Document ID: EPA-HQ-OPPT-2003-0010-0051
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-03-12T05:00Z

Date
Time
GENERAL
March
19,
2002
CONTACT
I
4:
30
­
6:
00
P.
M.
REPORT
Name
/
Organization
Chemical
Control
Division
/
Chemical
Testing
&
Information
Branch
Name
of
EPARep.
Cheek
1Contact
Ininator
Richard
Leukroth
(
OPPTS/
OPPT);
Michel
Stevens,
and
Robert
DeWoskin
(
ORD/
NCEA)
Type
of
Contact
Telephone
X
Meeting
at
SOT
Nashville,
TN
~
Other
Name
of
MFG
IOrg
Rep.
0
Check
if
Contact
Initiator
HAP
Task
Force:
Mike
Gargus,
and
Lisa
Sweeney
(
Sapphire
Group),
and
Ross
Jones
(
Occidental
Chemicals)

Topic
Covered:
Note
any
resolutions
and/
or
additional
Actions
Required
on
this
Form.

At
the
request
ofthe
HAP
Task
Force,
EPA
provided
an
opportunity
for
a
technical
consultation
meeting
to
discuss
points
raised
in
EPA
correspondence
dated
March
1,
2002
(
see
attachments).
EPAs
letter
raised
four
points
related
to
Appendix
C
of
the
draft
ECA
on
ethylene
dichioride
that
needed
further
clarification
by
the
HAP
Task
Force.

Point
#
1:
Discussion
focused
on
the
use
of
GSH
depletion
as
the
dose
metric
for
GSH
conjugation
and
whether
or
not
to
include
additional
measures
for
specific
urine
metabolites.
Gargas
supported
the
view
that
GSH
depletion
was
a
good
surrogate
since
not
all
ofthe
metabolites
were
known
and
it
would
be
difficult
to
estimate
concentrations
of
the
putative
toxic
glutathione
conjugate
from
concentrations
ofmetabolites
downstream.
Gargas
and
DeWoskin
exchanged
literature
citations
and
reached
agreement
that
it
would
be
challenging
to
develop
a
complete
listing
of
EDC
metabolites
and
to
characterize
the
uniqueness
of
those
metabolites
to
EDC
metabolism.
Gargas
noted
that
previous
modeling
efforts
made
effective
use
of
the
GSH
depletion
approach.
It
was
noted
that
Appendix
Cl
of
the
draft
ECA
omits
discussion
of
the
rational
for
selecting
this
approach.
Gargas
indicated
that
this
could
be
included
in
a
revised
Appendix
Cl
along
with
detailed
citations
ofrelevant
journal
publications
and
submission
of
supporting
data.

Point
#
2:
Gargas
supported
the
view
that
GSH
depletion
was
a
good
surrogate
since
not
all
of
the
metabolites
were
known
and
it
would
be
difficult
to
estimate
concentrations
of
the
putative
toxic
glutathione
conjugate
from
concentrations
of
metabolites
downstream.
Gargas
and
DeWoskin
exchanged
literature
citations
and
reached
agreement
that
it
would
be
challenging
to
develop
a
complete
listing
of
EDC
metabolites
and
to
characterize
the
uniqueness
of
those
metabolites
to
EDC
metabolism.
In
addition,
he
noted
that
the
protocol
indicted
that
predictions
of
brain
concentration
would
be
determined
from
model
simulations
and
that
frozen
tissue
for
several
organs
(
including
brain)
would
be
set
aside
in
the
event
follow­
up
measurements
may
be
needed
following
the
Tier
I
Program
Review.
Concern
was
raised
that
Appendix
C
was
silent
on
the
handling
of
the
frozen
samples.
Gargas
explained
that
the
tissues
from
treated
animals
will
be
frozen
along
with
spike
samples
to
determine
Page
1
of
2
RECEIVED
OPPT
NCIC
2003
MAR12
4:
47PM
OPPT­
2003­
0010­
0051
GENERAL
CONTACT
REPORT
continued
March
19,
2002
possible
effect
of
freezing
on
future
EDC
measurements.
Gargas
suggested
that
additional
detail
regarding
the
disposition
of
the
frozen
samples
and
additional
explanation
supporting
the
use
ofcirculating
blood
concentration
as
a
measure
for
brain
concentration
could
be
included
in
Appendix
C.

Point#
3:
DeWoskin
noted
that
Appendix
C
was
not
clear
on
how
the
PKIMECH
data
would
support
extrapolation
from
water
and
oil
gavage
to
drinking
water
ad
libitum.
Gargas
noted
that
periodicity
would
be
determined
from
the
planned
studies
and
that
certain
additional
assumptions
would
be
applied.
Gargas
supported
the
view
that
GSH
depletion
was
a
good
surrogate
since
not
all
of
the
metabolites
were
known
and
it
would
be
difficult
to
estimate
concentrations
of
the
putative
toxic
glutathione
conjugate
from
concentrations
of
metabolites
downstream.
Gargas
and
DeWoskin
exchanged
literature
citations
and
reached
agreement
that
it
would
be
challenging
to
develop
a
complete
listing
of
EDC
metabolites
and
to
characterize
the
uniqueness
of
those
metabolites
to
EDC
metabolism.
Gargas
agreed
that
the
rationale
could
be
added
to
a
revised
Appendix
C.

Point
#
4:
Gargas
noted
that
the
correct
citation
to
include
in
Table
1
footnote
#
5
is
D'Souza
et
al.,
(
1987,
1988).
EPA
will
revise
Table
1
accordingly.

h­
i
addition,
Gargas
noted
that
the
HAP
Task
Force
has
recently
discovered
that
the
highest
achievable
concentration
in
water
for
EDC
is
lower
than
originally
stated.
This
relates
directly
to
the
physiochemical
properties
of
EDC.
The
maximum
achievable
concentration
in
water
will
be
about
40­
50
mg/
kg..
This
will
be
reflected
in
the
revised
Appendix
C.

Next
Steps:
The
HAP
Task
Force
will
take
these
discussions
into
consideration
in
preparing
a
response
to
EPAs
letter
ofMarch
1,
2002.

Attachment
#
1:
3/
1/
02
letter
to
the
HAP
Task
Force
Attachment
#
2:
3/
11/
0
1
c­
mails
between
Peter
Voytek
and
Rich
Leukroth
KEY
WORDS:
HAPs
ECA,
ethylene
dichloride,
PKJMECH
Signature
of
EPA
Official
&
Date:
Page
2
of
2
Richard
Leukroth,
Robert
DeWoskin
3/
26/
02
.
teo
Si
4
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
n~.
~
~
`_~
If..~_~­
 
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~~`­
0
/
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~
o
~
4gPRO1~
°
/
(_/
(
f
f
c_
n
­~

­
2/
op
March
1,
2002
OFFICE~
F
PREVENTION,
PE~
t~
IDESAND
TOXIC
SUBStfi~
i4CES
Dr.
Peter
Voytek
HAP
Task
Force,
Manager
Regulatory
Sciences
International
King
Street
Station
1800
Diagonal
Road,
Suite
500
Alexandria,
VA.
22~.
14­
2808
RE:
PBPK
Testing
Protocols
for
Ethylene
Dichloride
(
EDC)
(
OPPTS
­
42l97C)

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.

SI
I
OC~
T~
N,.
\~~­,

I
Ii
I
40020@
00022
~

Internet
Address
(
URL)
http://
wwwepa.
gov.
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Recycled/
Recyclable
.
Printed
with
Vegetable
Oil
Based
Inks
on
Re~'
cI
f~
aper­~.
Miñin~
um
25%
Postconsurner)
Doc~
U
$
E~
UO?
44
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
data
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
To:
Rich
Leukroth/
DC/
USEPA/
US@
EPA
cc:
Mike
Gargas
<
mlg@
thesapphiregroup.
com>,
John
Schaeffer/
DC/
USEPA/
US@
EPA
Sublect:
Response
to
ERAs
Review
Letter
on
PBPK
Testing
Protocols
for
EDC
We
have
reviewed
your
comments
concerning
the
three
technical
points
that
you
raised
that
need
resolution
as
defined
in
your
letter
dated
March
I,
2002.
Secondly,
we
are
particularly
concerned
regarding
the
monitoring
of
glutatione
metabolites
and
how
they
may
hinder
the
ability
of
the
model
to
effectively
perform
route
to
route
extrapolations.
We
would
be
interested
in
EPA
identifring
appropriate
metabolites
[
via
GSHanctoxidat.
ive
pathways]
and
providing
the
rationale
and
relevance
as
to
how
The
use
of
these
metabolites
would
better
validate
the
model
and
better
estimate
potential
EDC
health
risk
over
what
has
been
proposed
in
the
draft
ECA.

In
order
to
address
these
issues
in
a
timely
manner,
I
propose
that
we
have
another
meeting
at
the
upcoming
SOT
meeting
in
Nashville.
Let
me
know
if
this
is
acceptable
to
you
so
I
can
have
the
appropriate
technical
people
present.

Peter
Peter
Voytek
<
pvoytek@
crosslink.
n
et>

03/
11/
02
04:
20
PM
Rich
Leukroth
To:
pvoytek
©
crosslink.
net
~
03/
12/
02
1245
PM
cc:
Charles
Auer/
DC/
USEPA/
U5
©
EPA,
Frank
\
~
.
Kover/
DC/
USEPA/
US@
EPA,
Michel
~
°
.
Stevens/
RTP/
USEPA/
US@
EpA,
Rob
Dewoskin/
RTP/
USEPA/
US
©
EPA,
John
Schaeffer/
DC/
USEPA/
US@
EPA
Subject:
Re:
SOT
Technical
Consult
Meeting
on
EDO
Response
to
3/
11/
02
e~
mailfrom
Peter
Voytek
Li
Dear
Peter:

An
SOT
Technical
Consult
Meeting
is
an
excellent
suggestion
and
an
efficient
use
of
travel
resources.
This
will
provide
an
opportunity
to
discuss
your
questions
on
EPA
comments
on
the
appendices
to
the
draft
ECA
for
ethylene
dichloride
as
noted
in
EPAs
March
1,
2002
response
to
the
HAP
Task
Force.
It
is
my
understanding
that
this
technical
consult
meeting
will
focus
on
the
following
four
points:

1)
The
use
of
GSH
depletion
as
the
dose
metric
for
GSH
conjugate
formation
and
possible
implications
for
not
including
a
specific
measure(
s)
of
metabolite(
s),

2)
Details
regarding
how
parent
compound
will
be
measured
in
brain
tissue,

3)
Consideration
for
ad//
b/
turn
drinking
water
in
the
PK/
MECH
data
development,
and
4)
Clarification
of
citations
used
in
Table
1,
footnote
5
and
Appendix
0.5
of
the
draft
ECA.

Representing
EPA
will
be:
Richard
Leukroth,
Michel
Stevens,
and
Robert
DeWoskin.

I
suggest
that
we
plan
to
meet
either
Monday
3/
18/
02
12:
30~
1:
30p.
m.
or
Tuesday
3/
19/
02
4:
30
6:
00
p.
m.
Will
either
of
these
times
work
for
your
representative(
s)?
Any
suggestions
for
a
convenient
meeting
place
entry­
way
to
the
exhibit
hall?
As
an
alternative,
we
could
meet
in
my
room
since
Ill
be
staying
within
the
convention
complex.

Richard
W.
Leukroth,
Jr.
Environmental
Scientist
/
Toxicologist
Chemical
Control
Division
U.
S.
Environmental
Protection
Agency
Mall
Stop
7405;
Room
4328
5
1200
Pennsylvania
Avenue,
N.
W.
Washington,
DC
20460
Phone:
202~
564~
8167
FAX:
202~
564~
4765
E­
mail:
leukroth.
rich
©
epa.
gov