AGENDA
FIFRA
SCIENTIFIC
ADVISORY
PANEL
(
SAP)
OPEN
MEETING
THURSDAY,
DECEMBER
2,
2004
FIFRA
SAP
WEB
SITE
http://
www.
epa.
gov/
scipoly/
sap/
OPP
Docket
Telephone:
(
703­
305­
5805)
Docket
Number:
OPP­
2004­
0343
Holiday
Inn
Rosslyn
at
Key
Bridge
1900
North
Fort
Myer
Drive,
Arlington,
VA
22209
Telephone:
(
703­
807­
2000)

Use
of
Pharmacokinetic
Data
to
Refine
Carbaryl
Risk
Estimates
from
Oral
and
Dermal
Exposure
°
8:
30
AM
Introduction
and
Identification
of
Panel
Members
­
Steven
G.
Heeringa,
Ph.
D.
(
FIFRA
SAP
Session
Chair)
°
8:
45
AM
Administrative
Procedures
by
Designated
Federal
Official
­
Mr.
Joseph
E.
Bailey
°
8:
50
AM
Welcome
­
Mr.
Joseph
J.
Merenda,
Jr.
(
Director,
Office
of
Science
Coordination
and
Policy,
EPA)
°
8:
55
AM
Opening
Remarks
­
Randolph
Perfetti,
Ph.
D.
(
Health
Effects
Division,
Office
of
Pesticide
Programs,
EPA)
°
9:
00
AM
Presentation:
Use
of
Pharmacokinetic
Data
to
Refine
Carbaryl
Risk
Estimates
from
Oral
and
Dermal
Exposure
­
Kit
Farwell,
D.
V.
M.
(
Health
Effects
Division,
Office
of
Pesticide
Programs,
EPA)
°
10:
00
AM
BREAK
°
10:
15
AM
Presentation:
Continued
°
12:
00
AM
LUNCH
°
1:
00
PM
Public
Comments
°
2:
00
PM
Panel
Discussion
Charge
Question
1
­
Design
of
Pharmacokinetic
Studies:

A
series
of
pharmacokinetic
and
metabolism
studies
were
completed
that
serve
as
the
basis
for
the
proposed
approach
associated
with
childrens'
exposure
to
carbaryl
after
lawn
treatments.
These
studies
included
dosing
rats
via
several
routes
(
i.
e.,
oral,
dermal,
and
intravenous).
In
a
subsequent
study,
carbaryl
was
administered
to
rats
via
the
oral
and
dermal
routes
simultaneously
at
exposure
levels
similar
to
those
calculated
in
the
Agency's
deterministic
exposure
assessment
for
toddlers
playing
on
treated
lawns.
(
A)
Please
comment
on
the
design
of
these
experiments
with
respect
to
the
usefulness
of
results
to
estimate
peak
tissue
levels
for
risk
assessment
purposes.

(
B)
The
design
of
the
multi­
route
study
was
intended
to
mimic
the
concurrent
oral
and
dermal
exposures
of
toddlers
playing
on
treated
lawns.
Please
comment
on
this
approach.

°
3:
00
PM
BREAK
°
3:
15
PM
Panel
Discussion
Charge
Question
2
­
Pharmacokinetic
Approach:

Historically,
risk
assessments
completed
by
the
Agency
have
been
based
on
comparison
of
endpoints
associated
with
total
administered
dose
levels
from
toxicology
studies
with
daily
human
exposure.
The
proposed
pharmacokinetic
approach
presented
in
this
paper
instead
relies
on
the
use
of
peak
internal
dose
at
the
target
tissue.
Because
of
the
rapid
pharmacokinetics
and
pharmacodynamics
of
carbaryl,
a
more
appropriate
dose
metric
may
be
the
use
of
peak
target
tissue
levels
for
calculating
exposure
estimates
instead
of
total
daily
absorbed
dose
values.

(
A)
Please
comment
on
the
appropriateness
of
using
peak
levels
for
estimating
exposure.

(
B)
This
pharmacokinetic
approach
assumes
that
toddlers
put
their
hands
in
their
mouths
at
a
rate
of
20
times
an
hour
for
2
hours.
A
laboratory
dosing
regimen
that
exactly
mimics
this
toddler
behavior
is
impractical.
As
such,
oral
doses
were
administered
in
the
multi­
route
rat
study
once
per
hour
for
2
hours.
The
proposed
approach
uses
an
algorithm
to
adjust
the
results
for
2
hourly
bolus
doses
to
that
of
a
toddler
which
occurs
20
times
per
hour.
Given
the
rapid
metabolism
of
carbaryl,
please
comment
on
whether
this
algorithm
can
be
reasonably
used
to
predict
the
expected
pharmacokinetic
behavior
of
carbaryl.

(
C)
To
convert
the
four
24­
hour
time
periods
in
the
biomonitoring
study
to
a
shorter
time
period
and
to
account
for
plateau
tissue
concentrations,
Bayer
proposed
extrapolating
results
from
the
rat
mixed­
dose
study
to
the
biomonitoring
study
in
this
manner.
Because
the
margin­
of­
exposure
calculated
using
estimated
plateau
brain
concentrations
was
approximately
20­
fold
greater
than
the
margin­
ofexposure
calculated
using
EPA's
SOPs
For
Residential
Exposure
Assessment,
Bayer
proposed
multiplying
results
from
the
biomonitoring
study
by
an
adjustment
factor
of
20.
Please
comment
on
whether
this
approach
is
appropriate
for
extrapolating
from
results
in
the
rat
pharmacokinetic
study
to
the
biomonitoring
study.

°
5:
00
PM
ADJOURNMENT
Please
be
advised
that
agenda
times
are
approximate.
For
further
information,
please
contact
the
Designated
Federal
Official
for
the
meeting,
Joseph
E.
Bailey,
via
telephone:
(
202)
564­
8450;
fax
(
202)
564­
8382;
or
email:
bailey.
joseph@
epa.
gov
