitotic
disturbance
by
carbaryl
and
the
metabolite
1­
naphthol
may
induce
kinase­
mediated
phosphorylation
of
1­
naphthol
to
the
protein
21
OTHER
MUTAGENIC
EFFECTS
Mutagenicity
­
UDS
Assay
In
a
UDS
Assay
in
primary
rat
hepatocytes
(MRID
41370301),
under
the
conditions
of
two
independent
trials,
six
doses
of
carbaryl
technical
(99.3%)
ranging
from
0.5
to
25.0
µg/
mL
in
the
first
assay
and
six
doses
ranging
from
5.0
to
25.0
µg/
mL
in
the
repeat
assay
did
not
induce
an
appreciable
increase
in
the
net
nuclear
grain
counts
of
treated
rat
hepatocytes.
Doses
>25.0
µg/
mL
were
severely
cytotoxic;
reduced
cell
survival
(
25%)
was
observed
at
25.0
µg/
mL
in
both
assays.
Although
an
increase
in
the
percentage
of
cells
with
$
6
grains
per
nucleus
was
seen
in
the
initial
test,
the
increase
was
confined
to
a
single
dose
(10
µg/
mL)
and
was
not
dose­
related
or
reproducible.
The
study
demonstrated
that
carbaryl
is
not
genotoxic
in
this
test
system
at
doses
of
5.0
to
25.0
µg/
mL.
The
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirements
(§
84­
2)
for
a
unscheduled
DNA
synthesis
in
mammalian
cells
in
culture.

STUDIES
FROM
THE
OPEN
LITERATURE
Studies
in
the
open
literature
indicate
that
Carbaryl
is
not
mutagenic
in
bacteria
but
produced
conflicting
results
in
Chinese
hamster
V79
gene
mutation
assays
[negative
in
the
study
of
Onfelt
and
Klasterska
2
but
weakly
positive
minus
S9
metabolic
activation
as
reported
by
Ahmed
et
al.
3
Nonactivated
carbaryl
induced
aneuploidy
and
sister
chromatid
exchanges
in
V79
cells;
the
addition
of
S9
or
an
excess
of
glutathione
eliminated
these
responses
(Onfelt
and
Klasterska
4,2
).
In
the
former
study,
multiple
chromatid
exchanges
(quadriradials
and
complex
rearrangements)
plus
chromosome
breaks
were
also
induced
by
100
mM
carbaryl;
this
effect
was
largely
abolished
by
the
simultaneous
addition
of
S9
or
glutathione.
There
are
positive
data
for
DNA
damage
in
a
human
lymphoblastoid
cell
line
(induction
of
CYP1A1
genes);
carbaryl
also
activated
other
stress
genes
known
to
be
sensitive
to
oxidative
damage
(Delescluse
et
al.
5
).
Also,
carbaryl
causes
depolymerization
of
spindle
microtubules
and
an
apparent
uncoupling
of
karyokinesis
and
cytokinesis
in
cultured
V79
cells
(Renglin
et
al,
6,7
).
phosphatase
inhibitor
1­
naphthyl
phosphate.
Mutagenesis
13:
345­
352.

7
Renglin,
A.,
Harmala­
Brasken,
A.,
Eriksson,
J.,
Onfelt,
A.
(1999).
Mitotic
aberrations
by
carbaryl
reflect
tyrosine
kinase
inhibition
with
coincident
up­
regulation
of
serine/
threonine
protein
phosphatase
activity:
implications
for
coordination
of
karyokinesis
and
cytokinesis.
Mutagenesis
14:
327­
333.

8
Usha
Rani,
M.
V.,
Reddi,
O.
S.
and
Reddy,
P.
P.
(1980).
Mutagenicity
Studies
Involving
Aldrin,
Endosulfan,
Dimethoate,
Phosphamidon,
Carbaryl
and
Ceresan.
Bull
Environm.
Contam.
Toxicol
25:
277­
282.

9
Dzwonkowska,
A.,
Hubner,
H.
(1986).
Induction
of
chromosomal
aberrations
in
the
Syrian
hamster
by
insecticides
tested
in
vivo.
Arch
Toxicol
58(
3):
152­
156.

22
In
contrast
to
the
in
vitro
data,
carbaryl
administered
by
oral
gavage
at
1/
3
of
the
LD50
(146
mk/
kg/
day)
for
2
consecutive
days
was
negative
for
micronuclei
induction
in
Swiss
albino
male
mice
(Usha
Rani
et
al.
8
).
Carbaryl
was
also
negative
for
the
induction
of
chromosome
aberrations
in
bone
marrow
cells
of
Syrian
hamsters
treated
with
1/
10,
1/
5
and
½
of
the
LD50
and
the
LD50
(Dzwonkowska
and
Hubner
9
).

5
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base
The
data
base
is
adequate
for
FQPA
considerations.
The
following
acceptable
studies
are
available:
­­
Acute
delayed
neurotoxicity
study
in
hen
­­
Acute
and
subchronic
neurotoxicity
studies
in
rats
­­
Developmental
toxicity
studies
in
rats
and
rabbits
­­
Multi­
generation
reproduction
study
in
rats
­­
Developmental
neurotoxicity
study
in
rats
5.2
Neurotoxicity
Carbaryl
was
not
a
delayed
neurotoxicant
in
the
hen.
In
the
acute
neurotoxicity
study
with
gavage
administration,
FOB
changes
(increased
tremors
and
ataxia,
decreased
body
temperature
and
arousal)
and
decreased
motor
activity
were
observed
in
males
and
females
at
50
and
125
mg/
kg.
Decreases
in
plasma
(males
only),
whole
blood,
RBC
and
brain
cholinesterase
were
seen
at
10,
50
and
125
mg/
kg/
day.

In
the
subchronic
neurotoxicity
study
with
gavage
administration,
there
was
an
increased
incidence
of
tremors
and
salivation
in
males
and
females
at
30
mg/
kg/
day.
FOB
changes
(increases
in
tremors,
gait
alteration,
pinpoint
pupils,
salivation,
etc.)
were
observed
in
males
and
females
at
10
and
30
mg/
kg/
day.
Motor
activity
was
decreased
in
males
and
females
at
30
mg/
kg/
day.
Plasma,
RBC,
whole
blood
and
brain
ChE
were
decreased
in
males
and
females
at
10
and
30
mg/
kg/
day.
At
necropsy,
there
was
an
increase
in
dark
areas
of
the
meninges
of
the
30
mg/
kg/
day
males.
23
In
the
developmental
neurotoxicity
study
with
gavage
administration,
changes
in
FOB
parameters
(increases
in
pinpoint
pupils,
tremors,
ataxia,
overall
gait
incapacity)
were
seen
in
the
maternal
animals
at
10
mg/
kg/
day.
RBC
and
whole
blood
ChE
was
decreased
on
gestation
day
(GD)
20
and
lactation
day
(LD)
10
at
10
mg/
kg/
day.
Plasma
ChE
was
decreased
on
GD
20,
LD4
and
LD10
at
10
mg/
kg/
day.
Brain
ChE
was
decreased
at
10
mg/
kg/
day.
In
both
the
F1
pups
and
adults,
there
were
differences
in
the
morphometric
measurements
from
the
control
group
at
10
mg/
kg/
day.

In
the
chronic
dog
study
with
dietary
administration,
clinical
signs
of
neurotoxicity
(emesis,
lacrimation,
salivation
and
tremors)
were
observed
in
females
at
1250
ppm
(31.3
mg/
kg/
day).
Plasma
and
brain
ChE
were
decreased
in
females
at
doses
of
125
ppm
(3.1
mg/
kg/
day)
and
above
and
in
males
at
400
ppm
(10
mg/
kg/
day)
and
above.
RBC
ChE
was
decreased
in
males
and
females
at
400
ppm
and
above.
In
a
five­
week
study
done
to
upgrade
the
chronic
study,
plasma
ChE
was
decreased
in
males
at
125
ppm
(3.83
mg/
kg/
day),
the
highest
dose
tested.

In
the
mouse
carcinogenicity
study
with
dietary
administration,
there
were
clinical
signs
of
toxicity
(hunched
posture,
thin
and
languid
appearance,
squinted
and
opaque
eyes,
etc.)
at
8000
ppm
(M:
1248.93
mg/
kg/
day;
F:
1440.62
mg/
kg/
day)
but
they
were
not
the
usual
signs
seen
with
cholinesterase
inhibiting
chemicals.
RBC
cholinesterase
(ChE)
was
statistically
significantly
decreased
in
the
1000
ppm
(145.99
mg/
kg/
day)
(23%
9
)
and
8000
ppm
(30%
9
)
group
males
at
week
53.
RBC
ChE
was
decreased
in
the
8000
ppm
group
females
(24%
9
)
at
week
105,
although
the
change
was
not
statistically
significant.
Brain
ChE
was
statistically
significantly
decreased
in
the
1000
and
8000
ppm
group
males
at
both
weeks
53
and
105
(13­
18%
9
for
the
1000
ppm
group;
40­
57%
9
for
the
8000
ppm
group)
and
in
the
8000
ppm
females
(34­
47%
9
).
Brain
ChE
was
also
significantly
decreased
(13%
9
)
in
the
1000
ppm
(180.86
mg/
kg/
day)
group
females
at
week
53.
However,
the
percentage
decreases
from
the
control
level
were
less
than
20%
for
the
1000
ppm
group
males
and
females
at
both
weeks
53
and
105.
Therefore,
the
biological
significance
of
these
findings
is
questionable.
Plasma
ChE
values
were
not
affected
by
treatment.

In
the
rat
combined
chronic
toxicity/
carcinogenicity
study
with
dietary
administration,
there
were
increased
signs
of
toxicity
in
the
7500
ppm
(M:
349.5
mg/
kg/
day;
F:
484.6
mg/
kg/
day)
group,
but
they
were
not
the
usual
signs
seen
with
cholinesterase
inhibiting
chemicals.
Plasma
cholinesterase
was
decreased
in
the
7500
ppm
males
(27­
42%)
and
females
(46­
57%)
at
all
of
the
testing
intervals
(weeks
27,
53,
79
and
105),
however
all
of
the
changes
were
not
statistically
significant.
RBC
cholinesterase
was
decreased
in
the
7500
males
(19­
37%)
and
females
(25­
38%)
and
in
the
1500
ppm
(60.2
mg/
kg/
day)
males
(10­
23%)
and
females
(12­
26%)
at
most
of
the
testing
intervals.
At
weeks
53
and
105,
brain
cholinesterase
was
statistically
significantly
decreased
in
the
7500
ppm
males
(8­
28%)
and
females
(22­
31%).
In
the
recovery
group,
cholinesterase
values
had
returned
to
normal
levels
by
week
56.
24
5.3
Developmental
Toxicity
Prenatal
developmental
toxicity
study
in
the
rat
In
a
developmental
toxicity
study
(MRID
44732901),
carbaryl
(99%
a.
i.)
in
an
aqueous
methylcellulose
suspension
was
administered
by
gavage
at
0,
1,
4,
and
30
mg/
kg/
day
to
pregnant
Crl:
CD
(SD)
BR
rats
(25/
dose)
during
gestation
days
(GDs)
6
through
20.
At
GD
21,
surviving
dams
were
sacrificed
and
necropsied.

There
were
no
treatment­
related
gross
pathologic
findings
noted
in
any
of
the
dams.
There
were
no
differences
of
toxicological
concern
in
mortality,
pregnancy
rate,
numbers
of
corpora
lutea,
implantations,
viable
fetuses,
pre­
and
post­
implantation
losses,
placental
weights,
and
sex
ratio.

At
30
mg/
kg/
day,
at
least
one
occurrence
of
post­
dosing
salivation
occurred
in
18/
25
of
the
dams
(vs
0/
25
controls).
This
clinical
sign
appeared
within
20
minutes
of
treatment,
disappeared
after
approximately
one
hour,
and
was
observed
from
GD
13
to
20.
There
were
no
deaths
and
no
other
treatment­
related
clinical
signs.
Body
weights
of
the
high­
dose
dams
were
3­
8%
less
than
controls
throughout
the
study
(not
statistically
significant);
their
corrected
(for
gravid
uterine
weight)
body
weights
and
body
weight
gains
were
decreased
(p
0.01)
by
7
and
38%,
respectively.
Body
weight
gains
in
this
group
were
decreased
immediately
after
initiation
of
dosing
(GDs
6­
9,
9
108%,
p
0.01)
and
throughout
treatment
(overall,
9
27%,
p
0.01).
Food
consumption
(g/
animal/
day)
was
decreased
throughout
the
treatment
period
(
10­
17%,
p
0.01).

There
were
no
differences
of
toxicological
concern
observed
in
the
mid­
and
low­
dose
groups.

The
maternal
LOAEL
is
30
mg/
kg/
day
based
on
clinical
signs
of
toxicity,
decreased
body
weight
gains
and
food
consumption.
The
maternal
NOAEL
is
4
mg/
kg/
day.

In
the
high­
dose
fetuses,
mean
fetal
body
weights
were
reduced
(
7­
8%,
p
0.01).
Additionally,
the
following
were
observed
in
the
high­
dose
male
and
female
fetuses:
(i)
an
increase
in
incomplete
ossification
of
the
5th
sternebra,
(ii)
unossified
7th
cervical
centrum,
(iii)
incomplete
ossification
of
7th
cervical
centrum,
and
(iv)
unossified
1st
metatarsal.
No
effects
on
fetal
viability
were
observed.

There
were
no
treatment
related
effects
in
developmental
parameters
observed
in
the
mid­
and
low­
dose
groups.

The
developmental
LOAEL
is
30
mg/
kg/
day
based
on
decreased
fetal
body
weights
and
increased
incomplete
ossification
of
multiple
bones.
The
developmental
NOAEL
is
4
mg/
kg/
day.

The
developmental
toxicity
study
in
the
rat
is
classified
as
acceptable
(§
83­
3(
a))
and
does
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rat.
25
Prenatal
developmental
toxicity
study
in
the
rabbit
In
a
developmental
toxicity
study
(MRID
44904202),
carbaryl
(99%
a.
i.)
in
an
aqueous
methylcellulose
suspension
was
administered
by
gavage
at
doses
of
0,
5,
50
or
150
mg/
kg/
day
to
pregnant
New
Zealand
White
rabbits
(22/
dose)
during
Gestation
Days
(GD)
6­
29.
On
GD
25,
blood
was
collected
1
hour
post­
dosing
for
plasma
and
red
blood
cell
(RBC)
cholinesterase
(ChE)
measurements.
At
GD
30,
surviving
dams
were
sacrificed
and
necropsied;
fetuses
were
examined
for
evidence
of
developmental
effects.
Maternal
toxicity
at
150
mg/
kg/
day
was
observed
as
statistically
significant
decreased
body
weight
gain
as
compared
to
the
control
value
during
GD
6­
9
(208%),
GD
6­
29
(dosing
period,
53%),
GD
3­
30
(33%)
and
gestation
(GD
0­
GD
30,
38%).
Corrected
body
weight
change
was
also
decreased
at
this
dose
(­
219.73
g
vs
­81.86
g
in
the
control).
Although
not
statistically
significant,
the
body
weight
decreases
at
50
mg/
kg/
day
can
be
considered
biologically
significant
for
GD
6­
9
(55%),
GD
6­
29
(25%),
GD
3­
30
(14%)
and
gestation
(14%).
There
was
no
treatment­
related
effect
on
food
consumption.
Statistically
significantly
decreases
in
plasma
(46­
68%)
and
RBC
(19­
27%)
ChE
were
seen
at
50
and
150
mg/
kg/
day.

Maternal
LOAEL
=
50
mg/
kg/
day
based
on
decreased
body
weight
gain
and
decreased
plasma
and
RBC
ChE;
Maternal
NOAEL
=
5
mg/
kg/
day
The
only
evidence
of
developmental
toxicity
was
a
statistically
significant
decrease
in
fetal
body
weights
of
10%
(when
calculated
for
all
fetuses
or
individually
for
males
and
females)
at
150
mg/
kg/
day.
There
were
no
treatment­
related
developmental
effects
observed
in
the
mid­
and
low­
dose
groups.

Developmental
Toxicity
LOAEL
is
150
mg/
kg/
day
based
on
decreased
fetal
weight.
Developmental
Toxicity
NOAEL
is
50
mg/
kg/
day
The
developmental
toxicity
study
in
the
rabbit
is
classified
as
acceptable/
guideline
and
does
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rabbit.

5.4
Reproductive
Toxicity
In
a
two­
generation
reproduction
study
(MRID
45448101),
carbaryl
(99.1%
a.
i,
Lot
No.
E1208008)
was
given
in
the
diet
to
groups
of
30
male
and
30
female
F0
and
F1
rats
(CD
®
[SD]
IGS
BR
(Sprague­
Dawley))
at
concentrations
of
0,
75,
300,
or
1500
ppm.
The
dietary
concentrations
corresponded
to
doses
of
4.67,
31.34,
and
92.43
mg/
kg/
day
for
F0
males;
0,
5.56,
36.32,
and
110.78
mg/
kg/
day
for
F0
females;
0,
5.79,
23.49,
and
124.33
mg/
kg/
day
for
F1
males;
and
0,
6.41,
26.91,
and
135.54
mg/
kg/
day
for
F1
females
averaged
over
the
premating
period.
Each
group
received
treated
or
control
diet
continuously
for
70
days
prior
to
mating
and
during
mating,
gestation,
and
lactation
of
one
litter
per
generation.
F1
pups
selected
to
parent
the
F2
generation
were
weaned
onto
the
same
food
as
their
parents.
Parental
males
were
sacrificed
after
delivery
of
their
litters
and
parental
females
were
sacrificed
after
weaning
of
their
litters.

No
treatment­
related
deaths,
clinical
signs,
organ
weight
changes,
gross
lesions,
or
26
microscopic
lesions
were
observed
in
adult
rats
of
either
generation.
No
treatment­
related
effects
were
observed
on
body
weights,
weight
gain,
feed
consumption,
or
food
efficiency
in
75­
or
300­
ppm
group
F0
or
F1
male
or
female
rats
at
any
time
during
the
study
including
the
gestation
and
lactation
periods
of
the
females.
F0
and
F1
male
and
female
rats
fed
the
1500­
ppm
diet
weighed
significantly
(p<
0.01
or
<0.05)
less
and
gained
less
weight
during
the
premating
period.
The
F0
males
weighed
5­
6%
less
than
controls
during
premating,
gained
14­
23%
less
weight
during
three
weekly
intervals
up
to
day
45,
and
gained
9%
less
weight
over
the
entire
premating
period;
they
also
gained
8%
less
weight
than
controls
over
the
mating/
postmating
period.
The
F1
males
weighed
10­
19%
less
than
controls
during
the
entire
study,
gained
16%
and
11%
less
weight
during
the
first
two
weekly
intervals,
and
gained
8%
less
weight
than
controls
averaged
over
the
entire
premating
period.
The
F0
females
weighed
4­
5%
less
than
controls
during
the
first
42
days
of
premating,
gained
27%
less
weight
during
the
first
week,
and
7%
(N.
S.)
less
averaged
over
the
entire
premating
period.
The
F1
females
weighed
8­
22%
less
than
controls
throughout
premating
and
gained
9%
less
weight
during
the
first
week;
weight
gain
for
the
remaining
weekly
intervals
and
for
the
entire
premating
period
was
similar
to
that
of
controls.
Food
consumption
and
food
efficiency
for
F0
and
F1
rats
followed
patterns
similar
to
that
of
body
weight
and
weight
gain;
the
largest
difference
between
the
1500­
ppm
groups
and
controls
occurred
during
the
early
part
of
the
premating
period.
When
averaged
over
the
entire
premating
period,
F0
and
F1
males
consumed
6­
7%
less
food
than
control
and
had
food
efficiency
values
similar
to
those
of
the
controls.
Feed
consumption
and
food
efficiency
for
the
F0
females
were
similar
to
those
of
the
control
group,
whereas
F1
females
consumed
9%
(p<
0.01)
less
feed
and
had
a
food
efficiency
value
10%
(p<
0.01)
greater
than
that
of
controls.
F0
and
F1
females
in
the
1500
ppm
group
weighed
less
and
gained
less
weight
than
controls
during
gestation,
with
the
effect
being
greater
in
the
F1
females.
During
lactation
weight
gain
was
markedly
reduced
in
F1
females
during
the
first
4
days,
but
was
greater
than
that
of
controls
averaged
over
the
entire
lactation
period.

The
lowest­
observed­
effect
level
(LOAEL)
for
parental
systemic
toxicity
is
1500
ppm
(92.43­
124.33
mg/
kg/
day
for
males
and
110.78­
135.54
mg/
kg/
day
for
females)
based
on
decreased
body
weight,
weight
gain,
and
feed
consumption.
The
no­
observed­
adverseeffect
(NOAEL)
level
is
300
ppm
(23.49­
31.34
mg/
kg/
day
for
males
and
26.91­
36.32
mg/
kg/
day
for
females).

No
treatment­
related
effects
were
observed
on
the
estrous
cycle
of
either
F0
or
F1
females
at
any
dose
level
or
on
percent
motile
sperm,
sperm
count,
percent
progressively
motile
sperm,
epididymal
sperm
count,
spermatid
head
count,
daily
sperm
production,
or
efficiency
of
daily
sperm
production
in
F0
or
F1
males
at
any
dose
level.
There
was
a
dose­
related
increase
in
the
percentage
of
abnormal
sperm
in
the
treated
males
but
no
statistical
significance
at
any
dose
level.
No
treatment­
related
gross
or
microscopic
effects
were
observed
in
male
or
female
rats
of
either
generation.
No
treatment­
related
effects
were
observed
on
any
parameter
of
reproductive
performance
including,
mating
and
fertility
indexes,
gestation
index,
pregnancy
index,
precoital
duration,
gestation
length,
or
number
of
females
producing
live
litters.
27
The
LOAEL
for
reproductive
toxicity
could
not
be
established
because
no
effects
were
observed
at
any
dose
level;
therefore,
the
NOAEL
is
$
1500
ppm
(92.43­
124.33
mg/
kg/
day
for
males
and
110.78­
135.54
mg/
kg/
day
for
females).

No
treatment­
related
effects
were
observed
on
implantation
sites/
litter,
number
of
live
pups
born/
litter,
number
of
dead
pups
born/
litter,
live
birth
index,
sex
ratio,
clinical
signs,
or
organ
weight
or
necropsy
findings
in
pups
surviving
to
21
days.
Pup
survival
was
decreased
at
300
and
1500
ppm
for
both
generations.
Increased
number
of
deaths
in
the
F2
generation
males
and
females
resulted
in
an
18­
19%
decrease
in
mean
litter
size
on
postnatal
day
4
(p<
0.01
or
<0.05)
and
decreased
viability
and
lactation
indexes
at
1500
ppm.
A
large
number
of
pups
that
died
had
no
milk
in
their
stomachs.
In
addition,
pup
weight/
litter
and
pup
weight
gain
in
the
1500­
ppm
group
pups
were
reduced
for
both
generations
starting
with
postnatal
day
4
(11­
15%
for
F1
and
13­
23%
for
F2
pups);
body
weight
gain
was
reduced
throughout
lactation
with
the
greatest
effect
occurring
during
the
first
7
days
for
F1
pups
and
the
first
14
days
for
F2
pups.
Sexual
maturation
was
delayed
in
1500­
ppm
group
F1
offspring
as
evidenced
by
delayed
balanopreputial
separation
in
the
males
(+
2.1
days)
and
vaginal
patency
in
the
females
(+
1.4
days).
The
differences
remained
statistically
significant
after
adjustment
for
body
weight
decreases.
Anogenital
distance
was
significantly
reduced
in
F2
male
pups
in
the
1500­
ppm
group,
but
not
when
the
distance
was
adjusted
for
body
weight.

The
LOAEL
for
offspring
toxicity
was
300
ppm
(23.49­
31.34
mg/
kg/
day
for
males
and
26.91­
36.32
mg/
kg/
day
for
females)
based
on
increased
numbers
of
F2
pups
with
no
milk
in
the
stomach
and
decreased
pup
survival.
The
NOAEL
is
75
ppm
(4.67­
5.79
mg/
kg/
day
for
males
and
5.56­
6.41
mg/
kg/
day
for
females).

This
study
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
twogeneration
reproductive
study
(OPPTS
870.3800;
OECD
416)
in
the
rat.

5.5
Developmental
Neurotoxicity
(Executive
Summary
has
been
revised
based
on
new
morphometric
measurements
from
MRID
45456701)

In
a
developmental
neurotoxicity
study
(MRID
#
44393701,
45456701,
45456702,
45456703),
26
pregnant
female
Sprague­
Dawley
rats/
group
were
administered
carbaryl
(99.1%
a.
i.)
by
gavage
from
Gestation
Day
(GD)
6
through
Lactation
Day
(LD)
10
at
doses
of
either
0,
0.1,
1.0
or
10
mg/
kg/
day.
An
additional
6
pregnant
females/
group
were
dosed
at
the
same
levels
for
the
cholinesterase
(ChE)
phase
of
the
study.
ChE
measurements
were
done
pre­
dosing
(GD
6)
and
post­
dosing
at
time
of
peak
effect
(1
hour
post­
dosing)
on
GD
6,
15
and
20
and
LD
4
and
10.
Functional
Observational
Battery
(FOB)
measurements
were
performed
at
approximately
0.5
and
2
hours
post­
dosing
on
the
same
days
as
body
weight
measurements
during
the
dosing
period
(GD
0,
6,
9,
12,
15,
18
and
20
and
LD
4,
7,
11,
13
and
21).
Measures
of
reproductive
performance
were
evaluated.
Offspring
were
examined
for
body
weight,
physical
development
landmarks
(tooth
eruption
and
eye
opening),
FOB
assessments
(days
4,
7,
11,
13,
17
and
21)
and
motor
activity
(days
13,
17
and
21).
On
LD
11,
1
animal/
sex/
litter
was
sacrificed
for
brain
weights;
of
these,
six/
sex
were
randomly
selected
for
neuropathological
evaluation.
The
eyes
from
all
dose
groups
were
examined.
After
LD
21,
28
3
animals/
sex/
litter
were
separated
from
the
dams
and
constituted
the
F1
adult
generation.
These
animals
were
evaluated
for
body
weight,
physical
development
(vaginal
opening
and
preputial
separation),
motor
activity
(day
60),
startle
habituation
response
(days
22
and
60),
passive
avoidance
(day
23)
and
water
maze
behavior
(day
60).
After
completion
of
the
behavior
test
period
(at
approximately
10
weeks
of
age),
12
animals/
sex/
group
were
anesthetized
and
perfused
for
post­
mortem
examination.
Tissues
from
6
animals/
sex
of
the
control
and
high
dose
group
were
processed
for
neuropathological
evaluation
and
morphometric
measurements;
the
eyes
from
the
low
and
mid­
dose
group
of
all
perfused
animals
were
examined.

For
the
F0
generation
animals,
there
were
no
carbaryl­
associated
deaths.
No
treatment­
related
clinical
signs
of
toxicity
were
observed.
There
was
a
statistically
significant
decrease
(92%)
in
body
weight
gain
for
females
in
the
10
mg/
kg/
day
group
for
the
period
GD
6­
9.
Unfortunately,
food
consumption
was
not
measured
during
the
study.
During
the
FOB
measurements,
the
incidence
of
females
in
the
10
mg/
kg/
day
group
with
decreased
pupil
size
(pinpoint
pupils)
was
increased
on
all
occasions
during
the
dosing
period.
An
increased
incidence
of
dams
with
slight
tremors
affecting
the
head,
body
and/
or
limbs
was
noted
on
the
majority
of
assessment
occasions
in
the
dosing
period.
There
were
also
occasional
occurrences
of
ataxic
gait/
overall
gait
incapacity
which
was
considered
to
be
of
toxicological
significance
due
to
other
effects
upon
gait.

For
the
10
mg/
kg/
day
group,
RBC
and
whole
blood
ChE
levels
were
statistically
significantly
decreased
(28%
and
32­
34%,
respectively)
on
GD
20
and
LD
10.
Although
the
plasma
ChE
levels
were
not
statistically
significantly
altered,
the
percentage
decreases
on
GD
20,
LD
4
and
LD
10
were
32­
39%.
Brain
ChE
levels
were
statistically
significantly
decreased
(42%).
There
were
no
treatment­
related
effects
on
gross
necropsy
findings
for
the
F0
generation
animals.
There
were
no
effects
observed
on
maternal
performance
parameters
of
pregnancy
rate,
gestation
index,
length
of
gestation,
numbers
of
live
pups,
dead
or
malformed
pups,
implantation
scars,
sex
ratio
or
post­
implantation
loss.
There
was
a
slight
(P>
0.05)
increase
in
the
number
of
dead
pups
in
the
10
mg/
kg/
day
group,
however
the
value
was
within
the
historical
control
range
for
this
strain.

For
the
F1
generation
pups,
there
were
no
treatment­
related
effects
on
pup
weight,
pup
survival
indices,
developmental
landmarks
(tooth
eruption
and
eye
opening),
FOB
measurements
or
motor
activity
assessments.
At
sacrifice
on
LD
11,
there
were
no
treatmentrelated
effects
on
brain
weight
and
gross
or
microscopic
pathology.
Significant
differences
noted
in
the
morphometric
measurements
included
an
increase
in
Line
B
of
the
right
forebrain
and
Line
F
of
the
left
cerebellum
in
the
10
mg/
kg/
day
males.
In
the
10
mg/
kg/
day
females,
Line
F
through
both
the
right
and
left
cerebellum
was
decreased
(15%
and
22%,
respectively).

For
the
F1
generation
adults,
there
were
no
treatment­
related
effects
on
clinical
condition,
body
weight,
physical
development
(vaginal
opening
and
preputial
separation),
motor
activity,
auditory
startle
response,
passive
avoidance
and
water
maze
measurements.
At
sacrifice,
there
were
no
gross
or
microscopic
neuropathological
lesions
observed
for
animals
examined
in
this
study
that
were
attributable
to
treatment
with
the
test
article.
There
was
an
increased
incidence
of
retinal
fold/
rosette
in
the
10
mg/
kg/
day
group
(1/
12
for
control
vs.
4/
12
for
males;
0/
12
for
control
vs.
2/
12
for
females).
The
finding
was
not
considered
of
toxicological
significance
since
the
incidence
was
within
the
historical
control
range
for
10
Personal
communication
with
Robert
Chapin,
one
of
the
study
authors
29
males,
occurred
at
a
low
rate
and
was
not
dose­
dependent.
For
the
morphometric
measurements,
there
was
a
significant
bilateral
decrease
in
Line
A
through
the
forebrain
(7.7­
9.8%)
and
a
significant
increase
in
Line
F
through
the
right
cerebellum
of
the
10
mg/
kg/
day
males.
Increases
originally
noted
in
the
10
mg/
kg
adult
females
in
Line
G,
width
of
the
cerebellum,
were
found
to
be
based
on
erroneous
measurements,
and
additional
measures
were
submitted.
Now,
for
the
10
mg/
kg/
day
females,
there
were
significant
bilateral
increases
in
Line
F
through
the
cerebellum
(7.4­
15%).
Measurements
of
the
size
of
the
thickness
of
lobes
and
of
the
granule
cell
layers
of
the
cerebellum
in
high
dose
pups
and
adults
did
not
differ
from
those
of
controls.
While
additional
statistical
analyses
by
the
registrant
indicated
no
treatment
related
effects,
HED's
additional
statistical
analyses
did
indicate
treatment
related
effects.

The
maternal
toxicity
LOAEL
was
10
mg/
kg/
day
based
on
decreased
body
weight
gain,
alterations
in
Functional
Observational
Battery
measurements
and
RBC,
plasma,
whole
blood
and
brain
cholinesterase
inhibition.
The
maternal
NOAEL
was
1.0
mg/
kg/
day.

The
developmental
neurotoxicity
LOAEL
was
10
mg/
kg/
day
based
bilateral
decrease
in
the
size
of
the
forebrain
(Line
A)
in
adult
males
(7.7­
9.8%);
a
bilateral
decrease
in
the
length
of
the
cerebella
(Line
F)
in
female
pups
(15­
22%);
and
a
bilateral
increase
in
the
length
of
the
cerebella
(Line
F)
in
female
adults
(7.4­
15%).

The
developmental
NOAEL
was
1.0
mg/
kg/
day.
Morphometric
assessment
at
the
mid
and
low
doses
could
not
be
conducted
due
to
inadequate
tissue
storage;
however,
based
on
the
minimal
findings
at
the
LOAEL,
it
is
HED's
judgment
that
effects
would
be
unlikely
to
occur
at
1
mg/
kg/
day,
which
is
10%
of
the
LOAEL.

This
developmental
neurotoxicity
study
is
classified
acceptable
and
does
satisfy
the
guideline
requirement
for
a
developmental
neurotoxicity
study
(OPPTS
870.6300)
in
rats.

5.6
Additional
Information
from
Literature
Sources
In
an
unpublished
study
from
the
National
Health
and
Ecological
Effects
Research
Laboratories,
EPA,
and
the
National
Institute
for
Environmental
Health
Sciences/
National
Toxicology
Program,
pregnant
Sprague­
Dawley
rats
(n=
36
or
38)
were
dosed
by
gavage
with
carbaryl
at
doses
of
0,
6,
12
or
25
mg/
kg/
day.
10
The
following
description
of
the
study
design
and
findings
was
extracted
from
tables
and
posters
discussing
various
aspects
of
the
study.
The
dams
were
dosed
from
gestational
day
(GD)
14
to
postnatal
day
(PND)
7,
after
which
the
pups
were
directly
dosed
with
the
same
dose
levels
until
PND
21
(weaning)
or
PND
42.
Analyses
for
carbaryl
and
1­
naphthol
in
the
dam's
plasma
and
milk
and
pup's
plasma
were
performed.
A
sample
of
milk
was
incubated
with
a
preparation
of
rat
brain
to
provide
a
bioassay
of
ChE
activity.
The
brains
were
taken
from
a
dam
and
two
fetuses
sacrificed
at
various
times
after
dosing
on
GD
18
to
measure
ChE.
Some
pups
(n=
4­
6/
dose/
sex)
were
sacrificed
on
PND
1,
7,
21
and
47
and
body
and
brain
weights
recorded.
FOB
and
motor
11
Pant
N,
Shankar
R,
Srivastava
SP
(1996).
Spermatotoxic
effects
of
carbaryl
in
rats.
Human
Exp
Toxicol
15(
9);
736­
38.

30
activity
were
measured
on
PND
26/
27,
47/
48,
62/
63
and
81/
82.
In
the
post­
weaning
period,
cognitive
function
was
evaluated
using
a
simple
test
of
associative
learning,
passive
avoidance,
and
in
adulthood
by
assessing
between­
session
habituation
of
motor
activity.
Sperm
counts,
organ
weights
and
clinical
pathology
were
done
on
males
at
necropsy.
Carbaryl
or
1­
naphthol
were
not
present
in
the
pups'
plasma
above
the
limit
of
detection
at
any
exposure
concentration.
In
the
dams'
plasma,
carbaryl
was
below
the
limit
of
detection
for
the
6
mg/
kg/
day
dose,
but
was
present
in
some
or
most
of
the
animals
from
the
other
two
doses.
1­
naphthol
was
present
in
all
treated
groups
in
a
dose­
related
increase.
In
general,
milk
concentrations
followed
the
trends
seen
in
plasma,
however
1­
napthol
was
about
3­
5
times
lower
in
milk
compared
to
plasma.
There
was
a
dose­
related
suppression
of
brain
ChE
produced
by
the
blood
samples.
There
was
a
dose­
related
decrease
in
ChE
activity
in
the
brain
and
blood
of
dams
at
GD
19,
and
fetuses
taken
at
that
time
also
showed
a
very
similar
level
of
inhibition
in
fetal
brain.
There
was
a
decrease
in
the
number
of
live
pups/
litter
in
the
25
mg/
kg/
day
group
at
PND
0,
7,
and
21.
The
average
pup
weight
was
decreased
in
the
25
mg/
kg/
day
group
at
PND
1,
7,
14
and
21.
There
were
no
changes
in
cognitive
function.
For
brain
weights
measured
on
PND
0,
7,
21
and
47,
the
only
change
was
on
PND
21
when
the
25
mg/
kg/
day
group
was
decreased
in
males
and
the
low
and
high
dose
groups
were
decreased
in
females.
Equivocal
changes
in
FOB
parameters
were
observed
in
males
at
PND62/
63
and
in
females
at
PND
47/
48.
There
were
no
evidence
of
an
effect
on
the
necropsy
parameters.

In
a
1996
study
in
the
open
literature,
carbaryl
was
administered
to
four
groups
of
6
young
and
6
adult
Druckery
albino
rats
per
group
at
doses
of
0,
25,
50
or
100
mg/
kg/
day
for
60
days.
11
Body
weight
was
recorded
at
initiation
and
completion
of
the
study.
On
the
61st
day,
the
animals
were
sacrificed
and
the
testes,
epididymides,
seminal
vesicles,
ventral
prostrate
and
coagulating
glands
were
weighed.
Epididymal
sperm
were
used
for
sperm
counts
and
examination
of
motility
and
morphology.
No
overt
toxicity
or
mortality
was
observed.
There
were
dose­
related
effects
on
body
weight
for
the
50
and
100
mg/
kg/
day
groups.
The
absolute
weights
of
the
testes,
epididymides,
seminal
vesicle,
ventral
prostrate
and
coagulating
glands
were
significantly
decreased
at
100
mg/
kg/
day
for
young
rats.
The
relative
organ
weights
were
not
affected
at
any
doses.
The
organ
weights
were
not
affected
in
adult
animals.
Young
rats
receiving
carbaryl
50
mg/
kg/
day
had
a
24.4%
and
25%
decrease
in
sperm
motility
and
sperm
count,
respectively;
the
changes
at
100
mg/
kg/
day
were
42.9%
and
37.5%,
respectively.
Adults
receiving
the
50
mg/
kg/
day
dose
had
a
15.1%
and
12.5%
reduction
in
sperm
motility
and
count,
respectively;
the
changes
at
100
mg/
kg/
day
were
26.4%
and
25%,
respectively.
The
percentage
of
young
rats
with
abnormal
sperm
was
19.8%
and
33.7%
at
50
and
100
mg/
kg/
day,
respectively.
In
adults,
the
percentages
were
16.1%
and
23.1%
for
the
respective
doses.

In
another
study
from
this
laboratory,
three
groups
of
8
male
Wistar
rats
per
group
were
12
Pant
N,
Srivastava
SC,
Prasad
AK,
Shankar
R,
Srivastava
SP
(1995).
Effects
of
Carbaryl
on
the
Rat's
Male
Reproductive
System.
Vet
Human
Toxicol
37(
5):
421­
425.

13
Narotsky
MG,
Kavlock
RJ
(1995).
A
Multidisciplinary
Approach
to
Toxicological
Screening:
II.
Developmental
Toxicity.
Journal
of
Toxicology
and
Environmental
Health
45:
145­
171.

31
administered
carbaryl
by
gavage
at
doses
of
0,
50
or
100
mg/
kg/
day
for
90
days.
12
Body
weight
was
measured
periodically
throughout
the
study.
On
the
91st
day,
the
animals
were
sacrificed
and
the
male
reproductive
glands
were
weighed.
One
testis
from
each
animal
was
preserved
for
histopathology
and
the
other
was
homogenized
for
testicular
enzyme
assay.
Epididymal
sperm
were
used
for
sperm
counts
and
examination
of
motility
and
morphology.
No
clinical
signs
of
toxicity
were
observed,
except
for
lethargy.
Body
weights
were
decreased
in
the
100
mg/
kg/
day
group
after
60
days.
There
were
no
changes
in
the
weights
of
reproductive
organs.
There
were
significant
changes
in
the
testicular
enzymes
of
the
100
mg/
kg/
day
group:
decreases
in
SDH
and
G6PDH
and
increases
in
GGT
and
LDH.
At
both
doses,
there
were
significant
decreases
in
the
total
epididymal
sperm
count,
percent
sperm
motility
and
increases
in
the
percent
with
morphological
abnormalities
in
head,
neck
and
tail.
At
50
mg/
kg/
day,
the
testes
had
slight
to
moderate
congestion
and
edema.
A
few
tubules
showed
moderately
depressed
spermatogenesis
and
loss
of
sperm.
There
was
moderate
atrophy
of
seminiferous
tubules
with
prominent
interstitial
spaces
in
the
center
of
the
testes,
but
the
Leydig
cells
were
intact.
At
100
mg/
kg/
day,
there
were
increases
in
the
intensity
of
congestion
and
the
edematous
reaction
was
seen
both
peripherally
and
in
the
central
region.
Most
of
the
seminiferous
tubules
had
disturbed
spermatogenesis
as
well
as
accumulations
of
cellular
masses
in
their
lumens.

In
a
study
conducted
at
EPA's
Health
Effects
Research
Laboratory,
16
pregnant
Fischer
344
rats
were
administered
carbaryl
by
gavage
on
gestation
days
(GD)
6­
19
at
doses
of
78
or
104
mg/
kg/
day;
21
control
animals
were
used.
13
The
high
dose,
selected
to
produce
overt
maternal
toxicity,
was
based
on
the
results
of
a
14­
day
repeated
dose
study
in
nonpregnant
female
rats.
The
low
dose
was
75%
of
the
high
dose.
Maternal
body
weights
were
determined
on
GD
6,
8,
10,
13,
16
and
20.
All
rats
were
examined
periodically
for
clinical
signs
of
toxicity.
Pups
in
each
litter
were
examined
and
counted
on
postnatal
day
(PD)
1,
3,
and
6
and
weighed
collectively
on
PD
1
and
6.
After
the
final
litter
examination,
the
dams
were
killed
and
uterine
implantation
sites
counted.
Females
that
did
not
deliver
by
GD
24
were
killed
and
their
uteri
examined
for
pregnancy
status.
Clinical
signs
of
toxicity
observed
in
the
dams
included
tremors,
motor
depression,
and
lacrimation,
usually
during
the
first
three
days
of
treatment.
Jaw
clonus
was
observed
throughout
the
treatment
period.
(The
article
does
not
indicate
if
clinical
signs
were
observed
at
both
doses.)
Marked
weight
loss
was
observed
early
in
treatment.
Over
the
entire
treatment
period,
carbaryl
produced
extrauterine
weight
loss
at
the
high
dose
and
reduced
weight
gains
at
the
low
dose.
There
was
increased
prenatal
mortality
at
the
high
dose;
this
effect
was
attributed
to
two
(15%)
fully
resorbed
litters
in
this
group.
In
addition,
high
dose
pup
weights
were
significantly
reduced
on
PD
1.
The
PD­
1
pup
weights
in
the
low
dose
and
the
PD
6
pup
weights
in
both
carbaryl­
exposed
groups
were
also
significantly
reduced,
but
only
when
analyzed
using
the
number
of
live
pups
on
PD
1
as
the
14
Savitz
DA,
Arbuckle
T,
Kaczor
D,
Curtis
KM
(1997).
Male
Pesticide
Exposure
and
Pregnancy
Outcome.
Am
J
Epidemiol
146(
12):
1025­
36.

32
covariate.

In
a
recent
epidemiology
study,
the
effects
of
exposure
of
male
farmers
in
Ontario,
Canada,
to
agricultural
pesticides
and
pregnancy
outcome
was
investigated.
14
Miscarriage
risk
was
not
associated
with
participation
in
farm
activities
for
all
types
of
chemical
applications,
but
was
increased
in
combination
with
reported
use
of
thiocarbamates,
carbaryl
and
unclassified
pesticides
on
the
farm
(Odds
ratio
=
1.9,
95%
C.
I.
1.1­
3.1).
There
was
no
association
between
use
of
carbaryl
and
preterm
delivery,
small
for
gestational
age
or
altered
sex
ratio
measurements.

At
the
1996
Joint
Meeting
on
Pesticide
Residues
(JMPR),
it
was
concluded
that
carbaryl
induces
developmental
toxicity,
manifested
as
deaths
in
utero,
reduced
fetal
weight,
and
malformations,
but
only
at
doses
that
cause
overt
maternal
toxicity.
The
shortcomings
of
the
developmental
studies
made
them
inadequate
for
identifying
NOAELs
for
developmental
toxicity
that
could
be
used
for
assessing
risk
under
conditions
of
exposure
other
than
in
the
diet.
The
Committee
recommended
studies
of
teratogenicity
in
rats
and
rabbits
and
study
of
developmental
neurotoxicity
and/
or
screening
for
acute
or
subchronic
neurotoxicity.
Two
dog
studies
were
cited
in
the
report.
In
these
studies,
maternal
toxicity
(dystocia,
at
parturition
only)
was
observed
at
a
dose
of
3.1
mg/
kg/
day.
Various
birth
defects
were
observed
in
the
pups
at
doses
$
5
mg/
kg/
day.
Thus
the
LOAEL
for
maternal
toxicity
was
3.1
mg/
kg/
day,
which
was
the
NOAEL
for
birth
defects
in
the
offspring.

The
report
states
that
studies
on
reproductive
toxicity
were
conducted
some
time
ago
and
had
some
deficiencies
in
relation
to
currently
acceptable
scientific
standards.
The
Meeting
recommended
that
a
new
two­
generation
reproductive
toxicity
study
should
be
carried
out
on
rats,
with
special
attention
to
the
male
reproductive
system
since
effects
on
this
system
were
observed
in
some
long­
term
studies
of
toxicity
at
gavage
doses
significantly
lower
than
those
evaluated
in
the
dietary
studies
of
reproductive
toxicity.

5.7
Determination
of
Susceptibility
There
was
no
evidence
of
quantitative
or
qualitative
susceptibility
following
in
utero
exposures
in
developmental
studies
in
the
rat
and
rabbit.

In
the
reproduction
study,
there
was
evidence
of
quantitative
susceptibility
of
offsprings.
The
LOAEL
for
parental
systemic
toxicity
was
based
on
decreased
body
weight,
weight
gain,
and
feed
consumption;
the
NOAEL
was
27
mg/
kg/
day
in
males
and
30
mg/
kg/
day
in
females.
In
the
offspring
the
LOAEL
was
based
on
increased
numbers
of
F2
pups
with
no
milk
in
the
stomach
and
decreased
pup
survival;
the
NOAEL
was
5
mg/
kg/
day
in
males
and
6
mg/
kg/
day
in
females.
No
adverse
effects
were
observed
in
the
reproductive
parameters;
the
NOAEL
was
the
highest
dose
tested.
33
In
the
developmental
neurotoxicity
study,
there
was
evidence
of
qualitative
susceptibility.
For
maternal
toxicity,
the
LOAEL
was
based
on
decreased
body
weight
gain,
alterations
in
Functional
Observational
Battery
measurements
and
inhibition
of
plasma,
whole
blood
and
brain
cholinesterase
activity;
the
NOAEL
was
1
mg/
kg/
day.
For
developmental
neurotoxicity,
the
LOAEL
was
based
on
the
morphometric
changes
seen
in
the
brain
of
the
offsprings;
the
NOAEL
was
1
mg/
kg/
day.

5.8
Degree
of
Concern
Analysis
and
Residual
Uncertainties
The
HIARC
concluded
that
there
is
no
residual
concern
in
the
two­
generation
reproduction
study
because
the
dose­
response
effects
in
pups
are
well­
characterized
and
the
NOAEL
for
the
offspring
effects
is
above
that
was
used
for
establishing
the
chronic
Reference
Dose
(RfD)
for
chronic
dietary
risk
assessment.

The
HIARC
selected
the
LOAEL
of
3.1
mg/
kg/
day
established
in
the
chronic
toxicity
study
in
dogs
for
establishing
the
chronic
RfD.
Since
a
LOAEL
was
used,
an
additional
uncertainty
factor
of
3X
was
applied
(i.
e,
lack
of
a
NOAEL)
to
the
LOAEL.
Although
a
NOAEL
was
not
established
in
this
study,
the
HIARC
determined
that
a
3X
was
adequate
(as
opposed
to
a
higher
value)
because:
1)
cholinesterase
inhibition
in
females
was
not
accompanied
by
clinical
signs;
2)
no
inhibition
was
seen
for
any
cholinesterase
compartment
in
males
at
this
dose;
3)
the
magnitude
of
inhibition
of
plasma
cholinesterase
inhibition
(12­
23%
decrease)
was
comparable
to
the
magnitude
of
inhibition
(22%)
seen
in
the
5­
week
study
in
dogs
indicating
no
cumulative
effects
following
long­
term
exposure;
4)
the
study
was
wellconducted
and
there
are
sufficient
data
from
subchronic
and
chronic
duration
studies
in
the
other
species
which
support
cholinesterase
inhibition
as
the
critical
effect.

In
addition,
based
on
the
cholinesterase
inhibition
data,
the
dog
appears
to
be
more
sensitive
than
the
rat
in
long­
term
studies.
Furthermore,
use
of
the
LOAEL
of
3
mg/
kg/
day
from
the
1­
year
dog
study
with
an
uncertainty
factor
of
300
results
in
a
NOAEL
of
1
mg/
kg/
day.
This
extrapolated
NOAEL
is
identical
to
that
of
the
offspring
NOAEL
of
1.0
mg/
kg/
day
established
in
the
the
developmental
neurotoxicity
study.

Thus,
the
NOAEL
of
1
mg/
kg/
day
used
for
establishing
the
chronic
RfD
is
below
the
NOAEL
of
5
mg/
kg/
day
for
offspring
toxicity
and
the
chronic
RfD
would
be
protective
of
the
effects
of
concern
for
infants
and
children
following
chronic
dietary
exposures.

With
regard
to
the
developmental
neurotoxicity
study,
the
HIARC
concluded
that
there
was
a
low
level
of
concern
based
on
the
following
residual
uncertainties
°
The
first
uncertainty
was
the
lack
of
a
demonstrated
effect
level
since
morphometric
measurements
of
brains
in
the
offsprings
were
not
performed
at
the
mid­
dose
(1
mg/
kg/
day).
However,
this
concern
was
negated
since
even
at
the
high
dose
of
10
mg/
kg/
day,
the
morphometric
changes
were
minimal
and
therefore,
it
is
unlikely
that
adverse
effects
would
be
seen
at
1
mg/
kg/
day,
which
is
10%
of
the
LOAEL.
°
The
second
uncertainty
was
the
lack
of
comparative
data
in
adults
and
offspring
for
cholinesterase
inhibition.
This
concern
was
negated
since
no
FOB
alterations
were
seen
in
pups.
Other
studies
in
the
data
base
have
shown
that
when
FOB
alterations
34
were
seen
in
adult
animals,
they
are
usually
accompanied
with
cholinesterase
inhibition.
Also,
the
results
of
the
National
Institute
for
Environmental
Health
Sciences
study
(discussed
below)
showed
no
difference
in
cholinesterase
inhibition
in
pups
and
adults.
There
was
a
dose­
related
decrease
in
cholinesterase
activity
in
the
brain
and
blood
of
dams
at
gestation
day
19
and
fetuses
taken
at
this
time
also
showed
a
very
similar
level
in
fetal
brain
cholinesterase.

The
HIARC
concluded,
that
the
NOAEL
of
1
mg/
kg/
day
selected
for
establishing
the
acute
RfD
would
address
the
low
level
of
concern
for
the
residual
concerns
and
would
be
protective
of
the
effects
of
concern
for
infants
and
children
following
a
single
oral
exposure.

5.9
Hazard
Based­
Special
FQPA
Safety
Factor
Recommendation
The
HIARC
concluded
that
the
hazard
based
special
FQPA
safety
factor
should
be
reduced
to
1x
based
on
the
following
reasons:

1.
The
toxicology
database
is
complete
2.
There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
in
rat
or
rabbit
fetuses
following
in
utero
exposures
3.
There
was
evidence
of
qualitative
susceptibility
and
a
low
level
of
concern
due
to
some
residual
uncertainties
in
the
developmental
neurotoxicity
study.
However,
as
discussed
in
Section
I.
3,
the
acute
RfD
would
address
these
residual
uncertainties
and
would
be
protective
of
the
pre­
pre/
post
natal
toxicity
following
an
acute
dietary
exposure.
4.
There
was
evidence
of
increased
susceptibility
in
the
offsprings
in
the
two
generation
reproduction
study,
but
there
was
no
residual
uncertainties.
The
chronic
RfD
would
be
protective
of
the
pre­
pre/
post
natal
toxicity
following
chronic
dietary
exposures.
5.
The
dose
selected
for
residential
exposures,
would
be
protective
of
the
pre­
pre/
post
natal
toxicity
following
non­
dietary
exposures.
35
6.
HAZARD
CHARACTERIZATION
Carbaryl
is
a
carbamate
insecticide.
Its
mode
of
toxic
action
is
through
plasma,
RBC
and
brain
cholinesterase
inhibition
(ChEI).
In
most
studies
in
which
ChE
was
measured,
it
was
the
endpoint
used
for
setting
the
NOAEL.
Carbaryl
is
relatively
acutely
toxic
by
the
oral
route
(Toxicity
Category
II)
but
non­
toxic
acutely
by
the
dermal
and
inhalation
routes.
It
is
not
a
dermal
or
eye
irritant
or
a
dermal
sensitizer.

Carbaryl
was
negative
for
delayed
neurotoxicity
in
the
hen.
Clinical
signs
compatible
with
ChEI
were
seen
in
most
of
the
short­
and
long­
term
studies
in
rodents
and
non­
rodents.
There
was
no
evidence
of
structural
neuropathology
in
the
acute
and
subchronic
neurotoxicity
studies
in
rats.
In
the
developmental
neurotoxicity
study
in
the
rat,
changes
in
brain
morphometric
measurements
were
observed
in
female
offspring;
however,
their
toxicological
significance
is
unknown.

Carbaryl
has
been
classified
as
a
Likely
to
be
carcinogenic
to
humans
based
on
an
increased
incidence
of
hemangiosarcomas
and
combined
hemangiomas/
hemangiosarcomas
in
CD­
1
mice
at
100
ppm
(15
mg/
kg/
day)
and
above.
Other
tumors,
including
kidney
tubular
cell
tumors
in
male
mice,
liver
tumors
in
female
mice,
thyroid
tumors
in
male
rats,
bladder
tumors
in
male
and
female
rats
and
liver
tumors
in
female
rats
were
observed
at
excessive
doses.
Mechanistic
metabolism
studies
were
considered
inadequate
to
demonstrate
a
mode
of
action
for
the
vascular
tumors.
The
default
linear
extrapolation
will
be
used
for
risk
assessment;
the
Q1*
is
8.75
x
10
­4
in
human
equivalents
based
on
the
based
on
the
mouse
vascular
tumors.

Maternal
toxicity
was
observed
at
the
same
dose
as
developmental
toxicity
in
both
the
rat
and
rabbit;
the
studies
showed
no
evidence
of
a
qualitative
or
quantitative
increased
susceptibility.
In
the
twogeneration
reproduction
study,
there
was
evidence
of
increased
quantitative
and
qualitative
susceptibility
of
offspring.
The
parental
NOAEL
level
was
approximately
27
mg/
kg/
day
for
males
and
30mg/
kg/
day
for
females)
based
on
decreased
body
weight,
weight
gain,
and
feed
consumption
at
approximately
108
mg/
kg/
day
for
males
and
124
mg/
kg/
day
for
females.
The
offspring
NOAEL
was
approximately
5
mg/
kg/
day
in
males
and
6
mg/
kg/
day
in
females
based
on
based
on
increased
numbers
of
F2
pups
with
no
milk
in
the
stomach
and
decreased
pup
survival
at
approximately
27
mg/
kg/
day
in
males
and
30
mg/
kg/
day
in
females.
In
the
developmental
neurotoxicity
study,
evidence
of
maternal
neurotoxicity
(FOB
alterations,
cholinesterase
inhibition)
was
observed
at
the
same
dose
as
changes
in
brain
morphometric
measurements
in
offspring.

7.
DATA
GAPS
90­
day
inhalation
study
in
the
rat
with
cholinesterase
measurements
21­
day
dermal
toxicity
study
in
the
rat
with
cholinesterase
measurements
Micronucleus
study
36
8.
ACUTE
TOXICITY
Acute
Toxicity
of
Carbaryl
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
Acute
Oral
­
rat
00148500
LD50
for
males
=
302.6
mg/
kg;
for
females
=
311.5
mg/
kg;
combined
=
301.0
mg/
kg
II
81­
2
Acute
Dermal
rabbit
00148501
LD50
>
2000
mg/
kg
III
81­
3
Acute
Inhalation
rat
00148502
LC50
>
3.4
mg/
L
IV
81­
4
Primary
Eye
Irritation
00148503
not
a
primary
eye
irritant
IV
81­
5
Primary
Skin
Irritation
00148504
not
a
primary
skin
irritant
IV
81­
6
Dermal
Sensitization
00148505
negative
81­
7
Acute
Delayed
Neurotoxi
city
(Hen)
*
negative
at
2000
mg/
kg
(approximate
LD50)

81­
8
Acute
Neurotoxicity
­
rat
43845201­
43845204
systemic
LOEL
=
10
mg/
kg
for
males
and
females
based
on
significant
inhibition
of
RBC,
plasma,
whole
blood
and
brain
cholinesterase;
NOEL
<
10
mg/
kg
*
Carpenter,
C.
P.,
Weil,
C.
S.,
Palm,
P.
E.,
Woodside,
N.
W.,
Nair,
J.
H.
and
Smyth,
H.
F.
Mammalian
Toxicity
of
1­
napthyl­
N­
methyl
carbamate
(Sevin
Insecticide).
J.
Agric.
Food
Chem.
9(
1):
30­
39,
1961.
37
9.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
for
Carbaryl:

EXPOSURE
SCENARIO
DOSE
(mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
NOAEL
=
1
UF
=
100
FOB
alterations
on
first
day
of
dosing
in
maternal
animals
Developmental
Neurotoxicity
­
rat
Acute
RfD
=
0.01
mg/
kg
Chronic
Dietary
LOAEL
=
3.1
UF
=
300
decrease
in
brain
cholinesterase
in
females
Chronic
toxicity
dog
Chronic
RfD
=
0.01
mg/
kg/
day
Short­
Term
Oral
Incidental
NOAEL
=
1
FOB
alterations
on
first
day
of
dosing
in
maternal
animals
Developmental
Neurotoxicity
­
rat
IntermediateTerm
Oral
Incidental
Oral
NOAEL=
1.0
increased
incidence
of
FOB
changes;
decrease
in
RBC,
whole
blood,
plasma
and
brain
cholinesterase
subchronic
neurotoxicity
study
­
rat
Short­
Term
(Dermal)
a
NOAEL
=
1
FOB
alterations
on
first
day
of
dosing
in
maternal
animals
Developmental
Neurotoxicity
­
rat
IntermediateTerm
(Dermal)
a
Oral
NOAEL=
1.0
increased
incidence
of
FOB
changes;
decrease
in
RBC,
whole
blood,
plasma
and
brain
cholinesterase
subchronic
neurotoxicity
study
­
rat
Long­
Term
(Dermal)
a
LOAEL
=
3.1
decrease
in
brain
cholinesterase
in
females
chronic
toxicity
dog
Short
Term
(Inhalation)
b
NOAEL
=
1
FOB
alterations
on
first
day
of
dosing
in
maternal
animals
Developmental
Neurotoxicity
­
rat
Intermediate
Term
(Inhalation)
b
Oral
NOAEL=
1.0
increased
incidence
of
FOB
changes;
decrease
in
RBC,
whole
blood,
plasma
and
brain
cholinesterase
subchronic
neurotoxicity
study
­
rat
Long
Term
(Inhalation)
LOAEL
=
3.1
decrease
in
brain
cholinesterase
in
females
chronic
toxicity

dog
Cancer
Q1*
=
8.75
x
10
­4
male
mouse
hemangiosarcoma
tumors
carcinogenicity

mouse
a
Since
an
oral
NOAEL/
LOAEL
was
selected,
a
dermal
absorption
factor
of
12.7%
should
be
used
in
route­
to­
route
extrapolation.
b
Since
an
oral
NOAEL
was
selected,
an
inhalation
factor
of
100%
should
be
used
in
route­
to­
route
extrapolation.
