DATA
EVALUATION
RECORD
OXAMYL/
103801
NON­
GUIDELINE
STUDY
STUDY
TYPE:
ASCENDING
ORAL
TOXICITY
STUDY
IN
HUMANS
MRID
44912301
Prepared
for
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
1801
Bell
Street
Arlington,
VA
22202
Prepared
by
Toxicology
and
Hazard
Assessment
Group
Life
Sciences
Division
Oak
Ridge
National
Laboratory
Oak
Ridge,
TN
37831
Task
Order
No.
74­
2005
Primary
Reviewer:
Judith
H.
Moyer,
Ph.
D.,
D.
A.
B.
T.
Signature:
Date:
Secondary
Reviewers:
Signature:
Sylvia
Milanez,
Ph.
D.,
D.
A.
B.
T.
Date:
Robert
H.
Ross,
M.
S.,
Group
Leader
Signature:
Date:
Quality
Assurance:
Lee
Ann
Wilson,
M.
A.
Signature:
Date:

Disclaimer
This
review
may
have
been
altered
subsequent
to
the
contractors'
signatures
above.

Oak
Ridge
National
Laboratory
managed
and
operated
by
UT­
Battelle,
LLC.,
for
the
U.
S.
Department
of
Energy
under
Contract
No.
DE­
AC05­
00OR22725.
EPA
Reviewer:
Elissa
Reaves,
Ph.
D.
Signature:
Reregistration
Branch
2,
Health
Effects
Division
(
7509C)
Date
EPA
Secondary
Reviewer:
Anna
Lowit,
Ph.
D.
Signature:
Reregistration
Branch
2,
Health
Effects
Division
(
7509C)
Date
Template
version
11/
01
TXR#:
0052872
DATA
EVALUATION
RECORD
STUDY
TYPE:
Ascending
Oral
Toxicity
­
Humans,
non­
guideline.

PC
CODE:
103801
DP
BARCODE:
308714
TEST
MATERIAL
(
PURITY):
Ethanimidothioic
acid,
2­(
dimethylamino)­
N{[(
methlamino)
carbonyl]
oxy}]­
2­
oxo,
methyl
ester
(
97.6%)

SYNONYMS:
Oxamyl
technical,
DPX­
D1410
Technical,
Methyl
2­(
dimethylamino)­
N­
[(
methylamino)
carbonyl)
oxy)­
2­
oxo­
ethanimidothioate,
Methyl
N',
N'­
dimethyl­
N­[(
methyl
carbonyl)
oxythiooxaminidate
CITATION:
McFarlane,
P.,
Freestone,
S.
(
1999)
A
randomized
double
blind
ascending
oral
dose
study
with
oxamyl.
Inveresk
Clinical
Research,
Riccarton,
Edinburgh,
EH14
4AP,
Scotland.
Laboratory
Project
ID:
HLO­
1998­
01505,
August
10,
1999.
MRID
44912301.
Unpublished.

SPONSOR:
E.
I.
du
Pont
de
Nemours
and
Company,
Newark,
Delaware
19714­
0050
EXECUTIVE
SUMMARY:
In
a
non­
guideline,
ascending
acute
oral
toxicity
study
(
MRID
44912301),
40
healthy
human
male
volunteers,
aged
19
­
39
years,
were
each
given
a
single
oral
dose
of
oxamyl
technical
(
approximately
97.6%
a.
i.,
batch
#:
DPX­
D140­
196)
in
a
gelatin
capsule
at
doses
of
0,
0.005,
0.015,
0.03,
0.06,
0.09,
or
0.15
a.
i.
mg/
kg
bw.
Volunteers
were
admitted
to
the
clinic
the
afternoon
prior
to
the
morning
dosing.
The
volunteers
were
fasted
for
9
hours
prior
to
breakfast.
Study
volunteers
were
dosed
approximately
5
minutes
following
a
"
standard"
breakfast,
and
observed
for
two
nights
and
one
follow­
up
visit
7
("
2)
days
post­
dose.
All
volunteers
remained
under
close
medical
and
nursing
supervision
throughout
the
study.
The
study
was
conducted
as
a
double­
blind
ascending­
dose
escalation
clinical
trial,
and
each
male
was
treated
at
one
of
nine
dosing
sessions.
Volunteers
received
a
complete
screening
physical
examination,
testing
for
Hepatitis
B,
C,
and
HIV
infection,
and
drug­
screening
of
urine
within
14
days
of
study
commencement.
Blood
pressure
and
heart
rate
were
measured
at
screening
(
within
14
days
prior
to
dosing),
16
hours
pre­
dose
(
admission),
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8
,
and
24
hours
post­
dose.
Oral
temperature
was
recorded
at
screening,
16
hours
and
30
minutes
pre­
dose,
and
2,
4,
and
24
hours
post­
dose.
A
12­
lead
ECG
was
obtained
at
screening,
30
minutes
pre­
dose,
and
30
minutes,
1,
2,
and
24
hours
post­
dose.
Hematology
and
clinical
chemistry
testing
was
performed
at
screening,
30
minutes
pre­
dose,
and
24
hours
post­
dose.
Urinalysis
was
conducted
at
screening
and
24
hours
post­
dose.
Pupillometry
was
performed
16
hours
and
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8,
and
24
hours
post­
dose.
Saliva
was
collected
and
quantified
by
weight
16
hours
and
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8,
and
24
hours
postdose
Plasma
and
red
blood
cell
cholinesterase
activity
were
assayed
at
screening,
and
2
days,
16
hours,
and
30­
minutes
pre­
dose,
and
at
0.25,
0.5,
0.75,
1.0,
1.25,
1.5,
1.75,
2,
3,
4,
6,
8,
12,
and
24
hours
post­
dose,
and
at
7
("
2)
days
post­
dose.
Clinical
signs
were
reported
by
a
total
of
7
individuals
from
both
the
placebo
(
3
volunteers)
and
oxamyl
dose
groups
(
4
volunteers).
These
clinical
observations
did
not
correspond
with
peak
ChE
inhibition
and
were
therefore
not
considered
to
be
treatment
related.
Clinical
observations
from
the
placebo
volunteers
included
bleeding
gums,
headache,
fever,
tremor,
muscular
pains,
and
right
sided
groin
pain.
Symptoms
reported
by
the
two
volunteers
in
the
0.015
mg/
kg
dose
group
included
headache
(
pre­
dose),
brief
nausea
(
57
minutes
post­
dose
to
61
minutes),
and
abdominal
pain
(
46
hours
post­
dose
to
46.5
hours
post­
dose).
Examination
of
the
volunteer
with
the
brief
nausea
revealed
no
inhibition
of
cholinesterase
activity
or
effects
on
pupil
size
or
salivation
and
so
was
deemed
unlikely
related
to
the
test
compound.
An
earache
was
noted
by
one
volunteer
(
46
hours
post­
dose
to
46.5
hours
post­
dose)
of
the
0.03
mg/
kg
dose
group.
At
0.15
mg/
kg,
one
volunteer
experienced
a
headache
(
6
hours
50
minutes
lasting
15
hours
15
minutes)
and
increased
generalized
sweating
(
10
hours
50
minutes
lasting
3
hours
55
minutes).
Both
of
these
symptoms
were
considered
possibly
related
to
study
compound
but
further
investigation
revealed
the
time
course
of
symptoms
were
not
consistent
with
the
cholinesterase
activity
inhibition
observed.
Therefore,
the
adverse
events
were
not
likely
to
be
truly
related
to
the
test
compound.

The
mean
percent
change
in
plasma
cholinesterase
activity
was
statistically
decreased
compared
to
placebo
in
the
high
dose
(
0.15
mg/
kg)
beginning
at
the
first
time
point
(­
14%,
15
min)
until
3
hours
post­
dosing
(­
8%),
with
peak
inhibition
at
45
minutes
post­
dosing
(
43%,
p<
0.001).
Plasma
cholinesterase
activity
returned
to
baseline
by
6
hours
post­
dosing.
For
the
group
exposed
to
0.09
mg/
kg,
plasma
cholinesterase
activity
was
significantly
inhibited
starting
at
75
minutes
post­
dosing
(­
12%
peak,
p=
0.026)
until
2
hours
post­
dosing
(­
10%,
p=
0.039)
with
recovery
at
3
hours
post­
dosing.
Within
the
0.06
mg/
kg
dose
group,
the
maximum
plasma
cholinesterase
inhibition
was
­
7%
at
75
minutes
post­
dosing
(
non­
statistical,
p=
0.22).
Plasma
cholinesterase
activity
was
similar
to
placebo
in
the
0.005,
0.015
and
0.03
mg/
kg
dose
groups
at
all
time
points.
However,
when
the
linear
trend
was
tested
for
dose
at
each
time
point,
the
test
was
significant
for
every
time
point
except
at
4,
8,
12,
and
24
hours,
and
7
days
post­
dosing.
The
inclusion
or
exclusion
of
outlying
values
did
not
alter
the
results
for
plasma
cholinesterase
activity.

The
mean
RBC
cholinesterase
activity
of
the
high
dose
group
(
0.15
mg/
kg)
was
inhibited
significantly
beginning
at
30
minutes
(­
23%,
p<
0.001)
with
peak
inhibition
at
45
and
60
minutes
(­
28%
and
­
27%,
respectively
with
p<
0.001
for
both)
until
2
hours
post­
dosing
(­
8%,
p=
0.011)
and
recovery
to
baseline
by
3
hours
post­
dosing.
For
the
0.09
mg/
kg
dose
group,
the
mean
RBC
cholinesterase
activity
was
significantly
decreased
only
at
30
minutes
(­
7%,
p=
0.016)
with
recovery
following
at
45
minutes
post­
dosing.
RBC
cholinesterase
activity
was
statistically
similar
to
placebo
at
all
time
points
in
the
0.005,
0.015,
0.03,
and
0.06
mg/
kg
dose
groups.
Analysis
of
a
linear
trend
for
RBC
cholinesterase
activity
by
dose
at
varying
time
points
indicated
significance
from
30
minutes
until
105
minutes
post­
dosing.

Saliva
weight
when
examined
with
outliers
was
increased
in
the
two
highest
dose
groups
at
1
hour
post­
dosing
compared
to
the
placebo
group.
A
linear
trend
was
observed
for
saliva
weight
(
change
from
baseline),
which
increased
with
increasing
dose
and
was
only
significant
(
p=
0.002)
at
the
1
hour
time
point.
The
significance
of
saliva
weight
and
dose
was
not
achieved
at
any
other
time
point
during
the
study.

There
were
no
significant
decreases
in
minimum
pupil
size
and
recovery
pupil
size
relative
to
baseline
between
any
dose
level
and
placebo,
at
any
of
the
time
points.
Significant
increases
in
recovery
pupil
size
were
observed
at
2,4,
8
and
24
hour
post­
dosing
in
the
0.005
mg/
kg
group
when
compared
to
placebo.
However,
increases
in
pupil
size
are
contrary
to
the
expected
response
to
cholinergic
stimulation
by
the
test
substance.

Under
the
conditions
of
this
ascending
oral
dose
study
in
humans,
0.09
mg/
kg/
day
represents
a
level
where
7­
12%
plasma
and
RBC
ChE
inhibition
was
observed.
Three
of
5
volunteers
at
this
dose
(
0.09
mg/
kg/
day)
exhibited
greater
than
20%
plasma
ChE
inhibition.
Therefore,
0.06
mg/
kg/
day
is
considered
the
NOAEL.

The
Agency
generated
BMD
and
BMDL
estimates
based
on
the
RBC
ChE
data
from
this
study.
The
resulting
RBC
BMD10
is
0.083
mg/
kg
with
BMDL10
of
0.069
mg/
kg.

COMPLIANCE:
Signed
and
dated
Good
Clinical
Practice
Compliance,
Quality
Assurance,
and
No
Data
Confidentiality
statements
were
provided.
The
study
was
conducted
in
accordance
with
the
Declaration
of
Helsinki,
1964,
as
amended
by
the
29th
Medical
World
Assembly
in
Tokyo
(
1975),
the
35th
Medical
World
Assembly
in
Venice,
1983,
41st
Medical
World
Assembly
in
Hong
Kong,
1989,
and
the
48th
General
Assembly,
Somerset
West,
Republic
of
South
Africa,
October
1996.

I.
MATERIALS
AND
METHODS
A.
MATERIALS:
1.
Test
Material:
Oxamyl
technical
Description:
White
solid;
"
appeared
to
be
stable"
under
study
conditions.
Analyses
were
conducted
to
assess
the
accuracy,
homogeneity
and
stability
of
the
preparation
prior
to
the
initiation
of
dosing
Lot/
Batch
#:
Batch
No.
DPX­
D1410­
196
Purity:
Approx.
97.6%
a.
i.,
approx.
2.25%
inerts.
.
CAS
#
of
TGAI:
23135­
22­
0
Chemical
structure:

2.
Vehicle
and/
or
positive
control:
Oxamyl
technical
was
administered
in
a
gelatin
capsule
as
an
oxamyl/
lactose
blend.
Placebo
was
lactose
administered
in
a
matching
capsule.

3.
Volunteers:
Species:
Human
(
Male)
Strain:
N.
A.
Age/
weight
at
dosing:
Age:
19
­
39
years;
Weight:
60.8
­
95.5
kg
Source:
Volunteers
recruited
and
screened
for
inclusion
in
the
study
by
Inveresk
Clinical
Research
clinical
staff.
Housing:
Admitted
to
clinic
the
afternoon
prior
to
morning
dosing,
and
discharged
approx.
24
hours
post­
dose.
Diet:
"
Standard"
breakfast
approx.
5
minutes
before
dosing;
fasted
until
approx.
3
hours
post­
dose
and
then
allowed
decaffeinated
fluids;
and
a
light
lunch
approx.
4
hours
post
dosing.
Water:
Water
consumption
not
specified.
Environmental
conditions:
Temperature:
Humidity:
Air
changes:
Photoperiod:
Not
specified
Not
specified
Not
specified
Not
specified
Acclimation
period:
Volunteers
admitted
to
clinic
the
afternoon
before
dosing
the
next
a.
m.

B.
STUDY
DESIGN
and
METHODS:

1.
Study
dates:
Start:
September
28,
1998,
End:
not
given
2.
Volunteer
population:
Forty
volunteers
were
assigned
to
the
test
groups
noted
in
Table
1,
and
were
admitted
to
the
clinic
the
afternoon
before
the
study.
All
volunteers
were
healthy
white
males;
thirty­
four
were
non­
smokers
and
six
were
previous
smokers.
Four
volunteers
were
non­
drinkers,
and
36
reported
the
regular
consumption
of
approximately
1
to
20
"
units"
of
alcohol/
week
(
1
unit
=
1
glass
wine
or
beer,
or
measure
of
spirit).

3.
Blinding:
The
study
design
was
double
blind
and
placebo
controlled,
with
the
exception
of
Session
1
in
which
both
volunteers
received
placebo.
Dose
escalation
was
not
to
occur
if
there
were
clinically
significant
symptoms/
signs
of
carbamate
toxicity
or
if
any
volunteer
had
$
40%
inhibition
of
RBC
cholinesterase
at
a
single
time
point
or
$
25%
inhibition
at
2
consecutive
time
points.
If
there
were
associated
symptoms/
signs
of
carbamate
toxicity,
no
further
administration
of
that
particular
dose
would
occur.
The
allocation
of
the
test
substance
or
placebo
was
randomized
and
based
on
the
randomization
code
generated
by
the
Statistics
Department
of
Inveresk
Research.
A
copy
of
the
randomization
code
was
held
by
the
ICR
phamacist
where
it
was
required
for
dispensing
purposes
and
by
the
Regulatory
Affairs
Department
at
Inveresk
Research.
Sealed
disclosure
envelopes
were
also
provided
to
ICR.
In
the
event
of
an
emergency
requiring
identification
of
the
drug
administered
to
a
volunteer,
the
Study
Director
could
request
that
the
envelope
be
opened.

4.
Experimental
Design:
Approximately
5
minutes
after
the
completion
of
a
"
standard"
breakfast,
the
volunteers
were
given
a
single
dose
of
an
oxamyl/
lactose
blend
(
Batch
No.
DPX­
D140­
196)
or
placebo
in
a
gelatin
capsule
while
sitting,
with
150
mL
water.
The
dosing
schedule
is
presented
in
Table
1.
Based
on
available
animal
data,
the
starting
dose
(
0.005
mg/
kg
bw)
was
predicted
to
have
no
detectable
effects
on
humans.
The
volunteers
remained
seated
or
recumbent
until
approximately
3
hours
post­
dosing,
when
they
were
allowed
to
be
ambulant
and
have
decaffeinated
fluids.
A
light
lunch
was
provided
approximately
4
hours
post­
dosing.
Volunteers
were
discharged
about
24
hours
postdosing
with
their
agreement
to
return
within
7
(")
days
for
follow­
up
evaluation
of
wellbeing
any
outstanding
adverse
events,
and
for
measurement
of
plasma
and
red
blood
cell
(
RBC)
cholinesterase
activity.
TABLE
1.
Study
design
Doses
Administered
(
mg/
kg
bw)
and
number
of
volunteers
Session
Numbers
0
(
Placebo)
0.005
0.015
0.03
0.06
0.09
0.15
1
2
2
1
1
3
1
4
1
4
1
4
1
5
1
4
1
6
1
4
1
7
1
4
8
1
1
9
1
4
Total
Volunteers
10
5
5
5
5
5
5
Data
obtained
from
p.
20,
MRID
44912301.

5.
Clinical
evaluation:
Volunteers
received
a
complete
screening
physical
examination,
testing
for
Hepatitis
B,
C,
and
HIV
infection,
and
drug­
screening
of
urine
within
14
days
of
study
commencement.
Blood
pressure
and
heart
rate
were
measured
at
screening
(
within
14
days
prior
to
dosing),
16
hours
pre­
dose
(
admission),
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8
,
and
24
hours
post­
dose.
Oral
temperature
was
recorded
at
screening,
16
hours
and
30
minutes
pre­
dose,
and
2,
4,
and
24
hours
post­
dose.
A
12­
lead
ECG
was
obtained
at
screening,
30
minutes
pre­
dose,
and
30
minutes
post­
dose,
and
1,
2,
and
24
hours
post­
dose.
Hematology
and
clinical
chemistry
testing
was
performed
at
screening,
30
minutes
pre­
dose,
and
24
hours
post­
dose.
Urinalysis
was
conducted
at
screening
and
24
hours
post­
dose.
Pupillometry
was
performed
16
hours
and
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8,
and
24
hours
post­
dose
using
the
optical
unit
(
pupilscan,
hand­
held
electronic
pupillometer).
Saliva
was
collected
and
quantified
by
weight
16
hours
and
30
minutes
pre­
dose,
and
1,
2,
3,
4,
8,
and
24
hours
post­
dose
by
having
the
volunteers
place
2
sterilin­
treated,
weighed
dental
rolls
opposite
the
2nd
molar
on
the
upper
cheek
pouch
on
both
sides
for
5
minutes.
The
dental
rolls
were
then
replaced
in
the
sterilin
and
the
pre­
and
post­
collection
weights
were
used
to
determine
the
salivary
weight.
Plasma
and
red
blood
cell
cholinesterase
activity
were
assayed
at
screening,
and
2
days,
16
hours,
and
30­
minutes
pre­
dose,
and
at
0.25,
0.5,
0.75,
1.0,
1.25,
1.5,
1.75,
2,
3,
4,
6,
8,
12,
and
24
hours
post­
dose,
and
at
7
("
2)
days
post­
dose.
Plasma
and
red
cell
fraction
(
except
screening
and
post­
study
samples)
were
separated
and
immediately
snap
frozen
in
liquid
nitrogen.
The
collected
plasma
and
red
cell
samples
were
assayed
for
cholinesterase
activity
according
to
the
method
of
Ellman
(
1961)
adapted
as
a
clinical
chemistry
kit
and
analyzed
on
a
Hitachi
clinical
chemistry
analyzer
(
IR/
SOP/
CLC/
043).

6.
Statistics:
The
SAS
(
v6.07)
statistical
package
was
used
to
perform
statistical
analyses.
The
parameters
evaluated
included
the
mean,
standard
deviation,
minimum,
maximum,
and
number
at
each
timepoint
for
pupillometry
(
initial,
minimum,
recovery,
and
change
from
initial
to
minimum),
vital
signs,
saliva
collection,
and
plasma
and
RBC
cholinesterase
activity.
These
parameters
were
analyzed
and
summarized
by
dose
level
and
timepoint.
The
percentage
change
from
baseline
at
each
time
point
was
calculated
on
an
individual
basis
and
tabulated
by
dose
level.
Baseline
was
defined
as
the
mean
of
all
available
pre­
dose
values
(
for
that
individual)
(
screening,
2
days,
16
hours,
or
30
minutes
pre­
dose).

A
repeated
measures
analysis
of
variance
(
ANOVA)
­
including
terms
for
dose
level,
timepoint,
and
dose
level
by
timepoint
interaction
­
were
used
to
analyze
the
percentage
change
from
baseline
in
RBC
and
plasma
cholinesterase
activity,
pupillometry,
and
saliva
collection.
At
each
timepoint,
a
test
for
linear
trend
with
dose
was
performed
using
a
linear
contrast.
Using
the
error
variance
from
the
ANOVA,
pairwise
comparisons
between
placebo
and
each
dose
level
were
carried
out
at
each
timepoint
using
the
Student's
`
t'­
test.
If
the
test
for
linear
trend
was
significant
at
the
5%
level,
then
the
pairwise
comparisons
at
that
timepoint
were
not
adjusted
for
multiple
comparisons.
If
the
test
for
linear
trend
was
not
significant
at
the
5%
level,
a
Bonferroni
adjustment
was
applied
to
the
pairwise
comparisons
at
that
timepoint
(
i.
e.,
each
comparison
was
tested
at
the
0.83%
significance
level).
Treatment
group
LSMeans
(
i.
e.,
means
adjusted
for
any
imbalance
in
the
model)
were
presented
together
with
the
significance
level
of
the
`
t'
tests
and
the
test
for
linear
trend.

Normality
of
distribution
was
examined
using
a
Shapiro­
Wilk
test,
while
homogeneity
of
variance
was
assessed
by
plotting
the
residuals
against
the
predicted
values
for
the
model.
If
there
was
significant
non­
normality
that
could
not
be
resolved
by
transforming
the
data,
the
data
were
analyzed
excluding
outliers.
If
the
omission
of
outliers
had
no
effect
on
the
conclusions,
the
results
of
the
full
data
set
only
were
reported.

Descriptive
statistical
methods
were
used
to
summarize
demographic
data,
ECG,
urinalysis,
and
adverse
events
by
dose
level
and,
where
appropriate,
by
timepoint.
Adverse
events
were
summarized
under
each
dose
level
by
tabulating
the
frequency
of
reports
of
each
unique
event,
and
were
coded
using
the
WHO
Adverse
Reaction
Terminology
(
1997).

II.
RESULTS:

A.
CLINICAL
FINDINGS:

1.
Clinical
observations:
A
total
of
13
clinical
effects
were
reported
by
a
total
of
7
study
volunteers.
No
clinical
signs
were
reported
for
the
0.005,
0.06
or
0.09
mg/
kg
dose
groups.
Three
placebo
volunteers
reported
clinical
signs
that
included
bleeding
gums;
secondary
to
trauma,
headache,
fever,
tremor
"
feeling
shaky",
muscular
pains,
and
discomfort
in
right
groin;
and
slightly
enlarged
inguinal
nodes
on
the
right
side
were
noted.
In
the
0.015
mg/
kg
group,
clinical
signs
were
reported
for
3
volunteers
and
included
nausea
(
4
minutes)
and
headache;
pre­
dose,
and
abdominal
pain;
46
hours
postdose
for
30
minutes.
An
earache
was
reported
by
one
volunteer
in
the
0.03
mg/
kg
group.
Headache,
sweating
and
epistaxis
(
nosebleed)
were
reported
in
the
0.15
mg/
kg
dose
group
by
one
volunteer.
The
sweating
began
10
hours
50
minutes
post­
dose
and
lasted
for
3
hours
and
55
minutes.
The
nose
bleed
began
22
hours
and
50
minutes
post­
dose.
All
reported
clinical
signs
in
all
volunteers
were
gone
by
the
post­
study
visit.
The
symptoms
reported
by
the
volunteers
typically
do
not
correspond
with
the
peak
ChE
inhibition
and
fall
outside
the
time
of
ChE
recovery.
Therefore,
the
clinical
observations
are
not
considered
to
be
treatment
related.

2.
Vital
signs
and
ECG:
No
dose
group
had
changes
in
vital
signs
or
ECGs.
3.
Cholinesterase
inhibition:
see
Tables
2
and
3.

Individual
cholinesterase:
Four
of
the
5
volunteers
of
the
high
dose
(
0.15
mg/
kg)
group
demonstrated
a
greater
than
­
40%
inhibition
of
plasma
cholinesterase
activity
from
that
individuals
baseline
(
baseline
consisted
of
the
mean
of
screening,
­
2
days,
­
16
hours,
and
­
30
minutes
pre­
dosing).
One
of
these
4
volunteers
also
has
greater
than
­
40%
RBC
ChE
inhibition.
The
first
volunteer
had
­
46%,
­
45%,
and
­
42%
plasma
cholinesterase
activity
at
60,
75,
and
90
minutes
post­
dosing.
The
corresponding
peak
RBC
ChE
inhibition
occurred
at
60
minutes
(­
43%).
The
second
volunteer
also
displayed
inhibited
plasma
cholinesterase
activity
at
30
(­
54%),
45
(­
58%),
60
(­
49%),
and
75
(­
39%)
minutes
postdosing
Peak
RBC
ChE
inhibition
of
­
38%
occurred
at
45
minutes
post­
dosing.
Plasma
cholinesterase
inhibition
occurred
beginning
at
30
minutes
(­
61%)
in
the
third
volunteer
until
60
minutes
(­
40%)
post­
dosing.
A
maximum
of
­
34%
RBC
ChE
inhibition
occurred
at
45
minutes
post­
dosing.
Plasma
cholinesterase
inhibition
for
the
fourth
volunteer
occurred
at
45
minutes
post­
dosing
only
(­
41%)
with
peak
RBC
ChE
inhibition
of
­
35%
at
45
minutes
post­
dosing.

Three
of
the
5
volunteers
of
the
0.09
mg/
kg
dose
group
exhibited
a
­
20%
or
greater
inhibition
of
plasma
cholinesterase
activity
beginning
at
45
minutes
post­
dosing.
These
3
volunteers
of
the
0.09
mg/
kg
dose
group
exhibited
­
23%
plasma
(­
7%
RBC
at
45
minutes),
­
21%
plasma
(­
18%
RBC
at
30
minutes),
and
­
20%
plasma
(­
15%
RBC
at
120
minutes)
cholinesterase
inhibition
at
45,
75,
and
120
minutes
post­
dosing,
respectively.

Plasma
cholinesterase:
Statistical
analysis
of
the
group
mean
by
time
point
was
not
performed.
Instead,
statistical
analysis
was
performed
on
the
percent
change
from
baseline
(
average
of
values
at
screening,
­
2
days,
­
16
hr,
and
­
30
min).
The
mean
percent
change
in
plasma
cholinesterase
activity
was
statistically
decreased
compared
to
placebo
in
the
high
dose
(
0.15
mg/
kg)
beginning
at
the
first
time
point
(­
14%,
15
min)
until
3
hours
post­
dosing
(­
8%),
with
peak
inhibition
at
45
minutes
post­
dosing
(
43%,
p<
0.001).
Plasma
cholinesterase
activity
returned
to
baseline
by
6
hours
post­
dosing.
For
the
group
exposed
to
0.09
mg/
kg,
plasma
cholinesterase
activity
was
significantly
inhibited
starting
at
75
minutes
post­
dosing
(­
12%
peak,
p=
0.026)
until
2
hours
post­
dosing
(­
10%,
p=
0.039)
with
recovery
at
3
hours
post­
dosing.
Maximum
plasma
ChE
inhibition
varied
among
volunteers
with
a
maximum
of
­
23%
at
45
minutes
until
approximately
2
hours
(­
20%)
post­
dosing.
Within
the
0.06
mg/
kg
dose
group,
the
maximum
plasma
cholinesterase
inhibition
was
­
7%
at
75
minutes
post­
dosing
(
non­
statistical,
p=
0.22).
Plasma
cholinesterase
activity
was
similar
to
placebo
in
the
0.005,
0.015
and
0.03
mg/
kg
dose
groups
at
all
time
points.
However,
when
the
linear
trend
was
tested
for
dose
at
each
time
point,
the
test
was
significant
for
every
time
point
except
at
4,
8,
12,
and
24
hours,
and
7
days
post­
dosing.
The
inclusion
or
exclusion
of
outlying
values
did
not
alter
the
results
for
plasma
cholinesterase
activity.

Red
blood
cell
(
RBC)
cholinesterase:
As
with
plasma
cholinesterase
activity,
RBC
cholinesterase
activity
was
analyzed
as
the
percent
change
from
baseline
compared
to
placebo
at
varying
time
points
post­
dosing.
The
mean
RBC
cholinesterase
activity
of
the
high
dose
group
(
0.15
mg/
kg)
was
inhibited
significantly
beginning
at
30
minutes
(­
23%,
p<
0.001)
with
peak
inhibition
at
45
and
60
minutes
(­
28%
and
­
27%,
respectively
with
p<
0.001
for
both)
until
2
hours
post­
dosing
(­
8%,
p=
0.011)
and
recovery
to
baseline
by
3
hours
post­
dosing.
For
the
0.09
mg/
kg
dose
group,
the
mean
RBC
cholinesterase
activity
was
significantly
decreased
only
at
30
minutes
(­
7%,
p=
0.016)
with
recovery
following
at
45
minutes
post­
dosing.
Volunteer
variation
of
RBC
ChE
activity
at
this
dose
at
30
minutes
ranged
from
+
8%
to
­
18%.
RBC
cholinesterase
activity
was
statistically
similar
to
placebo
at
all
time
points
in
the
0.005,
0.015,
0.03,
and
0.06
mg/
kg
dose
groups.
Analysis
of
a
linear
trend
for
RBC
cholinesterase
activity
by
dose
at
varying
time
points
indicated
significance
from
30
minutes
until
105
minutes
post­
dosing.

Table
2.
Plasma
and
RBC
cholinesterase
activity
change
from
baseline
(%)
over
time
in
volunteers
receiving
oxamyl
(
outlying
values
included)
Dosage
Group
(
mg/
kg
bw)
Time
0
0.005
0.015
0.03
0.06
0.09
0.15
Plasma
cholinesterase
(
mean
"
SD)

15
mins
postdose
­
1.3
"
6.3
­
3.0
"
7.7
2.7
"
11.5
0.4
"
2.1
­
2.4
"
1.7
­
4.1
"
8.6
­
14.1*"
12.0
30
mins
postdose
­
4.7
"
4.8
­
4.8
"
6.2
0.1
"
8.0
2.0
"
1.6
­
5.4
"
3.5
­
5.6
"
9.1
­
35.9**"
21.9
45
mins
postdose
­
7.3
"
7.4
­
4.6
"
5.3
0.1
"
8.7
0.5
"
2.3
­
2.1
"
14.7
1.2
"
17.7
­
43.4**"
14.7
1
h
postdose
­
1.7
"
5.7
1.3
"
7.0
0.7
"
7.4
­
1.2
"
4.8
­
5.6
"
4.8
­
6.2
"
8.4
­
40.4**"
7.2
1
h
15
mins
postdose
­
1.5
"
5.4
­
0.4
"
6.9
3.6
"
8.2
­
0.3
"
3.3
­
7.1
"
4.8
­
11.6*
"
8.2
­
35.9**"
6.0
1
h
30
mins
postdose
­
3.3
"
4.7
­
2.6
"
6.4
3.4
"
8.1
­
2.2
"
5.9
­
4.1
"
4.9
­
10.1
"
6.4
­
30.2**"
7.5
1
h
45
mins
postdose
­
4.0
"
5.1
­
1.3
"
6.7
3.0
"
10.3
­
0.8
"
4.5
­
3.9
"
4.2
­
9.5
"
4.5
­
25.3**"
4.6
2
h
postdose
­
1.0
"
4.4
1.9
"
5.7
2.8
"
7.3
­
2.1
"
2.1
­
5.7
"
3.3
­
10.2*
"
6.0
­
20.9**"
4.8
3
h
postdose
0.4
"
5.7
3.2
"
5.1
6.6
"
5.3
5.4
"
2.3
­
3.3
"
5.4
1.3
"
5.9
­
8.0
"
5.8
4
h
postdose
­
1.0
"
5.3
0.9
"
4.1
7.4
"
7.3
3.5
"
4.8
­
1.0
"
4.5
1.4
"
3.5
­
1.7
"
2.7
6
h
postdose
­
4.4
"
5.0
­
11.7
"
7.0
3.9
"
15.5
0.9
"
4.9
­
4.5
"
3.3
­
1.7
"
4.6
5.8
"
26.0
8
h
postdose
­
3.7
"
5.3
­
8.5
"
5.1
10.8
"
16.4
2.0
"
4.5
­
2.4
"
4.9
0.8
"
4.8
2.5
"
24.8
12
h
postdose
­
5.5
"
6.7
­
13.0
"
3.7
2.6
"
16.2
1.8
"
7.3
­
4.0
"
2.3
­
2.2
"
5.1
1.6
"
16.8
RBC
cholinesterase
(
mean
"
SD)

15
mins
postdose
4.9
"
10.6
2.0
"
7.6
­
0.4
"
10.8
4.8
"
14.6
­
1.3
"
7.2
1.0
"
8.9
­
2.3
"
16.6
30
mins
postdose
7.8
"
11.2
11.6
"
4.8
1.5
"
8.5
5.5
"
10.9
­
2.4
"
7.8
­
7.3*"
8.3
­
23.2**"
13.8
45
mins
postdose
6.5
"
10.8
­
0.2
"
6.2
­
4.8
"
16.0
3.0
"
13.8
­
4.3
"
8.2
0.2
"
12.2
­
27.9**"
12.7
1
h
postdose
9.4
"
10.3
4.9
"
8.1
3.0
"
3.9
1.9
"
16.3
5.9
"
11.1
­
0.3
"
7.5
­
27.1**"
10.1
1
h
15
mins
postdose
5.5
"
10.3
2.5
"
12.4
1.0
"
9.9
7.3
"
11.3
1.6
"
14.0
­
0.7
"
7.2
­
16.8**"
15.0
1
h
30
mins
postdose
11.1
"
8.8
3.2
"
9.9
2.9
"
6.6
6.0
"
11.1
4.5
"
9.0
1.8
"
6.2
­
15.9**"
9.3
1
h
45
mins
postdose
4.5
"
14.7
2.1
"
11.0
2.5
"
9.5
­
0.1
"
10.5
1.9
"
4.1
­
1.1
"
5.8
­
9.2*"
7.2
2
h
postdose
7.9
"
9.7
0.3
"
2.8
­
2.3
"
7.3
­
0.5
"
5.4
­
2.8
"
12.6
­
2.1
"
7.8
­
8.0
"
9.7
3
h
postdose
10.3
"
10.9
9.2
"
9.5
­
3.7
"
9.5
7.8
"
13.4
3.2
"
11.6
­
0.2
"
14.0
­
0.4
"
6.8
4
h
postdose
12.4
"
10.4
8.4
"
11.5
9.6
"
8.2
­
0.5
"
5.2
2.3
"
7.2
3.0
"
13.4
3.7
"
11.0
6
h
postdose
3.5
"
13.8
10.6"
10.7
4.8
"
12.9
6.5
"
7.5
5.1
"
5.2
21.3*"
14.0
10.9
"
6.6
Data
obtained
from
pp.
415­
416,
and
419­
420,
MRID
44912301.
*
Statistically
significant
at
p
<
0.05,
compared
with
controls.
**
Statistically
significant
at
p
#
0.001,
compared
with
controls.
mins
=
minutes,
h
=
hours
Table
3.
Mean
values
for
Plasma
and
RBC
cholinesterase
activity
in
all
volunteers
receiving
oxamyl
(
outlying
values
included)

Dosage
Group
(
mg/
kg
bw)
Time
0
0.005
0.015
0.03
0.06
0.09
0.15
Plasma
cholinesterase
screening
5013"
648.9
5306"
817
5082"
1008
5314"
842
5125"
804
5014"
552
4682"
837
Day
­
2
5685"
671.5
6541"
929
5221"
784
6153"
1409
6137"
1000
5301"
586
5158"
935
­
16
h
5473"
603.9
6379"
1017
5460"
1030
5664"
1412
5787"
900
5142"
412
4945"
920
­
30
mins
5346"
593.6
6117"
1259
5388"
844
5943"
964
5809"
951
5297"
791
4871"
777
15
mins
postdose
5321"
767.4
5902"
934
5455"
1367
5776"
1055
5571"
812
4978"
605
4158*"
465
30
mins
postdose
5130"
639.4
5799"
954
5320"
1175
5881"
1151
5396"
830
4894"
496
3140**"
1153
45
mins
postdose
4981"
646.0
5825"
1050
5308"
1135
5785"
1091
5527"
758
5233"
878
2758**"
739
1
h
postdose
5287"
651.3
6180"
1088
5355"
1192
5677"
1047
5385"
833
4859"
448
2913**"
566
1
h
15
mins
postdose
5307"
703.7
6051"
894
5484"
1082
5737"
1059
5303"
843
4574*"
285
3138**"
567
1
h
30
mins
postdose
5208"
682.6
5919"
914
5475"
1057
5609"
981
5466"
818
4658"
386
3431**"
743
1
h
45
mins
postdose
5174"
676.5
6014"
1025
5450"
1105
5708"
1082
5480"
838
4692"
301
3673**"
705
2
h
postdose
5325"
579.8
5988"
1105
5440"
1040
5650"
1114
5380"
796
4667*"
533
3890**"
758
3
h
postdose
5402"
640.4
6282"
971
5628"
916
6057"
1053
5518"
919
5268"
602
4513"
793
4
h
postdose
5337"
725.4
6151"
1023
5680"
1063
5951"
1096
5663"
974
5268"
446
4822"
787
6
h
postdose
5149"
665.0
5340"
580
5462"
1060
5793"
1016
5462"
939
5110"
521
5105"
1122
8
h
postdose
5189"
688.0
5555"
759
5809"
1018
5878"
1190
5591"
1079
5242"
535
4941"
979
12
h
postdose
5080"
634.9
5278"
663
5361"
889
5867"
1227
5500"
966
5082"
503
4938"
812
24
h
postdose
5301"
744.9
5738"
840
5713"
840
6276"
1111
5996"
1010
5355"
457
4568"
484
post
study
5672"
640.8
5978"
1000
5450"
767
6038"
1179
5838"
722
5292"
542
5180"
975
RBC
cholinesterase
screening
8433"
1539
8898"
943
9808"
1242
9457"
1007
9006"
633
7870"
901
8557"
585
Day
­
2
12063"
928
12380"
1105
12143"
1114
11866"
601
12194"
1179
11349"
1344
11863"
1065
­
16
h
11501"
1200
12839"
1419
12127"
1023
11776"
991
12570"
784
11092"
587
11299"
850
­
30
mins
11457"
868
12534"
1148
11714"
655
12599"
619
12246"
699
11437"
2026
10686"
1644
15
mins
postdose
11402"
1430
11887"
890
11397"
1346
11959"
1547
11324"
501
10512"
1238
10346"
1822
30
mins
postdose
11698"
1336
13009"
862
11645"
1442
12061"
1458
11198"
602
9618*"
713
8125**"
1477
45
mins
postdose
11551"
1303
11656"
1157
10887"
1861
11766"
1654
11015"
1144
10407"
1249
7605**"
1043
1
h
postdose
11878"
1358
12250"
1379
11781"
596
11642"
1898
12178"
1286
10354"
767
7695**"
874
1
h
15
mins
postdose
11458"
1328
11914"
1197
11606"
1785
12298"
1816
11655"
1372
10309"
655
8753**"
1079
1
h
30
mins
postdose
12088"
1448
12028"
1261
11760"
571
12095"
1230
12015"
1027
10612"
1244
8881**"
640
1
h
45
mins
postdose
11286"
1239
11911"
1469
11748"
1426
11418"
1314
11719"
663
10270"
649
9599*"
444
2
h
postdose
11703"
1121
11931"
981
11170"
865
11380"
941
11191"
1699
10174"
909
9713*"
731
3
h
postdose
11946"
1130
12758"
1481
11056"
1580
12309"
1493
11901"
1685
10321"
967
10530"
217
4
h
postdose
12211"
1394
12628"
1309
12573"
1528
11363"
747
11757"
904
10649"
869
10956"
873
6
h
postdose
11187"
1231
12910"
1618
11986"
1565
12164"
906
12102"
984
12536"
436
11723"
320
8
h
postdose
11850"
1876
11047"
974
12679"
1865
12826"
1170
11050"
1159
11947"
1502
11570"
773
12
h
postdose
12056"
1323
12628"
1687
11337"
1063
11641"
1152
11764"
753
12066"
1145
12056"
997
24
h
postdose
11639"
1418
11710"
1218
12906"
1605
12131"
1406
12275"
471
11574"
1002
11809"
1638
post
study
12333"
1887
13120"
865
13368"
1274
12984"
1386
12775"
1379
12296"
1463
12690"
1534
Data
obtained
from
pp.
419­
420,
and
435­
447,
MRID
44912301.
*
Statistically
significant
at
p
<
0.05,
compared
with
controls.
**
Statistically
significant
at
p
#
0.001,
compared
with
controls.
mins
=
minutes,
h
=
hours
4.
Pupillometry:

With
Outliers:
When
all
outlying
values
were
included,
the
percent
change
of
the
mean
initial
pupil
size
from
baseline
(­
30
minutes
pre­
dose)
compared
to
placebo
was
decreased
in
the
0.06
and
0.09
mg/
kg
dose
groups
one
hour
post­
dose
(­
14.6%,
p=
0.4
and
­
17.7%
,
p=
0.77,
respectively).
The
0.06
mg/
kg
group
mean
initial
pupil
size
returned
to
+
2.6%
of
baseline
by
4
hours
post­
dose,
and
the
0.09
mg/
kg
group
returned
to
+
1.9%
of
baseline
at
8
hours
post­
dose.
The
high­
dose
group
mean
pupil
size
(
initial)
was
reduced
the
most
at
3
hours
post­
dose
(­
10.7%
of
baseline,
p=
0.42);
subsequent
values
did
not
show
a
gradual
increase
over
time.
None
of
these
reductions
were
statistically
significant.

Without
Outliers:
When
the
outlying
values
were
included
however,
the
test
for
distributional
assumption
of
normality
(
Shapiro­
Wilk
test)
was
not
satisfied.
As
a
result,
the
pupillometry
data
were
re­
analyzed
without
outliers.
Approximately
75%
of
the
outliers
were
found
in
the
0.005
mg/
kg
dose
level.
When
the
outlying
values
were
excluded,
a
linear
trend
(
Bonferroni
adjustment)
was
apparent
at
every
time
point.

There
were
no
significant
decreases
in
minimum
pupil
size
and
recovery
pupil
size
relative
to
baseline
between
any
dose
level
and
placebo,
at
any
of
the
time
points.
Significant
increases
in
recovery
pupil
size
were
observed
at
2,4,
8
and
24
hour
postdosing
in
the
0.005
mg/
kg
group
when
compared
to
placebo.

5.
Increased
salivation:
Saliva
weight
(
including
outliers)
was
increased
in
the
0.09
and
0.15
mg/
kg
groups
(
97.6%,
p=
0.19;
and
160.7%,
p=
0.01,
change
from
baseline
at
­
30
minutes)
at
1
hour
post­
dose
when
compared
to
the
placebo
group.
A
linear
trend
with
increasing
dose
was
only
significant
(
p=
0.002)
at
the
1
hour
time
point;
percentage
change
from
baseline
saliva
collection
increased
with
dose.
At
subsequent
time
points
during
the
study,
neither
the
mean
saliva
weight
nor
the
trend
with
dose
were
significant.

B.
CLINICAL
CHEMISTRY:
1.
Hematology,
clinical
chemistry,
and
urinalysis:
No
treatment­
related
effects
were
found
at
any
test
dose.

III.
DISCUSSION
AND
CONCLUSIONS:

A.
INVESTIGATORS'
CONCLUSIONS:

The
study
authors
concluded
that
the
0.005,
0.015,
0.03,
and
0.06
mg/
kg
dose
groups
had
no
treatment­
related
and
biologically
relevant
inhibition
in
RBC
or
plasma
cholinesterase
activity,
increase
in
salivary
secretion,
decrease
in
pupil
size,
or
effect
on
ECGs,
vital
signs,
body
temperature,
clinical
chemistry,
urinalysis,
or
clinical
signs.

"
The
0.9
mg/
kg
dose
group
did
not
have
any
statistically
significant
increases
in
salivary
secretion.
There
were
no
compound­
related
effect
on
ECGs,
vital
signs,
body
temperature,
hematology,
clinical
chemistry,
urinalysis,
or
clinical
signs
at
any
timepoint.
Plasma
cholinesterase
activity
was
decreased
at
the
1
hour
15
minute
(­
11.6%
from
baseline),
1
hour
30
minutes
(­
10.1%
from
baseline),
and
2
hours
(­
10.2
from
baseline)
timepoint,
and
RBC
cholinesterase
activity
was
statistically
decreased
at
30
minutes
(­
7.3%).
Although
these
depressions
were
statistically
significant,
they
were
not
considered
to
be
adverse
since
they
were
relatively
small
in
magnitude
(
less
than
20%)
and
similar
to
depressions
in
plasma
and
RBC
cholinesterase
that
occurred
in
individual
volunteers
within
the
placebo
group
during
the
course
of
the
study.
A
statistically
significant
decrease
in
initial
pupil
size
occurred
at
the
1
hour
timepoint.
This
was
not
of
clinical
significance
as
minimum
and
recovery
pupil
sizes
for
that
timepoint
were
not
significantly
decreased
and
there
were
no
adverse
effects
on
blood
cholinesterase."

"
The
0.15
mg/
kg
dose
group
had
no
compound
related
effects
on
ECG,
vital
signs,
body
temperature,
hematology,
clinical
chemistry,
urinalysis
or
clinical
signs
at
any
timepoint.
At
the
1­
hour
assessment,
there
was
a
statistically
significant
decrease
in
initial
pupil
size
and
a
statistically
significant
increase
in
saliva
collected.
In
addition,
statistically
significant
depressions
in
plasma
cholinesterase
activity
were
present
at
all
time
points
up
to
and
including
3
hours
post­
dosing
and
statistically
significant
depressions
in
RBC
cholinesterase
activity
was
observed
from
30
minutes
up
to
and
including
1
hour
45
minutes.
The
period
of
maximum
depression
occurred
at
45
and
60
minutes
for
plasma
cholinesterase
and
from
30
to
60
minutes
for
RBC
cholinesterase.
Plasma
and
RBC
cholinesterase
activities
returned
to
baseline
within
4
and
3
hours
following
administration
of
the
test
substance,
respectively."
B.
EPA
CONCLUSIONS:

No
dose
group
had
changes
in
respiratory
rate,
ECGs,
vital
signs,
hematology,
clinical
chemistry,
urinalysis,
or
clinical
signs.
There
were
no
significant
decreases
in
minimum
and
recovery
pupil
sizes
in
any
dose
group
compared
to
placebo.
Plasma
and
RBC
cholinesterase
activity
typically
returned
to
normal
by
3
hours
post­
dosing
in
all
groups.
In
the
high
dose
(
0.15
mg/
kg)
plasma
and
RBC
cholinesterase
activity
both
peaked
(
43%
and
28%,
respectively)
at
45
minutes
post­
dosing
with
recovery
by
3
to
4
hours
postdosing
Plasma
cholinesterase
inhibition
peaked
at
75
minutes
(­
12%)
and
recovered
by
3
hours
post­
dosing
in
the
0.09
mg/
kg
dose
group.
RBC
cholinesterase
inhibition
was
statistically
decreased
(­
7%)
at
30
minutes
only.
No
differences
in
plasma
or
RBC
cholinesterase
activities
were
observed
in
the
other
dose
groups
compared
to
control.
Under
the
conditions
of
this
ascending
oral
dose
study
in
humans,
0.09
mg/
kg/
day
represents
a
level
where
7­
12%
plasma
and
RBC
ChE
inhibition
was
observed.
Three
of
5
volunteers
at
this
dose
(
0.09
mg/
kg/
day)
exhibited
greater
than
20%
plasma
ChE
inhibition.
Therefore,
0.06
mg/
kg/
day
is
considered
the
NOAEL.

Additionally,
the
Agency
used
the
RBC
ChE
inhibition
time­
course
data
for
input
into
the
Agency's
BMDS
model.
The
BMD10
is
0.083
mg/
kg
and
BMDL10
of
0.069
mg/
kg.
The
BMD
and
BMDL
were
considered
for
the
NMC
carbamate
cumulative
risk
assessment
for
refinement
of
the
interspecies
extrapolation
factor
for
oxamyl.

C.
DEFICIENCIES:

There
were
no
study
deficiencies
identified
that
would
have
affected
the
outcome
and
conclusions
of
this
study.
