Document ID: EPA-HQ-ORD-2006-0187-0013
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-22T05:00Z

Reviewed
by:
Joycelyn
E.
Stewart,
Ph.
D.
Registration
Action
Branch
(
H7509C)
Secondary
Reviewer:
William
Sette,
Ph.
D.
Science
Analysis
Branch
I
(
H7509C)

DATA
EVALUATION
REPORT
STUDY
TYPE:
Subchronic
oral/
human
volunteers
TOX.
CHEM.
No.:
328
MRID
No.:
442488­
01
GUIDELINE
#:
Non­
guideline
TEST
MATERIAL:
2,2
dichlorovinyl
dimethyl
phosphate
SYNONYMS:
dichlorvos,
DDVP,
dedevap,
Vapona
STUDY
NUMBERS:
XH6063
SPONSOR:
Amvac
Chemical
Corporation
TESTING
FACILITY:
Central
Toxicology
Laboratory
Adderly
Park,
Macclesfield,
Cheshire,
U.
K.

TITLE
OF
REPORT:
Dichlorvos:
A
Single
Blind,
Placebo
Controlled,
Randomized
Study
to
Investigate
the
Effects
of
Multiple
Oral
Dosing
on
Erythrocyte
Cholin­
esterase
Inhibition
in
Healthy
Male
Volunteers.

AUTHORS:
Miss
A.
J.
Gledhill
REPORT
ISSUED:
March
24,
1997
EXECUTIVE
SUMMARY:
In
a
single
blind
oral
study
fasted
male
volunteers
were
administered
DDVP
in
capsules
daily
at
a
dosage
of
7
mg
(
equivalent
to
approximately
0.1
mg/
kg/
day)
in
corn
oil
for
21
days.
Control
subjects
received
corn
oil
as
a
placebo.
Any
adverse
events
suffered
by
the
participants
were
recorded
on
adverse
events
forms.
Baseline
values
for
RBC
cholinesterase
activity
for
each
study
participant
were
determined
on
days
­
14,
­
12,
­
10,
­
7,
­
5,
­
3,
and
immediately
prior
to
dosing,
and
RBC
cholinesterase
activity
was
monitored
on
days
2,
4,
7,
9,
11,
14,
16,
and
18.

No
toxicity
was
reported
which
could
be
attributed
to
DDVP
administration.
While
there
were
significant
decrements
in
RBC
cholinesterase
activity
in
DDVP
treated
subjects
at
some
reporting
periods,
the
overall
mean
reduction
from
pretreatment
values
did
not
exceed
16
percent
at
any
time.
The
cholinesterase
activity
values
used
to
calculate
the
individual
means
varied
by
up
to
21
percent.
The
LOEL
for
RBC
cholinesterase
inhibition
is
0.1
mg/
kg/
day.
The
study
is
classified
Acceptable­
Non
Guideline.

MATERIALS:

Dichlorvos
(
lot
#
608002S074),
98%
a.
i.,
described
as
a
clear
colorless
liquid,
was
the
test
chemical.
Corn
oil
(
CTL
reference
#
00790/
007/
007,
was
the
vehicle.
Nine
healthy
Caucasion
male
volunteers,
age
19­
34
years,
weighing
61
to
90
kg
were
the
test
subjects.
In
order
to
be
included
in
the
study,
participants
had
to
be
between
the
ages
of
18
and
45
years
old,
of
a
single
ethnic
group,
be
within
normal
range
with
respect
to
history
and
physical
examinations,
and
EKG,
routine
clinical
chemistry,
hematology,
urinalysis;
have
RBC
cholinesterase
values
of
10,000
IU/
L,
be
negative
for
hepatitis
B
antigen
and
the
human
immunodeficiency
virus,
and
negative
screen
for
drugs
of
abuse.

METHODS:

1.
Dosing
Preparation
Dichlorvos
was
dissolved
in
corn
oil
at
14
mg/
mL,
placed
in
capsules
which
were
passed
through
a
disposable
sterile
filter
(
0.2
Fm
Sartorius
V115
filtraton
unit)
into
a
sterile
container,
then
dispensed
into
sterile
red
#
0
gelatin
capsules.
Capsules
were
stored
individually
in
sterile
screw
top
containers.
Two
staff
members
were
always
present
during
the
preparation
of
the
dose
formulations
and
dosing
capsules
in
order
to
ensure
accuracy
in
compound
and
dose
preparation.
Capsules
were
prepared
on
a
weekly
basis.
The
dichlorvos
content
of
the
dosing
formulations,
the
dosing
capsules
and
the
stability
of
dichlorvos
in
the
dosing
formulation
and
capsules
were
determined
by
gas
chromatography.
Dosing
volume
was
0.5
mL.

2.
Study
Design
The
study
was
a
single
blind,
randomized,
placebo
controlled
study.
Nine
healthy
males
were
selected
from
the
Medeval
Volunteer
Panel.
Each
study
participant
was
given
a
complete
medical
history
review
and
was
given
a
thorough
physical
examination.
Blood
was
drawn
for
standard
hematology
and
biochemistry,
determination
of
hepatitis
B
antigen,
humanimmunodeficiency
virus,
and
erythrocyte
cholinesterase
activity.
Heart
rate,
blood
pressure
and
EKG
were
measured,
and
urine
was
collected
for
standard
urinalysis
and
a
drugs
of
abuse
screen.

On
the
day
of
dosing,
participants
were
fasted
from
midnight
then
randomly
assigned
to
treatment
groups
receiving
either
1
mg/
kg
of
dichlorvos
in
corn
oil
or
the
corn
oil
vehicle
administered
in
gelatin
capsules
for
twenty
one
days.
Dosing
volume
was
500
FL.
Each
capsule
was
administered
with
150
ml
of
water.
RBC
cholinesterase
activity
was
measured
on
study
days
­
14,
­
12,
­
10,
­
7,
­
5,
­
3,
and
immediately
pre­
compound
administration
to
establish
baseline
cholinesterase
activity.
Following
compound
administration
RBC
cholinesterase
activity
was
measured
on
days
1,
2,
4,
7,
9,
11,
14,
16,
18,
25,
28,
and
29/
30.
Additional
samples
were
taken
from
volunteers
2,
3,
5,
and
6
on
day
24
for
determination
of
cholinesterase
activity.

Blood
was
collected
into
heparinized
tubes
and
centrifuged
at
2000
rpm
at
ambient
temperature
for
15
minutes
to
separate
plasma
from
red
blood
cells.
Plasma
was
snap
frozen
using
dry
ice
and
acetone
and
stored
at
­
20EC
for
possible
additional
study.
RBC
were
analysed
for
cholinesterase
using
a
modified
Ellman
method
and
a
Kone
Specific
analyser
(
specifications
to
follow)

3.
Protection
of
Subjects
The
study
was
conducted
in
accordance
with
the
Declaration
of
Helsiinki
including
all
amendments
up
to
and
including
the
Hong
Kong
revision.

4.
Exclusion
fron
the
Study
The
following
persons
were
excluded
from
participation
in
the
study:
persons
with
frequent
or
regular
use
of
medication
or
therapy;
participation
in
another
study
within
three
months
before
the
start
of
the
study;
any
acute
illness
within
two
weeks
of
the
start
of
the
study;
persons
with
suspected
or
definite
personal
or
family
history
of
adverse
drug
reactions
or
hypersensitivity
to
chemicals
with
a
structure
similar
to
that
of
dichlorvos;
persons
with
history
of
g.
i.,
hepatic
or
renal
disease;
donation
of
more
than
1500
mL
of
blood
in
the
12
month
period
up
to
the
end
of
the
study;
excessive
alcohol
intake;
treatment
within
the
previous
three
months
with
any
drug
known
to
have
a
well
defined
potential
of
toxicity
to
a
major
organ;
persons
exposed
to
organophosphorus
compounds
within
the
last
three
months;
smokers
of
over
10
cigarettes
per
day;
persons
with
planned
need
for
general
anesthesia
within
two
months
of
the
last
day
of
study
participation;
and
volunteers
who,
in
the
opinion
of
their
physician
should
not
participate
in
the
study;.

QUALITY
ASSURANCE:
Signed
and
dated
quality
assurance
statements
were
included
in
the
submission.

STATISTICAL
ANALYSIS:
Differences
in
group
mean
cholinesterase
activity
between
control
and
dichlorvos
treated
individuals
at
each
time
point
were
analysed
by
repeated
measures
analysis
of
variance
using
the
MIXED
procedure
in
SAS.
The
Leased­
Squares
Mean
(
LSM)
for
each
period
and
treatment
group
were
calculated,
and
the
differences
between
the
dichlorvos
treated
group
LSM
and
the
placebo
treated
group
LSM
were
compared
using
a
two­
sided
Student's
t
test
based
on
the
standard
error
in
the
analysis.

Differences
between
pre­
study
and
subsequent
group
means
for
each
treatment
at
each
time
point
were
compared
using
a
paired
t­
test.

Differences
between
pre­
study
and
subsequent
cholinesterase
levels
for
each
individual
were
compared
using
the
Good
permutation
test.

RESULTS:
Several
study
participants
reported
non­
specific
symptoms
but
there
were
no
sympatomatology
which
could
be
attributed
to
DDVP
administration.
Of
the
three
control
subjects,
one
(
volunteer
1)
reported
mild
dizziness
on
day
1,
and
coughing
days
10
to
16;
one
(
volunteer
5)
reported
forgetfulness
and
tiredness
on
days
3­
7,
and
flatulence
on
days
16­
18,
and
backache
days
4
through
the
end
of
the
study.
This
subject
was
administered
analgesics
by
the
study
nurse
on
days
9
and
10.
Of
the
six
participants
treated
with
DDVP,
one
(
volunteer
8)
complained
of
mild
headache,
one
(
volunteer
6)
suffered
a
nosebleed,
one
(
volunteer
2)
reported
tiredness
on
days
0­
4,
and
one
(
volunteer
4)
complained
of
nausea
on
day
1
and
tiredness
on
days
1­
22.
The
symptoms
reported
did
not
seem
to
be
associated
with
the
results
of
the
RBC
cholinesterase
measurements.

The
results
of
the
RBC
Cholinesterase
activity,
taken
from
the
investigators'
report,
are
shown
in
the
following
two
tables
Table
1.
Mean
RBC
Cholinesterase
Activity
(
I.
U.)
in
Male
volunteers
administered
7
mg
DDVP
(
0.1
mg/
kg/
day)
for
21
days
placebo
treated
n
=
3
DDVP
treated
n
=
6
Time
Mean
"

S.
D
%
Mean
"

S.
D.
%

Pre­
dose
18484"
1347
100
17738"
1713
100
Day
1
17930"
1404
97
17628"
1914
99
Day
2
18180"
1565
98
16817*"
1547
95
Day
4
18740"
1771
101
16933**"
1598
95
Day
7
18530"
1888
100
16182"
1796
91
Day
9
18460"
1007
100
16708"
2505
94
Day
11
19210"
1036
104
16037"
**
1654
90
Day
14
18490"
1642
100
15333**"
1250
86
Day
16
17706"
2470
96
15912**"
1063
86
Day
18
18260"
2299
99
14855**"
1199
84
*
significantly
different
from
pre­
dose
values
group
(
t
test
based
on
repeated
measures
analysis
of
variance)
p
<
0.05
**
significantly
different
from
placebo
treated
group
p<
0.05.

Table
2
Individual
RBC
Cholinesterase
Activity
(
IU)
in
volunteers
Administered
DDVP
0.1
mg/
kg/
day
for
21
days
Volunteers
11
2
3
4
51
6
7
8
91
Predose
Mean
18727
17204
17141
17480
17031
17069
16380
21156
19692
Day
1
17630
(
94)
16940
(
98)
17320
(
101)
19380
(
111)
16700
(
98)
16180
(
95)
15490
(
95)
20460
(
97)
19670
(
100)

Day
2
18320
(
98)
17150
(
100)
16770
(
98)
15550
(
89)
16550
(
97)
16430
(
96)
15360
(
94)
19640
(
93)
19670
(
100)

Day
4
19090
(
102)
17280
(
100)
16090
(
94)
16650
(
97)
16820
(
99)
16370
(
96)
15300
(
94)
19910
(
94)
20310
(
103)

Day
7
18400
(
98)
15230
(
89)
15700
(
92)
14570
(
83)
16710
(
98)
16790
(
98)
15350
(
94)
19910
(
94)
20310
(
103)

Day
9
17950
(
96)
15080
(
88)
16130
(
94)
15180
(
87)
17810
(
105)
17640
(
103)
14850
(
91)
21370
(
101)
19620
(
100)

Day
11
19630
(
105)
15680
(
91)
15610
(
91)
15020
(
86)
18030
(
106)
16300
(
95)
14450
(
88)
19160
(
91)
19970
(
101)

Day
14
19300
(
103)
14500
(
84)
15380
(
90)
14580
(
83)
16600
(
97)
15300
(
90)
14490
(
88)
17750
(
84)
19570
(
99)

Day
16
18670
(
100)
14710
(
86)
15460
(
90)
14530
(
83)
14900
(
87)
14420
(
84)
14800
(
90)
17230
(
81)
19550
(
99)

Day
18
19340
(
103)
15800
(
92)
15490
(
90)
14680
(
84)
15620
(
92)
13310
(
78)
13610
(
83)
16240
(
77)
19820
(
101)

postdose
17410
(
93)
14130
(
82)
13970
(
82)
13840
(
79)
16470
(
97)
15190
(
89)
13920
(
85)
17310
(
82)
19630
(
100)

(
)
indicates
percent
of
individual
predose
mean,
which
was
derived
from
7
measurements
done
prior
to
dosing
1
indicates
placebo
treated
subject
DISCUSSION:
As
shown
in
Table
1,
mean
RBC
cholinesterase
activity
was
significantly
reduced
in
DDVP
treated
male
subjects
when
compared
to
control
subjects
on
days
7,
11,
14,
16,
and
18.
However,
when
compared
to
the
pre­
treatment
means,
the
mean
RBC
cholinesterase
activity
was
reduced
14
percent
on
days
14
and
16,
and
16
percent
post
dose
on
day
18.
It
should
be
noted
that
the
pretreatment
mean
for
the
DDVP
treated
subjects
was
lower
that
of
the
placebo
treated
subjects.
It
should
also
be
noted
that
even
in
the
controls,
there
were
up
to
21
percent
differences
in
individual
RBC
cholinesterase
activity.
The
reduction
in
RBC
cholinesterase
activity
was
considered
by
the
HAZARD
ID
Committee
to
be
biologically
significant.
With
respect
to
the
use
of
male
subjects
only
in
this
study,
the
NTP
used
lower
doses
in
males
in
the
mouse
oncogenicity
study
based
on
information
that
males
are
more
sensitive
to
the
effects
of
DDVP
than
are
females.
SignOff
Date:
3/
24/
1998
DP
Barcode:
D235158
HED
DOC
Number:
012541
Toxicology
Branch:
RAB2