Document ID: EPA-HQ-OPPT-2003-0010-0050
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-03-11T05:00Z

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UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
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op
March
1,
2002
OFFICE~
F
PREVENTION,
PE~~~
IDESAND
TOXIC
SUBS~)
JCES
Dr.
Peter
Voytek
HAP
Task
Force,
Manager
Regulatory
Sciences
International
King
Street
Station
1800
Diagonal
Road,
Suite
500
Alexandria,
VA22~.
l4­
2808
RE:
PBPK
Testing
Protocols
for
Ethylene
Dichloride
(
EDC)
(
OPPTS
­
42197C)

Dear
Dr.
Voytek:

EPA
has
completed
review
of
the
HAP
Task
Force
comments
on
the
draft
ECA
agreement
and
testing
protocols
for
the
ethylene
dichloride
(
EDC)
HAP
testing
program,
as
presented
in
the
October
30,
2001,
submission
by
the
HAP
Task
Force.
This
letter
focuses
on
remaining
technical
points
identified
during
our
review
of
the
testing
protocols.
Overall,
the
testing
program
looks
acceptable
and
concurs
with
discussions
and
suggestions
for
improvement
made
to
date.
However,
there
are
still
several
points
of
clarification
and
additional
changes
to
the
Appendix
C
protocols
that
EPA
believes
are
needed
before
the
draft
ECA
can
be
finalized.
These
are
detailed
below.

Technical
agreement
on
the
following
point
is
confirmed,
with
notation
of
potential
impact
at
the
Tier
I
Program
Review:

°
The
HAP
Task
Force
would
use
GSH
depletion
as
a
dose
metric
for
GSH
conjugate
formation,
based
on
the
practical
argument
that
it
is
too
difficult
and
expensive
to
directly
monitor
the
multitude
of
GSH
conjugate
metabolites,
or
even
a
"
representative"
metabolite
directly.
EPA
notes
that
the
HAP
Task
Force
should
be
aware
that
not
monitoring
metabolites
may
hinder
the
ability
of
the
model
to
effectively
perform
the
route­
to­
route
extrapolations.
This
point
will
receive
due
attention
during
discussions
at
the
Tier
I
Program
Review
stage
of
the
testing
program.
Additional
thought
and
even
a
written
rationale
by
the
Task
Force
on
this
issue
would
be
appreciated.

40020@
00022
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(
URL)
http://
wwwepa.
gov.
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RECEIVED
OPPT
NCIC
2003
MAR11
5:
03PM
OPPT­
2003­
0010­
0050
Technical
points
that
need
resolution:

°
Details
about
the
assay
for
parent
compound
in
the
brain
tissue
needs
clarification.
At
present,
the
protocols
in
Appendix
C.
1
state
only
that
brain
tissue
will
be
collected
and
frozen
for
possible
subsequent
assay.
As
noted
in
footnote
9
of
Table
1
"
model
simulations
are
to
provide
point
and
uncertainty
estimates
for
internal
dose
metrics
(
parent
chemical
peak
and
AUC)
concentrations
in
blood
and
brain.
The
HAP
Task
Force
protocol
must
specify
the
assay(
s)
to
be
performed
on
the
frozen
brain
tissues.
Also
needed
is
some
assurance
that
any
assays
done
on
these
frozen
tissues
will
accurately
reflect
what
is
present
in
the
non­
frozen
brain
at
the
time
of
its
removal.

°
The
HAP
Task
Force
Appendix
C
protocols
support
development
of
PK/
MIECH
da~
from
oral
gavage
and
do
not
include
development
of
PK/
MECH
data
to
support
exposure
from
ad
libitum
drinking
water.
EPA
notes
that
the
rationale
and
data
to
support
using
only
a
gavage
PK
study
for
the
drinking
water
exposure
extrapolation
must
be
adequately
described
since
the
extant
studies
to
be
used
for
Tier
II
route­
to­
route
extrapolation
include
ad
libitum
drinking
water.

°
There
is
a
discrepancy
in
the
ECA
Table
1,
footnote
5
vis­
a­
vis
Appendix
C.
5
as
to
which
model
will
be
refined
through
the
testing
done
under
this
ECA
 
the
Table
lists
Gargas
et
aL,
(
1989,
1990)
and
the
Appendix
cites
D'Souza
et
al.
(
1987,
1988).
This
discrepancy
needs
to
be
resolved
and
the
full
referenced
titles
and
citations
included
in
the
Appendix.
(
Additionally,
copies
of
these
references
need
to
be
supplied
by
the
Task
Force).

Based
on
the
significant
progress
made
to
date
in
developing
this
ECA,
I
anticipate
that
these
technical
additions
and
changes
to
the
protocols
can
be
addressed
within
a
60
day
turnaround
I
look
forward
to
successfully
concluding
a
signed
ECA
for
EDC
within
the
near
future.
If
you
have
any
questions
please
contact
John
Schaeffer
at
(
202)
564­
8173
or
Richard
Leukroth
at
(
202)
564­
8167.

Sincerel
Charles
M.
Auer,
Director
Chemical
Control
Division
cc:
Michel
Stevens
Richard
W.
Leukroth,
Jr.
W.
Caffey
Norman,
III
John
Schaeffer
Docket
OPPTS
42197C