EPA/600/R-12/047F4 | August 2012 | www.epa.gr
United States
Environmental Protection
Agency
Inhalation Health Effect Reference
Values for Xylene - All Isomers
(CASRNs Mixed Isomers- 1330-20-7;
m-Xylene - 95-47-6; o-Xylene - 108-38-3;
CASRN 95-47-6
CASRN 108-38-3
o
CASRN 106-42-3
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC
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August 2012
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; /7-Xylene -106-42-3)
Overview
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/recordisplay.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 (CeH/^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
average 0.18 ppb (0.78 |ig/m3) in remote rural areas and up to 99 ppb (430 |ig/m3) 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).
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August 2012
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. A Temporary Emergency Exposure Level (TEEL) value
of 400 mg/m3 for a zero (0) severity level was included in the Revision 26 listing (DOE, 2010),
which is defined as "the threshold concentration below which most people will experience no
adverse health effects "; however, DOE dropped the TEEL-0 level from their tables for all
chemicals in the Revision 27 listing (DOE, 2012), therefore TEEL-0 values are not included in
the table or figure for this summary on xylenes.
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,
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August 2012
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 ACGffl TLV®. Similarly, both of the short-term exposure
limits (STELs) for exposures less than 15 minutes developed by NIOSH and ACGIH were
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 (TDLH) 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/m3 (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
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August 2012
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.
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.
Summary
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).
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Research Triangle Park, NC
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Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 1. Inhalation health effect reference value array for xylene
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Table 1. Details on derivation of the available health effect reference values for inhalation exposure to xylenes
Xylenes
August 2012
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Reference
Value Name
AEGL-3
AEGL-2
AEGL-1
Duration
10 minutes
30 minutes
1 hour
4 hours
8 hours
10 minutes
30 minutes
1 hour
4 hours
8 hours
10 minutes
30 minutes
1 hour
4 hours
8 hours
Reference Value
(mg/m3)
>LEL5o%
16,000
11,000
5,600
4,300
11,000
5,600
4,000
2,200
1,700
560
560
560
560
560
(ppm)
>LEL50%2
3600
2500
1300
1000
2500
1300
920
500
400
130
130
130
130
130
Health Effect
Rats
exhibited
prostration
followed by full
recovery
Rats
exhibited
poor coordination
2 h into a 4-h
exposure
Eye irritation in
human volunteers
exposed to mixed
xylenes
Point of
Departure
2800 ppm
(4 hours,
used in
PBPK
model)
1300 ppm
(2 hours,
used in
PBPK
model)
400 ppm
(30 minutes)
Qualifier
NOAEL
for
Lethality
LOAEL
LOAEL
Principal
Study
Carpenter
etal. (1975)
Carpenter
etal. (1975)
Hastings et
al. (1986)
Uncertainty
Factors1
Total UF = 3
UFH=3
UFA=1
Total UF = 3
UFH=3
UFA=1
Total UF = 3
UFH=3
UFA=1
Notes on
Derivation
A human
PBPK model
was run for
each time
period to
determine the
exposure
producing the
target internal
dose
No duration
scaling due to
irritant effects
Review
Status
Final
(NRC,2010)
1 UFH - inter-human variability; UFA - animal to human variability; UFL - LOAEL to NOAEL adjustment; UFS - subchronic to chronic adjustment;
UFDB - database uncertainty
2 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
August 2012
Occupational
Reference
Value Name
OSHA PEL
(TWA)
NIOSH STEL
NIOSHREL
(TWA)
NIOSH IDLH
ACGffl
TLV-STEL
ACGffl
TLV-TWA
EEGLs
CEGL
SMACs
Duration
8 hour TWA
< 10 minutes
10 hour
TWA
30 minutes
< 1 5 minutes
8 hour TWA
1 hour
24 hour
90 days
1 hour
24 hour
7 day and
30 day
180 day
1000 days
Reference Value
(mg/m3)
435
655
435
3710
651
434
870
435
217
217
74
74
37
6.5
(ppm)
100
150
100
900
150
100
200
100
50
50
17
17
8.5
1.5
Health Effect
Irritant, narcotic,
and chronic effects
Irritation and
narcotic effects,
with potential for
chronic effects
Acute inhalation
toxicity data in
animals
Potential for eye
and upper
respiratory
irritation; also
protective for
narcosis
Eye irritation
Eye irritation
(repeated)
Eye and throat
irritation
Eye, nose, and
throat irritation and
headache
Neurotoxicity
(motor function)
Ototoxicity
Point of
Departure
NR
Various
Various
Various
200 ppm
100 ppm
200 ppm
100 ppm
50 ppm
50 ppm
(2 hours)
50 ppm
(3 months)
250 ppm
1000 ppm
(Rat, 18h/d,
61 days)
8.5 ppm
Qualifier
NR
NA
NA
Effects
levels
LOAEL
(Human)
NOAEL
(Human)
Various
NOAEL
NOAEL
LOAEL
NOAEL
(rat)
LOAELADJ
LOAEL
(rat)
180 d
SMAC
Principal
Study
NR
NIOSH
(1975)
Various3
Carpenter et
al. (1975)
Nelson et al.
(1943)
Various4
Hake et al.
(1981)
Various5
Ernstgard et
al. (2002)
Korsak et al.
(1994)
Nylen and
Hagman
(1994)
Uncertainty
Factors1
NR
NA
NA
NA
None
None
total Ur — 3
UFL=3
Total UF = 3
UFA=3
Total UF = 30
UFL=10
UFA=3
Notes on
Derivation
NR
WOE Approach
WOE Approach
WOE Approach
Not adjusted,
concentration
dependent
No time
adjustment
Duration
adjusted using
C x t (Haber's)
1 80 d SMAC
adjusted to
1000 d
Review
Status
Final
(NIOSH, 2007)
Final
(NIOSH, 2007)
Final
(ACGIH,
2007)
Final
(NRC, 2008a)
Final
(NRC, 2008b)
1 (DeCeaurrizetaL 1981: Harper etal. 1975: Cameron etal.. 1942)
' (Hastings et al.. 1986: Hake etal.. 1981: Carpenter et al.. 1975)
1 (Ungvary. 1990: Carpenter et al.. 1975: Jenkins et al.. 1970)
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Xylenes
August 2012
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Reference
Value Name
Acute
CA-REL
(Mild Effects)
Acute ATSDR
MRL
Intermediate
ATSDR MRL
Chronic
CA-REL
Chronic
ATSDR MRL
Chronic RfC
(TRIS)
Duration
1 hour
1 -14 days
15-365 days
Chronic
Chronic
(> 1 year)
Chronic
Reference Value
(mg/m3)
22
8.7
2.6
0.7
0.22
0.1
(ppm)
5
2.0
0.6
0.2
0.05
0.02
Health Effect
Subjective reports
of eye, nose, and
throat irritation (50
healthy human
volunteers)
Discomfort in the
eyes and nose,
detection of solvent
smell, and feeling of
intoxication
Dose-related
increase in the
failure rate of rats
on the rotarod
performance test
Eye irritation, sore
throat, floating
sensation, and poor
appetite (175
exposed and 241
control workers)
neurotoxicity
(anxiety,
forgetfulness,
floating sensation),
and nasal, throat
and
eye irritation
Impaired motor
coordination
(decreased
rotarod
performance) in a
subchronic
inhalation
study in male rats
Point of
Departure
50 ppm
100 ppm
50 ppm
(human
volunteers,
2 hours)
50 ppm
5.1 ppm
14.2 ppm
(Human, 7-yr
avg.)
14 ppm
(Human, 7-yr
avg.)
39 mg/m3
217 mg/m3
(50 ppm)
100 ppm
Qualifier
NOAELADJ
NOAEL
(30-min)
LOAEL
LOAEL
LOAELAD,
LOAEL
LOAEL
LOAELAD,
LOAEL
LOAEL
Principal
Study
Hastings et al.
(1986)
Ernstgard et
al. (2002)
Korsak et al.
(1994)
Uchida et al.
(1993)
Uchida et al.
(1993)
Korsak et al.
(1994)
Uncertainty
Factors1
Total UF = 10
UFH=10
Total UF = 30
UFH= 10
UFL=3
Total UF = 90
UFA=3
UFH=10
UFL=3
Total UF = 30
UFL=3
UFH= 10
Total UF = 300
UFH=10
UFL=10
MF6 = 3
Total UF = 300
UFA=3
UFH= 10
UFL=3
UFDB = 3
Notes on
Derivation
Duration
extrapolation
via Cn x t
(n=l) from 30-
min to 1 hr
Adjustments:
occupational
breathing rate
(10 m vs.
20 m3) and
5 days per
week.
Not adjusted
due to rapid
clearance of
xylene from the
body
NOAEL
adjusted from 6
h/d and 5 d/wk
to continuous
exposure
(24 h/d, 7 d/wk)
Review
Status
Final
(OEHHA,
2008)
Final
(ATSDR,
2007)
Final
(OEHHA,
2000)
Final
(ATSDR,
2007)
Final
(U.S. EPA,
2003)
' A Modifying Factor was applied to account for the lack of supporting studies evaluating the chronic neurotoxicity of xylene.
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August 2012
Further Reading
U.S. EPA (U.S. Environmental Protection Agency). Xylenes, Air Toxics Web Site.
http://www.epa.gov/ttn/atw/hlthef/xylenes.html
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2007). 2007 TLVs and
BEIs: Based on the documentation of the threshold limit values for chemical substances
and physical agents and biological exposure indices. Cincinnati, OH.
AT SDR (Agency for Toxic Substances and Disease Registry). (2007). Toxicological profile for
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
Cameron, GR: Courtice, FC: Foss, GL. (1942). Effect of exposing different animals to a low
concentration of phosgene 1:1,000,000 4 mg/m3 for 5 hours (third report). In First report
on phosgene poisoning (pp. Chapter IX). (Porton Report No. 2349). Washington, DC:
British Embassy Defense Staff.
Carpenter. CP: Kinkead. ER: Geary. PL. Jr: Sullivan. LJ: King. JM. (1975). Petroleum
hydrocarbon toxicity studies V Animal and human response to vapors of mixed xylenes.
Toxicol Appl Pharmacol 33: 543-558.
DeCeaurriz, JC: Micillino, JC: Bonnet P; Guenier, JP. (1981). Sensory irritation caused by
various industrial airborne chemicals. Toxicol Lett 9: 137-143.
http://dx.doi.org/10.1016/0378-4274(81)90030-8
DOE (U.S. Department of Energy). (2010). PAC Database Revision 26; Table 2: Protective
Action Criteria (PAC) Rev 26 based on applicable 60-minute AEGLs, ERPGs, or TEELs
[Database]. Retrieved from http://www.atlintl.com/DOE/teels/teel/Table2.pdf
DOE (U.S. Department of Energy). (2012). Protective Action Criteria (PAC): Chemicals with
AEGLs, ERPGs, & TEELs. Tables in PDF and Excel format (Rev 27). Available online
at http ://www. atlintl. com/DOE/teel s/teel/teel_pdf. html
Ernstgard, L; Gull strand, E; Lof, A; Johanson, G. (2002). Are women more sensitive than men to
2-propanol and m-xylene vapours? Occup Environ Med 59: 759-767'.
http://dx.doi.org/10.1136/oem.59.ll.759
Hake. CL: Stewart. RD: Wu. A: Graff SA: Forster. HV: Keeler. WH: Lebrun. AJ: Newton. PE:
Soto, RJ. (1981). p-Xylene: Development of a biologic standard for the industrial worker
by breath analysis. (NIOSH-MCOW-ENVM-XY-77-3). Cincinnati, OH: National
Institute for Occupational Safety and Health.
Harper, C; Drew, RT; Fouts, JR. (1975). Benzene and p-xylene: A comparison of inhalation
toxicities and in vitro hydroxylations. In J Jollow (Ed.), Biological reactive intermediates,
formulation, toxicity, and inactivation (pp. 302-311). New York, NY: Plenum Press.
Hastings, L; Cooper, GP: Burg, W. (1986). Human sensory response to selected petroleum
hydrocarbons. In HN MacFarland; CE Holdsworth; JA MacGregor; RW Call; ML Lane
(Eds.), Advances in Modern Environmental Toxicology Volume VI Applied Toxicology
of Petroleum Hydrocarbons (pp. 255-270). Princeton, NJ: Princeton Scientific Publishers.
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Office of Research and Development
National Centerfor Environmental Assessment
Research Triangle Park, NC Xylenes
August 2012
Henderson, RF. (2001). Aromatic hydrocarbons: Benzene and other alkylbenzenes. In E
Bingham; B Cohrssen; CH Powell (Eds.), Patty's toxicology (5 ed., pp. 231-301). New
York, NY: John Wiley and Sons.
IARC (International Agency for Research on Cancer). (1999). Re-evaluation of some organic
chemicals, hydrazine, and hydrogen peroxide. Lyon, France.
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