EPA/600/R-12/047F3 | August 2012 | www.epa.gov
United States
Environmental Protection
Agency
Inhalation Health Effect Reference Values
for Toluene (CASRN 108-88-3) ^M
hLC
CASRN 108-88-3
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 Toluene
(CASRN 108-88-3)
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
toluene.
Background
Toluene (CeHsCHa; MW = 92.1) is a colorless, non-corrosive, flammable liquid with an
aromatic odor similar to that of benzene. The odor threshold for toluene ranges between 2.5 and
8 ppm, and is irritating at 750 ppm (Henderson, 2001). Toluene has a density of 0.867 g/mL and
vapor pressure of 28.4 mm Hg at 25 °C. The water solubility of toluene is 0.59 mg/mL at 25 °C
with a wateroctanol partition coefficient of Log Kow of 2.72 (U.S. EPA, 2005).
Production and Uses
Toluene is one of the BTEX aromatics (benzene, toluene, ethylbenzene, and xylene).
Global production of toluene in 2009 was nearly 18.4 million metric tons (SRI, 2011). Toluene is
a leading petrochemical building block (used in the production of benzene, p-xylene, toluene
diisocyanate [TDI], caprolactam, benzoic acid, and other compounds), and is also used as a
solvent and an octane enhancer in gasoline.
Exposure Potential
Inhalation is the primary route of exposure to toluene. Evaporation of gasoline and
automobile exhaust are the largest sources of toluene in the environment, with industries using
toluene as a solvent as the second largest emission source (U.S. EPA, 1991). Toluene is also
found in indoor air due to use of common household products and as a component of cigarette
smoke (ATSDR. 2000). The Toxic Release Inventory (TRI) for the 2010 reporting year (U.S.
EPA, 2010) reported a total of29,012,231 pounds of toluene were emitted to air from all
industrial sources in the United States, with 16,960,245 pounds emitted from point sources
(stacks, vents, ducts, or pipes) and 12,051,986 pounds coming from fugitive sources (equipment
leaks, evaporative losses from surface impoundments and spills, and releases from building
ventilation systems). Ambient air concentrations in the United States have been reported to range
from an median 0.66 ppb (2.5 |ig/m3) in remote rural areas, with up to 5.5 ppm (20.7 mg/m3)
near industrial facilities and 1.1 ppm (4.14 mg/m3) in urban areas with emissions dominated by
traffic (NLM. 1998).
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Potential Health Effects
Toluene is a central nervous system (CNS) depressant, and a skin and mucous membrane
irritant - severe dermatitis may result from its drying and defatting action. Other effects observed
in humans after accidental or intentional inhalation (abuse situations) include renal (kidney)
toxicity, cardiac arrhythmias, blood dyscrasias, enlargement of the liver, and developmental
abnormalities (Henderson, 2001).
Cancer Potential
EPA found that "there is inadequate information to assess the carcinogenic potential" for
toluene (U.S. EPA, 2005). Likewise, IARC noted that there is "inadequate evidence" in humans
for the carcinogen!city of toluene, that there is "evidence suggesting lack of carcinogenicity" of
toluene in experimental animals, with an overall assessment that toluene is "not classifiable as to
its carcinogenicity to humans (Group 3)" (IARC, 1999).
Emergency Response Values
The emergency response values for toluene include interim Acute Exposure Guideline
Level (AEGL) values and final Emergency Response Planning Guideline (ERPG) values 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 AEGL values are interim and were
still in discussion at the 42nd meeting of the National Advisory Committee for AEGLs
(NAC/AEGL, 2007b) where findings from a paper presented at the 2004 meeting of the Society
of Toxicology (Oshiro and Bushnell, 2004) lead to the use of a 70-minute exposure to 2400 ppm
(9050 mg/m3 - identified as a NOAEL) in Long-Evans rats as the critical effect level; an internal
dose (blood level) in the rat was calculated using a PBPK model and extrapolated to humans to
derive the current AEGL-2 values. The Oshiro and Bushnell study has since been published in a
more complete form (Bushnell et al., 2007) which indicates that exposures to the lowest
concentration tested (1200 ppm, 4524 mg/m3) for a period of 34 minutes was a LOAEL, with a
NOAEL at 1200 ppm observed for a 22 minute exposure. More recently, AIHA revisited the
ERPG values for toluene in 2010 with no resulting change in values (AIHA, 2010). In comparing
between the emergency response values, the ERPG values are approximately one-quarter of the
exposure levels set for the comparable severity level AEGLs.
Occupational Exposure Limits
ACGIH based the TLV-TWA value of 20 ppm on effects to the CNS (reaction times and
changes in color vision) as observed in workers and potential increases in spontaneous abortions
for exposed female workers. ACGIH did not find an adequate basis for development of a short-
term exposure limit (STEL) or to indicate that toluene is a sensitizing agent. ACGIH noted that
toluene was not assigned a "skin" notation based on study evidence showing slow absorption.
The OSHA Permissible Exposure Limit (PEL) for toluene (OSHA, 2006c) is 200 ppm on
a TWA basis. In addition, exposures shall not exceed 300 ppm (ceiling) with the exception for a
single time period up to 10 minutes for any 8-hour shift of not more than 500 ppm (peak). For
the Construction Industry (OSHA, 2006b) the same 200 ppm PEL-TWA applies, as does for
Maritime Industries (OSHA. 2006a). The basis for the OSHA PEL refers to the same NIOSH
background document (NIOSH, 1973), which is the same document used for the NIOSH
Recommended Exposure Level (REL). The NIOSH REL was established at 100 ppm based on
effects of'" ...changes in muscle coordination, reaction time, and production of mental confusion
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August 2012
and irritation of mucous membranes..." being observed at 200 ppm exposures to toluene, and a
lack of those observed effects at 100 ppm. Toluene does not carry the "skin" designation from
either NIOSH or OSHA, despite the observation that "repeated or prolonged skin contact with
liquid toluene has a defatting action, causing drying, Jissuring, and dermatitis'" (NIOSH, 1978).
NIOSH also developed an Immediately Dangerous to Life and Health (IDLH) value for toluene
at 500 ppm based on observations of acute inhalation toxicity data in humans (NIOSH, 1994).
Discrepancies between the emergency response values (AEGLs and ERPGs) were
discussed previously. The NIOSH IDLH value is lower than either the AEGL-3 or the ERPG-3
values - another apparent discrepancy. This discrepancy is due in large measure from use of
debilitating yet non-fatal effects in humans (effects which may lead to an increase in accidental
death) to derive the IDLH value (NIOSH, 1994) while animal lethality studies were used in the
derivations of both the emergency response values (see Table 1).
Special Use Occupational Values
Specialty occupational values for exposures to toluene in submarines were developed by
the National Research Council (NRC, 2008a) in the form of Emergency Exposure Guidance
Levels (EEGLs) of 1 and 24 hour duration, and Continuous Exposure Guideline Levels (CEGLs)
for durations of up to 90 days. NRC also developed spacecraft maximum acceptable limits
(SMACs) for toluene (NRC. 2008bX with values derived for 1 and 24 hours, and 7, 30, 180 and
1000 days. The SMACs for 1 and 24 hours were set at 16 ppm (60 mg/m3) based on
neurotoxicity (dizziness), and the 7 through 1000 day values were all set at 4 ppm (15 mg/m3) for
auditory and visual toxicity effects with additional effects of a reduction in reproductive
hormones associated with the 180 and 1000 day values.
The NRC derived SMACs using the same concentration level (40 ppm, 151 mg/m3) as
the point-of-departure: as a NOAEL from the study of Andersen et al. (1983) for the short
durations (1 and 24 hours); and as a LOAEL taken from a series of studies (Vrca et al., 1997;
VrcaetaL 1996: VrcaetaL 1995) for the longer duration values (7 - 1000 days). The LOAEL
was divided by a simple factor of 10 to account for use in lieu of a NOAEL, resulting in a final
SMAC value of 4 ppm for the 7 through 1000 day duration values. The 40 ppm exposure
concentration NOAEL for the shorter duration study (6-hours) was adjusted by a factor of 0.4 -
the square root of 16 divided by 10 (16"2/10) due to the low number (16) of human study subjects
to derive the final SMAC value of 16 ppm for 1 and 24 hours. Application of this factor is
essentially equivalent to application of a UF of 2.5, and that is how it is represented in Table 1.
Please refer to the technical support document (NRC, 2008b) for a more detailed discussion on
these derivations.
General Public Values (Routine Non-emergency Exposures)
Values for the general public include California Reference Exposure Levels (CA-RELs,
developed by the Office of Environmental and Hazard Assessment - OEHHA) for both acute
(1 hour) and chronic (lifetime) durations; Minimal Risk Levels (MRLs) developed by the
Agency for Toxic Substances and Disease Registry (ATSDR) for chronic exposures (periods
longer than 1 year) and for durations of 1-14 days; and a chronic Reference Concentration (RfC)
developed by the U.S. Environmental Protection Agency (EPA) for the Integrated Risk
Information System (IRIS) database.
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The acute CA-REL and acute MRL were both derived from the NOAEL of 40 ppm
(151 mg/m3) identified in the study by Andersen et al. (1983): however, the final values derived
differ due to the varying definition of "acute" used by each organization, with a one-hour value
derived for the acute CA-REL and a 24-hour value derived for the acute MRL.
For the chronic general public values, the point-of-departure on which each value was
based on similar concentration levels and all were adjusted from intermittent to continuous
exposure, but there are variations in endpoint, study selection, and application of uncertainty
factors. The chronic CA-REL (OEHHA, 2000) is based on observations of changes in brain
weight and dopamine receptor binding in a subchronic study in rats (Hillefors-Berglund et al.,
1995), leading to application of an uncertainty factor of 10 for use of a subchronic study (UFS)
and again for variation within the human population (UFn), but a factor of one applied for animal
to human extrapolation (UFA). The chronic MRL (ATSDR, 2000) was based on a series of
studies with a LOAEL for changes in color discrimination among exposed workers for multiple
years (Zavalic etal., 1998b: Zavalic etal., 1998a): hence uncertainty factors of 10 each were
applied for use of a LOAEL in lieu of a NOAEL (UFL) and for human variability (UFn).
A more comprehensive consideration of multiple neurological effects in occupational
exposures was taken in developing the RfC for toluene (U.S. EPA, 2005), with identification of
34 ppm as the NOAEL in worker populations (Neubert et al., 2001b: Cavalleri et al., 2000; Eller
etal., 1999: Zavalic et al., 1998a: Boevetal., 1997: Vrcaetal., 1995: Abbateetal., 1993:
Murataetal., 1993: Nakatsuka et al., 1992: Foo etal., 1990), which was adjusted to reflect the 5-
day per week work schedule and with an assumption that workers breathe 10m3 during that
duration versus a standard 20 m3 breathed per day by the average person. The only uncertainty
factor applied in deriving the RfC was a factor of 10 to account for human variability (UFn).
Summary
In conclusion, the effects most noted in association with exposure to toluene across all
durations are neurotoxic in nature (narcosis/intoxication, incoordination, headache, color vision,
etc.). Short-duration exposures to elevated concentrations (e.g., > 100 ppm) have been associated
with irritation of the eyes and upper respiratory system, with higher exposure concentrations
showing effects on the kidney. Longer duration exposures may elicit a depression in reproductive
hormone levels, depression in immunological response, and potential changes in brain weight
and function.
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Toluene: Comparison of Reference Values
ACUTE
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NIOSH IDLH* V O AEGL
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• SMACs* 4
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Short Term
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^SMACs*<
ATSDR-MRL(1-14d)
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Subchronic
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CEGLs*
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ATSDR-MRL(>1yr)
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OSHA-PEL (TW
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NIOSH-REL(TW
ACGIH-TLV(TW
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EPA/IRIS RfC
CA-REL (Chronic
— i
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A)*
«)*
June 2011
— •— AEGL-3
— •- AEGL-2
A ERPG-3
A ERPG-2
A ERPG-1
0 SMACs*
0 NIOSH-STEL*
0 CEGLs*
0 EEGLs*
O OSHA-Ceiling*
• NIOSH IDLH*
0 ACGIH-TLV(TWA)*
-•*- NIOSH-REL(TWA)*
0 OSHA-PEL (TWA)*
X CA-REL (Acute)
-»-ATSDR-MRL(1-14d)
A ATSDR-MRL(>1yr)
X CA-REL (Chronic)
-•-EPA/IRIS RfC
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0.1 1 10 100 1000 10000 100000 1000000
Duration (hours)
* 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 toluene
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Toluene
August 2012
Table 1. Details on derivation of the available health effect reference values for inhalation exposure to toluene
Emergency Response
Reference
Value Name
AEGL-3
AEGL-2
AEGL-1
ERPG-3
ERPG-2
ERPG-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
1 hour
1 hour
1 hour
Reference Value
(nig/m3)
48,970
23,000
17,000
11,300
9040
11,680
6030
4520
2980
2450
753
753
753
753
753
3750
1125
187.5
(ppm)
13,000
6100
4500
3000
2500
3100
1600
1200
790
650
200
200
200
200
200
1000
300
50
Health Effect
Threshold for
lethality
Threshold for
narcosis in the
rat
Effects <
notable
discomfort in 17
clinical studies
<5%ofthel-hr
LC50 in rats
Muscular
weakness and
incoordination in
humans
Mild symptoms of
fatigue,
drowsiness,
headache,
dizziness, and
intoxication in
humans
Point of
Departure
6250 ppm (2
hours)
2400 ppm (70
mins)
200 ppm
(various
durations)
26,700 ppm
(1 hour)
300 ppm
(8 hours)
100 ppm
(various
durations)
Qualifier
NOAEL
NOAEL
for |CNS
in rats
NOAEL
LC50 in rats
Effect
Level
Effect
Level
Principal
Study
1982)
Oshiro and
Bushnell
(2004)
Various2
Pryor et al.
(1978)
vonOettingen
etal. (1942)
Various
Uncertainty
Factors1
Total UF = 3
UFA=1;
TTF — T.
UrH j
Total UF = 3
UFH = 3
Total UF = 1
NA
Notes on
Derivation
Duration
extrapolation
performed
using a rat to
human PBPK
model
No duration
extrapolation
NA
Review
Status
Interim
(NAC/AEGL,
2007a)
Final
(AIHA,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 Including: Astrand et al. (1972); Gamberale and Hultengren (1972); Stewart et al. (1975); and Baelum et al. (1990)
3 Including: vonOettingen et al. (1942): Andersen et al. (1983); and Gamberale and Hultengren (1972)
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Toluene
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Occupational
Reference
Value Name
OSHA Ceiling
OSHA Max.
Peak
OSHA PEL
(TWA)
NIOSH STEL
NIOSHREL
(TWA)
NIOSH IDLH
ACGffl
TLV-TWA
EEGLs
CEGL
SMACs
Duration
< 1 5 minutes
<10 minutes
8 hour TWA
< 1 5 minutes
10 hour
TWA
30 minutes
8 hour TWA
1 hour
24 hour
90 days
1 & 24 hours
7,30, 180 &
1000 days
Reference Value
(mg/m3)
1125
1880
750
750
375
1880
75
750
375
75
60
15
(ppm)
300
500
200
200
100
500
20
200
100
20
16
4
Health Effect
Irritation - Eye,
Nose, Throat,
Skin;
Moderate Narcosis
Muscle
coordination,
reaction time,
mental confusion,
and irritation
Acute inhalation
toxicity data in
humans
CNS effects; visual
impairment;
pregnancy loss
Minimal CNS
effects and
irritation
Cognition,
vigilance, CNS
Neurotoxicity
(dizziness)
Auditory and
visual effects;
^reproductive
hormone
Point of
Departure
NR
200 ppm
100 ppm
Various cone.
and durations
(<200-1400
ppm , 2-8 hrs)
42 ppm (color
vision)
200 ppm
100 ppm
25 ppm
40 ppm
(human, 6 h)
40 ppm
(human, 20.3
yrs avg. worker
exposure)
Qualifier
NR
LOAEL
(Human)
NOAEL
(Human)
Effects
levels,
worker
studies
LOAEL
(Human)
LOAEL
NOAEL
NOAEL
LOAEL
LOAEL
Principal
Study
NR
(Carpenter et
al.. 1944;
vonOettingen
etal.. 1942)
Various 4
Various 5
Various 6
Various 7
Various8
(Andersen et
al.. 1983)
Vrca et al.
(1997; 1996;
1995);
Uncertainty
Factors1
NR
NA
NA
NA
None
2.59
TIP — in
u-r LOAEL lu
Notes on
Derivation
NR
WOE Approach
WOE Approach
WOE Approach
Adjusted for
sample size
NA
Review
Status
Final
(NIOSH, 2007)
Final
(NIOSH, 2007)
Final
(ACGIH.
2007)
Final
(NRC. 2008a)
Final
(NRC. 2008b)
(Gamberale and Hultengren. 1972: Wilson. 1943: vonOettingen etal.. 1942)
5 (Roberts etal.. 2003: Campagnaetal.. 2001: Cavalleri etal. 2000: Ng et all 1992)
6 (Astrand et al.. 1972: Gamberale and Hultengren. 1972)
7 (Baelum et al.. 1990: Nielsen etal.. 1985: Andersen et al.. 1983: Stewart etal.. 1975: Ogata etal.. 1970)
8 (Gericke etal. 2001: Neubertetal. 2001a: Neubertetal.. 200Ib)
9 A factor [(16"2)/10 = 0.4] was multiplied to the POD, which is effectively the same as division by an uncertainty factor of 2.5. Refer to the SMAC document (NRC.
2008b) for details regarding this adjustment.
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Toluene
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General Public
Reference
Value Name
Acute
CA-REL
(Severe
Effects)
Acute ATSDR
MRL
Chronic
CA-REL
Chronic
ATSDR MRL
Chronic RfC
(TRIS)
Duration
6 hour
1 -14 days
Chronic
Chronic
(> 1 year)
Chronic
Reference Value
(mg/m3)
37
3.8
0.3
0.3
5.0
(ppm)
9.8
1.0
0.07
0.08
1.3
Health Effect
^reaction time and
headache,
dizziness,
intoxication, and
slight eye and nose
irritation
fmucus flow,
irritation of eyes
and nose,
headaches and
dizziness
jbrain weight,
altered dopamine
receptor binding
Color vision
impairment in
occupational
exposures
Neurological
effects in
occupationally-
exposed workers
Point of
Departure
98 ppm,
40 ppm
(human,
6 hours for
4 days)
10 ppm
40 ppm
(human,
6 hours for
4 days)
7 ppm
40 ppm
(rat, 6 h/d,
5d/wk)
8 ppm
35 ppm
(human, 8 hr/d,
5d/wk)
46 mg/m3
128 mg/m3
(human, 8 h/d,
5d/wk)
Qualifier
NOAELADJ
NOAEL
NOAELHEC
NOAEL
NOAELHEC
NOAEL
LOAELHEc
LOAEL
NOAELADJ
NOAEL
Principal
Study
Andersen et
al. (1983)
Andersen et
al. (1983)
Hillefors-
Berglund et
al. (1995)
Various 10
Various11
Uncertainty
Factors1
Total UF = 10
UFH=10
Total UF = 10
UFH = 10
Total UF = 100
UFS=10
UFH = 10
UFA=1
Total UF = 100
UFL=10
UFH = 10
Total UF = 10
UFH = 10
Notes on
Derivation
Duration
extrapolation
via Cn x t
(n = 2) from
6 hrs to 1 hr
HEC derived
from 6 h/day to
24 h/day
HEC derived
from 6-h/d,
5-d/wk for
4 weeks
HEC derived
from 8 h/d and
5 d/wk for
several years
Adjustments:
occupational
breathing rate
(10 m3 vs.
20 m ) and
5 days per
week.
Review
Status
Final
(OEHHA,
2008)
Final
(ATSDR,
2000)
Final
(OEHHA,
2000)
Final
(ATSDR,
2000)
Final
(U.S. EPA,
2005)
10 (Zavalic et al.. 1998b: Zavalic et al.. 1998a)
11 (NeubertetaL2001b: Cavalleri et aL 2000: Elleretal.
Nakatsuka et al.. 1992: Foo et al.. 1990)
1999: Zavalic etal. 1998a: Boeyetal.. 1997: VrcaetaL 1995: Abbateetal. 1993: MurataetaL 1993:
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Further Reading
U.S. EPA (U.S. Environmental Protection Agency). Toluene, Air Toxics Web Site.
http://www.epa.gov/ttn/atw/hlthef/toluene.html
REFERENCES
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to toluene: An electrophysiologic study. Int Arch Occup Environ Health 64: 389-392.
http://dx.doi.org/10.1007/BF00517943
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.
AIHA (American Industrial Hygiene Association). (2010). 2010 ERPG update set. Fairfax:
AIHA Guideline Foundation.
Andersen, I; Lundqvist GR: Molhave, L; Pedersen, OF; Proctor, DF; Vaeth, M; Wyon, DP.
(1983). Human response to controlled levels of toluene in six-hour exposures. Scand J
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Astrand, I; Ehrner-Samuel, H; Kilbom, A; Ovrum, P. (1972). Toluene exposure I Concentration
in alveolar air and blood at rest and during exercise. Scand J Work Environ Health 9:
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AT SDR (Agency for Toxic Substances and Disease Registry). (2000). Toxicological profile for
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Services, Public Health Service, http://www.atsdr.cdc.gov/ToxProfiles/tp56.pdf
Baelum, J: Lundqvist GR: Molhave, L; Andersen, NT. (1990). Human response to varying
concentrations of toluene. Int Arch Occup Environ Health 62: 65-71.
Boey, KW: Foo, SC: Jeyaratnam, J. (1997). Effects of occupational exposure to toluene: A
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Bushnell. PJ: Oshiro. WM: Samsam. TE: Benignus. VA: Krantz. QT: Kenyon. EM. (2007). A
Dosimetric Analysis of the Acute Behavioral Effects of Inhaled Toluene in Rats. Toxicol
Sci99: 181-189. http://dx.doi.org/10.1093/toxsci/kfml46
Campagna. D: Stengel B: Merglen D: Limasset JC: Diebold. F: Michard. D: Huel G. (2001).
Color vision and occupational toluene exposure. Neurotoxicol Teratol 23: 473-480.
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