UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
TXR
No.
0053055
MEMORANDUM
DATE:
June
23,
2005
SUBJECT:
Weight
of
Evidence
Comparison
of
Human
and
Animal
Toxicology
Studies
and
Endpoints
for
DDVP
DP
Barcode:
312212
Reregistration
Case#:
0310
PC
Code:
084001
MRID
No.:
several
TO:
Ray
Kent,
Ph.
D.,
Chief
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

FROM:
William
Dykstra,
Ph.
D.,
Toxicologist
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

THRU:
Susan
Hummel,
Branch
Senior
Scientist.
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

Dichlorvos
is
an
organophosphate
insecticide
that
is
toxic
to
mammals,
including
humans,
through
inhibition
of
the
acetylcholinesterase(
s)
of
the
peripheral
and/
or
central
nervous
system.
The
technical
registrant
for
dichlorvos
has
submitted
a
number
of
toxicity
studies
involving
direct
dosing
of
humans
to
support
their
contention
that
humans
are
no
more
or
less
sensitive
to
the
effects
of
dichlorvos
than
rats,
dogs
or
other
experimental
animals.
OPP
management
has
requested
that,
whenever
human
studies
support
a
risk
assessment,
HED
compare
the
strengths
and
weaknesses
of
the
human
and
animal
toxicity
studies
and
present
how
the
human
studies
"
fit
in"
with
the
animal
studies,
i.
e.,
are
the
human
data
consistent
with
animal
data
in
terms
of
types
of
effects
and
effect
levels
or
are
there
notable
differences
between
animals
and
humans.
Page
2
of
16
P
O
O
H
3
CO
OCH
3
Cl
Cl
This
document
focuses
on
three
human
studies
in
which
humans
were
intentionally
dosed
with
dichlorvos;
a
single
dose
oral
study
(
MRID
44248802),
a
repeated
dose
oral
study
(
MRID
44248801)
and
a
chronic
inhalation
study
(
MRIDs
45812001,
00060486).
The
human
data
are
compared
with
animal
data
from
similar
studies,
and
recommendations
for
endpoint
selection
are
made
based
on
the
most
appropriate
studies
and
uncertainty
factors.
All
of
the
studies
are
discussed
in
summary
form
and
then
the
weight
of
evidence
discussion
of
endpoint
selection
follows.

Chemical
and
Hazard
Characterization
of
Dichlorvos
Dichlorvos
is
a
phosphate
triester
with
a
molecular
formula
of
C
4
H
7
O
4
PCl
2
and
a
molecular
weight
of
221.
It
is
a
liquid
at
room
temperature
with
a
relatively
high
vapor
pressure
of
0.032
mm
(
30
C).

The
high
vapor
pressure
of
dichlorvos
is
the
basis
for
its
use
as
a
fumigant
for
processed
food
commodities,
food
warehouses
and
food­
handling
establishments.
Because
of
its
volatility,
dichlorvos
is
also
incorporated
into
resin
strips
for
use
at
many
sites
including
family
homes.

Like
most
other
cholinesterase­
inhibiting
phosphotriesters,
dichlorvos
is
asymmetrical
with
respect
to
the
ester
substituents,
with
two
relatively
difficult
to
hydrolyze
methyl
groups
and
a
dichlorovinyl­
"
leaving
group"
which
is
more
readily
hydrolyzed
and
is
the
group
displaced
when
dichlorvos
reacts
at
the
active
site
of
cholinesterases.
Many
sulfur­
containing
organophosphate
cholinesterase
inhibitors
require
metabolic
activation
to
convert
an
unsubstituted
phosphoroussulfur
(
P=
S)
group
to
an
phosphorus­
oxygen
oxon
(
P=
O)
group
before
inhibition
of
cholinesterase
can
occur;
however,
dichlorvos
already
exists
in
the
oxon
form
and
needs
no
activation
to
inhibit
cholinesterases.

Dichlorvos
is
well
absorbed
by
all
routes
of
exposure
and
extensively
metabolized
with
excretion
of
metabolic
products
occurring
mostly
in
the
urine
and
through
exhalation
as
CO
2
.
Absorbed
dichlorvos
is
initially
inactivated
by
an
esterase
found
in
plasma
and
liver.
The
esterase
catalyzes
the
hydrolysis
of
dichlorvos
to
dimethyl
phosphate
and
dichlorovinyl
alcohol
which
spontaneously
rearranges
to
2,2,­
dichloroacetaldehyde
which
is
then
metabolized
further.
Dichlorvos
may
also
be
inactivated
by
a
glutathione­
dependent
reaction
to
form
desmethyl
dichlorvos.
The
half­
life
of
dichlorvos
in
the
blood
is
very
short,
15
minutes
or
less.

Dichlorvos
inhibits
plasma,
erythrocyte,
and
brain
cholinesterase
in
a
variety
of
species,
but
does
not
cause
organophosphate­
induced
delayed
neurotoxicity
(
OPIDN)
in
the
hen
(
MRID
43433501).
In
acute
and
90­
day
neurotoxicity
studies
in
rats
(
MRIDs
42497901,
41004101,
there
was
no
neuropathology
associated
with
changes
in
FOB
and
motor
activity.
Subchronic
and
chronic
oral
exposures
in
rats
and
dogs
(
MRIDs
41004701,
41593101)
as
well
as
chronic
Page
3
of
16
inhalation
exposure
in
rats
MRIDs
00057695,
00532569)
resulted
in
significant
decreases
in
plasma,
red
blood
cell
and/
or
brain
cholinesterase
activity.
Animal
toxicity
studies
do
not
show
evidence
of
gender
susceptibility.
Repeated,
oral
subchronic
exposures
in
male
humans
was
associated
with
statistically
and
biologically
significant
decreases
in
red
blood
cell
cholinesterase
activity
(
MRID
44248801).
Inhalation
exposure
in
humans
over
several
months
was
associated
with
a
marginally
increased
incidence
of
headaches
and
red
blood
cell
cholinesterase
depression
greater
than
20%
at
the
highest
exposure
conditions
in
the
study
which
was
during
the
winter
when
indoor
exposure
was
highest.
Both
headaches
and
RBC
cholinesterase
depression
occurred
in
children
as
well
as
adults
in
this
study
(
MRIDs
45812001,
00060486).

There
was
no
evidence
of
increased
susceptibility
following
in
utero
exposure
to
rats
and
rabbits
as
well
as
pre/
post
natal
exposure
to
rats
in
developmental
and
reproduction
studies
(
MRIDs
41802401,
41951501,
42483901).
However,
increased
sensitivity
to
dichlorvos­
induced
inhibition
of
brain
cholinesterase
activity
was
observed
in
repeated
gavage
studies
in
preweaning
rats
in
comparison
to
young
adult
rats
(
MRID
46153304).
These
findings
necessitated
that
a
special
Food
Quality
Protection
Act
(
FQPA)
3x
safety
factor
be
retained
for
assessment
of
risks
(
other
than
risks
from
acute
exposure)
where
the
endpoint
is
based
on
RBC
cholinesterase
inhibition
as
a
result
of
repeated
exposure.
A
factor
of
3x
is
considered
appropriate
since
the
differences
in
brain
cholinesterase
inhibition
were
minimal.
The
factor
of
3x
is
not
needed
for
assessing
acute
risks,
since
there
was
no
increased
sensitivity
in
brain
cholinesterase
activity
in
preweaning
rats
in
comparison
to
young
adults
following
a
single
gavage
dose
of
dichlorvos.

Specific
Toxicity
Studies
Single
Dose
Oral
Studies:

A.
Human
In
a
single
dose
human
study
with
DDVP
(
MRID
44248802),
the
NOAEL
for
RBC
cholinesterase
depression
is
1.0
mg/
kg
bw
based
on
the
absence
of
statistically
significant
ChE
depression
in
6
fasted
young
healthy
male
volunteers
administered
a
70
mg
oral
dose
of
DDVP.
In
this
study,
the
first
cholinesterase
measurement
was
recorded
24
hours
after
dosing.
In
another
study
(
MRID
46153303)
on
the
measurement
of
RBC
and
brain
ChE
activity
in
pre­
weaning
and
adult
female
rats
treated
with
a
single
dose
of
15
mg/
kg
dichlorvos,
time­
course
data
demonstrate
that
the
time
of
peak
effect
for
both
RBC
and
brain
ChE
measurements
is
1­
3
hours
post­
dosing
and
that
by
24
hours
post­
dosing,
RBC
cholinesterase
activity
has
recovered
to
levels
similar
to
the
controls
(
MRID
46153303).
Therefore,
the
absence
of
biologically
significant
RBC
ChE
depression
in
the
human
study
may
be
due
to
the
absence
of
blood
sampling
at
the
time
of
peak
effect
(
1­
3
hours),
since
in
the
human
study,
the
first
measurement
did
not
occur
until
24
hours
after
dosing.
Page
4
of
16
B.
Animals
Single
dose
comparative
cholinesterase
studies
in
preweaning
and
adult
rats
which
measured
both
RBC
and
brain
ChE
depression
at
1
hour
following
oral
exposure
were
analyzed
by
a
Benchmark
Dose
(
BMD)
procedure
(
MRIDs
45805703,
45842301).
The
BMDS
(
Benchmark
Dose
Software
version
1.3.2)
model
was
used
to
derive
the
BMD
10
,
the
estimated
dose
that
results
in
10%
inhibition
of
cholinesterase,
and
the
BMDL,
the
lower
95%
confidence
interval
on
the
BMD
10
,
for
the
cholinesterase
data
evaluated.
For
this
analysis,
the
continuous
polynomial
model
was
used
with
the
default
option
of
relative
deviation
for
the
benchmark
response
(
BMR)
type.
A
BMR
factor
of
0.1
was
the
basis
for
BMD
and
BMDL
derivation.

A
BMDL
of
0.8
mg/
kg
based
on
female
brain
ChE
depression
was
selected
as
the
lowest
value
of
all
the
studies
available
which
were
analyzed.
BMD
analysis
of
studies
with
pup
and
adult
ChE
depression
results
did
not
demonstrate
any
substantial
age­
related
numerical
differences
in
BMDL
values
(
all
values
were
approximately
1
mg/
kg)
for
either
RBC
or
brain
cholinesterase.

Repeated
Dose
Oral
Studies
A.
Human
In
a
single
blind
oral
study
(
MRID
44248801),
6
fasted
male
volunteers
were
administered
7
mg
of
DDVP
in
corn
oil
(
equivalent
to
approximately
0.1
mg/
kg/
d)
via
capsule
daily
for
21
days.
Three
control
subjects
received
corn
oil
as
a
placebo.
Baseline
values
for
RBC
cholinesterase
activity
for
each
study
participant
were
determined.
After
dosing
started,
RBC
cholinesterase
activity
was
monitored
on
days
2,
4,
7,
9,
11,
14,
16,
and
18,
then
on
day
25
or
28
post
dosing.
No
toxicity
attributable
to
administration
of
DDVP
was
reported.
Mean
RBC
cholinesterase
activity
was
statistically
significantly
reduced
in
treated
subjects
on
days
7,
11,
14,
16,
and
18.
These
values
were
8,
10,
14,
14,
and
16
percent
below
the
pre­
dose
mean.
Although
the
percent
mean
depression
was
less
than
20%,
the
blood
samples
were
not
taken
until
just
before
the
next
day's
dose,
at
the
point
of
maximum
recovery.
Under
the
conditions
of
the
study,
a
LOAEL
for
RBC
cholinesterase
inhibition
was
established
at
0.1
mg/
kg/
d
based
on
the
consistent,
statistically
significant
ChE
depression
over
time,
although
ChE
depression
during
the
study
was
less
than
20%.
A
NOAEL
was
not
established.

The
repeated
dose
human
study
has
been
criticized
for
a
number
of
reasons
including:

1)
Too
few
subjects.
There
were
six
treated
adult
males
and
three
adult
males
served
as
placebo
controls.
All
of
the
treated
males
responded
to
some
extent
to
repeated
dosing
of
dichlorvos
with
a
mean
response
of
16%.
If
there
had
been
no
response,
then
the
argument
that
there
were
insufficient
subjects
might
have
more
merit,
however,
the
Agency
has
determined
that
the
administered
dose
is
a
LOAEL.

2)
Use
of
males
only.
All
subjects
were
adult
males.
Animal
toxicity
studies
do
not
show
evidence
of
gender
susceptibility.
Page
5
of
16
3)
Administration
of
only
a
single
dose
level.
A
single
dose
level
of
7
mg
per
person
per
day
was
administered
for
21
days.
This
dose
resulted
in
sufficient
RBC
cholinesterase
inhibition
that
we
consider
the
response
to
be
a
LOAEL.
If
there
had
been
no
response,
interpretation
of
the
results
would
have
been
problematic.

4)
Blood
sampling
did
not
occur
until
24
hours
after
dosing.
This
is
considered
a
critical
deficiency
for
the
single
dose
study;
however,
after
21­
days
there
is
a
clear
response
which
the
Agency
considers
a
LOAEL.
If
blood
had
been
sampled
at
1­
3
hours
after
dosing,
RBC
cholinesterase
inhibition
may
have
been
somewhat
greater.

B.
Animal
Comparative
cholinesterase
(
7­
day
rat).
In
a
comparative
cholinesterase
inhibition
study
(
MRID
46153304),
dichlorvos
was
administered
by
gavage
in
seven
daily
doses
of
0,
0.1,
7.5,
or
15
mg/
kg/
day
to
groups
of
5
rats/
sex
beginning
on
either
PND
12
(
pre­
weaning
rats)
or
42
(
young
adults)
and
animals
were
sacrificed
one
hour
after
the
last
dose.
RBC
and
brain
ChE
activities
were
measured
in
all
animals
in
each
study.
In
pre­
weaning
rats,
tremors
were
observed
in
5/
5
males
and
5/
5
females
at
15
mg/
kg/
day
on
3­
5
days
of
the
dosing
interval.
In
young
adult
rats
at
15
mg/
kg/
day,
tremors
were
observed
in
3/
5
males
and
5/
5
females
on
one
to
four
days
of
the
dosing
interval.
In
addition,
tremors
were
seen
in
one
adult
male
after
the
last
dose
of
7.5
mg/
kg/
day.
No
clinical
signs
of
toxicity
were
observed
in
the
remaining
groups.
Dose­
related
inhibition
of
RBC
and
brain
ChE
activities
was
apparent
after
repeated
dosing
in
both
adult
and
pre­
weaning
rats.
Biologically
significant
inhibition
of
RBC
enzyme
activity
(>
50%)
occurred
at
doses
of
7.5
and
15
mg/
kg/
day
in
both
sexes
of
adults
and
pre­
weaning
and
at
the
low
dose
for
adult
animals
(
11­
17%).
Brain
enzyme
activity
was
statistically
and
biologically
inhibited
in
both
sexes
at
doses
of
7.5
and
15
mg/
kg/
day
for
adults
(>
50%)
and
at
all
doses
for
pups
(>
20%).
The
LOAEL
for
inhibition
of
RBC
cholinesterase
was
0.1
mg/
kg/
day
and
a
NOAEL
was
not
identified
based
on
findings
in
young
adults.
The
LOAEL
for
inhibition
of
brain
cholinesterase
was
0.1
mg/
kg/
day
and
a
NOAEL
was
not
identified
based
on
findings
in
pre­
weaning
pups.

Subchronic
neurotoxicity
(
90­
day
rat).
In
a
subchronic
oral
neurotoxicity
study
(
MRID
42958101),
dichlorvos
was
administered
in
deionized
water
to
15
Sprague­
Dawley
rats/
sex/
group
at
gavage
doses
of
0,
0.1,
7.5,
or
15.0
mg/
kg/
day
for
90
days.
Within
each
dose
group,
10
rats/
sex
were
allocated
for
brain
cholinesterase
determination
and
5
rats/
sex
were
allocated
for
neuropathology
evaluation.
Additionally,
blood
samples
were
collected
for
cholinesterase
measurements
prestudy
and
on
study
weeks
3,
7,
and
13
.
Five
rats/
sex/
dose
from
the
cholinesterase
group
and
5/
sex/
dose
from
the
neuropathology
group
were
evaluated
with
the
Functional
Observational
Battery
(
FOB)
and
motor
activity
tests
pretest
and
on
study
weeks
3,
7,
and
12.
Body
weight
and
food
consumption
were
measured
weekly.

There
was
no
treatment­
related
mortality.
Mean
body
weight
in
high­
dose
females
was
consistently
lower
than
the
control
(
11­
21%)
throughout
the
study.
No
body
weight
effects
were
observed
in
any
other
animals,
and
there
was
no
treatment­
related
effect
on
food
consumption.
Tremors,
salivation,
exophthalmos,
lacrimation,
and
clear
material
on
the
forelimbs
were
observed
Page
6
of
16
in
high­
dose
males
and
females
approximately
15
minutes
post­
dosing.
Rales,
chromodacryorrhea,
and
red/
yellow/
orange
material
around
the
nose
and
mouth
were
also
seen
in
high­
dose
rats.
Tremors
were
observed
in
three
mid­
dose
males
and
nine
mid­
dose
females.
Generally,
the
clinical
signs
occurred
during
the
third
week
of
treatment
in
the
mid­
dose
animals
and
as
early
as
the
first
week
of
dosing
and
throughout
the
study
in
the
high­
dose
rats.
Cholinesterase
activity
was
decreased
in
mid­
and
high­
dose
male
and
female
rats
as
follows:
plasma
30­
58%;
erythrocyte
8­
35%;
brainstem
and
brain
cortex
10­
16%.
There
were
no
treatment­
related
effects
in
the
FOB
or
motor
activity
tests.
No
treatment­
related
neurohistopathological
lesions
and
no
apparent
changes
in
brain
weight
or
size
were
observed.
Based
on
decreased
cholinesterase
activity
and
clinical
cholinergic
signs,
the
LOAEL
for
dichlorvos
is
7.50
mg/
kg
and
the
NOAEL
is
0.1
mg/
kg.

Chronic
(
One­
year
dog).
In
a
chronic
feeding
study
(
MRID
41593101),
groups
of
4/
sex/
dose
beagle
dogs
were
administered
dichlorvos
by
capsule
for
52
weeks
at
dose
levels
of
0,
0.1,
1.0
and
3.0
mg/
kg/
day.
The
0.1
mg/
kg/
day
dose
was
lowered
to
0.05
mg/
kg/
day
on
day
22
due
to
the
inhibition
of
plasma
cholinesterase
noted
after
12
days
(
plasma
cholinesterase
was
decreased
in
males
(
21.1%)
and
females
(
25.7%)
at
week
2
in
the
0.1
mg/
kg/
day
group).
At
time
points
after
week
2,
plasma
cholinesterase
activity
was
only
significantly
reduced
in
males
(
39.1
to
59.2%)
and
females
(
41.0
to
56.7%)
in
the
mid­
dose
group
and
in
males
(
65.1
to
74.3%)
and
females
(
61.1
to
74.2%)
in
the
high
dose
group.
Although
RBC
cholinesterase
activity
was
reduced
in
males
(
23.6%)
and
females
(
50.1%)
at
week
6
in
the
low­
dose
group,
this
was
believed
to
be
residual
effect
on
RBC
cholinesterase
of
the
higher
dose
of
0.1
mg/
kg/
day.
RBC
cholinesterase
inhibition
was
not
observed
in
this
group
after
week
6.
At
time
points
after
week
6,
RBC
cholinesterase
activity
was
only
significantly
decreased
in
males
(
43.0
to
53.9)
and
females
(
38.0
to
51.9)
in
the
mid­
dose
group
and
in
males
(
81.2
to
86.9%)
and
females
(
79.2
to
82.5%)
in
the
high­
dose
groups.
Brain
cholinesterase
activity
was
significantly
reduced
in
males
(
22%)
in
the
mid­
dose
group
and
in
males
(
47%)
and
females
(
29%)
in
the
high
dose
group.
The
NOAEL
was
0.05
mg/
kg/
day
and
the
LOAEL
was
0.1
mg/
kg/
day
based
on
plasma
and
RBC
cholinesterase
inhibition
in
males
and
females.

Other
animal
studies.
There
are
several
other
animal
studies
by
the
oral
route
in
which
RBC
and
plasma
cholinesterase
were
measured:
1)
90­
day
rat
subchronic
in
rats
(
MRID
41004701),
LOAEL
=
1.5
mg/
kg/
day
based
on
plasma
and
RBC
cholinesterase
inhibition,
NOAEL
=
0.1
mg/
kg/
day;
2)
Range­
finding
study
for
the
rabbit
developmental
study
(
MRID
41802401),
LOAEL
=
1
mg/
kg/
day
based
on
RBC
cholinesterase
inhibition,
NOAEL
=
0.1
mg/
kg/
day.
Repeated
dose
(
28­
day)
delayed
neurotoxicity
study
in
hens
(
MRID
43433501),
LOAEL
=
0.3
mg/
kg/
day
based
on
inhibition
of
brain
cholinesterase,
NOAEL
=
0.1
mg/
kg/
day.

Long­
Term
Inhalation
Exposure
Studies
A.
Humans
In
a
chronic
inhalation
toxicity
(
Arizona
II)
study
(
MRIDs
45812001,
00060486),
dichlorvos
technical­
DDVP­
20%
insecticide
resin
strips
were
studied
in
a
residential
setting
in
Tuscon,
Page
7
of
16
Arizona.
There
were
64
human
subjects,
29
adults
and
35
children,
selected
as
participants
in
the
study
which
represented
15
families
divided
by
lot
into
4
groups
as
shown
in
the
Table
below.

Group
Number
Subjects
Treatment
I
4
Families
(
J,
K,
L,
Q)
7
adults,
7
children
(
ages
2­
19)
20%
DDVP
by
weight
in
10
inch
Vapona
insecticide
strips
II
4
Families
(
A,
B,
H,
P)
8
adults,
15
children
(
ages
4­
17)
20%
DDVP
resin
strips
enclosed
in
a
sealed
plastic
wrapper
permeable
to
DDVP
III
4
Families
(
C,
D,
E,
F)
7
adults,
10
children
(
ages
5­
14)
20%
DDVP
resin
strips
of
reduced
dimensions
containing
the
same
amount
of
DDVP
as
other
groups
IV
3
Families
(
G,
M,
N)
7
adults,
3
children
(
ages
9­
17)
Non­
active
resin
strip
having
the
same
dimensions
and
weight
as
10
inch
strips
in
Group
I
Strips
were
placed
in
the
homes
at
the
rate
of
one
strip
per
1000
cu
feet
(
label
directions)
with
replacement
monthly
for
all
strips
for
a
total
duration
of
6
months.
The
number
of
strips
used
ranged
from
4
to
18
per
home.
Atmospheric
concentrations
of
DDVP
were
measured
throughout
the
study.
All
participants
received
thorough
medical
evaluations
including
plasma
and
RBC
ChE
determinations,
clinical
chemistry
evaluations,
and
physician
evaluations.
All
complaints
and
symptoms
were
also
recorded.

The
human
study
was
not
originally
designed
as
a
toxicity
study,
although
plasma
and
RBC
cholinesterase
measurements
were
included
in
the
protocol.
It
appears
that
the
cholinesterase
measurements
were
included
as
a
precaution
or
perhaps
to
demonstrate
that
a
labeled
use
rate
(
although
high
end
labeled
rate)
did
not
result
in
cholinesterase
depression.
The
reanalysis
of
the
study
was
commissioned
by
the
technical
registrant
almost
35
years
after
the
study
took
place.

From
air
concentration
data
in
the
published
study
[
Leary,
J.
S.
et
al.,
Arch.
Environ.
Health,
Volume
29,
Dec.
1974]
and
additional
Shell
archive
records
on
biochemical
and
clinical
findings,
a
re­
analysis
of
the
study
comparing
DDVP
exposure
to
reported
clinical
findings
was
undertaken.
The
original
Leary
et
al.,
analysis
failed
to
identify
any
treatment­
related
clinical
signs
or
ChE
toxicity
in
any
of
the
DDVP
treated
groups.
In
the
re­
analysis,
the
DDVP
exposed
families
were
grouped
on
the
basis
of
measured
air
concentrations
of
DDVP
over
the
6­
month
exposure
period.
The
new
re­
analysis
grouping
of
the
families
consisted
of
Group
A
(
families
A,
B,
P
exposed
to
Group
Average
(
Oct­
Jan):
0.113
µ
g/
l),
Group
B
(
families
K,
L
exposed
to
Group
Average
(
Oct­
Jan):
0.145
µ
g/
l)
and
Group
C
(
families
C,
D,
E,
F,
H,
J,
Q
exposed
to
Group
Average
(
Oct­
Jan):
0.180
µ
g/
l).
Assessment
of
the
study
by
EPA
reviewers
of
the
raw
data
present
in
the
original
1968
EPA
submission
(
MRID
00060486)
substantiates
the
values
present
in
the
Exponent
(
MRID
45812001)
re­
analysis.
Since
Group
B
had
2
families
which
included
7
subjects
(
4
adults
and
3
children)
and
there
are
no
significant
differences
in
air
concentrations
between
Groups
A
and
B,
Page
8
of
16
EPA
reviewers
combined
the
Groups
A
and
B.
The
average
air
concentrations
during
October
to
January
were
0.125
µ
g/
L.

Review
of
the
self­
reported
clinical
symptoms
in
Appendix
C
of
the
re­
analysis
and
Appendix
4
in
the
1968
submission
reveal
that
5
subjects
(
D20,
E22,
E23,
E24,
and
E25)
had
one
or
more
days
with
headaches.
These
same
subjects
were
all
grouped
together
in
the
re­
analysis
under
Group
C
(
0.180
µ
g/
L
which
is
the
highest
DDVP
exposure
concentration).
Further
examination
of
the
data
indicate
that
the
headaches
occurred
during
August,
September
and
October.
There
were
no
biologically
significant
decreases
(>
20%)
in
RBC
Cholinesterase
during
the
3
month
period
when
the
headaches
occurred
(
D20
=
123%,
E22
=
100%,
95%,
E23
=
95%,
99%,
E24
=
106%,
and
E25
=
98%).
Four
of
the
5
subjects
with
headaches
(
family
E)
were
in
the
same
family
and
were
exposed
to
12
pesticide
strips/
house,
whereas
child
D20
was
exposed
to
10
strips/
home.
An
equivocal
relationship
may
exist
between
the
presence
of
self­
reported
headaches
and
the
highdose
exposure
in
Group
C,
although
this
possible
relationship
was
not
substantiated
by
the
RBC
cholinesterase
activity.
The
remaining
reported
symptoms
in
the
study
were
randomly
distributed.

Because
of
significant
individual
variability
in
plasma
ChE,
these
data
were
not
considered
appropriate
to
measure
ChE
inhibition
in
the
exposed
individuals
in
the
study.
The
RBC
cholinesterase
activity
(%
of
baseline)
for
participants
in
Exposure
Group
C
in
the
month
of
January
showed
that
nine
subjects
out
of
30
measured
(
30%)
had
depressions
of
>
20%.

The
NOAEL
of
0.125
µ
g/
L
[
Group
A
and
B]
for
the
study
is
based
on
the
headaches
and
RBC
depression
at
the
LOAEL
of
0.180
µ
g/
L
[
Group
C].

Although
children
and
adults
are
represented
in
the
group
with
RBC
cholinesterase
depression
and
headaches,
more
children
than
adults
are
represented
in
both
groups
with
adverse
effects.
The
following
table
illustrates
this
point.

Children
with
Headaches
ChE
Depression
D20
(
12
years)
M
D19
(
10
years)
F
E24
(
8
years)
M
D20
(
12
years)
M
E25
(
7
years)
F
E24
(
8
years)
M
E25
(
7
years)
F
E26
(
5
years)
M
H38
(
8
years)
M
Adults
with
Page
9
of
16
Headaches
ChE
Depression
E22
(
M)
C15
(
F)
E23
(
F)
D18
(
M)
E22
(
M)

There
are
some
limitations
of
the
study.
Clinical
signs
were
based
on
self­
reporting
of
symptoms
and
the
subjects
were
members
of
the
contractor
staff
conducting
the
study
(
or
their
families)
so
there
might
have
been
incentive
to
under
report
symptoms.
Nevertheless
the
study
indicates
that
there
was
RBC
cholinesterase
inhibition
and
signs
consistent
with
cholinergic­
mediated
neurotoxicity
at
the
highest
concentrations
in
the
study.

B.
Animals
Groups
of
50/
sex/
dose
Carworth
rats
(
MRIDs
00057695,
00632569)
were
exposed
to
atmospheres
containing
dichlorvos
vapors
for
23
hours/
day,
7
days/
week
at
concentrations
of
0,
0.05,
0.5
and
5
mg/
m3
equivalent
to
0.055,
0.5,
and
5.0
mg/
kg/
day
for
two
years.
Animals
were
observed
for
clinical
signs
of
toxicity,
hematology,
clinical
chemistry,
and
plasma
and
RBC
cholinesterase
activity.
Brain
cholinesterase
was
measured
at
study
termination.

There
were
no
toxic
signs,
organ
weight
changes,
or
hematological
changes
attributable
to
DDVP.
Body
weights
were
significantly
decreased
in
mid
and
high
dose
males
up
to
study
termination,
and
in
high
dose
females
throughout
the
study.
Plasma,
RBC,
and
brain
cholinesterase
activity
were
significantly
reduced
in
the
mid
and
high
dose
groups
(
76,
72,
and
90
and
83,
68,
and
90
percent
of
control
in
mid
dose
males
and
females,
and
to
38,
4,
and
21,
and
22,
5,
and
16
percent
of
control
in
the
high
dose
male
and
female
groups,
respectively).
RBC
cholinesterase
activity
was
reduced
to
88
percent
of
control
in
the
low
dose
females
but
this
was
not
considered
to
be
sufficient
to
regard
the
low
dose
as
a
LOAEL.
The
NOAEL
for
cholinesterase
inhibition
was
0.05
mg/
m3
(
0.055
mg/
kg/
day)
and
the
LOAEL
was
0.5
mg/
m3
(
0.5
mg/
kg/
day).
This
is
the
same
inhalation
study
which
has
been
used
by
the
Agency
RfD/
RfC
Work
Group
in
deriving
an
RfC
for
DDVP.
Page
10
of
16
Endpoint
Selection.

Acute
RfD.
In
the
past,
the
acute
dosing
study
in
humans
was
considered
suitable
for
use
in
establishing
an
acute
RfD,
but
recently
received
time­
course
data
in
rats
indicate
that
peak
inhibition
of
RBC
cholinesterase
occurs
1­
3
hours
after
oral
dosing
and
that
by
24­
hours
postdosing
cholinesterase
activity
returns
to
near
control
levels.
The
risk
assessment
team
concludes
that
the
lack
of
cholinesterase
measurements
prior
to
24
hours
post­
treatment
in
the
acute
human
study
is
a
deficiency
so
critical
that
it
has
opted
not
to
rely
on
the
acute
human
study
for
either
establishing
an
acute
RfD
or
to
decrease
the
interspecies
uncertainty
factor.

The
rat
acute
BMDL,
0.8
mg/
kg,
was
selected
for
assessment
of
acute
exposure
scenarios.
An
uncertainty
factor
of
100
(
10x
for
interspecies
differences
and
10x
for
intraspecies
variation)
was
applied.
It
was
concluded
that
an
additional
special
FQPA
factor
is
not
needed,
since
BMD
analysis
of
studies
with
pup
and
adult
ChE
depression
results
for
either
RBC
or
brain
cholinesterase
inhibition
did
not
demonstrate
any
substantial
numerical
differences
in
the
acute
BMDL
values
for
either
RBC
or
brain
cholinesterase
inhibition
(
all
values
were
approximately
1
mg/
kg).
Based
on
this
assessment,
an
acute
RfD
of
0.008
mg/
kg/
day
for
the
general
population
was
derived
for
DDVP.

Short
and
intermediate
term
residential
&
occupational
exposure.
There
are
a
number
of
repeated
dose
studies
that
are
under
consideration,
either
individually
or
collectively,
for
providing
appropriate
endpoints
for
risk
assessment
for
short­
and
intermediate­
term
durations.
­
The
21­
day
repeated
dose
study
in
humans
with
a
LOAEL
for
RBC
cholinesterase
inhibition
of
0.1
mg/
kg/
day
is
of
an
adequate
duration
for
selection
of
endpoints.
­
In
the
7­
day
repeated
dose
comparative
cholinesterase
study
in
rats,
the
LOAEL
for
adult
rats
for
RBC
cholinesterase
inhibition
was
0.1
mg/
kg/
day,
whereas
in
pre­
weaning
rats,
0.1
mg/
kg
was
a
NOAEL
for
RBC
cholinesterase
inhibition.
­
In
the
7­
day
repeated
dose
comparative
cholinesterase
study
in
rats,
the
NOAEL
for
inhibition
of
brain
cholinesterase
inhibition
in
adult
rats
was
0.1
mg/
kg/
day,
whereas
0.1
mg/
kg/
day
was
a
LOAEL
in
preweaning
rats.
­
The
NOAEL
in
a
90­
day
rat
subchronic
neurotoxicity
study
was
0.1
mg/
kg/
day
and
the
LOAEL
was
7.5
mg/
kg/
day
based
on
clinical
signs
of
neurotoxicity
and
inhibition
of
plasma,
RBC
and
brain
cholinesterase.
­
In
a
chronic
feeding
study
in
dogs,
the
LOAEL
for
plasma
and
RBC
cholinesterase
inhibition
was
0.1
mg/
kg/
day
and
the
NOAEL
was
0.05
mg/
kg/
day
measured
at
3
and
6
weeks.
The
NOAEL
for
brain
cholinesterase
inhibition
measured
at
the
end
of
the
study
was
0.05
mg/
kg/
day.

The
findings
in
the
repeated
dose
studies
are
consistent
across
species
and
over
study
durations
ranging
from
seven
days
to
one
year,
with
the
LOAEL
or
NOAEL
fluctuating
around
0.1
mg/
kg/
day
for
RBC
or
brain
cholinesterase
inhibition.
The
HED
dichlorvos
risk
assessment
team
is
of
the
opinion
that
the
endpoint
of
RBC
cholinesterase
inhibition
in
the
human
repeated
dose
study
is
well
supported
by
several
animal
studies
and
should
serve
as
the
basis
for
comparison
in
assessing
short­
and
intermediate­
term
risks.
A
MOE
of
100
is
recommended
to
account
for
intraspecies
variability
(
10x),
the
lack
of
NOAEL
in
this
study
(
3x)
and
a
Special
FQPA
factor
of
Page
11
of
16
3x.
The
Special
FQPA
factor
is
based
on
residual
concern
for
the
sensitivity
shown
by
young
rats
to
brain
cholinesterase
inhibition
in
the
repeated
dose
comparative
cholinesterase
study
(
MRID
46153304).
A
Special
Factor
of
3x
is
considered
sufficient
since
the
percent
inhibition
(
25%)
in
brain
cholinesterase
in
preweaning
rats
at
0.1
mg/
kg/
day
is
not
substantial.
The
factor
should
be
applied
in
any
situation
where
the
endpoint
is
based
on
RBC
cholinesterase
inhibition.
A
factor
of
3x
rather
than
10x
was
used
to
account
for
a
lack
of
a
NOAEL
since
the
RBC
cholinesterase
inhibition
in
humans
during
the
exposure
period
of
21
days
was
minimal.

Chronic
RfD
and
long
term
residential
&
occupational.
The
same
rationale
described
under
short­
and
intermediate­
term
scenarios
could
be
used
for
long­
term
scenarios
since
study
duration
didn't
seem
to
make
any
difference
in
the
NOAELs
and
LOAELs;
however,
the
risk
assessment
team
concluded
that
it
would
be
difficult
to
justify
using
a
21­
day
human
study
for
chronic
or
long­
term
scenarios.
The
risk
assessment
team
recommends
continuing
to
use
the
one­
year
dog
study
for
establishing
a
chronic
oral
RfD
and
to
assess
long­
term
occupational
or
residential
risk.

For
the
chronic
dog
study
with
a
NOAEL
of
0.05
mg/
kg/
day,
an
uncertainty
factor
of
300x
was
selected
(
10x
for
interspecies
variation,
10x
for
intraspecies
extrapolation,
and
3x
for
a
Special
FQPA
factor
as
described
above.
The
risk
assessment
team
considered
reducing
the
interspecies
factor
to
3x
based
on
the
similarity
of
the
human
data
to
the
dog
data,
but
chose
to
continue
with
the
standard
10x
value
based
again
on
the
difficulty
in
justifying
use
of
a
21­
day
study
(
with
a
LOAEL)
to
decrease
the
interspecies
factor
for
a
chronic
study.
Based
on
this
information,
a
chronic
oral
RfD
of
0.00017
mg/
kg/
day
was
established
for
DDVP
based
on
the
dog
study.

Short,
intermediate
and
long­
term
inhalation
scenarios.
The
dichlorvos
risk
assessment
team
considered
two
studies,
one
a
chronic
(
two­
year)
rat
inhalation
study
(
MRIDs
00057695,
00632569)
and
the
other
a
study
of
human
families
exposed
to
dichlorvos
vapors
in
the
home.
­
The
NOAEL
from
the
rat
chronic
inhalation
study
was
0.05
mg/
m3
and
the
LOAEL
was
0.5
mg/
m3
based
on
inhibition
of
RBC
and
brain
cholinesterase.
Because
the
rats
were
exposed
23
hours
per
day,
seven
days
a
week
for
two
years,
the
human
equivalent
(
continuous)
concentration
is
also
0.05
mg/
m3.
­
The
NOAEL
calculated
for
the
human
study
was
0.125
mg/
m3
based
on
clinical
signs
(
headaches)
and
RBC
depression
at
the
LOAEL
of
0.180
mg/
m3.
The
subjects
were
estimated
to
spend
about
59%
of
their
time
in
the
house
during
the
study
so
the
NOAEL
adjusted
to
a
24
hour
continuous
equivalent
is
0.074
mg/
m3.

The
NOAELs
from
the
two
studies
are
in
good
agreement.
The
adjusted
NOAEL
from
the
human
study
lies
between
the
NOAEL
and
the
LOAEL
from
the
rat
study.
Accordingly,
the
HED
dichlorvos
risk
assessment
team
recommends
that
the
human
study
be
used
for
assessment
of
risks
from
inhalation
of
vapors
for
all
durations
of
exposure.
A
MOE
of
30
(
10x
for
intraspecies
variations
and
a
special
FQPA
factor
of
3)
is
sufficient.
The
special
FQPA
factor
of
3
is
required,
since
the
possible
differences
in
brain
ChE
displayed
between
pup
and
adult
rats
exposed
to
seven
oral
doses
is
not
addressed
in
the
human
inhalation
study.
A
chronic
RfC
for
DDVP
based
on
the
human
study
is
0.0025
mg/
m3.
Page
12
of
16
Table
I.
Guideline
Toxicology
Studies
for
Dichlorvos
in
Experimental
Animals
and
Humans
Study
Type/
Guideline
No.
MRID
No.
Results
Acute
Oral
Cholinesterase
Inhibition
Study
(
1st)
in
Adult
Rats/
870.1100
(
modified)
45805701
Acceptable
ChEI
NOAEL
(
RBC
and
Brain)
=
not
established
ChEI
LOAEL
(
RBC
and
Brain)
=
2.1
mg/
kg
Acute
Oral
Cholinesterase
Inhibition
Study
(
2nd)
in
Adult
Rats/
870.1100
(
modified)
45805702
Acceptable
ChEI
NOAEL
(
RBC
and
Brain)
=
1
mg/
kg
ChEI
LOAEL
(
RBC
and
Brain)
=
not
established
Acute
Oral
Cholinesterase
Inhibition
Study
(
3rd)
in
Adult
Rats/
870.1100
(
modified)
45805703
Acceptable
ChEI
NOAEL
(
RBC
and
Brain)
=
1
mg/
kg
ChEI
LOAEL
(
RBC
and
Brain)
=
5
mg/
kg
RBC
ChE
(
F/
M)
BMD
10
=
1.4/
1.7
mg/
kg;
RBC
ChE
(
F/
M)
BMDL
10
=
1.2/
1.3
mg/
kg;
Brain
ChE
(
F/
M)
BMD
10
=
1.3/
1.6
mg/
kg
Brain
ChE
(
F/
M)
BMDL
10
=
0.8/
1.0
mg/
kg
Acute
Oral
Cholinesterase
Inhibition
Study
in
Preweaning
Rat
Pups/
870.1100
(
modified)
45842301
Acceptable
ChEI
NOAEL
(
RBC)
=
not
established
ChEI
LOAEL
(
RBC)
=
1
mg/
kg
ChEI
NOAEL
(
Brain)
=
1
mg/
kg
ChEI
LOAEL
(
Brain)
=
5
mg/
kg
PND8
RBC
ChE
(
F/
M)
BMD
10
=
1.5/
1.8
mg/
kg;
PND8
RBC
ChE
(
F/
M)
BMDL
10
=
1.0/
1.3
mg/
kg;
PND8
Brain
ChE
(
F/
M)
BMD
10
=
2.2/
1.8
mg/
kg
PND8
Brain
ChE
(
F/
M)
BMDL
10
=
1.6./
1.5
mg/
kg
PND15
RBC
ChE
(
F/
M)
BMD
10
=
1.3/
1.5
mg/
kg;
PND15
RBC
ChE
(
F/
M)
BMDL
10
=
1.1/
1.2
mg/
kg;
PND15
Brain
ChE
(
F/
M)
BMD
10
=
1.4/
1.6
mg/
kg
PND15
Brain
ChE
(
F/
M)
BMDL
10
=
1.0./
1.3
mg/
kg
Study
Type/
Guideline
No.
MRID
No.
Results
Page
13
of
16
Single
Dose
Cholinesterase
Inhibition
Study­
Humans
(
Non­
Guideline)
44248802
Un­
Acceptable
NOAEL
=
1.0
mg/
kg/
day
LOAEL
=
not
established
70
mg/
person,
single
oral
(
capsule)
dose
to
6
male
volunteers
with
no
placebos
­
missed
time
of
peak
effect
Time
Course
of
Cholinesterase
Inhibition
in
Preweaning
and
Adult
Rats/
870.8223
(
Non­
Guideline)
46153303
Acceptable
Brain
and
RBC
enzyme
activities
were
maximally
inhibited
one
hour
after
single
dosing
in
both
adult
and
preweaning
female
rats.
Thereafter,
ChE
inhibition
in
both
compartments
decreased
to
approximately
control
levels
by
8
hours
post
dosing.

7­
Day,
Repeat
Dose
Cholinesterase
Inhibition
Study
in
Preweaning
and
Adult
Rats/(
Non­
Guideline)
46153304
Acceptable
PND
18
(
M/
F)
ChEI
NOAEL
(
Brain)
=
not
established
PND
18
(
M/
F)
ChEI
LOAEL
(
Brain)
=
0.1
mg/
kg/
d
PND
48
(
M/
F)
ChEI
NOAEL
(
Brain)
=
0.1
mg/
kg/
d
PND
48
(
M/
F)
ChEI
LOAEL
(
Brain)
=
7.5
mg/
kg/
d
PND
18
(
M/
F)
ChEI
NOAEL
(
RBC)
=
0.1
mg/
kg/
d
PND
18
(
M/
F)
ChEI
LOAEL
(
RBC)
=
7.5
mg/
kg/
d
PND
48
(
M/
F)
ChEI
NOAEL
(
RBC)
=
not
established
PND
48
(
M/
F)
ChEI
LOAEL
(
RBC)
=
0.1
mg/
kg/
d
21­
Day
Oral
(
capsule)
Cholinesterase
Inhibition
Study­
Humans
(
Non­
Guideline)
44248801
Acceptable
NOAEL
=
not
established
LOAEL
=
0.1
mg/
kg/
day
(
RBC
ChE)
7
mg/
day
for
21
Days
in
6
male
volunteers
plus
3
male
volunteers
as
placebos
Single
Dose
and
Repeated
Dose
Cholinesterase
Inhibition
Studies­
Humans
(
Non­
Guideline)
44317901
Acceptable
Phase
I
(
Single
Dose
of
35
mg)
NOAEL
=
0.5
mg/
kg/
day
(
RBC
ChE)

Phase
II
(
Repeated
Dose
of
21
mg/
day
for
12
or
15
Days)
NOAEL
=
not
established
LOAEL
=
0.3
mg/
kg/
day
(
RBC
ChE)

28­
Day
Delayed
Neurotoxicity­
Hen/
870.6100
43433501
Acceptable
Cholinesterase
inhibition
(
brain
ChEI)
NOAEL
=
0.1
mg/
kg/
day
LOAEL
=
0.3
mg/
kg/
day
No
neuropathology.

90­
Day
Subchronic
Oral
Toxicity
­
Rat/
870.3100
41004701
Acceptable
NOAEL
=
0.1
mg/
kg/
day
LOAEL
=
1.5
mg/
kg/
day
(
plasma
and
RBC
ChE)
Study
Type/
Guideline
No.
MRID
No.
Results
Page
14
of
16
90­
Day
Neurotoxicity
­
Rat/
870.6200
42958101
Acceptable
NOAEL
=
0.1
mg/
day
LOAEL
=
7.5
mg/
kg/
day
(
plasma,
red
blood
cell
(
RBC)
and
brain
ChEI).

Chronic­
Feeding­
Dog/
870.4100
41593101
Acceptable
NOAEL
=
0.05
mg/
kg/
day
LOAEL
=
0.1
mg/
kg/
day
(
plasma
and
RBC
ChEI
in
both
sexes).

Chronic­
Inhalation­
Rats/
Guideline
00057695,
00632569
Acceptable
NOAEL
=
0.00005
mg/
L
LOAEL
=
0.0005
mg/
L
based
on
plasma,
RBC
and
brain
cholinesterase
inhibition.

Chronic­
Inhalation­
Human/
870.4100
45812001,
00060486
Acceptable
NOAEL
=
0.125
µ
g/
L
(
0.000125
mg/
L)
LOAEL
=
0.180
µ
g/
L
(
0.000180
mg/
L)
(
Headaches
and
RBC
ChEI)

Developmental
Toxicity­
Rat/
870.3700
41951501
Acceptable
Maternal
toxicity
NOAEL
=
3
mg/
kg/
day
LOAEL
=
21
mg/
kg/
day
(
clinical
signs,
decreased
body
weight
gain
and
reductions
in
food
consumption
and
efficiency)
Developmental
toxicity
NOAEL
=
>
21
mg/
kg/
day
(
HDT)

Developmental
Toxicity­
Rabbit/
870.3700
41802401
Acceptable
Maternal
toxicity
NOAEL
=
0.1
mg/
kg/
day
LOAEL
=
2.5
mg/
kg/
day
(
mortality,
decreased
body
weight
gain
at
LOAEL)

Developmental
toxicity
NOAEL=
>
7
mg/
kg/
day
(
HDT)
ChEI
was
not
measured.
in
main
study
Range­
Finding:
Doses
were
0,
0.1,
1.0,
2.5,
5.0,
10
mg/
kg/
day
Maternal
toxicity
ChE
NOAEL
=
0.1
mg/
kg/
day
ChE
LOAEL
=
1.0
mg/
kg/
day
Study
Type/
Guideline
No.
MRID
No.
Results
Page
15
of
16
Reproductive
Toxicity
­
Rat/
870.3800
42483901
Acceptable
Parental/
Systemic
NOAEL
=
2.3
mg/
kg/
day
LOAEL
=
8.3
mg/
kg/
day
(
decreased
%
of
females
with
estrous
cycle
and
increased
%
of
females
with
abnormal
cycling)
Offspring
NOAEL=
2.3
mg/
kg/
day
LOAEL
=
8.3
mg/
kg/
day
(
reduced
#
dams
bearing
litter,
fertility
index,
pregnancy
index
and
pup
weight).

Preliminary
Developmental
Neurotoxicity
­
Rat/(
Non­
Guideline)
46153301
Acceptable
Systemic
NOAEL
=
7.5
mg/
kg/
day
Maternal
Systemic
LOAEL
=
not
identified
Maternal
RBC
ChEI
NOAEL
=
0.1
mg/
kg/
day
Maternal
RBC
ChEI
LOAEL
=
1.0
mg/
kg/
day
Maternal
Brain
ChEI
NOAEL
=
1.0
mg/
kg/
day
Maternal
Brain
ChEI
LOAEL
=
7.5
mg/
kg/
day
Maternal
Systemic
NOAEL
=
7.5
mg/
kg/
day
Offspring
Systemic
LOAEL
=
not
identified
Offspring
RBC
ChEI
NOAEL
=
1.0
mg/
kg/
day
Fetuses
(
GD
22)
RBC
ChEI
LOAEL
=
7.5
mg/
kg/
day
Fetuses
(
GD
22)

Brain
ChEI
NOAEL
=
1.0
mg/
kg/
day
Fetuses
(
GD
22)
Brain
ChEI
LOAEL
=
7.5
mg/
kg/
day
Fetuses
(
GD22)

Offspring
(
Pups)
did
not
demonstrate
ChEI
during
PND
2­
22
Study
Type/
Guideline
No.
MRID
No.
Results
Page
16
of
16
Developmental
Neurotoxicity
­
Rat/
870.6300
46153302
Notacceptable
Maternal
LOAEL/
NOAEL
could
not
be
identified
due
to
low
viability
indices
Offspring
LOAEL/
NOAEL
could
not
be
identified
due
to
low
viability
indices
Offspring
Effects
at
7.5
mg/
kg/
day
(
HDT)
included
increased
startle
response
in
males
on
PND
23,
impaired
memory
in
males
on
PND
27
and
62,
and
alterations
in
brain
morphometry
on
PND
62.

Study
is
unacceptable/
not
upgradable
Developmental
Neurotoxicity
­
Rat/
870.6300
46239801
Notacceptable
LOAEL/
NOAEL
could
not
be
identified
due
to
low
viability
index
in
controls.

No
maternal
or
offspring
effects
in
FOB,
motor
activity,
auditory
startle
reflex
habituation,
learning
and
memory
tests,
brain
weight,
neuropathology
and
morphometry
at
7.5
mg/
kg/
day
(
HDT).

Study
is
unacceptable/
not
upgradable
