Rich
Leukroth
To:
Pvoytek@
crosslink.
net
 
~
.
cc:
John
Schaeffer/
DC/
USEPA/
US@
EPA
/
05/
13/
2003
03.55
PM
Subject:
TCE
revised
Table
1
and
Appendix
C.
5
Peter,

Thanks
for
your
comments
on
the
initial
draft
revisions
to
Table
1
modifications
for
Tier
II
TCE
testing
and
reporting
activities.
Your
points
are
well
taken.
I've
had
some
discussions
with
the
folks
in
ORD
and
we
come
back
to
you
with
a
revision
that
I
believe
will
work
for
everyone.
Also
included
in
the
attached
file
are
modification
to
ECA
Appendix
0.5
regarding
the
route­
to­
route
extrapolation
reporting.
These
modifications
are
needed
to
reflect
changes
in
Tier
II
activities
described
in
Table
1
and
to
enhance
transparency
of
the
final
reporting
products.

Give
me
a
call
if
you
have
questions
or
need
to
discuss
further.

RevFootnotes
TbIl
5­
13­
03.
wp
*************************
*************************

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
0067
Table
1.

Tier
II
Testing
and/
or
Extrapolation
Reporting
Acute
neurotoxicity
extrapolation
of
Tier
II
drinking
water
acute
neurotoxicity
data
to
inhalation
2
Subchronic
neurotoxicity
(
drinking
water)

Subchronic
neurotoxicity
extrapolation
of
Tier
II
drinking
water
subchronic
neurotoxicity
data
to
inhalation
2
Developmental
toxicity
(
drinking
water)

Developmental
toxicity
extrapolation
of
Tier
II
drinking
water
developmental
toxicity
data
to
inhalation
~

Reproductive
toxicity
(
drinking
water)

Reproductive
toxicity
extrapolation
of
Tier
II
drinking
water
reproductive
toxicity
study
data
to
inhalation
~

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

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

ECA
Appendix
C
40
CFR
§
799.9620
(
as
annotated
in
ECA
Appendix
D.
3)

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

ECA
Appendix
C
40
CFR
§
799.93
80
(
as
annotated
in
ECA
Appendix
D.
5)

ECA
Appendix
C
ECA
Appendix
C
ECA
Appendix
C
Required
Testing,
Test
Standards,
and
Reporting
Requirements
for
1,1
,2­
Trichloroethane:
Modifications
to
Tier
II
Testing
and
Reporting
Activities
Testing
Required
testing
Test
standard
Deadline
Segment
for
final
report1
(
Months)

Acute
neurotoxicity
(
drinking
water)
12
15
18
21
24
27
30
33
9
6
inhalation
~
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
linal
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.

2
Quantitative
route­
to­
route
extrapolations
based
on
the
Tier
II
acute
and
suhchronic
drinking
water
neurotoxicity
study
data,
and
developed
for
each
of
the
following
dose
metrics:
parent
compound
in
venous
blood
and
brain,
as
maximum
concentration
(
Cmax)
and
as
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
or
brain
per
day
normalized
to
organ
weight.

~
Quantitative
route­
to­
route
extrapolations
based
on
the
Tier
II
drinking
water
developmental
toxicity
study
data,

and
developed
for
each
of
the
following
dose
metrics:
parent
compound
in
venous
blood,
as
maximum
concentration
(
Cmax)
and
as
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
per
day
normalized
to
liver
weight.

~
Quantitative
route­
to­
route
extrapolations
based
on
the
Tier
II
Drinking
water
reproductive
effects
toxicity
study
data,
and
developed
for
each
of
the
following
dose
metrics:
parent
compound
in
venous
blood,
as
maximum
concentration
(
Cmax)
and
as
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
per
day
normalized
to
liver
weight.

Quantitative
route­
to­
route
extrapolations
based
on
the
data
of
Sanders
et
al.
(
1985),
and
developed
for
each
of
the
following
dose
metrics:
parent
compound
in
venous
blood
and
spleen,
as
maximum
concentration
(
Cmax)
and
as
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
or
spleen
per
day
normalized
to
organ
weight.

6
Quantitative
route­
to­
route
extrapolations
based
on
the
data
of
NCI
(
1978),
and
developed
for
each
of
the
following
dose
metrics:
parent
compound
in
venous
blood
and
liver,
as
maximum
concentration
(
Cmax)
and
as
the
area
under
the
time­
concentration
curve
(
AUC),
and
metabolite,
as
amount
metabolized
in
the
liver
per
day
normalized
to
liver
weight.
C.
5
General
Outline
for
Route­
to­
Route
Extrapolation
A
total
of
six
route­
to­
route
extrapolation
reports
will
be
generated,
one
for
each
of
the
following
endpoints:
acute
neurotoxicity,
subchronic
neurotoxicity,
developmental
toxicity,
reproductive
effects
toxicity,
immunotoxicity,
and
carcinogenicity.
Each
of
these
reports
will
follow
the
general
outline
presented
below.

1.0.
Introduction
 
Summary
of
HAPS
Framework
 
Summary
of
PBPK
Model
2.0.
Summary
of
Key
Study
 
For
acute
neurological,
subchronic
neurological,
developmental,
and
reproductive
toxicity,
the
design
and
results
of
the
Tier
II
testing
will
be
summarized
 
For
immunotoxicity,
the
design
and
results
of
Sanders
et
al.
(
1
995)
and
White
et
al.
(
1
985)
will
be
summarized
 
The
design
and
results
of
NCI
(
1978)
will
be
summarized
3.0.
Selection
and
Discussion
of
Critical
En~
point~
s~
?
nd
Do~
eMeas~
re(~

 
Develop
~
for
each
of
the
followin.~
dose
metrics:
parent
.
pornpou~
din
v.~
nousblood
and
brain~
as
maximum
concentration
(
çmax.)
an
~
the
time­
concentration
curv~{~
UC)~
aboliteas
gin
tmetabolizeiijn
the
liver
or
brain
çr
day
p~
j~
gljzed
to
or~
anwei
ht.

 
Develop
a
~
effects
toxicifyjor
earh
of
the
following
dose
metrjcs:
parent
corr~
poundin
venous
blood.~
as
maximum
concentration
.(
Cmax)
and
as
the
area
under
the
time­
concentration
curve
~(
AJ~
ç)~
~

­
For
immunotoxicity,
the
route­
to­
route
extrapolations
are
based
on
the
data
of
Sanders
et
al.
~~
j~
eveloa
~
~
r
fjh~
jo~
jpg~
metrics
parent
comj~
oundin
venous
blood
anç
sp1een~
as
ma~
j
urn~
and
as
the
areaunder
the
time­
concentration
curve
(~
JQ,
and
rnetabolite~
gsamounL
metabolized
~

­
For
carcinogenicity,
the
route
to­
route
extrapolations
are
based
on
the
data
of
NCI
(
1978).
Develop
a
quantitative
route­
to­
route
extrapolation
for
each
of
the
fo1lowip~
dose
metrics:
parent
compou.
pd
in
venous
blood
apd
live~
a~
jPA~'
mçpncentratiop~
ma~~
p~
d
as
the
area
under
the
time
concentration
curve
ndmetg~
olto
metabolizedin
the
li
ver
~
ormalizedtoliverweiht.

4.0
Route­
to­
Route
Extrapolation
Results
 
Quantitative
calculation
of
the
inhalation
dose­
response
curve
based
upon
the
PBPK
model
and
the
oral
data.

5.0.
Sensitivity,
Uncertainty,
and
Variability
Analysis
 
Discussion
of
the
sensitivity
analysis
for
impact
of
change
in
each
parameter
to
the
PBPK
siinu
lation
and
to
the
resultin
route
to­
route
extra
olatioi~.

­
Qualitative
(
or
if
possible,
quantitative)
assessment
of
the
variability
and
uncertainty
in
the
~
odelarameter~
alues.
6.0.
Conclusions
7.0.
References
8.0.
Appendices
 
PBPK
niodel
(.
CSL)
and
conmiand
(
CMI))
files
that
include
the
procedures
used
to
~
eTIeratc
~
Iliesccit~
icd~
ei~
rics.

 
PBPK
model
simulation
daia
in
tabular
and/
or
~
raphicaIform.
and
accumpam~
uiganaivse~
that
~
