Page
1
of
17
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON
D.
C.,
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
TXR
No.
0053990
MEMORANDUM
DATE:
March
20,
2006
SUBJECT:
Human
Studies
Review
Board:
Final
Weight
of
Evidence
Comparison
of
Human
and
Animal
Toxicology
Studies
and
Endpoints
for
DDVP
Human
Health
Risk
Assessment
and
Discussion
of
Interspecies
Extrapolation
in
the
Organophosphate
Cumulative
Risk
Assessment.

DP
Barcode:
327499
Reregistration
Case#:
0310
PC
Code:
084001
MRID
#:
several
FROM:
Ray
Kent,
Ph.
D.,
Chief
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

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

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

This
weight
of
evidence
(
WOE)
document
for
dichlorvos
(
DDVP)
describes
the
Agency's
rationale
for
selecting
a
repeated
dose
human
toxicity
study
(
MRID
44248801)
to
assess
risks
from
short­
and
intermediate
term
residential
and
occupational
exposure
to
DDVP.
In
addition,
the
WOE
document
also
discusses
why
an
acute
human
toxicity
study
(
MRID
44248802)
was
not
considered
appropriate
to
assess
risks
from
a
single
exposure
to
DDVP.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
this
study
in
the
cumulative
risk
assessment
for
the
OPs.
Page
2
of
17
Background.
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.
In
this
document,
HED
scientists
compare
the
strengths
and
weaknesses
of
the
human
and
animal
toxicity
studies
and
present
how
the
human
studies
compare
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.

This
document
focuses
on
two
human
studies
in
which
humans
were
intentionally
dosed
with
dichlorvos;
a
single
dose
oral
study
(
MRID
44248802)
and
a
repeated
dose
oral
study
(
MRID
44248801).
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
C4H7O4PCl2
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
phosphorous­
sulfur
(
P=
S)
group
to
a
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
CO2.
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
Page
3
of
17
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
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
exposure
in
male
humans
was
associated
with
statistically
and
biologically
significant
decreases
in
red
blood
cell
cholinesterase
activity
(
MRID
44248801).

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
preweaning
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
Page
4
of
17
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.

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
BMD10,
the
estimated
dose
that
results
in
10%
inhibition
of
cholinesterase,
and
the
BMDL10,
the
lower
95%
confidence
interval
on
the
BMD10,
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
BMD10
and
BMDL10
derivation.

A
BMDL10
of
0.8
mg/
kg
(
BMD
=
1.6
mg/
kg)
based
on
female
brain
ChE
depression
was
selected
as
the
lowest
value
of
all
the
studies
available
which
were
analyzed.
Consistent
with
EPA's
Draft
Technical
Benchmark
Dose
Guidance
(
2000),
the
BMDL,
not
the
BMD,
is
used
to
extrapolate
risk.
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
Page
5
of
17
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.

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.
Page
6
of
17
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
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.

Endpoint
Selection.
Page
7
of
17
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
BMDL10,
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
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
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
DDVP
risk
assessment
team
concludes
that
the
21­
day
human
study
is
sufficiently
robust
and
is
more
reflective
of
the
short­
term
exposure
duration
of
30
days
or
less,
and
has
therefore
selected
that
study
for
assessment
of
short­
term
risks
via
all
routes
of
exposure.

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
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.
­
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.
Page
8
of
17
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
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.

The
dichlorvos
risk
assessment
team
acknowledges
that
there
may
be
some
uncertainty
associated
using
the
21­
day
study
for
exposures
up
to
6
months
in
duration,
particularly
given
that
steady
state
has
not
yet
been
reached
in
the
human
study.
However,
the
Team
notes
that
for
purposes
of
quantitative
risk
assessment,
use
of
the
steady
state
BMDL10
of
0.4
mg/
kg/
day
from
the
rat
90
day
subchronic
study
(
see
below)
with
10X
factors
for
intra­
and
inter­
species
extrapolation
yields
a
regulatory
endpoint
of
0.004
mg/
kg/
day.
Use
of
the
human
LOAEL
of
0.1
mg/
kg/
day
with
a
3X
for
LOAEL
to
NOAEL
with
a
10X
factor
for
intra­
species
extrapolation
yields
a
regulatory
endpoint
of
0.003
mg/
kg/
day.
These
two
approaches
provide
very
similar
regulatory
endpoints.
Thus,
the
human
LOAEL
provides
a
reasonable
endpoint
for
extrapolating
human
health
intermediate­
term
risk.

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.
Page
9
of
17
Note
on
Human
Studies
Cited
in
MacGregor
et
al
(
2005)

In
its
submissions
to,
and
discussions
with
the
Agency
about
the
risk
assessment
of
dichlorvos,
the
registrant
has
consistently
made
the
argument
that
the
body
of
experimental
animal
and
human
data
indicate
that
humans
are
no
more
sensitive
to
the
cholinesterase­
inhibiting
effects
of
dichlorvos
than
are
laboratory
animals,
and
therefore,
the
interspecies
factor
reflecting
uncertainty
about
sensitivity
across
species
should
be
1x.
In
a
publication
appearing
last
year
(
MacGregor
et
al,
2005),
the
registrant
and
its
consultants
reiterated
their
argument
for
removing
the
interspecies
factor
and
cited
key
human
and
experimental
animal
studies
conducted
over
four
decades
in
support
of
their
thesis.

EPA
has
looked
at
these
studies
and
remain
of
the
opinion
that
a
weight
of
evidence
argument
such
as
MacGregor
et
al.
present
is
only
as
robust
as
the
individual
studies
that
are
used
to
build
the
argument.
The
publication
lists
29
studies
"
available
for
assessment
of
DDVP
toxicity
potential",
but
only
11
of
these
are
used
for
the
quantitative
interspecies
comparison
(
capsulized
in
Appendix
A).
There
are
four
oral
studies
listed
for
quantitative
comparison,
two
of
which
are
discussed
in
this
weight
of
evidence
document
(
Gledhill,
1997a,
1997c).
One
of
the
remaining
oral
studies,
(
Slomka
and
Hine,
1981)
utilizes
a
slow­
release
formulation
of
dichlorvos
entrained
in
plastic
beads.
The
availability
of
dichlorvos
in
this
formulation
is
unknown.
The
remaining
study
(
Gledhill,
1997b)
is
deficient
as
well
(
Appendix
A).

There
are
7
human
inhalation
studies,
3
of
which
use
children
as
subjects
and
are
therefore
are
excluded
in
accord
with
the
Human
Studies
Rule.
Two
of
the
remaining
4
studies
(
Smith
et
al.,
1972
and
Witter
et
al.,
1961)
limit
exposure
to
2
hours
or
less
which
is
of
little
use
in
assessing
current
use
patterns,
or
for
comparing
with
animal
data.
One
study
(
Stein
et
al.,
1966)
monitors
exposure
to
workers
over
a
few
weeks,
but
it
isn't
possible
from
the
study
to
determine
what
the
actual
exposures
to
the
subjects
were.
One
study
(
Ueda
and
Nishimura,
1967)
in
which
four
subjects
were
exposed
to
relatively
high
levels
for
2
days
may
have
limited
use
for
comparing
with
animal
data.

The
Agency
has
concluded
that
these
studies
are
insufficient
to
support
a
weight
of
evidence
argument
that
the
interspecies
factor
should
be
reduced
to
1X.
Page
10
of
17
OP
Cumulative
Risk
Assessment
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
organophosphate
pesticides
(
OPs)
as
a
common
mechanism
group
and
in
accordance
with
FQPA
has
developed
a
cumulative
risk
assessment
for
this
group
of
pesticides
(
USEPA,
2002a).
DDVP
is
a
member
of
the
OP
common
mechanism
group.

OPP
has
developed
a
guidance
document
for
developing
cumulative
risks
assessments
under
FQPA
(
USEPA,
2002b).
This
guidance
indicates
that
when
developing
multi­
chemical
hazard
assessments,
comparison
of
toxic
potency
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
OP
cumulative
risk
assessment,
brain
ChE
data
from
rat
toxicity
studies
in
duration
of
28
days
and
longer
have
been
used
by
EPA
to
estimate
relative
potency
and
to
develop
the
points
of
departure
for
extrapolating
cumulative
risk.
ChE
inhibition
of
OPs
typically
reaches
steady
state
in
rats
at
or
near
28
days
of
exposure.
Thus,
potency
estimates
for
exposures
in
duration
from
approximately
one
month
or
longer
are
consistent
and
show
less
variation
than
potency
estimates
for
shorter
exposure
durations.
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
tend
to
have
less
variation
and
thus
confer
less
uncertainty
on
cumulative
risk
estimates.

In
the
DDVP
human
multi­
dosing
study,
the
subjects
exhibited
8,
10,
14,
14,
and
16
percent
below
the
pre­
dose
mean
on
days
7,
11,
14,
16,
and
18
respectively.
These
data
indicate
that
there
is
an
increase
in
inhibition
from
days
7
to
18
of
exposure.
As
such,
steady
state
in
humans
may
not
have
yet
been
reached
during
the
DDVP
study.
The
Agency
notes
given
the
relatively
small
increase
(
2%)
in
inhibition
observed
from
days
14
to
18,
it
is
unlikely
that
RBC
ChE
inhibition
would
increase
substantially
with
prolonged
exposure.

Incorporation
of
the
results
from
the
DDVP
human
multi­
dosing
study
may
create
a
mismatch
with
the
relative
potency
factors
and
points
of
departure
being
used
in
the
cumulative
risk
assessment
which
are
based
on
ChE
inhibition
at
steady
state.
The
Agency
has
determined
that
for
the
cumulative
risk
assessment,
the
inter­
species
factor
for
oral
exposure
to
DDVP
will
be
10X.
This
determination
is
based,
in
part,
on
uncertainties
associated
with
lack
of
steady
state
ChE
inhibition
in
the
human
study
and
potential
mis­
matching
with
the
data
being
used
for
relative
potency
and
points
of
departure.
The
10X
inter­
species
extrapolation
factor
is
further
supported
by
a
comparison
of
the
results
from
the
human
study
with
RBC
BMD10s
estimated
by
EPA
previously
(
USEPA,
2001)
from
the
DDVP
rat
subchronic
study
where
steady
state
was
reached
(
MRID
no.
41004701;
see
table
below).
Dividing
rat
BMD10
of
approximately
0.6
mg/
kg/
day
by
the
human
endpoint
(
0.1
mg/
kg/
day)
yields
a
rat
to
human
extrapolation
factor
of
approximately
6X.
It
is
notable
that
rat
benchmark
response
is
based
on
10%
RBC
ChE
Page
11
of
17
inhibition
whereas
the
human
endpoint
is
16%.
It
is
reasonable
to
expect
that
the
dose
to
result
in
10%
RBC
ChE
inhibition
in
humans
would
be
lower
than
that
resulting
in
16%
RBC
ChE
inhibition.
As
such,
the
6X
ratio
is
likely
to
be
higher
(
ie,
closer
to
10X).

Sex
and
Age
RBC
Human
(
male)
16%
at
0.1
mg/
kg/
day
on
Day
18
Rat
BMD10
BMDL10
Male
0.57­
0.60
0.41
 
0.49
Female
0.65
0.45
 
0.54
Page
12
of
17
Bibliography
Gledhill,
A.
(
1997)
Dichlorvos:
A
Single
Blind,
Placebo
Controlled,
Randomised
Study
to
Investigate
the
Effects
of
Multiple
Oral
Dosing
on
Erythrocyte
Cholinesterase
Inhibition
in
Healthy
Male
Volunteers:
Lab
Project
Number:
CTL/
P/
5392:
XH6063.
Unpublished
study
prepared
by
Zeneca
Central
Toxicology
Lab.
52
p.
(
MRID
44248801)

Gledhill,
A.
(
1997)
Dichlorvos:
A
Study
to
Investigate
the
Effect
of
a
Single
Oral
Dose
on
Erythrocyte
Cholinesterase
Inhibition
in
Healthy
Male
Volunteers:
Lab
Project
Number:
CTL/
P/
5393:
XH6064.
Unpublished
study
prepared
by
Zeneca
Central
Toxicology
Lab.
44
p.
(
MRID
44248802)

USEPA,
2000.
"
Benchmark
Dose
Technical
Guidance
Document"
Draft
report.
Risk
Assessment
Forum,
Office
of
Research
and
Development,
U.
S.
Environmental
Protection
Agency.
Washington,
DC.
EPA/
630/
R­
00/
001
USEPA
(
2001).
Preliminary
Organophosphorus
Pesticide
Cumulative
Risk
Assessment.
Office
of
Pesticide
Programs,
U.
S.
Environmental
Protection
Agency.
Washington,
DC.
http://
www.
epa.
gov/
pesticides/
cumulative/
pra_
op/.

USEPA
(
2002a).
"
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
(
2002b).
Revised
Organophosphorus
Pesticide
Cumulative
Risk
Assessment.
Office
of
Pesticide
Programs,
U.
S.
Environmental
Protection
Agency.
Washington,
DC.
June
10,
2002.
http://
www.
epa.
gov/
pesticides/
cumulative/
rra_
op
Page
13
of
17
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)
BMD10
=
1.4/
1.7
mg/
kg;
RBC
ChE
(
F/
M)
BMDL10
=
1.2/
1.3
mg/
kg;
Brain
ChE
(
F/
M)
BMD10
=
1.3/
1.6
mg/
kg
Brain
ChE
(
F/
M)
BMDL10
=
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)
BMD10
=
1.5/
1.8
mg/
kg;
PND8
RBC
ChE
(
F/
M)
BMDL10
=
1.0/
1.3
mg/
kg;
PND8
Brain
ChE
(
F/
M)
BMD10
=
2.2/
1.8
mg/
kg
PND8
Brain
ChE
(
F/
M)
BMDL10
=
1.6./
1.5
mg/
kg
PND15
RBC
ChE
(
F/
M)
BMD10
=
1.3/
1.5
mg/
kg;
PND15
RBC
ChE
(
F/
M)
BMDL10
=
1.1/
1.2
mg/
kg;
PND15
Brain
ChE
(
F/
M)
BMD10
=
1.4/
1.6
mg/
kg
PND15
Brain
ChE
(
F/
M)
BMDL10
=
1.0./
1.3
mg/
kg
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.
Page
14
of
17
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)

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.
Page
15
of
17
aChronic­
Inhalation­
Human/
870.4100
45812001,
00060486
Acceptable
NOAEL
=
0.125
Fg/
L
(
0.000125
mg/
L)
LOAEL
=
0.180
Fg/
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
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).

a
Although
this
study
has
been
used
previously
to
assess
inhalation
risk,
children
are
included
in
the
study
as
subjects,
and
therefore
the
study
can
not
be
relied
on
for
risk
assessment
purposes
in
compliance
with
the
[
HS
Rule].
Page
16
of
17
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
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
Page
17
of
17
Appendix
A.

MacGregor
et
al,
2005
Human
Studies
Usable?
Citation
Oral
studies
used
in
the
interspecies
comparison
No
_
Missed
peak
effect
Gledhill,
A.
(
1997a)
Dichlorvos:
A
Study
to
Investigate
the
Effect
of
a
Single
Oral
Dose
on
Erythrocyte
Cholinesterase
Inhibition
in
Healthy
Male
Volunteers:
Lab
Project
Number:
CTL/
P/
5393:
XH6064.
Unpublished
study
prepared
by
Zeneca
Central
Toxicology
Lab.
44
p.
No
_
Missed
peak
effect
(
acute)
&
Gledhill
1997b
dose
is
lower
(
multidose)
Gledhill,
A.
(
1997b)
Dichlorvos:
A
Study
to
Investigate
Erythrocyte
Cholinesterase
Inhibition
Following
Oral
Administration
to
Healthy
Male
Volunteers:
Lab
Project
Number:
XH5170:
CTL/
P/
5251.
Unpublished
study
prepared
by
Central
Toxicology
Lab.
66
p.

Yes
_
Multidose
study
used
in
the
RA
Gledhill,
A.
(
1997c)
Dichlorvos:
A
Single
Blind,
Placebo
Controlled,
Randomised
Study
to
Investigate
the
Effects
of
Multiple
Oral
Dosing
on
Erythrocyte
Cholinesterase
Inhibition
in
Healthy
Male
Volunteers:
Lab
Project
Number:
CTL/
P/
5392:
XH6063.
Unpublished
study
prepared
by
Zeneca
Central
Toxicology
Lab.
52
p.
No
_
Plastic
bead
formulation
_
limited
bioavailability
Slomka,
M.
B.
and
C.
H.
Hine.
1981.
Clinical
pharmacology
of
dichlorvos.
Acta.
Pharmacol.
Toxicol.
49(
Suppl.
5):
105_
108.

Inhalation
studies
used
in
the
interspecies
comparison
No
_
children
exposed
Funckes,
A.
J.,
Miller,
S.,
Hayes,
W.,
1963.
Initial
field
studies
in
upper
volta
with
dichlorvos
residual
fumigant
as
a
malaria
eradication
technique.
Bull.
World
Health
Org.
29,
243_
246.
No
_
children
exposed
_
study
had
been
used
in
RA
Johnston,
J.
E.,
Barraj,
L.,
Petersen,
B.,
Youngren,
S.
H.,
2002.
A
reanalysis
of
observations
on
occupants
of
Arizona
homes
containing
20%
vapona
insecticide
resin
strips,
Arizona
II
home
study,
Exponent
Inc.,
Project
Identification
Number
DDVP_
02_
01,
December
4,
2002.

No
_
children
exposed
Shell
Chemical
Com
pany,
1970.
The
third
Arizona
home
study:
quantitation
of
DDVP
residues
in
foods
consumed
by
human
volunteers
exposed
to
No_
Pest
Strip
insecticide.
May
1970,
unpublished
report
from
Shell
Chemical
Company.

No
_
1
hr
exposure
_
not
relevant
to
use
Smith,
P.
W.,
Mertens,
H.,
Lewis,
M.
F.,
Funkhouser,
G.
E.,
Higgins,
E.
A.,
Crane,
C.
R.,
Sanders,
D.
C.,
Endecott,
B.
R.,
Flux,
M.,
1972.
Toxicology
of
dichlorvos
at
operational
aircraft
cabin
altitudes.
Aerosp.
Med.
43,
473_
478.
No
_
Exposure
levels
to
individuals
uncertain
Stein,
W.
J.,
Miller,
S.,
Fetzer,
L.
E.,
1966.
Studies
with
dichlorvos
residual
fumigant
as
a
malaria
eradication
technique
in
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III.
Toxicological
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Am.
J.
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Hyg.
15,
672_
675.
Limited
_
4
subjects
exposed
2
days
to
high
conc.
Ueda,
K.;
Nishimura,
M.
(
1967)
Effect
of
Vapona/
Strips
to
Human
Beings.
(
Unpublished
study
prepared
by
Tokyo
Dental
College,
Japan)

No
_
1­
2
hr
exposure
_
not
relevant
to
current
use
Witter,
R.
F.;
Gaines,
T.
B.;
Short,
J.
G.;
et
al.
(
1961)
Studies
on
the
safety
of
DDVP
for
the
disinsection
of
commercial
aircraft.
Bulletin
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24(?):
635_
642.
