~
c~
0~

(~)
I:
q~.~
o~
c~
°
PROGRAM
REVIEW
REPORT
ON
THE
ENFORCEABLE
CONSENT
AGREEMENT
FOR
1,1,2­
TRICHLOROETHANE
CAS
No.
79­
00­
5
e­
Docket
No.
OPPT
2002­
005
6
DATE
April
21,
2003
U.
S.
E.
P.
A.

Office
of
Pollution
Prevention
and
Toxics
Office
of
Research
and
Development
OPPT­
2002­
0056­
0059
RECEIVED
OPPT
NCIC
2003
JUN23
9:
50AM
Program
Review
Report
on
the
Enforceable
Consent
Agreement
for
1,1,2­
Trichioroethane
TABLE
OF
CONTENTS
Page
I.
Introduction
1
II.
Description
of
the
TCE
Alternative
Testing
Program
3
III.
EPA
Program
Review
Approach
4
IV.
Program
Review
Findings
5
V.
Conclusions
and
Recommendations
10
VI.
References
11
VII.
List
of
Contributors
13
Appendix
1:
ECA
Required
Testing,
Test
Standards,
Reporting
and
Other
Requirements
for
1,1
,2­
Trichloroethane
14
 
1
 
I.
INTRODUCTION
1,1
,2­
Trichloroethane
(
TCE)(
CAS
No.
79­
00­
05)
is
used
as
a
feedstock
intermediate
in
the
production
of
vinylidene
chloride
and
some
tetrachioroethanes.
It
is
also
used
as
a
solvent
where
its
high
solvency
for
chlorinated
rubbers
and
other
substances
is
needed,
and
for
pharmaceuticals
and
electronic
components.
TCE
was
listed
as
a
hazardous
air
pollutant
(
HAP)
under
revisions
to
the
Clean
Air
Act
of
1990
(
42
U.
S.
C.
7413).

On
June
26,
1997,
the
Environmental
Protection
Agency
(
EPA)
proposed
a
test
rule
for
21
HAP
chemicals
including
TCE
(
61
FR
33178;
62
FR
67466;
63
FR
5915;
and
63
FR
19694).
1
While
the
rulemaking
proposed
that
all
testing
be
conducted
by
the
inhalation
route
of
exposure,
it
also
invited
the
submission
of
alternative
testing
proposals
supporting
the
development
of
physiologically­
based
pharmacokinetic
(
PBPK)
computational
models
for
route­
to­
route
extrapolation
ofdose­
response
to
predict
response
for
inhalation
exposure.
Computational
dosimetry
models
could
take
advantage
of
studies
(
acceptable
to
EPA)
that
were
conducted
by
routes
other
than
inhalation
and
allow
for
route­
to­
route
extrapolation
of
dose­
response
to
inhalation
exposure
scenarios.
Alternative
testing
proposals
that
incorporate
PBPK
dosimetry
modeling,
if
acceptable
to
EPA,
could
provide
the
basis
to
develop
a
tailored
approach
to
inhalation
testing
proposed
in
the
HAP
rulemaking
via
the
enforceable
consent
agreement
(
ECA)
process
(
40
CFR
790.22(
b)).

On
November
22,
1996,
the
Hazardous
Air
Pollutant
Task
Force
(
HAP
Task
Force)
2
submitted
an
alternative
testing
proposal
for
TCE
(
HAP
Task
Force
1996).
EPA
evaluated
this
proposal
and
determined
that
it
formed
a
sufficient
basis
to
initiate
ECA
discussions
to
develop
an
ECA
for
TCE
(
U.
S.
EPA
1997).
Discussions
to
develop
an
ECA
for
TCE
were
initiated
at
a
public
meeting
on
January
12,
1998
(
62
FR
66628;
December
19,
1997).
These
discussions
led
to
the
development
of
a
successful
ECA
and,
under
the
authority
ofsection
4
ofthe
Toxic
1
The
official
record
for
the
proposed
HAP
rulemaking,
including
the
public
version,
is
established
under
EPA
docket
control
number
OPPTS
­
42198B.
The
EPA
Docket
Center
is
located
in
Room
B
102­
Reading
Room,
EPA
West,
1301
Constitution
Avenue,
N.
W.,
Washington,
DC.
The
EPA
Docket
Center
is
open
from
8:
30
a.
m.
to
4:
30
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.

2
Member
companies
of
the
HAP
Task
Force
include:
The
Dow
Chemical
Company,
Vulcan
Materials
Company,
Occidental
Chemical
Corporation,
Oxy
Vinyls,
LP,
CONDEA
Vista
Company,
Georgia
Gulf
Corporation,
Westlake
Chemical
Corporation,
PPG
Industries,
Inc.,
and
Formosa
Plastics
Corporation,
U.
S.
A.
The
Borden
Chemicals
&
Plastics
Operating
Limited
Partnership
is
undergoing
Chapter
11
and
has
withdrawn
from
the
HAP
Task
Force.

1
Substances
Control
Act
(
TSCA)
(
15
U.
S.
C.
2603),
EPA
and
member
Companies
ofthe
HAP
Task
Force
entered
into
an
ECA
to
conduct
testing
for
TCE
(
65
FR
37550).~

EPA
announced
the
receipt
oftest
results
for
testing
conducted
under
the
Tier
I
and
Tier
I
Program
Review
segments
ofthe
ECA
for
TCE
(
67
FR
17429,
April
10,
2002;
67
FR
17996,
April
12,
2002;
and
67
FR
53001,
August
14,
2002).
Specifically,
EPA
announced
receipt
of
four
reports
entitled:

1.
"
Acute
Inhalation
Toxicity
(
with
Histopathology)
Study
of
1,1
,2­
Trichloroethane
(
1,
l,
2­
TCE)
in
Rats
by
V/
IL
Research
Laboratories,
Inc."
(
67
FR
17429,
April
10,
2002),

2.
"
Pharmacokinetics
of
1,1
,2­
Trichloroethane
in
Rats
and
Mice
by
Battelle
Pacific
Northwest
Laboratories."
(
67
FR
17996,
April
12,
2002).

3.
"
A
90­
Day
Inhalation
Toxicity
Study
of
1,1
,2­
Trichloroethane
(
1,1,2­
TCE)
in
Rats
(
With
Satellite
Groups
for
Pharmacokinetic
Evaluations
in
Rats
and
Mice)"
(
67
FR
53001,
August
14,
2002),

4,
"
Physiologically
Based
Pharmacokinetic
Model
Development,
Simulations,
and
Sensitivity
Analysis
for
Repeated
Exposure
to
1,1
,2­
Trichloroethane"
(
67
FR
53001,
August
14,
2002).

On
October
16,
2002,
EPA
announced
the
initiation
of
a
program
review
to
evaluate
data
received
under
the
Tier
I
Program
Review
Testing
segment
ofthe
ECA
for
TCE
(
67
FR
639
13).~
This
announcement
solicited
public
comment
on
the
Tier
I
Program
Review
testing
reports
submitted
by
the
HAP
Task
Force
(
see
above
#
2
and
#
4)
and
asked
whether
or
not
it
is
feasible
and
appropriate
to
apply
this
data
and
other
studies
acceptable
to
EPA
to
inform
the
TCE
model
~
The
official
record
for
developing
the
ECA
alternative
testing
program
for
TCE,
including
the
public
version,
is
established
under
EPA
docket
control
number
OPPTS­
42198B,
while
the
official
record
for
data
developed
under
this
ECA,
including
the
public
version,
is
established
under
EPA
docket
control
number
OPPTS­
42198C.
The
EPA
Docket
Center
is
located
in
Room
B
102­
Reading
Room,
EPA
West,
1301
Constitution
Avenue,
N.
W.,
Washington,
DC.
The
EPA
Docket
Center
is
open
from
8:
30
a.
m.
to
4:
30
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.

~
The
official
record
for
this
action
is
established
under
EPA
e­
Docket
OPPT­
2002­
0056.
The
EPA
Docket
Center
is
located
in
Room
B
102­
Reading
Room,
EPA
West,
1301
Constitution
Avenue,
N.
W.,
Washington,
DC.
The
EPA
Docket
Center
is
open
from
8:
30
a.
m.
to
4:
30
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.
An
electronic
version
ofthis
public
docket
is
available
through
EPA's
electronic
public
docket
system,
EPA
Dockets
at
http://
www.
epa.
govfedocket/.
Once
in
the
system,
select
"
search,"
then
key
in
OPPT­
2002­
0056.

2
for
quantitative
computational
route­
to­
route
dosimetry
extrapolations
of
endpoints
listed
under
the
Tier
II
testing
segment
of
the
ECA
for
TCE.
Comments
received
from
this
announcement
would
be
used
to
inform
EPA's
Program
Review.
In
conjunction
with
this
announcement,
EPA's
Office
of
Prevention,
Pollution
and
Toxics
(
OPPT),
Chemical
Control
Division
(
CCD)
requested
that
EPA's
Office
of
Research
and
Development's
(
ORD),
National
Center
for
Environmental
Assessment
(
NCEA)
review
the
TCE
ECA
Tier
I
Program
Review
model
development
and
related
pharmacokinetics
and
mechanistic
(
PKIMECH)
data
to
determine
if
these
materials
are
sufficient
to
advance
the
ECA
testing
to
the
Tier
II
segment
ofthe
ECA
for
TCE.

The
findings
and
conclusions
for
the
EPA
Program
Review
activity
are
described
in
this
report.
This
report,
along
with
a
copy
of
the
letter
sent
to
the
HAP
Task
Force
informing
it
of
EPA's
Program
Review
conclusions,
and
comments
received
from
the
October
16,
2002
Federal
Register
announcement
will
be
placed
in
the
record
for
this
action.
4
II.
DESCRIPTION
OF
THE
TCE
ALTERNATIVE
TESTING
PROGRAM
The
alternative
testing
program
approach
to
address
dataneeds
for
TCE
identified
in
the
HAP
rulemaking
includes
new
testing
by
both
the
inhalation
and
oral
routes
ofexposure,
development
of
PK/
MECH
data
directed
at
characterizing
the
mode­
of­
action
ofTCE,
development
of
a
computational
dosimetry
model
based
upon
the
PK/
MECH
data
to
support
quantitative
route­
to­
route
extrapolation
from
acceptable
extant
studies
and
studies
conducted
under
the
TCE
alternative
testing
program,
and
extrapolations
for
route
and
species
differences
from
acceptable
extant
studies
in
the
literature
for
TCE
and
new
testing
conducted
under
the
ECA.
There
are
four
segments
to
the
alternative
testing
program
for
TCE:
1)
Tier
I
HAPs
Testing;
2)
Tier
I
Program
Review
Testing;
3)
EPA
Program
Review;
and
4)
Tier
II
Testing
and/
or
Extrapolation
Reporting.
Testing
under
these
segments
is
summarized
in
Table
1
of
the
ECA
for
TCE
(
see
Appendix
1
of
this
report).

The
Tier
I
HAP
Testing
included
endpoint
testing
for
acute
and
subchronic
toxicity
by
inhalation
exposure.
EPA
determined
that
the
existing
cytogenicity
studies
conducted
by
Mazzulo
et
a!.
(
1986)
and
Doherty
et
al.
(
1996)
were
adequate
to
characterize
the
mutagenicity~
of
TCE.

The
Tier
I
Program
Review
Testing
included:
(
1)
development
ofa
computational
dosimetry
model
specific
for
TCE
in
rats
and
mice,
(
2)
simulation
testing
of
the
predictive
capability
ofthe
model
against
an
inhalation
test
data
set,
and
(
3)
demonstration
ofthe
model's
utility
in
supporting
quantitative
route­
to­
route
dosimetry
extrapolations.
In
addition,
the
HAP
Task
Force
conducted
studies
generating
PKIMECH
data
needed
to
develop
the
model
for
the
endpoints
listed
in
Tier
II
ofthe
ECA
for
TCE.
Specifically,
the
model
and
the
PKIMECH
data
developed
under
the
Tier
I
Program
Review
Testing
are
used
to:
(
1)
simulate
the
dose­
response
curve
that
would
result
from
an
inhalation
exposure
based
upon
the
results
observed
in
existing
3
immunotoxicity
data
in
mice
administered
TCE
via
drinking
water
(
Sanders
et
al.,
1985),
(
2)
simulate
the
dose­
response
from
an
inhalation
exposure
based
upon
the
results
observed
in
existing
mouse
cancer
bioassay
data
in
mice
administered
TCE
via
corn
oil
gavage
(
NCI,
1978),
and
(
3)
demonstrate
the
overall
utility
ofthe
PBPK
model
for
route­
to­
route
(
oral­
to­
inhalation)
dose­
response
extrapolation
for
other
endpoints
based
upon
oral
exposure
studies
(
to
be
conducted
in
Tier
II)
including:
(
a)
neurotoxicity
based
on
an
oral
drinking
water
study
in
rats,
(
b)
developmental
toxicity
based
on
oral
drinking
water
exposure
in
rats
and
mice,
and
(
c)
reproductive
effects
toxicity
based
on
oral
drinking
water
exposure
in
rats.

The
Program
Review
segment
was
included
in
the
ECA
for
TCE
as
a
mechanism
to
address
uncertainty
regarding
model
structure
and
the
impact
of
new
insights
identified
from
the
Tier
I
and
Tier
I
Program
Review
testing
on
the
model
structure
and
Tier
II
route­
to­
route
dosimetry
extrapolations.
Since
modeling
is
an
iterative
process
the
Program
Review
provides
opportunity
for
the
EPA
and
the
HAP
Task
Force
to
incorporate
additional
changes,
if
necessary,
into
the
model
development
and/
or
the
Tier
II
testing
and
route­
to­
route
dosimetry
extrapolation
reporting.

The
Tier
II
Testing
and
Extrapolation
Reporting
segment
of
the
ECA
for
TCE
will
include:
acute
neurotoxicity,
subchronic
neurotoxicity,
developmental
toxicity,
and
reproductive
effects
toxicity
testing
by
the
oral
route
of
exposure,
and
computational
route­
to­
route
doseresponse
extrapolation
for
acute
neurotoxicity,
subchronic
neurotoxicity,
developmental
toxicity,
reproductive
effects
toxicity,
immunotoxicity,
and
carcinogenicity.

III.
EPA
PROGRAM
REVIEW
APPROACH
As
stated
in
the
ECA
for
TCE,
the
purpose
of
the
Program
Review
is
to
determine:
(
1)
if
the
submitted
toxicity
and
PKIMECH
data,
the
PBPK
model,
and
the
reports
submitted
by
the
HAP
Task
Force
(
see
above
Section
I)
are
per
the
specifications
defined
in
Part
VI
including
Table
1
and
the
accompanying
Appendices
ofthe
ECA
for
TCE;
(
2)
whether
it
is
feasible
and
appropriate
to
apply
Tier
I
Program
Review
Testing
data
and
data
from
other
studies
acceptable
to
EPA
to
inform
route­
to­
route
dosimetry
extrapolations
for
endpoints
listed
in
the
Tier
II
Testing
segment;
(
3)
whether
the
data
from
the
Tier
I
Program
Review
Testing
segment
(
see
Part
VI.
B.
ofthe
ECA
for
TCE)
provide
a
sufficient
basis
for
conducting
the
endpoint
testing
and/
or
the
route­
to­
route
dosimetry
extrapolations
specified
in
the
Tier
II
Testing
segment
ofthe
ECA
for
TCE;
and/
or
(
4)
the
nature
and
scope
of
any
additional
work
that
may
be
required
prior
to
the
commencement
of
Tier
II
Testing
and
extrapolation
reporting
(
e.
g.,
additional
PKIMECH
data
as
described
in
Part
VII.
ofthe
ECA
for
TCE).

EPA's
ORD/
NCEA
conducted
a
comprehensive
review
of
the
data
and
reports
submitted
to
the
Agency
under
the
Tier
I
HAPs
Testing
and
the
Tier
I
Program
Review
Testing.
The
initial
step
included
checking
the
toxicity
and
PK!
MECH
data,
the
PBPK
model,
and
the
reports
for
4
quality
and
completeness
of
the
information
in
accordance
with
the
specifications
established
under
Part
VI
and
including
Table
1
and
the
accompanying
Appendices
of
the
ECA
for
TCE.
EPA
then
assessed
how
well
the
PK/
MECH
data
characterized
the
mode
ofaction
and
supported
the
biological
plausibility
of
the
HAP
Task
Force
PBPK
model
for
TCE.
In
addition,
EPA
assessed
the
quality
and
predictive
capability
ofthe
TCE
PBPK
model
for
simulating
a
doseresponse
from
an
inhalation
exposure
based
upon
oral
exposure
data.
The
criteria
for
this
component
ofthe
EPA
review
was
based
on
accepted
practice
described
in
the
scientific
literature
and
outlined
in
Part
V
ofthe
ECA
for
TCE.
This
aspect
of
the
model
evaluation
also
included
consideration
ofthe
inhalation
and
oral
exposure
data
generated
in
the
Tier
I
and
Tier
I
Program
Review
segments
of
the
alternative
testing
program
for
TCE
and
how
well
the
TCE
PBPK
model
performed
in
simulating
the
calibration
and
test
data
sets
provided
by
the
HAP
Task
Force.
EPA
then
considered
the
utility
ofthe
TCE
PBPK
model
for
extrapolating
doseresponse
curves
from
oral­
to­
inhalation
exposures
based
only
upon
existing
oral
exposure
data
(
or
oral
exposure
data
to
be
generated
in
Tier
II)
for
the
following
data
needs
­
neurotoxicity,
developmental
toxicity,
and
reproductive
effects
toxicity
in
the
F344
rat;
and
developmental
toxicity,
immunotoxicity,
and
carcinogenicity
in
the
mouse.
Finally,
based
on
new
findings
from
the
Tier
I
and
Tier
I
Program
Review
Testing,
the
EPA
review
identified
the
nature
and
scope
of
additional
considerations
to
be
addressed
in
the
Tier
II
protocol
development
and
route­
to­
route
extrapolation
reporting.

Specifically,
EPA
conducted
a
five
step
evaluation
of
the
TCE
PBPK
model
that
addressed:
1)
model
purpose,
2)
model
structure
and
biological
plausibility,
3)
mathematical
representation
and
computer
implementation,
4)
model
calibration
(
data
used
and
derivation
of
parameter
values,
data
support
for
parameter
values,
sensitivity
analysis,
optimization),
and
5)
predictive
utility
ofthe
model
for
TCE.

IV.
PROGRAM
REVIEW
FINDINGS
A.
COMPLETENESS
OF
REPORTED
INFORMATION
EPA's
review
of
the
Tier
I
Program
Review
PKJMECH
data
and
Tier
I
toxicity
studies
indicate
that
they
were
conducted
in
accordance
with
the
protocols
and
specifications
ofthe
ECA.
The
available
study
records
are
sufficient
to
allow
an
evaluation
of
the
quality
of
the
data
and
reports.
The
TCE
PBPK
model
is
chemical­
specific
and
based
on
an
understanding
from
the
data
for
the
kinetics
and
mode
of
action
ofthe
various
endpoint
toxicities
for
TCE
for
which
there
are
data.
The
species,
dose
level,
exposure
regimens,
and
vehicles
used
were
as
specified
in
the
ECA
for
Tier
I
and
Tier
I
Program
Review
Testing.

5
B.
APPLICATION
OF
TIER
I
TEST
RESULTS
TO
ROUTE­
TO­
ROUTE
EXTRAPOLATION
The
rat
PBPK
model
is
parameterized
to
fit
the
blood
concentration­
time
course
for
the
rat
kinetic
data
from
exposures
via
inhalation
(
100
ppm),
gavage
oil
(
94
mg/
kg/
day),
and
gavage
water
(
1.66
mg/
kg/
day).
Metabolic
parameters
(
Vmax
and
Km)
were
optimized
for
the
inhalation
data.
The
absorption
rates
for
the
oil
and
water
vehicles
were
optimized
to
fit
the
respective
gavage
data.
The
resulting
model
was
then
used
to
simulate
all
data
sets
without
further
changes
in
the
parameter
values.

The
mouse
PBPK
model
is
parameterized
to
fit
the
blood
concentration­
time
course
for
the
mouse
kinetic
data
from
exposures
via
inhalation,
gavage
oil,
and
gavage
water.
Vmax
was
optimized
for
the
oil
gavage
data,
and
terms
were
added
to
the
model
to
simulate
a
proposed
suicide
inhibition
ofenzyme
from
binding
to
a
reactive
intermediate
that
occurs
only
in
females.
Absorption
rates
for
the
oil
and
water
vehicles
were
optimized
to
fit
the
respective
gavage
data.
The
resulting
model
was
then
used
to
simulate
the
inhalation
data
without
further
changes
in
the
parameter
values.

The
Tier
I
Program
Review
PKIMECH
data
demonstrated
that
periodicity
was
achieved
for
the
studies
that
supported
the
model
development.
Periodicity,
as
defined
in
U.
S.
EPA
(
1994),
is
achieved
when
the
internal
concentration
ofthe
dose
metric
of
interest
(
e.
g.,
parent
venous
concentration)
versus
time
profile
is
the
same
for
90%
of
the
exposure
period.

The
PBPK
model
simulations
are
within
a
factor
of
2
fold
(
on
average)
ofthe
fitted
data
as
specified
under
the
ECA,
except
for
the
fits
to
the
corn
oil
gavage
dose
in
rats.
EPA
notes
that
further
optimization
of
the
parameter
values
for
absorption
or
maximum
metabolic
rate
(
Vmaxc)
would
likely
improve
the
fit.
Since
the
sensitivity
ofthe
model
output
to
the
value
for
the
maximum
metabolic
rate
depends
upon
the
dose
levels
specified
in
the
Tier
II
study
protocols
(
i.
e.,
depends
upon
the
levels
of
parent
compound
achieved
in
the
tissue
relative
to
Km),
EPA
considers
further
adjustments
to
parameter
values
to
improve
fit
should
be
an
important
consideration
for
the
HAP
Task
Force
to
address
in
developing
Tier
II
protocols
C.
BASIS
FOR
CONDUCTING
THE
ENDPOINT
TESTING
AND/
OR
THE
ROUTE­
TO­
ROUTE
DOSIMETRY
EXTRAPOLATIONS
IN
TIER
II
The
Tier
I
Testing
Program
results
support
the
use
of
the
PBPK
model
for
route­
to­
route
dosimetry
extrapolations
for
the
extant
and
proposed
Tier
II
studies.
Periodicity
was
demonstrated.
Although
effects
on
nasal
epithelial
tissues
were
noted
in
Tier
I
inhalation
testing,
these
changes
were
not
deemed
to
significantly
impact
the
systemic
distribution
ofthe
parent
compound,
and
first
pass
effects
can
be
accounted
for
in
the
HAP
Task
Force
PBPK
model
for
TCE.
The
structure
ofthe
PBPK
model
for
TCE
supports
simulations
for
a
variety
of
internal
dose
metrics
allowing
choice
for
the
dose
metric
that
will
be
most
relevant
to
the
endpoints
6
identified
for
Tier
II.
This
PBPK
model
for
TCE
includes
simulation
of
the
carcinogenicity
and
immunotoxicity
dose­
response
data
from
existing
studies,
and
for
the
developmental,
reproductive
effects,
and
neurotoxicity
dose­
response
data
to
be
developed
in
the
Tier
II
testing.

At
the
time
when
the
ECA
for
TCE
was
developed,
EPA
and
the
HAP
Task
Force
specified
whether
the
parent
compound
or
measures
of
metabolite
production
should
be
used
for
the
route
dosimetry
extrapolations
for
each
ofthe
Tier
II
endpoints.
These
specifications
were
based
on
the
best
available
understanding
for
the
mode
ofaction
for
TCE
at
that
time.
Since
then,
the
Tier
I
testing
developed
new
information
regarding
potential
portal
ofentry
effects
and
a
proposed
mechanism
of
suicide
inhibition.
EPA
believes
that
considerations
for
these
new
data
must
be
incorporated
into
Tier
II
Testing
because
the
most
appropriate
internal
measure
of
dose
is
ultimately
determined
by
mode
of
action
data
or
dose­
response
data
allowing
evaluation
ofthe
degree
ofcorrelation
ofthe
dose
metric
and
the
response.
In
the
absence
of
adequate
information,
alternative
dose
metrics
should
be
evaluated
for
the
Tier
II
route­
to­
route
dosimetry
extrapolations.
For
risk
assessment
purposes,
EPA
intends
to
select
the
extrapolation
which
EPA
considers
to
be
most
conservative
(
i.
e.,
the
most
health
protective).

For
TCE,
the
dose
metrics
for
the
parent
compound
include
the
maximum
concentration
(
Cmax)
and
the
area
under
the
curve
(
AUC)
for
venous
blood,
spleen,
or
brain.
Both
Cmax
and
AUC
in
blood
will
be
calculated
for
the
developmental,
reproductive
effects,
and
neurotoxicity
studies.
Cmax
and
AUC
will
be
calculated
in
spleen
for
the
immunotoxicity
study,
(
as
indicated
in
Appendix
C.
2
of
the
ECA
for
TCE),
and
in
blood
and
brain
for
the
neurotoxicity
studies
(
as
indicated
in
Table
1
­
Tier
II
Testing
and/
or
Extrapolation
Reporting
of
the
ECA
for
TCE).
The
route
dosimetry
extrapolations
to
inhalation
will
be
conducted
using
both
dose
metrics.
To
the
extent
that
additional
information
on
the
mode­
of­
action
or
correlations
with
response
is
available
to
support
one
dose
metric
over
the
other,
this
information
will
be
available
in
the
Tier
II
reporting
consistent
with
Appendix
C.
5
point
3.0
(
which
indicates
dose
measure
will
be
determined
by
Tier
II
testing).
In
the
absence
of
a
toxic
response
for
the
endpoint
of
concern,
there
is
no
need
to
calculate
dose
metrics
or
conduct
the
route
dosimetry
extrapolation.
Should
mode
ofaction
data
be
available
to
support
a
dose
metric
other
than
Cmax
orAUC
for
parent
compound
(
e.
g.
time
above
a
critical
concentration
as
is
sometimes
used
in
phannaceutical
applications)
that
dose
metric
will
be
derived
and
added
to
the
overall
evaluation.

The
dose
metric
for
metabolite
will
be
the
amount
metabolized
per
day
normalized
to
liver
weight.
A
gender
difference
in
metabolic
time­
concentration
profiles
has
been
observed
in
mice
that
will
affect
the
route
dosimetry
extrapolations
based
upon
the
extant
mouse
data
for
carcinogencity.
The
time­
concentration
profile
data
for
female
mice
from
the
oil
gavage
studies
conducted
in
Tier
I,
and
a
previously
observed
reduction
in
aniline
hydroxylase
in
female
mice
only
(
White
et
al.,
1985)
support
a
mechanism
of
suicide
inhibition
of
enzyme
by
TCE
in
female
mice,
but
not
males.
In
the
case
of
no
difference
in
dose­
response
between
males
and
females,
the
Agency
will
favor
the
more
health
protective
route­
extrapolation
based
upon
the
female
kinetic
data
(
i.
e.,
the
presence
ofsuicide
inhibition)
for
the
dose­
response
analyses.

7
Table
1
of
the
ECA
indicates
that
metabolite
in
blood
will
be
evaluated
for
the
Tier
II
acute
neurotoxicity
study.
Given
the
Tier
I
study
results
and
the
reactive
nature
ofthe
metabolites
formed,
metabolite
in
blood
is
not
a
reasonable
dose
metric
for
neurotoxicity.
Appropriately,
the
HAP
Task
Force
did
not
include
this
in
the
pharmacokinetic
model
developed
in
Tier
1.
However,
EPAbelieves
that
it
is
plausible
that
damage
caused
by
reactive
metabolites
could
impact
dosimetry
extrapolations
for
both
the
neurotoxicity
and
immunotoxicity
endpoints
(
although
narcotic
effects
would
be
expected
to
arise
from
the
parent
compound).
Ideally
this
should
be
assessed
by
estimating
the
formation
of
reactive
metabolites
in
potential
target
tissue
(
e.
g.
CNS,
spleen).
Based
upon
current
understanding
of
cytochrome
p450
(
CYP2E1)
activity,
EPA
anticipates
that
there
will
be
substantial
uncertainty
in
estimating
the
extent
of
metabolism
in
such
target
tissues.
Target
tissue
specific
metabolism
could
simply
be
modeled
as
a
low
fraction
of
liver
activity
(
e.
g.
0.1%
is
suggested
for
brain
by
Tinberg
and
Ingelman­
Sundberg,
1996)
for
these
Tier
II
route
dosimetry
extrapolations.
Alternately,
the
HAP
Task
Force
could
use
the
amount
metabolized
per
day
normalized
to
liver
weight
as
a
target
tissue
surrogate,
if
first
pass
metabolism
in
the
liver
is
relatively
low
(
i.
e.,
less
than
15%).
The
HAP
Task
Force
should
further
discuss
this
point
and
provide
the
rationale
for
the
approach
selected
as
a
component
of
protocol
development
under
Tier
II
activities.

The
above
discussion
on
dose
metrics
underscores
the
need
for
the
HAP
Task
Force
to
apply
the
expanded
Tier
I
PBPK
model
for
TCE
in
developing
Tier
II
study
protocols
and
proposed
dose
selections
for
newtesting
to
be
performed
under
Tier
II.
For
example,
model
simulations
for
several
of
the
dose
metrics
will
be
sensitive
to
how
the
dose
is
modeled
via
drinking
water.
EPA
believes
that
the
details
of
such
considerations
must
be
fully
transparent
prior
to
conduct
of
the
Tier
II
studies.
While
the
ultimate
selection
ofthe
most
appropriate
dose
metric
will
be
based
upon
the
study
results,
EPA
believes
that
clarification
ofthe
options
for
a
route
dosimetry
extrapolation
relative
to
each
endpoint
(
e.
g.,
the
probable
dose
metric
and
the
preferred
pattern
to
model
a
drinking
water
exposure)
are
best
incorporated
into
the
Tier
II
protocol
development.

D.
NATURE
ANDSCOPE
OF
ANYADDITIONAL
WORK
The
EPA
Program
Review
ofthe
ECA
for
TCE
identified
additional
considerations
for
the
HAP
Task
Force
to
incorporate
into
Tier
II
testing
and
Extrapolation
Reporting.

1.
Applying
PK/
MECH
data
and
the
TCE
model
in
Tier
II
EPA
notes
that
it
would
be
highly
advantageous
to
use
the
PBPK
model
developed
in
Tier
I
to
simulate
various
dose
metrics
for
the
proposed
Tier
II
study
designs
as
part
ofthe
protocol
development
and
selection
of
the
appropriate
drinking
water
concentrations.
Applying
the
PBPK
model
in
this
way
will
improve
the
design
ofthe
studies
by
identifying
whether
the
modeling
predicts
kinetically
distinguishable
internal
dose
metrics
for
the
concentrations
proposed.
In
addition,
this
will
support
choosing
the
most
scientifically
8
defensible
dose
metric
based
upon
comparisons
with
the
dose­
response
data
from
existing
studies.
Applying
the
current
iteration
ofthe
PBPK
model
to
each
ofthe
Tier
II
study
designs
is
also
an
important
exercise
to
further
evaluate
whether
the
pharmacokinetic
studies
in
Tier
I
adequately
characterized
the
dose
ranges
specified
in
Tier
II
studies,
and
whether
the
parameter
estimates,
particularly
for
Vmax,
are
adequate.
Ideally,
the
blood
concentrations
in
the
various
pharmacokinetic
studies
should
span
the
relevant
range
to
be
simulated
in
the
toxicity
studies.
If
the
doses
in
the
toxicity
studies
range
from
sub­
saturating
to
saturating,
then
an
additional
PK
study
at
a
high
dose
may
be
needed
to
better
characterize
Vmax
in
the
rats.
Conversely,
if
dose
levels
in
the
toxicity
study
lead
to
essentially
sub­
saturating
internal
levels
(
evaluated
by
comparing
the
venous
concentration
exiting
the
liver
with
the
Km),
then
the
relative
importance
ofVmax
is
diminished
and
additional
data
to
refine
Vmax
may
not
be
needed.

2.
Modeling
Drinking
Water
EPA
notes
that
there
are
a
number
of
dosing
patterns
that
can
be
used
in
the
PBPK
model
to
simulate
the
drinking
water
exposures
proposed
in
the
Tier
II
study
protocols
or
cited
in
the
existing
carcinogenicity
and
immunotoxicity
studies.
While
the
total
amount
metabolized
(
normalized
by
liver
weight)
may
not
be
very
sensitive
to
one
or
another
drinking
water
pattern,
estimates
of
Cmax
will
be
highly
dependent
upon
the
pattern
used
in
the
simulation,
and
it
is
unclear
the
degree
to
which
AUC
would
be
affected.
Real­
time
continuous
measures
ofdrinking
water
behavior
during
toxicity
studies
to
be
performed
under
Tier
II
are
not
expected.
Modeling
approaches
for
water
consumption
are
traditionally
based
upon
an
estimate
of
the
average
behaviors
of
rats
and
mice.
Yuan
(
1993)
describes
some
modeling
approaches
to
food
and
water
consumption
using
drinking
water
data
previously
published
by
Johnson
and
Johnson
(
1990).
The
HAP
Task
Force
may
want
to
propose
other
approaches
to
modeling
drinking
water
behavior.
Regardless
of
the
modeling
pattern
selected
for
Tier
II,
EPA
believes
that
it
is
critical
for
the
HAP
Task
Force
to
incorporate
the
rationale
for
selecting
a
modeling
approach
(
acceptable
to
EPA)
in
the
Tier
II
study
protocols,
because
this
will
have
a
significant
effect
on
at
least
one
ofthe
dose
metrics
and
potentially
impact
route
dosimetry
extrapolations
for
the
Tier
II
endpoints.

In
addition,
EPA
believes
that
the
HAP
Task
Force
can
take
advantage
of
both
the
available
data
from
extant
drinking
water
toxicity
studies
of
TCE
and
the
data
to
be
collected
from
Tier
II
testing
to
better
understand
drinking
water
patterns
relevant
to
TCE
exposures.
For
example,
the
White
et
al.,
1985
publications
on
immuntoxicity
and
subchronic
toxicity
in
the
mice
provide
data
on
average
drinking
water
consumption
for
male
and
female
animals
during
each
month
of
the
90­
day
study.
These
studies
show
that
the
high
dose
males
have
a
significant
reduction
in
water
consumption
and
body
weight.
Such
data
may
be
relevant
for
PBPK
modeling,
especially
if
such
a
high
dose
was
subsequently
used
in
a
benchmark
dose
determination.
Whether
there
will
be
any
effects
on
water
consumption
in
the
Tier
II
studies
remains
to
be
seen;
however,
incorporating
considerations
for
the
effects
observed
in
the
White
et
al.
(
1985)
publications
would
further
refine
the
model.

9
V.
CONCLUSION
AND
RECOMMENDATIONS
The
EPA
Program
Review
concludes
that
the
TCE
Tier
I
Program
Review
Testing
PK/
MECH
data
development,
PBPK
model
development,
and
associated
reports
are
acceptable
to
inform
and
support
Tier
II
testing
for
the
endpoints
and
associated
route­
to­
route
dosimetry
extrapolation
reporting
specified
in
Table
1
of
the
ECA
for
TCE.
The
ORD/
NCEA
recommends
that
OPPT
notify
the
Companies
in
writing
that
Tier
II
endpoint
testing
and
computational
routeto
route
dosimetry
extrapolation
reporting
can
proceed
for
the
endpoints
included
in
Tier
II
ofthe
ECA
for
TCE.
EPA's
Program
Review
identified
the
need
to
incorporate
additional
model
simulations
to
be
conducted
in
conjunction
with
the
Tier
II
Testing
protocol
development
and
route
dosimetry
extrapolation
reporting
activities.

10
VI.
REFERENCES
Andersen,
M.
E.,
11.3.
Clewell,
III
and
C.
B.
Frederick.
1995.
Applying
simulation
modeling
to
problems
in
toxicology
and
risk
assessment­­
A
short
perspective.
Tox.
Appl.
Pharm.
133­
187.

Buchanan,
J.
R.,
L.
T.
Burka,
and
R.
L.
Melnick.
1997.
Purpose
and
guidelines
for
toxicokinetic
studies
within
the
National
Toxicology
Program.
Environ.
Hlth.
Perspect.
105(
5):
468­
471.

Doherty
AT,
Ellard
S,
Pany
EM,
et
al.
1996.
An
investigation
into
the
activation
and
deactivation
of
chlorinated
hydrocarbons
to
geneotoxics
in
metabolically
competent
human
cells.
Mutagenesis
11
(
3):
247­
274.

HAP
Task
Force
1996.
Proposal
for
Pharmacokinetics
Study
of
1,1
,2­
Trichloroethane.
Prepared
by
ChemRisk
­
A
Division
of
McLaren!
Hart.
(
Available
from
EPA
e­
Docket
OPPT­
2002­
0056).

Johnson,
R.
F.
and
Johnson,
A.
K.
(
1990)
Light­
dark
cycle
modulates
drinking
to
homeostatic
challenges.
Am
J
Physiol
R
259,
103
5­
1042
Kohn,
M.
C.
1997.
The
importance
ofanatomical
realism
for
validation
of
physiological
models
of
disposition
ofinhaled
toxicants.
Tox.
Appi.
Pharm.
147:
448­
458.

Mazzulo
M,
Colacci
A,
Grilli
5,
et
al.
1986.
l,
l,
3­
Trichlorethane:
Evidence
ofgenotoxicity
from
short­
term
tests.
Jpn
J
Canc
Res
77:
532­
539,

NCI.
1978.
Bioassay
of
l,
l,
2­
trichloroethane
for
possible
carcinogenicity.
Report.
ISS
DHEW/
PUB/
NIH­
78­
1324.
NCI­
CG­
TR­
74.
PB­
283337.

Sanders
VM,
Whiet
KL,
Shopp
GM,
and
Munson
AE.
1985.
Humoral
and
cell­
mediated
immune
status
ofmice
exposed
to
1,1
,2­
trichloroethane.
Drug
and
Chemical
Toxicology.
8(
5):
357­
372.

TinbergN
and
Ingelman­
SundbergM
(
1996)
Expression,
catalytical
activity,
and
inducibility
of
cytochrome
P450
2El
(
CYP2E1)
in
the
rat
central
nervous
system.
J
Neurochem
67(
5):
2066­
2073.

Ultman,
J.
S.
1994.
Dosimetry
modeling:
Approaches
and
issues.
Inhal.
Toxicol.
6:
59­
71.

U.
S.
Environmental
Protection
Agency
1997.
Preliminary
EPA
Technical
Analysis
ofProposed
Industry
Pharmacokinetics
(
PK)
Strategy
for
1,1
,2­
Trichloroethane.
(
Available
from
the
OPPTS
DocketNo.
42l87B).

11
Woodruff,
T.
J.,
F.
Y.
Bois,
D.
Auslander
and
R.
Spear.
1992.
Structure
and
parameterization
of
pharmacokinetics
models:
Their
impact
on
model
predictions.
Risk
Anal.
12:
189­
201.

Yuan,
J.
(
1993)
Modeling
blood/
plasma
concentrations
in
dose
feed
and
dose
drinking
water
toxicology
studies.
Toxicol
Appl
Pharmacol
119,
13
1­
141.

12
VII.
LIST
OF
CONTRIBUTORS
The
following
table
lists
EPA
staff
and
their
contributions
in
the
preparation
of
this
report
on
EPA's
Program
Review
segment
ofthe
ECA
for
TCE.

TrF.
1~'
1'
ATier
I
Prnorr~
mP~
view~
t~
ff
Scientific
Analysis
~
4'
i)
~
...
1
~
~
~
~
~
~
~
i1II~~
UI
1~~
uaI
tat
auu
IJL~
vUIup1IavaaI
~.,
IIItv
ui
i
uaauLIuJa
i
a
~
v~
aatauaa
auu
i
Technical
Review
Workgroup
j
ECA
Coordination
Workgroup
ORD/
NHEERL
ORD/
NCEA
ORD/
NCEA
Hugh
Barton
Rob
DeWoskin
Michel
Stevens
EPA
Reviewers
Annie
Jarabek
Gary
Foureman
Woody
Setzer
Elaina
Kenyon
Marina
Evans
Report
Preparation
and
Coordination
Richard
Leukroth
OPPT
/
CCD
John
Schaeffer
OPPT
/
CCD
EPA
Reviewer
Laura
Bunte
ORD/
NCEA
ORD/
NCEA
ORD/
NHEERL
ORD/
NHEERL
ORD/
NHEERL
OPPT/
CCD
13
APPENDIX
1
ECA
required
testing,
Test
Standards,
Reporting
and
Other
Requirements
for
1,1
,2­
Trichloroethane
14
Appendix
1.
ECA
REQUIRED
TESTING,
TEST
STANDARDS,
REPORTING
AND
OTHER
REQUIREMENTS
FOR
1,1,2­
TRICHLOROETHANE
~
As
specified
in
Part
VI.
A.
of
the
TCE
ECA,
EPA
has
determined
that
the
cytogenicity
studies
reported
by
Mazzulo
eta!.
(
1986)
and
Doherty
et
al.
(
1996)
adequately
fulfill
the
HAPs
rulemaking
testing
requirement
for
in
vivo
cytogenicity
testing
for
1,1,2­
trichloroethane.
TIER
I
HAPs
Testing
for
TCE
Test
Standard
Acute
Toxicity
(
inhalation)

Subchronic
Toxicity
(
inhalation)
§
799.9135
(
as
annotated
in
Appendix
D.
1
ofthe
TCE
ECA)

in
vivo
cytogenetics
§
799.9346
(
as
annotated
in
Appendix
D.
2
ofthe
TCE
ECA)

See
Appendix
E.
1
of
the
TCE
ECA5
15
TIER
I
Program
Review
Testing
for
TCE6
Test
Standard
PK]
MECH
data
to
support
model
validation
and
As
described
in
Appendix
C(
l)
of
verification
of
oral­
to­
inhalation
extrapolation
the
TCE
ECA.
for
the
following
data
needs
in
the
F344
rat7:
a.
Neurotoxicity5
b.
Developmental
toxicity5
c.
Reproductive
toxicity5
PK/
MECH
data
to
support
model
development,
As
described
in
Appendix
C(
1­
3)
validation,
and
verification
oforal­
to­
inhalation
of
the
TCE
ECA.
extrapolation
for
the
following
data
needs
in
the
mouse:
a.
Developmental
toxicity8
a.
Immunotoxicity9
b.
Carcinogenicity1
°
PBPK
model
simulations11
As
described
in
Appendix
C(
l
­
5)
ofthe
TCE
ECA
6
As
described
in
Part
VI.
C.
ofthe
TCE
ECA,
before
work
under
the
Tier
II
testing
segment
is
conducted,
EPA
will
conduct
a
Program
Review
of
the
Tier
I
Program
Review
Testing
data
and
data
from
other
studies
acceptable
to
EPAthat
could
be
used
to
inform
quantitative
computational
dosimetry
modeling
for
route­
to­
route
extrapolations.

`~
Previously
published
inhalation
PBPK
model
(
Gargas
et
a!.,
1989;
1990)
to
be
extended
and
validated
to
(
1)
periodic
inhalation
exposures
based
on
PKIMECH
data
to
be
acquired
as
part
ofthe
90­
day
inhalation
study
and
(
2)
oral
administration
via
either
corn
oil
gavage
or
drinking
water.

8
Drinking
water
administration.

Relevant
to
the
extant
data
in
mice
administered
via
drinking
water
of
Sanders
et
al.
(
1985).

10
Relevant
to
the
extant
data
in
mice
administered
via
corn
oil
gavage
of
NCI
(
1978).

11
The
model
simulations
are
to
(
a)
evaluate
model
validation
and
(
b)
model
verification
by
demonstrating
the
accuracy
of
quantitative
route­
to­
route
extrapolations
in
order
to
evaluate
the
acceptability
of:
(
1)
neurotoxicity
testing
oforal
exposure
via
drinking
water
in
rats;
(
2)
developmental
toxicity
testing
via
drinking
water
in
rats
and
mice;
(
3)
reproductive
toxicity
testing
via
drinking
water
in
rats;
(
4)
extant
immunotoxicity
data
(
SRBC
assay)
of
Sanders
et
al.
(
1985)
in
mice
via
drinking
water;
and
(
5)
extant
NCI
(
1978)
cancer
bioassay
data
in
mice
via
corn
oil
gavage.

16
12
Quantitative
route­
to­
route
extrapolation
documented
graphically
and
with
tabular
data.
Ability
to
characterize
parent
and
metabolite
blood
and
CNS
time­
course
data,
if
possible,
for
both
oral
and
inhalation
routes
demonstrated.

~
Quantitative
route­
to­
route
extrapolation
documented
graphically
and
with
tabular
data;
parent
and
total
amount
metabolized
in
a
24­
hour
period
to
be
explored
as
a
potential
dose
metric.

14
Quantitative
route­
to­
route
extrapolation
documentedgraphically
and
with
tabular
data
using
parent
compound
as
dose
metric.

~
Quantitative
route­
to­
route
extrapolation
based
on
the
PKIMECH
data
developed
under
this
ECA
and
the
data
of
Sanders
eta!.
(
1985)
documented
graphically
and
with
tabular
data
using
parent
compound
as
dose
metric.

16
Quantitative
route­
to­
route
extrapolation
based
on
the
PKIMECH
data
developed
under
this
ECA
and
the
data
of
NCI
(
1978)
documented
graphically
and
with
tabular
data
using
the
total
amount
metabolized
in
a
24­
hour
period
and
parent
compound
as
dose
metric.
Dose­
response
analysis
to
be
performed
using
genotoxic
assumption
(
linear
extrapolation)
procedure.
Tier
II
Testing
and/
or
Extrapolation
Renortirn!'

Acute
Neurotoxicity:
a)
testing
by
the
oral
route
Test
Standard
b)
route
to
route
extrapolation'
2
Subchronic
Neurotoxicity:
§
799.9620
(
as
annotated
in
Appendix
D.
3
ofthe
TCE
ECA)

a)
testing
by
the
oral
route
Appendix
C
ofthe
TCE
ECA
b)
route
to
route
extrapolation'
°
§
799.9620
(
as
annotated
in
Appendix
D.
3
of
the
TCE
ECA)

Developmental
Toxicity:
a)
testing
by
the
oral
route
Appendix
C
ofthe
TCE
ECA
b)
route
to
route
extrapolation'
3
§
799.9370
(
as
annotated
in
Appendix
D.
4
ofthe
TCE
ECA)

Reproductive
toxicity:
a)
testing
by
the
oral
route
Appendix
C
ofthe
TCE
ECA
b)
route
to
route
extrapolation14
§
799.9380
(
as
annotated
in
Appendix
D.
5
ofthe
TCE
ECA)

Immunotoxicity
(
extrapolation
of
extant
data)'
5
Appendix
C
ofthe
TCE
ECA
Carcinogenicity
(
extrapolation
of
extant
data)
16
Appendix
C
ofthe
TCE
ECA
Appendix
C
17
