UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
Office
of
Prevention,
Pesticides
and
Toxic
Substances
DATE:
May
24,
2002
TXR
#:
0050726
MEMORANDUM
SUBJECT:
CARBARYL:
UPDATED
TOXICOLOGY
CHAPTER
FOR
RED
FROM:
Virginia
A.
Dobozy,
VMD,
MPH,
Veterinary
Medical
Officer
Reregistration
Branch
I
Health
Effects
Division
(7509C)

THRU:
Whang
Phang,
PhD,
Branch
Senior
Scientist
Reregistration
Branch
I
Health
Effects
Division
(7509C)

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

and
Betty
Shackleford/
Anthony
Britten
Special
Review
and
Reregistration
Division
(7508C)

PC
Code:
056801
DP
Barcode:
D282980
Submission:
S615586
Case:
818954
Attached
is
the
Updated
Toxicology
Chapter
for
Carbaryl
for
the
RED.
It
replaces
the
chapter
dated
December
7,
1999.
CARBARYL
PC
Code:
056801
Updated
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date
completed:
May
24,
2002
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
Prepared
by:
Virginia
A.
Dobozy,
VMD,
MPH
TABLE
OF
CONTENTS
1.
0
HAZARD
CHARACTERIZATION
................................................
4
2.
0
REQUIREMENTS..............................................................
6
3.
0
DATA
GAP(
S).................................................................
8
4.
0
HAZARD
ASSESSMENT
.......................................................
8
4.
1
Acute
Toxicity
...........................................................
8
4.
2
Subchronic
Toxicity.......................................................
8
4.
3
Prenatal
Developmental
Toxicity
...........................................
12
4.4
Reproductive
Toxicity
....................................................
13
4.
5
Chronic
Toxicity
........................................................
17
4.6
Carcinogenicity
.........................................................
19
4.
7
Mutagenicity
...........................................................
24
4.
8
Neurotoxicity...........................................................
27
4.
9
Metabolism
............................................................
32
5.0
TOXICITY
ENDPOINT
SELECTION
.............................................
36
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
.................................
36
5.
2
Dermal
Absorption
.......................................................
36
5.3
Classification
of
Carcinogenic
Potential
......................................
36
6.
0
FQPA
CONSIDERATIONS
.....................................................
39
6.
1
Degree
of
Concern
Analysis
and
Residual
Uncertainties
.........................
39
6.2
Hazard
Based­
Special
FQPA
Safety
Factor
Recommendation
.....................
40
7.
0
REFERENCES
...............................................................
41
8.
0
APPENDICES
................................................................
45
9.
1
Toxicity
Profile
Summary
Tables
...........................................
46
9.1.1
Acute
Toxicity
Table
...............................................
46
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
..........................
46
9.2
Summary
of
Toxicological
Endpoint
Selection
for
Carbaryl
......................
51
4
1.0
HAZARD
CHARACTERIZATION
The
toxicology
data
base
is
of
good
quality
and
is
essentially
complete.
A
90­
day
inhalation
study
with
cholinesterase
measurements
is
required.
The
database
provides
sufficient
information
for
selecting
toxicity
endpoints
for
risk
assessment
and
therefore,
supports
a
reregistration
eligibility
decision
for
the
currently
registered
uses.

Carbaryl
is
a
carbamate
insecticide.
Its
primary
mode
of
toxic
action
is
through
cholinesterase
inhibition
(ChEI)
after
single
or
multiple
exposures.
In
most
of
the
toxicology
studies
in
which
ChE
was
measured,
it
was
the
endpoint
used
to
set
the
Lowest
Observed
Adverse
Effect
Level
(LOAEL).

The
acute
toxicity
studies
showed
that
carbaryl
was
relatively
toxic
with
acute
oral
dosing
(Tox.
Category
II);
but
the
acute
dermal
and
inhalation
toxicities
were
low
(Tox.
Categories
III
and
IV,
respectively).
Carbaryl
was
not
a
dermal
or
eye
irritant
and
was
not
a
dermal
sensitizer.

The
neurotoxicity
data
showed
that
carbaryl
was
not
a
delayed
neurotoxicant
in
the
hen.
In
the
acute
neurotoxicity
study
in
the
rat
after
a
single
dose
of
10
mg/
kg
carbaryl,
ChEI
was
observed
in
plasma,
whole
blood,
red
blood
cells
(RBC)
and
brain.
At
the
next
higher
dose
(50
mg/
kg),
clinical
signs
typical
of
carbamate
toxicity
were
observed.
In
the
subchronic
neurotoxicity
study
after
90
days
of
administration,
clinical
signs
of
toxicity
were
seen
at
the
same
dose
(10
mg/
kg/
day)
as
plasma,
whole
blood,
RBC
and
brain
ChEI.
There
was
no
evidence
of
structural
neuropathology
in
these
studies.

No
subchronic
studies
in
the
rat
or
dog
are
available,
except
for
the
subchronic
neurotoxicity
study
in
rats
and
4­
week
dermal
toxicity
studies
in
rats
(one
with
technical
chemical
and
two
with
formulations).
One
of
the
dermal
toxicity
studies
was
useful
for
risk
assessment.
In
this
study,
the
systemic
NOAEL
was
20
mg/
kg/
day
based
on
decreased
RBC
ChE
in
males
and
females
and
brain
ChE
in
males
at
50
mg/
kg/
day.
The
chronic
toxicity
data
showed
that,
in
dogs,
decreases
in
plasma,
RBC
and
brain
ChE
were
observed
at
10
mg/
kg/
day;
clinical
signs
of
toxicity
were
also
observed
in
both
sexes
at
31
mg/
kg/
day.
Brain
and
plasma
ChE
were
decreased
in
female
dogs
at
3.1
mg/
kg/
day.
In
the
mouse,
clinical
signs
of
toxicity
were
not
typical
of
ChEI,
but
there
was
ChEI
(plasma,
RBC
and
brain)
at
146
mg/
kg/
day.
In
the
chronic
toxicity
study
in
rats,
carbaryl
at
the
highest
dose
(350
mg/
kg/
day
in
males
and
485
mg/
kg/
day
in
females)
caused
a
variety
of
toxic
effects
in
the
liver,
kidneys
and
urinary
bladder.
It
also
induced
an
increase
in
the
incidence
of
thyroid
follicular
cell
hypertrophy
and
degeneration
of
sciatic
nerves
and
skeletal
muscle.
RBC
ChE
was
decreased
in
males
at
60
mg/
kg/
day
and
in
females
at
79
mg/
kg/
day.
The
lowest
LOAEL
in
the
chronic
studies
was
in
the
chronic
dog
study,
i.
e.,
3.1
mg/
kg/
day,
which
was
the
lowest
dose
in
females.
In
a
follow­
up
5­
week
study
in
dogs
to
clarify
the
NOAEL
for
ChEI,
plasma
ChE
was
decreased
in
males
at
3.83
mg/
kg/
day;
no
effects
were
observed
at
1.43
mg/
kg/
day.

In
a
prenatal
developmental
toxicity
study
in
the
rat,
maternal
toxicity
was
observed
at
the
same
dose
(10
mg/
kg/
day)
as
developmental
toxicity;
the
NOAEL
was
4
mg/
kg/
day.
Developmental
effects
included
decreased
fetal
body
weight
and
increased
incomplete
ossification
of
multiple
bones.
In
a
prenatal
developmental
toxicity
study
in
the
rabbit,
the
maternal
and
developmental
LOAELs
were
50
mg/
kg/
day
and
150
mg/
kg/
day,
respectively.
The
respective
NOAELs
were
5
mg/
kg/
day
and
50
mg/
kg/
day.
The
only
evidence
of
developmental
toxicity
was
a
decrease
in
fetal
body
weight.
These
studies
showed
no
evidence
of
a
qualitative
or
quantitative
increased
susceptibility.
In
the
reproduction
study,
there
was
evidence
of
a
quantitative
offspring
susceptibility.
The
LOAEL
for
parental
systemic
toxicity
was
1500
5
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).
In
the
developmental
neurotoxicity
study,
there
was
evidence
of
qualitative
susceptibility.
Clinical
signs
of
toxicity
and
plasma
and
brain
ChEI
were
seen
in
maternal
animals
at
the
same
dose
(10
mg/
kg/
day)
as
changes
in
brain
morphometric
measurements
(decreases
in
cerebellar
measurements
in
females
on
Day
11
post­
partum)
were
observed
in
offspring;
however,
brain
measurements
were
not
conducted
at
the
next
lower
dose.

The
Health
Effects
Division's
(HED)
Cancer
Assessment
Review
Committee
(CARC)(
11/
7/
01)
classified
carbaryl
as
Likely
to
be
carcinogenic
in
humans
based
on
an
increased
incidence
of
hemangiosarcomas
in
male
mice
at
all
doses
tested
(100,
1000
and
8000
ppm).
The
Q1*,
based
on
the
CD­
1
mouse
dietary
study
with
¾
Interspecies
Scaling
Factor,
is
8.75
x
10
­4
(mg/
kg/
day)
­1
in
human
equivalents.
In
addition
to
the
required
carcinogenicity
studies
in
mice
and
rats,
the
registrant
submitted
a
special
study
in
genetically
modified
mice.
Carbaryl
was
administered
to
heterozygous
p53­
deficient
(knockout)
male
mice
in
the
diet
at
concentrations
of
up
to
4000
ppm
(716.6
mg/
kg/
day)
for
six
months.
There
was
no
evidence
of
neoplastic
or
preneoplastic
changes
in
the
vascular
tissues
of
any
organ.
A
model
validation
study
demonstrated
that
vascular
tumors
occur
in
heterozygous
p53
deficient
mice
within
six
months
of
administration
of
a
known
genotoxic
carcinogen
(urethane).

A
recent
review
of
the
data
from
the
submitted
studies
and
the
published
literature
show
that
carbaryl
is
clastogenic
in
vitro.
The
wide
variety
of
induced
aberrations
(both
simple
and
complex)
was
consistent
between
the
submitted
micronucleus
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.
Carbaryl
was
also
negative
for
DNA
binding
in
the
livers
of
mice
treated
with
8000
ppm
for
2
weeks.
Metabolism
studies
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,
the
CARC
concluded
that
there
is
a
concern
for
mutagenicity,
which
is
somewhat
lessened
because
of
the
lack
of
an
effect
in
in
vivo
mutagenicity
studies.

The
metabolism
data
in
the
rat
indicated
that
radiolabeled
carbaryl
was
readily
absorbed
with
oral
dosing,
distributed
to
various
organs,
metabolized
and
formed
conjugated
metabolites
with
compounds
such
glucuronic
acid.
A
total
of
20
components
was
found,
and
2
major
metabolites
were
identified,
naphthyl
sulfate
and
naphthyl
glucuronide.
Much
of
the
radioactivity
was
eliminated
within
24
hours
after
dosing
(86%
in
urine
and
11%
in
feces).
Seven
days
post
dosing,
negligible
amounts
of
the
administered
dose
were
found
in
tissues.
Several
special
metabolism
studies
were
conducted
to
explore
a
mechanism
for
the
increase
in
tumor
incidence
in
mice.
The
results
appear
to
show
that
high
doses
of
carbaryl
treatment
(1154
mg/
kg)
led
to
a
"phenobarbital"
type
of
induction
of
liver
xenobiotic­
metabolizing
enzymes
and
6
interaction
of
carbaryl
with
chromatin
protein
in
mice.

A
dermal
absorption
study
indicated
that
12.7%
of
a
carbaryl
formulation
(43.9%
a.
i.)
was
absorbed
systemically.

2.0
REQUIREMENTS
The
requirements
(CFR
158.340)
for
food
use
for
CARBARYL
are
in
Table
1.
Inclusion
of
the
new
guideline
numbers
does
not
imply
that
the
new
(1998)
guideline
protocols
were
used.
7
Table
1.
Carbaryl
­
Data
Requirements
Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
...........................
870.1200
Acute
Dermal
Toxicity
........................
870.1300
Acute
Inhalation
Toxicity
......................
870.2400
Primary
Eye
Irritation
.........................
870.2500
Primary
Dermal
Irritation
......................
870.2600
Dermal
Sensitization
..........................
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(rodent)
.......................
870.3150
Oral
Subchronic
(nonrodent)
....................
870.3200
21­
Day
Dermal
..............................
870.3250
90­
Day
Dermal
..............................
870.3465
90­
Day
Inhalation
............................
yes
yes
yes
no
yes
yes
a
yes
b
yes
c
no
no
870.3700a
Developmental
Toxicity
(rodent)
.................
870.3700b
Developmental
Toxicity
(nonrodent)
..............
870.3800
Reproduction
................................
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(rodent)
......................
870.4100b
Chronic
Toxicity
(nonrodent)
...................
870.4200a
Oncogenicity
(rat)
............................
870.4200b
Oncogenicity
(mouse)
.........................
870.4300
Chronic/
Oncogenicity
.........................
yes
yes
yes
yes
yes
yes
b
yes
yes
b
yes
yes
870.5100
Mutagenicity—
Gene
Mutation
­
bacterial
..........
870.5300
Mutagenicity—
Gene
Mutation
­
mammalian
.......
870.5385
Mutagenicity—
Structural
Chromosomal
Aberrations
870.5550
Mutagenicity—
Other
Genotoxic
Effects
...........
yes
yes
yes
yes
yes
yes
yes
d
yes
870.6100a
Acute
Delayed
Neurotox.
(hen)
..................
870.6100b
90­
Day
Neurotoxicity
(hen)
.....................
870.6200a
Acute
Neurotox.
Screening
Battery
(rat)
...........
870.6200b
90
Day
Neuro.
Screening
Battery
(rat)
............
870.6300
Develop.
Neuro
..............................
yes
no
yes
yes
yes
yes
no
yes
yes
yes
870.7485
General
Metabolism
..........................
870.7600
Dermal
Penetration
...........................
yes
yes
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(rat)
..............................
Subchronic
Oral
(rat)..........................
Six­
month
Oral
(dog)
..........................
no
no
no
a
Satisfied
with
chronic
toxicity
study
b
Satisfied
with
combined
chronic
toxicity/
carcinogenicity
study
c
Satisfied
with
4­
week
non­
guideline
study
which
was
satisfactory
for
risk
assessment
d
Micronucleus
study
required
by
the
CARC
was
unacceptable
because
the
doses
were
not
high
enough.
However,
two
studies
from
the
open
literature
tested
carbaryl
up
to
the
LD50
or
1/
3
of
the
LD50,
which
was
higher
than
the
high
dose
in
the
submitted
study
and
negative.
8
3.0
DATA
GAP(
S)

90­
day
inhalation
study
with
cholinesterase
measurements
4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
The
chemical
is
moderately
acutely
toxic
by
the
oral
route
(Toxicity
Category
II),
relatively
nontoxic
by
the
dermal
and
inhalation
routes
(Toxicity
Category
III
and
IV,
respectively),
not
a
primary
eye
or
skin
irritant
or
a
dermal
sensitizer.

The
acute
toxicity
data
on
CARBARYL
Technical
is
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
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
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
Subchronic
Toxicity:
There
are
no
acceptable
subchronic
toxicity
studies
in
rodents
or
nonrodents.
However,
there
are
acceptable
chronic
studies,
including
a
chronic
toxicity
study
in
the
dog
and
a
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat.
Therefore,
the
requirements
for
subchronic
toxicity
studies
in
dogs
and
rats
can
be
waived.
There
is
an
acceptable
subchronic
neurotoxicity
study
in
the
rat
(discussed
under
G.
Neurotoxicity).
Three
4­
week
non­
guideline
9
dermal
toxicity
studies
in
the
rat
were
conducted.
One
with
technical
carbaryl
was
classified
as
acceptable/
non­
guideline
and
was
used
for
the
risk
assessment.
The
other
two
with
formulations
were
classified
as
unacceptable/
non­
guideline.
No
additional
dermal
toxicity
studies
are
required
at
this
time.

MRID
45630601
In
a
non­
guideline
four­
week
dermal
toxicity
study
(MRID
45630601),
Carbaryl
Technical
(99.49%
a.
i.,
Lot
211048078)
was
applied
to
the
shaved
skin
of
10
Crl:
CD
(SD)
IGS
BR
rats/
sex/
dose
at
dose
levels
of
0,
20,
50
or
100
mg/
kg
bw/
day,
6
hours/
day
for
5
days/
week
during
a
4­
week
period.
The
parameters
measured
included
the
following:
clinical
observations,
body
weight,
body
weight
gain,
food
consumption,
RBC
and
brain
cholinesterase
and
signs
of
dermal
irritation.

There
was
no
treatment­
related
effect
on
mortality,
clinical
observations,
body
weight
or
dermal
irritation.
The
only
statistically
significant
body
weight
gain
changes
were
a
decrease
(27%)
in
the
100
mg/
kg/
day
males
during
Days
5
to
12
and
an
increase
(37%)
in
50
mg/
kg/
day
males
during
Days
19
to
26.
However,
there
were
non­
significant
decreases
in
the
100
mg/
kg/
day
males
at
Days
­3
to
5
(16%),
12
to
19
(17%)
and
­3
to
26
(12%)
which
are
considered
toxicologically
significant.

The
only
statistically
significant
decreases
in
food
consumption
were
in
the
50
mg/
kg/
day
females
on
Days
12
to
19
and
50
and
in
the
100
mg/
kg/
day
females
on
Days
19
to
26.
The
effects
are
not
considered
treatment­
related
as
there
was
no
dose­
response
and
the
decreases
were
minimal
(9%
and
8%
in
the
50
and
100
mg/
kg/
day
groups,
respectively).

RBC
cholinesterase
was
measured
before
dosing
on
Day
­4
and
on
Days
1,
8,
15
and
22.
The
only
statistically
significant
effects
were
in
the
100
mg/
kg/
day
males
at
Days
8
(11%
decrease)
and
22
(13%).
Using
the
repeated
measures
statistical
test,
there
were
also
significant
decreases
in
the
50
and
100
mg/
kg/
day
females
(11%
and
10%,
respectively)
on
Day
22.
These
effects
were
determined
to
be
not
toxicologically
significant
because
they
were
inconsistent.

Measurements
were
also
performed
within
1
hour
after
test
material
removal
on
Days
5,
12,
19,
and
26.
Statistically
significant
decreases
were
observed
in
the
50
mg/
kg/
day
(12%
decrease)
and
100
mg/
kg/
day
(15%)
males
on
Day
5
and
in
the
100
mg/
kg/
day
males
on
Days
12
(21%)
and
19
(16%).
Using
the
repeated
measures
statistical
test,
there
was
also
a
significant
decrease
(10%)
in
the
50
mg/
kg/
day
males
on
Day
12.
In
females,
statistically
significant
decreases
were
observed
in
the
50
and
100
mg/
kg/
day
groups
on
Days
5
(13%
and
12%,
respectively)
and
Day
12
(20%
and
13%,
respectively).

Brain
cholinesterase
was
statistically
significantly
decreased
in
the
50
mg/
kg/
day
males
(15%)
and
in
the
100
mg/
kg/
day
males
(15%)
and
females
(24%).
There
was
also
a
non­
significant
decrease
in
the
50
mg/
kg/
day
females
(9%).

The
systemic
LOAEL
is
conservatively
established
at
50
mg/
kg/
day
based
on
statistically
significant
decreases
in
RBC
cholinesterase
in
males
and
females
and
brain
cholinesterase
in
males.
The
systemic
NOAEL
is
20
mg/
kg/
day.
10
The
dermal
LOAEL
was
not
established.
The
dermal
NOAEL
was
100
mg/
kg/
day.

This
4­
week
dermal
toxicity
study
in
the
rat
is
acceptable
(non­
guideline).
The
study
was
intended
to
establish
endpoints
for
short­
term
and
intermediate­
term
occupational
and
residential
postapplication
dermal
exposure.
Although
the
study
does
not
meet
guideline
requirements,
it
is
useful
for
risk
assessment
for
the
following
reasons:
1)
in
all
oral
studies
in
which
cholinesterase
was
measured,
it
was
the
most
sensitive
endpoint;
therefore,
other
guideline
parameters
would
most
likely
not
establish
a
lower
LOAEL;
2)
plasma
cholinesterase
was
not
measured;
however,
in
all
the
oral
studies
in
rats,
all
three
compartments
(plasma,
RBC
and
brain)
were
affected
at
the
same
dose
level.
Therefore,
it
is
likely
that
plasma
cholinesterase
would
not
have
been
inhibited
at
a
lower
level,
especially
given
the
minimal
effects
on
RBC
and
brain
cholinesterase.

MRID
45630602
In
a
non­
guideline
four­
week
dermal
toxicity
study
(MRID
45630602),
Sevin®
XLR
Plus
(44.82%
a.
i.,
Lot
60618902)
was
applied
to
the
shaved
skin
of
8
Crl:
CD
(SD)
IGS
BR
rats/
sex/
dose
at
dose
levels
of
0,
20,
50
or
100
mcL/
kg
bw/
day
(0,
9.6,
24
or
48
mg/
kg/
day),
6
hours/
day
for
5
days/
week
during
a
4­
week
period.
The
parameters
measured
included
the
following:
clinical
observations,
body
weight,
body
weight
gain,
food
consumption,
RBC
cholinesterase
and
signs
of
dermal
irritation.

There
were
no
treatment­
related
effects
on
clinical
observations
or
body
weight
or
evidence
of
dermal
irritation.
Females
treated
at
100
mcL/
kg/
day
gained
167%,
65%,
144%
and
40%
of
control
values
for
Days
­3
to
5,
5
to
12,
12
to
19
and
19
to
26,
respectively.
Overall
(Days
­3
to
26)
body
weight
gain
was
not
affected.
It
is
difficult
to
determine
if
there
was
a
treatment­
related
effect
immediately
after
dosing
as
the
first
body
weight
measurement
was
not
done
until
Day
5
of
dosing.
Although
not
statistically
significant,
there
does
appear
to
be
a
treatment­
related
decrease
on
the
body
weight
gain
(Days
5
to
12)
of
females
treated
at
100
mcL/
kg/
day.

RBC
cholinesterase
was
measured
before
dosing
on
Week
­1
and
on
Days
1,
8,
15
and
22.
There
was
no
evidence
of
a
treatment­
related
effect
at
these
time
periods.
Measurements
were
also
performed
within
1
hour
after
test
material
removal
on
Days
5,
12,
19,
and
26.
In
males,
the
only
statistically
significant
difference
from
control
values
was
on
Day
26
in
the
animals
dosed
at
50
mcL/
kg/
day;
the
decrease
was
only
8%.
Although
not
statistically
significant,
the
RBC
cholinesterase
on
Day
12
in
males
treated
at
100
mcL/
kg/
day
was
decreased
by
10%.
In
females
treated
at
100
mcL/
kg/
day,
values
were
significantly
decreased
on
Day
5
(12%),
Day
12
(12%)
and
non­
significantly
decreased
on
Days
19
(5%)
and
Day
26
(7%).
There
were
also
significant
decreases
in
the
50
mcL/
kg/
day
females
on
Days
19
(9%)
and
26
(14%)
and
in
the
20
mg/
kg/
day
group
on
Day
26
(10%).
Although
statistically
significant,
the
RBC
cholinesterase
decreases
are
not
judged
to
be
toxicologically
significant
due
to
the
small
magnitude
of
the
effect
and
the
lack
of
a
dose­
response
on
Days
19
and
26.

The
systemic
LOAEL
in
females
was
100
mcL/
kg/
day
(48
mg/
kg/
day)
based
on
decreased
body
weight
gain.
The
systemic
NOAEL
was
50
mcL/
kg/
day
(24
mg/
kg/
day).
The
systemic
LOAEL
in
males
was
not
established.
The
systemic
NOAEL
was
100
mcL/
kg/
day
(48
mg/
kg/
day).

The
dermal
LOAEL
was
not
established.
The
dermal
NOAEL
was
100
mcL/
kg/
day
(48
mg/
kg/
day).

This
4­
week
dermal
toxicity
study
in
the
rat
is
unacceptable
(
non­
guideline).
The
study
was
intended
for
use
in
the
short­
term
and
intermediate­
term
occupational
and
residential
handler
risk
assessments
for
11
the
liquid
formulations
of
carbaryl.
It
is
considered
unacceptable
and
not
upgradeable
because
RBC
cholinesterase
results
were
inconsistent
and
plasma
and
brain
cholinesterase
were
not
measured.
In
another
dermal
toxicity
study
(MRID
45630601),
brain
cholinesterase
inhibition
was
the
most
sensitive
and
reliable
endpoint.
Determination
of
cholinesterase
inhibition
in
all
three
compartments
would
have
helped
define
the
effect
level.

MRID
45630603
In
a
non­
guideline
four­
week
dermal
toxicity
study
(MRID
45630603),
Sevin®
80S
(80.07%
a.
i.,
Lot
C8I168025A)
was
applied
to
the
shaved
skin
of
8
Crl:
CD
(SD)
IGS
BR
rats/
sex/
dose
at
dose
levels
of
0,
20,
50
or
100
mg/
kg
bw/
day,
6
hours/
day
for
5
days/
week
during
a
4­
week
period.
The
parameters
measured
included
the
following:
clinical
observations,
body
weight,
body
weight
gain,
food
consumption,
RBC
cholinesterase
and
signs
of
dermal
irritation.

There
was
no
treatment­
related
effect
on
mortality,
clinical
observations,
body
weight
or
dermal
irritation.
Body
weight
gain
(relative
to
control
values)
in
the
100
mg/
kg/
day
males
was
highly
variable
between
time
periods.
There
were
non­
significant
decreases
of
15%
and
20%
on
Days
­3
to
5
and
19
to
26,
respectively
but
increases
of
9%
and
53%
were
observed
on
Days
5
to
12
and
12
to
19,
respectively.
Since
body
weight
was
not
measured
at
treatment
initiation,
it
is
difficult
to
determine
if
there
was
an
effect
during
the
first
time
period.
However,
food
consumption
was
significantly
decreased
by
12%
on
Days
­1
to
5
in
this
group,
which
correlates
with
an
initial
treatment­
related
effect.
Therefore,
the
decrease
in
body
weight
gain
in
the
100
mg/
kg/
day
males
is
considered
treatment­
related.

RBC
cholinesterase
was
measured
before
dosing
on
Week
­1
and
on
Days
1,
8,
15
and
22.
Statistically
significant
decreases
were
observed
in
the
50
and
100
mg/
kg/
day
females
on
Day
8
(10%
and
12%,
respectively).
These
effects
are
not
considered
toxicologically
significant
given
the
inconsistency
of
the
findings.
Measurements
were
also
performed
within
1
hour
after
test
material
removal
on
Days
5,
12,
19,
and
26.
In
males,
statistically
significant
decreases
were
observed
in
animals
treated
at
50
mg/
kg/
day
on
Days
12
(10%),
19
(13%)
and
26
(8%).
In
males
treated
at
100
mg/
kg/
day,
there
were
significant
decreases
on
Days
12
(20%),
19
(19%)
and
26
(19%).
Although
not
statistically
significant,
there
was
also
a
12%
decrease
on
Day
5
in
this
group.
In
females,
statistically
significant
decreases
were
observed
in
animals
treated
at
50
mg/
kg/
day
on
Days
12
(16%)
and
19
(12%).
Using
the
repeated
measures
ANOVA
test,
there
was
also
a
significant
decrease
on
Day
5
(12%)
in
this
group.
In
females
at
100
mg/
kg/
day,
there
were
significant
decreases
on
Days
12
(18%)
and
19
(15%)
and
Day
26
(15%).

The
systemic
LOAEL
is
50
mg/
kg/
day
based
on
statistically
significant
decreases
in
RBC
cholinesterase
in
males
and
females.
The
systemic
NOAEL
is
20
mg/
kg/
day.

The
dermal
LOAEL
was
not
established.
The
dermal
NOAEL
was
100
mg/
kg/
day.

This
4­
week
dermal
toxicity
study
in
the
rat
is
unacceptable
(
non­
guideline).
The
study
was
intended
for
use
in
the
short­
term
and
intermediate­
term
occupational
and
residential
handler
risk
assessments
for
the
solid
formulations
of
carbaryl.
It
is
considered
unacceptable
and
not
upgradeable
because
only
RBC
cholinesterase
was
measured.
In
the
dermal
toxicity
study
with
the
technical
chemical
(MRID
45630601),
brain
cholinesterase
inhibition
was
the
most
sensitive
and
reliable
endpoint.
While
this
study
does
support
the
RBC
cholinesterase
effects
in
MRID
45630601,
the
lack
of
plasma
and
brain
cholinesterase
12
measurements
makes
the
study
unacceptable
for
use
in
risk
assessment.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
There
are
acceptable
prenatal
developmental
toxicity
studies
in
the
rat
and
rabbit.
There
was
no
evidence
of
increased
fetal
susceptibility
in
these
studies.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
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
13
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
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rat.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
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
postdosing
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.

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
In
the
reproduction
study
in
rats,
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.
Several
articles
have
been
published
in
the
open
literature
describing
effects
on
spermatogenesis
and
developmental/
reproduction
parameters
at
high
doses.
There
is
also
an
epidemiology
study
conducted
in
farmers
exposed
to
multiple
pesticides,
which
concluded
that
the
miscarriage
rate
was
14
increased
in
parents
where
the
father
was
exposed
to
carbaryl.
There
was
no
association
between
the
use
of
carbaryl
and
preterm
delivery,
small
for
gestational
age
or
altered
sex
ratio
measurements.
The
studies
and
articles
are
summarized
below.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
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
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,
15
weight
gain,
and
feed
consumption.
The
no­
observed­
adverse­
effect
(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.

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
two­
generation
reproductive
study
(OPPTS
870.3800;
OECD
416)
in
the
rat.

Literature
Articles
In
a
1996
study
in
the
open
literature,
carbaryl
was
administered
to
four
groups
of
6
young
and
6
adult
1
Pant
N,
Shankar
R,
Srivastava
SP
(1996).
Spermatotoxic
effects
of
carbaryl
in
rats.
Human
Exp
Toxicol
15(
9);
736­
38.

2
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.

16
Druckery
albino
rats
per
group
at
doses
of
0,
25,
50
or
100
mg/
kg/
day
for
60
days.
1
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
administered
carbaryl
by
gavage
at
doses
of
0,
50
or
100
mg/
kg/
day
for
90
days.
2
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
3
Narotsky
MG,
Kavlock
RJ
(1995).
A
Multidisciplinary
Approach
to
Toxicological
Screening:
II.
Developmental
Toxicity.
Journal
of
Toxicology
and
Environmental
Health
45:
145­
171.

4
Savitz
DA,
Arbuckle
T,
Kaczor
D,
Curtis
KM
(1997).
Male
Pesticide
Exposure
and
Pregnancy
Outcome.
Am
J
Epidemiol
146(
12):
1025­
36.

17
control
animals
were
used.
3
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
covariate.

In
a
recent
epidemiology
study,
the
effects
of
exposure
of
male
farmers
in
Ontario,
Canada,
to
agricultural
pesticides
and
pregnancy
outcome
was
investigated.
4
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.

4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
In
the
chronic
toxicity
study
in
dogs,
at
the
lowest
dose
tested,
plasma
ChEI
in
females
and
brain
ChEI
in
males
were
observed.
In
a
5­
week
study
to
establish
the
ChEI
NOAEL,
plasma
ChEI
was
the
basis
for
setting
the
NOAEL/
LOAEL.

870.4100b
Chronic
Toxicity
­
Dog
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
18
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
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),
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.
19
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
treatment­
related
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;
the
NOAEL
was
$
125
ppm.

Together,
these
studies
are
acceptable
and
satisfy
the
guideline
requirements
for
a
chronic
toxicity
study
in
a
nonrodent
species
(83­
1).

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
In
both
the
rat
combined
chronic
toxicity/
carcinogenicity
study
and
the
mouse
carcinogenicity
study,
there
was
an
increase
incidence
of
tumors,
including
kidney,
liver
and
vascular
tumors,
in
the
treated
groups.
However,
the
highest
dose
in
both
studies
was
considered
excessive
based
on
evidence
of
severe
toxicity.
In
addition
to
the
required
carcinogenicity
studies
in
mice
and
rats,
the
registrant
submitted
a
special
study
in
genetically
modified
mice.
Carbaryl
was
administered
in
the
diet
to
heterozygous
p53­
deficient
(knockout)
male
mice
at
concentrations
of
up
to
4000
ppm
(716.6
mg/
kg/
day)
for
six
months.
There
was
no
evidence
of
neoplastic
or
preneoplastic
changes
in
the
vascular
tissues
of
any
organ.
A
model
validation
study
demonstrated
that
vascular
tumors
occur
in
heterozygous
p53
deficient
mice
within
six
months
of
administration
of
a
known
genotoxic
carcinogen
(urethane).
The
CARC
(11/
7/
01)
considered
all
the
available
toxicity
data
and
concluded
that
the
malignant
vascular
tumors
(hemangiosarcomas)
in
male
mice
occurred
at
doses
which
were
adequate
and
not
excessive.
In
females
these
tumors
occurred
only
at
the
highest
dose
which
was
excessively
toxic.
Nevertheless,
the
findings
in
female
mice
were
supportive
of
vascular
tumors
in
male
mice.
The
CARC
classified
carbaryl
as
"Likely
to
be
carcinogenic
in
humans"
based
on
an
increased
incidence
of
hemangiosarcomas
in
male
mice
at
all
doses
tested
(100,
1000
and
8000
ppm).
The
Q1*,
based
on
the
CD­
1
mouse
dietary
study
with
¾
Interspecies
Scaling
Factor,
is
8.75
x
10
­4
(mg/
kg/
day)
­1
in
human
equivalents.

870.4200b
Carcinogenicity
(feeding)
­
Mouse
In
a
carcinogenicity
study
(MRID
No.
42786901),
80
CD­
1®
mice/
sex/
group
were
administered
technical
Carbaryl
(99.3%
a.
i.)
in
the
diet
at
dosages
of
either
0,
100,
1000
or
8000
ppm
for
104
weeks
(males:
0,
14.73,
145.99
and
1248.93
mg/
kg/
day;
females:
0,
18.11,
180.86
and
1440.62
mg/
kg/
day,
20
respectively.)
Four
males
in
the
8000
ppm
group
died
during
the
first
week
of
treatment;
the
cause
of
death
was
not
determined.
Survival
rates
were
not
affected
by
treatment.

Animals
in
the
8000
ppm
group,
especially
the
females,
developed
clinical
signs
of
toxicity,
including
hunched
posture,
thin
and
languid
appearance,
squinted
and
opaque
eyes,
urine
stains,
redness
to
various
body
areas,
rough
hair
coat,
soft
feces
and
low
body
temperature.
Mean
body
weights
were
statistically
significantly
decreased
for
the
8000
ppm
males
and
females
for
the
majority
of
the
study
(males
9­
13%;
females
5­
14%).
Mean
body
weight
gain
for
the
8000
ppm
males
and
females
was
decreased
throughout
the
study
(males
23­
38%;
females
10­
32%).
Mean
food
consumption
was
statistically
significantly
decreased
in
the
8000
ppm
females
(7­
10%).
Hematology
parameters,
including
RBC,
hemoglobin
and
hematocrit,
were
statistically
significantly
decreased
in
the
8000
ppm
females
at
week
53
and
8000
ppm
group
males
at
week
105.
Total
leukocyte
count
and
counts
of
lymphocytes
and
eosinophils
were
significantly
increased
in
the
8000
ppm
group
females
at
week
53.
Platelet
counts
were
significantly
increased
in
this
group
at
week
105.

RBC
cholinesterase
(ChE)
was
statistically
significantly
decreased
in
the
1000
ppm
(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
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.

There
were
no
treatment­
related
macroscopic
effects
at
the
week
53
sacrifice,
however
at
the
week
105
sacrifice
the
incidence
of
opaque
eyes
was
increased
in
the
8000
ppm
group
(males:
1/
37
controls
vs.
4/
30;
females:
2/
34
controls
vs.
16/
32).
The
most
consistent
organ
weight
changes
at
both
necropsies
were
increased
relative
liver
and
kidney
weights.
On
microscopic
examination,
there
was
an
increased
incidence
of
chronic
progressive
nephropathy
in
the
1000
ppm
males
and
8000
ppm
males
and
females
at
the
interim
sacrifice.
The
severity
of
extramedullary
hematopoiesis
and
pigment
in
the
spleen
in
the
8000
ppm
males
and
females
was
increased
at
the
interim
sacrifice.
There
was
a
dose­
related
increased
incidence
of
intracytoplasmic
protein­
like
droplets
in
the
urinary
bladder
in
the
1000
and
8000
ppm
group
males
and
females
at
the
terminal
and
unscheduled
sacrifices.
The
incidence
of
animals
with
cataracts
was
increased,
but
not
dose­
related,
in
the
8000
ppm
group
males
and
females.

The
study
demonstrated
that
Carbaryl
is
carcinogenic
in
mice
at
doses
of
100
ppm
(14.73
mg/
kg/
day)
and
higher
in
males
and
8000
ppm
(1440.62
mg/
kg/
day)
in
females.
There
was
an
increased
incidence
of
vascular
neoplasms
(hemangiomas
and
hemangiosarcomas)
in
all
treated
males
and
in
the
8000
ppm
group
females
at
the
terminal
and
unscheduled
necropsies
but
not
at
week
53.
Considering
all
animals,
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.
The
HED
CPRC
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,
21
clinical
signs
of
toxicity
and
histopathological
changes
in
the
bladder,
kidneys
and
spleen
in
both
sexes.

The
systemic
LOAEL
was
1000
ppm
(M:
145.99
mg/
kg/
day;
F:
180.86
mg/
kg/
day)
based
on
an
increased
incidence
of
intracytoplasmic
droplets
in
the
superficial
epithelial
cells
of
the
urinary
bladder
in
males
and
females
and
chronic
progressive
nephropathy
in
males.
The
systemic
NOAEL
was
100
ppm
(M:
14.73
mg/
kg/
day;
F:
18.11
mg/
kg/
day).

The
RBC
cholinesterase
inhibition
LOAEL
in
males
was
1000
ppm
(23%
9
at
week
53);
the
NOAEL
was
100
ppm.
The
RBC
cholinesterase
inhibition
LOAEL
in
females
was
8000
ppm
(24%
9
at
week
105);
the
NOAEL
was
1000
ppm.

The
plasma
cholinesterase
inhibition
LOAEL
was
>8000
ppm
(M:
1248.93
mg/
kg/
day;
F:
1440.62
mg/
kg/
day);
the
NOAEL
was
$
8000
ppm.

The
brain
cholinesterase
inhibition
LOAEL
for
males
and
females
was
8000
ppm
(M:
40­
57%
9
;
F:
34­
47%
9
);
the
NOAEL
was
1000
ppm.

This
study
is
classified
as
Acceptable
and
satisfies
the
guidelines
for
a
carcinogenicity
study
in
mice
(§
83­
2).

870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
rat
In
a
combined
carcinogenicity/
chronic
toxicity
study
(MRID
No.
42918801),
70
Sprague­
Dawley
Crl:
CD®
BR
rats/
sex/
group
were
administered
technical
Carbaryl
(99%
a.
i.)
in
the
diet
at
dosages
of
either
0,
250,
1500
or
7500
ppm
for
104
weeks
(males:
0,
10.0,
60.2
and
349.5
mg/
kg/
day;
females:
0,
12.6,
78.6
and
484.6
mg/
kg/
day).
An
additional
10
animals/
sex/
dose
were
administered
the
same
doses
and
were
sacrificed
after
53
weeks.
Another
10
animals/
sex
from
the
control
and
high
dose
group
animals
were
sacrificed
at
week
57
after
switching
the
diet
of
the
high
dose
animals
to
control
feed
for
weeks
53­
57
of
the
study.

There
was
no
treatment­
related
effect
on
survival.
There
was
an
increased
incidence
of
clinical
signs
of
toxicity,
including
hunched
posture,
thin
appearance,
chromodacryorrhea
and
urine
stains
in
the
7500
ppm
group
males.
There
was
an
increased
incidence
of
alopecia
and
urine
strains
in
the
7500
ppm
group
females.

Statistically
significant
decreases
in
mean
body
weight
were
observed
in
the
7500
ppm
males
(24­
35%)
and
females
(24­
45%)
and
the
1500
ppm
females
(4­
12%).
Mean
body
weight
gain
over
the
course
of
the
study
was
decreased
in
the
7500
ppm
males
(53%)
and
females
(69%).
There
was
a
18%
decrease
in
body
weight
gain
in
the
1500
ppm
females
for
the
week
0­
104
period
only.
Food
consumption
in
the
7500
ppm
group
males
and
females
was
decreased
(4­
16%
in
males;
11­
21%
in
females)
during
the
study.
In
the
recovery
group,
rebound
in
food
consumption
and
body
weight
gain
was
seen,
but
mean
body
weight
was
still
decreased
23%
for
both
the
7500
ppm
males
and
females
at
week
57.

There
was
an
increased
incidence
of
unilateral
and
bilateral
cataracts
in
the
7500
ppm
males
and
females.
A
consistent
decrease
in
WBC
and
lymphocyte
count
in
the
7500
ppm
males
and
females
was
seen.
22
Alterations
in
clinical
chemistry
in
the
7500
ppm
males
and
females
included
significant
increases
in
cholesterol
and
BUN
and
significant
decreases
in
AST,
ALT
and
CPK.
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
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.

There
was
a
slightly
increased
incidence
of
erythrocytes
in
the
urine
of
the
7500
ppm
males
and
occult
blood
in
the
7500
ppm
males
and
females.
An
increased
incidence
of
dark
urine
in
the
1500
ppm
females
and
in
the
7500
ppm
males
and
females
was
also
found.

There
were
no
treatment­
related
macroscopic
findings
at
the
week
53
and
57
necropsies.
At
the
week
105
necropsy,
the
macroscopic
findings
at
an
increased
incidence
in
the
7500
ppm
males
and
females,
which
were
also
associated
with
microscopic
changes,
included
pale
areas
in
the
lungs
and
liver
and
urinary
bladder
masses.
A
decreased
absolute
weight
and
an
increased
relative
weight
of
the
kidneys,
lungs,
spleen
and
liver
were
found
in
the
7500
ppm
males
and
females.
At
the
week
53
necropsy,
there
were
slight
increases
in
the
incidence
of
microscopic
changes
in
the
kidney
and
liver
of
the
7500
ppm
males
and
females.
At
the
week
105
necropsy,
there
was
a
wide
variety
of
changes
in
multiple
organs
of
males
and
females
in
the
7500
ppm
group.
In
the
liver,
there
was
an
increased
incidence
in
the
following:
hepatocytic
hypertrophy
in
males
and
females;
and
eosinophilic
foci
and
pigment
in
females.
In
the
urinary
bladder,
there
was
an
increased
incidence
of
transitional
cell
hyperplasia,
squamous
metaplasia,
high
mitotic
index
and
atypia
in
males
and
females.
In
the
lung,
there
was
an
increased
incidence
of
focal
pneumonitis
and
foamy
macrophages
in
males
and
females.
In
the
kidney,
there
was
an
increased
incidence
of
transitional
cell
hyperplasia
in
males.
In
the
thyroid,
there
was
an
increased
incidence
of
follicular
cell
hypertrophy
in
males
and
females.
Degeneration
of
the
sciatic
nerve
and
skeletal
muscle
was
observed
at
an
increased
incidence
in
males
and
females.

The
study
demonstrated
that
Carbaryl
is
carcinogenic
in
male
and
female
rats
at
7500
ppm.
There
was
an
increased
incidence
of
liver
adenomas
in
females.
In
the
bladder,
there
was
an
increased
incidence
of
benign
transitional
cell
papilloma
and
transitional
cell
carcinomas
in
males
and
females.
One
transitional
cell
carcinoma
was
also
observed
in
the
kidney
of
a
male
rat.
In
the
thyroid,
the
incidence
of
benign
follicular
cell
adenomas
was
increased
in
males;
one
follicular
cell
carcinoma
was
also
seen
in
a
male.

The
HED
CPRC
evaluated
the
toxicity
data
on
Carbaryl
and
considered
7500
ppm
to
be
an
excessive
dose
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
systemic
LOAEL
was
1500
ppm
(78.6
mg/
kg/
day)
in
females
based
on
decreased
body
weight
and
body
weight
gain;
the
NOAEL
was
250
ppm
(12.6
mg/
kg/
day).
The
systemic
LOAEL
was
7500
ppm
(349.5
mg/
kg/
day)
in
males
based
on
an
increased
incidence
of
clinical
signs
of
toxicity,
decreases
in
23
body
weight,
body
weight
gain
and
food
consumption,
an
increased
incidence
of
cataracts,
alterations
in
clinical
pathology
parameters,
organ
weight
changes,
and
an
increased
incidence
of
nonneoplastic
microscopic
changes.
The
systemic
NOAEL
was
1500
ppm
(60.2
mg/
kg/
day)
in
males.

The
LOAEL
for
plasma
cholinesterase
inhibition
was
7500
ppm
in
males
(27­
47%
decrease)
and
females
(46­
57%
decrease);
the
NOAEL
was
1500
ppm.

The
LOAEL
for
RBC
cholinesterase
inhibition
was
1500
ppm
in
males
(10­
23%
decrease)
and
females
(12­
26%
decrease);
the
NOAEL
was
250
ppm.

The
LOAEL
for
brain
cholinesterase
inhibition
was
7500
ppm
in
males
(8­
28%
decrease)
and
females
(22­
31%
decrease);
the
NOAEL
was
1500
ppm.

This
study
is
classified
as
Acceptable
and
satisfies
the
guidelines
for
a
combined
carcinogenicity/
chronic
toxicity
feeding
study
in
rats
(83­
5).

Carcinogenicity
and
Other
Studies
in
p53
Knockout
Mice
In
a
special,
non­
guideline
study
(MRID
45281801,
45281802,
45236603),
heterozygous
p53­
deficient
(knockout)
male
mice
(20/
group)
were
administered
carbaryl
in
the
diet
at
concentrations
of
0,
10,
30,
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.
24
4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
mutagenicity
is
considered
complete
and
no
additional
studies
are
required
at
this
time.
A
recent
review
of
the
data
from
the
submitted
studies
and
the
published
literature
were
in
general
agreement
and
showed
that
carbaryl
was
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
were
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
(see
Section
4.6)
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.
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.

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
25
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.

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
41370304).
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
26
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.

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.
27
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
(1984)
but
weakly
positive
minus
S9
metabolic
activation
as
reported
by
Ahmed
et
al.
(1977)].
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
1983,
1984).
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
were
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.,
2001).
Also,
carbaryl
caused
depolymerization
of
spindle
microtubules
and
an
apparent
uncoupling
of
karyokinesis
and
cytokinesis
in
cultured
V79
cells
(Renglin
et
al,
1988,
1989).

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.,
1980).
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,
1986).

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
Available
neurotoxicity
studies
are
adequate
to
satisfy
the
guideline
requirements.
There
was
no
evidence
of
delayed
neurotoxicity
in
hens.
In
the
acute
neurotoxicity
study
in
rats,
the
LOAEL
was
based
on
plasma,
RBC
and
brain
ChEI;
a
NOAEL
could
not
be
established.
In
the
subchronic
neurotoxicity
study
in
rats,
clinical
signs
of
toxicity
were
seen
at
the
same
dose
as
plasma,
whole
blood,
RBC
and
brain
ChEI.
There
was
no
evidence
of
structural
neuropathology
in
these
studies.
In
the
developmental
neurotoxicity
study
in
rats,
clinical
signs
of
toxicity
and
plasma
and
brain
ChEI
were
seen
in
maternal
animals
at
the
same
dose
as
changes
in
brain
morphometric
measurements
in
offspring.
The
HED
Hazard
Identification
Assessment
Committee
(HIARC)
determined
that
this
was
evidence
of
qualitative
susceptibility.
5
Carpenter,
C.
P.,
Weil,
C.
S.,
Palm,
P.
E.
et
al.
Mammalian
Toxicity
of
1­
napthyl­
N­
methyl
carbamate
(Sevin
Insecticide).
J.
Agri.
Food
Chem.
9(
1):
30­
39,
1961.

28
870.6100
Delayed
Neurotoxicity
Study
­
Hen
In
a
study
by
Carpenter
et
al
5
,
Carbaryl
was
negative
for
delayed
neuropathy
at
a
dose
of
2000
mg/
kg,
the
approximate
LD50
in
hens.

870.6200
Acute
Neurotoxicity
Screening
Battery
In
an
acute
neurotoxicity
study
(MRID
#
43845201­
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,
30
and
90
mg/
kg
doses.
Peak
inhibition
of
cholinesterase
occurred
during
the
time
of
FOB
and
motor
activity
measurements.
Based
on
the
data
in
this
study,
the
systemic
LEL
=
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.
Although
significant
signs
of
cholinergic
toxicity
were
observed
in
this
study,
there
was
no
definitive
evidence
of
a
neurotoxic
effect
for
Carbaryl
technical
grade
in
this
study.
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
an
acute
neurotoxicity
study
(§
81­
8)
in
rats.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
In
a
subchronic
neurotoxicity
study
(MRID
44122601),
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
29
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
cholinesterase
values
(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
cholinesterase
values
(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
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
in
the
1
mg/
kg/
day
group
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.
30
The
subchronic
neurotoxicity
study
in
the
rat
is
classified
acceptable/
guideline
and
does
satisfy
the
guideline
requirement
for
a
subchronic
neurotoxicity
study
(OPPTS
870.6200)
in
the
rat.

870.6300
Developmental
Neurotoxicity
Study
In
a
developmental
neurotoxicity
study
(MRID
#
44393701,
44904204,
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
were
no
treatment­
related
effects
on
gross
necropsy
findings
for
the
F0
generation
animals.
31
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
postimplantation
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
treatment­
related
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
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.
32
4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
Available
metabolism
data
are
adequate
to
satisfy
the
guideline
requirements
and
have
delineated
the
metabolic
pathway
in
the
rat.
Carbaryl
was
broken
down
into
over
20
metabolites.
The
major
route
of
elimination
was
via
the
urine.
No
significant
tissue
accumulation
was
reported.
Additional
special
studies
have
been
conducted
to
determine
if
there
are
alterations
in
metabolism
at
high
doses.

870.7485
Metabolism
­
Rat
In
a
rat
metabolism
study
(MRID
#
43332101),
14
C­
Carbaryl
was
administered
orally
in
carboxymethylcellulose
or
intravenously
in
sodium
phosphate
buffer
(pH
6.8)
to
groups
(5
sex/
dose)
of
male
and
female
Sprague­
Dawley
rats
at
nominal
doses
of
1
mg/
kg
(single
and
repeated
low
oral
doses;
intravenous
dose)
and
50
mg/
kg
(single
high
oral
dose).
Absorption
was
essentially
complete
for
all
dose
groups
of
male
and
female
rats.
At
168
hours
post­
dose,
there
were
negligible
percentages
of
the
dose
found
in
any
tissue
examined.
On
a
µg/
g
tissue
basis,
kidney
and
blood
were
found
to
contain
the
highest
concentrations
of
residual
radioactivity,
with
female
rats
showing
slightly
higher
values
than
males.
Excretion
of
carbaryl
derived
radioactivity
was
largely
through
urine,
where
88­
95%
of
the
dose
was
recovered
for
all
dose
groups.
There
were
no
significant
dose­
or
sex­
related
differences
in
excretion.

Conjugated
metabolites
of
carbaryl
identified
in
this
study
included
the
glucuronic
acid
conjugate
of
dihydro­
dihydroxy
carbaryl
(2.2%
of
the
dose),
the
S(
N­
acetylcysteine)
conjugate
of
dihydro­
hydroxy
carbaryl
(3.7%
of
the
dose),
naphthyl
glucuronide
(2.0%
of
the
dose),
and
naphthyl
sulfate
(6.4%
of
the
dose).
Non­
conjugated
metabolites
identified
were
1­
naphthol,
5­
hydroxycarbaryl,
5,6­
dihydro­
5,6­
dihydroxycarbaryl,
4­
hydroxycarbaryl,
and
N­(
hydroxymethyl)­
hydroxycarbaryl.
These
accounted
for
14.5%,
12.8%,
8.2%,
6.3%,
and
5.7%
of
the
administered
dose,
respectively.
Three
new
metabolites
were
identified
in
this
study
which
were
the
N­(
hydroxymethyl)­
hydroxycarbaryl
metabolite,
hydroxy­
desmethylcarbaryl
(0.5%
of
the
dose),
and
the
S­(
N­
acetylcysteinyl)­
dihydro­
dihydroxycarbaryl
conjugate.
Based
on
these
data,
a
metabolic
scheme
for
carbaryl
was
proposed.
This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
data
requirements
for
a
metabolism
study
in
rats
under
Subdivision
F
guideline
§85­
1.

Metabolism
­
Special
Study
In
a
rat
metabolism
study
(MRID
No.
44402501),
1­
naphthyl­
14
C­
labeled
carbaryl
(ca
100%
a.
i.)
was
administered
to
15
month
old
male
Iffa
Credo
CD
(Sprague­
Dawley
derived)
rats
(5
animals/
group)
as
a
single
oral
gavage
dose
of
50
mg/
kg
(group
A)
or
as
a
daily
oral
dose
of
2
mg/
kg
for
7
days
following
a
83­
day
dietary
administration
with
non­
radioactive
carbaryl
(25
animals/
group)
at
0
(group
B),
250
(group
C),
1500
(group
E),
or
7500
ppm
(group
D).
This
study
was
designed
to
"investigate
the
mechanisms
that
caused
the
appearance
of
an
increased
incidence
of
tumors
during
the
final
year
of
a
chronic
dietary
feeding
study
in
the
rat
at
the
high
dose
level
of
7500
ppm."

In
all
dietary
dosing
regimens,
urinary
and
fecal
excretion
totaled
96­
103%
of
the
administered
dose.
Most
of
the
radioactivity
was
eliminated
in
the
urine
and
feces
within
24
hours
after
dosing.
In
the
33
group
A,
86%
and
11%
of
the
test
compound
administered
was
excreted
in
the
urine
and
feces,
respectively,
over
a
7­
day
period
after
a
single
dose
via
gavage
of
radiolabeled
carbaryl
at
50
mg/
kg.
In
the
groups
B­
E
(0,
250,
1500,
and
7500
ppm),
3
days
after
the
7th
consecutive
administration
of
radiolabeled
carbaryl,
79­
89%
and
7­
10%
of
the
total
administered
dose
(sum
of
the
7
daily
doses)
were
excreted
in
the
urine
and
feces,
respectively.
Tissue
distribution
study
showed
that
the
levels
of
radioactivity
in
the
tissues
of
the
animals
from
group
A
were
0.4%
of
the
administered
dose
at
sacrifice
(168
hours
after
dosing).
In
groups
B­
E,
the
levels
of
radioactivity
in
the
tissues
ranged
from
0.4­
0.8%
of
the
administered
dose
3
days
after
the
7th
dose
of
radiolabeled
carbaryl
at
2
mg/
kg.
This
indicates
that
the
potential
for
bioaccumulation
of
carbaryl
in
rats
is
minimal.

HPLC
analysis
of
carbaryl
metabolites
in
24­
hour
urine
samples
showed
a
total
of
23
components.
Four
components
identified
by
LC/
MS
technique
were
as
follows:
UMET/
8
(trans­
5,6­
dihydro­
5,6­
dihydroxy­
1­
naphthyl
N­
methylcarbamate)
(accounted
for
3.75­
6.38%
of
the
dose);
UMET/
11
(glucuronide
of
dihydro­
dihydroxy­
1­
naphthyl
N­
methylcarbamate)
(18.55%­
28.46%
of
the
dose);
UMET/
18
(
­naphthyl
$
­D­
glucuronide
sodium
salt
or
"
­naphthyl
sulfate
potassium
salt
(15.69­
21.75
%
of
the
dose);
and
UMET/
23
(naphthyl
sulfate)
(17.78%­
30.01%
of
the
dose).

A
total
of
20
components
was
detected
in
the
24­
hour
feces
by
HPLC
analysis.
One
component
(FMET/
15)
was
identified
as
parent
and
accounted
for
0.2­
1.4%
of
the
administered
dose
by
LC/
MS
technique.
The
remaining
19
components
were
not
identified
because
the
levels
of
radioactivity
in
these
components
were
too
low.

There
were
2
major
metabolites
in
the
tissues
from
groups
B­
E
at
6
hours
after
administration
of
14
Ccarbaryl
These
metabolites
were
confirmed
by
LC/
MS
analysis
as
naphthyl
sulfate
(found
in
plasma,
kidney,
and
urinary
bladder)
and
naphthyl
glucuronide
(found
in
the
kidney
and
urinary
bladder).
Quantitative
identification
for
these
metabolites
was
not
available
because
the
levels
of
radioactivity
in
these
tissues
were
too
low.

The
sulfate
conjugation
pathway
appears
to
be
saturable
following
a
subchronic
(83­
day)
feeding
of
carbaryl
at
a
high
dose
(group
D,
7500
ppm).
This
saturation
of
the
sulfate
conjugation
pathway
is
seen
in
the
urinary
levels
of
UMET/
23
(naphthyl
sulfate)
between
the
dose
groups
following
the
83­
day
dietary
administration
of
non­
radioactive
carbaryl.
The
level
of
radioactivity
associated
with
UMET/
23
(naphthyl
sulfate)
was
higher
(23­
27%
of
the
dose)
in
0,
250,
and
1500
ppm
dose
groups
and
lower
(12%
of
the
dose)
in
the
7500
ppm
group.
On
the
other
hand,
the
level
of
radioactivity
associated
with
UMET/
11
(naphthyl
glucuronide)
was
lower
(15­
21%
of
the
administered
dose)
in
0,
250,
and
1500
ppm
dose
groups
and
higher
(28%)
in
the
group
7500
ppm
group.

Statistically
significant
decreases
(p<
0.05
or
p<
0.01)
in
body
weight
(9­
20%)
when
compared
to
the
control
group
were
observed
only
in
the
7500
ppm
group
as
early
as
study
day
14
and
sustained
throughout
the
remainder
of
the
study.
In
the
7500
ppm
group,
the
statistically
significant
decreases
(p<
0.05
or
p<
0.01)
in
food
consumption
were
observed
at
week
1
(74%),
week
2
(61%),
week
3
(40%),
and
weeks
4­
11
(19­
31%).
In
the
1500
ppm
group,
the
statistically
significant
decreases
(p<
0.05)
in
food
consumption
were
observed
at
week
5
(8%),
week
10
(21%),
and
week
11
(12%).
34
Significant
increases
(statistical
analyses
were
not
performed)
in
kidney,
spleen,
and
thyroid
weights
were
observed
in
the
1500
or
7500
ppm
groups
when
compared
to
the
control
group.
Absolute
and
relative
liver
weights
increased
18%
and
39%,
respectively,
at
7500
ppm.
Absolute
spleen
weight
increased
30%
at
7500
ppm
and
relative
spleen
weight
increased
24%
and
30%
at
7500
and
1500
ppm,
respectively.
Absolute
thyroid
weight
increased
63%
and
69%
at
7500
and
1500
ppm,
respectively,
and
relative
thyroid
weight
increased
103%
and
121%
at
7500
and
1500
ppm,
respectively.
Statistically
significant
increases
(p<
0.01)
in
total
glutathione
concentrations
(higher
by
79%
per
g
of
liver
or
102%
per
g
of
protein)
were
observed
at
7500
ppm
only,
compared
to
the
controls.

The
incidences
of
hepatocellular
adenoma
(benign)
were
1/
5,
0/
5,
0/
5,
and
2/
5
at
0,
250,
1500,
and
7500
ppm,
respectively.
Although
the
authors
concluded
that
"there
was
no
treatment­
related
change
in
the
incidence
of
tumors
under
carbaryl
treatment,"
definite
conclusion
cannot
be
made
from
this
finding
based
on
the
limited
number
of
animals
used.

Significant
treatment­
related
changes
were
noted
in
liver,
thyroid
glands,
and
kidneys
at
7500
ppm
only.
The
incidences
of
centrilobular
hypertrophy
of
the
hepatocytes,
pericholangitis
(an
inflammatory
cell
infiltrate
around
biliary
ducts),
and
bile
duct
hyperplasia
were
5/
5,
3/
5,
and
3/
5,
respectively.
The
incidences
of
follicular
cell
hypertrophy
of
the
thyroid
glands
were
0/
5,
3/
5,
5/
5,
and
5/
5
and
the
incidences
of
transitional
cell
hyperplasia
of
the
renal
pelvis
were
0/
5,
0/
5,
1/
5
and
2/
5
at
0,
250,
1500,
and
7500
ppm,
respectively.

This
metabolism
study
in
the
rat
is
classified
acceptable
for
its
intended
purpose
of
investigating
"the
mechanisms
that
caused
the
appearance
of
an
increased
incidence
of
tumors
during
the
final
year
of
a
chronic
dietary
feeding
study
in
the
rat
at
the
high
dose
level
of
7500
ppm."
Although
the
study
supplies
some
information
to
the
Agency,
this
study
does
not
satisfy
the
guideline
requirement
for
a
metabolism
study
(85­
1)
in
rats.

Metabolism
­
Special
Study
The
present
investigation
(MRID
#
43832601)
was
conducted
to
identify
and
phenotype
the
potential
for
Carbaryl
to
induce
hepatic
cytochrome
P­
450
in
male
CD­
1
mice
following
dietary
administration
of
8000
ppm
Carbaryl
in
the
diet.
The
data
in
this
study
represent
results
from
mice
used
in
a
previous
study
(MRID
#
432822­
01)
whose
livers
had
been
stored
for
biochemical
analyses.
These
mice
had
received
pre­
treatment
with
8000
ppm
(1143
mg/
kg/
day)
Carbaryl
for
14
days.
The
results
of
biochemical
analyses
in
the
liver
can
be
summarized
as
follows:
Carbaryl
pre­
treatment
produced
significant
increases
in
microsomal
protein
(132%
of
control),
cytochrome
P­
450
(134%
of
control),
ethoxyresorufin
O­
deethylase
activity
(190%
of
control),
pentoxyresorufin
O­
depentylase
activity
(313%
of
control),
and
increases
in
specific
testosterone
hydroxylase
activities
(6­
alpha,
2ß­,
11ß,­
and
16ß­
hydroxylase
activities).
Taken
together,
these
data
appear
to
indicate
a
`phenobarbital­
type'
of
induction
of
liver
xenobiotic­
metabolizing
enzymes
as
a
result
of
Carbaryl
pre­
treatment
at
a
high
oral
dose
(1154
mg/
kg/
day).
The
similarity
of
the
pattern
of
induction
of
liver
xenobiotic­
metabolizing
enzymes
by
Carbaryl
and
phenobarbital
is
supported
in
part
by
literature
data
(Kelley
et
al.,
Biochem.
Pharmacol.
15;(
39)
12:
1991­
1998).
While
this
study
provides
useful
information
on
the
general
type
of
induction
observed
after
pretreatment
with
a
high
oral
dose
of
Carbaryl,
the
actual
relationship
of
induction
to
35
Carbaryl
toxicity
was
not
addressed,
as
no
metabolites
of
Carbaryl
after
this
type
of
exposure
were
investigated.
This
study
is
classified
as
acceptable
(non­
guideline)
and
demonstrates
the
inductive
effect
of
repeated
high
dose
exposure
to
Carbaryl
by
the
oral
route.

Metabolism
­
Special
Study
In
a
special
study
(MRID
#
43282201),
[1­
14
C]­
naphthyl­
N­
methylcarbamate
(14­
C
carbaryl)
was
tested
for
the
ability
to
bind
to
liver
DNA
in
male
CD1
mice
treated
with
a
single
radiolabelled
dose
of
carbaryl
(75
mg/
kg)
or
in
mice
pretreated
with
8000
ppm
(approximately
1143
mg/
kg/
day)
unlabelled
carbaryl
in
the
diet
for
two
weeks
followed
by
a
single
75
mg/
kg
radiolabelled
dose.
Binding
of
radiolabel
to
chromatin
protein
isolated
from
the
livers
of
mice
treated
with
a
single
dose
or
in
pretreated
mice
was
similar
(specific
activities
ranging
from
340.3­
537.0
dpm/
mg).
No
radioactivity
was
detectable
in
DNA
samples
isolated
from
mice
treated
with
radiolabelled
carbaryl
(Covalent
Binding
Index
<
0.1).
According
to
the
report,
this
maximum
binding
ability
of
carbaryl
is
more
than
5
orders
of
magnitude
below
the
Covalent
Binding
Index
of
aflatoxin
B1,
and
more
than
4000
times
lower
than
the
Covalent
Binding
Index
for
2­
acetylaminofluorene.
This
study
demonstrated
the
interaction
of
carbaryl
with
chromatin
protein,
but
no
significant
interaction
with
DNA
in
the
liver
of
male
CD1
mice
treated
with
either
a
single
75
mg/
kg
dose
or
in
mice
pretreated
with
8000
ppm
(1143
mg/
kg/
day)
carbaryl
in
the
diet
followed
by
a
single
75
mg/
kg
radiolabelled
dose.
This
study
was
not
conducted
to
satisfy
a
specific
guideline
requirement,
but
fulfills
the
purpose
for
which
it
was
conducted.

870.7600
Dermal
Absorption
­
Rat
Two
dermal
absorption
studies
in
rats
were
conducted.
In
the
study
with
a
formulation
containing
43.9%
carbaryl
(MRID
43552901),
animals
were
exposed
for
0.5,
1,
2,
4,
10
or
24
hours
at
doses
of
35.6,
403
or
3450
µg/
cm
2
.
Percent
absorbed
ranged
from
2.14
to
24.9,
1.01
to
24.7
and
0.07
to
3.17
for
the
35.6,
403
or
3450
µg/
cm
2
doses,
respectively
(see
Section
5.2
below).
The
HIARC
determined
that
a
12.7%
absorption
(relative
to
an
oral
dose)
should
be
used
for
risk
assessment.
This
rate
was
based
on
the
highest
absorption
rate
at
10
hours,
which
is
considered
the
duration
of
possible
occupational
exposure
during
a
work
day.
36
5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table
(page
51).

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
12.7
%
from
MRID
43552901
(findings
discussed
above)

The
dermal
absorption
factor
is
required
for
long­
term
dermal
and
inhalation
risk
assessments
since
oral
doses
were
selected
for
these
exposure
periods.

In
a
dermal
absorption
study
(MRID
#
43552901),
radiolabeled
14
C­
Carbaryl
LXR
Plus
(43.9%
a.
i.)
was
applied
to
the
skin
of
three
groups
of
four
male
rats/
group
at
doses
of
35.6,
403
or
3450
µg/
cm
2
for
0.5,
1,
2,
4,
10
or
24
hours.
The
ranges
for
percent
of
carbaryl
absorbed
for
the
35.6,
403
and
3450
µg/
cm
2
groups
were
2.14­
24.9,
1.01­
24.7
and
0.07­
3.17,
respectively;
the
percent
absorbed
at
10
hours
was
12.7,
7.44
and
1.93,
respectively.

This
study
is
classified
as
Acceptable
(guideline)
and
satisfies
the
guidelines
for
a
dermal
absorption
study.

In
a
dermal
absorption
study
(MRID
#
43339701),
radiolabeled
14
C­
Carbaryl
Sevin
(80.1%
a.
i.)
was
applied
to
the
skin
of
three
groups
of
four
male
rats/
group
at
doses
of
63,
626
or
3410
µg/
cm
2
for
0.5,
1,
2,
4,
10
or
24
hours.
The
ranges
for
percent
of
carbaryl
absorbed
for
the
63,
626
and
3410
µg/
cm
2
doses
were
0.66­
16.6,
<0.01­
1.27
and
0.07­
1.2,
respectively;
the
percent
absorbed
at
10
hours
was
8.90,
0.62
and
0.48,
respectively.

This
study
is
classified
as
Acceptable
(guideline)
and
satisfies
the
guidelines
for
a
dermal
absorption
study.

5.3
Classification
of
Carcinogenic
Potential
5.3.1
The
CARC
concluded
that
carbaryl
was
carcinogenic
to
male
mice
at
doses
which
were
adequate
and
not
excessive.
Tumors
in
male
and
female
rats
and
female
mice,
as
well
as
other
tumors
in
male
mice,
occurred
at
excessively
toxic
high
dose
levels.
However,
preneoplastic
lesions
in
the
target
organs
in
male
rats
occurred
at
the
mid
dose
level
which
was
below
the
dose
adequate
for
testing
the
carcinogenic
potential
of
carbaryl.
The
findings
of
the
rat
combined
chronic
toxicity/
carcinogenicity
study
are
discussed
below.

1.
The
reanalyses
of
rat
tumor
data
showed
that
male
rats
had
significant
increasing
trends
and
significant
differences
in
pair­
wise
comparisons
of
the
7500
ppm
dose
group
with
the
controls
for
thyroid
follicular
cell
adenomas
and
combined
adenomas/
carcinomas,
as
well
as
for
urinary
bladder
transitional
cell
papillomas,
carcinomas,
and
combined
papillomas/
carcinomas,
all
at
p<
0.01.
The
increase
in
the
incidence
of
combined
thyroid
follicular
cell
adenomas/
carcinomas
at
37
7500
ppm
was
driven
by
the
adenomas.
At
7500
ppm,
the
incidences
of
thyroid
follicular
cell
adenomas,
as
well
as
combined
urinary
transitional
cell
papillomas
and
carcinomas,
exceeded
their
respective
range
for
the
historical
controls.
The
female
rats
had
a
significant
increasing
trend
(p<
0.01)
and
a
significant
increase
by
pair
wise
comparison
of
the
7500
ppm
dose
group
with
the
controls
for
hepatocellular
adenomas
(p<
0.05).
The
re­
read
of
tumor
data
by
the
Pathology
Working
Group
(PWG)
showed
that
the
female
rats
had
a
significant
increasing
trend
for
urinary
bladder
transitional
cell
papillomas,
carcinomas
and
combined
papillomas/
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
combined
carcinomas/
papillomas
(p<
0.01).
The
incidences
of
hepatocellular
adenomas,
urinary
bladder
transitional
cell
papillomas
and
urinary
transitional
cell
carcinomas
exceeded
the
respective
ranges
for
the
historical
controls.
The
CARC
noted
that
at
the
week
53
necropsy,
transitional
epithelial
hyperplasia,
a
preneoplastic
stage,
was
observed
in
the
urinary
bladder
of
mid
dose
tested
(MDT)
males
and
highest
dose
tested
(HDT)
males
and
females.
After
the
4­
week
recovery
period,
this
change
was
still
present
in
HDT
males
and
females.
At
the
terminal
necropsy,
the
transitional
cell
hyperplasia
was
observed
in
HDT
males
and
females,
along
with
an
increased
incidence
of
squamous
cell
metaplasia,
high
mitotic
index
and
atypia.

The
HDT
was
judged
to
be
excessive
based
on
a
significant
(p<
0.5)
decrease
in
body
weight
gains
during
week
13
for
males
and
females
by
40%
and
52%,
respectively,
as
compared
to
controls.
Decreased
food
efficiency
and
alterations
in
hematology
and
clinical
chemistry
values
were
also
reported
in
both
sexes
at
the
high
dose
level.
By
weeks
52­
53,
plasma,
RBC
and
brain
cholinesterase
(ChE)
activities
were
significantly
(p<
0.05)
decreased
in
males
by
40%,
22%
and
28%,
respectively,
and
in
females
by
56%,
36%
and
37%,
respectively,
as
compared
to
controls.
By
week
104,
plasma,
RBC
and
brain
ChE
activities
were
significantly
decreased
in
males
by
42%,
30%
and
9%,
respectively,
and
in
females
by
46%,
38%
and
22%,
respectively.

The
MDT
was
judged
to
be
below
the
adequate
dose
for
testing
the
carcinogenic
potential
of
carbaryl.
At
this
dose,
there
was
no
effect
on
body
weight/
body
weight
gain
and
only
minor
ChE
inhibition
(less
than
20%
inhibition
of
plasma,
RBC
and
brain
ChE
in
males
and
females
at
week
53,
except
for
26%
inhibition
of
RBC
in
females;
at
week
105,
only
female
RBC
and
brain
ChE
were
decreased
(22%
and
16%,
respectively).
The
CARC
noted
that
the
MDT
male
rats
had
transitional
cell
hyperplasia
of
the
bladder,
a
preneoplastic
lesion,
at
the
week
53
necropsy.
If
the
dose
had
been
adequate,
bladder
tumors
seen
at
the
HDT
may
have
occurred
at
the
MDT.

2.
The
reanalyses
of
mouse
tumor
data
showed
that
male
mice
had
significant
increasing
trends
in
kidney
tubule
cell
adenomas
(p<
0.05),
carcinomas
(p<
0.05)
and
combined
adenomas/
carcinomas
(p<
0.01).
In
mice,
hemangiomas
in
the
liver
and
spleen
can
progress
to
hemangiosarcomas.
Therefore,
the
incidence
of
hemangiomas
and
hemangiosarcomas
at
various
sites
was
combined
and
analyzed.
There
were
significant
differences
(p<
0.05)
in
the
pair­
wise
comparison
of
the
$
100
ppm
(all
doses
tested)
with
the
controls
for
hemangiosarcomas
and
in
combined
hemangiomas/
hemangiosarcomas
at
1000
and
8000
ppm.
In
addition,
a
significant
difference
in
the
pair­
wise
comparison
of
the
8000
ppm
dose
group
with
controls
was
noted
for
combined
kidney
tubule
cell
adenomas/
carcinomas
(p<
0.05).
38
The
female
mice
had
significant
increasing
trend
in
hepatocellular
adenomas
(p<
0.01),
combined
hepatocellular
adenomas/
carcinomas
(p<
0.01),
hemangiosarcomas
(p<
0.01),
and
combined
hemangiomas/
hemangiosarcomas
(p<
0.05).
There
were
also
significant
differences
in
the
pairwise
comparison
of
the
8000
ppm
dose
group
with
the
controls
for
hepatocellular
adenomas
(p<
0.05),
combined
hepatocellular
adenomas/
carcinomas/
hepatoblastomas
(p<
0.01),
and
hemangiosarcomas
(p<
0.05).
Appropriate
historical
control
data
for
various
types
of
tumors
were
not
available
for
comparison.
However,
based
on
recently
submitted
historical
control
data
on
vascular
tumors
in
the
liver
and
spleen
(sites
for
most
hemangiomas/
hemangiosarcomas),
the
incidence
of
hemangiosarcomas
exceeded
the
range
for
the
historical
controls
in
both
male
and
female
mice.

The
CARC
considered
the
dosing
at
the
HDT
in
male
and
female
mice
to
be
excessive
because
the
decrease
in
body
weight
gain,
clinical
signs
and
ChE
inhibition,
and
histopathological
changes
in
various
organs
were
indicative
of
excessive
toxicity.
The
CARC
concluded
that
the
malignant
vascular
tumors
(hemangiosarcomas)
in
male
mice
occurred
at
doses
which
were
adequate
and
not
excessive.
In
females
these
tumors
occurred
only
at
the
highest
dose
which
was
excessively
toxic.
Nevertheless,
the
findings
in
female
mice
were
supportive
of
vascular
tumors
in
male
mice.

Carbaryl
produces
epoxides
and
its
genotoxicity
is
manifested
as
chromosomal
aberrations
in
cultured
mammalian
cells
while
older
in
vivo
studies
indicate
negative
results
for
aberrations.
More
recent
studies
with
cultured
cells
have
demonstrated
effects
on
microtubule
assembly,
karyokinesis
and
cytokinesis
as
well
as
stress
genes
associated
with
oxidative
damage.

5.3.2
Classification
of
Carcinogenic
Potential
In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(July,
1999),
the
CARC
classified
carbaryl
into
the
category
"Likely
to
be
carcinogenic
to
humans"
based
on
the
following
weight­
of­
the­
evidence
considerations:

1.
Carbaryl
induced
a
statistically
significant
increase
in
urinary
bladder
tumors
in
male
and
female
rats,
thyroid
tumors
in
male
rats
and
liver
tumors
in
female
rats.
These
tumors
were
induced
at
an
excessively
toxic
dose
(7500
ppm)
and,
therefore,
were
not
relevant
for
human
cancer
risk
assessment.
However,
there
was
evidence
of
preneoplastic
lesions
in
the
bladder
in
males
at
1500
ppm,
a
dose
which
was
below
the
adequate
dose
for
testing
the
carcinogenic
potential
of
carbaryl.
In
mice,
a
treatment­
related
increase
in
malignant
vascular
tumors
(hemangiosarcomas)
was
noted
in
males
at
all
doses,
both
excessive
and
adequate,
whereas
in
females,
this
same
tumor
type
was
seen
only
at
excessive
doses.

2.
Carbaryl
is
clastogenic
in
in
vitro
studies
with
effects
on
aberrations;
aneuploidy­
associated
events
are
also
observed
and
further,
a
single
report
from
the
published
literature
suggests
that
carbaryl
may
induce
oxidative
stress.
These
types
of
effects
may
contribute
to
carbaryl­
induced
tumors.
Nevertheless,
carbaryl
is
negative
for
micronucleus
induction
in
one
mouse
strain,
not
clastogenic
in
Syrian
hamsters,
and
negative
in
a
p53
knockout
transgenic
mouse
bioassay.
39
5.3.3
Quantification
of
Carcinogenic
Potential
The
Committee
recommended
a
low­
dose
linear
extrapolation
approach
using
all
dose
levels
for
the
quantification
of
human
cancer
risk
based
on
the
most
potent
vascular
tumors
in
mice.
This
approach
was
supported
by
the
lack
of
confirmation
of
a
mode
of
action.
The
Q1*,
based
on
the
CD­
1
mouse
dietary
study
with
¾
Interspecies
Scaling
Factor,
is
8.75
x
10
­4
(mg/
kg/
day)
­1
in
human
equivalents.

6.0
FQPA
CONSIDERATIONS
6.1
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.
40
°
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
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
doserelated
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.

6.2
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.
41
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23,
1997.
Unpublished
MRID
No.
44402501.
Totis,
M.
(1997)
Investigation
of
the
Metabolism
of
14
C­
Carbaryl
in
the
15­
Month­
Old
Male
Rat
Following
Chronic
Dietary
Administration.
Final
Report.
Rhone­
Poulenc
Agrochimie,
Centre
de
Recherche,
355
rue
Dostoievski,
BP.
153,
F­
06903
Sophia
Antipolis,
France.
Study
No.
95288.
Oct.
3,
1997.
Unpublished
MRID
44732901.
Repetto­
Larsay,
M.
(1998)
Carbaryl
Developmental
Toxicity
Study
in
the
Rat
by
Gavage.
Rhône­
Poulenc
Agro
Centre
de
Recherche,
Sophia
Antipolis,
France.
Study
SA
98070,
October
21,
1998.
Unpublished
MRID
44904202.
Tyl,
RW;
Marr,
MC;
Myers,
CB.
(1999)
Developmental
Toxicity
Evaluation
(with
Cholinesterse
Assessment)
of
Carbaryl
Administered
by
Gavage
to
New
Zealand
White
Rabbits.
Reproductive
&
Developmental
Toxicology
Laboratory,
Center
for
Life
Sciences
and
Toxicology,
Research
Triangle
Park,
NC.
RTI
Identification
No.
65C­
7297­
200/
100,
June
3,
1999.
Unpublished.

MRID
44904204.
Robinson,
K.
and
Broxup,
B.
(1999)
A
Developmental
Neurotoxicity
Study
of
Orally
Administered
Carbaryl,
Technical
Grade,
in
the
Rat.
ClinTrials
BioResearch
Ltd.,
Senneville,
Quebec,
Canada.
Laboratory
Project
I.
D.
97391,
June
1,
1999.
Unpublished.

MRID
45281801.
Chu
zel
F
(1999).
Carbaryl
6­
Month
Carcinogenicity
Study
in
p53
Knockout
Mice
by
Dietary
Administration.
Rhône­
Poulenc
Agro
Centre
de
Recherche,
Sophia
Antipolis
Cedex,
France.
Study
Number
SA98155,
July
8,
1999.
Unpublished.

MRID
45281802.
Bigot
D
(1999).
Validation
on
Transgenic
Mice
­
p53
Knockout
Mice
­
to
Predict
Rodent
Carcinogenicity.
Rhône­
Poulenc
Agro
Centre
de
Recherche,
Sophia
Antipolis
Cedex,
France.
Study
Number
SA97040,
November
10,
1999.
Published
with
the
following
citation:
Carmichael
NG,
Debruyne
EL,
Bigot­
Lasserre
D
(2000).
The
p53
heterozygous
knockout
mouse
as
a
model
for
chemical
carcinogenesis
in
vascular
tissue.
Environ
Health
Perspect
108(
1):
61­
5.

MRID
45236603.
Dan
ge
M
(1998).
Carbaryl,
Prelimina
ry
28­
Day
Toxicity
Study
in
the
Male
TSG
p53
Wild
Type
Mouse
by
Dietary
Administration.
Rhône­
Poulenc
Agro
Centre
de
Recherche,
Sophia
Antipolis
Cedex,
France.
Study
Numbers
SA
97499
and
SA
97538,
April
10,
1998.
Unpublished.

MRID
45448101.
Tyl,
R.,
C.
Myers,
M.
Marr.
(2001).
Two­
generation
reproductive
toxicity
evaluation
of
carbaryl
(RPA007744)
administered
in
the
feed
to
CD
®
(Sprague­
Dawley)
rats.
Reproductive
and
Developmental
Laboratory,
Center
for
Life
Sciences
and
Toxicology,
Chemistry
and
Life
Sciences,
Research
Triangle
Institute,
Life
Sciences
and
Toxicology,
Research
Triangle
Park,
NC
27709.
Laboratory
report
number
65C­
07407­
400,
May
24,
2001.
Unpublished.
44
MRID
45456701.
Robinson
K,
and
Broxup
B.
(2001)
Final
Report
Amendment
No.
2
Supplement
to
MRID
44393701­
A
Developmental
Neurotoxicity
Study
of
Orally
Administered
Carbaryl,
Technical
Grade,
in
the
Rat.
ClinTrials
BioResearch
Ltd.,
Quebec,
Canada.
Laboratory
Project
I.
D.
97391.
July
10,
2001.
Unpublished.

MRID
45456702.
Hamelin
N,
Yipchuck
G.
(2001)
Morphometric
Evaluation
of
Rat
Brain
Areas
for
Developmental
Neuropathology.
ClinTrials
Bioresearch
Ltd.,
Quebec,
Canada.
Laboratory
Project
I.
D.
99579.
July
9,
2001.
Unpublished.

MRID
45456703.
Robinson
K,
and
Broxup
B.
(2001)
Final
Report
Amendment
No.
1
Supplement
to
MRID
44393701­
A
Developmental
Neurotoxicity
Study
of
Orally
Administered
Carbaryl,
Technical
Grade,
in
the
Rat.
ClinTrials
BioResearch
Ltd.,
Quebec,
Canada.
Laboratory
Project
I.
D.
97391.
July
6,
2001.
Unpublished.

MRID
45630601.
Austin,
E.
W.
(2002).
4
Week
Repeated­
Dose
Dermal
Toxicity
Study
with
Carbaryl
Technical
in
Rats.
Covance
Laboratories,
Madison,
WI.
Laboratory
Study
Identification
Number
6224­
268,
March
8,
2002.
Unpublished.

MRID
45630602.
Austin,
E.
W.
(2002).
4
Week
Repeated­
Dose
Dermal
Toxicity
Study
with
SEVIN®
XLR
Plus
in
Rats.
Covance
Laboratories,
Madison,
WI.
Laboratory
Study
Identification
Number
6224­
267,
March
7,
2002.
Unpublished.

MRID
45630603.
Austin,
E.
W.
(2002).
4
Week
Repeated­
Dose
Dermal
Toxicity
Study
with
SEVIN®
80S
in
Rats.
Covance
Laboratories,
Madison,
WI.
Laboratory
Study
Identification
Number
6224­
266,
March
8,
2002.
Unpublished.
45
9.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
46
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Table
1:
Toxicology
Profile
of
Carbaryl
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
N/
A
870.3150
90­
Day
oral
toxicity
in
nonrodents
N/
A
870.3200
21/
28­
Day
dermal
toxicity
with
technical
carbaryl
45630601(
2002)
acceptable/
nonguideline
0,
20,
50,
100
mg/
kg/
day
systemic
NOAEL
=
20
mg/
kg/
day
systemic
LOAEL
=
50
mg/
kg/
day
based
on
decreased
RBC
cholinesterase
in
males
and
females
and
brain
cholinesterase
in
males
dermal
NOAEL
=
100
mg/
kg/
day
dermal
LOAEL
not
established
870.3200
21/
28­
Day
dermal
toxicity
with
Sevin®
XLR
Plus
(44.82%
a.
i.)
45630602
(2002)
unacceptable/
nonguideline
0,
20,
50,
100
mcL/
kg/
day
(0,
9.6,
24,
48
mg/
kg/
day)
systemic
NOAEL
=
50
mcL/
kg/
day
(24
mg/
kg/
day)
systemic
LOAEL
=
100
mcL/
kg/
day
(48
mg/
kg/
day)
based
on
decreased
body
weight
gain
dermal
NOAEL
=
100
mcL/
kg/
day
(48
mg/
kg/
day)
dermal
LOAEL
not
established
870.3200
21/
28­
Day
dermal
toxicity
with
Sevin®
80S
(80.07%
a.
i.)
45630603
(2002)
unacceptable/
nonguideline
0,
20,
50,
100
mg/
kg/
day
systemic
NOAEL
=
20
mg/
kg/
day
systemic
LOAEL
=
50
mg/
kg/
day
based
on
decreased
RBC
cholinesterase
in
males
and
females
dermal
NOAEL
=
100
mg/
kg/
day
dermal
LOAEL
not
established
870.3250
90­
Day
dermal
toxicity
N/
A
870.3465
90­
Day
inhalation
toxicity
N/
A
870.3700a
Prenatal
developmental
in
rats
44732901
(1998)
acceptable/
guideline
0,
1,
4,
30
mg/
kg/
day
(oral
gavage)
Maternal
NOAEL
=
4
mg/
kg/
day
LOAEL
=
30
mg/
kg/
day
based
on
clinical
signs,
decreased
body
weight
gain
(BWG)
and
food
consumption
Developmental
NOAEL
=
4
mg/
kg/
day
LOAEL
=
30
mg/
kg/
day
based
on
decreased
fetal
body
weight
and
incomplete
ossification
of
multiple
bones
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
47
870.3700b
Prenatal
developmental
in
rabbits
44904202
(1999)
Acceptable/
guideline
0,
5,
50,
150
mg/
kg/
day
(oral
gavage)
Maternal
NOAEL
=
5
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day
based
on
decreased
BWG
and
plasma
cholinesterase
inhibition
(ChEI)
Developmental
NOAEL
=
50
mg/
kg/
day
LOAEL
=
150
mg/
kg/
day
based
on
decreased
fetal
weight
870.3800
Reproduction
and
fertility
effects
45448101
(2001)
acceptable/
guideline
0,
75,
300,
1500
ppm
(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)
Parental
NOAEL
=
300
ppm
(23.49­
31.34
mg/
kg/
day
for
males
and
26.91­
36.32
mg/
kg/
day
for
females)
Parental
LOAEL
=
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
Reproductive
toxicity
NOAEL
is
$
1500
ppm
(92.43­
124.33
mg/
kg/
day
for
males
and
110.78­
135.54
mg/
kg/
day
for
females)
Reproductive
toxicity
LOAEL
not
be
established
Offspring
NOAEL
=
75
ppm
(4.67­
5.79
mg/
kg/
day
for
males
and
5.56­
6.41
mg/
kg/
day
for
females).
Offspring
LOAEL
=
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.

870.4100a
Chronic
toxicity
in
rodents
N/
A
870.4100b
Chronic
toxicity
in
dogs
40166701
(1987)
0,
125,
400,
1250
ppm
(0,
3.1,
10,
31.3
mg/
kg/
day)

42022801
(1991)
0,
20,
45,
125
ppm
(5
weeks)
(M:
0,
0.59,
1.43,
3.83;
F:
0,
0,64,
1.54,
4.11
mg/
kg/
day)
Together,
the
studies
are
Acceptable/
guideline
MRID
40166701:
NOAEL
=
not
established
in
females
LOAEL
=
125
ppm
based
based
on
plasma
and
brain
ChEI
MRID
42022801:
NOAEL
=
45
ppm
in
males
LOAEL
=
125
ppm
in
males
based
on
plasma
ChEI
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
48
870.4200
Carcinogenicity
in
mice
42786901
(1993)
Acceptable/
guideline
0,
100,
1000
or
8000
ppm
(M:
0,
14.73,
145.99,
1248.93
mg/
kg/
day;
F:
0,
18.11,
180.86,
1440.62)
systemic
LOAEL
=
1000
ppm
based
on
increased
intracytoplasmic
droplets
in
bladder
in
males
and
females,
chronic
progressive
nephropathy
in
males;
NOAEL
=
100
ppm
RBC
ChEI
LOAEL
for
males
=
1000
ppm
,
for
females
=
8000
ppm;
NOAEL
=
100
ppm
for
males,
1000
ppm
for
females
plasma
ChEI
for
males
and
females
LOAEL
>
8000
ppm;
NOAEL
$
8000
ppm
brain
ChEI
for
males
and
females
LOAEL
=
8000
ppm;
NOAEL
=
1000
ppm
increase
in
vascular
tumors
in
all
treated
males
and
in
females
at
8000
ppm
increase
in
adenomas,
multiple
adenomas,
carcinomas
of
kidney
in
males
at
8000
ppm
increase
in
hepatic
neoplasms
(adenomas,
carcinomas,
one
hepatoblastoma)
in
females
at
8000
ppm
870.4300
Chronic
Toxicity/
Carcinogenicity
in
rats
42918801
(1993)
Acceptable/
guideline
0,
250,
1500
&
7500
ppm
(M:
0,
10,
60.2,
349.5
mg/
kg/
day;
F:
0,
12.6,
78.6,
484.6
mg/
kg/
day)
systemic
LOAEL
=
1500
ppm
in
females
based
on
decreased
BW
and
BWG;
7500
ppm
in
males
based
on
increased
clinical
signs,
decreased
BW,
BWG
and
food
consumption,
increase
in
cataracts,
clinical
pathology
changes,
organ
weight
changes,
nonneoplastic
changes;
NOAEL
=
250
ppm
in
females
and
1500
ppm
in
males
plasma
ChEI
LOAEL
=
7500
ppm
in
males
and
females;
NOAEL
=
1500
ppm
RBC
ChEI
LOAEL
=
1500
ppm
in
males
and
females;
NOEL
=
250
ppm
brain
ChEI
LOAEL
=
7500
ppm
in
males
and
females;
NOEL
=
1500
ppm
at
7500
ppm,
increase
in
liver
adenomas
in
females,
increase
in
benign
transitional
cell
papillomas
and
transitional
cell
carcinomas
in
males
and
females,
transitional
cell
carcinoma
in
kidney
of
one
male,
increase
in
benign
thyroid
follicular
cell
adenomas
in
males,
follicular
cell
carcinoma
in
one
male
Bacterial
reverse
mutation
test
870.5100
41370303
(1989)
Acceptable/
guideline
5­
1000
ug/
plate
No
evidence
of
mutagenicity
in
strains
TA1535,
TA
1537,
TA1538,
TA98
and
TA100
with
and
without
metabolic
activation
In
vitro
mammalian
chromosome
aberration
test
(Chinese
hamster
ovary
cells)
870.5385
41370304
(1989)
Acceptable/
guideline
without
S9
activation:
5­
100
ug/
mL,
harvest
at
20
hrs.;
with
S9
activation:
25­
300
ug/
mL,
harvest
at
30
hrs
Increase
in
chromosome
aberrations
with
S9
activation
In
vitro
mammalian
chromosome
aberration
test
870.5385
41370302;
41420201
(1989)
Unacceptable/
guideline
S9
activation:
1­
300
ug/
mL
in
3
trials;
without
S9
activation:
1­
300
ug/
mL
in
2
trials
Results
provide
no
clear
indication
of
a
mutagenic
response,
however
study
had
several
deficiencies
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
49
Mammalian
erythrocyte
micronucleus
test
870.
5395
44069301
(1996)
Unacceptable/
guideline
single
oral
gavage
dose
of
50,
100,
200
mg/
kg
Carbaryl
did
not
induce
a
clastogenic
or
aneugenic
effect,
however
there
was
no
convincing
evidence
that
MTD
was
achieved
Unscheduled
DNA
synthesis
870.5550
41370301;
41810601
(1989)
Acceptable/
guideline
0.5
­
25.0
ug/
mL
Negative
870.6200a
Acute
neurotoxicity
screening
battery
in
rats
MRID:
43845201­
43845204
(1995)
Acceptable/
guideline
0,
10,
50,
125
mg/
kg
(oral
gavage)
Separate
study
for
ChE:
0,
10,
30,
50
mg/
kg;
ChE
done
1,
8,
24,
48
hrs
post­
dosing
Systemic
LOAEL
=
10
mg/
kg
based
on
decreased
RBC,
plasma,
blood,
brain
ChE;
NOAEL
<
10
mg/
kg
870.6200b
Subchronic
neurotoxicity
screening
battery
in
rats
MRID:
44122601
(1996)
Acceptable/
guideline
0,
1,
10,
30
mg/
kg/
day
(oral
gavage)
LOAEL
for
neurotoxicity
=
10
mg/
kg/
day
based
on
increased
FOB
changes;
NOAEL
=
1
mg/
kg/
day
LOAEL
for
ChEI
=
10
mg/
kg/
day
based
on
decreased
plasma,
blood,
RBC,
brain
ChE;
NOAEL
=
1
mg/
kg/
day
870.6300
Developmental
neurotoxicity
in
rats
44393701
(1997)
Acceptable/
guideline
0,
0.1,
1.0,
10
mg/
kg
(oral
gavage)
Maternal
NOAEL
=
1.0
mg/
kg/
day
LOAEL
=
10
mg/
kg/
day
based
on
decreased
BWG;
FOB
changes;
RBC,
plasma,
whole
blood,
brain
ChEI
Offspring
tentative
NOAEL
=
1.0
mg/
kg/
day
tentative
LOAEL
=
10
mg/
kg/
day
based
on
alterations
in
morphometric
measurements
(measurements
were
not
done
at
lower
doses)

870.7485
Metabolism
and
pharmacokinetics
in
rats
43332101
(1994)
Acceptable/
guideline
1
mg/
kg
(single
and
repeated
oral
doses;
intravenous
dose)
and
50
mg/
kg
(single
oral
dose)
Absorption
was
complete
at
all
doses.
At
168
hrs.,
post­
dose,
negligible
percentages
of
dose
in
any
tissues.
Kidney
and
blood
contained
highest
concentrations
of
radioactivity.
Excretion
mostly
through
urine.
A
metabolic
scheme
with
conjugated
and
nonconjugated
metabolites
was
proposed.

870.7485
Metabolism
and
pharmacokinetics
in
rats
44402501
(1997)
Acceptable/
nonguideline
50
mg/
kg
(single
oral
radiolabeled
dose);
daily
oral
radiolabeled
dose
of
2
mg/
kg
for
7
days
followed
by
83
daily
unlabeled
doses
of
0,
250,
1500
or
7500
ppm;
males
only
In
all
dosing
regimens,
urinary
and
fecal
excretion
was
93­
103%
of
administered
dose
and
tissue
levels
of
radioactivity
were
minimal
at
168
hrs.
post­
dosing.
Two
major
metabolites
in
tissues
at
6
hrs.
post­
dosing
were
naphthyl
sulfate
and
naphthyl
glucuronide,
however
quantitation
was
not
possible.
A
total
of
23
and
20
components
were
identified
in
the
urine
and
feces,
respectively.
The
sulfate
conjugation
pathway
appears
to
be
saturable
following
a
83­
day
feeding
at
7500
ppm.
BW
and
food
consumption
were
decreased
at
7500
ppm.
Increases
in
kidney,
spleen
and
thyroid
weights
were
observed
at
1500
and
7500
ppm.
Non­
neoplastic
changes
in
liver,
thyroids
and
kidneys
were
observed
at
7500
ppm.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
50
870.7600
Dermal
penetration
in
rats
43552901
(1995)
43.9%
a.
i.
Acceptable
35.6,
403,
3450
ug/
cm
2
%
absorbed
at
10
hrs.:
12.7,
7.44
and
1.93
at
35.6,
403
and
3450
ug/
cm
2
,
respectively
870.7600
Dermal
penetration
in
rats
43339701
(1994)
80.1%
a.
i.
Acceptable
63,
626,
3410
ug/
cm
2
%
absorbed
at
10
hrs:
8.90,
0.62
and
0.48
at
63,
626
and
3410
ug/
cm
2
,
respectively
Special
studies
in
mice
43282201
(1994)
Acceptable/
nonguideline
male
mice:
single
radiolabeled
dose
of
75
mg/
kg;
pretreatment
with
8000
ppm
unlabeled
carbaryl
for
2
wks.,
then
single
radiolabeled
dose
of
75
mg/
kg
Negative
for
DNA
binding
in
liver
Special
studies
in
mice
43832601
(1994)
Acceptable/
nonguideline
continuation
of
MRID
43282201
in
liver
from
mice
treated
at
8000
ppm,
increase
in
microsomal
protein,
cytochrome
P450,
ethoxyresorufin
O­
deethylase,
pentoxyresorufin
O­
depentylase,
and
testosterone
hydrolases
indicates
phenobarbital
type
of
induction
of
metabolizing
enzymes
Special
study
in
mice
45281801,
45281802,
45236603
(1998­
1999)
Acceptable/
nonguideline
0,
10,
30,
100,
300,
1000
and
4000
ppm
(0,
1.8,
5.2,
17.5,
51.2,
164.5
and
716.6
mg/
kg/
day)
There
was
no
evidence
of
neoplastic
or
preneoplastic
changes
in
vascular
tissue
in
heterozygous
p53­
deficient
male
mice
treated
with
carbaryl
for
six
months.

N/
A
Not
Available
51
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
CARBARYL
for
Use
in
Human
Risk
Assessment
1
Table
2:
Summary
of
Toxicology
Endpoint
Selection
for
Carbaryl
Exposure
Scenario
Dose
(mg/
kg/
day)
UF
/MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
Dietary
Risk
Assessments
Acute
Dietary
general
population
including
infants
and
children
NOAEL
=
1
UF
=
100
Acute
RfD
=
0.01
mg/
kg/
day
1
Developmental
Neurotoxicity
­
rat
LOAEL
=
10
mg/
kg/
day
based
on
an
increased
incidence
of
FOB
changes
on
the
first
day
of
dosing
in
maternal
animals
Chronic
Dietary
all
populations
LOAEL=
3.1
UF
=
300
Chronic
RfD
=
0.01
mg/
kg/
day
1
Chronic
toxicity
­
dog
LOAEL
=
3.1
mg/
kg/
day
based
on
plasma
and
brain
cholinesterase
inhibition
in
females.

Incidental
Oral
Short­
Term
(1
­
30
Days)

Residential
Only
NOAEL=
1
MOE=
TBD
1
Developmental
Neurotoxicity
­
rat
LOAEL
=
10
mg/
kg/
day
based
on
an
increased
incidence
of
FOB
changes
and
decreases
in
RBC,
whole
blood,
plasma
and
brain
cholinesterase
Incidental
Oral
Intermediate­
Term
(1
­
6
Months)

Residential
Only
NOAEL=
1
MOE
=
TBD
1
Subchronic
Neurotoxicity
­
rat
LOAEL
=
10
mg/
kg/
day
based
on
increased
incidence
of
FOB
changes;
decrease
in
RBC,
whole
blood,
plasma
and
brain
cholinesterase.
Exposure
Scenario
Dose
(mg/
kg/
day)
UF
/MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
52
Non­
Dietary
Risk
Assessments
Dermal
Short­
Term
(1
­
30
days)
Dermal
NOAEL=
20
4­
week
dermal
toxicity
­
rat
systemic
LOAEL
=
50
mg/
kg/
day
based
on
statistically
significant
decreases
in
RBC
cholinesterase
in
males
and
females
and
brain
cholinesterase
in
males.
Residential
MOE
=
TBD
1
Occupational
100
1
Dermal
Intermediate­
Term
(1
­
6
Months)
Dermal
NOAEL=
20
4­
week
dermal
toxicity
­
rat
systemic
LOAEL
=
50
mg/
kg/
day
based
on
statistically
significant
decreases
in
RBC
cholinesterase
in
males
and
females
and
brain
cholinesterase
in
males.
Residential
MOE
=
TBD
1
Occupational
100
1
Dermal
Long­
Term
a
(>
6
Months)
Oral
NOAEL=
3.1
Chronic
toxicity
­
dog
LOAEL
=
3.1
mg/
kg/
day
based
on
plasma
and
brain
cholinesterase
inhibition
in
females.
Residential
MOE
=
TBD
1
Occupational
300
1
Inhalation
Short­
Term
b
(1
­
30
days)
Oral
NOAEL=
1
Developmental
Neurotoxicity
­
rat
LOAEL
=
10
mg/
kg/
day
based
on
an
increased
incidence
of
FOB
changes
and
statistically
significant
decreases
in
RBC,
whole
blood,
plasma
and
brain
cholinesterase
Residential
MOE
=
TBD
1
Occupational
100
1
Inhalation
Intermediate­
Term
b
(1
­
6
Months)
Oral
NOAEL=
1
Subchronic
Neurotoxicity
­
rat
LOAEL
=
10
mg/
kg/
day
based
on
increased
incidence
of
FOB
changes;
decrease
in
RBC,
whole
blood,
plasma
and
brain
cholinesterase.
Residential
MOE
=
TBD
1
Occupational
100
1
Inhalation
Long­
Term
b
(>
6
Months)
Oral
NOAEL=
3.1
Chronic
toxicity
­
dog
LOAEL
=
3.1
mg/
kg/
day
based
on
plasma
and
brain
cholinesterase
inhibition
in
females.
Exposure
Scenario
Dose
(mg/
kg/
day)
UF
/MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
53
Residential
MOE
=
TBD
1
Occupational
300
1
Cancer
Classification:
Q1*
=
8.75
x
10
­4
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.
TBD
=
To
Be
Determined.
Target
MOEs
for
residential
exposures
will
be
determined
by
the
FQPA
Safety
Factor
Committee.
