Page
1
of
4
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
November
5,
2004
SUBJECT:
Transmission
of
Background
Materials
and
Charge
to
the
Panel
for
the
Session
of
the
December
2,
2004
FIFRA
Scientific
Advisory
Panel
Entitled
"
Use
of
Pharmacokinetic
Data
to
Refine
Carbaryl
Risk
Estimates
from
Oral
and
Dermal
Exposure".

TO:
Joe
Bailey,
Designated
Federal
Official,
Office
of
Science
Coordination
and
Policy
Scientific
Advisory
Panel
(
7201M)

FROM:
Kit
Farwell,
D.
V.
M.,
Toxicologist;
Jeff
Dawson,
Risk
Assessor
Health
Effects
Division
(
7509C)
Office
of
Pesticide
Programs
THRU:
Jeff
Herndon
Acting
Director,
Health
Effects
Division
(
7509C)
Office
of
Pesticide
Programs
Attached
are
the
document
entitled,
"
Use
of
Pharmacokinetic
Data
to
Refine
Carbaryl
Risk
Estimates
from
Oral
and
Dermal
Exposure",
charge
to
the
FIFRA
Scientific
Advisory
Panel
(
SAP),
and
supporting
appendices.

The
Food
Quality
Protection
Act
of
1996
requires
EPA
to
reassess
all
previously
approved
pesticide
tolerances
by
August
2006.
As
part
of
the
reassessment
process,
EPA's
Office
of
Pesticide
Programs
(
OPP)
has
completed
the
Phase
5
risk
assessment
for
carbaryl
which
incorporates
public
comments
and
error
corrections
from
the
registrant,
Bayer
CropScience.

The
carbaryl
registrant,
Bayer
CropScience,
has
proposed
an
approach
using
pharmacokinetic
data
to
refine
carbaryl
exposure
estimates
from
oral
and
dermal
exposure.
Page
2
of
4
Appendices:

Appendix
1
E­
file
name:
Bayer
proposal.
pdf
Application
of
carbaryl
pharmacokinetic
data
in
the
estimation
of
potential
postapplication
health
risks
associated
with
broadcast
lawn
care
products.
Ross,
J;
Driver,
J;
Lunchik,
C.
Bayer
CropScience.
September
8,
2004.
40
pages.

Appendix
2
E­
file
name:
Bayer
metabolism
study.
pdf
Metabolism
of
[
14C]
Carbaryl
in
Rats.
Krolski,
et
al.
Bayer
CropScience.
May
7,
2004.
230
pages.

Appendix
3
E­
file
name:
Bayer
mixed­
dose
study.
pdf
Metabolism
and
Pharmacokinetics
of
[
14C]
Carbaryl
in
Rats
Following
Mixed
Oral
and
Dermal
Exposure.
Krolski,
et
al.
Bayer
CropScience.
May
7,
2004.
53
pages.

Appendix
4
E­
file
name:
MOE_
Derivation_
HtM_
EPAScenario_
10Jun04.
xls
Spreadsheet
for
calculation
of
plateau
brain
concentrations,
Bayer
CropScience.

Appendix
5
E­
file
name:
Proposed
Path
in
Rats.
pdf
Page
3
of
4
Charge
to
the
Panel:

This
section
has
the
questions
the
Agency
wishes
the
Panel
to
consider
pertaining
to
the
use
of
pharmacokinetic
data
to
refine
carbaryl
exposure
estimates
from
oral
and
dermal
exposure.

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
assessement
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.

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.
Page
4
of
4
(
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
of­
exposure
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.
