United
States
Environmental
Protection
Agency
Office
of
Pollution
Prevention
and
Toxics
XYLENES
(CA$
Reg.
No.
1330­
20­
7)

PROPOSED
ACUTE
EXPOSURE
GUIDELINE
LEVELS
(AEGLs)

"PUBLIC
DRAFT"

Federal
Register
­
May
2002
I
PROPOSED
I:
5/
2002
XYLENE$
(CAS
Reg.
No.
1330­
20­
7)

PROPOSED
ACUTE
EXPOSURE
GUIDELINE
LEVELS
(AEGLs)

Oak
Ridge
National
Laboratory,
managed
by
UT­
Battelle,
LLC,
for
the
U.
S.
Dept.
of
Energy
under
contract
DE­
AC05­
000R22725
2
XYLENES
Proposed
1:
5/
2002
1
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2%
29
30
31
32
PREFACE
Under
the
authority
of
the
Federal
Advisory
Committee
Act
(FACA)
P.
L.
92­
463
of
1972,
the
National
Advisory
Committee
for
Acute
Exposure
Guideline
Levels
for
Hazardous
Substances
(NAC/
AEGL
Committee)
has
been
established
to
identify,
review
and
interpret
relevant
toxicologic
and
other
scientific
data
and
develop
AEGLs
for
high
priority,
acutely
toxic
chemicals.

AEGLs
represent
threshold
exposure
limits
for
the
general
public
and
are
applicable
to
emergency
exposure
periods
ranging
from
10
minutes
to
8
hours.
Three
levels
­
AEGL­
1,
AEGL­
2
and
AEGL­
3
­
are
developed
for
each
of
five
exposure
periods
(10
and
30
minutes,
1
hour,
4
hours,
and
8
hours)
and
are
distinguished
by
varying
degrees
of
severity
of
toxic
effects.
The
three
AEGLs
are
defined
as
follows:

AEGL­
1
is
the
airborne
concentration
(expressed
as
parts
per
million
or
milligrams
per
cubic
meter
[ppm
or
mg/
m3])
of
a
substance
above
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
notable
discomfort,
irritation,
or
certain
asymptomatic,
non­
sensory
effects.
However,
the
effects
are
not
disabling
and
are
transient
and
reversible
upon
cessation
of
exposure.

AEGL­
2
is
the
airborne
concentration
(expressed
as
ppm
or
mg/
m3)
of
a
substance
above
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
irreversible
or
other
serious,
long­
lasting
adverse
health
effects
or
an
impaired
ability
to
escape.

AEGL­
3
is
the
airborne
concentration
(expressed
as
ppm
or
mg/
m3)
of
a
substance
above
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
life­
threatening
health
effects
or
death.

Airborne
concentrations
below
the
AEGL­
1
represent
exposure
levels
that
could
produce
mild
and
progressively
increasing
but
transient
and
nondisabling
odor,
taste,
and
sensory
irritation
or
certain
asymptomatic,
non­
sensory
effects.
With
increasing
airborne
concentrations
above
each
AEGL,
there
is
a
progressive
increase
in
the
likelihood
of
occurrence
and
the
severity
of
effects
described
for
each
corresponding
AEGL.
Although
the
AEGL
values
represent
threshold
levels
for
the
general
public,
including
susceptible
subpopulations,
such
as
infants,
children,
the
elderly,
persons
with
asthma,
and
those
with
other
illnesses,
it
is
recognized
that
individuals,
subject
to
unique
or
idiosyncratic
responses,
could
experience
the
effects
described
at
concentrations
below
the
corresponding
AEGL.

1
3
XYLENES
Proposed
11:
512882
1
TABLE
OF
CONTENTS
2
PREFACE
.................................................................
i
3
TABLE
OF
CONTENTS
.....................................................
11
4
LISTOFTABLES
.........................................................
iv
5
FIGURE
.................................................................
iv
6
EXECUTIVE
SUMMARY
....................................................
v
7
I
.
TNTRODUCTION
........................................................
1
..

8
9
10
11
12
13
14
15
16
2
.

17
3
.
18
19
20
21
22
23
24
25
26
27
28
29
HUMANTOXICITYDATA
................................................
2
2.1.
Acute
Lethality
.......................................................
2
2.2.
Nonlethal
Toxicity
....................................................
3
2.2.1.
Case
Reports
...................................................
3
2.2.2.
Controlled
Exposures
.............................................
4
2.3.
DevelopmentaVReproductive
Effects
.....................................
12
2.4.
Genotoxicity
........................................................
12
2.5.
Carcinogenicity
.....................................................
12
2.6.
Summary
..........................................................
12
ANIMALTOXICITYDATA
..............................................
14
3.1.1.
Cats
.........................................................
14
3.1.2.
Rats
.........................................................
14
3.1.3.
Mice
.........................................................
17
18
3.2.2.
Dogs
........................................................
18
3.2.2.
Rats
.........................................................
18
3.1.
Acute
Lethality
......................................................
14
...................................................
3
.2
.
Nonlethal
Toxicity
3.2.3.
Mice
.........................................................
22
3.3.
DevelopmentaVReproductive
Effects
.....................................
24
3.5.
Carcinogenicity
......................................................
27
........................................................
3.4.
Genotoxicity
27
3.6.
Summary
..........................................................
28
............................................
30
4
.
SPECIAL
CONSIDERATIONS
30
31
32
33
4.4.
Other
Relevant
Information
34
34
35
4.1.
Metabolism
and
Disposition
............................................
30
4.2.
Mechanism
of
Toxicity
........................................
:
.......
32
4.4.1.
Interspecies
Differences
..........................................
34
4.4.2.
Intraspecies
Differences
...........................................
35
36
4.4.3.
Concentration­
Exposure
Duration
Relationship
........................
35
............................................

11
Y
.....
..­
_­
9
10
11
12
13
14
15
16
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18
19
20
XYLENES
Proposed
1:
5/
2002
5
.
DATA
ANALYSIS
AND
PROPOSED
AEGL­
1
................................
38
5.1.
Human
Data
Relevant
to
AEGL­
1
.......................................
38
5.2.
Animal
Data
Relevant
to
AEGL­
1
.......................................
38
5.3.
Derivation
of
AEGE­
1
................................................
38
6
.
DATA
ANALYSIS
AND
PROPOSED
AEGL­
2
................................
39
6.1.
Human
Data
Relevant
to
AEGL­
2
.......................................
39
6.2.
Animal
Data
Relevant
to
AEGL­
2
.......................................
39
6.3.
Derivation
of
AEGL­
2
................................................
39
7
.
DATA
ANALYSIS
AND
PROPOSED
AEGL­
3
................................
41
7.1.
Human
Data
Relevant
to
AEGL­
3
........................................
41
7.2.
Animal
Data
Relevant
to
AEGL­
3
.......................................
41
7.3.
DerivationofAEGL­
3
................................................
41
8
.
SUMMARY
OF
PROPOSED
AEGLs
........................................
42
8.1.
AEGL
Values
and
Toxicity
Endpoints
....................................
42
8.2.
Comparisons
with
Other
Standards
.......................................
42
8.3.
Data
Quality
and
Research
Needs
........................................
43
9
.
REFERENCES
.........................................................
45
APPENDIX
A:
Derivation
of
AEGL
Values
......................................
58
APPENDIX
B:
Time­
Scaling
Calculations
.......................................
62
APPENDIX
C:
Derivation
Summary
for
Xylene
AEGLs
............................
66
...
111
5
__
.
_...
..
­
1
XYLENES
LIST
OF
TABLES
Proposed
1:
5/
2002
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Summary
of
Proposed
AEGL
Values
for
Xylenes
..................................
vii
1
.
Physicochemical
Data
for
Xylenes
.............................................
2
2
.
SensoryThresholds
5
3
.
Summary
of
Controlled
Human
Exposures
to
Xylene
.............................
13
4
.
Mortality
of
Male
Rats
Exposed
to
Xylene
Vapor
for
4
Hours
......................
15
4
Hours
Following
Pretreatment
with
Drugs
6
.
Mortality
of
Rats
Exposed
to
Xylene
Vapor
....................................
16
7
.
Mortality
of
Mice
Exposed
to
Xylene
Vapor
8
.
Effect
of
Xylene
Exposure
on
Self­
stimulation
Behavior
in
Rats
.....................
21
BO
.
Summary
of
Nonlethal
Inhalation
Data
in
Laboratory
Animals
.......................................................

5
.
Mortality
of
Male
Rats
Exposed
to
Xylene
Vapor
for
..................................
16
...................................
18
28
.....................
29
.........................
9
.
Summary
of
Lethal
Inhalation
Data
in
Laboratory
Animals
1
B
.
Relationship
Between
Xylene
Exposure
Concentration
12
.
AEGL­
1
Values
for
Xylenes
13
.
AEGL­
2
Values
for
Xylenes
[ppm
(mg/
m3)]
(In
Air)
and
Blood
Xylene
Concentration
in
Human
Volunteers
.....................
37
14
.
AEGL­
3
Values
for
Xylenes
...............................................
42
15
.
Summary/
Relationship
of
AEGL
Values
......................................
42
16
.
Extant
Standards
and
Guidelines
for
Xylenes
..............................................
39
40
..................................

...................................
43
FIGURE
...............................................
1
.
Metabolic
scheme
for
xylenes
32
iv
G
....
.............
I­
XYLENES
Proposed
1:
5/
2002
1
2
3
4
5
6
7
8
9
10
I1
12
13
14
15
16
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18
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20
21
22
23
24
25
26
27
28
29
30.
31
32
33
34
35
36
37
38
39
40
41
42
EXECUTIVE
SUMMARY
Xylene
is
found
in
a
number
of
consumer
products,
including
solvents,
paints
or
coatings,
and
as
a
blend
in
gasoline.
Mixed
xylenes
are
comprised
of
3
isomers:
m­
xylene,
o­
xylene,
and
p­
xylene,
with
the
m­
isomer
predominating.
Ethyl
benzene
is
also
present
in
the
technical
product
formulation.
Absorbed
xylene
is
rapidly
metabolized
and
is
excreted
almost
exclusively
in
the
urine
as
methylhippuric
acid
isomers
in
humans
and
as
methylhippuric
acid
isomers
and
toluic
acid
glucuronides
in
animals.
In
both
humans
and
animals,
xylene
causes
irritation
and
effects
the
central
nervous
system
following
acute
inhalation
exposure.
No
consistent
developmental
or
reproductive
effects
were
observed
in
the
studies
found
in
the
available
literature.
Commercial
xylene
and
a11
3
isomers
have
generally
tested
negative
for
genotoxicity.
Xylenes
are
currently
not
classifiable
as
to
its
carcinogenicity
by
IARC
or
the
U.
S.
EPA
because
of
inadequate
evidence.

The
AEGL­
1
is
based
upon
slight
eye
irritation
noted
during
a
30­
minute
exposure
to
400
ppm
mixed
xylenes
(Hastings
et
al.,
1986).
An
interspecies
uncertainty
factor
was
not
applied
because
the
key
study
used
human
data.
An
intraspecies
uncertainty
factor
of
3
was
applied
because
the
toxic
effect
(slight
irritation)
was
less
severe
than
that
defined
for
the
AEGL­
1
tier
(notable
discomfort).
The
resulting
value
of
130
ppm
is
supported
by
several
other
studies,
including:
a
150
ppm
p­
xylene
exposure
resulting
in
eye
irritation
in
a
contact
lens
wearer
(Hake
et
al.,
1981);
a
15­
mimte
exposure
to
230
ppm
mixed
xylenes
resulting
in
mild
eye
irritation
and
dizziness
in
one
individual;
and
a
3­
hour
exposure
to
200
ppm
m­
or
p­
xylene
(Ogata
et
al.,
1970),
a
4­
hour
exposure
to
200
ppm
m­
xylene
(Savolainen
et
ai.,
1981),
and
a
5.5
hour
exposure
to
200
ppm
m­
xylene
(Laine
et
al.,
1993)
all
representing
no­
effect
levels.

The
AEGL­
2
is
based
upon
poor
coordination
resulting
when
rats
were
exposed
to
1300
ppm
mixed
xylenes
for
4
hours
(Carpenter
et
al.,
1975).
This
concentration
represents
the
threshold
for
reversible
equilibrium
disturbances.
This
concentration
and
endpoint
are
consistent
with
the
preponderance
of
available
data
for
4­
hour
exposures
in
rats:
the
EC,,
for
decreased
rotarod
performance
was
1982
ppm
(Korsak
et
al.,
1993);
the
minimum
narcotic
concentrations
for
m­,
o­,
and
p­
xylene
ranged
from
1940­
2180
ppm
(Molnir
et
al.,
1986);
and
exposure
to
1600
ppm
p­
xylene
resulted
in
hyperactivity,
fine
tremor,
and
unsteadiness
(Ehshnell,
1989),
induced
flavor
aversion
(Bushnell
and
Peele,
1988),
and
caused
changes
in
the
flash
evoked
potential
suggestive
of
increased
arousal
(Dyer
et
al.,
1988).
In
dogs,
exposure
to
1200
ppm
for
4
hours
represented
a
threshold
for
eye
irritation
(Carpenter
et
al.,
1975).
An
interspecies
uncertainty
factor
of
1
was
applied
because
rats
receive
a
greater
systemic
dose
of
inhaled
xylene
as
compared
to
humans.
An
intraspecies
uncertainty
factor
of
3
was
applied
because
the
MAC
(minimum
alveolar
concentration)
for
volatile
anesthetics
should
not
vary
by
more
than
a
factor
of
2­
3­
fold
among
humans.
A
3­
fold
factor
is
also
adequate
to
account
for
moderate
physical
activity
during
exposure,
which
would
result
in
greater
uptake
of
the
chemical.

The
AEGL­
3
derivation
is
based
upon
prostration
occurring
in
all
10
rats
exposed
for
4
hours
to
2800
ppm
mixed
xylenes,
with
recovery
occurring
within
1
hour
of
exposure
(Carpenter
et
al.,
1975).
Although
coordination
initially
remained
poor,
it
returned
to
normal
the
following
day.
This
concentration
also
represents
a
no­
effect
level
for
lethality.
An
interspecies
uncertainty
factor
of
1
was
applied
because
rats
receive
a
greater
systemic
dose
of
inhaled
xylene
as
compared
to
humans.
An
intraspecies
uncertainty
factor
of
3
was
applied
because
the
MAC
for
volatile
V
7
XYLENES
Proposed
1:
5/
2002
1
2
3
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9
10
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12
13
14
15
16
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22
23
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29
30
anesthetics
should
not
vary
by
more
than
a
factor
of
2­
3­
fold
among
humans.
A
3­
fold
factor
is
also
adequate
to
account
for
moderate
physical
activity
during
exposure,
which
would
result
in
greater
uptake
of
the
chemical.

The
two
primary
effects
of
concern
for
xylene
are
those
of
irritation
and
central
nervous
system
effects.
Irritation
is
considered
a
threshold
effect
and
therefore
should
not
vary
over
time,
The
AEGL­
1
value
based
on
irritation
is
therefore
not
scaled
across
time,
but
rather
the
threshold
value
is
applied
to
all
times.

Data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity.
Pharmacokinetic
modeling
in
both
humans
and
rats
indicate
that
venous
blood
concentrations
rapidly
increase
during
the
first
15
minutes
of
exposure,
followed
by
minimal
increases
in
blood
concentrations
with
continuing
exposure
(i.
e.,
increases
follow
a
hyperbolic
curve).
Likewise,
available
human
data
indicate
that
once
the
initial
increase
in
blood
xylene
concentration
is
reached,
blood
concentrations
level
off
with
increasing
exposure
duration.
Conversely,
available
human
and
animal
data
demonstrate
that
increasing
exposure
concentrations
correlate
with
increases
in
venous
blood
xylene
concentrations.
Therefore,
the
AEGL
2­
and
­3
values
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
1
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes.

The
AEGL
values
should
be
protective
of
human
health.
The
AEGL­
1
values
are
consistent
with
other
human
studies,
and
represent
a
value
consistent
with
exposure
concentrations
that
might
result
in
mild
eye
irritation.
The
AEGL­
2
levels
are
protective,
especially
when
considering
numerous
human
studies
investigating
the
effects
of
exposure
to
200
ppm
xylene
with
20­
minute
peak
exposures
to
400
ppm,
in
some
cases
additionally
combining
peak
exposures
with
physical
exercise
resulting
in
greater
uptake
of
the
chemical,
and
finding
only
minimal
central
nervous
system
effects.
The
difficultly
in
defining
an
AEGL­
2
level
for
xylene
comes
from
its
"all­
or­
nothing"
continuum
of
toxicity:
toxicity
ranges
from
mild
irritation
to
narcosis,
with
little
happening
in
between.
The
AEGL­
3
levels
represent
the
threshold
for
narcosis,
and
are
protective
as
supported
by
human
data
demonstrating
that
exposure
to
690
ppm
for
15
minutes
resulted
in
lightheadedness/
dizziness
and
a
30
minute
exposure
to
700
ppm
resulted
in
nausea,
vomiting,
dizziness
or
vertigo.

31
The
proposed
values
are
listed
in
the
tables
below.

vi
8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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Proposed
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Summary
of
Proposed
AEGL
Values
for
Xylenes
[ppm
(mg/
m3)]

Classification
I
10­
minute
AEGL­
1
AEGL­
3
2
100
(Lethal)
(9100)

References
Bushnell,
P.
J..
1989.
Behavioral
effects
of
acute
p­
xylene
inhalation
in
rats:
Autoshaping,
motor
activity,
and
reversal
learning.
Neurotoxicology
and
Teratology
10:
569­
577.

Bushnell,
P.
J.,
and
Peele,
D.
B.
1988.
Conditioned
flavor
aversion
induced
by
inhaled
p­
xylene
in
rats.
Neurotoxicology
and
Teratology
10:
273­
277.

Carpenter,
C.
P.,
Kinkead,
E.
R.,
Geary,
D.
L.
Jr.,
Sullivan,
L.
J.,
and
King,
J.
M.
1975b.
Petroleum
hydrocarbon
toxicity
studies.
V.
Animal
and
human
response
to
vapors
of
mixed
xylene.
Toxicology
and
Applied
Pharmacology
3
3
:
543
­5
8.

Dyer,
R.
S.,
Bercegeay,
M.
S.,
and
Mayo,
L.
M.
1988.
Acute
exposures
to
p­
xylene
and
toluene
alter
visual
information
processing.
Neurotoxicology
and
Teratology
10:
147­
1
53.

Hake,
C.
R.
L.,
Stewart,
R.
D.,
Wu,
A.,
et
al.
1981.
p­
Xylene:
Development
of
a
biological
standard
for
the
industrial
worker.
Report
to
the
National
Institute
for
Occupational
Safety
and
Health,
Cincinnati,
OH,
by
the
Medical
College
of
Wisconsin,
Inc.,
Milwaukee,
WI.
PB82­
152844.

Hastings,
L.,
Cooper,
G.
P.,
and
Burg,
W.
1986.
Human
sensory
response
to
selected
petroleum
hydrocarbons.
In:
MacFarland,
H.
N.
ed.
Advances
in
Modern
Environmental
Toxicology.
Vol.
VI.
Applied
Toxicology
of
Petroleum
Hydrocarbons.
Princeton,
NJ:
Princeton
Scientific
Publishers,
pp.
255­
270.

Korsak,
Z.,
Swiercz,
R.,
and
Jedrychowski,
R.
1993.
Effects
of
acute
combined
exposure
to
­

n­
butyl
alcohol
and
m­
xylene.
Polish
Journal
of
Occupational
Medicine
and
Environmental
Health
6:
35­
41.

Laine,
A.,
Savolainen,
K.,
Riihimaki,
V.,
et
al.
1993.
Acute
effects
of
m­
xylene
inhalation
on
vii
Y
1
2
3
4
5
6
7
8
9
10
11
XYLENES
Proposed
I:
92002
body
sway,
reaction
times,
and
sleep
in
man.
International
Archives
of
Qccupational
and
Environmental
Health
65:
179­
188.

Molnar,
J.,
Paksy,
K.
A.,
and
Naray,
M.
1986.
Changes
in
the
rat's
motor
behavior
during
4­
hr
inhalation
exposure
to
prenarcotic
concentrations
of
benzene
and
its
derivatives.
Acta
Physiologica
Hungarica
67;
349­
3
54.

Ogata,
M.,
Tomokuni,
K.,
and
Takatsuka,
Y.
1970.
Urinary
excretion
of
hippuric
acid
and'm­
QX­

p­
methylhippuric
acid
in
the
urine
of
persons
exposed
to
vapours
of
toluene
and
m­
orp­
xylene
as
a
test
of
exposure.
British
Journal
of
Industrial
Medicine
27:
43­
50.

Savolainen,
K.,
Riihimaki,
V.,
Laine,
A.,
and
Kekoni,
J.
31981.
Short­
term
exposure
of
human
subjects
to
m­
xylene
and
1,
l
,
1
­trichloroethane.
International
Archives
of
Occupational
Environmental
Health
49:
89­
98.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
I.
INTRODUCTION
Commercial
or
mixed
xylene
is
comprised
of
three
isomers:
meta­
xylene
(m­
xylene),
ortho­
xylene
(0­
xylene),
and
para­
xylene
(p­
xylene),
of
which
the
m­
isomer
usually
predominates
(44­
70%
of
the
mixture)
(Fishbein,
1988;
ATSDR,
1995).
The
exact
composition
of
the
isomers
is
dependent
upon
the
xylene
formulation.
Ethylbenzene
is
often
present
in
mixed
xylenes;
in
fact,
the
technical
product
contains
approximately
40%
m­
xylene
and
approximately
20%
each
of
0­,

and
p­
xylene
and
ethylbenzene
(Fishbein,
1988).
Other
minor
contaminants
of
xylene
include
toluene
and
C9
aromatic
fractions.
Uses
of
mixed
xylene
include
its
use
in
the
production
of
the
individual
isomers
or
ethylbenzene,
as
a
solvent,
in
paints
and
coatings,
or
as
a
blend
in
gasoline
(Fishbein,
1988;
ATSDR,
1995).
The
annual
production
capacity
of
mixed
xylene
has
been
estimated
to
be
13.1
billion
pounds,
with
1990
and
1991
production
estimates
of
approximately
6
billion
pounds
(ATSDR,
1995).

The
odor
of
xylenes
is
described
as
that
of
an
aromatic
hydrocarbon
odor.
The
odor
threshold
is
reported
to
range
between
0.8­
40
ppm,
and
the
irritating
concentration
is
reported
to
be
100
ppm
(Ruth,
1986).
XYLENES
Proposed
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1
2
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9
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21
22
23
24
25
26
27
28
29
Parameter
Synonyms
~~
­

Chemical
formula
Molecular
weight
CAS
registry
no.

Physical
state
Color
Solubility
Vapor
pressure
at
2OoC
Density
Melting
point
Boiling
point
Conversion
factors
in
TABLE
1.
Physicochemical
Data
for
Xylenes
Value
I
Reference
Dimethylbenzene
(1,2­;
1,3­;
or
1,4­);
xylol,
m­
xylene
(m­
isomer);
o­
xylene
(0­
isomer);
p­
xylene
(p­
isomer);
methyl
toluene
Budavari
et
al.,
1996;
ACGIH,
1991
I
Budavari
et
al.,
1996
106.17
I
Budavari
et
al.,
1996
1330­
20­
7
108­
38­
3
(m­
isomer)
95­
47­
6
(0­
isomer)
106­
42­
3
(p­
isomer)

Liquid
I
Budavarietal.,
1996
colorless
I
Budavari
et
al.,
1996
Practically
insoluble
in
water;
130
mg/
L
ATSDR,
1995
6­
16
mmHg
ATSDR,
1995
0.864
g/
cm'
ATSDR,
1995
No
data
for
mixture^
­47.4"
C
(m­
isomer)
­25OC
(0­
isomer)
13­
14°
C
(p­
isomer)
Budavari
et
al.,
1996
137­
140°
C
I
Budavari
et
al.,
1996
3.12­
3.20
I
ATSDR,
1995
1
ppm
=
4.34
mg/
m3
1
mg/
m3
=
0.23
ppm
NRC,
1984
2.
HUMAN
TOXICITY
DATA
2.1.
Acute
Lethality
Three
men
were
employed
to
paint
a
double­
bottomed
tank
in
the
engine
room
of
a
ship
(Morley
et
al.,
1970).
Solvent
comprised
34%
of
the
total
weight
of
the
paint,
with
xylene
comprising
in
excess
of
90%
of
the
solvents,
with
only
a
trace
amount
of
toluene
present.
The
men
started
work
at
10:
30
am,
and
after
being
reported
missing
later
that
evening,
were
found
unconscious
at
5:
OO
am
the
next
day.
The
first
patient
was
dead
upon
admission
to
the
hospital.
Autopsy
revealed
severe
pulmonary
congestion
with
focal
alveolar
hemorrhage
and
acute
pulmonary
edema,
hepatic
congestion
with
swelling
and
vacuolization
of
many
cells
in
the
centrilobular
areas,
and
microscopic
petechial
hemorrhages
in
both
the
grey
and
white
matter
of
the
brain.
In
addition,
evidence
of
axonal
neuronal
damage
was
indicated
by
swelling
and
loss
of
Nissl
substance.
The
second
patient
was
admitted
to
the
hospital
unconscious,
exhibiting
only
a
slight
response
to
painfkl
stimuli.
He
was
also
hypothermic,
had
a
flushed
face,
and
had
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2002
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peripheral
cyanosis.
Medium­
grade
moist
sounds
were
present
in
his
lungs,
and
a
chest
x­
ray
revealed
patchy
diffuse
opacity
in
both
lungs.
Five
hours
following
treatment
with
tracheal
aspiration
and
oxygen,
the
patient
regained
consciousness,
but
was
amnesic
for
2­
3
days.
Evidence
of
renal
damage
was
indicated
by
an
increase
in
blood
urea
of
59
mg/
lOO
mL
to
204
rngA00
mL
three
days
after
admission.
Endogenous
creatinine
clearance
was
also
reduced
at
this
time.
Slight
hepatic
impairment
was
indicated
by
a
rise
in
serum
transaminase
to
100
i.
u.
over
48
hours,
followed
by
a
return
to
normal
levels.
Patient
3
recovered
consciousness
following
admission,
and
was
confused
and
amnesic,
had
slurred
speech,
and
was
ataxic
upon
walking.
Within
24
hours
of
admission,
he
was
hlly
conscious
and
alert,
and
the
ataxia
disappeared
over
48
hours.
There
was
no
evidence
of
renal
impairment,
and
slight
hepatic
impairment
was
indicated
by
a
slight
rise
in
serum
transaminase
(52
i.
u.)
over
48
hours,
followed
by
a
return
to
normal
levels.

The
circumstances
of
the
accident
were
recreated
by
the
study
authors.
Based
on
the
quantity
of
paint
applied,
the
volume
of
the
space,
and
the
assumption
of
still
air
conditions
(based
on
the
limited
ventilation
present),
the
probable
xylene
concentration
was
estimated
to
be
10,000
ppm.
Although
two
cans
of
cleaning
fluid
primarily
comprised
of
toluene
were
allso
found
at
the
scene,
neither
of
the
survivors
remembered
using
the
cleaning
fluid.
Therefore,
it
was
assumed
by
the
study
authors
that
exposure
was
primarily
limited
to
xylene.

2.2.
Nonlethal
Toxicity
2.2.1.
Case
Reports
Two
case
reports
of
seizures
following
exposure
to
xylene­
based
products
have
been
reported
in
the
literature.
Goldie
(1960)
reported
a
case
where
8
painters
were
exposed
to
paint
containing
80%
xylene
and
20%
methylglycolacetate.
When
the
painters
were
painting
the
inside
of
a
gun
tower,
adequate
ventilation
was
not
present
because
the
draft
created
by
the
ventilation
system
created
too
great
of
a
draft
for
painting.
The
workers
complained
of
headache,
vertigo,
gastric
discomfort,
dryness
of
the
throat,
and
slight
drunkenness
after
30
minutes
of
exposure;
therefore,
the
painters
worked
in
the
unventilated
area
for
30
minutes
at
a
time
followed
by
10
minute
breaks
for
breathing
fresh
air.
After
working
for
approximately
two
months,
an
18­
year­
old
boy
exhibited
behavior
indicative
of
a
convulsive
seizure
one
day
after
leaving
work.
Signs
included
weakness,
dizziness,
inability
to
speak,
unconsciousness,
eyes
and
head
rotated
to
one
side,
chewing
but
no
foaming,
and
short,
sharp
interrupted
jerks
of
the
upper
and
lower
limbs.
The
boy
recovered
consciousness
20
minutes
later.
Although
the
boy
experienced
another
shorter
fit
following
admission
to
the
hospital,
hospital
tests
were
unable
to
confirm
the
diagnosis.
In
another
case,
Arthur
and
Curnock
(1982)
reported
that
an
adolescent
boy
developed
major
and
minor
seizures
following
the
use
of
a
xylene­
based
glue
used
for
building
model
airplanes.
Neither
case
reports
provide
an
exposure
concentration,
and
exposures
were
not
limited
to
xylene
alone.

Klaucke
et
al.
(1982)
reported
that
during
work
one
day,
fifteen
employees
of
a
small
community
hospital
reported
at
least
2
of
the
following
symptoms
lasting
from
2
to
48
hours:
headache,
nausea,
vomiting,
dizziness
or
vertigo,
eye
irritation,
or
nose
or
throat
irritation.
The
frequency
of
the
symptoms
were
as
follows:
headache:
12/
15;
nausea:
10/
15,
eye
irritation:
8/
15;
nose
or
throat
irritation:
7/
15;
dizziness
or
vertigo:
7/
15;
and
vomiting:
6/
15.
Fourteen
of
the
15
/33
XYLENES
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36
37
affected
employees
noted
an
unusual
odor
15­
30
minutes
prior
to
the
onset
of
symptoms.
After
investigation,
it
was
determined
that
the
"illness"
was
caused
when
one
liter
of
liquid
xylene
was
poured
down
a
drain
in
a
pathology
laboratory,
and
the
vapors
were
then
drawn
into
the
room
containing
a
ventilation
fan
which
distributed
the
vapors
throughout
the
affected
area
of
the
hospital.
It
was
estimated
that
workers
were
exposed
to
levels
as
high
as
700
ppm.

2.2.2.
Controlled
Exposures
Twenty­
three
male
volunteers
(mean
age
of
23
years)
were
divided
in
groups
of
4
or
5
and
exposed
to
air
containing
measured
concentrations
of
100
or
200
ppm
m­
xylene,
p­
xylene,
or
toluene
for
3
hours
or
for
7
hours
with
a
1­
hour
lunch
break
(Ogata
et
al.,
1970).
Vapor
concentrations
were
analyzed
every
half­
hour
by
gas
chromatography.
Systolic
and
diastolic
blood
pressure,
pulse
rate,
flicker
value,
and
reaction
time
were
assessed
in
all
volunteers
at
the
beginning
and
the
end
of
exposures.
Exposure
to
m­
or
p­
xylene
did
not
significantly
affect
any
of
these
parameters.

A
group
of
6
or
7
volunteers
(21­
60
years
of
age)
were
exposed
to
air
containing
measured
concentrations
of
mixed
xylenes
(p­
xylene:
7.84%;
m­
xylene:
65.0
1%;
o­
xylene:
7.63%;
ethyl
benzene:
19.27%)
for
15
minutes
in
the
following
order:
230,
110,
460,
or
690
ppm,
with
exposures
limited
to
one/
day
(Carpenter
et
al.,
1975b;
methods
in
Carpenter
et
al.,
1975a).
Volunteers
provided
written
responses
at
1
­minute
intervals
throughout
the
15­
minute
exposure.
Xylene
concentration
was
analyzed
by
gas
chromatography.
Results
of
the
exposure
are
summarized
in
Table
2.
Effects
at
110
ppm
were
limited
to
mild
throat
discomfort
in
one
volunteer
during
the
lSt
and
7th
minute
of
exposure;
this
individual
did
not
experience
discomfort
during
exposure
to
230
ppm.
Exposure
to
230
ppm
resulted
in
one
volunteer
reporting
eye
irritation
during
the
4*,
5*
and
15"
minute
of
exposure;
another
noting
sleepiness
at
the
13*
minute
followed
by
eye
wetness
(but
no
tears
formed)
at
the
14*
and
15*
minute
of
exposure;
one
volunteer
reporting
possible
mild
nasal
irritation;
and
another
volunteer
reporting
intermittent
dizzinedlight­
headedness
(with
no
loss
of
coordination)
during
the
last
2
minutes
of
exposure.
At
460
ppm,
4
volunteers
reported
intermittent
or
continuous
mild
eye
irritation,
with
one
additionally
reporting
eye
wetness
when
leaving
the
chamber;
one
volunteer
noted
mild
dizziness
at
the
6*
minute
of
exposure
that
persisted
throughout
the
15­
minute
exposure
(same
individual
that
noted
dizziness
at
230
ppm);
and
one
volunteer
reported
possible
mild
nasal
and
throat
irritation
(same
individual
reporting
nasal
irritation
at
230
ppm).
Exposure
to
690
ppm
resulted
in
dizzinesdlight­
headedness
in
4
volunteers.
Three
of
the
volunteers
reported
the
dizziness
to
be
mild
and
not
associated
with
a
loss
of
balance,
while
the
other
volunteer
reported
a
slight
loss
of
balance.
Eye,
nose,
and
throat
irritation
was
noted
during
exposure,
but
ceased
within
10
minutes
post
exposure.
It
was
concluded
that
exposure
to
100
ppm
xylene
would
not
be
objectionable
to
most
people,
while
none
of
the
volunteers
thought
that
690
ppm
xylene
could
be
tolerated
over
an
%hour
work
day.
2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
XYLENES
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Number
oflwith
'able
taken
from
Carpenter
et
al.,
1975b.

Volunteer,
male
college
students
age
18­
30
years
old
were
exposed
to
air
containing
0,
100,
200,
or
400
ppm
(0,
0.43,
0.86,
or
1.72
m
a
)
mixed
xylenes
for
30
minutes
(p­
xylene:
7.84%;
m­
xylene:
65.01%;
o­
xylene:
7.63%;
ethyl
benzene:
19.27%)
(Hastings
et
al.,
1986).
The
students
were
exposed
using
an
olfactometer
delivery
hood
made
of
transparent
Lucite
which
allowed
adequate
air
flow.
Solvent
or
distilled
water
(for
control
exposures)
were
delivered
via
a
motorized
syringe,
and
heating
tapes
vaporized
the
solvent
or
water
before
introduction
into
the
hood.
Samples
of
air
taken
from
the
breathing
zone
in
the
hood
were
analyzed
by
gas
chromato­
graphy
for
the
actual
exposure
concentrations
and
were
found
to
be
acceptable.
A
contact
electrode
was
taped
near
the
skin
of
the
outer
canthus
of
one
eye
on
each
subject
to
measure
eye
blinks,
and
an
indifferent
electrode
was
clipped
to
the
ipsilateral
ear.
Respiratory
measurements
were
recorded
with
the
aid
of
a
thermistor
placed
near
one
naris.
Behavioral
tests,
two
measuring
psychomotor
performance
(consisting
of
the
Michigan
Eye­
Hand
Coordination
Test
and
a
visuomotor­
skill
TV
game)
and
one
measuring
cognitive
performance
(choice
reaction
time),
were
administered
before,
during,
and
after
exposure
(ie.,
10
minutes
after
placement
in
the
hood
when
exposed
to
control
air,
during
the
last
5
minutes
of
the
30
minute
exposure
to
xylene,
and
again
10
minutes
after
the
subjects
were
again
exposed
to
control
air
for
10
minutes).
The
reader
is
referred
to
the
study
for
additional
details
about
the
behavioral
testing.
Additionally,
the
subjects
were
asked
every
5
minutes
during
the
experiment
if
they
detected
any
odor
or
experienced
eye,
nose,
or
throat
irritation.

The
effects
of
the
exposure
to
xylene
were
mild.
Eye
irritation
was
reported
by
56,
60,
70,
and
90%
of
the
subjects
in
the
0,
100,
200,
or
400
ppm
groups,
respectively,
with
none
of
the
percentages
reaching
statistical
significance
as
compared
with
the
high
control
percentage
(Hastings
et
al.,
1986).
No
definitive
increase
in
the
percentage
of
exposed
subjects
experiencing
nose
or
throat
irritation
was
observed
as
compared
with
controls.
The
number
of
eye
blinks
per
minute
and
respiration
rate
(breathdminute)
were
not
statistically
increased
in
any
of
the
exposure
groups
as
compared
with
the
controls,
confirming
that
the
reported
irritation
was
mild.
Lastly,
no
statistically
significant
differences
in
the
performance
of
the
behavioral
tasks
by
the
exposed
subjects
were
observed
as
compared
with
controls.

Gamberale
et
al.
(1978)
conducted
two
series
of
experiments
assessing
the
effects
of
xylene
exposure
in
healthy
male
volunteers
age
21
to
33
years
old.
In
the
first
experiment,
groups
of
5
males
were
exposed
to
0,
100,
or
300
ppm
xylene
for
70
minutes
on
day
1,2,
or
3,
with
the
XYLENES
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sequence
of
the
exposure
balanced
among
the
3
groups
(ie.,
on
day
1,
group
1,2,
and
3
were
exposed
to
0,300,
or
100
ppm
xylene,
respectively).
In
the
second
experiment,
a
group
of
8
volunteers
(who
had
also
participated
in
the
first
series)
was
also
exposed
to
300
ppm
xylene
for
70
minutes;
however,
the
volunteers
exercised
on
a
bicycle
ergometer
(100
W)
the
first
30
minutes
of
the
exposure,
and
sat
in
a
chair
the
last
40
minutes
of
the
exposure.
In
both
experiments,
a
breathing
valve
with
low
resistance
was
used
to
supply
the
air
or
xylene,
and
menthol
crystals
were
placed
in
the
tube
of
the
mouthpiece
to
mask
the
odor
of
solvent.
A
total
hydrocarbon
analyzer
was
used
to
continuously
measure
the
inspired
xylene
concentration
during
exposure,
and
a
gas
chromatographic
technique
was
used
to
measure
the
alveolar
air
concentration
of
xylene
(fbrther
details
were
not
provided).
Heart
rate
was
checked
regularly.
Five
performance
tests
were
administered
to
volunteers
during
the
exposures:
one
administered
at
the
beginning
of
the
exposure
period
and
all
five
during
the
last
35
minutes
of
exposure.
The
performance
tests
included:
critical
flicker
hsion,
reaction
time
addition,
simple
reaction
time,
short
term
memory,
and
choice
reaction
time.
All
of
the
tests
utilized
visual
stimulation
with
electronic
recording
of
responses.
Lastly,
after
each
exposure
trial,
subjects
were
requested
to
fill
out
a
questionnaire
addressing
subjective
symptoms
observed
by
the
subjects
during
exposures.

The
concentration
of
xylene
in
the
alveolar
air
of
exposed
subjects
at
30
minutes
and
70
minutes
of
exposure
corresponded
with
the
exposure
concentration:
the
alveolar
air
concentration
in
the
300
ppm
group
was
3
times
that
of
the
100
ppm
group
(Gamberale
et
al.,
1978).
Following
exercise
with
exposure
to
300
ppm
group,
however,
the
alveolar
xylene
concentration
was
increased
3.7­
and
2.2­
fold
at
30
and
70
minutes,
respectively,
as
compared
with
exposure
to
300
ppm
at
rest.
No
exposure­
related
changes
in
heart
rate
were
observed.
Although
a
slight
increase
in
the
frequency
of
the
subjective
symptoms
of
headache,
sickness,
and
intoxication
were
noted,
the
number
of
subjects
affected
was
not
provided.
However,
the
authors
stated
that
most
of
the
subjects
reported
no
or
only
negligible
subjective
symptoms.
Xylene
exposure
at
rest
did
not
significantly
S
e
c
t
the
results
of
the
performance
tests
of
subjects
exposed
to
100
or
300
ppm
xylene.
When
xylene
exposure
was
combined
with
lOOW
of
work,
impaired
performance
was
observed
on
all
tests,
significantly
so
(p<
0.05)
in
the
reaction
time
addition
test
and
the
short
term
memory
test
(fbrther
details
not
provided).

Exposure
of
groups
of
4
male
volunteers
to
70
ppm
p­
xylene,
80
ppm
toluene,
or
a
combination
of
50
ppm
toluene
and
20
ppm
p­
xylene
for
4
hours
did
not
affect
the
results
of
choice
reaction
time,
simple
reaction
time,
or
short
term
memory
performance
tests
as
assessed
by
microcomputers
immediately
upon
entry
into
the
exposure
chamber,
after
2
hours
of
exposure,
or
after
4
hours
of
exposure
as
compared
to
control
air
exposure
(Olson
et
al.,
1985).
Solvent
exposure
also
did
not
affect
heart
rate
or
the
reporting
of
subjective
symptoms
recorded
by
questionnaire
at
the
end
of
the
exposures.

Groups
of
two,
healthy,
male
volunteers
age
22­
35
years
old
were
exposed
in
random
sequence
to
air
containing
100
ppm
toluene,
100
ppm
xylene,
a
mixture
of
50
ppm
toluene:
50
ppm
xylene,
or
to
control
air
for
4­
hour
sessions,
with
each
exposure
session
separated
by
7
day
intervals
(Dudek
et
al.,
1990).
Further
characterization
of
the
solvents
was
not
provided
(i.
e.,
no
information
about
the
purity
or
composition
of
xylene
was
provided).
Exposures
occurred
in
an
exposure
chamber,
with
the
test
solvent
concentrations
controlled
by
monitoring
with
gas
chromatography
and
infrared
spectrophotometry.
Terpon
vapors
were
used
to
mask
the
XYLENES
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odor
of
the
test
solvents.
A
battery
of
9
psychological
tests
was
used
to
evaluate
the
effects
of
the
solvents
on
the
subjects
during
exposure.
The
tests
evaluated
memory
(Sperling's
test),
interference
of
cognitive
processes
(Stroop's
test),
cognitive
processes
(Sternberg's
test),
motor­
visual
coordination
(Flanagan's
test),
speed
and
precision
of
hand
movements
(aiming),
psychomotor
efficiency
(simple
reaction
time,
choice
reaction
time,
and
Santa
Ana),
and
mood
(Profile
of
Mood
State).
The
subjects
had
a
training
session
on
taking
the
performance
tests
a
week
prior
to
the
exposure.
On
the
day
of
the
exposure,
the
tests
were
administered
one
hour
before
the
exposure,
at
the
commencement
of
the
exposure,
and
3
hours
into
the
exposure.
Only
the
results
of
the
xylene
exposure
are
reported
here.
Xylene
exposure
for
3
hours
resulted
in
a
statistically
decreased
performance
of
the
simple
reaction
time
test
(prolongation
of
simple
reaction
time;
p<
O.
OOl)
and
the
choice
reaction
time
test
(p<
O.
OOl).
No
statistically
significant
effects
were
observed
in
any
of
the
other
psychological
tests.

An
average
of
10
subjects
(mix
of
males
and
females)
were
exposed
to
xylene
in
a
1200
cubic
foot
gas
chamber
for
3
to
5
minutes,
and
the
level
of
irritation
experienced
by
the
subjects
was
recorded
upon
exit
from
the
chamber
(Nelson
et
al.,
1943).
Further
experimental
details
were
not
provided.
The
study
authors
reported
that
exposure
to
200
ppm
xylene
resulted
in
eye,
nose,
and
throat
irritation
in
the
majority
of
the
subjects
and
was
classified
as
objectionable.
The
majority
of
the
subjects
stated
that
they
thought
exposure
to
100
ppm
xylene
for
an
8­
hour
exposure
would
be
tolerable.

In
1981,
Hake
et
al.
published
the
results
of
a
study
that
established
the
relationship
between
exposure
magnitude
and
p­
xylene
body
burden
as
measured
by
urine,
blood,
and
breath,
and
saliva,
and
evaluated
the
effects
of
repeated
p­
xylene
vapor
exposure
on
human
health.
A
total
of
9
Caucasian
males
and
7
Caucasian
females
were
exposed
at
rest
to
p­
xylene
vapors.
The
subjects
were
subdivided
into
three
daily
groups
for
7%
hours,
3
hours,
or
1
hour
of
daily
exposures.
Males
and
females
were
exposed
the
first
week
(5
consecutive
days)
to
100
ppm
p­
xylene.
Males
additionally
were
exposed
to
20
ppm
the
second
week,
150
ppm
the
third
week,
and
fluctuating
concentrations
of
50
to
150
ppm
(for
a
time
weighted
average
of
100
ppm)
the
fourth
week.
Subjects
were
exposed
to
0
ppm
Thursday
and
Friday
of
the
week
preceding
xylene
exposure,
and
Monday
and
Tuesday
the
week
following
the
last
week
of
xylene
exposure
to
provide
control
data.
Exposures
were
conducted
in
a
controlled
environment
chamber
(20
x
20
x
8
fi).
p­
Xylene
vapor
was
introduced
into
the
chamber's
circulating
air
by
a
stream
of
air
sweeping
vapor
from
a
warm
flask.
p­
Xylene
chamber
vapor
concentrations
were
continuously
monitored
and
an
infrared
spectrometer
with
a
gas
chromatograph
serving
as
a
back­
up
monitor.
Endpoints
selected
to
evaluate
p­
xylene
toxicity
included
neurological
testing
(modified
Romberg,
heel­
to­
toe
test,
EEG,
and
visual
evoked
potentials),
cardio­
pulmonary
function
tests,
cognitive
testing
(Flanagan
coordination
test,
time
estimation
tests,
arithmetic
test,
inspection
test),
and
subjective
responses
(noted
by
subjects
during
the
exposure
or
during
the
first
3
hours
of
exposure).

Irritation
was
the
only
subjective
response
noted
that
appeared
to
be
related
to
xylene
exposure
(Hake
et
al.,
1981).
In
males,
eye
irritation
was
noted
7
times
and
8
times
during
the
week­
long
exposures
to
100
ppm
or
150
ppm
respectively,
compared
with
3
mentions
during
the
4
control
days.
Of
these
notations,
one
individual
in
the
7.5­
hour
exposure
group
wearing
contacts
noted
eye
irritation
almost
everyday,
while
another
subject
complained
twice
at
100
ppm
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and
3
times
at
150
ppm.
No
irritation
was
noted
by
males
during
any
3­
hour
exposure,
but
one
subject
complained
of
eye
irritation
during
a
1
­hour
exposure
to
150
ppm.
No
visible
reddening
of
the
eyes
or
conjunctiva
was
observed.
Irritation
was
also
noted
by
females,
but
was
confined
to
nose
or
throat
irritation.
During
the
5­
day
exposure
to
100
ppm,
irritation
was
noted
17
times,
compared
with
5
times
during
2
control
days.
No
significant
neurological,
cardio­
pulmonary,
or
cognitive
abnormalities
were
definitively
correlated
with
exposure
to
any
concentration
of
p­
xylene,
Although
a
decrement
in
the
performance
of
the
Flanagen
coordination
test
was
noted
in
males
exposed
to
150
ppm
p­
xylene
for
7.5
hourdday,
the
decrement
was
due
almost
entirely
to
the
performance
of
one
subject
who
had
previously
been
ill.
The
changes
in
EEG
activity
(increase
in
delta
activity)
observed
in
7.5­
hour
males
when
exposed
to
100
or
150
pprn
p­
xylene
c
d
d
not
definitely
be
ascribed
to
exposure
because
the
changes
were
not
evident
during
every
exposure
and
were
not
correlated
with
exposure
concentrations.

Nine
male
student
volunteers
(age
of
20­
25
years)
were
exposed
at
rest
to
200
ppm
m­
xylene,
200
or
400
ppm
trichloroethane,
or
a
combination
of
200
ppm
xylene
and
400
ppm
trichloroethane
for
4
hours/
day,
once
a
week,
with
a
6­
day
interval
between
succeeding
exposures
over
6
consecutive
weeks
(Savolainen
et
al.,
1981;
Seppalainen
et
al.,
1983).
The
exposures
were
single
blind,
with
each
subject
acting
as
his
own
control.
The
endpoints
examined
by
each
author
were:
body
sway,
reaction
times,
flicker
fusion,
and
subjective
symptoms
(Savolainen
et
al.,
1981)
or
pattern
visual
evoked
potential
(VEP)
(Seppalainen
et
al.,
1983).
Body
sway
along
the
anteroposterior
and
lateral
axes
was
recorded
with
a
strain
gauge
platform
with
the
eyes
open
and
closed,
and
was
measured
1
hour
before
exposure,
and
after
20
minutes
and
3.75
hours
of
exposure.
Reaction
time
(manual
response
to
stimuli)
and
tapping
of
the
dominant
hand
was
measured
before
exposure,
and
after
1
and
3
hours
of
exposure.
Flicker
fksion
was
assessed
before
exposure
and
at
1.5
and
3.5
hours
of
exposure.
Pattern
VEP
was
measured
before
exposure,
and
5­
30
minutes
after
the
end
of
exposure.
Exposure
to
xylene
alone
did
not
result
in
any
marked
adverse
effects.
A
slight
improvement
in
performance
was
observed
as
a
slight
decrease
in
body
sway
and
slightly
shortened
reaction
time
(Savolainen
et
al.,
1981).
No
effects
on
tapping
speed
were
observed,
and
a
slight
increase
in
the
critical
firsion
thresholds
were
noted
in
the
afternoon
sessions
(Savolainen
et
al.,
1981).
No
statistically
significant
effects
were
observed
in
the
pattern
VEP
following
exposure
to
m­
xylene
(Seppalainen
et
al.,
1983).

Nine
male
student
volunteers
(mean
age
of
21
years)
in
three
groups
of
three,
were
exposed
for
3
hours
in
the
morning
and
40
minutes
in
the
afternoon,
with
a
40­
minute
lunch
break
in
between,
to
air
containing
a
fixed
concentration
of
200
ppm
m­
xylene,
a
basal
concentration
of
135
ppm
m­
xylene
with
20
minute
peak
concentrations
of
400
ppm
at
the
beginning
of
the
morning
and
afternoon
sessions,
or
to
control
air
(Seppalainen
et
al.,
1989;
Seppalainen
et
al.,
1991;
Laine
et
al.,
1993).
The
subjects
were
exposed
sedentary
or
with
10
minutes
of
exercise
(1OOW)
at
the
beginning
of
each
exposure
session.
The
exposures
occurred
on
6
separate
days,
with
a
minimum
of
a
5­
day
interval
separating
the
xylene
exposures.
The
subjects
were
exposed
in
a
dynamic
chamber,
and
the
concentration
of
atmospheric
xylene
was
continuously
monitored
(hrther
details
not
provided).
Peppermint
oil
was
used
to
mask
control
exposure
and
the
solvent
odor,
with
the
experiment
being
a
single­
blind
experiment
with
crossover
design,
with
each
subject
acting
as
his
own
control.
The
endpoints
examined
by
each
author
were:
visual
evoked
potentials
and
brainstem
auditory
evoked
potentials
(BAEPs)
(Seppalainen
et
al.,
1989);

_.
.
..
._.
.
...
.
..
.lll
XYLENES
Proposed
I:
5/
2002
1
2
3
4
5
6
a
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
electroencephalograph
(EEGs)
recordings
(Seppalainen
et
al.,
1991);
and
body
sway
and
reaction
times
(Laine
et
al.,
1993).

Visual
evoked
potentials
(VEPs)
were
recorded
in
the
morning
before
the
subjects
entered
the
exposure
chamber,
and
at
the
end
of
the
morning
and
afternoon
exposure
session
(Seppalainen
et
al.,
1989).
For
pattern
VEPs
(pattern
reverse
stimulus),
latencies
of
P50,
N70,
P100,
N135,
P170,
and
the
peak­
to­
peak
amplitude
of
N70
to
PlOO
were
measured.
For
flash
VEPs
(light
flash),
latencies
ofP50,
N70,
P100,
N150,
P200,
and
the
peak­
to­
peak
amplitude
of
PlOO
to
N4.50
were
measured.
Additionally,
brainstem
auditory
evoked
potentials
(BAEPs)
were
recorded.
The
results
from
the
study
demonstrated
that
xylene
exposure
at
rest
did
not
result
in
any
consistent
effects
on,
VEPs,
while
xylene
exposure
combined
with
exercise
resulted
in
minor
but
statistically
significant
decreases
in
the
latencies
of
N135
in
the
pattern
VEP
and
of
P200
in
the
flash
VEP
at
fluctuating
concentrations
of
400
ppm.
No
exposure
related
changes
were
noted
in
BAEPs.
The
study
authors
suggested
that
exposure
to
"the
most
intensive
exposure
situations"
may
result
in
an
aroused
state,
but
that
the
changes
did
not
indicate
any
health
hazards
to
healthy
workers.

EEG
recordings
were
made
in
the
exposure
chamber
during
the
first
18
minutes
of
the
morning
and
afternoon
exposure
sessions,
and
included
10
minutes
of
exercise
and
3­
4
minutes
after
exercise
ceased
on
the
days
subjects
were
exercising
(Seppalainen
et
al.,
1991).
Five­
minute
recordings
were
also
made
1
and
2
hours
after
the
subject
entered
the
chamber
in
the
morning,
and
45
minutes
after
the
afternoon
exposure
ceased.
Exposure
to
m­
xylene
resulted
in
minor
changes
that
suggested
a
stimulating,
excitatory
effect
(slight
alpha
activation).

Body
sway
and
reaction
times
were
measured
before
exposure
in
the
morning,
20
and
120
minutes
after
the
beginning
of
the
morning
exposure,
20
minutes
after
the
beginning
of
the
afternoon
exposure,
and
50
minutes
after
the
end
of
the
afternoon
exposure
(Laine
et
al.,
1993).
Body
sway
along
the
anteroposterior
and
lateral
axes
was
recorded
with
a
strain
gauge
platform
with
the
eyes
open
and
closed.
Simple
reaction
time
of
the
dominant
hand
following
visual
stimuli
and
choice
reaction
time
following
auditory
and
visual
stimuli
were
used
to
assess
reaction
times.
The
authors
also
measured
gaze
deviation
nystagmus.
Exposure
to
peak
concentrations
of
m­
xylene
(400
ppm)
resulted
in
decreased
body
sway
both
in
sedentary
and
exercising
subjects.
No
definitive
conclusions
on
the
effects
of
m­
xylene
exposure
on
reaction
times
could
be
drawn
because
reaction
times
did
not
consistently
change
with
the
intensity
of
exposure.
In
the
afternoon,
longer
simple
reaction
times
were
noted
following
exposure
to
peaks
of
m­
xylene
at
rest,
while
prolonged
audiomotor
choice
reaction
times
were
prolonged
following
exposure
to
peaks
of
m­
xylene
while
exercising.
No
effect
of
nystagmus
was
noted.

Laine
et
al.
(1993)
additionally
exposed
12
healthy
male
volunteers
(4
groups
of
3)
at
rest
to
stable
concentrations
of
200
ppm
m­
xylene
for
5
hours
and
30
minutes
on
2
days,
with
1
week
separating
the
exposures.
Body
sway
and
reaction
times
(auditory,
visual,
and
associative
signals)
were
measured
in
the
morning
before
exposure
and
after
cessation
of
the
exposure.
Recordings
of
body
movements
while
the
subjects
slept
were
made
the
night
of
the
exposure
at
the
subjects'
homes
using
a
static
charge
sensitive
bed.
No
effect
on
body
sway
were
observed,
and
no
statistical
differences
in
reaction
times
were
noted.
The
only
statistically
significant
effect
observed
when
the
subjects
were
sleeping
was
a
slightly
decreased
number
of
body
movements.

9
XYLENES
Proposed
1:
5/
2002
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
No
effect
on
active
and
quiet
sleep
was
observed.
No
differences
in
body
sway
or
reaction
times
were
observed
the
morning
following
the
exposure.

Nine
male
student
volunteers
(mean
age
of
21
years)
in
three
groups
of
three
were
exposed
for
3
hours
in
the
morning
and
1
hour
in
the
afternoon,
with
a
40­
minute
lunch
break
in
between,
to
air
containing
a
fixed
concentration
of
200
ppm
m­
xylene,
a
basal
concentration
of
135
ppm
m­
xylene
with
20
minute
peak
concentrations
of
400
ppm
at
the
beginning
of
the
morning
and
afternoon
sessions,
or
to
control
air
(Savolainen
et
a].,
1984;
1985a;
1985b).
The
subjects
were
exposed
sedentary
or
with
10
minutes
of
exercise
(1OOW)
at
the
beginning
of
each
exposure
session.
The
exposures
occurred
at
6
day
intervals
during
6
succeeding
weeks.
The
subjects
were
exposed
in
a
dynamic
chamber,
and
the
concentration
of
atmospheric
xylene
was
continuously
monitored
with
an
infrared
monitor.
Peppermint
oil
was
used
to
mask
control
exposure
and
the
solvent
odor,
with
the
experiment
being
a
single­
blind
experiment
with
crossover
design,
with
each
subject
acting
as
his
own
control.
The
endpoints
examined
by
each
author
were:
body
sway
(Savolainen
et
al.,
1985a);
and
body
sway
and
reaction
times
(Savolainen
et
al.,
1984;
1985b).
Body
sway
along
the
anteroposterior
and
lateral
axes
was
recorded
with
a
strain
gauge
platform
with
the
eyes
open
and
closed,
and
was
measured
before
exposure
in
the
morning,
at
the
time
of
peak
exposure
and
exercise
(about
15­
20
minutes
into
exposure),
and
after
exposure
(Savolainen
et
al.,
1984;
1985b).
Simple
reaction
time
of
the
dominant
hand
following
visual
stimuli
(Savolainen
et
al.,
1984;
1985b)
and
choice
reaction
time
following
auditory
stimuli
(Savolainen
et
al.,
1984)
or
auditory
and
visual
stimuli
(Savolainen
et
al.,
1985b)
were
used
to
assess
reaction
times.

Savolainen
et
al.
(1984)
reported
that
body
sway
along
the
anteroposterior
axis
was
impaired
by
exposure
to
peak
xylene
concentrations
at
rest,
but
improved
with
peak
xylene
concentrations
with
exercise.
Opposite
results
were
observed
when
body
sway
was
measured
along
the
lateral
axis:
only
fluctuating
concentration
with
exercise
impaired
balance,
while
body
sway
improved
(decreased)
with
exposure
at
rest.
Savolainen
et
al.
(1985b)
found
that
body
sway
was
negatively
correlated
with
xylene
concentrations;
i.
e.,
xylene
exposure
improved
(decreased)
body
sway,
while
no
correlation
was
evident
between
blood
xylene
concentrations
and
body
sway.
In
contrast,
Savolainen
et
al.
(1985a)
reported
that
changes
in
body
sway
were
positively
correlated
with
blood
xylene
concentrations
from
exposure
to
stable
and
fluctuating
m­
xylene
concentrations.

No
consistent,
significant
effects
on
reaction
times
following
exposure
to
m­
xylene
were
found
by
Savolainen
et
al.
(1985b).
Savolainen
et
al.
(1984)
reported
that
choice
reaction
times
as
assessed
using
auditory
stimuli
were
statistically
impaired
in
subjects
exposed
to
peak
m­
xylene
concentrations
with
exercise
during
the
afternoon
session.
In
the
afternoon
sessions,
simple
reaction
times
were
impaired
in
sedentary
subjects
following
peak
exposure
to
m­
xylene,
but
improved
in
subjects
exposed
to
peak
concentration
with
exercise.

A
total
of
twenty­
two
male
student
volunteers
(mean
age
of
24
years)
were
exposed
to
laboratory
grade
m­
xylene
(Riihimaki
and
Savolainen,
1980;
Savolainen
and
Riihimaki,
198
1).
Six
sedentary
subjects
were
exposed
for
6
hours/
day
(with
a
1­
hour
lunch
break)
for
5
consecu­
tive
days
and
for
1­
3
days
after
a
2­
day
weekend.
Exposures
on
Monday­
Friday
were
to
stable
concentrations
of
100
ppm
for
the
morning
and
afternoon
sessions
except
on
Friday
afternoon
10
20
Proposed
1:
5/
2002
t
XYLENES
when
the
concentration
was
doubled
to
200
ppm.
'
fixposurei
on
Monday­
Wednesday
of
the
following
week
were
to
fluctuating
concentrations
of
m­
xylene:
subjects
were
exposed
to
an
approximate
baseline
concentration
of
70
ppm
with
peaks
of
200
ppm
lasting
10
minutes
(TWA
of
100
ppm).
On
Wednesday
afternoon,
exposure
concentrations
were
doubled.
The
remaining
16
subjects
were
divided
into
two
groups
of
8
each.
Both
groups
exercised
on
a
bicycle
ergo­
meter
at
lOOW
4xlday
for
10
minutes,
exercising
at
1
and
2
hours
of
exposure
in
the
morning
and
afternoon
sessions.
One
group
was
exposed
to
a
stable
concentration
of
100
ppm
m­
xylene,
with
concentrations
doubled
to
200
ppm
Friday
afternoon,
and
the
other
group
was
exposed
to
fluctu­
ating
concentrations
(baseline
concentration
of
70
ppm
with
hourly
peaks
of
200
ppm
over
10
minutes;
mean
concentration
of
100
ppm),
with
concentrations
doubled
on
the
last
day.
The
subjects
were
exposed
in
a
dynamic
chamber,
with
peppermint
oil
used
to
mask
control
exposure
and
the
solvent
odor.
Control
days
preceded
and
succeeded
exposure
days,
so
that
each
subject
acted
as
his
own
control.
The
endpoints
examined
by
each
author
were:
body
sway
Fihimaki
and
Savolainen,
1980;
Savolainen
and
Riihimaki,
198l),
and
subjective
symptoms,
choice
and
simple
reaction
times,
critical
flicker
fusion,
Santa
Ana
manual
dexterity
test,
nystagmus,
and
EEG
recordings
on
a
limited
number
of
subjects
(Riihimaki
and
Savolainen,
1980).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
20
21
22
23
24
25
26
27
28
29
30
31
i
9
32
33
34
35
36
37
38
39
40
41
42
43
Body
balance
was
affected
when
a
rapid
increase
in
blood
xylene
concentrations
occurred
(i.
e.,
after
peak
exposures
to
fluctuating
concentrations,
particularly
to
400
ppm),
with
tolerance
developing
with
continuing
exposures
(Riihimaki
and
Savolainen,
1980;
Savolainen
and
Riihimaki,
198
1).
Changes
in
EEG
recordings
suggestive
of
a
slight
decrease
in
vigilance
(increased
number
of
slow
occipital
transients)
were
observed
in
4/
4
subjects
following
exposure
to
peak
concentrations
of
xylene
combined
with
exercise
(Riihimaki
and
Savolainen,
1980).
One
subject
additionally
exhibited
bilateral
spike
and
wave
complexes.
Although
Riihimaki
and
Savolainen
(1980)
reported
impairment
of
simple
and
choice
reaction
times
following
exposure
to
xylene
with
the
development
of
tolerance
with
continuing
exposures,
hrther
details
were
not
provided.
Xylene
exposure
did
not
effect
nystagmus,
Santa
Ana
manual
dexterity
test,
or
critical
flicker
fusion
mihimaki
and
Savolainen,
1980).
Subjective
symptoms
were
limited
to
mild
nose
and
throat
irritation
reported
by
1/
6
sedentary
subjects
during
the
400
ppm
peaks
(Riihimaki
and
Savolainen,
1980).
It
should
be
noted
that
the
results
of
testing
of
the
6
sedentary
subjects
and
of
the
16
volunteers
(divided
into
2
groups
of
8)
were
also
reported
in
Savolainen
et
al.
(1979)
and
Savolainen
et
al.
(1980),
respectively.

Savolainen.
and
Linnavuo
(1979)
assessed
the
body
balance
of
17
healthy
male
volunteers
(mean
age
24
years)
by
means
of
a
strain
gauge
transducer.
Then,
6
of
the
17
volunteers
were
exposed
to
m­
xylene
in
the
morning
for
3
hours
to
a
TWA
of
100
ppm
with
hourly
peaks
of
200
ppm,
and
in
the
afternoon
for
3
hours
to
a
TWA
of
200
ppm
with
hourly
peaks
of
400
ppm,
with
a
one­
hour
lunch
break
separating
the
morning
and
afternoon
exposures.
Body
balance
was
assessed
1
hour
before
the
morning
exposure,
and
at
the
end
of
the
morning
and
the
afternoon
exposures.
Control
days
preceded
and
succeeded
exposure
days.
Although
no
differences
in
body
balance
were
observed
following
xylene
exposure
in
the
morning
session,
impairment
of
body
balance
was
noted
in
the
subjects
during
the
afternoon
session,
particularly
with
the
eyes
closed.

Using
6
xylene
concentrations
(composition
not
specified)
and
18
subjects
familiar
with
the
smell
of
xylene,
the
odor
threshold
for
xylene
was
reported
as
0.1­
0.4
ppm
(reported
as
11
21
XYLENES
Proposed
1:
92002
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
0.6­
1.9
mg/
m3)
for
the
minium
perceptible
concentration
and
0.09­
0.3
ppm
(0.4­
1.4
mg/
m3)
for
the
maximum
imperceptible
concentration
(Gusev,
1965).
EEG
recordings
made
of
4
subjects
exposed
to
xylene
for
6
minutes
indicated
a
decrease
in
the
electrical
activity
of
the
cerebral
cortex
at
a
concentration
of
0.07
ppm
(0.32
mg/
m3>,
but
not
at
0.05
ppm
(0.21
mg/
nn3).
The
reason
for
these
effects
at
such
low
exposure
concentrations
is
unknown.

2.3.
Developmental/
Reproductive
Effects
A
limited
number
of
studies
suggest
an
association
between
xylene
exposure
and
an
increased
risk
of
spontaneous
abortions
(Taskinen
et
al.,
1994;
Windham
et
al.,
1991)
or
developmental
toxicity
(Holmberg
and
Nurminen,
1980;
Kucera,
1968;
Taskinen
et
al.,
1989).
A
number
of
limitations
preclude
the
usefulness
of
these
studies,
however,
including:
small
sample
sizes,
no
quantified
exposure
concentrations,
and/
or
concurrent
exposures
to
other
solvents.

2.4.
Genotoxicity
No
increase
in
the
frequency
of
sister
chromatid
exchanges
were
observed
in
peripheral
lymphocytes
from
individuals
exposed
to
xylene
in
an
occupational
setting
(Haglund
et
al.,
1980;
Pap
and
Varga,
1987)
or
an
experimental
setting
(Richer
et
al.,
1993).

2.5.
Carcinogenicity
Occupational
exposure
to
xyIene
has
been
associated
with
an
increased
risk
of
leukemia
(Arp
et
al.,
1983;
Wilcosky
et
al.,
1984;
Anttila
et
al.,
1995),
non­
Hodgkin's
lymphoma
(Wilcosky
et
al.,
1984;
Anttila
et
al.,
1995),
and
cancer
of
the
rectum
(Siemiatycki
1991;
Gerin
et
al.,
1998),
colon
(Seimiatycki,
1991;
Gerin
et
al.,
1998),
or
nervous
system
(Spirtas
et
al.,
1991;
Anttila
et
al.,
1995).
Despite
these
associations,
however,
a
number
of
limitations
preclude
the
usefulness
of
these
data,
including:
small
sample
sizes,
no
quantified
exposure
concentrations,
and/
or
concurrent
exposures
to
other
solvents.

2.6.
Summary
A
summary
of
the
effects
of
xylene
exposure
in
humans
is
provided
in
Table
3,
Central
nervous
system
disturbances
following
acute
and
chronic
inhalation
exposure
to
xylene
include
headache,
vertigo,
nausea,
fatigue,
irritability,
dizziness,
impaired
concentration,
or
confusion.
Case
reports
of
xylene
exposure
following
inhalation
have
indicated
signs
and
symptoms
including
seizures,
unconsciousness/
coma,
acute
pulmonary
edema,
and
transient
renal
and
hepatic
impairment.
Death
has
occurred
due
to
pulmonary
failure
following
inhalation
to
approximately
10,000
ppm
xylenes.
XYLENES
Proposed
1:
5/
2002
1
2
3
4
5
6
a
8
9
10
11
12
13
14
15
16
17
18
19
TABLE
3.
Summary
of
Controlled
Human
Exposures
to
Xylene"

Effect
Duration
15
min
Isomer
Mixed
Reference
Intermittent
throat
irritation
(1
/6)
Carpenter
et
al.,
1975b
Eye
irritation
(I
f
7
affected);
dizziness
(In)
230
Eye
irritation
(4/
6
affected);
dizziness
(1/
6),
mild
nosehhroat
irritation
690
Eye
irritation
(4/
6
affected);
dizziness
(416,
with
one
having
loss
of
balance),
eyehoselthroat
irritation
0,
100,200,
400
30
inin
Mixed
Eye
irritation
reported,
but
incidence
not
statistically
signscant:
(56,60,70,90%,
respectively)
No
nose
or
throat
irritation
No
change
in
behavioral
tests
(performance
or
cognitive)
or
respiratory
measurements
Hastings
et
al.,
1986
0,100,300
70
inin
?
No
effect
on
5
performance
test,
heart
rate,
subjective
symptoms
*Note:
exposure
via
a
breathing
valve;
used
menthol
to
mask
odor
Gamberale
et
al.,
1978
300
w/
exercise
70
min
?
Significantly
decreased
performance
on
short
term
memory
and
reaction
time
(2/
5
tests)
*Note:
exposure
via
a
breathing
valve;
used
menthol
to
mask
odor
Significantly
affected
performance
of
simple
and
choice
reaction
time
tests
*Note:
used
terpon
to
mask
odor
Gamberale
et
al.,
1978
100
3
h
?
Dudek
et
al.,
1990
100,200
3
h
or
7hwll
hr
break
m­,
p­
No
effect
on
blood
pressure,
pulse
rate,
flicker
value,
or
reaction
time
(total
of
23
volunteers)
Ogata
et
al.,
1970
70
4h
P­
No
effect
on
choice
reaction
time,
simple
reaction
time,
short
term
memory,
heart
rate,
or
subjective
symptoms
Olson
et
al.,
1985
200
4
h
m­
No
adverse
effect
on
VEP,
tapping
speed,
body
sway,
reaction
time,
critical
flicker
fusion
No
effect
on
body
sway,
reaction
times,
active
or
quiet
sleep
­
only
effect
was
sleep
movements
slightly
decreased
during
night
after
exposure
Savolainen
et
al.,
198
1
;
Seppalainen
et
al.,
1983
200
5.5
11
m­
Laine
et
al.,
1993
Mild
eye
irritation,
primarily
in
person
wearing
contacts­
100
or
150
7.5
11
Hake
et
al.,
1981
P­

No
effect
on
performance
tests
a
lunch
break
are
not
included
in
this
table.
Note:
Exposures
which
were
separated
53
XYLENES
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
3.
ANIMAL
TOXICITY
DATA
3.1.1.
Cats
3.1.
Acute
Lethality
Four
male
cats
of
mixed
breed
were
exposed
to
air
containing
a
mean
measured
concentration
of
9500
ppm
mixed
xylenes
(p­
xylene:
7.84%;
m­
xylene:
65.01%;
o­
xylene:
7.63%;
ethyl
benzene:
19.27%)
(Carpenter
et
al.,
1975b).
Clinical
signs
during
the
exposure
included
salivation,
ataxia,
tonic
and
clonic
spasms,
and
anesthesia.
All
cats
were
dead
within
2
hours
of
the
exposure.
Necropsy
did
not
reveal
any
exposure­
related
histological
lesions.

3.1.2.
Rats
Groups
of
10
female,
Sprague­
Dawley
rats
were
exposed
to
a
mixture
of
xylenes
(comprised
of
0­,
p­,
and
m­
xylene;
percentage
of
each
not
provided)
by
inhalation
in
a
60
L
chamber
for
4
hours
(Lundberg
et
al.,
1986).
Xylene
concentrations
were
not
provided,
but
it
was
stated
that
they
were
administered
in
a
geometric
series.
Solvent
concentration
in
the
chamber
was
monitored
by
infrared
analysis
of
a
stream
of
chamber
air
continuously
drawn
through
an
infrared
analyzer,
and
exposure
levels
were
adjusted
accordingly.
Animals
were
observed
for
mortality
for
24
hours
after
the
start
of
the
exposure.
A
4­
hour
LC50
value
of
11,000
ppm
(reported
as
47,635
mg/
m3;
95%
confidence
limits:
10,000­
12000
ppm)
was
determined
using
the
Weil
method.
In
an
additional
study,
rats
were
exposed
to
concentrations
of
1/
32
to
?h
of
the
LC,,
value,
and
liver
damage
was
assessed
by
measuring
serum
levels
of
sorbitol
dehydrogenase
or
by
histological
analysis
of
liver
sections.
Xylene
exposure
at
these
concentrations
did
not
result
in
any
measurable
hepatotoxicity.

Bonnet
et
al.
(1982)
exposed
groups
of
12
male
Sprague­
Dawley
rats
to
various
concen­
trations
of
o­
xylene
(98%
purity),
m­
xylene
(97%
purity)
or
p­
xylene
(98%
purity)
for
6
hours.
Vapor
concentrations
were
determined
by
gas
chromatrography.
Animals
were
observed
for
mortality
for
14
days
after
exposure
and
LC50
values
were
calculated
using
the
method
of
Bliss
(1938).
Individual
exposure
concentrations
and
mortalities
were
not
provided
in
the
study.
Clinical
signs
reported
for
rats
exposed
to
m­
xylene
and
o­
xylene
consisted
of
a
loss
of
muscle
tone
and
somnolence,
while
rats
exposed
to
p­
xylene
additionally
exhibited
tremor,
shaking,
and
repetitive
movements.
The
6­
hour
LC50
values
with
95%
confidence
limits
were:
m­
xylene:
5984
[5796­
61811;
o­
xylene:
4330
ppm
[4247­
44321;
and
p­
xylene:
4591
ppm
[4353­
50491.

Groups
of
15
or
16
male
albino
rats
(Harlan­
Wistar
strain)
approximately
5
weeks
of
age
were
exposed
for
4
hours
to
air
containing
measured
concentrations
of
580,
1300,2800,
6000,
or
9000
ppm
mixed
xylenes
(p­
xylene:
7.84%;
m­
xylene:
65.01%;
o­
xylene:
7.63%;
ethyl
benzene:
19.27%)
(Carpenter
et
al.,
1975b;
methods
are
given
in
Carpenter
et
al.,
1975a).
Ten
ratdgroup
were
used
for
the
LC50
determination,
while
5
rats1group
were
sacrificed
after
exposure
and
necropsied.
Animals
were
observed
continuously
for
the
first
5
minutes
of
exposure,
at
15
and
30
minutes,
and
then
at
30­
minute
intervals
until
1­
hour
post
exposure,
again
at
2­
hours
post
exposure,
and
daily
thereafter.
All
organs
were
evaluated
grossly
at
death
or
sacrifice.
Histo­
pathological
evaluation
was
made
of
the
respiratory
tract
and
liver
from
3
animals
(or
less)
per
exposure
concentration
at
the
end
of
the
4­
hour
exposure
and
after
2
days
post
exposure,
and
of
the
respiratory
tract,
liver,
kidney,
brain
and
bone
marrow
at
sacrifice
following
the
14­
day
post
14
2
Y
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
XYLENES
._I
Proposed
1:
5/
2002
exposure
observation.
Mortality
results
and
clinical
signs
are
reported
in
Table
4.
A
4­
hour
LC,,
of
6700
ppm
(95%
CI:
5100­
8500
ppm)
was
calculated
using
the
Thompson
method
of
moving
averages.
The
only
findings
at
necropsy
that
were
ascribed
to
treatment
were
2
cases
each
of
pulmonary
atelectasis,
hemorrhage,
and
interlobular
edema
in
rats
that
died
following
exposure
to
the
highest
concentration.
4"
/
$`.,
`

coordination
remained
1
I
601
1
I
4­
hr
LC,,
(calculated
by
probit
for
this
document)
Data
taken
from
Carpenter
et
al.,
1975b
Male
Long­
Evans
rats
weighing
between
150
and
300
g
were
exposed
to
a
mixture
of
o­
xylene,
m­
xylene,
p­
xylene,
and
ethyl
benzene
by
inhalation
for
4
hours,
and
were
observed
for
14
days
for
mortality
for
determination
of
a
4­
hour
LC,,
using
the
method
of
Lickfield
and
Wilcoxon
(Hine
and
Zuidema,
1970).
Information
not
provided
by
the
study
authors
included
the
number
of
ratdgroup,
the
exact
percent
of
each
component
in
the
mixture,
the
exposure
concentrations,
and
whether
the
LC,,
calculation
was
based
on
nominal
or
analytical
concentrations.
The
4­
hour
LC,,
was
determined
to
be
6350
ppm
[CI:
4670­
8640
ppm].
The
authors
reported
that
all
deaths
occurred
during
exposure,
and
that
survivors
were
comatose
upon
removal
from
the
chamber,
but
recovered
shortly
thereafter.

To
determine
the
effects
of
drugs
on
p­
xylene
toxicity,
adult
female
CD
rats
were
pretreated
with
saline,
75
mg/
kg
phenobarbital,
15
mg/
kg
chlorpromazine,
corn
oil,
or
20
mg/
kg
3
­methylcholanthrene
by
intraperitoneal
injections
for
3
consecutive
days
followed
by
exposure
p­
xylene
by
inhalation
for
4­
hours
for
determination
of
LC,,
s
(Harper
et
al.,
1975).
Methods
for
the
xylene
exposures
were
reported
to
be
the
same
as
those
employed
for
benzene
exposure
in
a
previous
study
(Drew
and
Fouts,
1974).
Chamber
concentrations
were
monitored
at
30­
minute
intervals
by
bubbling
the
air
containing
the
vapor
through
methanol,
and
the
vapor
absorbed
in
the
methanol
was
measured
using
a
spectrophotometer.
The
concentrations
used
to
determine
the
4­
hour
LC50
value
are
based
0.
n
the
arithmetic
means
of
8
determinations
over
the
4­
hour
exposure
period.
Animals
were
observed
for
14
days.
The
LC,,
values
and
the
corresponding
95%
confidence
levels
are
presented
in
Table
5.

15
ds
XYLENES
Proposed
I:
§/
2802
p­
Xylene
10
11
12
13
14
19,650
12
8/
10
4912
24­
28
0110
245
1
24
0110
1226
8
x
l
4
h
r
0110
TABLE
5.
Mortality
of
Male
Rats
Exposed
to
Xylene
Vapor
for
4
Hours
Following
Pretreatment
with
Drugs
3
­Methylcholanthrene
I
20
I
4960
I
4710­
5200
11
Table
taken
fi­
om
Harper
et
al.,
1975
Cameron
et
al.
(1938)
exposed
groups
of
10
male
and
female
albino
rats
or
mice
by
inhalation
to
0­,
m­,
or
o­
xylene
(source
and
purity
not
specified)
at
saturation
or
at
one­
half,
one­
fourth,
or
one­
eight
of
saturation,
and
reported
the
resultant
mortalities
(length
of
observation
not
provided).
Mortality
results
are
presented
in
Table
6.
No
treatment­
related
changes
were
noted
in
organs
from
animals
dying
after
exposure.

15
16
17
18
19
20
21
22
23
24
25
26
27
Groups
of
5
male
albino
rats
(Harlan­
Wistar
strain)
were
exposed
to
a
measured
concentra­
tion
of
11,000
ppm
mixed
xylene
for
2
hours
or
for
15,
30,
or
60
minutes
(p­
xylene:
7.84%;
m­
xylene:
65.01%;
o­
xylene:
7.63%;
ethyl
benzene:
19.27%)
(Carpenter
et
al.,
1975a;
b).
Animals
were
observed
constantly
during
the
exposure;
at
0.5,
1,2,
and
4
hours
post
exposure,
and
then
once
daily
for
7
days.
In
the
group
of
rats
exposed
for
2
hours,
eye
irritation
was
noted
immedi­
ately
at
the
start
of
the
exposure,
with
prostration
present
20
minutes
into
the
exposure
and
tremors
observed
45
minutes
into
the
exposure.
Mortality
was
observed
in
2/
5
rats
within
XYLENES
Proposed
1:
5/
2002
7
8
9
10
11
12
13
14
15
16
17
1%
19
20
21
22
23
24
25
26
27
2%
29
66
minutes
and
4/
5
within
80
minutes.
The
rat
that
survived
was
said
to
have
poor
coordination,
but
it
was
not
stated
how
long
the
incoordination
lasted.
No
mortality
was
observed
in
rats
exposed
to
11,000
ppm
mixed
xylene
for
15,30,
or
60
minutes.
Eye
irritation
was
again
noted,
and
prostration
was
observed
in
rats
exposed
for
30
minutes
or
60
minutes,
with
full
coordination­
returning
30
minutes
or
2
hours
post
exposure,
respectively.
The
Lt,,
was
determined
to
be
92
minutes.

§myth
et
al.
(1962)
reported
that
2
hours
was
the
maximum
exposure
time
resulting
in
no
mortality
within
14
days
of
exposure
to
a
concentrated
vapor
of
m­
xylene
in
albino
rats.
Inhalation
of
air
containing
a
nominal
concentration
of
8000
ppm
m­
xylene
for
4
hours
resulted
in
a
mortality
rate
in
rats
of
10/
12
within
the
14
day
observation
period.

3.1.3.
Mice
Bonnet
et
al.
(1979;
1982)
exposed
groups
of
20­
25
female
mice
(specific­
pathogen­
fee
of
stock
OF­
1)
to
various
concentrations
of
o­
xylene
(98%
purity),
m­
xylene
(97%
purity),
or
p­
xylene
(98%
purity)
for
6
hours.
Vapor
concentrations
measured
by
gas
chromatography
were
90­
100%
of
nominal
concentrations.
Animals
were
observed
for
mortality
for
14
days
after
exposure
and
LC,,
values
were
calculated
using
the
method
of
Bliss
(1938).
Individual
exposure
concentrations
and
mortalities
were
not
provided
in
the
study;
it
was
stated
that
mice
exposed
to
o­
xylene
had
incidences
of
delayed
mortality
between
5­
10
days
post
exposure.
The
6­
hour
LC,,
values
with
95%
confidence
limits
were:
m­
xylene:
5267
[5025­
54901;
o­
xylene:
4595
ppm
[4468­
47441;
and
p­
xylene:
3907
ppm
[3
747­
40
151.

The
concentrations
of
the
xylene
isomers
required
to
produce
narcosis
in
white
mice
were
3500­
4600
ppm
for
o­
xylene,
2300­
3500
ppm
for
m­
xylene,
and
2300
ppm
for
p­
xylene,
while
the
lethal
concentrations
were
6900
ppm
for
o­
xylene,
11,500
ppm
for
m­
xylene,
and
3500­
8100
ppm
for
p­
xylene
(Lazarew,
1929).

Cameron
et
al.
(1938)
exposed
groups
of
10
male
and
female
mice
by
inhalation
to
0­,
m­,
or
o­
xylene
(source
and
purity
not
specified)
at
saturation
or
at
one­
half,
one­
fourth,
or
one­
eight
of
saturation,
and
reported
the
resultant
mortalities
(length
of
observation
not
provided).
Mortality
results
are
presented
in
Table
7.
No
treatment­
related
changes
were
noted
in
organs
from
animals
dying
after
exposure.

17
27
XYLENES
Proposed
1:
5/
2002
4
5
245
1
24
0110
1226
8
x
1
4
h
r
0/
10
6
Data
taken
from
Cameron
et
al.,
1938.

7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3.2.
Nonlethal
Toxicity
3.2.2.
Dogs
Lacrimation
was
observed
in
male
beagle
dogs
(number
of
animals
not
provided)
exposed
to
1200
ppm
mixed
xylene
for
4
hours,
while
a
4­
hour
exposure
to
530
ppm
mixed
xylene
had
no
observable
effects
(xylene
comprised
of:
p­
xylene:
7.84%;
m­
xylene:
65.01%;
o­
xylene:
7.63%;
ethyl
benzene:
19.27%)
(Carpenter
et
al.,
1975b;
methods
reported
in
Carpenter
et
al.,
1975a).
It
is
not
clear
if
the
concentrations
are
nominal
or
are
corrected
for
the
50­
60%
loss
that
occurred
during
exposures.

3.2.2.
Rats
Flash
evoked
potentials
PEPS)
were
assessed
in
groups
of
adult,
male,
Long­
Evans
hooded
rats
following
a
4­
hour
exposure
to
air
containing
0,
800,
or
1600
ppm
p­
xylene
(99.8%
pure;
number
of
animals
not
provided)
(Dyer
et
al.,
1988).
Exposure
to
1600
ppm
p­
xylene
resulted
in
a
significant
depression
(p<
0.003)
in
the
amplitude
of
peak
N3
dependent
upon
time,
with
a
return
to
control
levels
75
minutes
post­
exposure.
The
authors
postulated
that
the
depression
in
the
N3
peak
was
the
result
of
increased
arousal
from
the
p­
xylene
exposure,
and
is
supported
by
a
similar
depression
in
the
N3
peak
observed
following
amphetamine
administration
in
rats.

To
assess
the
potential
for
p­
xylene
exposure
to
alter
serum
enzyme
activities,
groups
of
female,
Sprague­
Dawley
rats
were
exposed
to
air
containing
0,
1000,
1500,
or
2000
ppm
p­
xylene
for
4
hours
(Pate1
et
al.,
1979).
Blood
samples
were
collected
from
the
heart
from
4
animals/
group
immediately
after
exposure
and
24
hours
after
the
initiation
of
the
exposure.
By
24
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
XYLENES
Proposed
1:
5/
2002
hours,
increases
were
observed
in
the
activities
of
serum
glutamic
pyruvic
transaminase,
oxaloacetic
transaminase,
and
5'­
nucleotidase
in
all
exposure
groups,
and
of
glucose­
6­
phosphate
dehydrogenase,
isocitric
dehydrogenase,
glutathione
reductase,
and
lactic
dehydrogenase
in
the
1500
and
2000
ppm
groups.
In
general,
the
activities
of
the
enzymes
were
increased
in
a
concentration­
related
manner.
Pseudocholinesterase
activity
exhibited
a
concentration­
related
increase
immediately
after
exposure,
but
activity
returned
to
control
levels
24
hours
later.
.(
i
The
toxicity
of
inhaled
p­
xylene
was
investigated
in
male,
Long­
Evans
rats
using
a
condition­
ed
flavor
aversion
paradigm,
which
operates
on
the
premise
that
pairing
the
consumption
of
a
novel
compound,
such
as
saccharin,
with
a
toxic
agent
results
in
a
conditioned
aversion
of
the
novel
flavor
(Bushnell
and
Peele,
1988).
After
acclimation
for
one
week,
rats
were
placed
on
a
restricted
water
schedule
of
30
minutedday
for
10
days.
Then,
rats
were
given
a
0.1%
saccharin
solution
for
30
minutes
instead
of
water
on
Day
11,
followed
30
minutes
later
by
exposure
to
p­
xylene
(99.7%
pure).
Rats
were
exposed
for
4
hours
to
0,
50,
100,
200,
400,
800,
or
1600
ppm,
or
for
0.5,
1,2,4,
or
8
hours
to
0
or
400
ppm
p­
xylene.
A
third
group
of
rats
were
exposed
to
0,
200,
or
800
ppm
p­
xylene
following
a
24
hour
delay
after
saccharin
exposure.
Following
exposure
to
p­
xylene,
rats
were
kept
on
a
restricted
water
schedule,
but
were
offered
a
choice
between
tap
water
or
a
0.1%
saccharin
solution.
A
concentrated­
related
decrease
in
relative
saccharin
consumption
was
observed
in
all
groups
exposed
to
p­
xylene
for
4­
hours,
with
maximal
aversion
occurring
in
the
800
and
1600
ppm
groups.
In
rats
exposed
to
400
ppm
p­
xylene
for
various
time­
periods,
maximal
aversion
was
noted
at
2­
8
hours.
Although
exposure
to
p­
xylene
affected
saccharin
intake,
total
water
consumption
was
not
affected.
Rats
exposed
to
p­
xylene
following
a
24
hour
delay
after
saccharin
exposure
did
not
exhibit
any
aversion
to
saccharin,
demonstrating
that
there
must
be
close
temporal
pairing
of
p­
xylene
and
saccharin
to
produce
conditioned
flavor
aversion.

Groups
of
8
male
Long­
Evans
hooded
rats
exposed
to
1600
ppm
p­
xylene
for
4
hours/
day
for
1­
5
days
had
improved
autoshaping
compared
with
controls
as
assessed
by
retraction
of
a
single
response
lever
on
a
variable
35
second
schedule
followed
by
delivery
of
a
food
pellet
(Bushnell,
1989).
When
the
force
of
the
lever
was
doubled,
however,
xylene
exposure
did
not
facilitate
autoshaping
as
compared
with
controls.
Assessment
of
motor
activity
following
daily
exposures
found
that
horizontally­
directed
movement
in
xylene­
exposed
rats
was
increased
by
3
0%
for
the
first
15
minutes
of
testing,
while
vertically­
directed
movement
was
not
affected.
Activity
levels
of
xylene­
exposed
animals
returned
to
control
levels
every
day,
and
no
difference
in
activity
levels
of
xylene­
exposed
rats
was
observed
in
exposed
rats
3.5
hours
post
exposure
compared
with
0.5
hours
post
exposure.
Clinical
signs
in
rats
noted
after
exposure
to
1600
ppm
p­
xylene
included
slight
activation,
fine
tremor,
and
unsteadiness.

Ghosh
et
al.
(1987)
investigated
the
effects
of
xylene
exposure
on
fixed­
ratio
responding
in
male
F344
rats.
The
mixed
xylenes
comprised
m­,
p­,
and
o­
xylene
with
ethyl
benzene
present
as
a
contaminant;
the
exact
percent
composition
was
not
provided.
Xylene
exposures
and
behavioral
testing
were
both
carried
out
in
an
inhalational
behavioral
dynamic
exposure
chamber.
Chamber
concentrations
were
measured
by
gas
chromatography
at
15­
minute
increments.
For
6­
8
weeks,
rats
were
first
trained
to
push
a
lever
24
times
(FR24)
which
resulted
in
receipt
of
a
5%
sucrose
solution.
Following
the
initial
training,
the
rats
were
then
divided
into
3
different
groups
for
hrther
training
specific
to
the
experimental
protocol
of
interest.
In
all
3
experiments,
the
XYLENES
Proposed
1:
5/
2002
1
2
3
4
5
6
7
8
9
10
I1
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2s
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
recording
of
the
stabilized
reinforcement
rate
for
3­
4
days
prior
to
xylene
exposure(
s)
served
as
the
control.
In
the
first
group,
4
rats
were
hrther
trained
for
6.25
hour­
long
sessions,
where
lever
pressing
was
rewarded
onlythe
last
15­
minute
period
of
each
hour.
Following
training,
rats
were
successively
exposed
to
graded
concentrations
of
P
13,216,
and
430
ppm
xylenes
for
2
hours
each.
A
concentration­
related
decrease
in
the
reinforcement
rate
was
observed
during
the
first,
third,
and
fifth
hours,
while
no
significant
change
was
observed
at
the
second,
fourth,
and
sixth
hours,
indicating
that
tolerance
had
developed.
In
the
second
group,
5
rats
were
trained
for
2.25
hour­
long
sessions,
where
behavioral
performance
was
restricted
to
the
second
and
fourth
15­
minute
periods
of
each
hour
(i.
e.,
15­
30,45­
60,
75­
90,
and
105­
120
minutes).
Following
training,
rats
were
exposed
for
2
hours
to
114,
212,
or
446
ppm
xylenes,
with
a
minimum
of
7
days
separating
each
of
the
exposures
so
that
tolerance
would
not
develop.
A
significant
decrease
in
the
reinforcement
rate
was
noted
at
all
3
concentrations
during
the
45­
60
minute
period
(20%,
27%,
and
23%
decrease
in
the
114,212,
and
446
ppm
groups,
respectively).
Although
some
decreases
in
performance
were
also
present
in
the
212
ppm
group
at
75­
90
minutes
(1
1%
decrease)
and
in
the
446
ppm
group
at
75­
90
and
105­
120
minutes
(19%
and
17%,
respectively),
the
differences
were
not
statistically
significant.
In
the
last
group,
four
rats
were
trained
for
5.25­
hour
long
sessions
where
behavioral
performance
was
limited
to
the
last
15­
minute
period
of
each
hour.
Rats
were
then
exposed
to
98.5.
ppm
xylenes
for
5
hours.
No
effects
on
behavioral
performance
were
observed
at
any
of
the
time
periods
during
the
exposure.
The
study
authors
therefore
concluded
that
the
minimum
effective
concentration
for
xylenes
to
cause
a
decrease
in
reinforcement
rate
was
1
13
ppm.

In
a
similarly
designed
experiment,
Wimolwattanapun
et
al.
(1987)
investigated
the
effects
of
xylene
exposure
on
intracranial
self­
stimulation
behavior
in
male
F344
rats.
The
mixed
xylenes
comprised
m­,
p­,
and
o­
xylene
with
ethyl
benzene
present
as
a
contaminant;
the
exact
percent
composition
was
not
provided.
Xylene
exposures
and
behavioral
testing
were
both
carried
out
in
an
inhalational
behavioral
dynamic
exposure
chamber.
Chamber
concentrations
were
measured
by
gas
chromatography
at
15­
minute
increments.
To
study
the
effects
of
xylene
exposure
on
intracranial
self­
stimulation
behavior
in
rats,
groups
of
male
F344
rats
had
bipolar
electrodes
surgically
implanted
into
the
ventral
tegmental
area
of
the
rats.
One
week
following
surgery,
rats
were
trained
to
press
a
lever
to
receive
reinforcing
electrical
stimulation.
Following
the
initial
training,
the
rats
were
then
divided
into
3
different
groups
for
hrther
training
specific
to
the
experimental
protocol
of
interest.
In
all
3
experiments,
the
recording
of
the
stabilized
reinforce­
ment
rate
for
3­
4
days
prior
to
xylene
exposure(
s)
served
as
the
control,
and
rates
of
response
during
exposures
were
recorded
for
20
minute
periods,
with
the
first
and
last
20­
minute
periods
being
control
exposures.
In
the
first
group,
five
rats
were
fhrther
trained
for
2.67
hour
periods.
Following
training,
rats
were
exposed
to
102,
192,
419,
or
613
ppm
xylenes
for
2
hours,
with
a
minimum
of
7
days
separating
the
exposures
so
that
tolerance
would
not
develop.
Significant
decreases
(p<
0.05)
in
the
rate
of
response
were
observed
in
rats
exposed
to
at
least
192
ppm;
results
are
presented
in
Table
8.
In
the
second
experiment,
no
effects
on
self­
stimulation
behavior
were
observed
in
four
rats
trained
for
4.67
hour­
long
sessions
followed
by
exposure
to
106
ppm
for
4
hours.
The
third
experiment
consisted
of
exposure
of
4
rats
to
444
ppm
xylenes
for
2­
hour
periods
for
5
consecutive
days.
Results
indicated
the
development
of
tolerance.
Rates
of
response
were
significantly
decreased
during
the
4
,
periods
the
third
day;
during
the
6th
period
on
the
fourth
day;
and
at
no
time
periods
the
fifth
day.
th
5th
,
and
6*
periods
the
first
day;
during
all
20
36
XYLENES
Proposed
I:
5/
200%

1
2
3
4
5
6
7
%

9
10
11
12
13
14
15
16
17
1%
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
3%
39
Data
taken
from
Wimolwattanapun
et
al.,
1987
To
assess
the
effects
of
xylene
exposure
on
motility,
groups
of
eight,
CFY
white,
male
rats
were
exposed
by
inhalation
for
4
hours
to
at
least
six
concentrations
each
of
m­
xylene
096%
pure),
o­
xylene
(>
99%
pure),
or
p­
xylene
(>
99%
pure)
(individual
concentrations
not
provided)
(Molnar
et
al.,
1986).
Animals
were
exposed
in
a
30L
cylindrical
glass
chamber,
with
a
solvent­
saturated
airstream
diluted
with
clean
air
introduced
at
the
top
of
the
chamber
and
exhausted
at
the
bottom
of
the
chamber.
Concentrations
were
determined
every
30
minutes
by
use
of
a
uv
spectrophotometer.
Motility
during
exposure
was
assessed
by
means
of
four
electromechanical
transducers
housed
in
metal
tubes
placed
perpendicularly
throughout
the
exposure
chamber.
An
electric
counter
continuously
recorded
the
number
of
nose
touches.
The
experiments
required
more
than
one
day
for
completion,
but
it
was
not
stated
if
rats
were
reused
for
the
various
exposures.
It
was
stated
that
exposure
to
130
to
1500
ppm
m­
xylene
and
400
to
1500
ppm
p­
xylene
resulted
in
a
concentration­
related
increase
in
group
motility,
while
exposure
to
150
to
1800
ppm
o­
xylene
resulted
in
a
slight
depression
of
activity.
At
higher
concentrations,
activity
was
decreased
in
all
groups,
with
the
minimum
narcotic
concentration
for
the
three
isomers
reported
as
2180
ppm
for
o­
xylene,
2100
ppm
for
m­
xylene,
and
1940
ppm
for
p­
xylene.

To
determine
the
medial
effective
concentration
(EX,,)
of
xylene
on
rotarod
performance,
groups
of
10
male
Wistar
rats
were
exposed
to
1050,
2030,2610,
2710,4130,
or
4700
ppm
xylene
(reagent
grade
0,
my
p­
xylene)
for
4
hours,
with
a
parallel
control
group
of
15
rats
exposed
to
0
pprn
(Korsak
et
al.,
1988).
Chamber
concentrations
were
analyzed
by
gas
chromatography.
The
rotarod
test
was
run
both
before
and
immediately
after
the
exposure.
All
animals
survived
the
exposures.
The
EC,,
for
decreased
rotarod
performance
with
the
95%
confidence
interval
was
4520
ppm
[3800­
5390
ppm].

Korsak
et
al.
(1990)
exposed
groups
of
ten,
male
Wistar
rats
for
6
hours
to
approximately
3000
ppm
0­,
m­,
or
p­
xylene
to
determine
any
potential
differences
in
the
toxicity
of
the
individual
isomers
as
measured
by
a
rotarod
test.
Exposures
were
conducted
in
a
dynamic
inhalation
chamber
(1.3
m3),
and
xylene
concentrations
were
measured
in
the
air
of
the
inhalation
chambers
using
gas
chromatography.
Rats
were
trained
on
the
rotarod
for
at
least
one
week
before
exposure.
During
testing,
rotarod
performance
was
measured
before
and
after
termination
of
the
exposure.
The
results
of
the
testing
given
in
terms
of
the
number
of
failurednumber
of
tested
animals
was
as
follows:
o­
xylene
at
average
concentration
of
3027
ppm
was
19/
20;
m­
xylene
at
average
concentration
of
3093
ppm
was
6/
20;
p­
xylene
at
average
concentration
of
3065
XYLENES
Proposed
1:
512002
1
2
3
4
5
6
a
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
ppm
was
1/
20.
From
this
limited
experiment,
it
appeared
that
o­
xylene
was
more
toxic
than
the
other
two
isomers.

In
a
later
experiment
in
which
only
m­
xylene
was
tested,
Korsak
et
al.
(1993)
exposed
groups
of
8­
10
male
Wistar
rats
to
varying
concentrations
of
m­
xylene
in
a
dynamic
inhalation
chamber
for
4
hours,
immediately
followed
by
rotarod
testing
or
measurement
of
spontaneous
motor
activity
by
an
actometer
for
one
hour
post
exposure.
Xylene
concentrations
were
measured
in
the
exposure
chamber
in
30
minute
increments
by
gas
chromatography.
Exact
exposure
concentrations
were
not
provided,
but
graphical
representation
of
data
show
exposure
concen­
trations
of
approximately
500,
1000,
1500,2000,
or
3000
ppm
m­
xylene.
The
effect
of
exposure
on
spontaneous
motor
activity
was
biphasic,
with
lower
concentrations
(up
to
2000
ppm)
resulting
in
increased
motor
activity,
and
higher
concentrations
(3000
ppm)
resulting
in
decreased
motor
activity.
The
4­
hour
EC50
for
m­
xylene
on
rotarod
performance
was
determined
to
be
1982
ppm
(95%
confidence
interval:
1530­
2565
ppm).
It
should
be
noted
that
this
is
lower
than
the
concentration
used
in
the
previous
Korsak
et
al.
(1990)
experiment,
in
which
the
toxicity
of
the
individual
isomers
was
assessed
in
rats
by
comparing
rotarod
performance
following
exposure
to
3000
ppm
for
6
hours.

To
assess
erythrocyte
fragility
following
exposure
to
xylene,
groups
of
5
male
albino
rats
(Harlan­
Wistar
strain)
were
exposed
to
air
containing
metered
concentrations
of
0
or
15,000
ppm
(64
mgL)
mixed
xylene
(corrected
concentration
approximately
8800
ppm;
comprised
of
p­
xylene:
7.84%;
m­
xylene:
65.01%;
o­
xylene:
7.63%;
ethyl
benzene:
19.27%)
for
45
minutes
(Carpenter
et
al.,
1975a;
b).
Following
exposure,
the
rats
were
killed
and
their
blood
was
collected.
Erythrocyte
fragility
was
determined
by
placing
one
drop
of
blood
in
a
tube
with
varying
concentrations
of
saline
to
determine
the
concentration
of
saline
causing
initial
and
complete
hemolysis.
Hemolysis
in
the
exposed
rats
was
comparable
to
the
controls.
No
increase
in
erythrocyte
fragility
was
observed
in
exposed
rats
compared
with
controls.

3.2.3.
Mice
Groups
of
6
male,
Swiss
OF,
mice
were
exposed
to
air
containing
at
least
four
different
concentrations
of
o­
xylene
to
determine
the
concentration
of
o­
xylene
associated
with
a
50%
decrease
in
respiratory
rate
(RD5J
(De
Ceaurriz
et
al.,
1981).
The
exact
test
concentrations
were
not
stated,
and
although
it
was
stated
that
xylene
was
of
a
high
purity,
the
actual
purity
was
not
provided.
Animals
were
exposed
in
a
200
L
exposure
chamber
with
adjustable
air
flow.
The
air
concentration
of
o­
xylene
in
the
test
chamber
was
determined
by
sweeping
a
sample
loop
through
the
cell
atmosphere
and
analyzing
the
sample
by
gas
chromatography.
Respiratory
rate
was
measured
using
a
body
plethysmograph.
Recordings
were
made
for
10
minutes
prior
to
exposure,
and
then
the
mice
were
placed
into
an
exposure
cell
with
a
predetermined
concentration
of
o­
xylene
until
the
maximum
decrease
in
respiration
was
reached.
Exposures
were
generally
for
only
5
minutes.
Based
on
the
results
from
these
exposures,
the
RD,,
for
o­
xylene
was
1467
ppm.

Korsak
et
al.
(1988)
determined
the
RD,,
for
mixed
xylene
(reagent
grade
0,
m,
p­
xylene;
hrther
details
not
provided),
toluene,
and
their
50%
volume:
50%
volume
mixture
in
groups
of
2­
4
Balb/
C
male
mice.
For
determination
of
the
xylene
RD,,,,
mice
were
exposed
to
2600,
4000,
4600,
or
7000
ppm
xylene,
and
the
respiratory
rate
of
the
mice
was
measured
using
a
body
22
3
3
XYLENES
Proposed
1:
542002
1
2
3
4
5
6
7
8
9
PO
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
plethysmograph
continuously
before
exposure,
during
6
minutes
of
exposure,
and
2­
3
minutes
after
termination
of
the
exposure.
The
RD,,
for
xylene
was
2440
ppm.

Korsak
et
al.
(1993)
also
determined
the
RD,,
for
m­
xylene,
n­
butyl
alcohol,
and
their
50%
volume:
50%
volume
mixture
(supplied
by
Reachim
and
the
Polish
Chemical
Reagent
company,
fbrther
information
not
provided)
in
groups
of
8­
10
Balb/
C
male
mice
using
a
body
plethys­
mograph.
Actual
test
concentrations
used
were
not
provided.
The
RD,,
for
m­
xylene
was
reported
to
be
1361
ppm.
In
another
paper,
Korsak
et
al.
(1990)
exposed
groups
of
6
Bdb/
C
male
mice
to
3000
ppm
p­,
0­,
or
m­
xylene,
and
the
respiratory
rate
ofthe
mice
was
measured
using
a
body
plethysmograph
continuously
before
exposure,
during
6
minutes
of
exposure,
and
3
minutes
after
termination
of
the
exposure.
The
maximum
decrease
in
respiratory
rate
was
measured
during
the
first
minute
of
exposure,
and
was
54%,
46%,
or
43%
of
controls
for
the
p­
xylene,
o­
xylene,
or
m­
xylene
exposed
mice,
respectively.

Carpenter
et
al.
(1975a;
b)
exposed
Swiss­
Webster
male
mice
to
air
containing
measured
concentrations
of
mixed
xylenes
(p­
xylene:
7.84%;
m­
xylene:
65.01%;
0­
xylene:
7.63%;
ethyl
benzene:
19.27%)
for
1
minute
and
then
measured
respiratory
rate
during
a
15­
minute
post­
exposure
period.
A
50%
decrease
or
more
of
respiratory
rate
were
observed
in
5/
5
rats
at
12,000
ppm,
4/
6
rats
at
6500
ppm,
2/
6
rats
at
2500
ppm,
and
2/
6
rats
at
1300
ppm.
A
50%
decrease
in
respiratory
rate
was
not
observed
in
any
of
the
rats
exposed
to
460
ppm.

A
fbnctional
observational
battery
(FOB)
was
adapted
to
mice
to
evaluate
acute
behavioral
effects
of
alkylbenzenes
(Tegeris
and
Balster,
1994).
Groups
of
eight,
adult
male
CFW
albino
mice
were
exposed
to
air
containing
0,2000,4000,
or
8000
ppm
m­
xylene
(98%
purity)
for
20
minutes
under
static
conditions.
After
individual
mice
were
placed
into
29
L
glass
jars
sealed
with
a
lid,
xylene
was
injected
onto
a
filter
paper
in
the
jar,
with
a
fan
blade
in
the
chamber
equally
distributing
the
vapors.
Analysis
of
air
by
infrared
spectrometry
confirmed
nominal
vapor
concentrations
and
demonstrated
that
maximal
concentrations
were
reached
within
3
minutes
of
turning
the
fan
on
and
remained
stable
throughout
the
exposure.
Within
10­
15
seconds
following
exposure,
mice
were
removed
from
the
jar
and
evaluated
according
to
a
complete
FOB.

During
the
last
two
minutes
of
the
exposure,
dose­
related,
statistically
significant
effects
were
observed
as
decreased
arousal
and
rearing,
abnormal
posture,
altered
palpebral
closure,
and
disturbances
of
gait
(Tegeris
and
Balster,
1994).
Because
the
statistical
significance
of
the
effects
was
reported
as
affecting
2
2
doses,
it
is
generally
not
known
if
the
effects
were
limited
to
the
4000
and
8000
ppm
groups,
or
extended
to
the
2000
ppm
group
as
well.
It
was
stated
that
exposure
to
all
concentrations
including
2000
ppm
resulted
in
decreased
rearing.
Following
exposure,
the
FOB
revealed
statistically
significant
decreases
in
the
8000
ppm
group
in
the
percentage
of
animals
with
a
successful
inversion
in
the
inverted
screen
test,
in
the
percentage
of
animals
with
a
normal
ranking
of
the
righting
reflex
response,
and
in
mean
forelimb
grip
strength.
Statistically
increased
mean
hindlimb
foot
splay
was
observed
in
all
exposure
groups.
Exposure
to
xylene
also
resulted
in
decreased
responsiveness
to
stimulus
presentation.
It
is
important
to
note
that
the
study
authors
stated
that
because
the
purpose
of
the
study
was
to
make
a
qualitative
comparison
between
six
alkylbenzenes,
no
attempt
was
made
to
determine
minimally
effective
concentrations.

23
33
1
2
3
4
5
6
4
S
9
10
11
12
13
14
15
16
17
1s
19
20
21
22
23
24
25
26
27
2s
29
30
31
32
33
34
35
36
37
3s
39
40
41
42
43
XYLENES
Proposed
1:
92002
The
effects
of
the
individual
xyle
rcial
xylene
mixture
on
operant
responding
and
motor
performance
were
assessed
in
CD­
1
male
albino
mice
(Moser
et
al.,
1985).
All
exposures
occurred
in
a
29L
glass
chamber
under
static
conditions,
with
measurements
of
chamber
air
by
an
infi­
ared
spectrophotometer
confirming
that
solvent
concentrations
remained
stable
throughout
the
exposures.
To
measure
operant
response
following
xylene
exposure,
fifteen
mice
were
feed­
deprived
throughout
the
study.
The
mice
were
tested
in
3
squads,
with
the
order
of
each
isomer
counterbalanced
among
the
squads
and
a
week
separating
the
testing
of
each
isomer.
The
xylene
mixture
was
tested
during
the
last
week
for
all
squads.
Mice
were
exposed
on
Tuesday
through
Friday
of
each
week
to
air
or
ascending
xylene
concentrations
of
500,
800,
1400,
2400,
4000,
5000,
or
7000
ppm
for
30
minutes.
Immediately
following
exposure,
mice
were
placed
in
an
operant
chamber.
Prior
to
exposure,
the
mice
were
trained
to
lever­
press
during
daily
15
minute
sessions,
followed
by
a
differential
reinforcement
of
low
rates
(DRL)
10­
second
schedule
Motor
performance
was
assessed
by
measuring
the
performance
of
mice
in
an
inverted
screen
test
study
following
exposure
to
the
solvent.
Groups
of
12
mice
(2
squads
of
6
mice)
were
exposed
to
at
least
3
concentrations
producing
between
0
and
100%
effects
(ranged
from
2000
to
7000
ppm).
It
is
assumed
that
the
exposure
duration
was
also
30
minutes,
but
it
was
not
stated
definitively
in
the
paper.

The
results
of
the
operant
studies
indicated
that
the
order
of
exposure
to
the
xylene
isomers
or
mixture
had
no
effect
on
the
data
(Moser
et
al.,
1986).
The
minimally
effective
concentration
for
disruption
of
operant
performance
was
1400
ppm
for
all
isomers,
with
an
EC,,
(concentration
producing
half­
maximal
decreases
in
response
rate)
of
6
176,
5
179,
or
561
1
ppm
for
m­
xylene,
o­
xylene,
and
p­
xylene,
respectively.
The
operant
response
was
biphasic,
with
concentrations
of
1400
to
2400
ppm
producing
increased
rates
of
response,
and
a
concentration
of
7000
ppm
suppressing
the
response
rate
and
also
producing
gross
ataxia
and
prostration.
The
min­
imally
effective
concentrations
for
the
inverted
screen
test
were
3000
ppm
for
m­
and
o­
xylene,
and
2000
ppm
for
p­
xylene,
while
the
EC,,
values
for
performance
on
the
inverted
screen
test
were
3790,
3640,
and
2676
ppm
for
m­
xylene,
o­
xylene,
and
p­
xylene,
respectively.
Motor
ability
was
recovered
approximately
5
to
15
minutes
after
exposure.
The
study
authors
concluded
that
there
was
no
consistent,
significant
difference
in
the
potency
of
the
individual
isomers.
While
o­
xylene
exhibited
a
more
potent
effect
on
operant
behavior,
p­
xylene
more
severely
affected
motor
performance
.

3.3.
Developmental/
Reproductive
Effects
In
a
one­
generation
reproduction
study,
groups
of
male
and
female
CD
rats
were
exposed
to
0,
60,
250,
or
500
ppm
mixed
xylenes
(Groups
I,
11,111,
and
IV,
respectively;
technical
grade
xylene:
2.4%
toluene,
12.8%
ethyl
benzene,
20.3%
p­
xylene,
44.2%
m­
xylene,
20.4%
o­
xylene)
by
inhalation
for
6
hourdday,
5
dayslweek,
for
13
1
days
prior
to
mating,
with
exposure
continued
in
the
females
during
GD
1­
20
and
lactation
days
5­
20
(Bio/
dynamics
Inc.,
1983).
Two
additional
500
ppm
groups
were
included:
only
the
males
were
exposed
in
Group
V,
and
only
the
females
were
exposed
in
Group
VI.
Potential
pup
exposure
to
xylenes
was
only
through
milk.
No
definite,
exposure­
related
adverse
effects
were
noted
in
F,
adults
or
pups.
Although
marginal
decreases
in
pup
weights
in
exposed
groups
were
observed,
they
were
not
considered
an
adverse
effect
of
exposure
because
the
control
group
had
an
elevated
mean
pup
weight
potentially
caused
by
a
smaller
mean
litter
size
(mean
number
of
live
pupdlitter:
9.6,
11.8,
12.5,
12.4,
10.8,
and
11.8
24
3
Y
XYLENES
Proposed
1:
5/
2002
1
2
.3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
for
Groups
I­
VI,
respectively)
and/
or
because
no
marginal
decreases
in
body
weights
were
observed
in
pups
from
Group
VI,
in
which
dams
were
exposed
to
the
same
concentration
of
xylene
for
the
same
period
of
time
as
dams
in
Group
IV.

To
assess
developmental
toxicity,
one­
half
of
the
Group
I
Fo
females
(20
females;
control
group)
and
Group
IV
F,
females
(12
females;
500
ppm
mixed
xylenes
by
inhalation
for
6
hr/
day,
5
d/
week,
for
13
1
days
prior
to
mating
and
during
GD
1­
20)
were
killed
on
GD
2
1
for
developmental
toxicity
evaluation
(Bio/
dynamics
Inc.,
1983).
No
exposure­
related
maternal
effects
were
observed.
No
statistically
significant
differences
were
noted
between
treated
and
control
groups
for
mean
number
of
corpora
lutea,
implantations,
resorption
sites,
live
fetuses,
mean
percentage
of
live
fetuses/
implants,
or
fetal
sex
ratios.
No
definitive
treatment­
related
external,
visceral,
or
skeletal
malformations/
variations
were
observed.
The
report
stated
that
high­
dose
fetuses
had
a
slightly
higher
incidence
of
unossified
sternebrae
and
incompletely
ossified
cervical
vertebral
transverse
processes,
but
the
incidences
were
provided
in
terms
of
fetal
incidence
instead
of
litter
incidence.
Mean
fetal
body
weights
on
GD
21
were
marginally
but
statistically
decreased
in
female
fetuses
from
Group
IV
(93%
of
controls);
however,
male
fetal
weights
were
comparable
to
controls.
This
marginal
decrease
in
body
weight
only
in
female
pups
is
difficult
to
assess
due
to
the
small
sample
size:
only
12
litters
from
exposed
dams
were
evaluated
compared
with
20
for
controls.

No
maternal
or
developmental
effects
were
observed
following
exposure
of
pregnant
CRL:
COBS
CD
(SD)
BR
rats
to
0,
100,
or
400
ppm
xylene
(52%
m­
xylene;
11%
o­
xylene;
0.3
1%
p­
xylene,
36%
ethylbenzene)
for
6
hourdday
on
GD
6­
15
(Litton
Bionetics,
1978a).
The
NOAEL
is
therefore
2400
ppm.

To
evaluate
the
effects
of
prenatal
exposure
on
postnatal
development,
pregnant
(Mol:
WIST)
rats
were
exposed
by
inhalation
to
0
or
500
ppm
xylenes
(19%
o­
xylene;
45%
m­
xylene;
20%
p­
xylene;
15%
ethyl
benzene)
for
6
hour/
day
on
GD
7­
20
and
were
allowed
to
litter
(Hass
et
al.,
1995).
Litter
size
was
not
standardized,
but
litters
with
less
than
six
pups
were
not
used.
From
each
litter,
two
males
and
two
females
were
kept
for
behavioral
testing,
1
male
and
1
female
were
kept
in
standardized
housing
and
left
undisturbed
other
than
feeding
and
taking
body
weight
measurements
until
3
months
when
they
were
tested
in
the
Morris
water
maze
test,
and
1
male
and
1
female
were
kept
in
enriched
housing
(cages
contained
various
toys)
and
tested
for
rotarod,
open
field,
and
Morris.
maze
performance
at
about
3
months
of
age.
The
only
potential
effect
observed
was
that
offspring
from
xylene­
exposed
rats
raised
in
the
standard
housing
had
impaired
performance
in
the
Morris
maze
test
compared
with
controls.
Testing
at
12
weeks
showed
a
nonsignificant
trend
(p=
0.059)
for
increased
latency
for
finding
the
platform
in
the
beginning
of
the
learning
test.
At
16
weeks,
they
used
significantly
more
time
to
find
a
platform
hidden
in
the
center
of
the
pool.
Further
analysis
revealed
the
effect
was
limited
to
the
female
offspring,
and
that
these
females
had
an
increase
in
the
swimming
length,
while
swim
speed
was
unaffected.
Offspring
from
xylene­
exposed
rats
that
were
raised
in
the
enriched
environment
showed
no
difference
in
the
Morris
maze
test
compared
with
controls.

In
a
study
designed
to
investigate
the
persistence
of
the
decreased
Morris
water
maze
test
performance
of
the
offspring
from
the
xylene­
exposed
(Mo1:
WIST)
female
rats,
the
female
offspring
raised
in
the
standard
housing
were
continued
on
the
study
and
evaluations
were
25
35
XYLENES
Proposed
1:
5/
2002
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
additionally
made
at
28
and
52
weeks
(Hass
et
al.,
1997).
At
28
weeks,
an
increased
latency
for
finding
a
platform
that
was
moved
to
a
new
position
was
observed
in
the
female
offspring
from
exposed
rats
only
during
the
first
trial
of
a
testing
block,
while
the
next
two
trials
resulted
in
similar
latencies
between
exposed
and
control
rats.
The
increased
latency
again
corresponded
with
increased
swimming
length.
No
other
significant
differences
were
observed
for
other
testing
situations
in
the
Morris
maze
test.
At
55
weeks,
no
statistically
significant
differences
were
observed
between
groups.

The
Hass
et
al.
studies
(1995;
1997)
found
that
prenatal
exposure
to
xylenes
affected
the
performance
of
female
offspring
in
the
Morris
water
maze
test:
it
took
the
female
offspring
longer
to
find
the
platform.
While
swim
length
was
increased,
swim
speed
was
unaffected,
indicating
a
cognitive
rather
than
motor
effect.
This
study
is
limited,
however,
in
that
a
concentration­
response
is
lacking
because
only
one
concentration
was
tested.
Additionally,
no
clear
effect
was
observed
in
any
of
the
other
neurological
tests.

Groups
of
36
pregnant,
female
Wistar
rats
were
exposed
to
air
containing
0
or
200
ppm
technical
xylene
(exact
composition
not
provided)
for
6
hours/
day
during
GD
6­
20
(Hass
and
Jakobsen,
1993).
On
GD
21,
two­
thirds
of
the
rats
were
killed
and
were
used
to
assess
developmental
toxicity,
while
one­
third
of
the
rats
were
allowed
to
litter
and
developmental
milestones
and
rotarod
performance
assessed
in
8
offspring
(4
males
and
4
females)
from
each
litter.
No
maternal
toxicity
was
observed
in
the
exposed
dams.
The
only
effect
noted
in
fetuses
from
exposed
dams
was
an
increased
incidence
of
delayed
ossification
of
os
maxczllare
in
the
skull,
with
18/
26
exposed
litters
affected
vs.
2/
22
control
litters.
In
the
postnatal
study,
statisti­
cally
decreased
rotarod
performance
was
observed
in
female
pups
on
postnatal
days
22
and
23
and
in
male
pups
on
postnatal
day
23.
This
study
is
limited
in
that
only
one
exposure
concen­
tration
was
tested
and
only
a
limited
battery
of
behavioral
tests
were
used.
Additionally,
Hass
et
al.
(1995)
refer
to
the
fact
that
the
testers
were
not
blind
to
the
exposure
status
of
the
animals.

Exposure
of
pregnant
Sprague­
Dawley
rats
to
800
or
1600
ppm
p­
xylene
(3500
or
7000
mg/
m3;
99%
pure)
on
GD
7­
16
did
not
affect
litter
size
or
weight
of
pups
at
birth
or
on
post
natal
day
(PND)
3;
central
nervous
system
development
as
measured
by
the
acoustic
startle
response
on
PND
13,
17,
21,
and
63
or
the
figure­
8
maze
activity
evaluated
on
PND
22
and
65;
or
the
growth
rate
of
the
pups
(Rosen
et
al.,
1986).
The
only
effect
of
exposure
was
a
significant
decrease
in
maternal
body
weight
gain
in
the
1600
ppm
dams
(74%
of
controls).

To
investigate
the
effect
of
xylene
inhalation
on
the
liver
of
pregnant
and
nonpregnant
rats
and
pups
of
exposed
litters,
pregnant
Wistar
rats
were
exposed
to
2600
ppm
xylenes
(1
1,284
mg/
m3)
(purity
and
composition
not
stated)
for
8
hourdday
on
GD
6
until
term
(GD
21),
nonpregnant
rats
were
exposed
to
2600
ppm
xylenes
for
the
same
period,
and
a
control
group
of
pregnant
rats
inhaled
clean
air
(not
stated
if
nonpregnant
controls
were
also
included)
(Kukner
et
al.,
1997/
98).
Biochemical
analysis
of
the
livers
fiom
pregnant
rats
exposed
to
xylene
revealed
minimal
increases
in
aspartate
aminotransferase
(AST;
18%;),
alanine
aminotransferase
(ALT;
19%;),
alkaline
phosphatase
(ALP;
17%)
and
arginase
(63%).
Electron
microscopic
evaluation
of
pregnant
and
nonpregnant
rat
liver
tissue
revealed
mitochondria
that
concentrated
near
the
periphery
of
hepatocytes
and
nuclei,
increased
number
of
lysosomes,
and
expanded
smooth
endoplasmic
reticulum.
In
fetal
liver
from
exposed
litters,
findings
included
expanded
smooth
endoplasmic
XYLENES
Proposed
1:
92002
1.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
reticulum,
structurally
deformed
mitochondria,
and
granular
endoplasmic
reticulum.
No
structural
defects
were
observed
in
the
kidneys
or
pancreas
from
exposed
pregnant
or
nonpregnant
rats,
or
from
fetuses
from
exposed
litters.

A
number
of
other
developmental
toxicity
studies
were
identified
in
the
literature
but
were
limited
by
several
factors
including,
but
limited
to:
composition
and/
or
purity
of
the
xylenes
was
not
stated,
absolute
values
for
the
toxicity
endpoints
were
not
provided,
fetal
incidences
instead
of
litter
incidences
were
reported,
and/
or
inadequate
sample
sizes
were
available
(Hudak
and
Ungvary,
1978;
Ungvary
et
al.,
1980;
Ungvary
and
Tatrai,
1985;
Mirkova
et
al.,
1983).

3.4.
Genotoxicity
The
genotoxicity
of
commercial
xylene
and
all
3
individual
isomers
has
been
extensively
tested
and
the
results
have
generally
been
consistently
negative.
All
studies
evaluated
by
the
GENETOX
panel
and
cited
in
the
GENETOX
database
were
negative
except
for
one
study
for
which
no
conclusion
was
drawn
(GENETOX,
1999).
Xylene
was
not
mutagenic
in
bacterial
test
systems
with
Salmonella
typhimerium
(Bos
et
al.,
1981;
Florin
et
al.,
1980;
NTP,
1986)
and
Escherichia
coli
(McCarroll
et
al.,
198
1)
or
in
cultured
mouse
lymphoma
cells
(Litton
Bionetics,
1978b).
Xylene
also
did
not
induce
chromosomal
aberrations
or
sister
chromatid
exchanges
in
Chinese
hamster
ovary
cells
(Anderson
et
al.,
1990)
or
cultured
human
lymphocytes
(Gerner­
Smidt
and
Friedrich,
1979,
chromosomal
aberrations
in
rat
bone
marrow
(Litton
Bionetics,
1978b),
micronuclei
in
mouse
bone
marrow
(Mohtashamipur
et
al.,
1985),
or
sperm
head
abnormalities
in
rats
(Washington
et
al.,
1983).
Technical
grade
xylene,
but
not
0­
and
rn­
xylene,
was
weakly
mutagenic
in
Drosophila
recessive
lethal
tests
(Donner
et
al.,
1980).

3.5.
Carcinogenicity
No
studies
were
found
in
the
searched
literature
regarding
the
potential
for
inhaled
xylene
to
cause
cancer
in
animals.

In
a
National
Toxicology
Program
(NTP,
1986)
chronic
toxicity
and
carcinogenesis
bioassay,
groups
of
50
male
and
50
female
Fischer
344
rats
and
50
male
and
50
female
B6C3F1
mice
were
administered
mixed
xylene
(60%
m­
xylene,
13.6%
p­
xylene,
17.0%
ethylbenzene,
and
9.1%
0­

xylene)
in
corn
oil
by
gavage
at
doses
of
0,250,
or
500
mg/
kg/
day
(rats)
and
0,
500,
or
1000
mglkglday
(mice)
for
5
days/
week
for
103
weeks.
Histopathologic
examination
of
the
rats
revealed
an
increased
incidence
of
interstitial
cell
tumors
in
the
testis
of
high­
dose
male
rats
following
survival­
adjusted
analysis,
but
this
increase
was
believed
to
be
the
result
of
the
incidence
recorded
in
high­
dose
animals
dying
between
weeks
62­
92.
The
overall
incidence
of
interstitial
cell
tumors
between
groups
was
comparable
(43/
50,
38/
50,
and
41/
49
for
the
control,
low­
dose,
and
high­
dose
groups,
respectively).
Therefore,
the
marginal
increase
in
this
tumor
was
not
ascribed
to
treatment.
The
NTP
(1986)
reported
no
significant
nonneoplastic
or
neoplastic
effects
in
male
or
female
mice.

Maltoni
et
al.
(1983,
1985)
exposed
groups
of
40
male
and
40
female
Sprague­
Dawley
rats
to
0
or
500
mg
xylene/
kg
bw
(mix
of
0­,
p­,
and
m­
xylenes;
proportion
of
each
isomer
not
stated)
in
olive
oil
orally
by
gavage
4­
5
days/
week
for
104
weeks,
followed
by
discontinuation
of
dosing
to
27
3
7
XYLENES
Proposed
1:
5/
2002
­­
Conc.
(ppm)
I
Duration
I
Isomer
I
Cat
9500
1
2
I
Mixed
I
Killed
all
4
cats
I
Carpenter
et
al.,
1975b
Mortality
and
Other
Effects
Reference
I
B
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
study
termination
at
141
weeks.
Although
Maltoni
et
al.
reported
an
increase
in
the
overall
number
of
malignant
tumors
in
both
treated
males
(1440
vs.
11/
50
for
controls)
and
females
(22/
40
vs.
10/
50
for
controls),
fbrther
study
data
were
not
provided.

IARC
(1989)
has
concluded
there
is
inadequate
evidence
for
the
carcinogenicity
of
xylene
in
humans
or
in
experimental
animals,
and
therefore
stated
that
xylene
is
not
classifiable
as
to
its
carcinogenicity
in
humans
(Group
3).
The
U.
S.
EPA
(1997)
has
classified
xylenes
as
Category
D
.
Chemicals
in
this
category
are
considered
not
classifiable
as
to
human
carcinogenicity.

3.6.
Summary
Xylenes
is
an
anesthetic
gas
resulting
in
narcosis
and
ultimately
death
at
high
atmospheric
concentrations.
In
rats
and
mice,
4­
hour
LC,,
values
ranging
from
3907­
1
1,000
ppm
have
been
reported
(see
Table
9).
At
lower
concentrations,
central
nervous
system
disturbances
and
irritation
are
evident
(see
Table
10).
No
consistent
developmental
or
reproductive
effects
were
observed
in
the
studies
found
in
the
available
literature.
Commercial
xylene
and
all
3
individual
isomers
have
generally
tested
negative
for
genotoxicity.
Xylenes
is
currently
not
classifiable
as
to
its
carcinogenicity
by
IARC
(1989)
or
the
U.
S.
EPA
(1997)
because
of
inadequate
evidence.

II
TABLE
9.
Summary
of
Lethal
Inhalation
Data
in
Laboratory
Animals
XYLENES
Proposed
11:
5/
2002
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
TABLE
10.
Summary
of
Nonlethal
Inhalation
Data
in
Laboratory
Animals
3nc.
(ppm)
Duration
I
Isomer
I
Effects
References
530
I
4
I
Mixed
]Noeffect
level
I
Carpenter
et
al.,
1975b
1200
I
4
1
Mixed
/Lacrimation
I
Rat
~
~~

Carpenter
et
al.,
1975b
5
80
No
effect
level
1300
Poor
coordination
2
h
into
exposure,
recovered
post
exposure
2800
Mixed
++
T
Irritation;
rats
prostrate
within
2.5­
3
h
into
exposure;
recovered
within
1
h,
but
poor
coordination
until
following
day.

Changes
flash
evoked
potential
suggest
increased
arousal
1600
Dyer
et
al.,
1988
Minimum
narcotic
concentration
Molnar
et
al.,
1986
2100
2180
4
!
0­

1940
4
I
P
­I
4
I
P
­
800,
1600
Induced
flavor
aversion
Hyperactivity,
fine
tremor,
unsteadiness
Bushnell
and
Peele,
1988
Bushnell,
1989
1600
4
I
P­
Minimum
effective
concentration
for
I
Ghosh
et
al.,
1987
113
Mixed
decreased
reinforcement
rate
Lowest
concentration
resulting
in
decrease
in
the
rate
of
response
for
self­
stimulation
behavior
98.5
Ghosh
et
al.,
1987
192
Wimolwattanapun
et
a1
1987
Mixed
4520
EC50
for
rotarod
performance
Korsak
et
al.,
1988
4
m­
EC50
for
rotarod
performance
I
Korsak
et
al.,
1993
I
Mouse
1982
1467
0­
m50
De
Ceaurriz
et
al.,
1981
1361
m­
m50
Korsak
et
al.,
1993
2440
Mixed
R
D
5
0
Korsak
et
al.,
1988
Note:
not
recommended
strain
of
mice
Note:
not
recommended
strain
of
mice
2000,4000,
0.33
m­
Increased
mean
hindlimb
foot
splay,
Tegeris
and
Balster,
8000
(static)
decreased
rearing
1994
3790
0.5
(static)
m­
ECso
for
inverted
screen
test
Moser
et
al.,
1985
3640
0.5
(static)
o­

2676
0.5
(static)
p­

29
37
XYLENES
Proposed
I:
92002
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1s
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
TABLE
16).
Summary
of
Nonlethal
Inhalation
Data
in
Laboratory
Animals
Effects
I
References
I
6176
0.5
(static)
m­
ECso
for
disruption
of
operant
performance
Moser
et
al.,
1985
5179
1
0.5
(static>
1
o­
I
5611
I
0.5
(static)
I
P­
I
I
4.
SPECIAL
CONSIDERATIONS
4.1.
Metabolism
and
Disposition
Pulmonary
retention
of
inhaled
xylene
in
humans
has
been
reported
to
range
between
49.8
and
72.8%
(ATSDR,
1995).
No
difference
in
retention
has
been
observed
among
the
individual
isomers
(Sedivec
and
Flek,
1976)
or
between
sexes
(Senczuk
and
Orlowski,
1978),
but
is
increased
by
exercise
(Astrand
et
al.,
1978;
Gamberale
et
al.,
1978).
Following
uptake
from
the
lungs,
xylene
is
distributed
by
the
blood
to
the
body.
The
values
for
the
human
b1ood:
air
partition
coefficient
are
26.4,
3
1.9,
and
32.5
for
m­
xylene;
31.1,
35.2,
34.9
for
o­
xylene;
and
37.6,
39.0,
and
44.7
for
p­
xylene
(Sat0
and
Nakajima,
1979;
Pierce
et
al.,
1996;
Gargas
et
al.,
1989),
and
the
values
for
the
rat
b1ood:
air
partition
coefficient
are
46.0
for
m­
xylene;
44.3
for
o­
xylene,
and
41.3
for
p­
xylene
(Gargas
et
al.,
1989).
In
human
blood,
xylene
was
primarily
associated
with
serum
proteins
mihimaki
et
al.,
1979).
Distribution
to
adipose
tissue
has
been
estimated
to
be
between
3.7­
10%
of
total
uptake
following
inhalation
exposure
in
humans
(Eingstrom
and
Riihimaki,
1979;
Astrand,
1982).
Inhalation
exposures
of
mice
and
rats
to
radiolabeled
xylene
have
demonstrated
that
xylene
is
rapidly
taken
up
from
the
lungs
by
the
blood
and
immediately
distributed
to
the
kidneys,
brain,
subcutaneous
body
fat,
bone
marrow,
spinal
cord
and
spinal
nerves,
liver,
and
nasal
mucosa,
and
is
rapidly
eliminated
from
these
tissues
with
the
exception
of
fat
@ergman,
1983;
Carlsson,
198
1;
Kumarathasan
et
al.,
1997).
Ghantous
et
al.
(1990)
additionally
reported
an
accumulation
of
xylene
metabolites,
primarily
methyl
hippuric
acid,
in
the
nasal
mucosa
and
olfactory
bulb
of
the
brain
in
mice
following
inhalation
of
radiolabeled
p­
xylene.
Xylene
has
also
detected
in
the
placenta,
fetus,
and
amniotic
fluid
after
maternal
exposure,
but
the
concentrations
were
much
lower
than
in
the
maternal
tissues
(Ghantous
and
Danielsson,
1986,
Ungvary
et
al.,
1980).

The
primary
metabolic
pathway
in
humans
is
side­
chain
dehydroxylation
by
hepatic
mixed
finction
oxidases
to
toluic
acids
(see
Figure
1).
The
toluic
acids
are
then
conjugated
with
glycine
to
form
methylhippuric
acid
isomers
and
are
excreted
in
the
urine.
The
methylhippuric
acid
isomers
are
produced
almost
exclusively
in
humans,
with
urine
concentrations
accounting
for
95­
97%
of
the
absorbed
dose
in
humans
(Engstrom
et
al.,
1984;
Sedivec
and
Flek,
1976;
Riihimaki
et
al.,
1979).
Less
than
10%
of
the
absorbed
dose
is
excreted
unchanged
by
the
lungs
or
kidneys
(Sedivec
and
Flek,
1976;
Riihimaki
et
al.,
1979),
or
as
minor
metabolites
including
urinary
xylenols
(Sedivec
and
Flek,
1976;
Riihimaki
et
al.,
1979;
Engstrom
et
al.,
1984),
toluic
acid
glucuronides
(Ogata
et
al.,
1979;
1980)
or
mercapturic
acid
(Norstrom
et
al.,
1988).
Miller
and
Edwards
(1999)
have
found
evidence
that
of
the
3
xylene
isomers,
m­
xylene
is
preferentially
metabolized
to
methylhippuric
acid
in
the
presence
of
the
other
2
isomers,
regardless
of
the
30
XYLENES
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2
10
11
12
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14
15
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19
isomer
composition.
The
relevance
of
this
finding
in
assessing
the
toxicity
of
the
individual
isomers
is
not
known
at
this
time.

Metabolism
of
xylenes
in
animals
is
also
via
hepatic
side­
chain
dehydroxylation
by
mixed
function
oxidases
to
toluic
acids,
but
hrther
metabolism
is
dependent
upon
species
and
isomer
composition,
with
fluctuations
primarily
occurring
in
the
ratio
of
urinary
methylhippuric
acid
and
toluic
acid
glucuronides
(Ogata
et
al.,
1980;
Bray
et
al.,
1949;
Tardifet
al.,
1989).
It
has
been
proposed
that
the
differences
observed
between
humans
and
animals
in
xylene
metabolism
may
be
due
to
the
differences
in
the
size
ofthe
doses
administered
to
each:
the
larger
doses
received
by
the
animals
may
saturate
the
glycine­
conjugation
pathway
(ATSDR,
1995).

In
humans,
excretion
of
xylenes
following
inhalation
is
rapid
and
occurs
primarily
via
urine
almost
exclusively
as
methylhippuric
acid
isomers
with
aminor
amount
as
toluic
acid
glucuronides
(Rtihimaki
et
al.,
1979;
Engstrom
et
al.,
1984;
Senczuk
and
Orlowski,
1978;
Ogata
et
al.,
1970;
1980).
Only
a
minor
amount
(­
4­
5%)
of
the
absorbed
xylene
is
excreted
unchanged
by
the
lungs
(Sedivec
and
Flek,
1976;
Riihimaki
et
al.,
1979).
Riihimaki
et
al.
(1979)
have
estimated
that
excretion
of
xylene
in
air
and
urine
has
an
initial
half­
life
of
1
hour,
followed
by
a
slow
phase
with
an
estimated
half­
life
of
20
hours.
In
general,
a
linear
correlation
has
been
found
between
the
intensity
of
xylene
exposure
and
the
amount
of
methylhippuric
acid
isomers
excreted
in
the
urine
(Kawai
et
al.,
1991;
Inoune
et
al.,
1993;
Imbriani
et
al.,
1987;
Kawai
et
al.,
1992;
Lundberg
and
Sollenberg,
1986).
XYLENES
1
Proposed
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
free
0­
tduio
acid?

urine
f
10.
para.
0.0026%)

amnmtic
u
d
n
q
excretion
as
sulphate,
+
ethergluCuronide57
4
WmDIvlSaon
(&
­
0.86%
mta
­
1
.sa%
para
­
0.05%)

Figure
1.
Metabolic
scheme
for
xylenes
­
humans
(taken
from
ATSDR,
1995).
4.2.
Mechanism
of
Toxicity
Xylene
exposure
in
humans
and
animals
has
resulted
in
nervous
system
disturbances.
Central
nervous
system
effects
in
humans
following
acute
and
chronic
inhalation
exposure
to
xylene
have
included
headache,
vertigo,
nausea,
fatigue,
irritability,
dizziness,
impaired
concentration,
or
confbsion
(Hipolito,
1980;
Klaucke
et
al.,
1982;
Carpenter
et
ai.,
1975b).
Case
reports
of
individuals
exposed
to
high
concentrations
of
xylenes
by
inhalation,
ingestion,
or
intravenous
injection
have
reported
severe
respiratory
effects
including
respiratory
failure
(Morley
et
al.,
1970;
Abu
Al
Ragheb
et
al.,
1986;
Recchia
et
al.,
1985;
Sevcki
et
al.,
1992).
The
respiratory
effects
were
most
likely
a
secondary
response
to
depression
of
the
respiratory
center
of
the
brain.
Nonlethal
effects
following
exposure
to
high
concentrations
of
xylenes
(­
10,000)
included
unconsciousness,
slurred
speech,
and/
or
ataxia
(Morley
et
al.,
1970).
Controlled
acute
inhalation
exposures
in
human
males
have
yielded
in
mixed
results
following
neurobehavioral
testing.
A
number
of
studies
have
found
that
xylene
exposure
to
p­
or
m­
xylene
concentrations
ranging
from
70­
400
ppm
for
up
to
4
hours
either
did
not
affect
the
performance
of
subjects
in
neurobehavioral
testing
(Olson
et
al.,
1985)
or
actually
improved
performance
(Laine
et
al.,
1993;
Savolainen
et
al.,
1985b;
1981).
Other
studies
have
found
a
correlation
between
acute
exposure
to
m­
xylene
at
32
_­*­­­
XYLENES
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7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
concentrations
ranging
from
64­
400
ppm
for
up
to
4
hours
and
impaired
performance
(Savolainen
et
al.,
1979b;
1980;
1984;
1985a;
Savolainen
and
Linnavo,
1979;
Savolainen
and
Riihimaki,
1981;
Dudek
et
al.,
1990;
Gamberale
et
al.,
1978;
Seppalainen
et
al.,
1983;
1989;
1991).
Some
of
the
studies
evaluating
the
effects
of
acute
exposure
of
m­
xylene
have
indicated
the
development
of
tolerance
in
exposed
subjects
(Savolainen
et
al.,
1980;
Savolainen
and
Riihimaki,
1981).

Central
nervous
system
effects
following
acute
exposure
to
xylenes
were
also
reported
in
animals.
Pre­
anesthetic
effects
of
exposure
to
high
concentrations
of
xylenes
include
poor
coordination
and
prostration
(Carpenter
et
al.,
1975b);
increased
hindlimb
foot
splay
(Tegeris
and
Bdster,
1985);
decreased
performance
on
the
inverted
screen
test
(Moser
et
a,,
1985)
and
rotarod
(Korsak
et
al.,
1988;
1993);
and
disrupted
operant
performance
(Moser
et
al.,
1985).
Central
nervous
system
effects
following
exposure
to
lower
concentrations
of
xylenes
include
changes
in
flash
evoked
potentials
(Dyer
et
al.,
1988),
induced
flavor
aversion
(Bushnell
and
Peele,
1988),
decreased
reinforcement
rates
of
fixed­
ratio
responding
(Ghosh
et
al.,
1987),
decreased
rates
of
response
for
self­
stimulation
behavior
(Wimolwattanapun
et
al.,
1987),
and
facilitated
autoshaping
Pushnell,
1989).
Evidence
of
tolerance
was
also
reported
in
animals
(Ghosh
et
al.,
1987;
Wimolwattanapun
et
al.,
1987).

The
low
molecular
weight
and
lipophilic
nature
of
xylenes
allow
the
solvent
to
readily
cross
the
b1ood:
brain
barrier.
Studies
investigating
the
distribution
of
radiolabeled­
xylenes
following
inhalation
exposure
have
confirmed
high
concentrations
of
xylenes
in
the
brain
and
central
and
peripheral
nervous
system
immediately
after
exposure,
with
elimination
often
occurring
by
1
hour
post­
exposure
(Bergman,
1983;
Carlsson,
198
1;
Kumarathasan
et
al.,
1997;
Ghantous
and
Danielsson,
1986).
The
transient
nature
of
many
of
the
xylene­
induced
nervous
system
disturbances
is
likely
attributable
to
this
rapid
elimination
of
xylene.
The
mechanisms
whereby
xylenes
affect
the
nervous
system
are
not
known,
however.
An
in
vitro
study
using
human
and
rat
cell
membranes
demonstrated
that
xylene
and
other
solvents
with
anesthetic
properties
could
bind
in
hydrophobic
pockets
in
integral
cell
membrane
proteins,
thereby
altering
the
properties
of
integral
enzymes
(Tahti,
1992).
Other
studies
have
found
that
xylene
exposure
affected
the
enkephalinergic
neuromodulatory
system
(de
Gandarias
et
al.,
1999,
catecholamine
neurotransmission
by
altering
levels
of
dopamine
and
noradrenaline
(Andersson
et
al.,
198
l),
and
levels
of
brain
acetylcholine
and
glutamine
(Honma
et
al.,
1983).
Xylene
exposure
also
decreased
transport
of
cellular
materials
to
axons
and
nerve
ending
regions
in
rats
(Padilla
and
Lyerly,
1989),
affected
microsomal
superoxide
dismutase
activity
in
the
brain
of
rats
(Savolainen
et
al.,
1979a),
and
resulted
in
findings
compatible
with
astrogliosis
in
gerbils
(increased
brain
concentrations
of
glial
fibrillary
acidic
protein,
S­
100
protein,
and
DNA)
(Rosengren
et
al.,
1986).
Xylene
exposure
did
not
greatly
affect
neutral
or
basic
aminopeptidase
activities
in
the
brains
of
rats
(De
Gandarias
et
al.,
1993).

37
38
39
40
41
42
Data
demonstrating
that
xylene
is
hepatotoxic
are
limited.
In
humans,
data
were
primarily
limited
to
case
reports,
Morley
et
al.
(1970)
reported
an
accidental
exposure
to
approximately
10,000
ppm
xylenes.
The
autopsy
of
a
worker
that
died
revealed
hepatic
congestion
with
swelling
and
vacuolization
of
cells
in
the
centrilobular
areas.
The
other
two
exposed
workers
that
survived
had
only
slight
hepatic
impairment
as
indicated
by
a
rise
in
serum
transaminase
over
48
hours
following
the
exposure,
followed
by
a
return
to
normal
levels.
Hepatic
changes
in
rats
sometimes
33
43
XYLENES
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3
4
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7
%
9
10
11
12
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18
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20
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22
23
24
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26
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31
32
33
34
35
36
37
38
39
40
41
42
followed
subchronic
oral
or
inhalation
exposure
to
xylenes
and
have
been
consistent
with
an
adaptative
response
(Tatrai
and
Ungvary,
1980;
Ungvary
1990;
Tatrai
et
al.,
1981).

Developmental
toxicity
in
animals
has
generally
been
observed
only
at
doses
or
concentrations
similar
to
or
exceeding
those
resulting
in
maternal
toxicity.
Two
studies
were
found
investigating
the
potential
mechanism
for
xylene­
induced
developmental
toxicity
(retardations
and
lethal
effects).
In
a
study
investigating
the
role
of
maternal
sex
steroid
production
and
metabolism
in
p­
xylene
embryotoxicity,
Ungvary
et
al.
(1981)
reported
that
exposure
of
pregnant
rats
to
690
ppm
p­
xylene
(3000
mg/
m3)
on
GD
10
or
GD
9­
10
did
not
affect
maternal
ovarian
and
uterine
circulation
or
ovarian
hormone
secretion
rate
as
measured
on
GD
1
1
as
compared
with
controls.
However,
exposure
to
p­
xylene
for
48
hours
(GD
9­
10)
did
result
in
a
statistically
significant
decrease
in
the
peripheral
levels
of
progesterone
and
@­
estradiol
and
significantly
decreased
fetal
body
weights
(actual
data
not
provided).
It
was
proposed
that
the
hepatic
enzyme
induction
by
p­
xylene
was
responsible
for
increased
metabolism
of
the
sex
hormones,
which
in
turn
was
responsible
for
the
fetal
effects.
In
another
study,
Ungvary
and
Donath
(1984)
found
that
exposure
of
pregnant
rats
to
approximately
350
ppm
p­
xylene
resulted
in
hyperinnervation
or
degeneration
of
noradrenergic
nerves
of
reproductive
organs
(uterus,
ovaries).
They
proposed
that
damage
to
the
peripheral
noradrenergic
nerves
can
result
in
altered
control
of
uterine
and
ovarian
blood
flow
and
steroid
production,
resulting
in
fetal
toxicity.

4.4.
Other
Relevant
Information
4.4.1.
Interspecies
Differences
Pharmacokinetic
data
in
humans
and
rats
were
available
for
xylene
isomers
(see
section
4,
l).
A
comparison
of
the
b1ood:
air
partition
coefficients
in
humans
and
rats
suggest
that
small
rodents
will
experience
greater
systemic
uptake
than
humans.
Another
value
to
take
into
consideration
is
the
tissue:
blood
coefficient.
Unfortunately
those
values
were
not
determined
specifically
for
the
central
nervous
system,
but
rather
for
richly
perfused
tissues
in
general
which
would
include
the
values
for
the
liver
and
kidney
and
are
4.42
in
humans
and
1.97
in
rats.
Pelekis
and
Krishnan
(in
press)
looked
at
a
total
composite
of
factors
which
should
be
included
in
determining
a
toxicokinetic
uncertainty
factor
for
several
volatile
organic
compounds
and
concluded
that
the
most
critical
factors
are
the
tissue:
blood
partition
coefficient,
b1ood:
air
partition
coefficient,
hepatic
extraction
ratio,
the
fraction
of
cardiac
output
reaching
the
liver,
and
the
body
weight­
normalized
alveolar
ventilation
rate.
Based
upon
these
criteria,
they
proposed
numbers
with
which
the
rat
m­
xylene
exposure
concentration
should
be
divided
to
obtain
the
toxicokinetic­
equivalent
m­
xylene
exposure
concentration
of
systemically
active
chemicals
in
humans.
These
numbers
are:
2.24
for
richly
perhsed
tissues,
3.30
for
slowly
perfused
tissues,
2.30
for
liver,
and
1.93
for
fat.

The
interspecies
factor
is
comprised
of
the
pharmacodynamic
component
as
well.
A
view
of
the
data
indicate
little
difference
in
interspecies
sensitivity
to
xylene.
Lethality
data
for
mice
and
rats
were
nearly
identical
(Cameron
et
al.,
1938;
Bonnet
et
al.,
1982).
Death
was
preceded
by
narcosis
and
was
likely
the
result
of
depression
of
the
central
nervous
system
resulting
in
respiratory
arrest.
A
similar
effect
has
been
proposed
for
humans.
Nonlethal
effects
in
both
humans
and
animals
are
similar
in
nature
and
consist
primarily
of
irritation
and
central
nervous
system
effects.

34
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
XYLENES
4.4.2.
Intraspecies
Differences
Proposed
8
:
512002
All
available
data
point
to
a
2­
3­
fold
difference
in
interindividual
sensitivity
to
xylenes.

Xylene
acts
as
an
anesthetic
(Fang
et
al.,
1996).
Studies
indicate
that
children,
and
particularly
infants,
are
more
resistant
than
adults
to
the
effects
of
various
volatile
anesthetics
(Gregory
et
al.,
1969;
Katoh
and
Ikeda
et
al.,
1992;
Lerman
et
al.,
1983;
Matthew
et
al.,
1996;
Stevens
et
al.,
1975;
LeDez
and
Eerman,
1987).
The
susceptibility
of
individuals
of
different
ages
has
been
extensively
studied
in
the
anesthesia
literature
where
the
concentrations
of
various
anesthetic
gases
in
the
lung
which
produce
"anesthesia"
(Le.,
lack
of
movement)
have
been
measured.
Values
are
usually
reported
as
the
Minimum
Alveolar
Concentration
(MAC)
which
produces
lack
of
movement
in
50%
of
persons
exposed
to
that
concentration.
MAC'S
for
several
anesthetic
gases
have
been
measured
as
a
fbnction
of
age.
The
results
consistently
show
a
pattern
with
maximal
sensitivity
(lowest
MAC)
in
newborns,
particularly
prematures,
pregnant
women,
and
the
elderly.
The
least
sensitive
(highest
MAC
values)
occur
in
older
infants,
toddlers,
and
children
as
compared
to
normal
adults.
The
total
range
of
sensitivity
is
2­
3
fold.
On
the
basis
of
this
knowledge,
it
is
not
unreasonable
to
assume
that
the
same
2­
3
fold
difference
in
sensitivity
among
individuals
would
apply
for
xylenes.

Exercise
has
been
found
to
increase
alveolar
and
blood
levels
of
xylenes
during
exposure
(Gamberale
et
al.,
1978;
Riihimaki
et
al.,
1979).
Using
a
physiologically­
based
pharmacokinetic
model
for
m­
xylene
in
humans
to
assess
various
interindividual
factors
in
determining
the
internal
dose,
Kaneko
et
al.
(1991)
reported
that
physical
activity
(50W)
during
a
simulated
8­
hour
.
exposure
to
50
ppm
resulted
in
a
2.5­
fold
increase
in
blood
concentration
when
compared
to
exposure
at
rest.

Fang
et
al.
(1996)
determined
the
MAC
in
rats
of
the
individual
isomers.
The
MAC
of
0­,
m­,
and
p­
xylene
was
0.001
18
f
0.00009,
0.00139
f
0.00010,
and
00.00151
f
0.0007
atm,
respectively,
with
a
difference
of
MAC
values
of
less
than
30%
among
the
isomers.

4.4.3.
Concentration­
Exposure
Duration
Relationship
The
two
primary
effects
of
xylene
exposure
are
those
of
irritation
and
central
nervous
system
effects.
Irritation
is
considered
a
threshold
effect
and
therefore
should
not
vary
over
time.
An
AEGL
value
based
on
irritation
is
therefore
not
scaled
across
time,
but
rather
the
threshold
value
is
applied
to
all
times.

The
central
nervous
system
effects
of
xylene
are
attributed
to
the
low
molecular
weight
and
lipophilic
nature
of
xylene
allowing
the
solvent
to
readily
cross
the
b1ood:
brain
barrier
(see
section
4.2).
Distribution
studies
of
xylene
following
inhalation
exposures
have
confirmed
high
concentrations
of
xylene
in
the
brain
and
central
and
peripheral
nervous
system
immediately
after
exposure,
with
elimination
often
occurring
by
1
hour
post
exposure.
The
rapid
onset
of
central
nervous
system
effects
combined
with
the
transient
nature
of
the
xylene­
induced
nervous
system
disturbances
is
likely
attributable
to
direct
interaction
of
the
chemical
with
the
central
nervous
system
followed
by
the
rapid
elimination
of
xylene.
Based
on
the
above
information,
the
xylene­
blood
concentration
will
be
a
key
determinant
in
central
nervous
system
effects.
Pharmacokinetic
35
1
2
3
4
5
6
7
8
9
10
11
12
13
XYLENES
Proposed
1:
5/
2002
modeling
in
both
humans
and
rats
indicate
that
venous
blood
concentrations
rapidly
increase
during
the
first
15
minutes
of
exposure,
followed
by
minimal
increases
in
blood
concentrations
with
continuing
exposure
(i.
e,,
increases
follow
a
hyperbolic
curve)
(Tardif
et
al.,
1993;
1995).
Likewise,
available
human
data
indicate
that
once
the
initial
increase
in
blood
xylene
concentration
is
reached,
blood
concentrations
level
off
with
increasing
exposure
duration
(see
Table
1
1)
(Hake
et
al.,
1981;
Savolainen
et
al.,
1980;
1981;
1985b).
Conversely,
available
human
and
animal
data
demonstrate
that
increasing
exposure
concentrations
correlate
with
increases
in
venous
blood
xylene
concentrations
(Hake
et
al.,
1981;
Tardif
et
al.,
11993;
Laine
et
al.,
1993).
These
data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity.
Therefore,
the
AEGL
values
based
upon
central
nervous
system
effects
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
1
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes
(see
Appendix
2).
XYLENES
Proposed
1:
5/
2002
TABLE
11.
Relationship
Between­
gylene
Exposure
Concentration
(In
Air)
and
Blood
Xylene
Concentration
in
Human
Volunteers
1
2
3
4
5
6
7
8
9
10
11
12
13
Venous
blood
subjects
concentration
exposure
xylene
Comments
Exposure
concent
ration
Reference
I
I
I
a
11
I
18.4
f
5.3
(pmol/
L,)
I
m­
Xylene,
javolainen
et
al.
~

.980
100"
I
odor
masked
with
peppermint
oil
B
.67
13.3
f
2.2
121.6
f
6.3
1
­
­­
I
3
I
13.4
f
2.9
1
9
10.25
I
16.6
f
4.8
(pmolL)
I
m­
Xylene,
4aine
et
al.,
1993
ZOO"
odor
masked
with
peppermint
oil
0.33
17.3
Jr
5.5
10.67
121.3
Jr
5.4
I
2
28.5
f
5.2
I
24.9
f
2.1
(p
m
o
l
)
m­
Xylene,

26.7
f
3.4
odor
masked
with
peppermint
oil
(<
1.0
3.75
28.6
f
3.5
PPm)
1
0.24
(ppm;
wlw)
p­
Xylene,
Subjects
were
sub­
divided
into
3
daily
3
0.41
f
0.09
7.5
0.42
f
0.03
groups
for
1,
3,
or
7.5
hour­
long
exposures.
Males
were
exposed
to
1
1.23
f
0.18
3
1.65
f
0.50
100
ppm
for
the
lst
week
(5
daydweek),
20
ppm
the
2nd
week,
and
150
7.5
1.29
f
0.21
1
2.04
f
0.76
ppm
the
31d
week.
Values
reported
are
for
~~

the
first
exposure
day
of
,3
3.18
f
0.11
6
javolainen
et
al.,
1981
200
1
3ake
et
al.,
1981
20
2
3
100
2
2
4
150
2
2
4
17.5
13.86
f
0.65
I
each
new
week.
Exposure
protocol
was:
3
hour
exposure
in
the
morning,
40
Mnute
break
for
lunch,
follow
.by
exposure
for
1
or
3
hours
in
afternoon.
Only
values
for
continuous
exposure
in
the
morning
session
are
reported.

37
XYLENES
Proposed
1:
5/
2002
1
2
3
4
5
6
7
%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
5.
DATA
ANALYSIS
AND
PROPOSED
AEGL­
1
5.1.
Human
Data
Relevant
to
AEGL­
1
Exposure
to
100,
200
or
400
ppm
mixed
xylenes
for
30
minutes
resulted
in
nonstatistically
increased
incidences
of
eye
irritation;
no
nose
or
throat
irritation
were
noted
and
no
changes
in
behavioral
tests
or
respiratory
measurements
were
evident
(Hastings
et
al.,
1986).
That
the
eye
irritation
was
mild
is
supported
by
observation
that
the
number
of
eye
blinks/
minute
were
not
affected
by
exposure.
Exposure
to
100
or
150
ppm
p­
xylene
for
7.5
hourslday,
5
daydweek
resulted
only
in
mild
eye
irritation,
most
often
in
one
male
wearing
contact
lenses
(irritation
was
noted
on
the
first
exposure
day)
(Hake
et
a1.,
198l).
No
effects
on
performance
tests
were
observed.
Exposure
to
110
ppm
mixed
xylenes
for
15
minutes
resulted
in
intermittent,
mild
throat
irritation
in
1/
6
individuals,
while
exposure
to
230
ppm
mixed
xylenes
for
15
minutes
resulted
in
eye
irritation
and
mild
dizziness
in
1/
7
individuals
(Carpenter
et
al.,
1975b).

A
number
of
controlled
human
exposures
reported
no
effects
following
exposure
to
xylenes.
Exposure
to
100
or
200
ppm
m­
or
p­
xylene
for
3
or
7
hours
did
not
effect
blood
pressure,
pulse
rate,
flicker
value,
or
reaction
time
(Ogata
et
al.,
1970).
Olson
et
al.
(1985)
found
exposure
to
70
ppm
p­
xylene
for
4­
hours
did
not
effect
choice
reaction
time,
simple
reaction
time,
short
term
memory,
heart
rate,
or
subjective
symptoms
in
exposed
volunteers.
No
adverse
effects
on
visual
evoked
potential,
tapping
speed,
body
sway,
reaction
time,
or
critical
flicker
fusion
were
measured
in
volunteers
exposed
to
200
ppm
m­
xylene
for
4
hours
(Savolainen
et
al.,
1981;
Seppalainen
et
al.,
1983).
Body
sway,
reaction
times,
and
active
or
quiet
sleep
were
not
effected
by
exposure
to
200
ppm
for
5.5
hours
(Line
et
al.,
1993).

5.2.
Animal
Data
Relevant
to
AEGL­
1
No
effects
were
observed
in
dogs
exposed
to
530
ppm
or
in
rats
exposed
to
580
ppm
mixed
xylenes
for
4
hours
(Carpenter
et
al.,
1975b).
Lacrimation
in
dogs
and
poor
coordination
in
rats
were
observed
at
the
next
higher
exposure
concentrations
of
1200
ppm
and
1300
ppm,
respectively
(Carpenter
et
al.,
1975b).

5.3.
Derivation
of
AEGL­
1
The
AEGL­
1
is
based
upon
slight
eye
irritation
noted
in
the
Hastings
et
al.
(1986)
study
during
a
30­
minute
exposure
to
400
ppm
mixed
xylenes.
The
Hastings
et
al.
(1986)
study
was
chosen
because
the
exposure
was
to
mixed
xylenes
as
opposed
to
individual
isomers,
and
the
exposure
concentration
represented
a
concentration
at
which
an
effect
was
observed,
i.
e.,
that
of
mild
eye
irritation.
An
interspecies
uncertainty
factor
was
not
applied
because
the
key
study
used
human
data,
An
intraspecies
uncertainty
factor
of
3
was
applied
because
the
toxic
effect
(slight
irritation)
was
less
severe
than
that
defined
for
the
AEGL­
1
tier
(notable
discomfort).
Because
irritation
is
considered
a
threshold
effect
and
should
therefore
not
vary
over
time,
the
threshold
value
is
applied
to
all
times.
AEGL­
1
values
are
presented
in
Table
12.
BO
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
XYLENES
Proposed
1:
5/
2002
TABLE
12.
AEGE­
1
Values
for
Xylenes
[ppm
(mg/
m3)]

lO­
nlhute
30­
minute
1­
hour
.
4­
hour
I
I
I
%hour
I
I
I
I
130
(560)
I
130
(560)
I
130
(560)
I
130
(560)
I
130
(560)

%&
e
130
pprn
value
is
supported
by
several
other
studies,
including:
the
150
gpm
p­
xylene
exposure
resulting
in
eye
irritation
in
a
contact
lens
wearer
(represents
sensitive
population;
Hake
et
al.,
1981);
the
15­
minute
exposure
to
230
ppm
mixed
xylenes
resulting
in
mild
eye
irritation
and
dizziness
in
one
individual;
and
the
3­
hour
exposure
to
200
ppm
m­
or
p­
xylene
(Ogata
et
al.,
1970),
the
4­
hour
exposure
to
200
ppm
m­
xylene
(Savolainen
et
al.,
1981),
and
the
5.5
hour
exposure
to
200
ppm
m­
xylene
(Laine
et
al.,
1993),
all
representing
no­
effect
levels.

4.
DATA
ANALYSIS
AND
PROPOSED
AEGL­
2
6.1.
Human
Data
Relevant
to
AEGL­
2
One
of
six
or
seven
individuals
noted
dizziness
during
a
fifteen
minute
exposure
to
230
ppm
(during
the
last
2
minutes
of
exposure)
or
460
ppm
mixed
xylenes
(starting
at
the
6"
minute
and
continuing
to
the
end
of
exposure;
same
individual),
while
a
15­
minute
exposure
to
690
ppm
mixed
xylenes
resulted
in
dizziness/
lightheadedness
in
4/
6
individuals
(Carpenter
et
al.,
1975b).
In
the
same
study,
a
15­
minute
exposure
resulted
in
eye
irritation
in
1/
7,
4/
6
and
4/
6
individuals
exposed
to
230,
460,
or
690
ppm
mixed
xylene,
respectively.

6.2.
Animal
Data
Relevant
to
AEGL­
2
Exposure
to
1200
ppm
or
1300
ppm
mixed
xylenes
for
4
hours
represents
a
threshold
for
lacrimation
in
dogs
and
poor
coordination
(reversible)
in
rats,
respectively
(Carpenter
et
al.,
1975b).
The
4­
hour
m­
xylene
EC50
for
decreased
rotarod
performance
in
rats
was
1982
ppm
(Korsak
et
al.,
1993),
and
the
4­
hour
minimum
narcotic
concentrations
for
the
3
xylene
isomers
in
rats
ranged
from
1940­
2180
ppm
(Molnar
et
al.,
1986).
Exposure
of
rats
to
1600
ppm
p­
xylene
for
4­
hours
resulted
in
hyperactivity,
fine
tremor,
and
unsteadiness
(Bushnell,
1989),
induced
flavor
aversion
(Bushnell
and
Peele,
1
988),
and
caused
changes
in
the
flash
evoked
potential
suggestive
of
increased
arousal
(Dyer
et
al.,
1988).

Following
30­
minute
static
exposures
in
mice,
Moser
et
al.,
(1985)
determined
the
EC,,
for
decreased
performance
on
the
inverted
screen
test
to
be
3790
ppm
for
m­
xylene,
3640
ppm
for
o­
xylene,
and
2676
ppm
for
p­
xylene,
while
the
EC,,
for
disruption
of
operant
performance
was
6
176
ppm
for
m­
xylene,
5
179
ppm
for
o­
xylene,
and
56
1
1
ppm
for
p­
xylene.

6.3.
Derivation
of
AEGL­
2
The
AEGL­
2
is
based
upon
poor
coordination
resulting
when
rats
were
exposed
to
1300
ppm
mixed
xylenes
for
4­
hours
(Carpenter
et
al.,
1975b).
This
concentration
represents
the
threshold
for
reversible
equilibrium
disturbances.
This
concentration
and
endpoint
are
consistent
with
the
preponderance
of
available
data
for
4­
hour
exposures
in
rats:
the
EC50
for
decreased
rotarod
performance
was
1982
ppm
(Korsak
et
al.,
1993);
the
minimum
narcotic
concentrations
for
m­,
o­
,
and
p­
xylene
ranged
from
1940­
2180
ppm
(Molnar
et
al.,
1986);
and
exposure
to
1600
ppm
p­

39
5
4
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
XYLENES
Proposed
1:
5/
2002
v
­4
"
8­

xylene
resulted
in
hyperactivity,
fine
tremor,
and
unsteadiniss
(Bushnell,
1989),
induced
flavor
aversion
(Bushnell
and
Peele,
1988),
and
caused
changes
in
the
flash
evoked
potential
suggestive
of
increased
arousal
(Dyer
et
al.,
1988).
In
dogs,
exposure
to
1200
ppm
for
4
hours
represented
a
threshold
for
eye
irritation
(Carpenter
et
ai.,
197%).

An
interspecies
uncertainty
factor
of
1
was
applied
because
rats
receive
a
greater
systemic
dose
ofinhaled
xylene
as
compared
to
humans.
An
intraspecies
uncertainty
factor
of
3
was
applied
because
the
MAC
(minimum
alveolar
concentration)
for
volatile
anesthetics
should
not
vary
by
more
than
a
factor
of
2­
3­
fold
among
humans.
A
3­
fold
factor
is
also
adequate
to
account
for
moderate
physical
activity
during
exposure,
which
would
result
in
greater
uptake
of
the
chemical.

Data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity
(see
Section
4.4.3).
Therefore,
the
AEGL­
2
values
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
1
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes
(see
Appendix
B).

AEGL­
2
values
are
presented
in
Table
13
TABLE
13.
AEGL­
2
Values
for
Xylenes
[ppm
(mg/
m3)]

PO­
minute
30­
minute
1­
hour
4­
hour
8­
hour
I
I
I
I
I
990
(4300)
I
480
(2
100)
I
430
(1900)
I
430
(1900)
I
430
(1900)

The
human
data
reported
by
Carpenter
et
al.
(1975b)
were
not
used
for
the
AEGL­
2
derivation
because
the
exposure
duration
was
for
only
a
short
time
(1
5
minutes)
and
because
it
not
consistent
with
the
preponderance
of
human
data
from
other
controlled
human
exposures.
If
one
were
to
use
the
highest
exposure
concentration
(690
ppm
which
resulted
in
eye
irritation
and
dizziness
in
4/
6
individuals;
threshold
for
equilibrium
effects)
and
apply
the
intraspecies
uncertainty
factor
of
3,
one
obtains
a
value
of
230
ppm.
This
concentration
is
supposed
to
represent
a
concentration
at
which
exposed
individuals
could
experience
irreversible
or
other
serious,
long­
lasting
adverse
health
effects,
or
have
an
impaired
ability
to
escape.
However,
a
number
of
studies
demonstrate
that
this
concentration
has
no
adverse
effects
upon
exposed
individuals:
no
adverse
effects
were
observed
following
exposure
to
100
or
200
ppm
m­
or
p­
xylene
for
3
or
7
hours
(Ogata
et
al.,
1970);
200
ppm
m­
xylene
for
4
hours
(Savolainen
et
al.,
1981;
Seppalainen
et
al.,
1985),
or
200
ppm
for
5.5
hours
(Laine
et
al.,
1993).

Additionally,
numerous
human
studies
investigated
the
effects
of
exposure
to:
200
ppm
m­
xylene
with
20
minute
peaks
of
400
ppm
(Seppalainen
et
al.,
1989;
1991;
Laine
et
al,,
1993;
Savolainen
and
Linnavuo,
1979);
135
ppm
m­
xylene
with
20
minute
peaks
of
400
ppm
(Savolainen
et
al.,
1984;
1985a;
1985b);
or
140
ppm
m­
xylene
with
10
minute
peaks
of
400
ppm
(Riihimaki
and
Savolainen,
1980;
Savolainen
and
Riihimaki,
1981).
The
studies
also
combined
peak
exposures
with
exercise,
thereby
increasing
the
uptake
of
the
chemical.
These
studies
found
either
no
effect,
or
reported
only
minimal
central
nervous
system
effects.
1
2
3
4
5
6
3
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
XYLENES
7.
DATA
ANALYSIS
AND
PROPOSED
AEGL­
3
7.8.
Human
Data
Relevant
to
AEGL­
3
Proposed
1:
5/
2002
Morley
et
al.
(1970)
reported
the
cases
of3
individuals
exposed
to
approximately
10,000
ppm
xylene
for
approximately
18
hours.
One
individual
died,
while
the
other
two
individuals
were
found
unconscious
but
experienced
a
full
recovery.

7.2.
Animal
Data
Relevant
to
AEGL­
3
Two
cats
exposed
to
9500
ppm
mixed
xylenes
exhibited
central
nervous
system
effects
followed
by
death
2
hours
into
the
exposure
(Carpenter
et
al.,
1975b).
In
rats,
4­
hour
LC5,
s
values
for
mixed
xylenes
have
been
reported
as
6350
ppm
(fine
and
Zuidema,
1970),
601
1
ppm
(Carpenter
et
al.,
1975b),
and
11,000
ppm
(Lundberg
et
al.,
1986),
and
for
p­
xylene
as
4645
ppm
(Harper
et
al.,
1975).
Six­
hour
LC,,
values
for
the
m­,
0­,
and
p­
isomers
were
5984,4330,
and
4591
ppm
in
rats,
respectively,
and
5267,4595,
and
3907
ppm
in
mice,
respectively
(Bonnet
et
al.,
1979;
1982).

A
no­
effect
level
for
death
in
rats
following
exposure
to
mixed
xylenes
for
4
hours
was
2800
ppm
(Carpenter
et
al.,
1975b).
Clinical
signs
observed
during
exposure
to
2800
ppm
included
prostration
between
2­
3.5
hours
into
the
exposure.
Recovery
occurred
within
1­
hour
post
exposure,
but
coordination
remained
poor
until
the
following
day.
At
the
next
lower
concentration
of
1300
ppm,
poor
coordination
was
noted
2
hours
into
the
exposure,
with
coordination
returning
to
normal
after
the
exposure.
Molnar
et
al.
(1986)
reported
4­
hour
minimum
narcotic
concentrations
of
2100,
2180,
and
1940
ppm
for
the
m­,
0­,
and
p­
xylene
isomers,
respectively.

R
D
5
0
values
in
mice
were
1467
ppm
for
o­
xylene
(De
Ceaurriz
et
al.,
1981),
1361
ppm
for
m­
xylene
(Korsak
et
al.,
1993),
and
2440
ppm
for
mixed
xylenes
(Korsak
et
al.,
1988).
It
should
be
noted,
however,
that
Korsak
et
al.
(1993;
1988)
did
not
use
the
recommended
strain
of
mice.

7.3.
Derivation
of
AEGL3
The
AEGL­
3
derivation
is
based
upon
prostration
occurring
in
all
10
rats
exposed
for
4
hours
to
2800
ppm
mixed
xylenes,
with
recovery
occurring
within
1
hour
of
exposure
(Carpenter
et
al.,
1975b)
Although
coordination
initially
remained
poor,
it
returned
to
normal
the
following
day.
This
concentration
also
represents
a
no­
effect
level
for
lethality.

An
interspecies
uncertainty
factor
of
1
was
applied
because
rats
receive
a
greater
systemic
dose
of
inhaled
xylene
as
compared
to
humans.
An
intraspecies
uncertainty
factor
of
3
was
applied
because
the
MAC
(minimum
alveolar
concentration)
for
volatile
anesthetics
should
not
vary
by
more
than
a
factor
of
2­
3­
fold
among
humans.
A
3­
fold
factor
is
also
adequate
to
account
for
moderate
physical
activity
during
exposure,
which
would
result
in
greater
uptake
of
the
chemical.

Data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity
(see
Section
4.4.3).
Therefore,
the
41
XYLENES
Proposed
I:
§/
2002
Classification
10­
Minute
AEGL­
1
(Nondisabling)
130
(560)
1
2
3
30­
Minute
1­
Hour
4­
Hour
8­
Hour
130
(560)
130
(560)
130
(560)
130
(560)
4
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
AEGL­
3
values
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
I
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes
(see
Appendix
B).

AEGE­
3
values
are
presented
in
Table
14.

TABLE
14.
AEGL­
3
Values
for
Xylenes
[ppm
(mg/
m3))
l
10­
minute
I
30­
minute
I
1­
hour
I
&hour
I
$­
hour
I
I
I
2100
(9100)
1000
(4300)
I
930
(4000)
I
930
(4000)
I
930
(4000)
I
I
Available
data
indicated
that
these
values
should
be
protective
of
human
health.
A
15­
minute
exposure
to
690
ppm
for
15
minutes
resulted
in
eye
irritation
and
dizziness
and/
or
lightheadedness
(Carpenter
et
al.,
1975b),
and
a
30
minute
exposure
to
concentrations
as
high
as
700
ppm
xylene
resulted
in
headache,
nausea,
vomiting,
dizziness
or
vertigo,
eye
irritation,
or
nose
or
throat
irritation
(Klaucke
et
al.,
1982).

8.
SUMMARY
OF
PROPOSED
AEGLs
8.1.
AEGL
Values
and
Toxicity
Endpoints
The
proposed
AEGL
values
for
xylenes
are
summarized
in
Table
15.

I
~G
L
­~
(Disabling)
I
990(
4300)
I
480(
2100)
I
430
(1900)
I
430(
1900)
I
430
(1900)
11
IGL­~
Gethall
I
2100(
9100)
I
lOOO(
4300)
I
930(
4000)
I
930(
4000)
I
930(
4000)
I
8.2.
Comparisons
with
Other
Standards
Standards
and
guidance
levels
for
workplace
and
community
exposures
are
listed
in
Table
16.
TABLE
16.
Extant
Standards
and
Guidelines
for
Xylenes
II
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
losure
Dura
ion
4­
hour
8­
hour
Guideline
AEGL­
1
130
ppm
AEGL­
2
990
ppm
AEGE­
3
2
100
ppm
10­
min
15­
min
30­
min
130
ppm
1­
hour
130
ppm
430
ppm
930
ppm
480
ppm
1000
ppm
NIOSHmLHa
I
I
900
ppm
OSHATWA'
1
1
100
ppm
+
100
ppm
OSHA
PEL
ACGIH
TLV­
TWA~

ACGIH
STELK
150
ppm
SMAC
(1996)
200
ppm
100
ppm
440
mg/
m3
100
ppm
*
2
10
mg/
m3
I
MAKg
MAC
(Dutch)
"

NIOSH
1994,
1997
NIOSH,
1997
'
OSHA,
1996
ACGM,
2000
e
NRC,
1984
NRC,
1996
g
German
Research
Association,
1999
Ministry
of
Social
Affairs
and
Employment,
2000
I
50ppm
25
8.3.
Data
Quality
and
Research
Needs
Human
data
appropriate
for
use
in
AEGL
derivations
were
limited.
Although
numerous
studies
investigating
controlled
human
exposures
were
available,
the
effects
noted,
if
any,
were
generally
less
serious
than
those
defined
by
the
AEGL
definitions.
Human
lethality
data
were
limited
to
a
case
report
where
one
of
three
individuals
exposed
to
approximately
10,000
ppm
for
almost
19
hours
died
(Morley
et
al.,
1970).
Nonlethal
animal
data
were
available
in
dogs,
cats,
rats,
and
mice,
although
the
majority
of
the
data
investigating
central
nervous
system
effects
following
acute
exposures
was
in
rats.
Lethality
data
were
available
in
rats
and
mice,
and
indicated
little
difference
in
sensitivity
between
these
species.
26
27
28
29
30
31
32
33
A
number
of
developmental
toxicity
studies
were
available,
but
results
were
equivocal.
One
study
did
not
identify
a
maternal
or
developmental
toxicity
LOAEL
at
the
concentrations
tested.
Another
series
of
studies
identified
an
effect
on
postnatal
development
only
in
female
offspring
as
34
35
36
43
r3
XYLENES
Proposed
1:
5/
2002
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
assessed
by
the
Morris
water
maze
test;
no
other
effects
were
observed.
Although
retarded
development
of
fetuses
from
exposed
dams
was
evident
in
several
studies
as
indicated
by
incomplete
or
non­
ossification
of
skeletal
structures
and/
or
decreased
fetal
body
weights,
these
studies
were
generally
limited
because
the
data
were
reported
as
fetal
incidences
instead
of
litter
incidences,
and
generally
lacked
the
reporting
of
other
key
data.
Therefore,
an
adequate
assessment
of
the
data
was
not
possible.

Because
of
inadequate
evidence,
xylene
is
currently
not
classifiable
as
to
its
carcinogenicity
by
IARC
or
the
U.
S.
EPA.
However,
commercial
xylene
and
all
three
individual
isomers
have
generally
tested
negative
for
genotoxicity.

The
proposed
AEGL
values
should
be
protective
of
human
health.
The
key
study
used
for
the
AEGL­
1
derivation
(Hastings
et
al.,
1986)
was
an
acceptable
study,
but
could
have
been
improved
had
the
number
of
volunteers
been
reported.
However,
the
data
are
consistent
with
other
human
studies,
and
represent
a
value
consistent
with
exposure
concentrations
that
might
result
in
mild
eye
irritation.
The
key
study
for
the
AEGL­
2
and
­3
derivation
(Carpenter
et
al.,
1975)
was
a
well­
conducted
study
in
rats.
The
AEGL­
2
levels
are
protective,
especially
when
considering
numerous
human
studies
investigated
the
effects
of
exposure
to
200
ppm
xylene
with
20­
minute
peak
exposures
to
400
ppm,
in
some
cases
additionally
combining
peak
exposures
with
physical
exercise
resulting
in
greater
uptake
of
the
chemical,
and
found
only
minimal
central
nervous
system
effects.
The
difficultly
in
defining
an
AEGL­
2
level
for
xylene
comes
from
its
"all­~
r­
nothing~~
continuum
of
toxicity:
toxicity
ranges
from
mild
irritation
to
narcosis,
with
little
happening
in
between.
The
AEGL­
3
levels
are
supported
by
human
data
demonstrating
that
exposure
to
690
ppm
for
15
minutes
resulted
in
lightheadedneddizziness
and
a
30
minute
exposure
to
700
ppm
resulted
in
nausea,
vomiting,
dizziness
or
vertigo.
XYLENES
Proposed
1:
5/
2002
1
9.
REFERENCES
2
3
Abu
Al
Ragheb,
S.,
Salhab,
A.
S.,
and
Amr,
S.
S.
1986.
Suicide
by
xylene
ingestion:
A
case
report
and
review
of
literature.
Am.
J.
Forensic
Med.
Path.
7:
327­
329.

4
5
6
ACGm
(American
Conference
of
Governmental
Industrial
Hygienists).
199
1.
Documentation
of
the
Threshold
Limit
Values
and
Biological
Exposure
Indices:
(Xylene
(0­,
m­,
and
p­
isomers)).
Sixth
Ed.,
ACGIH,
Cincinnati,
OH.,
pp.
1732­
1740.

7
S
9
10
ACGIH
(American
Conference
of
Governmental
Industrial
Hygienists).
2000.
TLVs
and
BEIs.
Based
on
the
Documentations
of
the
Threshold
Limit
Values
for
Chemical
Substances
and
Physical
Agents
and
Biological
Exposure
Indices:
(Xylene
(0­,
m­,
and
p­
isomers)).
Sixth
Ed.,
ACGM,
Cincinnati,
OH.,
p.
72.

11
12
13
chemicals.
Environ.
Mol.
Mutagen.
16;
Suppl.
18:
55­
137.
Anderson,
B.
E.
,
Zeiger,
E.,
Shelby,
M.
D.,
Resnick,
M.
A.,
Gulati,
D.
K.,
Ivett,
J.
L.,
and
Loveday,
K.
S.
1990.
Chromosome
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and
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chromatid
exchange
test
results
with
42
14
15
16
17
Andersson,
K.,
Fuxe,
K.,
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O.
G.,
Toftgard,
R.,
Eneroth,
P.,
and
Gustafsson,
J.­
A.
1981.
Production
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in
dopamine
and
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and
turnover
in
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the
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brain
following
exposure
to
xylene,
ortho­,
meta­,
and
para­
xylene,
and
ethylbenzene.
Toxicol.
Appl.
Pharmacol.
60:
535­
548.

1s
19
20
Anttila,
A,,
Riala,
R.,
Pukkala,
E.,
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M.,
Hernberg,
S.,
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Hemminki,
K.
1995.
Occupational
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Finnish)
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cited
in
Lynge
et
al.,
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21
22
Arp,
E.
W.,
Jr.,
Wolf,
P.
H.,
and
Chekoway,
H.
1983.
Lypmphocytic
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other
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the
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23
24
Br.
Med.
J.
284:
1787.
Arthur,
L.
J.,
and
Curnock,
D.
A.
1982.
Xylene­
induced
epilepsy
following
innocent
glue
sniffing.

25
Astrand,
I.
1982.
Work
load
and
uptake
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solvents
in
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of
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In:
Mehlman,
M.
A.,
ed.,
26
27
Press:
141­
152.
Advances
in
Modern
Environmental
Toxicology.
Vol.
2.
Princeton
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NJ:
Senate
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29
Astrand,
I.,
Engstrom,
J.,
and
Ovrum,
P.
1978.
Exposure
to
xylene
and
ethylbenzene.
I.
Uptake,
distribution,
and
elimination
in
man.
Scand.
J.
Work
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4:
185­
194.

30
31
32
33
ATSDR
(1995)
Agency
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Toxic
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and
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Toxicological
profile
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xylene
(update).
ATSDR,
Chamblee,
GA.
270pp.

Bergman,
R.
1983.
Application
and
results
of
whole­
body
autoradiography
in
distribution
studies
of
organic
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CRC
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Rev.
Toxicol.
12:
59­
1
18.
XYLENES
Proposed
1:
5/
2002
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Bio/
dynamics
Inc.
1983.
Parental
and
fetal
reproduction
toxicity
study
in
rats
with
mixed
xylene.
EPA/
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16­
24.

Seppalainen,
A.
M.,
Salmi,
T.,
Savolainen,
K.,
and
Riihimaki,
V.
1983.
Visual
evoked
potentials
in
short­
term
exposure
of
human
subjects
to
m­
xylene
andl,
1
,
1­
trichloroethane.
Appl.
Behav.
Pharmacol.
Toxicol.
349­
352.

Sevcik,
P.,
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A.,
and
Peslova,
M.
1992.
Intravenous
xylene
poisoning.
Intensive
Care
Med.
18:
377­
378.

Siemiatycki,
J.,
ed.
1991.
Risk
Factors
for
Cancer
in
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Workplace.
Boca
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FL
(USA):
CRC
Press:
1­
325
(as
cited
in
Lynge
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al.,
19971.

Smyth,
H.
F.,
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C.
P.,
Weil,
C.
S.,
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C.,
and
Striegel,
J.
A.
1962.
Range­
finding
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data:
List
VI.
h
e
r
,
Indust.
Hyg.
Assoc.
J.
23:
95­
107.

Spirtas,
R.,
Stewart,
P.
A.,
Lee,
J.
S.,
Marano,
D.
E.,
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C.
D.,
Grauman,
D.
J.,
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H.
M.,
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A.,
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R.
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and
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J.
L.
1991.
Retrospective
cohort
mortality
study
of
workers
at
an
aircraft
maintenance
facility.
I
Epidemiological
results.
Br.
J.
Ind.
Med.
48:
515­
530.

Stevens,
W.
C.,
Dolan,
W.
M.,
Gibbons,
R.
T.,
White,
A.,
Eger,
E.
I.,
Miller,
R.,
deJong,
R.
H.,
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R.
M.
1975,
Minimum
alveolar
concentration
(MAC)
of
isoflurane
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and
without
nitrous
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in
patients
of
various
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Anesthesiology.
42:
196­
200.

Tahti,
H.
1992.
The
neurotoxicity
of
organic
solvents,
studied
with
in
vitro
models.
Altern.
Lab.
Anim.
20:
290­
296.
XYLENES
Proposed
1:
5/
2002
1
2
3
4
5
6
7
8
9
18
I1
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Tardif,
R.,
Lapare,
S.,
Charest­
Tardif,
G.,
Brodeur,
J.,
and
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K.
1995.
Physiologically­
based
pharmacokinetic
modeling
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mixture
of
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fisk.
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15:
335­
342.

Tardif,
R.,
kapare,
S
.,
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K.,
and
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J.
1993.
Physiologically
based
modelling
on
the
toxicokinetic
interaction
between
toluene
and
m­
xylene
in
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Toxicol.
Appl.
PharmacoP.
120:
266­
273.

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H.,
Anttila,
A.,
Lindbohm,
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L.,
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K.
1989.
Spontaneous
abortions
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congenital
malformations
among
the
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of
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exposed
to
organic
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Scand.
J.
Work
Environ.
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352.

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M.,
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and
Lindbohm,
M.­
J.
1994.
Laboratory
work
and
pregnancy
outcome.
J.
Occup.
Med.
36:
31
1­
319.

Tardif,
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J.,
and
Plaa,
G.
L.
1989.
Simultaneous
high­
performance
liquid
chromatographic
analysis
of
hippuric
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meta­,
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methylhippuric
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316.

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E.,
and
Ungvary,
G.
1980.
Changes
induced
by
o­
xylene
inhalation
in
the
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Acta
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216.

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V.
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1.
The
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term
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xylene
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ten
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1986.
Concentration­
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1990.
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1984.
Effect
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9
10
11
12
13
14
XYLENES
Proposed
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5/
2002
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G.,
Varga,
B.,
Horvath,
E.,
Tatrai,
E.,
and
Folly,
G.
1981.
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o
~c
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1997,
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1983.
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P
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237.

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1984.
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81
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L.,
Jr.,
and
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S.
N.
1987.
Effect
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of
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stimulation
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Neuropharmacology.
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1632.

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G.
C.,
Shusterman,
D.,
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H.,
Fenster,
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B.
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Exposure
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organic
solvents
and
adverse
pregnancy
outcome.
Am.
J.
Ind.
Med.
20:
241­
259.
1
XYLENES
.

APPENDIX
A:
Rerivation
of
AEGL
Values
58
6J
XYLENES
Proposed
I:
5/
2QQi!

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Key
study:

Toxicity
endpoint:

Scaling:

Uncertainty
factors:
Derivation
sf
AEGL­
1
Hastings
et
al.,
1986
Eye
irritation
in
human
volunteers
exposed
to
400
ppm
mixed
xylenes
for
30
minutes
Data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity.
Therefore,
the
MGL
2­
values
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
1
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes.

1
for
interspecies
variability
3
for
intraspecies
variability
Modif)­
ing
factor:
Not
applicable
10­
minute,
3
0­
minute,

1­
hour.
4­
hour,
8­
hour
AEGL­
1:
Concentration
producing
effect
applied
to
all
times:
400
ppd3
=
130
ppm
59
XYLENES
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Key
study:

Toxicity
endpoint:

Scaling:

Uncertainty
factors:
Derivation
of'
AEGL­
2
Carpenter
et
aP.,
197%

Rats
exposed
to
1300
ppm
for
4
hours
exhibited
poor
coordination
Data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity.
Therefore,
the
AEGL­
2
values
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
1
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes
(see
Appendix
B).

1
for
interspecies
variability
3
for
intraspecies
variability
Modifling
factor:
Not
applicable
1
0­
minute,
30­
minute
AEGL­
2:
Concentration
producing
effect
extrapolated
back
to
]I
0­
and
30­
minutes
(see
Appendix
B):
990
and
480
ppm,
respectively
1­
hour,
4­
hour,
%hour
AEGL­
2:
Concentration
producing
effect
applied
to
all
times:
1300
ppd3
=
430
ppm
eo
70
XYLENES
Proposed
1:
5/
2002
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Key
study:

Toxicity
endpoint:

Scaling:

Uncertainty
factors:
Derivation
of
AEGL­
3
Carpenter
et
al.,
1975b
Rats
exposed
to
2800
ppm
for
4
hours
exhibited
prostration
followed
by
full
recovery
Data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity.
Therefore,
the
AEGL­
3
values
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
1
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes
(see
Appendix
B).

1
for
interspecies
variability
3
for
intraspecies
variability
Modifying
factor:
Not
applicable
10­
minute,
30­
minute
AEGL­
3
:
Concentration
producing
effect
extrapolated
back
to
10­
and
30­
minutes
(see
Appendix
B):
2100
and
1000
ppm,
respectively
1­
hour,
4­
hour.
8­
hour
AEGL­
3:
Concentration
producing
effect
applied
to
all
times:
2800
ppd3
=
930
ppm
61
71
XYLENES
1
Proposed
1:
5/
2002
APPENDIX
B:
Time­
Scaling
Calculations
XYLENES
Proposed
1:
5/
2002
conc
(mmoVL)

10
min
B
65
(mean)
55
(­
2
SD)
50
(­
3
SD)

1165
ppm
985
ppm
896
ppm
2
3
4
5
6
a
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Derivation
of
AEGL­
2
(10
minutes
and
30
minutes)

Because
the
key
study
for
the
AEGL­
2
derivation
is
a
study
with
a
4­
hour
exposure
duration,
extrapolation
to
shorter
time
periods
was
necessary.
It
was
decided
to
use
a
toxicokinetic
approach
to
calculate
AEGL­
2
values
for
10
minutes
and
for
30
minutes.

The
following
assumptions
were
made:

(i)
the
toxicological
endpoint
and
the
intensity
of
toxicological
effect
should
be
the
same
as
(ii)
it
is
the
concentration
and
not
the
amount
of
the
substance
(AUC)
which
is
responsible
for
(iii)
the
data
from
kinetic
studies
in
human
volunteers
(see
Table
11,
page
37)
are
appropriate
(iv)
the
data
of
m­
xylene
were
used
to
represent
the
mixture
of
all
xylenes
(v)
the
kinetics
of
m­
xylene
are
linear
in
the
concentratioddose
range
which
is
under
observed
after
administration
of
430
ppm
for
4
hours
the
effect,
qualitatively
and
quantitatively
for
hrther
kinetic
calculations
consideration.

Calculations:
The
data
of
three
studies
were
used.
The
external
concentration
in
the
air
multiplied
by
inhalation
volume
and
frequency
was
used
as
input
rate.
A
one­
compartment
body
model
described
the
data
appropriately.
The
calculations
were
done
using
NONMEM
program.
After
the
concentration
at
4
hours
was
calculated,
the
input
rate
to
reach
this
concentration
with
10
minutes
and
30
minutes,
respectively,
was
estimated.
As
we
assumed
inhalation
volume
and
frequency
being
constant,
the
external
air
concentration
was
obtained
by
eliminating
the
constant.
\

The
outcome
of
the
calculations
was
as
follows:
k
which
is
the
first
order
elimination
constant
was
2.74/
hour;
the
corresponding
half
life
is
0.25
hours.
The
concentration
at
4
hours
was
6.5
f
10
mmol/
L
(mean
f
2
SD)
for
430
ppm.
The
external
air
concentration
to
reach
this
concentration
within
10
minutes
is
1165
f180
ppm
(mean
f
2
SD)
and
within
30
minutes
is
570f87.5
(meanf2
SD).

Calculating
the
lower
boundary
value
for
2
SD
results
in
10
min:
985
ppm
30
min:
482.5
ppm
Calculating
the
lower
boundary
value
for
3
SD
results
in
10
min:
896
ppm
30
min:
438.4
pprn
30
min
1
570
ppm
I
483
ppm
1
438
ppm
I(

Please
see
Figure.
XYLENES
Proposed
8
:
5/
208)
2
­~
B
2
3
4
5
6
a
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Derivation
of
AEGL­
3
(10
minutes
and
30
minutes)

Because
the
key
study
was
a
study
with
a
4­
hour
exposure
duration,
extrapolation
to
shorter
time
periods
was
necessary.
It
was
decided
to
use
a
toxicokinetic
approach
to
calculate
AEGL­
3
values
for
10
and
for
30
minutes.

The
following
assumptions
were
made:

(i)
the
toxicological
endpoint
and
the
intensity
of
toxicological
effect
should
be
the
same
as
(ii)
it
is
the
concentration
and
not
the
amount
of
the
substance
(AUC)
which
is
responsible
for
(iii)
the
data
from
kinetic
studies
in
human
volunteers
(see
Table
11,
page
37)
are
appropriate
(iv)
the
data
of
m­
xylene
were
used
to
represent
the
mixture
of
all
xylenes
(v)
the
kinetics
of
m­
xylene
are
linear
in
the
concentratioddose
range
which
is
under
observed
after
administration
of
930
ppm
for
4
hours
the
effect,
qualitatively
and
quantitatively
for
fbrther
kinetic
calculations
consideration.

Calculations:
The
data
of
three
studies
were
used.
The
external
concentration
in
the
air
multiplied
by
inhalation
volume
and
frequency
was
used
as
input
rate.
A
one­
compartment
body
model
described
the
data
appropriately.
The
calculations
were
done
using
NONMEM
program.
After
the
concentration
at
4
hours
was
calculated,
the
input
rate
to
reach
this
concentration
within
10
minutes
and
30
minutes,
respectively,
was
estimated.
As
we
assumed
inhalation
volume
and
frequency
being
constant,
the
external
air
concentration
was
obtained
by
eliminating
the
constant.

The
outcome
of
the
calculations
was
as
follows:
k
which
is
the
first
order
elimination
constant
was
2.74/
hour;
corresponding
half
life
is
0.25hours.
The
concentration
at
4
hours.
was
141
f
25
mmol/
L
(mean
i
2
SD)
for
930
ppm.
The
external
air
concentrations
to
reach
this
concentration
within
10
minutes
is
2526
f
455
gpm
(mean
f
2SD)
and
within
30
minutes
is
1237
f
221
ppm
(mean
f
2
SD).

Calculating
the
lower
boundary
value
for
2
SD
results
in
10
min:
2071
ppm
30
min.
1016
ppm
Calculating
the
lower
boundary
value
for
3
SD
results
in
10
min:
1790
ppm
30
min:
963
ppm
!I
11
conc
(mmol/
L)
141
(mean)
I
116
(­
2
SD)
103.5
(­
3
SD)

30
min
1237
ppm
I1016ppm
I
963
ppm
1
Please
see
Figure.
XYLENES
*'
.
i
*

I
"i
­

Concentration­
time
prediction
upper:
930ppm
lower:
43Oppm
Proposed
1:
512002
0
50
100
150
2M)
250
300
time
[min]
XYLENES
1
Proposed
I:
5/
2002
APPENDIX
C:
Derivation
Summary
for
Xylene
AEGLs
XYLENES
Proposed
1:
512002
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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22
23
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ACUTE
EXPOSURE
GUIDELINES
FOR
XYLENES
CAS
Reg.
No.
1330­
20­
7
DERIVATION
SUMMARY
AEGL­
1
VALUES
10
minutes
I
30minutes
I
1
hour
I]
ibhouss
1
$hours
I
I
130
ppm
130
ppm
130
ppm
130
ppm
130
ppm
Key
Reference:
Hastings,
L.,
Cooper,
G.
P.,
and
Burg,
W.
1986.
Human
sensory
response
to
selected
petroleum
hydrocarbons.
In:
MacFarland,
H.
N.
ed.
Advances
in
Modern
Environmental
Toxicology.
Vol.
VI.
Applied
Toxicology
of
Petroleum
Hydrocarbons.
Princeton,
NJ:
Princeton
Scientific
Publishers,
pp.
255­
270.

Test
Swcies/
Strain/
Number:
Volunteer
human
&le
Exposure
Route/
ConcentrationsDurations:
Subjects
were
exposed
by
inhalation
via
an
olfactometer
delivery
hood
to
0,
100,200,
or
400
ppm
mixed
xylene
for
30
minutes
Effects:
Mild
eye
irritation
reported
by
56,
60,70,
and
90%
of
subjects
exposed
to
0,
100,200,
or
400
ppm
EndpoinlfConcentratiodRationale:
Mild
eye
irritation
was
noted
by
90%
of
the
subjects
exposed
to
400
ppm
Uncertainty
Factors/
Rationale:
Total
uncertainty
factor:
3
mixed
xylene,
respectively;
no
effects
observed
on
behavioral
test
results
Interspecies:
1
­
human
data
used
Intraspecies:
3
­
the
toxic
effect
(slight
irritation)
was
less
severe
than
that
defined
for
the
AEGL­
1
tier
(notable
discomfort).

Modifylng
Factor:
NA
(1)

Animal
to
Human
Dosimetric
Adjustment:
NA
­
human
data
used
Time
Scaling:
Irritation
is
considered
a
threshold
effect
and
therefore
should
not
vary
over
time.
The
AEGL­
1
value
based
on
irritation
is
therefore
not
scaled
across
time,
but
rather
the
threshold
value
is
applied
to
all
times.

been
reported.
However,
the
data
are
consistent
with
other
human
studies,
and
represent
a
value
consistent
with
exposure
concentrations
that
might
result
in
mild
eye
irritation.
Data
Adequacy:
This
was
an
acceptable
study,
but
could
have
been
improved
had
the
number
of
volunteers
67
77
XYLENES
Proposed
1:
5/
2002
I
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
AEGL­
2
VALUES
18
minutes
30
minutes
1
hour
4
hours
8
hours
990
ppm
480
ppm
430
ppm
438
ppm
430
ppm
Key
Reference:
Carpenter,
C.
P.,
Kinkead,
E.
R.,
Geary,
D.
L.
Jr.,
Sullivan,
L.
J.,
and
King,
J.
M.
1975.
Petroleum
hydrocarbon
toxicity
studies.
V.
Animal
and
human
response
to
vapors
of
mixed
xylene.
Toxicol.
Appl.
Pharmacol.
33:
543­
58.

Test
SpeciesIStrainlNumber:
10
male
albino
rats
(Harlan­
Wistar
strain)
approximately
5
weeks
old/
group
Exposure
Route/
Concentrations/
Durations:
Rats
were
exposed
by
inhalation
to
580,
1300,2800,4000,
or
9000
ppm
mixed
xylene
for
4
hours
Effects:
Conc.(
mm)
Mortalitv
Other
effects
580
0110
none
observed
1300
0110
poor
coordination
after
2
hours,
returned
to
normal
2800
6000
9900
10110
none
stated
0/
10
4110
irritation;
all
rats
prostrate
between
2­
3.5
hours
recovered
within
1
hr,
coordination
returned
to
normal
next
day
rats
prostrate
within
30
minutes;
all
survivors
prostrate
but
recovered
promptly
EndpointEoncentrationIRationale:
Exposure
to
1300
ppm
for
4
hours
resulted
in
poor
coordination
Uncertainty
Factorsktionale:
Total
uncertainty
factor:
3
Interspecies:
1
­
An
interspecies
uncertainty
factor
of
1
was
applied
because
rats
receive
a
greater
systemic
Intraspecies:
3
­
The
MAC
(minimum
alveolar
concentration)
for
volatile
anesthetics
should
not
vary
by
dose
of
inhaled
xylene
as
compared
to
humans.

more
than
a
factor
of
2­
3­
fold
among
humans.
A
3­
fold
factor
is
also
adequate
to
account
for
moderate
physical
activity
during
exposure,
which
would
result
in
greater
uptake
of
the
chemical.

Modifying
Factor:
NA
(1)

Animal
to
Human
Dosimetric
Adjustment:
NA
Time
Scaling:
Data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity.
Therefore,
the
AEGL­
2
values
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
1
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes.

Data
Adequacy:
This
was
a
well­
designed
and
conducted
study.
The
data
are
supported
by
numerous
other
studies
in
rats,
as
well
as
a
study
in
dogs.
The
AEGL­
2
levels
are
protective
of
human
health,
especially
when
considering
numerous
human
studies
investigated
the
effects
of
exposure
to
200
ppm
xylene
with
20­
minute
peak
exposures
to
400
ppm,
in
some
cases
additionally
combining
peak
exposures
with
physical
exercise
resulting
in
greater
uptake
of
the
chemical,
and
found
only
minimal
central
nervous
system
effects.
XYLENES
Proposed
1:
5/
2002
,1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
AEGL­
3
VALUES
Key
Reference:
Carpenter,
C.
P.,
Kinkead,
E.
R.,
Geary,
D.
L.
Jr.,
Sullivan,
L.
J.,
and
King,
J.
M.
1975.
Petroleum
hydrocarbon
toxicity
studies.
V.
Animal
and
human
response
to
vapors
of
mixed
xylene.
Toxicol.
Appl.
Pharmacol.
33:
543­
58.

Test
Species/
Strain/
Number:
10
male
albino
rats
(Harlan­
Wistar
strain)
approximately
5
weeks
oldgroup
Exposure
Route/
Concentrations/
Durations:
Rats
were
exposed
by
inhalation
to
580,
1300,
2800,4000,
or
9000
gpm
mixed
xylene
for
4
hours
Effects:
Conc.(
mm)
Mortality
Other
effects
580
0/
10
none
observed
1300
0/
10
poor
coordination
after
2
hours,
returned
to
normal
2800
6000
9900
10/
10
none
stated
040
4/
10
irritation;
all
rats
prostrate
between
2­
3.5
hours
recovered
within
1
hr,
coordination
returned
to
normal
next
day
rats
prostrate
within
30
minutes;
all
survivors
prostrate
but
recovered
promptly
EndpointKoncentratiodRationale:
Exposure
to
2800
ppm
for
4
hours
resulted
in
prostration
followed
by
full
recoverv
~­

Uncertainty
Factors/
Rationale:
~o
t
a
l
incertainty
factor:
3
Interspecies:
1
­
An
interspecies
uncertainty
factor
of
1
was
applied
because
rats
receive
a
greater
systemic
dose
of
inhaled
xylene
as
compared
to
humans.
Intraspecies:
3
­
The
MAC
(minimum
alveolar
concentration)
for
volatile
anesthetics
should
not
vary
by
more
than
a
factor
of
2­
3­
fold
among
humans.
A
3­
fold
factor
is
also
adequate
to
account
for
moderate
physical
activity
during
exposure,
which
would
result
in
greater
uptake
of
the
chemical.

Modifying
Factor:
NA
(1)

Animal
to
Human
Dosimetric
Adjustment:
NA
Time
Scaling:
Data
indicate
that
once
steady
state
is
reached,
concentration,
not
duration,
is
the
prime
determinant
in
xylene­
induced
central
nervous
system
toxicity.
Therefore,
the
AECGL­
3
values
are
set
equal
across
time
once
steady
state
is
approached
(starting
at
approximately
1
hour),
while
pharmacokinetic
modeling
was
used
to
extrapolate
to
exposure
durations
of
10­
and
30­
minutes.

Data
Adequacy:
This
was
a
well­
conducted
study.
The
AEGL­
3
levels
are
supported
by
human
data
demonstrating
that
exposure
to
690
ppm
for
15
minutes
resulted
in
lightheadednesddizziness
and
a
30
minute
exposure
to
700
ppm
resulted
in
nausea,
vomiting,
dizziness
or
vertigo.

69
79
