Document ID: EPA-HQ-ORD-2006-0187-0109
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-06T04:00Z

1
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
Methomyl
is
a
member
of
the
N­
methyl
carbamate
(
NMC)
common
mechanism
group
based
on
its
ability
to
inhibit
acetylcholinesterase
via
carbamylation.
The
Agency
has
previously
completed
the
acute,
aggregate
(
single
chemical,

multi­
route)
risk
assessment
of
methomyl.
At
the
present
time,
the
Agency
is
considering
the
use
of
the
methomyl
acute
oral,
human
toxicity
study
to
inform
the
inter­
species
uncertainty
factor
used
in
the
cumulative
risk
assessment
of
the
NMCs.
2
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
1.
Scientific
considerations:

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.
3
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations:

a.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:


Whether
the
investigators'
decision
to
administer
a
dose
to
additional
subjects
in
session
3,
when
one
subject
receiving
that
dose
in
session
2
displayed
RBC
ChEI
greater
than
40%,
a
response
that
triggered
the
protocol's
anti­
escalation
provision,
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
4
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

a.
cont'd.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:


Whether
the
timing
of
the
investigators'
report
to
the
ethics
committee
of
the
adverse
effects
observed
in
one
subject
during
session
2
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
5
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

a.
cont'd.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:


Whether
the
failure
of
the
investigators
to
request
approval
from
the
ethics
committee
for
certain
amendments
to
the
approved
protocol,
as
required
by
the
protocol,
when
the
changes
were
administrative
and
had
no
effect
on
the
safety
of
the
subjects
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
6
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

a.
cont'd.
The
Agency
requests
that
the
Board
provide
comment
on
the
following:


Whether
the
absence
from
the
protocol
of
discussion
of
the
potential
risks
to
subjects
or
benefits
to
society
of
conducting
the
proposed
research
(
as
required
by
the
Declaration
of
Helsinki,
Principle
#
5)
should
be
considered
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted;
and
7
Methomyl
Methomyl
Charge
to
the
HSRB
Charge
to
the
HSRB
2.
Ethical
considerations,
cont'd:

b.
The
Agency
asks
that
the
Board
provide
comment
on
the
following,
taking
into
account
all
that
is
known
about
the
ethical
conduct
of
this
study:


OPP's
conclusion
that
there
is
not
clear
and
convincing
evidence
that
the
conduct
of
the
research
was
fundamentally
unethical.


Whether
there
is
clear
and
convincing
evidence
that
the
conduct
of
the
study
was
significantly
deficient
relative
to
the
ethical
standards
prevailing
when
the
study
was
conducted