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Xylenes
Inhalation Health Effect Reference Values for Xylene - All Isomers
(CASRNs: Mixed Isomers - 1330-20-7; m-Xylene - 95-47-6; 0-Xylene -
108-38-3; p-X ylene - 106-42-3)
The reader is strongly encouraged to read Section 1 of the following report for critical
background information regarding the health effect reference values discussed in this summary:
Graphical Arrays of Chemical-Specific Health Effect Reference Values for Inhalation Exposures
[FinalReport] (U.S. EPA. 2009). This report is available on-line at
http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=211003.
In general, inhalation health effect reference values have been included which have been
developed and formally reviewed by an authoritative governing body (government agency or
professional association) for use in assessments of risk to support regulatory decision-making.
This is a review of existing reference values, including the basis for each of the reference values
as provided in the available technical support documents for those values, along with some basic
contextual references; this is not a comprehensive review of the health effects literature for
xylene.
Background
Xylene (CeHz^CHa^); MW = 106.17) can occur as one of three isomers: ortho - 1,2-
dimethylbenzene or o-xylene; meta - 1,3-dimethylbenzene or w-xylene; and para -
1,4-dimethylbenzene or /^-xylene. Synonyms for mixed xylenes include dimethylbenzene,
methyltoluene, and xylol. Commercial grade xylene is most often a mixture of isomers, which is
predominantly w-xylene (up to 60%) with approximately equal levels of o- and /^-xylene (-20%
each); technical grade xylene also contains ethylbenzene between 6% and 15%. Xylene is a
colorless, non-corrosive, flammable liquid with an aromatic odor similar to that of benzene
(Henderson. 2001). The odor threshold for xylene ranges from 0.09 to 0.4 ppm, and is
noticeably irritating for very short durations at 750 ppm.
Production and Uses
Xylene is one of the BTEX aromatics (benzene, toluene, ethylbenzene, and xylene).
Global production of xylene in 2010 was nearly 44 million metric tons (SRI. 2011). Mixed
xylene is used as a solvent for cleaning and in paints and coatings, and is blended into gasoline.
Specific isomers are used as a feedstock in chemical manufacturing with a diverse array of final
products associated with each isomer.
Exposure Potential
Xylene is typically detected in ambient air, and can also be found in groundwater and
food (ATSDR. 2007). Ambient air concentrations in the United States have been reported to
3 3
average 0.18 ppb (0.78 |ig/m ) in remote rural areas and up to 99 ppb (430 |ig/m ) near industrial
facilities and roadways (NLM. 1998). The Toxic Release Inventory (TRI) for the 2010 reporting
year (U.S. EPA. 2010) reported a total of 12,871,595 pounds of xylene were emitted to air from
all industrial sources in the United States, with 8,344,898 pounds emitted from point sources
(stacks, vents, ducts, or pipes) and 4,526,697 pounds coming from fugitive sources (equipment
leaks, evaporative losses from surface impoundments and spills, and releases from building
ventilation systems).
Overview
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Xylenes
Xylene can be absorbed into the human body via inhalation, ingestion, or dermal. There
are more similarities between the isomers than differences on key issues, including: toxic
potency; physical characteristics; toxicokinetics (how it behaves once absorbed); and
toxicodynamics (how the body handles it). Each of the reference values discussed in this
summary handles the individual isomers and any mixture of isomers as the same compound.
Potential Health Effects
Acute inhalation exposure to mixed xylenes in humans has been associated with
shortness of breath, and irritation of the nose and throat; gastrointestinal effects (e.g., nausea,
vomiting, and gastric discomfort); mild transient eye irritation; and neurological effects (e.g.,
impaired short-term memory, impaired reaction time, decreases in numerical ability, and
alterations in equilibrium and body balance) (ATSDR. 2007). Exposure to a mixture of toluene
and xylenes resulted in more than additive respiratory and neurological toxicity in humans and
animals. Acute animal studies have also reported cardiovascular, liver, and kidney effects from
inhalation exposure to mixed xylenes in addition to the effects previously noted.
Chronic inhalation exposures to xylenes in worker cohorts have primarily shown
neurological effects such as headache, dizziness, fatigue, tremors, incoordination, anxiety,
impaired short-term memory, and inability to concentrate (ATSDR. 2007). Other effects
reported from chronic exposure include labored breathing, impaired pulmonary function,
increased heart palpitation, severe chest pain, abnormal EKG, and possible effects on the
kidneys. Mixed xylenes have not been extensively tested for chronic effects, although animal
studies show effects on the liver and CNS from inhalation and oral exposures and effects on the
kidneys from oral exposure to mixed xylenes.
Cancer Potential
The U.S. EPA (2003) found that "data are inadequate for an assessment of the
carcinogenic potential of xylenes " Similarly, IARC (1999) assessed the cancer potential and
found that "Xylenes are not classifiable as to their carcinogenicity to humans (Group 3). "
Therefore, no reference values for cancer (e.g., cancer slope factors) are available for xylene.
Emergency Response Values
The emergency response reference values for xylene are limited to the Acute Exposure
Guideline Levels (AEGLs); no Emergency Response and Planning Guideline (ERPG) values
have been developed for xylene. Interim AEGL values for xylene were developed for all three
severity levels (1 = mild, transient effects; 2 = irreversible effects or impeding ability to escape;
and 3 = threshold for life threatening effects). The Protective Action Criteria developed by the
U.S. Department of Energy adopts the AEGL (or ERPG) values when available for the three
severity levels defined by the AEGLs, and also includes a Temporary Emergency Exposure
Level (TEEL) value for a zero (0) severity level, which is defined as "the threshold
concentration below which most people will experience no adverse health effects. "
Occupational Exposure Limits
The occupational values for xylene show a very high level of concordance. All of the
values based on a time-weighted average (TWA) for daily exposures (up to 10 hours per day,
and 5 days a week) for a working career (up to 40 years) were set at 100 ppm, which include the
OSHA PEL, NIOSH REL, and the ACGIH TLV®. Similarly, both of the short-term exposure
limits (STELs) for exposures less than 15 minutes developed by NIOSH and ACGIH were
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established at 150 ppm. All of the occupational values for xylene were based on irritation and a
concern for neurotoxicity in the form of narcosis. In addition to the TWA and STEL values,
NIOSH has also developed an Immediately Dangerous to Life and Health (IDLH) value of 900
ppm for a 30 minute exposure.
Special Use Occupational Values
In addition to the standard occupational values, a set of special use occupational values
are also available which have been developed by and/or reviewed by the National Research
Council (NRC): Spacecraft Maximum Acceptable Concentrations (SMACs) for durations of 1
and 24 hours, and 7, 30, 180, and 1000 days; and values derived for submarine crews - the
Emergency Exposure Guideline Levels (EEGLs) for 1 and 24 hours, and the Continuous
Exposure Guideline Levels (CEGL) for 90 days. The EEGL values (150 ppm for 1-hour and 100
ppm for 24-hours) are fairly consistent with the AEGL-1 and traditional occupational TWA
values. Largely due to the confined working environment with no opportunity to be removed
from exposure, however, the CEGL value of 50 ppm is lower than the 100 ppm occupational
TWA values. Similarly, all of the SMACs are lower than other occupational reference values for
similar durations, including the EEGLs. The SMACs for durations of 7-days or longer were
based on concerns for potential narcosis and neurotoxic effects, including hearing loss
(ototoxicity) for the 180 and 1000 day values.
General Public Values (Routine Non-emergency Exposures)
Several reference values have been developed for exposures of the general public to
xylene. The California Reference Exposure Levels (CA-RELs) were developed by the Office of
Environmental Health Hazard Assessment (OEHHA 2008. 2000) for both acute (1-hour, 22
mg/m3 or 5 ppm) and chronic (0.7 mg/m3 or 0.2 ppm) durations. Minimal Risk Levels (MRLs)
were developed by the Agency for Toxic Substances and Disease Registry (ATSDR 2007) for
acute (1-14 days,), intermediate (15-365 days), and chronic (>1 year) durations. A Reference
Concentration (RfC) value of 0.1 mg/m (0.02 ppm) was developed by the U.S. Environmental
Protection Agency (U.S. EPA 2003) for the Integrated Risk Information System (IRIS).
Both of the acute values (CA-REL and MRL) use the exposure level of 50 ppm as the
point-of-departure (POD). The 50 ppm POD for the acute 1-hour CA-REL was the result of an
adjustment to the 100 ppm NOAEL for a 30-minute exposure observed in the study by Hastings
et al. (1986) using a simple C x t relationship (e.g., Haber's rule), whereas the 50 ppm LOAEL
for a 2-hour exposure in humans from the study by Ernstgard et al. (2002) was not duration-
adjusted for the acute MRL. Regardless, these organizations arrive at very different final values
based on differences in the application of uncertainty factors (UF); a Total UF of 10 was applied
in deriving the CA-REL versus 30 applied in derivation of the acute MRL; details on the
application of UFs are presented in Table 1.
The intermediate MRL was based on a study on neurotoxicity in rats (Korsak et al..
1994). which was also used in the derivation of the RfC; however, there was no duration
adjustment in the derivation of the POD for the MRL (50 ppm), while in the derivation of the
RfC the POD was adjusted to match a continuous exposure scenario. Other differences in the
derivation of the RfC and intermediate MRL values from this study was in the application of
uncertainty factors (UFs): a total UF of 90 was applied in the derivation of the intermediate
MRL, whereas the RfC was calculated with a total UF of 300.
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Xylenes
Likewise, both the chronic CA-REL and chronic MRL were derived based on the same
study (Uchida et al.. 1993) with an observed lowest observed adverse effect level (LOAEL) of
14 ppm for a combination of irritation and neurological effects in workers. The POD for the CA-
REL was based on duration adjustments and a total UF of 10, whereas the chronic MRL made no
duration adjustments but applied a total UF of 300 which included a modifying factor of 3 for
database uncertainty. As noted in Table 1, these differences in derivation lead to final reference
values which diverged considerably from the use of the same observations.
In conclusion, the effects most noted in association with exposure to xylene across all
durations are neurotoxic in nature (narcosis/intoxication, incoordination, headache, ototoxicity,
etc.). Short-duration exposures to elevated concentrations (e.g., > 50 ppm) have been associated
with irritation of the eyes and upper respiratory system. At higher exposure levels, changes in
body weight, liver morphology, liver weight, and enzymatic functions have all been noted (U.S.
EPA. 2003). In addition, gestational exposure of animals to xylenes has resulted in
neurodevelopmental and other possible developmental effects, but only at levels above those at
which neurobehavioral effects in adult rats were reported. Finally, no reproductive effects have
been reported in a one-generation reproductive/developmental study of male and female rats
exposed to 500 ppm xylenes or in male rats exposed to 1000 ppm (U.S. EPA 2003).
Summary
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Xylene (mixed isomers): Comparison of Reference Values
June 2011
1.E+05
1.E+04 v O
CO
£
o>
E
6
c
o
o
»
X
ACGIH-STEL'
1 E+03 --NI0SH-STEL
1.E+02 -
1.E+01 -
1.E+00 -
1.E-01 -
1.E-02
'TEEL-0
o SMAC
X
CA-REL (Acute)
O CEGL*
O SMAC* O SMAC*<> SMAC*
+ SMAC*
ATSDR-MRL (1-14 d)
I
~ SM/ C*
ATSDR-MRL (15-365d)
*-
I
-X
CA-REL (Chronic)
X X
ATSDR-MRL (>1yr)
™
tttH
EPA/IRIS RfC
H-
—AEGL-3
O AEGL-2
^^AEGL-1
O TEEL-0
O ACGIH-STEL*
• NIOSH-STEL*
• NIOSHIDLH*
- O OSHA-PEL (TWA)*
-O ACGIH-TLV (TWA)*
O NIOSH-REL(TWA)*
• SMAC*
O EEGL*
O CEGL*
X CA-REL (Acute)
-X- ATSDR-MRL(1-14d)
-X- ATSDR-MRL(15-365d)
-X- ATSDR-MRL(> 1yr)
—X— CA-REL (Chronic)
—¦— EPA/IRIS RfC
0.1
10
-100^. ..1000 . 10000
Duration (hours)
100000 1000000
O Cl
05
Q.
D
O
O
O
o
n
D
Q_
TO
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Table 1. Details on derivation of the available health effect reference values for inhalation exposure to xylenes
Reference
Reference Value
Point of
Principal
Uncertainty
Notes on
Review
Value Name
Duration
(mg/m3)
(ppm)
Health Effect
Departure
Qualifier
Study
Factors2
Derivation
Status
AEGL-3
10 minutes
30 minutes
1 hour
4 hours
8 hours
>LEL5o%
16,000
11,000
5,600
4,300
^ELsoo,3
3600
2500
1300
1000
Rats
exhibited
prostration
followed by full
recovery
2800 ppm
(4 hours,
used in
PBPK
model)
NOAEL
for
Lethality
Carpenter
etal. (1975)
Total UF = 3
UFH=3
UFa=1
A human
PBPK model
was run for
each time
period to
determine the
exposure
producing the
target internal
Final
(NRC, 2010)
4>
AEGL-2
10 minutes
30 minutes
1 hour
11,000
5,600
4,000
2500
1300
920
Rats
exhibited
poor coordination
2 h into a 4-h
exposure
1300 ppm
(2 hours,
used in
PBPK
model)
LOAEL
Carpenter
etal. (1975)
Total UF = 3
UFh=3
UFa=1
dose
=
©
4 hours
2,200
500
a
VI
8 hours
1,700
400
w
=
0)
0/j
•~
E
AEGL-1
10 minutes
30 minutes
1 hour
4 hours
8 hours
560
560
560
560
560
130
130
130
130
130
Eye irritation in
human volunteers
exposed to mixed
xylenes
400 ppm
(30 minutes)
LOAEL
Hastings et
al. (1986)
Total UF = 3
UFh=3
UFa=1
No duration
scaling due to
irritant effects
TEEL-0
1 hour
400
100
NR
NR
NR
NR
NR
(DOE, 2008)
Revision 26
(DOE. 2010)
2 UFh - inter-human variability; UFA - animal to human variability; UFL - LOAEL to NOAEL adjustment; UFS - subchronic to chronic adjustment;
UFdb - database uncertainty
3 LEL = Lower Explosive Limit. The AEGL-3 for 10 minutes = 7,200 ppm which is greater than 50% of the lower explosive limit for xylene.
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Xylenes
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Reference
Reference Value
Point of
Principal
Uncertainty
Notes on
Review
Value Name
Duration
(mg/m3)
(PPm)
Health Effect
Departure
Qualifier
Study
Factors2
Derivation
Status
OSHA PEL
8 hour TWA
435
100
Irritant, narcotic,
NR
NR
NR
NR
NR
Final
(TWA)
and chronic effects
(NIOSH. 2007)
NIOSH STEL
<10 minutes
655
150
Irritation and
narcotic effects,
Various
NA
NIOSH
(1975)
NA
WOE Approach
Final
(NIOSH, 2007)
NIOSHREL
(TWA)
10 hour
TWA
435
100
with potential for
chronic effects
Various
NA
NIOSH IDLH
30 minutes
3710
900
Acute inhalation
toxicity data in
animals
Various
Effects
levels
Various4
NA
ACGIH
<15 minutes
651
150
Potential for eye
200 ppm
TOAET
Carpenter et
NA
WOE Approach
Final
TLV-STEL
and upper
respiratory
irritation; also
protective for
narcosis
(Human)
al. (1975)
(ACGIH,
2007)
ACGIH
8 hour TWA
434
100
100 ppm
NOAET
Nelson et al.
TLV-TWA
(Human)
(1943)
EEGLs
1 hour
870
200
Eye irritation
200 ppm
Various
Various^
None
WOE Approach
Final
(NRC. 2008a)
24 hour
435
100
Eye irritation
100 ppm
NOAET
Hake et al.
(repeated)
(1981)
=
©
CEGL
90 days
217
50
Eye and throat
50 ppm
NOAET
Various"
a
3
irritation
SMACs
1 hour
217
50
Eye, nose, and
throat irritation and
headache
50 ppm
(2 hours)
TOAET
Emstgard et
al. (2002)
None
Not adjusted,
concentration
dependent
Final
(NRC, 2008b)
w
w
o
24 hour
74
17
Total UP = 3
UFl=3
7 day and
74
17
Neurotoxicity
50 ppm
NOAET
Korsak et al.
Total UP = 3
No time
30 day
(motor function)
(3 months)
(rat)
(1994)
UFa=3
adjustment
180 day
37
8.5
Ototoxicity
250 ppm
1000 ppm
(Rat, 18 h/d,
61 days)
TOAETadj
TOAET
(rat)
Nylen and
Hagman
(1994)
Total UF = 30
UFl= 10
UFa=3
Duration
adjusted using
C x t (Haber's)
1000 days
6.5
1.5
8.5 ppm
180 d
SMAC
180 d SMAC
adjusted to
1000 d
4 (DeCeaurriz et al.. 1981: Harper et al.. 1975: Cameronet al.. 1942)
5 (Hastings et al.. 1986: Hake et al.. 1981: Carpenter et al.. 1975)
6 (Ungvarv. 1990: Carpenter et al.. 1975: Jenkins et al.. 1970)
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Reference
Reference Value
Point of
Principal
Uncertainty
Notes on
Review
Value Name
Duration
(mg/m3)
(ppm)
Health Effect
Departure
Qualifier
Study
Factors2
Derivation
Status
Acute
CA-REL
(Mild Effects)
1 hour
22
5
Subjective reports
of eye, nose, and
throat irritation (50
healthy human
volunteers)
50 ppm
100 ppm
NOAELadj
NOAEL
(30-min)
Hastings et al.
(1986)
Total UF = 10
UFh= io
Duration
extrapolation
via Cn x t
(n = 1) from 30-
min to 1 hr
Final
COEHHA.
2008)
Acute ATSDR
1-14 days
8.7
2.0
Discomfort in the
50 ppm
LOAEL
Emstgard et
Total UF = 30
Final
MRL
eyes and nose,
detection of solvent
smell, and feeling of
intoxication
(human
volunteers,
2 hours)
al. (2002)
ufh= io
UFl = 3
(ATSDR.
2007)
Intermediate
15-365 days
2.6
0.6
Dose-related
50 ppm
LOAEL
Korsak et al.
Total UF = 90
ATSDR MRL
increase in the
failure rate of rats
on the rotarod
performance test
(1994)
UFa=3
ufh= io
UFL =3
Chronic
Chronic
0.7
0.2
Eye irritation, sore
5.1 ppm
LOAEL ADJ
Uchida et al.
Total UF = 30
Adjustments:
Final
CA-REL
throat, floating
sensation, and poor
14.2 ppm
LOAEL
(1993)
UFl=3
UFh = 10
occupational
breathing rate
(OEHHA,
2000)
3
s
a.
appetite (175
exposed and 241
control workers)
(Human, 7-yr
avg.)
(10 m3 vs.
20 m3) and
5 days per
week.
«
Chronic
Chronic
0.22
0.05
neurotoxicity
14 ppm
LOAEL
Uchida et al.
Total UF = 300
Not adjusted
Final
e
0
ATSDR MRL
(> 1 year)
(anxiety,
forgetfulness,
floating sensation),
and nasal, throat
and
eye irritation
(Human, 7-yr
avg.)
(1993)
UFh = 10
ufl = 10
MF7 = 3
due to rapid
clearance of
xylene from the
body
(ATSDR,
2007)
Chronic RfC
Chronic
0.1
0.02
Impaired motor
39 mg/m3
LOAEL ADJ
Korsak et al.
Total UF = 300
NOAEL
Final
(IRIS)
coordination
(decreased
rotarod
performance) in a
subchronic
inhalation
study in male rats
217 mg/m3
(50 ppm)
100 ppm
LOAEL
LOAEL
(1994)
UFa=3
UFh = 10
UFl=3
UFdb = 3
adjusted from 6
h/d and 5 d/wk
to continuous
exposure
(24 h/d, 7 d/wk)
(U.S. EPA,
2003)
7 A Modifying Factor was applied to account for the lack of supporting studies evaluating the chronic neurotoxicity of xylene.
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Further Reading
U.S. EPA (U.S. Environmental Protection Agency). Xylenes, Air Toxics Web Site.
http://www.epa.gov/ttn/atw/hlthef/xylenes.html
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xylene [ATSDR Tox Profile], Atlanta, GA: U.S. Department of Health and Human
Services, Public Health Service.
http://www.atsdr.cdc. gov/ToxProfiles/tp.asp?id=296&tid=53
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Bingham; B Cohrssen; CH Powell (Eds.), Patty's toxicology (5 ed., pp. 231-301). New
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I ARC (International Agency for Research on Cancer). (1999). Re-evaluation of some organic
chemicals, hydrazine, and hydrogen peroxide. Lyon, France.
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toluene, o-xylene, and cumene on experimental animals. Toxicol Appl Pharmacol 16:
818-823.
Korsak. Z; Wisniewska-Knypl. J: Swiercz. R. (1994). Toxic effects of subchronic combined
exposure to n-butyl alcohol and m-xylene in rats. Int J Occup Med Environ Health 7:
155-166.
Nelson. KW: Ege. JF. Jr; Ross. M; Woodman. LE; Silverman. L. (1943). Sensory response to
certain industrial solvent vapors. J Ind Hyg Toxicol 25: 282-285.
NIOSH (National Institute for Occupational Safety and Health). (1975). Criteria for a
recommended standard occupational exposure to xylene. (75-168). Washington, DC.
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