Formetanate
HCl
Meeting
July
20,
2004
Name
Vincent
J
Piccirillo/
Consultant
Demson
Fuller/
SRRD
US
EPA
Betsy
Codrea/
Gowan
Vicki
Dellarco/
HED
US
EPA
Cindy
Baker/
Gowan
John
Doherty/
HED
US
EPA
Teung
Chin/
USDA
Cathy
Eiden/
HED
US
EPA
Karl
Baetcke/
HED
US
EPA
Laura
Parsons/
SRRD
US
EPA
Dannete
Drew/
HED
US
EPA
Susan
Lewis/
SRRD
US
EPA
The
purpose
of
this
meeting
was
to
discuss
the
rationale
behind
the
human
health
risk
assessment
for
formetanate
HCl.
The
comment
period
for
this
chemical
closed
on
May
24
and
the
registrant,
Gowan
Company,
requested
a
meeting
with
the
Agency
to
discuss
the
responses
they
had
submitted.

The
meeting
began
at
2:
00
PM.
Introductions
were
given.

Gowan
wanted
clarification
as
to
why
a
10X
database
uncertainty
factor
was
needed
for
formetanate.
They
stated
that
available
data
for
fometanate
indicates
that
age
dependent
sensitivity
would
not
be
seen.
This
argument
was
based
on
the
HIARC
report
for
formetanate.
HIARC
concluded
"
that
the
there
was
no
quantitative
or
qualitative
increase
in
the
susceptibility
of
young
animals
in
either
the
rate
or
rabbit
developmental
toxicity
studies.

EPA
explained
that
this
statement
is
made
in
the
context
of
the
traditional
results
from
the
standard
2­
gen
and
prenatal
toxicity
studies
which
do
not
include
measures
of
cholinesterase
inhibition,
which
is
the
principle
effect
of
concern
and
mode
of
action
for
the
N­
methyl
carbamates.

Gowan
wanted
further
evidence
by
the
Agency
regarding
the
issue
of
susceptibility.
Based
on
their
literature
search
regarding
other
cholinesterase
inhibitors,
increased
sensitivity
to
the
young
was
not
present.

EPA
responded
by
stating
that
there
are
limited
data
on
the
comparative
sensitivity
to
cholinesterase
inhibition
for
the
N­
methyl
carbamates.
However,
the
absence
of
data
is
not
a
basis
to
dismiss
a
concern
for
the
young,
particularly
in
light
of
the
fact
that
the
Agency
has
data
on
another
class
of
cholinesterase
inhibitors
­
organophosphate
(
OPs)
pesticides.
Certain
OPs
can
result
in
age­
dependent
sensitivity
to
cholinesterase
inhibition
(
i.
e.,
cholinesterase
inhibition
in
the
young
will
occurred
at
lower
doses
of
the
chemical
or
the
young
will
show
a
higher
level
of
cholinesterase
inhibition
at
comparable
doses).
For
OPs
the
limited
ability
of
the
young
to
detoxify
the
OP
appears
to
be
involved
in
their
age
dependent
sensitivity.
For
example
OPs
bind
to
carboxylesterases,
a
reaction
which
effectively
lessens
the
amount
of
pesticide
available
for
inhibiting
cholinesterase.
N­
methyl
carbamates
can
also
interact
with
carboxylesterases,
albeit
we
do
not
have
data
demonstrating
this
may
be
involved
in
age
dependent
sensitivity
to
cholinesterase
for
this
class
of
pestcide.
Gowan
spoke
about
reversibility.
In
regards
to
carbamates,
since
the
compounds
have
a
quick
acting
recovery,
there
could
potentially
be
no
neurological
effects
to
the
young.

The
Agency
responded
by
stating
the
rapid
reversibility
of
N­
methyl
carbamates
is
not
a
basis
to
dismiss
the
concern
for
the
young.
Both
cholinesterase
and
acetylcholine
are
highly
conserved
molecules
which
have
multiple
roles
in
the
developing
nervous
system
as
well
as
extraneuronal
functions.
Furthermore,
because
of
the
presence
of
critical
periods
of
development
for
the
nervous
system,
adverse
effects
on
the
developing
nervous
could
result
from
a
single
exposure
to
a
chemical.
Thus,
is
it
important
to
evaluate
whether
age­
dependent
sensitivity
exists
for
a
cholinesterase
inhibitor
to
determine
if
the
adult
cholinesterase
data
are
adequate
in
protecting
the
young.

Gowan
believes
that
the
Agency
does
not
have
a
"
for
cause"
to
apply
the
safety
factor.
Based
on
Agency
guidance,
it
states
that
"
when
additional
data
are
required,
consideration
of
the
factor
would
generally
occur
only
when
a
study
is
being
required
`
for
cause',
that
is,
if
a
significant
concern
is
raised
based
upon
a
review
of
existing
information".
Gowan
finds
no
evidence
that
increased
sensitivity
will
occur
in
young
from
use
of
formetanate,
therefore,
the
rationale
of
for
cause
should
be
applied.

EPA
has
generic
information
and
science
literature
that
raises
the
issue
for
cause.
The
existing
information
does
not
have
to
be
chemical
specific
but
can
come
from
a
general
scientific
understanding,
which
in
this
case
is
for
cholinesterase
inhibiting
pesticides.

EPA
further
stated
that
for
formetanate,
a
comparative
cholinesterase
assay
(
CCA)
study
would
be
needed
that
looks
at
age
dependent
sensitivity.
This
study
was
conducted
for
the
OPs
and
is
validated.
Further
information
regarding
the
protocol
for
this
study
could
be
obtained
from
the
EPA
Office
of
Research
and
Development
in
Research
Triangle
Park,
North
Carolina.

Gowan
was
concerned
about
the
cost,
finding
a
suitable
lab
to
conduct
the
work,
and
the
timing
of
the
study.
Gowan
stated
that
they
would
consider
the
study
and
get
back
to
the
Agency
by
the
following
week
with
a
decision.

Gowan
asked
if
there
were
any
other
areas
in
the
risk
assessment
that
could
be
refined.
EPA
mentioned
that
formetanate
dietary
risk
could
possibly
be
lowered
if
the
company
could
submit
a
validated
Level
of
Detection
(
LOD)
for
field
trial
data.
Gowan
said
they
would
look
into
this
issue.

Gowan
stated
that
they
would
follow
up
with
EPA
on
Monday,
July
26,
2004
regarding
the
CCA
study
and
the
validated
LOD.
EPA
stated
that
they
would
provide
Gowan
with
assumptions
that
were
used
in
the
dietary
assessment.

Meeting
adjourned.
