Document ID: EPA-HQ-ORD-2006-0187-0030
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-28T05:00Z

Page
1
of
19
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
TXR
No.
0054126
MEMORANDUM
DATE:
March
17,
2006
SUBJECT:
Human
Studies
Review
Board:
Final
Weight
of
Evidence
Comparison
of
Human
and
Animal
Toxicology
Studies
and
Endpoints
for
ALDICARB
Human
Health
Risk
Assessment
[
PC
Code:
098301;
DP
Barcode:
D299876]
and
Discussion
of
Interspecies
Extrapolation
in
the
N­
Methyl
Carbamate
Cumulative
Risk
Assessment
[
DP
Barcode
321873]

FROM:
Linda
L.
Taylor,
Ph.
D.,
Toxicologist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

THRU:
Whang
Phang,
Ph.
D.,
Branch
Senior
Scientist.
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

TO:
Tina
E.
Levine,
Ph.
D.,
Director
Health
Effects
Division
(
7509C)

Aldicarb
is
a
N­
methyl
carbamate
pesticide
that
exerts
its
pesticidal
activity
and
elicits
adverse
toxic
effects
by
inhibition
of
cholinesterase
activity
[
ChEI],
which
has
been
demonstrated
in
whole
blood,
plasma,
red
blood
cells,
and
brain
of
rats,
mice,
and
dogs
following
acute,
subchronic,
and
chronic
exposure
and
in
plasma
and
RBC
in
humans
following
acute
exposure.

N­
methyl
carbamate
pesticides
typically
exhibit
rapid
ChE
recovery
(
minutes
to
hours),
following
maximum
inhibition
of
ChE.
The
available
data
indicate
a
peak
effect
within
an
hour
of
dosing
followed
by
recovery
within
24
hours.
As
a
result,
a
comparable
degree
of
inhibition
occurs
whether
delivered
once
or
following
subchronic
or
chronic
dosing.

There
is
an
acute
oral
exposure
study
on
aldicarb
[
MRID
42373001]
involving
direct
dosing
of
humans
in
which
plasma
and
RBC
cholinesterase
activity
and
Page
2
of
19
clinical
signs
were
monitored.
There
is
also
a
full
database
of
animal
toxicity
studies.

OPPTS
management
has
requested
that
when
human
studies
support
a
risk
assessment,
HED
should
compare
the
strengths
and
weaknesses
of
the
human
and
animal
toxicity
studies,
present
how
the
human
studies
could
be
used
in
endpoint
selection,
including
whether
the
human
data
are
consistent
with
animal
data
in
terms
of
types
of
effects
and
effect
levels,
and
if
notable
differences
exist
between
animals
and
humans.

The
first
section
of
this
document
focuses
on
a
single
human
acute
oral
exposure
study
in
which
humans
were
intentionally
dosed
with
aldicarb.
This
beginning
section
will
focus
on
the
human
study
in
regards
to
the
single
chemical
risk
assessment.
The
human
data
from
this
study
are
compared
with
animal
data
from
the
available
aldicarb
animal
studies,
and
recommendations
for
endpoint
selection
are
then
presented
based
on
the
most
appropriate
studies
and
uncertainty
factors.
All
of
the
studies
are
listed
in
summary
form,
followed
by
weight
of
evidence
discussion
for
endpoint
selection.
Although
there
is
another
(
1971)
human
study
on
aldicarb
[
MRID
00101911],
it
has
not
been
considered
here.
The
1971
study
was
flawed
by
the
absence
of
a
control
group
or
a
means
of
"
blinding".

In
summary,
the
aldicarb
team
for
the
single
chemical
risk
assessment
recommends
that
the
rat
subchronic
neurotoxicity
study
[
MRID
43829602]
and
the
rat
acute
neurotoxicity
study
(
MRID
45068601;
Moser)
be
used
as
co­
critical
studies
for
endpoint
selection.
The
results
of
the
acute
oral
human
study
[
MRID
42373001]
suggest
that
animals
and
humans
have
similar
toxic
responses
to
aldicarb
allowing
reduction
of
the
interspecies
safety
factor
to
3X.
A
factor
of
3X
was
retained
for
extrapolation
from
rats
to
humans
because
of
the
limitations
of
the
human
study
as
discussed
in
detail
later
in
this
document.
The
recommended
endpoint
selection
is
summarized
in
Table
3,
column
4,
together
with
two
other
possible
options
for
endpoint
selection
in
column
2
(
use
of
human
study)
and
column
3
(
use
of
animal
data
without
considering
human
data).
For
consistency,
column
5
of
Table
3
also
lists
the
human
RBC
BMDL10
as
the
point
of
departure.

The
last
section
of
this
document
provides
the
rationale
for
incorporation
of
the
human
toxicity
study
into
the
N­
methyl
carbamate
pesticide
(
NMC)
preliminary
cumulative
risk
assessment.
Brain
ChE
data
from
acute
rat
toxicity
studies
are
relied
on
by
the
Agency
to
provide
the
basis
for
potency
determination,
therefore,
the
Agency
must
consider
interspecies
extrapolation
(
i.
e.,
animal
to
human)
in
its
cumulative
risk
assessment.
The
human
study
provides
RBC
ChE
data
for
comparison
to
the
available
RBC
and
brain
ChE
rat
data.
The
BMD
and
BMDL
estimates
for
the
rat
and
human
data
suggest
similar
ChE
responses
to
aldicarb
(
Table
4).
Alternative
approaches
and
the
resulting
uncertainties
surrounding
the
interspecies
factors
are
summarized
and
presented
in
Table
5.
Page
3
of
19
For
the
cumulative
risk
assessment,
the
Agency
recommends
the
use
of
the
RBC
BMD10
ratios
of
rat
and
human
for
a
2X
interspecies
extrapolation
factor
for
aldicarb.

Toxicity
Studies
 
Single
Dose
Oral
Studies:

A.
Human
In
a
single
oral
dose
human
study
with
aldicarb
(
MRID
42373001),
following
an
overnight
fast,
subjects
were
dosed
with
aldicarb
or
placebo
in
orange
juice
at
breakfast
[
consumed
over
15­
30
minutes].
Cholinesterase
[
ChE]
activity
[
plasma
and
RBC]
was
monitored
hourly
for
the
first
6
hours
post
dose
and
at
24
hours.
Study
design
and
number
of
subjects/
dose
are
provided
in
Table
1.

The
NOAEL
for
males
for
RBC
and
plasma
ChEI
and
clinical
signs
is
0.01
mg/
kg.
The
LOAEL
is
0.025
mg/
kg
based
on
sweating,
plasma
[
36%]
and
RBC
[
12%]
ChEI
at
0.025
mg/
kg
in
males.
Females
were
not
tested
at
0.01
mg/
kg,
however,
plasma
ChEI
was
50%
and
RBC
ChEI
was
20%
at
0.025
mg/
kg.
Although
mean
ChEI
was
different
between
males
and
females
at
the
two
mid
doses,
the
standard
error
of
the
means
of
ChEI
in
females
was
greater
than
the
standard
error
of
the
means
in
males.
The
duration
of
ChEI
was
longer
in
males
[
at
0.050
mg/
kg:
plasma
(
males
1­
21
hours)
vs
(
females
1­
4
hours);
RBC
(
males
1­
6
hours)
vs
(
females
1­
4
hours)]
than
in
females.
Additionally,
females
did
not
display
clinical
signs
at
either
dose.
Both
sexes
show
effects
[
ChEI]
at
0.025
mg/
kg
[%
inhibition
listed
above]
and
at
0.05
mg/
kg
[
plasma
(
males
52%/
females
68%);
RBC
(
males
29%/
females
36%)].
Because
of
uncertainty
surrounding
the
lack
of
females
at
the
lowest
dose,
the
lowest
dose
tested
[
0.01
mg/
kg]
is
not
considered
an
overall
NOAEL
for
the
study
in
the
current
assessment
[
was
considered
the
NOAEL
in
original
DER].

Table
1:
Summary
of
Dosing
Regimen
for
Single­
Dose
Human
Oral
Toxicity
Study
for
Aldicarb
There
were
a
total
of
38
men
and
9
women,
with
6
men/
5
women
participating
in
two
sessions
[
one
placebo
session
and
one
aldicarb
session].
The
study
consisted
of
several
phases/
sessions
such
that
all
subjects
were
not
dosed
during
the
same
time
frame.
However,
there
were
a
total
of
4
females
at
each
dose
level
and
4­
8
males
at
each
dose
level.
Page
4
of
19
Phase/
Session
Placebo
0.01
mg/
kg
0.025
mg/
kg
0.05
mg/
kg
0.075
mg/
kg
a
3
 
4
1
 
I
males
b
5
 
 
3
4*

c
4
2
2
2
 

d
1
3
1
 
 
II
males
e
3
3
1
2
 

f
1
 
1
1
 

g
2
 
1
1
 
III
females
h
3
 
2
2
 

#
of
subjects;
*
one
subject
received
a
dose
of
0.06
mg/
kg,
due
to
BW
error.

Strengths
­
Double­
blind
study
design
­
Use
of
both
sexes
at
mid
dose
levels.
Both
sexes
were
dosed
at
0.025
mg/
kg
and
0.05
mg/
kg
thus
allowing
comparisons
between
male
and
female
subjects.

­
Administration
of
multiple
dose
levels
provides
quality
dose­
response
information.
There
were
four
dose
groups
of
males
[
0.01,
0.025,
0.05,
0.075
mg/
kg]
and
two
dose
groups
of
females
[
0.025
and
0.05
mg/
kg].
For
example,
RBC
ChE
inhibition
in
males
ranges
from
little
to
no
inhibition
at
0.01
mg/
kg
to
38%
at
0.075
mg/
kg.

­
Blood
sampling
at
multiple
time
points.
Cholinesterase
activity
was
monitored
at
1,
2,
3,
4,
5,
6,
and
24
hours
post
dose
in
the
human
study.
These
data
provide
information
regarding
time
to
recovery.

Weaknesses
­
Females
only
tested
at
mid
doses.
Females
were
dosed
only
at
two
dose
levels
compared
to
4
dose
levels
for
males;
importantly
females
were
not
tested
at
the
lowest
dose
(
0.01
mg/
kg).
As
shown
in
Table
2
below,
greater
mean
plasma
and
RBC
ChE
inhibition
occurred
in
females
at
0.05
mg/
kg
compared
to
male
subjects.
The
variance
surrounding
the
mean
in
females
was
greater,
however,
than
the
variance
in
males.
Additionally,
the
recovery
data
from
samples
taken
every
hour
indicate
the
time
of
peak
effect
likely
occurred
prior
to
the
1
hour
sampling
event.
Thus,
the
difference
in
ChEI
observed
in
males
and
females
may
be
due
to
a
combination
of
factors
of
variance
and
timing
of
peak
effect.
Furthermore,
the
lack
of
dose­
response
information
for
females
at
the
low
dose
(
0.01
mg/
kg)
provides
additional
uncertainty
for
this
study.
Page
5
of
19
­
Blood
sampling.
The
first
measurement
of
cholinesterase
activity
post
dose
was
at
one
hour,
which
may
have
been
after
the
peak­
effect
time.
Clinical
signs
along
with
cholinesterase
inhibition
have
been
observed
in
rats
as
early
as
0.5
hour
and
0.75
hours,
respectively.

­
ChEI
methodology.
Because
ChE
inhibition
recovers
within
24
hours
following
exposure
to
N­
methyl
carbamates,
the
laboratory
protocol
used
to
measure
ChE
inhibition
is
an
important
component
of
evaluating
ChE
inhibition
data
for
Nmethyl
carbamates.
Specifically,
under
certain
conditions
recovery
can
occur
prior
to
analysis
and
thus
underestimating
actual
ChE
inhibition.
In
the
case
of
the
aldicarb
human
study,
some
details
surrounding
the
protocol
for
the
modified
Ellman
were
provided.
These
details
suggest
that
samples
were
diluted
to
some
degree.
It
is
unknown
the
degree
to
which
this
may
have
underestimated
ChE
inhibition.
A
modified
Ellman
assay
was
also
used
in
the
guideline
acute
and
subchronic
neurotoxicity
studies
in
rats.
As
noted
below
and
in
Table
2,
results
using
a
radiometric
method
(
preferred
over
Ellman)
provided
more
inhibition
at
common
dose
levels.

B.
Animals
1.
In
an
acute
[
guideline]
neurotoxicity
study
in
rats
(
MRID
43442301),
oral
doses
of
0,
0.05,
0.1,
or
0.5
mg/
kg
of
aldicarb
were
administered
via
gavage
[
vehicle
water]
to
both
sexes
of
young
adult
SD
rats
[
5/
sex/
group].
Blood
and
brain
ChE
determination
were
made
at
estimated
time
of
peak
effect
(
0.75
hours)
and
8
hours
post­
dosing.
Dose­
related
increase
in
the
inhibition
of
whole
blood
[
at
0.05
mg/
kg:
males
no
change
from
pre­
test;
females
23%
inhibition
from
pretest
value],
RBC
[
at
0.05
mg/
kg:
males
no
inhibition;
females
10%
inhibition
from
pre­
test
value],
and
plasma
[
at
0.05
mg/
kg:
males
56%;
females
64%]
cholinesterase
activities
was
observed
at
0.75
hours
after
dosing
[
estimated
time
of
peak
effect],
although
statistical
significance
was
not
always
attained
at
the
lower
dose
levels.
Examination
of
the
standard
deviation
of
the
means
for
blood
ChE
measurements,
especially
RBC,
revealed
greater
variability
in
females
than
males.
At
termination,
brain
cholinesterase
activity
was
decreased
significantly
[
males
45%/
females
50%
of
control
value]
at
0.5
mg/
kg
[
highest
dose
tested].
In
general,
mean
ChE
inhibition
was
greater
in
females
than
males,
especially
at
the
higher
dose
levels.
At
0.5
mg/
kg,
clinical
signs
of
ChEI
[
at
0.5
hours
post
dose:
tremors,
lacrimation,
salivation,
increased
respiration,
decreased
body
temperature,
arousal,
activity,
reactivity,
fore­/
hind
limb
grip
strength]
and
decreased
motor
activity
[
1
hour
post
dose]
were
observed.
At
0.1
mg/
kg,
there
was
decreased
fore
limb
grip
strength
in
females
only.
Recovery
occurred
by
8
hours
after
dosing.
Time
course
of
these
effects
were
not
measured
in
this
study.
The
risk
assessment
team
concludes
that
0.05
mg/
kg
can
be
considered
the
LOAEL
for
the
guideline
acute
study.
This
is
an
acceptable
guideline
study.

Strengths:
­
Sufficient
number
of
animals
used
[
5
animals/
sex/
dose]
­
Both
sexes
tested
at
all
dose
levels
Page
6
of
19
­
Concurrent
control
­
3
dose
levels
provided
quality
dose­
response
information
­
ChEI
and
clinical
signs
measured
at
estimated
peak
effect
time
(
0.75
hours)
and
8
hours
postdosing
Weaknesses:
­
Ellman
method
[
modified]
used;
a
radiometric
method
provides
a
more
appropriate
method
for
measuring
cholinesterase
inhibition
because
the
factors
that
promote
reversibility
are
minimized.
­
No
time
course
data
of
ChE
recovery
or
clinical
signs
2.
In
an
acute
[
non­
guideline]
neurotoxicity
study
(
MRID
45068601;
Moser),
adult
and
young
(
pre­
weanling;
PND
17)
Long­
Evans
rats
[
4/
sex/
group]
were
directly
dosed
with
aldicarb
via
gavage
[
vehicle
corn
oil]
at
dose
levels
of
0,
0.05,
0.1,
0.2,
or
0.3
mg/
kg.
At
0.05
mg/
kg
(
lowest
dose
tested)
in
PND
17
rats,
whole
blood
ChE
inhibition
was
75%­
81%
and
brain
ChE
inhibition
was
24­
28
%;
in
adult
rats,
whole
blood
ChE
inhibition
was
84%
and
brain
inhibition
was
10­
12%.
No
difference
between
the
sexes
was
identified
in
either
age
group.
This
study
shows
an
increase
in
sensitivity
only
in
terms
of
percent
brain
ChE
inhibition
for
PND
17
rats
in
comparison
to
adults.
Both
age
groups
had
greater
than
75%
whole
blood
ChE
inhibition
at
all
dose
levels.
The
LOAEL
is
0.05
mg/
kg.
This
study
was
classified
acceptable/
non­
guideline.

Strengths:
­
Both
sexes
at
all
doses
­
Concurrent
control
group
­
4
treatment
dose
levels
provided
quality
dose­
response
information
­
4
animals/
sex/
group
­
Radiometric
method
used.
­
Adult
and
juvenile
animals
evaluated
providing
information
on
age­
related
sensitivity
Weaknesses:
­
Fewer
animals
per
group
than
used
in
guideline
study
­
Significant
inhibition
observed
at
all
dose
levels
(>
75%
whole
blood
inhibition
at
lowest
dose
level
in
adult
and
juvenile
animals.)

!
Repeated
Dose
Oral
Studies
A.
Human
There
is
no
repeated­
dose
study
on
aldicarb
in
humans.
However,
based
on
the
reversibility
of
the
effects
observed
within
24
hours
following
acute
oral
exposure
of
human
and
following
oral
exposures
of
varying
lengths
to
rats,
toxicity
Page
7
of
19
observed
in
the
acute
oral
human
study
is
considered
representative
of
all
exposure
durations.

B.
Animal
1.
Subchronic
neurotoxicity
(
90­
day
rat).
In
a
subchronic
neurotoxicity
study
(
MRID
43829602),
Crl:
CDR(
SD)
BR
rats
were
dosed
via
gavage
with
0
[
water
vehicle],
0.05,
0.20,
or
0.40
mg/
kg/
day
of
aldicarb
(
tech.,
98.9%)
for
at
least
13
weeks.
Twelve
animals/
sex/
group
were
selected
for
functional
observational
battery
(
FOB)
[
pre­
study
and
at
weeks
4,
8,
13
at
approximately
0.5
to
1
hour
post
dose]
and
motor
activity
(
MA)
testing,
and
15
animals/
sex/
group
were
selected
for
serial
acetylcholinesterase
(
ChE)
analyses
[
pre­
study
and
at
weeks
4,
8,
13
at
approximately
0.75
hour
post
dose].
Six
rats/
sex/
dose
were
anesthetized,
perfused,
and
sacrificed
for
histopathology.
CNS
sections
were
embedded
in
paraffin,
while
peripheral
nerves
and
spinal
ganglia
were
embedded
in
plastic.

No
treatment­
related
deaths
occurred.
Body
weight
and
body­
weight
gains
were
decreased
in
the
high­
dose
males,
as
was
food
consumption/
efficiency,
but
these
parameters
were
comparable
among
the
females
groups.
Dose­
related
tremors
and
salivation
were
observed
in
both
sexes
in
the
mid
and
high
dose
group.
Treatment­
related
clinical
signs
of
cholinesterase
inhibition/
neurotoxicity
[
home
cage
and
arena
tremors,
pinpoint
pupils,
decreased
tail
pinch
response,
decreased
hindlimb/
forelimb
grip
strength,
increased
tail
flick
latency
times]
were
observed
in
both
sexes
at
various
time
points
during
the
study,
with
the
severity
increasing
with
dose,
and
there
was
some
evidence
that
females
were
more
sensitive.
Additionally,
motor
activity
was
decreased
in
both
sexes
at
the
midand
high­
dose
levels
throughout
the
study.
Ophthalmoscopic
examination
[
performed
at
study
termination
and
not
at
peak
effect
time],
gross
and
histopathological
evaluations
did
not
show
any
treatment­
related
effects.

There
was
a
dose­
related
inhibition
in
plasma
[
61%­
90%],
whole
blood
[
42%­
87%],
and
RBC
[
24%­
70%]
ChE
in
both
sexes
and
at
all
doses.
Statistical
significance
was
not
attained
for
plasma
ChEI
for
the
low­
dose
rats
of
either
sex.
Whole
brain
ChE
inhibition
was
observed
in
both
sexes
at
the
mid­
and
highdose
levels,
and
in
females
at
the
low
dose,
as
well
as
in
cerebellum
in
low­
dose
females.
The
level
of
whole
brain
ChE
inhibition
at
the
mid­
[
males
26%­
42%;
females
33%­
46%]
and
high­
[
males
58%­
64%;
females
57%­
68%]
dose
appear
to
show
some
increase
across
weeks
4­
13.
Ophthalmoscopic
examination
and
gross
and
histopathological
evaluations
did
not
reveal
significant
aldicarb­
related
changes.
An
increased
incidence
of
slight
axonal
degeneration
in
the
sciatic
nerve,
described
as
affecting
only
individual
nerve
fibers,
were
found
in
3
high
dose
males
vs
one
control
rat,
and
2
high
dose
females
vs
one
control
rat,
but
these
findings
lacked
statistical
significance.
Page
8
of
19
The
LOAEL
is
0.05
mg/
kg/
day,
based
on
the
FOB
findings
(
e.
g.,
pinpoint
pupils)
and
ChE
inhibition
in
blood
and
brain.
The
NOAEL
is
<
0.05
mg/
kg/
day.

In
Summary,
the
available
data
on
the
rat
indicate
a
peak
effect
within
an
hour
of
dosing,
and
the
inhibition
recovers
within
24
hours.
Although
this
study,
in
which
several
time
periods
were
investigated,
shows
an
apparent
increase
in
percent
ChEI
in
some
sections
of
the
brain
at
the
high
dose
levels,
there
was
no
decrease
in
the
NOAEL
or
LOAEL
for
ChEI
with
time.
For
aldicarb
RBC
and/
or
whole
blood
ChE
inhibition
are
the
most
sensitive
endpoints.
In
all
available
studies
RBC
and/
or
whole
blood
ChE
inhibition
do
not
increase
with
repeated
exposures.

2.
Chronic
and
subchronic
(
dog).
In
a
1
year
dog
feeding
study
(
MRID
40695901),
groups
of
5
beagle
dogs/
sex/
dose
were
administered
aldicarb
technical
in
the
diet
daily
for
52
weeks
at
0,
1,
2,
5,
and
10
ppm
(
0,
0.028,
0.056,
0.13,
and
0.25
mg/
kg­
day).
Blood
(
plasma
and
red
blood
cell)
cholinesterase
determinations
were
made
3
times
prior
to
exposure
and
during
weeks
5,
13,
26,
and
52,
two
hours
after
the
2
hour
feeding
period.
Brain
measures
were
made
at
study
termination.

In
the
one­
year
study,
no
effects
were
seen
on
mortality,
body
weight
gain,
food
consumption,
clinical
signs,
clinical
chemistry,
hematology,
urinalysis,
organ
weights,
ophthalmology,
gross
pathology
or
histopathology.
At
the
3
highest
dose
levels,
dogs
showed
significant
dose­
related
inhibition
in
plasma
ChE
activity
in
both
sexes.
At
the
lowest
dose,
there
was
significant
plasma
cholinesterase
inhibition
in
males
(
18­
26%).
Significant
dose
related
decreases
in
RBC
Cholinesterase
were
seen
at
the
2
highest
doses
in
males
and
the
highest
dose
in
females.
Brain
cholinesterase
was
significantly
inhibited
only
at
the
high
dose
in
males
(
22%).
Based
on
plasma
ChEI,
a
NOAEL
for
ChE
inhibition
in
the
study
was
not
established
in
the
one­
year
study
[
LOAEL
of
0.028
mg/
kg/
day].

In
a
subsequent
subchronic
study
(
MRID
41919901),
6
beagle
dogs/
sex/
dose
were
administered
aldicarb
via
the
diet
at
0,
0.35,
0.7,
and
2
ppm
[
0,
0.01,
0.02,
and
0.06
mg/
kg/
day].
Plasma
and
RBC
cholinesterase
determinations
were
made
at
­
3,
­
2,
­
1
weeks
prior
to
dosing
and
at
2
and
5
weeks,
two
hours
after
a
limited
2­
hour
feeding
period.

In
this
subsequent
5­
week
study
in
dogs,
a
NOAEL
for
plasma
and
RBC
cholinesterase
activity
inhibition
was
established
at
0.020
mg/
kg/
day;
LOAEL
is
0.06
mg/
kg.

 
Benchmark
Dose
(
BMD)
Analysis
A
dose­
response
analysis
and
estimation
of
the
BMD10s
were
performed
using
the
whole
blood
ChEI
data
from
the
two
acute
animal
studies
[
guideline
and
Page
9
of
19
Moser],
as
well
as
the
whole
blood
ChEI
data
from
the
guideline
subchronic
neurotoxicity
study.
An
exponential
model
similar
to
that
used
in
the
OP
Cumulative
Risk
Assessment
and
supported
by
the
FIFRA
SAP
was
used.
The
BMD10s
for
whole
blood
ranged
from
0.0031
to
0.012
mg/
kg
in
adult
animals
and
0.0038
to
0.0073
mg/
kg
in
juvenile
animals.
The
BMD10s
for
brain
ranged
from
0.024
to
0.031
mg/
kg
in
adult
animals
and
0.014
to
0.020
mg/
kg
in
juvenile
animals.
Lack
of
dose­
response
data
in
whole
blood
(
all
doses
>
75%
inhibition)
provide
less
confidence
in
the
BMD10s
compared
to
those
calculated
for
brain
ChE
inhibition.
Ratios
of
the
BMD10s
for
brain
ChE
inhibition
between
juvenile
and
adult
animals
suggest
that
juvenile
animals
are
2X
more
sensitive
than
adult
rats.

Endpoint
Selection.

Acute
RfD.
The
risk
assessment
team
concludes
that
the
similarity
of
response
between
humans
and
rats
following
acute
oral
exposure
allows
for
the
use
of
both
sets
of
data
in
considering
toxicity
endpoint
selection
and
uncertainty
factors
(
grey
column
in
Table
3).
Table
2
provides
ChE
inhibition
observed
in
rats
and
humans
at
a
dose
level
common
to
several
studies,
0.05
mg/
kg.
As
shown
in
Table
2,
there
is
remarkable
similarity
between
the
human
study
and
rat
studies
(
subchronic
and
acute),
which
used
a
modified
Ellman
technique
(
subchronic
rat,
acute
rat,
acute
human).
The
Moser
study,
which
considered
both
adult
and
juvenile
animals,
measured
ChE
inhibition
using
a
preferred
methodology,
the
radiometric
method.
It
is
also
important
to
note
that
the
Moser
study
used
corn
oil
as
the
gavage
vehicle,
which
may
promote
more
absorption
compared
to
water
used
as
the
gavage
vehicle
in
the
subchronic
and
acute
rat
studies
performed
by
the
pesticide
registrant.

Table
2.
Comparison
of
%
ChEI
at
0.05
mg/
kg
compartment/
sex/
stu
dy
subchronic
rat
[
week
4]
rat
acute
human
acute
rat
acute
[
Moser]

males
RBC
32%
­
29%
not
measured
plasma
61%
44%
55%
not
measured
whole
blood
42%
­
N/
A
84%

females
RBC
24%
­
36%
not
measured
plasma
65%
36%
68%
not
measured
whole
blood
47%
23%
N/
A
81%

The
risk
assessment
team
considered
the
rat
subchronic
neurotoxicity
study
and
the
non­
guideline
acute
neurotoxicity
study
(
Moser)
to
be
co­
critical
for
Page
10
of
19
assessment
of
the
acute
exposure
scenarios.
Due
to
the
fact
that
reversibility
of
ChEI
occurs
within
24
hours
following
aldicarb
exposure,
the
use
of
this
subchronic
neurotoxicity
study
in
rats
for
endpoint
selection
is
considered
appropriate
(
repeated
dosing
is
considered
a
series
of
acute
exposures).
The
cholinesterase
inhibition
in
the
acute
human
study
and
rat
subchronic
study
were
comparable
at
the
0.05
mg/
kg
dose
level.
As
noted
above
for
the
human
study,
there
are
uncertainties
regarding
the
lack
of
female
subjects
at
the
lowest
dose
(
0.01
mg/
kg),
larger
standard
errors
of
the
means
for
female
ChEI,
and
no
measurement
at
the
estimated
time
of
peak
effect
(<
1
hour).
Mean
female
ChE
inhibition
was
greater
at
the
0.025
and
0.05
mg/
kg
levels
1
hour
post­
dosing
compared
to
male
subjects.
Although
no
rat
studies
have
established
a
NOAEL
for
brain,
RBC
and/
or
whole
blood
ChE
inhibition,
the
database
of
rat
studies
includes
studies
where
animals
of
both
sexes
were
tested
at
each
dose
level,
studies
comparing
adult
and
juvenile
animals,
measurement
of
clinical
signs
at
<
1
hour,
and
evaluation
using
both
Ellman
and
radiometric
methods.
Thus,
the
rat
database
provides
a
solid
basis
for
developing
the
point
of
departure
for
aldicarb.
The
similarity
in
response
between
humans
and
rats
at
0.05
mg/
kg
(
Table
2),
however,
allows
for
the
reduction
of
the
interspecies
factor
[
Table
3,
Column
4]
from
10X
to
3X.
A
factor
of
3X
was
retained
for
extrapolation
from
rats
to
humans
because
of
the
limitations
of
the
human
study.
These
limitations
include:

!
Use
of
the
Ellman
method
for
human
ChEI
measurements
rather
than
the
more
sensitive
radiometric
method
which
was
used
in
the
co­
critical
Moser
study;

!
Human
females
were
not
dosed
at
the
lowest
dose
level,
and
females
may
be
slightly
more
sensitive
than
males
(
either
in
time
of
peak
effect,
time
of
recovery,
or
magnitude
of
inhibition);
therefore,
an
adequate
comparison
of
human
and
rat
females
could
not
be
made;

An
additional
10X
uncertainty
factor
is
needed
to
account
for
extrapolating
from
a
LOAEL
to
NOAEL.
It
is
notable
that
greater
than
75%
whole
blood
ChEI
was
observed
in
both
age
groups
at
the
LOAEL.
The
10X
LOAEL
to
NOAEL
factor
is
supported
by
the
estimated
whole
blood
rat
BMD10s
[
0.003­
0.012].
In
addition,
female
human
subjects
at
the
lowest
dose
(
0.025
mg/
kg)
had
20%
RBC
inhibition.
Given
these
uncertainties,
an
additional
10X
is
appropriate
to
extrapolate
from
a
LOAEL
of
0.05
mg/
kg
to
NOAEL
of
0.005
mg/
kg.
Therefore,
a
total
uncertainty
factor
of
300
(
10X
for
intraspecies
variations,
3X
for
interspecies
differences,
and
10X
LOAEL
to
NOAEL)
is
appropriate.

FQPA
Safety
Factor
Considerations
For
the
recommended
endpoints
selected
from
animal
studies,
a
Special
Hazard
Based
FQPA
safety
factor
is
not
needed.
As
shown
by
the
BMD
analysis,
juvenile
animals
are
approximately
2X
more
sensitive
than
adult
rats.
Using
the
recommended
approach,
this
sensitivity
is
accounted
for
in
the
point
of
departure
of
0.005
mg/
kg/
day
as
the
BMDs
for
the
young
were
estimated
to
be
0.0038­
Page
11
of
19
0.0073mg/
kg/
day
for
whole
blood
ChE
inhibition.
The
extrapolated
NOAEL
of
0.005
mg/
kg/
day
incorporates
this
potential
sensitivity
since
the
point
of
departure
risks
are
not
likely
to
be
under­
estimated
based
on
the
NOAEL
=
0.005
mg/
kg/
day.
The
database
for
aldicarb
is
complete,
including
both
rat
[
MRID
41004501]
and
rabbit
[
MRID
00132668]
developmental
toxicity
studies,
a
rat
2­
generation
reproduction
study
[
MRID
42148401],
acute
and
subchronic
rat
neurotoxicity
studies,
a
rat
developmental
neurotoxicity
study
[
MRID43829601],
as
well
as
a
special
acute
neurotoxicity
study
(
Moser).
Therefore,
an
FQPA
database
UF
is
also
not
required.
There
is
no
evidence
of
increased
sensitivity
in
any
of
the
guideline
studies.

Alternatively,
if
the
endpoint
from
the
human
study
were
to
be
selected
for
risk
assessment
there
are
no
juvenile
data
from
the
human
study
to
address
the
FQPA
safety
factor.
However,
the
acute
neurotoxicity
study
(
Moser)
in
rats
indicates
the
magnitude
of
the
brain
ChEI
in
the
PND
17
pups
was
only
2X
greater
than
that
of
the
adult
rat.
There
is
currently
no
information
to
suggest
that
the
difference
in
rat
brain
ChEI
would
be
different
than
human
brain
ChEI.
Therefore,
the
acute
neurotoxicity
study
supports
a
FQPA
safety
factor
of
2X
[
see
Table
3;
column
2].

NOTE:
There
are
no
residential
uses
of
aldicarb.

Short
and
intermediate
term
residential
&
occupational
exposure.

Based
on
the
fact
that
reversibility
of
effects
within
24
hours
is
seen
in
both
the
human
and
animal
studies
and
on
the
fact
that
dosing
in
the
subchronic
neurotoxicity
study
in
rats
and
special
acute
neurotoxicity
study
are
considered
a
series
of
acute
exposures,
the
same
co­
critical
studies
are
considered
appropriate
for
endpoint
selection.

Chronic
RfD
and
long
term
residential
&
occupational
exposure.

The
risk
assessment
team
recommends
the
use
of
the
same
co­
critical
studies
for
establishing
a
chronic
RfD
and
to
assess
long­
term
occupational
or
residential
risk.
However,
the
team
has
determined
that
a
chronic
risk
assessment
is
not
needed,
since
risks
resulting
from
aldicarb
exposure
are
better
described
as
a
series
of
acute
risks.

Furthermore,
any
chronic
risks
would
necessarily
be
lower
than
those
estimated
for
acute
exposure
since
long­
term
average
exposure
levels
rather
than
daily
high­
end
exposure
estimates
would
be
used
to
calculate
chronic
risks.

Short,
intermediate
and
long­
term
inhalation
exposure.
same
as
above
Page
12
of
19
Table
3.
Comparison
of
Endpoint
Selection
Possibilities
Parameter
Human
study1
Rat
study2
Rat
(
human)
3
(
recommended)
Human
BMDL10
4
LOAEL
0.01
mg/
kg
0.05
mg/
kg
0.05
mg/
kg
0.013
mg/
kg
UF
LOAEL­
to­
NOAEL
3X
10X
10X
1X
NOAEL
0.0033
mg/
kg
0.005
mg/
kg
0.005
mg/
kg
0.013
mg/
kg
UF
(
intraspecies)
10X
10X
10X
10X
UF
(
interspecies)
1X
10X
3X
1X
FQPA
SF
2X
1X
1X
2X
acute
RfD
0.00033
mg/
kg
0.00005
mg/
kg
0.00017
mg/
kg
0.0013
mg/
kg
acute
PAD
0.00017
mg/
kg
0.00005
mg/
kg
0.00017
mg/
kg
0.00065
mg/
kg
chronic
RfD
0.00033
mg/
kg/
day
0.00005
mg/
kg/
day
0.00017
mg/
kg/
day
0.0013
mg/
kg/
day
chronic
PAD
0.00017
mg/
kg/
day
0.00005
mg/
kg/
day
0.00017
mg/
kg/
day
0.00065
mg/
kg/
day
endpoint
RBC/
plasma
ChEI
whole
blood/
brain
ChEI
whole
blood/
brain
ChEI
RBC
ChEI
1Human
study
=
Endpoints
and
Points
of
Departure
using
human
study
2Rat
Study
=
Endpoints
and
Points
of
Departure
using
animal
studies
without
consideration
of
human
study
3Rat
(
human)
=
Endpoints
and
Points
of
Departure
using
animal
data
for
endpoint
selection,
comparing
animal
data
to
human
data
to
reduce
interspecies
safety
factor,
both
considered
as
part
of
weight­
ofevidence
determination
4Human
BMDL=
Endpoint
and
Point
of
Departure
using
RBC
ChEI
human
data
for
the
BMD
analysis
 
Part
B
of
Weight
of
Evidence:
Integration
of
Aldicarb
into
the
Preliminary
N­
Methyl
Carbamate
(
NMC)
Cumulative
Risk
Assessment
1.
Background:

The
Food
Quality
Protection
Act
(
FQPA)
was
passed
by
Congress
in
1996.
The
FQPA
made
key
changes
to
the
approaches
used
by
EPA
to
assess
pesticide
chemicals.
One
of
these
changes
was
the
requirement
to
consider
cumulative
risk
to
those
pesticides
which
act
by
a
common
mechanism
of
toxicity.
Pesticides
are
determined
to
have
a
"
common
mechanism
of
toxicity"
if
they
act
the
same
way
in
the
body­­
that
is,
the
same
toxic
effect
occurs
in
the
same
organ
or
tissue
by
essentially
the
same
sequence
of
major
biochemical
events.
OPP
established
the
N­
methyl
carbamate
pesticides
(
NMCs)
as
a
common
mechanism
group
and
in
accordance
with
FQPA
has
developed
a
preliminary
cumulative
risk
assessment
for
this
group
of
pesticides
(
USEPA,
2005).
Aldicarb
is
a
member
of
the
NMC
common
mechanism
group.

OPP
has
developed
a
guidance
document
for
developing
cumulative
risk
assessments
under
FQPA
(
USEPA,
2002).
This
guidance
indicates
that
when
developing
a
multi­
chemical
hazard
assessment,
comparison
of
toxic
potency
Page
13
of
19
should
be
made
using
a
uniform
basis
of
comparison,
by
using
to
the
extent
possible
a
common
response
derived
from
a
comparable
measurement
methodology,
species,
and
sex
for
all
the
exposure
routes
of
interest.
In
the
preliminary
cumulative
risk
assessment,
the
Agency
considered
RBC
and
brain
ChE
inhibition
as
potential
endpoints.
Plasma
cholinesterase
data
were
not
considered
since
the
primary
enzyme
in
plasma
is
butylcholinesterase
and
not
acetylcholinesterase.
Ultimately,
brain
ChE
data
from
acute
rat
toxicity
studies
measured
at
or
near
the
time
of
peak
effect
have
been
used
by
EPA
to
estimate
a
relative
potency
factor
(
RPF)
and
to
develop
the
points
of
departure
(
PoD)
for
extrapolating
cumulative
risk.
For
instance,
the
brain
BMD10
has
been
used
to
calculate
the
RPF
while
the
brain
BMDL10
establishes
the
PoD
in
the
preliminary
cumulative
risk
assessment.
Brain
data
have
been
selected
over
RBC
data
as
brain
ChE
inhibition
represents
a
direct
measure
of
the
target
tissue
(
as
opposed
to
blood
data
which
is
considered
a
surrogate
measure)
and
brain
ChE
inhibition
data
tend
to
have
less
variation
and
thus
confer
less
uncertainty
on
cumulative
risk
estimates.

Because
data
from
rat
studies
provide
the
basis
for
potency
determination,
the
Agency
must
consider
interspecies
extrapolation
(
i.
e.,
animal
to
human)
in
its
cumulative
risk
assessment.
As
such,
human
data
may
be
used
by
the
Agency
to
inform
the
pesticide­
specific
interspecies
extrapolation.
In
the
specific
case
of
aldicarb,
MRID
42373001
is
available.

2.
Aldicarb
Human
Study
Summary:

The
aldicarb
human
study
involved
both
male
and
female
volunteers,
with
males
only
at
the
lowest
dose
(
0.01
mg/
kg)
and
highest
dose
(
0.075
mg/
kg).
Blood
samples
were
taken
for
ChE
activity
every
hour,
beginning
at
1
hour
post­
dosing
until
6
hours
and
then
at
24
hours.
The
multiple
sampling
over
time
provides
the
progression
of
enzyme
inhibition
along
with
enzyme
reactivation.
Peak
ChE
inhibition,
however,
likely
occurred
prior
to
the
first
sampling
event
at
1
hour.

The
human
toxicity
study
for
aldicarb
does
not
provide
brain
ChE
data,
for
obvious
reasons,
but
does
provide
ChE
data
for
both
males
and
females.
The
blood
ChE
activity
(
plasma
and
RBC)
provided
in
the
human
study
is
considered
appropriate
surrogate
measures
of
potential
effects
on
peripheral
nervous
system
(
PNS)
acetylcholinesterase
(
AChE)
activity,
and
of
potential
effects
on
the
central
nervous
system
(
CNS)
when
brain
ChE
data
are
lacking
(
USEPA
2000).
AChE
is
the
target
enzyme
for
the
cumulative
risk
assessment
and
is
the
primary
form
of
ChE
found
in
RBCs.
Butylcholinesterase
(
BChE),
on
the
other
hand,
is
the
primary
for
of
ChE
found
in
plasma.
BChE
is
considered
a
measure
of
exposure
but
has
not
been
shown
to
be
of
toxicological
significance.
RBC
ChE
data,
therefore,
is
being
utilized
by
the
Agency
to
inform
the
pesticidespecific
interspecies
extrapolation.
Page
14
of
19
The
measured
RBC
ChE
activity
from
the
human
study
is
adequate
for
estimation
of
BMD
and
BMDL
estimates.
The
RBC
ChE
data
from
the
aldicarb
human
study
was
utilized
in
the
model
in
the
same
manner
as
the
acute
rat
data
(
brain
and
RBC)
that
are
available
for
the
NMCs
of
the
cumulative
hazard
assessment
(
USEPA
2005).
The
BMD10
and
BMDL10
estimates
for
both
rat
(
RBC,
brain)
and
human
(
RBC)
are
included
in
Table
4
below.
It
should
be
noted
that
the
samples
collected
at
the
hour
time
point
only
provide
a
brief
look
at
ChE
inhibition
at
that
specific
moment
in
time.
Uncertainties
still
exist
regarding
the
timing
and
magnitude
of
peak
ChE
inhibition
in
the
male
versus
the
female
prior
to
1
hour.

Based
on
the
FIFRA
SAP
(
2005)
approval
of
statistical
analyses
for
the
BMD
model,
the
single
RBC
BMD
estimate
for
aldicarb
indicates
similar
ChE
activity
in
males
and
females
(
0.02
mg/
kg,
M
and
F).
Although
the
mean
values
for
the
RBC
ChE
in
females
of
the
study
were
greater
than
males
at
the
two
mid
doses,
the
BMD
analysis
of
the
standard
error
of
the
means
indicate
no
differences
between
sexes.

ChE
inhibition
from
the
two
compartments
also
appears
to
be
similar
(
brain
and
RBC).
For
example,
rat
BMD10
for
rat
brain
(
0.05
mg/
kg
F,
0.06
mg/
kg
M)
is
similar
to
the
BMD10
for
rat
RBC
(
0.03
mg/
kg,
M
and
F).
As
such,
the
estimate
from
the
aldicarb
human
study
provides
useful
information
into
the
sensitivity
of
RBC
ChE
inhibition
of
rats
compared
to
humans.

Table
4.
Oral
BMD10s
and
BMDL10s
Generated
from
Rat
ChE
(
RBC,
brain)
and
Human
ChE
(
RBC)
Data
for
Aldicarb.

Rat
Human
Brain
RBC
RBC
Chemical
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
Aldicarb
F=
0.05
M=
0.06
F=
0.03
M=
0.03
0.03
0.02
0.02
0.01
BMD
estimates
are
presented
as
a
single
estimate
when
there
are
no
differences
between
sexes.
Human
RBC
data
obtained
from
MRID
42373001
Rat
brain
and
RBC
data
obtained
from
MRIDs
43442302,
43442305,
43829601,
43829602,
45068601.

3.
Discussion
Several
studies
for
aldicarb
are
available
that
provide
quality
dose­
response
and
ChE
inhibition
data
from
both
the
rat
and
human.
For
purposes
of
the
cumulative
risk
assessment,
the
difficulty
lies
in
extrapolating
information
across
compartments
(
blood­
brain).
The
preliminary
NMC
cumulative
risk
assessment
relies
on
rat
brain
ChE
data
for
the
relative
potency
factors
(
RPFs)
and
points
of
departure
(
PoDs).
The
FIFRA
SAP
supported
the
Agency's
use
of
brain
ChE
data
in
August
2005
(
FIFRA
SAP
2005).
Page
15
of
19
By
outlining
the
available
data
for
aldicarb
it
is
apparent
that
a
couple
of
approaches
are
available
for
application
of
the
interspecies
extrapolation
factor
for
the
preliminary
cumulative
risk
assessment.
Table
5
below
highlights
for
aldicarb
the
potential
approach,
BMD10
ratio,
interspecies
factor
and
confidence
level,
and
the
pros,
cons,
or
uncertainties
surrounding
these
options
for
interspecies
calculation.
The
first
approach
is
the
use
of
the
Agency's
default
10X
factor
for
extrapolation
of
animal
to
human.
The
second
approach
is
the
ratio
of
RBC
BMD10
rat
(
both
sexes)
to
RBC
BMD10
human
(
both
sexes).
The
estimated
factor
and
confidence
interval
are
based
on
the
modeling
of
both
rat
and
human
RBC
data.
The
uncertainties
surrounding
both
of
these
approaches
are
highlighted
in
the
table
below.
It
should
also
be
noted
that
an
additional
approach
is
the
ratio
of
rat
brain
BMD10
to
human
RBC
BMD10.
This
option
would
compare
brain
data
relied
on
in
the
cumulative
risk
assessment
with
available
RBC
data
from
the
human
studies.
This
ratio
does
not
compare
ChE
data
from
the
same
compartment
and,
therefore,
is
less
appropriate
for
interspecies
extrapolation
for
aldicarb.

At
the
present
time,
the
BMD
analysis
for
aldicarb
indicates
females
and
males
are
similar
in
sensitivity
to
ChE
inhibition
at
low
doses,
which
is
the
appropriate
measurement
for
the
cumulative
risk
assessment.
Other
evidence
to
consider
is
the
mean
and
variance
of
ChE
inhibition
of
females
and
males
from
the
human
study.
Based
strictly
on
mean
percent
ChE
inhibition
at
the
1
hour
time
point,
females
had
greater
ChE
inhibition
than
males.
The
variance
of
the
ChE
mean,
however,
was
also
greater
in
females
than
in
males.
Additionally,
the
timecourse
data
indicate
the
time
of
peak
effect
is
likely
less
than
1
hour.
There
was
no
measurement
prior
to
the
one
hour
time
point
in
the
study
for
the
elucidation
of
time
of
peak
effect
in
either
males
or
females.
Recovery
ChE
data
also
indicate
males
(
1­
6
hours)
are
slower
to
recover
than
females
(
1­
4
hours).
As
for
rat
data,
there
are
conflicting
ChE
inhibition
data.
One
acute
neurotoxicity
study
(
Moser)
indicated
no
sex
differences
in
ChE
inhibition
in
juvenile
rats.
However,
another
acute
neurotoxicity
study
(
MRID
43442301)
indicated
greater
ChE
inhibition
of
adult
females
than
adult
males,
but
only
at
the
higher
dose
levels.

As
for
compartment
differences,
given
the
similarity
between
brain
and
RBC
ChE
in
rats,
the
Agency
is
not
aware
of
any
biological
or
physiological
reason
that
human
brain
ChE
would
be
more
sensitive
than
the
rat
brain.
The
Agency,
therefore,
proposes
to
use
the
RBC
BMD10
ratios
of
rats
and
human
for
a
resulting
interspecies
extrapolation
factor
2X
for
aldicarb
(
CI
1.1­
3.6).
This
interspecies
extrapolation
factor
would
be
in
addition
to
the
other
uncertainty
factors
for
the
cumulative
risk
assessment
that
includes
intraspecies
variability
(
human
variability)
and
FQPA.
The
acute
neurotoxicity
study
(
Moser)
will
likely
be
considered
for
defining
the
FQPA
safety
factor.
Page
16
of
19
Table
5.
Comparison
of
the
Alternative
Choices
and
the
Resulting
Uncertainties
Surrounding
the
Refinement
of
the
Interspecies
Extrapolation
Factor
for
Aldicarb
in
the
NMC
Cumulative
Risk
Assessment
Option
of
Refinement
for
Interspecies
Factor
Resulting
Interspecies
Factor
Ratio
Confidence
Interval
Pros
Cons
or
Uncertainties
1.
Default
Factor
for
Risk
Assessment
10X
NA
1.
Standard
uncertainty
factor
for
interspecies
extrapolation.
2.
Accounts
for
uncertainty
regarding
lack
of
female
data
at
low
dose.
3.
Accounts
for
uncertainty
regarding
lack
of
ChE
brain
data
in
humans.
1.
Ratio
of
RBC
BMDs
indicate
2X.

2.
Ratio
of
RBC
BMD10
rat
vs.
human
RBC
BMD10
2X1
1.1
to
3.6
1.
BMD10
ratio
is
based
on
the
same
compartment
(
RBC)
in
rat
(
both
sexes)
and
human
(
male
only
at
low
dose).
2.
Inhibition
of
RBC
ChE
in
rats
is
similar
between
sexes.
1.
Uncertainty
remains
for
lack
of
brain
ChE
inhibition
in
humans.
2.
Uncertainty
remains
for
lack
of
female
data
at
low
dose.

1The
resulting
2X
interspecies
factor
based
on
the
innovative
BMD
approach
is
concordant
with
the
3X
interspecies
factor
of
the
single
chemical
assessment,
which
was
based
on
the
traditional
HED
approach
of
establishing
an
interspecies
factor.

FIFRA
SAP
(
2005).
Meeting
Minutes
of
the
FIFRA
Scientific
Advisory
Panel
Held
August
23­
26,
2005.
SAP
Minutes
No.
2005­
04.
Preliminary
N­
Methyl
Carbamate
Cumulative
Risk
Assessment.
October
13,
2005.

USEPA
(
2000).
"
The
Use
of
Data
on
Cholinesterase
Inhibition
for
Risk
Assessments
of
Organophosphorous
and
Carbamate
Pesticides";
August
18,
2000.
Available:
http://
www.
epa.
gov/
pesticides/
trac/
science/
cholin.
pdf
USEPA
(
2002).
"
Guidance
on
Cumulative
Risk
Assessment
of
Pesticide
Chemicals
That
Have
a
Common
Mechanism
of
Toxicity."
January
14,
2002.
(
67
FR
2210;
January
16,
2002)
http://
www.
epa.
gov/
oppfead1/
trac/
science/#
common
USEPA
(
2005).
Preliminary
N­
Methyl
Carbamate
Cumulative
Risk
Assessment.
Office
of
Pesticide
Programs,
U.
S.
Environmental
Protection
Agency.
Washington,
DC.
http://
www.
epa.
gov/
scipoly/
sap/
index.
htm#
sept
Page
17
of
19
APPENDIX
I
Aldicarb
Toxicology
Endpoint
Selection.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF1
Hazard­
Based
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
DIETARY
EXPOSURES
Acute
Dietary:
General
US
Population
[
MRID
No.
43829602,
45068601,
&
42373001]
LOAEL=
0.05
mg/
kg/
day
UF=
300
Acute
RfD=
0.00017
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.00017
mg/
kg/
day
Rat
subchronic/
acute
neurotoxicity
study
LOAEL=
0.05
mg/
kg/
day,
based
on
whole
blood
and
brain
ChEI
and
FOB
findings
(
pinpoint
pupils)
Human
study
[
reduction
of
interspecies
factor
to
3x]

Chronic
Dietary:
General
US
Population
[
MRID
No.
43829602,
45068601,
42373001]
LOAEL=
0.05
mg/
kg/
day
UF=
300
Chronic
RfD=
0.00017
mg/
kg/
day
FQPA
SF=
1X
cPAD=
chronic
RfD
FQPA
SF
=
0.00017
mg/
kg/
day
Rat
subchronic/
acute
neurotoxicity
study
LOAEL=
0.05
mg/
kg/
day,
based
on
whole
blood
and
brain
ChEI
and
FOB
findings
(
pinpoint
pupils)

Human
study
[
reduction
of
interspecies
factor
to
3x]

Dermal
Exposures2
Short­
Term
(
1­
30
days);

Intermediate­
Term
(
30
days
to
several
months)
[
MRID
No.
43829602,
45068601,
42373001]
Oral
study
LOAEL=
0.05
mg/
kg/
day
Absorption
Factor=
100%
LOC
for
MOE=
3001
Rat
subchronic/
acute
neurotoxicity
study
LOAEL=
0.05
mg/
kg/
day,
based
on
whole
blood
and
brain
ChEI
and
FOB
findings
(
pinpoint
pupils)

Human
study
[
reduction
of
interspecies
factor
to
3x]

Inhalation
Exposures2
Any
Duration
[
MRID
No.
43829602,
45068601,
42373001]
Oral
study
LOAEL=
0.05
mg/
kg/
day
Absorption
Factor=
100%
LOC
for
MOE=
3001
Rat
subchronic/
acute
neurotoxicity
study
LOAEL=
0.05
mg/
kg/
day,
based
on
whole
blood
and
brain
ChEI
and
FOB
findings
(
pinpoint
pupils)
Human
study
[
reduction
of
interspecies
factor
to
3x]

1
The
combined
UF
of
300
includes
3X
for
interspecies
extrapolation,
10X
is
for
intraspecies
variability,
and
a
database
UF
of
10X
for
extrapolation
from
the
LOAEL
to
the
NOAEL.

2
Appropriate
route­
to­
route
extrapolation
should
be
performed
for
these
risk
assessments.
For
both
dermal
and
inhalation
risks,
a
100%
absorption
factor
should
be
used
to
convert
relevant
exposure
estimates
to
equivalent
oral
doses
and
compared
to
the
oral
LOAEL.
Page
18
of
19
APPENDIX
II
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
Results
870.3150
90­
Day
oral
toxicity
in
non­
rodents
(
dogs)
2
hours
post
dose
41919901
(
1991)
Acceptable
NOAEL
=
0.02
mg/
kg/
day
LOAEL
=
0.06
mg/
kg/
day
based
on
plasma,
RBC
Cholinesterase
Inhibition
in
male
and
female
dogs
870.3700a
Prenatal
developmental
in
rodents
(
rats)
41004501
(
1988)
Acceptable
Maternal
NOAEL
=
0.125
mg/
kg/
day
LOAEL
=
0.25
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption.
Developmental
NOAEL
=
0.125
mg/
kg/
day
LOAEL
=
0.25
mg/
kg/
day
based
on
ecchymosis
of
the
trunk.

870.3700b
Prenatal
developmental
in
non­
rodents
(
rabbits)
00132668
(
1983)
Acceptable
Maternal
NOAEL
=
0.1
mg/
kg/
day
LOAEL
=
0.25
mg/
kg/
day
based
on
decreased
body
weight,
pale
kidneys,
hydroceles
on
the
oviducts.
Developmental
NOAEL
=
>
0.5
mg/
kg/
day
870.3800
Reproduction
and
fertility
effects
at
termination
42148401
(
1991)
Acceptable
Parental/
Systemic
NOAEL
=
0.4
mg/
kg/
day
LOAEL
=
0.7­
0.9
mg/
kg/
day
based
on
decreased
body
weight
gains
and
RBC
ChEI
(&);
plasma
ChEI
(%).
Reproductive
NOAEL
=
0.7­
0.9
mg/
kg/
day
LOAEL
=
1.4­
1.7
mg/
kg/
day
based
on
decreased
viability
and
body
weights,
and
signs
of
debilitation.

870.4100a
Chronic
toxicity
rodents
am
sample
43045401
(
1993)
Acceptable
NOAEL
=
0.047
mg/
kg/
day
LOAEL
=
0.47
mg/
kg/
day
based
on
plasma,
RBC,
cholinesterase
inhibition
(%).

870.4100b
Chronic
toxicity
dogs
beagle
2
hours
after
feeding
40695901,
42191501
(
1988)
Acceptable
NOAEL
<
0.028
mg/
kg/
day
LOAEL
=
0.028
mg/
kg/
day
based
on
plasma
ChEI.

870.6200a
Acute
neurotoxicity
screening
battery
Sprague­
Dawley
Crl:
CD(
SD)
BR
rat
peak
effect
time
0.75
hour
43442301
(
1994)
Acceptable
NOAEL
=
0.05
mg/
kg/
day
LOAEL
=
0.1
mg/
kg/
day
based
on
behavioral
changes;
plasma
ChEI.
at
0.05
mg/
kg
870.6200b
Subchronic
neurotoxicity
screening
battery
Sprague­
Dawley
Crl:
CD(
SD)
BR
rat
peak
effect
time
0.75
hour
43829602
(
1995)
Acceptable
NOAEL
<
0.05
mg/
kg/
day
LOAEL
=
0.05
mg/
kg/
day
based
on
pinpoint
pupils
and
blood
and
brain
ChEI.
Page
19
of
19
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
Results
870.6300
Developmental
neurotoxicity
Sprague­
Dawley
Crl:
CD(
SD)
BR
rat
ChE
activity
monitored
2
hours
post
dose
43829601
(
1995)
Acceptable
Maternal
NOAEL
=
0.05
mg/
kg/
day
LOAEL
=
0.1
mg/
kg/
day
based
on
plasma
ChEI.
Offspring
NOAEL
=
0.05
mg/
kg/
day
LOAEL
=
0.1
mg/
kg/
day
based
on
reduced
body
weights
and
decreased
motor
activity.

Acute
neurotoxicity
Special
studies
Moser
VC
Long­
Evans
rat
peak
effect
time
1
hour
45068601
(
1999)
TAP
157
94­
106
Acceptable
NOAEL
<
0.05
mg/
kg.
PND
17
day
pups
2x
as
sensitive
as
adults
in
brain
ChEI.
LOAEL
=
0.05
mg/
kg
pups
blood
(%,&),
brain
ChEI
(%)

Acute
oral
­
human
ChE
activity
monitored
at
1,
2,
3,
4,
5,
6,
24
hours
post
dose
42373001
(
1992)
Acceptable
NOAEL
for
males
0.01
mg/
kg,
based
on
RBC
and
plasma
ChEI
and
sweating
at
LOAEL
of
0.025
mg/
kg
NOAEL
not
determined
in
females;
LOAEL
=
0.025
mg/
kg,
based
on
RBC
and
plasma
ChEI