Burden
Estimates
for
the
Enforceable
Consent
Agreement
for
Ethylene
Dichloride
DRAFT
 
DOES
NOT
CONTAIN
TSCA
CBI
­­

Prepared
by:

Economic
and
Policy
Analysis
Branch
Economics,
Exposure
and
Technology
Division
Office
of
Pollution
Prevention
and
Toxics
U.
S.
ENVIRONMENTAL
PROTECTION
AGENCY
401
M
STREET
S.
W.
WASHINGTON,
D.
C.
20460
January
31,
2002
RECEIVED
OPPT
NCIC
2003
MAR11
5:
03PM
OPPT­
2003­
0010­
0020
Burden
Estimates
for
the
Enforceable
Consent
Agreement
for
Ethylene
Dichloride
Introduction
The
enforceable
consent
agreement
(
ECA)
for
ethylene
dichioride
requires
named
manufacturers
to
undertake
a
tiered
testing
program.
The
testing
requirements
are
outlined
in
the
ECA,
particularly
Table
1
and
several
appendices
of
the
ECA.
This
memo
presents
estimates
of
the
burden
associated
with
meeting
the
requirements
of
the
ECA,
i.
e.,
performing
the
required
testing
and
associated
modeling,
as
explained
below.

In
general,
the
ECA
requires
the
named
manufacturers
to
conduct
testing
for
a
series
of
endpoints
in
the
P344
rat.
All
testing
will
be
conducted
via
the
oral
route.
The
ECA
then
requires
that
data
obtained
from
the
testing
program
be
run
through
a
physiological­
basedpharmacokinetic
(
PBPK)
model,
to
extrapolate
results
from
the
oral
route
to
the
inhalation
route.
In
addition,
a
series
of
studies,
specified
in
Appendix
C.
1
(
Pharmacokinetic
Studies
for
F344
Rats)
of
the
ECA,
must
also
be
performed
to
generate
supporting
data
for
the
PBPK
modeling
effort.
The
specific
requirements
of
the
ECA
are
listed
in
Table
1
of
this
report.

Methodology
for
Calculating
Burden
The
burden
associated
with
the
requirements
of
the
ECA
includes
the
administrative
burden
associated
with
conducting
the
required
toxicological
testing
in
addition
to
the
burden
associated
with
running
a
required
pharmacokinetic
(
PBPK)
model,
The
administrative
burden
of
testing
includes
time
devoted
to
arrange
for,
monitor,
and
report
the
test
results.
To
develop
estimates
of
administrative
burden,
EPA
uses
a
methodology
for
converting
testing
costs
to
administrative
burden.
This
methodology
is
similar
to
the
approach
used
in
the
Economic
Assessmentfor
the
Amended
Proposed
TSCA
Section
4(
a)
TestRule
for
21
Hazardous
Air
Pollutants
(
HAPs
EA)
as
well
as
the
TSCA
Section
4
Information
Collection
Request.
The
approach
can
be
summarized
as
follows:

a.
Administrative
burden
is
calculated
from
an
estimate
of
administrative
costs.
Administrative
costs
are
assumed
to
be
proportional
to
the
laboratory
cost.
EPA's
Economics
and
Policy
Analysis
Branch
assumes
that
administrative
costs
are
25%
of
laboratory
costs,
meaning
that
for
every
$
100
of
laboratory
testing
costs
incurred,
$
25
in
administrative
costs
will
also
be
incurred.
b.
Administrative
costs
are
then
converted
to
administrative
burden
using
the
weighted
average
labor
rate
of
$
69.28
per
hour
($
2001)
(
EPAB
2001).
This
rate
is
based
on
the
assumption
that
the
administrative
burden
reflects
a
20/
60/
20
mix
of
managerial,
technical,
and
clerical
time.
The
estimated
wage
rate
for
managerial
time
is
$
98.34
($
2001),
for
technical
time
it
is
$
72.89
($
2001),
and
for
clerical
time
is
$
29.39
($
2001).
Therefore,
the
average
labor
rate
is
calculated
as
(
898.34*.
2)+($
72.89*,
6)+($
29.39*.
2)
$
69.28.
Administrative
costs
are
divided
by
$
69.28
to
estimate
administrative
burden
associated
with
the
testing
activity.
The
costs
are
then
used
to
develop
an
estimate
of
the
administrative
burden
associated
with
meeting
the
testing
conditions
of
the
ECA.

Those
subject
to
the
ECA
are
also
expected
to
incur
burden
associated
with
the
PBPK
modeling
itself.
It
is
assumed
that
those
subject
to
the
ECA
will
utilize
an
existing
computer­
based
model
that
incorporates
the
logic
and
procedures
shown
in
Appendix
C.
5
of
the
ECA
(
PBPK
Mode!
Description
and
Coding).
It
is
further
assumed
that
this
model
has
been
compiled
into
a
userfriendly
form.
Under
Tier
I
requirements
of
the
ECA,
the
model
will
be
validated
using
acute
and
subchronic
toxicity
data
also
developed
in
that
tier.
The
model
validation
is
estimated
to
require
24
burden
hours.

Once
validated,
the
model
will
be
used
to
extrapolate
oral
data
developed
in
Tier
II
to
inhalation.
Running
the
model
will
entail
drawing
the
necessary
input
data
from
the
studies
and
tests
conducted,
instructing
the
model
to
perform
the
extrapolations,
and
generating
or
recording
the
output.
These
activities
are
estimated
to
require
a
total
of
two
hours
of
labor
(
burden)
time
for
each
model
run.
Table
1.
Enforceable
Consent
Agreement
Requirements
for
Ethylene
Dichloride
Tier
I
FLAPs
Testing
A.
Acute
toxicity
(
inhalation)
based
on
799.9135
B.
Acute
neurotoxicty
(
inhalation)
based
on
799.9620
C.
Developmental
toxicitya
Program
Review
Testing
D.
PKIMECH
data
to
support
model
validation
and
verification
oforal­
to­
inhalation
extrapolation
for
the
following
data
needs
in
the
F344
rat
a)
subchronic
toxicity,
b)
subchronic
neurotoxicity,
and
c)
reproductive
toxicity.
(
Requires
4
separate
studies).

E.
PBPK
model
simulations
to
validate
model
Tier
II
Testing
and/
or
Extrapolations
F.
Subchronic
toxicity,
extrapolation
of
extant
data
(
Daniel
et
al.
1994)
from
oral
to
inhalation
route.

.

U.
Subchronic
neurotoxicity
(
oral),
based
on
799.9620
H.
Subchronic
neurotoxicity
extrapolation
of
oral
data
to
inhalation
I.
Reproductive
toxicity
(
oral),
based
on
799.9380
J.
Reproductive
toxicity
extrapolation
oforal
data
from
study
to
inhalation
K.
Reproductive
toxicity
extrapolation
ofextant
literature
data
to
inhalation
a
Data
from
existing
studies
Payan
etal.
(
1995)
and
Rao
et
al.
(
1980)
deemed
adequate
to
fulfill
this
requirement.
No
new
testing
is
required.

Step
1.
Estimate
Administrative
Costs
To
estimate
the
testing
costs,
the
following
approach
was
used:
°
For
testing
required
to
obtain
necessary
endpoint
data,
cost
estimates
for
the
testing
protocols
specified
in
the
ECA
were
used.
These
were
obtained
from
a
database
of
test
cost
information
maintained
by
EPAB.
All
test
costs
have
been
updated
to
Q4
$
2001
using
the
Bureau
of
Labor
Statistics
Employment
Cost
Index.
In
some
cases
test
costs
were
available
for
tests
conducted
via
a
different
route
from
that
required
in
the
ECA
(
e.
g.,
gavage
instead
of
drinking
water).
In
such
cases,
the
costs
for
the
route
most
similar
to
that
required
in
the
ECA
were
used.
Inmost
cases
this
likely
results
in
a
higher
estimate
of
costs
compared
to
the
actual
route
required
in
the
ECA.
To
the
extent
this
is
true,
the
costs
ofthe
required
tests
may
be
overstated.
Because
administrative
burden
is
calculated
as
a
function
ofadministrative
costs,
it
is
possible
that
the
burdens
too,
are
overstated.

°
For
testing
required
to
support
the
PBPK
modeling
(
i.
e.,
the
five
studies
specified
in
Appendix
C.
I
of
the
ECA),
an
expert
toxicologist
reviewed
the
study
procedure
and
developed
a
best
professional
estimate
of
the
laboratory
cost
of
performing
the
testing
(
EPAB
2000).
These
costs
are
shown
in
Table
2.
Table
2.
Pharmacokinetic
Studies
for
Ethy~
neDichioride
Study
Species
Cost
Range
($
2001)

Best
Low
High
Study
I
Demonstration
of
periodicity
following
repeated
inhalation
exposure
Rats
$
43,290
$
34,727
$
52,523
Study
2
Demonstration
of
periodicity
following
repeated
oral
exposures
to
ethylene
dichloride
by
corn
oil
gavage
Rats
$
12,335
$
9,037
$
15,725
Study
3
Demonstration
of
periodicity
following
repeated
oral
exposure
to
ethylene
dichloride
by
aqueous
gavage
Rats
$
12,335
$
9,037
$
15,725
Study
5
Determination
of
partition
coefficients
Rat
brain,
kidney,
testes,
ovarya
$
6,152
$
5,173
$
7,213
Total
Costs
$
74,112
$
57,974
$
91,186
a
Based
on
costs
estimated
for
obtaining
partition
coefficients
formouse
blood,
rat
brain,
rat
spleendeveloped
for
the
ECA
for
l.
l.
2­
TCE
(
EPAB
2000).
Source:
EPAB
(
2000).

The
estimated
costs
of
testing
are
presented
in
Table
3.
The
paragraphs
that
follow
provide
explanatory
detail
on
the
cost
estimate
methodology
for
each
component
of
the
tiered
testing
requirements
for
ethylene
dichioride.

Tier
IHAPs
Testing
A.
Acute
toxicity
(
inhalation)
based
on
799.9135,
as
annotated
in
Appendix
D.
1
of
the
ECA.

Costs
for
this
test
are
based
on
existing
costs
for
799.9135
for
rats
via
inhalation.
The
best
estimate
of
the
cost
for
this
testing
element
is
$
93,889.

B.
Acute
neurotoxicity
(
inhalation)
based
on
799.9620,
as
annotated
in
Appendix
D.
2
of
the
ECA
Costs
for
this
test
are
based
on
existing
costs
for
799.9620
for
rats
via
inhalation.
The
best
estimate
of
the
cost
for
this
testing
element
is
$
103,108.

C.
Developmental
toxicity.
The
ECA
indicates
that
extant
data
reported
in
Payan
et
al.
(
1980)
in
rats
and
Rao
et
al.
(
1980)
in
rabbits
fulfills
the
testing
requirement.
See
Appendix
E.
3
of
the
ECA.
There
are
no
additional
costs.

4
Tier
I
Program
Review
Testing
D.
PKIMECH
data
to
support
model
validation
and
verification
of
oral­
to­
inhalation
extrapolation
for
the
following
data
needs
in
the
F344
rat:
a)
subchronic
toxicity,
b)
subchronic
neurotoxicity,
c)
reproductive
toxicity.

Costs
for
this
component
of
the
testing
requirements
are
represented
by
the
costs
for
Appendix
C.
1
(
ofthe
ECA)
studies
1
through
4
for
rats.
The
costs
for
these
tests
are
based
on
costs
developed
for
the
ECA
for
1,1
,2­
Trichloroethane
(
EPAB
2000).
The
best
estimate
of
the
cost
for
this
testing
element
is
$
74,111.

E.
PBPK
model
simulations.

It
has
been
assumed
that
the
burden
associated
with
model
simulations
and
development
will
be
24
hours.

Tier
II
Testing
and/
or
Extrapolation
Reporting
F.
Subchronic
toxicity,
extrapolation
of
extant
oral
data
to
inhalation,
based
on
Appendix
C.
2
and
C.
6
oftheECA.

This
requirement
relates
to
extrapolation
of
testing
results
from
existing
data
contained
in
Daniels
et
al.
(
1984).
The
extrapolation
of
data
generated
from
oral
route
testing
to
obtain
inhalation
data
is
done
via
the
PBPK
model.
Collecting
the
necessary
data,
calculating
the
model,
and
generating
or
recording
the
output
are
estimated
to
require
a
total
of
two
hours
of
labor
time.
This
labor
time
will
involve
a
20/
60/
20
mix
of
managerial,
technical,
and
clerical
time,
hence
the
two
hours
of
labor
time
has
been
valued
at
the
weighted
average
labor
rate
for
these
three
categories
of
labor,
which
is
$
69.28
per
hour
($
2001).
The
cost
ofthis
requirement
is
estimated
to
be
$
139.

G.
Subchronic
neurotoxicity
(
oral),
based
on
799.9620,
as
annotated
in
Appendix
D.
2
of
the
ECA.

The
cost
estimate
for
this
testing
are
based
on
costs
for
799.9620
reported
in
the
HAPs
Economic
Analysis
(
EA).
As
noted
in
the
EA,
the
costs
are
based
on
costs
for
the
similar
870.6200
protocol
(
Neurotoxicity
Screening
Battery,
Subchronic).
Costs
for
that
protocol,
however,
were
available
for
the
dietary
route
only.
These
costs
are
probably
somewhat
higher
than
the
costs
for
the
oral
route,
which
is
specified
in
Appendix
D.
2
of
the
ECA
as
drinking
water.
The
best
estimate
of
the
costs
for
799.9620
(
subchronic)
via
the
oral
route
is
$
145,373.

5
H.
Subchronic
neurotoxicity,
extrapolation
of
oral
data
to
inhalation,
as
annotated
in
Appendix
C
of
the
ECA.

See
explanation
of
costs
for
testing
elementG
above.
The
cost
of
this
requirement
is
estimated
to
be
$
139.

I.
Reproductive
toxicity
(
oral),
based
on
799.9380,
as
annotated
in
Appendix
D.
3
of
the
ECA.

The
cost
estimate
for
this
testing
was
based
on
costs
for
799.9380
reported
in
the
HAPs
EA.
As
noted
in
the
EA,
the
costs
are
based
on
costs
for
the
similar
870.3800
protocol
(
Reproduction/
Fertility
Effects).
Costs
for
that
protocol,
however,
were
available
for
the
gavage
route
only.
These
costs
are
probably
somewhat
higher
than
the
costs
for
the
oral
route,
which
is
specified
in
Appendix
D.
3
of
the
ECA
as
drinking
water.
The
best
estimate
ofthe
costs
for
799.9380
via
the
oral
route
at
$
506,837.

J.
Reproductive
toxicity
extrapolation
of
oral
data
to
inhalation,
as
annotated
in
Appendix
C
of
the
ECA.

See
explanation
of
costs
for
testing
element
G
above.
This
element
requires
extrapolation
of
the
oral
data
obtained
under
I
above.
The
cost
of
this
requirement
is
estimated
to
be$
139.

K.
Reproductive
toxicity
extrapolation
of
oral
data
to
inhalation,
as
annotated
in
Appendix
C
of
the
ECA.

See
explanation
of
costs
for
testing
element
G
above.
This
element
requires
extrapolation
of
extant
literature
data
from
the
oral
to
inhalation
route.
The
cost
of
this
requirement
is
estimated
to
be
$
139.

Step
2.
Estimate
Burden
Administrative
burden
associated
with
the
tests
conducted
is
calculated
by
multiplying
the
cost
of
testing
by
25
percent
and
then
dividing
this
cost
by
the
weighted
average
labor
rate
of
$
69.28.
These
estimates
are
shown
in
Table
3.

Additional
burden
is
estimated
to
occur
as
a
result
ofthe
development
and
execution
of
the
PBPK
model
(
see
item
D.
in
Table
1
ofthis
report).
It
is
estimated
to
take
24
hours
to
run
PBPK
model
simulations
and
to
refine
the
PBPK
model.
Once
the
model
is
developed,
each
run
of
the
model
to
extrapolate
from
oral
to
inhalation
data
is
estimated
to
take
2
hours
(
items
F,
H,
3,
and
K
in
Table
1
of
this
report).

6
Table
3.
Summary
of
Costs
and
Burdens
for
ECA
for
Ethylene
Dichloride
Testing
Segment
I
Required
testing
Cost
($
2001)
Admin.
Burden
(
Hrs)
Other
Burden
(
Hrs)

HAPs
Testing
A.
Acute
toxicity
(
inhalation)
based
on
799.9135
$
93,889
339
­­

.

B.
Acute
neurotoxicity
(
inhalation)
based
on
799.9620
$
103,108
372
­­

C.
Developmental
toxicitya
Subtotal
$
196,997
711
Program
Review
Testing
D.
PK/
MECH
data
to
support
model
validation
and
verification
of
oral­
to­
inhalation
extrapolation
for
the
following
data
needs
in
the
P344:
(
a)
subchronic
toxicity,
(
b)
subchronic
neurotoxicity,
and
(
c)
reproductive
toxicity.
$
74,111
267
E.
PBPK
model
simulations
to
validate
model
$
1,632
­­
24
Subtotal
$
145,020
291
Tier
II
Testing
and/
or
Extrapolation
Reporting
F.
Subchronic
neurotoxicity,
extrapolation
of
extant
data
$
139
­­
2
.

G.
Subchronic
neurotoxicity
(
oral),
based
on
799.9620
$
145,373
525
H.
Subchronic
neurotoxicity
extrapolation
oforal
data
to
inhalation
$
139
­­
2
I.
Reproductive
toxicity
(
oral),
based
on
799.9380
$
506,837
1,829
3.
Reproductive
toxicity
extrapolation
of
oral
data
from
I.
above
to
inhalation
$
139
­­
2
K.
Reproductive
toxicity
extrapolation
of
extant
data
to
inhalation
$
139
­­
2
Subtotal
$
652,766
2,362
TOTAL
(
may
not
add
due
to
rounding)
$
994,783
3,364
a
Data
from
existing
studies
Payan
et
al.
(
1995)
and
Rao
et
al.
(
1980)
deemed
adequate
to
fulfill
this
requirement.
No
new
testing
is
required.

7
Results
The
total
estimated
burden
for
the
ECA
is
3,364
hours.

References
EPAB
1997.
Economics
and
Policy
Analysis
Branch.
Economic
Assessment
for
the
Amended
PrOposed
TSCA
Section
4(
a)
Test
Rule
for
21
Hazardous
Air
Pollutants.
EPA/
OPPT/
EETD/
EPAB,
November
14,
1997.

EPAB
2000.
Economics
and
Policy
Analysis
Branch.
Burden
Estimates
for
Enforceable
Consent
Agreement
for
1,1,2­
trichloroethane.
EPA/
OPPT/
EETD/
EPAB,
February
14,
2000.

EPAB
2001.
Economics
and
Policy
Analysis
Branch.
Economic
Analysis
for
Renewed
Infromation
Collection
Request
for
the
TESSCA
Section
5(
a)(
2)
Significant
New
Use
Rule.
EPAJOPPT/
EETD/
EPAB,
September
2001.

8
