S?
41
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
~
PRO~

FEB
13
2001
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Dr.
Peter
Voytek
HAP
Task
Force,
Manager
Regulatory
Sciences
International
King
Street
Station
1800
Diagonal
Road,
Suite
500
Alexandria,
VA
223
14­
2808
RE:
ECA
Development
ofEthylene
Dichioride
(
EDC)
(
OPPTS
­
42197C)

Dear
Dr.
Voytek:

EPA
has
completed
a
detailed
review
of
the
HAP
Task
Force
March
19,
1999,
outline
of
testing
protocols
for
ethylene
dichloride
(
EDC).
As
was
the
case
for
1,1
,2­
trichloroethane
(
TCE),
the
HAP
Task
Force
did
an
excellent
job
in
preparing
this
initial
testing
outline.
The
purpose
of
this
letter
is
to
confirm
points
ofagreement
on
the
overall
testing
program,
identify
areas
where
the
PKIMECH
proposed
testing
needs
further
embellishment
or
clarification,
and
to
map
out
next
steps
for
developing
the
enforceable
consent
agreement
(
ECA)
for
EDC.
I
hope
we
will
be
able
to
build
on
prior
experience
from
working
with
the
HAP
Task
Force
on
the
TCE
ECA
so
as
to
expedite
the
completion
of
the
remaining
work
on
this
ECA.

The
following
points
ofagreement
are
confirmed
by
our
review
of
the
March
19,
1999
submission:

The
HAP
Task
Force
would
develop
inhalation
toxicity
data
for
1)
acute
toxicity
with
brochoalveolar
lavage
(
BAL)
and
histopathology
and
2)
acute
neurotoxicity.
This
testing
would
be
accomplished
using
a
combined
protocol
following
TSCA
guidelines
§
799.9135,
and
§
799.9620
modified
as
appropriate.
EPA
has
determined
that
the
macrophage
function
assay
reported
by
Sherwood
et.
al.,
(
1987)
is
adequate
to
partially
fulfill
the
HAP
rulemaking
testing
requirements
for
this
element
of
the
acute
toxicity
endpoint.
The
HAP
Task
Force
should
supply
this
reference
as
an
integral
part
ofthe
ECA
for
EDC,
including
hard
copy
as
an
appendix.

R~
cycIGdfR~
cycIab~
e
SPrinted
w~
hVe9etable
Oil
Based
Inks
on
100%
Recyded
Paper
(
40%
Postconsumer)
RECEIVED
OPPT
NCIC
2003
MAR11
5:
03PM
OPPT­
2003­
0010­
0038
­
2­

°
EPA
agrees
that
the
Payan
et
al.,
1995
study
in
rats
along
with
the
study
by
Rao,
1980
in
rabbits
are
adequate
to
fulfill
the
developmental
toxicity
testing
requirement
proposed
in
the
HAPs
rulemaking.
The
HAP
Task
Force
would
supply
these
references
as
an
integral
part
ofthe
ECA
for
EDC,
including
hard
copy
as
an
appendix.

°
The
PK/
MECH
data
to
be
developed
must
support
the
oral­
to­
inhalation
extrapolation
model
by
Gargas
et
al.,
1989;
1990.
The
HAP
Task
Force
would
supply
these
references
as
an
integral
part
ofthe
ECA
for
EDC,
including
hard
copy
as
an
appendix.

°
The
PK/
MECH
data
to
be
developed
must
support
oral­
to­
inhalation
extrapolation
of:
1)
oral
(
via
corn
oil
gavage)
subchronic
toxicity
data
in
rats
(
Daniel
et
al.,
1994;
2)
oral
(
via
drinking
water)
subchronic
neurotoxicity
data
in
rats;
3)
oral
(
via
drinking
water)
reproductive
toxicity
data
in
rats;
and
4)
each
dosing
paradigm
for
the
reproductive
toxicity
studies
by
Alumot
et
al.,
1976,
Rao
et
al.,
1980,
and
Lane
et
al.,
1982.
(
These
oral
studies
would
be
developed
or
(
in
the
case
oforal
subchronic
toxicity
and
reproductive
toxicity)
expanded
by
the
HAP
Task
Force
under
Tier
II
Testing
of
this
ECA.)
The
HAP
Task
Force
would
supply
these
references
as
an
integral
part
ofthe
ECA
for
EDC,
including
hard
copy
as
an
appendix.

°
Toxicity
data
to
be
developed
under
Tier
II
Testing
would
be
conducted
by
the
oral
route
(
via
drinking
water)
and
would
be
governed
by
protocols
following
TSCA
test
guidelines
(
with
modifications
as
appropriate)
for
subchronic
neurotoxicity
(
TSCA
Test
Guideline
§
799.9620)
and
for
reproductive
toxicity
(
TSCA
Test
Guideline
§
799.9380).

°
Tier
II
route­
to­
route
extrapolation
reporting
would
be
conducted
for
subchronic
toxicity
using
data
from
Daniel
et
al.,
1994,
and
data
obtained
from
the
Tier
II
subchronic
neurotoxicity
and
reproductive
toxicity
testing.

EPA's
review
of
the
pharmacokinetics
proposal
identified
several
elements
that
need
further
consideration
before
final
agreement
can
be
reached
on
this
aspect
ofthe
revised
proposal.
Specifically,
revisions
are
needed
in
the
approach
to
develop
PKIMECH
data
forthe
central
nervous
system
(
brain)
which
is
identified
as
a
potential
target
organ
of
concern
for
EDC.
The
HAP
Task
Force
PK
proposal
makes
certain
assumptions
regarding
selection
ofthe
parent
compound
in
circulating
blood
and/
or
the
use
of
urine
glutathione
(
GSH)
metabolites
as
the
dose
metric.
EPA
believes
that
this
hypothesis,
although
plausible,
has
not
been
tested
and
would
not
fully
inform
EPA
on
the
actions
ofEDC
under
the
HAP
Task
Force
proposal.
For
example,
the
lipid
content
of
the
brain
will
most
likely
make
EDC
brain
concentrations
closer
to
those
in
adipose
tissues
than
to
blood.
In
addition,
equilibration
of
EDC
in
the
brain
is
not
likely
to
be
instantaneous
due
to
the
action
of
the
blood­
brain
barrier,
resulting
in
brain
concentrations
that
­
3­

will
differ
from
the
blood
concentrations.
There
is
a
need
to
develop
data
to
support
a
comprehensive
understanding
of
the
central
nervous
system
(
CNS)
component
in
the
proposed
model.
A
preferable
approach
would
include
the
following:

1.
Develop
PK/
MECH
data
on
parent
compound
in
blood,
parent
compound
in
brain,
and
total
GSH
metabolites
for
use
as
potential
dose
metrics
in
order
to
compare
for
relevance
to
the
tissue
response.

2.
Develop
a
comprehensive
time
course
to
rule
out
potential
blood­
brain
diffusion
limitation.
A
potential
design
might
include
blood
and
brain
time
points
such
as
0.25,
0.5,
1,
2,
4,
8,
16,
and
24
hours
with
a
minimum
of3
animals
per
time
point.

We
consider
the
addition
of
this
information
to
be
an
essential
component
in
the
development
of
a
scientifically
sound
approach
to
route­
to­
route
extrapolation
for
EDC.
In
anticipation
that
the
HAP
Task
Force
will
concur
with
EPA's
view,
we
have
incorporated
this
approach
into
the
enclosed
draft
ECA.

The
Panel
is
requested
to
review
and
comment,
as
appropriate,
on
the
enclosed
draft
ECA
between
EPA
and
the
member
companies
ofthe
HAP
Task
Force
on
EDC.
Incorporating
PBPK
as
a
component
of
the
TSCA
Section
4
Chemical
Testing
Program
is
a
new
approach
for
EPA's
Office
of
Prevention,
Pesticides,
and
Toxic
Substances.
As
was
noted
for
l,
l,
2­
TCE,
it
is
essential
to
the
success
of
this
ECA
that
we
include
a
measure
to
ensure
that
the
data
set
used
to
inform
modeling
extrapolations
is
of
the
highest
quality.
For
this
reason,
as
I
indicated
during
our
previous
discussions,
EPA
has
included
a
Program
Review
step
in
this
ECA.
The
purpose
of
the
Program
Review
will
be
to
confirm
that
all
necessary
dataelements
have
been
adequately
developed
to
inform
the
extrapolations
specified
in
this
ECA
and
to
ensure
that
the
proposed
modeling
extrapolations
are
both
feasible
and
based
on
sound
science.

As
you
read
through
this
draft
ECA,
please
pay
particular
attention
to
the
information
provided
in
Table
1.
It
is
our
intent
that
the
HAP
Task
Force
will
develop
the
necessary
appendices
that
will
be
attached
to
the
ECA.
This
can
be
accomplished
either
by
enhancing
the
outline
to
provide
specific
reference
to
EPA
guidelines
or
by
submitting
photocopies
ofexisting
guidelines
that
include
annotations
as
needed.
Incorporating
PBPK
into
the
ECA
adds
a
level
of
complexity
that
can
be
difficult
to
follow
within
the
overall
testing
program.
For
this
reason,
we
suggest
that
the
first
appendix
be
a
flowchart
of
the
overall
testing
program.
The
flowchart
should
indicate
where
the
various
elements
ofthe
PBPK
data
will
be
obtained
within
the
overall
testing
program
(
i.
e.,
component
ofendpoint
testing,
or
stand
alone
study).

Please
submit
comments
on
the
draft
ECA
along
with
a
copy
of
the
various
attachment
appendices
(
without
existing
study
reprints)
by
March
9,
2001.
Once
EPA
and
the
member
Companies
of
the
HAP
Task
Force
have
reached
agreement
on
the
details
ofthe
ECA,
we
can
move
toward
finalizing
the
ECA
document
and
obtain
signature
approval
by
all
parties.
­
4­

As
you
are
aware,
EDC
has
been
included
as
one
ofthe
chemicals
available
for
sponsorship
under
the
Voluntary
Children's
Chemical
Evaluation
Program
(
VCCEP)
pilot
(
FR
65
FR
81699,
December
26,
2000).
As
described
in
the
VCCEP
notice,
Tier
1
information
includes
hazard
assessment,
exposure
assessment,
risk
assessment,
and
a
data
needs
assessment.
The
opportunity
to
voluntarily
sponsor
EDC
in
the
VCCEP
Pilot
runs
until
June
25,
2001.
While
the
testing
included
in
the
draft
ECA
under
the
HAPs
rulemaking
would
meet
many
of
the
hazard
data
needs
for
EDC
under
the
VCCEP
Pilot,
it
would
not
address
exposure
information
needs
and
there
would
also
be
deficiencies
with
regard
to
certain
toxicity
end
points
(
e.
g.,
developmental
neurotoxicity)
described
in
the
third
tier
of
the
VCCEP
Pilot.
In
the
event
that
this
ECA
can
be
concluded
in
the
near
future,
EPA
believes
that
a
workable
course
ofaction
would
be
for
the
HAP
Task
Force
to
separately
volunteer
to
sponsor
EDC
for
Tier
1
hazard
information
under
the
VCCEP
Pilot.
The
HAP
Task
Force
could
use
the
results
from
the
HAPs
ECA
when
developing
the
VCCEP
Tier
1
submission.
If
the
HAP
Task
Force
chooses
this
route,
I
could
foresee
that,
for
EDC,
the
delivery
date
for
Tier
1
VCCEP
information
and
assessment
could
be
adjusted
to
take
account
ofthe
timing
elements
in
the
HAPs
ECA.
In
the
event
that
the
HAPs
ECA
on
EDC
cannot
be
concluded
in
the
near
future,
EPA
will
consider
EDC
open
for
sponsorship
under
the
YCCEP
Pilot.

I
look
forward
to
successfully
concluding
an
ECA
for
EDC.
Ifyou
have
any
questions
please
contact
John
Schaeffer
at
(
202)
260­
1266
or
Richard
Leukroth
at
(
202)
260­
0321.

Sincerely,

Charles
M.
Auer,
Director
Chemical
Control
Division
Enclosure
cc:
Greg
Blumenthal
Jane
Caldwell
Richard
W.
Leukroth,
Jr.
W.
Caffey
Norman,
III
John
Schaeffer
Docket
OPPTS
42197C
ENFORCEABLE
CONSENT
AGREEMENT
FOR
ETHYLENE
DICHLORIDE
(
EDC)

CAS
No.
107­
06­
2
Docket
No.
OPPTS
­
42197C
DRAFT
February,
2001
ENFORCEABLE
CONSENT
AGREEMENT
FOR
ETHYLENE
DICHLORIDE
(
EDC)

Docket
No.
OPPTS­
42
197C
TABLE
OF
CONTENTS
I.
INTRODUCTION
1
II.
CHEMICAL
SUBJECT
TO
THE
ECA
1
III.
OBLIGATION
OF
SIGNATORY
COMPANIES
AND
ROLE
OF
THE
HAP
TASK
FORCE
1
IV.
PURPOSE
OF
THE
TESTING
PROGRAM
2
V.
SCOPE
OF
THE
TESTING
PROGRAM
3
VI.
DESCRIPTION
OF
THE
TESTING
PROGRAM
s
VII.
EPA
PROGRAM
REVIEW
OUTCOMES
7
VIII.
STANDARDS
FOR
CONDUCTING
TESTING
9
IX.
SUBMISSION
OF
STUDY
PLANS
10
X.
MODIFICATIONS
TO
ENFORCEABLE
CONSENT
AGREEMENT
10
XI.
FAILURE
TO
COMPLY
WITH
THE
ENFORCEABLE
CONSENT
AGREEMENT
...
10
XII.
EPA
MONITORING
OF
ENFORCEABLE
CONSENT
AGREEMENT
TESTING
....
11
XIII.
SUBMISSION
OF
DATA
11
XIV.
PUBLICATION
AND
DISCLOSURE
OF
TEST
RESULTS
11
XV.
CONFIDENTIALITY
OF
INFORMATION
11
XVI.
RESPONSIBILITIES
OF
THE
COMPANIES
11
XVII.
SEVERABILITY
OF
ENFORCEABLE
CONSENT
AGREEMENT
PROVISIONS..
12
DRAFT
ECA
for
EDC
2/
01
XVIII.
FINAL
AGENCYACTION
.
12
XIX.
PUBLIC
RECORD
12
XX.
EFFECTIVENESS
12
XXI.
RIGHTS
OF
THE
COMPANIES
13
XXII.
IDENTITY
OF
THE
COMPANIES
13
XXIII.
SIGNATURE
14
Table
1
REQUIRED
TESTING,
TEST
STANDARDS,
REPORTING
AND
OTHER
REQUIREMENTS
FOR
ETHYLENE
DICHLORJDE
25
APPENDICES
A.
Flow
Chart
ofTesting
Program
B.
TSCA
Guidelines
with
Annotations
as
Appropriate:
B.
1
Acute
Inhalation
Toxicity
with
BAL
and
Histopathology
B
.2
Acute
Inhalation
Neurotoxicity
B.
3
Subchronic
Neurotoxicity
B.
4
Reproductive
Toxicity
C.
PKIMECH
Procedures
and
Route­
to­
Route
Extrapolation
Reporting:
C.
1
Pharmacokinetic
Studies
for
F344
Rats
C.
2
Subchronic
Toxicity
C.
3
Subchronic
Neurotoxicity
C.
4
Reproductive
Toxicity
C.
5
PBPK
Model
Description
and
Coding
C.
6
General
Outline
for
Route­
to­
Route
Extrapolation
Reports
D.
Study
Protocols:
D.
1
Combined
Acute
Toxicity
with
BAL
and
Histopathology
and
Acute
Neurotoxicity
(
Inhalation)
D.
2
Subchronic
Neurotoxicity
(
Oral)
D.
3
Reproductive
Toxicity
(
Oral)

 
11
 
DRAFT
ECA
for
EDC
2/
01
APPENDICES
 
continued
E.
Existing
Toxicity
Studies:
E.
1
Existing
Acute
Toxicity
Study
a)
Sherwood
et
al.
(
1987)
E.
2
Existing
Subchronic
Toxicity
Study
a)
Daniel
et
al.
(
1994)
E.
3
Existing
Developmental
Toxicity
Studies
a)
Raoetal.
(
1980)
b)
Payan
et
al.
(
1995)
E.
4
Existing
Reproductive
Toxicity
Studies
a)
Alumot
et
al.
(
1976)
b)
Raoetal.
(
1980)
c)
Lane
et
al.
(
1982)

 
111
 
DRAFT
ECA
for
EDC
2/
01
I.
INTRODUCTION
Under
the
authority
of
section
4
of
the
Toxic
Substances
Control
Act
(
TSCA),
15
U.
S.
C.
2603,
the
United
States
Environmental
Protection
Agency
(
EPA)
and
The
Dow
Chemical
Company,
Vulcan
Materials
Company,
Occidental
Chemical
Corporation,
Oxy
Vinyls,
LP,
Georgia
GulfCorporation,
Westlake
Chemical
Corporation,
PPG
Industries,
Inc.,
Borden
Chemicals
&
Plastics
Operating
Limited
Partnership,
and
Formosa
Plastics
Corporation,
U.
S.
A.
(
hereinafter
collectively
"
the
Companies")
enter
into
this
enforceable
consent
agreement
(
ECA).
This
ECA
takes
effect
on
the
date
of
publication
ofthe
notice
in
the
Federal
Register
announcing
the
issuance
ofthe
testing
consent
order
(
Order)
that
incorporates
this
ECA.

In
EPA's
proposed
test
rule
for
hazardous
air
pollutants
(
HAP5)
published
on
June
26,
1996
(
61
FR
33178),
amended
on
December
24,
1997
(
62
FR
67466)
and
on
April
21,
1998
(
63
FR
19694),
EPA
invited
the
submission
of
alternative
testing
proposals
for
HAPs
that
would
apply
pharmacokinetics
studies
and
mechanistic
data
(
PKIMECH)
to
inform
route­
to­
route
extrapolation
of
data
from
studies
acceptable
to
EPA
that
were
performed
by
a
route
of
exposure
other
than
inhalation.
Such
proposals
would
be
used
to
develop
a
tailored
testing
program
to
provide
the
data
needs
identified
by
EPA
in
the
proposed
HAPs
rulemaking
via
an
ECA
process.
This
ECA
resulted
from
negotiations
conducted
as
a
part
ofan
ECA
process
for
the
HAP
ethylene
dichloride
(
62
FR
66626;
December
19,
1997).
The
official
record
for
this
ECA,
including
the
public
version,
is
established
under
EPA
docket
control
number
OPPTS­
42l97C.
The
procedures
for
ECA
negotiations
are
described
at
40
CFR
790.22(
b).

II.
CHEMICAL
SUBJECT
TO
THE
ECA
The
subject
of
this
ECA
is
the
chemical
substance
ethylene
dichloride
(
EDC),
CAS
No.
107­
06­
2.
The
ethylene
dichloride
to
be
tested
must
be
as
pure
as
can
be
reasonably
attained,
but
must
be
at
least
99.5?
percent
pure.

III.
OBLIGATION
OF
SIGNATORY
COMPANIES
AND
ROLE
OF
THE
HAP
TASK
FORCE
A.
Testing
will
be
sponsored
by
the
Companies,
which
are
responsible
for
complying
with
this
ECA.

B.
The
Companies
recognize
that
to
implement
this
ECA,
EPA
will
issue
an
Order
under
section
4
ofTSCA
that
incorporates
the
terms
of
this
ECA.
The
Companies
agree
that
all
terms
ofthis
ECA
will
take
effect
on
the
date
of
publication
of
the
notice
in
the
Federal
Register
announcing
the
issuance
ofthe
Order
that
incorporates
this
ECA,
and
all
applicable
time
periods
will
be
treated
as
beginning
on
that
publication
date.

DRAFT
ECA
for
EDC
2/
01
1
C.
The
Companies
are
members
ofthe
HAP
TASK
FORCE,
which
is
an
association
of
manufacturers
of
ethylene
dichioride.
The
HAP
TASK
FORCE
will
be
responsible
for
coordinating
and
administering
testing
under
this
ECA
and
communicating
with
EPA
about
study
plans,
protocols,
test
standards,
and
other
aspects
ofthe
testing
program.
In
performing
these
functions,
the
HAP
TASK
FORCE
will
be
acting
as
the
agent
of
the
Companies
for
purposes
of
compliance
and
communication
with
EPA.
EPA
and
the
Companies
recognize
that,
except
for
its
role
as
agent
as
specified
in
this
ECA,
the
HAP
TASK
FORCE
has
no
legal
responsibility
for
complying
with
this
ECA.
Responsibility
for
complying
with
the
ECA
rests
at
all
times
with
the
individual
Companies.

IV.
PURPOSE
OF
THE
TESTING
PROGRAM
The
purpose
ofthe
testing
program
specified
in
this
ECA
is
to
supplement
available
information
in
order
to
further
characterize
the
potential
for
acute
toxicity,
subchronic
toxicity,
neurotoxicity,
developmental
toxicity
and
reproductive
toxicity
effects
ofethylene
dichloride
from
inhalation
exposures.
One
component
of
this
testing
program
will
develop
PKJMECH
data
directed
at
characterizing
the
mode
of
action
of
ethylene
dichloride.
Such
information,
along
with
data
from
health
effects
studies
acceptable
to
EPA
and/
or
from
health
effects
studies
to
be
conducted
as
part
of
this
ECA
testing
program
for
ethylene
dichloride,
will
be
used
to
inform
the
route­
to­
route
extrapolations
that
are
specified
in
Table
1.
EPA
will
also
use
the
PK/
MECH
data
to
provide
the
basis
for
determining
the
feasibility
and
appropriateness
of
using
a
tailored
approach
to
testing
and
whether
route­
to­
route
extrapolations
can
be
used
to
meet
inhalation
testing
requirements
for
ethylene
dichloride
that
are
identified
in
the
proposed
HAPs
test
rule,
as
amended.

EPA
believes
that
the
PK/
MECH
studies
designed
to
construct
quantitative
dosimetric
characterization
ofthe
disposition
and
relevant
response
mechanisms
with
regard
to
ethylene
dichloride,
in
conjunction
with
the
studies
and
route­
to­
route
extrapolation
reporting
that
are
specified
in
Table
1
and
described
in
Appendices
B
through
E
to
this
ECA,
will
generate
data
needed
by
EPA
to
determine
whether
ethylene
dichloride
presents
an
unreasonable
risk
ofinjury
to
human
health
from
inhalation
exposures.
The
data
will
also
be
used
to
implement
several
provisions
of
section
112
ofthe
Clean
Air
Act,
including
determination
of
residual
risk,
estimation
of
the
risks
associated
with
accidental
releases
of
ethylene
dichloride,
and
determinations
regarding
whether
substances
should
be
removed
from
the
Clean
Air
Act
section
1
12(
b)(
1)
list
of
hazardous
air
pollutants.
In
addition,
the
data
will
also
be
used
by
other
Federal
agencies
(
e.
g.,
the
Agency
for
Toxic
Substances
and
Disease
Registry
(
ATSDR),
the
National
Institute
for
Occupational
Safety
and
Health
(
NIOSH),
the
Occupational
Safety
and
Health
Administration
(
OSHA),
and
the
Consumer
Product
Safety
Commission
(
CPSC))
in
assessing
chemical
risks
and
in
taking
appropriate
actions
within
their
programs.
It
is
intended
that
the
data
generated
under
this
ECA
will
satisfy
the
toxicological
data
needs
for
acute
toxicity,
subchronic
toxicity,
neurotoxicity,
developmental
toxicity
and
reproductive
toxicity
effects
of
ethylene
dichloride
as
identified
in
the
amended
proposed
HAPs
rulemaking.

DRAFT
ECA
for
EDC
2/
01
2
V.
SCOPE
OF
THE
TESTING
PROGRAM
The
Companies,
through
the
HAP
TASK
FORCE,
will
jointly
conduct
or
provide
for
the
performance
ofthe
testing
program
specified
in
this
ECA.
This
testing
program
will
consist
of:
1)
conducting
the
testing
listed
in
Table
1
in
accordance
with
the
test
standards
specified
in
Table
1
and
described
in
Appendix
B(
l­
4)
as
annotated
in
Appendix
D(
1­
3)
to
this
ECA
("
Test
Standards"),
and
performing
the
PBPK
studies
and
route­
to­
route
extrapolations
specified
in
Table
1
and
described
in
Appendix
C(
1
­
6)
to
this
ECA;
and
2)
submitting
the
reports
and
documents
specified
in
Table
1
in
accordance
with
the
deadlines
set
forth
in
Table
1.

The
use
ofPKIMECH
data
to
support
quantitative
route­
to­
route
extrapolation
is
a
new
approach
for
EPA's
Office
of
Pollution
Prevention
and
Toxics
(
OPPT)
in
the
TSCA
section
4
Chemical
Testing
Program.
It
is
essential
to
the
success
ofthis
ECA
testing
program
for
EPA
to
ensure
that
the
data
used
to
inform
the
route­
to­
route
extrapolations
is
ofthe
highest
quality.
For
this
reason,
a
program
review
requirement
has
been
incorporated
into
this
ECA
testing
program
(
see
Part
VI.
C.
and
Part
VII.
A.
­
D.
ofthis
ECA).

EPA
notes
that
the
generation
of
PKIMECH
data
to
support
development
ofdosimetry
(
e.
g.;
physiologically
based
pharmacokinetics
­­
PBPK)
models
should
be
chemical­
specific
and
based
on
an
understanding,
to
the
degree
possible,
ofthe
mode
ofaction
for
the
various
endpoint
toxicities.
Modeling
is
an
iterative
process.
The
nature
ofchemical
reactions
between
a
xenobiotic
agent
and
biological
tissues,
and
the
degree
to
which
they
are
understood,
have
a
profound
influence
on
the
scope
of
the
modeling
effort.
A
degree
ofuncertainty
regarding
the
model
structure
can
be
clarified
by
validation
of
the
predications
ofthe
PBPK
dosimetry
model
with
appropriately
designed
experiments.
New
insights
on
important
parameters
and
processes
can
then
be
additionally
tested
and
used
to
further
refine
the
model.
Because
these
chemical
and
toxicity­
specific
attributes
can
affect
both
the
type
of
PKJMECH
data
necessary
to
characterize
disposition
ofa
chemical
and
the
type
of
model
structure
that
would
be
adequate
to
describe
it,
EPA
does
not
have
guidelines
available
for
the
HAP
TASK
FORCE
to
utilize.
General
guidance
is
available
in
a
number
of
references
(
Woodruff
et
al.,
19921;
Ultman,
19942;
Andersen
et
al.,

1
Woodruff,
T.
J.,
F.
Y.
Bois,
D.
Auslander
and
R.
Spear.
1992.
Structure
andparameterization
of
pharmacokinetics
models:
Their
impact
on
model
predictions.
Risk
Anal.
12:
189­
201.

2
Ultman,
J.
S.
1994.
Dosimetry
modeling:
Approaches
and
issues.
Inhal.
Toxicol.
6:
59­
71.

DRAFT
ECA
for
EDC
2/
01
3
1995~
Kohn,
l997~
Buchanan
et
al.,
1
9975)~
Key
considerations
for
model
structure
include
the
degree
ofparameterization
and
whether
the
model
is
to
be
used
to
extrapolate
(
e.
g.,
across
species
or
across
routes)
versus
interpolate
data
(
Woodruff
et
al.,
1992).

The
source
ofeach
model
parameter
value
should
be
described,
indicating
whether
it
was:
1)
obtained
from
prior
literature
(
copy
ofreferences
cited
to
be
provided
by
the
HAP
TASK
FORCE),
2)
determined
directly
by
a
separate
experiment
described
in
the
submitted
report
or
peer­
reviewed
paper,
or
3)
estimated
by
the
fitting
ofmodel
output
to
experimental
data.
Parameter
estimates
derived
independently
oftissue
time­
course
or
dose­
response
data
are
preferred
(
Andersen
et
al.,
1995).
Determination
by
separate
experiment
is
preferred,
particularly
for
critical
target
tissue
parameters,
such
as
partition
coefficients.
Model
verification,
the
process
ofevaluating
the
sufficiency
ofthe
model
for
its
intended
purpose,
should
be
demonstrated
by
showing
the
ability
ofthe
model
to
predict
the
behavior
ofexperimental
data
different
from
those
on
which
it
was
based.
Model
validation
should
demonstrate
the
ability
ofthe
model
to
predict
the
behavior
ofthe
system
under
conditions
which
test
the
principal
aspects
ofthe
underlying
hypothetical
structure.
Objective
measures
of
variance
(
e.
g.,
statistical
goodness
offit)
that
can
be
compared
to
residual
variance
are
preferred,
but
accurate
prediction
ofthe
general
behavior
of
the
data
for
the
intended
application
(
e.
g.,
a
given
range)
may
be
a
more
important
consideration.
For
this
latter
consideration,
however,
a
factor
of
2­
fold
(
on
average)
will
be
a
general
criterion
applied
to
determine
"
reasonable"
agreement
of
the
model
with
the
experimental
data.

The
choice
ofwhich
dose
metric
to
use
in
the
model
to
characterize
a
given
endpoint
toxicity
should
be
based
on
some
knowledge
ofthe
mode
of
action
by
which
the
toxic
effects
are
induced.
The
mechanistic
information
does
not
necessarily
have
to
be
exhaustive
but
can
rather
be
related
to
general
aspects
of
the
nature
and
causes
of
a
particular
toxic
interaction.
Certainly
route­
specific
toxicity
needs
to
be
characterized,
both
the
effects
in
the
portal­
of­
entry
as
well
as
modulation
of
systemic
dose
at
remote
sites.
PKJMECH
data
must
be
developed
that
correspond
to
the
species,
dose
level,
exposure
regimen
and
vehicle
(
e.
g.,
intermittent
corn
oil
gavage
versus
drinking
water
ad
lib
versus
diet)
of
the
toxicity
datathat
are
the
object
ofthe
extrapolation.
For
the
extrapolation
ofthe
chronic
endpoint
data,
demonstration
ofperiodicity
during
the
experiments
used
to
generate
the
PKIMECH
data
is
required.
Periodicity,
as
defined
in
U.
S.
EPA
(
1994)
6,
is
achieved
when
the
internal
concentration
ofthe
dose
metric
of
interest
(
e.
g.,
parent
~
Andersen,
M.
E.,
H.
J.
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.

`~
Kohn,
MC.
1997.
The
importance
of
anatomical
realism
for
validation
of
physiological
models
of
disposition
of
inhaled
toxicants.
Tox.
Appl.
Pharm.
147:
448­
458.

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

6
U.
S.
EPA.
1994.
Methods
for
derivation
of
inhalation
reference
concentrations
and
application
of
inhalation
(
continued...)

DRAFT
ECA
for
EDC
2/
01
4
venous
concentration)
versus
time
profile
is
the
same
for
90%
of
the
exposure
period.
The
rationale
for
the
choice
of
various
dose
metrics
should
be
provided.

Andersen
et
al.
(
1995)
published
a
table
ofcharacteristics
ofa
good
modeling
paper
and
documentation;
EPA
will
utilize
these
same
reporting
requirements.
These
include:
(
1)
clear
presentation
ofall
equations;
(
2)
clear
definition
of
all
variables
and
parameters;
(
3)
clear
definition
ofunits
to
ensure
proper
dimensions;
(
4)
definition
of
criteria
to
evaluate
predictions
or
fits;
(
5)
specification
of
the
time,
species,
and
exposure
domain
where
the
model
is
valid;
and
(
6)
discussion
ofthe
hypothesis
testing
and
model
discrimination
as
necessary.
Graphical
display
of
model
fits
to
data
are
required;
including
both
parent
and
metabolite(
s)
blood
and
target
tissue
time
course
data.
EPA
also
requires
a
sensitivity
analysis
ofthe
model.
Documentation
ofmodel
code
with
comment
fields
must
be
provided.
Computer
hardware
and
software
actually
used
in
the
application
must
be
described.
If
specialized
software
functions
must
be
referred
to,
they
should
be
described
sufficiently
to
enable
someone
unfamiliar
with
the
software
to
understand
their
operation.
Standard
mathematical
forms
are
preferred
to
software
language
functional
forms.

VI.
DESCRIPTION
OF
THE
TESTING
PROGRAM
The
testing
program
has
four
segments
as
follows:
Tier
I
HAPs
Testing;
Tier
I
Program
Review
Testing;
EPA
Program
Review;
and
Tier
II
Testing.

A.
Tier
I
HAPs
Testing:
This
testing
will
consist
ofthe
following
endpoint
testing,
conducted
by
inhalation
exposure,
that
EPA
has
deemed
necessary
to
meet
certain
data
needs
identified
in
the
proposed
HAPs
test
rule,
as
amended:
1)
acute
toxicity
testing
with
BAL
and
histopathology,
and
2)
acute
neurotoxicity
testing.
EPA
will
not
finalize
the
testing
requirements
for
these
Tier
I
HAPs
Testing
endpoints
for
ethylene
dichloride
as
specified
in
the
proposed
HAPs
test
rule,
as
amended,
because
such
testing
will
be
conducted
under
this
ECA.
Furthermore,
EPA
considers
the
existing
study
by
Sherwood
et
al.
(
1987),
adequate
to
fulfill
the
macrophage
function
assay
portion
of
the
acute
toxicity
testing
requirement
(
see
Appendix
E.
1).
In
addition,
EPA
considers
the
existing
studies
by
Rao
et
al.
(
1980)
and
Payan
et
al.
(
1995),
adequate
to
characterize
the
developmental
toxicity
of
ethylene
dichloride
under
the
proposed
HAPs
rulemaking,
as
amended
(
see
Appendix
E.
3).
Thus,
EPA
will
not
finalize
the
testing
requirements
for
the
developmental
toxicity
and
macrophage
function
assay
Tier
I
HAPs
testing
endpoints
for
EDC
as
specified
in
the
HAPs
proposed
rule
as
amended,
because
available
studies
are
acceptable
for
HAPs
purposes.
Tier
1
testing
for
acute
toxicity
and
acute
neurotoxicity
and
the
extant
data
for
macrophage
function
assay
and
developmental
toxicity
testing
are
specified
in
6
(...
continued)

dosimetry.
Office
of
Research
and
Development.
Environmental
Criteria
and
Assessment
Office,
Research
Triangle
Park,
NC.
EPA/
600/
8­
90/
066F.

S
DRAFT
ECA
for
EDC
2/
01
the
"
Tier
I
HAPs
Testing"
segment
of
Table
1
and
described
in
Appendix
B(
1,2)
as
annotated
in
Appendix
D(
l)),
and
Appendix
E(
l,
3).

B.
Tier
I
Program
Review
Testing:
This
testing,
specified
in
the
"
Tier
I
Program
Review
Testing"
segment
of
Table
1
and
described
in
Appendix
C.
1,
will
develop
PK/
MECH
data
needed
to
inform
about
the
acceptability
of
an
alternate
route
to
inhalation
for
Tier
II
testing.
It
will
also
develop
and
validate
the
dosimetry
model
ofGargas
et
al.
(
1989;
1990)
in
rats
and
verify
the
ability
ofthe
model
to
perform
quantitative
route­
to­
route
extrapolations,
as
described
in
Appendix
C(
2­
5)
and
as
will
be
reported
following
guidance
provided
in
Appendix
C.
6.
Data
from
this
testing
will
be
the
subject
ofdiscussions
at
the
EPA
Program
Review.
While
EPA
believes
that
it
is
best
to
obtain
this
type
of
PKIMECH
data
in
conjunction
with
the
testing
specified
in
the
Tier
I
HAPs
Testing
(
see
Part
VI.
A.),
these
PK!
MECH
data
may
also
be
obtained
independently
from
stand­
alone
studies.
Specifically,
the
PKIMECH
data
will
support:
1)
oral­
toinhalation
extrapolation
of
existing
subchronic
toxicity
data
in
rats
administered
ethylene
dichloride
via
corn
oil
gavage
(
Daniel
et
al.,
1
994)(
see
Appendix
E.
2);
2)
oral­
to­
inhalation
extrapolation
ofsubchronic
neurotoxicity
data
in
rats
administered
ethylene
dichioride
via
drinking
water
(
see
Tier
II
testing);
and
3)
oral­
to­
inhalation
extrapolation
ofreproductive
toxicity
data
in
rats
administered
ethylene
dichloride
via
drinking
water
(
see
Tier
II
testing)
and
each
dosing
paradigm
of
existing
reproductive
toxicity
studies
by
Alumot
et
al.
(
1976),
Rao
et
al.
(
1980),
and
Lane
et
al.
(
l982)(
see
Appendix
E.
4).
The
PKIMECH
data
will
also
support
model
simulations
to
demonstrate
validation
and
verification
of
PBPK
models
for
route­
to­
route
extrapolation
in
order
to
evaluate
acceptability
of
oral
drinking
water
exposure
in
rats
in
the
Tier
II
testing
for
subchronic
neurotoxicity
and
reproductive
toxicity.

C.
EPA
Program
Review:
A
program
review
will
be
conducted
by
EPA
to
review
the
data
collected
from
the
Tier
I
Program
Review
Testing
segment
(
see
Part
VI.
B.
ofthis
ECA)
and
other
studies
acceptable
to
EPA
that
would
be
applied
to
route­
to­
route
extrapolations,
as
indicated
in
footnotes
4,
6,
and
8
ofTable
1.

The
purpose
ofthe
EPA
Program
Review
will
be
to
determine:
(
1)
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
extrapolations
for
endpoints
listed
in
the
Tier
II
Testing
segment;
(
2)
whether
the
data
from
the
Tier
I
Program
Review
Testing
segment
(
see
Part
VI.
B.
ofthis
ECA)
provide
a
sufficient
basis
for
conducting
the
endpoint
testing
and/
or
the
route­
to­
route
extrapolations
specified
in
the
Tier
II
Testing
segment;
and/
or
(
3)
the
nature
and
scope
ofany
additional
work
that
may
be
required
prior
to
the
commencement
ofTier
ii
Testing
and
extrapolation
reporting
(
e.
g.,
additional
PK/
MECH
data
as
described
in
Part
VII.
ofthis
ECA).

Opportunity
for
public
participation
in
the
EPA
Program
Review
will
be
provided
either
by
a
request
for
written
comments
or
through
an
announcement
of
a
public
meeting.
EPA
will
publish
the
request
for
public
comments
and/
or
the
announcement
of
a
public
meeting
in
the
Federal
Register.
Following
the
EPA
Program
Review,
EPA
will
place
in
the
record
for
this
DRAFT
ECA
for
EDC
2/
01
6
action
a
summary
describing
the
EPA
Program
Review
meeting,
if
such
a
meeting
is
held,
a
copy
ofcomments
received,
and
a
copy
ofthe
letter
sent
to
the
HAP
TASK
FORCE
informing
the
conclusions
ofEPA's
Program
Review.

D.
Tier
II
Testing:
This
segment
will
consist
of
additional
endpoint
testing
not
included
in
the
Tier
I
HAPs
Testing
segment,
as
specified
in
Table
1
and
described
in
Appendix
B
(
3­
4)
as
annotated
in
Appendix
D(
2­
3).
Specifically
this
testing
will
consist
of
oral
subchronic
neurotoxicity
testing
and
oral
reproductive
effects
testing.
Tier
II
will
also
consist
ofroute­
toroute
extrapolation
reporting
for
existing
subchronic
toxicity
data
of
Daniel
et
a!.
(
1994),
the
subchronic
neurotoxicity
and
reproductive
toxicity
data
obtained
from
Tier
II
testing,
and
extant
data
from
reproductive
toxicity
studies
by
Alumot
eta!.
(
1976),
Rao
eta!.
(
1980),
and
Lane
eta!.
(
1982),
as
specified
in
Table
1
and
Appendix
C(
2­
4)
and
reported
following
guidance
provided
in
Appendix
C.
6.
Following
a
successful
outcome
of
the
EPA
Program
Review
(
see
Section
VII.
A.
and
B.
l.
a.),
EPA
will
not
finalize
inhalation
testing
requirements
for
these
Tier
II
testing
endpoints
for
ethylene
dichloride,
as
specified
in
the
amended
proposed
HAPs
test
rule,
because
the
data
required
under
the
HAPs
rulemaking
will
be
developed
under
this
ECA.

VII.
EPA
PROGRAM
REVIEW
OUTCOMES
The
EPA
Program
Review
segment
can
result
in
several
possible
outcomes,
described
below.

A.
EPA
Accepts
Tier
IProgram
Review
Testin.~
Data:
EPA
may
determine
that
the
Tier
I
Program
Review
Testing
data
can
be
used
to
inform
and
support
Tier
II
testing
for
any
or
all
ofthe
endpoints
and/
or
associated
route­
to­
route
extrapolation
reporting
for
ethylene
dichloride
that
are
specified
in
Table
1.
In
such
an
instance,
EPA
will
notify
the
Companies
in
writing
that
Tier
II
endpoint
testing
and
route­
to­
route
extrapolation
reporting
must
be
conducted
for:
subchronic
toxicity,
subchronic
neurotoxicity,
and
reproductive
toxicity
for
ethylene
dichloride.
In
addition,
EPA
will
not
finalize
the
testing
requirements
for
these
endpoints
for
ethylene
dichloride
as
specified
in
the
proposed
HAPs
test
rule,
as
amended.

B.
EPA
IdentifIes
Limitations
in
the
Tier
IPro~
ramReview
Testin.~
Data:
EPA
may
determine
that
additional
Tier
I
Program
Review
Testing
is
needed
before
any
or
all
ofthe
Tier
II
endpoint
testing
and/
or
associated
route­
to­
route
extrapolation
reporting
that
are
specified
in
Table
1
for
ethylene
dichloride
can
be
conducted.
In
such
an
instance,
EPA
will
inform
the
Companies
by
letter
that
additional
Tier
I
Program
Review
Testing
is
needed
and
a
copy
ofthis
letter
will
be
placed
in
the
record
for
this
action.
EPA
may
initiate
technical
discussions
with
the
Companies
on
this
matter.

(
1)
Agreement
on
Additional
Tier
IProgram
Review
Testing:
If
EPA
and
the
Companies
agree
to
the
additional
testing,
modifications
to
the
relevant
Test
Standards
specified
in
the
Tier
I
Program
Review
Testing
section
ofTable
1
and
described
in
the
associated
DRAFT
ECA
for
EDC
2/
01
7
appendices
for
the
relevant
Test
Standards
may
be
made
according
to
the
procedures
contained
in
40
CFR
790.68
(
see
Part
X
of
this
ECA).
The
additional
Tier
I
Program
Review
Testing
will
be
conducted
in
accordance
with
these
modifications.
The
data
resulting
from
this
additional
testing
will
be
reviewed
to
determine
if
such
data
meet
EPA
needs.
This
review
may
include
one
or
more
meeting(
s)
between
the
Companies
and
EPA.
Opportunity
for
public
participation
will
be
provided
either
by
a
request
for
written
comments
and/
or
through
an
announcement
of
a
public
meeting.
Following
such
meeting(
s),
EPA
will
place
in
the
record
for
this
action
a
summary
of
each
meeting
along
with
a
copy
ofthe
comments
received.

(
a)
Additional
Tier
IProgram
Review
Testing
Meets
Data
Needs:
Ifand
when
the
Tier
I
Program
Review
Testing
data
are
determined
to
be
acceptable
to
EPA,
EPA
will
inform
the
Companies
by
letter
that
the
data
from
the
Tier
I
Program
Review
Testing
can
be
used
as
a
basis
to
inform
and
support
Tier
II
Testing
for
any
or
all
of
the
endpoints
and
associated
route­
to­
route
extrapolation
reporting
for
ethylene
dichloride
that
are
specified
in
Table
1.
In
addition,
the
letter
will
indicate
that
EPA
will
not
finalize
the
inhalation
testing
requirements
for
these
Tier
II
Testing
endpoints
for
ethylene
dichloride
as
specified
in
the
proposed
HAPs
test
rule,
as
amended.
A
copy
ofthe
letter
will
be
placed
in
the
record
for
this
action.

(
b)
Additional
Tier
IProgram
Review
Testing
Does
Not
Meet
Data
Needs:
If,
at
any
point,
EPA
determines
that
the
TierI
Program
Review
Testing
data,
as
supplemented
by
the
additional
Tier
I
Program
Review
Testing
data,
cannot
be
used
to
inform
and
support
Tier
II
testing
for
any
or
all
ofthe
endpoints
and/
or
associated
route­
to­
route
extrapolations
for
ethylene
dichloride
that
are
specified
in
Table
1,
thenthe
outcome
described
in
Part.
VII
.
C.
below
will
apply
to
these
endpoints.

(
2)
Failure
to
Agree
on
Additional
Needed
Tier
I
Program
Review
Testing:
If
the
Companies
and
EPA
do
not
agree
to
the
additional
Tier
I
Program
Review
Testing
that
EPA
has
determined
to
be
needed
the
outcome
described
in
Part
VII.
C.
below
will
apply
to
these
endpoints.

C.
EPA
Determines
Tailored
Approach
to
HAPs
Testing
is
not
Feasible:
EPA
may
determine
that
the
tailored
approach
to
HAPs
testing
set
forth
in
this
ECA,
for
any
or
all
Tier
I
Program
Review
Testing
as
applied
to
any
or
all
Tier
II
endpoint
testing
and
associated
route­
toroute
extrapolations,
is
not
feasible.
In
such
an
instance,
EPA
will
notify
the
Companies
by
certified
letter
or
Federal
Register
notice.
The
notification
will
include
the
reason(
s)
for
the
determination
and
will
be
placed
in
the
record
for
this
action.
IfEPA
issues
such
a
notification
for
any
endpoint(
s),
the
Companies'
obligations
to
conduct
testing
or
associated
route­
to­
route
extrapolations
for
that
endpoint(
s)
as
described
under
this
ECA
are
terminated.
EPA
may
pursue
testing
for
such
endpoint(
s)
under
the
HAPs
rulemaking,
a
new
rulemaking
,
or
develop
a
separate
ECA
for
the
purpose
ofobtaining
the
needed
data,
as
appropriate.

D.
Other
Possible
Outcomes:
If
the
EPA
Program
Review
or
Tier
II
endpoint
testing
and
associated
route­
to­
route
extrapolations
do
not
result
in
any
ofthe
outcomes
DRAFT
ECA
for
EDC
2/
01
8
described
above,
EPA
and
the
Companies
may
modify
this
ECA
according
to
the
procedures
contained
in
40
CFR
790.68
(
see
Part
X.
ofthis
ECA).

VIII.
STANDARDS
FOR
CONDUCTING
TESTING
A.
Testing
for
specific
toxicity
endpoints
(
acute
toxicity,
neurotoxicity,
and
reproductive
toxicity)
must
be
conducted
in
accordance
with
the
Test
Standards
listed
in
Table
1
and
described
in
Appendix
B(
l­
4)
as
annotated
in
Appendix
D(
1­
3)
to
this
ECA.
Certain
provisions
ofthese
Test
Standards
are
considered
to
be
mandatory
and
are
referred
to
as
"
requirements".
These
requirements
are
identified
by
the
use
ofthe
word
"
shall"
in
the
text
ofthe
Test
Standard.

Provisions
that
are
not
mandatory,
and
are
therefore
only
recommended,
are
identified
by
the
use
of
"
should"
statements.
In
the
event
such
"
should"
provisions
are
not
followed,
the
Companies
will
not
be
deemed
by
EPA
to
be
in
violation
ofthis
ECA
and
will
not
be
subject
to
penalties
or
other
enforcement
actions,
as
described
in
Part
XI.
ofthis
ECA.
However,
in
such
cases,
EPA
will
use
its
professional
judgement
to
determine
the
scientific
adequacy
and
validity
of
the
test
results
and
any
repeat
testing
that
is
determined
by
EPA
to
be
necessary
will
be
required
either
under
a
separate
ECA
or
pursuant
to
a
rule
promulgated
under
section
4(
a)
of
TSCA,
15
U.
S.
C.
2603(
a).

For
the
purpose
ofthis
ECA,
the
words
"
will"
and
"
must,"
if
they
appear
in
the
Test
Standards,
are
considered
equivalent
to
the
word
"
shall"
and
therefore
delineate
a
test
requirement
to
be
followed
or
met.

B.
The
development
ofPK/
MECH
data
to
be
used
in
this
ECA
testing
program
must
be
conducted
in
accordance
with
the
guidance
outlined
in
Appendix
C(
l­
4)
ofthis
ECA.
The
development
and
application
ofPKIMECH
data
is
expected
to
be
an
iterative
process
and,
as
such,
the
final
details
ofthe
testing
may
not
be
included
in
the
presently
available
Test
Standard(
s).
For
the
purposes
of
this
ECA,
Appendix
C(
1­
4)
will
be
the
"
Test
Standard(
s)"
for
testing
specified
in
Table
1
under
Tier
I
Program
Review
Testing
and
Tier
II
Route­
to­
Route
Extrapolation
Reporting.
The
PKIMECH
data
development
under
this
ECA
will
be
the
subject
of
discussions
at
the
EPA
Program
Review,
described
in
Part
VI.
C.
and
Part
VII.
A.
­
D.
ofthis
ECA.

C.
The
Companies,
through
the
HAP
TASK
FORCE,
and
EPA
will
consult
in
a
good
faith
effort
to
consider
the
need
for
Test
Standard
modifications
if
either
EPA
or
the
Companies
desire
such
modifications.
Modifications
to
this
ECA
will
be
governed
by
40
CFR
790.68
(
see
Part
X.
of
this
ECA).

D.
All
testing
required
by
this
ECA
must
be
conducted
in
accordance
with
the
EPA
Good
Laboratory
Practice
(
GLP)
Standards
contained
in
40
CFR
part
792.

DRAFT
ECA
for
EDC
2/
01
9
E.
All
final
reports
must
be
submitted
by
the
Companies
to
EPA
by
the
dates
specified
in
Table
1
unless
otherwise
authorized
by
EPA
pursuant
to
40
CFR
790.68.
Interim
status
reports
describing
the
status
of
all
studies
to
be
performed
under
this
ECA
testing
program
must
be
submitted
by
the
Companies
to
EPA
every
six
months
beginning
six
months
from
the
effective
date
ofthis
ECA
and
until
the
end
ofthe
ECA
testing
program.
These
interim
reports
should
contain
information
such
as
a
summary
of
the
interim
status
ofeach
study
being
performed
under
this
ECA
testing
program,
a
description
of
significant
activities
and/
or
difficulties
experienced
during
the
interim,
and
an
explanation
of
the
actions
taken
in
response
to
difficulties.
See
Part
XIII.
ofthis
ECA
regarding
submissions
to
EPA.

IX.
SUBMISSION
OF
STUDY
PLANS
The
Companies,
through
the
HAP
TASK
FORCE,
will
submit
a
study
plan
to
EPA
for
each
test
conducted
pursuant
to
this
ECA
prior
to
the
initiation
oftesting
in
accordance
with
40
CFR
790.62.
(
For
this
ECA,
EPA
will
not
require
the
study
plans
to
be
submitted
"
no
later
than
45
days
prior
to
the
initiation
oftesting,"
as
specified
at
40
CFR
790.62(
a)).
The
content
ofthe
study
plans
submitted
to
EPA
will
comply
with
40
CFR
790.62(
b).
Modifications
to
the
study
plans
will
be
governed
by
the
procedures
of40
CFR
790.62(
c).
All
study
plans
will
become
part
of
the
official
record
(
Docket
Control
Number
OPPTS­
42l97C).

X.
MODIFICATIONS
TO
ENFORCEABLE
CONSENT
AGREEMENT
EPA
and
the
Companies
recognize
that
in
some
instances
modifications
to
the
schedule
in
Table
1
may
be
needed
in
view
of
uncertainties
in
developing
PKIMECH
data.
Modifications
to
this
ECA,
if
any,
will
be
made
according
to
the
procedures
contained
in
40
CFR
790.68.

XI.
FAILURE
TO
COMPLY
WITH
THE
ENFORCEABLE
CONSENT
AGREEMENT
The
Companies
acknowledge
that
a
violation
ofthe
requirements
ofthis
ECA
will
constitute
a
"
prohibited
act"
under
section
15(
1)
of
TSCA,
15
U.
S.
C.
2614(
1),
and
will
trigger
all
provisions
applicable
to
a
section
15
violation.
In
addition,
noncompliance
with
any
term
ofthis
ECA
by
any
Company
will
constitute
conduct
"
in
violation
of
this
Act"
under
section
20(
a)(
1)
of
TSCA,
15
U.
S.
C.
26l9(
a)(
l),
and
could
result
in
a
citizen's
civil
action.

Under
the
penalty
provisions
of
section
16
ofTSCA,
15
U.
S.
C.
2615,
and
the
Federal
Civil
Penalties
Inflation
Adjustment
Act
of
1990,
28
U.
S.
C.
2461
note,
as
amended
by
the
Debt
Collection
Improvement
Act
of
1996,
31
U.
S.
C.
3701
note,
as
implemented
by
61
FR
69360
(
December
31,
1996),
a
non­
complying
Company
could
be
subject
to
a
civil
penalty
ofup
to
$
27,500
per
violation,
with
each
day
in
violation
potentially
constituting
a
separate
violation
under
section
15.
Knowing
or
willful
violations
may
lead
to
the
imposition
ofcriminal
penalties,

DRAFT
ECA
for
EDC
2/
01
10
or
a
fine
ofnot
more
than
$
27,500
for
each
day
of
violation,
or
imprisonment
for
not
more
than
one
year,
or
both.
In
addition,
EPA
could
enforce
this
ECA
pursuant
to
section
17
of
TSCA,
15
U.
S.
C.
2616,
by
seeking
an
injunction
to
compel
adherence
to
the
requirements
ofthis
ECA.

XII.
EPA
MONITORING
OF
ENFORCEABLE
CONSENT
AGREEMENT
TESTING
EPA
may
conduct
monitoring
activities
of
the
testing
conducted
under
this
ECA
such
as
laboratory
inspections
and
study
audits,
as
permitted
under
section
11
ofTSCA,
15
U.
S.
C.
2610.

XIII.
SUBMISSION
OF
DATA
All
data
submitted
to
EPA
under
this
ECA
will
be
identified
by
the
Docket
Number:
OPPTS­
42197C
and
the
name:
ethylene
dichloride.
Six
(
6)
copies
ofall
submissions
under
this
ECA
will
be
provided
to
EPA
at
the
address
specified
in
40
CFR
790.5(
b).

XIV.
PUBLICATION
AND
DISCLOSURE
OF
TEST
RESULTS
All
results
oftesting
conducted
pursuant
to
this
ECA
will
be
announced
to
the
public
by
EPA
in
accordance
with
the
procedures
specified
in
section
4(
d)
ofTSCA,
15
U.
S.
C.
2603(
d).
Disclosure
by
EPA
of
data
generated
by
such
testing
will
be
governed
by
section
14(
b)
of
TSCA,
15
U.
S.
C.
2613(
b),
and
40
CFRpart2.

XV.
CONFIDENTIALITY
OF
INFORMATION
Any
claims
ofconfidentiality
for
information
submitted
under
this
ECA
will
be
made
under
the
terms
of40
CFR
790.7.
If
no
claim
of
confidentiality
is
made
by
the
submitter
ofthe
information
at
the
time
ofsubmission,
the
information
will
be
deemed
by
EPA,
in
accordance
with
40
CFR
790.7,
to
be
public,
and
may
be
made
available
to
the
public
without
further
notice
to
the
submitter.
Information
claimed
as
confidential
will
be
treated
in
accordance
with
the
procedures
in
40
CFR
part
2
established
pursuant
to
section
14
of
TSCA,
15
U.
S.
C.
2613.

XVI.
RESPONSIBILITIES
OF
THE
COMPANIES
A.
The
Companies
are
bound
by
the
terms
ofthis
ECA
and
the
provisions
of40
CFR
790.62
and
790.65.

B.
The
Companies
will
comply
with
the
notification
requirements
of
section
12(
b)(
1)
of
TSCA,
15
U.
S.
C.
2611(
b)(
1),
and
40
CFR
part
707,
subpart
D,
if
they
export
or
intend
to
DRAFT
ECA
for
EDC
2/
01
11
export
ethylene
dichloride.
Any
other
person
who
exports
or
intends
tO
export
ethylene
dichloride
will
be
subject
to
these
export
notification
requirements
upon
promulgation
ofan
export
notification
rule
for
ethylene
dichioride
under
section
l2(
b)(
l)
ofTSCA.

C.
Ifethylene
dichloride
becomes
subject
to
a
rule
promulgated
under
TSCA
section
5(
a)(
2),
15
U.
S.
C.
2604(
a)(
2),
governing
significant
new
uses
ofethylene
dichloride,
then
the
Companies
will
be
subject
to
the
data
submission
requirements
imposed
by
section
5(
b)(
l)(
A)
of
TSCA,
15
U.
S.
C.
2604(
b)(
l)(
A),
as
if
the
testing
under
this
ECA
had
been
required
by
a
TSCA
section
4
test
rule.

XVII.
SEVERABILITY
OF
ENFORCEABLE
CONSENT
AGREEMENT
PROVISIONS
In
the
event
that
one
or
more
provisions
ofthis
ECA
are
determined
by
a
court
decision
to
be
unenforceable,
the
remaining
provisions
of
this
ECA
will
not
be
presumed
to
be
valid,
and
EPA
will
either
initiate
a
rulemaking
proceeding
to
require
testing
or
publish
in
the
Federal
Register
the
reasons
for
not
initiating
such
a
proceeding.

XVIII.
FINAL
AGENCY
ACTION
Issuance
ofthis
ECA
by
EPA
constitutes
final
EPA
action
forpurposes
of
5
U.
S.
C.
704.

XIX.
PUBLIC
RECORD
EPA
has
established
a
public
record
which
will
contain
this
ECA,
the
Order
that
incorporates
this
ECA,
the
Federal
Register
notice
announcing
issuance
ofthe
Order
incorporating
this
ECA,
and
any
and
all
relevant
information,
subject
to
the
confidentiality
provisions
of
section
14(
b)
ofTSCA
and
40
CFR
part
2.
The
official
record
for
this
ECA,
including
the
public
version,
which
does
not
include
any
information
claimed
as
CBI,
has
been
established
under
docket
control
number
OPPTS­
42197C.

XX.
EFFECTIVENESS
This
ECA
may
be
signed
in
separate
counterparts.
This
ECA
will
not
be
effective
unless
signed
by
each
ofthe
Companies
and
by
EPA.
This
ECA
will
take
effect
on
the
date
of
publication
ofthe
Federal
Register
notice
announcing
the
issuance
of
the
Order
that
incorporates
this
ECA.

DRAFT
ECA
for
EDC2/
01
12
XXI.
RIGHTS
OF
THE
COMPANIES
By
signing
this
ECA,
the
Companies
waive
their
right
to
challenge
EPA's
authority
to
assess
penalties
for
violations
of
the
terms
ofthis
ECA.
This
waiver
does
not
affect
any
other
rights
that
the
Companies
may
have
under
TSCA,
including
the
right
to
dispute
the
amount
ofany
penalty
or
to
dispute
factually
whether
a
violation
of
the
terms
of
this
ECA
has
occurred,
or
to
seek
judicial
review
ofany
rule
that
may
be
adopted
by
EPA
that
imposes
requirements
to
test
ethylene
dichloride.

XXII.
IDENTITY
OF
THE
COMPANIES
The
Companies
subject
to
this
ECA
are:

The
Dow
Chemical
Co.
Louisiana
Hwy
1
P.
O.
Box
150
Plaquemine,
LA
70765
Vulcan
Materials
Company
1200
Urban
Center
Drive
Birmingham,
AL35242
Occidental
Chemical
Corporation
5005
LBJ
Freeway
Dallas,
TX
75244
Oxy
Vinyls,
LP
Suite
500,
LB3O
5005
LBJ
Freeway
Dallas,
TX
75244
CONDEA
Vista
Company
P.
O.
Box
19029
900
Threadneedle
Houston,
TX
77079
Georgia
Gulf
Corporation
26100
LA
45
Plaquemine,
LA
70764
Westlake
Chemical
Corporation
2801
Post
Oak
Blvd.
Suite
600
Houston,
TX
77056
PPG
Industries,
Inc.
One
PPG
Place
Pittsburgh,
PA
15272
Borden
Chemicals
&
Plastics
Operating
Limited
Partnership
180
E.
Broad
Street
Columbus,
OH
43215
Formosa
Plastics
Corporation,
U.
S.
A.
9
Peach
Tree
Hill
Road
Livingston,
NJ
07039
DRAFT
ECA
for
EDC
2/
01
Ii
XXIII.
SIGNATURE
Date:
TEST
SPONSOR
The
Dow
Chemical
Company
Roger
L.
Bowlin
R&
D
Director
for
Chlorinated
Organics
The
Dow
Chemical
Company
Louisiana
Hwy
I
P.
O.
Box
150
Plaquemine,
LA70765­
0150
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
TEST
SPONSOR
Vulcan
Materials
Company
Date:
George
L.
Fish
Vice
President,
Technical
Vulcan
Chemicals
Division
Vulcan
Materials
Company
1200
Urban
Center
Drive
Birmingham,
AL
35242
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
Date:
TEST
SPONSOR
Occidental
Chemical
Corporation
Charles
L.
Mears
Vice
President
&
General
Manager
Electrochemicals
Occidental
Chemical
Corporation
5005
LBJ
Freeway
Dallas,
TX
75244
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
Date:
TEST
SPONSOR
CONDEA
Vista
Company
P.
L.
Jernigan
Vice
President
ofOperations
CONDEA
Vista
Company
P.
O.
Box
19029
900
Threadneedle
Houston,
TX
77079
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
Date:
TEST
SPONSOR
Georgia
Gulf
Corporation
Edward
A.
Schmitt
President
and
CEO
Georgia
Gulf
Corporation
26100
LA
45
Plaquemine,
LA
70764
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
TEST
SPONSOR
Westlake
Chemical
Corporation
Date:
Wayne
Morse
Senior
Vice
President,
Vinyls
Westlake
Chemical
Corporation
2801
Post
Oak
Blvd.,
Suite
600
Houston,
TX
77056
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
Date:
TEST
SPONSOR
PPG
Industries,
Inc.

James
A.
Barter,
Ph.
D.
Director,
Environmental
Health
Sciences
PPG
Industries,
Inc.
One
PPG
Place
Pittsburgh,
PA
15272
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
Date:
TEST
SPONSOR
Borden
Chemicals
&
Plastics
Operating
Limited
Partnership
Wayne
P.
Leonard
Executive
Vice
President
&
Chief
Operating
Officer
Borden
Chemicals
&
Plastics
Operating
Limited
Partnership
180
E.
Broad
Street,
Columbus,
OH
43215
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
Date:
TEST
SPONSOR
Formosa
Plastics
Corporation,
U.
S.
A.

Robert
F.
Kelly
Vice
President
for
Environment,
Health,
Safety
and
Communication
Formosa
Plastics
Corporation,
U.
S.
A.
9
Peach
Tree
Hill
Road
Livingston,
NJ
07039
DRAFT
ECA
for
EDC
2/
01
XXIII.
SIGNATURE
Date:
TEST
SPONSOR
Oxy
Vinyls,
LP
Duane
Stamp
Vice
President/
General
Counsel
Oxy
Vinyls,
LP
Suite
500,
LB3O
5005
LBJ
Freeway
Dallas,
TX
752
44
DRAFT
ECA
for
EDC
2/
01
XXIV.
SIGNATURE
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
Assistant
Administrator
Office
ofPrevention,
Pesticides,
and
Toxic
Substances
U.
S.
Environmental
Protection
Agency
Office
ofPollution
Prevention
And
Toxic
Substances
Ariel
Rios
Building
1200
Pennsylvania
Avenue,
N.
W.
Washington,
DC
20460
Date:

Address:

DRAFT
ECA
for
EDC
2/
01
Table
1
REQUIRED
TESTING,
TEST
STANDARDS,
REPORTING
AND
OTHER
REQUIREMENTS
FOR
ETHYLENE
DICHLORIDE
i~
estSiantlard
I)
t~
atIline
I(
I
(
citatiotis
are
t
°
40
(
°~
tot
mat
I
~
Testing
f~.
I~
I~(
~
alT
attached
to
this
~
I
(~
Jonths~

Acute
Toxicity
with
BAL
and
histopathology
(
inhalation)
2
Developmental
Toxicity
Number
of
months
after
the
effective
date
of
the
Order
that
incorporates
this
ECA
when
final
report
is
due.

Interim
status
reports,
describing
the
status
of
all
testing
to
be
performed
under
this
ECA,
must
be
submitted
by
the
Companies
to
EPA
every
6
months
beginning
six
months
from
the
effective
date
of
this
ECA
until
the
end
of
the
ECA
testing
program
(
see
Part
VIII.
E.
and
Part
XIII.
of
this
ECA).

2
Acute
toxicity
and
acute
neurotoxicity
testing
to
be
conducted
under
a
combined
protocol
following
§
799.9
135
and
§
799.9620
as
annotated
in
appendixDl.
As
specified
in
Part
VI.
A.
of
this
ECA,
EPA
has
determined
that
the
macrophage
function
assay
reported
by
Sherwood
et
al.
(
1987)
adequately
fulfills
the
rnacrophage
function
assay
portion
of
the
acute
toxicity
testing
requirement.
A
copy
of
this
report
is
included
as
Appendix
El.

~
As
specified
in
Part
VI.
A.
of
this
ECA,
EPA
has
determined
that
the
developmental
toxicity
studies
reported
by
Payan
etal.
(
1995),
in
rats,
and
Rao
eta
1
.
(
1980),
in
rabbits,
adequately
fulfill
the
HAPs
rulemaking
testing
requirement
for
developmental
toxicity
testing
for
ethylene
dichloride.
A
copy
of
these
reports
is
included
as
Appendix
E.
3.
§
799.9135
(
as
annotated
in
appendix
D.
1)
18?

AcuteNeurotoxicity
(
inhalation)
2
§
799.9620
(
as
annotated
in
appendix
D.
l)
18?

Appendix
E.
33
DRAFT
ECA
for
EDC
2/
01
TIER
I
Test
Standard
Deadline
Program
Review
Testing
(
citations
are
to
40
CFR;
for
Final
for
EDC4
appendices
are
attached
to
this
ECA)
Report
(
Months)

PK/
MECH
data
to
support
model
validation
and
verification
oforalto
inhalation
extrapolation
for
the
following
data
needs
in
the
F344
rat~:
a.
Subchronic
toxicity6
Appendix
C
(
1­
4)
15?
a..
Subchronic
Neurotoxicity7
b.
Reproductive
toxicity8
PBPK
model
simulations9
Appendix
C
(
1­
5)
24?

As
described
in
Part
VI.
C.
of
this
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
EPA
that
could
be
used
in
performing
quantitative
route­
to­
route
extrapolations.

~
Previously
published
inhalation
PBPK
model
(
Gargas
et
al.,
1989;
1990)
to
be
extended
and
validated
to
(
1)
periodic
inhalation
exposures
based
on
PKJ'MECH
data
to
be
acquired
as
part
ofthe
Tier
I
Inhalation
Toxicity'
and
(
2)
oral
administration
via
corn
oil
gavage
and
drinking
water.

6
Relevant
to
existing
data
in
rats
administered
EDC
via
corn
oil
gavage
(
Daniel,
et
al.
(
1994)

Relevant
to
drinking
water
administration
in
rats
8
Relevant
to
drinking
water
administration
and
capable
to
inform
route­
to­
route
extrapolation
from
each
dosing
paradigm
of
extant
data
by
Alumot,
et
a!.
(
1976),
Rao,
et
al.
(
1980),
and
Lane,
et
a!.
(
1982)

~
The
model
simulations
are
to
provide
point
and
uncertainty
estimates
of
internal
dose
metrics
(
parent
chemical
peak
and
area
under
the
curve
(
AUC)
concentrations
in
blood
and
brain,
and
24­
hour
total
glutathione­
dependent
metabolism)
in
rats
and
humans
to
allow
quantitative
route­
to­
route
extrapolations.
These
simulations
will
be
used
to
evaluate
the
acceptability
of:
(
1)
subchronic
neurotoxicity
testing
of
oral
exposure
via
drinking
water
in
rats;
(
2)
extant
oral
subchronic
toxicity
data
of
Daniel
et
a!.
(
1994)
in
rats
via
corn
oil
gavage,
and
(
3)
reproductive
toxicity
testing
of
oral
exposure
via
drinking
water
in
rats.

DRAFT
ECA
for
EDC
2/
01
Tier
II
Testing
and/
or
Extrapolation
Reporting
for
EDC
Test
Standard
(
citations
are
to
40
CFR;
appendices
are
attached
to
this
ECA)
Deadline
for
Final
Report
(
Months)

Subchronic
toxicity
(
route­
toroute
extrapolation
ofextant
data)'
°
Appendix
C.
2
and
C.
6
39?

Subchronic
neurotoxicity:
a)
testing
by
the
oral
route
§
799.9620
(
as
annotated
in
Appendix
D.
2)
42?

b)
route
to
route
extrapolation1'
Appendix
C.
3
and
C.
6
45?

Reproductive
toxicity:'
2
a)
testing
by
the
oral
route
§
799.9380
(
as
annotated
in
Appendix
D.
3)
54?

b)
route
to
route
extrapolation'
3
Appendix
C.
4
and
C.
6
57?

10
Quantitative
route­
to­
route
extrapolation
of
extant
data
of
Daniel
et
al.
(
1994)
documented
graphically
and
with
tabular
data
using
point
estimates
and
uncertainty
measures
for
parent
compound
(
peak
and
AUC)
and
total
amount
metabolized
by
glutathione­
dependent
pathways
to
develop
the
dose
metric.

~
Quantitative
route­
to­
route
extrapolation
of
subchronic
toxicity
testing
developed
under
Tier
II
Testing,

documented
graphically
and
with
tabular
data
using
point
estimates
and
uncertainty
measures
for
parent
compound
(
peak
and
AUC)
in
blood
and
brain
and
total
amount
metabolized
by
glutathione­
dependent
pathways
to
develop
the
dose
metric.
Ability
to
characterize
blood
and
CNStime­
course
data,
if
possible,
for
both
oral
and
inhalation
routes
must
be
demonstrated.

12
Control
and
high­
dose
groups
will
be
evaluated
for
fertility
index,
gestation
index,
gross
necropsy,
organ
weight
and
histopathology
to
confirm
lack
of
effect
reported
in
extant
studies
by
Alumot
eta!.,
1976;
Rao
et
a!.,
1980;
and
Lane
et
a!.,
1982.
Observation
of
an
effect
in
the
high­
dose
will
trigger
detailed
evaluation
of
low­
dose
and
mid­
dose
groups
for
the
above
mentioned
effects.
Estrous
cycle,
sperm
evaluation
(
vaginal
opening,
preputial
separation)
will
be
evaluated
for
all
dose
groups.

~
Quantitative
route­
to­
route
extrapolation
of
reproductive
toxicity
testing
developed
under
Tier
II
Testing
and
extant
data
from
Alumot,
et
a!.
(
1976),
Rao,
eta!.
(
1980),
and
Lane,
et
ci!.
(
1982)
documented
graphically
and
with
tabular
data
using
point
estimates
and
uncertainty
measures
for
parent
compound
(
peak
and
AUC)
and
total
amount
metabolized
by
glutathione­
dependent
pathways
to
develop
the
dose
metric.

DRAFT
ECA
for
EDC
2/
01
APPENDIX
A
FLOW
CHART
OF
TESTING
PROGRAM
*

*
To
be
provided
by
the
HAP
Task
Force
DRAFT
ECA
for
EDC
2/
01
APPENDIX
B
(
1­
4)

TSCA
Guidelines
with
Annotations
as
Appropriate
*

*
To
be
provided
by
the
HAP
Task
Force
DRAFT
ECA
for
EDC
2/
01
APPENDIX
C
(
1­
5)

PKIMECH
Procedures
and
Route­
to­
Route
Extrapolation
Reporting
*

*
To
be
provided
by
the
HAP
Task
Force
DRAFT
ECA
for
EDC
2/
01
APPENDIX
C.
6
General
Outline
for
Route­
to­
Route
Extrapolation
Reporting
for
EDC
A
total
of
three
route­
to­
route
extrapolation
reports
will
be
generated
for
EDC,
one
for
each
of
the
following
endpoints:
subchronic
toxicity,
subchronic
neurotoxicity,
and
reproductive
toxicity.
At
a
minimum,
each
of
these
reports
will
follow
the
general
outline
presented
below.

1.0.
Introduction
Statement
of
objectives
for
specific
endpoint
route­
to­
route
extrapolation
relevant
to
the
HAPs
testing
for
EDC
Application
ofthe
PBPK
Model
for
EDC
relevant
to
specific
endpoint
2.0.
Summary
of
Key
Study(
ies)
For
subchronic
toxicity,
the
design
and
results
of
Daniel
et
al.
(
1994)
will
be
summarized
relevant
to
the
route­
to­
route
extrapolation
and
results
from
Tier
I
Program
Review
Testing.

For
subchronic
neurotoxicity,
the
design
and
results
of
the
Tier
II
testing
will
be
summarized
relevant
to
the
route­
to­
route
extrapolation
and
results
from
Tier
I
Program
Review
Testing.

For
reproductive
toxicity,
the
design
and
results
ofthe
Tier
II
testing
will
be
summarized
and
the
design
and
results
ofAlumot
et
al.
(
1976),
Rao
et
al.
(
1980),
and
Lane
et
al.
(
1982)
will
be
summarized
relevant
to
the
route­
to­
route
extrapolation
and
results
from
Tier
I
Program
Review
Testing.

3.0.
Selection
of
Critical
Endpoint(
s)
and
Dose
Measure(
s)

For
subchronic
toxicity,
subchronic
neurotoxicity,
and
reproductive
toxicity,
the
endpoints
and
dose
measures
will
be
determined
from
the
Tier
II
testing.

4.0
Route­
to­
Route
Extrapolation
Results
Quantitative
calculation
ofinhalation
NOAEL
/
LOAEL
values
for
corresponding
oral
values
5.0.
Sensitivity
Analysis
Assessment
ofthe
contribution
of
variability/
uncertainty
in
each
parameter
to
PK
modeling
results
6.0
Conclusions
7.0
References
DRAFT
ECA
for
EDC
2/
01
APPENDIX
D
(
1­
3)

STUDY
PROTOCOLS
*

*
To
be
provided
by
the
HAP
Task
Force
DRAFT
ECA
for
EDC
2/
01
APPENDIX
E
(
1­
4)

EXISTING
TOXICITY
STUDIES
*

*
To
be
provided
by
the
HAP
Task
Foi­
ce
DRAFT
ECA
for
EDC
2/
01
