/
Rich
Leukroth
To:
pvoytek@
crosshnk.
net
cc:
John
Schaetfer/
DC/
USEPA/
US
©
EPA
04/
28/
2003
01:
16
PM
Subject:
TCE
ECA
Revised
TabIel
At
the
SOT
Program
Review
Technical
Consultation
meeting
last
month,
EPA
discussed
how
the
findings
from
Tier
I
and
Tier
I
Program
Review
testing
modify
some
of
the
original
thinking
about
some
of
the
Tier
II
activities.
These
changes
impact
the
footnotes
in
the
Tier
II
section
of
Table
1
in
the
ECA
agreement.
We
agreed
to
incorporate
these
changes
into
the
protocol
developmenl
aspect
for
TIER
II.

I
would
appreciate
your
comments
on
the
attached
revised
Table
1
for
Tier
II
activities.
Note:
The
testing
and
reporting
mix
stays
the
same
but
the
footnotes
for
the
route
dosimetry
extrapolations
are
changed
to
reflect
new
thinking
as
a
result
of
Tier
I
study
findings.
Give
me
a
call
at
202­
564­
8167
if
you
have
questions
or
need
to
discuss
further.

revisedTbl
1
4_
28_
03.
wpc
****
*
****
*******
******
******************
****,

Richard
W.
Leukroth,
Jr.
Environmental
Scientist
/
Toxicologist
Chemical
Control
Division
U.
S.
Environmental
Protection
Agency
Mail
Stop
7405;
Room
4328
S
1200
Pennsylvania
Avenue,
N.
W.
Washington,
DC
20460
Phone:
202­
564­
8167
FAX:
202­
564­
4765
E­
mail:
leukroth.
rich@
epa.
gov
Deliveries:
EPA­
East
Building
1201
Constitution
Avenue,
NW
Room
3166A
(
7401M)
Washington,
DC
20004
RECEIVED
OPPT
NCIC
2003
JUN24
8:
05AM
OPPT­
2002­
0056­
0065
Table
1.
Required
Testing,
Test
Standards,
and
Reporting
Requirements
for
TCE
­

Modifications
/
Revisions
(~)
to
Tier
H
Testing
and
Reporting
Activities
Testing
Required
testing
Test
standard
Deadline
for
Segment
final
report~
(
Months)

Tier
II
Testing
and/
or
Extrapolation
Reporting
Developmental
toxicity
(
oral)

Developmental
toxicity
extrapolation
of
oral
data
to
inhalation
Reproductive
toxicity
(
oral)

Reproductive
toxicity
extrapolation
of
oral
data
to
inhalation
~

Immunotoxicity
extrapolation
of
extant
oral
data
in
ECA
Appendix
E.
2
to
inhalation
`~

Carcinogenicity
extrapolation
of
extant
oral
data
in
ECA
Appendix
E.
3
to
inhalation
~
40
CFR
§
799.9620
(
as
annotated
in
ECA
Appendix
D.
3)

40
CFR
§
799.9370
(
as
annotated
in
ECA
Appendix
D.
4)

ECA
Appendix
C
40
CFR
§
799.9380
(
as
annotated
in
ECA
Appendix
D.
5)

ECA
Appendix
C
ECA
Appendix
C
ECA
Appendix
C
Number
of
months
after
the
effective
date
of
this
Federal
Register
Notice,
which
announces
that
EPA
has
concluded
the
EPA
Program
Review,
when
the
final
report
is
due.
In
addition,
every
6
months
from
the
effective
date
of
the
Order
until
the
end
of
the
ECA
testing
program,
interim
reports
describing
the
status
of
all
testing
to
be
performed
under
the
ECA
for
TCE
must
be
submitted
by
the
Companies
to
EPA.
40
CFR
§
799.9620
(
as
annotated
in
ECA
Appendix
D.
3)

ECA
Appendix
C
Acute
neurotoxicity
(
oral)

Acute
neurotoxicity
extrapolation
of
oral
data
to
inhalation
Subchronic
neurotoxicity
(
oral)

Subchronic
neurotoxicity
extrapolation
of
oral
data
to
inhalation
2
ECA
Appendix
C
12
15
18
21
24
27
30
33
9
6
I
Number
of
months
after
the
effective
date
of
this
Federal
Register
Notice,
which
announces
that
EPA
has
concluded
the
EPA
Program
Review,
when
the
final
report
is
due.
In
addition,
every
6
months
from
the
effective
date
of
the
Order
until
the
end
of
the
ECA
testing
program,
interim
reports
describing
the
status
of
all
testing
to
be
performed
under
the
Eca
forTCE
must
be
submitted
by
the
Companies
to
EPA.

2
Quantitative
route­
to­
route
extrapolation
documented
graphically
and
with
tabular
data.
Different
dose
metrics
to
be
evaluated
initially
at
the
protocol
development
stage
and
then
in
the
context
of
the
final
results.
Dose
metrics
to
consider
include
parent
compound
in
venous
blood
or
brain,
as
maximum
concentration
(
Cmax)
or
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
or
brain
per
day
normalized
to
organ
weight.
Should
mode
of
action
data
be
available
to
support
a
dose
metric
other
than
Cmax
or
AUC
for
parent
compound
(
e.
g.
time
above
a
critical
concentration
as
is
sometimes
used
in
pharmaceutical
applications)
that
dose
metric
will
be
derived
and
added
to
the
overall
evaluation.
The
choice
of
the
final
dose
metric
should
be
supported
with
mode­
ofaction
information
and
adiscussion
of
the
most
health
protective.

~
Quantitative
route­
to­
route
extrapolation
documented
graphically
and
with
tabular
data.
Different
dose
metrics
to
be
evaluated
initially
at
the
protocol
development
stage
and
then
in
the
context
of
the
final
results.
Dose
metrics
to
consider
include
parent
compound
in
venous
blood,
as
maximum
concentration
(
Cmax)
or
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
per
day
normalized
to
liver
weight.
The
choice
of
the
final
dose
metric
should
be
supported
with
mode­
of­
action
information
and
a
discussion
of
the
most
health
protective.

~
Quantitative
route­
to­
route
extrapolation
based
on
the
data
of
Sanders
et
al.
(
1985)
documented
graphically
and
with
tabular
data.
Dose
metrics
to
consider
include
parent
compound
in
venous
blood
or
spleen,
as
maximum
concentration
(
Cmax)
or
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
or
spleen
per
day
normalized
to
organ
weight.
The
choice
of
the
final
dose
metric
should
be
supported
with
mode­
of­
action
information
and
a
discussion
of
the
most
health
protective.

~
Quantitative
route­
to­
route
extrapolation
based
on
the
data
of
NCI
(
1978)
documented
graphically
and
with
tabular
data.
Dose
metrics
to
consider
include
parent
compound
in
venous
blood
or
liver,
as
maximum
concentration
(
Cmax)
or
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
per
day
normalized
to
liver
weight.
The
choice
of
the
final
dose
metric
should
be
supported
with
mode­
of­
action
information
and
a
discussion
of
the
most
health
protective.
Dose­
response
analysis
to
be
performed
using
genotoxic
assumption
(
linear
extrapolation)
procedure.
