Methomyl
&
Oxamyl:
Weight
of
Evidence
Comparison
of
Human
and
Animal
ChE
Data
for
Interspecies
Extrapolation
of
the
NMC
Cumulative
Assessment
Elissa
Reaves,
Ph.
D.

Elissa
Reaves,
Ph.
D.

U.
S.
EPA
U.
S.
EPA
Office
of
Pesticide
Programs
Office
of
Pesticide
Programs
April
4,
2006
April
4,
2006
2
Methomyl
Methomyl
&
Oxamyl
Oxamyl
in
the
NMC
CRA
in
the
NMC
CRA

The
Agency
has
previously
completed
the
acute,
aggregate
(
single
chemical,
multi­
route)
risk
assessment
of
methomyl
and
oxamyl

Methomyl
and
oxamyl
are
members
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group

Inhibition
of
acetylcholinesterase
(
AChE)
is
the
common
mechanism
of
toxicity

Rat
brain
ChE
data
provide
the
relative
potency
factor
(
RPF)
and
point
of
departure
(
PoD)
for
the
cumulative
assessment

At
the
present
time,
the
Agency
is
considering
the
methomyl
and
oxamyl
human
study
for
use
in
defining
the
respective
interspecies
uncertainty
factor
in
the
cumulative
risk
assessment
3
Methomyl
Methomyl
&
Oxamyl
Oxamyl
Human
Study
Details
Human
Study
Details
°
Methomyl
HS
1998,
oxamyl
HS
1999
°
Male
volunteers
only
°
Double­
blind
ascending­
dose
escalation
study
°
Single
oral
dose
in
a
capsule
after
"
standard"

breakfast
°
Tiered
exposure
sessions
°
All
volunteers
remained
under
close
medical
and
nursing
supervision
throughout
the
study
4
Methomyl
Methomyl
&
Oxamyl
Oxamyl
Human
Study
Details
Human
Study
Details
Methomyl
Oxamyl
Pre­
Exposure:
Pre­
Exposure:

N/
A
­
2
days
­
16
hours
­
16
hours
­
30
minutes
­
30
minutes
Post­
Exposure:
Post­
Exposure:

Every
15
minutes
until
2
hours
Every
15
minutes
until
2
hours
Every
hour
until
8
hours
3,
4,
6,
8,
12
hours
24
hours
24
hours
7
days
7
days
Table
1.
Schedule
of
Table
1.
Schedule
of
ChE
ChE
Sampling
Events
for
Measurement
of
Plasma
Sampling
Events
for
Measurement
of
Plasma
and
RBC
and
RBC
ChE
ChE
Activity
for
the
Activity
for
the
Oxamyl
Oxamyl
and
and
Methomyl
Methomyl
Human
Studies
Human
Studies

Multiple
sampling
events
showed
the
progression
of
ChE
inhibition,
peak
inhibition,
and
enzyme
recovery
for
each
volunteer
5
Session
Placebo
0.1
mg/
kg
0.3
mg/
kg
0.5
mg/
kg
0.75
mg/
kg
1.0
mg/
kg
1.5
mg/
kg
Session
1
1
1
Session
2
1
4
1
Session
3
1
4
1
Session
4
1
4
1
Session
5
1
4
1
Session
6
1
4
1
Session
7
1
4
Session
8
1
Total
Subjects
8
5
5
5
5
5
5
Table
2.
Target
Dosing
Schedule
for
Table
2.
Target
Dosing
Schedule
for
Methomyl
Methomyl
Human
Study
Human
Study
6
Session
Placebo
0.1
mg/
kg
0.3
mg/
kg
0.5
mg/
kg
0.75
mg/
kg
1.0
mg/
kg
1.5
mg/
kg
Session
1
1
1
Session
2
Session
3
Session
4
Session
5
Session
6
Session
7
Session
8
Total
Subjects
Table
3.
Actual
Dosing
Schedule
for
Table
3.
Actual
Dosing
Schedule
for
Methomyl
Methomyl
Human
Study
Human
Study
7
Session
Placebo
0.1
mg/
kg
0.3
mg/
kg
0.5
mg/
kg
0.75
mg/
kg
1.0
mg/
kg
1.5
mg/
kg
Session
1
1
1
Session
2
1
4
1*

Session
3
dropped
Session
4
Session
5
Session
6
Session
7
Session
8
Total
Subjects
*>
40%
ChE
inhibition
in
this
subject,
No
dosing
at
0.5
mg/
kg
occurred
in
Session
3
as
planned.

Table
3.
Actual
Dosing
Schedule
for
Table
3.
Actual
Dosing
Schedule
for
Methomyl
Methomyl
Human
Study
Human
Study
8
Session
Placebo
0.1
mg/
kg
0.3
mg/
kg
0.5
mg/
kg
0.75
mg/
kg
1.0
mg/
kg
1.5
mg/
kg
Session
1
1
1
Session
2
1
4
1*

Session
3
1
4
dropped
Session
4
Session
5
Session
6
Session
7
Session
8
Total
Subjects
Table
3.
Actual
Dosing
Schedule
for
Table
3.
Actual
Dosing
Schedule
for
Methomyl
Methomyl
Human
Study
Human
Study
*>
40%
ChE
inhibition
in
this
subject,
No
dosing
at
0.5
mg/
kg
occurred
in
Session
3
as
planned.
9
Session
Placebo
0.1
mg/
kg
0.2
mg/
kg
0.3
mg/
kg
0.5
mg/
kg
0.75
mg/
kg
1.0
mg/
kg
Session
1
1
1
Session
2
1
4
1*

Session
3
1
4
dropped
Session
4
1
5
Session
5
Session
6
Session
7
Session
8
Total
Subjects
4
5
5
5
0
0
0
Table
3.
Actual
Dosing
Schedule
for
Table
3.
Actual
Dosing
Schedule
for
Methomyl
Methomyl
Human
Study
Human
Study
*>
40%
ChE
inhibition
in
this
subject,
No
dosing
at
0.5
mg/
kg
occurred
in
Session
3
as
planned.
10
Session
0
(
Placebo)
0.005
mg/
kg
0.015
mg/
kg
0.03
mg/
kg
0.06
mg/
kg
0.09
mg/
kg
0.15
mg/
kg
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
Male
Volunteers
10
5
5
5
5
5
5
Table
4.
Dosing
Schedule
for
Table
4.
Dosing
Schedule
for
Oxamyl
Oxamyl
Human
Study
Human
Study
11
Male
only
Male
and
Female
Brain
ChE
RBC
ChE
NMC
CRA
Rat
Data
Not
available
RBC
ChE
Oxamyl
&
Methomyl
Human
Studies
Table
5.
Comparison
of
Rat
Table
5.
Comparison
of
Rat
ChE
ChE
Data
and
Data
and
ChE
ChE
Data
from
Data
from
the
the
Methomyl
Methomyl
&
Oxamyl
Oxamyl
Human
Studies
Human
Studies
°
For
the
cumulative
NMC
risk
assessment,
the
difficulty
lies
in
extrapolating
information
across
compartments
and
potential
uncertainty
from
information
solely
from
male
volunteers
12
Methomyl
Methomyl
&
Oxamyl
Oxamyl
HS
BMD
Results
HS
BMD
Results
Rat
Human
Brain
RBC
RBC
Chemical
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)
BMD10
(
mg/
kg)
BMDL10
(
mg/
kg)

Oxamyl
F=
0.145
M=
0.185
F=
0.111
M=
0.143
0.278
0.158
0.083
0.068
Methomyl
0.486
0.331
0.339
0.265
0.035
0.015
Table
6.
Oral
BMD
Table
6.
Oral
BMD
10
10s
and
BMDL
s
and
BMDL
10
10s
Generated
from
Rat
s
Generated
from
Rat
ChE
ChE
and
Human
and
Human
ChE
ChE
Data
for
Data
for
Methomyl
Methomyl
and
and
Oxamyl
Oxamyl
°
The
rat
data
indicate
no
sex
differences
in
ChE
activity
in
either
compartment
(
brain
or
blood)

°
Rat
data
also
indicate
similar
ChE
activities
in
brain
and
RBC
13
Agency
Approaches
of
Agency
Approaches
of
Methomyl
Methomyl
HS
into
NMC
CRA
HS
into
NMC
CRA
°
The
Agency
proposes
to
use
the
RBC
BMD
10
ratio
for
methomyl,
which
results
in
an
interspecies
extrapolation
of
9.5X
1.
Standard
Extrapolation
Factor
of
10X
A.
Is
supported
by
the
RBC
BMD
10
ratio
B.
Uncertainty
surrounding
lack
of
female
RBC
ChE
data,

lack
of
brain
data
in
humans
2.
Ratio
of
RBC
BMD
10
of
9.5X
A.
Refinement
of
standard
factor
based
on
RBC
data
from
rat
and
human
B.
Supported
by
rat
ChE
data;
no
compartment
difference,
no
sex
difference
14
Agency
Approaches
of
Agency
Approaches
of
Oxamyl
Oxamyl
into
NMC
CRA
into
NMC
CRA
1.
Standard
Extrapolation
Factor
of
10X
A.
Accounts
for
uncertainty
surrounding
lack
of
female
data
and
lack
of
brain
data
in
HS
B.
May
be
conservative;
BMD
ratio
estimate
is
3X
2.
Ratio
of
RBC
BMD
10
of
3X
A.
Refinement
of
standard
factor
based
on
RBC
data
from
rat
and
human
B.
Supported
by
rat
ChE
data;
no
compartment
difference,

no
sex
difference
°
The
Agency
proposes
to
use
the
RBC
BMD
10
ratio
for
oxamyl,
which
results
in
an
interspecies
extrapolation
of
3X
15
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
The
Agency's
WOE
document
and
DER
for
methomyl
describe
the
study
design
and
results
of
the
methomyl
acute
oral,
human
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
methomyl,
the
Agency
has
concluded
that
the
human
toxicity
study
supports
a
10X
inter­
species
uncertainty
factor
for
methomyl
in
the
cumulative
risk
assessment
of
the
NMCs.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
16
Oxamyl
Oxamyl
Charge
to
the
HSRB
Charge
to
the
HSRB
The
Agency's
WOE
document
and
DER
for
oxamyl
describe
the
study
design
and
results
of
the
oxamyl
acute
oral,
human
toxicity
study.
The
WOE
document
also
discusses
the
Agency's
conclusions
regarding
the
usefulness
of
the
human
study
in
the
cumulative
risk
assessment
for
the
NMCs.
For
oxamyl,
the
Agency
has
concluded
that
the
human
toxicity
study
is
sufficiently
robust
for
reducing
the
10X
interspecies
(
i.
e.,
animal
to
human)
uncertainty
factor
in
the
cumulative
risk
assessment.

Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
