Document ID: EPA-HQ-OPPT-2004-0128-0059
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-10-12T04:00Z

PROPOSED
1:
03/
2004
United
States
Environmental
Protection
Agency
Office
of
Pollution
Prevention
and
Toxics
VINYL
CHLORIDE
(
CAS
Reg.
No.
75­
01­
4)

PROPOSED
ACUTE
EXPOSURE
GUIDELINE
LEVELS
(
AEGLs)

"
PUBLIC
DRAFT"

Federal
Register
­
March
2004
2
PROPOSED
1:
3/
2004
VINYL
CHLORIDE
(
CAS
Reg.
No.
75­
01­
4)

PROPOSED
ACUTE
EXPOSURE
GUIDELINE
LEVELS
(
AEGLs)
Vinyl
chloride
PROPOSED
1:
3/
2004
iii
PREFACE
1
Under
the
authority
of
the
Federal
Advisory
Committee
Act
(
FACA)
P.
L.
92­
463
of
1972,
the
2
National
Advisory
Committee
for
Acute
Exposure
Guideline
Levels
for
Hazardous
Substances
3
(
NAC/
AEGL
Committee)
has
been
established
to
identify,
review
and
interpret
relevant
toxicologic
and
4
other
scientific
data
and
develop
AEGLs
for
high
priority,
acutely
toxic
chemicals.
5
AEGLs
represent
threshold
exposure
limits
for
the
general
public
and
are
applicable
to
emergency
6
exposure
periods
ranging
from
10
minutes
to
8
hours.
AEGL­
2
and
AEGL­
3
levels,
and
AEGL­
1
levels
as
7
appropriate,
will
be
developed
for
each
of
five
exposure
periods
(
10
and
30
minutes,
1
hour,
4
hours,
and
8
8
hours)
and
will
be
distinguished
by
varying
degrees
of
severity
of
toxic
effects.
It
is
believed
that
the
9
recommended
exposure
levels
are
applicable
to
the
general
population
including
infants
and
children,
and
10
other
individuals
who
may
be
sensitive
or
susceptible.
The
three
AEGLs
have
been
defined
as
follows:
11
AEGL­
1
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m
³
)
of
a
substance
above
which
it
12
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
notable
13
discomfort,
irritation,
or
certain
asymptomatic,
non­
sensory
effects.
However,
the
effects
are
not
disabling
14
and
are
transient
and
reversible
upon
cessation
of
exposure.
15
AEGL­
2
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m
³
)
of
a
substance
above
which
it
16
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
irreversible
or
17
other
serious,
long­
lasting
adverse
health
effects,
or
an
impaired
ability
to
escape.
18
AEGL­
3
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m
³
)
of
a
substance
above
which
it
19
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
life­
threatening
20
health
effects
or
death.
21
Airborne
concentrations
below
the
AEGL­
1
represent
exposure
levels
that
could
produce
mild
and
22
progressively
increasing
odor,
taste,
and
sensory
irritation,
or
certain
asymptomatic,
non­
sensory
effects.
23
With
increasing
airborne
concentrations
above
each
AEGL
level,
there
is
a
progressive
increase
in
the
24
likelihood
of
occurrence
and
the
severity
of
effects
described
for
each
corresponding
AEGL
level.
Although
25
the
AEGL
values
represent
threshold
levels
for
the
general
public,
including
sensitive
subpopulations,
it
is
26
recognized
that
certain
individuals,
subject
to
unique
or
idiosyncratic
responses,
could
experience
the
27
effects
described
at
concentrations
below
the
corresponding
AEGL
level.
28
Vinyl
chloride
PROPOSED
1:
3/
2004
iv
TABLE
OF
CONTENTS
1
PREFACE
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iii
2
EXECUTIVE
SUMMARY
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vii
3
1.
INTRODUCTION
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1
4
2.
HUMAN
TOXICITY
DATA
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2
5
2.1.
Acute
Lethality
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2
6
2.2.
Nonlethal
Toxicity
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3
7
2.2.1.
Neurotoxicity
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3
8
2.2.2.
Odor
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4
9
2.2.3.
Irritation
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5
10
2.2.4.
Cardiovascular
effects
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6
11
2.2.5.
Other
Endpoints
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6
12
2.3.
Developmental
/
Reproductive
Toxicity
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7
13
2.4.
Genotoxicity
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8
14
2.5.
Carcinogenicity
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8
15
2.6.
Summary
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9
16
3.
ANIMAL
TOXICITY
DATA
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10
17
3.1.
Acute
Lethality
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10
18
3.1.1.
Rats
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10
19
3.1.2.
Mice
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11
20
3.1.3.
Guinea
Pigs
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12
21
3.1.4.
Rabbits
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12
22
3.1.5.
Other
Species
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12
23
3.2.
Nonlethal
Toxicity
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14
24
3.2.1.
Dogs
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14
25
3.2.2.
Rats
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14
26
3.2.3.
Mice
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16
27
3.2.4.
Guinea
Pigs
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17
28
3.2.5.
Rabbits
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18
29
3.3.
Developmental/
Reproductive
Toxicity
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20
30
3.4.
Genotoxicity
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22
31
3.5.
Carcinogenicity
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24
32
3.6.
Summary
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33
4.
SPECIAL
CONSIDERATIONS
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30
34
4.1.
Metabolism
and
Disposition
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30
35
4.2.
Mechanism
of
Toxicity
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36
37
Vinyl
chloride
PROPOSED
1:
3/
2004
v
4.3.
Other
Relevant
Information
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33
1
4.3.1
PBPK­
Modeling
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.
33
2
4.3.2.
Interspecies
Variability
.
.
.
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.
33
3
4.3.3.
Intraspecies
Variability
.
.
.
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.
34
4
4.3.4.
Concurrent
Exposure
Issues
.
.
.
.
.
.
.
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.
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.
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.
.
.
35
5
5.
RATIONALE
AND
PROPOSED
AEGL­
1
.
.
.
.
.
.
.
.
.
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.
.
.
.
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.
.
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.
.
.
.
.
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.
.
.
.
.
.
.
35
6
5.1.
Human
Data
Relevant
to
AEGL­
1
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
.
35
7
5.2.
Animal
Data
Relevant
to
AEGL­
1
.
.
.
.
.
.
.
.
.
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.
.
.
35
8
5.3.
Derivation
of
AEGL­
1
.
.
.
.
.
.
.
.
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.
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.
.
.
36
9
6.
RATIONALE
AND
PROPOSED
AEGL­
2
.
.
.
.
.
.
.
.
.
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.
.
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.
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.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
37
10
6.1.
Human
Data
Relevant
to
AEGL­
2
.
.
.
.
.
.
.
.
.
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.
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.
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.
.
37
11
6.2.
Animal
Data
Relevant
to
AEGL­
2
.
.
.
.
.
.
.
.
.
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.
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.
.
37
12
6.3.
Derivation
of
AEGL­
2
.
.
.
.
.
.
.
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.
.
.
38
13
7.
RATIONALE
AND
PROPOSED
AEGL­
3
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
39
14
7.1.
Human
Data
Relevant
to
AEGL­
3
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
39
15
7.2.
Animal
Data
Relevant
to
AEGL­
3
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
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.
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.
.
.
.
.
.
39
16
7.3.
Derivation
of
AEGL­
3
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
40
17
8.
SUMMARY
OF
PROPOSED
AEGLs
.
.
.
.
.
.
.
.
.
.
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.
.
.
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.
.
.
.
.
41
18
8.1.
AEGL
Values
and
Toxicity
Endpoints
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
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.
.
.
.
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.
.
.
.
.
.
.
41
19
8.2.
Comparison
with
Other
Standards
and
Criteria
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
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.
.
.
42
20
8.3.
Data
Adequacy
and
Research
Needs
.
.
.
.
.
.
.
.
.
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.
44
21
9.
REFERENCES
.
.
.
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.
.
45
22
APPENDIX
A
­
Derivation
of
AEGL
values
.
.
.
.
.
.
.
.
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.
.
.
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.
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.
55
23
AEGL­
1
.
.
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.
56
24
AEGL­
2
.
.
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.
57
25
AEGL­
3
.
.
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.
.
58
26
APPENDIX
B
­
Time
Scaling
Calculations
for
Vinyl
Chloride
AEGLs
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
59
27
APPENDIX
C
­
Cancer
Assessment
of
Vinyl
Chloride
.
.
.
.
.
.
.
.
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.
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.
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.
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.
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.
.
.
.
.
.
.
.
.
67
28
APPENDIX
D
­
Occupational
epidemiological
studies
on
carcinogenicity
(
focus:
limited
exposure
29
time)
.
.
.
.
.
.
.
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.
.
79
30
APPENDIX
E
­
Derivation
Summary
for
Vinyl
Chloride
AEGLs
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
84
31
Vinyl
chloride
PROPOSED
1:
3/
2004
vi
LIST
OF
TABLES
1
TABLE
1:
CHEMICAL
AND
PHYSICAL
DATA
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
2
2
TABLE
2:
SUMMARY
OF
ACUTE
EFFECTS
IN
HUMANS
AFTER
INHALATION
OF
3
VINYL
CHLORIDE
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
7
4
TABLE
3:
SUMMARY
OF
ACUTE
LETHAL
INHALATION
DATA
IN
LABORATORY
ANIMALS13
5
TABLE
5:
QUANTITATIVE
ASSESSMENT
OF
CARCINOGENIC
POTENCY
OF
VC
BASED
ON
6
ANIMAL
EXPERIMENTS
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
27
7
TABLE
6:
METABOLIC
SATURATION
CONCENTRATIONS
OF
VC
IN
RATS
AND
8
MONKEYS
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
32
9
TABLE
7:
AEGL­
1
VALUES
FOR
VINYL
CHLORIDE
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
36
10
TABLE
8:
AEGL­
2
VALUES
FOR
VINYL
CHLORIDE
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
39
11
TABLE
9:
AEGL­
3
VALUES
FOR
VINYL
CHLORIDE
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
41
12
TABLE
10:
SUMMARY/
RELATIONSHIP
OF
PROPOSED
AEGL
VALUES
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
41
13
TABLE
11:
EXISTENT
STANDARDS
AND
GUIDELINES
FOR
VINYL
CHLORIDE
.
.
.
.
.
.
.
.
.
.
43
14
LIST
OF
FIGURES
15
FIGURE
1:
CATEGORICAL
REPRESENTATION
OF
VINYL
CHLORIDE
INHALATION
16
DATA.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
42
17
FIGURE
2:
REGRESSION
ANALYSIS
OF
THE
LOG­
LOG
TRANSFORMED
CONCENTRATION­
18
TIME
CURVE
REGARDING
UNCONSCIOUSNESS
IN
MICE
AND
GUINEA­
PIGS
.
.
.
.
.
62
19
FIGURE
3:
REGRESSION
ANALYSIS
OF
THE
LOG­
LOG
TRANSFORMED
CONCENTRATION­
20
TIME
CURVE
REGARDING
MUSCULAR
INCOORDINATION
IN
MICE
AND
GUINEA­
21
PIGS
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
64
22
FIGURE
4:
REGRESSION
ANALYSIS
OF
THE
LOG­
LOG
TRANSFORMED
CONCENTRATION­
23
TIME
CURVE
REGARDING
SIDE
POSITION
IN
MICE
AND
GUINEA­
PIGS
.
.
.
.
.
.
.
.
.
66
24
FIGURE
5:
EXTERNAL
CONCENTRATION
(
mg/
m3)
AND
DOSE
TO
LIVER
(
mg/
L)
AS
25
CALCULATED
BY
PBPK­
MODELING
BY
EPA
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
71
26
Vinyl
chloride
PROPOSED
1:
3/
2004
vii
EXECUTIVE
SUMMARY
1
Vinyl
chloride
(
VC)
is
a
colorless,
flammable
gas
with
a
slightly
sweet
odor.
It
is
heavier
than
air
2
and
accumulates
at
the
bottom
of
rooms,
tanks
etc.
Its
worldwide
production
is
approximately
27,000,000
3
tons.
Most
is
polymerized
to
PVC.
Combustion
of
VC
in
air
produces
carbon
dioxide
and
hydrogen
4
chloride.
Odor
thresholds
of
VC
were
reported
in
the
range
of
10
to
25,000
ppm.
Validated
studies
5
providing
a
quantitative
odor
recognition
and
detection
limit
are
not
available.
Therefore,
a
Level
of
Odor
6
Awareness
(
LOA)
can
not
be
derived.
7
Vinyl
chloride
is
an
anaesthetic
compound.
After
5
minute
exposure
to
16,000
ppm
VC,
8
volunteers
showed
dizziness,
lightheadedness,
nausea,
visual
and
auditory
dulling
(
Lester
et
al.,
1963).
9
Mild
headache
and
some
dryness
of
the
eyes
and
nose
were
the
only
complaints
of
volunteers
exposed
to
10
491
ppm
VC
for
several
hours
(
Baretta
et
al.,
1969).
No
data
on
developmental
or
reproductive
toxicity
of
11
VC
in
humans
after
acute
exposure
are
available.
Occurrence
of
chromosomal
aberrations
in
lymphocytes
12
of
humans
were
associated
with
accidental
exposure
to
VC.
After
chronic
occupational
exposure,
VC
is
a
13
known
human
carcinogen
inducing
liver
angiosarcoma,
possibly
hepatocellular
carcinoma
and
brain
14
tumors.
Evidence
for
tumors
at
other
locations
is
contradictory.
Two
recent
epidemiological
studies
(
Mundt
15
et
al.,
2000;
Ward
et
al.,
2001)
did
not
find
an
increased
Standard
Mortality
Ratio
after
5
years
of
16
occupational
exposure
to
VC,
whereas
one
other
study
suggested
such
an
increase
after
1
year
of
exposure
17
(
Boffetta
et
al.,
2003).
18
Acute
exposure
of
experimental
animals
to
VC
results
in
narcotic
effects
(
Mastromatteo
et
al.,
19
1960),
cardiac
sensitization
(
Clark
and
Tinston,
1973;
1982),
and
hepatotoxicity
(
Jaeger
et
al.,
1974).
20
Prodan
et
al.
(
1975)
reported
LC50
values
for
mice,
rats,
rabbits,
and
guinea
pigs
of
117,500
ppm,
150,000
21
ppm,
240,000
ppm
and
240,000
ppm,
respectively,
after
2
hours.
No
investigations
of
reproductive
or
22
developmental
toxicity
after
single
exposure
are
available.
After
repeated
exposure
developmental
toxicity
23
in
mice,
rats
and
rabbits
(
e.
g.
delayed
ossification)
was
only
observed
at
maternally
toxic
concentrations.
24
Embryo­
fetal
development
of
rats
was
not
affected
by
2­
week­
exposure
(
6h/
d)
up
to
1,100
ppm
(
Thornton
25
et
al.,
2002).
Positive
results
on
genotoxicity
after
in
vitro
and
single
and
repeated
in
vivo
treatment
have
26
been
reported
for
VC.
Elevated
etheno­
adducts
were
observed
after
single
and
short
term
exposure
and
27
associated
with
mutational
events
(
Swenberg
et
al.,
2000;
Barbin,
2000).
Higher
adduct
levels
were
seen
in
28
young
animals
than
in
adult
animals
after
identical
treatment
(
Fedtke
et
al.,
1990;
Laib
et
al.,
1989;
29
Ciroussel
et
al.,
1990,
Morinello
et
al.,
2002).
From
a
study
with
single
exposure
of
adult
rats
to
45
ppm
30
for
6
hours,
it
may
be
concluded
that
no
increase
of
relevant
etheno­
adducts
above
background
occurred
31
(
Watson
et
al.,
1991).
32
Induction
of
liver
tumors
has
been
reported
in
rats
after
short
term
(
5
week
and
33
days,
33
respectively)
exposure
(
Maltoni
et
al.,
1981;
1984;
Froment
et
al.,
1994).
Vinyl
chloride
induces
lung
34
tumors
in
mice
after
single
exposure
to
high
concentrations
of
VC
(
Hehir
et
al.,
1981).
Short
term
exposure
35
experiments
from
Drew
et
al.
(
1983),
Maltoni
et
al.
(
1981)
and
Froment
et
al.
(
1994)
indicated
increased
36
susceptibility
of
tumor
formation
in
newborn
and
young
animals.
37
The
AEGL­
1
was
based
on
the
study
of
Baretta
et
al.
(
1969)
with
4­
7
volunteers,
two
individuals
38
experienced
mild
headache
during
3.5
and
during
7.5
hours
(
3.5
hours,
0.5
hours
break,
3.5
hours)
of
39
exposure
to
491
ppm.
The
time
of
onset
of
headaches
is
not
clearly
stated
and
was
assumed
to
be
after
3.5
40
Vinyl
chloride
PROPOSED
1:
3/
2004
viii
hours.
A
total
uncertainty
factor
of
3
was
used.
Since
the
AEGL­
1
is
based
on
human
data
no
interspecies
1
extrapolation
was
used.
The
intraspecies
uncertainty
factor
of
3
is
used
to
account
for
both
toxicokinetic
2
and
toxicodynamic
differences
among
individuals.
The
other
exposure
duration­
specific
values
were
3
derived
by
time
scaling
according
to
the
dose­
response
regression
equation
Cn
x
t
=
k,
using
the
default
of
4
n=
3
for
shorter
exposure
periods
and
n=
1
for
longer
exposure
periods,
due
to
the
lack
of
suitable
5
experimental
data
for
deriving
the
value
of
n.
The
extrapolation
to
10
minutes
from
a
3.5
hour
exposure
is
6
justified
because
exposure
of
human
at
4,000
ppm
for
5
minutes
did
not
result
in
headache
(
Lester
et
al.,
7
1963).
8
The
AEGL­
2
was
based
on
prenarcotic
effects
observed
in
human
volunteers.
After
5
minute
9
exposure
to
16,000
ppm
VC,
5
of
6
persons
showed
dizziness,
lightheadedness,
nausea,
and
visual
and
10
auditory
dulling.
At
concentrations
of
12,000
ppm
one
of
six
persons
showed
dizziness
and
"
swimming
11
head,
reeling".
No
effects
were
observed
at
4,000
ppm
in
this
study.
A
single
person
reported
slight
effects
12
("
slightly
heady")
of
questionable
meaning
at
8,000
ppm
(
this
volunteer
felt
also
slightly
heady
at
sham
13
exposure
and
reported
no
response
at
12,000
ppm)
(
Lester
et
al.,
1963).
12,000
ppm
was
regarded
as
the
14
no
effect
for
impaired
ability
to
escape.
A
total
uncertainty
factor
of
3
is
used
to
account
for
toxicodynamic
15
differences
among
individuals.
As
the
unmetabolized
VC
is
responsible
for
the
effect,
no
relevant
16
differences
in
toxicokinetics
are
assumed.
In
analogy
to
other
anesthetics
the
effects
are
assumed
to
be
17
solely
concentration
dependent.
Thus,
after
reaching
steady
state
at
about
2
hours
of
exposure,
no
increase
18
in
effect
is
expected.
The
other
exposure
duration­
specific
values
were
derived
by
time
scaling
according
to
19
the
dose­
response
regression
equation
Cn
x
t
=
k,
using
an
n
of
2,
based
on
data
from
Mastromatteo
et
al.
20
(
1960).
Mastromatteo
et
al.
observed
various
time­
dependent
prenarcotic
effects
in
mice
and
guinea
pigs
21
after
less
than
steady
state
exposure
conditions.
Time
extrapolation
was
performed
from
5
to
10,
30,
60
22
minutes
and
2
hours,
where
the
steady
state
concentration
was
calculated.
23
The
AEGL­
3
was
based
on
cardiac
sensitization
and
the
no
effect
level
for
lethality.
Short
term
24
exposure
(
5
min)
of
dogs
to
VC
induced
cardiac
sensitization
towards
epinephrine
(
EC50:
50,000
or
71,000
25
ppm
in
two
independent
experiments)
(
Clark
and
Tinston,
1973;
Clark
and
Tinston,
1982).
Severe
cardiac
26
sensitization
is
a
life
threatening
effect,
but
at
50,000
ppm
no
animals
died.
A
total
uncertainty
factor
of
3
27
is
used
to
account
for
toxicodynamic
differences
among
individuals.
As
the
challenge
with
epinephrine
and
28
the
doses
of
epinephrine
used
represent
a
conservative
scenario,
no
interspecies
uncertainty
factor
was
29
used.
As
the
unmetabolized
VC
is
responsible
for
the
effect,
no
relevant
differences
in
toxicokinetics
are
30
assumed.
In
analogy
to
other
halocarbons
(
e.
g.,
Halon
1211,
HFC
134a)
which
lead
to
cardiac
sensitization
31
the
effects
are
assumed
to
be
solely
concentration
dependent.
Thus,
after
reaching
steady
state
at
about
2
32
hours
of
exposure,
no
increase
in
effect
is
expected.
The
other
exposure
duration­
specific
values
were
33
derived
by
time
scaling
according
to
the
dose­
response
regression
equation
Cn
x
t
=
k,
using
an
n
of
2,
34
based
on
data
from
Mastromatteo
et
al.
(
1960).
Mastromatteo
et
al.
observed
various
time­
dependent
35
prenarcotic
effects
(
muscular
incoordination,
side
position
and
unconsciousness,
effects
which
occur
36
immediately
before
lethality)
in
mice
and
guinea
pigs
after
less
than
steady
state
exposure
conditions.
Time
37
extrapolation
was
performed
from
5
to
10,
30,
60
minutes
and
2
hours,
where
the
steady
state
38
concentration
was
calculated.
39
The
calculated
values
are
listed
in
the
table
below.
40
Vinyl
chloride
PROPOSED
1:
3/
2004
ix
SUMMARY
TABLE
OF
PROPOSED
AEGL
VALUES
FOR
VINYL
CHLORIDE
1
Classificati
2
on
3
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
Endpoint
(
Reference)

AEGL­
1
4
(
Non­
5
disabling)
6
450
ppm
1200
mg/
m3
310
ppm
800
mg/
m3
250
ppm
650
mg/
m3
140
ppm
360
mg/
m3
70
ppm
180
mg/
m3
mild
headaches
in
2/
7
humans
(
Baretta
et
al.,
1969)

AEGL­
2#
7
(
Disabling)
8
2800
ppm
7300
mg/
m3
1600
ppm
4100
mg/
m3
1200
ppm
3100
mg/
m3
820
ppm
2100
mg/
m3
820
ppm
2100
mg/
m3
mild
dizziness
in
1/
6
humans
(
Lester
et
al.,
1963);
no
effect
level
for
impaired
ability
to
escape
AEGL­
3
9
(
Lethal)
10
12000
ppm*
31000
mg/
m3
6800
ppm*
18000
mg/
m3
4800
ppm*
12000
mg/
m3
3400
ppm
8800
mg/
m3
3400
ppm
8800
mg/
m3
cardiac
sensitization
(
Clark
and
Tinston,
1982;
1973);
no
effect
level
for
lethality
*
The
explosion
limits
for
VC
in
air
range
from
38,000
to
293,000
ppm.
The
AEGL­
3
values
at
11
10
minutes,
30
minutes,
and
1
hour
exceed
10%
of
the
lower
explosion
limit
(
LEL).
Therefore,
12
safety
considerations
against
the
hazard
of
explosion
must
be
taken
into
account.
13
14
#
Derived
AEGL­
2
values
do
not
protect
for
potential
mutations
or
malignancies
due
to
short
term
15
exposure
to
VC.
16
The
estimation
of
cancer
risk
was
based
on
the
study
of
Maltoni
et
al.
(
1981).
Newborn
rats
were
17
exposed
from
day
1
to
5
weeks
of
age
at
6,000
or
10,000
ppm
VC
by
inhalation
(
4
hr/
day,
5
d/
week).
18
Liver
angiosarcomas
were
found
in
17
of
42
newborn
rats
exposed
to
6,000
ppm
and
15
of
44
newborn
19
rats
exposure
to
10,000
ppm.
No
angiosarcomas
were
found
in
the
dams
exposed
identically.
A
6,000
20
ppm
exposure
in
rats
for
4
h/
day,
5
d/
week,
for
5
weeks
was
found
to
be
equivalent
to
a
continuous
human
21
exposure
of
51
ppm
using
a
PBPK
model.
From
this,
a
1
in
10,000
risk
was
calculated
to
be
at
33

g/
m3
22
and
24
hour
exposure
was
34.7
mg/
m3
(
13.2
ppm).
Further
exposure
duration
calculations
were
done
23
using
the
PBPK
model
for
VC
and
are
shown
in
the
following
table
and
Appendix
C.
It
must
be
24
emphasized
that
there
are
substantial
uncertainties
in
calculating
cancer
risk
from
a
single
exposure.
25
Vinyl
chloride
PROPOSED
1:
3/
2004
x
Estimation
of
carcinogenic
potency
(
10­
4
risk)
after
single
exposure
1
30­
minute
1­
hour
4­
hour
8­
hour
Maltoni
et
al.,
1981;
from
5­
weeks­
2
study;
Human
equivalent
dose
to
6000
3
ppm
4
1200
ppm
(
3100
mg/
m3)
350
ppm
(
910
mg/
m3)
81
ppm
(
210
mg/
m3)
40
ppm
(
100
mg/
m3)

The
values
corresponding
to
10­
5
and
10­
6
risk
are
in
Appendix
C.
The
risk
for
10
minutes
has
not
been
5
calculated
due
to
extreme
uncertainty.
6
The
occurrence
of
DNA­
adducts
and
tumorigenicity
after
single
exposure
at
or
below
AEGL­
7
concentrations
may
not
be
excluded.
No
increase
of
relevant
etheno­
adducts
above
background
is
expected
8
at
single
exposure
to
3.4
ppm
for
8
hours.
This
includes
extrapolation
for
sensitive
subgroups
like
9
newborns
by
the
use
of
an
uncertainty
factor
of
10
(
for
details,
see
calculation
D;
Appendix
C).
10
References
11
Barbin,
A.
2000.
Etheno­
adduct
forming
chemicals:
from
mutagenicity
testing
to
tumour
mutation
spectra.
12
Mut.
Res.
462:
55­
69
13
Baretta,
E.
D.,
R.
D.
Stewart,
and
J.
E.
Mutchler.
1969.
Monitoring
exposures
to
vinyl
chloride
vapor:
14
breath
analysis
and
continuous
air
sampling.
Am.
Ind.
Hyg.
Assoc.
J.
30:
537­
544.
15
Belej,
M.
A.,
D.
G.
Smith,
and
D.
M.
Aviado.
1974.
Toxicity
of
aerosol
propellants
in
the
respiratory
and
16
circulatory
systems.
IV.
Cardiotoxicity
in
the
monkey.
Toxicology
2:
381­
395.
17
Boffetta,
P.,
L.
Matisane,
K.
A.
Mundt,
and
L.
D.
Dell.
2003.
Meta­
analysis
of
studies
of
occupational
18
exposure
to
vinyl
chloride
in
relation
to
cancer
mortality.
Scand.
J.
Work
Environ.
Health.
29:
220­
229.
19
Ciroussel,
F.,
A.
Barbin,
G.
Eberle,
aqnd
H.
Bartsch.
1990.
Investigations
on
the
relationship
between
20
DNA
ethenobase
adduct
levels
in
several
organs
of
vinyl
chloride­
exposed
rats
and
cancer
susceptibility.
21
Biochem.
Pharm.
39:
1109­
1113.
22
Clark,
D.
G.,
and
D.
J.
Tinston.
1973.
Correlation
of
the
cardiac
sensitizing
potential
of
halogenated
23
hydrocarbons
with
their
physicochemical
properties.
Br.
J.
Pharm.
49:
355­
357.
24
Clark,
D.
G.,
and
D.
J.
Tinston.
1982.
Acute
inhalation
toxicity
of
some
halogenated
and
non­
halogenated
25
hydrocarbons.
Hum.
Toxicol.
1:
239­
247.
26
Vinyl
chloride
PROPOSED
1:
3/
2004
xi
Drew,
R.
T.,
G.
A.
Boorman,
J.
K.
Haseman,
E.
E.
McConnell,
W.
M.
Busey,
and
J.
A.
Moore.
1983.
The
1
effect
of
age
and
exposure
duration
on
cancer
induction
by
a
known
carcinogen
in
rats,
mice,
and
hamsters.
2
Toxicol.
Appl.
Pharmacol.
68:
120­
130.
3
Fedtke,
N.,
J.
A.
Boucheron,
V.
E.
Walker,
and
J.
A.
Swenberg.
1990.
Vinyl
chloride­
induced
DNA
adducts.
4
II.
Formation
and
persistence
of
7­(
2'
oxoethyl)
guanine
and
N2­
ethenoguanine
in
rat
tissue
DNA.
5
Carcinogenesis
11:
1287­
1292.
6
Froment,
O.,
S.
Boivin,
A.
Barbin,
B.
Bancel,
C.
Trepo,
and
M.
J.
Marion.
1994.
Mutagenesis
of
ras
proto­
7
oncogens
in
rat
liver
tumors
induced
by
vinyl
chloride.
Canc.
Res.
54:
5340­
5345.
8
Hehir,
R.
M.,
B.
P.
McNamara,
J.
McLaughlin,
D.
A.
Willigan,
G.
Bierbower
and
J.
F.
Hardisty.
1981.
9
Cancer
induction
following
single
and
multiple
exposure
to
a
constant
amount
of
vinyl
chloride
monomer.
10
Environ.
Health
Perspect.
41:
63­
72
11
Jaeger,
R.
J.,
E.
S.
Reynolds,
R.
B.
Conolly,
M.
T.
Moslen,
S.
Szabo,
and
S.
D.
Murphy.
1974.
Acute
hepatic
12
injury
by
vinyl
chloride
in
rats
pretreated
with
phenobarbital.
Nature
252:
724­
726.
13
Laib,
R.
J.,
K.
P.
Klein,
and
H.
M.
Bolt.
1985b.
The
rat
liver
foci
bioassay:
I.
Age­
dependence
of
induction
14
by
vinyl
chloride
of
ATPase­
deficient
foci.
Carcinogenesis
6:
65­
68.
15
Lester,
D.,
L.
A.
Greenberg,
and
W.
R.
Adams.
1963.
Effects
of
single
and
repeated
exposures
of
humans
16
and
rats
to
vinyl
chloride.
Am.
Ind.
Hyg.
Assoc.
J.
24:
265­
275.
17
Maltoni,
C.,
G.
Lefemine,
A.
Ciliberti,
G.
Cotti,
and
D.
Carretti.
1981.
Carcinogenicity
bioassays
of
18
vinylchloride
monomer:
A
model
of
risk
assessment
on
an
experimental
basis.
Environ.
Health
Perspect.
19
41:
3­
31.
20
Maltoni,
C.,
G.
Lefemine,
A.
Ciliberrti,
G.
Cotti,
and
D.
Carretti.
1984.
Experimental
Research
on
Vinyl
21
Chloride
Carcinogenesis.
Vol.
II:
Archives
of
Research
on
Industrial
Carcinogenesis.
Princeton
Scientific
22
Publishers
Inc.,
New
Jersey.
23
Mastromatteo,
E.,
A.
M.
Fisher,
H.
Christie,
and
H.
Danziger.
1960.
Acute
inhalation
toxicity
of
vinyl
24
chloride
to
laboratory
animals.
Am.
Ind.
Hyg.
Assoc.
J.
21:
394­
398.
25
Morinello,
E.
J.,
A.­
J.
L.
Ham,
A.
Ranasinghe,
J.
Nakamura,
P.
B.
Upton,
and
J.
A.
Swenberg.
2002.
26
Molecular
dosimetry
and
repair
of
N(
2),
3­
ethenoguanine
in
rats
exposed
to
vinyl
chloride.
Canc.
Res.
27
62:
5189­
5195.
28
Prodan,
L.,
I.
Suciu,
V.
Pislaru,
E.
Ilea,
and
L.
Pascu.
1975.
Experimental
acute
toxicity
of
vinyl
chloride
29
(
monochloroethene).
Ann.
NY
Acad.
Sci.
246:
154­
158.
30
Vinyl
chloride
PROPOSED
1:
3/
2004
xii
Swenberg,
J.
A.,
A.
Ham,
H.
Koc,
E.
Morinello,
A.
Ranasinghe,
N.
Tretyakova,
P.
B.
Upton,
and
K.
Wu.
1
2000.
DNA
adducts:
effects
of
low
exposure
to
ethylene
oxide,
vinyl
chloride
and
butadiene.
Mut.
Res.
2
464:
77­
86.
3
Thornton,
S.
R.,
R.
E.
Schroeder,
R.
L.
Robison,
D.
E.
Rodwell,
D.
A.
Penney,
K.
D.
Nitschke,
and
W.
K.
4
Sherman.
2002.
Embryo­
fetal
development
and
reproducitve
toxicology
of
vinyl
chloride
in
rats.
Toxicol.
5
Sci.
68:
207­
219.
6
Watson,
W.
P.,
D.
Potter,
D.
Blair,
and
A.
S.
Wright.
1991.
The
relationship
between
alkylation
of
7
haemoglobin
and
DNA
in
Fischer
344
rats
exposed
to
[
1,2­
14C]
vinyl
chloride.
In:
Garner,
R.
C.,
Farmer,
8
P.
B.,
Steele,
G.
T.,
Wright,
A.
S.:
Human
Carcinogen
Exposure.
Biomonitoring
and
Risk
Assessment,
9
Oxford
University
Press,
London,
421­
428.
10
Vinyl
chloride
PROPOSED
1:
3/
2004
1
1.
INTRODUCTION
1
2
Vinyl
chloride
(
VC)
is
a
colorless,
flammable
gas
with
a
slightly
sweet
odor.
It
is
heavier
than
air
3
and
accumulates
at
the
bottom
of
rooms,
tanks
etc.
Its
worldwide
production
is
approximately
27,000,000
4
tons.
Most
VC
is
polymerized
to
PVC,
which
subsequently
is
used
to
produce
packaging
materials,
5
building
materials,
electric
appliances,
medical
care
equipment,
toys,
agricultural
piping
and
tubing
and
6
automobile
parts.
Currently
the
largest
single
use
is
in
the
building
sector
(
WHO,
1999a).
About
10,000
7
tons
annually
go
into
the
production
of
1,1,1­
trichloroethane
and
other
chlorinated
solvents
(
Kielhorn
et
al.,
8
2000).
9
Most
VC
is
produced
either
by
hydrochlorination
of
acetylene,
mainly
in
Eastern
European
10
countries,
or
by
thermal
cracking
of
1,2­
dichloroethane.
It
is
stored
either
under
pressure
at
ambient
11
temperature,
or
refrigerated
at
atmospheric
pressure
(
WHO,
1999a).
Since
VC
does
not
polymerize
readily
12
it
is
stored
without
additives.
Combustion
of
VC
in
air
produces
carbon
dioxide
and
hydrogen
chloride
13
(
WHO,
1999a).
14
15
Relevant
chemical
and
physical
properties
are
listed
in
Table
1.
16
Vinyl
chloride
PROPOSED
1:
3/
2004
2
TABLE
1:
CHEMICAL
AND
PHYSICAL
DATA
1
Parameter
2
Value
Reference
Molecular
formula
3
C2H3Cl
WHO,
1999a
Molecular
weight
4
62.5
g/
mol
WHO,
1999a
CAS
Registry
Number
5
75­
01­
4
WHO,
1999a
Physical
state
6
gaseous
(
at
room
temperature)
WHO,
1999a
Color
7
colorless
WHO,
1999a
Synonyms
8
vinyl
chloride
monomer,
monochlorethene,
monochlorethylene,
1­
chloroethylene,
chlorethylene,
chloroethene
WHO,
1999a
Vapor
pressure
9
78
kPa
at
­
20
oC
165
kPa
at
0
oC
333
kPa
at
20
oC
WHO,
1999a
Density
10
0.910
g/
cm3
at
20
oC
WHO,
1999a
Melting
point
11
­
153.8
oC
WHO,
1999a
Boiling
point
12
­
13.4
oC
WHO,
1999a
Solubility
in
water
13
soluble
in
almost
all
organic
solvents,
slightly
soluble
in
water
WHO,
1999a
Odor
14
slightly
sweet
WHO,
1999a
Explosion
limits
in
air
15
3.8
­
29.3
vol%
in
air
at
20
oC
4
­
22
vol%
WHO,
1999a
Conversion
factors
16
1
ppm
=
2.59
mg/
m3
at
20
oC,
101.3
kPa
1
mg/
m3
=
0.386
ppm
WHO,
1999a
2.
HUMAN
TOXICITY
DATA
17
2.1.
Acute
Lethality
18
Danziger
(
1960)
describes
two
deaths
due
to
accidental
exposure
of
workers
to
VC.
No
19
concentration
or
exposure
time
is
given,
but
circumstances
suggest
inhalation
of
very
high
concentrations.
20
Autopsy
results
show
cyanosis,
congestion
of
lung
and
kidneys
and
failure
of
blood
coagulation
(
Danziger,
21
1960).
Citing
older
results
from
Schaumann
et
al.,
12%
VC
(
120,000
ppm)
is
given
as
"
dangerous
22
concentrations"
(
Danziger,
1960;
Oster
et
al.,
1947).
23
At
very
high
concentrations,
VC
causes
asphyxia
likely
due
to
narcosis­
induced
respiratory
failure
24
(
NLM,
2000).
25
Vinyl
chloride
PROPOSED
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2004
3
2.2.
Nonlethal
Toxicity
1
Only
few
data
on
acute
human
toxicity
of
VC
after
acute
exposure
are
available.
Whereas
a
large
2
experience
on
the
long
term
effects
of
VC
exposure
at
the
workplace
exists.
Relevant
data
are
described
3
below.
4
2.2.1.
Neurotoxicity
5
Vinyl
chloride
has
been
considered
as
a
potential
anaesthetic.
Narcotic
limit
concentration
for
man
6
is
7%
­
10%
(
70,000
­
100,000
ppm)
(
Oster
et
al.,
1947,
Danziger,
1960,
Lehmann
and
Flury,
1938).
7
Schauman
(
1934)
reported
somewhat
higher
concentrations
to
lead
to
narcosis.
Exposure
to
unknown
high
8
concentrations
(
e.
g.,
during
the
cleaning
of
autoclaves)
also
resulted
in
narcotic
effects
(
Suciu,
1975).
9
Acute
exposure
10
Lester
et
al.
(
1963)
exposed
6
volunteers
­
3
men,
3
women
­
to
0,
0.4,
0.8,
1.2,
1.6
or
2%
VC
(
0,
11
4,000,
8,000,
12,000,
16,000,
or
20,000
ppm,
nominal
concentration)
for
5
minutes
using
a
plastic
12
breathing
mask
covering
the
mouth
and
nose.
The
total
gas
flow
was
50
liters
per
minute.
The
desired
13
concentrations
were
obtained
by
metering
air
and
VC
(
gas
chromatography
of
the
liquid
phase
indicated
14
more
than
99%
VC)
through
flow
meters
and
passing
the
appropriate
flows
through
a
2
l
mixing
chamber.
15
The
concentration
was
continuously
monitored
by
a
thermal
conductivity
meter
(
less
than
5%
deviation
16
from
the
desired
concentration).
All
volunteers
were
exposed
to
every
concentration
in
a
randomized
17
fashion,
separated
by
a
6­
hour
interval.
Dizziness
("
slightly
heady")
was
experienced
by
1
of
6
volunteers
18
at
8,000
ppm
(
the
same
subject
reported
slight
dizziness
at
sham
exposure
and
reported
no
response
at
19
12,000
ppm).
At
12,000
ppm
4/
6
persons
reported
no
response,
one
subject
reported
reeling,
swimming
20
head
and
another
subject
was
unsure
of
some
effects.
He
had
a
somewhat
dizzy
feeling
in
the
middle
of
21
exposure.
At
16,000
ppm
5
of
6
and
at
20,000
ppm
6
of
6
persons
complained
of
dizziness,
nausea,
22
headache,
and
dulling
of
visual
and
auditory
cues.
All
symptoms
disappeared
shortly
after
termination
of
23
exposure;
headache
persisted
for
30
minutes
in
one
subject
after
exposure
to
20,000
ppm
24
Two
experimenters
were
exposed
to
25,000
ppm
(
nominal
concentration)
for
3
minutes
by
entering
25
an
exposure
chamber
which
resulted
in
dizziness
and
slight
disorientation
as
to
space
and
size
of
26
surrounding
objects
and
a
burning
sensation
in
the
feet.
They
immediately
recovered
on
leaving
the
27
chamber
and
complained
only
of
a
slight
headache
which
persisted
for
30
minutes.
No
further
details
were
28
presented
(
Patty
et
al.,
1930).
29
Baretta
et
al.
(
1969)
exposed
4
­
6
volunteers
to
59,
261,
491
ppm
VC
(
analytical
concentrations)
30
for
7.5
h
(
including
a
0.5
h
lunch
period;
corresponding
to
time
weighted
average
concentrations
of
48,
248
31
or
459
ppm
over
a
period
of
7.5
h),
seven
persons
were
exposed
to
491
ppm
for
only
3.5
hours.
Persons
32
were
exposed
in
an
exposure
chamber
(
41
feet
by
6
feet
wide
by
7.5
feet
high)
with
a
continuous
positive
33
air
supply
and
exhaust
system.
Air
was
recirculated
with
a
squirrel
cage
fan
through
a
series
of
inlet
and
34
outlet
ducts
spanning
the
length
of
the
chamber.
VC
concentration
was
monitored
by
an
infrared
35
spectrophotometer.
The
vapors
were
introduced
from
a
pressurized
storage
cylinder
through
6
feet
of
1/
8
36
inch
I.
D.
stainless­
steel
tubing
into
a
rotometer
prior
to
entering
the
circulating
air
duct.
A
heating
tape
37
wrapped
around
the
stainless­
steel
tubing
prevented
condensation
of
the
VC.
Subjective
and
neurological
38
responses
of
the
volunteers
as
well
as
clinical
parameters
were
measured.
The
only
complaints
were
those
39
Vinyl
chloride
PROPOSED
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2004
4
of
two
subjects
who
reported
mild
headache
and
some
dryness
of
their
eyes
and
nose
after
exposure
to
the
1
highest
concentration.
The
time
of
onset
of
headaches
is
not
clearly
stated.
It
is
assumed
that
headaches
2
occurred
in
both
experiments,
after
3.5
hours
and
during
or
after
7.5
hours.
3
According
to
a
literature
review
from
Schottek
(
1969),
acute
human
exposure
to
1000
ppm
for
1
4
hour
leads
to
fatigue
and
vision
disturbances
(
Lefaux,
1966).
5000
ppm
for
60
minutes
should
lead
to
5
nausea
and
disorientation
(
Oettel,
1954),
with
similar
effects
after
6000
ppm
for
30
minutes
(
Patty
et
al.,
6
1930).
6000
to
8000
ppm
are
said
to
lead
to
prenarcotic
symptoms
(
von
Oettingen,
1964).
Examination
of
7
the
primary
literature
sources
did
not
show
how
those
figures
were
derived.
No
experimental
background
or
8
observation
data
are
provided.
Thus,
the
referred
results
may
not
be
used
for
risk
assessment.
9
Occupational
exposure
10
Suciu
et
al.
(
1975)
report
acute
effects
after
VC
exposure
from
1684
workers
from
two
factories.
11
During
periods
with
high
air
concentrations
of
VC
between
the
years
1963
and
1964,
acute
and
subacute
12
poisonings
occurred:
After
the
first
breaths
of
exposure
to
"
a
high
concentration
of
VC"
several
symptoms
13
(
pleasant
taste
in
the
mouth,
euphoric
conditions,
slow
movements,
giddiness,
inebriety­
like
condition)
were
14
observed.
Continued
exposure
caused
more
pronounced
symptoms
(
somnolence,
complete
narcosis).
After
15
repeated
exposures
to
unknown
high
concentrations,
workers
complained
about
headaches,
irritability,
16
diminution
of
memory,
insomnia,
general
asthenia,
paresthesia,
tingling,
and
loss
of
weight.
In
addition
to
17
an
"
onset
of
an
asthenovegetative
syndrome"
various
other
systemic
and
local
effects
were
observed
(
e.
g.,
18
cardiovascular
effects,
hepatomegaly,
digestive
responses,
respiratory
changes).
Workplace
concentrations
19
in
this
factory
were
2300
mg/
m3
(
about
890
ppm)
in
1963
and
decreased
in
the
following
years.
This
20
reported
VC
concentration
in
air
may
have
been
an
average
exposure
(
not
specified
by
the
authors).
21
However,
no
information
on
peak
concentrations
and
duration
of
episodes
with
short
term
high
22
concentrations
of
VC
exposure
is
provided.
Some
of
the
reported
activities,
such
as
cleaning
autoclaves,
23
are
to
be
associated
with
very
high
exposures.
24
Occurrence
of
headache
in
workers
chronically
exposed
to
VC
has
been
described
by
several
25
authors.
However,
exposure
concentration
and
duration
were
not
specified
and
always
was
characterized
as
26
"
high"
(
Lilis
et
al.,
1975;
Suciu
et
al.,
1975;
EPA,
1987).
27
2.2.2.
Odor
28
Odor
thresholds
reported
vary
over
a
wide
range:
10
­
25,000
ppm
(
26
­
65,000
mg/
m3).
Hori
et
al.
29
(
1972)
reported
an
odor
threshold
of
20
ppm
in
production
workers
and
10
ppm
in
workers
from
other
30
departments
of
polyvinyl­
chloride
(
PVC)
facilities
(
number
of
workers
involved
not
presented).
The
VC­
31
odor
was
perceived
by
50%
of
the
"
non
production"
workers
at
200
ppm
and
by
50%
of
the
"
production"
32
workers
at
350ppm.
Odor
threshold
was
tested
by
two
methods.
PVC
was
diluted
with
air
at
fixed
33
concentrations
and
was
supplied
from
a
glass
injector
to
the
subject's
nostrils
at
a
rate
of
100
milliliters
34
over
5
to
10
seconds.
This
was
repeated
at
gradually
higher
concentrations
until
the
subject
perceived
VC.
35
The
second
method
involved
measurement
of
atmospheric
concentrations
of
VC.
Production
workers
were
36
less
sensitive
to
VC
than
workers
from
other
departments.
When
workders
from
different
facilities
were
37
compared
even
greater
ranges
were
observed.
However,
inter­
individual
differences
and
measurement
38
techniques
which
were
not
strictly
controlled.
This
odor
threshold
was
reviewed
by
the
AIHA.
The
value
39
has
been
rejected
based
on
specified
criteria
(
e.
g.
no
calibration
of
panel
odor
sensitivity,
not
stated
whether
40
Vinyl
chloride
PROPOSED
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2004
5
the
given
limit
was
due
to
recognition
or
detection,
number
of
trials
not
stated;
AIHA
1997).
1
Baretta
et
al.
(
1969)
reported,
that
none
of
six
subjects
perceived
odor
entering
an
exposure
2
chamber
at
59
ppm,
while
at
261
ppm
all
four
subjects
detected
a
very
slight
odor.
Five
of
seven
subjects
3
entering
the
exposure
chamber
at
491
ppm
were
able
to
detect
the
odor
of
VC,
but
after
5
minutes
of
4
exposure
the
odor
was
no
longer
perceived
(
for
study
details
see
above).
5
Two
persons
who
were
exposed
to
25,000
ppm
(
nominal
concentration)
for
3
minutes
while
6
entering
an
experimental
exposure
chamber
reported
a
"
fairly
pleasant
odor"
(
Patty
et
al.,
1930).
7
Amoore
and
Hautala
(
1983)
reported
an
odor
threshold
of
3,000
ppm
for
VC.
This
value
8
represents
the
geometric
average
of
three
literature
studies
(
individual
studies
not
mentioned),
studies
9
reporting
extreme
points
and
duplicate
quotations
were
omitted.
It
was
not
stated
whether
this
was
the
10
detection
or
recognition
threshold.
11
2.2.3.
Irritation
12
13
Acute
exposure
14
Irritating
effects
of
VC
are
only
observed
after
exposure
to
very
high
concentrations:
lesions
of
the
15
eyes
(
wedge
shaped
brown
discoloration
of
the
bulbar
conjunctiva,
palpebral
slits,
conjunctiva
and
cornea
16
appeared
dried
out)
were
observed
at
autopsy
in
a
worker
who
died
due
to
inhalation
of
very
high
17
concentrations
of
VC.
The
lesions
were
explained
by
the
local
effects
of
VC.
At
autopsy
intensely
18
hyperemic
lungs,
with
desquamation
of
the
alveolar
epithelium
were
observed
(
Danziger,
1960).
19
Chronic
exposure
20
Tribukh
et
al.
(
1949)
reported
mucous
irritation
of
the
upper
respiratory
tract
and
chronic
21
bronchitis
in
PVC
workers;
however,
these
effects
were
not
mentioned
by
Lilis
et
al.
(
1975)
and
Marsteller
22
et
al.
(
1975).
23
Suciu
et
al.
(
1975)
describe
coughing
and
sneezing
after
exposure
of
workers
to
VC
during
one
24
shift;
no
other
acute
pulmonary
effects
or
irritation
are
mentioned.
These
workers
had
been
regularly
25
exposed
to
VC
for
an
extended
time
period.
26
27
In
chronically
exposed
VC
workers,
evidence
for
adverse
respiratory
disease
is
conflicting.
Lung
28
function
(
respiratory
volume
and
vital
capacity,
oxygen
and
carbon
dioxide
transfer)
deteriorate
over
time.
29
Emphysema/
chronic
obstructive
pulmonary
disease
(
COPD),
respiratory
insufficiency,
dyspnea,
and
30
pulmonary
fibrosis
have
been
described
(
Suciu
et
al.,
1975;
Walker
et
al.,
1976;
Lloyd
et
al.,
1984).
Some
31
of
these
observations
have
been
attributed
to
smoking
as
a
possible
confounder.
32
Vinyl
chloride
PROPOSED
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6
2.2.4.
Cardiovascular
effects
1
2
A
slight
decrease
in
blood
pressure
in
VC
workers
has
been
attributed
to
the
narcotic
effects
of
VC
3
(
Suciu
et
al.,
1975).
In
older
exposure
experiments
in
human
volunteers
no
cardiovascular
parameters
have
4
been
measured
(
Lester
et
al.,
1963).
5
Chronic
exposure
6
In
VC
workers,
Raynauds
disease
has
been
correlated
to
extended
exposure
to
high
VC
7
concentrations
(
ATSDR,
1997),
with
histologic
alterations
of
small
vessels
(
Veltman
et
al.,
1975).
Other
8
symptoms
observed
in
VC
workers
are
splenomegaly,
hypertension,
portal
hypertension,
generally
9
increased
cardiovascular
mortality,
and
vasospastic
symptoms
(
ATSDR
1997;
Suciu
et
al.,
1975;
Byron
et
10
al.,
1976).
According
to
Kotseva,
elevated
occupational
exposure
to
VC
increases
the
incidence
of
arterial
11
hypertension,
but
there
is
no
conclusive
evidence
that
it
is
associated
on
its
own
with
an
increased
risk
of
12
coronary
heart
disease
(
Beck
et
al.,
1973).
13
2.2.5.
Other
Endpoints
14
Hematology
and
immunology
15
Blood
tests
in
VC
victims
indicated
failure
of
blood
coagulation
(
Danziger
et
al.,
1960).
16
Hepatotoxicity
17
More
or
less
pronounced
hepatitis
and
enlargement
of
the
liver
have
been
reported
in
chronic
18
exposed
workers
(
ECB,
2000;
Marsteller
et
al.,
1975).
Others
reported
impaired
liver
function
and
19
periportal
liver
fibrosis
in
workers
from
a
PVC
producing
plant
(
no
further
details
presented;
Lange
et
al.,
20
1974).
Liver
function
disturbances
have
been
reported
for
workers
from
PVC
factories
(
Fleig
and
Thiess,
21
1978).
Focal
hepatocellular
hyperplasia
and
focal
mixed
hyperplasia
has
been
observed
in
VC­
exposed
22
workers;
some
of
the
individuals
with
focal
mixed
hyperplasia
developed
liver
angiosarcoma
(
Tamburro
et
23
al.,
1984).
No
data
on
liver
effects
after
acute
exposure
are
available.
24
Vinyl
chloride
PROPOSED
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7
TABLE
2:
SUMMARY
OF
ACUTE
EFFECTS
IN
HUMANS
AFTER
INHALATION
OF
1
VINYL
CHLORIDE
2
Concentration
3
(
ppm)
4
Exposure
Time
Study
type
and
effects
Reference
very
high
5
not
stated
irritation
to
the
eyes
Danziger,
1960
25,000
ppm
6
3
min
dizziness,
disorientation
to
space
and
size,
burning
sensation
in
feet,
persisting
headache
Patty
et
al.,
1930
20,000
ppm
7
5
min
6/
6
dizziness,
lightheadedness,
nausea,
visual
and
auditory
dulling,
persisting
headache
in
1/
6
Lester
et
al.,
1963
16,000
ppm
8
5
min
5/
6
dizziness,
lightheadedness,
nausea,
visual
and
auditory
dulling;
no
effects
in
one
volunteer
Lester
et
al.,
1963
12,000
ppm
9
5
min
1/
6
volunteers
dizzy,
1/
6
"
swimming
head,
reeling",
second
person
was
"
unsure"
of
effects,
somewhat
dizzy
in
the
middle
of
exposure
Lester
et
al.,
1963
8,000
ppm
10
5
min
1/
6
volunteers
"
slightly
heady"
(
this
volunteer
felt
also
slightly
heady
at
sham
exposure
and
reported
no
effects
at
12,000
ppm)
Lester
et
al.,
1963
4,000
ppm
11
5
min
no
effects
Lester
et
al.,
1963
3,000
ppm
12
not
stated
odor
threshold
(
geometric
averages
of
three
studies,
omitting
extreme
points
and
duplicate
quotations)
Amoore
and
Hautala,
1983
not
specified,
13
high
14
not
stated
prenarcotic
and
narcotic
effects;
repeated
exposure:
headaches,
asthenovegetative
syndrome,
cardiovascular
effects
,
hepatomegaly
Suciu
et
al.,
1975
491
or
459
ppm
15
3.5
h
2/
7
volunteers
reported
mild
headache
and
dryness
of
the
eyes
and
nose
Baretta
et
al.,
1969
261
ppm
16
not
stated
detection
of
the
odor
by
4/
4
subjects
Baretta
et
al.,
1969
20
ppm
17
not
stated
odor
threshold
in
PVC
production
workers
Hori
et
al.,
1972
10
ppm
18
not
stated
odor
threshold
in
workers
from
a
PVC
facility,
not
working
in
PVC
production
Hori
et
al.,
1972
2.3.
Developmental
/
Reproductive
Toxicity
19
No
data
on
developmental
or
reproductive
toxicity
in
humans
after
single
exposure
to
VC
were
20
identified.
21
Vinyl
chloride
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8
2.4.
Genotoxicity
1
Huettner
and
Nikolova
(
1998)
investigated
lymphocyte
chromosomal
aberrations
in
29
non­
2
exposed
and
29
persons
exposed
to
VC
and
its
combustion
byproducts
after
a
train
accident
in
3
Schoenebeck,
Germany.
The
authors
found
increased
incidences
of
chromosomal
aberrations
(
gaps,
4
chromatid
breaks,
acentric
chromosomes).
Blood
samples
were
drawn
2
­
4
month
after
the
accident.
Sixty
5
per
cent
of
the
exposed
individuals
complaint
of
health
problems
ascribed
to
the
pollutants.
More
than
15
6
hours
after
the
accident,
atmospheric
VC
concentrations
were
1
­
8
ppm
(
Huettner
and
Nikolova,
1998).
7
Hahn
et
al.
(
1998)
reported
maximum
VC­
concentrations
of
30
ppm
near
the
center
of
the
accident.
8
Exposure
level
to
VC
and/
or
other
combustion
products
of
those
persons
included
into
the
investigation
is
9
highly
uncertain.
In
a
follow­
up
study
two
years
later
in
the
same
cohort
of
accidentally
exposed
people,
10
Becker
et
al.
(
2001)
found
enhanced
chromosome
aberrations
in
peripheral
lymphocytes
as
an
indicator
of
11
clastogenic
activity
of
VC,
while
no
increased
mutagenic
activity
(
mutations
in
the
hypoxanthine­
guanine­
12
phosphoribosyl­
transferase
(
HPRT)
gene)
was
observed
in
exposed
persons.
13
Chronic
exposure
14
Clastogenic
DNA
damage
has
been
detected
by
various
tests
in
chronically
VC
exposed
workers.
15
Chromosomal
defects
(
inversions,
translocations,
rings)
and/
or
micronuclei
have
been
detected
at
exposure
16
concentrations
estimated
at
1
ppm
(
Fucic
et
al.,
1995;
short
exposure
spikes
up
to
300
ppm
VC
were
17
reported),
and
5
ppm
VC
(
Graj­
Vrhovac
et
al.,
1990).
Also
increased
frequencies
of
sister
chromatid
18
exchanges
were
reported
(
Fucic
et
al.,
1992;
Sinués
et
al.,
1991).
Awara
et
al.
(
1998)
observed
an
19
increased
incidence
of
DNA
damage
(
detection
by
single­
cell
gel
electrophoresis)
in
workers
exposed
to
20
VC.
The
amount
of
DNA­
damage
was
increasing
with
exposure
time.
Average
VC
concentrations
were
21
highest
in
the
production
area
(
about
3
ppm).
22
Covalent
binding
to
macromolecules
due
to
VC
exposure
in
humans
has
not
been
directly
assessed.
23
However,
gene
mutations
were
found
in
human
tumors
associated
with
exposure
to
etheno­
adduct­
forming
24
chemicals
such
as
VC.
Specifically,
in
angiosarcoma
of
the
human
liver
in
5
of
6
cases
G­>
A
transitions
of
25
the
Ki­
ras
gene
and
A­>
T
transitions
of
p53
were
observed
in
3
of
6
cases,
which
may
be
attributed
to
the
26
formation
of
ethenobases
in
DNA
(
Barbin,
2000).
27
2.5.
Carcinogenicity
28
No
data
about
cancer
induction
in
humans
after
single
exposure
have
been
reported.
From
two
29
large
epidemiological
studies
of
occupational
exposure
of
adult
workers
(
Ward
et
al.,
2000;
Mundt
et
al.,
30
1999),
there
is
some
evidence
that
risk
for
liver
cancer
or
biliary
tract
cancer
was
only
increased
after
31
extended
exposure
time.
However,
conflicting
results
are
also
published
(
Weber
et
al.,
1981)
demonstrating
32
a
steep
increase
of
the
Standard
Mortality
Rate
after
very
limited
exposure
duration
(
for
details,
see
33
Appendix
D).
There
exist
no
epidemiological
studies
which
include
newborn
children
as
specific
risk
group.
34
Chronic
exposure
35
There
are
sufficient
epidemiological
data
demonstrating
a
statistically
significant
elevated
risk
of
36
liver
cancer,
specifically
angiosarcomas
(
ASL),
from
chronic
exposure
to
VC
(
summarized
in
EPA,
2000a,
37
b;
WHO,
1999a;
Boffetta
et
al.,
2003).
The
possible
association
of
brain,
soft
tissue,
and
nervous
system
38
cancer
with
VC
exposure
was
also
reported.
However,
the
evidence
supporting
a
causal
link
between
brain
39
cancer
and
VC
exposure
is
limited
(
EPA,
2000a,
b).
Some
other
studies
found
an
association
between
VC
40
Vinyl
chloride
PROPOSED
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2004
9
exposure
and
cancer
of
the
hematopoetic
lymphatic
systems
(
Simonato
et
al.,
1991;
Greiser
et
al.,
1982).
1
Lung
cancer
has
also
been
associated
with
VC
exposure,
but
the
increased
risk
of
lung
cancer
observed
in
2
some
cohorts
may
be
due
to
exposure
to
PVC
dust
rather
than
VC
monomer
(
Mastrangelo
et
al.,
2003).
In
3
angiosarcoma
of
the
human
liver,
mutations
were
observed
which
may
be
attributed
to
the
formation
of
4
ethenobases
in
DNA
(
Barbin,
2000).
5
Quantitative
risk
estimates
for
VC
based
on
epidemiologic
studies
have
been
derived
by
the
6
Netherlands
(
Anonymous,
1987;
unit
risk
1

10­
6
per
µ
g/
m3),
the
WHO
(
1987;
1999b;
unit
risk
1

10­
6
per
7
µ
g/
m3)
and
Clewell
et
al.
(
Clewell
et
al.,
2001;
unit
risk
0.2
­
1.7
x
10­
6).
8
2.6.
Summary
9
Odor
thresholds
of
VC
were
reported
in
the
range
of
10
to
25,000
ppm
(
Hori
et
al.,
1972;
Baretta
10
et
al.,
1969;
AIHA,
1997;
Patty
et
al.,
1930).
Amoore
and
Hautala
(
1983)
reported
an
odor
threshold
of
11
3,000
ppm
for
VC.
This
value
represents
the
geometric
average
of
three
literature
studies,
extreme
points
12
and
duplicate
quotations
were
omitted.
Validated
studies
detecting
the
recognition
and
the
detection
limit
13
are
not
available
from
literature.
Vinyl
chloride
is
an
anaesthetic
compound.
Effects
observed
in
acutely
14
exposed
VC
workers
and
human
volunteers
indicate
a
characteristic
sequence
of
events
from
euphoria
and
15
dizziness,
followed
by
drowsiness
and
loss
of
consciousness.
After
five
minutes
exposure
of
volunteers,
16
health
effects
have
been
described
at
concentrations

8,000
ppm,
no
effects
were
observed
at
4,000
ppm
17
(
Lester
et
al.,
1963).
25,000
ppm
VC
for
3
minutes
caused
dizziness,
slightly
disorientation
and
a
burning
18
sensation
in
feet
in
two
volunteers
(
Patty
et
al.,
1930).
Mild
headache
and
some
dryness
of
the
eyes
and
19
nose
were
the
only
complaints
of
volunteers
exposed
to
491
ppm
VC
(
the
onset
of
headaches
is
not
20
specified
and
is
assumed
to
have
occurred
after
3.5
hours
of
exposure)
(
Baretta
et
al.,
1969).
Irritation
of
21
the
eyes
was
reported
in
the
context
of
an
accidental
exposure
to
lethal
VC
concentrations
(
exposure
22
concentration
unknown)
(
Danziger
et
al.,
1960).
23
No
data
on
developmental
or
reproductive
toxicity
of
VC
in
humans
after
acute
exposure
are
stated
24
in
the
literature.
25
Occurrence
of
chromosomal
aberrations
in
lymphocytes
of
humans
accidentally
exposed
to
VC
26
were
reported
by
Huettner
and
Nikolova
(
1998).
More
than
15
hours
after
the
accident,
atmospheric
VC
27
concentrations
were
1
­
8
ppm.
In
a
two
year
follow
up
clastogenic
activity
was
still
detectable
(
Becker
et
28
al.,
2001).
29
Vinyl
chloride
is
a
known
human
carcinogen
inducing
liver
angiosarcoma
and
possibly
brain
30
tumors.
Evidence
for
other
tumor
locations
including
hepatocellular
carcinoma
is
contradictory
(
EPA,
31
2000a,
b).
In
angiosarcoma
of
the
human
liver
mutations
were
observed,
which
may
be
attributed
to
the
32
formation
of
ethenobases
in
DNA
(
Barbin,
2000).
Unit
risk
estimates
based
on
epidemiologic
studies
have
33
been
published
(
Anonymous,
1987;
WHO,
1987,
1999b;
Clewell
et
al.,
2001).
34
Vinyl
chloride
PROPOSED
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2004
10
3.
ANIMAL
TOXICITY
DATA
1
3.1.
Acute
Lethality
2
Acute
inhalation
toxicity
tests
were
performed
in
rats,
mice,
rabbits,
and
guinea
pigs.
However,
no
3
LC50
study
complying
with
today`
s
standards
is
available.
The
lethality
data
are
summarized
in
Table
3.
4
3.1.1.
Rats
5
Mastromatteo
et
al.
(
1960)
exposed
5
rats
per
group
to
10,
20,
30
or
40%
VC
(
100,000
to
400,000
6
ppm)
for
up
to
30
minutes
(
purity
99.5%
maximum).
The
animals
were
exposed
in
an
inhalation
chamber
7
of
56.6
liters.
The
VC
concentration
was
adjusted
by
mixing
VC
and
air
in
a
flow
meter
outside
of
the
8
exposure
chamber.
The
stream
of
air
and
VC
was
led
to
the
animal
chamber
inlet
to
deliver
a
continuing
9
stream
(
flow
not
given,
VC
concentrations
were
not
determined
in
the
test
chamber).
Observations
were
10
made
continuously
and
are
summarized
in
Table
3.
No
animals
died
after
exposure
to
100,000
and
200,000
11
ppm.
All
animals
died
after
15
minutes
exposure
to
300,000
ppm.
At
300,000
ppm
the
lungs
of
the
12
animals
which
died
revealed
congestion
with
hemorrhagic
areas,
in
addition
congestion
of
the
liver
and
the
13
kidney
were
observed.
14
Prodan
et
al.
(
1975)
exposed
rats
for
2
hours
in
exposure
chambers
of
the
Pravdin
type
with
580
15
liters
capacity
(
total
of
70
rats,
at
least
10
animals
per
group,
strain
not
given).
The
animals
were
exposed,
16
according
to
Krakov`
s
method,
to
variable
concentrations
of
VC.
After
the
animals
were
placed
in
the
17
exposure
chamber,
the
gas
was
introduced
at
the
beginning
at
the
lower
part
of
the
chamber,
without
any
18
ventilation.
The
gas
was
permanently
stirred
up
by
an
inside
pellet
and
was
measured
volumetrically
with
a
19
Zimmermann
type
spirometer.
At
VC­
concentrations
of
15,
16,
17,
20,
and
21%
(
150,000
to
210,000
ppm,
20
nominal
concentration)
the
lethality
was
23,
80,
90,
90,
and
100%,
respectively.
The
authors
calculated
a
21
LC50
of
15%
VC
(
about
150,000
ppm)
and
a
LC100
of
21%
(
about
210,000
ppm).
All
LC50
and
LC100
22
values
from
these
experiments
are
given
by
the
authors
for
2h
exposure
irrespective
of
the
time
of
death.
23
Findings
shortly
before
death
were
general
convulsions,
respiratory
failure,
exopthalmia
and
deflection
of
24
the
head
on
the
abdomen.
Surviving
animals
rapidly
recovered
after
termination
of
the
exposure.
At
25
autopsy,
dead
animals
showed
general
congestion
of
the
internal
organs
(
lungs,
liver,
kidney,
brain
and
26
spleen);
some
animals
(
no
number
given)
had
pulmonary
edema,
marmorated
liver
and
kidney
swelling.
27
In
the
context
of
a
teratology
study
John
et
al.
(
1981)
exposed
Sprague­
Dawley
rats
intermittently
28
with
500
or
2,500
ppm
VC
for
7
days.
At
2,500
ppm
VC
1
of
17
rats
died,
the
exact
day
of
death
was
not
29
specified
by
the
authors
(
for
study
details
see
3.3.).
30
Exposure
of
18
Sherman
rats
(
9
male;
9
female)
to
100,000
VC
for
8
hours
resulted
in
deep
31
anaesthesia,
with
consciousness
regained
5
to
10
minutes
after
removal
to
air.
After
two
exposures
one
32
female
rat
died
and
the
remaining
showed
signs
of
chronic
toxicity
(
not
specified)
prompting
the
authors
to
33
lower
the
VC
concentration
to
80,000
ppm
in
order
to
minimize
mortality.
Despite
this
decrease
mortality
34
was
considerable
especially
in
male
rats
exposed
for
longer
than
8
days.
The
animals
were
exposed
in
a
35
1100
liter
steel
chamber.
The
concentration
was
initially
raised
rapidly
to
the
desired
level
by
admitting
VC
36
without
admixture
with
air
until
the
effluent
from
the
(
mixing)
chamber
attained
the
desired
level
as
noted
37
on
the
thermal
conductivity
meter.
A
fan
mixed
the
VC
with
the
air
within
the
(
mixing)
chamber.
38
Thereafter,
the
effluent
from
the
2­
liter
mixing
vessel
was
admitted
to
the
chamber,
the
throughput
was
20
39
Vinyl
chloride
PROPOSED
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2004
11
l/
min
(
Lester
et
al.,
1963).
1
Exposure
of
2
Sherman
rats
in
a
10
liter
all
glass
exposure
chamber
to
150,000
ppm
resulted
in
2
deep
anaesthesia
within
five
minutes,
one
of
two
animals
died
due
to
respiratory
failure
after
42
minutes
3
(
Lester
et
al.,
1963)
(
study
details
see
above).
4
3.1.2.
Mice
5
Five
mice
were
exposed
to
10,
20,
30
or
40%
VC
(
100,000
to
400,000
ppm,
nominal
6
concentration)
for
up
to
30
minutes
(
for
study
details
see
3.1.1.)
(
Mastromatteo
et
al.,
1960).
One
mouse
7
died
after
25
min
exposure
to
200,000
ppm
and
all
mice
died
after
10
min
exposure
to
300,000
ppm.
No
8
death
occurred
at
100,000
ppm.
At
300,000
ppm
the
lungs
of
the
animals
which
died
revealed
congestion
of
9
the
lungs
with
hemorrhagic
areas,
in
addition
congestion
of
the
liver
and
the
kidney
were
observed.
10
In
ventilated
exposure
chambers
of
the
Pravdin
type,
100,000
ppm
VC
was
not
lethal
to
mice
11
during
2
hours,
whereas
150,000
ppm
killed
46/
61
mice
within
one
hour,
and
all
animals
within
2
hours.
12
The
authors
calculated
a
LC50
of
117,500
ppm
and
a
LC100
of
150,000
ppm
for
mice
(
for
study
details
and
13
symptoms
before
death
see
3.1.1.),
for
2
hours.
Under
unstirred
conditions
42,900
ppm
was
lethal
to
70%
14
(
13
of
20)
of
the
animals
within
less
than
an
hour
(
Prodan
et
al.,
1975).
15
Tátrai
and
Ungváry
(
1981)
exposed
CFLP
mice
to
1,500
ppm
VC
for
2,
4,
8,
12
or
24
hours
16
(
n=
20).
Animals
were
observed
for
24
hours
after
exposure.
In
addition,
40
animals
were
exposed
for
12
h
17
and
survivors
were
investigated
two
month
after
the
exposure.
Animals
were
exposed
in
dynamic
exposure
18
chambers
with
vertical
air
flow.
The
volume
of
the
exposure
chambers
was
0.3
m3;
the
vertical
flow
rate
of
19
the
air
was
3
m3/
hour
at
a
temperature
of
20
­
23
°
C
and
50
­
55%
relative
humidity.
After
24
hours
20
exposure
time
all
animals
died
within
24
h
after
exposure,
90%
of
the
mice
exposed
over
12
hours
died.
No
21
death
is
reported
in
animals
exposed
for
shorter
periods.
Exposure
caused
hemorrhages
and
vasodilatation
22
characteristic
of
shock
in
the
lungs.
Additionally,
shock­
liver
developed.
The
authors
do
not
comment
on
23
the
concentration
difference
between
their
experiments
and
earlier
reports
indicating
much
higher
total
VC
24
concentrations
as
lethal;
however,
in
these
studies
asphyxia
is
given
as
the
cause
of
death.
This
effect
is
not
25
conformed
in
other
studies.
26
In
a
study
designed
to
investigate
long
term
hepatic
effects
of
VC,
Lee
et
al.
(
1977)
exposed
CD­
1
27
mice
to
1,000
ppm
for
6
hr/
day.
Three
out
of
seventy­
two
mice
died
between
day
3
and
9;
all
other
mice,
as
28
well
as
replacement
mice
appeared
healthy
throughout
12
month
VC
exposure.
Upon
autopsy
animals
had
29
acute
toxic
hepatitis
with
diffuse
coagulation
type
necrosis
of
hepatocytes,
as
well
as
tubular
necrosis
in
the
30
renal
cortex.
31
In
the
context
of
a
teratology
study,
John
et
al.
(
1981)
exposed
mice
to
50
or
500
ppm
VC
for
7
h/
d
32
on
day
6
­
15
of
gestation.
At
500
ppm
VC
5
of
29
mice
died,
the
exact
day
of
death
was
not
specified
by
33
the
authors.
34
3.1.3.
Guinea
Pigs
35
Patty
et
al.
(
1930)
found
15
­
25%
VC
(
150,000
­
250,000
ppm)
to
be
lethal
to
guinea
pigs
within
36
Vinyl
chloride
PROPOSED
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2004
12
one
hour,
40%
VC
(
400,000
ppm)
resulted
in
death
of
the
animals
within
10
­
20
min.
Gross
pathology
1
examinations
of
these
animals
revealed
intense
congestion
and
edema
of
the
lungs
and
a
hyperaemia
of
the
2
kidneys
and
livers.
The
lungs
were
light
pink
in
color,
the
cut
section
was
uniformly
light
red,
and
bled
3
freely.
The
authors
concluded
that
VC
is
irritating
to
the
lungs.
No
eye
or
nasal
irritation
was
described.
4
However,
from
the
paper
it
is
unclear
whether
sufficient
mixing
of
the
atmosphere
had
occurred,
5
furthermore,
the
number
of
animals
per
group
was
not
mentioned.
6
Prodan
et
al.
(
1975)
reported
a
LC50
of
238,000
ppm
and
a
LC100
of
280,000
ppm
for
guinea
pigs
7
exposed
in
a
exposure
chamber
of
the
Pravdin
type
(
the
gas
was
permanently
stirred
up
by
an
inside
pellet;
8
study
details
are
described
in
3.1.1.)
for
2
hours.
No
animals
died
within
2
hours
at
200,000
ppm.
9
Yant
(
cited
from
Prodan
et
al.,
1975)
determined
a
lethal
concentration
of
400,000
ppm
for
10
min
10
for
guinea
pigs.
11
Exposure
of
guinea
pigs
to
10,
20,
or
30%
VC
(
100,000
­
300,000
ppm)
(
5
animals
per
group)
did
12
not
result
in
death
within
30
min
of
exposure
time,
but
one
animal
of
the
300,000
ppm
group
died
within
24
13
h
following
exposure.
Thirty
minutes
exposure
to
40%
VC
(
400,000
ppm)
resulted
in
death
of
one
animal,
14
another
animal
died
within
24
h
following
exposure
whereas
the
other
3
animals
recovered
(
Mastromatteo
15
et
al.,
1960;
for
study
details
see
3.1.1.).
The
liver
of
the
animal
which
died
at
300,000
ppm
showed
severe
16
fatty
degeneration,
the
liver
was
distended
and
very
friable,
the
liver
effects
were
less
pronounced
at
17
400,000
ppm.
There
was
marked
congestion
of
the
lungs
with
hemorrhages
in
the
dead
animals.
18
3.1.4.
Rabbits
19
Rabbits
were
exposed
for
2
h
in
exposure
chambers
of
the
Pravdin
type.
200,000
ppm
did
not
20
result
in
death
of
4
animals.
50%
of
the
animals
(
2/
4)
exposed
to
240,000
ppm
died
within
the
first
hour
of
21
exposure
and
all
animals
(
4/
4)
exposed
to
280,000
ppm
(
Prodan
et
al.,
1975)
(
for
details
see
3.1.1.).
22
In
the
context
of
a
teratology
study,
John
et
al.
(
1981)
exposed
rabbits
intermittently
to
500
or
23
2,500
ppm
VC
for
7
days.
At
2,500
ppm
VC,
1
of
7
rabbits
died,
the
exact
day
of
death
was
not
specified
24
by
the
authors.
25
3.1.5.
Other
Species
26
No
data
on
acute
lethality
in
other
species
are
available.
27
28
Vinyl
chloride
PROPOSED
1:
3/
2004
13
TABLE
3:
SUMMARY
OF
ACUTE
LETHAL
INHALATION
DATA
IN
LABORATORY
ANIMALS
1
Species
2
Concentration
(
ppm)
Exposure
Time
Number
of
animals
Effect
Reference
mouse
3
500
several
days
for
7
h/
d
29
LC17
John
et
al.,
1977;
1981
mouse
4
1000
at
least
3
x
6
h
72
LClow
Lee
et
al.,
1977
mouse
5
1500
8
h
20
LC0
Tátrai
and
Ungváry,
1981
mouse
6
1500
12
h
60
LC90
Tátrai
und
Ungváry,
1981
mouse
7
1500
24
h
20
LC100
Tátrai
und
Ungváry,
1981
mouse
8
100000
2
h
40
LC0
Prodan
et
al.,
1975
mouse
9
117500
2
h
39
LC50
Prodan
et
al.,
1975
mouse
10
150000
2
h
61
LC100
Prodan
et
al.,
1975
mouse
11
300000
10
min
5
LC100
Mastromatteo
et
al.,
1960
rat
12
100000
8
h
18
LC0
Lester
et
al.,
1963
rat
13
150000
2
h
10
LC50
Prodan
et
al.,
1975
rat
14
150000
2
h
2
LC50
Lester
et
al.,
1963
rat
15
200000
30
min
5
LC0
Mastromatteo
et
al.,
1960
rat
16
210000
2
h
10
LC100
Prodan
et
al.,
1975
rat
17
300000
15
min
5
LC100
Mastromatteo
et
al.,
1960
rabbit
18
200000
2
h
4
LC0
Prodan
et
al.,
1975
rabbit
19
240000
2
h
4
LC50
Prodan
et
al.,
1975
rabbit
20
280000
2
h
4
LC100
Prodan
et
al.,
1975
guinea
pig
21
100000
6
h
not
stated
LC0
Patty
et
al.,
1930
guinea
pig
22
200000
2
h
4
LC0
Prodan
et
al.,
1975
guinea
pig
23
240000
2
h
12
LC50
Prodan
et
al.,
1975
guinea
pig
24
150,000
to
250,000
18
­
55
min
not
stated
LC100
a
Patty
et
al.,
1930
guinea
pig
25
280000
2
h
4
LC100
Prodan
et
al.,
1975
guinea
pig
26
300000
30
min
5
LC20
Mastromatteo
et
al.,
1960
guinea
pig
27
400000
10
­
20
min
not
stated
LC100
a
Patty
et
al.,
1930
guinea
pig
28
400000
30
min
5
LC40
Mastromatteo
et
al.,
1960
a:
number
of
animals
per
group
and
animals
that
died
not
stated
29
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chloride
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2004
14
3.2.
Nonlethal
Toxicity
1
3.2.1.
Dogs
2
Oster
et
al.
(
1947)
exposed
2
beagle
dogs
to
50%
VC/
50%
oxygen
for
induction
of
anesthesia
(
no
3
time
given)
and
subsequently
with
7%
VC
(
70,000
ppm)
in
oxygen
for
narcosis
maintenance
(
no
further
4
study
details
described).
Narcosis
induction
was
rapid,
all
animals
showed
salivation.
Muscle
relaxation
5
was
incomplete
with
good
relaxation
of
the
abdomen,
and
rigidity
and
uncoordinated
movements
in
legs.
6
The
recovery
period
was
prompt
but
accompanied
by
violent
excitation.
In
four
dogs
anesthetized
with
10%
7
VC
(
100,000
ppm)
mixed
with
oxygen,
no
effects
on
blood
pressure
were
observed,
but
cardiac
8
irregularities
(
intermittent
tachycardia,
extraventricular
systoles
and
vagal
beats)
were
observed.
All
9
symptoms
disappeared
rapidly
upon
change
to
ethyl
ether,
as
well
as
after
termination
of
narcosis.
10
Cardiac
sensitizing
potential
of
VC
was
tested
in
beagle
dogs.
Conscious
dogs
(
4­
7
per
dose
group)
11
were
exposed
to
VC
by
means
of
a
face
mask
for
5
minutes.
Oxygen
was
added
when
high
concentrations
12
were
used.
During
the
last
10
seconds
of
the
exposure
period,
a
bolus
injection
of
epinephrine
(
5
µ
g/
kg)
was
13
given
via
a
cephalic
vein
and
the
ECG
changes
were
recorded.
A
further
injection
of
adrenaline
was
also
14
given
10
minutes
after
the
end
of
exposure.
Cardiac
sensitization
was
deemed
to
have
occurred
when
15
ventricular
tachycardia
or
ventricular
fibrillation
resulted
from
the
challenge
injection
of
epinephrine.
An
16
increased
number
of
ventricular
ectopic
beats
was
not
regarded
as
evidence
of
sensitization
since
they
could
17
often
be
produced
by
a
challenge
injection
of
epinephrine
during
control
air
exposures.
The
EC50
for
18
cardiac
sensitization
was
50,000
ppm
(
95
%
CI:
37,000
 
68,000
ppm).
The
post
exposure
injection
of
19
epinephrine
did
not
result
in
arrhythmias
(
Clark
and
Tinston,
1973).
20
A
second
study
on
cardiac
sensitization
to
epinephrine
in
beagle
dogs
(
6
male
or
female,
not
21
further
specified)
after
5
minutes
exposure
to
VC
was
published
by
Clark
and
Tinston
(
1982).
Methods
22
were
apparently
identical
to
the
study
published
in
1973
(
Beck
et
al.,
1973).
The
EC50
for
cardiac
23
sensitization
was
71,000
ppm
(
95%
CI:
61,000
 
83,000
ppm).
These
concentrations
were
below
the
24
concentrations
which
caused
effects
on
the
central
nervous
system
in
rats
(
EC50:
38,000
ppm
after
10
25
minutes
exposure).
The
authors
did
not
comment
on
their
earlier
findings
which
indicated
a
lower
EC50
for
26
cardiac
sensitization.
The
authors
discussed,
that
cardiac
sensitization
is
unlikely
to
occur
in
man
in
the
27
absence
of
any
effects
on
the
CNS
and
that
dizziness
should
act
as
an
early
warning
that
a
dangerous
28
concentration
was
reached.
29
3.2.2.
Rats
30
In
rats
exposed
to
100,000
ppm,
increased
motor
activity
occurred
after
5
min,
pronounced
tremor,
31
unsteady
gait
and
muscular
incoordination
occurred
after
15
min,
side
position
occurred
at
20
min,
and
32
deep
narcosis
occurred
after
30
min.
When
the
VC
concentration
was
increased,
deep
narcosis
occurred
at
33
200,000
ppm
after
15
min
and
at
300,000
ppm
after
5
min
and
muscular
incoordination
after
2
or
1
min,
34
respectively.
At
autopsy,
lungs
of
the
animals
of
the
100,000
ppm
group
showed
a
very
slight
hyperemia
35
even
2
weeks
after
exposure;
at
200,000
ppm
congestion
of
the
lung
in
all
animal
and
some
fatty
infiltration
36
in
the
liver
of
one
rat
were
observed.
Irritation
(
not
further
explained)
was
described
to
occur
immediately
37
after
onset
of
exposure
to
10,
20,
or
30%
VC
(
Mastromatteo
et
al.,
1960).
38
Lester
et
al.
(
1963)
exposed
Sherman
rats
for
up
to
2
hours
with
50,000
­
150,000
ppm
VC.
The
39
Vinyl
chloride
PROPOSED
1:
3/
2004
15
total
gas
flow
was
50
liters
per
minute.
The
desired
concentrations
were
obtained
by
metering
air
and
VC
1
(
gas
chromatography
of
the
liquid
phase
indicated
more
than
99%
VC)
through
flow
meters
and
passing
the
2
appropriate
flows
through
a
2
l
mixing
chamber.
The
desired
concentration
was
passed
through
a
10­
liter
3
all­
glass
exposure
chamber
containing
2
rats.
The
concentration
was
continuously
monitored
by
a
thermal
4
conductivity
meter
(
less
than
5%
deviation
from
the
desired
concentration).
At
50,000
ppm
VC
for
2
hours
5
moderate
intoxication
was
observed,
but
the
righting
reflex
was
lost;
at
60,000
ppm
for
2
hours
6
intoxication
was
more
intense
but
the
righting
reflex
was
still
present
(
lost
at
70,000
ppm).
The
corneal
7
reflex
was
lost
at
100,000
ppm
VC.
On
removal
from
the
chamber
the
animals
returned
to
the
pre­
exposure
8
state
rapidly.
Exposure
to
150,000
VC
resulted
in
deep
anesthesia
within
5
minutes,
one
of
two
animals
9
died
after
42
minutes
by
respiratory
failure.
Autopsy
revealed
edema
and
congestion
of
the
lungs.
The
10
second
rat
recovered
quickly
after
removal
from
the
exposure
chamber.
11
Exposure
of
18
Sherman
rats
to
100,000
VC
for
8
hours
resulted
in
deep
anesthesia,
with
con­
12
sciousness
regained
5
to
10
minutes
after
removal
to
air.
After
two
exposures
one
female
rat
died
and
the
13
remaining
showed
signs
of
toxicity
(
not
specified)
(
Lester
et
al.,
1963;
study
details
presented
in
3.1.1.).
14
Male
Holtzman
rats
were
exposed
once
to
0.5,
5
or
10%
VC
(
5,000,
50,000,
or
100,000
ppm)
for
15
6
h
in
a
dynamic
inhalation
chamber.
Animals
were
killed
24
hours
after
the
exposure
(
no
further
details
16
described).
Exposure
to
0.5%
or
5%
for
a
single
6
h
period
did
not
cause
a
substantial
rise
in
serum
17
alanine­
 ­
ketoglutarate
transaminase
(
AKT)
or
sorbitol
dehydrogenase
(
SDH),
two
cytoplasmic
liver
18
enzymes
whose
appearance
in
serum
correlates
with
liver
injury.
Only
after
exposure
to
10%
VC
was
a
19
slight
increase
in
either
parameter
of
hepatoxic
response
and
centrilobular
hepatocellular
vacuolization
20
noted.
At
the
lower
dose
levels
livers
were
histologically
normal.
During
exposure
to
10%
VC
animals
21
appeared
to
be
anesthetized
(
Jaeger
et
al.,
1974).
22
Rats
exposed
to
30,000
ppm
VC
for
4
hours
were
slightly
soporific
(
Viola
et
al.,
1970).
No
other
23
acute
toxicity
data
were
reported,
animals
were
exposed
for
total
of
12
month.
24
Tátrai
and
Ungváry
(
1981)
exposed
CFY
rats
to
1,500
ppm
VC
for
24
hours
(
n=
20;
study
details
25
are
presented
in
3.1.2.).
Livers
were
investigated
by
histochemical
methods.
No
morphological
changes
26
were
observed.
27
Fischer
344
or
Sprague­
Dawley
rats
were
treated
for
1
h
with
50,
500,
5,000
or
50,000
ppm
VC
28
(
about
90
animals
per
group).
The
chambers
were
Rochester
type,
stainless
steel,
1,000
liter,
constructed
to
29
provide
laminar
air
flow
and
ensure
uniform
exposures
to
VC
to
test
animals.
The
concentration
of
gas
in
30
the
inhalation
chamber
was
monitored
by
a
gas
chromatograph.
No
remarkable
signs
of
toxicity
were
31
observed.
Upon
removal
from
the
test
atmosphere,
all
animals
recovered
to
normal
appearance
within
24
32
hours
(
Hehir
et
al.,
1981).
Viola
et
al.
(
1971)
also
reported
that
exposure
of
rats
to
50,000
ppm
for
one
33
hour
did
not
result
in
toxicity.
34
Effects
after
repeated
exposure
35
Pregnant
rats
exposed
to
1,500
ppm
for
7
or
9
days
(
day
1­
9
or
8
­
14
of
gestation)
showed
36
increased
absolute
and
relative
maternal
liver
weight,
without
light
microscopic
visible
changes
(
liver
37
weight
to
body
weight
ratio
(%),
exposure
day
1­
9
of
gestation:
control:
3.71;
exposed:
4.25).
This
effect
38
was
not
observed
in
animals
treated
from
day
14­
21
of
gestation.
Additionally,
an
increased
number
of
39
Vinyl
chloride
PROPOSED
1:
3/
2004
16
resorbed
fetuses
and
fetal
losses
were
observed
in
animals
exposed
during
the
first
9
days
of
pregnancy
1
(
Ungváry
et
al.,
1978,
for
study
details
see
3.3.).
2
Intermittent
exposure
of
rats
to
500
ppm
or
2,500
ppm
VC
during
day
6
­
15
of
pregnancy
resulted
3
in
increased
relative
and
absolute
maternal
liver
weights
and
an
increased
number
of
absorbed
fetuses
and
4
fetal
losses
at
2,500
ppm
(
NOAEL
500
ppm)
(
absolute
liver
weight:
control:
14.27
g;
2500
ppm:
15.55
g;
5
relative
liver
weight:
control:
34.4
mg/
g
bw;
2500
ppm:
37.8
mg/
g
bw).
One
dam
died
at
2,500
ppm
(
John
6
et
al.,
1977,
1981;
for
details
see
3.3).
7
8
After
repeated
inhalation
exposure
(
4
weeks)
of
rats
to
5,000
ppm
VC
(
7h/
day,
5
days/
week)
9
vacuolized
hepatocytes
with
swollen
mitochondria
were
found
in
male
and
female
animals
(
Feron
et
al.,
10
1979).
After
13
weeks
inhalation
exposure
even
at
the
lowest
dose
level
(
10
ppm
VC)
an
increase
of
the
11
relative
liver
weight
was
seen
in
male
rats
and
centrilobular
hypertrophy
in
females
(
Thornton
et
al.,
2002).
12
3.2.3.
Mice
13
Mice
exposed
to
100,000
ppm
VC
for
30
min
showed
increased
motor
activity
after
5
min,
14
twitching
of
extremities
after
10
min
and
pronounced
tremor,
unsteady
gait
and
muscular
incoordination
15
occurred
after
15
min,
side
position
at
20
min,
and
deep
narcosis
occurred
after
30
min.
When
the
VC
16
concentration
was
increased
deep
narcosis
occurred
at
200,000
ppm
after
15
min
(
side
position
after
5
min)
17
and
at
300,000
ppm
after
5
min
(
lethal
after
10
min).
Mice
of
the
100,000
ppm
group
showed
slight
18
hyperemia
of
the
lungs,
one
of
five
animals
showed
degenerative
changes
in
the
tubular
epithelium
of
the
19
kidney
with
hydropic
swelling.
200,000
ppm
for
30
min
resulted
in
congestion
of
the
lungs
persisting
for
2
20
weeks.
Irritation
(
no
further
details)
was
described
to
occur
immediately
after
onset
of
exposure
to
10,
20,
21
or
30%
VC
(
Mastromatteo
et
al.,
1960).
22
Prodan
et
al.
(
1975)
exposed
white
mice
(
no
strain
specified)
for
2
hours
to
90,000
to
200,000
ppm
23
VC
with
ventilation
in
a
exposure
chamber
(
for
study
details
see
3.1.1.);
no
shorter
exposure
time
was
24
reported.
Salivation
and
lacrimation
appeared
shortly
after
onset
of
exposure,
with
narcosis
reached
within
25
less
than
one
hour
in
the
majority
of
the
animals.
Typical
narcosis
stages
of
excitement
with
tonic­
clonic
26
convulsions
and
muscular
contractions,
tranquility
and
relaxation
were
described.
Other
symptoms
were
27
accelerated
respiration,
proceeding
to
bradypnea,
Cheyne­
Stokes
type
of
respiration
and
respiratory
failure.
28
No
differentiation
of
the
symptoms
according
to
the
single
exposure
levels
were
made.
Concentrations
of
29
110,000
and
higher
were
lethal.
In
surviving
mice
all
symptoms
were
rapidly
reversible.
30
Male
mice
exposed
to
50,000
ppm
VC
for
1
h
exhibited
hyperventilation
after
45
min,
with
31
twitching
and
ataxia.
Female
mice
became
hyperactive
after
40
min
exposure
and
respiratory
difficulty
and
32
ataxia
was
observed
in
approximately
25%
of
the
female
mice
after
55
min.
At
5,000
ppm
no
mice
were
33
visibly
affected.
Study
details
are
presented
in
3.2.2
(
Hehir
et
al.,
1981).
34
Vinyl
chloride
PROPOSED
1:
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2004
17
Tátrai
and
Ungváry
(
1981)
exposed
CFLP­
mice
to
1,500
ppm
VC
for
2
to
24
hours.
After
2
hours,
1
histology
demonstrated
circulation
stasis
in
the
liver,
with
concomitant
decreases
in
enzyme
activities
2
(
succinic
dehydrogenase
and
acid
phosphatase),
subcellular
damage,
and
centriobular
necrosis.
After
24
h
3
shock
liver
developed.
Severity
of
changes
increased
with
exposure
time;
after
12
hours
the
lungs
showed
4
hemorrhages
and
vasodilatation
as
signs
of
circulatory
disturbances.
No
changes
were
observed
in
brain
5
and
kidney.
90%
of
the
animals
died
after
exposure
for
12
hours,
and
100%
after
24
hours.
6
Kudo
et
al.
(
1990)
exposed
male
ICR
mice
(
4
or
5
per
group)
to
5,000
and
10,000
ppm
VC
for
4
7
hours
on
5
or
6
successive
days,
respectively.
Basophilic
stippled
erythrocytes
indicating
disturbances
in
8
erythropoiesis
appeared
in
peripheral
blood
smears
on
the
second
day
indicating
possible
bone
marrow
9
damage
after
a
single
exposure;
no
difference
between
the
doses
was
observed,
reticulocyte
numbers
were
10
also
increased,
albeit
not
statistically
significant.
The
authors
discuss
that
the
increase
was
partly
due
to
11
repeated
blood
sampling
and
was
not
entirely
due
to
VC­
exposure.
Exposure
at
lower
concentrations,
i.
e.
12
30
­
40
ppm
induced
basophilic
stippled
erythrocytes
after
3
days.
13
Lee
et
al.
(
1977)
exposed
CD­
1
mice
with
1,000
ppm
for
6
hr/
day
in
the
context
of
a
long
term
14
hepatotoxicity
and
carcinogenicity
study.
Besides
5%
short
term
mortality
within
the
first
days
due
to
acute
15
toxic
hepatitis
no
sign
of
VC
toxicity
was
observed
in
the
other
animals.
16
Aviado
and
Belej
(
1974)
reported
that
exposure
of
mice
(
male,
Swiss
strain)
to
100,000
ppm
VC
17
for
6
minutes
did
not
cause
arrhythmia,
whereas
200,000
ppm
induced
a
2nd
degree
block
and
ventricular
18
ectopics
(
animals
were
anesthetized
with
sodium
pentobarbital).
Cardiac
sensitization
was
observed
after
6
19
min
exposure
to
100,000
ppm
VC
(
animals
were
anesthetized
with
sodium
pentobarbital).
Mice
were
20
exposed
through
a
face
mask
which
was
in
contact
with
a
6
l
flaccid
bag.
The
inhalation
gas
was
balanced
21
with
oxygen
in
order
to
prevent
asphyxia.
The
number
of
animals
per
dose
group
was
not
presented.
For
22
testing
cardiac
sensitization
the
animals
received
6
µ
g/
kg
adrenaline
hydrochloride
intravenously.
23
3.2.4.
Guinea
Pigs
24
Guinea
pigs
exposed
to
100,000
ppm
VC
for
30
min
showed
increased
motor
activity
after
5
min,
25
unsteady
gait
and
muscular
incoordination
occurred
after
15
min,
tremors
and
twitching
of
extremities
after
26
20
min,
and
side
position
with
tremors
after
30
min­
one
unconscious.
When
the
VC
concentration
was
27
increased
deep
narcosis
occurred
at
200,000
ppm
and
300,000
ppm
after
30
min
and
at
400,000
ppm
after
28
5
min.
Guinea
pigs
of
the
100,000
ppm
group
showed
only
slightly
hyperemic
lungs
2
weeks
after
29
exposure.
At
200,000
ppm
congestion
of
the
lungs
was
observed.
At
300,000
and
400,000
ppm
survivors
30
showed
marked
pulmonary
congestion
with
hemorrhagic
areas
and
edema.
In
one
animal
of
the
400,000
31
ppm
group
the
tracheal
epithelium
was
completely
absent.
In
the
same
animals
blood
was
unable
to
clot.
32
Irritation
(
no
further
details)
was
described
to
occur
immediately
after
onset
of
exposure
to
400,000
ppm
of
33
VC,
but
irritation
was
not
described
at
lower
dose
levels
(
Mastromatteo
et
al.,
1960).
34
Prodan
et
al.
(
1975)
exposed
Guinea
pigs
(
no
strain
given)
to
20
­
28%
VC
(
200,000
­
280,000
35
ppm)
for
2
hours.
Symptoms
of
progressing
anesthesia
as
described
for
mice
were
observed
in
a
time
36
depending
manner;
muscular
contractions
were
more
pronounced
in
guinea
pigs
than
in
mice.
Lethality
37
increaed
with
increasing
concentration,
in
surviving
animals
all
symptoms
were
rapidly
reversible.
38
Concentrations
of
200,000
ppm
were
not
lethal
within
2
h
(
n=
4).
Observation
of
the
animals
did
not
exceed
39
Vinyl
chloride
PROPOSED
1:
3/
2004
18
2
h.
1
Exposure
of
guinea
pigs
to
5,000
or
10,000
ppm
for
up
to
8
h
did
not
produce
any
visible
2
symptoms.
25,000
ppm
resulted
in
apparent
unconsciousness
and
deep
narcosis
after
90
min
and
a
slow,
3
shallow
respiration
within
6
to
8
h.
No
deaths
were
observed
within
8
h
lasting
exposure.
Similar
symptoms
4
were
observed
at
50,000
ppm
(
unconsciousness
within
50
min,
slow,
shallow
respiration
within
360
min,
5
no
death
within
6
h).
100,000
ppm
lead
to
an
incomplete
narcosis
already
2
minutes
after
onset
of
6
exposure,
none
of
the
animals
died
within
the
6
h
lasting
exposure
period
(
Patty
et
al.,
1930).
7
3.2.5.
Rabbits
8
Prodan
et
al.
(
1972)
exposed
rabbits
(
no
strain
given)
to
20
­
28%
VC
(
200,000
­
280,000
ppm)
9
for
2
hours.
Symptoms
of
progressing
anesthesia
as
described
for
mice
were
observed
in
a
time
dependent
10
manner,
rabbits
showed
heavy
respiration,
salivation
and
muscular
contractions.
Lethality
increased
with
11
increasing
VC
concentrations,
all
symptoms
were
rapidly
reversible
in
survivors.
No
death
was
observed
12
within
2
hours
(
n=
4).
13
Tátrai
and
Ungváry
(
1981)
exposed
20
New­
Zealand­
rabbits
to
1,500
ppm
VC
for
24
hours.
No
14
acute
clinical
effects
or
pathological
changes
of
the
liver
were
noted
24
h
after
exposure.
15
3.2.6
Monkeys
16
In
monkeys,
only
myocardial
depression
after
inhalation
of
2.5­
10%
VC
was
observed.
Rhesus
17
monkeys
were
anesthetized
by
i.
v.
injection
of
30
mg/
kg
sodium
pentobarbital.
An
electrocardiograph
was
18
implanted
for
continuous
monitoring.
3
monkeys
received
2.5,
5,
or
10%
of
VC.
The
inhalation
period
19
lasted
5
minutes,
alternating
with
room
air
for
10
minutes.
The
myocardial
force
was
reduced
by
2.3,
9.1
20
and
28.5%
respectively,
with
a
significant
effect
only
at
10%
VC.
There
was
no
effect
on
the
heart
rate
in
21
compasison
to
controls.
It
is
not
clearly
stated
whether
an
addition
challenge
with
epinephrine
was
applied
22
or
not
(
Belej
et
al.,
1974).
23
Vinyl
chloride
PROPOSED
1:
3/
2004
19
TABLE
4:
SUMMARY
OF
NON­
LETHAL
EFFECTS
IN
LABORATORY
ANIMALS
1
Species
2
Concentration
(
ppm)
Exposure
Time
Effect
Reference
dog
3
50000
5
min
EC50
cardiac
sensitization
towards
epinephrine
Clark
and
Tinston,
1973
dog
4
71000
5
min
EC50
cardiac
sensitization
towards
epinephrine
Clark
and
Tinston,
1982
dog
5
100000
not
stated
anesthesia
accompanied
by
cardiac
arrhythmia
Oster
et
al.,
1947
mouse
6
1500
2
h
stasis
of
blood
flow,
decreasing
enzyme
activities
in
liver,
subscellular
liver
damage,
centrilobular
necrosis
Tátrai
and
Ungváry,
1981
mouse
7
5000
1
h
no
clinical
signs
of
toxicity
Hehir
et
al.,
1981
mouse
8
50000
40
min
twitching,
ataxia,
hyperventilation,
hyperactivity
Hehir
et
al.,
1981
mouse
9
100000
6
min
no
induction
of
cardiac
arrhythmia
Aviado
and
Belej,
1974
mouse
10
100000
6
min
cardiac
sensitization
towards
adrenaline
Aviado
and
Belej,
1974
mouse
11
100000
15
min
pronounced
tremor,
unsteady
gait
and
muscular
incoordination
Mastromatteo
et
al.,
1960
mouse
12
100000
30
min
unconsciousness,
side
position
already
after
20
min;
lung
hyperemia
persisting
for
>
2
weeks
Mastromatteo
et
al.,
1960
mouse
13
100000
2
h
intense
salivation
and
lacrimation
immediately
after
onset
of
exposure,
narcosis
within
1
h
Prodan
et
al.,
1975
mouse
14
200,000
6
min
Induction
of
cardiac
arrhythmia
(
2nd
degree
block,
ventricular
ectopics)
Aviado
and
Belej,
1974
mouse
15
200000
30
min
deep
narcosis,
side
position
after
5
min,
congestion
of
the
lung
for
>
2
weeks
Mastromatteo
et
al.,
1960
rat
16
500
10
x
7
h
no
effects
on
liver
weight
(
LOAEL:
2,500
ppm)
(
exposure:
day
6­
15
of
pregnancy)
John
et
al.,
1977
rat
17
1500
24
h
no
acute
toxicity
reported
Tátrai
and
Ungváry,
1981
rat
18
1500
9
x
24
h
increased
relative
and
absolute
liver
weight;
increased
number
of
absorbed
fetuses
and
fetal
losses
(
exposure:
day
1­
9
of
pregnancy)
Ungváry
et
al.,
1978
rat
19
30000
4
h
slightly
soporific
Viola
et
al.,
1970
rat
20
50000
1
h
no
clinical
signs
of
toxicity
Viola
et
al.,
1971;
Hehir
et
al.
1981
rat
21
50000
2
h
moderate
intoxication
(
not
further
Lester
et
al.,
1963
Vinyl
chloride
PROPOSED
1:
3/
2004
TABLE
4:
SUMMARY
OF
NON­
LETHAL
EFFECTS
IN
LABORATORY
ANIMALS
Species
Concentration
(
ppm)
Exposure
Time
Effect
Reference
20
specified),
loss
of
righting
reflex
rat
22
50000
6
h
no
clinical
and
histological
signs
of
hepatic
toxicity
Jaeger
et
al.,
1974
rat
23
60000
2
h
intense
intoxication,
righting
reflex
still
present
Lester
et
al.,
1963
rat
24
100000
15
min
tremor,
ataxia
Mastromatteo
et
al.,
1960
rat
25
100000
30
min
deep
narcosis;
persisting
lung
hyperemia
for
>
2
weeks
Mastromatteo
et
al.,
1960;
Jaeger
et
al.,
1974
rat
26
100000
2
h
deep
anesthesia,
loss
of
corneal
reflex,
no
visible
gross
pathology
Lester
et
al.,
1963
rat
27
100000
6
h
anesthesia,
liver
centrilobular
vacuolization,
slight
increase
of
AKT
and
SDH
activity
in
serum
Jaeger
et
al.,
1974
rat
28
100000
8
h
deep
anesthesia
Lester
et
al.,
1963
rat
29
200000
2
min
muscular
incoordination
Mastromatteo
et
al.,
1060
rat
30
200000
30
min
deep
narcosis,
fatty
liver
infiltration,
lung
congestion
for
>
2
weeks
Mastromatteo
et
al.,
1960
guinea
pig
31
10000
8
h
no
visible
effects
Patty
et
al.,
1930
guinea
pig
32
25000
5
min
ataxia,
unsteadiness
on
feet
Patty
et
al.,
1930
guinea
pig
33
25000
90
min
quiet,
apparent
unconsciousness
Patty
et
al.,
1930
guinea
pig
34
25000
6
­
8
h
narcosis,
slow
and
shallow
respiration,
unsteadiness
Patty
et
al.,
1930
guinea
pig
35
100000
15
min
unsteady
gait
and
muscular
incoordination
Mastromatteo
et
al.,
1960
guinea
pig
36
100000
30
min
unconsciousness,
slightly
hyperemic
lungs
persisting
for
2
weeks
after
exposure
Mastromatteo
et
al.,
1960
guinea
pig
37
200000
30
min
congestion
of
the
lung
even
2
weeks
after
exposure
Mastromatteo
et
al.,
1960
guinea
pig
38
200000
2
h
deep
narcosis
Prodan
et
al.,
1975
rabbit
39
200000
2
h
deep
narcosis
Prodan
et
al.,
1975
monkey
40
25,000­
100,000
5
min
myocardial
depression
Belej
et
al.,
1974
3.3.
Developmental/
Reproductive
Toxicity
41
No
studies
concerning
the
effect
of
single
VC
exposure
on
developmental
or
reproductive
toxicity
42
have
been
identified.
John
et
al.
(
1977,
1981)
exposed
pregnant
CF­
1­
mice
to
50
or
500
ppm
VC,
Sprague­
43
Vinyl
chloride
PROPOSED
1:
3/
2004
21
Dawley­
rats
and
New­
Zealand­
rabbits
to
500
or
2,500
ppm
VC
during
organogenesis
(
7
h/
day,
days
6
­
15
1
for
mice
and
rats
and
days
6
­
18
in
rabbits).
Exposure
of
bred
animals
was
conducted
in
stainless
steel
2
chambers
of
3.7
m3
volume
under
dynamic
conditions.
The
atmosphere
of
VC
was
generated
by
diluting
3
gaseous
VC
with
filtered
room
air
at
a
rate
calculated
to
give
the
desired
concentration.
The
actual
4
atmosphere
was
measured
with
an
infrared
spectrophotometer
(
no
further
details
presented).
Animals
were
5
sacrificed
on
day
18
(
mice),
21
(
rats)
or
29
(
rabbits)
and
a
variety
of
parameters
determined.
6
Exposure
to
500
ppm
VC
was
maternally
toxic
to
mice
(
5
of
29
bred
females
died),
weight
gain,
7
food
consumption,
and
the
absolute
liver
weight
were
decreased.
Maternal
toxicity
was
not
evident
in
mice
8
exposed
to
50
ppm.
In
mice
exposed
to
500
ppm
VC,
the
number
of
live
fetuses
per
litter
and
fetal
weight
9
were
decreased,
this
was
probably
due
to
the
increased
maternal
toxicity,
and
fetal
resorption
was
10
increased.
Moreover,
fetal
resorption
was
within
the
range
of
historical
controls.
Fetal
crown
rump­
length
11
was
significantly
increased
in
mice
exposed
to
50
ppm
VC,
but
not
in
mice
of
the
500
ppm
group.
Delayed
12
ossifications
in
skull
and
sternum
bones
and
unfused
sternebrae
were
observed
at
500
ppm
in
mice
fetus.
13
Rats
exposed
to
500
ppm
gained
less
weight
than
controls,
but
the
body
weight
was
not
14
significantly
different
from
the
control.
At
2,500
ppm,
one
maternal
death
among
17
bred
females,
15
decreased
food
consumption
and
an
increase
in
absolute
and
relative
liver
weight
were
observed.
No
16
significant
changes
were
observed
in
rat
fetuses,
except
for
reduced
fetal
body
weight
and
increased
crown­
17
crump
length
at
500
ppm
(
both
effects
not
observed
at
2,500
ppm).
At
2,500
ppm
the
incidence
of
dilated
18
ureter
was
significantly
increased
in
comparison
to
the
control
group
and
the
number
of
lumbar
spurs
was
19
increased
at
500
ppm
but
not
at
2,500
ppm.
20
One
of
seven
bred
female
rabbits
died
at
2,500
ppm,
rabbits
exposed
to
500
ppm
showed
a
21
decreased
food
consumption,
but
body
weight
was
not
significantly
affected.
The
number
of
live
fetuses
per
22
litter
was
slightly
decreased
as
compared
to
concurrent
air
controls
among
litters
of
rabbits
exposed
to
the
23
lower
level
of
500
ppm
(
live
fetuses/
litter:
8
and
7
at
0
and
500
ppm,
respectively),
but
no
effect
on
litter
24
size
resulted
from
exposure
to
2,500
ppm
of
VC.
Ossification
of
the
sternebrae
was
delayed
at
500
ppm,
25
but
not
at
2,500
ppm.
26
Most
of
the
observed
effects
were
exaggerated
when
feeding
15%
ethanol
in
the
drinking
water
27
indicating
an
additive
fetotoxic
effect
of
ethanol
and
VC.
This
difference
between
species
should
be
28
correlated
to
the
doses
which
in
rats
and
rabbits
exceed
the
threshold
of
metabolic
saturation,
whereas
in
29
mice
this
threshold
likely
has
not
been
reached.
The
authors
attribute
the
observed
developmental
changes
30
to
maternal
toxicity
"
exposure
to
VC
did
not
cause
significant
embryonal
or
fetal
toxicity
and
was
not
31
teratogenic...".
32
CFY
rats
were
exposed
to
1,500
ppm
VC
for
24
h/
d
during
the
first
(
day
1­
9)),
second
(
day
8­
14)
33
or
third
trimester
(
day
14
to
21)
of
gestation.
The
volumes
of
the
inhalation
chambers
were
0.13
m3,
the
34
vertical
flow
rate
of
the
air
2
m3/
h
at
a
regulated
temperature
of
24
­
25
°
C
and
50
­
55%
relative
humidity.
35
VC
concentration
in
the
inhalation
chamber
was
determined
by
a
gas
chromatograph.
Section
was
36
performed
on
the
21st
day
of
gestation.
Treatment
resulted
in
significantly
increased
frequency
of
37
resorptions
in
the
group
exposed
during
the
first
trimester
(
2
fetuses
resorbed
in
the
control
group
vs.
12
38
fetuses
in
the
exposed
group;
fetal
loss
in
%:
1.7
in
the
control
group
and
5.5
in
the
exposed
group).
Two
39
cases
of
central
nervous
system
malformations
were
recorded
in
treated
animals
(
not
significant),
no
40
increase
in
other
malformations
were
detected.
The
absolute
and
relative
maternal
liver
weight
was
41
Vinyl
chloride
PROPOSED
1:
3/
2004
22
increased
in
animals
treated
in
the
first
and
second
week
of
pregnancy
without
light
microscopic
visible
1
changes,
but
not
in
animals
exposed
during
the
third
week
of
pregnancy
(
Ungváry
et
al.,
1978).
2
A
study
investigating
embryo­
fetal/
developmental
toxicity
and
reproduction
(
2­
generation)
was
3
conducted
by
Thornton
et
al.
(
2002).
In
the
developmental
toxicity
study,
Sprague­
Dawley
rats
were
4
exposed
during
day
6­
19
of
gestation
to
VC­
concentrations
of
0,
10,
100
or
1100
ppm
for
6
h/
day.
During
5
exposure
animals
were
housed
in
stainless
steel,
wire
mesh
cages
within
a
6000
liter
stainless
steel
and
6
glass
exposure
chamber.
Placement
of
the
animals
was
rotated
at
each
exposure.
No
feed
was
provided
7
during
exposure,
but
water
was
available
ad
libitum.
The
temperature
was
16­
28
degree
Celsius;
the
8
relative
humidity
was
29­
79
%;
the
air
flow
rate
was
1200
liters
per
minute.
VC
was
delivered
from
a
9
compressed
gas
cylinder
to
a
Scott
Specialty
Gases
regulator
equipped
with
inlet
and
outlet
back
pressure
10
gauges,
gas
test
atmosphere
was
analyzed
hourly
with
an
Ambient
Air
analyzer
equipped
with
a
strip
chart
11
recorder.
Maternal
body
weight
gains
were
slightly,
but
statistically
significantly
suppressed
at
all
exposure
12
levels
during
GD
15­
20
and
6­
20.
At
100
ppm
the
relative
kidney
weight
and
at
1100
ppm
the
relative
13
kidney
and
liver
weights
were
statistically
significantly
increased
in
maternal
animals.
No
further
adverse
14
effects
were
observed
in
this
study.
15
In
the
2
generation
study,
(
Thornton
et
al.,
2002)
exposure
started
10
weeks
pre­
mating.
Other
16
experimental
details
are
provided
above.
One
male
rat
in
the
10
ppm
group
and
one
female
rat
in
the
control
17
group
died.
Mating
indices
and
pregnancy
rates
for
the
F0
generation
were
comparable
between
control
and
18
VC
exposed
groups.
The
live
birth
index
was
significantly
decreased
while
the
number
of
stillborn
pups
19
was
significantly
increased
in
the
F0
generation
group
exposed
to
1100
ppm
(
the
authors
did
not
regard
20
these
effects
as
exposure
related
as
they
were
not
dose
dependent
and
in
the
range
of
the
historical
controls).
21
In
the
F0
generation
male
rats,
absolute
and
relative
liver
weights
were
significantly
increased
in
all
22
exposure
groups.
Absolute
epididymis
and
kidney
weights
were
increased
in
100
ppm
male
rats
of
the
F0.
23
Whereas
there
were
no
changes
in
the
liver
weight
of
female
F0
rats,
there
were
histological
alterations
in
24
the
liver
at
all
dose
groups
(
hepatocytes
were
enlarged
with
increased
acidophilic
cytoplasm
within
the
25
centrilobular
areas
of
the
liver).
Centrilobular
hypertrophy
was
observed
in
male
and
female
rats
exposed
to
26
100
and
1100
ppm
and
in
2
females
of
the
10
ppm
group.
27
One
male
rat
in
the
control
group
of
the
F1
died
due
to
unknown
reasons.
In
the
F2
litters,
there
28
was
a
statistically
significant
decrease
in
the
mean
number
of
pups
delivered
in
the
1100
ppm
group.
The
29
authors
regarded
this
effect
not
as
exposure
related
as
the
values
were
lower
than
respective
F1
control
30
group
values,
but
comparable
to
the
F0
control
group
values.
In
the
F1
there
was
a
statistically
significant
31
increase
in
the
absolute
and
relative
liver
weight
for
male
rats
exposed
to
100
and
1100
ppm
(
absolute
liver
32
weight
also
increased
in
female
rats,
but
not
statistically
significant).
Also
the
absolute
and
relative
spleen
33
weight
was
increased
in
male
rats
of
the
highest
dose
group.
Male
(
100
and
1100
ppm)
and
female
(
all
dose
34
groups)
rats
showed
centrilobular
hypertrophy.
Additionally,
altered
foci
(
acidophilic,
basophilic
and
clear
35
cell
foci)
were
observed
in
male
and
female
rats
of
the
F1
of
the
1100
ppm
group,
sometimes
even
at
the
36
100
ppm
group
(
foci
were
also
observed
in
2
male
rats
of
the
F0
at
1100
ppm).
37
3.4.
Genotoxicity
38
The
mutagenic
properties
of
VC
have
been
tested
in
a
variety
of
bacteria
with
the
Ames
test.
S.
39
typhimurium
TA
100
and
TA
1535
yield
positive
results
at
high
concentrations
and
long
exposure
times,
40
especially
with
metabolic
activation
systems
added.
In
other
test
systems
VC
is
genotoxic
only
after
41
metabolic
activation,
e.
g.
in
forward
mutation
assays
and
gene
conversion
assays
in
yeast,
cell
42
Vinyl
chloride
PROPOSED
1:
3/
2004
23
transformation
assays,
UDS
or
SCE
assays
in
mammalian
cells
(
summarized
in
WHO,
1999a).
The
tests
1
were
performed
either
with
5
­
100%
VC
in
the
atmosphere
or
0.025
­
50
mM
VC
in
the
culture
medium.
2
In
vivo
assays
for
genotoxicity
were
performed
with
mice,
rats,
and
hamsters.
VC
has
also
been
3
tested
in
Drosophila
melanogaster.
Increased
host­
mediated
forward
mutations
were
observed
after
oral
VC
4
exposure,
whereas
dominant
lethal
assays
in
mice
exposed
by
inhalation
and
rats
as
well
as
a
mouse
spot
5
test
gave
negative
results.
Micronucleus
formation
in
mice
(
50,000
ppm,
4
­
6h,
1,000
ppm
2
x
4h),
6
cytogenetic
aberrations
in
rats
(
1,500
ppm
for
1
­
12
weeks)
and
hamsters
(
25,000
ppm
for
6
­
24
hours)
7
and
loss
of
sex
chromosomes
in
Drosophila
melanogaster
(
50,000
ppm
for
48
hours)
indicated
dose
related
8
chromosomal
abnormalities.
Also,
increased
DNA
damage
was
demonstrated
by
alkaline
elution
assays
in
9
mice
and
SCE
formation
in
hamsters
(
summarized
in
WHO,
1999a).
Further
experiments
with
known
VC
10
metabolites
indicate
that
genotoxic
effects
are
likely
mediated
by
reactive
intermediates
with
chloroethylene
11
oxide
being
most
effective.
12
DNA
adducts
of
VC
metabolites
with
miscoding
properties
have
been
directly
detected
after
13
incubation
of
bacterial
or
phage
DNA
in
vitro
or
in
E.
coli
cells
with
DNA
adduct
indicator
systems
in
vivo
14
with
activated
VC
(
summarized
in
WHO,
1999a).
Covalent
binding
has
been
frequently
observed
after
15
single
and
short
term
exposure.
16
17
Bolt
et
al.
(
1980)
detected
irreversible
attachment
of
radioactivity
[
1,2­
14C]
VC
to
hepatic
18
macromolecules
in
the
rat.
After
single
exposure
of
adult
rats
to
250
ppm
[
14C]
VC
for
5
hours
the
total
19
amount
metabolized
per
individual
rat
was
37
µ
mol.
23
pmol
VC­
metabolites/
100
mg
liver
wet
weight
20
were
irreversibly
bound
to
DNA.
d­
guanosine
alkylation
products
amounted
to
0.35
pmol.
21
Laib
et
al.
(
1989)
exposed
adult
Wistar
rats
to
700
ppm
[
1,2­
14C]
VC.
The
animals
received
either
22
a
single
6­
h
exposure,
or
2
single
6­
h
exposures
separated
by
a
treatment
free
interval
of
15h.
The
23
following
amounts
of
[
14C]
VC­
derived
radioactivity
in
liver
DNA
was
observed:
after
a
single
exposure
of
24
male
rats
the
activity
was
3.6
±
0.2
pmol
7­(
2'­
oxoethyl)
guanine
(
OEG)
/
mg
DNA,
after
2
exposures
(
female
25
rats):
5.2
±
0.5
pmol
OEG/
mg
DNA
±
SD.
26
Watson
et
al.
(
1991)
exposed
adult
male
Fisher
344
rats
(
nose
only)
for
6
hours
to
atmospheres
27
containing
nominally
1,
10,
or
45
ppm
[
1,2­
14C]
VC.
The
alkylation
frequencies
of
OEG
in
liver
DNA
were
28
0.026,
0.28
and
1.28
residues
OEG
per
106
nucleotides
respectively.
These
data
indicate
a
linear
29
relationship
between
exposure
dose
and
DNA
dose
in
rats.
There
was
no
evidence
to
indicate
the
formation
30
of
the
cyclic
adducts
1,
N6­
ethenoadenine
(
 A)
or
3,
N4­
ethenocytosine
(
 C).
The
threshold
for
detection
of
31
these
adducts
were
about
1
adduct
per
1
x
108
nucleotides.
32
Swenberg
et
al.
(
2000)
reported
dose­
dependent
data
on
etheno­
adducts
using
a
new
combination
of
33
immunoaffinity
/
GC­
high
resolution
MS.
Adult
F344
rats
were
exposed
to
0,
10,
100,
1100
ppm
VC
for
6
34
hours/
day,
5
days/
week
for
1
or
4
weeks.
The
mean
for
N2,3­
ethenoguanine
(
 G)
in
a
mixed
liver
cell
35
suspension
from
unexposed
control
rats
was
90
±
40
fmol/
µ
mol
guanine.
Exposure
to
10
ppm
VC
for
1
or
36
4
weeks
resulted
in
200
±
50
and
530
±
11
fmol/
µ
mol
guanine,
while
exposure
to
100
ppm
VC
caused
680
37
±
90
and
2280
±
180
fmol
/
µ
mol
guanine
at
1
or
4
weeks,
respectively.
A
much
lesser
effect
was
evident
38
for
the
11­
fold
greater
exposure
of
1100
ppm
due
to
saturation
of
metabolic
activation,
with
1250
±
200
39
and
3750
±
550
fmol/
µ
mol
guanine
being
present
in
liver.
40
Vinyl
chloride
PROPOSED
1:
3/
2004
24
In
addition
to
these
studies,
there
exist
several
investigations
on
the
differences
in
sensitivity
of
1
young
(
preweanling)
vs.
adult
animals.
Laib
et
al.
(
1989)
tested
11­
day­
old
and
adult
Wistar
rats
by
2
exposure
to
700
ppm
[
1,2­
14C]
VC.
Adult
rats
received
either
a
single
6­
h
exposure,
or
2
single
6­
h
3
exposures
separated
by
a
treatment
free
interval
of
15h.
Pups
received
2
single
6h­
exposures,
according
to
4
the
same
treatment
schedule.
The
following
amounts
of
[
14C]
VC­
derived
radioactivity
in
liver
DNA
was
5
observed
after
2
exposures
(
female
adults,
male
and
female
pups):
5.2
±
0.5
pmol
OEG/
mg
DNA
±
SD
6
(
adults),
25.5
±
3.0
pmol
OEG/
mg
DNA(
pups).
After
a
single
exposure
of
adult
male
rats
the
activity
7
(
3.6
±
0.2
pmol
OEG/
mg
DNA)
was
close
to
the
observation
after
two
exposures.
8
After
a
five
day
exposure
of
F344
rats
to
600
ppm
(
4h/
d)
the
adduct
levels
in
the
liver
were
162
±
9
36
pmol
OEG/
µ
mol
guanine
and
1.81
±
0.25
pmol
 G
/
µ
mol
guanine
for
the
pups
and
43
±
7
pmol
OEG/
10
µ
mol
guanine
and
0.47
±
0.14
pmol
 G
/
µ
mol
guanine
for
the
adult
animals
(
Swenberg
et
al.,
1999).
11
Ciroussel
et
al.
(
1990)
compared
the
levels
of
1,
N6­
ethenodeoxyadenosine
(
 dAdo)
and
3,
N4­
12
ethenodeoxycytidine
(
 dCyd)
in
BD
VI
rats
with
pups
(
7
days
old)
vs.
adults
(
13­
week­
old
animals).
These
13
rats
had
been
exposed
to
500
ppm
VC
for
2
weeks
(
7h/
d,
7d/
w).
The
molar
ratios
(
x
10­
7)
in
the
liver
were
14
1.30,
1.31
(
two
analyses;
 dAdo/
dAdo)
and
4.92,
4.67
(
 dCyd/
dCyd)
for
the
newborn
compared
to
0.19
15
(
 dAdo/
dAdo)
and
0.8
(
 dCyd/
dCyd)
for
the
adult
animals.
16
Fedtke
et
al.
(
1990)
measured
the
 G
content
in
the
liver
of
lactating
Sprague­
Dawley
rats
and
their
17
10
days
old
pups
exposed
to
VC
(
600ppm,
5
days,
4h/
d).
 G
concentrations
found
in
DNA
livers
of
the
18
dams
were
470
±
140
(
adults)
compared
with
1810
±
250
fmol/
µ
mol
(
pups).
The
mean
background
found
in
19
the
control
DNA
was
60
±
40
fmol/
µ
mol
(
background
subtracted
from
 G
concentration).
Similarly,
20
Morinello
et
al.
(
2002)
demonstrated
higher
 G­
adduct
levels
in
hepatocytes
after
exposure
of
weanling
rats
21
to
10
ppm
for
1
week
(
6h/
d)
compared
to
adult
animals
(
control
adult:
0.55
±
0.14
mol
 G
/
107
mol
22
guanine;
pups:
0.16
±
0.01;
exposed
adult:
1.4
±
0.4;
pups:
4.1
±
0.8).
Adducts
largly
persisted
after
23
recovery
over
5
weeks.
24
Etheno
adducts
may
be
repaired
by
DNA
glycolases,
but
a)
did
not
fully
return
to
background
25
levels
after
a
exposure
free
period
of
14
days
(
 G:
directly
after
exposure
1,8
pmol/
µ
mol,
after
14
days:
26
0,47
pmol/
µ
mol;
control
level:
90
fmol/
µ
mol),
b)
have
a
miscoding
potential
in
vitro
and
in
vivo
(
Swenberg
27
et
al.,
1999).
28
Gene
mutations
were
found
in
animal
tumors
associated
with
exposure
to
etheno­
adduct­
forming
29
chemicals
such
as
VC.
Specifically,
in
rat
hepatocellular
carcinoma
in
7
of
8
cases
A­>
T
mutations
of
the
30
Ha­
ras
gene
have
been
found
and
in
angiosarcoma
of
the
rat
liver
in
10
of
25
cases
various
base
pair
31
substitutions
as
mutations
of
p53
were
observed,
which
may
be
attributed
to
the
formation
of
ethenobases
32
in
DNA
(
Barbin,
2000).
33
3.5.
Carcinogenicity
34
Inhalation
exposure
of
rats
to
VC
causes
liver
tumors,
especially
angiosarcomas
and
hepatocellular
35
carcinoma
and
neoplastic
liver
nodules.
Furthermore,
angiosarcomas
of
other
sites
are
reported.
36
Additionally,
tumors
at
other
locations
are
found,
e.
g.
Zymbal
gland,
neuroblastoma
and
nephroblastoma
in
37
rats;
lung
tumors
in
mice;
mammary
gland
tumors
in
rats,
mice,
and
hamsters,
and
skin
tumors
in
rabbits
38
and
hamsters
(
summarized
in
WHO,
1999a,
ATSDR
1997).
Similar
tumor
localizations
are
observed
after
39
Vinyl
chloride
PROPOSED
1:
3/
2004
25
oral
exposure.
There
is
evidence
that
liver
tumors
are
induced
in
female
rats
at
lower
doses
than
in
males.
1
There
is
also
evidence,
that
animals
are
more
susceptible
to
tumor
induction
early
in
life
(
WHO,
1999a).
2
Short
term
exposure
experiments
from
Drew
et
al.
(
1983)
and
Maltoni
et
al.
(
1981)
indicate
3
increased
susceptibility
of
newborn
and
young
animals.
Drew
et
al.
(
1983)
found
increased
incidences
of
4
tumors
in
rats,
mice
and
hamsters
when
exposed
for
the
first
6
month
in
life,
but
not
at
later
exposure
5
times,
e.
g.
exposure
of
rats
to
100
ppm
VC
during
month
0­
6
or
6­
12
resulted
in
a
tumor
incidence
6
(
hemangiosarcoma
of
the
liver)
of
5.3%
or
3.8%,
respectively,
but
no
tumors
occurred
when
rats
were
7
exposed
during
month
12
­
18
or
18
to
24.
8
Maltoni
et
al.
(
1981,
1984)
exposed
newborn
rats
postnatally
from
day
1
to
5
weeks
of
age
to
9
6,000
ppm
or
10,000
ppm
VC
by
inhalation
(
4
h/
d;
5
d/
w).
At
6,000
ppm
the
number
of
exposed
animals
10
were
42
(
18
male;
24
female);
at
10,000
ppm
the
respective
number
was
44
(
24
male;
20
female).
The
11
number
of
respective
breeders
were
6
for
each
exposure
concentration.
No
direct
control
group
was
used;
12
however,
in
parallel
experiments
breeders
and
newborn
animals
without
exposure
were
included
(
see
13
Experiment
BT
4001,
4006).
The
newborn
animals
were
simultaneously
exposed
to
milk
from
exposed
14
dams
(
D.
Soffritti,
Laboratory
of
Prof.
Maltoni,
personal
communication,
August,
2003).
The
authors
15
found
liver
angiosarcomas
in
newborn
SD
rats
in
17/
42
and
15/
44
animals
respectively,
exposed
to
6,000
16
ppm
or
10,000
ppm,
but
none
in
their
mothers
which
were
treated
identically.
No
angiosarcoma
were
found
17
in
a
control
group
of
304
rats
(
parallel
experiment).
Additionally,
hepatoma
incidence
was
increased
in
18
newborn
rats
(
20/
42
and
20/
42,
respectively),
but
no
hepatoma
were
observed
in
their
mothers.
Only
1
19
hepatoma
were
found
in
a
control
group
of
304
rats
(
parallel
experiment).
Results
were
provided
after
124
20
weeks
of
observation.
The
internal
concentration
of
VC
may
have
been
influenced
by
oral
uptake
from
milk
21
from
exposed
dams.
However,
due
to
the
very
high
inhalation
exposure
and
due
to
saturation
of
22
metabolism,
the
oral
uptake
by
contaminated
milk
may
have
contributed
only
a
limited
amount
to
the
23
overall
organ
concentration
of
VC
metabolites.
24
Froment
et
al.
(
1994)
exposed
4
female
Sprague­
Dawley
rats
together
with
their
pups
(
22
males
25
and
22
females)
for
8h/
d,
6d/
w
to
500
ppm
VC
from
day
3
through
28
postpartum.
At
day
28
postpartum,
26
the
young
animals
were
weaned,
and
the
males
and
females
were
separated
and
exposed
for
further
2
weeks
27
(
total
exposure:
33
days).
The
surviving
animals
were
all
sacrificed
at
19
month
of
age.
In
the
44
VC­
28
exposed
rats
66
hepatic
lesions
were
identified
including
nodular
hyperplasia,
endothel
cell
hyperplasia,
29
peliosis,
adenomas,
benign
cholangiomas,
angiosarcoma
of
the
liver
(
ASL)
and
hepatocellular
carcinoma
30
(
HCC).
Liver
tumors
included
8
HCC,
15
ASL
and
2
benign
cholangioma.
No
further
details
were
31
provided.
It
is
assumed
that
oral
exposure
via
mothers
´
milk
and
inhalation
exposure
occurred
32
simultaneously.
33
Maltoni
et
al.,
(
1981,
1984)
also
exposed
rats
30
breeders/
exposure
group
to
6,000
and
10,000
34
ppm
for
1
week
(
4h/
d;
12th
until
18th
day
of
pregnancy).
32
(
13
males;
19
females)
and
51
(
22
males;
29
35
females)
offsprings
were
investigated
after
exposure
to
the
lower
or
the
higher
concentration,
respectively.
36
Angiosarcoma
of
the
liver
and
hepatoma
were
not
increased
in
the
transplacentally
exposed
offsprings.
37
However,
Zymbal
gland
carcinoma
and
nephroblastoma
were
found
elevated
after
transplacental
exposure.
38
Differences
between
pre­
and
postnatal
exposure
and
carcinogenic
outcome
may
possibly
be
explained
by
39
hepatic
CYP2E1
activity,
which
is
expressed
to
a
lower
extent
prenatally
than
postnatally,
both
in
rats
40
(
Carpenter
et
al.,
1997)
and
in
humans
(
Cresteil,
1998).
41
Vinyl
chloride
PROPOSED
1:
3/
2004
26
Hehir
et
al.
(
1981)
found
increased
lung
tumor
incidences
in
ICR
mice
exposed
once
for
1
h
to
VC
1
(
age
of
the
animals
not
stated).
Animals
were
exposed
in
an
inhalation
chamber
to
single
one­
hour
doses
of
2
VC
ranging
from
50
to
50,000
ppm
(
Rochester
type
inhalation
chambers,
1,000
liter
with
laminar
air
flow)
3
and
were
then
observed
for
the
remainder
of
their
lives.
Tumor
response
was
dose
related:
Adenoma
of
the
4
lung
increased
from
12/
120
to
14/
139,
18/
139,
24/
143,
45/
137
respectively
for
exposure
to
0,
50,
500,
5
5000,
50000
ppm.
For
carcinoma
of
the
lung,
there
was
only
a
slight
occurrence
of
0/
120,
0/
139,
1/
143,
6
3/
137
(
data
from
both
sexes,
combined).
A
slight
increase
in
hepatic
cell
carcinoma
occurred
in
male
mice,
7
but
without
dose
response
(
2/
50;
2/
64;
9/
67;
6/
68;
4/
63).
No
increase
in
tumor
incidence
was
observed
in
8
liver
and
lung
of
rats
treated
in
an
identical
fashion.
Additional
studies
in
A/
J
mice
which
were
exposed
to
9
500
ppm
VC
for
1
h/
d
over
10
days
or
50
ppm
VC
for
1
h/
d
over
100
days
revealed
that
for
short
term
10
exposure
the
concentration
may
be
the
most
critical
factor.
In
both
experiments
primarily
pulmonary
11
adenomas
were
observed.
However,
the
incidence
in
the
induction
of
adenomas
and
progression
to
12
carcinoma
are
considered
only
marginal
and
not
statistically
significant
in
mice
exposed
to
50
ppm
for
100
13
times
(
44.1%
exposed;
34.5%
control)
whereas
a
significant
increase
of
pulmonary
adenomas
was
observed
14
in
animals
exposed
to
500
ppm
for
10
days
(
about
74%
exposed;
34.4%
control).
15
Suzuki
(
1983)
also
reported
that
short
term
exposure
(
6
h/
d;
5
d/
w;
4
weeks)
of
young
CD1
mice
16
(
5
­
6
weeks
old
at
first
exposure)
to
VC
resulted
in
tumor
formation.
At
sacrifice
12
weeks
after
exposure
17
pulmonary
tumors
were
observed
in
the
two
highest
dose
groups
(
300
and
600
ppm).
Forty
or
41
weeks
18
after
exposure
pulmonary
tumors
were
observed
in
all
animals
exposed
(
1
ppm
to
600
ppm)
but
not
in
19
control
mice.
In
addition,
subcutaneous
and
hepatic
hemangiosarcoma
were
found.
The
angiosarcoma
of
20
the
liver
occurred
in
one
animal
exposed
to
600
ppm
for
4
weeks
as
observed
at
necroscopy
56
weeks
after
21
exposure
(
Suzuki,
1981).
22
After
a
single
12
hour
exposure
to
1,500
ppm
of
mice
a
hepatocellular
adenoma
developed.
The
23
respective
concentration
was
lethal
to
most
of
the
animals
(
Tátrai
and
Ungváry,
1981).
However,
the
24
observed
effects
(
asphyxiation)
were
not
seen
in
other
studies
with
similar
concentrations.
25
26
In
addition
to
angiosarcoma
of
the
liver
several
studies
with
limited
exposure
duration
to
VC
27
confirm
the
occurrence
of
hepatocellular
carcinomas
and/
or
other
preneoplastic
parenchymal
changes
in
28
adult
animals
(
Feron
et
al.,
1979;
Thornton
et
al.,
2002).
However,
these
changes
were
seen
to
a
much
29
lesser
extent
than
angiosarcoma
in
the
adult
animals
or
hepatocellular
changes
in
young
animals
(
see
30
below).
31
In
accordance
with
these
investigations
in
newborn
rats,
Laib
et
al.
(
1985a,
b)
reported
that
32
hepatocellular
ATPase­
deficient
foci
(
pre­
malignant
stages)
were
observed
in
rats
which
were
exposed
to
33
VC.
The
exposure
regimen
was
a)
Wistar
­
rats
for
10
weeks
starting
on
day
1
after
birth
(
10
to
2,000
ppm;
34
5
d/
w;
8
h/
d)
(
Laib
et
al.,
1985a),
b)
Wistar
and
Sprague­
Dawley
rats
to
2.5
to
80
ppm
VC
for
3
weeks
35
(
8h/
d)
starting
on
day
3
of
life
(
Laib
et
al.,
1985a),
c)
Wistar
rats
exposed
to
2,000
ppm
VC
for
5,11,17,47
36
or
83
days
(
8h/
d;
7d/
w)
with
different
ages
(
after
birth
or
from
an
age
of
7
or
21
onwards)
at
the
start
of
37
exposure
(
Laib
et
al.,
1985b).
Exposure
to
2,000
ppm
did
not
result
in
ATPase
deficient
foci
in
very
young
38
(
exposure
period:
day
1
to
5)
or
in
adult
animals
(
exposure
period:
from
day
90
to
160).
However,
relevant
39
foci
areas
were
demonstrated
for
short
periods
during
animal
growth,
eg.,
exposure
for
11
days
(
exposure
40
period:
from
day
1
to
11)
or
for
21
days
(
from
day
7­
28).
The
foci
persisted
until
evaluation
at
the
age
of
4
41
month
(
Laib
et
al.,
1985b).
After
exposure
over
10
weeks,
induction
of
ATPase
deficient
foci
was
dose
42
dependent
(
nearly
linear)
for
concentrations
between
10
ppm
and
500
ppm
and
it
was
shown
for
both
43
strains
of
rat,
Wistar
and
Sprague­
Dawley.
This
finding
is
in
accordance
with
the
findings
that
VC­
44
Vinyl
chloride
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27
metabolism
follows
first
order
kinetics
until
saturation
occurs
at
high
exposure
concentrations
(
Laib
et
al.,
1
1985a).
2
Quantitative
risk
assessments
based
on
animal
experiments
have
been
published
by
several
authors
3
and
are
summarized
in
Table
5.
4
TABLE
5:
QUANTITATIVE
ASSESSMENT
OF
CARCINOGENIC
POTENCY
OF
VC
BASED
ON
5
ANIMAL
EXPERIMENTS
6
Author
7
Unit
Risk
(
per
µ
g/
m3)

Chen
und
Blancato,
1989
8
6.5
x
10­
7
­
1.4
x
10­
6
EPA,
2000
a,
b
9
8.8
x
10­
6
Clewell
et
al.,
1995
10
6
x
10­
7
­
2
x
10­
6
Clewell
et
al.,
2001
11
1.1
x
10­
6
Reitz
et
al.,
1996
12
5.7
x
10­
7
These
risk
estimates
are
based
on
the
experimental
data
in
adult
animals
exposed
for
lifetime
13
published
by
Maltoni
et
al.
(
1981;
1984).
There
are
only
slight
differences
in
the
human
cancer
risk
14
estimated
by
Clewell
and
Reitz
who
both
used
pharmacokinetic
(
PBPK)­
models
for
the
transfer
of
the
15
animal
data
on
the
human
situations.
These
data
are
in
good
agreement
with
the
unit
risk
estimates
derived
16
from
epidemiologic
data,
confirming
the
order
of
magnitude.
However,
these
risk
estimates
were
only
17
validated
with
data
from
adult
animals
and
epidemiologic
data
from
the
workplace.
A
higher
sensitivity
of
18
children
was
not
incorporated
into
quantification
(
see
data
from
Drew
et
al.,
1983;
Maltoni
et
al.,
1981).
19
Chen
and
Blancato
(
1989)
use
a
modified
multistage
model
for
risk
estimation
on
base
of
liver
20
tumors,
considering
pharmacokinetic
models.
Additionally,
increased
sensitivity
in
early
life
stages
has
been
21
considered.
They
evaluated
female
and
male
animals
separately,
expressed
by
the
range
of
tumor
22
incidences.
23
The
most
recently
published
risk
estimate
by
EPA
(
2000a,
b)
is
based
on
the
animal
experiments
24
published
by
Maltoni
et
al.
(
1981,
1984).
Differences
in
the
metabolism
between
animals
and
humans
have
25
been
taken
into
consideration
by
use
of
a
pharmacokinetic
model.
The
increased
sensitivity
of
children
was
26
taken
into
consideration.
Additionally,
tumors
in
sites
other
than
the
liver
were
considered.
Unit
risk
27
estimates
based
on
epidemiologic
studies
were
regarded
as
uncertain
due
to
the
shortcomings
of
the
28
epidemiologic
studies.
Besides
the
unit
risk
estimate
for
full
lifetime
exposure
(
birth
through
death)
of
8.8
x
29
10­
6
per
µ
g/
m3,
EPA
provided
an
estimate
of
risk
for
early
life
exposure
of
4.4
x
10­
6
per
µ
g/
m3
and
an
30
estimate
of
risk
for
adult
only
exposure
of
4.4
x
10­
6
per
µ
g/
m3.
This
unit
risk
for
adults
is
based
on
the
31
PBPK­
modeling
from
Clewell
et
al.
(
2001),
with
only
slight
modifications
in
some
parameters.
32
3.6.
Summary
33
Acute
exposure
of
experimental
animals
towards
VC
results
in
narcotic
effects,
cardiac
34
sensitization,
and
hepatotoxicity.
Narcotic
effects
are
characterized
by
a
typical
sequence
of
events
from
35
Vinyl
chloride
PROPOSED
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28
euphoria
and
dizziness,
followed
by
drowsiness
and
loss
of
consciousness.
Finally,
animals
die
due
to
1
respiratory
failure.
Prodan
et
al.
(
1975)
reported
LC50
values
for
mice,
rats,
rabbits,
and
guinea
pigs
of
2
117,500
ppm,
150,000
ppm,
240,000
ppm
and
240,000
ppm,
respectively,
for
2
hours.
Dead
animals
3
showed
congestion
of
the
internal
organs
(
especially
lung,
liver
and
kidney),
lung
edema
and
hemorrhagia
4
(
Prodan
et
al.,
1975;
Mastromatteo
et
al.,
1960).
No
lethality
was
seen
in
mice
after
exposure
to
100,000
5
ppm
for
2
hours
(
Prodan
et
al.,
1975).
However,
Tátrai
and
Ungváry
(
1981)
reported
that
exposure
of
mice
6
to
1,500
ppm
for
24
h
resulted
in
death
of
all
animals,
reduction
of
exposure
time
to
12
h
resulted
in
death
7
of
90%
of
the
animals.
These
results
are
not
in
accordance
with
other
lethality
data.
8
Short
term
exposure
(
up
to
30
minutes)
of
experimental
animals
to
VC­
concentrations
of
100,000
9
to
300,000
ppm
resulted
mainly
in
ataxia,
motor
activity,
side
position
and
unconsciousness,
slow
and
10
shallow
respiration,
the
typical
reactions
observed
before
the
onset
of
narcosis
(
Mastromatteo
et
al.,
1960).
11
Narcosis
was
observed
in
rats
and
mice
after
30
min
exposure
to
200,000
ppm
VC
(
Mastromatteo
et
al.,
12
1960).
Short
term
exposure
(
5
min)
of
dogs
to
VC
induced
cardiac
sensitization
towards
epinephrine
(
EC50:
13
50,000
or
71,000
ppm
in
two
independent
experiments)
(
Clark
and
Tinston,
1973;
1982).
These
effects
14
were
also
seen
in
mice
at
higher
concentrations
(
Aviado
and
Belej,
1974).
In
monkeys,
only
myocardial
15
depression
after
inhalation
of
2.5­
10%
VC
was
observed.
It
is
not
clearly
stated
whether
an
addition
16
challenge
with
epinephrine
was
applied
or
not
(
Belej
et
al.,
1974).
Single
inhalation
exposure
of
rats
for
6
17
hours
to
100,000
ppm
VC
resulted
in
histopathological
changes
of
the
liver
(
vacuolization),
but
was
not
18
observed
in
lower
concentrations
(
50,000
ppm)
(
Jaeger
et
al.,
1974).
However,
in
mice
Tátrai
and
Ungváry
19
(
1981)
reported
that
stasis
of
the
liver
developed
2
and
4
h
after
the
beginning
of
inhalation.
The
authors
20
observed
decreasing
enzyme
activities
in
liver
and
subcellular
liver
damage
at
exposure
concentrations
of
21
1,500
ppm
VC
for
2
h;
after
24
h
shock
liver
developed.
Repeated
exposure
of
rats
to
1,500
ppm
VC
for
22
up
to
9
days
during
pregnancy
caused
increased
relative
and
absolute
liver
weights
without
light
23
microscopic
visible
changes
(
Ungváry
et
al.,
1978).
In
another
developmental
study
increased
absolute
and
24
relative
liver
weights
have
been
observed
in
rats
exposed
intermittently
to
2,500
ppm
from
day
6
­
15
of
25
pregnancy,
the
NOAEL
was
500
ppm
(
John
et
al.,
1977;
1981).
In
rats
exposed
to
5,000
ppm
for
7
26
hours/
day
and
5
days/
week
after
4
weeks
vacuolized
liver
cells
were
observed
(
Feron
et
al.,
1979).
27
No
investigations
of
reproductive
or
developmental
toxicity
after
single
exposure
are
published.
28
John
et
al.
(
1977,
1981)
investigated
developmental
effects
after
repeated
exposure
in
mice,
rats
and
29
rabbits.
Developmental
toxicity
(
e.
g.
delayed
ossification)
was
only
observed
at
maternal
toxic
30
concentrations.
Ungváry
et
al.
(
1978)
reported
that
in
maternal
rats
which
were
exposed
to
1,500
ppm
VC
31
for
24
h/
d
during
the
first
(
day
1­
9)
or
second
(
day
8­
14)
trimester
of
gestation
maternal
liver
toxicity
32
occurred.
Frequency
of
resorptions
was
significantly
increased
in
the
group
exposed
during
the
first
33
trimester.
A
recently
published
developmental
toxicity
study
in
rats
(
exposure
on
day
6­
19
of
gestation
34
towards
10,
100
or
1100
ppm
VC,
6
h/
d)
indicated
that
up
to
1100
ppm
embryo­
fetal
development
was
not
35
affected
by
VC
exposure.
The
only
toxic
effects
observed
were
an
increased
relative
organ
to
body
weight
36
ratio
for
the
kidney
and
liver
at
1100
ppm
and
for
the
kidney
at
100
ppm
in
dams
(
Thornton
et
al.,
2002).
37
In
a
2­
generation
study
in
rats
no
adverse
effects
on
embryo­
fetal
development
or
reproductive
capability
38
were
observed
over
2
generations
in
concentrations
up
to
1100
ppm
(
F0:
exposure:
10
weeks
premating,
3­
39
weeks
mating,
gestation,
lactation;
F1:
identical
exposure
pattern;
F2:
until
postnatal
day
21).
The
primary
40
target
organ
of
VC,
the
liver,
was
affected
as
evidenced
by
an
increase
in
liver
weight
and/
or
41
histopathologically
identified
cellular
alterations,
such
as
centrilobular
hypertrophy
and
induction
of
altered
42
hepatocellular
foci
at
100
and
1,000
ppm,
with
increased
incidence
in
the
F1
generation
(
Thornton
et
al.,
43
2002).
44
Vinyl
chloride
PROPOSED
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2004
29
Positive
results
on
genotoxicity
after
in
vitro
and
single
and
repeated
in
vivo
treatment
(
e.
g.
1
induction
of
micronuclei,
4
­
6
h,
50,000
ppm;
chromosomal
aberrations,
6
­
24
h,
25,000
ppm)
have
been
2
reported
for
VC
(
WHO,
1999a).
Elevated
DNA­
adducts
were
seen
after
single
5
hour
exposure
of
adult
3
rats
to
250
ppm
(
Bolt
 
1976).
Watson
et
al.
(
1991)
exposed
adult
male
Fisher
344
rats
for
6
hours
to
4
atmospheres
containing
1,
10,
45
ppm
VC.
The
alkylation
frequencies
of
7­(
2'­
oxoethyl)
guanine
(
OEG)
in
5
liver
DNA
were
0.026,
0.28
and
1.28
residues
OEG
per
106
nucleotides
respectively.
With
these
air
6
concentrations,
there
was
no
evidence
to
indicate
the
formation
of
the
cyclic
adducts
1,
N6­
ethenoadenine
7
(
 A)
or
3,
N4­
ethenocytosine
(
 C).
The
threshold
for
detection
of
these
adducts
were
about
1
adduct
per
1
x
8
108
nucleotides.
Adult
rats
repeatedly
(
5
days)
exposed
to
10
ppm
VC
for
6
hours/
day
showed
slightly
9
elevated
etheno­
adducts
for
N2,3­
ethenoguanine
(
 G)
compared
to
control
(
200
±
50
vs.
90
±
40
fmol/
10
µ
mol
guanine)
(
Swenberg
et
al.,
2000).
Higher
adduct
levels
were
seen
in
young
animals
than
in
adult
11
animals
after
identical
treatment
(
Fedtke
et
al.,
1990;
Laib
et
al.,
1989;
Ciroussel
et
al.
(
1990).
OEG
are
12
not
likely
to
cause
mutations,
however,
the
cyclic
adducts
 A,
 C,
 G
have
miscoding
potential;
respective
13
mutations
(
e.
g.,
G­>
A
transitions,
A­>
T
transitions)
were
observed
in
VC­
induced
tumors
(
Barbin,
2000).
14
Despite
relevant
repair,
no
full
reduction
to
background
was
observed
for
these
adducts
two
weeks
after
a
5
15
day
exposure
(
4
hours/
day)
to
600
ppm
(
Swenberg
et
al.,
2000).
16
Induction
of
liver
tumors
has
been
reported
in
rats
after
subacute
(
5
week
and
33
days,
17
respectively)
exposure
(
Maltoni
et
al.,
1981;
1984;
Froment
et
al.
,
1994).
The
liver
is
the
primary
18
localization
of
tumors
after
chronic
exposure
(
for
review
see
EPA,
2000a,
b).
Vinyl
chloride
induces
lung
19
tumors
in
mice
after
single
one
hour
exposure
to
5,000
ppm
or
50,000
ppm
(
Hehir
et
al.,
1981).
After
a
20
single
12
hour
exposure
to
1,500
ppm
of
mice
a
hepatocellular
adenoma
developed.
The
respective
21
concentration
was
lethal
to
most
of
the
animals
(
Tátrai
and
Ungváry,
1981).
Suzuki
(
1983)
reported
that
22
short
term
exposure
(
6
h/
d;
5
d/
w;
4
weeks)
of
young
CD1­
mice
(
5
­
6
weeks
old
at
first
exposure)
to
VC
23
resulted
in
lung
tumor
formation.
Additionally,
subcutaneous
and
hepatic
hemangiosarcoma
were
found
in
24
this
study.
Short
term
exposure
experiments
from
Drew
et
al.
(
1983),
Maltoni
et
al.
(
1981)
and
Froment
et
25
al.
(
1994)
also
indicated
increased
susceptibility
of
newborn
and
young
animals
towards
tumor
formation.
26
Hepatoma
(
Maltoni
et
al.,
1981)
or
hepatocellular
carcinoma
(
Froment
et
al.,
1994)
developed
to
a
greater
27
extent
in
young
than
in
adult
animals.
Laib
et
al.
reported
that
hepatocellular
ATPase­
deficient
foci
(
pre­
28
malignant
stages)
were
observed
in
rats
which
were
exposed
to
VC.
Relevant
foci
areas
were
demonstrated
29
after
short
periods
of
exposure
during
animal
growth,
eg.,
exposure
to
2,000
ppm
for
11
days
(
exposure
30
period:
from
day
1
to
11)
or
for
21
days
(
from
day
7­
28).
The
foci
persisted
until
histological
examination
31
at
the
age
of
4
month
(
Laib
et
al.,
1985b).
32
Vinyl
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30
4.
SPECIAL
CONSIDERATIONS
1
4.1.
Metabolism
and
Disposition
2
Krajewski
et
al.
(
1980)
estimated
the
retention
of
VC
after
inhalation
through
a
gasmask
in
5
male
3
human
volunteers
by
measuring
the
difference
between
inhaled
and
exhaled
concentrations.
Exposure
to
4
concentrations
between
3
and
24
ppm
VC
for
6
hours
revealed
an
average
retention
of
42%,
independent
5
from
VC
concentration.
Thirty
minutes
after
the
beginning
initially
higher
retention
values
(
maximum
46%
6
on
average)
dropped
down
and
stayed
on
a
relative
constant
level.
Interindividual
retention
rates
varied
7
from
20.2%
to
79%
at
12
ppm.
Immediately
after
cessation
of
inhalation
the
VC
concentration
in
the
8
expired
air
dropped
rapidly.
After
30
minutes
less
than
5%
of
the
initial
chamber
concentration
could
be
9
measured.
Buchter
et
al.
(
1978)
determined
a
retention
rate
of
26
­
28%
at
2.5
ppm
VC
in
two
individuals
3
10
­
5
min
after
the
start
of
inhalation.
Given
the
variability
of
VC
retention
found
by
Krajewski
these
values
11
may
be
attributed
to
interindividual
differences.
WHO
(
1999a)
reports
an
average
of
30
­
40%
absorption
12
after
inhalation,
without
citing
the
relevant
studies.
13
An
absorption
of
inspired
VC
of
about
40%
was
calculated
for
rats
(
calculation
based
on
the
14
decline
of
14C­
VC
in
a
closed
system)
(
Bolt
et
al.,
1976).
In
Rhesus
monkeys
VC
is
also
efficiently
15
absorbed
after
inhalation
as
can
be
deduced
from
data
on
the
metabolic
elimination
(
no
further
16
quantification)
(
Buchter
et
al.,
1980).
17
Whole
body
(
excluding
the
head)
exposure
of
rhesus
monkeys
to
radioactive
VC
indicated
that
only
18
very
little
VC
was
absorbed
through
the
skin
(
about
0.031%
and
0.023%
at
800
and
7,000
ppm,
19
respectively
after
2
­
2.5
h)
(
ATSDR,
1997).
No
further
data
on
dermal
absorption
are
available.
20
The
percentage
of
the
dose
remaining
in
the
carcass
after
oral
application
after
72
h
was
10,
11,
21
and
2%
for
the
0.05,
1
and
100
mg/
kg
doses.
The
data
suggest
that
almost
complete
elimination
of
VC
22
occurred
(
Watanabe
et
al.,
1976b).
Seventy
two
hours
after
exposure
to
10
and
1,000
ppm
radioactive
VC
23
14
and
15%,
respectively,
of
the
recovered
14C­
activity
remained
in
the
carcass
of
rats,
VC
per
se
was
not
24
found
in
tissues.
Radioactivity
was
detected
in
the
liver,
skin,
plasma,
muscle,
lung
fat
and
kidney,
25
representing
non
volatile
metabolites
of
VC
(
Watanabe
et
al.,
1976a)
or
incorporation
into
C1­
pool
(
Laib
et
26
al.,
1989).
27
Data
on
serum
concentrations
of
VC
are
scarce.
Ungváry
et
al.
(
1978)
exposed
pregnant
rats
to
28
2,000
­
12,000
ppm
VC;
they
determined
blood
concentrations
ranging
from
19
µ
g/
ml
at
2,000
ppm
to
29
48.4
µ
g/
ml
at
12,000
ppm
VC
indicating
no
direct
proportionality
between
air
VC
concentration
and
blood
30
concentration.
Feron
et
al.
(
1975)
reported
a
peak
blood
concentration
of
1.9
µ
g/
ml
10
min
after
gavage
of
31
300
mg/
kg
VC;
this
value
is
much
smaller
than
expected
compared
to
blood
concentrations
after
inhalation
32
which
might
be
due
to
the
effective
presystemic
hepatic
clearance
of
VC
after
oral
uptake.
33
Similar
to
other
inhalation
anaesthetics,
maximal
blood
concentration
of
VC
after
inhalation
34
exposure
depends
on
the
partial
pressure
of
VC
in
the
air.
Blood
respectively
brain
concentration,
which
35
directly
correlates
with
the
depth
of
narcosis
(
see
below)
and
­
presumably
­
with
cardiac
sensitization
level,
36
can
be
controlled
by
changing
the
concentration
of
VC
in
the
air,
i.
e.
by
changing
the
partial
pressure
of
37
VC
in
the
air.
If
equilibrium
is
reached
between
the
partial
pressure
of
VC
in
the
air
and
in
the
blood
38
(
steady
state),
no
further
increase
of
VC
concentration
in
the
blood
is
possible,
even
if
the
exposure
time
is
39
prolonged
(
Forth
et
al.,
1987).
The
time
necessary
to
set
up
steady
state
mainly
depends
on
the
blood/
air
40
partition
coefficient
of
a
substance.
The
blood/
air
partition
coefficient
of
VC
in
humans
is
1.2
(
Csanady
41
Vinyl
chloride
PROPOSED
1:
3/
2004
31
and
Filser,
2001),
similar
to
that
of
the
inhalation
anaesthetic
isoflurane
(
1.4;
Forth
et
al.,
1987).
For
this
1
substance
the
equilibrium
is
reached
after
about
2
hours,
derived
by
graphical
extrapolation
of
the
data
on
2
isoflurane
(
Goodman
and
Gilman,
1975).
For
VC,
in
much
lower
concentrations
an
elimination
half­
time
of
3
VC
of
20.5
minutes
has
been
derived
(
Buchter,
1979;
Bolt
et
al.,
1981).
From
that,
for
low
concentrations
4
a
steady
state
concentration
for
VC
in
blood
of
about
5
x
20.5
=
102.5
minutes
can
be
calculated
by
5
standard
estimation
rules.
Thus,
in
high
or
low
concentrations
a
relevant
increase
of
internal
concentrations
6
of
VC
is
not
to
be
expected
after
more
than
2
hours
of
exposure.
However,
for
shorter
periods
of
exposure
7
a
relevant
influence
of
time
on
the
built­
up
of
VC
on
internal
concentrations
has
to
be
taken
into
account.
8
VC
is
oxidized
by
cytochrome
P450
2E1
to
the
highly
reactive
epoxide
2­
chloroethylene
oxide
9
which
can
directly
interact
with
DNA
and
proteins
or
spontaneously
rearrange
to
2­
chloroacetaldehyde
10
which
might
bind
to
proteins
and
DNA.
2­
Chloroethylene
oxide
can
also
be
transformed
to
glycol
aldehyde
11
by
epoxide
hydrolase
or
react
with
glutathione
leading
to
the
formation
N­
acetyl­
S­(
2­
hydroxyethyl)­
12
cysteine.
Chloroacetaldehyde
is
oxidized
by
aldehyde
dehydrogenase
to
2­
chloroacetic
acid
which
reacts
13
with
glutathione
leading
to
the
formation
of
thiodiglycolic
acid
(
which
leads
to
the
liberation
of
carbon
14
dioxide).
Comparison
of
in­
vitro
metabolism
with
rat
liver
microsomes
and
in­
vivo
experiments
in
rats
15
show
that
virtually
all
the
metabolic
activation
of
VC
in
vivo
occurs
in
the
liver
(
WHO,
1999a).
After
low
16
doses
VC
is
metabolically
eliminated
and
non
volatile
metabolites
excreted
mainly
in
the
urine.
At
doses
17
that
saturate
the
metabolism,
the
major
route
of
excretion
is
exhalation
of
unchanged
VC.
Excretion
of
18
metabolites
via
feces
is
only
a
minor
route,
independent
of
applied
dose
(
WHO,
1999a).
19
Buchter
et
al.
(
1980)
exposed
rhesus
monkeys
with
100
­
800
ppm
VC
and
measured
the
time­
20
dependent
disappearance
of
VC
from
the
atmosphere.
The
maximum
metabolic
rate
was
determined
at
45
21
µ
mol/
kg­
hr;
this
turnover
is
obtained
at
400
ppm
VC;
no
attempt
was
made
to
identify
the
metabolites
22
formed.
From
the
decrease
in
atmospheric
VC
concentration
metabolic
clearance
rates
were
calculated
in
23
liter
air/
hour/
kg
body
weight.
Clearance
rates
for
monkeys,
rabbit
and
humans
are
2.0
­
3.55
l/
hr­
kg,
for
24
gerbils
and
rats
11.0
to
12.5,
and
25.6
l/
hr­
kg
for
mice,
indicating
major
species
differences,
which
are
in
25
accordance
with
allometric
scaling.
26
After
oral
ingestion
of
0.05,
1.0
or
100
mg/
kg
body
weight,
male
rats
metabolize
VC
to
the
epoxide
27
which
is
further
metabolized
(
e.
g.
to
thiodiglycolic
acid:
about
25%
of
the
14C
containing
urinary
28
metabolites).
Of
the
total
dose,
9,
13.3
and
2.5%
are
excreted
as
CO2
or
1.4,
2.1
or
66.6%
VC,
respectively
29
at
the
low,
mid
and
high
dose
(
Watanabe
et
al.,
1976b).
At
100
mg/
kg
bw
pulmonary
elimination
showed
a
30
biphasic
clearance
with
an
initial
half
life
of
15
min
and
a
terminal
half
life
of
41
min.
After
0.05
and
1
31
mg/
kg
VC
only
monophasic
pulmonary
clearance
could
be
observed
with
half
life
values
of
53
­
58
min
32
(
Watanabe
et
al.,
1976b).
Initial
urinary
excretion
of
metabolites
followed
first
order­
kinetics
with
half
life
33
values
of
4.5
­
4.6
hours,
followed
by
a
slow
terminal
phase
(
Watanabe
et
al.,
1976b).
Thus,
the
34
equilibrium
concentration
for
metabolites
will
not
be
reached
within
8
hours
or
less.
The
ratio
of
the
35
metabolites
excreted
in
the
urine
does
not
vary
in
dependence
on
dose.
36
Vinyl
chloride
metabolism
is
saturated
at
concentrations
exceeding
380
ppm
in
Rhesus
monkeys
37
(
Buchter
et
al.,
1980)
(
see
table
6).
In
humans,
24
ppm
appears
to
be
below
the
threshold
of
saturation
38
(
Krajewski
et
al.,
1980)
since
no
difference
in
pulmonary
retention
could
be
observed
between
3,
6,
12
and
39
24
ppm
VC.
When
exposing
rats
in
a
closed
system
with
50
­
1,000
ppm
VC
metabolic
clearance
was
40
slowed
at
concentrations
above
220
ppm
as
evidenced
by
longer
half
lives
(
Hefner
et
al.,
1975).
Bolt
et
al.
41
(
1977)
exposed
rats
in
a
similar
system
and
found
metabolic
saturation
to
occur
at
250
ppm
(
see
table
6).
42
These
data
are
in
accordance
with
the
data
from
Watanabe
et
al.
(
1976a):
after
inhalation
of
1,000
ppm
in
43
Vinyl
chloride
PROPOSED
1:
3/
2004
32
rats
metabolism
was
saturated,
whereas
at
100
ppm
VC
saturation
was
not
evident
(
no
intermediate
1
concentration
was
tested).
2
Saturation
of
the
metabolism
has
also
been
observed
after
oral
application:
at
high
doses
(
100
3
mg/
kg)
metabolism
was
saturated
as
is
evident
from
the
increase
in
VC
expiration
from
2.1%
at
1
mg/
kg
to
4
66,6%
at
100
mg/
kg
(
Watanabe
et
al.,
1976b).
5
TABLE
6:
METABOLIC
SATURATION
CONCENTRATIONS
OF
VC
IN
RATS
AND
MONKEYS
6
Rhesus
Monkey
7
about
380
ppm
(
Buchter
et
al.,
1980)

Rat
8
250
ppm
(
Bolt
et
al.,
1977)

VC
metabolites
are
assumed
to
destroy
cytochrome
P450
enzymes
responsible
for
its
epoxidation
9
(
Du
et
al.,
1982;
Pessayre
et
al.,
1979).
On
the
other
hand
activity
of
glutathione­
S­
transferase
and
10
glutathione
reductase
is
elevated
after
VC
exposure
of
rats
(
glutathione
content
is
reduced)
representing
an
11
early
hepatocellular
adaption
to
VC
exposure
(
Du
et
al.,
1982).
12
4.2.
Mechanism
of
Toxicity
13
Acute
neurotoxicity
by
inhalation
of
high
VC
concentrations
is
likely
dependent
upon
VC
14
concentrations
and
independent
of
VC
metabolism.
This
assumption
is
supported
by
comparison
of
narcotic
15
concentrations
which
are
similar
for
the
four
species
guinea
pig,
mouse,
rabbit
and
rat
(
Prodan
et
al.,
1975;
16
Mastromatteo
et
al.,
1960).
Vinyl
chloride
has
been
investigated
as
a
possible
human
anesthetic
(
Oster
et
17
al.,
1947;
Peoples
and
Leake,
1933)
but
was
abandoned
because
of
its
induction
of
cardiac
arrhythmia.
18
Acute
toxicity/
lethality
is
mainly
accompanied
by
congestion
of
all
internal
organs,
pulmonary
19
edema,
liver
and
kidney
changes
(
up
to
necrosis)
(
Prodan
et
al.,
1975).
The
mechanism
of
action
is
not
20
evident,
toxic
effects
are
possible
mediated
by
reactive
metabolites.
21
VC
genotoxicity
and
carcinogenicity
has
been
attributed
to
formation
of
reactive
metabolites,
22
especially
2­
chloroethylene
oxide
and
2­
chloroacetaldehyde
(
see
WHO,
1999a).
2­
Chloroethylene
oxide
23
interacts
directly
with
DNA
and
produces
alkylation
products
(
Fedtke
et
al.,
1990).
This
alkylation
results
24
in
a
highly
efficient
base­
pair
substitution
that
leads
to
neoplastic
transformation
(
ATSDR,
1997).
VC­
25
DNA
ethenobases
are
shown
to
lead
to
miscoding
and
are
found
in
VC­
induced
tumors
in
animals
and
26
humans
(
Barbin,
2000).
Despite
relevant
repair,
no
full
reduction
to
background
was
observed
for
these
27
adducts
two
weeks
after
a
5
day
exposure
(
4
hours/
day)
to
600
ppm
(
Swenberg
et
al.,
1999).
For
vinyl
28
fluoride,
when
all
of
the
data
for
rats
and
mice
on
 G
and
hemangiosarcomas
were
compared
by
regression
29
analysis,
a
high
correlation
was
seen
(
r2=
0.88)
(
Swenberg
et
al.,
1999).
However,
in
case
of
VC
there
is
a
30
close
correlation
in
the
occurrence
of
 A,
 C,
 G
and
there
are
indications
that
also
 A
might
be
related
to
31
tumor
formation
(
Barbin,
1999;
Barbin,
2000).
In
adults,
nonparenchymal
cells
have
a
higher
rate
of
32
proliferation
than
hepatocytes.
Thus,
this
cell
population
is
more
likely
to
convert
promutagenic
DNA
33
adducts
into
mutations
(
Swenberg
et
al.,
1999).
During
rapid
growth
of
the
liver
this
relationship
may
be
34
changed:
Young
animals
demonstrate
a
high
rate
of
etheno­
adducts
in
the
liver
and
a
high
rate
of
35
preneoplastic
foci
of
the
liver.
These
foci
persisted
over
several
month
even
after
short
durations
of
36
exposure
(
Laib
et
al.,
1989).
In
young
animals
a
high
rate
of
hepatoma
and
hepatocellular
carcinoma
have
37
been
found
after
short
term
exposure
to
VC
(
Maltoni
et
al.,
1981;
1984;
Froment
et
al.,
1994).
38
Vinyl
chloride
PROPOSED
1:
3/
2004
33
In
humans
occupationally
exposed
to
VC
 
vinyl
chloride
disease"
(
characterized
by
Raynaud`
s
1
phenomena
and
scleroderma)
is
a
common
finding
after
prolonged
exposure.
No
similar
observations
have
2
been
made
in
experimental
animals
after
single
exposition
experiments.
These
effects
are
probably
due
to
3
immunological
abnormalities
(
caused
by
interaction
of
reactive
VC
metabolites
with
proteins)
as
has
been
4
proposed
by
Grainger
et
al.
(
1980)
and
Ward
et
al.
(
1976),
however,
no
definitive
mechanism
has
been
5
elucidated
to
date.
6
4.3.
Other
Relevant
Information
7
4.3.1
PBPK­
Modeling
8
Physiology­
based
pharmacokinetic
(
PBPK)
models
have
been
proposed
to
predict
VC
metabolism
9
and
cancer
risk
(
Reitz
et
al.,
1996;
Clewell
et
al.,
1995
and
Clewell
et
al.,
2001).
PBPK
models
have
been
10
developed
to
account
for
physiological
differences
among
species
relevant
to
VC
uptake,
distribution,
11
metabolism
and
excretion
and
should
allow
a
better
comparison
across
species.
12
Current
models
use
four
compartments
(
liver,
fat,
slowly
perfused
tissues,
richly
perfused
tissues)
13
and
partition
coefficients
determined
in
vitro.
Metabolism
is
modeled
by
one
(
Reitz
et
al.,
1996)
or
two
14
(
Clewell
et
al.,
1995)
saturable
pathways.
The
model
of
Clewell
et
al.
(
1995,
2001)
uses
one
high
affinity,
15
low
capacity
pathway
likely
pertaining
to
cytochrome
P450
2E1,
and
one
low
affinity,
high
capacity
16
pathway
tentatively
assigned
to
cytochromes
P450
2C11/
6
and
1A1/
2).
Since
VC
readily
reacts
with
17
glutathione
(
GSH)
and
is
known
to
deplete
hepatic
GSH
stores,
description
of
the
GSH
kinetics
was
also
18
included.
19
4.3.2.
Interspecies
Variability
20
A
comparison
of
the
metabolic
activity
across
species
indicates
mice
to
be
the
metabolically
most
21
active
species
with
a
first
order
metabolic
clearance
rate
for
VC
of
25.6
l/
h
per
kg
bw
at
VC
concentrations
22
below
metabolic
saturation
(
Buchter
et
al.,
1980).
Clearance
of
rats,
rhesus
monkey,
rabbits
and
men
is
23
lower
(
11.0,
3.55,
2.74
and
2.02
l/
h
per
kg
bw,
respectively).
Because
the
metabolism
of
VC
is
perfusion­
24
limited
(
Filser
and
Bolt,
1979),
comparison
of
clearance
rates
on
body
weight
basis
is
not
satisfying.
If
25
clearance
is
compared
on
a
body
surface
area
basis
these
mammalian
species
exhibit
similar
clearance
rates
26
(
WHO,
1999a).
27
Comparison
of
lethal
concentrations
(
lethality
occurring
in
the
context
of
narcosis)
in
mice,
rats,
28
rabbits
and
guinea
pigs
point
to
certain
interspecies
variations
with
the
guinea
pig
and
rabbit
being
less
29
sensitive
than
mice
and
rats.
Comparing
the
most
sensitive
species
(
mouse)
with
the
at
least
sensitive
30
species
(
rabbit
and
guinea
pig)
point
to
a
factor
of
2.
31
Vinyl
chloride
PROPOSED
1:
3/
2004
34
LC50
mouse;
exposure
time
2
h:
117,500
ppm
(
Prodan
et
al.,
1975)
1
LC50
rat;
exposure
time
2
h:
150,000
ppm
(
Prodan
et
al.,
1975;
Lester
et
al.,
1963)
2
LC50
rabbit;
exposure
time
2
h:
240,000
ppm
(
Prodan
et
al.,
1975)
3
LC50
guinea
pig;
exposure
time
2
h:
240,000
ppm
(
Prodan
et
al.,
1975)
4
Concerning
non
lethal,
pre­
narcotic
effects
marginal
interspecies
differences
are
observed
5
indicating
that
rats
and
mice
are
a
little
bit
more
sensitive
than
guinea
pigs:
e.
g.
thirty
minutes
exposure
of
6
guinea
pigs,
rats
and
mice
to
100,000
ppm
VC
resulted
in
the
same
symptoms:
unconsciousness
(
in
all
rats
7
and
mice
but
only
in
one
of
five
guinea
pigs)
and
a
lung
hyperaemia
persisting
for
more
than
2
weeks,
rats
8
and
mice
fell
aside
after
20
min
exposure
and
guinea
pigs
showed
side
position
after
30
min
exposure
9
(
Mastromatteo
et
al.,
1960).
No
comparable
data
on
humans
are
available.
Concerning
hepatic
effects
mice
10
seem
to
be
more
sensitive
than
rats
and
rabbits:
Exposure
of
mice
to
1,500
ppm
VC
for
2
h
caused
severe
11
liver
effects,
resulting
in
shock
liver
and
death
of
the
mice.
But
no
hepatic
and
lethal
effects
were
observed
12
in
rats
and
rabbits
treated
identically
for
24
h
(
Tátrai
and
Ungvary,
1981).
The
reasons
for
these
13
interspecies
differences
are
not
known.
Data
on
acute
hepatic
effects
of
VC
in
humans
are
not
available.
14
Concerning
the
similar
clearance
rates
of
VC
on
a
body
surface
area
there
does
not
seem
to
be
a
15
large
toxicokinetic
difference
between
various
species.
Due
to
these
findings
we
suggest
to
use
a
reduced
16
interspecies
factor
of
3,
accounting
for
toxicodynamic
differences,
in
cases
where
the
toxicity
of
VC
is
17
mediated
by
VC
metabolites.
18
With
respect
to
lethality
and
VC
induced
(
pre­)
narcotic
symptoms
there
seem
to
be
only
minimal
19
interspecies
differences.
Use
of
a
reduced
extrapolation
factor
of
3
is
recommended
in
this
context.
20
4.3.3.
Intraspecies
Variability
21
Cytochrome
P450
isoenzyme
2E1
is
the
key
enzyme
converting
VC
to
2­
chloroethylene
oxide.
22
CYP2E1
activity
in
human
liver
microsomes
may
vary
up
to
12­
fold
between
individuals
(
substrate:
p­
23
nitrophenol;
Seaton
et
al.,
1994).
These
data
indicate
a
potential
interindividual
variability
in
VC
24
metabolism.
25
Investigation
of
VC
retention
in
the
lung
of
human
volunteers
revealed
large
interindividual
26
differences
in
VC
retention
(
minimum
20.2%
of
the
exposure
concentration;
maximum
79%
of
the
27
exposure
concentration;
Krajewski
et
al.,
1980).
28
Interindividual
differences
in
the
response
of
human
subjects
to
varying
concentrations
of
VC
were
29
observed
by
Lester
et
al.
(
1963):
8,000
ppm
VC
did
not
cause
any
response
in
5
individuals,
but
one
person
30
felt
 
slightly
heady".
Other
subjects
complained
about
adverse
health
effects
at
concentrations
of

12,000
31
ppm,
indicating
that
there
are
only
small
interindividual
differences
in
the
response
to
neurotoxic
effects
of
32
VC.
33
Relevant
interindividual
differences
were
not
described
in
animal
experiments.
34
Due
to
these
observations
a
factor
of
3
is
used
for
the
characterization
of
intraspecies
variabilities
35
in
the
context
with
neurotoxic
effects
or
cardiac
sensitization.
A
factor
of
10
is
used
to
describe
intraspecies
36
differences
which
are
mediated
by
metabolites
of
VC.
37
Vinyl
chloride
PROPOSED
1:
3/
2004
35
4.3.4.
Concurrent
Exposure
Issues
1
Concurrent
administration
of
ethanol
and
VC
leads
to
an
increase
of
liver
angiosarcoma
in
rats
in
2
comparison
to
animals
exposed
only
to
VC.
This
effect
may
be
due
to
the
interaction
of
ethanol
(
a
known
3
CYP2E1
inducer)
with
VC
metabolism
(
WHO,
1999a).
4
Induction
of
certain
enzymes
of
the
mixed­
function
oxidase
system
by
pretreatment
with
5
phenobarbital
or
the
mixture
of
polychlorinated
biphenyls
enhanced
acute
hepatotoxicity
in
rats
as
6
measured
by
increased
activity
of
hepatic
enzymes
and
/
or
focal
hepatic
necrosis.
On
the
other
hand,
7
inhibitors
of
the
mixed­
function
oxidase
system
like
SKF­
525A
have
an
opposite
effect
(
WHO,
1999a).
8
5.
RATIONALE
AND
PROPOSED
AEGL­
1
9
5.1.
Human
Data
Relevant
to
AEGL­
1
10
Detection
of
261
ppm
VC
by
entering
the
exposure
chamber
was
reported
by
Baretta
et
al.
(
1969).
11
The
authors
also
described
that
5
of
7
persons
detected
the
odor
of
VC
entering
a
chamber
with
491
ppm
12
VC,
but
after
5
minutes
of
exposure
detection
was
not
any
longer
possible.
13
Amoore
and
Hautala
(
1983)
reported
an
odor
threshold
of
3,000
ppm
for
VC.
This
value
14
represents
the
geometric
average
of
three
studies,
extreme
points
and
duplicate
quotations
were
omitted.
It
15
was
not
stated
whether
it
is
the
detection
or
recognition
threshold.
16
A
"
fairly
pleasant
odor"
was
reported
by
two
persons
exposed
to
25,000
ppm
for
3
minutes.
At
17
these
concentrations
dizziness
and
slight
disorientation
occurred
(
Patty
et
al.,
1930).
18
Hori
et
al.
(
1972)
reported
an
odor
threshold
for
VC
of
10
­
20
ppm
(
20
ppm
in
production
19
workers
and
10
ppm
in
workers
from
other
sites).
This
value
was
reviewed
by
the
AIHA
and
the
value
has
20
been
rejected
because
of
several
shortcomings
of
the
experimental
procedure
(
e.
g.
no
calibration
of
panel
21
odor
sensitivity,
not
stated
whether
the
given
limit
was
due
to
recognition
or
detection,
number
of
trials
not
22
stated).
23
Irritating
effects
of
VC
are
only
observed
at
very
high
concentrations:
accidental
exposure
to
lethal
24
concentrations
was
accompanied
by
lesions
of
the
eyes
(
Danziger,
1960).
25
Baretta
et
al.
(
1969)
exposed
4
­
6
volunteers
to
59,
261,
491
ppm
VC
(
analytical
concentrations)
26
for
7.5
h
(
including
a
0.5
h
lunch
period;
corresponding
to
time
weighted
average
concentrations
of
48,
248
27
or
459
ppm
over
a
period
of
7.5
h),
seven
persons
were
exposed
to
491
ppm
for
only
3.5
hours.
The
only
28
complaints
were
those
of
two
subjects
who
reported
mild
headache
and
some
dryness
of
their
eyes
and
nose
29
during
exposure
to
the
highest
concentration
(
the
time
of
onset
of
headaches
is
not
specified
and
is
assumed
30
to
have
occurred
after
3.5
hours
of
exposure).
31
5.2.
Animal
Data
Relevant
to
AEGL­
1
32
Lacrimation
occurred
shortly
after
onset
of
exposure
in
animals
exposed
to
VC
(
exposure
of
mice,
33
rats,
guinea
pigs,
and
rabbits
to
concentrations
between
42,900
ppm
to
280,000
ppm,
no
differentiated
34
evaluation
according
to
lacrimation).
Lethal
effects
have
been
observed
in
mice
and
rats
even
in
the
lowest
35
Vinyl
chloride
PROPOSED
1:
3/
2004
36
exposure
concentrations
(
42,900
ppm
without
ventilation
in
mice
and
150,000
ppm
with
ventilation
in
rats)
1
(
Prodan
et
al.,
1975).
Mastromatteo
et
al.
(
1960)
described
that
irritation
(
no
further
details)
was
occurring
2
immediately
after
onset
of
exposure
to
100,000,
200,000
or
300,000
ppm
VC
in
rats
and
mice;
in
guinea
3
pigs
irritation
was
not
described
in
concentrations
below
400,000
ppm
VC.
However,
100,000
ppm
VC
4
already
resulted
in
unconsciousness
of
the
animals.
No
other
data
on
irritation
of
VC
in
animals
are
5
available
from
literature.
6
5.3.
Derivation
of
AEGL­
1
7
Vinyl
chloride
is
a
compound
with
poor
odor
warning
properties.
Reports
on
odor
threshold
vary
8
over
a
wide
range
(
10
to
25,000
ppm).
There
is
no
qualified
study
determining
the
detection
or
recognition
9
threshold.
According
to
the
report
of
Baretta
et
al.
(
1969)
people
seem
to
get
used
to
the
odor
of
VC.
In
10
humans
and
animals
irritation
is
only
reported
in
the
context
of
exposure
to
very
high
concentrations
which
11
are
lethal
or
cause
unconsciousness.
So,
derivation
of
AEGL­
1
values
on
base
of
the
odor
detection
or
12
irritation
is
not
possible.
13
Occurrence
of
headache
has
been
reported
by
Baretta
et
al.
(
1969)
in
two
subjects
after
acute
14
exposure
(
the
time
of
onset
of
headaches
is
not
specified
and
is
assumed
to
have
occurred
after
3.5
hours
of
15
exposure)
.
These
findings
are
supported
by
data
from
occupationally
exposed
persons
who
developed
16
headache
after
VC
exposure
(
Lilis
et
al.,
1975;
Suciu
et
al.,
1975).
The
endpoint
"
mild
headache"
in
the
17
study
from
Baretta
et
al.
(
1969)
can
be
regarded
as
a
no
effect
level
for
notable
discomfort
(
491
ppm
for
18
3.5
h).
An
intraspecies
factor
of
3
is
employed:
it
is
assumed
that
the
effects
are
due
to
VC
itself
and
not
19
due
to
a
metabolite,
so
only
small
interindividual
differences
are
expected.
The
relationship
between
20
concentration
and
duration
of
exposure
as
related
to
lethality
was
examined
by
Ten
Berge
et
al.
(
1986)
for
21
approximately
20
irritant
or
systemically­
acting
vapors
and
gases.
The
authors
subjected
the
individual
22
animal
data
sets
to
Probit
analysis
with
exposure
duration
and
exposure
concentration
as
independent
23
variables.
An
exponential
function
(
Cn
x
t
=
k),
where
the
value
of
n
ranged
from
0.8
to
3.5
for
different
24
chemicals
was
found
to
be
an
accurate
quantitative
descriptor
for
the
chemicals
evaluated.
Approximately
25
90
percent
of
the
values
of
n
range
between
n=
1
and
n=
3.
Consequently,
these
values
were
selected
as
the
26
reasonable
lower
and
upper
bounds
of
n
to
use
when
data
are
not
available
to
derive
a
value
of
n.
A
value
27
of
n=
1
is
used
when
extrapolating
from
shorter
to
longer
time
periods
because
the
extrapolated
values
are
28
conservative
and
therefore,
reasonable
in
the
absence
of
any
data
to
the
contrary.
Conversely,
a
value
of
29
n=
3
is
used
when
extrapolating
from
longer
to
shorter
time
periods
because
the
extrapolated
values
are
30
conservative
and
therefore
reasonable
in
the
absence
of
any
data
to
the
contrary.
The
default
values
for
"
n"
31
are
used,
as
the
mechanism
for
the
induction
of
headache
is
not
well
understood.
The
extrapolation
to
10
32
minutes
from
a
3.5
hour
exposure
is
justified
because
exposure
of
human
at
4,000
ppm
for
5
minutes
did
33
not
result
in
headache
(
Lester
et
al.,
1963).
34
TABLE
7:
AEGL­
1
VALUES
FOR
VINYL
CHLORIDE
35
AEGL
Level
36
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
AEGL­
1
37
450
ppm
1200
mg/
m3
310
ppm
800
mg/
m3
250
ppm
650
mg/
m3
140
ppm
360
mg/
m3
70
ppm
180
mg/
m3
6.
RATIONALE
AND
PROPOSED
AEGL­
2
38
6.1.
Human
Data
Relevant
to
AEGL­
2
39
Vinyl
chloride
PROPOSED
1:
3/
2004
37
Lester
et
al.
(
1963)
reported
that
5
min
exposure
to
8,000
ppm
caused
dizziness
in
1/
6
subjects
(
the
1
same
subject
reported
slight
dizziness
at
sham
exposure
and
no
effect
at
12,000
ppm).
No
complaints
were
2
made
by
any
volunteer
at
4,000
ppm.
At
12,000
ppm
one
subject
reported
clear
signs
of
discomfort
3
(
reeling,
swimming
head)
and
another
subject
another
was
unsure
of
some
effect;
he
had
a
"
somewhat
4
dizzy"
feeling
in
the
middle
of
exposure.
At
16,000
ppm
(
5/
6)
and
20,000
ppm
(
6/
6)
persons
complained
5
about
dizziness,
nausea,
headache,
dulling
of
visual
and
auditory
cues.
All
symptoms
disappeared
shortly
6
after
termination;
headache
persisted
for
30
minutes
in
one
subject
after
exposure
to
20,000
ppm.
7
Three
minutes
exposure
to
25,000
ppm
resulted
in
dizziness
and
slight
disorientation
as
to
space
8
and
size
of
surrounding
objects
and
a
burning
sensation
in
the
feet
in
two
persons.
They
immediately
9
recovered
on
leaving
the
chamber
and
complained
only
of
a
slight
headache
which
persisted
for
30
minutes
10
(
Patty
et
al.,
1930).
11
Baretta
et
al.
(
1969)
exposed
4
­
6
volunteers
to
59,
261,
491
ppm
VC
(
analytical
concentrations)
12
for
7.5
h
(
including
a
0.5
h
lunch
period;
corresponding
to
time
weighted
average
concentrations
of
48,
248
13
or
459
ppm
over
a
period
of
7.5
h),
seven
persons
were
exposed
to
491
ppm
for
only
3.5
hours.
The
only
14
complaints
were
those
of
two
subjects
who
reported
mild
headache
and
some
dryness
of
their
eyes
and
nose
15
during
exposure
to
the
highest
concentration
(
the
time
of
onset
of
headaches
is
not
specified
and
is
assumed
16
to
have
occurred
after
3.5
hours
of
exposure)
.
17
6.2.
Animal
Data
Relevant
to
AEGL­
2
18
Animal
toxicity
after
short
term
exposure
is
characterized
by
cardiac
sensitization,
(
pre­)
narcotic
19
and
hepatic
effects.
Short
term
exposure
(
5
min)
of
dogs
to
VC
induced
cardiac
sensitization
towards
20
epinephrine
(
EC50:
50,000
or
71,000
ppm
in
two
independent
experiments)
(
Clark
and
Tinston,
1973;
21
1982).
This
observation
is
confirmed
in
higher
concentrations
by
additional
experimental
data
).
22
Hehir
et
al.
(
1981)
reported
that
single
exposure
of
mice
to
50,000
ppm
VC
caused
twitching,
23
ataxia,
hyperventilation
and
hyperactivity,
beginning
40
min
after
start
of
exposure.
Consistent
with
these
24
data
Mastromatteo
et
al.
(
1960)
reported
that
100,000
ppm
VC
induced
pronounced
tremor,
unsteady
gait
25
and
muscular
incoordination
in
mice
15
min
after
onset
of
exposure.
Exposure
of
mice
to
1,500
ppm
VC
26
for
2
h
resulted
in
stasis
of
blood
flow,
decreasing
enzyme
activities
in
the
liver,
subcellular
liver
damage,
27
and
shock
liver
after
24
h
of
exposure
(
Tátrai
and
Ungváry,
1981).
28
Viola
et
al.
(
1970)
reported
that
rats
exposed
to
30,000
ppm
for
4
h/
d
were
slightly
soporific
(
no
29
further
details).
At
higher
concentrations
(
50,000
ppm
for
2
h)
moderate
intoxication
and
loss
of
righting
30
reflex
and
intense
intoxication
at
60,000
ppm
for
2
h
(
but
righting
reflex
still
present)
have
been
reported
31
by
Lester
et
al.
(
1963).
Intoxication
was
not
further
characterized.
Higher
VC
concentrations
(
100,000
32
ppm)
resulted
in
a
loss
of
the
corneal
reflex
(
exposure
for
2
h)
(
Lester
et
al.,
1963).
Already
15
min
after
33
onset
of
exposure
to
100,000
ppm
tremor
and
ataxia
were
observed
by
Mastromatteo
et
al.
(
1960).
Guinea
34
pigs
exposed
to
25,000
ppm
for
5
min
showed
motor
ataxia,
unsteadiness
on
feet,
after
90
min
the
animals
35
were
unconscious
(
NOAEL
10,000
ppm)
(
Patty
et
al.,
1930).
Mastromatteo
et
al.
(
1960)
reported
the
36
unsteady
gait
and
muscular
incoordination
in
guinea
pigs
exposed
for
15
min
to
100,000
ppm.
37
Vinyl
chloride
PROPOSED
1:
3/
2004
38
Single
inhalation
exposure
of
rats
for
6
hours
to
100,000
ppm
VC
resulted
in
histopathological
1
changes
of
the
liver
(
vacuolization),
but
was
not
observed
in
lower
concentrations
(
50,000
ppm)
(
Jaeger
et
2
al.,
1974).
However,
in
mice
Tátrai
and
Ungváry
(
1981)
reported
that
stasis
of
the
liver
developed
2
and
4
3
h
after
the
beginning
of
inhalation.
The
authors
observed
decreasing
enzyme
activities
in
liver
and
4
subcellular
liver
damage
at
exposure
concentrations
of
1,500
ppm
VC
for
2
h;
after
24
h
shock
liver
5
developed.
Repeated
exposure
of
rats
to
1,500
ppm
VC
for
up
to
9
days
during
pregnancy
caused
increased
6
relative
and
absolute
liver
weights
without
light
microscopic
visible
changes.
Also,
no
histopathological
7
effects
were
observed
in
rabbits
treated
identically
(
Ungváry
et
al.,
1978).
In
another
developmental
study
8
increased
absolute
and
relative
liver
weights
have
been
observed
in
rats
exposed
intermittently
to
2,500
9
ppm
from
day
6
­
15
of
pregnancy,
the
NOAEL
was
500
ppm
(
John
et
al.,
1977;
1981).
10
11
6.3.
Derivation
of
AEGL­
2
12
Short
term
exposure
(
5
min)
of
dogs
to
VC
induced
cardiac
sensitization
towards
epinephrine
13
(
EC50:
50,000
or
71,000
ppm
in
two
independent
experiments)
(
Clark
and
Tinston,
1973;
1982).
A
14
NOAEL
for
this
effect
can
be
reasonably
estimated
by
using
a
factor
of
3
on
EC50
(
50,000
ppm)
resulting
15
in
a
concentration
of
about
17,000
ppm.
This
concentration
already
leads
to
CNS­
effects
in
humans
after
5
16
minutes
exposure
(
Lester
et
al.,
1963).
Thus,
the
endpoint
of
cardiac
sensitization
would
not
be
the
critical
17
effect
for
AEGL­
2
derivation.
However,
the
AEGL­
2
derived
below
is
supported
by
the
data
on
cardiac
18
sensitization.
19
Liver
toxicity
is
a
major
endpoint
after
long
term
exposure
to
VC
and
may
possibly
be
linked
to
20
tumor
development
in
young
animals
(
see
section
4.2.
for
further
discussion).
The
NOAEL
for
irreversible
21
effects
to
the
liver
after
single
exposure
is
50,000
ppm
(
6h,
rat
data).
The
effects
seen
in
lower
22
concentrations
(
liver
weight
changes)
may
not
be
regarded
as
key
studies
for
AEGL­
2
derivation.
23
Narcotic
effects
seem
to
predominate
in
rats,
mice
and
guinea
pigs
acutely
exposed
to
high
24
concentrations
of
VC.
These
effects
are
relevant
AEGL­
2
endpoints
as
they
impair
the
possibility
to
escape.
25
Although
guinea
pigs
seem
to
be
less
sensitive
than
rats
and
mice
concerning
lethality
(
see
7.2)
they
are
26
more
sensitive
than
rats
and
mice
with
regard
to
early
signs
of
narcotic
effects:
exposure
of
guinea
pigs
for
27
5
min
to
25,000
ppm
resulted
in
early
signs
of
narcotic
effects
(
motor
ataxia,
unsteadiness
on
feet),
after
90
28
minutes
animals
were
unconscious
(
NOAEL
10,000
ppm)
(
Patty
et
al.,
1930).
Rats
exposed
to
30,000
ppm
29
VC
for
4
h
were
only
slightly
soporific
(
Viola
et
al.,
1970),
and
single
exposure
of
mice
to
50,000
ppm
VC
30
caused
twitching,
ataxia,
hyperventilation
and
hyperactivity,
beginning
40
min
after
start
of
exposure
31
(
Hehir
et
al.,
1981)
.
32
The
observations
in
animals
are
in
good
accordance
with
the
effects
observed
in
humans:
dizziness,
33
reeling,
swimming
head,
nausea
etc.,
which
can
be
regarded
as
early
signs
of
narcosis,
have
been
reported
34
in
humans
exposed
to
VC
in
concentrations

12,000
ppm
for
5
min.
No
effects
were
reported
at
4,000
ppm
35
(
Lester
et
al.,
1963).
The
effects
observed
at
12,000
ppm
(
dizziness,
reeling,
swimming
head)
were
only
36
seen
in
1
or
2
of
6
persons
(
one
person
was
unsure
of
an
effect)
and
do
not
yet
impair
the
capability
to
37
escape,
whereas,
the
effects
observed
at
concentrations

16,000
ppm
(
dizziness,
nausea,
headache,
dulling
38
of
visual
and
auditory
cues)
might
possibly
impair
escape.
Therefore,
12,000
ppm
is
interpreted
as
the
no
39
effect
level
for
impaired
ability
to
escape
and
is
used
to
derived
the
AEGL­
2
values.
40
Vinyl
chloride
PROPOSED
1:
3/
2004
39
By
analogy
to
other
anaesthetics
the
effects
are
assumed
to
be
solely
concentration
dependent.
1
Thus,
after
reaching
steady
state
at
about
2
hours
of
exposure,
no
increase
in
effect
is
expected.
The
other
2
exposure
duration­
specific
values
were
derived
by
time
scaling
according
to
the
dose­
response
regression
3
equation
Cn
x
t
=
k,
using
a
factor
of
n=
2,
based
on
data
from
Mastromatteo
et
al.
(
1960).
Mastromatteo
et
4
al.
observed
various
time­
dependent
prenarcotic
effects
in
mice
and
guinea
pigs
after
less
than
steady
state
5
exposure
conditions
(
For
details
see
Appendix
B).
With
this,
time
extrapolation
was
performed
from
5
to
6
10,
30,
60
minutes
and
2
hours,
where
the
steady
state
concentration
was
calculated.
However,
the
resulting
7
AEGL­
2
values
may
not
provide
a
sufficient
margin
safety
to
avoid
mutational
events
or
malignancies
after
8
short­
term
exposure
to
VC.
9
The
calculations
of
exposure
concentrations
scaled
to
AEGL­
2
time
points
are
shown
in
Appendix
10
A.
The
data
are
listed
in
the
table
below.
11
TABLE
8:
AEGL­
2
VALUES
FOR
VINYL
CHLORIDE
12
AEGL
Level
13
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
AEGL­
2
14
2,800
ppm
(
7300
mg/
m
³
)
1,600
ppm
(
4100
mg/
m
³
)
1,200
ppm
(
3100
mg/
m
³
)
820
ppm
(
2100
mg/
m
³
)
820
ppm
(
2100
mg/
m
³
)

7.
RATIONALE
AND
PROPOSED
AEGL­
3
15
7.1.
Human
Data
Relevant
to
AEGL­
3
16
Only
two
cases
of
accidental
death
due
to
VC
exposure
are
described
in
literature.
Exposure
17
concentrations
and
exposure
time
are
unknown,
but
circumstances
suggest
inhalation
of
very
high
18
concentrations.
At
autopsy
cyanosis,
congestion
of
lung
and
kidneys
and
blood
coagulation
failure
were
19
observed
(
Danziger,
1960).
20
7.2.
Animal
Data
Relevant
to
AEGL­
3
21
LC50
values
reported
for
mice,
rats,
rabbits
and
guinea
pigs
indicate
similar
sensitivity
of
mice
and
22
rats
and
of
rabbits
and
guinea
pigs.
According
to
the
data
presented
by
Prodan
et
al.
(
1975)
the
following
23
LC50
values
were
obtained:
24
mice
117,500
ppm
25
rats
150,000
ppm
26
rabbits
240,000
ppm
27
guinea
pigs
240,000
ppm
28
The
findings
in
rats
are
supported
by
the
data
of
Lester
et
al.
(
1963)
who
described
that
exposure
29
of
2
rats
to
150,000
ppm
for
2
hours
resulted
in
the
death
of
one
rat
whereas
the
other
rat
recovered
on
30
removal
to
air.
31
The
following
LC00
values
have
been
reported
for
these
species.
32
Vinyl
chloride
PROPOSED
1:
3/
2004
40
mice
100,000
ppm
(
2
h,
Prodan
et
al.,
1975)
1
rats
100,000
ppm
(
8
h,
Lester
et
al.,
1963)
2
200,000
ppm
(
0,5
h,
Mastromatteo
et
al.,
1960)
3
rabbits
200,000
ppm
(
2
h,
Prodan
et
al.,
1975)
4
guinea
pigs
100,000
ppm
(
6
h,
Patty
et
al.,
1930)
5
200,000
ppm
(
2
h,
Prodan
et
al.,
1975)
6
In
addition,
relevant
data
on
cardiac
sensitization
exist:
Short
term
exposure
(
5
min)
of
dogs
to
VC
7
induced
cardiac
sensitization
towards
epinephrine
(
EC50:
50,000
or
71,000
ppm
in
two
independent
8
experiments)
(
Clark
and
Tinston,
1973;
1982).
These
effects
were
also
seen
in
mice
at
higher
9
concentrations
(
Aviado
and
Belej,
1974).
In
monkeys,
only
myocardial
depression
after
inhalation
of
2.5­
10
10%
VC
was
observed.
It
is
not
clearly
stated
whether
an
addition
challenge
with
epinephrine
was
applied
11
or
not
(
Belej
et
al.,
1974).
12
7.3.
Derivation
of
AEGL­
3
13
Lethality
data
provide
AEGL­
3
values
that
are
marginally
higher
than
those
derived
based
on
14
cardiac
sensitization.
Thus,
animal
data
(
Clark
and
Tinston,
1973;
1982)
on
cardiac
sensitization
after
15
exposure
for
5
minutes
were
used
to
derive
AEGL­
3.
Severe
cardiac
sensitization
is
a
life
threatening
16
effect,
but
at
50,000
ppm
no
animal
died
in
the
reported
study
and
is
used
to
derive
AEGL­
3
values.
A
total
17
uncertainty
factor
of
3
is
used
to
account
for
toxicodynamic
differences
among
individuals.
As
the
18
challenge
with
epinephrine
and
the
doses
of
epinephrine
used
represent
a
conservative
scenario,
no
19
interspecies
uncertainty
factor
was
used.
As
the
unmetabolized
VC
is
responsible
for
the
effect,
no
relevant
20
differences
in
toxicokinetics
are
assumed.
In
analogy
to
other
halocarbons
(
e.
g.,
Halon
1211,
HFC
134a)
21
which
lead
to
cardiac
sensitization
the
effects
are
assumed
to
be
solely
concentration
dependent.
Thus,
after
22
reaching
steady
state
at
about
2
hours
of
exposure,
no
increase
in
effect
is
expected.
The
other
exposure
23
duration­
specific
values
were
derived
by
time
scaling
according
to
the
dose­
response
regression
equation
Cn
24
x
t
=
k,
using
an
n
of
2,
based
on
data
from
Mastromatteo
et
al.
(
1960).
Mastromatteo
et
al.
observed
25
various
time­
dependent
prenarcotic
effects
(
muscular
incoordination,
side
position
and
unconsciousness,
26
effects
which
occur
immediately
before
lethality)
in
mice
and
guinea
pigs
after
less
than
steady
state
27
exposure
conditions.
With
this,
time
extrapolation
was
performed
from
5
to
10,
30,
60
minutes
and
2
hours,
28
where
the
steady
state
concentration
was
calculated.
29
The
values
are
listed
in
the
table
below.
30
TABLE
9:
AEGL­
3
VALUES
FOR
VINYL
CHLORIDE
31
AEGL
Level
32
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
AEGL­
3
33
12,000
ppm
(
31,000
mg/
m
³
)
6,800
ppm
(
18,000
mg/
m
³
)
4,800
ppm
(
12,000
mg/
m
³
)
3,400
ppm
(
8,800
mg/
m
³
)
3,400
ppm
(
8,800
mg/
m
³
)

8.
SUMMARY
OF
PROPOSED
AEGLs
34
8.1.
AEGL
Values
and
Toxicity
Endpoints
35
Vinyl
chloride
PROPOSED
1:
3/
2004
41
The
derived
AEGL
values
for
various
levels
of
effects
and
durations
of
exposure
are
summarized
1
in
Table
10.
AEGL­
1
values
have
been
derived
based
on
mild
headaches
observed
in
volunteers
(
Baretta
et
2
al.,
1969);
odor
threshold
was
not
determined
in
a
validated
manner
and
seems
to
vary
over
a
wide
range.
3
AEGL­
2
values
are
based
on
CNS­
effects,
which
may
impair
escape
capacity
(
Lester
et
al.,
1963).
Data
on
4
cardiac
sensitization
(
Clark
and
Tinston,
1982;
1973)
are
supported
by
lethality
concentrations
(
LC00)
in
5
slightly
higher
concentrations
(
Prodan
et
al.,
1975)
and
are
used
for
AEGL­
3
derivation.
6
7
TABLE
10:
SUMMARY/
RELATIONSHIP
OF
PROPOSED
AEGL
VALUES
8
Classification
9
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
AEGL­
1
10
(
Non­
disabling)
11
450
ppm
1200
mg/
m3
310
ppm
800
mg/
m3
250
ppm
650
mg/
m3
140
ppm
360
mg/
m3
70
ppm
180
mg/
m3
AEGL­
2
12
(
Disabling)
13
2,800
ppm
7,300
mg/
m3
1,600
ppm
4,100
mg/
m3
1,200
ppm
3,100
mg/
m3
820
ppm
2,100
mg/
m3
820
ppm
2,100
mg/
m3
AEGL­
3
14
(
Lethal)
15
12,000
ppm
(
31,000
mg/
m3)
6,800
ppm
(
18,000
mg/
m3)
4,800
ppm
(
12,000
mg/
m3)
3,400
ppm
(
8,800
mg/
m3)
3,400
ppm
(
8,800
mg/
m3)

Inhalation
data
are
summarized
in
Figure
1
below.
The
data
were
classified
into
severity
categories
16
chosen
to
fit
into
definitions
of
the
AEGL
level
health
effects.
The
category
severity
definitions
are
"
No
17
effect";
"
Disabling";
"
Lethal"
and
"
AEGL".
18
Vinyl
chloride
PROPOSED
1:
3/
2004
42
10
100
1000
10000
100000
1000000
ppm
0
60
120
180
240
300
360
420
480
Minutes
Human
­
No
Effect
Human
­
Discomfort
Human
­
Disabling
Animal
­
No
Effect
Animal
­
Discomfort
Animal
­
Disabling
Animal
­
Partially
Lethal
Animal
­
Lethal
AEGL
Chemical
Toxicity
­
TSD
All
Data
Vinyl
chloride
AEGL­
3
AEGL­
1
AEGL­
2
FIGURE
1:
CATEGORICAL
REPRESENTATION
OF
VINYL
CHLORIDE
INHALATION
1
DATA
(
data
where
the
exposure
time
exceeded
500
min
are
not
included)
2
8.2.
Comparison
with
Other
Standards
and
Criteria
3
Other
standards
and
guidance
levels
for
workplace
and
community
exposures
are
listed
in
Table
4
11.
5
Vinyl
chloride
PROPOSED
1:
3/
2004
43
TABLE
11:
EXISTENT
STANDARDS
AND
GUIDELINES
FOR
VINYL
CHLORIDE
1
Guideline
2
Exposure
Duration
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
AEGL­
1
3
310
ppm
310
ppm
250
ppm
140
ppm
70
ppm
AEGL­
2
4
2,800
ppm
1,600
ppm
1,200
ppm
820
ppm
820
ppm
AEGL­
3
5
12,000
ppm
6,800
ppm
4,800
ppm
3,400
ppm
3,400
ppm
PEL­
TWA
(
OSHA)
a
6
1
ppm
STEL
(
OSHA)
b
7
5
ppm
[
for
15
min]

TLV­
TWA
8
(
ACGIH)
c
9
5
ppm
TEEL­
0
(
CSP)
d
10
1
ppm
TEEL­
1
(
CSP)
e
11
5
ppm
TEEL­
2
(
CSP)
f
12
5
ppm
TEEL­
3
(
CSP)
g
13
75
ppm
TRK
(
Germany)
h
14
2
(
3)
ppm
Einsatztoleranzwerte
(
Greim,
15
Germany)
i
16
100
ppm
Störfallbeurtei­
lungswert
(
VCI)
j
17
1,000
ppm
a
OSHA
PEL­
TWA
(
Occupational
Health
and
Safety
Administration,
Permissible
Exposure
Limits
­
Time
18
Weighted
Average)
(
OSHA,
2002)
is
the
time­
weighted
average
concentration
for
a
normal
8­
hour
19
workday
and
a
40­
hour
work
week,
to
which
nearly
all
workers
may
be
repeatedly
exposed,
day
after
day,
20
without
adverse
effect.
21
b
OSHA
PEL­
STEL
(
Permissible
Exposure
Limits
­
Short
Term
Exposure
Limit)
(
OSHA,
2002)
is
defined
as
a
22
15
minute
TWA
exposure
which
should
not
be
exceeded
at
any
time
during
the
workday
even
if
the
8­
23
hour
TWA
is
within
the
PEL­
TWA.
Exposures
above
the
PEL­
TWA
up
to
the
STEL
should
not
be
longer
24
than
15
minutes
and
should
not
occur
more
than
4
times
per
day.
There
should
be
at
least
60
minutes
25
between
successive
exposures
in
this
range.
26
C
ACGIH
TLV­
TWA
(
American
Conference
of
Governmental
Industrial
Hygienists,
Threshold
Limit
Value
27
­
Time
Weighted
Average)
(
ACGIH,
1998).
The
time­
weighted
average
concentration
for
a
normal
8­
28
hour
workday
and
a
40­
hour
work
week,
to
which
nearly
all
workers
may
be
repeatedly
exposed,
day
after
29
day,
without
adverse
effect.
The
value
was
based
on
a
calculation
of
the
carcinogenic
potency
of
vinyl
30
chloride
by
Gehring
and
coworkers.
The
TLV­
Committee
concluded
that
a
TLV­
TWA
of
5
ppm
should
31
not
result
in
a
detectable
increase
in
the
incidence
of
occupational
cancers,
specifically
angiosarcoma
of
32
the
liver.
33
Vinyl
chloride
PROPOSED
1:
3/
2004
44
d
TEEL­
0
(
U.
S.
department
of
Energy`
s
Chemical
safety
Program,
Temporary
Emergency
Exposure
Limit)
1
(
CSP,
2002).
The
threshold
concentration
below
which
most
people
will
experience
no
appreciable
risk
of
2
health
effects.
3
e
TEEL­
1
(
U.
S.
department
of
Energy`
s
Chemical
safety
Program,
Temporary
Emergency
Exposure
Limit)
4
(
CSP,
2002).
The
maximum
concentration
in
air
below
which
it
is
believed
nearly
all
individuals
could
be
5
exposed
without
experiencing
other
than
mild
transient
adverse
health
effects
or
perceiving
a
clearly
6
defined
objectionable
odor.
7
f
TEEL­
2
(
U.
S.
department
of
Energy`
s
Chemical
safety
Program,
Temporary
Emergency
Exposure
Limit)
8
(
CSP,
2002).
The
maximum
concentration
in
air
below
which
it
is
believed
nearly
all
individuals
could
be
9
exposed
without
experiencing
or
developing
irreversible
or
other
serious
health
effects
or
symptoms
that
10
could
impair
their
abilities
to
take
protective
action.
11
g
TEEL­
3
(
U.
S.
department
of
Energy`
s
Chemical
safety
Program,
Temporary
Emergency
Exposure
Limit)
12
(
CSP,
2002).
The
maximum
concentration
in
air
below
which
it
is
believed
nearly
all
individuals
could
be
13
exposed
without
experiencing
or
developing
life­
threatening
health
effects.
14
h
TRK
(
Technische
Richtkonzentrationen
[
Technical
Guidance
Concentration],
Deutsche
15
Forschungsgemeinschaft
[
German
Research
Association],
Germany)
(
DFG,
2001).
TRK
is
defined
as
16
the
air
concentration
of
a
substance
which
can
be
achieved
with
the
current
technical
standards.
TRK­
17
values
are
given
for
those
substances
for
which
no
maximum
workplace
concentration
can
be
established.
18
Compliance
of
the
TRK
should
minimize
the
risk
of
health
effects,
but
health
effects
cannot
be
excluded
19
even
at
this
concentration.
(
A
value
of
3
ppm
is
given
for
existing
plants
and
the
production
of
VC
and
20
PVC,
in
all
other
cases
2
ppm
should
not
be
exceeded.)
21
i
Einsatztoleranzwert
[
Action
Tolerance
Levels]
(
Vereinigung
zur
Förderung
des
deutschen
Brandschutzes
22
e.
V.
[
Federation
for
the
Advancement
of
German
Fire
Prevention])
(
Greim,
1995/
1996)
constitutes
a
23
concentration
to
which
unprotected
firemen
and
the
general
population
can
be
exposed
to
for
up
to
4
hours
24
without
any
health
risks.
The
value
is
based
on
the
observation
that
no
acute
toxic
effects
or
irritating
25
effects
have
been
observed
during
exposure
to
500
ppm
for
4
hours.
26
j
Störfallbeurteilungswert
[
Emergency
Assessment
Value]
(
VCI,
Verband
der
Chemischen
Industrie,
27
Deutschland
[
Association
of
the
Chemical
Industry
in
Germany])
(
VCI,
1990).
These
values
have
been
28
set
for
an
exposure
time
of
up
to
1
h.
Considering
that
VC
leads
to
anaesthesia
in
concentrations
of
7%,
to
29
pre­
narcotic
syndroms
at
0.5%,
and
to
respiratory
arrest
the
Emergency
Assessment
Value
has
been
set
at
30
1,000
ppm.
31
8.3.
Data
Adequacy
and
Research
Needs
32
As
VC
has
only
poor
warning
properties
there
is
only
a
very
limited
data
base
to
derive
AEGL­
1.
33
Additional
studies
with
volunteers
may
not
be
performed
due
to
ethical
reasons.
AEGL­
2
values
are
based
34
on
animal
experiments
regarding
CNS­
effects.
The
respective
concentration
range
is
well
established
but
35
excludes
potential
mutagenic
or
carcinogenic
effects
after
short
term
exposure,
which
might
occur
in
lower
36
concentrations.
However,
quantitative
estimates
of
the
respective
risk
are
highly
uncertain.
For
derivation
37
of
AEGL­
3
values,
the
dogs
studies
on
cardiac
sensitization
are
in
good
accordance
with
lethality
data
in
38
slightly
higher
concentrations.
39
Vinyl
chloride
PROPOSED
1:
3/
2004
45
9.
REFERENCES
1
ACGIH
(
American
Conference
of
Governmental
Industrial
Hygienists).
1998.
Documentation
of
the
2
Threshold
Limit
Values
and
Biological
Exposure
Indices.
Cincinnati,
OH.
3
AIHA
(
American
Industrial
Hygiene
Association).
1997.
Odor
Thresholds
for
Chemicals
with
Established
4
Occupational
Health
Standards.
Fairfax,
VA.
5
Amoore,
J.
E.,
and
E.
Hautala.
1983.
Odor
as
an
aid
to
chemical
safety:
odor
thresholds
compared
with
6
threshold
limit
values
and
volatilities
for
214
industrial
chemicals
in
air
and
water
dilution.
J.
Appl.
7
Toxicol.
3:
272­
290.
8
Anonymous.
1987.
A
scientific
basis
for
the
risk
assessment
of
vinyl
chloride.
Regul.
Toxicol.
Pharmacol.
9
7:
120­
127.
10
ATSDR
(
Agency
for
Toxic
Substances
and
Disease
Registry).
1997.
Toxicological
Profile
for
Vinyl
11
Chloride.
Update.
U.
S.
Department
of
Health
and
Human
Services;
Public
Health
Service.
12
Aviado,
D.
M.,
and
M.
A.
Belej,
1974.
Toxicity
of
aerosol
propellants
in
the
respiratory
and
circulatory
13
systems.
I.
Cardiac
arrhythmia
in
the
mouse.
Toxicology
2:
31­
42.
14
Awara,
W.
M.,
S.
H.
El­
Nabi,
and
M.
El­
Gohary,
1998.
Assessment
of
vinyl
chloride­
induced
DNA
damage
15
in
lymphocytes
of
plastic
industry
workers
using
a
single­
cell
gel
electrophoresis
technique.
Toxicology
16
128:
9­
16.
17
Barbin,
A.
1999.
Role
of
ethno
DNA
adducts
in
carcinogenesis
induced
by
vinyl
chloride
in
rats.
In:
Singer,
18
B.,
Bartsch,
H.:
IARC
Scientific
Publication
No.
150.
Exocyclic
DNA
Adducts
in
Mutagenesis
and
19
Carcinogenesis,
IARC,
International
Agency
for
Research
on
Cancer,
Lyon,
303­
313.
20
Barbin,
A.
2000.
Etheno­
adduct­
forming
chemicals:
from
mutagenicity
testing
to
tumour
mutation
spectra.
21
Mut.
Res.
462:
55­
69.
22
Baretta,
E.
D.,
R.
D.
Stewart,
and
J.
E.
Mutchler.
1969.
Monitoring
exposures
to
vinyl
chloride
vapor:
breath
23
analysis
and
continuous
air
sampling.
Am.
Ind.
Hyg.
Assoc.
J.
30:
537­
544.
24
Beck,
P.
S.,
D.
G.
Clark,
and
D.
J.
Tinston.
1973.
The
pharmacologic
actions
of
25
bromochlorodifluoromethane
(
BCF).
Toxicol.
Appl.
Pharmacol.
24:
20­
29.
26
Becker,
R.,
T.
Nikolova,
I.
Wolff,
D.
Lovell,
E.
Huettner,
and
H.
Foth.
2001.
Frequency
of
HPRT
mutants
27
in
humans
exposed
to
vinyl
chloride
via
an
environmental
accident.
Mut.
Res.
494:
87­
96.
28
Belej,
M.
A.,
D.
G.
Smith,
and
D.
M.
Aviado.
1974.
Toxicity
of
aerosol
propellants
in
the
respiratory
and
29
circulatory
systems.
IV.
Cardiotoxicity
in
the
monkey.
Toxicology
2:
381­
395.
30
Vinyl
chloride
PROPOSED
1:
3/
2004
46
Boffetta,
P.,
L.
Matisane,
K.
A.
Mundt,
and
L.
D.
Dell.
2003.
Meta­
analysis
of
studies
of
occupational
1
exposure
to
vinyl
chloride
in
relation
to
cancer
mortality.
Scand.
J.
Work
Environ.
Health.
29:
220­
229.
2
Bolt,
H.
M.,
H.
Kappus,
A.
Buchter,
and
W.
Bolt.
1976.
Disposition
of
[
1,214C]
vinyl
chloride
in
the
rat.
3
Arch.
Toxicol.
35:
153­
163;
cited
in
WHO
(
1999a).
4
Bolt,
H.
M.,
R.
J.
Laib,
H.
Kappus,
and
A.
Buchter.
1977.
Pharmacokinetics
of
vinyl
chloride
in
the
rat.
5
Toxicology
7:
179­
188.
6
Bolt,
H.
M.,
J.
G.
Filser,
R.
J.
Laib,
and
H.
Ottenwälder.
1980.
Binding
kinetics
of
vinyl
chloride
and
vinyl
7
bromide
at
very
low
doses.
Arch.
Toxicol.
Suppl.
3:
129­
142.
8
Bolt,
H.
M.,
J.
G.
Filser,
and
A.
Buchter.
1981.
Inhalation
pharmacokinetics
based
on
gas
uptake
studies.
9
III.
A
pharmacokinetic
assessment
in
man
of
"
peak
concentrations"
of
vinyl
chloride.
Arch.
Toxicol.
10
48:
213­
228.
11
Buchter,
A.
1979.
Erarbeitung
einer
speziellen
arbeitsmedizinischen
Überwachungsuntersuchung
in
12
Korrelation
zur
individuellen
Vinylchlorid­
Exposition.
Forschungsberichte
des
Landes
Nordrhein­
13
Westfalen,
Nr.
2813,
Fachgruppe
Medizin,
Westdeutscher
Verlag,
Opladen,
1979.
14
Buchter,
A.,
H.
M.
Bolt,
J.
Filser,
H.
W.
Georgens,
R.
J.
Laib,
and
W.
Bolt.
1978.
[
Pharmacokinetics
and
15
carcinogenesis
of
vinyl
chloride:
occupational
risk
evaluation].
Verhandlungen
der
Deutschen
Gesellschaft
16
für
Arbeitsmedizin
18:
111­
124;
cited
in
WHO
(
1999a).
17
Buchter,
A.,
J.
G.
Filser,
H.
Peter,
and
H.
M.
Bolt.
1980.
Pharmacokinetics
of
vinyl
chloride
in
the
Rhesus
18
monkey.
Toxicol.
Lett.
6:
33­
36.
19
Byron,
D.,
G.
Engholm,
A.
Englund,
and
P.
Westerholm.
1976.
Mortality
and
cancer
morbidity
in
a
group
20
of
Swedish
VCM
and
PVC
production
workers.
Environ.
Health
Perspect.
17:
167­
170.
21
Carpenter,
S.
P.,
D.
D.
Savage,
E.
D.
Schultz,
and
J.
L.
Raucy.
1997.
Ethanol­
mediated
transplacental
22
induction
of
CYP2E1
in
fetal
rat
liver.
J.
Pharm.
Exp.
Ther.
282:
1028­
1036.
23
Chen,
C.
W.,
and
J.
N.
Blancato.
1989.
Incorporation
of
biological
information
in
cancer
risk
assessment:
24
example
vinylchloride.
Cell
Biol.
Toxicol.
5:
417­
444.
25
Ciroussel,
F.,
A.
Barbin,
G.
Eberle,
aqnd
H.
Bartsch.
1990.
Investigations
on
the
relationship
between
26
DNA
ethenobase
adduct
levels
in
several
organs
of
vinyl
chloride­
exposed
rats
and
cancer
susceptibility.
27
Biochem.
Pharm.
39:
1109­
1113.
28
Clark,
D.
G.,
and
D.
J.
Tinston.
1973.
Correlation
of
the
cardiac
sensitizing
potential
of
halogenated
29
hydrocarbons
with
their
physicochemical
properties.
Br.
J.
Pharm.
49:
355­
357.
30
Clark,
D.
G.,
and
D.
J.
Tinston.
1982.
Acute
inhalation
toxicity
of
some
halogenated
and
non­
halogenated
31
hydrocarbons.
Hum.
Toxicol.
1:
239­
247.
32
Vinyl
chloride
PROPOSED
1:
3/
2004
47
Clewell,
H.
J.,
P.
R.
Gentry,
J.
M.
Gearhart,
B.
C.
Allen,
M.
E.
Andersen,
and
K.
S.
Crump.
1995.
1
Considering
pharmacokinetic
and
mechanistic
information
in
cancer
risk
assessments
for
environmental
2
contaminants:
examples
with
vinyl
chloride
and
trichloroethylene.
Chemosphere
31:
2561­
2578.
3
Clewell,
H.
J.,
P.
R.
Gentry,
J.
M.
Gearhart,
B.
C.
Allen,
and
M.
E.
Andersen.
2001.
Comparison
of
cancer
4
risk
estimates
for
vinyl
chloride
using
animal
and
human
data
with
a
PBPK
model.
Sci.
Total
Environ.
5
274:
37­
66.
6
Cresteil,
T.
1998.
Onset
of
xenobiotic
metabolism
in
children:
toxicological
implications.
Food
Add.
7
Contam.
15,
Suppl.:
45­
51.
8
Csanády,
G.
A.,
and
J.
G.
Filser.
2001.
The
relevance
of
physical
activity
for
the
kinetics
of
inhaled
gaseous
9
substances.
Arch.
Toxicol.
74:
663­
672
10
CSP,
Chemical
Safety
Program,
2002.
online:
http://
tis­
hq.
eh.
doe.
gov/
web/
chem_
safety/
teel/
table2.
pdf
11
(
printed
February
2002)
12
Danziger,
H.
1960.
Accidental
poisoning
by
vinyl
chloride:
Report
of
two
cases.
Can.
Med.
Assoc.
J.
13
82:
828­
830.
14
DFG,
Deutsche
Forschungsgemeinschaft.
2001.
MAK­
und
BAT­
Werte­
Liste
2001.
Senatskommission
zur
15
Prüfung
gesundheitsschädlicher
Arbeitsstoffe.
Mitteilung
37.
WILEY­
VCH
Verlag
GmbH,
Weinheim.
16
Drew,
R.
T.,
G.
A.
Boorman,
J.
K.
Haseman,
E.
E.
McConnell,
W.
M.
Busey,
and
J.
A.
Moore.
1983.
The
17
effect
of
age
and
exposure
duration
on
cancer
induction
by
a
known
carcinogen
in
rats,
mice,
and
hamsters.
18
Toxicol.
Appl.
Pharmacol.
68:
120­
130.
19
Du,
J.
T.,
M.
T.
Tseng,
and
C.
H.
Tamburro.
1982.
The
effect
of
repeated
vinyl
chloride
exposure
on
rat
20
hepatic
metabolizing
enzymes.
Toxicol.
Appl.
Pharmacol.
62:
1­
10.
21
ECB,
European
Chemicals
Bureau.
2000.
IUCLID,
International
Uniform
Chemical
Information
Database.
22
Edition
II,
European
Commission.
23
EPA,
Environmental
Protection
Agency.
1987.
Health
Advisories
for
25
Organics.
Office
of
Drinking
24
Water.
25
EPA,
Environmental
Protection
Agency.
2000a.
Toxicological
Review
of
Vinyl
Chloride.
U.
S.
26
Environmental
Protection
Agency,
Washington,
DC.
27
EPA,
Environmental
Protection
Agency.
2000b.
IRIS,
Integrated
Risk
Information
System.
CD­
ROM
28
Datenbank,
Silver
Platter,
USA.
29
Fedtke,
N.,
J.
A.
Boucheron,
V.
E.
Walker,
and
J.
A.
Swenberg.
1990.
Vinyl
chloride­
induced
DNA
adducts.
30
II.
Formation
and
persistence
of
7­(
2'
oxoethyl)
guanine
and
N2­
ethenoguanine
in
rat
tissue
DNA.
31
Vinyl
chloride
PROPOSED
1:
3/
2004
48
Carcinogenesis
11:
1287­
1292.
1
Feron,
V.
J.,
A.
J.
Speek,
M.
I.
Willems,
D.
van
Battum,
and
A.
P.
de
Groot.
1975.
Observations
on
the
oral
2
administration
and
toxicity
of
vinyl
chloride
in
rats.
Food
Cosm.
Toxicol.
13:
633­
638.
3
Feron,
V.
J.,
B.
J.
Spit,
H.
R.
Immel,
and
P.
Kroes.
1979.
One­
year
time­
sequence
inhalation
toxicity
study
4
of
vinyl
chloride
in
rats.
III.
Morphological
changes
in
the
liver.
Toxicology
13:
143­
154.
5
Filser,
J.
G.,
and
H.
M.
Bolt.
1979.
Pharmacokinetics
of
halogenated
ethylenes
in
rats.
Arch.
Toxicol.
6
42:
123­
136.
7
Fleig,
I.,
and
A.
M.
Thiess.
1978.
External
chromosome
studies
undertaken
on
persons
and
animals
with
VC
8
illness.
Mut.
Res.
53:
187.
9
Forth,
W.,
D.
Henschler,
and
W.
Rummel.
1987.
Allgemeine
und
spezielle
Pharmakologie
und
Toxikologie.
10
BI
Wissenschaftsverlag,
Mannheim,
Wien,
Zürich,
5.
Ed.
11
Froment,
O.,
S.
Boivin,
A.
Barbin,
B.
Bancel,
C.
Trepo,
and
M.
J.
Marion.
1994.
Mutagenesis
of
ras
proto­
12
oncogens
in
rat
liver
tumors
induced
by
vinyl
chloride.
Canc.
Res.
54:
5340­
5345.
13
Fucic,
A.,
V.
Garaj­
Vrhovac,
B.
Dinmitrovic,
and
M.
Skara.
1992.
The
persistence
of
sister­
chromatid
14
exchange
frequencies
in
men
occupationally
exposed
to
vinyl
chloride
monomer.
Mut.
Res.
281:
129­
132.
15
Fucic,
A.,
V.
Hitrec,
V.
Garaj­
Vrhovac,
D.
Barkovic,
and
D.
Kubelka.
1995.
Relationship
between
16
locations
of
chromosome
breaks
induced
by
vinyl
chloride
monomer
and
lymphocytosis.
Am.
J.
Ind.
Med.
17
27:
565­
571.
18
Goodman,
L.
S.,
and
A.
Gilman.
1975.
The
Pharmacological
Basis
of
Therapeutics.
Macmillan
Publishing
19
Co.,
Inc.,
New
York
20
Grainger,
R.
G.,
A.
E.
Walker,
and
A.
M.
Ward.
1980.
Vinyl
chloride
monomer­
induced
disease:
Clinical,
21
radiological
and
immunological
aspects.
In:
Preger,
L.
(
Ed.).
Induced
Disease.
Grune
&
Stratton,
New
22
York,
pp.
191­
214.
23
Graj­
Vrhovac,
V.,
A.
Fucic,
and
D.
Horvat.
1990.
Comparison
of
chromosome
aberration
and
24
micronucleus
induction
in
human
lymphocytes
after
occupational
exposure
to
vinyl
chloride
monomer
and
25
microwave
radiation.
Period.
Biol.
92:
411­
416.
26
Greim,
H.,
1995/
96.
Entwicklung
von
Verfahren
zur
Abschätzung
der
gesundheitlichen
Folgen
von
27
Großbränden.
Bericht
zum
Forschungsvorhaben
des
Bundesamts
für
Zivilschutz.
Institut
für
Toxikologie
28
und
Umwelthygiene
der
TU
München,
1995/
96.
29
Greiser,
E.,
W.
Reinl,
and
H.
Weber.
1982.
Vinylchlorid­
Exposition
und
Mortalität
deutscher
30
Chemiearbeiter
im
Vergleich
zur
Mortalität
nichtexponierter
Chemiearbeiter
und
PVC­
Verarbeiter.
31
Vinyl
chloride
PROPOSED
1:
3/
2004
49
Zentralbl.
Arbeitsmed.
Arbeitsschutz
Prophyl.
Ergonomie,
32:
44­
62.
1
Haber,
F.,
1924.
Zur
Geschichte
des
Gaskrieges.
In:
Fünf
Vorträge
aus
den
Jahren
1920­
1923.
Springer­
2
Verlag,
Berlin,
pp.
76­
92;
cited
in
NRC
(
2001).
3
Hahn,
A.,
H.
Michalak,
K.
Begemann,
G.
Heinemeyer,
and
U.
Gundert­
Remy.
1998.
Transportunfall
mit
Vinylchlorid.
4
Umweltmed.
Forsch.
Prax.
3:
144­
155.
5
Hefner,
R.
E.,
P.
G.
Watanabe,
and
P.
J.
Gehring.
1975.
Preliminary
studies
of
the
fate
of
inhaled
vinyl
6
chloride
monomer
in
rats.
Ann.
NY
Acad.
Sci.
246:
135­
148.
7
Hehir,
R.
M.,
B.
P.
McNamara,
J.
McLaughlin,
D.
A.
Willigan,
G.
Bierbower,
and
J.
F.
Hardisty.
1981.
8
Cancer
induction
following
single
and
multiple
exposure
to
a
constant
amount
of
vinyl
chloride
monomer.
9
Environ.
Health
Perspect.
41:
63­
72.
10
Hori,
M.,
Y.
Kobavashi,
and
Y.
Ota.
1972.
Vinyl
chloride
monomer
odor
concentration.
Plast.
Ind.
News,
11
18:
164­
168.
12
Huettner,
E.,
and
T.
Nikolova.
1998.
Cytogenetic
analysis
of
peripheral
lymphocytes
in
a
population
13
exposed
to
vinyl
chloride
through
an
accidental
release
into
the
environment.
Toxicol.
Lett.
96­
97:
143­
148.
14
Jaeger,
R.
J.,
E.
S.
Reynolds,
R.
B.
Conolly,
M.
T.
Moslen,
S.
Szabo,
and
S.
D.
Murphy.
1974.
Acute
hepatic
15
injury
by
vinyl
chloride
in
rats
pretreated
with
phenobarbital.
Nature
252:
724­
726.
16
John,
J.
A.,
F.
A.
Smith,
and
B.
K.
J.
Leong.
1977.
The
effects
of
maternally
inhaled
vinyl
chloride
on
17
embryonal
and
fetal
development
in
mice,
rats,
and
rabbits.
Toxicol.
Appl.
Pharmacol.
39:
497­
513.
18
John,
J.
A.,
F.
A.
Smith,
and
B.
A.
Schwetz.
1981.
Vinyl
chloride:
Inhalation
teratology
study
in
mice,
rats,
19
and
rabbits.
Environ.
Health
Perspect.
41:
171­
177.
20
Kielhorn,
J.,
C.
Melber,
U.
Wahnschaffe,
A.
Aitio,
and
I.
Mangelsdorf.
2000.
Vinyl
chloride:
still
a
cause
21
for
concern.
Environ.
Health
Perspect.
108:
579­
588.
22
Krajewski,
J.,
M.
Dobecki,
and
J.
Gromiec.
1980.
Retention
of
vinyl
chloride
in
the
human
lung.
Br.
J.
Ind.
23
Med.
37:
373­
374.
24
Vinyl
chloride
PROPOSED
1:
3/
2004
50
Kudo,
Y.
Y.,
S.
Yamada,
I.
Nakamura,
T.
Sakaguchi,
S.
Sakaguchi,
T.
Ohe,
H.
Kamagata,
A.
Naito,
and
1
S.
Nakazawa.
1990.
On
the
changes
in
peripheral
red
cells
in
mice
exposed
to
vinyl
chloride
monomer.
Pol.
2
J.
Occup.
Med.
3:
301­
310.
3
Laib,
R.
J.,
T.
Pellio,
U.
M.
Wünschel,
N.
Zimmermann,
and
H.
M.
Bolt.
1985a.
The
rat
liver
foci
bioassay:
4
II.
Investigations
on
the
dose­
dependent
induction
of
ATPase­
deficient
foci
by
vinyl
chloride
at
very
low
5
doses.
Carcinogenesis
6:
69­
72.
6
Laib,
R.
J.,
K.
P.
Klein,
and
H.
M.
Bolt.
1985b.
The
rat
liver
foci
bioassay:
I.
Age­
dependence
of
induction
7
by
vinyl
chloride
of
ATPase­
deficient
foci.
Carcinogenesis
6:
65­
68.
8
Laib,
R.
J.,
H.
M.
Bolt,
R.
Cartier,
and
H.
Bartsch.
1989.
Increased
alkylation
of
liver
DNA
and
cell
9
turnover
in
young
versus
old
rats
exposed
to
vinyl
chloride
correlates
with
cancer
susceptibility.
Toxicol.
10
Lett.
45:
231­
239.
11
Lange,
C.­
E.,
S.
Jühe,
G.
Stein,
and
G.
Veltman.
1974.
Die
sogenannte
Vinylchlorid­
Krankheit
­
eine
12
berufsbedingte
Systemsklerose?
Internat.
Arch.
Arbeitsmed.
32:
1­
32
13
Lee,
C.
C.,
J.
C.
Bhandari,
and
J.
M.
Winston.
1977.
Inhalation
toxicity
of
vinyl
chloride
and
vinylidene
14
chloride.
Environ.
Health
Perspect.
21:
25­
32.
15
Lefaux,
R.
1966.
Vinylchlorid.
In:
R.
Lefaux.
Chemie
und
Toxikologie
der
Kunststoffe.
Krausskopf
16
Verlag,
Mainz.
104­
107.
17
Lehmann,
K.
B.,
and
F.
Flury.
1938.
Vinylchlorid.
In:
K.
B.
Lehmann;
F.
Flury.
Toxikologie
und
Hygiene
18
der
technischen
Lösungsmittel.
Springer
Verlag,
Berlin.
130­
131.
19
Lester,
D.,
L.
A.
Greenberg,
and
W.
R.
Adams.
1963.
Effects
of
single
and
repeated
exposures
of
humans
20
and
rats
to
vinyl
chloride.
Am.
Ind.
Hyg.
Assoc.
J.
24:
265­
275.
21
Lilis,
R.,
H.
Anderson,
W.
J.
Nicholson,
S.
Daum,
A.
S.
Fishbein,
and
I.
R.
Selikoff.
1975.
Prevalence
of
22
disease
among
vinyl
chloride
and
polyvinyl
chloride
workers.
Ann.
NY
Acad.
Sci.
246:
22­
41.
23
Lloyd,
M.
H.,
S.
Gauld,
L.
Copland,
and
C.
A.
Soutar.
1984.
Epidemiological
study
of
the
lung
function
of
24
workers
at
a
factory
manufactoring
polyvinyl
chloride.
Br.
J.
Ind.
Med.
41:
328­
333.
25
Maltoni,
C.,
G.
Lefemine,
A.
Ciliberti,
G.
Cotti,
and
D.
Carretti.
1981.
Carcinogenicity
bioassays
of
26
vinylchloride
monomer:
A
model
of
risk
assessment
on
an
experimental
basis.
Environ.
Health
Perspect.
27
41:
3­
31.
28
Maltoni,
C.,
G.
Lefemine,
A.
Ciliberrti,
G.
Cotti,
and
D.
Carretti.
1984.
Experimental
Research
on
Vinyl
29
Chloride
Carcinogenesis.
Vol.
II:
Archives
of
Research
on
Industrial
Carcinogenesis.
Princeton
Scientific
30
Publishers
Inc.,
New
Jersey.
31
Vinyl
chloride
PROPOSED
1:
3/
2004
51
Marsteller,
H.
J.,
W.
K.
Lelbach,
R.
Müller,
and
P.
Gedigk.
1975.
Unusual
splenomegalic
liver
disease
as
1
evidenced
by
peritoneoscopy
and
guided
liver
biopsy
among
polyvinyl
chloride
production
workers.
Ann.
2
NY
Acad.
Sci.
246:
95­
134.
3
Mastrangelo,
G.,
U.
Feeli,
E.
Fadda,
G.
Milan,
A.
Turato,
and
S.
Pavanello.
2003.
Lung
cancer
risk
in
4
workers
exposed
to
poly(
vinyl
chloride)
dust:
a
nested
case­
referent
study.
Occup.
Environ.
Med..
60:
423­
5
428.
6
Mastromatteo,
E.,
A.
M.
Fisher,
H.
Christie,
and
H.
Danziger.
1960.
Acute
inhalation
toxicity
of
vinyl
7
chloride
to
laboratory
animals.
Am.
Ind.
Hyg.
Assoc.
J.
21:
394­
398.
8
Morinello,
E.
J.,
A.­
J.
L.
Ham,
A.
Ranasinghe,
J.
Nakamura,
P.
B.
Upton,
and
J.
A.
Swenberg.
2002.
9
Molecular
dosimetry
and
repair
of
N(
2),
3­
ethenoguanine
in
rats
exposed
to
vinyl
chloride.
Canc.
Res.
10
62:
5189­
5195.
11
Mundt,
K.
A.,
Dell,
L.
D.,
Austin,
R.
P.
and
Luippold,
R.
S.
(
January
8,1999).
Epidemiological
study
of
men
12
employed
in
the
vinyl
chloride
industry
between
1942
and
1972:
I.
Re­
analysis
of
mortality
through
13
December
31,
1982;
and
II.
Update
of
mortality
through
December
31,
1995.
Applied
Epidemiology,
Inc.,
14
P.
O.
Box
2424,
Amherst,
Massachusetts
01004
USA
15
Mundt,
K.
A.
Dell,
L.
D.,
Austin,
R.
P.,
Luippold,
R.
S.,
Noess,
R.
and
Bigelow,
C.
(
2000).
16
Historical
cohort
study
of
10109
men
in
the
North
American
vinyl
chloride
industry,
1942­
72:
17
update
of
cancer
mortality
to
31
December
1995.
Occup
Environ
Med
57:
774­
781.
18
NLM,
U.
S.
National
Library
of
Medicine.
2000.
HSDB,
Hazardous
Substances
Databank.
U.
S.
NLM,
19
CD­
ROM
Datenbank,
Silver
Platter,
USA.
20
NRC,
National
Research
Council.
2001.
Standing
Operating
Procedures
for
Developing
Acute
Exposure
21
Guideline
Levels
for
Hazardous
Chemicals.
National
Academy
Press,
Washington,
DC.
22
Oettel,
H..
1954.
Vinylchlorid.
In:
W.
Foerst.
Ullmann's
Enzyklopaedie
der
Technischen
Chemie,
Band
5.
23
Urban
&
Schwarzenberg,
München­
Berlin.
489.
24
OSHA,
Occupational
Safety
and
Health
Administration.
2002.
Vinyl
chloride.
Code
of
Federal
25
Regulations,
29,
Part
1910.1017,
online:
http://
www.
osha­
slc.
gov//
OshStd_
data/
1910_
1017.
html
(
printed
26
February
2002).
27
Oster,
R.
H.,
C.
J.
Carr,
J.
C.
Krantz,
and
M.
J.
Sauerwald.
1947.
Anesthesia:
XXVII.
Narcosis
with
vinyl
28
chloride.
Anesthesiology
8:
359­
361.
29
Patty,
F.
A.,
W.
P.
Yant,
and
C.
P.
Waite.
1930.
Acute
response
of
guinea
pigs
to
vapors
of
some
new
30
commercial
organic
compounds:
V.
Vinyl
Chloride.
Public
Health
Reports
45:
1963­
1971.
31
Peoples,
A.
S.,
and
C.
D.
Leake.
1933.
The
anesthetic
action
of
vinyl
chloride.
J.
Pharmacol.
Exp.
Ther.
32
48:
284.
33
Vinyl
chloride
PROPOSED
1:
3/
2004
52
Pessayre,
D.,
J.
C.
Wandscheer,
V.
Descatoire,
J.
Y.
Artigou,
and
J.
P.
Benhamou.
1979.
Formation
and
1
inactivation
of
a
chemically
reactive
metabolite
of
vinyl
chloride.
Toxicol.
Appl.
Pharmacol.
49:
505­
515.
2
Prodan,
L.,
I.
Suciu,
V.
Pislaru,
E.
Ilea,
and
L.
Pascu.
1975.
Experimental
acute
toxicity
of
vinyl
chloride
3
(
monochloroethene).
Ann.
NY
Acad.
Sci.
246:
154­
158.
4
Reitz,
R.
H.,
M.
L.
Gargas,
M.
E.
Andersen,
W.
M.
Provan,
and
T.
L.
Green.
1996.
Predicting
cancer
risk
5
from
vinyl
chloride
exposure
with
a
physiologically
based
pharmacokinetic
model.
Toxicol.
Appl.
6
Pharmacol.
137:
253­
267.
7
Rinehart,
W.
E.,
and
T.
Hatch.
1964.
Concentration­
time
product
(
CT)
as
an
expression
of
dose
in
sublethal
8
exposures
to
phosgene.
Ind.
Hyg.
J.
25:
545­
553;
cited
in
NRC
(
2001).
9
Schaumann,
O..
1934.
Über
die
Herzwirkung
einiger
Inhalationsnarkotica.
Medizin
und
Chemie
2:
139­
147.
10
Seaton,
M.
J.,
P.
M.
Schlosser,
J.
A.
Bond,
and
M.
A.
Medinsky.
1994.
Benzene
metabolism
by
human
liver
11
microsomes
in
relation
to
cytochrome
P450
2E1
activity.
Carcinogenesis
15:
1799­
1806.
12
Simonato,
L.,
K.
A.
L'Abbé,
A.
Andersen,
S.
Belli,
P.
Comba,
G.
Engholm,
G.
Ferro,
L.
Hagmar,
S.
13
Langard,
I.
Lundberg,,
R.
Pirastu,
P.
Thomas,
R.
Winkelmann,
and
R.
Saracci.
1991.
A
collaborative
14
study
of
cancer
incidence
and
mortality
among
vinyl
chloride
workers.
Scand.
J.
Work
Environ.
Health
15
17:
159­
169.
16
Sinués,
B.,
A.
Sanz,
M.
L.
Bernal,
A.
Tres,
A.
Alcala,
J.
Lanuza,
C.
Ceballos,
and
M.
A.
Sáenz.
1991.
17
Sister
chromatid
exchanges,
proliferating
rate
index,
and
micronuclei
in
biomonitoring
of
internal
exposure
18
to
vinyl
chloride
monomer
in
plastic
industry
workers.
Toxicol.
Appl.
Pharmacol.
108:
37­
45.
19
Suciu,
I.,
L.
Prodan,
E.
Ilea,
A.
Paduraru,
and
L.
Pascu.
1975.
Clinical
manifestations
in
vinyl
chloride
20
poisoning.
Ann.
NY
Acad.
Sci.
246:
53­
69.
21
Suzuki,
Y.
1981.
Electron
microscopic
observations
of
hepatic
and
subcutaneous
hemangiosarcomas
22
induced
in
mice
exposed
to
vinyl
chloride
monomer.
Am.
J.
Ind.
Med.
2:
103­
117.
23
Suzuki,
Y.
1983.
Nonneoplastic
effect
of
vinyl
chloride
in
mouse
lung
­
lower
doses
and
short­
term
24
exposure.
Environ.
Res.
32,
1983:
91­
103.
25
Swenberg,
J.
A.,
M.
S.
Bogdanffy,
A.
Ham,
S.
Holt,
A.
Kim,
E.
J.
Morinello,
A.
Ranasinghe,
N.
Scheller,
26
and
P.
B.
Upton.
1999.
Formation
and
repair
of
DNA
adducts
in
vinyl
chloride­
and
vinyl
fluoride­
induced
27
carcinogenesis.
In:
Singer,
B.,
Bartsch,
H.:
IARC
Scientific
Publication
No.
150.
Exocyclic
DNA
Adducts
28
in
Mutagenesis
and
Carcinogenesis,
IARC,
International
Agency
for
Research
on
Cancer,
Lyon,
29­
43.
29
Swenberg,
J.
A.,
A.
Ham,
H.
Koc,
E.
Morinello,
A.
Ranasinghe,
N.
Tretyakova,
P.
B.
Upton,
and
K.
Wu.
30
2000.
DNA
adducts:
effects
of
low
exposure
to
ethylene
oxide,
vinyl
chloride
and
butadiene.
Mut.
Res.
31
464:
77­
86.
32
Vinyl
chloride
PROPOSED
1:
3/
2004
53
Tamburro,
C.
H.,
L.
Makk,
and
H.
Popper.
1984.
Early
hepatic
histologic
alterations
among
chemical
1
(
vinyl
monomer)
workers.
Hepatology
4:
413­
418.
2
Tatrai,
E.,
and
G.
Ungváry.
1981.
On
the
acute
hepatotoxicity
of
inhaled
vinyl
chloride.
Acta
Morphol.
3
Acad.
Sci.
Hung.
29:
221­
226.
4
Ten
Berge,
W.
F.,
A.
Zwart,
and
L.
M.
Appelman.
1986.
Concentration­
time
mortality
response
relationship
5
of
irritant
and
systemically
acting
vapours
and
gases.
J.
Hazard.
Mater.
13:
301­
309.
6
Thornton,
S.
R.,
R.
E.
Schroeder,
R.
L.
Robison,
D.
E.
Rodwell,
D.
A.
Penney,
K.
D.
Nitschke,
and
W.
K.
7
Sherman.
2002.
Embryo­
fetal
development
and
reproducitve
toxicology
of
vinyl
chloride
in
rats.
Toxicol.
8
Sci.
68:
207­
219.
9
Tribukh,
S.
L.,
N.
P.
Tikhomirova,
S.
V.
Levin,
and
L.
A.
Kozlov.
1949.
Working
conditions
and
measures
10
for
their
sanitation
in
the
production
and
utilization
of
vinyl
chloride
plastics.
Gig.
Sanit.
10:
38­
45,
cited
in
11
ECB,
2000
12
Ungváry,
G.,
A.
Hudák,
E.
Tátrai,
M.
Lörincz,
and
G.
Folly.
1978.
Effects
of
vinyl
chloride
exposure
13
alone
and
in
combination
with
trypan
blue­
applied
systematically
during
all
thirds
of
pregnancy
on
the
14
fetuses
of
CFY
rats.
Toxicology
11:
45­
54.
15
Veltman,
G.,
C.
E.
Lange,
S.
Jühe,
G.
Stein,
and
U.
Bachner.
1975.
Clinical
manifestations
and
course
of
16
vinyl
chloride
disease.
Ann.
NY
Acad.
Sci.
246:
6­
17.
17
Viola,
P.
L.,
A.
Bigotti,
and
A.
Caputo.
1971.
Oncogenic
response
of
rat
skin,
lungs
and
bones
to
vinyl
18
chloride.
Canc.
Res.
31:
516­
522.
19
Viola,
P.
L.
1970.
Pathology
of
vinyl
chloride.
Med.
Lav.
61:
174­
180.
20
VCI,
Verband
der
chemischen
Industrie,
1990.
Konzept
zur
Festlegung
von
Störfallbeurteilungswerten
21
[
german].
Unpublished
manuscript,
no
year
given,
probably
around
1990
22
von
Oettingen,
W.
F..
1964.
Vinyl
Chloride.
In:
W.
F.
von
Oettingen.
The
Halogenated
Hydrocarbons
in
23
Industrial
and
Toxicological
Importance.
Elsevier
Monographs
on
Toxic
Agents.
Elsevier
Publishing
24
Company,
Amsterdam­
London­
New
York.
227­
233.
25
Walker,
A.
E.
1976.
Clinical
aspects
of
vinyl
chloride
disease:
skin.
Proc.
Royal
Soc.
Med.
69:
286­
289.
26
Vinyl
chloride
PROPOSED
1:
3/
2004
54
Ward,
E.,
Boffetta,
P.,
Andersen,
A.,
Colin,
D.,
Comba,
P.,
Deddens,
J.,
De
Santis,
M.,
Engholm,
G.,
1
Hagmar,
L.,
Langard,
S.,
Lundberg,
I.,
McElvenny,
D.,
Pirastu,
R.,
Sali,
D.,
and
Simonato,
L.
(
Sept.
2
2000).
Update
of
the
follow­
up
of
mortality
and
cancer
incidence
among
European
workers
employed
in
the
3
vinyl
chloride
industry.
IARC
Internal
Report
No.
00/
001
IARC,
Lyon,
France.
4
Ward,
E.,
Boffetta,
P.,
Andersen,
A.,
Colin,
D.,
Comba,
P.,
Deddens,
J.,
De
Santis,
M.,
Engholm,
5
G.,
Hagmar,
L.,
Langard,
S.,
Lundberg,
I.,
McElvenny,
D.,
Pirastu,
R.,
Sali,
D.,
and
Simonato,
L.
6
(
2001).
Update
of
the
follow­
up
of
mortality
and
cancer
incidence
among
European
workers
7
employed
in
the
vinyl
chloride
industry.
Epidemiology
12:
710­
718.
8
Ward,
A.
M.,
S.
Udnoon,
J.
Watkins,
A.
E.
Walker,
and
C.
S.
Darke.
1976.
Immunological
mechanisms
in
9
the
pathogenesis
of
vinyl
chloride
disease.
Br.
Med.
J.
1:
936­
938.
10
Watanabe,
P.
G.,
G.
R.
McGowan,
E.
O.
Madrid,
and
P.
J.
Gehring.
1976a.
Fate
of
[
14C]
vinyl
chloride
11
following
inhalation
exposure
in
rats.
Toxicol.
Appl.
Pharmacol.
37:
49­
59.
12
Watanabe,
P.
G.,
G.
R.
McGowan,
and
P.
J.
Gehring.
1976b.
Fate
of
[
14C]
vinyl
chloride
after
single
oral
13
administration
in
rats.
Toxicol.
Appl.
Pharmacol.
36:
339­
352.
14
Watson,
W.
P.,
D.
Potter,
D.
Blair,
and
A.
S.
Wright.
1991.
The
relationship
between
alkylation
of
15
haemoglobin
and
DNA
in
Fischer
344
rats
exposed
to
[
1,2­
14C]
vinyl
chloride.
In:
Garner,
R.
C.,
Farmer,
16
P.
B.,
Steele,
G.
T.,
Wright,
A.
S.:
Human
Carcinogen
Exposure.
Biomonitoring
and
Risk
Assessment,
17
Oxford
University
Press,
London,
421­
428.
18
Weber,
H.,
W.
Reinl,
and
E.
Greiser.
1981.
German
investigations
on
morbidity
and
mortality
of
workers
19
exposed
to
vinyl
chloride.
Environ.
Health
Perspect.
41:
95­
99.
20
WHO,
World
Health
Organization.
1987.
Air
Quality
Guidelines
for
Europe.
WHO
Regional
Publications.
21
European
Series,
No.
23.
Kopenhagen,
1987.
22
WHO,
World
Health
Organization.
1999a.
Environmental
Health
Criteria
215,
Vinyl
Chloride.
IPCS,
23
International
Programme
on
Chemical
Safety.
World
Health
Organization,
Geneva,
1999.
24
WHO,
World
Health
Organization.
1999b.
Update
and
Revision
of
WHO
Air
Quality
Guidelines
for
25
Europe.
http://
www.
who.
dk/
envhlth/
airqual.
htm
(
accessed:
29/
10/
1999).
26
Vinyl
chloride
PROPOSED
1:
3/
2004
55
APPENDIX
A
­
Derivation
of
AEGL
values
1
Vinyl
chloride
PROPOSED
1:
3/
2004
56
AEGL­
1
1
Key
study:
Baretta
et
al.
(
1969)
2
Toxicity
endpoint:
Mild
headache
in
2
subjects
during
exposure
to
highest
concentration
(
i.
e.
491
3
ppm
for
3.5
h)
4
Uncertainty/
Total
uncertainty
factor
of
3
for
intraspecies
variability
5
modifying
factors:
6
Time
Scaling:
C3
x
t
=
k
for
extrapolation
to
1­
hour
and
30­
minute
(
10­
minute
=
30­
minute
7
value);
C1
x
t
=
k
for
extrapolation
to
4­
and
8­
hour
8
k
=
(
491
ppm)
3
x
210
min
=
2.49
x
10E+
10
ppm3
min
9
k
=
(
491
ppm)
1
x
210
min
=
103110
ppm
min
10
Calculations:
11
10­
minute
AEGL­
1
C3
x
10
min
=
2.49
x
10E+
10
ppm3
min
12
C
=
1355
ppm
13
10­
min
AEGL­
1
=
1355
ppm/
3
=
450
ppm
(=
1170
mg/
m3)
14
15
30­
minute
AEGL­
1
C3
x
30
min
=
2.49
x
10E+
10
ppm3
min
16
C
=
939.25
ppm
17
30­
min
AEGL­
1
=
939
ppm/
3
=
310
ppm
(=
810
mg/
m3)
18
1­
hour
AEGL­
1
C3
x
60
min
=
2.49
x
10E+
10
ppm3
min
19
C
=
745.48
ppm
20
1­
h
AEGL­
1
=
745
ppm/
3
=
250
ppm
(=
640
mg/
m3)
21
4­
hour
AEGL­
1
C
x
240
min
=
103110
ppm
min
22
C
=
429.63
ppm
23
4­
h
AEGL­
1
=
430
ppm/
3
=
140
ppm
(=
370
mg/
m3)
24
8­
hour
AEGL­
1
C
x
480
min
=
103110
ppm
min
25
C
=
214.81
ppm
26
8­
h
AEGL­
1
=
214
ppm/
3
=
70
ppm
(=
190
mg/
m3)
27
Vinyl
chloride
PROPOSED
1:
3/
2004
57
AEGL­
2
1
Key
study:
Lester
et
al.
(
1963)
2
Toxicity
endpoint:
Prenarcotic
effects
were
observed
in
human
volunteers.
After
5
minute
exposure
to
3
16,000
ppm
VC
5
of
6
persons
showed
dizziness,
lightheadedness,
nausea,
visual
4
and
auditory
dulling.
At
concentrations
of
12,000
ppm
one
of
six
persons
showed
5
"
swimming
head,
reeling".
Another
individual
was
unsure
of
some
effect
and
was
6
somewhat
dizzy.
A
single
person
reported
slight
effects
("
slightly
heady")
of
7
questionable
meaning
at
8,000
ppm
(
this
volunteer
felt
also
slightly
heady
at
sham
8
exposure
and
reported
no
response
at
12,000
ppm).
No
effects
were
observed
at
9
4,000
ppm.
(
Lester
et
al.,
1963).
12,000
ppm
was
regarded
as
a
concentration
10
below
AEGL­
2
level
and
taken
as
NOAEL.
11
Uncertainty/
Total
uncertainty
factor
of
3
for
intraspecies
variability
12
modifying
factors:
13
Time
Scaling:
C2
x
t
=
k
for
extrapolation
2­
hour,
1­
hour,
30­
minute,
and
10­
minute,
flatlining
14
from
4h
to
8
h
(
based
on
2
hours
steady
state
concentration)
15
k
=
(
12,000
ppm)
2
x
5
min
=
7.2
x
10E+
8
ppm2
min
16
Calculations:
17
10­
minute
AEGL­
2
C2
x
10
min
=
7.2
x
10E+
8
ppm2
min
18
C
=
8485.28
ppm
19
10­
min
AEGL­
2
=
8485
ppm/
3
=
2800
ppm
(=
7300
mg/
m3)
20
21
30­
minute
AEGL­
2
C2
x
30
min
=
7.2
x
10E+
8
ppm2
min
22
C
=
4898.98
ppm
23
30­
min
AEGL­
2
=
4899
ppm/
3
=
1600
ppm
(=
4100
mg/
m3)
24
1­
hour
AEGL­
2
C2
x
60
min
=
7.2
x
10E+
8
ppm2
min
25
C
=
3464.11
ppm
26
1­
h
AEGL­
2
=
3464
ppm/
3
=
1200
ppm
(=
3100
mg/
m3)
27
2­
hour
steady
state
C2
x
120
min
=
7.2
x
10E+
8
ppm2
min
28
C
=
2449.49
ppm
29
2­
h
steady
state=
2450/
3
ppm/
3
=
820
ppm
(=
2100
mg/
m3)
30
4­
hour
AEGL­
2
=
2­
hour
steady
state/
3
=
820
ppm
(=
2100
mg/
m3)
31
8­
hour
AEGL­
2
=
4­
hour
AEGL­
2
=
820
ppm
(=
2100
mg/
m3)
32
Vinyl
chloride
PROPOSED
1:
3/
2004
58
AEGL­
3
1
Key
study:
Clark
and
Tinston,
1973;
1982
2
Toxicity
endpoint:
Short
term
exposure
(
5
min)
of
dogs
to
VC
induced
cardiac
sensitization
towards
3
epinephrine
(
EC50:
50,000
or
71,000
ppm
in
two
independent
experiments)
(
Clark
4
and
Tinston,
1973;
1982).
These
effects
were
also
seen
in
mice
at
higher
5
concentrations
(
Aviado
and
Belej,
1974).
50,000
ppm
was
used
as
NOAEL
for
life
6
threatening
effects
7
Uncertainty/
Combined
uncertainty
factor
of
3
8
modifying
factors:
1
for
interspecies
variability
9
3
for
intraspecies
variability
10
Time
Scaling:
C2
x
t
=
k
for
extrapolation
to
2­
hour,
1­
hour,
and
30­
minute
and
10­
minutes;
11
flatlining
from
4h
to
8
h
(
based
on
2
hours
steady
state
concentration)
12
k
=
(
50,000
ppm)
2
x
5
min
=
1,25
10E+
10
ppm2
min
13
14
Calculations:
15
10­
minute
AEGL­
3
C2
x
10
min
=
1,25
10E+
10
ppm2
min
16
C
=
35,355.34
ppm
17
30­
min
AEGL­
2
=
35,355
ppm/
3
=
12,000
ppm
(=
31,000
mg/
m3)
18
30­
minute
AEGL­
3
C2
x
30
min
=
1,25
10E+
10
ppm2
min
19
C
=
20,412.41
ppm
20
30­
min
AEGL­
2
=
20,412
ppm/
3
=
6,800
ppm
(=
18,000
mg/
m3)
21
1­
hour
AEGL­
3
C2
x
60
min
=
1,25
10E+
10
ppm2
min
22
C
=
14433.76
ppm
23
1­
h
AEGL­
2
=
14434
ppm/
10
=
4,800
ppm
(=
12,000
mg/
m3)
24
2­
hour
steady
state
C2
x
120
min
=
1,25
10E+
10
ppm2
min
25
C
=
10,206.21
ppm
26
2­
h
steady
state
=
10,206
ppm/
3
=
3,400
ppm
(=
8,800
mg/
m3)
27
4­
hour
AEGL­
3
=
2­
h
steady
state/
3
=
3,400
ppm
(=
8,800
mg/
m3)
28
29
8­
hour
AEGL­
3
=
4­
h
AEGL­
3
=
3,400
ppm
(=
8,800
mg/
m3)
30
Vinyl
chloride
PROPOSED
1:
3/
2004
59
APPENDIX
B
­
Time
Scaling
Calculations
for
Vinyl
Chloride
AEGLs
1
Vinyl
chloride
PROPOSED
1:
3/
2004
60
Time
Scaling
for
Vinyl
Chloride
AEGLs
1
The
relationship
between
dose
and
exposure
time
to
produce
a
toxic
effect
for
any
given
chemical
2
is
a
function
of
the
physical
and
chemical
properties
of
the
substance
and
the
unique
toxicologic
and
3
pharmacologic
properties
of
the
individual
substance.
Historically,
the
relationship
according
to
Haber
4
(
1924),
commonly
called
Haber`
s
rule
(
i.
e.,
C
x
t
=
k,
where
C
=
exposure
concentration,
t
=
exposure
5
duration,
and
k
=
a
constant)
has
been
used
to
relate
exposure
concentration
and
duration
to
a
toxic
effect
6
(
Rinehart
and
Hatch,
1964).
This
concept
states
that
exposure
concentration
and
exposure
duration
may
be
7
reciprocally
adjusted
to
maintain
a
cumulative
exposure
constant
(
k)
and
that
this
cumulative
exposure
8
constant
will
always
reflect
a
specific
quantitative
and
qualitative
response.
This
inverse
relationship
of
9
concentration
and
time
may
be
valid
when
the
toxic
response
to
a
chemical
is
equally
dependent
upon
the
10
concentration
and
the
exposure
duration.
However,
an
assessment
by
ten
Berge
et
al.
(
1986)
of
LC50
data
11
for
certain
chemicals
revealed
chemical­
specific
relationships
between
exposure
concentration
and
exposure
12
duration
that
were
often
exponential.
This
relationship
can
be
expressed
by
the
equation
Cn
x
t
=
k,
where
n
13
represents
a
chemical­
specific
and
even
a
toxic
endpoint­
specific
exponent.
The
relationship
described
by
14
this
equation
is
basically
the
form
of
a
linear
regression
analysis
of
the
log­
log
transformation
of
a
plot
of
C
15
vs.
t
(
NRC,
2001).
16
Acute
CNS­
toxicity
and
lethality
of
VC
are
dominated
by
its
narcotic
effects
characterized
by
a
17
typical
sequence
of
effects
(
increased
motor
activity,
tremor,
muscular
incoordination,
side
position,
18
unconsciousness,
resulting
in
deep
narcosis).
The
occurrence
and
time
sequence
of
these
effects
in
rats,
19
mice
and
guinea
pigs
has
been
described
by
Mastromatteo
et
al.
(
1960).
These
experimental
data
are
used
20
for
the
derivation
of
values
of
n
by
linear
regression
analysis
of
the
log­
log
transformed
plot
of
C
vs.
t.
21
Three
data
sets
of
toxic
effects
in
mice
and
rats
or
guinea
pigs
described
by
Mastromatteo
et
al.
22
(
1960)
were
analyzed.
As
the
time­
concentration
relationships
for
mice
and
rats
were
identical
the
following
23
evaluation
concentrates
on
the
data
obtained
in
mice
and
guinea
pigs.
Regression
analysis
has
been
24
performed
for
the
endpoints
unconsciousness,
muscular
incoordination,
and
side
position.
The
time­
25
concentration
relation
ships
are
described
below.
26
Time
dependency
is
only
true
as
long
as
no
steady
state
is
reached.
Similar
to
other
inhalation
27
anesthetics,
maximal
blood
concentration
of
VC
after
inhalation
exposure
depends
on
the
partial
pressure
28
of
VC
in
the
air.
Blood
respectively
brain
concentration,
which
directly
correlates
with
the
depth
of
narcosis
29
(
see
below)
and
­
presumably
­
with
cardiac
sensitization
level,
can
be
controlled
by
changing
the
30
concentration
of
VC
in
the
air,
i.
e.
by
changing
the
partial
pressure
of
VC
in
the
air.
If
equilibrium
is
31
reached
between
the
partial
pressure
of
VC
in
the
air
and
in
the
blood
(
steady
state),
no
further
increase
of
32
VC
concentration
in
the
blood
is
possible,
even
if
the
exposure
time
is
prolonged
(
Forth
et
al.,
1987).
The
33
time
necessary
to
set
up
steady
state
mainly
depends
on
the
blood/
air
partition
coefficient
of
a
substance.
34
The
blood/
air
partition
coefficient
of
VC
in
humans
is
1.2
(
Csanady
and
Filser,
2001),
similar
to
that
of
the
35
inhalation
anesthetic
isoflurane
(
1.4;
Forth
et
al.,
1987).
For
this
substance
the
equilibrium
is
reached
after
36
about
2
hours,
derived
by
graphical
extrapolation
of
the
data
on
isoflurane
(
Goodman
and
Gilman,
1975).
37
For
VC,
in
much
lower
concentrations
an
elimination
half­
time
of
VC
of
20.5
minutes
has
been
derived
38
(
Buchter,
1979;
Bolt
et
al.,
1981).
From
that,
for
low
concentrations
a
steady
state
concentration
for
VC
in
39
blood
of
about
5
x
20.5
=
102.5
minutes
can
be
calculated
by
standard
estimation
rules.
Thus,
in
high
or
40
low
concentrations
a
relevant
increase
of
internal
concentrations
of
VC
is
not
to
be
expected
after
more
41
Vinyl
chloride
PROPOSED
1:
3/
2004
61
than
2
hours
of
exposure.
However,
for
shorter
periods
of
exposure
a
relevant
influence
of
time
on
the
1
built­
up
of
VC
on
internal
concentrations
has
to
be
taken
into
account:
2
Unconsciousness:
3
The
time
after
which
unconsciousness
was
observed
in
mice
after
exposure
to
100,000,
200,000
or
4
300,000
ppm
VC
was
25
min,
10
min,
and
5
min,
respectively:
5
Time
min
6
Concentration
ppm
Log
time
Log
Concentration
5
7
300000
0.699
5.477
10
8
200000
1
5.301
25
9
100000
1.398
5
The
time
after
which
unconsciousness
was
observed
in
guinea
pigs
after
exposure
to
100,000,
200,
10
000,
300,000,
and
400,000
ppm
VC
was
30
min,
10
min,
5
min
and
5
min,
respectively:
11
Time
min
12
Concentration
ppm
Log
time
Log
Concentration
5
13
400000
0.699
5.602
5
14
300000
0.699
5.477
10
15
200000
1
5.301
30
16
100000
1.477
5
Regression
analysis
of
the
data
is
shown
in
figure
2:
17
Vinyl
chloride
PROPOSED
1:
3/
2004
62
y
=
­
0.6865x
+
5.968
R2
=
0.9951
y
=
­
0.6957x
+
6.019
R2
=
0.9586
4.9
5
5.1
5.2
5.3
5.4
5.5
5.6
5.7
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
log
time
[
min]
log
concentration
[
ppm]
Unconsciousness­
gpg
Unconsciousness­
mouse
FIGURE
2:
REGRESSION
ANALYSIS
OF
THE
LOG­
LOG
TRANSFORMED
1
CONCENTRATION­
TIME
CURVE
REGARDING
UNCONSCIOUSNESS
IN
MICE
AND
2
GUINEA­
PIGS
(
DATA
FROM
MASTROMATTEO
ET
AL.,
1960)
3
The
slope
of
the
regression
line
was
­
0.6865
and
­
0.6957
in
mice
and
guinea
pigs,
respectively,
4
corresponding
to
a
value
of
1.46
and
1.44
for
n.
5
Vinyl
chloride
PROPOSED
1:
3/
2004
63
Muscular
incoordination:
1
The
time
after
which
muscular
incoordination
was
observed
in
mice
after
exposure
to
100,000,
2
200,000
or
300,000
ppm
VC
was
15
min,
2
min,
and
1
min,
respectively:
3
Time
min
4
Concentration
ppm
Log
time
Log
Concentration
1
5
300000
0
5.477
2
6
200000
0.301
5.301
15
7
100000
1.176
5
The
time
after
which
muscular
incoordination
was
observed
in
guinea
pigs
after
exposure
to
8
100,000,
200,000,
300,000,
or
400,000
ppm
VC
was
15
min,
5
min,
2
min,
and
few
seconds,
respectively:
9
Time
min
10
Concentration
ppm
Log
time
Log
Concentration
few
seconds*
11
400000
­­
5.602
2
12
300000
0.301
5.477
5
13
200000
0.699
5.301
15
14
100000
1.176
5
*:
this
value
was
not
regarded
in
regression
analysis
15
Regression
analysis
of
the
data
is
shown
in
figure
3:
16
Vinyl
chloride
PROPOSED
1:
3/
2004
64
y
=
­
0.3919x
+
5.4523
R2
=
0.9845
y
=
­
0.5481x
+
5.6569
R2
=
0.9905
4.9
5
5.1
5.2
5.3
5.4
5.5
5.6
5.7
0
0.2
0.4
0.6
0.8
1
1.2
1.4
log
time
[
min]
log
concentration
[
ppm]
Muscular
incoordination­
gpg
Muscular
incoordination­
mouse
FIGURE
3:
REGRESSION
ANALYSIS
OF
THE
LOG­
LOG
TRANSFORMED
1
CONCENTRATION­
TIME
CURVE
REGARDING
MUSCULAR
INCOORDINATION
IN
MICE
2
AND
GUINEA­
PIGS
(
DATA
FROM
MASTROMATTEO
ET
AL.,
1960)
3
The
slope
of
the
regression
line
was
­
0.3919
and
­
0.5481
in
mice
and
guinea
pigs,
respectively,
4
corresponding
to
a
value
of
2.6
and
1.8
for
n.
5
Vinyl
chloride
PROPOSED
1:
3/
2004
65
Side
position:
1
The
time
after
which
side
position
was
observed
in
mice
after
exposure
to
100,000,
200,000
or
2
300,000
ppm
VC
was
20
min,
5
min,
and
2
min,
respectively:
3
Time
min
4
Concentration
ppm
Log
time
Log
Concentration
2
5
300000
0.301
5.477
5
6
200000
0.699
5.301
20
7
100000
1.301
5
The
time
after
which
side
position
was
observed
in
guinea
pigs
after
exposure
to
100,000,
200,000,
8
or
300,000
ppm
VC
was
30
min,
10
min,
2­
5
min
(
set
to
3.5),
respectively:
9
Time
min
10
Concentration
ppm
Log
time
Log
Concentration
35
11
300000
0.544
5.477
10
12
200000
1
5.301
30
13
100000
1.477
5
Regression
analysis
of
the
data
is
shown
in
figure
4:
14
Vinyl
chloride
PROPOSED
1:
3/
2004
66
y
=
­
0.479x
+
5.6268
R2
=
0.9989
y
=
­
0.5123x
+
5.7753
R2
=
0.9814
4.9
5
5.1
5.2
5.3
5.4
5.5
5.6
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
log
time
[
min]
log
concentration
[
ppm]
Side
position­
gpg
Side
position­
mouse
FIGURE
4:
REGRESSION
ANALYSIS
OF
THE
LOG­
LOG
TRANSFORMED
1
CONCENTRATION­
TIME
CURVE
REGARDING
SIDE
POSITION
IN
MICE
AND
GUINEA­
2
PIGS
(
DATA
FROM
MASTROMATTEO
ET
AL.,
1960)
3
The
slope
of
the
regression
line
was
­
0.479
and
­
0.5123
in
mice
and
guinea
pigs,
respectively,
4
corresponding
to
a
value
of
2.1
and
2.0
for
n.
5
Regarding
the
three
different
endpoints
and
the
data
obtained
for
mice
and
guinea
pigs
values
for
n
6
were
in
the
range
of
1.44
to
2.6
(
1.44;
1.46;
1.8;
2.0;
2.1;
2.6;
arithmetic
mean:
1.9
+/­
0.4).
Based
on
7
these
data
it
is
justified
to
use
a
value
of
n=
2
for
the
time
extrapolation
for
AEGL­
2
(
CNS­
effects)
and
8
AEGL­
3
(
cardiac
sensitization)
values
up
to
two
hours.
Concentrations
for
these
"
less­
than­
steady­
state"
9
durations
(
i.
e.
10,
30,
60
and
120
minutes)
should
be
calculated
according
to
10
C2
*
t
=
const.
11
Vinyl
chloride
PROPOSED
1:
3/
2004
67
APPENDIX
C
­
Cancer
Assessment
of
Vinyl
Chloride
1
Vinyl
chloride
PROPOSED
1:
3/
2004
68
Cancer
Assessment
of
Vinyl
Chloride
1
2
The
most
recently
published
risk
estimate
from
the
US
EPA
seems
to
be
the
best
unit
risk
estimate
3
currently
available
(
US
EPA
2000
a,
b).
The
values
are
8.8
x
10­
6
(

g/
m3)­
1
for
continuous
lifetime
4
exposure,
including
childhood,
and
4.4
x
10­
6
(

g/
m3)­
1
for
continuous
exposure
as
an
adult.
These
risk
5
values
indicate
that
exposure
during
childhood
results
in
a
similar
tumor
incidence
as
exposure
as
an
adult.
6
The
EPA
unit
risk
calculation
was
derived
by
using
the
PBPK
model
of
Clewell
et
al.
(
1995,
2002).
These
7
risk
values
are
based
on
model­
derived
estimates
of
internal
dose
of
the
active
metabolite
in
animals
and
the
8
continuous
external
exposure
in
humans
that
would
result
in
these
same
internal
dose
of
the
active
9
metabolite.
10
Several
calculations
for
cancer
risk
are
presented
below.
These
are:
11
Calculation
A:
based
on
the
unit
risk
for
continuous
lifetime
exposure
from
EPA
(
2002
a,
b),
transformed
12
to
a
single
24
hour
exposure
estimate
by
the
default
procedure
recommended
in
the
SOP
on
13
AEGL
development
(
that
is,
linear
transformation,
correction
by
a
factor
of
6
to
account
14
for
the
relevance
of
sensitive
stages
in
development).
Exposures
of
less
than
24
hours
are
15
derived
using
the
PBPK
model
of
Clewell
et
al.
(
1995,
2002).
16
Calculation
B:
based
on
the
unit
risk
for
childhood
exposure
only
(
possibly
the
first
10
years
of
age)
as
17
estimated
by
US
EPA
(
2002
a,
b),
transformed
to
a
single
24
hour
exposure
estimate
by
18
the
default
procedure
recommended
in
the
SOP
on
AEGL
development
(
that
is,
linear
19
transformation,
correction
by
a
factor
of
6
to
account
for
the
relevance
of
sensitive
stages
20
in
development).
Exposures
of
less
than
24
hours
are
derived
using
the
PBPK
model
of
21
Clewell
et
al.
(
1995,
2002).
22
Calculation
C:
based
on
the
cancer
incidence
as
evident
from
a
five­
weeks
animal
study
from
Maltoni
et
23
al.
(
1981),
assuming
that
5
weeks
of
exposure
of
animal
is
equivalent
to
about
150
weeks
24
exposure
of
humans,
with
linear
transformation
to
a
single
24
hour
exposure
without
25
further
correction
for
potential
sensitive
stages
of
tumor
development.
Exposures
of
less
26
than
24
hours
are
derived
using
the
PBPK
model
of
Clewell
et
al.
(
1995,
2002).
27
Calculation
D:
based
on
the
NOAEL
for
DNA
adducts
after
single
in
vivo
exposure
of
adult
animals
and
28
the
application
of
an
uncertainty
factor
for
intraspecies
variability.
29
Calculation
C
is
judged
to
be
the
best
basis
for
estimation
of
the
risk
for
carcinogenic
effects
after
single
30
exposure
and
is
included
into
the
main
part
of
the
TSD.
However,
substantial
uncertainties
on
risk
31
quantification
exist.
32
Calculation
A:
based
on
the
unit
risk
for
continuous
lifetime
exposure
from
EPA
(
2002
a,
b),
transformed
33
to
a
single
24
hour
exposure
estimate
by
the
default
procedure
recommended
in
the
SOP
on
34
AEGL
development
(
that
is,
linear
transformation,
correction
by
a
factor
of
6
to
account
35
for
the
relevance
of
sensitive
stages
in
development).
Exposures
of
less
than
24
hours
are
36
derived
using
the
PBPK
model
of
Clewell
et
al.
(
1995,
2002).
37
Vinyl
chloride
PROPOSED
1:
3/
2004
69
AEGL
SOP
Calculation
1
The
US
EPA's
unit
risk
estimate
for
continuous
lifetime
exposure
(
inclusive
of
childhood)
is
8.8
x
2
10­
6
(

g/
m3)­
1.
This
unit
risk
was
derived
using
the
PBPK
model
of
Clewell
et
al
(
1995,
2002)
which
3
relates
liver
tumor
incidence
in
animals
with
the
lifetime
average
daily
dose
of
the
vinyl
chloride
metabolite
4
in
the
liver
believed
responsible
for
the
tumor
response
(
that
is,
the
internal
dose
of
the
metabolite).
The
5
model
then
uses
human
parameters
to
transform
that
internal
dose
to
an
external
exposure
concentration
for
6
humans.
7
Unit
risk
for
continuous
lifetime
exposure:
8.8
x
10­
6
per

g/
m3
8
Exposure
at
a
risk
of
1
in
10,000:
11.36

g/
m3
9
To
convert
a
70
year
exposure
to
a
24
hour
exposure,
the
exposure
is
multiplied
by
the
number
of
days
in
10
70
years.
Under
this
strict
c
x
t
assumption,
these
exposures
are
considered
equipotent.
11
11.36

g/
m3
x
25,600
=
291
mg/
m3
12
To
account
for
uncertainty
regarding
the
variability
in
the
stage
of
the
cancer
process
at
which
VC
or
its
13
metabolites
may
act,
a
multistage
factor
of
6
is
applied
(
NRC,
2001).
14
291
mg/
m3
x
1/
6
=
48.5
mg/
m3
(
18.4
ppm)
15
Based
on
this
transformation,
a
24
hour
VC
exposure
at
this
concentration
would
result
in
a
10­
4
risk.
For
16
10­
5
and
10­
6
risk,
the
10­
4
value
is
reduced
by
10­
and
100­
fold,
respectively.
This
estimate
is
based
on
the
17
assumption
of
a
strict
c
x
t
relationship.
18
PBPK
model
calculations
for
an
exposure
less
than
24
hours
19
As
mentioned
above,
the
basis
of
US
EPA's
risk
estimate
is
the
internal
dose,
the
lifetime
average
20
daily
dose(
LADD)
of
VC
metabolite
in
the
liver.
For
numerous
reasons
this
metric
may
be
quite
different
21
after
a
single
exposure
of
less
than
24
hours.
Rather
than
make
any
assumption
about
the
extent
to
which
c
22
x
t
may
or
may
not
be
operative,
the
PBPK
model
was
used
to
estimate
directly
the
internal
dose
to
the
liver
23
under
different
external
exposure
regimes.
These
data
are
shown
in
the
table
and
figure
below.
24
From
above,
the
external
exposure
corresponding
to
a
10­
4
risk
with
a
24
hour
exposure
is
48.5
25
mg/
m3.
Values
for
less
than
24
hour
exposure
are
determined
by
interpolation
using
Table
1.
The
internal
26
dose
metric
(
mg/
L
Liver)
corresponding
to
a
10­
4
risk
with
a
24
hour
exposure
is
51.4
mg/
L
(
48.5
mg/
m3
27
divided
by
100
mg/
m3
times
106
mg/
L.
The
external
exposure
necessary
to
give
51.4
mg/
L
Liver
after
an
28
8
hour
exposure
is
147
mg/
m3
(
51.4
mg/
L
divided
by
35.0
mg/
L
times
100
mg/
m3).
A
corresponding
29
calculation
was
made
for
each
exposure
duration
(
0.5
hours,
1
hr,
4
hrs,
and
8
hrs)
and
each
risk
level
(
10­
30
4,
10­
5,
and
10­
6).
31
Dose
to
the
liver
(
mg/
L)
of
active
metabolite
at
24
hours
after
exposure
to
VC
32
mg/
m3
0.5
hr
1
hr
4
hr
8
hr
24
hr/
70
yrs
33
1
0.022
0.044
0.176
0.352
1.07
34
10
0.220
0.441
1.76
3.52
10.7
35
Vinyl
chloride
PROPOSED
1:
3/
2004
70
100
2.19
4.38
17.5
35.0
106
1
200
4.36
8.72
34.8
69.4
211
2
300
6.50
13.0
51.8
103
313
3
400
8.61
17.2
68.4
136
413
4
500
10.7
21.3
84.5
169
510
5
600
12.7
25.2
100
199
604
6
700
14.6
29.1
115
229
692
7
800
16.5
32.7
129
256
775
8
900
18.2
36.1
142
282
850
9
1000
19.9
39.3
153
304
917
10
2000
30.4
57.7
211
412
1220
11
3000
35.7
65.8
231
442
1300
12
4000
39.7
71.9
243
461
1350
13
5000
43.3
77.2
254
476
1390
14
6000
46.6
82.1
264
490
1420
15
7000
49.7
86.7
273
502
1460
16
8000
52.3
91.1
279
513
1490
17
9000
54.7
95.3
284
523
1520
18
10000
57.0
99.3
289
533
1540
19
Figure
5
shows
the
PBPK
modeling
results
graphically
(
with
a
cut­
off
for
the
external
concentration
at
20
2000
mg/
m3).
21
Vinyl
chloride
PROPOSED
1:
3/
2004
71
FIGURE
5:
EXTERNAL
CONCENTRATION
(
mg/
m3)
AND
DOSE
TO
LIVER
(
mg/
L)
AS
1
CALCULATED
BY
PBPK­
MODELING
BY
EPA
(
Personal
Communication,
Gary
Foureman,
US
2
EPA,
NCEA­
RTP,
June
2003)
3
If
the
exposure
is
limited
to
a
fraction
of
a
24­
hour
period,
the
exposure
corresponding
to
the
various
risk
4
levels
are
presented
in
the
table
below.
5
Exposure
Duration
6
10­
4
risk
10­
5
risk
10­
6
risk
8
hours
7
147
mg/
m3
(
55.9
ppm)
14.6
mg/
m3
(
5.55
ppm)
1.46
mg/
m3
(
0.555
ppm)

4
hours
8
298
mg/
m3
(
113
ppm)
29.2
mg/
m3
(
11.1
ppm)
2.92
mg/
m3
(
1.11
ppm)

1
hour
9
1780
mg/
m3
(
676
ppm)
117
mg/
m3
(
44.5
ppm)
11.6
mg/
m3
(
4.45
ppm)

30
minutes
10
7870
mg/
m3
(
2990
ppm)
236
mg/
m3
(
89.7
ppm)
23.3
mg/
m3
(
8.97
ppm)
Vinyl
chloride
PROPOSED
1:
3/
2004
72
Calculation
B:
based
on
the
unit
risk
for
childhood
(
possibly
first
10
years
of
age)
as
estimated
by
EPA
1
(
2000
a,
b),
transformed
to
a
single
exposure
estimate
by
the
default
procedure,
2
recommended
in
the
SOP
on
AEGL
development
(
i.
e.
linear
transformation,
correction
by
3
a
factor
of
6
to
account
for
the
relevance
of
sensitive
stages
in
development).
Exposures
of
4
less
than
24
hours
derived
using
the
PBPK
model
of
Clewell
et
al.
(
1995,
2002).
5
The
unit
risk
calculation
of
EPA
is
based
on
the
occurrence
of
angiosarcoma
in
newborn
rats
(
5
weeks
6
exposure)
which
were
observed
with
similar
incidences
as
in
adult
female
rats
(
52
weeks
exposure
7
beginning
at
13
weeks
of
age;
see
Table
C1).
Thus,
the
unit
risk
for
adults
(
long
term
study)
was
directly
8
calculated
and
was
assumed
to
be
roughly
identical
for
childhood
(
first
10
years
of
exposure).
9
unit
risk
for
continuous
childhood
exposure:
4.4
x
10­
6
per
µ
g/
m3
(
first
10
years)
10
dose
at
risk
1
:
10,000:
22.73
µ
g/
m3
11
To
convert
a
10
year
exposure
(=
10
x
365.7
=
3657)
to
a
24
hours
exposure,
the
dose
is
multiplied
by
the
12
number
of
days
in
10
years:
13
22.73
µ
g/
m3
x
3657
=
83.1
mg/
m3
14
To
account
for
uncertainty
regarding
the
variability
in
the
stage
of
the
cancer
process
at
which
VC
or
its
15
metabolites
may
act,
a
multistage
factor
of
6
is
applied
(
NRC,
2001):
16
83.1
mg/
m3
x
1/
6
=
13.85
mg/
m3
17
Therefore,
based
upon
the
potential
carcinogenicity
of
VC
during
early
life,
a
24
h
exposure
corresponding
18
to
a
10­
4
risk
would
be
13.85
mg/
m3
(
5.26
ppm).
For
10­
5
and
10­
6
risk
levels,
the
10­
4
values
are
reduced
by
19
10­
fold
and
100­
fold,
respectively.
20
If
the
exposure
is
limited
to
a
fraction
of
a
24­
hour
period,
the
exposure
corresponding
to
the
various
risk
21
levels
are
presented
in
the
table
below.
These
values
were
calculated
using
the
PBPK
model
for
vinyl
22
chloride
as
described
above
for
calculation
A.
23
Exposure
Duration
24
10­
4
risk
10­
5
risk
10­
6
risk
8
hours
25
42.1
mg/
m3
(
16.0
ppm)
4.21
mg/
m3
(
1.60
ppm)
0.421
mg/
m3
(
0.160
ppm)

4
hours
26
84.5
mg/
m3
(
32.1
ppm)
8.41
mg/
m3
(
3.20
ppm)
0.840
mg/
m3
(
0.329
ppm)

1
hour
27
342
mg/
m3
(
130
ppm)
33.6
mg/
m3
(
12.8
ppm)
3.36
mg/
m3
(
1.28
ppm)

30
minutes
28
709
mg/
m3
(
269
ppm)
67.5
mg/
m3
(
25.7
ppm)
6.72
mg/
m3
(
2.55
ppm)

Calculation
C:
based
on
the
cancer
incidence
as
evident
from
a
five­
weeks
animal
study
from
Maltoni
et
29
al.
(
1981),
assuming
that
5
weeks
of
exposure
of
animal
is
equivalent
to
about
150
weeks
30
Vinyl
chloride
PROPOSED
1:
3/
2004
73
exposure
of
humans,
with
linear
transformation
to
a
single
24
hour
exposure
without
1
further
correction
for
potential
sensitive
stages
of
tumor
development.
Exposures
of
less
2
than
24
hours
are
derived
using
the
PBPK
model
of
Clewell
et
al.
(
1995,
2002).
3
The
study
seems
to
be
relevant,
as
4
°
investigations
were
performed
with
newborn
rats
which
represent
a
sensitive
subgroup
for
the
5
endpoint
carcinogenesis
6
°
exposure
was
over
a
short
period
of
time
7
°
endpoints
(
incidence
of
liver
angiosarcoma)
are
relevant
for
humans.
8
Data
are
shown
in
table
C1:
9
TABLE
C1:
INCIDENCE
OF
TUMORS
IN
THE
STUDIES
FROM
MALTONI
ET
AL.,
1981,
10
(
EXPERIMENTS
BT
14
AND
BT
1),
CITED
FROM
EPA,
2000a
11
Administered
concentration
(
ppm)
12
Angiosarcoma
Hepatoma
4
hours/
day,
5
days/
week
for
5
weeks
starting
at
day
1
(
BT
14)
13
6000
14
20/
42
(
48%),
all*
17/
42
(
40.5%)
,
LAS*
20/
42
(
47,6
%)

10000
15
18/
44
(
41%),
all*
15/
44
(
34.1%),
LAS*
20/
44
(
45,4
%)

4
hours/
day,
5
days/
week
for
52
weeks
starting
at
age
13
weeks
(
BT
1)
16
6000
17
22/
42
(
52%),
all*
13/
42
(
31%),
LAS*
1/
27
(
3,7%)

10000
18
13/
46
(
28
%),
all*
7/
46
(
15%),
LAS*
1/
24
(
4,2%)

*
Angiosarcoma,
all
sites
include
extra­
liver
angiosarcoma,
including
angioma;
LAS:
liver
angiosarcoma
(
only
19
those
were
taken
for
further
risk
quantifications)
20
Derivation
on
the
Inhalation
Unit
Risk
21
Exposure
concentration:
6,000
ppm
22
liver
angiosarcoma
40.5
%
23
6,000
ppm
corresponds
to
a
human
equivalent
concentration
of
51
ppm
(
132
mg/
m3),
based
on
the
PBPK
24
model
published
by
Clewell
et
al.
(
1995).
Corresponding
data
are
shown
in
table
C2
(
note
that
rats
25
exposure
is
intermittent
(
4hours/
day;
5
days/
week)
compared
to
HEC
(
human
equivalent
exposure)
which
26
is
given
for
continuous
exposure
(
24
hours/
day)).
Note
further
that
saturation
in
rats
leads
to
only
minor
27
increases
of
metabolite
concentrations,
when
exposure
exceeds
250
ppm
(
intermittent
exposure).
The
28
derivation
of
the
Inhalation
Unit
Risk
is
based
on
the
assumption
that
the
tumor
response
is
a
linear
29
function
of
the
concentration
of
the
active
metabolite
in
the
liver
(
HEC).
See
Table
C2.
30
Vinyl
chloride
PROPOSED
1:
3/
2004
74
132
mg/
m3
=
40.5%;
1
=>
3.3
mg/
m3
=
1%;
2
=>
33
µ
g/
m3
=
0.01%
=
1:
10,000
3
dose
at
risk
(
1:
10,000):
33.0
µ
g/
m3
4
conversion
from
5
weeks
to
24
h
exposure:
5
Newborn
rats
grow
about
30
times
faster
than
newborn
humans
(
NRC,
1993),
which
is
similar
to
the
ratio
6
of
lifetime
75
years
(
human):
2.5
years
(
rat)
=
30.
5
x
7
x
30
=
1050
7
33,0
µ
g/
m3
x
1050
days
=
34.7
mg/
m3
(
14
ppm)
8
An
additional
factor
to
adjust
for
uncertainties
in
assessing
potential
cancer
risks
under
short
term
9
exposures
is
not
applied,
as
exposure
was
short­
term
in
the
underlying
study.
10
Therefore,
based
upon
the
potential
carcinogenicity
of
VC
during
early
life,
a
24
h
exposure
corresponding
11
to
a
10­
4
risk
would
be
34.7
mg/
m3
(
13.2
ppm).
For
10­
5
and
10­
6
risk
levels,
the
10­
4
values
are
reduced
by
12
10­
fold
and
100­
fold,
respectively.
13
If
the
exposure
is
limited
to
a
fraction
of
a
24­
hour
period,
the
exposure
corresponding
to
the
various
risk
14
levels
are
presented
in
the
table
below.
These
values
were
calculated
using
the
PBPK
model
for
vinyl
15
chloride
as
described
above
for
calculation
A.
16
Exposure
Duration
17
10­
4
risk
10­
5
risk
10­
6
risk
8
hours
18
106
mg/
m3
(
40.3
ppm)
10.5
mg/
m3
(
3.99
ppm)
1.05
mg/
m3
(
0.399
ppm)

4
hours
19
213
mg/
m3
(
80.9
ppm)
21.0
mg/
m3
(
7.98
ppm)
2.10
mg/
m3
(
0.798
ppm)

1
hour
20
922
mg/
m3
(
350
ppm)
84.4
mg/
m3
(
32.1
ppm)
8.40
mg/
m3
(
3.19
ppm)

30
minutes
21
3110
mg/
m3
(
1180
ppm)
170
mg/
m3
(
64.6
ppm)
16.8
mg/
m3
(
6.38
ppm)

A
similar
result
is
obtained
if
the
tumor
data
from
Froment
et
al.
(
1994)
are
used.
Froment
et
al.
exposed
22
the
newborn
animals
to
only
500
ppm.
Hence,
fewer
extrapolations
were
needed
compared
to
the
Maltoni
et
23
al.
data.
(
Data
and
calculation
not
shown).
For
both
calculations,
relevant
uncertainty
on
the
influence
of
24
the
oral
uptake
of
mothers
´
milk
has
to
be
stated.
Because
of
metabolic
saturation
at
high
level
inhalation
25
exposure,
this
influence
may
have
been
limited.
However,
no
estimate
of
the
quantitative
consequences
of
26
this
multi
pathway
exposure
may
be
given.
27
TABLE
C2:
CONVERSION
OF
ADMINISTERED
VC
DOSE
TO
A
HUMAN
EQUIVALENT
28
CONCENTRATION
(
data
from
EPA,
2000a,
b)
29
Admin.
conc.
(
ppm)
a
30
Metabolite
(
mg/
L
liver)
b
HEC
(
ppm)
c
Vinyl
chloride
PROPOSED
1:
3/
2004
75
0
1
0
0
1
2
0.59
0.2
5
3
2.96
1
10
4
5.9
2
25
5
14.61
4.6
50
6
31.27
10.1
100
7
55.95
19
150
8
76.67
26
200
9
90
31
250
10
103.45
35
500
11
116.94
40
2500
12
134.37
48
6000
13
143.72
51
a
Animals
exposed
4
hours/
day,
5
days/
week
for
52
weeks.
14
b
Dose
metric
(
lifetime
average
delivered
dose
in
female
rats)
calculated
from
PBPK
modeling
of
the
15
administered
animal
concentration.
16
c
Continuous
human
exposure
concentration
over
a
lifetime
required
to
produce
an
equivalent
mg
17
metabolite/
L
of
liver.
18
Calculation
D:
based
on
the
NOAEL
for
DNA
adducts
after
single
in
vivo
exposure
of
adult
19
animals
and
the
application
of
an
uncertainty
factor
for
intraspecies
variability.
20
DNA­
adducts
seem
to
be
relevant
and
quantitatively
linked
to
carcinogenic
potency
of
VC:
21
°
ethenobases
were
shown
to
possess
miscoding
properties
(
Barbin,
2000)
and
are
slowly
repaired
22
(
Morinello
et
al.,
2002a)
23
°
ethenobases
generate
mainly
base
pair
substitution
mutations
(
Barbin,
2000)
24
°
ethenobases
assumed
to
be
initiating
lesions
in
carcinogenesis
(
Barbin,
2000)
25
°
high
correlation
between
DNA­
adducts
formation
(
 G)
and
incidence
of
haemangiosarcoma
in
mice
26
after
exposure
to
vinyl
fluoride
(
Swenberg
et
al.,
1999)
27
Elevated
DNA­
adducts
were
seen
after
single
5
hour
exposure
of
adult
rats
to
250
ppm
VC
(
Bolt
et
28
al. 
1980).
Watson
et
al.
(
1991)
exposed
adult
male
Fisher
344
rats
for
6
hours
to
atmospheres
containing
1,
29
10,
or
45
ppm
VC.
The
alkylation
frequencies
of
7­(
2'­
oxoethyl)
guanine
(
OEG)
in
liver
DNA
were
0.026,
30
0.28
and
1.28
residues
OEG
per
106
nucleotides
respectively.
With
these
air
concentrations,
there
was
no
31
evidence
to
indicate
the
formation
of
the
cyclic
adducts
1,
N6­
ethenoadenine
(
 A)
or
3,
N4­
ethenocytosine
32
(
 C).
The
threshold
for
detection
of
these
adducts
were
about
1
adduct
per
1
x
108
nucleotides.
Swenberg
et
33
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76
al.
(
1999)
reported
a
factor
1/
10
­
1/
100
to
calculate
the
amount
of
N2,3­
ethenoguanine
(
 G)
in
relation
to
1
OEG.
Thus,
 G
would
be
lower
than
0.1
­
0.01
per
106
nucleotides
at
45
ppm.
This
would
equal
the
2
reported
background
of
 G
(
Swenberg
et
al.,
1999).
It
may
be
concluded
that
single
exposure
to
45
ppm
3
VC
(
6
hours)
would
not
lead
to
an
increase
of
relevant
cyclic
adducts
(
 A,
 C,
 G)
in
adult
rats.
4
5
With
higher
DNA­
adduct
levels
(
at
higher
single
exposure,
or
in
young
rats,
or
after
repeated
short
6
term
exposure)
there
apparently
is
a
relevant
correlation
to
mutations,
foci
or
carcinogenicity:
Adult
rats
7
repeatedly
(
5
days)
exposed
to
10
ppm
VC
for
6
hours/
day
showed
slightly
elevated
etheno­
adducts
(
 G)
8
compared
to
control
(
Swenberg
et
al.,
2000).
Higher
adduct
levels
were
seen
in
young
animals
than
in
adult
9
animals
after
identical
treatment
(
Fedtke
et
al.,
1990;
Laib
et
al.,
1989;
Ciroussel
et
al.,
1990,
Morinello
et
10
al.,
2002a).
Respective
mutations
(
e.
g.,
G­>
A
transitions,
A­>
T
transitions)
were
observed
in
VC­
induced
11
tumors
(
Barbin,
2000).
Despite
relevant
repair,
no
full
reduction
to
background
was
observed
for
these
12
adducts
two
weeks
after
a
5
day
exposure
(
4
hours/
day)
to
600
ppm
(
Swenberg
et
al.,
1999).
DNA­
adducts
13
formation
(
 G)
in
whole
liver
DNA
or
hepatocytes
increased
linearly
from
5
days
to
8
weeks
after
exposure
14
of
rats
to
500
ppm
or
10
ppm
VC
(
Morinello
et
al.,
2002a).
Table
C3
presents
the
data
for
relevant
DNA­
15
adducts
after
short
term
exposure
to
VC
for
different
concentrations
and
exposure
durations
and
gives
an
16
indication
about
the
reversibility.
17
TABLE
C3:
DNA­
ADDUCTS
AFTER
SINGLE
AND
SHORT
TERM
VC
EXPOSURE
18
VC­
inhalation
(
ppm)
19
0
1
10
45
100
600
7­(
2'­
oxoethyl)
guanine
(
OEG)
20
[
adducts/
nucleotides]
1
21
0.026/
106
0.28/
106
1.28/
106
1,
N6­
ethenoadenine
(
 A)
1
22
<
1/
108
3,
N4­
ethenocytosine
(
 C)
1
23
<
1/
108
N2,3­
ethenoguanine
(
 G)*
24

1/
108
for
comparison2:
25
 G­
Background
(
rat)
26
0.9/
107
 G,
5
days
27
2/
107
6.8/
107
 G,
20
days
28
5.3/
107
2.3/
106
 G,
4h/
d,
5d,
immed.
after
exposure
29
3.8/
106
 G,
4h/
d,
5d,
14
days
after
exposure
30
4.7/
107
 G­
Background
(
human)
31
6/
108
­
7/
107
*
estimated
(
 G)
by
the
authors
of
the
TSD
from
ratio

1/
100
OEG/
 G
in
other
VC
experiments
32
1
data
from
Watson
et
al.,
1991;
2
data
from
Swenberg
et
al.,
1999
33
Vinyl
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77
TABLE
C4:
ADDUCTS
RATIO
NEONATE:
ADULT
FOR
VINYL
CHLORIDE
1
Swenberg
et
al.,
1999
2
(
OEG)
3
600
ppm
4
5d,
4h/
d,
rat
5
Swenberg
et
al.,
1999
(
 G)
600
ppm
5d,
4h/
d,
rat
Ciroussel
et
al.,
1990
(
 dAdo/
dAdo)
500
ppm
2
weeks,
7h/
d,
rat
Ciroussel
et
al.,
1990
(
 dCyd/
dCyd)
500
ppm
2
weeks,
7h/
d,
rat
162/
43

3.8
6
1.81/
0.47

3.9
1.3/
0.19

6.8
4.92/
0.8

6.15
7
calculation
of
an
practical
threshold
("
NAEL")
for
short
term
exposure:
8
Intraspecies:
Because
of
the
high
sensitivity
of
young
animals
an
intraspecies
factor
of
10
is
9
regarded
as
necessary.
This
is
supported
by
comparisons
between
effects
at
different
ages
based
on
tumors,
10
foci
or
DNA­
adducts.
For
DNA­
adducts
a
comparison
is
shown
in
table
C4.
11
Interspecies:
There
is
no
apparent
higher
sensitivity
of
men
compared
to
rats,
which
is
supported
12
by
the
comparison
of
unit
risks
derived
from
animal
data
respectively
human
data
(
Clewell
et
al.,
2001).
13
This
leads
to
an
uncertainty
factor
for
interspecies
differences
of
1
(
EPA,
2000a).
14
Exponent
for
time
extrapolation:
Steady
state
is
not
reached
within
8
hours
as
evidenced
by
the
15
longer
halftime
of
metabolites.
Thus,
default
time
extrapolation
should
be
performed
based
on
the
observed
16
NOAEL
at
6
hours
exposure.
This
leads
to
an
estimated
close
to
background
level
as
quantified
by
the
17
calculations
below:
18
Key
study:
Watson
et
al.,
1991;
Swenberg
et
al.,
1999;
Barbin,
2000
19
Toxicity
endpoint:
DNA­
adducts;
background
adduct
levels
at
single
45
ppm
exposure
of
rats
is
20
taken
as
practical
"
NAEL"
(
6
hours)
21
Uncertainty/
Combined
uncertainty
factor
of
10
22
modifying
factors:
1
for
interspecies
variability
23
10
for
intraspecies
variability
24
Time
Scaling:
C3
x
t
=
k
for
extrapolation
to
4­
hour,
1­
hour,
and
30­
minute;
25
k
=
(
45
ppm)
3
x
360
min
=
3,2
x
10E+
7
ppm3
min
26
C1
x
t
=
k
for
extrapolation
to
8­
hours;
27
k
=
45
ppm
x
360
min
=
16,200
ppm1
min
28
29
30­
minute:
C3
x
30
min
=
3,2
x
10E+
7
ppm3
min
30
C
=
103
ppm
31
30­
min
NAEL
=
103
ppm/
10
=
10
ppm
(=
26
mg/
m3)
32
1­
hour:
C3
x
60
min
=
3,2
x
10E+
7
ppm3
min
33
C
=
81.8
ppm
34
1­
h
NAEL
=
81.8
ppm/
10
=
8.2
ppm
(=
21
mg/
m3)
35
Vinyl
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78
4­
hour:
C3
x
240
min
=
3,2
x
10E+
7
ppm3
min
1
C
=
51.5
ppm
2
4­
h
NAEL
=
51.5
ppm/
10
=
5.1
ppm
(=
13
mg/
m3)
3
8­
hour:
C
x
480
min
=
16200
ppm
min
4
C
=
33.75
ppm
5
8­
h
NAEL
=
34
ppm/
10
=
3.4
ppm
(=
8.8
mg/
m3)
6
Concluding
remark:
7
Table
C5
provides
an
overview
of
the
calculations
on
carcinogenic
potency
after
single
exposure
as
derived
8
above
compared
to
the
AEGL­
values
derived
based
on
nonmalignant
effects.
9
TABLE
C5:
COMPARISON
OF
AEGL
VALUES
(
VC)
BASED
ON
NONMALIGNANT
10
EFFECTS
AND
DIFFERENT
ESTIMATIONS
OF
CARCINOGENIC
RISK
AFTER
SINGLE
11
EXPOSURE
12
[
ppm]
13
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
AEGL­
1(
Baretta
et
al.,
UF:
3;
n=
3,1)
14
450
310
250
140
70
AEGL­
2
(
Lester
et
al.,
UF:
3;
n=
2
to
2h;
2h=
4h=
8h)
15
2800
1600
1200
820
820
AEGL­
3
(
Clark
&
Tinston;
UF:
3;
n=
2
to
2h;
16
2h=
4h=
8h)
17
12000
6800
4800
3400
3400
Estimation
of
carcinogenic
potency
(
10­
4
risk):
18
CALCULATION
A
(
unit
risk)
default
SOP;
linear
19
transformation
20
lifetime
unit
risk
x
6
21
2990
676
113
55.9
CALCULATION
B
(
unit
risk)
linear
22
transformation,
early
life=
10
years,
x
6
23
269
130
32.1
16
CALCULATION
C
(
Maltoni
et
al.,
1981,
risk­
direct
24
from
5w­
study);
Human
equivalent
dose
to
6000
ppm;
25
growth
rate
rat/
hum:
30
26
1180
350
80.9
40.3
CALCULATION
D
(
Watson
et
al.,
(
DNA)),
UF:
3;
27
n=
3:
30,60,
120,480
min;
n=
1:
8h;
10
min=
30min.
28
10
8.2
5.1
3.4
Calculation
C
is
judged
to
be
the
best
basis
for
estimation
of
the
risk
for
carcinogenic
effects
after
single
29
exposure
and
is
included
into
the
main
part
of
the
TSD.
However,
substantial
uncertainties
on
risk
30
quantification
persists.
31
Vinyl
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79
APPENDIX
D
­
Occupational
epidemiological
studies
on
carcinogenicity
(
focus:
limited
exposure
1
time)
2
Vinyl
chloride
PROPOSED
1:
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2004
80
Two
large
studies
of
workers
employed
in
the
VCM/
PVC
industry
prior
to
1974
were
completed.
1
Both
studies
were
retrospective
cohort
mortality
studies.
The
first
study
was
done
in
Europe
and
included
2
study
populations
in
Italy,
Norway,
Sweden
and
United
Kingdom.
The
second
study
included
plants
in
the
3
United
States
and
Canada.
Each
study
has
been
updated
multiple
times
and
has
been
the
subject
of
4
numerous
papers.
Only
the
results
from
the
most
recent
updates
are
discussed
here.
The
focus
is
to
review
5
the
liver
cancer
incidence
in
workers
exposed
to
VCM
for
relatively
short
time
periods
or
where
the
6
cumulative
dose
(
ppm­
years)
was
known
to
have
been
low.
Both
studies
have
more
deaths
than
expected
7
from
ASLs
among
workers
with
high
and/
or
long
exposure
to
VCM
(
Ward
et
al.,
(
2000)
and
Mundt
et
al.,
8
(
1999)).
A
third
study
from
Weber
et
al.
(
1981)
with
epidemiologic
data
from
Germany
shows
9
conflicting
results
to
the
above
cited
large
studies.
10
European
Study
11
The
European
study
includes
approximately
12,700
men
with
at
least
one
year
of
employment
in
12
the
VCM/
PVC
industry
from
1955
to
1974
(
Ward
et
al.,
2000).
Three
of
the
19
plants
had
incomplete
13
records
and
thus
the
starting
date
for
these
three
plants
ranged
from
1961
to
1974.
The
vital
status
follow­
14
up
was
complete
through
1997.
Age­
and
calendar
period­
specific
mortality
rates
for
males
from
Italy,
15
Norway,
Sweden
and
United
Kingdom
were
used
to
calculate
the
Standardized
Mortality
Ratios
(
SMR)
and
16
Confidence
Intervals
(
CI).
Typical
exposure
scenarios
were
estimated
by
industrial
hygienists
based
on
job
17
exposure
matrices.
These
job
exposure
matrices
were
based
primarily
on
job
title
and
were
reviewed
by
two
18
other
industrial
hygienists
with
several
years
of
experience
in
the
VC
industry.
Information
provided
in
the
19
job
exposure
matrix
was
used
to
develop
a
ranked
level
of
exposure
index.
Quantitative
estimates
of
20
exposure
were
obtained
for
82%
of
the
cohort.
21
The
total
number
of
person­
years
at
risk
by
the
cohort
is
324,701.
The
work
force
was
classified
22
by
duration
of
employment,
<
3,
3­
6,
7­
11,
12­
18
and
19+
ppm­
years.
The
SMR
(
CI)
for
liver
cancer
for
23
workers
with
less
than
3
years
experience
was
62
(
2­
345),
below
the
expected
value
(
Table
D1).
For
24
workers
exposed
to
VCM/
PVC
for
a
longer
time
period,
the
incidence
of
liver
cancer
was
higher
than
25
expected.
In
general,
the
incidence
of
liver
cancer
increased
with
years
of
employment
in
the
VCM/
PVC
26
industry.
27
In
addition,
Ward
et
al.,
(
2000),
examined
cumulative
exposure
for
the
cohort
(
Table
D2).
Again,
28
the
work
force
was
subdivided
into
0­
734,
735­
2379,
2380­
5188,
5189­
7531
and
7532+
ppm­
years.
The
29
SMR
(
CI)
was
107
(
54­
192)
based
on
11
observed
liver
cancers
and
10.26
expected.
Assuming
workers
30
are
employed
in
the
industry
for
up
to
30
years,
to
be
included
in
this
first
category,
the
highest
average
31
concentration
the
worker
would
have
been
exposed
to
was
~
25
ppm.
Workers
with
shorter
work
histories
32
may
have
been
exposed
to
much
higher
concentrations.
Under
this
scenario
there
was
no
increase
in
the
33
incidence
of
liver
cancer.
As
previously
noted,
the
incidence
of
liver
cancer
increased
with
cumulative
34
exposure
with
an
SMR
(
CI)
of
1140
(
571­
2050)
for
those
workers
with
a
cumulative
exposure
of
7532+
35
ppm­
years.
However,
of
the
11
liver
cancers
observed
in
the
0­
734
ppm­
year
cumulative
exposure
36
group,
fours
were
angiosarcomas.
These
four
angiosarcomas
occurred
in
individuals
with
287­
37
734
ppm­
years
cumulative
exposure
(
Ward
et
al.,
2001).
There
were
no
angiosarcomas
reported
38
in
workers
with
less
than
287
ppm­
years
cumulative
exposure.
39
Vinyl
chloride
PROPOSED
1:
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2004
81
North
American
Study
1
The
North
American
study
consists
of
approximately
10,100
men
employed
for
at
least
one
year
in
2
the
VCM/
PVC
industry
from
1942­
1974
(
Mundt
et
al.,
1999).
This
group
was
followed
through
December
3
31,
1995.
Thus,
most
workers
have
been
followed
for
at
least
twenty
one
years.
Since
the
VCM/
PVC
4
industry
was
located
in
16
states
and
one
Province
of
Canada,
mortality
rates
for
16
states
were
used
to
5
calculate
SMR's.
For
the
Province
of
Canada,
mortality
rate
data
from
the
state
of
Michigan
was
used
since
6
it
was
geographically
the
closest
to
the
plant.
As
of
December
31,
1995,
30%
of
the
study
group
were
7
deceased
Although
the
authors
of
previous
studies
had
attempted
to
categorize
individuals
by
exposures,
8
no
consistent
criteria
had
been
used
and
thus
no
attempt
was
made
to
estimate
exposure
levels
in
this
study.
9
The
age
at
first
exposure,
duration
of
exposure
and
year
of
first
exposure
appeared
to
be
related
to
10
cancer
of
the
liver
and
biliary
tract
(
data
not
shown).
Of
these,
duration
of
exposure
had
the
greatest
11
significance
and
appeared
to
be
independent
of
age
at
first
exposure
and
year
of
first
exposure
(
Table
D3).
12
Mundt
categorized
the
cohort
into
groups
working
1­
4,
5­
9,
10­
19
or
20+
years
in
the
VCM/
PVC
industry.
13
Nearly
half
of
the
cohort
worked
for
less
than
5
years
in
the
VCM/
PVC
industry
with
fewer
workers
in
14
each
of
the
subsequent
groups.
This
data
shows
that
working
in
the
VCM/
PVC
industry
for
1­
4
years
15
resulted
in
a
slightly
lower
liver
cancer
rate
than
expected.
Working
in
this
industry
for
longer
periods
of
16
time
resulted
in
higher
death
rates
than
expected
for
liver
and
biliary
tract
cancer.
Mundt
et
al.
(
2000)
also
17
examined
the
incidence
of
angiosarcomas
based
on
duration
of
exposure.
Three
individuals
working
in
the
18
VCM/
PVC
industry
for
1­
4
years
have
ASLs.
No
further
information
on
exposure
or
job
classification
19
was
provided.
20
Both
of
these
studies
have
shown
that
working
in
the
VCM/
PVC
industry
for
<
3
years
or
to
a
low,
21
but
still
relevant,
estimated
concentration
of
VCM
resulted
in
liver
cancer
rates
very
close
to
expected
22
values.
A
low
incidence
of
ASLs
was
reported
by
both
Ward
et
al.
(
2000)
and
Mundt
et
al.
(
2000)
but
23
based
on
the
Ward
study
appeared
to
be
related
to
higher
ppm­
years
exposure.
24
TABLE
D1:
LIVER
CANCER
INCIDENCE
FOR
ALL
EUROPEAN
COUNTRIES
BY
25
DURATION
OF
EMPLOYMENTA
26
Duration
of
Incidence
27
Employment
(
years)
28
Number
of
Individualsb
Number
of
person
years
(
Observed/
Expected)
SMR
(
95%
CI)
c
<
3
29
10961
91970
1/
1.61
62
(
2­
345)

3­
6
30
8999
79747
3/
1.44
208
(
43­
609)

7­
11
31
6919
65789
7/
1.35
517
(
208­
1060)

12­
18
32
4610
55149
5/
1.42
352
(
114­
821)

19+
33
2006
32050
13/
1.46
893
(
475­
1530)

Total
34
12700
324706
29/
7.29
398
(
267­
572)

a
From
Tables
T1.7
and
D7
of
Ward
et
al.,
(
2000).
35
b
Number
of
individuals
cited
for
various
employment
intervals
add
up
to
greater
than
12,700
since
36
individuals
can
meet
more
than
one
criteria
as
defined
by
the
author.
37
c
SMR
=
Observed/
Expected
*
100.
CI
=
Confidence
Intervals.
38
Vinyl
chloride
PROPOSED
1:
3/
2004
82
TABLE
D2:
LIVER
CANCER
INCIDENCE
FOR
ALL
EUROPEAN
COUNTRIES
BY
1
CUMULATIVE
EXPOSUREA
2
Cumulative
Exposure
3
(
ppm­
years)
4
Number
of
Individualsb
Number
of
person
years
Incidence
(
Observed/
Expected)
SMR
(
95%
CI)
c
Unknown
5
2243
52300
2/
3.19
63
(
8­
227)

0­
734
6
9552
188204
11/
10.26
107
(
54­
192)

735­
2379
7
2772
43174
9/
3.32
271
(
124­
515)

2380­
5188
8
1463
26480
10/
2.62
382
(
183­
703)

5189­
7531
9
515
9274
10/
1.77
566
(
271­
1040)

7532+
10
215
5274
11/
0.96
1140
(
571­
2050
Total
11
12700
324706
53/
22.11
240
(
1800­
3140)

a
From
Tables
12
and
D7
of
Ward
et
al.,
(
2000).
12
b
Number
of
individuals
cited
for
various
employment
intervals
add
up
to
greater
than
12,700
since
13
individuals
can
meet
more
than
one
criteria
14
c
SMR
=
Observed/
Expected
*
100.
CI
=
Confidence
Intervals.
15
TABLE
D3:
LIVER
AND
BILIARY
TRACT
CANCER
INCIDENCE
FOR
THE
UNITED
16
STATES
BY
DURATION
OF
EMPLOYMENTA
17
Duration
of
Employment
18
(
years)
19
Number
of
Individuals
Number
of
person
years
Incidence
(
Observed/
Expected)
SMR
(
95%
CI)
b
1­
4
20
4774
136200
7/
8.43
83
(
33­
171)

5­
9
21
2383
71806
10/
4.65
215
(
103­
396)

10­
19
22
1992
69015
39/
5.74
679
(
483­
929)

20+
23
960
39524
24/
3.49
688
(
440­
1023)

Total
24
10109
a
From
Tables
21
and
23
of
Mundt
et
al.,
(
1999).
25
b
SMR
=
Observed/
Expected
*
100.
CI
=
Confidence
Intervals.
26
Study
from
Weber
et
al.,
1981
27
Three
German
cohorts
were
investigated:
Group
1
(
VCM/
PVC
production;
7021
persons;
73734
28
person
years,
Group
2,
(
reference
group,
4910
persons;
76029
person
years),
Group
3
(
PVC
processing,
29
4007
persons;
52
896
person
years).
West
German
reference
mortality
rates
were
used
for
comparison.
30
Malignant
tumors
of
the
liver
occurred
in
12
cases
(
VCM/
PVC
production;
SMR=
1523)
or
4
cases
in
the
31
Vinyl
chloride
PROPOSED
1:
3/
2004
83
reference
group
(
SMR=
401)
or
3
cases
in
PVC
processing
(
SMR=
434).
No
confidence
intervals
were
1
provided.
No
exposure
concentration
is
known.
The
subclassification
according
to
duration
of
employment
2
demonstrates
increased
mortality
already
after
little
more
than
1
year
of
exposure
(
Table
D4).
Results
from
3
this
study
together
with
the
results
from
the
studies
cited
above
are
included
in
a
meta­
analysis
from
4
Boffetta
et
al.
(
2003)
and
illustrated
by
graphical
presentation
(
see
figure
1;
Boffetta
et
al.,
2003)
showing
5
the
conflicting
information
about
minimum
exposure
duration
for
adult
workers
to
have
a
increased
tumor
6
risk.
7
TABLE
D4:
LIVER
CANCER
IN
VCM/
PVC­
PRODUCTION
AND
DURATION
OF
8
EXPOSUREa
9
Duration
of
Employment
(
months)
10
Cases
SMR
<
12
11
0
­
­

13­
60
12
2
874
beyond
95th
confidence
interval
61­
120
13
3
1525
beyond
99th
confidence
interval
>
121
14
7
2528
beyond
99th
confidence
interval
Total
15
12
a
From
Table
3,
Weber
et
al.,
1981.
16
Vinyl
chloride
PROPOSED
1:
3/
2004
84
APPENDIX
E
­
Derivation
Summary
for
Vinyl
Chloride
AEGLs
1
Vinyl
chloride
PROPOSED
1:
3/
2004
85
ACUTE
EXPOSURE
GUIDELINES
FOR
VINYL
CHLORIDE
1
(
CAS
Reg.
NO.
75­
01­
4)
2
AEGL­
1
VALUES
3
10
minutes
4
30
minutes
1
hour
4
hours
8
hours
450
ppm
5
310
ppm
250
ppm
140
ppm
70
ppm
Reference:
Baretta,
E.
D.,
R.
D.
Stewart,
J.
E.
Mutchler,
1969.
Monitoring
exposures
to
vinyl
chloride
6
vapor:
breath
analysis
and
continuous
air
sampling.
American
Industrial
Hygiene
Association
Journal,
7
30,
537­
544.
8
Test
Species/
Strain/
Sex/
Number:
human
volunteers,
male,
4­
7
individuals
9
Exposure
Route/
Concentrations/
Durations:
inhalation;
3.5
hours;
459
­
491
ppm,
3.5
­
7.5
hours
10
Effects:
mild
headache,
some
dryness
of
eyes
and
nose
in
2/
7
subjects
11
Endpoint/
Concentration/
Rationale:
Endpoints
relevant
for
the
derivation
of
AEGL­
1
values
for
VC
have
12
are:
a)
headache,
b)
odor
recognition
or
detection,
c)
irritation.
Occurrence
of
mild
headache
has
been
13
reported
by
Baretta
et
al.
(
1969)
in
two
subjects
after
acute
exposure,
an
endpoint
which
can
be
regarded
14
as
NOAEL
for
AEGL­
1.
No
qualified
studies
on
odor
recognition
or
detection
are
reported
for
VC.
15
Irritation
in
humans
or
animals
is
only
reported
in
the
context
of
exposure
to
very
high
concentrations
16
which
are
lethal
or
cause
unconsciousness.
The
mechanism
by
which
headaches
developed
are
not
17
clearly
understood.
The
derived
AEGL­
1
does
not
necessarily
exclude
mutagenic
or
tumorigenic
effects
18
by
VC
at
similar
or
lower
concentrations.
19
Uncertainty
Factors/
Rationale:
The
intraspecies
uncertainty
factor
of
3
is
used
to
compensate
for
both,
20
toxicokinetic
and
toxicodynamic
differences
between
individuals.
For
headaches,
no
or
only
very
slight
21
effects
would
be
expected
for
the
general
public
after
inclusion
of
an
intraspecies
factor
of
3
on
the
22
"
mild"
effects
observed
in
volunteers.
23
Modifying
Factor:
not
applicable
24
Animal
to
Human
Dosimetric
Adjustment:
not
applicable
25
Time
Scaling:
The
duration­
specific
values
were
derived
by
time
scaling
according
to
the
dose­
response
26
regression
equation
Cn
x
t
=
k,
using
the
default
of
n=
3
for
shorter
exposure
periods
and
n=
1
for
longer
27
exposure
periods,
due
to
the
lack
of
suitable
experimental
data
for
deriving
the
concentration
exponent.
28
The
extrapolation
to
10
minutes
from
a
3.5
hour
exposure
is
justified
because
exposure
of
human
at
29
4,000
ppm
for
5
minutes
did
not
result
in
headache
(
Lester
et
al.,
1963).
30
Data
Adequacy:
The
study
of
Baretta
et
al.
(
1969)
has
been
regarded
as
qualified
for
the
derivation
of
31
AEGL­
1
values
and
the
endpoint
is
supported
by
several
findings
from
occupational
studies
(
Lilis
et
al.,
32
1975;
Suciu
et
al.,
1975;
EPA,
1987).
Confirmation
of
the
observed
effects
in
other
studies
with
33
controlled
exposure
would
be
helpful,
but
may
not
be
performed
due
to
ethical
reasons.
34
Vinyl
chloride
PROPOSED
1:
3/
2004
86
ACUTE
EXPOSURE
GUIDELINES
FOR
VINYL
CHLORIDE
1
(
CAS
Reg.
NO.
75­
01­
4)
2
AEGL­
2
VALUES
3
10
minutes
4
30
minutes
1
hour
4
hours
8
hours
2,800
ppm
5
1,600
ppm
1,200
ppm
820
ppm
820
ppm
Reference:
Lester,
D.,
L.
A.
Greenberg,
W.
R.
Adams,
1963.
Effects
of
single
and
repeated
exposures
of
6
humans
and
rats
to
vinyl
chloride.
American
Industrial
Hygiene
Association
Journal,
24,
265­
275;
7
Clark,
D.
G.,
D.
J.
Tinston,
1973.
Correlation
of
the
cardiac
sensitizing
potential
of
halogenated
8
hydrocarbons
with
their
physicochemical
properties.
Br.
J.
Pharm.,
49,
355­
357.
Mastromatteo,
E.,
9
A.
M.
Fisher,
H.
Christie,
H.
Danziger,
1960.
Acute
inhalation
toxicity
of
vinyl
chloride
to
laboratory
10
animals.
Am.
Ind.
Hyg.
Assoc.
J.,
21,
394­
398.
11
Test
Species/
Strain/
Sex/
Number:
human
male
(
n=
3)
and
female
(
n=
3)
volunteers,
6
persons
12
Exposure
Route/
Concentrations/
Durations:
Inhalation,
single
exposure,
0,
4,000,
8,000,
12,000,
16,000,
13
20,000
ppm
for
5
minutes
14
Effects:
After
5
minute
exposure
to
16,000
ppm
VC
5
of
6
persons
showed
dizziness,
lightheadedness,
15
nausea,
visual
and
auditory
dulling.
At
concentrations
of
12,000
ppm
one
of
six
persons
reported
16
"
swimming
head,
reeling",
another
was
unsure
of
an
effect
and
felt
somewhat
dizzy.
A
single
person
17
reported
slight
effects
("
slightly
heady")
of
questionable
meaning
at
8,000
ppm
(
this
volunteer
felt
also
18
slightly
heady
at
sham
exposure
and
reported
no
response
at
12,000
ppm).
No
effects
were
observed
at
19
4,000
ppm.
12,000
ppm
was
regarded
as
a
concentration
below
AEGL­
2
level
and
taken
as
NOAEL.
20
Derived
AEGL­
2
levels
are
supported
by
the
an
assumed
NOAEL
for
cardiac
sensitization
of
17,000
21
ppm
in
dogs
after
epinephrine
challenge
(
5
minutes
exposure;
Clark
and
Tinston,
1993),
leading
to
22
similar
values.
However,
the
resulting
AEGL­
2
values
may
not
provide
a
sufficient
margin
of
safety
to
23
avoid
mutational
events
or
malignancies
after
short­
term
exposure
to
VC.
24
Endpoint/
Concentration/
Rationale:
Severe
dizziness
may
influence
capability
to
escape
and
thus
is
25
relevant
as
endpoint
for
AEGL­
2.
At
12,000
ppm
no
such
effects
were
seen.
Derived
AEGL­
2
levels
are
26
supported
by
the
an
assumed
NOAEL
for
cardiac
sensitization
of
17,000
ppm
in
dogs
after
epinephrine
27
challenge
(
5
minutes
exposure;
Clark
and
Tinston,
1993),
leading
to
similar
values.
28
Uncertainty
Factors/
Rationale:
A
total
uncertainty
factor
of
3
is
used
to
compensate
for
both,
29
toxicokinetic
and
toxicodynamic
variability,
with
small
interindividual
differences
in
case
of
CNS­
30
effects.
As
the
unmetabolized
VC
is
responsible
for
the
effects
no
relevant
differences
in
kinetics
are
31
assumed.
32
Total
uncertainty
factor:
3
33
Interspecies:
1
34
Intraspecies:
3
35
Modifying
Factor:
Not
applicable
36
Animal
to
Human
Dosimetric
Adjustment:
Not
applicable
37
Vinyl
chloride
PROPOSED
1:
3/
2004
87
Time
Scaling:
In
analogy
to
other
anaesthetics
the
effects
are
assumed
to
be
solely
concentration
1
dependent.
Thus,
after
reaching
steady
state
(
about
2
hours),
at
4
and
8
hours
no
increase
of
effect­
size
2
by
duration
is
expected.
The
other
exposure
duration­
specific
values
were
derived
by
time
scaling
3
according
to
the
dose­
response
regression
equation
Cn
x
t
=
k,
using
a
factor
of
n=
2,
based
on
data
from
4
Mastromatteo
et
al.
(
1960).
Mastromatteo
et
al.
observed
various
time­
dependent
prenarcotic
effects
in
5
mice
and
guinea
pigs
after
less
than
steady
state
exposure
conditions.
With
this,
time
extrapolation
was
6
performed
from
5
to
10,
30,
60
minutes
and
2
hours,
where
the
steady
state
concentration
was
7
calculated.
8
Data
Adequacy:
The
overall
quality
of
the
key
study
(
Lester
et
al.,
1963)
is
medium.
There
is
an
9
observed
dose­/
response
relationship
supporting
the
quantitative
figures.
Subjective
reporting
of
effects
10
leads
to
limited
preciseness.
11
Vinyl
chloride
PROPOSED
1:
3/
2004
88
ACUTE
EXPOSURE
GUIDELINES
FOR
VINYL
CHLORIDE
1
(
CAS
Reg.
NO.
75­
01­
4)
2
AEGL­
3
VALUES
3
10
minutes
4
30
minutes
1
hour
4
hours
8
hours
12,000
ppm
5
6,800
ppm
4,800
ppm
3,400
ppm
3,400
ppm
References:
Clark,
D.
G.,
D.
J.
Tinston,
1973.
Correlation
of
the
cardiac
sensitizing
potential
of
6
halogenated
hydrocarbons
with
their
physicochemical
properties.
British
Journal
of
Pharmacology,
49,
7
355­
357.
Clark,
D.
G.,
D.
J.
Tinston,
1982.
Acute
inhalation
toxicity
of
some
halogenated
and
non­
8
halogenated
hydrocarbons.
Human
Toxicology,
1,
239­
247.,
Aviado,
D.
M.,
M.
A.
Belej,
1974.
Toxicity
9
of
aerosol
propellants
in
the
respiratory
and
circulatory
systems.
I.
Cardiac
arrhythmia
in
the
mouse.
10
Toxicology,
2,
31­
42.;
Belej,
M.
A.,
D.
G.
Smith,
D.
M.
Aviado,
1974.
Toxicity
of
aerosol
propellants
in
11
the
respiratory
and
circulatory
systems.
IV.
Cardiotoxicity
in
the
monkey.
Toxicology,
2,
381­
395;
12
Prodan,
L.,
I.
Suciu,
V.
Pislaru,
E.
Ilea,
L.
Pascu,
1975.
Experimental
acute
toxicity
of
vinyl
chloride
13
(
monochloroethene).
Ann.
NY
Acad.
Sci.,
246,
154­
158.
Mastromatteo,
E.,
A.
M.
Fisher,
H.
Christie,
H.
14
Danziger,
1960.
Acute
inhalation
toxicity
of
vinyl
chloride
to
laboratory
animals.
Am.
Ind.
Hyg.
Assoc.
15
J.,
21,
394­
398.
16
Test
Species/
Strain/
Sex/
Number:
dog,
beagle,
sex
not
reported,
4­
7
dogs/
dose
level
(
Clark
and
Tinston,
17
1973)
18
Exposure
Route/
Concentrations/
Durations:
inhalation
/"
several
doses"
/
5
minutes
(
Clark
and
Tinston,
19
1973)
20
Effects:
Short
term
exposure
(
5
min)
of
dogs
to
VC
induced
cardiac
sensitization
towards
epinephrine
21
(
EC50:
50,000
or
71,000
ppm
in
two
independent
experiments;
Clark
and
Tinston,
1973;
1982).
The
22
lower
reported
EC50
(
50,000
ppm)
was
taken
as
NOAEL
for
life
threatening
effects.
These
effects
were
23
also
seen
in
mice
at
higher
concentrations
(
Aviado
and
Belej,
1974).
In
monkeys,
only
myocardial
24
depression
after
inhalation
of
2.5­
10%
VC
was
observed.
It
is
not
clearly
stated
whether
an
addition
25
challenge
with
epinephrine
was
applied
or
not
(
Belej
et
al.,
1974).
Severe
cardiac
sensitization
is
a
life
26
threatening
effect,
but
at
50,000
ppm
no
animal
died
in
the
reported
study,
providing
a
NOAEL
for
27
AEGL­
3
derivation.
28
Endpoint/
Concentration/
Rationale:
Considering
possible
sensitive
subpopulations
and
increased
29
excitement
in
case
of
emergency
reaction
epinephrine
induced
cardiac
reactions
may
occur
and
may
be
30
enhanced
by
high
exposure
concentrations
to
VC.
The
respective
effects
are
well
known
for
certain
31
unsubstituted
and
halogenated
hydrocarbons.
The
test
method
using
beagle
dogs
is
well
established.
32
Supported
by
lethality
data
in
slightly
higher
concentrations
(
Prodan
et
al.,
1975).
33
Vinyl
chloride
PROPOSED
1:
3/
2004
89
Uncertainty
Factors/
Rationale:
A
total
uncertainty
factor
of
3
is
used
to
compensate
for
both,
1
toxicokinetic
and
toxicodynamic
differences
between
individuals
and
interspecies
differences.
As
the
2
challenge
with
epinephrine
and
the
doses
of
epinephrine
used
represent
a
conservative
scenario
an
3
interspecies
factor
of
1
was
employed.
As
the
unmetabolized
VC
is
responsible
for
the
effects
no
relevant
4
differences
in
kinetics
are
assumed.
5
Total
uncertainty
factor:
3
6
Interspecies:
1
7
Intraspecies:
3
8
Modifying
Factor:
Not
applicable
9
Animal
to
Human
Dosimetric
Adjustment:
Insufficient
data
10
Time
Scaling:
In
analogy
to
other
halocarbons
(
e.
g.,
Halon
1211,
HFC
134a)
which
lead
to
cardiac
11
sensitization
the
effects
are
assumed
to
be
solely
concentration
dependent.
Thus,
after
reaching
steady
12
state
(
about
2
hours),
at
4
and
8
hours
no
increase
of
effect­
size
by
duration
is
expected.
The
other
13
exposure
duration­
specific
values
were
derived
by
time
scaling
according
to
the
dose­
response
regression
14
equation
Cn
x
t
=
k,
using
a
factor
of
n=
2,
based
on
data
from
Mastromatteo
et
al.
(
1960).
Mastromatteo
15
et
al.
observed
various
time­
dependent
prenarcotic
effects
(
muscular
incoordination,
side
position
and
16
unconsciousness,
effects
which
occur
immediately
before
lethality)
in
mice
and
guinea
pigs
after
less
17
than
steady
state
exposure
conditions.
With
this,
time
extrapolation
was
performed
from
5
to
10,
30,
60
18
minutes
and
2
hours,
where
the
steady
state
concentration
was
calculated.
19
Data
Adequacy:
Due
to
some
discrepancies
between
the
two
studies
from
Clark
and
Tinston
(
1973,
20
1982)
the
data
quality
is
judged
to
be
medium
with
adequate
data
from
human
experience
lacking.
21